Transdermal Systems Containing Multilayer Adhesive Matrices to Modify Drug Delivery

Abstract

A transdermal drug-containing dosage unit comprises: a backing layer substantially impervious to the drug to be delivered transdermally; a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first delivery profile of the drug; a second polymeric adhesive matrix, in contact with said first polymeric adhesive matrix, having dispersed therein the drug and having a second delivery profile of the drug, wherein said second delivery profile is different from said first delivery profile; and a release liner in contact with the second polymeric adhesive matrix. The first polymeric adhesive matrix can release the drug more quickly or more slowly than the second polymeric adhesive matrix. Through the selection of the two matrices, the delivery profile of the drug through the skin can be selectively modified and controlled.

1 . The transdermal drug-containing dosage unit of  claim 37 , wherein said drug comprises a cardiovascular drug, an androgenic steroid, an estrogen, a progestational agent, a drug which acts on the central nervous system, a nutritional agent, an anti-inflammatory agent, an antihistamine, a miotic, a dermatological agent, an anti-spasmodic, an anti-depressant, an anti-cancer drug, an anti-diabetic, an anti-estrogen, an anti-psychotic, an anti-infective agent, an anti-allergenic, an anti-pyretic, an anti-migraine agent or a tranquilizer. 
     
     
         2 . The transdermal drug-containing dosage unit of  claim 37 , wherein said drug comprises an estrogen or a combination of an estrogen and a progestin. 
     
     
         3 . The transdermal drug-containing dosage unit of  claim 2 , wherein said estrogen comprises estradiol or mono- or di-esters thereof which are transdermally absorbable. 
     
     
         4 . The transdermal drug-containing dosage unit of  claim 2 , wherein said progestin comprises norethindrone acetate or levonorgestrel. 
     
     
         5 . The transdermal drug-containing dosage unit of  claim 37  which comprises from about 0.05% to about 40% w/w of drug. 
     
     
         6 . The transdermal drug-containing dosage unit of  claim 5 , which comprises from about 0.1% to about 4.0% w/w of drug. 
     
     
         7 . The transdermal drug-containing dosage unit of  claim 2 , which comprises from about 0.1% to about 4.0% of said estrogen. 
     
     
         8 . The transdermal drug-containing dosage unit of  claim 7 , which further comprises from about 0.1% to about 20% of a progestin. 
     
     
         9 . A method for administering a drug transdermally to an individual in need of such administration, comprising applying to skin of the individual a transdermal dosage unit comprising:
 a) a backing layer substantially impervious to the drug to be delivered transdermally;   b) a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first initial rate of delivery of the drug;   c) a second polymeric adhesive matrix, having dispersed therein the drug and having a second initial rate of delivery of the drug which is different from said first rate of delivery; and   d) at least one additional polymeric adhesive matrix sandwiched between said first and second polymeric matrices, each said additional adhesive matrix having an initial rate of delivery of the drug;   
       wherein said initial rate of delivery of each of said matrices is different from one another. 
     
     
         10 . A transdermal delivery device for the transdermal delivery of an active substance, for example a pharmacologically active substance, the device having first and second superimposed mutually contacting adhesive layers, of which said first layer is pressure sensitive adhesive and is in use brought into contact with the skin, the active substance being dissolved in both said layers, wherein the affinity of said first layer for said active substance is between about 1.15 and about 10 times lower than that of said second layer, the percent saturation of said active substance in both said layers being the same and being less than 100%, said first layer having a greater thickness than said second layer. 
     
     
         11 . A transdermal delivery device according to  claim 10 , wherein the ratio of the thickness of the first layer to the thickness of the second layer is in the range 1.2 to 7. 
     
     
         12 . A transdermal delivery device according to  claim 10 , wherein the thickness of each said layer when dry is in the range 5 to 150 μm. 
     
     
         13 . A transdermal delivery device according to  claim 12 , wherein the thickness of the first layer when dry is in the range 5 to 125 μm and the thickness of the second layer when dry is in the range 5 to 75 μm. 
     
     
         14 . A transdermal delivery device according to  claim 10  wherein the affinity of said first layer for said active substance is 1.15 to 1.75 times lower than that of said second layer. 
     
     
         15 . A transdermal delivery device according to  claim 10  wherein said first layer has a polymer matrix consisting substantially of at least one non-functional polymer component and said second layer has a polymer matrix consisting of at least one functional polymer component or a mixture of functional and non-functional polymer components. 
     
     
         16 . A transdermal delivery device according to  claim 15  wherein said second layer is composed of about 10 to about 90% of at least one functional polymer component and about 90 to about 10% of at least one non-functional polymer component, percentages being expressed relative to total weight of dry layer. 
     
     
         17 . A transdermal delivery device according to  claim 16  wherein said second layer is composed of about 20 to about 50% of at least one functional polymer component and about 50 to about 80% of at least one non-functional polymer component, percentages being expressed relative to total weight of dry layer. 
     
