Claims for Patent: 6,495,155

Summary for Patent: 6,495,155

Title:	Injectable opioid partial agonist or opioid antagonist microparticle compositions and their use in reducing consumption of abused substances
Abstract:	An injectable slow-release partial opioid agonist or opioid antagonist formulation is provided comprising a partial opioid agonist or opioid antagonist in a poly(D,L-lactide) excipient with a small amount of residual ethyl acetate. Upon intramuscular injection of the composition, a partial opioid agonist or opioid antagonist is released in a controlled manner over an extended period of time. The composition finds use in the treatment of heroin addicts and alcoholics to reduce consumption of the abused substances. Of particular interest are the drugs buprenorphine, methadone and naltrexone.
Inventor(s):	Tice; Thomas R. (Birmingham, AL), Staas; Jay K. (Alabaster, AL), Ferrell; Teresa M. (Vestavia Hills, AL), Markland; Peter (Birmingham, AL)
Assignee:	Southern Research Institute (Birmingham, AL)
Application Number:	09/648,255
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,495,155
Patent Claims:	1. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and a residual amount of ethyl acetate present in from about 0.1 to 3 weight %, wherein said composition provides a physiologically effective plasma level over a period of about 28 days of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal, and wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m. 2. A microparticle composition according to claim 1, wherein said buprenorphine is present in an amount in the range of 15 to 50 weight %, said poly(D,L-lactide) has an inherent viscosity in the range of about 0.3 to 0.4 dL/g and said ethyl acetate is present in from about 0.1 to 3 weight%. 3. A microparticle composition according to claim 1, wherein said buprenorphine is present in an amount in the range of 30 to 65 weight %, said poly(D,L-lactide) has an inherent viscosity in the range of about 1.0 to 1.1 dL/g and said ethyl acetate is present in from about 0.1 to 3 weight %. 4. A microparticle composition according to claim 1, wherein said poly(D,L-lactide) is a mixture of poly(D,L-lactide)s of differing inherent viscosity. 5. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein when administered intramuscularly to a mammal said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce consumption of at least one of heroin and alcohol, and wherein said microparticle composition comprises one or more characteristic selected from the group consisting of (a) at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, (b) a mixture of microparticles which differ in weight % of buprenorphine and (c) microparticles wherein said poly(D,L-lactide) is a mixture of poly(D,L-lactide)s of differing inherent viscosity. 6. A microparticle composition according to claim 1 or 5, wherein said microparticles are prepared by introducing a solution of said buprenorphine and poly(D,L-lactide) in ethyl acetate into an aqueous ethyl acetate containing solution of poly(vinyl alcohol) to form an emulsion and adding said emulsion to water to extract ethyl acetate to form microparticles, and isolating the resulting microparticles. 7. A formulation for injection comprising a microparticle composition according to claim 1 or 5, carboxymethyl cellulose, Tween and mannitol. 8. A method for reducing the consumption of at least one of heroin and alcohol by a subject abusing at least one of heroin and alcohol, said method comprising: administering intramuscularly to said subject an effective dose of a microparticle composition according to claim 1 or 5 in an amount to inhibit the consumption of heroin and alcohol, whereby the consumption of heroin and alcohol by said subject is reduced. 9. A method for reducing the consumption of at least one of heroin and alcohol by a subject abusing at least one of heroin and alcohol, said method comprising: administering to said subject an effective dose of a microparticle composition according to claim 1 or 5, which composition continues to release said buprenorphine for a period greater than 28 days at at least an effective dose; prior to the level of said buprenorphine falling below an effective dose, administering a second dose of said microparticle composition, whereby the combination of said original effective dose and said second dose provides an effective dose of said buprenorphine for a second period of at least an additional 28 days; and repeating said administration to have said buprenorphine being released from both a prior administration of said microparticle composition and the lately administered microparticle composition to maintain said effective dose of said buprenorphine. 10. The method according to claim 9, wherein at least one of said period and said second period is about 60 days. 11. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight %o ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said poly(D,L-lactide) is a mixture of poly(D,L-lactide)s of differing inherent viscosity, and wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal. 12. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 15 to 50 weight %, poly(D,L-lactide) as an excipient and 0.1 to 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said poly(D,L-lactide has an inherent viscosity in the range of about 0.3 to 0.4 dL/g, and wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal. 13. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 30 to 65 weight %, poly(D,L-lactide) as an excipient and 0.1 to 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said poly(D,L-lactide has an inherent viscosity in the range of about 1.0 to 1.1 dL/g, and wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal. 14. