HU225734B1 - Multilayer plaster for introducing peptidaceous pharmacons in living organisms and process for producing thereof - Google Patents

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

The present invention relates to multilayer patches for delivering peptide-like therapeutic agents to the body. The present invention also relates to a process for making patches.

Hungarian Patent Application P96 03327 and the corresponding International Patent Publication WO 98/24470 disclose topical pharmaceutical compositions for delivering peptide-like therapeutic agents to the body by transdermal absorption. The compositions described herein comprise (i) a peptide-like pharmaceutical agent, (ii) a topical vasodilator, namely capsaicin, histamine and / or asparagus extract, and (iii) an exfoliating agent, in admixture with conventional carriers and / or diluents for topical pharmaceuticals. In these compositions, the percutaneous absorption of the peptide-like pharmaceutical compound is provided by the co-presence of components (ii) and (iii); of these, component (ii) reacts with the peptide-like pharmaceutical agent. Preferred compositions of the compositions described herein are patches which contain the components listed above when applied to a skin adherent carrier.

There is no restriction on the production of patches or on the order of application of the component (ί) - (ίίί) in the two citations cited. In the examples provided, patches are prepared by preparing a solution of component (i) - (iii) and gelling it, or by applying component (i) - (iii) to an ointment base and applying the resulting mixture to a patch carrier.

Practical experience has shown that formulations containing components (i) to (iii) combined do not always have sufficient shelf-life. In principle, at least partial separation of the components is achieved, for example, by providing a multilayer patch to improve shelf life. However, it can be deduced from the literature that the use of multilayer patches for peptide-like therapeutic agents results in undesirable results.

Thus, for example, WO 94/04109, which discloses a patch consisting of an adhesive applied on a patch carrier, a source layer on the adhesive layer (containing the drug substance onto an adsorbent) and a new adhesive layer applied on the source layer, emphasizes that the adhesive layer absorption of the active substance. This is precisely the purpose of the application of the adhesive layers: thus, it is possible for some of the therapeutic agents (for example, nicotine, nitroglycerin) highlighted in the anterior to be absorbed for about 24 hours per patch. Enter the body by 4 pm and the body will take approx. Get 8 hours of rest without any drug load. However, this phenomenon is a drawback to peptide-like drugs, especially insulin, which must be avoided. In particular, in the treatment of peptide-like therapeutic agents, efforts are made to achieve as uniform a blood level as possible, which requires dosage forms which deliver the active ingredient as evenly as possible. Thus, according to the cited publication, it is not desirable to use multilayer patches to deliver peptide-like therapeutic agents to the body.

The cited anteriority mentions the occasional use of excipients to aid in the passage of the active ingredient through the skin, but only outlines how these materials can be applied to the patch. In particular, the International Publication Document considers such excipients to be capable of being applied to any layer of the patch, and even suggests that it is sufficient to pretreat the skin with penetration aids prior to application of the patch.

Surprisingly, in my studies, when the peptide-like drug (component (i)) and component (ii) - (iii), which enable the peptide-like drug to be absorbed through the skin, are applied to the patch carrier in a predetermined order, at least partially a multilayer patch not only improves the shelf life of the formulation, but can also make the absorption of the active ingredient more complete and more finely controlled. International Patent Publication No. WO 94/04109 did not allow for the latter result, and indeed the opposite was expected. A further advantage is that the multilayer patches of the present invention provide a more precise control of the amount of active ingredient applied. As a result, the doses required for treatment can be adjusted more sustainably and accurately.

Accordingly, the present invention relates to a multilayer patch for delivering peptide-like therapeutic agents to a body, comprising (i) a peptide-like therapeutic agent, (ii) capsaicin, histamine and / or ash beetle extract, and (iii) an exfoliating agent. In the patch of the present invention, component (i) and optionally component (ii) in a layer above the patch carrier (hereinafter referred to as "first layer"), component (ii) or the remainder of the component above the first layer specified herein a second layer (hereinafter "second layer"), while component (iii) is present in the second layer provided herein and / or in a further layer above (hereinafter referred to as "third layer").

