NZ298428A - Transdermal system to dispense (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazol or salt thereof - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £98428 9 New Zealand No 298428 International No PCT/EP96/00074 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 14 01 1995, Complete Specification Filed 10 01 1996 Classification (6) A61K9/70, A61K31/42 Publication date 28 October 1999 Journal No 1445 Title of Invention Transdermal therapeutic system for dispensing (s)-3-methyl-5-(1 -methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutical^ acceptable salts Name, address and nationality of applicant(s) as in international application form ABBOTT LABORATORIES, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, United States of America NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION \ 1 A transdermal therapeutic system for the administration of (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutical^ acceptable salts SPECIFICATION The present invention relates to an gdministration form for the administration of (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutical^ acceptable salts and to a process for its production The active substance (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole stands out for a highly specific agonistic effect on the parasympathetic nervous system, in particular on the nicotinic receptors Based on recent studies of the Alzheimer's disease therapy, the application of this active substance seems to improve the cognitive abilities of diseased persons to a considerable extent In this connection, however, regular and quantitatively constant administration of the active substance is an important factor to ensure constantly effective blood levels over extended periods So far the active substance has been administered exclusively by the oral route However, the oral administration of drugs to patients suffering from dementia imposes unacceptable requirements on the nursing staff, since the patient - owing to his disease - is not able to control the intake on his own.

It is the object of the present invention to provide an administration form for the administration of the active substance (s)-3-methyl-5-(1-methyl-2-pyrrolidenyl)-isoxazole to achieve a highly specific agonistic effect on the parasympathetic nervous system of patients suffering from dementia Replacing the hitherto required regular oral administration at short intervals, it can achieve a constantly effective blood level and - for the patients' well-being - relieves the nursing staff from the burden and alertness experienced as a disadvantage so far To achieve this object the present invention provides a new administration form to administer (s)-3-methyl-5- (1 -methyl-2-pyr-rolidenyU-isoxazole or one of its pharmaceutical^ acceptable salts, which consists in the fact that it is present in the form of a patch as a transdermal therapeutic system (TTS) Accordingly, the subject matter of the present invention is a TTS for the administration of (s)-3-methyl-5- (1-methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutical^ acceptable salts, which is present in the form of a patch and comprises a suitable backing layer, an active substance reservoir connected thereto, a membrane controlling the active substance release if other control mechanisms are absent, a pressure-sensitive adhesive facility to fix the system to the skin, and, if required, a protective layer removable prior to the application of the system The suitable backing layer may consist both of a flexible and inflexible material which is impermeable to active substances Substances suitable for its production include polymeric sheets or metallic foils, such as aluminum foils which may be used alone or coated with a polymeric substrate In addition, textile fabrics may also be used if the reservoir cannot penetrate through them owing to their physical property, or if penetration is prevented by an adequate layer The active substance reservoir may have either a layered or a bag-type structure.

