Title of Invention	" A METHOD FOR THE PRODUCTION OF A TRANSDERMAL THERAPEUTIC SYSTEM"
Abstract	The invention relates to a transdermal therapeutic system which is made up of exclusively light-permeable layers and which is free of fibrous constituents, and to a method for the production of such a transdermal therapeutic system, in which method a preparation containing active substance is applied by a printing method onto the pressure-sensitive adhesive layer of the transdermal therapeutic system.

Title of Invention

" A METHOD FOR THE PRODUCTION OF A TRANSDERMAL THERAPEUTIC SYSTEM"

Abstract

The invention relates to a transdermal therapeutic system which is made up of exclusively light-permeable layers and which is free of fibrous constituents, and to a method for the production of such a transdermal therapeutic system, in which method a preparation containing active substance is applied by a printing method onto the pressure-sensitive adhesive layer of the transdermal therapeutic system.

Full Text	Fibre-free transdermal therapeutic system and method for its production The present invention relates to transdermal therapeutic systems (TTSs) and to methods for their production. More particularly, the invention relates to transdermal therapeutic systems which do not contain any fibrous constituents. The invention further relates to methods for the production of transdermal therapeutic systems wherein said systems are produced without the use of fibrous constituents and are loaded with active substance by a printing method. Transdermal therapeutic systems are systems for the controlled administration of pharmaceutical active substances via the skin. They have been used for some time for treating various diseases, physical as well as mental dysfunc— tions, complaints and indispositions. Transdermal therapeutic systems are layered products in the form of patches comprising an active substance-impermeable backing layer, at least one active substance-containing reservoir layer or matrix layer, possibly a membrane controlling the rate of active substance release, and a detachable protective layer, which is peeled of f the TTS before the latter is used. To fix a transdermal therapeutic system to the skin and to ensure a controlled administration of the active substance, the TTS is provided with a pressure-sensitive adhesive layer. This pressure-sensitive adhesive layer may be identical with the active substaz~ce-containing matrix layer or with the skin-facing active substance-containing layer, but may also be provided in addition thereto if the (skinfacing) active substance-containing layer or the, optionally provided, membrane is not pressure-sensitive adhesive. Commonly used transdermal therapeutic systems are those which have an active substance-containing reservoir made up of a nonwoven fabric or a paper, that is, of a fibrous material. The nicotine-containing TTS Nicotinell may be mentioned as an example for such transdermal therapeutic systems. Such nonwoven-comprising TTSs can be produced, for example, in accordance with the method described in EP 0 261 402 Al. The backing layer of a TTS must be impermeable to the active substance contained in the TTS in order to prevent undesirable exiting of the active substance from the side of the TTS which is averted from the skin. Materials used for this purpose are, in particular, metal foils, special plastic films as well as composite laminates of these materials. The most frequently used materials are composite laminates of aluminium, and plastic materials such as polyethylene terephthalate. The advantage of these composite laminates is that aluminium foils can be produced at low cost and are impermeable to almost all pharmaceutical active substances. In addition, aluminium foils are impermeable to light, which affords a reliable protection against light, particularly for light-sensitive active substances. A disadvantage of transdermal therapeutic systems that are provided with a backing layer which comprises an aluminium foil and/or coloured plastic films consists in that they invariably are visually conspicuous on the user's skin. Even if the TTS adhering to the user's skin can be covered by wearing clothes, there is a danger that a TTS having such a backing layer will meet with very little acceptance on the part of the user. For this reason, TTSs have become recently available which comprise a transparent backing layer and wherein the other layers, too, are permeable to light. In use, these TTSs are almost invisible against the skin to which they adhere since the user's natural skin colour is visible through the TTS. A method for the production of transdermal therapeutic systems having a transparent backing layer is described in US patent 5,626,866. In this method, an active substance-containing gel is produced from the active substance, a mixture of different permeation enhancers and a gelatinising agent, and is extruded between two layers of adhesive. Subsequently, individual, active substance-containing patches are punched out from the thus produced active substance-containing laminate. WO 00/37058 Al discloses transparent nicotine TTSs exhibiting an opacity index of 17.04% and 19.66%, respectively. They are produced in accordance with the method described in US patent 5,004,610. Scotchpak 1220 from the 3M Coinpany, or Saranex from the Dow Chemical Company are used as transparent backing layers. Furthermore, a film made of Baranes may also be used as the transparent backing layer; Baranes® is a graft copolymer material of 73 to 77% acrylonitrile and about 27 to 23% methacrylate, which is produced in the presence of 8 to 18 percent by weight of butadiene/acrylonitrile copolymers containing about 70 percent by weight of butadiene-based polymer units. To produce nicotine-containing TTSs, the pad printing method known from EP 0 303 025 Al may be employed. In said process amounts of 91 ing of solution are printed onto a pressure-sensitive adhesive surface of acrylate using an oval silicone foam rubber pad of a Shore hardness of 6 and a 50 percent by weight solution of nicotine in Miglyol® 812. Finally, from DE 44 00 769, a method for the production of sheet-like administration forms is known wherein a flowable preparation is transferred, with great accuracy, onto a nonwoven-like substrate of defined area by means of a distributor plate of an application device, said distribution plate being provided with at least one passage and said substrate being brought into contact with said distributor plate. It was the object of the present invention to provide a transdermal therapeutic system and a method for the production thereof wherein the drawbacks described hereinabove are avoided. More particularly, the aim is to provide a fibre-free TTS as well as a printing method for its production. This object has been achieved by a transdermal therapeutic system which can do without fibrous constituents. In a preferred embodiment, the TTS according to the invention comprises an active substance-impermeable, light-permeable backing layer, at least one light-permeable pressure-sensitive adhesive layer, onto which an active substance-containing preparation has been applied, and a detacha~le protective layer. Said TTS is characterised in that it is free of fibrous constituents. Any further, optionally present reservoir layers or matrix layers are also free of fibres and permeable to light. Hence, this embodiment of the TTS according to the invention consists exclu sively of light-permeable layers and is free of fibrous constituents. A light-permeable layer is understood to be a transparent or translucent layer. A transparent