Patent Document

This application claims the benefit of Provisional application Ser. No. 60/283,350, filed Apr. 13, 2001. 
    
    
     FIELD OF THE INVENTION 
     The present invention provides a pharmaceutical composition containing Tetrahydro Cannabinol (THC), having analgesic, anti-emetic, anti-nausea and anti-glaucoma properties, which is easily absorbed into the body at a steady rate to achieve a desired concentration in the bloodstream. Further, methods are provided for forming the pharmaceutical composition into a gel or powder, and for applying the gel or powder to form of the pharmaceutical composition to a transdermal patch for application to a human or animal body. 
     BACKGROUND OF THE INVENTION 
     Marijuana contains many compounds. The major active compound thereof has been identified as DELTA.Sup Tetrahydrocannabinol (THC), also known as DELTA 9-THC depending on the carbon numbering convention used. THC and other compounds in marijuana have, in addition to promoting psychoactivity, been reported to provide beneficial effects. There are many research publications reporting beneficial activities like analgesic, antiemetic, and antiglaucoma effects. It has also been found that a major contributor of these beneficial effects is THC. 
     THC is effective as an analgesic, antiemetic, in anorexia, and for treating the nausea and frequent vomiting caused by cancer chemotherapy. THC is currently being given only orally, but is occasionally ineffective when taken in this form. For example, a metaanalysis study revealed a poor or only partial response to THC in approximately 65% of 750 courses of oral therapy. Thus, high single doses are administered which may cause undesirable side effects such as sedation, confusion and anxiety. Such poor response to oral administration of THC may be due to the limited aqueous solubility of THC, its extensive first pass metabolism following oral administration, and the resulting low absolute bioavailability of THC (13% on an average). 
     In addition, it has been noted that fasting or food deprivation could decrease the rate of absorption of THC from sesame oil capsules currently available in the market. Previous studies have also reported that another limitation of orally administered THC is the large intersubject variability in absorption. For this reason it would be important to titrate the THC dose on an individual basis, since the drug has biphasic activity and a relatively narrow therapeutic index. 
     In an attempt to overcome such problems, transdermal patches have been proposed. For example, U.S. Pat. No. 6,113,940 discloses a “patch-like” device, utilizing a backing layer with a reservoir for holding the cannabis. The cannabis preparation uses, as a carrier for the cannabis preparation, a polymer matrix (the cannabis being suspended within the polymer matrix.). This method uses a “porous membrane, nonporous membrane, polymer film, polymer membrane.” 
     As with the above delivery system, U.S. Pat. No. 6,132,762 consists of a “patch-like” device containing a reservoir for holding a cannabis preparation. The reservoir therein holds a gel comprised of at least one member selected from the group consisting of guar gum, gelatin, carboxymethylcellulose, carrageenan and agar. Additional steps of heating and cooling the formulation are needed prior to its intended use of treating joint pain, muscle pain or arthritis. Further, the backing layer contemplates an adhesive for holding the backing layer on/against the skin of the user. 
     U.S. Pat. No. 6,328,992 addresses the problems discussed above by providing a cannabis preparation comprising a 1-50 weight percent cannabis, 1-15 weight percent skin enhancer and about 10-90 weight percent of a transdermal carrier that may, as with a number of the previously discussed patents, be placed on a patch, strip, bandage and covering for holding the preparation. The transdermal carrier may be comprised of natural rubber, viscoelastic semi-solid materials, hydrogels, thermoplastic polymers, elastomer, amnd thermoelastomers, as well as an oil selected mineral oils, vegetable oils, fish oils, animal oils, carbon tetrachloride, ethanolic solutions of resins and pyrahexyl mixtures. To achieve its desired purpose, the preparation, an aggregation of numerous cannabinols, is delivered at a rate of 17 ug/sq.cm./hour. 
     However, all of the above encounter various problems. In view of the problems encountered with oral administration of THC as discussed above, the present inventors performed extensive research in order to provide a safe, reliable and effective method of delivery of THC, and a composition to use in performing same. It was then unexpectedly discovered by the present inventors that the problems associated with oral administration of THC can be minimized by the administration of the pharmaceutical composition containing THC of the present invention, which provides sustained low doses of THC via a transdermal route. Further, it was found that forming the composition of the present invention into a gel formulation as disclosed herein, which is applied on the skin of the patient&#39;s body, or by applying as a transdermal patch on the skin of the patient&#39;s body, provides a very effective method of delivery of the active ingredient. 
     Specifically, a pharmaceutical composition is provided consisting of between 1-10% by weight of THC (including specifically delta-9 THC, and more generally, all cannabinols), 1-5% of enhancer, 0.5%-5% neutralizer and a carrier containing approximately 70% alcohol and 25% water, rather than the enumerated oils and elastomer materials disclosed in U.S. Pat. No. 6,328,992. Further, there is no need in the present invention to use polyisoprene elastomers and styrene-butadiene block co-polymers in the formulation. Rather, the present invention uses polymers of acrylic acid and polymers of acrylic acid crosslinked with allylpetnearythritol. This composition of the present invention is able to overcome the difficulties discussed above, and achieve the objects of the present invention, by providing a pharmaceutical composition containing a relatively low dose of delta-9 THC (but with the potential to use other cannibinols) with a delivery rate of only 10.8 ug/sq.cm./hour (to treat nausea and loss of appetite). 
     SUMMARY OF THE INVENTION 
     In view of the deficiencies associated with the oral methods of delivery of THC discussed above, as well as conventional transdermal patches, it is an object of the present invention to provide a pharmaceutical composition containing tetrahydrocannabinol, which can be applied via a transdermal/transcutaneous route to a patient. 
     In view of the above, in a first embodiment of the present invention, a pharmaceutical composition is provided comprising tetrahydrocannabinol (THC), ethanol, polyethylene glycol, polymethacrylic acid, isopropyl myristate, carbopol, triethanolamine, propylene glycol, and acetone. 
     In a second embodiment of the present invention according to the first embodiment above, a pharmaceutical composition is provided, comprising: 
     from greater than 0 to 5 wt % tetrahydrocannabinol (THC); 
     40-70 wt % ethanol; 
     3-10 wt % polyethylene glycol; 
     5-20 wt % polymethacrylic acid; 
     from greater than 0 to 5 wt % isopropyl myristate; 
     from greater than 0 to 10 wt % carbopol; 
     from greater than 0 to 5 wt % triethanolamine; 
     5-50 wt % propylene glycol; and 
     20-50 wt % acetone. 
     In a third embodiment of the present invention according to the first embodiment above, a pharmaceutical composition is provided, comprising: 
     about 0.5 to about 2 wt % tetrahydrocannabinol (THC); 
     about 65 wt % ethanol; 
     about 4.7 to about 5.7 wt % polyethylene glycol; 
     about 10 to about 14 wt % polymethacrylic acid; 
     about 0.5 to about 1 wt % isopropyl myristate; 
     from greater than 0 to about 5 wt % carbopol; 
     from about 0.47 to about 1 wt % triethanolamine; 
     from about 10 to about 30 wt % propylene glycol; 
     about 35 wt % acetone, and 
     water. 
     In a fourth embodiment of the present invention, a pharmaceutical composition is provided according to the first embodiment described above, further containing a permeation enhancer. 
     In a fifth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the pharmaceutical composition contains 2-10 wt % permeation enhancer. 
     In a sixth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the pharmaceutical composition contains about 5 wt % permeation enhancer. 
     In a seventh embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is caproic acid. 
     In an eighth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is caprylic acid. 
     In a ninth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is lauric acid. 
     In a tenth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is oleic acid. 
     In an eleventh embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is TWEEN 80. 
