WO2013182170A1

WO2013182170A1 - Enhancement of dissolution rate from pharmaceutical composition comprising bazedoxifene acetate

Info

Publication number: WO2013182170A1
Application number: PCT/CZ2012/000048
Authority: WO
Inventors: Abid Riaz AHMED; Pawel STASIAK; Roman HAMTIL; Jaroslav Riha
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2012-06-07
Filing date: 2012-06-07
Publication date: 2013-12-12
Anticipated expiration: 2014-12-07

Abstract

A process of preparation of a tablet cores comprising bazedoxifene acetate, wherein the process comprises a step of preparing a pre-mix of micronised bazedoxifene acetate with at least one hydrophilic compound by intensive intimate contacting bazedoxifene acetate with the at least one hydrophilic compound performed - by intensive mixing of micronised bazedoxifene acetate with the at least one hydrophilic compound or - by co-grinding of bazedoxifene acetate with the at least one hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound s between 1:0.5-1:6.

Description

Enhancement of dissolution rate from pharmaceutical composition comprising bazedoxifene acetate FIELD OF THE INVENTION

The invention deals with a process for preparation of tablets comprising bazedoxefine acetate demonstrating enhanced dissolution rate.

BACGROUND OF THE INVENTION

Osteoporosis is a gender-related disease that is especially prevalent in postmenopausal women. Postmenopausal osteoporosis is an increasing worldwide health concern affecting an estimated 200 million individuals. The on-going need for new osteoporosis therapies has led to the development of new selective estrogen receptor modulators (SERMs) with an ideal tissue selectivity profile and beneficial effects on bone without undesirable effects on the endometrium and breast (Chines and Komm, 2009).

Bazedoxifene acetate (1-[4-(2-azepan-1 -yl-ethoxy)benzyl]-2-(4-hydroxyfenyl)-3-methyl-1 H- indol-5-ol acetic acid), having the chemical formula shown below, is a new, third-generation, oral, nonsteroidal, indole-based selective estrogen receptor modulator (SERM) being developed for the prevention and treatment of osteoporosis. This drug is used to treat postmenopausal osteoporosis in women with a high risk of fracture. Preclinical studies on bazedoxifene have demonstrated estrogen agonist effects on the skeleton and lipid metabolism but not on breast and uterine endometrium. In combination with estrogen, bazedoxifene antagonizes the stimulatory action of estrogens on proliferation of breast cancer cells and endometrium (Kung et al., 2009). Bazedoxifene acetate shows anti-fracture potential in the first few years after menopause and a greater anti-estrogen effect at the level of the uterus. This has made this compound an appropriate option in young postmenopausal women with osteoporosis and a risk of fractures.

The preparation of bazedoxifene acetate was published in the US patents 5,998,402 and 6,479,535. The bazedoxifene acetate preparation also appeared in numerous publications (e.g. Miller et AI. 2001; Miller et al. 2002; US 2005/0227965). There have been described different polymorphic forms of bazedoxifene acetate.

Two different polymorphic forms (A & B) of Bazedoxifene acetate have been disclosed in US patent applications Ser. Nos. 11/100,983 and 11/100,998. Bazedoxifene acetate form B is thermodynamically more stable than form A. In contrast, the polymorphic form A has higher solubility in aqueous and organic system than does form B. The higher solubility of polymorphic form A makes it potential candidate to prepare pharmaceutical formulations.

EP 2311805A 1 reports the Bazedoxifene acetate polymorphic form C which can be used in the preparation of pharmaceutical formulations.

US patent no. 8,063,041 discloses the Bazedoxifene acetate polymorphic form D and its preparation.

PCT application WO0203987A2 describes oral formulations of one or more poorly soluble estrogenic compounds comprising a carrier or excipient systems of a filler and disintegrant component and a lubricant component, preferably with an antioxidant. The formulations may be in any conventionally used oral forms (tablets, capsules, buccal forms, troches, lozenges, suspensions) and may be prepared by any conventional method without any closer specification (compression, wet granulation, dry granulation), with standard or delayed release of the API. The only example of formulation without antioxidant (Example 1 ) was shown to be chemically unstable (Example 5).

PCT application WO05099677A1 describes solid dispersion comprising bazedoxifene acetate and methods of their preparation. The solid dispersions are prepared by combining the bazedoxifene acetate either with a dispersing agent in solution and removing the solvent or with melted dispersing agent and solidifying the liquid mixture.