layer allows light to pass through it almost unhindered, whereas a translucent layer allows most of the light to pass through but scatters the light diffusely. The layers of a preferred embodiment of the inventive TTS are clear (totally) transparent. But at least one of the layers of the inventive TTS may also be tinted or - due to portions of organic and/or inorganic colour pigments - coloured such that the degree of their transparency depends on the wavelength of the light. In this way, totally or partially light-impermeable TTSs can be provided. In another preferred embodiment, the inventive TTS is skin-coloured. The TTS is thereby less conspicuous. As a rule, users indeed prefer inconspicuous patches so that other people are less likely to notice and find out about the user's need for treatment. To produce skin-coloured TTSs, the backing layer may be lacquered in a skin colour. Although it is not possible to provide the backing layer with a uniform opaque skin colour tone that will correspond to all skin colour tones present in the world population. But otherwise identical active substance patches can be provided with differently coloured backing layers, each colour being adapted to one of the skin colour tones present in the world population so that the patch will be acceptable to a rather large nuniber of users whose skin colour differs only in nuance. A fibrous constituent in the sense of the present invention is understood to mean relatively long, thin and flexible structures of natural or synthetic material. The fibrous constituents of natural materials include, for example, plant fibres, animal fibres and mineral fibres. Plant fibres, such as bast, cotton, hemp, coconut, linen, kapok or ran~ie, generally consist of cellulose. The animal fibres include silk and hair (wool). A naturally occurring mineral fibre is asbestos. The synthetic fibres include fibres of perlon, nylon, but also synthetic silk, glass fibres and carbon fibres. A number of fibres together form larger structures. Thus, textile fibres may jointly form a thread, a rope or a fabric. Cellulose fibres, for example, are used for the manufacture of paper and textiles. In the field of transdermal therapeutic systems, fibres are mainly used in the form of nonwovens, paper, long-fibre paper and textile sheet material having a supporting and/or distributing function or having a reservoir function. The pressure-sensitive adhesive layer and/or the optionally present reservoir layer(s) or matrix layer(s) of the TTS according to the invention may comprise a material which is selected from a group consisting pressure-sensitive adhesive polymers based on acrylic acid and/or methacrylic acid as well as esters thereof, polyacrylates, isobutylene, polyvinyl acetate, ethylene-vinyl acetate, natural and/or synthetic rubbers, for example acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, styrene-diene copolymers such as styrene-butadiene block copolymers, and hotmelt adhesives, or which is produced on the basis of pressure-sensitive adhesive silicone polymers or polysiloxanes. Preferably, the material comprising the pressure-sensitive adhesive layer is selected from the group comprising cationic copolymers based on dimethyla.minoethyl methacrylate and neutral methacrylic esters, for example Eudragit® E 100, and neutral copolymers based on butyl methacrylate and methyl methacrylates, for example Plastoid® B. For transparent or translucent TTSs, the pressure-sensitive adhesive layer of the TTS must be permeable to light. The pressure-sensitive adhesive layer is preferable clear-transparent, but can also be tinted or coloured. The backing layer, which is connected to the pressure-sensitive adhesive layer or to a reservoir layer or matrix layer, which is optionally provided in addition thereto, is impermeable to the active substance to be administered with the respective TTS and has occlusive properties. The backing layer of the TTS according to the invention may be permeable to light. It is free of fibrous constituents. In a particularly preferred embodiment, the backing layer is colourless, that is, it is clear-transparent. However, the light-permeable backing layer may also be tinted, or it may be coloured due to proportions of organic and/or inorganic colour pigments contained therein, so as to be totally or partially impermeable to light. In other embodiments, the TTS according to the invention may be entirely or partially impermeable to light. It is particularly preferred that the TTS be skin-coloured, for example by providing a backing layer that is lacquered in a skin colour. For the backing layer, any materials may be used that meet the aforementioned requirements. Such materials may, for example, be polymers from the group comprising polyethylene terephthalate, plasticised vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, poly urethane, polyvinylidene chloride, polypropylene, polyethylene or polyamide. The transdermal therapeutic system according to the invention contains at least one pharmaceutically active substance which can be delivered to a person via the skin. Suitable as the active substance are, in principle, any transdermally applicable pharmaceutical active substances which can be contained, as single active substances or in combination with one another, in a TTS and which can be administered transdermally. At room temperature, the active substance may be a solid but may also be liquid. Both nonvolatile active substances such as fentanyl, but also volatile active substances such as nicotine are suitable for administration with the TTS according to the invention. Further active substances, which may be contained in a TTS according to the invention, are, for example, alprostadil, buprenorphine, clonidine, dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also in combination with androgenic or progestinic active substances), fentanyl, flurbiprofen, lidocaine, methylphenidate, nitroglycerin, rotigotin, salicylic acid, scopolamine, testosterone and tulobuterol. The TTS according to the invention is manufactured without use of fibrous constituents, by applying the active substance by means of a suitable printing method onto the fibre-free pressure-sensitive adhesive layer. As printing method, the pad printing method is particularly suitable for loading the TTS with active substance. In this process, a flowable active substance preparation is transferred onto the pressure-sensitive adhesive layer by using a pad. This printing method is carried out at a constant temperature, thereby achieving high dosage accuracy. In a further suitable printing method, which, surprisingly, is suitable for the production of the transdermal therapeutic systems according to the present invention, the preparation containing the active substance is transferred, by a distributor plate of an application device, onto the fibre-free pressure-sensitive adhesive layer. To manufacture the TTS according to the invention, initially a fibre—free, preferably transparent, pressure-sensitive adhesive layer, located on an active substance-impermeable carrier layer, may be produced. Individually dosed portions of a preparation containing active substance are applied to said pressure-sensitive adhesive layer by employing a suitable printing method. In a further step, the backing layer is applied to the pressure-sensitive adhesive layer, which is provided with the active substance-containing preparation, in such a way that the active substance-containing preparation can no longer exit at that side of the resultant composite la.minate. Finally, individual TTSs are produced from the thus-obtained