FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
“PHARMACEUTICAL COMPOSITION COMPRISING TIBOLONE AND PROCESS FOR PRODUCING THE SAME"
CIPLA LIMITED, of 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

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PHARMACEUTICAL COMPOSITION COMPRISING TIBOLONE AND PROCESS FOR PRODUCING THE SAME
The present invention relates to pharmaceutical compositions comprising tibolone and: to processes for preparing them.
Tibolone (7.alpha.,17.alpha.)-17-hydroxy-7-methyl-19-nor-17-preghr5 (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-l7-pregn-5 (1O)-en-20-yn-3-one is known from US 3,340,279. 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-19-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.
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WO 00/23460 application by Peter et al dated April 27, 2000 teaches a method of addressing the impurity problem by synthesizing high purity tibolone having very low to' no impurity by ageing tibolone formed in water for at least 24 hrs.
EP 0 707 848 B1 by de Haan, Pieter et al dated January 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 6,399,594 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 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, com starch, wheat starch, and mixtures thereof, the group including modified starches, agglomerated starches, and granulated starches, most preferably com starch.
The document also teaches to include a stabiliser selected from the group consisting of antioxidants, chelating agents and their mixtures. Therefore, the document also claims to have increasing stability with such a formulation.
Another method for stabilizing a tibolone formulation is disclosed in US application 0030134832 by Brennan Tom et al dated July 17, 2003 using a pH-adjusting agent; the formulation is said to be stable with good dissolution characteristics.
EP 0 389 035 B1 by Sas et al dated December 15, 1993 describes the Polymorphous nature of tibolone. It also describes a 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.
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Form I being a most stable form has the least solubility and so formulations often fail to have the required dissolution characteristics to give therapeutic efficacy. -This problem worsens significantly during storage.
Form II has a better solubility but jt is unstable as compared to Form t and Polymorphous compound, which is already known. Form: II degrades further under storage conditions. The Polymorphous composition available on the market does not fully satisfy all the physico-chemical characteristics under elevated temperature and relative humidity.
There remains a need to formulate tibolone in a unit dosage form, which has better storage stability than the prior art compositions, and which displays good-dissolution characteristics.
We have found that, surprisingly, tibolone when formulated using a water-soluble starch product as a carrier, results in a formulation having better dissolution characteristics and enhanced storage stability.
It is the object of the present invention to provide a formulation comprising tibolone and a water-soluble starch in the carrier.
It is another object of the present invention to provide 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 using a simple wet granulation procedure or by employing solvents.
The present invention also provides a formulation which can be used in Hormone Replacement Therapy.
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The present invention discloses a stabilised steroidal pharmaceutical composition comprising the 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 i 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.
In one aspect, the present invention provides a pharmaceutical composition comprising tibolone and a water-soluble starch, and optionally a further pharmaceutical^ acceptable carrier.
The carrier may comprise the water-soluble starch itself, or one or more additional carriers may be used. Usually, the compositions of the invention will comprise a carrier in addition to the water-soluble starch.
The invention also provides an inclusion complex of tibolone and a water-soluble starch. Preferably, the water-soluble starch is a cyclodextrin preferably beta-cyclodextrin or hydroxypropyl beta-cyclodextrin, or mixtures thereof.
In the compositions of the invention, the water-soluble starch may be non-complexed with the active, but preferably an inclusion complex of the two will be present.
Accordingly, in a further aspect there is also provided an inclusion complex comprising tibolone and a cyclodextrin. Preferably inclusion complexes include those between tibolone and beta-cyclodextrin or hydroxypropyl beta-cyclodextrin, or. complexes between tibolone and a mixture of these cyclodextrins.
