AU738723B2

AU738723B2 - Active substance-containing wick systems

Info

Publication number: AU738723B2
Application number: AU91594/98A
Authority: AU
Inventors: Frank Becher
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 1997-08-21
Filing date: 1998-08-06
Publication date: 2001-09-27
Anticipated expiration: 2018-08-06
Also published as: NO20000815L; WO1999009961A3; EP1009392A2; DE19736315A1; NO20000815D0; AU9159498A; JP2001513548A; WO1999009961A8; KR20010023134A; WO1999009961A2; CA2299713A1

Description

Active Substance-Containing Wick Systems The invention relates to pharmaceutically/hygienically/cosmetically applicable wick systems and a process for the production thereof. The term "wick" is meant to designate that there is a strand-like body is present which can be rolled up and with which the active substance is combined prior to the manufacture of the active substance system. 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 substance. 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. Preferably, the strand is flat, but may also be a round wick, with the active substance usually being stored in the capillaries 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 performed 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 substancecontaining layer is formed, problems arise: 1. It is necessary to produce a mass, possibly under addition of solvents and/or a softener, wherein incompatibilities 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 substances 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, additional protective measures involving considerable effort must be taken.

4. In hot-melt adhesive systems wherein the active substance 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.

The feeding of the carrier and the dosing of active substance 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 carrier.

-3- 6. In "pouch systems/membrane systems", too, it is generally not possible to apply the active substance mass continuously, 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 surfaces together, with there still being the problem of negative effects on the active substance on the sealing surfaces.

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, subsequently, the systems are separated. The term strand here is understood as meaning narrow webs, with the active substance strand, however, having less width than the system strand.

S 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 absorption properties or otherwise similar receptive properties, depending on the chemical nature, optionally in form of a solution, similarly to 20 introduction into a wick. This product will be called active substance strand in o:o• the following.

The invention provides an active substance-containing device for dermal or muco-sal administration, said device including: a) at least one active substance strand which is a strand made from fiber(s) or fabric(s) and which contains at least one active substance; b) a system strand consisting of one or more components selected from the group of films, sheets and foils, wherein said active substance strand is combined with said system strand, and wherein said system strand projects beyond said active substance strand on both sides; c) if the system strand does not function as the backing layer, a ,C layer on one side of the system; and 17/07/01,td 1126.spe,3 -4d) on the other side of the system strand a removable protective layer.

The invention further provides a process for introducing active substances in systems for dermal or mucosal application by combining the active substance with a carrier, wherein said carrier is a strand made from fiber(s) or fabric(s), and that the active substance is continuously introduced into said carrier or applied thereto, thus producing an active substance strand; that the strand thus-obtained is combined with a broader system strand consisting of one or more components selected from the group of films, sheets and foils, and wherein said system strand projects beyond said 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 15 strands are then separated to form individual systems.

S* The protective layer is thus present in any case, independent of whether the system strand has the function of a backing layer or not.

i ce The invention relates especially to a process for the continuous introduction of active substances into continuously produced thin systems, preferably having a relatively large surface, e.g. wafers or active substance patches, by incorporating the active substance in an active substance strand and applying this strand to a system strand, and/or applying a system strand to an active substance-strand, and providing the final system with a detachable protective layer and optionally a backing layer, as well as to products produced according to this method.

17/07/01,td 11126.spe,4 The active substance may be applied in or onto the strandlike carrier, either as such or in the form of an active substance preparation, using, for instance, dipping methods, printing methods or similar methods. It is also possible 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 together 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), polyacrylatesor 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 cellulose, starch or modified starch.

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, possibly laminated together. By applying the active substance 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.

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 active 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 distribution of the active substance in the system strand without interfering with the rate of production. This is a preferred embodiment wherein, according to a particularly 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.

Combining strands having different active substances, which otherwise are incompatible with one another or the combination of which would require special measures. 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 membrane system with the active substances contained in the active substance strand to form a combination system, 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 activesubstance strands with different conventional systems, such as an all-over matrix, 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 materials must of course be permeable to the active substance at least on one side, and the active substance strand should be occluded immediately after application, 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 simultaneous 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 systems it is frequently demanded to prevent that a higher concentration of active substance occurs at the edges. Withsystems according to the invention, however, there are practically no precautionary measures needed in this respect since the transverse diffusion is low anyway. In this respect, too, the present invention has overcome prejudice.

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 corresponding 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 corresponding carriers or adhesive layers.

Extremely varied active substances are suitable for this invention, in particular transdermally applicable active substance are considered.

nicotine corticosteroids: hydrocortisone, prednisolone, beclomethasone propionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinoline acetonide, fluocinolone acetonide acetate, clobetasol propionate etc.

analgesic, anti-inflammatory agents: acetaminophen, mefenamino acid, flufenamino acid, diclofenac, diclofenac sodium aiclofenac, oxyphenbutazone, phenyl butazone, ibuprofene, fluorobiprofene, salicylic acid, 1-menthol, campher, sulindac tolmetine sodium, naproxene, fenbufene etc.

hypnotically active sedatives: phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, 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, bopindolol, bupranolol etc.

coronary active substances, such as ISDN, nitroglycerine and its compounds antihypertensively active diuretics: hydrothiazide, bendroflumethiazide, cyclopenthiazide etc.

antibiotics: penicillin, tetracyclin, oxytetracyclin, fradiomycin sulfate, erythromycin, chloramphenicol etc.

aneasthetics: lidocaine, benzocaine, ethylaminobenzoate etc.

antimicrobial agents: benzalkonium chloride, nitrofurazone, nystatin, acetosulfamin, clotrinazol etc.

anti-fungus agents: pentamycin, amphotericin B, pyrrolnitrin, clotrimazol etc.