intermediate product by cutting and/or punching; said intermediate product, as the case may be, may comprise further reservoir or matrix layers and/or an active substance release-controlling membrane which likewise is free of fibres and which, if required, is permeable to light. In the finished TTS, the active substance-impermeable carrier layer represents the detachable layer. However, after applying the active substance-containing preparation, but before applying the backing layer, it is also possible to singularise TTSs from the composite lami nate1 which has by then be formed and to subsequently cover the TTS5 with a backing layer Thus, the method for the production of a transdermal therapeutic system is characterised in that - an active substance-impermeable carrier layer or an optionally present reservoir layer or matrix layer is provided with a fibre-free pressure-senSitive adhesive layer; - by a printing method, individually dosed portions of a flowable, active substance-containing preparation are applied onto the pressure-sensitive adhesive layer; and - in a further step, an active substance-impermeable, fibre-free backing layer is applied to the pressure-sensitive adhesive layer, which has been provided with the active substance-containing preparation, with TTSs being able to be singularised, by cutting and/or punching, prior to or following the application of the active substance-containing preparation, from the composite laminate which has by then been formed. To produce the TTS according to the present invention, the active substance must be present in a flowable state which permits single dosage by means of a suitable printing method. In the case of active substances which under normal manufacturing conditions are present as solids, this is done by adding suitable solvents as well as, as the case may be, by adding further auxiliary substances by means of which the viscosity of the active substance preparation can be adjusted. S~iitable as solvents are, in principle, any of the conventional organic solvents, such as ethanol, isopropyl alcohol, heptane, hexane, ethyl acetate, petroleum ether, benzine, acetone, glycerol, DEET (,N-diethyl-3-methylbenzamide), THF as well as many oils, for Example silicone oil, paraffin, triglycerides, neutral oil or plant oils. Liquid active substances may be applied directly by means of the printing method. Usually, however, liquid active substances, too, are employed in the form of a liquid that exhibits the desired viscosity as a result of an addition of suitable solvents and/or auxiliary substances. The viscosity of the active substance-containing preparation to be used as the printing medium is preferably in the range of 10 to 100 dPa~s, especially preferably in a range of 15 to 25 dPas. By performing the printing method at a temperature which is as constant as possible, it is possible to achieve a high accuracy of dosage. The printing method is preferably performed at room temperature, but can also be carried out at lower or higher temperatures. In a preferred manufacturing process, the active substance is mixed with a solution, suspension or dispersion of a polymer that is also a constituent of the fibre-free pressure-sensitive adhesive layer of the TTS to be produced. In that case, the viscosity of the mixture can be adjusted by adjusting the ratio of active substance to pressure-sensitive adhesive such that the mixture can be employed as a printing medium. This mixture is then used as the printing medium. Preferred polymers for the production of the printing medium are cationic polymers based on dimethylamioethyl methacrylate and neutral methacrylic esters, such as Eudragit E 100, and neutral copolymers based on butyl methacrylate and methyl methacrylates, for example Plastoid® B. The method is especially well suited for active substances which at room temperature are liquid and/or highly volatile so that dissolving the active substance in the adhesive and drying at temperatures between 60 and 100 0C is not possible because the active substance is too highly volatile or too therinosensitive. These active substances include, for example, nicotine, nitroglycerin, bupropion, but also essential oils such as menthol, camphor, turpentine, or oils from mountain pine, peppermint, spearmint, lemon or cloves, as well as almost all of the polypeptides and proteins. DEET and DMSO also belong to the highly volatile substances. In a particularly preferred method, Eudragit® E 100 is dissolved in nicotine, and this active substance solution is used as the printing medium. The quantity ratio of nicotine to Eudragit is preferably 1:1 to 1:3, especially preferably 1.4:1 up to 2.4:1. Other active substances that are suitable for being applied with this method are alprostadil, buprenorphine, clonidine, dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also in combination with androgenic or progestinic active substances), fentanyl, flurbiprof en, lidocaine, methyl phenidate, nitroglycerin, rotigotin, salicylic acid, scopolamine, testosterone and tulobuterol. ExampleA pressure-sensitive adhesive mass, consisting of 2.0825 kg of a 40% solution of a self-crosslinking acrylate polymer (of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid and titanium chelate ester; commercially available under the designation Durotak® 280-2416 (National Starch & Chemical B.V.)) in a mixture of acetic acid ethyl ester, ethanol, hexane and menthol, 147 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic esters (Eudragit® E 100 from the R6hm-Pharma company), as well as 20 g of a mixed-acidic triglyceride of fractionated coconut fatty acids C8-C10 (Miglyol® 812 from the Dynamit Nobel company) was applied onto a protective layer which had been vapour-coated on one side and rendered abhesive on both sides. Subsequently, the solvent was evaporated at 50 to 80 0C. A pressure-sensitive adhesive layer having a weight per unit area of approximately 300 g/m2 was obtained. From the thus-produced pressure-sensitive adhesive layer, circular blanks of a diameter of 65 mm were punched, and the projecting margins were removed. A dose of 102 ing nicotine was applied onto the pressure-sensitive adhesive layer of each circular blank as active substance preparation in the form of a solution (140 g of nicotine in 100 g Eudragit E 100). To this end, a pad printer, with a steel printing plate, having a round depression of 39 mm and an etching depth of 240 pm as the printing style, was used for printing the blanks. As pad, an oval silicone foam rubber pad, with a Shore hardness of 6, was used. The nicotine-Eudragit solution was used as the printing medium, and circular layers of said printing medium were placed on the blanks by using the pad. A transparent, 15-pm-thick polyester film was immediately laminated, as a nicotine-impermeable backing layer, onto the "patches" produced in the above-described manner. Subsequently, the finished products were sealed in four-sidesealed bags made of a known composite packaging material (Barex®). Claims 1. Method for the production of a transdermal therapeutic system, characterised in that - an active substance-impermeable carrier layer or an op- tionally present reservoir layer or matrix layer is pro- vided with a fibre-free pressure-sensitive adhesive layer, - by a printing method, individually dosed portions of a flowable, active substance-containing preparation are ap- plied onto the pressure-sensitive adhesive layer, said flowable active substance-containing preparation compris- ing a polymer which is also a constituent of the fibre- free pressure-sensitive adhesive layer, and - in a further step, an active substance-impermeable, fi- bre-free backing layer is applied onto the pressure- sensitive adhesive layer, which has been provided with the active substance-containing preparation, with TTSs being able to be singularised, by cutting and/or punching, prior to or following the application of the active substance-containing preparation, from the composite laminate which has by then been formed. 