CS261241B2 - Method for producing dry substances - Google Patents

Abstract

A method for producing dry substances obtained by lyophilization, suitable for producing stable suspensions containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-diones, characterized in that the 4-hydroxy- or 4-acyloxy-4-androstene-3,17-diones are suspended in the presence of a combination consisting of at least one phospholipid and at least one polyethylene glycol in a ratio of 1:1 to 1:10 as a wetting agent and as a means for increasing the viscosity of the suspension composition in an aqueous suspension composition, and the suspensions obtained are lyophilized.

Description

The present invention relates to a process for the preparation of dry substances for the production of stable suspensions which contain 4-hydroxy- or 4-acyloxy-4-androstene-3,17-dione as active ingredient.

Aqueous suspensions, especially injectable suspensions with steroid compounds, usually contain, according to H. Sucker, P. Fuchs and P. Speiser, Pharmazeutische Technologie (1978), Verlag G. Thieme Stuttgart, p. 616, as suspending aids, e.g. concentrations such as 0.1 to 0.5 mg / ml polysorbate or 0.15 mg / ml dioctyl sodium sulfosuccinate, a protective colloid such as sodium carboxymethylcellulose or methylcellulose and a peptizer such as phosphate buffer. However, these excipients must be dosed within a very narrow range to ensure the physical stability of the suspension. However, if this composition is not optimal within a narrow range, there is a risk that the crystals of the suspended active substance will either grow or the suspended active substance will prematurely settle and after some time the suspension will no longer be homogeneous by shaking and no longer meet the ideal requirements. See Remington, Pharmaceutical Sciences (1980), (A. Osol), p.

Thus, there is a real need to prepare a stable aqueous suspension without the above disadvantages. In addition, there is a need in medicine to prepare droplets, since in many cases patients receive drops more easily than capsules or tablets. In particular, injectable suspensions may be parenterally administered to a patient in any condition.

Surprisingly, it has now been found that by freeze-drying a dry substance to produce stable suspensions and a stable suspension per se, in particular suspensions for injection which contain 4-hydroxy- or 4-acyloxy-4-androstene-3,17- as active ingredient. dione, wherein the dry substances comprise as a wetting agent and to increase the viscosity of the suspending agent a combination consisting of at least one phospholipid and at least one polyethylene glycol in a ratio of 1: 1 to 1:10.

Surprisingly, it has now been ensured that the ratio of the phospholipid / polyethylene glycol combination is of great importance for the lyophilization of the obtained dry substance to produce stable suspensions.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of freeze-dried dry substances suitable for the preparation of stable suspensions containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-dione, characterized in that -acyloxy-4-androstene-3,17-diones are suspended in the presence of a combination with at least one phospholipid and at least one polyethylene glycol in a ratio of 1: 1 to 1:10 as a wetting agent and as a viscosity enhancing agent for the suspension composition in the aqueous suspension composition; the obtained suspensions are lyophilized.

The ratio of the combination of phospholipids and polyethylene glycol is in particular in the range from 1: 1 to 1: 5.0, but preferably in the range from 1: 1 to 1: 3.0.

Suitable phospholipids for use as surfactants in combination with polyethylene glycol are mixtures of phosphatidylcholine, phosphatidylethanolamine, N-acylphosphatidylethanolamine or phosphatidylinositide, in particular phospholipids with a phosphatidylcholine content of 30 to 98%.

For example, the following commercial products may be used:

Phosphatidylcholine content

Epicuron 145 ^ about 45%

Lipoid S45 ^(R)

Epicuron 170 ^(R)

Lipoid E80 ^(R) up to 85%

Epicuron 200 ^(R) 90 to 98 »

Lipoid S100 ^<R)

In particular, combinations of different phospholipids have proven to be suitable.

An important aspect of the invention is the choice of polyethylene glycol since it has been found that the desired suspension stability is only achieved when higher molecular weight polyethylene glycol is used. Particularly reproducible results are obtained when exclusively solid polyethylene glycols having a molecular weight of 1,000 to 6,000 are used. Preferably, polyethylene glycols of molecular weight are used to produce suspensions containing in particular 4-hydroxy-4-androstene-3,17-dione. The use of these solid polyethylene glycols results in a slight increase in the viscosity of the suspending medium, which improves the suspendability of the active ingredient, and moreover, these polyethylene glycols serve as a scaffolding agent for subsequent freeze-drying. On the market are solid polyethylene glycols having molecular weights are referred to under various names, for example under the designation Polyglycol or Carbowax 1000 1500 ^'R \ 3000' ^R ', 4000 or 6000 ^.

