JP2010083826A - Method for producing solid preparation containing oxicam-based compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation of an oxicam-based compound, having a high solubility. <P>SOLUTION: This method for producing the solid preparation containing the oxicam-based compound is provided by dissolving the oxicam-based compound in an aqueous basic amino acid solution and then drying the obtained solution. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a solid preparation containing an oxicam compound.

  Since oxicam compounds are poorly soluble in water, various methods have been attempted so far.

  Patent Document 1 describes a method in which a basic inorganic salt that is an antacid is mixed and ground in an oxicam anti-inflammatory agent in order to improve the solubility of the oxicam anti-inflammatory agent.

  Patent Document 2 describes a method of vigorously mixing in an intimate contact with an alkaline substance containing a non-steroidal anti-inflammatory drug (NSAID) and an amino acid derivative by co-grinding or an equivalent method.

  By blending a basic inorganic salt, which is a so-called antacid, further secretion of gastric acid is promoted, and the blended formulation is burdensome for patients who have inflammation or the like in the stomach. Moreover, since the size of the solid preparation is increased by adding the basic inorganic salt, the prepared preparation is difficult to take.

  Furthermore, pretreatment such as mixing and pulverizing the drug substance and basic inorganic salt is indispensable, and there is a problem that the yield is poor particularly when fine pulverization is required.

Japanese Patent Laid-Open No. 03-240729 JP 2008-504307 A

  An object of the present invention is to provide a method for producing a solid preparation having high solubility of an oxicam compound.

  The present inventors have found that the above-mentioned problems can be solved by dissolving the oxicam compound in a high-concentration basic amino acid aqueous solution. Furthermore, it has been found that the above problems can be solved more effectively by drying the solution or by spraying / drying the solution directly onto a fluidized bed granulator. It was also found that the solubility of the oxicam compound was increased by adding an excipient to the solution.

  The present invention provides a method for producing a solid preparation containing an oxicam compound, which comprises dissolving the oxicam compound in an aqueous basic amino acid solution and drying the solution.

  In one embodiment of the invention, the aqueous basic amino acid solution comprises 1 to 10 parts basic amino acid and 10 to 40 parts water.

  In one embodiment of the present invention, the oxicam compound is 1 to 10 parts per 10 to 50 parts of the basic amino acid aqueous solution.

  In one embodiment of the invention, the basic amino acid comprises at least one of lysine or arginine.

  In one embodiment of the present invention, the pH of the basic amino acid aqueous solution is 7.0 to 12.0.

  In one embodiment of the present invention, the method further comprises adjusting the pH of the basic amino acid aqueous solution with an acidic amino acid.

  In one embodiment of the invention, the method further comprises adding an excipient to the aqueous basic amino acid solution. Examples of the excipient include polyvinyl pyrrolidone or hydroxypropyl cellulose.

  In one embodiment of the present invention, the basic amino acid in the solid preparation is 1 to 25 parts with respect to 100 to 200 parts of the solid preparation.

  In one embodiment of the invention, the solid formulation is an oral solid formulation.

  In one embodiment of the invention, the oxicam-based compound comprises at least one of lornoxicam, piroxicam, tenoxicam, or ampiroxicam.

In the method of the present invention, by using an aqueous solution in which a basic amino acid is dissolved, a solid preparation having high solubility of the oxicam compound can be obtained. Further, the high solubility can be achieved without the addition of an antacid. Moreover, since the solid formulation obtained by this invention has the high solubility of an oxicam type compound, it shows favorable bioavailability.
In the method of the present invention, the oxicam compound can be easily dissolved by using a basic amino acid aqueous solution in the production stage of the solid preparation. Therefore, an antacid may not be added to the aqueous solution.
The present invention also provides a high yield of solid preparation. This is because there is no need for mixing and pulverization, and there is no need for fine pulverization. When the conventional jet pulverization, mixed pulverization or fine pulverization is performed, the yield on a small scale is about 50% to 70%. However, when the method of the present invention is used, the pulverization treatment is not performed. Therefore, a yield of about 90% or more can be obtained.

