DD272604A5 - METHOD FOR PRODUCING A FILM FOR TRANSDERMAL APPLICATION - 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

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The pharmaceutical preparations with a delayed release of active ingredient known from the prior art have not always proved to be fully satisfactory in practice. On the one hand change tablets that are coated with a film, after sharing their shares / receive, on the other hand, the known from DE-OS 3,314,003 control of drug release by adjusting the grain size limits, since the grain size is not arbitrarily freely selectable , Due to technical problems, such as Inhomogeneity, minimum number of loaded with drug granules, the grain size is limited both upwards and downwards, so that not in each case an optimal release rate corresponding to the active ingredient can be adjusted *

Z iel the invention

The aim of the invention is to provide improved pharmaceutical preparations in which the sustained-release drug is adjustable and controllable.

Explanation of the essence of the invention

The invention has for its object to provide a method for producing a film for transdormal application available »

It has surprisingly been found that in a pharmaceutical preparation of one emulsion polymerized carrier material, the release rate by simple variation

the particle size of the emulsion polymerized Plylymerkügelchen can be adjusted as well by varying the glass transition temperature of the polymer.

Due to the combination of the variation of the particle size, the particle size and the glass transition temperature exists in powdered pharmaceutical preparations, such as. B, tablets or capsules the ability to adjust the drug release of the pharmaceutical preparation in a wide range. For pharmaceutical preparations in the form of transdermal films, the rate of release can be adjusted by varying the layer thickness in the range between 40 and 200 μm, preferably 60 to 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, and is 50 to 500 nm in the present invention. The particle size (diameter) can be adjusted depending on the polymerization conditions. A decrease in the particle size causes an increase in the release rate.

The glass transition temperature can be adjusted by changing the monomer composition and according to the invention is between ~ 20 ⁰ C and + 80 ⁰ G, preferably between -20 ⁰ C and + 40 ⁰ G, more preferably between -1o 'C and + 30 ⁰ G ,, A Increase in the glass transition temperature is associated with a decrease in the release rate «

The grain size is in a range between 10 and 500 nm _o For adjusting the grain size, the emulsion polymerized polymer having a defined particle size is dissolved together with the active ingredient in a suitable solvent, then to a? Cast film and the solvent evaporated. The film is then, optionally below its glass transition temperature, ground to the desired particle size and screened if necessary.

Suitable support materials are those polymers which can be prepared by the emulsion polymerization process, such as. As PVC, polylactides, polystyrene, polyvinyl acetate, polybutadiene, polyacrylonitrile, polyvinyl esters, polyvinyl ethers and their copolymers, Preferably, emulsion-polymerized Copolyme-. The methylate and / or ethyl esters of acrylic and methacrylic acid, The molecular weight of the emulsion polymers should be between 10 and 10. The recovery of the Trägermateriala as a paste z, B, by lyophilization, in this case the Polymersatteilchen remain in their shape and size.

The preparation of the pharmaceutical preparation according to the invention can be carried out by dissolving or suspending an emulsion polymer having the desired particle size and glass transition temperature together with the active substance in a solvent which is as volatile as possible.

As a solvent for the active ingredient and emulsion

polymer solution or suspension contain such solvents in embossing, which have a low evaporation point, such as. B ₀ low-boiling alcohols, wi-e z. B _{0 is} methanol, ethanol, acetone, methyl ethyl ketone, halogenated hydrocarbons such as, B ₀ methylene chloride, methyl and ethyl acetate, methyl and ethyl acetoacetate, or ethers, such as. As tetrahydrofuran or dioxane or dimethyl sulfoxide, low-boiling prigene, or ₀ and mixtures of these solvents

The Preigaberate of the drug can be additionally varied by adjuvants, ie diffusion-influencing substances. These so-called adjuvants include ζ. Β, polyvinylpyrrolidone, Celluloseester, amines, fats or higher alcohols _t If desired, these substances of the active substance solution can be added.

