CS264133B2 - Process for preparing pharmaceutical agent - Google Patents

Abstract

The pharmaceutical composition is in the form of a carrier material with a pharmaceutical agent with controlled and delayed release of agent. The release of the agent can be adjusted by varying the particle size and the glass transition temperature.

Description

The invention relates to a process for the manufacture of a pharmaceutical preparation in the form of a carrier material with a controlled-release and delayed-release active substance.

It is known to produce pharmaceutical preparations in the form of capsules, tablets and films, which ensure constant release of the active ingredient and thereby maintain a constant concentration of the active ingredient in the body. For capsules and tablets, the release of the active ingredient is usually controlled by suitable coatings, such as in the case of film tablets. Depot effect forms can be made from granular mixtures of different carriers that release the therapeutically active agent at different rates. Divisible slow release tablets are known from DE-OS 33 14 003. In this tablet made of polyacrylate which has been obtained by polymerization emulsion, the amount released is controlled by the particle size as well as the particle size distribution.

In transdermal delivery systems, the release of the active ingredient can be controlled by a separate membrane (cf. U.S. Pat. No. 3,731,683) or also by adjuvants such as amines, fats or higher alcohol.

The sustained-release pharmaceutical formulations known in the art have proven not always fully satisfactory in practice. On the one hand, the film-coated tablets change their release properties after they have been subdivided into smaller portions; on the other hand, they have the possibility of controlling the release of the active substance by adjusting the grain size known from DE-OS 33 14 003, its limits, because the grain is not arbitrarily optional. Due to technical problems, such as inhomogeneity, the minimum number of granules containing the active substance-containing granules, the grain size is limited both upwards and downwards, so that in any case the optimum release amount corresponding to the active substance cannot be adjusted.

Surprisingly, it has now been found that the pharmaceutical composition of the carrier material obtained by emulsion polymerization can be controlled by simply varying the particle size of the beads produced by the emulsion polymerization as well as by changing the glass temperature.

By combining variations in grain size, particle size and glass transition temperature, there is a possibility for powdered pharmaceutical preparations, such as tablets or capsules, to regulate the release of the active ingredient of the pharmaceutical preparation over a wide range. For pharmaceutical preparations in the form of transdermal films, the release amount can be controlled by varying the film thickness between 40 and 200 µm, preferably between 60 and 140 µm, the particle size and the glass transition temperature.

The particle size refers to the particle diameter of the polymeric material after its production in the process of the invention is 50 to 500 nm. The particle size (i.e., particle diameter) can be controlled depending on the polymerization conditions. Reducing the particle size results in an increase in the amount released.

The glass transition temperature can be controlled by varying the composition of the monomers and, in the process of the present invention, is between -20 ° C and +80 ° C, preferably between -20 ° C and +40 ° C, particularly preferably between -10 ° C and + Deň: 29 ° C. An increase in the glass transition temperature is associated with a decrease in the amount released.

The grain is in the range between 10 and 500 µm. In order to adjust the grain size, the polyacrylate or vinyl polymer obtained by emulsion polymerization with a defined particle size is dissolved together with the active ingredient in an organic solvent, then the solution is poured into a film and the solvent is evaporated. If desired, the resulting film is ground to the desired grain size below its glass transition temperature and sieved, if necessary.

Suitable carrier materials are those polyacrylate or vinyl polymers which can be prepared by emulsion polymerization, such as polyvinyl chloride, polyvinyl acetate, polyacrylonitrile, polyvinyl ester, polyvinyl ethers and copolymers thereof. Preferred are copolymers of methyl and / or ethyl esters of acrylic and methacrylic acid, which are obtained by emulsion polymerization. The molecular weight of the emulsion polymers should be between 10 and 10. The carrier material, as a solid, can be obtained, for example, by freeze-drying to obtain polymer particles retained in their original size and form.

It is an object of the present invention to provide a method of producing a sustained release pharmaceutical composition in the form of a tablet or a transdermal therapeutic system.

