Title of Invention

TRANSDERMAL DRUG DELIVERY DEVICE CONTAINING ORAL ANTIDIABETIC DRUG

Abstract

The invention disclosed in this applications relates to a matrix type transdermal drug delivery system containing an oral antidiabetic drug useful for the treatment of diabetes mellitus, which comprises a matrix of hydrophilic and hydrophobic polymers containing oral antidiabetic drug having coating of an aluminium foil or other backing membrane; the matrix also having coatings of a pressure sensitive adhesive agent and a release liner. This invention also relates to a membrane controlled transdermal drug delivery system containing an oral antidiabetic drug useful for the treatment of diabetes mellitus, which comprises a solution or dispersion or semi-solid mass of a hydrophilic polymer containing an oral antidiabetic drug that is sandwiched between a rate controlling membrane and backing membrane, the rate controlling membrane having a coating of a pressure sensitive adhesive and a release liner. In addition the invention also provides processes for the preparation of above delivery systems.

Full Text

The invention relates to transdermal drug delivery device containing antidiabetic drug for the treatment of diabetes mellitus. The transdermal drug delivery device of the present invention is useful for the treatment of diabetes mellitus Diabetes mellitus is a group heterogeneous metabolic disorders characterized by hyperglycemia and altered metabolism of lipids, carbohydrates and proteins. Its major manifestations include disordered metabolism and inappropriate hyperglycemia. A therapeutic classification includes two major types of diabetes mellitus. Type 1 diabetes (Insulin Dependent Diabetes Mellitus; IDDM) is a severe form associated with ketosis in the untreated state. Type 2 (Non Insulin Dependent Diabetes Mellitus; NIDDM) represents a heterogeneous group comprising milder form of diabetes that occurs predominately in adults. The vast majority (about 80-90%) of diabetic patients have NIDDM (Davis and Granner, 1996.). Most physicians currently prefer oral glucose lowering drugs as the initial pharmacologic approach. Sulfonylureas, bigaunides, alpha-glucosidase inhibitors and thiazolidinediones are approved hypoglycemic agents for oral monotherapy of NIDDM. The oral hypoglycemic agents increase the release of endogenous insulin as well as its peripheral effectiveness (Nolte and Karam, 2001; Rang et al., 2003). The currently available dosage forms (tablets) of oral antidiabetic drugs are known to produce severe hypoglycemia in the initial hours after administration, adverse gastrointestinal (GI) effects, as both drugs do not bypass GI tract and high fluctuations in plasma concentrations of drug. Hypoglycemia, the most common and severe complication, can be precipitated by an excessive dose, decreased food intake, vomiting or associated liver and kidney disease. Glibenclamide is best avoided in the elderly and in patients with even mild renal impairment because of the risk of hypoglycemia. These drugs are associated with patient non-compliance since they are usually intended to be taken for a longer period in multi-doses daily. The critical side effects of oral antidiabetic drugs and the heterogeneous pathogenesis and progressive natural history of NIDDM offer a formidable therapeutic challenge. Dual endocrine deficits of impaired insulin action (insulin resistance) and inadequate insulin secretion create an environment of chronic hyperglycemia and general metabolic disarray. This inflicts a heavy burden of morbidity and premature mortality from cardiovascular diseases, microvascular disorders and neuropathic conditions. Improving glycemic control delays the onset and reduces the severity of these long-term complications. However, even with intensive use of current antidiabetic agents, more than 50% of NIDDM patients suffer with poor glycemic control and 18% develop serious complications within 6 years of diagnosis. Owing to the progressive nature of NIDDM, currently available oral antidiabetic agents, even when used intensively are often unable to control the hyperglycemia and insulin injections seldom reinstate near-normal metabolic homeostasis (Arunachalam and Gunasekaran, 2002). These factors indicate a need of a new antidiabetic agent or controlled drug delivery systems for currently available drugs. Although