KR100844256B1 - Pharmaceutical composition and preparation for treatment of metabolic bone disease comprising risedronate and vitamin d - Google Patents

Abstract

A pharmaceutical composition comprising risedronate and vitamin D is provided to minimize side effects of the risedronate, deliver the vitamin D into the mucosa of small intestine effectively and improve the stability of the vitamin D by blocking the interaction between the vitamin D and the risedronate. A pharmaceutical composition for treating metabolic bone diseases comprises: a risedronate tablet including 1 part by weight of risedronate and a pharmaceutically acceptable excipient; a release-delay coating layer prepared by coating 0.01-0.3 part by weight of an enteric coating polymer on the risedronate tablet; and a vitamin D isolation coating layer prepared by coating 0.1-0.3 part by weight of a water-soluble polymer and 0.0001-0.01 part by weight of a vitamin D compound on the release-delay coating layer, wherein the enteric coating polymer is selected from the group consisting of a copolymer of methacrylic acid and acrylate, hydroxypropyl cellulose phthalate and cellulose acetate phthalate. Further, the water-soluble polymer is selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone or poly vinyl alcohol.

Description

Pharmaceutical composition and preparation for treatment of Metabolic Bone Disease Comprising Risedronate and Vitamin D}

The present invention relates to a pharmaceutical composition for treating metabolic bone diseases, including risedronate, a bone resorption inhibitor, and vitamin D, a bone formation promoter, and a method for preparing the same, particularly to minimize side effects of taking riseronate. The present invention relates to a composition having a formulation coated with a release delayed coating and separately coated with vitamin D so as to effectively perform concurrent administration, and a method of preparing the same.

Several methods have been used for the purpose of delaying the release of the upper part of the drug. However, the appropriate method may vary depending on the physical properties of the drug and the purpose of the formulation. In addition, when the drug reacts with gastric acid, when it is decomposed by gastric acid and stability is affected, and when side effects such as inflammation of the gastric mucosa need to be separated from the gastric acid, the upper protective coating is applied. In addition, even if the drug is easier to deliver when released after the small intestine than to release the stomach in the release delayed protective coating to deliver the drug to the desired site.

Separation coating is a method of increasing the stability when the combination of two or more drugs is expected or observed, such as increased side effects due to interactions, increase in soft substances, increase in degradation products.

Bisphosphonate is a derivative of pyrophosphate that controls the deposition and dissolution of minerals in vivo. Bisphosphonates used in the human body include the first generation of ethidronate (bone absorption inhibitory ability 1) and the clathronate (bone absorption inhibitory ability 10), the second generation of pamideronate (bone absorption inhibitory ability 100) and alendronate ( Bone resorption capacity 100-1,000) and third generation risedronate (bone resorption capacity 1,000-10,000) (Treatment of osteoporosis with bisphosphonates, Endocrinol. Metab. Clin. N. Am. 27: 419-439 , 1998). Risedronate is a biologically potent inhibitor of bone resorption that can have the same effect at lower doses, 10 times higher than alendronate, in inhibiting bone resorption. However, even at low doses, when epithelial and mucosal tissues of the mouth, mouth, pharynx, larynx and esophagus come into direct contact with the drug, erosion and ulceration occur.

Vitamin D acts on the small intestinal mucosa, helping to absorb calcium and phosphorus and reabsorb calcium in the kidneys. It also prevents the escape of calcium from the bones and helps the calcium collect in the bones and teeth. Therefore, vitamin D needs to be released from the stomach to work on the small intestine.

Therefore, synergism as a drug for the treatment of metabolic bone disease may be expected when administration of risedronate, a bone resorption inhibitor, together with vitamin D, a bone promoter, and the like. In addition, when administering risedronate and vitamin D together, it would be ideal if the side effects of risedronate and the mucosal tissues can be eliminated and the combined release effect can be maximized through proper release of vitamin D. The present invention relates to a composition capable of effectively co-administering risedronate, a third generation bone resorption inhibitor, and vitamin D, a bone formation promoter, and a method for producing the same.