SUMMARY OF THE INVENTION The drug substance is dissolved or suspended together with a polyacrylate or vinyl polymer obtained by emulsion polymerization having a particle size of 50 to 500 nm and a glass transition temperature between -20 ° C and +80 ° C in an organic solvent then the solution obtained is poured onto a smooth backing to form a film which is further processed into tablets or transdermal dosage forms.

Preferably, the drug drug is used together with the polyacrylate or vinyl polymer obtained by emulsion polymerization in a weight ratio of 0.05: 1 to 1: 4.

The weight ratio of polyacrylate or vinyl polymer obtained by emulsion polyineration to solvent is chosen between 1: 5 and 1: 10.

In the case of the preparation of the transdermal dosage form, the solution obtained is poured onto a smooth backing to form a film having a thickness of between 40 and 200 µm, the backing being an aluminum foil or other non-permeable material.

A further preferred embodiment of the process according to the invention is that the film formed after evaporation of the solvent is provided with a non-vapor-permeable layer and additionally optionally with an adhesive layer.

In the case of the preparation of a pharmaceutical preparation in the form of tablets, the film obtained is ground at a temperature below the glass transition temperature to a particle size between 10 and 500 µm, the mixture obtained is further blended with the usual excipients used for the manufacture of tablets and it is compressed into tablets or filled into capsules.

Suitable solvents for the solution or suspension containing the active ingredient and the polyacrylate or vinyl polymer obtained by emulsion polymerization are those which are readily volatile, such as low-boiling alcohols such as methanol, ethanol, acetone, methyl ethyl ketone, halogenated hydrocarbons , such as methylene chloride, methyl acetate, ethyl acetate, acetic acid methyl ester, ethyl acetate, or ethers such as tetrahydrofuran or dioxane or dimethylsulfoxide, low boiling frigens, and optionally also mixtures of these solvents.

In addition, the release amount of the active ingredient can be varied by auxiliary substances, i.e., substances that affect diffusion. These so-called excipients include, for example, polyvinylpyrrolidone, cellulose esters, amines, fats or higher alcohols. If desired, these may be added to the active compound solution.

This solution can then be further processed as follows:

In order to produce a pharmaceutical formulation containing the active ingredient in the form of a film for transdermal therapeutic application, a film having a defined layer thickness is prepared from the solution obtained by measuring a film thickness of between 40 and 200 µm, preferably 60 µm. up to 140 µm. The film may then be provided with a non-vapor-permeable backing layer and, optionally, an adhesive layer and treated to form a film. required size.

In order to produce a pharmaceutical preparation containing the active ingredient in the form of a powder, the solvent is evaporated from the solution described above, whereby moisture-sensitive or oxidation-sensitive drugs are optionally operated under a protective gas atmosphere and the residue obtained is ground below its temperature. a glass transition temperature to the desired particle size of 10 to 500 µm. If desired, grinding can also be carried out in the presence of inert excipients or carriers such as lactose, magnesium stearate, finely dispersed kieselguhr or similar finely dispersed glidants. The ratio between the polyacrylate or vinyl polymer obtained by emulsion polymerization containing the active ingredient and the finely dispersed filler can be varied within wide limits of about 10: 1 to 1: 4. Further processing into tablets or capsules is carried out according to known techniques. the use of conventional excipients such as binders, inert fillers, lubricants and tablet disintegrants.

A divisible tablet is a preferred embodiment, since the formulation produced by the process of the invention retains its advantageous properties also in each broken portion. In the production of films for transdermal application, the release amount can be controlled by varying the particle size and the glazing temperature at a predetermined film thickness and the incorporated amount of drug.

