FIELD OF THE INVENTION;

The present invention relates to formulations containing benzothiophene compounds, especially raloxifene or pharmaceutical salts thereof, preferably a crystalline non-solvated raloxifene hydrochloride as the active pharmaceutical ingredient and a process for preparing a composition.

BACKGROUND OF THE INVENTION;

Raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(l-piperidyl) eth- oxy] phenylj-methanone, is disclosed in U.S. Pat. No. 4,418,068 and is a selective estrogen receptor modulator and widely used for the treatment and prevention of osteoporosis in postmenopausal women.
Raloxifene is a pharmaceutically active compound, indicated for treatment and/or prevention of osteoporosis in women. In pharmaceutical formulations, it is used in the form of a hydrochloride salt and is marketed, e.g., under the brand name Evista® by Eli Lilly.

U.S. Patent Nos. 5,393,763, 5,457,117, 5,478,847, and 6,906,086, and U.S Reissue Patent Nos. RE 38,968 and RE 39,049, disclose methods of use of benzothiophenes for inhibiting bone loss.
U.S. Patent Nos. 5,811,120 and 5,972,383 disclose solid oral compositions comprising raloxifene in combination with a surfactant, polyvinylpyrrolidone, and a water soluble diluent, wherein surfactants comprise sorbitan fatty acid esters or polyoxyethylene sorbitan fatty acid esters, and the water soluble diluent is a polyol or a sugar.

U.S. Patent. No. 6,458,811 describes pharmaceutical compositions containing raloxifene having a mean particle size less than about 25 .mu.m, wherein about 90% of raloxifene particles have a size of less than about 50 .mu.m.

U.S. Patent. No. 6,894,064 discloses a pharmaceutical composition comprising a) raloxifene in particulate form, said particles having a mean particle size of less than about 25 .mu.m, with at least about 90% of said particles have a size of less than about 50 microns; b) a surfactant; and c) a water-soluble diluent.
U.S. Patent Publication 20100003319 describes pharmaceutical composition of raloxifene or a pharmaceutically acceptable salt having a mean particle size of at least about 25 [mu]m, preferably 25 [mu]m to 125 [mu]m, most preferably 30 [mu]m to 50 [mu]m.

PCT application WO2009146097 discloses pharmaceutical formulation of raloxifene hydrochloride having mean particle size 30 to 75 [mu]m and 90 % of particles do not exceed 60 to 150 [mu]m, having non^ionic surfactant and water-insoluble diluent, antioxidant, and a disintegrant.

US patent publication US20060099252 discloses compressed pharmaceutical dosage form wherein an active ingredient may be Raloxifene, oxcarbazepine or atorvastatin, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures composition comprising starch.

US patent publication US20090162444 discloses pharmaceutical composition comprising raloxifene hydrochloride having mean particle size of 5 to 20 [mu]m, 95% of particles are < 50 [mu]m, a mixed cellulose excipient and a disintegrant, wherein the composition is devoid of povidone or starch.
The bioavailability of raloxifene hydrochloride is quite low. A cursory review of prior art indicates that several attempts have been made to increase bioavailability in pharmaceutical formulations. Among which one attempt is by improving a physical form of Raloxifene i.e., decreasing particle size to increase its dissolution along with enhanced bioavailability. Even an amorphous raloxifene hydrochloride was also disclosed with enhanced bioavailability.

Various approaches were adopted to improve the solubility and dissolution of poorly soluble active ingredients, like salt formation, particle size reduction, pH adjustment, use of surfactants, inclusion complexes with cyclodextrins, formation of co-precipitates with hydrophilic polymers, and co-milling with hydrophilic excipients etc.

As raloxifene has poor solubility and poor bioavailability, there exists a need for developing improved formulations which does not require micronized raloxifene and still show improved dissolution even with higher particle size of raloxifene hydrochloride.

SUMMARY OF THE INVENTION;

In accordance with the above, the present invention provides a pharmaceutical composition which includes a novel excipient along with crystalline non-solvated raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns, which shows better dissolution.