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal, and wherein said microparticles are prepared by introducing a solution of said buprenorphine and poly(D,L-lactide) in ethyl acetate into an aqueous ethyl acetate containing solution of poly(vinyl alcohol) to form an emulsion and adding said emulsion to water to extract ethyl acetate to form microparticles, and isolating the resulting microparticles. 15. A formulation for injection comprising: a microparticle composition comprising a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal; and a vehicle comprising carboxymethyl cellulose; Tween; and mannitol. 16. A method for reducing the consumption of at least one of heroin and alcohol by a subject abusing at least one of heroin and alcohol, said method comprising: administering intramuscularly to said subject an effective dose of a microparticle composition comprising a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal in an amount to inhibit the consumption of heroin and alcohol, whereby the consumption of heroin and alcohol by said subject is reduced. 17. A method for reducing the consumption of at least one of heroin and alcohol by a subject abusing at least one of heroin and alcohol, said method comprising: administering to said subject an effective dose of a microparticle composition comprising a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal, which composition continues to release said buprenorphine for a period greater than 28 days at at least an effective dose; prior to the level of said buprenorphine falling below an effective dose, administering a second dose of said microparticle composition, whereby the combination of said original effective dose and said second dose provides an effective dose of said buprenorphine for a second period of at least an additional 28 days; and repeating said administration to have said buprenorphine being released from both a prior administration of said microparticle composition and the lately administered microparticle composition to maintain said effective dose of said buprenorphine. 18. The method according to claim 17, wherein at least one of said period and said second period is about 60 days. 19. A microparticle composition according to claim 1 or 5, wherein said buprenorphine free base is present in an amount in the range of 15 to 50 weight %, said poly(D,L-lactide) has an inherent viscosity in the range of about 0.3 to 0.4 dL/g and said ethyl acetate is present in from about 0.1 to 3 weight %. 20. A microparticle composition according to claim 1 or 5, wherein said buprenorphine is present in an amount in the range of 30 to 65 weight %, said poly(D,L-lactide) has an inherent viscosity in the range of about 1.0 to 1.1 dL/g and said ethyl acetate is present in from about 0.1 to 3 weight %. 21. A microparticle composition according to claim 1 or 5, wherein said poly(D,L-lactide) is a mixture of poly(D,L-lactide)s of differing inherent viscosity. 22. A microparticle composition comprising: a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein when administered intramuscularly to a mammal said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce consumption of at least one of heroin and alcohol, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m and wherein said composition is a mixture of microparticles which differ in at least one of weight % of buprenorphine or poly(D,L-lactide)s of differing inherent viscosity. 23. A formulation for injection comprising: a microparticle composition comprising a buprenorphine free base in an amount in the range of 10 to 70 weight %, poly(D,L-lactide) as an excipient and less than about 3 weight % ethyl acetate, wherein at least 90 weight % of said microparticle composition comprises microparticles having a diameter in the range of 20 to 125 .mu.m, wherein said composition provides, over a period of about 28 days, a physiologically effective plasma level of said buprenorphine free base to reduce the consumption of at least one of heroin and alcohol when administered intramuscularly in a mammal;and a physiologically acceptable vehicle. 24. The formulation according to claim 23, wherein said physiologicially acceptable vehicle comprises an aqueous solution, and at least one additive selected from the group consisting of (a) an additive that increases viscosity of said formulation, (b) an additive that diminishes discomfort from injection; and (c) a surfactant. 25. The formulation according to claim 24, wherein said additive (a) comprises carboxymethyl cellulose. 26. The formulation according to claim 25, wherein the amount of said carboxymethylcellulose comprises about 0.1 to 1 weight % of said vehicle. 27. The formulation according to claim 24, wherein said additive (b) comprises mannitol. 28. The formulation according to claim 27, wherein said mannitol comprises about 2 to 10 weight % of said vehicle. 29. The formulation according to claim 27 wherein said mannitol comprises about 4 to 7 weight % of said vehicle. 30. The formulation according to claim 24, wherein said additive(c) comprises a non-ionic detergent. 31. The formulation according to claim 30, wherein said non-ionic detergent is a Tween. 32. The formulation according to claim 31, wherein said Tween comprises about 0.05 to 0.2 weight % of said vehicle. 33. The formulation according to claim 24, wherein said aqueous solution is sterile water or phosphate buffered saline.

Details for Patent 6,495,155

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2019-08-27