KR20180036633A - Composite capsules with improved dissolution rate comprising raloxifene, and Vitamin D or its derivatives,and preparing method thereof - Google Patents

Abstract

The present invention relates to a composite capsule agent production method. To this end, a composite capsule agent is produced by the following steps: mixing raloxifene or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and adding a coupling solution containing a solubilizing agent so as to produce a granular first premixture part. The composite capsule agent contains: a raloxifene granule or a raloxifene tablet with enhanced elution rate; and a vitamin D granule or a vitamin D tablet containing vitamin D or a derivative thereof. The present invention further relates to a composite capsule agent produced by the production method.

Description

(Composite capsules with improved dissolution rate as raloxifene, and Vitamin D or its derivatives, and preparing method thereof) and a method for preparing the same,

The present invention relates to a composition for preventing or treating osteoporosis comprising raloxifene or a pharmaceutically acceptable salt thereof having improved dissolution rate, wherein the dissolution rate of the raloxifene is controlled by using a solubilizing agent in preparation of a poorly soluble raloxifene tablet And to a composition for preventing or treating osteoporosis, which improves the bioavailability of raloxifene. In addition, the present invention relates to a complex capsule containing a tablet of raxoxifen and vitamin D or a derivative thereof, which has increased compliance with medicines and secures stability of an active ingredient, and a preparation method thereof.

Osteoporosis is a skeletal disorder in which the bone mass is absolutely reduced due to the relatively high bone resorption due to a pathological breakdown of bone formation and bone resorption, . Bone mineral density (BMD), which is a major factor in determining osteoporosis, is the highest in the twenties, then declines slowly after menopause. The rapid decline in bone density after menopause is due to an increase in calcium loss due to estrogen deficiency during menopause, a decrease in calcium absorption capacity in the intestine, and a destruction of calcium balance due to insufficient calcium intake. Hormone replacement therapy has been studied to treat such osteoporosis.

Estrogen is administered to postmenopausal women to prevent osteoporosis and cardiovascular disease, resulting in a longer life span. However, many women are not receiving hormone replacement therapy (HRT), and there is a real problem that most women stop taking hormone replacement therapy in less than a year. The main reason for stopping the treatment is to develop an ideal estrogen preparation that does not adversely affect the breasts and the uterus while having a good effect on the bones and cardiovascular system in order to solve these problems due to anxiety and uterine bleeding. It became necessary.

Raloxifene is a selective estrogen receptor modulator (SERM) drug that prevents osteoporosis and cardiovascular disease and consequently prolongs the life span, inhibits endometrial tissue and mammary epithelial proliferation, It is known that lipid-lowering effect (Non-Patent Document 1).

The chemical name of the raloxifene is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene, 3. ≪ / RTI > Raloxifene is useful as an agent for the prevention and treatment of osteoporosis in postmenopausal women. In addition, La hydroxy pen containing the hydrochloride as an active ingredient Avista ^® tablet (Evista, Lilly) and is commercially available as an agent for preventing and treating osteoporosis, has been added invasive breast cancer related indications from the US FDA 2007 years.

In the treatment of osteoporosis, it is recommended that supplementation with cholecalciferol be given when administering the SERM-related osteoporosis drug, and 400 to 1,000 IU is usually used per day. Cholecalciferol is produced by ultraviolet radiation of 7-dehydrocholesterol present in the skin, metabolized to calcitriol by metabolism in the liver, and then metabolized to calcitriol in the kidney. Cholecalciferol is known to improve bone mineral density and vertebral fracture, as well as to affect nonvertebral fractures. Due to these reinforcing effects, a combination prescription of a combination of raloxifene and cholecalciferol is currently being performed (Non-Patent Document 2). However, there has been no report on a combination of two drugs that contain both drugs in a single unit dosage form, and in the case of complex formulation, the interaction between the active ingredients causes the administration of both raloxifene and cholecarpal The stability of cyperol is lowered and it is difficult to develop a complex agent. In addition, the content uniformity of the cholecalciferol purified portion in a trace amount (0.02 mg / T) of the active ingredient content has become a big issue in the development of a single agent and a complex agent.

Raloxiphen is slightly unstable in acid, base, and light conditions during forced degradation, and degradation products are produced, especially under oxidative conditions. According to Non-Patent Document 3, in the unstable condition, the raloxifene is decomposed by the decomposition product (N-Oxide, 6-Hydroxy-2- (4-hydroxyphenyl) benzo [b] thiophen- 1-yl-ethoxy) phenyl] methanone), and the content of raloxifene decreased by 2.5% after 30 minutes of incubation at room temperature after adding 3% hydrogen peroxide solution.

Raloxifene is a poorly soluble drug, exhibiting low solubility as a Biochemical Classification (BCS) class II drug, but exhibiting high bioavailability. In addition, it exhibits different solubilities depending on the liquid, and it is difficult to expect improvement in bioavailability due to low dissolution rate. Therefore, improvement of the dissolution rate through the solubilizing agent of the formulation containing the raloxifene is an essential requirement.

Cholecalciferol (vitamin D ₃ ) also has poor physico-chemical stability, so it is not easy to maintain stability with changes over time. Cholecalciferol is known to be generally susceptible to moisture, light, and heat, and it has been found that trans-vitamin D ₃ (Trans-Vitamin D ₃ , Formula 1), an inactive ingredient, is increased due to a photoreaction. Transvitamin D ₃ was increased by 1.2% and vitamin D ₃ content was also decreased by 10% in the light condition (1.2 million LUX optical chamber storage and 1.2 million LUX when stored for 18.44 hours) compared to the initial value.

 [Chemical Formula 1]

[Prior Art Literature]

[Patent Literature]

(Patent Document 1) U.S. Patent No. 4,133,814

(Patent Document 2) U.S. Patent No. 4,418,068

(Patent Document 3) U.S. Patent No. 4,380,635

[Non-Patent Document]

(Non-Patent Document 1)  V. Craig Jordan, Nature Reviews Cancer 7, 46-53 (2007)

(Non-Patent Document 2) G.Bovin, et al., The Journal of Clinical Endocrinology & Metabolism 88 (9), 4199-4205 (2003)

(Non-Patent Document 3) G. Sowjanya et al., Journal of Delivery & Therapeutics 2 (4), 175-181 (2012)

One aspect includes the steps of preparing a raloxifene granule or tablet comprising raloxifene or a pharmaceutically acceptable salt thereof; Preparing a vitamin D granule or tablet containing vitamin D or a derivative thereof; And filling the prepared rairoxifene granules or tablets and the prepared vitamin D granules or tablets into a separate, isolated layer in a hard capsule,

Wherein the step of preparing the < RTI ID = 0.0 > raloxifene < / RTI &

Adding a binding liquid comprising a solubilizing agent to a mixture comprising raloxifene or a pharmaceutically acceptable salt thereof, an excipient and a disintegrant to prepare a first premix on the granules; And mixing the first premixed portion with a pharmaceutically acceptable additive comprising a disintegrant to prepare a granule or tablet,

The step of preparing the vitamin D granules or tablets comprising the vitamin D or a derivative thereof,

Adding a binding liquid to a pharmaceutically acceptable additive to prepare a second premixed portion on the granules; And mixing the vitamin D or a derivative thereof, a binder and a lubricant in the second premixing part to prepare granules or tablets.

