JP2008247823A - Analgesic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an analgesic composition that has a higher safety than that of a conventional one. <P>SOLUTION: The analgesic composition comprises vitamin B<SB>12</SB>as an active ingredient. The analgesic composition preferably further contains folic acid. The dose of vitamin B<SB>12</SB>is preferably 0.025-1,500 mg/day and the dose of folic acid is preferably 1-2,000 mg/day. Since vitamin B<SB>12</SB>known as a nutrient essential for an organism is used, the analgesic composition has high safety. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an analgesic composition.

  “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.

  Existing analgesics can be divided into two categories. One is narcotic analgesics such as morphine, codeine and dihydrocodeine, and the other is non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen.

On the other hand, Vitamin B ₁₂ is one of water-soluble vitamins that play an important role in hematopoiesis with folic acid. The daily intake required is very small and may be deficient in vegetarians and the elderly, but it is known that there are few side effects from overdose. Labeling as a nutritionally functional food is permitted because it is a nutrient that assists in the formation of red blood cells, and as a pharmaceutical (see, for example, Patent Document 1), it is used for the following symptoms.
1. Prevention and treatment of vitamin B ₁₂ deficiency.
2. Replenishment when demand for vitamin B12 increases due to debilitating diseases, hyperthyroidism, pregnant women, lactating women, etc., and intake from the diet is insufficient.
3. Giant erythroblast anemia, broad-headed fibroids, neuropathy associated with pernicious anemia, malabsorption syndrome.
4). Deficiency or disease metabolic disorder is implicated in the vitamin B _12.
Japanese Patent Laid-Open No. 10-36270

  Traditionally used analgesics have problems such as gastric mucosal damage and contraindications with other drugs, so it is recommended for patients with other diseases such as the elderly and patients with gastrointestinal weakness. It was difficult to use and lacked versatility. Therefore, development of an analgesic composition having higher safety and an excellent analgesic action has been expected.

  In view of the above-mentioned present situation, an object of the present invention is to provide an analgesic composition that is safer than conventional analgesics and that exhibits an analgesic action equal to or higher than that.

The present inventors have made intensive studies, as a result, the high vitamin B ₁₂ with requisite known as nutrient safety to the living body has an excellent analgesic effect unexpectedly, and, when combined with vitamin B ₁₂ and folic acid The present inventors have found that a more excellent analgesic action can be obtained and have reached the present invention.

That is, the present invention is an analgesic composition comprising vitamin B ₁₂ as an active ingredient. The analgesic composition preferably further contains folic acid. In this case, with respect to folic acid 1 part by weight, the vitamin _{B 12,} preferably contains from 0.0000125 to 1500 parts by weight. The dose of vitamin _{B 12} is preferably located in 0.025～1500Mg / day, the dose of folic acid, it is preferable that at 1 to 2000 mg / day.

Since the analgesic composition of the present invention contains vitamin B ₁₂ as an active ingredient, it is extremely safe even when compared with conventional analgesics. Furthermore, it can exhibit an excellent analgesic action even compared with conventional analgesics.

  The present invention is described in detail below.

Analgesic composition of the present invention contains a vitamin B ₁₂ as an active ingredient.

Vitamin B ₁₂ is a water soluble vitamin having a structure containing cobalt ions into the corrin 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.

Analgesic composition of the present invention, in addition to vitamin B _12, preferably contains folic acid. By combination of folic acid, analgesia with vitamin B ₁₂ is significantly enhanced. Folic acid is a member of the water-soluble vitamin B group and is pteroylglutamic acid.

Vitamin B ₁₂ and folic acid, convincing side effects and combination contraindications are not known, since there is no risk from overdose, analgesic composition of the present invention is extremely high safety.

In formulating the analgesic composition of the present invention is not particularly limited as the dose of vitamin _{B 12,} for example, dosage for an adult per body weight 60kg in the range of about 0.025Mg～1500mg / day And preferably in the range of 0.05 mg to 1500 mg / day. When used in combination folic acid, because folic acid enhances the analgesic effect, it is possible to reduce the dose of vitamin B _12.

  When folic acid is used in combination, the dose is not particularly limited. For example, the dose per adult with a body weight of 60 kg is in the range of 1 to 2000 mg / day, particularly preferably in the range of 2 to 2000 mg / day. is there.

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. Within this range, it is possible to preferably enhance the efficacy of vitamin B _12.

Analgesic compositions of the present invention may contain the vitamins other than vitamin B ₁₂ and folic acid. Examples of such vitamin groups include vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , niacin, biotin, pantothenic acid, 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.

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

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

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

  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.

  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 vitamin Bs 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 has an international unit of 250 to 5000 IU / day, and vitamin B is 60 kg per adult. ₁ 1～60Mg / day, vitamin _{B 2} is 1～60Mg / day, vitamin _{B 6} is 0.5～120Mg / day, niacin 1～60Mg / day, biotin 10Myuji～15mg / day, pantothenic acid 1 -60 mg / day, vitamin C 50-3000 mg / day, vitamin D in international units, 50-500 IU / day, vitamin E 10-500 mg / day, vitamin K 30 μg-50 mg / day.

