WO2013182169A1

WO2013182169A1 - Process of preparation of an antioxidant-free polymorphically and chemically stable formulation of bazedoxifene acetate

Info

Publication number: WO2013182169A1
Application number: PCT/CZ2012/000047
Authority: WO
Inventors: Abid Riaz AHMED; Pawel STASIAK
Original assignee: Zentiva, K. S.
Priority date: 2012-06-07
Filing date: 2012-06-07
Publication date: 2013-12-12

Abstract

An aqueous process for preparation of an antioxidant-free and polymorphically and chemically stable oral solid formulation of bazedoxifene acetate, comprising: a. Preparing a wet portion of the formulation in the form of granules prepared by wet granulation b. Preparing a dry portion of the final formulation prepared by direct mixing or by dry granulation c. Mixing the portions in a ratio that varies between 25:75 - 75:25 d. Optionally admixing of further powder excipients, such as one or more fillers, glidants and / or lubricants, and e. Manufacturing the final formulation by i/ compressing the blend into tablet cores and coating the cores with a coating comprising moisture protective polymers ii/ filling the blend into moisture protective capsules wherein the active compound bazedoxifene acetate is incorporated either into the wet portion or into the dry portion and wherein the preparation of the portion comprising the active compound bazedoxifene acetate comprises as the first step pre-blending bazedoxifene acetate with a hydrophilic filler.

Description

Process of preparation of an antioxidant-free polymorphically and chemically stable formulation of bazedoxifene acetate

FIELD OF THE INVENTION

The invention deals with a stable antioxidant-free formulation of bazedoxifene acetate prepared by wet aqueous processes.

BACKGROUND 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 ongoing 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 ai, 2009). Bazedoxifene acetate shows anti-fracture potential in the first few years after menopause and a greater antiestrogen 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. Generally, physico- chemical properties (e.g. melting point, solubility) of a compound all vary with the polymorphic form. Due to potential advantages associated with a specific polymorphic form of an active ingredient, it is desirable to prevent or minimize its polymorphic conversion. Such polymorphic conversions can occur during synthesis of active substance, storage and especially during preparation of pharmaceutical formulations and storage of a pharmaceutical dosage form.

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 2311805A1 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 combinig 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. Based on the above described facts, there is a need of a robust, reproducible and efficient method of preparation of chemically as well as poiymorphically stable oral formulations of bazedoxifene acetate. The process for preparation of chemically and poiymorphically stable antioxidant-free oral solid forms comprising bazedoxifene acetate described herein meets these needs.

SUMMARY OF THE INVENTION

The present invention relates to the manufacturing process of a stable, antioxidant-free pharmaceutical formulation of bazedoxifene acetate which comprises preparation of a wet portion prepared by the wet aqueous granulation and preparation of a dry portion and mixing the portions in different ratios.

DETAILED DESCRIPTION OF THE INVENTION

The aim of this invention was to find out a method of preparation of bazedoxifene acetate solid oral formulations where any polymorphic conversion would be prevented or minimized during the production as well as during the storage of the formulations, so that the desirable physico-chemical properties of the used active ingredient stay unaffected, while the resulting formulations being as well chemically stable against oxidation. Surprisingly, a process for preparation of formulations was found which fulfilled both these requirements, even without usage of any antioxidant in the composition of the tablets.

It was found that the dry processes (direct compression, roller compaction) were not suitable for preparation of the formulations according to this invention (Examples'! -4). Although direct compression is simple and cost effective method in comparison to roller compaction and wet granulation, serious problems of weight variation and content uniformity were observed. Roller compaction was used for increasing the bulk density of powders, whilst increasing the particle size, resulting in better flowing material. However, after roller compaction, the granules were difficult to compress on a fast rotary tableting machine due to loss of rework ability. Furthermore, variation in content uniformity was observed.

Wet aqueous granulation process improved flowability and compressibility of the granules. It also improved the content uniformity and the segregation was prevented during process. However, the dissolution was very poor. The release profile was too slow and low (Figure 1 ) because the formed granules were very compact and thick with limited possibilities of wettability.

