Solid dispersions comprising tacrolimus

Modified release compositions comprising tacrolimus

[0001] The present invention relates to a pharmaceutical composition and / or dosage forms, preferably unit oral dosage forms, comprising tacrolimus with modified release profiles when subjected to a conventional dissolution method, which is believed to reflect the index real and timing of the release of the active ingredient in vivo, effectively reducing or even avoiding the new composition the effects of CYP3A4 metabolism.

BACKGROUND OF THE INVENTION

[0002] Tacrolimus, also known as FK-506 or FR-900506, has the chemical tricyclic structure shown below:

which corresponds to C44H69NO12. Tacrolimus appears in the form of white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol and very soluble in methanol and chloroform.

[0003] The preparation of tacrolimus is described in EP-A-0 184 162 and analogues of tacrolimus are disclosed for example in EP-A-0 444 659 and US 6,387,918.

[0004] Tacrolimus is a macrolide compound with useful immunosuppressive activity, antimicrobial activity and other pharmacological activities and is of value for the treatment or prevention of rejection reactions by organ or tissue transplantation, graft versus host diseases, autoimmune diseases and infectious diseases. Tacrolimus prolongs the survival of the host and the transplanted graft in animal models of liver, kidney, heart, bone marrow and small intestine and pancreas, lung and trachea, skin, cornea and limb transplantation.

[0005] In animals, tacrolimus has been shown to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis and graft disease against host

[0006] Tacrolimus inhibits T lymphocyte activation, although the exact mechanism of action is unknown. Experimental evidence suggests that tacrolimus binds an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect can prevent the dephosphorylation and translocation of the nuclear factor of activated T cells, a nuclear component that is believed to initiate a genetic transcription for the formation of lymphokines. The net result is the inhibition of T lymphocyte activation, that is, immunosuppression.

[0007] Tacrolimus is extensively metabolized by the CYP3A4 isoenzyme in the wall of the intestine and liver. Therefore, drugs that affect this isoenzyme can influence the absorption and subsequent elimination of systemically absorbed tacrolimus. CYP3A4 inhibitors can increase tacrolimus levels, while CYP3A4 inducers can increase tacrolimus metabolism and reduce tacrolimus levels. Accordingly, tacrolimus can be administered together with one or more CYP3A4 inhibitors in order to improve overall bioavailability. [0008] Normally tacrolimus is administered orally and is therefore absorbed from the gastrointestinal tract. It has been observed that absorption is negatively influenced by simultaneous food intake. Thus, the speed and extent of tacrolimus absorption were higher under fasting conditions.

[0009] In general, it is known that the absorption and bioavailability of a therapeutically active substance can be affected by a variety of factors when administered orally. Such factors include the presence of food in the gastrointestinal tract and, in general, the gastric residence time of a pharmacological substance is significantly longer in the presence of food than in the fasting state. If the bioavailability of a drug substance is affected beyond a certain point due to the presence of food in the gastrointestinal tract, it is said that the drug substance exhibits a food effect. The effects of food are important because absorption, and therefore, plasma levels become highly variable depending on food intake. Absorption in blood flow can be adversely affected, to the point that the patient risks insufficient absorption to remedy the condition for which the medication was administered. On the other hand, concentrations of high maximum values ​​under fasting conditions may occasionally induce significant side effects of nephro-or neuro-toxic origin, as well as GI and other side effects.

[0010] The absorption of tacrolimus from the gastrointestinal tract after oral administration is rapid, with an average time to maximum concentration (tmax) of approximately 1-2 hours after administration to healthy subjects or kidney or kidney transplant patients. liver, but incomplete and variable. The bioavailability is generally as low as, approximately at most 20% after oral administration.

[0011] Frequently observed side effects are vomiting and nausea, but side effects such as tremor, headache, hypertension, renal dysfunction, hyperkalemia, hypomagnesemia, hyperglycemia, insomnia, diarrhea, constipation, abdominal pain, nephrotoxicity and neurotoxicity are also observed.

[0012] For oral administration, tacrolimus is currently formulated and marketed as soft gelatin capsules comprising the equivalent of 0.5, 1 or 5 mg of anhydrous tacrolimus and marketed under the trade name of Prograf® and Protropic®. The recommended initial oral dose is approximately 0.1 to 0.2 mg / kg / day in patients. The dose aims at a certain minimum concentration of the plasma level of about 5 to about 20 ng / ml. Prograf® is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants.

[0013] There remains a need for new pharmaceutical compositions and / or dosage forms comprising tacrolimus showing improved bioavailability. An increased bioavailability may allow a reduction in the dosage units taken by a patient, e.g. ex. lowering to a single daily dose, and can also reduce or cancel the need to eat food simultaneously with the dosage form, thus allowing patients more freedom on when the medication is ingested. In addition, it is contemplated that fluctuations in plasma concentration against the time profile can be significantly reduced. In addition, enhanced bioavailability may also result in a more reproducible release profile (ie, less variable compared to that of Prograf®).

[0014] WO 01/37808 A discloses a formulation obtainable by spraying a solution of tacrolimus, PEG-24 cholesterol ether (Solulan C-24), monoglycerides and deoxycholic acid in organic solvent on "nonpareil" seeds and, in addition, refers to the enhancement of oral bioavailability.

[0015] EP-A-1064942 discloses sustained release formulations obtainable by dissolving tacrolimus in molten glycerol monosterate or tetraglycerin triglyceric acid ester and mixing with HPMC or lactose.

[0016] WO 03/004001 A discloses a controlled agglomeration method to improve the bioavailability of poorly water soluble compounds in solid solutions or dispersions.

[0017] Honbo et al: "The oral dosage form of FK-506" in Transplantion Proceedings, 1987, vol. 19, No. 5 suppl. 6, p. 17-22 discloses capsules comprising a solid dispersion of tacrolimus in HPMC prepared by a solvent method.

[0018] The inventors have found that the bioavailability of tacrolimus can be significantly enhanced when tacrolimus is administered to a mammal in a controlled or modified release composition providing a release rate and timing of the active ingredient, that is, a release profile. in vivo, which effectively reduces or even prevents the effects of CYP3A4 metabolism.

[0019] Conventional in vitro dissolution methods are believed to correlate with or at least reflect the actual in vivo modified release profile in man. Accordingly, the present invention provides, in its first aspect, a solid pharmaceutical composition comprising tacrolimus, where less than 20% w / w tacrolimus is released in 0.5 hours, when subjected to an in vitro dissolution test using the USP palette method and using

0.9 N HCl as a dissolution medium, and less than 50% w / w of tacrolimus is released in 8 hours when subjected to an in vitro dissolution test using the USP paddle method and an aqueous dissolution medium adjusted to PH 4.5 with 0.005% hydroxypropyl cellulose.

[0020] This modified release profile is obtained by a pharmaceutical composition comprising a solid dispersion or a solid solution of tacrolimus in a hydrophilic or water miscible vehicle and one or more modified release agents selected from the group consisting of water miscible polymers, Water-insoluble polymers, oils and oil materials, and the vehicle comprises polyethylene glycol and a poloxamer in a ratio of between 1: 3 and 10: 1.

[0021] In another aspect, the invention relates to solid dosage forms, especially oral dosage forms, the composition of the invention comprising, the solid dosage forms showing a modified release profile. Delaying the release of tacrolimus to the distal part of the duodenum can reduce the gastrointestinal side effects related to the drug and the relatively high degree of metabolism in the proximal part of the gastrointestinal tract (CYP3A4 mediated metabolism). This can be done without losing systemic bioavailability due to the unique compositions of the invention, preferably compositions comprising the active substance completely or partially dissolved in a vehicle to form a solid dispersion and / or a solid solution at room temperature.

[0022] In other aspects, the invention relates to the use of the present pharmaceutical composition in the preparation of medicines or medicaments, especially in the preparation of useful solid dosage forms.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0023] As used herein, the term "active ingredient" or "active pharmaceutical ingredient" means any component that is intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the production of the drug product and are present in the drug product in a modified form intended to deliver the specified activity or effect

[0024] In the present context, the term "hydrophilic" describes that something "wants water", that is, a hydrophilic molecule or part of a molecule is one that is typically electrically polarized and is capable of forming hydrogen bonds with the molecules of water, allowing it to dissolve more easily in water than in oil or other "non-polar" solvents.

[0025] In the present context, the term "amphiphilic" describes a molecule (such as a surfactant) having a water-soluble polar group attached to a water insoluble hydrocarbon chain. Thus, one end of the molecule is hydrophilic (polar) and the other is hydrophobic (non-polar).

[0026] In the present context, the term "hydrophobic" denotes a compound that tends to be electrically neutral and non-polar, and thus preferring other neutral and non-polar solvents or molecular environments.

[0027] As used herein, the term "vehicle" means any solvent or carrier fluid in a pharmaceutical product that does not have a pharmacological role. For example, water is the vehicle for xylocaine and propylene glycol is the vehicle for many antibiotics.

[0028] In the present context, the term "solid dispersion" denotes a drug or active ingredient or substance dispersed at a particulate level in an inert carrier, carrier, diluent or matrix in the solid state, that is, usually a fine particulate dispersion. .

[0029] In the present context, the term "solid solution" denotes a drug or active ingredient or substance dissolved at a molecular level in an inert carrier, carrier, diluent or matrix in the solid state.

[0030] As used in this case, the term "analog" means a chemical compound that is structurally similar to another.

[0031] The term "drug" means a compound intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.

[0032] In this context, the term "dosage form" means the way in which the medication is delivered to the patient. This could be parenteral, topical, pill, oral (liquid or dissolved powder), suppository, inhalation, transdermal, etc.

[0033] As used herein, the term "bioavailability" denotes the degree of the means to which a drug or other substance is made available to the target tissue after administration. As used in this case, the term "bioequivalence" denotes a scientific basis on which generic and brand name drugs are compared with each other. For example, drugs are bioequivalent if they come into circulation at the same rate when they are given in similar doses under similar conditions. The parameters often used in bioequivalence studies are tmax, Cm, AUC0-infinity, AUC0-t. Other relevant parameters may be W50, W75 and / or MRT. Therefore, at least one of these parameters can be applied in determining whether bioequivalence is present. In addition, in the present context, two compositions are considered bioequivalent if the value of the parameter used is within 80-125% of that of Prograf® or a similar commercially available product containing tacrolimus used in the test.

[0034] In the present context "tmax" denotes the time to reach the maximum plasma concentration (Cmax) after administration, AUC0-infinity denotes the area under the plasma concentration against the time curve from time 0 to infinity , AUC0-t denotes the area under the plasma concentration against the time curve from time 0 to time t, W50 denotes the time in which the plasma concentration is 50% or more of Cmax, W75 denotes the time in which the plasma concentration is 75% or more of Cmax, and MRT denotes the average residence period for tacrolimus (and / or an analogue thereof).

[0035] In this context, the term "medicine" means a compound used to treat a disease, injury or pain. Medicine is properly distributed in "prophylactic," that is, the technique of preserving health, and "therapeutic," that is, the technique of restoring health.

[0036] In the present context, the terms "controlled release" and "modified release" are intended to be equivalent terms covering any type of tacrolimus release from a composition of the invention that is appropriate to obtain a specific prophylactic or therapeutic response. after administration to a subject. One skilled in the art knows how controlled release / modified release of tablet release differs.

or simple capsules. The terms "controlled release" or "modified release" have the same meaning, as stated above. The terms include slow release (resulting in a lower Cmax and delayed tmax, but t1 / 2 remains unchanged), extended release (resulting in a lower coaxial, a delayed tmax, but apparently t1 / 2 is longer), delayed release (resulting in an invariant Cmax, but the lapse time and, therefore, tmax is delayed, and t1 / 2 remains unchanged) as well as pulsatile release, burst release, sustained release, prolonged release, chrono-optimized release, rapid release (to obtain an improved appearance of the action), etc. Included in the terms is also p. ex. the use of specific conditions in the body p. ex. Different enzymes or changes in pH to control the release of the drug substance.

[0037] In this context, the term "erosion" or "eroding" means a gradual decomposition of the surface of a material or structure, for example of a tablet or the coating of a tablet.

[0038] The present invention provides pharmaceutical compositions and solid dosage forms for improved treatment of conditions that respond to tacrolimus treatment, especially compositions and dosage forms that provide modified release of the active ingredient to improve its bioavailability.

[0039] The active ingredient in the inventive compositions is tacrolimus (aka FK-506 or FR-900506). However, within the scope of the present invention, it is tacrolimus in any physical form (crystals, amorphous powder, any possible polymorph, any possible solvate, including hydrate, anhydrate, complexes thereof, etc.). Also included are any derivative or active metabolite of tacrolimus, salts, solvates, complexes and pharmaceutically acceptable prodrugs thereof.