     
         18 . A transdermal delivery device according to  claim 15  wherein the or each said functional polymer component of said second layer has functional groups selected from —COOH and —OH. 
     
     
         19 . A transdermal delivery device according to  claim 10  wherein said first and second layers are composed of polymer components selected from acrylic polymers, polyisobutylenes and silicone elastomers. 
     
     
         20 . A transdermal delivery device according to  claim 10  wherein each said layer is composed of one or more acrylic polymer components. 
     
     
         21 . A transdermal delivery device according to  claim 10  wherein at least one of the first and second layers comprises at least one permeation enhancer. 
     
     
         22 . A transdermal delivery device according to  claim 10  wherein the amount of permeation enhancer in each of said layers, expressed as percent of the dry weight of each layer, is between 3.5 and 22%. 
     
     
         23 . A transdermal delivery device according to  claim 10  wherein the pharmacologically active substance is selected from fentanyl, alfentanyl, sufentanyl, carfentanyl, lofentanyl, buprenorphine and the derivatives and pharmaceutically acceptable salts thereof. 
     
     
         24 . A transdermal delivery device according to  claim 10  wherein the pharmacologically active substance is nicotine or one of its pharmaceutically acceptable salts and derivatives. 
     
     
         25 . A transdermal delivery device according to  claim 10  wherein the pharmacologically active substance is fentanyl or one of its pharmaceutically acceptable salts or derivatives. 
     
     
         26 . A transdermal delivery device according to  claim 25  wherein the first layer to be in intimate contact with the skin has an initial fentanyl base content of 2 to 4%, expressed as percentage of the dry weight of said first layer. 
     
     
         27 . A transdermal delivery device according to  claim 25  wherein the second layer has an initial fentanyl base content of 4 to 10%, expressed as percentage of the dry weight of said second layer. 
     
     
         28 . A transdermal delivery device according to  claim 25 , adapted to release a therapeutically effective dose of the active substance during at least three days. 
     
     
         29 . A process for the manufacture of a device for the transdermal administration of an active substance according to  claim 10 , which comprises the following steps:
 (a) coating and drying a first precursor adhesive layer that will be the second layer of said device onto a temporary release liner;   (b) laminating said first precursor adhesive layer together with the temporary release film onto a backing layer;   (c) coating and laminating onto a final release liner a second precursor adhesive layer that will be the first layer of said device; and   (d) detaching the temporary release film and laminating said second precursor adhesive layer adhered to the final release liner obtained in ©) to said first precursor adhesive layer obtained in (b) that is adhered to the backing layer.   
     
     
         30 . A process according to  claim 29 , wherein the respective amounts of said active substance in said first and second precursor adhesive layers differ from the amounts in said device when ready for use, and after step (d) the active substance is allowed to equilibrate its percent saturation between the respective layers. 
     
     
         31 . A transdermal delivery device for the transdermal delivery of an active substance, for example a pharmacologically active substance, the device having first and second superimposed mutually contacting adhesive layers, of which said first layer is pressure sensitive adhesive and is in use brought into contact with the skin, the active substance being dissolved in both said layers, wherein the affinity of said first layer for said active substance is between about 1.15 and about 10 times lower than that of said second layer, the percent saturation of said active substance in both said layers being the same and being less than 100%. 
     
     
         32 . A transdermal delivery device for the transdermal delivery of an active substance, for example a pharmacologically active substance, the device having first and second superimposed mutually contacting adhesive layers, of which said first layer is pressure sensitive adhesive and is in use brought into contact with the skin, the active substance being dissolved in both said layers, wherein the difference in drug delivery rate of said active substance in said first layer is between about 10% and about 100% higher than that of said active substance in said second layer, the percent saturation of said active substance in both said layers being the same and being less than 100%. 
     
     
         33 . The transdermal delivery device of  claim 32 , wherein the difference in drug delivery rate of said active substance in said first layer is between about 10% and about 87% higher than that of said active substance in said second layer. 
     
     
         34 . The transdermal delivery device of  claim 32 , wherein the difference in drug delivery rate of said active substance in said first layer is between about 15% and about 60% higher than that of said active substance in said second layer. 
     
     
         35 . The transdermal delivery device of  claim 32 , wherein the difference in drug delivery rate of said active substance in said first layer is between about 15% and about 60% higher than that of said active substance in said second layer. 
     
     
         36 . The transdermal delivery device of  claim 32 , wherein the difference in drug delivery rate of said active substance in said first layer is between about 14% and about 83% higher than that of said active substance in said second layer. 
     
