WO2017017679A1

WO2017017679A1 - Compositions comprising atorvastatin or a pharmaceutically acceptable salt thereof

Info

Publication number: WO2017017679A1
Application number: PCT/IL2016/050819
Authority: WO
Inventors: Ron Schlinger; Gilat NIZRI; Moran Feldman
Original assignee: Dexcel Pharma Technologies Ltd.
Priority date: 2015-07-29
Filing date: 2016-06-27
Publication date: 2017-02-02

Abstract

An oral dosage form of atorvastatin or a pharmaceutically acceptable salt thereof, methods for its production and use thereof are disclosed. In particular, the oral dosage form is composed of a plurality of coated pellets admixed with a disintegrant.

Description

COMPOSITIONS COMPRISING ATORVASTATIN OR A

PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

TECHNICAL FIELD An oral dosage form comprising atorvastatin or a pharmaceutically acceptable salt thereof, methods for its production and use thereof are disclosed.

BACKGROUND

Atorvastatin, a 3 -hydroxy-3 -methyl glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, blocks the metabolic pathway that produces sterols, including cholesterol, in the liver. Atorvastatin is typically administered in oral dosage form for the treatment of hypercholesterolemia, dysbetalipoproteinemia and homozygous familial hypercholesterolemia.

WO 2010/038691 discloses a granular pharmaceutical composition for oral administration, wherein a drug-containing particle is coated with a coating comprising a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer and a water-soluble polymer.

WO 2011/121824 discloses an orally disintegrating tablet which contains grains obtained by coating cores, which contain atorvastatin or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate, with a coating material that contains a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer or a polyvinyl acetal diethylamino acetate and a water-soluble polymer material; and a carbonate or a hydrogen carbonate.

US 2006/0257482 discloses a multiple unit dosage form comprising multiple units, each unit comprising: at least one core having an outer surface; a first coating layer surrounding at least a portion of the outer surface of the core and having an outer surface, the coating layer including one or both of one or more active pharmaceutical ingredients and one or more rate controlling polymers; and an outer layer, the outer layer comprising a material that is one or both of elastic and compressible.

CN 100411612 discloses a fast disintegrated atorvastatin calcium tablet which is prepared from atorvastatin calcium, disintegrant, flavoring, filler and lubricant proportionally.

US 2007/0196494 discloses a rapidly disintegrating orally administratable solid dosage formulation that includes at least one active ingredient, at least one first disintegration agent that is at least one type-C methacrylic acid copolymer according to the U.S. Pharmacopoeia National Formulary US/NF, a second disintegration agent of crospovidone or a cross-linked povidone polymer derivative thereof, and a non- cariogenic diluent that does not increase glucose blood levels.

US 2008/0206324 discloses an active compound-containing pellet, comprising: a polymer coating of an anionic (meth)acrylate copolymer; and a pharmaceutically active substance, embedded in a polymer matrix of one or more polymers, said pellet having a particle size in the range from 300 to 1 , 100 μπι, a friability of at most 0.1%, measured using 200 g of pellets in a screening machine having a 200 μπι screen, a screening diameter of 20 cm and 1.5 mm shaking amplitude at a shaking frequency of 50 1/sec for 10 min in the presence of six rubber cubes having a 1.8 cm edge length, with the proviso that the pellet releases no more than 10% of the active compound in a release test according to USP in artificial gastric juice at pH 1.2 after 120 min.

US 2010/0278901 and US 2015/0004240 disclose a taste-masked pharmaceutical composition comprising: a drug-resin complex and a highly compressible, free-flowing pharmaceutical excipient, wherein the resin is present in an amount effective to reduce the taste of the drug in the drug resin complex by more than about 15 percent relative to an otherwise identical pharmaceutical composition without the resin; and wherein the highly compressible, free-flowing pharmaceutical excipient aids release of the drug-resin complex in the mouth. US 2014/0154328 discloses an oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion-exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material, wherein the bioadhesive material is selected from the group consisting of optionally cross-linked homopolymers of acrylic acid or an alkylacrylic acid and optionally cross-linked copolymers of acrylic acid or methacrylic acid with a (Cio-C3o)alkyl acrylate.

US 2014/0178484 discloses a multi-particulate pharmaceutical composition suitable for administration in a sprinkle dosage form said particles being less than 2 mm in diameter and comprising a) inert core particles b) an inner layer surrounding said inert core particles, said layer comprising atorvastatin calcium, methyl methacrylate butyl methacrylate-dimethylaminoethyl methacrylate copolymer and disintegrant and c) an outer taste masking layer surrounding the inner layer, said outer layer comprising methyl methacrylate butyl methacrylate-dimethylaminoethyl methacrylate copolymer.

There is an unmet need for compositions comprising atorvastatin or a pharmaceutically acceptable salt thereof in the form of orally disintegrating tablets in which the atorvastatin bitter taste is masked, while affording good dissolution characteristics.

BRIEF SUMMARY

The present disclosure relates to a composition, such as an orally disintegrating composition, comprising pellets comprising atorvastatin or a pharmaceutically acceptable salt thereof which are admixed with at least one excipient comprising a disintegrant, wherein after administration, the composition substantially disintegrates in the oral cavity of a subject within less than about 60 seconds, preferably within less than about 30 seconds. The composition provides an in vitro dissolution profile of the active ingredient which is substantially the same as the dissolution profile of a non-orally disintegrating composition while affording substantially complete masking of atorvastatin bitter taste. The present disclosure further relates to methods of preparing said composition and use thereof in the treatment of, inter alia, hypercholesterolemia.

The present disclosure is based, in part, on the unexpected finding of an atorvastatin formulation, preferably an orally disintegrating tablet, which provides good dissolution characteristic combined with high compliance with the end-user. It was not previously realized that pellets coated with a plurality of coating layers in which the drug-containing layer contains a cationic polymer and the taste-masking layer contains a water-insoluble polymer in specific proportions, provide improved dissolution of the active ingredient as well as its robust taste-masking even after compression.

According to a first aspect, there is provided an orally disintegrating composition comprising (i) a plurality of pellets, wherein each pellet comprises an inert core coated with a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof and a cationic polymer, and a second coating layer comprising a water-insoluble polymer; and (ii) at least one pharmaceutically acceptable excipient comprising a disintegrant, wherein the composition substantially disintegrates in the oral cavity of a subject within less than about 60 seconds after administration, and wherein in vitro drug release in 20 minutes at pH 6.8 is about 5% or less. In certain embodiments, the orally disintegrating composition substantially disintegrates in the oral cavity of a subject within less than about 30 seconds after administration.

According to another aspect, there is provided a composition comprising a plurality of pellets, wherein each pellet comprises an inert core coated with a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof and a cationic polymer, and a second coating layer comprising a water-insoluble polymer, wherein the composition provides in vitro drug release in 20 minutes at pH 6.8 of about 5% or less. In one embodiment, the pellets are compressed. In another embodiment, the pellets are admixed with at least one excipient comprising a disintegrant prior to being compressed. In some embodiments, the composition disclosed herein provides an in vitro drug release in 20 minutes at pH 6.8 of about 3% or less.

In one embodiment, the atorvastatin or a pharmaceutically acceptable salt thereof is in a crystalline form or an amorphous form, with each possibility representing a separate embodiment.

In another embodiment, the atorvastatin or a pharmaceutically acceptable salt thereof comprises an atorvastatin alkaline earth metal salt.

In a particular embodiment, the atorvastatin alkaline earth metal salt comprises atorvastatin calcium.