     In a twelfth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is selected from the group consisting of caproic acid, caprylic acid, lauric acid, oleic acid and TWEEN 80. 
     In a thirteenth embodiment of the present invention, a method of manufacturing the composition of the first through tenth embodiments described above is provided, the method comprising: 
     (a) combining/mixing ethanol, polyethylene glycol, polymethacrylic acid, tetrahydrocannabinol (THC), isopropyl myristate, carbopol, triethanolamine, optionally a permeation enhancer, propylene glycol, acetone, and water to form a complex; 
     (b) drying the complex using heat to form a dried complex; 
     (c) milling the dried complex to form a powder; and 
     (d) adding a lower alcohol to the powder to form a gel. 
     In a fourteenth embodiment of the present invention according to the thirteenth embodiment above, a method of manufacturing the composition of the first through eighth embodiments described above is provided, the method further comprising: 
     mixing the elements in step (a) at a temperature of from 25-70° C. 
     In a fifteenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising: 
     drying the complex is step (b) at a temperature of from 25-70° C. 
     In an sixteenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising: 
     performing the drying step (b) for 4-12 hours. 
     In an seventeenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising: 
     mixing the components in step (a) for 1-4 hours. 
     In an eighteenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising: 
     mixing the components in step (a) at a stirring rate of 60-300 RPM&#39;s. 
     In a nineteenth embodiment of the present invention, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising: 
     (a) combining/mixing ethanol, polyethylene glycol, polymethacrylic acid, tetrahydrocannabinol (THC), isopropyl myristate, carbopol, triethanolamine, a permeation enhancer, propylene glycol, acetone, and water at a temperature of from 25-70° C., and stirring same at a rate of 60-300 RPM&#39;s for 1-4 hours to form a complex; 
     (b) drying the complex at a temperature of from 25-70° C. for 1-4 hours to form a dried complex; 
     (c) milling the dried complex to form a powder; and 
     (d) adding a lower alcohol to the powder to form a gel. 
     In a nineteenth embodiment of the present invention, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising: 
     (a) combining/mixing ethanol, polyethylene glycol, polymethacrylic acid, tetrahydrocannabinol (THC), isopropyl myristate, carbopol, triethanolamine, a permeation enhancer, propylene glycol, acetone, and water at a temperature of from 40-60° C., and stirring same at a rate of 60-300 RPM&#39;s for 1-4 hours to form a complex; 
     (b) drying the complex at a temperature of from 40-60° C. for 1-4 hours to form a dried complex; 
     (c) milling the dried complex to form a powder; and 
     (d) adding a lower alcohol to the powder to form a gel. 
     In a twentieth embodiment of the present invention, a method of manufacturing the pharmaceutical composition of the first through twelfth embodiment described above is provided comprising: 
     mixing carbopol and polymethacrylic acid in ethanol to form a first solution; 
     mixing polyethylene glycol or polypropylene glycol in ethanol to form a second solution; 
     mixing the first and second solutions to form a third solution; 
     mixing isopropyl myristate and triethanolamine into the third solution as necessary; 
     mixing tetrahydrocannabinol with ethanol to form a fourth solution; 
     mixing the third and fourth solutions to form a pharmaceutical composition according to the present invention. 
     In an twenty first embodiment of the present invention, a transdermal/transcutaneous delivery system for THC is provided comprising the pharmaceutical composition of the first through twelfth embodiments described above. 
     A twenty second embodiment of the present invention is provided according to the twenty first embodiment described above, wherein the transdermal/transcutaneous delivery system further comprises a gel, patch or cloth for application onto the skin of a patient. 
     In twenty third embodiment of the present invention, a method for manufacturing the gel, patch or cloth of the twenty second embodiment described above is provided comprising addition of the gel formed in the second embodiment to a patch or cloth suitable for application in human or animal skin. 
     In a twenty fourth embodiment of the present invention, a method of manufacturing a transdermal patch or cloth containing a pharmaceutical composition containing THC is provided comprising addition of carbopol/poly methacrylic acid in Ethanol to Poly ethylene glycol or Propylene glycol in ethanol to form a first solution, mixing the first solution with a solution containing isopropyl myristate or triethanolamine to form a second solution, mixing the second solution with a mixture of tetrahydrocannabinol and ethanol to obtain a viscous solution or gel, and applying the viscous solution or gel to a transdermal patch or cloth for direct application to human or animal skin. 
     In the twenty-fifth embodiment of the present invention, a method of manufacturing gel containing a pharmaceutical composition containing tetrahydrocannibinol (Δ9 THC) is provided comprising a first step of mixing carbopol and trolamine in an ethanol:water mixture to form a first viscous solution, a second step of mixing the first viscous solution with a second solution containing ethanol and isopropyl myristate to obtain a third solution, and a third step comprising mixing the third solution with a fourth solution containing Δ9 THC and ethanol to obtain a gel for the direct application to human and/or animal skin. 
     In the twenty-sixth embodiment of the present invention, a method for manufacturing a pharmaceutical composition comprising a transdermal gel containing extracts of cannabis is provided comprising a first supercritical fluid extraction step wherein 9 THC is extracted from cannabis, a second step comprising dispersing the 9 THC in an ethanol:water mixture, a third step comprising adding trolamine to the ethanol:water mixture to form a first solution, a fourth step comprising mixing the first solution with a second solution containing ethanol and isopropyl myristate to form a third solution, wherein the third solution is a translucent gel for direct application to human skin. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is graph illustrating the standard curve for concentration of THC in a solution vs. the peak area. 
     FIG. 2 is a graph illustrating the diffusion profile (cumulative amount of THC permeated into a section of skin vs. time) for Formulation 3 of the present invention. 
     FIG. 3 is a graph illustrating the diffusion profile (cumulative amount of THC permeated into a section of skin vs. time) for Formulation 4 of the present invention. 
     FIG. 4 is a graph illustrating the diffusion profiled (cumulative amount of THC permeated into a section of skin vs. time) for Formulation 43 of the present invention. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Drug transportation rates through the skin are generally low, but therapeutic plasma levels can be achieved for drugs with suitable properties. That is, the drug should be highly potent, the daily dose requirement should be low, and therapeutic plasma levels should be ˜10 nanograms/ml. Plasma levels for therapeutic effects of THC are in the range of 10 nanograms/ml, making THC a suitable candidate for transdermal administration. 
     The source of THC and related compounds used are usually crude extracts of marijuana plants, the purified form of the drug being obtained by supercritical fluid extraction (SCFE) of the crude extracts or other suitable extraction methods. However, synthetic forms may be utilized. 
     Solubility of the active ingredient THC in the carrier is a very important consideration when preparing the pharmaceutical composition of the present invention, and should be assessed before making any transdermal delivery. Thus, solubility of THC alone was determined by the present inventors in a 70:30 water:alcohol (v/v) mixture, a 50:50 water:alcohol (v/v) mixture, as well in 30:70 water:alcohol (v/v) mixtures containing various permeation enhancers. The solubility tests for each of the samples was performed as follows: 
     Approximately 50-60 mg of THC was placed into each of six different centrifuge tubes. In each of these centrifuge tubes, 1 ml of ethanol:water solution (70:30 v/v) and 5% v/v (volume solute per volume of solvent) of permeation enhancer (caproic acid, caprylic acid, TWEEN 80, lauric acid and oleic acid, for each of test samples 3-7, respectively) was added thereto. The centrifuge tubes were then mechanically agitated at room temperature for 24 hours. The samples were then centrifuged at 3500 rpm for 5 minutes and filtered through a 0.2μ whatman filter. The filtrate was diluted and analyzed by HPLC. The solubility of THC in test samples 1-7 is given in Table I below. 
     
