Claims for Patent: 5,658,583

Summary for Patent: 5,658,583

Title:	Apparatus and methods for improved noninvasive dermal administration of pharmaceuticals
Abstract:	An apparatus, product formulation, and method for improved dermal permeation of pharmaceuticals wherein the apparatus includes a thin drug formulation reservoir and a heat-generating chamber separated by a first non-permeable wall, wherein the reservoir and chamber are formed in or supported by a housing. The drug formulation reservoir houses or is capable of housing a predetermined amount of a formulation containing pharmaceutically-active agent(s). The heat-generating/temperature-regulating chamber includes a medium for generating controlled heat, preferably a chemical composition made of carbon, iron, water and/or salt which is activated upon contact with air (oxygen). The function of the heat-generating/temperature-regulating element is to heat the user's skin, rapidly bring the skin temperature to a desired and elevated narrow range and keep it in this range for sufficient time to obtain more rapid, enhanced and less variable dermal absorption of selected pharmaceutically-active agents and to obtain improved clinical effects. Structure for controlling the generation of heat is also disclosed. The apparatus may optionally include a spacing or standoff structure which spans the drug formulation reservoir between the non-permeable wall and the user's skin surface for maintaining a predetermined thickness of the drug formulation on the user's skin surface. Also, a novel product formulation which can be used with the apparatus which uses high percentage of eutectic mixture of local anesthetics to reduce the overall degradation rate of the local anesthetic compound(s) in formulations which are subject to hydrolysis.
Inventor(s):	Zhang; Jie (Salt Lake City, UT), Zhang; Hao (Salt Lake City, UT)
Assignee:
Application Number:	08/508,463
Patent Claims:	1. An apparatus for enhancing dermal absorption of pharmaceutical(s) comprising: a hollow frame having a first open end and a second open end; a non-permeable wall disposed between said hollow frame's first and second open ends; a first chamber defined by said hollow frame, said non-permeable wall, and said hollow frame first open end; a second chamber defined by said hollow frame, said non-permeable wall, and said hollow frame second open end, said second chamber configured for housing a pharmaceutically active formulation; and a heating element for heating the user's skin and regulating the temperature thereof, said heating element comprising a heat-generating means disposed within said first chamber. 2. The apparatus of claim 1, wherein said heat-generating means is a heat-generating medium comprising a chemical composition made of carbon, iron, water, salt, or a combination thereof which is activated upon contact with ambient air. 3. The apparatus of claim 2, wherein said hollow frame first open end is capped with a structure for controlling ambient air contact with said heat-generating medium. 4. The apparatus of claim 3, wherein said structure comprises a cover non-permeable to air with opening(s) therein, or area(s) comprising a membrane with desired permeability to air. 5. The structure in claim 4, wherein said cover is made of material(s) having thermal insulation properties. 6. The apparatus of claim 4, wherein the structure further comprises means for adjusting the effective surface area of the opening(s) or portion(s) comprising a membrane with desired permeability to air. 7. The apparatus of claim 1, wherein said heating element is capable of elevating the user's skin temperature to within a desired range. 8. The apparatus of claim 1, wherein said heating element is adapted to maintain said skin temperature within a desired temperature range for a predetermined length of time. 9. The apparatus of claim 1, further including spacing means disposed between said non-permeable wall and said hollow frame second open end for substantially maintaining a predetermined depth between said non-permeable wall and said hollow frame second open end. 10. The apparatus of claim 9, wherein said spacing means is selected from a group comprising a grid, parallel baffles, concentric circles, pins, posts, or a 3-D sponge matrix which substantially maintains a predetermined depth between said non-permeable wall and said hollow frame second open end while still allowing said pharmaceutically-active formulation to reside within said second chamber. 11. The apparatus of claim 1, wherein said hollow frame comprises a flexible foam which is substantially deformable to conform to an irregular or non-planar surface. 12. The apparatus of claim 1, wherein said hollow frame further includes an adhesive surface adjacent said hollow frame second open end. 13. The apparatus of claim 1, further including a pharmaceutically-active formulation containing local anesthetic(s) disposed in said second chamber. 