In the compositions and inclusion complexes of the invention, tibolone may be present as polymorphic Form I, or as Form II, or as a mixture of Form I and Form II. Mixture ratios (by weight) of Form I: Form II of from 80:20 to 50:50 are preferred, with a ratio of from 70:30 to 85:15 being particularly preferred. The invention thus enables satisfactory stabilisation of compositions comprising or containing Form II tibolone.
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In another aspect, therefore, the invention provides an inclusion complex comprising a. mixture of Form I and Form II tibolone whereto the ratio of Form I: Form II is from 70J3G to 85:15 by percentage Weight of the active; and a cyclodextrin.
Preferably, a composition or Inclusion complex of the Invention comprises a ratio of tibolone to cyclodextrin by weight of from 1:5 to 1:20.
When desired, any suitable mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin may be used, but we prefer to use mixtures wherein the weight ratio of the first to the second is from 1:10 to 10:1, or from 1:5 to 5:1.
A composition comprising tibolone beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, a polyoxyethylene hydrogenated castor oil and, optionally, further pharmaceutically acceptable excipients is one preferred formulation.
Another preferred composition comprises tibolone, a cyclodextrin, a carrier, a disintegrant, a binder and a lubricating agent. In particular, a composition comprising tibolone, beta-cyclodextrin, lactose, a disintegrant such as croscarmellose sodium, and a lubricant such as magnesium stearate is particularly suitable.
The compositions of the invention may, for example, be provided in tablet or capsule form. Normally, for maximum advantage, the cyclodextrin (or other water-soluble starch) and the tibolone will be present as an inclusion complex!
In another aspect, the invention provides a process for making a tablet comprising a composition of the invention, which process comprises mixing tibolone, cyclodextrin, a carrier and a disintegrant; granulating with a binder; lubricating the granules with a lubricating agent; and compressing the granules to form tablets.
In a further aspect, the invention also provides a process for making a pharmaceutical composition comprising a tibolone-cyclodextrin complex, which process comprises adding solvent to a premix comprising tibolone and a cyclodextrin; blending the
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ingredients to allow the complex to form; and formulating the-blend, along with pharmaceutically acceptable excipients into a final dosage form
The cornpositions and inclusion complexes of the invention are suitable for use as medicaments. For example, Hormone Replacement Therapy arid associated treatments are contemplated uses.
Cyclodextrin s are enzymatically-modified starches formed by action of the enzyme cyctodextrin 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. These can all be used in the present invention.
Among the three cyclodextrins, gamma-cyclodextrin is the most soluble followed by alpha and then beta.
Because of their unique properties, cyclodextrin s can be used to carry all kinds of active ingredients such as drugs, fragrances, flavours, vitamins and other wide variety of formulations.
We have found that when used as a carrier for tibolone, cyclodextrin surprisingly increased tibolone's stability and also improved its solubility significantly. Further studying this altered property it was found that, particularly in the presence of a solvent or a wetting agent, tibolone forms a complex with cyclodextrin s which has altered physical properties and increased chemical stability then when used alone or with any other conventional earners like lactose, starch, mannitol, microcrystalline, cellulose, etc.
Complexation with cyclodextrin s can be carried out with various methods known to a person skilled in the art. Some of the common techniques employed include 1) Co-
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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 OF 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 mixing.
Hydroxypropyl beta-cyclodextrin (HPBCD) can be produced from beta-cyclodextrin (BCD) by addition of propylene oxide to some of the hydroxy! groups of BCD. This modification results In greater solubility of HPBCD and it complexes more readily as compared to BCD.
Along with cyclodextrins other conventional carriers such as lactose, starch, mannitol, ascorbyl palmitate, celluloses such as microcrystalline cellulose can be used, and other excipients required for example for tabletting such as disintegrants, binders, anti adherents, and lubricants can be included. Disintegrants like croscarmellose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycollate and the like may be used. As a binder, starch paste, polyvinyl pyrrolidone (PVP K-30), gelatine may suitably be used. The blend may, for example be lubricated with suitable lubricants such as magnesium stearate, or sodium stearyl fumarate, and compressed into tablets or filled in suitable capsule shells.
