# US 9,040,088 B2 · Nanoparticulate megestrol formulations > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,040,088 B2 - Document ID: US9040088B2 - Status: Granted - Kind: B2 - Application number: 14/536,517 - Filed: 2014-11-07 - Published: 2015-02-26 - Granted: 2015-05-26 - Earliest claimed: 2002-04-12 - Assignees: Alkermes Pharma Ireland Limited - Applicants: Alkermes Pharma Ireland Limited - Inventors: Douglas Hovey; John Pruitt; Tuula Ryde - Web page: https://patentgrep.com/patent/US9040088B2 ## CPC - A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)} - A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)} - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 9/10: Dispersions; Emulsions - A61K 9/145: {with organic compounds} - A61K 9/146: {with organic macromolecular compounds} - A61K 9/5123: {Organic compounds, e.g. fats, sugars} - A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin} - A61K 9/5169: {Proteins, e.g. albumin, gelatin} - A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone - A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} - A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) - A61K 47/38: Cellulose; Derivatives thereof - A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34) - A61P 5/24: of the sex hormones - A61P 15/18: Feminine contraceptives - A61P 35/00: Antineoplastic agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 1 A method of increasing the body mass in a human patient suffering from anorexia, cachexia, or loss of body mass comprising administering to the human patient a megestrol acetate formulation, wherein: (a) the megestrol acetate formulation is a dose of about 40 mg to about 800 mg in about a 5 mL dose of an oral suspension; (b) the megestrol acetate formulation comprises megestrol acetate particles, wherein about 80% of the particles are between about 250 nm and about 50 nm, and at least one surface stabilizer is associated with the surface of the megestrol acetate particles; and (c) the administration is once daily; wherein after a single administration in a human subject of the formulation there is no substantial difference in the Cmax of megestrol when the formulation is administered to the subject in a fed versus a fasted state, wherein fasted state is defined as the subject having no food within at least the previous 10 hours, and wherein fed state is defined as the subject having a high-calorie meal within approximately 30 minutes of dosing. ### Claim 2 (depends on 1) The method of claim 1, wherein about 80% of the particles are between about 230 nm and about 70 nm. ### Claim 3 (depends on 1) The method of claim 1, wherein the anorexia, cachexia or loss of body mass is associated with a diagnosis of HIV or AIDS in the human patient. ### Claim 4 (depends on 1) The method of claim 1, wherein the anorexia, cachexia or loss of body mass is associated with a diagnosis of cancer in the human patient. ### Claim 5 (depends on 1) The method of claim 1, wherein there is a difference in the mean Tmax for the nanoparticulate megestrol acetate formulation when administered in fed versus fasted states, and that difference is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%. ### Claim 6 (depends on 1) The method of claim 1, wherein the formulation exhibits a mean Cmax, selected from the group consisting of greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130% greater than about 140%, and greater than about 150% of the mean Cmax exhibited by a standard commercial, non-nanoparticulate composition of megestrol, administered at the same dosage. ### Claim 7 (depends on 1) The method of claim 1, wherein there is a difference in absorption (AUC) when the formulation is administered in fed versus fasted states, and the difference is selected from the group consisting of 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%, and less than about 3%. ### Claim 8 (depends on 1) The method of claim 1, wherein a maximum blood plasma concentration of megestrol is attained in about 1 hour or less after administration of the megestrol acetate formulation in fasting subjects. ### Claim 9 (depends on 1) The method of claim 1, wherein a maximum blood plasma concentration of megestrol of at least about 700 ng/ml is obtained. ### Claim 10 (depends on 9) The method of claim 9, wherein the maximum blood plasma concentration of megestrol is at least about 700 ng/ml and is attained in less than 5 hours after administration of the megestrol acetate formulation. ### Claim 11 (depends on 1) The method of claim 1, wherein the maximum blood plasma concentration of megestrol is at least about 400 ng/ml and is attained in less than 5 hours after administration of the megestrol acetate formulation. ### Claim 12 (depends on 1) The method of claim 1, wherein a mean Cmax of about 300 ng/ml to about 2000 ng/ml is obtained after a single administration of the formulation in the human subject in a fasted state. ### Claim 13 (depends on 1) The method of claim 1, wherein the surface stabilizer is selected from the group consisting of nonionic surfactants, cationic surfactants, ionic surfactants, and zwitterionic surfactants. ### Claim 14 (depends on 1) The method of claim 1, wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, polyoxyethylene alkyl etherspolyoxyethylene sorbitan fatty acid esters, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, lysozyme, and random copolymers of vinyl pyrrolidone and vinyl acetate. ### Claim 15 (depends on 14) The method of claim 14, wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, dioctylsulfosuccinate, and a combination thereof. ### Claim 16 A method of increasing the body mass in a human patient suffering from anorexia, cachexia, or loss of body mass comprising administering to the human patient a megestrol acetate formulation, wherein: (a) the megestrol acetate formulation is a dose of about 40 mg to about 800 mg in about a 5 mL dose of an oral suspension; (b) the megestrol acetate formulation comprises megestrol acetate particles, wherein about 90% of the particles are less than or equivalent to about 250 nm, and about 10% of the particles are less than or equivalent to about 50 nm, and at least one surface stabilizer is associated with the surface of the megestrol acetate particles; and (c) the administration is once daily; wherein after a single administration in a human subject of the formulation there is no substantial difference in the Cmax of megestrol when the formulation is administered to the subject in a fed versus a fasted state, wherein fasted state is defined as the subject having no food within at least the previous 10 hours, and wherein fed state is defined as the subject having a high-calorie meal within approximately 30 minutes of dosing. ### Claim 17 (depends on 16) The method of claim 16, wherein about 90% of the particles are less than or equivalent to about 230 nm, and about 10% of the particles are less than or equivalent to about 70 nm. ### Claim 18 (depends on 16) The method of claim 16, wherein the anorexia, cachexia or loss of body mass is associated with a diagnosis of HIV or AIDS in the human patient. ### Claim 19 (depends on 16) The method of claim 16, wherein the anorexia, cachexia or loss of body mass is associated with a diagnosis of cancer in the human patient. ### Claim 20 (depends on 16) The method of claim 16, wherein the surface stabilizer is selected from the group consisting of nonionic surfactants, cationic surfactants, ionic surfactants, and zwitterionic surfactants. ### Claim 21 (depends on 16) The method of claim 16, wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, polyoxyethylene alkyl etherspolyoxyethylene sorbitan fatty acid esters, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, lysozyme, and random copolymers of vinyl pyrrolidone and vinyl acetate. ### Claim 22 (depends on 21) The method of claim 21, wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, dioctylsulfosuccinate, and a combination thereof. ### Claim 23 A method of increasing the body mass in a human patient suffering from anorexia, cachexia, or loss of body mass comprising administering to the human patient a megestrol acetate formulation, wherein: (a) the megestrol acetate formulation is a dose of about 40 mg to about 800 mg in about a 5 mL dose of an oral suspension; (b) the megestrol acetate formulation comprises megestrol acetate particles, wherein about 90% of the particles have a size less than or equivalent to about 250 nm and about 90% of particles have a size greater than or equivalent to about 50 nm, and at least one surface stabilizer is associated with the surface of the megestrol acetate particles; and (c) the administration is once daily; wherein after a single administration in a human subject of the formulation there is no substantial difference in the Cmax of megestrol when the formulation is administered to the subject in a fed versus a fasted state, wherein fasted state is defined as the subject having no food within at least the previous 10 hours, and wherein fed state is defined as the subject having a high-calorie meal within approximately 30 minutes of dosing. ### Claim 24 (depends on 23) The method of claim 23, wherein about 90% of the particles have a size less than or equivalent to about 230 nm and about 90% of particles have a size greater than or equivalent to about 70 nm. ### Claim 25 (depends on 23) The method of claim 23, wherein the anorexia, cachexia or loss of body mass is associated with a diagnosis of HIV or AIDS in the human patient. ### Claim 26 (depends on 23) The method of claim 23, wherein the anorexia, cachexia or loss of body mass is associated with a diagnosis of cancer in the human patient. ### Claim 27 (depends on 23) The method of claim 23, wherein the surface stabilizer is selected from the group consisting of nonionic surfactants, cationic surfactants, ionic surfactants, and zwitterionic surfactants. ### Claim 28 (depends on 23) The method of claim 23, wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, polyoxyethylene alkyl etherspolyoxyethylene sorbitan fatty acid esters, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, lysozyme, and random copolymers of vinyl pyrrolidone and vinyl acetate. ### Claim 29 (depends on 19) The method of claim 19, wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, dioctylsulfosuccinate, and a combination thereof.