AU9159498A - Active substance-containing wick systems - Google Patents

Description

Active Substance-Containing Wick Systems The invention relates to pharmaceutically/hygienic ally/cosmetically applicable wick systems and a process for the production thereof. The term "wick" is meant to desig nate that there is a strand-like body is present which can be rolled up and with which the active substance is com bined prior to the manufacture of the active substance sys tem. Said strand may consist of uniform material or of a mixture of materials. The active substance may be present as such or in the form of an active substance preparation. The active substance may be dissolved in the strand. In the case of a solid active substance, it is also possible that an auxiliary substance is dissolved in the active sub stance. Both alternatives can be useful to attain a usable - for example, sufficiently tear-resistant - consistency or to improve the diffusion properties. It is also possible for the strand to possess a microporous or even macroporous structure. What is important is that the active substance can be released from the strand to the environment. Pref erably, the strand is flat, but may also be a round wick, with the active substance usually being stored in the cap illaries and transported through the same. It is important that during the manufacture of the products according to the invention, the active substance strand can be applied, like a loop scrim, in a continuous process, e.g. from a roll, which term also comprises a spool, or from any other storage vessel, to the patches or system strands, respectively, and that the separating can be per formed subsequently, in a continuous process, e.g. with the aid of a punching tool or a punching roll, simultaneously with the separating of the patches.

2 In conventional systems, the active substance is present in a discrete room, e.g. in a reservoir, in the form of a flat pouch or bag, or in the entire layer on the carrier sheet (matrix patch); a number of variants and mixtures are also known. In those cases, however, where an active substance containing layer is formed, problems arise: 1. It is necessary to produce a mass, possibly under ad dition of solvents and/or a softener, wherein incompati bilities between active substance and the mass or adhesive mass, the resin and the solvent, and the like, may arise. It is particularly problematic where several active sub stances and, in addition, a softener, agents enhancing skin permeability (enhancers) and/or similar additives are used. 2. It is possible that a - relatively volatile - active substance is withdrawn along with those substances intended to be withdrawn when the system is being dried. 3. If the active substance is toxic or light-sensitive, ad ditional protective measures involving considerable effort must be taken. 4. In hot-melt adhesive systems wherein the active sub stance is incorporated in the mass, it is possible that the active substance is changed or negatively affected by the high temperature of the molten mass. 5. The feeding of the carrier and the dosing of active sub stance and/or active substance carrier can generally only be accomplished in technically complicated cycles. This also applies where - as in the case of the "tablet patch" a carrier, such as a nonwoven, is initially applied to the web, and then the active substance applied onto the car rier.

3 6. In "pouch systems/membrane systems", too, it is gener ally not possible to apply the active substance mass con tinuously, instead it must be extruded or spray-coated in cycles, either separately or together with a carrier mass, or metered otherwise in cycles. 7. In other, in any case continuous, production processes e.g. multichannel systems - it is necessary to seal sur faces together, with there still being the problem of nega tive effects on the active substance on the sealing sur faces. It is thus the object of the present invention to ensure a continuous introduction of the active substance onto or, respectively, in a strand material, from which, subse quently, the systems are separated. The term strand here is understood as meaning narrow webs, with the active sub stance strand, however, having less width than the system strand. This object is achieved according to the invention in that the active substance is applied as such, or in a suitable manner, in a thin, strand-shaped primary carrier having ab sorption properties or otherwise similar receptive proper ties, depending on the chemical nature, optionally in form of a solution, similarly to introduction into a wick. This product will be called active substance strand in the fol lowing. The subject matter of the invention is an active substance containing device for dermal application which is charac terized in that it is made up of: a) an active substance strand b) a system strand, of larger width, which markedly pro jects beyond the active substance strand on both sides, and 4 c) if the system strand does not function as the backing layer, a backing layer on one side, and d) on the other side of the system a removable protective layer. A further subject matter of the invention is a process for introducing active substances in systems for dermal appli cation by incorporating the active substance in a carrier, which is characterized in that the active substance is con tinuously introduced into a carrier or applied thereto, thereby producing an active substance strand, that the strand thus-obtained is combined with a broader system strand, which projects beyond the active substance strand on both sides, that this system is, on one side, provided with a removable protective layer and, if the system strand does not function as a backing layer, is provided with a backing layer on the other side, and that the combined strands are then separated in such a manner that no notice able amounts of active substance may escape at the edges. The protective layer is thus present in any case, independ ent of whether the system strand has the function of a backing layer or not. The invention relates especially to a process for the con tinuous introduction of active substances into continuously produced thin systems, preferably having a relatively large surface, e.g. wafers or active substance patches, by incor porating the active substance in an active substance strand and applying this strand to a system strand, and/or apply ing a system strand to an active substance-strand, and pro viding the final system with a detachable protective layer and optionally a backing layer, as well as to products pro duced according to this method.

