WO2008038423A1 - Antiphlogistc and analgetic composition for oral use - Google Patents

Abstract

It is intended to provide an antiphlogistic and analgetic composition for oral use wherein the antiphlogistic effect (antiinflammatory effect) of a phenylpropionic acid-based antiphlogistic and analgetic agent has been potentiated. It is also intended to provide a method of potentiating the antiphlogistic effect of a phenylpropionic acid-based antiphlogistic and analgetic agent having bitterness and simultaneously relieving the bitterness. Namely, (a) a phenylpropionic acid-based antiphlogistic and analgetic agent is used together with (b) glucosamine, its derivative or a salt thereof or (b) glucosamine its derivative or a salt thereof and (c) chondroitin, chondroitin sulfate or its salt.

Description

 Specification

 Oral pharmaceutical composition for anti-inflammatory analgesia

 Technical field

 [0001] The present invention relates to an oral pharmaceutical composition for anti-inflammatory analgesia. More specifically, the present invention relates to an anti-inflammatory analgesic oral pharmaceutical composition containing a phenylpropionic anti-inflammatory agent as an active ingredient. Furthermore, the present invention relates to a method for reducing the bitter taste of a phenolpropionic acid anti-inflammatory analgesic having a bitter taste.

 Background art

 [0002] Ferpropionic acid-based anti-inflammatory analgesics such as ibuprofen have been widely used as drugs for inflammatory diseases and the accompanying pain and fever because they have excellent analgesic and anti-inflammatory properties. In particular, ibuprofen is suitably used as a therapeutic agent for arthralgia accompanied by inflammation because it has a high anti-inflammatory action especially in the periphery among known anti-inflammatory analgesics. However, phenylpropionic acid anti-inflammatory analgesics are prone to side effects such as peptic ulcer and gastrointestinal bleeding because they tend to cause damage to the gastric mucosa. Various attempts have been made to devise measures for enhancing the action effect of the substance and to reduce the gastrointestinal disorder itself (see, for example, Patent Documents 1 to 10).

 [0003] Further, since ibuprofen is a drug having a bitter taste, in order to prepare it as an internal preparation (oral pharmaceutical composition), masking the bitter taste improves the ingestibility of the preparation and improves the dosage. This is important for discriminating against products. From this viewpoint, various methods for masking and reducing the bitterness of anti-inflammatory analgesics such as ibuprofen have been proposed (see, for example, Patent Document 11 or 12).

[0004] However, a method for enhancing the anti-inflammatory action (anti-inflammatory action) of phenylpropionic acid anti-inflammatory drugs such as ibuprofen and reducing the side effects while reducing the bitter taste is still known. Wow!

 Patent Document 1: Japanese Patent Publication No. 64-8602

Patent Document 2: Japanese Patent Publication No. 1-24131 Patent Document 3: JP-A-5-148139

 Patent Document 4: JP-A-9-48728

 Patent Document 5: JP-A-7-188004

 Patent Document 6: JP-A-10-259130

 Patent Document 7: JP-A-11-12187

 Patent Document 8: Japanese Patent Laid-Open No. 11-158066

 Patent Document 9: Japanese Unexamined Patent Application Publication No. 2006-920

 Patent Document 10: Japanese Patent Application Laid-Open No. 2004-59579

 Patent Document 11: Japanese Patent Laid-Open No. 2000-273037

 Patent Document 12: Japanese Patent Laid-Open No. 2001-106639

 Disclosure of the invention

 Problems to be solved by the invention

[0005] An object of the present invention is to provide an anti-inflammatory analgesic oral pharmaceutical composition in which the anti-inflammatory action (anti-inflammatory action) of a phenylpropionic acid anti-inflammatory drug is enhanced. In particular, an object of the present invention is to provide an oral pharmaceutical composition for anti-inflammatory analgesia in which side effects are reduced by enhancing the anti-inflammatory action (anti-inflammatory action) of a phenylpropionic anti-inflammatory analgesic. To do. In addition, the present invention provides a method for solving the problem of a phenolpropionic acid-type anti-inflammatory analgesic having a bitter taste while simultaneously enhancing the anti-inflammatory action and reducing the bitter taste.

[0006] The inventors of the present invention have intensively studied to solve the above-mentioned problems. As a result, phenylpropionic acid-based compounds are obtained by using darcosamine hydrochloride in combination with a phenolpropionic acid-based anti-inflammatory analgesic such as ibuprofen. It was found that the anti-inflammatory action of anti-inflammatory analgesics is enhanced, and that the anti-inflammatory action is further enhanced by using chondroitin sulfate in combination with this. In addition, the present inventors have not only enhanced the anti-inflammatory effect by using dalcosamine hydrochloride or dalcosamine hydrochloride and chondroitin sulfate in combination with a phenylpropionic acid anti-inflammatory analgesic, but at the same time, the phenylpropionic acid anti-inflammatory agent. It was found that an oral preparation which can significantly mask the bitter taste of analgesics and is easy to take can be prepared. [0007] The present invention has been developed on the basis of strong knowledge and has the following aspects:

 Item 1. An anti-inflammatory analgesic oral pharmaceutical composition comprising (a) a phenylpropionic acid anti-inflammatory analgesic and (b) darcosamine, a derivative thereof, or a salt thereof.