     
         37 . A transdermal drug-containing dosage unit which comprises a laminate comprising:
 a) a backing layer substantially impervious to the drug to be delivered transdermally;   b) a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first initial rate of delivery of the drug;   c) a second polymeric adhesive matrix, having dispersed therein the drug and having a second initial rate of delivery of the drug, said second polymeric matrix in contact with a release liner; and   d) at least one additional adhesive matrix, laminated in between said first and second polymeric adhesive matrices, having dispersed therein the drug; each said additional adhesive matrix having an initial rate of delivery of the drug;   
       wherein said initial rates of delivery of at least two of said matrices are different from one another. 
     
     
         38 . The transdermal drug-containing dosage unit of  claim 37 , wherein each of said initial rates of delivery is different from said other initial rates of delivery. 
     
     
         39 . The transdermal drug-containing dosage unit of  claim 37 , which comprises one additional adhesive matrix in between said first and second polymeric adhesive matrices, such that said additional adhesive matrix is in contact with said first adhesive matrix and with said second adhesive matrix. 
     
     
         40 . The transdermal drug-containing dosage unit of  claim 37 , which comprises more than one additional adhesive matrix in between said first and second polymeric adhesive matrices. 
     
     
         41 . The transdermal drug-containing dosage unit of  claim 37 , wherein either said first and second adhesive matrices or said additional adhesive matrix comprises an acrylic adhesive. 
     
     
         42 . The transdermal drug-containing dosage unit of  claim 41 , wherein said non-acrylic adhesive matrix or matrices comprise(s) a silicone adhesive or a polyisobutylene adhesive. 
     
     
         43 . The transdermal drug-containing dosage unit of  claim 37 , wherein one matrix comprises an acrylic adhesive, one matrix comprises a polyisobutylene adhesive and one matrix comprises a silicone adhesive. 
     
     
         44 . A transdermal drug-containing dosage unit which comprises a laminate comprising:
 a) a backing layer substantially impervious to the drug to be delivered transdermally;   b) a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first initial rate of delivery of the drug;   c) a second polymeric adhesive matrix, having dispersed therein the drug and having a second initial rate of delivery of the drug; said second polymeric matrix in contact with a release liner; and   d) a third polymeric adhesive matrix, in between and in contact with said first and second polymeric adhesive matrices, having dispersed therein the drug and having a third initial rate of delivery of the drug;   wherein said initial rates of delivery of at least two of said matrices are different from one another.   
     
     
         45 . A method for preparing a transdermal drug-containing dosage unit comprising a laminate consisting of a backing layer, a first polymeric adhesive matrix, a second polymeric adhesive matrix, a third middle polymeric adhesive matrix, and a release liner, said method comprising the steps of:
 a) providing the backing layer substantially impervious to the drug to be delivered transdermally;   b) providing the first polymeric adhesive matrix and laminating it to the backing layer, wherein the first polymeric adhesive matrix has dispersed therein the drug and has a first initial rate of delivery of the drug;   c) providing the second polymeric adhesive matrix and laminating to the release liner, wherein the second polymeric adhesive matrix has dispersed therein the drug and has a second initial rate of delivery of the drug; and   d) providing the third polymeric adhesive matrix and laminating it to either the first or second polymeric adhesive matrices, wherein the third polymeric adhesive matrix has dispersed therein the drug and has a third initial rate of delivery of the drug; and   e) laminating the combined laminate comprising the third and first or second adhesive matrices which has resulted from step (d) to the second or first adhesive matrix, such that said third adhesive matrix is in between said first and second adhesive matrices;   
       wherein said initial rates of delivery of at least two of said matrices are different from one another. 
     
     
         46 . A method for preparing a transdermal drug-containing dosage unit comprising a laminate consisting of a backing layer, a first polymeric adhesive matrix, a second polymeric adhesive matrix and a release liner, said method comprising the steps of:
 a) providing the backing layer substantially impervious to the drug to be delivered transdermally;   b) providing the first polymeric adhesive matrix and laminating it to the backing layer;   c) providing the second polymeric adhesive matrix and laminating it to the release liner; and   d) laminating the first and second adhesive matrices to one another;   
       wherein a drug to be delivered transdermally is initially suspended or dispersed within at least one of said first and second adhesive matrices and wherein if said drug is suspended or dispersed within both of said first and second adhesive matrices, said drug is initially delivered from said first adhesive matrix at a rate which is different from the initial rate of delivery of said second adhesive matrix. 
     
     
         47 . A method for administering a drug transdermally to an individual in need of such administration, comprising applying to skin of the individual a transdermal dosage unit comprising a laminate comprising:
 a) a backing layer substantially impervious to the drug to be delivered transdermally;   b) a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first initial rate of delivery of the drug;   c) a second polymeric adhesive matrix, in contact with the first adhesive matrix, having dispersed therein the drug and having a second initial rate of delivery of the drug; and   d) at least one additional adhesive matrix, in between said first and second polymeric adhesive matrices, having dispersed therein the drug; each said additional adhesive matrix having an initial rate of delivery of the drug;   wherein said initial rates of delivery of at least two of said matrices are different from one another.