PCT application WO2007024961 describes oral formulations of bazedoxifene acetate polymorphic form A prepared by dry processes, preferably by direct mixing, comprising a carrier or excipient system that prevents or minimizes the polymorphic conversion of the active ingredient. According to the description, it was believed that the use of water and wet granulation, or roller compaction process with a power input for an extended period of time can increased the potential polymorphic conversions during processing and storage the bazedoxifene acetate formulations. The usage of a surfactant was not recommended because it was believed to facilitate the polymorphic conversion of the API. The formulations were prepared by the direct blending.

Solubility of bazedoxifene is pH-dependent and at pH below 5.0 is approx. 0.5 mg/ml {EMA Assessment Report for Conbriza, 2009). Low solubility of bazedoxifene in water leads to technological issues in immediate release solid preparations. Following slow dissolution rate, rate of the drug absorption from gastrointestinal tract is limited. Therefore, preparation of solid drug forms demonstrating enhanced dissolution rate and allowing for fast absorption would be valuable for therapy with bazedoxifene.

SUMMARY OF THE INVENTION

The present invention relates to a process of preparation of a tablet for oral administration of bazedoxifene acetate with enhanced release of the active compound from the formulation. The process of the invention comprises intensive intimate contacting the active compound bazedoxifene acetate with a hydrophilic compound. This is achieved either by intensive mixing of micronised bazedoxifene acetate with a hydrophilic compound, or by co-grinding of the bazedoxifene acetate together with a hydrophilic compound at a ratio 1 :0.5-1 :6. These pre-mixes are then used for preparation of solid formulations demonstrating enhanced dissolution rate, preferably by forming a rapidly disintegrating tablet core by method of direct compression, dry granulation or wet granulation. The tablet core can be optionally coated with a protective polymeric film.

DETAILED DESCRIPTION OF THE INVENTION

The present invention presents a process of preparation of tablets comprising bazedoxifene acetate with enhanced dissolution wherein the micronized active substance is intensively mixed or co-grinded with hydrophilic compounds. In addition, the proper selection of excipients allows for rapid disintegration of the formulation and thus fast onset of bazedoxifene acetate dissolution. Such a combination of the process and the suitable excipients was found which resulted in disintegration time of the tablet core not more than 5 minutes and at least 80% of bazedoxifene acetate was dissolved within 15 minutes (Fig. 1 ). This allows for high concentration of the active substance in stomach and its fast absorption to the blood circulation system.

The main aspect of the invention is a process for preparation of bazedoxifene acetate tablets, the process comprising a step of preparation of a pre-mix of bazedoxifene acetate with a hydrophilic compound by intensive intimate contacting bazedoxifene acetate with the hydrophilic compound. This is achieved either by intensive mixing of micronised bazedoxifene acetate with a hydrophilic compound, or by co-grinding of the bazedoxifene acetate together with a hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5-1 :6. These pre-mixes are blended with other pharmaceutically acceptable excipients and further processed by method of direct compression, dry granulation, wet granulation or their combination.

In one embodiment of the present invention, the pre-mix of bazedoxifene acetate with a hydrophilic compound can be prepared by intensive mixing of micronized bazedoxefine acetate with a hydrophilic compound. The mixing can be performed in a high shear mixer for at least 60 seconds, preferably for 5-15 minutes, most preferably for 10 min, with the mixer speed 1200-2500 rpm and the chopper speed 1500-2500 rpm, preferably with the mixer speed 1500-1800 rpm and the chopper speed 1800-2000 rpm. The mixing can be also performed in a turbula mixer for at least 10 minutes, preferably for 15 minutes, at 20-50 rpm, preferably at 30 rpm.

In another embodiment of the present invention the pre-mix of bazedoxifene acetate with a hydrophilic compound can be prepared by co-grinding of the non-micronized bazedoxifene acetate together with a hydrophilic compound using a jet mill at 1-3 bar pressure, preferably at 3 bar, wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5 and 1 :6, preferably between 1 :0.5 and 1 :3, still more preferably between 1 :0.5 and 1 : 1 and most preferably is 1 : 1. The micronized bazedoxifene acetate in the pre-mix, i.e. after the mixing or after the co- grinding process, is such that the D₉₀ value is lies below 50 μιη, preferably between 5-20 μηι and more preferably between 10-15 μιη, the D₉₀ shall be understood to mean that 90% of the particles having a particle size smaller than or equal to the indicated value as determined by conventional laser diffraction technique.

