Compositions and medical device for transdermal delivery of a drug and methods of making and using same

• US 20030060479A1
• Filed: 08/15/2002
• Published: 03/27/2003
• Est. Priority Date: 08/17/2001
• Status: Active Grant

• Current Assignee: Thallium Holding Company, LLC
• Original Assignee: Lavipharm Laboratories Inc (Lavipharm SA)
• Inventors: Hunt, Brian, Rudella, Michael, Osborne, James, Brown, Teletha A., Malik, Vinod
• Granted Patent: US 7,247,315 B2
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/7069 obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• CPC Class Codes: A61K 9/7092 Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/02 without antiinflammatory effect

Abstract

The invention relates to transdermal delivery patches comprising a drug-containing drug reservoir wherein the drug reservoir comprises a plasticizer composition selected to adjust the rate of drug flux out of the transdermal delivery patch device. The invention also specifically relates to methods of producing the transdermal delivery patches of the invention, the methods comprising the use of an alcohol drug dispersing agent. The invention further specifically relates to methods of treating acute and chronic pain and methods of inducing and maintaining analgesia with the transdermal delivery patches of the invention.

Claims

1. A composition suitable for use in a medical device for transdermal administration of a drug through an area of human skin, the composition comprising a drug selected from the group consisting of fentanyl, oxymorphone, oxycodone, hydromorphone, porphine, buprenorphine and analgesically effective derivatives thereof;

a polydimethylsiloxane matrix material and a drug flux rate lowering effective amount of a polydimethylsiloxane plasticizer;

A. wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 20 to 12,500 centistoke;

B. wherein the drug flux rate lowering effective amount of the polydimethylsiloxane plasticizer is between 4 and 7% w/w of the composition; and

C. wherein the polydimethylsiloxane matrix material has a molecular weight of between 100,000 and 5,000,000.

2. The composition of claim 1 wherein the composition comprises no less than 5% w/w and no more than 6% w/w of the polydimethylsiloxane plasticizer, wherein the polydimethylsiloxane plasticizer has a viscosity of 300 to 400 centistoke.

3. The composition of claim 1 wherein the composition further comprises at least 1.00 mg of drug.

4. The composition of claim 1 wherein the composition further comprises at least 4% w/w of drug and no more than 6% w/w drug.

5. A medical device for transdermal administration of a drug through an area of human skin during an administration period, the medical device comprising a solid drug reservoir, wherein the solid drug reservoir comprises:

a pain treating effective amount of a drug selected from the group consisting of fentanyl, oxymorphone, oxycodone, hydromorphone, porphine, buprenorphine and analgesically effective derivatives thereof;

a drug flux rate lowering effective amount of a polydimethylsiloxane plasticizer; and

a polydimethylsiloxane matrix material; and

A. wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 20 to 12,500 centistoke;

B. wherein the drug flux rate lowering effective amount of the polydimethylsiloxane plasticizer is between 4 and 7% w/w of the solid drug reservoir layer; and

C. wherein the polydimethylsiloxane matrix material has a molecular weight of between 100,000 and 5,000,0000.

D. wherein the pain treating effective amount of the drug is at least 1 mg.

6. The medical device of claim 5, further comprising a backing layer having a top side and a bottom side, wherein

A. the solid drug reservoir layer has a top side and a bottom side and an external edge;

B. the bottom side of the backing layer is contiguously disposed to the top side of the solid drug reservoir layer; and

C. the external edge of the solid drug reservoir layer is not completely sealed by the backing layer.

7. The medical device of claim 5, wherein:

A. the solid drug reservoir layer has a top side and a bottom side, and wherein;

i. at least 2% w/w of the solid drug reservoir layer is drug and no more than 15% w/w of the solid drug reservoir layer is drug;

ii. at least 70% w/w of the solid drug reservoir layer is polydimethylsiloxane matrix material; and

iii. at least 5% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer and no more than 6% of the solid drug reservoir is polydimethylsiloxane plasticizer;

