KR20190139601A - Combination formulation comprising bazedoxifene and vitamin D - Google Patents

Abstract

The present invention relates to a combined formulation containing bazedoxifene and vitamin D. According to the present invention, the combined formulation of bazedoxifene and vitamin D, prepared by manufacturing granules, which contain bazedoxifene or a pharmaceutically acceptable salt thereof, and then mixing the same with vitamin D, can be a homogeneous mixture of bazedoxifene granules and vitamin D due to similar densities of bazedoxifene granules and vitamin, thereby minimizing titer content deviation, maintaining a high dissolution rate of bazedoxifene, maintaining the stability of vitamin D, and exhibiting excellent content uniformity.

Description

Combination formulation comprising bazedoxifene and vitamin D}

The present invention provides a composition comprising a first composition comprising granules comprising bazedoxifen or a pharmaceutically acceptable salt thereof or a hydrate thereof; And a second composition comprising a vitamin D, and a method for preparing the same.

Bazedoxifen (1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5 of the formula -Ol) belongs to the class of drugs commonly referred to as selective estrogen receptor modulators (SERMs).

Consistent with this classification, bazedoxifen shows an affinity for the estrogen receptor (ER), but exhibits a tissue selective estrogen effect. For example, Vagedoxifen shows little or no stimulation in the uterine response in a preliminary clinical model of uterine stimulation. Conversely, bazedoxifen has an estrogen agonist-like effect that prevents bone loss and reduces cholesterol in ovarian resected rat models of osteopenia. Meanwhile, in MCF-7 cell line (human breast cancer cell line), bazedoxifen behaves as an estrogen antagonist. These data demonstrate that bazedoxifen is estrogenous in bone and cardiovascular lipid parameters and antiestrogenic in uterine and breast tissues and thus can treat many different diseases or disease-like conditions involving estrogen receptors. . Bazedoxifene preparations have indications for the treatment and prevention of postmenopausal female osteoporosis, but supplements should be taken if the patient has insufficient calcium and vitamin D intake from food.

On the other hand, vitamin D not only increases the absorption of calcium from the small intestine, but also plays an important role in the differentiation of bone cells and the production of good bone matrix by osteoblasts. It is important to increase the therapeutic effect. Vitamin D is a fat-soluble vitamin that can lead to deficiency in the body due to insufficient sun exposure or food intake, the main biological action of which is to promote the absorption of dietary calcium in the small intestine to maintain blood calcium levels within the normal range. Vitamin D or derivatives thereof are used for the treatment of rickettsia, osteomalacia and hypocalcemia.

Vitamin D dysfunction and deficiency are recognized as the cause of metabolic bone disease in adults. Vitamin D deficiency is severely characterized by abnormal calcium uptake, secondary hyperparathyroidism, hypophosphatemia, low or normal blood calcium and abnormal bone mineralization. Depending on the extent of vitamin D and calcium deficiency, the histological structure may indicate osteomalacia, osteoporosis or one of the two. If there is a history of vitamin D dysfunction and deficiency, a group of patients susceptible to or suffering from conditions such as osteoporosis or osteopenia and subjects performing SERM-based drug treatment of these conditions require additional vitamin D intake. Proper vitamin D intake facilitates bone formation and mineralization while minimizing the potential or occurrence of vitamin D dysfunction.

Vitamin D has active forms such as calcitriol and alphacalcidol, and inactive forms such as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D is a basic substance used in the treatment of osteoporosis, which increases bone mineral density and decreases fracture rate by increasing muscle strength, muscle contraction and nerve function control as well as skeletal health. Therefore, most osteoporosis treatments are recommended to take vitamin D, and vitamin D is also taken in the clinical trials of osteoporosis efficacy of new drugs.

In addition to the clinical effects of the two drugs in the treatment of osteoporosis, the development of the combination of Bazedoxifen and Vitamin D is not only different in physical properties such as the density of the two active ingredients, but also Bazepox, a poorly soluble drug. Since vitamin D is contained in a relatively small amount in the formulation of the weight ratio to increase the dissolution of siphene compared to the granules containing bazedoxifen, it is not easy to develop a complex formulation having a uniform content and is not developed.

Under these circumstances, the present inventors have made diligent efforts to develop an oral preparation in which the two components are co-formulated by overcoming the difference in physical properties of the two components. When mixed, Badoxifen granules have a density similar to that of Vitamin D, so that they can be mixed homogeneously with Vitamin D, thereby minimizing variation in titer content, maintaining a high dissolution rate of Badoxifen, and maintaining the stability of Vitamin D. The present invention was completed by confirming that it was possible to manufacture a composite formulation having excellent content uniformity.

One object of the present invention is a first composition comprising granules comprising bazedoxifen, a pharmaceutically acceptable salt thereof or a hydrate thereof; And it provides a combination formulation comprising a second composition comprising vitamin D.

Another object of the present invention is to prepare a granule mixture by adding 1) at least one pharmaceutically acceptable additive to bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof; 2) wet-associating the granule mixture with a binding solution containing purified water; 3) milling and granulating the wet union prepared above to granulate to obtain a first composition comprising granules; And 4) mixing the second composition with vitamin D to the first composition.

Hereinafter, the present invention will be described in more detail.