In another aspect,

A raloxifene independent layer containing raloxifene or a pharmaceutically acceptable salt thereof; And a vitamin D independent layer containing vitamin D or a derivative thereof.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect includes the steps of preparing a raloxifene granule or tablet comprising raloxifene or a pharmaceutically acceptable salt thereof; Preparing a vitamin D granule or tablet containing vitamin D or a derivative thereof; And filling the prepared rairoxifene granules or tablets and the prepared vitamin D granules or tablets into a separate, isolated layer in a hard capsule,

Wherein the step of preparing the < RTI ID = 0.0 > raloxifene < / RTI &

Adding a binding liquid comprising a solubilizing agent to a mixture comprising raloxifene or a pharmaceutically acceptable salt thereof, an excipient and a disintegrant to prepare a first premix on the granules; And mixing the first premixed portion with a pharmaceutically acceptable additive comprising a disintegrant to prepare a granule or tablet,

The step of preparing the vitamin D granules or tablets comprising the vitamin D or a derivative thereof,

Adding a binding liquid to a pharmaceutically acceptable additive to prepare a second premixed portion on the granules; And mixing the vitamin D or a derivative thereof, a binder and a lubricant in the second premixing portion to prepare granules or tablets.

As used herein, the independent layer means a layer in which one pharmacologically active ingredient-containing layer is separated from other pharmacologically active ingredients. The independent layer need not necessarily be a continuous layer and may exist as an intermittent form, such as a plurality of granules, without incorporation of a plurality of pharmacologically active ingredients.

As used herein, the term " separated from each other " means a state in which a plurality of active ingredients are separated from each other during storage of the preparation, so that no mutual interaction occurs.

The licoxifene independent layer and the vitamin D independent layer may each independently be in the form of granules or tablets. As each independent layer is present as a granule or tablet, there can be no separate phenomenon in which the independent layers are mixed with each other and can exist separately from each other in the capsule. In one embodiment, at least one of the licoxifene independent layer and the vitamin D independent layer is a tablet. When present in tablets, the degree to which the licoxifene independent layer and the vitamin D independent layer are present without being intermixed and separated can be more complete. Thus, in another embodiment, both the raloxifene independent layer and the vitamin D independent layer are tablets.

In one embodiment, the step of preparing the first premixed portion on the granules and the step of preparing the second premixed portion on the granules in the above manufacturing method may be by a wet granulation method. "Wet granulation" is a method commonly used in the production of granules. It is a method of adding a solution of a binder to a raw material powder, mixing the mixture with a softener or the like, and assembling the mixture through assembly, drying and sizing processes do. At this time, an excipient, a binder or a disintegrant is required as an additive, and it is necessary to select an appropriate binder depending on the properties of the raw material powder.

In addition, the step of tabletting may be carried out by a direct tableting method in which a mixture of an active ingredient and a pharmaceutical additive is prepared by mixing immediately after mixing, or may be prepared by an indirect tableting method in which granules are prepared by preliminarily preparing granules . When the tablets are prepared by tableting the above mixture or granules, tabletting can be carried out according to a conventional tablet preparation method. The appropriate hardness of the tablet is, for example, 1 to 30 kp. The measurement of the tablet hardness can be performed before forming any film coating layer on the tablet.

The pharmaceutically acceptable excipients may be selected from, but not limited to, diluents, disintegrants, binders, stabilizers, lubricants, colorants, and any combination thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, ruddy press, mannitol, calcium dihydrogenphosphate, starch, low-substituted hydroxypropylcellulose, and any combination thereof, but is not limited thereto. The diluent may be used in an amount ranging from about 1% to about 99% by weight, specifically from about 5% to 90% by weight, based on the total weight of the granule or tablet.

The binder may be selected from the group consisting of silicate derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copovidone, macrogol, light silicic anhydride, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; Phosphates such as calcium hydrogen phosphate; Carbonates such as calcium carbonate; And any combination thereof, but is not limited thereto. The binder may be used in an amount ranging from about 1 to 30% by weight, specifically from about 2 to 15% by weight, based on the total weight of the granule or tablet.

The stabilizer may be an antioxidant, an acidifying agent or a basic agent. The antioxidant may be selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitic acid, ethylenediamine tetraacetic acid (EDTA), sodium pyrosulfite, But the present invention is not limited thereto. In one embodiment, the antioxidant is butylated hydroxytoluene. The acidifying agent may be an organic acid such as fumaric acid, citric acid, tartaric acid, succinic acid, lactic acid, malic acid, tosylic acid, oxalic acid, ascorbic acid, glutamic acid, alginic acid, maleic acid and adipic acid; Inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and boric acid; And any combination thereof, but is not limited thereto. Specifically, the acidifying agent may be selected from fumaric acid, citric acid, tartaric acid, phosphoric acid, and any combination thereof.

The basicizing agent may be a basic mineral such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium dihydrogenphosphate, potassium hydrogenphosphate, or tribasic calcium phosphate; But are not limited to, arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, and any combination thereof. Specifically, the basicizing agent may be selected from sodium bicarbonate, calcium carbonate, magnesium carbonate, and any combination thereof.

The stabilizing agent may be selected according to the characteristics of the pharmacologically active ingredient contained in the independent layer, and the stabilizing agent may be used in an amount of about 0.01 to 10% by weight based on the total weight of the pharmacologically active ingredient.

The lubricant may be selected from the group consisting of stearic acid metal salts, stearic acid metal salts such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high melting wax, glyceryl fatty acid esters, glycerol dibehenate , And any mixture thereof, but is not limited thereto. The glidant may be used in an amount ranging from about 0.2 to about 5% by weight, specifically from about 0.3 to about 3% by weight, based on the total tablet weight.

