Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof

[0001] The present invention relates to cyclodextrin sulfoalkyl ether derivatives having improved physical properties and methods for their preparation.

BACKGROUND OF THE INVENTION [0002] The profile of the non-chemical physical properties of compositions can dramatically change process processing and performance, and possibly the in vitro or in vivo performance of a particular material. In other words, a given chemical composition having a first physical profile may be suitable for inhalation; while the same chemical composition having a second different physical profile may not be suitable for inhalation. Similarly, a particular excipient having a first physical property profile may be more suitable for compression by compression than the same excipient having a second different physical property profile.

[0003] For example, the suitability of the different physical forms of the material used as a carrier for inhalation of dry powder will vary according to the profile of the non-chemical physical properties of the different physical forms of the material. The delivery of the drug by inhalation allows the drug to be deposited in various sections of the respiratory tract, e.g. throat, trachea, bronchi and alveoli. Generally, the smaller the particle size, the longer the molecule will remain suspended in the air, and the further down the airway the drug can be delivered. Drugs are delivered by inhalation using a nebulizer, metered dose inhaler (MDI) or dry powder inhaler (DPI).

[0004] Dry powder inhalers provide patients with pharmaceutical powders in the form of an aerosol. To generate an aerosol, the powder in static state must be fluidized and introduced into the air stream inhaled by the patient. The powder is exposed to many cohesive and adhesive forces that must be overcome if it is to be dispersed. Fluidization and lifting requires an energy input to the static powder bed. The particle size, shape, surface morphology and chemical composition of the carrier particles may affect the aerosol dispersion. Increased dispersion and deposit of the drug is usually observed with a smaller carrier size and an increased proportion of fine particles. Elongated carriers usually increase the dispersibility of the aerosol and FPF of the drug (fine particle fraction), possibly by the increased duration of drag in the air stream. Carriers with smooth surfaces make the fractions easier to inhale. Fractions that are more difficult to inhale have been obtained from carriers with macroscopic surface roughness or smooth surfaces, with easier-to-inhale fractions obtained from carriers with microscopic surface roughness, where the smaller surface protrusions had less contact area and reduced drug adhesion. Thus, the carrier particle size for dry powder inhalation formulations should be chosen based on the balance between these related performance characteristics. Especially the intermolecular forces should be such that the drug molecules adhere to the carrier (to promote mixing, homogeneity and allow the drug to float to the inhaled air stream), but also allow fine drug particles to separate from the surfaces of the thicker carrier particles so that it can be facilitated pulmonary delivery. Accordingly, the various physical forms of the known solid lactose carrier may or may not be suitable for dry powder for inhalation.

[0005] The same overall effect of the physical form on the behavior of the excipient is true for other pharmaceutical processes used to prepare the dosage form, such as tablet, liquid, suspension, emulsion, film, laminate, pellet, powder, bead, granule, suppository , ointment, cream, etc. In other words, a single excipient will have to be made in different physical forms to make it more suitable for specific purposes. For example, for improved tabletting by compression, the excipient will preferably have an improved flow. Good flow characteristics are desirable to facilitate handling and processing in a tablet press or capsule filling machine. It will also have compressibility within a specific range, depending on the role of the excipient in the tablet. If the excipient is to be used in a constitutable liquid formulation, the excipient will preferably not clump when placed in liquid and will dissolve completely and quickly. Although many of these features are very desirable in solid excipients, it is very difficult to obtain any single excipient having all these features. Among other things, for this reason, many different types of excipients are being developed in the pharmaceutical industry.

[0006] Drying methods, such as, but not limited to, plate dryer drying, freeze drying, spray drying, fluid bed spray granulation and fluid bed spray agglomeration are used in the pharmaceutical industry to prepare solids from administered solutions, emulsions, suspensions or thick suspensions. . The physical properties of the isolated solid will depend on the properties of the fed material and the parameters used in the apparatus used for the drying method used.

[0007] Spray drying causes atomization of a fed solution or suspension containing solids to form atomized droplets directed to the hot gas in the drying chamber, thereby causing the liquid carrier to evaporate from the droplets, resulting in the formation of spherical particles. Fluidized bed spray drying is a modified form of spray drying in which the drying process is carried out in the presence of a fluidized bed (fluidized by a hot gas stream) of fine particles, so that the atomized droplets collide and adhere to the fluidized particles. By modifying the solids content of the fed solution and in the drying chamber, the spray drying apparatus can be set to agglomerate or granulate solids in a process called fluidized bed spray agglomeration or fluidized bed spray granulation, respectively. In addition, the use of rectangular spray drying apparatus, in relation to cylindrical ones, will affect the physical properties of the obtained product.

[0008] In an exemplary fluidized bed agglomeration / spray granulation using a cylindrical apparatus, the powder feed passes through the solids feed input at a controlled rate, and the liquid feed of the liquid spray system from the top or bottom of the fluidized bed to the material. Heated fluidizing gas flows upward from the inlet through the bottom shutter, fluidizing the powder feed or grain particles in the fluidized bed chamber. At the same time, the classifying gas flows upwards through the unloading tube, at a speed that is controlled to blow fine particles back into the fluidized bed, allowing only larger particles with a falling velocity greater than the speed of the classifying air in the unloading tube to be discharged through the unloading tube. This allows you to control the product's particle size while keeping the product dust-free. Dust removed from the exhaust air by the external dust removal equipment of the circulation units can be recirculated to the recycling inlet for further processing. During this process, smaller particles merge with each other or with larger particles to form agglomerates. As a result, the particle size distribution in the fluidized bed increases such that the percentage of fine particles present in the product is reduced compared to the fluidized feed material.

[0009] Solubilization of poorly water-soluble compounds in an aqueous medium is often very difficult. Therefore, those skilled in the art use solubilization enhancers, such as cyclodextrins in an aqueous medium. Parent (non-derivatized) cyclodextrins and their derivatives are well known excipients that contain 6, 7 or 8 glucopyranose units and are called α-, β- and γ-cyclodextrin, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at positions 2 and 3 and a primary hydroxyl group at position 6. Cyclodextrins can be represented as hollow truncated cones with external hydrophilic surfaces and internal hydrophobic cavities.

[0010] It is reported that β-CD has been prepared in many different forms using various finishing processes. American Maize Products (French Patent No. 2,597,485) recommends lyophilization and spraying as suitable methods for recovering cyclodextrin ethers from aqueous solutions. However, powders obtained according to these different techniques have poor solubility. In addition, these powders do not flow well and have average compression properties.

[0011] US Patent No. 6,555,139 Sharma discloses a method of microfluidization of β-CD in combination with a hydrophobic drug to obtain a smooth latex-like microsuspension.

[0012] US Patent No. 5,674,854 Bodley et al. Discloses a composition comprising an β-CD inclusion complex and diclofenac. The composition can be prepared by spray agglomeration.

[0013] US Patent Application Publication No. 20040234479 Schleifenbaum discloses a flavoring or aroma substance comprising cyclodextrin particles comprising cyclodextrin particles and a flavor or aroma substance wherein the cyclodextrin particle has a particle size in the range of 50 to 1000 μ. The cyclodextrin particle comprises cellulose ether and cyclodextrin, wherein the cyclodextrin particle is obtained by a one-step method in a fluidized bed from a spray mixture, and wherein the gas injection temperature is from 80 ° to 180 ° C and the gas outlet temperature is from 40 ° to 95 ° C.

[0014] European Patent Application No. EP 392 608 describes a method for producing powdered cyclodextrin complexes in which the particle size is less than 12 μ, preferably less than 5 μ. Suitable methods for doing this include spray drying and freeze drying. The '608 application states that small CD particle sizes often present reduced confluency or flow and can easily form dust. For this reason, the field suggests the use of cyclodextrin complex molecules having a particle size of at least 50 μ.

[0015] US Patent Application Publication No. 20030065167 Lis et al. Discloses a method of producing directly compressible β-CB. The method comprises a "dehydrating step of hydrated beta-cyclodextrin to a water content of less than 6%, preferably less than 4% and even more preferably even less than or equal to 2% by mass, followed by forced rehydration to a water content greater than 10%, preferably greater than 12% and even more preferably greater than or equal to 13% by mass.

[0016] The effect of the drying step or the final step in the preparation of hydroxypropyl ^ -cyclodextrin (ΗΡ-β-CD) obtained from a syrup containing it was studied. Publication of US Patent Application No. 20030028014 Sikorski et al. Discloses agglomerated ΗΡ-βCD and a method for its production. The agglomerated product is produced in a double drum dryer. It has been reported to have less dust formation and good water solubility. The product particle size is about 30 to 200 μ.

[0017] US Patent No. 5,756,484 Fuertes et al. Discloses a powdered composition of ΗΡ-βCD and a method for its preparation. ΗΡ-β-CD has a centered particle size free of fine particles and significantly improved solubility in an aqueous medium. ΗΡ-β-CD is made by spraying a ΗΡ-β-CD solution onto a moving powdered bed of ΗΡ-β-CD molecules.

[0018] The physical and chemical properties of parent cyclodextrins can be modified by derivatizing hydroxyl groups with other functional groups. One such derivative is cyclodextrin sulfoalkyl ether.

<img file="PL2335707T3_D0001.tif" />

MH)_2I._n| ub (- (CH ^ SO ^ Na ^ where n = 6.0-7.1 ₅ Β-cyclodextrin sulfobutyl ether (Captisol®) [0019] Cyclodextrin sulfoalkyl ether derivatives (SAE-CD) are well known, as are their applications in a wide range of applications. SAE-CD derivatives are especially useful in solubilizing and / or stabilizing drugs. A sulfobutyl ether derivative of beta cyclodextrin (SBE ^ -CD), especially a derivative with an average of about 7 substituents per cyclodextrin molecule (SBE7 ^ -CD) has been commercialized by CyDex, Inc. as CAPf ISOL®. The anionic sulfobutyl ether substituent dramatically improves the water solubility of parent cyclodextrin. In addition, the presence of charges reduces the ability of the molecule to form cholesterol complexes, compared to a hydroxypropyl derivative. Reversible, non-covalent formation of drug complexes with cyclodextrin CAPUSOL® usually results in increased solubility and stability of drugs in aqueous solutions.

[0020] CAPfISOL®, prepared by spray drying, is used in commercial formulations VFEND® and GEODON®. It has become a leading derivative of cyclodextrin for use in pharmaceutical formulations and therefore important for industry.

[0021] Methods for preparing SAE-CD derivatives are different, but usually contain general sulfoalkylation steps followed by isolation. The chemical profile of SAE-CD is determined during the sulfoalkylation step. For example, changing reaction conditions during sulfoalkylation may change the average degree of substitution and the average regiochemical distribution of sulfoalkyl groups in SAE-CD. The alkyl chain length of the sulfoalkyl functional group is determined by the sulfoalkylating substance used. And the use of a particular alkalizing substance during alkylation would result in the formation of a specific SAE-CD salt, unless an ion exchange step was carried out after sulfoalkylation.

[0022] Generally known methods of the sulfoalkylation step include, for example: 1) exposure of the non-derivatized parent cyclodextrin under alkaline conditions to an alkylating substance, e.g., alkylsultone or haloalkylsulfonate; 2) optionally adding another alkylating substance to the reaction medium to absorb excess alkylating substance; and 3) neutralizing the reaction medium with an acidifying substance. The overwhelming majority of literature methods perform a sulfoalkylation step in an aqueous medium; however, some sources disclose the use of pyridine, dioxane or DMSO as the reaction solvent for sulfoalkylation. The literature discloses the use of an alkalizing substance to accelerate the sulfoalkylation reaction. After the sulfoalkylation step, the SAE-CD isolation and purification step is performed.

[0023] Several different methods for the isolation of SAE-CD following sulfoalkylation and neutralization have been described. Generally, the SAE-CD containing aqueous liquid is dried to remove water to form a solid. Literature suggests various ways to remove water from an SAE-CD containing aqueous solution. Such methods include conventional lyophilization, spray drying, drying in a drier, drying in a vacuum dryer, drying on a rotary evaporator under reduced pressure, vacuum drying or vacuum drying in a drum. See, for example, Ma (STP Pharma Sciences (1999), 9 (3), 261-266), CAPTISOL® (sodium beta-cyclodextrin sulfobutyl ether; Pharmaceutical

Excipients 2004; Eds. RC Rowe, PJ Sheskey, SC Owen; Pharmaceutical Press and American Pharmaceutical Association, 2004) and other sources regarding the preparation of SAE-CD derivatives.

