DE4341156C2 - Use of water-redispersible plastic dispersion powders as drug carriers - Google Patents

Description

The invention relates to the use of redis in water Pearable plastic dispersion powders as medicines carriers in drug forms with controlled release of active ingredient.

EP-A 313 535 relates to pharmaceutical formulations for sustained release of buspirone in oral applications on, the active ingredient in tablet formulations with what serially insoluble polymer powders or mixtures of these polymers powder is applied. Shaped bodies, which pharmaceutical Active substances and hydrophobic polymer powder as matrix material are the subject of EP-A 168 522. EP-A 463 833 describes the use of vinyl acetate / ethylene copolyme Risks as matrix polymers in pharmaceutical formulations with a sustained release effect. The use of water insoluble Chen polymers cause a pH-independent retar effective effect; however, the inhomogeneous one is disadvantageous Distribution of the active ingredient in the manufacture and the gene rell very low permeability when using her conventional polymers with compact grain.

From EP-A 253 490 is known as a drug carrier for the sustained release of a combination of active ingredients, mixtures from water-soluble polymers and water-insoluble To use polymers. The disadvantage is the expense production of the pharmaceutical preparation. The USA 3,629,393 describes a mixture which is difficult to produce Granules with active ingredient and hydrophobic polymer, granules with water-swellable polymer and pharmaceutical carrier material and granules of pharmaceutical carrier.

DE-A 34 32 573 describes drug carriers made from hydrogel Compositions of two non-crosslinked thermoplastic Polymers, one of which is hydrophilic, the other hydrophobic is. The composition is prepared by dissolving the components in an organic solvent and Ab evaporate the solvent. Not to mention the Emis Sion problems with this manufacturing process are so no drug carriers with core-shell structure accessible Lich.

DE-C 34 43 587 relates to a pharmaceutical carrier based on a mixture of water-soluble components ten: hydroxypropylmethyl cellulose, hydroxypropyl cellulose and carboxy vinyl polymer. The production takes place through a multiple mixing. The manufacture of drug carriers, which are water-insoluble regardless of the pH value is also included a mixture of water-soluble components possible.

From DE-A 41 38 513 drug carriers are known which from a mixture of water-insoluble polyacrylate and what are made of serially soluble hydroxyalkyl cellulose and Melt extrusion can be produced at 50 to 200 ° C. Abge see from the increased temp temperatures are drug carriers with a core-shell structure and variable porosity as well as homogeneous distribution of active ingredients inaccessible.

Redispersible powders of anionic methacrylic acid co polymers with methyl methacrylate or ethyl acrylate are in Eudragit® Info F-2 (company lettering of Röhm GmbH) as suitable nete matrix substances for pharmaceutical formulations with right tarded drug release described. The disadvantage is here the pH-dependent solubility.

There was therefore the task of drug carriers on the To provide the basis of polymer powders, which irrespective of the pH, which are insoluble in water Production of a homogeneous distribution of the active ingredient component ensure and which the delayed diffusion of action effect component.

Surprisingly, it has been found that this task involves Plastic dispersion powder is soluble, which so far only as a binder for construction adhesives, mortar and dispersions colors were known.

The invention relates to the use of in water redispersible plastic dispersion powders as medicines Medium carriers in dosage forms with controlled release of active ingredients be, characterized in that the plastic dispersion powder particles have a core-shell structure and

• a) 5 to 95 wt .-% of one or more water-insoluble core polymers with a glass transition temperature T _g of -50 ° C to + 50 ° C and
• b) contain 95 to 5% by weight of one or more water-soluble or water-swellable shell polymers with a T _{g of} 30 ° C., and the drug forms are prepared by direct compression of the powdered drug carrier with the active ingredients and other customary additives.

The content of water-insoluble core polymer a) is preferably 50 to 85% by weight. The T _{g of} the water-insoluble core polymer is preferably from -20 ° C. to + 50 ° C. The particle size of the redispersible core-shell dispersion powder is preferably 5 to 400 microns. With regard to the particle morphology, the redispersible plastic dispersion powder consists of porous or non-porous, spherical particles which are composed of a hydrophobic, water-insoluble core and a hydrophilic, water-soluble or water-swellable shell, and whose porosity increases with an increasing proportion of shell polymer.