  The preparation of the present invention may not contain an antacid, but may be added as necessary. Antacids include sodium bicarbonate, calcium hydrogen phosphate, magnesium aluminate metasilicate, magnesium hydroxide, and synthetic hydrotalcite. Therefore, secretion of gastric acid is not promoted in those who have received the preparation of the present invention. Therefore, compared with a preparation containing an antacid, the burden on a person having inflammation or the like in the stomach is reduced. Moreover, since there is no mixing | blending of an antacid, the shape of a solid formulation can be made small.

In the present invention, the “oxicam compound” includes oxicam anti-inflammatory drugs, oxicam anti-inflammatory drugs, and oxicam anti-inflammatory drugs. Examples of oxicam compounds include, but are not limited to, lornoxicam, piroxicam, tenoxicam, ampiroxicam, droxicam, meloxicam, chronoticam, tenoxicam, piroxicam. The oxicam compound is preferably lornoxicam, piroxicam, tenoxicam or ampiroxicam. The oxicam compound may be used as a pharmaceutically acceptable salt, ester or prodrug.
“Oxicam compounds” are used as, for example, but not limited to, anti-inflammatory drugs, anti-inflammatory drugs, anti-inflammatory analgesics, and all oxicam compounds will be approved by the Ministry of Health, Labor and Welfare as pharmaceuticals at present or in the future. Can be used for various applications.
The content of the oxicam compound can be appropriately adjusted according to the solid preparation to be produced. The content of the oxicam compound is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, more preferably 1 to 4% by weight, based on the weight of the manufactured solid preparation. More preferably, it is 2-3 weight%.

In the present invention, the solid preparation is preferably a solid preparation for internal use or oral use.
In the present invention, the solid preparation includes tablets, coated tablets, troches, and granules.

  In the present invention, as a result of the addition of the oxicam compound to the basic amino acid aqueous solution, the oxicam compound may be dissolved or suspended in the aqueous solution. Alternatively, a part of the added oxicam compound may be dissolved and the rest may be suspended.

  In the present invention, “basic amino acid” includes, but is not limited to, lysine, arginine, histidine, ornithine, or a pharmaceutically acceptable derivative thereof, or a combination thereof. The “basic amino acid” is preferably lysine, arginine, histidine or ornithine, more preferably lysine or arginine, and even more preferably arginine.

  In the present invention, the basic amino acid aqueous solution contains 1 part to 10 parts of basic amino acid with respect to 10 parts to 40 parts of water. In preparing the basic amino acid aqueous solution, the basic amino acid can be dissolved in warm water in order to dissolve the basic amino acid aqueous solution.

In the present invention, the amount of the oxicam compound added to the basic amino acid aqueous solution is 1 part to 10 parts of the oxicam compound with respect to 10 parts to 50 parts of the basic amino acid aqueous solution.
The content of the basic amino acid is appropriately selected according to the solid preparation to be produced, but preferably 0.1 to 20 parts, preferably 1 to 20 parts, based on 160 parts of the produced solid preparation. More preferably 5 to 15 parts, most preferably 8 parts.

  The pH of the basic amino acid aqueous solution is preferably 7.0 to 14.0, more preferably 8.0 to 13.0, and still more preferably 10.0 to 12.0.

  The pH of the basic amino acid aqueous solution may be adjusted with any pH adjusting agent. Examples of the pH adjusting agent include citric acid, tartaric acid, maleic acid, lactic acid, glycolic acid, malic acid, salicylic acid, fumaric acid, methanesulfonic acid, acetic acid, EDTA-2 sodium or an organic acid such as an acidic amino acid or their Examples include, but are not limited to, organic acid salts or inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or hydrobromic acid. Examples of acidic amino acids include aspartic acid or glutamic acid. The pH adjuster may be used alone or multiple pHs may be used together.

  The pH adjusting agent can be added to the basic amino acid aqueous solution as a pH adjusting agent or an aqueous solution of a pH adjusting agent. Alternatively, the amount of the pH adjuster to be added may be examined in advance, and the pH adjuster may be added to water together with the basic amino acid when preparing the basic amino acid aqueous solution.

  In the present invention, “water” is ethanol water (ethanol: water weight ratio = 1: 1) or water, preferably pure water, distilled water, desalted water or ultrapure water, more preferably ultrapure water. It is water.

  The basic aqueous amino acid solution may be prepared as a stock solution or may be prepared upon addition of the oxicam compound.

