KR101379664B1 - Pharmaceutical composition comprising risedronic acid or its salt and vitamin D - Google Patents

Abstract

The present invention provides a pharmaceutical composition for preventing or treating osteoporosis comprising risedronic acid or a salt thereof and vitamin D. The present invention also provides oral tablets obtained by tableting a mixture comprising risedronic acid or a salt thereof and vitamin D in the form of granules; And oral capsules obtained by homogeneously dispersing risedronic acid or its salt and vitamin D in a mixed solvent of soybean oil and coconut oil and filling the capsule.

Risedronic acid, cholecalciferol

Description

Pharmaceutical composition comprising risedronic acid or its salt and vitamin D}

The present invention relates to a pharmaceutical composition for preventing or treating osteoporosis comprising risedronic acid or a salt thereof and vitamin D. The present invention also relates to oral tablets and capsules capable of maintaining the content uniformity and stability of risedronic acid or its salts and vitamin D.

Risedronic acid, whose chemical name is 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid, treats and prevents osteoporosis in postmenopausal women, and in the long term, systemic corticosteroids A drug used to maintain or increase bone density in male and female patients undergoing systemic corticosteroid treatment. Risedronic acid is known in various salt forms, including sodium salt, and risedronic acid sodium salt may exist in the form of anhydride, monohydrate, 2.5 hydrate, and the like, and various polymorphs are known (WO 2003/086355 and Korean Patent Publication No. 10-2004-0101447.

Sodium risedronate is poorly absorbed from the gastrointestinal tract at levels of about 1% [B.J. Gertz et al, Clinical Pharmacology of Alendronate Sodium, Osteoporosos Int. Sulll. 3: S13-16 (1993) and B.J. Gertz et al., Studies of the oral bioavailability of alendronate, Clinical Pharmacology & Therapeutics, vol. 58, number 3, pp. 288-298, (1995). Therefore, in order to compensate for the low bioavailability from the gastrointestinal tract, a large amount of administration is required, and also, since a certain amount of fasting is required to minimize the effects of food, there is a problem of low drug compliance.

Korean Patent Publication No. 10-2005-0110814 discloses a pharmaceutical composition comprising an alendronate and a vitamin D compound. When a combination of the alendronate and the vitamin D compound is administered, bone absorption is suppressed by the alendronate and the absorption of the calcium salt is enhanced by the vitamin D compound. This is because the major biological action of vitamin D helps to maintain calcium homeostasis by increasing the intestinal efficacy of absorbing dietary calcium.

This prior document discloses a mixture of alendronate and vitamin D compounds, but does not specifically disclose whether it is equally applicable to other bisphosphonates (eg risedronic acid or salts thereof). In addition, when preparing oral preparations containing vitamin D and bisphosphonates, the content of vitamin D is relatively very small compared to the bisphosphonates, it is difficult to ensure the uniformity of the content in the manufacturing process, as well as oil phase Due to vitamin D, there is a problem in that it is difficult to formulate and the stability of the obtained formulation is lowered.

In order to solve the problems of the prior art, the present inventors conducted pharmacological activity and formulation studies on a combination composition of various bisphosphonates and vitamin D. As a result, when risedronic acid or its salt and vitamin D are formulated at the same time as oral preparations, a synergistic effect can be expected to strongly inhibit bone absorption, promote absorption of calcium salt and maintain calcium homeostasis. Turned out. In addition, when formulated in tablet form using vitamin D in the form of granules or in the form of capsules by dispersing risedronic acid or its salt and vitamin D in a specific solvent, it is possible to ensure the content uniformity of the main components. However, it has been found that stability can also be greatly increased.

Accordingly, the present invention aims to provide a pharmaceutical composition containing risedronic acid or a salt thereof and vitamin D.

It is also an object of the present invention to provide oral tablets or capsules containing risedronic acid or salts thereof and vitamin D, which can maintain content uniformity and stability.

According to one aspect of the invention, there is provided a pharmaceutical composition for preventing or treating osteoporosis comprising risedronic acid or a salt thereof and vitamin D.

According to another aspect of the present invention there is provided an oral tablet obtained by tableting a mixture comprising risedronic acid or a salt thereof and vitamin D in the form of granules.

