WO2019235898A1

WO2019235898A1 - Combined preparation containing bazedoxifene and vitamin d

Info

Publication number: WO2019235898A1
Application number: PCT/KR2019/006915
Authority: WO
Inventors: 김태경; 한태희; 김남혁; 황온; 홍혜숙; 박세홍
Original assignee: 알보젠코리아 주식회사
Priority date: 2018-06-08
Filing date: 2019-06-07
Publication date: 2019-12-12
Also published as: KR102136459B1; KR20190139601A

Abstract

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

Description

Combination preparations containing bazedoxifen 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 a second composition comprising vitamin D and a lubricant.

Another object of the present invention is to 1) wet granulate bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to obtain a first composition comprising granules;

2) preparing a second composition comprising vitamin D and a lubricant;

3) preparing a first mixture by mixing the first composition of the first step in the same amount as the second composition to the second composition prepared in step 2); And

4) preparing a second mixture by mixing the first composition of the first step in the same amount as the first mixture to the first mixture prepared in step 3)

It includes, to provide a method for producing a composite formulation.

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. Preferably, the present invention comprises a first composition comprising granules comprising bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And a second composition comprising vitamin D and a lubricant.

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 hardly soluble in water, as well as in the gastrointestinal and intestinal tract, and exhibits a significantly lower dissolution rate if the proper weight of the appropriate solubilizer and 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, a method of increasing the solubility and dissolution rate by micronization of particles of bazedoxifen is disclosed, but there may be a change in physicochemical properties during the grinding 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.

The co-formulation of the present invention may be a co-formulation or a drug release control composition exhibiting the following pharmacokinetic profile when orally administered to a healthy person:

For bazedoxifen, mean maximum blood concentration (Cmax / dose) of 3 to 7 ng / ml and area under the concentration-time curve (AUCt) of 40 to 120 hng / ml; And

For cholecalciferol, the mean maximum blood concentration (Cmax / dose) of 1 to 3 ng / ml and the area under the concentration-time curve (AUCt) of 30 to 75 hng / ml.

The co-formulation of the present invention may be a co-formulation or a drug release control composition exhibiting the following pharmacokinetic profile when orally administered in a healthy person:

About Bazedoxifen,

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

(b) AUCt (hng / mL): 80.95 ± 35.86

And

About 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, including lactose, or a hydrate thereof, cellulose derivatives, starches, gelled starches, including microcrystalline cellulose, sucrose, Rudy press (Ludipress ^®), mannitol, alcohol, calcium phosphate, aluminum silicate, calcium sulfate, sugar, including sorbitol 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 (derivement agent) may include, but are not limited to, hypromellose, polyvinyl alcohol, ethyl cellulose, titanium oxide, polyethylene glycol, and Opadry. 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 the 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 with 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, it 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 an 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 a pharmaceutical composition comprising the steps of: 1) wet granulating bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to obtain a first composition comprising granules;

2) preparing a second composition comprising vitamin D and a lubricant;

It provides, a method for producing a composite formulation.

Steps 3) and 4) may use the same weight distribution mixing method. Specifically, the amount of the second composition comprising vitamin D prepared in step 2) is small compared to the amount of the first composition comprising granules of bazedoxifen prepared in step 1). The amount is dispensed and mixed in the same amount as the second composition or mixture. That is, in step 3), the first composition is prepared by mixing the first composition of step 1) with the same amount as the second composition with the second composition prepared in step 2). In step 4), the second mixture is prepared by mixing the first composition again in the same amount as the first mixture prepared in step 3).

In addition, the preparation method of the present invention uses the same weight distribution mixing method in the same manner as in step 4), by mixing the first composition of step 1) in the same amount as the mixture in the mixture prepared in the previous step, the mixture It further comprises the step of, wherein the step may be performed repeatedly 3 to 10 times. For example, the manufacturing method of the present invention,

5) preparing a third mixture by mixing the first composition of the first step in the same amount as the second mixture to the second mixture prepared in step 4);

6) preparing a fourth mixture by mixing the first composition of the first step in the same amount as the third mixture to the third mixture prepared in step 5); And

7) preparing a fifth mixture by mixing the first composition of the first step in the same amount as the fourth mixture to the fourth mixture prepared in step 6).

It may further include. According to the same weight-distribution mixing method, the production method of the present invention can be repeatedly performed until the entire amount of the first composition of step 1) is mixed, for example, the production method of the present invention up to the tenth mixture It may comprise the step of manufacturing.

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 By mixing the same amount of the second composition comprising the same, and by preparing a composite formulation in the same weight distribution mixing method of mixing the mixture and the first composition from the same by less weight deviation between the formulations, the content uniformity is excellent and bar detoxification Maintaining a high dissolution rate of sifen, characterized in that the preparation of a combination formulation of bazedoxifen and vitamin D to maintain the stability of vitamin D.