2. Method according to claim 1, characterised in that said printing method is a pad printing method. 3. Method according to claim 1, characterised in that said printing method is a method wherein the active sub stance-containing preparation is transferred onto the fi- bre-free pressure-sensitive adhesive layer by a distributor plate -of an application device, said distributor plate be- ing provided with at least one passage. 4. Method according to any one of the preceding claims, characterised in that the polymer is selected from the group comprising cationic copolymers based on dimethylami- noethyl methacrylate and neutral methacrylic esters, and neutral copolymers based on butyl methacrylate and methyl methacrylates. 5. Method according to any one of the preceding claims, characterised in that the viscosity of the flowable, active substance-containing preparation is adjusted by adding aux- iliary substances. 6. Method according to any one of the preceding claims, characterised in that the backing layer is completely or partially light-permeable, light-impermeable or skin- coloured. 7. Method according to any one of the preceding claims, characterised in that the backing layer is lacquered skin- coloured. 8. Method according to any one of the preceding claims, characterised in that the backing layer is free of fibres and consists of a material selected from the group compris- ing polyethylene terephthalate, plasticised vinyl acetate- vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene or polyamide. 9. Method according to any one of the preceding claims, characterised in that the pressure-sensitive adhesive layer is free of fibres and comprises a material which is se- lected from the group consisting of pressure-sensitive ad- hesive polymers based on acrylic acid and/or methacrylic acid as well as esters thereof, polyacrylates, isobutylene, polyvinyl acetate, ethylene-vinyl acetate, natural and/or synthetic rubbers, for example acrylonitrile-butadiene rub- ber, butyl rubber or neoprene rubber, styrene-diene copoly- mers such as styrene-butadiene block copolymers, and hot- melt adhesives, or which is produced on the basis of pres-sure-sensitive adhesive silicone polymers or polysiloxanes. 10. TTS according to claim 9, characterised in that the material is selected from the group comprising cationic co- polymers based on dimethylaminoethyl methacrylate and neu tral methacrylic esters, and neutral copolymers based on butyl methacrylate and methyl methacrylates. 11. Method according to any one of the preceding claims, characterised in that at room temperature the active sub stance is a liquid or solid. 12. Method according to any one of the preceding claims, characterised in that the active substance is selected from the group comprising alprostadil, buprenorphine, bupropion, clonidine, dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also in combination with androgenic or progestinic active substances), fentanyl, flurbiprofen, lidocaine, methylphenidate, nicotine, nitro-glycerin, rotigotin, salicylic acid, scopolamine, testos-terone, tulobuterol and essential oils. 13. Transdermal therapeutic system (TTS) comprising an ac- tive substance-impermeable backing layer, at least one pressure-sensitive adhesive layer onto which an active sub- stance-containing preparation has been applied, and a de- tachable protective layer, characterised in that said transdermal therapeutic system is free of fibrous constitu- ents and that the active substance-containing preparation comprises a polymer which is also a constituent of the fibre-free pressure-sensitive adhesive layer. 14. TTS according to claim 13, characterised in that said TTS, or the backing layer and the pressure-sensitive adhe- sive layer of the TTS, is/are permeable to light. 15. TTS according to claim 13, characterised in that said TTS is completely or partially impermeable to light. 16. TTS according to claim 15, characterised in that the backing layer is completely or partially impermeable to light. 17. TTS according to claim 13, characterised in that said TTS is skin-coloured. 18. TTS according to claim 17, characterised in that the backing layer is lacquered skin-coloured. 19. TTS according to any one of claims 1 to 18, character ised in that the backing layer is free of fibres and con sists of a material selected from the group comprising polyethylene terephthalate, plasticised vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copoly- mers, plasticized polyvinyl chloride, polyurethane, polyvi- nylidene chloride, polypropylene, polyethylene or polyam- ide. 20. TTS according to any one of claims 1 to 19, character- ised in that the pressure-sensitive adhesive layer is free of fibres and comprises a material which is selected from the group consisting of pressure-sensitive adhesive poly- mers based on acrylic acid and/or methacrylic acid as well as esters thereof, polyacrylates, isobutylene, polyvinyl acetate, ethylene-vinyl acetate and natural and/or syn thetic rubbers, or which is produced on the basis of pres- sure-sensitive adhesive silicone polymers or polysiloxanes. 21. TTS according to claim 19, characterised in that the material is selected from the group comprising cationic co- polymers based on dimethylaminoethyl methacrylate and neu- tral methacrylic esters, and neutral copolymers based on butyl methacrylate and methyl methacrylates. 22. TTS according to claims 1 to 21, characterised in that the TTS has at least one further reservoir layer or matrix layer, said further reservoir layer or matrix layer or said further reservoir layers or matrix layers being free of fi- bres and comprising a material which is selected from the group consisting of pressure-sensitive adhesive polymers based on acrylic acid and/or methacrylic acid as well as esters thereof, polyacrylates, isobutylene, polyvinyl ace- tate, ethylene-vinyl acetate, natural and/or synthetic rub- bers, for example acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, styrene-diene copolymers such as styrene-butadiene block copolymers, and hot-melt adhesives, or which is produced on the basis of pressure-sensitive ad- hesive silicone polymers or polysiloxanes. 23. TTS according to claim 22, characterised in that the material is selected from the group comprising cationic co- polymers based on dimethylaminoethyl methacrylate and neu- tral methacrylic esters, and neutral copolymers based on butyl methacrylate and methyl methacrylates. 24. TTS according to any one of claims 1 to 23, character ised in that at room temperature the active substance is a liquid or a solid. 25. TTS according to any one of claims 1 to 24, character ised in that the active substance is selected from the group comprising alprostadil, buprenorphine, bupropion, clonidine, dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also in combination with androgenic or progestinic active substances), fentanyl, flurbiprofen, lidocaine, methylphenidate, nicotine, nitro- glycerin, rotigotin, salicylic acid, scopolamine, testos- terone, tulobuterol and essential oils. 26. Transdermal therapeutic system (TTS) substantially as herein described with reference to the foregoing description and the accompanying example. To The Controller of Patents The Patent Office New Delhi

