TRANSDERMAL DRUG DELIVERY SYSTEM HAVING IONIC POLYMER NETWORKS

Abstract: The transdermal drug delivery system prepared using polyelectrolyte gel matrix with the maximum ionic concentration based on IPNs (interpenetrating networks) concept and loading the ionizable drug into the polyelectrolyte gel matrix by ionic bond, is an advanced form of transdermal drug delivery system where the loading amount is maximized due to increase of ionic functional group in polyelectrolyte gel matrix and the drug release rate is controlled by dissociation of the ionic bond between the ionic functional group of polyelectrolyte gel matrix and ionizable drug, as well as diffusion of drug in matrix.

Description: TRANSDERMAL DRUG DELIVERY SYSTEM HAVING IONIC POLYMER NETWORKS BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to transdermal drug delivery system, and more particulary, to the transdermal drug delivery system using ionic polymer (polyelectrolyte) networks. Description of the Related Arts Recent advances in drug delivery have shown that intact skin con serve as on effective route of administration for drug and much interest has been focused or the development of transdermal drug delivery system. At this time, a number of transdermal delivery system have been described. They may be classified broadly into three general categories. Firstly, it is membrane moderated transdermal drug delivery system. This system is composed of a drug reservoir in the form of a suspension of drug in a liquid medium. This is encapsulated a compartment surrounded in an impermeable laminate. This compartment is enclosed by a permeation-controlling polymeric membrane. Transdermal drug delivery system of this type, which have been described, include Transderm Scop., Transderm Nitro and Estraderm, which are available commercially from Ciba Geigy Corporation (Drug Dev. Ind. Pharm.. 9,627,1983; Am. Heart J.. 108, 217, 1984; U.S. Pat. No. 4,397,454; U.S. Pat. No. 4,618,584). Secondly, it is matrix diffusion controlled transdermal drug delivery system. The matrix is manufactured by homogeneously dispersing the drug in a polymer matrix which is then molded into a disc with defined surface area and thickness. Transdermal drug delivery system of this type, which have been described include Nitrodur and Nitrodur II systems, which are available commercially from KEY/SCHERING-PLOUGH corporation. Further, the matrix diffusion controlled transdermal drug delivery system is disclosed in EP patent application No. 91 306 457.2 of Chatfield Pharmaceutical Company. However, this system has the disadvantage that the amount of ionizable drug loading into sodium alginate matrix is limited because sodium alginate used in the present invention has low concentration of ionic group. Thirdly, the microsealed category is represented by the Nitro-Disc device which is available from SEAR E Corporation. In this system, the reservoir is formed by dispersing nitroglycerin absorbed to lactose in a hydrophilic solvent, which is subsequently distribute in a silicone elastomer by mechanical force to form thousands of microscopic drug compartment. SUMMARY OF THE INVENTION It is an object of the present invention to provide a transdermal drug delivery system using polyelectrolyte gels with high loading amount of ionizable drug at specific pH condition. The drug loading amount can be easily controlled by changing the composition of polyelectrolyte gel. It is further object of the invention to provide a transdermal drug delivery system which is capable of controlling the drug release rate because drug release is controlled by dissociation of the ionic bond between the ionized functional group of polyelectrolyte gel and that of ionized drug, as well as the diffusion of drug through the gel matrix. The present invention provides a transdermal drug delivery system comprising a polyelectrolyte gel matrix composed of two chemically independent polymers resulting in interpenetrating networks (IPNs) . With the formation of IPNs, the ionic concentration of polyelectrolyte gel matrix increase significantly. The present invention also provides a process for preparing transdermal drug delivery system comprising the steps of dissolving an ionic polymer (polyelectrolyte) in the water to prepare a first solution, dissolving a polymer in the water to prepare a second