AU6434000A

AU6434000A - Transdermal therapeutic system for the utilization of tolterodine

Info

Publication number: AU6434000A
Application number: AU64340/00A
Authority: AU
Inventors: Thomas Strungmann
Original assignee: Hexal AG
Current assignee: Hexal AG
Priority date: 1999-07-13
Filing date: 2000-07-12
Publication date: 2001-01-30
Also published as: WO2001003678A2; WO2001003678A3; EP1194134A1; DE19932651A1

Description

Transdermal therapeutic system for administration of tolterodine The invention relates to an active ingredient containing transdermal therapeutic system for administration of tolterodine, 5-hydroxymethyltolterodine and/or the pharmaceutically acceptable salts thereof. Tolterodine [ (R) -N,N-diisopropyl-3- (2-hydroxy 5-methylphenyl)-3-phenylpropylamine] is a novel, very effective and competitive muscarine receptor antagonist (parasympatholytics) . It has a great affinity and specificity for the muscarine receptor. Tolterodine is used for the treatment of bladder incontinence and other conditions whose cause is to be found in an unstable bladder. On oral administration of tolterodine, the active ingredient is rapidly absorbed in the gastrointestinal tract and then undergoes extensive first-pass metabolism in the liver. The metabolism takes place by two pathways: oxidation of the 5-methyl group and dealkylation on the nitrogen. The absolute bioavailability is 30-40%. The usual and recommended oral dose is 1-2 mg twice a day because in this way the side effects caused by the metabolites, such as dry mouth, visual disturbances, gastrointestinal problems etc., remain tolerable for the patient. It is now an object of the present invention to provide a dosage form comprising tolterodine, 5-hydroxy methyltolterodine and/or the pharmaceutically acceptable salts thereof with which the disadvantages of previously used oral or intravenous dosage forms can be avoided. It has now been found, surprisingly, that the active ingredient tolterodine, its derivative 5-hydroxy methyltolterodine and the salts thereof penetrate through the skin to an extent such that they can be used to produce effective, efficient transdermal therapeutic systems, which was not to be expected on the basis of the molecular structure. The great advantage of transdermal therapeutic systems is that the active ingredient has a direct systemic action after permeation through the skin. The necessary therapeutically effective dose can thus be markedly reduced and a constant level of active ingredient in the blood plasma can be guaranteed. By avoiding the hepatic metabolism, which is very pronounced in this case, of the active ingredient it is possible to increase the bioavailability considerably, to diminish the stress on the liver and to reduce the side effects caused by the metabolites, such as dry mouth, gastrointestinal problems and visual disturbances, to a minimum. The use of plasters is simple and convenient in contrast to oral administration, and they retain their full efficacy over several days, which is likewise a considerable advantage for the patient. Since the system is applied externally, it can carry out its intended function for a very long time without being changed. This is simply impossible with oral systems because, owing to the digestive activity, they leave the body after no longer than one day.

The object on which the invention is based is now achieved by a transdermal therapeutic system with a content of tolterodine, 5-hydroxymethyltolterodine, the pharmaceutically acceptable salts thereof or a mixture thereof. Pharmaceutically acceptable salts of tolterodine or 5-hydroxymethyltolterodine mean acid addition salts. These are obtained by reacting the active ingredient which is in t,he form of the free base with pharmaceutically acceptable acids. Pharmaceutically acceptable acids are inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g. acetic, propionic, hydroxyacetic, lactic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic and pamoic acids). Solvates with the active ingredient are likewise referred to as acid addition salts. Examples of such solvates are hydrates, alcoholates and the like. Examples of possible preferred pharmaceutically acceptable salts are tolterodine tartrate, in particular tolterodine (R,R) tartrate and tolterodine hydrochloride. The transdermal therapeutic system of this invention can be represented by a plaster. This plaster may be a matrix or membrane system which has an impermeable covering layer and a detachable protective layer.