[0024] Thus, there is a lack of teaching in the art about methods of making and using SAE-CD derivatives having specific non-chemical physical properties profiles.

Given the great importance of SAE-CD for the pharmaceutical industry, it would be a significant improvement in the field to provide SAE-CD derivatives having specific non-chemical physical properties profiles so that such forms can be tailored to specific purposes.

SUMMARY OF THE INVENTION [0025] The present invention seeks to overcome the disadvantages present in known SAE-CD dry powder compositions. As such, a sulfoalkyl ether cyclodextrin (SAE-CD) composition is provided. The present SAE-CD composition excludes the main active substance. However, the composition has unexpected beneficial physical properties that occur as a result of the method used to remove water from the SAE-CD containing aqueous medium. The composition prepared by the method of the invention provides solid SAE-CD in molecular form.

[0026] The physical properties of SAE-CD are modulated by various techniques to obtain different types of SAE-CD (SAE-CD type or SAE-CD composition), each adapted for use in specific dosage forms such as tablets, capsules , constitutable powder, dry powder inhaler, sachets, pastilles and lozenges. Properties can also be modified to improve handling, packaging, storage, and other related activities. The chemical properties can also be adapted to specific methods by changing the identity of the counterion, changing the length of the alkyl chain, the average degree of substitution, or the size of the cyclodextrin parent ring from which SAE-CD is made. The properties can also be adapted to specific applications by changing the non-chemical physical properties of SAE-CD, such as by changing the average or average particle diameter, the distribution size of the particles, the SA SA water content, the characteristics of the surface of the SAE-CD particles, the dissolution rate of particles, the bulk density bulk density, density, CARR, compressibility, flowability and more.

[0027] The SAE-CD compositions of the invention have a number of advantages over known SAECD compositions, e.g. those prepared according to known methods, which differ in steps after sulfoalkylation. The SAE-CD compositions of the description provide unexpectedly improved dissolution rates in water, crush strength on compression, ease of tabletting and / or improved solids treatment.

[0028] One provided form of the SAE-CD composition contains no more than about 20 wt. humidity. The SAECD composition may be included in a dry formulation in admixture with the active ingredient such that all or substantially all of the active ingredients do not form a complex with SAE-CD. The SAE-CD composition may be included in a dry formulation in admixture with one or more excipients. The SAECD composition may also be included in a constitutable formulation.

[0029] The molecular SAE-CD compositions of the invention have morphological and physicochemical properties that predispose them to dissolve faster than previously known SAE-CD compositions, such as those prepared by spray drying. SAE-CD compositions prepared by the methods described herein have particular combinations of morphological and physicochemical properties. In some embodiments, the method is fluidized bed spray agglomeration. In some embodiments, the SAE-CD molecular composition is prepared by fluid bed spray granulation, and the resulting SAE-CD composition has a different combination of physical properties than the SAE-CD composition prepared by fluid bed spray agglomeration.

[0030] When the SAE-CD molecules are prepared by known methods, they do not have a favorable combination of physical properties of the SAE-CD compositions of the invention. The SAE-CD composition disclosed herein is prepared by a method comprising:

providing a water-containing liquid containing water and SAE-CD; and subjected to a liquid feed to a combination of fluidized bed spray drying methods, wherein the SAE-CD is agglomerated (and / or granulated) and dried to the following flow point to produce a specific SAE-CD composition, including agglomerated (and / or granular) particles at least 90% of the volume of the particles in the SAE-CD composition is made of particles having a calculated diameter greater than or equal to about 25 microns. (The particle diameter abscissa for a 10% cumulative volume fraction is 25 microns or more.) The SAE-CD composition may have a bulk density with a slope in the range of about 0.66 to 0.75 g / cm³when determined according to USP <616> method 1 and / or bulk density in the range from about 0.55 to 0.66 g / cm³ or about 0.38 to about 0.66 g / cm3³when determined according to USP <616> method 1. For a particular SAE-CD composition, the bulk density is higher than the bulk density.

[0031] The moisture content of the SAE-CD composition is below the melting point. However, specific embodiments include those having a moisture content of &lt;18% by mass, &lt;16% by mass, &lt;15% by mass, &lt;10% by mass or &lt;5% by mass

[0032] The SAE-CD composition is molecular and has an average particle diameter of from about 92 to about 200 microns, or less than or equal to about 110 microns or less or equal to about 200 microns. The average particle diameter was determined according to example 3 using a Malvem device. This device measures the particle diameter by scattering the small angle laser light and calculates the particle diameter based on the volume of the assumed spherical shape. The term "mean particle diameter" is defined as the mean moment of volume, otherwise known as De Broucker's mean diameter, D [4,3]. The SAE-CD composition can be prepared by fluid bed spray agglomeration or fluid bed spray granulation. [0033] The SAE-CD composition has a combination of physical properties that make it more suitable than previously known SAE-CD compositions for use in compressed tablet formulations. For example, the SAE-CD composition has a crush strength on compression in the range of about 1.0 to about 20 kP, when 200 mg of the SAE-CD composition is compressed into a tablet having a diameter of 0.345 inches using Pmax (peak compression pressure) in the range of about 30 to about 275 MPa and the SAE-CD composition has a moisture content in the range of about 2 to about 3 wt%, as determined by LOD. Alternatively, the SAE-CD composition has a compressive strength when compressed in the range of about 0.5 to 11 KP, when 200 mg of the SAE-CD composition is compressed into a tablet having a diameter of 0.345 inches using a Pmax MPa in the range of about 15-70 MPa and SAE-CD have a moisture content in the range of about 5-6% by mass.

[0034] The SAE-CD composition has a more rapid dissolution rate in water than SAE-CD prepared by conventional spray drying. When 2.5 g of the SAE-CD composition is analyzed according to example 6, it has an average dissolution time of 2.5 minutes or less or 4.5 minutes or less, or 3.5 minutes or less when placed in water.

[0035] A SAE-CD composition having a favorable flow property is provided by the invention. For example, the SAE-CD composition has a minimum gravity flow opening diameter of about 3-7 mm or 4-6 mm, or less than about 10 mm or less than about 20 mm. You can follow the method of Example 5 to determine the diameter of the hole of the minimum gravity flow.

[0036] The density of the SAE-CD composition can be controlled. The SAE-CD composition has an actual density of 1.25 to 1.35 g / cm³ or 1.1 to 1.5 g / cm³. Embodiments of the SAE-CD composition include those having a bulk density of from about 0.55 to about 0.66 g / cm3³, about 0.38 to less than about 0.55 g / cm3³ or about 0.38 to about 0.66 g / cm3³when determined according to USP <616> method 1. Other embodiments of the composition have a slump bulk density (slump bulk density) of from about 0.66 to about 0.75 g / cm³when determined according to USP <616> method 1. Additionally or alternatively, the SAE-CD composition has a CARR of less or about 24% or less than or about 18% or less than or about 16%.

[0037] Another aspect of the invention provides a SAE-CD composition having a moisture content below its melting point, bulk density in the range of about 0.55 to 0.66 g / cm³, and bulk density with a density in the range of about 0.66 to 0.75 g / cm3³, a CARR of less than or about 24%; and optionally a moisture content of less than about 18% by mass, optionally an actual density in the range of from about 1.1 to 1.5 g / cm³, optionally a minimum diameter of the gravitational flow opening of less than about 20 mm, wherein optionally the SAE-CD composition is prepared by fluid bed spray agglomeration or fluid bed spray granulation.

[0038] Another aspect is provided by the use of the SAE-CD composition as tabletting excipients, capsule excipients, DPI excipients (dry powder inhaler), extrusion excipients, PMDI (pressure inhaler with dispenser), drug delivery vehicles via DPI or PMDI, excipients orodispersible tablets, ingestible powders, dry granulation excipients, excipients for pelleting, sugar-starch pearls (, excipients of powders capable of forming an aerosol and / or constitutable powders.

[0039] The SAE-CD composition may be included in a formulation (e.g., solid, liquid, gel, suspension, emulsion or other known formulation) containing one or more active substances and one or more excipients. Therefore, the invention also provides a method of treating a disease or disorder by administering to the subject a SAE-CD composition in a formulation further comprising an active substance.

[0040] In one embodiment, the properties of the SAE-CD composition may be modulated so that different physicochemical properties are matched to those of the drug molecules to optimize dispersion from dry powder inhalers.

[0041] Additional embodiments of the invention include those wherein: 1) the SAE-CD composition is a compound of Formula 1 or a mixture thereof; 2) the formulation containing the SAE-CD composition also contains an antioxidant, acidifying substance, alkalizing substance, buffering substance, solubility enhancer, penetration enhancer, electrolyte, odor, glucose, glidant, stabilizer, bulking agent, antifreeze, plasticizer, flavors, sweeteners, surface tension modifiers, density modifier, volatility modifiers or combinations thereof; and / or 3) SAE-CD is a compound of formula 2 or a mixture thereof.

[0042] Another aspect of the invention provides an improved solid formulation, the improvement includes incorporating into the formulation the SAE-CD composition of the invention, wherein the SAE-CD was made by a fluid bed spray drying method (agglomeration or granulation) or the SAE-CD composition has a profile physical properties as defined herein. These and other aspects of this invention will be apparent by reference to the following detailed description, examples, claims and attached figures.

BRIEF DESCRIPTION OF THE FIGURES [0043] The following figures are provided by way of illustration only and are not intended to limit the scope of the present invention.

Fig. 1 is a SEM photograph (scanning electron microscope) of an exemplary series of SAE-CD compositions made according to the invention. SAE-CD particles were made according to various methods after sulfoalkylation.

Fig. 2 shows the overall arrangement of an exemplary fluidized bed spray dryer.

Fig. 3 shows the general arrangement of another exemplary fluidized bed spray dryer.

Fig. 4 is a graph illustrating the relationship between crush strength and compression pressure for the SAE-CD compositions of the invention containing different amounts of humidity.

DETAILED DESCRIPTION OF THE INVENTION [0044] The SAE-CD compositions are adapted for use in specific applications. When used in these applications, the present SAE-CD compositions have the advantage and provide improved performance over previously known SAE-CD compositions for these applications. By changing the finishing conditions (steps after sulfoalkylation; steps after the sulfoalkylation step), you can modify the physicochemical and morphological properties of SAE-CD. For example, various SAE-CD compositions can be obtained by changing the drying and isolation conditions.

[0045] Although the SAE-CD composition of the invention does not require abrasion, it can be abrasion to provide even further SAE-CD compositions. For example, abrasion of a SAE-CD composition prepared by fluid bed spray drying may result in a SAE-CD composition having different bulk density, bulk density and / or particle diameter. The term abrasion as used herein means physical rubbing of a solid to reduce its particle size. Any such method used in the pharmaceutical industry is suitable for use in the method of the invention. Wiping methods include, by way of example and not limitation, micronization, ball milling, jet milling, hammer milling, milling in a cake mill, tumbling, screening and the use of a mortar and pestle. Both low and high energy methods can be used.

[0046] The present invention provides "SAE-CD compositions", meaning a cyclodextrin sulfoalkyl ether composition having a combination of different physical properties and excluding the active substance or pharmaceutical excipient. As for the SAE-CD composition, the term "excludes" means not intentionally added. Therefore, it is possible that the SAE-CD composition will contain endogenous excipients for its production method. For example, the first SAE-CD composition will have a first combination of physical properties, i.e., the first physical property profile, and the second SAE-CD composition will have a second combination of physical properties. Because of the different combinations of physical properties, the first SAE-CD composition will be more advantageous for a particular application, and the second SAE-CD composition will be more preferred for another specific application.

[0047] The present invention provides a SAE-CD composition, wherein SAE-CD is a compound of formula 1 or a combination thereof:

<img file="PL2335707T3_D0002.tif" />

n is 4, 5 or 6;

Ri, R2, R3, R4, Rs, Ró, R7, Rs and R9 are each independently -O- or a group -O (C2-C6alkylene) -SO3-, where at least one of Ri to R9 is independently an O- group (C2-C6-alkylene) -SO3-, preferably the group -O- (CH2)_mSO3-, where m is 2 to 6, preferably 2 to 4, (e.g. -OCH2CH2CH2SO3 - or -OCH2CH2CH2H2SO3-); and Si, S2, S3, S4, S5, Só, S7, Ss and S9 are, independently of each other, a pharmaceutically acceptable cation which includes, for example, H⁺, alkali metals (e.g. Li⁺, Na⁺, K⁺, alkaline earths (e.g., Ca⁺², Mg⁺²), ammonium ions and amine cations such as (C 1 -C 6) alkylamines, piperidine, pyrazine, (C 1 -C 6) -alkanolamine and (C 4 -C 8) -cycloalkanolamine.

