Compressed pills with retarded liberation of active material, and process for their preparation

(42) Date of commencement of the patent: 15. 6.1986 (45) Date of issue: 12. 1.1987

<td>(56) Documents:</td><td>(73) Patent owner:</td>

<td>DE-0S2207635 DE-0S2836044 GB-PS 1325209 US-PS 3976071 US-PS 4181983 WO-A1 78/00011</td><td>CHEMIE LINZ AKTIENGESELLSCHAFT LINZ, UPPER AUSTRIA (AT).</td>

<td></td><td>(72) Inventor:</td>

<td></td><td>KORSATKO WERNER DR. GRAZ, STYRIA (AT). KORSATKO-WABNEGG BRIGITTA GRAZ, STYRIA (AT).</td>

(54) PROCESS FOR PREPARING PRESS LENGTHS WITH RETARDED ACTIVE INGREDIENT EXTRACTION (57) The invention relates to a process for the production of sustained release compacts for oral and parenteral administration. The method consists in that the active compound with at least 20 wt .-? 5 poly-D - (-) - 3-hydroxybutyric acid, based on the amount of active ingredient, and optionally mixed with other customary in pharmaceutical auxiliaries and additives in a mechanical manner and is homogenized, whereupon produced from the resulting homogenate under a pressure of 98.1-1962 N / mm compacts.

AT 38Z 076

WR 0078248

Nr.382076

The invention relates to a process for the production of sustained-release tablets for oral and parenteral long-term administration of drugs.

It has been known for some time that drug forms which ensure a long-lasting, continuous outflow of the active ingredient after a single administration offer significant advantages in clinical practice. For a large number of pharmacologically important substances are therefore already galenic dosage forms with delayed release of active ingredient for oral and parenteral administration (see. see Remington's Pharmaceutical Sciences, publisher Mack Publishing Company, Euston, Pennsylvania, USA, 1975, pp. 1618-1643), but also for topical application (e.g. GB Patent No. 1,351,409).

A known method for the preparation of sustained-release preparations consists in embedding the active ingredient in an indigestible or insoluble framework (matrix) and then processing into drug forms. The builders or auxiliaries used are usually indigestible, acid-insoluble macromolecules, for example cellulose derivatives or plastics, such as polyvinyl chloride, polyvinyl acetate, polyethylene or polymethacrylate. Although these builders provide a long-lasting and continuous release of the drug and can be pressed relatively well, but have the disadvantage that they are not biodegradable. As a result, on the one hand in peroral administration of the sustained-release preparation unwanted stresses on the gastrointestinal tract and on the other hand, for example, when using implants remaining after release of the drug in the body, non-biodegradable scaffold must be removed by surgery. There has therefore been no lack of attempts in the production of depot dosage forms biodegradable polymers as an excipient or to be used as a drug carrier.

Thus, for example, GB-PS No. 1,305,209 and US Pat. No. 3,976,071 describe pharmaceutical preparations for parenteral use, in particular implants, as well as dosage forms corresponding to DE-OS 2207635 for topical application, which comprise a drug in intimate combination containing a biodegradable polymer and releasing the drug for a predetermined period of time.

In these preparations, the carrier material is hydrolytically cleaved after administration, thereby releasing the active ingredient, so that the matrix is ​​biodegraded after completion of the drug release.

Polylactides, polyglycolides or copolymers derived therefrom, in which the comonomer component is a unit derived from higher .alpha.-, .beta.- or .gamma.-hydroxy acids, for example also from .beta.-hydroxybutyric acid, are mainly suitable as polymeric carrier materials for the pharmaceutical substance is. The naturally occurring and microbially obtained poly-D (-) - 3-hydroxybutyric acid is not described as a carrier material.

A disadvantage with the use of the known, biodegradable polymers is that the dosage form encounters difficulties and is technically complicated. Because of the poor miscibility, the strong electrostatic charge and the poor flow properties and the high elasticity of these polymeric materials it is hardly possible or only with great effort, such as working under nitrogen to produce homogeneous mixtures with drugs and to compress them directly.

