HRP930588A2 - Therapeutic transdermal system having physostigmine as an active ingredient, and process for its development - Google Patents

Description

The branch of technology to which the invention belongs

The invention belongs to the field of current life needs and pharmaceuticals. The international patent classification symbols are A61L 17/06, A61L 15/03, A61K 51/645, C09J 7/02 and C09J 3/14.

Technical problem

The technical problem is how to create a system for transdermal administration of the drug, which is achieved by creating a medicinal form that is applied to the skin by gluing and from the system, in which the medicinal substance is deposited, which consists of several layers based on textile fabrics and plastic material conveniently aligned the medicinal substance is isolated or resorbed.

State of the art

The use of physostigmine for the treatment of Alzheimer's disease is described in the literature, whereby the effect is evaluated differently by different authors. Since the alkaloid has a high first pass effect - the bioavailability of physostigmine after oral administration is 5% - the deviating results must be reduced to application variants.

DE-OS 35 28 979 describes a composition which, in addition to physostigmine, contains a carboxylic acid of medium chain length, this composition can be worn on a bandage, pad or compresses, which is applied by means of bonding. This type of application in itself does not represent a therapeutic system, which is why it is intended that the bandage, compress or insoles be supplied with an inner layer in the form of a container, an impermeable protective film or an impermeable protective film and that a membrane, which regulates the diffusion that is applied between the container and the skin is not described in detail. Neither the diffusion-regulating membrane nor the protective foil are described in detail. Carbonic acids are indicated exclusively as an active transport vehicle for the administration of a drug through the skin, which otherwise could not penetrate the skin barrier. This statement is not scientifically tenable.

DE-PS 36 06 892 describes the delayed application of physostigmine and other active substances, which can be performed transdermally. The special formulation is not disclosed, on the contrary, reference is made to the already described formulation /US-PS 3, 921, 363/.

In addition to only unspecified versions of transdermal therapeutic systems, none of the two previously mentioned documents exposed to inspection do not address the instability of physostigmine, which was already observed earlier /Eber, W. Pharmaz. Ztg. 37, 483/ 1888/; Herzij, J. Mayer, H., Mh.Chem. 18, 379 /1897/; Herzig, J. Lieb, H. ibid. 39, 285 /1918/; Solvay, A. A., J. Chem. Soc. /London/ 101, 978 /1912/; instability based on fast decomposition places narrow limits on the use of physostigmine in pharmacy.

Description of the solution to the technical problem with implementation examples and a list and brief description of the drawing images

The invention relates to a process for the production of a transdermal therapeutic system, which contains physostigmine as an active ingredient. The task of the invention is therefore to make available physostigmine or one of its pharmaceutically acceptable salts in the form of a transdermal therapeutic system, which releases physostigmine or its pharmaceutically acceptable salt in a controlled manner within a time interval of 24 hours and guarantees that physostigmine does not degrade significantly during storage of the previously made transdermal therapeutic system.

The task is solved by dissolving at least 25% of physostigmine in a solution or solvent mixture, which must be physiologically replaceable, since it must be taken into account that not only physostigmine but also the solvent migrates through the matrix. This solution can be pressed by means of a pressing process, as for example described in DE-OS 36 29 304, onto a textile surface on which a matrix has previously been applied, which has previously been provided with a protective layer impermeable to the active substance, which in the given case can be re-applied separate. Then, the pressed textile product and the matrix are covered with a previously made covering layer, which is also impermeable to the active substance. Using a suitable cutting tool, the surface of which is round and significantly larger than the surface of the non-woven fabric, it is cut centrally. Then the edge of the adhesive, which does not contain the active substance, is separated with a grid.

The subject of this invention is a process for making a transdermal therapeutic system for administering physostigmine on the skin, which contains a cover layer impermeable to the active substance, a container layer that adheres by gluing and, in a given case, a protective layer that can be separated again, which is indicated by a matrix layer that is prepared in advance, self-adhesive, which in a given case is supplied with a protective layer that can be separated, is placed by a textile fabric, physostigmine or one of its pharmaceutically acceptable salts is applied in solution to the textile fabric, creating a depot of the active substance, after which the matrix and depot active substances supply a covering layer.

The subject of the invention is further a carrier for transdermal administration of physostigmine, which consists of a last layer impermeable to the active substance, a layer that adheres, which is suitable for receiving the active substance, as well as in the given case a protective layer that can be separated again, which is indicated by the fact that it is a container layer, which adheres and contains 50 - 99.9 wt. % of polymer material, 0-20 wt.% of softener as well as 0.1-30 wt.-% of solvent for physostigmine.

