MXPA99004990A - Method for producing a therapeutic system in the form of plaster - Google Patents

Abstract

The invention relates to the production, conveyance and storage of a therapeutic system in the form of plaster comprising an active layer which is oversaturated with an active substance. Said layer contains the active substance in a homogenous dispersion or solution. The method is characterized in that when it is carried out it avoids procedural parameters which favour or trigger crystallization of the active substance and avoids all type of pressure effects on the plaster and especially the active layer during implementation.

Description

PROCEDURE FOR THE MANUFACTURE OF A THERAPEUTIC SYSTEM IN THE WAY OF EMPLASTO DESCRIPTION OF THE INVENTION The invention relates to a process for the manufacture, transport and storage of a transdermal therapeutic system (TTS) as a poultice with an active supersaturated layer of active substance containing the active substance in homogeneous dispersion or in solution. .

The transdermal therapeutic systems are usually composed of a back layer impermeable to active and auxiliary substances, a reserve layer containing the active substance and which is often adherent by contact, and a protective layer also impermeable to the active substance, which must be removed before the application. In order to achieve a sufficient release of active substance for therapeutic purposes it may be necessary to supersaturate the active substance of the active substance. Although this type of supersaturated transdermal therapeutic systems then possess a high thermodynamic activity for therapeutic purposes, they nevertheless involve the latent risk that the active substance will crystallize in its entirety or in part. It is known that the crystallization of the active substance is extremely detrimental to its release, greatly reduces it or even prevents it altogether. It is also known that the crystallization of the active substance is favored and / or REF .: 30416 activated by the action of pressure on a layer containing active substance.

The manufacture of transdermal therapeutic systems in the form of a plaster is usually carried out by coating the removable protective layer with the adhesive mass containing the active substance, and coating it with the posterior layer. Subsequently, the laminate produced in this way on the basis of a backing layer, a supersaturated layer of active substance and a removable protective layer is rolled up, and the wide roll obtained in this way is cut to form narrow rolls.

In carrying out these operations, pressure is exerted for a short time on the layer containing the active substance. Due to its short duration, this effect of the pressure does not have a negative influence on the crystallization behavior of the active substances in the supersaturated layer of active substance.

In the further course of the manufacturing process, individual plasters are punched from the narrow rolls described above. For this it is necessary to unroll the laminate from the narrow rolls and transport it through the machine, exerting traction. For this purpose, some trailers are used to hold the laminate on the side and transport it through the machine. For this it is inevitable that pressure is exerted for a relatively long time on the supersaturated layer of active substance, with the consequence that crystallizations of the active substance are initiated.

The object of the invention is to describe a process for manufacturing, transporting and storing a transdermal therapeutic system in the form of a plaster, by means of which the crystallization of the active substance is prevented.

The solution to this problem is achieved by a method of the kind described in the general concept of claim 1 of the invention, by virtue of the fact that it is done by avoiding the process parameters that favor or cause the crystallization of the active substance, and because in its implementation, any kind of pressure effect on the plaster and especially on the active layer is avoided.

Surprisingly, it has been found that the crystallization of the active substance in the oversaturated layer of active substance is avoided when carrying out the process of manufacturing, transporting and storing a therapeutic system in the form of a plaster avoids any kind of prolonged action of pressure on the plaster and especially on the active layer. This can be achieved by using vacuum to hold the plaster or parts of it during the transport process between the manufacturing or packaging operations. The clamping of the plaster or parts thereof by means of vacuum devices avoids any pressure effect.

Another possibility to avoid the effect of the pressure is achieved according to the invention when using clamping or clamping devices during or between the working operations for manufacturing, packaging or transport, making their attack always separated from the contour of a plaster or the active layer thereof, for example in the area between the separated individual plasters.

Finally, the effects of the pressure on the finished plaster during the packaging and its dispatch to the final distributor are avoided by packing the finished plasters individually in a package that has shape stability, and that at least in a limited way is resistant to pressure.

The process for manufacturing transdermal therapeutic systems in the form of a plaster according to the invention is preferably used for those groups of active substances which tend to recrystallization in the supersaturated phase.

This includes active substances chosen from groups comprising: α-adrenoceptor-agonists such as xylometazolin, adrenolon, clonidine, ephedrine, thiamenidine, ß-adrenoceptors-agonists such as for example formoterol, terbuterol, ritodrine, α-adrenoceptors-blockers such as dapiperazole, doxazosin, prezosin, yohimbine, trimazosin β-adrenoceptors-blockers such as acebutolol, atenolol, bisoprolol, bupindolol, bupranolol, propranolol, metoprolol, nadolol, pindolol, timolol, anabolic agents such as androstenediol, bolandiol, clostebol, 4-hydroxy-19-nortestosterone, methenolone, Analgesics (narcotics) such as alfentanil, buprenorphine, codeine, dimenoxadol, fentanyl, isomethadone, logentanil, methadone, morphine, morphine derivatives, normethadone, normorphine, propiram, sufentanil, tilidine.

