NANOP ARTICULATE IVACAFTOR FORMULATIONS

FIELD OF THE INVENTION

The present invention relates to nanoparticulate compositions of ivacaftor or a pharmaceutically acceptable salt thereof, and methods of making and using such compositions. The compositions comprise ivacaftor particles having an effective average particle size of less than about 2000 nm.

BACKGROUND OF THE INVENTION

Ivacaftor is a potent and selective CFTR potentiator approved for the treatment of cystic fibrosis with a certain mutations in CFTR gene. It is approved as tablet and granules for oral administration under the brand name KALYDECO ^® . Ivacaftor is chemically known as N-(2,4- di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3- carboxamide and has the following structural formula:

U.S. Patent No. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and also discloses methods of treating CFTR transporter mediated diseases using such modulators.

U.S. Patent No. 7,553,855 discloses a pharmaceutical composition comprising: N-(5-hydroxy- 24-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (Ivacaftor), PEG 400, and PVP K30. U.S. Patent No. 8,410,274 discloses solid dispersion of amorphous N-[2,4-bis(l,l- dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3 -carboxamide, pharmaceutical compositions thereof and methods therewith.

U.S. Patent No. 8,163,772 discloses solid forms of ivacaftor in form of co-forms with 2-methyl butyric acid, propylene glycol, PEG400.KOAc, lactic acid, isobutyric acid, propionic acid, ethanol, 2-propanol, water, besylate, hemibesylate, and besylate monohydrate. U.S. Patent No. 8,883,206 discloses a pharmaceutical composition of ivacaftor in form of solid dispersion with HPMCAS along with other excipients.

U.S. Patent Publication No. 2015/0010628 discloses a pharmaceutical composition comprising a solid dispersion of amorphous or substantially amorphous ivacaftor, a filler, a sweetener, a disintegrant, a glidant and a lubricant, and optionally a wetting agent.

U.S. Patent No. 8,471,029 discloses crystalline form C of N-[2,4-bis(l,l -dimethyl ethyl)-5- hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide.

US Patent No. 8,674,108 discloses crystalline solvates of ivacaftor, which are designated as Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form W and hydrate B and their preparation.

Ivacaftor is a white to off-white powder. It is freely soluble in methylethyl ketone/water mixture, soluble in 2-methyl tetrahydrofuran and PEG 400, slightly soluble in methanol, acetone and ethanol and practically insoluble in water (<0.05 microgram/mL) and buffers with pH 1.0 - 7.0. Ivacaftor has been isolated in two physical forms, an amorphous form and a crystalline form. Various crystalline polymorphic forms are known and Form C is the most thermodynamically stable form. The absorption of ivacaftor in mouse, rats, rabbits and dogs is rapid, following oral administration of aqueous suspensions of the amorphous form, and bioavailability ranged from 30 to 100%. At the same time the crystalline form in suspension had a low oral bioavailability.

Due to low solubility and low bioavailability of crystalline form of ivacaftor, the marketed KALYDECO ^® tablet is prepared in two stages- manufacture of spray dispersion and tabletting. The spray-dried dispersion (SDD) is manufactured using solvent based spray-drying followed by secondary drying to remove residual solvents. In the second stage, the amorphous SDD is blended with additional excipients, compressed into a core tablet, film-coated and printed to form the final drug product. Due to ivacaftor being insoluble in water, it needs to be spray-dried with excipients to produce an amorphous form of the active substance, which circumvents the solubility limited bioavailability issues of the crystalline form and hence is better absorbed. The KALYDECO ^® granules are pre-compressed amorphous SDD blended with other excipients.

The exposure of ivacaftor increased approximately 2.5-to 4-fold when given with food that contains fat. Therefore, KALYDECO ^® tablet is administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. KALYDECO ^® granules (2 x 75 mg) had similar bioavailability as the 150 mg tablet when given with fat- containing food in adult subjects. The effect of food on ivacaftor absorption is similar for KALYDECO ^® granules and the 150 mg tablet formulation.

Clinical study during KALYDECO ^® product development shows clear food affect. After oral administration of a single 150 mg dose to healthy volunteers in the fasted state, the mean (SD) for AUCo and were 3620 (1840) ng*hr/mL and 218 (110) ng/mL, respectively. In the same study, oral administration of a single 150 mg dose in the fed state led to a substantial increase in exposure: AUCo was 10600 (5260) ng*hr/mL and Cmax was 768 (233) ng/mL. The exposure of ivacaftor increased approximately 2- to 4-fold when given with food containing fat. Therefore, KALYDECO ^® is administered with fat-containing food. There is a clear effect of concomitant food intake on the speed and magnitude of absorption of ivacaftor. In healthy volunteers high fat breakfast increased and AUC of 150 mg tablet formulation by an order of magnitude around 2- to 4 and delayed Tmax from 3 to 5 hours. A consistent effect was observed in patients with CF and pancreatic insufficiency in whom ivacaftor 275 mg oral solution was given. In this later case a standard CF meal (which contains up to 200% of the fat content of a standard meal) was compared with a fasted state. The impact of food on the PK of ivacaftor may have implications in clinical practice. Clinical studies were conducted advising patients to take ivacaftor with food containing fat. A recommendation that ivacaftor to be taken with food or shortly after a meal is included in the labeling information issued by the FDA and EMEA in respect of the KALYDECO ^® . If a patient does not take its dose exactly as indicated, sub-therapeutic levels of ivacaftor can occur. Further, different fat content might result in relevantly different exposure to ivacaftor, there is every chance of variability of ivacaftor in blood with different food content. The dissolution rate and bioavailability of known ivacaftor formulations are not optimal. A similar bioavailability of ivacaftor formulation irrespective of the polymorphic forms of active ingredient is the need of the hour. Furthermore, the effectiveness of ivacaftor may be enhanced if it could be formulated to be taken with or without food, thus decreasing the likelihood of patient compliance problems.

A formulation that enhances the bioavailability of ivacaftor would facilitate reduction of the dosage strength with the possibility of achieving a better safety profile.

Nanoparticulate active agent compositions, first described in US5145684, are particles comprising a poorly soluble therapeutic or diagnostic agent having adsorbed onto, or associated with, the surface thereof a non-cross linked surface stabilizer.