Preferred water-insoluble core polymers a) are:
Vinyl acetate homopolymers;
Vinyl acetate / ethylene copolymers;
Copolymers of vinyl acetate with (meth) acrylic acid esters of alcohols with 1 to 10 carbon atoms, such as methyl acrylate, methyl methacrylate, ethyl acrylate, n-butyl acrylate, 2-ethylhexyl acrylate, for example vinyl acetate / butyl acrylate copolymer;
Copolymers of vinyl acetate with vinyl esters of C₃-C₁₈ car acids such as vinyl propionate, vinyl laurate, vinyl pivalate, VeoVa9 or VeoVa10 (vinyl esters of α-branched carboxylic acids with 9 or 10 C atoms, a commercial product of Shell), for example vinyl acetate / vinyl laurate Copolymer or Vinylace tat / VeoVa9 copolymer;
Copolymers of vinyl acetate with esters of ethylenically unsaturated dicarboxylic acids, for example vinyl acetate / diisopropyl fumarate;
Vinyl propionate homopolymers;
Copolymers of vinyl propionate with (meth) acrylic acid and / or (meth) acrylic acid esters of alcohols with 1 to 10 carbon atoms;
Homopolymers and copolymers of (meth) acrylic acid esters of alcohols with 1 to 10 carbon atoms, which may also contain acrylic acid and / or methacrylic acid units, for example butyl acrylate / methyl methacrylate copolymer;
Vinyl chloride / ethylene copolymers and copolymers of vinyl chloride, ethylene with vinyl esters of C₃-C₁₈ carboxylic acids, for example vinyl chloride / ethylene / vinyl laurate copolymers;
Vinyl chloride / vinyl acetate copolymers and copolymers of vinyl chloride with acrylic acid esters of alcohols having 1 to 10 carbon atoms, for example vinyl chloride / butyl acrylate copolymers.

Copolymers of styrene, for example styrene-butyl acrylate, Styrene-2-ethylhexyl acrylate or styrene-butadiene copolymers sate.

Mixtures of the homo- or Copolymers are used.

Preferred water-soluble or water-swellable shell polymers b) are:
Polyvinyl alcohol or partially hydrolyzed polyvinyl acetate did with a degree of hydrolysis of 40 to 80 mol%; fully or partially hydrolyzed vinyl acetate-isopropenylacetate copolymers; Polyvinyl pyrrolidone or vinyl pyrrolidone / vinyl acetate copolymers;
Cellulose derivatives such as methyl cellulose or hydroxypropyl cellulose;
Starch or starch derivatives such as hydroxyalkyl ether starches;
Homopolymers of acrylic acid or methacrylic acid and copolymers of acrylic acid or methacrylic acid with small proportions of comonomers from the group of vinyl esters of C₃- to C₁₈-carboxylic acids, (meth) acrylic esters of alcohols with 1 to 10 carbon atoms, maleic acid, fumaric acid, itaconic acid, and Salts of the homo- and copolymers of (meth) acrylic acid mentioned;
Copolymers of styrene with maleic acid and sulfonated polystyrenes;
sulfonated and non-sulfonated melamine formaldehyde resins, phenol formaldehyde resins and naphthalene formaldehyde resins.

Mixtures of the homo- and Copolymers are used.

Plastic dispersion powders are particularly preferred tend

• a) 50 to 85 wt .-% of a water-insoluble core polymer with a glass transition temperature T _g of -20 ° C to + 50 ° C from the group polyvinyl acetate, vinyl acetate / ethylene copolymer, vinyl acetate / butyl acrylate copolymer, vinyl acetate / vinyl laurate Copolymer, vinyl acetate / VeoVa9 copolymer, vinyl acetate / diisopropyl fumarate, vinyl chloride / ethylene copolymer, vinyl chloride / ethylene / vinyl laurate copolymer, vinyl chloride / vinyl acetate copolymer, and
• b) 15 to 50 wt .-% of a water-soluble or water-swellable shell polymer with a T _g 30 ° C from the group polyvinyl alcohol, partially hydrolyzed polyvinyl acetate did with a degree of hydrolysis of 40 to 80 mol%, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, starch , Polyacrylic acid.