solution mixing said first solution and said second solution to form a polymer solution mixture, the coagulation of polymer solution mixture to form a solidified polyelectrolyte gel matrix having interpenetrating networks, and immersing said polyelectrolyte gel matrix into drug solution. The present inventors developed polymer matrix with the maximum ionic concentration using the concept of IPNs, and applied to transdermal drug delivery system to solve the problems of conventional matrix diffusion controlled transdermal drug delivery system. In the above transdermal drug delivery system of the present invention, drug is ionized at specific pH condition and it is loaded into polyelectrolyte gel matrix in the form of ionic bond. However, although the drug delivery system of the present invention uses the concept of matrix diffusion controlled transdermal drug delivery system, it is an advanced form of transdermal drug delivery system where drug is dispersed in polymer matrix with the form of ionic bond. BRIEF DESCRIPTION OF THE INVENTION FIG. 1 is a schematic representation of gelation mechanism of sodium alginate; FIG. 2 is a schematic representation of IPNs structure of polysaccharide and polyacrylic acid; FIG. 3 is a schematic cross-sectional view of one embodiment of the transdermal drug delivery systems according to the present invention; FIG. 4 is a schematic view of the apparatus for measuring * the drug release from transdermal drug delivery system; FIG.5 shows the drug release from the transdermal drug delivery system containing sodium alginate/polyacrylic acid; FIG. 6 shows the drug release from the transdermal drug delivery system containing acylamide/polyacrylic acid. FIG. 7 shows the drug release from the transdermal drug delivery system containing agar/polyaerylie acid. DETAILED DESCRIPTION OF THE PRESENT INVENTION According to the present invention, a transdermal drug delivery system comprises a polyelectrolyte gel matrix having interpenetrating networks and an ionizable drug ionically bonded to the ionic functional group of polyelectrolyte In the present invention, the polyelectrolyte gel matrix comprises a polymer having a cosolvent where polymer or monomer is capable of dissolving together with polyelectrolyte to increase the concentration of ionic group. It is preferable that the polymer of the present invention is one or the mixture selected from the group consisting of polysaccharide, acrylic polymer and methacrylic polymer. The polysaccharide is preferably one or the mixture selected from the group consisting of sodium alginate, pectin, Xanthomonas campestris, agar and carboxymethyl cellulose. The acrylic polymer may be' one or the mixture selected from the group consisting of acrylamide, isopropyl acrylamide and their derivatives. Preferably, the methacrylic polymer is one or the mixture selected from the group consisting of methyl methacrylate, ethoxy methacrylate, methoxyethoxyethyl methacrylate, aminoethyl methacrylate and diethylaminoethyl methacrylate. It is preferable that polyelectrolyte is one or the mixture selected from the group consisting of polyacrylic acid, polyamino acid, polysulfonic acid and polyethylamine. The mixing ratio of the polymer having a cosolvent where polymer or monomer are capable of dissolving together with polyelectrolyte to polyelectrolyte is 100 - 20 : 0 - 80. If the mixing ratio exceeds the above limitation, the polyelectrolyte gel matrix is collapsed. The polyelectrolyte gel matrix may further comprises initiator and/or cross-linking agent. The process for preparing transdermal drug delivery system of the present invention is described below. Aqueous polymer solution is prepared from sodium alginate which is a representative example of polysaccharides, and aqueous polyelectrolyte solution is prepared from polyacrylic acid which is a representative example of polyelectrolyte. The polymer solution mixtures are prepared by mixing two above solutions, followed by coagulation of the polymer solution mixture with the addition of CaCl 2 solution. At this time, sodium alginate forms a gel matrix as illustrated in Fig. 1, and polyacrylic acid entangles through the coagulated sodium alginate to form IPNs (Interpenetrating Networks) as shown in Fig. 2. The role of sodium alginate is to provide the crosslinked gel networks, and that