       
         
               
               
               
               
               
             
           
               
                 TABLE I 
               
               
                   
               
               
                   
                   
                   
                 Amount of 
                   
               
               
                 Test 
                 Amount of 
                   
                 THC in the 
                 Solvent 
               
               
                 Sample 
                 THC in diluted 
                 Dilution 
                 solubilized 
                 System 
               
               
                 Number 
                 sample 
                 factor 
                 sample 
                 alcohol:water 
               
               
                   
               
             
             
               
                 1. (THC 
                  57.14 ug/ml 
                 50 
                  2.86 mg/ml 
                 50:50 
               
               
                 alone) 
               
               
                 2. (THC 
                 404.22 ug/ml 
                 50 
                 20.21 mg/ml 
                 70:30 
               
               
                 alone) 
               
               
                 3. (THC &amp; 
                 344.65 ug/ml 
                 50 
                 17.23 mg/ml 
                 70:30 
               
               
                 Caproic acid) 
               
               
                 4. (THC &amp; 
                 809.48 ug/ml 
                 50 
                 40.47 mg/ml 
                 70:30 
               
               
                 Caprylic acid) 
               
               
                 5. (THC &amp; 
                 363.42 ug/ml 
                 50 
                 18.17 mg/ml 
                 70:30 
               
               
                 TWEEN 80) 
               
               
                 6. (THC &amp; 
                 738.86 ug/ml 
                 50 
                 36.94 mg/ml 
                 70:30 
               