Component (iii) is thus completely separated, whereas component (ii) is at least partially separated from component (i).

The present invention also relates to a method of making a multilayer patch for delivering peptide-like pharmaceutical agents to a living body by applying to the patch carrier a layer comprising the above-mentioned components in the above order.

Components (i) to (iii) in the patches of the invention may be as disclosed in Hungarian P96 03327 and its corresponding WO 98/24470. These documents and their2

The contents of other publications cited herein are hereby incorporated by reference.

One of the most important representatives of peptide-like therapeutic agents is insulin. With this in mind, the present invention will now be described with reference to insulin-containing patches; the teachings of this disclosure can be readily adapted to the formation of patches containing other peptide-like therapeutic agents based on the ordinary skill of the art.

In the patches of the invention, the "first" layer of component (i) of the layers comprising components (i) to (iii) is closest to the patch carrier. This layer is preferably located directly on the patch carrier; however, if desired, one or more other layers may be included between the patch carrier and the first layer, which may, for example, contain one or more other therapeutic agents to supplement the therapy and / or improve the mechanical properties, durability or diagnostic value of the patch. These layers are hereinafter referred to as "auxiliary layers". Examples of such auxiliary layers for insulin-containing patches are: a layer containing zinc ions (as an additional therapeutic agent); water retention / drainage layer; a layer indicating the presence of insulin by a color reaction (detector layer); a layer for enhancing mechanical stability; adhesion enhancing layer; protective layer, etc. Such auxiliary layers in the patch of the invention may optionally be provided between the "first" and "second" (and optionally "third") layers and may be applied to the "second" or "third" layer.

The "first" layer contains, in addition to insulin, one or more film-forming polymers, which may conveniently be water-soluble or water-swellable film-forming polymers. Examples are methyl, ethyl, butyl and carboxymethyl cellulose, polyvinyl alcohol, polyvinyl acetate, copolymers of the latter, acrylates, viscose and other natural and artificial film-forming polymers. These polymers are suitably mixed in the form of an aqueous solution or aqueous dispersion with the therapeutic agent (in this example, insulin). These aqueous compositions are usually commercially available directly. The "first" layer contains, in addition to insulin and film-forming polymer, a pharmaceutically acceptable non-toxic surfactant. For example, cationic and nonionic surfactants, preferably polyethylene glycol surfactants, ethoxylated fatty acids and fatty acid esters, may be used. Commercially available film-forming polymer solutions or dispersions usually already contain the required surfactants. The first layer may optionally contain, in addition to the components listed, one or more conventional film-forming additives and / or excipients. Optionally, the "first" layer may include an indicator and / or an additional therapeutic agent to detect the presence of insulin by a visual reaction. The essential requirement for the listed components of the "first" layer is to be physiologically acceptable and not to adversely affect the peptide-like therapeutic agent or its constituents present.

As stated above, the "first" layer may optionally comprise a portion of component (ii). For example, in the case of insulin-containing patches, 0.1-1% by weight of component (ii) based on insulin may be incorporated into the "first" layer.

The "second layer" comprises, in addition to component (ii), and optionally component (iii), film-forming materials which may be, for example, the film-forming agents listed in the "first" layer. Optionally, this layer may also contain surfactants and / or other additives and / or excipients. In particular, it is desirable to incorporate the surfactant into the second layer when this layer contains all of component (iii) and no other layer is present above it. The materials constituting the 'second' layer must also be physiologically acceptable; however, there is no requirement for inertness to the drug in the "first" layer. The same applies to materials other than component (iii) forming "third layer" patches. It is noted that most of the exfoliating agents, i.e. components (iii), are acidic and some of them can cause undesirable skin irritation upon contact with the skin. Skin irritation can be eliminated primarily by appropriate selection of the quality and amount of component (iii). Malic acid, citric acid, thioglycolic acid and their derivatives, including salts, have proven particularly advantageous in this regard. Alternatively, the pH of the layer in direct contact with the skin (which may be the "second" layer, the "third layer, or a separate auxiliary layer") may be adjusted to the pH of the skin (5.5 to 7.0) and / or skin soothing agents which do not adversely affect the effect of the exfoliating agent may also be incorporated.