Nanoparticulate active agent compositions and methods of making nanoparticulate active agent compositions are disclosed in US5298262, US5302401, US5336507, US5340564, US5346702, US5352459, US5429824, US5470583, US5510118, US5518187, US5534270, US5543133/US5560931, US5560932, US5565188, US5569448, US5571536, US5573783, US5580579, US5585108, US5587143, US5591456, US5622938, US5662883, US5665331, US5718388, US5834025, US5862999, US6011068, US6031003, US6211244, US6264922, US6267989, US6270806, US6313146, US6316029, US6375986, US6406718, US6428814, US6431478, US6432381, US6582285, US6592903, US6723068, US6742734, US6745962, US6811767, US6908626, US6969529, US6976647, US6991191, US7198795, US7244451, US7288267, US7320802, US7390505, US7459283, US7521068, US7575184, US7695739/US7713551, US7763278, US7780989, US7825087, US7842232, US7850995, US7879360, US7910577, US7927627, US7931917, US8119163, US8293277, US8779004,US9012511, USRE41884, US20030087308, US20030215502, US20040015134, US20040105778,US20040105889, US20040115134, US20040156895, US20040173696, US20040195413,US20040258757, US20050147664, US20080124393, US20080152585, US20080171091, US20080213374, US20080213378, US20080220074, US20080226734, US20080248123, US20080254114, US20080317843, US20090035366, US20090074873, US20090155331, US20090238884, US20090252807, US20090269400, US20090291142, US20090297596, US20090304801, US20100028439, US20100221327, US20100247636, US20100260858, US20100260859, US20100316725, US20110008435, US20110027371, US20110064803, WO2009002427.

US4783484 discloses amorphous small particle compositions; US4826689 discloses method for making uniformly sized particles from water-insoluble organic compounds; US4997454 discloses method for making uniformly-sized particles from insoluble compounds. These are also specifically incorporated herein by reference.

None of the above references describes nanoparticulate compositions of ivacaftor or a pharmaceutically acceptable salt thereof.

The present invention relates to nanoparticulate ivacaftor compositions, such as nanoparticulate ivacaftor or a pharmaceutically acceptable salt thereof, which addresses the needs described above by providing nanoparticulate ivacaftor compositions which overcome the shortcomings of known non-nanoparticulate ivacaftor formulations.

SUMMARY OF THE INVENTION

The present invention relates to stable nanoparticulate compositions comprising ivacaftor or a pharmaceutically acceptable salt thereof. The ivacaftor nanoparticles have good stability and have an effective average particle size of less than about 2000 nm. One aspect of the invention relates to a stable nanoparticulate ivacaftor composition comprising solid particles of ivacaftor or a pharmaceutically acceptable salt thereof having an effective average particle size of less than about 2000 nm.

Another aspect of the invention relates to a stable nanoparticulate ivacaftor composition comprising ivacaftor or a pharmaceutically acceptable salt thereof in a crystalline form, an amorphous form, a semi-crystalline form, or mixtures thereof.

One aspect of the invention relates to a stable nanoparticulate composition comprising ivacaftor or a pharmaceutically acceptable salt thereof and at least one surface stabilizer. The nanoparticulate ivacaftor compositions of the invention may further comprise one or more pharmaceutically acceptable excipients, carriers and the like.

Another aspect of the invention relates to a stable nanoparticulate ivacaftor composition comprising solid particles of ivacaftor or a pharmaceutically acceptable salt thereof having an effective average particle size of less than about 2000 nm and at least one surface stabilizer. Further, the composition comprises at least one surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, an ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer.

Another aspect of the invention relates to a stable nanoparticulate ivacaftor composition comprising solid particles of ivacaftor or a pharmaceutically acceptable salt thereof having an effective average particle size of less than about 2000 nm and at least one surface stabilizer, wherein at least one surface stabilizer is selected from the group consisting of copolymers of vinylpyrrolidone and vinyl acetate or copovidone, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, docusate sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyoxyethylene sorbitan fatty acid esters, block copolymers based on ethylene oxide and propylene oxide, polyvinylpyrrolidone, deoxycholic acid sodium salt, sodium lauryl sulphate, benzalkonium chloride, lecithin, distearyl palmitate glyceryl, albumin, lysozyme, gelatin, macrogol 15 hydroxystearate, tyloxapol and polyethoxylated castor oil, cellulose derivates, dioctylsulfosuccinate, casein, dextran, gum acacia, cholesterol, tragacanth, stearic acid, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol, 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, polyethylene oxide-containing fatty acid esters like Stearoyl macrogol-32 glycerides, Lauroyl macrogol-32 glycerides (e.g. Gelucire ^® ) or a mixture thereof. Another aspect of the invention relates to a stable nanoparticulate ivacaftor composition comprising solid particles of ivacaftor or a pharmaceutically acceptable salt thereof, wherein the composition is formulated: (a) for administration selected from the group consisting of oral, pulmonary, intravenous, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, soft gelatin capsules, gels, aerosols, ointments, creams, tablets, sachets and capsules; (c) into a dosage form selected from the group consisting of lyophilized formulations, fast melt formulations, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination (a) (b), and (c).

One aspect of the invention relates to a stable nanoparticulate ivacaftor composition comprising solid crystalline particles of ivacaftor or a pharmaceutically acceptable salt thereof having an effective average particle size of less than about 2000 nm, wherein the solid crystalline particles of ivacaftor or a pharmaceutically acceptable salt thereof are substantially free from amorphous form.

Another aspect of the invention relates a stable nanoparticulate ivacaftor composition comprising solid crystalline particles of ivacaftor or a pharmaceutically acceptable salt thereof having an effective average particle size of less than about 2000 nm and at least one surface stabilizer, wherein the solid crystalline particles of ivacaftor or a pharmaceutically acceptable salt thereof are substantially free from amorphous form.

Another aspect of the invention relates a stable nanoparticulate ivacaftor composition comprising solid crystalline particles of ivacaftor or a pharmaceutically acceptable salt thereof and at least one surface stabilizer.

One aspect of the invention relates to a composition comprising a stable nanoparticulate of ivacaftor, or a pharmaceutically acceptable salt thereof exhibits substantially similar oral bioavailability whether ivacaftor or a pharmaceutically acceptable salt thereof is in a crystalline form or an amorphous form or a semi-crystalline form, or mixtures thereof. Another aspect of the invention relates a composition comprising nanoparticulate composition of ivacaftor is bioequivalent to the commercially available KALYDECO ^® . This nanoparticulate composition of ivacaftor is irrespective of the form of ivacaftor in the formulation. Preferably a crystalline form of ivacaftor in form of nanoparticles present in a tablet formulation or suspension is bioequivalent to KALYDECO ^® tablet or suspension dosage form.

One aspect of the invention relates to a composition comprising a stable nanoparticulate of ivacaftor, or a pharmaceutically acceptable salt thereof shows enhanced bioavailability. Another aspect of the invention relates to a composition comprising a stable nanoparticulate of ivacaftor, or a pharmaceutically acceptable salt thereof shows a reduced "food effect" as compared to non- nanoparticulate ivacaftor compositions. The compositions exhibit substantially similar oral bioavailability in fed and fasted subjects.

One aspect of the invention relates to a composition comprising a stable nanoparticulate of ivacaftor, or a pharmaceutically acceptable salt thereof exhibits improved bioavailability as compared to known non-nanoparticulate ivacaftor compositions having an effective average particle size of greater than 2000 nm.