there are new agents in development to reinforce the relief of insulin resistance and stimulate insulin secretion, there is no immediate panacea to restore normal insulin sensitivity and eliminate chronic complications. Discovering a new medicine is a very expensive and time-consuming undertaking. However, re-designing the modules and means to transport medicine into the body is a less demanding and more lucrative task. The developmental cost of a new drug may be about $250 million and takes about 12 years to reach the market place; whereas an existing drug molecule can get a second life with newer drug delivery systems that can be developed in half of the time with 20% cost of the new drug discovery. In addition to the cost containment, controlled drug delivery systems can impart important advantages such as extending the duration of drug activity, which allows greater patient compliance owing to the elimination of multiple dosing schedules and reducing side effects due to optimization of blood concentration-time profiles (Bailey, 2000; Bemer and Kydonieus, 1996). Transdermal drug delivery devices offer many advantages over the conventional dosage forms or controlled release peroral delivery systems. Transdermal drug delivery system provides constant blood levels, reduces side effects, avoids first-pass metabolism of drug, bypasses the drug from GI tract and increases patient compliance; interruption or termination of treatment when necessary is possible and dose dumping never occurs (Panchagnula, 1997). Hence, development of transdermal drug delivery devices for presently available oral antidiabetic drugs would be an appropriate approach to overcome the complications like severe hypoglycemia, gastrointestinal side effects and patient noncompliance associated with oral therapy. Types of transdermal devices General types of transdermal drug delivery devices are given below (Knepp et al, 1987; Moore and Chien, 1988; Franz et al, 1992). 1. Matrix type: The drug reservoir is made by dispersing the drug into a hydrophilic or lipophilic polymer. This polymeric matrix modulates the release of drug and thus functions as the rate controlling medium. 2. Membrane controlled type device: The device consists of a drug reservoir sandwiched between a rate controlling membrane and drug impermeable backing laminate. 3. Membrane-Matrix hybrid type: It is essentially a modification of the membrane controlled type device. The liquid type of the drug reservoir is replaced with a solid polymer matrix, which is sandwiched between the rate controlling membrane and the drug impermeable backing laminate. 4. Microreservoir type: The drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water miscible drug solubilizer. The drug suspension is homogeneously dispersed by high shear mechanical force in a lipophilic polymer, forming thousands of unleachable microscopic drug reservoirs. This dispersion is quickly stabilized by immediately cross-linking the polymer chains in situ, which produces a medicated polymer disk of a specific area and a fixed thickness. An occlusive base plate mounted between the medicated disk and an adhesive foam backing prevents the loss of drug through the backing. 5. Drug-in-adhesive type: These systems are formulated by incorporating the drug directly in a pressure-sensitive adhesive polymer. It can be made of single or multilaminate adhesive layers which function both as the drug reservoir and the rate-controlling matrix. The drug loading level in the multilaminate adhesive layers is increased proportionately to compensate for the time dependent increase in the diffusional path as a result of drug release. Some of the drugs attempted to develop different types of transdermal devices are given below. Matrix type devices: Propranolol hydrochloride, Levobunolol hydrochloride, Captopril, Buprenorphine, Estradiol, Piroxicam, Fentanyl, Primaquine, Testosterone, Ethinylestradiol, Flurbiprofen, Gestodene, Diltiazem hydrochloride, Indomethacin, Diclofenac diethylammonium, Progesterone, Dehydroepiandrosterone, Triprolidine, Pinacidil, Lidocaine, Atenolol, Antiestrogen, Ondansetron hydrochloride, Chloroquine, Prednisolone, Verapamil hydrochloride and Haloperidol. Membrane controlled type device: 9-P-arabinofuranosyladenine, Isisorbide dinitrate, Acemetacin, Terodiline, Chlorpheniramine maleate. Propranolol hydrochloride, Amlodipine