WO2005084682A1

WO2005084682A1 - Pharmaceutical composition comprising cyclodextrin complex of tibolone

Info

Publication number: WO2005084682A1
Application number: PCT/CZ2004/000012
Authority: WO
Inventors: Tim Van Engelgem; Julie Marechal
Original assignee: Pharmaceutical Services Inc. (Psi Nv.); Zentiva, A. S.
Priority date: 2004-03-08
Filing date: 2004-03-08
Publication date: 2005-09-15

Abstract

A pharmaceutical composition comprising a cyclodextrin complex of (7α, 17α)-17-hydroxy7-methyl-l9-nor-l7-pregn-5(10)-en-20-yn-3-one (Tibolone) and methods for the manufacture thereof.

Description

PHARMACEUTICAL COMPOSITION COMPRISING CYCLODEXTRIN COMPLEX OF TIBOLONE

Technical Field

The present invention relates to pharmaceutical compositions or more particularly to a composition of (7α,17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one.

Background Art

(7α,17α)-17-Hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (Tibolone) is known from the patents US 3,340,279 or US 4,701,450. The active substance is used as a hormone having combined estrogenic, progestagenic effects for treatment of disorders or diseases related to menopause.

A problem associated with Tibolone is that it is particularly sensitive to degradation under certain conditions. The major degradation product is an isomer of Tibolone, i.e. (7α,17α)-17- hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one (Isotibolone). The potential for significant degradation of Tibolone makes it difficult to formulate and provide a pharmaceutical composition with acceptable storage life time for a market product.

A pharmaceutical composition comprising crystalline Tibolone was first described in EP 389035. The tablet contained 2.5 mg Tibolone, 10 mg starch, 0.2 mg ascorbylpalmitate, 0.5 mg magnesium stearate and lactose up to 100 mg.

According to patent application WO 98/47517, the above mentioned formulation is more stable under a humid atmosphere (e.g. 50 to 70% relative humidity) than under a relatively dry atmosphere (e.g. 45% relative humidity or below that). According to the patent application, stability of the preparation would improve if the starch content rose to 50 or better to 90% by weight. A problem was still, according to the EP 1121375, in the fact that the Isotibolone content increased during the dosage unit preparation. According to example 2 of the cited patent, Tibolone containing less than 0.1% Isotibolone has been prepared. However, the content of Isotibolone in the freshly prepared pharmaceutical formulation (example 4) was already 0.4% and 1.6 % after 6 months.

Now, it has been found that if Tibolone cyclodextrin composition is used for the pharmaceutical composition, the rate of conversion to undesired Isotibolone considerably decreases.

Disclosure of Invention

The subject of this invention is therefore a pharmaceutical composition comprising a cyclodextrin complex of (7α,17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3- one of Formula I

Formula I

Among different types of cyclodextrin or its derivatives, β-cyclodextrin appeared as the most convenient one. Cyclodextrin may be present in the composition in the ratio to tibolone of about 5 : 1 to 1000 : 1. A preferred cyclodextrin : tibolone weight ratio is about 20 : 1 to 200 : 1. A preferred Tibolone concentration is 0.5 to 2% by weight.

The pharmaceutical composition can further contain fillers, disintegrants, binders and lubricants. Suitable filers are for example lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose or its derivatives (microcrystalline cellulose), calcium sulphate, xylitol and lactitol. Suitable binders include for example polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum, wax binders, microcrystalline cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate. Suitable disintegrants include for example crosscarmellόse sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropylcelulose and suitable lubricants include for example magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate.

Additional conventional excipients which may be added include preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherants or glidants.

It has been found that lactose, especially lactose monohydrate, further improves stability of the preparation. Preferable lactose contents in the composition are about 3 to 10% by weight.

A second embodiment of this invention is a method of preparing the pharmaceutical composition. A preferred method is formation of the complex in an aqueous suspension of the cyclodextrin and Tibolone. The crucial parameter of this method is time of mixing, which is about 2 to 24 hours depending on the suspension concentration and the stirrer rate. The most preferred reaction duration useful for industrial applications is 4 to 6 hours.

A second method comprises dissolving Tibolone in an organic solvent and precipitation of the complex by an aqueous solution or suspension of cyclodextrin. For this procedure, organic solvents in which tibolone is well soluble can be used. Examples of these solvents have been given in EP 389 035, where they were used for crystallization of Tibolone. Preferred solvents are lower ketones (C3 -C5) or lower alcohols (C2 to C4). The most preferred solvent is acetone.