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A combination of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin is particularly preferred as It has enhanced complexation property thereby enhancing the stability and solubility of tibolone. Hydroxypropyl beta-cyclodextrin also has good binding properties which may eliminate the need for a separate binder.
Complexes of the invention may be formed by using any of the techniques mentioned above. The preferred method is by using a solvent. The solvent can be any of the commonly used solvents like water, ethanol diethyl ether, isopropyl alcohol, acetone, etc. Water is preferred, 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-cyclodextrin and/or hydroxypropyl beta-cyclodextrin, other stabilisers such as antioxidants and chelating agents may also be incorporated.
Optionally in addition to cyclodextrins wetting agents, surface-acting agents, solubilising agents may also be incorporated. Preferably, wetting agents like Tweens, Spans, sodium lauryl sulphate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil (Cremaphore RH40) are used for example in concentration of from 0.01 to 1.0% by weight of the formulation to enhance dissolution. Apart from dissolution enhancement these agents also enhance the complexation of tibolone with cyclodextrins. Generally these agents can be added directly or by dissolving in a suitable solvent.
Cremaphore RH40 may, for example, be used in an amount of from 0.01 to 1.0% by weight of the composition, preferably 0.3% by weight to provide wetting and enhancement of complexation. Cremaphore RH40 is suitably dissolved in a minimum quantity of water and added for proper distribution.
The compositions of the present invention may be formulated In any suitable dosage form, such as tablets, capsules, pellets, caplets, gel caps, sachets, powders or
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granules, solutions, suspension and modified release dosage forms of the same. Tabletting may; for example, be by any of the three methods known in the art. wet –granulation, dry granulation and direct compression.
In one preferred embodiment, the complex or compositions are formed by addition of a wetting agent dissolved in a minimum quantity of solvent (for example, Water) to a premix. Preferably, the premix has binding properties, owing to the presence of. for example, hydroxy propyl beta cyclodextrin. After addition the blend is preferably kneaded thoroughly for approximately 5 minutes to allow complexation to complete. When the complexation is complete the remaining part of the carrier, which preferably comprises one or more of lactose, mannitol, starch, microcrystalline cellulose etc (preferably in a directly compressible grade) is added and mixed well to absorb any excess of water remaining and mixed to homogenize for. for example, approximately 15 minutes during which tibolone-cyclodextrin complex gets evenly distributed throughout the carrier Drying is preferably not required since preferabty only a small amount of solvent (water) is 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 may be added and mixed, for example, for 10 minutes.
The resulting blend may, for example, 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, and drying under fluidised bed which increases the degradation of tibolone thereby increasing imp urity levels at the initial stage is avoided.
The water content of the blend is preferably sufficiently low enough to avoid compression problems like poor flow, sticking, etc.
In another preferred embodiment, the complex or composition may be formed by a sim ple wet granulation process. Tibolone is mixed with cyclodextrin and sifted together thus forming a complex. Carriers, disintegrating agents are added to the complex. The complete mixture is called as a Premix-I. The premix is then granulated using suitable
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binder solution. The granules are further mixed with lubricating agents, disintegrants, and such other pharmaceutically acceptable suitable excipients and compressed to form tablets;
The amount of tibolone in the complex or composition may for example; Vary from 0.1 -to 10% by weight, and. Is preferably around 2.5% by weight. Tibolone can be used as either pure Form lor as a mixture of polymorphic-Form I and II. The said mixture may comprise 80:20:to 50:50 percentage by weight polymorphic Form I: polymorphic Form II, or preferably the said ratio is from 70:30 to 85:15.
The following Examples illustrates the present invention. Examples 6 and 7 contain 60:40 of Form 1: Form 2 tibolone by weight, whereas in Examples 1-5 and 8 the corresponding ratio is 80:20. Example 9 was performed using corresponding ratios of 70:30 and 85:15.
Example 1:

