KR100593794B1 - Composition for oral administration containing meloxycamp - Google Patents

Abstract

The present invention relates to a composition for oral administration containing meloxycamp, and in particular, 1 part by weight of meloxycam, 0.25 to 1.5 parts by weight of sodium citrate and 2.5 to 30 parts by weight of polyethylene glycol.

The composition of the present invention, by combining the meloxycamp, sodium citrate and polyethylene glycol in the optimum ratio, to promote the solubilization of the Meloxycamp and significantly improve the dissolution rate, the preparation process of the formulation is simple, there is an effect of reducing the cost.

Description

Composition comprising meloxicam for oral administration

The present invention relates to a composition for oral administration containing meloxycamp, and in particular, 1 part by weight of meloxycam, 0.25 to 1.5 parts by weight of sodium citrate and 2.5 to 30 parts by weight of polyethylene glycol.

Meloxicam (4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) has strong anti-inflammatory, low Nonsteroidal anti-inflammatory drugs (NSAIDs) of enolic-acid type with ulcerogenic action and low nephrotoxicity, which inhibit the activity of cyclooxygenase (COX) It inhibits the synthesis of (prostaglandin) and exhibits anti-inflammatory action, and more selectively inhibits cyclooxygenase-2 (COX-2) than cyclooxygenase-1 (COX-1).

Meloxycam is a poorly soluble drug that is difficult to dissolve in water and shows pH dependent solubility, and has low solubility in acidic or neutral media (less than 0.5 µg / ml). Therefore, since it is a complicated and difficult process when preparing a pharmaceutical preparation, there are many difficulties in developing an effective formulation. In addition, meloxycam has a low solubility in water, so reabsorption is not easy, resulting in uneven plasma levels in vivo. Maximum plasma levels are reached within 2 to 8 hours depending on the formulation.

In general, in order for a drug to be absorbed into the human body and exhibit high pharmacological activity in vivo, it must first be eluted rapidly. It depends on the solubility of. Therefore, since the solubility is poor when the drug is poorly soluble in water, various methods have been studied to improve the solubility.

Typical solubilization methods for poorly soluble drugs include 1) reducing the particle size to increase the surface area, 2) using a cosolvent, and 3) attaching a large ion to the poorly soluble material to form salts of acids or bases. Making method, 4) making a polymer compound or ligand to make it soluble, and 5) forming a micelle using a surfactant, taking a poorly soluble material, and increasing solubility. However, the solubilization method using the co-solvent 2) of the above method mainly uses ethanol-based solvents due to toxic relationship, there is a problem of the amount and stability used. 3) The method of making a poorly soluble substance into a soluble salt is mainly a strong acid or strong base, which causes problems such as abdominal pain and tissue irritation. In addition, 5) in the case of using the surfactant there is a problem that the drug is precipitated when the concentration of the surfactant in the formulation is diluted below the critical micelle concentration. Therefore, a lot of researches on the solubilization method of poorly soluble drugs.

Meanwhile, clathrate compounds using various chlorides and water-soluble glycoside-based cyclic compounds have been studied in order to improve the poor solubility of water of meloxycam.

International Publication No. 99/09988 discloses 3: 7 inclusion complexes of meloxycam and cyclodextrin. It is much more soluble than meloxycam alone and has improved pharmacodynamic properties. However, the solubilization method using cyclodextrin includes spray drying or lyophilization, which makes the manufacturing process complicated, increases the manufacturing cost, lacks stability, and has a bitter taste. And upon oral administration, these active agents do not always provide enough plasma concentrations to exert a quick effect in a short time. International Publication No. 1999/49867 discloses meglumine salts of melocampam and show faster release and absorption than cyclodextrin inclusion complexes. However, this raises the problem of polymorphism and hygroscopicity.

Therefore, the inventors of the present invention, while many studies to solve the above problems of Meloxycum, by combining the Meloxycum, sodium citrate and polyethylene glycol in the optimum ratio, the solubilization of Meloxycum is improved and the dissolution rate is significantly improved. Confirmed and completed the present invention.

The present invention is to provide a composition for oral administration comprising meloxycamps, sodium citrate and polyethylene glycol.

The present invention provides a composition for oral administration comprising meloxycam, sodium citrate and polyethylene glycol.

Hereinafter, the present invention will be described in detail.

The present invention provides a composition for oral administration comprising 1 part by weight of meloxycamp, 0.25 to 1.5 parts by weight of sodium citrate and 2.5 to 30 parts by weight of polyethylene glycol.

