Solubility parameter based drug delivery system and method for altering drug saturation concentration

Abstract

The method of adjusting the saturation concentration of a drug in a transdermal composition for application to the dermis, which comprises mixing polymers having differing solubility parameters, so as to modulate the delivery of the drug. This results in the ability to achieve a predetermined permeation rate of the drug into and through the dermis. In one embodiment, a dermal composition of the present invention comprises a drug, an acrylate polymer, and a polysiloxane. The dermal compositions can be produced by a variety of methods known in the preparation of drug-containing adhesive preparations, including the mixing of the polymers, drug, and additional ingredients in solution, followed by removal of the processing solvents. The method and composition of this invention permit selectable loading of the drug into the dermal formulation and adjustment of the delivery rate of the drug from the composition through the dermis, while maintaining acceptable shear, tack, and peel adhesive properties.

What is claimed is:  
     
         1 . An improved pressure-sensitive adhesive composition of the type suitable for controlled release of a bioactive agent from a pressure-sensitive adhesive matrix, the composition comprising: 
 a blend of a first polymeric adhesive having a first solubility parameter and a second polymeric adhesive having a second solubility parameter, the first and second solubility parameters being different from one another by an increment of at least 2 (J/cm 3 ) ½  and resulting in a characteristic net solubility parameter of the blend which can selectably adjust the saturation concentration of a bioactive agent contained in the pressure-sensitive adhesive composition and thereby modulate the release of the bioactive agent.    
     
     
         2 . The pressure-sensitive adhesive composition of    claim 1    further comprising a bioactive agent.  
     
     
         3 . The pressure-sensitive adhesive composition of    claim 2    wherein the net solubility parameter of the blend adjusts the saturation concentration of the bioactive agent upward.  
     
     
         4 . The pressure-sensitive adhesive composition of    claim 2    wherein the net solubility parameter of the blend adjusts the saturation concentration of the bioactive agent downward.  
     
     
         5 . The pressure-sensitive adhesive composition of    claim 2    wherein the bioactive agent is a drug.  
     
     
         6 . The pressure-sensitive adhesive composition of    claim 5    wherein the drug is a steroid.  
     
     
         7 . The pressure-sensitive adhesive composition of    claim 6    wherein the steroid is an estrogen selected from the group consisting of conjugated estrogens, esterified estrogens, estropipate, 17-β estradiol, equilin, mestranol, estrone, estriol, ethinyl estradiol, and diethylstilbestrol.  
     
     
         8 . The pressure-sensitive adhesive composition of    claim 7    wherein the estrogen is 17-β estradiol and the 17-β estradiol is present in the drug-containing polymeric diffusion matrix in an amount of from about 1% to 5% by weight.  
     
     
         9 . The pressure-sensitive adhesive composition of    claim 6    wherein the steroid is a progestational agent.  
     
     
         10 . The pressure-sensitive adhesive composition of    claim 9    wherein the progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17-alpha-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinyl-estrenol, norgestrel, demegestone, promegestone, and megestrol acetate.  
     
     
         11 . The pressure-sensitive adhesive composition of    claim 10    wherein the progestational agent is norethindrone acetate and the norethindrone acetate is present inthe drug-containing polymeric diffusion matrix in an amount of from about 1% to 5% by weight.  
     
     
         12 . The pressure-sensitive adhesive composition of    claim 5    wherein the drug is a β 2 -adrenergic agonist.  
     
     
         13 . The pressure-sensitive adhesive composition of    claim 12    wherein the β 2 -adrenergic agonist is selected from the group consisting of metaproterenol, terbutaline, albuterol, carbuterol, rimiterol, salmefamol, fenoterol, soterenol, tratoquinol, and quinterenol.  
     
     
         14 . The pressure-sensitive adhesive composition of    claim 13    wherein the β 2 -adrenergic agonist is albuterol and the albuterol is present in the drug-containing polymeric diffusion matrix in an amount of less than about 30% by weight.  
     