In certain embodiments, the inert core comprises a sugar sphere. In other embodiments, the inert core comprises microcrystalline cellulose.

In some embodiments, the cationic polymer comprises an amino group.

In other embodiments, the cationic polymer comprises a primary, secondary, tertiary or quaternary amino group. Each possibility represents a separate embodiment.

In several embodiments, the cationic polymer comprises at least one of cationic starches, cationic polyvinyl alcohols, cationic vinyl polymers, cationic styrene containing polymers, cationic polyurethanes, cationic cellulose-based polymers, cationic polysaccharides, cationic acrylic polymers or copolymers, and cationic (meth)acrylate polymers or copolymers. Each possibility represents a separate embodiment.

In various embodiments, the cationic polymer comprises poly acrylamide, a copolymer of acrylamide, and combinations thereof, with each possibility representing a separate embodiment. In certain embodiments, the cationic polymer comprises a cationic methacrylate polymer or copolymer. In one embodiment, the cationic polymer comprises methyl methaciylate-butyl methacrylate- dimethylaminoethyl methacrylate copolymer. In some embodiments, the water-insoluble polymer comprises at least one of ethyl cellulose, polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), and (meth)acrylate polymers or copolymers including methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer. Each possibility represents a separate embodiment.

In a particular embodiment, the cationic polymer and the water-insoluble polymer each comprise a methyl methacrylate-butyl methacrylate- dimethylaminoethyl methacrylate copolymer.

In some embodiments, the ratio between the cationic polymer and the water- insoluble polymer is in the range of from about 1 : 1 to about 1 :4 (w/w), including all iterations of ratios within the specified range. In one embodiment, the ratio between the cationic polymer and the water-insoluble polymer is in the range of from about 1 :2 to about 1 :4 (w/w), including all iterations of ratios within the specified range. In another embodiment, the ratio between the cationic polymer and the water-insoluble polymer is in the range of from about 1 :2.5 to about 1 :3.5 (w/w), including all iterations of ratios within the specified range.

In certain embodiments, each pellet further comprises a third coating layer which is an intermediate layer between the first and the second coating layers. In several embodiments, the third coating layer comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol. Each possibility represents a separate embodiment.

It will be recognized by one of skill in the art that each of the coating layers may further comprise a plasticizer, a surfactant, a filler, a lubricant, an anti-tacking agent or a combination thereof. Each possibility represents a separate embodiment. According to some aspects and embodiments, the composition comprises at least one pharmaceutically acceptable excipient comprising a disintegrant. In exemplary embodiments, the disintegrant is selected from the group consisting of crospovidone (cross-linked PVP), croscarmellose sodium, a sugar alcohol, a cellulose derivative, cross-linked derivatives of starch, pregelatinized starch and any combination or mixture thereof. Each possibility represents a separate embodiment. In some embodiments, the sugar alcohol is selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, and any combination or mixtures thereof. Each possibility represents a separate embodiment. In other embodiments, the cellulose derivative is selected from the group consisting of methylcellulose, cross-linked carboxylic methylcellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, low substituted hydroxypropyl cellulose and any combination or mixture thereof. Each possibility represents a separate embodiment. In yet other embodiments, the cross-linked derivatives of starch comprise sodium starch glycolate. In certain embodiments, the aforementioned disintegrants are absent from the coating layers of the pellets.

In further embodiments, the composition disclosed herein comprises a plurality of excipients comprising a disintegrant and at least one of a binder, a filler, a diluent, a surfactant, a glidant, a lubricant, a plasticizer, an anti-tacking agent, a stabilizer, a tonicity enhancing agent, a wetting agent, a buffering substance, a preservative, a flavoring agent, an opacifier, a colorant, an anti-oxidant or a mixture or combination thereof. Each possibility represents a separate embodiment. The excipients may be incorporated in the pellets and/or admixed with the pellets.

In some embodiments, the composition disclosed herein is in a form of an orally disintegrating tablet. In accordance with these embodiments, the orally disintegrating tablet is characterized by hardness of at least about 30 Newtons, for example about 30-80 Newtons, or about 40-70 Newtons, including each integer within the specified range. Each possibility represents a separate embodiment.

In further embodiments, the composition disclosed herein provides an in vitro dissolution profile of the atorvastatin which is substantially the same as the in vitro dissolution profile of a non-orally disintegrating composition comprising atorvastatin.

In further embodiments, the composition results in a C_max or AUC after administration which is substantially equivalent to a non-orally disintegrating composition comprising atorvastatin. In specific embodiments, the orally disintegrating composition disclosed herein provides an in vivo atorvastatin release profile which is substantially the same as the release profile of a non-orally disintegrating composition comprising atorvastatin. In particular embodiments, the composition according to the principles disclosed herein comprises (i) a plurality of pellets comprising: (a) inert cores in an amount of about 5% to about 20% by weight, including each integer within the specified range; (b) a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof in an amount of about 4% to about 10% by weight and a cationic polymer in an amount of about 1% to about 10% by weight, including each integer within the specified ranges; (c) a second coating layer comprising a water- insoluble polymer in an amount of about 5% to about 15% by weight, including each integer within the specified range; and (d) optionally an excipient selected from a binder, a filler, an anti-tacking agent, a lubricant, a glidant, a surfactant, a plasticizer and any combination thereof in an amount of not more than about 20% by weight, including each integer within the specified range; (ii) at least one disintegrant in an amount of about 4% to about 15% by weight, including each integer within the specified range; and (iii) optionally an excipient selected from a binder, a filler, an anti-tacking agent, a lubricant, a glidant, a surfactant, a plasticizer, a flavoring agent, and any combination thereof in an amount of not more than about 50% by weight, including each integer within the specified range, wherein presence of all components add to 100%). In one embodiment, the pellets of the composition disclosed herein further comprise a third coating layer which is an intermediate layer between the first and the second coating layers in an amount of about 1% to about 15% by weight, including each integer within the specified range.

The composition of the present disclosure is useful for treating hypercholesterolemia. Accordingly, there is provided a method of treating hypercholesterolemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition disclosed herein.

Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWING

Figure 1. illustrates characteristic in vitro dissolution release profiles of atorvastatin orally disintegrating tablets according to certain embodiments of the disclosure. The medium used: t=0 to t=5 minutes: 0.1N HCl; t=5 to t=45 minutes: phosphate buffer at pH 6.8. Also shown for comparison is the in vitro dissolution release profile of Lipitor^® tablets.

DETAILED DESCRIPTION There is provided an oral dosage form comprising a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided an orally disintegrating dosage form that enables fast disintegration of the composition in the oral cavity. The orally disintegrating dosage form is particularly suitable for patients who may be incapable of, or are having difficulties in swallowing.

According to certain aspects and embodiments, there is provided a taste- masked composition comprising a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof which rapidly disintegrates in the oral cavity after oral administration. In particular embodiments, the composition is in a form of an orally disintegrating tablet (ODT) or a fast disintegrating tablet (FDT). As used herein, the terms "orally disintegrating composition" or "orally disintegrating dosage form" refer to a composition or dosage form, respectively, that disintegrates in the oral cavity of the subject upon coming into contact with the mucosal tissue of the tongue, cheek, and/or mouth within a short period of time, for example in less than about 60 seconds, preferably in less than about 30 seconds after administration. Upon administration of the orally disintegrating pharmaceutical composition to the oral cavity of a subject, the composition disintegrates rapidly into the subject's oral cavity to form a smooth suspension of particles comprising the pellets that can be readily swallowed. It is to be understood that the terms "orally disintegrating composition" or "orally disintegrating dosage form" refer to the disintegration of the composition or dosage form, respectively, in the oral cavity after administration and not the disintegration of the pellets which remain substantially intact in the oral cavity.