Accordingly, the present invention provides novel pharmaceutical composition comprising,

a) raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns;

b) at least one surfactant,

c) at least one water soluble diluent, and

d) optionally at least one water insoluble diluent.

In a preferred embodiment of present invention provides pharmaceutical formulation comprising a crystalline non-solvated raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns, a surfactant & a water soluble diluent and optionally at least one water insoluble diluent.

The surfactant is selected from ionic or non-ionic surfactant. One preferable surfactant is polysorbate 80.

The water soluble diluent for the purpose of the present invention is an amino acid and/or sugar. One preferable amino acid is glycine and one preferable sugar is lactose monohydrate.

The pharmaceutical composition of the present invention optionally comprises at least one water insoluble diluent. One preferable water insoluble diluent Micro crystalline cellulose.

Accordingly, the preferred embodiment of the invention comprises a crystalline non-solvated raloxifene hydrochloride as an active ingredient; at least one surfactant, preferably polysorbate 80; a water soluble diluent such as an amino acid and/or sugar, preferably glycine, preferably lactose monohydrate; optionally at least one water insoluble diluent, preferably micro crystalline cellulose.

The pharmaceutical composition of the present invention exhibits higher dissolution even with raloxifene hydrochloride having mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns, which has been achieved with the use of higher to unknown excipients. Such dissolution of raloxifene is achieved with the inclusion of a water soluble diluent preferably glycine and/or lactose monohydrate into the tablet or capsule formulation.

Another aspect of present invention relates to process for the preparation of pharmaceutical formulation comprising a crystalline non-solvated raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns, wherein the dissolving of raloxifene hydrochloride & surfactant is carried out in a solvent mixture specifically mixture of water and acetone.

Another aspect of present invention relates to process for the preparation of pharmaceutical formulation comprising a crystalline non-solvated raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having at least 60 microns, wherein the dissolving of raloxifene hydrochloride & surfactant is carried out in a solvent mixture specifically mixture of water and acetone.

A further aspect of present invention relates to process for the preparation of pharmaceutical formulation comprising a step of blending crystalline non-solvated raloxifene hydrochloride having a mean particle size of about 35 to about 65 microns & 90 percent of particles having about 60 to about 110 microns along with a water soluble diluent and disintegrant with a mixture of surfactant & binder solution, which is dried and further compressed into tablets.

DETAILED DESCRIPTION OF THE INVENTION;
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention provides novel pharmaceutical composition with higher dissolution, which comprises,

a) raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns

b) at least one surfactant,

c) at least one water soluble diluent, and

d) optionally at least one water insoluble diluent.

The surfactant is selected from ionic or non-ionic surfactant. One preferable surfactant is polysorbate 80.

The water soluble diluent for the purpose of the present invention is an amino acid or sugar One preferable amino acid is glycine. Use of other suitable aminoacids falls also within the purview of this invention. One preferable sugar is lactose monohydrate. Use of other suitable sugars falls also within the purview of this invention.

The pharmaceutical composition of the present invention optionally comprises at least one water insoluble diluent. One preferable water insoluble diluent is micro crystalline cellulose. A person skilled in the art may also select variety of diluents, those are water soluble to achieve the instant invention.

Accordingly a novel pharmaceutical composition disclosed herein comprises a crystalline non-solvated raloxifene hydrochloride as an active ingredient; at least one surfactant, preferably polysorbate 80; a water soluble diluent such as an amino acid, and/or sugar, preferable amino acid is glycine, preferable sugar is lactose monohydrate; optionally at least one water insoluble diluent, preferably micro crystalline cellulose.

In one embodiment, manufacturing process of pharmaceutical formulation according to the invention comprises

a) dissolving a crystalline non-solvated raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of particles having about 60 to about 120 microns, & surfactant in a solvent mixture specifically acetone-water mixture,

b) spraying the mixture of step (a) on to the water soluble diluent, preferably glycine, c) blending with extra granular material,

d) compressing into tablets, and

e) finally coating the tablets with opadry dispersion in water.

