Use of cannabidiol prodrugs in topical and transdermal administration with microneedles

Abstract

Described herein are microneedle drug delivery systems comprising a pharmaceutical compositions comprising pharmaceutically active agents (e.g., cannabidiol and prodrugs of cannabidiol) and microneedle arrays suitable for local and systemic delivery of the active agent to a mammal. Also described herein are methods of using a microneedle transdermal or topical drug delivery systems comprising pharmaceutical compositions, comprising cannabidiol and prodrugs of cannabidiol, and microneedle arrays in the treatment disease, including pancreatitis and pancreatic cancer.

1 . A microneedle drug delivery system for transdermal or topical administration of a cannabidiol prodrug to a mammal comprising:
 a) a pharmaceutical composition comprising a cannabidiol prodrug having the formula:   
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  can be the same or different and are each independently selected from the group consisting of: a hydrogen, an ester, an oxygenated ester, an oxaester, pegylated ester, a hydroxylated ester, an alkyl ester, an amino ester, an alkylamino ester, a dialkylamino ester, a trialkylammonium ester, a carbonate, an alkyl carbonate, an amino carbonate, an alkylamino carbonate, a dialkylamino carbonate, a trialkylammonium carbonate, a carbamate, an alkyl carbamate, an amino carbamate, an alkylamino carbamate, a dialkylamino carbamate, a trialkylammonium carbamate, a substituted phosphate ester, an unsubstituted phosphate ester, an unsubstituted diphosphate ester, a substituted diphosphate ester, an unsubstituted triphosphate ester, a substituted triphosphate ester, a phosphonate ester, a substituted sulfate esters, an unsubstituted sulfate esters, a sulphonate ester, an alpha-acyloxyalkyl, an alpha-phosphoryloxyalkyl, an alpha-sulphonyloxyalkyl; and wherein R 1  and R 2  cannot both be a hydrogen atom; and 
         
         b) a microneedle array. 
       
     
     
         2 . The drug delivery system of  claim 1 , wherein the cannabidiol prodrug is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The drug delivery system of  claim 1 , wherein the cannabidiol prodrug selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X −  is a counter ion derived from pharmaceutically acceptable acids. 
       
     
     
         4 . The drug delivery system of  claim 1 , wherein the cannabidiol prodrug is present in an amount of about 0.1% to about 50% (wt/wt) of the pharmaceutical composition. 
     
     
         5 . The drug delivery system of  claim 1 , wherein the cannabidiol prodrug is present in an amount of about 0.1% to about 40% (wt/wt) of the pharmaceutical composition. 
     
     
         6 . The drug delivery system of  claim 1 , wherein the cannabidiol prodrug is present in an amount of about 5% to about 30% (wt/wt) of the pharmaceutical composition. 
     
     
         7 . The drug delivery system of  claim 1 , wherein the cannabidiol prodrug is present in an amount of about 10% to about 20% (wt/wt) of the pharmaceutical composition. 
     
     
         8 . The drug delivery system of  claim 1 , wherein the pharmaceutical composition is in a form of a hydrogel. 
     
     
         9 . The drug delivery system of  claim 8 , wherein the hydrogel is incorporated into a matrix- or reservoir-type patch. 
     
     
         10 . The drug delivery system of  claim 1 , wherein the pharmaceutical composition further comprises a COX inhibitor selected from the group consisting of: a non-specific COX inhibitor, a COX-1 inhibitor and a COX-2 inhibitor. 
     
     
         11 . The drug delivery system of  claim 9 , wherein the non-specific COX inhibitor is selected from the group consisting of: aspirin, diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, olsalzine, oxaprozin, piroxicam, salsalate, sulfasalazine, sulindac and tolmetin. 
     
     
         12 . The drug delivery system of  claim 9 , wherein the COX-1 inhibitor is selected from the group consisting of: mofezolac, SC-560 and FR122047. 
     
     
         13 . The drug delivery system of  claim 9 , wherein the COX-2 inhibitor is selected from the group consisting of: etodolac, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib and etoricoxib. 
     
     
         14 . The drug delivery system of  claim 1 , wherein the pharmaceutical composition further comprises is an antioxidant selected from the group consisting of: citric acid, butylated hydroxytoluene, ascorbic acid, glutathione, retinol, α-tocopherol, β-carotene, α-carotene, ubiquinone, butylated hydroxyanisole, ethylenediaminetetraacetic acid, selenium, zinc, lignan, uric acid, lipoic acid, and N-acetylcysteine. 
     
     
         15 . The drug delivery system of  claim 1 , wherein the pharmaceutical composition further comprises a penetration enhancer selected from the group consisting of: isostearic acid, octanoic acid, oleic acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropyl myristate, butyl stearate, methyl laurate, diisopropyl adipate, glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ethers, polyethylene oxide dimethyl ethers, dimethyl sulfoxide, glycerol, acetoacetic ester, N-alkylpyrrolidone, terpenes, n-octanol, sodium oleate, D-limonene, monoolein, cineol, oleyl oleate, ethanol, propanol, butanol, 2-butanol, pentanol, 2-pentanol, hexanol, octanol, nonanol, decanol, benzyl alcohol, Polyxamer 231, Polyxamer 182, Polyxamer 184, Polysorbate 20, Polysorbate 60, Brij 30, Brij 93, Brij 96, Brij 99, Span 20, Span 40, Span 60, Span 80, Span 85, Tween 20, Tween 40, Tween 60, Tween 80), Myrj 45, Myrj 51, Myrj 52) and Miglyol 840. 
     
