KR100821208B1 - Composition comprising meloxicam having improved bioavailability and process for preparation thereof - Google Patents

Abstract

The present invention relates to an anti-inflammatory composition comprising a compression molded product of melocampal and a disintegrant, and a method for preparing the same. The composition according to the present invention promotes the disintegration of melancholyme, which is poorly water-soluble, and improves dissolution rate. Improves bioavailability.

Meloxycam, Disintegrant, Compression Molding

Description

Composition containing meloxicam having improved bioavailability and process for preparation according to the present invention

1 is a graph showing the dissolution rate of the meloxycamp capsule of the present invention and the comparative formulation.

Figure 2 is a graph showing the blood concentration of the meloxycamps capsules and the comparative formulation of the present invention.

The present invention relates to an anti-inflammatory composition comprising a compression molded product of meloxycamp and a disintegrant, and a method for preparing the same. It is related to the improvement of the dissolution rate by promoting the disintegration of the poorly water-soluble meloxycam by providing.

The disintegration rate of the drug is proportional to the dissolution rate of the drug, and the dissolution rate of the drug determines the rate of absorption in the body. Thus, the disintegration or solubility of the drug acts as an important indicator of drug concentration in the blood. Therefore, in general, in order for a drug to be absorbed into the human body and exhibit high pharmacological activity in vivo, it must first disintegrate rapidly and elute rapidly.

However, in the case of poorly water-soluble drugs that are difficult to dissolve in the body, various solubilization methods have been studied to improve their solubility. Typical solubilization methods include reducing the size of particles to increase the surface area, using co-solvents, adding ions to poorly soluble materials to form soluble salts of acids or bases, and combining polymeric compounds or ligands. Method and the like. In addition, a method of increasing the solubility of poorly soluble substances by forming micelles using surfactants has been studied in recent years.

However, the solubilization method using a co-solvent mainly uses a ethanol-based solvent, the problem of the amount and stability of the organic solvent has been raised. In addition, a method of making a poorly soluble substance into a soluble salt is mainly used a strong acid or strong base, which may cause problems such as abdominal pain or tissue irritation. In the case of using the surfactant, the drug is precipitated when the surfactant concentration in the formulation is diluted below the critical micelle concentration.

Meloxycham is an enolic acid-based nonsteroidal anti-inflammatory drug (NSAID _S ), the formula of 4-hydroxy-2-methyl-N- (5-methyl -2-thiazyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. It has a molecular weight of 351.4 and, like other NSAIDs, inhibits the activity of cyclooxygenase (COX), thereby inhibiting the synthesis of prostaglandins and thus exhibits anti-inflammatory activity. More selectively inhibits (COX-2).

Cyclooxygenases are of two isomers, COX-1 and COX-2. Among them, COX-1 is a constitutive isoform found in blood vessels, gastrointestinal, and kidneys that regulates the amount of local prostaglandins involved in the maintenance of blood flow, cell differentiation, and production of mucus and bicarbonate in tissues. Therefore, when NSAIDs inhibit the activity of COX-1, side effects of the gastrointestinal tract and kidney and antiplatelet action are observed. In addition, COX-2 is an inducible isoform that is induced by cytokines and other inflammatory mediators when inflamed, and is found primarily in the brain and kidneys. Some are also found in inflammatory cells, especially in inflamed areas. In other words, high concentrations of prostaglandins in inflammatory sites play an important role as mediators of inflammation and pain.

NSAIDs are one of the most commonly prescribed agents but have been problematic due to the occurrence of side effects, particularly gastrointestinal side effects, due to COX-1 inhibition. Unlike conventional NSAIDs that non-selectively inhibit cyclooxygenase, selective COX-2 inhibitors can reduce inflammation and pain, while they do not affect COX-1, which is safe for gastrointestinal system It is suggested that. Therefore, the present inventors have devised a formulation that selectively inhibits COX-2 with little inhibition of COX-1 which is not induced at the inflammatory site.

Meloxycamp developed as a COX-2 selective inhibitor is a drug concentration (IC ₅₀ ) to inhibit the [COX-2 IC ₅₀ ] / [COX-1 IC ₅₀ ] ratio by 50% in vitro (IC ₅₀ ) Is 0.013-0.8, which is about 2-77 times more selective for COX-2 than for COX-1. Meloxicam is piroxicam (IC _50: 33-250), indomethacin (IC _50: 15-107) and more, compared to traditional NSAIDs, such as COX-2 selective or celecoxib (IC _50: 0.0027, COX It is also referred to as COX-2 inhibitors because it has limited selectivity compared to 375 times more selective at -2) and rofecoxib (IC ₅₀ : 0.0012, more than 800 times more selective at COX-2). . Meloxycam is also known to reduce COX-2 selectivity at high doses.