[0040] Thus, in a preferred embodiment, the present invention provides a solid pharmaceutical composition comprising tacrolimus, where less than 20% w / w of the active ingredient is released in 0.5 hours, when subjected to an in vitro dissolution test. using a USP vane method and using 0.1 N HCl as the dissolution medium, preferably where less than 20% w / w, more preferably less than 10% w / w of the active ingredient is released in 3 hours.

[0041] Such a release profile is believed to significantly enhance the bioavailability of tacrolimus in mammals, since all or a greater part of the active ingredient is in fact released in the gastrointestinal tract, such that the CYP3A4 metabolism is substantially avoided or at least significantly reduced. It is further contemplated that this effect is correlated with, or at least reflected in the in vitro dissolution profile of the solid pharmaceutical composition and / or dosage forms of the invention, this profile is easily found when the composition is subjected and / or dosage form to a conventional in vitro dissolution method according to p. ex. USP It is believed that any USP in vitro dissolution method is useful for the present purpose.

[0042] For example, the solid pharmaceutical composition of the invention releases at least 50% w / w of the active ingredient in 4 hours, preferably in 2.5 hours, when subjected to an in vitro dissolution test using a USP paddle method. and using 0.1N HCl as a dissolution medium during the first two hours and then using a dissolution medium with a pH of 6.8.

[0043] Using a less conventional dissolution medium, the composition of the invention releases less than 50% w / w, especially less than 40% w / w of the active ingredient in 8 hours, preferably in 15 hours, when subjected to an in vitro dissolution test using a USP vane method and an aqueous solution medium adjusted to pH 4.5 with 0.005% hydroxypropyl cellulose.

[0044] The desired modified release profile of the pharmaceutical composition can be provided using a pharmaceutical composition comprising a solid dispersion or solid solution of active ingredient, ie, tacrolimus or an analogue thereof, in a hydrophilic or water miscible vehicle and one or more modified release agents.

[0045] In one embodiment of the invention, a pharmaceutical release composition modified with tacrolimus is provided with the active ingredient dissolved or dispersed in a hydrophilic or water miscible vehicle, comprising polyethylene glycol in admixture with a poloxamer. A specific example of a useful mixture is a mixture of 70% w / w polyethylene glycol 6000 (PEG6000) and 30% w / w poloxamer 188.

[0046] The composition of the invention can show an oral AUClAUCPrograf® value of at least about 1.3 after oral administration, the AUC values ​​being determined under similar conditions.

[0047] As seen in the examples, the bioavailability obtained here after administration of a composition according to the invention is markedly improved. Thus, the value of AUC / AUCPrograf® is at least about 1.5 as well as about 1.75 or more, about 1.8 or more, about 1.9 or more, about

<dl><dt>2.0</dt><dd> or more, about 2.5 or more, about 2.75 or more, about 3.0 or more, about </dd></dl>

<dl><dt>3.25 </dt><dd>or more, approximately 3.5 or more, approximately 3.75 or more, approximately 4.0 or more, approximately 4.25 or more, approximately 4.5 or more, approximately 4.75 or more or approximately 5.0 or more, the AUC values ​​being determined under similar conditions. </dd></dl>

[0048] After oral administration of a pharmaceutical composition according to the present invention, it is contemplated that the plasma concentration versus time profile shows an extended time period in which the plasma concentration is maintained in the therapeutic window (ie, the Plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in the maximum value concentration is also observed.

[0049] The composition of the invention can release, after oral administration to a mammal that needs it, tacrolimus in a controlled manner and display a Cmax that is at most approximately 80% of that of Cmax for Prograf® tablets such as, p. ex. at most about 75%, at most about 70%, at most about 65%, at most about 60%, at most about 55%, at most about 50%, at most about 45% or at most about 40%.

[0050] In the present context, the terms controlled release and modified release, are intended to be equivalent terms covering any type of tacrolimus release of a composition of the invention that is appropriate to obtain a specific prophylactic or therapeutic response after administration. to a subject One skilled in the art knows how controlled / modified release differs from the release of simple tablets or capsules. The terms "controlled release" or "modified release" have the same meaning as stated above.

[0051] The terms controlled release / modified release include slow release (resulting in a lower Cmax and delayed tmax, but t1 / 2 remains unchanged), extended release (resulting in a lower Cmax, delayed tmax, but apparently t1 / 2 is longer), delayed release (which implies a Cmax without changes, but time of lapse and, therefore, the tmax is delayed, and t1 / 2 does not present changes) as well as pulsatile release, burst release, Sustained release, prolonged release, optimized chrono release, rapid release (to obtain an improved appearance of the action), etc. Included in the terms is also p. ex. the use of specific conditions in the body p. ex. different enzymes or pH changes to control the release of the pharmaceutical substance. [0052] To be more specific, after oral administration to a mammal, including a human, of a pharmaceutical composition according to the present invention with a dose of 5 mg tacrolimus, tacrolimus is released in a controlled manner and shows a Cmax which is at most about 30 ng / ml such as, e.g. ex. at most about 25 ng / ml or at most about 20 ng / ml.

[0053] However, a reduction in the maximum value concentration may not lead to a reduction in the therapeutic effect since the plasma concentration of tacrolimus is maintained in the therapeutic window. Accordingly, the present invention also relates to a pharmaceutical composition, wherein W50 is at least about 2 hours, such as, e.g. ex. at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or about 14 hours or more.

[0054] In addition or on the other hand, a composition according to the invention has a Cdiff = [Cmax -Ct (t = 12 hours)] which is lower than that of Prograf® under the same conditions. If Cdiff for Prograf® is set to 100, then Cdiff of a composition according to the invention is normally 90 or less such as, e.g. ex. approximately 85 or less, approximately 80 or less, approximately 75 or less, approximately 70 or less, approximately 65 or less, approximately 60 or less, approximately 55 or less, approximately 50 or less, approximately 45 or less, or approximately 40 or less .

[0055] More specifically, after oral administration to a mammal, including a human, of a pharmaceutical composition of the invention with 5 mg of tacrolimus, tacrolimus is released in a controlled manner and shows a Cdiff of approximately 20 ng / ml. or less such as, p. ex. approximately 15 ng / ml or less, approximately 13 ng / ml or less or approximately 10 ng / ml or less.

[0056] A pharmaceutical composition according to the invention releases tacrolimus in a controlled manner to extend the therapeutic action of tacrolimus. In one aspect the release can be pH dependent, that is, the release predominantly develops after passage through the stomach. Such pH dependent release is mainly provided by means of enteric coating material as described herein. The release can also be independent of pH, e.g. ex. providing the composition with a controlled release coating, such as, e.g. ex. a cellulose based coating such as p. ex. ethyl cellulose, or providing the composition in the form of a matrix composition such as, e.g. ex. a type of hydrophilic cellulose polymer matrix p. ex. HPMC based. A combination of course can also be used.

[0057] In general, the change in bioavailability and / or changes in other related bioavailability parameters are normally determined by in vivo studies in a suitable animal model examining the compositions in question together with p. ex. Prograf® or a similar product commercially available with tacrolimus. The use of a dog model to establish evidence of the bioavailability of certain formulations is a general practice in the pharmaceutical industry.

[0058] The studies relevant to tacrolimus are non-radomized, crossover studies, where each dog is its own control. Four dogs, and four treatments are normally applied. As no iv injections are given, the bioavailability obtained is relative.

[0059] In addition, it has surprisingly been discovered that the need for simultaneous food intake to ensure sufficient absorption of tacrolimus is significantly reduced or even completely eliminated.

[0060] Thus, the pharmaceutical compositions according to the invention provide a significantly higher bioavailability of tacrolimus, which can reduce the number of daily dosing units administered, and reduce or eliminate the need for administration in conjunction with food intake, which provides a higher degree of freedom for the recipient of pharmaceutical compositions, and consequently the acceptance of patients and / or adaptability can be significantly improved. In addition, the compositions provide a significant reduction of side effects, especially side effects related to a high concentration of maximum value (such as, eg, nephro- and neurotoxicity, diarrhea, constipation, abdominal pain, nausea, etc.) and provide an extended release of tacrolimus leading to better therapy.

[0061] As mentioned above, one of the biggest challenges regarding the formulation of tacrolimus compositions is to avoid an adverse effect of the food. In general, tacrolimus is much better absorbed when administered orally without food. There is therefore a great variation in bioavailability after administration with or without food. This dependence makes it difficult to give precise guidelines as to how large a dose should be administered and, in addition, it requires informing the patient about the dosage regimen. The present invention aims at the provision of compositions in which the adverse effect of food is reduced. Thus, the present invention provides a composition, which does not show a significant adverse effect of food after administration of the composition to a mammal in need of such treatment as it becomes visible with a value of (AUCfed / AUCfasted) of at least about 0.85 with a confidence limit of less than 90% of at least 0.75.

[0062] More specifically , a pharmaceutical composition according to the invention has a value of (AUCfed / AUCfasted) of about 0.9 or more, such as, e.g. ex. about 0.95 or more, about 0.97 or more or about 1 or more such as, e.g. ex. up to about 1.1 or up to about 1.2.

[0063] Another advantage of a composition of the present invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to traditional oral treatment. Therefore, by oral administration to a mammal in need thereof of a pharmaceutical composition according to the invention, it releases tacrolimus or an analogue thereof in a controlled manner and the composition is essentially bioequivalent to Prograf® or a similar commercially available product. with tacrolimus when administered in a dose that is approximately at most approximately 85% w / w such as, e.g. ex. at most about 80% w / w, at most about 75%, at most about 70% w / w, at most about 65% w / w, at most about 60% w / w, at most about at 55% w / w

or at most about 50% w / w of the dose of tacrolimus administered in the form of Program® or a similar product commercially available with tacrolimus.

[0064] Parameters frequently used in bioequivalence studies are tmax, cmax, AUC0-infinity, AUC0-t. Other relevant parameters may be W50, W75 and / or MRT. Therefore, at least one of these parameters should be applied when determining whether bioequivalence is present. In addition, in the present context, two compositions are considered as bioequivalent if the value of the parameter used is within 80-125% of that of Prograf® or a similar commercially available product with tacrolimus used in the test.

[0065] In the present context "tmax" denotes the time to reach the maximum plasma concentration (cmax) after administration, AUC0-infinity denotes the area under the plasma concentration against the time curve from time 0 to infinity , AUC0-t denotes the area under the plasma concentration against the time curve from time 0 to time t, W50 denotes the time in which the plasma concentration is 50% or more of Cmax, W75 denotes the time in which the plasma concentration is 75% or more of Cmax, and MRT denotes the average residence period for tacrolimus ( and / or an analogue thereof).

[0066] Two other main disadvantages associated with treatment or prophylaxis with tacrolimus are the relatively high incidence of side effects and a relatively high interindividual variation. It is envisioned that a composition according to the invention will lead to a reduction in side effects. The reduction can be in terms of reduced frequency or in terms of severity. The side effects in question include p. ex. Nephro-and neurotoxicity, diarrhea, constipation, abdominal pain, nausea, etc. In one aspect, the invention concerns a pharmaceutical composition in particulate form comprising tacrolimus or an analogue thereof together with one or more pharmaceutically acceptable excipients, where the composition through oral administration to a mammal that needs it releases tacrolimus or an analogue thereof in a controlled manner and reduces the side effects compared to those of Prograf® administered under the same conditions and at a dose that provides a therapeutic effect. equivalent.

[0067] By increasing bioavailability, the area under the curve (AUC) will normally reduce the intra and inter variability related to the absorption of a pharmacological substance. This is particularly true, provided that low and damaged bioavailability is a consequence of poor water solubility. It is contemplated that the compositions according to the invention will provide a CV (Coefficient of Variation) in the AUC data having a significantly lower value than with Prograf® products and the like.

[0068] As mentioned above, one of the basic features of the present invention is that it is possible to obtain an improvement in bioavailability by oral administration of a composition of the present invention. Normally, a low bioavailability of a drug substance after oral administration is a barrier to the design of a controlled or modified release composition of the drug substance due to the fact that it is almost impossible to obtain effective drug levels for a prolonged period of time. . However, with the present technology it is possible to obtain a significantly improved bioavailability and thus it is possible to design, for example, controlled, modified or delayed release compositions.

[0069] Tacrolimus is extensively metabolized by the CYP3A4 isoenzyme in the wall of the intestine and liver. Accordingly, a suitable controlled release composition may be a composition that is designed to release tacrolimus in a delayed manner to avoid or reduce CYP3A4 metabolism in the gastrointestinal tract.

[0070] Delayed release is mainly caused by some type of enteric coating. While the semipermeable coating will show some type of delayed release, it may not "delay" the release precious enough. Additionally, it requires a certain amount of time to release the content. The coating sought for this invention is a pH dependent coating. This type of coating is very resistant to release the drug until it reaches a certain pH within a small increase in the pH value, 1/10, the film alters the properties and becomes permeable. Examples of pH sensitive polymers, which are relatively insoluble and impervious to the pH of the stomach, but which are more soluble and permeable in the pH of the small intestine and colon include, but are not limited to, polyacrylamides, phthalate derivatives such as phthalates. carbohydrate acids, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, Hydroxypropylcellulose acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, hydrogen polyvinyl acetate phthalate, sodium cellulose acetate phthalate, copolylate phthalate dibutyl acrylate phthalate maleic acid, styrene-polyvinyl acetate copolymer of maleic acid, styrene and maleic acid copolymers, polyacrylic acid derivatives, as copolymers of acrylic acid and acrylic ester, polymethacrylic acid and esters thereof, copolymers of poly acrylic acrylic acid, shellac, and copolymers of vinyl acetate and crotonic acid.