Full Text

Fibre-free transdermal therapeutic system and method for
its production

The present invention relates to transdermal therapeutic systems (TTSs) and to methods for their production. More particularly, the invention relates to transdermal therapeutic systems which do not contain any fibrous constituents.

The invention further relates to methods for the production of transdermal therapeutic systems wherein said systems are produced without the use of fibrous constituents and are loaded with active substance by a printing method.

Transdermal therapeutic systems are systems for the controlled administration of pharmaceutical active substances via the skin. They have been used for some time for treating various diseases, physical as well as mental dysfunc— tions, complaints and indispositions. Transdermal therapeutic systems are layered products in the form of patches comprising an active substance-impermeable backing layer, at least one active substance-containing reservoir layer or matrix layer, possibly a membrane controlling the rate of active substance release, and a detachable protective layer, which is peeled of f the TTS before the latter is used.

To fix a transdermal therapeutic system to the skin and to ensure a controlled administration of the active substance, the TTS is provided with a pressure-sensitive adhesive layer. This pressure-sensitive adhesive layer may be identical with the active substaz~ce-containing matrix layer or with the skin-facing active substance-containing layer, but

may also be provided in addition thereto if the (skinfacing) active substance-containing layer or the, optionally provided, membrane is not pressure-sensitive adhesive.

Commonly used transdermal therapeutic systems are those which have an active substance-containing reservoir made up of a nonwoven fabric or a paper, that is, of a fibrous material. The nicotine-containing TTS Nicotinell may be mentioned as an example for such transdermal therapeutic systems. Such nonwoven-comprising TTSs can be produced, for example, in accordance with the method described in EP 0 261 402 Al.

The backing layer of a TTS must be impermeable to the active substance contained in the TTS in order to prevent undesirable exiting of the active substance from the side of the TTS which is averted from the skin. Materials used for this purpose are, in particular, metal foils, special plastic films as well as composite laminates of these materials. The most frequently used materials are composite laminates of aluminium, and plastic materials such as polyethylene terephthalate. The advantage of these composite laminates is that aluminium foils can be produced at low cost and are impermeable to almost all pharmaceutical active substances. In addition, aluminium foils are impermeable to light, which affords a reliable protection against light, particularly for light-sensitive active substances.

A disadvantage of transdermal therapeutic systems that are provided with a backing layer which comprises an aluminium foil and/or coloured plastic films consists in that they invariably are visually conspicuous on the user's skin. Even if the TTS adhering to the user's skin can be covered by wearing clothes, there is a danger that a TTS having

such a backing layer will meet with very little acceptance on the part of the user.

For this reason, TTSs have become recently available which comprise a transparent backing layer and wherein the other layers, too, are permeable to light. In use, these TTSs are almost invisible against the skin to which they adhere since the user's natural skin colour is visible through the

TTS.

A method for the production of transdermal therapeutic systems having a transparent backing layer is described in US patent 5,626,866. In this method, an active substance-containing gel is produced from the active substance, a mixture of different permeation enhancers and a gelatinising agent, and is extruded between two layers of adhesive. Subsequently, individual, active substance-containing patches are punched out from the thus produced active substance-containing laminate.

WO 00/37058 Al discloses transparent nicotine TTSs exhibiting an opacity index of 17.04% and 19.66%, respectively. They are produced in accordance with the method described in US patent 5,004,610. Scotchpak 1220 from the 3M Coinpany, or Saranex from the Dow Chemical Company are used as transparent backing layers. Furthermore, a film made of Baranes may also be used as the transparent backing layer; Baranes® is a graft copolymer material of 73 to 77% acrylonitrile and about 27 to 23% methacrylate, which is produced in the presence of 8 to 18 percent by weight of butadiene/acrylonitrile copolymers containing about 70 percent by weight of butadiene-based polymer units.

To produce nicotine-containing TTSs, the pad printing method known from EP 0 303 025 Al may be employed. In said

process amounts of 91 ing of solution are printed onto a

pressure-sensitive adhesive surface of acrylate using an

oval silicone foam rubber pad of a Shore hardness of 6 and

a 50 percent by weight solution of nicotine in Miglyol®

812.

Finally, from DE 44 00 769, a method for the production of sheet-like administration forms is known wherein a flowable preparation is transferred, with great accuracy, onto a nonwoven-like substrate of defined area by means of a distributor plate of an application device, said distribution plate being provided with at least one passage and said substrate being brought into contact with said distributor plate.

It was the object of the present invention to provide a transdermal therapeutic system and a method for the production thereof wherein the drawbacks described hereinabove are avoided. More particularly, the aim is to provide a fibre-free TTS as well as a printing method for its production.

This object has been achieved by a transdermal therapeutic system which can do without fibrous constituents.

In a preferred embodiment, the TTS according to the invention comprises an active substance-impermeable, light-permeable backing layer, at least one light-permeable pressure-sensitive adhesive layer, onto which an active substance-containing preparation has been applied, and a detacha~le protective layer. Said TTS is characterised in that it is free of fibrous constituents. Any further, optionally present reservoir layers or matrix layers are also free of fibres and permeable to light. Hence, this embodiment of the TTS according to the invention consists exclu

sively of light-permeable layers and is free of fibrous constituents.

A light-permeable layer is understood to be a transparent or translucent layer. A transparent layer allows light to pass through it almost unhindered, whereas a translucent layer allows most of the light to pass through but scatters the light diffusely. The layers of a preferred embodiment of the inventive TTS are clear (totally) transparent. But at least one of the layers of the inventive TTS may also be tinted or - due to portions of organic and/or inorganic colour pigments - coloured such that the degree of their transparency depends on the wavelength of the light. In this way, totally or partially light-impermeable TTSs can be provided.

In another preferred embodiment, the inventive TTS is skin-coloured. The TTS is thereby less conspicuous. As a rule, users indeed prefer inconspicuous patches so that other people are less likely to notice and find out about the user's need for treatment.

To produce skin-coloured TTSs, the backing layer may be lacquered in a skin colour. Although it is not possible to provide the backing layer with a uniform opaque skin colour tone that will correspond to all skin colour tones present in the world population. But otherwise identical active substance patches can be provided with differently coloured backing layers, each colour being adapted to one of the skin colour tones present in the world population so that the patch will be acceptable to a rather large nuniber of users whose skin colour differs only in nuance.

A fibrous constituent in the sense of the present invention is understood to mean relatively long, thin and flexible

structures of natural or synthetic material. The fibrous constituents of natural materials include, for example, plant fibres, animal fibres and mineral fibres. Plant fibres, such as bast, cotton, hemp, coconut, linen, kapok or ran~ie, generally consist of cellulose. The animal fibres include silk and hair (wool). A naturally occurring mineral fibre is asbestos. The synthetic fibres include fibres of perlon, nylon, but also synthetic silk, glass fibres and carbon fibres. A number of fibres together form larger structures. Thus, textile fibres may jointly form a thread, a rope or a fabric. Cellulose fibres, for example, are used for the manufacture of paper and textiles. In the field of transdermal therapeutic systems, fibres are mainly used in the form of nonwovens, paper, long-fibre paper and textile sheet material having a supporting and/or distributing function or having a reservoir function.