  The analgesic composition of the present invention may be a pharmaceutical product, or a food, preferably a health food, particularly a food for specified health use or a nutritional functional food. In the case of health foods, so-called supplements (dietary supplements) having different forms from normal foods (for example, forms such as tablets, capsules, powders, etc.) may be used.

  When the analgesic composition of the present invention is a pharmaceutical product, the following drug may be blended. Antipyretic analgesics such as acetaminophen, ibuprofen, aluminoprofen, loxoprofen, aspirin, isopropylantipyrine, etezamide; ephedrine hydrochloride, dl-methylephedrine hydrochloride, noscapine, bromhexine hydrochloride, codeine phosphate, dihydrocodeine phosphate, hydrobromic acid Antitussives such as dextromethorphan, tipipedin hibenzate, dimemorphan phosphate; expectorants such as potassium guaiacol sulfonate, guaifenesin, ammonium chloride; antihistamines such as clemastine fumarate, chlorpheniramine maleate, diphenhydramine hydrochloride, mequitazine; isopropamide iodide Antinasal secretion agent such as lysozyme chloride; Anti-inflammatory agent such as glycyrrhetinic acid and glycyrrhizic acid; Peonies extract Mao extract, Nantenjitsu extract, Spruce extract, Licorice extract, Oxalis extract, Fennel extract, Oyster extract, Quail extract, Gentiana extract, Gypsophila extract, Pepper extract, Clove extract, Ginseng extract, Earth dragon extract, Chixetsu carrot extract, Extract carrot extract Herbal medicines such as isoleucine, phenylalanine and cysteine; sedatives such as bromvalerylurea and allylisopropylacetylurea; analgesics and drowsiness removing agents such as caffeine and anhydrous caffeine; Gastric mucosa protective agents such as magnesium aluminate and magnesium carbonate, and mucopolysaccharides such as sodium chondroitin sulfate.

  The route for administering the analgesic composition of the present invention as a pharmaceutical is not particularly limited, but oral administration, sublingual administration, rectal administration, transdermal administration, inhalation, topical administration, injection (intraarterial, intravenous, muscle And the like, and oral administration is 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 invention, it is preferable to use a combination of water and one or more alcohols as the solvent, and it is more preferable that the solvent contains alcohols in a proportion of 50% by weight or more, and 50 to 95% by weight. It is more preferable to contain it in the ratio of%. 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 which is a pharmaceutical product 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 is not particularly limited, but 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. Pain caused by pain substances in the body, preferably due to external disturbances, eg back pain, muscle pain, stiff shoulder pain, fracture pain, bruise pain, sprain pain, trauma pain, post-extraction or post-surgical pain Sore throat, ear pain, more preferably muscle pain, fracture pain, bruise pain, sprain pain, trauma pain. 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.

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 1-7 and Comparative Examples 1 and 2
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. Ibuprofen used in Comparative Example 1 is a well-known analgesic agent, and tranexamic acid is known as a component that enhances the analgesic action of ibuprofen (see JP-A-9-48728).

  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、ビタミンＢ_１２のみを投与した系（実施例１）において、有意にライジングの発生回数が減少した。すなわち、ビタミンＢ_１２が鎮痛作用を持つことが示された。しかも、その鎮痛効果は、従来強力な鎮痛作用を有することが知られるイブプロフェンとトラネキサム酸とを併用した系（比較例１）と同等のものであった。

As is clear from Table 1, in the system administered with only vitamin B ₁₂ (Example 1), the number of occurrences of rising was significantly reduced. That is, vitamin B ₁₂ is shown to have analgesic activity. And the analgesic effect was equivalent to the system (comparative example 1) which combined ibuprofen and tranexamic acid known conventionally having a strong analgesic action.

Furthermore, in the system (Examples 2 to 7) in which vitamin B ₁₂ and folic acid are used in combination (Examples 2 to 7), the number of occurrences of rising is remarkably reduced. It showed some excellent analgesic effect. On the other hand, the group administered only with folic acid showed almost no analgesic effect (Comparative Example 2). This the system has a very good analgesic effect, folic acid shown to have an effect to synergistically enhance the analgesic effect of vitamin B _12. Thus, in many vitamins are present, it found that the analgesic effect resides in a high vitamin B ₁₂ safety, has been shown to synergistically improve the effect folate otherwise an analgesic effect.

Formulation Examples 1-30
Film coating agents were prepared according to the formulations described in Tables 2-5. 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３１〜３３
表６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 31-33
According to the formulation described in Table 6, 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３４〜３６
表７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 34-36
Analgesics were prepared according to the formulation described in Table 7. Specifically, it was weighed according to the prescription, kneaded with water, granulated, and dried to produce granules.

Claims (5)

An analgesic composition comprising vitamin B ₁₂ as an active ingredient.   The analgesic composition according to claim 1, further comprising folic acid. Relative to folic acid 1 part by weight, the vitamin _{B 12,} an analgesic composition according to claim 2, characterized in that it contains from 0.0000125 to 1500 parts by weight. The dose of vitamin _{B 12} is an analgesic composition according to any one of claims 1 to 3, characterized in that at 0.025～1500Mg / day.   The analgesic composition according to any one of claims 2 to 4, wherein the dose of folic acid is 1 to 2000 mg / day.