If one or more auxiliary layers are present in the patches of the present invention, the materials and composition thereof will be determined by the function of the auxiliary layer. The materials and composition of the auxiliary layers can be readily determined by one skilled in the art of film-making and pharmaceutical technology, taking into account the only additional requirement that the auxiliary layers should not impede the ingestion of the active ingredient.

The amount and ratio of the components (i), (ii) and (iii) in the patches of the present invention can be extremely precisely controlled by selecting the composition of the layers comprising them and / or adjusting the thickness of the applied layers accordingly.

By way of example, in the case of insulin-containing patches, the amount of insulin in the "first" layer is 0.05-2 g / cm ² , the thickness of the layer is 30-80 micrometers, and the amount of component (ii) in the "second" layer is 0.01-0-0. 25 g / cm ² , layer thickness 15-35 micrometers, while in the "third" layer the amount of component (iii) is 0.001-0.15 g / cm ² , layer thickness 5-20 micrometers; or the patch has no "third" layer and the specified amount of component (iii) is contained in the "second" layer having an increased thickness (e.g., 18-50 micrometers).

HU 225 734 Β1

Because the peptide-like drug substance in the patches of the present invention is in a layer (often separated by one or more intermediate layers), which is often separated from the acidic exfoliating agent, any adverse effects of the exfoliating agent on the drug can be completely eliminated. shelf-life. However, in the patches of the invention, the layer containing the epithelial agent is in direct contact with or closest to the patient's skin, with the advantage that the skin is sufficiently loosened prior to diffusion of the therapeutic agent into the lower layers. This phenomenon further improves the absorption of the active ingredient through the skin. Because the diffusion of the peptide-like drug is facilitated or accelerated by the skin's moisture content, there is no need to fear premature diffusion when stored in a patch protected from moisture, which would lead to damage when the drug and acidic exfoliating agent come into contact.

In a very preferred embodiment, the paper used is a high absorbency paper, i.e., capable of absorbing at least 80% of its weight. However, other known patch carriers, such as parchment or various sponge polymers, may be used for this purpose. The patch carrier itself may be multilayer; such as papers and sponges combined with PVC, polyolefins, polyacrylates, polyisocyanates and / or aluminum foil.

Patches containing peptide-like drugs are prepared by applying the layers listed above in the appropriate order to the patch carrier. The layers may be formed by any of the methods suitable for film formation / application. For example, the customary patching technique may be used, whereby individual layers are applied to the patch carrier by lubrication. If necessary, the existing layer is dried before applying another coat. Alternatively, the materials constituting each layer are formed into a solution or paste and the film or paste is extruded into a film. Multiple head extruders can produce multiple films at the same time; the films leaving the extruder heads are then combined with each other and the carrier.

In a highly preferred embodiment, each layer is applied to the patch carrier by printing technique. In this case, it is preferable to use paper as the patch carrier and apply the individual layers by conventional printing techniques (e.g., intaglio, high, flexo, offset, flat or screen printing, sheet or roll, teletone or raster). This solution differs essentially from printing methods well known to those skilled in the art of printing, in that only the printing / film forming mixtures listed above are used instead of printing inks.

In a particularly preferred embodiment, the layers are known by roll printing methods known in the art [for detailed instructions, e.g.