Therefore, robust formulation was developed with improved dissolution rate of bazedoxifene acetate as a poorly soluble drug. The present invention relates to the manufacturing process of a stable, antioxidant-free pharmaceutical composition of bazedoxifene acetate which comprises mixing of a first dry portion with a second portion of granules prepared by wet aqueous granulation, optionally with further admixing of other powdered excipients, wherein ratio between the dry portion and the granules prepared by wet aqueous granulation varies between 25:75 - 75:25. The active compound may be incorporated either into the wet granules or into the dry portion. This mixture can be filled into capsules or compressed into tablets.

The process of preparation of the formulation according to the invention

The process of the preparation of the antioxidant-free chemically and polymorphically stable pharmaceutical composition of the present invention comprises following steps:

a. Preparing dry portion of the final formulation by direct mixing or by dry granulation (e.g. by compaction)

b. Preparing wet portion of the final formulation by wet granulation

c. Mixing the portions in a ratio that varies between 25:75 - 75:25

d. Optionally admixing of further powder excipients, such as one or more fillers, glidants and / or lubricants

e. Compressing the blend into tablets or filling the blend into capsules.

f. Coating with a coating comprising moisture protective polymers.

The wet portion prepared by wet granulation process

The expression "wet portion" used in the text of this application means the part of the formulation that is in the form of granules prepared by the wet aqueous granulation. The mixture for preparation of the portion of granules prepared by the wet granulation may or may not comprise the active compound bazedoxifene acetate. If the bazedoxifene acetate is present, the mixture comprises also at least one hydrophilic filler which is intensively blended with the bazedoxifene acetate prior addition of the rest of excipients. The mixture further comprises at least one additional filler, at least one binder, at least one disintegrant selected from the group of sodium starch glycolate, sodium croscarmellose and crospovidone and at least one surfactant.

The wet granules can be prepared in a high shear mixer or by a fluid bed granulation process. In the high shear mixer, first the micronized bazedoxifene acetate (if present) and the hydrophilic filler (if bazedoxifene acetate is present in the wet portion of granules) are intensively blended and after that this mixture is intensively blended with the rest of the excipients in a manner commonly known to a skilled person. Without or with few experiments a skilled person can adjust the necessary conditions (premixing time, speed of granulation liquid addition, amount of the liquid, speed of the mixture etc.). The amount of granulation water and time of granulation was adjusted so that the granulate was of a size that did not require wet milling prior to drying. The wet-granulate was dried in a fluid bed dryer at less than 40 °C to obtain dried granulate and the granules were milled through 1.0 mm sieve after drying. The milled dried granulate had excellent flow ability and could be easily compressed into tablets with a suitable hardness and friability.

As an alternative, the fluid bed granulation process was used to prepare the wet aqueous granulation portion. The pre-mix of bazedoxifene acetate (if present in the wet portion of granules) with at least one hydrophilic filler (if bazedoxifene acetate is present in the wet portion of granules) was intensively blended with at least one additional filler, at least one binder, at least one disintegrant selected form the group of sodium starch glycolate, sodium croscarmellose and crospovidone and at least one surfactant in fluid bed before the start of the liquid spraying. The mixture was then sprayed with water, optionally comprising dissolved and/or dispersed one or more binders. The necessary process parameter can be adjusted by a skilled person with or without few experiments. The amount of water with or without binders and time of spray were adjusted to avoid agglomerate formation. The wet- granulate was further dried in a fluid bed dryer at less than 40 °C to obtain dried granulate and the dried granules were milled through 1.0 mm sieve. The milled dried granulate had excellent flow ability and could be easily compressed into tablets with a suitable hardness and friability.

The dry portion

The expression "dry portion" used in the text of this application means the part of the formulation that is prepared by a dry process (direct blending, dry granulation, roller compaction).

The dry portion may or may not comprise the active compound bazedoxifene acetate. If the bazedoxifene acetate is present in the wet granules portion, it is not present in the dry portion and vice versa, if the bazedoxifene acetate is not present in the wet granules portion, it is present in the dry portion. The mixture for the dry portion comprises further at least one hydrophilic filler (if bazedoxifene acetate is present), at least one additional filler, at least one binder, at least one disintegrant selected from the group of sodium starch glycolate, sodium croscarmellose and crospovidone, at least one surfactant and optionally a lubricant.