 Item 2. The oral pharmaceutical composition for anti-inflammatory analgesia according to Item 1, further comprising (c) chondroitin, chondroitin sulfate or a salt thereof.

 Item 3. Item 1 or 2 containing (b) darcosamine, a derivative thereof or a salt thereof in an amount of 0.001 to 5000 parts by weight per 1 part by weight of (a) a phenylpropionic acid anti-inflammatory analgesic Oral pharmaceutical composition for anti-inflammatory analgesia described in 1.

 Item 4. The method according to Item 2 or 3, comprising (c) chondroitin, chondroitin sulfate or a salt thereof in a ratio of 0.0001 to 5 parts by weight with respect to 1 part by weight of the (a) phenylpropionic acid anti-inflammatory analgesic. Oral pharmaceutical composition for anti-inflammatory analgesia.

 Item 5. (a) The oral pharmaceutical composition for anti-inflammatory analgesia according to any one of Items 1 to 4, wherein the phenol-propionic acid anti-inflammatory agent is ibuprofen.

[0008] Item 6. Phenylpropionic acid anti-inflammatory analgesics having a bitter taste include (b) darcosamine, a derivative thereof or a salt thereof, or (b) darcosamine, a derivative thereof or a salt thereof and (c) chondroitin, chondroitin A method for reducing the bitter taste of the phenylpropionic acid anti-inflammatory analgesic, characterized by using sulfuric acid or a salt thereof together.

 Item 7. The method of reducing bitterness according to Item 6, which is ibuprofen, a phenol propionic acid anti-inflammatory agent.

 The invention's effect

[0009] According to the oral antiphlogistic analgesic composition of the present invention, (a) furpropionic acid antiphlogistic analgesic includes (b) darcosamine, a dalcosamine derivative or a salt thereof, or (b) darcosamine, dalcosamine. The combined use of (c) chondroitin, chondroitin sulfate or its salt with a derivative or salt thereof significantly enhances the anti-inflammatory action inherent in furpropionic acid-based anti-inflammatory analgesics. The effective amount of the propionic acid-type anti-inflammatory analgesic can be reduced, and as a result, an excellent anti-inflammatory effect can be exerted using a small amount of a phenol propionic acid-type anti-inflammatory analgesic. For this reason, it has been a problem that Side effects (gastrointestinal disorders) of lupropionic acid anti-inflammatory analgesics can be reduced.

 [0010] Ibuprofen is an excellent antiphlogistic of peripheral joints such as joints, among the propylene acid antiphlogistic analgesics. For this reason, the anti-inflammatory analgesic oral pharmaceutical composition of the present invention containing ibuprofen as an active ingredient is an anti-inflammatory analgesic (internal use) for arthritis, tendonitis, or stiff shoulder with inflammation, joint pain, low back pain or neuralgia. Useful.

 [0011] Furthermore, the oral pharmaceutical composition for anti-inflammatory analgesia of the present invention comprises (a) a furpropionic acid-based anti-inflammatory analgesic, (b) darcosamine, a dalcosamine derivative or a salt thereof, or (b) darcosamine, a dalcosamine derivative. Alternatively, the bitterness of a phenol-propionic acid anti-inflammatory analgesic is masked by using the salt in combination with (c) chondroitin, chondroitin sulfate, or a salt thereof. it can.

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0012] L ^ m ma .m%

 The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention comprises (a) a phenylpropionic acid-based anti-inflammatory analgesic

(Hereinafter also referred to as “component (a)”) and (b) darcosamine, a derivative thereof or a salt thereof (hereinafter collectively referred to as “darcosamines”) This is a feature.

 [0013] By using the above-described darcosamines in combination with a phenol-propionic acid-type anti-inflammatory analgesic, the anti-inflammatory action of the phenyl-propionic acid-type anti-inflammatory analgesic is synergistically enhanced and has an excellent anti-inflammatory effect. In addition to being able to exert this effect, the bitterness of the phenol propionic acid anti-inflammatory analgesic is reduced, and an internal preparation that is easy to take can be obtained.

 [0014] (a) Phenylpropionic acid anti-inflammatory analgesic

In the present invention, phenylpropionic acid anti-inflammatory analgesic means a drug having an antiphlogistic action, analgesic action or Z and antipyretic action having phenylpropionic acid skeleton, for example, aluminoprofen, ibuprofen. , Ketoprofen, oxaprozin, zaltoprofen, thiaprofenic acid, nabumetone, naproxen, fenoprofen (calcium salt), pranoprofen, flurbiprofen or loxoprofen (sodium salt). These can be used alone or in any combination of two or more. Preferably, flurbiprofen, ketoprofen, ibuprofen, planop Oral phen, more preferably ibuprofen [a scientific name: 2- (4-isobutylphenol) propionic acid].