[0048] Suitable methods for preparing the SAE-CD raw material for use in making the SAE-CD compositions of the invention are disclosed in US Patent Nos. 5,376,645, No. 5,874,418 and 5,134,127 to Stella et al .; Patent No. 3,426,011 Parmerter et al .; Lammers et al. (Rec. Trav. Chim. Pays-Bas (1972), 91 (6), 733-742); Staerke (1971), 23 (5), 167-171); Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221); U.S. Patent No. 5,241,059 to Yoshinaga; U.S. Patent No. 6,153,746 Shah; International PCT Publication No. WO 2005/042584 Stella et al .; Adam et al. (J. Med. Chem. (2002), 45, 1806-1816); International PCT Publication No. WO 01140316 Zhang et al .; Tarver et al. (Bioorganic &amp; Medicinal Chemistry (2002), 10, 1819-1827); Ma (STP Pharma. Sciences (1999), 9 (3), 261-266); Jung et al. (J. Chromat. 1996, 755, 81-88); and Luna et al. (Carbohydr. Res. 1997, 299, 103-110), whose full disclosures are incorporated herein by reference.

[0049] The raw SAE-CD material is contained in the liquid feed used in the fluid bed spray drying process used to prepare the SAE-CD compositions of the invention.

[0050] The SAE-CD composition of the invention may also include a combination of derivatized cyclodextrin (SAE-CD) and non-derivatized cyclodextrin. For example, the SAE-CD composition may be prepared that contains non-derivatized cyclodextrin in an amount of from 0 to less than 50% by weight. total cyclodextrin present. Exemplary embodiments of the SAE-CD composition include those containing 0-5 wt.%, 5-50 wt.%, Less than 5%, less than 10%, less than 20%, less than 30%, less than 40% or less than 50% non-derivatized cyclodextrin.

[0051] The terms "alkylene" and "alkyl" as used herein (e.g., in the group -O- (C2-C6-alkylene) SO310 or in alkylamines) include linear, cyclic or branched, and saturated or unsaturated (e.g., containing double bond) divalent alkylene groups or monovalent alkyl groups. Similarly, the term "alkanol" in this text includes both linear, cyclic and branched, saturated and unsaturated alkyl components of the alkanol groups in which the hydroxyl groups may be located at any position on the alkyl moiety. The term "cycloalkanol" includes unsubstituted or substituted (e.g., methyl or ethyl) cyclic alcohols.

[0052] Some embodiments of the present invention provide a composition comprising a single type of cyclodextrin derivative having the structure shown in formula (I), wherein the composition generally contains an average of at least 1 and up to 3n + 6 alkylsulfonic acid moieties per cyclodextrin molecule. The invention also includes compositions comprising cyclodextrin derivatives having a narrow or wide range of degree of substitution and high or low degree of substitution. These combinations can be optimized as needed to provide cyclodextrin having specific properties.

[0053] Exemplary SAE-CD derivatives include SBE4-3-CD, SBE7-P-CD, SBEll-βCD, SBE7-y-CD and SBE5-y-CD, which correspond to SAE-CD derivatives of formula I, where respectively = 5, 5, 5, 6 and 6; m is 4; and there are on average 4, 7, 11, 7 and 5 sulfoalkyl ether substituents, respectively. Other exemplary SAE-CD derivatives include those of formula SAEx-R-CD (formula 2), where SAE is sulfomethyl ether (SME), sulfoethyl ether (SEE), sulfopropyl ether (SPE), sulfobutyl ether (SBE), sulfopentyl ether ( SPtE) or sulfohexyl ether (SHE); x (average or specific degree of substitution) is 1-18, 1-21, 1-24 when R (parent cyclodextrin ring structure) is α, β or γ, respectively; and CD means cyclodextrin. The SAE functional group includes a cationic counterion as disclosed herein or as generally used in the pharmaceutical industry for the counterion of any acid group.

[0054] Since SAE-CD is a polyanionic cyclodextrin, it can be provided in the form of various salts. Suitable counterions for the SAE functional group (s) include atoms or molecules of organic cations and atoms or molecules of inorganic cations. SAE-CD may comprise a single type of counterion or a mixture of different counterions. The properties of SAE-CD can be modified by changing the identity of the current counterion. For example, the first SAE-CD salt form may have a higher electrostatic charge than the other second SAE-CD salt form. It was found that the calcium salt form is more electronegative than the sodium salt form. Similarly, SAE-CD having a first degree of substitution may have a higher electrostatic charge than a second SAECD, having a different degree of substitution.

[0055] When the SAE-CD composition is to be administered pulmonarily, the median particle diameter may range from about 0.1 to about 10 microns or about 0.5 to about 6.4 microns. If it is desirable that the molecules reach the lower respiratory tract, e.g., alveoli and end bronchioles, then the median particle diameter range may be in the range from about 0.5 to about 2.5 microns. If it is desired that the particles reach the upper respiratory tract, then the particle diameter range may be in the range between 2.5 microns and 10 microns. A SAE-CD composition with this median particle diameter size can be prepared by abrasion of the SAE-CD composition having a larger range of median particle diameter sizes. [0056] The diameter diameter of the particle (defined as the ratio = (average particle diameter of 90. percentiles - the average particle diameter of the 10th percentile) / the average particle diameter of the 50th percentile) of the SAE-CD composition may also affect its performance. SAE-CD having a wide medium and narrow particle size distribution can be used in the invention. A larger spread indicates a wider particle size distribution, and a smaller spread indicates a narrower particle size distribution. Specific embodiments include those where the range is from about 1.5 to 2.9; 1.1 to 1.9 or 1.4 to 1.7.

[0057] Because the molecules are present as size distribution, the distribution can be monomodal, bimodal or polymodal, with monomodal distribution being preferred.

[0058] The SAE-CD composition is a molecular composition comprising agglomerated and non-agglomerated molecules. Agglomerated particles can be prepared by fluid bed spray drying, which may include agglomeration and / or granulation. The term agglomeration, which can be used interchangeably with granulation, is intended to mean a process in which fine molecules in a composition are combined with other molecules in the composition to form coarser molecular compositions, thereby reducing the amount of fine particles and increasing the overall average particle diameter of the composition. The collection of particles that can be obtained can be called agglomerate or granulate. The SAE-CD composition of the invention is distinguishable by SEM from other SAE-CD compositions made according to other methods. Fig. 1 shows the SEM of an example SAE-CD composition made by fluid bed spray drying. The particles have a rough surface texture and contain a significant amount of agglomerated particles.

[0059] Exemplary methods of making the SAE-CD composition include fluidized bed spray agglomeration or fluidized bed spray granulation. [0060] Fig. 2 shows an exemplary fluidized bed spray dryer system that can be used to prepare the SAE-CD composition of the invention. This system includes the fed liquid tank (1), cylindrical fluidized bed spray drying device (2), cyclone particle classifier (3), final product collection container (4), gas filtering device (5), waste collection container (6), condensers (7) and fluidized bed chambers (8-10). The system can be operated as follows. To start the process, an aqueous feed liquid containing raw SAE-CD material is transferred from the tank (1) to the dryer (2) through the pipe (M). Liquid feed is atomized into the drying chamber in a countercurrent manner to the hot gas stream (A) to form the initial fluidized bed of particles. The fine particles formed come out of the drying chamber and are led through a conduit (B) to a cyclone (3), which classifies the particles and returns fine particles of the right size through the conduit (C) back to the top of the drying chamber, in an adjacent place and in a manner counter-current for liquid supply. In addition, liquid supply is atomized to the drying chamber, where larger particles and fine particles are created, and larger particles (those not considered as "fine" particles) form a fluidized bed in the chamber (8). When the particles reach the intended average particle diameter, they are led to the chamber (9) and then to the chamber (10). Each chamber contains its own gas and contains a bed of particles. The gas inlet to the chamber (8) is the main stream of hot gas (A) which fluidizes the bed of particles of the drying chamber (8). The gas stream (N) of the chamber (9) has a lower temperature than stream (A), and stream (P) has an even lower temperature. The particles are cooled as they move from the chamber (8) to the chamber (9) and then the chamber (10). The final SAE-CD composition is collected from the chamber (10) and led to the container (4) via a conduit (F). The fine particles present in the chambers (9) and (10) are led through the conduit (G) to the cyclone (3). The gas leaving the cyclone is led through the conduit (H) to the filter device (5) to collect any particles that are not otherwise recycled through the cyclone into the drying chamber. The particles collected in the filtering device are loaded into a collecting container (6) for possible reprocessing. The gas leaves the filter device and is led through a condenser (e) (7), which removes moisture from the gas. Finally, the gas is either vented or returned to the drying chamber via a conduit (L) and / or gas streams (A, N or P).

[0061] Fig. 3 shows another exemplary fluidized bed spray dryer system that can be used to prepare the SAE-CD composition of the invention. This arrangement is similar to that of Fig. 2; however, exclude chambers (9-10), particle recycling tube (G) and condenser (e) (7). In addition, the cyclone returns fine particles to the drying chamber via conduit (C), followed by conduit (Cl) and / or conduit (C2). When fine particles are introduced into the drying chamber through a conduit (Cl), they are introduced in a co-current manner with the flow of the supplied liquid, which is atomized, into the drying chamber. When the fine particles are introduced into the drying chamber through a conduit (C2), the fine particles are introduced in a direction that is tangent to or perpendicular to the flow of the gas stream (A) which enters the drying chamber and / or the gas inlet (L) . It should be noted that this example system does not return gas from the filter device back to the drying chamber; however, it can be modified for such work.

[0062] Most particles in such fluidized bed chambers typically do not reach the height of the atomized liquid feed cloud. However, fine particles formed during the process that are recycled back into the drying chamber can be introduced at a location adjacent to the liquid feed atomizer or at a location between the atomizer and the fluidized bed.

[0063] During operation of any of the systems, the flow of the gas stream may be adjusted at various locations within the system to modify bed fluidization, drying rate, fine particle classification and / or speed of feeding fine particles into the drying chamber.

The fluid bed spray drying method includes:

providing a liquid (solution, suspension or thick suspension) feed including the liquid carrier and optionally SAE-CD;

providing in the drying chamber of the fluidized bed SAE-CD particles having a first average particle diameter size, wherein the bed is fluidized by a stream of hot gas flowing in the first direction;

atomizing the fluid feed on a fluidized bed in a drying chamber to form a specific SAE-CD composition, comprising agglomerated particles having a larger second average particle diameter size, where atomization is carried out in the other direction and most of the liquid carrier has been removed from the particle composition; and collecting the molecular composition to form a SAE-CD composition.

[0064] Specific embodiments of the methods include those wherein: 1) the method further comprises recycling some of the smaller particles in a particular composition back to the drying chamber; 2) the recycled part of the particles is introduced into the drying chamber, in a place adjacent to the liquid feed point; 3) the recycled part of the particles is introduced into the drying chamber in a tangential or perpendicular direction to the direction of liquid feeding into the drying chamber; 4) the recycled part of the particles is introduced into the drying chamber, in a place adjacent to the cone of the drying chamber; 5) the method is conducted in a co-current manner; 6) the method is conducted in a counter-current manner; 7) the method is carried out in a mixed flow manner; 8) the specific composition comprises less than 18 wt. liquid carrier; 9) the liquid carrier is aqueous; 10) the liquid supply contains SAE-CD; 11) the SAE-CD composition has a combination of physical properties as described herein; and 12) the fluid bed spray dryer has a cylindrical and / or conical drying chamber.

[0065] In a co-current fluidized bed spray drying method, the flow direction of the atomized liquid feed in the drying chamber is the same as the flow direction of the hot air used to fluidize the particle bed. The atomizer can be a spray nozzle or a rotary atomizer (e.g. a rotary disk). The air current can be controlled so that primarily laminam or turbulent flow occurs.

[0066] In a counter-flow fluid bed spray drying method, the hot air used to fluidize the bed passes through the drying chamber in the opposite direction to this atomized liquid feed.

[0067] In a fluid-bed spray-drying method with mixed flow, the particles pass through the drying chamber in both the co-current and counter-current phases. This mode requires the use of a nozzle atomizer spraying upwards for the incoming air flow or an atomizer spraying drops downward towards an integrated fluidized bed where the air inlet and outlet are located on top of the drying chamber. Additional air inlets will direct the flow upwards to fluidize the particle bed.

