WO2006097938A1

WO2006097938A1 - Stable liquid suspension formulation comprising tibolone and process for producing the same

Info

Publication number: WO2006097938A1
Application number: PCT/IN2005/000084
Authority: WO
Inventors: Venkat Subramanian Iyer; Shivaraj Basavaraj Katageri; Suresh Venkatram; Prashant Kumar Chakrabarti
Original assignee: Strides Arcolab Limited
Priority date: 2005-03-16
Filing date: 2005-03-16
Publication date: 2006-09-21

Abstract

Disclosed herein is a stable, liquid suspension formulation of Tibolone, encapsulated into soft gelatin capsules and process for preparing the same. The formulation disclosed herein employing a suitable matrix comprises combination of antioxidants, a stabilizer, viscosity imparting agent, purified water and vehicle to enhance the stability of formulation.

Description

STABLE LIQUID SUSPENSION FORMULATION COMPRISING TIBOLONE AND PROCESS FOR PRODUCING THE SAME

Field of the Invention In general, this invention relates to stable pharmaceutical formulations comprising a synthetic steroid. More specifically, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, this invention describes a stable, liquid suspension formulation of Tibolone employing a suitable matrix, encapsulated into soft gelatin capsules and process for preparing the same.

Background of the Invention

The lack of hormone estrogen in women at menopause can cause problems for them. The symptoms usually include hot flushes, night sweats, insomnia, mood swings, vaginal dryness, fatigue and tiredness, poor memory and concentration, poor libido. There is also an increased risk of osteoporosis and bone fractures occurring after the menopause. Being a natural event that every woman goes through, it is not possible to prevent the menopause. The mainstay of treatment for these troublesome menopausal symptoms has been the 'Hormone Replacement Therapy' (HRT).

Though hormone replacement therapy (HRT) has significant long-term benefits, like, some protection against cardiovascular disease, prevention of bone loss, decrease in incidence of Alzheimer's disease, protection against colorectal cancer, patient adherence to the regimens has been poor. One of the main reasons for this non- compliance is the return of monthly bleeding.

The success key to any therapy is adherence to the prescribed therapy. Therapies that are not associated with bleeding may be the way forward to a compliant regimen. Tibolone is one such treatment that holds promise.

Tibolone is a synthetic steroid that has estrogenic, progestogenic, and androgenic properties. Structurally, it is related to 19-nortestosterone derivatives such as norethynodrel and norethisterone and is chemically (7α, 17α)-17-hydroxy-7-methyl-19- nor-17-pregn-5(10)-en-20-yn-3-one. Tibolone has shown efficacy in treating climacteric symptoms resulting from natural or surgical menopause and in the prevention of postmenopausal osteoporosis without stimulation of the endometrium or breast.

Along with an effective and desirable therapeutic agent, a suitable dosage form is the key to a successful therapeutic regimen. It has been found that Tibolone is polymorphous in nature. The differences in crystal structure may lead to a difference in physico-chemical properties such as stability, melting point, rate of dissolution, analytical data, which are influenced by the crystal form present in the polymorphous compound. The conversion of one crystal form to another during storage makes the formulation instable. The stability problem associated with Tibolone formulations is mainly due to conversion of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en- 20-yn-3-one [Δ⁵⁽¹⁰⁾] to (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-ρregn-4-en-20-yn-3- one [Δ⁴] (herein after also denoted as 4-impurity) during manufacturing and also during storage.

Various attempts have been done to overcome the stability problem of the Tibolone formulation. The known arts differ from each other with respect to the different formulations and processes thereof.

PCT International Publication No. WO 03/032924 A2 to Brennan, et al., discloses the inclusion of pH adjusting agents to increase the stability of oestrene derivatives such as Tibolone formulations. The dosage unit forms exemplified in this patent include 2.5 mg of Tibolone in a tablet form or 100 mg of a pharmaceutically acceptable powder in capsules. Though, this patent indicates that the composition of the invention may be presented as discrete units such as capsules, caplets, gelcaps, sachets, pills or tablets each containing predetermined amount of the active ingredient as a powder or granules; as a solution or suspension in an aqueous liquid or a non aqueous liquid or as an oil in water liquid emulsion or a water in oil emulsion and as a bolus, there is no specific disclosure on components of suspension/solution suitable for encapsulation into soft gelatin capsules which is a critical stage in development of the Tibolone in Soft gelatin capsules. European Patent No. 159739 to Kelder, et al., discloses a number of tablet formulations of Tibolone containing conventional tablet excipients. However, this patent discloses the immunomodulating properties of Tibolone and does not address the stability problems associated with Tibolone formulations.