In the oral tablet of the present invention, the mixture comprises at least one disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, and alginic acid; One or more excipients selected from the group consisting of lactose, microcrystalline cellulose, and corn starch; And a lubricant selected from the group consisting of magnesium stearate, stearic acid, talc, and silicon dioxide. In addition, the tablet may further comprise a film coating layer comprising a mixture of hydroxypropyl methyl cellulose and polyethylene glycol, the weight ratio of the hydroxypropyl methyl cellulose and polyethylene glycol is 5 to 15: 1, more preferably May be in the range of 10: 1.

According to another aspect of the present invention, there is provided an oral capsule obtained by homogeneously dispersing risedronic acid or its salt and vitamin D in a mixed solvent of soybean oil and hydrogeneated coconut oil and filling the capsule.

In the oral capsule of the present invention, the weight ratio of the soybean oil and coconut oil is 7-11: 5, more preferably 9: 5. In addition, the mixed solvent may further include lead and lecithin as a dispersant or surfactant, the total amount of the lead and lecithin may be in the range of 1 to 3 parts by weight based on 10 parts by weight of the mixed solvent.

According to the present invention, when risedronic acid or its salt and vitamin D are simultaneously formulated as an oral preparation, a synergistic effect of strongly inhibiting bone absorption, promoting absorption of calcium salt and maintaining calcium homeostasis can be expected. It turns out that.

In addition, the pharmaceutical composition in the form of a tablet or capsule according to the present invention can ensure the uniformity of the content of the drug in each formulation, namely risedronic acid or a salt thereof and vitamin D, and has excellent stability.

As used herein, "risedronic acid or a salt thereof" refers to 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid or a salt thereof, wherein the salt is a sodium salt, Potassium salts, calcium salts, magnesium salts, ammonium salts and the like are all included, preferably sodium salts. In addition, risedronic acid or a salt thereof, preferably risedronic acid sodium salt, includes all known forms of anhydrides, monohydrates, 2.5 hydrates, and the like, and various polymorphs. In the composition of the present invention, the content of risedronic acid or salt thereof can be used in a therapeutically effective amount, which can be easily selected by those skilled in the art. The unit dosage form according to the composition of the present invention is about 10-20% by weight relative to the total weight of the composition (e.g., about 35 mg based on the total weight of the composition of about 220 mg or about 35 mg of the total weight of the composition of 286 mg mg) of risedronic acid or a salt thereof, preferably risedronic acid sodium salt, but is not limited thereto.

The term "vitamin D" refers to any form of vitamin D. The term "vitamin D" includes activated and inactivated forms of vitamin D and precursors and metabolites of such forms. Precursors of these activated forms include vitamin D ₂ (ergocalciferol) and vitamin D ₃ (cholecalciferol). Inactive metabolites of vitamins D ₂ and D ₃ include hydroxylated forms of vitamins D ₂ and D _3. In the compositions of the present invention, vitamin D may be used in a therapeutically effective amount, such as 700 IU, 1,400 IU, 2,800 IU, 4,200 IU, 5,600 IU, 7,000 IU, 8,400 IU per unit dosage, but is not limited thereto. no.

According to the present invention, when formulated with risedronic acid or a salt thereof and vitamin D at the same time, oral preparations, a synergistic effect of strongly inhibiting bone absorption and promoting calcium salt absorption and maintaining calcium homeostasis can be expected. It turns out that. Accordingly, the present invention includes a pharmaceutical composition for preventing or treating osteoporosis comprising risedronic acid or a salt thereof and vitamin D.

The present invention includes oral tablets comprising risedronic acid or a salt thereof and vitamin D in the form of granules. The oral tablet according to the present invention can be formulated by granulating vitamin D, so that the content of the main component in the resulting tablet can be kept uniform. That is, since the granular form of vitamin D has excellent flowability, when mixed with excipients, disintegrants, glidants and the like, it is possible to achieve uniform mixing, so that vitamin D used in very small amounts (for example, 40 IU Vitamin D has a mass of approximately 1 μg), thereby ensuring uniformity of content.

