SI8912407A - Process for the preparation of transdermal therapeutic system having physostigmine as the active ingradient - Google Patents

Abstract

The invention refers to the procedure for the preparation of transdermal therapeutic system for the application of physostigmine to the skin consisting of the cover layer impermeable to the active ingredient, of the clinging and sticking reservoir layer and possibly removable protective layer. It is characterised by the fact that the active substance physostigmine together with the ingredients of the clinging and sticking reservoir layer, possibly in the solution is homogeneously mixed and applied to the cover layer that is impermeable to the active substance, possibly the solvent is removed and the sticking reservoir layer is covered with the protective layer, where the reservoir layer contains 10-90 % by weight of polymer material gathered from the groups consisting of bloccopolymers on the basis of styrol and 1,3 dienen, polyisobutylene, polymers on acrylate and/or methacrylate basis and esters of hydrated colophony, 0-30 % by weight of softeners on the basis of hydrocarbons and/or esters and 0.1-20 % by weight of physostigmine.

Description

Process for making transdermal therapeutic system with chizoatigmine as active ingredient

FIELD OF THE INVENTION

The invention belongs to the field of liquid necessities and pharmacy. Symbols of the International Patent Classification are: A 61 L 15/06, A 61 L 15/03, A 61 K 31/645, C 09 J 7/02 and C 09 J 3/14.

A technical problem

The technical problem is how to create a system for transdermal administration of a medicinal ingredient, which is achieved by the production of a medicinal form, which is applied by adhesion to the skin and from a system in which the medicinal ingredient is deposited and which consists of several suitable layers based on polymeric materials. compound and such properties that they do not affect the stability of the active ingredient and which slowly releases the active ingredient so that it can be absorbed through the skin.

The state of the art

The use of physostigmine to address Alzheimer's disease has been reported in the literature, evaluating the efficacy of substances by different authors. As the alkaloid has a high first pass effect - the bioavailability of physostigmine after oral administration lies at 5% - we need to look for causes of deviating results in the application variants.

DE-OS 35 28 979 describes a composition comprising, in addition to physostigmine, a medium chain carbonic acid; this composition can be worn on a bandage, insert, or compresses that are secured with a bandage. This type of application does not in itself constitute any therapeutic system, which is why it is intended to equip the bandage, compressor or insert with a reservoir inner layer of an impermeable guard foil or an impermeable guard film and attach the rned reservoir and skin to a more detailed control membrane. diffusion. Neither the diffusion control membrane nor the protective foil are described more closely. Carboxylic acid is specifically designated as an effective means of delivery through the skin that would otherwise not enter through the skin barrier. However, this statement is not scientifically defensible.

DE-PS 36 06 892 describes retarded administration of physostigmine and other active substances which may be transdermal. The special formulation is not disclosed, but refers to the formulation already described (US-PS 3, 921,363).

In addition to the very vague implementation of transdermal therapeutic systems, the instability of physostigmine, which has been recognized early on (Liber, W., Pharmaz. Ztg. 37, 483 (1888); neither Herzig, J. Mayer, H) ., Mh. Chem. 10, 379 (1897); Henzig J., Lieb, H., ebenda 39, 285 (1918): Solvay, A.A., J. Chem. Soc. (London) 101, 978, (1912). Instability based on rapid breakdown puts the use of physostigmine in pharmacy by a narrow margin.

Solution to a technical problem with description of implementation examples

The object of the invention is therefore to provide physostigmine or one of its pharmaceutically acceptable salts in the form of a transdermal therapeutic eitem, which emits physostigmine or its pharmaceutically acceptable salts in a controlled manner for 24 hours and ensures that physostigmine will not be noticeably degraded during storage of the previously transdermal therapeutic system.

The present invention is solved by the fact that physostigmine or one of its pharmaceutically acceptable salts is contained in an existing reservoir layer made from a specially selected material, wherein the components of this reservoir, namely polymers, resins and plasticizers, contain neither hydroxyl groups nor polyethoxy groups. The constituents for the resin and for the softening of the polymer layer were therefore selected from the class of ester or hydrocarbon compounds.

The stability of the active substance can be further improved by selecting a suitable solvent or solvent. solvent mixtures for the manufacture of a transdermal therapeutic system. The solvents or the solvents are preferably used. mixtures of solvents which, at low boiling point and thereby allowing drying, achieve extremely low residual moisture of less than 0.5, preferably less than 0.4%.