  In the present invention, “drying” may be performed by a conventional technique in the art, and is preferably performed by evaporation to dryness, spray drying, freeze drying or standing drying. By using spray drying, the components in the solid preparation become uniform. The drying is preferably performed using a fluidized bed granulator / dryer.

  In the present invention, the formulation may be carried out by a conventional technique in the art. Preferably, the coarse granules obtained by evaporation to dryness are granulated with a granulator, and the granules are beaten in the presence of a lubricant. This is done by molding with a tablet machine. In the present invention, the formulation may be performed by spray granulation.

  In the present invention, the obtained solid preparation can be further coated with a film. The film coating can be performed using methods known to those skilled in the art.

In the present invention, “excipient” refers to sugars such as glucose, fructose, lactose, anhydrous lactose, sucrose, maltose, mannitol, erythritol, xylitol, sorbitol, corn starch, partially pregelatinized starch, potato starch, wheat starch, croscarme Starches such as loin, hydroxypropyl starch, carmellose, celluloses such as crystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, or pullulan, dextrin, gum arabic, agar, gelatin, tragacanth , Fatty acids such as sodium alginate, polyvinyl pyrrolidone, polyvinyl alcohol, stearic acid or salts thereof, and waxes . The excipient can preferably comprise hydroxypropylcellulose or polyvinylpyrrolidone.
The excipient may be added in the granulation step, or an aqueous solution of the excipient may be added to the basic amino acid aqueous solution in which the oxicam compound is dissolved before granulation.

  In the present invention, NISSO HPC series manufactured by Nippon Soda Co., Ltd., particularly HPC-SSL, HPC-SL or HPC-L can be used as the hydroxypropyl cellulose, but it is not limited thereto.

  In the present invention, as the above-mentioned polyvinyl pyrrolidone, Kollidon 12PF, Kollidon 17PF, Kollidon 25, Kollidon 30 or Kollidon 90F manufactured by BASF Japan, or Plasdon K-29 / 32 and Plasdon K-25 manufactured by ISP are used. , Plasdon K-90, Plasdon K-90D or Plasdon K-90M can be used, but is not limited thereto.

  The content of the hydroxypropyl cellulose or the polyvinyl pyrrolidone is appropriately selected according to the solid preparation to be produced, but is preferably 0.1 to 20 parts, preferably 160 parts by weight with respect to 160 parts by weight of the produced tablet. 1 to 20 parts, more preferably 5 to 15 parts, most preferably 8 parts.

  The basic amino acid concentration in the manufactured solid preparation is 1 to 25 parts, preferably 5 to 20 parts, relative to 100 to 200 parts of the solid preparation.

  Examples are shown below. In addition, these do not limit this invention.

Tablets containing lornoxicam were produced according to the formulation shown below.

  8.0 parts of L-arginine and 20.0 parts of water were heated to 50 ° C. in a warm bath and dissolved by stirring to obtain an aqueous solution. Furthermore, 4.0 parts of lornoxicam was added to the aqueous solution and dissolved to obtain a drug substance solution. Separately, D-mannitol, crystalline cellulose, and hydroxypropyl cellulose were stirred and mixed with a high-speed stirring granulator (fluidized bed granulator multiplex (FD-MP-01), manufactured by Powrex Corporation). Next, the drug substance solution was added to the granulator to obtain a compound by wet granulation. The obtained compound was transferred to a fluidized bed dryer (fluidized bed granulator multiplex (FD-MP-01), manufactured by Powrex Co., Ltd.) and dried. The obtained dried coarse granules were further passed through a granulator (Comil (QC-197S), manufactured by Powerex Co., Ltd.) (600 μ) to obtain granules. The obtained granule was transferred to a V-type mixer (V-type mixer (V-10 type, manufactured by Tokuju Kogakusho Co., Ltd.), mixed with low-substituted hydroxypropylcellulose and calcium stearate, and the resulting mixture was obtained. The powder was compressed into tablets of 160 mg with a rotary tableting machine (rotary type tableting machine (VELA5), manufactured by Kikusui Seisakusho Co., Ltd.).

Tablets containing lornoxicam were produced according to the formulation shown below.