It is known that as the amount of active ingredient in the carrier material increases, the release amount is greatly increased so that a sustained release of the active ingredient can no longer be ensured. This could be compensated by increasing the grain size, but there is a risk that the minimum number of granules containing the active ingredient content in the tablet will fall below the critical value of 400 (but no homogeneous distribution of the drug substance from tablet to tablet). According to the present invention, this problem can be solved by higher vitrification temperature of the carrier material obtained by emulsion polymerization and by a larger particle size, while the grain size can be kept substantially constant. This makes it possible for tablets, capsules or films to significantly increase the drug loading of the carrier material.

According to the invention, more advantageous proportions of the drug substance to the carrier material can also be adjusted, and thus the depot principle can be extended to medicaments dispensed at higher doses, since the release amount can be controlled within wide limits even at higher drug loading. parameters, i.e. particle size, grain and glass vitrification temperature.

The pharmaceutical preparations produced by the process according to the invention contain between 0.1 and 30% by weight of active substance, preferably between 1 and 10% by weight of active substance.

Examples:

A) Movies

Example 1

The emulsion polymerization polyacrylates listed in Table I are processed to transdermal films and examined for the amount of active ingredient released.

Table I

Polyacrylate obtained by emulsion polymerization

latex particle diameter glass temperature handle 50-100 nm - 8 ° C. AND 50-100 nm + 29 ° C В 100-150 nm - 8 ° C C

The latex particles are obtained by drying water from the respective dispersion. 21.3 g of dried polyacrylate are dissolved together with 1.6 g of colonidine in 142 g of acetone and the solution is poured on a flat surface to form films. The layer thickness was 80 µm after evaporation of the solvent. The amount released is determined relative to an aqueous environment of pH 7 at 37 ° C. The amount released is monitored by high performance liquid chromatography.

Table II shows the diffusion coefficients found for three different types of latex.

Table II

handle diffusion coefficient D | cm ^ / day | AND 5.5 x IC ⁶ В 4.4 x 10 ' ⁶ C 1.4 x 10 ^-6

Fig. 1 shows the release rates for three physically different types of latex. As can be seen from the course of the curves, this release behavior can be influenced by both the particle size and the glass vitreous temperature of the latex.

Giant. 1 shows a comparison of the curves that show the release amount of the active ingredient for three physically different types of E 300 latexes.

The у axis shows the clonidine release values. The x axis shows Time in days.

AND indicates progress curves for handle AND. β indicates progress curves for handle В a C indicates progress curves for handle C.

Example 2

The copolymers of vinyl chloride and acrylic ester obtained by emulsion polymerization, which are listed in Table III, are processed into trensdermal films and these films are examined for the amount of active ingredient released.

Table III

VA 318A VA 381B the solids content of the polymer in the dispersion 44,6% 44.7% temperature at which the film is formed (approximately corresponds to the glass temperature) about 67 ° C about 0 ^Q C latex particle diameter (particle size) 261 nm 262 nm

The two materials obtained by emulsion polymerization differ in the glass temperature and thus the softness of the polymer; the latex particle size is the same for both products. The polymer is obtained by drying the aqueous dispersion. The dry residue, together with the drug substance, i.e. clonidine, is dissolved in methylene chloride and by pouring the solution on a flat surface, a film of about 100 µm thickness is formed. Drug release from CPA (controlled percutaneous application) film of 3 cm ² is detected in a USP tester. The active substance content is determined by high performance liquid chromatography.

Table IV shows the amounts of clonidine (in percent) released at various time intervals. The released amount decreases with increasing glass temperature, i.e. the harder the latex, the slower the release of the active substance.

Table IV

amount of colonidine released in% time in days VA 381A VA 3B18 0, 33 26.3 50.9 1 47.2 67.7 4 66.8 73.0 5 70.2 74.4

Film thickness: 100 µm, 0.7 clonidine per

B) Tablets'

Three different types of polyacrylate are formulated together with the active ingredient into tablets. Their release behavior is shown in Figure 2.