One of ordinary skill in the art could not assume that in addition to the above ratio of the combination of phospholipids and polyethylene glycol, the average molecular weight would have such a significant effect on the physical stability of the suspension.

As already mentioned, a combination of both excipients results in a suspension medium with a slightly increased viscosity, in which the active substance of different crystalline structure and concentration is homogeneously dispersible. A particular advantage of this suspension medium is the fact that the suspensions obtained can be freeze-dried, whereby any existing problems, i.e. stability-related problems, can be minimized. Lyophilization is carried out, for example, by filling a certain amount of suspension produced, usually in a suitable container, such as a puncture glass ampoule, then freezing at about -40 ° C and then lyophilizing at 20 to 60 Pa at a final temperature of about 25-35 ° C.

The dry substance thus formed is reconstituted as a suspension before use, for example before injection in physiological solutions or also in physiological solutions of sugars, such as glucose solution or distilled water. Short shaking again results in a homogeneous suspension which, due to its phospholipid content, does not adhere to the container wall and can be removed easily and completely by syringe.

Surprisingly, for the first time, freeze-drying of a dry substance and reconstitutable suspensions containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-diones, which are physically stable and suitable for injection, have been successfully produced.

Accordingly, the present invention also provides for the preparation of a stable suspension for injection suitable for particular use as an injectable preparation. Thus, stable suspensions, especially for injection purposes, containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-dione, but preferably 4-hydroxy-4-androstene-3,17-dione, can be used as ready - to - use preparations ¹ .

Suspensions for use as orally or injectable preparations may, if desired, be administered by known methods in conjunction with conventional pharmaceutical ingredients, conventional carriers and / or flavorants and / or preservatives and / or antioxidants orally or parenterally .

For the preparation of dry substances and reconstitutable suspensions therefrom, suitable for oral or injectable preparations, between 10 and 1000 mg, preferably between 50 and 250 mg, of an active compound of the formula I in which:

O

STEED

R represents a hydrogen atom or an acyl group containing 2 to 12 carbon atoms.

Suitable acyl groups are those which are commonly used in steroid chemistry, in particular acetyl, heptanoyl or benzoyl.

The active compound of the formula I is preferably used in micronized form.

When the active ingredient is used in micronized form, the particles are in the range of from 2 to 20 microns, but preferably with an average particle size of from 3 to 6 microns. The micronization of the active compound is carried out by means of an ultrasonic disintegrator (for example Branson Sonifier) by known methods (J. Pharm. Sci. 53 (9), 1040-45 (1985)).

The active compound of the formula I is preferably used in micronized form with a particle size of 2 to 20 µm, preferably of an average particle size of 3 to 6 µm.

The compounds of formula (1) are already known. They are described as aromatase inhibitors that inhibit the conversion of 4-androstene-3,17-dione to estrogens on human placental microsomes (cf. Endocrinology 100 0-9773 »1684-1695 and U.S. Pat. No. 4,235,893). These compounds may inhibit the development of estrogen-mediated breast tumors in rats.

Furthermore, DE-OS 3 339 295 describes the use of compounds of the formula I for the prophylaxis and therapy of prostate hyperplasia.

The following examples illustrate the invention but do not limit it in any way

Example 1

Composition of the dry filling of the puncture ampoule (dry filling for vials):

4-hydroxy-4-androstene-3,17-dione, micronized 250 mg

Epicuron 170 * ^R '5 mg

Epicuron 200 ^R 45 mg

Carbowax 4000 * ^R '150 mg thiomersal 0.05 mg

The production is carried out under a stream of nitrogen and under antimicrobial conditions. Up to 6.407 g (R) of filtered and sterilized suspension medium (17.0 mg Epicuron 170 152.5 mg

Epicuron 200?, 508.5 mg of polyethylene glycol 4000? ^R 'is added 847.5 mg of micronized sterile 4-hydroxy-4-androstene-3,17-idone and suspended. The suspension is then admixed with IR)

2.746 g by filtration of sterilized thiomersal solution (0.170 mg thiomersal ¹ ). The pH of the suspension is adjusted to 5.0-6.0 by adding about 1 drop by filtering sterilized 0.1N sodium hydroxide solution. Using an ultrasonic disintegrator, the suspension is homogenized (desagglomerated). The suspension is then filled in 2.95 g into 6 ml puncture vials. The thus-filled suspension in the puncture ampoules is frozen at -40 ° C in a freezer and then freeze-dried at 40 Pa and a final temperature of +35 ° C.

