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Claims for Patent: 9,101,540

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Claims for Patent: 9,101,540

Title:Nanoparticulate megestrol formulations
Abstract: The present invention is directed to nanoparticulate compositions comprising megestrol. The megestrol particles of the composition have an effective average particle size of less than about 2000 nm.
Inventor(s): Hovey; Douglas (Trooper, PA), Pruitt; John (Collegeville, PA), Ryde; Tuula (Malvern, PA)
Assignee: ALKERMES PHARMA IRELAND LIMITED (Dublin, IE)
Application Number:10/878,623
Patent Claims: 1. A pharmaceutical composition in the form of a stable oral suspension comprising: (i) nanoparticulate megestrol acetate particles having an effective average particle size of less than 150 nm in water at a concentration of about 115 mg to about 135 mg megestrol acetate per ml of said composition; and (ii) at least one surface stabilizer adsorbed on the surface of the megestrol acetate particles, wherein upon administration, about 575 mg to about 675 mg of said composition is bioequivalent to 800 mg of a conventional, microparticulate megestrol acetate composition.

2. The composition of claim 1, wherein the concentration of the nanoparticulate megestrol acetate particles in water is selected from the group consisting of 115 mg/ml, 125 mg/ml, and 135 mg/ml.

3. The composition of claim 1, wherein the difference in absorption of the megestrol acetate, when administered in the fed versus the fasted state, is selected from the group consisting of less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, and less than 3%.

4. The composition of claim 3, wherein the difference is less than about 60%.

5. The composition of claim 1, wherein the composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.

6. A pharmaceutical composition comprising: (i) nanoparticulate megestrol acetate particles having an effective average particle size of less than 150 nm; and (ii) hydroxypropyl methylcellulose and dioctyl sodium sulfosuccinate as surface stabilizers, wherein the amount of the megestrol acetate is about 575 mg, and wherein after administration to a subject in need thereof under fed conditions: (a) a C.sub.max of 1421.+-.421 ng/mL is obtained; and (b) an AUC.sub..infin.of 14743.+-.4451 h.ng/mL is obtained.

7. A pharmaceutical composition comprising: (i) nanoparticulate megestrol acetate particles having an effective average particle size of less than 150 nm; and (ii) hydroxypropyl methylcellulose and dioctyl sodium sulfosuccinate as surface stabilizers, wherein the amount of the megestrol acetate is about 625 mg, and wherein after administration to a subject in need thereof under fed conditions: (a) a C.sub.max of 1517.+-.389 ng/mL is obtained; and (b) an AUC.sub..infin. of 16082.+-.5563 h.ng/mL is obtained.

8. A method of treating anorexia, cachexia, or loss of body mass comprising orally administering a megestrol acetate composition comprising: (i) nanoparticulate megestrol acetate particles having an effective average particle size of less than 150 nm; and (ii) at least one surface stabilizer adsorbed on the surface of the megestrol acetate particles, to a fasted human subject in need, wherein a C.sub.maxof about 300 ng/ml to about 2000 ng/ml is obtained after administration.

9. The method of claim 8, wherein in comparative pharmacokinetic testing with a standard commercial composition of megestrol acetate, administered at the same dosage, the composition of claim 8 exhibits a C.sub.max greater than about 100% of the C.sub.max exhibited by the standard commercial megestrol acetate composition.

10. The composition of claim 1, wherein the megestrol acetate is selected from the group consisting of a crystalline phase, an amorphous phase, and a semi-crystalline phase.

11. The composition of claim 1, wherein the effective average particle size of the nanoparticulate megestrol acetate particles is selected from the group consisting of less than 100 nm, less than 75 nm, and less than 50 nm.

12. The composition of claim 1, wherein the composition is formulated into a dosage form selected from the group consisting of controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.

13. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

14. The composition of claim 1, wherein: (a) the megestrol acetate is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the megestrol acetate and at least one surface stabilizer, not including other excipients; (b) at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 95%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the megestrol acetate and at least one surface stabilizer, not including other excipients; or (c) a combination thereof.

15. The composition of claim 1, comprising at least two surface stabilizers.

16. The composition of claim 15, wherein: (a) a first surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and random copolymers of vinyl acetate and vinyl pyrrolidone; and (b) a second surface stabilizer is selected from the group consisting of sodium lauryl sulfate and dioctyl sodium sulfosuccinate.

17. The composition of claim 1, wherein the at least one surface stabilizer is selected from the group consisting of an ionic surface stabilizer, a non-ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer.

18. The composition of claim 1, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipid, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C.sub.12-15dimethyl hydroxyethyl ammonium chloride, C.sub.12-15dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy).sub.4 ammonium chloride, lauryl dimethyl (ethenoxy).sub.4 ammonium bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and C(.sub.12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C.sub.12 trimethyl ammonium bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 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, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, lysozyme, and cationic guar.

19. The composition of claim 1 having a viscosity selected from the group consisting of less than 1/200, less than 1/175, less than 1/150, less than 1/125, less than 1/100, less than 1/50, and less than 1/25 of the viscosity of a standard commercial liquid oral megestrol acetate formulation at about the same concentration per ml of megestrol acetate.

20. The composition of claim 1 having a viscosity selected from the group consisting of from about 175 mPa s to about 1 mPa s, from about 150 mPa s to about 1 mPa, from about 125 mPa s to about 1 mPa s, from about 100 mPa s to about 1 mPa s, from about 75 mPa s to about 1 mPa s, from about 50 mPa s to about 1 mPa s, from about 25 mPa s to about 1 mPa s, from about 15 mPa s to about 1 mPa s, and from about 5 mPa s to about 1 mPa s.

21. The composition of claim 15, wherein the composition comprises hydroxypropyl methylcellulose and dioctyl sodium sulfosuccinate as surface stabilizers.

22. The pharmaceutical composition of claim 1, wherein the effective average particle size is greater than 50, 75 or 100 nm.

23. The pharmaceutical composition of claim 6, wherein the effective average particle size is greater than 50, 75 or 100 nm.

24. The pharmaceutical composition of claim 7, wherein the effective average particle size is greater than 50, 75 or 100 nm.

25. The method of claim 7, wherein the effective average particle size is greater than 50, 75 or 100 nm.
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