JP2008247822A - Analgesic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an analgesic composition that enhances an analgesic action exhibited by a propionic acid-based analgesic such as ibuprofen etc., and has an excellent safety. <P>SOLUTION: The analgesic composition comprises a propionic acid-based analgesic and two or more kinds of vitamin Bs. The total amount of the vitamin Bs mixed is preferably 0.001-100 pts.wt. based on 1 pt.wt. of the propionic acid-based analgesic. The propionic acid-based analgesic is preferably ibuprofen and the vitamin Bs are preferably vitamin Bs containing at least vitamin B<SB>12</SB>or folic acid. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an analgesic composition comprising a propionic acid type analgesic such as ibuprofen.

  “Pain” is a sensation that occurs regardless of the presence or absence of tissue damage when there is a noxious stimulus from the outside or the living body is in a pathological state, but it is a very unpleasant sensation and an experience with unpleasant emotions. is there. Although it is important as a warning system of a living body, it causes a “vicious circle of pain”, so that an appropriate analgesic treatment is required. For such analgesic treatment, various anti-inflammatory agents and analgesics are used.

  Among them, ibuprofen classified as a propionic acid-based analgesic is one of the most widely used drugs worldwide as a non-steroidal anti-inflammatory, antipyretic and analgesic. The mechanism of action is the same as that. By inhibiting the action of okinase, it inhibits prostan synthesis and relieves inflammation and pain. Its action is said to be stronger than aspirin, and since it has a good balance of anti-inflammatory, analgesic and antipyretic effects, it is effective in calming the inflammation of the fever, pain, nose and throat associated with colds. It is also included in many cold medicines. Furthermore, it is known to be effective for rheumatic diseases, headache, low back pain, joint pain, neuralgia, tendonitis, menstrual pain and the like. However, its action is still mild, and since side effects on the gastric mucosa are known, it is difficult to say that it can be comfortably treated and is a component that is desired to be improved.

Conventionally, various combinations of ibuprofen and other components have been studied in order to improve the drug efficacy of ibuprofen. For example, Patent Documents 1 and 2 describe that an excellent analgesic action can be obtained by combining tranexamic acid with ibuprofen.
Japanese Patent Laid-Open No. 9-48728 JP 2005-187328 A

  However, the enhancement of the analgesic action of ibuprofen in combination with other components has not always been sufficient.

  In view of the above-mentioned present situation, an object of the present invention is to provide an analgesic composition that enhances the analgesic action exhibited by a propionic acid type analgesic such as ibuprofen and is excellent in safety.

  As a result of intensive studies, the present inventors have found that the analgesic action of the former is increased by using a propionic acid-based analgesic agent such as ibuprofen in combination with two or more vitamin Bs, and the present invention has been achieved. .

  That is, the present invention is an analgesic composition comprising a propionic acid type analgesic and two or more vitamin Bs.

In this invention, it is preferable that the compounding quantity of the said vitamin B is 0.001-100 weight part in total with respect to 1 weight part of the said propionic acid type analgesics. It is preferable that the propionate analgesic is ibuprofen, the vitamin B is preferably one containing at least vitamin B ₁₂ or folic acid.

  The analgesic composition of the present invention can enhance the analgesic action possessed by propionic acid type analgesics such as ibuprofen and is highly safe. Since the analgesic action is enhanced, the dose of the propionic acid type analgesic can be suppressed, and the side effects can be reduced.

  The present invention is described in detail below.

  The analgesic composition of the present invention contains at least a propionic acid type analgesic and two or more vitamin Bs. In the present invention, the combined use of two or more types of vitamin B enhances the analgesic action of the propionic acid type analgesic.

  Propionic acid-based analgesics are drugs belonging to propionic acids, specifically phenylpropionic acids, among non-steroidal analgesics. Although not particularly limited, for example, ibuprofen, aluminoprofen, ketoprofen, flurbiprofen, zaltoprofen, naproxen, pranoprofen, loxoprofen sodium, oxaprozin, thiaprofenic acid, nabumetone, naproxen, fenoprofen calcium and the like can be mentioned. These may be used alone or in combination of two or more. Of these, ibuprofen is preferred.

  In formulating the analgesic composition of the present invention, the dose of the propionic acid-based analgesic is not particularly limited as long as it has a medicinal effect, but the dose of the propionic acid-based analgesic in the known analgesic composition and It may be similar. For example, the dose per adult with a body weight of 60 kg is about 60 to 3210 mg / day, preferably 60 to 1800 mg / day, more preferably 60 to 600 mg / day, still more preferably 100 to 450 mg / day. is there. In addition, since the present invention enhances the drug efficacy by the combined use with two or more kinds of vitamin Bs, it is also possible to suppress the dose of the propionic acid type analgesic. This can reduce the side effects of propionic acid-based analgesics such as adverse effects on the gastric mucosa, rash, asthma, decreased liver and kidney functions, and shock symptoms.