Anaglycemic (non-narcotic) aminopyrin, antipyrine, aspirin, benoxaprofen, bucetin, clometacin, etholocac, felbinac, fenoprofen, flubiprofen, ibufenac, indomethacin, indoprofen, ketoprofen, Ceterolac, miroprofen.

Androgens such as boldenone, fluoximesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17a-methyl-testosterone-3-cyclopentyl enol ether, noretandrolone, normetandrona, oxadrolone, oxymetholone, prasterone, stanolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone 17ß-cypionate, testosterone enanthate, testosterone nicotinate, testosterone phenylacetate, testosterone propionate, thiomesterone, Anesthetics such as amylacine, amylocaine, bifenamine, cocaine, diperodon, ecgonidine, eurprocin, fenalcomin, fomocaine, hexabarbital, hexicaine, hydroxydione, hydroxyprocaine, hydroxytetracaine, ketamine, leucinecaine mesylate, levoxadrol, lidocaine, mepivacaine, meprilcaine, metabutoxicaine, methohexital, midazolan , naepain, octacaine, orthocaine, oxetazain, paretoxicain, phenacaine, pipericaine, polidocanol, pramoxin, prilocaine, procaine, propanocaine, propofol, risocaine, tetracaine, tialbarbital, tiamilal, thiobutabarbital, thiopental, tolicaine, trimacaine, zolamine.

Antiallergics such as for example amlexanox, astemzol, acelastin, cromolyn, fenpipran, histamine, repirisnast, thiaramide, tranilast, traxanox, urushiol, Cetotifen, nedocromil,, oxatomid, pentigetid.

Antiandrogens such as bifluranol, cioctol, cyproterone, oxendolone, Antiangiosins such as amlodipine, amyl nitrite, cinepazet, maleate, imolamin, isosordid dinitrate, limaprost, molsidomine, nitroxyalcilamide derivatives Antiarrhythmics such as acecainide, adenosine, ajmaline, alprenolol, amorpoxan, aprindine, bretilium tosylate, buolumol, bunaftin, butidrine, butobendin, meobentin, mexiletine, moricin, pirmenol, pronetalol, propafenon, pirinoline, Penicillins such as amdinocillin, pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, acidocillin, azlocillin, bacampicillin, benzylpenicillin, carbenicillin, carfecillin, carindacillin, clometocycline, cloxacillin, cyclacline, dicloxacillin, diphenylcylin, epicillin, fenbenicillin, floxicillin, hetacycline, lenampicillin, metampicillin, methicillin, mezlocillin, nafcillin, oxacillin, penamecillin, penetamate hydriodid, penicillin G benetamine, penicillin G benzathine, penicillin G bencidrylamine, penicillin G calcium, penicillin G hydrabamin, penicillin N, penicillin O, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, feneticilin, piperacillin, pivapicillin, propicillin, quinacillin, sulbenicillin, talampicillin, temocillin, ticarcillin.

Antidiabetics such as, for example, sulfonylurea, acetohexamide, carbutamide, chloropropamide, glibornurid, gliclazide, glimeripid, glipizid, gliquidone, glisoxepide, glyburide, glibutiazole, glibuzol, glihexamide, glimidine, glipyramide, fenbutamide, tolazamide, tolbuta ida, tolciclamide, acarb, benzylthiazolidin- 2, 4-dion, calcium mesoxalate, miglitol.

Antihistamines such as for example acrivastine, bamipine, bromopheniramine, chlorpheniramine, dimetindene, metron S, feniramin, pyrrobutamine, tenaldine, tolpropamine, tripolidine, bietanautin, bromodiphenhydramine, carbinoxamine, clemastine, diphenylpyraline, doxylamine, enfranmin, medrylamine, mefenhydramine, p-methyldiphenhydramine, orphenadrine , phenyltoloxamine, piprinhydrinate, setastine, aloclamide, chloropyramine, chloroten, histapyridine, etafurilen, metaphenylene, metapyrilene, phenybenzamine, pyrilamine, talastine, tenyldiamine, toncilamine, tripenle-namine, zolamine, cetirizine, chlorocyclicine, clocinicine, hydroxyzine, tricyclics.