According to various aspects and embodiments, there is provided a composition, e.g. an orally disintegrating tablet (ODT) or a fast disintegrating tablet (FDT), having in vitro drug release in 20 minutes at pH 6.8 which is less than about 5%, for example about 0-5%, preferably about 0-3%, including each integer within the specified range. While the in vitro drug release in 20 minutes at pH 6.8 is less than about 5%), the in vitro dissolution profile of the composition after 5 minutes in 0.1N hydrochloric acid followed by 15 minutes at pH 6.8 corresponds to a release of at least about 70% of the atorvastatin active ingredient from the formulation. Preferably, the in vitro dissolution profile of the composition after 5 minutes in 0.1N hydrochloric acid followed by 15 minutes at pH 6.8 corresponds to release of at least about 80% of the atorvastatin active ingredient from the formulation.

According to other aspects and embodiments, there is provided an orally disintegrating tablet or a fast disintegrating tablet characterized by hardness of at least about 30 Newtons, e.g. about 30-80 Newtons, or about 40-70 Newtons, including each integer within the specified ranges, while still allowing disintegration in the oral cavity in less than about 60 seconds, preferably in less than about 30 seconds after administration. In certain embodiments, the hardness of the orally disintegrating tablet or fast disintegrating tablet is about 30 N, about 35 N, about 40 N, about 45 N, about 50 N, about 55 N, about 60 N, about 65 N, about 70 N, about 75 N, or about 80 N, with each possibility representing a separate embodiment.

According to some aspects and embodiments, there is provided a composition comprising taste-masked pellets comprising a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof. The pellets are optionally compressed. In various embodiments, there is provided a composition comprising a mixture of taste-masked pellets comprising a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient comprising a disintegrant. The composition is optionally compressed into a solid dosage form (e.g. a tablet). As used herein, the terms "taste-masked pellets" or "taste-masked composition" refer to pellets or composition, respectively, having substantial reduction or elimination of an unpleasant taste which may be imparted by the active ingredient atorvastatin, including aftertaste which may be left in the oral cavity, following administration. The taste-profile of the composition may be determined using various taste assays as is known in the art. In certain embodiments, the taste- profile is determined using electronic tongue. The electronic tongue is comprised of a sensor or a plurality of sensors which are configured to sense various tastes including bitterness, sweetness, sourness, saltiness and umami when in contact with a sample and to generate an electrical signal in response. The electrical signal (i.e. sensor's response) is detected by detection means and optionally conveyed to a processing unit for subsequent analysis.

By comparing the response obtained when exposing the sensor(s) to the composition of the disclosure with a response obtained from a known sample, evaluation of taste-masking can be obtained. For example, the composition of the disclosure can be compared with negative control samples, i.e. placebo compositions containing no active ingredient, or positive control samples, i.e. compositions containing the active ingredient with no taste masking. A statistically significant difference in the response of the sensor(s) between the composition of the disclosure and the positive control samples indicates that the composition of the disclosure is "taste-masked". The term "statistically significant difference" as used herein refers to a statistically significant quantitative difference or variation between the response of the test sample and the response of a control sample. A statistically significant difference can be determined by any test known to the person skilled in the art including, but not limited to, t-test, ANOVA1, Kruskal-Wallis, Wilcoxon, Mann- Whitney and odds ratio. A difference such as an increase or decrease in the response signal as compared to a control or reference value or mean control level or reference value, or a change, variation or deviation from a control or reference value, can be considered to exist if a difference of about 5% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, or about 50% or more compared to the control level or reference value is found. Alternatively, a difference in the response signal can be considered to exist if the response signal is at least one standard deviation 1 [SD] larger or smaller than the mean response signal of positive control samples. More preferably, the response signal is at least 2[SD] or 3[SD] larger or smaller than the mean response signal of positive control samples. Statistical significance may alternatively be calculated as P<0.05. Methods of determining statistical significance are known and are readily used by a person of skill in the art.

Alternatively, the response signal may be characterized by a pattern which significantly differs from the patterns of control samples. In accordance with these embodiments, analysis may be performed using pattern recognition algorithms comprising artificial neural networks, such as multi-layer perception (MLP), generalized regression neural network (GRNN), fuzzy inference systems (FIS), self- organizing map (SOM), radial bias function (RBF), genetic algorithms (GAS), neuro- fuzzy systems (NFS), adaptive resonance theory (ART) and statistical methods such as hierarchical linear modeling (HLM), principal component analysis (PCA), partial least squares (PLS), multiple linear regression (MLR), principal component regression (PCR), discriminant function analysis (DFA) including linear discriminant analysis (LDA), and cluster analysis including nearest neighbor. Each possibility represents a separate embodiment.

In various embodiments, each of the taste-masked pellets comprises an inert core coated with at least two coating layers, a first coating layer, interchangeably the drug-containing layer, and a second coating layer, interchangeably the taste-masking layer. According to the principles disclosed herein, the drug-containing layer comprises a cationic polymer and the taste-masking layer comprises a water-insoluble polymer.

Surprisingly, it is now being disclosed that pellets that are at least double coated, namely coated with a drug-containing layer and taste-masking layer comprising a cationic polymer and a water-insoluble polymer, respectively, can be mixed with at least one pharmaceutical excipient comprising a disintegrant and compressed into orally disintegrating compositions (e.g. tablets) without adversely affecting the stability and/or dissolution profile of the active ingredient while still affording masking of the bitter taste associated with the active ingredient. It is believed that the coatings of the pellets disclosed herein are characterized by excellent mechanical properties such that their integrity is maintained at compression thereby providing robust taste-masking while still affording adequate dissolution of the active ingredient.

As used herein, the term "pellet" refers to a particle which comprises an inert core coated with at least a drug-containing layer and taste-masking layer. Included within this term are beads, spheroids and/or granules known to those of skill in the art.

The inert core can be comprised of any pharmaceutically inert compound, e.g., a filler. Within the scope of the present disclosure are inert cores comprising a single compound or a plurality of compounds such as inert granules or seeds coated with a layer comprising excipient(s). The inert core onto which the drug-containing layer and the taste-masking layer are applied is usually comprised of sugars, starch or cellulosic materials or combinations thereof, for example sugar derivatives such as lactose, sucrose, hydrolyzed starch (maltodextrins) or celluloses or mixtures thereof. In one embodiment, the inert core comprises a nonpareil seed comprising a blend of starch and sugar. The nonpareil seeds, also called sugar spheres, typically comprise spheres composed of sucrose and starch (for example maize starch). In another embodiment, the inert cores comprise microcrystalline cellulose particles.

In various aspects and embodiments, the inert core is coated with a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof and a cationic polymer. Atorvastatin, as used herein refers to [R-(R*, R*)]-2-(4- fluorophenyl)-B, 5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l-heptanoic acid.

It is contemplated that any pharmaceutically acceptable form of the atorvastatin or a pharmaceutically acceptable salt thereof including, but not limited to, solvates (e.g. hydrates), isomers, isomorphs, polymorphs, pseudopolymorphs, and prodrugs thereof are within the scope of the disclosure.