The subject of the invention is a process for the manufacture of a transdermal therapeutic system for administering physostigmine to the skin from the active substance of the impermeable cover layer, the adhesive-adhesive reservoir layer and, if possible, the removable protective layer, characterized in that the active substance is physostigmine together with the constituent of the physostigmine together with the ingredient if possible, the solution is homogeneously mixed in the solution and applied to the active substance an impermeable cover layer, eventually the solvent is removed and the adhesive reservoir is covered with a protective layer, containing the reservoir layer of 10-90% by weight of polymeric material selected from the groups existing from blocks, existing from groups styrene and 1,3 dienene, polyisobutylene, acrylate and / or methacrylate polymers and hydrated rosin esters,. 0-30% by weight of hydrocarbon and / or ester based softeners and 0.1-20% by weight of physostigmine.

The subject of the invention is further a carrier for use in the transdermal administration of physostigmine, existing from an active substance of an impermeable back layer, a adhesive-adhesive layer suitable for receiving the active substance, and possibly a re-removable protective layer, characterized in that the reservoir layer is adhesive. sticky and contains 50-100% by weight of polymeric material as well as 0-50% by weight of plasticizers.

In this case, there may be an impermeable cover layer of flexible or inflexible material for the active substance. Substances that can be used to make it are polymer films or metal foils, such as aluminum foil used alone or coated with a polymer substrate. Textile planes may also be used if the components of the reservoir cannot penetrate them due to their physical condition. In a preferred embodiment, the coating layer is a bonded material of aluminum foil.

The reservoir layer consists of a polymer matrix and an active substance, the polymer matrix having the property of guaranteeing the consistency of the system. It is made of basic polymer and possibly of conventional additives. The choice of basic polymer is based on the chemical and physical properties of physostigmine. Suitable polymers are rubber, rubber-like synthetic homo, co- or block-polymers, polyacrylic acid ester and copolymers thereof. In principle, all polymers used in the manufacture of adhesive adhesives are physiologically sound and do not exhibit physostigmine. Particularly preferred are those existing from styrene blocker copolymers and 1,3-dienene, polyisobutylene or acrylate and / or methacrylate polymers. In particular, styrene-isoprene-block copolymers are used between styrene-based and 1,3-dienene block copolymers.

Acrylate-based polymers favor the acrylate copolymers of 2-ethylhexylacrylate, vinyl acetate and acrylic acid with or. free of titanic acid ester. The preferred methacrylates are dimethylaminoethyl methyl methacrylate and neutral methacrylic acid copolymers. Preferably, in particular, its methyl and glycerine esters are used as the hydrated rosin ester.

The type of additives available depends on the polymer used and the active substance: by their function, they can be divided into plasticizers, adhesives, stabilizers, carriers, diffusion and penetration control additives. or chargers. The substances that are suitable for this are known to the person skilled in the art. The reservoir layer has its own adhesiveness to ensure lasting contact with the skin.

Examples of suitable plasticizers are dicarboxylic acid diester, e.g. di-n-butyladipate as well as triglycerides, in particular the medium chain triglycerides of caprylic / capric acid of coconut oil. Further examples of suitable plasticizer are isopropyl myristate, dioctylcyclohexane and others.

The removable buffer layer, which is in contact with the reservoir layer and is removed before use, consists, for example, of the same materials used to make the cover layer, provided.

so that removable jivas can be made, such as. with silicone o b de. lava. Other removable protective layers are e.g. polytetrafluoroethyls, treated paper, cellophane, polyvinyl chloride and the like, if the laminate according to the invention is split prior to the placement of the protective layer into formats suitable for therapy (patches), the protective layer formats may then be provided with an over-standing end, with which help can be more easily pulled off the patch.

The transdermal therapeutic system of the invention is made by mixing the active substance together with the components of the adhesive-reservoir reservoir, homogeneously in solution, and applying an impermeable cover layer to the active substance, after which any solvent or solvents are removed.

The adhesive layer is then fitted with a suitable protective layer. The invention will be explained on the basis of the following examples:

Example 1:

g of n-heptane and 80 g of methylethylketone are mixed. 7.2 g of physostigmine, free base, were dissolved in 90 g of this mixture. After complete dissolution of the active substance, 40 g of glycerinester completely hydrated rosin and 40.0 g of linear styrene-isoprene-styrene-block copolymer as well as 5.6 g of coconut oil capryl / capric acid triglyceride (medium chain triglycerides, DAB 8) are added in portions. The light was stirred at room temperature for 8 hours to dissolve completely and applied to aluininized and siliconized polyethylene film.

