KR20050071888A - Oral solid composition of meloxicam having improved solubility and stability - Google Patents

Abstract

The present invention relates to an orally administered meloxycam solid composition for improved solubility and stability, and more particularly, a conventional solid formulation containing meloxycam has a low solubility in an acidic or neutral medium, thereby lowering bioavailability. In order to overcome this problem, arginine, an essential amino acid salt, and citric acid or sodium citrate are contained in a predetermined amount. It relates to a pharmacologically stabilized orally administered meloxycam solid composition.

Description

Oral solid composition of meloxicam having improved solubility and stability}

The present invention relates to a composition for oral administration of hydroxycam solids with improved solubility and stability, and more particularly, a conventional medicament containing meloxycam has a low solubility in an acidic or neutral medium to lower bioavailability. In order to overcome this problem, by providing a certain amount of the essential amino acid salts arginine and citric acid or sodium citrate to improve the elution of the Meloxycham solids, and to stabilize the formulation, it is possible to see the initial effect and sustained efficacy during oral administration It relates to a pharmacologically stabilized orally administered meloxycam solid composition.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for long-term treatment of chronic rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. An enzyme for the action of NSAIDs is cyclooxygenase (COX), a ratease of prostaglandins.

Meloxycamp [4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxyamide-1,1-dioxide in such NSAIDs] Is a new enolic acid type nonsteroidal anti-inflammatory drug (NSAID) with strong anti-inflammatory, low ulcerative action and low nephrotoxicity, and an effective anti-inflammatory, antipyretic and analgesic effect (cyclooxygena with selectivity for isoenzyme COX-2) In addition to an inhibitor, it is known to inhibit the development of colorectal cancer.

Meloxycam precipitates into four different proton transitions, namely anionic, acidic enol, amphoteric and cationic, depending on the pH value of the solution. Meloxycam has a low solubility in acidic or neutral media, which leads to a complicated and difficult process in the preparation of pharmaceutical preparations. Furthermore, because Meloxycamp has low solubility, it is not easily absorbed and therefore, plasma in vivo The level is uneven.

Looking at the literature on pharmaceutical preparations containing meloxycamps are as follows.

International Patent Publication No. 01/251650 discloses a clathrate containing mexocampm with cyclodextrin, and describes a practical clathrate with a molar ratio of 1: 2.5 of melooxycamp to cyclodextrin. . However, the complex manufacturing step is required, and thus, a solution for a simple and inexpensive preparation method cannot be provided.

International Patent Publication No. 01/97813 discloses an aqueous solution of cyclodextrin-free Meloxycham for oral and parenteral administration containing one or more suitable excipients, and a high concentration solution of Meloxycham salt of 10 mg / ml or more. Formed to improve the shelf life of the formulation to 24 months or more. However, although a highly concentrated long-term preservation meloxycam composition which did not contain cyclodextrin was prepared, it contained excessively ethanol.

International Patent Publication No. 99/09988 discloses the bioavailability and effect of meloxycam by modifying the crystal structure through ball mill and mechanically dry or wet grinding together with components selected from the group consisting of oligosaccharides and dissolution enhancers or alkalizers. Improved, one layer is immediate release The other layer is described with respect to a composition which serves as a tablet of sustained release two-layer structure. However, pulverization, which is a method of preparing a composition, may be mixed in a drug due to peeling of the device or the like, and care should be taken when pulverizing pharmaceuticals. In addition, aggregation may occur in the drying step, resulting in lowering solubility and elution, which may be a problem.

Therefore, the present inventors have studied to improve the problem of the conventional Meloxycham solid composition as described above is difficult to apply biodegradation due to low solubility in acidic and neutral media, Melocampa increases the pH of the solvent during dissolution to increase the dissolution rate The present invention has been completed by knowing that arginine and citric acid or sodium citrate, which are used as buffers for the stability of the composition, are effective in improving the elution property, maintenance, and pharmaceutical stabilization of the Meloxycam solids.

Accordingly, an object of the present invention is to provide an improved, retained, and pharmaceutically stabilized meloxycam solidifying agent composition.

The present invention provides a conventional adjuvant including 2.5 to 10% by weight of meloxycamp, 3 to 15% by weight of arginine, 5 to 20% by weight of citric acid or sodium citrate, and a water-soluble high molecular substance, a disintegrant, an inert diluent and a lubricant. It is characterized by the solid dosage form for oral administration containing 85% by weight.