It has also been found that the combination use with certain excipients, disintegrants, and glidants is particularly useful for ensuring content uniformity of the main component. Thus, according to one embodiment of the invention, risedronic acid or a salt thereof; Vitamin D in the form of granules; Disintegrating agents selected from the group consisting of crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, and alginic acid; One or more excipients selected from the group consisting of lactose, microcrystalline cellulose, and corn starch; And a lubricant selected from the group consisting of magnesium stearate, stearic acid, talc, and silicon dioxide.

In addition, it has been found that the oral tablet may further have excellent stability by additionally including a film coating layer, and in particular, further comprising a film coating layer comprising a mixture of hydroxypropylmethylcellulose and polyethylene glycol. It has been found that it is possible to maintain stability for a long time. The weight ratio of the hydroxypropyl methyl cellulose and polyethylene glycol may be in the range of 5 to 15: 1, more preferably 10: 1. If necessary, the film coating layer may include a light shielding agent such as titanium oxide.

The present invention also provides an oral capsule obtained by filling a capsule by homogeneously dispersing risedronic acid or its salt and vitamin D in a mixed solvent of soybean oil and hydrogeneated coconut oil.

As the vitamin D contained in the oral capsule of the present invention, as described above, any form of vitamin D may be used, and preferably vitamin D _3, that is, cholecalciferol. The vitamin D, for example vitamin D ₃ or cholecalciferol, is used in relatively small amounts relative to the total weight of the composition. As described above, the amount of vitamin D used may be 700 IU to 8,400 IU, preferably about 2,800 IU, 4,200 IU, 5,600 IU, per unit dosage, which is a relatively small amount relative to the total weight. 40 IU of vitamin D has a mass of approximately 1 μg. Since the oral capsule of the present invention performs formulation by completely dissolving vitamin D in oil, the content of each of the obtained compositions can be kept uniform. That is, the oral capsules of the present invention can be uniformly dispersed in risedronic acid or its salts and vitamin D using a mixture of soybean oil and coconut oil as a solvent, and then filled into the capsule to ensure the content uniformity of the main components have.

In the oral capsule of the present invention, the weight ratio of the soybean oil and coconut oil is 7-11: 5, more preferably 9: 5. The amount of the mixed solvent comprising soybean oil and coconut oil is not particularly limited, and may be, for example, in the range of 15 to 30 parts by weight, preferably about 20 parts by weight, based on 10 parts by weight of risedronic acid or salts thereof. In addition, the mixed solvent may further include a mixture of lead and lecithin as a dispersant or surfactant. The amount of lead and lecithin may be used in an amount necessary to achieve uniform dispersion / dissolution, for example, the total amount thereof may range from 1 to 3 parts by weight based on 10 parts by weight of the mixed solvent, but It is not limited.

The soft capsule base may be a capsule base conventionally used in the pharmaceutical field, for example, a capsule base such as gelatin or succinate gelatin, and may include pharmaceutical additives such as concentrated glycerin as necessary; Sorbitol solution 70%; Purified water; Coloring agents such as yellow No. 5 and yellow 203; A capsule base solution can be prepared using a light shielding agent such as titanium oxide, calcium carbonate and alumina.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are illustrative of the present invention, and the present invention is not limited thereto.

Example  1 to 5

To prepare a tablet comprising risedronic acid sodium salt and cholecalciferol according to the ingredients and contents of Table 1 below.

Risedronic acid sodium salt (content in Table 1 shows the content as anhydride), cholecalciferol, lactose monohydrate and microcrystalline cellulose were mixed for about 10 minutes in a Double-cone mixer (ERWEKA Gmbh, Germany). . Kpospovidone was added to the mixture and mixed for about 5 minutes, and then magnesium stearate was added and mixed for about 5 minutes. The resulting mixture was compressed to about 217 mg / tablet in a tablet press (FETTA Perfecta 1, Germany). A film coating base solution was prepared using hypromellose, polyethylene glycol 6000, titanium oxide, talc, iron yellow oxide, and red iron oxide. In the film coating machine, using the film coating base solution prepared above, the uncoated tablet obtained above was subjected to the coating and dried to prepare a tablet having a film coating layer. The obtained tablet had an average weight of about 223 mg per tablet.