The solubilizing agent may be selected from the group consisting of docusate sodium, glyceryl monooleate, polyethylene alkyl ether, polysorbate, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid esters, and any combination thereof, And the polysorbate may be polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, but most preferably polysorbate 80. The solubilizing agent may be used in an amount ranging from about 0.5 to 16.7% by weight, from about 0.5 to 13% by weight, or from about 1 to 12% by weight, based on the major component of the granule or tablet. In the case of polysorbate, preferably polysorbate 80, the solubilizing agent is used in an amount of 1 to 16.7% by weight, 1 to 13% by weight, 3 to 13% by weight, 5 to 13% by weight, Or 5 to 12% by weight.

When the solubilizing agent is included within the above range, the composite capsule according to the present invention can have an excellent dissolution rate and can maintain stability regardless of the kind of the packaging material.

In one embodiment, the composite capsule preparation method may be such that the disintegrant is added in the same amount in each of the steps of preparing the first premixed portion and granules or tablets from the first premixed portion. The composite capsule may be prepared by preparing a first premixed part and then mixing the additional pharmaceutically acceptable additives to prepare granules or tablets. In this case, in the step of preparing the first premixed part, The disintegrant and the disintegrant in the step of preparing granules or tablets from the first premixed portion are added in the same parts by weight.

The disintegrant can be any disintegrant that can be used as a disintegrant in the manufacture of granules or tablets, including, for example, crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glycolate , Croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or a sodium salt thereof, and any combination thereof, but is not limited thereto. The disintegrant may be used in an amount ranging from about 1 to 35% by weight, based on the total weight of the granule or tablet.

In one embodiment, the disintegrant may be a sodium ion-free disintegrant that does not contain sodium ions. If the disintegrant is a sodium ion-containing disintegrant containing sodium ions, the sodium ion of the disintegrant may react with the raloxifene to inhibit elution of the raloxifene.

In one embodiment, the sodium ion-free disintegrant may be a nonionic disintegrant.

As a result of the test, when the tablets or granules of the raloxifene or the vitamin D or its derivative constituting the composite capsule according to one embodiment of the present invention contain the sodium ion-free disintegrant as the disintegrant, the sodium ion-containing Compared to the inclusion of disintegrants (eg starch glycolic acid sodium, croscarmellose sodium, sodium alginate), the generation of the raloxifene suppositories was significantly less in the accelerated storage stability test. Accordingly, it has been found that the composite capsule according to the present invention can further secure the improved stability of the active ingredient when a sodium ion-free disintegrant is included. The sodium ion-free disintegrant can be any disintegrator known to be used in the manufacture of granules or tablets, including, for example, crospovidone, low-substituted hydroxypropylcellulose, pregelatinized starch, corn starch, methyl Cellulose, hydroxypropylmethylcellulose, alginic acid, and any combination thereof. ≪ RTI ID = 0.0 >

In one embodiment, the composite capsule preparation method may further comprise the step of coating the tablets when tablets of raxifen or tablets of vitamin D are prepared in the step of preparing tablets.

The coating agent for preparing the coating layer which may additionally be contained in the surface of the granules or tablets may be a film-coating polymer which is conventionally used in the field of granules or tablets. The coating agent may be selected from, for example, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and any combination thereof, no. The amount of the coating agent to be used is preferably kept to a minimum in consideration of the size of the preparation and efficient production while maintaining the function of the coating layer, and is about 1 to 20% by weight, specifically about 2 to 20% by weight, 10% by weight.

The colorant may be selected from the group consisting of red iron oxide, yellow iron oxide, titanium oxide, blue No. 1, blue No. 2, and any mixture thereof, but is not limited thereto. The amount of the coloring agent to be used may be in the range of about 0.001 to about 2% by weight, specifically about 0.01 to about 1.5% by weight based on the total weight of the granules or tablets.

Another aspect relates to a pharmaceutical composition comprising a raloxifene independent layer containing raloxifene or a pharmaceutically acceptable salt thereof produced by the above described manufacturing method; And a vitamin D independent layer containing vitamin D or a derivative thereof.

In an embodiment, the capsule constituting the composite capsule may be a hard capsule. The hard capsule may be any ordinary hard capsule used in the manufacture of medicines. The base of the hard capsule may be selected from, but is not limited to, for example, gelatin, hypromellose, pullulan (Capsugel, NP caps, etc.), polyvinyl alcohol, and any combination thereof .

The size of the hard capsule may be a general capsule size used in pharmaceutical products. Depending on the size of the capsule, a variety of lake capsules are commonly used. Large capsules, such as capsule No. 00 (capsule diameter 8.5 mm, capsule length 23.3 mm), are used by patients with small body sizes such as elderly or young children And the portable convenience due to an increase in volume may also be deteriorated. The composite capsules according to the present invention can be used as capsules No. 0, No. 1, No. 2, No. 3 or No. 4 due to the mass limit of tablets or granules to be filled in capsules. More specifically, 2, or 3 capsules may be used.

The racxifene independent layer contains either racxifene or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of the foregoing raloxifene are known in the art and are disclosed, for example, in British Patent No. 2293382 and German Patent No. 19534744. Examples of pharmaceutically acceptable salts of said raxifene include pharmaceutically acceptable non-toxic organic acids or inorganic acid addition salts such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and the like. In one embodiment, the laloxifene independent layer contains laloxifene hydrochloride.

In one embodiment, the composite capsule of the present invention may further comprise a coating layer of the at least one tablet.

The granules or tablets may each independently include a coating layer on the surface. The coating layer can further improve the degree to which the raloxifene independent layer and the vitamin D independent layer are separated from each other without being intermixed. The coating layer may be present in an amount of about 1 to 20 wt% based on the total weight of the granule or tablet. In one embodiment, at least one of the respective independent layers is a tablet, and the tablet may further comprise a coating layer on the surface.

The daily dose of the above-mentioned raloxifene or a pharmaceutically acceptable salt thereof is about 10 to 1,000 mg, particularly 30 to 300 mg, more specifically 60 to 80 mg, based on 60 kg of an adult, The amount may vary depending on race, ethnicity, age, sex, degree of disease progression, etc., and may be appropriately adjusted by the skilled practitioner in the field. In one embodiment, the composite capsule according to the present invention contains about 60 to 80 mg of raloxifene or a pharmaceutically acceptable salt thereof per unit dosage form.