Korean Patent Registration No. 10-0317935 describes a pharmaceutical composition for treating metabolic bone disease, which is a combination of a second generation bone resorption inhibitor, alendronate and a bone resorption accelerator, calcitriol, and a preparation method thereof. The composition is a once-daily dose that improves the side effects of the upper stomach, and once a week, the drug is needed to improve the frequency of frequent doses. In addition, calcitriol acts on the small intestinal mucosal cells to help the absorption of calcium and phosphorus is preferably released in the stomach, in the present composition there is a problem that the two components of the alendronate and calcitriol enteric coating is not effective.

Korean Patent Application No. 10-2005-0110814 describes a bone absorption inhibiting composition and method comprising a pharmaceutically effective amount of alendronate and vitamin D3 suitable for weekly administration. Although the composition improves the convenience of taking once a week, it does not enteric coating bisphosphonates, so erosion and ulceration are caused by direct contact with epithelial and mucosal tissues of the mouth, mouth, pharynx, larynx and esophagus, which are disadvantages of the preparation. It is difficult to take because of the problems that occur. In addition, if a third generation bone resorption inhibitor having a stronger potency was used instead of the second generation bone resorption inhibitor, alendronate, it would be possible to further reduce side effects by reducing the dosage.

Korean Patent Publication No. 10-0274734 describes risedronate delayed-release compositions comprising a safe effective amount of a pharmaceutical composition consisting of a resetronate active ingredient and a pharmaceutically acceptable excipient. This is a single agent containing only bisphosphonate, a bone resorption inhibitor, which delays release through an enteric coating to improve the disadvantage of bisphosphonate drugs.

It is an object of the present invention to provide a pharmaceutical composition for treating metabolic bone diseases, which can be effectively administered in combination with risedronate, a third generation bone resorption inhibitor, and vitamin D, a bone formation promoter, and a method of manufacturing the same. In particular, in the present invention, in the administration of risedronate and vitamin D, the purpose of relieving side effects on the epithelial and mucosal tissue of risedronate and maximize the combined effect through the proper release of vitamin D It is done.

To this end, in the present invention, enteric release delay coating for risedronate to solve the erosion ulceration problem occurs when risedronate is in direct contact with epithelial and mucosal tissue, vitamin D is separated from risedronate The coating allows vitamin D to work effectively on the small intestinal mucosa and also prevents the degradation of vitamin D that may be caused by interaction with risedronate.

Other objects and advantages of the present invention will be described below and will be better understood by practice of the present invention.

In the present invention,

(a) risedronate tablets comprising 1 part by weight of risedronate and a pharmaceutically acceptable excipient;

(b) a release delay coating layer coated with 0.01 to 0.3 parts by weight of an enteric polymer on the risedronate tablet;

(c) a vitamin D separation coating layer coated with 0.1 to 0.3 parts by weight of a water-soluble polymer and 0.0001 to 0.01 parts by weight of a vitamin D compound is mixed on the release delay coating layer. A pharmaceutical composition for treating metabolic bone diseases is provided.

As used herein, "risedronate" means both risedronate and acceptable salts thereof.

As used herein, "vitamin D" refers to both vitamins D2 and D3. “Vitamin D compounds” include vitamin D2 (ergocalciferol) and vitamin D3 (cholcalciferol), 7-dehydrocholesterol and vitamin D2 precursors and vitamin D3 precursors, and derivatives, isomers and esters thereof, or their It means all mixtures.

As osteoabsorbent drugs in this composition, risedronate and its acceptable salts, which are biologically more potent drugs that can be administered at lower levels, even among bisphosphonate preparations, are used.

Excipients included in the risedronate tablets are not particularly limited as long as they are pharmaceutically acceptable excipients, and may be used in the present compositions as long as they are available to those skilled in the art. Excipients may preferably be used in an amount of 0.2 to 10 parts by weight, and more preferably 0.5 to 6 parts by weight, considering the appropriate size of the final drug. However, the amount of excipient may be used beyond the above range as needed, which is obvious to those skilled in the art. In particular, excipients that may be used in the compositions include all binders, disintegrants, excipients, and glidants.

The enteric polymer is preferably a copolymer of methacrylic acid and an acrylate-based commercially available as Eudragit ™; Hydroxy prosyl cellulose phthalate; Phthalic acid cellulose acetate and the like can be used, and more preferably, Eudragit L30D55 ™ (a water-based 1: 1 copolymer of methacrylic acid-ethylacrylate, a methacrylic acid-ethylacrylate copolymer (1: 1) aqueous dispersion) Can be used.