György Péter and Tamás Szilágyi in a technical paper entitled "Roll Printing" (Technical Publisher, Budapest, 1983) and other publications cited there]. For printing a full surface, it is preferable to use screen or intaglio printing for high film thicknesses, flexo or intaglio printing for medium film thicknesses, flexo, flat or offset printing for low film thicknesses. Any of the conventional roll printing machines can be used for the printing layer. Depending on the particular machine type and printing technique, the layers may be formed on the patch carrier in one or more steps. In a particularly preferred embodiment, roll-to-roll printing is used to form the layers by attaching as many print rollers and cups to the printing press as many layers to be applied to the patch carrier. The thickness of the applied layer can be easily controlled by the proper selection of the cup personality. In the case of patches where the thickness of each layer is equal or the thickness of the thicker layers is an integer multiple of the thickness of the thinner layers, it is also possible to maintain the cup personality at a predetermined constant and the thicker layers to be more cylindrical. and using a cup. The thicker layers thus deposited, although considered to be multiple layers for printing purposes, are considered to be a single layer for purposes of the present invention.

Typically, the layers applied to the printing process are teletonic (i.e., the layers that cover the entire surface) and can be only partially fillable. The latter include raster-printing layers, where the film-forming mixture is formed of a plurality of discrete dots (raster dots) on the surface to be printed. By appropriately selecting the density and geometry of the raster points, the dose applied can be extremely finely controlled. With this solution, ultra-thin films (e.g., 1-2 µm thick) can be applied in the form of very small (e.g., 0.1 mm ² area) raster dots, which means that the dose applied per unit area can be controlled to the accuracy of thousands of milliliters.

The invention is illustrated by the following example.

Example

Production of insulin-containing patches

With the help of high-absorbency so-called volumetric paper roll technique, the following layers have been successively formed:

first layer: 60 micrometer thick dry film with 0.1 g / cm ² insulin [a commercially available 4.4 wt% aqueous polyvinyl alcohol solution containing surfactant in which insulin was dissolved; this solution was applied to the substrate by gravure printing];

second layer: 30 micrometer thick dry film containing 0.01 g / cm ² histamine (commercially available 6 wt% aqueous polyvinyl alcohol solution containing surfactant,

HU 225 734 Β1 in which histamine was dissolved; this solution was applied to the dried first layer by flexo technique];

third layer: 15 micrometer thick dry film containing 0.1 wt% malic acid and 3 wt% sodium thioglycolate (commercially available 5 wt% aqueous polyvinyl alcohol solution containing surfactant, in which malic acid and sodium thioglycolate were dissolved; this solution was applied to the dried second layer by flexo technique].

The roll leaving the press was cut into a presetting machine (5, 2, 1 cm ² ) and the patches leaving the wrapping were packed in a self-adhesive polyvinyl acetate wrapper.

Claims (7)

A multilayer patch for delivering a peptide-like pharmaceutical agent to a living organism, comprising (i) a peptide-like pharmaceutical agent, (ii) capsaicin, histamine and / or ash beetle extract, and (iii) an exfoliating agent, wherein component (i) and optionally a portion of component (ii) in the first layer above the patch carrier, component (ii) or the remainder in the second layer above the first layer, and component (iii) in the second layer and / or the third layer above. layer. A patch according to claim 1, characterized in that the layers listed in claim 1 contain a film-forming film compatible with the component (s) (i) to (iii). A patch according to claim 2, characterized in that it comprises a water-soluble or water-swellable polymer as a film-forming agent. A patch according to claim 3, characterized in that it comprises polyvinyl alcohol or methyl cellulose as film-forming agent. 5. A patch according to any one of claims 1 to 3, characterized in that it further comprises a surfactant in the layers comprising component (i) and component (iii). 6. A process for the preparation of a topical patch for delivering peptide-like pharmaceutical agents to a living organism, comprising applying to a patch carrier, in the order set forth in Claims 1 to 5, a patch carrier. Layers comprising the components specified in any one of claims 1 to 4. 7. A method according to claim 6, characterized in that the layers are applied by printing.