AU727267B2 - Patch for transdermal application of pergolid - Google Patents

Abstract

The invention relates to a plaster for the transdermal application of pergolide and the pharmaceutically acceptable salts thereof.

Description

Patch for Transdermal Application of Perqolid The invention relates to a patch or plaster for transdermal application of pergolid and its pharmaceutically harmless salts.

Pergolid (D-6-n-propyl-88-methylmercaptomethylergoline) is a dopamine receptor coenzyme and is administered among other things as an anti-Parkinson agent (EP-A 0 003 667), for the treatment of addiction caused by psycho-stimulants (EP-A O 204 954), and for nicotine addiction (GB-A 2 204 240).

Various orally administered formulations of pergolid are known from EP-A 0 003 667 and EP-A 0 527 835. The therapeutically effective daily dose is 0.01 to 20 mg.

Generally it can be said that the biological activity of drugs administered orally or intravenously is often unsatisfactory. The hepatic metabolism of the drug upon the first passage through the liver can lead to undesired concentrations and toxic by-products, or to the loss of or reduction of effect, ,Compared to oral administration, the transdermal administration of drugs or agents has various advantages. The drug supply can be better controlled over a longer time interval, whereby significant blood plasma fluctuation is avoided. In addition, the required therapeutic dosage can usually be' distinctly reduced.

Furthermore, a patch is often more preferred by the patient than one or more tablets to be taken daily.

In oral application, pergolid has a low bio-activity.

Consequently, it is difficult to achieve a constant blood 00'* 9S00# MVS Is Sld31309 f96EG9 68 6V+ 99:0T 866ThzMaiH plasma level over a longer time period, so that three doses daily are required.

The object of the present invention is to provide a transdermal system for the systematic application of pergolid or one of its pharmaceutically harmless salts where the drawbacks of oral administration forms are avoided.

The object underlying the invention is now solved with a transdermal therapeutic system with an amount of pergolid or one of its pharmaceutically harmless salts.

The agent pergolid can be applied as a free pergolid base, pergolid mesylate and/or pergolid hydrochloride.

Pergolid or one of its pharmaceutically acceptable salts as the active agent can also be used in combination with one or more further known substances, particularly in two-fold or three-fold combinations. These further known agents can modify, enhance, synergize or alter the potency of the pergolid effect. For example, dopamine coenzymes can be provided.

Particularly suitable further agents include levodopa, carbidopa, selegelihe, tracrine, physostingmine, galanthamine, 1-hydroxytacrine and/or chemical derivatives thereof, metabolites thereof and/or pharmaceutically acceptable salts thereof.

Suitable permeation promoters include singly and/or multivalent aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols with up to 8 C atoms, for example ethanol, 12propandiol, dexpanthenol and/or polyethylene glycol; alcohol/water mixtures; saturated and/or unsaturated fatty alcohols with 8 to 18 carbon atoms; saturated and/or O'd 9900# E3nvs 9 sSi3igoe Z-6EG9 68 6 99:01 866T.ZSI*VZ 0d 900# ~nv~ z96~g9 68 9~OT 866T.z~a~ unsaturated fatty acids with 8 to 18 carbon atoms; their esters; natural vitamin E; synthetic vitamin E; and/or vitamin E derivatives.

Since pergolid is light-sensitive to a certain extent, stabilizers can be employed, for example as is known from US- A 5 114 948 or EP-B 0 314 387. Examples include polyvinylpyrrolidone, alpha-tocopherolsuccinate, propylgallate, methionine, cysteine and/or cysteine hydrochloride.

The transdermal therapeutic system according to the invention can be a patch, particularly with an impermeable cover layer and removable protection layer, especially a matrix system or a membrane system.

The cover layer can be polyester, polypropylene, polyethylene or polyurethane, optionally provided with a metallisation or pigment. The removeable protection layer can be polyester, polypropylene or paper with a silicone and/or polyethylene coating.

The transdermal therapeutic system according to the invention may be a matrix patch with an impermeable cover layer a drug-containing self-adhesive matrix layer or a drugcontaining matrix layer which is coated with an adhesive, a removeable protection layer and pergolid or one of its pharmaceutically acceptable salts as the active agent (drug), optionally with further active agents and/or permeation promoters and/or stabilisers.

The matrix can be based on polyacrylate, silicone, 900'd 9;00# YdnV9 s Fyl3309 Z96CS9 68 6 9S:OT 866TNCI'bZ 900d 900# ~96%9 68 9~Ot 866T.z~a~ polyisobutylene, butyl rubber, styrene/butadiene copolymer or styrene/isoprene copolymer. Such matrix materials common in the medical field are known in the prior art. Examples of acrylate adhesives include DuroTak adhesives.

A further embodiment of the invention relates to a membrane system including an impermeable cover layer, a drug-containing reservoir or a drug-containing reservoir layer, a semi-permeable membrane, a facultative adhesive layer, a removeable protection layer and pergolid or one of its pharmaceutically acceptable salts, optionally, further active agents and/or permeation promoters, stabillsers, emulsifying agents, thickening agents and/or common membrane system or reservoir patch additives.

The drug-containing reservoir layer can thus be provided in an intermediate space formed between the covering layer and the membrane. The reservoir is filled with the active agents (drug) and facultative additives.

Inert polymers are suitable for the membrane, particularly on the basis of polypropylene, polyvinylacetate or silicone.

When a membrane is provided, it d n have the effect of controlling drug release depending on the pore size.

In the following, the invention is illustrated through examples.