Without limiting the technical effect of the present invention, the polymorphic form C was used herein as the most preferred for its suitable physic-chemical properties. In the following description, any reference to bazedoxifene acetate is intended to include bazedoxifene acetate polymorphic form C, if not explicitly indicated to the contrary. Polymorphic form C of Bazedoxifene acetate was selected and used because it was proved to exhibit the best combination of the physico-chemical properties that are advantageous for the pharmaceutical formulations compared to polymorphic forms A, B and amorphous form (Table 1 ). The polymorphic form C of Bazedoxifene acetate together with form B is chemically more stable, has higher polymorphic stability and is less hygroscopic than form A and amorphous. Hygroscopicity is the ability of a substance to attract and hold water molecules (e.g. atmospheric moisture) from the surrounding environment through either absorption or adsorption with the absorbing or adsorbing material becoming physically "changed". It is one of the indicators of the stability of active ingredients. Hygroscopic substances need to be specifically stored (e.g. aluminium foil + desiccant) to remain unchanged. Hygroscopicity of polymorphic form C of Bazedoxifene acetate is comparable with form B whereas form A sorbed significantly higher amount of water. Hygroscopicity of amorphous form is immense.

Table 1 : Chemical stability and hygroscopicity of bazedoxifene polymorphic forms A, B and C and the amorphous form

The hydrophilic compounds comprise at least one hydrophilic filler, most preferably from the group of monosaccharaides or disaccharides or their derivatives, and optionally other hydrophilic compounds, e.g. such as surfactants, specified below. The hydrophilic filler can be selected from those known in the art, including lactose (e.g. anhydrous or monohydrate), saccharose, raffinose, compressible sugar (commercially available combination of 95.0 to 98.0% sucrose and 2 to 5% dried glucose syrup or maltodextrin), glucose, fructose, dextrose and other sugars and mixtures thereof, and sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof. The preferred hydrophilic fillers are lactose and mannitol, more preferred is lactose, mostly lactose monohydrate. Additional excipients, such fillers, binders, disintegrants, surfactants, lubricants and glidants may be added to the pre-mixes of bazedoxifene acetate with the hydrophilic compounds.

The filler can comprise any substance of this function known in the art for the preparation of the solid oral forms, including the hydrophilic fillers. The pharmaceutically acceptable filler can be selected for example from microcrystalline cellulose, powdered cellulose, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate, lactose (e.g. anhydrous or monohydrate), saccharose, raffinose, compressible sugar, glucose, fructose, dextrose and other sugars, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof. Preferred excipients are microcrystalline cellulose, lactose and mannitol and any mixtures thereof.

Examples of pharmaceutically acceptable binders are (but not limited to) polyvinylpyrrolidones of different K-values (i.e. exhibiting different viscosities in solution), microcrystalline cellulose, hydroxypropylmethylcellulose or other cellulose esters, cellulose ethers, starch, pre-gelatinized starch, polymethacrylate and any mixtures thereof. The preferred binders are povidone and pregelatinized starch, the most preferred is pregelatinized starch.

The disintegrant shall be selected most preferably from the group of sodium starch glycolate, croscarmelosse sodium, crospovidone and any their mixture. These disintegrants were selected for that they showed contribution to the technical effect of this invention.

The surfactant can be selected form the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, sugar esters of fatty acids and glycerides of fatty acids or mixtures thereof. The preferred surfactant is sodium lauryl sulfate.

The glidant can be selected from the group of stearic acid and its metallic salts, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, colloidal silica and any mixtures of thereof. The preferred glidants are metallic stearates and colloidal silica; the most preferred is colloidal silica. Examples of lubricants as excipients include stearic acid or stearic acid salts, such as magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, and any mixtures thereof. Preferred is magnesium stearate or sodium stearyl fumarate, mostly magnesium stearate.

The composition of the tablet core according to the invention comprises:

^■ 1-20% of micronized bazedoxifene acetate

^■ 10-60% of hydrophilic excipient

- 20-50% of filler

- 2-15% of binder

^■ 2-15% of disintegrant

^■ optionally up to 5% of surfactant

^■ optionally up to 5% of glidant

^■ optionally up to 5% of lubricant

The tablet cores can be optionally coated by a commonly used coating. The function of the coating can be as for strengthen the tablet, control its release, improve its taste, colour it, make it easier to handle and package, and protect it from moisture. Preferably, a moisture protective coating is used.