A third embodiment of this invention is a method of preventing Tibolone conversion to its isomer Isotibolone in the pharmaceutical preparation, comprising Tibolon complexation with cyclodextrin, mixing with at least one pharmaceutical ingredient and working the mixture out to form the pharmaceutical composition. As demonstrated in example 6, it has been surprisingly found that the conversion rate decreased of about 50% when Tibolone cyclodextrin complex was used.

The following examples show a few types of applications of the invention, however, without limiting the scope of the invention.

Example 1 Manufacturing process of 10 000 tablet cores Tibolone 2.5 mg, having the following composition:

Procedure: Step I: Sieving of materials: All the materials are rechecked for identity and correct quantity and then sieved through # 60 mesh individually and collect in separate polythene bag lined HDPE drums and labelled properly. Step II: Dry mixing of Tibolone and Betadex

Transfer one kg of Betadex and 25 g of Tibolone into octagonal blender and mix well for about 5 mins and unload the blended mixture in a double polythene lined HDPE drum. Step III: Complexation of Tibolone with β-cyclodextrin:

III A) Take about 1.0L of purified water in a clean and sanitized S.S.Tank fitted with a stirrer and slowly add the above blended mixture of Tibolone and betadex with continuous stirring till all the material is added and continue stirring for 6 hrs to ensure complete complex formation.

Step rV: Granulation

Load the remaining amount of Betadex i.e 1 kg and Lactose monohydrate into the mass mixer and granulate with the above mentioned complex of tibolone and betadex and use aerosil 200 to absorb the excess of moisture and then sieve down through # 16 mesh and then dry using a Fluid bed dryer at 60 °C till the moisture content brought down to below 10%

Step V: Sifting & Sieving:

Remove the dried granules from the FBD and pass through a # 20 mesh. Collect the undersized granules in a polythene bag lined HDPE drum. Size reduce the granules left on the 20 mesh by passing through a multimill fitted with 0.5 mm mesh and finally sieve through # 20 mesh.

Step VI: Sieving of Lubricants and Disintegrants: Sift the following items through # 60 mesh and collect in polythene bag lined HDPE drums and load into double cone blender

Talc: 20 g s

Magnesium stearate: 20 gms

Sodium Starch Glycolate: 135 gms

Step VI: Lubrication

Load the above mentioned materials and dried # 20 mesh granules in a double cone blender and blend for 3-5 mins. Take samples from 5 different places to evaluate the percentage of the drug in blend. Based on assay content of tibolone found in sample analyzed the exact time required for blending is determined. Step VII: Compression

Unload the lubricated granulation into Polythene bag lined HDPE drums, weighed, properly labelled, and transfer to compression zone for compression into tablets.

A Tablet Press fitted with 8.50 mm concave punches and Compress the granulation at the following specifications:

Average weight: 2.60 gms /10 tablets

Diameter: 8.50 mm + 0.2 mm

Thickness: 4.50 mm + 0.2 mm Hardness: 2-6 kg/cm²

Friability: NMT 1.0%

Disintegration time: NMT 15 mins

Dissolution: NLT 80% in 45 mins

Control the weight, hardness and thickness of the cores of tablets every 30 mins.

Example 2

Complexation of Tibolone with β-cyclodextrin

2000 gms of β-cyclodextrin were poured to about 4900 gms of purified water in a tank fitted with a mechanical stirrer stirring till all the material is added and stirring was continued for another 10 mins which leads to formation of a slurry of β-cyclodextrin. 25 gms of solid Tibolone (crystalline form I) were added to the solution with continuous stirring till complete material is added to it and the container containing Tibolone was rinsed with water. Samples of the slurry were taken in every hour. The samples were then dried in a laboratory hot air oven at 60 °C until a dry mass was obtained. The mass was subsequently milled and passed through # 100 mesh. The dried complex sample was weighed and transferred into dissolution vessels containing 900 ml of 1% Sodium lauryl sulphate in purified water. Tibolone in solution was determined after 45 minutes.

Percentages of dissolved Tibolone are summarized in the following table.

To accomplish Tibolone complexation in water 4 hours of mixing are needed.

