KR20030069373A - Solubilized Piroxicam Dispersible Tablets and it's Manufacturing Method - Google Patents

Abstract

PURPOSE: Provided are a dispersible tablet containing solubilized piroxicam and a manufacturing method thereof. The manufactured dispersible tablet is easily eluted and absorbed and has excellent pharmacological activity. CONSTITUTION: A dispersible tablet is manufactured by dissolving 0.1-3 wt.% of L-arginine in 1-5 wt% of purified water containing ethanol; adding 0.1-30 wt.% of diethanolamine and 0.1-50 wt.% of piroxicam to the dissolution and dissolving them to give a mixed solution of piroxicam and L-arginine; and adding 1.0-60 wt.% of excipient, 1.0-30 wt.% of powder binding agent, 1.0-20 wt.% of a sweetener, 0.1-5.0 wt.% of lubricant, 0.5-25 wt.% of disintergrant to 1.0-20 wt.% of the mixed solution.

Description

Solubilized Piroxicam Dispersible Tablets and it's Manufacturing Method

The present invention relates to a composition of a solubilized pyroxycam-containing preparation and a method for preparing the same, and more particularly, to a solubilization of solubilized pyroxycamp in water to make a complex using an amino acid-based material. It relates to a cam-containing composition and a diffusion formulation containing the same as an active ingredient.

That is, the present invention relates to a method for preparing a diffusion tablet and also a method for preparing a diffusion tablet containing the same, solubilizing poorly soluble pyroxicam in water to increase the solubility and improve the dissolution rate to provide a high pharmacological activity, oral administration Rapid disintegration and dissolution can lead to high therapeutic effects.

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. However, since the solubility of the drug is poorly soluble in water, various methods have been studied to improve the solubility. Representative solubilization methods include reducing the size of particles to increase the surface area, using co-solvents, adding salts to acids or bases by attaching counterions to poorly soluble materials, and combining soluble polymers or ligands. There is a way to make a complex. In addition, a method of increasing the solubility by forming a micelle using a surfactant and taking a poorly soluble material therein has been studied in recent years. The solubilization method using co-solvent uses ethanol-based solvents mainly due to toxic relationship, which raises the issue of the amount and stability used. The method of making a poorly soluble substance into a soluble salt is mainly used a strong acid or strong base, which causes problems such as abdominal pain or tissue irritation. In addition, when using a 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.

On the other hand, pyroxicam is a nonsteroidal anti-inflammatory analgesic substance having the following structural formula (I), which is a white, white crystalline powder and hardly soluble in water. The peak blood concentration at about oral administration is about 3-5 hours and the half-life is known to be about 50 hours (30-86 hours). In order to alleviate these shortcomings and provide adequate bioavailability, many studies are being conducted.

(Ⅰ)

Pyroxycams reach their highest blood levels between 3-5 hours upon oral administration due to poor water solubility. In order to improve this point, clathrate compounds using various chloride and water-soluble glycoside-based cyclic compounds have been studied. Italian Republic Patent No. 1,196,033 (filed Feb. 22, 1984) describes a 1: 2.5 inclusion complex of pyroxycam and cyclotextrin, in particular US Patent Application No. 268980 (June 1, 1981). There is known an injectable solution of pyroxycam and lysine or arginine salt to be suitable for parenteral administration. This complex is much more soluble than pyricampam alone and has improved pharmacodynamic properties. However, the solubilization method using cyclotextrin may include spray drying or lyophilization, which may be complicated in manufacturing, increase in manufacturing cost, lack stability, and have a bitter taste, and lysine or arginine salt may be stirred and heated in a steam bath. It is obtained only by intravenous injection containing distilled water and PH adjuster.

The present invention was made to improve the poor solubility and complex solubilization method of pyoxycamp, and the solubility of the drug was induced by making a soluble complex using the alkaline amino acid L-arginine. In view of the relatively high melting point of pyroxycam (198-200 ° C), it is insoluble in the water of pyroxycam, which has a very large crystalline lattice energy, and has high hydrophobicity due to intramolecular hydrogen bonding inside the molecule. It is assumed that this is due to the large cohesive force. Therefore, the complex was prepared using L-arginine to change the crystal structure to reduce the crystal energy or increase the solubility by increasing the entropy due to the complex formation, the complex formation was confirmed through thermal analysis .

The present invention is to develop a diffusion tablet that solubilizes pyroxicam and exhibits rapid disintegration using excipients which are pharmaceutically usable.

FIG. 1 is a differential calorimetry chart (DSC) of arginine (1), pyroxycam (2), and pyroxycam L-arginine complex (3),

2 is a graph of dissolution comparison test results according to Example (-◆-) and Comparative Example (… Δ…).