Vitamin B is a nutrient that is classified as a water-soluble vitamin and has no known side effects or contraindications. Therefore, the analgesic composition of the present invention is extremely safe. No particular limitation is imposed on the vitamin B, e.g., vitamin B _1, vitamin B _2, vitamin B _6, vitamin B _12, folic acid, niacin, biotin, or the like pantothenic acid.

Vitamin B ₁ is not particularly limited, and examples thereof include thiamine hydrochloride, thiamine sulfate, bisthiamine nitrate, thiamine disulfide, and thiamine dicetyl sulfate.

Vitamin B ₂ is not particularly limited, and examples thereof include riboflavin, riboflavin butyrate, and sodium riboflavin phosphate.

Vitamin B ₆ is not particularly limited, and examples thereof include pyridoxine hydrochloride and pyridoxal phosphate.

Vitamin B ₁₂ is a water-soluble vitamin having a structure containing cobalt ions in the choline ring. The vitamin B _12, cyanocobalamin depending on the type of ligand to cobalt ions, hydroxocobalamin, adenosyl cobalamin, methylcobalamin, Akokobaramin, nitrilase Toco rose Min, although sulfite cobalamin like that are known to exist, the Any form can be used in the invention. It can also be used organic or inorganic salts of these compounds as a vitamin B _12. Preferred are cyanocobalamin, methylcobalamin (mecobalamin), hydroxocobalamin acetate, and hydroxocobalamin hydrochloride.

  Folic acid is a member of the water-soluble vitamin B group and is pteroylglutamic acid.

  Niacin is not particularly limited, and examples thereof include nicotinic acid and nicotinamide.

  Although it does not specifically limit as pantothenic acid, For example, pantenol, calcium pantothenate, sodium pantothenate etc. are mentioned.

These blending amounts are not limited as long as the effects of the present invention are exhibited. For example, the dosage per adult with a body weight of 60 kg is 1 to 60 mg / day for vitamin B ₁ and vitamin B ₂ for 1~60mg / day, vitamin B ₆ is 0.5~120mg / day, vitamin B ₁₂ is 0.025~1500mg / day, folic acid 1~2000mg / day, niacin is 1~60mg / day, biotin 10μg~ 15 mg / day and pantothenic acid is 1-60 mg / day.

  In the present invention, at least two of these vitamin Bs are used in combination. Only two types may be used, three types may be used, or more than that. The total amount of vitamin Bs in the analgesic composition of the present invention is not particularly limited. For example, the dose per adult with a body weight of 60 kg is 1 to 3500 mg / day.

  The blending ratio of vitamin Bs in the analgesic composition of the present invention is preferably in the range of, for example, 0.001 to 100 parts by weight in total when the total blending amount of the propionic acid-based analgesic is 1 part by weight. The range of 0.002 to 40 parts by weight is more preferable, and the range of 0.004 to 25 parts by weight is more preferable. Within these ranges, the efficacy of the propionic acid-based analgesic can be preferably enhanced.

In this invention, there exists an effect by mix | blending in combination of 2 or more types of vitamin Bs. Preferably, at least vitamin B ₁₂ or folic acid is blended, and more preferably, at least vitamin B ₁₂ and folic acid are blended. Thereby, the medicinal effect of the propionic acid type analgesic can be enhanced more strongly. In this case, another vitamin B (at least one selected from the group consisting of vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , niacin, biotin, and pantothenic acid) may be used in combination.

When vitamin B ₁₂ is blended as vitamin B, the blending ratio of vitamin B ₁₂ and propionic acid-based analgesic is not particularly limited, but vitamin B ₁₂ is, for example, 0 per 1 part by weight of propionic acid-based analgesic. The range is preferably 0.0006 to 5 parts by weight, more preferably 0.00011 to 3.5 parts by weight, still more preferably 0.001 to 3.5 parts by weight, and 1 to 3.5 parts by weight. A range is particularly preferred. If it is in this range, the medicinal effect of the propionic acid type analgesic can be preferably enhanced.

