NZ265949A

NZ265949A - Transdermal therapeutic system; comprises an indole derivative as an active ingredient

Info

Publication number: NZ265949A
Application number: NZ265949A
Authority: NZ
Inventors: Harald List
Original assignee: Lohmann Therapie Syst Lts
Priority date: 1993-05-06
Filing date: 1994-04-25
Publication date: 1997-10-24
Also published as: PL179353B1; ZA942872B; NO954414D0; DK0697869T3; SK138095A3; NO954414L; GR3031639T3; AU6648094A; AU686159B2; PL311591A1; HUT74865A; DE4314976C1; HU9503167D0; IL109509A0; WO1994026270A1; DE59408643D1; CZ289395A3; CA2160776A1; EP0697869B1; FI955260A

Abstract

The invention concerns a transdermal therapeutic system for the systemic administration of active substances, the system being characterized in that at least one of the active substances is a serotonin agonist selected from the indole derivatives, e.g. sumatriptan.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £65949 New Zealand No. 265949 International No. PCT/EP94/01280 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 06.05.1993; Complete Specification Filed: 25.04.1994 Classification:^) A61K31/40; A61K9/70; A61L15/44; A61M37/00 Publication date: 24 October 1997 Journal No.: 1421 Title of Invention: Transdermal therapeutic systems for the administration of serotonin agonists Name, address and nationality of applicant(s) as in international application form: LTS LOHMANN THERAPIE-SYSTEME GMBH & CO. KG, Irlicher Strasse 55, D-56567 Neuwied, Federal Republic of Germany NO NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION l Transdermal therapeutic systems for administering active substances The present invention relates to transdermal therapeutic systems for the systemic administration of active substances, to a process for the production thereof and to the use of these systems for the treatment of diseases. Many people suffer from migrainous headache whose pathophysiology has not been elucidated so far: both a severe dilatation of the cerebral blood vessels and a perivascular aseptic inflammation in the region of the dural arteries are regarded as the causes. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is said to play a key role in regulating the vascular tone. Frequently, migraine is accompanied by sickness and vomiting and a sensitivity to light and noise. Cluster headache is a very intense hemicrania occuring in intervals. These complaints are treated by administering pain relieving drugs (analgesics, such as ASS (acetylsalicylic acid), or paracetamol) and/or substances tonizising the vessels (dihydroergotamine), in case of sickness and vomiting, preferably in the form of injections or rectal applications but also as controlled dosage aerosols. However, in many cases the effect of such therapeutic procedures is insufficient - for example, the vasoconstrictive action of ergota-mine is not selectively limited to the cerebral vessels and results in undesired side effects. To reduce the frequency of migraine attacks, betablockers, calcium antagonists and 5-HT2-antagonists are prophylactically employed with varying success. 2659 2 The use of serotonin itself which seems to be obvious at first, is not appropriate from the therapeutic point of view, since 5-HT acts on various organ systems and many undesired concomitant effects occur. Serotonin was given its name because of the powerful vasoconstrictive action. Serotonin deficiency results in a vasodilatation causing the migrainous headache. The onset of action is effected via 5-HT-j-re-ceptors in the region of the vascular walls of cerebral arteries. In the last few years, the chemical structure of serotonin has been modified in various manners, resulting in changes of the pharmacological properties. For example, indole derivatives were synthesized which cause the cerebral vessels to be selectively tonizised (contracted) combined with a rapid improvement of the symptoms. These are so-called serotonin agonists having a particular affinity for 5-HT-)"receptors. In this connection, an active substance introduced in the treatment is SUMATRIPTAN (INN) having the structural formula H,C NSOaCH CH, CH^N, CH, CH3 (3- (2- (dimethylamino)ethyl)- N- methyl- 1H - indole- 5-methane sulfonamide). Synthesis is carried out according to British patent No. 2 162 522. In the meantime, the pharmacological findings with respect to SUMATRIPTAN are reflected in many patents describing oral, 3 265 949 parenteral and intranasal as well as rectal applications (e.g., DE 35 27 648, EP 503 440 and EP 500 086). The use of the active substances in transdermal therapeutic systems is not mentioned therein. The disadvantages of SUMATRIPTAN are due to the pharmacokinetics: the half-life of SUMATRIPTAN after subcutaneous and oral application merely amounts to about 2 hours. The bioavailability in case of oral application merely amounts to 14% due to the presys-temic metabolism, while it amounts to 96% when injected subcu-taneously. Owing to the short half-life of SUMATRIPTAN the migraine symptoms can soon occur again, requiring new application. When injected, side effects may occur as a burning and redness at the puncture point, when administered orally, the bitter taste can be avoided by coating the tablet. Also, a temporary sensation of heat, pressure, narrowness or heaviness is generally observed after the application of SUMATRIPTAN. A constriction of systemic arteries may occur when it is injected subcutaneously, a fact that is to be considered with patients suffering from hypertension or coronary heart disease??. It is the object of the present invention to find an administration form avoiding the described disadvantages and increasing the efficacy of the active substance. The above object is achieved by a transdermal therapeutic system according to claim 1, by a process for the production thereof according to claim 10 and by the use according to claim li. The subclaims relate to preferred embodiments of the present invention. • N.Z. PATENT OFFICE 18 AUS 1997 I L 4 The invention relates to a transdermal therapeutic system for the systemic administration of active substances which is characterized by the fact that at least one of the active substances is a serotonin agonist of the group including indole derivatives and/or its pharmaceutically acceptable salts. In a particularly