               
                 Lauric acid) 
               
               
                 7. (THC &amp; 
                 244.44 ug/ml 
                 50 
                 12.22 mg/ml 
                 70:30 
               
               
                 Oleic acid) 
               
               
                   
               
             
          
         
       
     
     As shown above, Test Sample #1 was dissolved in a 50:50 ethanol:water solution, but after centrifugation and filtration, the concentrated solution was hazy. After analyzation, solubility in such a solution without permeation enhancer and a high concentration of water was found to be very low (2.86 mg/ml). When the solvent system was changed to 70:30 (ethanol: water) solubility of THC was increased appreciably (20.21mg/ml). However, it was found that the solubility of THC could be dramatically increased (almost doubled) be including either of two permeation enhancers, caprylic acid or lauric acid, in the THC containing solution. 
     The pharmaceutical composition of the present invention may be formed into a gel or powder composition for transdermal/transcutaneous application. The methods of manufacturing such variations of the pharmaceutical composition are shown below. However, the methods of manufacturing said composition should not be limited solely to the examples below. 
     Formulation of Powder: 
     Polymethacrylic acid (PMA 100,000) and polyethylene glycol (PEG-8000) were dissolved in ethanol in two different beakers utilizing a stirring waterbath (40-45° C.). The ratio of polymethacrylic acid to polyethylene glycol (PMA:PEG) was 2:1. Both the solutions were mixed until they formed a clear solution. The solutions were then cooled to room temperature. Water was then added to each of the two solutions in increments of 1 g, and at the addition of 10 g, the solution formed a whitish gel. The gel was collected and dried in an oven. The dried mass (PMA-PEG complex) was then ground to powder. A powder complex was prepared with PEG-20000, but the agglomerate was so hard that it was difficult to grind to powder. Therefore, PEG-8000 was used for making the complex to get a free flowing powder. 
     A 10% solution was made by dissolving the PMA-PEG complex made above in a 65:35 acetone:ethanol mixture using continuous stirring. The resulting solution formed a viscous solution. 
     THC (tetrahydrocannabinol) solution was then prepared by dissolving THC in ethanol. This THC solution was then added to the PMA-PEG complex solution produce above, as well as with a permeation enhancer. Initially, two formulations (formulations 1 &amp;2) were prepared (containing 25 mg/ml and 14.6 mg/ml of THC each, respectively) and analyzed to determine the percent recovery. Later six formulations (formulations 3 to 8) were prepared containing differing amounts of THC alone and in combination with permeation enhancers. Another PMA of low molecular weight 15000 was also used forming a complex with PEG-8000. Six more formulations (Formulations 9 to 14) were prepared using the complex powder and permeation enhancer. For these six formulations 9-14, the ratio of the solvent system of acetone:ethanol: water was 65:25:10, respectively. 
     A powder complex could not be prepared by using Polyacrylic acid (PAA 450,000) and PEG 8000 because a gel was instantly formed and, after drying, the gel formed a plastic-like mass which was difficult to grind. 
     All of the above formulations 1-14 were then analyzed by HPLC. The results of the HPLC analysis are shown below in Table II. 
     
       
         
               
               
               
               
               
             
           
               
                 TABLE II 
               
               
                   
               
               
                   
                   
                   
                 Amount of 
                   
               
               
                   
                 Permeation 
                   
                 THC 
                 Percent 
               
               
                 Test Product 
                 enhancer: 
                 Polymers: 
                 added: 
                 recovery 
               
               
                   
               
             
             
               
                 Formulation-1 
                 — 
                 PMA100000- 
                 14.16 
                 79.02 
               
               
                   
                   
                 PEG 8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-2 
                 — 
                 PMA100000- 
                 25.1 
                 71.39 
               
               
                   
                   
                 PEG 8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-3 
                 — 
                 PMA100000- 
                 10.16 
                 84.61 
               
               
                   
                   
                 PEG 8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-4 
                 Oleic acid 
                 PMA100000- 
                 10 mg/ml 
                 98.74 
               
               
                   
                   
                 PEG 8000 
               
               
                   
                   
                 complex 
               
               
                 Formulation-5 
                 Lauric acid 
                 PMA100000- 
                 10 mg/ml 
                 99.71 
               
               
                   
                   
                 PEG 8000 
               
               
                   
                   
                 complex 
               
               
                 Formulation-6 
                 Caproic acid 
                 PMA100000- 
                 11.96 
                 89.16 
               
               
                   
                   
                 PEG 8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-7 
                 Caprylic acid 
                 PMA100000- 
                 9.46 
                 91.15 
               
               
                   
                   
                 PEG 8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-8 
                 TWEEN 80 
                 PMA100000- 
                 10.03 
                 93.03 
               
               
                   
                   
                 PEG 8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-9 
                 Lauric acid 
                 PMA15000- 
                 10.46 
                 88.14 
               
               
                   
                   
                 PEG8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-10 
                 Oleic acid 
                 PMA15000- 
                 10.43 
                 84.75 
               
               
                   
                   
                 PEG8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-11 
                 Caprylic acid 
                 PMA15000- 
                 10.46 
                 88.81 
               
               
                   
                   
                 PEG8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-12 
                 Caproic acid 
                 PMA15000- 
                 10.36 
                 86.1 
               
               
                   
                   
                 PEG8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-13 
                 Tween 80 
                 PMA15000- 
                 10.26 
                 86.5 
               
               
                   
                   
                 PEG8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                 Formulation-14 
                 — 
                 PMA15000- 
                 9.26 
                 82.2 
               
               
                   