Referring to the present invention in more detail as follows.

In the present invention, in the solid composition containing meloxycam, the conventional meloxycam has a low solubility in an acidic or neutral medium, so that when it is applied in vivo, it is not easy to absorb so that it is difficult to formulate. Arginine, a water-soluble basic organic compound that improves and maintains the dissolution rate of Meloxycum, and an orally administered Meloxycum solid formulation containing a predetermined amount of citric acid or sodium citrate to improve the stability of Meloxycum and improve bioabsorption rate. It is characterized by.

The solid agent composition of the present invention preferably contains 2.5 to 10% by weight of meloxycamp, 3 to 15% by weight of arginine, 5 to 20% by weight of citric acid or sodium citrate, a water-soluble high molecular substance, a disintegrant, an inert diluent and a lubricant. It is good to contain 60 to 85 weight% of the usual adjuvant containing.

If the content of the meloxycamp is less than 2.5% by weight of the drug efficacy is lowered, if it exceeds 10% by weight may cause a problem of toxicity.

The water-soluble basic organic compound used for improving and maintaining the dissolution rate of meloxycam is, for example, one selected from water-soluble basic amino acids such as arginine, lysine and histidine, and basic compounds such as meglumine, egamine, and organic amine salts. Or two or more kinds may be used. In particular, in the present invention, the produced NO (Nitric oxide) acts as an oxidizing agent to protect the gastric mucosa by oxygen radicals, it is more preferable to use arginine excellent in solubilization effect. The water-soluble basic organic compound is preferably used 3 to 15% by weight, the content is less than 3% by weight can not achieve the desired effect, if the content exceeds 15% by weight of the effect of the increase in the amount of use is obtained It is not economically desirable.

In addition, if the content of citric acid or sodium citrate, which is used as an alkaline buffering agent and contributes to the pharmaceutical stability improvement of meloxycam, is less than 5% by weight, the desired stability improvement cannot be expected. It is not preferable due to problems such as an increase in weight and lack of remarkable effect when filling the capsule.

The present invention is characterized by using a predetermined amount of a water-soluble basic organic compound, citric acid or sodium citrate in order to increase the elution and stability of the meloxycamp solid composition, thereby improving the effect for the purpose It is used by adding a conventional pharmaceutically common adjuvant.

Such conventional auxiliaries may be water-soluble polymer materials, disintegrants, inert diluents, lubricants and the like. It is preferable to use 60 to 85% by weight of the conventional auxiliary agent, and when the amount of use is out of the range, it causes a change in the content of other components relatively, so that the desired effect cannot be obtained.

As the water-soluble high molecular material, anything that can be adsorbed to poorly soluble melocampum to improve the dissolution rate can be used. For example, polyvinylpyrrolidone (povidone), polyethylene glycols, hydroxypropyl cellulose, hydroxypropylmethyl One or two or more selected from cellulose, gum arabic, gelatin, hydroxyethyl cellulose, floxamer and carboxyvinyl polymer may be used.

Disintegrants are generally used pharmaceutically, for example, sodium starch glycolate, low-substituted hydroxypropyl cellulose, alginic acid, crosslinked polyvinylpyrrolidone, magnesium silicate and croscarmellose sodium and the like can be used. .

In addition, lubricants such as stearic acid, magnesium stearate, zinc stearate, zinc, talc, magnesium silicate, magnesium aluminum silicate, magnesium aluminum silicate, light anhydrous silicic acid, hydrogenated vegetable oil, and microcrystalline cellulose, lactose, mannitol, starch, calcium hydrogen phosphate, and sulfuric acid Inert diluents, such as calcium, etc. can be added and used.

On the other hand, the method for producing a meloxycam solids improved in the elutability improvement, maintenance and stability according to the present invention is as follows.

First, meloxycam and a water-soluble basic compound are mixed to prepare granules and then dried. Citric acid or sodium citrate is mixed with the dried granules and dispersed in a conventional adjuvant to prepare granules.

Solid preparations for oral administration thus prepared include tablets, powders, capsules or granulating agents, and such solid preparations may be prepared by mixing with conventional auxiliaries described above.

The solid preparation for oral administration according to the present invention usually contains 7.5 to 15 mg of hydroxycampham per solid preparation in order to have an anti-inflammatory analgesic effect, and is taken once per adult by 1 capsule.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited to the examples.