5 The active substance may be applied in or onto the strand like carrier, either as such or in the form of an active substance preparation, using, for instance, dipping meth ods, printing methods or similar methods. It is also possi ble to prepare a mass into which the active substance is incorporated, and to extrude this mass, possibly applying it directly - under formation of an active substance strand - to the system strand, e.g. by spray-coating or extrusion, or also to spin, weave or - as in a nonwoven - join to gether active substance-containing strands from extruded strands, threads or fibers. It is also possible to cast the mass onto the system strand - using solvents, or as a hot-melt, or in form of powder as in coating - possibly dry it, let it cool down or fix it by supplying energy, thus producing it in situ, cut it to the shape of a strand, and later apply it "from the roll". An active substance strand may also be formed or consist of fibers, woven fabrics, nonwovens or suitable fabrics - also polymers - which are loaded with the active substance. In this respect, suitable active substance carriers are, for example, the usual plastics, e.g. polymers, copolymers and block copolymers based on polyisobutylene (PIB), ethylene vinyl acetate (EVA), polyacrylates or acrylate resins, silicones, styrene-isobutyl-styrene(SIS) block copolymers and others. Such carrier materials in dermal or transdermal systems are known to those skilled in the art from: a) Martin C. Musolf: "Pressure-Sensitive Adhesives: "Science and Engineering" in Transdermal Controlled Systemic Medications, ed. by Y.W. Chien, Marcel Dekker Inc., New York 1987, p.93-112 b) "Handbook of Adhesives", ed. by Irving Skeist, Van Nostrand Reinhold, New York 1990, 3rd edition. In oral flat-shaped systems, such as wafers, it is possible to use, for instance, hydroxypropyl cellulose, methyl cel lulose, starch or modified starch.

6 According to a preferred embodiment, the active substance carrier is applied in a continuous process, in a strand, on the system strand, and, in one operation, dimensioned by separating/punching to form the individual systems. Here, a great number of possibilities are considered: 1. The "system strand" usefully consists of one or more plastics and/or aluminium films/sheets or foils, pos sibly laminated together. By applying the active sub stance strand to a film or foil and laminating this with the system strand, the active substance strand can be enclosed between the films/sheets or foils. 2. The active substance strand may be applied "from the roll" onto the system strand. 3. Applying the active substance strand to a system strand which at the same time serves as the backing layer of the system. 4. Application to a layer of adhesive, which is located on a protective sheet or foil. 5. Coating the active substance strand with a hot-melt adhesive coating, which may possibly also be adhesive at normal temperatures, or with an adhesive coating mass containing solvents, all-over on the entire ac tive substance strand and/or on part of or the entire surface of the patch web. 6. Spray-coating or extruding the active substance strand directly onto the system strand. 7. Forming the backing layer-carrier layer by one of these coatings having the required properties such as strength and impermeability to active substance. 8. Laying-in of proper strand threads. 9. Inserting several, possibly a large number of active substance strands in a system strand. In this way it is possible to attain a particularly uniform distribu tion of the active substance in the system strand without interfering with the rate of production. This is a preferred embodiment wherein, according to a par- 7 ticularly useful embodiment, active substance strands are arranged parallelly to the system strand and/or in the shape of loops, so that patterns are formed, as in a woven fabric. This, too, improves the uniformity of the distribution. 10. Combining strands having different active substances, which otherwise are incompatible with one another or the combination of which would require special meas ures. It is thereby possible, to join, in the same or in another concentration, active substances contained, for example, in the matrix or in the liquid of a mem brane system with the active substances contained in the active substance strand to form a combination sys tem, e.g. physostigmine and scopolamine, estrogen and gestagens. This, too, is a preferred embodiment. 11. According to a further preferred embodiment, it is possible to combine active substance strands with dif ferent conventional systems, such as an all-over ma trix, membrane etc., so that different systems, e.g. concentrations and release mechanisms, can be created, in a simple manner, in the surface or in the layers of the system in order to improve the controlled release; in this way it is possible, for example, to lay highly concentrated strands in layers which are farther away from the skin and strands with lower concentration in the layer which is near the skin (or vice versa), so that initially a low and later a higher release takes place (or vice versa). 12. According to a further embodiment, light-sensitive and/or toxic or readily volatile active substances can be processed such that the active substance strand is completely or partially encapsulated. Such capsule ma terials must of course be permeable to the active sub stance at least on one side, and the active substance strand should be occluded immediately after applica- 8 tion, for example, by applying an additional layer, e.g. by laminating. 13. Heat-sensitivity of the active substance contained in the active substance strand during the processing with hot-melt adhesives or sensitivity occurring during the drying process can be taken into account by applying the active substance to the strand on that side which is facing away from the liquid hot-melt adhesive. In this case, the rearward layer of the active substance strand has a temperature-insulating effect. 14. In some cases, when separating the systems, a simulta neous or additional pressure may be exerted, in the kind of an embossing, by which the edges are closed in such a manner that no active substance amounts worth mentioning may escape from them. In conventional sys tems it is frequently demanded to prevent that a higher concentration of active substance occurs at the edges. With systems according to the invention, how ever, there are practically no precautionary measures needed in this respect since the transverse diffusion is low anyway. In this respect, too, the present in vention has overcome prejudice. 15. In a further preferred embodiment the active substance strands can also be applied in form of a scrim net, loop fabric and the like, continuously, onto the cor responding system strands (carrier, intermediate or adhesive layers). It is possible, here, to proceed such that a second active substance is integrated in the same manner , e.g. by 16. applying two or more different scrim nets with active substances to the system strand or to the correspond ing carriers or adhesive layers. Extremely varied active substances are suitable for this invention, in particular transdermally applicable active substance are considered.

