DEPRENYL FOR SYSTEMIC TRANSDERMAL ADMINISTRATION

Abstract: N-methyl-N-(1-phenyl-2-propyl)-2-propinylamine in racemic or optically active form and the pharmaceutically acceptable acid addition salts thereof are useful for systemic transdermal administration.

Description: _ t _ Deprenyl for systemic transdermal administration . The present invention provides the systemic transdermal appli¬ cation of deprenyl. Deprenyl[N-methyl-N-(l-phenyl-2-propyl)-2-propinylamine ] of formula I has been disclosed in the literature as a monoamine oxidase inhibitor. The preparation of the racemic mixture is described e.g. in Fr. pat. H 2635, whereas Dutch Patent Application 6,605,956, for instance, discloses the (-)-form of the compound (also known as L-Deprenil, L-Deprenaline or Selegiline). The antidepressive and antiparkinson activity of the racemate and the (-)-form have been reported in various publications. It has now surprisingly been found that the compound of formula I in racemic or optically active form as well as the pharmaceuti¬ cally acceptable acid addition salts thereof, hereinafter referred to as compounds for administration according to the invention, exhibit unexpectedly good skin penetration when administered percutaneously. The penetration through the skin of the compounds for admini¬ stration according to the invention may be observed in standard in vitro or in vivo tests. One in vitro test is the well known diffusion test which may be effected according to the principles set out in GB 2098865 A and by T.J. Franz in J. Invest. Dermatol. (1975) 64, 194 - 195. The composition containing the active agent in unlabelled or radio- actively labelled form is applied to one side of isolated pieces of intact human skin or hairless rat skin about 2 cm 2 in area. The other side of the skin is in contact with physiological saline. The amount of active agent in the saline is measured in conventional manner, e.g. by HP C or spectrophotometric techniques, or by determining the radioactivity. In this test using rat skin the following penetration rates, for example, have been found: Composition Is Compound of formula I (solution) in (-)-form as hydrochloride 35 mg Ethanol 970 mg Polyol-polyether-fatty acid ester, e.g. Cetiol HE* 30 mg Composition 2: Compound of formula I (polymer film) in (-)-form as hydrochloride 10 X Hydroxypropylcellulose, e.g. Klucel LF* 90 % Composition 3: Compound of formula I (solution) in (-)-forra as hydrochloride 7.3 mg Ethanol 0.2 ml Isopropylmyristate ad 1.0 ml Registered Trade Mark **: Corresponds to 6.0 x 10~ 8 mole/cm 2 /hour Moreover it has been found that transdermal administration of the compounds for administration according to the invention induces a long-lasting and constant inhibition of monoamine oxidase activity as indicated in standard tests, with a slow onset of action, which is particularly advantageous with respect to the tolerability of these compounds. Thus the present invention provides a pharmaceutical composition for systemic transdermal administration incorporating as active agent the compound of formula I in racemic or optically active form or a pharmaceutically acceptable acid addition salt thereof. Preferably such a pharmaceutical composition has a penetration rate of at least 10~ 9 mole/cm 2 /hour, more preferably of at least 10" 8 mole/cm 2 /hour. Suitably the penetration rate after 24 hours is at least 3 %, preferably at least 10 X. The compound of formula I is preferably present in (-)-form and as hydrochloride. In a further aspect the present invention provides the use of the compound of formula I in racemic or optically active form or a pharmaceutically acceptable acid addition thereof, as active agent in the manufacture of a pharmaceutical composition suitable for systemic transdermal administration. In yet a further aspect the present invention provides a method of syste ically administering the compound of formula I in racemic or optically active form or a pharmaceutically acceptable acid addition salt thereof, which comprises applying a pharma¬ ceutical composition according to the invention onto the skin. The active agent may be administered in any conventional liquid or solid transdermal pharmaceutical composition, e.g. as described in Remington's Pharmaceutical Sciences 16th Edition Mack; Sucker, Fuchs and Spieser, Pharmazeutische Technologie 1st Edition, Springer and in GB 2098865 A or DOS 3212053 the contents of which are incorporated herein by reference. Conveniently the composition is in the form of a viscous liquid, ointment or solid reservoir or matrix. For example, the active agent is dispersed throughout a solid reservoir or matrix made of a gel or a solid polymer, e.g. a hydrophilic polymer as described in European Patent Application No. 155,229. The active agent may be incorporated in a plaster. The compositions for transdermal administration may contain from about 1 to about 50 X by weight of active agent. The pharmaceutical compositions for transdermal administration may be used for the same indications as for oral or intravenous administration. The amount of pharmaceutically active agent to be administered will individually depend on the drug release characteristics of the pharmaceutical compositions, the drug penetration rate observed in in vitro and in vivo tests, the potency of active agent, the size of the skin contact area, the part of the body to which the unit is stuck, and the duration of action required. The amount of active agent and area of the pharmaceutical composition etc. may be determined by routine bioavailability tests comparing the blood levels of active agents after administration of the active agent in a pharmaceutical composition according to the invention to intact skin and blood levels of active agent observed after oral or intravenous administration of a therapeutically effective dose of the pharma¬ cologically active agent. Given the daily dose of a drug for oral administration, the choice of a suitable quantity of drug to be incorporated in a transdermal composition according to the invention will depend upon the phar acokinetic properties of the active agent, taking into account that there is no first pass effect; the amount of drug which can be absorbed through the skin from the matrix in question for a given area of application and in a given time; and the time for which the composition is to be applied. Thus, a drug with a high first pass effect may require a relatively low quantity in the transdermal composition when compared with the oral daily dose, since the first pass effect will be avoided. On the other hand, generally a maximum of only approximately 50 X of the drug in the matrix is. released through the skin in a 3 day period! The pharmaceutical compositions of the invention in general have for example an effective contact area of drug reservoir on the skin of from about 1 to about 50 square centimetres, preferably about 2 to 20 square centimetres, and are intended to be applied for from 1 - 7 days, preferably 1 - 3 days. Unit dosage forms preferably contain from about 1 mg to about 50 mg of the compound for administration according to the invention. The compounds for administration according to the invention may for example be administered at a dose of 10 mg in a patch of ca. 10 cm 2 , once every three days. The compositions according to the invention may contain further active substances, e.g. further agents which exhibit activity in the treatment of Parkinson's disease, such as levodopa or bromocriptine, or agents with antidepressive activity such as 1-phenylalanine. They may thus be used for the treatment of various conditions including Parkinson's disease and depression. The compositions according to the invention are preferably used for the treatment of Parkinson's disease. The present invention thus more particularly provides a method of treating a subject suffering from Parkinson's disease, wherein a pharmaceutical composition of the invention is applied onto the skin. The following example illustrates the invention. EXAMPLE; Preparation of a transdermal composition containing a hydrophilic polymer Composition Compound of formula I in (-)-form as hydrochloride 20 X Hydrophilic polymer,- e.g. Eudragit E 100* 30 X Non swellable acrylate polymer, e.g. Durotack 280 - 2416** 44 X Plasticizer, e.g. Brij 97*** 6 X * : Registered Trade Mark, available from Rohm, Darmstadt, W. Germany ** : Registered Trade Mark, available from Delft National Chemie Zutphen, Netherlands ***: Registered Trade Mark, available from Atlas Chemie, W. Germany The components are added to acetone or ethanol or another appropriate volatile organic solvent and mixed to give a viscous mass. The mass is spread on top of an aluminised polyester foil (thickness 23 microns) using a conventional apparatus, to produce a film of thickness 0.2 mm when wet. The film is allowed to dry at room temperature over 4 to 6 hours. The aluminium foil is then cut up into patches about 10 sq cm in area.