Further, when formulating a combination of a vitamin B ₁₂ and folic acid, the mixing ratio is not particularly limited with respect to folic acid 1 part by weight, the vitamin B _12, for example, in the range of 0.0000125 to 1500 parts by weight Preferably, the range is 0.0125 to 500 parts by weight, more preferably 0.0125 to 50 parts by weight, still more preferably 0.5 to 10 parts by weight, and 0.5 to 5 parts by weight. Part ranges are particularly preferred. If it is in this range, the medicinal effect of the propionic acid type analgesic can be preferably enhanced.

  The analgesic composition of the present invention may contain a vitamin group other than vitamin Bs. Examples of such vitamin groups include vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, and the like.

  Although it does not specifically limit as vitamin A, For example, retinol acetate, retinol palmitate, vitamin A oil, liver oil, strong liver oil, etc. are mentioned.

  Although it does not specifically limit as vitamin C, For example, ascorbic acid, calcium ascorbate, sodium ascorbate etc. are mentioned.

  Although it does not specifically limit as vitamin D, For example, ergocalciferol, cholecalciferol, etc. are mentioned.

  Although not particularly limited as vitamin E, for example, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, Examples thereof include d-α-tocopherol and dl-α-tocopherol.

  These vitamins may be used alone or in combination of two or more. These compounding amounts are not limited as long as the effects of the present invention are exhibited. For example, vitamin A is administered to an adult with a body weight of 60 kg, vitamin A is 250 to 5000 IU / day in international units, vitamin C Is 50 to 3000 mg / day, vitamin D is an international unit, 50 to 500 IU / day, vitamin E is 10 to 500 mg / day, and vitamin K is 30 μg to 50 mg / day.

  You may mix | blend the following chemical | medical agents with the analgesic composition of this invention. Antipyretic analgesics such as acetaminophen, aspirin, isopropylantipyrine, etezamide; ephedrine hydrochloride, dl-methylephedrine hydrochloride, noscapine, bromhexine hydrochloride, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, tipepidine hydrobenzoate, Antitussives such as dimemorphan phosphate; expectorants such as potassium guaiacol sulfonate, guaifenesin and ammonium chloride; antihistamines such as clemastine fumarate, chlorpheniramine maleate, diphenhydramine hydrochloride and mequitazine; nasal secretion inhibitors such as isopropamide iodide; Anti-inflammatory enzymes such as lysozyme; anti-inflammatory agents such as glycyrrhetinic acid and glycyrrhizic acid; peony extract, mao extract, nantenjitsu extract, prawn extract, kang Herbal medicines such as cucumber extract, fennel extract, fennel extract, cabbage extract, cinnamon extract, gentian extract, burdock extract, ginger extract, clove extract, peanut extract, ground dragon extract, chikutsujinjin extract, extract carrot extract; isoleucine, phenylalanine, cysteine Amino acids such as bromvalerylurea, allylisopropylacetylurea, etc .; Analgesic / drowsiness removers such as caffeine and anhydrous caffeine; stomachs such as dry aluminum hydroxide gel, magnesium oxide, magnesium aluminate metasilicate, magnesium carbonate, etc. Mucopolysaccharides such as mucosal protective agents and sodium chondroitin sulfate.

  The route for administering the analgesic composition of the present invention is not particularly limited, but oral administration, sublingual administration, rectal administration, transdermal administration, inhalation, topical administration, injection (intraarterial, intravenous, intramuscular, subcutaneous) , Intradermal, intrathecal, etc.), and oral administration and rectal administration (suppository) are preferred.

  Examples of the dosage form for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as syrups. These preparations can be prepared by conventional methods.

  In the case of a solid preparation, a coating such as a sugar coating or a film coat can be applied. The film coat can enhance stability and the like while considering ease of taking. In this case, a polymer such as hydroxypropylmethylcellulose or macrogol and a powder component such as titanium oxide or talc mixed in a solvent can be used as a film coating agent, and carnauba wax, palm wax, paraffin wax, etc. can be used as a lubricant. . In the present invention, it is preferable to use a combination of water and one or more alcohols as the solvent, and it is more preferable to contain alcohols in a proportion of 50% by weight or more in the solvent. More preferably, it is contained in a proportion by weight. Ethanol is preferred as the alcohol. The coating method is not particularly limited, but spray coating is a particularly preferable method. Thereby, the formulation stability of the analgesic composition of the present invention can be enhanced.