Pyroxycam-containing diffusion type tablet of the present invention and its manufacturing method,

Manufactured by dissolving 0.1 to 3% by weight of L-arginine in 1 to 5% by weight of ethanol-containing purified water (10:13), adding 0.1 to 30% by weight of diethanolamine and 0.1 to 50% by weight of pyroxicam. 1.0 to 20% by weight of one pyroxycam and L-arginine complex solution, 1.0 to 60% by weight excipient, 1.0 to 30% by weight powder binder, 1.0 to 20% by weight sweetener, 0.1 to 5.0% by weight lubricant and 0.5 to disintegrant A pyroxycam-containing diffused tablet having an anti-inflammatory action containing 25% by weight,

It is prepared by dissolving 0.1 to 3% by weight of L-arginine in 1 to 5% by weight of ethanol-containing purified water (10:13), then adding 0.1 to 30% by weight of diethanolamine and 0.1 to 50% by weight of pyroxicam. 1.0 to 20% by weight of a pyroxycam and L-arginine complex solution are mixed with 1.0 to 60% by weight of excipient and 1.0 to 30% by weight of powder binder to form granules, and 1.0 to 20% by weight of the sweetener and lubricant It is a method for producing a phyroxicam-containing diffusion tablet having an anti-inflammatory analgesic effect, which is prepared by mixing and tableting 0.1 to 5.0 wt% and 0.5 to 25 wt% of a disintegrant.

Compositions of the complex of pyricampam and L-arginine of the present invention and a method for producing a diffusion tablet containing the same are as follows. The solubilization of the present invention is to form a diffusion type tablet by granulating a solution obtained by dissolving a certain amount of pyroxycam, L-arginine and diethanolamine in purified water containing ethanol with a pharmaceutically acceptable excipient.

In more detail, about 0.1 to 3% by weight of L-arginine is dissolved in about 1 to 5% by weight of ethanol-containing purified water, followed by dissolution of diethanolamine and pyroxicam. Using this solution as a binder solution, granules may be granulated with a part of excipients and dried, and a disintegrating tablet having a high disintegration rate and a lubricant may be mixed at an appropriate ratio to prepare a diffusion tablet.

In the composition of the present invention, the amount of L-arginine in excess of 3% by weight increases the amount of use as the tablet becomes larger than necessary, and in less than 0.1% by weight, no complex is formed. The solvent is not wetted because of the contact angle between the pyricampam and water when ethanol is not added, so use about 1 to 5% by weight, and when the amount of purified water is increased, problems occur in association and drying time.

Diffusion tablets may also contain about 1-20% by weight of the pharmacologically solubilized pyroxicam complex with about 1.0-20.0% by weight of at least one selected from the sweetener aspartame or stevioside, D-sorbitol, xylitol, glucose, glucose About 1.0 to 60.0% by weight of at least one selected from fructose, fructose, mannitol and lactose and at least one powder binder selected from sodium microcrystalline cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose. About 0.1 to 5.0% by weight of one or more lubricants selected from weight% and magnesium stearate, talc, stearic acid and light silicon dioxide, crospovidone, dried corn starch, sodium starch glyconate, L-HPC, crosslinked carboxymethylcellulose Can be prepared using 0.5 to 25% by weight of one or more disintegrants selected from calcium. The.

If the amount of the lubricant is greater than 5.0% by weight, the disintegration may be further delayed, and at an amount less than 0.1% by weight, the lubricant is not effective. In addition, if the disintegrant is less than the range of 0.5% by weight, the disintegration rate is slow, and when more than 25% by weight, the disintegrant is easily disintegrated by the convention itself and the size of the tablet is also increased.

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)

Diffusion tablets with the following compositions were prepared in the following manner.

ingredient weight% Pyroxycam complex solution 9.6 Microcrystalline cellulose 12.8 D-sorbitol 19.0 Direct lactose 44.6 Hydroxypropyl cellulose 1.6 Crospovidone 4.8 Aspartame 6.4 Hard silicon dioxide 1.0 Talc 0.2 system 100

1) Preparation of Complex Solution

The L-arginine was dissolved in purified water containing ethanol with the following composition while dissolving the diethanolamine therein, followed by the addition of pyoxycamp to dissolve completely. The solution is left for one night and a part is volatilized to prepare a complex solution.

ingredient weight% Piroxycam 66.7 L-arginine 16.65 Diethanolamine 16.65 Ethanol-Contained Purified Water (10:13) 233.3 (volatile) system 100

2) Preparation of Diffusion Tablets

In the above composition, the direct milk lactose, the microcrystalline cellulose and the hydroxypropyl cellulose are mixed and fed together using the composite liquid as the binding liquid. Granules are made, dried, and then granulated, and the remaining excipients are mixed and compressed to produce diffusion tablets.

