CZ21562U1 - Tibolone composition with defined particle size - Google Patents

Description

Technical field

The present invention describes a pharmaceutical composition comprising (7a, 17a) -17-hydroxy-7-methyl-19-nor-17-pregn-5 (10) -en-20-yn-3-one (tibolone) as the active ingredient. The desired dissolution profile of the active ingredient is achieved using tibolone (Form I) with a defined particle size distribution.

BACKGROUND OF THE INVENTION

The active ingredient (7a, 17a) -17-hydroxy-7-methyl-19-nor-17-pregn-5 (10) -en-20-yn-3-one (tibolone) has been described, e.g., in U.S. Pat. 340 279 and US 4 701 450. It also has estrogenic, progestagenic and androgenic properties and belongs to a group of drugs called hormone replacement therapy. These drugs are used in menopausal women, relieve the symptoms associated with menopause, and stop the bone loss process due to a decrease in estrogen levels in the female body (see, e.g., US 5,037,817 and WO 98/47517).

In recent years, the metabolism of tibolone has been shown to be quite complicated and several metabolites are active in addition to tibolone. It is all the more difficult to determine in advance whether two tibolone-containing products are bioequivalent to each other or not.

For the preparation of the final tibolone dosage form, well-described wet granulation, dry granulation or direct mixing techniques can be used. A critical parameter for all of the aforementioned methods of preparation is the release of the active ingredient from the final dosage form (dissolution), which is directly related to the bioavailability of the drug (see, e.g., EP 1 444 247 B1 and WO 98/47517).

The dissolution can be influenced by selecting suitable excipients and adjusting the parameters of the active ingredient.

According to EP 0 389 035 B1 tibolone exists in two polymorphic forms. According to this document, the use of tibolone as a mixture of both polymorphic forms (called "polymorphic tibolone") in a single dosage form is very problematic compared to the use of pure crystalline forms. Differences in physicochemical properties cause, for example, differences in the rate of release of the active substance from the dosage form.

A solution to the above problem is described in EP 1 499 278 B1. It follows that in order to ensure the same degree of bioavailability when using 'polymorph tibolone' as a commercially available Livial® drug, the mean particle size of 'polymorph tibolone' must be less than 22.8 µm, preferably less than 22 µm. pm.

The present invention relates to a pharmaceutical composition for oral use which comprises substantially pure crystalline tibolone Form I and which can be guaranteed to release 75% tibolone within 45 min.

The essence of the technical solution

The present invention provides a stable pharmaceutical composition of crystalline tibolone Form I which provides a reproducible release profile of the active ingredient. This composition can guarantee the release of 75% tibolone within 45 min. Surprisingly, it has been found that achieving a reproducible and satisfactory dissolution profile even when using a pure crystalline form (Form I), depending on the particle size, not only the mean particle size, which must be equal to or less than 14 µm, but also the distribution profile particles (see Fig. 1).

The composition of the present invention comprises crystalline tibolone Form I with a mean particle size of less than or equal to 14 µm and with at least 30% of particles less than 10 µm, and excipients.

-1GB 21562 Ul

A preferred solution is a composition comprising crystalline tibolone Form I with a mean particle size of less than or equal to 14 gm and with at least 45% of particles less than 10 gm, and an excipient.

Well-described wet granulation, dry granulation or direct mixing techniques can be used to prepare the composition.

A preferred embodiment of the invention is a tablet, preferably made by direct mixing technology. Using this technology, the crystalline form of tibolone (Form I) is maintained in the final dosage form. Direct mixing technology is particularly advantageous due to the time and energy demands of the process and the relative simplicity of execution.

The excipients in the preparation of the pharmaceutical composition can be fillers, binders, stabilizers, glidants, lubricants, disintegrants and optionally colorants. Various types of lactose, purified cellulose (Avicel®), starch and its derivatives, or mixtures thereof, can be used as fillers. When using wet granulation technology, substituted cellulose, polyvinylpyrrolidone (e.g.

Kolidone (K30) and various forms of treated gelatin, or mixtures thereof. In the present invention, stabilizing agents fulfill the function of an antioxidant. Ascorbyl palmitate can be used. Glidants such as colloidal silicon dioxide and lubricants such as magnesium stearate, talc and optionally hydrogenated vegetable oils can be added to the composition to improve flow properties and reduce the adhesion of the material to the surface of the production equipment.

In a preferred embodiment, the tablet comprises 0.5 to 5 wt. % of tibolone (Form Ϊ) with a mean particle size of less than or equal to 14 μπι and with at least 30% of particles less than 10 gm, 85 to 98% by weight % of one or more fillers, 0 to 5 wt. % of one or more stabilizers and 0 to 5 wt. % of one or more lubricants and / or glidants.

The optimum composition of the tablet dosage form of the present invention is as follows: 2.5 wt. % of tibolone (Form I) with a mean particle size of less than or equal to 14 gm and 30% of smaller particles

10 gm, 74.5 wt. % lactose monohydrate for direct tabletting, 12.5 wt. % micronized lactose monohydrate, 9.5 wt. % potato starch, 0.5 wt. % ascorbyl palmitate and 0.5 wt. % magnesium stearate.