In the present invention, granules comprising bazedoxifen, its pharmaceutically acceptable salts or hydrates thereof can be prepared by wet granulation. The wet granulation method comprises the steps of: (i) adding at least one pharmaceutically acceptable additive to bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to prepare a mixture; (ii) wet associating the mixture with a binding solution comprising purified water; And (iii) grinding, sizing, and granulating the wet union prepared above to obtain a first composition comprising granules.

Preferably, the present invention

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

The binder solution including purified water used in step (ii) 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 (iii) is a step of obtaining a granule having a constant bulk density by grinding, sizing and granulating the prepared wet union to a constant particle size.

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 after 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 of bazedoxifen, a vitamin D complex preparation (Example 4-4), and a bazedoxifen single formulation, 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 medium 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.

실시예 1-1, 비교예 1-1 및 1-2: 과립화 방식에 따른 바제독시펜 아세테이트 및 비타민 D의 복합제제의 제조Examples 1-1, Comparative Examples 1-1 and 1-2: Preparation of a Combination Formulation of Bazedoxifen Acetate and Vitamin D According to Granulation Method

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.

실시예 1-1Example 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: Badoxidofen acetate 22.6 g, lactose monohydrate 67.4 g, microcrystalline cellulose 140.0 g, gelated starch 56.0 g, ascorbic acid 6.0 g, light anhydrous silicic acid 0.6 g, sodium starch glycolate 24.0 g, sodium lauryl sulfate 6.0 g Was 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.

비교예 1-1Comparative 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 Composite preparations were prepared in the same manner as in 1-1.

비교예 1-2Comparative 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, the lactose hydrate was 134.8 g, and vitamin D (cholecalciferol concentrated powder) 800 IU was added. In step 3, the lactose and vitamin D were excluded. 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.

실험예 1-1: 비타민 D의 안정성 평가Experimental Example 1-1: Evaluation of 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 with vitamin D in contact 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.

실험예 1-2: 비타민 D의 제제균일성 평가Experimental Example 1-2: Evaluation of Formulation Uniformity of Vitamin D

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 pharmacopeias 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.

실시예 2: 정제 총중량에 따른 복합제제의 제조Example 2 Preparation of a Co-Formulation According to Tablet Total Weight

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.

실시예 2-1Example 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: Badoxifen acetate 22.6g, lactose monohydrate 173.4g, microcrystalline cellulose 35.0g, gelated starch 55.0g, ascorbic acid 6.0g, hard silicic anhydride 0.6g, sodium starch glycolate 24.0g, sodium lauryl sulfate 6.0g Was mixed.

실시예 2-2Example 2-2

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

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.

실시예 2-3Example 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.

실시예 2-4Example 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 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.

실험예 2-1: 비타민 D의 제제균일성 평가Experimental Example 2-1: Evaluation of Formulation Uniformity of Vitamin D

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 pharmacopeias 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.

실험예 2-2 : 바제독시펜 아세테이트의 용출률 평가Experimental Example 2-2: dissolution rate evaluation of bazedoxifen 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.

실시예 3: 비타민 D 단일제제의 제조Example 3: Preparation of a Vitamin D 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.

실시예 3-1Example 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.

실시예 3-2Example 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.

실험예 3-1: 입자 혼합물의 부피밀도 측정Experimental Example 3-1: Measurement of the bulk density of the particle mixture

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

실험예 3-2: 비타민 D의 제제균일성 평가Experimental Example 3-2: Evaluation of Formulation Uniformity of Vitamin D

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 pharmacopeias 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.

실시예 4: 부피밀도 조절 및 분배혼합에 따른 복합제제의 제조Example 4 Preparation of a Composite Agent According to 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 ensure 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 the dispensing mixing process of the granules.

실시예 4-1Example 4-1

Step 1: Badoxidofen acetate 22.6g, lactose monohydrate 173.4g, microcrystalline cellulose 35.0g, gelated starch 55.0g, ascorbic acid 6.0g, hard silicic anhydride 0.6g, sodium starch glycolate 24.0g, lauryl sulphate 6.0g Was mixed.

실시예 4-2Example 4-2

Step 1: 22.6 g of Bazedoxifene acetate, 142.8 g of lactose monohydrate, 140.0 g of microcrystalline cellulose, 56.0 g of gelled starch, 6.0 g of ascorbic acid, 0.6 g of hard silicic anhydride, 24.0 g of sodium starch glycolate, 6.0 g of sodium lauryl sulfate Was mixed.

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.