  8.0 parts of L-arginine and 20.0 parts of water were heated to 50 ° C. in a warm bath and dissolved by stirring to obtain an aqueous solution. Further, 4.0 parts of lornoxicam was added to the aqueous solution and dissolved to obtain a drug substance solution. Separately, 8.0 parts of polyvinylpyrrolidone was stirred and dissolved in 72.0 parts of water, and this was added to the drug substance solution to add a binding solution. Separately, 78.4 parts of D-mannitol and 25.0 parts of low-substituted hydroxypropylcellulose were mixed with a fluidized bed granulator (fluidized bed granulator multiplex (FD-MP-01), manufactured by Powrex Co., Ltd.), and then a binding solution. Was sprayed and granulated / dried to obtain coarse granules. In Example 2, since the amount of liquid to be introduced was too large in the high speed agitation granulator, spray granulation was performed with a fluidized bed dryer. The obtained coarse granules were further passed through a granulator (600 μ) to obtain granules. The obtained granules are transferred to a V-type mixer, and 5.0 parts of low-substituted hydroxypropyl cellulose and 1.6 parts of calcium stearate are added and mixed. The resulting mixed powder is compressed into 160 mg tablets by a rotary tableting machine. Made.

Tablets containing lornoxicam were produced according to the formulation shown below.

In Example 3, the base material polyvinylpyrrolidone used in Example 2 was changed to hydroxypropylcellulose.
8.0 parts of L-arginine and 20.0 parts of water were heated to 50 ° C. in a warm bath and dissolved by stirring to obtain an aqueous solution. To this aqueous solution, 4.0 parts of lornoxicam was added and dissolved to obtain a drug substance solution. Separately, 8.0 parts of hydroxypropyl cellulose was dissolved in 40.0 parts of water by stirring, and this was added to the drug substance solution to obtain a binding solution. Separately, 78.4 parts of D-mannitol and 25.0 parts of low-substituted hydroxypropylcellulose were mixed in a fluidized bed granulator, and then the binding liquid was sprayed to granulate / dry to obtain coarse granules. The obtained coarse granules were further passed through a granulator (600 μ) to obtain granules. The obtained granules are transferred to a V-type mixer, 10.0 parts of low-substituted hydroxypropylcellulose and 1.6 parts of calcium stearate are added and mixed, and the resulting powder mixture is compressed into 160 mg tablets with a rotary tableting machine. Made.

Film-coated tablets containing lornoxicam were produced with the following formulation.

In the present Example 4, the tablet manufactured according to Example 3 was manufactured by applying a film coat.
An uncoated tablet part was produced according to Example 3. In 90.0 parts of ethanol water (weight ratio 1: 1), 8.3 parts of hypromellose, 1.0 part of macrogol and 0.7 parts of titanium oxide were added and dissolved to obtain a mixed solution of the film coat part. Using a coating apparatus (Dria Coater (DRC-300), manufactured by Powrex Co., Ltd.), the uncoated tablet part was coated with a film to produce a film-coated tablet. Ethanol water (weight ratio 1: 1)) is removed by evaporation during the coating process.

[Comparative Example 1]
A tablet containing lornoxicam was produced according to the formulation shown below.

  Lornoxicam, lactose hydrate, crystalline cellulose and hydroxypropylcellulose were mixed with stirring using a high-speed stirring granulator. Next, ethanol water (weight ratio 1: 1) was added to obtain a compound by wet granulation. The obtained compound was transferred to a fluid bed dryer and dried. The obtained dried coarse granules were passed through a granulator (600 μ) to obtain granules. The obtained granules were transferred to a V-type mixer, and partially pregelatinized starch and calcium stearate were added and mixed. The obtained mixed powder was compressed into a tablet of 152 mg by a rotary tableting machine to produce a tablet.

[Comparative Example 2]
A tablet containing lornoxicam was produced according to the formulation shown below. In Comparative Example 2, unlike Comparative Example 1, sodium bicarbonate, which is a basic inorganic salt, was used.