Examples 1-3 and Comparative Example 1

Weighed to the ingredients and contents shown in Table 1 above. Solids were prepared from meloxycam, a water-soluble basic organic compound, and a conventional adjuvant, followed by drying.

After granulating the dried solid agent, excipients were added to form capsules or tableted to prepare tablets.

division Example 1 (mg / cap) Example 2 (mg / cap) Example 3 (mg / cap) Comparative Example 1 (mg / cap) Meloxycam  15.0   7.5   7.5 7.5 Arginine   5.0  10.0  30.0 10 Corn starch 115.5 118.0  98.0 118.0 Microcrystalline cellulose  85.0  85.0  85.0 85.0 Sodium starch glycolate  12.0  12.0  12.0 12.0 Povidone   5.0   5.0   5.0 5.0 Magnesium stearate   2.5   2.5   2.5 2.5 Sodium citrate  50.0  50.0  50.0 -

Comparative Example 2

The following dissolution test was carried out by placing 15 mg of Mobigcapsule of Boehringer Ingelheim Korea, which is currently widely marketed as Meloxycampase, as Comparative Example 2.

Experimental Example 1

The dissolution test of Examples 1 to 3 and Comparative Example 2 was performed. In the dissolution test, the dissolution rate test and analysis were performed under the conditions shown in the following Table 2 according to the Paddle Method of the Korean Pharmacopoeia General Test Method.

Dissolution Test analysis Dissolution test device VK-7000, Vankel Analyzer UV-1700, shimadzu Eluate     900 ml pH 1.2, pH 4.0, purified water Detection wavelength 365 nm Rotation speed 50 rpm Dilution concentration 0.0075 mg / ml Eluent temperature 37 ± 0.5 ℃ Sampling time 0, 30, 120, 300 minutes Sample count 3

The dissolution test results of Examples 1 to 3 and Comparative Example 2 are shown in FIGS. 1, 2, and 3. 1 and 2 show the cumulative ratios of the respective eluted at pH 1.2 and pH 4.0 of Example 1 and Comparative Example 2, and Example 1 was improved by 2 to 3 times as compared to Comparative Example 2 during the same time. The dissolution rate showed a significant improvement in dissolution rate compared to commercially available products. In addition, Figure 3 shows the dissolution rate in purified water (H ₂ O) of Examples 1 to 3 and Comparative Example 2, and also in the same time Examples 1 to 3 compared to Comparative Example 2 by about 10 to 30% It was confirmed that the dissolution rate was improved compared to the commercially available products showing the improved dissolution rate of.

Experimental Example 2

Examples 1 to 3 and Comparative Example 1 were stored at room temperature and 40 ° C./75% RH accelerated test conditions to evaluate changes in the main component content.

As a result, Examples 1 to 3 containing citric acid or sodium citrate had a meloxycamp content of 97% or more, whereas Comparative Example 1 containing no citric acid or sodium citrate showed a meloxycamp content of 80% or less. . Therefore, as a result, it was confirmed that the solidification composition of the example was more stable.

As described above, oral administration of hydroxycam solids containing a water-soluble basic organic compound, citric acid or sodium citrate can improve the solubility and control the dissolution rate of hydroxycampa, so that the initial administration In addition to the rapid effect, you can see the continuous effect, and will have a stable effect on the pharmaceutical formulation.

Figure 1 shows the results of the dissolution test in the aqueous solution of pH 1.2 of Examples 1 to 3 and Comparative Example 2 according to the present invention.

Figure 2 shows the results of the dissolution test in the aqueous solution of pH 4.0 of Examples 1-3 and Comparative Example 2 according to the present invention.

Figure 3 shows the results of the dissolution test in purified water of Examples 1 to 3 and Comparative Example 2 according to the present invention.

Claims (3)

Meloxam 2.5 to 10% by weight, arginine 3 to 15% by weight, 5 to 20% by weight citric acid or sodium citrate, and 60 to 85% by weight of conventional adjuvants including a water-soluble high molecular substance, a disintegrant, an inert diluent and a lubricant Solid preparation composition for oral administration, characterized in that it contains. The method of claim 1, wherein the water-soluble high molecular material is polyvinylpyrrolidone (povidone), polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gum arabic, gelatin, hydroxyethyl cellulose, poloxamer and carboxyvinyl Solid composition for oral administration, characterized in that one or two or more selected from polymers. The solid composition for oral administration according to claim 1, wherein the solid agent is a tablet, powder, capsule or granule.