The dry portion of the final formulation can be produced either by direct blending of the ingredients or by a roller compaction, i.e. the ingredients are blended and compacted using the roller compactor with a force of 1 -20 KN/cm, most preferably between 3-7 KN/cm. In both cases, if present in the dry portion, the bazadoxifene acetate and the hydrophilic filler are first intensively pre-blended and only after that the rest of excipient is added and intensively blended with the pre-mix of bazedoxifene acetate and the hydrophilic filler. Prior to the compaction, the blend is to be lubricated by a lubricant. If the final formulation is in a form of tablet, the amount of the lubricant used in the dry portion is approximately one quarter of the total amount of the lubricant in the final formulation. The final formulation

The final blend for the final formulation comprises a wet portion and a dry portion wherein the ratio between the wet portion and the dry portion varies between 25:75 - 75:25. As stated above, the active compound may be incorporated into the wet portion or into the dry portion. Both portions are blended together and optionally further powdered excipients, such as glidants, lubricants and fillers, can be admixed. This final blend can be filled into moisture protective capsules or compressed into tablet cores and coated with a moisture protection polymer.

In a preferred embodiment, the formulation is in a form of tablets prepared by blending of a wet portion and a dry portion wherein the ratio between the wet portion and the dry portion varies between 25:75 - 75:25 and to this blend is further admixed a lubricant and optionally a glidant. This final blend exhibits excellent flow ability and can be easily compressed into tablets with suitable hardness and friability. The tablets are coated with a moisture protection polymer. The final formulation can be packed into PVC, PVC-AI or AI-AI blisters, or into, bottles, in normal atmosphere (air) or under an inert atmosphere (nitrogen, argon).

All the formulations produced by the method of the invention showed no sign of polymorphic conversion (see Examples, Figure 2). The stress and stability study showed that all the formulations according to the invention were chemically stable under dry and humid-heat conditions as well (Table 2).

Composition of the formulation The formulation is composed of two portions, the wet portion and the dry portion. The bazedoxifene acetate may be incorporated either into the wet portion or into the dry portion.

The composition of the portion (either wet or dry) comprising the bazedoxifene acetate is following: a/ 7 - 25% micronized bazedoxifene acetate

b/ 18 - 48% hydrophilic filler

c/ 24 - 35% filler other than in b/

d/ 4 - 6% binder

el 5 - 17% disintegrant selected from sodium starch glycolate, sodium

carboxymethylcellulose, crospovidone and any their mixture

f/ 1 - 5% surfactant

g/ optionally up to 2% glidant The percentages listed above indicate percentages by weight of the total weight of the components of the portion comprising the bazedoxifene actetate.

The composition of the portion (either wet or dry) without the bazedoxifene acetate is following: a/ 65 - 87% filler

b/ 8 - 17% binder

c/ 4 - 17% disintegrant selected from sodium starch glycolate, sodium

carboxymethylcellulose, crospovidone and any their mixture

d/ optionally up to 2% glidant

The percentages listed above indicate percentages by weight of the total weight of the components of the portion without the bazedoxifene acetate.

Components of the formulations

Active compound

The active compound of the formulations according to the invention is micronized bazedoxifene acetate with D90 particle size of (i.e. 90 percent of the particle size distribution lies below) about 100 μΐτι, preferably about 50 μητι, more preferably about 20 μΐη and still more preferably about 15 μιη. The polymorphic form of the bazedoxifene acetate shall be substantially pure and will stay stable when formulated according to this invention. 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 polymorphic forms of bazedoxifene acetate were monitored using the state of the arte technique (X-ray powder diffraction, XRPD, X'Pert PRO PANalytical diffractometer, CuKa radiation (I = 1.542 A) in the range of 4 - 40° 2Θ with the increment of 0.008).

Excipients

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), 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.

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, 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 from the group of sodium starch glycolate, croscarmellose sodium, crospovidone and any their mixture. 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 are magnesium stearate or sodium stearyl fumarate, mostly magnesium stearate.