European Patent No. 389035 to Gerard, et al., describes the production of two pure polymorphic forms (Form I & II) of Tibolone. This patent further postulates that polymorph I is appreciably more stable than the polymorph II. Allegedly more stable preparations comprising a crystalline pure or virtually pure form which is completely or virtually completely free from the other crystalline form are disclosed and are presently marketed under the trademark LIVIAL hi UK in tablet form.

PCT International Publication No. WO 98/47517 to Haan, et al., describes the use of a high percentage (above 10%) of starch in a Tibolone formulation with an improved stability, particularly under relatively dry storage conditions or with lower doses of Tibolone. The patent discloses the improved stability of the Tibolone formulation as the percentage of starch is increased.

United States Patent No. 6,514,958 and United States Patent No. 6,399,594 to de Haan, et al., disclose a stabilized pharmaceutical dosage unit comprising Tibolone, such as a tablet or a capsule, comprising an effective amount of Tibolone, in an amount of from

0.1% to 10% by weight of the dosage unit, and a pharmaceutically acceptable carrier, the carrier comprising a water-insoluble starch product in an amount at least 40% by weight of the dosage unit, where in the dosage unit is contained in a humid atmosphere of 50 to 70% RH until administration.

United States Patent Application No. 20020032171 and United States Patent No. 6267985 to Chen, et al., relates to pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents. This patent discloses the inclusion of a triglyceride and a carrier, where the carrier is formed from a combination of at least two surfactants, at least one of which is hydrophilic. Upon dilution with an aqueous solvent, the composition forms a clear, aqueous dispersion of the triglyceride and surfactants. A number of therapeutic agents that are suitable for use in the composition and methods of this invention are disclosed. This patent is not specific to either any particular drug or any particular dosage form.

PCT International Publication No. WO 01/54699 to Labrie Fernand, teaches novel methods for reduction or elimination of hot flashes and menopausal symptoms. This invention provides the use of an estrogen selected from the group consisting of 17p estradiol, 17p estradiol esters, 17α estradiol, 17α estradiol esters, dienestrol, menstranol, Tibolone, etc., in combination with a selective estrogen receptor modulator (SERM).

United States Patent No. 6,096,338 to Lacy, et al., discloses a carrier system for a hydrophobic drug, which comprises of digestible oil, a hydrophilic surfactant and a lipophilic surfactant.

United States Patent No. 4,727,064 to Pitha, et al., discloses use of Cyclodextrin complex to improve the dissolution properties of the drugs and hence its absoption by the body. The composition claimed in this invention pertains to tablet, liquid and semi liquid form. There is no specific disclosure on use of cyclodextrin to stabilize Tibolone cited in this prior art. No claims with respect to soft gelatin capsules cited in this particular invention.

United Staes Patent No. 4,596,795 to Pitha, et. al., discloses a method of treating using sex hormone, which comprises of injecting by the buccal route a regimen of 0.1 - 2.5mg per diem of a compound consisting of testosterone, progesterone and estradiol as an inclusion complex with poly-beta-cyclodextrin or hydroxypropyl betacyclodextrin. There is no specific disclosure or claims made on stabilization of Tibolone in soft gelatin capsules.

Although the approaches found in the known art may, to some extent improve some of the problems associated with Tibolone formulations including the problems of stability, there remains a need to identify compositions and methods better suited to arrive to stable as well as liquid form of Tibolone suitable for encapsulation into soft gelatin capsules. In the present invention, there are provided suitable matrix systems to overcome the stability problems associated with Tibolone formulations and also provided is a stable liquid suspension formulation of Tibolone suitable for encapsulation into soft gelatin capsules.

Summary of the Invention

It is a principal aspect of the present invention to provide a stable liquid suspension formulation of Tibolone, wherein the formulation comprising employing a suitable matrix containing synergistic combination of antioxidants, stabilizer, viscosity imparting agent and vehicle to enhance the stability of formulation and encapsulating the same into soft gelatin capsule.