Plastic dispersion powders are most preferred holding

• a) 50 to 85 wt .-% of a water-insoluble core polymer with a glass transition temperature T _g of -20 ° C to + 50 ° C from the group polyvinyl acetate, vinyl acetate / ethylene copolymer, vinyl chloride / ethylene copolymer, vinyl chloride / ethylene / vinyl laurate Copolymer, and
• b) 15 to 50 wt .-% of a water-soluble or water-swellable Ren polymer with a T _g 30 ° C from the group polyvinyl alcohol and partially hydrolyzed polyvinyl acetate with a degree of hydrolysis of 40 to 80 mol%.

The core polymer a) is prepared according to Emulsion polymerization process and is used in the usual Reactors carried out. The polymerization can be discounted Nuclear or continuous, with or without the use of Seed latices, with presentation of all or individual components of the reaction mixture, or with partial submission and Replenishment of the or individual components of the reacti onsgemisches, or according to the dosing process without a template be performed. The polymerization is carried out in a tempe temperature range from 0 to 100 ° C and with the for the emulsion polymerization usually used what initiated radical formers. As a disperser all can usually medium in the emulsion polymer used emulsifiers and protective colloids will.

The shell polymer b) is a protective colloid such as in suspension polymerization be set. These polymers are commercially available Lich, which is why their manufacture is not discussed further becomes.

For the production of the redispersible plastic dispersion The core polymer a) is powdered as an aqueous latex set. The shell polymer b) is preferred to this latex added as an aqueous solution. After mixing the aqueous latex of the core polymer a) with the aqueous Lö solution of the shell polymer b) by means of conventional techno logic, for example in agitators, the resulting Dispersion using thin film, spray or freeze drying dried, preferably spray or freeze dried, particularly preferably spray-dried. Spray drying can on known devices such. B. spraying through Multi-component nozzles or with the disc in one if necessary heated dry gas flow can be used. Generally I do not use temperatures above 250 ° C. The optimum temperature of the dry gas can be Chen be determined; often temperatures have exceeded 60 ° C especially proven. Powder is obtained, the particles of which are hy drophobic core polymer a) exist, which  is coated with hydrophilic shell polymer b).

The redispersible plastic dispersion powders are suitable yourself as a drug carrier in Tablets. In addition to active ingredient and Plastic dispersion powders can optionally also be inert fillers such as cellulose, lactose or dextrose be applied. Lubricants such as talc can also be used or magnesium stearate in the usual amounts will.

For the production of solid pharmaceutical forms under use of the plastic dispersion powders are the aforementioned Components preferably dry, with that in the drug conventional technology, for example with Compulsory mixers, mixed. For the production of tablets the mixtures with the usual tabletting devices pressed directly.

In comparison to the drug known from the prior art medium carriers have the advantage of ver according to the invention used redispersible plastic dispersion powder in that the physical and physicochemical Properties of the drug carrier and thus indirect of the pharmaceutical forms thus produced over a wide range vary richly. The particle size and particles size distribution can be done using the drying process control, with the most preferred spray drying very fine particles result. The porosity and therefore the Diffusion permeability of the carrier substances increases increasing content of hydrophilic shell polymer b). over the ratio of core polymer a) to shell polymer b) the hydrophilicity of the Drug carrier and thus the compatibility to each used active ingredient and its homogeneous distribution in the Influence dosage form. Another advantage of the invention according to drug carrier used is that the se by the content of hydrophobic, water-insoluble core polymer a) remain insoluble regardless of pH and therefore both in acid gastric juice and in neutral to basi intestinal tract a delayed release of the Active ingredient.

