KR20100001602A - Pharmaceutical preparation containing solubilized niflumic acid - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation containing niflumic acid is provided to improve elution rate inside the body and enhance storage stability. CONSTITUTION: A pharmaceutical formulation having solubilized niflumic acid contains a base selected from polyethylene glycol, propylene glycol, diethyleneglycol monoethylether, glycerin or triacetin and a solubilizing agent selected from ethanolamine, diethanolamine, triethanolamine, sodium lauryl sulfate, or basic amino acid. The pharmaceutical formulation contains polyvinylpyrrolidone. The pharmaceutical formulation is soft capsule or hard capsule.

Description

Pharmaceutical preparation containing solubilized niflumic acid

The present invention relates to pharmaceutical preparations in which niflumic acid is poorly soluble in water.

Niflumic acid (2- (3- (trifluoromethyl) anilino) nicotinic acid) is a non-sterileal anti-inflammatory drug (NSAID) drug mainly used for pain treatment and inflammation inhibition. Cyclooxygenase-1 And 2 selectively block the synthesis of prostaglandin by inhibiting prostaglandin, thereby reducing the production of prostaglandin precursors, which is a known active ingredient that shows excellent efficacy in treating combustible rheumatoid arthritis and antipyretic analgesic. Such niflumic acid is used for pain relief after surgery, after trauma, or after extraction and for the treatment of inflammation and pain in inflammatory diseases such as rheumatoid arthritis and osteoarthritis. The dose of niflumic acid is administered 250 mg three times daily for adults, and 750 mg three times daily for severe diseases. The method of administration is usually taken orally.

Niflumic acid is a pale yellow crystalline powder, highly hygroscopic and hardly soluble in water. The drug developed to improve this point is Talniflumate, which is a prodrug-type drug that has significantly improved side effects compared to niflumic acid, but is expected to have a certain effect due to high doses and severe variation among individuals. Is not easy.

Niflumic acid is a drug that is not metabolized in the stomach and is metabolized through the first pass in the liver, and gastrointestinal toxicity, liver toxicity and kidney toxicity are representative side effects. Currently known toxicity is 250 mg / kg LD50 when administered orally to rats. Currently, formulations containing niflumic acid are developed and marketed in the form of hard capsules, but side effects cannot be prevented because an excessive amount of drug must be taken.

Therefore, it is necessary to reduce the dosage by improving the solubility of poorly soluble niflumic acid in water, and as a result, a preparation for reducing the side effects of niflumic acid is required.

Meanwhile, US Pat. No. 5,141,961 discloses an ethanol-containing liquid formulation in which ibuprofen is solubilized using ethanol, polyethylene glycol, and polyvinylpyrrolidone as a method for improving the solubility of drugs that are poorly soluble in water. U.S. Patent No. 5,071,643 discloses a method for solubilizing ibuprofen using a mixed solvent system of glycerin, polyethylene glycol, polyvinylpyrrolidone and water, but this formulation may affect softening and curing of soft capsules. It is not desirable when a soft capsule formulation is to be prepared. In addition, since the composition of US Patent No. 5,141,961 is an ethanol-containing composition, there is a concern that a problem of precipitation of contents due to ethanol content change during long-term storage occurs. Therefore, the method of solubilizing the drug without using purified water or ethanol is more effective in the soft capsule formulation.

Therefore, the technical problem to be achieved by the present invention is to provide a niflumic acid-containing pharmaceutical formulation with improved solubility of niflumic acid to improve the dissolution rate in the body.

In order to achieve the above technical problem, the present invention (a) niflumic acid; (b) at least one base selected from the group consisting of polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, glycerin, and triacetin; And (c) at least one solubilizer selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, sodium lauryl sulfate, and basic amino acids.

Preferably, the present invention provides a niflumic acid solubilized pharmaceutical preparation, characterized in that the pharmaceutical formulation is a soft capsule containing a transparent liquid solution or a hard capsule containing a transparent liquid contents.