 These components may be formulated as hydrates or solvates. For example, loxoprofen can be used as loxoprofen sodium dihydrate.

 [0016] The ratio of the (a) phenylpropionic antiphlogistic analgesic contained in the antiphlogistic analgesic oral pharmaceutical composition is not limited, but usually, per day of the oral antiphlogistic analgesic oral pharmaceutical composition. (A) Component strength Sl is preferably 0 to 2000 mg, more preferably 100 to 1000 mg, more preferably 150 to 600 mg. In order to be within this range, the content of component (a) in 100% by weight of the anti-inflammatory analgesic oral pharmaceutical composition is 0.1 to 99.9% by weight, preferably 0.2 to 90% by weight. It can adjust suitably from a range.

 [0017] (b) Glucosamine Street

 Darcosamines are, for example, monosaccharides constituting chitin contained in shells of shellfish such as salmon, shrimp or salmon, or cartilage cartilage, and chitosan obtained by hydrolyzing chitin with an acid such as concentrated hydrochloric acid.

 [0018] In the present invention, in addition to being used as darcosamine, it can also be used in the form of its derivative. Derived darcosamine derivatives that have been confirmed in nature include acylated derivatives such as N-acetylated derivatives, sulfated derivatives such as N-sulfated derivatives and O-sulfated derivatives, N-glycolyl derivatives, etc. And glycolyl lysate derivatives thereof. N-Acetyldarcosamine is preferred.

[0019] These darcosamines or derivatives thereof can also be used in the form of pharmacologically (pharmaceutically) or physiologically acceptable salts. Examples of strong salts include lactate, acetate, butyrate, trifluoroacetate, fumarate, maleate, tartrate, succinate, succinate, malonate, methanesulfonate, Examples thereof include organic acid salts such as toluenesulfonate, tosylate, bartiminate and stearate; inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide and phosphate. Preferred examples of the salt of darcosamine include darcosamine hydrochloride and darcosamine sulfate, more preferably darcosamine hydrochloride. The salt of darcosamine may be D, L, or DL. These can be used individually by 1 type or in combination of 2 or more types. [0020] In the present invention, darcosamine hydrochloride is preferably darcosamine hydrochloride.

 [0021] The ratio of darcosamines contained in the oral pharmaceutical composition for anti-inflammatory analgesia is not particularly limited, but usually 1 to 3000 mg of dalcosamines is administered per day of the oral pharmaceutical composition for anti-inflammatory analgesia. Preferably 40 to: It is desirable that it is contained in such a ratio that it becomes LOOOmg. The content ratio of darcosamines in 100% by weight of the anti-inflammatory analgesic oral pharmaceutical composition is suitably adjusted within the range of 0.1 to 99.9% by weight, preferably 5 to 90% by weight. can do.

 [0022] As a suitable ratio of darcosamines that enhance the anti-inflammatory action of the phenylpropionic acid-based anti-inflammatory analgesic [component (a)], 0.001 to 5000 parts by weight relative to 1 part by weight of component (a), Preferably 0.1 to 500 parts by weight, more preferably 1 to 500 parts by weight can be mentioned. Among them, the ratio of suitable darcosamines that enhance the anti-inflammatory action of the component (a) and mask its bitterness is 0.01 to 5000 parts by weight, preferably 0.1 to 1 part by weight of the component (a). -50 parts by weight, more preferably 0.1-3 parts by weight.

 [0023] In addition, the oral pharmaceutical composition for anti-inflammatory analgesia of the present invention comprises (a) a ferpropionic acid-type anti-inflammatory analgesic and (b) darcosamines, and (c) chondroitin or chondroitin. Sulfuric acid or a salt thereof (hereinafter collectively referred to as “chondroitins”) can be blended.

 [0024] (c) Chondroitin Street

 Chondroitins can be extracted from the cartilage strength of fish such as sharks and mammals such as cows, regardless of their origin, but they are derived from fish from the viewpoint of safety.

 [0025] Here, the salt of chondroitin sulfate may be any salt that is pharmacologically (pharmaceutical) or physiologically acceptable, and is usually an alkali metal salt such as sodium salt or potassium salt, calcium salt. Examples thereof include alkaline earth metal salts such as salts, and aluminum salts. These can be used alone or in any combination of two or more. The sodium salt is preferred.

In the present invention, chondroitin is preferably sodium chondroitin sulfate. [0027] The ratio of chondroitin contained in the antiphlogistic analgesic oral pharmaceutical composition is not particularly limited, but usually, chondroitin caustic agent per day administration of the antiphlogistic analgesic oral pharmaceutical composition. ~ 2000mg, preferably 0.1 ~: It is desirable to be included in harm ij such as LOOOmg! /. So that this range, appropriate content of chondroitin acids in 100 wt% for the oral pharmaceutical composition antiinflammatory, 0.000002 to 85 weight _^0/0, preferably also range force of 0.0001 to 6 5 wt% Can be adjusted.