INGREDIENTS
Dry mix
Tibolone
Starch
Ascorbyl Palmitate
Hydroxy propyl Beta Cyclodextrin
Beta Cyclodextrin
Solvent
Cremophore RH40
Purified Water
Lubrication
Granulated Blend
Mannitol (Pearlitol SD200)
Magnesium Stearate
Total

Qty/Tab (mg)
2.5
5.0
0.1
15.0
35.0

0.15
Q.S
QS to 100mg
2.0
100.0

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Manufacturing Process:
1. tibolone, starch, ascorbyl palmitate, hydroxy propyl beta cyclodextrin was co
sifted through 80 mesh. This is premix.
2 Premix was mixed- along with beta cyclodextrin arid passed through; 40 mesi
twice
3 Cremophore RH40 was dissolved in minimum quantity of purified Water .
4 The solvent was slowly added to the above blend and kneaded well to form a
complex.
5. Mannitol (Pearlitol SD200) was added to the said complex and mixed well.
6. The blend was passed through 16 mesh, followed by 30 and 40 mesh.
7. The blend was lubricated with magnesium stearate.
8. The said blend was compressed in to tablets of 100 mg 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
1. Tibolone, starch, hydroxy propyl beta cyclodextrin were co-sifted through 80 mesh. This is premix.
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2. Premix was mixed along with beta cyclodextrin and passed through 40 mesh twice.
3. The solvent was added slowly to the above blend and kneaded well lo form a complex,
4. Mannitol (Pearlitol SD200) was added to the said complex arid mixed Well.
5. The blend was passed-.through 16 mesh, followed by 30 and 40 mesh.
6. The blend was lubricated with magnesium stearate.
7. The said blend was compressed into tablets of 100 mg using suitable toolings.
Example 3:
Qty/Tab (mg)
2.5 5.0 0.1 35.0
0.25
Q.S

QS to 100mg
2.0
100.0
INGREDIENTS
Dry mix
Tibolone
Starch
Ascorbyl Palmitate
Beta Cyclodextrin
Solvent
Cremophore RH40
Purified Water
Lubrication
Mannitol (Pearlitol SD200)
Magnesium Stearate
Total
Manufacturing Process:
1. Tibolone, starch and ascorbyl palmitate were co-sifted through 80 mesh. This is premix.
2. Premix was mixed along with beta-cyclodextrin and passed through 40 mesh twice.
3. Cremophore RH40 was dissolved in minimum quantity of purified water.
4. The solvent was slowly added to the above blend and kneaded well to form a complex.
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5. Starch and mannitol (Pearlitol SD200) were added to the said complex and
mixed well.
6. The blend was passed through 16 fresh, followed by 30 end 40 rnesh
7. The blend was lubricated with magnesium stearate.
8. The said blend was further compressed into tablets of 100 mg using suitable toolings
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Example 4:
INGREDIENT Qty/Tab
(mg)
Drymix
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) . OS to 100 mg
Total 100.0
Manufacturing Process: Same as Example 1 and compressed into tablets of 100 mg using suitable toolings.

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Example 5: INGREDIENTS
Basic granulate
Lactose monohydrate
Binder
Starch
Purified Water
Lubrication
Basic Granulate passing through 80#
Tibolone
Starch
Ascorbyl Palmitate
Magnesium Stearate
Total

Qty/Tab (mg)
QS to 100 mg
2.0 QS
QS 2.5 8.0 0.1 1.0 100.0

Manufacturing Process:
1. Lactose monohydrate was sifted through 40 mesh and granulated using starch paste.
2. The wet mass was dried and sized through 30 mesh. This is basic granulate.
3. Tibolone, ascorbyl palmitate, starch were co-mixed and sifted through 80 mesh. This is Drug premix.
4. Fines passing through 80 mesh were removed frombasic granulate.
5. 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.
6. The blended granules were lubricated with magnesium stearate and compressed into tablets of 100 mg using suitable toolings.

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Example 6:
INGREDIENTS Qty/Tab:
(mg)
Dry
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 100 mg
Magnesium Stearate 2.0
Total 100.0


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Example 7:
INGREDIENTS Qty/Tab (mg)
Basic granulate
Lactose monohydrate QS to 100 mg
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

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Example 8: INGREDIENTS
Basic granulate
Starch
Lactose monohydrate
Binder
Starch
Purified Water
Lubrication
Basic Granulate passing through 80#
Tibolone
Ascorbyl Palmitate
Magnesium Stearate
Total

Qty/Tab . (mg)
57.5
SQSto 100 mg
2.5 Q.S
QS 2.5 0.1 0.5
100.0

Manufacturing Process:
1. Starch and lactose monohydrate were co-sifted through 40 mesh and granulated using starch paste.
2. The wet mass was dried and sized through 30 mesh. This is basic granulate.
3. Tibolone and ascorbyl palmitate were co-mixed and sifted through 80 mesh.
4. This is drug premix.
5. 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.
6. The blended granules were lubricated with magnesium stearate and
compressed into tablets of 100 mg using suitable toolings.
The tablets made from Examples 1 to 8 were packed in PVC-ALU and stored for one mo nth at 25°C and 60 RH and 40°C and 75% RH. The content (in %), dissolution (in
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%) and decomposition product chiefly delta ketone impurity (in %) are given in Table Nos. 1 and 2.
The specific dissolution parameters for this set of experiments were as follows. USP type ll/50RPM/500ml 0.5% W/W sodium lauryl sulfate/37°C±5°C Detection: at 210 nm
Table No. 1