  Lornoxicam and sodium hydrogen carbonate (antacid) were co-ground using a hammer mill (Lab Mill (LM-05), manufactured by Dalton Co., Ltd.) to obtain a triturate. Lactose hydrate, crystalline cellulose, and hydroxypropylcellulose were stirred and mixed with the resulting triturate with a high-speed stirring granulator. Next, ethanol water (weight ratio 1: 1) was added to obtain a compound by wet granulation. The obtained compound was transferred to a fluid bed dryer and dried. The obtained dry coarse granules were further passed through a granulator (600 μ) to obtain granules. The obtained granule was transferred to a V-type mixer, partially pregelatinized starch and calcium stearate were added and mixed, and the resulting mixed powder was compressed to 160 mg per tablet with a rotary tableting machine to produce a tablet.

[Comparative Example 3]
A tablet containing lornoxicam was produced according to the formulation shown below. In this comparative example 3, arginine is added as a powder.

  Lornoxicam and L-arginine were placed in a plastic bag and a triturate was obtained by hand mixing. Lactose hydrate, crystalline cellulose and hydroxypropyl cellulose were added to the obtained triturate, and the mixture was stirred and mixed in a high-speed stirring granulator. Next, ethanol water (weight ratio 1: 1) was added to obtain a compound by wet granulation. The obtained compound was transferred to a fluid bed dryer and dried. The obtained dry coarse granules were further passed through a granulator (600 μ) to obtain granules. The obtained granule was transferred to a V-type mixer, and partially pregelatinized starch and calcium stearate were added and mixed. The obtained mixed powder was compressed to 160 mg by tablet using a rotary tableting machine to produce a tablet.

[Comparative Example 4]
A tablet containing lornoxicam was produced according to the formulation shown below. In this comparative example 4, arginine is added as a powder.

  Lornoxicam and L-arginine were placed in a plastic bag and a triturate was obtained by hand mixing. D-mannitol, crystalline cellulose and hydroxypropyl cellulose were added to the obtained triturate, and the mixture was stirred and mixed in a high-speed stirring granulator. Next, ethanol water (weight ratio 1: 1) was added to obtain a compound by wet granulation. The obtained compound was transferred to a fluid bed dryer and dried. The obtained dry coarse granules were further passed through a granulator (600 μ) to obtain granules. The obtained granule was transferred to a V-type mixer, low-substituted hydroxypropylcellulose and calcium stearate were added and mixed, and the resulting mixed powder was compressed to 160 mg per tablet with a rotary tableting machine to produce a tablet.

  Below, prescription of Examples 1-3 and Comparative Examples 1-4 is shown.

実施例１〜３及び比較例１〜４で得られた錠剤について、第十五改正日本薬局方に収載の溶出試験法パドル法（第１０５〜１０８頁）に従い、溶出試験第１液（pH1.2）900mLにより溶出試験を実施した。その結果、図１に示す溶出結果が得られた。

For the tablets obtained in Examples 1 to 3 and Comparative Examples 1 to 4, the dissolution test first solution (pH 1. 5) according to the dissolution test method paddle method (pages 105 to 108) listed in the 15th revision Japanese Pharmacopoeia. 2) The dissolution test was conducted with 900 mL. As a result, the elution results shown in FIG. 1 were obtained.