9 - nicotine - corticosteroids: hydrocortisone, prednisolone, beclo methasone propionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinoline acetonide, fluocinolone acetonide acetate, clobetasol propionate etc. - analgesic, anti-inflammatory agents: acetaminophen, mefenamino acid, flufenamino acid, diclofenac, diclo fenac sodium alclofenac, oxyphenbutazone, phenyl buta zone, ibuprofene, fluorobiprofene, salicylic acid, 1-menthol, campher, sulindac tolmetine sodium, naprox ene, fenbufene etc. - hypnotically active sedatives: phenobarbital, amobar bital, cyclobarbital, triazolam, nitrazepam, loraze pam, haloperidol etc. - opiates such as diamorphine, morphine base, morphine hydrochloride, dihydrocodeine, buprenorphine, fentanyl - tranquilizers: fluphenazine, thioridazine, lorazepam, flunitrazepam, chloropromazine etc. - antihypertinsives: pindolol, indenolol, nifedipine, lofexidine, nipradinol, bucumolol, clonidin, bopin dolol, bupranolol etc. - coronary active substances, such as ISDN, nitroglycer ine and its compounds - antihypertensively active diuretics: hydrothiazide, bendroflumethiazide, cyclopenthiazide etc. - antibiotics: penicillin, tetracyclin, oxytetracyclin, fradiomycin sulfate, erythromycin, chloramphenicol etc. - aneasthetics: lidocaine, benzocaine, ethylaminobenzo ate etc. - antimicrobial agents: benzalkonium chloride, nitrofu razone, nystatin, acetosulfamin, clotrimazol etc, - anti-fungus agents: pentamycin, amphotericin B, pyr rolnitrin, clotrimazol etc.

10 - vitamines: vitamine A, ergocalciferol, chlolecalcif erol, octotiamine, riboflavin butyrate etc. - antiepileptics: nitrazepam, meprobamate, clonazepam etc. - coronary vasodilators: dipyridamol, erythrite tetrani trate, pentaerythrite tetranitrate, propatyl nitrate etc. - antihistaminics: diphenylhydramine-hydro-chloride, chlorpheniramin, diphenylimidazol etc. - antitussivs: dertromethorphane (hydrobromide), terbu taline (sulfate), ephedrine (hydrochloride), salbuta nol (sulfate), isoproterenol (sulfate, hydrochloride) etc. - sex hormones: progesterone, estradiol, testosterone etc. - thymoleptics: doxepine etc. - further remedies: 5-fluorouracil,I, desmopressin, dom perdon, scopolamine (hydrobromide), physostigmine, naltrexon, naloxon, peptides etc. As a matter of course this list is not comprehensive. The products according to the present invention are suit able for dermal, but particularly for transdermal applica tion on the epidermis or mucosis in all forms. This term also comprises the use as hygiene wafers, i.e. oral hygiene wafers. These are flat-shaped systems serving to improve oral hygiene by cleaning and/or odour-reducing or odour masking active substances or active substance combinations. Such oral hygiene wafers are thus applied orally and may be completely dissolvable in the mouth; but peroral applica tion is also possible, administering, perorally, products that are not rigid but very plastic and whose components are selected such that they can be completely dissolved in the body fluids and physiologically degraded. Oral wafers of this kind can also contain pharmaceutic ac tive substances instead of hygienic active substances.