Example 1 Example 2 Example 3 Example 4 Example 5 Sodium riseronate 35 mg 35 mg 35 mg 35 mg 35 mg Cholecalciferol 2,800 IU 2,800 IU 4,200 IU 5,600 IU 5,600 IU Lactose baggage 73 mg 93 mg 66 mg 59 mg 57 mg Microcrystalline cellulose 73 mg 50 mg 66 mg 59 mg 59 mg Crospovidone 4 mg 4 mg 4 mg 4 mg 6 mg Magnesium stearate 4 mg 4 mg 4 mg 4 mg 4 mg Hypromellose 4.50 mg 4.50 mg 4.50 mg 4.50 mg 4.50 mg Polyethylene Glycol 6000 0.45 mg 0.45 mg 0.45 mg 0.45 mg 0.45 mg Titanium oxide 1.11 mg 1.11 mg 1.11 mg 1.11 mg 1.11 mg Talc 0.01 mg 0.01 mg 0.01 mg 0.01 mg 0.01 mg Yellow iron oxide Quantity Quantity Quantity Quantity Quantity Red iron oxide Quantity Quantity Quantity Quantity Quantity

Example  6 to 9

According to the ingredients and contents shown in Table 2 below, a soft capsule containing risedronic acid sodium salt and cholecalciferol was prepared.

Risedronic acid sodium salt (the content in Table 1 shows the content as anhydride), cholecalciferol, soybean oil, coconut oil, lead, and lecithin, and then homogeneously mixed using a homogenizer The contents solution was prepared. Gelatin or succinate gelatin, concentrated glycerin, 70% sorbitol solution, purified water, yellow No. 5, yellow 203, and titanium oxide were mixed to prepare a soft capsule base solution. In the continuous soft capsule maker, using the soft capsule base solution prepared above, the content solution obtained above was subjected to the epidermal coating and dried to prepare a soft capsule. The resulting soft capsule had an average amount of liquid per capsule of about 135 mg.

Example 6 Example 7 Example 8 Example 9 Risedronic acid sodium salt 35 mg 35 mg 35 mg 35 mg Cholecalciferol 2,800 IU 4,200 IU 5,600 IU 5,600 IU Soybean oil 45 mg 45 mg 45 mg 45 mg Coconut Cured Oil 25 mg 25 mg 25 mg 25 mg Beeswax 10 mg 10 mg 10 mg 10 mg lecithin 3 mg 3 mg 3 mg 3 mg gelatin 47 mg 47 mg 47 mg Succulent gelatin 47 mg Concentrated glycerin 14 mg 14 mg 14 mg 14 mg Sorbitol solution 70% 17 mg 17 mg 17 mg 17 mg Purified water 34 mg 34 mg 34 mg 34 mg Yellow 5 2.2 μg 2.2 μg 2.2 μg 2.2 μg Yellow 203 2.2 μg 2.2 μg 2.2 μg 2.2 μg Titanium oxide 0.8 mg 0.8 mg 0.8 mg 0.8 mg

Test Example  One. Disintegration test

The disintegration test was performed on the tablets and soft capsules prepared in Examples 1 to 9 under the following conditions.

(1) Disintegration test conditions

   Specimen: 6 tablets or 6 capsules

   Disintegrant: Water

   Temperature: 37.0 ± 0.5 ℃

(2) Disintegration test results

As a result of the disintegration test in water, all the tablets of Examples 1 to 5 were completely disintegrated within about 5 minutes, and all the soft capsules of Examples 6 to 9 were disintegrated within about 30 minutes.

Test Example 2: Dissolution Test (Sodium Ledronate)

The dissolution test was carried out under the following conditions for the tablets prepared in Examples 1 to 5.

(1) Dissolution test conditions

   Sample: 12 tablets

   -Dissolution Law: 9th Amendment to the Korean Pharmacopoeia (Paddle Law)

   Eluent: 900 mL of water, artificial gastric juice (pH1.2), pH 4.0 liquid, artificial intestine (pH6.8) buffer

   Temperature: 37.0 ± 0.5 ℃

   -Rotation speed: 50rpm

(2) Preparation of the test liquid

5 mL of each eluate was tested at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes at the start of elution.