The vitamin D independent layer comprises vitamin D or a derivative thereof. The term vitamin D or its derivatives as used herein means any vitamin D or derivative thereof that is known or may be developed to be effective in the treatment of osteoporosis, including improvement of bone density. In one embodiment, the vitamin D or derivative thereof is cholecalciferol. The daily dose of cholecalciferol is about 200 to 2,000 IU, specifically about 400 to 1,000 IU, based on a 60 kg adult. The dose may vary depending on race, ethnicity, age, sex, degree of disease progression, etc., and can be appropriately adjusted by the specialist in the field. In one embodiment, the composite capsule according to the present invention contains about 400 to 1,000 IU of cholecalciferol per unit dosage form.

The complex capsule according to the present invention can be prepared by using a drug selected from the group consisting of selective estrogen receptor modulator, raloxifene as a first active ingredient, and vitamin D or a derivative thereof as a second active ingredient, D or a derivative thereof, as well as for the treatment of any disease which can be detected as an indication in the future. As used herein, "treatment" is used as a concept that includes treatment, improvement, amelioration, and management of disease. In one embodiment, the composite capsule may be used for the treatment or prevention of bone mineral density enhancement, vertebral fracture, non vertebral fracture, osteoporosis, or noninvasive breast cancer.

The composite capsule according to the present invention may be administered orally, buccally, or sublingually, and is orally administered according to one embodiment.

The composite capsule according to the present invention can be continuously used for the prevention or treatment of osteoporosis. The combined capsule contains both active ingredients effective for the prevention and treatment of osteoporosis in one unit dosage form, thereby significantly improving the compliance of patients with osteoporosis who are to be continuously taken. In addition, it is possible to provide a pharmaceutical composition containing vitamin D or a derivative thereof, which is capable of effectively exhibiting its drug efficacy even in non-vertebral fractures, in one unit dosage form, It can be used as a therapeutic agent for osteoporosis, and thus it is a very useful combination agent in terms of its efficacy. In addition, the composite capsule is a combination of two active ingredients, which can solve the problem of instability over time due to interactions between active ingredients, which are problematic in manufacturing, and is preferable in that a stable pharmaceutical effect can be obtained. Also, it is difficult to expect bioavailability improvement due to low dissolution rate. However, the composite capsule according to the present invention increases the dissolution rate by selecting an appropriate solubilizing agent and using an appropriate amount (Example 1 and Comparative Example 3), maintaining an increased dissolution rate even at pH 4.0, and ensuring stability at the same time .

In one embodiment, the composite capsule according to the present invention comprises racxifene and vitamin D or a derivative thereof in separate form within the capsule, whereby the two active ingredients may be present in a completely separated form have. Accordingly, it is possible to maximize the therapeutic effect by minimizing the reactivity between the active ingredients and the product stability due to the change over time, and also to provide a method for analyzing the stability of the product, There are advantages to use.

The raloxifene granules or tablets containing the raloxifene or the pharmaceutically acceptable salts thereof produced by the manufacturing method according to one aspect have an improved dissolution rate and thus have a lower bioavailability of the raloxifene having a lower dissolution rate .

A radiolipin-independent layer containing a radiolipin or a pharmaceutically acceptable salt thereof having an improved dissolution rate by the method of manufacture; And a vitamin D independent layer containing vitamin D or a derivative thereof, the stability of the active ingredient is not deteriorated due to the interaction between the active ingredients, You can expect. It can also be used for the treatment of osteoporosis, which is effective for both vertebral and non-vertebral fractures due to the reinforcing effect between the active ingredients.

1 is a schematic view of a composite capsule according to one embodiment of the present invention.
2 is a schematic view of a composite capsule according to another embodiment of the present invention.
3 is a schematic view of a composite capsule according to another embodiment of the present invention.
4 is a graph showing the dissolution test results of 0.1% polysorbate 80 of the raloxifene tablet according to Examples 1 to 4 of the present invention.
5 is a graph showing the dissolution test results of 0.1% polysorbate 80 of the raloxifene tablet according to Comparative Examples 1 to 6 of the present invention.
6 is a graph showing the dissolution test results of the raloxifene tablets according to Examples 1 to 4 of the present invention at pH 4.0.
7 is a graph showing the dissolution test results of the raloxifene tablets according to Comparative Examples 1 to 6 of the present invention at pH 4.0.
FIG. 8 is a graph showing a dissolution profile of the raloxifene purification unit after applying the thermal condition for two weeks in Example 4 of the present invention. FIG.
FIG. 9 is a graph showing the dissolution profile after applying the heat / moisture condition for two weeks in the raloxifene tablet in Example 4 of the present invention. FIG.
FIG. 10 is a graph showing a dissolution profile after applying a two-week moisture supersaturation condition of a raloxifene tablet in Example 4 of the present invention. FIG.
Fig. 11 is a graph showing the dissolution profiles of the cholecalciferol purification unit after 2 weeks of heat treatment in Example 4 of the present invention. Fig.
12 is a graph showing the dissolution profile after applying heat / moisture conditions for 2 weeks of the cholecalciferol purification in Example 4 of the present invention.
FIG. 13 is a graph showing the dissolution profiles after applying the supersaturation conditions of the cholaclycerol refining part for two weeks in Example 4 of the present invention. FIG.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Also, the numerical values set forth herein are considered to include the meaning of " about " unless explicitly stated.

EXAMPLES 1 TO 3: Preparation of Raloxifene Granules and Tablets

Povidone K30 and polysorbate 80 were dissolved in ethanol and purified water according to the composition shown in Table 1 below as a binding solution. Mixed with low-substituted hydroxypropylcellulose and crospovidone (5.8 mg), wet-granulated with the above-mentioned binding liquid, and then formed into 30-mesh and dried to prepare a whole mixture portion on the granules . Then, the lacticin granules were prepared by mixing lactose hydrate and light anhydrous silicic acid, crospovidone (5.8 mg), and magnesium stearate in the above-prepared whole mixed portion.

Then, the dried rairoxifene granules were tableted using a circular punch having a diameter of 5.5 mm to prepare a raloxifene tablet. Then, Opa Dry White was dissolved in purified water and ethanol to prepare a coating solution, and then coated with the prepared raxoxifen tablet.