11 The process according to the invention and the products thus-obtained afford a number of advantages. Thus, the pro duction rate of the systems can be increased, since produc tion cycles, vertical movements relative to the guidance of the system web are unnecessary. The necessary separation can - likewise in a continuous manner - be accomplished by rotating cutting rolls which possibly also produce an em bossing at the edges. Furthermore, a particular advantage is the improved quality and the prevention of scraps due to the absolute homogeneity of the distribution of the active substance in the strand, which strand can be checked prior to commencement of the production. The problem of dosing, which otherwise occurs in the course of manufacture, is di minished by the fact that - once the strand has been pro duced in a geometrically defined manner - the final dosing is accomplished solely by way of the length (respectively, volume, length, area and thickness) of the strand in the patch, i.e. preferably by way of the length of the patch, given a defined width of the "patch web", i.e. the system strand. If hot-melt adhesive coatings are used, this method affords a particular advantage because the temperature at that moment when the coating is being applied is already markedly lower than the temperature prevailing during the preparation of the mass, interference with the active sub stance in the strand is thus less likely. The invention is also of particular advantage with the con ventional (including, flat-shaped) active agent-containing oral systems since by way of an increased active substance concentration in the active substance strand - which is simply inserted in the oral, active substance-containing system - it is possible to compensate a reduction in con centration occurring at the outer surfaces and thereby com pensate diminished active substance delivery. This applies, in particular, where a plurality of active substance 12 strands, possibly also containing different active sub stances, are used, possibly with different concentrations. By using active substance strands of the most different kind with respect to the active substance, its concentra tion and/or the kind of "wick" material, it is possible to exert any influence on the controlled release behaviour.

Claims (20)

1. Active substance-containing device for dermal applica tion, characterized in that is made up of: a) an active substance strand b) a system strand which markedly projects beyond the active substance strand on both sides, and c) if the system strand does not function as the backing layer, a backing layer on one side and d) on the other side of the system a removable protective layer.

2. Device according to Claim 1, characterized in that it is closed at the edges by an embossing.

3. Device according to Claims 1 or 2, characterized in that between active substance strand and system strand, on the one hand, and the removable protective layer, on the other, there is a membrane enabling the controlled release of active substance.

4. Device according to one or more of Claims 1 to 3, characterized in that the active substance is dissolved in the strand, or that the active substance strand has a porous structure, in whose pores the active substance is stored.

5. Device according to one or more of Claims 1 to 4, characterized in that the system strand consists of one or more films/sheets or foils of plastic and/or aluminium, possibly laminated to one another.

6. Device according to one or more of Claims 1 to 5, characterized in that the active substance strand is ar- 14 ranged parallelly to the system strand, at right angles, diagonally or in the shape of loops.

7. Device according to one or more of Claims 1 to 6, characterized in that it contains a combination of strands with at least two different active substances or active substance concentrations.

8. Device according to one or more of Claims 1 - 7, char acterized in that it contains active substance strands with different conventional systems.

9. Device according to one or more of Claims 1 to 8, characterized in that it is present in form of a large area, thin system, preferably a wafer or an active sub stance patch, especially for transdermal application.

10. Device according to one or more of Claims 1 to 9, characterized in that the active substance strand is pres ent encapsulated completely or partially by a membrane.

11. Process for introducing active substances in systems for dermal application by combining the active substance with a carrier, characterized in that the active substance is continuously introduced into a carrier or applied thereto, thus producing an active substance strand, that the strand thus-obtained is combined with a broader system strand which markedly projects beyond the active substance strand on both sides, that this system is, on one side, provided with a removable protective layer and, if the sys tem strand does not function as a backing layer, is pro vided with a backing layer on the other side, and that the combined strands are then separated in such a manner that no amounts of active substance worth noticing may escape at the edges. 15

12. Process according to Claim 11, characterized in that the active substance strand is applied, from a roll, con tinuously onto the system strand, and that, subsequently, the latter is separated continuously.

13. Process according to Claim 11 or 12, characterized in that the active substance is introduced in a strand-like carrier having absorption properties.

14. Process according to one or more of Claims 11 to 13, characterized in that the active substance is combined with the strand material by dipping or printing methods.

15. Process according to one or more of Claims 11 to 14, characterized in that the active substance strand is pro duced by extrusion of an active substance-containing mass and preferably extruded or spray-coated onto the system strand.

16. Process according to one or more of Claims 11 to 14, characterized in that the active substance strand is pro duced by applying an active substance-containing powder and is preferably applied on the system strand and solidified by supply of energy.

17. Process according to one or more of Claims 11 to 16, characterized in that the combined strands are separated to form patches.

18. Process according to one or more of Claims 11 to 17, characterized in that the active substance strand is ap plied to a film/sheet or foil, and that the product thus obtained is enclosed with the system strand between films/ sheets or foils. 16

19. Process according to one or more of Claims 11 to 18, characterized in that the active substance strand is pro vided with a coating of adhesive, or is processed in encap sulated form.

20. Modification of the process according to Claim 11, characterized in that an active substance-containing mass is applied directly to the system strand under formation of an active substance strand, and that the product thus obtained is processed further according to the process of one or more of Claims 10 to 17.