KR102462607B1 - Pharmaceutical composition with improved stability comprising novel salt of pelubiprofen as an active ingredient - Google Patents

Abstract

본 발명에 따른 상기 약학적 조성물은 저치환도히드록시프로필셀룰로오스, 전분 및 이들의 혼합물로 이루어지는 군으로부터 선택되는 1 이상의 붕해제를 포함하고, 이에 따라 우수한 안정성을 보인다. A pharmaceutical composition comprising felubiprofen tromethamine salt represented by the following formula (2) as a main component is provided, and the pharmaceutical composition according to the present invention has the effect of reducing side effects of gastrointestinal disorders.
[Formula 2]

The pharmaceutical composition according to the present invention includes at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and mixtures thereof, and thus exhibits excellent stability.

Description

Pharmaceutical composition with increased stability comprising a novel salt of felubiprofen as a main ingredient {PHARMACEUTICAL COMPOSITION WITH IMPROVED STABILITY COMPRISING NOVEL SALT OF PELUBIPROFEN AS AN ACTIVE INGREDIENT}

The present invention relates to a pharmaceutical composition comprising a novel salt of felubiprofen. More specifically, the present invention relates to a pharmaceutical composition comprising, as a main component, felubiprofen tromethamine salt having excellent solubility and significantly improved gastrointestinal side effects. The present invention relates to a pharmaceutical composition with excellent stability comprising felubiprofen tromethamine salt, and to a pharmaceutical composition comprising a specific disintegrant.

Felubiprofen represented by the following Chemical Formula 1 is disclosed in Japanese Patent No. 1637767 and Korean Patent No. 0922519. Felubiprofen is a nonsteroidal anti-inflammatory analgesic with various pharmacological activities such as anti-inflammatory, analgesic, and antipyretic, and is an excellent drug for treating arthritis, low back pain, and upper respiratory tract inflammation.

[Formula 1]

However, felubiprofen is a poorly soluble drug, and since it is an acidic drug with high solubility at basic pH, there is a problem of low solubility at acidic pH. In addition, felubiprofen has significantly reduced gastrointestinal side effects compared to existing nonsteroidal anti-inflammatory drugs, but still has gastrointestinal side effects.

Accordingly, there is a need for research and development on a pharmaceutical composition of felubiprofen, which can significantly improve solubility in acidic pH conditions and significantly improve gastrointestinal side effects. An attempt has been made to provide a formulation with excellent bioavailability by increasing the dissolution rate by controlling the However, only pharmaceutical means such as controlling the particle size have limitations in changing the physical properties of the main ingredient itself, and it is difficult to provide a drug with reduced gastrointestinal side effects.

Accordingly, the present inventors provide a pharmaceutical composition containing a novel salt of felubiprofen as a main component, thereby providing a pharmaceutical with significantly improved gastrointestinal side effects, and at the same time providing a novel salt of felubiprofen excellent in stability by using a specific excipient as the main component. A study on a pharmaceutical composition comprising

Korean Patent No. 0922519 Japanese Patent No. 1637767

The object of the present invention is to exhibit excellent physicochemical properties such as better solubility and improved stability than felubiprofen to minimize the generation of related substances, and it is possible to apply mass production in manufacturing and to achieve high purity with homogeneous quality. It is to provide a pharmaceutical composition with excellent stability by including a specific disintegrant in a novel salt of felubiprofen with improved gastrointestinal side effects, a method for preparing the same, and a pharmaceutical composition comprising the same as a main component.

Specifically, the present invention provides a pharmaceutical composition comprising felubiprofen tromethamine salt as a main component, comprising at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and mixtures thereof. It relates to a pharmaceutical composition with increased stability.

In order to solve the above problem, the present invention has developed felubiprofen tromethamine salt, which is a novel salt of felubiprofen, and a pharmaceutical composition with increased stability containing it as a main component. Felubiprofen tromethamine salt has superior solubility in various pH conditions compared to felubiprofen. In particular, it was confirmed that felubiprofen tromethamine salt can improve gastrointestinal side effects by minimizing gastric mucosal damage when compared with felubiprofen.