Composition of the device used for reconstitution:

sodium chloride 18 mg water up to 2 ml

To prepare a ready-to-use suspension, add 2.0 ml of 0.9% sodium chloride solution to the dry-substance vial using a syringe. After shaking briefly, a homogeneous suspension is obtained which contains 250 mg of 4-hydroxy-4-androstene-3,17-dione.

Example 2

Composition of the dry filling of the puncture ampoule (dry filling for vials):

4-hydroxy-4-androstene-3,17-dione,

micronized 250.00 mg Epikuron 200 50.00 mg Carbowax 4,000 ' ^R ' 75,00 mg thiomersal 0.05 mg

ascrobyl palmitate 0.005 mg

Using the appropriate amounts, the procedure was as in Example 1.

Composition of the device used for reconstitution:

water for injection 2 ml

Example 3

Ingredients of dry filling ampoule:

4-hydroxy-4-androstene-3,17-dione,

micronized 500 mg Epikuron 170 ^(R) 50 mg Polyglycol 3 000 ^(R) 100 mg thiomersal 0.05 mg tocopherol 0.0 6 mg For use accordingly otherwise the same amounts are used as in the above

in example 1.

Composition of the device used for reconstitution:

sodium chloride 22.5 mg water for injections up to 2.5 ml

Example 4

Composition of the dry filling of the puncture ampoule (dry filling for vials):

4-hydroxy-4-androstene-3,17-dione, micronized (R)

Epikuron 170

000 mg 50 mg

Epicuron 200 ^(R) polyethylene glycol thlomersal tocopherol mg 300 mg

0.05 mg 0.12 mg

Otherwise, using the appropriate amounts, the same procedure as described in Example 1 is followed.

Composition of the device used for reconstitution:

glucose

250.0 mg water for injections up to 5 ml

Example 5

Preparation of microcrystals:

250 mg of 4-hydroxy-4-androstene-3,17-dione are dissolved in 7.5 ml of acetone. This solution is mixed with 75 ml of water in an ultrasonic disintegrator. The precipitated microcrystals of the active substance, i.e. 4-hydroxy-4-androstene-3,17-dione, are separated by filtration and washed twice with 10 ml of water on the filter. The washed microcrystals are dried at a temperature of 40 ° C and at a pressure higher than 10,000 Pa.

Claims (9)

SUBJECT OF THE INVENTION Process for the preparation of dry substances obtained by lyophilization, suitable for the preparation of stable suspensions containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-diones, characterized in that 4-hydroxy- or 4-acyloxy is used. The 4-androstene-3,17-diones are suspended in the presence of a combination consisting of at least one phospholipid and at least one polyethylene glycol in a ratio of 1: 1 to 1:10 as a wetting agent and as a viscosity enhancing agent of the suspension composition in the aqueous suspension composition and the suspension obtained. lyophilize. 2. A process for the preparation of dry substances containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-diones according to claim 1, characterized in that a combination of a wetting agent and a viscosity enhancing agent is used in combination. consisting of at least one phospholipid and at least one polyethylene glycol in a ratio of 1: 1 to 1: 5. 3. A process according to claim 1, wherein the combination of at least one phospholipid and at least one polyethylene glycol in a ratio of 1: 1 to 1: 3 is used as a wetting agent and as a viscosity enhancer. 4. A process according to any one of claims 1 to 3, wherein the polyethylene glycol is a solid polyethylene glycol. 5. A process according to claim 1, wherein the polyethylene glycol is a solid polyethylene glycol having a molecular weight of 1,000 to 6,000. 6. A process for the preparation of dry substances containing 4-hydroxy-4-androstene-3,17-dione according to claims 1 to 3, wherein the polyethylene glycol is a solid polyethylene glycol having a molecular weight of 3,000 to 4,000. 7. A process according to claim 1, wherein the 4-hydroxy or 4-acyloxy-4-androstene-3,17-dione is used in the micronized state. A process for the preparation of dry matter containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-dione in micronized form, having a particle size of 2 to 20 pan, characterized in that the 4-hydroxy or -4- acyloxy-4-androstene-3,17-diones micronize. A process for the preparation of dry matter containing 4-hydroxy- or 4-acyloxy-4-androstene-3,17-dione in micronized form, having a particle size of 3 to 6 µm, characterized in that 4-hydroxy or 4- acyloxy-4-androstene-3,17-diones micronize.