The layered reservoir may optionally consist of a polymeric matrix and the pure active substance or of a suitable active substance formulation, wherein the cohesion of the system as such is 3 provided by the polymer properties The reservoir consists of a base polymer and conventional additives The choice of the polymer matrix and the base polymer depends on the physicochemical properties of the active substance on the one hand, and on the desired release from the system on 5 the other hand In principle, any polymei is suitable that is used in the production of pressure-sensitive adhesives and which is compatible with the active substance Examples thereof include rubber, rubber-like homo-, co- or block polymers, poiyacrylates and their copolymers, and hot-melt adhesives Particularly preferred are polymers based on styrene and 1,3-10 dienes, polyisobutylenes and polyterpenes, polymers based on conventional acrylate monomers and their derivatives, or ethylene-vinyl-a^etate copolymers Among the block polymers based on styrene and 1,3-dienes linear styrene-isoprene-block-polymers are preferably used Preferred polymers based on acrylate are acrylic acid copolymers of 2-ethylhexyl 1 5 acrylate, vinyl acetate and acrylic acid with or without cross-linking agents Methacrylates are primarily understood as copolymeis based on dimethylaminomethacrylate and neutral methacrylic acid esters with or without cross-linking agents Other preferred polymers include esters of the hydiogenated colophony, in particular methyl or glyercol esters of hydrogenated colophony The kind and amount of possible additives depends on the polymer matrix used and on the active substance According to their function they may be 25 classified into the following groups plasticizers, tackifiers, stabilizers, carrier substances, diffusion and penetration regulating additives, or fillers The physiologically acceptable substances suitable for this purpose are known to pharmacists The plasticizer may be present in concentration of 0-30%, preferably 5-20%, relative to the total weight of the matrix The plasticizer may comprise at least one component selected from the groups of hydrocarbons, alcohols, carboxylic acids and their derivatives, ethers, esters or amines Preferably, the plasticizer comprises a natural or partially synthetic triglyceride or a mixture of these triglycerides in a concentration ranging from 0-30%, preferably in the range 5-20%, relative to the total weight of the matrix The permeation enhancer, if present, may be in a concentration ranging from 0-30%, preferably in the range 5-20%, relative to the total weight of the matrix Preferably, the permeation enhancer comprises at least one component selected from the groups of hydrocarbons, alcohols, carboxylic acids and their derivatives, ethers, esters, or amines Alternatively the permeation enhancer comprises at least one component selected from the group consisting of mono-, di- or sesquiter- penes As a further alternative, the permeation enhancer comprises at least one component selected from the group consisting of polyoxyethylene derivatives Alternatively, the permeation enhancer comprises a component selected from the group consisting of nitrogen-containing heterocycles and their derivatives As a further alternative, the permeation enhancer comprises a component selected from the group consisting of pyrrohdone derivatives A bag-type reservoir system may consist of the pure active substance or of a highly viscous or semisolid or thixotropic active substance preparation Particularly suitable are oily or aqueous gels which are dosed into a bag made of suitable sheetings or membrane materials In this connection, production of the active substance preparation may be carried out on the basis of lipophilic or hydrophilic bases In this case, the back of the bag, which is averted from the skin, must be impermeable to the active @ substance Preferably, a membrane which is permeable to the active substance can control the active substance release In the absence of other control mechanisms, the reservoir may be 5 combined with a membrane controlling the active substance release and a pressure-sensitive adhesive device to fix the system to the skin A reservoir not sufficiently adhering to the skin represents a particular case, this is combined with a special pressure-sensitive adhesive layer ensuring permanent contact of the system to the skin In principle, the same 10 materials as those used for the polymer matrix of the reservoir are suitable for the pressure-sensitive adhesive facility The protective layer which, if required, is to be removed prior to application may consist of the same materials as those used for the backing layer of 1 5 the system provided that they have been rendered removable, e g , by a silicone treatment However, it is also possible to use other protective layers, such as paper treated with polytetrafluoroethylene, cellophane, polyvinyl chlorido, polyvinylidene chloride, and the like If the laminate according to the present invention is divided into formats adequate for 20 therapy (patches) prior to application of the protective layer, the formats of the protective layer to be applied then may have a projecting end to make their removal from the patch easier In accordance with the layered or bag-type construction of the transdermal 25 systems described hereinabove, two different production processes are described a The active substance is homogeneously mixed with the components of the active substance reservoir, optionally in solution or under heating and 30 cooling, and applied to the cover layer which is permeable to the active substances or to a textile fabric lying thereon, whereupon the solvent/s is/are removed, if necessary Depending on whether the reservoir layer is

Claims (2)