base, Nifedipine, Bendroflumethiazide, Testosterone, Nicardipine, Nimodipine and Diltiazem hydrochloride. Drug-in-Adhesive type: Levobunolol hydrochloride, Nonivamide, Primaquine, Timolal maleate, Physostigmine, Nitrendipine, Nicotine and Bupropion Membrane-Matrix hybrid type: Captopril, Propranolol hydrochloride and Isosorbide-5-mononitrate. Some of the marketed transdermal drug delivery systems (Tan and Pfister, 1999; Panchagnula, 1997): Although above reports and literature are available on different transdermal devices of several drugs, no patents are available on transdermal devices containing oral antidiabetic agents like glibenclamide and glipizide. The present application, however, is related only to matrix type and membrane controlled type device. Therefore it is the main objective of the present invention to provide a transdermal drug delivery device containing an oral antidiabetic drug for the treatment of diabetes mellitus, which overcomes the severe hypoglycemia, GI side effects and patient noncompliance. It is another objective of the present invention to provide a transdermal device useful for the treatment of diabetes mellitus, which employs matrix transdermal system or membrane controlled transdermal system as the carrier to transport the active agent (drug) Still another objective of the present invention to provide a transdermal drug delivery device useful for the treatment of diabetes mellitus which employs oral antidiabetic drug as the active agent (drug) Yet another objective of the present invention to provide a transdermal drug delivery device useful for the treatment of diabetes mellitus which retains the effective concentration of the active substance (drug) in plasma for a long time say for a period in the range of 0 to 48 hours Still another objective of the present invention to provide a transdermal drug delivery device useful for the treatment of diabetes mellitus which is convenient and quantitative on the basis of the amount of active substance (drug) to be delivered into systemic circulation through skin. Further objective of the present invention to provide a process for the preparation of the matrix type and membrane controlled transdermal devices for the treatment of diabetes mellitus employing the solvent casting and sandwiching methods respectively. Accordingly the present invention provides a matrix type transdermal drug delivery system useful for the treatment of diabetes mellitus, which comprises a solid matrix made up of hydrophilic and hydrophobic polymers, the matrix containing an oral antidiabetic drug, and having coatings of a backing membrane, a pressure sensitive adhesive agent and a release liner. According to another embodiment of the present invention there is provided a membrane controlled transdermal drug delivery system useful for the treatment of diabetes mellitus, which comprises a solution or dispersion or semi-solid mass of a hydrophilic polymer, the solution or dispersion or semi-solid mass containing an oral antidiabetic drug, which is sandwiched between a rate controlling membrane and backing membrane, the surface of the rate controlling membrane which comes in contact with the skin, has a coating of a pressure sensitive adhesive and a release liner being provided below the pressure sensitive adhesive coating. In the matrix type transdermal device of the present invention, the drug is incorporated into the matrix of hydrophilic and hydrophobic polymers by dispersing/ dissolving the drug in the solution of hydrophilic and lipophilic polymers in hydrophilic or hydrophobic solvents. The resulting polymeric solution containing drug is then casted on aluminum foil or mercury surface. After evaporation of the solvent, a film like solid matrix is remained on the aluminum foil or mercury surface, which will be peeled out from the aluminum foil or mercury surface carefully. Later the film like matrix containing drug will be coated with pressure sensitive adhesive and the pressure sensitive adhesive coated surface will be covered with release liner and other surface will be covered with a backing membrane. In this type of device, polymeric matrix modulates the release of the drug and thus functions as the rate-controlling medium. In the case of membrane controlled transdermal device, the drug reservoir which is a solution or dispersion or semi-solid mass