Meanwhile, each of the descriptions and the embodiments disclosed herein may be applied to each of the other descriptions and the embodiments. That is, all combinations of the various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific description described below.

In addition, one of ordinary skill in the art can recognize or identify numerous equivalents to certain aspects of the invention described in this application using conventional experiments only. Also, such equivalents are intended to be included in the present invention.

The present invention to solve the above problems as one embodiment, the present invention comprises a first composition containing granules comprising bazedoxifen, a pharmaceutically acceptable salt thereof or a hydrate thereof; And it provides a combination formulation comprising a second composition comprising vitamin D.

The present invention relates to a combination preparation of bazedoxifen and vitamin D. Badodoxifen is a poorly water-soluble substance, and in the preparation of a mixture of badodoxifen and vitamin D, since badodoxifen and vitamin D show remarkable physical properties such as density, particle size, fluidity, and the like, There has been a difficulty in preparing fixed unit composites having a uniform content. In the present invention, it was first identified that it is possible to prepare a combination formulation of badodoxifen and vitamin D having excellent content uniformity and minimizing variation in titer through the granulation process with addition of some additives.

The active ingredient 'bazedoxifene' of the present invention is a chemical name represented by the following Chemical Formula 1 (1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4 -Hydroxy-phenyl) -3-methyl-1H-indol-5-ol).

[Formula 1]

Bazedoxifene is a third generation selective estrogen receptor modulators (SERMs) that act as agents for bone receptors and antagonists for receptors located in uterus or breast cancer. In addition, it is known to be used in the treatment of breast cancer, fibrocystic disease, prostate cancer, and benign prostatic hyperplasia according to the anti-estrogen and anti-androgen efficacy, and is known to treat or prevent osteoporosis in postmenopausal women.

Bazedoxifene is a poorly soluble substance that is almost insoluble in water as well as in the gastrointestinal tract and intestinal tract, and exhibits a significantly lower dissolution rate if the proper weight of the appropriate solubilizer and the agent is not properly maintained, and the bioavailability is only about 6%. Pharmaceutically, it is used in the form of acid-addition salts, among which bazedoxifene acetate salts are common. However, bazedoxifen acetate is still poorly soluble, and much research has been conducted to increase bioavailability. For example, there is disclosed a method of increasing the solubility and dissolution rate by micronization of particles of bazedoxifen, but there may be a change in physicochemical properties in the grinding process of bazedoxifen, and micronized particles There is a problem that the bulk density of is greatly increased, which leads to many restrictions in formulation.

In the present invention, the bazedoxifen is separated from a natural source, or obtained from a natural source and prepared by chemical modification, or a person skilled in the art can be easily synthesized and prepared by known synthetic methods. Alternatively, commercially manufactured products can be purchased and used.

In the present invention, `` pharmaceutically acceptable salts '' are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid and fumaric acid. And acid addition salts with organic acids such as maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, or ammonium salts, alkali metal salts, alkaline earth metal salts, or amino acid salts. have.

In the present invention, the bazedoxifen or a pharmaceutically acceptable salt thereof, or a hydrate thereof is 5 mg to 50 mg, specifically 10 mg to 40 mg, more specifically 20 to 30 in consideration of the daily dose. The amount of mg may be included in the combination formulation of the present invention, but is not limited thereto. In addition, the bazedoxifen or pharmaceutically acceptable salts, or hydrates thereof, may be included in the formulation in the form of fine powder. In addition, the content in the formulation of bazedoxifen or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be 1 to 30% by weight, specifically 3 to 20% by weight, more specifically 4 to 10% by weight, based on the total weight of the co-formulation. It may be included as, but is not limited thereto.

When the co-formulation of the present invention is eluted at 50 rpm at pH 1.2 according to the USP dissolution test method 2 (paddle method), 40 to 50% of the total weight of the combined preparation after 30 minutes of bazedoxifen ( w / w), 50 to 60% (w / w) based on the total weight of the composite formulation at 60 to 120 minutes is characterized in that the elution profile is eluted.

When the combination preparation of the present invention is administered orally in a healthy person. It may be a composition for controlling drug release exhibiting the following pharmacokinetic profile:

Bazedoksifen

(a) Cmax / dose (ng / mL): 5.1 ± 1.53,

(b) AUCt (hng / mL): 80.95 ± 35.86

And

Cholecalciferol

(a) Cmax / dose (ng / mL): 1.98 ± 0.47,

(b) AUCt (hng / mL): 49.85 ± 15.93.

Specifically, in one embodiment of the present invention, the combination of the Bazedoxifen of the formulation (a) Cmax / dose (ng / mL): 5.1 ± 1.53, (b) Tmax (h): 2.0, (c) T 1/2 (h): 26.14 ± 12.55 (d) AUCt (hng / mL): 80.95 ± 35.86 and (e) AUC∞ (hng / mL): 89.07 ± 42.75 with a pharmacokinetic profile of said co-formulation Ferrol is (a) Cmax / dose (ng / mL): 1.98 ± 0.47, (b) Tmax (h): 12.0 (c) T1 / 2 (h): 10.56 ± 4.14 (d) AUCt (hng / mL): 49.85 ± 15.93 and (e) AUC∞ (hng / mL): 51.68 ± 15.59.