In accordance with one preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone, wherein the formulation includes a Betacyclodextrin as a stabilizer, which is providing the better stability of the formulation by the way of forming complex with Tibolone.

In accordance with another preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone, wherein the formulation includes combination of antioxidants such as Sodium Ascorbate and Ascorbyl Palmitate to avoid conversion of Δ^{5 (10)} to Δ⁴ impurity or other related impurities and enhance stability of the formulation.

In accordance with one other preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone, wherein the formulation includes a viscosity-imparting agent such as Glyceryl monosterate to avoid oil separation and settling of Tibolone in the formulation.

In accordance with yet another preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone, wherein the formulation includes suitable vehicle such as super refined sesame oil, which has low peroxide value. In accordance with yet another preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone encapsulated into a soft gelatin capsule.

In accordance with yet another preferred embodiment, the present invention provides for a stable liquid suspension formulation of Tibolone encapsulated into a soft gelatin capsule, wherein the formulation comprises of about 2% by weight of Tibolone, about 0.5 to 2.0 % by weight of Sodium Ascorbate, about 0.5 to 2.0% by weight of Ascorbyl Palmitate, about 36 to 40% of Betacyclodextrin, about 5 to 10% by weight of Glyceryl monosterate, about 0.5 to 2.0% by weight of Purified water and about 32 to 55.5% by weight of super refined Sesame oil.

In accordance with yet another preferred embodiment, the present invention provides for a stable liquid suspension formulation of Tibolone encapsulated into a soft gelatin capsule, wherein the formulation comprises of about 2% by weight of Tibolone, about 0.5 to 2.0 % by weight of Sodium Ascorbate, about 0.5 to 2.0% by weight of Ascorbyl Palmitate,about 36 to 40% of Hydroxypropyl Betacyclodextrin, about 5 to 10% by weight of Glyceryl monosterate, about 0.5 to 2.0% by weight of Purified Water and about 32 to 55.5% by weight of super refined Sesame oil.

In accordance with yet another preferred embodiment, there is provided a process for producing soft gelatin capsule containing a stable liquid suspension formulation of Tibolone, the process comprising the steps of, preparation of Tibolone - Betacyclodextrin complex by adequate mixing of wet mass of Tibolone & Betacyclodextrin mixture in a high shear mixer & drying further to get dried powder of Tibolone - Betacyclodextrin complex. Further steps include melting of Glyceryl monosterate in super refined sesameoil at 45-50°C , then adding sifted Ascorbyl pamitate &Sodium Ascorbate below 30°C with continuous stirring, followed with addition of purified water with continuous stirring, finally adding the Tibolone- Betacyclodextrin complex with continuous stirring & mixing will be continued till uniform distribution obtained.

In still another preferred embodiment, there is provided a shell composition of soft gelatin capsule comprising of about 44.5% by weight of Gelatin, about 9.3% by weight of Sorbitol Solution, 70% (non-crystallizable), about 14.0% by weight of Glycerin and about 32.2% by weight of Purified water.

In still another preferred embodiment, there is provided a shell composition of soft gelatin capsule comprising of about 44.5% by weight of Gelatin, about 9.3% by weight of Glycerin, about 14.0% by weight of Sorbitol Solution 70% (non-crystallizable) and about 32.2% by weight of Purified water.

In still another preferred embodiment, there is provided a shell composition of soft gelatin capsule comprising of about 44.5% by weight of Gelatin, about 14.0% by weight of Glycerin,, about 9.3% by weight of Sorbitol and Sorbitan esters (Anidrisorb 85/70) and about 32.2% by weight of Purified water.

In still another preferred embodiment, there is provided a shell composition of soft gelatin capsule comprising of about 44.5% by weight of Gelatin, about 25% by weight of Sorbitol Solution, 70% (non-crystallizable) and 30.5% by weight of Purified water.

In still another preferred embodiment, there is provided a shell composition of soft gelatin capsule comprising of about 44.5% by weight of Gelatin, about 25% by weight of Sorbitol & Sorbitan (non-crystallizable) and 33.0% by weight of Purified water.