of a hydrophilic polymer containing drug is encapsulated between a rate controlling membrane and a backing membrane. The surface of the rate controlling membrane, which comes in contact with skin, is coated with pressure sensitive adhesive and release liner. For providing the pressure sensitive adhesive coating, adhesives like polyisobutylene or silicone adhesive or acrylate adhesive may be used. Such a coating is provided to enhance the adhesion of the transdermal device with skin. The polymers used for preparing the film like matrix of the matrix type transdermal device are blends of hydrophilic and hydrophobic polymers. As examples of such polymers mentioned is made to the blends of hydrophilic and hydrophobic polymers like ethyl cellulose, Eudragit RS-100, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, Eudragit RL-100, etc. Preferred polymers materials with the desired properties like plasticity, film-forming ability, compatibility etc are ethyl cellulose, polyvinyl alcohol, Eudragit RS (hydrophobic polymers) and polyvinyl pyrrolidone, Eudragit RL, hydroxypropyl methylcellulose (hydrophilic polymers). More preferable polymeric blends, which can be used according to the present invention, are the mixture of polymers containing ethyl cellulose/polyvinyl pyrrolidone and Eudragit RL/Eudragit RS. In a preferred embodiment of the invention the ratio of the polymers used (hydrophilic to-hydrophobic polymer) may range from 0.5:4.5 to 4.5:0.5. The concentration of the polymer used ranges from 0.5-2%. According to another embodiment of the present invention there is provided 4 process for the preparation of a matrix type transdermal device containing an oral antidiabetic drug useful for the treatment of diabetes mellitus which comprises dissolving blends of hydrophilic and hydrophobic polymers containing the oral antidiabetic drug in an organic or hydrophilic solvent, casting the resulting solution over a glass mold lined with aluminum foil or mercury, evaporating the solvent to form a film like matrix on the surface of aluminum foil or mercury, carefully removing the film from the glass mold containing aluminum foil or mercury surface, providing on the surface of the film a coating of a pressure sensitive adhesive and finally provided with another coating of a release liner consisting of paper or aluminum foil or hydrophobic synthetic polymer. In an embodiment of the invention the solvent to dissolve the polymers used is selected fi'om varying ranges of hydrophilicity and may be organic or aqueous solvents . According to another feature of the invention there is provided a process for the preparation of a membrane controlled transdermal device which comprises preparing a solution or dispersion or semisolid mass of an oral antidiabetic drug by dissolving or suspending the drug and hydrophilic polymer in an organic or hydrophilic solvent, sandwiching the resulting solution between a rate controlling membrane and backing membrane, providing a coating of a pressure sensitive adhesive and finally with another coating of a release liner of paper or aluminium foil or hydrophobic synthetic polymer on the rate controlling membrane. In an embodiment of the present invention the ratios of the polymers used may range of 0.5:4.5 ((hydrophilic-to-hydrophobic polymer) to 4.5:0.5 (hydrophilic-to-hydrophobic polymer). The rate controlling membrane, which controls the release of drug from reservoir, is prepared using microporous synthetic, semi-synthetic or natural polymer. The backing membrane is prepared using aluminum foil or synthetic hydrophobic polymer. The polymers used in the preparation of membrane controlled transdermal device are natural, synthetic or semi synthetic hydrophilic polymers. Preferred materials with the desired properties like gellying ability, viscosity, compatibility etc are carbopol, hydroxypropyl methylcellulose, hydroxy propyl cellulose, chitosan and sodium carboxy methylcellulose. More preferable polymers, which can be used according to the present invention, are carbopol and hydroxypropyl methylcellulose. The solvents like water or organic solvents along with cosolvents like propylene glycol, polyethylene glycol, ethanol, etc may be used to dissolve or disperse the drug and polymer to get solution or dispersion or semisolid mass. The matrix or membrane controlled transdermal device can be retained on