PLASTER FOR INTRODUCING PHARMACEUTICAL COMPOSITIONS IN LIVING ORGANISMS

Abstract: The invention relates to a topically applicable plaster for introducing a peptidaceous pharmacon in a living organism, which comprises a plaster support and (i) a peptidaceous pharmacon, (ii) capsaicine, histamine and/or cantharis extract, and (iii) an epithelizing agent applied thereon. In the plaster according to the invention component (i) is, optionally together with a part of component (ii), in a layer ("first layer") above the plaster support, component (ii) or its remainder is in a separate layer ("second layer") above said first layer, and component (iii) is in said second layer and/or in a separate layer ("third layer") above said second layer. The invention also relates to a plaster containing a pharmaceutically active substance whenever prepared by applying onto a plaster support by typography at least one layer comprising a pharmaceutically active substance and a typographically applicable film-forming agent compatible therewith.

Description: PLASTER FOR INTRODUCING PHARMACEUTICAL COMPOSITIONS IN LIVING ORGANISMS The invention relates to plasters applicable for introducing pharmaceutically active substances in a living organism. The invention also relates to a process for the preparation of the plasters. In a preferred form the invention relates to plasters for introducing peptidaceous pharmacons in a living organism and to a process for their preparation. Hungarian patent application No. P9603327 and the respective international patent application publication No. WO 98/24470 disclose topically applicable pharmaceutical compositions which enable one to introduce peptidaceous pharmacons in a living organism by transdermal resorption. The compositions disclosed therein contain (i) a peptidaceous pharmacon, (ii) a local vasodilatating agent, which is capsaicine, histamine and/or cantharis extract, and (iii) an epithelizing agent in admixture with carriers and/or diluents conventionally used in topically applicable pharmaceutical compositions. Preferred representatives of the compositions disclosed in the cited references are plasters, in which the components listed above are applied onto a support capable of adhering to skin. The references cited above do not contain specific provisions either for the preparation of the plasters or for the order of applying components (i)-(iii). According to the examples disclosed therein the plasters are prepared in such a way that either components (i)-(iii) are dissolved in a solvent and the resulting solution is gellified, or components (i)-(iii) are worked into an ointment base, and the resulting mixture is applied onto a plaster support. Now I have found that when components (i)-(iii) are applied onto the plaster support in a prescribed order, partially separated from one another, a composition with improved storability is obtained, the individual components get storable for a prolonged period, the amount of the active agent applied can be regulated more accurately, and more complete and more finely controllable resorption of the active agent can be attained. As a result of these factors, the doses required for therapy can be adjusted more accurately. Thus, in this aspect the invention relates to a topically applicable plaster for introducing peptidaceous pharmacons in a living organism, which comprises a plaster support and (i) a peptidaceous pharmacon, (iii) capsaicine, histamine and/or cantharis extract, and (iii) an epithelizing agent applied thereon. In the plaster according to the invention component (i) is, optionally together with^a part of component (ii), in a layer (further on: "first layer") above the plaster support, component (ii) or its remainder is in a separate layer (further on: "second layer") above said first layer, whereas component (iii) is in said second layer and/or in a separate layer (further on: "third layer") above said second layer. In a further aspect the invention relates to a process for the preparation of a topically applicable plaster for introducing a peptidaceous pharmacon in a living organism, in which the layers containing the components as discussed above are applied onto a plaster support in the order as given above. Components (i)-(iii) present in the plasters according to the invention may be those mentioned in Hungarian patent application No. P9603327 and in the corresponding international patent application publication No. WO 98/24470. The contents of these documents and of those cited therein are incorporated herein by reference. Insuline is an outstandingly important representative of peptidaceous pharmacons. Bearing this in mind, in the following I discuss the invention in connection with insuline-containing plasters. Based on routine knowledges, one skilled in the art can easily adapt the information disclosed in the present description for the preparation of plasters which contain another peptidaceous pharmacon