 [0028] As a suitable proportion of chondroitin that enhances the anti-inflammatory action of the phenylpropionic acid-type anti-inflammatory analgesic [component (a)] together with darcosamines, 0.001 part by weight of component (a) Up to 5 parts by weight, preferably <0.005 to 2 parts by weight, and more preferably <0.005 to 1 part by weight can be mentioned. In addition, the anti-inflammatory effect of component (a) is enhanced together with darcosamines, and at the same time, the ratio of suitable chondroitins masking the bitter taste of component (a) is 0.0001-5 parts per 1 part by weight of component (a). Part by weight, preferably from 0.0005 to 2 parts by weight, more preferably from 0.0005 to 1 part by weight.

 [0029] The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention comprises (b) darcosamines or (b) darcosamines and (c) chondroitin in addition to the above-mentioned (a) phenylpropionic anti-inflammatory analgesics. However, if it does not adversely affect the anti-inflammatory effect and bitterness-reducing effect of the present invention, other medicinal components such as medicinal components used in anti-inflammatory, analgesic or antipyretic applications It does not limit the presence or absence of blending.

[0030] More specifically, vitamins (lipid-soluble vitamins such as vitamins A, D, E, K, U; water-soluble vitamins such as vitamins B, C, P); antipyretic 'analgesic' anti-inflammatory drugs (Pyrine antipyretic analgesics such as sulpyrine; salicylic acid drugs such as sodium salicylate, aspirin, ethenzamide, salicylamide, and sazapyrine; alin drugs such as acetaminophen; ), Allylic acetates such as diclofenac sodium and indomethacin, pyrazolidines such as phenylbutazone and oxyphenylbutazone, pyrimidines such as bucolome, talented xycams such as piroxicam, isopropylantipyrine, etc.); antihistamine Drugs (clemastine fumarate, diphenhydramine hydrochloride, maleic acid Rufue - lamin, etc.); antitussives (e.g., Kodin phosphoric acid, phosphoric acid di Hidorokodin, Cloperastine, dextromethorphan, etc. benzonatate); expectorant ( For example, bromhexine hydrochloride); mucosal solution such as L-cystine hydrochloride, L-methylcystine hydrochloride, and acetyl cysteine; mucus repairing agents such as carbocystine; hypnotic sedatives such as gallysopropylpyrucetyl urea; tranexamic acid, etc. Antiplasmin agents; mucosal lubricants such as ambroxol hydrochloride; bronchodilators or asthma drugs (e.g. jew ephedrine, ephedrine hydrochloride, methylephedrine hydrochloride, terbutaline hydrochloride, isoproterenol, salbutamol, terbutaline) Theo

 2

 And xanthine drugs such as fylline, aminophylline, and proxyphylline, cromoglycic acid, etc.); caffeine; antacid; amino acids; These medicinal ingredients can be used alone or in combination of two or more.

 [0031] The dosage form of the anti-inflammatory analgesic oral pharmaceutical composition of the present invention is not particularly limited as long as it has an oral dosage form. For example, orally administered solid preparations such as powders, tablets, granules, pills, capsules (soft capsules, hard capsules), troches, chewable tablets and dry syrups; or solutions, suspensions and syrups, etc. Orally administered liquid formulation. Further, it may have a pharmaceutical form in which the release of medicinal ingredients is controlled (for example, immediate release preparation, sustained release preparation, etc.). Formulations having a robust dosage form can be prepared according to conventional methods in the art.

 [0032] The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention is formulated into various oral dosage forms as described above, and for its stability, various carriers that are pharmaceutically acceptable for oral administration and supplementary carotenants. (For example, refer to the Pharmacopeia or the “Pharmaceutical Additives Encyclopedia” (published by the Pharmaceutical Affairs Daily)).

 [0033] Carriers or additives for oral administration include lactose, sucrose, glucose, mannitol, sorbitol, corn starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, talc Excipients such as starch, OC

—Binders such as starch, agar, gelatin, gum arabic, dextrin, methylcellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose or its salts, crystalline cellulose; calcium carbonate, crospovidone, starch, Disintegration of carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethyl starch, etc. Agents: Lubricants such as magnesium stearate, talc, polyethylene glycol, and anhydrous carboxylic acid; Suspending agents such as polysorbate 80, polyoxyethylene hydrogenated castor oil, and pull nick; white sugar, talc, precipitated calcium carbonate, gelatin And coating agents such as gum arabic, pullulan, strength lunauba wax and hydroxypropylmethyl phthalate; and flavoring agents such as sucrose, glucose, sodium saccharin, sorbitol, citrate, and aspartame. In addition to the above components, as long as the effects of the present invention are not impaired, stabilizers, emulsifiers, dispersants, fluidizing agents, buffering agents, wetting agents, surfactants, and the like, which are usually acceptable as pharmaceutical additives, Optional components such as thickeners, preservatives, pH adjusters, colorants, solvents, and solubilizers can be added as desired.