The invention also relates to compositions comprising nanoparticulate ivacaftor or a pharmaceutically acceptable salt thereof providing a method of treating or lessening the severity of a disease in a patient comprising administering to said patient one of the compositions as defined herein, and said disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay- Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Char cot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, Gerstmann-Stra ussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Barrier's syndrome type III, Dent's disease, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia. Further, the composition also comprises at least one surface stabilizer, and optionally one or more pharmaceutically acceptable excipients, carriers, and optionally one or more active agents useful for the treatment of the said diseases.

The invention also relates to methods of making nanoparticulate ivacaftor compositions, or salt thereof. In some embodiments, the methods include contacting ivacaftor particles with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate ivacaftor composition having an effective average particle size of less than about 2000 nm. A suitable surface stabilizer can be added to a nanoparticulate ivacaftor composition either before, during, or after particle size reduction. Any suitable means can be used to achieve nanoparticles reduce the particle size of ivacaftor, including, but not limited to, milling, microfluidization, precipitation, freeze drying, homogenization and the like.

Both the foregoing summary of the invention and the detailed description of the invention are exemplary and explanatory and are intended to provide further details of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1: Comparative dissolution study of ivacaftor nanosuspension, its formulations and other forms of ivacaftor.

Fig 2: Differential Scanning Calorimetry (DSC) pattern of ivacaftor granulated nanosuspension (Formulation II), ivacaftor and MCC

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a composition comprising nanoparticulate ivacaftor, or a pharmaceutically acceptable salt thereof. The nanoparticles of ivacaftor or a pharmaceutically acceptable salt thereof have an effective average particle size of less than about 2000 nm. The compositions further comprise nanoparticulate ivacaftor, or a pharmaceutically acceptable salt thereof, and at least one surface stabilizer, which may be adsorbed onto or otherwise associated with the surface of the drug.

As described above, one of the problems present with known non-nanoparticulate ivacaftor compositions (KALYDECO ^® ) is that absorption of the drug (AUC) can differ by almost 2-4 fold when the drug is given under fed as compared to fasting conditions. This is highly undesirable, as it is generally recognized at least about 1/3 of all patients have poor compliance regarding consuming drugs per the labeling instructions. This means that for drugs having a wide variability in absorption when administered under fed as compared to fasting conditions, a large patient population does not receive a therapeutically desirable dosage. One aspect of the invention overcomes this problem as nanoparticulate ivacaftor compositions have minimal, if any, differences in absorption when the compositions are administered under fed as compared to fasting conditions.

Another problem with ivacaftor is low oral bioavailability of crystalline form as compared to amorphous form. Nanoparticulate ivacaftor compositions overcomes this problem as the bioavailability of nanoparticles of ivacaftor or a pharmaceutically acceptable salt thereof is substantially similar irrespective of the form of active ingredient. Ivacaftor is in crystalline form, amorphous form, semi-crystalline form, or mixtures thereof. Nanoparticulate ivacaftor compositions result in reduced or eliminated side effects. However, in general terms reducing the amount of drug to which patients are exposed, while at the same time maintaining efficacious levels, may help to reduce adverse effects and improve the safety profile of the product. Because nanoparticulate ivacaftor compositions have a greater bioavailability, the nanoparticulate ivacaftor compositions enable the use of a smaller dosage as compared to known non-nanoparticulate ivacaftor compositions, thereby facilitating a reduction in side effects.

The present invention also includes compositions further comprising one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for administration via any pharmaceutically acceptable means, including but not limited to, parental injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, bioadhesive, vaginal, nasal, rectal, ocular, local (powders, ointments, or drops), buccal, intraci sternal, intraperitoneal, or topical administrations, and the like. The small size of the ivacaftor particles (i.e. less than 2000 nm) makes the composition of the invention particularly advantageous for oral and parenteral formulations.

Oral administration is typically preferred, because of ease of administration and greater compliance. Oral dosage forms may be solid or liquid (e.g. syrup). Exemplary solid oral dosage forms include, but are not limited to, tablets, capsules (both hard gelatin and soft gelatin), sachets, lozenges, powders, pills, or granules, and the solid dosage form can be, for example, a fast melt dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, mixed immediate release and controlled release dosage form, or a combination thereof.

The present invention is described herein using several definitions, as set forth below and throughout the application.

As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. Nanoparticulate active agents or nanoparticles of active agents as defined herein have an effective average particle size of less than about 2000 nm. By way of contrast, the term "non-nanoparticulate active agent" has an effective average particle size of greater than 2000 nm.

The term "ivacaftor", as used herein, expressly includes ivacaftor salts and encompasses different crystal forms (polymorphs), solvates, co-crystals, and hydrates. It also includes racemic or substantially optically pure forms of the foregoing. The terms "drug" or "active agent," when used herein, typically refers to ivacaftor but may, if clearly indicated by its context, refer to another drug.

The compositions of the invention comprise nanoparticulate ivacaftor, or a pharmaceutically acceptable salt thereof. The ivacaftor salt may be an addition salt formed with a suitable organic or inorganic acid such as for example HCl, HBr, H ₂ SO ₄ , phosphoric acid, sulphamic acid, oxalic acid, lactic acid, malic acid, maleic acid, malonic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, citric acid, 4-hydroxy benzoic acid, 2,5-dihydroxy benzoic acid, adipic acid, glycoli acid, decanoic acid, un-decanoic acid, cholic acid, dexo-cholic acid, mandelic acid, d-camphonic acid, benzoic acid, methansulphonic acid, ethanesulphonic acid, benzesulphonic acid, p- toluenesulphonic acid and the like These molecules can also be used as a co-former for solvates, and co-crystals of ivacaftor. . Further, U.S. patent no. 7,927,613 can be used as a reference for co-formers. The ivacaftor may be present in racemic form or as a substantially optically pure enantiomer. Different polymorphic forms, co-crystals, hydrates, solvates of ivacaftor are disclosed in various references can be used to prepare nanoparticulate composition of ivacaftor. The present invention may be practiced with any single polymorph or a mixture thereof. Preferably the composition comprises ivacaftor in the form of a substantially pure single polymorph, which may be amorphous form, Form A, Form B or Form C or a mixture thereof, preferably Form C. The compositions of the invention comprise nanoparticulate ivacaftor or a pharmaceutically acceptable salt thereof, in which the particles can be in a crystalline form, semi-crystalline form, amorphous form, or a combination thereof.

The term "effective average particle size," as used herein, means that at least about 50% of the nanoparticulate ivacaftor particles have a size of less than about 2000 nm (by weight or by other suitable measurement, such as by volume, number, etc.), when measured by, for example, sedimentation flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, and other techniques known to those of skill in the art.