The final tablet can be prepared by method of direct compression, dry granulation, wet granulation, or their combination.

The process of preparation of pharmaceutical composition of the present invention by direct compression technique may comprise the following steps:

a) Preparation of the pre-mix of bazedoxifene acetate with at least one hydrophilic compound either by

a. intensive mixing of micronised bazedoxifene acetate with the at least one hydrophilic compound, or

b. co-grinding of the bazedoxifene acetate together with the at least one hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5 and 1 :6

b) Addition of the rest of excipients such as fillers, binders, disintegrants, surfactants, lubricants and/or glidants to the pre-mix

c) Blending the resulting mixture

d) Compressing the resulting mixture into tablets and e) Optionally coating of the tablet cores

The process of preparation of pharmaceutical composition of the present invention by dry granulation may comprise the following steps:

a) Preparation of the pre-mix of bazedoxefine acetate with at least one hydrophilic compound either by

b) Addition of other excipients such fillers, binders, disintegrants, surfactants, lubricants and/or glidants to the pre-mix

c) Blending the resulting mixture

d) Compressing the resulted blend into the compacts

e) Milling the compacts into the granules

f) Admixing of a lubricant and optionally other additional powdered excipient (e.g. filler, disintegrant, binder, glidant) to the granulate

g) Compressing the resulting mixture into tablets

h) Optionally coating of the tablet cores.

The process of preparation of pharmaceutical composition of the present invention by wet granulation may comprise the following steps:

c) Blending the resulting mixture

d) Wet granulation of the blend obtained in the step c) with the granulation liquid using the high shear mixer or the fluid-bed granulator e) Admixing of a lubricant and optionally other additional powdered excipient (e.g. filler, disintegrant, binder, glidant) to the granulate

f) Compressing the resulting mixture into tablets

g) Optionally coating of the tablet cores

The granulation liquid can be water or its mixtures with pharmaceutically acceptable organic solvents (preferably ethanol) at any ratio, aqueous solution of binders or solution of binders in an organic solvent or its mixture with water at any ratio. The process of preparation of pharmaceutical composition of the present invention by combination of wet granulation and dry granulation may comprise the following steps: a) preparation of first part of granules by dry granulation process comprising:

a. optionally preparation of the pre-mix of bazedoxifene acetate with at least one hydrophilic compound either by

i. intensive mixing of micronised bazedoxifene acetate with the at least one hydrophilic compound, or

ii. co-grinding of the bazedoxifene acetate together with the at least one hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5 and 1 :6 b. Addition of first parts of other excipients such fillers, binders, disintegrants, surfactants, lubricants and/or glidants to the pre-mix

c. Blending the resulting mixture

d. Compressing the resulted blend into the compacts

e. Milling the compacts into the granules

b) preparation of second part of granules by wet granulation process comprising following steps:

a. if not comprised in the step a) then preparation of the pre-mix of bazedoxefine acetate with at least one hydrophilic compound either by

ii. co-grinding of the bazedoxifene acetate together with the at least one hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5 and 1 :6 b. Addition of the rest of the other excipients such fillers, binders, disintegrants, surfactants, lubricants and/or glidants to the pre-mix

c. Blending the resulting mixture d. Wet granulation of the blend obtained in the step c) with the granulation liquid using the high shear mixer or the fluid-bed granulator

c) blending of the granules produced in the steps a) with the granules produced in the step b)

d) Admixing of a lubricant and optionally other additional powdered excipient (e.g. filler, disintegrant, binder, glidant) to the blend of the step c)

e) Compressing the resulting mixture into tablets

f) Optionally coating of the tablet cores.

Examples

The invention is illustrated but in any way not limited by the following examples:

Example 1 : Composition of 20 mg tablet core

The final composition of the tablet cores is shown in the table.