[0068] The fine or small particles used to form the fluidized bed in the drying chamber can be prepared separately, such as by spray drying, milling, grinding, or other abrasion, screening or other suitable means. Otherwise, fine particles can be prepared in situ by the operation of an apparatus such as a conventional spray dryer and then the operation of an apparatus such as a fluid bed spray dryer. In one embodiment, the fine or small particles are obtained by separating these particles from the material removed from the drying chamber and recycling the fine or small particles back to the drying chamber. The invention includes methods whereby fine particles are introduced into the drying chamber and / or are produced in situ based on the drying of the atomized liquid feed.

[0069] The method of the invention may be carried out in a continuous or semi-continuous manner, wherein the liquid feed containing the raw SAE-CD material is fed into the drying chamber continuously or semi-continuously, and the SAE-CD composition is removed continuously or semi-continuously from the fluidized bed.

[0070] The aqueous liquid carrier used in the liquid feed, which may be a solution or a thick suspension, may or may not contain other material, such as by-product (s) of the sulfoalkylation reaction and subsequent alkalization of the reaction medium. The liquid carrier used herein is any aqueous medium used in pharmaceutical science used for agglomeration or granulation of solids.

[0071] The solids content of the SAE-CD liquid feed may range from 0.1 to 80% by mass, 10 to 70% by mass, 30 to 70% by mass or 40 to 60% by weight of solids. Some embodiments of the liquid feed include: 1) only sulfoalkyl ether cyclodextrin and water; or 2) only cyclodextrin sulfoalkyl ether, water and by-products of the synthesis process used to make the cyclodextrin sulfoalkyl ether. The sulfoalkyl ether cyclodextrin used in the liquid feed is sometimes referred to herein as the raw material sulfoalkyl cyclodextrin ether.

[0072] The liquid feed may be cooled or heated before entering the drying chamber. Temperature can be used to control the viscosity of the liquid feed: the higher the temperature, the lower the viscosity. The liquid supply temperature can be 0 ° C to 100 ° C or be an ambient temperature of up to 70 ° C.

[0073] The gas used to guide the particles through the system is usually a gas such as air, helium or nitrogen. The system may include a gas supply device for loading gas for operation, cleaning and refilling.

[0074] The incoming gas temperature can be used to control the particle drying rate, production rate, degree of agglomeration, water content of the SAE-CD composition and / or type of agglomeration. The temperature may vary from about 100 ° to about 300 ° C, from about 130 ° C to about 180 ° C, from about 150 ° C to about 170 ° C, or from about 210 ° C to about 250 ° C.

[0075] The SAE-CD composition has a minimum gravity flow opening diameter of from about 3-7 mm or 4-6 mm, or less than about 10 mm or less than about 20 mm. The term "minimum gravity flow hole diameter" means mini14 .Λ., .-,;. ·. »The small diameter of the hole through which the SAE-CD composition will provide acceptable mass flow. The example below defines this term more precisely. This parameter is determined according to the method of Example 5 where FLOWDEX apparatus (Hanson Research Corp., Northridge, CA) was used. The inventors have been able to produce the SAECD composition that has a significantly different minimum hole diameter than that produced by conventional spray drying.

[0076] The SAE-CD composition has a CARR of less or about 24% compressibility or less than or about 18% compressibility or less than or about 16% compressibility. The "compressibility" used in this context refers to the relative percentage reduction that the molecular weight will undergo when determining the bulk density with slump. The CARR is a measure of the compressibility of a SAE-CD composition. It is based on bulk density and bulk density with material density. The CARR has been determined according to example 8 below. The inventors have been able to produce a spray agglomerated SAE-CD composition having a CARR coefficient significantly different from other SAE-CD compositions prepared by spray drying, lyophilization or spray agglomeration.

[0077] SAE-CD has an actual density in the range of about 1.25 to 1.35 g / cm³ or 1.1 to 1.5 g / cm³ 1.29 to 1.32 g / cm³. The actual density was determined according to example 8 below. The SAE-CD composition of the invention has a significantly different actual density than the SAE-CD composition prepared by spray drying. [0078] The SAE-CD composition has a bulk density of from about 0.55 to 0.66 g / cm³, about 0.38 to less than about 0.55 g / cm3³ or about 0.38 to about 0.66 g / cm3³. The SAE-CD composition made according to the spray agglomeration method of the invention has a higher bulk density than this SAE-CD composition prepared by another dry spray agglomeration method.

[0079] The SAE-CD composition has a slump bulk density (slug density) from about 0.66 to 0.75 g / cm³when determined according to USP <616> method 1. A SAE-CD composition made according to the spray agglomeration method of the invention has a higher bulk density than this SAE-CD composition prepared by another dry spray agglomeration method.

[0080] Since the solid SAE-CD composition can be used for the production of tablets, especially compressed tablets, its compressive strength at compression has been determined at different peak compression pressures with the SAE-CD composition having different moisture contents. The method of example 7 was used to determine this compound. The performance of the SAE-CD composition was compared (Fig. 4) to that of Avicel PH-200, lactose and Dical, which are three excipients commonly used in the manufacture of tablet formulations. The SAE-CD composition of the invention is very advantageous because its compression behavior can be improved by changing the moisture content, particle size and / or particle shape.

[0081] Tablet hardness or tablet crush strength in kilopond units (kP) relative to peak compression pressure (Pmax) in megapascals (MPa) is shown for the SAE-CD (SBE7-P-CD) composition sample (B3, B4) ) from this invention used "as is", e.g. as obtained from a fluid bed spray-drying process and equilibrated (B3 Eq and B4 Eq) on saturated magnesium nitrate. The performance of these samples was compared with that of commercial direct fillers, e.g. microcrystalline cellulose or MCC (Avicel PH 200, FMC), lactose monohydrate (SuperTab, The Lactose Co. from New Zealand), dibasic calcium phosphate dihydrate (Emcompress, Penwest Pharm What.). For the apparatus used in this test, 100 MPa is approximately equivalent to 6 kN. The water content of the SAE-CD composition of the invention was 2.77% and 2.36% for B3 and B4, respectively, as determined by drying loss (LOD) at 110 ° C using a Computrac model 2000XL (Arizona Instruments, Tempe , AZ). The equilibrated LOD water content was 5.46% and 5.50% for B3 Eq and B4 Eq, respectively.

[0082] At lower levels of moisture content, e.g. in the range of from about 2 to about 3 wt. (as determined by LOD carried at 104 ° to 110 ° C) the SAE-CD composition has a crush strength when compressed in the range of from about 1 to about 20 kP (kiloponds) when compressed into a tablet using Pmax (peak compression pressure) in range from about 30 to about 275 MPa (megapascals). At higher levels of moisture content, e.g. in the range from about 5 to about 6% by mass. (as defined by LOD) the SAE-CD composition has a crush strength when compressed in the range of about 0.5 to about 11 kP when compressed into a tablet using a Pmax in the range of about 15 to about 70 MPa. The mean particle diameter, particle diameter size distribution and morphology of the SAE-CD composition are already modified to match the very different characteristics of the micronized drug that are presented to the formulator in the art. An advantage of the present invention is the ability of a person skilled in the art to modulate the physicochemical properties of the SAE-CD composition to match or supplement the formulation or methods of preparation, drug properties or excipient properties, thus resulting in an optimal product.

[0083] The dosage form of the invention can be used to administer a wide range of active substances. Active substances typically include physiologically or pharmacologically active substances that have systemic or local effects or effects on animals and human beings. Active substances also include pesticides, herbicides, insecticides, antioxidants, plant growth initiators, sterilizers, catalysts, chemical reagents, food products, nutrients, cosmetics, vitamins, minerals, dietary supplements, sterility inhibitors, fertility initiators, microorganisms, flavors, sweeteners, cleaning substances and other such compounds for pharmaceutical, veterinary, gardening, home, food and culinary uses, agricultural, cosmetic, industrial, cleaning, confectionery and flavoring.

[0084] The active substance can be selected independently at each occurrence from pharmaceutical active substances such as an antibiotic substance, antihistamine, decongestant, anti-inflammatory substance, anti-parasitic substance, anti-viral substance, local anesthetic, anti-fungal substance, anti-bacterial substance, anti-bacterial substance anti-cilia substance, analgesic substance, anti-arthritis substance, antiasthmatic substance, anti-coagulant substance, anticonvulsant substance, antidepressant substance, antidiabetic substance, antitumor substance, antipsychotic substance, neuroleptic substance, antihypertensive substance, hypnotic substance, sedative substance, anti-toxin substance, anti-toxin substance muscle relaxant anti-malarial substance, hormonal substance, contraceptive substance, sympatomimetic substance, hypoglycemic substance, antihyperglyceridemic substance, anti-sliplipidemic substance, cholesterol-lowering substance, bile acid absorption inhibitor, antiliplipemic substance, ophthalmic substance, electrolytic substance, electrolytic substance, inhibitory substance anti-ulcer anti-flatulence substance, anti-urinary incontinence substance, cardiovascular substance, corticosteroid, B2 adrenoreceptor agonist, dopamine D2 receptor agonist, anticholinergic substance, IL5 inhibitor, IL-5 antisense modulators, milrinone lactate, tryptase inhibitor, tachykinin receptor antagonist 5-lipoxygenase, anti-IgE antibody, protease inhibitor or combination thereof.

[0085] Other specific active substances that can be used according to the invention include pentamidine isethionate, albuterol sulfate, metaproterenol sulfate, flunizolide, sodium cromolin, sodium cromoglycate, ergotamine tartrate, levalbuterol, terbutaline, reproterol, salbutamol, salmeterol, formoterol, cleterol , bambuterol, tulobuterol, broxaterol, epinephrine, isoprenaline or hexoprenaline, an anticholinergic substance such as tiotropium, ipratropium, oxitropium or glycopyrronium; a leukotriene antagonist such as andolast, iralukast, pranlukast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; a phosphodiesterase inhibitor such as filaminast or piclamilast; a paf inhibitor such as apafant, forapafant or israpafant; a potassium channel opener, such as amiloride or furosemide; an analgesic such as morphine, fentanyl, pentazocine, buprenorphine, pethidine, thilyidine, methadone or heroin; a potency enhancer such as sildenafil, alprostadil or phentolamine; a peptide or protein such as insulin, erythropoietin, gonadotropin or vasopressin; calcitonin, factor IX, granulocyte colony stimulating factor, granulocyte macro phage colony, growth hormone, heparin, heparin (low molecular weight), interferon alpha, interferon beta, interferon gamma, interleukin 2, luteinizing hormone releasing hormone, somatostatin analog, amylin ciliary neurotrophic factor, growth hormone releasing factor, insulin-like growth factor, insulinotropin, interleukin 1 receptor antagonist, interleukin 3, interleukin 4, interleukin 6, stimulating macrophage colony, factor (mcsf), nerve growth factor, parathyroid hormone, thymosine alpha 1, inhibitor iib / iiia, alpha-1 antitrypsin, anti-rsv antibody, gene of transmembrane cystic fibrosis (cftr), deoxyribonuclease (dnase) , bactericide / permeability (ards), increasing the anti-cmv protein antibody, interleukin 1 receptor or a pharmaceutically acceptable derivative or salt of these compounds.

[0086] The active substances (drugs) mentioned herein should not be understood as exhaustive, but only exemplary of many embodiments considered within the scope of the invention. Many other active substances can be administered with the composition of the present invention. Appropriate drugs are selected from the list of drugs included herein as well as from many other USFDA approved drugs or similar recognized institution in Canada (Health Canada), Mexico (Mexico Department of Health), Europe (European Medicines Agency (EMEA)), South America (especially in Argentina (Administración Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT) and Brazil (Ministerio da Saude)), Australia (Department of Health and Aging), Africa (especially in South Africa (Department of Health) and Zimbawe (Ministry of Health and and Child Welfare),) or Asia (especially Japan (Ministry of Health, Labor and Welfare), Taiwan (Executive Yuans Department of Health) and China (Ministry of Health People's Republic of China)) suitable for administration to humans or animals. Some embodiments of the invention include those in which the active substance is pharmacologically or biologically active or in which the environment of use is the digestive tract of a mammal.

[0087] The active substance may be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, epimeric, isomeric, enantiomerically pure, racemic, solvate, hydrate, anhydrous, chelate, derivative, analog, esterified, non-validated or other conventional form. Each time an active substance is mentioned, all available forms are included.