Brief Description of the Drawing

While the specification concludes with claims particularly pointing out and distinctly claiming the subject matter which is regarded as forming the present invention, it is believed that the invention will be better understood from the following drawing description

Fig.l a graph representation, shows the stability data and comparative evaluation of level of Delta 4 impurity at 40°C/75%RH (after 7days, 14days and 21days)

Detailed Description of the Invention

Embodiments of the present invention disclose a stable liquid suspension formulation of Tibolone, using a suitable matrix system and process for producing such formulation and also soft gelatin capsule which is used to administer such liquid suspension formulation.

Tibolone was found unstable when formulated because Tibolone has tendency to convert into Δ⁴-impurity and other related impurities. Several trials have been taken to arrive at a stable form of Tibolone liquid suspension formulation suitable for encapsulation in soft gelatin capsules. Various systems comprising oils, antioxidants, solubilizers and surfactants in different permutations and combinations have been tried

^• during development of stable form of Tibolone. Different types of ingredients used during development include Betacyclodextrin or other Cyclodextrins, diethylene glycol-mono-ethyl ether, capfylo-caproyl-macrogol glycerides, ethyl alcohol, maisine,

Ascorbyl Palmitate, Citric Acid, Sodium Ascorbate, Sodium Citrate, hydrogenated

, vegetable oil, beeswax, PEG 400, medium chain triglyceride, etc.

It is found that the addition of Betacyclodextrin as a stabilizing agent surprisingly prevent conversion of Tibolone into Δ⁴-impurity and other related impurities by forming a complex with tibolone, thereby avoiding the stability problem and other disadvantages of the conventional formulation.

It is also found that the combination of about 0.5 to 2.0% by weight of Sodium Ascorbate and about 0.5 to 2.0% by weight of Ascorbyl Palmitate in the formulation further improvethe stability of the said formulation. . Also the addition of 0.5 to 2.0% of purified water in suspension of Tibolone contributed for stabilization of Tiblolone in formulation

As Tibolone is present in the liquid suspension formulation, tendency of oil separation and settling of Tibolone has been observed. It is disclosed in the present invention that by adding 5-10% of Glyceryl monosterate in the formulation, the oil separation and settling of Tibolone can be prevented.

Preferred formulations contain Ascorbyl Palmitate used as an antioxidant for drugs unstable to oxygen and used as stabilizer for oils in oral pharmaceutical formulations. It is practically insoluble in water, but soluble in alcohol (A. Wade, P.J.Weller, Hand book of Pharmaceutical Excipients, 2^nd Edition, 19(1994)). Ascorbyl Palmitate has been used to improve the stability of Tibolone in the formulation.

Preferred formulations contain Sodium Ascorbate used as an antioxidant .It occurs as a white or slightly yellow colored, practically odourless, crystalline powder with a pleasant saline taste. (A. Wade, P.J.Weller, Hand book of pharmaceutical Excipients, 2^nd Edition, page no: 431, 19(1994).

Preferred formulations contain Glyceryl monosterate used as a non-ionic emulsifier, stabilizer, emollient and plasticizer in variety of pharmaceutical applications. (A. Wade, P.J.Weller, Hand book of pharmaceutical Excipients, 2^nd Edition, page no: 207, 19(1994). Glyceryl monosterate has been used to improve the stability of the Tibolone in the formulation & also used as viscocity imparting agent in this formulation.

Preferred formulations contain Refined Sesame oil is a clear, pale yellow coloured liquid with a slight, pleasant odour and a bland taste. (A. Wade, P.J.Weller, Hand book of pharmaceutical Excipients, 2^nd Edition, page no: 420, 19(1994). Refined Sesame oil used as a vehicle in the Tibolone formulation.

Preferred ^'formulations contain Cyclodextrins. Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosaccharides derived from starch. Cyclodextrins used to form inclusion complexes with a variety of drug molecules resulting primarily in improvements to dissolution and bioavailability due to enhanced solubility and improved chemical and physical stability. Inclusion complexes have also been used to mask the unpleasant taste of active materials and to convert a liquid substance in to a solid material. Betacyclodextrin is the most commonly used Cyclodextrin although it is the least soluble. Betacyclodextrin derivatives tend to be nontoxic when used orally. (A. Wade, P.J.Weller, Hand book of pharmaceutical Excipients, 2ⁿ Edition, page no: 145, 19(1994).

