US 2005O266061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0266061 A1 Stinchcomb et al. (43) Pub. Date: Dec. 1, 2005 (54) TRANSIDERMAL DELIVERY OF (52) U.S. Cl. ............................................ 424/448; 514/454 CANNABINOIDS (76) Inventors: Audra L. Stinchcomb, Lexington, KY (57) ABSTRACT (US); Buchi N. Nalluri, Lexington, KY (US) The present invention overcomes the problems associated Correspondence Address: with existing drug delivery Systems by delivering cannab Hoffman, Warnick & D’Alessandro LLC inoids transdermally. Preferably, the cannabinoids are deliv Three E-Comm Square ered via an occlusive body (i.e., a patch) to alleviate harmful Albany, NY 12207 (US) Side effects and avoid gastrointestinal (first-pass) metabo Appl. No.: 11/157,034 lism of the drug by the patient. A first aspect of the invention (21) provides a method for relieving Symptoms associated with (22) Filed: Jun. 20, 2005 illness or associated with the treatment of illness in a mammalian Subject, comprising the Steps of Selecting at Related U.S. Application Data least one cannabinoid from the group consisting of cannab inol, cannabidiol, nabilone, levonantradol, (-)-HU-210, (+)- (63) Continuation-in-part of application No. 10/032,163, HU-210, 11-hydroxy-A-THC, A-THC-11-oic acid, CP filed on Dec. 21, 2001. 55,940, and R(+)-WIN 55,212-2, selecting at least one permeation enhancer from the group consisting of propylene (60) Provisional application No. 60/257,557, filed on Dec. glycol monolaurate, diethylene glycol monoethyl ether, an 22, 2000. oleoyl macrogolglyceride, a caprylocaproyl macrogolglyc Publication Classification eride, and an oleyl alcohol, and delivering the Selected cannabinoid and permeation enhancer transdermally to treat (51) Int. Cl." ......................... A61K 31/353; A61L 15/16 an illness. Patent Application Publication Dec. 1, 2005 Sheet 1 of 12 US 2005/026.6061 A1 NNN ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ ØI 83 I'9IJI NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN 3303 93 §§§§§§§§§§§ No.ZZZZZZZZZZZZZZZZZZZZZ ZZZZZZZZZZZZZØø2NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN Patent Application Publication Dec. 1, 2005 Sheet 2 of 12 US 2005/026.6061 A1 FG. 2 Representative Permeation Profile G 5. w C O 2 a 40 CD 2 S s O 1 O O Time (hr) Patent Application Publication Dec. 1, 2005 Sheet 3 of 12 US 2005/026.6061 A1 FIG. 3 9. 3. L g- 2 g 6 8 Permeability X 10 (cm/h) Patent Application Publication Dec. 1, 2005 Sheet 4 of 12 US 2005/026.6061 A1 FIG. 4 BRJ 6% g E. n BRU 0.5% Ul as i 2 o D t BR6% c o BRU 0.5% BRs. Permeability X 10 (cm/h) Patent Application Publication Dec. 1, 2005 Sheet 5 of 12 US 2005/026.6061 A1 FIG. SA 1 4 2 as 's E 1 O 9 Me d ve X ce s s E G al BSA 4% BRU 6% BR6% BSA 4% BRU SA CTR CTR BSA 4% CTR CR SUBJECT1 SUBJECT 2 SUBJECT 3 Receiver fluid Patent Application Publication Dec. 1, 2005 Sheet 6 of 12 US 2005/026.6061 A1 F.G. SB a HBSA 4%. Control G ABRJ 6%. Control S. w -O-BRIJ 6% (48h) - BSA 4%(48 h) O E CC c 2 E O Patent Application Publication Dec. 1, 2005 Sheet 7 of 12 US 2005/026.6061 A1 F.G. 6 BRIJ 6% : BSA 6% BSA 4% BRU 6% BSA 6% : 2 L BSA 4% c 2 G BRIJ 6%. 8 9 Y BSA 6% BSA 4% BRIJ 6%. 8 BSA 6% i BSA 4% 2 3 Permeability X 10 (cm/h) Patent Application Publication Dec. 1, 2005 Sheet 8 of 12 US 2005/026.6061 A1 FIG. 7 His BR6 INT s s BRIJ 6% STRS w - BRIJ 0.5% INT ?o o BRIJ 0.5% STR 2 BSA 6% NT d - s BSA 6% STR c N H BSA 4% NT 9 L s s BSA 4% STR e - BSA 4 INT d U s BSA 4% STR 6 8 10 12 14 Permeability X 10 (cm/h) Patent Application Publication Dec. 1, 2005 Sheet 9 of 12 US 2005/026.6061 A1 FG. 8 Maximum Flux of Cannabidiol from Saturated Mineral Oil Solutions 4%BSA 6%Brij98 4%BSA 6%Brij98 Subject 1 Subject 2 Subject 3 Receiver Fluid Patent Application Publication Dec. 1, 2005 Sheet 10 of 12 US 2005/026.6061 A1 Human Skin Permeation Profiles of Cannabidiol (CBD) with and without Lauroglycol-90(LG-90) and Transcutol-HP(TC-HP) -- CBD -- CBD+LG-90 45 OO OO - - CBD+TC-HP 23 FIG. 9 Human Skin Permeation Profiles of Cannabidiol (CBD) with and without Labrasol (LB), Labrafil 1944 CS (LF) and 800 Novol NF (OA) 6 O O 5 E S 5 O O geO 400 d S 3. O O h G 2 OO FIG 10 Patent Application Publication Dec. 1, 2005 Sheet 11 of 12 US 2005/026.6061 A1 s C O SE O 8 s 9. O (Tuffu)uOle Jueduoo eu Seld OHL Patent Application Publication Dec. 1, 2005 Sheet 12 of 12 US 2005/026.6061 A1 t O) . O) (u?ou) UOleUeoUOO euSed CEO US 2005/0266061 A1 Dec. 1, 2005 TRANSIDERMAL DELIVERY OF CANNABINOIDS 0009. A first aspect of the invention provides a method for relieving Symptoms associated with illness or associated CROSS-REFERENCE TO RELATED with the