[0088] The active substance contained within this formulation may be present as its pharmaceutically acceptable salt or salt-free form. "Pharmaceutically acceptable salt" as used herein refers to derivatives of the disclosed compounds where the active substance is modified by reacting it with an acid or base as needed to form an ionically bound vapor. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example formed from non-toxic inorganic or organic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those of ordinary skill in the art. Salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, lemon, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic acid , fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic and other known to those of ordinary skill in the art, The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from a parent active substance that contains a basic or acidic moiety. Lists of other suitable sols are found in Remington's Pharmaceutical Sciences, ed. 17, Mack Publishing Company, Easton, PA, 1985, the respective disclosure of which is incorporated herein by reference.

[0089] The phrase "pharmaceutically acceptable" is used herein to name those compounds, materials, compositions and / or dosage forms that are within reasonable medical judgment, suitable for use in contact with human and animal tissue without excessive toxicity, irritation , allergic response or other problems or complications commensurate with the rational benefit / risk ratio.

[0090] The term "patient" or "individual" as used herein is intended to mean a warm-blooded animal such as mammals, for example cats, dogs, mice, guinea pigs, horses, cattle cows, sheep and humans.

[0091] The formulation of the invention may contain the active substance present in an effective amount. By the term "effective amount" is meant the amount or size of the active substance that is sufficient to elicit the required or desired response, or in other words, the amount that is sufficient to elicit a discernible biological response when administered to a subject.

[0092] The formulation of the invention can be used to deliver one or more different active ingredients. Special combinations of active ingredients can be provided by this formulation. Some combinations of active substances include: 1) a first drug from the first therapeutic class and another second drug from the same therapeutic class; 2) first drug from the first therapeutic class and another second drug from a different therapeutic class; 3) a first drug having a first type of biological activity and another second drug having almost the same biological activity; 4) a first drug having a first type of biological activity and another second drug having a different second type of biological activity. Exemplary combinations of active substances are described herein.

[0093] When combinations of active substances are used, one or both active substances may be present in a subtherapeutic amount. The subtherapeutic amount used herein is that amount of the first drug that provides less than the usual therapeutic response in the patient being administered the first drug in the absence of the second drug in combination. In other words, the first and second drugs may jointly provide enhanced, improved, additional or synergistic therapeutic benefits compared to administering each drug alone, e.g., in the absence of another drug.

[0094] Once prepared, the SAE-CD composition may be included in any known pharmaceutical formulation or dosage form. The compositions and formulations of the invention are suitable for administration to a subject by any means used in the pharmaceutical industry. Exemplary modes of administration include, without limitation, intrabronchial (pulmonary, intratracheal, intravesical), oral, transoral, ocular, ocular, aural, sublingual, buccal, transdermal, transmucosal, rectal, vaginal, intrauterine, intraocular, intrathecal, intranasal, intranasal intraperitoneal, intramuscular and subcutaneous.

[0095] The dosage form is available in single or multiple dose form, containing, inter alia, the amount of active ingredient and SAE-CD composition, said amount is one or more of the predetermined doses of the dosage form are usually required for a single therapeutic administration. For multiple dose forms, such as a divided tablet, said defined unit will be one fraction, such as half or quarter of the multiple dose form. It should be understood that the specific dose level for any patient will depend on a variety of factors, including the indication being treated, the active substance being used, the active substance activity, the severity of the indication, health, age, gender, weight, patient diet, and pharmacological response used. specific dosage form and other such factors.

[0096] Once the SAE-CD composition has been prepared, it can be used to prepare a formulation where the SAE-CD composition forms a complex with or does not form a complex with the active substance. By "forming a complex" is meant "being part of a clathrate or an inclusion complex with", e.g., the active substance forming the complex is part of a clathrate or inclusion complex with a cyclodextrin derivative.

[0097] By active substance / CD complex is generally meant a clathrate or inclusion complex of a cyclodextrin derivative and active substance. The ratio of active substance: CD present in the molecular complex may vary and may range from about 10 to about 0.1, calculated on a molar basis. Thus, CD will usually, but need not be, present in an excess of active substance. The amount of excess will be determined by the intrinsic solubility of the substance, the expected dose of the substance, and the binding constant of the inclusion complex between the specific drug (substance) and the specific CD derivative used. It should be noted that the cyclodextrin derivative may be present in an uncomplexed form and thus in amounts in a significant excess of the active ingredient present. The mass or molar ratio of derivatized cyclodextrin to the active substance may exceed 100, 1000 or even more.

[0098] Under certain conditions, the SAE-CD composition may form one or more ionic bonds with a positively charged acid ionizable compound. Therefore, it is possible that the compound will be complexed by means of an inclusion complex with derivatized cyclodextrin and will not be covalently but ionically bonded with the derivatized cyclodextrin.

[0099] Although the SAE-CD composition may be the only carrier or active substance in the formulation, it is possible to add other carriers to the formulation to further improve its performance.

[0100] The SAE-CD composition may be included in any formulation requiring derivatized cyclodextrin. The active substance contained in the formulation can be delivered according to the rapid, immediate, pulsating, temporal, targeted, delayed and / or prolonged release of the formulation.

[0101] By "immediate release" is meant the release of the active substance into the environment over a period of seconds to no more than 30 minutes, from the start of the release and release starting within no more than about 2 minutes after administration. Immediate release does not show a significant delay in drug release.

[0102] By "rapid release" is meant the release of the active substance into the environment over a period of 1-59 minutes or 0.1 minutes to three hours, from the start of the release and the release may start several minutes after administration or after the delay period has expired (time delays) after administration.

[0103] An extended release formulation containing the SAE-CD composition will release the drug in an extended manner. Mechanisms used for such delivery may include the release of the active substance which is pH dependent or pEf independent; controlled by diffusion or dissolution; pseudo-zero order (approaching zero order release), zero order, pseudo first order (approaching first order release) or first order; or fast, slow, delayed, temporary or sustained release or other controlled release. The release profile of the active substance can also have a s-shaped shape, where the release profile includes initially a slow release rate, then a medium fast release rate and finally a slow release rate. The term "extended release" profile as used herein adopts a definition widely recognized in the field of pharmaceutical sciences. The sustained release dosage form will release the drug at a substantially constant rate over an extended period of time, or a substantially constant amount of drug will be released cumulatively over an extended period of time. The term "sustained release", in the context of drug release, includes the terms "controlled release", "sustained release", "extended release" or "slow release", as these terms are used in pharmaceutical science. Controlled release may start a few minutes after administration or after the delay period (delay time) has elapsed after administration. Prolonged release may start a few minutes after administration or after the delay period (delay time) has elapsed after administration.

[0104] By "controlled release" is meant the release of the active substance into the environment over a period of from about eight hours to about 12 hours, 16 hours, 18 hours, 20 hours, a day or even more than a day. By "sustained release" is meant the sustained release of the active substance to maintain a constant level of the drug in the blood or target tissue of the subject being administered the device. Controlled release may start a few minutes after administration or after the delay period (delay time) has elapsed after administration.

[0105] A time release dosage form is one that starts drug release after a predetermined period of time, measured from the time of initial exposure to the environment of use.

[0106] The slow release dosage form is one that provides a low drug release rate such that the drug is released slowly and suitably continuously over a period of, for example, 3 hours, 6 hours, 12 hours, 18 hours, day, 2 or more days, a week or 2 or more weeks.

[0107] Target release dosage form generally refers to an oral dosage form that is designed to deliver a drug to a particular portion of the gastrointestinal tract of a subject. An example of a targeted dosage form is an enteral dosage form that delivers the drug into the lower digestive tract, but not to the stomach or mouth of an individual. Other targeted dosage forms may deliver to other sections of the gastrointestinal tract, such as the stomach, jejunum, ileum, duodenum, cecum, large intestine, small intestine, colon or rectum. [0108] A pulsatile release dosage form is one that provides pulses of concentration of the highly active ingredient interspersed with low concentration throws. A pulsating profile with two peaks can be described as "bimodal".

[0109] The pseudo first order release profile is one that approaches the first order release profile. The first order release profile characterizes the release profile of the dosage form which releases a constant percentage of the initial drug charge per unit of time.

[0110] The pseudo zero order release profile is one that approaches the zero order release profile. The zero order release profile characterizes the release profile of a dosage form that releases a constant amount of drug per unit of time.

[0111] Sustained-release formulations can be made according to the procedures described herein or in Biorelated Polymers and Gels: Controlled Release and Applications in Biomedical Engineering (ed. Terno Okano; 1998); Encyclopedia of Controlled Drug Delivery (ed. Edith Mathiowitz; 1999); Futura Strategies for Drug Delivery with Particulate Systems (ed. JE Diederichs; 1998); Controlled Release Series (published by JM Anderson; 1987); Controlled Drug Delivery Series (SD ed Bruck; 1983); Controlled Release of Drugs Series (ed. M. Rosoff; 1989); Controlled Release Technology: Pharmaceutical

Applications (ACS Symposium Series No. 348) (edited by PI Lee and WR Good; 1987); Extended Release Dosage Forms (published by L. Krawczyński; 1987); Handbook of Pharmaceutical Controlled Release Technology (ed. DL Wise; 2000); Intelligent Materials for Controlled Release (SM Dinh; 1999); Multicomponent Transport in Polymer Systems for Controlled Release (Polymer Science and Engineering Monograph Series) (ed. A. Polishchuk; 1997); Pharmaceutical Technology: Controlled Drug Release (M. ed. Rubenstein; 1987); Polymers for Controlled Drug Delivery (published by PJ Tarcha; 1991); Tailored Polymeric Materials for Controlled Delivery Systems (ACS Symposium Series No. 709) (published by I. McCulloch; 1998); Oral Colon-Specific Drug Delivery (published by DR Friend, 1992); and other publications known to those of ordinary skill in the art whose full disclosures are incorporated herein by reference.

[0112] The sustained release layer may be diffusion, erosion, dissolution of the matrix, or a disintegrated controlled composition, comprising a drug and one or more rate-modifying excipients and other optional excipients.

[0113] By "delayed release" is meant that the initial release of the drug from the respective drug-containing layer occurs after the expiration of the respective delay (or delay) period. For example, if drug release from the sustained release layer is delayed by two hours, then drug release from this layer begins about two hours after administration of the multilayer tablet to the subject. In general, delayed release is the opposite of immediate release, in which drug release begins no more than a few minutes after administration. Accordingly, the drug release profile from a particular layer may be delayed-prolonged release or delayed-fast release. The "delayed-sustained" release profile is one in which the sustained release of the drug begins after the initial period of delay has expired. The "delayed-quick" release profile is one in which rapid release begins after the initial delay period has expired.

[0114] Although not necessary, the formulation of the present invention may include antioxidants, acidifying substances, alkalizing substances, buffering substances, solubilizers, penetration enhancers, electrolytes, fragrances, glucose, glidants, stabilizers, bulking agents, substances antifreeze, plasticizers, flavors, sweeteners, surface tension modifiers, density modifiers, volatility modifiers, hydrophyte polymers, preservatives, antibacterial substances, dyes, antifungal substances, complexing agents, solvents, salt, water, tonicity modifiers, antifoaming agents, oils, penetration enhancers, other excipients known to ordinary persons skills in the field for use in pharmaceutical formulations, or a combination thereof. At each occurrence, these materials may be independently contained in the molecules containing the active substance or carrier molecules. For example, the carrier may include one or more of these materials, and the molecules containing the active substance may also contain one or more of these materials.

[0115] As used herein, the term "glidant" is intended to mean a substance used to promote the flowability of dry powder. Such compounds include, by way of example and without limitation, magnesium stearate, sodium dodecyl sulfate, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silica, gel hydrogel and other materials known to those of ordinary skill in the art. [0116] As used herein, the term "antioxidant" is intended to mean a substance that inhibits oxidation and is therefore used to prevent the oxidative process from destroying formulations. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphoric acid, monoglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium citrate sodium, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, sodium pentetate and metabisulfite and others known to those of ordinary skill in the art.

[0117] As used herein, the term "alkalizing substance" is intended to mean a compound used to provide a basic medium when the dry powder of the invention is exposed to water. Such compounds include, by way of example and not limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amino bases, basic amino acids and trolamine and other known people with ordinary skills in the field.