In certain embodiments, the form of atorvastatin or a pharmaceutically acceptable salt thereof comprises a crystalline form or an amorphous form, alone or in combination. In other embodiments, the composition comprises an atorvastatin salt. Preferably, the composition comprises an alkaline earth metal salt of atorvastatin such as, but not limited to, calcium or magnesium salt of atorvastatin. In currently preferred embodiments, the atorvastatin salt comprises atorvastatin calcium in crystalline or amorphous form. Suitable atorvastatin calcium forms include, but are not limited to, the hemi-calcium salt of atorvastatin described in U.S. 5,273,995; atorvastatin calcium designated Forms I, II, and IV described in WO 97/03959 and U.S. 5,969,156; amorphous atorvastatin calcium described in WO 97/03960 and WO 00/71116; atorvastatin calcium designated Form III described in WO 97/03958 and U.S. 6, 121,461; and atorvastatin calcium designated Form V described in WO 01/36384. Each possibility represents a separate embodiment. According to the principles of the disclosure, the drug-containing layer further comprises a cationic polymer. Suitable cationic polymers include, but are not limited to, polymers comprising an amino group which may be a primary, secondary, tertiary or quaternary amino group. Each possibility represents a separate embodiment.

As used herein, the term "primary amine" or "primary amino group" designates a compound of formula R H₂ wherein R' is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, or heteroaryl.

As used herein, the term "secondary amine" or "secondary amino group" designates a compound of formula R'R" H wherein each of R and R" is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, or heteroaryl. The secondary amine may also be a cyclic amine.

As used herein, the term "tertiary amine" or "tertiary amino group" designates a compound of formula R'R"R"'N wherein each of R', R" and R'" is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, or heteroaryl. The tertiary amine may also be a cyclic amine. As used herein, the term "quaternary ammonium compound" or "quaternary amino group" designates a compound of formula RR"R"R""N⁺X^" wherein each of R, R", R" and R"" is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, or heteroaryl and X^" is a counter-ion. Suitable cationic polymers within the scope of the present disclosure include, but are not limited to, cationic starches, cationic polyvinyl alcohols, cationic vinyl polymers, cationic styrene containing polymers, cationic polyurethanes, cationic cellulose-based polymers, cationic polysaccharides, cationic acrylic polymers and copolymers, and cationic (meth)acrylate polymers and copolymers. Each possibility represents a separate embodiment. Exemplary cationic polymers include, but are not limited to, a copolymer of styrene and divinylbenzene with quaternary ammonium functionality available under the trade name DUOLITE™ API 43/1083, and a cross- linked acrylic polymer with quaternary ammonium functionality available under the trade name AMBERLITE™ IRA 458.

Additional cationic polymers include, but are not limited to, poly acrylamide, a copolymer of acrylamide, and combinations thereof and a cationic methacrylate polymer or copolymer. In one embodiment, the cationic polymer comprises methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, commercially available as e.g. Eudragit^® E, Eudragit^® EPO, etc. It is contemplated that the incorporation of the cationic polymer into the drug-containing layer imparts improved dissolution characteristics of the formulation such that the dissolution profile of the composition of the disclosure may be substantially equivalent to the dissolution profile of a conventional composition which contains the same dose of atorvastatin or salt thereof and which is not an orally disintegrating composition. It is contemplated that the composition results in a C_max or AUC after administration which is substantially equivalent to a conventional composition which is not an orally disintegrating composition. As used herein, the term "a composition which is not an orally disintegrating composition" refers to an oral dosage form which is designed to be swallowed as a whole e.g. swallowable tablets and capsules.

In certain aspects and embodiments, the drug-containing layer comprises atorvastatin or a pharmaceutically acceptable salt thereof and a cationic polymer at ratios of about 3 : 1 to about 1 : 1 (w/w), preferably at a ratio of about 2: 1 (w/w), including all iterations of ratios within the specified range. The drug-containing layer may be applied to the inert core in the form of an organic or aqueous solution or dispersion. Each possibility represents a separate embodiment. In currently preferred embodiments, the drug-containing layer is applied to the inert core in the form of an aqueous dispersion. The application of the drug- containing layer may be conducted as is known in the art using standard equipment such as, but not limited to, a fluid bed coater (e.g. a Wurster coater or a rotary bed coater), extruder, or spray dryer.

Within the scope of the present disclosure are inert cores coated with a drug- containing layer over the cores and a taste-masking layer comprising a water- insoluble polymer over the drug-containing layer. The taste-masking layer is applied to substantially reduce or eliminate the bitter taste which may be imparted by the active ingredient, atorvastatin or a pharmaceutically acceptable salt thereof. The oral dosage form disclosed herein provides substantially complete masking of the bitter taste which is known to be associated with atorvastatin or a pharmaceutically acceptable salt thereof. Contrary to dosage forms in which pellets are inserted into capsules for oral administration through the gastrointestinal tract, the composition of the present disclosure is typically compressed and is designed to disintegrate in the oral cavity of a subject where it remains for several minutes (e.g. 2-3 minutes) until it is swallowed, usually without water or other fluids. The composition of the disclosure provides unexpected and robust taste-masking in which the taste-masking layer remains intact even when compressed without losing its taste-masking characteristics. The taste-masking coating used in the composition therefore maintains its integrity in the oral cavity while affording the desired release of the active ingredient in the gastrointestinal tract.

In certain aspects and embodiments, the taste-masking layer comprises a water-insoluble polymer. The term "water-insoluble polymer" as used herein designates a polymer which has solubility in water of less than about 10 grams, for example about 7.5, about 5, about 2.5, about 1, about 0.5 grams or less in 100 grams of distilled water at 25°C and 1 atmosphere. Each possibility represents a separate embodiment. In some embodiments, the water-insoluble polymer comprises a polymer which is substantially insoluble in water at neutral or near-neutral environment presented by the saliva of the oral cavity. In one embodiment, the water- insoluble polymer becomes soluble at pH of about 5 or less. Suitable water-insoluble polymers include, but are not limited to, water-insoluble celluloses and water- insoluble homo- or copolymers of styrene, ethylene, propylene, ethylene terephthalate, acrylates or methacrylates. Currently preferred water-insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), and (meth)acrylate polymers or copolymers including methyl methacrylate- butyl methacrylate-dimethylaminoethyl methacrylate copolymer, commercially available under the trade name Eudragit^® E polymers.

The taste-masking layer may be applied to the active cores (inert cores coated with a drug-containing layer) in the form of an organic or aqueous solution or dispersion. Each possibility represents a separate embodiment. In currently preferred embodiments, the taste-masking layer is applied to the active cores from an organic solvent solution or dispersion. The organic solvent may be any solvent known to those of skill in the art including, but not limited to, an alcohol such as ethanol, isopropyl alcohol and the like, acetone or mixtures thereof. In various embodiments, the proportions of the cationic polymer in the first coating layer and the water-insoluble polymer in the second coating layer are designed to impart the composition of the present disclosure its beneficial attributes. Particularly, the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 : 1 to about 1 :4 (w/w) for example, about 1 :2 to about 1 :4 (w/w) or about 1 :2.5 to about 1 :3.5 (w/w), including all iterations of ratios within the specified ranges.

The pellets may optionally comprise an additional intermediate layer, interchangeably, subcoating between the first and second coating layers. Suitable subcoating within the scope of the present disclosure may comprise a substance which affords physical separation between the drug-containing layer and the taste-masking layer. It is believed that the subcoating layer imparts the composition with improved stability both during manufacturing and during storage. Typically, the subcoating comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol. Each possibility represents a separate embodiment. In some embodiments, the two or more coating layers on the inert cores substantially cover the cores or the inner layer onto which they are applied. In other embodiments, the two or more coating layers on the cores cover the cores or the inner layer onto which they are applied by at least about 25% of the surface area. In particular embodiments, the two or more coating layers on the cores cover the cores or the adjacent inner layer onto which they are applied by at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) (substantially complete coverage) of the surface area, with each possibility representing a separate embodiment.