of polyacrylic acid is to increase the ion concentration in gel networks. Polyelectrolyte gel matrix can be prepared in the form of paper type, bead type, or linear type in accordance with the coagulation condition. Various polyelectrolyte gels can be prepared based on the IPNs concepts. Firstly, a monomer solution is prepared using acrylamide, and a polyelectrolyte solution is prepared from polyacrylic acid as a polyelectrolyte. The prepared two solutions are mixed at a prescribed ratio and an appropriate amount of initiator and cross-linking agents are added and then ultraviolet ray is irradiated for the polymerization. Then, acrylamide forms a crosslinked gel network and polyacrylic acid entangles through crosslinked gel networks resulting in IPNs. The role of acrylamide is to provide a crosslinked gel networks and that of polyacrylic acid is to increase the ion concentration in gel networks. Agar, instead of sodium alginate, can be used to prepare polyelectrolyte gel matrix by mixing agar and water, followed by adding polyacrylic acid as an polyelectrolyte at a prescribed mixing ratio. The polymer solution mixture is heated to 80 "C to dissolve the reactants completely, and is cooled to room temperature to coagulate the polymer solution mixture. Then agar forms a crosslinked gel networks and polyacylic acid entangles through crosslinked gel network resulting in IPNs. The role of agar is to provide a crosslinked gel networks and that of polyacrylic acid is to increase the ion concentration in gel networks. The polyelectrolyte gel matrix prepared by the methods described above is immersed into nicotine solution as model drug to form ionic bond between nicotine and carboxyl group of polyelectrolyte gel at pH 4 - 5. Then, nicotine-loaded gel is prepared within a short time, which can be used as matrix for the transdermal drug delivery system as shown in Fig. 3. The transdermal drug delivery system of the present invention is an advanced form of drug delivery system which has the additional advantage of controlling the drug release rate by ionic bond between the ionic functional group in polyelectrolyte gel matrix and drug, as well as the diffusion of in the gel matrix. The drug delivery system of the present invention has a strong advantage of controlling the drug loading amount and the drug release rate because the system of the present invention has higher concentration of ionic group than that of EP patent application of 91 306 457.2 mentioned above. The present invention will now be described more specifically with reference to the preferred embodiments described below only by way of example. EXAMPLE 1 2 wt % aqueous polymer solution was prepared from sodium alginate selected as polysaccharide and -2 wt % aqueous polymer solution was prepared from polyacrylic acid selected as polyacrylic acid. Two prepared aqueous polymer solutions were mixed with the ratio of 50 : 50 by weight to prepare aqueous polymer mixture solution, which was cast on glass plate with gadner film knife in thickness of 3 mm, and it was added to calcium chloride, and then it was coagulated in the form of paper. The disc-type polyelectrolyte gel matrix was obtained using a punch of 1 cm radius and immersed into nicotine solution to form ionic bond between carboxylic group of polyelectrolyte gel and nicotine at pH 4 - 5. After 12 hours, nicotine-leaded gel matrix was obtained. The nicotine release experiment was performed using diffusion cell as illustrated in Fig. 4. Phosphate buffer solution was used in the receiving compartment. EXAMPLE 2 2 g of acrylamide, instead of sodium alginate used in EXAMPLE 1, was added to 100 g of water to prepare aqueous monomer solution, and 2 g of polyacrylic acid as polyelectrolyte was mixed with 100 g of water to prepare aqueous polyelectrolyte solution. Two obtained aqueous solutions were mixed with the ratio of 50 : 50 by weight to prepare aqueous polymer solution mixture solution, and 0.1 g of N,N'-methylene bisacrylamide as cross- linking agent and ammonium persulfate as polymerization initiator was added, and then UV was irradiated for 15 minutes. Consequently, acrylamide was polymerized to polymer gel, polyacrylic acid entangled through the crosslinked gel networks resulting in IPNs. The disc¬ type polyelectrolyte gel matrix was obtained using a punch of 1 cm radius