the skin for a prolonged period of upto 48 hours by the incorporation of pressure sensitive adhesive which is coated on the matrix that comes in contact with skin. The pressure sensitive adhesive, which can be used, is selected from polyisobutylene, acrylate adhesives or silicone adhesives. Once the device is adhered onto the skin the device slowly releases the oral antidiabetic drug which permeates into the skin and finally reaches the systemic circulation. The term drug agent as used herein includes without limitation physiologically or pharmacologically active substances that are given orally for the treatment of diabetes mellitus. Drugs used with the transdermal device may preferably be glibenclamide and glipizide. To those skilled in the art, other oral antidiabetic drugs that can be permeated through skin can be utilized in the described delivery system. The amount of drug, which is incorporated into the transdermal device, depends upon the desired release profile, the concentration of the drug required for a biological effect and the length of time that the drug has to be released for the treatment. There is no critical upper limit on the amount of the drug incorporated into the device except for that of an acceptable solution or dispersion or gel viscosity. The lower limit of the drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for the treatment. In a preferred embodiment of the present invention, the matrix device may contain 18 mg of glibenclamide and 15 mg of glipizide to obtain the desired release characteristics like maintenance of required plasma concentration of oral antidiabetic drug for antidiabetic activity for a period of 24 hours. The membrane controlled transdermal device or oral antidiabetic drug may preferably contain 12 mg of glibenclamide and 10 mg of glipizide. The matrix type transdermal device and membrane controlled transdermal device slowly releases the drug on to skin surface and then the drug is permeated through skin. The details of the invention are described in the examples given below which are provided only to illustrate the invention and therefore they should not be construed to limit the scope of the invention. EXAMPLE 1 In this example, the method of preparation of matrix type transdermal device containing oral antidiabetic agent is explained. The matrix type transdermal device of oral antidiabetic drug was prepared using different ratios of ethyl cellulose/polyvinylpyrrolidone and Eudragit RL-100/Eudragit RS-100 as shown in Table 1. The polymers were weighed in requisite ratios keeping the total polymer weight 300 mg and dissolved in chloroform. di-n-Butyl phthalate was used as plasticizer. Glibenclamide / glipizide (18 mg and 15 mg respectively) was added and mixed slowly with mechanical stirrer. The polymeric solution of the drug (5 ml) was poured on to the surface of mercury placed on a glass plate (25 cm2) and dried at room temperature. After 24 h, the films were cut into 12 cm (3 cm x 4 cm) area and backmg membrane (polypropylene film) was then glued. The other side of the film like matrix was coated with polyisobutylene pressure sensitive adhesive and further coated with a glossy paper with smooth surface as release liner. Description of Table 1: EC=Ethyl cellulose; PVP=Polyvinylpyrrolidone; ERL=Eudragit RL-100; ERS=Eudragit RS 100. The in vitro skin permeation experiments of the matrix devices contammg oral antidiabetic drug as shown in Table 1 were conducted using vertical type diffusion cell having receptor compartment capacity of 20 ml. Membrane for the permeability studies was the dorsal section of full thickness skin from Swiss albino mice, 6-8 weeks old, whose hair had been removed on the previous day with an electric clipper. The results of in vitro skin permeation studies are shown in Fig. 1 and 2 of the drawing accompanying this specification. Fig 1 shows the results of in vitro skin permeation studies of matrix type transdermal devices of glibenclamide. Cumulative amount of glibenclamide permeated (μg/cm2) across mouse skin from matrix transdermal devices prepared with different proportions of ethyl cellulose and polyvinylpyrrolidone (Fig. a) and Eudragit RL-100 and Eudragit RS-100 (Fig. b) was plotted against time. Each point represents Mean+SD, n=3; * significant compared to EC:PVP (4.5:0.5); * significant compared to ERLiERS (2:3). Fig 2 shows the