MX336930B

Ganaxolone formulations and methods for the making and use thereof.

Abstract

The present invention relates to a pharmaceutical composition comprising solid stabilized particles comprising ganaxolone, a hydrophilic polymer, a wetting agent and an effective amount of a complexing agent which is a small organic molecule having a molecular weight of less than 550 and having a fraction Phenol, an aromatic ester moiety or an aromatic acid moiety; The stabilized particles have a volume-weighted average diameter (D 50) of about 50 nm to about 500 nm, wherein the complexing agent is present in an amount of about 0.05% to 5% w / w based on the weight of the particles Of the solid, or the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight, Or the complexing agent is present in an amount of about 0.05% to 5% w / w based on the weight of the particles of the solid and the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight and; Wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives and excipients. In a preferred embodiment, the solid stabilized particles are in the form of a powder, and / or are incorporated into a dosage form selected from an aqueous dispersion, a tablet or a capsule. Wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives and excipients. In a preferred embodiment, the solid stabilized particles are in the form of a powder, and / or are incorporated into a dosage form selected from an aqueous dispersion, a tablet or a capsule. Wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives and excipients. In a preferred embodiment, the solid stabilized particles are in the form of a powder, and / or are incorporated into a dosage form selected from an aqueous dispersion, a tablet or a capsule.

MX336930B, drawing sheet 1 — Sheet 1 of 5

Term

0.2 yearsleft in the term

Expires 28 November 2026.

46 claims: 3 independent, 43 dependent

1
Una composición farmacéutica que ^Ampronrio partículas estabilizadas sólidas que comprenden ganaxolona, un polímero hidrofílico, un agente humectante, y una cantidad efectiva de un agente complejante el cual es una molécula orgánica pequeña que tiene un peso molecular menor que 550 y que contiene un resto seleccionado del grupo que consiste de un resto de fenol, un resto de éster aromático y un resto de ácido aromático, en donde las partículas estabilizadas sólidas tienen un diámetro medio ponderado por volumen (D50) de aproximadamente 50 nm a aproximadamente 500 nm, el agente complejante está presente en una cantidad de aproximadamente 0.05 % a aproximadamente 5% peso/peso, con base en el peso de las partículas estabilizadas sólidas;la composición farmacéutica comprende además uno o más aditivos farmacéuticamente aceptables seleccionados del grupo que consiste de un diluyente, un aglutinante, un desintegrante, un plastificante, un estabilizador, y mezclas de cualquiera de los anteriores, siendo la composición farmacéutica una forma de dosificación sólida oral.
2
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 1, en donde el polímero hidrofílico está en una cantidad de INDUSTRIAL ^ea_ aproximadamente 3% a aproximadamente 50%, peso/peso, con base en el peso de las partículas sólidas.
3
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 2, en donde el agente humectante se encuentra en una cantidad de aproximadamente 0.01% a aproximadamente 10%, peso/peso, con base en el peso de las partículas sólidas.
4
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 1, en donde las partículas estabilizadas presentan un aumento en el diámetro medio ponderado por volumen (D50) de no más de aproximadamente 150% cuando las partículas se dispersan en el fluido gástrico simulado (SGF) o en el fluido intestinal simulado (SIF) a una concentración de 0.5 a 1 mg ganaxolona/ml y se coloca en un baño calentado a 36°C a 38 °C durante 1 hora en comparación con la D50 de las partículas estabilizadas cuando las partículas se dispersan en agua destilada en las mismas condiciones, en donde el diámetro medio ponderado por volumen (D50) de las partículas estabilizadas dispersadas en SGF o en SIF es menor que aproximadamente 750 nm.
5
La composición farmacéutica IN3T0Sa estabilizadas sólidas de conformidad con la reivindicación 1, -tfii,»n.....i-·- ............... ii en donde la ganaxolona está en una cantidad de aproximadamente 10% a aproximadamente 80% con base en el peso de las partículas estabilizadas.
6
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 5, en donde la ganaxolona está presente en una cantidad de aproximadamente 50% a aproximadamente 80%, con base en el peso de las partículas estabilizadas.
7
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 5, en donde el agente complejante se selecciona del grupo que consiste de uno o más parabenos, ácido benzoico, fenol, metil antranilato, sales farmacéuticamente aceptables de los mismos, y mezclas de cualquiera de los anteriores.
8
La composición farmacéutica de conformidad con la reivindicación 7, en donde el agente complejante es uno o más parabenos o una sal farmacéuticamente aceptable del mismo. i (vi/tu * i m *"
9
La composición farmacéutica de conformidad con la reivindicación 7, en donde el agente complejante es ácido benzoico o una sal farmacéuticamente aceptable del mismo.
10
La composición farmacéutica de conformidad con la reivindicación 1, en donde el agente complejante es el metil antranilato.
11
La composición farmacéutica de conformidad con la reivindicación 1, en donde el agente complejante es fenol.
12
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 8, en donde el parabeno se selecciona del grupo que consiste de metilparaben, etilparaben, propilparaben, sales farmacéuticamente aceptables de los mismos y mezclas de los mismos.
13
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 1, en donde el polímero hidrofílico se selecciona del grupo que consiste de un polímero celulósico, un polímero de vinilo y mezclas de los mismos. IPÍ/WJICU/Ut Ι·»
14
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 13, en donde el polímero celulósico es un éter de celulosa.
15
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 14, en donde el éter de celulosa es hidroxipropilmetilcelulosa.
16
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 13, en donde el polímero de vinilo es el alcohol de polivinilo.
17
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 16, en donde el polímero de vinilo es el copolímero de vinilpirrolidona/acetato de vinilo (S630).
18
La composición farmacéutica de partículas estabilizadas sólidas de conformidad con la reivindicación 1, en donde el agente humectante se selecciona del grupo que consiste de lauril sulfato de sodio, una sal farmacéuticamente aceptable de docusato, y mezclas de los mismos.
19
La composición farmacéutica de reivindicación 7, que comprende además un modulador de dispersión iónico en una cantidad de aproximadamente 1% a aproximadamente 50% peso/peso, con base en el peso de las partículas sólidas, y es una sal inorgánica que se selecciona del grupo que consiste de una sal de magnesio, una sal de calcio, una sal de litio, una sal de potasio, una sal de sodio y mezclas de las mismas, o una sal orgánica seleccionada del grupo que consiste de una sal de citrato, una sal de succinato, una sal de fumarato, una sal de malato, una sal de maleato, una sal de tartrato, una sal de glutarato, una sal de lactato, y mezclas de las mismas.
20
La composición farmacéutica de conformidad con la reivindicación 7, que comprende además un una cantidad efectiva de un material de liberación controlada de tal manera que la forma de dosificación proporciona un efecto terapéutico durante aproximadamente 8 a aproximadamente 24 horas después de la administración.
21
La composición farmacéutica de conformidad con la reivindicación 20, la cual es una forma de dosificación oral sólida que comprende (i) un componente de liberación controlada que comprende una primera porción de dichas partículas de ganaxolona estabilizadas sólidas;,N de liberación controlada, y (ii) un componente de liberación inmediata que comprende una segunda porción de dichas partículas de ganaxolona estabilizadas sólidas.
22
La composición farmacéutica de conformidad con la reivindicación 20, en donde el componente de liberación controlada está en la forma de (i) una pluralidad de perlas farmacéuticamente aceptables cubiertas con la primera porción de dichas partículas de ganaxolona estabilizadas sólidas y recubiertas con el material de liberación controlada, o (ii) una pluralidad de matrices que comprenden la primera porción de dichas partículas de ganaxolona estabilizadas sólidas dispersadas en el material de liberación controlada, o (iii) una tableta que comprende la primera porción de las partículas de ganaxolona dispersadas en un material de liberación controlada, o (iv) una granulación que comprende la primera porción de las partículas de ganaxolona y el material de liberación controlada.
23
La composición farmacéutica de conformidad con la reivindicación 20, en donde el componente de liberación controlada es una tableta y el componente de liberación inmediata se recubre sobre la tableta. ¢5 ΙΑ
24
La composición farmacéutica de conformidad^Medíf· la1-—- reivindicación 7, en donde las partículas de""lTraiidXOlOUd T" estables están en una forma que se selecciona de la forma cristalina, la forma amorfa, la forma semi-cristalina, la forma semi-amorfa, y mezclas de las mismas.
25
La composición farmacéutica de conformidad con la reivindicación 20, que comprende además un polímero dependiente del pH, la composición farmacéutica proporciona una liberación retardada de la ganaxolona de un período de tiempo de aproximadamente 2 a aproximadamente 12 horas después de la administración.
26
La composición farmacéutica de conformidad con la reivindicación 5, en donde la composición farmacéutica es una tableta comprimida.
27
La composición farmacéutica de conformidad con la reivindicación 20, en donde la composición farmacéutica es una tableta comprimida.
28
La composición farmacéutica de conformidad con la reivindicación 5, en donde la composición farmacéutica está contenida dentro de una cápsula. ϊ··:. LA mvjricLvw
29
La composición farmacéutica de conf ormi Já?^TR1don^±H— reivindicación 22, en donde la composición farmatéULldá está contenida dentro de una cápsula.
30
La composición farmacéutica de conformidad con la reivindicación 5, incorporada en una tableta o cápsula, en donde la forma de dosificación provee una proporción promedio en plasma sanguíneo alimentado AUC o-T) a en ayunas AÜC(o-T) de aproximadamente 1:1 a aproximadamente 4:1.
31
La composición farmacéutica de conformidad con la reivindicación 5, la cual provee una proporción promedio en plasma sanguíneo alimentado Cmax a en ayunas Cmax de aproximadamente 1.5:1 a aproximadamente 7:1.
32
La composición farmacéutica de conformidad con la reivindicación 30, en donde las partículas tienen un diámetro medio ponderado por volumen (D50) de aproximadamente 50 ni a aproximadamente 1,000 nm, y la forma de dosificación provee un promedio en plasma sanguíneo AUC(0-24) horas, de aproximadamente 100 a aproximadamente 375 ng*h/ml, cuando una dosis de 200 mg a 500 mg de la ganaxolona se administra por vía oral a sujetos adultos en ayunas. DE LA PRO¿r-5DÁr i'ñ
33
La composición farmacéutica de conformidSE^ra^n'^^g^as reivindicación 5, la cual provee un ρΓΟΪΪΪδΤίΐΌ^^^ΓΤ-^ρΐ#®»^^. sanguíneo Cmax de aproximadamente 25 a aproximadamente 70 ng/ml cuando una dosis de 200 mg a 500 mg de la ganaxolona se administra por vía oral a sujetos adultos en ayunas.
34
La composición farmacéutica de conformidad con la reivindicación 30, la cual provee un promedio en plasma sanguíneo AUC(0-48) horas de aproximadamente 400 a aproximadamente 1,200 ng*h/ml, cuando una dosis de 200 mg a 500 mg de la ganaxolona se administra por vía oral a sujetos adultos en estado alimentado.
35
La composición farmacéutica de conformidad con la reivindicación 5, la cual provee un promedio en plasma sanguíneo Cmax de aproximadamente 60 a aproximadamente 250 ng/ml cuando una dosis de 200 mg a 500 mg de la ganaxolona se administra por vía oral a sujetos adultos en estado alimentado.
36
La composición farmacéutica de conformidad con la reivindicación 5, la cual provee un promedio en js^Lasma sanguíneo Cmax/Cmin de no más de aproximadamente 4 a 1 en estado estacionario con una dosis de 200 a 500 mg de la ganaxolona a sujetos adultos en el estado ayunas. -
37
Una composición farmacéutica que comprende partículas estabilizadas sólidas que comprenden ganaxolona, un polímero hidrofílico, un agente humectante, y una cantidad efectiva de un agente complejante seleccionado del grupo que consiste de metilparaben, propilparaben, y mezclas de los mismos, y que está presente en una cantidad de aproximadamente 0.05 % a aproximadamente 5% peso/peso con base en el peso de las partículas del sólido;la composición farmacéutica comprende además uno o más aditivos farmacéuticamente aceptables seleccionados del grupo que consisten de un diluyente, un aglutinante, un desintegrante, un plastificante, un estabilizador, y mezclas de cualquiera de los anteriores, en donde las partículas estabilizadas tienen un diámetro medio ponderado por volumen (D50) de aproximadamente 50 nm a aproximadamente 500 nm, la composición farmacéutica es una forma de dosificación sólida oral e incluye de aproximadamente 50 mg a aproximadamente 800 mg de ganaxolona.
38
La composición farmacéutica de conformidad con la reivindicación 37, en donde la forma de dosificación sólida es una forma de dosificación de liberación inmediata.
39
La composición farmacéutica de corifornadad^^nr'^ra^^- reivindicación 37, que comprende además un una cantidad efectiva de un material de liberación controlada de tal manera que la forma de dosificación proporciona un efecto terapéutico durante aproximadamente 8 a aproximadamente 24 horas después de la administración.
40
La composición farmacéutica de conformidad con la reivindicación 37, la cual es una forma de dosificación sólida oral que comprende (i) un componente de liberación controlada que comprende una primera porción de dichas partículas de ganaxolona estabilizadas sólidas;y un material de liberación controlada, y (ii) un componente de liberación inmediata que comprende una segunda porción de dichas partículas de ganaxolona estabilizadas sólidas.
41
La composición farmacéutica de conformidad con la reivindicación 40, en donde el componente de liberación controlada está en la forma de (i) una pluralidad de perlas farmacéuticamente aceptables cubiertas con la primera porción de dichas partículas de ganaxolona estabilizadas sólidas y recubiertas con el material de liberación controlada, o (ii) una pluralidad de matrices que comprenden la primera porción de dichas partículas de ganaxolona estabilizadas sólidas dispersadas en el material de liberación controlada/A26:T;^irf-^:uJ una tableta que comprende la primera porción de Τ3ΊΓ”""” partículas de ganaxolona dispersadas en un material de liberación controlada, o (iv) una granulación que comprende la primera porción de las partículas de ganaxolona y el material de liberación controlada.
42
La composición farmacéutica de conformidad con la reivindicación 41, en donde el componente de liberación controlada está en la forma de (i) una pluralidad de perlas farmacéuticamente aceptables cubiertas con la primera porción de dichas partículas de ganaxolona estabilizadas sólidas y recubiertas con el material de liberación controlada, o (ii) una pluralidad de matrices que comprenden la primera porción de dichas partículas de ganaxolona estabilizadas sólidas dispersadas en el material de liberación controlada, o (iii) una granulación que comprende la primera porción de las partículas de ganaxolona y el material de liberación controlada;en donde la composición farmacéutica está contenida dentro de una cápsula.
43
La composición farmacéutica de conformidad con la reivindicación 39, en donde la composición farmacéutica es una tableta comprimida. 44. Una composición farmacéutica qtf§ partículas estabilizadas sólidas que comprendan ganaxolona, un polímero hidrofílico, un agente humectante, y una cantidad efectiva de un agente complejante seleccionado del grupo de moléculas orgánicas pequeñas que tienen un peso molecular menor que 550 y que contienen un resto seleccionado del grupo que consiste de un resto de fenol, un resto de éster aromático y un resto de ácido aromático;la composición farmacéutica comprende además uno o más aditivos farmacéuticamente aceptables seleccionados del grupo que consiste de un diluyente, un aglutinante, un desintegrante, un plastificante, un estabilizador, y mezclas de cualquiera de los anteriores, las partículas estabilizadas sólidas tienen un diámetro medio ponderado por volumen (D50) de aproximadamente 50 nm a aproximadamente 500 nm, la concentración de ganaxolona en las partículas estabilizadas sólidas es de al menos 50% en peso y la composición incluye de aproximadamente 50 mg a aproximadamente 800 mg de ganaxolona, en donde la composición farmacéutica es una forma de dosificación sólida oral.
45
La composición farmacéutica de conformidad con la reivindicación 44, en donde el agente complejante se selecciona del grupo que consiste en parabenos, ácido benzoico, metil antranilato, y sales farmacéuticamente aceptables de los mismos y mezclas de los mismos.
46
La composición farmacéutica de conformidad con la reivindicación 44, en donde la ganaxolona está presente en una cantidad mayor que 50% a aproximadamente 80%, con base en el peso de las partículas.
47
La composición farmacéutica de conformidad con la reivindicación 44, en donde las partículas se incorporan en una forma de dosificación seleccionada del grupo que consiste de una tableta o una cápsula.

Independent claims46

862 paragraphs in 22 sections, as filed

GANAXOLONE FORMULATIONS AND PARTITION METHODS MANUFACTURING AND THE USE OF THE SAME

This application claims the priority of United States Provisional Application No. 60 / 758,171 filed January 11, 2006, Provisional Application No. 60 / 740,174 of the United States filed November 28, 2005, Provisional Application No. 60 / 740,208 filed November 28, 2005, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

FIELD OF THE INVENTION

Described herein are ganaxolone formulations which provide greater stability, better physical and chemical properties and may provide improved pharmacokinetic properties for achieving an optimal balance between pharmacodynamic profiles and side effects in mammals, as well as dosage forms which Contain them, in addition to methods for making the formulations of ganaxolone and their use in the treatment of diseases related to

. R; Eur-lex.europa.eu eur-lex.europa.eu V epilepsy and other disorders of the rhetiwirxs-o system; central.

BACKGROUND OF THE INCENTION

Positive GABAFT receptor modulators have long been used in the treatment of disorders of the central nervous system, including epilepsy, anxiety, sleep disorders, abnormal muscle tone, including spasticity, and alcohol withdrawal syndrome (McDonald and Olsen (1994) and Mehta and Ticku (1999) and Mohler et al. (2001) .These pharmacological agents also have medical uses for inducing anesthesia and amnesia (Chapouthier and Venault, 2002;

Antkowiak, 2004). Among the normal positive modulators of GABAa receptors are neuroactive steroids, benzodiazepines, non-benzodiazepine benzodiazepine site agonists, barbiturates, propofol, chlormethiazole, and anesthetics such as etomidate, propofol, isoflurane and sevoflurane (Trapani The results of the present study are summarized in Table 1 and Table 2.

Antkowiak, 2005). Γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the nervous system. GABA acts on several targets, including GABAa receptors. GABAa receptors are ionotropic receptors that transport chloride ions through the membranes of neuronal cells, which induce hyperpolarization and deflect excitation stimuli, thus inhibiting the excitability of neurons. GABAa receptors are heteropentamera which are generally composed of three or more distinct subunits. The composition of GABAa receptor subunits is a determinant of the receptor's pharmacological sensitivity (Mohler et al., 2001; Sieghart and Sperk, 2002). For example, Sensitivity to benzodiazepines and non-benzodiazepine benzodiazepine site agonists requires the presence of a γ2 subunit and there is no response if an a4 subunit or an a6 subunit substitutes for the most common subunits a1, a2 and a3. In contrast, neuroactive steroids that act as positive modulators of GABAa receptors do not require γ2 and are sensitive, even if they contain a4 and a6 receptors (Lambert et al., 2003). Although GABAa receptors containing subunit 3 do not respond to benzodiazepines or benzodiazepine site ligands, (Jones-Davis et al., 2005), they are more sensitive to neurosteroids than receptors containing the y2L subunit, which Is more abundant (Adkins et al., 2001, Brown et al., 2002, Wohlfried et al., 2002). ------- A2 and a3. In contrast, neuroactive steroids that act as positive modulators of GABAa receptors do not require γ2 and are sensitive, even if they contain a4 and a6 receptors (Lambert et al., 2003). Although GABAa receptors containing subunit 3 do not respond to benzodiazepines or benzodiazepine site ligands, (Jones-Davis et al., 2005), they are more sensitive to neurosteroids than receptors containing the y2L subunit, which Is more abundant (Adkins et al., 2001, Brown et al., 2002, Wohlfried et al., 2002). ------- A2 and a3. In contrast, neuroactive steroids that act as positive modulators of GABAa receptors do not require γ2 and are sensitive, even if they contain a4 and a6 receptors (Lambert et al., 2003). Although GABAa receptors containing subunit 3 do not respond to benzodiazepines or benzodiazepine site ligands, (Jones-Davis et al., 2005), they are more sensitive to neurosteroids than receptors containing the y2L subunit, which Is more abundant (Adkins et al., 2001, Brown et al., 2002, Wohlfried et al., 2002). ------- Although GABAa receptors containing subunit 3 do not respond to benzodiazepines or benzodiazepine site ligands, (Jones-Davis et al., 2005), they are more sensitive to neurosteroids than receptors containing the y2L subunit, which Is more abundant (Adkins et al., 2001, Brown et al., 2002, Wohlfried et al., 2002). ------- Although GABAa receptors containing subunit 3 do not respond to benzodiazepines or benzodiazepine site ligands, (Jones-Davis et al., 2005), they are more sensitive to neurosteroids than receptors containing the y2L subunit, which Is more abundant (Adkins et al., 2001, Brown et al., 2002, Wohlfried et al., 2002). -------

Neurosteroids, and in particular ganaxolone, act in different populations of GABA receptors than benzodiazepines. The distribution of benzodiazepine-sensitive GABAa receptors differs in the brain to the distribution of receptors responsive to neuroactive steroids (Sieghart and Sperk, 2002). In addition, benzodiazepines increase the physiological activity of GABAa receptors through different effects on receptor opening and closure than neuroactive steroids (Twyman and McDonald, 1992; Wohlfarth et al., 2002). Barbiturates act preferentially on GABAa receptors containing 3 subunits as partial agonists (Feng et al., 2002, 2004). However, barbiturates, unlike benzodiazepines and neurosteroids, Act on molecular targets different from those of GABAa receptors, the most important of which are voltage-dependent calcium channels (French-Mullen et al., 1993; Rudolph and Antkowiak, 2005). Therefore, the major classes of drugs acting on GABAa receptors have different activity spectra, and neuroactive steroids act on a series of targets that do not coincide with any other class. In addition, pharmaco-

INDUSTRIAL have shown that these diverse classes of drugs interact with heteromeric GABAa receptor complexes at pharmacologically distinguishable sites (Lambert et al., 2003). Specifically, the actions of neuroactive steroids occur at sites of GABAa receptors that are distinct from the sites of action of benzodiazepines or barbiturates. Another important distinction between the mode of action of benzodiazepines and neuroactive steroids is that benzodiazepine seems to act largely on synaptic GABA receptors and thus directly inhibit GABAergic receptors. In contrast, neuroactive steroids may act more prominently on extrasynaptic or perisynaptic GABA receptors that are not intermediaries of inhibitory synaptic transmission,

Neuroactive steroids have a different selectivity pattern for different isoforms of GABAa receptors (subunit combinations) of other types of positive allosteric modulators of GABAa receptors. In addition, the functional effects of

Neuroactive steroids differ from those of the GABAa receptor modulators. For example, neuroactive steroids are more effective than benzodiazepines (Kokate et al., 1994) and act in specific ways to modify the opening and closing of GABAa receptors (Bianchi and McDonald, 2003). ). It is not known that neuroactive steroids affect other ion channels and receptor systems within the same range of concentrations as they affect GABAa receptors, whereas other modulators of GABAa receptors have effects on various molecular targets. Another difference between neuroactive steroids and other positive modulators of GABAa receptors is that tolerance does not occur in neuroactive steroids with anticonvulsive effects in general (Kokate et al. 1998) and neuroesteroid ganaxolone in particular (Reddy and Rogawski, 2000). In humans, tolerance to the sedative effects of ganaxolone occurs (Monaghan et al., 1999). Tolerance develops rapidly in contrast to the sedative activity of benzodiazepines and more slowly than its anticonvulsant activity.

Ganaxolone, a neurosteroid also known as 3α-hydroxy-3β-methyl-5α-pregnan-20-one, is the synthetic 3β-methylated analog of the endogenous metabolite of progesterone, 3-hydroxy-5α-pregnan-20-one A Rj

MEXICAN INSTITUTE

DELA fROPlFDAD \ Τ · INDUSTRIAL

Alopregnanolone). It is a member of a new class of neuroactive steroids that act as positive allosteric modulators of the γ-aminobutyric receptor (GABAa) complex of the central nervous system through interaction with a unique recognition site that is distinguished from the binding sites of the Barbiturates and benzodiazepines (Carter et al., 1997). Ganaxolone has shown potent anticonvulsant, anti-anxiety and anti-migraine activity in the preclinical models. Ganaxolone has also been shown to lengthen the life of mice with a storage of lysosomal lipids due to disruption of the NPC1 gene in mouse homologs, a loci bound to Niemann Pick C in humans. Further, Ganaxolone has been used clinically in adults for the treatment of complex refractory partial seizures and of children with refractory infantile spasms and other types of epilepsy. Appropriate ganaxolone formulations also have potential for the treatment of sleep-related disorders.

Ganaxolone is different from other neurosteroids in that the alcohol at position 3 is blocked from oxidation by the ketone. The 3-keto functionality imparts sensitive steroidal activity, for which ganaxolone is distinct from the endogenous neuroesteroid (3a, 5a-P) which can be metabolized in vivo to a 3-keto functionality. Active steroid compound. Therefore, ganaxolone is not a steroid and does not have to be handled with the same care and protection as steroids during its manufacture and packaging.

It has been very difficult to formulate therapeutically effective dosage forms which are specific for neurosteroids such as ganaxolone. Ganaxolone is a poorly soluble drug that does not provide good blood levels after oral administration. Previous dosage forms of ganaxolone have also shown particularly large differences in fed and fasted subjects. Based on this difficulty, there is a need in the state of the art to improve formulations and dosage forms of ganaxolone. In the present patent application, solid dosage formulations of ganaxolone are addressed which address this need and provide improved pharmacokinetic properties that maintain efficacy while reducing side effects and improving patient compliance.

All references discussed in the foregoing patent application are incorporated by reference in all or all of the corresponding purposes.

SUMMARY OF THE INVENTION

In the present patent application, compositions, pharmaceutical compositions, methods for the treatment, methods for the formulation, production methods, manufacturing methods, treatment strategies and pharmacokinetic strategies using ganaxolone are described.

In one aspect of the invention, there is provided a solid oral dosage form of ganaxolone comprising at least 200 mg of ganaxolone and having a total weight of less than 800 mg.

A formulation of ganaxolone composed of particles containing ganaxolone combined with a small molecule of complexing agent which provides greater stability and superior physical properties, such as freeze / thaw stability, thermal stability and particle size stability. The types of complexing agents are not anticipated to provide such benefits and are small molecules which do not contain sulfonic acid or a sulfonate fraction attached to less than 2 atoms. ^ Cz la plomead

INHIBIT.

A formulation of ganaxolone to which an ionic dispersion modulator has been added to re-disperse the ganaxolone-containing particles from a solid dosage form without considerable agglomeration.

The present invention also provides a pulsed-release oral ganaxolone dosage form comprising: (a) a first dosage unit comprising a first dose of ganaxolone which is substantially immediately released following oral administration of the dosage form To the patient, (b) a second dosage unit comprising a second dose of ganaxolone which is released approximately 3 to 7 hours after administration of the dosage form to the patient.

In the present invention are understood the methods of manufacturing the solid dosage forms of ganaxolone, including the oral dosage forms of pulsatile release of ganaxolone.

The inventors of the present application have prepared submicron stable particles of ganaxolone with particularly advantageous pharmaceutical properties. The stable ganaxolone particles described in the present application comprise a complex of gamoxolone

INDUSTRIAL with a complexing agent.

Additional factors affecting stability and particle size are also described in the present patent application.

In one aspect of the present invention are compositions comprising ganaxolone in which the ganaxolone has at least one of the following properties: (a) more than 90% of ganaxolone by weight is in the form of submicron particles, B) at least 20% of ganaxolone by weight is in the form of an amorphous powder, (c) at least 50% of ganaxolone by weight is in the form of a single polymorph crystalline powder, (d) at least one 50% of ganaxolone by weight is in the form of semicrystalline powder (e) ganaxolone is presented as irregular particles, (f) ganaxolone is presented as non-uniform particles; (G) at least 80% of the ganaxolone has the same general shape while having a particle size distribution; (H) ganaxolone is in the form of particles having a Gaussian size distribution; (I) ganaxolone is in the form of particles having a non-Gaussian size distribution; (J) ganaxolone is in the form of particles in which the particle size distribution is the sum of two Gaussian distributions,

OF INDUSTRIAL PRCHSDAD particles; (K) ganaxolone is in the form of particles having multi-modal particle size distribution; (1) ganaxolone is in the form of particles having single-mode particle size distribution; (M) ganaxolone is in the form of particles in which about 50% of the particles by weight have an effective particle size of less than 500 nm; (N) ganaxolone is in the form of particles in which at least 60% (or at least 70%, at least 80%, at least 90%) of the particles by weight have an effective particle size less than 1000 nm; (Or) ganaxolone is in the form of particles, In which the particle size distribution is described with a three-part model in which a certain percentage has an effective particle size by weight of about 10 nm and 300 nm, a certain percentage has an effective particle size by weight of Approximately 300 nm and 600 nm, and a certain percentage has an effective weight particle size above 600 nm, and furthermore in which the three-part model is identified as x% / y% / z%, respectively Example, 40% / 30% / 30%); (P) ganaxolone has a three-part distribution selected from the group consisting of 40% / 30% / 30%, 50% / 30% / 20, 60% / 30% / 10%, 40% / 40% / 20 %, 50% / 40% / 10%, 70% / 20% / 10%, 50% / 45% / 5%, 70% / 25% / 5%, 60% / 35% 15% / 5%, 70% / 30% / 0%, 60% / 40% / 0%, 90% / 10% / 0%, and 100% / 0% / 0%; (Q) ganaxolone comes in the form of particles, In which the standard deviation of the particle size distribution divided by the volume-weighted average diameter is less than about 30%, less than about 25%, less than about 20%, less than about 15% , Or less than about 10%; (R) ganaxolone does not come in particulate form; (S) ganaxolone is in the form of a particle coated with another material; (T) the ganaxolone covers, at least one portion another material; (U) ganaxolone is microencapsulated in another material, and (v) ganaxolone is presented as a particle, in which the particle size distribution is determined by a laser scattering method. In other embodiments of the present invention, The ganaxolone in the composition has at least two of the properties mentioned; At least three of the aforementioned properties, at least four of the aforementioned properties, or at least five of the aforementioned properties. Another aspect of the present invention are pharmaceutical formulations comprising ganaxolone, wherein the formulation has at least one of the following characteristics: (a) ganaxolone is selected from one of the aforementioned compositions comprising ganaxolone, (b) The formulation is suitable for administration to a mammal; (C) ganaxolone is suitable for administration to a human, (D) ganaxolone is suitable for administration to a human patient having a disease or disorder of the central nervous system (e) the formulation is suitable for administration to a human less than 2 years of age; (F) the formulation is suitable for administration to a person between the ages of 2 and 16, (g) the formulation is suitable for administration to an adult; (H) the formulation is suitable for administration to a preadolescent human, (i) the formulation is suitable for administration to a human post-teen; (J) the formulation is suitable for administration to a person over 65 years of age; (K) the formulation contains pharmaceutically acceptable excipients; (1) the formulation is suitable for administration to a patient having or suspected of having epileptic seizures; (M) the formulation is in the form of a pharmaceutically acceptable solid dosage form; (N) the formulation is in the form of a pharmaceutically acceptable non-solid dosage form; (O) the formulation is in the form of a pharmaceutically acceptable suspension; (P) the formulation further comprises water; (Q) the formulation further comprises a pharmaceutically acceptable agent which improves viscosity; (R) the formulation further comprises a dispersing agent; (S) the formulation further comprises a pharmaceutically acceptable wetting agent; (T) the formulation further comprises a sweetener; (U) the formulation further comprises at least one preservative; (V) the formulation is suitable for administration to a patient by means of a route selected from oral, intranasal, intravenous, subcutaneous, intramuscular, buccal, and transdermal routes; (W) the formulation is in the form of a pharmaceutically acceptable oral solid dosage form; (X) the formulation further comprises a pH sensitive coating; Also adding the formulation further comprising a pH insensitive coating (and) the formulation is designed for a pulsatile release; (Z) the formulation further comprises a preservative; (Aa) the formulation comprises a pH independent coating; (Ab) the formulation is designed by spraying in layers on a sphere or a bead; (Ac) the formulation comprises an inhibitor of crystalline DNA; ganaxolone; (D) the formulation is in the form of a microencapsulated drug; (Ae) the formulation is in the form of an aqueous dispersion in which the concentration of ganaxolone is between 25 and 50 mg / ml of solution; (Af) the formulation can be resuspended until it is converted into a homogeneous suspension by agitation; (Ag) the formulation comprises ganaxolone in an excipient bead; (Ah) the formulation has an amount of ganaxolone of from about 20% to about 40% by weight; The formulation has an amount of ganaxolone of from about 40% to about 65% by weight; (A) the formulation is in the form of a pharmaceutically acceptable tablet or capsule; (Aj) the formulation is in the form of a solid dispersion; (Ak) the formulation comprises ganaxolone available for immediate release in a patient and ganaxolone for intermediate release in a patient; (A) the formulation has an enteric layer; (Am) the formulation is designed to release more than about 70%, about 80%, or about 90% of the ganaxolone metered (by weight) into the patient's stomach and small intestine; (A) the formulation is designed so that about 70%, about 80%, or about 90% of the ganaxolone particles dosed by weight are absorbed within 6 to 7 hours after administration; (Ao) the formulation is produced with a method comprising a milling step; (Ap) the formulation is produced with a method comprising a grinding step; (Aq) the formulation is produced by a method comprising a spray-drying step; (Ar) the formulation is produced with a method comprising a super critical fluid; (S) the formulation is produced with a method comprising a crystallization step; (At) the formulation is produced with a method comprising a crushing step; (Au) the formulation is produced with a method comprising a spraying step; (Av) the formulation is produced with a method comprising a step of rapid expansion of the supercritical fluids; (Aw) the formulation is produced with a method comprising an ultrasonication step; (A) the formulation is produced with a method comprising a fluidized bed process; (Az) the formulation is produced with a method comprising a Wurster column; (Ba) the formulation is produced with a method comprising a coating step; (Bb) the formulation is produced by a method comprising a fracture step of supercritical phenols; (B) the formulation is provided with a method comprising a microfluidizer; (Bd) the formulation is produced by a method comprising a high pressure homogenization step; Or (b) the formulation is produced by a method comprising a hot melt stage. In other embodiments of the present invention, the formulation has at least two of the properties mentioned; At least three of the aforementioned properties, at least four of the aforementioned properties, at least five of the aforementioned properties,

In another aspect are methods for treating a disease or disorder in a patient comprising administering a pharmaceutical formulation comprising ganaxolone, wherein the method comprises at least one of the following steps or features: (a) the patient At least one of the aforementioned formulations of ganaxolone is administered, (b) the disease or disorder is of the central nervous system; (C) the disease or disorder is epilepsy, (d) the disease or disorder is GABAergic (e) the disease or disorder is of the neurosteroids; (F) ganaxolone is administered to induce sedation; (G) ganaxolone is administered as an anticonvulsant agent (h) ganaxolone is administered as a kyphoteric agent. (I) ganaxolone is administered in a manner that maintains plasma levels of approximately 50 ng / ml at steady state in the patient (Cmin), (j) ganaxolone is administered in a manner that maintains plasma levels of approximately 25 ng / Ml at steady state in the patient (Cmin), (k) ganaxolone is administered in a form that maintains plasma levels of about 100 ng / ml at steady state in the patient (Cmj.n); (1) the Cmax / Cmin of ganaxolone in the plasma of the stable patient is less than about 2.5, less than about 2.0, or less than about 1.5; (M), the fasting AUCen / aUCen of ganaxolone in the patient's plasma at steady state is less than about 3.0, 2.0, less than about 1.8, or less than about 1.5; (N) ganaxolone is administered as an oral suspension for children approximately every 6 hours, approximately every 8 hours, approximately every 12 hours, as needed; (Or) ganaxolone is administered as an oral suspension to the children to maintain a plasma level of ganaxolone of about 10 to 50 ng / ml in plasma (Cmin) over a period of 8 hours, 12 hours or 24 hours; (P) ganaxolone is administered with a rapid release component which achieves a Tmax of about 0.5 and 2 hours, (q) Ganaxolone is administered with an extended release component which creates a second release profile at the point of concentration of the initial level in Tmax, which reaches about 80% of the level in Tmax, Which reaches approximately 70% of the level in Tmx / which reaches approximately 60% of the level at or reaches approximately 50% of the level in Tmax. In the embodiments given, the levels of ganaxolone are maintained such that the plasma level is less than about 50 ng / ml before the next dose, which can be administered, for example, at intervals of 4, 6, 8, 12 or 24 hours; (R) ganaxolone is administered with a pH-dependent release component which produces a second drug absorption peak which is about 80% of the T 1 level, about 70% of the Tmax level, about 60% of the Level of Tmax, or that is approximately 50% of the level of Tmax), And the level of ganaxolone is maintained such that the plasma level is less than about 50 ng / ml before the next dose, which may be administered, for example, at 4, 6, 8, 12 or 24 hour intervals; (S) ganaxolone is administered twice a day; (T) ganaxolone reduces the incidence of seizures in patients; (U) the gain xa Ion to sa- ^. Administered in a form with a higher dissolution kinetics; (V) ganaxolone is administered in a dose and form providing absorption (> 70% by weight) within approximately 4 and 6 hours after administration; (W) ganaxolone is administered with at least one other antiepileptic agent; (X) ganaxolone is administered with at least one other anticonvulsant agent; (And) ganaxolone is administered with an anti-anticoagulant agent; (Z) ganaxolone is used to treat infantile spasms; (Aa) ganaxolone is used to treat status epilepticus; (Ab) ganaxolone is used to treat partial seizures; (Ac) ganaxolone is used to treat a metabolic disorder, or (ad) ganaxolone is used to treat catamenial epilepsy. In certain alternative embodiments of the present invention, the method has at least two of the aforementioned steps or characteristics, at least three of the above-mentioned steps or characteristics, at least four of the above-mentioned steps or characteristics, at least five of the Steps or characteristics, or at least six of the aforementioned steps or characteristics. (Ab) ganaxolone is used to treat partial seizures; (Ac) ganaxolone is used to treat a metabolic disorder, or (ad) ganaxolone is used to treat catamenial epilepsy. In certain alternative embodiments of the present invention, the method has at least two of the aforementioned steps or characteristics, at least three of the above-mentioned steps or characteristics, at least four of the above-mentioned steps or characteristics, at least five of Steps or characteristics, or at least six of the aforementioned steps or characteristics. (Ab) ganaxolone is used to treat partial seizures; (Ac) ganaxolone is used to treat a metabolic disorder, or (ad) ganaxolone is used to treat catamenial epilepsy. In certain alternative embodiments of the present invention, the method has at least two of the aforementioned steps or characteristics, at least three of the above-mentioned steps or characteristics, at least four of the above-mentioned steps or characteristics, at least five of Steps or characteristics, or at least six of the aforementioned steps or characteristics.

In some embodiments, this invention is directed to stable ganaxolone particles using a complexing agent.

In certain embodiments, the present invention is directed to pharmaceutical compositions containing stable ganaxolone particles comprising a ganaxolone complex exhibiting a proportion of D50 after storage in SGF or SIF at a temperature of 36 ° C to 38 ° C for 1 At 3 hours at D50 prior to storage of less than about 3: 1.

In other embodiments, the present invention is directed to a method of milling pharmaceutical products comprising a pharmaceutically active agent (eg, ganaxolone), optionally, a suitable amount of simethicone, milling beads and optional pharmaceutically acceptable excipients in a mill , And grinding the mixture for a suitable period to obtain submicron particles.

In yet other embodiments, the present invention is directed to a pharmaceutical composition comprising particles comprising the ganaxolone therein, and simethicone, in an amount, for example, from about 0.0001% to about 0.1%, depending on the total weight of the composition. L / C?

Another aspect of the present invention is directed to a pharmaceutical composition comprising ganaxolone particles therein and a vinyl polymer, the particles having a D 50 of less than about 500 nm, wherein the Cmax and AUC (oT) after Administration of the composition are reduced in comparison to the composition without the vinyl polymer.

In other embodiments, the present invention is directed to a pharmaceutical composition comprising particles comprising ganaxolone, the composition provides a higher AUC-x) in the fasted state.

In other embodiments, the present invention is directed to a pharmaceutical composition comprising particles comprising ganaxolone, the composition provides a higher Cmax in the fasted state.

In another aspect, the present invention is directed to a pharmaceutical composition comprising particles comprising ganaxolone, the composition provides an average AUC blood plasma (o-24> of about 100 and 300 ng * h / ml after administration of 200 to about 500 mg of ganaxolone to fasted adult subjects.

In still another aspect, the present invention is directed to a pharmaceutical composition comprising particles comprising ganaxolone, the composition provides a blood plasma Cmax of about 20 to about 85 ng / ml after being administered from 200 to about 500 mg Of ganaxolone to fasting adult subjects.

In still another aspect, the present invention is directed to a pharmaceutical composition comprising particles comprising ganaxolone, the composition provides an average AUC (o-24) blood plasma of from about 300 to about 1200 ng * h / ml after Administer from 200 to about 500 mg of ganaxolone to fed subjects.

In still another aspect, the present invention is directed to a pharmaceutical composition comprising particles comprising ganaxolone, the composition provides a blood plasma Cmax average of about 60 to about 350 ng / ml after being administered from 200 to about 500 mg Of ganaxolone to adult subjects in the fed state.

In another embodiment, the present invention is directed to pharmaceutical particles comprising an active agent (eg, ganaxolone); The particles are ground for a sufficient time to provide a proportion of D50 four weeks later, milled to D50 at the end of the milling, at least. In some embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, and a volume-weighted average diameter (D 50) of about 50 nm to 500 nm. The composition may have at least one excipient selected from the group consisting of a hydrophilic polymer, a wetting agent, a complexing agent, an ionic dispersion modulator, a water soluble spacer and a mixture of the foregoing.

In certain embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, and an effective amount of a complexing agent to stabilize the growth of the particles after reaching an initial growth and an end point, wherein the diameter Volume-weighted average (D50) of the particles before the initial growth is from about 50 to about 200 nm and the D50 after reaching the end point is about 100 nm and 350 nm.

In some embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, and an effective amount of an ionic dispersion modulator for redistribution

The agglomeration of the particles, wherein the volume-weighted average diameter (D50) of the particles is from about 50 nm to about 350 nm.