The term "one," "a," or "an," as used herein, is not limited to singular forms but also encompasses the plural equivalent. As used herein, the phrase "therapeutically effective amount" shall mean that drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that a therapeutically effective amount of a drug that is administered to a particular subject in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.

The compositions of the invention comprising nanoparticulate ivacaftor can exhibit increased bioavailability as compared to the same non-nanoparticulate ivacaftor (in other words compared to a composition wherein the ivacaftor component is present at a particle size greater than 2000 nm). Moreover, the compositions of the invention are expected to require smaller doses, and smaller tablet or other solid dosage form size as compared to prior known non-nanoparticulate formulations of the same ivacaftor to achieve the same pharmacological effect. The increased bioavailability is significant because it means that the nanoparticulate ivacaftor dosage form will likely exhibit significantly greater drug absorption compared to the same amount of ivacaftor presented in the form of particles greater than about 2000 nm.

The invention also enables production of compositions comprising nanoparticulate ivacaftor having a desirable pharmacokinetic (PK) profile when administered to mammalian subjects. Standard PK parameters routinely used to assess the behavior of a dosage form in vivo (in other words when administered to an animal or human subject) include Cma _X (peak concentration of drug in blood plasma), Tma _X (the time at which peak drug concentration is achieved) and AUC (the area under the plasma concentration vs time curve). Methods for determining and assessing these parameters are well known in the art. The desirable pharmacokinetic profile of the compositions comprising nanoparticulate ivacaftor may comprise but is not limited to: (1) a Cmax for a nanoparticulate ivacaftor when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the Cmax for a non-nanoparticulate ivacaftor, administered at the same dosage; and/or (2) an AUC for nanoparticulate ivacaftor when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the AUC for a non-nanoparticulate ivacaftor, administered at the same dosage; and/or (3) a Tma _X for nanoparticulate ivacaftor when assayed in the plasma of a mammalian subject following administration, that is preferably less than the Tma _X for a non-nanoparticulate formulation of the same drug administered at the same dosage. Preferably the composition exhibits a PK profile having a combination of two or more of the features (1), (2) and (3) in the preceding sentence. The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose.

In one embodiment, a composition comprising nanoparticulate ivacaftor exhibits, in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same drug, administered at the same dosage, a Tmax not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the T _max exhibited by the non- nanoparticulate ivacaftor formulation.

In another embodiment, the composition comprising nanoparticulate ivacaftor exhibits in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same drug, administered at the same dosage, a Cmax which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax exhibited by the non-nanoparticulate formulation.

In yet another embodiment, the composition comprising nanoparticulate ivacaftor exhibits in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same drug, administered at the same dosage, an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the non-nanoparticulate formulation. In one embodiment of the invention, the T _max of nanoparticulate ivacaftor when assayed in the plasma of the mammalian subject is less than about 6 hours. In other embodiments of the invention, the of the ivacaftor is less than about 5.5 hours, less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.5 hours, less than about 2 hours, less than about 1.5 hours less than about 1 hour, less than about 45 minutes, or less than about 30 minutes after administration.

In another embodiment of the invention, the compositions when tested in fasting subjects in accordance with standard pharmacokinetic practice, are proposed to produces a maximum blood plasma concentration profile in less than about 6 hours, less than about 5.5 hours, less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.5 hours, less than about 2 hours, less than about 1.5 hours, less than about 1 hour, less than about 45 minutes, or less than about 30 minutes after the initial dose of the composition.

The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of nanoparticulate ivacaftor. The compositions can be formulated in any way as described herein and as known to those of skill in the art.

The invention encompasses compositions comprising nanoparticulate ivacaftor wherein the pharmacokinetic profile of the drug is not substantially affected by the fed or fasted state of a subject ingesting the composition. In other words the composition does not produce significantly different absorption levels when administered under fed as compared to fasted conditions. This means that there is no substantial difference in the quantity of drug absorbed (AUC), the rate of drug absorption (C _max ), or the length of time to C _m a _x (T _max ), when the nanoparticulate ivacaftor compositions are administered in the fed versus the fasted state.

The difference in absorption (AUC) or Cma _x of the nanoparticulate ivacaftor compositions of the invention, when administered in the fed versus the fasted state, preferably is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.

The difference in Tma _x of the nanoparticulate ivacaftor compositions of the invention, when administered in the fed versus the fasted state, preferably is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.

The invention also encompasses a composition comprising nanoparticulate ivacaftor in which administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.

In one of the embodiment of the invention, the nanoparticulate composition of ivacaftor is bioequivalent to the commercially available KALYDECO®. This nanoparticulate composition of ivacaftor is irrespective of the form of ivacaftor in the formulation. Preferably a crystalline form of ivacaftor in form of nanoparticles present in a tablet or granules formulation is bioequivalent to KALYDECO® tablet or granules dosage form.

When formulated into a solid dosage form, the compositions comprising nanoparticulate ivacaftor are proposed to have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to greater bioavailability and faster onset of action. To improve the dissolution profile and bioavailability of ivacaftor it would be useful to increase ivacaftor dissolution so that it could attain a level close to 100% dissolution of the drug substance.

The nanoparticulate ivacaftor compositions of the invention, when formulated into a solid dosage form, preferably have a dissolution profile in which within about 5 minutes at least about 5% of the composition is dissolved. In other embodiments of the invention, at least about 10%, at least about 20%, at least about 30% or at least about 40% of the ivacaftor composition is dissolved within about 5 minutes. In yet other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the ivacaftor composition is dissolved within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the ivacaftor composition is dissolved within 20 minutes.

The compositions of the present invention provide a method of treating or lessening the severity of a disease in a patient comprising administering to said patient one of the compositions as defined herein, and said disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay- Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Char cot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, Gerstmann-Stra ussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Barrier's syndrome type III, Dent's disease, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia. Further, the composition also comprises at least one surface stabilizer, and optionally one or more pharmaceutically acceptable excipients, carriers, and optionally one or more active agents useful for the treatment of the said diseases.

The invention provides compositions comprising nanoparticulate ivacaftor and at least one surface stabilizer. The at least one surface stabilizer is preferably adsorbed on, or otherwise associated with, the surface of the ivacaftor particles. Surface stabilizers may physically adhere on, or associate with, the surface of the ivacaftor particles, but ideally do not chemically react with the ivacaftor particles or itself. Individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.

The present invention also includes nanoparticulate ivacaftor compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for any pharmaceutically acceptable method of administration, such as parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like. A preferred route of administration is oral administration.

Accordingly, compositions of the invention may be formulated: (a) for administration selected from the group consisting of oral, pulmonary, intravenous, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, soft gelatin capsules, gels, aerosols, ointments, creams, tablets, sachets and capsules; (c) into a dosage form selected from the group consisting of lyophilized formulations, fast melt formulations, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; and (d) combinations of (a), (b), and (c).