or any other pharmaceutically active substance. Of the layers which contain components (i)-(iii), the "first" layer which contains component (i) is the most close to the plaster support. Preferably this layer is situated directly on the plaster support; however, if desired, one or more other layer(s), which may contain e.g. one or more other pharmaceutically active substance(s) for complementing the therapy and/or which may improve mechanical characteristics, storability or diagnostical evaluability of the plaster, can also be inserted between the plaster support and the "first" layer. These other layers are referred to in the following as "auxiliary layer(s)". Examples of such auxiliary layers which may be used in insuline-containing plasters are as follows: a layer comprising zinc ions as therapy complements; a water absorbing/releasing layer; a layer which indicates the presence of insuline by colour reaction (detector layer); a layer for increasing mechanical stability; an adhesion-improving layer; a protective layer against damaging; etc. In the plasters according to the invention such auxiliary layers can optionally also be formed between the "first" and "second" (and, if present, "third") layers, or can be applied onto the "second" or "third" layer. The "first" layer contains, beside insuline, one or more film-forming polymers, which can be preferably soluble or swellable in water. Examples of such film-form- ing polymers are as follows: methyl, ethyl, butyl and carboxymethyl cellulose; poly- vinyl alcohol; polyvinyl acetate; copolymers of the latter ones; acrylates; viscose; other natural or synthetic film-forming polymers. These polymers are admixed with the pharmaceutically active substance (in the present example, with insuline) preferably as aqueous solutions or aqueous dispersions. These aqueous polymer compositions are generally commercially available. The "first" layer also contains, beside insuline and the film-forming polymer, a pharmaceutically acceptable non-toxic surfactant. For this purpose e.g. cationic and nonionic tensides, preferably polyethylene glycol type tensides, ethoxylated fatty acids and esters, can be used. The commercially available solutions or dispersions of film-forming polymers generally already contain the required tensides. The "first" layer may optionally also contain, beside the components listed before, one or more conventional film-forming additive^) and/or auxiliary agent(s). Optionally an indicator for detecting the presence of insuline by a visually observable change and/or a therapy-complementing agent may also be present in the "first" layer. A basical requirement for the listed components of the "first" layer is that they should be physiologically acceptable and should not exert harmful effects either on the peptidaceous pharmacon itself or on the structural parts thereof. As discussed above, the "first" layer may optionally also contain a part of component (ii). For example, when insuline-containing plasters are concerned, 0.1-1 % by weight of component (ii), calculated for the weight of insuline, can be built into the "first" layer. Beside component (ii) and component (iii), if present, the "second" layer also contains one or more film-forming agent(s), which may be e.g. those listed in connection with the "first" layer. Optionally this layer may also contain tensides and/or other additives and/or auxiliary agents. It is preferred to introduce a tenside into the "second" layer primarily when this layer contains the total amount of component (iii) and no further layer is situated above it. The substances which form the "second" layer should also be physiologically acceptable; inertness against the pharmaceutically active agent present in the "first" layer is, however, not required. For plasters which contain a "third" layer, too, the same relates to those materials of the "third" layer which are other than component (iii). It should be noted here that most of the epithelizing agents (components /iii/) are acidic materials, and some of them may cause undesired irritations when contacted with skin. Such skin irritations can be excluded primarily by the appropriate selection of the type and amount of component (iii). From this aspect malic acid, citric acid, thioglycolic acid and derivatives thereof, including their salts, proved to be particularly preferable. As an alternative solution, the pH of the layer which is in direct contact with the skin (which may be the "second" layer, the "third" layer or a separate auxiliary layer) can be adjusted to a, skin-neutral value of 5.5 to 7.0, and/or a skin irritation alleviating agent which has no adverse influence on the effects of the epithelizing agent can also be built into this layer. If the plasters according to the invention contain one or more auxiliary layers), too, the materials and compositions of these layers are determined by the functions of the layers concerned. One skilled in film-forming