Furthermore, in preparing a pharmaceutical composition using felubiprofen tromethamine salt as a main component, the present inventors have disclosed that, as a disintegrant, at least one boron selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and mixtures thereof. In the case of including release, the present invention was reached by discovering the knowledge that it exhibits a desired dissolution rate and excellent stability. Hereinafter, the present invention will be described in detail.

The present invention provides felubiprofen tromethamine salt. The felubiprofen tromethamine salt of the present invention is a compound represented by the following formula (2).

[Formula 2]

Felubiprofen tromethamine salt has good solubility in various pH conditions. In addition, felubiprofen tromethamine salt can significantly improve the side effects of gastrointestinal disorders, and is useful as a pharmaceutical for inflammatory diseases.

Felubiprofen tromethamine salt is prepared by reacting felubiprofen and tromethamine in methanol, ethanol, 2-propanol, butanol, acetone, ethyl acetate, methylene chloride or a mixed solvent thereof, followed by acetone, methyl ethyl ketone. , ethyl acetate, n-hexane, isopropyl ether, isopropyl alcohol, and an anti-solvent selected from the group consisting of a mixed solvent thereof to form a felubiprofen tromethamine salt, followed by filtration and drying. It may be prepared, but is not limited thereto, and may be prepared by adopting a salt formation method known to those skilled in the art.

A pharmaceutical composition comprising felubiprofen tromethamine salt as a main component can be prepared by formulation by including a pharmaceutically acceptable carrier, excipient or diluent known to those skilled in the art.

The diluent that can be used in the present invention is, but is not limited to, for example, it may be selected from calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, lactose, sucrose, mannitol, sorbitol, dextrin, and the like, Preferably, it may be selected from anhydrous calcium hydrogen phosphate, microcrystalline cellulose, lactose, and mannitol, and may be used in an amount of 0.5 to 5 parts by weight based on 1 part by weight of felubiprofen tromethamine salt.

Binders that can be used in the present invention include, but are not limited to, for example, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium methylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, It may be selected from hydroxypropyl starch, polyvinyl alcohol, polyvinyl pyrrolidone, and the like, preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrillidone, and Felubipro. It may be used in an amount of 0.05 to 1 part by weight based on 1 part by weight of phentromethamine salt.

Lubricants that can be used in the present invention include, but are not limited to, for example, silicon dioxide, calcium stearate, magnesium stearate, hydrogenated vegetable oil, aluminum stearate, zinc stearate, talc, sodium lauryl sulfate, synthetic It may be selected from aluminum silicate, magnesium aluminometasilicate, silicic anhydride, and the like, preferably silicon dioxide, magnesium stearate, talc, synthetic aluminum silicate, magnesium aluminometasilicate, and silicic anhydride. It may be used in an amount of 0.05 to 1 part by weight based on 1 part by weight of the phentromethamine salt.

The pharmaceutically acceptable carrier, excipient or diluent is not limited as long as it does not impair the effects of the present invention, but according to the study of the present inventor, the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, starch and mixtures thereof. It was found that a desired dissolution rate can be obtained only by using at least one disintegrant selected, and at the same time, stability is maintained. In addition, in the case of at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and mixtures thereof, it is preferable to include 0.1 to 1 part by weight of the felubiprofen tromethamine salt based on 1 part by weight. When used in an amount of less than 0.1 part by weight, a desired dissolution rate cannot be obtained, and when used in an amount of more than 1 part by weight, a stability degradation problem may occur.

The pharmaceutical composition according to the present invention is preferably effective immediately after administration. For this purpose, it can be completely disintegrated within 20 minutes in water, and can exhibit a dissolution rate of 30% or more in 10 minutes and 80% or more in 30 minutes at pH 6.8.