Anti-migraine agents, hydragenated ergot alkaloids, ß-adrenoreceptors-blockers, Ca antagonists, serotonin antagonists, thrombocyte aggregation inhibitors, antidepressants such as alpiropide, dihydroergotamine, ergocornin, ergocorninin, ergocryptine, ergot, ergotamine, flumedroxon acetate, fonacina, metisergid, oxetoron, pizotilina, sumatriptan, anagrelid, argatroban, ciostazol, daltroban defibrotid, enoxaparin, Fraxiparin®, indofuben, lamoparan, ozagrel, picotamid, plafibrid, tedelparin, ticlopidin, triflusal.

Bronchodilators such as eg ephedrine derivatives such as albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chlorprenaline, dioxetedrine, eprocinol, etaphedrine, ethylnorepinephrine, phenterol, hexoprenaline, isoetarin, isoproterenol, mabuterol, metaproterenol, N-methylephedrine, pirbuterol, procaterol , protocilol, reproterol, rimiterol, soterenol, terbutaline, tulobuterol.

Estrogens such as bencestrol, broparoestrol, chlorotrianisen, dienestrol, diethylstilbestrol, diethylstilbestrol dipropionate, dimestrol, fosfestrol, hexestrol, metalenestril metestrol, colpormon, equilenin, equilin, estrogen hormones, conjugated estrogenster, estropipat, 17β-estradiol, estradiol, estradiol benzoate, estradiol 17ß-cypionate, estriol, estrol, ethinyl, estradiol, mestranol, moxestrcl, mitatrienediol, polyestradiol phosphate, quinestradiol, quinestrol.

Gestagenic agents such as allystrenol, anageston, chlormadinon acetate, delmatinon acetate, demegestone, desogestrel, dimetisterone, digrogesterone, ethinyl tolrenol, ethisterone, ethinodiol, ethinoldiol diacetate, fluorgestone acetate, gestoden, gestonorone, caproate, haloprogesterone, 17-hydroxy-1-methyleneprogesterone, 17a-hydroxyprogesterone, 17a-hydroxygesterone caproate, levonorgestrel, linestrenol, medrogestone, medroxyprogesterone, megestrol acetate, melengestrol, norentindrone, norentindrone acetate, norentil-nodrel, norgesterone, norgestimat, norgestrel, norgestrienone, 19-norprogesterone, norvinisterone, pentagestrone, progesterone, pro egestone, quingestrone, trengestone.

Vasodilators such as benziclan, cyclinicate, cyclinicin, citicoline, diisopropylamine dichloroacetate, eburnamonin, phenolxedil, ibusilast, ifenprodil, naphronil, nicamethate, nicergoline, nimodipine, papaverine, pentifillin, tinofedrine, vicanmin, vinpocetine, amotrifen, bendazole, benfurodil, hemisuccinate, benzodicarbon Chlorocycline, Chromonate, Clobenfurol, Clonitrate, Dilazepide, Dipiridamol, Droprenilamine, Effloxate, Erythritol, Erythritol tetranite, Etafenone, Floredil, Ganglefen, Hexestrol bis (ß-Diethylaminoethyl ether), Hexobenzene, Isosorbido-Dinitrate, Itomin tosylate, Khellin, Lypoflacin, Mannitol -hexanitrate, medibacin, nicorandil, pentaerythritol-tetranitrate, pentrinitrol, pimefilin, prenylamine, propathyl nitrate, pyridofylline, trapidil, tricoyl, trimetracidin, trolnitrate-phosphate, visnadin, bamethane, betahistine, bradykinin, brovincamine, bufeniod, buflomedil, butalamine, cetiedil , cyclinicate, cinepazid, cyclandelate, eledoisin, hepronicate, inositol niacinate, isoxsuprine, calidin, kallikrein, moxisilit, nicofuranose, nilidrine, piribedil, suloctidil, xanthine and niacinate.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (4)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Process for the manufacture, transport and storage of a therapeutic system in the form of a poultice with an active supersaturated layer of active substance containing the active substance in homogeneous dispersion or in solution, characterized because it is carried out avoiding the process parameters that favor or provoke the crystallization of the active substance, and because in its implementation any kind of pressure effect on the plaster and especially on the active layer is avoided.

2. Process according to claim 1, characterized in that for the dragging of the plaster or parts thereof during the transport processes between the different manufacturing or packaging operations, the vacuum is used.

3. Method according to claims 1 or 2, characterized in that in the case of clamping or clamping devices are used during or between the work operations for manufacturing, packaging or transport, their clamping always takes place separated from the contour of a poultice or the active layer , for example in the area between separate individual plasters.

4. Process according to one or more of claims 1 to 3, characterized in that the finished plaster is packaged individually in a package in a stable manner, resistant at least to compression.