Suitable as impermeable covering layer are sheets of acetal, acrylate, acrylonitrile/butadiene/styrene, acrylonitrile (methyl methacrylate) copolymer, acrylonitrile copolymer, ethylene ethyl acrylate, ethylene methyl acrylate, ethylene vinyl acetate, ethylene vinyl acetate copolymer, ethylene vinyl alcohol polymer, ionomers, nylon (polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate, polyester, polyethylene terephthalate, thermoplastic polyester copolymer, polyethylene copolymer (high density) , polyethylene (high molecular weight, high density), polyethylene (intermediate molecular weight, high density), polyethylene (linear low density), polyethylene (low density), polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated), polypropylene (oriented), polystyrene, polyurethane, polyvinyl acetate, polyvinyl chloride, polyvinylidene chloride and/or styrene/acrylonitrile, each of which may be metallized or pigmented if required. Suitable for the detachable protective layer are polyester, polyethylene, polypropylene, polysiloxane, polyacrylate, ethylene/vinyl acetate, polyurethane, polyisobutene or paper, usually coated with silicone and/or polyethylene, or a mixture thereof. The amount of tolterodine, 5 hydroxymethyltolterodine, the pharmaceutically acceptable salts thereof or a mixture thereof employed in the transdermal therapeutic system of the invention ranges from 0.5 to 80 mg. The matrix plaster consists of an impermeable covering layer, of one or more self-adhesive matrix layer(s) containing the active ingredient and/or permeation promoter and of one or more matrix layer(s) which are coated with a pressure-sensitive adhesive, and of a detachable protective layer. The active ingredient present in the matrix is tolterodine, 5-hydroxymethyltolterodine, the pharmaceutically acceptable salts thereof or a mixture thereof. The matrix formers customary in medicine such as polyacrylate, silicone, polyisobutylene, rubber, rubber-like synthetic homopolymers, copolymers or block copolymers, butyl rubber, styrene/isoprene copolymer, polyurethanes, copolymers of ethylene, polysiloxanes, styrene/butadiene copolymer or a mixture thereof, as provided in the prior art, are used for the matrix. Adhesives which can be used are polydimethylsiloxane, polyacrylates, polyisobutylene, polyacrylate with C 4

-C

10 alkyl alcohol esters, ammine resistant silicone in ethyl acetate or n-heptane, polyisobutylene/mineral oil or a mixture thereof. Another embodiment of the invention is represented by a membrane system. This consists of an impermeable covering layer, of an active ingredient-containing reservoir or of a reservoir layer, of a semipermeable membrane, of an optional pressure-sensitive adhesive layer and of a detachable protective layer. The reservoir contains tolterodine, 5-hydroxymehyltolterodine, the pharmaceutically acceptable salts thereof or a mixture thereof and/or permeation promoters, stabilizers, emulsifiers, thickeners and/or conventional membrane system or reservoir plaster aids. The reservoir or the reservoir layer is located between the covering layer and the membrane. Gel formers which can be used if required are methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, sodium plyoxilate, carboxymethylcellulose or a mixture thereof. The membrane, which normally consists of inert polymers, in particular based on polypropylene, polyvinyl acetate, polyamide, ethylene/vinyl acetate copolymers and/or silicone, may, depending on the pore size, have an effect controlling the release of active ingredients. A pressure-sensitive adhesive based, for example, on polyurethane, polyisobutylene, polyvinyl ether, silicone, polyacrylate or a mixture thereof can be chosen for the pressure-sensitive adhesive layer. The silicone-based adhesive may comprise silicone adhesives which are based on two main constituents: a polymer or adhesive, in particular polysiloxane, and a tack increasing resin. The polysiloxane adhesive is usually prepared with a crosslinker for the adhesive, typically with a high molecular weight polydiorganosiloxane, and with the resin, in order to result via an appropriate organic solvent in a three-dimensional silicate structure. Admixture of the resin to the polymer is the most important factor for changing the physical properties of the polysiloxane adhesives: cf., for example, Sobieski et al., "Silicone Pressure Sensitive Adhesives", Handbook of Pressure Sensitive Adhesive Technology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New sive Technology, 2nd ed., pp. 508 517 (D. Satas, ed), Van Nostrand Reinhold, New York (1989). Another example of a silicon-based pressure-sensitive adhesive is trimethylated silicon dioxide which has been treated with polydimethylsiloxane or with terminal trimethylsiloxy.groups. The acrylate-based adhesives may comprise any suitable homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives. The polyacrylate-based adhesives may comprise any suitable homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives. Thus, the polyacrylates may be polymers of one or more monomers of acrylic acids and other copolymerizable monomers. The acrylate polymers may additionally comprise copolymers of alkyl acrylates and/or alkyl methacrylates and/or copolymerizable secondary monomers or monomers with functional groups. It is possible by changing the amount of each type added as monomer to change the cohesive properties of the acrylate polymers resulting therefrom. In general, the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, 0 to 20% of a functional monomer, copolymerizable with acrylate, and 0 to 50% of another monomer.

