FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
[See section 10; rule 13]
"A stabilized steroidal composition."
(a) CIPLALTD.
(b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956


The following specification particularly describes the nature of the invention:

Technical Field:
The present invention relates to a stabilized steroidal pharmaceutical composition comprising Tibolone in a therapeutically effective amount and a water-soluble pharmaceutically acceptable carrier, in particular a water-soluble starch product.
Background and Prior Art:
Tibolone (7.alpha., 17.alpha.)-17-hydroxy-7-methyl-19-nor-17-pregn-5 (10)-en-20-yn-3-one is a steroid derived from norethynodrel that has oestrogenic, progestogenic and weak androgenic property. It is used as menopausal Hormone replacement therapy in the treatment of menopausal vasomotor symptoms and in the prevention of postmenopausal osteoporosis.
Tibolone (7.alpha., 17.alpha.)-17-hydroxy-7-methyl-19-nor-17-pregn-5 (10)-en-20-yn-3-one is known from US3, 340,279. Tablets are available on the market under the name of Livial.RTM.
A typical known formulation for Tibolone is a tablet having 2.5 mg of Tibolone contained therein, a relatively small amount (e.g. approximately 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically comprises of 10% by weight of starch, e.g. potato starch, and 90% by weight of lactose, optionally with other non-starch ingredients such as amylopectin (see, e.g., U.S. Pat. No. 4,701,450). A problem in the preparation of pharmaceutical dosage units is that during the preparation the relative amount of impurities may increase. In particular, the amount of one of the impurities which is already present in the bulk preparation i. e. (7a, 17a)- 17-hydroxy-7-methyl-l 9-nor-17-pregn-4-en-20-yn-3-one (Org OM38) tends to increase during the process of making pharmaceutical dosage units. It is furthermore known that the amounts of Org OM38 in compositions comprising Tibolone increase upon storage.

The end of shelf life specification with respect to the amount of Org OM38 formed during storage is 5%. A minimum acceptable shelf life period for these dosage units is 1 year. It is an object of the present invention to improve upon the storage stability i. e. to enhance the shelf-life of the dosage units.
To further solve this problem, WO 00/23460 application by Peter et al dated April 27, 2000 teaches a method of solving the impurity problem by synthesizing high purity Tibolone having very less to no impurity by ageing Tibolone formed in water for atleast 24 hrs.
EP 0 707848 Bl by de Haan, Pieter et al dated Jan 09, 2002 teaches a solid pharmaceutical composition comprising a water insoluble non-cross linked polymeric excipient capable of binding water and less than 7% by weight of an oil or oily substance having a mean particle size greater than 150 micrometer and a process for the preparation of said solid composition.
US Patent 6399594 dated June 4, 2002 by de Haan et al teaches a pharmaceutical dosage unit comprising at least 40% water insoluble starch in the carrier and in another independent claim, it is stated that the formulation comprises of at least 10% of the water insoluble starch and in that formulation the Tibolone content is 2% or less. The water insoluble starch product is selected from the group consisting of Starch 1500, potato starch, corn starch, wheat starch, and mixtures thereof, the group including modified starches, agglomerated starches, and granulated starches, most preferably Corn starch.
The invention also teaches to include a stabilizer selected from the group consisting of antioxidants, chelating agents and their mixtures. Therefore, the patent document also claims to have increasing stability with such a formulation, which means that the percentage of degradation products formed is as low as possible.

Another method for stabilizing the Tibolone formulation is disclosed in US application 0030134832 by Brennan Tom et al dated July 17, 2003 using a pH-adjusting agent; the said formulation is stable with, better dissolution characteristics.
EP 0 389035 Blby Sas et al dated Dec 15, 1993 describes the Polymorphous nature of the Tibolone. It also describes the method for separating Form I and Form II, it also describes Form I which is chemically more stable than already known polymorphous compound. The difference in crystal structure can lead to a difference in physico-chemical properties such as stability, rate of dissolution, melting point, and the like. It also describes that a composition substantially containing Form I more than 90% would be more stable than the polymorphous composition or Form II composition.
Form I being a most stable form had the least solubility thereby formulation fails to have the required dissolution characteristics to give therapeutic efficacy. This problem aggravates significantly further under storage conditions.
Form II has a better solubility but it is unstable as compared to Form I and Polymorphous compound, which is already known. Form II degrades further under storage conditions. The Polymorphous composition available in the market is not fully satisfying all the physico - chemical characteristics under elevated temperature and Relative humidity.
Therefore there prevails an immense need to formulate Tibolone in a unit dosage form, which has better storage stability and good dissolution characteristics.
Surprisingly, it has been seen that Tibolone when formulated using a water-soluble starch product as a carrier, results in a formulation having better dissolution characteristics and enhanced storage stability.