B. wherein the medical device further comprises;

i. a backing layer having a top and a bottom side, wherein the bottom side of the backing layer is contiguously disposed with respect to the top side of the solid drug reservoir layer; and

ii. a rate controlling membrane having a top and a bottom side;

wherein the top side of the rate controlling membrane is contiguously disposed with respect to the bottom side of the drug reservoir layer;

wherein the rate controlling membrane comprises;

(a) one or more compositions selected from the group consisting of;

low density polyethylene, polyethylene-(vinyl acetate) copolymer, heat sealable polyester and elastomeric polyester block copolymer;

(b) a polyethylene-(vinyl acetate) copolymer with up to 33% vinyl acetate, the polyethylene-(vinyl acetate) copolymer having a molecular weight of 10,000 or greater;

(c) the thickness and vinyl acetate content of the rate controlling membrane are selected to provide a 0.5 to 10 μ

m/cm²hr permeation rate through the rate controlling membrane at 32 degrees C.; and

iii. an adhesive layer having a top and a bottom side;

wherein the top side of the adhesive layer is contiguously disposed with respect to the bottom side of the rate controlling membrane;

wherein the adhesive layer is adapted to be maintained in drug-transferring relationship to the human skin;

wherein;

(1) at least 5% w/w and no more than 6% w/w of the adhesive layer is polydimethylsiloxane plasticizer, wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 300-400 centistoke;

(2) at least 70% w/w of the adhesive layer is polydimethylsiloxane matrix material, wherein the polydimethylsiloxane matrix material has a molecular weight of between 500,000 to 1,500,000.

8. The medical device of claim 7, wherein:

A. at least 4.5% w/w of the solid drug reservoir layer is drug and no more than 5.5% w/w of the solid drug reservoir layer is drug;

B. at least 5% w/w of the solid drug reservoir layer is polydimethylsiloxane plasticizer and no more than 6% w/w of the solid drug reservoir layer is polydimethylsiloxane plasticizer; and

C. at least 5% w/w of the adhesive layer is polydimethylsiloxane plasticizer; and

no more than 6% w/w of the adhesive layer is polydimethylsiloxane plasticizer.

9. The medical device of claim 5, wherein:

A. the solid drug reservoir layer is a drug reservoir adhesive layer having a top side and a bottom side, and wherein the solid drug reservoir adhesive layer comprises;

i. at least 2% w/w of the solid drug reservoir adhesive layer is drug and no more than 15% w/w of the solid drug reservoir layer is drug;

ii. at least 70% w/w of the solid drug reservoir layer is polydimethylsiloxane matrix material; and

iii. at least 5% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer and no more than 6% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer;

iv. wherein the drug reservoir adhesive layer is adapted to be maintained in drug-transferring relationship to the human skin; and

B. wherein the medical device further comprises a backing layer having a top and a bottom side, wherein the bottom side of the backing layer is contiguously disposed to the top side of the solid drug reservoir adhesive layer.

10. A process for making a solid drug reservoir layer for a medical device for transdermal administration of a drug selected from the group consisting of fentanyl, oxymorphone, oxycodone, hydromorphone, porphine, buprenorphine and analgesically effective derivatives thereof, through an area of human skin during an administration period, the process comprising the steps of:

A. dispersing the drug in an initial amount of the drug in an alcohol dispersing agent to form a drug-alcohol dispersion comprising 10 to 50% w/w drug dispersed in the alcohol dispersing agent, wherein the drug-alcohol dispersion does not contain polydimethylsiloxane; and

then

B. combining the drug-alcohol dispersion with a polydimethylsiloxane matrix material.

11. The process of claim 10 wherein the fentanyl-alcohol dispersion comprises 30 to 50% w/w drug dispersed in the alcohol dispersing agent;

and further comprising the steps of;

A. then admixing a polydimethylsiloxane matrix material and a drug flux rate lowering effective amount of a low molecular weight polydimethylsiloxane plasticizer; and

B. then casting the resulting mixture as a film and applying heat to reduce the amount of all solvents, including the alcohol dispersing agest, to less than 100 ppm in the medical device casting the resulting mixture as a film and applying heat to reduce the amount of all solvents, including the alcohol dispersing agest, to less than 100 ppm in the medical device..

