Claims for Patent: 5,227,169

Summary for Patent: 5,227,169

Title:	Sorbitan esters as skin permeation enhancers
Abstract:	Skin permeation enhancer compositions are provided which increase the permeability of skin to transdermally administered pharmacologically active agents. The compositions contain a sorbitan ester in addition to the selected pharmacologically active agent, and may also contain a C.sub.1 -C.sub.4 aliphatic alcohol. Methods and transdermal drug delivery systems for using the compositions are also provided.
Inventor(s):	Heiber; Sonia (Salt Lake City, UT), Patel; Dinesh (Murray, UT), Ebert; Charles D. (Salt Lake City, UT)
Assignee:	Theratech, Inc. (Salt Lake City, UT)
Application Number:	07/848,110
Patent Claims:	1. A laminated composite for administering a pharmacologically active agent through a selected area of skin over a sustained time period, comprising: (a) a backing layer that is substantially impermeable to the pharmacologically active agent, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the pharmacologically active agent, and (d) a permeation enhancer which consists essentially of a sorbitan ester having the structural formula ##STR2## wherein R.sub.1 has the formula --O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R.sub.2 and R.sub.3 are independently selected from the group consisting of hydroxyl and --O(CO)R'. 2. The laminated composite of claim 1 wherein the adhesive polymer is selected from the group consisting of polysiloxanes, polyacrylates, polyurethanes and tacky rubbers. 3. The laminated composite of claim 1 wherein R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 11-21 carbon atoms optionally containing 1-3 hydroxyl groups, and R.sub.2 and R.sub.3 are both hydroxyl. 4. The laminated composite of claim 3 wherein the sorbitan ester is selected from the group consisting of sorbitan monooleate or sorbitan monolaurate. 5. The laminated composite of claim 1 wherein the pharmacologically active agent is pindolol. 6. The laminated composite of claim 1 wherein the reservoir layer further includes a pharmaceutically acceptable inert vehicle. 7. A laminated composite for administering a pharmacologically active agent through a selected area of skin over a sustained time period, comprising: (a) a backing layer that is substantially impermeable to the pharmacologically active agent, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the pharmacologically active agent, and (d) a permeation enhancer which consists essentially of a sorbitan ester having the structural formula ##STR3## wherein R.sub.1 has the formula --O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R.sub.2 and R.sub.3 are independently selected from the group consisting of hydroxyl and --O(CO)R', and a C.sub.1 -C.sub.4 aliphatic alcohol. 8. The laminated composite of claim 7 wherein the adhesive polymer is selected from the group consisting of polysiloxanes, polyacrylates, polyurethanes and tacky rubbers. 9. The laminated composite of claim 7 wherein R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substitutents of 11-21 carbon atoms optionally containing 1-3 hydroxyl groups, and R.sub.2 and R.sub.3 are both hydroxyl. 10. The laminated composite of claim 9 wherein the sorbitan ester is selected from the group consisting of sorbitan monooleate or sorbitan monolaurate. 11. The laminated composite of claim 7 wherein the C.sub.1 -C.sub.4 aliphatic alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, t-butanol, and mixtures thereof. 12. The laminated composite of claim 7 wherein the pharmacologically active agent is pindolol. 13. A laminated composite for administering a pharmacologically active agent through a selected area of skin over a sustained time period, comprising: (a) a backing layer that is substantially impermeable to the pharmacologically active agent; (b) an active agent-permeable membrane, the backing layer and membrane defining (c) a reservoir therebetween which contains the pharmacologically active agent and a permeation enhancer, said reservoir having a periphery smaller than the backing layer and membrane such that portion of the backing layer and membrane extends outwardly from the periphery of the reservoir; (d) a first peelable active agent formulation-impermeable layer underlying the reservoir and a portion of said outwardly extending portion of the backing layer and membrane; (e) an adhesive layer that underlies and covers the first peelable active agent formulation-impermeable layer and said portion of said outwardly extending portion of the backing layer and membrane; (f) a second peelable active agent formulation-impermeable layer that underlies and covers the adhesive layer; (g) a permanent heat seal about the periphery of the reservoir between the backing layer and the membrane; and (h) a peelable heat seal underlying the permanent heat seal between the backing and the first peelable layer, wherein the peel strengths between the adhesive layer and the first and second peelable layers are greater than the force required to break the peelable heat seal, whereby when the second peelable layer is removed from the device, the peelable heat seal is broken and the first peelable layer and underlying portion of the adhesive layer is removed therewith, further wherein the permeation enhancer consists essentially of a sorbitan ester having the structural formula ##STR4## wherein R.sub.1 has the formula --O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R.sub.2 and R.sub.3 are independently selected from the group consisting of hydroxyl and --O(CO)R', or a sorbitan ester having the above described structural formula in combination with a C.sub.1 -C.sub.4 aliphatic alcohol. 