Claims for Patent: 6,790,458

Summary for Patent: 6,790,458

Title:	Pharmaceutical compositions using semi-solid delivery vehicle
Abstract:	A semi-solid delivery vehicle contains a polyorthoester and an excipient, and a semi-solid pharmaceutical composition contains an active agent and the delivery vehicle. The pharmaceutical composition may be a topical, syringable, or injectable formulation; and is suitable for local delivery of the active agent. Methods of treatment are also disclosed.
Inventor(s):	Steven Y. Ng, Hui-Rong Shen, Jorge Heller
Assignee:	Heron Therapeutics LLC
Application Number:	US10/409,408
Patent Claims:	1. A pharmaceutical composition, comprising: (a) an active agent; and (b) a semi-solid delivery vehicle comprising: (i) a polyorthoester of formula I or formula II where: R is a bond, —(CH2)a—, or —(CH2)b—O—(CH2)c—; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5; R* is a C1-4 alkyl; n is an integer of at least 5; and A is R1, R2, R3, or R4, where R1 is: where: p is an integer of 1 to 20; R5 is hydrogen or C1-4 alkyl; and R6 is: where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R7 is hydrogen or C1-4 alkyl; R2 is: R3 is: where: x is an integer of 0 to 30; y is an integer of 2 to 200; R8 is hydrogen or C1-4 alkyl; R9 and R10 are independently C1-12 alkylene; R11 is hydrogen or C1-6 alkyl and R12 is C1-6 alkyl; or R11 and R12 together are C3-10 alkylene; and R4 is a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups; in which at least 0.1 mol percent of the A units are of the formula R1, and (ii) a pharmaceutically acceptable, polyorthoester-compatible liquid excipient selected from polyethylene glycol ether derivatives having a molecular weight between 200 and 4000, polyethylene glycol copolymers having a molecular weight between 400 and 4000, mono-, di-, or tri-glycerides of a C2-19 aliphatic carboxylic acid or a mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and their C1-4 alkyl ethers and C2-19 aliphatic carboxylic acid esters, and biocompatible oils. 2. The composition of claim 1 where the concentration of the polyorthoester ranges from 1% to 99% by weight of the delivery vehicle. 3. The composition of claim 1 where the polyorthoester has a molecular weight between 1000 and 20,000. 4. The composition of claim 1 where the fraction of the A units that are of the formula R1 is between 1 and 90 mol percent. 5. The composition of claim 1 where the polyorthoester is of formula I, where: none of the units have A equal to R2; R3 is: where: x is an integer of 0 to 10; y is an integer of 2 to 30; and R6 is: where: s is an integer of 0 to 10; t is an integer of 2 to 30; and R5, R7, and R8 are independently hydrogen or methyl. 6. The composition of claim 5 where: R3 and R6 are both —(CH2—CH2—O)2—(CH2—CH2)—; R5 is methyl; and p is 1 or 2. 7. The composition of claim 5 where: R3 and R6 are both —(CH2—CH2—O)9—(CH2—CH2)—; R5 is methyl; and p is 1 or 2. 8. The composition of claim 1 where the fraction of the active agent is from 1% to 60% by weight of the composition. 9. The composition of claim 8 where the fraction of the active agent is from 5% to 30% by weight of the composition. 10. The composition of claim 1 where the composition is in topical, syringable, or injectable form. 11. The composition of claim 1 where the active agent is selected from anti-infectives, antiseptics, steroids, therapeutic polypeptides, anti-inflammatory agents, cancer chemotherapeutic agents, narcotics, local anesthetics, antiangiogenic agents, vaccines, antigens, DNA, and antisense oligonucleotides. 12. The composition of claim 11 where the active agent is a therapeutic polypeptide. 13. The composition of claim 12 where the active agent is bone morphogenic protein. 14. The composition of claim 11 where the active agent is a local anesthetic. 15. The composition of claim 14 further comprising a glucocorticosteroid. 16. The composition of claim 11 where the active agent is an antiangiogenic agent. 17. The composition of claim 11 where the active agent is a cancer chemotherapeutic agent. 18. The composition of claim 11 where the active agent is an antibiotic. 19. The composition of claim 11 where the active agent is an anti-inflammatory agent. 20. A method of treating a disease state treatable by controlled release local administration of an active agent, comprising locally administering a therapeutically effective amount of the active agent in the form of a pharmaceutical composition of claim 1. 21. The method of claim 20 where the active agent is selected from anti-infectives, antiseptics, steroids, therapeutic polypeptides, anti-inflammatory agents, cancer chemotherapeutic agents, narcotics, local anesthetics, antiangiogenic agents, vaccines, antigens, DNA, and antisense oligonucleotides. 22. A method of preventing or relieving local pain at a site in a mammal, comprising administering to the site a therapeutically effective amount of a local anesthetic in the form of a pharmaceutically acceptable composition of claim 14. 23. A method of preventing or relieving local pain at a site in a mammal, comprising administering to the site a therapeutically effective amount of a local anesthetic in the form of a pharmaceutically acceptable composition of claim 15. 24. A process for the preparation of the pharmaceutical composition of claim 1 where the active agent is in solid form, comprising: (1) optionally milling the active agent to reduce the particle size of the active agent; (2) mixing the active agent and the delivery vehicle; and (3) optionally milling the composition to reduce the particle size of the active agent.