[0071] pH sensitive polymers of specific interest include shellac, phthalate derivatives, particularly cellulose phthalate, polyvinyl phthalate, and hydroxypropylmethylcellulose phthalate, polyacrylic acid derivatives, particularly polymethyl methacrylate mixed with acrylic acid copolymers and acrylic ester, and copolymers of vinyl acetate and crotonic acid.

[0072] The release of the active substance from a composition having a delayed-release coating could also be an enzymatic reaction, if, for example, mixtures of ceine or mono- / diglycerides are used as the coating material

[0073] Through oral administration to a mammal in need thereof, including a human, a controlled release pharmaceutical composition according to the present invention releases tacrolimus such that a plasma concentration of at least 5 ng / ml is obtained such for example, at least about 7.5 ng / ml or at least about 10 ng / ml for a period of at least about 24 hours. In a specific aspect of the invention the difference between the maximum value plasma concentration and the plasma concentration measured 24 hours after administration is at most about 20 ng / ml such as, e.g. ex. at most about 10 ng / ml, at most about 7.5 ng / ml or at most about 5 ng / ml.

[0074] The composition of the invention is designed to have a modified release of tacrolimus and may in particulate form, comprising tacrolimus together with one or more pharmaceutically acceptable excipients, through oral administration to a mammal in need thereof, having a release. delayed tacrolimus and / or an analogue thereof, so that at most 10% w / w such as, p. ex. at most about 7.5% w / w or at most about 5% w / w of the total amount of tacrolimus or an analogue thereof is released in the first two hours such as, e.g. ex. in the first hour after administration.

[0075] The following conditions are met with respect to the in vitro dissolution test performed under acidic conditions:

i) at most approximately 30% w / w such as, p. ex. at most about 25% w / w, at most about 20% w / w, at most about 15% w / w at most about 10% w / w tacrolimus is released in 2 hours in an in vitro dissolution test that use a dissolution medium with a pH of at most about 5 such as, e.g. ex. at most about 4.5, at most about 4, at most about 3.5, at most about 3, at most about 2, or at most about 1.5, ii) at most about 10% w / w such as, p. ex. at most about 7.5% w / w, at most about 5% w / w at most about 2.5% w / w of tacrolimus is released in 2 hours in an in vitro dissolution test using a dissolution medium with a pH of as much about 5 such as, p. ex. at most about 4.5, at most about 4, at most about 3.5, at most about 3, at most about 2 or at most about 1.5, iii) at most about 60% w / w such as, p. ex. at most about 50% w / w, at most about 40% w / w at most about 30% w / w of tacrolimus is released in 15 hours such as, e.g. ex. in about 12 hours, when tested in an in vitro dissolution test using a dissolution medium with a pH of at most about 4.5 such as, e.g. ex. at most about 4.0, at most about 3.5, at most about 3, at most about 2 or at most about 1.5 iv) at most about 40% w / w such as, p. ex. at most about 30% w / w, at most about 25% w / w at most about 20% w / w of tacrolimus is released in 6 hours when tested in an in vitro dissolution test using a dissolution medium with a pH of at most about 4.5 such as, e.g. ex. at most about 4.0, at most about 3.5, at most about 3, at most about 2 or at most about 1.5, and / or v) at most about 30% w / w such as, e.g. ex. at most about 25% w / w, at most about 20% w / w at most about 15% w / w of tacrolimus is released in 4 hours when tested in an in vitro dissolution test using a dissolution medium with a pH of at most about 4.5 such as, e.g. ex. at most about 4.0, at most about 3.5, at most about 3, at most about 2 or at most about 1.5.

[0076] Apart from tacrolimus, the composition of the invention may also comprise a therapeutically, prophylactically and / or diagnostically active substance. Of particular interest are combinations of tacrolimus with at least one of the following active substances: substances that are indicated for use in relation to organ transplantation such as, e.g. ex. steroids, calcineurin inhibitors and / or antiproliferative agents. Specific examples include prednisone, prednisolone, methylprednisone, cyclosporine, mycophenolate, azathioprine, sirolimus, everolimus, mycophenolate sodium, and FTY720 (Novartis).

[0077] The pharmaceutical compositions can be prepared by any convenient method such as, for example, granulation, mixing, spray drying, etc. A particularly useful method is the method described in WO 03/004001. Here we describe a process for the preparation of particulate material by a controlled agglomeration method, that is, a method that allows a controlled growth of the particle size. The method involves spraying a first composition comprising p. ex. tacrolimus and a carrier, which has been melted, on a second solid carrier medium. Normally, the meltable carrier has a melting point of at least 5 ° C but less than the melting point of tacrolimus. The melting point of the carrier may be in the range of 10 ° C to 150 ° C, such as, e.g. ex. in the range of 30 ° C to 100 ° C or in the range of 40 ° C to 50 ° C is the most preferred.

[0078] It is among the skills of the average professional to select a suitable carrier that is pharmaceutically acceptable, capable of dissolving or at least partially dissolving the tacrolimus and with a melting point in the desired range using general knowledge and routine experimentation. Suitable candidates for carriers are described in WO 03/004001, which is incorporated herein by reference.

[0079] In the present context, they are suitable carriers p. ex. those mentioned as an oil or an oil-like material (as discussed hereinafter) as well as those described in WO 03/004001.

[0080] An advantage of using the controlled agglomeration method described in WO 03/004001 is that it is possible to apply a relatively large amount of a fusion to a particulate material without having an undesirable growth in particle size. Accordingly, the particulate material of a pharmaceutical composition of the invention has an average diameter of geometric weight dgw of 10 10 µm such as, e.g. ex. 20 µm, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g. ex. from about 100 to about 1500 µm, from about 100 to about 1000 µm or from about 100 to about 700 µm, or at most from about 400 µm or at most 300 µm such as, p. ex. from about 50 to about 400 µm such as, e.g. ex. from about 50 to about 350 µm, from about 50 to about 300 µm, from about 50 to about 250 µm or from about 100 to about 300 µm, when prepared using the controlled agglomeration method.

[0081] The particulate material obtained by the above-mentioned method has adequate properties with respect to fluidity and / or compressibility and is therefore suitable for further treatment in pharmaceutical dosage forms.

Solid dispersion and / or solid tacrolimus solution

[0082] The solid dispersion or solid dispersion used in a preferred embodiment of the invention comprises tacrolimus dispersed or dissolved in a hydrophilic or water-miscible vehicle with a melting point (freezing point or pour point) of at least 20 ° C at a concentration of between about 0.01% w / w and about 15% w / w, and whose dispersion forms a solid dispersion or solid solution at room temperature (ambient temperature).

[0083] The concentration of the active ingredient in the hydrophilic or water-miscible vehicle is at most 15% w / w, preferably at most 10% w / w, preferably at most 8% w / w, more preferably at most 6% w / p, at most even more preferably 5% w / w, at most 4% w / w, especially at most 3% w / w, in particular at most 2% w / w, and / or is at least about 0.05% w / w, preferably at least about 0.1% w / w, more preferably at least about 0.5% w / w, especially at least about 0.7% w / w, in particular at least about 1% w / w.

[0084] Physically the combination of active ingredient and vehicle can either form a solid dispersion, that is, the active ingredient is dispersed in the vehicle in particulate form, or it can form a solid solution, that is, the active ingredient is dissolved in the vehicle at a molecular level. The active ingredient and the vehicle can also form a solid dispersion having a part of the active ingredient dissolved at a molecular level. The physical state of the dispersion and / or solution can be determined using various techniques such as hot phase microscopy (HSM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) optionally in combination with X-ray Dispersive Energy (EDX), and X-ray powder diffraction. In a preferred embodiment, the active ingredient is completely dissolved in the vehicle to form a solid solution at room temperature.

[0085] Examples of hydrophilic or water miscible vehicles useful for use according to this invention are selected from the group consisting of polyethylene glycols, poloxamers, and mixtures thereof.

[0086] In a preferred embodiment of the invention, the vehicle is a polyethylene glycol (PEG), in particular a PEG with an average molecular weight of at least 1500, preferably at least 3000, more preferably at least 4000, especially at least 6000, mixed with a poloxamer in a proportion (on a weight / weight basis) of between 1: 3 and 10: 1, preferably between 1: 1 and 5: 1, more preferably between and 3: 2 4: 1 , especially between 2: 1 and 3: 1, in particular approximately 7: 3. A specific example of a useful mixture is a mixture of PEG 6000 and poloxamer 188 in the 7: 3 ratio.

[0087] For polyethylene glycols (PEG), the melting point (freezing point or pour point) increases as the average molecular weight increases. For example, PEG 400 is in the range of 4-8 ° C, PEG 600 is in the range of 20-25 ° C, PEG1500 is in the range of 44-48 ° C, PEG2000 is about 52 ° C, PEG 4000 it is approximately 59 ° C, PEG 6000 is approximately 65 ° C and PEG 8000 is approximately 61 ° C.

[0088] Useful poloxamers (also called polyoxypropylene-polyoxyethylene block copolymers) are for example poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide such as Pluronic® series and / or Tetronic®. Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of approximately 3,000 or more, such as, e.g. ex. from about 4,000 to about 20,000 and / or a viscosity (Brookfield) from about 200 to about 4,000 cps such as, e.g. ex. from about 250 to about 3,000 cps. Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8, etc. Suitable block copolymers of the Tetronic® series include polymers with a molecular weight of approximately 8,000 or more such as, e.g. ex. from about 9,000 to about 35,000 and / or a viscosity (Brookfield) of about 500 to about 45,000 cps, such as, p. ex. from about 600 to about 40,000. The viscosities mentioned are determined at 60 ° C for substances that are pastes at room temperature and at 77 ° C for substances that are solid at room temperature.

[0089] In a preferred embodiment of the present invention, the poloxamer is poloxamer 188, which has an average molecular weight of about 8400 and a melting point of about 50-54 ° C.

Pharmaceutically acceptable excipients

[0090] Examples of excipients suitable for use in a solid composition or dosage form according to the present invention include fillers, diluents, disintegrants, binders, lubricants and the like and mixtures thereof. Since the composition or solid dosage form according to the invention can be used for different purposes, the choice of excipients is usually made taking into account such different uses. Other pharmaceutically acceptable excipients for proper use are e.g. ex. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and / or solubilizing agents, flavors and perfumes, humectants, sweetening agents, humidifying agents and the like.

[0091] Examples of suitable fillers, diluents and / or binders include lactose (eg, spray dried lactose, a-lactose, 1-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floc ®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (with low degree of substitution), hydroxypropylmethylcellulose (HPMC) (eg Methocel E , F and K, Metolose SH of Shin-Etsu, Ltd, such as, p. ex. 4,000 cps of Methocel E and Metolose 60 SH, 4,000 cps of Methocel F and Metolose 65 SH, 4,000, 15,000 and 100,000 cps of Methocel K, and 4,000, 15,000, 39,000, and 100,000 grades of Metolose 90 SH ), methylcellulose polymers (such as, e.g. Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other chemical derivatives of cellulose, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starch or starch starches , corn starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen, etc.

[0092] Specific examples of diluents are p. ex. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar, etc.

[0093] Specific examples of disintegrants are p. ex. alginic acid or alginates, microcrystalline cellulose, hydroxypropylcellulose and other chemical derivatives of cellulose, croscarmellose sodium, crospovidone, polacriline potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (eg Exota Primogel® ®), etc.

[0094] Specific examples of binders are p. ex. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch, etc.

[0095] Slippers and lubricants can also be included in the composition. Examples include stearic acid, magnesium stearate, calcium stearate or other metal stearate, talc, waxes and glycerides, light mineral oil, peg, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyglycol glycols , alkyl sulfates, sodium benzoate, sodium acetate, etc.

[0096] Other excipients that can be included in a solid composition or dosage form of the invention are e.g. ex. flavoring agents, coloring agents, flavoring masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, humidifying agents, moisture adjusting agents, surfactants, suspending agents, absorption enhancers, agents for modified release, etc.

[0097] Other additives in a composition or solid dosage form according to the invention may be antioxidants such as p. ex. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sulfoxylate formaldehyde, sodium metabisulphite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol, tocopherol, tocopherol, tocopherol, tocoferol of tocopherol, TPGS or other tocopherol derivatives, etc. The carrier composition may also contain p. ex. stabilizing agents The concentration of an antioxidant and / or a stabilizing agent in the carrier composition is usually from about 0.1% w / w to about 5% w / w.

