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):	Ng; Steven Y. (San Francisco, CA), Shen; Hui-Rong (Fremont, CA), Heller; Jorge (Woodside, CA)
Assignee:	AP Pharma Inc. (Redwood City, CA)
Application Number:	10/409,408
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 ##STR16## where: R is a bond, --(CH.sub.2).sub.a --, or --(CH.sub.2).sub.b --O--(CH.sub.2).sub.c --; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5; R* is a C.sub.1-4 alkyl; n is an integer of at least 5; and A is R.sup.1, R.sup.2, R.sup.3, or R.sup.4, where R.sup.1 is: ##STR17## where: p is an integer of 1 to 20; R.sup.5 is hydrogen or C.sub.1-4 alkyl; and R.sup.6 is: ##STR18## where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R.sup.7 is hydrogen or C.sub.1-4 alkyl; R.sup.2 is: ##STR19## R.sup.3 is: ##STR20## where: x is an integer of 0 to 30; y is an integer of 2 to 200; R.sup.8 is hydrogen or C.sub.1-4 alkyl; R.sup.9 and R.sup.10 are independently C.sub.1-12 alkylene; R.sup.11 is hydrogen or C.sub.1-6 alkyl and R.sup.12 is C.sub.1-6 alkyl; or R.sup.11 and R.sup.12 together are C.sub.3-10 alkylene; and R.sup.4 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 R.sup.1, 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 C.sub.2-19 aliphatic carboxylic acid or a mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and their C.sub.1-4 alkyl ethers and C.sub.2-19 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 R.sup.1 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 R.sup.2 ; R.sup.3 is: ##STR21## where: x is an integer of 0 to 10; y is an integer of 2 to 30; and R.sup.6 is: ##STR22## where: s is an integer of 0 to 10; t is an integer of 2 to 30; and R.sup.5, R.sup.7, and R.sup.8 are independently hydrogen or methyl. 6. The composition of claim 5 where: R.sup.3 and R.sup.6 are both --(CH.sub.2 --CH.sub.2 --O).sub.2 --(CH.sub.2 --CH.sub.2)--; R.sup.5 is methyl; and p is 1 or 2. 7. The composition of claim 5 where: R.sup.3 and R.sup.6 are both --(CH.sub.2 --CH.sub.2 --O).sub.9 --(CH.sub.2 --CH.sub.2)--; R.sup.5 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.