Example 3 Tibolone β-cyclodextrin complex ratio 1 : 20 (by weight)

250 mg of Tibolone form II and 5 g β-cyclodextrin were mixed and sieved through # 60 mesh. The mixture was further shaken in an angular vessel for 5 minutes. The solid mixture was being poured to the flask with 5 ml distilled water for 30 minutes. Suspension was mixed by magnetic stirrer for further 6 hours. The complex was filtered and dried at 50 °C and 20 torr until the humidity was less then 8%. The loss of crystalline form of tibolone has been approved by infrared spectoroscopy. The FTIR spectrogram is included in Fig 1. Two bands exhibiting tibolone form II at 3265 and 3492 cm^'1 disappeared after the complex had been formed.

Example 4 Other type of Tibolone complexation

120 gms of β-cyclodextrin were poured into about 500 gms of purified water in a tank fitted with a mechanical stirrer stirring till all the material is added and stirring was continued for another 10 mins which leads to formation of a slurry of β-cyclodextrin. In a separate beaker, 2.5 gms of Tibolone were dissolved in 100 gms of acetone. The acetone solution was slowly added to cyclodextrin slurry with continuous stirring. The stirring is continued until the pasty complex is formed.

The resulted complex was used for the preparation of tablets having the following composition:

Example 5 Isotibolone impurity content in the tablets prepared according to example 1.

The content of the most relevant impurity Isotibolone has been determined in three batches:

Isotibolone content is lower than that referred to in the formulation of EP 1121375 which was 0.4%.

Example 6 Tibolone conversion to isotibolone The isomerisation rate was measured in 900 ml 0.1 N HCl, in which 2.5 mg of tibolone in the crystalline form I, or the cyclodextrin complex prepared according to example 1 (202.5 mg of the complex) had been dissolved. The isotibolone content was measured using UV light at 210 nm where the ratio of isotibolone and tibolone responses is 72. Conversion of Tibolone to isotibolone (percentage of the starting Tibolone) is summarized in the following table:

(*) CD standing for cyclodextrin One can conclude that the rate of conversion to isotibolone decreased by about 50% when the CD complex was used.

Claims

1. A pharmaceutical composition comprising a cyclodextrin complex of (7α, 1 la)- 17- hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one, i. e. Tibolone, of Formula I

Formula I and at least one further pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1 comprising beta-cyclodextrin and Tibolone in the weight ratio of from about 5 : 1 to about 1000 : 1.

3. The pharmaceutical composition according to claim 2 comprising the ratio of betacyclodextrin and Tibolone from about 20 : 1 to about 200 : 1.

4. The pharmaceutical composition according to any of the preceding claims comprising 0.5 to 2% by weight of Tibolone.

5. The pharmaceutical composition according to claim 4 comprising 3 to 10% by weight of lactose as the further pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 4 further comprising additional conventional excipients.

7. A method for the manufacture of the pharmaceutical composition according to any of the preceding claims comprising mixing cyclodextrin and Tibolone with water and separating the complex, optionally followed by addition of pharmaceutically acceptable excipients to the separated complex.

8. The method according to claim 7 wherein cyclodextrin is beta-cyclodextrin.

9. The method according to claim 8 wherein the weight ratio of beta-cyclodextrin to Tibolone is about 5 : 1 to about 1000 : 1.

10. The method according to claim 9 wherein the weight ratio of beta-cyclodextrin to Tibolone is about 20 : 1 to about 200 : 1.

11. The method according to claim 7 comprising mixing for about 2 to about 24 hours.

12. The method according to claim 11 comprising mixing for about 4 to about 6 hours.

13. A method for the manufacture of the pharmaceutical composition according to any of claims 1 to 6, comprising dissolution of Tibolone in an organic solvent followed by precipitation of the complex by adding a suspension or solution of cyclodextrin in water, and optionally followed by addition of pharmaceutically acceptable excipients to the precipitated complex.

14. The method according to claim 13 wherein cyclodextrin is beta-cyclodextrin.

15. The method according to claim 14 wherein the weight ratio of beta-cyclodextrin to Tibolone is about 5 : 1 to about 1000 : 1.

16. The method according to claim 15 wherein the weight ratio of beta-cyclodextrin to Tibolone is about 20 : 1 to about 200 : 1.

17. The method according to claim 13 characterized by that the organic solvent is acetone.

18. A method of preventing conversion of Tibolone to its isomer Isotibolone in a pharmaceutical composition, comprising complexing Tibolone with cyclodextrin, mixing with at least one pharmaceutically acceptable excipient and working the mixture out to form a pharmaceutical composition.

19. The method according to claim 18, wherein complexing Tibolone with cyclodextrin is made by a method according to any of claims 7 to 17.