The compositions disclosed herein may further comprise at least one excipient such as a binder, a filler, an anti-tacking agent, a lubricant, a glidant, a surfactant, a plasticizer or any combination thereof. Each possibility represents a separate embodiment. In additional embodiments, the compositions further comprise a stabilizer, a tonicity enhancing agent, a buffering agent, a preservative, a diluent, an emulsifying agent, a wetting agent, a flavoring agent, a colorant, a complexing agent or any combination thereof. Each possibility represents a separate embodiment. The excipients may be added to the pellets and/or admixed with the pellets and at least one disintegrant to form the compositions disclosed herein. Each possibility represents a separate embodiment.

Suitable binders include, but are not limited to, polyvinylpyrrolidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, starch, gelatin, or sugars. Sugars include, but are not limited to, sucrose, dextrose, molasses, and lactose. Each possibility represents a separate embodiment. Suitable fillers include, but are not limited to, sugars as detailed above and derivatives therefore (e.g. amino sugars), ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like. Each possibility represents a separate embodiment.

Suitable anti-tacking agents include, but are not limited to, talc, colloidal silicon and the like among others. Each possibility represents a separate embodiment. Suitable lubricants include, but are not limited to, sodium stearyl fumarate, stearic acid, or stearates, such as magnesium stearate and calcium stearate. Each possibility represents a separate embodiment.

A suitable glidant is e.g., colloidal silicon dioxide. Suitable surfactants include, but are not limited to, non-ionic, anionic or cationic surfactants. Typically, surfactants may have one lipophilic and one hydrophilic group in the molecule. The surfactant may optionally comprise one or more of soaps, detergents, emulsifiers, dispersing and wetting agents. More specifically, surfactants may optionally comprise, for example, one or more of polysorbate, stearyltriethanolamine, sodium lauryl sulfate, sodium taurocholate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose among others. Each possibility represents a separate embodiment.

Suitable plasticizers include, but are not limited to, cetyl alcohol, dibutyl sebacate, polyethylene glycol, polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol among others. Each possibility represents a separate embodiment.

Suitable tonicity enhancing agents are selected from ionic and non-ionic agents. For example, ionic compounds include, but are not limited to, alkali metal or alkaline earth metal halides, such as, for example, CaCl₂ KBr, KCl, LiCl, Nal, NaBr or NaCl, or boric acid. Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol (PEG), or dextrose. Each possibility represents a separate embodiment.

Examples of preservatives are quaternary ammonium salts such as benzalkonium chloride, benzoxonium chloride or polymeric quaternary ammonium salts, alkyl-mercury salts of thiosalicylic acid, such as, for example, thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, parabens, such as, for example, methylparaben or propylparaben, alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives, such as, for example, chlorohexidine or polyhexam ethylene biguanide, sorbic acid or ascorbic acid. Each possibility represents a separate embodiment. In one embodiment, the composition of the present disclosure does not contain antioxidants.

Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, sugars, lactose, calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, and dry starch. Each possibility represents a separate embodiment. Suitable wetting agents include, but are not limited to, glycerin, starches, and the like. Each possibility represents a separate embodiment.

Suitable buffering substances include, but are not limited to, acidic buffering agents such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid and fumaric acid; and basic buffering agents such as tris, sodium hydroxide, potassium hydroxide and magnesium hydroxide. Each possibility represents a separate embodiment.

Suitable colorants include, but are not limited to, alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, β-carotene, cochineal extract, carmine, potassium sodium copper chlorophyllin (chlorophyllin- copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide greens, guanine, mica-based pearlescent pigments, pyrophyllite, mica, dentifrices, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide or a mixture or combination thereof. Each possibility represents a separate embodiment.

Suitable stabilizers include, but are not limited to, alkalizing agents such as organic and inorganic alkaline substances. Exemplary organic alkaline substances include, but are not limited to, basic amino acids such as arginine and lysine, amine derivatives and salts, amino sugars such as meglumine, salts of stearic acid such as sodium stearate and the like. Each possibility represents a separate embodiment. Exemplary inorganic alkaline substances include, but are not limited to, hydroxides such as sodium or potassium hydroxide, carbonates such as calcium, magnesium or zinc carbonate, bicarbonates such as sodium bicarbonate and the like. Each possibility represents a separate embodiment. In one embodiment, the composition of the present disclosure is substantially devoid of carbonates or bicarbonates.

Suitable flavoring agents include, but are not limited to, sweeteners such as sucralose and synthetic flavor oils and flavoring aromatics, natural oils, extracts from plants, leaves, flowers, and fruits, and combinations thereof. Exemplary flavoring agents include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot. Each possibility represents a separate embodiment.

Suitable complexing agents include, but are not limited to, low molecular weight polyvinyl pyrrolidone and low molecular weight hydroxypropyl methyl cellulose. Each possibility represents a separate embodiment.

In certain embodiments, the pellets are admixed with at least one excipient comprising a disintegrant. In some embodiments, the taste-masked coated pellets are admixed with a plurality of excipients comprising at least one disintegrant. Suitable disintegrants include, but are not limited to, crospovidone, croscarmellose sodium, a sugar alcohol, a cellulose derivative, cross-linked derivatives of starch (e.g. sodium starch glycolate), pregelatinized starch, cross-linked sodium carboxymethyl cellulose, low substituted hydroxypropylcellulose and any combination or mixture thereof. Each possibility represents a separate embodiment. Additional disintegrants include, but are not limited to, silicates, carbonates, polyoxy ethylene sorbitan fatty acid esters, stearic monoglyceride, guar gum, and lactose. Each possibility represents a separate embodiment. Suitable sugar alcohols include, but are not limited to, mannitol, sorbitol, maltitol, xylitol, and any combination or mixtures thereof. Each possibility represents a separate embodiment. Additional sugar alcohols include, but are not limited to, arabitol, isomalt, erythritol, glycerol, lactitol, and mixtures thereof. Each possibility represents a separate embodiment. Suitable cellulose derivatives include, but are not limited to, methylcellulose, cross-linked carboxylic methylcelluloses, microcrystalline cellulose and any combination or mixture thereof. Each possibility represents a separate embodiment. In particular embodiments, at least one of the aforementioned disintegrants is admixed with the pellets which are substantially devoid of disintegrants.

The pellets of the composition disclosed herein as well as the pharmaceutically acceptable excipient(s) which form the tablet matrix typically have average sizes of less than about 1,000 μιη. For example, the pellets of the composition are typically characterized by sizes in the range of about 100 μιη to about 900 μπι, about 200 μιη to about 800 μπι, about 300 μιη to about 700 μπι, or about 400 μιη to about 600 μπι, including each integer within the specified ranges, thereby affording reduced sensation of roughness when the composition disintegrates in the oral cavity. Each possibility represents a separate embodiment. In additional embodiments, the pellets of the composition have a size of about 100 μπι, about 150 μπι, about 200 μπι, about 250 μπι, about 300 μπι, about 350 μπι, about 400 μπι, about 450 μπι, about 500 μπι, about 550 μπι, about 600 μπι, about 650 μπι, about 700 μπι, about 750 μπι, about 800 μπι, about 850 μπι, about 900 μπι, about 950 μπι, or about 1,000 μπι, with each possibility representing a separate embodiment.

