Pharmaceutical compositions providing enhanced drug concentrations

• US 9,457,095 B2
• Filed: 03/16/2015
• Issued: 10/04/2016
• Est. Priority Date: 12/23/1999
• Status: Active Grant

• 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:
  US14/659,271
• Publication Number:
  US 20150190518A1
• Time in Patent Office: 568 Days
• US Class Current: 1/1
• 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 form that is a crystalline highly soluble salt form other than the crystalline hydrochloride salt, wherein the crystalline highly soluble salt form has an aqueous solubility at least 1.25-fold the aqueous solubility of the more soluble of the crystalline free base and the crystalline hydrochloride salt forms of the drug; and

(b) a concentration-enhancing polymer,

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 molecular dispersion.

2. The composition of claim 1, which is formulated into a capsule.

3. The composition of claim 1 wherein said composition, after introduction to a use environment, (i) provides a maximum concentration of said drug in said use environment that is at least 1.25 fold an equilibrium concentration of said drug in said use environment, and (ii) provides a concentration of said drug in said use environment that exceeds said equilibrium concentration for a longer time period than does a control composition that is free from said concentration-enhancing polymer and comprises an equivalent quantity of said drug.

4. The composition of claim 3 wherein said use environment is in vitro.

5. The composition of claim 3 wherein said maximum concentration of said drug in said use environment is at least 2 fold said equilibrium concentration.

6. The composition of claim 3 wherein said composition provides a maximum concentration in said use environment that is at least 1.25 fold the maximum drug concentration in said use environment provided by said control composition.

7. The composition of claim 3 wherein said use environment is in vivo.

8. The composition of claim 1 wherein said composition provides a relative bioavailability of at least 1.25.

9. The composition of claim 1 wherein said concentration-enhancing polymer is selected from cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, 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, 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, vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, and cyclicamido, and mixtures thereof.