results of in vitro skin permeation studies of matrix type transdermal devices of glipizide. Cumulative amount of glipizide permeated μg/cm2) across mouse skin from matrix transdermal devices prepared with different proportions of ethyl cellulose and polyvinylpyrrolidone (Fig. a) and Eudragit RL-100 and Eudragit RS-100 (Fig. b) was plotted against time. Each point represents Mean±SD, n=3; * significant compared to EC:PVP (4.5:0.5); significant compared to ERL:ERS (2:3). Form the Fig. 1 and 2 the following can be observed. The matrix type transdermal devices of glibenclamide with ethyl cellulose:polyvinylpyrrolidone (3:2) and Eudragit RL-100:Eudragit RS-lOO (4:1) exhibited the greatest (262.92±15.25 and 254.58115.52μg respectively) cumulative amounts of drug permeation, which were significantly (p significantly (p EXAMPLE 2 In this example, the method of preparation of membrane controlled transdermal device containing oral antidiabetic agent is explained. The membrane controlled transdermal device consisted of a rate controlling membrane, reservoir of oral antidiabetic drug specifically glibenclamide and glipizide as shown in Table 2 and a backing membrane. The system was fabricated by encapsulating the drug reservoir within a shallow compartment molded from a drug impermeable backing laminate and a rate controlling membrane. Eudragit RL-100, Eudragit RS-100 and ethyl cellulose and ethylene vinyl acetate copolymer (EVA) membranes were used as rate controlling membranes. Eudragit RL-100, Eudragit RS-100 and ethyl cellulose membranes were prepared by dissolving 250, 300 and 300 mg of respective polymers in 5 ml chloroform. di-n-Butyl phthalate (30% w/w of polymer) was used as plasticizer. The polymeric solution was poured on the mercury surface of 25 cm2 area and dried at room temperature. Ethylene vinyl acetate membranes used contained 2%, 9% and 19% vinyl acetate content. The reservoir (0,5% carbopol gel) of the oral antidiabetic drug was prepared as per the formula given in Table 2, Carbopol was soaked in 5 ml water and neutralized using triethanolamine (q.s,) to form a gel. Drug in 5 ml ethanol was added slowly to carbopol gel with constant stirring. Accurately weighed quantity of gel (1 g) containing drug (12 mg of glibenclamide/10 mg of glipizide) was placed on a sheet of backing layer (a polyester film) covering 3 cm x 4 cm area. A rate controlling membrane prepared with Eudragit RL-100, Eudragit RS-lOO, ethyl cellulose and ethylene vinyl acetate was placed over the gel and the edges of 3 x 4 cm area was heat-sealed to obtain a leak proof device. To ensure intimate contact of the patch to the skin, a pressure sensitive adhesive, polyisobutylene, was applied onto rate controlling membrane (3 ml; 10% w/v in petroleum ether). A release liner (a fluropolymer coated polyester film) was placed over the adhesive coated rate controlling membrane. Table 2. Reservoir of the glibenclamide and glipizide membrane controlled transdermal systems The in vitro skin permeation experiments of membrane controlled transdermal devices containing oral antidiabetic drug were conducted using vertical type diffusion cell having receptor compartment capacity of 20 ml. Membrane for the permeability studies was the dorsal section of full thickness skin from Swiss albino mice, 6-8 weeks old, whose hair had been removed on the previous day with an electric clipper. The results of in vitro skin permeation studies are shown in Fig. 3 and 4. Fig. 3 shows the results of in vitro skin permeation studies of membrane controlled transdermal devices of glibenclamide. Cumulative amount of glibenclamide permeated (μg/cm2) across mouse skin from membrane controlled transdermal devices prepared using ethyl cellulose (EC), Eudragit RL-100 (ERL), Eudragit RS-100 (ERS) and ethylene vinyl acetate (EVA) rate controlling membranes containing 2%, 9% and 19% vinyl acetate (EVA2%, EVA9% and EVA19% respectively) was plotted against time. Each point represents MeanlSD, n=3; * significant compared to EVA2%. Fig 4 shows the results of in vitro skin permeation studies of membrane controlled transdermal devices of glipizide. Cumulative amount of glipizide permeated (μg/cm ) across mouse skin from membrane controlled transdermal devices prepared using ethyl cellulose (EC), Eudragit RL-100 (ERL), Eudragit RS-100 (ERS) and ethylene vinyl acetate (EVA) rate controlling