WO2005120517A1

WO2005120517A1 - Stable liquid suspension formulation comprising synthetic steroids and process for producing the same

Info

Publication number: WO2005120517A1
Application number: PCT/IN2004/000159
Authority: WO
Inventors: Venkat Subramanian Iyer; Shivaraj Basavaraj Katageri
Original assignee: Strides Arcolab Limited
Priority date: 2004-06-07
Filing date: 2004-06-07
Publication date: 2005-12-22

Abstract

Disclosed herein is a stable, liquid suspension formulation of Tibolone, encapsulated into soft gelatin capsules and process for producing the same. The formulation disclosed comprises combination of antioxidants, combination of viscosity imparting agents and vehicle to enhance the stability of formulation.

Description

STABLE LIQUID SUSPENSION FORMULATION COMPRISING SYNTHETIC STEROIDS AND PROCESS FOR PRODUCING THE SAME

[0001] Field of the Invention

[0002] In general, this invention relates to stable pharmaceutical formulations comprising a synthetic steroid. More particularly, the present invention provides for a stable, liquid suspension formulation of Tibolone, encapsulated into soft gelatin capsules and process for producing the same.

[0003] Background of the Invention

[0004] 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 n'atural 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).

[0005] 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.

[0006] 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.

[0007] 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 (la, 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.

[0008] Alongwith 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 (la, . 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one [Δ⁵⁽¹⁰⁾] to (la, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one [Δ⁴] (herein after also denoted as 4-impurity) during manufacturing and also during storage.

[0009] 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.

[0010] 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 nori 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.

[0011] 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. [0012] 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 in UK in tablet form.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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).

[0017] 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.

[0018] 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.

[0019] 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.

[0020] Summary of the Invention

[0021] In accordance with one preferred embodiment, there is provided a stable liquid suspension formulation of Tibolone employing a suitable matrix containing synergistic combination of antioxidants, combination of viscosity imparting agents and vehicle to enhance the stability of formulation.

[0022] 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 citrate and ascorbyl palmitate or butylated hydroxy anisole and butylated hydroxy toluene to avoid conversion of Δ^{5 (10)} to Δ4 impurity or other related impurities and enhance stability of the formulation.

[0023] In accordance with one another preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone, wherein the formulation includes combination of viscosity imparting agents such as hydrogenated vegetable oil and bees wax to avoid oil separation and settling of Tibolone in the formulation.

[0024] In accordance with yet another preferred embodiment, the present invention provides a stable liquid suspension formulation of Tibolone encapsulated into a soft gelatin capsule. The soft gelatin capsule formulation of Tibolone has enhanced bioavailability compared to solid Tibolone formulations.

[0025] 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 0.8% by weight of sodium citrate, about 1.6% by weight of ascorbyl palmitate, about 4% by weight of hydrogenated vegetable oil, about 4% by weight of beeswax and about 87.6% by weight of medium chain triglycerides.

[0026] 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 0.2% by weight of butylated hydroxy anisole, about 0.2% by weight of butylated hydroxy toluene, about 4% by weight of hydrogenated vegetable oil, about 4% by weight of beeswax and about 89.6% by weight of medium chain triglycerides.

[0027] 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 0.4% by weight of butylated hydroxy anisole, about 4% by weight of hydrogenated vegetable oil, about 4% by weight of beeswax and about 89.6% by weight of medium chain triglycerides.

[0028] 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 0.4% by weight of butylated hydroxy toluene, about 4% by weight of hydrogenated vegetable oil, about 4% by weight of beeswax and about 89.6% by weight of medium chain triglycerides. [0029] 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, melting the mixture of viscosity imparting agents at temperature of 75 to 80°C, adding vehicle to melted viscosity imparting agents to form a first mixture, separately mixing antioxidants and screening the same through 0.5 mm screen on multi/cadmill with impact forward with fast speed to form a second mixture, further adding second mixture to first mixture to form a suitable matrix, geometrically mixing the Tibolone into the matrix at a temperature below 30°C, and encapsulating the same into soft gelatin capsule.