Therefore, it was confirmed that the combination preparation of the present invention was a bazedoxifen single preparation and vitamin D and an excellent combination preparation in which pharmacokinetics in vivo were equally represented (Experimental Example 4-3).

Granules comprising bazedoxifen, pharmaceutically acceptable salts thereof or hydrates thereof in the present invention may be prepared by conventional granulation processes. For example, it may be prepared by a dry granulation process or a wet granulation process, but preferably may be prepared by a wet granulation process.

The granules comprising bazedoxifen, its pharmaceutically acceptable salts or hydrates thereof may have a bulk density of 0.3 to 0.7 g / mL, specifically 0.3 to 0.6 g / mL, but are not limited thereto. no. The bulk density in the above range is similar to the bulk density of vitamin D, and thus may be more homogeneously mixed with vitamin D.

In one embodiment of the present invention by controlling the bulk density of the first composition comprising the bazedoxifen granules and the second composition containing vitamin D similarly, it was confirmed that the uniformity of the formulation can be improved (experimental Example 3

The granules comprising bazedoxifen, its pharmaceutically acceptable salts or hydrates thereof may be used in addition to bazedoxifen, its pharmaceutically acceptable salts or their hydrates, as disintegrants, excipients, solubilizers, glidants, It may further include an additive such as a coating agent.

Examples of disintegrants may include crospovidone, croscarmellose, croscarmellose sodium salt, alginic acid, methylcellulose, carboxymethylcellulose or calcium salts thereof, starch, gelled starch, pregelatinized starch, sodium starch glycolate, and the like. It doesn't work. In the present invention, the disintegrant may be included in an amount of 2 to 15% by weight, specifically 3 to 12% by weight, and more specifically 5 to 8% by weight, based on the total weight of the composite formulation, but is not limited thereto.

Examples of excipients include lactose or its hydrates, cellulose derivatives including microcrystalline cellulose, starch, gelled starch, white sugar, sugar alcohols including Ludipress®, mannitol, sorbitol and the like, calcium phosphate, aluminum silicate, calcium sulfate and the like. Inorganic salts and the like, but is not limited thereto. In the present invention, the excipient may be included in 30 to 70% by weight, specifically 40 to 55% by weight relative to the total weight of the composite formulation, but is not limited thereto.

Examples of solubilizing agents may include, but are not limited to, polysorbate, poloxamer, sodium lauryl sulfate, and the like. In the present invention, the solubilizer may be included as 0.01 to 10% by weight, specifically 0.1 to 5% by weight, more specifically about 0.5 to 2% by weight relative to the total weight of the composite formulation, but is not limited thereto.

Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, hard silicic anhydride, polyethylene glycol, corn starch, wax, talc, but are not limited thereto, but preferably hard Silicic acid anhydride. In the present invention, the lubricant may include 0.1 to 5% by weight, specifically 0.2 to 3% by weight, more specifically 0.4 to 0.8% by weight, based on the total weight of the composite formulation, but is not limited thereto.

Examples of the coating agent (depilation agent) include, but are not limited to, hypromellose, polyvinyl alcohol, ethyl cellulose, titanium oxide, polyethylene glycol, Opadry®, and the like. In the present invention, the coating agent may be included in an amount of 0.1 to 10% by weight, specifically 2 to 7% by weight, more specifically about 5% by weight, based on the total weight of the composite formulation, but is not limited thereto.

Vitamin D (vitamin D), another active ingredient of the present invention, is a fat-soluble vitamin, which contributes to the absorption of calcium necessary for the formation of the skeleton in the large intestine and kidneys, and also the parathormon and calcitonin produced in the parathyroid gland. ) Is known to play a crucial role in transporting calcium into the bone marrow, making the skeleton large in shape.

In the present invention, vitamin D may be present in an active or inactive form, specifically cholecalciferol, calcifediol, calcitriol, ergocalciferol, or these It may be a mixture of. More specifically, it may be cholecalciferol, and even more specifically, it may be a concentrated cholecalciferol powder having a titer of 90,000 IU / g to 120,000 IU / g which has been antioxidant treated by butylated hydroxytoluene (BHT). However, it is not limited to these.

The vitamin D may be included in the combination formulation of the present invention in an amount of 400 to 2,000 IU, specifically 400 to 1,000 IU in consideration of the daily dose, but is not limited thereto. In addition, the content of vitamin D may be included in 0.1 to 10% by weight, specifically 0.5 to 7% by weight, more specifically 0.7 to 5% by weight relative to the total weight of the combination, but is not limited thereto.

The vitamin D can also be isolated from natural sources, or can be readily synthesized and prepared chemically by those skilled in the art by known synthetic methods. Alternatively, commercially manufactured products can be purchased and used.

The co-formulations of the present invention may further comprise one or more additives known in the art. For example, it may include detackifiers, antifoams, buffers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavoring agents, colorants, fragrances, clearing agents, suspending agents, fillers, plasticizers, lubricants, and mixtures thereof. The amount of such additives to be added may be easily determined by those skilled in the art, depending on certain specific properties.

The composite formulation of the present invention can be prepared in various formulations, for example, can be formulated into tablets, powders, granules or capsules, such as uncoated tablets, film coated tablets, single-layered tablets, double-layered tablets, multi-layered tablets or nucleated tablets. have. Preferably, the pharmaceutical co-formulation of the present invention may be a tablet.