In preparing such tablets, the active ingredient was homogenized with potato starch, ascorbyl palmitate and lactose monohydrate. The resulting mixture was then tabletted on a rotary tablet machine after subsequent homogenization with magnesium stearate. The process chosen ensures reproducibility of the manufacturing process and provides a solid dosage form with the desired dissolution profile and stability.

The dependence of drug release rate on the particle size of the drug used was studied by a detailed comparison of the dissolution profiles of the individual formulations.

It has been shown that using the direct mixing technology of the present invention, a reproducible dissolution profile of the final dosage form can be achieved (75% of the declared amount of tibolone is released within 45 min) using an active substance with a mean particle size equal to or less than 14 μπι less than 10 gm at least 30%.

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1: Dependence of dissolution of the final dosage form on the proportion of active agent particles smaller than 10 gm.

Giant. 2: Particle size distribution of the active substance.

Examples

Example 1: Composition of the dosage form:

(7α, 17a) -17-hydroxy-7-methyl-19-nor-17-pregn-5 (10) -en-20-yn-3-one (tibolone) active ingredient

Lactose monohydrate - filler

-2EN 21562 Ul

Potato starch - filler Askorbyl palmitate - stabilizing agent Magnesium stearate - lubricant

The active ingredient was homogenized with potato starch, ascorbyl palmitate and lactose monohydrate. After subsequent homogenization with magnesium stearate, the resulting mixture was tabletted on a rotary tabletting machine. The process chosen ensures reproducibility of the manufacturing process and provides a solid dosage form with the desired dissolution profile and stability.

Example 2: Dissolution Method

Equipment: equipment for dissolution testing according to Ph. Eur. (paddles) io Dissolution medium: phosphate buffer pH 4.5 + 0.05% Tween 80

Volume; 900 ml Temperature: (37 ± 0.5) ° C Speed: 100 rpm Sampling time; 45 min

Sample volume: 5 ml

Procedure: 1 tablet was placed in each dissolution vessel and a dissolution test was performed under the conditions described above. At regular intervals a 5 ml sample was taken and undissolved particles were removed by centrifugation for 10 min at 4000 rpm. Pure supernatant was used to determine the dissolved tibolone content by HPLC.

Evaluation:

Level Number of tablets tested Acceptance criteria Si 6 Each unit contains min. Q + 5%. s ₂ 6 The average value of 12 units (Si + S ₂ ) is equal to or greater than Q, and no unit contains less than Q -15%.

Q represents 75% of the declared amount of tibolone per tablet.

Examples 3 to 8:

Tablets were prepared according to the procedure described in Example 1. The active ingredient used was tibolone crystalline form I of various particle sizes. The composition of the dosage form and the particle size distribution of the active ingredient are shown in the following tables.

Ingredients:

unit dosage form contains:

Starting materials Weight (mg) Active substance Tibolon 1 2,5 Excipients Lactose monohydrate (micronized) 12.5 Lactose monohydrate (for direct tabletting) 74.5 Potato starch 9.5 Askorbyl palmitate 0.5 Magnesium stearate _

Total weight of 1 unit dosage form: 100 mg

Claims (9)

A pharmaceutical composition for oral administration which, after 45 minutes, releases at least 75% of the tibolone contained in the composition, wherein the composition comprises: 5 tibolone in crystalline form I, the mean particle size of which is equal to or less than 14 gm and at least 30% of the particles are less than 10 gm, and the excipients. 2. A pharmaceutical composition for oral administration which, after 45 minutes, releases at least 75% of the tibolone contained in the composition, wherein the composition comprises tibolone in crystalline form I having a mean particle size equal to or less than 14 gm and at least 45 gm. % of the particles is less than 10 gm, and excipients. Pharmaceutical composition according to claim 1 or 2, characterized in that the auxiliaries are one or more substances from the group of fillers, stabilizers, lubricants and / or glidants, and optionally one or more substances from the group of binders, disintegrants and dyes. Pharmaceutical composition according to claim 3, characterized in that it is preferably 15 in the form of a tablet. Pharmaceutical composition according to claim 4, characterized in that it contains 0.5 to 5 wt. % tibolone, 85 to 98 wt. % of one or more fillers, 0 to 5 wt. % of one or more stabilizers and 0 to 5 wt. % of one or more lubricants and / or glidants. 20 May Pharmaceutical composition according to claim 5, characterized in that the filler used is lactose monohydrate, purified cellulose, starches and derivatives thereof, or a combination of two or more of these fillers. Pharmaceutical composition according to claim 6, characterized in that the stabilizing agent used is ascorbyl palmitate. 25 Pharmaceutical composition according to claim 7, characterized in that the lubricant used is one or more of magnesium stearate, talc and hydrogenated vegetable oils. Pharmaceutical composition according to claims 1 to 8, characterized in that it contains 2.5 wt. % tibolone, 12.5 wt. % micronized lactose monohydrate, 74.5 wt. % Of lactose monohydrate for direct tabletting, 9.5 wt. % potato starch, 0.5 wt. % ascorbyl palmitate and 0.5 wt. % magnesium stearate.