The following examples serve for further explanation the invention:

To determine the release of active ingredient were used as a model effect substances selected theophylline and quinine sulfate as these Compounds remain stable over a wide pH range and due to the UV activity of these compounds their free setting can be observed well.

The following basic recipe was used to manufacture the tablets door selected:

19% by weight of active ingredient, 78% by weight of dispersion powder and 3% by weight of Mg Stearate.

30 mg of theophyl lin or 50 mg quinine sulfate with 120 mg or 200 mg Disper sion powder and with 4.4 mg or 7.3 mg magnesium stearate in mixed intensively with an agate mortar. With a manual Tablet press were tablets with a pressure of 150 Nm of the above composition with a diameter of 8 mm pressed.

The following were used as the dispersion powder:
(The T _g was determined using the DSC method. Since the T _g value in polyvinyl alcohol depends on the residual water content, the literature value of 85 ° C is given).

Dispersion powder A:
a) 89% by weight polyvinyl acetate (T _g = 33 ° C)
b) 11% by weight polyvinyl alcohol (T _g = 85 ° C)
Dispersion powder B:
a) 94% by weight polyvinyl acetate (T _g = 33 ° C)
b) 6% by weight of polyvinyl alcohol (T _g = 85 ° C)
Dispersion powder C:
a) 85% by weight vinyl acetate / ethylene copolymer (T _g = -8 ° C)
b) 15% by weight of polyvinyl alcohol (T _g = 85 ° C)
Dispersion powder D:
a) 85% by weight vinyl acetate / butyl acrylate copolymer (T _g = 15 ° C.)
b) 15% by weight of polyvinyl alcohol (T _g = 85 ° C)
Dispersion powder E:
a) 85% by weight vinyl acetate / vinyl laurate copolymer (T _g = 12 ° C)
b) 15% by weight of polyvinyl alcohol (T _g = 85 ° C)
Dispersion powder F:
a) 85% by weight vinyl chloride / ethylene / vinyl laurate copolymer (T _g = 1 ° C)
b) 15% by weight of polyvinyl alcohol (T _g = 85 ° C).

The measurements were in artificial gastric juice or artificial chem intestinal juice of the following recipe:

A) Artificial gastric juice:
2.0 g NaCl, 3.2 g pepsin and 25 g 10% HCl were made up to 1000 ml with distilled water (pH = 1.2).
B) Artificial intestinal juice:
6.8 g of KH₂PO₄ were dissolved in 250 ml of distilled water.
400 ml of distilled water were added to this solution and 10.0 g of pancreatin were dissolved therein. The pH of the solution was then adjusted to 7.5 with 0.1 molar NaOH and finally made up to 1000 ml with distilled water.
Measuring method for determining the active ingredient release:
To determine the active ingredient release, 6 tablets were used per measured value and the result of the individual measurements was averaged. The solution tests were carried out with a Philips PU 8505/60 Tablet Dissolution Monitoring System, which was equipped with 6 baths and baskets for sample holding. The baths were filled with 900 ml of artificial gastric juice or artificial intestinal juice. The measurements were carried out with stirring at 100 ± 1 rpm and at a temperature of 37.0 ± 0.2 ° C. The temperature and stirring rate were kept constant during the measurements. The tablets were added to the baths filled with artificial gastric juice using the baskets and the release of active ingredient was monitored over 3 hours. The artificial gastric juice was then exchanged for artificial intestinal juice in the baths, the tablets were put back into the medium and the release of active ingredient from the tablets in the intestinal juice was followed in an analogous manner over 5 hours. To measure the release of active ingredient in the media, samples were taken from the 6 baths at intervals using perestaltic pumps and the active ingredient release was monitored in a Philips PU 8620 UV-VIS spectrophotometer by measuring the UV absorption in quartz cuvettes. The absorption data were passed on to a computer and evaluated there using the Weibull equation.
Weibull equation:
F (t) = F _∞ (1-exp [- (t / td) β]))
F (t) = active ingredient content released at time t 0 F (t) 1
F _∞ = total active ingredient released during the measurement
t _d = point in time at which 63.3% of the active ingredient is released.
β = Qualitative value for the degree to which the active substance release is influenced by parallel processes, such as diffusion or decay.

example 1

The drug delivery of 30 mg theophylline and 120 mg Disper tablets containing artificial powder in gastric juice and then in artificial intestinal juice was in each six parallel measurements using the one just described Method followed. The following Table 1 gives the results measurements of the preparations with the individual Dispersion powders again.