The procedure is known in principle and described in DE-OS 36 29 304. Nevertheless, the above-mentioned document exposed for inspection serves the nicotine base as a substance. Since the nicotine base is liquid at room temperature, the procedure could not be easily adapted. On the contrary, physostigmine had to be translated into a high percentage, i.e. at least a 25% solution, since the individual dosing of powder ingredients is in use in the technology of solid forms of drugs, but is completely unknown in the technology of semi-solid forms of drugs, since this question has not been raised so far. At the same time, the solvent must meet three more important requirements:

- very unstable physostigmine must not decompose,

- must be physiologically unquestionable,

- must enable physostigmine to be well expressed during the production of the system, but only slightly soluble during storage.

Carbonic acids, which have more than 10 carbon atoms, meet the above requirements. When physostigmine is mixed with these compounds, it dissolves, as does the formation of salts. but in principle such preparations are liquid at room temperature.

The solubility of the active substance in the matrix is reduced by adding a higher proportion of the base polymer to the matrix, for example copolymers with a cationic character based on dimerylaminoethyl methacrylate and other neutral methacrylic acid esters. This results in an acid-base reaction after the application of the matrix between the carbinic acid and the base polymer, which significantly reduces the solubility of the active substance. Based on the release of the recipe example, it can be shown that the release of the meal increases with the proportion of the base polymer in the matrix.

Next, the construction of the system should be schematically explained.

The cover layer (4) can consist of flexible or non-flexible material and can be multi-layered. Substances that can be used for its production are polymer substances, such as polyethylene, polypropylene, polyethylene terephthalate, polyamide. Metal foils, such as aluminum foils, alone or coated with a layer of polymer substrate /in the latter case (5)/ can also be used as further materials. Textile flat products can also be used, if the ingredients of the container cannot penetrate through the textile material based on their physical properties. In the assumed embodiment, the cover layer /4/ is a connecting material, which gives the laminate strength and serves as a barrier against the loss of the laminate components. In addition, foils on which aluminum or bonding materials are applied in a vapor state are also suitable.

The matrix (1) is attached to the cover layer. During the fourteen-day storage, physostigmine moves from the depot (2) of the active substance to the matrix (1) and protects it, so that the matrix becomes a reservoir layer. The matrix has the property of guaranteeing the solidity of the system. It consists of a basic polymer and, in a given case, the usual additives. The choice of base polymer is governed by the chemical and physical properties of physostigmine. Examples of polymers are rubber, rubber-like homo-, co- or block polymers, polyacrylic acid esters and their copolymers. In principle, all polymers, which are used in the production of adhesives for adhesion, come into consideration. They are physiologically unquestionable and do not break down physostigmine. In particular, those that consist of block polymers based on styrene and 1,3-diene, polyisobutylene or polymers from acrylates and/or methacrylates are assumed. Of the block polymers based on styrene and 1,3-diene, linear styrolisoprene block polymers are especially used.

Acrylic copolymers with or without titanium chelate ester are assumed to be acrylate-based polymers. Methacrylates are assumed to be copolymers based on dimethylaminoethyl methacrylate esters and neutral methacrylic acid esters. As esters of hydrogenated rosin, especially its methyl and glycerine esters are used in the first place. The type of possible additives depends on the used polymer and active substance: according to their function, they can be divided into softeners, adhesives, stabilizers, carriers, additives that regulate diffusion and penetration, or fillers. For this, physiologically unquestionable substances that come into consideration are known to the expert. The container layer has such tackiness to ensure a permanent skin contact.

Examples of emollients, suitable emollients are diesters of dicarboxylic acids, for example do-n-butyldidipate, as well as triglycerides, especially the medium chain triglycerides of caprylic/capric acid of coconut oil.

between the matrix (1) and the cover layer (4) there is a depot (2) of the active substance. It consists of a textile flat product and a solution of physostigmine.

The textile flat product can be a circle made of non-woven fabric/mixture of fibers, textile fibers/cotton 50:50, with a surface mass of 40 g/m2 or 80 g/m2 with a diameter of 20 to 50 mm. Other textile materials and other diameters are possible.

More fatty acids are assumed to be compounds with at least one acid group, since the magnitude of possible skin irritations caused by migrating acids depends on the length of the acid chain. Examples of suitable acids are oleic acid, isostearic acid, undecenoic acid and versatic acid.

The removable protective layer, which is in contact with the container layer and is removed before application, consists of, for example, the same materials as were used to make the cover layer (4), assuming that they are made detachable, for example by silicone treatment.

Other removable protective layers are, for example, polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride, etc. If the laminate according to the invention is divided into formats suitable for therapy /adhesive tape/ before applying the protective layer, then the formats of the protective layer to be applied can have protruding ends, with which they can be more easily removed from the adhesive tape.