This solution can be processed as follows:

To prepare a pharmaceutical preparation containing active ingredient in the form of a film for transdermal therapeutic application, the resulting solution is poured into a film of defined layer thickness, which is dimensioned so that the film after evaporation of the solvent has a layer thickness between 40 and 200 jam, preferably 60 to 140 am , having. Subsequently, the film can be provided with a double-impermeable backing layer and, if appropriate, an adhesive layer

in coy

For the preparation of a pharmaceutical preparation containing active ingredient in powder form, the solvent of the solution described above, in the case of moisture-sensitive or oxidation-sensitive medicaments, is withdrawn, if appropriate under protective gas, and the residue obtained is heated below its glass transition temperature to the desired particle size between 10 and 500. If e3 is required, milling may also be carried out in the presence of inert excipients or excipients, such as lactose, magnesium stearate, finely divided silica or similar finely divided lubricants The mass ratio of active substance shearable emulsion polymer to finely divided filler can be within wide limits The further processing into tablets or capsules is carried out by known processes with customary excipients, such as binders, inert fillers, lubricants and lubricants

A preferred embodiment is a divisible tablet, since the preparation according to the invention retains its advantageous properties in every fragment. In the preparation of films for transdermal application, the release rate can be adjusted by variations in particle size and glass transition temperature at given film thickness and amount of drug incorporated.

It is known that at an increased loading of the carrier material, the FiSLsetzungsrate is significantly increased, so that a delayed release dea agent is no longer guaranteed. This could be compensated by increasing the grain size, here

However, there is a risk that the minimum number of loaded granules in a tablet below the critical number of 400 drops (this is a homogeneous distribution of the drug from tablet to tablet is no longer guaranteed). According to the invention, the problem can be solved by a higher glass transition temperature of the emulsion-polymerized support material and a larger particle size, while the particle size can be kept substantially constant. This allows for tablets, capsules or films a much higher loading of the carrier material with a drug,

According to the invention, more favorable ratios of drug to carrier material can also be set and thus the depot principle can be extended to higher-dose drugs, since the release rate can be adjusted within a wide range even at higher loading through the described parameters, particle size, grain size and glass transition temperature.

In general, the formulations of the invention contain zv / regard 0.1 and 30 Gev .-%, preferably 1 to 10 wt _e -% of active ingredient.

embodiment

The invention is explained in more detail below with reference to some examples.

Examples A) Films

For example, 1;

The emulsion-polymerized polyacrylates listed in Table I are processed into transdermal films and examined for their release rates

Tbο I: emulsion-polymerized polyacrylate.

Particle diameter Glasteraperatur Filmoharge of the latex particles

50-100 mn 50-100 nm

100-150 nm

The latex particles are obtained by drying the water from the respective dispersion (Röhm GmbH, Darmstadt). 21.3 g of the dried polyacrylate are dissolved together with 1.6 g of clonidine in 142 g of acetone and poured on a flat surface to form films. The layer thickness after evaporation of the solvent was 80 μm. The release rate was compared to an aqueous medium of pH 7, at 37 ⁰ G, determined, the release analysis was carried out by means of HPLG,

-8th ⁰ C A +29 ⁰ G B - 8th ⁰ C G

The diffusion coefficients determined for the three different types of latex are listed in Table II:

Tab. II:

Film charge diffusion coefficient

D / "on

A 5.5 10 " ⁶

B 4.4 10 " ⁶

C-1.4 10 " ⁶

Fig. I shows the release rates for the three physically different latices. As can be seen from the curves, the release behavior can be influenced both by the particle size and the glass transition temperature of the latices.

toy

Example 2:

The reaction-polymerized copolymers of vinyl chloride and acrylic ester listed in Tab. Ill are processed into transdermal films and analyzed for their rate of release.

Table III

VA 381A VA 381 B

Solids content on polymers 44.6 % 44.7% in the dispersion

Film Formation / 067 ⁰ C ^ O ⁰ C

(λ / -Glastemperatur)

Diameter of the latices 261 ηφ 262 nm

(Particle size)

The two materials obtained via the emulsion polymerization differ in the glass transition temperature and thus in the softness of the polymer, the latex size is in both. Products same. The polymer is obtained by drying the aqueous dispersion, then it is dissolved together with the drug "clonidine in methylene chloride and poured out in the known manner into films of approximately 100 μm layer thickness The release of drug from the CPA film of the size 3 cm becomes determined in the USP tester and the content determined by HPLC.

* CPA = Controlled Percutaneous Application

In Table IV, the amounts of glonidine released at different times (in percent) are listed. The release rate decreases with increasing glass transition temperature, the ₀ h, the harder the latices, the slower the release.

