DD265327A5 - METHOD FOR PRODUCING A PHARMACEUTICAL PREPARATION WITH DELAYED ACTIVE INGREDIENTS - 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

Oils invention relates to processes for the preparation of a pharmaceutical preparation in the form of a carrier material with a controlled-release and sustained-release drug substance.

characteristics άοα known prior art

It is known to produce pharmaceutical preparations in the form of capsules, tablets and films "which ensure a constant release of active ingredient and thus maintain a constant concentration of the active ingredients in the body." Capsules and tablets are usually the release of the active ingredient by suitable coatings, such as in film-coated tablets Controlled »Oepotformen can also be prepared from Oranulatgemlsohen different Trfigerstoffe that release the drug at different rates» A divisible tablet with delayed release of active ingredient is known from DE-08 3 314 003 «In this made of an emulsion polymerized polyaurate tablet will you. Release rate via grain size as controlled by particle size distribution »

Gel eystemen for trandermal application, the release of the active ingredient by special membrane (US-P8 3,731,683) or even with the help of adjuvants, such as amines, fats or higher alcohols, can be adjusted »

Oie known from the prior art pharmaceutical

Preparations with a sustained release of active ingredient have never been fully satisfactory in practice. On the one hand change tablets that are coated with a film, after the division their Fre. G gabeverhalten, on the other hand dor from DE-OS 33 14 003 recognized control of drug release by dxa setting the grain size limits, since the Korngrw ^ e not arbitrary "Due to technical problems, such as B, inhomogeneity, minimum number of loaded with drug granules, the grain size is limited both upwards and downwards, so that not in each coat an optimal release rate can be adjusted to the drug ,

Object of the invention

The aim of the invention is the provision of improved pharmaceutical preparations in which the sustained release of active substance is adjustable and controllable »

Presentation of the invention of the invention

The object of the invention is to find suitable agents and processes for the preparation of pharmaceutical preparations with the desired properties.

Surprisingly, it has been found that in the case of a pharmaceutical preparation of an emulsion-polymerized carrier material, the release rate is achieved by simple variation of the particle size of the emulsion polymerized polymer strips.

- 2 B -

as you can be adjusted by varying the temperature of the glass of the polymers. "

The combination of the variation of the grain size, the particle size and the glass transition temperature beeteht with powdered pharmaceutical preparations such as "B _# tablets or Kapeeln the possibility to set the Wirkstofffreigäbe of the pharmaceutical preparation in a wide range" For pharmaceutical preparations in the form of transdermal films can the release rate 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 size of the polymeric material after its preparation and is 50 to 500 nm according to the invention. The particle size (diameter) can be adjusted depending on the polymerisation 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 is between -20 ° and + 8O ⁰ C according to the invention, preferably between -20 ° and + 40 ° C, more preferably between -10 and + 30 ⁰ C. An increase in the glass transition temperature a decrease in the release rate.

The grain size is in a range between 10 and SOO. To adjust the particle size, the emulsion-polymerized polymer having a defined particle size is dissolved together with the active ingredient in a suitable solvent, then cast into a 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 carrier materials are those polymers which can be prepared by the emulsion polymerization process, e.g. PVC, polylactides, polystyrene, polyvinyl acetate, polybutadiene, polyacrylonitrile, polyvinyl esters, polyvinyl ethers and their copolymers

 Preference is given to emulsion-polymerized copolymers of methyl 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 carrier material as a solid may be e.g. by lyophilization, in this case the polymer particles remain in their shape and size.

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

 suspended.

Suitable solvents for the active ingredient and emulsion polymer are solutions which have a low evaporation point, e.g. low boiling alcohols, e.g. Methanol, ethanol, acetone, methyl ethyl ketone, halogenated hydrocarbons, e.g. Methylene chloride, methyl and ethyl acetate, methyl and ethyl acetoacetate, or ethers, e.g. Tetrahydrofuran or dioxane or dimethyl sulfoxide, low-boiling Frigene, or mixtures of these solvents.