Object of the invention;
It is the object of the present invention to provide for a formulation comprising
Tibolone and a water soluble starch in the carrier.
It is another object of the present invention to provide for a formulation comprising an
inclusion complex of Tibolone along with the water soluble starch carrier.
It is also another object of the present invention to provide for a formulation that results
in having better dissolution profiles and enhanced storage stability.
The present invention further aims at providing a process of preparing such a
formulation involving a simple wet granulation procedure, which is easy and does not
require exceptional skill.
The present invention also provides a formulation, which can be used in Hormone Replacement Therapy.
Summary of the invention:
The present invention discloses a stabilized steroidal pharmaceutical composition comprising a steroid Tibolone in a therapeutically effective amount and a water soluble pharmaceutically acceptable carrier, in particular a water soluble starch product. More particularly, the present invention discloses the said steroidal pharmaceutical composition comprising a stable complex of the said steroid and the water soluble starch. A process of making the said composition and its uses thereof are also disclosed.
Detailed description of the invention;
Cyclodextrins are enzymatically-modified starches formed by action of the enzyme cyclodextrin glucosyl transferase on starch to make a water-soluble ring shaped molecule, capable of holding another oil-like organic substance in its cavity. They are doughnut-shaped molecules, which can interact with organic molecules to form complexes.

Three types of Cyclodextrins are typically formed, alpha, beta and gamma Cyclodextrin, which contain six, seven and eight glucose molecules in the ring respectively.
Among the three Cyclodextrins, Gamma -Cyclodetrin is the most soluble followed by Alpha and then Beta.
Because of its unique property, Cyclodextrins can be used to carry all kinds of active ingredients such as drugs, fragrances, flavors, vitamins and other wide variety of formulations.
Cyclodextrin when used as a carrier for steroids such as Tibolone surprisingly increased its stability and also improved it's solubility significantly. Further studying this altered property it was found that in the presence of a solvent or a wetting agent Tibolone forms a complex with Cyclodextrins which has altered physical property and chemically stable than alone or with any other conventional carriers like lactose, starch, mannitol, microcrystalline cellulose, etc.,
Complexation with Cyclodextrins can be carried out with various methods known to a person skilled in the art. Some of the common techniques employed were 1) Co-precipitation-in which Cyclodextrin is dissolved in water and the guest is added while stirring the Cyclodextrin solution. The solution of Cyclodextrin and guest must be cooled while stirring before a precipitate is formed. The precipitate can be collected by decanting, centrifugation or by filtration. 2) Slurry Complexation- in which Cyclodextrin is added to water in a higher concentration and stirred. Guest molecule will complex with the cyclodextrin in solution and as the Cyclodextrin-Guest complex saturates the water phase, the complex will crystallize or precipitate out of the aqueous Phase. 3) Paste Complexation-in, which only a small quantity of water is added to form a paste, which is mixed with the Cyclodextrin using a mortar and pestle or on a large scale using a kneader. The resulting complex can be dried directly or washed with a

small amount of water and collected by filtration or centrifugation. 4) Damp mixing and heating- in which little or no water is used. The guest and Cyclodextrin are thoroughly mixed and placed in a sealed container. The sealed container and its contents are heated to about 100°C and then the contents are removed and dried. 5) Extrusion-in which Cyclodextrin, guest and water can be premixed or mixed and added to the extruder. The extruded material can be dried. 6) Dry mixing- in which complex is formed by simply adding guest to the Cyclodextrin and mixed.
Hydroxypropyl beta-cyclodextrin (HPBCD) is produced from beta-cyclodextrin (BCD) by addition of propylene oxide to some of the hydroxyl groups of BCD. This modification results in greater solubility of HPBCD and it complexes more as compared to BCD.
Using Beta-Cyclodextrins and Hydroxypropyl beta-cyclodextrin to increase stability, water solubility, reduction in odor and in controlled release formulation is well known in the art.
Along with Cyclodextrins other conventional carriers like Lactose, Starch, Mannitol, celluloses such as microcyrstalline cellulose can be used, other excipients required for tabletting like disintegrant, binder, anti adherent, and lubricant can be included. Normally used disintegrants like Croscarmellose Sodium, Cross-linked polyvinyl pyrrolidone, Sodium starch glycollate etc can be used. As a binder Starch paste, Polyvinyl pyrrolidone (PVP K-30), Gelatin etc can be used. Finally the blend will be lubricated with suitable lubricants like Magnesium stearate, Sodium stearyl fumarate, etc and compressed or filled in suitable capsule shells.
A combination of Beta-Cyclodextrins and Hydroxypropyl beta-cyclodextrin is preferred as it has enhanced complexation property thereby enhancing stability and solubility of Tibolone. Hydroxypropyl beta-cyclodextrin also has a binding property thereby eliminating the addition of binder separately.