In some embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, and a complexing agent in an amount of about 0.1% to about 5%, w / w, based on the total weight of the composition, in the compositions. That the volume-weighted average (D50) of the particles is from about 50 nm to about 350 nm.

In some embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, and an ion dispersion modulator in an amount of about 1% to about 50%, w / w, based on the total weight of the composition, In which the volume-weighted average diameter (D 50) of the particles is from about 50 nm to about 350 nm.

In some embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, a hydrophilic polymer and a wetting agent, wherein the volume-weighted average diameter (D 50) of about 50 is approximately 500 nm. ""

In some embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, a hydrophilic polymer, a wetting agent and a complexing agent, wherein the volume-weighted average diameter (D 50) of the particles is about 50 Nm to about 500 nm.

In still further embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone, a hydrophilic polymer, a wetting agent and an ionic dispersion modulator.

In certain embodiments, the present invention is directed to a composition comprising particles comprising ganaxolone in an amount from about 10% to about 80%, w / w, based on the total weight of the composition, a hydrophilic polymer, in an amount From about 3% to about 50%, w / w, based on the total weight of the composition, a wetting agent in an amount of about 0.05% to about 2%, w / w, based on the total weight of the composition. composition; A complexing agent in an amount of about 0.1% to about 5%, w / w, based on the total weight of the composition, and a modulator of u

Ionic in an amount of about 1% to about 50%, w / w, based on the total weight of the composition.

As compared to the D 50 of the ganaxolone particles when the formulation is dispersed in distilled water under the same conditions, wherein the volume-weighted average diameter (D50) of the ganaxolone particles dispersed in distilled water is L- 1 to about 50 nm to about 1000 nm, NJU is about 100 nm to about 500 nm to about 100 nm to about 350 nm. The solid formulation may be, for example, a powder, a tablet, a capsule, among others. From about 50 nm to about 1000 nm, from about 100 nm to about 500 nm to about 100 nm to about 350 nm. The solid formulation may be, for example, a powder, a tablet, a capsule, among others. From about 50 nm to about 1000 nm, from about 100 nm to about 500 nm to about 100 nm to about 350 nm. The solid formulation may be, for example, a powder, a tablet, a capsule, among others.

In certain aspects, the solid formulation is in the form of a tablet or capsule containing the stable particles of ganaxolone and at least one excipient, the stable particles of ganaxolone exhibit an increase in volume-weighted average diameter (D50) From 0% to not more than about 200%, not more than about 150%, not more than about 100%, or not more than about 50%, when the tablets or capsules are dispersed in SGF or SIF (at any suitable volume , Eg from 15 ml to 1000 ml) in a concentration of 0.5 to 1 mg ganaxolone / ml at a temperature of 36 ° C to 38 ° C using a Type II dissolving apparatus and a stirring rate of 75 rpm per 1 hour,As compared to the D 50 of the ganaxolone particles when the tablets or capsules are dispersed in distilled water under the same conditions, wherein the volume-weighted average diameter (D50) of the ganaxolone particles when the tablets or capsules are found Dispersed in distilled water is from about 50 nm to about 1000 nm,

Yield approximately 500 nm, or from about 100 nm to about 350 nm.

In other aspects, the present invention is directed to a solid formulation (eg, a powder, an immediate release dosage form, or a controlled release dosage form) comprising stable particles of ganaxolone and at least one pharmaceutically acceptable excipient Acceptable, stable ganaxolone particles exhibit a volume-weighted average diameter (D50) increase of less than about 750 nm when the formulation is dispersed in simulated gastric fluid (SGF) for one hour, followed by simulated intestinal fluid ( SIF) for a further three hours, at a concentration of about 0.5 and 1 mg ganaxolone / ml (at any suitable volume, for example from 15 ml to 1000 ml) at a temperature of 36 ° C to 38 ° C.

In still other aspects, the solid formulation is a tablet or capsule containing the stable particles of ganaxolone and at least one excipient, the stable particles of ganaxolone exhibit an increase in the volume-weighted average diameter (D50) of at least about 750 nm when the tablets or capsules are dispersed in the simulated gastric fluid (SGF) for one hour, followed by the simulated enteral fluid (SIF) for three more hours, at a concentration of approximately 0.5 and 1 mg ganaxolone / Ml (at any suitable volume, for example from 15 ml to 1000 ml) at a temperature of 36 ° C to 38 ° C using a Type II dissolving apparatus and a stirring rate of 75 rpm.

In some embodiments of the present invention, the stable particles are prepared by contacting the ganaxolone particles with the excipient such that the particle size exhibits an increase in the volume-weighted average diameter of from about 20% to about 300% and which is Reaches an end point, so that the particles are stable.

The end point may be, for example, from about 1 to about 20 days.

In other aspects, the present invention is directed to a solid oral dosage form comprising (i) a controlled release component comprising a first portion comprising ganaxolone particles, and a controlled release material, and (ii) a Immediate release component comprising a second portion of particles comprising ganaxolone, the first and second portions of the ganaxolone particles have a volume-weighted average diameter (D 50) of about 50 nm a. , | , & Quot; About 1000 nm, from about 100 nm to about 450 nm, or from about 100 to about 350 nm. The ratio of controlled release to controlled release ganaxolone may be, for example, from about 4: 1 to about 1: 4, from about 3: 2 to about 2: 3, or about 1: 1. The controlled release component may have any shape, comprising, but not limited to, (i) a plurality of pharmaceutically acceptable beads coated with the first portion of ganaxolone particles and coated with the controlled release material (optionally, a film coating which Comprises a material such as hydroxypropylmethylcellulose or polyvinyl alcohol which may be included in the beads prior to coating with the ganaxolone particles), (ii) a plurality of matrices comprising the first portion of the ganaxolone particles dispersed in the controlled release material, (Iii) a tablet comprising the first portion of ganaxolone particles dispersed in the controlled release material, Or (iv) a granulation comprising the first portion of ganaxolone particles and the controlled release material. The immediate release component can. . ,. . . (I) a plurality of pharmaceutically acceptable beads coated with the second portion of ganaxolone particles (ii) a plurality of matrices comprising the second portion of particles Of ganaxolone dispersed in an excipient, (iii) a tablet comprising the second part by ganaxolone particles dispersed in the excipient or (iv) a granulation comprising the second portion of the ganaxolone particles and the excipient. Alternatively, the immediate release component may be included in the dosage form in the form of a powder.

In certain embodiments, the controlled release component and the immediate release component are contained in a capsule.

In other embodiments, the controlled release component is a tablet and the immediate release component is coated onto the tablet.

In still further embodiments, the controlled release component and the immediate release component are in a double layer tablet.

In yet other embodiments, the controlled release component comprises a plurality of pharmaceutically acceptable beads, coated with the first portion of ganaxolone particles and coated therein. controlled release and <- ητηηηη <* η · ^ Γρ immediate release comprising a plurality of pharmaceutically acceptable beads coated with the second portion of ganaxolone particles, the controlled release component and the immediate release component being contained in a capsule.

In another aspect, the controlled release component comprises a plurality of pharmaceutically acceptable beads, covered in the first portion of ganaxolone particles and coated with the controlled release material and the immediate release component comprising a tablet comprising the second portion of Ganaxolone particles dispersed in an excipient, the controlled release component and the immediate release component being in a capsule.

In yet other embodiments, the controlled release component comprises a plurality of pharmaceutically acceptable beads coated with the first portion of ganaxolone particles and coated with the controlled release material and the immediate release component comprising a granulation comprising the second portion Ganaxolone particles and an excipient, the controlled release component and the immediate component being contained in a capsule.

In another embodiment, the controlled release component comprises a plurality of pharmaceutically acceptable beads, coated with the first portion with ganaxolone particles and coated with the controlled release material, and the immediate release component comprises a granulation comprising the second portion of Ganaxolone particles and an excipient, the controlled release component being dispersed in the immediate release component in the form of a compressed tablet.

In other embodiments, the controlled release component comprises a compressed tablet and the immediate release component is compression coated onto the controlled release tablet.

In certain embodiments, the dosage forms of the present invention provide the pulsatile release of two or more doses of ganaxolone. That dosage form may provide an immediate release dose after administration and at least one additional dose after a certain time of administration selected from the group consisting of 3 to 8 hours, 6 to 10 hours, 10 to 14 hours , From 14 to 18 hours, from 16 to 20 hours and from 22 to 24 hours.

In certain embodiments, the invention is directed to a solid oral dosage form comprising ganaxolone particles and a controlled release material, the ganaxolone particles have a volume-weighted average diameter (D 50) of About 50 nm to 1000 nm, the dosage form provides a controlled release of ganaxolone which provides a therapeutic effect of about 8 to about 24 hours after administration.

In other embodiments, the invention is directed to a solid oral dosage form comprising particles comprising ganaxolone, and a pH-dependent polymer, the ganaxolone particles have a volume-weighted average diameter (D 50) of from about 50 nm to about 50 nm to about 1000 nm, the dosage form provides a delayed release of ganaxolone for a period of time from about 2 to about 12 hours after administration.

Compared to the D50 under the same conditions after being dispersed in distilled water. The volume-weighted average diameter (D50) of the coated beads prior to dispersion may be, for example from about 0.1 nm to about 5.0 nm.

In other aspects, the invention is directed to an immediate release solid oral dosage form comprising ganaxolone particles, and at least one pharmaceutically acceptable excipient, the ganaxolone particles have a volume-weighted average diameter (D 50) of about 50 nm At approximately 1000 nm.

In some embodiments, the present invention is directed to a pharmaceutical dosage form (for example, a liquid or solid dosage form) comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient. A volume-weighted average diameter (D50) of from about 50 nm to about 1000 nm, the dosage form provides an average ratio of AUC (oT) to fasting AUC (oT) blood plasma from about 1: 1 to about 4: 1, from about 1.3: 1 to about 4: 1, or from about 1: 1 to about 3: 1.

In other embodiments, the present invention is directed to a pharmaceutical dosage form (for example, a liquid or solid dosage form) comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient, the particles have a Volume (D50) of from about 50 nm to about 1000 nm, the dosage form provides an average ratio of Cmax to Cmax fasting plasma plasma from about 15: 1 to about 7: 1, from about 2.5: 1 to about 7: 1, or from about 1.5: 1 to about 4: 1.

In other embodiments, the present invention is directed to a pharmaceutical dosage form comprising particles comprising ganaxolone, and to the pharmaceutically acceptable excipient, 1-6 particles have a weighted average diameter per Volume (D50) from about 50 nm to about 1000 nm, the dosage form provides an average proportion of AUC (o-24) hours of blood plasma from about 100 to about 375 ng * h / ml when orally administered a dose of 200 mg to 500 mg of ganaxolone to fasting adult subjects.

In still further embodiments, the present invention is directed to a pharmaceutical dosage form comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient, the particles have a volume-weighted average diameter (D 50) of from about 50 nm to about 1000 Nm, the dosage form provides an average Cmax blood plasma of about 25 to about 70 ng / ml when a dose of 200 ng to 500 mg ganaxolone is administered orally to fasted adult subjects.

In yet another embodiment, the present invention is directed to a pharmaceutical dosage form comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient, the particles have a volume-weighted average diameter (D 50) of from about 50 nm to about 50 nm to about 1000 nm, the dosage form provides an AUC-fed (~ 48) blood plasma of about 400 to about 1200 ng * hr / ml when a dose of 200 to 500 mg of ganaxolone is administered orally to adult subjects in Fed state.

In still further embodiments, the present invention is directed to a pharmaceutical dosage form comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient, the particles have a volume-weighted average diameter (D50) of from about 50 nm to about 1000 Nm, the dosage form provides an average plasma Cmax of about 60 to about 250 ng / ml when a 200 to 500 mg dose of ganaxolone is given orally to fed subjects in the fed state.

In other aspects, the present invention is directed to a pharmaceutical dosage form comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient, the particles have a volume-weighted average diameter of from about 50 nm to about 1000 nm, the form Provides an average plasma blood Cmax / Cmin ratio of not more than about 4 to 1 steady state with a dose of 200 to 500 mg of ganaxolone to adult subjects in a fasting state.

In still other aspects, the present invention is directed to a liquid pharmaceutical dosage form comprising particles comprising ganaxolone, and at least one pharmaceutically acceptable excipient, the particles have a volume-weighted average diameter of from about 50 nm to about 1000 nm, The dosage form provides a mean plasma Cmin value of about 10-40 ng / ml in infants (greater than 4 months and less than 2 years of age) at a dose of ganaxolone of about 10 mg / kg at steady state.

In other aspects, the present invention is directed to a liquid oral pharmaceutical suspension comprising ganaxolone, the suspension provides an average Cmax blood plasma of about 30 to 45 ng / ml and an average plasma AUC (o-24) of approximately 160 to 210 ng * h / ml, based on a 200 mg dose of ganaxolone for fasting subjects, or an average Cmax blood plasma of approximately 37 ng / ml and a mean plasma AUC (0-24) of Approximately 185 ng * h / ml, based on a 200 mg dose of ganaxolone for fasting subjects.

In more than 15% after 60 days storage at room temperature, or at more than 15% after 80 days storage at room temperature. In certain aspects, the volume-weighted average diameter (D 50) of the stable ganaxolone particles prior to storage is from about 100 nm to about 450 nm, or from about 100 nm to about 350 nm.

In certain embodiments, the present invention relates to a liquid oral dosage form wherein the volume-weighted average diameter (D50) of the stable particles of ganaxolone does not vary by more than 15% When placed in a glass vial and heated to 100 ° C in an oil bath for 20 minutes, does not vary by more than 15% when placed in a glass vial and heated to 100 ° C in a Oil bath for 4 hours, does not vary by more than 10% when placed in a glass vial and heated to 100 ° C in an oil bath for 20 minutes, does not vary by more than 5% when placed In a glass vial and heated to 100 ° C in an oil bath for 20 minutes or not more than 3% when placed in a glass vial and heated to 100 ° C in an oil bath For 20 minutes.

In still other embodiments, the present invention is directed to a liquid oral dosage form in which the volume-weighted average diameter (D 50) of the stable particles of ganaxolone does not vary by more than 25% when placed in an HDPE , And freezes and thaws, three times or more, with a freezing time for each cycle of at least 12 hours. The freezing temperature may be any suitable freezing temperature, for example about -80 ° C to about -20 ° C. The present invention is also directed to the

Liquid dosage in frozen form.

In certain embodiments, the oral liquid dosage form is prepared by contacting the ganaxolone particles with the excipient, wherein the particle size exhibits an increase in the volume-weighted average diameter (D 50) of from about 20% to about 300 % And reaches an end point, such that the particles are stable.

In other aspects, the present invention is directed to pharmaceutical particles comprising ganaxolone or a pharmaceutically acceptable salt thereof, the particles being stable, such that their volume-weighted average diameter (D50) would not increase by more than about 50% After 28 days storage at ambient temperature and conditions, its volume-weighted average diameter (D50) before storage being from about 50 nm to about 1000 nm; The particles are ground for a time sufficient to achieve stability. In other respects, the volume-weighted average diameter (D 50) of the particles does not vary by more than about 25% after 28 days of storage at ambient temperature and conditions, Does not vary by more than about 15% after 28 days of UL. Storage at ambient temperature and conditions does not vary by more than about 10% of the storage days at ambient temperature and conditions, or does not vary by more than 10 days. Approximately 50% after 40 days storage at ambient temperature and conditions.

The present invention is further directed to a method of stabilizing the growth of pharmaceutical particles comprising milling ganaxolone to a volume-weighted average diameter (D 50) of from about 50 nm to about 1000 nm and for a time sufficient for the diameter (D50) of the particles does not vary by more than 50% after 28 days of storage at ambient temperature and conditions, does not vary by more than 25% after 28 days storage at ambient temperature and conditions, Varies by more than 15% after 28 days of storage at ambient temperature and conditions, or does not vary by more than 10% after 28 days of storage at ambient temperature and conditions.

In still other embodiments, the present invention is directed to a pharmaceutical composition comprising particles comprising (i) ganaxolone, or a pharmaceutically acceptable salt thereof, and (ii) a trace amount of simethicone , Particles and

In some embodiments, the simethicone is in an amount from about 0.001% to about 1%, or 0.005% to about 0.02% by weight. % Simethicone, weight / weight, based on the weight of the particles.

In other embodiments, the present invention is directed to a milling method of ganaxolone, comprising incorporating ganaxolone, a suitable amount of simethicone, milling beads and optional pharmaceutically acceptable excipients in a mill; And grinding the mixture for a suitable period of time to obtain nanometric particles. The simethicone may be in the form of an emulsion, for example, with a content of about 20% to 50% of simethicone. In addition, the amount of simethicone present in the milling blend may be, for example, from about 0.01% to about 5%, or from about 0.02% to about 1%, or from about 0.04% to about 0.6%, weight / weight , Based on the weight of ganaxolone.

The present invention is also directed to a method of stabilizing pharmaceutical particles which comprises preparing the particles comprising ganaxolone or a pharmaceutically acceptable salt having a volume-weighted average diameter (D 50) From about 50 nm to about 450 nm, contacting the ganaxolone particles with a complexing agent wherein the volume-weighted average diameter (D 50) of the particles is increased from about 20% to about 300%, and reaches an end point of Such that the particles are stable. In other embodiments, the complexed particles are subject to sonication to decrease the volume-weighted average diameter (D 50) of about 10 to about 60% before reaching the end point.

The present invention is also directed to a method of preparing pharmaceutical particles which comprises preparing particles comprising ganaxolone or a pharmaceutically acceptable salt thereof having a volume-weighted average diameter (D 50) of from about 50 nm to about 450 nm, and Contacting a vinyl polymer with the ganaxolone particles such that the Cmax provided by the particles is reduced from about 25% to 80%.

The present invention is also directed to a method of preparing pharmaceutical particles which comprises preparing the particles comprising ganaxolone or a pharmaceutically acceptable salt thereof having a volume-weighted average diameter (D50) of from about 50 nm to about 450 nm, And contacting a vinyl polymer with the ganaxolone particles such that the AUC provided by the particles is reduced from about 25% to 80%.

The present invention is further directed to methods of preparing the compositions disclosed in the present application, including, but not limited to, ganaxolone particles, liquid formulations, and solid oral dosage forms (eg, immediate release, Sustained release, delayed release and pulsatile release).

The present invention is also directed to methods of treatment involving the administration of any of the compositions disclosed in the present application, including, but not limited to, ganaxolone particles, liquid formulations and oral solid dosage forms , Immediate release, sustained release, delayed release and pulsatile release).

In the above embodiments, the ganaxolone compositions of the present invention (eg, liquid or solid) comprise an excipient selected from the group consisting of a hydrophilic polymer, a wetting agent,

MEXICAN complexing agent, an ionic dispersion modulator, a water-soluble spacer and a mixture thereof.

In certain embodiments, the excipient comprises a complexing agent. The complexing agent may be a substance containing a phenol moiety, an aromatic ester moiety or an aromatic acid moiety. Particular complexing agents are selected from the group consisting of parabens, organic acids, carboxylic acids, aromatic acids, aromatic esters, acid salts of amino acids, methyl anthranilate, sodium metabisulfite, ascorbic acid and its derivatives, malic acid, isoascorbic acid, Citric acid, tartaric acid, sodium sulfite, sodium bisulfate, tocopherol, fat and water soluble tocopherol derivatives, sulfites, bisulfites and hydrogen sulphites, para-aminobenzoic acids and esters, 2,6-di- Alpha-dimethylamino-p-cresol, t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone,

In some embodiments, the excipient comprises a hydrophilic polymer. The hydrophilic polymer may be selected from the group consisting of a cellulosic polymer, a vinyl polymer and mixtures thereof. Particular cellulosic polymers include cellulosic polymers such as cellulose ethers (eg, hydroxypropylmethylcellulose) or a vinyl polymer such as a polyvinyl alcohol.

In certain embodiments, the excipient comprises a wetting agent. The wetting agent may be selected from the group consisting of sodium lauryl sulfate, a pharmaceutically acceptable salt of docusate, and mixtures thereof.

In some embodiments, the excipient comprises an ionic dispersion modulator. The ionic dispersion modulator may be a salt, such as an organic or inorganic salt. The inorganic salt may be selected from the group consisting of a magnesium salt, calcium salt, lithium salt, potassium salt, sodium salt and mixtures thereof, and the organic salt may be selected from the group consisting of a salt of Citrate, succinate salt, fumarate salt, malate salt, maleate salt, tartrate salt, glutarate salt, lactate salt and mixtures thereof.

In some embodiments, the preferred excipient. JunjI MEXICAN INSTITUTE OF THE P * G?! E! M> water soluble spacer. The water soluble spacer may be a saccharide or an ammonium / saccharide salt may be selected from the group consisting of fructose, sucrose, glucose, lactose, mannitol, and mixtures thereof.

In embodiments directed to solid formulations, the complexing agent may be in an amount of about 0.05% to about 5%, w / w, based on the weight of the solid formulation; The hydrophilic polymer may be in an amount from about 3% to about 50%, w / w, based on the weight of the solid formulation; The cellulose ether may be in an amount from about 3% to about 50%, w / w, based on the weight of the solid formulation; The polyvinyl alcohol may be in an amount from about 0.1% to about 5%, w / w, based on the weight of the solid formulation, the wetting agent may be in an amount of about 0.01% to about 10%, w / w , Based on the weight of the solid formulation, The ionic dispersion modulator may be in an amount from about 1% to about 50%, w / w, based on the weight of the formulation VL-U3iR. Solid; And the water-soluble spacer may be in an amount of about 2% to about 60%, w / w, based on the weight of the solid formulation. Percentages by weight are not intended to be limiting.

In the embodiments of the present invention which are directed to the ganaxolone coated beads, the controlled release material may be coated onto the bead with drug layers, for example, from about 3% to about 25%, or from about 8% To about 12%, based on the total weight of the component.

In certain solid formulations, the ganaxolone particles are dispersed in a liquid to form a suspension and the suspension is spray coated onto a plurality of substrates, or spray-granulated with the plurality of substrates. In still further embodiments, the ganaxolone particles are dispersed in a liquid to form a slurry and the slurry is spray dried to a powder which is coated onto the plurality of substrates. The slurry may be, for example, from about 5% to about 35%, or from about 15% to about 25% total solids. The concentration of ganaxolone in solids may be, for example, about 75%.

In embodiments directed to solid dosage forms using substrates, these may be, for example, inert beads, or may be selected from the group consisting of lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, Microcrystalline cellulose, powdered cellulose, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and mixtures thereof.

In embodiments directed to sustained or delayed dosage forms, the dosage form may be a granulation comprising ganaxolone particles and the controlled release material (eg, a hydrophobic polymer or a pH dependent material), the granulation is Compressed into a tablet or filled into a capsule.

In embodiments directed to sustained or delayed dosage forms, the dosage form may be a plurality of pharmaceutically acceptable beads, coated with the ganaxolone particles and coated with the controlled release material (eg, a polymer) Hydrophobic or a pH-dependent material), the coated beads are compressed into a tablet or filled into a capsule.

In embodiments directed to liquid dosage forms, it may include at least one excipient selected from polyvinyl alcohol, sodium lauryl sulfate, methylparaben, propylparaben, sodium benzoate, citric acid, sodium citrate, simethicone, sucralose and flavorants. For example, the liquid dosage form may comprise about 5% ganaxolone, about 1% polyvinyl alcohol, about 0.1% sodium lauryl sulfate, about 0.1% methylparaben, about 0.02% propylparaben, about 0.09% sodium benzoate , About 0.12% citric acid, about 0.009% sodium citrate, about 0.01% simethicone, about 0.02% sucralose and flavorants. Ingredients and percentages are not intended to be limiting.

In certain embodiments, the present invention is directed to a liquid oral dosage form comprising stable particles of ganaxolone, hydroxymethylpropylcellulose, sodium lauryl sulfate, simethicone, sucralose, methylparaben, propylparaben,

Sodium benzoate, citric acid, sodium citrate, and flavorants, the liquid has a pH of about 3.8 to about 4.2.

In some embodiments, the present invention is directed to a liquid oral dosage form comprising from about 2.5% to about 5% stable ganaxolone particles, from about 2% to about 5% hydroxymethylpropylcellulose, from about 0.1% to about 0.3% % Sodium lauryl sulfate, from about 0.005% to about 0.02% simethicone, from about 0.01% to about 0.03% sucralose, from about 0.05% to about 0.1% methylparaben, from about 0.01% to about 0.02% propylparaben , From about 0.05% to about 0.1% sodium benzoate, from about 0.1% to about 0.15% citric acid, from about 0.005% to about 0.01% sodium citrate and from about 0%.002% to about 0.004% flavor, the liquid has a pH of about 3.8 to about 4.2, wherein all percentages are by weight percent relative to the total weight of the liquid formulation.

In certain embodiments, the present invention is directed to a liquid oral dosage form comprising stable particles of glycine, hydroxymethylpropylcellulose, polyvinyl alcohol, sodium lauryl sulfate, simethicone, sucralose, methylparaben, propylparaben, sodium benzoate, citric acid, Sodium and flavors, the liquid has a pH of about 3.8 to about 4.2, wherein all percentages are by weight percent relative to the total weight of the liquid formulation.

In some embodiments, the present invention is directed to a liquid oral dosage form comprising from about 2.5% to about 5% stable ganaxolone particles, from about 2% to about 5% hydroxymethylpropylcellulose, from about 0.5% to about 1.5% % Polyvinyl alcohol, from about 0.1% to about 0.3% sodium lauryl sulfate, from about 0.005% to about 0.02% simethicone, from about 0.01% to about 0.03% sucralose, from about 0.05% to about 0.1% of Methylparaben, from about 0.01% to about 0.02% propylparaben, from about 0.05% to about 0.1% sodium benzoate, from about 0.05% to about 0.15% citric acid and from about 0%.005% to about 0.01% sodium citrate and from about 0.002% to about 0.004% flavor, the liquid has a pH of about 3.8 to about 4.2, wherein all percentages are by weight percent relative to the total weight of the Liquid formulation.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1. Cure of ganaxolone particles preserved with paraben and sodium benzoate: particle size growth was partially reversed for 1 min sonication (adjusted at low power) at the initial stage of the healing process . FIGURE 2. Cure of ganaxolone particles preserved with paraben and sodium benzoate: Particles containing parabens were fully cured within 5 to 7 days, while particles preserved with sodium benzoate required approximately 3 weeks to stabilize D50 without sonication). FIGURE 3. Stability graph (D50 vs time) of the ganaxolone particles that do not contain a complexing agent: The ganaxolone particles without complexing agents that were milled for less than 2 hours of milling residence time continued to gradually increase in size for several months, while the milled particles for more than 2 hours residence time did not change in six months. FIGURE 4. Feeding of a grinding run using a DYNO-Mill KDL mill equipped with four 64 mm polyurethane agitator disks followed by measurement of the particle size value (D50) of the ganaxolone particles as a function of residence time . FIG. 5. Distribution of the particle size (after 1 minute of low-power sonication) of resuspended solid dosage forms containing sodium chloride in SGF at room temperature: with and without complexing agent (methylparaben).

DETAILED DESCRIPTION OF THE INVENTION

Now, detailed reference will be made to the embodiments of the compositions, formulations and methods disclosed in the present invention. Some examples of the preferred embodiments appear in the following Examples section. Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as understood by those skilled in the art to which the invention described in the present application pertains. All patents and publications referred to in the present application are incorporated by reference.

Definitions

As used in the present patent application, the terms "comprising", "including", "containing" and "as" are used in an open and non-limiting sense.

The term "about" is used as a synonym for the term "about". As would be understood by one skilled in the art, the exact limit of "about" or "about" will depend on the component of the composition. Illustratively, the use of the term "about" or "about" indicates that the values slightly depart or go beyond the quoted values, ie, about 0.1% to 10%, which are also effective And insurance. Therefore, compositions which are slightly outside the aforementioned ranges are also within the scope of the present Application.

"Anti-foaming agents" reduce foaming during processing, which may result in the coagulation of the aqueous dispersions, bubbles in their final form, or in general affect the processing. Some examples of antifoam agents are the emulsions of Silicon to sorbitan sesquioleate.

"Antioxidants" include, for example, butylated hydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate and tocopherol. The combination of one or more antioxidants may also be used.

The "binders" impart cohesive qualities and include, for example, alginic acid and salts thereof, cellulose derivatives such as carboxymethylcellulose, methylcellulose (eg, Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose , Klucel®), ethylcellulose (eg, Ethocel®), and microcrystalline cellulose (eg, Avicel® PH101 and Avicel® PH102); Silicified microcrystalline cellulose (ProSolv SMCC®), microcrystalline dextrose; Amylose; Aluminum and magnesium silicate; Polysaccharide acids; Bentonites; jelly; Polyvinylpyrrolidone / vinyl acetate copolymer; Crospovidone; Povidone, starch, such as corn starch, potato starch, wheat starch, rice starch, pregelatinized starch; Tragacanth, dextrin, sugar,

Xylitab®) and lactose, a natural or synthetic gum, such as acacia, tragacanth, gum ghatti, mucilage of isapol pods, polyvinyl alcohol, polyvinylpyrrolidone (eg, Povidone® CL, Kollidon® CL, Polyplasdone® XL-10), Larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. The combination of one or more binders may also be used.

The term "Bioavailability" refers to the extent to which a drug is available at the site (s) of action following administration. By way of example, the bioavailability of a ganaxolone formulation refers to the weight percent of ganaxolone dosed which is released into the general circulation of the animal or human being being studied. The total exposure (AUC (o-eo)) of a drug when administered intravenously is usually defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which ganaxolone is absorbed in the general circulation when the pharmaceutical composition is taken orally as compared to the intravenous injection route.

"Blood serum concentration" or "blood plasma concentration" or "serum or plasma concentration or level" is normally measured in mg, pg or ng of a drug per ml, di, or 1 of absorbed serum or plasma In the bloodstream after administration. As used in the present patent application, plasma concentrations are usually measured in ng / ml or pg / ml. It is understood that the plasma concentration of ganaxolone may vary significantly from subject to subject, due to variability with respect to metabolism and / or possible interactions with other therapeutic agents. According to one aspect of the present invention, the blood plasma concentration of ganaxolone may vary from subject to subject. In the same way, Values such as the measured concentration of the active agent in plasma at the point of the maximum concentration (Cmax) or time to reach the maximum plasma concentration (Tmax) or the total area under the plasma concentration time curve (AUC - <*>)) may vary from subject to subject. OF THE INDUSTRIAL FRAMEWORK **,

The term "AUCfo- ,;" or "exposure" is the area under the curve of a graph of active agent concentration (generally plasma concentration) vs time (t), measured from time 0 to X. AUC <o-τ) is also used to define exposure to the drug over a period of time. Because of the variability, the amount needed to constitute a "therapeutically effective amount" of ganaxolone may vary from subject to subject.

"Carrier materials" include any excipients commonly used in the pharmaceutical industry and should be selected on the basis of their compatibility with ganaxolone and the properties of the release profile of the desired dosage form. Examples of the carrier materials include binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.

Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; And Pharmaceutical Dosage Forms and Drug

Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

The term "conventional ganaxolone formulations", as used in the present patent application, refers to the ganaxolone formulations previously administered to the subjects. Such formulations include ganaxolone formulated with β-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin. Since the published data are dominated by the use of the complex 1: 1 l / ύ riwncu / \ L> κ falls; Ganaxolone / p-cyclodextrin, this standard formulation is preferable for comparing the α-ganaxolone formulations described in the present patent application.

The term "cure" means a sufficient time until an end point is reached, such that, the D50 does not change or substantially change after a time in consecutive measurements separated by about 72 hours, for example, in a Greater than the accuracy of the measuring instrument of + 5% within 72 hours after the cure period. The preferred cure times are 1 to 20 days, 2 to 15 days or 3 to 10 days.

"Dispersion agents" and / or "viscosity modulating agents" include materials that control the diffusion and homogeneity of a drug by liquid media or by a granulation or mixing method. In some embodiments, these agents also facilitate the effectiveness of the coating matrix or erosion. Some examples of the diffusion / dispersion facilitating agents include hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP, commercially known as Plasdone®), and carbohydrate dispersing agents such as Hydroxypropylcelluloses (for example, Pharmacoat 603, HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), for example, hydroxypropylcelluloses (e.g., HPC,, Nfff), DADyr HPC-L), hydroxypropylmethylcelluloses Carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, non-crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate stearate (HPMCAS). Other dispersing agents are magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4- (1,1,3,3-tetramethylbutyl) -phenol polymer with Ethylene and formaldehyde (also known as tyloxapol), poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); And poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®,

AL having a molecular weight of about 300 to about 6000, from about 3350 to about 4000, or from about 7000 to about 5400, polysorbate-80, sodium alginate, gums, such as gum tragacanth and Acacia gum, guar gum, xanthanes, including xanthan gum, sugars, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, povidone, carbomers, alginates, chitosans and combinations thereof. Plasticizers such as cellulose or triethyl cellulose may also be used as dispersing agents. The dispersing agents particularly useful in the liposomal dispersions and in the self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural egg phosphatidylcholine, natural egg phosphatidylglycerol,

The term "complex" or "ganaxolone complex" indicates an association of molecules and / or a particle including ganaxolone and, optionally, other molecules which give rise to a better stability of the ganaxolone particles or some other desirable effect. In some cases the complexing agents initially increase the particle size (D50), before imparting

. Stability or other attributes beneficial to the formulation. In some embodiments, the ganaxolone complexes made by the addition of complexing agents require a cure time.

"Complexing agents" are molecules which, when added to a composition of small particles (D 50 from about 75 to about 400 nm), under appropriate conditions act as a stabilizing agent.

Addition of a complexing agent may also impart additional stability to the slurry during the freeze / thaw and boil cycles if sterilization is required. Complexing agents include small molecular weight (MW) compounds 550 which do not contain a counterion group of sulfonic acid or sulphonic acid / inorganic salt at the end of an alkyl chain containing more than one saturated carbon atom bound to the atom Of carbon bearing the sulphonic acid moiety. Complexing agents include, but are not limited to, phenols and phenolic salts, aromatic acids and esters, carboxylic acids and salts and their esters, inorganic acids and bases, and amino acids and esters and salts thereof. Some examples include, but are not limited to, phenol, methylparaben, Prolonged release, pulsatile release and delayed release. Controlled-release dosage forms can provide levels of a drug that are therapeutically effective over an extended period of time and thus provide a longer therapeutic period relative to the immediate release forms.

The term "Delayed Release", according to its use in the present patent application, refers to a dosage form which releases a drug at any time other than immediately after administration and / or anywhere else in the gastrointestinal More distant than would otherwise have been achieved with an immediate release dosage form. The enteric coated coated dosage forms are an example of delayed release dosage forms.

The "diluents" increase the volume of the composition to facilitate compression or to create sufficient volume for a homogenous mixture for filling the capsules. These compounds include, to lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; Dibasic calcium phosphate, dicalcium phosphate dihydrate; Tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compressible sugar, such as Di-Pac® (Amstar); Mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose based diluents, confectionery sugar; Calcium sulfate monobasic monohydrate, calcium sulfate dihydrate; Calcium lactate trihydrate, dextrates; Hydrolyzed cereals, amylose; Cellulose powder, calcium carbonate, glycine, kaolin; Mannitol, sodium chloride; Inositol, bentonite, and other similar compounds.

Mixtures of one or more diluents may also be used.

The term "disintegrating" is the dispersion of the dosage form upon contact with the gastrointestinal fluid or with a dispersing agent. "Disintegrating agents" or "disintegrating agents" facilitate the decomposition or disintegration of a formulation. Examples of disintegrating agents include, for example, starch, natural starch such as corn or potato starch, pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as Wood products, microcrystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose , Or a reticulated cellulose, Such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, a crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, an alginate such as alginic acid Or a salt of alginic acid such as sodium alginate, a clay, such as Veegum® HV (magnesium aluminum silicate), a gum, such as, Agar, guar, carob, karaya, pectin, or tragacanth VSTRwn sodium starch glycolate (Explotab®), bentcmite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, lauryl Sodium sulfate, sodium lauryl sulfate in combination with starch, and the like. Or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, a crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum, such as, PROPERTY V /? Agar, guar, carob, karaya, pectin, or tragacanth VSTRwn sodium starch glycolate (Explotab®), bentcmite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, lauryl Sodium sulfate, sodium lauryl sulfate in combination with starch, and the like. Or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, a crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum, such as, PROPERTY V /? Agar, guar, carob, karaya, pectin, or tragacanth VSTRwn sodium starch glycolate (Explotab®), bentcmite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, lauryl Sodium sulfate, sodium lauryl sulfate in combination with starch, and the like. Crosslinked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay, such as Veegum® HV (magnesium aluminum silicate), a gum, such as, Agar, guar, carob, karaya, pectin, or tragacanth VSTRwn sodium starch glycolate (Explotab®), bentcmite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, lauryl Sodium sulfate, sodium lauryl sulfate in combination with starch, and the like. Crosslinked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay, such as Veegum® HV (magnesium aluminum silicate), a gum, such as, Agar, guar, carob, karaya, pectin, or tragacanth VSTRwn sodium starch glycolate (Explotab®), bentcmite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, lauryl Sodium sulfate, sodium lauryl sulfate in combination with starch, and the like.

The term "drug absorption" or "absorption" usually refers to the process of circulating the drugs from the site of administration of a drug through a barrier to enter the blood vessels, or to the site of action, for example , When a drug moves from the gastrointestinal tract to the portal vein or to the lymphatic system.

The term "effective particle size" is used in turn with "D50". The term "D50" means that 50% of the particles are below and 50% of the particles are above a given measurement. The term D50 can be used to describe various parameters (volume, length, number, area, among others). The term "effective particle size" or D50, as used in the present patent application, indicates a volume-weighted average diameter, as measured by a light / laser scattering method or equivalent, wherein 50% Of the particles, by volume, have a smaller diameter, while 50% by volume have a larger diameter. The volume-weighted D50 also refers to the weight percentage of the particle by virtue of a certain size. For example, a D50 of 500 nm means that 50% of the mass of particles has a diameter of less than 500 nm and 50% of the mass of particles has a diameter greater than 500 nm. Effective particle size is measured by conventional particle size measurement techniques well known to those skilled in the art. These techniques include, for example, fractionation of the sedimentation flux field, photon correlation spectroscopy, light scattering (eg with Microtrac UPA 150), laser diffraction and disk centrifugation. For purposes of the compositions, formulations and methods described in the present patent application, The effective particle size is the mean diameter per volume determined by light / laser scattering methods and instruments, for example, a Horiba LA-910, or a Horiba LA-950. Similarly, "D90" is a volume- weighted diameter , in which 90% of particles by volume have a smaller diameter, while 10% by volume have a larger diameter and "DIO" is a Diameter, in which 10% of the particles, by volume, have a smaller diameter, while 90% by volume have a larger diameter. It is sometimes useful to express the D50 value after sonication for 1 minute or less, using 40 watts sonication potency at room temperature (15 ° C to 30 ° C).

An "enteric layer" is a substance that remains substantially intact in the stomach but dissolves and releases the drug into the small intestine and / or colon. In general, the enteric layer is composed of a polymeric material which prevents release into the environment at low pH of the stomach, but which is ionized or dissolved at a higher pH, generally a pH of 5 to 7, but At least above 3.0, more or above 5, or even, more specifically, at a pH of about 5.5 to about 7, and therefore dissolves sufficiently in the small intestine and / or colon to release the agent Active in it. In some embodiments, the enteric layers release more than 50% of the ganaxolone that is coated in the small intestine. In other embodiments,

An "enteric layer" ganaxolone formulation means that part or most of the ganaxolone has been coated with an enteric layer to ensure that at least a portion of the drug is released after entering the small intestine, rather than into the small intestine. Acidic environment of the stomach. In some embodiments, from about 40 to about 60% of the coated ganaxolone particles are released in the mid-region of the small intestine to minimize interaction with bile acids and minimize the effects of food. In some embodiments, enteric layer formulations release more than 80% of ganaxolone into the small intestine.

The material of the enteric layer should not be toxic and should be predominantly soluble in the intestinal fluid but substantially insoluble in the gastric fluid. Examples include polyvinyl acetate phthalate (PVAP), commercially available under the trade names Opadry® Enteric from Colorcon®, hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), C * copolymer. *. Hydroxypropylmethylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, hydroxypropylmethylcellulose hexahydrophthalate, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose phthalate propionate, cellulose acetate maleate , Cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate,

Other examples include natural resins, such as shellac, SANDARAC, collophorium copal, and combinations comprising one or more of the aforementioned polymers. Still other further examples of enteric polymers include the synthetic resin with carboxyl groups. Methacrylic acid: Ethyl acrylic acid copolymers available commercially available under the trade names "Eudragit® L", such as Eudragit® L 30-D55 from Degussa.

"Erosion facilitators" include the erosions that control the erosion of a particular material in the gastrointestinal fluid. Erosion facilitators are well known to those skilled in the art. Some examples of erosion facilitators include hydrophilic polymers, electrolytes, proteins, peptides, and amino acids. In the present invention the combination of one or more erosion facilitators with one or more diffusion facilitators may also be used.

The "fillers" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrates, dextran, starch, pregelatinized starch , Sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like. "Flavoring agents" and / or "sweeteners" useful in the ganaxolone formulations described in the present patent application comprise both natural and artificial agents, for example acacia syrup, acesulfame K, alitame, anise, apple, aspartame Banana, Bavarian cream, berries, black currant, butterscotch butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon,

The term "milling medium" refers to the material used in milling to physically reduce the particle size of a compound. For grinding operations, the preferred motile means are spherical zirconium oxide beads stabilized with yttrium, glass or plastic resin.

"Gastrointestinal fluid" is the fluid in the gastrointestinal tract of a subject, its saliva or its equivalent. An "equivalent" of a "gastric or stomach secretion" is an in vitro fluid having a content and / or pH similar to that of stomach secretions, such as simulated gastric fluid (SGF), prepared using the USP guide of a solution In water of about 0.1N HCl containing about 0.03M NaCl at a pH of about 1.2. In addition, an "equivalent" of "intestinal secretion" is an in vitro fluid having a similar content and / or pH to intestinal secretions, such as simulated intestinal fluid (SIF) prepared using the USP guide in a buffer system Of aqueous phosphates at a pH of 6.7-6.9.