treatment of illness in a mammalian Subject, com APPLICATIONS prising the Steps of Selecting at least one cannabinoid from the group consisting of cannabinol, cannabidiol, nabilone, 0001. This application is a continuation-in-part applica levonantradol, (-)-HU-210, (+)-HU-210, 11-hydroxy-A- tion of co-pending U.S. patent application Ser. No. 10/032, THC, A-THC-11-oic acid, CP 55,940, and R(+)-WIN 163, filed Dec. 21, 2001, which claims priority to U.S. 55,212-2, Selecting at least one permeation enhancer from Provisional Patent Application No. 60/257,557, filed Dec. the group consisting of propylene glycol monolaurate, dieth 22, 2000, each of which is hereby incorporated herein by ylene glycol monoethyl ether, an oleoyl macrogolglyceride, reference. a caprylocaproyl macrogolglyceride, and an oleyl alcohol, and delivering the Selected cannabinoid and permeation BACKGROUND OF THE INVENTION enhancer transdermally to treat an illness. 0002) 1. Technical Field 0010) A second aspect of the invention provides an occlusive body for the delivery of cannabinoids, comprising 0003. The present invention generally relates to the trans an impermeable backing, a rate-controlling microporous dermal delivery of cannabinoids. More particularly, the membrane, Said backing and membrane defining a cavity present invention relates to a method and mode of transder therebetween, a cannabinoid disposed within the cavity, a mally delivering cannabinoids to treat various illnesses permeation enhancer disposed within the cavity, and a and/or Symptoms. Viscous flowable gel confined between the backing and the 0004 2. Background Art membrane within the cavity for immobilizing the cannab inoid and the permeation enhancer. 0005 The use of cannabinoids to treat medical illnesses 0011 A third aspect of the invention provides a method is of great interest to the medical community. Specifically, for increasing the concentration of cannabinoids or cannab illnesses Such as AIDS and cancer are often accompanied inoid metabolites in a Subject, comprising contacting the with a lack of appetite. Moreover, patients receiving cancer Subject's skin with a compound Selected from the group chemotherapy often experience nausea and vomiting side consisting of cannabinol, cannabidiol, nabilone, levonantra effects. Chronic pain (especially neuropathic pain), malig dol, (-)-HU-210, (+)-HU-210, 11-hydroxy-A-THC, nant tumors, Spasticity (in multiple Sclerosis and Spinal cord A-THC-11-oic acid, CP 55,940, and R(+)-WIN 55,212-2 injury), and or dystonia are additional therapeutic targets for and contacting the Subject's skin with a permeation enhancer cannabinoid therapy. The capability to control or eliminate Selected from the group consisting of propylene glycol these problems would greatly increase the quality of life for monolaurate, diethylene glycol monoethyl ether, an oleoyl many patients. macrogolglyceride, a caprylocaproyl macrogolglyceride, 0006. Heretofore, attempts have been made at adminis and an oleyl alcohol. tering the cannabinoid A-THC (Dronabinol) orally, in the 0012. The preferred embodiment of the present invention form of a capsule. However, Severely nauseated patients are is designed to Solve the problems herein described and other often not able to retain the capsule in their Stomachs long problems not discussed, which are discoverable by a skilled enough for the drug to take effect. This problem is com artisan. pounded by the fact that four to Six doses of the capsule must be taken around chemotherapy. Another issue with capsules, BRIEF DESCRIPTION OF THE DRAWINGS as well as Smoked marijuana, is that patients absorb the drug relatively rapidly (as compared to controlled drug delivery 0013 FIG. 1 is a cross-sectional view of an occlusive rates that a patch produces) and receive high drug concen body in accordance with the present invention. trations in their body. These high drug concentrations, or peak levels, are often associated with Serious psychoactive 0014 FIG. 2 is a permeation profile of showing the and other central nervous System side effects. delivery of a cannabinoid acroSS Skin. 0015 FIG. 3 is a bar graph showing permeability of skin 0007. In view of the above, there is a long felt need in the art for A-THC and other cannabinoids to be delivered Samples to a cannabinoid for various receiver Solutions. transdermally (across the skin). Preferably, Such cannab 0016 FIG. 4 is a bar graph showing permeability of skin inoids will be delivered by patch, bandage, topical formu Samples to a cannabinoid for various receiver Solutions. lation or the like and release the appropriate dose of can 0017 FIG.