Examples 1 and 2: Direct compression

The tablet mixture was prepared by direct blending. First blend was prepared by blending of micronized bazedoxifene acetate, lactose and sodium lauryl sulphate for 10 min. Second blend was prepared by addition of the remaining excipients except lubricant to the first blend and blending for 15 min. After that lubricant was added to the second blend, followed by mixing for 3 min. The core tablets were then coated with a moisture protection polymer.

Although the lubricated mixture had very good flow ability and could be easily compressed into tablets with suitable hardness and friability, and although the method of direct compression is simple and cost effective, serious problems of weight variation and content uniformity were observed because of segregation of the active ingredient and the excipients caused by differences in their densities and due to the static charge that is induced during the dry mixing. Example 1 : Composition of 20 mq film coated tablet prepared by direct compression

Composition/tablet

Tablet core

mg %

Bazedoxifene acetate 22.55 5.64

Lactose monohydrate 144.00 36.00

Avicel PH 101 105.45 26.36

Sodium lauryl sulfate 4.00 1.00

Ac-di-sol 25.00 6.25

Avicel PH 102 95.00 23.75

Colloidal anhydrous silica 1.00 0.25

Magnesium stearate 3.00 0.75

Total 400.00 100.00

Film coating mg %

Methocel E 5 12.00 48.78

HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

Demineralized water 200.00

Total (Solid) 24.60 100.00

Example 2: Composition of 20 mq film coated tablet prepared by direct compression

Examples 3 and 4: Roller compaction

A first blend was prepared by mixing of micronized bazedoxifene and rest of excipients in a blender for 10 min. A second blend was prepared by blending 1/4^th lubricant (e.g. magnesium stearate) of the composition with the first blend for 3 min. The second blend was compacted with a force of 1 -20 KN/cm, the most preferable between 3-7 KN/cm. The compacts were milled to granules by sieving through 1 .0 mm sieve. The resulted dry granulate further lubricated with rest of the lubricant and compressed in to tablet cores. The tablet cores were coated with a moisture protection polymer.

The granules prepared by compaction had excellent flow ability and could be easily compressed into tablets with suitable hardness and friability. However, after roller compaction, granules were difficult to compress on a fast rotary tableting machine due to loss of rework ability. Due to this disadvantage there is limitation of selection of suitable excipients. Further, variation in content uniformity was observed, the micronized bazedoxifene acetate segregated from the excipients during blending and no robust formulation was achieved.

Example 3: Composition of 20 mq film coated tablet prepared by granulation by roller compaction

Composition/tablet

Tablet core

mg %

Bazedoxifene acetate 22.55 5.64

Lactose monohydrate 144.00 36.00

Avicel PH 101 105.45 26.36

Sodium lauryl sulfate 4.00 1.00

Ac-di-sol 25.00 6.25

Avicel PH 102 95.00 23.75

Colloidal anhydrous silica 1.00 0.25

Magnesium stearate 3.00 0.75

Total 400.00 100.00

Film coating mg %

Methocel E 5 12.00 48.78

HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

Demineralized water 200.00

Total (Solid) 24.60 100.00

Example 4: Composition of 20 mq film coated tablet prepared by granulation by roller compaction

Composition/tablet

Tablet core

mg %

Bazedoxifene acetate 22.55 5.64

Lactose monohydrate 144.00 36.00

Avicel PH 101 105.45 26.36

Pregelatinised starch 30.00 7.50

Sodium starch glycolate 30.00 7.50

Sodium lauryl sulfate 4.00 1.00

Avicel PH 102 60.00 15.00

Colloidal anhydrous silica 1.00 0.25

Magnesium stearate 3.00 0.75

Total 400.00 100.00

Film coating mg %

Methocel E 5 12.00 48.78

HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

Demineralized water 200.00

Total (Solid) 24.60 100.00

Example 5: Wet granulation

Bazedoxifene acetate was intensively mixed with lactose for 10 min. After that all the other excipients except the magnesium stearate were added and the mixture was blended for additional 15 min. Finally, the magnesium stearate was admixed for 3 min. The blend was then granulated in the high shear mixture by water. The granulate was dried at 40°C, milled to through 1.0 mm sieve and compressed into the tablet cores. The tablet cores were then film-coated.