Various acrylate monomers which can be polymerized alone or in a mixture are listed hereinafter, such as, for example, acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate. It is additionally possible to employ functional monomers which are copolymerizable with the above-mentioned acrylates, such as, for example, acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylamino ethyl methacrylate, tert-butylaminoethyl acrylate, tert butylaminoethyl methacrylate, methoxyethyl acrylate, vinyl acetate and methoxyethyl methacrylate, for the copolymerization. Further details and examples of pressure-sensitive acrylates which are suitable for the invention are described in Satas Handbook of Pressure Sensitive Adhesive Technology "Acrylic Adhesives" 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989). Permeation promoters which can be used are monohydric and/or polyhydric aliphatic, cycloalphatic and/or aromaticaliphatic alcohols with, in each case, up to eight C atoms, e.g. ethanol, 1,2-propanediol, dexpanthenol and/or polyethylene glycol; alcohol/water mixtures; saturated and/or unsaturated fatty alcohols with, in each case, 8-18 C atoms; terpenes; e.g. cineol, carveol, menthone, trepineol, verbenon, menthol, limonene, thymol, cymene, terpinen-4-ol, neomenthol,- geraniol, fenchon; mixtures of terpenes and etanol and/or propylene glycol; tea tree oil; saturated and/or unsaturated cyclic ketones; alkyl methyl sulfoxides; saturated and/or unsaturated fatty acids with, in each case, 8-18 C atoms; their esters and salts; natural vitamin E; synthetic vitamin E and/or vitamin E derivatives; sorbitan fatty acid esters and ethoxylated sorbitan fatty acid esters; Azone (laurocapram); Azone mixed with alcohols; urea; 1 alkylpryrrolidone; block copolymers such as polyethylene glycol and dimethylsiloxane with cationic group at one end; folate/polyethylene glycol liposome, proliposome; polyoxyethylene 10 stearyl ether; mixture of polyoxyethylene 10 stearyl ether and glyceryl dilaurate; dodecyl 2-(N,N dimethylamino) propanoltetradecanoate and/or dodecyl 2- (N,N dimethylamino)propianate; N-acetylprolinate ester with >8 C atoms; nonionic surfactants, e.g. lauryl ethers, esters of polyoxyethylene; ethosome (phospholipid vesicle); dimethyl(arylimino)sulfurane; mixture of oleic acid analogs and propylene glycol; mixture of padimate 0, octyl salicylate, octyl methoxycinnimate, laurocapram; isopropyl myristate, isopropyl palmitate or a mixture of individual components. The invention is explained in detail by the following examples without, however, thereby restricting the scope of the invention. Example 1 (matrix plaster) 1.6 g of tolterodine are dissolved in 75 g of acetone, and 8 g of Copherol F1300 and 8 g of propylene glycol are added. The clear solution is added to 127.3 g of an approx. 49% strength acrylate copolymer (Duro- Tak 387-2287, Nat. Starch & Chemical B.V.) and stirred. The homogeneous solution is sprayed on a siliconized polyester sheet (e.g. 75 pm) or on siliconized paper and dried at 35 0 C to 85 0 C to result in a matrix dry weight of 80 + 10% g/m 2 . The detachable protective layer (e.g. polyester 15 pm) is then laminated onto the matrix side. TTS with an area of 10 cm 2 are punched out. Example 2 (reservoir plaster) 1st Step: 50 g of tolterodine are dissolved by stirring in 950 g of a mixture of ethanol abs. 65% (V/W), glycerol 20% (V/W) Copherol F1300 10% (V/W) and hydroxypropyl cellulose 1% (V/W). 2nd Step: an acrylate adhesive (ERA 1, Adhesives Research) is dissolved depending on its dry weight content in sufficient ethyl acetate to result in an approx. 60% strength solution. The coating solution is sprayed on a siliconized PET sheet and dried at 35 0 C to 85 0 C to result in a matrix dry weight of 50 + 10% g/m 2 . A microporous membrane (e.g. CoTran 9711, 3M Medica) is then laminated onto the matrix. 3. The active drug solution is supplied by a tubing pump. The laminate from step 2 is welded to a heat-sealable protective sheet apart from a filling orifice. After filling with 400 + 5% mg of active drug solution (step 1), the reservoir is sealed shut and the TTS is punched out. Amount of substances per TTS: Tolterodine: 20 mg Ethanol abs.: 220 mg Copherol F1300: 76 mg Glycerol: 80 mg Hydroxypropylcellulose: 4 mg

Claims

1. A transdermal therapeutic system with a content of tolterodine, its pharmaceutically acceptable salts, derivatives or a mixture thereof.

2. A transdermal therapeutic system as claimed in claim 1, characterized by tolterodine and/or tolterodine tartrate and/or tolterodine hydrochloride and/or 5-hydroxymethyl tolterodine as active ingredient.

3. A transdermal therapeutic system as claimed in either of the preceding claims in the form of a plaster with an impermeable covering layer and a detachable protective layer, in particular in the form of a matrix or membrane system.