The present invention is useful as a preventive and therapeutic agent for arthritis, back pain, upper respiratory tract inflammation, etc., dermatitis, acute or chronic upper respiratory tract inflammation, fever, inflammatory bowel disease, asthma, osteoarthritis, rheumatoid arthritis, bronchitis, Th-2 autoimmune disease, systemic Erythematodes, myasthenia gravis, chronic GVHD, clonal disease, degenerative spondylitis, low back pain, gout, inflammation after surgical trauma, remission of swelling, neuralgia, laryngitis, cystitis, hepatitis, hepatitis B, hepatitis C and arteriosclerosis. It can be used as a preventive or therapeutic agent for an inflammatory disease selected from the group.

The present invention may be a pharmaceutical composition for preventing or treating inflammatory diseases by administering felubiprofen tromethamine salt in an amount of 25 mg as felubiprofen and administered 3 times a day.

The pharmaceutical composition according to the present invention can increase the stability of the formulation by lowering the amount of impurities generated during the storage process of the product by using a specific disintegrant. In particular, felubiprofen tromethamine salt, which is the main component of the pharmaceutical composition according to the present invention, has an effect of reducing side effects of gastrointestinal disorders.

1 shows the gastrointestinal effect test results of felubiprofen tromethamine salt.
2 shows the stability test results of the pharmaceutical composition according to the present invention.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Preparation Example 1. Preparation of felubiprofen tromethamine salt

Compound 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (felubiprofen, 5 g, 19.36) prepared in the same manner as described in Japanese Patent No. 1637767 mmol) in methanol (25 mL) to prepare a solution, and in the solution, 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (felubiprofen) 1.0 2-amino-2-(hydroxymethyl)propane-1,3-diol (tromethamine, 2.35 g, 19.40 mmol) was added dropwise in a molar ratio of about 1.002 equivalents to the equivalent, followed by stirring at 40° C. for 1 hour. . Then, methanol was concentrated under reduced pressure (76 cmHg) after cooling to room temperature (20-25 ° C.) Acetone (70 mL) was slowly added dropwise to the concentrate, followed by stirring at room temperature (20-25 ° C. for 2 hours), followed by filtration. After washing the filtrate with 100 mL of a mixed solvent of methanol and acetone (methanol:acetone = 1:3 v/v), the obtained solid was vacuum-dried at 40° C. to obtain felubiprofen tromethamine salt, Experimental Examples below and in Examples.

- Yield: 7.8 g

- Yield: 94%

- Purity: 98.5%

¹ H-NMR (500 MHz, CH ₃ OD) δ7.46-7.38 (m, 5H), 3.66-3.61 (m, 7H), 2.88-2.85 (m, 2H), 2.51 (t, 2H), 1.96- 1.91 (m, 2H), 1.81-1.76 (m, 2H), 1.45 (d, 3H).

Experimental Example 1. Solubility test

As a result of the solubility test according to pH, it was confirmed that the solubility of felubiprofen tromethamine salt was superior to that of felubiprofen.

Felubiprofen tromethamine salt (5 g) and felubiprofen (5 g) according to Preparation Example 1, which are the subject of solubility test evaluation, were respectively mixed with purified water (5 mL), pH 1.2 solution (5 mL), pH 4.0 solution (5 mL) ), pH 6.8 solution (5 mL), stirred for 24 hours, filtered with PVDF, a calibration curve was prepared by HPLC analysis, and the concentration of the saturated solution was calculated from the linear function of the prepared calibration curve.

The results are shown in Table 1 below.

ingredient Solubility (mg/mL) Purified water pH 1.2 pH 4.0 pH 6.8 Felubiprofen 0.13 0.03 0.07 4.05 Felubiprofen tromethamine salt 851.60 654.29 355.36 436.67

Looking at the solubility of felubiprofen in Table 1, it was confirmed that the solubility was the lowest at 0.03 mg/mL in acidic (pH 1.2) conditions, since it is an acidic drug with high solubility at basic pH. However, in the case of felubiprofen tromethamine salt, it was confirmed that the solubility was increased by about 21,807 times under acidic (pH 1.2) conditions.