Example 2: Methods of preparation of the tablet cores by the dry granulation

The tablet cores of the composition shown in the Example 1 were prepared by several different methods of the invention:

a. pre-mix of micronised bazedoxifene acetate with lactose b. co-grinding of bazedoxifene acetate with lactose in the ratio 1 : 1 c. comparative: micronised bazedoxifene acetate without pre-mixing with lactose d. comparative: non-micronised bazedoxifene acetate Example 2a

The micronised bazedoxifene acetate (equivalent to 20 mg bazedoxifene per tablet) was provisionally mixed with lactose monohydrate and sodium lauryl sulphate. The blend was sieved through the screen (0.63 mm) and mixed in a high shear mixer for 10 min (mixer speed 1500 rpm, chopper speed 1800 rpm. The resulting pre-mix was complemented with two thirds of sieved microcrystalline cellulose, two thirds of the sodium starch glycolate and with pregelatinised starch and mixed for 10 minutes in a tubular mixer at 30 rpm. One third of the magnesium stearate was admixed for additional 3 minutes. The blend was granulated using roller-compaction process with a force between 3-7 KN/cm. The compacts were milled through 1.0 mm sieve and resulting granules were mixed with remaining microcrystalline cellulose, sodium starch glycolate and with colloidal anhydrous silica for 10 minutes in turbula mixer at 30 rpm. The remaining magnesium stearate was added and mixed for 3 min in turbula mixer at 30 rpm. The final blend was compressed into 400 mg tablet cores using rotary tablet press. The tablet cores were coated with a moisture protection polymer. Example 2b

The non-micronised bazedoxifene acetate (equivalent to 20 mg bazedoxifene per tablet) was provisionally mixed with part of lactose monohydrate, so that the ratio between the bazedoxifene acetate and lactose was 1 :1. This mix was subjected to the jet-milling at 3 bar pressure. The resulting pre-mix was complemented with the rest of lactose, two thirds of sieved microcrystalline cellulose, two thirds of the sodium starch glycolate and with pregelatinised starch and sodium lauryl sulphate and mixed in a high shear mixer for 5 min (mixer speed 1500 rpm, chopper speed 1800 rpm. One third of the magnesium stearate was admixed for additional 3 minutes. The blend was granulated using roller-compaction process and resulting granules were mixed with remaining microcrystalline cellulose, sodium starch glycolate and with colloidal anhydrous silica for 10 minutes in turbula mixer at 30 rpm. The remaining magnesium stearate was added and mixed for 3 min in turbula mixer at 30 rpm. The final blend was compressed into 400 mg tablet cores using rotary tablet press. The tablet cores were coated with a moisture protection polymer. Example 2c

The process of preparation of the tablet cores was similar to the process of example 2a, only the step of pre-mixing of the micronised bazedoxifene acetate with lactose and the sodium lauryl suplhate was not performed.

Example 2d

The process of preparation of the tablet cores was similar to the process of example 2c, only the used bazedoxifene acetate was not micronised. Example 3: Composition of 20 mg tablet core

Example 4: Methods of preparation of the tablet cores by the wet granulation

The tablet cores of the composition shown in the Example 3 were prepared by several different methods of the invention:

a. pre-mix of micronised bazedoxifene acetate with lactose

b. co-grinding of bazedoxifene acetate with lactose in the ratio 1 : 1 c. comparative: micronised bazedoxifene acetate without pre-mixing with lactose d. comparative: non-micronised bazedoxifene acetate

Example 4a

The micronised bazedoxifene acetate (equivalent to 20 mg bazedoxifene per tablet) was provisionally mixed with lactose monohydrate and sodium lauryl sulphate. The blend was sieved through the screen (0.63 mm) and mixed in a high shear mixer for 10 min (mixer speed 1700 rpm, chopper speed 2000 rpm). The resulting pre-mix was complemented with two thirds of sieved microcrystalline cellulose, two thirds of the Sodium carboxymethylcellulose and with pregelatinised starch and mixed for 5 minutes in a high shear mixer at 1500 rpm. The blend was wet granulated with aqueous solution of pregelatinised starch using a fluid bed dryer. The resulting granules were mixed with remaining microcrystalline cellulose, Sodium carboxymethylcellulose and with colloidal anhydrous silica for 10 minutes in turbula mixer at 30 rpm. The remaining magnesium stearate was added and mixed for 3 min in turbula mixer at 30 rpm. The final blend was compressed into 400 mg tablet cores using rotary tablet press. The tablet cores were coated with a moisture protection polymer.