(3) Preparation of Standard Solution

About 35 mg of risedronic acid sodium salt standard solution as an anhydride was precisely taken into a 100 mL volumetric flask and dissolved in each eluate, and the eluate was aligned with each other. 10 mL of this solution was precisely taken into a 100 mL volumetric flask, and the solution prepared by marking the respective eluents was used as the standard solution.

(4) Analysis condition

20 μl of the sample solution and the standard solution were tested according to the liquid chromatograph method of the Korean Pharmacopoeia General Test Method under the following conditions.

-Detector: ultraviolet absorbance photometer (wavelength: 263nm)

Column: Ionpak As-7

Mobile phase: pH9.5 EDTA buffer

Flow rate: 0.8 mL / min

(5) Dissolution test result

The results of the dissolution test of risedronic acid sodium salt for the tablets of Examples 1 to 5 under the pH 1.2 condition are shown in Table 3 below. The pH 1.2 solution is a solution in which 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid are dissolved in 1,000 mL of water.

Dissolution rate of sodium risedronate in eluate pH1.2 (%) 5 minutes 10 minutes 15 minutes Example 1 75.3 85.7 90.3 Example 2 70.3 83.2 88.8 Example 3 75.8 86.2 89.8 Example 4 77.2 90.5 90.7 Example 5 80.0 88.1 93.1

The results of the dissolution test of risedronic acid sodium salt for the tablets of Examples 1 to 5 at pH 4.0 were as shown in Table 4 below. The pH 4.0 solution is a solution in which a mixture (41: 9) of 0.05 mol / L acetic acid and 0.05 mol / L sodium acetate is adjusted to pH 4.0. (Capacity ratio 63:37)

Dissolution rate of sodium risedronate in eluate pH4.0 (%) 5 minutes 10 minutes 15 minutes Example 1 70.3 84.2 92.3 Example 2 68.8 83.2 92.1 Example 3 72.7 85.9 92.3 Example 4 74.2 86.5 91.6 Example 5 88.3 92.1 -

The results of the dissolution test of risedronic acid sodium salt for the tablets of Examples 1 to 5 in water are shown in Table 5 below.

Dissolution rate of sodium risedronate in the eluate water (%) 5 minutes 10 minutes 15 minutes Example 1 65.4 88.3 92.3 Example 2 63.2 84.7 90.3 Example 3 67.1 88.8 92.2 Example 4 65.5 89.0 91.7 Example 5 86.7 93.0 -

The results of the dissolution test of risedronic acid sodium salt for the tablets of Examples 1 to 5 under the pH6.8 condition are shown in Table 6 below. The pH6.8 solution is a solution prepared by adding 118 mL of 0.2 M sodium hydroxide solution and water to 250 mL of 0.2 M potassium dihydrogen phosphate solution. (Capacity ratio 63:37)

Dissolution rate of sodium risedronate in eluate pH6.8 (%) 5 minutes 10 minutes 15 minutes Example 1 72.4 85.8 93.4 Example 2 68.8 84.4 92.1 Example 3 74.1 86.9 91.9 Example 4 77.2 89.4 92.9 Example 5 87.8 94.2 -

Test Example 2  : Dissolution test ( Cholecalciferol )

The dissolution test was carried out under the following conditions for the tablets prepared in Examples 1 to 5.

(1) Dissolution test conditions

   Sample: 12 tablets

   -Dissolution Law: 9th Amendment to the Korean Pharmacopoeia (Paddle Law)

   Eluent: 900 mL of water, artificial gastric juice (pH1.2), pH 4.0 liquid, artificial intestine (pH6.8) buffer

   Temperature: 37.0 ± 0.5 ℃

   -Rotation speed: 50rpm

(2) Preparation of the test liquid

5 mL of each eluate was tested at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes at the start of elution.