However, meloxycamp is a poorly water-soluble drug that reaches the highest blood concentration after 7-11 hours upon oral administration, and thus, it takes a long time until the drug is effective.

In order to improve this, clathrate compounds using various chlorides or water-soluble glycoside-based cyclic compounds have been studied. International Publication No. 99/09988 describes 3: 7 inclusion complexes of meloxycam and cyclodextrins. Italian Patent Publication No. 01251650 also describes a 1: 2,5 complex of meloxycam and cyclodextrin. It is much more soluble than meloxycam alone and has improved pharmacodynamic properties. However, the solubilization method using cyclodextrin may include a spray drying or lyophilization process, which may result in a complicated manufacturing process, an increase in manufacturing cost, a lack of stability, and 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.

Korean Patent Laid-Open Publication No. 2001-0034698 describes meglumine salts of meloxycam, which exhibit faster release and absorption than cyclodextrin inclusion complexes. However, this raises the problem of polymorphism and hygroscopicity of various hydrates.

Therefore, the present inventors can easily improve the disintegration of meloxycam without problems as in the prior art by making a mixture using a disintegrant which disintegrates immediately in contact with the body fluid, and compression molding under high pressure and then undergoing a grinding and sizing process. Confirmed that the present invention was completed.

In particular, the present invention focuses on the fact that the water insolubility of meloxycam having a high melting point is due to large crystalline lattice energy, hydrophobicity due to intramolecular hydrogen bonding, and strong cohesive force between particles. The preparation of the mixture particles using dissolution can result in changes in the crystal structure as the formulation disintegrates (Burst effect) to reduce crystal energy or increase solubility with an increase in entropy.

Accordingly, an object of the present invention is to provide an improved bioavailability of Meloxycham by promoting the disintegration of poorly soluble Meloxycum in water to improve the dissolution rate, the faster dissolution of the composition than oral administration of the general Meloxycam formulation Due to the high anti-inflammatory effect can be expected.

The present invention relates to anti-inflammatory compositions comprising compression moldings of meloxycam and disintegrants.

In addition, the present invention comprises the steps of mixing the meloxycam and disintegrant; Compression molding the mixture; And it relates to a method for producing an anti-inflammatory composition comprising the step of crushing and sizing the compression molding.

The anti-inflammatory composition according to the present invention includes melocampal as an active ingredient and a disintegrant for the solubilization of melocampal.

In the composition of the present invention, the amount of meloxycam used as the main component is preferably 1 to 40 parts by weight based on the total weight. If the amount of meloxycamp is less than 1 part by weight, it is difficult to expect the pharmacological effect of meloxycam, and the maximum amount of meloxycam in the composition is 40 weight because it may remain in the blood for a long time due to the poor solubility of meloxycam. It is preferable not to exceed a part.

The disintegrant used in the present invention is preferably crospovidone, dried starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium croscarmellose, carboxymethyl cellulose calcium, and pregelatinized starch. It is one or more selected. More preferably, at least one selected from the group consisting of carboxymethyl cellulose calcium, crospovidone, dried starch, and croscarmellose sodium can be used.

The dried starch of the disintegrant is mainly used dried corn, wheat, potatoes, sweet potato starch, etc., preferably corn starch is dried for 10 hours at 100 ℃ to remove about 11% moisture, Effective as a disintegrant. In addition, crospovidone means crosslinked polyvinylpyrrolidone, showing the strongest disintegration among disintegrants.

The amount of disintegrant used is preferably 0.5 to 35 parts by weight based on the total weight. At this time, if the amount of disintegrant exceeds 35 parts by weight, the formulation becomes larger than necessary or is conventionally condensed to self-disintegrate, and less than 0.5 parts by weight relative to the total weight does not promote disintegration to expect the effect of the present invention Hard.

The anti-inflammatory composition according to the present invention may further comprise one or more selected preferably from binders, excipients and glidants.

The binder is preferably at least one selected from the group consisting of povidone, microcrystalline cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and gelatinized starch. More preferably, it is at least one selected from the group consisting of povidone, microcrystalline cellulose, and hydroxypropyl cellulose.

A preferred amount of the binder in the composition of the present invention is 1 to 20 parts by weight based on the total weight. In this case, when the amount of the binder is less than 1 part by weight based on the total weight, the binding force is weak and the molding is not performed. When the amount of the binder is more than 20 parts by weight, the formulation is hard, so that disintegration is further delayed or the total amount is too large. .