[0098] A solid composition or dosage form according to the invention may also include one or more surfactants.

or substances with surfactant properties. It is contemplated that such substances are involved in the humidification of the slightly soluble active substance and thus, contributes to improved solubility characteristics of the active substance.

[0099] Excipients suitable for use in a composition or a solid dosage form according to the invention are surfactants such as, e.g. ex. amphiphilic surfactants such as those described in WO 00/50007 on behalf of Lipocina, Inc. Examples of suitable surfactants are

i) polyethoxylated fatty acids such as, e.g. ex. mono- or diesters of polyethylene glycol fatty acid or mixtures thereof such as, e.g. ex. mono-or diesters of polyethylene glycol with lauric acid, oleic acid, acid stearic acid, myristic acid, ricinoleic acid, and polyethylene glycol can be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000, ii) polyethylene glycol glycerol fatty acid esters, that is, esters such as those mentioned above but in the form of glyceryl esters of individual fatty acids, iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters, for example, vegetable oils as per example hydrogenated castor oil, almond oil, palms oil, castor oil, castor oil, Apricot kernel oil, olive oil, peanut oil, hydrogenated palms oil and Similar, iv) polyglycerated fatty acids, such as polyglycerol stearate, polyglycerol oleate, ricinoleate polyglycerol, polyglycerol linoleate, v) propylene glycol fatty acid esters such as, for example propylene glycol monolaurate, ricinoleate of propylene glycol and the like, vi) mono- and diglycerides such as glyceryl monooleate, glyceryl dioleate, mono- and / or dioleate glyceryl, glyceryl caprylate, glyceryl caproate, etc., vii) sterol and sterol derivatives, viii) polyethylene glycol sorbitan fatty acid esters (PEG sorbitan fatty acid esters) such as PEG esters, and the various molecular weights indicated above, and the various Tween ® series, ix) polyethylene glycol alkyl ethers such as, for example PEG x) sugar esters such as sucrose monopalmitate and sucrose monolaurate, xi) polyethylene glycol alkyl phenols such as the Triton® X or N series, xii) polyoxyethylene-polyoxypropylene block copolymers, such as, for example, the Pluronic® series, the Synperonic®, Emkalyx®, Lutrol®, Supronic® series, etc. The generic term for these polymers is "poloxamers" and relevant examples in the present context are poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407, xiii) sorbitan fatty acid esters such as the Span® series or Ariacel® series such as, for example sorbinan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, etc., xiv) lower alcohol fatty acid esters such as oleate, isopropyl myristate, palmitate isopropyl, etc., xv) ionic surfactants, including cationic, anionic, and bipolar surfactants such as, for example fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates and sulfonates, etc.

[0100] When a surfactant or a mixture of surfactants is present in a solid composition or dosage form of the invention, the concentration of the surfactant (s) is usually in a range from about 0.1-80% w / w such as, for example, from about 0.1 to about 20% w / w, from about 0.1 to about 15% w / w, from about 0.5 to about 10% w / w, or alternatively, from about 0.10 to about 80% w / w such as, for example from about 10 to about 70% w / w, from about 20 to about 60% w / w from about 30 to about 50% w / w.

[0101] One of the one or more pharmaceutically acceptable excipients may be selected from the group consisting of silica acid or a derivative or salt thereof, including silicates, silicon dioxide and polymers thereof, magnesium aluminosilicate and / or magnesium aluminometasilicate, Bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite.

[0102] Such materials are specifically useful as absorption materials for oils or oil-like materials in drugs, cosmetics and / or edibles. In a specific embodiment, the material is used as an absorption material for oils or oleaginous materials in drugs. The material that has the capacity to function as an absorption material for oils or oil-like materials is also called "oil absorption material". Furthermore, in the present context the term "absorption" is used to indicate "absorption" as well as "adsorption". It should be understood that whenever one of the terms is used, an attempt is made to cover the phenomenon of absorption as well as adsorption.

[0103] Particularly, the pharmaceutically acceptable excipient may comprise a silica acid or a derivative or salt thereof such as, for example, silicon dioxide or a polymer thereof, as a pharmaceutically acceptable excipient. Depending on the quality used, a silicon dioxide can be a lubricant or it can be an oil absorbing material. The qualities that perform this last function seem to be more important.

[0104] The solid composition or dosage form according to the invention may comprise a pharmaceutically acceptable excipient which is a silicon dioxide product having corresponding properties with Aeroperl® 300 (available from Degussa, Frankfurt, Germany).

[0105] The use of an oil absorption material in compositions or dosage forms according to the invention is very advantageous for the preparation of pharmaceutical, cosmetic, nutritional and / or food compositions, where the composition comprises oil or an oil-like material. One of the advantages is that it is possible to incorporate a relatively large amount of oil and oil-like material and still have a material that is solid. Thus, it is possible to prepare solid compositions with a relatively high load of oil or oleaginous materials using an oil absorbing material according to the invention. In the pharmaceutical field it is an advantage to be able to incorporate a relatively large amount of an oil or an oil-like material in a solid composition especially in that situation in which the active substance does not have adequate properties with respect to water solubility (e.g. ex. low water solubility), stability in the aqueous medium (ie degradation occurs in the aqueous medium), oral bioavailability (eg low bioavailability), etc., or in those situations where it is desired to modify the release of a active substance of a composition to obtain a distribution, controlled, released, sustained and / or pulsed of the active substance. Thus, in a specific embodiment it is used in the preparation of pharmaceutical compositions.

[0106] The oil absorbing material for use in the treatment in solid compositions normally absorbs about 5% w / w or more, such as, for example, about 10% w / w or more, about 15% w / w more, approximately 20% w / w or more, approximately 25% w / w or more, approximately 30% w / w or more, approximately 35% w / w or more, approximately 40% w / w or more, approximately 45 % p / po more, approximately 50 p / po more, approximately 55% w / w or more, approximately 60% w / w or more, approximately 65% ​​w / w or more, approximately 70% w / w or more, approximately 75% w / w or more, approximately 80% w / w / po more, approximately 85% w / w or more, approximately 90% w / w or more or approximately 95% w / w or more of an oil or an oil material and remains a solid material.

[0107] Another aspect of the invention relates to compositions or solid dosage forms comprising an oil

or an oil material.

[0108] In the present context the term "oils and oil materials" is used in a very broad sense including oils, waxes, semi-solid materials and materials that are normally used as solvents (such as organic solvents) or cosolvents in industry pharmaceutical, and the term also includes prophylactically and / or therapeutically active substances that are in liquid form at room temperature, the term also includes emulsions such as, microemulsions and nanoemulsions and suspensions. Oils and oleaginous materials that can be absorbed will normally be liquid at room temperature or high (for practical reasons the maximum temperature is approximately 250 ° C). These may be hydrophilic, lipophilic, hydrophobic, and / or amphiphilic materials.

[0109] Oils and oil-like materials that are suitable for use in the present context are substances or materials, which have a melting point of at least about 0 ° C and at most about 250 ° C.

[0110] In specific embodiments of the invention, the oil or oil-like material has a melting point of about 5 ° C or more, such as, for example, about 10 ° C or more, about 15 ° C or more , about 20 ° C or more or about 25 ° C or more.

[0111] In other embodiments of the invention, the oil or oil-like material has a melting point of at least about 25 ° C such as, for example, at least about 30 ° C, at least about 35 ° C, or at least about 40 ° C. For practical reasons, the melting point may not normally be too high, thus, the oil or oil-like material usually has a melting point of at most about 300 ° C such as, for example, at most about 250 ° C, such as much about 200 ° C, at most about 150 ° C or at most about 100 ° C. If the melting point is higher, a relatively high temperature can promote, for example, oxidation or other degradation of an active substance in those cases where, for example, therapeutically and / or prophylactically active substance is included.

[0112] In the present context, the melting point is determined by DSC (differential scanning calorimetry). The melting point is determined as the temperature at which the linear increase of the DSC curve intersects with the temperature axis

[0113] Interesting oils or oleaginous materials are generally substances, which are used in the production of drugs such as so-called fusion binders or solid solvents (in the form of solid dosage form), or as cosolvents or ingredients in drugs for use. topical

[0114] It can be hydrophilic, hydrophobic and / or have surfactant properties. In general, hydrophobic and / or hydrophilic oleaginous oils or materials are suitable for use in the production of a pharmaceutical composition comprising a therapeutically and / or prophylactically active substance having a relatively low water solubility and / or when the release of the Active substance of the pharmaceutical composition is designed to be immediate or unmodified. Hydrophobic oil or oleaginous type materials, on the other hand, are normally used in the production of a modified-release pharmaceutical composition. The considerations made above are simplified to illustrate general principles, but there are many cases in which other combinations of oils or oil-like materials and other purposes are relevant and, therefore, the above examples should not limit the invention in any way.

[0115] Typically, a suitable hydrophilic oil or oil type material is selected from the group consisting of: polyether glycols such as, for example, polyethylene glycols, polypropylene glycols, polyoxyethylenes, polyoxypropylenes, poloxamers and mixtures thereof, or may be selected of the group consisting of: xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13, other types of Gelucire such as, for example, Gelucire 44/14, etc., Gelucire 50/10, Gelucire 62/05, sucro-ester 7, sucro-ester 11, sucro-ester 15, maltose, mannitol and mixtures thereof.

[0116] A suitable hydrophobic oil or oleaginous type material may be selected from the group consisting of: saturated linear chain hydrocarbons, sorbitan esters, paraffins, fats and oils such as, for example, cocoa butter, beef tallow, lard, polyether glycol esters, higher fatty acids such as, for example stearic acid, myristic acid , palmitic acid, higher alcohols such as, for example, cetanol, stearyl alcohol, low melting point waxes such as, for example, glyceryl monostearate, glyceryl monooleate, hydrogenated tallow, myristyl alcohol, stearyl alcohol, unsubstituted and / or substituted monoglycerides, unsubstituted and / or substituted diglycerides, unsubstituted and / or substituted triglycerides, yellow beeswax, white beeswax, carnauba wax, castor wax, Japan, acetylate monoglycerides, NVP polymers, PVP polymers, acrylic polymers, or mixtures thereof.

[0117] In an interesting embodiment, the oil or oil-like material is a polyethylene glycol with an average molecular weight in a range from about 400 to about 35,000 such as, for example, from about 800 to about 35,000, from about 1,000 to approximately 35,000 such as, for example, polyethylene glycol 1,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6000, polyethylene glycol7,000, polyethylene glycol 8,000, polyethylene glycol 9,000, polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000. In certain situations polyethylene glycol can be used with a molecular weight from about 35,000 to about 100,000.

[0118] In another interesting embodiment, the oil or oil-like material is polyethylene oxide with a molecular weight from about 2,000 to about 7,000,000 such as, for example from about 2,000 to about 100,000, from about 5,000 to about 75,000, from approximately 10,000 to approximately 60,000, from approximately 15,000 to approximately 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 such as, for example, from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400,000 or from about 100,000 to about 300,000.

[0119] In another embodiment, the oil or oil-like material is a poloxamer such as, for example Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide such as Pluronic® series and / or Tetronic® series. Suitable block copolymers of the Pluronic® series include polymers with a molecular weight of about 3,000 or more such as, for example from about 4,000 to about 20,000 and / or a viscosity (Brookfield) of about 200 to about 4,000 cps such as, for example, from about 250 to about 3,000 cps. Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8, etc. Suitable block copolymers of the Tetronic® series include polymers with a molecular weight of about 8,000 or more such as, for example, from about 9,000 to about 35,000 and / or a viscosity (Brookfield) from about 500 to about 45,000 cps such as , for example, from about 600 to about 40,000. The viscosities given above are determined at 60 ° C for substances that are pastes at room temperature and 77 ° C for substances that are solid at room temperature.

[0120] The oil or oil-like material may also be a sorbitan ester such as, for example, sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate , sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquiestearate, sorbitan triisostearate, sorbitan trioleate, sorbitan sadarate or mixtures thereof.

[0121] The oil or oleaginous type material may of course comprise a mixture of different oils or oleaginous type materials such as, for example, a mixture of hydrophilic and / or hydrophobic materials.

[0122] Other suitable oils or oleaginous materials may be of semi-solid solvents or excipients such as, for example, propylene glycol, polyglycosed glycerides including Gelucire 44/14, complex fatty materials of plant origin, including theobroma oil, carnauba wax, vegetable oils as per example, almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soybean oil, olive oil, castor oil, palm kernel oil, peanut oil, nabine oil, grape seed oil, etc., hydrogenated vegetable oils such as, for example, hydrogenated peanut oil, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor, hydrogenated coconut oil, natural fatty materials of animal origin, including beeswax, lanolin, fatty alcohols including fatty alcohols of cetyl, stearyl, lauric, mymitic palmitic, stearic acid, esters including glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate, liquid intersterified 810/812 semi-synthetic glycerides, fatty acid amide or alkolamides, including steramide ethanol, coconut fatty acid diethanolamide, acid esters acetic acid mono and diglycerides, citric acid esters of mono and diglycerides, lactic acid esters of mono and diglycerides, mono and diglycerides, polyglycerol esters of fatty acids, polyglycerol polyyricinoleate, fatty acid propylene glycol esters, sorbitan monostearates, sorbitan sadarates, sodium stearoyl lactylates, calcium stearoyl lactylates, monoacetyl diacetyl tartaric acid esters, etc.

