Active Agent Formulations, Methods of Making, and Methods of Use

• US 20080050450A1
• Filed: 06/26/2007
• Published: 02/28/2008
• Est. Priority Date: 06/26/2006
• Status: Abandoned Application

• Current Assignee: Mutual Pharmaceutical Co Inc (Takeda Pharmaceutical Company Limited)
• Original Assignee: Mutual Pharmaceutical Co Inc (Takeda Pharmaceutical Company Limited)
• Inventors: Feng, Hengsheng, Arnold, Kristin, Nielsen, Kurt
• Application Number:
  US11/768,476
• Publication Number:
  US 20080050450A1
• Time in Patent Office: Days
• US Class Current: 424/501
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Active agent compositions comprising active agent particles having an effective average particle size of less than 2000 nm, wherein the compositions comprise a particle sequestrant are disclosed. Compositions having an effective average particle size of less than 2000 nm, wherein the compositions comprise no added surfactants, phospholipids, or combinations thereof, are also disclosed. In some embodiments, the active agent is fenofibrate. In other embodiments, the fenofibrate compositions are in a treatment form that that is bioequivalent to TriCor® 145 mg or 48 mg.

Claims

1. A fenofibrate composition comprising

fenofibrate nanoparticles having an effective average particle size of less than 2000 nm, and

a particle sequestrant.

2. The fenofibrate composition of claim 1, comprising no added surfactant, phospholipid, or a combination thereof.

3. The fenofibrate composition of claim 1, further comprising the fenofibrate nanoparticles and the particle sequestrant disposed on an inert core particle to form a fenofibrate granulate.

4. The fenofibrate composition of claim 3, wherein the inert core particle comprises a sugar, microcrystalline cellulose, calcium phosphate, lactose, a polymer, or a combination comprising one or more of the foregoing inert core particles.

5. The fenofibrate composition of claim 1, wherein the particle sequestrant comprises a pH-sensitive copolymer having both hydrophobic (meth)acrylate units and acid-soluble (meth)acrylate units.

6. The fenofibrate composition of claim 1, wherein the particle sequestrant comprises a butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate copolymer.

7. The fenofibrate composition of claim 3, wherein the particle sequestrant comprises a pH-sensitive copolymer having both hydrophobic (meth)acrylate units and acid-soluble (meth)acrylate units.

8. The fenofibrate composition of claim 3, wherein the particle sequestrant comprises butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate copolymer.

9. The fenofibrate composition of claim 1, wherein the fenofibrate composition is in a treatment form that is bioequivalent to the reference drug product of NDA #021656.

10. The fenofibrate composition of claim 1, wherein the composition is in a treatment form that exhibits a ratio of a logarithmic transformed geometric mean AUC_0-∞

of the composition to a logarithmic transformed geometric mean AUC_0-∞

of a reference drug of within about 0.80 to about 1.25 and a ratio of a logarithmic transformed geometric mean C_max of the composition to a logarithmic transformed geometric mean C_max of a reference drug of within about 0.80 to about 1.25;

wherein the reference drug is the reference drug product of NDA #021656.

12. The fenofibrate composition of claim 1, wherein the composition is in a treatment form that exhibits a ratio of a logarithmic transformed geometric mean AUC_0-∞

of the composition to a logarithmic transformed geometric mean AUC_0-∞

of a reference drug of within about 0.80 to about 1.25 and a ratio of a logarithmic transformed geometric mean C_max of the composition to a logarithmic transformed geometric mean C_max of a reference drug of within about 0.80 to about 1.25;

wherein the reference drug is 145 or 48 mg fenofibrate formulations comprising nanoparticles of fenofibrate having associated with the surface thereof a surface stabilizer comprising hypromellose, sodium lauryl sulfate and dioctyl sodium sulfosuccinate.

13. The fenofibrate composition of claim 1, wherein the fenofibrate composition redisperses in a biorelevant medium.

158. The fenofibrate composition of claim 1, wherein the composition is in the form of a suspension comprising an aqueous particle sequestrant solution having dispersed therein the fenofibrate nanoparticles and the particle sequestrant.

159. The fenofibrate composition of claim 1, wherein the composition is a dosage form.

160. The fenofibrate composition of claim 159, wherein the dosage form exhibits a ratio of a logarithmic transformed geometric mean AUC_0-∞

of the composition administered in a non-fasted state to a logarithmic transformed geometric mean AUC_0-∞

of the composition administered in a fasted state of within about 0.80 to about 1.25, and a ratio of a logarithmic transformed geometric mean C_max of the composition administered in a non-fasted state to a logarithmic transformed geometric mean C_max of the composition administered in a fasted state of within about 0.80 to about 1.25.

11. (canceled)

14-87. -87. (canceled)

88. An active agent composition comprising

active agent nanoparticles having an effective average particle size of less than 2000 nm, and

a pH-sensitive copolymer having both hydrophobic (meth)acrylate units and acid-soluble (meth)acrylate units, wherein the active agent nanoparticles and the copolymer are disposed on an inert core particle.

89-112. -112. (canceled)

113. A method of improving bioavailability of an active agent, comprising administering an active agent dosage form, the active agent dosage form comprising active agent nanoparticles having an effective average particle size of less than 2000 nm, wherein the active agent nanoparticles and a particle sequestrant are disposed on an inert core particle, and wherein the particle sequestrant is a pH-sensitive copolymer having both hydrophobic (meth)acrylate units and acid-soluble (meth)acrylate units.

115. The method of claim 113, wherein the active agent comprises fenofibrate, metaxalone, or oxcarbazepine.

116. The method of claim 113, wherein the active agent dosage form comprises no added surfactant, phospholipids, or a combination thereof.

166. The method of claim 113, wherein the dosage form exhibits a ratio of a logarithmic transformed geometric mean AUC_0-∞

of the composition administered in a non-fasted state to a logarithmic transformed geometric mean AUC_0-∞

of the composition administered in a fasted state of within about 0.80 to about 1.25, and a ratio of a logarithmic transformed geometric mean C_max of the composition administered in a non-fasted state to a logarithmic transformed geometric mean C_max of the composition administered in a fasted state of within about 0.80 to about 1.25.

114. (canceled)

117-157. -157. (canceled)

161. A method of making a fenofibrate granulate, comprising

forming an aqueous buffered solution of a pH-sensitive copolymer having both hydrophobic (meth)acrylate units and acid-soluble (meth)acrylate units;

adding fenofibrate to the solution to form a fenofibrate suspension;

milling the fenofibrate suspension to form a fenofibrate nanoparticulate suspension;

spraying the fenofibrate nanoparticulate suspension over a powder bed comprising a plurality of inert cores to form the fenofibrate granulate.

162. The method of claim 161, further comprising forming the fenofibrate granulate into a tablet or capsule.

163. The method of claim 161, wherein the aqueous buffered solution further comprises an alcohol as a wetting agent.

165. The method of claim 163, wherein the fenofibrate formulation further comprises the fenofibrate nanoparticles and the particle sequestrant disposed on an inert core particle to form a fenofibrate granulate.

164. A method of increasing subject compliance in a subject in need of treatment with a lipid-regulating agent, comprising

administering a fenofibrate composition comprising

fenofibrate nanoparticles having an effective average particle size of less than 2000 nm, and

a particle sequestrant.