The compositions of the invention comprise at least one surface stabilizer. However, combinations of more than one surface stabilizer have been found to be useful and can be used in the invention. Where a plurality of surface stabilizers is used there may be a primary surface stabilizer that is present in greater concentration than the other (secondary) surface stabilizer(s). Preferably the composition will comprise a primary surface stabilizer and at least one secondary surface stabilizer. Useful surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Exemplary surface stabilizers include nonionic and ionic (e.g., anionic, cationic, and zwitterionic) stabilizers. Without wishing to be bound by any particular theory, it is believed that polymeric materials adhering to a particle surface can present a steric barrier preventing particle aggregation, while in the case of ionic stabilizers the stabilizing action may be attributed to electrostatic interactions.

Representative examples of surface stabilizers include albumin, including but not limited to human serum albumin and bovine albumin, hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., Tween 20 ^® and Tween 80 ^® ); polyethylene glycols (e.g., Carbowax 3550 ^® and 934 ^® ), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanol amine, polyvinyl alcohol (PVA), polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer (Soluplus ^® ), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68 ^® and F108 ^® , which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908 ^® , also known as, Poloxamine 908 ^® , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine); Tetronic 1508 ^® (T-1508), Tritons X-200 ^® , which is an alkyl aryl polyether sulfonate; Crodestas F-110 ^® , which is a mixture of sucrose stearate and sucrose distearate; p-isononylphenoxypoly-(glycidol), also known as Olin-lOG ^® or Surfactant 10-G ^® ; Crodestas SL-40 ^® ); and SA90HCO, which is Ci8H37CH ₂ (CON(CH ₃ )~CH ₂ (CHOH)4(CH ₂ OH) ₂ ; decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n- dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n- heptyl^-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n- octyl^-D-glucopyranoside; octyl β-D-thioglucopyranoside; PEG-phospholipid, PEG- cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.

Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammonium bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate. Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2- chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, CI 2- 15 dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C 14- 18)dimethyl -benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (CI 2- 14) dimethyl 1 -napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts and dialkyl- dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N- tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14) dimethyl 1- naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, CI 2, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly- diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336 ^® ), polyquaternium 10 (POLYQUAT 10 ^® ), tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di- stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers (MIRAPOL ^® and ALKAQUAT ^® ), alkyl pyridinium salts; amines, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, Ν,Ν-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts; protonated quaternary acrylamides; methylated quaternary polymers, such as poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]; and cationic guar. Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation(Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry(Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants. Organic Chemistry, (Marcel Dekker, 1990).

Nonpolymeric surface stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quaternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxyl ammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quaternary ammonium compounds.

Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanol ammonium POE (10) oletyl ether phosphate, diethanol ammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HC1, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.

The following surface stabilizers may be particularly useful in the practice of the present invention copolymers of vinylpyrrolidone and vinyl acetate or copovidone (e.g., Plasdone S630, which is a random copolymer of vinyl acetate and vinyl pyrrolidone); docusate sodium (DOSS); hydroxypropylcellulose (HPC, such as HPC-SL which has a viscosity of 2.0 to 2.9 mPas in aqueous 2% w/v solution at 20°; hydroxypropylmethylcellulose (HPMC, such as Pharmacoat ^® 603; polysorbates or polyoxyethylene sorbitan fatty acid esters (e.g. Tween ^® 20 (polyoxyethylene 20 sorbitan monolaurate), Tween ^® 40 (polyoxyethylene 20 sorbitan palmitate) or Tween ^® 80 (polyoxyethylene 20 sorbitan monooleate)); block copolymers based on ethylene oxide and propylene oxide, also known as poloxamers (e.g., poloxamer 407 (*Lutrol ^® F127), poloxamer 188 (Lutrol ^® F68) or Poloxamer 338 (Lutrol ^® F108); a polyvinylpyrrolidone (PVP), e.g. Plasdone ^® C29/32, Plasdone ^® C-30, Plasdone ^® C17 and Plasdone ^® C12; deoxycholic acid sodium salt, sodium lauryl sulphate (SLS also known as sodium dodecyl sulphate or SDS), benzalkonium chloride (also known as alkyldimethylbenzylammonium chloride), lecithin, distearyl palmitate glyceryl or a combination thereof. Other preferred stabilizers include albumin, lysozyme, gelatin, macrogol 15 hydroxystearate (e.g. Solutol ^® 15), tyloxapol and polyethoxylated castor oil (e.g. Cremophor ^® EL), polyethylene oxide-containing fatty acid esters like Stearoyl macrogol-32 glycerides, Lauroyl macrogol-32 glycerides (e.g. Gelucire ^® ).

The surface stabilizers are commercially available and/or can be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (R. C. Rowe et al (ed.) 6th Edition, The Pharmaceutical Press, 2009), specifically incorporated by reference.

The preferable surface stabilizer is copolymers of vinylpyrrolidone and vinyl acetate or copovidone, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, docusate sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyoxyethylene sorbitan fatty acid esters, block copolymers based on ethylene oxide and propylene oxide, polyvinylpyrrolidone, deoxycholic acid sodium salt, sodium lauryl sulphate, benzalkonium chloride, lecithin, distearyl palmitate glyceryl, albumin, lysozyme, gelatin, macrogol 15 hydroxystearate, tyloxapol and polyethoxylated castor oil, cellulose derivates, dioctylsulfosuccinate, casein, dextran, gum acacia, cholesterol, tragacanth, stearic acid, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol, 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, polyethylene oxide-containing fatty acid esters like Stearoyl macrogol-32 glycerides, Lauroyl macrogol-32 glycerides or a mixture thereof.

Pharmaceutical compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients. Such excipients are known in the art. Non limiting examples of filling agents include lactose monohydrate, lactose anhydrous, and various starches; examples of binding agents include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ^® PH101 and Avicel ^® , microcrystalline cellulose, and silicified microcrystalline cellulose; lubricantsinclude colloidal silicon dioxide, such as Aerosil ^® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel; sweeteners include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame. Examples of flavoring agents are Magnasweet ^® , bubble gum flavor, and fruit flavors, and the like; preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride; diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel ^® PHI 01 and Avicel ^® PHI 02; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ^® DCL21; dibasic calcium phosphate such as Emcompress ^® ; mannitol; starch; sorbitol; sucrose; and glucose; disintegrants include lightly cross linked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross- povidone, sodium starch glycolate, and mixtures thereof.

Examples of effervescent agents include effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present.