and immersed into nicotine solution to form ionic bond between carboxylic group of polyelectrolyte gel and nicotine at pH 4 - 5. After 12 hours, nicotine-leaded gel matrix was obtained. The nicotine release experiment was performed using diffusion cell as illustrated in Fig. 4. Phosphate buffer solution was used in the receiving compartment. EXAMPLE 3 2 g of agar, instead of sodium alginate used in EXAMPLE 1, was added to 100 g of water to prepare aqueous polymer solution, and 2 g of polyacrylic acid as polyelectrolyte was mixed with 100 g of water to prepare aqueous polyelectrolyte solution. Two obtained aqueous solutions were mixed with the ratio of 50 : 50 by weight to prepare aqueous polymer solution mixture solution, and it was heated at 80 "C to dissolve the mixed materials completely, and then cooled at room temperature to solidify agar. The coagulated agar formed crosslinked gel networks, and polyacrylic acid entangled through the crosslinked gel network resulting in IPNs. The disc-type polyelectrolyte gel matrix was obtained using a punch of 1 cm radius and immersed into nicotine solution to form ionic bond between carboxylic group of polyelectrolyte gel and nicotine at pH 4 - 5. After 12 hours, nicotine-leaded gel matrix was obtained. The nicotine release experiment was performed using diffusion cell as illustrated in Fig. 4. Phosphate buffer solution was used in the receiving compartment. COMPARATIVE EXAMPLE 1 The experiment was performed by the same method as that of EXAMPLE 1 except that the polyelectrolyte was not used. COMPARATIVE EXAMPLE 2 . The experiment was performed by the same method as that of EXAMPLE 2 except that the polyelectrolyte was not used. COMPARATIVE EXAMPLE 3 The experiment was performed by the same method as that of EXAMPLE 3 except that the polyelectrolyte was not used. FIG. 5 shows release experiment using nicotine- loaded polymer matrices obtained in the above EXAMPLE 1 and COMPARATIVE EXAMPLE 1. High loading of nicotine could be accomplished using IPNs composite composed of sodium alginate and polyacylic acid which was prepared according to EXAMPLE 1. This system showed excellent loading efficiency comparing with the matrix prepared by sodium alginate only according to COMPARATIVE EXAMPLE 1 as described in European Patent Application No. 91306457.2. The precisely regulated drug release could be achieved by the polymer matrix of EXAMPLE 1. This was because the drug release could be controlled by the dissociated of ionic bond between gel matrix and drug as well as the diffusion of drug in the matrix. FIG. 6 shows the release experiment using nicotine- loaded polymer matrices obtained in the above EXAMPLE 2 and COMPARATIVE EXAMPLE 2. High loading of nicotine could be accomplished using IPNs composite composed of acrylamide and polyacrylic acid which was prepared according to EXAMPLE 2. This system showed excellent loading efficiency comparing with the matrix prepared by acrylamide only according to COMPARATIVE EXAMPLE 2. The precisely regulated drug release * could be achieved by the polymer matrix of EXAMPLE 2. This was because drug release could be controlled by the dissociation of ionic bond between gel matrix and drug as well as the diffusion of drug in the matrix. FIG. 7 shows the release experiment using nicotine- loaded polymer matrices obtained in the above EXAMPLE 3 and COMPARATIVE EXAMPLE 3. High loading of nicotine could be accomplished using IPNs composite composed of agar and polyacylic acid which was prepared according to EXAMPLE 3. This system showed excellent loading efficiency comparing with the matrix prepared by agar only according to COMPARATIVE EXAMPLE 3. The precisely regulated drug release could be achieved by the polymer matrix of EXAMPLE 3. This was because the drug release could be controlled by the dissociation ionic bond between gel matrix and drug as well as the diffusion of drug in the matrix. In the transdermal drug delivery system of the present invention, excellent drug loading was accomplished using IPNs composite by controlling the composition of IPNs composite and the precisely regulated drug release rate was also accomplished because it is controlled by both diffusion of drug in matrix, and the dissociation of ionic bond between the ionic functional group of polyelectrolyte gel matrix and the ionizable drug.