     
         15 . The pressure-sensitive adhesive composition of    claim 5    wherein the drug is a cardioactive agent.  
     
     
         16 . The pressure-sensitive adhesive composition of    claim 15    wherein said cardioactive agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrates, quinidine sulfate, procainamide, benzydroflumethiazide, bendroflumethiazide, chlorothiazide, nifedipine, nicardipine, verapamil, diltiazem, timolol, propranolol, captopril, clonidine and prazosin.  
     
     
         17 . The pressure-sensitive adhesive composition of    claim 16    wherein the cardioactive agent is nitroglycerin and the nitroglycerin is present in the drug-containing polymeric diffusion matrix in an amount of less than about 25% by weight.  
     
     
         18 . The pressure-sensitive adhesive composition of    claim 5    wherein the drug is a cholinergic agonist.  
     
     
         19 . The pressure-sensitive adhesive of    claim 18    wherein the cholinergic agonist is selected from the group consisting of choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine, and arecoline.  
     
     
         20 . The pressure-sensitive adhesive composition of    claim 19    wherein the cholinergic agonist is pilocarpine and the pilocarpine is present in the drug-containing polymeric diffusion matrix in an amount of less than about 30% by weight.  
     
     
         21 . The pressure-sensitive adhesive composition of    claim 2    further including, optionally, enhancers, fillers, co-solvents, and excipients.  
     
     
         22 . The pressure-sensitive adhesive composition of    claim 1    wherein the first and second solubility parameters are different from one another by an increment of at least 4 (J/cm 3 ) 1/2 .  
     
     
         23 . The pressure-sensitive adhesive composition of    claim 1    wherein said first polymeric adhesive is a polyacrylate.  
     
     
         24 . The pressure-sensitive adhesive composition of    claim 23    wherein the second polymeric adhesive has a solubility parameter different than the solubility parameter of polyacrylate by at least 2(J/cm 3 ) ½ .  
     
     
         25 . The pressure-sensitive adhesive composition of    claim 24    wherein the second polymeric adhesive is a polysiloxane.  
     
     
         26 . The pressure-sensitive adhesive composition of    claim 25    wherein the polyacrylate is present in an amount ranging from about 2-96% by weight of the pressure-sensitive adhesive composition and the polysiloxane is present in an amount ranging from about 98-4% by weight of the pressure-sensitive adhesive composition.  
     
     
         27 . A dermal adhesive composition comprising: 
 a) a multiple polymer adhesive system consisting essentially of a blend of 2-96% by weight of an acrylic-based polymer and 98-4% by weight of a silicone-based polymer, the multiple polymer adhesive system being in an amount of about 99-50% by weight of the dermal adhesive composition;    b) a bioactive agent in the amount of 0.3-50% by weight of the dermal adhesive composition;    c) a co-solvent for the bioactive agent in the amount of 0-30% by weight of the dermal adhesive composition; and    d) an enhancer in the amount of 0-20% by weight of the dermal adhesive composition.    
     
     
         28 . The dermal adhesive composition of    claim 27    further comprising fillers and excipients in an amount of about 1% to 15% by weight of the dermal adhesive composition.  
     
     
         29 . A transdermal drug delivery device comprising a blend of: 
 (a) a first polymeric material having a first solubility parameter; and    (b) a second polymeric material having a second solubility parameter, said first and second solubility parameters being different from one another and resulting in a characteristic net solubility parameter of the blend; and    a drug intimately mixed with said polymeric material blend, the saturation concentration of the drug in the blend being responsive to the characteristic net solubility parameter.    
     
     
         30 . The transdermal drug delivery device of    claim 29    wherein the blend is a pressure-sensitive adhesive.  
     
     
         31 . The transdermal drug delivery device of    claim 30    further comprising: 
 a backing material superimposed on one surface of the pressure sensitive adhesive, said backing material being impermeable to the drug contained therein.  
 