                   
                 PEG8000 
                 mg/ml 
               
               
                   
                   
                 complex 
               
               
                   
               
             
          
         
       
     
     The following gel and film formulations were prepared with PMA (100000) and PEG (8000). 
     Formulation of Gel: 
     1.26 g of polymethacrylic acid (PMA 100,000) was dissolved in a 75% v/v alcohol: 25% v/v water mixture using continuous stirring at 45-50C. After 2 hours of continuous stirring, a viscous solution was formed. Then, about 2.0 g of PEG-8000 was dissolved in alcohol with continuous stirring in a water bath at a temperature 45-50° C.). Both the PMA and PEG solutions were mixed until they formed a clear solution. The clear solution was kept at room temperature. The PMA: PEG ratio was 1.25:2.74 mg of THC was then dissolved in 1 ml of alcohol, and the resulting THC solution was then poured into the viscous PMA:PGA complex solution, and continuously stirred. A clear gel was formed (Formulation-16). Five more formulations (Formulations 17 to 21) were then prepared in the same method. However, a 5 wt % of permeation enhancer was added to each of formulations 17-21. 
     Five more formulations (Formulation 28 to 32) were prepared using a solution having a PMA:PEG ratio of 2:1. All these formulations were then subjected to HPLC analysis to determine the percent recovery and physical appearance of the gel formulation, the results of these HPLC tests being shown in Table III below: 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE III 
               
               
                   
               
               
                   
                   
                   
                 Physical 
                   
               
               
                   
                   
                   
                   
                 Percent 
               
               
                   
                 Permeation 
                 Amount of 
                 appearance 
                 re- 
               
               
                 Test product 
                 enhancer: 
                 THC added: 
                 of gel: 
                 covery: 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Formulation-16 
                 — 
                 74.0 mg 
                 Transparent and 
                 88.6 
               
               
                   
                   
                   
                 light yellow in 
               
               
                   
                   
                   
                 color 
               
               
                 Formulation-17 
                 Lauric acid 
                 99.8 mg 
                 Transparent and 
                 103.56 
               
               
                   
                   
                   
                 reddish yellow 
               
               
                   
                   
                   
                 in color 
               
               
                 Formulation-18 
                 Tween 80 
                 97.8 mg 
                 Translucent, 
               
               
                   
                   
                   
                 very light yellow 
               
               
                   
                   
                   
                 and TWEEN 80 
               
               
                   
                   
                   
                 separated 
               
               
                 Formulation-19 
                 Oleic acid 
                 75.5 mg 
                 Translucent and 
                 63.22 
               
               
                   
                   
                   
                 very light yellow 
               
               
                   
                   
                   
                 in color 
               
               
                 Formulation-20 
                 Caprylic 
                 70.00 mg 
                 Transparent and 
                 89.61 
               
               
                   
                 acid 
                   
                 reddish yellow 
               
               
                   
                   
                   
                 in color 
               
               
                 Formulation-21 
                 Caproic acid 
                 76.5 mg 
                 Transparent and 
                 92.98 
               
               
                   
                   
                   
                 reddish yellow 
               
               
                 Formulation-28 
                 Oleic acid 
                 80.5 mg 
                 Translucent and 
                 81.29 
               
               
                   
                   
                   
                 gray colored 
               
               
                 Formulation-29 
                 Lauric acid 
                 83.0 mg 
                 Translucent and 
                 89.41 
               
               
                   
                   
                   
                 light yellow in 
               
               
                   
                   
                   
                 color 
               
               
                 Formulation-30 
                 Caprylic 
                 85.5 mg 
                 Transparent and 
                 82.27 
               
               
                   
                 acid 
                   
                 light yellow in 
               
               
                   
                   
                   
                 color 
               
               
                 Formulation-31 
                 Caproic acid 
                 89.3 mg 
                 Transparent and 
                 84.47 
               
               
                   
                   
                   
                 light yellow in 
               
               
                   
                   
                   
                 color 
               
               
                 Formulation-32 
                 — 
                 78.6 mg 
                 Transparent and 
                 84.30 
               
               
                   
                   
                   
                 light yellow in 
               
               
                   
                   
                   
                 color 
               
               
                   
               
             
          
         
       
     
     Gel formulations were prepared with Polymethacrylic acid (PMA 15000) and Polyacrylic acid (60000). Both of these compounds are commercially available as a sodium salt solution. However, formulations containing these compounds failed to form a gel after mixing with PEG-8000 solution. Polyacrylic acid (450,000) formed a gel with PEG-8000. But, it was an opaque gel, and not used since all the gel formulations should preferably be transparent. 
     Initially, two placebo gel formulations #1 and #2, for use in vivo testing, were prepared using two different concentrations of Carbopol as follows: 
     Placebo Gel Formulation #1 
     Carbomer 934 (lot# 00-218) 0.1 g 
     Deionized water 5.41 g 
     Isopropyl myristate (Lot#00-219) 0.148 g 
     Alcohol (200 Proof) 14.2 g 
     Trolamine (triethanolamine) (lot# 00-220) 0.095 g 
     Placebo Gel Formulation #2 
     Carbomer 934 (lot# 00-218) 0.105 g 
     Propylene glycol (lot# 98-048) 8.81 g 
     Sodium hydroxide (0.5% in propylene glycol) 0.15 g 
     Alcohol (200 proof) 1.0 g 
     However, Placebo Gel Formulation #1 formed a turbid solution rather than a gel. Formulation #2 did form a gel. 
     Five more Formulations 33-37 were then prepared by adding carbomer to about 8.8 g of propylene glycol, the solution then being continuously stirred in a container overnight. Once the carbomer went into solution, permeation enhancer and THC were dissolved in 0.5 ml alcohol, and the THC solution then mixed well with carbomer solution and stirred for 15 minutes. The resulting gel formulations 33-37 were then analyzed by HPLC to determine the percent recovery (the amount of THC remaining in the gel formulation after preparation thereof). The results of these HPLC tests are shown below in Table IV. 
     