The "ionic dispersion modulator" is defined as an organic or inorganic molecule which, when added to a composition of small particles will change at least one of the following parameters: viscosity, the amount of certain ingredients necessary to stabilize the particles during Retreat of INO'JMKJ / .L. Solvent and / or the amount of certain ingredients necessary to stabilize the solid dosage forms or mixtures when resorbed in SGF and SIF as described in Example 28. The ionic dispersion modulator does not contain a sulphonic acid or a Sulphonic acid / inorganic salt group at the end of an alkyl carbon chain containing at least 1 saturated carbon atom bonded to the carbon atom bearing the sulphonic acid moiety.

The term "immediate release" means a dosage form which releases at least 80% of the drug within 2 hours after administration, more specifically, within 1 hour after being added to a commonly accepted mock gastric fluid . Generally, the immediate release compositions are tested in dissolution apparatus (type II, most common) in an amount considered therapeutic in patients and at a volume of SGF of 500 to 1000 ml.

"Lubricants" and "slippers" are compounds that prevent, reduce or inhibit the adhesion or friction of materials. Some examples of lubricants include stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, a hydrocarbon such as mineral oil, or a hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®), the acids And their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate , Sodium chloride, leucine, polyethylene glycol (for example, PEG-4000) or a methoxypolyethylene glycol such as Carbowax ™, sodium oleate, sodium benzoate, glyceryl behenate,

The "Empty Mill Chamber Volume" is the open volume in a milling chamber available to the milling mix after the milling means has been added. The empty mill chamber volume is related to the amount of milling media (% by volume) and the volume of open space when the spherical beads are stacked on top of each other (empty volume of the milling medium). In the case of the spherical grinding media of 0.2 mm to 0.4 mm, a range of about 36% to 42% of the volume occupied by the grinding beads is the empty volume of the grinding medium. The Empty Camera Volume

INLHOlKiAL grinding (mi) = Volume of the total grinding chamber (mi) - Volume of the grinding medium (mi) + Empty volume of the grinding medium (mi).

"Grinding residence time" is the time in which a particle is present in the grinding chamber during the total grinding time to obtain the desired particles. The milling residence time (MRT) is defined as: MRT (minutes) = Empty chamber volume (ml) x Total milling time (minutes) / Volume of the milling mix ).

The term "milling blend" refers to a suspension containing the drug for particle size reduction and other ingredients to facilitate the milling process. The composition of the milling blend is usually not the composition of the final formulation.

The term "milling medium" refers to the components of the milling mix minus the active pharmaceutical ingredient (s).

The term "grinding mix" refers to the grinding mixture after being reduced to a suspension of small particles by grinding. Preferred grinding mixtures for dispersion in a liquid are those whose particles have a size and composition which can be diluted in water and with the appropriate ingredients to obtain the final formulation. In the case of solid dosage forms, the preferred milled mixtures are those which can be used with minimal manipulation to obtain the final solid dosage form.

The term "Pharmacodynamics" refers to the factors that determine the biological response observed in relation to drug concentration at the site of action.

"Particle size" refers to the measured particle size distribution and is usually expressed as the "volume-weighted average" size unless otherwise specified. The particle size measurement for the ganaxolone formulations described in the present patent application uses a Horiba LA-910 or Horiba LA-950 laser light scattering instrument with approximately 120 ml of distilled water in the sample chamber, the Recirculation mode set to 4, stirring set to 1. If the particle size is measured after sonication, the sonication power is set to "low" (40 watts) and the sonication time is 1 minute. These settings correspond to low sonication and short

Duration, effectively break the very V aggregates that do not usually affect the yield of the formulation.

In the case of ganaxolone the relative refractive index value is set at 115-010 and the sample is added to give a tungsten (blue) light transmission value of about 75%. In measuring the liquid dispersion of ganaxolone, the particle size can be measured by adding the liquid composition through a plastic pipette directly into the sample chamber or by diluting to about 0.5 mg of ganaxolone / ml and adding it through a pipette From plastic to sample chamber. When measuring a solid composition of ganaxolone in which all the particles are soluble in water, the solid is dispersed in at least 15 ml of distilled water, stirred manually and then added through a plastic pipette into the sample chamber . The solid composition contains water-insoluble excipients, These can be removed by filtration through a 5 micron filter, or in case the suspension can not be filtered, and the particle size can be determined by subtracting the signal from insoluble components which are not ganaxolone. This is described in the methods section of the present patent application.

The term "Pharmacokinetics" refers to the factors that determine the extent and maintenance of the appropriate concentration of the drug at the site of action.

"Plasticizers" are compounds used to soften microencapsulation material, film layers or pharmaceutical blends for compression, to make them less brittle. Some of the suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. In some embodiments, plasticizers may also be used as dispersing agents or wetting agents.

"Condoms" are compounds that inhibit microbial growth and are often added to the dispersions to prevent the growth of microbes. Normally, the quantities of condoms required to pass antimicrobial efficacy tests as described by the USP and EU methodology are used to test appropriate levels of condoms. Some preservatives include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acids such as butyl rubber, 1- alcohols Such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.

A "pulsatile release" dosage form is a dosage form capable of providing more than one peak blood plasma concentration after a single administration. The "pulsatile release" formulation may contain a mixture of immediate, sustained release formulations and / or delayed release formulations in the same dosage form.

"Pharmacokinetic parameters" are parameters that describe the in vivo characteristics of the drug over time, such as its plasma concentration. Pharmacokinetic parameters include Cmax, Tmax, and AUCo-T (each discussed above).

"Solubilizers" include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hitaLoae Bile salts, polyethylene glycol 200 to 600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide, miglyol, isopropoxyphosphoric acid, Glycerol, glycerol, and other like compounds.

The term "spray drying" is a process by which a solvent is removed from a composition producing a dry form of the ingredients of the composition. The drying is effected by spraying the composition through a nozzle in a heated environment containing a vacuum or an inert air or gas stream. Spray drying can produce amorphous powder or granulations of the drugs, which in turn can be converted into a solid dosage form by those skilled in the art.

"Spray Layering" (or "Spray Layering") is a process by which a solution or suspension containing the ingredients is sprayed through a nozzle in a fluidized bed containing the particles, which are coated with a Film containing the composition of the solution or suspension as the solvent is removed with a stream of heated gas. The formation of layers by spraying usually involves a

Inert nucleus, generally composed of a sugar and starch, or celluloses or combinations thereof. Such cores usually have a mesh size of 20 to 35. The spray layering is widely used for the application of layers (finished or enteric) to solid dosage formulations, as well as spherical beads containing a drug for use In the formulation of a capsule or tablet.

The term "Stable" means that the D50 does not change significantly (more than 50%) after defining a first period (eg after milling or a curing period (1 to 3 weeks)) and up to 4 months storage at room temperature (15 to 25 ° C). For example, stable ganaxolone particles described in the present patent application in an aqueous dosage form do not exhibit an effective particle size increase greater than 50% over four months of storage, and preferably not Will have an increase in effective particle size greater than 50% over a two-year storage period. Likewise, the stable ganaxolone particles described in the present patent application in a solid oral dosage form, Do not exhibit an increase in effective particle size greater than 50% to four ΙΓO I ·. Ι ·. ' Fig. (C) after the dispersion (the dispersions are described in the Examples section, below). In some embodiments, the formulations described in the present patent application do not produce unidentified ganaxolone degrading impurities up to 4 months of storage at room temperature (15 to 25 ° C) at individual levels of greater than 0.1% at Weight, as compared to the levels of the impurities at the time of the initial designation. 25 C) after dispersion (the dispersions are described in the Examples section, below). In some embodiments, the formulations described in the present patent application do not produce unidentified ganaxolone degrading impurities up to 4 months of storage at room temperature (15 to 25 ° C) at individual levels of greater than 0.1% at Weight, as compared to the levels of the impurities at the time of the initial designation. 25 C) after dispersion (the dispersions are described in the Examples section, below). In some embodiments, the formulations described in the present patent application do not produce unidentified ganaxolone degrading impurities up to 4 months of storage at room temperature (15 to 25 ° C) at individual levels of greater than 0.1% at Weight, as compared to the levels of the impurities at the time of the initial designation.

"Stabilizers" include agents which maintain a desirable attribute of the formulation over a certain period of time, including, but not limited to, mechanical, chemical and temperature stress tests that can be performed in a laboratory. Such attributes comprise a stable particle size or homogeneity which results in concentrations consistent with indicated potency and maintaining purity. Some of the attributes are listed above, but they are not all existing.

The term "stable state" as used in the present patent application is when the amount of drug administered is equal to the amount of drug removed within a dosing interval, resulting in a plateau or an exposure Of the constant drug.

The term "subject", as used in the present patent application, is any mammal. Subjects include people in need of treatment for ganaxolone (patients) and people who do not need ganaxolone treatment (eg normal healthy volunteers). Humans are the preferred subjects and patients.

Acetate stearate, hydroxyethyl cellulose hydroxymethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, for example tragacanth and acacia gum, guar gum, xanthan, including xanthan gum, sugars, polyethoxylated sorbitan monolaurate, povidone, aluminum magnesium silicate , 4- (1,1,3,3-tetramethylbutyl) phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers, pluronic, and the like. Combinations of HPMC and PVA are especially useful. 3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers, pluronic, and the like. Combinations of HPMC and PVA are especially useful. 3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers, pluronic, and the like. Combinations of HPMC and PVA are especially useful.

The term "sustained release", according to its use in the present patent application, means a dosage form which allows at least a reduction of the dosing frequency per day, as compared to the drug in conventional form, as A solution or an immediate release solid dosage form.

The "surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, acacia gum, cholesterol, tragacanth, stearic acid, Benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, alkyl polyoxyethylene ethers (eg, macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, acid esters Polyoxyethylene sorbitan fatty acids (for example, Tweens®, commercially available as Tween 20® and Tween 80® (ICI Specialty Chemicals)); Polyethylene glycols (for example, Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, Sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), poly (4- 1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde (also known as tyloxapol, superione and triton), poloxamers (eg Pluronics F68® and F108® which are block copolymers of ethylene oxide and propylene's OXID); Poloxamines (for example, Tetronic 908®, also known as Poloxamine 9085®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)); Tetronic 1508® (T-1508, a poloxamine) (BASF Wyandotte Corporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); P-isononylphenoxypoly- (glycidol), also known as Olin-IOG® or Surfactant 10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc), and SA90HCO, which is C8H37CH2C (O) N (CH3) -CH2 (C HOH) 4 (CH20H) 2 (Eastman Kodak Co); Decanoyl-N-methylglucamide; N-decyl β-D-glucopyranoside; N-decyl β-D-maltopyraniside; N-dodecyl β-D-glucopyranoside; N-dodecyl β-D-maltoside; Heptanoyl-N-methylglucamide; N-heptyl-β-β-glucopyranoside; N-heptyl β-D-thioglucoside; N-hexyl β-D-glucopyranoside; Nonanoyl-N-methylglucamide; N-noyl β-D-glucopyranoside; Octanoyl-N-methylglucamide; Η-οοόί-β-β-glucopyranoside; Octyl-β-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, vinyl acetate vinyl pyrrolidone random copolymers. The foregoing surfactants are commercially available or can be prepared by techniques known in the art. Many are described in detail in the Handbook of Pharmaceuticals.

Pharmacologically Excipient), published jointly by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated herein by reference.

A "therapeutically effective amount" or "effective amount" is that amount of a pharmaceutical agent necessary to achieve a pharmacological effect. The term "therapeutically effective amount" comprises, for example, a prophylactically effective amount. An "effective amount" of ganaxolone is necessary to achieve the desired pharmacological effect or a therapeutic improvement without adverse side effects. The effective amount of ganaxolone will be selected by those skilled in the art depending on the patient and the disease. It is understood that the "effective amount" or "therapeutically effective amount" may vary from subject to subject, due to variation in the metabolism of ganaxolone, age, weight, general condition of the subject,

The term "Treat" or "Treatment" refers to any treatment of a disorder or disease, such as preventing the onset of the disease or disorder in a subject who may be predisposed to them, but who has not yet You have been diagnosed; The inhibition of the disease or disorder, for example by stopping its development, relieving it, causing its regression, alleviating a disease caused by the disease or disorder, or reducing its symptoms.

"Viscosity-improving agents" are agents which are normally added to a dispersion of particles to increase their viscosity and prevent or delay the settling of the particles. Viscosity-improving agents in solid dosage forms are sometimes used to form a gel matrix as the water permeates the solid dosage form and may delay the release of the pharmaceutically active ingredients. Viscosity enhancers include, but are not limited to, methyl cellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

Ufe LA rrtt.JrJ tu'AiJ W

The "wetting agents" include surfactants and are used to improve the dispersibility of a drug in a composition or after administration of the composition in the subject. Wetting agents may also act As stabilizers Some examples of wetting agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, oleate Sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and the like. I. Formulations and Compositions of Ghanaxolone

Ganaxolone is sparingly soluble in water and other pharmaceutically acceptable solvents. As a result of their low aqueous solubility, there is a need in the state of the art for ganaxolone formulations which provide greater bioavailability and therapeutic efficacy of ganaxolone. However, it is known that the increased bioavailability of an active agent also causes the possibility of an increase in side effects.

Certain compositions and formulations of ganaxolone described in the present patent application exhibit improved pharmacokinetic (PK) and pharmacodynamic (PD) profiles and / or minimization of side effects as compared to the conventional formulations of ganaxolone known in the prior art. Specifically, some of the ganaxolone formulations described in the present patent application provide a greater therapeutic benefit as a consequence of having higher PK / PD properties, including increased exposure of fasting or fed ganaxolone, improved maintenance of ganaxolone in the (Cmax) of ganaxolone compared to the levels immediately preceding the next steady-state dose (Cmin).

Certain formulations described in the present patent application reduce the risk of side effects caused by ganaxolone, including ataxia, sedation and drowsiness compared to conventional formulations of ganaxolone. In some embodiments, improved performance compared to conventional formulations of ganaxolone, can be seen in acute doses. In other embodiments, the maximum benefit of the ganaxolone formulations described in the present application may be seen in the stable state.

The ganaxolone formulations described in the present patent application may be administered to subjects by means of the traditional routes of administration. Solid oral dosage forms and aqueous oral suspensions of ganaxolone are included in the present application. Also included in the present patent application are controlled and pulsatile modified release dosage forms.

It is to be understood that any of the dosage forms described in the present patent application comprise a formulation of ganaxolone, either alone or when it is. Administered in combination with another drug, can provide at least one or more of the above-described improved pharmacokinetic properties and minimize the side effects resulting from the reduction of blood plasma levels of ganaxolone Tmax and Cmax. II. Particles of Ghanaxolone

The ganaxolone formulations described in the present patent application comprise stable particles of ganaxolone existing in crystalline, amorphous, semi-crystalline, semi-amorphous form and mixtures thereof. In some embodiments, the ganaxolone formulations comprise amorphous ganaxolone whose particles have an average effective particle size of up to about 10 microns. In other embodiments, the ganaxolone formulations comprise amorphous ganaxolone, which may be as a coating or encapsulated with an excipient matrix, the matrix has an effective particle size of up to about 300 microns In other embodiments, The ganaxolone formulations comprise a non-amorphous form of ganaxolone comprising ganaxolone particles having a weight average effective particle size of less than about 500 nm. In other embodiments, the ganaxolone particles have a weight average effective particle size of less than about 400 nm, a weight average effective particle size of less than about 300 nm, an effective average particle size by weight of less than About 200 nm, or a weight average effective particle size of less than about 100 nm, as measured by the aforementioned techniques. In yet another embodiment,

In other embodiments, the ganaxolone particles by weight have a particle size of 500 nm, ie, less than about 500 nm, less than about 400 nm, less than about 3% Of about 200 nm, or less than about 100 nm, with less than at least about 20%, at least about 15% or at least about 10% of the total particles having a size greater than 1 micron.

In one embodiment, the ganaxolone particles have a particle size of about 300 nm with a distribution in which 90% of the particles by weight have an effective particle size by weight of between about 100 nm and 800 nm. In another embodiment, the ganaxolone particles have a particle size of about 100 nm and a distribution in which 90% of the particles by weight have an effective particle size by weight of between about 50 nm and 250 nm.

In other embodiments, the ganaxolone compositions disclosed in the present patent application comprise stable particles of ganaxolone having a particle size by weight of less than 500 nm formulated with ganaxolone particles having a particle size by weight greater than 500 nm . In such embodiments, the formulations have a particle size distribution in which from about 10% to about 100% of the ganaxolone particles by weight are from about 100 nm to about 300 nm, from about 0% to about 90% of The ganaxolone particles by weight are between about 300 nm and 600 nm, and from about 0% to about 30% of the ganaxolone particles by weight are greater than about 600 nm. In one embodiment, The formulation has a particle size distribution in which about 20% of the ganaxolone particles by weight are between about 100 nm and about 300 nm, about 40% of the ganaxolone particles by weight are between about 300 nm and about 600 Nm, and about 30% of the ganaxolone particles by weight are greater than about 600 nm. In yet another embodiment, the formulation has a particle size distribution in which about 30% of the ganaxolone particles by weight are between about 100 nm and about 300 nm, about 40% of the ganaxolone particles by weight are between About 300 nm and about 600 nm, and about 30% of the ganaxolone particles by weight are greater than about 600 nm. In yet another embodiment, the formulation has a particle size distribution in which about 50% of the ganoxolone particles by weight are between about 100 nm and about 300 nm, about 40% of the Ganaxolone particles by weight are between about 300 nm and about 800 nm, and about 10% of the ganaxolone particles by weight are greater than about 800 nm. III. Benefits of Small Particle Size in Slightly Soluble Drugs About 40% of the ganaxolone particles by weight are between about 300 nm and about 800 nm, and about 10% of the ganaxolone particles by weight are greater than about 800 nm. III. Benefits of Small Particle Size in Slightly Soluble Drugs About 40% of the ganaxolone particles by weight are between about 300 nm and about 800 nm, and about 10% of the ganaxolone particles by weight are greater than about 800 nm. III. Benefits of Small Particle Size in Slightly Soluble Drugs

The particle size of ganaxolone particles is an important factor that can affect bioavailability, mixing uniformity, segregation and flow properties. In general, the smaller size in the particles of a drug increases the rate of drug absorption of the permeable drugs with poor solubility in water, increasing the surface and rate of kinetic dissolution. The size of the ganaxolone particles may also affect the suspending or mixing properties of the pharmaceutical formulation. For example, smaller particles are less likely to settle and therefore form a better suspension.

In various embodiments, the ganaxolone formulations, in aqueous dispersions or as "dry" powders (which may be administered directly, as a powder for suspension, or be used in a solid dosage form ) May include a non-amorphous form of ganaxolone compatible with excipients having an effective particle size by weight of less than about 500 nm or less than about 400 nm or less than about 300 nm or less than about 200 nm Nm, or less at about 100 nm. In other embodiments, the ganaxolone formulations comprise an amorphous form of ganaxolone with compatible excipients having a weight average effective particle size of up to about 10 microns.

Effects of the Low Solubility of Particle Size Range

The amount of a water insoluble permeable drug (<1 mg / ml in water at pH 7) that can be absorbed is related to particle size. In various embodiments, stable particles of ganaxolone with a D 50 of less than about 100 nm at 500 nm can be obtained. As the particles are further reduced, the rate of kinetic dissolution increases as a function of the surface of the drug. In general, the reduction of the particle size of the drugs by half, doubles the surface area of the particles. When the poorly soluble drugs (<1 mg / ml solubility in water at pH 7 to 7.4) are thoroughly ground (at a prolonged milling residence time), small particles of about 100 nm can be obtained. These particles tend to have an average value of about 25 to 30% of the average, A standard deviation of less than about 50% of the D50 value and a D90 of about 1.5 to 1.75 times the value of D50. Very small particles (from 50 nm to 200 nm) with a narrow distribution around the D50 value as described above may result in elevated peak plasma levels, but occasionally lower total exposures (AUCo-τ) can be achieved That the extended release is lost due to the dissolution of the particles.

In some cases it is desirable not to have a high Cmax generally associated with small particle formulations. In the case of the compounds having a high in vivo removal, it is also desirable to extend the absorption phase to minimize the frequency with which the subject needs to be dosed. It is an aspect of the present invention that the ganaxolone complexes formed after the addition of a complexing agent and any resulting clustering can achieve this objective in that the surface area of the aggregates is generally much larger than a single particle of That size. In addition, in the case of dispersion of dosage forms in gastrointestinal fluids (simulated or in vivo administration), Loose aggregates that can be substantially dissociated during gastrointestinal transit can provide a broad phase of drug absorption, which is desirable. With each compound one has to determine the effect of these loose and tight aggregates, but it is normal that loose aggregates that can be quickly reversed with a small amount of energy (40 watts sonication in water for 1 minute or less) will not affect performance Of the drug exposure and may extend the duration of drug release and minimize Cmax plasma levels in the subject. In the case of a composition containing stable particles of ganaxolone, it is desirable to have a D50, with or without sonication between 100 nm and 500 nm, and not more than about 15% of the ganaxolone particles greater than 1 micron in size. It is sometimes desirable to obtain a wider distribution of the stable particles than that obtained only with milling to optimize both the maximum and total exposure levels obtained after a dose of the drug. In various embodiments, the ganaxolone formulations (both liquid and solid) have been added a complexing agent, which not only serves to stabilize particle growth, but also provides a broader range of particles to increase exposure to the particles. Ganaxolone in a given dose. This extended particle size range is especially desirable in compounds having the feature of being extensively metabolized by the liver after oral administration. In one embodiment, a ganaxolone dispersion has a particle size of about 300 nm, An average of about 800 nm, a D90 of about 600 nm, a standard deviation of about 1.8 microns, and about 7% to 8% of particles greater than 1 micron. IV. Dosage Forms

The ganaxolone compositions described in the present invention may be formulated to be administered to a subject through any conventional means,

(Including, but not limited to, the parenteral (e.g., subcutaneous or intramuscular) pathways, including, but not limited to, ), Buccal, intranasal or by transdermal administration.

Multiparticulate formulations and mixed formulations of immediate release and controlled release. In some embodiments, the ganaxolone formulations provide a therapeutically effective amount of ganaxolone over a range of about 30 minutes to about 8 hours after administration, allowing, for example, once-daily administration, two Times a day (bid), or three times a day (tid), if desired. In one embodiment, the ganaxolone particles are formulated into a controlled release or pulsatile solid dosage form to be administered twice daily. In other embodiments, the ganaxolone particles are dispersed in an aqueous dispersion to be administered twice daily. In general terms,

Dosage Forms Characterized by Disintegration Profiles

The various formulations of the above-mentioned release doses can be characterized by their disintegration profile. A profile is characterized by the selected test conditions. Therefore the decay profile can be generated in a type of

The apparatus, at a speed of the axis, temperature, at a pH of the dispersion medium, is set to 1 ° C. For example, a first disintegration profile can be measured at a pH level close to that of the stomach (at about pH 1.2); a second disintegration profile can be obtained Measured at a pH close to that of a point in the gut or at various pH levels near multiple gut points (from about 6.0 to about 7.5, more specifically, from about 6.5 to 7.0.) Another disintegration profile can be measured using distilled water.

The release of the formulations may also be characterized by their pharmacokinetic parameters, for example O, Omax, Tmax and AUC (ox).

In one embodiment the present invention provides a solid oral dosage form providing a controlled or pulsating release with which from 30% to 60% of the ganaxolone particles by weight are released from the dosage form within about 2 hours After administration and about 90% of the ganaxolone particles by weight are released from the dosage form within about 7 hours after administration.

In another embodiment, a broad distribution of the ganaxolone particles by weight is dispersed in an aqueous dispersion comprising ganaxolone particles of different effective particle sizes, such that the smaller particles provide a rapid absorption of ganaxolone and The larger particles provide a delayed absorption of ganaxolone. In another embodiment, the solid dosage form is an immediate release form, with> 80% of the ganaxolone particles being released from the dosage form within about 2 hours after administration.

Solid Oral Dosage Forms

In some embodiments, the solid dosage forms of the present invention may be in the form of a tablet, (including slurry tablets, quick melt tablets, chewable tablets, quick disintegrating tablets, effervescent tablets, or an elongate tablet), A tablet, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including soft and hard capsules, for example, capsules made of animal jelly or those of HPMC of vegetable origin , Or "sprinkling capsules"), solid dispersion, soluble solution

Institute μγ: '! Π ··.: ·: Ο \ W-

Biodegradable dosage form, controlled-release formulations, pulsed-release dosage forms, multiparticulate dosage forms, pills (or pearls), and / ), Granules or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. And in other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a quick melt tablet. In addition, the pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage forms. In other embodiments, the pharmaceutical formulation is administered in two, three or four capsules or tablets.

In some embodiments, solid dosage forms, for example, tablets, effervescent tablets and capsules, are prepared by mixing ganaxolone particles with one or more pharmaceutical excipients to form a bulk blended composition. By referring to these bulk blended compositions as homogeneous, this means that the ganaxolone particles are uniformly dispersed throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablet, DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION: Individual unit doses may also include coating films, which disintegrate after oral ingestion or after contact with diluents.

Preparation of Solid Dosage Forms

Conventional pharmaceutical techniques for the preparation of solid dosage forms include, for example, a method, or a combination of methods: (1) dry blending, (2) direct compression (3), grinding, (4) dry granulation Or non-aqueous, (5) wet granulation, or (6) melt. See for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, (1986). Other methods include, for example, spray drying, tray coating, melt granulation, granulation, drying or spray coating in a fluidized bed (eg Wurster coating), tangential coating, top spray, tabletting, extrusion, and others Methods.

Components of the Formulation Sti-Jtomsycan:

INDUSTRIAL

The solid dosage dosage forms disclosed in the present application may include the described ganaxolone compositions and one or more pharmaceutically acceptable additives as compatible carriers, binders, complexing agents, ionic dispersion modulators, fillers, suspending agents, flavoring agents , Sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, defoamers, antioxidants, preservatives or the blending of one or more combinations thereof . In still other aspects, using standard coating procedures as described in Remington's Pharmaceutical Sciences, 20th Edition (2000),

In one embodiment, some or all of the ganaxolone particles are coated. In one embodiment, some or all of the ganaxolone particles are microencapsulated. In a further embodiment, part or all of the ganaxolone is coated with an amorphous and / or microencapsulated material with β g Xg ^ j | J, and. · V '··' V; Inert excipients. In another embodiment, The ganoxolone particles are not microencapsulated nor are they to be used in the preparation of the compounds.

Which are coated with a polyamide.

Carriers suitable for use in the solid dosage forms described in the present application include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate , Sodium caseinate, soya lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose nacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and Other similar compounds.

Suitable fillers for use in the solid dosage forms described in the present application include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose (e.g. Avicel® PH102, Avicel® PH105, among others), powdered cellulose, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCAS) , Sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

Since ganaxolone is insoluble in water and is relatively permeable, it exhibits a strong correlation between its rate of dissolution and bioavailability. It is therefore important to optimize the rate of dissolution in biological matrices in order to improve the in vivo absorption of the drug. In order to liberate the ganaxolone from the matrix of a solid dosage form as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with a binder. The disintegrators help to break the matrix of the dosage form by swelling or by the action of capillarity, when the dosage form absorbs moisture. In some embodiments of the invention, The solid dosage formulation of ganaxolone has a proportion greater than about 1% by weight of a disintegrant. In some embodiments of the invention, the solid dosage formulations of ganaxolone have from about 1% to about 11% by weight, or from about 2% to about 8% by weight

Of the disintegrant. In other ways, Mexican, Mexican

Formulations of ganaxolone have more than about 2% by weight of the disintegrant. In some embodiments, the disintegrant combination provides improved dispersion characteristics as compared to a single disintegrant in a similar total weight percent.

Some disintegrators suitable for use in the solid dosage forms described in the present application include, but are not limited to, starch, eg, natural starch such as corn or potato starch, pregelatinized starch such as National 1551 or Amijel ®, or sodium starch glycolate such as Promogel ® or Explotab ®, a cellulose such as a wood product, microcrystalline cellulose, e.g. Avicel ®, Avicel ® PH101, Avicel ® PH102, Avicel ® PI1105, Elcema ® P100, Emcocel ® , Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, a crosslinked starch such Such as sodium starch glycolate, a crosslinked polymer such as crospovidone,A crosslinked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, such a clay as E.coli (magnesium aluminum silicate), a gum such as agar Guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, sodium lauryl sulfate, Sodium in combination of starch, and other similar compounds.A natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination of starch, and the like.A natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination of starch, and the like.

In one embodiment, the Ac-Di-Sol is the disintegrant. The amount of Ac-Di-Sol used in direct tabletting compression may vary depending on the typical usage levels between 1 and 3 percent. If added to granulations, the same percentage is generally used as in direct compression formulations. It is often added to both wet and dry granulations and mixtures. The amount of Ac-Di-Sol used in the capsule formulations generally ranges from 3 to 6 percent. Reducing the contact between particles within a capsule facilitates the need to have high levels of disintegrants. The capsules that are filled in automatic dosing equipment, as opposed to those filled in semi-automatic or manual machines, are denser and have a harder structure, Because larger compression forces are required to form the stopper and satisfactorily transferred to the cap, gelatin, or HPMC. A higher hardness results in a higher efficacy of Pb Culi. Binders provide cohesion in the formulations of solid oral dosage forms: in the case of capsule formulations filled with Powder, assist in the formation of a cap that can be filled into the soft or hard capsules and into tablet formulations, the binders ensure that the tablet remains intact after compression and help to ensure the uniformity of the mixture prior to step Some materials suitable for use as binders in the solid dosage forms described in the present application include,

THE INDUSTRIAL PROSECUTION - pregelatinized; Tragacanth, dextrin, a sugar such as sucrose (e.g. Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (for example, Xylitab®) and lactose, a natural or synthetic gum such as acacia, tragacanth , Gum ghatti, mucilage of isapol pods, polyvinylpyrrolidone (eg Povidone® CL, Kollidon® CL, Polyplasdone® XL-12 and Povidone® K-12), arabogalactan from larches, Veegum®, polyethylene glycol, waxes, alginate Sodium, and other similar compounds.

In general, 20% to 70% levels are used in binders for formulations of powder filled gelatin capsules. The level of use of binders in tablet formulations is a function of whether direct compression, wet granulation, roller compaction, or other excipients such as fillers are used, which in turn may act as moderate binders . Those skilled in the art can determine the level of the binders in the formulations, but it is normal to use up to 70% level in the tablet formulations.

Some lubricants or slippers suitable for use in the solid dosage forms described in the present application include, but are not limited to, stearic acid, calcium hydroxide, talc, sodium starch, sodium stearyl fumarate, salts Alkali metal and alkaline earth metals, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearates, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine , A polyethylene glycol or methoxypolyethylene glycol such as Carbowax ™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium, and the like.

Some diluents suitable for use in the solid dosage forms described in the present application include but are not limited to sugars (including lactose, sucrose, dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, Xylitol, and sorbitol), cyclodextrins, and the like.

Non-water soluble diluents are compounds commonly used in the formulation of pharmaceutical products, such as calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose and microcellulose (eg, (For example, Avicel, powdered cellulose), and talc.

Some examples of wetting agents suitable for use in the solid dosage forms described in the present application include, but are not limited to, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, sorbitan monooleate of Polyoxyethylene, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like. Wetting agents include surfactants.

Some surfactants suitable for use in the solid dosage forms described in the present application include, for example, docusate and its pharmaceutically acceptable salts, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, salts Bile, glyceryl monostearate, ethylene oxide and propylene oxide copolymers, eg Pluronic® (BASF), and the like.

Some suitable industrial suspending agents - the solid dosage forms described in the present application include, but are not limited to, polyvinylpyrrolidone , eg polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, for example, Polyethylene glycol may have a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 18000, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium alginate, gums, for example tragacanth and gum Acacia, guar gum, xanthan, including xanthan gum, sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose,Hydroxyethylcellulose, polysorbate-80, polyethoxylated sorbitan monolaurate, povidone, and the like.

Some antioxidants suitable for use in the solid dosage forms described in the present application include, for example, butylated hydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium ascorbate, vitamin E TPGS, ascorbic acid, sorbic acid and tocopherol.

It should be noted that there is an overlapping efer ^ chVó. INSTITUTE OF TRAFFIC. INDUST.-JA1. - between the additives used in the solid dosage forms described in the present application. Therefore, the abovementioned additives should be taken merely as examples, and not to be interpreted restrictively, of the types of additives which may be included in the solid dosage forms of the present invention. The amount of these additives can be readily determined by one skilled in the art, according to the particular properties desired.

In other embodiments, one or more layers of the pharmaceutical formulation are plastified. Illustratively, a plasticizer, in general, is a solid or liquid with a high boiling point. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate and castor oil.

Tablets

The compressed tablets are solid forms prepared by compacting the bulk blend of the above-described ganaxolone formulations. In various embodiments, compressed tablets which have been designed to dissolve in the mouth will comprise one or more flavoring agents. In other embodiments, the compressed tablets will have a film surrounding the final compressed tablet. In some embodiments, the coating film may provide delayed release of the ganaxolone formulation. In other embodiments, the coating film aids patient compliance (for example, Opadry® or sugar coatings). Coating films comprising Opadry® typically range from about 1% to about 3% by weight of the tablet. Coating films for delayed release generally comprise from 2% to 6% by weight of a tablet, or from 7% to 15% by weight of a bead with spray layers. In other embodiments, the compressed tablets comprise one or more excipients.

Formulations of Caplen

A capsule may be prepared by, for example, placing the bulk mixture of the above-described ganaxolone formulation into a capsule. In the embodiments, the ganaxolone formulations (nonaqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the ganaxolone formulations are placed in standard gelatin capsules or non-gelatin capsules, such as capsules comprising HPMC. In other embodiments, the ganaxolone formulations are placed in sprinkling capsules, in which the capsule can be ingested whole, or it can be opened and its contents can be sprayed onto the food before being eaten. In some embodiments of the present invention, the therapeutic dose is divided into multiple capsules (eg, two, three or four). In some embodiments, the entire dose of the ganaxolone formulation is provided in a capsule form. For example, the capsule may comprise from about 100 mg to about 600 mg of ganaxolone. In some embodiments, the capsule may comprise from about 100 mg to about 500 mg of ganaxolone. In other embodiments, the capsule may comprise from about 300 mg to about 400 mg of ganaxolone. 1 i VJL i i The capsule may comprise from about 300 mg to about 400 mg of ganaxolone. 1 i VJL i i The capsule may comprise from about 300 mg to about 400 mg of ganaxolone. 1 i VJL i i

Another useful capsule has an indexing membrane material which limits the rate, including any of the already exposed coating materials, and is filled with ganaxolone particles. A particular advantage of this embodiment is that the capsule can be prepared independently of the ganaxolone particles, therefore, process conditions which could adversely affect the drugs in preparing the capsule can be avoided. A preferred embodiment is a capsule having a shell made of a porous pH-sensitive polymer made by a thermal forming process. A particularly preferred embodiment is a capsule shell in the form of an asymmetric membrane, i.e. a membrane having a thin skin on a surface, The majority of its thickness being composed of a highly porous and permeable material. A preferred process for the preparation of asymmetric membrane capsules comprises a solvent exchange phase inversion in which a polymer solution coated in a capsule shaped mold is induced to the phase separation by exchanging the solvent By a non-miscible solvent. Some examples of asymmetric membranes are disclosed in the specification of the PaLefcrce ^ Εμχο Is induced to the phase separation by the exchange of the solvent by a non-miscible solvent. Some examples of asymmetric membranes are disclosed in the specification of the PaLefcrce ^ Εμχο Is induced to the phase separation by the exchange of the solvent by a non-miscible solvent. Some examples of asymmetric membranes are disclosed in the specification of the PaLefcrce ^ Εμχο

INSTITUTE OF PHILOSOPHY OF PHILOSOPHY OF PHILOSOPHY. SA * -357 369 Bl.

There is another useful capsule, a "device with inflatable plug", can be used. Ganaxolone particles may be incorporated into a capsule half that does not dissolve from the device, which is sealed at one end with a hydrogel plug. This hydrogel plug swells in an aqueous medium and after swelling for a predetermined time exits the capsule, thereby opening a port through which the ganaxolone can exit the capsule and be released into the aqueous environment. Preferred hydrogel cap capsules are those which lack substantial release of ganaxolone from the dosage form until they have exited the stomach and have had a residence time in the small intestine of about 15 minutes or more, preferably about 30 minutes or more, Thus ensuring that a minimum of ganaxolone is released into the stomach. Hydrogel plug capsules of this type were described in patent application WO 90/19168, which is incorporated herein by reference. A ganaxolone inflatable cap device may be prepared by loading ganaxolone into the half of a non-soluble capsule shell which may be formed with a wide variety of materials including but not limited to

Polyethylene, polypropylene, poly (methyl methacrylate), polyvinyl chloride, polystyrene, polyesters, polytetrafluoroethylene, nylons, polyfunctionaldehyde, polyethylene terephthalate, polyethylene terephthalate, Polyesters, cellulose acetate and nitrocellulose The open end of the capsule shell is then "capped" with a cylindrical cap formed of a hydrogel material including, but not limited to, a crosslinked homo or co-poly (alkylene oxide) By reaction with isocyanate or unsaturated cyclic ether groups as described in PCT application WO 90/09168 The composition and length of the hydrogel "plug" are selected to minimize the release of ganaxolone in the stomach to decrease the Incidence and / or severity of gastrointestinal side effects.

The half of the capsule having the cap is finally sealed with another half of the water-soluble capsule, for example gelatin, which is placed over the end having the hydrogel plug of the non-soluble half-shell containing ganaxolone . In an embodiment of the "inflatable plug device", the sealed device is coated with a pH-sensitive enteric polymer or a mixture of polymers, for example, cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate The weight of the enteric layer Of polymer will generally be from 2% to about 5% by weight, preferably from 4 to 15% by weight, of the weight of the uncoated sealed capsule. When this "inflatable cap device covered with enteric layer" is ingested orally, The enteric layer prevents the release of ganaxolone in the stomach. The enteric layer dissolves rapidly, for example within 15 minutes, into the duodenum, causing swelling of the hydrogel plug, releasing it and releasing the ganaxolone incorporated into the gastrointestinal tract, in a time greater than about 15 minutes later, And preferably greater than about 30 minutes thereafter, that the dosage form has been passed from the stomach to the duodenum. Unfilled prototypes of the "inflatable plug devices" can be obtained from Scherer DDS Limited, Clydebank, Scotland under the name Pulsincap ™. Releasing and releasing the ganaxolone incorporated into the gastrointestinal tract, at a time greater than about 15 minutes later, and preferably greater than about 30 minutes thereafter, that the dosage form has been passed from the stomach to the duodenum. Unfilled prototypes of the "inflatable plug devices" can be obtained from Scherer DDS Limited, Clydebank, Scotland under the name Pulsincap ™. Releasing and releasing the ganaxolone incorporated into the gastrointestinal tract, at a time greater than about 15 minutes later, and preferably greater than about 30 minutes thereafter, that the dosage form has been passed from the stomach to the duodenum. Unfilled prototypes of the "inflatable plug devices" can be obtained from Scherer DDS Limited, Clydebank, Scotland under the name Pulsincap ™.

In one embodiment, a ganaxolone formulation comprising dried ganaxolone particles may be filled into a capsule. An example of the process for making the ganaxolone particles is grinding / evaporation process. A suspension of ganaxolone particles comprising from 10% to 30% of the total weight of ganaxolone, from 1% to 10% of the total weight of ganaxolone. Hydroxypropylmethylcellulose (Pharmacoat 603), 0.5% of the total weight of sodium lauryl sulfate. . 0.001% to 0.05% of the total emulsion weight of simethicone (30% in water), 0.5% to 5% sucrose and 0.1% to 2% NaCl in water is sprayed in a spray granulator using parameters Standard well known to those skilled in the art. Each% by weight is based on the total weight of the suspension. The water is evaporated under vacuum at a temperature of 70 ° C to 90 ° C. The resulting ganaxolone particles comprise from about 50% to 80% by weight of ganaxolone, based on the total weight of the solid particles. Additional excipients such as magnesium stearate, mannitol and a disintegrant may be added to have flow and redispersion properties. The particles generally have a mean (D50) particle size, from about 50 nm to about 1000 nm, more specifically, from about 100 nm to about 500 nm. In one embodiment the capsule is a device with an inflatable cap. In another embodiment, the inflatable cap device is further coated with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate. In another embodiment,

In another embodiment, the complex formulation of ganaxolone comprising a complex granulation of dry ganaxolone can be filled. The complex suspension of ganaxolone particles comprising from about 10% to 30% by weight of ganaxolone, from 1% to 10% by weight of hydroxypropylmethylcellulose (Pharmacoat 603), from 0.05% to 0.5% by weight of sodium lauryl sulfate , From 0.015% to 0.2% by weight of parabens, such as methyl paraben, from 0.001% to 0.05% by weight of simethicone emulsion (30% in water), from 0.5% to 5% sucrose and from 0.1% to 2% % NaCl in water is pumped to a spray granulator using standard parameters well known to those skilled in the art. Each% by weight of the complex suspension of ganaxolone particles is based on the total weight of the suspension. The water is evaporated under vacuum at a temperature of 70 ° C to 90 ° C. The resulting granulation of ganaxolone comprises from about 50% to 80% by weight of ganaxolone, based on the total weight of the solid. Additional excipients such as magnesium stearate, mannitol and a disintegrant may be added to have flow and redispersion properties. The dispersed solids (in SGF or SIF) generally have an average particle size (D50), from about 50 nm to about 1000 nm, more specifically, about 100 nm to about modality, The capsule is a device with a swollen cap In another embodiment, the swollen cap device is further recovered with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate. The resulting granulation of ganaxolone comprises from about 50% to 80% by weight of ganaxolone, based on the total weight of the solid. Additional excipients such as magnesium stearate, mannitol and a disintegrant may be added to have flow and redispersion properties. The dispersed solids (in SGF or SIF) generally have an average particle size (D50), of from about 50 nm to about 1000 nm, more specifically, about 100 nm to about modality, The capsule is a device with a swollen cap In another embodiment, the swollen cap device is further recovered with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate. The resulting granulation of ganaxolone comprises from about 50% to 80% by weight of ganaxolone, based on the total weight of the solid. Additional excipients such as magnesium stearate, mannitol and a disintegrant may be added to have flow and redispersion properties. The dispersed solids (in SGF or SIF) generally have an average particle size (D50), of about 50 nm to about 1000 nm, more specifically, about 100 nm to about modality, The capsule is a device with a swollen cap In another embodiment, the swollen cap device is further recovered with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate. Based on the total weight of the solid. Additional excipients such as magnesium stearate, mannitol and a disintegrant may be added to have flow and redispersion properties. The dispersed solids (in SGF or SIF) generally have an average particle size (D50), from about 50 nm to about 1000 nm, more specifically, about 100 nm to about modality, The capsule is a device with a swollen cap In another embodiment, the swollen cap device is further recovered with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate. Based on the total weight of the solid. Additional excipients such as magnesium stearate, mannitol and a disintegrant may be added to have flow and redispersion properties. The dispersed solids (in SGF or SIF) generally have an average particle size (D50), of from about 50 nm to about 1000 nm, more specifically, about 100 nm to about modality, The capsule is a device with a swollen cap In another embodiment, the swollen cap device is further recovered with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate.