[0123] Normally, a pharmaceutical composition or solid dosage form according to the invention has a concentration of the oil or oil-like material in the composition of about 5% w / w or more such as, for example, about 10% w / w or more , approximately 15% w / w or more, approximately 20% w / w or more, approximately 25% w / w or more, approximately 30% w / w or more, approximately 35% w / w or more, approximately 40% w / w or more, approximately 45% p / po more, approximately 50 p / po more, approximately 55% p / po more, approximately 60% p / po more, approximately 65% ​​p / po more, approximately 70% p / po more, approximately 75% p / po more, approximately 80% p / po more, approximately 85% p / po more, approximately 90% p / po more or approximately 95% p / po more.

[0124] The concentration of the oil or oil-like material in a solid composition or dosage form of the invention may be in a range from about 20% to about 80% w / w such as, for example, from about 25% to about 75% w / w

[0125] One of the advantages is that it is possible to incorporate a relatively large amount of oil and oil-like material and still have a material that is solid. Thus, it is possible to prepare solid compositions with a relatively high load of oil or oleaginous materials using an oil absorbing material according to the invention. In the pharmaceutical field it is an advantage to be able to incorporate a relatively large amount of an oil or an oil-like material in a solid composition especially in that situation where the active substance does not have adequate properties with respect to water solubility (e.g. low solubility in water), stability in aqueous medium (i.e. degradation occurs in the aqueous medium), oral bioavailability (eg. low bioavailability), etc., or in those situations where it is desired to modify the release of an active substance from a composition to obtain a controlled, delayed, sustained and / or pulsed delivery of the active substance.

[0126] Another advantage is that the particulate material obtained is a free flowing powder therefore it is easily processable in for example solid dosage forms such as tablets, capsules or sachets. Normally, the particulate material has properties that are adapted to produce pellets by direct compression without adding large amounts of more additives. A suitable test to examine the fluidity of particulate material is the method described in Ph.Eur. and measuring the flow rate of the material of a funnel with a nozzle diameter (hole) of 10.0 mm.

[0127] At least a part of tacrolimus is present in the composition in the form of a solid solution including a molecular dispersion and a solid dispersion. Normally, 10% or more, such as, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, such as, for example, 95% or more or about 100% w / w tacrolimus is present in the composition in the form of a solid dispersion.

[0128] A solid dispersion can be obtained by different routes, for example, using organic solvents or by dispersing or dissolving the active substance in another suitable medium (eg an oil or an oil-like material that is in liquid form at room temperature or at high temperatures).

[0129] Solid dispersions (solvent method) can be prepared, for example, by dissolving a physical mixture of the active substance (eg a pharmacological substance) and the carrier in a common organic solvent, followed by evaporation of the solvent. The carrier is often a hydrophilic polymer. Suitable organic solvents include a pharmaceutically acceptable solvent in which the active substance is soluble such as methanol, ethanol, methylene chloride, chloroform, ethyl acetate, acetone or mixtures thereof.

[0130] Suitable water-soluble carriers include polymers such as polyethylene glycol, poloxamers, polyoxyethylene stearates, poly-s-caprolactone, polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-polyvinyl acetate copolymer PVP-PVA (Kollidrosimeta VA64, polyethylene VAragon (polyethylene VA64) Eudragit RL, Eudragit NE, Eudragit E) and polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, and poly (ethylene oxide) (PEO).

[0131] Polymers with functional acidic groups may be suitable for solid dispersions, which release the active substance in a preferred pH range providing acceptable absorption in the intestines. Such polymers may be one or more selected from the group comprising hydroxypropylmethylcellulose phthalate (HMPCP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Ecrylic acid, Ecitric acid ), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacriline, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.

[0132] In relation to the amount of the active substance and the polymer in the solid dispersion, the weight ratio of active substance to polymer may be in a range from about 3: 1 to about 1:20. However, narrower intervals from about 3: 1 to about 1: 5 can also be used, such as, for example, from about 1: 1 to about 1: 3 or about.

[0133] The solid dispersion is preferably formed by spray drying, controlled agglomeration, lyophilization or coating on carrier particles or any other solvent removal process. The dried product contains the active substance present in the form of a solid dispersion including a molecular dispersion and a solid solution.

[0134] As an alternative to the use of organic solvents, the medicament and polymer can be co-crushed or extruded at elevated temperatures (melt extrusion).

[0135] Pharmaceutical compositions comprising tacrolimus at least partially in the form of a dispersion

or solid solution can be prepared in principle using any suitable method to prepare pharmaceutical compositions known in the art.

[0136] In addition to using the organic solvent based method, the solid dispersion or solid solutions of tacrolimus can be obtained by dispersion and / or dissolution of tacrolimus in the carrier composition used in the controlled agglomeration method. Stabilizing agents, etc., can be added to ensure the stability of the dispersion / solid solution.

[0137] In another aspect, the invention relates to a method for the preparation of a pharmaceutical composition according to the invention. In general, any suitable method of the pharmaceutical field can be used. However, to allow the incorporation of a relatively high amount of an oil or an oil-like material, the method described in WO 03/004001 has proven to be especially useful. The method comprises spraying a first composition in liquid form, said composition comprising a first vehicle or carrier and with a melting point greater than 5 ° C on a second composition comprising a second support or carrier material, said second composition being for example in a fluidized state and having a temperature below the melting point of the first vehicle or carrier. The active substance may be present in the first carrier or carrier composition and / or in the second carrier or carrier composition. However, in those cases in which the tacrolimus is present, at least partially, in the form of a solid dispersion, it is advantageous to incorporate or dissolve the tacrolimus in the first carrier or carrier composition.

Solid dosage forms

[0138] The pharmaceutical composition according to the invention is in particulate form and can be used as such. However, in many cases it is more convenient to present the composition in the form of granules, granules, microspheres, nanoparticles and the like or in the form of solid dosage forms, including pills, capsules and envelopes and the like. A solid dosage form according to the invention may be a unit dosage form or it may contain in the form of a polydepositive dosage a plurality of individual units such as, for example, tablets, beads and / or granules.

[0139] Normally, a pharmaceutical composition or a solid dosage form of the invention is intended for oral, oral or sublingual route administration.

[0140] The invention also relates to the form of presentation mentioned above. Within the scope of the invention there are compositions / solid dosage forms that are intended to release tacrolimus and / or analogs thereof in a rapid release, delayed release or modified release manner. All these ways are considered as a controlled way. In addition, a pH-dependent release is also covered by the term "controlled manner."

[0141] A solid dosage form according to the present invention comprises a pharmaceutical composition in particulate form as described above. The details and particularities described in this main aspect of the invention apply mutatis mutandis to the other aspects of the invention. Therefore, the properties with respect to the increase in bioavailability, changes in the parameters of bioavailability, the reduction in the adverse effect of food, as well as the release of tacrolimus and / or an analogue etc., described and / or claimed herein for pharmaceutical compositions in particulate form are analogous to a solid dosage form according to the present invention.

[0142] Normally, the concentration of the pharmaceutical composition in particulate form is in a range from about 5 to 100% w / w such as, for example, from about 10% to about 90% w / w, from about 15% to about 85% w / w, from about 20% to about 80% w / w, from about 25% to about 80% w / w, from about 30% to about 80% w / w, from about 35% to about 80% w / w, from about 40% to about 75% w / w, from about 45% to about 75% w / w from about 50% to about 70% w / w in the form of dosage. For example, the concentration of the pharmaceutical composition in the particulate form is 50% w / w or more of the dosage form.

[0143] A solid dosage form according to the invention is obtained by treating the particulate material according to the invention by techniques well known to one skilled in the art. Normally, it implies another addition of one or more of the pharmaceutically acceptable excipients mentioned herein.

[0144] The composition or solid dosage form according to the invention can be designed to release tacrolimus and / or an analogue thereof in any suitable manner as long as the increase in bioavailability is present. Thus, the active substance can be released relatively quickly to obtain an enhanced onset of action, it can be released to follow zero order and first order kinetics or it can be released in a modified way to obtain a predetermined release model. All of these pathways are considered controlled ways. Simple formulations are also within the scope of the present invention.

[0145] The recommended dosage range for Prograf® is 0.1 to 0.2 mg / kg / day every 12 hours in two divided doses. More importantly, blood levels have to be monitored.

[0146] The typical level for 1 -3 months is 7-20 ng / mL and 4-12 months the levels should be 5 -15 ng / mL. These are only guide values ​​and may vary depending on the type of transplant and ethnicity.

[0147] The following data have been discovered for kidney transplant patients.

<dl><dt>Caucasian n = 114 </dt><dd>black n = 56 </dd></dl>

<dl><dt>Time after transplant </dt><dd>dose (mg / kg) minimum concentrations (ng / mL) dose (mg / kg) minimum concentrations (ng / mL) </dd></dl>

<dl><dt>Day 7 </dt><dd> 0.18 12.0 0.23 10.9 </dd></dl>

<dl><dt>Month 1 </dt><dd> 0.17 12.8 0.26 12.9 </dd></dl>

<dl><dt>6 month </dt><dd> 0.14 11.8 0.24 11.5 </dd></dl>

<dl><dt>12 month </dt><dd> 0.13 10.1 0.19 11.0 </dd></dl>

[0148] The recommended dose recommendation of the products of the present invention will be from 0.02 mg / kg / day to 0.15 mg / kg / day, dosed once a day.

[0149] The solid composition or dosage form according to the invention can also be coated with a film coating, an enteric coating, a modified release coating, a protective coating, a non-stick coating, etc.

[0150] A solid dosage form according to the invention can also be covered to obtain suitable properties e.g. ex. with respect to the controlled release of the active substance. The coating can be applied in individual unit dosage forms (eg pills, capsules) or it can be applied in a polydeposit dosage form or in its individual units.

[0151] Suitable coating materials are p. ex. methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol, sodium carboxymethyl cellulose, cellulose acetate, cophacrylic acid methacrylic acid acetate sucrose, titanium dioxide, carnauba wax, microcrystalline wax, glyceryl monostearate, ceine.

[0152] Plasticizers and other ingredients can be added to the coating material. The same or different active substance may also be added to the coating material.

[0153] In preferred embodiments of the invention, solid dosage forms are designed to release tacrolimus and / or an analogue thereof in a controlled manner. In the present context, the term "controlled manner" is intended to include all types of release that differ from the release of simple pills. Thus, the term includes so-called "controlled release", "modified release", "sustained release", "pulsed release", "prolonged release", "burst release", "slow release", "extended release", like than the terms "delayed release" and pH dependent release. However, a specific aspect of the invention relates to a delayed release composition or dosage form, which in this context is intended to indicate a composition.

or dosage form that at most releases 10% w / w of the active substance in the first 2 hours after administration and / or after the start of a dissolution test using a dissolution medium with a pH of at most approximately 3.

Modified Release Systems

[0154] A first modified release system includes matrix systems, in which tacrolimus is introduced or dispersed in a matrix of another material that serves to retard the release of tacrolimus in an aqueous environment (ie, the luminal fluid of the GI tract ). When tacrolimus is dispersed in such a matrix, the release of the drug develops mainly from the surface of the matrix. Thus, the medication is released from the surface of a device, which incorporates the matrix after it diffuses through the matrix or when the surface of the device erodes, exposing the medication. In some embodiments, both mechanisms can operate simultaneously. Matrix systems can be large, that is, pill size (approximately 1 cm), or small (&lt;0.3cm). The system can be unitary (e.g. a bolus), may be divided by virtue of being composed of different subunits (for example, different capsules constituting a single dose) that are administered substantially simultaneously, or may comprise a plurality of particles, also called a multiparticulate. A multiparticulate can have numerous formulation applications. For example, a multiparticulate can be used as a powder to fill a capsule shell, or used per se to be mixed with food to facilitate ingestion.

[0155] A useful multiparticulate matrix comprises a plurality of particles with tacrolimus, each tacrolimus and / or analog particle thereof comprising p. ex. in the form of a solid solution / dispersion with one or more excipients selected to form a matrix capable of controlling the dissolution rate of tacrolimus in an aqueous medium. Matrix materials are generally hydrophobic materials such as waxes, some cellulose derivatives, or other hydrophobic polymers. If necessary, the matrix materials can optionally be formulated with hydrophobic materials, which can be used as binders or as enhancers. Matrix materials useful for the production of these dosage forms such as: ethyl cellulose, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, and the like, as well as synthetic polymers such as, poly ( vinyl chloride), poly (vinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene, and the like. Hydrophilic or water soluble binders or modified release agents that may be optionally formulated in the matrix include hydrophilic polymers such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, poly (N-vinyl-2-pyrrolidinone) (PVP), poly (ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), xanthan gum, carrageenan, and other natural and synthetic materials of this type. In addition, materials whose function as release modifying agents include water-soluble materials such as sugars or salts. Preferred water-soluble materials include lactose, sucrose, glucose, and mannitol, as well as hydrophilic polymers such as e.g. ex. HPC, HPMC, and PVP.