The compositions of the invention comprise nanoparticulate ivacaftor particles having an effective average particle size of less than about 2000 nm (i.e., 2 microns), less than about 1950 nm, less than about 1900 nm, less than about 1850 nm, less than about 1800 nm, less than about 1750 nm, less than about 1700 nm, less than about 1650 nm, less than about 1600 nm, less than about 1550 nm, less than about 1500 nm, less than about 1450 nm, less than about 1400 nm, less than about 1350 nm, less than about 1300 nm, less than about 1250 nm, less than about 1200 nm, less than about 1150 nm, less than about 1100 nm, less than about 1050 nm, less than about 1000 nm, less than about 950 nm, less than about 900 nm, less than about 850 nm, less than about 800 nm, less than about 750 nm, less than about 700 nm, less than about 650 nm, less than about 600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm less than about 100, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods. Apart from the methods referred to herein, other methods suitable for measuring effective average particle size are known to a person of ordinary skill in the art.

By "an effective average particle size of less than about 2000 nm" it is meant that at least 50% of the particles have a particle size less than the effective average, by weight (or by other suitable measurement techniques, such as by volume, number, etc.), i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above-noted techniques. In other embodiments of the invention, at least about 60%, at least about 70%, at least about 80% at least about 90%, at least about 95%, or at least about 99% of the ivacaftor particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.

The amounts of nanop articulate ivacaftor and one or more surface stabilizers may vary. The optimal amount of the individual components can depend, for example, upon the particular form of ivacaftor (such as the specific salt) selected, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.

The concentration of the ivacaftor in the nanoparticulate composition may be from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the ivacaftor and at least one surface stabilizer, not including other excipients.

The concentration of the ivacaftor may be present in any amount sufficient to achieve therapeutically effective levels upon administration and may vary depending on the manner in which the composition is formulated. For example, when considering ivacaftor particles dispersed in a liquid medium, the ivacaftor may typically be present in an amount from about 0.5% to about 90% by weight (salt or free base equivalent) based on the total combined weight of the drug substance, stabilizers, any added excipients and the weight of the dispersion medium. Or, in the case of a solid dosage form the ivacaftor may typically be present in an amount from about 0.1% to about 90% by weight, preferably 0.5% to 60% by weight, and more preferably 1.0% to 40% by weight (salt or free base equivalent) based on the total combined weight of the drug substance, stabilizers, and excipients. (It will be appreciated that the calculation of a weight based concentration will depend on whether the concentration is determined as that of a particular ivacaftor salt or the free base equivalent.)

Any concentration of surface stabilizer(s) which is sufficient to form stable nanoparticles of ivacaftor may be used. For example, the concentration of the at least one surface stabilizer may be present from about 0.001% to about 99.99%, from about 5.0% to about 95.0%, or from about 10% to about 90.0%, by weight, based on the total combined dry weight of the ivacaftor and at least one surface stabilizer, not including other excipients. When considering dispersed ivacaftor particles, the at least one stabilizer may typically be present in an amount from about 0.01% to about 30% by weight based on the total combined weight of the drug substance, stabilizers, any added excipients and the weight of the dispersion medium. Or, in the case of a solid dosage form the at least one stabilizer may typically be present in an amount from about 0.001% to about 90% by weight, preferably 0.5% to 50% by weight, and more preferably 1.0% to 30% by weight based on the total combined weight of the drug substance, stabilizers, and excipients. When more than one surface stabilizer is utilized the stabilizer present in the greatest concentration is the primary stabilizer and the other stabilizers are secondary stabilizers. For example the composition may typically comprise a primary surface stabilizer in an amount from about 0.001% to about 50% w/w (by weight of the total composition (including any dispersion medium)) and one or more secondary surface stabilizers each present in an amount, less than that of the primary stabilizer, ranging from about 0.01% to about 5% w/w (by weight of the total composition (including any dispersion medium). The combination of a primary stabilizer with one or more secondary stabilizers can be advantageous over the use of a single stabilizer. For example a plurality of stabilizers can be used to combine the steric and electrostatic stabilization effects of different types of surface stabilizer molecules.

The present invention further relates to a method of making a nanoparticulate ivacaftor, or a pharmaceutically acceptable salt thereof, composition comprising contacting particles of a ivacaftor with at least one surface stabilizer for a time and under conditions sufficient to provide a composition comprising particles of ivacaftor having an effective average particle size of less than about 2000 nm.

The compositions comprising nanoparticulate ivacaftor can be made using, for example, milling or attrition (including but not limited to wet milling, dry milling and micro fluidization), homogenization, precipitation, crystal engineering, cryogenic spraying, cyclodextrin complexation, solid lipid nanoparticles (SLN), solid/liquid self-emulsifying drug delivery systems (SEDDS), freeze drying, template emulsion techniques, supercritical fluid techniques, nanoelectrospray techniques, combination thereof or and any other techniques known to those of skill in the art. Exemplary methods of making nanoparticulate compositions are described in various references mentioned above, all of which are specifically incorporated by reference.

Milling ivacaftor to obtain nanoparticulate ivacaftor dispersion comprises dispersing the particles in a liquid dispersion medium in which the ivacaftor is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the ivacaftor to the desired effective average particle size. The dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol or a mixture thereof, a preferably dispersion medium is water.

The ivacaftor particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, nanoparticulate ivacaftor can be contacted with one or more surface stabilizers after attrition. Other compounds, such as a diluent, can be added to the ivacaftor/surface stabilizer composition during the size reduction process. Dispersions can be manufactured continuously or in a batch mode.

The grinding media can comprise particles that are preferably substantially spherical in shape, e.g., beads, consisting essentially of polymeric or copolymeric resin or metal like stainless steel etc. Alternatively, the grinding media can comprise a core having a coating of a polymeric or copolymeric resin adhered thereon. The grinding media preferably ranges in size from about 0.01 to about 3 mm. For fine grinding, the grinding media is preferably from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size.

In a preferred grinding process the ivacaftor particles are made continuously. Such a method comprises continuously introducing an ivacaftor composition according to the invention into a milling chamber, contacting the ivacaftor composition according to the invention with grinding media while in the chamber to reduce the ivacaftor particle size of the composition according to the invention, and continuously removing the nanoparticulate ivacaftor composition from the milling chamber. The grinding media is separated from the milled nanoparticulate ivacaftor composition according to the invention using known separation techniques, in a secondary process such as by simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.

Another method of forming the desired nanoparticulate ivacaftor is by microprecipitation. This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities. Such a method comprises, for example: (1) dissolving ivacaftor in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent step (3) removal of solvent by various known methods. The method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by known means.

In homogenization method comprises dispersing ivacaftor particles in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of ivacaftor to the desired effective average particle size. The ivacaftor particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the ivacaftor particles can be contacted with one or more surface stabilizers either before or after attrition. Other compounds, such as a diluent, can be added to the ivacaftor/surface stabilizer composition either before, during, or after the ivacaftor particle size reduction process. Dispersions can be manufactured continuously or in a batch mode.