In specific embodiments, the composition disclosed herein comprises pellets comprising: inert cores in an amount of about 5% to about 20% by weight, including each integer within the specified range; atorvastatin or a pharmaceutically acceptable salt thereof in an amount of about 4% to about 10% by weight, including each integer within the specified range and a cationic polymer in an amount of about 1% to about 10%) by weight, including each integer within the specified range in a first coating layer; a water-insoluble polymer in an amount of about 5% to about 15%> by weight, including each integer within the specified range in a second coating layer; and optionally at least one additional excipient other than a disintegrant in an amount of not more than about 20% by weight, including each integer within the specified range; the composition further comprises at least one disintegrant in an amount of about 4% to about 15%) by weight, including each integer within the specified range; and optionally at least one additional excipient other than a disintegrant in an amount of not more than about 50% by weight, including each integer within the specified range, wherein presence of all components add to 100%. The composition may further comprise an intermediate layer between the first and the second coating layers in an amount of about 1% to about 15% by weight, including each integer within the specified range.

In some embodiments, the orally disintegrating composition is an orally disintegrating tablet that comprises:

• a plurality of pellets that include inert cores coated with a drug coating layer, optionally a subcoating layer, and a taste-masking layer;

o the inert cores comprise a filler, e.g. sugar spheres and/or microcrystalline cellulose particles;

o the drug coating layer covering the inert cores comprises atorvastatin or a pharmaceutically acceptable salt thereof; a cationic polymer, e.g. amino methacrylate copolymer; a binder, e.g. hydroxypropylmethyl cellulose (HPMC) and/or polyvinylpyrrolidone (PVP) and/or polyethylene glycol (PEG); and optionally a surfactant, e.g. polysorbate; and/or an anti-tacking agent, e.g. talc;

o the optional subcoating layer covering the drug coating layer comprises a binder, e.g. hydroxypropylmethyl cellulose (HPMC) and/or hydroxypropyl cellulose (HPC); an anti-tacking agent, e.g. talc; and optionally a glidant, e.g. colloidal silicon dioxide;

o the taste-masking layer covering the drug coating layer or the subcoating layer comprises a taste-masking polymer, e.g. an amino methacrylate copolymer; a gildant, e.g. colloidal silicon dioxide; and optionally an anti-tacking agent, e.g. talc and/or a surfactant, e.g. sodium lauryl sulfate; and

• one or more disintegrants, e.g. crospovidone; and optionally one or more fillers, e.g. mannitol and/or microcrystalline cellulose; one or more flavoring agents, e.g. grape flavor; and sweetener, e.g. sucralose, one or more lubricants, e.g. sodium stearyl fumarate; a gildant, e.g. colloidal silicon dioxide; blended with the pellets and compressed into a tablet.

In some embodiments, the pellets comprising a plurality of inert cores having two or more coatings described herein are in an amount of about 20% to about 80% of the total orally disintegrating tablet composition mass, including each integer within the specified range. The total orally disintegrating tablet composition mass as used herein refers to the weight of the plurality of pellets, including the inert cores and all applied coatings in addition to the tablet matrix and all other tablet excipients. In other embodiments, the pellets are in an amount of about 30% to about 70% of the total orally disintegrating tablet composition mass, including each integer within the specified range. In yet other embodiments, the pellets are in an amount of about 40% to about 60% of the total orally disintegrating tablet composition mass, including each integer within the specified range. In further embodiments, the pellets are in an amount of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% of the total orally disintegrating tablet composition mass, with each possibility representing a separate embodiment.

According to some embodiments, the orally disintegrating composition substantially disintegrates in the oral cavity of a subject, and after swallowing provides an in vivo release profile of the atorvastatin or a pharmaceutically acceptable salt thereof which is substantially the same as the release profile of a conventional composition of atorvastatin which is not an orally disintegrating composition. As used herein, the term "substantially the same" refers to an in vivo release profile of the composition of the present disclosure which varies in less than about 20%, for example, about 15%, about 10%, about 5% or which is substantially identical to the release profile of a non-orally disintegrating composition which contains about the same dosage of atorvastatin or a pharmaceutically acceptable salt thereof. In particular embodiments, the orally disintegrating composition of the present disclosure is substantially bioequivalent to a non-orally disintegrating composition (e.g. Lipitor^®) which contains about the same dosage of atorvastatin or a pharmaceutically acceptable salt thereof.

The compositions disclosed herein can be manufactured using conventional processes as is known in the art such as, but not limited to, spray drying, spheronization, milling, de-agglomeration, precipitation, and/or crystallization. Each possibility represents a separate embodiment. Optionally, the method of manufacturing of the orally disintegrating composition further involves additional processing steps including, but not limited to heating, drying, sieving, and lubricating as is known in the art.

Exemplary method of preparing an orally disintegrating tablet (ODT) comprises the following steps: (a) applying an aqueous dispersion of atorvastatin or a pharmaceutically acceptable salt thereof, a cationic polymer and optionally a pharmaceutically acceptable excipient onto a plurality of inert cores to obtain active cores; (b) optionally applying a subcoating onto the active cores of step (a) ; (c) applying a taste-masking layer comprising a water-insoluble polymer onto the active cores obtained in step (a) or (b) to obtained pellets; (d) blending the pellets of step (c) with particles comprising at least one excipient comprising a disintegrant; and (e) compressing the blend obtained in step (d) into an orally disintegrating tablet as is known in the art.

The pharmaceutical composition disclosed herein is useful for inhibiting sterol formation in the treatment of hypercholesterolemia. Accordingly, there is provided a method of treating hypercholesterolemia, the method comprising administering to a subject in need thereof the composition of the present disclosure. The subject in need thereof is typically a mammal, preferably a human.

The composition may be administered in a solid dosage form to be placed on the tongue (lingual administration), or under the tongue (sublingual administration), or applied to the buccal mucosa (buccal administration). Lingual administration typically stimulates saliva generation, which enhances disintegration of the composition. In some embodiments, the composition is a dosage form suitable for forming a suspension of undissolved particles in saliva, which can then be swallowed, allowing for adsorption of the active ingredient in the GI tract. In some embodiments, the composition is not a sprinkle dosage form designed to be added onto food or liquid.

The amount of a composition to be administered depends on various factors including the subject being treated (age and gender) and the severity of the disease, and can be determined by the judgment of the prescribing physician. Because of patient-to-patient variability, dosages are a guideline only and the physician may adjust doses of the compounds to achieve the level of effective treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as the age of the patient and the presence of other diseases or conditions. The compositions of the present disclosure may contain any dosage of the atorvastatin or a pharmaceutically acceptable salt thereof, for example from about 1 mg to about 100 mg of the active ingredient, including each integer within the specified range. Typical dosages of atorvastatin in a composition include, but are not limited to, 10 mg, 20 mg, 40 mg and 80 mg. Each possibility represents a separate embodiment.

The terms "therapeutically effective amount" or "an effective amount" as used herein refer to a quantity of a compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered. The effective amount, according to the principles disclosed herein, can be determined by any one of ordinary skill in the art and can be tested on various models both in vitro and in vivo.

