FI88674B - FRAMEWORK FOR THE PRODUCTION OF PHARMACEUTICAL PRODUCTS - 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

1 88674

Method for the preparation of a pharmaceutical preparation - For the preparation of a pharmaceutical product

The present invention relates to a process for the preparation of a pharmaceutical preparation which has a controlled and delayed release of the active ingredient and which contains a carrier based on an emulsion polymer, with the exception of preparations consisting of emulsion polyacrylates having a particle size of about 140 nm and a glass transition temperature of about 30 ° C.

It is known to prepare pharmaceutical preparations in the form of capsules, tablets and films which allow a sustained release of the active ingredient and thus maintain a constant concentration of the active ingredient in the body, usually by means of suitable coatings, such as film-coated tablets. Depot forms can also be prepared from granular mixtures of different carriers which release the active ingredient at different rates. DE-OS 33 14 003 discloses a dispersible tablet in which the release of the active ingredient is delayed. In this tablet, which is made of emulsion polymerized polyacrylate, the release rate is controlled by the grain size as well as the grain size distribution.

In systems for transdermal application, the release of the active ingredient can also be controlled with special membranes (US-PS 3,731,683) or also with the aid of excipients such as, for example, amines, fats or higher alcohols.

Prior art pharmaceutical preparations with a slow release of the active ingredient have not always proved to be completely satisfactory in practice. On the one hand, tablets coated with a film change their release properties after dispensing, on the other hand, adjusting the grain size limits the possibility of controlling the release of the active ingredient known from DE-OS 33 14 003, since the grain size cannot be chosen arbitrarily. The size of the granule 2 88674 is limited by both top and bottom technical problems, such as the inhomogeneity and the lowest amount of granulate-loaded particles loaded with the active ingredient, so that in all cases the optimal release rate corresponding to the active ingredient cannot be adjusted.

Surprisingly, it has been found that in a pharmaceutical preparation from an emulsion-polymerized carrier material, the release rate can be controlled simply by changing the particle size of the emulsion-polymerized polymer beads and by changing the glass transition temperature of the polymer.

With the combination of changes in grain size, particle size and glass transition temperature, it is possible to control the release of the active ingredient of a pharmaceutical preparation over a wide range when using powdered pharmaceutical preparations such as tablets or capsules. When the pharmaceutical preparations are in the form of transdermal films, the rate of release can be adjusted by varying the layer thickness between 40 and 200, preferably 60 to 140, the particle size and the glass transition temperature.

Particle size means the particle diameter of the polymeric material after its preparation, being 50 to 500 nm according to the invention. The particle size (diameter) can be adjusted by the polymerization conditions. Reducing the particle size increases the release rate.

The glass transition temperature can be adjusted by changing the monomer composition. According to the invention it is between -20 and + 80 ° C, most preferably between -20 and + 40 ° C, particularly preferably between -10 and + 30 ° C. An increase in the glass transition temperature is associated with a decrease in the release rate.

The grain size is between 10 and 500 pm. To adjust the grain size, an emulsion polymerized polymer of a certain particle size is dissolved together with the active ingredient in a suitable solvent, then poured into a film and the solvent is evaporated.

3 8 B 6 74 The film is then ground to the desired grain size, possibly below its glass transition temperature, and screened if necessary.

Suitable carriers are polymers which can be prepared by an emulsion polymerization process, such as PVC, polylactide, polystyrene, polyvinyl acetate, polybutadiene, polyacrylonitrile, polyvinyl ester, polyvinyl ether and copolymers thereof. Emulsion polymerized copolymers of methyl and / or ethyl esters of acrylic and methacrylic acid are best preferred. The molecular weight of the emulsion polymer should be between 104 and 107. The recovery of the carrier as a solid can take place, for example, by freeze-drying, whereby the polymer particles retain their shape and size.

According to the invention, the pharmaceutical preparation can be prepared by suspending a polymerized emulsion polymer having a glass transition temperature between -20 ° C and + 80 ° C with a particle size of 50 to 500 nm in a solvent, (a) the active ingredient-containing polymer solution is cast into a film and the film containing the possible active substance is provided with a vapor-impermeable backing layer and made into the desired shape, or • - (b) the solvent is evaporated, the solid drug-containing emulsion polymer is ground to a particle size of a decrease in particle size accelerates the release of the active ingredient, and an increase in the glass transition temperature decreases the release rate.