'a 9900# *d2nlis I SIU1209 Z96E99 68 6 99:OT 866T,Z2Q'* Example I (Matrix patch) The following components are dispersed in a sufficient amount of ethyl acetate: pergol id 10 g natural vitamin E 10 g propylene glycol 15 g acrylate adhesive 65 g (as 35 solution in ethyl acetate e.g. DuroTak 326-1753) In a commercial coating machine, the obtained dispersion is applied to a silicone-treated polypropylene foil, which results in a surface weight of the dried drug-containing adhesive matrix of 100 g/m 2 In a coating station, a 50 pm thick polyurethane foil is applied. Thereaftez, 20 cm 2 or optionally 10, 30, 40 or 50 cm 2 patches are stamped out of the laminate.

Example 2 (Reservoir

TTS)

The following comlpon'en'ts are dispersed in ethanol/water; pergolid (or a corresponding amount of pergolid salt, e.g. pergolid mesylate) 5 to optionally, natural vitamin E and/or polyvinylpyrrolidonie as stabiliser.

For the production of the patches, the following elements are foreseen: covering layer of for example polyethylene SOO'd 9900# Egn'ig I SU1309 80C~ 9;o# ~flV ~96ES9 68 6 99:01 866T.MZ'QZ semi-permeable membrane, e.g. CoTan 9711 adhesive for adhesive layer, e.g. Duro-Tak 326-1753 removeable protection layer, e.g. Gelroflex.

In a first step, a laminate is produced in a common machine with the adhesive, the membrane and the protection layer. In a second step, an empty TTS is produced from the laminate and the covering layer. In a third step, the empty TTS is filled with the active agent dispersion. In a fourth step, the filled TTS is closed and in a fifth step patches are stamped out in the desired size.

"ccmprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, steps or compnents but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof .7.

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Claims (16)

1. Transdermal therapeutic system comprising an amount of pergolid or one of its therapeutically acceptable salts at least one permeation promoter selected from the group consisting of natural vitamin E, synthetic vitamin E, and vitamin E derivatives and optionally an additional permeation promoter.

2. Transdermal therapeutic system of claim 1, characterised by the free pergolid base, pergolid mesylate and/or pergolid hydrochloride as the active agent (drug).

3. Transdermal therapeutic system of either claim 1 or 2, characterised by pergolid or one of its pharmaceutically acceptable salts as active agent in combination with one or more further common agents, in particular in two-fold or three-fold combination.

4. Transdermal therapeutic system of claim 3, characterised by at least one further common active agent, which modifies, enhances, synergises or affects the potency of the pergolid effect, in particular another dopamine coenzyme.

Transdermal therapeutic system of either claim 3 or 4, characterised by levodopa, carbidopa, selegeline, tacrine, physostigmine, galanthamine, 1- hydroxytacrine and/or chemical derivatives thereof, metabolites thereof and/or pharmaceutically acceptable salts thereof.

6. Transdermal therapeutic system according to any one of the preceding claims, characterised by an additional permeation promoter, selected from the group consisting of cycloaliphatic and/or aromatic-aliphatic alcohol, which is single or multi-valent and has up to 8 C atoms, an alcohol-water mixture, a saturated and/or unsaturated fatty alcohol with 8 to 18 C atoms, a saturated and/or fatty acid with 8 to 18 C atoms and/or its esters. 8

7. Transdermal therapeutic system according to claim 6, characterised by ethanol, 1,2-propandiol, dexpanthenol and/or polyethylene glycol as the permeation promoter.

8. Transdermal therapeutic system of any one of the preceding claims, characterised by a known stabiliser, in particular polyvinylpyrrolidone, alpha- tcopherolsuccinate, propylgallate, methionine, cysteine and/or cysteine hydrochloride.

9. Transdermal therapeutic system of any one of the preceding claims in the form of a patch with an impermeable cover layer and a removable protection layer, in particular in the form of a matrix system or a membrane system.

Transdermal therapeutic system of claim 9, characterised by a cover layer on the basis of polyester, polypropylene, polyethylene or polyurethane, optionally S° being metallized or provided with pigments.

11. Transdermal therapeutic system of either claim 9 or 10, characterised by a S* removable protection layer on the basis of polyester, polypropylene or paper with a silicone and/or polyethylene coating.

12. Transdermal therapeutic system of any one of claims 9, 10 or 11, comprising of a matrix system including: an impermeable cover layer, a drug-containing self-adhesive matrix layer or a drug-containing matrix layer coated with an adhesive, removable protection layer, and pergolid or one of its pharmaceutically acceptable salts as active agent (drug).

13. Transdermal therapeutic system of claim 12, characterised by a matrix layer on the basis of polyacrylate, silicone, polyisobutylene, butyl rubber, styrene/butadiene copolymer or styrene/isoprene copolymer.

14. Transdermal therapeutic system of any one of claims 9, 10 or 11, comprising a membrane system including: an impermeable cover layer, a agent-containing reservoir or a drug-containing reservoir layer, a microporous or semi-permeable membrane, a faculative adhesive layer, a removeable protection layer and pergolid or one of its pharmaceutically acceptable salts as active agent (drug).

15. Transdermal therapeutic system of claim 14, characterised by known I. emulsifying agents, thickening agents and/or known membrane system additives.

16. Transdermal therapeutic system of either claim 14 or 15, characterised by S* a membrane on the basis of an inert polymer, in particular polypropylene, polyvinyl acetate or silicone. DATED this 2 7 h day of September 2000 HEXAL AG WATERMARK PATENT AND TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA KJS:RBP:VRH P6184AUOO.DOC