실시예 4-3Example 4-3

실시예 4-4Example 4-4

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

Step 3: 800 IU of vitamin D (cholecalciferol concentrated powder) and 0.3 g of hard silicic anhydride were added thereto to prepare a mixture.

Step 4: The same amount of granules of Step 2 was added to the mixture of Step 3 and mixed to prepare a mixture. An equal amount of granules of Step 2 were added to the mixture and mixed again to prepare a mixture. By using the same weight-distribution mixing method as described above, by dispensing the granules of step 2 by mixing the same amount of granules of step 2 in the prepared mixture, by performing this 3 to 10 additional repetitions, The dry matter of step 2 was mixed thoroughly.

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

Step 6: 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.

실시예 4-5Example 4-5

In the same manner as in Example 4-4, except that 140.8 g of lactohydrate was added in Step 1 of Example 4-4, and 1,000 IU of vitamin D (cholecalciferol concentrated powder) was added in Step 3 The formulation was prepared.

실시예 4-6Example 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.

실험예 4-1: 입자 혼합물의 부피밀도 측정Experimental Example 4-1: Measurement of the bulk density of the particle mixture

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, and then the measuring cylinder was vibrated to measure the tap density. 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.

실험예 4-2 : 비타민 D의 제제균일성 평가Experimental Example 4-2: Evaluation of Formulation Uniformity of Vitamin D

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 pharmacopeias 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 the 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.

실험예 4-3 : 바제독시펜 아세테이트의 용출률 평가Experimental Example 4-3 dissolution rate evaluation of bazedoxifen 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 Bazedoxifene acetate, a pre-release product, were compared. 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.

실험예 4-4 : 바제독시펜 아세테이트와 비타민 D 복합제의 약물동력학 시험Experimental Example 4-4: Pharmacokinetic Test of Bazedoxifen Acetate and Vitamin D Complex

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 exhibited 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 are Phoenix WinNonlin (Pharsight, CA, USA) Using Ver 7.0, using the non-compartmental method, AUCt (Blood-Time Curve Area from Dosing Time to Final Blood Concentration Time t), AUCi ( Area under the blood concentration-time curve from dosing time to infinite time), Cmax (highest blood concentration), Tmax (highest blood concentration reaching 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

A first composition comprising granules comprising bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof; And a second composition comprising vitamin D and a lubricant.
The combination formulation of claim 1, wherein the granules have a bulk density of 0.3 g / mL to 0.6 g / mL.
The method according to claim 1, wherein the content of bazedoxifen or a pharmaceutically acceptable salt thereof is 10 mg to 40 mg, the vitamin D is concentrated cholecalciferol and its content is 400 IU to 2,000 IU, Combinations.
According to claim 1, wherein the total weight of the combination is characterized in that 300 to 500mg, the combination.
The combination formulation of claim 1, wherein the lubricant is hard silicic anhydride.
According to claim 1, when dissolving the co-formulation at 50 rpm at pH 1.2 according to the USP dissolution test method 2 (paddle method), Bazedoxifene is 40 to 40 based on the total weight of the co-formulation after 30 minutes 50% (w / w), 50 to 60% (w / w) at 60 to 120 minutes, eluting profile, characterized in that the dissolution profile.
The combination formulation of claim 1, wherein the combination formulation shows the following pharmacokinetic profile when orally administered to a healthy person:

For bazedoxifen, mean maximum blood concentration (Cmax / dose) of 3 to 7 ng / ml and area under the concentration-time curve (AUCt) of 40 to 120 hng / ml; And

For cholecalciferol, the mean maximum blood concentration (Cmax / dose) of 1 to 3 ng / ml and the area under the concentration-time curve (AUCt) of 30 to 75 hng / ml.
The combination formulation of claim 1, wherein the combination formulation shows the following pharmacokinetic profile when orally administered to a healthy person:

About Bazedoxifen,

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

(b) AUCt (hng / mL): 80.95 ± 35.86

And

About cholecalciferol,

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

(b) AUCt (hng / mL): 49.85 ± 15.93
1) wet granulating bazedoxifen, a pharmaceutically acceptable salt thereof, or a hydrate thereof to obtain a first composition comprising granules;

2) preparing a second composition comprising vitamin D and a lubricant;

3) preparing a first mixture by mixing the first composition of the first step in the same amount as the second composition to the second composition prepared in step 2); And

4) preparing a second mixture by mixing the first composition of the first step in the same amount as the first mixture to the first mixture prepared in step 3)

A method of producing a composite formulation comprising a.
The method according to claim 9, further comprising the step of preparing a mixture by mixing the first composition of step 1) with the same amount as the mixture with the mixture prepared in the previous step in the same manner as in step 4), The step is characterized in that it is repeated 3 to 10 times, manufacturing method.
The method of claim 9, wherein the lubricant is hard silicic anhydride.