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Suitable solvents for the suspension containing the active ingredient and the emulsion polymer are low-volatile solvents, such as low-boiling alcohols, such as methanol, ethanol, acetone, methyl ethyl etetone, halogenated hydrocarbons, such as methylene chloride, ethyl acetate and ethyl acetate. and ethyl ester, or ethers, such as, for example, tetrahydrofuran or dioxane, or dimethyl sulfoxide, low-boiling frigenes, or also mixtures of these solvents.

In addition, the release rate of the active ingredient can be varied with suitable excipients, i. diffusion active substances. These so-called excipients include, for example, polyvinylpyrrolidone, ethyl esters, amines, fats and higher alcohols. If desired, these substances can be added to the active ingredient-1.

This solution can be further processed as follows:

The active ingredient-containing pharmaceutical preparation in the form of a film for transdermal therapeutic application is prepared by pouring the resulting solution into a film of a specified layer thickness, dimensioned so that after evaporation of the solvent, the film thickness is between 40 and 200 μm, preferably 60-140 μm. The film can then be provided with a vapor-impermeable backing layer and possibly an adhesive layer and shaped.

The active pharmaceutical preparation in powder form is prepared by removing the solvent of the solution described above, in the case of drugs sensitive to moisture or oxidation, optionally under a protective gas, and grinding the resulting residue below its glass transition point to the desired grain size between 10 and 500. If necessary, grinding can also be carried out with inert excipients or carriers such as lactose, magnesium stearate, finely divided diatomaceous earth or similar finely divided lubricants. The weight ratio of active ingredient-containing emulsion polymer to finely divided excipient can be varied within wide limits in a ratio of about 10: 1 to 1: 4. Further processing into tablets or capsules is carried out by known methods using customary excipients, such as binders, inert fillers, lubricants and lubricants.

A preferred embodiment is a distribution tablet, because the preparation obtained according to the invention retains its advantageous properties also in each broken body. When preparing films for transdermal application, the release rate can be adjusted by changing the particle size and vitrification temperature once the film thickness and the amount of drug processed have been administered.

With a higher load on the carrier, the release rate is known to increase considerably, so that a delayed release of the active ingredient is no longer possible. This could be compensated by increasing the grain size, but there was a risk that the minimum amount of loaded particles in the tablet would fall below the critical amount of 400 (in which case it would no longer be possible to ensure a homogeneous distribution of the active ingredient from tablet to tablet). According to the invention, this problem can be; to be solved by means of a higher glass transition temperature and a larger particle size of the emulsion-polymerized support, whereby the grain size can then be largely kept constant. This makes it possible for the carrier material in tablets, capsules or films to be substantially more loaded with the drug.

According to the invention, it is also possible to adjust the ratio of drug to carrier to a more favorable one and thus to extend the depot principle to more drugs to be dispensed, because with a higher load the release rate can be adjusted over a wider range of particle size, grain size, and glass transition temperature.

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The preparations according to the invention generally contain between 0.1 and 30% by weight, preferably from 1 to 10% by weight, of active ingredient.

Examples A) Films

Example 1:

The emulsion polymerized polyacrylates shown in Table I are made into transdermal films and their release rates are studied.

Table I: Emulsion polymerized polyacrylate.

Particle diameter of latex particles Glass transition temperature Film batch

50-100 nm-8 ° C A

50-100 nm + 29 ° C B

100-150 nm-8 ° C

The latex particles are obtained by drying water from the dispersion used in each case (Rohm GmbH, Darmstadt). 21.3 g of dried polyacrylate and 1.6 g of clonidine are dissolved together in 142 g of acetone and poured into films on a flat surface. After evaporation of the solvent, the layer thickness was 80 μιη. The release rate was determined at 37 ° C against aqueous medium (pH 7). Release analyzes were performed by HPLC.

Table II gives the diffusion coefficients obtained for the three different types of latex:

Table II:

the diffusion coefficient

Film batch D / cm2 / day / A 5.5 10 ~ 6 - B 4.4 10 "6 C 1.4 10'6 7 88674

Figure I shows the release rates for three physically different latexes. From the course of the curves, it can be seen that the release rate can be influenced by both the particle size of the latexes and the glass transition temperature.

Example 2:

The emulsion polymerized copolymers of vinyl chloride and acrylic acid ester shown in Table III are made into transdermal films and their release rates are studied.

Table III

_VA 381A VA 381B

Polymer solids content in the dispersion 44.6% 44.7%

Kaivonmuodostumislämpötila

(~ glass transition temperature) -67 ° C ~ 0 ° C

Latex diameter (particle size) 261 nm 262 nm

Both materials obtained by emulsion polymerization differ in their glass transition temperature and thus in the softness of the polymer. The latex size is the same in both products. The polymer is obtained by drying an aqueous dispersion, which is then dissolved together with the clonidine drug in methylene chloride and cast in a known manner into films with a layer thickness of about 100. Drug release from a 3 cm 3 CPA membrane (CPA = controlled percutaneous application) is obtained in a USP tester. The concentration is determined by HPLC.