Another method of forming the desired nanoparticulate ivacaftor is by template emulsion. Template emulsion creates nanostructured ivacaftor particles with controlled particle size distribution and rapid dissolution performance. The method comprises an oil-in-water emulsion where ivacaftor is dissolved in oil and dispersed into fine oil globules in water. The particle size distribution of ivacaftor is a direct result of the size of the emulsion droplets which can be controlled and optimized in this process. Furthermore, through selected use of solvents and stabilizers, emulsion stability is achieved with no or suppressed Ostwald ripening. Subsequently, the solvent and water are removed, and the stabilized nanostructured ivacaftor particles are recovered. Various ivacaftor particle morphologies can be achieved by appropriate control of processing conditions.

Another method of forming the desired nanoparticulate ivacaftor is by spray freezing into liquid (SFL). This technology comprises an organic or organoaqueous solution of ivacaftor with stabilizers, which is injected into a cryogenic liquid, such as liquid nitrogen. The droplets of ivacaftor solution freeze at a rate sufficient to minimize crystallization and particle growth, thus formulating nanostructured ivacaftor particles. Depending on the choice of solvent system and processing conditions, the nanoparticulate ivacaftor particles can have varying particle morphology. In the isolation step, the nitrogen and solvent are removed under conditions that avoid agglomeration or ripening of the ivacaftor particles. As a complementary technology to SFL, ultra rapid freezing (U F) may also be used to created equivalent nanostructured ivacaftor particles with greatly enhanced surface area. URF comprises an organic or organoaqueous solution of ivacaftor with stabilizers onto a cryogenic substrate.

In electrospray ionization a liquid is pushed through a very small charged, usually metal, capillary. This liquid contains the desired substance, e.g., ivacaftor, dissolved in a large amount of solvent, which is usually much more volatile than the analyte. Volatile acids, bases or buffers are often added to this solution as well. The analyte exists as an ion in solution either in a protonated form or as an anion. As like charges repel, the liquid pushes itself out of the capillary and forms a mist or an aerosol of small droplets about 10 μπι across. This jet of aerosol droplets is at least partially produced by a process involving the formation of a Taylor cone and a jet from the tip of this cone. A neutral carrier gas, such as nitrogen gas, is sometimes used to help nebulize the liquid and to help evaporate the neutral solvent in the small droplets. As the small droplets evaporate, suspended in the air, the charged analyte molecules are forced closer together. The drops become unstable as the similarly charged molecules come closer together and the droplets once again break up. This is referred to as Coulombic fission because it is the repulsive Coulombic forces between charged analyte molecules that drive it. This process repeats itself until the analyte is free of solvent and is a lone ion. In nanotechnology the electrospray method may be employed to deposit single particles on surfaces, e.g., ivacaftor particles. This is accomplished by spraying colloids and ensuring that on average there is not more than one particle per droplet. Consequent drying of the surrounding solvent results in an aerosol stream of single ivacaftor particles. Here the ionizing property of the process is not crucial for the application but may be put to use in electrostatic precipitation of the particles.

Nanoparticulate ivacaftor compositions can also be made in methods utilizing supercritical fluids. In such a method ivacaftor is dissolved in a solution or vehicle which can also contain at least one surface stabilizer. The solution and a supercritical fluid are then co-introduced into a particle formation vessel. If a surface stabilizer was not previously added to the vehicle, it can be added to the particle formation vessel. The temperature and pressure are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid. Chemicals described as being useful as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane.

The resultant nanoparticulate ivacaftor compositions or dispersions can be utilized in any pharmaceutically acceptable dosage form, including but not limited to injectable dosage forms, liquid dispersions, soft gelatin capsules, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations, etc.

The invention also provides a method of treating a mammal in need comprising administering a stable nanoparticulate ivacaftor composition comprising: (a) particles of ivacaftor or a pharmaceutically acceptable salt thereof having an effective average particle size of less than about 2000 nm; and (b) at least one surface stabilizer.

The invention provides a method of increasing bioavailability (e.g., increasing the plasma levels) of ivacaftor in a subject. Such a method comprises administering to a subject, via any pharmaceutically acceptable means, an effective amount of a composition comprising nanoparticulate ivacaftor. A preferred administration method is oral administration. The compositions of the invention may be useful in the treatment of cystic fibrosis.

The compositions of the invention comprising nanoparticulate ivacaftor can be administered to a subject via any pharmaceutically acceptable means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. In some embodiments, oral administration is preferred. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non- human. The terms patient and subject may be used interchangeably.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The compositions may also comprise adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include, but are not limited to, capsules (Both Hard Gelatin and Soft Gelatin), tablets, pills, powders, and granules. In such solid dosage forms, the active agent is admixed with at least one of the following: inert excipients,fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents, adsorbents, lubricants, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the drug, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl eneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

"Therapeutically effective amount" as used herein with respect to, for example an ivacaftor dosage shall mean that dosage that provides the specific pharmacological response for which ivacaftor administered in a significant number of subjects in need of such treatment. It is emphasized that "therapeutically effective amount," administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a "therapeutically effective amount" by those skilled in the art. It is to be further understood that ivacaftor dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.

One of ordinary skill will appreciate that effective amounts of ivacaftor can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form. Actual dosage levels of ivacaftor in the nanoparticulate compositions of the invention may be varied to obtain an amount of a ivacaftor that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of ivacaftor, the desired duration of treatment, and other factors.

Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.

EXAMPLES

The following examples are provided to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples.

Example 1:

Nanoparticulate Ivacaftor Preparation

methylcellulose

Plasdone S-630/C-30 0.15

Docusate sodium 0.05 0.02 0.05

Gelucire 0.1

Tween 80 0.1

Pluronic 0.15

HPC-SL 0.2 0.2

Water q.s q.s q.s q.s q.s q.s

A suspension of ivacaftor and a surface stabilizer and optionally excipients was prepared in distilled water and mixed well. The suspension was mixed by a High pressure Homogenizer at different speed, pressure and time. The nanoparticulate of ivacaftor can also be prepared by using ball milling apparatus. Ivacaftor formulations were processed under varied milling conditions. All milling was performed on a ball mill apparatus using a smooth or pegged agitator. The chamber was loaded to 40-90% working volume attrition media and the remaining working volume of the chamber was filled with the mixture to be milled (the "slurry"). Each formulation was further processed using either a lyophilizing process or sprayed drying procedure to remove the milling media.

The resulting nanoparticulate ivacaftor dispersion (NCD) was examined first by microscopy and laser diffraction PSA.

In example 1, a suspension of 1.0% (w/w) of ivacaftor, 0.1% (w/w) of Polaxomer and deionised water to 100% (w/w), mixed well using a high speed homogenizer for 15 minutes and followed by nanonised with a high pressure homogenizer at 1500-2000 bar. The dispersion medium was then removed by lyophilization or spray drying. The same formulation iwa also prepared using ball milling apparatus. 1.0% (w/w) of ivacaftor, 0.1% (w/w) of Polaxomer and deionised water to 100% (w/w), was milled for 30 minutes at vibrational frequency at 3-30 Hz, in a 50 mL chamber using a smooth agitator.