(3) Preparation of Standard Solution

About 15 mg of cholecalciferol standard was precisely taken into a 100 mL volumetric flask, dissolved in isopropyl alcohol, and aligned. 1 mL of this solution was precisely taken into a 100 mL volumetric flask, diluted with IPA, and aligned. The solution was precisely taken into a 10 mL volumetric flask, and the solution prepared by using the respective eluents as standard solution.

(4) Analysis condition

100 μl of the sample solution and the standard solution were tested according to the liquid chromatograph method of the pharmacopeia general test method under the following conditions.

-Detector: ultraviolet absorbance photometer (wavelength: 280nm)

Column: Capcellpak C18

Mobile phase: methanol

Flow rate: 1.0 mL / min

(5) Dissolution results

The dissolution test of cholecalciferol was performed on the tablets of Examples 1, 3, and 4 at pH 1.2. The pH 1.2 solution is a solution in which 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid are dissolved in 1,000 mL of water.

Elution rate of cholecalciferol in eluate pH 1.2 (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Example 1 0.0 3.9 7.8 7.9 9.8 10.2 10.3 12.2 Example 3 0.0 3.2 5.8 5.9 7.2 8.3 8.8 9.3 Example 4 0.0 2.0 3.9 4.3 5.4 5.9 6.4 6.6

The dissolution test of cholecalciferol was performed on the tablets of Examples 4 and 5 at pH 4.0. The pH 4.0 solution is a solution in which a mixture (41: 9) of 0.05 mol / L acetic acid and 0.05 mol / L sodium acetate is adjusted to pH 4.0. (Capacity ratio 63:37)

Elution rate of cholecalciferol in eluate pH4.0 (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes 180 minutes 240 minutes 300 minutes 360 minutes Example 4 0.0 1.1 2.3 2.2 2.2 2.9 2.7 2.2 3.6 2.0 3.2 3.8 Example 5 0.0 1.2 2.2 2.2 2.2 2.3 2.5 2.8 2.9 3.0 3.0 2.8

The dissolution test of cholecalciferol for the tablets of Examples 1, 3, and 4 in water is shown in Table 9 below.

Elution Rate of Cholecalciferol in Eluent Water (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes 180 minutes 240 minutes 300 minutes 360 minutes Example 1 20.4 28.9 30.2 33.9 35.7 35.6 35.0 35.4 35.9 35.5 35.8 36 Example 3 19.5 27.2 27.5 27.9 27.6 28.3 30.2 29.8 29.5 29.0 29.3 29.9 Example 4 13.7 17.5 17.8 17.3 17.7 16.7 19.1 18.9 18.8 18.1 18.7 18.4

The dissolution test of cholecalciferol was performed on the tablets of Examples 4 and 5 at pH6.8. The pH6.8 solution is a solution prepared by adding 118 mL of 0.2 M sodium hydroxide solution and water to 250 mL of 0.2 M potassium dihydrogen phosphate solution. (Capacity ratio 63:37)

Elution rate of cholecalciferol in eluate pH6.8 (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes 180 minutes 240 minutes 300 minutes 360 minutes Example 4 9.3 14.6 14.1 14.8 14.6 14.3 14.4 14.5 14.1 14.4 14.4 14.3 Example 5 12.2 14.3 14.5 14.7 14.7 14.6 14.4 14.9 15.3 14.5 14.8 14.2

The dissolution test of cholecalciferol was performed on the tablets of Examples 4 and 5 at pH 1.2 + 1% polysorbate 80. The results are shown in Table 11 below. The pH 1.2 + 1% polysorbate 80 solution is a solution in which 1% polysorbate 80 is added to a solution in which 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid are dissolved in 1,000 mL of water.