membranes containing 2%, 9% and 19% vinyl acetate (EVA2%, EVA9% and EVA19% respectively) was plotted against time. Each point represents Mean±SD, n=3; * significant compared to EVA2%. From the details in the Fig, 3 and 4 the following is observed. The membrane (.uiurolled transdermal devices with Eudragit RL-100 rate controlling membrane exhibited the greatest (332.54±13.36 μg and 340.25±10.54 μg for glibenclamide and glipizide respectively) cumulative amounts of drug permeation followed by Eudragit RS-100 (291.57±12.31 μg and 294.36±12.01 μg for glibenclamide and glipizide respectively), ethyl cellulose (270.23±12.62 μ and 272.52±10.25 μg for glibenclamide and glipizide respectively), ethylene vinyl acetate membrane containing 19% vinyl acetate (267.25±10.28μg and 269.05±8.05μg for glibenclamide and glipizide respectively), ethylene vinyl acetate membrane containing 9% vinyl acetate (224.58±12.61μg and 228.34± 10.68 μg for glibenclamide and glipizide respectively) and ethylene vinyl acetate membrane containing 2% vinyl acetate (165.58±9.65 μg and 172.25±8.97μg for glibenclamide and glipizide respectively) membrane containing devices at the end of 24 h. In vivo evaluation of matrix type and membrane controlled type transdermal devices The in vivo evaluation of the matrix type and membrane-controlled types of transdermal devices was carried out in adult Swiss albino mice (6-8 weeks old) of either sex, weighing 25-30 g. The animals were housed in polypropylene cages, 4 per cage, with free access to standard laboratory diet and water. They were kept at 25i:l °C and 45-55% RH with a 12 h light/dark cycle. The in vivo experimental protocol was approved by the Institutional Animal Ethical Committee, Manipal (Approval No: IAEC/KMC/57/ 2001). The hypoglycemic activity of transdermal devices in normal and diabetic mice was carried out by determining the blood glucose levels were at different time intervals. The pharmacokinetic evaluation of the transdermal devices was carried out by withdrawing the blood samples at different time intervals and determining the plasma concentration of drug. The results are shown in Fig. 5 and 6. Fig. 5 shows the results of pharmacokinetic studies of transdermal devices of glibenclamide. Plasma concentration of glibenclamide was plotted against time after oral and transdermal device treatment in mice. Each point represents Mean±SE, n=6. TP=Transdermal patch; TP-R=Membrane controlled transdermal device; GLB=Glibenclamide. * significant compared to GLB-Oral (p Fig 6 shows the results of pharmacokinetic studies of transderma;l devices of glipizide. Plasma concentration of glipizide was plotted against time after oral and transdermal device treatment in mice. Each point represents Mean±SE, n==6. TP=Transdennal patch; TP-R=Membrane controlled transdermal device; GPZ=Glipizide. * significant compared to GPZ-Oral (p From the details in the Fig. 5 and 6, the following is observed. The pharmacokinetic parameters obtained with glibenclamide and glipizide transdermal drug delivery devices were significantly (p Advantages of the invention 1. The devices overcome the severe hypoglycemia, GI side effects and patient noncompliance. 2. The devices employ matrix or membrane controlled system as the carrier to transport the active agent (drug), which helps in the permeation of drug through skin in a controlled manner. 3. The devices retain the effective concentration of the active substance (drug) in plasma for a long time say for a period in the range of 0 to 48 hours. Therefore sustained release of oral antidiabetic drug through skin can be achieved with these devices. 4. The device is convenient and quantitative on the basis of the amount of active substance (drug) to be delivered into systemic circulation through skin. 5. The device is user friendly. We claim 1. A matrix type transdermal drug delivery system, which comprises a solid matrix made up of hydrophilic and hydrophobic polymers, the matrix containing an oral antidiabetic drug, and having coatings of a backing membrane, a pressure sensitive adhesive agent and a release liner. 2. A membrane controlled transdermal drug delivery system, which comprises a solution or dispersion or semi-solid mass of a hydrophilic polymer that is containing an oral antidiabetic drug, which is sandwiched between a rate controlling membrane and backing membrane, the external surface of the rate controlling membrane (which comes in contact with the skin) has a coating of a pressure sensitive adhesive and a release liner being provided below the pressure sensitive adhesive coating. 