Complex can be formed by using any of the techniques mentioned above. Most preferred method is by using a solvent. Solvent can be any of the commonly used solvents like Water, Ethanol, Diethyl ether, Isopropyl alcohol, Acetone, etc. Water is the most commonly used solvent. The more soluble the cyclodextrin in the solvent, the more molecules become available for complexation. The guest must be able to displace the solvent from the cyclodextrin cavity. Water can be displaced easily, so water is preferred.
Optionally in addition to the stabilizing effect provided by Beta-Cyclodextrins and Hydroxypropyl beta-cyclodextrin other stabilizers known prior like antioxidants, chelating agents can also be incorporated.
Optionally in addition to Cyclodextrins wetting agents, surface acting agents, solublizing agents can also be incorporated. Normally used wetting agents like Tweens, Spans, Sodium Lauryl sufate, Polyoxyethylene castor oil, Polyoxyethylene hydrogenated Castor oil (Cremaphore RH40) etc can be used in concentration from 0.01 to 1.0 % by weight to enhance dissolution. Apart from dissolution enhancement these agents enhance the complexation of Tibolone with Cyclodextrins. Generally these agents can be added directly or by dissolving in a suitable solvent.
Cremaphore RH40 is used in an amount 0.01 to 1.0 % by weight preferably 0.3% by weight to provide wetting and enhancement of complexation. Cremaphore RH40 is dissolved in minimum quantity of water and added for proper distribution.
The formulation of the present invention can be formulated in dosage forms such as tablets, capsules, pellets, caplets, gel caps, sachets, powders or granules, solutions, suspension and modified release dosage forms of the same. Tabletting can be made by three methods known in the art by wet granulation, dry granulation and direct compression.

The present invention involves addition of wetting agent dissolved in a minimum quantity of solvent (Water) to a premix, which has binding property, by itself due to Hydroxy propyl beta cyclodextrin. After addition the blend is kneaded thoroughly for approximately 5 minutes to allow complexation to complete. When the complexation is complete the remaining part of carrier preferably Lactose, Mannitol, Starch, Microcrystalline cellulose etc preferably directly compressible grade is added and mixed well to absorb the excess of water remaining and mixed to homogenize for approximately 15 minutes during which Tibolone-Cyclodextrin complex gets evenly distributed throughout the carrier. Drying is not required since only less amount of solvent (Water) was added and moreover it will be completely absorbed by the carrier added at later stage. After mixing, disintegrant if needed can be added and mixed. Finally lubricant is added and mixed for 10 mins.
The resulting blend can be either compressed to form tablets or can be directly filled into capsules.
By this process exposure of Tibolone to harsh conditions like pre-heating, drying under Fluidized bed which increases the degradation of Tibolone thereby increase in impurity level in the beginning stage itself is avoided.
The water content of the blend is sufficiently low enough to avoid compression problems like poor flow, sticking, etc.
The amount of Tibolone can vary from 0.1 to 10 % by weight, preferably 2.5% by weight. Tibolone can be used as either pure form I or as a mixture of polymorphic form I and II. The said mixture comprises 80:20 to 50:50 percentage to polymorphic form I: polymorphic form II.
Following are non-limiting exemplary embodiments of the present invention.