In yet another embodiment, the ganaxolone particles coated with spray layers or complexed ganaxolone particles coated with spray layers can be filled into a capsule. An example of the process of making the coated ganaxolone particles with spray layers or complexed ganaxolone particles coated with spray layers is the fluidized bed spray process. The ganaxolone suspensions or suspensions of ganaxolone complexes described above were sprayed onto beads (mesh size 20 to 35) of sugar or microcrystalline cellulose (MCC) with the addition of Wurster column at an inlet temperature of 50 ° C at 60 ° C and at an air temperature of 30 ° C to 50 ° C. Comprise from about 30% to about 70% by weight of ganaxolone, based on the total weight of the particles. In one embodiment, the capsule is a gelatin capsule of size 0. In one embodiment the capsule is a device with an inflatable cap. In another embodiment, the inflatable cap device is further coated with cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate.

In some embodiments the capsule comprises at least 250 mg (or at least 300 mg, or at least 400 mg) of ganaxolone and has a total weight less than 800 mg (or less than 700 mg).

The capsule may contain a plurality of beads containing ganaxolone, eg beads with spray-formed layers. In some embodiments, the beads are composed of 12% to 25% ganaxolone, by weight. In some embodiments, some or all ganaxolone-containing beads are coated with an M1 ----- coating comprising 6% to 15% (or 8% to 12%) of the total weight of the beads.

Optimization works usually involve lower loading levels and pearls constitute 30% to 60% of the weight of finished beads. Instead of or in addition to beads containing ganaxolone, the capsule may contain a granulated ganaxolone composition, comprising ganaxolone, or ganaxolone and an ionic dispersion modulator. In some embodiments, the compositions further involve a complexing agent and an organic or inorganic salt. For example, the granulated composition in some embodiments comprises from 0.3% to 20% (or from 1% to 10%, or from 1% to 5%) by weight of an organic or inorganic salt. These granulations also typically contain from 5% to 30% of a binder, from 2% to 25% of a water-soluble spacer and a wetting agent (from 0.5% to 2%),

The capsule may be a pulsed-release oral ganaxolone dosage form, comprising: (a) a first dosage unit comprising a first dose of ganaxolone which is substantially immediately released following oral administration of the dosage form to the patient; (B) a second dosage unit comprising a second dose of ganaxolone

A. Approximately 3 to 7 hours after administration of the dosage form to the patient.

In the case of pulsatile release capsules containing beads, they may be coated with a coating comprising 6% to 15% (or 8% to 12%) of the total weight of the beads. In some embodiments, the layer is insoluble at a pH of 1 to 2, and is soluble at a pH greater than 5.5.

In certain embodiments, the pulsatile release capsule comprises from 30% to 50% by weight of the first dose of ganaxolone and from 50% to 70% of the second dose of ganaxolone. This pulsatile release capsule may contain a plurality of beads, some of which are immediate release and others are formulated, for example, by the use of a coating, for the modified release, generally 3 to 10 hours after administration. In other embodiments, the pulsatile release capsule contains a plurality of beads formulated for the modified release, and ganaxolone powder, for example, spray-granulated ganaxolone, for immediate release.

Formulations Containing Particles N DeLVV · INi, i. -

Coated

In some embodiments, the ganaxolone particles coated with spray layers or complexed ganaxolone particles coated with spray layers which are present in the formulations of ganaxolone, such as the capsule formulation described above, are coated. The ganaxolone particles may have a modified release coating, such as a coating of cellulose acetate phthalate or copolymers of methacrylic acid and methyl methacrylate. In one embodiment, the enteric layer may be present in an amount of about 0.5% to about 15% by weight, more specifically, from about 8% to about 12% by weight, based on the weight of particles formed with spray layers. In one embodiment, The ganaxolone particles formed with spray layers or the complexed ganaxolone particles formed with layers which are coated with enteric layer can be filled into a modified release capsule in which both the enteric coated beads and the ganaxolone beads Of immediate release, are filled in a soft gelatin capsule. Other suitable excipients may also be filled with water,

INDUSTRIAL capsule with coated particles.

In another embodiment, mixtures of ganaxolone particles formed with spray layers or complex ganaxolone particles formed with spray layers which are coated with enteric layer and without enteric layer in suitable proportions, can be encapsulated into a suitable immediate release capsule. The uncoated particles release ganaxolone immediately after administration, while the coated particles do not release ganaxolone until they reach the gut. By controlling the proportions of coated and uncoated particles, desired pulsatile release profiles can be obtained. In some embodiments, the ratio of uncoated and coated particles is 20/80, or 30/70, or 40/60, or 50/50, w / w to obtain the desired release

Tablet Dosage Forms with Spray Layers

In some embodiments, the ganaxolone particles coated with spray layers or complexed ganaxolone particles coated with spray layers may be compressed in tablets with excipients. Suitable for forming the coating may be used to make the tablets with a layer of ink in the fluidized bed coating using a Wurster column, Powder in coating trays or in rotary coaters; dry coating with double compression technique; coating the tablet with a film and the like See, for example, U.S. Patent No. 5,322,655; Remington's Pharmaceutical Sciences Handbook: Chapter 90, "Coating of Pharmaceutical Dosage Forms ", 1990.

In various embodiments, the spray layer coated ganaxolone particles or the above-mentioned spray layer coated ganaxolone particles and one or more excipients may be dry blended and compressed to form a mass, such as a tablet, Which has sufficient hardness to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes or less, after approximately 60 minutes, after administration & amp;

Say

Oral IM, thus releasing the formulation of ganaxolone in gastrointestinal fluid.

In other embodiments, ganaxolone particles coated with spray layers or complexed ganaxolone particles coated with spray layers may be dry blended and compressed to form a mass, such as a tablet. In one embodiment, the enteric layer particles in the tablet substantially prevent the release of ganaxolone, eg, less than 15% by weight, into the stomach, but substantially release all of the ganaxolone (having enteric layer), for example , More than 80% by weight, in the intestine.

In still other embodiments, a pulsatile release ganaxolone formulation comprises a first dosage unit comprising a formulation of ganaxolone-containing granules made from a spray-drying or spray-granulation process, or a formulation made from A ganaxolone complex containing granules made from a spray drying or spray granulation process without enteric layers and a second dosage unit comprising ganaxolone particles coated with spray or liquid layers $. Complexed ganaxolone particles coated with enteric layers. In ... a modality, The first metering unit and the second metering unit are wet or dry mixed and compressed into a mass to form a pulsatile release tablet. In one embodiment, the weight ratio of uncoated to coated particles is from -1: 4 to 4: 1.

In another embodiment, the binders, lubricants and disintegrants are mixed (wet or dry) with the ganaxolone beads coated with spray layers or with the beads coated with spray layers of complexed ganaxolone to make a compressible blend. The first and second metering units are compressed separately and then compressed together to form a bilayer tablet.

In yet another embodiment, the first dosage unit is in the form of a cover, which completely covers the second dosage unit.

Microencapsulated Formulations

In one aspect of the present invention, the dosage forms may include microencapsulated ganaxolone formulations. In some embodiments, one or more compatible materials are present in the microencapsulation material. Some

Such materials include, but are not limited to, complexing agents, ionic dispersion modulators, pH modifiers, erosion facilitators, antifoaming agents, anti-oxidants, flavoring agents , And to carrier materials such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents and extenders.

Some of the materials useful for microencapsulation described in the present application include materials compatible with ganaxolone that sufficiently isolate ganaxolone from other non-compatible excipients. Materials compatible with the ganaxolone of the present invention are those which retard the release of ganaxolone in vivo. Some examples of microencapsulation materials useful for retarding the release of formulations comprising ganaxolone include, but are not limited to, hydroxypropyl cellulose (HPC) ethers such as Klucel® or Nisso HPC, hydroxypropyl cellulose ethers with low substitution ( L-HPC), hydroxypropyl methyl cellulose (HPMC) ethers such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methoce®-E, Opadry YS,

PrimaFlo, Benecel MP824, Benecel MP843, methylcellulose such as Methocel®-A, Hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolosa®, ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol®, carboxymethylcelluloses and carboxymethylcellulose (CMC) salts such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers Such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit ® L100-55, Eudragit ® L100, Eudragit ® S100, Eudragit ® RD100, Eudragit ® E100, Eudragit ® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepfilms such as mixtures of HPMC and stearic acid, cyclodextrins, parabens, sodium chloride and mixtures of these materials.

In still other embodiments, some plasticizers such as polyethylene glycols, for example, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid and JL- Triacetin, in the microcapsule material. V,

In other embodiments, the microencapsulation material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

Microencapsulated ganaxolone can be formulated with methods well known to those skilled in the art. Such known methods include spray drying processes, rotary disk solvent processes, hot melt processes, spray cooling methods, fluidized bed spray granulation, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization In liquid-gas or solid-gas interface, pressure extrusion or solvent extraction bath by spray. In addition to these, various chemical techniques could also be used, for example, complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, liquid drying and desolvation in liquid medium.

The rotating disk method allows: 1) an increase in the production rate due to a higher feed rate and the use of a higher solids loading in the feed solution, 2) the production of more spherical particles, 3) the Production of a more uniform coating, and 4) limited obstruction of the spray nozzles during the process.

Fluidized bed spray granulation is usually more readily available for scaling. In various embodiments, the material used in the spray-granulation encapsulation process is emulsified or dispersed in the core material in a concentrated form, for example from 10% to 60% solids.

The microencapsulation material is, in one embodiment, emulsified until particles or droplets of about 1 to 3 pm are obtained. Once dispersion of the ganaxolone and the encapsulating material is obtained, the emulsion is fed as droplets into the hot chamber of the spray granulator. In some embodiments, these particles or droplets are sprayed into the chamber or rotated on a rotating disk. The microspheres are then dried in the hot chamber and dropped to the bottom of the chamber. Collected. _

Roller compaction, involving the dry granulation of a single powder or a combined powder mixture using pressure to form dense compacts (said compacts are then ground to a desired particle size), provides another alternative. It is a simple process that is readily available for use, and does not involve the use of solvents for granulation. In this way, the compacting roller eliminates the exposure of the delicate active pharmaceutical ingredients to moisture and drying. Roller compaction may also provide improved stability and taste masking characteristics of the active drugs by diluting and isolating the components in a granulated matrix of compatible ingredients.

Extrusion / spheronization is another method consisting of a wet kneading of the active pharmaceutical ingredients, followed by extrusion of the wet mass through a perforated plate to produce small cylindrical rods. These rods are then placed in a fast spheronizer

Rotation to give them the shape of the legs, and FIG. 4 is a cross-sectional view of FIG. Eur-lex.europa.eu eur-lex.europa.eu

These spheres are then dried using a fluidized bed dryer and then coated with a functional coating using a fluidized bed equipped with a Wurster attachment and a spray nozzle.

Coacervation involves microencapsulation of materials as active pharmaceutical ingredients and involves a three part process of forming particles or droplets, forming a coagulated wall, and insulation of the capsule. This method can produce microcapsules with a very small particle size (from 10 to 70 microns).

In one embodiment, the ganaxolone particles are microencapsulated before being formulated into one of the above-described forms. In yet another embodiment, part or most of the ganaxolone particles are coated before being formulated using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

Coated or Plasticized Formulations

In other embodiments, solid dosage ganaxolone formulations are plasticized (coated) with one or more layers. Illustratively, a plastid is generally a solid or liquid with a high boiling point. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate and castor oil.

In other embodiments, a powder comprising the ganaxolone formulations described in the present application may be formulated to comprise one or more pharmaceutical excipients and flavorants. Said powder may be prepared, for example, by mixing the ganaxolone formulation and optional pharmaceutical excipients to form a bulk blended composition. Other embodiments involve a suspending agent and / or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packages or multiple dosage unit packages. The term "uniform" means that the homogeneity of the bulk blend is maintained substantially during the packaging process. In some embodiments, at least about 75% to about 1% and & gt; Ü <, The ganaxolone has an effective particle size by weight of less than about 500 nm to about 100 nm. In other embodiments, ganaxolone comprises at least 90% ganaxolone particles having an effective particle size by weight of less than about 500 nm to 100 nm.

Effervescent Powders

In still other embodiments, effervescent powders are also prepared in accordance with the present invention.

Effervescent salts have been used to disperse medicines into the water for oral administration. The effervescent salts are coarse granules or powders containing a medicinal agent in a dry mixture, generally composed of sodium bicarbonate, citric acid and / or tartaric acid. When the salts of the present invention are added to the water, the acids and the base react by releasing carbon dioxide gas, thereby causing "effervescence". Examples of effervescent salts include, for example, sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any base-acid combination that generates the release of carbon dioxide can be used instead of the bicarbonate combination.

INDUCED Citric and tartaric acid, provided the ingredients are suitable for pharmaceutical use and give rise to a pH of about 6.0 or higher.

The effervescent granulation method of the present invention employs three basic processes: wet granulation, dry granulation and melting. The melting method is used for the preparation of most commercial effervescent powders. It should be noted that, while these methods are intended for the preparation of granules, the effervescent salt formulations of the present invention may also be prepared as tablets, according to the known technology for the preparation of tablets.

Wet and Dry Granulation

Granulation is one of the oldest methods of granule preparation. The individual steps in the wet granulation tablet preparation process include grinding and screening of ingredients, dry powder blending, wet kneading, granulation, drying and final grinding.

In various embodiments, the ganaxolone composition is added to the other excipients of the pharmaceutical formulation after being wet granulated. . J! "

Dry granulation involves the compaction of the granules. A. - blending powder into a raw tablet or a plate in an industrial rotary tablet press. Said raw tablet or slab is then divided into granular particles by means of a grinding operation, usually by passing them through an oscillating granulator. The individual steps include the mixing of the powders, compression (formation of the raw tablet or plate) and grinding (reduction or granulation of the plate). A wet or wetting binder is not involved in any of the steps. In some embodiments, the ganaxolone formulation is dry granulated with other excipients of the pharmaceutical formulation. In other embodiments,

Solid Dispersions

In other embodiments, the ganaxolone formulations described in the present application are solid dispersions. Methods of producing such solid dispersions are well known in the art and include, but are not limited to, for example, those of U.S. Patents 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,1 ' The US Patent Application No. 2004/0013734, all of which have been specifically incorporated by reference, are incorporated herein by reference. In some embodiments, the solid dispersions of the present invention comprise both amorphous and non-amorphous ganaxolone, and may have a higher bioavailability compared to conventional formulations of ganaxolone. In still other embodiments, The ganaxolone formulations described in the present application are solid solutions. The solid solutions incorporate a substance together with the active agent plus other excipients so that upon heating the mixture the drug is diluted and the resulting composition is subsequently cooled to obtain a solid mixture which can be formulated directly or added to a capsule or compressed up Turn it into a tablet. Methods of producing such solid solutions are well known in the art and include, but are not limited to, for example, those of U.S. Patents No. 4,151,273, 5,281,420, and 6,083,518 all of which have been Specifically incorporated by reference. So that upon heating the mixture the drug is diluted and then the resulting composition is cooled to obtain a solid mixture which can be formulated directly or added to a capsule or compressed into a tablet. Methods of producing such solid solutions are well known in the art and include, but are not limited to, for example, those of U.S. Patents No. 4,151,273, 5,281,420, and 6,083,518 all of which have been Specifically incorporated by reference. So that upon heating the mixture the drug is diluted and then the resulting composition is cooled to obtain a solid mixture which can be formulated directly or added to a capsule or compressed into a tablet. Methods of producing such solid solutions are well known in the art and include, but are not limited to, for example, those of U.S. Patents No. 4,151,273, 5,281,420, and 6,083,518 all of which have been Specifically incorporated by reference.

Release Dosage Forms Including Controlled Release and Delayed Release

Solid oral dosage forms comprising the ganaxolone formulations described in the present application may further be formulated to provide a modified or controlled release of ganaxolone.

In some embodiments, the solid dosage forms described in the present application may be formulated as a delayed release dosage form, such as delayed release enteral oral dosage forms, ie an oral dosage form of a Pharmaceutical composition, as described in the present patent application, which uses an enteric layer to produce release into the small intestine of the gastrointestinal tract. The dosage form with enteric layer may be a compressed or molded or extruded tablet (with or without coating) containing granules, powders, beads or particles of the active ingredient and / or other components of the composition, which in turn are Coated or uncoated.

In other embodiments, the ganaxolone formulations described in the present application are released using a pulsatile dosage form. Pulsatile dosage forms comprising the ganaxolone formulations described in the present application may be administered using a plurality of formulations known in the art. For example, such formulations include, but are not limited to, those disclosed in U.S. Patents 5,011,692, 5,017,381, 5,229,135, and 5,840,329 all of which have been specifically incorporated by reference. Other dosage forms suitable for use with the ganaxolone formulations are described, for example, in U.S. Patents 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284, All of which have been specifically incorporated by reference. In one embodiment, the dosage form is a controlled release solid oral dosage form, pulsatile release comprising at least two groups of particles, each of 1Ρ "ο ί ·. N. I

Which contains the formulation of Example 1 described in the present application. The prime particulate group provides a substantial dose of ganaxolone immediately after it is ingested by the subject. The first group of particles may or may not have a coating and / or sealant. The second group is comprised of coated particles, comprising from about 2% to about 75%, and preferably from about 2.5% to about 70%, and still more preferably from about 40% to about 70%, by weight, of the total Of the dose of ganaxolone of said formulation, mixed with one or more binders. The coating comprises a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of about 2 to about 7 hours after ingestion before the second dose is released. Suitable coatings may include one or more differentially degradable coatings, such as those, by way of example only, pH-sensitive coatings (enteric layers) such as acrylic resins (eg, Eudragit® EPO, Eudragit® L30D-55, Eudragit Eudragit® L100.5, Eudragit® S12.5 and Eudragit® NE30D, Eudragit® NE4D), and Eudragit® L100-5, Eudragit® L100-5, Eudragit® S100, Eudragit® Either alone or in admixture with cellulose, eg ethylcellulose, or non-enteric coatings of variable thickness,

There are many other types of controlled release systems well known to those skilled in the art and are suitable for use with the ganaxolone formulations described in the present application. Examples of such release systems include, for example, polymer-based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; Porous matrices, non-polymeric based systems which are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-, di- and triglycerides; Hydrogel release systems; Silastic systems, peptide-based systems, wax coatings, biodegradable dosage forms, Compressed tablets using conventional binders and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., Pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983 all of which have been specifically incorporated by reference.

In another embodiment, the modified release dosage formulation may comprise a combination of: (a) a compressed tablet core comprising a poorly soluble active agent in water, a pharmaceutically acceptable water swellable polymer, and an osmotic agent ; And (b) an outer coating layer completely covering the tablet core and comprising a pH sensitive coating. An optional sealing layer may be applied to the compressed tablet core and an optional coating layer comprising an enteric coating agent below the outer coating layer as an inner coating or as an extra layer on the outer coating layer. The tablet core can be compressed using a soft-faced tablet die. In one embodiment,

The osmotic agent of this dosage form is any non-toxic pharmaceutically acceptable water soluble compound which dissolves in sufficient water and increases the osmotic pressure xSior. Of the tablet core. Suitable osmotic agents include simple sugars and salts such as sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, sucrose, lactose, glucose, sorbitol, Fructose, mannitol, glucose, magnesium succinate, potassium acid phosphate, and other similar compounds. The preferred osmotic agent for the tablet core is a simple sugar, such as anhydrous lactose in the range of about 0% to 50% by weight, based on the weight of the uncoated compressed tablets.

The water swellable polymer may be any pharmaceutically acceptable polymer which swells and expands in the presence of water to slowly release the ganaxolone. These polymers include polyethylene oxide, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. In a preferred embodiment, the water swellable polymer will be polyethylene oxide (obtained from Union Carbide Corporation, under the trade name Polyox WSR Coagulant or Polyox WSR N 80). These materials form a viscous gel in water or any other solvent system in sufficient concentration to control the release of ganaxolone. A concentration of the pharmaceutically acceptable water-swellable polymer of about 0% to 50% of the weight of the uncoated compressed tablets is required.

The outer coating comprises a pH sensitive coating which functions as an enteric polymer in the sense that it does not begin to dissolve until the pH conditions above the pH of the stomach are encountered. The pH-sensitive coating is the same type of material as described above. The pH sensitive coating may be present in an amount of about 0.5% to 15% by weight, more specifically, about 8% to 12% by weight, based on the weight of the core of the coated tablet.

Some controlled release formulations may release less than about 20% by weight of the formulation ganaxolone within the first three hours after administration and more than about 60% of the ganaxolone within about 3 to about 10 hours. Other controlled-release formulations of ganaxolone may release less than about 50% within the first three hours after administration and about 50% of ganaxolone within about 3 hours. 10 hours.

Enteric Layers

The enteric layers should be applied with a sufficient thickness so that the pH does not dissolve completely appreciably in the gastrointestinal fluids a pH less than about 5 after 1 hour, but at a pH of about 5 and higher. It is expected that any anionic polymer exhibiting a pH dependent solubility profile can be used as an enteric layer in the practice of the present invention to achieve release into the lower part of the gastrointestinal tract. In some embodiments, the polymers to be used in the present invention are the anionic carboxylic polymers.

In other embodiments, some of the compatible polymers and mixtures thereof, and some of their properties, include, but are not limited to:

The shellac. Also called purified shellac, a refined product that is obtained in the resinous secretion of an insect. This layer dissolves in a medium of pH> 7.

Acrylic polymers. The performance of the acrylic polymers (mainly their solubility in biological fluids) may vary depending on the substitution. Examples of suitable acrylic polymers include the methacrylic acid copolymers and the ammonia methacrylate copolymers. The Eudragit E, L, S, RL, RS and NE series (Rohm Pharma) are available as solubilisables in organic solvents, aqueous dispersions or in dry powders. Eudragit's RL, NE and RS series is insoluble in the gastrointestinal tract, but is permeable and is mainly used for targets or sites of action located in the colon. The Eudragit E series dissolves in the stomach. The L-30D and S series of Eudragit is not soluble in the stomach and dissolves in the intestine;

Derivatives of cellulose. Examples of suitable cellulose derivatives are the following: ethyl cellulose, the reaction mixtures of partial acetate asters of cellulose with phthalic anhydride. Their performance may vary depending on the degree and type of replacement. Cellulose acetate phthalate (CAP) dissolves at pH> 6. The Aquateric (FMC) is a water based system and is a spray dried pseudolatex CAP with particles <1 pm. Other components of the Aquateric may include pluronic, Tweens, and acetylated monoglycerides. INSTALLATION.

Other suitable cellulose derivatives include cellulose acetate (Eastman); (Pharmacoat, Methocel); Hydroxypropylmethylcellulose phthalate (HPMCP); Hydroxypropylmethylcellulose succinate (HPMCS), and hydroxypropylmethylcellulose acetate succinate (for example, AQOAT (Shin Etsu)). Their performance may vary depending on the degree and type of replacement. For example, HPMCP such as HP-50, HP-55, HP-55S, HP-55F are suitable. Their performance may vary depending on the degree and type of replacement. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF) which is dissolved at pH 5, AS-MG (MF) which dissolves at pH 5.5, and AS-HG HF) which dissolves at a higher pH. These polymers are provided as granules,

Polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH> 5 and is much less permeable to water vapor and gastric fluid.

In some embodiments the coating may, and is generally so, contain a plasticizer and possibly other coating excipients such as dyes, talc, and / or magnesium stearate, which are well known in the art. Suitable plasticizers include citrate (Citroflex 2), triacetin (glyceryl triacetate). Triethyl citrate acetate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, the anionic carboxylic acrylic polymers typically contain from 10% to 25% by weight of plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques, such as spraying or tray coating, are used to apply the coatings. The thickness of the coating should be sufficient to ensure that the oral dosage form is maintained intact until the desired topical delivery site is reached in the intestinal tract.

Colorants, anti-adhesives, surfactants, antifoaming agents, lubricants (eg carnuba wax or PEG) may be added to the coatings as well as plasticizers to solubilize or disperse the coating material and to improve the performance of the coating and the coated product.

A particularly suitable methacrylic copolymer is Eudragit L®, particularly L-30D® and Eudragit 100-55®, manufactured by Rohm Pharma, Germany. The ratio of free carboxyl groups and groups of asters is about 1: 1. On the other hand, the copolymer is known to be insoluble in gastrointestinal fluids having a pH below 5.5, and generally 1.5 to 5.5, ie the pH which is usually present in the fluid of the upper gastrointestinal tract, but is readily Soluble or partially soluble at pH greater than 5.5, ie at pH values present in the small intestine.

In some embodiments, these materials include shellac, acrylic polymers, cellulose derivatives, polyvinyl acetate phthalate, and mixtures thereof.

In other embodiments, these materials comprise the Eudragit® series E, L, RL, RS, NE, L, L300, S, 100-55, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethylcellulose, hydroxypropylmethylcellulose phthalate, Hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate and Cotteric.

Liquid Formulations

The ganaxolone particles having a smaller effective particle size are absorbed more rapidly and the ganaxolone particles having a larger size are absorbed more slowly. In some embodiments, the aqueous dispersion or suspension is an immediate release formulation. In another embodiment, an aqueous dispersion comprising amorphous ganaxolone particles is formulated such that about 50% of the ganaxolone particles are absorbed approximately 3 hours after administration and about 90% of the ganaxolone particles are approximately absorbed 10 hours after administration.

In other embodiments, the addition of a complexing agent to the aqueous dispersion results in a longer duration of the ganaxolone-containing particles, extending the drug absorption phase such that between 50% and 80% Are absorbed in the first 3 hours and about 90% are absorbed in about 10 hours.

The suspension is "substantially uniform" when it is mostly homogeneous, that is, when the suspension is composed of approximately the same concentration of ganaxolone at any point. Preferred embodiments are those which provide essentially the same concentrations (within 15%) if measured at different points in an aqueous oral formulation of ganaxolone after shaking. Especially preferred are aqueous suspensions and dispersions, which maintain homogeneity (with a variation of up to 15%) when measured 2 hours after stirring. Homogeneity must be determined by a sampling method consistent with that which determines the homogeneity of the entire composition. In one embodiment, An aqueous suspension can be resuspended in a homogeneous slurry by means of physical stirring for less than 1 minute. In another embodiment, an aqueous slurry may be resuspended in a homogenous slurry by means of physical agitation for less than 45 seconds. In yet another embodiment, an aqueous slurry may be resuspended in a homogeneous slurry by means of physical agitation for less than 30 seconds. In yet another

The stirring is necessary to maintain a homogeneous aqueous dispersion.

In some embodiments, the ganaxolone powders of the aqueous dispersion described in the present application involve stable ganaxolone particles having an effective particle size by weight of less than 500 nm formulated, wherein the ganaxolone particles have an effective particle size By weight exceeding 500 nm. In such embodiments, the formulations have a particle size distribution in which from about 10% to about 100% of the ganaxolone particles by weight are from about 75 to about 500 nm, from about 0% to about 90% of the Ganaxolone particles by weight are from about 150 to about 400 nm, and from about 0% to about 30% of the ganaxolone particles by weight are greater than about 600 nm.

In one embodiment, the aqueous suspensions or dispersions described in the present application comprise ganaxolone particles or complexes of a concentration of about 20 mg / ml of suspension. In another embodiment, the suspensions Or aqueous dispersions described in the present application comprise ganaxolone particles or complexes in a concentration from about 25 mg / ml to about 75 mg / ml solution. In yet another embodiment, the aqueous suspensions or dispersions described in the present application comprise Particles or complexes of ganaxolone at a concentration of about 50 mg / ml suspension.

The aqueous dispersions described in the present application are especially beneficial for the administration of ganaxolone to infants (<2 years of age), to children less than 10 years of age, and to any group of patients unable to swallow or ingest forms Of solid oral dosage.

Dosage forms with liquid ganaxolone formulations for oral administration may be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., Pp. 754-757 (2002). In addition to (1) ganaxolone, liquid dosage forms may include additives, such as, for example: (a) disintegrating agents; (B) dispersing agents; (C) wetting agents; (D) at least one preservative, (e) viscosity improving agents, (f) at least one sweetening agent, (g) at least one flavoring agent, (h) a complexing agent and (i) a dispersing modulator Ionic. In some embodiments,

Some examples of the disintegrating agents to be used in the aqueous suspensions and dispersions include, but are not limited to, a starch, for example, a natural starch such as corn or potato starch, pregelatinized starch such as National 1551 or Amijel® or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, microcrystalline cellulose, eg Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a crosslinked cellulose such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, A crosslinked starch such as sodium starch glycolate, a crosslinked polymer such as crdBF.Crosslinked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, carob, Karaya, Pectin, or tragacanth, a sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and Other similar compounds.A natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.A natural sponge, a surfactant, a resin such as a cation exchange resin, a citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

Polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer (Plasdone®, for example, S-630), 4- (1,1,3,3-tetramethylbutyl) phenol polymer with ethylene oxide and formaldehyde Known as tyloxapol), poloxamers (for example, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); And poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)). In other embodiments, the dispersing agent is selected from a group which does not comprise one of the following agents: hydrophilic polymers; Electrolytes; Tween® 60 or 80; PEG; Polyvinylpyrrolidone (PVP); Hydroxypropylcellulose and hydroxypropyl cellulose ethers (eg, HPC, HPC-SL and HPC-L); Hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (for example, HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); Carboxymethylcellulose sodium; Methylcellulose, hydroxyethylcellulose; Hydroxypropylmethylcellulose; Stearate uccLaLU 'hydroxypropylmethylcellulose; Non-crystalline elastase, magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®). HPC-SL and HPC-L); Hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (for example, HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); Carboxymethylcellulose sodium; Methylcellulose, hydroxyethylcellulose; Hydroxypropylmethylcellulose; Stearate uccLaLU 'hydroxypropylmethylcellulose; Non-crystalline elastase, magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®). HPC-SL and HPC-L); Hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (for example, HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); Carboxymethylcellulose sodium; Methylcellulose, hydroxyethylcellulose; Hydroxypropylmethylcellulose; Stearate uccLaLU 'hydroxypropylmethylcellulose; Non-crystalline elastase, magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®). HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu); Carboxymethylcellulose sodium; Methylcellulose, hydroxyethylcellulose; Hydroxypropylmethylcellulose; Stearate uccLaLU 'hydroxypropylmethylcellulose; Non-crystalline elastase, magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®). HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu); Carboxymethylcellulose sodium; Methylcellulose, hydroxyethylcellulose; Hydroxypropylmethylcellulose; Stearate uccLaLU 'hydroxypropylmethylcellulose; Non-crystalline elastase, magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®). Magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®). Magnesium and aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); Polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®).

Wetting agents (including surfactants) suitable for the aqueous suspensions and dispersions described in the present application are well known in the art and include, but are not limited to, acetyl alcohol, glycerol monostearate, fatty acid esters of Polyoxyethylene sorbitan (for example, Tweens®, commercially available as Tween 20® and Tween 80® (ICI Specialty Chemicals)); Polyethylene glycols (for example, Carbowaxs 3550® and 1450®, and Carpool 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, sorbitan monolaurate Of polyoxyethylene, sodium oleate, lauryl

UC LA Γ! Λ / '. . · 'Ι.Ι.' Sodium sulfate, sodium docusate, triacetate, vitamin E TPGS, sodium taurocholate, phosphotidylcholine and other similar compounds.

Some preservatives suitable for the aqueous suspensions and dispersions described in the present application include, for example, potassium sorbate (eg methylparaben and propylparaben) and their salts, benzoic acid and its salts, other asters of parahydroxybenzoic acid Such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. The preservatives, as used in the present application, are incorporated into the dosage form in a concentration sufficient to inhibit microbial growth. In one embodiment, the aqueous liquid dispersion may comprise methylparaben and propylparaben in a concentration of about 0.01% to about 0.3% methylparaben by weight, In relation to the weight of the aqueous dispersion and 0.005% to 0.03% of propylparaben by weight, relative to the total weight of the dispersion. In yet another embodiment, the aqueous liquid dispersion may comprise methylparaben from 0.05% to about 0.1% by weight and propylparaben of from 0.01% to 0.02% by weight, based on the weight of the mixture. ·. The dispersion. -

Some viscosity enhancers suitable for the aqueous suspensions and dispersions described in the present application include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,

Plasdone® S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity enhancing agents will depend on the agent selected and on the desired viscosity.

Examples of natural and artificial sweetening agents suitable for the aqueous suspensions and dispersions described in the present application include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berries, blackcurrant , Sugar butterscotch, citric acid citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cherry soda , Cyclamate, cilamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey. MEXICAN INSTITUTE. Isomalt, lemon, lime, lemon cream, τΟφο-ι- ± monoammonium (MagnaSweet®), maltol, mannitol, maple. Bonbon, menthol, mint cream, mixed berries, Prostate®, Raspberry, Root Beer, Rum, Saccharin, Safrole, Sorbitol, Peppermint Cream, Peppermint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose , Sucrose, saccharin, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, Switzerland cream, tagat, mandarin, taumatin, fruits, vanilla, walnut, watermelon, wild cherry, xylitol, or any combination Such as aniseed, cherry-anise, cinnamon-orange, cinnamon-cherry, mint-chocolate, honey-lemon, lime-lemon, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint And mixtures thereof. In one embodiment, the aqueous liquid dispersion may comprise a sweetening or flavoring agent in a concentration of about 0. 0001% to about 10.0% by weight of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion may comprise a sweetening or flavoring agent in a concentration of about 0.0005% to about 5.0% by weight of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion may comprise an agent

In a concentration of about 0.0001% to 0.1% by weight, from about 0.001% to about 0.01% by weight or from about 0.0005% to 0.004% by weight of The aqueous dispersion.

In addition to the additives listed above, liquid formulations of ganaxolone may also comprise inert diluents commonly used in the state of the art, such as water or other solvents, solubilizing agents and emulsifiers.

EMULSIONS

In some embodiments, the pharmaceutical formulations of ganaxolone described in the present application may be self-emulsifying drug delivery systems (SEDDSs). Emulsions are dispersions from one miscible phase to another, generally in the form of particles or Droplets. In general, the emulsions are created by a vigorous mechanical dispersion. SEDDS, unlike emulsions or microemulsions, spontaneously form emulsions when added to excess water without any mechanical dispersion or external stirring. One of the advantages of SEDDS is that it is only necessary to mix them gently to distribute the particles or droplets throughout the solution. The water or the aqueous phase may be added directly to the administration thereof, Which guarantees the stability of an unstable or hydrophobic active ingredient. Thus, SEDDS provide an effective effective delivery system for the oral and parenteral release of hydrophobic active ingredients. SEDDS can provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing the self-emulsifying dosage forms are well known in the art and include, but are not limited to, for example, those of U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, which Have been specifically incorporated by reference. SEDDS can provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing the self-emulsifying dosage forms are well known in the art and include, but are not limited to, for example, those of U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, which Have been specifically incorporated by reference. SEDDS can provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing the self-emulsifying dosage forms are well known in the art and include, but are not limited to, for example, those of U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, which Have been specifically incorporated by reference.

Examples of emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, esters of Cholesterol, taurocholic acid, phosphotidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, «^ 0A :? Sorbitan, or mixtures of these substances, and the like.

Intranasal Formulations

Intranasal formulations are well known in the art and are described, for example, in U.S. Patents 4,476,116, 5,116,817 and 6,391,452 which have been specifically incorporated by reference. The formulations of ganaxolone prepared with these and other techniques known in the art are produced as solutions in saline using benzyl alcohol or other preservatives, fluorocarbons and / or other dispersing solubilizing agents well known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth ed. (nineteen ninety five). Preferably these compositions and formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients.

Edition, 2005, a standard reference in station technique. The choice of suitably suitable carriers is to a large extent the exact nature of the desired nasal dosage form, for example, solutions, suspensions, ointments or gels. Nasal dosage forms often contain large amounts of water, in addition to the active ingredient. Small amounts of other ingredients, such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gellants, complexing or buffering agents and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

Oral Formulations

Buccal formulations comprising the ganaxolone formulations described in the present application may be administered using a plurality of formulations well known in the art. For example, such formulations include, but are not limited to, those disclosed in U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136 which have been specifically incorporated by reference. In addition, the forms of

Dosage compositions described herein may include a polymeric carrier (hydrolyzable) which also serves to adhere the dosage form to the buccal mucosa. The oral dosage form is manufactured so that it gradually degrades for a predetermined period of time, in which the release of ganaxolone is provided essentially all the time.

Oral drug delivery, as will be appreciated by those skilled in the art, avoids the drawbacks encountered with oral administration of drugs, eg, slow absorption, degradation of the active agent in the gastrointestinal tract fluids and / or The first step inactivation in the liver. With respect to the biodegradable (hydrolyzable) polymeric carrier, it is appreciated that practically any carrier can be used, provided the desired drug release profile is not understood and the carrier is compatible with ganaxolone and with any other component that may be present In the oral dosage unit. In general, The polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the moist surface of the buccal mucosa. Some examples of this include: Polymer carriers useful herein include polymers and copolymers. Acrylic acid, for example those known as "carbomers" (Carbopol®, which can be obtained from BF Goodrich, is one of these polymers.) Other components which may also be incorporated into the dosage forms Buccal compositions disclosed in the present application include, but are not limited to, disintegrants, diluents, binders, lubricants, flavorants, colorants, preservatives and the like. Polymer carriers useful herein include polymers and copolymers. Acrylic acid, for example those known as "carbomers" (Carbopol®, which can be obtained from BF Goodrich, is one of these polymers.) Other components which may also be incorporated into the dosage forms Buccal compositions disclosed in the present application include, but are not limited to, disintegrants, diluents, binders, lubricants, flavorants, colorants, preservatives and the like. Polymer carriers useful herein include polymers and copolymers. Acrylic acid, for example those known as "carbomers" (Carbopol®, which can be obtained from BF Goodrich, is one of these polymers.) Other components which may also be incorporated into the dosage forms Buccal compositions disclosed in the present application include, but are not limited to, disintegrants, diluents, binders, lubricants, flavorants, colorants, preservatives and the like.

Transdermal Formulations

The transdermal formulations described in the present application may be administered using a plurality of devices described in the prior art. For example, such devices include, but are not limited to, those described in the patents of the

United States No. 3,598,122, 3,598,123, 3,731,683, 3,731,953, 3,742,951, 3,814,097, 3,972,995, 3,993,072, 3,993,073, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,307, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144 all of which have been specifically incorporated by reference. In some embodiments, the releasing device UNO. Transdermal derivative used with the ganaxolone formulations described herein comprises a source of power, radio frequency or a brief electric current connected to microelectrodes In the skin, creating "channels" or "pores" in the stratum corneum to facilitate the release of the formulation of ganaxolone, Such methods are well known in the art and are described, for example, in U.S. Patents 6,611,706, 6,708,060 and 6,711,435, which have been specifically incorporated by reference. In other embodiments, the transdermal delivery device may be a means for generating pores in the stratum corneum, for example, micropunting, sonic energy application, or hydraulic puncture, to facilitate release of the ganaxolone formulation, such methods are well Known in the state of the art and are described, for example, in U.S. Patents 6,142,939 and 6,527,716, which have been specifically incorporated by reference. The pores described by these methods are generally about 20 to 50 microns deep and do not extend into the innervation or vascularization zones. INSTITUI- »muiuv.'w

The transdermal dosage forms of the present application may include, - pharmaceutically acceptable excipients which are conventional in the state of the art. In general, the transdermal formulations described in the present application comprise at least three components: (1) a formulation of ganaxolone or a ganaxolone complex; (2) a penetration enhancer, and (3) an aqueous adjuvant. In addition, the transdermal formulations may include additional components, such as, but not limited to, gelling agents, creams and ointment bases and the like. In some embodiments,

In other embodiments, the transdermal formulations described in the present application may maintain a saturated or supersaturated state to promote diffusion into the skin.

Injectable Formulations

Formulations of ganaxolone suitable for intramuscular, subcutaneous or intravenous injections may be comprised of solutions, dispersions, Λ VJJL. Physiologically acceptable aqueous suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents, carriers, aqueous and nonaqueous carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor and other similar compounds), suitable mixtures thereof, vegetable oils Olive oil) and injectable organic esters such as ethyl oleate. In addition, ganaxolone can be dissolved in concentrations of> 1 mg / ml using water-soluble beta cyclodextrins (eg, Beta-sulfobutyl-cyclodextrin and 2-hydroxypropylbetacyclodextrin). Suitable fluidity may be maintained, for example, by the use of a coating such as lecithin, maintaining the appropriate particle size in the case of the dispersions, and by the use of surfactants. Ganaxolone formulations suitable for subcutaneous injection may also contain additives such as preservatives, humectants, emulsifiers and dispersants. Prevention of the growth of microorganisms can be ensured with various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to administer isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the drugs from the injectable dosage form can be brought about by the use of delaying absorption agents, such as aluminum monostearate and gelatin. Ganaxolone suspension formulations designed for extended delivery by subcutaneous or intramuscular injection may avoid first pass metabolism and lower doses of ganaxolone will be required to maintain plasma levels of approximately 50 ng / ml. In such formulations, the particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle. V. Sterile Formulations of Ghanaxolone Such as aluminum monostearate and gelatin. Ganaxolone suspension formulations designed for extended delivery by subcutaneous or intramuscular injection may avoid first pass metabolism and lower doses of ganaxolone will be required to maintain plasma levels of approximately 50 ng / ml. In such formulations, the particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle. V. Sterile Formulations of Ghanaxolone Such as aluminum monostearate and gelatin. Ganaxolone suspension formulations designed for extended delivery by subcutaneous or intramuscular injection may avoid first pass metabolism and lower doses of ganaxolone will be required to maintain plasma levels of approximately 50 ng / ml. In such formulations, the particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle. V. Sterile Formulations of Ghanaxolone Ganaxolone suspension formulations designed for extended delivery by subcutaneous or intramuscular injection may avoid first pass metabolism and lower doses of ganaxolone will be required to maintain plasma levels of approximately 50 ng / ml. In such formulations, the particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle. V. Sterile Formulations of Ghanaxolone Ganaxolone suspension formulations designed for extended delivery by subcutaneous or intramuscular injection may avoid first pass metabolism and lower doses of ganaxolone will be required to maintain plasma levels of approximately 50 ng / ml. In such formulations, the particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle. V. Sterile Formulations of Ghanaxolone The particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the dissolution rate in fat or muscle. V. Sterile Formulations of Ghanaxolone The particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the dissolution rate in fat or muscle. V. Sterile Formulations of Ghanaxolone

Some of the formulations of ganaxolone described in the present application may be sterilized by filtration. This property eliminates the need for heat sterilization, which can damage or degrade

Ganaxolone, in addition to resulting in effective particle size growth.