The pressure-sensitive adhesive layer and/or the optionally present reservoir layer(s) or matrix layer(s) of the TTS according to the invention may comprise a material which is selected from a group consisting pressure-sensitive adhesive polymers based on acrylic acid and/or methacrylic acid as well as esters thereof, polyacrylates, isobutylene, polyvinyl acetate, ethylene-vinyl acetate, natural and/or synthetic rubbers, for example acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, styrene-diene copolymers such as styrene-butadiene block copolymers, and hotmelt adhesives, or which is produced on the basis of pressure-sensitive adhesive silicone polymers or polysiloxanes.

Preferably, the material comprising the pressure-sensitive adhesive layer is selected from the group comprising cationic copolymers based on dimethyla.minoethyl methacrylate and neutral methacrylic esters, for example Eudragit® E

100, and neutral copolymers based on butyl methacrylate and methyl methacrylates, for example Plastoid® B.

For transparent or translucent TTSs, the pressure-sensitive adhesive layer of the TTS must be permeable to light. The pressure-sensitive adhesive layer is preferable clear-transparent, but can also be tinted or coloured.

The backing layer, which is connected to the pressure-sensitive adhesive layer or to a reservoir layer or matrix layer, which is optionally provided in addition thereto, is impermeable to the active substance to be administered with the respective TTS and has occlusive properties. The backing layer of the TTS according to the invention may be permeable to light. It is free of fibrous constituents. In a particularly preferred embodiment, the backing layer is colourless, that is, it is clear-transparent. However, the light-permeable backing layer may also be tinted, or it may be coloured due to proportions of organic and/or inorganic colour pigments contained therein, so as to be totally or partially impermeable to light.

In other embodiments, the TTS according to the invention may be entirely or partially impermeable to light. It is particularly preferred that the TTS be skin-coloured, for example by providing a backing layer that is lacquered in a skin colour.

For the backing layer, any materials may be used that meet the aforementioned requirements.

Such materials may, for example, be polymers from the group comprising polyethylene terephthalate, plasticised vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, poly

urethane, polyvinylidene chloride, polypropylene, polyethylene or polyamide.

The transdermal therapeutic system according to the invention contains at least one pharmaceutically active substance which can be delivered to a person via the skin. Suitable as the active substance are, in principle, any transdermally applicable pharmaceutical active substances which can be contained, as single active substances or in combination with one another, in a TTS and which can be administered transdermally. At room temperature, the active substance may be a solid but may also be liquid. Both nonvolatile active substances such as fentanyl, but also volatile active substances such as nicotine are suitable for administration with the TTS according to the invention.

Further active substances, which may be contained in a TTS according to the invention, are, for example, alprostadil, buprenorphine, clonidine, dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also in combination with androgenic or progestinic active substances), fentanyl, flurbiprofen, lidocaine, methylphenidate, nitroglycerin, rotigotin, salicylic acid, scopolamine, testosterone and tulobuterol.

The TTS according to the invention is manufactured without use of fibrous constituents, by applying the active substance by means of a suitable printing method onto the fibre-free pressure-sensitive adhesive layer.

As printing method, the pad printing method is particularly suitable for loading the TTS with active substance. In this process, a flowable active substance preparation is transferred onto the pressure-sensitive adhesive layer by using

a pad. This printing method is carried out at a constant temperature, thereby achieving high dosage accuracy.

In a further suitable printing method, which, surprisingly, is suitable for the production of the transdermal therapeutic systems according to the present invention, the preparation containing the active substance is transferred, by a distributor plate of an application device, onto the fibre-free pressure-sensitive adhesive layer.

To manufacture the TTS according to the invention, initially a fibre—free, preferably transparent, pressure-sensitive adhesive layer, located on an active substance-impermeable carrier layer, may be produced. Individually dosed portions of a preparation containing active substance are applied to said pressure-sensitive adhesive layer by employing a suitable printing method.

In a further step, the backing layer is applied to the pressure-sensitive adhesive layer, which is provided with the active substance-containing preparation, in such a way that the active substance-containing preparation can no longer exit at that side of the resultant composite la.minate. Finally, individual TTSs are produced from the thus-obtained intermediate product by cutting and/or punching; said intermediate product, as the case may be, may comprise further reservoir or matrix layers and/or an active substance release-controlling membrane which likewise is free of fibres and which, if required, is permeable to light. In the finished TTS, the active substance-impermeable carrier layer represents the detachable layer.

However, after applying the active substance-containing preparation, but before applying the backing layer, it is also possible to singularise TTSs from the composite lami

nate1 which has by then be formed and to subsequently cover the TTS5 with a backing layer

Thus, the method for the production of a transdermal therapeutic system is characterised in that

- an active substance-impermeable carrier layer or an optionally present reservoir layer or matrix layer is provided with a fibre-free pressure-senSitive adhesive layer;

- by a printing method, individually dosed portions of a flowable, active substance-containing preparation are applied onto the pressure-sensitive adhesive layer; and

- in a further step, an active substance-impermeable, fibre-free backing layer is applied to the pressure-sensitive adhesive layer, which has been provided with the active substance-containing preparation,

with TTSs being able to be singularised, by cutting and/or punching, prior to or following the application of the active substance-containing preparation, from the composite laminate which has by then been formed.

To produce the TTS according to the present invention, the active substance must be present in a flowable state which permits single dosage by means of a suitable printing method. In the case of active substances which under normal manufacturing conditions are present as solids, this is done by adding suitable solvents as well as, as the case may be, by adding further auxiliary substances by means of which the viscosity of the active substance preparation can be adjusted. S~iitable as solvents are, in principle, any of the conventional organic solvents, such as ethanol, isopropyl alcohol, heptane, hexane, ethyl acetate, petroleum ether, benzine, acetone, glycerol, DEET (,N-diethyl-3-methylbenzamide), THF as well as many oils, for Example

silicone oil, paraffin, triglycerides, neutral oil or plant oils.