In Comparative Example 1, the elution rates at 5 minutes, 15 minutes, 30 minutes and 60 minutes were 15.2%, 26.7%, 31.1% and 34.5%, respectively, and sufficient elution was obtained. It is not done. In Comparative Example 3, the elution rates at 5 minutes, 15 minutes, 30 minutes, and 60 minutes were 18.4%, 37.5%, 50.2%, and 57.6%, respectively. Thus, a sufficient elution improvement effect was not obtained.
In Comparative Example 3, it was found that lactose hydrate had a Maillard reaction with arginine. In Comparative Example 4, as a result of changing lactose hydrate to D-mannitol, it was found that Maillard reaction due to the presence of arginine did not occur.
Furthermore, in Comparative Example 3, it was found that the partially pregelatinized starch adsorbed the lornoxicam / arginine lysate. In Comparative Example 4, it was found that as a result of changing the partially pregelatinized starch to low-substituted low-substituted hydroxypropylcellulose, the lornoxicam / arginine lysate was not adsorbed.
However, in Comparative Example 4, the elution rates at 5 minutes, 15 minutes, 30 minutes, and 60 minutes were 17.0%, 33.5%, 48.6%, and 53.4%, respectively. On the other hand, a sufficient elution improvement effect was not obtained.
The elution rates of Example 1 were 32.4%, 58.9%, 74.6%, and 81.2%, respectively, at 5 minutes, 15 minutes, 30 minutes, and 60 minutes. Compared with 1, 3 or 4, elution improvement effect was recognized.
In Example 2, as a result of selecting polyvinylpyrrolidone as a base material, lornoxicam and arginine were dissolved at the same time. And in Example 2, the better elution improvement effect than Example 1 was recognized. In the tablet obtained in Example 2, dissolution rates of 22.2%, 47.8%, 76.5% and 95.8% were obtained at 5 minutes, 15 minutes, 30 minutes and 60 minutes, respectively. It was.
In Example 3, the base material of Example 2 was changed from polyvinyl pyrrolidone to hydroxypropyl cellulose. As a result, in Example 3, the elution improvement effect equivalent to or exceeding that of Comparative Example 2 was observed. In the tablet obtained in Example 3, dissolution rates of 78.0%, 92.0%, 97.0% and 98.0% were obtained at 5 minutes, 15 minutes, 30 minutes and 60 minutes, respectively. . Also, the dissolution rate (76.5%) achieved by the tablet of Example 2 in 30 minutes is already exceeded by the tablet of Example 3 (78.0%) in 5 minutes. That is, it was found that the tablet of Example 3 can obtain faster disintegration and elution than Example 2.

When the tablets obtained in Example 3 and the tablets obtained in Comparative Example 2 were subjected to a dissolution test according to the dissolution test method paddle method (pages 105-108) listed in the 15th revision Japanese Pharmacopoeia The elution results shown in FIGS. 2 and 3 were obtained. In addition, the following four types of dissolution test solutions were conducted: dissolution test first solution (pH 1.2), dissolution test second solution (pH 6.8), diluted McIlvaine buffer solution (pH 4.0), and ion-exchanged water. (Refer to page 236 of the 15th revised Japanese Pharmacopoeia for the first and second solutions of the dissolution test.)
In the preparation according to Comparative Example 2, a slightly poor dissolution tendency was observed. In the diluted McIlvaine buffer, the elution rates at 10 minutes and 30 minutes are 69.1% and 85.9%, respectively. On the other hand, in the preparation of Example 3, good dissolution was obtained in any of the above four types of dissolution test solutions. Also in the diluted McIlvaine buffer, the elution rates at 10 minutes and 30 minutes are 93.7% and 96.0%, respectively.

It is a graph which shows the elution result of Examples 1-3 and the formulation of Comparative Examples 1-4. It is a graph which shows the elution result in various pH of the formulation of Example 3. It is a graph which shows the elution result in various pH of the formulation of the comparative example 3.

Claims (12)

A method for producing a solid preparation containing an oxicam compound,
The method comprising dissolving an oxicam compound in an aqueous basic amino acid solution and drying the solution.   The method according to claim 1, wherein the aqueous basic amino acid solution comprises 1 part to 10 parts of basic amino acid and 10 parts to 40 parts of water.   The method according to claim 1 or 2, comprising 1 part to 10 parts of the oxicam compound with respect to 10 parts to 50 parts of the basic amino acid aqueous solution.   The method according to any one of claims 1 to 3, wherein the basic amino acid comprises at least one of lysine or arginine.   The method according to any one of claims 1 to 4, wherein the pH of the aqueous basic amino acid solution is 7.0 to 14.0.   The method according to claim 5, further comprising adjusting the pH of the aqueous basic amino acid solution with an acidic amino acid.   The method according to any one of claims 1 to 6, further comprising adding an excipient to the basic aqueous amino acid solution.   The method according to claim 7, wherein the excipient is polyvinylpyrrolidone.   The method of claim 7, wherein the excipient is hydroxypropylcellulose.   The method according to any one of claims 1 to 9, wherein the basic amino acid in the solid preparation is 1 to 25 parts with respect to 100 to 200 parts of the solid preparation.   The method according to any one of claims 1 to 10, wherein the solid preparation is an oral solid preparation.   The method according to any one of claims 1 to 11, wherein the oxicam-based compound comprises at least one of lornoxicam, piroxicam, tenoxicam or ampiroxicam.

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