  Ingredients that can be used to prepare the solid preparation include, for example, excipients such as lactose, starch, mannitol, crystalline cellulose, crospovidone; binders such as hydroxypropylcellulose, carboxymethylcellulose, gelatin, sodium carboxymethylcellulose, gum arabic Disintegrating agents such as carboxymethylcellulose calcium, polyvinylpyrrolidone or a crosslinked product thereof, and low-substituted hydroxypropylcellulose; nonionic surfactants such as sucrose fatty acid ester and polyoxysorbitan fatty acid ester; calcium stearate, magnesium stearate, dimethylpolysiloxane , Lubricants such as talc, polyethylene glycol, hydrogenated oil, tar colorants, colorants such as copper chlorophyllin sodium, xylitol, sodium saccharin, asthma Sweetening agents such as Rutemu like. If necessary, coating may be performed using a coating agent such as hydroxypropylmethylcellulose, Eudragit, polyethylene glycol, shellac, methylcellulose, ethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose phthalate, sucrose, Sugar coating may be performed using rubber, calcium carbonate, talc, gelatin or the like.

  Ingredients that can be used for liquid formulation include, for example, purified water, glycerin, sucrose, propylene glycol, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, aluminum meta-hydroxide, agar, tragacanth gum , Solubilizing agents such as ethanol, buffering agents such as phosphates, preservatives such as sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, fragrances, colorants, D-sorbitol, sucrose, etc. And thickeners such as xanthan gum.

  The analgesic composition of the present invention may be a compounding agent or a kit comprising two or more drugs.

  Furthermore, the analgesic composition of the present invention may be filled in a light-shielding packaging material such as aluminum, or may be filled with nitrogen.

  The analgesic composition of the present invention can be used to reduce or eliminate physical pain. Such physical pain may be accompanied by exogenous chemical stimulation, may be caused by inflammation, or may not be caused by inflammation. Examples of pain that can be treated with the analgesic composition of the present invention include neuralgia, joint pain, back pain, muscle pain, stiff shoulder pain, fracture pain, bruise pain, sprain pain, trauma pain, headache, toothache, after extraction or Pain after operation, sore throat, ear pain, menstrual pain, gout, pain in rheumatic diseases, pain associated with inflammation, and the like. Neuralgia, joint pain, low back pain, menstrual pain, and pain associated with inflammation are preferred. Moreover, in addition to analgesia, it can also be used for the purpose of performing anti-inflammation (anti-inflammatory) and / or antipyretic at the time of fever.

  In addition to the above, pain that can be suitably treated with the analgesic composition of the present invention is pain caused by a pain substance generated in the body due to an external disorder, such as low back pain, muscle pain, and stiff shoulder pain. Fracture pain, bruise pain, sprain pain, trauma pain, pain after tooth extraction or surgery, sore throat, ear pain, muscle pain, fracture pain, bruise pain, sprain pain, trauma pain are more preferable.

  In addition, since it has been confirmed that ibuprofen is effective for the following diseases or symptoms, it can be similarly applied when ibuprofen is used in the analgesic composition of the present invention: (1) Disease extinguishing / analgesic: rheumatoid arthritis, arthralgia / arthritis, neuralgia / neuritis, dorsal low back pain, cervical shoulder syndrome, upper respiratory tract inflammation (pharyngitis, laryngitis), uterine adnexitis, dysmenorrhea, erythema (nodule) Erythema, polymorphic exudative erythema, efferent annular erythema). (2) Anti-inflammatory / analgesic after surgery or trauma. (3) Fever and analgesia of acute upper respiratory tract inflammation.

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
Examples 1-12 and Comparative Examples 1-4
An analgesic test by the acetic acid rising method was performed as follows.

  As a test animal, a mouse which was grown to about 30 g after being acclimated to a male mouse (ddy, SPF) of about 25 g at 5 weeks of age was used. On the day before the test, each mouse was fasted.

  Each test substance was weighed as shown in Table 1 and turbid in 0.5 mL of 1% xanthan gum solution. In addition, the compounding quantity of each component in Table 1 is displayed with mg. Tranexamic acid used in Comparative Example 2 is known as a component that enhances the analgesic action of ibuprofen.

  The total amount of the resulting solution was orally administered to each group of 6 mice. However, 0.5 mL of 1% xanthan gum solution not containing the test substance was orally administered to the control group.

  45 minutes after the oral administration, a physiological saline solution containing 1% acetic acid was intraperitoneally injected at a rate of 0.1 mL with respect to 10 g of mouse body weight. The number of stretching (rising) performed for 15 minutes after 5 minutes from the intraperitoneal injection was counted.