Liquid active substances may be applied directly by means of the printing method. Usually, however, liquid active substances, too, are employed in the form of a liquid that exhibits the desired viscosity as a result of an addition of suitable solvents and/or auxiliary substances.

The viscosity of the active substance-containing preparation to be used as the printing medium is preferably in the range of 10 to 100 dPa~s, especially preferably in a range of 15 to 25 dPas.

By performing the printing method at a temperature which is as constant as possible, it is possible to achieve a high accuracy of dosage. The printing method is preferably performed at room temperature, but can also be carried out at lower or higher temperatures.

In a preferred manufacturing process, the active substance is mixed with a solution, suspension or dispersion of a polymer that is also a constituent of the fibre-free pressure-sensitive adhesive layer of the TTS to be produced. In that case, the viscosity of the mixture can be adjusted by adjusting the ratio of active substance to pressure-sensitive adhesive such that the mixture can be employed as a printing medium. This mixture is then used as the printing medium. Preferred polymers for the production of the printing medium are cationic polymers based on dimethylamioethyl methacrylate and neutral methacrylic esters, such as Eudragit E 100, and neutral copolymers based on butyl methacrylate and methyl methacrylates, for example Plastoid® B.

The method is especially well suited for active substances which at room temperature are liquid and/or highly volatile so that dissolving the active substance in the adhesive and drying at temperatures between 60 and 100 0C is not possible because the active substance is too highly volatile or too therinosensitive. These active substances include, for example, nicotine, nitroglycerin, bupropion, but also essential oils such as menthol, camphor, turpentine, or oils from mountain pine, peppermint, spearmint, lemon or cloves, as well as almost all of the polypeptides and proteins. DEET and DMSO also belong to the highly volatile substances.

In a particularly preferred method, Eudragit® E 100 is dissolved in nicotine, and this active substance solution is used as the printing medium. The quantity ratio of nicotine to Eudragit is preferably 1:1 to 1:3, especially preferably 1.4:1 up to 2.4:1.

Other active substances that are suitable for being applied with this method are alprostadil, buprenorphine, clonidine, dexamethasone, dextroamphetamine, diclofenac, dihydrotestosterone, estradiol (also in combination with androgenic or progestinic active substances), fentanyl, flurbiprof en, lidocaine, methyl phenidate, nitroglycerin, rotigotin, salicylic acid, scopolamine, testosterone and tulobuterol.

ExampleA pressure-sensitive adhesive mass, consisting of 2.0825 kg of a 40% solution of a self-crosslinking acrylate polymer (of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid and titanium chelate ester; commercially available under the designation Durotak® 280-2416 (National Starch & Chemical

B.V.)) in a mixture of acetic acid ethyl ester, ethanol, hexane and menthol, 147 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic esters (Eudragit® E 100 from the R6hm-Pharma company), as well as 20 g of a mixed-acidic triglyceride of fractionated coconut fatty acids C8-C10 (Miglyol® 812 from the Dynamit Nobel company) was applied onto a protective layer which had been vapour-coated on one side and rendered abhesive on both sides. Subsequently, the solvent was evaporated at 50 to 80 0C. A pressure-sensitive adhesive layer having a weight per unit area of approximately 300 g/m2 was obtained. From the thus-produced pressure-sensitive adhesive layer, circular blanks of a diameter of 65 mm were punched, and the projecting margins were removed.

A dose of 102 ing nicotine was applied onto the pressure-sensitive adhesive layer of each circular blank as active substance preparation in the form of a solution (140 g of nicotine in 100 g Eudragit E 100). To this end, a pad printer, with a steel printing plate, having a round depression of 39 mm and an etching depth of 240 pm as the printing style, was used for printing the blanks. As pad, an oval silicone foam rubber pad, with a Shore hardness of 6, was used. The nicotine-Eudragit solution was used as the printing medium, and circular layers of said printing medium were placed on the blanks by using the pad.

A transparent, 15-pm-thick polyester film was immediately laminated, as a nicotine-impermeable backing layer, onto the "patches" produced in the above-described manner. Subsequently, the finished products were sealed in four-sidesealed bags made of a known composite packaging material (Barex®).

Claims
1. Method for the production of a transdermal therapeutic
system, characterised in that
- an active substance-impermeable carrier layer or an op-
tionally present reservoir layer or matrix layer is pro-
vided with a fibre-free pressure-sensitive adhesive
layer,
- by a printing method, individually dosed portions of a
flowable, active substance-containing preparation are ap-
plied onto the pressure-sensitive adhesive layer, said
flowable active substance-containing preparation compris-
ing a polymer which is also a constituent of the fibre-
free pressure-sensitive adhesive layer, and
- in a further step, an active substance-impermeable, fi-
bre-free backing layer is applied onto the pressure-
sensitive adhesive layer, which has been provided with
the active substance-containing preparation,
with TTSs being able to be singularised, by cutting and/or punching, prior to or following the application of the active substance-containing preparation, from the composite laminate which has by then been formed.
2. Method according to claim 1, characterised in that
said printing method is a pad printing method.
3. Method according to claim 1, characterised in that
said printing method is a method wherein the active sub
stance-containing preparation is transferred onto the fi-
bre-free pressure-sensitive adhesive layer by a distributor
plate -of an application device, said distributor plate be-
ing provided with at least one passage.
4. Method according to any one of the preceding claims,
characterised in that the polymer is selected from the
group comprising cationic copolymers based on dimethylami-
noethyl methacrylate and neutral methacrylic esters, and

neutral copolymers based on butyl methacrylate and methyl methacrylates.
5. Method according to any one of the preceding claims,
characterised in that the viscosity of the flowable, active
substance-containing preparation is adjusted by adding aux-
iliary substances.
6. Method according to any one of the preceding claims,
characterised in that the backing layer is completely or
partially light-permeable, light-impermeable or skin-
coloured.
7. Method according to any one of the preceding claims,
characterised in that the backing layer is lacquered skin-
coloured.
8. Method according to any one of the preceding claims,
characterised in that the backing layer is free of fibres
and consists of a material selected from the group compris-
ing polyethylene terephthalate, plasticised vinyl acetate-
vinyl chloride copolymers, nylon, ethylene-vinyl acetate
copolymers, plasticized polyvinyl chloride, polyurethane,
polyvinylidene chloride, polypropylene, polyethylene or
polyamide.
9. Method according to any one of the preceding claims,
characterised in that the pressure-sensitive adhesive layer
is free of fibres and comprises a material which is se-
lected from the group consisting of pressure-sensitive ad-
hesive polymers based on acrylic acid and/or methacrylic
acid as well as esters thereof, polyacrylates, isobutylene,
polyvinyl acetate, ethylene-vinyl acetate, natural and/or
synthetic rubbers, for example acrylonitrile-butadiene rub-
ber, butyl rubber or neoprene rubber, styrene-diene copoly-
mers such as styrene-butadiene block copolymers, and hot-