(Comparative Example)

A capsule having the following composition was prepared by the following method.

ingredient weight% Piroxycam 3.8 Lactose 59.8 Starch 26.3 Talc 1.9 Sodium Starch Glyconate 1.9 PVP 0.3 Hard silicon dioxide 6.0 system 100.0

Preparation of pyroxycam containing capsule

All components are mixed in the above composition and filled into hard capsules to prepare capsules.

Test Example 1 Differential Scanning Calorimetry (DSC)

After leaving the complex solution prepared in (Example) overnight, the spray-drying to prepare a fine powder, and then confirmed the formation of the complex of pyricam and L- arginine by DSC analysis. (See Fig. 1)

As can be seen in FIG. 1, the endothermic peaks appearing near the melting points of pyroxycam (2) and L-arginine (1) were lost in the composite (3). It can be seen that pyroxium and L-arginine form a complex to change the crystal structure, thereby reducing crystal energy or causing lattice change.

Test Example 2 Dissolution Comparison Test

Six samples of each of Examples and Comparative Examples shall be taken and subjected to a comparative dissolution test in accordance with the Pyroxicam term of the notification of the Food and Drug Administration.

Temperature: 37 ± 0.5 ℃

Eluent: first solution

Dissolution Law: Second Act

Stirring Speed: 50rpm

Test Method: Each sample was subjected to the dissolution test by the above method, and the content was measured by measuring the absorbance at 333 nm wavelength with UV light.

Results: The dissolution comparison test results are shown in FIG.

As can be seen in Figure 2, almost three-fold increase in elution is observed in the first solution compared to the comparative example, so that the oral administration can be rapidly eluted and absorbed in the stomach can be expected excellent pharmacological activity.

Soluble complex solution was prepared using L-arginine as phyroxicam, and a phyroxicam-containing diffusion tablet which elutes rapidly upon oral administration with excipients, powder binders, sweeteners, glidants, and disintegrants as a main ingredient. It is an industrially superior invention that can be manufactured.

Claims (4)

Manufactured by dissolving 0.1 to 3% by weight of L-arginine in 1 to 5% by weight of ethanol-containing purified water (10:13), adding 0.1 to 30% by weight of diethanolamine and 0.1 to 50% by weight of pyroxicam. 1.0 to 20% by weight of one pyroxycam and L-arginine complex solution, 1.0 to 60% by weight excipient, 1.0 to 30% by weight powder binder, 1.0 to 20% by weight sweetener, 0.1 to 5.0% by weight lubricant and 0.5 to disintegrant A pyroxycam-containing diffused tablet having anti-inflammatory analgesic content containing 25% by weight. The method of claim 1, wherein the excipient contains at least one selected from D-sorbitol, xylitol, white sugar, glucose, fructose, mannitol, or lactose, and as a powder binder, microcrystalline cellulose, methyl cellulose, hydroxypropyl methyl cellulose, At least one selected from hydroxypropyl cellulose or carboxymethyl cellulose sodium, and at least one selected from aspartame or stevioside as a sweetener, At least one selected from magnesium stearate, talc, stearic acid, or hard silicon dioxide as a lubricant, and as a disintegrant, crospovidone, dried corn starch, sodium starch glyconate, L-HPC or crosslinked carboxymethyl cellulose A phyroxicam-containing diffusion tablet having an anti-inflammatory analgesic effect containing one or more of calcium. It is prepared by dissolving 0.1 to 3% by weight of L-arginine in 1 to 5% by weight of ethanol-containing purified water (10:13), then adding 0.1 to 30% by weight of diethanolamine and 0.1 to 50% by weight of pyroxicam. 1.0 to 20% by weight of a pyroxycam and L-arginine complex solution are mixed with 1.0 to 60% by weight of excipient and 1.0 to 30% by weight of powder binder to form granules, and 1.0 to 20% by weight of the sweetener and lubricant A method for producing a phyroxicam-containing diffusion tablet having an anti-inflammatory analgesic effect, which is prepared by mixing and tableting 0.1 to 5.0 wt% and 0.5 to 25 wt% of a disintegrant. The method of claim 3, wherein the excipient contains at least one selected from D-sorbitol, xylitol, white sugar, glucose, fructose, mannitol, or lactose, and as a powder binder, microcrystalline cellulose, methyl cellulose, hydroxypropyl methyl cellulose, At least one selected from hydroxypropyl cellulose or carboxymethyl cellulose sodium, at least one selected from aspartame or stevioside as a sweetener, At least one selected from magnesium stearate, talc, stearic acid or light silicon dioxide as a lubricant, and as a disintegrant, crospovidone, dried corn starch, sodium starch glyconate, L-HPC or crosslinked carboxymethyl cellulose calcium A method for producing a pyroxycam-containing diffusion tablet having an anti-inflammatory analgesic effect containing one or more types.