In the present invention, the total weight of the co-formulation may be 50 to 600 mg, specifically 100 to 500 mg, more specifically 300 to 500 mg, but is not limited thereto. The smaller the total weight of the formulation, the higher the proportion of vitamin D contained in the formulation, which may result in higher uniformity, but it may be difficult to ensure the dissolution rate of poorly soluble bazedoxifen. Therefore, the total weight of the formulation needs to be controlled to ensure content uniformity while the dissolution rate of bazedoxifen remains the same as that of a single formulation. According to the embodiment of the present invention, when the total weight is 300 to 500 mg, and preferably 400 mg, it was confirmed that the dissolution rate of bazedoxifen in the combination formulation was remarkably improved (Experimental Example 2-2).

The second composition in the co-formulation of the present invention may further comprise a lubricant. Specifically, the lubricant may be light anhydrous silicic acid, but is not limited thereto.

The combination formulation of the present invention can be used for the prevention or treatment of osteoporosis. Osteoporosis encompasses diseases caused by bone loss as the balance between bone resorption and remodeling breaks down and bone resorption speeds up.

Another aspect of the present invention provides a method for preparing granules, comprising the steps of: 1) adding at least one pharmaceutically acceptable additive to bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof; 2) wet-associating the granule mixture with a binding solution containing purified water; 3) milling and granulating the wet union prepared above to granulate to obtain a first composition comprising granules; And 4) mixing the second composition with vitamin D to the first composition.

In the manufacturing method, the additive may be at least one selected from the group consisting of excipients, disintegrants, solubilizers, lubricants and antioxidants. Each material is as described above.

As described above, in the preparation of a composite formulation of two or more active ingredients, there is a high possibility that a large weight deviation between tablets or a poor content uniformity may occur due to differences in physical and chemical properties between the active ingredients, Since the dissolution rate and stability of the active ingredient must also be taken into consideration, it is very difficult to find an optimal co-formulation method suitable for the properties of bazedoxifen and vitamin D having different properties.

The present invention is to prepare a first composition containing granules containing bazedoxifen in order to prepare a combination formulation of badodoxifen and vitamin D excellent in uniform content, and then the first composition and vitamin D Bazedoxifene and vitamin D, which maintain the dissolution rate of bazedoxifene and maintain the stability of vitamin D, have a high content uniformity due to low weight deviation between the preparations by mixing the second composition including It is characterized by preparing a composite formulation of.

In the present invention, granules comprising bazedoxifen, its pharmaceutically acceptable salts or hydrates thereof can be prepared by wet granulation.

Specifically, the additives added in the process of preparing the granule mixture in step 1) are as described above.

The binder solution including purified water used in step 2) may be included in an amount of 10 to 60% (w / w), specifically 25 to 50% (w / w), based on the total weight of the complex formulation, but is not limited thereto.

Specifically, step 3) is a step of obtaining a granule having a predetermined bulk density by grinding, sizing and granulating the prepared wet union to a certain particle size.

In step 4), the second composition may be prepared by mixing one or more pharmaceutically acceptable additives including a lubricant and an excipient with vitamin D.

Specifically, step 4) comprises the steps of 4-1) preparing a second composition in which vitamin D is mixed with one or more pharmaceutically acceptable additives including glidants and excipients; And 4-2) mixing the first composition of the third step with the same amount as the second composition to the second composition obtained in step 4-1). More specifically, step 4-1) and step 4-2) may be repeated 5 to 10 times, but is not limited thereto.

In the case of the composite preparation prepared by wet granulation of bazedoxifen and vitamin D together, formulation uniformity can be secured, but the stability of vitamin D is poor.

On the other hand, vitamin D is not granulated with bazedoxifen, but when mixed simply, stability is secured, but the formulation uniformity of vitamin D is inferior. In the present invention, after the preparation of the bazedoxifen granules by a wet granulation method, and then mixed with vitamin D, and in the case of producing a composite formulation through the same weight distribution mixing process of mixing the first composition and the second composition, The bulk density of the first composition comprising the bazedoxifen granules and the second composition comprising the vitamin D are similarly controlled, and the in vivo pharmacokinetics of the bazadoxifen monotherapy and vitamin D on the market are equally controlled. I confirmed the fact that it appeared.

Thereafter, the method may further comprise the step of preparing a tablet by tableting the mixture comprising bazedoxifen granule and vitamin D obtained in step 4).

The grinder used to grind the wet coalesce may include, for example, a hammer mill, a ball mill, a jet grinder, a colloid mill, an electric mesh, an oscillator, a commill, and the like. However, neither means is particularly limited.

Moreover, although a mixing apparatus of each component is mentioned, for example, a V type mixer, a ribbon type mixer, a container mixer, a high speed stirring mixer, etc., Usually, if it is a method which can uniformly mix each component uniformly, it is an apparatus and a means. All are not particularly limited.

As a tableting apparatus, a rotary tableting machine, a single-shot tableting machine, etc. are mentioned, for example, If it is a method by which a compression molding (suitably tablet) is manufactured normally, both an apparatus and a means are not specifically limited.