The term "treating" as used herein refers to stopping or slowing down the progression of the disease. The term "treating" further includes the reduction in the occurrence of various symptoms associated with hypercholesterolemia. In certain embodiments, the term "treating" as used herein refers to reducing the risk of myocardial infarction (MI), stroke, revascularization procedures, and angina in patients without coronary heart disease (CHD), but with multiple risk factors. In other embodiments, the term "treating" as used herein refers to reducing the risk of MI and stroke in patients with type II diabetes without CHD, but with multiple risk factors. In yet other embodiments, the term "treating" as used herein refers to reducing the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for coronary heart failure (CHF), and angina in patients with CHD. In additional embodiments, the term "treating" as used herein refers to reducing elevated total-C, LDL-C, apolipoprotein B, and triglyceride (TG) levels and increasing HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia. In further embodiments, the term "treating" as used herein refers to reducing elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia. In other embodiments, the term "treating" as used herein refers to reducing total-C and LDL-C in patients with homozygous familial hypercholesterolemia. In yet other embodiments, the term "treating" as used herein refers to reducing elevated total-C, LDL-C, and apolipoprotein B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.

As used herein the term "about" refers to ±10%.

As used herein and in the appended claims the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a layer" includes a plurality of such layers and equivalents thereof known to those skilled in the art, and so forth. It should be noted that the term "and" or the term "or" are generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

The following examples are presented in order to more fully illustrate some embodiments of the invention. They should, in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

EXAMPLES: EXAMPLE 1.

An orally disintegrating tablet was prepared as follows: Inert sugar spheres were coated with an aqueous dispersion containing atorvastatin (in an amount equivalent to 40 mg) and Eudragit^® EPO at a 1/1 to a 2/1 w/w ratio, in the presence of povidone, copovidone or HPMC as binders and talc as an anti-tacking agent. A subcoating layer containing HPC or HPMC was then applied. A taste masking layer containing Eudragit^® E100 and talc was further applied over the subcoating layer. The taste-masked pellets were mixed with a mixture of powders containing crospovidone as disintegrant, lubricated and compressed into an orally disintegrating tablet. Exemplary formulations according to certain embodiments are detailed in Tables 1-7 below:

Table 1.

Substance mg/tab

Sugar spheres 80

Atorvastatin calcium 43

Eudragit^® EPO 43

Talc 65

Polyvinylpyrrolidone 22

Hydroxypropylcellulose 29

Silicon dioxide 21

Eudragit^® El 00 57

Pharmaburst^® 335

Colloidal Silica 6

Sucralose 2

Strawberry flavor 6

Microcrystalline cellulose 81

Sodium stearyl fumarate 19

Total 809

Table 2.

Substance mg/tab

Sugar spheres 80

Atorvastatin calcium 43

Eudragit^® EPO 21

Talc 49

Polyvinylpyrrolidone 22

Hydroxypropylmethylcellulose/hypromellose 8

Polyethylene glycol 400 1

Eudragit^® El 00 60

Pharmaburst^® 250

Colloidal Silica 4

Sucralose 1

Strawberry flavor 3

Crospovidone 19

Sodium stearyl fumarate 9

Total 570

Table 3.

Substance mg/tab

Sugar spheres 80

Atorvastatin calcium 43

Eudragit^® EPO 21

Talc 63

Polyvinylpyrrolidone 22

Hydroxypropylmethylcellulose/hypromellose 8

Polyethylene glycol 400 1

Eudragit^® El 00 45

Pharmaburst^® 262

Colloidal Silica 3

Sucralose 2

Grape flavor 6

Microcrystalline cellulose 64

Sodium stearyl fumarate 15

Total 635

Table 4.

Substance mg/tab

Sugar spheres 80

Atorvastatin calcium 43

Eudragit^® EPO 21

Talc 86

Polyvinylpyrrolidone 22

Hydroxypropylmethylcellulose/hypromellose 8

Polyethylene glycol 400 1

Eudragit^® El 00 70

Pharmaburst^® 308

Colloidal Silica 7

Sucralose 2

Strawberry flavor 6

Microcrystalline cellulose 75

Sodium stearyl fumarate 18

Total 747

Table 5.

Substance mg/tab

Sugar spheres 80

Atorvastatin calcium 43

Eudragit^® EPO 21

Talc 86

Hydroxypropylmethylcellulose/hypromellose 30

Polyethylene glycol 400 1

Eudragit^® El 00 70

Pharmaburst^® 308

Colloidal Silica 7

Sucralose 2

Strawberry flavor 6

Microcrystalline cellulose 75

Sodium stearyl fumarate 18

Total 747

Table 6.

Substance mg/tab

Sugar spheres 80

Atorvastatin calcium 43

Eudragit^® EPO 21

Talc 62

Hydroxypropylmethylcellulose/hypromellose 8

Polyethylene glycol 400 1

Eudragit^® El 00 45

Pharmaburst^® 256

Colloidal Silica 3

Sucralose 1

Grape flavor 3

Crospovidone 19

Sodium stearyl fumarate 9

Total 551

Table 7.

EXAMPLE 2.

In-vitro dissolution of exemplary orally disintegrating tablets according to embodiments set forth in Tables 1-4 was measured and compared to the presently marketed commercial product, Lipitor^® (Pfizer), used as control. The following conditions were used: Apparatus: USP apparatus II (paddle method); 75 rpm

Medium: t=0 to t=5 minutes: 0.1N hydrochloric acid; t=5 to t=45 minutes: pH 6.8 (phosphate buffer)

Temperature: 37°C ± 0.5°C - Detector: Agilent liquid chromatograph equipped with a UV detector at 248 nm.

Dissolution% was normalized according to atorvastatin assay. The results are depicted in Figure 1 and Table 8:

Table 8.

The results show that orally disintegrating tablets according to embodiments of the disclosure have dissolution profile which is comparable to that of Lipitor^® tablets.

EXAMPLE 3.

Friability and disintegration of exemplary orally disintegrating tablets according to embodiments set forth in Tables 1-4 were tested. The acceptable ranges are not more than 1.0% for friability and not more than 60 seconds for disintegration. The results are depicted in Table 9: Table 9.

EXAMPLE 4.

In order to evaluate the release of the active ingredient in a media that simulates the oral cavity, in vitro dissolution tests at pH 6.8 (phosphate buffer) in USP apparatus Π fitted with paddles, at 75 RPM and 37°C were performed on orally disintegrating tablets according to embodiments set forth in Tables 2 and 4. The release was determined using a Varian UV automatic spectrophotometer with a detection wavelength of 248nm. The results are depicted in Table 10: Table 10.

The results indicate that the coating layers maintain their integrity during compression allowing negligible release of active ingredient in the oral cavity. EXAMPLE 5.

Taste-masking of exemplary orally disintegrating tablets according to embodiments of the disclosure are measured using electronic tongue (INSENT SA402B) equipped with various sensors including COO, BTO and AE1. Initially, atorvastatin solutions at concentrations of 0.001-5mM are tested in order to assess the linearity range of the sensor. The electrical signal (in millivolts) generated by orally disintegrating tablets according to certain embodiments of the disclosure is measured at 37°C when placing the tablets in lOmM KCl solution or a phosphate buffer at pH 6.8 every five minutes for a total of 30 minutes. For after-taste assessment, the sensor is washed with a solution of 30 mM KCl and 0.3 mM tartaric acid immediately after the initial measurement and the electrical signal is measured again after 30 minutes. The electrical signal is compared to a placebo ODT and an ODT with no taste-masking layer.

While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

Claims

An orally disintegrating composition comprising (i) a plurality of pellets, wherein each pellet comprises an inert core coated with a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof and a cationic polymer, and a second coating layer comprising a water-insoluble polymer; and (ii) at least one pharmaceutically acceptable excipient comprising a disintegrant, wherein the composition substantially disintegrates in the oral cavity of a subject within less than about 60 seconds after administration, and wherein in vitro drug release in 20 minutes at pH 6.8 is about 5% or less.