Soft capsules or liquid capsules containing liquid contents, the contents of these capsule formulations are largely divided into two types. First, generally known methods include vegetable oils such as soybean oil, palm oil, sunflower seed oil, sesame oil, perilla oil, olive oil, and the like. A method of suspending a drug as a main ingredient in a base having an oily property such as a medium chain fatty acid triglyceride by using a suspending agent, and a second method is to solubilize or suspend the drug as a main ingredient in a liquid base such as polyethylene glycol.

In the present invention, to improve the dissolution rate by using niflumic acid as a soft capsule formulation, the method of suspending in a base having an oily property, the first method did not improve the dissolution rate, and also a second method of water-soluble base The method used may help to improve the solubility of niflumic acid than the first method, but the effect is not great, and the base such as polyethylene glycol alone may cause precipitation of niflumic acid during storage.

Accordingly, the present invention provides a composition comprising (a) niflumic acid; (b) at least one base selected from the group consisting of polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, glycerin, and triacetin; And (c) at least one solubilizer selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, sodium lauryl sulfate, and basic amino acids.

As the basic amino acid in the dissolution aid according to the present invention, lysine, arginine, histidine and the like may be used. However, in the case of histidine, lysine and arginine are more preferable than the case of using lysine and arginine.

In the niflumic acid solubilizing pharmaceutical preparation according to the present invention, the base is polyethylene glycol, and the dissolution aid is more preferably ethanolamines such as ethanolamine, diethanolamine, triethanolamine, etc. in terms of improving the dissolution rate of niflumic acid. Do. As polyethyleneglycol, polyethyleneglycol 300 or 400 is preferable.

In the niflumic acid solubilized pharmaceutical preparation according to the present invention, the soft capsule or the hard capsule of the hard liquor comprises 2-10% by weight of niflumic acid relative to the total weight of the liquid; Base 80-97 wt%; And 1-11% by weight of a dissolution aid. If it is out of this range, the effect of improving the dissolution rate of niflumic acid is weak, or niflumic acid may precipitate during storage. In addition, when the dissolution aid is excessively used, the size of the formulation may be too large, and the commerciality may be lowered. When the dissolution aid is excessively used, such as diethanolamine, softening of the soft capsule film may cause softening of the soft capsule, resulting in deterioration of stability in terms of properties. have.

The niflumic acid solubilizing pharmaceutical preparations according to the present invention may further contain polyvinylpyrrolidone for the purpose of improving solubility of niflumic acid and increasing storage stability, in which case the content of polyvinylpyrrolidone is 1-10% by weight based on the total weight of the soft capsule or hard capsule content is preferred, in which case the content of the base may be reduced by an additional amount of polyvinylpyrrolidone.

Soft capsule coating in the present invention can be prepared by a conventional manufacturing method by a soft gel formulation containing gelatin, plasticizer, and the like generally used. In addition, the solubilized soft capsule containing the niflumic acid of the present invention may be manufactured by molding in a conventional filling method using a rotary automatic charger which is currently a general method and then drying.

In addition, the pharmaceutical preparation of the present invention may be prepared as a hard capsule that may contain the contents of the liquid, and as the main component of the hard capsule film, vegetable capsules such as hydroxypropyl methyl cellulose, pullulan, etc. are stored to prevent dissolution rate reduction. This is desirable in terms of stability.

The present invention provides a pharmaceutical formulation with improved solubility and dissolution rate of poorly soluble niflumic acid. It is thought that the pharmaceutical preparations according to the present invention will improve the dissolution rate of niflumic acid, thereby improving the absorption rate in the body.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Example 1>

25 g of niflumic acid was mixed with 520 g of polyethylene glycol 400, and then dissolved by heating at about 95 ° C., and 15 g of diethanolamine was added to completely dissolve it. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of a content in which niflumic acid was solubilized.