[0118] The term "acidifying agent" as used herein is intended to mean a compound used to provide an acidic medium when the dry powder of the invention is exposed to water. Such compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and other known to ordinary persons in the field. [0119] As used herein, the term "buffering substance" is intended to mean a compound used to counteract a change in pH when exposed to a medium at a different pH. Buffers are used in the present compositions to adjust the pH to a range of between about 2 and about 8, about 3 to about 7 or about 4 to about 5. By controlling the pH of the dry powder, respiratory irritation can be minimized. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate and anhydrous sodium citrate and dihydrate and other known to those of ordinary skill in the art. Other buffers include a citric acid / phosphate mixture, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mellvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), Veronal Acetate, MES (2- (Nmorpholinoethanesulfonic acid), BIS-TRIS (bis (2-hydroxyethyl) iminotris (hydroxymethyl) methane), ADA (N- (2-acetamido) -2-iminodiacetic acid), ACES (N- (carbamoylmethyl) -2-aminoethanesulfonic acid) PIPES (piperazine-N, N'bis (2-ethanesulfonic acid)), MOPSO (3- (N-morpholino) -2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis (tris (hydroxymethyl) methylamino)) propane), BES (N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid), MOPS (3- (Nmorpholinojpropanesulfonic acid), TES (N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid), HEPES (N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic), DIPSO (3- (N, N-bis (2-hydroxyethyl) amino) -2-hydroxypropanesulfonic acid), MOBS (4- (N-morpholino) -butanesulfonic acid), TAPSO (3- (N-tris (hydroxymethyl) methylamino) -2-hydroxypropanesulfonic acid), TRIZMA ™ (tris (hydroxymethylaminomethane), HEPPSO (N- (2-hydroxyethyl) acid piperazine-N '- (2-hydroxypropanesulfonic), POPSO (piperazine N, N'-bis (2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N- (2-hydroxyethyl) piperazine-N' - (3-propanesulfonic acid) , TRICINE (N-tris (hydroxymethyl) methylglycine), GLYGLY (glycylglycine), BICINE (N, N-bis (2-hydroxyethyl) glycine), HEPBS (N- (2-hydroxyethyl) piperazine-N '- (4-butanesulfonic acid)), TAPS (Ntris (hydroxymethyl) methyl-3-aminopropanesulfonic acid) , AMPD (2-amino-2-methyl-1,3-propanediol), and / or any other buffers known to those of skill in the art. [0120] A complex enhancer is a compound or compounds that (which) enhances (enhances) the formation of complexes of the active ingredient with derivatized cyclodextrin. When a complex enhancer is present, it may be necessary to change the required ratio of derivatized cyclodextrin to active substance such that less derivatized cyclodextrin is required. Suitable complex enhancers include one or more pharmacologically inert polymers, water-soluble polymers, hydroxy acids, and other organic compounds, typically used in liquid formulations to enhance the formation of complexes of a particular substance with cyclodextrin. Suitable water-soluble polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (such as water-soluble cellulose derivatives) and water-soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectins, alginine and agar derivatives, and polypeptides such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, mixed ethers thereof, such as hydroxypropyl methyl cellulose and other mixed ethers, such as hydroxyethyl ethyl cellulose, hydroxypropyl ethyl cellulose, and hydroxyethyl cellulose, and hydroxyethyl cellulose, and hydroxyethyl cellulose. Synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various acrylic acid copolymers (e.g., carbomer). Suitable hydroxy acids include, by way of example and not limitation, citric acid, malic acid, lactic acid, tartaric acid and other known to those of ordinary skill in the art.

[0121] The term "preservative" as used herein is intended to mean a compound used to prevent the growth of microorganisms. Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgammapicolinium chloride, benzoate potassium, sodium benzoate, sodium propionate, sorbic acid, thymol and methyl, ethyl parabens, propyl or butyl and other known to those of ordinary skill in the art.

[0122] As used herein, the term "dye" is intended to mean a compound used to add color to pharmaceutical preparations. Such compounds include, by way of example and without limitation, FD&amp;C No. 3 red, FD&amp;C No. 20, FD&amp;C No. 6 yellow, FD&amp;C No. 2, D&amp;C No. 5 green, D&amp;C No. 5 orange, D&amp;C No. 8, caramel and iron oxide ( black, red, yellow), other FD &amp; C pigments. and natural coloring agents such as grape skin extract, red beet powder, beta carotene, annatto, carmine, turmeric, paprika, combinations thereof and other such materials known to those of ordinary skill in the art.

[0123] The term "tonicity modifier" as used herein is intended to mean a compound or compounds that can be used to adjust the tonicity of a liquid formulation. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those of ordinary skill in the art.

[0124] As used herein, the term "anti-foaming agent" is intended to mean a compound or compounds that prevent or reduce the amount of foam that forms on the fill surface of the composition. Suitable anti-foaming agents include, by way of example and not limitation, dimethicone, simethicone, octoxynol and other known to those of ordinary skill in the art.

[0125] Hydrophilic polymers can be used to improve the performance of a cyclodextrin containing formulation. Loftsson (US Pat. Nos. 5,324,718 and 5,472,954) disclosed numerous polymers suitable for combined use with cyclodextrin (non-derivatized or derivatized) to enhance the action and / or properties of cyclodextrin. Suitable polymers are disclosed in Pharmaza (2001), 56 (9), 746-747; International

Journal of Pharmaceutics (2001), 212 (1), 29 &lt;10; Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium, 10, Ann Arbor, MI, United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp .: Adrian, Mich.); International PCT Publication No. WO 9942111; Pharmazie, 53 (11), 733-740 (1998); Pharm. Technol. Eur., 9 (5), 26-34 (1997); J. Pharm. Sci. 85 (10), 1017-1025 (1996); European Patent Application EP0579435; Proceedings of the International Symposium on Cyclodextrins, 9th, Santiago de Comostela, Spain, May 31 - June 3, 1998 (1999), 261-264 (publishers): Labandeira, JJ Torres; Vila-Jato, JL Kluwer Academic Publishers, Dordrecht, Neth); STP Pharma Sciences (1999), 9 (3), 237-242; ACS Symposium Series (1999), 737 (Polysaccharide Applications), 24-45; Pharmaceutical Research (1998), 15 (11), 1696-1701; Drug Development and Industrial Pharmacy (1998), 24 (4), 365-370; International Journal of Pharmaceutics (1998), 163 (1-2), 115-121; Book of Abstracts, 216th ACS National Meeting, Boston, August 23-27 (1998), CELL-016, American Chemical Society; Journal of Controlled Release, (1997), 44/1 (95-99); Pharm.Res. (1997) 14 (11), 5203; Investigative Ophthalmology &amp; Visual Science, (1996), 37 (6), 1199-1203; Proceedings of the International Symposium on Controlled Release of Bioactive Materials (1996), 23rd, 453-454; Drug Development and Industrial Pharmacy (1996), 22 (5), 401-405; Proceedings of the International Symposium on Cyclodextrins, 8th, Budapest, March 31 - April 2, (1996), 373-376. (publisher (s): Szejtli, J .; Szente, L. Kluwer: Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2 (6), 277-279; European Journal of Pharmaceutical Sciences, (1996) 4 (SUPPL.), S144; Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland, UK September 15-17, 1996; Pharmazie, (1996), 51 (1), 39-42; Eur. J. Pharm. Sci. (1996), 4 (suppl), S143; US patents 5,472,954 and 5,324,718; International Journal of Pharmaceutics (Netherlands), (December 29, 1995) 126, 73-78; abstracts of the work of the American Chemical Society, (02 APR 1995) 209 (1), 33-CELL; European Journal of Pharmaceutical Sciences, (1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11 (10), S225; International Journal of Pharmaceutics (Netherlands), (11 April, 1994) 104, 181-184; and International Journal of Pharmaceutics (1994), 110 (2), 169-77, full disclosures of which are incorporated herein by reference.

[0126] Other suitable polymers are well-known excipients commonly used in the field of pharmaceutical formulations and are, for example, contained in Remington's Pharmaceutical Sciences, 18th edition, Alfonso R. Gennaro (publisher), Mack Publishing Company, Easton, PA, 1990, pp. . 291-294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition (Lea &amp; Febinger, Philadelphia, PA, 1983, pp. 592-638); AT Florence and D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition, MacMillan Press, London, 1988, pp. 281-334. Full disclosures of the references cited herein are incorporated herein by reference. Still other suitable polymers include water soluble polymers natural, water-soluble semi-synthetic polymers (such as water-soluble cellulose derivatives) and water-soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, alginine derivatives (e.g. sodium alginate) and agar, and polypeptides such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, mixed ethers thereof, such as hydroxypropyl methyl cellulose and other mixed ethers, such as hydroxyethyl ethyl cellulose, hydroxypropyl ethyl cellulose, and hydroxyethyl cellulose, and hydroxyethyl cellulose, and hydroxyethyl cellulose. Synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various acrylic acid copolymers (e.g., carbomer). Other natural, semi-synthetic and synthetic polymers not listed here that meet the criteria of water solubility, pharmaceutical acceptability, and pharmacological inactivity are similarly considered to fall within the scope of the present invention.

[0127.] A solubility enhancer may be added to the formulation of the invention. A solubilizer is a compound or compounds that (which) enhances (enhances) the solubility of the active substance in an aqueous or humid environment, such as the lining of the airways. Suitable solubilizing substances include one or more organic solvents, detergents, soaps, surfactants and other organic compounds typically used in liquid formulations to enhance the solubility of a particular substance. Suitable organic solvents include, for example, ethanol, glycerin, polyethylene glycols, propylene glycol, (poly) propylene glycols, poloxamers and others known to those of ordinary skill in the art.

[0128] The term "antifreeze" as used herein is intended to mean a compound used to protect an active substance against physical or chemical degradation during lyophilization. Such compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol and other known to those of ordinary skill in the art.

[0129] Plasticizers can also be included in the formulations of the invention to modify their properties and characteristics. The term "plasticizer" as used herein includes all compounds capable of plasticizing or softening the polymer or linker used in the invention. The plasticizer should be able to lower the melting point or glass transition temperature (softening point temperature) of the polymer or fastener. Plasticizers such as low molecular weight PEG generally broaden the average molecular weight of the polymer in which they are contained, thereby lowering its glass transition temperature or softening point. Plasticizers usually also reduce the viscosity of the polymer. It is possible that the plasticizer will add some particularly favorable physical properties to the osmotic device of the invention.

[0130] Plasticizers useful in the invention may include, by way of example and not limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester type plasticizers, glycol ethers, poly (propylene glycol), multi-block polymers, single-block polymers, low molecular weight poly (ethylene) glycol, citrate ester plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers may also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly (ethylene) glycol compounds, monopropylene glycol monisopropyl ether, glycol monoethyl ether propylene, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from companies such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention that a combination of plasticizers can be used in the formulation of the invention. PEG-based plasticizers are commercially available or can be made by various methods, such as disclosed in Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (JM Harris, ed .: Plenum Press, NY), the disclosure of which is included in the description by reference. [0131] The term "taste" as used herein is intended to mean a compound used to add a pleasant taste and often flavor to a pharmaceutical preparation. Exemplary taste change substances or flavors include synthetic flavor oils and flavors and / or natural oils, extracts from plants, leaves, flowers, fruits and so on and combinations thereof. These may also include cinnamon oil, winter oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, and '-λ oil. and * · ·· .- '- pineapple, bitter almond oil and cassia oil. Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so on. Flavorings that have proven to be particularly useful include commercially available orange, grape, cherry and chewing gum flavors and mixtures thereof. The amount of flavor may depend on many factors, including the desired organoleptic effect. Flavorings will be present in any amount desired by those of ordinary skill in the art. Special flavors are grape and cherry flavors and citrus flavors such as orange.

[0132] As used herein, the term "sweetener" is intended to mean a compound used to add sweetness to a formulation. Such compounds include, for example and without limitation, aspartan, dextrose, glycerin, mannitol, sodium saccharin, sorbitol, fructose, fructose rich corn syrup, maltodextrin, sucralose, sucrose, other materials known to a person of ordinary skill in the art and combinations thereof.