In the following, the production should be explained:

First, the matrix (1) is created, the composition of which is specified in individual recipe examples. After removing the cover film, a round non-woven fabric is placed, the surface of which is 13.72 cm2. A non-woven material is used as a non-woven fabric - a mixture of fibers artificial fibers cotton 70:30, surface mass 40 g/m2. Then, a rectangular area of 56 cm2 is cut out of the matrix covered with non-woven fabric. The nonwoven fabric and the matrix are represented in Figure 1 and Figure 2. Using a suitable device, for example a dropper, physostigmine dissolved in 25% oleic acid or 35% undecenoic acid is applied to the nonwoven fabric. The exact amounts are specified in the individual recipe examples.

After application, the depot (2) of active substances and the matrix (1) are covered with a cover layer (4). The cover layer is an adhesive coating, which consists of a multiacrylic copolymer, which is coated on a 15 μ polyester film. After removing the solvent, the surface mass is 30 g/m2. After covering, a round surface of 21.23 cm2 is cut out, so that the non-woven fabric soaked in the solution of the active substance rests in the middle (pictures 3 and 4). Then the edges are separated with a grid and the transdermal therapeutic system is stored for 14 days at 40 oC.

The creation of the system according to the invention is presented in Figures 1 to 4. Figure 1 shows the appearance of a non-woven fabric (2), which is placed on a matrix (1). After placing the non-woven fabric (2) on the matrix (1), a liquid preparation of the active substance is applied, which creates a depot (2) of the active substance. Then the covering layer (4) is laminated over the matrix (1) and over the depot (2) of the active substance. Then it is cut out. The edges are removed using a grid. Figures 2 and 3 schematically show in appearance (figure 2) and in cross-section (figure 3) how the depot of the active substance rests on the matrix (1) and the final covering (3) after removal by the grid.

The system is fully presented in cross-section in Figure 7. In Figures 1 to 4, they mean:

1 matrix

2 depot active substances

3 protective layer

4 cover layer

5 met foil

Examples of recipes:

Example 1

Production of matrix: 10.91 kg of 40% solution of self-crosslinking acrylate copolymer from 2-ethylhexylacrylate, vinyl acetate and acrylic acid with titanium chelate ester, solvent mixture: ethyl acetate, ethanol, heptane, methanol 64:25:9:2 and 2.4 kg of a 50% solution of a cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters in ethyl acetate are mixed with 360 g of triglycerides of caprylic/capric acids with stirring at ambient temperatures. With the help of an adjustable knife, the aluminum is coated with steamed polyester foil and covered with LDPE foil. The surface mass should lie between 260.0 g and 275 g/m2.

Matrix composition: 1:

self-crosslinking acrylate copolymer ACP1 74 %

methacrylate copolymer MCP 20 %

triglycerides of caprylic/capric acids /TriG/ 6%

100%

The LDPE film is removed and the non-woven fabric is placed. A mixture of 12 mg of physostigmine and 36 g of oleic acid is applied to the non-woven fabric using a drop pipette.

All further examples and Example I are listed in the following tables. In vitro release was determined in a water bath with a shaker at 37 oC. The medium for acceptance was a solution of 100 ml of physiological table salt, which was completely replaced after 2, 4 and 8 hours. Concentrations were determined after 2, 4, 8 and 24 hours via UV-spectroscopy.

The release values listed in the tables are always the sums of the measured concentrations.

Table 1 shows the construction and in vitro release of Examples I-IV. In these examples, the same matrix was always used, but the amount of application was changed; physostigmine, 25% dissolved in oleic acid, was applied.

Table 1:

Release (mg) %

Example Physostigmine FG 2h 4h 8h 24h 24h

I 12 mg 260 1.64 2.28 3.17 5.62 46.8

II 12 mg 180 3.28 4.60 6.29 9.19 76.6

III 16 mg 260 2.77 4.03 6.71 10.38 56.1

IV 20 mg 180 6.43 9.15 12.76 17.47 87.4

PG = surface mass of the matrix /G/m2/

It can be seen that with an increased proportion of physostigmine, not only the absolute but also the relative release increases.

In examples IV - XXIII, 20 mg of physostigmine - which was dissolved in 60 mg of oleic acid - was added by dosing. The percentage compositions of matrix and surface mass /FG/ were changed. Data with matrices are again given in Table 2.