and in pharmacotech- nology can easily select the appropriate materials and compositions for such auxiliary layers, taking into account the only additional requirement that the auxiliary layers should not inhibit the active agent from entering the living organism. In the plasters according to the invention the amounts and ratios of components (i), (ii) and (iii) can be controlled with a very high accuracy by the appropriate selection of the compositions of the layers comprising them and/or by the appropriate adjustment of the thicknesses of the layers applied. It is given as an example that for insuline-containing plasters the "first" layer may contain 0.05-2 g/cm 2 of insuline and may be 30-80 μ thick, the "second" layer may contain 0.01-0.25 g/cm 2 of component (ii) and may be 15-35 μ thick, whereas the "third" layer may contain 0.001-0.15 g/cm 2 of component (iii) and may be 5-20 μ thick; or the plaster may have no "third" layer and may contain the indicated amount of component (iii) in the "second" layer of increased (e.g. 18-50 μ) thickness. As the plasters according to the invention contain the peptidaceous pharmacon and the frequently acidic epithelizing agent in different layers, which are sometimes separated from one another by one or more in-between layer(s), too, the possible adverse effects exerted on the pharmacon by the epithelizing agent can safely be avoided, and this significantly improves the storability of the plaster. At the same time in the plasters according to the invention the layer which contains the epithelizing dgent is in direct contact with or the most close to the skin of the patient, which involves the advantage that the skin gets appropriately loosened even before the pharmacon enters the lower layers by diffusion. This phenomenon further improves the transdermal resorption of the active agent. Considering that it is the moisture content of the skin which enables or accelerates the diffusion of the peptidaceous pharmacon, with plasters stored under moisture-proof conditions a risk of premature diffusion, which would lead to damages when the pharmacon contacts the acidic epithelizing agent, does not appear. According to a particularly preferred method a highly absorbent paper, capable to take up moisture in an amount of at least 80 % of its own weight, is applied as plaster support. However, other conventional plaster supports, such as parchment paper or various spongy polymers, can also be utilized. Even the plaster support itself may consist of more layers; examples of these are various papers and sponges combined with PVC, polyolefins, polyacrylates, polyisocyanates and/or aluminium foil. Plasters containing a peptidaceous pharmacon are prepared so that the layers discussed above are applied in the proper order onto the plaster support. The layers can be formed by any of the methods suitable for film-formation, coating or layer application. Thus e.g. the conventional plaster-forming technique can be used, according to which the individual layers are applied onto the plaster support by smearing. If necessary, the already applied layer is dried before the application of the further one. According to another method a solution or paste is formed from the materials of the individual layers, and the solution or paste is extruded then to a film. Using a multihead extruder several films can be formed simultaneously; the films exiting the individual extruder heads are combined then with one another and with the plaster support. According to a particularly preferred method the individual layers are applied onto the plaster support by typographic techniques. In this instance preferably paper is used as plaster support, and the individual layers are applied onto the support by conventional methods of printing, e.g. by gravure, relief, flexographic, offset, planographic or screen printing, using sheet-fed or web-fed presses, in full-tone or dot-matrix (raster) form. This method differs from the conventional printing methods well known to those skilled in the art essentially ony in that printing ink is replaced by the layer-forming/film-forming mixtures discussed above. According to an outstandingly preferred method the layers are formed on the paper support by well known web printing methods, detailed information on which can be found e.g. in Peter, Gy. and Szilagyi, T. "Tekercsnyomtatas" ("Web Printing", in Hungarian) published by Mϋszaki Kόnyvkiadό, Budapest in 1983, and in the other references cited in this textbook. When full surface is to be printed, it is preferred to use screen or gravure printing for thick layers, flexographic or gravure printing for medium layers, and flexographic, planographic or offset printing for thin layers. Any of the conventional web-fed presses can be used to apply the layers by typography. Depending on the type of press and on the printing method used, the layers can be formed on the plaster support by single-step or multistep