According to the present invention, a combination preparation of bazedoxifen and vitamin D prepared by preparing granules comprising bazedoxifen or a pharmaceutically acceptable salt thereof and mixing the same with vitamin D in an appropriate manner, Detoxifene granules can be mixed homogeneously with vitamin D by having a density similar to that of vitamin D, thereby minimizing the variation in titer content, maintaining a high dissolution rate of bazedoxifen, maintaining the stability of vitamin D, and excellent Since the content is uniform, it can be used as a complex preparation for the prevention or treatment of osteoporosis without variation in drug efficacy.

1 is a view showing a comparison of the dissolution pattern of bazedoxifen according to the total weight of the formulation of the Bazedoxifen and vitamin D complex preparation.
Figure 2 schematically shows the process diagram of Example 4-4, which is a combination of bazedoxifen and vitamin D.
FIG. 3 is a diagram comparing bazedoxifen elution patterns of bazedoxifen and vitamin D complex preparations (Examples 2-1 and 4-4) and bazedoxifen single preparations which are substrate products.
FIG. 4 is a diagram comparing in vivo pharmacokinetic test results for bazedoxifen, a vitamin D complex preparation (Example 4-4), and a bazedoxifen single preparation, which is a substrate product.
FIG. 5 is a diagram comparing in vivo pharmacokinetic test results of bazedoxifen, a vitamin D complex preparation (Example 4-4), and a vitamin D single preparation, which is a substrate product.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Example  1-1, Comparative example  1-1 and 1-2: Granulation  By way Bazedoksifen  Preparation of a Combination of Acetate and Vitamin D

In order to prepare a combination of bazedoxifen acetate and vitamin D (cholecalciferol concentrated powder), the most suitable granulation method for the addition of vitamin D was explored.

Example  1-1

According to the following steps was added to wet granules of Bazedoxifen acetate and mixed with vitamin D to prepare a combination formulation.

Step 1: 22.6 g of bazedoxifen acetate, 67.4 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 ascorbic acid, 0.6 g of hard silicic anhydride, 24.0 g of sodium starch glycolate, and 6.0 g of sodium lauryl sulfate Mixed.

Step 2: 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: The granules of step 2 were mixed with 67.4 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 400.0 mg.

Comparative example  1-1

Bazedoxifen acetate and vitamin D was wet granulated with purified water according to the following steps to prepare a composite formulation.

Example 1-1 Example 1-1, the lactose hydrate was 134.8g, vitamin D (cholecalciferol concentrated powder) 800IU was added, except that in step 3 lactose and vitamin D were not used A composite formulation was prepared in the same manner as in 1-1.

Comparative example  1-2

Combination formulations were prepared by wet granulating bazedoxifen acetate and vitamin D using isopropyl alcohol according to the following steps.

In step 1 of Example 1-1, 134.8 g of lactohydrate was added, 800 IU of vitamin D (cholecalciferol concentrate powder) was added, and lactose and vitamin D were excluded in step 3, and purified water waso-isolated in step 2. It was changed to propyl alcohol (IPA, Iso-propyl alcohol), and the drying conditions were prepared in the same manner as in Example 1-1 except that the drying conditions were changed to 60 ℃, 2 hours.

Experimental Example  1-1: Evaluation of the Stability of Vitamin D

The stability analysis of vitamin D was performed on the combined tablets of bazedoxifen acetate and vitamin D prepared in Example 1-1, Comparative Example 1-1, and Comparative Example 1-2. Storage conditions were stored for 2 weeks at 60 ℃, 80% RH.

As a result, it was confirmed that Comparative Examples 1-1 and 1-2 granulated by contacting vitamin D with purified water or isopropyl alcohol were inferior in stability in the amount of pre-Vit D generated and the content of vitamin D. . This is summarized in Table 2.

Experimental Example  1-2: of vitamin D Formulation Uniformity  evaluation

Formulation uniformity (content uniformity) of vitamin D was evaluated for the combined tablets of bazedoxifen acetate and vitamin D prepared in Examples 1-1 to Comparative Examples 1-1 and 1-2. Formulation homogeneity evaluation was performed according to the pharmacokinetic uniformity test method.

As a result, as in Example 1-1, it was confirmed that vitamin D was not granulated with bazedoxifen, but the formulation uniformity of vitamin D was poor in a simple mixed complex preparation. This is summarized in Table 3.

Example  2: preparation of a composite formulation according to the total weight of the tablet

In the preparation of the combination formulation of bazedoxifen acetate and vitamin D (cholecalciferol concentrated powder), the combination formulation was prepared by changing the total weight of the tablet and the ratio of solubilizer.

Example  2-1

According to the following steps, Example 2-1 prepared a co-formulation so that the total weight of the formulation is 400 mg.

Step 1: 22.6 g of bazedoxifen acetate, 173.4 g of lactose monohydrate, 35.0 g of microcrystalline cellulose, 55.0 g of gelled starch, 6.0 ascorbic acid, 0.6 g of light anhydrous silicic acid, 24.0 g of sodium starch glycolate, and 6.0 g of sodium lauryl sulfate Mixed.

Step 2: 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: The granules of step 2 were mixed with 67.4 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 400.0 mg.