In the composition of the present invention, sodium citrate is used as an alkalizing agent, and the content includes 0.25 to 1.5 parts by weight based on 1 part by weight of hydroxycampham. If the content of sodium citrate is less than 0.25 parts by weight, it does not sufficiently improve the solubility of meloxycamp, and shows a low dissolution rate. If it exceeds 1.5 parts by weight, the solubility of meloxycamp is sufficiently improved. The problem is that the stability is significantly lowered.

Also, in the composition of the present invention, polyethylene glycol is used as a dissolution aid, and includes polyethylene glycol 4000 to 20000, with polyethylene glycol 6000 being particularly preferred. If less than polyethylene glycol 4000 (eg, polyethylene glycol 400) is used, the melting point of polyethylene glycol is not easy to prepare into granules, and as the molecular weight is lowered, hygroscopicity is increased, causing stability problems. The content includes 2.5 to 30 parts by weight with respect to 1 part by weight of meloxycamp, and if the content is less than 2.5 parts by weight, the solubility of the meloxam may not be sufficiently improved to show a low dissolution rate. Solubility of is sufficiently improved, but the drying time increases with the increase of the amount of granules, the possibility of oxidation of polyethylene glycol is increased, and the problem is that the size is not suitable for the patient to take.

Method for producing a composition according to the present invention is as follows.

Meloxycam, polyethylene glycol and lactose are mixed with a high speed stirring mixer (blade: 200 rpm, chopper: 2000 rpm). To this was added 20% (w / w) sodium citrate purified water and coalescing to prepare granules. It is dried at 50 ° C. for 2 hours, upright and filled into capsules.

The dissolution rate of the composition of the present invention is 55-60% higher at pH 4.0 than when Meloxycham and Polyethylene Glycol 6000 are combined (Comparative Example 1) and when Meloxycam and Sodium Citrate are combined (Comparative Example 2). . In addition, the pH of 6.8 is 30 to 40% higher than that of the combination of Meloxycam and polyethylene glycol 6000 (Comparative Example 1) and the combination of Meloxycam and sodium citrate (Comparative Example 2).

Therefore, the composition of the present invention can enhance the solubilization of melocampal and significantly improve the dissolution rate by combining melocampal, sodium citrate and polyethylene glycol in an optimal ratio.

In order to prepare the composition of the present invention in a dosage form for oral administration, it may further contain additives such as conventional excipients, binders, disintegrants, lubricants and the like used pharmaceutically.

Excipients can be starch, lactose, white sugar, mannitol, sorbitol, glucose, microcrystalline cellulose, calcium dihydrogen monoxide and the like.

Binders include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium; Starch, gelatin, polyvinylpyrrolidone, gum arabic and the like.

Disintegrants include starch; Starch derivatives such as sodium starch glycolate; Carboxymethyl cellulose derivatives such as carboxymethyl cellulose calcium and crosslinked carboxymethyl cellulose; Microcrystalline cellulose, crosslinked polyvinylpyrrolidone, and the like.

The glidants may be stearic acid and its pharmaceutically acceptable alkali metal salts or amine salts, colloidal silicon dioxide, silicates, talc and the like.

The composition of the present invention can be prepared in various oral solid preparations such as tablets, powders, granules and capsules by conventional methods.

The composition of the present invention may contain about 250 mg of the weight of the preparation in one unit, and 7.5 mg of meloxycam. Dosage ranges depending on the weight, age, sex, health status, diet, administration time, administration method, excretion rate and severity of the disease of the patient, it is preferable to administer once or several times a day.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples.

Example  1-6  : Preparation of Capsule

Meloxycam, polyethylene glycol 6000, and lactose were mixed with a high speed stirring mixer (blade: 200 rpm, chopper: 2000 rpm), and 20% (w / w) of sodium citrate was added thereto and combined. It was dried at 50 ° C. for 2 hours, sieved to No. 18 sieve, and 250 mg of No. 2 capsules were filled.

Comparative example  One

Meloxycam, polyethylene glycol 6000, and lactose were mixed with a high speed stirring mixer (blade: 200 rpm, chopper: 2000 rpm), and purified water was added thereto. It was dried at 50 ° C. for 2 hours, sieved to No. 18 sieve, and 250 mg of No. 2 capsules were filled.

Comparative example  2

Meloxycam and lactose were mixed by a high speed stirring mixer (blade: 200 rpm, chopper: 2000 rpm), and 20% (w / w) sodium citrate was added thereto and combined. It was dried at 50 ° C. for 2 hours, sieved to No. 18 sieve, and 250 mg of No. 2 capsules were filled.