In the composition, the vitamin D compound is used as an osteogenesis agent drug. As the water-soluble polymer to form a separation coating layer with the vitamin D compound, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like can be used, preferably hydroxypropyl methyl cellulose can be used.

 In the present invention, riseronate, a bone resorption inhibitor, is released from the intestine by the upper protective coating of the stomach, and the osteogenesis accelerator is released from the stomach to be applied to the small intestinal mucosa cells separately coated with the risedronate to maximize the co-administration effect .

Method for producing a pharmaceutical composition for treating metabolic bone diseases of the present invention comprising risedronate and vitamin D compound comprises the following steps (a), (b), (c).

(a) 1 part by weight of risedronate is mixed with a pharmaceutically acceptable excipient to prepare a tablet. In this step, a general tablet manufacturing method in the pharmaceutical field may be applied as it is. In an embodiment of the present invention, risedronate tablets were prepared by granulation and granulation.

(b) 0.01 to 0.3 parts by weight of the enteric polymer is coated on the risedronate tablet tableted in the above step to form a release delay coating layer. The coating method is not particularly limited, and in the examples of the present invention, the enteric polymer is coated by dissolving and spraying the enteric polymer in ethanol.

(c) After dispersing 0.0001 to 0.01 parts by weight of the vitamin D compound in an aqueous polymer solution containing 0.1 to 0.3 parts by weight of a water-soluble polymer, the dispersion is coated on the release delay coating layer formed above to form a vitamin D separation coating layer. In one embodiment of the present invention, a water-soluble polymer was dissolved in a mixture of ethanol and purified water to form an aqueous polymer solution, and then dispersed by coating a vitamin D compound in the aqueous solution.

Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the scope of the present invention is not limited by the following examples, and those skilled in the art to which the present invention pertains should be within the equivalent scope of the technical concept of the present invention and the claims to be described below. Of course, various modifications and variations are possible.

Examples 1-3

Risedronate definition manufacturing

Next, risedronate tablets were prepared to form a central part of the pharmaceutical composition of the present invention with the composition shown in Table 1 below.

(1) Example 1: A binding solution was prepared by dissolving 10 mg of hydroxypropyl cellulose in 0.01 mL of purified water.

Example 2 A binding solution was prepared by dissolving 10 mg of povidone K30 in 0.01 mL of purified water.

Example 3: A binding solution was prepared by dissolving 10 mg of copovidone in 0.01 mL of purified water.

(2) After the risedronate and lactose were mixed, the binder solution prepared in (1) was added, granulated, and dried.

(3) The granules obtained in (2) were mixed with crospovidone and magnesium stearate, and then compressed with a SJ-6 tableting machine to prepare uncoated tablets.

Examples 4-5

Preparation of Emission Delay Coating Layer

A release delay coating layer was formed on the risedronate tablet prepared in Example 1 with the composition shown in Table 2 below.

(1) Example 4: 20 mg of Eudragit L30D55 was stirred alone to prepare a release delay coating solution.

   Example 5: 20 mg of hydroxypropylmethylcellulose phthalate was dissolved in 0.2 mL of ethanol to prepare a release delay coating solution.

(2) The release delay coating layer was sprayed onto the risedronate tablet prepared in Example 1 to form a release delay coating layer.

Example 6

vitamin D3 Separation coating

Vitamin D3 separation coating layer was formed on a riseronate tablet including a release delay coating layer prepared in Example 4, as shown in Table 3 below.

(1) 10 mg of hydroxypropyl methyl cellulose was dissolved in a mixture of ethanol and purified water.

(2) 70 µg of vitamin D3 was dispersed in the solution of (1).

(3) The dispersion prepared in (2) was sprayed on the release delay coating layer formed in Example 4 by a conventional coating method to form a vitamin D3 separation coating layer.

Comparative Example 1

In order to evaluate and compare the vitamin D3 with the composition of the present invention, a separate coated risedronate delayed release tablet was prepared with the composition shown in Table 4 below.

(1) D-mannitol was mixed with a mixture of vitamin D3 and ethanol, and then ethanol, antioxidant, and binder were further mixed.

(2) Apart from obtaining the vitamin D3 granules, risedronate, mannitol and absorption enhancer were mixed and then ethanol and binder were mixed again.