[0133] As used herein, the penetration enhancer is a substance or combination of substances that enhances the penetration of the active substance through the tissue. Penetration enhancers that may be included in the formulation of the invention include, by way of example and not limitation, calcium chelating agents such as EDTA, methylated cyclodextrin, and polycarboxylic acids; surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate, camitin, camitin esters and tween; bile salts such as sodium taurocholate; fatty acids such as oleic and linolenic acids; and non-surfactant substances such as AZONE ™ and dialkyl sulfoxides; E-flux inhibitors such as AV171 (AyMax, Inc., South San Francisco, CA), polyethylene glycol 100 D-atocopheryl succinate (TPGS), and peppermint oil; chitosan and chitosan derivatives such as N-methylchitosan, N-trimethylchitoate, mono-N-carboxymethylchitosan, quatized chitosan derivatives; SNĄC (N- (8- (2-hydroxybenzoyl) amino) caprylate) and SNAD (N- (10 (2-hydroxybenzoyl) amino) decanoate) (Emisphere Technologies, Inc., Tarrytown, NY); N-acylated non-alpha amino acids; HEMISPHERE supply substances; Gelucire 44/14 or vitamin E TPGS; CARBOPOL® 934P; other known to those of ordinary skill in the art; and their combinations.

[0134] The fragrance used herein is a relatively volatile substance or combination of substances that produces a perceptible aroma, odor or odor. Exemplary fragrances include those generally accepted by FD&amp;C.

[0135] A "surface tension modifying substance" is a material or combination of materials capable of modifying the surface properties of a composition according to the invention. The surface tension modifying substance may include a surfactant, detergent or soap. It may be contained in carrier molecules, molecules containing the active substance, or both.

[0136] A "density modifying substance" is a material or combination of materials that is included in the composition of the invention to increase or decrease its density. It may be contained in carrier molecules, molecules containing the active substance, or both. The density modifying substance can be used to increase or decrease (when necessary) the density of the carrier to enhance the dispersion of the active substance from the carrier. Similarly, a density modifying substance can be used to increase or decrease (when necessary) the density of the carrier to enhance the dispersion of the active substance from the carrier.

[0137] A "volatility modifying substance" is a material or combination of materials added to modify the volatility of an active substance. In one embodiment, the volatility modifying substance increases the volatility of the active substance. In another embodiment, the volatility modifying substance reduces the volatility of the active substance. [0138] The term "stabilizer" as used herein is intended to mean a compound used to stabilize a therapeutic substance against a physical, chemical or biochemical process that will reduce the therapeutic activity of the substance. Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprate sodium and others known to ordinary skill in the art.

[0139] The term "bulking agent" as used herein is intended to mean a compound used to add volume to a freeze-dried product and / or to help control the properties of the formulation during freeze-drying. Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethyl sulfoxide, glycerol, albumin, calcium lactobionate and other known to those of ordinary skill in the art.

[0140] It should be understood that compounds used in the field of pharmaceutical formulations typically have many functions or purposes. Thus, if the compound given herein is mentioned only once or is used to designate more than one term, its purpose or function should not be understood as limited to that named (s) purpose or function.

[0141] In view of the above description and examples below, a person of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples, which specify specific procedures for making the compositions and formulations of the present invention. All references to these examples are given for illustration only. The following examples should not be considered exhaustive but merely illustrative of several of the many embodiments contemplated by the present invention.

EXAMPLE 1

Exemplary formulations were made according to the following general procedures.

Method A. Solid formulation in admixture.

[0142] The solid composition containing cyclodextrin is mixed with the solid composition containing the active substance until homogeneous. Compositions containing cyclodextrin and active ingredient contain less than about 20 wt. water. Mixing of the two compositions may also involve their simultaneous attrition or attrition may be performed as a separate method step. For example, a composition containing cyclodextrin and a composition containing the active ingredient are subjected to abrasion separately prior to mixing. One or more excipients may be included in the SAE-CD composition and / or active substance composition.

Method B. Liquid formulation.

[0143] The SAE-CD composition is mixed with a liquid carrier, optionally containing the active ingredient. The SAE-CD composition may be mixed with the liquid carrier either before, after or during the addition of the active substance, if present. One or more excipients may be included in the formulation. If desired, heat can be used to promote mixing or dissolution.

EXAMPLE 2

Preparation of solid SAE-CD compositions.

[0144] In methods A and B below, SAE-CD starter material was provided in an aqueous liquid carrier and SAE-CD starter material was prepared according to a method known in the literature. Specific embodiments included the SAE-CD starter material dissolved in water. The SAE-CD concentration in the liquid carrier was varied as needed to provide a liquid supply with the desired viscosity or solids content. Method A. Fluid bed spray drying [0145] The SAE-CD carrier was prepared by spray agglomeration in a fluid bed spray drying apparatus FSD-16 (GEA Niro Inc., Columbia MD). Several solutions of beta-cyclodextrin sulfobutyl ether (degree of substitution -7, SBE7-BCD) in 20.1-49.8% solids were agglomerated in FSD-16 using a top mounted Spraying Systems pressure nozzle at an atomization pressure of 1.500 -2.000 psig and supply temperature ~ 25 ° C. The process conditions were: entry / exit temperatures of 210-250 / 83-100 ° C, fluidized bed entry temperatures of 80-100 ° C, and liquid product bed temperatures of 67-87 ° C. The return of fine particles at the atomizer nozzle and at the chamber cone was examined during separate rounds. The drying gas flows are electrically heated.

[0146] The fed solutions containing SAE-CD were prepared by adding powdered ingredients to the required amount of water during heating and agitation in the feed tank.

Method B. Fluidized bed spray drying [0147] The SAE-CD composition was prepared by spray agglomeration in a fluid bed spray drying apparatus FSD-12.5 (GEA Niro Inc., Columbia MD) with a 3-chamber fluid bed attached. The inner fluidized bed chamber (chamber 1) was directly open to the drying chamber and was used for final agglomeration, drying of agglomerates and dedusting. The outer annular fluidized bed chambers 2 and 3 are connected in series to chamber 1 such that the product flows from chamber 1 to chamber 2 to chamber 3 in a manner controlled by process conditions. Chamber 2 was used for post-drying and continuous dedusting. Chamber 3 was used for cooling and final dust removal. The final product was taken from chamber 3. The drying gas flows (N2) are electrically heated and the main drying gas is introduced into the drying chamber through a ceiling air dispersant. The drying gas to the three fluidized bed chambers was distributed evenly through the perforated plates. Drying gas flows have been individually tailored to different fluidized bed chambers.

[0148] Solutions of beta-cyclodextrin sulfobutyl ether (degree of substitution ~ 7, SBE7-BCD) at 48-52 wt. solids were agglomerated in FSD-12.5 using a Spraying Systems pressure nozzle mounted on top of the spray systems at an atomization pressure of 10-50 bar and a solution temperature of 4555 ° C. The process conditions were: in / out temperatures of 150-170 / 70-90 ° C, fluidized bed inlet chamber 1 temperatures of 100-150 ° C, and fluidized bed chamber 1 product temperatures of 60-100 ° C. The fine particles were returned to the atomizer nozzle.

EXAMPLE 3 [0149] The diameter distribution (particle size) of several SAE-CD compositions (beta-cyclodextrin sulfobutyl ether, degree of substitution ~ 7) was determined by laser diffraction (Malvem Instruments Inc, Model 2000, South Borough, MA) equipped with an instrument for dry powder administration. A dispersion pressure against the particle size curve was generated and based on a dispersion pressure of 60 psi. Powder samples were taken using a 500 sweep detector for statistical validation. Obfuscation values ​​were monitored to ensure relevant data was obtained. A detector lens with a focal length of 300 mm was used, providing a size range from 5.8 to 564 μ.

[0150] Particle size analysis data for exemplary SAE-CD compositions of beta-cyclodextrin sulfobutyl ether with an average degree of substitution of ~ 7, SBE7-BCD, are provided in the table below. The data for each composition indicate the particle diameters in microns, corresponding to the De Broucker average diameter (D [4.3]) or cut-offs of the particle size of 10%, 50% or 90% of the cumulative volume fraction (μ is to denote micron.)

Average diameter Particle size cut off at specific per (D [4.3j) centiles by volume distribution

<td>SAE-CD set</td><td>Size (μ)</td><td>10.00% D [v, 0,1]</td><td>50.00% D [v, 0,5]</td><td>90.00% D [v, 0.9]</td>

<td>* B3</td><td> 78,7</td><td> 28,7</td><td> 67,9</td><td> 138,1</td>

<td>B4</td><td> 86,9</td><td> 30,2</td><td> 79,1</td><td> 154,1</td>

<td>B5</td><td> 83,8</td><td> 33,1</td><td> 76,7</td><td> 145,4</td>

<td>B9</td><td> 104,9</td><td> 34,9</td><td> 96,5</td><td> 184,9</td>

<td>** A1</td><td> 175</td><td></td><td></td><td></td>

<td>A2</td><td> 194</td><td></td><td></td><td></td>

<td>A3</td><td> 119</td><td></td><td></td><td></td>

<td>A4</td><td> 125</td><td></td><td></td><td></td>

<td>A5</td><td> 92</td><td></td><td></td><td></td>

<td>A6</td><td> 187</td><td></td><td></td><td></td>

<td>A7</td><td> 164</td><td></td><td></td><td></td>

* "B #" means the SAE-CD composition made according to Example 2, Method B, where is the sample set number * "A #" means the SAE-CD composition made according to Example 2, Method A, where "#" means the sample set number [0151] Samples Al, A2, A5, A6 and A7 are included herein as reference examples. EXAMPLE 4 [0152] The moisture content of the SAECD composition was measured by the Karl Fisher method (USP <921>, method Ia) or the moisture balance method.

Moisture balance method [0153] Moisture balance Computrac Model 200 XF (Arizona Instruments, Tempe, AZ) was used to determine the weight loss of selected powder samples while the powder was exposed to infrared heating. The powders were weighed (approximately 1 g for each sample), heated at 110 ° C until no change in the observed weight was observed, and the percentage weight loss was calculated.

EXAMPLE 5 [0154] The flowability of solid SAE-CD compositions was determined by experimental equipment (Flodex ™, Hanson Research Corp., Northridge, California) having:

- a stainless steel cylinder with a capacity of approximately 200 ml;

- a series of stainless steel discs. Each disk having a precise hole in the center in graduated sizes differing by 1-2 mm in diameter, so that it is easy to attach to form the bottom of the cylinder;

- an aperture that covers the opening and which can be quickly removed without vibration, allowing the powder to flow through the selected opening;

- adaptable funnel for loading the sample cylinder with free falling of the tested powder;

- a suitable container for collecting the powder that flows through the device.

[0155] The plug was mounted above the cylinder so that the bottom of the funnel was close but did not touch the surface of the powder when it was loaded into the cylinder. The disc was inserted into the bottom of the cylinder and the opening in the disc was closed. A load of 50 g of powder was poured through the funnel into the center of the cylinder. The powder was allowed to stabilize in the cylinder for at least 30 seconds, then the hole in the disk was opened quickly and without vibration. Then the flow through the hole in the disc was observed. A positive result was recorded when the powder flowed through the hole, leaving an inverted truncated cavity in 3 of 3 trials and the powder that falls covered the entire height of the powder (not less than 60 mm).

[0156] A negative result was recorded when the powder fell sharply through the hole, forming a cylindrical cavity in the remaining powder.

[0157] If the result was positive, the procedure was repeated with discs having a smaller hole diameter until the smallest diameter hole was also found to give a positive result in 3 of 3 trials.

[0158] If the result was negative, the procedure was repeated with discs having a larger hole diameter until a hole with the smallest diameter giving a positive result in 3 of 3 trials was determined.

[0159] The measurement results for the SAE-CD (beta-cyclodextrin sulfobutyl ether substitution grade -7, SBE7-B-CD) composition are given below.

SBE7-B-CD set Minimum hole diameter (mm)

<td>B4</td><td> 6</td>

<td>B9</td><td> 6</td>

<td>Al</td><td> 9</td>

<td>A2</td><td> 8</td>

<td>A3</td><td> 5</td>

<td>A4</td><td> 4</td>

<td>A5</td><td> 10</td>

<td>A6</td><td> 12</td>

<td>A7</td><td> 10</td>

EXAMPLE 6 [0160] The average dissolution time of the SAE-CD (sulfobutylether betacyclodextrin medium substitution grade -7, SBE7-BCD) composition was determined by a flow dissolution device including a glass filter holder (Millipore Corp., Billerica, MA) attached to the pump and water tank. The filter holder consisted of a funnel with a capacity of -300 ml and a sintered glass base held together by a metal clamp.

[0161] The test was carried out by placing 2.5 g of the sample powder on a 47 mm x 10 micron filter fitted between the filter holder sections. Water at -25 ° C was pumped at a rate of 100 ml per minute through the bottom of the apparatus so that the water rose through the filter and into the tank. The sample was observed to determine the time required for all solids to dissolve. If the sample floated and required more than 2.5 minutes to dissolve, the pump was stopped after delivering 250 ml.