1. 10. 15. 20. 6. is/are removed, if necessary Depending on whether the reservoir layer is self-adhesive or not, a pressure-sensitive adhesive device for permanent attachment to the skin is introduced between the reservoir and the protective layer which is removed in case of need b Within an adequate device, the liquid active substance or the liquid or semisolid or thixotropic active substance formulation is dosed onto a membrane which is permeable to the active substance and coveted with a suitable sheeting, avoiding the formation of voids as far as possible, whereupon the membrane and the sheeting are tightly sealed to form a bag Optionally, dosage may be carried out into a textile fabric which can additionally serve as a support It is also possible to dose into preformed bags The reservoir bag filled with active substance is additionally combined with a pressure-sensitive adhesive device, which may also have a multilayered structure and be provided with a control function for active substance release, and is subsequently covered with a protective layer which is removed in the case of need Preferably, when a hot-melt adhesive is incorporated, the components of the hot-melt adhesive are incorporated prior to the addition of the active substance, under heating to preferably 11 0 to 1 70°C until a homogenous melt of 70 to 100°C is obtained Where appropriate, the homogenous, active-substance-containing hot- melt adhesive mass is applied by means of extrusion, casting, roller coating, knife coating or by a printing process 7. i (J CLAIMS 1 An administration form for the administration of (s)-3-methyl-5-(1 -methyl-2-pyrrolidenyl)-isoxazole or one of its pharmaceutical^ acceptable 5 salts wherein it is present as a transdermal therapeutic system in the form of a patch, comprising a layered structure including a suitable backing layer, an active substance reservoir laminated thereon, in the absence of other control mechanisms, a membrane controlling the active substance release, a pressure-sensitive adhesive device to attach the system to the 10 skin, and, if required, a protective layer removable to prior to application, the active substance reservoir comprising a base material of at least one polymer selected from the groups of polyacrylates and their copolymers, polyisobutyienes, polyterpenes, ethylene-vinyl-acetate-copolymers, block polymers, synthetic rubbers, and hot-melt adhesives 15 2.The administration form according to claim 1 wherein the backing layer of the system is impermeable to moisture and active substar.rc 3.The administration form according to claim 1 wherein the backing layer 20 is permeable to the active substance 4 The administration form according to any one of claims 1-3 wherein the polymer layer comprises esters of the hydrogenated colophony 25. 5.The administration form according to claim 4 wherein the polymer layer comprises methyl or glycerol esters of hydrogenated colophony 6 The administration form according to any one of the preceding claims which comprises a plasticizer in a concentration of 0-30% relative to the 30 total weight of the matrix , .. ~ G c r *■ inn ";° *-c., 'TO 5 10 15 20 25 7.The administration form according to claim 6 which comprises a plasticizer in a concentration of 5-20% relative to the total weight of the matrix 8.The administration form according to claim 6 or claim 7 wherein the plasticizer comprises at least one component selected from the groups of hydrocarbons, alcohols, carboxylic acids and their derivatives, ethers, esters, or amines 9.The administration form according to claim 6 or claim 7 wherein the plasticizer comprises a natural or partially synthetic triglyceride or a mixture of triglycerides in a concentration ranging from 0-30% relative to the total weight of the matrix 10.The administration form according to claim 9 wherein the plasticizer is in a concentration ranging from 5-20% relative to the total weight of the matrix 11.The administration form according to any one of the preceding claims which comprises a permeation enhancer in a concentration ranging form 0-30% relative to the total weight of the matrix 12.

2 The administration form according to claim 11, wherein the permeation enhancer is in a concentration ranging from 5-20% relative to the total weight of the matrix 13. The administration form according to claim 11 or claim 12 wherern the permeation enhancer comprises at least one component selected from the groups of hydrocarbons, alcohols, carboxylic acids and their derivatives, ethers, esters or amines 9. 14. The administration form according to claim 11 or claim 1 2 wherein the permeation enhancer comprises at least one component selected from the group consisting of mono-, di- or sesquiter- penes 5 15.5 The administration form according to claim 11 or claim 1 2 wherein the permeation enhancer comprises at least one component selected from the group consisting of polyoxyethylene derivatives 16.6 The administration form according to claim 11 or claim 1 2 wherein the 10 permeation enhancer comprisies a component selected from the group consisting of nitrogen-containing heterocycles and their derivatives 17. The administration form according to claim 11 or claim 12 wherein the permeation enhancer comprises a component selected from the group 15 consisting of pyrrolidone derivatives 18. The administration form according to any one of the preceding claims which has a bag-type active substance reservoir filled with a liquid or semisolid or thixotropic matrix 20 19.The administration form according to claim 18 wherein a gel former is the base of the semisolid or thixotropic active substance reservoir 20 A process for the production of the administration form according to 25 any one of the preceding claims in which (s)-3-methyl-5-(1 -methyl-2- pyrrolidenylHsoxazole or its pharmaceutical^ acceptable salt is applied in solution on a textile fabric provided on a prefabricated matrix which is optionally provided with a protective layer, whereupon matrix and active substance depot are provided with a cover layer 30. m^Ecid]r -.. OF OrFfc "6 /3SS -5§cr/yeo 10 21.The process according to claim 20 in which components of a hot-melt adhesive are incorporated, prior to the addition of the active substance, under heating until a homogeneous malt of 70 to 100°C is obtained 22.The process according to claim 20 in which the components of the hot-melt adhesive are incorporated under heating to 110 to 170°C 23.The process according vo any one of claims 20 to 22 in which the homogeneous, active-substtince-oontaining hot-melt adhesive mass is applied by means of extrusion, casting, roller coating, knife coating, or by a printing process 24.An administration form according to any one of claims 1 to 19, substantially as herein described 25 A process according to any one of claims 20 to 23, substantially as herein < ^scribed SEE ALSO COMPLETE SPECIFICATION END OF CLAIMS .