Example 5: Composition of 20 mq film coated tablet prepared by wet aqueous granulation

Composition/tablet

Tablet core

mg %

Bazedoxifene acetate 22.55 5.64

Lactose monohydrate 144.00 36.00

Avicel PH 101 105.45 26.36

Pregelatinised starch 30.00 7.50

Sodium starch glycolate 30.00 7.50

Sodium lauryl sulfate 4.00 1.00

Avicel PH 102 60.00 15.00

Colloidal anhydrous silica 1.00 0.25

Magnesium stearate 3.00 0.75

Total 400.00 100.00

Film coating mg %

Methocel E 5 12.00 48.78

HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

Demineralized water 200.00

Total (Solid) 24.60 100.00 Examples 6 and 7: Formulations prepared from a wet portion comprising bazedoxifene acetate and a dry portion

Wet portion

Bazedoxifene acetate was intensively mixed with lactose for 10 min. After that all the other excipients of the wet portion (as indicated in the table of composition) were added and the mixture was blended for additional 15 min. The blend was then granulated by water in the high shear mixture. The granulate was dried at 40°C and milled to 1.0 mm sieve.

Dry portion

All the excipients of the dry portion (as indicated in the table of composition) were blended in a blender for 15 min. After that 1/4^th of the total amount of magnesium stearate was added and the blend was mixed for additional 3 min. This blend was compacted with a force between 3-7 KN/cm. The compacts were milled to granules sieving through 1.0 mm sieve.

The final formulation

The wet portion and the dry portion were blended together for 15 min. The resulting bled was lubricated with the rest of the lubricant and compressed in to tablet cores. The tablet cores were coated with a moisture protection polymer.

Example 6: Composition of 20 mq film coated tablet prepared by combining of 25% wet portion comprising bazedoxifene acetate with 75% dry portion

Composition/tablet

Portion Tablet core

mg %

Bazedoxifene acetate 22.55 23.9

Lactose monohydrate 24.55 26.0

Wet

Avicel PH 101 23.30 24.7

(25% of total Pregelatinised starch 5.00 5.3 formulation) Sodium starch glycolate 15.00 15.9

Sodium lauryl sulfate 4.00 4.2

Total wet portion 94.40 100.00

Lactose monohydrate 1 19.60 39.5

Avicel PH 101 78.00 25.8

Dry Pregelatinised starch 25.00 8.3

(75% of total Sodium starch glycolate 15.00 5.0 formulation) Avicel PH 102 64.00 21.2

Colloidal anhydrous silica 1.00 0.3

Total drv portion 302.60 100.00

Lubricant Magnesium stearate 3.00

Total tbl core 400.00

Film coating mg %

Methocel E 5 12.00 48.78

Film coating HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

water Demineralized water 200.00

Total tbl (Solid) 24.60 100.00

Example 7: Composition of 20 mq film coated tablet prepared by combining of 75% wet portion comprising bazedoxifene acetate with 25% dry portion

Dry/wet Composition/tablet

Tablet core

portion mg %

Bazedoxifene acetate 22.55 7.4

Lactose monohydrate 144.00 47.1

Wet Avicel PH 101 105.45 34.5

(75% of total Pregelatinised starch 15.00 4.9 formulation) Sodium starch glycolate 15.00 4.9

Sodium lauryl sulfate 4.00 1.3

Total wet portion 306.00 100.00

Pregelatinised starch 15.00 16.5

Dry Sodium starch glycolate 15.00 16.5

(25% of total Avicel PH 102 60.00 65.9 formulation) Colloidal anhydrous silica 1.00 1.1

Total dry portion 91.00 100.00

Lubricant Magnesium stearate 3.00

Total tbl core 400.00

Film coating mg %

Methocel E 5 12.00 48.78

Film coating HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

water Demineralized water 200.00

Total tbl (Solid) 24.60 100.00

Examples 8 and 9: Formulations prepared from a wet portion and a dry portion comprising bazedoxifene acetate

Wet portion

All the excipients of the wet portion (as indicated in the table of composition) were blended in a blender for 15 min. The blend was then granulated by water in the high shear mixture. The granulate was dried at 40°C and milled to through 1.0 mm sieve.