Example  2-2

According to the following steps, Example 2-2 was prepared in a combination formulation so that the total weight of the formulation is 200 mg.

Step 1: Badoxifen acetate 22.6 g, lactose monohydrate 88.8 g, microcrystalline cellulose 10.0 g, gelled starch 18.0 g, ascorbic acid 3.0 g, light silicic anhydride 0.6 g, sodium starch glycolate 12.0 g, sodium lauryl sulfate 6.0 g Was mixed.

Step 2: 100.0 g of purified water was added to the mixture of step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: To the granules of step 2, 30.0 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 1.0 g of magnesium stearate were added and mixed.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 200.0 mg.

Example  2-3

According to the following steps, Examples 2-3 prepared a co-formulation such that the total weight of the preparation was 200 mg.

In step 1 of Example 2-2, sodium lauryl sulfate was mixed to 3.0 g and lactose hydrate to 91.8 g, and the remaining steps were prepared in the same manner as in Example 2-2.

Example  2-4

According to the following steps, Example 2-4 was prepared in a combination formulation such that the total weight of the formulation was 180 mg.

Step 1: Badoxidofen acetate 22.6g, lactose monohydrate 71.8g, microcrystalline cellulose 10.0g, gelling starch 18.0g, ascorbic acid 3.0g, hard silicic anhydride 0.6g, sodium starch glycolate 12.0g, sodium lauryl sulfate 3.0g Was mixed.

Step 2: 80.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: To the granules of step 2, 30.0 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 1.0 g of magnesium stearate were added and mixed.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 180.0 mg.

Each example is shown in Table 4 below.

Experimental Example  2-1: of vitamin D Formulation Uniformity  evaluation

Formulation uniformity of vitamin D was evaluated for the combined tablet of bazedoxifen acetate and vitamin D prepared in Examples 2-1 to 2-4. Formulation homogeneity evaluation was performed according to the pharmacokinetic uniformity test method.

As a result, it was confirmed that the formulation uniformity was improved in the case of a tablet having a small total weight, that is, a high ratio of vitamin D contained in one tablet.

This is summarized in Table 5.

Experimental Example  2-2: Bazedoksifen  Dissolution Rate Evaluation of Acetate

The dissolution rate of bazedoxifen acetate was evaluated for the composite tablet of bazedoxifen acetate and vitamin D prepared in Examples 2-1 to 2-4. The dissolution test was conducted by USP 2 method at pH 1.2 in consideration of the maximum absorption concentration time (Tmax) and solubility of bazedoxifen acetate.

As a result, it was confirmed that the dissolution rate of the tablet having a total weight of 400 mg was the highest and that the total weight of the tablet was more important than the absolute amount of sodium lauryl sulfate used as a dissolution aid. The dissolution pattern of each example is shown in detail in FIG. 1.

Example 3: vitamin  D Preparation of Single Agent

To determine the effect of bulk density of the particle mixture on the formulation uniformity of vitamin D (cholecalciferol concentrated powder), the following formulation was prepared.

Example  3-1

Step 1: 82.9 g of microcrystalline cellulose, 0.6 g of hard silicic anhydride, 800 IU of vitamin D (cholecalciferol concentrated powder) and 0.5 g of magnesium stearate were mixed.

Step 2: The granulated granules of Step 1 were tableted by compression molding to a total weight of 100.0 mg.

Example  3-2

The preparation was prepared in the same manner as in Example 3-1, except that microcrystalline cellulose was changed to lactose hydrate and mixed in Example 3-1.

Experimental Example  3-1: Determination of Bulk Density of Particle Mixtures

Bazedoxifen acetate granules mixture prepared in Examples 2-1 and 2-2 and the vitamin D-additive mixture and vitamin D (cholecalciferol concentrated powder) prepared in Examples 3-1 and 3-2, respectively 20 g was placed in a 100 mL measuring cylinder to measure the bulk density. Then, the measuring cylinder was vibrated to measure the tap density, and the Carr's index (C = 100 x (Pt-Pb) / Pt, Pt = tap density, Pb = bulk density) was calculated. The results are shown in Table 6 below.

Experimental Example  3-2: of vitamin D Formulation Uniformity  evaluation

Formulation uniformity (content homogeneity) of vitamin D was evaluated for the tablets of Examples 2-1, 2-2, 3-1, and 3-2. Formulation homogeneity evaluation was performed according to the pharmacokinetic uniformity test method.

As a result, it was confirmed that the formulation uniformity is improved in the case of the formulation using a small dose of Bazedoxifene acetate granules similar in volume density to vitamin D (cholecalciferol concentrated powder). This is summarized in Table 7.

Example  4: Preparation of complex preparation by volume density control and distribution mixing

As a result of comprehensive consideration through the above examples, in order to maintain the dissolution rate of bazedoxifen acetate, at least a certain amount of tablet gross weight is required, and the granulation process of bazedoxifen acetate and the mixing process of vitamin D need to be separated. Confirmed. In order to secure the uniformity of the formulation of vitamin D, which occupies about 2% of the main component ratio of the total weight of the tablet, a composite formulation was prepared according to the bulk density control and distribution mixing process of the granules.