       
         
               
               
               
               
               
               
             
           
               
                 TABLE IV 
               
               
                   
               
               
                   
                 Amount 
                 Name and amount of 
                   
                   
                 Physical 
               
               
                   
                 of 
                 permeation enhancer 
                 Amount of 
                 Percent 
                 appearance 
               
               
                 Test product 
                 carbomer: 
                 added: 
                 THC added: 
                 recovery: 
                 of gel: 
               
               
                   
               
             
             
               
                 Formulation-33 
                 0.103 gm 
                 — 
                 0.075 gm 
                 77.39 
                 Transparent 
               
               
                 Formulation-34 
                 0.1043 gm 
                 Lauric acid, 0.101 gm 
                 0.0695 gm 
                 84.39 
                 Transparent 
               
               
                 Formulation-35 
                 0.100 gm 
                 Oleic acid, 0.0958 gm 
                 0.089 gm 
                 93.15 
                 Transparent 
               
               
                 Formulation-36 
                 0.1043 gm 
                 Caproic acid, 
                 0.075 gm 
                 88.83 
                 Transparent 
               
               
                   
                   
                 0.0911 gm 
               
               
                 Formulation-37 
                 0.106 gm 
                 Caprylic acid, 
                 0.092 gm 
                 94.98 
                 Transparent 
               
               
                   
                   
                 0.0966 gm 
               
               
                   
               
             
          
         
       
     
     Five more gel formulations 38-42 were prepared according to the above method, and in addition, adding polymethacrylic acid to the solution. All the formulations were desirably transparent. Gel formulations 38-42 were then subjected to HPLC analysis to determine percent recovery, the results of these tests being shown in Table V below: 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE V 
               
               
                   
               
               
                   
                   
                 Name and 
                   
                   
                   
               
               
                   
                 Amount of 
                 amount of 
                   
                   
                 Physical 
               
               
                   
                 polymethacrylic 
                 permeation 
                 Amount of 
                 Percent 
                 appearance of 
               
               
                 Test product 
                 acid: 
                 enhancer: 
                 THC: 
                 recovery: 
                 gel: 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Formulation-38 
                 1.02 gm 
                 — 
                 0.055 gm 
                 101.06 
                 Transparent 
               
               
                 Formulation-39 
                 1.0 gm 
                 Oleic acid 
                 0.054 gm 
                 95.65 
                 Transparent 
               
               
                   
                   
                 0.299 gm 
               
               
                 Formulation-40 
                 1.001 gm 
                 Caproic acid 
                 0.056 gm 
                 94.87 
                 Transparent 
               
               
                   
                   
                 0.3 gm 
               
               
                 Formulation-41 
                 1.002 gm 
                 Caprylic acid 
                 0.060 gm 
                 82.82 
                 Transparent 
               
               
                   
                   
                 0.297 gm 
               
               
                 Formulation-42 
                 1.0 gm 
                 Lauric acid 
                 0.066 gm 
                 96.92 
                 Transparent 
               
               
                   
                   
                 0.301 gm 
               
               
                   
                   
                 (1% 
               
               
                   
                   
                 solution) 
               
               
                   
               
             
          
         
       
     
     Formulation of Film of THC: 
     About 1.0 g of PMA (100,000) was dispersed in 7.5 ml of alcohol and 2.5 ml of water, the resulting mixture then being continuously stirred for about 2 hours. Once the PMA went into solution, about 1.0 g of PEG 8000 was dissolved in 2 ml of alcohol, and this PEG solution was added to the PMA solution and continuously stirred overnight. After overnight stirring, a clear, viscous solution was obtained. 
     Five PMA-PEG complex solutions were prepared according to the method above, and 5% w/w permeation enhancer was added to the solution. THC was then dissolved in 1 ml of alcohol, the resulting THC solution was added to the PMA-PEG complex solution, and the mixture was continuously stirred for 20 minutes to form Formulations 23-27. Each of Formulations 23-27 were then individually spread on a petri dish covered with para-film and dried in a drying oven at a temperature below 35° C. to form a film formulation. The prepared films were translucent, and the thickness thereof varied from 0.25 mm to 0.45 mm. A fixed area of film for each Formulation 23-27 was then cut and subjected to HPLC analysis, the results of the HPLC analysis being shown in Table VI below: 
     
       
         
               
               
               
               
               
               
             
           
               
                 TABLE VI 
               
               
                   
               
               
                   
                 Perm- 
                   
                   
                   
                   
               
               
                   
                 eation 
                 Amount 
                 Amount of 
                 Amount 
                 Percent 
               
               
                   
                 enhancer 
                 of PMA 
                 PEG 
                 THC 
                 re- 
               
               
                 Test product 
                 (5% w/w) 
                 Added: 
                 Added: 
                 Added: 
                 covery: 
               
               
                   
               
             
             
               
                 Formulation-23 
                 Caprylic 
                 1.021 gm 
                 1.024 gm 
                 67.4 gm 
                 70.96 
               
               
                   
                 acid 
               
               
                 Formulation-24 
                 Caproic 
                 1.00 gm 
                 1.01 gm 
                 81.7 mg 
                 59.49 
               
               
                   
                 acid 
               
               
                 Formulation-25 
                 Oleic 
                 1.012 gm 
                 1.014 gm 
                 66.0 mg 
                 62.52 
               