After removing the solvent by drying at 50'C for 25 minutes, cover the adhesive film with polyester foil for 15 hours. Using suitable cutting tools, cut a 16 cm ² surface and remove the edges with the mesh. The release schedules of Example 1 are given in FIG. 1-2. The graphs show the controlled release of the active substance both into the saline solution and through the rodent's excised skin.

The curve in FIG. 1, whose line is not broken, from in-vitro releases with specimens examined immediately after their production. The broken curve was obtained by release with the samples after three months of storage at room temperature. Since the two curves overlap approximately equally, the above stability can be demonstrated very effectively. Figure 2 shows that the penetration rate of samples that were investigated directly after fabrication or. after three months of storage, also about the same.

The stability of the active substance in the system has also been demonstrated by determining the content directly after manufacture or. after three months' storage. No known degradation products of eserolin and rubreserin have been found in the literature, nor have they been described previously. For this purpose, the following method was used:

Preparation of Mackerel:

One scissors patch was quartered with scissors, the cover film was removed and, together with portions of the patch, in a sealed 50.0 ml tetrahydrofuran glass vial (pa) shaken for at least 2 hours, ultrasonically treated for 10 minutes. and then centrifuged. Dilution for HPLC with methanol and re-centrifugation.

The content of physostigrin in the centrifuge was then determined by HPLC.

Example 2:

The procedure is carried out as in Example 1 except that instead of 5.6 g of caprylic / capric acid triglyceride 3.2 g of di-n-butyladipate are used. The release graphs are given for recipe example 2 in Figures 3-4. The graphs show the controlled release of the active substance both into the saline solution and through the rodent's excised skin. As in Example 1, the continuous line curve shows the release of the sample directly after fabrication. Dotted line. stems from the release of samples stored for three months at room temperature. Even in these samples, the curves run almost equally overlapping, so that in this case the patches were stable as well.

As in Example 1, the physostigrin content was also determined without demonstrating the breakdown product after three months of wetting.

Example 3:

Weigh 2,0 g of physostigrin, free base, into the retort. While stirring, 25 g of a 60% solution of the glycerinolpho10 ny ester in butanone and 25 g of a 40% solution of the styro-butadiene block copolymer in a 1: 2 mixture of n-heptane and butanone are added. After internal stirring, another 2.5 g of methyl ester of hydrated rosin and 1.95 g of capryl / capric acid triglyceride are added while stirring. A further embodiment is as described in Example 1, the release graphs are shown in Figures 5-6. The graphs show the controlled release of the active substance both into the saline solution and through the rodent's excised skin.

As in Examples 1 and 2, the continuous line curve shows the release of the sample directly after fabrication. Unlike the samples presented, the release was not determined only after three months, but after six months of storage. All three curves run again so that they overlap each other so that even after six months the same release is achieved as directly after production.

As in Examples 1 and 2, no degradation product could be demonstrated by HPLC after six months of storage.

Example 4:

8.5 g of freebase physostigmine is dissolved together with 21.3 g of dimethylaminoethyl methyl methacrylate cationic copolymerate and methacrylic acid neutral ester in 21.4 g of ethyl acetate. While stirring, 8.5 g of caprylic / capric acid triglyceride and 68.3 g of non-self-propelled acrylic acid are added to the rats name from 2-ethylhexylacrylate, vinyl acetate and acrylic acid (50% in ethyl acetate). After stirring at room temperature for up to half an hour, the adhesive is homogeneous.

Further processing was performed as described in Example 1. The release data are given in Figures 7-8. The graphs show the controlled release of the active substance both into saline and through the rodent's excised skin.

As in the previous cases, the continuous line curve shows the release of samples directly after fabrication. Unlike with. the previous samples were not released only after three months, but also after six months of storage. All three. the curves run again with approximately the same overlap, so that after half a year of storage the same release is achieved as directly after production.

As in the previous cases, no product was decomposed by the HPLC method described in Example 1 after storage for six months.

Example 5:

The embodiment is as described in Example 4 except that the acrylate copolymer does not dissolve 50% in ethyl acetate but 40% in a solvent mixture (ethyl acetate: ethanol: heptane: methanol 64: 25: 9: 2) and contains a solvent. Release schedules are given in Figures 9-10.