Lacoxifene-containing layer Example 1
Example 2
Example 3
Additive substance Amount (mg) Relative to main ingredient
ratio(%) Amount (mg) Relative to main ingredient
ratio(%) Amount (mg) Relative to main ingredient
ratio(%) Raloxifene hydrochloride 30.00 100.00 30.00 100.00 30.00 100.00 Low-substituted hydroxypropylcellulose 26.30 87.67 27.80 92.67 26.60 88.67 Lactose baggage 16.40 54.67 16.40 54.67 16.40 54.67 Crospovidone 11.60 38.67 11.60 38.67 11.60 38.67 Povidone K30 1.60 5.33 1.60 5.33 1.60 5.33 Polysorbate 80 1.50 5.00 0.30 1.00 3.60 12.00 Light anhydrous silicic acid 1.60 5.33 1.60 5.33 1.60 5.33 Magnesium stearate 1.00 3.33 1.00 3.33 1.00 3.33 Opa Dry White 4.50 15.00 4.50 15.00 4.50 15.00 Purified water (36.00) - (36.00) - (36.00) - ethanol (12.00) - (12.00) - (12.00) -

Comparative Example  1 to 5: Raloxifene  Preparation of granules and tablets

The raloxifene granules and tablets were prepared according to the composition shown in Table 2 below.

Specifically, in Examples 1 to 3, except that the amount and the amount of the solubilizing agent to be added to the binding solution, the amount to be added, and the type of solubilizing agent (polysorbate 80, sodium lauryl sulfate, and sorbitan monooleate 80) Was prepared in the same manner as described.

Lacoxifene-containing layer Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Additive substance Amount (mg) Amount (mg) Amount (mg) Amount (mg) Amount (mg) Raloxifene hydrochloride 30.00 30.00 30.00 30.00 30.00 Low-substituted hydroxy
Propyl cellulose 27.80 27.60 23.80 26.60 26.60 Lactose baggage 16.40 16.40 16.40 16.40 16.40 Crospovidone 11.60 11.60 11.60 11.60 11.60 Povidone K30 1.60 1.60 1.60 1.60 1.60 Polysorbate 80 - 0.20 4.00 - - Sodium lauryl sulfate - - - 1.20 - Sorbitan monooleate 80 - - - - 1.20 Light anhydrous silicic acid 1.60 1.60 1.60 1.60 1.60 Magnesium stearate 1.00 1.00 1.00 1.00 1.00 Opa Dry White 4.50 4.50 4.50 4.50 4.50 Purified water (36.00) (36.00) (36.00) (36.00) (36.00) ethanol (12.00) (12.00) (12.00) (12.00) (12.00)

Example  4: Preparation of composite capsules I

Vitamin D tablets were prepared according to the composition shown in Table 3 below.

Specifically, povidone K30 was dissolved in purified water to prepare a binding solution. Lactose hydrate, microcrystalline cellulose, and crospovidone were mixed, wet granulated with the above-mentioned binding liquid, followed by sizing to 20 mesh and drying to prepare a whole mixed portion Respectively. Then, vitamin D, light silicic anhydride, and magnesium stearate were mixed with the above-prepared whole mixed portion to prepare cholecalciferol granules. The dried cholecalciferol granules were then tableted using a circular punch having a diameter of 5.5 mm to prepare cholecalciferol tablets.

Cholecalciferol-containing layer Additive substance Amount (mg) Cholecalciferol concentrated powder (109,000 IU / g) 7.34 Lactose baggage 58.66 Microcrystalline cellulose 10.00 Crospovidone 4.00 Povidone K30 3.00 Light anhydrous silicic acid 0.50 Magnesium stearate 1.50 Opa Dry White 2.50 Blue No. 2 Suitable amount Purified water (15.00) ethanol (5.00)

Two tablets of the obtained vitamin D tablet and two tablets of the raxoxene tablet according to Example 1 were filled in hard capsule No. 1, which is a gelatin-based tablet, to obtain a composite capsule containing 60 mg of raxoxin and 800 IU of cholecalciferol . A schematic diagram of the prepared capsule is shown in Fig.

Comparative Example 6: Preparation of composite capsule preparation II

A composite capsule containing 60 mg of raloxifene and 800 IU of cholecalciferol was prepared in the same manner as in Example 4 except that the raloxifene tablet was according to Comparative Example 3.

Test Example 1: Dissolution Test I

Examples 1 to 4 and Comparative Examples 1 to 6 were subjected to a dissolution test using the FDA recommended dissolution test method.

In the case of raloxifene, 1,000 mL of 0.1% polysorbate 80 solution was used as the eluent. The test method was the paddle method, the temperature of the eluent was 37 ± 5 ° C, and the stirring speed was 50 rpm. In addition, a dissolution test at pH 4.0 was carried out in consideration of the absorption site of the raloxifene. For this purpose, pH 4.0 (see General Test Methods for Korean Pharmacopoeia) and 900 ml of purified water were used as the eluent, and the remaining conditions were the same as those set forth above. Then, cholecalciferol was used as an eluant in 500 mL of a 0.3% sodium lauryl sulfate solution. The test method was a paddle method, the temperature of the eluent was 37 ± 5 ° C., and the stirring rate was 75 rpm. 3 mL of the sample was taken at 5, 10, 15, 20, 30 and 45 minutes after the elution test, and an equal amount of eluate was added to maintain a constant total eluate. Then, the solution obtained by the dissolution test was filtered through a 0.45 탆 membrane filter, and then subjected to high performance liquid chromatography under the following conditions. Cholecalciferol was centrifuged to prepare a sample solution, and then a high performance liquid The analysis was carried out through chromatography.

≪ Conditions for analysis of release of raloxifene >

Used equipment: HPLC (Hitachi 2000 series, Japan)

Detector: Ultraviolet absorptiometer (measurement wavelength: 290 nm)

Column: A column (Zorbax CN Column) filled with silica gel for liquid chromatography with a diameter of 5 占 퐉 and having a diameter of about 4.6 mm and a length of about 15 cm,

Mobile phase: Add 500 mL of water to 500 mL of acetonitrile, add 2.0 mL of triethylamine, mix well and adjust to pH 4.0 with phosphoric acid.

Flow rate: 2.0 mL / min

Column temperature: 30 ° C

≪ Conditions for analysis of cholecalciferol dissolution test >

Used equipment: HPLC (Hitachi 2000 series, Japan)

Detector: Ultraviolet absorptiometer (measuring wavelength: 265 nm)

Column: A column (Platinum EPS C18 Column) filled with octadecyl silica gel for liquid chromatography having a particle diameter of 3 占 퐉 was inserted into a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 15 cm.

Mobile phase: acetonitrile: water = 93: 7 (v / v)

Flow rate: 1.5 mL / min

Column temperature: 30 ° C

The results of the elution of raloxifene and cholecalciferol measured under the above analysis conditions are shown in Tables 4 to 6 below.