               
                   
                 acid 
               
               
                 Formulation-26 
                 Lauric 
                 1.017 gm 
                 1.012 gm 
                 62.4 mg 
                 69.09 
               
               
                   
                 acid 
               
               
                 Formulation-27 
                 — 
                 1.013 gm 
                 1.027 gm 
                 63.3 Mg 
                 72.38 
               
               
                   
               
             
          
         
       
     
     Each of the film formulations 23 to 27 shown above were used for in vitro skin permeation studies. 
     In Vitro Skin Permeation Studies: 
     Permeation experiments were assessed using a Franz diffusion assembly. Both rat and human skin were used for the study. Initially, full thickness normal rat skin was used. Hairs were removed from the skin using a clipper. Before mounting into the diffusion cell, the subcutaneous fat layer was separated from the skin. It was cut according to the size of the donor cell, with a surface area of 0.64 cm 2 . The skin was mounted in between the donor and receiver compartment. The receiver compartment contained a 50% hydro-alcoholic (water:ethanol) solution for ensuring the pseudo-sink conditions by increasing the solubility of THC in the medium. Temperature was maintained at 37° C. Two formulations, Formulations 3 and 4, were tested to determine the permeation ability of the formulations into skin. 
     Formulation 3 contained 8.6 mg/ml of THC, and Formulation 4 contained 9.86 mg/ml of THC. The donor compartment contained 0.5ml of the formulation, and the receiver compartment contained 5.1 ml of the hydro-alcoholic solutions. Two hundred microliters (200 μl) of sample was withdrawn and replaced with fresh amount of fluid. Samples were withdrawn from the tested skin at 0, 1, 2, 3, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 42, 43, 44, 45, 46, 47, and 48 hours. The results of the permeations tests are shown graphically herein in FIGS. 2 and 3. 
     Samples were then analyzed by HPLC. The results of the HPLC analysis for Formulation 3 is shown in Table VII below, and the results of the HPLC analysis of Formulation 4 is shown in Table VIII below: 
     
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE VII 
               
               
                   
               
               
                 Time 
                 Peak 
                 Conc. 
                 Amt. perm. 
                 Cumu/sqcm 
                 Flux 
                   
               
               
                 (Hours) 
                 Area 
                 (ug/mL) 
                 (mg) 
                 0 
                 0 
                 % Amt. perm. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 1 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 2 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 3 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 16 
                 268534 
                 7.26 
                 0.037 
                 0.05785062 
                 0.00445 
                 0.861032542 
               
               
                 18 
                 323474 
                 8.77 
                 0.046 
                 0.07213067 
                 0.00714 
                 1.073572689 
               
               
                 19 
                 349958 
                 9.49 
                 0.052 
                 0.08066048 
                 0.00853 
                 1.200528071 
               
               
                 20 
                 395377 
                 10.74 
                 0.060 
                 0.09355707 
                 0.012897 
                 1.392477294 
               
               
                 21 
                 427690 
                 11.63 
                 0.067 
                 0.10397773 
                 0.010421 
                 1.547575536 
               
               
                 22 
                 458520 
                 12.47 
                 0.073 
                 0.11435121 
                 0.010373 
                 1.70197149 
               
               
                 23 
                 480791 
                 13.08 
                 0.079 
                 0.12311778 
                 0.008767 
                 1.832450688 
               
               
                 24 
                 534427 
                 14.55 
                 0.089 
                 0.13893254 
                 0.015815 
                 2.067833201 
               
               
                 25 
                 564912 
                 15.39 
                 0.096 
                 0.15014572 
                 0.011213 
                 2.234726962 
               
               
                 43 
                 1432401 
                 39.19 
                 0.221 
                 0.34461227 
                 0.010804 
                 5.129112784 
               
               
                 44 
                 1431227 
                 39.16 
                 0.228 
                 0.35660281 
                 0.011991 
                 5.307576646 
               
               
                 45 
                 1414268 
                 38.69 
                 0.234 
                 0.36513225 
                 0.008529 
                 5.434526478 
               
               
                 46 
                 1410365 
                 38.59 
                 0.241 
                 0.37637069 
                 0.011238 
                 5.601796298 
               
               
                 47 
                 1391135 
                 38.06 
                 0.246 
                 0.38422476 
                 0.007854 
                 5.718694174 
               
               
                 48 
                 1413615 
                 38.68 
                 0.254 
                 0.39611817 
                 0.011893 
                 5.895712372 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE VIII 
               
               
                   
               
               
                 Time 
                 Peak 
                 Conc. 
                 Amt. perm. 
                 Cumu/sqcm 
                 Flux 
                   
               
               
                 (Hours) 
                 Area 
                 (ug/ml) 
                 (mg) 
                 0 
                 0 
                 % Amt. perm. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 1 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 2 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 3 
                 0 
                 0.00 
                 0 
                 0 
                 0 
                 0 
               
               
                 16 
                 173295 
                 4.65 
                 0.024 
                 0.03702877 
                 0.0028484 
                 0.480698018 
               
               
                 18 
                 237486 
                 6.41 
                 0.034 
                 0.05251479 
                 0.007743 
                 0.68173357 
               
               
                 19 
                 269662 
                 7.29 
                 0.039 
                 0.0615518 
                 0.009037 
                 0.799049766 
               
               
                 20 
                 305780 
                 8.28 
                 0.046 
                 0.07172651 
                 0.0101747 
                 0.931135215 
               
               
                 21 
                 352797 
                 9.57 
                 0.054 
                 0.0845937 
                 0.0128672 
                 1.09817378 
               