Example 1:

INGREDIENTS Qty/Tab
(mg)
Dry mix
Tibolone 2.5
starch 5.0
Ascorbyl Palmitate 0.1
Hydroxy propyl Beta Cyclodextrin 15.0
Beta Cyclodextrin 35.0
Solvent
Cremophore RH40 0.15
Purified Water Q.S
Lubrication
Granulated Blend -
Mannitol (Pearlitol SD200) QS to 100mg
Magnesium Stearate 2.0
Total 100.0
Manufacturing Process:
> Tibolone, Starch, Ascorbyl Palmitate, Hydroxy propyl Beta Cyclodextrin was co sifted through 80mesh. This is PreMix.
> PreMix was mixed along with Beta Cyclodextrin and passed through 40 mesh twice.
> Cremophore RH40 was dissolved in minimum quantity of Purified Water
> The solvent was slowly added to the above blend and kneaded well to form a
complex.
> Mannitol (Pearlitol SD200) was added to the said complex and mixed well.
> The blend was passed through 16 mesh, followed by 30 and 40 mesh.
> The blend was lubricated with Magnesium stearate.
> The said blend was compressed in to tablets of 100mg using suitable toolings.

Example 2;
INGREDIENTS Qty/Tab
(mg) Dry mix
Tibolone 2.5
starch 5.0
Hydroxy propyl Beta Cyclodextrin 15.0
Beta Cyclodextrin 35.0
Solvent
Purified Water Q.S
Lubrication
Granulated Blend
Mannitol (Pearlitol SD200) QS to 100mg
Magnesium Stearate 2.0
Total 100.0
Manufacturing Process:
> Tibolone, starch, Hydroxy propyl Beta Cyclodextrin were co sifted through 80mesh. This is PreMix.
> PreMix was mixed along with Beta Cyclodextrin and passed through 40 mesh twice.
> The solvent was added slowly to the above blend and kneaded well to form a complex.
> Mannitol (Pearlitol SD200) was added to the said complex and mixed well.
> The blend was passed through 16 mesh, followed by 30 and 40 mesh.
> The blend was lubricated with Magnesium stearate.
> The said blend was compressed in to tablets of 100mg using suitable toolings.

Example 3:

INGREDIENTS Qty/Tab
(mg)
Dry mix
Tibolone 2.5
starch 5.0
Ascorbyl Palmitate 0.1
Beta Cyclodextrin 35.0
Solvent
Cremophore RH40 0.25
Purified Water Q.S
Lubrication
Mannitol (Pearlitol SD200) QS to 100mg
Magnesium Stearate 2.0
Total 100.0
Manufacturing Process:
> Tibolone, starch and Ascorbyl Palmitate were co sifted through 80mesh. This is PreMix.
> PreMix was mixed along with Beta Cyclodextrin and passed through 40 mesh twice.
> Cremophore RH40 was dissolved in minimum quantity of Purified Water.
> The solvent was slowly added to the above blend and kneaded well to form a complex.
> Starch and Mannitol (Pearlitol SD200) were added to the said complex and mixed well.
> The blend was passed through 16 mesh, followed by 30 and 40 mesh.
> The blend was lubricated with Magnesium stearate.
> The said blend was further compressed in to tablets of 100mg using suitable
toolings.

Example 4:
INGREDIENTS Qty/Tab
(mg) Dry mix
Tibolone 2.5
starch 5.0
Ascorbyl Palmitate 0.1
Hydroxy propyl Beta Cyclodextrin 5.0
Beta Cyclodextrin 25.0
Solvent
Cremophore RH40 0.3
Purified Water Q.S
Lubrication
Mannitol (Pearlitol SD200) QS to 100mg
Magnesium Stearate 2.0
Total 100.0
Manufacturing Process: Same as Example 1 and Compressed into tablets of lOOmg using suitable toolings.

Example 5:
INGREDIENTS Qty/Tab
(mg)
Basic granulate
Lactose monohydrate QS to 100mg
Binder
Starch 2.0
Purified Water Q.S
Lubrication
Basic Granulate passing through 80# QS
Tibolone 2.5
Starch 8.0
Ascorbyl Palmitate 0.1
Magnesium Stearate 1.0
Total 100.0
Manufacturing Process:
> Lactose monohydrate was sifted through 40 mesh and granulated using Starch paste.
> The wet mass was dried and sized through 30 mesh. This is Basic granulate.
> Tibolone, Ascorbyl palmitate,starch were co mixed and sifted through 80 mesh. This is Drug premix.
> Fines passing through 80 mesh were removed from Basic granulate.
> Drug premix was mixed geometrically with the fines removed and the whole blend was added to the remaining basic granulate and blended sufficiently for uniform distribution of the active.
> The blended granules were lubricated with magnesium stearate and compressed into tablets of 100mg using suitable toolings.