Experimental Example 2. Gastrointestinal side effect improvement effect test

Male Sprague Dawley rats (6 weeks old, 160-240 g) were purchased from Orient Bio (38-25 Sungnam, Gyeonggi-do, South Korea), and from Notus (Guri, Gyeonggi-do, South Korea). Animal experiments were performed. All male Sprague Dawley rats received water and food ad libitum for 1 week after animal acquisition. The male Sprague Dawley rats were divided into 3 groups of 10 rats per group. Specifically, the weight of the rats before dosing was measured and calculated as the average weight, and the test drug felubiprofen 300 mg/kg and felubiprofen tromethamine salt 440.7 mg/kg (felubiprofen) at 0.5% CMC. 300 mg/kg) was suspended as Group G1 is a group not administered with felubiprofen tromethamine salt or felubiprofen of the present invention, group G2 is a group administered with felubiprofen 300 mg/kg, and group G3 is felubiprofen The group administered 440.7 mg/kg of tromethamine salt. Fasting was started 48 hours before drug administration. The experimental animals were fixed by the skin fixation method on the dorsal region, and directly administered into the stomach of the rats of the G2 and G3 groups using an oral zonde. After anesthesia with diethyl ether 6 hours after drug administration, the gastric mucosa was removed and the mucosal surface of the stomach was photographed with a digital camera, and image data captured with a digital camera was analyzed. The damaged area of the gastric mucosa was analyzed using Image J software (NIH, Bethesda, MD). The analysis results are shown in Table 2 and FIG. 1 .

army drug injection Stomach injury area (%) G1 - 0.00 ± 0.00 G2 Felubiprofen 4.06 ± 3.53 G3 Felubiprofen tromethamine salt 1.99 ± 1.49

Examples 1-7. Preparation of the pharmaceutical composition according to the present invention

50 mg of felubiprofen tromethamine salt, which uses at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and mixtures thereof, as a main component A pharmaceutical composition comprising

All components except magnesium stearate were mixed to prepare granules. The granules were lubricated with magnesium stearate to obtain final granules, and then tablets were prepared using a tableting machine.

Ingredient name Amount (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Felubiprofen
tromethamine salt 50 50 50 50 50 50 50 Low-substituted hydroxypropyl cellulose 50 - - 25 3 - - pregelatinized starch - 50 - 25 - 10 - corn starch - - 50 - - - 10 Anhydrous calcium hydrogen phosphate Hydroxypropyl Cellulose 5 5 5 5 5 5 5 Magnesium Aluminometasilicate 5 5 5 5 5 5 5 Magnesium Stearate 8 8 8 8 8 8 8

Comparative Example 1-7. Preparation of Pharmaceutical Compositions Containing Other Disintegrants

Examples of pharmaceutical compositions containing 50 mg of felubiprofen tromethamine salt as a main component, using a disintegrant other than the disintegrant used in Examples 1-7, according to the raw drug amount shown in Table 4 below It was prepared in the same way as the manufacturing method described in 1-7.

Ingredient name Amount (mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Felubiprofen
tromethamine salt 50 50 50 50 50 50 50 Low-substituted hydroxypropyl cellulose - - - - pregelatinized starch - - - - - corn starch - - - - - - Croscarmellose
salt 50 - - - - - - crospovidone - 50 - - - - - Sodium starch glycolate - - 50 - - - - Carboxymethylcellulose calcium - - - 50 - - - Anhydrous calcium hydrogen phosphate 50 50 50 Hydroxypropyl Cellulose 5 5 5 5 5 5 5 Magnesium Aluminometasilicate 5 5 5 5 5 5 5 Magnesium Stearate 8 8 8 8 8 8 8

Experimental Example 3. Stability evaluation according to disintegrant

For the pharmaceutical compositions according to Examples 1-7 and Comparative Examples 1-7, the total amount of related substances was confirmed after storage for 4 weeks at 90 %RH, and the results are shown in Table 5 and FIG. 2 .

division Total related substances (%) division Total related substances (%) Example 1 0.37 Comparative Example 1 1.87 Example 2 0.25 Comparative Example 2 2.15 Example 3 0.29 Comparative Example 3 4.42 Example 4 0.35 Comparative Example 4 1.66 Example 5 0.27 Comparative Example 5 1.12 Example 6 0.24 Comparative Example 6 1.03 Example 7 0.26 Comparative Example 7 0.91

As can be seen above, it was confirmed that the stability was excellent when low-substituted hydroxypropyl cellulose and/or pregelatinized starch were used as disintegrants.