Table IV shows the amounts of clonidine released by different time points (in percentages). The release rate decreases with increasing glass transition temperature, i. the harder the latex, the slower the release.

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Table IV

Amount of clonidine released,%

Time Product Product

days VA 381A VA 381B

0.33 26.3 50.9 1 47.2 67.7 4 66.8 73.0 5 70.2 74.4

Film thickness: 100 μιη, load amount: 0.7 mg clonidine / cm2 B) Tablets:

Three different types of polyacrylate are processed together with the active ingredient into tablets. The release properties of these are shown in Figure II.

Polymers D (Eudragit E 30 D) and E are emulsion polymerized polyacrylates, polymer F (Eudragit RS 100) is Rohm GmbH, Darmstadt, the company's polymerized polyacrylate. Both polymer types E and F have approximately the same glass transition temperature (Tg to 30 ° C), but are physically in different forms: Spherical latex (E) or polymer bead (F). Polyacrylate D, which is also a spherical latex, has a glass transition temperature of Tg = -8 ° C. The glass transition temperature can be adjusted by varying the proportions of polymer-forming monomers under the polymerization conditions.

Example 1:

In a suitable vessel, 23.75 g of polymer E and 400 ml of acetone are mixed together until a clear solution is formed, after which a solution of the active ingredient containing 1.25 g of B-HT 933 base in 100 ml of methanol is added. From the solution thus obtained, the solvent is evaporated under a protective gas atmosphere (N2) and the remaining film loaded with active ingredient is cooled with dry ice to about -40 ° C and ground with high lactose in a 9: 1 ratio while cooling in a mill with 9,887,774 rotating knives. An easily flowable powder is obtained in which the active ingredient-loaded polyacrylate is normally logarithmically distributed between 65 and 500 μm.

The mixture obtained as described above is compressed in the next step by known methods with conventional tabletting excipients, such as lactose, corn starch, colloidal silicic acid and / or magnesium stearate, into tablets with an active ingredient load of 5% based on the polymer carrier.

Example 2:

According to Example 1, 95 g of polymer F dissolved in 250 ml of dichloromethane and 5.0 g of B-HT 933 base in 40 ml of methanol are processed into a film, ground and compressed into tablets.

Example 3:

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

The in vitro release of the tablets was performed in a USP XVII tester at 37 ° C with water, pH 7 as the acceptor. The analyzes were performed by HPLC.

It can be seen from Figure II that the active ingredient of the polymerized polyacrylate is almost completely released after only 2 hours, while the emulsion-polymerized polyacrylate can be adjusted to the desired release profile by means of the glass transition temperature, for example to drug release values of: 19 * 6h 6 °%

Claims (7)

10 S8674 A process for the preparation of a pharmaceutical preparation which has a controlled and delayed release of the active ingredient and which contains a carrier based on an emulsion polymer, with the exception of preparations consisting of emulsion polyacrylates having a particle size of about 140 nm and a glass transition temperature of about 30 ° C, 50 to 500 nm of a polymerized emulsion polymer having a glass transition temperature of -20 ° C to + 80 ° C together with the active drug in a solvent, (a) the polymer solution containing the active substance is cast into a film and after evaporation , or (b) the solvent is evaporated, the solid drug-containing emulsion polymer is ground to a grain size between 10 and 500 μm below a settling temperature n, is processed with conventional tableting aids and compressed into tablets or used in capsules, whereby a decrease in particle size accelerates the release of the active ingredient, and an increase in the glass transition temperature reduces the release rate. Process according to Claim 1, characterized in that the glass transition temperature of the emulsion polymer is between -10 and + 30 ° C. Process according to Claim 1 or 2, characterized in that the carrier with the active pharmaceutical ingredient has a grain size of 10 to 500 μτη. 11 88674 Method according to Claim 1 or 2, characterized in that the film thickness is between 40 and 200 μm, preferably between 60 and 140 μπ. Process according to Claim 1, 2, 3 or 4, characterized in that the support consists of an emulsion-polymerized copolymer. Process according to Claim 5, characterized in that the polymer consists of an emulsion-polymerized copolymer of methyl and / or ethyl esters of acrylic and methacrylic acid. Process according to one of Claims 1 to 6, characterized in that it contains between 0.1 and 30%, preferably 1 to 10%, of active ingredient. 12 88674