Table 1

The results in Table 1 show that the release of active ingredient started immediately, as was also to be expected with uncoated tablets. The F _∞ values are close to 100, which means that there are no unusual solution phenomena. The β-values are generally less than 1. That is, in artificial gastric juice, the release of active substance starts spontaneously at a relatively high rate and then gradually increases to the final value. After a slight initial effect, the active ingredient release is approximately constant according to a zero order kinetics. In artificial intestinal juice, drug delivery continues in the same way, without significant changes. The t _d values show that with the dispersion powders A to F as a drug carrier, a delayed release of active ingredient is achieved.

Example 2

The drug delivery of 50 mg quinine sulfate and 200 mg dis Tablets containing persion powder in an artificial stomach juice was measured in six parallel measurements using the followed the method just described. The following table le 2 gives the results of the measurements for the preparations with the individual dispersion powders again.

Table 2

Only the results of the tests in artificial gastric juice are shown in Table 2, since the measurements in artificial intestinal juice did not produce any significant results due to the low solubility of the free quinine base in this medium. The t _d values show that, especially with the dispersible powders E and F as drug carriers, a delayed release of active ingredient is achieved. The β values for these powders are less than 1. That means that the active ingredient release starts spontaneously at a relatively high rate and then gradually increases to the final value. After a slight initial effect, the active ingredient release is almost constant according to zero order kinetics.

Claims (5)

1. Use of water-redispersible plastic dispersion powders as pharmaceutical carriers in pharmaceutical forms with controlled release of active substance, characterized in that the plastic dispersion powder particles have a core-shell structure and

• a) 5 to 95 wt .-% of one or more water-insoluble core polymers with a glass transition temperature T _g of -50 ° C to + 50 ° C and
• b) contain 95 to 5% by weight of one or more water-soluble or water-swellable shell polymers with a T _{g of} 30 ° C., and

the dosage forms by direct compression of the powder gene drug carriers with the active ingredients and other usual Additives are produced. 2. Use according to claim 1, characterized in that the plastic dispersion powder

• a) 50 to 85% by weight of a water-insoluble core polymer having a glass transition temperature T _{g of} from -20 ° C. to + 50 ° C. from the group polyvinyl acetate, vinyl acetate / ethylene copolymer, vinyl acetate / butyl acrylate copolymer, vinyl acetate / vinyl laurate copolymer, Vinyl acetate / VeoVa9 copolymer, vinyl acetate / diisopropyl fumarate, vinyl chloride / ethylene copolymer, vinyl chloride / ethylene / vinyl laurate copolymer, vinyl chloride / vinyl acetate copolymer, and
• b) 15 to 50 wt .-% of a water-soluble or water-swellable shell polymer with a T _g 30 ° C from the group polyvinyl alcohol, partially hydrolyzed polyvinyl acetate with a degree of hydrolysis of 40 to 80 mol%, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, starch , Contain polyacrylic acid.

3. Use according to claim 1, characterized in that the plastic dispersion powder

• a) 50 to 85 wt .-% of a water-insoluble core polymer with a glass transition temperature T _g of -20 ° C to + 50 ° C from the group polyvinyl acetate, vinyl acetate / ethylene copolymer, vinyl chloride / ethylene copolymer, vinyl chloride / ethylene / vinyl laurate Copolymer, and
• b) 15 to 50 wt .-% of a water-soluble or water-swellable shell polymer with a T _g 30 ° C from the group polyvinyl alcohol and partially hydrolyzed polyvinyl acetate with a degree of hydrolysis of 40 to 80 mol%.

4. Use of drug carriers according to claim 1 to 3 for the production of tablets.