[0030] 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.

[0031 ] 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.

[0032] 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.

[0033] 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.

[0034] 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. [0035] Detailed Description of the Invention

[0036] 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.

[0037] 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 diethylene glycol-mono-ethyl ether, caprylo-caproyl-macrogol glycerides, ethyl alcohol, maisine, ascorbyl palmitate, citric acid, sodium citrate, hydrogenated vegetable oil, beeswax, PEG 400, medium chain triglyceride, etc.

[0038] Tibolone was found unstable when formulated without incorporation of antioxidants. In the absence of these antioxidants, Tibolone has converted into Δ4- impurity and other related impurities. Different types of antioxidants such as citric acid, butylated hydroxy anisole, sodium citrate, Calcium ascorbate and ascorbyl palmitate have been incorporated in different proportions and combinations to prevent conversion of Tibolone into impurities.

[0039] Surprisingly, it is found that the combination of about 0.8% by weight of sodium citrate and about 1.6% by weight of ascorbyl palmitate in the formulation prevent conversion of Tibolone into Δ4-impurity and other related impurities, thereby avoiding the stability problem and other disadvantages of the conventional formulation.

[0040] The combination of about 0.8% by weight of sodium citrate and about

1.6% by weight of Calcium Ascorbate was also found very effective to prevent conversion of Tibolone into Δ4-impurity and other related impurities, thereby avoiding the stability problem and other disadvantages of the conventional formulation. [0041] 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 a combination of about 4% by weight of hydrogenated vegetable oil and about 4% by weight of beeswax in the formulation, the oil separation and settling of Tibolone can be prevented.

[0042] 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.

[0043] Preferred formulations contain Sodium citrate used primarily as a pH adjusting agent and in this formulation it is also used as an anti-oxidant in combination with ascorbyl palmitate (A. Wade, P.J.Weller, Hand book of pharmaceutical Excipients, 2^nd Edition, 19(1994)). Sodium citrate used to improve the stability of Tibolone in the formulation, is practically insoluble in ethanol, and is soluble 1 part in 1.5 part of water.

[0044] Preferred formulations contain Butylated Hydroxy Toluene (BHT) that acts as an antioxidant to prevent conversion of Tibolone into its Δ4-impurity. It is mainly used to reduce or prevent oxidative rancidity of fats and oils and loss of activity of oil soluble vitamins. BHT occurs as a white or pale yellow crystalline solid or powder with a faint characteristic odor.

[0045] Preferred formulations contain Butylated Hydroxy Anisole, which is frequently used in combination with other antioxidants, particularly BHT and alklylating gallates, and with sequestrants or synergist such as ciric acid. BHA occurs as a white or almost white solid or powder with a faint characteristic odor.

[0046] Preferred formulations contain Hydrogenated Vegetable Oil, it is a mixture of triglycerides of stearic and palmitic acids of vegetable origin (Martindale, 33^rd edition, 19 (1994)), practically insoluble in water, soluble in chloroform, petroleum spirit and hot propan-2-ol. Hydrogenated Vegetable oil is used as a viscosity imparting agent in the formulation. [0047] Preferred formulations contain Yellow Bees Wax used as an Emulsion stabilizer, stiffening agent, (A Wade, P.J. Weller, Hand book of Pharmaceutical Excipients, 2^nd Edition, 19 (1994)), is practically insoluble in water, soluble in ether, chloroform, fixed oils, volatile oil and warm carbon disulfide. Beeswax along with Hydrogenated vegetable oil is used as a stiffening agent and also as viscosity imparting agent in the formulation.

[0048] Preferred formulations contain Caprylic/Capric triglyceride or medium chain triglycerides (Labrafac CC, Gattefosse) used as oily vehicles for oral, topical, rectal and parenteral preparations.

[0049] Preferred formulations contain Calcium Ascorbate, which is used as antioxidant in formulation. Calcium Ascorbate is a white to slightly yellowish crystalline powder. Freely soluble in water, practically insoluble in alcohol. A 10% solution in water has a pH between 6.8 to .4. (Reference: Martindale, 33^rd edition, P. No 1389)

[0050] Preferred embodiments are further illustrated in the following examples.