4. A transdermal therapeutic system as claimed in claim 3, characterized by a covering layer based on acetal, acrylate, acrylonitrile/butadiene/styrene, acrylonitrile (methyl methacrylate) copolymer, acrylonitrile copolymer, ethylene ethyl acrylate, ethylene methyl acrylate, ethylene vinyl acetate, ethylene vinyl acetate copolymer, ethylene vinyl alcohol polymer, ionomers, nylon (polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate, polyester, polyethylene terephthalate, thermoplastic polyester copolymer, polyethylene copolymer (high density), polyethylene (high molecular weight, high density), polyethylene (intermediate molecular weight, high density), polyethylene (linear low density), polyethylene (low density), polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated), polypropylene (oriented), polystyrene, polyurethane, polyvinyl acetate, polyvinyl chloride, polyvinylidene chloride and/or styrene/acrylonitrile, each of which may be metallized or pigmented if required.

5. A transdermal therapeutic system as claimed in claim 3, characterized by a detachable protective layer based on polyester, polyethylene, polypropylene, polysiloxane, polyacrylate, ethylene/vinyl acetate, polyurethane, polyisobutene or paper, where appropriate coated with silicone and/or polyethylene.

6. A transdermal therapeutic system as claimed in claim 3, 4 or 5, characterized in that it comprises a matrix system with = an impermeable covering layer, * one or more active ingredient-containing self-adhesive matrix layer(s) or one or more active ingredient-containing matrix layer(s) which are coated with a pressure-sensitive adhesive, " a detachable protective layer and " tolterodine, 5-hydroxymethyltolterodine, the pharma ceutically acceptable salts thereof or a mixture thereof as active ingredient.

7. A transdermal therapeutic system as claimed in claim 6, characterized by a matrix layer based on polyacrylate, silicone, polyisobutylene, rubber, rubber-like synthetic homopolymers, copolymers or block copolymers, butyl rubber, styrene/isoprene copolymer, polyurethanes, copolymers of ethylene, polysiloxanes, styrene/butadiene copolymer or a mixture thereof.

8. A transdermal therapeutic system as claimed in claim 3, 4 or 5, characterized in that it comprises a membrane system with " an impermeable covering layer, " an active ingredient-containing reservoir or an active ingredient-containing reservoir layer, e a microporous or semipermeable membrane, " an optional pressure-sensitive adhesive layer, " tolterodine, 5-hydroxymethyltolterodine, the pharma ceutically acceptable salts thereof or a mixture thereof as active ingredient.

9. A transdermal therapeutic system as claimed in claim 8, characterized by known emulsifiers, thickeners and/or known membrane system aids.

10. A transdermal therapeutic system as claimed in claim 9, characterized by methylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, sodium plyoxlate, carboxymethyl cellulose or a mixture thereof as thickener.

11. A transdermal therapeutic system as claimed in claim 8, 9 or 10, characterized by a membrane based on inert polymers, in particular polypropylene, polyvinyl acetate, polyamide, ethylene/vinyl acetate copolymers, silicone or a mixture thereof.

12. A transdermal therapeutic system as claimed in any of the preceding claims, characterized by a permeation promoter, in particular monohydric and/or polyhydric aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols with, in each case, up to eight C atoms; alcohol/water mixtures; saturated and/or unsaturated fatty alcohols with, in each case, 8-18 C atoms; terpenes; mixtures of terpenes and etanol and/or propylene glycol; tea tree oil; saturated and/or unsaturated cyclic ketones; alkyl methyl sulfoxides; saturated and/or unsaturated fatty acids with, in each case, 8-18 C atoms; esters and salts thereof; natural vitamin E; synthetic vitamin E and/or vitamin E derivatives; sorbitan fatty acid esters and ethoxylated sorbitan fatty acid esters; Azone (laurocapram); Azone mixed with alcohols; urea; 1 alkylpryrrolidone; block copolymers of polyethylene glycol and dimethylsiloxane with cationic group at one end; folate/polyethylene glycol liposome, proliposome; polyoxyethylene 10 stearyl ether; mixture of polyoxyethylene 10 stearyl ether and glyceryl dilaurate; dodecyl 2-(N,N dimethylamino)propanoltetradecanoate and/or dodecyl 2-(N,N dimethylamino)propianate; N-acetylprolinate ester with >8 C atoms; nonionic surfactants; esters of polyoxyethylene; ethosome (phospholipid vesicle); dimethyl (arylimino) sulfurane; mixture of oleic acid analogs and propylene glycol; mixture of padimate 0, octyl salicylate, octyl methoxycinnimate, laurocapram; isopropyl myristate, isopropyl palmitate or a mixture of individual components.