The release rate of the drug may be controlled by adjuvants, i. Diffusion-influencing substances are additionally varied. These so-called adjuvants include e.g. Polyvinylpyrrolidone, cellulose esters, amines, fats or higher alcohols. If desired, these substances may be added to the drug solution.

This solution can be processed as follows:

To produce a pharmaceutical preparation containing active ingredient in the form of a film for transdermal therapeutic application, the solution obtained 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 .mu.m, preferably 60 to 140 um, has. Subsequently, the film can be provided with a vapor-impermeable backing layer and optionally an adhesive layer and assembled.

To prepare a pharmaceutical preparation containing active ingredient in powder form, the solvent of the solution described above, in the case of moisture or oxidation-sensitive drugs, if appropriate under protective gas, withdrawn and ground the obtained residue below its glass transition temperature to the desired particle size between 10 and 500 μπ \. If necessary, the milling may also be carried out in the presence of inert adjuvants such as e.g. Lactose, magnesium stearate, finely divided silica or similar fine-particle lubricant. The mass ratio of active substance-containing emulsion polymer to finely divided filler can be varied within wide limits and is about 10: 1 to 1: 4. The further processing into tablets or capsules is carried out by known methods with customary auxiliaries, such as e.g. Binders, inert fillers, lubricants and disintegrators.

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

It is known that at an increased loading of the carrier material, the release rate is significantly increased, so that a delayed release of the drug is no longer guaranteed. This could be compensated by increasing the grain size, but there would be a risk that the minimum number of

ns

loaded granules particles in a tablet below the critical number of 400 drops (This is a homogeneous distribution of Arzelmittelwirketoffs from tablet to tablet no longer guaranteed) "According to the invention, the problem can be solved by a higher glass transition temperature of the emuleionspolymerieierten carrier material and a larger particle size Grain size can be kept constant at the same time. "For tablets, capsules or films, this enables a significantly higher loading of the carrier material with a drug.

According to the invention, even more favorable ratios of drug to carrier material can be set and thus the Oepot principle can be extended to higher-dose drugs "since the pre-ginning rate can be adjusted within a wide range even at higher loading by the described parameters" particle size "grain size and oil temperature"

As a rule, the preparations according to the invention contain between 0.1 and 30% by weight of preferably 1 to 10% by weight of active ingredient.

Ausführunosbeispiel

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

ICS321

Examples

A) Movies

Example 1;

The omulsion polyols listed in Tab.

merisierten polyacrylates processed into transdermal films and examined for their release rates.

Tab. I: emulsion polymerized polyacrylate

Particle diameter of the latex particles Glass transition temperature F ilmch 50 - - 8 ° C A 50 - + 29 ⁰ C B 100 - - 8 ⁰ C C   100 nn. - 100 nm - 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 rate of release was compared with an aqueous medium of pH 7, determined at 37 ° C, the free analysis was carried out by means of HPLC.

JCS

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

Tab. II:

Filmcharge diffusion coefficient

D [cm / day]

A 5.5 10 " ⁶

B 4.4 10 " ⁶

C 1.4 10 " ⁶

In Fig. I the release rates for the dre.i. physically different latices listed. As can be seen from the curves, the release behavior can be influenced as much by the particle size as the glass transition temperature of the latices.

Abbr. I

RELEASE IN X g ₀ CLONIOIN

807060504030

COMPARISON OF THE RELEASE CURES FOR THREE PHYSICALLY DIFFERENT E 3CC LATICES

TIME IN DAYS 5 6

10

Example 2:

The emu] onspolymerisierte copolymers of vinyl chloride and acrylic acid ester listed in Tab. III are processed to transdermal films and examined for their release rate.