               
                 22 
                 375114 
                 10.18 
                 0.059 
                 0.0924639 
                 0.0078702 
                 1.200342689 
               
               
                 23 
                 396636 
                 10.77 
                 0.064 
                 0.10035163 
                 0.0078877 
                 1.302739152 
               
               
                 24 
                 445259 
                 12.11 
                 0.073 
                 0.1143489 
                 0.0139973 
                 1.484448136 
               
               
                 25 
                 474235 
                 12.90 
                 0.080 
                 0.12446767 
                 0.0101188 
                 1.61580746 
               
               
                 43 
                 901926 
                 24.64 
                 0.142 
                 0.22200489 
                 0.0054187 
                 2.882010786 
               
               
                 44 
                 884752 
                 24.17 
                 0.145 
                 0.2259493 
                 0.0039444 
                 2.933216102 
               
               
                 45 
                 880096 
                 24.04 
                 0.149 
                 0.23248325 
                 0.0065339 
                 3.018038091 
               
               
                 46 
                 871258 
                 23.80 
                 0.152 
                 0.23806297 
                 0.0055797 
                 3.090472659 
               
               
                 47 
                 871824 
                 23.81 
                 0.157 
                 0.2456229 
                 0.0075599 
                 3.188613655 
               
               
                 48 
                 867988 
                 23.71 
                 0.162 
                 0.25306393 
                 0.007441 
                 3.285211246 
               
               
                   
               
             
          
         
       
     
     Further, in vitro skin permeation studies were conducted using Formulation #43, a transdermal gel, which was prepared as follows: 
     Pemulen was first dissolved in a mixture of ethanol and water, triethanolamine was added thereto, and the resultant mixture was mixed well to firm a first pemulen solution. Tetrahydrocannabinol (THC) was then dissolved in a portion of alcohol, and isopropylmyristate was then added thereto, to form a second THC solution. Both the first pemulen solution and the second THC solution were mixed for 30 minutes, and a transparent gel was subsequently formed. 
     This gel had a pH of 6.0. There were no gritty particles. An irritation study was conducted for the formulation on a rat, the results of this study indicating that the formulation did not induce any redness associated with erythema when applied transdermlly. The Formulation #43 had the following formula: 
     Tetrahydrocannbinol(Δ9 THC) 1.0% 
     Triethanolamine 0.5% 
     Isopropylmyristate 1.0% 
     Pemulen (polymers of acrylic acid) 1.0% 
     Ethanol-200 proof 70.0% 
     Purified water 26.5.0% 
     Permeation experiments on rat skin were performed for Formulation 43, as described above for Formulations 3 and 4. The results of these permeation experiments are shown below in Table IX. 
     
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE IX 
               
               
                   
               
               
                 Time 
                 Peak 
                 Conc. 
                 Amt. perm. 
                 Cumu. 
                 Flux 
                 % Amt. 
               
               
                 (Hours) 
                 Area 
                 (ug/mL) 
                 (mg) 
                 mg/sqcm 
                 mg/sq.cm.hr 
                 perm 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 0 
                 0 
                   
                   
                 0 
                   
                   
               
               
                 2 
                 98.3 
                  2.599688069 
                 0.01351838 
                 0.02112247 
                 0.010561233 
                 0.26769 
               
               
                 17 
                 942.5 
                 24.54406031 
                 0.12814905 
                 0.20023289 
                 0.011940695 
                 2.5376 
               
               
                 20 
                 1057.24 
                 27.52664414 
                 0.1485673 
                 0.2321364 
                 0.010634504 
                 2.94193 
               
               
                 26 
                 1460.97 
                 38.02131531 
                 0.20864492 
                 0.32600768 
                 0.015645213 
                 4.13158 
               
               
                 41 
                 2002.67 
                 52.10241747 
                 0.28947091 
                 0.4522983 
                 0.008419374 
                 5.7321 
               
               
                 44 
                 2064.32 
                 53.70496491 
                 0.30822464 
                 0.481601 
                 0.009767568 
                 6.10346 
               
               
                 47 
                 2235.19 
                 58.14660775 
                 0.34206218 
                 0.53447215 
                 0.017623717 
                 6.77351 
               
               
                   
               
             
          
         
       
     
     The data presented above in Table IX was then graphed to illustrate the permeation of THC into the skin over time. This graph is shown in FIG. 4 herein. 
     Thus, after extensive experimentation, the present inventors discovered that transdermal THC administration overcomes the problem of variation in absorption and metabolism associated with oral administration. Further, it was unexpectedly discovered that transdermal administration increases bioavailability and the efficacy of THC by avoiding the liver first-pass inactivation, which significantly lowers the plasma, and brain concentration, of THC administered orally. Therefore, small doses of THC can be administered to a patient, resulting in fewer side effects, and the drug is more tolerable and more effective in treating patients. 
     Additionally, as THC is heavily metabolized by the liver, transdermal/transcutaneous administration of THC, as opposed to oral administration, may help to reduce drug-drug interactions with the other drugs that are also extensively metabolized by the liver. The in vitro skin permeation data shown in FIGS. 2-4 suggests that zero order kinetics were followed from all formulations, and that 10.8 g/sq.cm./hr transdermal gel delivery is feasible to achieve the desired systemic effect. A steady state flux of 8.8 g/sq.cm./hr was estimated based on the total clearance and minimum effective concentration. 
     The pharmaceutical composition of the present invention is useful, but not limited to, treating pain, nausea, vomiting (particularly that associated with chemotherapy in cancer patients), glaucoma, arthritis, dementia, multiple sclerosis, and for deterring weight loss in AIDS patients.

Technology Category: 1