Examples Initial
Assay(%) Impurity Disso (60 Mins)
Delta ketone Unknown 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

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Table No. 2

1 Month 25°C and 60% RH 1 Month 40°C and 75% RH
Examples Assay (%) Impurity- Disso(60Mins) Assay (%) Impurity Disso(60Mins)
Delta ketone Unknown Total Delta Ketone Unknown Total (%)
1 98 0.13 0.26 0.68 96 96 0.38 0.26 1.07 94
2 99 0.12 0.25 0.70 90 98 0.39 0.29 1.1.1 89
3 102 0.12 0.27 0.70 93 103 0.38 0.28 1.08 93
4 98 0.14 0.41 0.79 94 97 0.40 0.55 1.10 94
5 99 0.26 0.89 1.72 70 99 0.5 1.11 1.94 65
6 96 0.15 0.46 0.97 95 95 0.44 0.54 1.14 94
7 94 1.24 2.1 3.85 90 92 1.35 3.10 4.95 89
8 99 0.24 1.05 1.51 90 98 0.4 1.24 1.88 84
Comparing Example 1 with 2 it can be seen that a 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 one month storage than the conventional tibolone formulation with 10% 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 stabilises even tibolone (polymorphous with 60% Form I and 40% Form II) than a conventional tibolone formulation with 10% 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 stabilises

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WO 2005/117899 PCT/GB2005/002158
tibolone, and has better dissolution characteristics than with formulation having 60% starch as a part of carrier.

Example 9
INGREDIENTS Qty/Tab
(mg)
Dry mix
Tibolone 2.50
Lactose 33.67
Croscarmellose Sodium 2.00
Beta-cyclodextrin 20.00
Binder
Lactose 5.00
Purified water Q.S
Lubricant
Croscarmellose sodium 1.50-
Magnesium stearate 0.33
Total 65.00
Manufacturing Process:
1. Sift tibolone through 80-mesh sieve and lactose, croscarmellose sodium and beta-cyclodextrin through 40-mesh sieve.
2. Mix tibolone and twice as much beta cyclodextrin and co-sift through 40-mesh sieve. This is premix I.
3. Co-sift premix I again with the remaining quantity of beta-cyclodextrin, twice. This is premix II.
4. Load premix II and croscarmellose sodium sandwiched between two approximately equal portions of lactose In FBE.
5. Prepare binder by dispersing lactose in water and dissolving by application of heat and slow stirring to obtain a clear solution.
6. Mix and granulate using fluidised bed apparatus, employing spraying of binder solution.
7. Sift granules through 40 mesh.

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WO 2005/117899 PCT/GB2005/002158
8. Blend suitably sieved magnesium stearate and croscarmellose sodium with sized granules.
9. Compress blend into tablets of 65 mg using suitable toolings.

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CLAIMS:
1. A pharmaceutical composition comprising tibolone and a cyclodextrin , and optionally a further pharmaceutically acceptable carrier, wherein the
5 cyclodextrin is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin or a mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin .
2. A composition according to claim 1. comprising an inclusion complex of tibolone and a cyclodextrin wherein the cyclodextrin is beta-cyclodextrin or
10 hydroxypropyl beta-cyclodextrin or a mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin .
3. An inclusion complex comprising tibolone and a cyclodextrin, wherein the cyclodextrin is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin or a
15 mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin.
4. A composition according to claim 1 or 2 or an inclusion complex according to claim 3 wherein the ratio of tibolone to cyclodextrin by weight is from 1:5 to 1:20.
5. A composition according to claim 1, 2 or 4 or an inclusion complex according to claim 3 comprising beta cyclodextrin and hydroxypropyl beta-cyclodextrin in a weight ratio of from 1:10 to 10:1.
6. A composition or inclusion complex according to claim 5 wherein the said weight ratio is from 1:5 to 5:1.
7. A composition according to any one of claims 1, 2, 4, 5 and 6, further comprising a wetting agent, a surface-active agent or a solubilising agent.
30
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8. A composition according to claim 7, wherein the wetting agent is a polysorbate, a sorbitan ester, sodium lauryl sulphate, a polyoxyethylene castor oil or a polyoxyethylene hydrogenated castor oil.
5 9. A composition according to claim 7 or 8 wherein the wetting agent is present at a concentration of from 0.01 to 1.0% by weight of the composition.
10. A composition according to any one of claims 1, 2 or 4 to 9 further
comprising a carrier, a disintegrant, a binder and a lubricating agent.
10
11. A composition according to any one of claims 1, 2 or 4 to 10 or an
inclusion complex according to claim 3, 4, 5 or 6, wherein tibolone consists
essentially of polymorphic Form I., or polymorphic Form II, or a mixture of
Form I and II.
15
12. A composition or inclusion complex according to claim 11 wherein the
ratio of Form I: Form II in the mixture is from 80:20 to 50:50 by percentage
weight of the active.
20 13. A composition or inclusion complex according to claim 12 wherein the said ratio is from 70:30 to 85:15 by percentage weight of the active.
14. A composition according to any one of claims 1,2 or 4 to 13 comprising
tibolone, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin , a
25 polyoxyethylene hydrogenated castor oil and, optionally, further pharmaceutical^ acceptable excipients.
15. A composition according to any one of claims 1,2 or 4 to 13 comprising
tibolone, a cyclodextrin, a carrier, a disintegrant, a binder and a lubricating
30 agent, wherein the cyclodextrin is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin or a mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin.
25