vitamines: vitamine A, ergocalciferol, chlolecalciferol, octotiamine, riboflavin butyrate etc.

antiepileptics: nitrazepam, meprobamate, clonazepam etc.

coronary vasodilators: dipyridamol, erythrite tetranitrate, pentaerythrite tetranitrate, propatyl nitrate etc.

antihistaminics: diphenylhydramine-hydro-chloride, chlorpheniramin, diphenylimidazol etc.

antitussivs: dertromethorphane (hydrobromide), terbutaline (sulfate), ephedrine (hydrochloride), salbutanol (sulfate), isoproterenol (sulfate, hydrochloride) etc.

sex hormones: progesterone, estradiol, testosterone etc.

thymoleptics: doxepine etc.

further remedies: 5-fluorouracil,I, desmopressin, domperdon, 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 suitable for dermal, but particularly for transdermal application 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 odourmasking active substances or active substance combinations.

Such oral hygiene wafers are thus applied orally and may be completely dissolvable in the mouth; but peroral application 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 active 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 production rate of the systems can be increased, since production 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 embossing 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 diminished by the fact that once the strand has been produced 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, 15 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 S because the temperature at that moment when the coating is being applied is eeo.

already markedly lower than the temperature prevailing during the preparation of the mass, interference with the active substance in the strand is thus less a: 20 likely.

Preferred Embodiment The preferred embodiment has a wick system having a flat, active substancecontaining strand which is formed of polymer fibers and which is loaded with active substance by dipping. This active substance-strand is applied, in a continuous process, onto a system strand consisting of one or more plastic sheet(s) and which serves as a backing layer, such that said system strand projects beyond said active substance strand on both sides. Furthermore, the active substance strand is coated with an adhesive coating. Finally, the wick system is provided with a detachable protective layer, and individual systems are obtained by punching.

17/07/01,td 1 126.spe.1 I 11a- The invention is also of particular advantage with the conventional (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 concentration occurring at the outer surfaces and thereby compensate diminished active substance delivery. This applies, in particular, where a plurality of active substance 17/07/01,td 11126.spe,11 12 strands, possibly also containing different active substances, are used, possibly with different concentrations.

By using active substance strands of the most different kind with respect to the active substance, its concentration and/or the kind of "wick" material, it is possible to exert any influence on the controlled release behaviour.

Claims

1. An active substance-containing device for dermal or muco-sal administration, said device including: a) at least one active substance strand which is a strand made from fiber(s) or fabric(s) and which contains at least one active substance; b) a system strand consisting of one or more components selected from the group of films, sheets and foils, wherein said active substance strand is combined with said system strand, and wherein said system strand projects beyond said active substance strand on both sides; c) if the system strand does not function as the backing layer, a backing layer on one side of the system; and d) on the other side of the system strand a removable protective layer. 1

2. The device according to Claim 1, wherein it is closed at the edges by an embossing.

3. The device according to Claim 1 or 2, wherein 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. The device according to any one of Claims 1 to 3, wherein 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.

The device according to any one of Claims 1 to 4, wherein the system strand consists of one or more films/sheets or foils of plastic and/or aluminium, possibly laminated to one another.

6. The device according to any one of Claims 1 to 5, wherein the active substance strand is arranged parallelly to the system strand, at right angles, diagonally or in the shape of loops.

7. The device according to any one of Claims 1 to 6, wherein it contains a combination of strands with at least two different active substances or active substance concentrations. Ic, 17107/01,tdl 1126.spe, 13 OFR -14-

8. The device according to any one of Claims 1 to 7 wherein it is present in form of a large-area, thin system, preferably a wafer or an active substance patch, especially for transdermal application.

9. The device according to any one of Claims 1 to 8 wherein the active substance strand is present encapsulated completely or partially by a membrane.

A process for introducing active substances in systems for dermal or mucosal application by combining the active substance with a carrier, wherein said carrier is a strand made from fiber(s) or fabric(s), and that the active substance is continuously introduced into said carrier or applied thereto, thus producing an active substance strand; that the strand thus- obtained is combined with a broader system strand consisting of one or more components selected from the group of films, sheets and foils, and wherein said system strand projects beyond said 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 oo oi S provided with a backing layer on the other side; and that the combined e strands are then separated to form individual systems. t*l.

11. The process according to Claim 10, wherein the active substance S20 is applied, from a roll, continuously onto the system strand. C: l

12. The process according to Claim 10 or 11, wherein the active substance is introduced in a carrier having absorption properties.

13. The process according to any one of Claims 10 to 12 wherein the active substance is combined with the strand material by dipping or printing methods.

14. The process according to any one of Claims 10 to 13 to wherein the active substance strand is produced by extrusion of an active substance- containing mass and preferably extruded or spray-coated onto the system strand.

15. The process according to any one of Claims 10 to 14, wherein the active substance strand is produced by applying an active substance- containing powder to said carrier and by fixing said powder to said carrier by 17/07/01,tdl1 126.spe,14 supply of energy.

16. The process according to any one of Claims 10 to 15, wherein the combined strands are separated to form patches.

17. The process according to any one of Claims 10 to 16, wherein the active substance strand is applied to a film/sheet or foil, and that the product thus-obtained is enclosed with the system strand between films/ sheets or foils.

18. The process according to any one of Claims 10 to 17, wherein the active substance strand is provided with a coating of adhesive, or is processed in encapsulated form.

19. Modification of the process according to Claim 10, wherein 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 15 Claims 10 to 18. Dated this 17 t h day of July, 2001. LTS LOHMANN THERAPIE-SYSTEME GMBH

20 By their Patent Attorneys: CALLINAN LAWRIE iX^ A fi/ 17/07/01,tdl 1126.spe.15