The dosage form is limited in the polymers mentioned as a matrix material, for example, on the production of microcapsules and microspheres by spray drying or phase separation or on various melt processes, such as melt pressing. However, only thermally stable drugs are suitable for the melting process and the use of organic solvents in the spray drying or phase separation requires considerable technical protection for reasons of health and environmental protection so that both methods are reluctant. The preparation of compacts, such as dragées or tablets, is described neither in GB-PS No. 1,305,209, US-PS No. 3,976,071 nor in DE-OS 2207635.

Furthermore, WO-A1-78 / OOOH depot dosage forms for oral or parenteral administration are known in which the drug is enclosed in a biodegradable matrix consisting of synthetic polycondensation products of a dicarboxylic acid, hydroxycarboxylic acid or physiologically acceptable amino acids or of several of these acids consists. Naturally occurring polymers, such as the poly-D (-) - 3-hydroxybutyric acid are not in the WO-Al-78 / OOOll

No. 382076. The process for the preparation of these depot dosage forms consists of dispersing the still water-soluble polycondensate together with the drug in a weakly polar dispersant with stirring and then completing the condensation to the water insolubility of the polycondensate.

U.S. Patent No. 4,181,983 discloses a polymeric filling material which is assimilable to the human body and which can be implanted, for example, in cavities resulting from the extraction of teeth. The addition of active ingredients is not provided. For this filler are polymers, preferably Polylafctide, in question, which consist of saturated aliphatic hydroxycarboxylic acid units. Synthetic polymers of o- or S-hydroxybutyric acid units are also mentioned, but the use of the chiral, natural poly-D (-) - 3-hydroxybutyric acid is not intended. The implants are produced either by lyophilization or phase separation of the polymer dissolved in organic solvents, but in no case by compression.

Finally, a process for the preparation of microspheres as pharmaceutical sustained-release forms for oral and parenteral administration is described in DE-OS 2,83,604. The method consists in dissolving or dispersing a drug in a solution of a polymer and adding a phase separation agent at a temperature of -40 to -100 ° C whereby the polymer precipitates and the particles of the drug are coated with a polymeric outer layer. In addition to a variety of natural and synthetic polymers such as cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, natural or synthetic gums, polyacrylates, polystyrene, lactic acid polymers and polyglycolic acid, an unspecified polyhydroxybutyric acid and its copolymer is also referred to as a useful outer layer. From the fact that no advantages are given for any of the polymers listed, it can be concluded that the nature of the polymer plays only a minor role in the process of DE-OS No. 2,836,044, since the polymeric material worn only as an outer layer and not is mixed with the active ingredient as a matrix. Compact dosage forms, such as compacts in the form of tablets or dragees are not described in DE-OS 2836044.

It has now surprisingly been found that one can combine the advantage that biodegradable, homogeneous matrix forms, with simple methods in drug formulation, when using as a polymeric carrier material, the natural microbially produced poly -D (-) -3-hydroxybutyric acid ,

The invention accordingly provides a process for the production of compacts with delayed release of active ingredient for oral or parenteral administration of medicaments using an active substance and a biodegradable polymeric carrier material, characterized in that the active ingredient contains at least 20% by weight of poly-D (- ) -3-hydroxybutyric acid, based on the amount of active ingredient, and optionally mixed with auxiliaries and additives customary in galenics in a mechanical manner and homogenized, whereupon from the resulting homogenate under a pressure of 98.1 to 1962 N / mm² Preßlinge are produced.

In particular, tablets of any size and shape as well as dragee cores are suitable as sustained-release tablets produced by this process. However, it is of course also possible to produce other dosage forms by this process, for example very small compresses, which are subsequently filled into capsules. Likewise, multi-layer tablets or dragees can be produced if, in addition to the delayed-release layer, non-retarded active substances are to be contained in a layer.