Claims: What is claimed is: 1. A transdermal drug delivery system comprising: a polyelectrolyte gel matrix having interpenetrating networks; and an ionizable drug ionically bonded to said polyelectrolyte gel matrix. 2. The transdermal drug delivery system of claim 1, wherein raid polyelectrolyte gel matrix comprises: a polymer having a cosolvent where polymer or monomer is soluble of dissolving with ionic polymer; and a polyelectrolyte to increase the ionic concentration in the gel matrix. 3. The transdermal drug delivery system of claim 2, wherein said polymer is one or the mixture selected from the group consisting of polysaccharide, acrylic polymer, and methacrylic polymer. 4. The transdermal drug delivery system of claim 3, wherein said polysaccharide is one or the mixture selected from the group consisting of sodium alginate, pectin, Xanthomonas campestris. agar, and carboxymethyl cellulose. 5. The transdermal drug delivery system of claim 3, wherein said acrylic polymer is one or the mixture selected from the group consisting of acrylamide, isopropyl acrylamide and their derivatives. 6. The transdermal drug delivery system of claim 3, wherein said methacrylic polymer is one or the mixture selected from the group consisting of methyl methacrylate, methoxy methacrylate, methoxyethoxyethyl methacrylate, aminoethyl methacrylate and diethylaminoethyl methacrylate. 7. The transdermal drug delivery system of claim 2, wherein said ionic polymer is one or the mixture selected from the group consisting of polyacrylic acid, polyamino acid, polysulfonic acid and polyethylamine. 8. The transdermal drug delivery system of claim 2, the mixing ratio of said polymer having a cosolvent where polymer or monomer is capable of dissolving with polyelectrolyte, to said polyelectrolyte is 100 - 20 : 0 - 80. 9. A process for preparing transdermal drug delivery "system comprising the steps of: dissolving an polyelectrolyte in the water to prepare a first solution, to increase the ionic concentration of polyelectrolyte gel matrix; dissolving a polymer into water to prepare a second solution, said polymer having a cosolvent where polymer or monomer is soluble with said polyelectrolyte; mixing said first solution and said second solution to form a coagulated polyelectrolyte gel matrix having interpenetrating networks; and immersing said polyelectrolyte gel matrix into drug solution. 10. The process for preparing transdermal drug delivery system of claim 9, wherein said polymer is one or the mixture selected from the group consisting of polysaccharide, acrylic polymer, and methacrylic polymer. 11. The process for preparing transdermal drug delivery system of claim 10, wherein said polysaccharide is one or the mixture selected from the group consisting of sodium alginate, pectin, Xanthomonas campestris. agar, and carboxymethyl cellulose. 12. The process for preparing transdermal drug delivery system of claim 10, wherein said acrylic polymer is one or the mixture selected from the group consisting of acrylamide, isopropyl acrylamide and their derivatives. 13. The process for preparing transdermal drug delivery 'system of claim 10, wherein said methacrylic polymer is one or the mixture selected from the group consisting of methyl methacrylate, methoxy methacrylate, methoxyethoxyethyl methacrylate, aminoethyl methacrylate and diethylaminoethyl methacrylate. 14. The process for preparing transdermal drug delivery system of claim 9, wherein said ionic polymer is one or the mixture selected from the group consisting of polyacrylic acid, polyamino acid, polysulfonic acid and polyethylamine. 15. The process for preparing transdermal drug delivery system of claim 9, the mixing ratio of said polymer having a cosolvent where monomer is capable of dissolving with ionic polymer, to said ionic polymer is 100 - 20 : 0 - 80. AMENDED CLAIMS [received by the International Bureau on 15 September 1995 ( 15.09.95 ) ; origi nal cl aims 1 and 2 amended ; remai ning cl aims unchanged ( 1 page) ] 1. A transdermal drug delivery system comprising: a polyelectrolyte gel matrix having interpenetrating networks, said interpenetrating networks including a polymer and a polyelectrolyte, and said polymer and said polyelectrolyte being physically entangled in said interpernt rating networks; and an ionizable drug ionically bonded to said polyelectrolyte gel matrix. 2. The transdermal drug delivery system of claim 1, wherein said polymer has a cosolvent where polymer or monomer is soluble with said polyelectrolyte, and said polyelectrolyte increases the ionic concentration in the gel matrix. 3. The transdermal drug delivery system of claim 2, wherein said polymer is one or the mixture selected from the group consisting of polysaccharide, acrylic polymer, and methacrylic polymer. 4. The transdermal drug delivery system of claim 3, wherein said polysaccharide is one or the mixture selected from the group consisting of sodium alginate, pectin, Xanthomonas campestris. agar, and carboxymethyl cellulose. 5. The transdermal drug delivery system of claim 3, wherein said acrylic polymer is one or the mixture selected from the group consisting of acrylamide, isopropyl acrylamide and their derivatives. 6. The transdermal drug delivery system of claim

Inventors: CHO SUN HANG, LEE HAI BANG, YUK SOON HONG, CHO, SUN, HANG, LEE, HAI, BANG, YUK, SOON, HONG
Applicants: CHO SUN HANG, KOREA RES INST CHEM TECH, LEE HAI BANG, YUK SOON HONG, CHO, SUN, HANG, KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY, LEE, HAI, BANG, YUK, SOON, HONG
Application year: 1995
Main classification: A61K9
IPC codes: A61K9