[0156] A multiparticulate product can also be treated by controlled agglomeration. In this case, tacrolimus is dissolved or partially dissolved in a suitable meltable carrier and sprayed onto carrier particles comprising the matrix substance. Suitable meltable carriers have been mentioned here previously.

[0157] Alternatively, tacrolimus is dissolved in an organic solvent together with the matrix substance and spray dried or applied on carrier particles, cf. then. Solvents typically used for the process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more.

[0158] Once formed, the multiparticulate matrix of tacrolimus can be mixed with compressible excipients, such as lactose, microcrystalline cellulose, dicalcium phosphate, and the like, and the mixture can be compressed to form a tablet. Disintegrants such as cross-linked sodium starch glycolate or polyvinyl pyrrolidone are also useful. The tablets prepared by this method disintegrate when placed in an aqueous medium (such as

GI tract), thus exposing the multiparticulate matrix, which releases tacrolimus from there.

[0159] The matrix system may also be in the form of a hydrophilic matrix tablet with tacrolimus and / or an analog thereof (eg in the form of a solid dispersion) as a multiparticulate product and an amount of hydrophilic polymer sufficient to provide a useful degree of control over the dissolution of tacrolimus. Hydrophilic polymers useful for matrix formation include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), poly (ethylene oxide), polyvinyl alcohol, xanthan gum, carbomer, carrageenan, and zooglan. A preferred material is HPMC. Other similar hydrophilic polymers can also be used. In use, the hydrophilic material is swollen by, and eventually dissolved in, water. Tacrolimus is released by both, by diffusion of the matrix and by erosion of the matrix. The dissolution rate of tacrolimus of these hydrophilic matrix tablets can be controlled by the amount, molecular weight and gel strengths of the hydrophilic polymer employed. In general, using a higher amount of the hydrophilic polymer reduces the dissolution rate, as is done using a higher molecular weight polymer. Using a polymer of lower molecular weight usually increases the dissolution rate. A matrix tablet typically comprises about 20 to 90% by weight of tacrolimus and about 80 to 10% by weight of polymer.

[0160] A preferred matrix tablet comprises by weight, about 30% to about 80% solid dispersion with tacrolimus and / or an analog thereof, about 15% to about 35% matrix former (such as, e.g. HPMC), 0% to about 35% lactose, 0% to about 20% microcrystalline cellulose, and about 0.25% to about 2% lubricant (such as, eg magnesium stearate).

[0161] Matrix systems as a class frequently exhibit non-constant release of the drug from the matrix. This result may be a consequence of the diffusive drug release mechanism, and modifications in the geometry of the dosage form can be advantageously used to make the drug release rate more constant.

[0162] A second class of controlled release dosage forms of tacrolimus of this invention includes moderate membrane or reservoir systems. In this class, a deposit of tacrolimus p. ex. In a solid solution / dispersion as a multiparticulate product it is surrounded by a speed limiting membrane. Tacrolimus crosses the membrane through mass transport mechanisms well known in the art, including but not limited to dissolution in the membrane followed by diffusion through the membrane or diffusion through pores filled with liquid in the membrane. These individual dosage forms of the deposition system can be large, as in the case of a tablet with a single large deposit, or multiparticulate, as in the case of a capsule or polydepositive tablets with a plurality of deposit particles, each individually coated with a membrane. The coating can be non-porous, even permeable to tacrolimus (for example, tacrolimus can diffuse directly through the membrane), or it can be porous. As with other embodiments of this invention, the particular transport mechanism is not believed to be critical.

[0163] Sustained release coatings as are known in the art can be used to make the membrane, especially polymer coatings, such as a cellulose ester or ether, an acrylic polymer, or a mixture of polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer can be applied as a solution in an organic solvent or as an aqueous dispersion or latex. The coating operation can be carried out in standard equipment such as a fluid bed liner, a Wurster liner, or a rotating fluid bed liner.

[0164] If desired, the permeability of the coating can be adjusted by mixing two or more materials. A particularly useful process for making the porosity of the coating comprises the addition of a predetermined amount of a finely divided water-soluble material, such as sugars or water-soluble salts or polymers to a solution or dispersion (eg an aqueous latex) of the forming polymer of membrane to be used. When the dosage form is ingested in the aqueous medium of the GI tract, these water-soluble membrane additives are filtered out of the membrane, leaving pores that facilitate the release of the drug. The membrane coating can also be modified by the addition of plasticizers, as is known in the art.

[0165] A particularly useful variation of the process for applying a membrane coating comprises dissolving the coating polymer in a chosen solvent mixture so that the coating dries, a phase inversion takes place in the applied coating solution, giving as a result a membrane with a porous structure.

[0166] In general, a support is not required to mechanically reinforce the membrane.

[0167] Membrane morphology is not critically important as long as the permeability characteristics listed here are achieved. The membrane can be amorphous or crystalline. It can have any category of morphology produced by any particular process and can be, for example, an interfacially polymerized membrane (comprising a thin skin of speed limitation in a porous support), a hydrophilic porous membrane, a hydrophobic porous membrane, a membrane of hydrogel, an ionic membrane, and other materials of

This type is characterized by controlled permeability against tacrolimus.

[0168] It is an objective to reduce the exposure of the upper GI tract to high concentrations of tacrolimus. Accordingly, suitable dosage forms include those forms, which incorporate a specific delay before the onset of controlled release of tacrolimus. An exemplary embodiment can be illustrated by a tablet (or a particulate material) comprising a core with tacrolimus coated with a first coating of a polymeric material of the type useful for sustained release of tacrolimus and a second coating of the type useful for release delayed drug when the dosage form is ingested. The first coating is applied on and surrounds the tablet or the individual particles. The second coating is applied on and surrounds the first coating.

[0169] A tablet can be prepared by techniques well known in the art and contains a therapeutically useful amount of tacrolimus plus those excipients that are necessary to form the tablet by such techniques.

[0170] The first coating may be a sustained release coating as is known in the art, especially polymeric coatings for manufacturing the membrane, as discussed above for deposit systems. Or this could be a controlled release matrix core, which is coated a second time with a delayed release material.

[0171] Materials useful for preparing the second coating on the tablet include polymers known in the art as enteric coatings for delayed drug release. These are very commonly pH sensitive materials, such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl cellulose phthalate, polyvinyl acetate phthalate and acrylic copolymers such as Eudragit L-100 (Röhm Pharma) and related materials, such as it is detailed more fully below in "delayed release". The thickness of the delayed release coating is adjusted to give the desired delay property. In general, thicker coatings are more resistant to erosion and, consequently, produce a longer and more effective delay. Preferred coatings range from about 30 µm thick to about 3 mm thick.

[0172] When a hydrophobic matrix material is used as glyceryl monostearate, no delay coating is necessary. The tablet will not release tacrolimus until an area of ​​enzymatic degradation has been reached, more specifically after the duodenum.

[0173] When ingested, the doubly coated tablet passes through the stomach, where the second coating prevents the release of tacrolimus under the predominant acidic conditions there. When the pill leaves the stomach and enters the small intestine, where the pH is higher, the second coating erodes or dissolves according to the physicochemical properties of the chosen material. After erosion or dissolution of the second coating, the first coating prevents immediate or rapid release of tacrolimus and modulates the release to prevent the production of high concentrations of high maximum value, thus minimizing side effects.

[0174] Another example is a multiparticulate in which each particle is doubly coated as described above in the case of the tablets, first with a polymer designed to produce a sustained release of tacrolimus and then coated with a polymer designed to delay start of release in the environment of the GI tract when the dosage form is ingested.

[0175] The tacrolimus release rate of the sustained release multiparticulates (ie, the multiparticulates before receiving the delayed release coating) and the methods of coating modification are also controlled by the previously treated factors for multiparticulates of tacrolimus from deposit system

[0176] The second membrane or coating for multiparticulates with double coating is a delayed release coating that is applied on the first sustained release coating, as described above in the case of the pads, and may be formed of the same materials . It should be noted that the use of materials called "enteric" to practice this embodiment differs significantly from its use to produce conventional enteric dosage forms. With conventional enteric forms, the object is to delay the release of the drug until the dosage form has passed the stomach and then deliver the dose into the duodenum. The dosage of tacrolimus directly and completely to the duodenum may be undesirable, however, due to the side effects that are intended to be minimized or avoided with this invention. Therefore, if conventional enteric polymers are to be used to implement this embodiment, it may be necessary to apply them significantly thicker than in conventional practice, to delay the release of the drug until the dosage form reaches the tract Lower GI. However, it is also possible to make a controlled or sustained delivery of tacrolimus after the delayed release coating has dissolved or eroded, therefore, the benefits of this embodiment can be realized with an appropriate combination of release character. delayed with sustained release character, and the delayed release portion alone may or may not necessarily conform to the enteric criteria of USP. The thickness of the delayed release coating is adjusted to give the desired delay property. In general, thicker coatings are more resistant to erosion and, consequently, produce a longer delay.

[0177] A first delayed release dosage form is a "pH dependent coated dosage form" such as, e.g. ex. A pill or a capsule. In the case of a tablet it comprises a tablet core comprising tacrolimus p. ex. in a solid solution / dispersion as a multiparticulate product, a controlled release matrix of p. ex. HPMC, a disintegrant, a lubricant, and one or more pharmaceutical carriers, said core being with a material, preferably a polymer, which is substantially insoluble and impermeable to the pH of the stomach, and which is more soluble and permeable to the pH of the small intestine . Preferably, the coating polymer is substantially insoluble and impermeable at pH &lt;5.0, and water soluble at pH&gt; 5.0. The core of the tablet may be coated with a sufficient amount of polymer to ensure that substantially no release of tacrolimus occurs from the dosage form until the dosage form has left the stomach and has remained in the small intestine for approximately 15 minutes. or more, preferably about 30 minutes or more, thus ensuring that a minimum of tacrolimus is released into the duodenum. Mixtures of a pH sensitive polymer with a water insoluble polymer can also be used. The tablets are coated with an amount of polymer comprising from about 10% to about 80% of the weight of the tablet core containing tacrolimus. Preferred tablets are coated with an amount of polymer comprising about 15% to about 50% of the weight of the tacrolimus tablet core.

[0178] pH-sensitive polymers that are very insoluble and impervious to the pH of the stomach, but that are more soluble and permeable to the pH of the small intestine and colon include polyacrylamides, derivatives of phthalates such as carbohydrate acid phthalates, amylose acetate phthalate , cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, hydrogen polyvinyl acetate phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-dibutyl copolymer, maleic acid phthalate, styrene-polyvinyl acetate copolymer acetate copolymer, of maleic acid and styrene, polyacrylic acid derivatives, such as copolymers of acrylic acid and acrylic ester, polymethacrylic acid and its esters, copolymers of poly acrylic acrylic acid, shellac, and copolymers of vinyl acetate and crotonic acid.

[0179] Preferred pH sensitive polymers include shellac, phthalate derivatives, particularly cellulose phthalate, polyvinyl acetate phthalate, and hydroxypropylmethyl cellulose phthalate, polyacrylic acid derivatives, particularly polymethyl methacrylate mixed with acrylic acid and ester copolymers acrylic, and copolymers of vinyl acetate and crotonic acid.

[0180] The delay time before the release of tacrolimus, after the "pH-dependent coated tablet" dosage form has left the stomach, can be controlled by the choice of relative amounts of Eudragit-L® and Eudragit -S® in the coating, and by the choice of the thickness of the coating. Eudragit-L® films dissolve above pH 6.0, and Eudragit-S® films dissolve above 7.0, and the mixtures dissolve at an intermediate pH. Since the pH of the duodenum is approximately 6.0 and the pH of the colon is approximately 7.0, coatings composed of mixtures of Eudragit-L® and Eudragit-S® provide protection to the duodenum of tacrolimus. If it is desired to delay the release of tacrolimus until the "pH-dependent coated tablet" with tacrolimus has reached the colon, Eudragit-S® should be used as the coating material, as described by Dew et al. (Br. J. Clin. Pharmac. 14 (1982) 405-408). In order to retard the release of tacrolimus for about 15 minutes or more, preferably 30 minutes or more, after the dosage form has left the stomach, preferred coatings comprise from about 9: 1 to about 1: 9 of Eudragit- L® / Eudragit-S®, more preferably from about 9: 1 to about 1: 4 of Eudragit-L® / Eudragit-S®. The coating may comprise from about 3% to about 70% of the weight of the uncoated tablet core. Preferably, the coating comprises from about 5% to about 50% of the weight of the tablet core.