The excipient is preferably at least one selected from the group consisting of lactose, straight lactose, pregelatinized starch, mannitol, sorbitol, sodium citrate and calcium phosphate, more preferably lactose and / or sodium citrate. At this time, it is preferable to use an excipient of 10 to 80 parts by weight based on the total weight, since the formulation is larger than necessary in the excess of 80 parts by weight relative to the total weight and too small at less than 10 parts by weight relative to the total weight.

As the lubricant, at least one selected from the group consisting of magnesium stearate, talc, stearic acid, and hard silicon dioxide is used, and preferably magnesium stearate and / or hard silicon dioxide are used. Preferred amount of the lubricant is 0.1 to 2 parts by weight based on the total weight. If the amount of the lubricant is less than 0.1 parts by weight, there is a risk of lack of lubrication and compression molding or there is no fluidity when filling the capsule, if the amount of lubricant is more than 2 parts by weight disintegration is delayed to effect the present invention May decrease.

Method for producing an anti-inflammatory composition according to the present invention comprises the steps of mixing the meloxycam and disintegrant; Compression molding the mixture; And pulverizing and sizing the compression molding.

Meloxycam and disintegrant are first mixed homogeneously in a mixer such as cylindrical, V-type, etc., to which the mixture may be preferably added one or more selected from binders, excipients and glidants.

In this case, preferably, the method may further include granulating, drying and sizing the mixture, followed by mixing a disintegrant.

Granulation is a process of making granules of suitable particle size using a dry method or a wet method, which is a commonly used pharmaceutical method, and in the dry method, a granulator such as a slug purifier or a chilsonator ^® is used. In the wet method, an extrusion granulator, a fluid granulator, and a spray-dry granulator are used.

Drying is a process necessary only when granulation is performed by a wet method, and drying is performed using a hot air dryer or the like commonly used in the art. At this time, the drying loss is preferably 3% or less.

The dried mixture is then sized to a constant particle size using a sieve and further mixed with the disintegrants exemplified above. Formulation is a process of sifting agglomerates of granules to a uniform size, which is a pretreatment process required to produce a stable formulation because it affects the following filling or tableting process to make the final formulation.

In the above, the mixture obtained by simply mixing or further granulating the mixture, then drying and sizing the mixture is compression molded at a high pressure using a tablet press or a roller compacter to form a compression molded product. The disintegrant can effectively perform the disintegration action for Meloxycham only through this process, and in the case of preparing an oral preparation by simply mixing Meloxycham with the Disintegrant without this compression molding process, the disintegrating agent is hydroxy by the disintegrant. It is difficult to expect Kam's effective disintegration effect.

The compression molded product thus formed is pulverized using a pulverizing device commonly used in the art, such as a hammer mill, a ball mill, a colloid mill, and is sized to have a constant particle size using a sieve.

The composition according to the present invention prepared by the above method may be administered in the form of powder in powder form, granulated in a predetermined size, or administered in the form of fine granules or granules, or filled into capsules and administered in capsules. Preferably, the powder or granules may be filled into hard capsules and administered in capsule form.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, this does not limit the scope of the invention.

Example

Example 1.

Hard capsules having the following composition were prepared in the following manner.

16.2 kg of sodium citrate and 7.5 kg of meloxycamp were first mixed in a v-type mixer, followed by additional mixing of 179.3 kg of perilla milk, 54 kg of croscarmellose sodium and 10 kg of povidone. Subsequently, the roller compactor with a steel stirrer was compressed by force, pulverized and sieved. 3 kg of magnesium stearate was further mixed and filled into No. 2 hard capsules with an automatic capsule charger to prepare 1,000,000 hard capsules.

Example 2.

Hard capsules having the following composition were prepared in the following manner.

16.2 kg of sodium citrate and 7.5 kg of meloxycamp were first mixed in a v-type mixer, followed by further mixing of 160.3 kg of perilla milk and 50 kg of carboxymethylcellulose calcium, followed by granulation with a binder solution in which 10 kg of povidone was dissolved in about 5 times of water. Thereafter, the mixture was dried and granulated at a loss of 3% or less, and 4 kg of croscarmellose sodium was further mixed. The tablets were made by tableting with a forced stirrer with a forced stirrer to make tablets and pulverized them.

2 kg of magnesium stearate was further mixed and filled into No. 2 hard capsules with an automatic capsule charger to prepare 1,000,000 hard capsules.

Example 3.

Hard capsules having the following composition were prepared in the following manner.