The chemical structure of the poly-D (-) - 3-hydroxybutyric acid is that of a linear polymer, whereby 500 to 25000 repeating units can be found. For the preparation according to the invention of the matrix forms, polymers having a molecular weight of from 25,000 to 1,000,000 are particularly suitable. The amount of poly-D (-) - 3-hydroxybutyric acid required for the preparation of the compacts depends on the desired rate of release of the active ingredient and is at least 20% by weight, based on the amount of active ingredient, but otherwise is not limited to achieve a good sustained-release effect , The sustained release effect is highly dependent on the amount of added poly-D (-) - 3-hydroxybutyric acid, so that the rate of release of the active ingredient in the period of several hours to several months can be set practically arbitrarily (see Fig.l to 3).

- 4 No. 382076

For the preparation of sustained-release preparations for oral administration are matrix forms with a high active ingredient content and a low proportion of poly-D (-) - 3-hydroxybutyric acid, which, depending on the type of active ingredient and the desired release rate, for example 20 to 40 wt .-%, based on the total weight of active ingredient and poly-D (-) - 3-hydroxybutyric acid, may be particularly suitable. For parenteral application, for example, for the production of implants, in the application of the active ingredient after implantation in the body should be released evenly with the biodegradation of the carrier material according to the invention in the period of one week to several months, are matrix forms with a low Active ingredient content and a high proportion of poly-D (-) - 3-hydroxybutyric acid, for example from 60 to more than 95% by weight, Based on the total weight of active ingredient and poly-D (-) - 3-hydroxybutyric acid, recommended.

The poly-D (-) - 3-hydroxybutyric acid required for the purpose according to the invention is relatively easily obtainable, for example, according to the biological method of Lafferty et al., Chem. Rundschau 30 (41) 14 to 16, 1977, also in large quantities.

In contrast to the polylactides, the poly-D (-) - 3-hydroxybutyric acid, on the one hand, has low elastic properties and low electrostatic charging tendency and on the other hand has good lubricating and sliding properties. The active ingredient can therefore be easily mixed with the carrier material according to the invention and brought into a homogeneous form. The homogenization can be done with small amounts by means of powder grate and pestle or a powder mixing can. Large batches can be homogenized using rotating drums, paddle mixers, plate mixers, mixing screws, ribbon mixers, cone mixers, double-cone mixers and twin-blender (V-mixers).

The homogenates obtained in this way can be compressed directly without further treatment and without further additives to tablets, dragee cores or other comprets of any shape. Taking into account the difficulties that occur in the previously known biodegradable matrix forms in drug formulation, so it is surprising for a person skilled in the art can produce according to the invention by simple mixing and pressing solid matrix dosage forms with almost any variable release rate.

The homogenates obtainable according to the invention from the active substance and the poly-D (-) - 3-hydroxybutyric acid can, of course, be processed into granules before the pressing or after one of the customary granulation processes or, if desired, mixed with auxiliaries and additives customary in galenicals become.

The production of the compacts is possible with all conventional manual or automatic presses, which can be omitted due to the good lubricating and sliding properties of poly-D (-) - 3-hydroxybutyric acid addition of lubricants or lubricants.

The pressure can be over the range of 98.1 to 1962 N / mm² can be varied as desired. The rate of release of the active ingredient, with a variation of the pressing pressure in the range of 98.1 to 981 N / mm² no significant dependence on the pressure (see Fig.5).

Biodegradation of poly-D (-) - 3-hydroxybutyric acid occurs in the body either hydrolytically or enzymatically. The active ingredient is released from the matrix form obtained according to the invention partly by surface erosion, partly by diffusion processes over a long period of time uniformly and with complete biological degradation of the matrix in its entirety. The release rate can be varied by the ratio of active ingredient to the matrix (Fig.l to 3), by the tablet size (Figure 4) and to a small extent by the pressing pressure at which the compacts are produced (Figure 5) influence.