<Example 2>

20 g of polyvinylpyrrolidone was added to 500 g of polyethylene glycol 400 and completely dissolved. Then, 25 g of niflumic acid was added thereto, followed by heating at about 95 ° C., and 15 g of diethanolamine was added to dissolve completely. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

<Example 3>

12.5 g of niflumic acid and 25 g of polyvinylpyrrolidone K-30 were mixed with 515 g of polyethylene glycol 400, and then dissolved by heating at 95 ° C., and then adding 7.5 g of diethanolamine to completely dissolve it. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

<Example 4>

25 g of niflumic acid was mixed with 525 g of polyethylene glycol 400, and after heating and dissolving at 95 ° C., 10 g of sodium lauryl sulfate was added and completely mixed. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

Example 5

25 g of niflumic acid and 7 g of meglumine were mixed with 510 g of polyethylene glycol 400, followed by heating and dissolving at 95 ° C. to 8 g of diethanolamine and 10 g of sodium lauryl sulfate. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

<Example 6>

After mixing 25 g of niflumic acid in 515 g of polyethylene glycol 400, 20 g of diethanolamine was added after dissolving warmly at 95 ° C. and completely mixed. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

<Example 7>

25g of niflumic acid is mixed with 525g of propylene glycol, and then dissolved by heating at 95 ° C, and 10g of diethanolamine is added and mixed thoroughly. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

<Example 8>

25 g of niflumic acid and 25 g of polyvinylpyrrolidone K-30 were mixed with 500 g of propylene glycol, and 10 g of diethanolamine was added after mixing and heating to 95 ° C., followed by complete mixing. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

Example 9

25 g of niflumic acid and 10 g of sodium lauryl sulfate were mixed with 500 g of triacetin, and then, after heating and dissolving at 95 ° C., 25 g of diethanolamine was added and completely mixed. After confirming that the solution became completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of niflumic acid solubilized contents.

<Example 10>

25 g of niflumic acid was mixed with 495 g of diethylene glycol monoethyl ether, and after heating and dissolving at 95 ° C, 40 g of diethanolamine was added and mixed thoroughly. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

Comparative Example 1

25 g of niflumic acid was mixed with 535 g of polyethylene glycol 400, and then heated and completely dissolved at a temperature of about 95 ° C. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

Comparative Example 2

25 g of niflumic acid was mixed with 470 g of polyethylene glycol 400, and then warmed and warmed at a temperature of about 95 ° C., followed by addition of 65 g of diethanolamine to completely dissolve it. After confirming that it was dissolved and completely transparent, the temperature was cooled to room temperature and bubbles were removed using a vacuum pump to obtain 560 g of the solubilized content of niflumic acid.

<Production of Film>

For the preparation of soft capsule coating, a soft capsule coating formulation containing generally known gelatin, plasticizer, and the like was used. Composition containing 250 mg of gelatin, 87.5 mg of glycerin, 37.5 mg of di-sorbitol solution, 1.1 mg of ethylaniline, 1.0 mg of paraoxybenzoate, and 0.07 mg of paraoxybenzoic acid Was used, and prepared by a conventional preparation method.

The soft capsule production of niflumic acid dissolved according to the present invention was molded into Oblong # 9.5 by a conventional filling method using a rotary automatic filling machine which is generally used, and then made into a prototype by drying and screening.

Comparative Example 3

25 g of niflumic acid and 10 g of lactose were mixed well, and 0.5 g of magnesium stearate was finally mixed to obtain a mixture of 35.5 g. 355 mg of the mixture was filled into hard gelatin capsules to prepare a comparative test prototype for comparison with the prototype prepared in the Examples of the present invention.

Experimental Example 1 Dissolution Rate Test and Comparative Evaluation

The solubilization degree of the Examples and Comparative Example 3 was compared and evaluated through the dissolution test. The temperature of the elution medium was 37 ℃, was tested according to the Paddle method of the KEPCO dissolution test method, the stirring speed was 150rpm, pH 1.2 hydrochloric acid solution with 2% sodium lauryl sulfate was used as the elution medium. An appropriate amount of the elution medium was collected at a predetermined time during the dissolution test, filtered with a 0.45 membrane filter, and the absorbance was measured at 287 nm using an ultraviolet visible absorbance spectrometer. The results are shown in Table 1 below.