The compositions of the components of Examples 1 to 6 and Comparative Examples 1 and 2 are shown in Table 1.

                                                             (Unit: parts by weight) Meloxycam Sodium citrate Polyethylene Glycol 6000 Lactose Example 1 7.5 2 192.5 48 Example 2 7.5 5 192.5 45 Example 3 7.5 10 192.5 40 Example 4 7.5 10 20 212.5 Example 5 7.5 10 100 132.5 Example 6 7.5 10 217.5 15 Comparative Example 1 7.5 - 192.5 50 Comparative Example 2 7.5 10 - 232.5

Experimental Example  : Dissolution Test

One. pH  Over time in 4.0 Dissolution Test

Eight capsules (Examples 1 to 6 and Comparative Examples 1 and 2) were tested according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia General Test Method. The eluate was eluted at 900 mL (pH 4.0), at 37 ° C., and at a rotational speed of 50 rpm. After 5, 10, 15, 30, and 60 minutes, the eluate was taken, filtered through a 0.45 μm filter, and analyzed by HPLC to determine the dissolution rate over time. The dissolution rate constant (K) was also calculated in accordance with the Korsmeyer-Peppas model (Paulo Costa, Drug Dev. Ind. Pharm., 2001, 27 (8), 811-817).

As a commercial product, Boringer Ingelheim's Mobig capsule was used.

The results are shown in Table 2.

% Dissolution over time Dissolution Rate Constant (K) 5 minutes 10 minutes 15 minutes 30 minutes 60 minutes Example 1 2.04 3.78 15.27 28.56 42.13 1.55 Example 2 5.04 6.78 18.70 35.91 52.26 2.20 Example 3 4.86 8.89 27.24 57.15 75.42 3.31 Example 4 2.54 3.82 14.57 25.93 40.33 1.36 Example 5 2.51 7.2 15.31 33.17 49.99 2.06 Example 6 5.01 9.15 28.55 59.75 77.29 3.42 Comparative Example 1 1.64 1.55 4.49 9.85 13.68 0.46 Comparative Example 2 1.58 11.80 16.68 19.20 19.86 0.81 Commercial product (Mobic capsule) 3.39 8.26 13.37 17.45 21.51 1.40

As shown in Table 2, the dissolution rate of the capsules of Examples 3 and 6 at pH 4.0 was combined with hydroxycampham and polyethylene glycol 6000 (Comparative Example 1), when hydroxycampham and sodium citrate were combined. (Comparative Example 2) and 55-60% higher than the commercial product.

2. pH  Over time at 6.8 Dissolution Test

Three capsules of the specimens (Example 3 and Comparative Examples 1 and 2) were tested according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia general test method. The eluate was eluted at 900 mL (pH 4.0), at 37 ° C., and at a rotational speed of 50 rpm. After 60 minutes and 120 minutes, the eluate was taken out, filtered through a 0.45 μm filter, and analyzed by HPLC to obtain an elution rate over time.

The results are shown in Table 3.

% Dissolution over time 60 minutes 120 minutes Example 3 84.1 98.3 Comparative Example 1 52.7 66.5 Comparative Example 2 45.4 59.9

As shown in Table 3, the dissolution rate of the capsule of Example 3 at pH 6.8 is a combination of Meloxycamp and polyethylene glycol 6000 (Comparative Example 1) and the combination of Meloxycamp and sodium citrate (Comparative Example 2 30 ~ 40% higher than).

Therefore, the composition of the present invention can be seen that the dissolution rate is excellent when included in 1 part by weight of melocampum, 0.25-1.5 parts by weight of sodium citrate and 2.5-30 parts by weight of polyethylene glycol.

The composition of the present invention, by combining the meloxycamp, sodium citrate and polyethylene glycol in the optimum ratio, to promote the solubilization of the Meloxycamp and significantly improve the dissolution rate, the preparation process of the formulation is simple, there is an effect of reducing the cost.

Claims (4)

Meloxycham, sodium citrate and polyethylene glycol 4000-20000 composition for oral administration. The composition for oral administration according to claim 1, comprising 1 part by weight of meloxycam, 0.25-1.5 parts by weight of sodium citrate, and 2.5-30 parts by weight of polyethylene glycol. delete The composition for oral administration according to claim 1, wherein the polyethylene glycol is polyethylene glycol 6000.