Dry portion

Bazedoxifene acetate was intensively mixed with lactose for 10 min. After that all the other excipients of the wet portion (as indicated in the table of composition) were added and the mixture was blended for additional 15 min. After that 1/4^th of the total amount of magnesium stearate was added and the blend was mixed for additional 3 min. This blend was compacted with a force between 3-7 KN/cm. The compacts were milled to granules through 1.0 mm sieve.

The final formulation

The wet portion and the dry portion were blended together for 15 min. 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 8: Composition of 20 mq film coated tablet prepared by combining of 25% wet portion with 75% dry portion comprising bazedoxifene acetate

Example 9: Composition of 20 mq film coated tablet prepared by combining of 75% wet portion with 25% dry portion comprising bazedoxifene acetate

Dry /wet Composition/tablet

Tablet core

portion mg %

Lactose monohydrate 120.70 39.5

Wet Avicel PH 101 145.00 47.4

(75% of total Pregelatinised starch 25.00 8.2 formulation)

Sodium starch glycolate 15.00 4.9

Total wet portion 305.70 100.00

Bazedoxifene acetate 22.55 24.7

Lactose monohydrate 16.85 18.5

Avicel PH 101 26.90 29.5

Dry Pregelatinised starch 5.00 5.5

(25% of total

Sodium starch glycolate 15.00 16.4

formulation)

Sodium lauryl sulfate 4.00 4.4

Colloidal anhydrous silica 1.00 1.1

Total dry portion 91.30 100.00

Lubricant Magnesium stearate 3.00 0.75

Total tbl core 400.00 100.00

Film coating mg %

Methocel E 5 12.00 48.78

HPC-EF 3.00 12.20

Film coating

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

water Demineralized water 200.00

Total tbl (Solid) 24.60 100.00 Examples 10 and 11 : Formulations prepared from a wet portion comprising bazedoxifene acetate and a dry portion

The process of preparation of the formulations according to Examples 10 and 1 1 are identical to the processes described in the Examples 6 and 7.

Example 10: Composition of 20 mq film coated tablet prepared by combining of 40% wet portion comprising bazedoxifene acetate with 60% dry portion

Composition/tablet

Portion Tablet core

mg %

Bazedoxifene acetate 22.55 14.1

Lactose monohydrate 68.55 42.8

Wet Avicel PH 101 39.20 24.5

(40% of total Pregelatinised starch 6.90 4.3

Sodium

formulation) 18.00 11.2

Sodium lauryl sulfate 5.00 3.1

Total wet portion 160.20 100^00

Lactose monohydrate 77.00 19.2

Avicel PH 101 62.00 15.5

Dry Pregelatinised starch 19.00 4.8

Sodium

(60% of total 21.00 5.2

carboxymethylcellulose

formulation)

Avicel PH 102 60.00 15.0

Colloidal anhydrous silica 1.00 0.3

Total dry portion 243.00 100.00

Lubricant Magnesium stearate 3.00

Total tbl core 400.00

Film coating mg %

Methocel E 5 12.00 48.78

Film coating HPC-EF 3.00 12.20

Macroqol 6000 1.80 7.32

Talc 3.00 12.20 .

Titanium dioxide 4.80 19.51

water Demineralized water 200.00

Total tbl (Solid) 24.60 100.00 Example 1 1 : Composition of 20 mq film coated tablet prepared by combining of 60% wet portion comprising bazedoxifene acetate with 40% dry portion

Composition/tablet

Portion Tablet core

mg %

Bazedoxifene acetate 22.55 9.4

Lactose monohydrate 106.55 44.4

Wet

Avicel PH 101 65.30 27.2

(60% of total Pregelatinised starch 11.20 4.7 formulation) Crospovidone 29.60 12.3