Filtration sterilization may be difficult because of the small particle size required in the composition. However, this method is suitable and is normally used with dispersions comprising nanoparticles. Filtration is an effective method for sterilizing homogeneous solutions when the pore size of the filter membrane is less than or equal to approximately 0.2 microns (200 nm) because a 0.2 micron filter is sufficient to remove virtually all bacteria. Filtration sterilization is not normally used to sterilize the conventional suspensions of ganaxolone with particle sizes of microns because the ganaxolone particles are too large to pass through the pores of the membrane.

Because some of the formulations of ganaxolone complexes described in the present application can be sterilized in an autoclave, and since the formulations may have a very small average effective particle size of the ganaxolone particles, some sterile ganaxolone formulations Are suitable for parenteral administration. In addition, a sterile formulation of ZZZ. Ganaxolone is particularly useful in the treatment of immunocompromised patients, juvenile patients, patients with traumatic brain injury, and the elderly. Combination Therapies

The compositions and methods described in the present patent application may also be used in combination with other well known therapeutic agents selected for their particular utility against the condition being treated. In general, the compositions described in the present application and, in the embodiments where combination therapy is used, other agents do not have to be administered in the same pharmaceutical composition and, owing to the different physical and chemical characteristics, may have to be administered By different routes of administration. Determination of the mode of administration and the desirability of administration, whenever possible, in the same pharmaceutical composition, is well known within the general knowledge of the skilled practitioner.

The initial administration can be done according to established protocols well known in the prior art, and then, based on the observed effects, the dose, modes of administration time of administration can be modified by- Medical expert.

The particular choice of the compounds used will depend on the diagnosis of the physicians and their evaluation of the patient's condition and the appropriate treatment protocol. The compounds may be administered concurrently (eg, simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending on the nature of the proliferative disease, the condition of the patient and the choice of the compounds used. The determination of the order of administration and the number of replicates of the administration of each therapeutic agent during a treatment protocol is well known within the knowledge of the skilled practitioner after an evaluation of the disease being treated and the condition of the patient .

It is understood that the dosage regimen for treating, preventing or ameliorating the condition or conditions for which relief is sought may be modified according to a plurality of factors. These factors include the disorder that the subject suffers, as well as their age, weight, sex, diet and medical condition. Therefore, the present dosage regimen is widely used and can therefore be used as an adjuvant. The dosage regimens set forth in the present patent application.

The pharmaceutical agents comprising the combination therapy disclosed in the present application may be in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents composing the combination therapy may also be administered sequentially, with any therapeutic compound intended to be administered for a regimen requiring two-step administration. The two-stage regimen of administration may require the sequential administration of the active agents or a spaced administration of the separate active agents. The time period between the multiple administration steps may range from a few minutes to several hours, depending on the properties of each pharmaceutical agent,

Circadian variation in target and target molecule concentration may also determine the optimal dose range.

In some embodiments, the formulation is administered with at least one other anticoagulant. In other embodiments, the ganaxolone formulation is administered with at least one other antiepileptic agent. In yet other embodiments, the ganaxolone formulation is administered with at least one other anti-anticoagulant agent. In still other embodiments, the ganaxolone formulation is administered with at least one other antidepressant agent. VII. Pharmacokinetic Profiles of Ghanaxolone Formulations

The formulations and dosage forms of ganaxolone described in the present application exhibit pharmacokinetic profiles which can generate steady state blood plasma levels of ganaxolone Cmin from about 10 ng / ml to about 100 ng / ml. In one embodiment, the ganaxolone formulations described in the present application provide blood plasma levels immediately before the next steady state dose (Cmin) of about 25 ng / ml to about 100 ng / ml. In another embodiment, the ganaxolone formulations described in the present application provide stable plasma blood Cmin levels of about 40 ng / ml to about 75 ng / ml. In yet another embodiment, the ganaxolone formulations described in the application, Provide Cmin levels in plasma or in a stable state of about 50 ng / ml. In addition to improved steady-state pharmacokinetics, these ganaxolone formulations can provide controlled release of ganaxolone such that the Cmax / Cmin ratio of ganaxolone levels in blood plasma is less than or equal to 4 in steady state In the case of an orally administered dispersion, and 3 or less in a solid dosage form. In one embodiment, the ganaxolone formulations described in the present application provide the controlled release of ganaxolone, such that the Cmax / Cmin ratio of ganaxolone levels in blood plasma ranges from 1.5 to 3.5 steady state. In another embodiment, the ganaxolone formulations described in the present application,

Vlla. Increased exposure of Ganaxolona

The formulations and dosage forms of ganaxolone described in the present application, exhibit an ιΓ · aspect; U'jj. 4. In particular, increased fasting exposure, as compared to prior conventional ganaxolone formulations when administered at the same dose and under the same conditions.

As noted above, elevated levels of ganaxolone in blood plasma may cause undesirable side effects. Therefore, low doses of ganaxolone are desired which may achieve the same therapeutic effects or even better than those observed with high doses of the conventional formulations of ganaxolone.

Such low doses may be achieved with the ganaxolone formulations described in the present application as a result of increased exposure observed with the present formulations of ganaxolone as compared to conventional formulations of ganaxolone. The ganaxolone formulations described in the present application exhibit fasted exposure, as compared to conventional formulations of ganaxolone, in a range of at least about 100% to about 500%, preferably between about 150% to about 300% , Of the specified therapeutic parameter (eg AUCo-οο or AUC0-T) when T is greater than or equal to 24

PROPERTY HOURS. In one embodiment, the formulation is a water dispersion which exhibits fast bioavailability compared to conventional formulations of ganaxolone, in the range of about 150% to about 300%. In another embodiment, the ganaxolone formulation is a solid oral dispersion exhibiting fasting exposure compared to conventional formulations of ganaxolone, ranging from about 150% to about 400%. In yet another embodiment, the ganaxolone formulation is an intranasal dosage form exhibiting potent pharmacodynamic effects as compared to a similar oral dose of the conventional formulation. In yet another embodiment,

For example, Monaghan et al. Has previously reported that conventional formulations of ganaxolone administered to human subjects in a high fat consumption state exhibit pharmacokinetic profiles such that blood plasma AUC (o-oe) values range from about 1564 ± 566

Cí. LA (ng / hr / ml) to about 2826 ± 316 (ng / hr) at doses of 900 mg to 1500 mg, by comparison, ) In an administered plasma dose of 900 mg to 1500 mg of the ganaxolone formulation described in the present application are at least 50% higher than the AUC (o-) values in blood plasma exhibited by a conventional formulation of Ganaxolone administered fasted, in the same dose and under the same conditions.

Vllb. Proportions of Ghanaxolone Reduced in

Blood plasma

The ganaxolone formulations described in the present application may exhibit reduced levels of gmaxolone Cmax / Cmin in stable plasma blood compared to conventional formulations of ganaxolone given at the same dose and under the same conditions. For example, Monaghan et al. Has previously reported that conventional formulations of ganaxolone exhibit pharmacokinetic profiles such that multiple doses of conventional formulations of ganaxolone administered over 14 days result in gamaxolone Cmax / Cmin ratios in blood plasma of 13.8 (50 mg), 4.4 (200 Mg) and 6.7 (500 mg). In some embodiments of the invention, the proportions of the gmaxolone formulations Cmax / Cmin in blood plasma described in the present application, Are less than 4 in steady state. In one embodiment, the ganaxolone formulations described in the present application provide ratios of gmaxolone Cmax / Cmin in blood plasma from about 1.5 to about 3.5 steady state. In another embodiment, the ganaxolone formulations described in the present application provide proportions of gmaxolone Cmax / Cmin in blood plasma of about 2.5 steady state. In some embodiments, transdermal formulations of ganaxolone provide proportions of gmaxolone Cmax / Cmin in blood plasma of less than 1.5 steady state. The ganaxolone formulations described in the present application provide proportions of gmaxolone Cmax / Cmin in blood plasma of about 2.5 steady state. In some embodiments, transdermal formulations of ganaxolone provide proportions of gmaxolone Cmax / Cmin in blood plasma of less than 1.5 steady state. The ganaxolone formulations described in the present application provide proportions of gmaxolone Cmax / Cmin in blood plasma of about 2.5 steady state. In some embodiments, transdermal formulations of ganaxolone provide proportions of gmaxolone Cmax / Cmin in blood plasma of less than 1.5 steady state.

Vilo. Controlled Exposure Profiles

In certain embodiments, about 40% of the ganaxolone is released from the dosage form within about 3 hours, and about 95% of the ganaxolone is released from the dosage form within about 10 hours after administration . In yet another embodiment, about 30% of the ganaxolone is released from the dosage form within about 90% of the ganaxolone in a dosage form within about 10 Hours after administration. In yet another embodiment, about 80% of the ganaxolone is released from the dosage form within about 2 hours, And about 90% of the ganaxolone is released from the dosage form within about 10 hours after administration. VIId. Reduced Effects on Feeding / Fasting Associated with the Administration of Ghanaxolone

It is generally known in the prior art that if a positive effect is seen in the fed / fasted state with a pharmaceutical agent, it is usually related to the dose of the administered active agent, such that a lower dose of active agent Will have a lower AUC (increased) / AUC (fasting) ratio and a higher dose of active agent will have a higher AUC (fed) / AUC (fasted) ratio. In addition, it is known that dosage forms which substantially eliminate Effects of food in the therapeutic window (levels of efficacy vs. levels that give side effects) are safer than those dosage forms that do not. Therefore, the dosage forms which, Ι provide lower effects in fed / fasting conditions provide lower risks and reduce the potential for side effects, thus increasing the safety and compliance of the subject. Feeding / fasting conditions conform to FDA guidelines for exposure testing on fed and fasted drugs.

Conventional formulations of ganaxolone exhibit large effects on fed / fasted state, in a manner that is not only limited to dose dependence. The ganaxolone formulations described in the present application are less affected by the fed / fasted state of the subject to which the formulation is administered.

The systemic exposure of the ganaxolone formulations described in the present application is less sensitive to the type of food ingested than conventional formulations of ganaxolone. This means that there is a reduction in the difference of the ganaxolone AUC (oT) values when the ganaxolone formulations are administered in the fed versus fasted state at therapeutically effective doses. Thus, the present patent application discloses formulations of ganaxolone which can be used to reduce INSTITUTOI-XlC.WUγ. The effect of the pharmacokinetics of ganaxolone. In one embodiment, the formulation of ganaxolone is an aqueous dispersion which, when administered to a human less than two years of age, provides a ratio in the values of ganaxolone AUC (o-,

In another embodiment, the ganaxolone formulation is a solid oral dosage form which, when administered to a human greater than twelve years of age, provides a proportion in the ganaxolone AUC <o-τ values, when administered in the Fed versus fasting state, less than approximately. In another embodiment, the ganaxolone formulation is a solid oral dosage form which, when administered to a human greater than twelve years of age, provides a ratio in ganaxolone AUC (ox) values, when administered in the fed state Versus fasting, less than about 2. In yet another embodiment, the ganaxolone formulation is a solid oral dosage form which, when administered to a human greater than twelve years of age, provides a proportion in the

When the fed versus fasted state is administered, less than about 1.5 mg / kg ganoxolone AUCt3 is administered. In yet another embodiment, the ganaxolone formulation is a solid oral dosage form which, when administered to a human greater than twelve years of age, provides a ratio in the ganaxolone AUC-Î ± values, when administered in the Fed versus fasting state, ranging from about 3 to about 1. In another embodiment, the ganaxolone formulation is a solid oral dosage form which, when administered to a human greater than twelve years of age, provides a proportion in the Values of ganaxolone AUCto4), when administered in the fed versus fasting state, of about 2. VIII. Amount of Dose

The ganaxolone formulations described in the present application are administered and dosed according to good medical practice, taking into account the clinical condition of each patient, the site and manner of administration, the schedule of administration, and other factors well known to physicians . In human therapy, the dosage forms disclosed in this application release formulations of guanaulum which maintain a therapeutically effective amount of ganaxolone of at least 20 ng / ml or generally of at least 50 ng / Ml in steady-state plasma, while reducing the side effects associated with elevated Cmay ganaxolone level in blood plasma.

In various other embodiments of the present invention, the amount of ganaxolone administered to a subject through a solid dosage form to achieve a therapeutically effective concentration of ganaxolone is generally in the range of about 50 mg to about 800 mg, or about 300 mg to about 700 mg. In one embodiment, the ganaxolone formulation is administered in a solid dosage form in a concentration of about 250 mg to about 650 mg. In another embodiment, the ganaxolone formulation is administered in a solid dosage form in a concentration of from about 300 mg to about 400 mg. In another aspect, the solid oral dosage form may be administered twice a day (bid, for its acronym in English). In yet another aspect,

A therapeutically effective concentration of an oral aqueous suspension or dispersion comprising one of the formulations of ganaxolone described in the present application, administered according to the methods described, is usually in the range of about 20 mg / ml to about 150 mg / ml In the final concentration. In one embodiment, the ganaxolone formulation is administered in an aqueous oral suspension at a concentration of about 25 mg / ml to about 100 mg / ml at the final concentration.

In another embodiment, the ganaxolone formulation is administered in an aqueous oral suspension at a concentration of about 50 mg / ml at the final concentration. The aqueous oral suspension comprising a ganaxolone formulation described in the present application may be administered either in a single dose per day or on multiple occasions over a period of 24 hours. In one aspect, the oral suspension 1 ' Γ. . • Aqueous water may be given three times a day (tid). In another aspect, the aqueous oral suspension may be administered twice a day (bid).

The compositions contemplated in the present invention provide a therapeutically effective amount of ganaxolone over a range of about 30 minutes to about 8 hours after administration, allowing, for example, twice daily administration Daily, three times a day, and so on, if desired.

In other embodiments, more than about 95%, or more than about 90%, or more than about 80%, or more than about 70% of ganaxolone dosed by weight, is absorbed into the bloodstream within 8 hours after Of the administration.

In other embodiments, the pharmaceutical formulations provide a release profile for an immediate release dosage form of ganaxolone, which, by the methods described in Example 29, releases about 80% (or about 70%, or about 90%) of Of ganaxolone from the dosage form within 1 hour in SGF, and for a delayed release ganaxolone dosage form, releases approximately 60% (or preferably 70%, or 80%) of the composition in a plate For about 3 hours in SIF. IX. Methods of Making Ghanaxolone Formulations Comprising Submicron Particles

The ganaxolone formulations described in the present application may comprise ganaxolone particles having a D 50 of less than about 500 nm. The initial ganaxolone composition may be predominantly crystalline, predominantly amorphous, or a mixture thereof. These ganaxolone particles may be made using any method known in the art to achieve a particle size of less than 500 nm including, for example, grinding, homogenization, supercritical fluid fracture or precipitation techniques. Some examples of methods are described in U.S. Patents Nos. 4,540,602 and 5,145,684, which have been specifically incorporated by reference.

Methods for making compositions comprising nanoparticles are also disclosed in U.S. Patents 5,518,187; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; 5,510,118; 5,470,583 and the patent application of the

U.S.A. No. 2004/0067251, which are incorporated herein by reference in their entirety, are incorporated by reference herein. A. Milling for Obtaining Ghassaxolone Dispersions comprising Submicron Particles

The milling process can be a dry process, for example a dry roller milling process or a wet milling process, i.e., wet milling. In some embodiments, this invention is practiced in accordance with the wet milling process disclosed in U.S. Patent Nos. 4,540,602, 5,145,684, 6,976,647 and European Patent No. 498,482, which have been specifically incorporated by reference. Thus, the wet milling process can be practiced in conjunction with a liquid dispersion medium and dispersing agents or wetting agents, as described in said publications. Useful liquid dispersion media include water, safflower oil, aqueous salt solutions, ethanol, n-butanol, hexane, glycol, and the like.

The grinding media for the particle size reduction step may be selected from rigid, preferably spherical or particulate, for example beads. However, it is expected that other grinding media having no spherical shape will be useful in the practice of the present invention.

The grinding media preferably has an average particle size of about 500 microns. In other embodiments of the present invention, the particles of the milling media have an average particle size, preferably less than about 500 microns, less than about 100 microns, less than about 75 microns, less than about 50 microns, less than about 25 microns, less than about 5 microns, less than about 3 mm, less than about 2 mm, less than about 1 mm, less than about 0.25 mm, less than about 0.05 mm. For fine grinding, the particles of the grinding medium are preferably of a size of about 0.05 mm to about 0.6 mm, more preferably, about 0.1 mm to about 0.4 mm.

In the selection of material, high density milling media, for example, glass (2.6 g / cm 3), zirconium silicate (3.7 g / cm 3) and zirconium oxide (5.4 g / cm 3) are preferred for further milling efficient. Zirconium oxide grinding media such as magnesia-stabilized 95% zirconium oxide, zirconium silicate and glass provide particles with levels of contamination which are believed to be acceptable for the preparation of diagnostic or therapeutic compounds. However, other media, such as yttrium-stabilized stainless steel, titania, agate, glass, alumina and 95% zirconium oxide, are also believed to be useful. Polymeric media normally having a density of from about 1 g / cm 3 to about 2 g / cm 3 are also expected to be useful.

If polymeric grinding media are used, they may include particles consisting essentially of polymeric resin. Alternatively, the milling means may include particles having a core with a coating of the polymer resin thereon. The polymer resin will preferably have a density of 0.8 g / cm @ 3 at 3.0 g / cm @ 3. Higher density resins are preferred insofar as they are believed to provide a more efficient particle size reduction. In general, the polymer resins suitable for use described in the present application are chemically and physically inert, substantially free of metals, solvents and monomers, and of sufficient hardness and friability, which enables them to avoid chipping or crushing during grinding. Suitable polymer resins include, But are not limited to, crosslinked polystyrenes such as divinylbenzene crosslinked polystyrenes, styrene copolymers, polycarbonates, polyacetals such as Delrin ™, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly (tetrafluoroethylenes), for example, Teflon ™ And other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethylacrylate, silicone containing polymers such as polysiloxanes and other similar resins. The polymeric polymers may be biodegradable. Some examples of biodegradable polymer polymers include poly (lactide), poly (glycolide), lactide and glycolide copolymers, polyanhydrides, poly (hydroxyethyl methacylate), poly (imino)

The core material may preferably be selected from materials known to be useful as grinding media when fabricated as spheres or particles. Suitable core materials include, but are not limited to, zirconium oxides (such as yttrium or magnesia stabilized 95% zirconium oxide), zirconium silicate, glass, stainless steel, titania, alumina, ferrite and other compounds Similar. Preferred base materials have a density greater than about 2.5 g / cm 3.

It is believed that the selection of high density core materials helps to facilitate particle size reduction.

It is believed that the useful thicknesses of the polymeric polymer layer in the core range from 1 to 500 microns, although other thicknesses outside this range may be useful in some applications. The thickness of the layer a and preferably will be less than the diameter of the core. ______________

The cores can be coated with the polymer resin by techniques well known in the art. Some suitable techniques are spray coating, fluidized bed coating and melt coating. Layers that promote adhesion or drawability can also be provided to improve cohesion between the core and the coating resin. Adherence of the polymer coating the core material can be improved by treating the core material with adhesion promoting processes, such as core surface hardening, corona discharge treatments and the like.

In some embodiments, the ganaxolone may be prepared having a micrometric particle size, for example of at least about 500 nm. In some embodiments, the particles may be prepared with an effective particle size by weight of less than about 400 nm. In some embodiments, particles having an effective particle size by weight of less than 300 nm can be prepared in accordance with the present invention. J j ί.1Λ; <- »---

In other embodiments, particles having an effective particle size by weight of less than 200 nm and about 100 nm can be prepared in accordance with the present invention.

The grinding can be carried out in any suitable mill. Some of the suitable mills include the air jet mill, roller mill, ball mill, wear mill, vibratory mill, planetary mill, sand mill and bead mill. A high power media mill is preferred when small particles are desired. The mill may have a rotary shaft.

Preferred ratios of grinding media, ganaxolone, optional dispersion liquid medium and dispersing agents, wetting agents or other particulate stabilizing agents present in the grinding chamber may vary within wide limits and depend, for example, The size and density of the grinding medium, the type of mill selected, the milling time, among others. The process can be carried out continuously, batch or half-life. In high power media mills, it may be desirable to fill from 80% to 95% of the volume of the grinding chamber with milling means. On the other hand, in roller mills, it is often desirable to leave the milling chamber filled with air, the remaining volume compo- nating with the modulus, And the liquid dispersion medium, if present. This allows a cascade effect inside the grinding chamber and on the rollers, which allows efficient grinding. However, when foaming is a problem during wet milling, the grinding chamber may be completely filled with the dispersing liquid medium or an antifoaming agent may be added to the dispersing liquid medium.

The wear time can vary widely and depends in the first instance on the drug or agent, the mechanical means and the selected residence conditions, the desired initial and final particle size, among others. In the case of roller mills, it may be necessary to use processing times from several days to several weeks. On the other hand, residence times during milling of less than about 2 hours are generally required when using high power media mills.

After completion of the wear, the milling media is separated from the product of milled ganaxolone particles (either in dry or liquid dispersion form), using conventional separation techniques, such as

INS lüvlv V. · ^. For example, by filtration, sieving through a similar apparatus. ~

In one aspect of the present invention, the grinding media involves beads having a size ranging from about 0.05 mm to 4 mm, preferably 0.1 mm to 0.4 mm. For example, high power grinding of ganaxolone with 0.4 mm beads stabilized yttrium zirconia for a grinding residence time of 25 minutes to 1.5 hours in recirculation mode at 2500 rpm. Another example is the high power grinding of ganaxolone with zirconium oxide beads of 0.1 mm during a residence time of grinding of 2 hours in batch mode. In addition, the grinding temperature should not exceed 50 ° C, since the viscosity of the suspension could change drastically. High temperatures can also result in the precipitation of certain polymers in the grinding mix and increase wear on the mill seals. If the molten suspension supplies exceed the volume of the empty grinding chamber, this process will require the recycling of the materials to a cooled holding tank and re-grinding the material until the desired particle size (D50) is achieved and The suitable properties are achieved in a continuous mode and the mill is also coated with a cooled jacket. In another aspect, the mill may have a cover or hood to control the internal temperature both in the continuous mode and in the batch mode.

The grinding medium is defined as the weight of the mixture being ground, minus the weight of the drug in the mixture. In one embodiment, the concentration is 25% ganaxolone by weight vs. the grinding medium (by weight). In one embodiment, the milling medium contains at least one viscosity adjusting agent so that the desired particles are uniformly suspended, and a wetting and / or dispersing agent may be applied to cover the initial suspension of ganaxolone so that A uniform feed rate is applied in the continuous milling mode. In another embodiment, the batch mode is used with a milling medium containing at least one viscosity adjusting agent and / or to provide a wetting effect so that the ganaxolone is well dispersed between the grinding medium.

For. Grinding to obtain stable particles

A concern in the preparation of any suspension of small particles is the stability of the milled particles. The milled particles, after a period of time (for example, four weeks) after milling, may tend to agglomerate and generate an increase in particle size compared to the size of the particles immediately after milling . When creating small particle formulations (<500 nm) most compositions never stabilize and continue to grow until they have large particles (1 to 30 microns). The proportion at which these particles grow depends on the composition and residence time of the mill. The state of the art around the production of small particle compositions of organic molecules has been focused on various methods and compositions to eliminate the growth or aggregation of the particles. An unanticipated and novel concept discussed in the present patent application is to add complexing agents to initially provide rapid particle size growth over a period of curing time, which then becomes a very stable formulation of small molecules. This growth in particle size is observed particularly at the beginning, after the addition of sodium methoxide with or without propylparaben or benzylic acid. A non-preservative complexing agent is methylanthranilate.

The final stable particle size, measured as volume-weighted average (D50), depends on the concentration of the complexing agents and / or residence time during milling. When the concentration of complexing agents is maintained constant, the growth after grinding of the particles correlates closely with the residence time. Therefore, some aspects of the present invention are directed to the unexpected observation that the residence time at which the particles of the active agent (eg the ganaxolone particles) are subjected during the grinding process, impacts the variability Of particle size growth after grinding.

The residence time during grinding is defined by the following equation:

Milling residence time = (empty volume of the milling chamber / volume of the milling mix) X milling time (Equation 1).

When grinding under recirculation conditions (by passing several times through a mill by creating a circuit between the grinding mixture of a container and the mill) the reported residence times are obtained using flow rates ranging from 1/4 of the volume Empty calculated / minute to 3 times (3x) the empty volume of the calculated chamber / minute. The ideal is to use flow rates of 0.5X empty volume from the camera per minute to 1.5x empty volume per minute.

As shown in the examples, it has been observed that after obtaining the desired particle size, continuing the grinding does not significantly reduce particle size, but produces particles with more stable growth compared to lower residence times of grinding. The size of

. Eur-lex.europa.eu eur-lex.europa.eu The particle of the ganaxolone complexes can be controlled with the amount of complexing agents or by re-grinding the stable particles after curing. See Example 45, which shows that re-grinding stabilizes the particle size of the ganaxolone complexes. One factor that may contribute to the growth of particle size is the association of a complexing agent with a ganaxolone particle. It is also possible that this complex may also be associated with other excipient particles, for example, with a viscosity improving agent or a wetting agent. These complexes, which are initially reversible under sonication, harden after a time to become larger and more permanent particles. (See FIGURE 1). Curing time is the time required to harden the complex and to become a stable particle. The effect of residence time during grinding can affect growth variability because prolonged grinding produces more particles with softer surfaces that have less contact surface and are less likely to aggregate. As shown below, stable suspensions of ganaxolone containing particles with a D50 of 100 nm at 350 nm can be obtained by grinding a mixture for less time and agitation. Complexing agent, or grinding the mixture at higher rates for longer periods of time. The effect of residence time during grinding can affect growth variability because prolonged grinding produces more particles with softer surfaces having less contact surface and less likely to aggregate. As shown below, stable suspensions of ganaxolone containing particles with a D50 of 100 nm at 350 nm can be obtained by grinding a mixture for less time and agitation. Complexing agent, or grinding the mixture at higher rates for longer periods of time. The effect of residence time during grinding can affect growth variability because prolonged grinding produces more particles with softer surfaces having less contact surface and less likely to aggregate. As shown below, stable suspensions of ganaxolone containing particles with a D50 of 100 nm at 350 nm can be obtained by grinding a mixture for less time and agitation. Complexing agent, or grinding the mixture at higher rates for longer periods of time. Stable suspensions of ganaxolone containing particles with a D50 of 100 nm at 350 nm can be obtained by grinding a mixture for less time and agitation. Complexing agent, or grinding the mixture at higher rates for longer periods of time. Stable suspensions of ganaxolone containing particles with a D50 of 100 nm at 350 nm can be obtained by grinding a mixture for less time and agitation. Complexing agent, or grinding the mixture at higher rates for longer periods of time.

With the understanding that grinding residence time has a significant impact on the stability of ganaxolone, further grinding experiments were performed. The objectives of the additional milling experiments were (a) to prepare ganaxolone formulations comprising particles having a particle size range including particles with a volume-weighted D50 of less than 500 nm; (B) preparing ganaxolone formulations comprising particles having a D50 of less than 500 nm containing at least one complexing agent; (C) preparing ganaxolone formulations comprising particles (a) and (b) exhibiting minimal particle size growth in simulated gastric and intestinal fluid at a temperature of from 36 ° C to 38 ° C; (D) preparing ganaxolone formulations comprising particles of (a) to (c) which are flavored with artificial sweeteners sweetened with a sweetener, preserved to pass antimicrobial efficacy tests and other ingredients to improve palatability. The results of these experiments are presented in the Examples section. F.NLJUi: OAl, "**« -.

Based on this unexpected observation, certain embodiments of the present invention provide pharmaceutical particles comprising ganaxolone which exhibit a time-stable growth profile, i.e. the particles provide a proportion of D50 four weeks after grinding or 4 weeks after Period of cure, if a complexing agent is added to D50 at the end of milling of 1.5: 1 or less. The novel nature of the addition of a complexing agent of small molecules is seen in some embodiments in which the mode of particle size (the most population particle size) can be reproducibly increased by about two times in 5 To 7 days. After this period, the particle size and mode of the particles remain stable for many months.

Certain embodiments of the present invention also provide a method for stabilizing the growth of pharmaceutical particles comprising grinding an active agent (including, but not limited to, ganaxolone); For a time sufficient for the particles to provide a ratio of D50 four weeks after grinding to D50 at the end of grinding, of 1.5: 1 or less.

In other embodiments, the particles have a D50 ratio four months after curing or after a long grind residence time of about 1.25: 1 or less; Or 1.15: 1 or less. In order for the milled ganaxolone particles of the present invention to provide a stable growth profile with ganaxolone particles in the range of 100 nm to 350 nm (D50), the particles have a preferable grinding residence time of at least 40 Minutes if a complexing agent is added, at least 100 minutes, or at least 120 minutes without complexing agent. However, these times are not intended to be restrictive. The residence time required to obtain a stable growth formulation may be determined by one skilled in the art,

The particles resulting from the milling process disclosed herein may have a D 50 of less than 500 nm, less than 400 nm, less than 300 nm, less than 200 nm or less than 100 nm. The resulting particles may also have a D90 of less than 1 mer, less than 500 nm, less than 400 nm, less than 300 nm or less than 200 nm.

For the case of the particulate compositions disclosed herein, the particles may optionally include, a complexing agent, as disclosed in the present patent application. The complexing agent may be a preservative such as methylparaben, propylparaben, benzoic acid / sodium benzoate, a phenolic compound, an organic acid, an organic acid salt, an inorganic acid, an inorganic salt, or a combination thereof.

The process used to obtain the stable particles may be any known to one skilled in the art for the production of small particles, for example the processes described in section IXA of the present patent application.

The final product of the milling processes for obtaining growth particles may be particles of active agent suspended in a dispersing agent (i.e., a suspension).

Xb. Complexing Agents as Particle Growth Stabilizers

It was found that the addition of a complexing agent during or preferably after milling improves the physical stability of the formulations of ganaxolone particles (for example, the 5- Liquid suspension). - = -

It is believed that the improvement in physical stability is the result of complex formation of ganaxolone particles with complexing agents that cause an increase in the particle size of ganaxolone. Without being supported by the theory, it is hypothesized that the increase in the particle size of ganaxolone in formulations containing complexing agents is achieved through a process of complexing of particles. For example, complexing agents may act as aggregation or agglutination agents for the ganaxolone particles to adhere together to form aggregates of ganaxolone associated with the complexing agent and possibly with other ingredients in the suspension. These aggregates are relatively weak during the early stages (the first 2 to 3 days) of complex formation, eg in the case of methylparaben, methylparaben and propylparaben, or paraben and benzoic acid / sodium benzoate. This becomes evident since the sonication of the formulation at this stage may reduce the size of the particles of the complex, apparently due to the loose and / or lax nature of the newly formed complexes. Over a period of time, the aggregates are hardened, or the particle size of the aggregates is not reduced by sonication. At this point, the curing process is complete. Of complex formation is illustrated in FIGURE 1. Or parabens and benzoic acid / sodium benzoate. This becomes evident since the sonication of the formulation at this stage may reduce the size of the particles of the complex, apparently due to the loose and / or lax nature of the newly formed complexes. Over a period of time, the aggregates are hardened, or the particle size of the aggregates is not reduced by sonication. At this point, the curing process is complete. Of complex formation is illustrated in FIGURE 1. Or parabens and benzoic acid / sodium benzoate. This becomes evident since the sonication of the formulation at this stage may reduce the size of the particles of the complex, apparently due to the loose and / or lax nature of the newly formed complexes. Over a period of time, the aggregates are hardened, or the particle size of the aggregates is not reduced by sonication. At this point, the curing process is complete. Of complex formation is illustrated in FIGURE 1.

Different complexing agents affect the formation of complexes differently. For example, ganaxolone complexes with methylparaben typically require 5 to 7 days to cure, whereas the addition of sodium benzoate and / or benzoic acid to ganaxolone, require much longer (up to 3 weeks) to cure, as illustrated In FIGURE 2. FIGURE 2 shows particle size growth schemes of methylparaben and propylparaben and sodium benzoate (adjusted to pH 4.0) with ganaxolone particles from 100 nm to 200 nm. Both formulations contain 5% ganaxolone, 5% HPMC, 1% PVA, 0.1% to 0.2% SLS. The paraben formulation contains 0.1% methylparaben, 0.02% propylparaben and 0.1% simethicone, while the sodium benzoate formulation contains 0.17% sodium benzoate, 0.13% citric acid and 0.1% sodium benzoate. 01% sodium citrate (pH 4.0). It has recently been discovered that the addition of methyl anthranilate can form a complex which does not change after sonication after 1 day. In the case of the methyl anthranilate, about 40% by weight. CfSV- "was added to a non-complex suspension of ganaxolone at 180 nm and a D50 of 390 nm was observed after 72 hours.The percentages of the liquid formulations are given in% w / w (% w / Total weight of the formulation). Was added to a non-complex suspension of? Ganaxolone phosphates at 180 nm and a D50 of 390 nm was observed after 72 hours. The percentages of the liquid formulations are given in% by weight / weight (% by weight / total weight of the formulation). Was added to a non-complex suspension of? Ganaxolone phosphates at 180 nm and a D50 of 390 nm was observed after 72 hours. The percentages of the liquid formulations are given in% by weight / weight (% by weight / total weight of the formulation).

The cured ganaxolone particles appear to have much better physical stability than the ganaxolone particles which do not contain the complexing agent. Once the ganaxolone particle complexes are formed, no further substantial increase in the particle size of ganaxolone is observed.

The ganaxolone particles that were milled for less than 2 hours of milling residence time and did not contain complexing agents continued to increase in size gradually over several months (FIGURE 3).

The concentration of the complexing agents also affect the curing process of the complex. At higher concentrations larger particles are produced and faster healing. For example, two formulations with identical ganaxolone particles (140 nm D50) with 0.1% and 0.2% methylparaben had D50 values of 190 and 300 nm, respectively, after 5 to 7 days. JN DU5TPÍA-

The particle size range (in addition to grinding residence time) prior to contact with the particle growth stabilizer also affects the curing process of the aggregates. In some embodiments, the ganaxolone particles of about 140 nm grew to about 300 nm after curing. On the other hand, the ganaxolone particles of about 300 nm only grew to about 350 nm after curing.

In some embodiments, the complexing agent may be a preservative. The complexing agent is selected from the group consisting of organic acids, carboxylic acids, acid salts of amino acids, sodium metabisulfite, ascorbic acid and its derivatives, mellic acid, isoascorbic acid, citric acid, tartaric acid, sodium sulfite, Sodium bisulfate, tocopherol, water and fat soluble tocopherol derivatives, sulfites, bisulfites and hydrogen sulfites, anthranilic acid and esters thereof, para-aminobenzoic acid and its esters, 2,6-di-t-butyl-alpha Dimethylamino-p-cresol, t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), methylparaben ethylparaben, propylparaben, as well as salts of parabens, pyrocatechol, pyro Propyl / gallate,

Parabens are esters of para-hydroxybenzoic acid. Parabens which may be used in the present invention include methylparaben, ethylparaben, propylparaben and butylparaben. Other parabens which may be used in the present invention include isobutylparaben, isopropylparaben, and benzylparaben. Pharmaceutically acceptable salts, for example, sodium and potassium salts, may also be used in the present invention. Particularly preferred parabens for use in the present invention include methylparaben, propylparaben and their sodium salts. If the sodium salts of the parabens are used an equimolar amount of an organic acid, eg citric acid, should be added.

Further proof that methyl and propyl paraben are acting as complexing agents is that in the preferred embodiments in which 25% by weight of ganaxolone contains from 0.1% to 0.3% sodium lauryl sulfate and from 2% To 5% by weight of HPMC (Pharmacoat 603-) 73Âμm with a residence time of 35 to 40ÂμlULU and with a particle size range of D50 of 120 nm to 170 nm and 0.1% of methylparaben and 0.02% Of propylparaben, the mode of particle size (the particle size range with the largest population) approximately doubles, the composition becomes visibly thick and it is not possible to filter it through a 5 μπ filter or with smaller filters, and then From 5 to 10 days the particles stop growing and stable particles are achieved. As will be shown below, The particles that already form these complexes (complexed particles) and that are cured, present different desirable attributes that the non-complexed formulations do not have. Further evidence of the role of methylparaben and propylparaben in the formation of ganaxolone particle complexes is that when doing antimicrobial efficacy studies under USP conditions a typical preservative effect is shown during the first 7 to 14 days, which is then lost And microbial growth is again triggered, as there is little methylparaben and free propylparaben available to act as a preservative. In fact, preferred oral suspensions of ganaxolone use two or three> v. Air,

The complexing agent may be present in any suitable amount, for example, from about 0.001% to about 5%, from 0.01% to about 2.5%, from about 0.015% to about 1%, from about 0.1% to about 0.5% From about 0.02% to about 0.1%, based on the weight of the milling blend.

Some embodiments of the invention are directed to the initial growth of the particles due to the association of the ganaxolone particles and the complexing agent. These embodiments are directed to pharmaceutical particles comprising ganaxolone associated with a complexing agent, wherein the particles exhibit a proportion of D50 after incubation in SGF or SIF at a temperature of 36 ° C to 38 ° C for 1 to 3 hours at D50 before incubation in SGF or SIF of less than about 3: 1; Less than about 2.7: 1, less than about 2.5: 1, less than about 2: 1, or less than about 1.5: 1. In some embodiments, the present invention is directed to pharmaceutical particles comprising ganaxolone particles aggregated with a complexing agent, Wherein the particles exhibit a proportion of D50 after incubation for 1 to 3 hours at the D50 before incubation of approximately 1.5: 1 and 3: 1; From about 1.8: 1 to about 2.7: 1, or from about 2: 1 to about 1.5: 1.

Some embodiments of the invention are directed to the "uncured" ganaxolone complexes, which are not as tightly bound as evidenced by the reduction of particle size by sonication. These embodiments are directed to pharmaceutical particles comprising ganaxolone added with a particle growth stabilizer, wherein the particles exhibit a proportion of D50 after incubation in SGF or SIF for 1 hour at 37 ° C and sonication for 1 minute To D50 before incubation of less than 2: 1; Less than about 1.7: 1, less than about 1.5: 1, less than about 1.4: 1. Other embodiments exhibit a ratio of D50 after incubation in SGF or SIF for 1 hour and sonication for 1 minute to D50 before storage of about 1: 2 and 2: 1;

OF FROPITTY

Certain embodiments of the invention are directed to the "cured" ganaxolone complexes exhibiting stable particle size. These embodiments are directed to pharmaceutical particles comprising ganaxolone complexed with a complexing agent, wherein the particles Are cured for a sufficient time until an endpoint is reached such that the D50 does not change by more than about 5% when measured after 3 days after curing.

In other embodiments, the particles are cured for a sufficient time until an endpoint is reached such that the D 50 does not change by more than about 12%, by more than about 10%, by more than about 8%, or by More than about 5% after 1 month to the healing period.

In other embodiments, the particles are cured for a sufficient time until an endpoint is reached such that the D50 does not change by more than about 5%, (on instrument variability in particle size measurement) after 20 days of cure, 40 days after curing, 60 days after curing, or 80 days after curing under storage conditions of approximately 5 ° C to 25 ° C.

The end point needed to achieve stable particles can be determined by one skilled in the art. For example, the endpoint may be attained in from about 5 to about 25 days; About 5 to about 7 days, about 7 to about 14 days, about 14 to about 21 days or about 10 to about 15 days.

In certain embodiments, the particles have a D 50 before storage of less than 350 nm, less than 250 nm or less than 150 nm. In other embodiments the particles have a D50 before storage of from about 50 nm to about 350 nm, from about 75 nm to about 250 nm, or from about 100 nm to about 150 nm.

The formulation comprising the complexed ganaxolone particles may include complexes suspended in a dispersing agent (i.e., a suspension).

It was also found that the addition of a complexing agent in ganaxolone suspension formulations reduces the side effects of ganaxolone while achieving adequate exposure. Without being supported by the theory, it is believed that fewer side effects are achieved through a greater overall particle size distribution of the ganaxolone condom complexes, while "adequate exposure is achieved by means of a larger surface area Of the complex versus an individual particle of the same size.

In some embodiments, desirable formulations may be obtained by use of suitable amounts of a complexing agent, a hydrophilic polymer such as HPMC and / or PVA and other components in the ganaxolone suspension formulations to achieve an optimal balance between maximum bioavailability and minimum side effects. An example of a ganaxolone suspension formulation comprises about 5 wt% ganaxolone, about 5 wt% HPMC, about 0.1 wt% SLS, about 0.1 wt% methylparaben, about 0.02 wt% propylparaben, 0.09% sodium benzoate, 0.12% citric acid, 0.006% sodium citrate, 0.03% simethicone emulsion (30% in water) and about 1% by weight of PVA, based on the total weight of the formulation Of final suspension. Additional ingredients may be added as flavoring and sweetening agents at the appropriate levels to make these formulations more palatable. Another example of formulation comprises the same composition

The above, but with reduced levels of a ^ 2.5% and without PVA. "

It was found that ganaxolone suspensions comprising HPMC, SLS, methylparaben, propylparaben and PVA provide desirable pharmacokinetic results in animal studies. A composition without PVA gave greater exposure (twice), but also gave superior results in sedation in dogs. Whether PVA is convenient or not in humans depends on the relative therapeutic ratio.