Table IV

Time in days

Released amount of glonidine in %

Product VA 381 Λ

Product VA 381 B

0.33 1

26.3 47.2 66.8 70.2

50.9 67.7 73.0 74.4

Film thickness: 100 / μm, loading amount 0.7 mg Clonidine / cn '

B) tablets

Three different polyacrylate types are processed into tablets together with an active ingredient and their release behavior is shown in Fig. II.

The polymers D (Eudragit E 30 D), and E are emulsionspolyraerisierte polyacrylates, the polymer P (Eudragit RS 100) substanzpolymerisiertes polyacrylate Company Röhin GmbH, Darmstadt _c have the two types of polymers E and F is approximately the same Gla3temperatur (Tg ^ 3o ⁰ C ), but are physically in different forms: spherical latex (E) or as a polymer ball (F). The glass transition temperature of the polyacrylate D, also a spherical latex, is Tg = -8 C. The glass transition temperature can be adjusted by varying the quantitative ratio of the monomers constituting the polymer, the shape by the polymerization conditions.

example 1

In a suitable vessel 23.75 g deb polymers E are stirred together with 400 ml of acetone until a clear solution is formed, then the drug solution consisting of 1.25 g of B-HT 933 base in 100 ml of methanol was added. From the solution thus obtained, the solvent is evaporated under a protective gas atmosphere (Np) and cooled down remaining drug-loaded film using dry ice to about -40 ⁰ C and together with lactose in the ratio 9: 1 in a mill mil; rotating knives are ground in portions with cooling. This gives a free-flowing powder in which the active substance-loaded polyacrylate is present logarithmically normally distributed between 65 and 500 microns.

The mixture obtained in the manner described above is in a further step by known methods with conventional Tablettierhilfastoffen, such as. As lactose, corn starch, colloidal silica and / or magnesium stearate, pressed into tablets, which have a 5% active ingredient loading, based on the polymer carrier.

Example 2

In analogy to Example 1, 95 g of the polymer P, 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 pressed into tablets.

Example 3

In analogy to Example 1, 95 g of the polyacrylate E dissolved in 500 ml of acetone and 5.0 g of B-HT 933 Base in 40 ml of methanol are processed to a mushroom, ground and pressed into tablets.

The in vitro ~ I? Reigabe of the tablets was at 37 ⁰ O in a USP performed XVII tester was taken as the receptor medium wherein water of pH. 7 The analysis was carried out by means of HPLG ₀

As can be seen from FIG. 2, the active substance is almost completely released from the substance-polymerized polyacrylate after only 2 hours, while in the case of an emulsion: 3-polymerized polyacrylate, a desired release profile, depending on the glass transition temperature, z, B ^ ⁰ ^ release to drug, can be adjusted.

Claims (4)

ZK C, o * t claims 1c A process for the preparation of a film transdermal application, characterized in that one dissolves the active pharmaceutical ingredient together with the Einu.lsionspolymerisat in an organic solvent, poured into a film and the solvent evaporates, the film formed with a vapor-impermeable backsize and optionally with an adhesive layer provides and assembles. 2. The method according to claim 1, characterized in that the film has a layer thickness between 40.and 200 μm, preferably 60 to 140 μm. 3. The method according to claim 1, characterized in that the emulsion polymer has a particle size of 50 to 500 nm and a glass transition temperature between -20 ⁰ C and +80 ⁰ G. 4. The method according to claim 1 and 3, characterized in that the emulsion polymer has a glass transition temperature between -10 ⁰ C and +30 ⁰ G. Process for the derivation of a transdermal application Field of application of the invention The invention relates to methods for producing a film for transdermal application, Characteristic of the known state of the art It is bekfinnt to produce pharmaceutical preparations in the form of capsules, tablets and films, which ensure a constant drug release and thus maintain a constant concentration of the drug in the body. In the case of capsules and tablets, the release of the active ingredient is usually controlled by suitable coatings, such as film-coated tablets. Depot forms can also be prepared from granule mixtures of different carriers which release the active pharmaceutical ingredient at different rates. A divisible tablet with delayed drug release is known from DE-OS 3,314,003. In the case of this tablet produced from an emulsion-polymerized polyacrylate, the release rate is controlled by the particle size as well as the particle size distribution. In systems for transdermal administration, the release of the active substance can be adjusted by means of special membranes (US Pat. No. 3,731,693) or else with the aid of adjuvants, for example amines, fats or higher alcohols,