Example  4-1

Step 1: 22.6 g of bazedoxifen acetate, 173.4 g of lactose monohydrate, 35.0 g of microcrystalline cellulose, 55.0 g of gelled starch, 6.0 ascorbic acid, 0.6 g of light anhydrous silicic acid, 24.0 g of sodium starch glycolate, and 6.0 g of lauryl sulfate Mixed.

Step 2: 100.0 g of purified water was added to the mixture of step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: The granules of step 2 were mixed with 67.4 g of lactose, 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 400.0 mg.

Example  4-2

Step 1: 22.6 g of bazedoxifen acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 ascorbic acid, 0.6 g of light anhydrous silicic acid, 24.0 g of sodium starch glycolate, and 6.0 g of sodium lauryl sulfate Mixed.

Step 2: 100.0 g of purified water was added to the mixture of step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate were added to the granules of step 2 and mixed.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 408.0 mg.

Example  4-3

Step 1: 22.6 g of bazedoxifen acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 ascorbic acid, 0.6 g of light anhydrous silicic acid, 24.0 g of sodium starch glycolate, and 6.0 g of sodium lauryl sulfate Mixed.

Step 2: 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: 800 IU of vitamin D (cholecalciferol concentrated powder) and 2.0 g of magnesium stearate were added to the granules of step 2 and mixed.

Step 4: The granulated granules of step 3 were tableted by compression molding to a total weight of 408.0 mg.

Example  4-4

Step 1: 22.6 g of bazedoxifen acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 ascorbic acid, 0.6 g of light anhydrous silicic acid, 24.0 g of sodium starch glycolate, and 6.0 g of sodium lauryl sulfate Mixed.

Step 2: 200.0 g of purified water was added to the mixture of Step 1, mixed, granulated, and dried using a drier. Drying conditions were performed at 60 degreeC and 12 hours.

Step 3: 800 IU of vitamin D (cholecalciferol concentrated powder) and 0.6 g of hard silicic anhydride were added thereto to prepare a mixture.

Step 4: Add the dry of Step 2 to the mixture of Step 3 in the same amount and mix. The same weight distribution mixing method as described above was distributed by mixing in the same manner about 5 to 10 times to mix the entire dry matter of step 2.

Step 5: 2.0 g of magnesium stearate was added to the mixture of Step 4 and mixed.

Step 4: The granulated granules of Step 5 are tableted by compression molding to a total weight of 408.3 mg.

The flowchart of Example 4-4 was concretely shown in FIG.

Example  4-5

By the same method as in Example 4-4, except that 140.8 g of lactohydrate in Step 1 of Example 4-4 was added, and 1,000 IU of vitamin D (cholecalciferol concentrate powder) was added in Step 3. Composite formulations were prepared.

Example  4-6

The lactose hydrate was 130.8 g in Example 1-4, and 2,000 IU of vitamin D (cholecalciferol concentrated powder) was added in step 3, except that the compound was mixed in the same manner as in Example 4-4. The formulation was prepared.

Experimental Example  4-1: Determination of Bulk Density of Particle Mixtures

Bazedoxifene acetate granule mixture prepared in Examples 4-1 to 4-4 and vitamin D (cholecalciferol concentrated powder) prepared in step 3 of Examples 4-4 and used in the first step of dispensing mixing 20 g of each and a hard silicic anhydride mixture were put into a 100 mL measuring cylinder to measure the bulk density. Then, the measuring cylinder was vibrated to measure the tap density, and the fluidity and compression property of the granules were confirmed. Carr's index (C = 100 × (Pt-Pb) / Pt, Pt = tap density, Pb = bulk density) was calculated.

The results showed that the density increased with increasing amount of purified water used for granulation, and the flowability was improved when lactose hydrate was used for total granulation of bazedoxifen acetate instead of post-mixing with vitamin D. Detailed results are shown in Table 9 below.

Experimental Example  4-2: Vitamin D Formulation Uniformity  evaluation

Formulation uniformity (content uniformity) of vitamin D (cholecalciferol concentrated powder) was evaluated in Examples 4-1 to 4-6. Formulation homogeneity evaluation was performed according to the pharmacokinetic uniformity test method.

As a result, the bulk density is similar to that of vitamin D (cholecalciferol concentrate powder), and the addition of hard anhydrous silicic acid in the vitamin D mixing process makes the Bazedoxifen granule mixture and Carr's index similar to each other. In the case of formulations, it was confirmed that formulation uniformity was improved. This is summarized in Table 10 in detail.

Experimental Example  4-3: Bazedoksifen  Dissolution Rate Evaluation of Acetate

In Example 4-1 to 4-4, the dissolution rate of Example 4-4, which is the best formulation homogeneity of vitamin D, and Bazedoxifen Acetate single formulation, a pre-release product, were evaluated. The dissolution test was conducted by the USP 2 method (paddle method) at pH 1.2 in consideration of the maximum absorption concentration time (Tmax) and solubility of bazedoxifen acetate.

As a result, it was confirmed that the dissolution rate was the same as that of the composite agent of Example 2-1 and the bazedoxifen acetate single agent. Each dissolution rate evaluation results are shown in detail in FIG. 3.