The nanoparticulate dispersion of ivacaftor was then combined with various biorelevant media to determine the likely dissolution profile of the composition in vivo. Other nanoparticulate ivacaftor compositions from the examples were also prepared by using the same method as above. Example 2:

Formulations containing nanoparticulate Ivacaftor

The excipients were mixed with nanoparticulate of ivacaftor, and was used for compressing into tablets or capsules filling directly or granulated using various methods like dry granulation, wet granulation, melt granulation either compressed into tablets or filled into capsules or sachets. Further, the nanoparticulate solution was sprayed onto sugar spheres in FBP or used to granulate a mixture of excipients, dried, mixed with other excipients for tablet compression or capsule filling. The nanoparticulate solution was also sprayed onto tablet cores with a combination of sugar coating and film coating. The solution was also used for spray drying/free drying and the dried nanoparticles formulated further into a solid dosage form. The nanoparticulate ivacaftor can also be used in melt extrusion and extrusion spheronization process to prepare various dosage forms like tablets, capsules or granules for sachets.

Example 3 :

Ivacaftor nanoparticles using PVP K29/32 as surface stabilizer by wet media milling process: Formulation I: Nanosuspension Ivacaftor 5g

PVP k29/32 2.5g

Water 600ml

To the surface stabilizer solution comprising 2.5g of PVP in 600ml purified water, 2.5g Ivacaftor was added and homogenized forl5mins at 1200rpm for 15mins. The suspension was charged into a 0.6L stainless steel chamber of a dyno mill (KDL-A) with Zirconium beads (0.3mm) at a temperature of 20-25°C and milled to the desired particle size.

Process parameters used in the milling process are listed below:

Volume of bead: 360ml; Milling speed: 2000-4200rpm

Pump rate: 40-300ml/min; Milling time: lOhrs

The particle size distribution of the nanosuspension was measured by Beckman-Coulter LS13- 320 as below.

The nanosuspension formulation was further processed into granules using wet granulation process.

Formulation II: Granules of nanosuspension of ivacaftor

The nanosuspension prepared in formulation I was added to a mixture of MCC 102, PVP and SLS, mixed well and dried. The dried granules prepared were passed through a sieve. Formulation III: Lyophilized powder

The nanosuspension was lyophilized in a LabconcoFreezone® Triad freeze dryer.

Formulation IIIA: Lyophilized Ivacaftor nanosuspension

Formulation IIIB: Lyophilized Ivacaftor nanosuspension with 5% sucrose

The processing parameters for lyophilization of the nanosuspension were as below.

After lyophilization, the particle size of the nanosuspension was again measured by Beckman- Coulter LSI 3 -320 after re-suspending the dry powder with purified water. The measured particle size for the lyophilized batches IIIA and IIIB were as follows:

Example 4:

Ivacaftor nanoparticles using HPC-LF and SLS as surface stabilizers by wet media milling process:

Formulation IV

Ivacaftor 5g

HPC-LF 0.9g

SLS 0.045g

Water 600ml

To the surface stabilizer solution comprising 0.9g of HPC-LF and 0.045g of SLS in 600ml purified water, 5g of Ivacaftor was added and the suspension was homogenized for 15mins at 1200rpm. The suspension was then charged into a 0.6L stainless steel chamber of a dyno mill (KDL-A) with Zirconium beads (0.3mm) at a temperature of 20-25°C and milled. The process parameters for wet media milling in the dyno mill were as below.

Process Parameters:

Volume of bead: 480ml

Milling speed: 2500rpm

Pump rate: 300ml/min

Milling time: 6hrs

The particle size distribution following milling was as below.

Example 5:

Ivacaftor nanoparticles using HPC-LF as surface stabilizer using wet media milling process: Formulation V

Ivacaftor 1 Og

HPC-LF 2.5g

Water 600ml

To the surface stabilizer solution comprising 2.5g of HPC-LF in 600ml purified water, 5g of Ivacaftor was added and the suspension was homogenized for 15mins at 1200rpm. The suspension was then charged into a 0.6L stainless steel chamber of a dyno mill (KDL-A) with Zirconium beads (0.3mm) at a temperature of 20-25°C and milled. The process parameters for wet media milling in the dyno mill were as below.

Process Parameters:

Volume of bead: 480ml

Milling speed: 3200rpm

Pump rate: 300ml/min

Milling time: 2hrs

The particle size distribution following milling was as below.

Example 6 (Comparative Example):

Solid dispersion of Ivacaftor with HPMCAs:

Formulation VI

Ivacaftor 500g

HPMCAs 500g

Acetone 70ml

Solid dispersion of Ivacaftor with HPMCAs polymer was prepared by rotary evaporation at bath temperature 43 °C and 200rpm for 30mins using acetone as the solvent. The solid dispersion was dried overnight and milled.

Example 7 (Comparative Example):

Drug Excipient mixture:

Formulation VII A (Drug Excipient Slurry)

Ivacaftor 50mg

PVP k29/32 25mg

Water 50ml

Formulation VII B (Drug Excipient Physical mixture)

Ivacaftor 50mg

PVP k29/32 48mg

MCC 102 360mg

SLS 2.7mg

Formulation VII A was prepared by simple dispersion of ivacaftor in PVP solution. Formulation VII B was prepared by mixing ivacaftor with PVP, MCC and SLS, passed through sieve and mixed well.

Dissolution studies were performed to observe the % release from 50mg drug equivalent formulations of Ivacaftor nanoparticulate formulations I and II in comparison with that of the corresponding microcrystalline ivacaftor (30 microns), microcrystalline ivacaftor slurry (Formulation VII A), physical mixture (Formulation VII B) and amorphous dispersion (Formulation VI). The dissolution media used was a modified fasted simulated intestinal fluid (FaSSIF) wherein Lecithin and Taurocholate were replaced with 0.25% SLS in a 6.5pH phosphate buffer solution. A USP II method at 65 rpm was used for all the dissolution studies. The results are illustrated in Fig 1. The nanoparticulate formulations show significant enhancement of drug release compared to the amorphous and microcrystalline formulations.

The DSC of ivacaftor granulated nanosuspension (formulation II) shows melting point corresponding to that of ivacaftor form B indicating the drug is in the crystalline form in the granulated nanosuspension formulation II.

These examples are not intended to limit the claims in any respect, but rather to provide exemplary tablet formulations of ivacaftor which can be utilized in the methods of the invention. Such exemplary tablets may also include a coating agent.

Fed/Fast Pharmacokinetics of oral nanoparticulate ivacaftor tablet and KALYDECO ^® Tablets is determined by conducting a bio-study.

It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present inventions without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modification and variations of the invention provided they come within the scope of the appended claims and their equivalents.