     
     
         32 . The transdermal drug delivery device of    claim 30    further comprising a release liner superimposed on another surface of the pressure sensitive adhesive.  
     
     
         33 . The transdermal drug delivery device of    claim 29    wherein the first polymeric material is a polyacrylate and the second polymeric material is a polysiloxane.  
     
     
         34 . The transdermal drug delivery device of    claim 33    wherein the polyacrylate is present in an amount ranging from about 2-96% by weight of the blend and the polysiloxane is present in an amount ranging from about 98-4% by weight of the blend.  
     
     
         35 . The transdermal drug delivery device of    claim 33    wherein the drug is a steroid.  
     
     
         36 . The transdermal drug delivery device of    claim 35    wherein the steroid is an estrogen selected from the group consisting of conjugated estrogens, esterified estrogens, estropipate, 17-β estradiol, equilin, mestranol, estrone, estriol, ethinyl estradiol, and diethylstilbestrol.  
     
     
         37 . The transdermal drug delivery device of    claim 35    wherein the steroid is a progestational agent.  
     
     
         38 . The transdermal drug delivery device of    claim 37    wherein the progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxy-progesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17-alpha-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone, promegestone, and megestrol acetate.  
     
     
         39 . The transdermal drug delivery device of    claim 33    wherein the drug is a β 2 -adrenergic agonist.  
     
     
         40 . The transdermal drug delivery device of    claim 39    wherein the β 2 -adrenergic agonist is selected from the group consisting of metaproterenol, terbutaline, albuterol, carbuterol, rimiterol, salmefamol, fenoterol, soterenol, tratoquinol, and quinterenol.  
     
     
         41 . The transdermal drug delivery device of    claim 33    wherein the drug is a cardioactive agent.  
     
     
         42 . The transdermal drug delivery device of    claim 41    wherein said cardioactive agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrates, quinidine sulfate, procainamide, benzydroflumethiazide, bendroflumethiazide, chlorothiazide, nifedipine, nicardipine, verapamil, diltiazem, timolol, propranolol, captopril, clonidine and prazosin.  
     
     
         43 . The transdermal drug delivery device of    claim 33    wherein the drug is a cholinergic agonist.  
     
     
         44 . The transdermal drug delivery device of    claim 43    wherein the cholinergic agonist is selected from the group consisting of choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine, and arecoline.  
     
     
         45 . A method of making a transdermal drug delivery system of the type having a drug-containing pressure-sensitive adhesive, the method comprising the step of: 
 forming a pressure-sensitive adhesive diffusion matrix by blending at least two polymers having differing solubility parameters so that the net solubility parameter of the composition selectably adjusts the saturation concentration of a drug in the pressure-sensitive diffusion matrix and thereby modifies the delivery rate of the drug from the pressure-sensitive diffusion matrix and through the dermis.    
     
     
         46 . The method of    claim 45    wherein the at least two polymers comprise a polyacrylate and a polysiloxane.  
     
     
         47 . The method of    claim 46    wherein the ratio of polyacrylate to polysiloxane is from about 2:98 to about 96:4 by weight of the pressure-sensitive adhesive diffusion matrix.  
     
     
         48 . The method of    claim 47    wherein the ratio of polyacrylate to polysiloxane is from about 2:98 to about 90:10 by weight of the pressure-sensitive adhesive diffusion matrix.  
     
     
         49 . The method of    claim 48    wherein the ratio of polyacrylate to polysiloxane is from about 2:98 to about 86:14 by weight of the pressure-sensitive adhesive diffusion matrix.  
     
     
         50 . The method of    claim 45    comprising the further step of intimately mixing a drug with the pressure-sensitive adhesive diffusion matrix.  
     
     
         51 . The method of    claim 50    wherein the drug is present in an amount ranging from 0.3 to 50% by weight of the drug-containing pressure-sensitive adhesive diffusion matrix.  
     