[0162] Representative data for beta-cyclodextrin sulfobutyl ether with an average degree of substitution of 7 (SBE7-CD) are provided in the table below.

<td rowspan="2">Composition SBE7-CD</td><td colspan="3">Dissolution time (minutes)</td>

<td>Round 1</td><td>Round 2</td><td>Average</td>

<td>B3</td><td> 3,0</td><td> 3,5</td><td> 3,25</td>

<td>B4</td><td> 2,0</td><td> 2,25</td><td> 2,13</td>

<td>B5</td><td> 2,0</td><td> 2,0</td><td> 2,0</td>

<td>B6</td><td> 2,5</td><td> 2,5</td><td> 2,5</td>

<td rowspan="2">Composition SBE7-CD</td><td colspan="3">Dissolution time (minutes)</td>

<td>Round 1</td><td>Round 2</td><td>Average</td>

<td>B8</td><td> 2,0</td><td> 2,5</td><td> 2,25</td>

<td>B10</td><td> 2,25</td><td> 2,0</td><td> 2,13</td>

<td>A5</td><td> 2,0</td><td> 2,0</td><td> 2,0</td>

EXAMPLE 7 [0163] SAE-CD compositions were compared in thickening studies to commercial powder samples used for tablet preparation, e.g. microcrystalline cellulose (Avicel 200), lactose USP, and dibasic calcium phosphate dihydrate (DiCal).

[0164] The powders were compressed on a equipped Colton single station press operating at 15 tablets per minute. The press was equipped with the upper and lower punching force and displacement. The sample weight was 200 mg and the samples were compressed into three different tablet hardnesses of approximately 5, 10 and 15 kP using flat surface punches with a diameter of 0.345 inches. Strength and displacement data were collected using a 4-channel, 12-bit digital oscilloscope (model # 420, Nicolet Instrument Corp., Madison, WI, USA); samples were collected every msec simultaneously for each of the four channels. The matrix was coated with a lubricant - 10% (w / v) dense suspension of magnesium stearate in acetone, applied with a cotton swab. To maintain tablet-to-tablet consistency, a standardized procedure was applied for applying a cotton swab and drying a thick slurry on the matrix wall. Matrix wall coverage was also checked by visual inspection. To reduce signal noise, a fast Fourier Transform (FFT) was performed on the upper and lower punch data using Igor Pro version 3.1 (Wavemetrics, Inc., Oregon). Igor Pro was also used to find Pmax in the mean tablet pressure curve (i.e. maximum punch pressure) after FFT, the software algorithm found the minimum using the derivative of the curve.

[0165] The tablet breaking strength was measured with a KEY® HT300 hardness testing device (Englishtown, NJ). A screw-on indicator was used to measure the height of the tablet after compression. Typically, 5 tablets were compressed and tested for hardness at each of the three target hardness levels.

EXAMPLE 8 [0166] The density and compressibility of the SAE-CD composition was determined by the following methods:

Method A. Bulk density [0167] The bulk density of the SAE-CD composition was determined according to USP <616> method I, using a 100 ml graduated cylinder.

Method B. Bulk density with density [0168] Bulk density of composition SAE-CD was determined according to USP <616> method I, using a 100 ml measuring cylinder.

Method C. CARR compressibility factor [0169] The CARR compressibility factor of the SAE-CD composition was calculated according to the formula:

% pressability bulk density with solids - bulk density bulk density with solids

X100%

Method D. Real density [0170] The actual density of the SAE-CD composition was determined by means of a device

Multivolume Pycnometer (Micromeritics Instrument Corp., Model 1305, Norcross, GA) according to the USP method <699>. Sample holder having a volume of one cm³ was used for all measurements.

[0171] The measurement results for SAE-CD (beta5 cyclodextrin sulfobutyl ether with average substitution degree ~ 7, SBE7-BCD) are given in the table below.

<td>SBE7BCD sample</td><td>Bulk density (g / cm³)</td><td>Bulk density with density (g / cm³)</td><td>CARR coefficient (%)</td><td>Real density (g / cm³)</td>

<td>B3</td><td> 0,610</td><td> 0,731</td><td> 16,06</td><td> 1,29</td>

<td>B4</td><td> 0,594</td><td> 0,701</td><td> 15,3</td><td> 1,30</td>

<td>B5</td><td> 0,601</td><td> 0,708</td><td> 15,1</td><td> 1,30</td>

<td>B6</td><td> 0,604</td><td> 0,692</td><td> 12,8</td><td></td>

<td>B8</td><td> 0,573</td><td> 0,670</td><td> 14,6</td><td></td>

<td>B9</td><td></td><td></td><td></td><td> 1,28</td>

<td>B10</td><td> 0,595</td><td> 0,694</td><td> 14,2</td><td></td>

<td>Al</td><td> 0,429</td><td> 0,564</td><td> 23,9</td><td></td>

<td>A2</td><td> 0,410</td><td> 0,539</td><td> 23,9</td><td></td>

<td>A3</td><td> 0,549</td><td> 0,670</td><td> 18,1</td><td></td>

<td>A4</td><td> 0,549</td><td> 0,661</td><td> 16,9</td><td></td>

<td>A5</td><td> 0,481</td><td> 0,574</td><td> 16,0</td><td></td>

<td>A6</td><td> 0,433</td><td> 0,528</td><td> 18,0</td><td></td>

<td>A7</td><td> 0,381</td><td> 0,495</td><td> 23,0</td><td></td>

EXAMPLE 9 [0172] A dry powder formulation suitable for administration by means of a DPI device includes one or more active substances, a SAE-CD composition carrier and optionally one or more excipients selected from the group consisting of an antioxidant, acidifying substance, an alkalizing substance, buffering substance, solubility enhancer, penetration enhancer, electrolyte, odor, glucose, glidant, stabilizer, bulking agent, antifreeze, plasticizer, flavors, sweeteners, surface tension modifiers, density modifiers, volatility modifiers or a combination thereof. The SAE-CD carrier contains about 50% to 99.9% by mass. formulation and has a median particle diameter of less than 420 microns. The active substance-containing molecules have a median particle diameter between about 0.1 to 10 microns. The carrier has a span of about 1.5 to 2.9, and the carrier was made according to the invention and optionally rubbing the solid to produce a molecular carrier. The SAE20 CD used in the carrier has an average DS in the range of about 1 to 12.

EXAMPLE 10 [0173] Rapid-release pressed tablet containing beta-cyclodextrin sulfobutyl ether with an average degree of substitution of 4 (SBEzt-PCD, SAE-CD composition), and piroxicam is prepared according to the following formula and procedure.

<td>Ingredient</td><td>Quantity (mg)</td>

<td>1: Piroxicam</td><td> 10</td>

<td>1: SBE₄-pCD</td><td> 77</td>

<td>2: Sorbitol</td><td> 45</td>

Quantity (mg)

Ingredient

<td>2: Dextrose</td><td> 50</td>

<td>2: Citric acid</td><td> 10</td>

<td>2: Xylitol</td><td> 47,5</td>

<td>2: PEG 3350</td><td> 9</td>

<td>3: magnesium stearate</td><td> 1,5</td>

<td>3: matted silicon dioxide</td><td> 1,5</td>

<td>3: croscarmellose sodium</td><td> 5,5</td>

<td>Together</td><td> 257</td>

[0174] The above ingredients were used to prepare 257 mg tablet core having a rapid release profile. The numbers after the ingredients indicate the general order of addition. After each group of added ingredients, the mixture is dry-mixed for 510 min. Magnesium stearate, fumed silicon dioxide (CABOSIL ™ M5P) and carmellose sodium are added separately (step 3) from the other ingredients and an additional 5 minute mixing step is added to the general procedure.

[0175] Next, the powder is pressed to form a tablet with a hardness of about 8-10 kg.

EXAMPLE 11 [0176] A controlled release tablet containing the SAE-CD composition, beta-cyclodextrin sulfobutyl ether with an average degree of substitution of 7 (SBE7-3CD) and prednisolone is prepared according to the following formula and procedure.

Ingredient Quantity (mg)

Prednisolone 15

SBE₇-pCD 210

Hydroxypropyl methylcellulose (HPMC K 100 M) 75

A total of 300 [0177] The above ingredients were used to make 300 mg tablet core having a controlled release profile. The ingredients are mixed by hand and the individual tablets are prepared on a press forming a pressure of 1 ton for 7 seconds. The tablets are prepared using a 5/16 "standard concave device with a cup.

EXAMPLE 12 [0178] An orodispersible immediate release tablet containing SAE-CD composition, gamma-cyclodextrin sulfobutyl ether with an average degree of substitution of 7 (SBE7-yCD) and zaleplon is prepared according to the following formula and procedure.

Ingredient Amount per tablet (mg)

<td>zaleplon</td><td> 5</td>

<td>Croscarmellose sodium (Ac-Di-Sol)</td><td> 24</td>

<td>SBE₇-yCD</td><td> 118</td>

<td>Microcrystalline cellulose (Avicel PHI02)</td><td> 150</td>

<td>Colloidal Silicon Dioxide (Cab-O-Sil)</td><td> 1,5</td>

<td>Magnesium stearate</td><td> 1,5</td>

<td>Together</td><td> 300</td>

[0179] The tablet ingredients are sieved through a 40-mesh screen (US standard) before weighing, and then all ingredients except magnesium stearate (Mg) are mixed in a glass bottle using a geometric dilution technique. The powder mix is ​​then passed twice through a 40 mesh screen to facilitate homogeneous mixing of all ingredients. Mg stearate is added before mechanical pressing, followed by mixing for an additional minute. Finally, the final blend is compressed into tablets with a 7 mm concave device using a rotary tablet press to give the tablet a hardness of approximately 3.0 kiloponds (kp). EXAMPLE 13 [0180] A constitutive powder formulation of lamotrigine and SAE-CD, beta-cyclodextrin sulfobutyl ether with an average degree of substitution of 7 (SBE7f3CD) was prepared using the formula below.

Ingredient Quantity (g)

<td>lamotrigine</td><td> 7,50</td>

<td>SBE₇-PCD</td><td> 37,5</td>

<td>USP citric acid</td><td> 3,75</td>

<td>xylitol</td><td> 300</td>

<td>Sodium saccharin</td><td> 0,75</td>

<td>Benzoic acid</td><td> 1,28</td>

<td>Strawberry flavor</td><td> 1,4</td>

<td>Xanthan gum</td><td> 1,5</td>

<td>Together</td><td> 353,6:</td>

[0181] Sodium saccharin, benzoic acid, strawberry flavor, citric acid and xanthan gum are combined and mixed well. Lamotrigine is added to the blend with further mixing, then SBEyPCD is added and mixing is continued. Then geometrically diluted xylitol is added to the obtained powder and further mixed.

[0182] The powder can be formed with water, giving a final volume of 750 ml. [0183] The following terms are defined as detailed below.

<td>TERM</td><td>DEFINITION</td>

<td>Agglomerate</td><td>a set of molecules that are connected to each other and act as a larger particle.</td>

<td>Bulk density</td><td>bulk density divided by bulk volume</td>

<td>CARR coefficient</td><td>measure of the powdered bulk flow properties.</td>

<td>CD</td><td>cyclodextrin</td>

<td>dPI</td><td>dry powder inhaler</td>

<td>KF</td><td>Karl Fisher analysis</td>

<td>MDI</td><td>inhaler with a dispenser, or more correctly, a metering inhaler driven by a propellant</td>

<td>monodisperse on</td><td>regarding particle size refers to a population of molecules that have the same particle size</td>

<td>nC</td><td>nanocell, charge measure</td>

<td>ND</td><td>indefinite</td>

4 ' "ϋί # Μ« ί'9ί.Λ>;

pMDI pressure inhaler with dispenser

SEM scanning electron microscopy

Bulk density of bulk powder divided by the volume of packed powder powder (after compaction of the powder by vertical whipping) [0184] The term "about" as used herein means +/- 10% of the indicated value.

[0185] The above is a detailed description of specific embodiments of the invention. It should be understood that while specific embodiments of the invention have been described herein to illustrate, various modifications may be made without departing from the spirit of the invention. Accordingly, the invention is not limited except by the limitation of the appended claims. All of the embodiments disclosed and claimed herein may be prepared and made without undue experimentation in light of the present disclosure.