Example 6:
INGREDIENTS Qty/Tab
(mg) Dry mix
Tibolone 2.5
Ascorbyl Palmitate 0.1
Hydroxy propyl Beta Cyclodextrin 5.0
Beta Cyclodextrin 25.0
Solvent
Cremophore RH40 0.3
Purified Water Q.S
Lubrication
Granulated Blend
Mannitol (Pearlitol SD200) QS to 100mg
Magnesium Stearate 2.0
Total 100.0
Manufacturing Process: Same as Example 4 and Compressed into tablets of 100mg using suitable toolings.

Example 7:
INGREDIENTS Qty/Tab
(nig)
Basic granulate
Lactose monohydrate QS to 100mg
Binder
Starch 2.0
Purified Water Q.S
Lubrication
Basic Granulate passing through 80# QS
Tibolone 2.5
Starch 8.0
Ascorbyl Palmitate 0.1
Magnesium Stearate 1.0
Total 100.0
Manufacturing Process: Same as Example 5 and Compressed into tablets of lOOmg using suitable toolings.

Example 8:
INGREDIENTS Qty/Tab
(mg)
Basic granulate
Starch 57.5
Lactose monohydrate QS to100mg
Binder
Starch 2.5
Purified Water Q.S
Lubrication
Basic Granulate passing through 80# QS
Tibolone 2.5
Ascorbyl Palmitate 0.1
Magnesium Stearate 0.5
Total 100.0
Manufacturing Process:
> Starch and Lactose monohydrate were Co-sifted through 40 mesh and granulated using Starch paste.
> The wet mass was dried and sized through 30 mesh. This is Basic granulate.
> Tibolone and Ascorbyl palmitate were co mixed and sifted through 80 mesh. This is Drug premix.
> Fines passing through 80 mesh were removed from Basic granulate.
> Drug premix was mixed geometrically with the fines removed and the whole blend was added to the remaining basic granulate and blended sufficiently for uniform distribution of the active.
> The blended granules were lubricated with magnesium stearate and compressed into tablets of 100mg using suitable toolings.
The tablets made from Examples 1 to 8 were packed in PVC-ALU and stored for 1
month at 25°C and 60% RH and 40°C and 75% RH. The content (in %),

Dissolution (in %) and Decomposition product chiefly Delta ketone impurity (in %) are given in Table no 1 & 2
The specific dissolution parameters for this set of experiments were as follows. USP type II/50RPM/500ml 0.5% WAV Sodium Lauryl Sulfate/ 37°C±5°C Detection: At 210 nm
Table No: 1

Examples Initial

Assay(%) Impurity Disso (60 Mins)

Delta keton e Un
know
n Total (%)
1 99 0.09 0.2 0.5 97
2 99 0.10 0.2 0.55 91
3 104 0.09 0.13 0.36 95
4 99 0.07 0.4 0.73 96
5 105 0.15 0.51 1.45 77
6 96 0.12 0.4 0.88 95
7 101 0.15 0.55 0.95 99
8 101 0.2 0.88 1.35 95

Table No:2

Comparing Example 1 with 2 it can be understood that wetting agent slightly helps in dissolution.
Comparing Examples 1, 2, 3, 4 with 5 from Table 1 and Table 2 it can be understood that Beta-cyclodextrin and Hydroxy propyl betacyclodextrin - tibolone complex has improved stability and dissolution characteristics initially and after 1 Month storage than the conventional Tibolone formulation with 9% Starch as a part of carrier.
Comparing Example 6 with 7 from Table 1 and Table 2 it can be understood that using Beta-cyclodextrin and Hydroxy propyl betacyclodextrin as a part of carrier stabilizes

even Tibolone (polymorphous with 60% Form I and 40% Form II) than conventional Tibolone formulation with 9% Starch as a part of carrier.
Comparing Example 1 with 8 from Table 1 and Table 2 it can be understood that using Beta-cyclodextrin and Hydroxy propyl betacyclodextrin as a part of carrier stabilizes Tibolone and has better dissolution characteristics than with formulation having 60% Starch as a part of carrier.
Dated this 1st day of June 2004
Dr. Gopakumar G. Nair Agent for Applicant