 [0034] The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention can be prepared and administered as the aforementioned solid or liquid oral preparation (internal preparation). The dose of the anti-inflammatory analgesic oral pharmaceutical composition of the present invention depends on the patient's age, sex, degree of symptoms to be treated, and administration method, and is contained in (a) phenyl. Examples of the propionic acid-based anti-inflammatory analgesic dose power per adult can be 0 to 2000 mg, preferably 100 to 1000 mg, more preferably 150 to 600 mg. Within this dosage range, the dosage can be divided into 1 to several times a day.

 [0035] The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention can be preferably used for the purpose of suppressing inflammation. In addition to the anti-inflammatory action, the ferulpropionic acid anti-inflammatory analgesic, which is an active ingredient, has both an analgesic action and an antipyretic action. It can also be used for the purpose of suppressing palliative (analgesic) fever (antipyretic).

 [0036] The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention, particularly the oral pharmaceutical composition for anti-inflammatory analgesia containing ibuprofen as a phenylpropionic acid-based anti-inflammatory analgesic, is a joint with arthritis, tendonitis or inflammation. It can be suitably used for the purpose of improving (anti-inflammatory) or analgesic peripheral inflammation such as pain, low back pain, neuralgia, muscle pain or stiff shoulders.

[0037] The oral pharmaceutical composition for anti-inflammatory analgesia of the present invention comprises (a) a phenylpropionic acid-based anti-inflammatory analgesic, wherein (b) darcosamine or (b) darcosamine and (c) chondroitin described above When used in combination, the anti-inflammatory action of the phenylpropionic acid anti-inflammatory analgesic is enhanced, and an excellent anti-inflammatory action can be exerted in a small amount. For this reason, It is possible to avoid the occurrence of side effects such as gastrointestinal disorders, which have been a problem with on-acid anti-inflammatory analgesics, and can also be used as a preferred anti-inflammatory analgesic in terms of efficacy and side effects.

 [0038] Further, the oral pharmaceutical composition for anti-inflammatory analgesia of the present invention comprises (a) a phenylpropionic acid anti-inflammatory analgesic, wherein (b) darcosamine, or (b) darcosamine and (c) chondroitin described above are used. By using in combination, the bitter taste of phenylpropionic acid anti-inflammatory analgesics is reduced, so that it can be provided as an easily taken oral preparation.

 [0039] II. Method for reducing taste of phenylpropionic acid anti-inflammatory analgesic

 According to the method of the present invention, (a) a phenylpropionic acid anti-inflammatory analgesic is used by combining (b) darcosamines described above or (b) darcosamines and (c) chondroitins. Can be implemented.

 [0040] Examples of the target phenylpropionic anti-inflammatory analgesics include the drugs described in (I) above and having a bitter taste. Preferred are ibuprofen, ketoprofen and pranoprofen, and more preferred is ibuprofen.

 [0041] (b) The darcosamines used in combination with the phenpropionic acid-type anti-inflammatory analgesic include the dalcosamines and dalcosamine derivatives (preferably N-acetyldarcosamine) described in (I) above or the like. Can be mentioned. Preferred is a pharmaceutically acceptable salt of darcosamine, preferably darcosamine hydrochloride or dalcosamine sulfate, more preferably darcosamine hydrochloride.

[0042] The ratio of the darcosamines used in combination with a phenolpropionic anti-inflammatory analgesic is that the propylene-based anti-inflammatory analgesia without adversely affecting the anti-inflammatory effect enhanced by the combined use of both. There is no particular limitation as long as the bitterness of the drug can be reduced. For example, as a use ratio of darcosamines to 1 part by weight of a phenylpropionic acid type anti-inflammatory analgesic, a range force of usually 0.01 to 5000 parts by weight can be appropriately selected. The range is preferably 0.1 to 50 parts by weight, more preferably 0.1 to 3 parts by weight.

[0043] Further, (c) chondroitin used in combination with (a) a phenolpropionic anti-inflammatory analgesic and (b) darcosamines include chondroitin and chondroxin described in (I) above. A reuterine sulfate or its salt can be mentioned. Preferred is a pharmaceutically acceptable salt of chondroitin sulfate, and more preferred is sodium chondroitin sulfate.

 [0044] The proportion of chondroitin used in combination with a ferropropionic acid-type anti-inflammatory analgesic and darcosamines is such that there is no adverse effect on the anti-inflammatory effect enhanced by the combined use of the three components. There is no particular limitation as long as it can reduce the bitter taste of propionic acid anti-inflammatory analgesics. For example, as a use ratio of chondroitin to 1 part by weight of a phenol propionic acid type anti-inflammatory analgesic, a range force of usually 0.0001 to 5 parts by weight can be appropriately selected. The range is preferably 0.0005 to 2 parts by weight, more preferably 0.0005 to 1 part by weight.