3. The matrix transdermal device as claimed in claim 1, wherein the ratio of the polymers used (hydrophilic-to-hydrophobic polymer) ranges from 0.5:4.5 to 4.5:0.5. 4. The membrane controlled transdermal device as claimed in claims 2, wherein the concentration of the polymer used ranges from 0.5-2%. 5. The matrix transdermal device as claimed in claims 1 & 3, wherein the solvent to dissolve the polymers used is selected from the class of organic or aqueous solvents. 6. The membrane controlled transdermal drug delivery device as claimed in claims 2 & 4, wherein the solvent to prepare the dispersion or solution or semisolid mass is selected from aqueous solvents (like water), organic solvents and other solvents like ethanol, propylene glycol, polyethylene glycol, etc. 7. The transdermal device as claimed in claims 1 to 6 wherein the oral antidiabetic drug used is selected from oral antidiabetic drugs specifically glibenclamide and glipizide. 8. A process for the preparation of a matrix type transdermal device as defined in claim 1 which comprises dissolving blends of hydrophilic and hydrophobic polymers containing an oral antidiabetic drug in a suitable solvent (organic solvent or aqueous solvent or blend of organic and aqueous solvent) and casting the resulting solution over a glass mold lined with aluminum foil or mercury, evaporating the solvent, removing the film like matrix formed from the glass mold and providing a coating on the surface of the matrix with adhesive and finally with another coating of a release liner. 9. A process for the preparation of a membrane controlled transdermal device as claimed in claim 2 which comprises preparing a solution or dispersion or semisolid mass of an oral antidiabetic drug by dissolving or suspending the drug and a hydrophilic polymer in a suitable solvent (organic solvent or aqueous solvent or blend of organic and aqueous solvent) and sandwitching the solution or dispersion or semisolid mass beiween a rate controlling membrane and backing membrane, providing a coating of pressure sensitive « adhesive to external surface of rate controlling membrane and finally with another coating of a release liner over the rate controlling membrane. 10. The process as claimed in claim 8 wherein the polymers used are selected fi'om the class of hydrophilic and hydrophobic polymers. 11. The process as claimed in claim 9 wherein the polymers used are selected from the class of hydrophilic polymers. 12. A process as claimed in claims 8 and 10, wherein the ratio of the polymers used (hydrophilic-to-hydrophobic polymer) used ranges from 0.5:4.5 to 4.5:0.5. 13. A process as claimed in claims 9 and 11 wherein the concentration of the polymer used ranges from 0.5-2%. 14. A process as claimed in claims 8 to 13 wherein the solvents used are selected from varying ranges of hydrophilicity and from the class of organic or aqueous solvents. 15. The process as claimed in claims 8 to 14 wherein the oral antidiabetic drug used is selected from the classes of oral antidiabetic drugs like sulfonylurea class and others types of oral antidiabetic drugs. 16. A matrix type transdermal drug delivery system containing an oral antidiabetic drug substantially as herein described with reference to the Example 1. 17. A membrane controlled transdermal drug delivery system containing an oral antidiabetic drug substantially as herein described with reference to the Example 2. 18. A process for the preparation of matrix type transdermal drug delivery system containing an oral antidiabetic drug substantially as herein described with reference to the Example 1. 19. A process for the preparation of membrane controlled transdermal drug delivery system containing an oral antidiabetic drug substantially as herein described with reference to the Example 2.

Documents:

169-che-2004- abstract.pdf

169-che-2004- claims duplicate.pdf

169-che-2004- claims original.pdf

169-che-2004- correspondence others.pdf

169-che-2004- correspondence po.pdf

169-che-2004- description complete duplicate.pdf

169-che-2004- description complete original.pdf

169-che-2004- drawings.pdf

169-che-2004- form 1.pdf

169-che-2004- form 19.pdf