Polymers D (Eudragit E 30 D) and E are polyacrylates obtained by emulsion polymerization, polymer F (Eudragit RS 100) is a mass-polymerized polyacrylate (manufactured by Rohm GmbH, Darmstadt). Both types of polymers E and F have approximately the same glass temperature (about 30 ° C), but are physically in various forms: spherical latex (E) or as a polymer ball (F). The glazing temperature of polyacrylate D, i.e. also of spherical latex, is -8 ° C. The glazing temperature can be controlled by varying the ratios in the amount of monomers from which the polymer is built, the shape can be influenced by the polymerization conditions.

Example 1

In a suitable vessel, 23.75 g of polymer E are mixed together with 400 ml of acetone until a clear solution is obtained. A solution of the active substance consisting of 1.25 g of B-HT 933 base in 100 ml of methanol is then added to the solution obtained. From the solution obtained, the solvent is evaporated under a protective atmosphere (under nitrogen) and the remaining active ingredient film is cooled to about -40 ° C using solid carbon dioxide and ground together with lactose in a ratio of 9: 1 to each other under cooling in a mill. with rotating knives (grinding is done in parts). A free-flowing powder is obtained in which the active ingredient-containing polyacrylate is present in logarithmically normally dispersed particles of between 65 and 500 µm in size.

The mixture obtained in the manner described above is compressed in a further step according to known methods using conventional tableting aids such as lactose, corn starch, colloidal silicic acid and / or magnesium stearic acid, into tablets containing 5% of the active ingredient. %, based on the polymeric carrier.

Example 2

In an analogous manner to that described in Example 1, 95 g of polymer F, which is dissolved in 250 ml of dichloromethane, and 5.0 g of B-HT 933 base in 40 ml of methanol are processed to film, milled and compressed into tablets.

Example 3

In an analogous manner to Example 1, 95 g of polyacrylate E, which is dissolved in 500 ml of acetone, and 5.0 g of B-HT 933 base in 40 ml of methanol are processed to a film, which is ground and compressed into tablets.

The release of the active substance from the tablets in vitro is carried out at 37 ° C in a USP XVII tester using water of pH 7 as the medium. The analysis is carried out by high performance liquid chromatography.

Giant. 2 depicts the% release of the active ingredient (y-axis) versus time in hours (x-axis).

The letters F, D and E show the dependence pattern for polymer carriers (with 5% active ingredient) F, D and E.

As can be seen from FIG. 2, the active substance is almost released from the polymerized polyacrylate after 2 hours, whereas the polyacrylate obtained by emulsion polymerization can be used to control the desired release rate of the active substance, e.g. 1 hour 19% of the released active substance and at 6 hours 60% of the released active substance (drug).

Claims (6)

SUBJECT OF THE INVENTION A process for the manufacture of a sustained release pharmaceutical composition in the form of a tablet or transdermal therapeutic system, characterized in that the drug active substance is dissolved or suspended together with a polyacrylate or vinyl polymer obtained by emulsion polymerization having a particle size of 50%. up to 500 nm and a glass transition temperature between -20 ° C and +80 ° C, in an organic solvent, and then the solution obtained is poured onto a smooth substrate to form a film which is processed into tablets or a transdermal dosage form. 2. A method according to claim 1, wherein the drug active substance is used together with a polyacrylate or vinyl polymer obtained by emulsion polymerization in a weight ratio of 0.05: 1 to 1: 4. 3. A process according to claim 1 or 2, wherein the polyacrylate or vinyl polymer obtained by emulsion polymerization is used with respect to the solvent in a ratio of 1: 5 and 1: 10. Method according to one of Claims 1 to 3, characterized in that the solution obtained is poured into a film having a thickness of between 40 and 200 µm, the substrate being aluminum foil or other material which is not permeable to the active substance. Method according to claim 1, characterized in that the film formed after evaporation of the solvent is provided with a vapor-impermeable layer and additionally with an adhesive layer. 6. The process of claim 1, wherein the film obtained is ground at a temperature below the glass transition temperature to a particle size between 10 and 500 .mu.m, mixed with excipients used in the manufacture of tablets and compressed into tablets or is filled into capsules.