14. A laminated composite for administering a steroid drug through a selected area of skin over a sustained time period, comprising: (a) a backing layer that is substantially impermeable to the steroid drug, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the steroid drug, and (d) a permeation enhancer which consists essentially of a sorbitan ester having the structural formula ##STR5## wherein R.sub.1 has the formula --O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R.sub.2 and R.sub.3 are independently selected from the group consisting of hydroxyl and --O(CO)R'. 15. The laminated composite of claim 14 wherein the adhesive polymer is selected from the group consisting of polysiloxanes, polyacrylates, polyurethanes, and tacky rubbers. 16. The laminated composite of claim 14 wherein R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 11-21 carbons atoms optionally containing 1-3 hydroxyl groups, and R.sub.2 and R.sub.3 are both hydroxyl. 17. The laminated composite of claim 16 wherein the sorbitan ester is selected from the group consisting of sorbitan monooleate or sorbitan monolaurate. 18. The laminated composite of claim 14 wherein the steroid is selected from the group consisting of estradiol, progesterone, norethindrone acetate, and mixtures thereof. 19. The laminated composite of claim 14 wherein the reservoir layer further includes a pharmaceutically acceptable inert vehicle. 20. A laminated composite for administering a steroid drug through a selected area of skin over a sustained time period, comprising: (a) a backing layer that is substantially impermeable to the steroid drug, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the steroid drug, and (d) a permeation enhancer which consists essentially of a sorbitan ester having the structural formula ##STR6## wherein R.sub.1 has the formula --O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R.sub.2 and R.sub.3 are independently selected from the group consisting of hydroxyl and --O(CO)R', and a C.sub.1 -C.sub.4 aliphatic alcohol. 21. The laminated composite of claim 20 wherein the adhesive polymer is selected from the group consisting of polysiloxanes, polyacrylates, polyurethanes, and tacky rubbers. 22. The laminated composite of claim 20 wherein R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 11-21 carbon atoms optionally containing 1-3 hydroxyl groups, and R.sub.2 and R.sub.3 are both hydroxyl. 23. The laminated composite of claim 22 wherein the sorbitan ester is selected from the group consisting of sorbitan monooleate or sorbitan monolaurate. 24. The laminated composite of claim 20 wherein the steroid is selected from the group consisting of estradiol, progesterone, norethindrone acetate, and mixtures thereof. 25. The laminated composite of claim 20 wherein the reservoir layer further includes a pharmaceutically acceptable inert vehicle. 26. A laminated composite for administering a steroid drug through a selected area of skin over a sustained time period, comprising: (a) a backing layer that is substantially impermeable to the steroid; (b) an active agent-permeable membrane, the backing layer and membrane defining (c) a reservoir therebetween which contains the steroid drug and a permeation enhancer, said reservoir having a periphery smaller than the backing layer and membrane such that a portion of the backing layer and membrane extends outwardly from the periphery of the reservoir; (d) a first peelable steroid drug formulation-impermeable layer underlying the reservoir and a portion of said outwardly extending portion of the backing layer and membrane; (e) an adhesive layer that underlies and covers the first peelable steroid drug formulation-impermeable layer and said portion of said outwardly extending portion of the backing layer and membrane; (f) a second peelable steroid drug formulation-impermeable layer that underlies and covers the adhesive layer; (g) a permanent heat seal about the periphery of the reservoir between the backing layer and the membrane; and (h) a peeleable heat seal underlying the permanent heat seal between the backing and the first peelable layer, wherein the peel strengths between the adhesive layer and the first and second peelable layers are greater than the force required to break the peelable heat seal, whereby when the second peelable layer is removed from the device, the peelable heat seal is broken and the first peelable layer and underlying portion of the adhesive layer is removed therewith, further wherein the permeation enhancer consists essentially of a sorbitan ester having the structural formula ##STR7## wherein R.sub.1 has the formula --O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R.sub.2 and R.sub.3 are independently selected from the group consisting of hydroxyl and --O(CO)R', or a sorbitan ester having the above described structural formula in combination with a C.sub.1 -C.sub.4 aliphatic alcohol. 27. The laminated composite of claim 26 wherein the steroid is selected from the group consisting of estradiol, progesterone, norethindrone acetate, and mixtures thereof.