     
         16 . The drug delivery system of  claim 15 , wherein the penetration enhancer is present in an amount of about 0.1% to about 40% (wt/wt) of the pharmaceutical composition. 
     
     
         17 . The drug delivery system of  claim 15 , wherein the penetration enhancer is present in an amount of about 0.1% to about 30% (wt/wt) of the pharmaceutical composition. 
     
     
         18 . The drug delivery system of  claim 15 , wherein the penetration enhancer is present in an amount of about 1% to about 20% (wt/wt) of the pharmaceutical composition. 
     
     
         19 . The drug delivery system of  claim 15 , wherein the penetration enhancer is present in an amount of about 1% to about 10% (wt/wt) of the pharmaceutical composition. 
     
     
         20 . The drug delivery system of  claim 1 , wherein the pharmaceutical composition further comprises a lower alcohol selected from the group consisting of: ethanol and isopropanol. 
     
     
         21 . The drug delivery system of  claim 1 , wherein the pharmaceutical composition delivers a therapeutically effective amount of the cannabidiol prodrug over a period of time selected from the group consisting of: about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 5 days, about 6 days or about 7 days. 
     
     
         22 . A method of treating a disease state in a mammal in need thereof, comprising the step of:
 (a) applying a microneedle drug delivery system as described in any of  claims 1  to  20 ;
 wherein the disease state is selected from the group consisting of: acute pancreatitis, chronic pancreatitis, pancreatic cancer, nausea, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, systemic lupus erythematosus, melanoma, anti-inflammatory, anti-convulsant, anti-psychotic, antioxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, osteoarthritis, rheumatoid arthritis, synovitis, juvenile rheumatoid arthritis and inhibition of hair growth. 
   
     
     
         23 . A microneedle drug delivery system for transdermal or topical administration of a cannabidiol prodrug to a mammal comprising:
 (a) a pharmaceutical composition comprising
 (i) about 0.1% to about 40% of a cannabidiol prodrug having the formula: 
   
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  can be the same or different and are each independently selected from the group consisting of: a hydrogen, an ester, an oxygenated ester, an oxaester, pegylated ester, a hydroxylated ester, an alkyl ester, an amino ester, an alkylamino ester, a dialkylamino ester, a trialkylammonium ester, a carbonate, an alkyl carbonate, an amino carbonate, an alkylamino carbonate, a dialkylamino carbonate, a trialkylammonium carbonate, a carbamate, an alkyl carbamate, an amino carbamate, an alkylamino carbamate, a dialkylamino carbamate, a trialkylammonium carbamate, a substituted phosphate ester, an unsubstituted phosphate ester, an unsubstituted diphosphate ester, a substituted diphosphate ester, an unsubstituted triphosphate ester, a substituted triphosphate ester, a phosphonate ester, a substituted sulfate esters, an unsubstituted sulfate esters, a sulphonate ester, an alpha-acyloxyalkyl, an alpha-phosphoryloxyalkyl, an alpha-sulphonyloxyalkyl; and wherein R 1  and R 2  cannot both be a hydrogen atom; and 
           (ii) about 0.1% to about 20% of one or more co-solvents; 
           (iii) about 15% to about 95% a lower alcohol; and 
           (iv) water in a quantity sufficient for the composition to total 100% (wt/wt) 
         
         (b) a microneedle array. 
       
     
     
         24 . The drug delivery system of  claim 23 , wherein the cannabidiol prodrug is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The drug delivery system of  claim 23 , wherein the cannabidiol prodrug selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X −  is a counter ion derived from pharmaceutically acceptable acids. 
       
     
     
         26 . The drug delivery system of  claim 23 , wherein the cannabidiol prodrug is present in an amount of about 5% to about 30% (wt/wt) of the pharmaceutical composition. 
     
     
         27 . The drug delivery system of  claim 23 , wherein the cannabidiol prodrug is present in an amount of about 10% to about 20% (wt/wt) of the pharmaceutical composition. 
     
     
         28 . The drug delivery system of  claim 23 , wherein the co-solvents is selected from the group consisting of: ethanol, benzyl alcohol and mixtures of the foregoing. 
     
     
         29 . The drug delivery system of  claim 23 , wherein the pharmaceutical composition is in the form of a hydrogel. 
     
     
         30 . The drug delivery system of  claim 29 , wherein the hydrogel is incorporated into a matrix- or reservoir-type patch. 
     
     
         31 . The drug delivery system of  claim 23 , wherein the pharmaceutical composition further comprises a COX inhibitor selected from the group consisting of: a non-specific COX inhibitor, a COX-1 inhibitor and a COX-2 inhibitor. 
     
     
         32 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X −  is a counter ion derived from pharmaceutically acceptable acids.