 [0045] According to the method of the present invention, (a) a furpropionic acid anti-inflammatory drug is used in combination with (b) darcosamine or (b) darcosamine and (c) chondroitin as described above. By using these components, it is possible to mask and reduce the preferred bitterness of the phenylpropionic acid anti-inflammatory analgesic while maintaining the anti-inflammatory effect enhanced by the combined use of these components. Therefore, the present invention can be effectively used for preparing and providing an orally administered type anti-inflammatory analgesic having a good taste without bitterness.

 Example

 Hereinafter, the present invention will be described with reference to experimental examples and examples, but the present invention is not limited to these examples and the like.

[0047] Experimental Example 1

 Phenolpropionic acid anti-inflammatory analgesics are known as drugs that exert anti-inflammatory and antipyretic analgesic activity by inhibiting the production of inflammatory mediators such as prostaglandin E2 (PGE2). Therefore, ibuprofen was used as a phenylpropionic anti-inflammatory analgesic and the inhibition rate of PGE2 production against cultured cells was measured to evaluate the anti-inflammatory effect of the oral anti-inflammatory analgesic composition of the present invention (Chong-Jeh Lo et al. al., Journal of trauma, Vol. 45, No.l,

 1998, pp.19-24). Here, darcosamine hydrochloride was used as darcosamines, and sodium chondroitin sulfate was used as chondroitins.

[0048] Specifically, the mouse macrophage cell line RAW264 (RIKEN BioResource 0.2 g / mL in the presence of the test compositions listed in Table 1 (Comparative Examples 1-12, Examples 1-4) or in the absence of the test composition (control group). The culture supernatant was collected by incubating with a medium containing endotoxin (LPS) (MEM medium containing 10% fetal calf serum (FCS)) for 24 hours (stimulated with LPS). Next, the amount of PGE2 contained in the collected supernatant was measured by the absorbance method, and the amount was compared with the result of the control group to calculate the PGE2 production inhibition rate. The results are also shown in Table 1.

[0049] [Table 1]

 [0050] Fig. 1 shows a graph comparing the results of Comparative Examples 5 and 8 and Example 1; Fig. 2 shows a graph comparing the results of Comparative Examples 5, 8, 11 and 12 and Examples 1 and 2; and Comparative Example A graph comparing the results of Examples 2, 4, and 6 with Examples 3 and 4 is shown in FIG.

[0051] As shown in Figure 1, darcosamine hydrochloride 1 μg / mL alone (Comparative Example 8) has almost no inhibitory effect on PGE2 production, but it can be combined with ibuprofen 1 μg / mL. The effect of oral fen on PGE2 production was significantly improved (Example 1). In addition, as shown in FIG. 2, darcosamine hydrochloride 1 μg / mL (Comparative Example 8), chondroitin sulfate 1 μg / mL (ratio Comparative Example 11) and Darcosamine Hydrochloride 1 μg / mL + Sodium Chondroitin Sulfate 1 μg / mL (Comparative Example 12) can be combined with ibuprofen 1 μg / mL in spite of almost no inhibitory effect on PGE2 production. In addition, the inhibitory effect of ibuprofen on PGE2 production was significantly improved (Example 2). In particular, the combined use of ibuprofen, darcosamine hydrochloride, and sodium chondroitin sulfate (Example 2) further enhanced the inhibitory effect on PGE2 production compared to the combination of ibuprofen and dalcosamine hydrochloride (Example 1). The PGE2 production suppression rate approached 100%. From these results, it was clarified that the anti-inflammatory effect of ibuprofen is synergistically improved by combining ibuprofen with darcosamine hydrochloride or glucosamine hydrochloride and sodium chondroitin sulfate.

 [0052] In addition, as shown in Fig. 3, ibuprofen 0.1 μg / mL alone has a PGE2 production inhibition rate of 20% (Comparative Example 2), but this can be achieved by combining darcosamine hydrochloride 50 g / mL. (Example 3), ibuprofen 0.5 μg / mL alone (Comparative Example 4) has almost the same inhibitory effect on PGE2 production, and ibuprofen 0.1 μg / mL was added with darcosamine 500 g / mL. As a result of the combination (Example 4), it was revealed that the PGE2 production inhibitory effect almost equivalent to that of ibuprofen 10 μg / mL alone (Comparative Example 6) was obtained.

 [0053] From these, it is possible to significantly reduce the effective amount of ibuprofen by combining dalcosamine hydrochloride or dalcosamine hydrochloride and chondroitin sulfate sodium with ibuprofen, and as a result, side effects such as gastrointestinal disorders possessed by ibuprofen. It became clear that the occurrence can be prevented.

 [0054] Experimental Example 2

 In order to evaluate the anti-inflammatory effect on arthritis of the oral anti-inflammatory analgesic composition of the present invention, the following experiment was conducted.