Experimental Example 4. Evaluation of dissolution

For the pharmaceutical composition according to Examples 1-7, dissolution evaluation was performed as follows.

The dissolution test was performed according to the first method (basket method) using 900 mL of the pH 6.8 dissolution solution (the second solution of the dissolution test of the Korean Pharmacopoeia), and the test temperature was set at 37±0.5 °C. The collected eluate was filtered using a 0.45 μm PVDF filter and used as a sample solution, and felubiprofen was quantitatively analyzed by HPLC. Table 6 shows the dissolution evaluation results.

division Dissolution rate (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 10 minutes 65.2 55.1 47.2 60.7 37.1 38.9 32.5 30 minutes 98.9 99.1 98.9 99.3 86.7 83.8 81.2

As can be seen above, it was confirmed that the pharmaceutical composition according to the present invention exhibited an immediate-release dissolution rate of at least 30% at 10 minutes and at least 80% at 30 minutes at pH 6.8.

Experimental Example 5. Disintegration evaluation

For the pharmaceutical composition according to Examples 1-7, disintegration evaluation was performed as follows.

The disintegration test was carried out according to the general test method of the Korean Pharmacopoeia, and water was used as the test solution. After putting the sample in the auxiliary plate and moving it up and down, the state of the sample was observed to confirm the residue of the sample. It was judged that disintegration was completed when there was no residue in the glass tube, or if there was a material on the sponge or a little soft material. The disintegration evaluation results are shown in Table 7.

division Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Disintegration time (min) 8 11 11 10 15 18 19

As can be seen above, it was confirmed that the pharmaceutical composition according to the present invention was completely disintegrated within 20 minutes in water.

The pharmaceutical composition according to the present invention is used as an antipyretic, analgesic, anti-inflammatory agent, etc., and has the advantage that the drug effect can appear in a short time due to the immediate release rate and rapid disintegration.

By providing a pharmaceutical composition with reduced gastrointestinal side effects and increased stability compared to conventional pharmaceutical compositions containing felubiprofen as a main component, immediate use in the pharmaceutical industry is possible.

Claims (5)

A pharmaceutical composition comprising felubiprofen tromethamine salt represented by the following formula (2) as a main component,
[Formula 2]

The pharmaceutical composition is to include one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, and mixtures thereof,
The pharmaceutical composition with increased stability, characterized in that the disintegrant is included in an amount of 0.1 to 1 part by weight based on 1 part by weight of the felubiprofen tromethamine salt. delete The method of claim 1, wherein the pharmaceutical composition is
felubiprofen tromethamine salt;
Low-substituted hydroxypropyl cellulose, at least one disintegrant selected from starch;
diluent of anhydrous calcium hydrogen phosphate;
a binder of hydroxypropyl cellulose;
at least one lubricant selected from magnesium stearate and magnesium aluminometasilicate;
A pharmaceutical composition with increased stability comprising a. A pharmaceutical composition comprising felubiprofen tromethamine salt represented by the following formula (2) as a main component,
[Formula 2]

The pharmaceutical composition is in the form of a tablet, and in a dissolution test using a pH 6.8 eluate at a temperature of 37±0.5 °C, a pharmaceutical composition, characterized in that it exhibits a dissolution rate of 30% or more at 10 minutes and 80% or more at 30 minutes. The pharmaceutical composition according to claim 4, wherein the tablet completely disintegrates within 20 minutes in water when the disintegration test is performed according to the general test method of the Korean Pharmacopoeia.

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