One of the most important properties of the betacyclodextrins is their ability to form inclusion compounds in solution as well as crystalline clathrate with a large variety of guest molecules. Generally, interactions between host and guest are Van der Waal links. In the case of polar guest, however, one or two hydroxyl groups are engaged in hydrogen bonding to the hydrophilic group of the guest. For a polar guest smaller than the cavity and entirely included in it, it is obvious that the formation of hydrogen bonds between the host and its own guest is only possible with primary hydroxyl groups when they are oriented towards the cavity.

The betacyclodextrin used herein the present invention is formed complex with Tibolone to provide the stability of the formulation, wherein the outer surface of the beta-cyclodextrin ring is hydrated, but the water molecules in the ring cavity are in an energetically unfavourable position because of the non-polar surface of the cavity. The potential guest molecule, here Tibolone, repels the water molecules. The result of the complex is that the nonpolar side of the guest molecule penetrates into the non-polar cavity, thereby establishing an energetically favourable nonpolar-nonpolar interaction.

Preferred embodiments are further illustrated in the following examples.

Example 1

SOFT GEL CAPSULE (130 mg)

Ingredients Amount per Capsule (mg)

Tibolone 2.5

Betacyclodextrin 45.4

Sodium Ascorbate 2.0

Ascorbyl Palmitate 2.0

Purified water 2.0

Glyceryl monostearate 10.0

Refined Sesame oil 66.1

Process of Preparation: I. Preparation of Tibolone - Betacyclodextrin complex: a) Mixing Tibolone and Betacyclodextrin in suitable high shear mixer & wetting with appropriate quantity of purified water, continue mixing to get Tibolone accumulated in cavities of Betacyclodextrin. b) Drying the wet mass of step (a) & sifting the dried complex through suitable lead free sieve.

II. Preparation of fill: a) Heating the refined Sesame oil in suitable mixing vessel at around 40-50°c. ^' b) Adding Glyceryl monosterate to step (a) with stirring, continue mixing till Glyceryl monosterate is completely melted. Allowing the fill to cool. c) Adding Sodium Ascorbate, Ascorbyl Palmitate and Purified water to step (b) with continuous stirring. d) Adding Tibolone - Betacyclodextrin complex prepared in stage (I) to step (c) & mixing the same till uniform distribution is obtained.

Fill as prepared above will be taken for encapsulation using suitable gelatin paste.

Example 2

SOFT GEL CAPSULE (130 mg)

Ingredients Amount per Capsule (mg)

Tibolone 2.5

Hydroxy propyl Betacyclodextrin _; 47.5

Sodium Ascorbate 2.0

Ascorbyl Palmitate 2.0

Purified water 2.0

Glyceryl monostearate 10.0

Refined Sesame oil 64.0

Process of Preparation:

I. Preparation of Tibolone-Hydroxy propyl Betacyclodextrin complex: a) Mixing Tibolone and Hydroxy propyl^' Betacyclodextrin in suitable high shear mixer & wetting with appropriate quantity of purified water, continue mixing to get Tibolone accumulated in cavities of Hydroxypropyl Betacyclodextrin. b) Drying the wet mass of step (a) & sifting the dried complex through suitable lead free sieve.

II. Preparation of fill: a) Heating refined Sesame oil in suitable mixing vessel at around 40-50°c. b) Adding Glyceryl monosterate to step (a) with stirring, continue mixing till Glyceryl monosterate is completely melted. Allowing the fill to cool. c) Adding Sodium Ascorbate, Ascorbyl Palmitate and Purified water to step (b) with continuous stirring. d) Adding Tibolone - Hydroxypropyl Betacyclodextrin complex prepared in stage (I) to step (c) & mixing till uniform distribution is obtained. Fill as prepared above will be taken for encapsulation using suitable gelatin paste.

In general, gelatin capsule formulations for soft gelatin capsules comprise raw gelatin and one or more plasticizers added to adjust the hardness of the capsule. Typical plasticizers include glycerin, sorbitol and Anidrisorb 85/70. A preferred plasticizer is Anidrisorb 85/70, an aqueous solution of D-sorbitol and sorbitans. One preferred gelatin formulation for the soft gelatin capsules used in accordance with preferred embodiments includes gelatin in the range of about 40% to 48% by weight and a plasticizer ranging in amount from about 16% to 25% by weight. Another preferred plasticizer is sorbitol solution 70% BP, a non-crystallizing sorbitol solution. When either a 70%, non-crystallizing sorbitol solution or Anidrisorb 85/70 are used alone, the amount of plasticizer used preferably ranges from about 20% to 25% by weight. Capsule formulations can also include other suitable additives, for example coloring agents, which impart specific characteristics such as the look and feel of the capsule. FD&C ' dyes and D&C dyes are examples of pharmaceutically acceptable coloring agents that may be used in preferred embodiments. Gelatin shell may contain suitable antioxidants.