Sodium lauryl sulfate 5.00 2.1

Total wet portion 160.20 100.00

Lactose monohydrate 49.20 30.3

Avicel PH 101 35.80 22.0

Dry Pregelatinised starch 23.40 14.4

(40% of total Crospovidone 21.60 13.3 formulation) Avicel PH 102 28.60 17.6

Colloidal anhydrous silica 1.00 0.6

Total dry portion 243.00 100.00

Lubricant Magnesium stearate 3.00

Total tbl core 400.00

Film coating mg %

Methocel E 5 12.00 48.78

Film coating HPC-EF 3.00 12.20

Macrogol 6000 1.80 7.32

Talc 3.00 12.20

Titanium dioxide 4.80 19.51

water Demineralized water 200.00

Total tbl (Solid) 24.60 100.00

Example 12: The stress and stability study of the formulations

The formulations according to the invention (Examples 6, 7 and 8) as well as the comparative formulations according to Examples 2 and 5 were exposed to dry- and humid-heat conditions. The samples of the mixtures for tableting, the tablet cores, the milled tablet, the coated tablets, the tablets packed into the AI/AI blister and the tablets packed into the AI/AI blister under nitrogen were tested.

The total amount of impurities was measured by the HPLC method. The results are shown in the Table 2. In all cases the formulations according to the invention were chemically stable and exhibited lower contents of total impurities than the comparative formulations even under the hard conditions of temperature of 80°C at the relative humidity of 75% for 48 h. All the samples were tested on the bazedoxifene acetate polymorphic form. In all the samples no conversion to other form was detected. The results of the coated tablets according to Examples 6, 7 and 8 exposed to the temperature of 80°C at the relative humidity of 75% for 48 h are shown in the Figure 2.

Table 2: Stress test of different formulations prepared without antioxidant

Process Analytical results

Stress test (sum of impurities, %)

Sample

Technology Example Room Temp./ 80°C/75%

80°C/ 48h

96 h r.h.l 48h

API - - - 0.48 0.72

Direct compression 2 0.26 0.56 0.82

100% wet granulation 5 0.25 0.56 0.88

Mixture for

25% wet/API + 75% dry 6 0.11 0.20 0.51 tableting

75% wet/API + 25% dry 7 0.12 0.22 0.53

25% wet + 75% dry/API 8 0.19 0.30 0.63

Direct compression 2 0.33 0.90 1 .04

100% wet granulation 5 0.30 0.76 1 .08

Core tablet 25% wet/API + 75% dry 6 0.23 0.45 0.82

75% wet/API + 25% dry 7 0.22 0.43 0.84

25% wet + 75% dry/API 8 0.24 0.48 0.81

Direct compression 2 - 0.56 0.88

100% wet granulation 5 - 0.43 1.00

Milled tablet 25% wet/API + 75% dry 6 - 0.28 0.77

75% wet/API + 25% dry 7 - 0.30 0.79

25% wet + 75% dry/API 8 - 0.30 0.74

Direct compression 2 - 0.69 0.96

100% wet granulation 5 - 0.63 1 .09

Coated tablets 25% wet/API + 75% dry 6 - 0.39 0.78

75% wet/API + 25% dry 7 - 0.44 0.83

25% wet + 75% dry/API 8 - 0.45 0.79

Direct compression 2 - - 0.48 00% wet granulation 5 - - 0.61

Packed -

25% wet/API + 75% dry 6 0.13 - 0.31 AI/AI

75% wet/API + 25% dry 7 0.17 - 0.35

25% wet + 75% dry/API 8 0.18 - 0.38

Direct compression 2 - - 0.22

100% wet granulation 5 - - 0.28

Packed -

25% wet/API + 75% dry 6 - - 0.15 AI/AI under N2

75% wet/API + 25% dry 7 - - 0.18

25% wet + 75% dry/API 8 - - 0.18 References:

1. Chines, A.A., Komm, B.S. Bazedoxifene acetate: A novel selective estrogen receptor modulator for the prevention and treatment of postmenopausal osteoporosis. Drugs Today (Bare). 45(7) 2009:507-20.

2. Kung, Annie W. C; Chu, Eva Y. W.; Xu, Ling. Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. Expert Opinion on Pharmacotherapy. 10(8) 1377-1385 (2009).

3. Miller, C. P., Collin, M.D., Tran, B. D. Design, synthesis and preclinical characterization of novel, highly selective indole estrigens. J. Med. Chem. 44: 1654-7 (2001 ).

4. Miller et al., Bazedoxifene acetate, Drugs of the future. 27(2): 1 17-121 (2002).

5. US 5,998,402

6. US 6,479,535.

7. US 2005/0227965

8. EP 231 1805A1

9. Miller et Al. 2001 ; Miller et al. 2002.

10. US 1 1/100,983

1 1. US1 1/100.998.

