KR100394830B1 - Scopolamine patch - Google Patents

Abstract

The scopolamine-containing transdermal therapeutic system in the form of a patch of the present invention is characterized in that the active substance-containing layer comprises a copolymer of acrylic acid or methacrylic acid derivatives as the base polymer and the scopolamine base is selected so that the saturation solubility in the whole vehicle formulation is 50 To 100%, preferably from 60 to 100%.

Description

Scopolamine patch

The scopolamine is transdermally administered by the systemic action of a commercial plasters system. The scopolamine is preferably used as a gaseous agent, for example, to prevent nausea and vomiting due to repeated equilibrium manual changes that occur during travel.

A therapeutic advantage of the transdermal administration method is that the active substance supply is made in a gradual controlled manner through the transdermal system. Thus, it is possible to reliably encounter the therapeutic field of the relatively narrow scopolamine, while achieving a therapeutically effective plasma level without worrying about side effects from overdosage. The structure of a commercially available system is disclosed in US Pat. No. 3,797,494. It consists mainly of a backing layer, an active substance reservoir, a microporous membrane, a skin adhesive layer of active material, and a protective layer to be removed before use. The reservoir and skin adhesive layer consist of a mixture of polyisobutylene and mineral oil with different molecular weights. The active material is dispersed in the mixture as a viscous liquid. The transdermal system in which the active substance-containing component is made according to the above conditions has disadvantages to be considered. Under certain conditions, spontaneous crystallization occurs that affects the bioavailability of the active material of the patch. U.S. Patent No. 4,832,953 discloses in detail the unstable state over its entire length. This publication describes a method of preventing crystallization by continuous heat treatment of already packaged patches. According to this patent publication, the scopolamine hydrate crystallizes in particular.

It is a disadvantage to note that the active substance contained in the dosage form under certain conditions which can hardly be defined changes the aggregation state by the simultaneous action on the bioavailability in unpredictable times after production.

Starting from such a state of the art, the object of the present invention is to provide a polymer preparation which is replaced by an active substance scopolamine base which does not have the above-mentioned disadvantages.

In a transdermal therapeutic system of the kind described in the preamble of claim 1, the object is achieved when the active substance-containing layer of the patch has a saturation solubility in the whole vehicle preparation of 50-100%, preferably 60-100% Is achieved by the present invention comprising a copolymer of acrylic acid or a methacrylic acid derivative and a scopolamine base in a substantial concentration as a base polymer.

Other embodiments of the invention are set forth in the dependent claims.

According to the literature, the scopolamine base is a viscous liquid. However, it is not understandable to a person skilled in the art that a relatively polar material having a molecular weight of 303.35 is a stable aggregated liquid. Nevertheless, the scopolamine base can be crystallized under suitable conditions. A white solid material with a melting point of about 68 DEG C is obtained. Therefore, the active substance is contained in a conventional patch as an unstable variant. Thus, perhaps the hydrate of the scopolamine base is not crystallized, but the liquid-solid transition of the scopolamine base itself will take place. It is known to those skilled in the art that the liquid scopolamine base has a higher energy content compared to the crystalline scopol amine base so that the scopolamine base is dissolved in the polymer itself at a concentration exceeding the saturation concentration It follows the law. Thus, crystallization can occur not only in the dispersed portion of the active material, but also in the polymer itself.

The present invention advantageously provides a novel formulation of a base polymer containing scopolamine that overcomes the known disadvantages associated with the efficiency of the patch. According to the invention, advantageously the use of a polymer containing the active substance in its fully dissolved form at or below a saturation concentration, or at most at the same concentration as the saturation concentration, can prevent instability of the active substance scopolamine and its crystallization in the patch. As such, these polymers must have increased solubility of the scopolamine base relative to those formulations known in the art. It has been found that self-adhesive copolymers based on polyacrylic acid and derivatives thereof are suitable polymers. For such polymers, the scopolamine base has a solubility of about 10-20% (w / w) depending on the exact composition of the copolymer and the amount and type of adjuvant added. This is more than an amount sufficient to be contained in a patch having a size of about 2.5 cm ² and a thickness of a conventional transdermal system for the amount of active substance required, for example, for three days of treatment to prevent motion sickness. The properties of the polyacrylate adhesive with respect to adhesion, cohesion and solubility can be varied depending on the monomers used in the preparation and the choice of the molecular weight that can be predetermined according to the polymerization conditions. According to the present invention, firstly, the dissolving power of the scopolamine base is important. Because the scopolamine base is a relatively polar material, polyacrylate adhesives with polar functional groups are suitable. Examples of these groups usually present in a polyacrylate adhesive include a carboxyl group, a hydroxyl group and an amino group. Examples of suitable monomers from which these groups can be incorporated as adhesives include methacrylic acid, acrylic acid, semiesters of diols and acrylic acid and methacrylic acid, and esters of these acids with amino alcohols.

