pH-sensitive block copolymers for pharmaceutical compositions

• US 7,094,810 B2
• Filed: 06/25/2003
• Issued: 08/22/2006
• Est. Priority Date: 06/08/2001
• Status: Expired due to Term

• Current Assignee: Paladin Pharma Incorporated
• Original Assignee: Labopharm Incorporated (Endo International PLC)
• Inventors: Leroux, Jean-Christophe, Sant, Vinayak
• Primary Examiner(s): Kishore, Gollamudi S.
• Assistant Examiner(s): SILVERMAN, ERIC E
• Application Number:
  US10/607,446
• Publication Number:
  US 20040072784A1
• Time in Patent Office: 1,154 Days
• Field of Search: None
• US Class Current: 514/772.1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

The present invention relates to a pharmaceutical composition of a biologically active agent and a block copolymer composed of a poly(ethylene oxide) forming hydrophilic segment and a poly(butyl (alkyl)acrylate-co-(alkyl)acrylic acid) that is capable of forming supramolecular assemblies or micelles under favourable conditions. The supramolecular assemblies or micelles formed from said polymers associate or dissociate reversibly upon changes in the environmental pH. The pharmaceutical compositions of the present invention contain hydrophobic drugs, cations or polycationic compounds, which can be delivered to the body by oral route or other routes of administration.

Claims

1. A pharmaceutical composition comprising:

a diblock copolymer of poly(ethylene oxide) and poly(butyl (alkyl)acrylate-co-(alkyl)acrylic acid); and

at least one biologically active agent.

2. The polymer of claim 1 wherein said poly(ethylene oxide) segment has a molecular weight in the range of about 200–

80,000 Da.

3. The polymer of claim 1 wherein said poly(butyl (alkyl)acrylate-co-(alkyl)acrylic acid) segment has a molecular weight in the range of about 200–

80,000 Da.

4. The polymer of claim 1 wherein said alkyl is an alkyl chain having from 0 to about 10 carbon atoms.

5. The polymer of claim 1 wherein said butyl portion of the butyl (alkyl)acrylate is a linear or branched chain.

6. The polymer of claim 1 wherein said butyl (alkyl)acrylate:

(alkyl)acrylic acid is in a molar ratio in the range of about 5;

95 to 95;

5.

7. The pharmaceutical composition of claim 1 wherein said diblock polymer is poly(ethylene oxide)-block-poly(n-butyl acrylate-co-methacrylic acid) having an n-butyl acrylate:

methacrylic acid molar ratio of about 50;

50.

8. The pharmaceutical composition of claim 1 in the form of supramolecular assemblies or micelles.

9. The pharmaceutical composition of claim 8 wherein said supramolecular assemblies or micelles are in a size range of about 5 to 1000 nanometers.

10. The pharmaceutical composition of claim 8 wherein said supramolecular assemblies associate or dissociate reversibly in response to environmental pH changes.

11. The pharmaceutical composition of claim 1 wherein release rate of said biologically active agent increases with increase in pH.

12. The pharmaceutical composition of claim 8 wherein the biologically active agent is a hydrophobic drug incorporated in said supramolecular assemblies by physical or chemical methods.

13. The pharmaceutical composition of claim 12 wherein the hydrophobic drug is fenofibrate.

14. The pharmaceutical composition of claim 8 wherein the biologically active agent is a cation or polycation.

15. The pharmaceutical composition of claim 14 wherein said polycation is a peptide or protein bearing cationic residues.

16. The pharmaceutical composition of claim 14 wherein the cation or polycation interacts electrostatically with said (alkyl)acrylic acid units.

17. The pharmaceutical composition of claim 14 wherein the cation is verapamil hydrochloride.

18. The pharmaceutical composition of claim 8 wherein the biologically active agent forms metal coordination complexes with said (alkyl)acrylic acid units.

19. The pharmaceutical composition of claim 18 wherein the biologically active agent is cisplatin.

20. The pharmaceutical composition of claim 18 wherein the biologically active agent is carboplatin.

21. The pharmaceutical composition of claim 12 wherein incorporation of a hydrophobic drug in the supramolecular assemblies enhances the bioavailability of the hydrophobic drug upon oral administration.

22. The pharmaceutical composition of claim 8 which is administered by oral, intravenous, intra-arterial, subcutaneous, intramuscular, intraperitoneal, rectal, vaginal or topical route.

23. The pharmaceutical composition of claim 8 having a targeting ligand on a surface thereof.