Applications

[0181] The pharmaceutical composition of the invention can be used in the preparation of a solid oral dosage form such as pills, capsules or sachets, or for the preparation of granules, granules, microspheres or nanoparticles.

[0182] Preferably the pharmaceutical composition is used in the preparation of a solid dosage form of immediate release or a solid dosage form of delayed release.

[0183] Another advantage of a composition of the present invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to a traditional oral treatment. Thus, it is contemplated that the solid dosage form of the invention, when administered orally to a mammal in need thereof at a dose that is at most about 85% w / w such as, e.g. ex. at most about 80% w / w, at most about 75%, at most about 70% w / w, at most about 65% w / w, at most about 60% w / w, at most about 55% w / w or at most approximately 50% w / w of the dose of tacrolimus administered in the form of Prograf® or a similar product commercially available with tacrolimus, It is essentially bioequivalent with Prograf® or a similar product commercially available with tacrolimus.

[0184] Any of the dosage forms and compositions with tacrolimus of the invention can improve the treatment of conditions that respond to the treatment of tacrolimus.

[0185] Tacrolimus is indicated (or has been recommended) for the treatment of diseases such as, e.g. ex. Rejection reactions due to the transplantation of organs or tissues such as the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc. , graft versus host reactions after bone marrow transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc., infections caused by pathogenic microorganisms (eg Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroids, etc.), inflammatory or hyperproliferative diseases of the skin or cutaneous manifestations of immunologically mediated diseases (eg. Psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, lupus erythematosus, acne acne, and acne disease eye (e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleucoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves ophthalmopathy, Vogt-Koyrati-Syndrome (dry eye), flicténulo, iridociclitis, sarcoidosis, endocrine ophthalmopathy, etc.), reversible diseases of airway obstruction [asthma (eg. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), particularly chronic or inveterate asthma (eg late asthma and hyperreactivity of the respiratory tract) bronchitis, etc., mucosal or vascular inflammations (eg . gastric ulcer, ischemic or thrombotic vascular lesion, ischemic diseases of the intestine, enteritis, necrotizing enterocolitis, intestinal damage associated with thermal burns, diseases mediated by leukotriene B4), inflammation / intestinal allergies (e.g. celiac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis), food-related allergic diseases with remote symptomatic manifestation of the gastrointestinal tract (eg migraine, rhinitis and eczema), kidney diseases (eg. intestinal nephritis, Goodpasture syndrome, hemolytic uremic syndrome, and diabetic nephropathy), nervous diseases (e.g. multiple myositis, Guillain-Barre syndrome, Meniere's disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS) and radiculopathy), ischemic brain disease (eg cranial trauma hemorrhage in the brain

<dl><dt>(p.</dt><dd> ex. subarachnoid hemorrhage, intracerebral hemorrhage), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (ATI), hypertensive encephalopathy, cerebral infarction), endocrine diseases (eg hyperthyroidism, and Basedow disease), blood diseases (e.g. pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, and aneritroplasia), bone diseases (eg osteoporosis), respiratory diseases (eg sarcoidosis , pulmonary fibrosis, and idiopathic interstitial pneumonia), skin diseases (e.g. dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity and cutaneous T-cell lymphoma), circulatory diseases (eg arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, and myocardosis), collagen diseases (eg scleroderma, Wegener's granuloma, and Sjogren's syndrome), adiposis, eosinophilic fasciitis, periodontal diseases (eg gum damage, periodontium, alveolar bone or substantia ossea dentis), nephrotic syndrome (eg. glomerulonephritis), male pattern alopecia, senile alopecia, muscular dystrophy, pyoderma syndrome and Sezary syndrome, diseases associated with chromosomal abnormalities </dd></dl>

<dl><dt>(p.</dt><dd> ex. Down syndrome), Addison's disease, active oxygen mediated diseases [p. ex. organ injury (eg, ischemic organ circulation disorders (eg heart, liver, kidney, digestive tract, etc.) associated with conservation, transplantation, or ischemic diseases (eg thrombosis , heart attack, etc.)), intestinal diseases (eg endotoxic shock, pseudomembranous colitis, and drug or radiation-induced colitis), kidney diseases (p. ex. acute ischemic renal failure, chronic renal failure), pulmonary diseases (eg toxicosis caused by pulmonary oxygen or drugs (eg paracort, bleomycin, etc.), lung cancer, and pulmonary episema), eye diseases (p eg cataracts, iron storage disease (bulbi siderosis), retinitis, pigment, senile plaques, vitreous scarring, alkali corneal burn), dermatitis</dd></dl>

<dl><dt>(p.</dt><dd> ex. erythema multiforme, linear bullous dermatitis due to immunoglobulin A, cement dermatitis), and other diseases (eg gingivitis, periodontitis, sepsis, pancreatitis, and diseases caused by environmental contamination (eg. air pollution), aging, carcinogen, carcinoma metastasis, and hypobaropathy)], diseases caused by the release of histamine or C4 leukotrienes, coronary artery restenosis after angioplasty and prevention of postoperative adhesions, autoimmune diseases and inflammatory conditions (p eg primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male sterility, juvenile diabetes mellitus, vulgar pemphigus, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, chronic active hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis arthritis (e.g. deforming arthritis), or polychondritis), human immunodeficiency virus (HIV) infection, AIDS, allergic conjunctivitis, hypertrophic scar and keloid due to trauma, burn, or surgery. </dd></dl>

[0186] In addition, tricyclic macrolides such as p. ex. Tacrolimus have regenerative activity of the liver and / or activities to stimulate hypertrophy and hyperplasia of hepatocytes. Therefore, the pharmaceutical composition of the present invention is useful for increasing the effect of therapy and / or prophylaxis of liver diseases [p. ex. immunogenic diseases (e.g. chronic autoimmune liver diseases such as autoimmune liver diseases, primary biliary cirrhosis or sclerosing cholangitis), partial resection of the liver, acute liver necrosis (eg, necrosis caused by toxins, viral hepatitis, shock, or anoxia), hepatitis B, hepatitis no A no B, hepatocirrosis, and liver failure (e.g. fulminant hepatitis, late onset hepatitis and "acute-to-chronic" liver failure (acute liver failure in chronic liver diseases))].

[0187] In addition, a composition of the present invention is useful for increasing the effect of prevention and / or treatment of various diseases due to the useful pharmacological activity of tricyclic macrolides, such as activity of increasing the activity of chemotherapeutic effect, activity of cytomegalovirus infection, anti-inflammatory activity, inhibiting activity against peptidyl-propyl isomerase or rotamase, antimalarial activity, antitumor activity and so on.

Materials and methods

materials

[0188]

Tacrolimus (supplied by Eurotrade), lot No. RD 03-111 Lactose Monohydrate 200 mesh (from DMV) Granulated Silicon Oxide, Aeroperl® 300, (Degussa) Polyethylene glycol 6000, Pluracol® E6000 (from BASF) Poloxamer 188, Pluronic® F-68 (from BASF) Glyceryl monostearate, Rylo® MD50, (from Danisco Cultor), Ph.Eur., Lot # 4010056276 Avicel PH200 (microcrystalline cellulose) (from FMC) Lactose DCL 11 (from DMV) Magnesium stearate Croscarmellose sodium, Ac-Di-Sol® (from FMC) Eudragit® L30D.55 (from Degussa), Triethyl Citrate (from Merck), Anti-foam emulsion (from Unikem) Micro talc HPMC refers to Metalose 90SH (type 2910, 2208) or Metolose 60SH (type 2910) of ShinEtsu available in various degrees of polymerization (viscosity 3-100,000cP).

[0189] The tablets, capsules or granules may be enteric coated with different types of polymers such as hydroxypropylmethylcellulose acetate succinate (Aqoat), CAP cellulose acetate phthalate, HPMCP hydroxypropylmethylcellulose phthalate or methacrylic acid copolymers such as Eudragit L30D , Eudragit 100 / S, Eudragit 100 / L.

Comparison of the prior art of tacrolimus formulation:

[0190] Prograf © hard gelatin capsules, manufactured by Fujisawa Ireland Ltd.

Mg ingredients Tacrolimus, anhydrous 1.0 Gelatin 6.9 Hypromellose 1.0 Lactose Monohydrate 24.7 0.3 mg magnesium stearate Shellac cs Soybean Lecithin cs Red iron oxide (E172) cs Titanium Dioxide (E171) cs Dimethicone (E900) cs

Methods

Determination of weight variations

[0191] The tablets prepared in the examples of this document were subjected to a test for weight variation carried out in accordance with Ph. Eur.

Determination of the average hardness of the tablet Determination of the decay time

[0193] The time for a tablet to disintegrate, that is, to decompose into particles or agglomerates, was determined according to Ph. Eur.

Determination of the average diameter of the geometric weight dgw

[0194] The average diameter of geometric weight was determined by the use of a laser diffraction method by dispersing the particulate material obtained (or the raw material) in the air. The measurements were made at 1 bar of dispersive pressure in Sympatec Helos equipment, which records the distribution of the equivalent spherical diameter. This distribution conforms to a normal log distribution of volume-size.

[0195] When used here, "average diameter of geometric weight" means the average diameter of the normal log distribution of volume-size.

In vitro dissolution tests

[0196] The following test methods were applied to the compositions and dosage forms of the present invention.

Test 1:

[0197] In vitro dissolution test according to USP method A, delayed release items (USP paddle method; rotation speed: 50 rpm, 37 ° C, after 2 hours in acidic medium, the medium is changed to buffer of phosphate pH 6.8.).

Test 2:

[0198] In vitro dissolution test in aqueous solution medium adjusted to pH 4.5 (900 ml of water with 0.005% HPC (hydroxypropyl cellulose) adjusted to pH 4.5, 37 ° C, USP paddle method, rotation speed: 50 rpm ).

[0199] The pharmaceutical compositions and dosage forms of the invention are exemplified in Examples 1-7. The results of the in vitro dissolution tests of the compositions and dosage forms of the invention are found in example 8.

EXAMPLE 1

[0200] Modified release polydeposit capsule based on a swollen hydrocolloid hydroxypropylcellulose matrix

Substance% mg Tacrolimus 0.50 1.00 HPMC 20.00 40.00 Lactose mesh 200 30.00 60.00 PEG 6000 34.65 69.30 Poloxamer 188 14.85 29.70 Total 100.00 200.00

[0201] Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (70:30 w / w ratio) at 70 ° C. The solution was sprayed on a mixture of 150 g of lactose and 100 g of HPMC in a Strea-1 fluid bed. The granulated product was screened through a 0.7 mm sieve and filled into hard gelatin capsules (200 mg).

EXAMPLE 2

[0202] Modified release matrix tablet based on swollen hydrocolloid hydroxypropyl cellulose matrix

Substance% mg Tacrolimus 0.50 1.00 HPMC 19.90 40.00 Lactose 200 mesh 29.85 60.00 PEG 6000 34.48 69.30 Poloxamer 188 14.78 29.70 Magnesium Stearate 0.50 1.01 Total 100.00 201.01

[0203] Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (70:30 w / w ratio) at 70 ° C. The solution was sprayed on 250 g of lactose in a Strea-1 fluid bed. The resulting granulated product was screened through a 0.7 mm sieve and mixed with HPMC and magnesium stearate for 0.5 min in a Turbula mixer.

5 [0204] The mixture was compressed into 8 mm tablets of 1 mg of active ingredient (200 mg tablet) with cup-shaped compound. [0205] Average disintegration time: 20 minutes. Hardness: 45 N 10 EXAMPLE 3 Enteric Coating [0206] The capsules and tablets of Examples 1 and 2 were subsequently coated with the following enteric coating 15 to obtain a delayed release of active ingredient after administration.

<dl><dt>Ingredients </dt><dd> % </dd></dl>

<dl><dt>Eudragit® L30D </dt><dd> 40 </dd></dl>

<dl><dt>Purified water </dt><dd> 52 </dd></dl>

<dl><dt>Triethyl Acetyl Citrate </dt><dd> 1.8 </dd></dl>

<dl><dt>Anti-foam emulsion </dt><dd> 0.2 </dd></dl>

<dl><dt>talcum powder </dt><dd> 6 </dd></dl>

<dl><dt>Total </dt><dd> 100 </dd></dl>

[0207] The coating suspension was prepared by mixing triethyl acetylcitrate, anti-foam emulsion and purified water in the Ultra Turrax apparatus at 9500 rpm for 30 min. After 1 minute, talc was added. The mixture was passed through sieve # 300 and stirred with a magnetic stirrer. The Eudragit was passed through sieve # 300 and added to the mixture, which was stirred for 5 minutes.

[0208] The conditions of the coating process were as follows, an inlet temperature of 40 ° C, an outlet temperature of 31 ° C, an air inlet of 140 cbm per hour and a coating time of approx. 50 25 minutes (300 g of coating material). Approx. 400 g of pills, or 200 g of capsules.

[0209] The film-coated tablets and capsules were polymerized for 48 hours at 30 ° C before the dissolution test.