Dissolution time (minutes) Dissolution rate (%) Comparative Example 3 Example 1 Example 3 Example 4 Example 5 Example 8 Example 9 Example 10 5 1.4 3.3 4.5 1.7 3.8 3.1 3.3 1.2 10 7.2 14.9 16.8 9.8 15.2 12.4 10.5 8.9 15 33.1 74.6 76.8 41.8 75.1 46.8 42.8 41.1 20 39.8 83.4 84.2 50.8 82.6 59.6 54. 47.5 25 45.2 90.3 93.3 61.2 89.6 72.3 62.8 56.7 30 49.3 91.2 94.5 77.2 90.4 85.6 71.9 63.1

As can be seen in Table 1, the niflumic acid solubilizing formulation according to the present invention can improve the dissolution rate of the existing formulation, such a soft capsule formulation pharmacologically by increasing the dissolution rate of niflumic acid significantly improve the human absorption rate It seems to be able to greatly increase the effect.

In addition, polyethylene glycol (Example 1), propylene glycol (Example 8), triacetin (Example 9) and diethylene glycol monoethyl ether (Example 10) were preferred as a base for niflumic acid solubilization. As a dissolution aid, diethanolamine (Example 1) was much more preferable than sodium lauryl sulfate (Example 4).

Experimental Example 2 Evaluation of Stability

Appropriate samples were selected from the above examples and comparative examples, and subjected to a change over time and a content test for 6 months under an acceleration condition of 40 ° C. Table 2 shows the change in the content of niflumic acid, and Table 3 shows the results of the observation.

The content of niflumic acid was tested in accordance with the Niflumic acid capsules section of the Korean Food and Drug Administration Notice No. 1998-127. In other words, take 20 capsules of the prototype, weigh the contents, powder it, dissolve 400 mg of niflumic acid in 80 ml of dimethylformamide, add 3 drops of thymol blue solution, and blue with 0.1 mol / L sodium methoxide solution. Titrate until 1 ml of 0.1 mol / L sodium methoxide corresponds to 28.22 mg of niflumic acid.

Elapsed time (months) content(%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 0 100.3 100.4 100.5 100.1 100.2 100.1 100.8 100.6 100.0 100.4 100.2 100.3 101.3 One 95.3 97.1 100.2 99.9 100.1 99.9 98.3 98.4 99.8 100.0 99.5 100.1 100.8 2 92.5 95.5 100.3 100.3 100.0 99.9 97.3 98.6 99.6 100.2 98.9 99.9 100.4 4 89.3 92.3 100.4 100.3 100.2 100.3 96.4 98.3 99.8 99.3 99.1 100.1 101.1 6 85.1 91.1 99.8 100.2 100.1 100.1 95.1 97.9 98.7 99.4 98.4 100.1 100.5

As shown in Table 2, it was found that the content of niflumic acid was maintained in the niflumic acid composition according to the present invention.

division 6 months accelerated condition Comparative Example 1 Comparative Example 2 Example 1 Example 3 Example 4 Example 5 Example 7 Example 8 Example 9 Example 10 Change of appearance - - - - - - - - - - Precipitation +++ ++ - - - - - - - -

In Table 3, ++++ has a lot of precipitation, +++ has a lot of precipitation, ++ is a moderate precipitation, + is a little precipitation,-means no precipitation.

As shown in Table 3, the niflumic acid-containing composition according to the present invention did not change in appearance or brown color. On the other hand, Comparative Examples 1 and 2 did not produce browning when stored under accelerated conditions for 6 months, but precipitates were formed.

Claims (6)

Niflumic acid; Any one or more bases selected from the group consisting of polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, glycerin and triacetin; And At least one dissolution aid selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, sodium lauryl sulfate and basic amino acids; Niflumic acid solubilized pharmaceutical formulation comprising a. The niflumic acid solubilized pharmaceutical formulation according to claim 1, wherein the base is polyethylene glycol. The niflumic acid solubilized pharmaceutical preparation according to claim 1, wherein the dissolution aid is ethanolamine, diethanolamine, triethanolamine or a mixture thereof. The niflumic acid solubilized pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation comprises polyvinylpyrrolidone. The niflumic acid solubilized pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is a soft capsule or a hard capsule containing a clear solution. According to claim 5, wherein the contents solution is 2 to 10% by weight of niflumic acid relative to the total weight of the solution; Base 80-97 wt%; And 1-11% by weight of a dissolving aid.