The dissolution rate of raloxifene (0.1% polysorbate 80 solution) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 1 18.8% 32.2% 82.6% 97.7% 101.3% Example 2 21.4% 42.1% 67.9% 88.4% 95.4% Example 3 37.3% 61.2% 86.3% 101.7% 105.9% Example 4 13.4% 27.8% 80.1% 95.8% 99.3% Comparative Example 1 7.5% 38.4% 57.5% 77.6% 86.2% Comparative Example 2 12.8% 47.8% 66.6% 79.2% 86.8% Comparative Example 3 31.9% 58.7% 72.4% 97.1% 104.1% Comparative Example 4 10.5% 37.2% 72.6% 76.4% 79.1% Comparative Example 5 8.7% 39.4% 75.5% 79.8% 82.4% Comparative Example 6 25.2% 55.1% 69.7% 98.3% 103.8%

The dissolution rate of raloxifene (pH 4.0 solution) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 1 28.7% 79.5% 95.2% 100.8% 102.3% Example 2 18.3% 35.2% 73.5% 89.4% 94.9% Example 3 25.5% 77.6% 97.4% 101.5% 101.0% Example 4 8.2% 32.5% 72.8% 96.3% 100.1% Comparative Example 1 6.2% 27.7% 59.2% 79.2% 88.6% Comparative Example 2 15.3% 51.2% 69.3% 81.7% 89.8% Comparative Example 3 55.6% 71.3% 95.6% 103.2% 105.7% Comparative Example 4 13.1% 41.7% 78.4% 80.2% 82.6% Comparative Example 5 17.7% 45.2% 79.2% 81.8% 85.9% Comparative Example 6 53.2% 70.8% 93.2% 100.9% 105.5%

Cholecalciferol dissolution rate 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 4 21.8% 38.9% 86.8% 97.6% 100.9% Comparative Example 6 19.2% 62.7% 84.3% 98.8% 103.3%

As shown in the dissolution results of Table 4, in Examples 1 to 3 of Examples 1 to 3 of the dissolution of the tablet of Roxxin, the dissolution rate of 100% level was observed in Example 1 and Example 3 at 45 minutes, In Example 2, the dissolution rate was rather low, and in the case of Example 4, which is a composite capsule, it was confirmed to be similar to dissolution of a single tablet. In the case of the comparative example, a significantly improved dissolution rate could be confirmed in Comparative Example 3 (about 13.4% by weight when the amount of the raxifene hydrochloride was 100) in which a proper amount of the solubilizer was added. In Comparative Example 2 in which the amount of the solubilizing agent was small, A dissolution profile similar to that of Comparative Example 1 in which no agent was added was confirmed. In addition, in Comparative Examples 4 to 5 using a solubilizer other than polysorbate, a low dissolution rate was confirmed.

As shown in the results of the elution of Table 5, in the case of Examples 1 to 3, elution of the tablet of raloxifene was also effected at an environment of pH 4.0. In Example 1 and Example 3, a dissolution rate of 100% The dissolution rate was slightly lower in Example 2, which is a small amount, and in Example 4, which is a composite capsule, similar to the dissolution of a single tablet. In the case of the comparative example, the dissolution rate remarkably improved in Comparative Example 3 (about 13.4% by weight when the amount of the lacixphene hydrochloride was 100) in which an appropriate amount of the solubilizer was added was confirmed, but in Comparative Example 2 in which the amount of the solubilizing agent was small, A dissolution profile similar to that of Comparative Example 1 in which no solubilizing agent was added was confirmed. In addition, in Comparative Examples 4 to 5 using a solubilizer other than polysorbate, a low dissolution rate was confirmed.

In the case of elution of cholecalciferol, similar elution was confirmed for both Example 4 and Comparative Example 6.

Accordingly, it can be seen that the content of the solubilizing agent and the type of the solubilizing agent are important as compared with other forms of the granules or tablets of the present invention. Also, it can be seen that the improved dissolution rate of the saccharoloxifene granules or tablets is maintained by the composite capsule according to one embodiment of the present invention, and the dissolution of cholecalciferol also maintains excellent dissolution rate and stability.

Test Example 2: Stability test

After storing the raloxifene single tablet and the composite capsule obtained in Examples 1 to 4 and Comparative Examples 1 to 6 under the following accelerating conditions, the raloxifene suppository and the cholecalciferol And the degree of occurrence of the flexible material was analyzed.

<Accelerated Storage Conditions>

HDPE bottle, PTP (PVDC-Al) packing condition at storage condition: 40 and relative humidity 75%

Testing time: Initial (before storage), 1 month, 3 months and 6 months

Analyzes are: raloxifene, cholecalciferol

&Lt; Analysis conditions of the flexible substance which is a raloxifene and a raloxifene group &

Used equipment: HPLC (Hitachi 2000 series, Japan)

Detector: Ultraviolet absorptiometer (measuring wavelength: 280 nm)

Column: A column (Inertsil C8 Column) filled with silica gel for liquid chromatography having a particle diameter of 5 占 퐉 was inserted into a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 25 cm.

Mobile phase A - phosphate buffer (pH 3.0): acetonitrile = 75: 25

Mobile phase B-phosphate buffer (pH 3.0): acetonitrile = 50: 50

Phosphate buffer solution (pH 3.0): Add 9.0 g of anhydrous potassium dihydrogenphosphate to 1 liter of water, add 0.5 ml of phosphoric acid, and adjust pH to 3.0 with phosphoric acid or potassium hydroxide solution.

Mobile phase Gradient Condition: Table 7

Flow rate: 1.0 mL / min

Column temperature: 35 ° C

Time (minutes) Mobile A (%) Mobile phase B (%) 0 100 0 5 100 0 36.25 0 100 38.25 100 0 48 100 0

&Lt; Chromatocarboperoxylate &lt; / RTI &gt;

Used equipment: HPLC (Hitachi 2000 series, Japan)

Detector: Ultraviolet absorptiometer (measuring wavelength: 265 nm)

Column: A column (Phenosphere ODS Column) filled with octadecyl silica gel for liquid chromatography having a particle size of 3 占 퐉 was inserted into a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 15 cm.

Mobile phase A - 0.025% aqueous phosphoric acid solution

Mobile phase B - acetonitrile: mobile phase A mixture = 99: 1 (v / v)

Mobile phase Gradient conditions: Table 8

Flow rate: 1.2 mL / min

Column temperature: 25 ° C

Time (minutes) Mobile A (%) Mobile phase B (%) 0 51.5 48.5 16 13 87 39 10 90 43 0 100 57 0 100 57.1 51.5 48.5 65 51.5 48.5

The types and levels of the radioactive materials of the raloxifene and cholecalciferol measured under the above analysis conditions are shown in Tables 9 to 12 below.