15 kg of sodium citrate and 7.5 kg of meloxycam are mixed first in a v-type mixer, and 159.5 kg of persimmon oil and 71 kg of dry corn starch are mixed, and then granulated with luxury corn starch obtained by heating 6 kg of dried corn starch with about 10 times of water. It was done. Thereafter, the mixture was dried and granulated at a loss of 3% or less, and further mixed with 8 kg of dried corn starch. The tablets were made by tableting with a forced stirrer with a forced stirrer to make tablets and pulverized them.

3 kg of magnesium stearate was further mixed and filled into No. 2 hard capsules with an automatic capsule charger to prepare 1,000,000 hard capsules.

Comparative Example 1.

Hard capsules having the following composition were prepared in the following manner.

16.2 kg of sodium citrate and 7.5 kg of meloxycamp were first mixed in a v-type mixer, followed by additional mixing of 179.3 kg of perilla milk, 54 kg of croscarmellose sodium and 10 kg of povidone. 3 kg of magnesium stearate was further mixed therein, and No. 2 hard capsules were filled with an automatic capsule charger to prepare 1,000,000 hard capsules.

Comparative Example 2.

Hard capsules having the following composition were prepared in the following manner.

15 kg of sodium citrate and 7.5 kg of meloxycam are mixed first in a v-type mixer, and 159.5 kg of straight-lactose lactose and 71 kg of dry corn starch are further mixed, and then granulated with luxury corn starch, which is heated with about 10 times the amount of 6 kg of dry corn starch. It was done. After drying and sizing to below 3% of drying loss, 8 kg of dried corn starch and 3 kg of magnesium stearate were further mixed. Thereafter, No. 2 hard capsules were filled with an automatic capsule charger to prepare 1,000,000 hard capsules.

Test Example

Test Example 1. Comparative Dissolution Test

Each of the six samples prepared in (Example 1), (Example 2), (Example 3), (Comparative Example 1), and (Comparative Example 2) was subjected to a comparative dissolution test under the following conditions.

Temperature: 37 ± 0.5 ℃

Eluent: Purified Water

Dissolution Law: Law 2 (Paddle Law)

Stirring Speed: 50rpm

Test Method: Each sample was subjected to the dissolution test by the above method to measure the absorbance at a wavelength of 361nm with a UV spectrophotometer and to calculate the average dissolution rate is shown in Table 1 and FIG.

Table 1. Dissolution test results (unit%)

As shown in Table 1, the dissolution rate of the preparation prepared by the method according to the present invention was significantly improved than that of the comparative example.

Test Example 2 Comparative Blood Concentration Test

2 capsules of each of the specimens of (Example 1) and (Comparative Example 1) were alternately administered orally twice to 24 healthy adult male volunteers, and blood was collected at 11 time points up to 48 hours. Comparative blood concentration test was performed.

Detector: UV absorbance photometer (wavelength 355 nm)

Column: Capcell PAK C18 (filled with 5 μm octadecylsilylated silica gel in a stainless steel pipe with an inner diameter of about 4.6 mm and a length of about 250 mm)

Mobile phase: 50 mM phosphate buffer: acetonitrile mixture (70: 30)

Flow rate: 0.4 mL / min

Injection volume: 50µl

Test method: Each sample was analyzed by the above method to measure the blood concentration and the average value thereof is shown in Table 2 and FIG.

Table 2. Blood Concentration Test Results (Unit ng / mL)

As shown in Table 2, the formulation prepared in the same manner as in the present invention has greatly improved bioavailability than the comparative example.

Through the present invention, it is possible to simply improve the disintegration of meloxycam by using only a disintegrating agent and a compression molding process without going through a complicated process, and does not cause problems of polymorphism and hygroscopicity when using the meloxycam salt. Do not.

In addition, the composition according to the present invention has the advantage that can be expected to improve the bioavailability of Meloxycum by improving the dissolution rate by promoting the disintegration of Meloxycum compared to the general Melokcam formulation.

Claims (8)

delete delete delete delete Mixing meloxycam and a disintegrant; Tableting the mixture; And Method for producing an anti-inflammatory formulation comprising the step of grinding and sizing the tablets. The method of claim 5, Mixing meloxycam and a disintegrant; Granulating, drying and granulating the mixture; Tableting by further mixing a disintegrant into the granules; And Method for producing an anti-inflammatory formulation comprising the step of grinding and sizing the tablets. 7. The process according to claim 5 or 6, wherein the disintegrant is selected from the group consisting of dry corn starch, crospovidone and croscarmellose sodium. 7. A process according to claim 5 or 6 wherein the formulation is a capsule.

Images