operation. According to a particularly preferred method the layers are formed by "common impression" printing, wherein the printing machine is equipped with as many printing cylinders and troughs as many layers should be applied onto the plaster support. The thickness of the applied layer can be regulated very easily by appropriately adjusting the trough depth. When plasters are to be formed where the indididual layers are of the same thickness, or where the thickness of a thicker layer is the integral multiple of that of a thinner layer, one may also proceed so that the trough depth is maintained on a pre-adjusted constant value, and the thicker layer is formed by using as many cylinders and troughs as high the multiplier is. Although from typographical aspects a thus-formed thicker layer is a multiple layer, it is regarded as a single layer from the aspects of the invention. The layers applied by typography may be either full-tone layers which cover the whole surface, or they may cover the surface only partially. Of the latter those prepared by raster printing are to be mentioned, where the layer formed from the film-forming mixture on the surface to be printed consists really of a multitude of discrete dots (raster dots). The appropriate selection of the density and geometry of raster dots enable a very fine control of the dose applied. By this method extremely thin films, e.g. 1-2 μ in thickness, can also be applied in the form of very small raster dots, e.g. 0.1 mm 2 in area, which means that the dose applied onto unit area can be controlled with an accuracy of some thousandth millilitre. The typographic methods discussed above for the preparation of multilayer plasters containing peptidaceous pharmacons can also be used to prepare single- layer or multilayer plasters containing any desired pharmaceutically active substance. Typographical methods have not been used before to produce plasters for therapeutical purposes. Over the very accurate adjustment of the dose, which has been discussed above in detail, typographical methods have the additional advantages that they are very quick, productive, and can be adapted very flexibly to the existing requirements. Thus, in a further aspect, the invention relates to a process for the preparation of a plaster containing a pharmaceutically active substance, in which at least one layer comprising a pharmaceutically active substance and a typographically applicable film-forming agent compatible therewith is applied onto a plaster support by typography. The scope of the invention also extends to the thus-prepared plasters. The film-forming agents and the optional film-forming additives present in such plasters may be those listed above. Like the plasters containing a peptidaceous pharmacon, these plasters may also contain more than one layer containing pharmaceutically active substance(s) and/or one or more auxiliary layer(s). Also with these plasters it may be advantageous to form an epithelizing agent-containing layer as a layer being in direct contact with the skin in order to assist the active agent to enter the organism. The typographical methods which can be used to apply the layers may also be the same as discussed above, including raster dot forming techniques, too. Since typographical methods used to apply the active agent involve incorporation of the active agent in a film, it is a further advantage that generally it is not necessary to form separate layers for protecting or sequestering the active agent. This advantage is of primary importance when undesired interactions between some components (e.g. multiple active agents, active agent and additives, etc.) of the composition should be safely excluded. A further outstanding advantage of the raster-dot method is that it enables to combine in a single composition numerous - even ten or more - active agents and additives which, due to incompatibility reasons or due to the risk of undesired interactions, cannot be combined in a single composition prepared by conventional techniques. Further details of the invention are elucidated by the aid of the following non- limiting examples. Example 1 Preparation of insuline-containing plasters Using a' web-fed press, the following layers were applied consecutively onto a so-called voluminoused paper of high absorption capacity: First layer, a dry film of 60 μ thickness, containing 0.1 g/cm 2 of insuline. A commercially available tenside-containing 4.4 % by weight aqueous solution of polyvinyl alcohol was used as film-forming agent, insuline was dissolved in it, and the resulting solution was applied onto the support by gravure printing. Second layer, a dry film of 30 μ thickness, containing 0.01 g/cm 2 of histamine. A commercially available tenside-containing 6 % by weight aqueous solution of polyvinyl alcohol was used as film-forming agent, histamine was dissolved in it, and the resulting solution was applied onto the dried first layer by flexographic