Pharmaceutical compositions providing enhanced drug concentrations

• US 8,501,231 B2
• Filed: 06/19/2012
• Issued: 08/06/2013
• Est. Priority Date: 12/23/1999
• Status: Expired due to Fees

• Current Assignee: Bend Research Inc. (Lonza Group AG)
• Original Assignee: Bend Research Inc. (Lonza Group AG)
• Inventors: Curatolo, William J., Shanker, Ravi M., Babcock, Walter C., Friesen, Dwayne T., Nightingale, James A. S., Lorenz, Douglas A.
• Primary Examiner(s): FUBARA, BLESSING M
• Application Number:
  US13/527,536
• Publication Number:
  US 20120259022A1
• Time in Patent Office: 413 Days
• Field of Search: 424/486, 424/493, 424/468, 424/489, 514/772.4
• US Class Current: 424/486
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1629 Organic macromolecular compounds
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

A drug in a solubility-improved form is combined with a concentration-enhancing polymer in a sufficient amount so that the combination provides substantially enhanced drug concentration in a use environment relative to a control comprising the same amount of the same solubility-improved form of drug without the concentration-enhancing polymer.

Claims

1. A composition comprising:

(a) a drug in a pharmaceutically acceptable solubility-improved form that is a high-energy crystalline form of said drug; and

(b) a concentration-enhancing polymer selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and hydroxypropyl methyl cellulose acetate succinate hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, carboxymethyl ethyl cellulose, acrylate and methacrylate copolymers, and mixtures thereof

wherein

said drug alone has an aqueous solubility of up to 2 mg/mL at pH 1 to 8, and said composition is not a dispersion.

2. The composition of claim 1 wherein said high-energy crystalline form of said drug is selected from hydrate crystalline forms, solvate crystalline forms, and polymorph crystalline forms.

9. The composition of any of claim 1, 3, or 6 wherein said drug alone has an aqueous solubility of less than 0.01 mg/mL at pH 1 to 8.

10. The composition of any of claim 1, 3, or 6 wherein said drug is selected from antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-parkinsonism agents, anti-Alzheimer'"'"'s disease agents, antibiotics, anti-depressants, and antiviral agents.

3. A composition comprising:

(a) a drug in a pharmaceutically acceptable solubility-improved form that is a solution of said drug substantially dissolved in a liquid to a concentration that is at least 10-fold the equilibrium concentration of said drug in a use environment; and

(b) a concentration-enhancing polymer selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and hydroxypropyl methyl cellulose acetate succinate hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, carboxymethyl ethyl cellulose, acrylate and methacrylate copolymers, and mixtures thereof

wherein

said drug alone has an aqueous solubility of up to 2 mg/mL at pH 1 to 8, and said composition is not a dispersion.

4. The composition of claim 3 wherein said liquid is selected from the group consisting of water-immiscible triglyceride vegetable oils, water-immiscible refined and synthetic and semi-synthetic oils, mono-, di- and tri-glycerides, water-miscible alcohols, and water-miscible polyethylene glycols.

5. The composition of claim 3 wherein said liquid comprises water and a water-soluble solubilizer.

6. A composition comprising:

(a) a drug in a pharmaceutically acceptable solubility-improved form that is a composition comprising a mixture of said drug and a solubilizing agent selected from the group consisting of surfactants, pH control agents, glycerides, partial glycerides, glyceride derivatives, polyoxyethylene and polyoxypropylene ethers and their copolymers, sorbitan esters, polyoxyethylene sorbitan esters, alkyl sulfonates, and cyclodextrins; and

(b) a concentration-enhancing polymer selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and hydroxypropyl methyl cellulose acetate succinate hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, carboxymethyl ethyl cellulose, acrylate and methacrylate copolymers, and mixtures thereof

wherein

said drug alone has an aqueous solubility of up to 2 mg/mL at pH 1 to 8, said composition is not a dispersion and said drug and said polymer are present as particles in a dry physical mixture.

7. The composition of claim 6 wherein said pH control agents are selected from the group consisting of buffers, organic acids, organic acid salts, organic and inorganic bases, and organic and inorganic base salts.

8. The composition of claim 6 wherein said drug is basic and said solubilizer is an organic acid selected from the group consisting of adipic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid, erythorbic acid, maleic acid, L-aspartic acid, L-glutamic acid, tannic acid, and D,L-tyrosine.