(3) The vitamin D3 mixture of (1) and the risedronate mixture of (2) were mixed, followed by the addition of the remaining disintegrant and lubricant components, followed by compression.

(4) The enteric polymer and triethyl citrate were dissolved in ethanol and then coated on the tablets of (3).

Experimental Example 1

in in vitro Dissolution rate  exam

Using the release delaying agent prepared in Example 6 and Comparative Example 1, the dissolution test was carried out in the artificial gastric juice of pH 1.2 for 2 hours, and the remaining tablets were transferred to the artificial intestinal fluid of pH 6.8 for dissolution test for 1 hour. The experimental results are shown in Tables 5 and 6 below. Table 5 shows the dissolution rate (%) of vitamin D3, and Table 6 shows the dissolution rate (%) of risedronate.

Example 6 vitamin D3 was eluted in artificial gastric juice and risedronate was eluted in artificial intestinal fluid at pH 6.8. In contrast, in Comparative Example 1, no elution occurred in the pH 1.2 artificial gastric juice, and both vitamin D3 and risedronate were eluted in the artificial intestinal fluid at pH 6.8. These results show that in the case of the composition of the present invention prepared in Example 6 vitamin D3 may act on the small intestinal mucosa to help calcium absorption, in the case of Comparative Example 1 can exert an effect in the intestine or more.

Experimental Example 2

Stability test

The accelerated test was carried out at 75 ° C and 40% relative humidity of the compositions prepared in Example 6 and Comparative Example 1. Table 7 below shows the stability results of vitamin D3 in the composition, and Table 8 shows the stability results of risedronate in the composition.

From the above experimental results, in the case of Comparative Example 1, it was found that risedronate and vitamin D3 reacted with each other to lower the titer of vitamin D3. However, in Example 6, in which the two components were completely separated and coated, it was confirmed that a stable state was maintained without affecting each other.

The composition of the present invention includes risedronate, a bone resorption inhibitor, and vitamin D, a bone formation promoter, as an effective formulation, to improve the problem that erosion ulceration occurs when risedronate is in direct contact with epithelial and mucosal tissues. The separate coating of dronate and vitamin D optimizes the release of vitamin D for efficient delivery to the small intestinal mucosa acting for calcium absorption, and improves the stability of vitamin D by preventing interaction with risedronate. According to the present invention, side effects of risedronate can be minimized, and effective combination administration of risedronate and vitamin D can be performed.

Claims (5)

(a) risedronate tablets comprising 1 part by weight of risedronate and a pharmaceutically acceptable excipient; (b) a release delay coating layer coated with 0.01 to 0.3 parts by weight of an enteric polymer on the risedronate tablet; (C) a pharmaceutical composition for treating metabolic bone disease, comprising: a vitamin D separation coating layer coated with 0.1 to 0.3 parts by weight of a water-soluble polymer and 0.0001 to 0.01 parts by weight of a vitamin D compound on the release delay coating layer. The method of claim 1, wherein the vitamin D compound is vitamin D2 (ergocalciferol); Vitamin D3 (cholecalciferol); 7-dehydrocholesterol; Vitamin D2 precursors; Vitamin D3 precursors; A pharmaceutical composition for treating metabolic bone diseases selected from the group consisting of derivatives, isomers, esters, and mixtures thereof. The method of claim 1, wherein the enteric polymer, methacrylic acid and an acrylate copolymer; Hydroxy prosyl cellulose phthalate; A pharmaceutical composition for treating metabolic bone disease selected from the group consisting of cellulose acetate phthalate. The method of claim 1, wherein the water-soluble polymer, hydroxypropyl methyl cellulose; Polylipinylpyrrolidone; A pharmaceutical composition for treating metabolic bone diseases selected from the group consisting of polyvinyl alcohol. (a) mixing 1 part by weight of risedronate with a pharmaceutically acceptable excipient to prepare a tablet; (b) coating 0.01 to 0.3 parts by weight of the enteric polymer in the risedronate tablet prepared in (a) to form a release delay coating layer; (c) dispersing 0.0001 to 0.01 parts by weight of the vitamin D compound in an aqueous polymer solution containing 0.1 to 0.3 parts by weight of a water-soluble polymer, and then coating the dispersion on the release delay coating layer formed in (b) to form a vitamin D separation coating layer. Method for producing a pharmaceutical composition for treating metabolic bone disease comprising a.