The following examples illustrate preferred embodiments of several soft gelatin shell Tibolone formulations. These examples illustrate particular embodiments of the invention and are not intended to limit the scope of the invention in any way.

Example 3

Ingredient Percentage by Weight

Gelatin 44.5

Sorbitol Solution, 70% (non-crystallizable) 9.3

Glycerin 14.0

Purified Water 32.2 Example 4

Ingredient Percentage by Weight

Gelatin 44.5

Sorbitol Solution, 70% (non-crystallizable) 14.0

Glycerin 9.3

Purified Water 32.2

Example 5

Ingredient Percentage by Weight

Gelatin 44.5

Glycerin 14.0

Sorbitol and Sorbitan esters 9.3

(Anidrisorb 85/70)

Purified Water 32.2

Example 6

Ingredient Percentage by Weight

Gelatin 44.5

Sorbitol Solution, 70% (non-crystallizable) 25.0

Purified Water 30.5

Example 7

Ingredient Percentage by Weight

Gelatin 44.5

Sorbitol & Sorbitan (non-crystallizable) 25.0

Purified Water 33.0

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention, which is limited only by the following claims.

Claims

We Claim:

1. A stable, liquid suspension formulation of Tibolone comprising: a stabilizer, a viscosity imparting agent; a vehicle a mixture of antioxidants; and purified water, wherein said formulation is encapsulated into a soft gelatin capsule.

2. The stable, liquid suspension formulation according to claim 1, wherein the amount of Tibolone is about 2% by weight of liquid suspension.

3. The stable, liquid suspension formulation according to claim 1, wherein the stabilizer is Betacyclodextrin.

4. The stable, liquid suspension formulation according to claim 3, wherein the amount of Betacyclodextrin is about 36% to 40% by weight of liquid suspension.

5. , The stable, liquid suspension formulation according to claim 1, wherein the stabilizer is Hydroxypropyl Betacyclodextrin.

6. The stable, liquid suspension formulation according to claim 5, wherein the amount of Hydroxy propyl Betacyclodextrin is about 36% to 40% by weight of liquid suspension.

7. The stable, liquid suspension formulation according to claim 1, wherein said viscosity imparting agent is Glyceryl monosterate.

8. The stable, liquid suspension formulation according to claim 7, wherein the amount of Glyceryl monosterate is about 5% to 10% by weight of liquid suspension.

9. The stable, liquid suspension formulation according to claim 1, wherein the vehicle is super refined Sesame oil.

10. The stable, liquid suspension formulation according to claim 9, wherein the amount of super refined Sesame oil is about 32% to 55% by weight of liquid suspension.

11. The stable, liquid suspension formulation according to claim 1, wherein the mixture of antioxidants comprises of Ascorbyl Palmitate and Sodium Ascorbate.

12. The stable, liquid suspension formulation according to claim 11, wherein the amount of Ascorbyl Palmitate is about 0.5% to 2.0% by weight of liquid suspension.

13. The stable, liquid suspension formulation according to claim 11, wherein the amount of Sodium Ascorbate is about 0.5% to 2.0% by weight of liquid suspension.

14. The stable, liquid suspension formulation according to claim 1, wherein the amount of Purified water is about 0.5% to 2.0% by weight of liquid suspension.

15. A process for preparing a stable suspension formulation of Tibolone according to any of claim 1 through to 14, wherein the process comprising: preparing Tibolone-Betacyclodextrin complex by adequate mixing of wet mass of Tibolone & Betacyclodextrin mixture in a high shear mixer & drying the same to get a dried powder of Tibolone - Betacyclodextrin complex; preparing a fill by melting the Glyceryl monosterate in super refined sesame oil, adding mixture of Ascorbyl pamitate & Sodium Ascorbate to the same with continuous stirring, followed with addition of purified water; further, adding the Tibolone-Betacyclodextrin complex into the fill with continuous stirring & mixing till uniform distribution obtained and encapsulating the same in a soft gelatin capsule.