14. The apparatus of claim 13, wherein said pharmaceutically-active formulation containing local anesthetic comprises: an emulsion with an oil phase and an aqueous phase; said oil phase being a eutectic mixture of local anesthetics wherein at least one local anesthetic in said eutectic mixture is subject to hydrolytic degradation when in contact with water, the weight percentage of said eutectic mixture of local anesthetics in the said formulation being higher than the percentage above which further increasing said percentage does not shorten the anesthesia onset time significantly, but does significantly reduce the rate of overall loss of said local anesthetic(s) in said formulation to said hydrolytic degradation; and said formulation containing at least one compound that acts as an emulsifying agent, gelling agent, or thickening agent. 15. An apparatus for enhancing dermal absorption of pharmaceutical(s) comprising: a hollow frame of flexible foam which is substantially deformable to conform to an irregular or non-planar surface, said hollow frame having a first open end and a second open end; a non-permeable wall disposed between said hollow frame first and second open ends; a first chamber defined by said hollow frame, said non-permeable wall, and said hollow frame first open end; a second chamber defined by said hollow frame, said non-permeable wall, and said hollow frame second open end said second chamber configured for housing a pharmaceutically active formulation; a heating element for heating the user's skin and regulating the temperature thereof into a desired and elevated range for a desired length of time, said heating element comprising a heat-generating medium disposed within said first chamber and being a composition made of carbon, iron, water, salt, or a combination thereof which is activated upon contact with ambient air; said hollow frame first open end being capped with a structure for controlling ambient air contact with said heat-generating medium, said structure comprising an opening(s) or area(s) of said cap comprising a membrane with desired permeability to air; spacing means disposed between said non-permeable wall and said hollow frame second open end for substantially maintaining a predetermined depth between said non-permeable wall and said hollow frame second open end, said spacing means selected from a group comprising a grid, parallel baffles, concentric circles, pins, posts, or a 3-D sponge matrix which substantially maintains a predetermined depth between said non-permeable wall and said hollow frame second open end while still allowing said pharmaceutically-active formulation to reside within said second chamber; and means for adhering said frame to the skin of a user with said hollow frame second open end in contact therewith. 16. A method for enhancing dermal absorption of pharmaceutical(s) comprising: providing a patch comprising: a) a hollow frame having a first open end and a second open end; b) a non-permeable wall disposed between said hollow frame's first and second open ends; c) a first chamber defined by said hollow frame, said non-permeable wall, and said hollow frame first open end; d) a second chamber defined by said hollow frame, said non-permeable wall, and said hollow frame second open end said second chamber configured for housing a pharmaceutically active formulation; and e) a medium for heating and regulating the temperature of a user's skin, said heat-generating medium disposed within said first chamber; inserting a predetermined amount of pharmaceutically-active formulation into said second chamber, either during the fabrication of said patch or immediately prior to use thereof; activating said heating medium; affixing said patch to said user's skin such that said pharmaceutically-active formulation is in direct contact therewith; and allowing said patch to remain on said user's skin for a predetermined duration of time. 17. The method of claim 16, wherein said heat-generating medium is a chemical composition made of carbon, iron, water, salt, or a combination thereof which is activated upon contact with ambient air. 18. The method of claim 16, further comprising heating the user's skin and regulating the temperature thereof into a desired and elevated narrow range for extended length of time. 19. The method of claim 17 further comprising controlling the rate of heat-generation of said heat-generating medium subsequent to application to said user's skin. 20. The method of claim 19, wherein said control is effected by adjustment of air flow to said heat-generating medium. 21. The method of claim 20, wherein said air flow adjustment is effected by adjusting the surface area of contact between said heat-generating medium and air exterior to said frame. 22. The method of claim 16, further including substantially maintaining the depth of said second chamber after affixation of said device to said user's skin. 23. The method of claim 22, wherein said depth is maintained by interposing a mechanical structure between said non-permeable wall and said second open end. 24. The method of claim 16, further comprising deforming said patch to conform to said user's skin upon affixation thereto. 