12. The process of claim 11 wherein the alcohol dispersing agent is isopropyl alcohol.

13. A method of treating acute and chronic pain by transdermally administering a drug, the method comprising the step of:

applying and maintaining a medical device for transdermal administration of a drug in drug flow permitting contact with an area of human skin during an administration period;

wherein the medical device comprises a solid drug reservoir, wherein the solid drug reservoir comprises;

a flux rate lowering effective amount of a polydimethylsiloxane plasticizer, a pain treating effective amount of a drug selected from the group consisting of fentanyl, oxymorphone, oxycodone, hydromorphone, porphine, buprenorphine and analgesically effective derivatives thereof; and

a polydimethylsiloxane matrix material; and

A. wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 20 to 12,500 centistoke;

B. wherein the drug flux rate lowering effective amount of the polydimethylsiloxane plasticizer is between 4 and 7% w/w of the composition; and

C. wherein the polydimethylsiloxane matrix material has a has a molecular weight of 100,000 to 5,000,000.

D. wherein the pain treating effective amount of the drug is at least 1 mg.

14. The method of claim 13, further comprising a backing layer having a top side and a bottom side, wherein

A. the solid drug reservoir layer has a top side and a bottom side and an external edge;

B. the bottom side of the backing layer is contiguously disposed to the top side of the solid drug reservoir layer; and

C. the external edge of the solid drug reservoir layer is not completely sealed by the backing layer.

15. The method of claim 13, wherein:

A. the solid drug reservoir layer has a top side and a bottom side, and wherein;

i. at least 2% w/w of the solid drug reservoir layer is drug and no more than 15% w/w of the solid drug reservoir layer is drug;

ii. at least 70% w/w of the solid drug reservoir layer is polydimethylsiloxane matrix material; and

iii. at least 5% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer and no more than 6% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer;

B. wherein the medical device further comprises;

i. a backing layer having a top and a bottom side, wherein the bottom side of the backing layer is contiguously disposed with respect to the top side of the solid drug reservoir layer; and

ii. a rate controlling membrane having a top and a bottom side;

wherein the top side of the rate controlling membrane is contiguously disposed with respect to the bottom side of the drug reservoir layer;

wherein the rate controlling membrane comprises;

(a) one or more compositions selected from the group consisting of;

low density polyethylene, polyethylene-(vinyl acetate) copolymer, heat sealable polyester and elastomeric polyester block copolymer;

(b) a polyethylene-(vinyl acetate) copolymer with up to 33% vinyl acetate, the polyethylene-(vinyl acetate) copolymer having a molecular weight of 10,000 or greater;

(c) the thickness and vinyl acetate content of the rate controlling membrane are selected to provide a 0.5 to 10 μ

m/cm²hr permeation rate through the rate controlling membrane at 32 degrees C.; and

iii. an adhesive layer having a top and a bottom side;

wherein the top side of the adhesive layer is contiguously disposed with respect to the bottom side of the rate controlling membrane;

wherein the adhesive layer is adapted to be maintained in drug-transferring relationship to the human skin;

wherein;

(1) at least 5% and no more than 6% w/w of the adhesive layer is polydimethylsiloxane plasticizer, wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 300 to 400 centistoke;

(2) at least 70% w/w of the adhesive layer is polydimethylsiloxane matrix material, wherein the polydimethylsiloxane matrix material has a molecular weight of 500,000 to 1,500,000.

16. The method of claim 15, wherein:

A. at least 4.5% w/w of the solid drug reservoir layer is drug and no more than 5.0% w/w of the solid drug reservoir layer is drug;

B. at least 5% w/w of the solid drug reservoir layer is polydimethylsiloxane plasticizer and no more than 6% w/w of the solid drug reservoir layer is polydimethylsiloxane plasticizer; and

C. at least 5% w/w of the adhesive layer is polydimethylsiloxane plasticizer; and

no more than 6% w/w of the adhesive layer is polydimethylsiloxane plasticizer.