According to the following formula, the reduction rate of the number of occurrences of rising in each group, that is, the analgesic effect was calculated. The results are shown in Table 1.
Analgesic effect (%) = (1−total number of risings in test group / total number of risings in control group) × 100

表１から明らかなように、プロピオン酸系鎮痛剤のみでは、その鎮痛効果は３割程度のものであった（比較例１）。更に従来プロピオン酸系鎮痛剤の効果を増強する成分として知られるトラネキサム酸との併用によっても、本試験系においては、同様に３割程度の鎮痛効果であり、格別向上されるということはなく、生物学的にみて同等の効果（有意差なし）であった（比較例２）。また、プロピオン酸系鎮痛剤にビタミンＢ類を１種のみ配合しても、プロピオン酸系鎮痛剤と同等の鎮痛効果を奏するのみであった（比較例３，４）。しかしながら、プロピオン酸系鎮痛剤にビタミンＢ類２種以上を組み合わせて投与した系では、生物学的に有意な差をもって、ライジングの発生回数が減少し、４割を超える優れた鎮痛効果を奏した（実施例１〜１２）。このように、プロピオン酸系鎮痛剤とビタミンＢ類２種以上を併用することにより、初めてその鎮痛作用が相乗的に向上されることが示された。トラネキサム酸など、従来の増強成分はその薬効上、他の薬剤との併用禁忌や副作用が知られるところ、それに比して非常に安全であるビタミンＢ類２種以上の組み合わせが、当該鎮痛剤増強効果を有することは驚くべきことである。

As is clear from Table 1, the propionic acid-based analgesic alone had an analgesic effect of about 30% (Comparative Example 1). Furthermore, even in combination with tranexamic acid known as a component that enhances the effect of a conventional propionic acid-based analgesic, in this test system, the analgesic effect is similarly about 30%, and it is not exceptionally improved. Biologically, it was equivalent (no significant difference) (Comparative Example 2). Moreover, even if only one vitamin B was added to the propionic acid-based analgesic agent, only an analgesic effect equivalent to that of the propionic acid-based analgesic agent was obtained (Comparative Examples 3 and 4). However, in the system in which two or more vitamin Bs were administered in combination with a propionic acid-based analgesic agent, the number of rises was reduced with a biologically significant difference, and an excellent analgesic effect exceeding 40% was achieved. (Examples 1-12). Thus, it was shown that the analgesic action is synergistically improved for the first time by using a propionic acid type analgesic and two or more vitamin Bs in combination. Conventional enhancement ingredients such as tranexamic acid are known to have contraindications and side effects in combination with other drugs due to their medicinal properties, but a combination of two or more vitamin Bs that are very safe compared to them is a potent analgesic It is surprising to have an effect.

Formulation Examples 1-23
Film coating agents were formulated according to the formulations described in Tables 2-4. Specifically, uncoated tablets were prepared by weighing other than hydroxypropylmethylcellulose, titanium oxide, carnauba wax and macrogol according to the prescription, adding water, kneading, granulating, drying and tableting. Further, a mixture of hydroxypropylmethylcellulose, titanium oxide and macrogol in a solvent was coated on the uncoated tablet by spray coating, and the surface was treated with carnauba wax to produce a film coating agent. As a solvent for hydroxypropylmethylcellulose, titanium oxide and macrogol, a water / ethanol mixture is used, and the mixing ratio (weight ratio) of water and ethanol is water: ethanol = 60: 40, 50:50, 25:75 and Four types of 5:95 were used.

処方例２４〜２６
表５に記載の処方に従って、定法により液体製剤の鎮痛剤を製造した。この場合、キサンタンガムにより液剤の粘度を高めることで、水に溶けにくい成分を分散させることが可能となった。

Formulation Examples 24-26
According to the formulation described in Table 5, a liquid preparation analgesic was produced by a conventional method. In this case, by increasing the viscosity of the liquid agent with xanthan gum, it becomes possible to disperse components that are hardly soluble in water.

処方例２７〜２９
表６に記載の処方に従って鎮痛剤を製造した。具体的には、処方に従って量りとり、水を加えて混練し、造粒し、乾燥して顆粒剤を製造した。

Formulation examples 27-29
Analgesics were prepared according to the formulation described in Table 6. Specifically, it was weighed according to the prescription, kneaded with water, granulated, and dried to produce granules.

Claims (4)

  An analgesic composition comprising a propionic acid type analgesic and two or more vitamin Bs.   The analgesic composition according to claim 1, wherein the amount of the vitamin B compound is 0.001 to 100 parts by weight in total with respect to 1 part by weight of the propionic acid type analgesic.   The analgesic composition according to claim 1 or 2, wherein the propionic analgesic is ibuprofen. The analgesic composition according to claim 1, wherein the vitamin B contains at least vitamin B ₁₂ or folic acid.