Example 4b

The non-micronised bazedoxifene acetate (equivalent to 20 mg bazedoxifene per tablet) was provisionally mixed with part of lactose monohydrate and with the sodium lauryl sulphate, so that the ratio between the bazedoxifene acetate and lactose was 1 : 1 . This mix was subjected to the jet-milling at 3 bar pressure. The resulting pre-mix was complemented with the rest of lactose, two thirds of sieved microcrystalline cellulose, two thirds of the Sodium carboxymethylcellulose and with pregelatinised starch and mixed in a high shear mixer for 5 min (mixer speed 1500 rpm, chopper speed 1800 rpm). The blend was wet granulated and further processed as described in the Example 4a.

Example 4c

The process of preparation of the tablet cores was similar to the process of example 4a, only the step of pre-mixing of the micronised bazedoxifene acetate with lactose and the sodium lauryl sulphate was not performed.

Example 4d

The process of preparation of the tablet cores was similar to the process of example 4c, only the used bazedoxifene acetate was not micronised. Example 5: Composition of 20 mg tablet core

Example 6: Methods of preparation of the tablet cores partially by the wet granulation and partially by the dry granulation

The tablet cores of the composition shown in the Example 5 were prepared by several different methods of the invention:

a. co-grinding of bazedoxifene acetate with lactose in the ratio 1 : 1

b. comparative: micronised bazedoxifene acetate without pre-mixing with lactose Example 6a

The non-micronised bazedoxifene acetate (equivalent to 20 mg bazedoxifene per tablet) was provisionally mixed with part of lactose monohydrate and with the sodium lauryl sulphate, so that the ratio between the bazedoxifene acetate and lactose was 1 : 1. This mix was subjected to the jet-milling at 3 bar pressure. The rest of the excipients for the wet granulation, as indicated in the Example 5, was added to the pre-mix, mixed in a high shear mixer for 5 min (mixer speed 1500 rpm, chopper speed 1800 rpm) and wet granulated with aqueous solution of pregelatinised starch using a fluid bed dryer.

The excipients for the dry granules, as indicated in the table of the Example 5, were blended for 10 minutes in a tubular mixer at 30 rpm. One third of the magnesium stearate was admixed for 3 min at 30 rpm. This lend was compacted with a force between 3-7 KN/cm. The compacts were milled through 1.0 mm sieve.

Both parts of granules were blended for 15 min in the turbula mixer at 30 rpm. The resulting blend was lubricated with the rest of the lubricant and compressed into tablet cores. The tablet cores were coated with a moisture protection polymer.

Example 6b

The process of preparation of the tablet cores was similar to the process of example 6a, only the step of pre-mixing of the micronised bazedoxifene acetate with lactose and the sodium lauryl sulphate was not performed.

Example 7: Dissolution and release profiles

The dissolution of the tablets and the profiles of bazedoxifene acetate release were measured for the tablets produced in the Example 2a-d, Example 3a-d and Example 4. The dissolution profiles were measured in phosphate buffer at pH 4.5 with 0.1 % of Tween 20 in a paddle apparatus at a speed of 50 rpm for first 45 min and then at 150 rpm for the rest of measurement. The results are shown in Figures 1-3.

Example 8: Dry granulation with different ratios between bazedoxifene acetate and hydrophilic compounds in the pre-mix

Tablet cores of composition from the Example 2 were prepared by the method described in the Example 2b (dry granulation, co-grinding) except that different ratios of bazedoxifene acetate and the hydrophilic compounds were tested. The tested ratios are shown in the table below:

The dissolution profiles of these tablets are shown in the Figure 4. There was evident effect of the co-grinding of the bazedoxifene acetate with the hydrophilic compounds versus the comparative tablet. However, the differences among the tablets a-d were minor. The co- grinding with and without sodium lauryl sulphate gave similar results. The differences in dissolution profiles among the tablets prepared by co-grinding at the ratios bazedoxifene acetate to hydrophilic compounds lying between 1 :0.5 and 1 :6 were minor. The best results were achieved with the ratio 1 :1.

Higher ratios of bazedoxifene acetate to lactose were tested as well (results not shown); however, uniformity problems during manufacturing of such tablets occurred.

Claims

Claims:

1 . A process of preparation of a tablet cores comprising bazedoxifene acetate, wherein the process comprises a step of preparing a pre-mix of micronised bazedoxifene acetate with at least one hydrophilic compound by intensive intimate contacting bazedoxifene acetate with the at least one hydrophilic compound performed

- by intensive mixing of micronised bazedoxifene acetate with the at least one hydrophilic compound or

- by co-grinding of bazedoxifene acetate with the at least one hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound s between 1 :0.5-1 :6.