17. A method of inducing and maintaining analgesia by transdermally administering a drug, the method comprising the step of:

applying and maintaining a medical device for transdermal administration of a drug in drug flow permitting contact with an area of human skin during an administration period;

wherein the medical device comprises a solid drug reservoir, wherein the solid drug reservoir comprises;

a flux rate lowering effective amount of a polydimethylsiloxane plasticizer, a pain treating effective amount of a a drug selected from the group consisting of fentanyl, oxymorphone, oxycodone, hydromorphone, porphine, buprenorphine and analgesically effective derivatives thereof; and

a polydimethylsiloxane matrix material; and

A. wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 20 to 12,500 centistoke;

B. wherein the drug flux rate lowering effective amount of the polydimethylsiloxane plasticizer is between 4 and 7% w/w of the composition;

C. wherein the polydimethylsiloxane matrix material has a molecular weight of 100,000 to 5,000,000;

D. wherein the pain treating effective amount of the drug is at least 1 mg.

18. The method of claim 17, further comprising a backing layer having a top side and a bottom side, wherein

A. the solid drug reservoir layer has a top side and a bottom side and an external edge;

B. the bottom side of the backing layer is contiguously disposed to the top side of the solid drug reservoir layer; and

C. the external edge of the solid drug reservoir layer is not completely sealed by the backing layer.

19. The method of claim 17, wherein:

A. the solid drug reservoir layer has a top side and a bottom side, and wherein;

i. at least 2% w/w of the solid drug reservoir layer is drug and no more than 15% w/w of the solid drug reservoir layer is drug;

ii. at least 70% w/w of the solid drug reservoir layer is polydimethylsiloxane matrix material; and

iii. at least 5% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer and no more than 6% w/w of the solid drug reservoir is polydimethylsiloxane plasticizer;

B. wherein the medical device further comprises;

i. a backing layer having a top and a bottom side, wherein the bottom side of the backing layer is contiguously disposed with respect to the top side of the solid drug reservoir layer; and

ii. a rate controlling membrane having a top and a bottom side;

wherein the top side of the rate controlling membrane is contiguously disposed with respect to the bottom side of the drug reservoir layer;

wherein the rate controlling membrane comprises;

(a) one or more compositions selected from the group consisting of;

low density polyethylene, polyethylene-(vinyl acetate) copolymer, heat sealable polyester and elastomeric polyester block copolymer;

(b) a polyethylene-(vinyl acetate) copolymer with up to 33% vinyl acetate, polyethylene-(vinyl acetate) copolymer having a molecular weight of 10,000 or greater;

(c) the thickness and vinyl acetate composition of the rate controlling membrane are selected to provide a 0.5 to 10 μ

m/cm²hr permeation rate through the rate controlling membrane at 32 degrees C.; and

iii. an adhesive layer having a top and a bottom side;

wherein the top side of the adhesive layer is contiguously disposed with respect to the bottom side of the rate controlling membrane;

wherein the adhesive layer is adapted to be maintained in drug-transferring relationship to the human skin;

wherein;

(1) at least 5% w/w and no more than 6% w/w of the adhesive layer is polydimethylsiloxane plasticizer, wherein the polydimethylsiloxane plasticizer is dimethicone with a viscocity of 20 to 12,500 centistoke; and

(2) at least 70% w/w of the adhesive layer is polydimethylsiloxane matrix material, wherein the polydimethylsiloxane matrix material has a molecular weight of 100,000 to 5,000,000.

20. The method of claim 19, wherein:

A. at least 4.5% w/w of the solid drug reservoir layer is drug and no more than 5% w/w of the solid drug reservoir layer is drug;

B . at least 5% w/w of the solid drug reservoir layer is polydimethylsiloxane plasticizer and no more than 6% w/w of the solid drug reservoir layer is polydimethylsiloxane plasticizer; and

C. at least 5% w/w of the adhesive layer is polydimethylsiloxane plasticizer; and

no more than 6% w/w of the adhesive layer is polydimethylsiloxane plasticizer.