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16. A process for making a tablet comprising a composition according to
claim 15 which process comprises mixing tibolone, cyclodextrin. a carrier and
a disintegrant; granulating with a binder; lubricating the granules with a
5 lubricating agent; and compressing the granules to form tablets, wherein the cyclodextrin is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin or a mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin.
17. A process for making a pharmaceutical composition comprising a
10 tibolone-cyclodextrin complex, which process comprises adding solvent to a
premix comprising tibolone and a cyclodextrin; blending the ingredients to allow the complex to form; and formulating the blend along with pharmaceutical acceptable excipients into a final dosage form, wherein the cyclodextrin is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin or a
15 mixture of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin.
18. A process according to claim 17 wherein the solvent contains a wetting
agent, suitably polyoxyethylene hydrogenated castor oil.
20 19 A process according to claim 17 or 18 wherein the solvent is water.
20. A composition according to any of claims 1, 2 or 4 to 15, which is a tablet or capsule.
25 21. A composition according to any of claims 1, 2, 4 to 15 or 20, or an inclusion complex according to any of claims 3 to 6 or 11 to 13 for use as a medicament.
22. Use of a composition according to any of claims 1, 2, 4 to 15 or 20, or
30 an inclusion complex according to any of claims 3 to 6 or 11 to 13 in the
manufacture of a medicament for treating or preventing menopausal related
26

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conditions, including menopausal vasomotor symptoms and postmenopausal osteoporosis.
23. An inclusion complex comprising a mixture of Form I and Form II
tibolone wherein the ratio of Form I : Form II is from 70:30 to 85:15 by
percentage weight of the active, and a cyclodextrin, wherein the cyclodextrin
is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin or a mixture of beta-
cyclodextrin and hydroxypropyl beta-cyclodextrin

24. A pharmaceutical composition and/or an inclusion complex comprising and/or a
process for making a tablet comprising and/or use of a composition substantially as
hereinbefore described with reference to the foregoing examples.
Dated this 13th day of December. 2006.

27

(GOUTAM BHATTACHARYYA)
Of K&S PARTNERS
AGENT FOR THE APPLICANT(S)

ABSTRACT
"PHARMACEUTICAL COMPOSITION COMPRISING TIBOLONE AND PROCESS FOR
PRODUCING THE SAME"
A pharmaceutical composition comprises tibolone, a water-solute starch and optionally a further pharmaceutical acceptable carrier. Preferred compositions comprise an inclusion complex of tibolone and a water-soluble starch, in particular cyclodextrin. A process for making a tablet comprising a composition of the invention comprises mixing tibolone cyclodextrin, a carrier and disintegrant; granulating with a binder, lubricating the granules with a lubricating agent; and compressing the granules to form tablets. In another embodiment, a process for making a composition of the invention comprises adding solvent to a premix comprising tibolone and a cyclodextrin; blending the ingredients to allow the complex to form; and formulating the blend along with pharmacieutically acceptable excipients into a final dosage form.