Cured ganaxolone particle complexes are more convenient as these compositions will provide a more uniform result due to less change in particle size over time, better thermal stability and lower aggregation in the gastrointestinal tract.

As noted above, ganaxolone has very low aqueous solubility. One method for improving the bioavailability of ganaxolone is through the use of smaller ganaxolone particles (eg, less than 500 nm). However, increased bioavailability is also expected to cause an increase in side effects (eg, sedation). Cured formulations comprising complexes of ganaxolone having a suitable particle size (eg, from 200 nm to 350 nm) may minimize side effects, while maintaining adequate exposure. In the case of solid dosage forms of ganaxolone in which disintegration with other techniques and with drugs without sedative side effects can be controlled,

As will be shown below, once the curing period is complete, the material can be retreated to obtain smaller, stable particles, if desired.

It has also been found that formulations containing ganaxolone complexes reduce the variability in pharmacokinetic parameters between fed and fasted fed ganaxolone.

Example 18, below, shows the effect of the preservative on the ganaxolone particles in Cmax and AUC (0-T).

In view of the unexpected effect of methylparaben and propylparaben on the Cmax and AUC (oj) of the ganaxolone particles, the present invention is directed to pharmaceutical compositions, wherein the ratio of

Fasting Cmax provided by the compositions with ganaxolone complexes to the Cmax provided by the compositions without parabens complexes is less than about 1: 2; Is less than about 1.6, or is less than about 1: 1.4. In certain embodiments, the proportion of the fasting AUC (oj) provided by the compositions with an agent completing the AUC (or (j) provided by the compositions without a complexing agent is less than 1.4: 1; Less than about 1.3: 1; Or less to about 1.2: 1. In other embodiments, the ratio of Cmax in fed state provided by the stable composition with the Cmax complexing agent provided by the composition without the complexing agent is less than 1: 1.4; Less than about 1: 1.2; Or less to about 1: 1. The present invention is also directed to formulations containing stable compositions of ganaxolone with complexing agents wherein the proportion of the AUC (o-x) fed to the fasting AUC (oxy) providing the composition is about 1.5: 1 to about 5: 1, from about 2: 1 to about 4: 1; Or from about 2.5: 1 to about 3: 1. In other aspects, the ratio of Cmax to Cmax fed to the proposed CmaX by the composition is about 2: 1 to about 7: 1, from about 2.5: 1 to about 5: 1, Or from about 2.8: 1 to about 3.8: 1.

Xc._ Vinyl Polymers as Modifiers

Pharmacokinetics

The use of vinyl polymers (eg, polyvinyl alcohol (PVA)) during or after milling appears to have little effect on post-milling particle size under storage conditions at room temperature. However, the data suggest that vinyl polymers prevent the flocculation of ganaxolone particles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The reduction of flocculation of the ganaxolone particles in SGF and SIF is greater in the suspension formulations of ganaxolone containing vinyl polymers and complexing agents.

Once the healing period is over, the complexed ganaxolone particles are stable and no stabilization added by the PVA to suppress the agglomeration / flocculation is observed.

It was also found that the use of vinyle polymers reduces the exposure levels of ganaxolone and reduces the exposure to variability between the fed and fasted state. It was further discovered that the use of vinyl polymers in the ganaxolone formulations (for example, in the suspensions) reduces the ratio of Cmax to AUCjo (j). In Example 18, Table 7 some data showing the effect of vinyl polymers on the variability of exposure between the fed and fasted state and the ratio of Cmax to AUC-x), where PVA is exemplified, are given in Table 7.

The preferred vinyl polymer in the present invention is polyvinyl alcohol. The amount of vinyl polymer may be in an amount of from about 0.01% to about 5% based on the total weight of the particles, or it may be in an amount from about 0.1% to about 2% based on the total weight of the particles , Or from about 0.5% to about 1.5% based on the total weight of the liquid formulation.

In view of this unexpected effect of vinyl polymers on the pharmacokinetics of ganaxolone, certain embodiments of the present invention are directed to those pharmaceutical compositions having particles comprising the ganaxolone thereof And a vinyl polymer, the particles having a D 50 of less than about 500 nm. In certain embodiments, the particles have a D90 of less than about 500 nm.

The pharmaceutical compositions of the present invention containing ganaxolone and a vinyl polymer may have the proportion of the fasting Cmax provided by the composition having the vinyl polymer to C max provided by the composition without the vinyl polymer less than about 0.75: 1; Less than about 0.60: 1, or less to about 0.50: 1.

In certain embodiments, the proportion of the fasting Cmax provided by the composition having the vinyl polymer to the Cmax provided by the composition without the vinyl polymer is greater than about 0.20: 1; Greater than about 0.30: 1 or greater than about 0.40: 1.

In other embodiments, the ratio of fasting AUC <oT) provided by the composition having the vinyl polymer to the AUC (ox) provided by

• Composition without the vinyl polymer, is less than about 0.8: 1; Less than about 0.7: 1, or less to about 0.6: 1.

In certain embodiments, the proportion of the fed state Cmax provided by the composition having the vinyl polymer to the Cmax provided by the composition without the vinyl polymer is less than about 0.95: 1; Less than about 0.85: 1 or less to about 0.75: 1.

In other embodiments, the proportion of the fed state Cmax provided by the composition having the vinyl polymer to the Cmax provided by the composition without the vinyl polymer is greater than about 0.2: 1; Greater than about 0.3: 1 or greater than about 0.4: 1.

In other embodiments, the proportion of the fed state AUC (0-T) provided by the composition having the vinyl polymer to the AUC (ox) provided by the composition without the vinyl polymer is less than about 0.9: 1; To about 0.8: 1 or less to about 0.7: 1.

In some embodiments, the ratio of the fed state to the fasting AUC (oX) provided by the PVA composition is from about 1: 1 to about 5: 1, from about 1.5: 1 to about 4: 1, or from about 2: 1 to about 3: 1.

In other embodiments, the ratio of Cmax in fed state to the fasted Cmax provided by the PVA composition is from about 1.5: 1 to about 2.5: 1, from about 1.6: 1 to about 2.4: 1, or from about 1.8: 1 To about 2.2: 1.

The use of vinyl polymers with ganaxolone also causes a reduction in the flocculation of the particles. In some embodiments containing vinyl polymers, the D50 does not increase by more than about 25%, by no more than about 20%, or by no more than about 15% after 3 hours in SGF. In other embodiments, the D50 does not increase by more than about 25%, by no more than about 20%, or by no more than about 15% after 3 hours in SIF.

INDUSTJUAL

In embodiments containing ganaxolone and a vinyl polymer, ganaxolone may be complexed with ingredients such as parabens, organic acids, salts of organic acids, aromatic and aromatic asters, inorganic acids, inorganic salts, pharmaceutically acceptable salts or a combination of the same.

In certain embodiments containing vinyl polymers and at least one complexing agent, the D50 does not increase by more than 15%, by no more than about 12%, or by no more than about 8% after 1 hour in SGF. In other embodiments, the D50 does not increase by more than 15%, by no more than about 10%, or by no more than about 8% after 1 hour in SIF.

A pharmaceutical composition comprising particles comprising ganaxolone, the particles have a D50 of less than 500 nm, the composition provides a fasting AUC (oT) fed to AUC <oT) ratio in Beagle dogs of approximately 1: 1 To about 2.5: 1, from about 1.2: 1 to about 1.9: 1 or from about 1.4: 1 to about 1.8: 1.

While examples of certain formulations providing particular pharmacokinetic parameters have been shown, certain embodiments of DE LA FRL: The present invention is directed to the ganoxolone formulations which provide particular pharmacological profiles irrespective of the excipients used in the formulation. The profiles include (i) a portion of Cmax in the fed state at fasting C max, of about 1.5: 1 to 4: 1; Of about 1.6: 1 to about 3: 1; Or from about 1.8: 1 to about 2.5: 1; (Ii) an AUC <-24) of about 100 to about 375 ng * h / ml or about 150 to about 325 ng * h / ml for a dose of 200 mg to 500 mg of ganaxolone administered to an adult human in Fasting; (Iii) a CME from about 25 to about 85 ng / ml following administration of a 200 mg to 500 mg dose of ganaxolone to a fasting adult subject, (iv) an AUC (o-24) hours of about 250 to Approximately 1200 ng * h / ml or from about 400 to about 1000 ng * h / ml for after a dose of 200 mg to 500 mg of ganaxolone was administered to an adult subject in the fed state, and (v) a Cmax of about 60 To about 350 ng / ml or from about 80 to about 275 ng / ml after a dose of about 200 mg to about 500 mg of ganaxolone to a fed subject adult. ΒFVDL? GT / JAL? (Iv) an AUC (o-24) hours of about 250 to about 1200 ng * h / ml or from about 400 to about 1000 ng * h / ml following a dose of 200 mg to 500 mg of ganaxolone to a (V) a Cmax of about 60 to about 350 ng / ml or about 80 to about 275 ng / ml after a dose of about 200 mg to about 500 mg of ganaxolone to an adult subject In the fed state. ΒFVDL? GT / JAL? (Iv) an AUC (o-24) hours of about 250 to about 1200 ng * h / ml or from about 400 to about 1000 ng * h / ml following a dose of 200 mg to 500 mg of ganaxolone to a (V) a Cmax of about 60 to about 350 ng / ml or about 80 to about 275 ng / ml after a dose of about 200 mg to about 500 mg of ganaxolone to an adult subject In the fed state. ΒFVDL? GT / JAL? And (v) a Cmax of about 60 to about 350 ng / ml or about 80 to about 275 ng / ml after a dose of about 200 mg to about 500 mg of ganaxolone to a fed subject adult. ΒFVDL? GT / JAL? And (v) a Cmax of about 60 to about 350 ng / ml or about 80 to about 275 ng / ml after a dose of about 200 mg to about 500 mg of ganaxolone to a fed subject adult. ΒFVDL? GT / JAL?

Xla. Milling with Simethicone as an Anti-Foaming Agent

Foaming during nano-sizing of the pharmaceutical products may present problems in the formulation and may have negative consequences for the reduction of particle size. For example, having high foam levels or air bubbles in grinding can cause a drastic increase in viscosity, making the grinding process impossible. Even a very low level of air presence can greatly reduce the efficiency of grinding, so that the desired particle size can not be achieved. This may be due to the air in the mill damping the milling beads, thus reducing their effectiveness. Air can also form a microemulsion with ground ingredients,

Simethicone is well known as antifoaming agent. However, simethicone is not soluble in water and, therefore, is expected to interfere with the determination of particle size by the laser / light scattering method. Therefore, simethicone would not be expected to be an adequate defoamer to be Γ-. - V.7 * used in the reduction of the particles of the pharmaceutical agents. 1

Regardless of this expectation, the present invention is directed to the observation that simethicone is suitable for use as an antifoaming agent in reducing the particle size of pharmaceuticals as it does not interfere with the measurement of the particles.

This may be because simethicone is transparent to tungsten light and laser.

Simethicone may be added to the milling process, for example, in a 30% emulsion sold by Dow Corning (Dow Corning 7-9245 or Dow Corning Q7-2587), however, any suitable percentage of simethicone may be used, in any Formulation.

The amount of 30% simethicone emulsion used in the particle reduction processes of the present invention may be any suitable amount, eg 500 ppm or less, or 350 ppm or less, 100 ppm or less, to eliminate or eliminate Substantially the foam in the grinding mixture of ganaxolone, facilitating the exclusion of air from the mill.

One skilled in the art would be able to determine the amount of simethicone from simethicone formulations with varying percentages.

In view of the observation that simethicone, Certain anti-foaming agents suitable for use in particle reduction, certain embodiments of the present invention are directed to a method of milling pharmaceuticals comprising the incorporation of a pharmaceutically active agent, a suitable amount of simethicone, beads Grinding and optional pharmaceutically acceptable excipients in a mill; And grinding the mixture for a suitable time to obtain the nano-sized particles. In the preferred embodiments, the active agent is ganaxolone. Optional pharmaceutically acceptable excipients may be any of the excipients used in the preparation of small particles, as disclosed in the present application.

The simethicone may be added in its pure liquid form (100%) or may be mixed with a suitable carrier prior to incorporation into the milling process of the present invention. For example, simethicone may be added in the form of a diluted liquid including, but not limited to, a solution or an emulsion or a suspension. The concentration of simethicone in the liquid may be from about 1% to about 99%; From about 20% to about 80% or from about 20% to about 50%.

Preferably, the simethicone is in an emulsion

The amount of simethicone present in the milling blend may be any suitable amount which provides the benefits described above. The amount used with good results ranges from 50 to 300 ppm.

In some embodiments, the recovered ganaxolone particles contain a number of traces of simethicone in the final product. The final product comprising ganaxolone particles which may comprise from about 0.001% to about 0.1% simethicone, or from about 0.005% to about 0.05% simethicone, based on the total weight of the composition.

The final product of milling processes using simethicone may comprise active agent particles suspended in a dispersing agent (i.e., a suspension).

Xlb. Microprecipitation to Obtain Ghanaxolone Dispersions comprising Nanoparticles

The ganaxolone particles may also be prepared by homogenous nucleation and precipitation in the presence of a wetting or dispersing agent, as described in US Pat. Nos. 5,560, 932 and 5,665,331, which have been incorporated herein by reference. These ganaxolone particles are stable and do not exhibit a perceptible increase in size over time. It is a method of preparing stable dispersions of ganaxolone in the presence of one or more dispersing or wetting agents and one or more surface active agents which improve the stability of the colloid. This method comprises, for example: (1) dispersing the ganaxolone in a suitable liquid medium; (2) adding the mixture of step (1) to a mixture comprising at least one dispersing agent or wetting agent such that,

The method may be followed by the removal of any salt which has been formed by dialysis or filtration and concentration of the dispersion by conventional means. In one embodiment, the ganaxolone particles are present in essentially pure form and are dispersed in a suitable liquid dispersion medium.

A preferred means of liquid dispersion is water. However, other liquid media may be used including, for example, aqueous salt solutions, eg. Ur. (Eg, safflower, olive or cream oil), solvents such as ethanol, t-butane, and the like. Aqueous dispersion may be adjusted by techniques well known in the art In this embodiment, the ganaxolone particles comprise a discrete phase after being mixed with a dispersing agent or wetting agent. Useful dispersing or wetting agents are determined Experimentally, but effectively minimize the difference in the lipophilicity of ganaxolone and the dispersion medium by inducing a non-covalent ordered complex between the medium, The wetting agent and ganaxolone. XIc. Homogenization to Obtain Nanoparticulate Ghanaxolone Dispersions

In yet another embodiment, the ganaxolone particles described in the present application are produced by high pressure homogenization (see generally U.S. Patent No. 5,510,118). This method involves the dispersion of ganaxolone particles in a liquid dispersion medium, and then subjecting the dispersion to repeated homogenizations to reduce the particle size of the ganaxolone to the desired average effective particle size.

The ganaxolone particles may be reduced in the presence of at least one dispersing agent or a wetting agent. Alternatively, the ganaxolone particles may be contacted with a dispersing agent or a wetting agent before or after wear. Other compounds, such as diluents, may be added to the ganaxolone / dispersing agent composition before, during or after the size reduction process. In one embodiment, unprocessed ganaxolone can be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of ganaxolone in the liquid medium may range from about 0.1% to 60% w / w and is preferably about 5% to 30% (w / w). It is preferable, but not essential, That the dispersing agents or the wetting agents are present in the premix. The concentration of the dispersing agents or wetting agents may range from about 0.1% to 90%, and preferably is from about 1% to 75%, and more preferably from about 20% to 60% by weight, based on the combined weight Total of ganaxolone and dispersing agents or wetting agents. The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise. The premix may then be transferred to the microfluidized polymer, which is then added to the microfluidizer. Continuously, first at low pressures and then ^ 'a' " The maximum capacity with a fluid pressure of about 3000 and 30000 psi until reduction to the desired particle size is achieved. The particles should be reduced in size to a temperature that does not significantly degrade the drug or does not cause significant particle size growth through solubilization. Then, one of two methods can be used to collect the mixture and re-pass it through the microfluidizer. The "discrete step" method collects each passage through the microfluidizer until all the mixture has been passed before being reintroduced back into the microfluidizer. This ensures that the whole substance or particle has "seen" the interaction chamber the same number of times.

The dispersing agents and / or the wetting agents, if not present in the premix, may be added to the dispersion after the wear, in the amount described above for the premix. Subsequently, the dispersion can be mixed, for example, by vigorously stirring. Optionally, the dispersion can be subjected to a step of the "S", for example, using an ultrasonic power source. For example, the dispersion may be subjected to ultrasonic energy at a frequency of about 20 to 80 kHz for a period of about 1 to 120 seconds.

The relative amount of ganaxolone and dispersing agents and / or wetting agents can vary widely. The dispersing agents and / or wetting agents are preferably present in an amount of from about 0.1 mg to 10 mg per square meter of ganaxolone surface area. The dispersing agents or wetting agents may be present in an amount of 0.1% to 90%, preferably 5% to 50% by weight, based on the total weight of the dried ganaxolone particles during particle size reduction.

The resulting ganaxolone dispersion is stable and consists of the liquid dispersion medium and particles described above. The dispersion of the ganaxolone particles can be spray coated onto sugar beads or beads or onto a pharmaceutical excipient in a fluidized bed with techniques well known in the art.

MEXICAN INSTITUTE> <-DE LA ΟΓΕΟΓ-ίΕΠΛΓ. ' W - '* INDUSTRIAL

Xld. Granulation in Fluidized Bed by Sprinkling to Obtain Amorphous Compositions of Ganaxolone

In yet another embodiment, the ganaxolone particles described in the present application are produced by spray drying or by spray drying in a fluidized bed. This method comprises spraying a mixture of ganaxolone and at least one solubility enhancer and / or a wetting agent and / or a viscosity improving agent and, optionally, a solvent crystallization inhibiting compound comprising one or More organic solvents or a mixture of water and one or more alcohols, under conditions that allow the solvent to be withdrawn from said mixture with sufficient speed in the case of the fluidized bed so that amorphous or semi-orphorphous material is deposited in a carrier bead or, In the case of direct spray drying on the excipient mixture to produce a powder.

In one embodiment, the process is generally carried out by (a) introducing a carrier carrier in the form of dry powder, spray granules or microgranules in a fluidized bed dryer wherein the bed is maintained from about 40 ° C to about 200 ° C, preferably from 50 ° C to 100 ° C, b) by spraying in the fluidized bed of the carrier.

(Eg, ethanol, n-butanol, methanol and mixtures thereof) or a solution of organic solvent (acetone, ethyl acetate, toluene) comprising ganaxolone and at least one solubility enhancer (eg (Eg, Povidone K-12, hydroxypropylmethylcellulose acetate stearate (HPMCAS) and a binder (lactose, sucrose, starch) which can be rendered amorphous by spray drying, Such that there are stable particles of the ganaxolone solution admixed with the carrier excipient, wherein said stable ganaxolone particles are amorphous or a combination of amorphous and crystalline material having a wide range of particle sizes of from about 200 nm to 2 microns .

The resulting ganaxolone particles are stable and maintain increased kinetic dissolution properties as determined by standard dissolution methods (in vitro) for a period of 1 year at 25 ° C in a solid dosage form. The ganaxolone-containing mixture may further be processed into a solid or packaged dosage form so that it is reconstituted by the enzyme. Aqueous dispersion.

In another embodiment, the process is carried out by: (a) introducing a carrier carrier in the form of a dry powder, spray granules or microgranules in a fluidized bed dryer wherein the bed is maintained between 50 ° C to about 200 ° C, Preferably from about 50 ° C to about 100 ° C; B) by spraying on the fluidized bed of excipient a mixture containing water of ganaxolone and at least one solubility enhancer, a crystal inhibitor and a dispersing agent, such that there are stable particles containing ganaxolone mixed with the Carrier excipient, wherein said stable ganaxolone particles have an effective particle size of from about 500 m to about 1 μm.

The carrier excipient is preferably a highly water soluble compound or a polymer. The resulting mixture of the water-soluble carrier excipient, such as sugar or sugar alcohol, and ganaxolone has advantages because the carrier excipient can be dispersed in water, thereby increasing the rate of DEP. - the ganaxolone particles in the aqueous media.

Useful carrier excipients which may be employed in the fluidized bed for the pharmaceutical compositions include, but are not limited to, saccharides, such as sugars and sugar alcohols (eg, lactose or sucrose, mannitol, or sorbitol), starches , Flour, cellulose preparations and / or salts, such as carbonates, bicarbonates and phosphates, for example tricalcium phosphate or calcium phosphate and hydrogen.

Sugars and sugar alcohols used as carrier excipients include, to sugar or sugar alcohols having a molecular weight of less than 500 daltons, and are capable of readily dispersing and dissolving in water, thereby improving the dissolution rate of the Ganaxolone. Some examples of sugars and sugar alcohols usable in the present invention include xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, mannose, galactose, sucrose, lactose and the like. They may be used alone or as a mixture of two or more of these compounds. In a preferred embodiment, the sugars are sucrose or mannitol.

Some useful solubility enhancers, organic solvents, that may be employed in the fluidized bed for the pharmaceutical compositions include, but are not limited to, propylene glycol, PEG having a molecular weight greater than 400 daltons, cholesterol, lecithin, cremophor, Vitamin E TPGS, Triacetin, olive oil and castor oil.

Useful crystal inhibitors which may be employed with spray drying for the pharmaceutical compositions include, but are not limited to, hydroxypropylmethylcellulose acetate stearate, polyvinylpyrrolidones (eg, povidone K-12), and propylene glycol.

The ganaxolone particles generated by any of the described methods can be used in solid or liquid liquid dosage formulations, such as controlled release formulations, pulsatile dosage forms, multiparticulate dosage forms, fast bulk solid dosage formulations Melt, lyophilized formulations, tablets, capsules, aqueous dispersions, or aerosols. XII. Methods of Making Formulations of Ghanaxolone with Small Particles

Formulations of ganaxolone with particles; May be manufactured using the methods described, for example, in U.S. Patent Nos. 4,783,484, 4,826,689, 4,997,454, 5,741,522 and 5,776,496, which have been specifically incorporated by reference.

Such methods comprise: (1) Formulating a solution of ganaxolone in a suitable organic solvent. This may occur as ganaxolone is synthesized as a dissolved solid, or it may be done simply by dissolving ganaxolone particles in the chosen solvent. Any solvent which is miscible in water is satisfactory, and for example dimethylacetamide (DMA), dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) are understood. (2) Dilute the solution with a non-solvent that does not cause the ganaxolone to precipitate. The non-solvent causes a greater dispersion of the dissolved ganaxolone molecules in the liquid phase. Such greater dilution of the solution with the non-solvent produces larger particles, and less dilution of the solution with the non-solvent produces smaller particles. The non-solvent should not precipitate the ganaxolone when it is added to the solution. Non-solvents in which the compound is slightly more soluble than in water, for example, lower aliphatic alcohols, are preferred. ethanol. On the other hand, the proportions of non-solvent and solvent at a rate of 2 or more can produce particles of 1 to 3 microns in size (depending on other parameters), and a rate of less than 2 produces submicron particles, at least in Which applies to DMSO solutions diluted with ethanol. (3) To precipitate the ganaxolone from the solution to the desired particle size, An aqueous solution having a surfactant and / or a soluble binder and dispersing agents in an amount sufficient to perform ganaxolone precipitation and stabilizing the resulting suspension of particles against aggregation is prepared. The surfactant provides stabilization against aggregation, and water is the precipitating agent.

The presence of extra surfactant is advisable to ensure stabilization so that the precipitated particles suspended in liquids do not aggregate, forming particles of an inadequately large size. Surfactants are chosen for their compatibility with the compound and for their ability to stabilize a suspension of ganaxolone particles. For example, a 5% solution of C-30 or 0.1% of C-15 of polyvinylpyrrolidone (PVP) in water is preferred, but also 5% of Pluronic F-68, 0.33% of gelatin, may also be used. I., L; Gelatin plus 0.6% Hetastarch, 0.33% gelatin, 0.002% propylene glycol, 2% polyvinylpyrrolidone / vinyl acetate copolymer, and 0.33% gelatin plus 2% sucrose. Another embodiment uses 5% HPMC (Pharmacoat 603), 0.3% SLS and 1% PVA. To precipitate the ganaxolone particles in the desired size, the aqueous solution and the organic solution are combined under controlled conditions of temperature, rate of infusion at agitation rate and ratio of non-solvent to solvent in the dispersed solution. Precipitation of ganaxolone occurs exothermically, heating the organic solution and the resulting suspension. The temperature of the solution and the resulting slurry is subject to control to achieve the desired particle size of the precipitate. Higher temperatures in the solution during precipitation produce larger particles, and lower temperatures in the solution during precipitation produce smaller particles. Further, A higher rate of infusion at a constant stirring rate of the organic solution produces smaller particles, and the lower infusion velocity produces larger particles. (4) When the precipitation is complete, an extra-aqueous surfactant solution may be added to stabilize the particles of the water. V INDUST! '.,. U, suspended against aggregation. The extra solution can be added at a rapid rate, since all ganaxolone has already been precipitated into particles of uniform size. The precipitated particles are rapidly separated from the organic solvents to prevent them being re-dissolved and the particles re-precipitate into undesired sizes. Centrifugation is the preferred way of doing this.

The ganaxolone particles generated by any of the methods described herein can be used in solid or liquid liquid dosage formulations, such as controlled release formulations, lyophilized formulations, tablets, capsules, aqueous dispersions or aerosols. XIII. Other Formulations that Use Small Particles of Ghanaxolone

In certain embodiments, the present invention is

I is directed to pharmaceutical compositions comprising particles comprising (i) ganaxolone, (ii) a cellulosic polymer and (iii) lauryl sulfate in which 90% Of the particles by weight, have an effective particle size of less than about 500 nm. Another embodiment comprises (i), (ii), (iii) and (iv) a complexing agent. In other embodiments, the particles comprise (i), (ii) and (iii), and (i), (ii), (iii) and (iv) which may have any effective particle size, range, or any Another feature (e.g., pharmacokinetic profile) as disclosed in the present patent application. In addition, an ionic dispersion modulator and a water soluble spacer may be added.

In some embodiments, the cellulose polymer of (ii) is hydroxypropylmethylcellulose (Pharmacoat 603).

In certain embodiments, the present invention is directed to pharmaceutical compositions comprising particles comprising (i) ganaxolone, (ii) a polymer selected from the group consisting of polyvinylpyrrolidone, polysaccharides, carboxycarboxylic acid,

INDUSTRIAL Vinyl acetate and vinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl alcohol, carboxyalkylcelluloses and mixtures thereof, and (iii) a material selected from the group consisting of sodium lauryl sulfate and sodium dioctyl sulfosuccinate ; Wherein 90% of the particles by weight have an effective particle size of less than about 500 nm. In other embodiments, the particles comprising (i), (ii) and (iii) mentioned above may have any effective particle size, range, or any other characteristic (e.g., pharmacokinetic profile) as disclosed in Present patent application. These formulations may also contain a cellulose polymer.

In some embodiments, the polymer of (ii) is a copolymer of vinyl acetate and vinyl pyrrolidone.

In certain embodiments the ionic dispersion modulator is an organic or inorganic salt which does not contain sulfonic acid or sulfonic acid / inorganic salt counterion group at the end of an alkyl chain containing more than one saturated carbon atom bound to the Carbon bearing the sulphonic acid moiety. X. X%

In certain embodiments the soluble spacer k is a saccharide or an inorganic salt which does not contain sulphonic acid or sulfonic acid / counter ion group of inorganic salt at the end of an alkyl chain containing more than one saturated carbon atom bonded to the carbon atom it carries The sulfonic acid fraction.

The formulations of the present invention may also include a complexing agent including, but not limited to, parabens, organic acids, salts of organic acids, aromatic and aromatic esters, inorganic acids, inorganic salts, or a combination thereof . Complexing agents which do not contain a counterion group of sulfonic acid or sulphonic acid / counterion group of inorganic salt at the end of an alkyl chain containing more than one saturated carbon atom bound to the carbon atom bearing the sulphonic acid moiety.

The formulations of the present invention may also include preservatives including, but not limited to, parabens, organic acids, salts of organic acids, aromatic acids, aromatic esters, inorganic acids, inorganic salts, pharmaceutically acceptable salts or a combination of the Themselves.

Wetting agents such as lauryl sulfate also do not appear to affect the size of the particle by grinding under storage conditions at room temperature. However, the addition of wetting agents during the milling process improves processing properties, such as reduction of the back pressure and allows for more efficient milling by reducing the overall viscosity of the milling mix.

An antifoam agent can also be added to improve the milling process. For example, the presence of simethicone (eg at a 0.01% level) during the milling process did not alter the formulation characterization and greatly improved the efficiency and reliability of the milling process. The addition of simethicone also produces a final aqueous formulation with less foam and provides a more accurate dosage for the patient. In some embodiments, the ranges of ganaxolone, HPMC, PVA, SLS, parabens, benzoic acid / sodium benzoate and simethicone in grinding and final suspension formulations are given in Table 1 as a percentage by weight (wt%). , Based on the total weight of the respective compositions.

JL Ψ, M_;

The above disclosed particles may be prepared according to any of the methods disclosed in the present application or in accordance with the methods described in U.S. Patents No. 6,375,986; 6,428,814; 6,432,381; 6,592,903; 6,908,626; Or 6,969,529, which have been specifically incorporated by reference.

In certain embodiments, the present invention is directed to pharmaceutical compositions comprising i. I V i Λ. J particles comprising (i) ganaxolone, WDUST. The polymer selected from the group consisting of polyvinylpyrrolidone, polysaccharides, copolymers of vinyl acetate and vinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl alcohol, carboxyalkylcelluloses, cellulose polymers and mixtures thereof, and (iii) a material Selected from the group consisting of sodium lauryl sulfate and sodium dioctyl sulfosucinate (DOSS) and (iv) an ionic dispersion modulator and (v) a water soluble spacer, wherein 90% of the particles by weight have a size Effective particle size of less than about 500 nm (or any effective particle size range,

In some embodiments, the controlled release component provides a release type selected from the group consisting of sustained release or

INDUSTRIAL delayed. _____

In some embodiments, the controlled release component comprises a coating comprising a hydrophobic material, coated on the second portion of the particles.

In some embodiments, the controlled release component comprises a matrix comprising the second portion of the particles, dispersed in a hydrophobic material.

In some embodiments, the immediate release component and the controlled release component are independently selected from the group consisting of a tablet, a pill, multiparticulates, a powder, a capsule, a solid dispersion, a solid solution, a tablet or A granule.

In some embodiments, the hydrophobic material is selected from the group consisting of an acrylic polymer, a cellulose polymer, shellac, zein, fatty alcohols, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, waxes, stearic acid , Stearyl alcohol and mixtures thereof.

In some embodiments, the hydrophobic material comprises an enteric polymer. IinL / Ui »

In some embodiments, the enteric polymer is selected from the group consisting of shellac, acrylic polymers, cellulose derivatives, polyvinyl acetate phthalate and mixtures thereof.

In some embodiments, the delayed release component provides a dose of ganaxolone or a pharmaceutically acceptable salt thereof delayed from about 2 to about 12 hours after administration.

In some embodiments, the delayed release component provides a dose of ganaxolone or a pharmaceutically acceptable salt thereof, delayed from about 2 to about 8 hours after administration.

In some embodiments, the delayed release component provides a dose of ganaxolone or a pharmaceutically acceptable salt thereof, delayed from about 3 to about 7 hours after administration.

In some embodiments, the controlled release component provides a dose of ganaxolone or a pharmaceutically acceptable salt thereof, delayed from about 2 to about 6 hours after administration.

In some embodiments, the controlled release component provides a dose of ganaxolone or a pharmaceutically acceptable salt thereof, delayed from about 3 to about 10 hours after administration.

In some embodiments, the coating further comprises a plasticizer, a dye, a tackifier, a surfactant, an antifoaming agent, a lubricant or mixtures thereof.

In some embodiments, the immediate release component and the controlled release component independently comprise one or more pharmaceutically acceptable additives from the group consisting of carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, Dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof.

The pharmaceutical dosage forms disclosed herein having an immediate release component and a controlled release component in this section (XIII), may provide any profile

I NSTll UTO WX »UA in O pharmacokinetics in accordance with the disclosed> present patent application. _____-,

Dosage forms may be prepared according to any of the methods disclosed in the present application or in accordance with the methods described in U.S. Patents 5,209,746; 5,213,808; 5,221,278; 5,260,068; 5,260,069; 5,308,348; 5,312,390; 5,318,588; 5,340,590; 5,391,381; 5,456, 679; 5,472,708; 5,508,040; 5,840,329; 5,980,508; 6,214,379; 6,228,398; 6,248,363; 6,514,518; 6,569,463; 6,607,751; 6,627,223; 6,730,325; 6,793,936; 6,902,742 and 6,923,988, which have been specifically incorporated by reference. XIV. Methods of Use of Ghanaxolone Formulations

The ganaxolone formulations described in the present application may be administered in therapeutically effective amounts for the treatment of a subject who has presented or is expected to present a convulsive condition, including but not limited to, epileptic conditions, epileptic seizures or spasms. Specific types of epileptic seizures include, but are not limited to, tonic-clonic (Grand Mal), partial (focal) seizures, catamenial seizures, acute repetitive seizures, psychomotor seizures (complex seizures or seizure of absence Petit Mal), and myoclonic seizures.

The ganaxolone formulations described in the present application are also used to treat infant spasms (IS). Childhood spasm is a specific type of attack that is seen in the Childhood Epilepsy Syndrome known as West Syndrome. It shoots predominantly in the first year of life, usually between 3 and 6 months.

The typical IS pattern is a sudden forward bending and a tightening of the body, arms and legs, although there may also be arching of the trunk. Spasms usually begin shortly after waking from sleep. Individual spasms usually last from 1 to 5 seconds and occur in groups, ranging from 2 to 100 spasms at a time. Infants can have dozens of groups and several hundred spasms per day. Infantile spasms usually stop at the age of 5 years, but are often replaced by other types of seizures. West Syndrome is characterized by infantile spasms, abnormal and chaotic patterns in brain waves, as well as mental retardation.

Other conditions in which the ganaxolone small particle formulations described in the present application may be used include, but are not limited to, the treatment of anxiety, stress, panic,. Depression and disorders related to depression (eg, postpartum depression), insomnia, premenstrual syndrome, PTSD, substance abuse abstinence (alcohol, benzodiazepines, barbiturates and cocaine) and hypertension. The ganaxolone formulations described in the present application may also be used to treat migraine headaches, pain and headaches related to the pre and post menstrual period.

Other conditions in which the ganaxolone formulations described in the present application may be used include, but are not limited to, the treatment of sphingolipid storage disorders such as Neimann Pick Type-C (NPC) and lipid accumulation of the Mucolipidosis Type IV (ML-IV).

In addition, the ganaxolone formulations described in the present application may be used for the treatment of neurodegenerative diseases, including, but not limited to, dementia associated with AIDS, Alzheimer's disease, Huntington's disease and Parkinson's disease.

The dosage levels of ganaxolone of the compound of formula (I) And the present application may be adapted to obtain an amount of active ingredient which is effective to obtain the desired therapeutic response for a particular composition and a particular delivery method. Therefore, the dose level selected depends on the desired therapeutic effect, on the route of administration, on the duration of the treatment desired and on other factors. However, one aspect of the formulations and compositions described in the present application, Is to provide formulations of ganaxolone comprising therapeutically effective amounts of ganaxolone such that the levels of ganaxolone in blood plasma are maintained at steady state from about 10 ng / ml to about 100 ng / ml (Cmin) after administration. In one embodiment, the ganaxolone formulations described in the present application may be used for the treatment of childhood spasms or an epilepsy-related disorder, wherein the formulation provides a therapeutically effective amount of ganaxolone (Cmin) of about 25 Ng / ml at 50 ng / ml ganaxolone in stable plasma blood plasma.

In another embodiment, the ganaxolone formulations described in the present application may be

Fig. J used for the treatment of epilepsy-related disorder, wherein the Î³FITOTSó 1 δΐΓ "η" provides a therapeutically effective amount of ganaxolone (Cmin) from about 15 ng / ml to 30 ng / ml of ganaxolone in the plasma Blood in the stable state XV Pharmacokinetic Analysis

Any standard pharmacokinetic protocol may be used to determine the blood plasma concentration profile in humans following the administration of one of the ganaxolone formulations described in the present application, and therefore, determine whether that formulation meets the criteria Pharmacokinetics established in the present invention. For example, a single dose randomized crossover study may be performed with a group of healthy adult human subjects. The number of subjects should be sufficient to provide adequate control of the variation in statistical analysis, and is usually about 10 or greater, although for a few purposes a smaller group may suffice. Each subject receives at time zero, single dose administration (eg, 300 mg) of a test formulation of ganaxolone, usually at about 8 am after overnight fasting. The subjects continue to fast and remain upright for 4 hours after administration of the ganaxolone formuTaHTorr. Blood samples are collected from each of the subjects prior to administration (eg, 15 minutes) and at various intervals after administration. For the present purpose it is preferable to take several samples during the first hour and to take samples less frequently thereafter. As an example, blood samples could be taken at 15, 30, 60 and 120 minutes after administration and then every hour from the second hour (hour 2) to 10 hours after administration. After the night fast. The subjects continue to fast and remain upright for 4 hours after administration of the ganaxolone formuTaHTorr. Blood samples are collected from each of the subjects prior to administration (eg, 15 minutes) and at various intervals after administration. For the present purpose it is preferable to take several samples during the first hour and to take samples less frequently thereafter. As an example, blood samples could be taken at 15, 30, 60 and 120 minutes after administration and then every hour from the second hour (hour 2) to 10 hours after administration. After the night fast. The subjects continue to fast and remain upright for 4 hours after administration of the ganaxolone formuTaHTorr. Blood samples are collected from each of the subjects prior to administration (eg, 15 minutes) and at various intervals after administration. For the present purpose it is preferable to take several samples during the first hour and to take samples less frequently thereafter. As an example, blood samples could be taken at 15, 30, 60 and 120 minutes after administration and then every hour from the second hour (hour 2) to 10 hours after administration. Blood samples are collected from each of the subjects prior to administration (eg, 15 minutes) and at various intervals after administration. For the present purpose it is preferable to take several samples during the first hour and to take samples less frequently thereafter. As an example, blood samples could be taken at 15, 30, 60 and 120 minutes after administration and then every hour from the second hour (hour 2) to 10 hours after administration. Blood samples are collected from each of the subjects prior to administration (eg, 15 minutes) and at various intervals after administration. For the present purpose it is preferable to take several samples during the first hour and to take samples less frequently thereafter. As an example, blood samples could be taken at 15, 30, 60 and 120 minutes after administration and then every hour from the second hour (hour 2) to 10 hours after administration.

Blood samples could also be taken later, for example at 12 and 24 hours after administration. If the same subjects are to be used for the study of a second test formulation, a minimum period of 7 days must elapse before the administration of the second formulation. The plasma is separated from the blood samples by centrifugation and the separated plasma Is screened for ganaxolone by a validated high performance liquid chromatography / tandem weight spectrometry (LC / APCI-MS / MS) procedure such as, for example, that described by Ramu et al., Journal of Chromatography B, 751 (2001) 49-59).

The plasma concentrations of ganaxolone referred to in the present application are total concentrations of ganaxolone comprising both free and bound ganaxolone.

Any formulation that yields the desired pharmacokinetic profile is suitable for administration according to the methods herein. Some examples of the types of formulations which give such profiles are the liquid dispersions and solid dosage forms of the ganaxolone formulations described in the present application. Aqueous dispersions of ganaxolone are stable at temperatures of about 4 ° C to 40 ° C for at least 3 months.

EXAMPLES

The present invention is further illustrated by the following examples, which should not be construed as limiting. Those skilled in the art in the manufacture of pharmaceutical formulations will readily appreciate that certain modifications may be necessary in the examples described, particularly changes in the batch size of the formulation. Any method, material, or excipients not specifically described is widely known and available to those skilled in the art of drug design and testing and in pharmacokinetic analyzes.

Particle size data, in the examples reporting a particle size of ganaxolone, were obtained using a Horiba LA-910 laser light scattering particle size analyzer (Horiba Instruments, Irvine, California) and Reported as volume-weighted average (D50). Studies of the ganaxolone particles in liquids, beads, powders and immediate release dosage forms in SGF and SIF are performed by dispersing an appropriate amount of the ganaxolone formulation in 20 ml of SGF or SIF in a vial to obtain a measurement Of ganaxolone concentration of about 0.5 mg / ml. For example, in one embodiment, 200 mg of a suspension ganaxolone formulation containing 5% by weight ganaxolone and suitable levels of HPMC, PVA, SLS and condoms in 20 ml of SGF or SIF in a vial for measurement. The vial is immersed in an oil bath which is maintained at a temperature of 36 ° C to 38 ° C for 3 hours. The sample is visually evaluated for flocculation symptoms and the particle size is measured on a Horiba LA-910 to obtain the D50 values.

Abbreviations

The following abbreviations are used in the examples below. Other abbreviations used in the examples will be readily understood by those skilled in the art in the manufacture of pharmaceutical formulations. GNX Ghanaxolone HDPE High density polyethylene HPMC Hydroxypropylmethylcellulose PVA Polyvinyl alcohol SLS Sodium lauryl sulfate DOSS Sodium docusate SGF Simulated gastric fluid SIF Simulated intestinal fluid p Weight

Example 1

The purpose of this example is to describe the preparation of an aqueous dispersion of ganaxolone comprising particles having an effective particle size of less than 500 nm. -Β-- Si- - the · '· · ·' '1

The crystalline ganaxolone is premez \ polyvinylpyrrolidone / vinyl acetate (S-630), and lauryl

Sodium sulfate at concentrations of 30%, 10% and 0.1% (weight / weight of the grinding mix) In deionized water, respectively, and is milled under high power milling conditions (Dyno®-Mill (Willy Bachofen AG)) in a water jacket with a grinding medium consisting of ΖΠΟ 2 with a size range of 0.4 Nm to 0.6 mm. The crystalline ganaxolone is milled with the grinding medium for a total of 1 hour. The milling temperature is not allowed to exceed 50 ° C. The milling concentration is about 30% ganaxolone by weight vs. the milling medium. The grinding medium contains about 10% w / v PVP / VA (S-630) and 0.1% SLS. The resulting mixed dispersion of ganaxolone is separated from the grinding medium by filtration through a 5 micron filter, To produce a ganaxolone dispersion whose yield can then be evaluated in animal pharmacokinetic tests. The liquid aqueous dispersions are formulated by diluting the ground dispersion with deionized water to a final concentration of 50 mg / ml after the addition of sucrose, methyl and propylparaben and an artificial strawberry flavorant (0.005% by volume).