preferred embodiment SUMATRIPTAN (3- (2- (dimethylamino)ethyl)- N- methyl-1H- indole- 5- methane sulfonamide) or one of its derivatives is used as active substance. Additionally the present invention relates to a process for producing the transdermal therapeutic system for the systemic administration of active substances, wherein an effective amount of at least one active substance is introduced into the system in solid or microencapsulated form, in solution or in dispersion. Accordingly, a transdermal therapeutic system is used which achieves a systemic effect due to transdermal absorption. A therapeutic system is defined as a drug-containing device or administration form continuously releasing one or more drugs at a predetermined rate over a defined period of time to a defined site of application (quoted according to Heilmann "Therapeutische Sy-steme", Ferdinand-Enke-Verlag, Stuttgart 1984). The advantages of a TTS lie in the continuous active substance release, improved pharmacodynamics of substances having a short half-life, increased efficiency by avoiding the first-pass effect of the liver, avoiding discomfort and risks of an intraveneous treatment, avoiding side effects in the region of the gastrointestinal tract in case of oral medication, and good patient acceptance. Absorption peaks involving the risk of systemic side effects are avoided. As compared to the repeated application required in some cases, the total dose can be reduced. 9 Sickness and vomiting typically occuring in migraine make an oral application of the active substance impossible so that - from this point of view too - the administration by means of a transdermal therapeutic system offers considerable advantages. In this respect a TTS may have different designs and structures, corresponding to the latest state of the art. The technical realization of transdermal therapeutic systems is possible on the basis of the following fundamental solutions which have resulted in respective products on the market: 1. membrane controlled systems 2. matrix controlled systems. The object of the systems is to ensure a controlled, generally constant active substance release over a defined period of time. Patches formed as membrane controlled system are disclosed, for example, in U.S.-patents Nos. 3 742,951; 3 797 494; 3 996 934; and 3 031 894. In principle these patches consist of a backing layer representing one surface, a pressure sensitive adhesive layer permeable to the active substance and representing the other surface, and, finally, a reservoir comprising the active substance between the two layers forming the surfaces. Alternatively, the active substance may be contained within a variety of microcapsules distributed within a pressure sensitive adhesive layer which is permeable to the active substance. In this case the material of the capsule may also act as controlling membrane. A patch as matrix controlled system (i.e., with matrix-diffusion-control) is described in DE-PS 33 15 272, for example. It consists 6 26*949 of an impermeable backing layer, a reservoir of a polymeric matrix, which is attached to the backing layer and has a particular construction and comprises the active substance at a concentration which optionally is above the saturation concentration, a pressure sensitive adhesive layer bonded to the reservoir and permeable to the active substance, and a protective layer which covers the pressure sensitive adhesive layer and can be removed prior to use may also be present. If the reservoir matrix itself is pressure sensitive adhesive, the additional pressure sensitive adhesive layer may be dispensed with. According to a particular embodiment of the present invention, the TTS as matrix controlled system in the form of a patch comprises a backing layer, an active substance reservoir connected therewith and having a polymeric matrix controlling the release of active substances, and a pressure sensitive adhesive layer permeable to the active substances to attach the system to the skin. In particular, a TTS whose active substance reservoir comprises the active substances at a concentration above the saturation concentration proves to be excellently suitable to solve the problem stated in the present invention. In a particular embodiment of the invention the transdermal therapeutic system for the systemic administration of active substances may comprise as active substance SUMATRIPTAN (3- (2- (dimeth-ylamino)ethyl)- N- methyl- 1H - indole- 5-methane sulfonamide) or one of its derivatives. Preferably, a TTS can be used which comprises a protective layer that can be removed from the pressure sensitive adhesive layer. The TTS in patch form according to the present invention proved 2 to be particularly suitable when an impermeable backing layer was used. The dosage of SUMATRIPTAN or another pharmacologically acceptable indole derivative must be selected such that the effective serum level is achieved during the intended period of application. For SUMATRIPTAN these serum levels amount to about 50 to 70 fjg per liter. These TTS are used for the production of a ready-for-use drug. For this purpose parameters have to be defined, e.g., choice of active substance, dosage, control of release and release rate, composition of the reservoir, and addition of adjuvants. It may be useful to add as adjuvants at least one representative of the group comprising penetration enhancers, anti-ageing agents, stabilizers, carriers, blood flow stimulants, and fillers. Suitable penetration enhancers include, for example, carboxylic acids, such as octanoic acid, stearic acid, oleic acid, etc. The use of the above-mentioned additives which - among others - depends on the kind of the active substances, are known to those skilled in the art. Also, another principle of improving the permeation of active substances through the skin can be considered, i.e., the application of electric current (iontophoresis). The active substances may be introduced into a TTS in different forms (solid, in solution, in dispersion); they may also be microencapsulated. The SUMATRIPTAN content of such an administration system preferably amounts to between 10 and 200 mg. In this connection it becomes apparent that the TTS for the systemic administration of active substances according to the present </div>