Experimental Example 4-1 to 4-3 Bazedoxifene acetate and vitamin D (cholecalciferol concentrated powder) complex formulation of Example 4-4 in the dissolution rate of the Bazedoxifene acetate component and the single agent It has an equal dissolution rate and it can be seen that vitamin D (cholecalciferol concentrate powder) is uniformly contained.

Experimental Example  4-4: Bazedoksifen  Of acetate and vitamin D complex Pharmacokinetics  exam

In vivo pharmacokinetic tests were carried out on the bazedoxifen acetate and vitamin D (cholecalciferol concentrated powder) complexes of Example 4-4 and the bazadoxifen acetate monosaccharide and vitamin D single formulation, which were previously released products. .

As a result, it was confirmed that the in vivo pharmacokinetics of Example 4-4, which showed the same dissolution rate as that of bazedoxifen acetate monoagent, appeared to be equal. Each pharmacokinetic evaluation result is shown in detail in FIGS. 4 and 5.

Clinical trials were performed to determine the body kinetics of the drugs after oral administration of Example 4-4 and the control agent Vivian tablet and vitamin D single agent to about 45 to 75 healthy persons.

Humans were given oral administration of Example 4-4 (bazedoxifene 20 mg, vitamin D 800 IU) and two tablets of biantant tablet (bazedoxifene 20 mg single agent) and vitamin D 800 IU formulation as control, and blood was collected at a fixed time. Plasma was isolated and then the concentrations of bazedoxifen and vitamin D were measured.

Blood collection time was taken at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120 hours for vitamin D and 2, 4, 6, 8 for , 10, 12, 14, 16, 24, 36, 48, 60, 72, 96 hours. Pharmacokinetic parameters were measured using AUCt (dose time to final blood concentration time t) using a non-compartmental method, using Phoenix WinNonlin® (Pharsight, CA, USA) Ver 7.0. Area under the curve), AUCi (area under the blood-time curve from dosing time to infinity), Cmax (highest blood concentration), Tmax (highest blood concentration attainment time) and t1 / 2 (blood loss half-life) were calculated . The result is as Table 11, Table 12, FIG. 4, FIG.

Experimental Example 4-4 through the Bazedoxifen acetate and vitamin D (cholecalciferol concentrated powder) complex preparation of Example 4-4 is the same in vivo drug as bazedoxifen acetate mono- and vitamin D mono- The kinetics indicate that there is no significant variation in the bioavailability of vitamin D.

Claims (19)

A first composition comprising granules comprising bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And a second composition comprising vitamin D.
The combination according to claim 1, wherein the granules are prepared by a wet granulation process.
The combination formulation of claim 1, wherein the granules have a bulk density of 0.3 g / mL to 0.6 g / mL.
The combination preparation according to claim 1, wherein the content of bazedoxifen or a pharmaceutically acceptable salt thereof is 10 mg to 40 mg.
The combination according to claim 1, wherein the vitamin D is concentrated cholecalciferol.
The combination preparation according to claim 1, wherein the content of vitamin D is 400 IU to 2,000 IU.
The combination formulation of claim 1, wherein the total weight of the combination formulation is 300 to 500 mg.
The combination formulation of claim 1, wherein the second composition further comprises a lubricant.
The combination according to claim 8, further comprising light silicic anhydride as a lubricant.
The method according to claim 1, wherein when dissolving bazedoxifen contained in the combination formulation at a pH of 1.2 at 50 rpm according to USP dissolution test method 2 (paddle method), after 30 minutes 40 to 50% (w / w) based on the total weight of the co-formulation, 50 to 60% (w / w) at 60 to 120 minutes to satisfy the dissolution profile.
The composition of claim 10, wherein the combination formulation exhibits a pharmacokinetic profile when orally administered to a healthy person.
Bazedoksifen
(a) Cmax / dose (ng / mL): 5.1 ± 1.53,
(b) AUCt (hng / mL): 80.95 ± 35.86
And
Cholecalciferol
(a) Cmax / dose (ng / mL): 1.98 ± 0.47,
(b) AUCt (hng / mL): 49.85 ± 15.93
The combination preparation according to claim 1, wherein the combination preparation is a tablet.
1) preparing a granule mixture by adding at least one pharmaceutically acceptable additive to bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof;
2) wet-associating the granule mixture with a binding solution containing purified water;
3) milling and granulating the wet union prepared above to granulate to obtain a first composition comprising granules; And
4) A method comprising the step of mixing a second composition comprising vitamin D in the first composition.
The method of claim 13,
The additive is one or more selected from the group consisting of excipients, disintegrants, solubilizers, lubricants and antioxidants.
The method of claim 13,
Purified water in the step 2) will be included in 25 to 50% (w / w) relative to the total weight of the composite formulation, manufacturing method.
The method of claim 13,
In the step 4), the second composition is prepared by mixing vitamin D with one or more pharmaceutically acceptable additives including a lubricant and an excipient.
The method of claim 13,
Step 4)
4-1) preparing a second composition in which vitamin D is mixed with one or more pharmaceutically acceptable additives including glidants and excipients; And
4-2) comprising the step of mixing the first composition of the third step in the same amount as the second composition to the second composition obtained in step 4-1).
18. The method according to claim 17, wherein steps 4-1) and 4-2) are repeated 5 to 10 times.
The method of claim 13, wherein the second composition further comprises light silicic anhydride as a lubricant.

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