The extra granular material is selected from Micro crystalline cellulose, Crosspovidone, croscarmellose sodium and/or low substituted hydroxy propyl cellulose.

The novel pharmaceutical composition prepared as per the above process with higher dissolution according to the invention is depicted in table 1 below:

Table 1
Dissolution Table of Raloxifene HCl 60 mg tablets:
Dissolution profile in Purified water with 0.1% Polysorbate 80
Time(niinutes) % drug released

The dissolution of crystalline non-solvated raloxifene hydrochloride is achieved upto 95 % in just 30 minutes, where the formulation comprises the dissolving of raloxifene hydrochloride in acetone water mixture with higher particle size.

In another embodiment, manufacturing process of pharmaceutical composition comprising aqueous granulation of crystalline non-solvated raloxifene hydrochloride having a mean particle size of about 35 to about 65 microns & 90 percent of particles having about 60 to about 110 microns, along with a water soluble diluent such as an amino acid, preferably glycine and/or sugar preferably lactose monohydrate and a disintegrant with a mixture of surfactant specifically polysorbate 80 & binder solution, followed by drying & blending with extra granular materials and compressing into tablets. The tablets thus obtained are finally coated with opadry dispersion in water.

The binder used according to the invention is selected from Povidone k29/32, hydroxy propyl methyl cellulose and/or hydroxy propyl cellulose.

The disintegrant used according to the invention Is selected from Cross Povidone XL, crosscarmellose sodium and/or low substituted hydroxy propyl cellulose.

The novel pharmaceutical composition prepared as per the above process with higher dissolution according to the invention is depicted in table 2 below:
Table 2

Dissolution Table of Raloxifene HCl 60 mg tablets:

Dissolution profile in Purified water with 0.1% polysorbate SO
Tinie(niinutes) % drug released

The dissolution of crystalline non-solvated raloxifene hydrochloride is achieved upto 97.3 % in just 30 minutes, where the formulation comprises aqueous granulation of raloxifene hydrochloride of higher particle size & glycine and/or lactose monohydrate.

Particle size distribution of raloxifene hydrochloride, is tested using a Horiba Laser Scattering Particle Size distribution analyzer LA-950, where mean particle size is observed to be at least about 35 microns; and 90% of particles have sizes about 60 to about 120 microns.

The present invention also provides methods of using pharmaceutical formulations according to the invention for preventing and/or treating osteoporosis in postmenopausal women.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples
Example 1:

Step 3- Blending & Compression

Manufacturing procedure:

1. Crystalline non-solvated raloxifene hydrochloride having mean particle size of at least about 35 microns and d90 of at least 60 microns, Povidone and polysorbate-80 were dissolved in acetone-purified water mixture in a ratio of 60:40.

2. The above solution was sprayed on to the mixture of Glycine and Crospovidone XL by using Fluid bed equipment.

3. Material of step 2 was granulated in Rapid mixer granulator with purified water and further dried.

4. The dried granulation material of above step was blended with extra granular material. Micro crystalline cellulose, Crospovidone XL and lubricated with magnesium stearate.

5. The resultant blend of step 4 was compressed into tablets and

6. Finally coated with Opadry dispersion in water.

Example 2:
S. No. Ingredients mg/tab
Step 1- Granulation

Manufacturing procedure:
1. Crystalline non-solvated raloxifene hydrochloride having mean particle size of at least about 35 microns and d90 of at least 60 microns, Povidone and polysorbate-80 were dissolved in acetone-purified water mixture in a ratio of 60:40.

2. The above solution was sprayed on to the mixture of Glycine and Crospovidone XL by using Fluid bed equipment.

3. Material of step 2 was granulated in Rapid mixer granulator with purified water and further dried.

4. The dried granulation material of above step was blended with cross povidone and lubricated with magnesium stearate.

5. The resuhant blend of step 4 was compressed into tablets and

6. Finally coated with Opadry dispersion in water.

Example 3:

Manufacturing procedure:

1. Povidone and polysorbate -80 were dissolved in purified water to form a solution

2. Crystalline non-solvated raloxifene hydrochloride having mean particle size of about 35 to about 65 microns and d90 of about 60 to about 110 microns, Crosspovidone XL and glycine were granulated in rapid mixer granulator along with the solution of step 1 and dried.