2. The process of claim 1 , wherein the micronised bazedoxifene acetate is intensively mixed with the hydrophilic compound in a high shear mixer for at least 60 seconds with the mixer speed 1200-2500 rpm and the chopper speed 1500-2500 rpm.

3. The process according to claim 2, wherein the mixing is performed for 5-15 minutes.

4. The process according to claim 2, wherein the mixing is performed with the mixer speed 1500-1800 rpm and the chopper speed 1800-2000 rpm.

5. The process of claim 1 , wherein the micronised bazedoxifene acetate is intensively mixed with the hydrophilic compound in a turbula mixer for at least 10 minutes with the mixer speed 20-50 rpm.

6. The process according to claim 5, wherein the mixing is performed with the mixer speed 30 rpm.

7. The process of claim 1 , wherein the bazedoxifene acetate is co-grinded with the at least one hydrophilic compound wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5-1 :6 using a jet mill at 1 -3 bar pressure.

8. The process of claim 7, wherein the pressure is 3 bar.

9. The process according to claims 7-8, wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is between 1 :0.5 and 1 :3.

10. The process according to claims 8-9, wherein the ratio of the bazedoxifene acetate to the hydrophilic compound is 1 : 1 .

1 1. The process according to any of preceding claims, wherein the at least one hydrophilic compound is selected from the group hydrophilic fillers and/or surfactants.

12. The process according to claim 1 1 , wherein the hydrophilic compound is a monosaccharide, a disaccharide, a sugar alcohol or any their combination.

13. The process according to claim 1 1 , wherein the at least one hydrophilic compound is selected from the group comprising lactose, saccharose, raffinose, compressible sugar, glucose, fructose, dextrose, mannitol, sorbitol, maltitol, xylitol, lactitol, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, sugar esters of fatty acids and glycerides of fatty acids or mixtures thereof.

14. The process according to claims 1 1-13, wherein the at least one hydrophilic compound is lactose anhydrous, lactose monohydrate, mannitol, sodium lauryl sulphate or any combination thereof.

15. The process according to claim 1 , wherein the pre-mix of micronised bazedoxifene acetate with the at least one hydrophilic compound is combined with other pharmaceutically acceptable excipients and processed by a direct compression, dry granulation and/or wet granulation methods to the tablet cores.

16. The process according to claim 15, wherein the tablet cores of bazedoxifene comprises

^■ 1-20% of micronized bazedoxifene acetate

• 10-60% of hydrophilic excipient selected from the group comprising lactose, saccharose, raffinose, compressible sugar, glucose, fructose, dextrose, mannitol, sorbitol, maltitol, xylitol, lactitol, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, sugar esters of fatty acids and glycerides of fatty acids or mixtures thereof

■ 20-50% of filler selected form the group of microcrystalline cellulose, powdered cellulose, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate, lactose, saccharose, raffinose, compressible sugar, glucose, fructose, dextrose, mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof

^■ 2-15% of binder selected from the group of polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropylmethylcellulose, cellulose ethers, starch, pre-gelatinized starch, polymethacrylate and any mixtures thereof

^■ 2-15% of disintegrant selected from the group of sodium starch glycolate, croscarmelosse sodium, crospovidone and any their mixture

^■ optionally up to 5% of surfactant selected form the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, sugar esters of fatty acids and glycerides of fatty acids or mixtures thereof

^■ optionally up to 5% of glidant selected from the group of stearic acid and its metallic salts, magnesium palmitat, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, colloidal silica and any mixtures of thereof

• optionally up to 5% of lubricant selected form the group of stearic acid or stearic acid salts, such as magnesium stearate, magnesium palmitat, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, and any mixtures thereof.

17. The process of claim 16, wherein the tablet cores comprise

^■ 1-20% of micronized bazedoxifene acetate

^■ 10-60% of hydrophilic excipient being lactose monohydrate

^■ 20-50% of filler being microcrystalline cellulose, lactose monohydrate or their combination

^■ 2-15% of binder being microcrystalline cellulose, pre-gelatinized starch, or their combination

^■ optionally up to 5% of surfactant being sodium lauryl sulfate

^■ optionally up to 5% of glidant colloidal silica

^■ optionally up to 5% of lubricant being magnesium stearate.

18. The process according to claim 17, wherein the process further comprises the coating of the tablet cores by a coating.