The abbreviations in the tables mean:

ACP1: self-crosslinking acrylate copolymer from 2-ethylhexylacrylate, vinyl acetate, acrylic acid with titanium chelate ester as a crosslinker;

ACP2: a non-self-crosslinking acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid;

NCP: copolymer based on dimethylaminoethyl methacrylate and natural esters of methacrylic acid;

TriG: triglycerides of caprylic/capric acid:

K.E.: rosin acid ester with glycerin.

Table 2

Table matrix composition and in vitro release

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In examples XXIV - XXXI, 20 mg of physostigmine was always added by dosing - mixed with 27 mg of undecenoic acid. The percentage compositions of the matrix and surface mass were varied; data with matrices are again given in Table 3.

Table 3

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Figures 5 and 6 show the in vitro release behavior of Example XXX, which was randomly drawn. Since the released amount applied according to time, as in almost all examples - gives the right, it can be said that the systems have been developed, which matrix-managed controlled release of the active substance, since the requirements of the Miguchi model are clearly met.

It is shown that the release of the molar ratio of carboxylic acids is determined according to the base polymer. It can be shown that the less acid and the more base polymer is mixed in, the greater the release. The release is all the more, the less undissociated acid is present in the system after storage; since less undecenoic acid is applied in molar amounts than oleic acid, it is also understandable why, with the same matrix, the undecenoic acid sample releases more physostigmine than the oleic acid sample. By adjusting the plasticizer, it can be shown that the plasticizer has no effect on the in vitro release.

Claims (18)

1. Procedure for making a transdermal therapeutic system for the administration of physostigmine on the skin, which contains a cover layer impermeable to the active substance, a container layer that sticks to the adhesive and, in the given case, a removable protective layer, indicated by the fact that the pre-made, self-adhesive, in the given case in the case with a removable protective layer, the provided matrix layer is placed by a textile flat product, physostigmine or one of its pharmaceutically acceptable salts in solution is applied to the textile flat product while creating a depot of the active substance, after which the matrix and the depot of the active substance are supplied with a cover layer. 2. The method according to claim 1, characterized by the fact that the transdermal therapeutic system is stored for 14 days after its manufacture, whereby physostigmine from the depot of the active substance passes into the matrix, so that the matrix becomes the container layer. 3. The method according to claim 1, characterized in that the container layer contains 10. 90 wt.- polymer material, selected from the group consisting of block polymers based on styrene and 1,3-diene, polyisobutylene polymers based on acrylate and/or methacrylate and hydrogenated rosin esters, o - 30 wt.- hydrocarbon-based plasticizer and/or ester and that the active substance depot contains 15 to 85 wt. -% 0.1 to 70 wt.-% solution of physostigmine. 4. The method according to claim 1, characterized in that the polymer material contains a self-crosslinking acrylate copolymer from 2-ethylhexyl acrylate vinyl acetate, acrylic acid and titanium chelate ester. 5. The method according to claim 1, characterized in that the polymer material is not a self-crosslinking acrylate copolymer from 2-ethylhexyl acrylate, vinyl acetate and acrylic acid. 6. The method according to claim 1, characterized in that the polymer material contains, as a polymer based on methacrylate, a copolymer based on dimethylamine ethyl methacrylate and neutral esters of methacrylic acid. 7. The method according to claim 1, characterized in that the polymer material contains, as an ester of hydrogenated rosin, its methyl ester. 8. The method according to claim 1, characterized in that the polymer material contains its glycerine ester as an ester of hydrogenated rosin. 9. The method according to claim 1, characterized in that the container layer contains dioctycyclohexane as a softener. 10. The method according to claim 1, characterized in that the reservoir layer contains do-n-butyldidipate as a softener. 11. The method according to claim 1, characterized in that the container layer contains triglycerides as a softener. 12. The method according to claim 1, characterized in that the container layer contains isopropyl myristate as a softener. 13. The method according to claim 1, characterized in that the solvent of the physostigmine solution in the active substance depot has at least one acidic group. 14. The method according to claim 13, characterized in that the compound with at least one acidic group is a carboxylic acid. 15. The method according to claim 14, characterized in that the carboxylic acid comprises oleic acid or undecenoic acid. 16. The method according to claim 14, characterized in that the carboxylic acid comprises a mixture of octadecanoic acids. 17. The method according to claim 14, characterized in that the carboxylic acid comprises versatic acid. 18. Carrier for the application of transdermal administration of physostigmine, which consists of a rear side impermeable to the active substance, a layer that adheres by gluing, which is suitable for receiving the active substance, as well as in a given case a removable protective layer, indicated by the fact that the layer of the container which is adhesively glued and contains 10 - 90 wt.% of polymer material, 0-30 wt.% of plasticizer and 0.1 - 70 wt.% of physostigmine solvent.