Claims: WHAT WE CLAIM IS: 1. A pharmaceutical composition for systemic transdermal administration, incorporating as active agent N-methyl-N- • (l-phenyl-2-propyl)-2-propinylaraine in racemic or optically active form or a pharmaceutically acceptable acid addition salt thereof. 2. A pharmaceutical composition according to claim 1, wherein the active agent is the hydrochloride of the (-)-form. 3. A pharmaceutical composition for systemic transdermal administration, substantially as hereinbefore described with reference to the Example. 4. The use of N-methyl-N-(l-phenyl-2-propyl)-2-propinylamine in racemic or optically active form or a pharmaceutically acceptable acid addition salt thereof, as active agent in the manufacture of a pharmaceutical composition suitable for systemic transdermal administration. 5. The use of the (-)-N-methyl-N-(l-phenyl-2-propyl)-2- propinylamine-hydrochloride, as active agent in the manu¬ facture of a pharmaceutical composition according to claim Z. 6. The use of N-methyl-N-(l-phenyl-2-propyl)-2-propiπylamine in racemic or optically active form or a pharmaceutically acceptable acid addition salt thereof, as active agent in the manufacture of a pharmaceutical composition suitable for systemic transdermal administration in the treatment of Parkinson's disease. 7. The use of the (-)-N-methyl-N-(l-phenyl-2-propyl)-2- propinylamine-hydrochloride, as active agent in the manu¬ facture of a pharmaceutical composition according to claim 2, for the treatment of Parkinson's disease. 8. A method of systemically administering N-methyl-N-(l- phenyl-2-propyl)-2-propinylamine in racemic or optically active form or a pharmaceutically acceptable acid addition salt thereof, which comprises applying a pharmaceutical composition according to claim 1 onto the skin. 9. A method of systemically administering the (-)-N-methyl-N- (l-phenyl-2-propyl)-2-propinylamine-hydrochloride, which comprises applying a pharmaceutical composition according to claim 2 onto the skin. 10. A method of treating a subject suffering from Parkinson's disease wherein a pharmaceutical composition according to claim 1 is applied onto the skin.

Inventors: KAROBATH MANFRED, REINHARDT JOERG, KAROBATH, MANFRED, REINHARDT, JOERG
Applicants: SANDOZ AG, SANDOZ-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT M.B.H., SANDOZ-PATENT-GMBH
Application year: 1989
Main classification: A61K31
IPC codes: A61K9, A61K31, A61L15, A61P25