melt adhesives, or which is produced on the basis of pres-sure-sensitive adhesive silicone polymers or polysiloxanes.
10. TTS according to claim 9, characterised in that the
material is selected from the group comprising cationic co-
polymers based on dimethylaminoethyl methacrylate and neu
tral methacrylic esters, and neutral copolymers based on
butyl methacrylate and methyl methacrylates.
11. Method according to any one of the preceding claims,
characterised in that at room temperature the active sub
stance is a liquid or solid.
12. Method according to any one of the preceding claims,
characterised in that the active substance is selected from
the group comprising alprostadil, buprenorphine, bupropion,
clonidine, dexamethasone, dextroamphetamine, diclofenac,
dihydrotestosterone, estradiol (also in combination with
androgenic or progestinic active substances), fentanyl,
flurbiprofen, lidocaine, methylphenidate, nicotine, nitro-glycerin, rotigotin, salicylic acid, scopolamine, testos-terone, tulobuterol and essential oils.
13. Transdermal therapeutic system (TTS) comprising an ac-
tive substance-impermeable backing layer, at least one
pressure-sensitive adhesive layer onto which an active sub-
stance-containing preparation has been applied, and a de-
tachable protective layer, characterised in that said
transdermal therapeutic system is free of fibrous constitu-
ents and that the active substance-containing preparation
comprises a polymer which is also a constituent of the
fibre-free pressure-sensitive adhesive layer.
14. TTS according to claim 13, characterised in that said
TTS, or the backing layer and the pressure-sensitive adhe-
sive layer of the TTS, is/are permeable to light.

15. TTS according to claim 13, characterised in that said
TTS is completely or partially impermeable to light.
16. TTS according to claim 15, characterised in that the
backing layer is completely or partially impermeable to
light.
17. TTS according to claim 13, characterised in that said
TTS is skin-coloured.
18. TTS according to claim 17, characterised in that the
backing layer is lacquered skin-coloured.
19. TTS according to any one of claims 1 to 18, character
ised in that the backing layer is free of fibres and con
sists of a material selected from the group comprising
polyethylene terephthalate, plasticised vinyl acetate-vinyl
chloride copolymers, nylon, ethylene-vinyl acetate copoly-
mers, plasticized polyvinyl chloride, polyurethane, polyvi-
nylidene chloride, polypropylene, polyethylene or polyam-
ide.
20. TTS according to any one of claims 1 to 19, character-
ised in that the pressure-sensitive adhesive layer is free
of fibres and comprises a material which is selected from
the group consisting of pressure-sensitive adhesive poly-
mers based on acrylic acid and/or methacrylic acid as well
as esters thereof, polyacrylates, isobutylene, polyvinyl
acetate, ethylene-vinyl acetate and natural and/or syn
thetic rubbers, or which is produced on the basis of pres-
sure-sensitive adhesive silicone polymers or polysiloxanes.
21. TTS according to claim 19, characterised in that the
material is selected from the group comprising cationic co-
polymers based on dimethylaminoethyl methacrylate and neu-
tral methacrylic esters, and neutral copolymers based on
butyl methacrylate and methyl methacrylates.

22. TTS according to claims 1 to 21, characterised in that
the TTS has at least one further reservoir layer or matrix
layer, said further reservoir layer or matrix layer or said
further reservoir layers or matrix layers being free of fi-
bres and comprising a material which is selected from the
group consisting of pressure-sensitive adhesive polymers
based on acrylic acid and/or methacrylic acid as well as
esters thereof, polyacrylates, isobutylene, polyvinyl ace-
tate, ethylene-vinyl acetate, natural and/or synthetic rub-
bers, for example acrylonitrile-butadiene rubber, butyl
rubber or neoprene rubber, styrene-diene copolymers such as
styrene-butadiene block copolymers, and hot-melt adhesives,
or which is produced on the basis of pressure-sensitive ad-
hesive silicone polymers or polysiloxanes.
23. TTS according to claim 22, characterised in that the
material is selected from the group comprising cationic co-
polymers based on dimethylaminoethyl methacrylate and neu-
tral methacrylic esters, and neutral copolymers based on
butyl methacrylate and methyl methacrylates.
24. TTS according to any one of claims 1 to 23, character
ised in that at room temperature the active substance is a
liquid or a solid.
25. TTS according to any one of claims 1 to 24, character
ised in that the active substance is selected from the
group comprising alprostadil, buprenorphine, bupropion,
clonidine, dexamethasone, dextroamphetamine, diclofenac,
dihydrotestosterone, estradiol (also in combination with
androgenic or progestinic active substances), fentanyl,
flurbiprofen, lidocaine, methylphenidate, nicotine, nitro-
glycerin, rotigotin, salicylic acid, scopolamine, testos-
terone, tulobuterol and essential oils.

26. Transdermal therapeutic system (TTS) substantially as herein described with reference to the foregoing description and the accompanying example.
To
The Controller of Patents The Patent Office New Delhi

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Patent Number

263589

Indian Patent Application Number

6881/DELNP/2007

PG Journal Number

45/2014

Publication Date

07-Nov-2014

Grant Date

04-Nov-2014

Date of Filing

05-Sep-2007

Name of Patentee

LTS LOHMANN THERAPIE-SYSTEME AG

Applicant Address

LOHMANNSTRASSE 2, 56626 ANDERNACH, GERMANY.

Inventors:

#	Inventor's Name	Inventor's Address
1	MECONI, REINHOLD	ALEMANNENSTRASSE 42, 56567 NEUWIED, GERMANY.
2	SCHUMANN, KLAUS	BOSENERSTRASSE 6,56567 NEUWIED, GERMANY.

PCT International Classification Number

A61K 9/70

PCT International Application Number

PCT/EP2006/001840

PCT International Filing date

2006-02-28

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	102005 010 255.7	2005-03-07	Germany