Example 1

[0051] Process of Preparation:

[0052] Mixture of hydrogenated vegetable oil and beeswax is melted at temperature of 75 to 80°C, medium chain triglyceride is added to the melted mixture to form a first mixture. Separately, calcium ascorbate and sodium citrate are mixed and milled through 0.5 mm screen on multi/cadmill with impact forward with fast speed to prepare a second mixture. The second mixture is added to the first mixture to form a suitable matrix and Tibolone is mixed geometrically with the matrix, at a temperature below 30°C and then the same is encapsulated into soft gelatin capsules.

Example 2

[0053] Process of Preparation:

[0054] Mixture of hydrogenated vegetable oil and beeswax is melted at temperature of 75 to 80°C, medium chain triglyceride is added to the melted mixture to form a first mixture. Separately, ascorbyl palmitate and sodium citrate are mixed and milled through 0.5 mm screen on multi/cadmill with impact forward with fast speed to prepare a second mixture. The second mixture is added to the first mixture to form a suitable matrix and Tibolone is mixed geometrically with the matrix, at a temperature below 30°C and then water is added to this mixture and mixed. The same is encapsulated into soft gelatin capsules.

[0055] Surprisingly we found that the presence of around 2% of water in fill preparation does not have any impact on stability of tibolone. Example 3

[0056] Process of Preparation:

[0057] Mixture of hydrogenated vegetable oil and beeswax is melted at temperature of 75 to 80°C, medium chain triglyceride is added to the melted mixture, then mixture of Ascorbyl Palmitate and sodium citrate is milled on multimill/cadmill using 0.5mm screen and is added to the melted mixture to form a suitable matrix and Tibolone is mixed geometrically with the matrix, at a temperature below 30°C and then the same is encapsulated into soft gelatin capsules.

Example 4

[0058] Process of Preparation:

[0059] Mixture of hydrogenated vegetable oil and beeswax is melted at a temperature of 75 to 80°C, medium chain triglyceride is added to the melted mixture, then mixture of Calcium ascorbate and sodium citrate is milled on multimill/cadmill using 0.5 mm screen and is added to the melted mixture to form a suitable matrix and Tibolone is mixed geometrically with the matrix, at a temperature below 30°C and then Potassium hydroxide is added to this mixture and mixed. The same is encapsulated into soft gelatin capsules.

[0060] We also found that the presence of Potassium hydroxide at level of around

0.8% in fill preparation leads to instability of Tibolone. In the presence of Potassium hydroxide the conversion of Tibolone to its Δ4-impurity (Delta 4) increases.

[0061] Following figures are bar graphs representation showing the stability data and comparative evaluation of level of Δ4-impurity and level of Tibolone at various temperature conditions (after 12 days and after 20 days). Below data is generated based on stability data as per above example Nos 1 to 4.

Fi . 1

B Initial ■ l2days 03 □ 20days Q

Example Nos 1 2 3 Storage condn. 40°C/75%RH Fig. 2

Example Nos Storage condn. 30°C/65%RH

Fig. 3 comparative evaluation of Delta 4

3 Storage condn. 25°c/60%RH Fig. 4

Comparative evalution of Tibolone content

Storage condn. 40°C/75%RH

Fig. 5

Example Nos Storage Condn. 30°C/65%RH Fig. 6

Comparative evalution of Tibolone content

Storade Condn. 25°C/60%RH

Example 5

[0062] Process of Preparation:

[0063] Mixture of hydrogenated vegetable oil and beeswax is melted at temperature of 75 to 80°C, medium chain triglyceride is added to the melted mixture to form a first mixture. Separately, Ascorbyl Palmitate, Sodium citrate, butylated hydroxy anisole and butylated hydroxy toluene are mixed and milled through 0.5 mm screen on multi/cadmill with impact forward with fast speed to prepare a second mixture. The second mixture is added to the first mixture to form a suitable matrix and Tibolone is mixed geometrically with the matrix, at a temperature below 30°C and then the same is encapsulated into soft gelatin capsules.