EXAMPLE 2

The purpose of this example is to describe the preparation of an aqueous dispersion of ganaxolone comprising particles having an effective particle size of less than 150 nm.

The crystalline ganaxolone is premixed with polyvinylpyrrolidone / vinyl acetate (S-630), and sodium dioctyl sulfosuccinate in concentrations of 30%, 2.5% and 0.05% (w / w) in deionized water, respectively, and is milled under (Dyno®-Mill (Willy Bachofen AG)), in a water jacket, with a milling medium consisting of zirconium oxide beads having a size range of 0.1 nm to 0.2 mm. The crystalline ganaxolone is milled with the grinding medium for a total of 1 hour. The milling temperature is not allowed to exceed 50 ° C. The milling concentration is about 30% ganaxolone by weight vs. the milling medium. The milling medium contains about 10% w / v PVP / VA (S-630) and 0.05% DOSS (w / w) and deionized water.

D¿ LA Π '. V can then be evaluated in animal pharmacokinetic tests. The liquid dispersions are formulated by diluting the ground dispersion with deionized water to a final concentration of 50 mg / ml after the addition of sucrose, methyl and propylparaben and an artificial strawberry flavorant (0.01 % Volume / volume).

EXAMPLE 3

The purpose of this example is to describe the preparation of an aqueous dispersion of ganaxolone comprising particles having an effective particle size of less than 150 nm.

The crystalline ganaxolone is premixed with hydroxypropylmethylcellulose and DOSS at concentrations of 25%, 10%, and 0.3% (w / w) in deionized water respectively (in alternative methods, the HPMC may be in the range of about 0.5% to 5% Or 1.5% to 3%), and is milled under high power milling conditions (Dyno®-Mill (Willy Bachofen AG)) in a water jacket with a grinding medium consisting of zirconium oxide beads with A size range of 0.1 nm to 0.2 mm. The crystalline ganaxolone is ground with the milling medium for a total of 1 hour. The milling temperature is not allowed to exceed 50 ° C. The milling concentration is about 30% by weight and the grinding media. The grinding medium consists of beads of ZrC> 2 from 0.1 nm to 0. 2 mm which fill 85% of the volume of the grinding chamber (volume / volume). The resulting mixed dispersion of ganaxolone is separated from the grinding medium by filtration through a 5 micron filter to produce a ganaxolone dispersion whose yield can then be evaluated in animal pharmacokinetic tests. Liquid aqueous dispersions are formulated by diluting the ground dispersion with deionized water containing 2% HPMC and 0.1% SLS (Weight / Weight) to a final concentration of 20 mg / ml for the animal tests. Dispersions suitable for human use would require addition of sucrose, methyl and propylparaben and an artificial strawberry flavoring (0.005% v / v). The resulting mixed dispersion of ganaxolone is separated from the grinding medium by filtration through a 5 micron filter to produce a ganaxolone dispersion whose yield can then be evaluated in animal pharmacokinetic tests. Liquid aqueous dispersions are formulated by diluting the ground dispersion with deionized water containing 2% HPMC and 0.1% SLS (Weight / Weight) to a final concentration of 20 mg / ml for the animal tests. Dispersions suitable for human use would require the addition of sucrose, methyl and propylparaben and an artificial strawberry flavoring (0.005% v / v). The resulting mixed dispersion of ganaxolone is separated from the grinding medium by filtration through a 5 micron filter to produce a ganaxolone dispersion whose yield can then be evaluated in animal pharmacokinetic tests. Liquid aqueous dispersions are formulated by diluting the ground dispersion with deionized water containing 2% HPMC and 0.1% SLS (Weight / Weight) to a final concentration of 20 mg / ml for the animal tests. Dispersions suitable for human use would require the addition of sucrose, methyl and propylparaben and an artificial strawberry flavoring (0.005% v / v). Liquid aqueous dispersions are formulated by diluting the ground dispersion with deionized water containing 2% HPMC and 0.1% SLS (Weight / Weight) to a final concentration of 20 mg / ml for the animal tests. Dispersions suitable for human use would require the addition of sucrose, methyl and propylparaben and an artificial strawberry flavoring (0.005% v / v). Liquid aqueous dispersions are formulated by diluting the ground dispersion with deionized water containing 2% HPMC and 0.1% SLS (Weight / Weight) to a final concentration of 20 mg / ml for the animal tests. Dispersions suitable for human use would require the addition of sucrose, methyl and propylparaben and an artificial strawberry flavoring (0.005% v / v).

EXAMPLE 4

The purpose of this example is to describe the preparation of an aqueous dispersion of ganaxolone comprising particles having an effective particle size of less than 100 nm.

The crystalline ganaxolone is preferably 25%, 2%, and 0.1% (w / w) concentrations in deionized water, respectively (in alternative methods, HPMC may Being in a range of about 0.5% to 10% or from 1.5% to 3%), and is milled under high power grinding conditions (Dyno®-Mill (Willy Bachofen AG)) in a water jacket with a medium Of grinding consisting of zirconium oxide beads with a size range of 0.1 nm to 0.2 mm. The crystalline ganaxolone is milled with the grinding medium for a total of 2 hours at an ejection speed of 15 meters / second. The milling temperature is not allowed to exceed 50 ° C.

The milling concentration is about 25% ganaxolone by weight vs. the milling medium. The grinding media contains about 2% w / w HPMC and 0.1% SLS (w / w) in deionized water. The resulting mixed dispersion of ganaxolone is separated from the grinding medium by filtration through a 5 micron filter to produce a ganaxolone dispersion whose yield can then be evaluated in animal pharmacokinetic tests by diluting it with distilled water containing 2% HPMC and 2.5% sucrose (w / w) to a final concentration of 20 mg / ml.

EXAMPLE 5

In Example 5, ganaxolone particles having an effective particle size of less than 500 nm were obtained using the parameters of Example 1, using 30% ganaxolone, 10% polyvinylpyrrolidone / vinyl acetate, 0.3% DOSS, ZrC> 2 from 0.1 nm to 0.2 mm at 85% volume, with a milling residence time of about 30 minutes.

EXAMPLE 6

In Example 6, ganaxolone particles having an effective particle size of less than 500 nm were obtained using the parameters of Example 1, using 30% ganaxolone, 10% HPMC, 0.3% DOSS, ZrC> 2 beads of 0.1 nm to 0.2 mm at 85% volume, with a milling residence time of about 30 minutes.

EXAMPLE 7

In Example 7, ganaxolone particles having an effective particle size of less than 200 nm were obtained using the parameters of Example 1, using 30% ganaxolone, 2% HPMC, 0.1% SLS, ZrC> 2 beads of 0.1 nm to 0.2 mm at 80% volume, with a grinding residence time of about 2 hours.

EXAMPLE 8

In example 8, ganaxolone particles having an effective particle size of less than 250 nm were obtained using the parameters of Example 1, using 30% ganaxolone, 10% polyvinylpyrrolidone / vinyl acetate, 0.1% SLS, Glass of about 0.4 nma 0.6mmaun 85% of the volume, with a milling residence time of about 1 hour.

EXAMPLE 9

The dispersion of an earlier example prior to addition of the flavorings / sweeteners / preservatives is sprayed into a fluidized bed granulator (eg, a Wurster column) by maintaining a bed temperature of 80 ° C on spherical sucrose beads of About 50 μπ in diameter. The ganaxolone composition is sprayed at a level of about 30 to 40% by weight, to the beads and is dried. These ganaxolone microparticle beads may be filled into gelatin capsules for immediate release formulation or some of the beads may be reintroduced into the granulator and an Eudragit L30 D 55 dispersion applied with spray guns directed downward to a level of Coating (weight / weight). These coated beads are now pped ^ n,

EXAMPLE 10

Dissolution Tests for Ghanaxolone Formulations:

In general, all experiments are carried out at a temperature of 36 ° C to 38 ° C. The preferred dissolution medium is SGF or SIF with 10% sodium lauryl sulfate (SLS). The volume of the medium is 900 ml. The operating speed is 75 rpm for Apparatus 1 (basket) and 50 rpm for Apparatus 2 (paddle) in the case of solid oral dosage forms and 25 rpm in the case of suspensions. A sieve with a 40 mesh is used in most baskets, but other mesh sizes may also be used when this need is documented with supporting data.

In general, Tablet Device 2 is preferred.

In general, the Capsule Apparatus 1 is preferred and for dosage forms which tend to float or disintegrate slowly. A few paces of platinum wire. Can be used to prevent the capsules from floating.

The test time is generally about 30 to 60 minutes with a single specification relative to a time point for pharmacopoeial effects. To allow for normal disintegration times, test times of less than 30 minutes should be based on demonstrated needs. Test times and dissolution specifications are generally established based on an evaluation of the dissolution profile data. The normal specifications for the amount of dissolved active substance, expressed as a percentage of the labeled content (Q), are in the range of 70% to 80% of dissolved Q. Generally, a Q value exceeding 80% is not usually used, since there should be margins for the test ranges and uniformity of content.

For the case of oral dispersions, 20 ml or one equivalent in volume to 1000 mg of ganaxolone is added to each type II chamber at a paddle speed of 75 rpm, with 500 ml of SGF containing 10% SLS at a temperature of 36 ° C to 38 ° C and 45 minutes to obtain a 5 ml sample through a syringe. 3 ml of each container is filtered through a syringe equipped with a disk filter (0.45 microns) in an Eppendorf type iNBUS'íKW-i tube and centrifuged at 10,000 rpm for 30 minutes. Minutes. Carefully pipette 2 ml of the tubes supernatant into a 10 ml volumetric flask. It is diluted to 10 ml with methanol, capped and inverted at least 5 times.

A sample of each volumetric is analyzed in duplicate by a validated HPLC assay, in accordance with the following test conditions:

Column: Waters, SunFire, 250 x 4.6 mm, 5 μια Mobile phase: ACN / MeOH / water = 65/5/30 (v / v)

Flow rate: 1.0 ml / min Detection: RI

Sample concentration: 0.1 mg / ml to 0.4 mg / ml in MeOH

Running Time: 45 min Injection Volume: 50 μΐ Ghanaxolone: RT ~ 20 min

A standard solution of 1 mg / ml ganaxolone in methanol is made and diluted to 0.5, 0.25 and 0.125 mg / ml in methanol and 50 μΐ of each concentration is injected before and after the run of each duplicate. The results against the standard curve are plotted to determine the% of dissolved ganaxolone. In the case of pulsating solid dosage forms or

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Il / USTRIAL, the general method is similar except that initially 0.1 N HCl is used (first hour) and then the SIF medium containing 10% SLS is replaced and another dissolution period (3 hours) is evaluated. Using USP intestinal fluid adjusted to pH 6.8, about 70% of the weight of the enteric layer coated ganaxolone particles will be released within 3 hours at a blade speed of 75 rpm.

For drug release profiles for the ganaxolone formulations, see Example 29.

Example 11

Beagle breed dogs are bred for the purpose and are housed in USDA approved facilities in accordance with AAALAC guidelines. The expected weight of the dogs is 8.0 to 12.0 kg at the beginning of the evaluation, and they are weighed before each study period. Random blocks are made with the animals to form groups of 3 per treatment. Each study will test the formulations of ganaxolone (as described in examples 1 to 3) together with a reference group to which a standard formulation of ganaxolone-β-cyclodextrin (INdI Referring to Fig. Animals designated to be fasting undergo night fasting before each study day. Dogs designated to be in the fed state are fed a can of Alpo "Chunks with beef" (about 400 g) which has 55% of the total calories of fat, approximately 45 minutes before administration. When administered to the aqueous dispersions, the aqueous test ganaxolone dispersion formulations and the reference ganaxolone formulations are diluted with deionized water within 2 hours of dosing to release approximately 10 mg / kg of ganaxolone in a volume of 2.0 Ml / kg. If the liquid suspension is to be administered without dilution, a dose of 5 to 10 mg / kg is given per oral probe followed by a water wash of 7.5 and 10 ml / kg. When administering ganaxolone capsules, both test and reference capsules, Are given in a dose of about 10 mg / kg. The capsules are administered orally, as is usually done. Standard laboratory food and water ad libitum is offered 4 hours after administration. To eliminate the variability of drug absorption among dogs, all studies should be

INDUSTRIAL Random cross design. Approximately 2 ml of blood sample is taken with a 21G needle and by direct venipuncture sampling before dosing at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h and 48 h. The blood is immediately transferred to a blood collection tube with EDTA and potassium (VACUTAINER, Becton Dickinson, Franklin Lakes, NJ, USA) and stored on ice until the samples are centrifuged at 2500 at 4000 rpm for 15 min. The plasma is transferred to polypropylene tubes, and the samples are stored at -70 ° C until analyzed by liquid chromatography / tandem weight spectrometry (LC / MS / MS).

A validated method using liquid chromatography / tandem mass spectrometry with atmospheric pressure and chemical ionization (LC / APCI-MS / MS) was used to determine the ganaxolone in the plasma of the dogs and to analyze all the samples. This method is carried out in accordance with the previously published validated method (Ramu et al Journal of Chromatography B, 751 (2001) 49-59).

Example 12. PK Data Processing

If using WinNonlin v. 3.1 (Scientific Consulting, Inc., Apex, NC) for the non-compartmentalized analysis of the data. The area under the plasma concentration versus time curve (AUCo-72h) is calculated from the plasma concentrations observed from 0 to 72 h. Any plasma concentration below the quantification limit will be equal to zero. The geometric and arithmetic mean and the geometric standard error of the mean (SEM) of the AUC, the maximum observed plasma concentration (Cmax), and the time of Cmax (Tmax) can be calculated with Microsoft Excel. The effects of treatment and animals on the observed AUC and Cmax values are determined with SAS statistical programs (SAS Institute, Inc, Cary, NC, USA). We also examine a model of interaction between the dog, the formulation, And the fed / fasted state to confirm the interaction of the food with the formulation. The AUC and Cmax values are converted to logarithm to normalize the distribution. The Wilcoxon-related paired-sign test is used to evaluate differences in Tmax values between groups. The differences were only considered as significant when p <0.05.

Example 13. Suspensions of Submicron Particles of Ghanaxolone

The formulations of ganaxolone in suapeñsión Όώή. "Submicron particles comprising HPMC, SLS and WHUlMIII, as well as stabilizers exhibit useful stability profiles under storage conditions. Submicron particle formulations containing 5 wt% ganaxolone based on the total weight of the formulation and varying amounts of HPMC, SLS and PVA were stored at room temperature for 7 months. Visual evaluations were made with respect to their appearance. Results are shown in table 2.

Jxí'.z:

Example 14. Physical Stability in Simulated Gastric and Intestinal Fluid

The physical stability of the formulations with ganaxolone particles suspended in simulated gastric and intestinal fluid were tested at a temperature of 36 ° C to 38 ° C without stirring, unless otherwise specified.

Formulations of ganaxolone in suspension with HPMC and a surfactant such as SLS or sodium docusate (DOSS), prepared as described in Example 39, were flocculated in SGF and SIF. The results of the tests of two formulations, Ex-39F (15% GNX, 7.5% HPMC and 0.3% SLS) and Ex-39E (15% GNX, 2.5% HPMC and 0.1% DOSS) are shown in Table 3. Particle size growth occurred mainly in the first 1 to 1.5 h after treatment as the D 50 values reached warmer levels after 90 min (inputs 2 and 3, Table 3). It is interesting to note that these formulations are quite stable in deionized water (inputs 1 and 5).

Example 15. Suspension Formulations of Suspension containing Polyvinyl Alcohol (PVA)

The stabilizing effect of PVA is demonstrated with the formulation Ex-40A. This formulation was prepared by diluting the final milling blend as described in Example 40 (Ex-40) with a diluent containing appropriate amounts of HPMC, PVA and SLS (Table 4, inputs 1 and 2) in deionized water. After 3h, the D 50 values grew only about 19 nm from the initial 142 nm -: - By comparison, the Ex-40 grinding mixture containing no PVA was flocculated at Same conditions whereby their D50 values increased to 360 nm in SIF and to 699 nm in SGF from the same initial value of 142 nm (inputs 4 to 5). In addition, the formulation Ex-49A, having a composition almost identical to that of Ex-40A formulation, except that it does not contain PVA,

Percentages based on% by weight / total weight of the formulation and conditions include storage at a temperature of 36 ° C to 38 ° C without agitation. Eur-lex.europa.eu eur-lex.europa.eu I. 1 . (I.e.

EXAMPLE 16. Effect of the Gain ratio 1 aa / fo! CTd-C efr- Stability of the Formulations of Canaueltma Suspension in SGF and SIF

The Ghanaxolone to HPMC ratio is important for the stability of the suspended ganaxolone formulations in SGF and SIF. Formulations of ganaxolone in suspension containing 15% by weight of ganaxolone, 3% by weight of HPMC, 1% by weight of PVA, 0.1% by weight of methylparaben, 0.02% by weight of propylparaben and from 0.05% to 0.2% by weight of Weight of SLS in deionized water showed an increase in the D50 value from 155 nm to 261 nm in SGF (inputs 2 to 3, Table 5) after 2 h. The increase in D50 does not correlate with SLS concentrations. Dilution of these formulations with additional HPMC up to 5% by weight of ganaxolone and 5% by weight of HPMC while keeping the remaining components constant resulted in particle size growth of only <28 nm in 70 min (inputs 5 a 11 and 13, Table 5). As shown in Table 3, Particle size growth occurred mainly during the first 1 to 1.5 h of treatment. Therefore, these formulations were significantly more stable in SGF than those having the highest proportion of ganaxolone to HPMC. Increasing the HPMC level to 8.5% yielded few benefits. Additional stabilization. The results showed that the exact level of SLS in these formulations had little impact on gastrointestinal stability. Additional stabilization. The results showed that the exact level of SLS in these formulations had little impact on gastrointestinal stability. Additional stabilization. The results showed that the exact level of SLS in these formulations had little impact on gastrointestinal stability.

The formulations of inputs 14 to 16 of Table 5 had 0.2% methylparaben and had similar stability performance in SGF and SIF.

1 _ , . . . , .INSTITUTQ MEXICANO t '

The test temperature is the same as the temperature of the test. Example 14.

Example 17. Formulations Containing Sodium Benzoate as a Condom

Formulations of ganaxolone in suspension containing sodium benzoate were also evaluated as a preservative with citric acid / sodium citrate (pH 4.0) as a buffering agent. With an amount of 0.17% by weight of sodium benzoate, 0.13% by weight of citric acid and 0.01% by weight of sodium citrate, added; Two formulations containing 5% by weight of ganaxolone, 5% by weight of HPMC, 1% by weight of PVA and 0.1% by weight of SLS in deionized water with initial values of D50 of 196 nm and 321 nm respectively, showed good stability Against flocculation in both SGF and SIF (Table 6).

1 The test temperature is the same as that described in Example 14.

Example 18. Effect of PVA on the C .. · ^

Addition of PVA to suspension ganaxolone formulations reduces Cmax levels. Cmax levels of ganaxolone suspension formulations containing 1: 1 GNX / HPMC (% by weight), SLS (2% to 4% SLS / GNX), and with and without PVA (20% PVA / GNX) were determined. Particles of 110 nm, 140 nm and 320 nm were administered orally to Beagle dogs at a fed and fasted 5 mg / kg dose. Pharmacokinetic results are shown in Table 7. The PVA-free formulation (Ex-18A) achieved a higher exposure than those having PVA (Ex-18B and Ex-18C). However, the addition of PVA reduced variability in both fed and fasted states, especially at AUC values. The Cmax to AUC ratio was also lower when PVA was added. The

Ex-18C formulation is identical to the Ex-18B formulation except that preservatives (0.1% in methylene paraben, 0.02% by weight of propylparabyl and 11,19% in weight of sodium benzoate at pH 4) were added and the size Particle size is higher due to the presence of the condom. It was surprisingly found that the Ex-18C formulation had greater exposure than the Ex-18B formulation even though the Ex-18C particle size (D50) is more than twice that of Ex-18B (320 nm vs 140 nm). The Ex-18C formulation exhibits even less variability as well as greater overall exposure compared to the smaller particle size formulation (Ex-18A). The effect of food is slightly higher in the optimized suspension due to prolonged absorption of the drug due to the larger particle size.

The data presented in Table 8 further demonstrate the reduction of the variability of the formulations of ganaxolone with PVA in both fed and fasted state. The Ex-18D formulation has a particle size of 120 nm, which is very similar to that of the above Ex-18A formulation. This formulation was identical to Ex-18A except that PVA was added. In this study, a fed / fasted effect of 1.6-1.7X AUC0-72 (fed): AUC0-72 (fasting) was obtained.

Example 19. Use of Simethicone in the Milling Process

The presence of simethicone (eg, at a level of 0.1% by weight) during the milling process produces more stable ganaxolone suspensions (i.e., particles undergo smaller growth of size) And post-milling particle as compared to simethicone produced during the experimental results of two nearly identical milling runs, except for the simethicone levels, are shown in Table 9.

Example 20. Controlling the Particle Size By Setting the Residence Time in Milling

Grinding runs are carried out in deionized water with 1% by weight of PVA and appropriate amounts of preservatives in addition to HPMC (from 3% to 5% by weight) and SLS (from 0.05 to 0.1% by weight) using oxide beads Of zirconium from 0.1 to 0.2 mm (entries 1 to 4, Table 10). Each weight percentage is based on the total weight of the milling mix (without 1

D the pac-pi; The ad v * w

INOUJTS.AL Zirconium oxide). For the case of inputs 1, 3 and 4, the preservatives were 0.1 wt% methylparaben and 0.02 wt% propylparaben, and in case of inlet 5, the preservative was 0.1 wt% buffered sodium benzoate With 0.12% by weight of citric acid and 0.0093% by weight of sodium citrate. After reaching the effective particle size (D50) of 150 nm at 170 nm, runs 2 and 3 were stopped, and run 1 was allowed to continue. The data suggest that continued grinding did not reduce particle size even further. However, it did produce more stable particles compared to the sessions that had a shorter residence time. Further,

Grinding runs were performed only with HPMC and SLS. PVA and preservatives were added after milling (inputs 5 to 9, Table 10). As in the case of Run 1, a longer residence time produced more stable particles.

to. A concentration of ganaxolone (15%), PVA (1%), methylparaben (0.1%) and propylparaben (0.02%) was present during milling; B. A concentration of ganaxolone (25%), PVA (1%), sodium benzoate (0.1%) citric acid (0.12%), sodium citrate (0.0093%) and simethicone (0.025%) was present during milling; C. A concentration of ganaxolone (25%), PVA (1%), methylparaben (0.1%) and propylparaben (0.02%) was present during milling; D. The grinding mixture of the inlet 3 (diluted 2x) was re-ground after 2 days; and. The particle size was measured on a Horiba LA-910 particle size analyzer; F. PVA (1%), methylparaben (0.1%) and propylparaben (0.02%) were added after milling.

Example 21. Preparation of Ghanaxolone Formulations in Pharmaceutically Useful Suspension (50 mg / ml) from the Milling Mixture Method A (one-step dilution): A milling mixture with a known concentration of ganaxolone prepared as described in Examples 37 to 52 are diluted with an appropriate amount of diluent containing the appropriate levels of excipients and other necessary components such as preservatives, flavorings, sweeteners and antifoaming agent to a concentration of 50 mg / ml of drug. Method B (two-step dilution): A milling mixture prepared as described in Examples 37 to 52 is first diluted to an intermediate drug concentration (ca. 80 mg / ml) with an appropriate amount of diluent containing appropriate levels of excipients and other necessary components such as preservatives, flavorings, sweeteners and antifoaming agent. For example, for a milling mixture having an initial concentration of ganaxolone of 25% by weight, it is diluted by mixing a part of the milling mixture with two parts of the diluent, which will give the intermediate concentration of 8% by weight, which is equivalent About 80 mg / ml (assuming that the density of the mixture is approximately 1 g / ml). Suitable excipients and other components for the diluent are selected so that all components are present at the desired levels after the intermediate dilution. The precise concentration of ganaxolone is determined by suitable assays (eg, HPLC). The final dilution is carried out, with the proper amount of diluent containing the correct levels of all the excipients and other components.

Example 22. Effect of HPMC, SLS, and FVA levels on Ghanaxolone Suspension Formulations Containing Parabens

The effect of HPMC, SLS, and PVA levels on the stability of parabens-containing ganaxolone particle formulations was studied. Each of the aqueous suspension formulations contains 5% by weight of ganaxolone, 0.1% by weight methylparaben and 0.02% by weight propylparaben, based on the total weight of the formulation and varying amounts of HPMC, SLS and PVA in deionized water. Visual evaluations were performed after 7 months storage at room temperature to evaluate the stability of the formulation. The results of the stability compositions are shown in Table 11. ............--

The data in Table 11 show that Formullaulolithoxolone with 5% by weight of HPMC and 0.3% by weight of SLS showed good stability with the amount of 1% to 3% by weight of PVA (inputs 2 to 6) . When PVA levels are increased up to 3.5% to 4% by weight, while the other components are kept constant, a certain settling of particles in the bottom and a clear liquid at the top of the formulations (Entries 7 and 8).

The formulations listed at entries 9 to 11 showed good stability with an amount of PVA ranging from 1% to 2% by weight, while the amounts of HPMC (3% by weight) and SLS (0.2% by weight) were They remained constant. When PVA levels were increased from 2.5% to 4% by weight, while the other components were kept constant, some particle settling was observed at the bottom and clear liquid at the top of the formulations (inputs 12 to 15 ).

There appears to be an optimum compositional range for obtaining good stability in the formulations.

A lesser or equal percentage of 3.5% by weight of PVA (or 0.5 to 2.5% by weight) is desirable for obtaining good stability in the ganaxolone formulations containing parabens, especially at 5% by weight Weight) or lower concentrations of HPMC.

Example 23. Effect of Condoms on the Stability of Formulations of Ghanaxolone Suspension in SGF and SIF

The effect of a preservative on the stability of suspended ganaxolone formulations in SGF and SIF was studied. The formulations listed in entries 1 to 6, Table 12A contain from 8% to 9.5% by weight of GNX, from 4% to 4.8% by weight of HPMC, from 0.24% to 0.29% by weight of SLS, from 6% to 7% by weight of sucrose, based on the total weight of the formulation. Various amounts of parabens were added as shown in Table 12A immediately prior to dispersion and storage in SGF and SIF at a temperature of 36 ° C to 38 ° C.

It can be seen from Table 12A that the parabens have a stabilizing effect on the formulations with ganaxolone particles in SGF and SIF when they are added immediately before their dispersion in these media.

The average particle size (D50) grew at about 200 nm to 270 nm from the initial value of 106 nm. These results were compared favorably with those of the base formulation (no parabens), whose D 50 exceeded 1 ml after 90 minutes in SGF or SIF4 as shown in Table 2. On the other hand, one minute sonication of the formulations after Of one hour storage reduces the particle size from about 141 nm to 147 nm.

It is significant that when parabens or sodium benzoate are added as complexing agents after grinding and the ganaxolone particles are allowed to cure to the end point where the particles become stable, dispersion and storage in SGF and SIF At a temperature of 36 ° C to 38 ° C for 3h practically did not cause any increase in particle size (D50). The results are shown in Table 12B.

A The test formulation composition has 5% ganaxolone, 5% HPMC, 0.1% SLS (all based on the total weight of the formulation).

Example 24. Synergistic Effect of Condoms and FVA in Combination on the Physical Stability of Ghanaxolone Suspension Formulations

The synergistic effect of preservatives and PVA in combination on the physical stability of ganaxolone suspension formulations was studied. All formulations contain from 4.5% to 8% by weight of GNX, 2.2% to 4% by weight of HPMC, from 0.09% to 0.24% by weight of SLS, from 4.5% to 9% by weight of sucrose, based on The total weight of the formulation and varying amounts of parabens and PVA, as shown in Table 13.

The test temperature is the same as that described in Example 14.

The results in Table 13 indicate that ganaxolone suspension formulations containing both parabens and PVA showed additional physical stability in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Whereas the particle size of ganaxolone in formulations containing parabens only increased by more than 80 nm in lh in both simulated gastric fluid and simulated intestinal fluid (Table 13, entries 1 to 2), in those formulations containing ca. 1% of PVA in addition to parabens, only grew slightly (less than 30 nm) (inputs 3 to 4). These results suggest the existence of synergism between parabens and PVA in the stabilization of ganaxolone particles in gastric fluid e. , Intestinal. On the other hand,

Example 25. Effects of Multiple Condoms on Pharmacokinetics (PK)

In the following examples, the effect of the combination of parabens and sodium benzoate and / or benzoic acid on pharmacokinetics versus the effect of sodium benzoate and / or benzoic acid without parabens was studied. The particle size of both formulations was similar (320 nm for the formulation Ex-18C and 360 nm for the formulation Ex-25A). Studies were performed on fasting and fed Beagle dogs and the PK results are summarized in Table 14.

The results in Table 14 indicate that ganaxolone suspension formulations preserved with a paraben / sodium benzoate / benzoic acid combination provide a lower feed effect (approximately 3-fold) than formulations containing only sodium benzoate 4 times) in doses of 5 mg / kg. On the other hand, ganaxolone suspension formulations preserved with a combination of paraben / sodium benzoate / benzoic acid showed a significant improvement in the variabilitás <3i> 2 exposure compared to formulations containing only sodium benzoate.

For the liquid formulations the amounts of the components of the formulation are given as a percentage of the total weight of the formulation (% w / w) unless otherwise noted. For the case of solid dosage forms, the components of the formulation are given as a percentage of ganaxolone (% by weight / GNX). For example, in a solid dosage form, 100% HPMC indicates that the weight of HPMC in the formulation equals the weight of the ganaxolone in the formulation.

Particle size measurements of liquid suspensions of ganaxolone were performed an average-cold with a Horiba LA 910 particle size analyzer by adding the liquid suspension of ganaxolone with a 5 ml pipette into the chamber of the Horiba (containing approximately 125 ml of distilled water which has been used as the target for calibration) to achieve a tungsten light transmission of 75% to 80%. Other measurement conditions are a recirculation of 4, a stirring of 1, and a relative refractive index of 115 to 010.

EXAMPLE 26. Spray Layer Ghanaxolone Formulations 100 g of a sphere (with a mesh size of 20 to 35) are added to a Glatt GPCG-3 fluidized bed with a Wurster column attachment (4 inches), inlet temperature From 50 ° C to 60 ° C and air temperature from 30 ° C to 50 ° C (total air volume from about 150 to 200 cc / h). A mixture having a total solids content of 17.6% containing ganaxolone (197 nm, 71% solids content), hydroxymethylpropylcellulose (Phannacoat 603, 14.9% solids), SLS (0.1% solids), sucrose Solids) and 30% of a simethicone emulsion (DC7-9245, 0.1% solids) with a total spray weight of 6971Ng (> 574 ml water) is sprayed (bottom spray) through Of nozzles from 1.2 mm to 10 ml / min and 1.

Dispersion in water (1g in 300 ml) at a temperature of 36 ° C to 38 ° C shaken at 75 rpm showed a total disintegration in 10 minutes. Dissolution of the ganaxolone coated sugar beads in SGF or 0.5 mg / ml SIF at a temperature of 36 ° C to 38 ° C for 1 hour showed agglomeration (settling in the container) and an effective particle size of> 5 Μιη.

Example 27. Preparation of Dry Solid Ghanaxolone Particle Formulations

A suspension of ganaxolone particles (1.0 g), prepared as described below in Examples 37 to 52, is placed in a 25 ml glass scintillation vial on a Buchi rotary evaporator. The vial is rotated at about 150 rpm and the temperature of the water bath is adjusted between 70 ° C and 90 ° C. Vacuum is applied gradually for the first 2 minutes to minimize knocking. After the patter

(Ca. 2 to 4 mbar), until vacuum is applied to the water-free or condensation-free powder (approx. 10 min). Vial in the evaporator for an additional period of 10 to 15 minutes.In cases where additional components are required to be added to the suspension of ganaxolone particles prior to drying, these components are first weighed into the vial and about 0.5 g Of deionized water to obtain a complete solution To this solution 1.0 g of the suspension of ganaxolone particles is then added The contents of the vial are manually agitated After the contents are well mixed the vial is placed in the evaporator Rotating Buchi to dry the contents as described above.

Example 28. Preparation of Simulated Gastric and Intestinal Fluid

Simulated Intestinal Fluid (SIF).

Monobasic potassium phosphate (6.8 g) and sodium hydroxide (0.616 g) are added in 250 ml of distilled water in a 1000 ml volumetric flask and stirred until dissolved. 700 ml of distilled water are added and the pH is checked. The pH is adjusted to pH 6.8 +/- 0.1 by adding. Either 0.2 N sodium hydroxide or 2-chlorosulphonic acid and the volume is removed at 1000 ml. ____

Simulated Gastric Fluid (SGF).

Sodium chloride (2 g), 750 ml of distilled water and 7.0 ml of concentrated hydrochloric acid are added to a 1000 ml volumetric flask. The flask is shaken to mix and the volume is flushed to 1000 ml with distilled water. The pH should be approximately 1.2.

Example 29. Dispersion Tests of Solid Ghanaxolone Particle Formulations on Simulated Gastric and Intestinal Fluid

The formulation of solid ganaxolone particles is dispersed in simulated gastric and intestinal fluid and their dispersibility is monitored by visual assessment for flocculation and particle size measurement is monitored using a Horiba-LA-910 particle analyzer. The procedure is described in detail below.

Liquid or Immediate Release Liquid Dispersal in Process.

In a 25 ml translucent HDPE vial (total filling volume) with a HDPE stopper a suitable amount of the formulation of gandi is placed. 9.8 mg dry ganaxolone powder with 76% ganaxolone and suitable excipient levels) to achieve a final concentration of ganaxolone of about 0.5 mg / ml when diluted with 15 ml of simulated gastric or intestinal fluid. After adding the dispersant, the vial is shaken manually until the formulation is fully dispersed. The vial is then placed in an oil bath heated to 37 ° C, without stirring unless otherwise specified, for the desired time in the test. The vial is then removed from the bath and a visual inspection is made for signs of flocculation. It is then shaken before measuring the particle size using a Horiba-LA-910 particle analyzer. Normally, the materials are incubated for 3 hours to approximate the period of human gastric emptying.

Measurement of Particle Size.

If coated beads are measured whose core contains insoluble material, the weight of the core is calculated in the SIF or SGF experiment, an equal amount by weight of the core is dispersed in the same volume of SIF or SGF and the total amount is poured into 120 G of distilled water in the chamber of the Horiba LA-910. The instrument is calibrated and drained. Distilled 120 are added and the total amount of incubated formenlanion (in 15 ml of SGF or SIF) is poured into the Horiba chamber. The particle size is measured. This process eliminates any interference with size. Of particle of the nuclei of the beads. In the case of MCC cores, which are insoluble, the particle size is measured with the method used for the liquid suspension. After the initial measurement of the particle size of the redispersed ganaxolone formulation, Is sonicated at low power on the Horiba LA-910 for 1 minute, unless otherwise specified, and the particle size is remeasured. As with any suspension or dispersion study the difference of D50, as well as the overlap of 2 traces, which can give a qualitative indication of which part of the formulation constitutes a loose agglomerate.

Dispersion of Ghanaxolone Suspensions, Tablets and Capsules (Immediate and Delayed Release).

Place the solid dosage form of ganaxolone in a Type II dissolving apparatus with a basket at a temperature of 37 ° C with SGF at a concentration of ganaxolone of about 0.5 to 1.0 mg / ml for the immediate release component. Stir at 75 rpm and take a sample 1 hour later to analyze D'el ·:: particle size. Measure the particle size described above (a 15 ml aliquot) using a direct measurement method if all the excipients are water-soluble or filter through a 5-micron filter or calibrated using the same amount of mixture without ganaxolone dispersed under Same conditions as the immediate release of the ganaxolone coated beads described above. If it is a delayed or pulsatile release dose, after incubation in SGF, Replace the SGF with SIF (to have 0.5 and 1 mg / ml of ganaxolone in the delayed release component). Use the same conditions as with the SGF but let it shake for 3 hours. Take the sample and measure the particle size as described above for the SGF part of the study.

Example 30. Results of Ghanaxolone Dispersion Tests

Table 15 shows test results of a suspension formulation of ganaxolone particles (12.6% ganaxolone, 2.6% HPMC, 0.026% SLS, 0.018% simethicone emulsion (30% simethicone in water) and 2.4% Sucrose) and two other dry forms (rotary evaporation drying and formation, by spray on sucrose beads or microcrystalline cellulose). The spray layered form was prepared by evaporating the layer blend onto sugar beads (Paulaur with mesh size 30/35) through a fluidized bed coating process yielding approximately 35% ganoxolone loading (% By weight of GNX / total weight% of the beads), as tested in the refractive index-HPLC. Although the initial liquid formulation had D50 values of 343 nm and 361 nm after 3 h in gastric and intestinal fluid at a temperature of 36 ° C to 38 ° C, both dry forms had D 50 values in a range of 11 To 25 microns in the same test. In addition, the 1-minute sonication action did not return the D50 to its original value.

_______.-. ΗτΤίΤ'Τ'η MRAllAiV'J Y_S ^

X The temperature of the tests in SGF and SIF is the same as that described in Example 14.

Example 31. Effects of Sucrose, HPMC, SLS and EVA on Ghanaxolone Particle Formulations Without Complexing Agent (Table 16)

As the data in Table 16 show, a higher level of SLS produces less particle growth when dispersed in simulated gastric and intestinal fluid (inputs 1 to 2) in the case of uncomplexed ganaxolone particle formulations.

Duplication of the sucrose level from 46.6% to 98.3%, while maintaining the SLS level constant showed positive effects, but lower at the time of dispersion (entry 3). Add ca. 10% of PVA showed an effect similar to that of doubling the level of sucrose at the same level of SLS (entry 4).

1 The conditions are the same as in Example 14. Example 32. Dispersion of Formulations of Solid Ghanaxolone Particles with a Parabenous Complexing Agent

Example 32a. Solid Particles Prepared From a 6 Months Suspension Formulation Containing Complexing Agents.

The solid particles of ganaxolone prepared from a stable suspension formulation of 6 months old as described in Example 45 (Ex-45) containing 52% HPMC, 10.4% PVA, 1.25% parabens and 1.0% Of SLS, are redispersed well in simulated gastric and intestinal fluid at a temperature of 36 ° C to 38 ° C (entry 5, Table 17). The addition of 54.8% sucrose further enhances redispersibility, especially simulated gastric fluid (entry 3). The addition of SLS to this formulation further reduces the growth of the particles at the time of dispersion, particularly in the simulated gastric fluid (inlet 4). Duplicating the level of sucrose also has a positive stabilizing effect (input 2).

0.04% of methylparaben and 0.21% of propylparaben; the temperature of the tests in SGF and SIF is the same as that described in Example 14.

Example 32b Solid Particles Prepared from a One Week Antigen Suspension Formulation Containing Methylparaben as Complexing Agent.

Solid particle dispersion tests were performed from a 1-week old methylparaben suspension containing 0.98% methylparaben plus 24.4% HPMC, 0.15% simethicone ( Emulsion in 30% water), 1.46% SLS, in both gastric and intestinal fluid simulated at a temperature of 36 ° C to 38 ° C (Table 18) .According to previous observations, a higher level of SLS produces less Growth of particle size at the time of dispersion (entry 2) in gastric and intestinal fluid The addition of 25% sucrose to the above formulation further reduces the growth of particle size at the time of dispersion (entry 3 ) The addition of 9.76% PVA provides a less obvious benefit.

Redispersion conditions: A: simulated gastric fluid, from 36 ° C to 38 ° C, 3h. B: simulated intestinal fluid, from 36 ° C to 38 ° C, 3h. SE = simethicone.

EXAMPLE 33. Face to Face Comparison of the Redispersibility of Solid Ghanaxolone Particles in Simulated Gastric and Intestinal Fluids: With and Without the Addition of Complexing Agent (Methylparaben)

Two liquid formulations of ganaxolone particles were prepared as described in examples 51 and 52, respectively: one containing 0.98% methylparaben plus 24.3% HPMC and 1.46% SLS (Ex-51) and the other containing only comparable levels Of HPMC and SLS (Ex-52). When performing simultaneous tests with these two liquid formulations in simulated gastric and intestinal fluid at 37 ° C, the Ex-51 formulation containing complexing agent (entry 1, Table 19) showed significantly lower particle growth compared to the Ex- Without the complexing agent (entry 2, Table 19). Adding additional amounts of HPMC and SLS (enter Table 4), similar results were obtained. These results are consistent with those discussed above.

Dispersion conditions: A: Simulated gastric fluid, from 36 ° C to 38 ° C, 3h. B: Simulated intestinal fluid, from 36 ° C to 38 ° C, 3h. INSTITUTE Í'.K \

Comparative studies were carried out in addition to the dispersion of solid particles of naravin and non-parabens in simulated gastric and intestinal fluid. The ganaxolone particles with 0.98% methylparaben as the complexing agent (allowed to cure for 1 week) showed lower particle size growth at the time of dispersion at 37 ° C than those containing no complexing agent (inputs 2 to 3 , Table 20). The presence of 9.4% to 9.8% of PVA did not significantly alter the dispersion behavior of ganaxolone solid particles with and without complexing agent (inputs 1 and 4, 2 and 3, Table 20). In the case of the formulation listed in entry 4, Table 19, the addition of ca. 52% sucrose significantly reduced particle size growth at the time of dispersion (entry 8, Table 6.6). However, doubling the sucrose level showed no significant additional benefit (entry 9, Table 20). The same trend is observed in the case of solid formulations of ganaxolone without complexing agents (inputs 6 and 7, 10 and 11, Table 20). Compared with the formulation listed in entry 8, Table 20, lower levels of sucrose, HPMC and SLS results in a larger particle size at the time of the dispersion, especially in fluid ¥ yiggÍJu ^ a5S: simulated (entry 5, Table 20). - Compared with the formulation listed in entry 8, Table 20, lowering the levels of sucrose, HPMC and SLS results in a larger particle size at the time INSTITUTO MZMCM * V, dispersion, especially in fluid i ¥ yiggÍJu ^ a5S: simulated (entry 5, Table 20). - Compared with the formulation listed in entry 8, Table 20, lowering the levels of sucrose, HPMC and SLS results in a larger particle size at the time INSTITUTO MZMCM * V, dispersion, especially in fluid i ¥ yiggÍJu ^ a5S: simulated (entry 5, Table 20). -

X The temperature of the tests in SGF and SIF is the same as that described in Example 14.