[0055] <Method of experiment>

(1) Ficher344 male rats (5 weeks old) weighing approximately 100 g (Nihon SLC Co., Ltd.) were inoculated with dairy cattle bacteria as an adjuvant on the rear left foot to induce arthritis. Test composition daily from day 12 after inoculation [Comparative Example 13: ibuprofen (daily dose 30 mg / kg body weight), Example 5 (3-component combination): ibuprofen (daily dose 30 mg / kg body weight) + Darcosamine hydrochloride (daily dose 33.2mg / kg body weight) + chondroitin sulfate sodium (daily dose) 0.00264 mg / kg body weight)] was orally administered, and the foot volume of the left foot (adjuvant injured foot) was measured on the 10th and 15th day after administration. As a control, the foot volume of the left foot (adjuvant-inoculated foot) was measured in the same manner in the untreated group that was not treated after adjuvant inoculation.

[0056] From the foot volumes obtained for the test composition administration group and the untreated group, the edema rate and edema suppression rate were calculated according to the following formula (Eiichi Fujihira, “Rat-adjuvant disease for drug efficacy test” “Rheumatism” ,

 Vol. 8, 1968, p.14).

[0057] [Equation 1] Edema rate (%) = C (A-B) / B] x 100

 A: Foot volume after administration of test composition

 B: Foot volume before administration of test composition

[0058] [Equation 2] Edema suppression rate (%) = C (a-b) Z a] X 100

 a: Untreated group edema rate

 : Edema rate of test composition administration group

[0059] (2) Further, 15 days after administration of the test composition, the right limb (non-adjuvant was inoculated) was cut, and the severity of arthritis was confirmed by histopathological examination (number of specimens: 3).

[0060] <Result>

 (1) The results of evaluating the edema inhibition rate are shown in Table 2 and FIG.

[0061] [Table 2]

この結果から、イブプロフェン単独（比較例 13)よりも、イブプロフェンに塩酸ダルコサ ミンとコンドロイチン硫酸ナトリウムを併用することによって（実施例 5)、関節炎によつ て生じた浮腫を抑制する効果 (消炎効果)が顕著に増強することが明らかになった。 [0063] (2)病理組織学検査の結果 (所見）を表 3に示す。

From this result, it was found that the combination of ibuprofen with dalcosamine hydrochloride and sodium chondroitin sulfate (Example 5) suppresses edema caused by arthritis (anti-inflammatory effect) rather than ibuprofen alone (Comparative Example 13). Was found to be significantly enhanced. [0063] (2) Results of histopathological examination (findings) are shown in Table 3.

 In Table 3, the numbers indicate the number of applicable samples.

[0064] [Table 3]

 Severity:-: No change, +: Mild, ++: Moderate, +++: High

[0065] As can be seen from these results, the combination of ibuprofen with dalcosamine hydrochloride and sodium chondroitin sulfate (Example 5), compared with ibuprofen alone (Comparative Example 13), significantly reduced the symptoms of arthritis. It became clear.

 [0066] Experimental Example 3

 The bitterness-reducing effect of phencopropionic acid-type anti-inflammatory analgesics by the combination of darcosamines or dalcosamines and chondroitins is shown as darcosamine hydrochloride as dalcosamines, sodium chondroitin sulfate as chondroitins, and ibuprofen as an anti-inflammatory analgesic of ferulpropionic acid. Was used to evaluate.

 [0067] Specifically, each component described in Table 4 was formulated according to a general powder manufacturing method to prepare a powdery formulation (Comparative Examples 14-15, Examples 6-15). This was taken by a taste paneler consisting of 6 members (holding in the mouth for 10 seconds) and, according to the following evaluation criteria, (1) bitterness, (2) mouthfeel [feeling of irritation when taken ( The presence or absence of tingling) was scored. (3) The overall feeling of taking (comparison example 14 (ibuprofen lOOmg)) compared with the feeling of improving the feeling of taking was calculated by multiplying each person's points (1) and (2).

 [0068] <Evaluation criteria>

5 points: No bitterness

4 points: almost no bitterness 3 points: Slightly bitter

 2 points: bitter

 1 point: Strongly bitter.

[0069] (2) Mouth

 3 points: Very good taste

 2 points: Slightly good taste

 1 point: Neither.

[0070] (3) What

 The following criteria evaluated the effect of improving the feeling of administration when compared with Comparative Example 14 (Ibuprofen lOOmg):

 12 15 points: The feeling of taking is greatly improved

 9 Less than 12 points: The feeling of taking is considerably improved!

 6 Less than 9 points: Improved feeling

 3 Less than 6 points: Slightly improved feeling

 1 Less than 3 points: The feeling of taking is unchanged.

[0071] The results are also shown in Table 4. The results are shown as the average of 6 panelists.

[0072] [Table 4]

[0073] As shown in Table 4, by adding darcosamine hydrochloride to ibuprofen, the bitter taste of ibuprofen was significantly reduced. In particular, by adding 10 mg of darcosamine hydrochloride to lbumg of ibuprofen, all panelists feel almost no bitterness, and by adding glucosamine hydrochloride at a rate of 300 mg, all panelists do not feel bitterness completely. It was possible to mask the bitter taste of ibuprofen. Also darcosamine hydrochloride The bitter taste masking effect was enhanced by the combined use of chondroitin sodium sulfate.