The process of the invention will be explained with reference to the following examples:

Example 1:

<td>recipe</td><td>1 piece</td><td>Approach for 30000 pieces</td>

<td>7-Hydroxyäthyltheophyllin</td><td>56 mg</td><td>1.68 kg</td>

<td>Poly-D (-) -3-hydroxybutyric acid</td><td></td><td></td>

<td>with a MG of about 100,000</td><td>14 mg</td><td>0.42 kg</td>

Nr.382076

Processing:

The ingredients are sieved, blended and homogenized in a cone mixer. The homogenate is at a compression pressure of 981 N / mm², pressed into tablets. Tablet mass: 70 mg

Active ingredient content: 80% by weight (56 mg)

Diameter; 6.0 mm

Height: 2.0 mm

Breaking strength: 64 N (solidified with Schleuninger Mod. 2E / 205)

Prepared under the same processing conditions, as indicated above, the following active ingredient content of 7-Hydroxyäthyltheophyllin:

were tablets with

Matrix 30 wt% Matrix 40 wt% Matrix 50 wt% Matrix 50 wt% Matrix 70 wt% Matrix 80 wt% Matrix 90 wt% Matrix 95 wt%

Example 2: Active ingredient content 70% by weight (49 mg)

Example 3: Active ingredient 60% by weight (42 mg)

Example 4: Active substance content 50% by weight (35 mg)

Example 5: Active substance content 40% by weight (28 mg)

Example 6: Active substance content 30% by weight (21 mg)

Example 7: Active ingredient content 20% by weight (14 mg)

Example 8: Active substance content 10% by weight (7 mg)

Example 9: Active substance content 5% by weight (3.5 mg)

The breaking strength of the tablets reaches a value of 64 N with an active ingredient content of 80% to 82 N with an active substance content of 5%.

Example 10 In Vitro Release Rate of Theophylline

For in vitro study of the release rates, the tablets were shaken according to physiological conditions in 100 ml of 0.9% sodium chloride solution (NaCl: OAB) in 200 ml capped amber bottles at 17 ° C. The analytical evaluation was carried out by spectrophotometric measurement at 273 nm directly or in dilution.

The results are shown in Fig.l to 3, wherein the numbers of the Liberationskurven refer to the examples 1 to 9. The letter h on the abscissa of Fig.l means hours, the letter d on the abscissa of Figures 2 and 3 mean days.

Example 11:

Recipe 1 piece

7-Hydroxyethyl theophylline 7 mg

Poly-D (-) - 3-hydroxybutyric acid 63 mg

Batch for 10,000 g g homogenized 630 g and the homogenate at one press. The ingredients are as in Example

<td>pressure of 981 N / mm²</td><td>compressed into tablets.</td>

<td>Tablet mass:</td><td>70 mg</td>

<td>Active substance content:</td><td>10% (7 mg)</td>

<td>Diameter:</td><td>6.0 mm</td>

<td>Height:</td><td>2.0 mm</td>

<td colspan="2">The Liberationskurve is in Fig.4, Nr.l,</td>

of Fig.4 means days. Example 12:

shown. The letter d on the abscissa

recipe

Piece approach for 10000 pieces

7-Hydroxyethyl theophylline 9 mg

Poly-D (-) - 3-hydroxybutyric acid 81 mg g 810 g

The ingredients are homogenized as in Example 1 and the homogenate at a pressure of 981 N / mm² compressed into tablets.

Tablet mass: 90 mg

Active substance content: 10% (9 mg)

- 6 - No.382076

Diameter: 8.0 mm Height: 2.0 mm

The Liberationskurve is shown in Figure 4, No.2. The letter d on the abscissa of Fig.4 means days.

Example 13:

Recipe 1 piece batch for 10000 pieces

7-Hydroxyethyl theophylline 7 mg. 70 g

Poly-D (-) - 3-hydroxybutyric acid 63 mg 630 g

The ingredients are homogenized as in Example 1 and the homogenate is at a

Pressing pressure of 196.2 N / mm² (Mark above the Liberationskurve in Figure 5), 392.4, 588.6, 784.8 and 981 N / mm² (Marking below the Liberationskurve in Figure 5) pressed. The release rates show little dependence on the pressing pressure in the range of 196.2 to 981 N / mm² and lie on the Liberationskurve shown in Figure 5 within the range indicated by the vertical markings. The letter d on the abscissa of Fig.5 means days.