The orally disintegrating composition of claim 1, wherein the composition substantially disintegrates in the oral cavity of a subject within less than about 30 seconds after administration.

The orally disintegrating composition of claim 1, wherein in vitro drug release in 20 minutes at pH 6.8 is about 3% or less.

The orally disintegrating composition of claim 1 in the form of an orally disintegrating tablet.

The orally disintegrating composition of claim 4, wherein the tablet is characterized by hardness of at least about 30 Newtons.

The orally disintegrating composition of claim 1, wherein the inert core comprises a sugar sphere.

The orally disintegrating composition of claim 1, wherein atorvastatin or a pharmaceutically acceptable salt thereof comprises atorvastatin calcium.

The orally disintegrating composition of claim 1, wherein the cationic polymer comprises an amino group.

The orally disintegrating composition of claim 8, wherein the cationic polymer comprises a primary, secondary, tertiary or quaternary amino group.

10. The orally disintegrating composition of claim 1, wherein the cationic polymer comprises at least one of cationic starches, cationic polyvinyl alcohols, cationic vinyl polymers, cationic styrene containing polymers, cationic polyurethanes, cationic cellulose-based polymers, cationic polysaccharides, cationic acrylic polymers and copolymers, and cationic (meth)acrylate polymers and copolymers.

11. The orally disintegrating composition of claim 10, wherein the cationic polymer comprises a cationic methacrylate polymer or copolymer.

12. The orally disintegrating composition of claim 11, wherein the cationic polymer comprises a methyl methaciylate-butyl methacrylate- dimethylaminoethyl methacrylate copolymer.

13. The orally disintegrating composition of claim 1, wherein the water-insoluble polymer comprises at least one of ethyl cellulose, polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), and (meth)acrylate polymer or copolymer.

14. The orally disintegrating composition of claim 13, wherein the water-insoluble polymer comprises methyl methaciylate-butyl methacrylate- dimethylaminoethyl methacrylate copolymer.

15. The orally disintegrating composition of claim 1, wherein the cationic polymer and the water-insoluble polymer each comprise methyl methaciylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer.

16. The orally disintegrating composition of claim 1, wherein the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 : 1 to about 1 :4 (w/w).

17. The orally disintegrating composition of claim 16, wherein the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 :2 to about 1 :4 (w/w).

18. The orally disintegrating composition of claim 17, wherein the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 :2.5 to about 1 :3.5 (w/w).

19. The orally disintegrating composition of claim 1, further comprising a third coating layer between the first and the second coating layers.

20. The orally disintegrating composition of claim 19, wherein the third coating layer comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol.

21. The orally disintegrating composition of claim 1, wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, a sugar alcohol, a cellulose derivative, cross-linked derivatives of starch, pregelatinized starch and a combination or mixture thereof.

22. The orally disintegrating composition of claim 21, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, and a combination or mixture thereof.

23. The orally disintegrating composition of claim 21, wherein the cellulose derivative is selected from the group consisting of methylcellulose, cross- linked carboxylic methylcellulose, crosslinked sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose and a combination or mixture thereof.

24. The orally disintegrating composition of claim 21, wherein the cross-linked derivatives of starch comprise sodium starch glycolate.

25. The orally disintegrating composition of claim 1, further comprising at least one of a binder, a filler, an anti-tacking agent, a lubricant, a glidant, a surfactant, a plasticizer or any combination thereof.

26. The orally disintegrating composition of claim 1, comprising:

(i) a plurality of pellets comprising: (a) inert cores in an amount of about 5% to about 20% by weight;

(b) a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof in an amount of about 4% to about 10% by weight and a cationic polymer in an amount of about 1% to about 10% by weight;

(c) a second coating layer comprising a water-insoluble polymer in an amount of about 5% to about 15% by weight; and

(d) optionally an excipient selected from a binder, a filler, an anti- tacking agent, a lubricant, a glidant, a surfactant, a plasticizer and any combination thereof;

(ii) at least one disintegrant in an amount of about 4% to about 15% by weight; and

(iii) optionally an excipient selected from a binder, a filler, an anti-tacking agent, a lubricant, a glidant, a surfactant, a plasticizer and any combination thereof; wherein presence of all components add to 100%.

27. The orally disintegrating composition of claim 26, further comprising a third coating layer between the first and the second coating layers of the pellets in an amount of about 1% to about 15% by weight.

28. The orally disintegrating composition of any one of claims 1 to 27, for use in treating hypercholesterolemia.

29. A method of treating hypercholesterolemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of the orally disintegrating composition of any one of claims 1 to 27.

30. A composition comprising a plurality of pellets, wherein each pellet comprises an inert core coated with a first coating layer comprising atorvastatin or a pharmaceutically acceptable salt thereof and a cationic polymer, and a second coating layer comprising a water-insoluble polymer, wherein the composition provides in vitro drug release in 20 minutes at pH 6.8 of about 5% or less.

31. The composition of claim 30, wherein the inert core comprises a sugar sphere.

32. The composition of claim 30, wherein atorvastatin or a pharmaceutically acceptable salt thereof comprises atorvastatin calcium.

33. The composition of claim 30, wherein the cationic polymer comprises an amino group.

34. The composition of claim 33, wherein the cationic polymer comprises a primary, secondary, tertiary or quaternary amino group.

35. The composition of claim 30, wherein the cationic polymer comprises at least one of cationic starches, cationic polyvinyl alcohols, cationic vinyl polymers, cationic styrene containing polymers, cationic polyurethanes, cationic cellulose-based polymers, cationic polysaccharides, cationic acrylic polymers and copolymers, and cationic (meth)acrylate polymers and copolymers.

36. The composition of claim 35, wherein the cationic polymer comprises a cationic methacrylate polymer or copolymer.

37. The composition of claim 36, wherein the cationic polymer comprises a methyl methaciylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer.

38. The composition of claim 30, wherein the water-insoluble polymer comprises at least one of ethyl cellulose, polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), and (meth)acrylate polymer or copolymer.

39. The composition of claim 38, wherein the water-insoluble polymer comprises methyl methaciylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer.

40. The composition of claim 30, wherein the cationic polymer and the water- insoluble polymer each comprise methyl methacrylate-butyl methacrylate- dimethylaminoethyl methacrylate copolymer.

41. The composition of claim 30, wherein the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 : 1 to about 1 :4 (w/w).

42. The composition of claim 41, wherein the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 :2 to about 1 :4 (w/w).

43. The composition of claim 42, wherein the ratio between the cationic polymer in first coating layer and the water-insoluble polymer in the second coating layer is in the range of from about 1 :2.5 to about 1 :3.5 (w/w).

44. The composition of claim 30, further comprising a third coating layer between the first and the second coating layers.

45. The composition of claim 44, wherein the third coating layer comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol.

46. The composition of claim 30, further comprising at least one of a binder, a filler, an anti-tacking agent, a lubricant, a glidant, a surfactant, a plasticizer or any combination thereof.

47. The composition of claim 30, wherein the pellets are compressed.

48. The composition of claim 47, wherein the pellets are admixed with at least one excipient comprising a disintegrant prior to being compressed.

49. The composition of any one of claims 30 to 48, for use in treating hypercholesterolemia.

50. A method of treating hypercholesterolemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 30 to 48.