3. The dried granules of step 2 was blended with extra granular material, Micro crystalline cellulose, cross povidone and lubricated with magnesium stearate.

4. The resultant blend of step 3 was compressed into tablets and

5. Coated with Opadry dispersion in water.

Example 4:

Manufacturing procedure:

1. Povidone and polysorbate-80 were dissolved in purified water to form a solution

2. Crystalline non-solvated raloxifene hydrochloride having mean particle size of about 35 to about 65 microns and d90 of about 60 to about 110 microns, Crosspovidone XL and glycine was granulated in rapid mixer granulator along with the solution of step 1 and dried.

3. The dried granules of step 2 was blended with Cross Povidone and lubricated with magnesium stearate.

4. The resultant blend of step 3 was compressed into tablets and

5. Coated with Opadry dispersion in water.

Example 5:

Manufacturing procedure:

1. Crystalline non-solvated raloxifene hydrochloride having mean particle size of at least about 35 microns and d90 of at least 60 microns. Povidone and polysorbate-80 were dissolved in acetone-purified water mixture in a ratio of 60:40.

2. The above solution was sprayed on to the mixture of lactose monohydrate and Crospovidone XL by using Fluid bed equipment.

3. Material of step 2 was granulated in Rapid mixer granulator with purified water and further dried.

4. The dried granulation material of above step was blended with cross povidone and lubricated with magnesium stearate.

5. The resultant blend of step 4 was compressed into tablets and

6. Finally coated with Opadry dispersion in water.

Example 6:

Manufacturing procedure:

1. Crystalline non-solvated raloxifene hydrochloride having mean particle size of at least about 35 microns and d90 of at least 60 microns, Povidone and polysorbate-80 were dissolved in acetone-purified water mixture in a ratio of 60:40.

2. The above solution was sprayed on to the mixture of lactose monohydrate and Crospovidone XL by using Fluid bed equipment.

3. Material of step 2 was granulated in Rapid mixer granulator with purified water and further dried.

4. The dried granulation material of above step was blended with cross povidone and lubricated with magnesium stearate.

5. The resultant blend of step 4 was compressed into tablets and

6. Finally coated with Opadry dispersion in water.

WE CLAIM,

1. A pharmaceutical formulation comprising

a) raloxifene or a pharmaceutically acceptable salts thereof, having a mean particle size of at least about 35 microns;

b) at least one surfactant;

c) at least one water soluble diluent; and

d) optionally at least one water insoluble diluent.

2. The pharmaceutical formulation of claim 1, wherein the water soluble diluent is an amino acid and/or sugar

3. The pharmaceutical formulation of claim 2, wherein the amino acid is glycine and the sugar is lactose.

4. The pharmaceutical formulation of claim 1, wherein the raloxifene is a non-solvated crystalline raloxifene hydrochloride, having a mean particle size of at least about 35 microns «fe 90 percent of particles having about 60 to about 120 microns.

5. A pharmaceutical formulation comprising

raloxifene hydrochloride having a mean particle size of at least about 35 microns & 90 percent of
particles having about 60 to about 120 microns

b) at least one surfactant, preferably polysorbate 80;

c) at least one water soluble diluent, preferably glycine and/or lactose monohydrate and

d) at least one water insoluble diluent.

6. The pharmaceutical formulation of claim 5, wherein a water insoluble diluent is micro crystalline cellulose.

7. The pharmaceutical formulation of any of the claims 1-6, further comprises at least one binder and at least one disintegrant.

8. The pharmaceutical formulation of claim 7, wherein the binder is povidone and disintegrant is cross povidone.

9. The pharmaceutical formulation of claim 5, wherein the formulation is prepared by wet granulation using solvents selected from ketonic solvent, preferably acetone, water or mixture thereof.

10. The pharmaceutical formulation according to any one of proceeding claims, wherein said formulation is a tablet or capsule composition.