Example 6

[0064] Process of Preparation:

[0065] Mixture of hydrogenated vegetable oil and beeswax is melted at temperature of 75 to 80°C, medium chain triglyceride is added to the melted mixture, then butylated hydroxy anisole, Calcium ascorbate and Sodium citrate mixed, milled on multimill cadmill using 0.5mm screen and is added to the melted mixture to form a suitable matrix and Tibolone is mixed geometrically with the matrix, at a temperature below 30°C and then the same is encapsulated into soft gelatin capsules.

[0066] 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 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.

[0067] 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 10

[0068] 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 comprising: an active pharmaceutical ingredient, a mixture of viscosity imparting agents; a vehicle; and a mixture of antioxidants, wherein said formulation is encapsulated into a soft gelatin capsule.

2. The stable, liquid suspension formulation according to claim 1, wherein the active pharmaceutical ingredient is a synthetic steroid.

3. The stable, liquid suspension formulation according to claim 2, wherein the synthetic steroid is Tibolone.

4. The stable, liquid suspension formulation according to claim 3, wherein the amount of Tibolone is about 2% by weight of liquid suspension.

5. The stable, liquid suspension formulation according to claim 1, wherein the mixture of viscosity imparting agents comprises hydrogenated vegetable oil (HVO) and beeswax.

6. The stable, liquid suspension formulation according to claim 5, wherein the amount of hydrogenated vegetable oil is about 3% to 8% by weight of liquid suspension.

7. The stable, liquid suspension formulation according to claim 5, wherein the amount of beeswax is about 3% to 5% by weight of liquid suspension.

8. The stable, liquid suspension formulation according to claim 1, wherein the vehicle is a medium chain triglyceride.

9. The stable, liquid suspension formulation according to claim 8, wherein the amount of medium chain triglyceride is about 80% to 90% by weight of liquid suspension.

10. The stable, liquid suspension formulation according to claim 1, wherein the mixture of antioxidants is selected from a group comprising ascorbyl palmitate, sodium citrate, butylated hydroxy toluene, calcium ascorbate and butylated hydroxy anisole.

11. The stable, liquid suspension formulation according to claim 10, wherein the mixture of antioxidants comprises of ascorbyl palmitate and sodium citrate.

12. The stable, liquid suspension formulation according to claim 11, wherein the amount of ascorbyl palmitate is about 1% to 3% by weight of liquid suspension.

13. The stable, liquid suspension formulation according to claim 11, wherein the amount of sodium citrate is about 0.5% to 1.5% by weight of liquid suspension.

14. The stable, liquid suspension formulation according to claim 10, wherein the mixture of antioxidants comprises of butylated hydroxy anisole and butylated hydroxy toluene.

15. The stable, liquid suspension formulation according to claim 14, wherein the amount of butylated hydroxy anisole is about 0.2% to 0.5% by weight of liquid suspension.

16. The stable, liquid suspension formulation according to claim 14, wherein the amount of butylated hydroxy toluene is about 0.2% to 0.5% by weight of liquid suspension.

17. The stable, liquid suspension formulation according to claim 10, wherein the mixture of antioxidants comprises of calcium ascorbate and sodium citrate.

18. The stable, liquid suspension formulation according to claim 17, wherein the amount of calcium ascorbate is about 1% to 3% by weight of liquid suspension.

19. The stable, liquid suspension formulation according to claim 17, wherein the amount of sodium citrate is about 0.5% to 1.5% by weight of liquid suspension.

20. A process for producing a stable, liquid suspension formulation comprising: melting the mixture of viscosity imparting agents at temperature of 75 to 80°C; adding a vehicle to melted viscosity imparting agents to form a first mixture; mixing antioxidants to form a second mixture; screening the second mixture through 0.5 mm screen on multi/cadmill with impact forward with fast speed; adding the second mixture to the first mixture to form a suitable matrix; and geometrically mixing an active pharmaceutical ingredient into said matrix at a temperature below 30°C; and encapsulating the resultant into a soft gelatin capsule wherein the active pharmaceutical ingredient is a synthetic steroid.