Polyacrylate adhesives have miscibility with various low molecular weight materials. These materials can be added to control the solubility of a given polyacrylate adhesive by the compound. In practice, this means that a relatively polar inert component should be added to the polyacrylate adhesive with insufficient number of polar groups, and a relatively non-polar inert component should be added to the polyacrylate adhesive with an excessive number of polar groups. Since the thermodynamic activity of the active substance is not dependent on the absolute concentration, but on the ratio of the actual concentration to the saturation solubility, the latter is achieved by reducing the solubility of the scopolamine base in a polyacrylate adhesive having a high solubility of the active substance It is important to reduce the active material. Considering the above situation, it is considered that the saturation solubility of the scopolamine base in the adhesive or the adhesive / inactive ingredient mixture is 10 to 30% by weight as the optimum condition of the present invention.

Because the scopolamine base is a relatively polar material, it can be used to lower saturation solubility, especially by adding liquid hydrocarbons. Dioctylcyclohexane has proved to be particularly suitable. Fatty acids, aliphatic alcohols, polyethylene or polypropylene glycols, glycerol derivatives, and pantothenyl alcohol may be predominantly used as the more polar substance which increases the saturation solubility. Fatty acids such as oleic acid have proved to be particularly suitable.

Based on these adhesives or adhesive / adjuvant formulations, it has been found that transdermal matrix systems and membrane systems, for example, have biological equivalence with commercial competing products in in vitro permeation experiments on human skin . The structure of such a transducer system is shown in Figs. From a structural point of view, the simplest transducer system is a matrix system. It consists of a backing layer 1.3 which is substantially impermeable to the active substance and the adjuvant, a self-adhesive polymer preparation (1.2) containing the active substance, and a protective film 1.1 to be removed before use. Suitable materials for the backing layer and the protective layer are known to those skilled in the art. Films based on polyethylene terephthalate can in fact be used with at least a protective film which is further silicified on the side at least in contact with the adhesive in order to facilitate the removal of the patches. When the pressure-sensitive adhesive force of the polymer preparation is too low, a pressure-sensitive adhesive layer in contact with the skin (not shown) may be added.

The membrane system consists of a backing layer 2.5, an active substance reservoir 2.4, a membrane 2.3, a skin contact layer 2.2 and a protective layer 2.1 which has to be removed before use.

The active material reservoir layer and the skin contact layer may have the same or different composition. In the present invention, the only important fact is that at least the reservoir is based on a polyacrylate adhesive and the solubility of the scopolamine base is from 10 to 30% by weight. Suitable materials for the membrane are known to those skilled in the art. Films based on copolymers of ethylene and vinyl acetate have proved to be particularly suitable in combination with the polyacrylate adhesives of the present invention. The flow rate of the active material passing through these membranes can be controlled by the content of vinyl acetate and the film thickness. When the content of vinyl acetate is high and the thickness is small, the membrane permeability of the scopolamine base is high. Films having a vinyl acetate content of 4% or more and a thickness of 50 to 100 mu m proved to be suitable. It has been found that films with a vinyl acetate content of 9-20% and a thickness of 50 [mu] m are particularly suitable for patches not exceeding 5 cm < ^{2 &} gt ;.

The results of the transmission experiment using the matrix system of the present invention are shown in Table 1 and Diagram 1. This test was performed on Franz permeable cells and human skin (chest skin during chest contraction).

The results obtained using the membrane system of the present invention are shown in Table 2 and Diagram 2.

[Table 1]

Permeability measurement using the matrix system of Examples 1 and 2

[Table 2]

Permeability measurements using the membrane systems of Examples 3 and 4

From the above transmission test results, it can be clearly seen that the patch of the present invention has the same efficiency as the sample of the comparative example, but does not have the disadvantage of the sample of the comparative example. Since the active material concentration does not exceed the saturation solubility, there is no risk of recrystallization. In addition, it is impossible to produce crystalline scopolamine amine hydrate. This is because polyacrylate formulations due to their physicochemical properties have the ability to dissolve scopolamine hydrate enough to prevent recrystallization by virtue of the water content actually present in the adhesive.