12. US 7,771 ,744.32

13. EP 231 1805A1

Claims

CLAIMS:

1. An aqueous process for preparation of an antioxidant-free and polymorphically and chemically stable oral solid formulation of bazedoxifene acetate, comprising: a. Preparing a wet portion of the formulation in the form of granules prepared by wet granulation

b. Preparing a dry portion of the final formulation prepared by direct mixing or by dry granulation

c. Mixing the portions in a ratio that varies between 25:75 - 75:25

d. Optionally admixing of further powder excipients, such as one or more fillers, glidants and / or lubricants, and

e. Manufacturing the final formulation by

i/ compressing the blend into tablet cores and coating the cores with a coating comprising moisture protective polymers

ii/ filling the blend into moisture protective capsules wherein the active compound bazedoxifene acetate is incorporated either into the wet portion or into the dry portion and

wherein the preparation of the portion comprising the active compound bazedoxifene acetate comprises as the first step pre-blending bazedoxifene acetate with a hydrophilic filler.

2. The process according to claim 1 , wherein the portion with incorporated the active compound bazedoxifene acetate comprises: a/ 7 - 25% micronized bazedoxifene acetate

b/ 18 - 48% hydrophilic filler

c/ 24 - 35% filler other than in b/

d/ 4 - 6% binder

el 5 - 17% disintegrant selected from sodium starch glycolate, sodium

carboxymethylcellulose, crospovidone and any their mixture

f/ 1 - 5% surfactant

g/ optionally up to 2% glidant and/or lubricant the percentages indicating the percentages by weight of the total weight of the components of the portion comprising bazedoxifene acetate.

3. The process according to claim 2, wherein the portion without incorporated the active compound bazedoxifene acetate comprises: a/ 65 - 87% filler

bl 8 - 17% binder

c/ 4 - 17% disintegrant selected from sodium starch glycolate, sodium

carboxymethylcellulose, crospovidone and any their mixture

d/ optionally up to 2% glidant and/or lubricant the percentages indicating the percentages by weight of the total weight of the components of the portion without incorporated bazedoxifene acetate.

4. The process according to claims 1 or 2, wherein the hydrophilic filler is selected from the group comprising lactose anhydrous, lactose monohydrate, saccharose, raffinose, compressible sugar, fructose, dextrose, mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof.

5. The process according to claim 4, wherein the hydrophilic filler is selected from lactose anhydrous, lactose monohydrate and mannitol.

6. The process according to claims 1 , 2 or 3, wherein the filler is selected from the group comprising microcrystalline cellulose, powdered cellulose, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate, lactose anhydrous, lactose monohydrate, saccharose, raffinose, compressible sugar, fructose, dextrose, mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof.

7. The process according to claims 1 , 2 or 3, wherein the binder is selected from the group comprising polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropylmethylcellulose, starch, pregelatinized starch, polymethacrylate and any mixtures thereof.

8. The process according to claim 2, wherein the surfactant is 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.

9. The process according to claims 1 , 2 or 3, wherein the glidant is selected from the group comprising stearic acid, metallic stearates, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, colloidal silica and any mixtures of thereof.

10. The process according to claims 1 , 2 or 3, wherein the lubricant is selected from the group comprising stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, and any mixtures thereof.

1 1. The process according to claims 1 , 2 or 3, wherein the hydrophilic filler is lactose monohydrate, the filler is selected from the group consisting of lactose monohydrate, microcrystalline cellulose and their combinations, the binder is pregelatinized starch, the disintegrant is sodium starch glycolate, the surfactant is sodium lauryl sulphate, the glidant is colloidal silica and the lubricant is magnesium stearate.

12. The process according to claims 1-11 , wherein active compound bazedoxifene acetate is in the polymorphic form C.

13. The process according to claims 1 -12, wherein the particle size of the active compound bazedoxifene acetate is defined by the D90 value of 15 μΐη.

14. The process according to claims 1 -12, wherein the formulation is packed into an AI/AI blister.

15. The process according to claim 14, wherein the formulation is packed in the nitrogen atmosphere.