Flexible substance of raloxiprene (HDPE bottle packaging) sample
Early 1 month 3 months 6 months N-Oxide Total N-Oxide Total N-Oxide Total N-Oxide Total Example 1 0.00% 0.04% 0.04% 0.08% 0.06% 0.12% 0.10% 0.22% Example 2 0.01% 0.05% 0.03% 0.07% 0.07% 0.13% 0.08% 0.24% Example 3 0.01% 0.05% 0.03% 0.09% 0.06% 0.14% 0.09% 0.22% Example 4 0.01% 0.03% 0.03% 0.09% 0.08% 0.14% 0.09% 0.23% Comparative Example 1 0.00% 0.07% 0.02% 0.11% 0.05% 0.13% 0.11% 0.23% Comparative Example 2 0.01% 0.03% 0.04% 0.10% 0.07% 0.14% 0.13% 0.27% Comparative Example 3 0.02% 0.07% 0.05% 0.12% 0.08% 0.12% 0.09% 0.23% Comparative Example 4 0.01% 0.07% 0.03% 0.08% 0.09% 0.13% 0.10% 0.18% Comparative Example 5 0.03% 0.05% 0.04% 0.11% 0.07% 0.12% 0.09% 0.25% Comparative Example 6 0.01% 0.06% 0.06% 0.09% 0.10% 0.15% 0.13% 0.28%

Cholecalciferol, a flexible substance (packaged in HDPE bottles) sample
Early 1 month 3 months 6 months Trans-VitD Ester total Trans-VitD Ester total Trans-VitD Ester total Trans-VitD Ester total Example 4 0.03% 0.23% 0.06% 0.31% 0.09% 0.43% 0.13% 0.56% Comparative Example 6 0.04% 0.26% 0.21% 0.61% 0.43% 0.78% 0.55% 0.91%

The flexible substance (PTP) sample
Early 1 month 3 months 6 months N-Oxide Total N-Oxide Total N-Oxide Total N-Oxide Total Example 1 0.02% 0.06% 0.05% 0.09% 0.08% 0.15% 0.12% 0.25% Example 2 0.01% 0.05% 0.07% 0.10% 0.06% 0.16% 0.10% 0.28% Example 3 0.02% 0.07% 0.06% 0.10% 0.07% 0.17% 0.13% 0.26% Example 4 0.01% 0.05% 0.04% 0.09% 0.07% 0.16% 0.13% 0.26% Comparative Example 1 0.01% 0.05% 0.08% 0.15% 0.11% 0.19% 0.14% 0.33% Comparative Example 2 0.02% 0.05% 0.09% 0.12% 0.12% 0.22% 0.16% 0.29% Comparative Example 3 0.02% 0.06% 0.06% 0.11% 0.09% 0.17% 0.14% 0.27% Comparative Example 4 0.01% 0.07% 0.05% 0.12% 0.08% 0.18% 0.15% 0.28% Comparative Example 5 0.01% 0.06% 0.07% 0.10% 0.09% 0.16% 0.16% 0.26% Comparative Example 6 0.02% 0.07% 0.06% 0.15% 0.13% 0.22% 0.19% 0.35%

The cholecalciferol group, a flexible substance (PTP) sample
Early 1 month 3 months 6 months Trans-VitD Ester total Trans-VitD Ester total Trans-VitD Ester total Trans-VitD Ester total Example 4 0.02% 0.22% 0.07% 0.34% 0.11% 0.53% 0.18% 0.64% Comparative Example 6 0.03% 0.24% 0.23% 0.65% 0.48% 0.79% 0.60% 0.99%

In Tables 9 to 12, it was found that the single agent showed similar stability irrespective of the capsule regardless of both the raxoxifene and the cholecalciferol, and the increase of the suppository was found to be very weak at the time of 6 months of acceleration. However, when Example 4, which is a combination agent, was compared with Comparative Example 6, it was confirmed that Comparative Example 6 was relatively increased in the amount of the flexible substance. In particular, Example 3, which is a raloxifene tablet containing 12% polysorbate, showed similar stability to other tablets, but in Comparative Example 6, which contained 13% or more polysorbate, . These results indicate that the type and content of the solubilizing agent in the complex capsules containing the raloxifene tablet and the cholecalciferol are very important for the stability of the formulation and the type and content of the solubilizer contained in the raloxifene- Lt; RTI ID = 0.0 &gt; cholaclycerol &lt; / RTI &gt;

Test Example 3: Porcelain test

The composite capsules of raloxifene and cholecalciferol obtained in Example 4 were evaluated for various container materials and stability and dissolution rate under temperature conditions. The storage conditions and the type of sachet are as shown in Table 13 below.

Item Control group Ten Heat / moisture ore Water supersaturation Exam conditions Room temperature 60 ° C 40 ° C, 75% RH 25 ℃, 1.2 million Lux 25 ° C, 90% RH Test cycle For each sample tested 1 week,
2 weeks 1 week,
2 weeks 24 hours,
48 hours 1 week,
2 weeks Porcelain - HDPE bottle packaging, PVDC / aluminum blister packaging, open-dish

(1) Evaluation of properties, thickness / mass change, and moisture content change

In the open-dish storage conditions of the conditions described in Table 13, the specific changes in the thickness and water content of the tablets of the raloxifene hydrochloride and the cholecalciferol were as shown in Table 14 (tablets of the raloxifene hydrochloride) and Table 15 Calciferol purification part).

Control group Heat / moisture
(40 DEG C / 75% RH) Water supersaturation
(25 DEG C / 90% RH) Thickness (mm) 3.80 4.22 4.16 Moisture (LOD,%) 4.30 7.90 9.16

Control group Heat / moisture
(40 DEG C / 75% RH) Water supersaturation
(25 DEG C / 90% RH) Thickness (mm) 3.50 3.62 3.52 Moisture (LOD,%) 3.68 4.24 5.24

As a result, the composite capsule of Example 4 showed no change in properties, thickness / mass change, and moisture content in HDPE bottle packaging and PVDC / aluminum blister packaging. However, in the open-dish under heat / moisture and water supersaturation conditions, it was confirmed that the tablets cracked due to the swelling phenomenon in the tablet of raxiphen hydrochloride inside the capsule. In addition, the thickness was increased as compared with that of the control (initial condition; Initail condition), and the water absorption was observed. However, in the case of cholecalciferol tablets, there was no significant change in the open-dish storage condition, and the water uptake rate was slightly increased. HDPE bottle packaging and PVDC / aluminum blister packaging are appropriate in terms of properties, thickness / mass change, and moisture content.