Example 1

27 g of a polyacrylate adhesive (Durotak 901-1051, solids content 52%), 3.4 g oleic acid, 0.12 g aluminum acetylacetonate, 4.0 g scopolamine base and 3.7 g ethanol were mixed carefully to give a thickness of 200 [ Is coated on the silicided polyester film. The solvent-containing film was dried at 50 DEG C for 30 minutes and then coated with a polyester film having a thickness of 23 mu m. Each patch system (area: 2.5 cm ² ) is punched from the entire laminate.

Example 2

27 g of polyacrylate adhesive (Durotak 901-1051, solids content 52%), 3.4 g of oleyl alcohol, 0.12 g of aluminum acetylacetonate, 3.0 g of scopolamine base and 3.7 g of ethanol were carefully mixed to form a thickness Is coated on the silicified polyester film as a film having a thickness of 200 mu m. The solvent-containing film was dried at 50 DEG C for 30 minutes and then coated with a polyester film having a thickness of 23 mu m. Each patch system (area: 2.5 cm ² ) is punched out of the complete laminate.

Example 3

73.6 g of a polyacrylate adhesive (Durotak 901-1051, solids content 52%), 9 g oleic acid, 0.38 g aluminum acetylacetonate, 12.0 g scopolamine base and 17 g ethanol are mixed carefully and used in the coating process do.

a. Manufacture of skin adhesive layer

The material is coated on the silicified polyester film as a film having a thickness of 50 mu m. The solvent-containing membrane was dried at 50 DEG C for 30 minutes and then coated with a film of an ethylene-vinyl acetate copolymer having a thickness of 50 mu m and a vinyl acetate content of 9%.

b. Manufacture of reservoir layer

The same material as in a is coated on another polyester film having a thickness of 150 mu m in the second coating step. After removing the solvent, it is coated with a polyester film having a thickness of 23 탆.

c. Preparation of the entire laminate layer

b is peeled off the polyester film and laminated on the film of the skin adhesive layer prepared according to a.

Each patch system is punched to a size of 2.5 cm ² from the entire laminate.

Example 4

73.6 g of a polyacrylate adhesive (Durotak 901-1051, solids content 52%), 9 g of oleyl alcohol, 0.38 g of aluminum acetylacetonate, 9.0 g of scopolamine base and 17 g of ethanol were carefully mixed to prepare a coating process .

The process of adding is the same as in Example 3.

Claims (8)

A backing layer, a pressure-sensitive adhesive active material reservoir, a matrix system comprising a removable protective film, Or a lamellar structure containing the active substance scopolamine group having a structure of a membrane system composed of a backing layer, a pressure-sensitive adhesive active substance reservoir, a membrane for regulating an active substance flow rate, an additional skin contact layer and a removable protective film In a patch-type transdermal therapeutic system, The active material-containing layer of the patch, A polar group-containing copolymer of acrylic acid or a methacrylic acid derivative as the base polymer, said copolymer being itself or mixed with a polar assistant to have a scopolamine base solubility of 10 to 30% by weight, Wherein the scopolamine substrate is present in a concentration corresponding to 50 to 100% saturation solubility in the final vehicle formulation. The method of claim 1, wherein the active material- Wherein the scopolamine substrate is present in a concentration corresponding to 60-100% saturation solubility in the total vehicle formulation. 2. The transducer treatment system according to claim 1, wherein the membrane for controlling the flow rate of the active material is made of a copolymer of ethylene and vinyl acetate. 4. The transdermal therapeutic system according to claim 3, wherein the membrane has a vinyl acetate content of 4-20%. The patch according to any one of claims 1, 2, 3, and 4, wherein the active substance-containing layer of the patch contains a hydrocarbon to reduce the saturation solubility of the scopolamine base. Treatment system. The patch according to any one of claims 1, 2, 3, and 4, characterized in that the active material-containing layer of the patch comprises a fatty acid or an aliphatic alcohol for increasing the saturation solubility of the scopolamine substrate Of the transdermal therapeutic system. 6. The transdermal therapeutic system according to claim 5, wherein the hydrocarbon is dioctylcyclohexane. The transdermal therapeutic system according to claim 6, wherein the fatty acid or aliphatic alcohol is oleic acid or oleyl alcohol.

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