Example 34. Effects of the Salts on the Dispersion of Ghanaxolone Particle Formulations with No Complexing Agent

Sodium chloride is very effective in improving the dispersion of a dried ganaxolone particle formulation (described in Example 51) cured with a complexing agent in both simulated gastric and intestinal fluid. The results are shown in Table 21. At a level of 1.5 wt% / GNX, sodium chloride reduced the D50 from 13.2 μιη to 3.17 μπι at the time of dispersion in simulated gastric fluid at room temperature (inputs 1 to 2 ). Increasing the sodium chloride level to 2.0% relative to ganaxolone, under the same conditions, decreases the D 50 to 0.54 8 μπι in the gastric fluid. Above 3.0%, sodium chloride essentially prevents growth of particle size at the time of dispersion in gastric and intestinal fluid (inputs 6 to 9, 11, Table 21). At low levels of sodium chloride, An additional stabilizing effect can be obtained by the addition of a water-soluble spacer having more plasticity than the salts. The water-soluble spacer used to illustrate this point is sucrose. As shown in the entry 4, at a level of 1.5% sodium chloride, the addition of 2.5% sucrose (relative to <SSftR1AL lir31-ganaxolone) reduced the D50 At the same level as the 3.0% sodium chloride. Increasing the 5% sucrose level, provided little additional benefit (entry 3). In the case of the formulation of solid stabilized ganaxolone particles containing methylparaben as a complexing agent and cured for> 7 days, the increase in D50 values is mainly caused by loose and / or loose aggregation at the time of dispersion .

In the case of the formulation of normal ganaxolone particles which has not been stabilized with a complexing agent, the addition of sodium chloride at a level as high as 23.5% relative to ganaxolone results in a D50 of 22.7 μπι at the moment Of the dispersion in simulated gastric fluid at room temperature. This significant increase in D 50 at the time of dispersion can only be reversed parsimoniously after 1 min of low power sonication (entry 12, Table 21). The actual distribution of particle traces (after 1 min of low potency sonication) of the intakes 9 (with methylparaben) and 12 (without methylphosphate) are shown in FIGURE 5.

Other salts are also effective to provide a redispersibility of the solid ganaxolone particles in simulated gastric and intestinal fluid. The results of sodium citrate are shown in Table 22.

Example 35. Preparation of Solids Containing Sucrose, Sodium Chloride, in addition to the Grinding Excipients. EXAMPLE 35 Preparation of Solids Containing Sucrose, Sodium Chloride, in addition to Milling Excipients

The following was placed in a 25 ml scintillation vial: 5.13 mg of sucrose crystals and 12.5 mg of a 25 wt% sodium chloride solution.

Deionized water (0.5 g) was then added to dissolve the sucrose crystals and to achieve a homogeneous solution.

Aqueous ganaxolone suspensions (1 g) containing 20.5% ganaxolone, 5.0% HPMC, 0.3% sodium lauryl sulfate, 0.2% methylparaben, 0.03% simethicone (30% water emulsion) % W / w) were added to the vial and the mixture was stirred to mix correctly. The contents of the vial were evaporated under reduced pressure (rotary evaporator in vacuo at 2 to 4 mbar) at a temperature of 70 to 85 ° C until a dry powder was obtained.

The examples listed in Table 23 were prepared in the same manner with suitable amounts of each component.

Example 36. Effect of Boiling on Ghanaxolone Formulations With and Without a Completion Agent

Approximately 2g of the Ex-51 and Ex-52 milling blend prepared as described in Examples 51 and 52, respectively, was placed in a 25 ml glass vial and the vial was tightly closed. The vials were heated in an oil bath at 100 ° C. The size of the Ex-51 particle containing methylparaben as the complexing agent did not change after heating. In contrast, Ex-52 which did not contain a complexing agent increased its D50 and the increase appeared to depend directly on time. Also, both formulations became more viscous, Ex-51 was converted into a semi-solid (diluted with water for particle size measurement).

Example 37. Results of the Dissolution Test of Solid Ghanaxolone Particle Formulations with Sodium Benzoate as Curing Agent in Simulated Gastric and Intestinal Fluid

Formulations with solid ganaxolone particles containing sodium benzoate / benzoic acid as a complexing agent were prepared according to the grinding method for paraben formulations as a complexing agent (see method described in Example 52) except using a suspension of particles of Ganaxolone containing 21.25% ganaxolone, 5% HPMC, 0.3% sodium lauryl sulfate, 0.03% simethicone emulsion (30%) with 0.09% sodium benzoate, 0.12% citric acid and 0.0093% citrate Of sodium added after grinding (all% are in weight / weight) (Ex-52) and cured for 12 days until the time of use.

As shown in Table 25, the solid ganaxolone particles prepared from the Ex-52 milling blend containing 23.5% HPMC, 1.41% SLS, and the quot; 0.14% simethicone emulsion (at 30%) showed poor redispersibility. The post-grinding addition of sodium benzoate (0.42%), citric acid (0.56%) and sodium citrate (0.043%) to this suspension improved its redispersibility in gastric and intestinal fluid (entry 3). As in the case of solid formulations containing parabens, the addition of sodium chloride (23.5%) further reduces its D50 at the time of dispersion in simulated gastric and intestinal fluid (entry 4).

INSTITUTE ΜΓ.Χί '..' -O \,;. Γ

Example 38. Filtration Capability of Ghanaxolone Particles with and without «

Complex (methylparaben)

The suspension of ganaxolone particles (247 mg, Ex-51) containing 20.5% ganaxolone, 5% HPMC, 0.3% sodium lauryl sulfate, 0.2% methylparaben and 0.03% of a simethicone emulsion (30% ) Was diluted with deionized water (100 ml) and thoroughly mixed to obtain 0.5 mg / ml ganaxolone concentration.

The suspension of ganaxolone particles (235 mg, Ex-52) containing 21.25% ganaxolone, 5% HPMC, 0.3% sodium lauryl sulfate, 0.03% of a simethicone emulsion was diluted with deionized water (100 ml) And thoroughly mixed to obtain 0.5% mg / ml of ganaxolone concentration.

The filtration capacity of the diluted suspensions was evaluated by means of transmittance (lamp) and particle size change before and after filtration. To obtain approximately 75% transmittance (pre-filtration), for the diluted Ex-51 suspension, 10 g were mixed with 120 ml of deionized water in the Horiba LA-910 sample chamber and the particle size . The chamber was drained and rinsed with water. Into the chamber 10 g of the diluted suspension filtered to

,, -. , Through a syringe filter of 11 æm fiber and 120 ml of deionized water, and the particle size was measured.

For the diluted Ex-52 suspension, 25 g of the suspension and 80 ml of deionized water were used. The transmittance (% T of the lamp) and D50 were compared before and after filtration to determine the amount of ganaxolone particles retained in the filter. A higher transmittance indicates a lower particle concentration in the measuring chamber. In addition, the decrease in D 50 after filtration indicates the removal of particles with altered physical properties (aggregates or membrane adhesion) during filtration. As indicated by the data in Table 26, A significant amount of ganaxolone particles complexed by methylparaben were retained by the filter as described by the loss of the transmittance value of the lamp which indicates how many particles are in the sample chamber (input 1). This assertion is also consistent with the significant reverse pressure encountered during filtration. In contrast, the ganaxolone particles not associated with a binding agent were not retained by the filter (entry 2). In this case, almost no reverse pressure was found.

EXAMPLE 37: Grinding of Ganaxolone Particles in Aqueous Medium Containing HFMC and Sodium Lauryl Sulfate (Batch Mode)

The ganaxolone particles in deionized water (180 g) containing 30 wt% ganaxolone (Marinus Pharmaceuticals Inc., Connecticut, USA), 3 wt% HPMC and 0.1 wt% sodium lauryl sulfate , Were milled in a DYNO KDL mill (Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzerland) with a 300 ml glass batch chamber and using zirconium oxide beads from 0.1 to 0.2 mm (85% camera). Grinding was performed for 120 min at a speed of 22.5 m / s. The particle size (D50) after milling was 106 nm.

MEXICAN INSTITUTE

Example 38. Grinding of an Aqueous Dispersion Containing HPMC (Continuous Mode)

The aqueous dispersion of pulverized ganaxolone (1200 g) comprising a mixture of 20 wt% ganaxolone and 3 wt% HPMC was ground in a DYNO KDL mill with a linear SiC continuous chamber of 600 ml and with oxide beads Zirconia stabilized with yttrium of 0.4 iran (88% charge volume). The grinding mixture was recirculated by means of a peristaltic pump (250 ml / min) through a holding tank with jacket of cooled stainless steel of 0 ° C to 12 ° C. The velocity was 10 m / s. The temperature of the product at the outlet was maintained below 45 ° C. The progress of the grinding operation was continued with the measurement of the particle size (D50) at various operation time points. After 2 hours of milling,

Example 39. Grinding of a Aqueous Ghanaxolone Dispersion Containing HPMC (Continuous Mode)

The aqueous dispersion of pulverized ganaxolone (1000 g) comprising a mixture of 15 wt% ganaxolone and 2.5 wt% HPMC was ground in a DYNO KDL UMUUSUUA * mill as described in Example 38. After 70 min of Residence time, the D 50 was 125 nm. The mixture was divided into 6 parts (Ex-39A to F) and different excipients added to each part. The final amounts of the excipients of each formulation are listed in Table 27.

EXAMPLE 40 Grinding of Ghanaxolone Particles in Aqueous Medium Containing HBMC and Sodium Lauryl Sulfate (Continuous Mode)

The ganaxolone particles in deionized water (1200 g) containing 15 wt% ganaxolone, 3 wt% HPMC, and 0.05 wt% sodium lauryl sulfate were milled in a DYNO KDL mill with a linear continuous SiC chamber Of 600 ml and with yttrium stabilized zirconium oxide beads of 0.4 ml (90% of the charge volume). The grinding mixture was recirculated by means of a peristaltic pump (250 ° C) through a holding tank with a stainless steel plate cooled between 0 ° C to 12 ° C. The velocity was 10 m / s. The temperature of the product at the outlet was maintained below 45 ° C. Approximately at 15 min of milling, 0.05% of additional SLS was added as a concentrated solution. The progress of this grinding run was followed by the measurement of the particle size (D50) at various time points of residence of the process (graph shown in FIGURE 4). After grinding, the mixture was filtered through a 10 μm cartridge and stored under refrigeration. Residence times of about 30 minutes or greater times produced submicron particles of ganaxolone with a D 50 of 100 nm at 150 nm.

EXAMPLE 41. Grinding of Ghanaxolone Particles in Aqueous Medium Containing HPMC, Sodium Lauryl Sulfate, Polyvinyl Alcohol, Methylparaben and Propylparaben (Continuous Mode)

The ganaxolone particles in deionized water (1000 g) containing 15% by weight of ganaxolone, 3% by weight of HPMC, 1% by weight of polyvinyl alcohol, 0.1% by weight of methylparaben and 0.02% by weight of propylparaben were milled In a DYNO KDL mill with a SiC linear continuous chamber of 600 ml and yttrium stabilized zirconium oxide beads of 0.4 mm (90% of the bead loading volume). Grinding was carried out according to the method described in Example 38. During grinding, two 0.025% (w / w) portions of sodium lauryl sulfate were added as a concentrated solution. After 72.9 min of residence time, the D 50 was 153 nm. The grinding mixture was divided into three containers, additional sodium lauryl sulfate was added to two of the containers so that the total SLS levels reached 0.1% and 0. 2% w / w, respectively. The mixtures were stored at room temperature and the particle size was completely stabilized after 6 days (D50: 205, 188 and 193, respectively).

Example 42. Ghrelinolol Particle Grinding in

Aqueous Medium Containing HPMC, Sodium Lauryl Sulfate, Polyvinyl Alcohol, Metililaben, Propylparaben and Simethicone (Continuous Mode)

The ganaxolone particles in deionized water (1200 g) containing 25 wt% ganaxolone, 5 wt% HPMC, 1 wt% polyvinyl alcohol, 0.1 wt% sodium lauryl sulfate, 0.1 wt% I ui υ rj jv; . Methylparaben, 0.02% by weight of propylparaben, DE4, .alpha., .beta. Is 2 wt.% Of simethicone in deionized water i in a DYNO KDL mill with a SiC linear continuous chamber of 600 ml and yttrium stabilized zirconium oxide beads of 0.4 mm (90% of the bead loading volume), Grinding was carried out according to the method described in Example 38. After 27.5 min of residence time, the D 50 was 180 nm.

The grinding mixture was filtered through a 10 μιη cartridge and diluted (2x) with a 5% (w / w) diluent of HMPC, 1% (w / w) polyvinyl alcohol, 0.1% (w / w ) Of sodium lauryl sulfate, 0.1% (w / w) methylparaben, 0.02% (w / w) propylparaben and 0.1% (w / w) simethicone and stored at room temperature so that the particle size would stabilize . The D50 became 327 nm after the particles were completely cured.

EXAMPLE 43: Grinding of Ghanaxolone Particles in Aqueous Medium Containing HPMC, Sodium Lauryl Sulfate, Polyvinyl Alcohol, Sodium Benzoate, Citric Acid and Sodium Citrate (Continuous Mode)

The ganaxolone particles in deionized water contain 25 wt% ganaxolone, 5 wt% HPMC, 1 wt% polyvinyl alcohol, 0.1 wt% sodium benzoate, 0.12 wt% acid Citric acid, 0.1% by weight of sodium lauryl sulfate, 0.0093% by weight of sodium citrate, and 0.025% by weight of simethicone were milled in a DYNO KDL mill with a linear SiC continuous chamber of 600 ml and with oxide beads of Zirconia stabilized with 0.4 mm yttrium (90% of the bead loading volume) Grinding was carried out in the same manner as described in Example 38. After 25.0 min of residence time the D50 was 160 The grinding mixture was filtered through a 10 μm cartridge and stored at room temperature. Its particle size (D50) was 361 nm after 4 weeks.

Example 44. Milking of Ghanaxolone Particles in Aqueous Medium Containing HPMC, Sodium Lauryl Sulfate, Polyvinyl Alcohol, Methylparaben and Propylparaben (Continuous Mode)

The ganaxolone particles in deionized water (1200 g) containing 25 wt.% Ganaxolone, 3 wt.% HPMC, 1 wt.% Polyvinyl alcohol, 0.1 wt.% Lauryl INSTITUTE Sodium sulfate, 0.1% by weight of and 0.02% by weight of propylparaben were molyzed., ..., DYNO KDL mill with a linear SiC continuous chamber of 600 ml and with stabilized zirconium oxide beads With yttrium of 0.4 mm (90% of the bead loading volume). Grinding was carried out according to the method described in Example 43. After 25.4 min of residence time, the D 50 was 162 nm. The grinding mixture was filtered through a 10 μιη cartridge and diluted (2x) with a diluent containing 7.5% (w / w) HPMC, 1% (w / w) polyvinyl alcohol, 0.1% (w / w ) Of sodium lauryl sulfate, 0. 1% (w / w) of methylparaben and 0.02% (w / w) of propylparaben in water to obtain a liquid dispersion. The dispersion was stored at room temperature so that the particle size would stabilize. The D50 was 306 nm after 2 days and 380 nm after 4 weeks. Additional additives, for example the flavoring agent and a sweetener, may be added to the liquid dispersion either before or after curing to obtain the final formulation of ganaxolone particles.

MEXICAN INSTITUTE

Example 45. Remolishing of the Ghana Mixture (A), which contains HPMC, Polyvinyl, Methylparaben and Propylparaben (Continuous Mode) Lauryl Sulfate of 5 ° C,

The final grinding mixture obtained in Example 4 was again re-ground two days later according to the method described in Example 44 for 69 min of residence time. The D50 was 164 nm. Said D50 became 200 nm in a time of 7 to 10 days and remained the same when the test was performed 6 months later.

Example 46. Grinding of a Aqueous Ghanaxolone Dispersion Containing HPMC (Continuous Mode)

The aqueous spray dispersion of ganaxolone (1200 g) comprising a mixture of 15 wt% ganaxolone and 3 wt% HPMC was ground in a DYNO KDL mill as described in Example 38. During milling, 2 portions of 0.05% w / w of sodium lauryl sulfate were added to keep the grinding mixture flowing. After 50.8 minutes of residence time, the D50 was 116 nm.

Example 47. Grinding of a Ghanaac Aqueous Dispersion Containing HPMC, Sodium Lauryl Sulfate and Simethicone (Continuous Mode)

The aqueous dispersion of pulverized ganaxolone (1200 g) comprising a mixture of 30 wt% ganaxolone and 5 wt% HPMC, 0.2 wt% sodium lauryl sulfate and 100 ppm simethicone was ground in a DYNO mill KDL as described in Example 38. After 24.0 minutes of residence time, the D 50 was 163 nm.

Example 48. Grinding of a Ghanaxolone Dispersion

Aqueous Containing HPMC, Sodium Lauryl Sulfate and Simethicone (Continuous Mode)

The aqueous dispersion of pulverized ganaxolone (1200 g) comprising a mixture of 25 wt% ganaxolone and 5 wt% HPMC, 0.3 wt% sodium lauryl sulfate and 100 ppm simethicone was ground in a DYNO mill KDL as described in Example 38. After 67.7 min of residence time, the D 50 was 145 nm.

Example 49. Grinding of a Dispersion of Ghanaxolone

Aqueous Containing HPMC, Sodium Lauryl Sulfate and Simethicone (Continuous Mode) i

The aqueous dispersion of pulverized ganaxolone (1500 g) comprising a mixture of 25% by weight of ganaxolone

DZ THE PROPERTY and 5% by weight of HPMC, 0.1% by weight of sodium lauryl and 0.028% by weight of a 30% strength emulsion in a DYNO KDL mill as described in Example 38, except that the speed Which was 15 m / s. After 39 minutes residence time, the D50 was 113 nm.

Example 50. Grinding of a Aqueous Ghanaxolone Dispersion Containing HPMC, Sodium Lauryl Sulfate and Simethicone (Continuous Mode)

Three additional milling runs were performed in the same manner as described by Example 46 but at higher scales. The residence time was 33 min, 35 min and 34 min, respectively, and at the end of the milling the D 50 was 143 nm, 139 nm and 155 nm (after 1 minute sonication), respectively. The milling mixtures of these runs were diluted in two-step manner as described in Example 21 for ganaxolone formulations of 21 to 50 mg / ml with levels of suitable excipients such as HPMC, PVA and SLS and other desirable components as preservatives , Sweeteners and artificial flavorings. The D 50 values of the 50 mg / ml formulations were 320 nm, 295 nm and 315 nm, respectively.

Example 51. Grinding of an Aqueous Dispersion with Complexing Agent for Solid Dosing Form.

The ganaxolone was ground with water in a 600 ml chamber using a DYNO KDL mill equipped with four 64 mm polyurethane agitator disks. The mill was operated at 3000 rpm or at a speed of 10 m / s. The mill was charged with 88 vol.% Of yttrium stabilized zirconium oxide beads of 0.4 mm. The milling mixture (1200 g) containing 25 wt% ganaxolone, 5 wt% hydroxypropylmethylcellulose (Pharmacoat 603), 0.0333 wt% of a 30% simethicone emulsion, 0.3 wt% sodium lauryl sulfate and 0.2 wt% % By weight of methyl paraben. This mixture was circulated through the mill by means of a peristaltic pump and sent back to a cooling tank from where it was recirculated through the mill. The mill was operated in this recirculation mode by maintaining the temperature of the milling mixture from 35 ° C to 40 ° C, for a total of 410 minutes. Using a free or void volume of 262 ml in the mill, a residence time of 90 minutes was calculated. The product of the blend was filtered through a 20 micron polypropylene cartridge filter to obtain 1185 g of milled ganaxolone blend. The particle size (D50)

Measured in a Horiba LA 910 was 164 ° C. Sonication / 153 nm with 1 min sonication at low power. After 7 days the particle size increased to 320 nm / 309 nm with sonication. The D50 no longer changed after this healing period, for the duration of time that all studies were carried out with this formulation.

Example 52. Tina Grinding Dispersion of Aqueous Ghanaolol without Complexing Agent for Forms

Solid dosing.

The ganaxolone was ground with water in a 600 ml chamber using a DYNO KDL mill equipped with four 64 mm polyurethane agitator disks. The mill was operated at 4000 rpm or at a speed of 15 m / s. The mill was charged with 88 vol.% Of yttrium stabilized zirconium oxide beads of 0.4 mm. The milling mixture (1200 g) containing 25 wt% ganaxolone, 5 wt% hydroxypropylmethylcellulose (Pharmacoat 603), 0.3% sodium lauryl sulfate and 0.033 wt% of a simethicone emulsion (30 wt% in Water, Dow Corning Q7-2587). This mixture was circulated through the mill by means of a peristaltic pump and was sent back to a cooled tank from where it was recirculated through the mill. The mill was operated in this mode of recirculating the temperature of the milling mixture from 40 ° C to 50 ° C. For ... a total of 340 minutes. Using a free or void volume of 262 ml in the mill, a residence time of 75 minutes was calculated. The product of the blend was filtered through a 20 micron polypropylene cartridge filter to obtain 1271 g ground milled ganaxolone blend. The particle size (D 50) measured on a Horiba LA 910 was 103 nm / 102 nm with sonication. After 7 days the particle size was increased to 136 nm / 112 nm with sonication.

Example 53. 300 mg Capsules of Immediate Release Ganaxolone with and without Complexing Agent

Suspensions (1200 g) were prepared in water containing 25 wt% ganaxolone, 5.0 wt% hydroxypropylmethylcellulose (Pharmacoat 603), 0.0333 wt% of a 30% simethicone emulsion, and 0.2 wt% lauryl sulfate Of sodium, either with 0.05% by weight of methylparaben (Ex. Capsule 1) or without methylparaben (Ex. 2 capsule, 5.2% by weight of HPMC instead of 5% by weight). Each% by weight was based on the total weight of the suspension.

The ganaxolone particles were ground using the conditions described in Example 51.

For formulations with Capsule 1 complexing agent, ganaxolone nanoparticles having a particle size (D50) of approximately 120 nm measured on a Horiba LA 910 particle size analyzer were immediately obtained from milling.

This volume-weighted average particle size grows to about 220 nm after 7 days of cure at room temperature, indicating that the ganaxolone complex has been formed.

The D50 does not change after this healing period for the duration of the study.

For Capsule Form 2 (without complexing agent), nanoparticles of ganaxolone having the same particle size (D50) (approximately 120 nm) are obtained immediately after grinding.

Capsules Form 1 and 2, sucrose (48.5 g) and NaCl (6.5 g) (together with about 13 wt% solids) and water (800 ml) were added to each suspension of ganaxolone for Capsule Form 1 and 2, and the resulting mixtures were Homogenized for 20 minutes for spray drying.

The compositions of the blends to be spray-dried are shown in Table 28.

(1)

For each Capsule Form 1 and 2, 100 g of microcrystalline cellulose beads (MCC) (for example Celsphere, having a mesh size of 30/35) are added to a Glatt GPCG-3 fluidized bed with a Wirster column insert (4 inches), at an inlet temperature of 55 ° C and at an air temperature of approximately 40 ° C (total air volume approximately 175 cm 3 / h). Approximately 2000 g of each spray mixture is sprayed (bottom spray) through nozzles from 1.2 mm to 11 ml / min and a pressure of 1.5 bar until a layer formation of about 400% by weight is achieved compared to the weight Of the pearls. INL> Ü3. * U «L -

Theoretical compositions of the ganaxolone complex particles which are formed in spray layers (Capsule Form 1) and ganaxolone particles (Capsule Forms 2) are shown in Table B.

The formation of spray layers yields theoretical> 90% for both forms 1 and 2.

Particles of ganaxolone complexes with spray-formed layers (Capsule Form 1) or ganaxolone particles (Capsule Form 2) are then filled into gelatin capsules with a filling weight of 518 to 520 mg of coated beads to obtain A dose of 300 mg.

Example 54. 300 mg Delayed Release Capsules (With and without Complexing Agent)

They are loaded directly into a granulator / rotary coater (Freund CF-360 granulator), immediate release beads containing ganaxolone (500 g, Capsule Form 1) or ganaxolone multiparticles (500 g, Capsule Form 2) prepared as described In Example 53 and as shown in Table 29, to carry out its enteric coating. The rotary particle bed is sprayed with a coating solution containing 50% by weight of Eudragit® L 30-D55, 2.5% by weight of talc, 1.5% by weight of dibutyl sebecate, 20% by weight of ethanol, 23.5 % By weight of isopropyl alcohol and 2.5% by weight of water. It achieves a. Coating level of about 8% by weight. The content of ganaxolone in each coated bead is about 53.4% by weight based on the total weight of the coated beads.

Approximately 295 mg of uncovered Capsule Forms 1 or 2 and 240 mg of capsule Shaped Capsule 1 or 2 beads obtained in this manner are filled by hand into gelatin capsules respectively to form 300 mg capsules Of modified release complexed ganaxolone (Capsule Form 3) or modified release capsules with 300 mg of ganaxolite (Capsule Form 4). These particles are substantially insoluble in the stomach thanks to the enteric layer but are substantially Soluble in the intestine The total filling weight of the capsule is 565 mg.

Example 55. Capsules give 300 mg of Pulsating Release Ganaxolone (With and without Complexing Agent)

For Capsule Form 5, uncovered ganaxolone beads obtained for Capsule Form 1, and as described in Table 29, are mixed with coated ganaxolone obtained for Capsule Form 3 (Example 54) at a ratio of 60 % By weight to 40% by weight to obtain a blend. Approximately 540 mg of the blended blend is filled by hand into hard gelatin capsules to obtain a 300 mg capsule of pulsed-release complexed ganaxolone.

Similarly, for Capsule Form 6, uncovered ganaxolone multiparticles obtained for Capsule Form 2, and as described in Table 29, are mixed with multiparticulates of coated ganaxolone obtained for Capsule Form 4 at a ratio From 40% by weight to 60% by weight to obtain a blend. The content of ganaxolone in the blend is about 55.5% by weight. Approximately 540 mg of the mixed blend is filled by hand into gelatin capsules to obtain a 300 mg capsule of pulsed release ganaxolone (no complexing agent).

Example 56. Ganaxolone 300 mg Capsules in Inflatable Cap Devices (With and without Complex Agent)

Approximately 520 mg of beads obtained in Example 53, Capsule Forms 1 and 2 are filled by hand in an inflatable cap device as previously described. The half shell of the capsule is composed of a poly (methylmethacrylate) material that does not dissolve in the stomach. The back end of the capsule shell is capped with a cylindrical cap composed of a crosslinked alkylene oxide copolymer by reaction with an unsaturated cyclic ether group. The half-capped capsule is finally sealed with a water-soluble gelatin to obtain a 300 mg capsule of complexed ganaxolone (Capsule Form 7) and a 300 mg capsule of ganaxolone (without methylparaben) (Capsule Form 8).

Example 57. 300 mg capsules of?

- - - - - - - - - - - -

Delayed release on devices with inflatable plug (with and without complex agent)

The sealed devices obtained in Example 56, with and without complexing agent, are further coated with an enteric layer to obtain a 300 mg delayed release complexed ganaxolone device (Capsule Form 9) and a 300 mg ganaxolone device ( Without methylparaben) (Capsule Form 10). For example, sealed devices are coated onto a Hi-Coater apparatus (Vector Corp., Marion, Iowa, USA) with a coating solution containing 50% by weight of Eudragit® L 30-D55, 2.5% by weight talc , 1.5% by weight of dibutyl sebecate, 20% by weight of ethanol, 23.5% by weight of isopropyl alcohol, and 2.5% by weight of water. A coating level of about 10% by weight is achieved.

EXAMPLE 58 Pulsating Release Ghanaxolone Tablets Containing an Internal Modified Release Core and Immediate Release Coating UL · a rRWiiL./.u/ y

The following is a process for preparing pulsatile release ganaxolone according to the present invention. In this formulation the relative amounts of the water-soluble film-forming substance (polyvinylpyrrolidone) and the water-insoluble film-forming substance (ethylcellulose) in the second layer of the encapsulated tablets are within the range of 1:20.

The suspension formulation of ganaxolone particles (12.6% ganaxolone, 2.6% HPMC, 0.026% SLS, 0.018% simethicone emulsion (simethicone in 30% water), 0.3% sodium chloride and 2.4% sucrose ) Is dried by rotary evaporation and spray layers are formed on sucrose beads. The spray layered form is prepared by evaporating the mixture which is used to form the layers onto sugar beads (Paulaur with a mesh size of 30/35) through a fluidized bed coating process yielding a ganaxolone Of about 60% (% by weight of GNX /% of the total weight of the beads).

The beads resulting from the formation of spray layers are dried (40 ° C, 5 to 10 h) and sieved first through a sieve with a mesh size of 12 to remove the aggregates and then onto a sieve

OF THE PROPERTY with a mesh size of 20 to eliminate thinner adiphytes. 1

The beads containing ganaxolone (25 kg) are emptied into a coating tray and sprinkled simultaneously with talc (USP, 1.28 kg) containing a blue dye (FD & C Blue No. 1 Lake Dye, 0.0129 kg) And sprayed with a solution of polyvinylpyrrolidone (0.0570 kg) and ethylcellulose (50 cps, 114 kg) in ethanol (95% alcohol, 27.3 kg). The second coating consists of 2% of a water-soluble film-forming substance, 46% of a non-water-soluble film-forming substance and 52% of dust for dusting. The resulting encapsulated beads are dried (40 ° C) to a moisture content of between 0.6% and 1.0% and screened successively through sieves having a mesh size of 12 and 20. The beads encapsulated in this manner , Are made up of sugar beads,

A mixture of anhydrous lactose (4 kg), microcrystalline cellulose (5.14 kg), ethylcellulose (50 cps, 2.8 kg) and hydrogenated vegetable oil (1.19 kg) is milled and mixed with 25 kg of encapsulated ganaxolone beads.

The resulting mixture is compressed to form tablets, each of which weighs 700 mg and each contains 30% of ganaxolone. The tabletting composition according to the present invention consists of 17.5% diluent, 22.7% diluent-binder, 12% binder and 5.22% hydrophobic lubricant and 42.5% ganaxolone. The tablets formed in this way consist of encapsulated beads and the tableting blend.

Example 59. Ghanaxolone Tablets With Enteric Layer

A suspension formulation of Ex-52 ganaxolone particles after curing for 7 days with the addition of 0.05% methylparaben is prepared as a spray granulation containing sucrose (3%) and sodium chloride (1.5%). The resulting granulate is dried (40 ° C, 5 to 10 h) and screened first through a sieve with a mesh size of 12 to remove the aggregates and then through a sieve with a mesh size of 20 to extract the finer aggregates.

Prosolv 90, spray granulated Ghanaxolone, and dipotassium phosphate powder are added sequentially to a Bohle Bin Blender type mixer (BL07C, Warminster, Pennsylvania, USA) and mixed for 10 ± 0.1 min at 11 ± 1 rpm . An additional amount of Prosolv 90 and Sodium Starch glycolate is then added and mixed for 10 ± 0.1 min at 11 ± 1 rpm. The material is then milled and passed through a 5 *** 1 mm (35 mesh) screen. _

The ganaxolone blend is loaded into a tablet compressing machine, such as the Fette 1200 B Tool Tablet Press (TP06) or some equivalent, and the tablets are formed using upper and lower oval punches. Tablets are obtained with an average tablet core weight of 750.0 mg (containing about 300 mg ganaxolone) with an acceptable mean of the upper and lower tablet weight limits of ± 5.0%.

The friability is determined in accordance with current USP guidelines <1216> at the beginning and end of each compression run and is 0.5% NMT. Disintegration times are determined in accordance with current USP guidelines <701> at the beginning and at the end INCTn'O 'T' of each compression batch. The time of desirifee. Is 5 minutes NMT. , ...................

An enteric layer is applied to the tablet cores as follows: The enteric layer comprises Opadry® Enteric from Colorcon® and the outer layer comprises transparent Opadry® applied sequentially as aqueous coating suspensions using a coating tray. The tablet cores are preheated to 46 ° C (exhaust air temperature). The speed of the tray is adjusted to provide adequate flow of tablets and the coating suspensions are sprayed onto the tablets at an atomizing air pressure of 18 to 30 psi; An inlet air temperature of 60 ° C to 70 ° C for the outer layer, and 42 ° C to 50 ° C for the enteric layer; An exhaust air temperature of 40 ° C to 50 ° C for the outer layer and 30 ° C to 35 ° C for the enteric layer, a spray rate of 15 to 50 ml / min; And an inlet air flow of 175 to 300 CFM. One skilled in the art will appreciate that the processing parameters for the coating depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% w / w -E. The core of the tablet. Can be used in and

INDUSTRIAL V Opadry enteric layer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one or more of the The above-mentioned enteric polymers.

Example 60: Ghanaxolone Immediate Release Tablet

A core of the ganaxolone tablet is prepared as described in Example 59. A clear outer coating of Opadry® is applied as an aqueous coating slurry using a coating tray. The tablet cores are preheated to 46 ° C (exhaust air temperature). The speed of the tray is adjusted to provide a suitable flow of tablets and the coating suspension is sprayed onto the tablets at an atomizing air pressure of 18 to 30 psi; An inlet air temperature of 60 ° C to 70 ° C, an exhaust air temperature of 40 ° C to 50 ° C, a spray rate of 15 to 50 ml / min; And an inlet air flow of 175 to 300 CFM. You can apply a * 1 '.>. :

EXAMPLE 62 Ghanaxolone Tablets with Enteric Layer Containing Sugar Beads

A suspension formulation of ganaxolone particles with or without complexing agent is prepared as described in Examples 52 (Ex-52A, containing 0.05% methylparaben and cured for 7 days) and 52 (Ex-52, without complexing agent ).

Sucrose (3%) and sodium chloride (1.5%) are added to each of these compositions. Sufficient water is added as in Example 53 to give a dispersion containing about 18% solids content.

For each of the particle suspensions, 100 g of sugar beads (such as Paulaur, mesh size 30/35) are added to a Glatt GPCG-3 fluidized bed with a Wurster column insert (4 inches), temperature Of 55 ° C and an air temperature of approximately 40 ° C (total air volume of approximately 17 5 cm 3 / h). Approximately 2000 g of each spray mixture is sprayed (bottom spray) through nozzles from 1.2 mm to 10 ml / min and to a DE LA PRO ?; And a pressure of 1.5 bar is reached until a layer shape of about 400 wt.% Is reached, the initial weight of the sugar beads is reduced. It is possible to obtain compositions of ganaxolone particles in spray-formed layers on sugar beads containing 60% Ghanaxolone or complexed ganaxolone particles, based on the total weight of beads. Lactose monohydrate, ganaxolone beads and dipotassium phosphate powder are added sequentially to a Bohle Bin Blender type mixer (BL07C, Warminster, Pennsylvania, USA) and mixed for 10 ± 0.1 min at 11 ± 1 rpm. An additional amount of Prosolv 90 and Sodium starch glycolate is added and mixed for 10 ± 0.1 min at 11 ± 1 rpm. The material is then ground and passed through a 0.5 mm screen (Mesh 35). Ganaxolone beads and dipotassium phosphate powder to a Bohle Bin Blender type mixer (BL07C, Warminster, Pennsylvania, USA) and mixed for 10 ± 0.1 min at 11 ± 1 rpm. An additional amount of Prosolv 90 and Sodium starch glycolate is added and mixed for 10 ± 0.1 min at 11 ± 1 rpm. The material is then ground and passed through a 0.5 mm screen (Mesh 35). Ganaxolone beads and dipotassium phosphate powder to a Bohle Bin Blender type mixer (BL07C, Warminster, Pennsylvania, USA) and mixed for 10 ± 0.1 min at 11 ± 1 rpm. An additional amount of Prosolv 90 and Sodium starch glycolate is added and mixed for 10 ± 0.1 min at 11 ± 1 rpm. The material is then ground and passed through a 0.5 mm screen (Mesh 35).

OF THE PROK'i'A ·)

The ganaxolone blend is loaded into a tablet compressor, such as a tablet PCT6 or an equivalent equipment, and the tablets are formed using upper and lower oval punches. The tablets are obtained with an average tablet core weight of 790 mg (containing 300 mg of ganaxolone) with an acceptable average of the upper and lower tablet weight limits of ± 5.0%.

Friability and disintegration times are determined as described in Example 59.

An enteric layer is applied to the tablet cores as follows: The enteric layer comprises Opadry® Enteric from Colorcon® and the outer layer comprises clear Opadry®, applied sequentially as aqueous coating suspensions using a coating tray . The tablet cores are preheated to 46 ° C (exhaust air temperature). The speed of the tray is adjusted to provide adequate flow of tablets and the coating suspensions are sprayed onto the tablets at an atomizing air pressure of 18 to 30 psi; An inlet air temperature of 60 ° C to 70 ° C for the outer layer, and 42 ° C to 50 ° C for the enteric layer; An exhaust air temperature of from 40 ° C to 50 ° C for the outer layer and from 30 ° C to 35 ° C for enteric digestion, A spray rate of 15 a.m. / m. , And an inlet air flow of 175 to 300 CFM. One skilled in the art will appreciate that the processing parameters for the coating depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers. And an inlet air flow of 175 to 300 CFM. One skilled in the art will appreciate that the processing parameters for the coating depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers. And an inlet air flow of 175 to 300 CFM. One skilled in the art will appreciate that the processing parameters for the coating depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers. One skilled in the art will appreciate that the processing parameters for the coating depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers. One skilled in the art will appreciate that the processing parameters for the coating depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers. Depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers. Depend in part on the size of the batch to be coated and accordingly can be adjusted as required. The enteric layer should be applied so that the tablet core achieves a weight gain of 8% to 15% by weight / weight of the tablet core. It may be used instead of the enteric layer Opadry, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, a methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, cellulose acetate trimellitate, or a combination comprising one Or more of the above-mentioned enteric polymers.

Example 63: Pharmacokinetic Analysis of a Completed Ghanaxolone Suspension of 200 mg (50mg / MI) Containing PVA Administered to 6 Healthy Volunteers in Fasting.

After an overnight fast of at least 10 h, 6 healthy subjects were given ganaxolone (4 ml of a 50 mg / ml suspension made as indicated in FIG. Example 50 for the complexed gariaxolone composition) with 240 ml (8 fluid ounces) of water. No food is allowed for at least 4 hours after dosing. Water is allowed as desired except for one hour before and after administration of the drug. Other oral fluids (such as juices, coffee, carbonated beverages, among others) were not allowed for 4 hours prior to dosing and up to 4 hours post-dosing. Ingestion of grapefruit and grapefruit juice was banned for the duration of the study. A standardized meal was provided 4 hours after dosing.

Blood samples (4 mL) were collected for PK analysis at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose using dipotassium EDTA as anticoagulant.

The plasma was separated by centrifugation at approximately 4 to 8 krpm for 15 minutes at 0 ° C, frozen below -20 ° C for storage and sent for analysis using a validated HPLC / MS / MS / MS with a LOQ of 1 ng / ml. The results showed an average Cmax of 37 ± 25 ng / ml and an AUC (0-24) of 184 + 104 ng * h / ml.

Example_64: _Effect_of_the_CiJc ^^^^^^

Freezing / Defrosting in the Stability of Ghanaxolone Phenolaclones With and Without a Complexing Agent

Ex-51 and Ex-52 ganaxolone formulations (with and without complexing agent as described in Examples 51 and 52 respectively) were tested for freeze-thaw stability as follows: 10 g of each Formulation were placed in a 25 ml HDPE scintillation vial with a HDPE cap. They were then placed in a 500 ml glass beaker containing about 1 inch of a polystyrene foam package (to encourage the freezing process) and placed in an insulated carton containing crushed dry ice. The vials were stored overnight and then thawed at room temperature for 1 hour. The same process was repeated for the same vials twice more (2x) finally comprising 3 freeze / thaw cycles.

The particle size of each formulation was measured with the method already described and compared to control material stored at room temperature in the same closed system container.

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60740174	United States of America	–	2005-11-28
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IL191759A	Israel	A	2015-05-31
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JP5748732B2	Japan	B2	2015-07-15
US2015313843A1	United States of America	A1	2015-11-05
MX336930BThis record	Mexico	B	2016-02-05
CN101583620B	China	B	2016-08-17
US9452176B2	United States of America	B2	2016-09-27
CN106667918A	China	A	2017-05-17
US2017202855A1	United States of America	A1	2017-07-20
US2019117673A1	United States of America	A1	2019-04-25
US2019117674A1	United States of America	A1	2019-04-25
EP1959966B1	European Patent Office (EPO)	B1	2020-06-03
ES2812250T3	Spain	T3	2021-03-16
US11071740B2	United States of America	B2	2021-07-27
FR24C1004I1	France	I1	2024-04-19

Ganaxolone formulations and methods for the making and use thereof.

Abstract

Term

FIELD OF THE INVENTION

BACKGROUND OF THE INCENTION

MEXICAN INSTITUTE

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION

INDUSTRIAL

EMULSIONS

OF FROPITTY

INDUSTJUAL

EXAMPLES

EXAMPLE 2

EXAMPLE 3

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6

EXAMPLE 7

EXAMPLE 8

EXAMPLE 9

EXAMPLE 10

MEXICAN INSTITUTE

MEXICAN INSTITUTE

Priority claims19

Members54

Numbers

Titles2

Classification

Abstract

Term

CROSS REFERENCE TO RELATED APPLICATIONS

FIELD OF THE INVENTION

BACKGROUND OF THE INCENTION

MEXICAN INSTITUTE

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION

INDUSTRIAL

EMULSIONS

OF FROPITTY

INDUSTJUAL

EXAMPLES

EXAMPLE 2

EXAMPLE 3

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6

EXAMPLE 7

EXAMPLE 8

EXAMPLE 9

EXAMPLE 10

MEXICAN INSTITUTE

MEXICAN INSTITUTE

Priority claims19

Members54

Numbers

Titles2

Classification