25. The method of claim 16 further comprising adhering said patch to said user s skin. 26. The method of claim 16, wherein said predetermined amount of a pharmaceutically-active formulation contains local anesthetic(s). 27. An apparatus for facilitating enhanced dermal absorption of pharmaceutical(s), comprising: a housing defining first and second superimposed, substantially laterally coextensive predominantly two-dimensional chambers separated by a wall; a heating and temperature-regulating element comprising said first chamber containing a heat-generating medium; and said second chamber for containing a pharmaceutically-active formulation. 28. The apparatus of claim 27, wherein said heat-generating medium is an exothermic chemical medium activated by contact with oxygen in the ambient air. 29. The apparatus of claim 28, wherein said first chamber is structured to control the degree of access of said ambient air to said heat-generating medium within said first chamber. 30. The apparatus of claim 29, wherein said ambient air access control structure is configured for adjustability of the surface area of said housing through which said ambient air may contact said heat-generating medium. 31. The apparatus of claim 27, wherein said second chamber is open over an area opposite and substantially coextensive with that of said wall for direct contact of a contained pharmaceutically-active formulation with the skin of a user to which said apparatus is applied. 32. The apparatus of claim 31, further including a standoff structure extending between said wall and said open area and defining a depth of said second chamber. 33. The apparatus of claim 27, wherein said housing is flexibly conformable to the exterior body contours of a patient. 34. The apparatus of claim 27, further including an adhesive placed on said housing about at least a portion of the periphery of said open area for affixation of said housing to the skin of a user. 35. The apparatus of claim 27, further including an adhesive for affixing said housing to the skin of a user with said open area in substantially complete contact therewith. 36. The apparatus of claim 27, further including a pharmaceutically-active formulation within said second chamber. 37. The apparatus of claim 36, wherein said pharmaceutically-active formulation is a gel containing at least 6% of eutectic mixture of local anesthetic(s). 38. A method of facilitating enhanced dermal absorption of pharmaceutically-active agent(s), comprising: providing a quantity of a selected pharmaceutically-active formulation; applying said formulation to the skin of a patient over a selected two-dimensional area thereof; and generating heat substantially over said two-dimensional area of said skin with said formulation interposed between said heat and said skin. 39. The method of claim 38, further including confining said formulation over a preselected area. 40. The method of claim 39, further including generating said heat within a housing also containing said formulation. 41. The method of claim 40, further comprising controlling the rate at which said heat is generated. 42. The method of claim 38, further comprising maintaining a substantially constant depth of said formulation adjacent said skin. 43. The method of claim 38, further comprising maintaining the temperature of said skin substantially within preselected upper and lower limits for a period of time sufficient to obtain a clinical effect from said formulation. 44. The method of claim 38, further comprising providing a heat source for generating said heat via a chemical reaction, placing said heat source and said formulation within a common housing separated by a wall substantially coextensive with the size and shape of said two-dimensional area, said housing being open on one side opposite said wall for direct contact of said formulation with said skin. 45. The method of claim 44, further comprising activating said chemical reaction and controlling the rate thereof by limiting contact between said heat source and ambient air. 46. An apparatus for facilitating enhanced dermal absorption of pharmaceutical(s), comprising: a housing defining predominantly two-dimensional chamber; a heating and temperature-regulating element comprising said chamber containing a heat-generating medium; and structure for affixation of said housing over the skin of a user over a separate drug delivery system. 47. The apparatus of claim 46, wherein said heat-generating medium is an exothermic chemical medium activated by contact with oxygen in the ambient air. 48. The apparatus of claim 47, wherein said chamber is structured to control the degree of access of said ambient air to said heat-generating medium therewithin. 49. The apparatus of claim 48, wherein said ambient air access control structure is configured for adjustability of the surface area of said housing through which said ambient air may contact said heat-generating medium. 50. The apparatus of claim 46, wherein said housing is flexibly conformable to the exterior body contours of a patient. 51. The apparatus of claim 46, wherein said structure for affixation comprises an adhesive associated with said housing.