printing. Third layer, a dry film of 15 μ thickness, containing 0.1 % by weight of malic acid and 3 % by weight of sodium thioglycolate. A commercially available tenside- containing 5 % by weight aqueous solution of polyvinyl alcohol solution was used as film-forming agent, malic acid and sodium thioglycolate were dissolved in it, and the resulting solution was applied onto the dried second layer by flexographic printing. The web exiting the press was fed into a cutting machine and was cut there to pieces of pre-adjusted dimensions (5, 2 or 1 cm 2 ). The plasters leaving the cutting machine were packed into self-adhesive polyvinyl acetate envelopes. Example 2 Preparation of an antirheumatic plaster 20 parts by weight of acetylsalicylic acid were dissolved in 80 parts by weight of a 3.8 % by weight aqueous solution of methyl cellulose, and the resulting solution was printed by screen technique onto a polyacrylate film web to form a dry film with a thickness of 90-100 μ. When printing, 0.2 cm wide strips were left blank on both edges of the A .4 cm wide polyacrylate film. 10 parts by weight of Diclofenac-Na were dissolved in 90 parts by weight of a 8 % by weight aqueous solution of modified (copolymerised) vinyl aldehyde/vinyl alcohol, and the resulting solution was printed by flexographic technique onto the previously dried film obtained in the previous step to form a dry film with a thickness of 60 μ. 3 parts by weight of capsaicine and 2 parts by weight of polyethylene glycol 200 were dissolved in 100 part by weight of a 30:70 v/v mixture of ethanol and water, and the resulting solution was printed by flexographic technique onto the previously dried film obtained in the previous step to form a dry film with a thickness of 10 μ. The web exiting the press was cut to pieces with 5 cm 2 of printed surface, and the resulting plasters were packed into paper envelopes. Example 3 Preparation of a plaster for treatment of calcification The method described in the first paragraph of Example 2 was followed with the difference that a mixture of 60 parts by weight of methyl cellulose solution and 40 parts by weight of acetylsalicylic acid was used to apply the layer. Example 4 Preparation of a plaster for treatment of influenza and chill diseases 65 parts by weight of a 6 % by weight aqueous solution of polyvinyl alcohol, also containing 10 % by weight of vaseline, was admixed with 20 parts by weight of a 62 % by weight aqueous solution of doxycycline and 15 % by weight of paracetamol. Using a sheet-fed press, offset printing and raster technique (5x5 rasters, loading /number of 1 mm 3 dots for 1 cm 2 /: 3:1 ), the resulting film-forming mixture was printed orito a paper backed with a bioxial polyethylene/polypropylene foil.

Claims: What I claim is: 1. A process for the preparation of a plaster containing a pharmaceutically active substance, characterised in that at least one layer comprising a pharmaceutically active substance and a typographically applicable film-forming agent compatible therewith is applied onto a plaster support by typography. 2. A plaster containing a pharmaceutically active substance, whenever prepared as claimed in claim 1 . 3. A topically applicable plaster for introducing a peptidaceous pharmacon in a living organism, which comprises a plaster support and (i) a peptidaceous pharmacon, (iii) capsaicine, histamine and/or cantharis extract, and (iii) an epithelizing agent applied thereon, characterised in that component (i) is, optionally together with a part of component (ii), in a layer ("first layer") above the plaster support, component (ii) or its remainder is in a separate layer ("second layer") above said first layer, and component (iii) is in said second layer and/or in a separate layer ("third layer") above said second layer. 4. A plaster as claimed in claim 3, characterised in that the individual layers also comprise a pharmaceutically acceptable film-forming agent compatible with component(s) (i)-(iii) present in the layers concerned. 5. A plaster as claimed in claim 4, characterised in that the film-forming agent is a polymer which is soluble or swellable in water. 6. A plaster as claimed in claim 5, characterised in that t e film-forming agent is polyvinyl alcohol or methyl cellulose. 7. A plaster as claimed in any of claims 4 to 6, characterised in that the layers which contain component (i) and component (iii) also contain a tenside. 8. A process for preparing a topically applicable plaster for introducing a peptidaceous pharmacon in a living organism, characterised in that the layers containing the components as given in any of claims 3 to 7 are applied onto a plaster support in the order as given in claim 3. 9. A process as claimed in claim 8, characterised in that the layers are applied by typography.

Inventors: DARDAI ZOLTAN, DARDAI, ZOLTAN
Applicants: DARDAI ZOLTAN, DARDAI, ZOLTAN
Application year: 2000
Main classification: A61L15
IPC codes: A61K9, A61L15