     
         52 . The method of    claim 50    wherein the drug is a steroid.  
     
     
         53 . The method of    claim 52    wherein the steroid is an estrogen selected from the group consisting of conjugated estrogens, esterified estrogens, estropipate, 17-β estradiol, equilin, mestranol, estrone, estriol, ethinyl estradiol, and diethylstilbestrol.  
     
     
         54 . The method of    claim 53    wherein the estrogen is 17-β estradiol and the 17-β estradiol is present in the drug-containing pressure-sensitive adhesive diffusion matrix in an amount of from about 1% to 5% by weight.  
     
     
         55 . The method of    claim 52    wherein the steroid is a progestational agent.  
     
     
         56 . The method of    claim 55    wherein the progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17-alpha-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone, promegestone, and megestrol acetate.  
     
     
         57 . The method of    claim 56    wherein the progestational agent is norethindrone acetate and the norethindrone acetate is present in the drug-containing pressure-sensitive adhesive diffusion matrix in an amount of from about 1% to 5% by weight.  
     
     
         58 . The method of    claim 50    wherein the drug is a β 2 -adrenergic agonist.  
     
     
         59 . The method of    claim 58    wherein the β 2 -adrenergic agonist is selected from the group consisting of metaproterenol, terbutaline, albuterol, carbuterol, rimiterol, salmefamol, fenoterol, soterenol, tratoquinol, and quinterenol.  
     
     
         60 . The method of    claim 59    wherein the β 2 -adrenergic agonist is albuterol and the albuterol is present in the drug-containing pressure-sensitive adhesive diffusion matrix in an amount of less than about 30% by weight.  
     
     
         61 . The method of    claim 50    wherein the drug is a cardioactive agent.  
     
     
         62 . The method of    claim 61    wherein said cardioactive agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrates, quinidine sulfate, procainamide, benzydroflumethiazide, bendroflumethiazide, chlorothiazide, nifedipine, nicardipine, verapamil, diltiazem, timolol, propranolol, captopril, clonidine and prazosin.  
     
     
         63 . The method of    claim 62    wherein the cardioactive agent is nitroglycerin and the nitroglycerin is present in the drug-containing pressure-sensitive adhesive diffusion matrix in an amount of less than about 25% by weight.  
     
     
         64 . The method of    claim 50    wherein the drug is a cholinergic agonist.  
     
     
         65 . The method of    claim 64    wherein the cholinergic agonist is selected from the group consisting of choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine, and arecoline.  
     
     
         66 . The method of    claim 65    wherein the cholinergic agonist is pilocarpine and the pilocarpine is present in the drug-containing polymeric diffusion matrix in an amount of less than about 30% by weight.  
     
     
         67 . A method of adjusting the saturation concentration of a drug in a transdermal drug delivery composition, for application to the dermis, which comprises blending a plurality of polymers having differing solubility parameters, so as to modulate the delivery of the drug from the composition and through the dermis.  
     
     
         68 . A method of modulating the delivery rate of a drug from a transdermal drug delivery system of the type having a drug-containing pressure-sensitive adhesive diffusion matrix, which method comprises the steps of: 
 a) selecting at least two immiscible polymeric materials as components of a multiple polymer adhesive system such that the system has a net solubility parameter which results in a modified saturation concentration of a drug in the system while keeping the diffusion coefficient of the drug in the system the same or greater; and    b) blending the at least two polymers to form a pressure-sensitive adhesive diffusion matrix.    
     
     
         69 . The method of    claim 68    wherein there is provided the further step of intimately mixing a drug in the pressure-sensitive adhesive diffusion matrix.  
     
     
         70 . The method of    claim 68    wherein said step of selecting comprises the step of measuring the flux rate from various weight ratios of the selected at least two immiscible polymers and choosing the ratio producing the maximum flux rate.