 [0074] It was also confirmed that the mouthfeel was improved by adding darcosamine hydrochloride to ibuprofen and further using sodium chondroitin sulfate.

[0075] Example 16: Formulation of 6 tablets (daily dose)

 Ibuprofen 450 mg

 Darcosamine hydrochloride 500 mg

 Sodium chondroitin sulfate 0.4 mg

 Crystalline cellulose 100 mg

 Lactose appropriate amount

 Corn starch 300 mg.

 Example 17 Formulation Example of Granule (Daily Dose)

 Ibuprofen 450 mg

 Darcosamine hydrochloride 500 mg

 Sodium chondroitin sulfate 0.4 mg

 Dextrin 500 mg

 Corn starch 300 mg

 Xylitol 1000 mg

 Hydroxypropylcellulose 100 mg

 Fragrance A trace amount.

 Brief Description of Drawings

 [0077] [Fig. 1] In Experimental Example 1, Comparative Example 5 (ibuprofen 1 μg / mL), Comparative Example 8 (darcosamine hydrochloride 1 μg / mL), Example 1 (Ibuprofen 1 μg / mL) The graph which compared the PGE2 production inhibitory effect of mL + darcosamine hydrochloride 1 microgram / mL) is shown.

[Fig. 2] In Experimental Example 1, Comparative Example 5 (ibuprofen 1 μg / mL), Comparative Example 8 (Darcosamine hydrochloride 1 μg / mL), Comparative Example 11 (Sodium chondroitin sulfate 1 μg / mL), Comparison Example 12 (dalcosamine hydrochloride 1 _μg / mL + sodium chondroitin sulfate 1 μg / mL), Example 1 (Ibupu Fen 1 μg / mL + Darcosamine hydrochloride 1 μg / mL) and Example 2 (Ibuprofen 1 μ g 2 is a graph comparing the PGE2 production inhibitory action of (/ mL + darcosamine hydrochloride 1 μg / mL + chondroitin sulfate sodium 1 μg / mL).

 [Fig. 3] In Experimental Example 1, Comparative Example 2 (ibuprofen 0.1 g / mL), Comparative Example 4 (ibuprofen 1 μg / mL), Comparative Example 6 (ibuprofen 10 μg / mL), Example 3 ( The graph which compared the PGE2 production inhibitory effect of ibuprofen 0.1 microgram / mL + darcosamine hydrochloride 50 microgram / mL) and Example 4 (ibuprofen 0.1 microgram / mL + darcosamine hydrochloride 500 microgram / mL) is shown.

[Fig. 4] In Experimental Example 2, in Comparative Example 13 (ibuprofen (daily dosage 30 mg / kg body weight)) and Example 5 (ibuprofen (daily dosage 30 mg / kg body weight) + darcosamine hydrochloride (daily dosage) (33. 2 mg / kg body weight) + chondroitin sulfate sodium (daily dose 0.00264 mg / kg body weight)) is a graph comparing the edema-inhibiting action.

Claims

The scope of the claims  [1] An oral pharmaceutical composition for anti-inflammatory analgesia comprising (a) a phenylpropionic acid-type anti-inflammatory analgesic and (b) darcosamine, a derivative thereof, or a salt thereof. 2. The anti-inflammatory analgesic oral pharmaceutical composition according to claim 1, further comprising (c) chondroitin, chondroitin sulfate or a salt thereof. [3] (a) The present invention comprises (b) darcosamine, a derivative thereof or a salt thereof in a ratio of 0.001 to 5000 parts by weight with respect to 1 part by weight of (a) a phenylpropionic acid anti-inflammatory analgesic. 2. An oral pharmaceutical composition for anti-inflammatory analgesia described in 2. [4] (a) The phenylpropionic acid anti-inflammatory analgesic containing 1 part by weight of (c) chondroitin, chondroitin sulfate or a salt thereof in a ratio of 0.0001 to 5 parts by weight 3. An oral pharmaceutical composition for anti-inflammatory analgesia described in 3. [5] The oral pharmaceutical composition for anti-inflammatory analgesia according to any one of claims 1 to 4, which is (a) phenylpropionic acid-based anti-inflammatory analgesic power ibuprofen. [6] Phenolpropionic acid anti-inflammatory analgesics having a bitter taste include (b) darcosamine, a derivative thereof or a salt thereof, or (b) darcosamine, a derivative thereof or a salt thereof and (c) chondroitin, It is characterized by using chondroitin sulfate or a salt thereof together And a method for reducing the bitter taste of the furpropionic acid anti-inflammatory analgesic. [7] The method for reducing bitterness according to claim 6, wherein the propylene acid-based anti-inflammatory analgesic power is S ibuprofen.