30 EXAMPLE 4

[0210] Enteric coated tablet with core based on PEG 6000 / Poloxamer 188 and enteric coated based on Eudragit L30D 55 Composition of the tablet core:

35 [0211]

<dl><dt>Substance </dt><dd>% mg </dd></dl>

<dl><dt>Tacrolimus </dt><dd> 1.98 2.00 </dd></dl>

<dl><dt>Lactose monohydrate, lactose 200 mesh </dt><dd> 40,50 40,91 </dd></dl>

<dl><dt>PEG 6000 </dt><dd> 33.26 33.60 </dd></dl>

<dl><dt>Poloxamer 188, Lutrol 68 </dt><dd> 14.40 14.40 </dd></dl>

<dl><dt>Magnesium stearate </dt><dd> 0.50 0.51 </dd></dl>

<dl><dt>talcum powder </dt><dd> 4.50 4.55 </dd></dl>

<dl><dt>Croscarmellose sodium, Ac-di-sol </dt><dd> 5.00 5.05 </dd></dl>

<dl><dt>100.00</dt><dd> 101.01 </dd></dl>

[0212] The tacrolimus tablet core was produced by dissolving in PEG 6000 at a temperature above 80 ° C. He

40 the poloxamer 188 was added, and the solution was heated to a temperature greater than 80 ° C. The solution was sprayed using the Phast FS1.7 feed unit onto 200 g of lactose monohydrate in a Phast FB100 fluid bed. The resulting granulate was screened through a 1397 grinder, 4500rpm, and mixed with sodium croscarmellose for 3 minutes in a Turbula mixer.

Four. Five [0213] Magnesium stearate and talc were sieved through sieve # 300 and mixed in a Turbula mixer for 3 minutes. The granulate was mixed with magnesium stearate and talc (1: 9) for 0.5 minutes in a Turbula mixer.

[0214] The resulting mixture was compressed into 6 mm tablets of 2 mg of active ingredient (100 mg tablet) with 25

cup shaped compound.

[0215] Average disintegration time: 7 minutes. Hardness: 65 N

5 Enteric Coating:

[0216] The enteric coating is based on an Eudragit L30D-55 acrylic polymer. Eudragit L30D is supplied as an aqueous latex suspension creating a water insoluble film when water evaporates during coating. The polymer is insoluble with pH values ​​below 5.0 and easily soluble with pH values

10 greater than 6.0. The composition of the film coating is:

<dl><dt>Substance </dt><dd>% p / p </dd></dl>

<dl><dt>Eudragit L30D-55 </dt><dd> 40 </dd></dl>

<dl><dt>Water </dt><dd> 52 </dd></dl>

<dl><dt>Triethyl citrate </dt><dd> 1.8 </dd></dl>

<dl><dt>Anti-foam emulsion </dt><dd> 0.2 </dd></dl>

<dl><dt>Talc (micro) </dt><dd> 6 </dd></dl>

<dl><dt>Total </dt><dd> 100 </dd></dl>

[0217] The amount of applied film polymer (Eudragit) was based on a calculation of mg of polymer film per cm2 of the surface of the tablet. The thickness of the enteric coating was 80 µm. A verification of the thickness of

fifteen The applied film was based on measuring the increase in the height of the tablet with a digital micrometer. The film coating process was performed on a Phast FB100 fluid bed equipped with a Wurster type insert. The process conditions were: incoming air temperature 50 ° C, incoming air flow 100m3 per hour, product temperature 38 ° C, supply speed 15g / min.

twenty [0218] After coating the appropriate film formation requires polymerization of the coated tablets, ie 30 ° C in 48 hours in an oven. Alternatively, the coated tablets could be more efficiently polymerized at 40 ° C in 24 hours.

EXAMPLE 5

25 [0219] PEG6000 / Poloxamer 188 controlled release tablet based on an HPMC matrix.

Composition of the tablet:

30 [0220]

<dl><dt>Substance </dt><dd>% mg </dd></dl>

<dl><dt>Tacrolimus </dt><dd> 1.21 2.00 </dd></dl>

<dl><dt>Lactose monohydrate, lactose 200 mesh </dt><dd> 24.75 40.91 </dd></dl>

<dl><dt>PEG 6000 </dt><dd> 20.33 33.60 </dd></dl>

<dl><dt>Poloxamer 188, Lutrol 68 </dt><dd> 8.71 14.40 </dd></dl>

<dl><dt>Magnesium stearate </dt><dd> 0.50 0.83 </dd></dl>

<dl><dt>talcum powder </dt><dd> 4.50 7.44 </dd></dl>

<dl><dt>Hydroxypropyl methylcellulose, Metolose 90SH 15000 </dt><dd> 40.00 66.12 </dd></dl>

<dl><dt>100.00 </dt><dd> 165.29 </dd></dl>

[0221] Tacrolimus was dissolved in PEG 6000 at a temperature above 80 ° C. Poloxamer 188 was added and the solution was heated to a temperature greater than 80 ° C. The solution was sprayed using the Phast 35 FS1.7 feed unit onto 200 g of lactose monohydrate in a Phast FB100 fluid bed. The granulated product was screened through a 1397 grinder, 4500 rpm, and mixed with hydroxypropyl methylcellulose for 3 min in a Turbula mixer.

[0222] Magnesium stearate and talc were sieved through sieve 300 and mixed in a Turbola mixer for 3 min. The granulate was mixed with magnesium stearate: talc (1: 9) for 0.5 min in a 40 Turbula mixer.

[0223] The mixture was compressed into 8 mm tablets compressed with 2 mg strength (165 mg tablet with cup-shaped compound).

Four. Five [0224] Average disintegration time: 2 hours 34 minutes, hardness: 50 N

EXAMPLE 6

part of the intragranular phase. Melting granulation Composition of the tablet: [0226]

<dl><dt>Ingredient </dt><dd>mg </dd></dl>

<dl><dt>Tacrolimus </dt><dd> 2 </dd></dl>

<dl><dt>Lactose </dt><dd> 80 </dd></dl>

<dl><dt>PEG 6000 </dt><dd> 15 </dd></dl>

<dl><dt>Poloxamer 188 </dt><dd> 6 </dd></dl>

<dl><dt>Metolose SH 90 </dt><dd> 80 </dd></dl>

<dl><dt>Avicel PH200 </dt><dd> 60 </dd></dl>

<dl><dt>Magnesium stearate </dt><dd> 2 </dd></dl>

<dl><dt>Total </dt><dd> 245 </dd></dl>

[0227] The formulation of the tablet was based on fusion granulation in a Pellmix 1/8 high shear mixer. 16g of micronized tacrolimus was mixed with 640 g of lactose mesh 125 and 120 g

10 [0228] Polyethylene glycol 6000, 48g of poloxamer 188 and 640g of hydroxypropylmethylcellulose Metolose SH 90 15,000 cP in the high shear mixer. The wrap of the mixing vessel was heated to 80 ° C and the mixture was heated at an impeller rotation speed of 1000 rpm to the melting point of the PEG and the poloxamer. After melting, kneading was continued for 4 minutes at 800 rpm The granulate was sieved through a sieve size of 0.7 mm and cooled in a tray. The granulate was mixed with 480 g of Avicel PH200 for 3 minutes and for and

fifteen after the addition of 16 g of magnesium stearate for another 0.5 minutes. The mixture was compressed into tablets in a Diaf TM20 single-point tablet making machine. Pickup diameter: 8 mm. Pill shape: round, cup-shaped compound.

EXAMPLE 7

twenty [0229] Enteric coated tablet formulation (fusion granulation and enteric coated tablets)

Composition of the tablet:

25 [0230]

<dl><dt>Ingredient </dt><dd>mg </dd></dl>

<dl><dt>Tacrolimus </dt><dd> 2 </dd></dl>

<dl><dt>Lactose </dt><dd> 80 </dd></dl>

<dl><dt>PEG 6000 </dt><dd> 15 </dd></dl>

<dl><dt>Poloxamer 188 </dt><dd> 6 </dd></dl>

<dl><dt>Avicel PH200 </dt><dd> 60 </dd></dl>

<dl><dt>Magnesium stearate </dt><dd> 2 </dd></dl>

<dl><dt>Total </dt><dd> 165 </dd></dl>

[0231] The formulation of the tablet was based on fusion granulation in a Pellmix 1/8 high shear mixer.

16g of micronized tacrolimus was mixed with 640g of lactose mesh 125 and 120g of polyethylene glycol 6000, 48g of 30 poloxamer 188 in the high shear mixer. The wrapper of the mixing vessel was heated to 80 ° C and the

mixture was heated at a propellant rotation speed of 1000 rpm to the melting point of the PEG and the

poloxamer. After melting, kneading was continued for 4 minutes at 800 rpm. The granulate was screened at

through sieve size of 0.7 mm and cooled in a tray. The granulate was mixed with 480 g of Avicel PH200

for 3 minutes and for and after the addition of 16 g of magnesium stearate for another 0.5 minutes. The mixture was compressed into tablets in a Diaf TM20 single-pronged tablet making machine. Diameter

tablet: 7 mm. Pill shape: round, cup-shaped compound.

[0232] The enteric coating of the tablets was performed according to the procedure described in example 11.

40 EXAMPLE 8

[0233] Dissolution data in vitro

[0234] The compositions and dosage forms according to the preceding examples were subjected to in vitro dissolution tests using two different means / dissolution tests.

A. Using the medium / dissolution test: 900 ml of aqueous medium with 0.005% HPC (hydroxypropylcellulose) adjusted to pH = 4.5 (USP vane method, rotation speed: 50 rpm), the following dissolution profiles were found:

<dl><dt>% release </dt>&lt;dd /&gt;</dl>

<dl><dt>Time (hours) </dt><dd>Ex. 1 Ex. 2 Ex. 4 -EC (Rsd%) Ex. 5 (Rsd%) </dd></dl>

<dl><dt>0 </dt>&lt;dd /&gt;<dt>0 </dt>&lt;dd /&gt;<dt>0 </dt><dd> 0 (0) 0 (0) </dd></dl>

<dl><dt>0.5 </dt>&lt;dd /&gt;</dl>

<dl><dt>1 </dt>&lt;dd /&gt;</dl>

<dl><dt>1.5 </dt><dd> 0 </dd></dl>

<dl><dt>2 </dt><dd> 0 0 </dd></dl>

<dl><dt>3 </dt>&lt;dd /&gt;</dl>

<dl><dt>4 </dt><dd> 1 3 0.8 (32.3) 7.4 (9.8) </dd></dl>

<dl><dt>5 </dt>&lt;dd /&gt;</dl>

<dl><dt>6 </dt><dd> 3 4 </dd></dl>

<dl><dt>8 </dt><dd> 5 7 0.4 (61.1) 13.3 (16.5) </dd></dl>

<dl><dt>10 </dt><dd> 20 14 </dd></dl>

<dl><dt>15 </dt><dd> 40 11.0 (17.3) 36.0 (5.8) </dd></dl>

<dl><dt>16 </dt><dd> 38 </dd></dl>

<dl><dt>17 </dt><dd> 13.2 (12.1) 44.5 (5.4) </dd></dl>

<dl><dt>20 </dt>&lt;dd /&gt;</dl>

<dl><dt>24 </dt>&lt;dd /&gt;</dl>

[0235] The dissolution profile for tablet cores of Example 4 in the dissolution media: 900 ml of aqueous medium with 0.005% HPC (hydroxypropylcellulose) adjusted to pH = 4.5. USP palette method. Rotation speed: 50 rpm:

<dl><dt>Time (minutes) </dt><dd>% release Rsd% </dd></dl>

<dl><dt>0 </dt>&lt;dd /&gt;<dt>0 </dt>&lt;dd /&gt;<dt>0 </dt>&lt;dd /&gt;</dl>

<dl><dt>5 </dt><dd> 27.2 15.1 </dd></dl>

<dl><dt>10 </dt><dd> 49.1 10.9 </dd></dl>

<dl><dt>20 </dt><dd> 80.7 8.0 </dd></dl>

<dl><dt>35 </dt><dd> 98.9 5.4 </dd></dl>

<dl><dt>42 </dt><dd> 102.7 3.6 </dd></dl>

<dl><dt>52 </dt><dd> 104.9 2.0 </dd></dl>

[0236] Enteric coated tablet dissolution profile of Example 4 in dissolution medium according to USP A method, delayed release articles. USP palette method. Rotation speed: 50 rpm:

<dl><dt>Time (minutes) </dt><dd>% release Rsd% </dd></dl>

<dl><dt>0 </dt>&lt;dd /&gt;<dt>0 </dt><dd>NA </dd></dl>

<dl><dt>120 </dt><dd>0 NA </dd></dl>

<dl><dt>155 </dt><dd> 84.8 12.8 </dd></dl>

<dl><dt>165 </dt><dd>102.9 NA</dd></dl>

<dl><dt>175 </dt><dd> 101.0 3.5 </dd></dl>