As in the previous cases, the continuous line curve shows the release of the sample directly after fabrication. Unlike in previous cases, the release was not determined only after three months, but also after six months of storage. All three curves run again with approximately the same overlap, so that even after half-year storage, the same release is achieved as directly after production.

It should be noted in Example 5 that physostigmine is exposed to a solvent, namely ethanol, which can hydrolytically cleave this active substance (Pfeifer, S.; Behusen, G. and Kuhn., L., Pharmazie 27, 639 (1972 )), but it is crucial that it only works briefly and when the light is turned off, since after smearing it has been removed without residue due to the protective drying.

For the reasons already explained, neither the basic polymer nor the hard resin or plasticizer attack the active substance.

It is crucial for the stability of the active substance that the polymers, resins and plasticizers used do not contain either free hydroxyl groups or polyethanes, since the proportion of active substance that is dissolved would otherwise be subject to hydrolysis. Therefore, resins and plasticizers from the ester compound class were selected.

For the stability of the active substance, the choice of the solvent or the solvent is also crucial. solvent mixtures, if this works before drying for hours on physostigmine. The portion to suppress the formation of blisters of the possibly higher boiling solvent required must be small. This is achieved in the present invention in Examples 1 to 3 by selecting a mixture of butanone and n-heptane.

forming an azeotropic mixture (.butanone ratio: n-heptane 70:30, boiling point 77 * C, boiling point of butanone 79.6'C, boiling point n-heptane 90.5C). This can achieve a maximum residual moisture content of less than 0.4% despite careful drying.

As polyacrylates do not tend to form blisters, this procedure was not necessary in cases 4 and 5.

Claims (15)

PATENT APPLICATIONS A process for the manufacture of a transdermal therapeutic system for administering physostigmine to the skin from the active substance of the impermeable cover layer, the adhesive-adhesive reservoir layer and, if possible, the removable protective layer, characterized in that the active substance is physostigmine together with the reservoir components possibly homogeneously mixed in the solution and applied to the active substance impermeable cover layer, possibly the solvent removed and the adhesive reservoir layer covered with a protective layer, containing a reservoir layer of 10-90% by weight of polymeric material selected from the groups consisting of block copolymers styrene and 1.3 dienene, polyisobutylene, acrylate and / or methacrylate based polymers and hydrated rosin esters, 0-30% by weight of hydrocarbon and / or ester based softeners and 0.1-20% by weight of physostigmine. Process according to claim 1, characterized in that the polymeric material contains a linear styrene-isoprene-styrene-block copolymer. Process according to claim 1, characterized in that the polymeric material contains a linear styrene-butadiene-styrene-block copolymer. Process according to claim 1, characterized in that the polymeric material contains a self-cross-linking acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid and ester titanelate. Process according to claim 1, characterized in that the polymeric material contains a non-cross-linking acrylate copolymer of 2-ethylhexylacrylate, vinyl acetate and acrylic acid. Process according to claim 1, characterized in that it comprises a polymeric material as a methacrylate-based polymer copolymer based on dimethylaminoethylmethacrylate and a neutral methacrylic acid ester. A process according to claim 1, characterized in that the polymeric material, such as hydrated rosin ester, is its methylester. Process according to Claim 1, characterized in that the polymeric material, as the hydrated rosin ester, contains its glycerinester. A process according to claim 1, characterized in that it contains a reservoir layer as a plasticizer dioctylcyclohexane. A process according to claim 1, characterized in that it contains a reservoir layer as a di-n-butyladipate softener. A process according to claim 1, characterized in that it contains a reservoir layer as a triglyceride softener. The method of claim 1, characterized in that it contains the reserved layer as isopropyl myristate as a plasticizer. A method for manufacturing a transdermal therapeutic system according to one of claims 1 to 12, characterized in that the components of the reservoir layer are dissolved in a low boiling solvent that allows drying to a maximum residual moisture of less than 0.4% by weight. A method for manufacturing a transdermal therapeutic system according to claim 13, characterized in that a solvent mixture of butanone and n-heptane is used. 15. A carrier for use in the transdermal administration of physostigmine, consisting of an active back impermeable backbone, an adhesive-adhesive layer suitable for receiving the active substance, as well as a possibly re-removable buffer layer, characterized in that the reservoir layer is adhesive-adhesive and iv contains 50-100% by weight of polymer mat, rial as well as 0-50% by weight of plasticizers.