Table III

VA 381A VA 381 B

Solids content of polymers 44.6% 44.7%

in * "dispersion

Aperatur (A ^ Glas temperature) .'- 67 C> -0 C

Diameter of the latices 261 nm 262 nm

(Tei1cnengröße)

Die) eide via emulsion polymerization materials obtained differ in the glass transition temperature and thus in the softness of the polymer, the latex size is equal in both products. The polymer is obtained by drying the aqueous dispersion, then dissolved together with the drug clonidine in Metnylenchlorid and poured out in the known manner to films of about 100 μιη layer thickness. The release of drug from the CPA film of size

2 3 cm is determined in the USP tester and the content determination

carried out by HPLC.

* CPA = Controlled Percutaneous Application

Table IV lists the levels released at different times, clonidine (in percent). The rate of release decreases with increasing glass transition temperature, i. the harder the latices' esto slower the release.

Table IV

released amount of clonidine in%

Time in product product

Tacen VA 381 A VA 381 B

50.9 67.7

7; \, o

74.4

0.33 26.3 1 47.2 4 66.8 5 '/ 0.2 Film Thickness: 100 μιη,

Loading amount 0.7 mg clonidine / cm

B) Tablet:

It werck \ d, processed egg different Polyacrylattypen together with an active agent into tablets and their Freigabeverh & soldering in Figure II shown..

The polymer "D (Eudragit E 30 D) and E are emulsion-polymerized polyacrylates, the polymer F (Eudragit RS loo) a substance-polymerized polyacrylate from Röhm GmbH, Darmstadt. The two polymer types E and F have approximately the same glass transition temperature (Tg ~ 30 ° C), but are physically in different forms: spherical latex (E) or as a polymer ball (F). The glass transition temperature of the polyacrylates D, also a spherical latex, Tg "-8 ⁰ C. The glass transition temperature can be adjusted by varying the amount ratio of the polymer constituting monomers, which form by the polymerization conditions.

example 1

In a suitable vessel, 23.75 g of the polymer 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 is added. From the solution thus obtained, the solvent is evaporated under a protective gas atmosphere (N ₂ ) and the residual active substance-loaded film cooled down to about -40 ° C by means of dry ice and ground in portions with lactose in a ratio of 9: 1 in a MHhIe with rotating knives under cooling. A free-flowing powder is obtained in which the active substance-loaded polyacrylate is present in a logarithmically normally distributed form between 65 and 500 μm.

The mixture obtained in the manner described above is in a further step by known methods with conventional tabletting excipients, such as. Lactose, corn starch, colloidal silica and / or magnesium stearate, compressed into tablets having a 5% active ingredient loading, based on the polymer carrier.

Example 2

In analogy to Example 1, 95 g of the 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 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 film, ground and pressed into tablets.

The in vitro release of the tablets was measured at 37 ⁰ C in a USP performed XVII tester, was taking as Rezptormedium water "om pH 7. Analysis was carried out by HPLC.

As can be seen from Fig. II, the active ingredient is almost completely released from the substantially polymerized polyacrylate after only 2 hours, whereas for an emulsion-polymerized polyacrylate, depending on the glass transition temperature, a desired frit release profile, e.g. t .. 19%, tan. 60% release of drug, can be adjusted.

POLYMERTRAEGER TIME IN Ii s * l «ai.ng; _ F 5 + J) * E HOURS 8th

Claims (2)

claim 1. Process cur Preparation of a pharmaceutical composition with delayed Wirkatofefreigäbe, characterized in that one dissolves the drug together with a Emulaionapolymeriaat with a particle size of 50 to 500 yum and a glass transition temperature between -20 and +80 ⁰ C in an organic solvent, Daa solvent evaporates, the solid active substance-containing Erüulsionspolymerisat at a temperature lying below glass transition temperature to a particle size between 10 and 100 microns, processed with conventional Tablettierhilfastoffen and pressed into tablets or filled into capsules. 2. The method according to claim 1, characterized in that the emulsion polymer has a glass transition temperature between -10 and +30 ⁰ C.