21. The process for preparing a stable, liquid suspension formulation according to claim 20, wherein the synthetic steroid is Tibolone.

22. The process for preparing a stable, liquid suspension formulation according to claim 21, wherein the amount of Tibolone is about 2% by weight of liquid suspension.

23. The process for preparing a stable, liquid suspension formulation according to claim 20, wherein the mixture of viscosity imparting agents comprises hydrogenated vegetable oil (HVO) and beeswax.

24. The process for preparing a stable, liquid suspension formulation according to claim 23, wherein the amount of hydrogenated vegetable oil is about 3% to 8% by weight of liquid suspension.

25. The process for preparing a stable, liquid suspension formulation according to claim 23, wherein the amount of beeswax is about 3% to 5% by weight of liquid suspension.

26. The process for preparing a stable, liquid suspension formulation according to claim 20, wherein the vehicle is medium chain triglyceride.

27. The process for preparing a stable, liquid suspension formulation according to claim 26, wherein the amount of medium chain triglyceride is about 80% to 90% by weight of liquid suspension.

28. The process for preparing a stable, liquid suspension formulation according to claim 20, wherein the mixture of antioxidants is selected from a group comprising ascorbyl palmitate, sodium citrate, calcium ascorbate, butylated hydroxy toluene and butylated hydroxy anisole.

29. The process for preparing a stable, liquid suspension formulation according to claim 28, wherein the mixture of antioxidants comprises of ascorbyl palmitate and sodium citrate.

30. The process for preparing a stable, liquid suspension formulation according to claim 29, wherein the amount of ascorbyl palmitate is about 1% to 3% by weight of liquid suspension.

31. The process for preparing a stable, liquid suspension formulation according to claim 29, wherein the amount of sodium citrate is about 0.5% to 1.5% by weight of liquid suspension.

32. The process for preparing a stable, liquid suspension formulation according to claim 28, wherein the mixture of antioxidants comprises of butylated hydroxy anisole and butylated hydroxy toluene.

33. The process for preparing a stable, liquid suspension formulation according to claim 32, wherein the amount of butylated hydroxy anisole is about 0.2% to 0.5% by weight of liquid suspension.

34. The process for preparing a stable, liquid suspension formulation according to claim 32, wherein the amount of butylated hydroxy toluene is about 0.2% to 0.5% by weight of liquid suspension.

35. The process for preparing a stable, liquid suspension formulation according to claim 28, wherein the mixture of antioxidants comprises of calcium ascorbate and sodium citrate.

36. The process for preparing a stable, liquid suspension formulation according to claim 35, wherein the amount of calcium ascorbate is about 1% to 3% by weight of liquid suspension.

37. The process for preparing a stable, liquid suspension formulation according to claim 35, wherein the amount of sodium citrate is about 0.5% to 1.5% by weight of liquid suspension.

38. A stable liquid suspension formulation of Tibolone, wherein the formulation comprises a mixture of antioxidants to avoid/reduce conversion to Δ4 impurities or other related impurities and enhance stability of the formulation.

39. The stable liquid suspension formulation according to claim 38, wherein the mixture of antioxidants comprises of about 0.5% to 1.5% sodium citrate and about 1% to 3% ascorbyl palmitate by weight of liquid suspension.

40. The stable liquid suspension formulation according to claim 38, wherein the mixture of antioxidants comprises of about 0.5% to 1.5% sodium citrate and about 1% to 3% calcium ascorbate by weight of liquid suspension.

41. A stable liquid suspension formulation of Tibolone, wherein the formulation comprises of a mixture of viscosity imparting agents to avoid oil separation and settling of Tibolone in the formulation.

42. The stable liquid suspension formulation according to claim 41, wherein the mixture of viscosity imparting agents comprises of about 3% to 8% hydrogenated vegetable oil and about 3% to 5% bees wax by weight of liquid suspension.