Claims

8 invention is particularly suitable for the production of a drug for the treatment of migraine and cluster headache. Finally, it may be useful to combine serotonin agonists with another active substance - aiming at a potentiation of action, sometimes, however, at a reduction of the single doses (e.g., with analgesics, antimimetics, psychopharmacologic agents, or sedatives). CLAIMS 9 265 949

1. A transdermal therapeutic system for the systemic administration of active substances, wherein the transdermal therapeutic system is characterized by having at least one serotonin agonist of the group including indole derivatives and/or its pharmaceutical^ acceptable salts, which transdermal therapeutic system is present in the form of a patch and comprises a backing layer, an active substance reservoir connected thereto, in the absence of other controlling mechanisms a membrane which controls the release of the active substance, and a pressure sensitive adhesive facility for fixing the system to the skin, characterized in that the active substance reservoir contains the active substances in a concentration which is above the saturation concentration, and that it contains at least one adjuvant of the group comprising penetration enhancers, anti-ageing agents, stabilizers, carriers, blood flow stimulants, and fillers.

2. The transdermal th erapeutic system for the systemic administration of active substances according to claim 1 characterized in that the active substance is SUMATRIPTAN (3- (2- (dimethyl-amino)ethyl)-N-methyl-1H- indole-5-methane sulfonamide) or a pharmaceutically acceptable salt thereof.

3. The transdermal therapeutic system according to claim 1 or 2 characterized in that the serotonin agonists and/or its pharmaceutically acceptable salt is combined with further active substances.

4. The transdermal therapeutic system for the systemic administration of active substances according to any one of claims 1 to 3 characterized in that atieast one of the active substances is present in a microencapsulated form.

5. The transdermal therapeutic system for the systemic administration .of active substances according to claim 4 characterized in r cmc 1 3 Ai/5 1S27 10 265 949 that the wall or the material of the capsule is formed as a membrane.

6. The transdermal therapeutic system for the systemic administration of active substances according to any one of claims 1 to 5 characterized in that it has a protective layer which can be removed from the pressure sensitive adhesive layer.

7. . The transdermal therapeutic system for the systemic administration of active substances according to any one of claims 1 to 6 characterized in that the backing layer is impermeable to the components of the reservoir.

8. . The transdermal therapeutic system for the systemic administration of active substances according to any one of claims 1 to 7 characterized in that it comprises 10 to 200 mg of SUMATRIPTAN.

9. . The transdermal therapeutic system for the systemic administration of active substances according to claim 1 characterized by the use of electrical current as penetration enhancer.

10. . A process for the production of the transdermal therapeutic system for the systemic administration of active substances according to any one of claims 1 to 9 , characterized in that an effective amount of a least one active substance is introduced into the system in solid form, in microencapsulated form, in solution or in dispersion.

11. . The use of the transdermal therapeutic system for the systemic administration of active substances according to any one of claims 1 to 9 'for producing a pharmaceutical product for the treatment of migraine and cluster headache. 265 949 n

12. A transdermal therapeutic system as claimed in claim 1, substantially as herein described and with reference to pages 4-8.

13. The process of claim 10 substantially as herein described. END OF CLAIMS