% Elution at eluate pH1.2 + 1% PSB 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Example 4 10.3 27.1 29.8 40.0 56.6 61.4 61.1 67.4 Example 5 16.2 30.2 32.3 42.8 57.0 62.3 63.7 68.2

The dissolution test of cholecalciferol was performed on the tablets of Examples 1, 3, and 4 at pH 4.0 + 1% polysorbate 80 under Table 12. The pH 4.0 + 1% polysorbate 80 solution was prepared by adjusting a mixture of 0.05 mol / L acetic acid and 0.05 mol / L sodium acetate (41: 9) to pH 4.0 with 1% polysorbate 80. Added solution. (Capacity ratio 63:37)

% Elution at eluate pH4.0 + 1% PSB 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes 180 minutes 240 minutes 300 minutes 360 minutes Example 1 0.0 15.2 25.4 48.8 57.7 57.9 60.2 68.2 77.2 85.2 85.6 86.4 Example 3 0.0 13.8 22.2 30.2 44.2 46.2 47.2 54.0 53.8 54.9 60.8 65.4 Example 4 0.0 9.1 14.8 25.0 30.0 31.9 33.8 36.2 39.9 45.0 43.7 44.6

The dissolution test of cholecalciferol was performed on the tablets of Examples 1, 2, and 4 at 80% of water + 1% polysorbate. The water + 1% polysorbate 80 solution is a solution in which 1% polysorbate 80 is added to 1,000 mL of water.

Eluent% by elution water + 1% PSB 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes 180 minutes 240 minutes 300 minutes 360 minutes Example 1 15.8 48.7 57.3 77.2 85.2 85.8 Example 2 20.3 52.3 60.4 80.3 87.2 88.3 Example 4 10.3 27.1 29.8 40.1 56.6 61.4 61.1 67.4 71.2 75.8 80.7 82.0

The dissolution test of cholecalciferol was performed on the tablets of Examples 4 and 5 at pH6.8 + 1% polysorbate 80. The results are shown in Table 14 below. The pH6.8 + 1% polysorbate 80 solution was added 250% of 0.2M potassium dihydrogen phosphate solution 118mL 0.2M sodium hydroxide solution and water to 1000mL solution to add 1% polysorbate 80 to the solution to be. (Capacity ratio 63:37)

% Elution at eluent pH6.8 + 1% PSB 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes 180 minutes 240 minutes 300 minutes 360 minutes Example 4 5.2 19.1 25.3 35.2 42.6 44.4 47.2 47.0 46.4 51.1 53.9 57.4 Example 5 8.2 21.3 28.0 36.2 43.5 45.2 46.9 47.2 48.6 50.3 53.9 58.2

Test Example  3. Stability test

The results of testing the stability of the tablets and capsules of Examples 1 to 9 at 40 ° C. and 75% relative humidity are shown in Table 15 below.

Sodium riseronate content (%) Cholecalciferol content (%) Early After 1 month 3 months later Early After 1 month 3 months later Example 1 102.0% 101.5% 101.2% 110.5% 109.1% 107.4% Example 2 102.4% 101.9% 101.8% 108.9% 108.0% 106.7% Example 3 102.8% 102.7% 102.4% 109.7% 109.1% 107.9% Example 4 102.7% 102.5% 102.1% 110.2% 108.8% 107.4% Example 5 102.0% 101.5% 101.0% 110.2% 109.0% 107.2% Example 6 102.4% 101.8% 102.4% 105.5% 102.1% 98.2% Example 7 102.2% 102.0% 101.4% 105.2% 102.1% 97.9% Example 8 102.3% 102.1% 102.5% 105.1% 102.1% 98.1% Example 9 101.4% 101.5% 101.2% 105.2% 103.2% 98.3%

From the results of Test Examples 1 to 3, all of the formulations showed good results, and the tablets, that is, tablets with a film coating layer, had better disintegration than soft capsules. The stability of risedronic acid sodium salt was good in all formulations, and the stability of vitamin D was better in tablets with a film coating layer than in soft capsules, and better in the case of using gelatin as a soft capsule base.

Claims (10)

delete An oral tablet obtained by tableting a mixture comprising risedronic acid or a salt thereof and vitamin D in granule form, comprising a film coating layer comprising a mixture of hydroxypropylmethylcellulose and polyethylene glycol on the tablet. Oral tablets. The disintegrant according to claim 2, wherein the mixture comprises at least one disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, and alginic acid; One or more excipients selected from the group consisting of lactose, microcrystalline cellulose, and corn starch; And at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, talc, and silicon dioxide. delete The oral tablet according to claim 2, wherein the weight ratio of hydroxypropylmethylcellulose and polyethylene glycol is 5 to 15: 1. delete delete delete delete delete