(2) Evaluation of stability

The degree of occurrence of the flexible material in various container materials and temperature conditions of the composite capsule of Example 4 was measured in the same manner as in Experimental Example 2. The conditions and results are shown in Table 16 below for each of the raloxifene hydrochloride and cholecalciferol ] And [Table 17]. Compound C, which is a flexible substance derived from laxoxy, and other unknown substances were measured.

Control group Ten
(60 DEG C) Heat / moisture
(40 DEG C / 75% RH) ore
(25 DEG C / 1.2 million Lux)
24 hours (1.2 million Lux), 48 hours (240 million Lux) Water supersaturation
(25 DEG C / 90% RH) Packaging material - HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish Compound C (NMT 0.3%) 0.0 0.1 0.1 0.1 0.0 0.1 0.1 0.0 0.1 0.1 0.0 0.0 0.1 Unknown flexible substance
(NMT 0.2%) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Sum of flexible materials
(NMT 1.0%) 0.1 0.2 0.3 0.3 0.2 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3

Control group Ten
(60 DEG C) Heat / moisture
(40 DEG C / 75% RH) ore
(25 DEG C / 1.2 million Lux)
24 hours (1.2 million Lux), 48 hours (240 million Lux) Water supersaturation
(25 DEG C / 90% RH) Packaging material - HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish HDPE bottle packing PVDC / Aluminum Blister Packaging open-dish Unknown flexible substance
(NMT 1.0%) 0.1 0.3 0.2 0.3 0.25 0.1 0.2 0.5 1.1 1.2 0.1 0.1 0.2 Sum of flexible materials
(NMT 3.0%) 0.3 0.3 0.3 0.3 0.4 0.4 0.4 0.7 2.1 2.0 0.4 0.5 0.3

(3) Evaluation of dissolution rate

The dissolution rates of the composite capsules of Example 4 were measured as in Experimental Example 1 under various container materials and temperature conditions, and the results are shown in Figs. 8 to 13.

As described in the above stability evaluation and dissolution rate evaluation, in the composite capsule of Example 4, the raloxifene hydrochloride exhibited a stable state under all conditions and all the materials. In addition, the cholecalciferol content of the purified tablets was stable in HDPE bottles in the light condition and increased in the PVDC / aluminum blisters. However, the stability level for product storage (NMT in Table 16 and 17 (no more) less than or equal to. In the dissolution test, the tablets of Raloxifene hydrochloride showed dissolution rate similar to that of the control group in all conditions, and the cholecalciferol tablets were also similar to those of the control group.

Therefore, the combination of the hydrochlorofacrol hydrochloride and the cholecalciferol capsule of the present invention is stable and stable even at a temperature of about 60 ° C, a temperature of about 40 ° C / about 75% RH, and a supersaturation of about 25 ° C / about 90% It can be seen that the dissolution rate can be maintained. In addition, it can be confirmed that the composite capsule of Example 4 can maintain stability regardless of the kind of the capsule, such as HDPE bottle packaging and PVDC / aluminum blister packaging.

The present invention has been described above with reference to preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (15)

Preparing a raloxifene granule or tablet comprising raloxifene or a pharmaceutically acceptable salt thereof;
Preparing a vitamin D granule or tablet containing vitamin D or a derivative thereof; And
Filling the hard capsules with the prepared rairoxifene granules or tablets and the prepared vitamin D granules or tablets to form independent layers separated from each other,
Wherein the step of preparing the &lt; RTI ID = 0.0 &gt; raloxifene &lt; / RTI &
Adding a binding liquid comprising a solubilizing agent to a mixture comprising raloxifene or a pharmaceutically acceptable salt thereof, an excipient and a disintegrant to prepare a first premix on the granules; And
Mixing the first premixed part with a pharmaceutically acceptable additive comprising a disintegrant to prepare granules or tablets,
The step of preparing the vitamin D granules or tablets comprising the vitamin D or a derivative thereof,
Adding a binding liquid to a pharmaceutically acceptable additive to prepare a second premixed portion on the granules; And
And mixing the vitamin D or a derivative thereof, a binder and a lubricant in the second premixing part to prepare granules or tablets. The method according to claim 1, wherein in the step of producing the first premixed portion, the solubilizing agent is polysorbate. The method according to claim 1, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and any combination thereof. 3. The process according to claim 2, wherein the polysorbate is about 0.5 to 16.7% by weight based on the amount of larixifene hydrochloride. The method according to claim 1, wherein the disintegrant used in the step of producing the granules or the tablet from the first premixing portion is equal to each other. The method according to claim 1, wherein the step of producing the first premixed portion in granules and the step of preparing the second premixed portion in granules are by the wet granulation method. The method according to claim 1, wherein the step of preparing the tablet of raxifen or the tablet of vitamin D further comprises coating the tablets. A process for producing a polyurethane foam, produced according to any one of claims 1 to 7,
A raloxifene independent layer containing raloxifene or a pharmaceutically acceptable salt thereof; And
A complex capsule preparation comprising a vitamin D independent layer containing vitamin D or a derivative thereof. 9. The composite capsule preparation according to claim 8, wherein the base of the capsule is selected from the group consisting of gelatin, hypromellose, pullulan, polyvinyl alcohol, and any combination thereof. [Claim 9] The composite capsule preparation of claim 8, wherein the pharmaceutically acceptable salt of rairoxifene is a hydrochloride salt. The composite capsule preparation according to claim 8, wherein the vitamin D or a derivative thereof is cholecalciferol. 9. The composite capsule of claim 8, wherein said at least one tablet further comprises a coating layer. The composite capsule of claim 12, wherein said coating layer is present in a weight of about 1 to 20 weight percent based on the total tablet weight. [Claim 9] The pharmaceutical composition according to claim 8, wherein the raloxifene granule or tablet containing the raloxifene or a pharmaceutically acceptable salt thereof contains about 60 mg to 80 mg of the raloxifene or a pharmaceutically acceptable salt thereof per unit dosage form And the vitamin D granule or the tablet containing the vitamin D or a derivative thereof contains about 400 to 1,000 IU of vitamin D or a derivative thereof. The combination capsule of claim 8, which is for the treatment or prevention of bone mineral density enhancement, or vertebral fracture, non vertebral fracture, osteoporosis, or noninvasive breast cancer.

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