JP6804190B2 - Pharmaceutical composition - Google Patents

Description

The present invention relates to a warming sensation-imparting agent, and more specifically, contains a propionic acid-based non-steroidal anti-inflammatory drug and shokyo and keihi as raw medicines, and has an excellent antipyretic effect and imparts a warming sensation during fever. The present invention relates to a warmth-imparting agent capable of alleviating unpleasant symptoms such as chills and peripheral cold sensation, and an anti-fever analgesic composition using the same.

The rise in body temperature (fever) occurs when the set temperature of the body temperature rises due to an abnormality in the thermoregulatory center. For example, in infectious diseases, when exogenous pyrogens such as bacteria and viruses invade the body, macrophages and monocytes are stimulated to produce exogenous pyrogens such as interleukin 1, tumor necrosis factor (TNF), and interferon. Will be done. As a result, arachidonic acid metabolism is activated and prostaglandin (PG) synthesis is promoted, and as a result, the set temperature of body temperature rises in the thermoregulatory center of the hypothalamus. When the set temperature rises, the skin blood vessels are contracted to suppress heat dissipation, and the muscles are shaken to promote heat production, thereby raising the body temperature.

Fever in infectious diseases and the like is a normal biological defense reaction for activating immune cells and preventing the growth of bacteria and viruses. However, fever affects metabolism, resulting in unpleasant conditions such as increased pulse rate and respiratory rate, headache, dizziness, loss of appetite, and loss of motivation. Also, when the body temperature rises, the muscles tremble to produce heat, but at that time, unpleasant chills may be felt. This strong reaction is the so-called chills horror, accompanied by involuntary tremors of skeletal muscles. In addition, as the skin blood vessels contract to suppress heat dissipation, an unpleasant peripheral cooling sensation may be felt in the limbs and the like.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a general term for a group of drugs other than steroids that have anti-inflammatory, analgesic, and antipyretic effects, and are acidic and basic due to their chemical structure. The acidic system includes salicylic acid system, phenamic acid system, acetic acid system, propionic acid system and the like. NSAIDs act primarily on the thermoregulatory center of the hypothalamus by inhibiting cyclooxinase (COX) in arachidonic acid metabolism and inhibiting prostaglandin (PG) synthesis, lowering the temperature setting. And show the antipyretic effect. If the body temperature is lowered by administration of NSAIDs, the unpleasant condition caused by high fever such as an increase in pulse rate and respiratory rate can be relieved. However, it could not be said that the chills and cold limbs when the body temperature rose were sufficiently alleviated or alleviated. In addition, it is generally known that when fever is reduced by administration of NSDIDs, it is exhausted due to sweating and the like, accompanied by a feeling of weakness, and it may be difficult to quickly recover the decreased appetite and motivation.

Therefore, it is an object of the present invention to provide a pharmaceutical composition capable of alleviating unpleasant symptoms such as chills during fever and cold limbs and alleviating weakness during fever reduction.

The present inventors have been conducting diligent research to solve the above problems, and by combining a propionic acid-based non-steroidal anti-inflammatory drug with the crude drug components Shokyo and Keihi, the antipyretic effect is improved. The present invention was completed by finding that a feeling of warming the body such as a feeling of warmth and a feeling of warmth is obtained, and therefore chills and a feeling of peripheral coldness when the body temperature rises are alleviated, and a feeling of weakness at the time of fever reduction is alleviated.

That is, the present invention is a warmth-imparting agent containing a propionic acid-based non-steroidal anti-inflammatory drug, ginger and cinnamon.

Further, the present invention is an antipyretic analgesic composition containing the above-mentioned warming agent.

The warming sensation-imparting agent of the present invention exhibits an excellent antipyretic effect, and immediately after taking the drug, a sensation of warming the body such as a warm feeling or a warm feeling occurs and continues, so that a chill or a peripheral cold feeling at the time of fever occurs. It is possible to alleviate unpleasant symptoms such as weakness at the time of fever reduction.

It is a graph which shows the body temperature change of the rat (solvent administration group (control), ibuprofen and crude drug combination group (IBP + crude drug), ibuprofen alone administration group (IBP)) of each group in Test Example 1.

The warming agent of the present invention contains a propionic acid-based non-steroidal anti-inflammatory drug and ginger and cinnamon as crude drugs. In the present invention, the feeling of warmth refers to a feeling of warming the body, such as a feeling of warmth or a feeling of warmth.

Examples of the propionic acid-based nonsteroidal anti-inflammatory drug include ibuprofen, flurbiprofen, ketoprofen, naproxen, pranoprofen, tiaprofenic acid, oxaprozin, loxoprofen, zaltprofen, fenoprofen, aluminoprofen, or pharmaceuticals thereof. Above, acceptable salts and the like can be exemplified, and these can be used alone or in combination of two or more. Of these, ibuprofen, loxoprofen sodium and the like are preferable because they are excellent in warming effect, and ibuprofen is particularly preferable. The amount of the propionic acid-based non-steroidal anti-inflammatory drug in the warming agent of the present invention is usually about 20 to 2000 mg per adult. Specifically, for example, ibuprofen is used for 1 adult. The daily dose is preferably 90 to 600 mg, more preferably 200 to 600 mg, and particularly preferably 300 to 600 mg. When using other propionic acid non-steroidal anti-inflammatory drugs, the daily dose for adults is 120 to 600 mg for naproxen, tiaprofenic acid, oxaprozin and aluminoprofen, 24-120 mg for flurbiprofen, and ketoprofen. It is preferable to combine 30 to 150 mg, 45 to 225 mg of pranoprofen, 36 to 180 mg of loxoprofen sodium (converted as an anhydride), 48 to 240 mg of zartprofen, and 360 to 1800 mg of phenoprofen.

The above-mentioned ginger includes the rhizome of ginger (Zingiber officinale Roscoe) of the family Zingiberaceae, or the one that has been processed with a general crude drug, and contains ginger, ginger powder, ginger extract, etc. Illustrated. As the ginger, for example, the one in which the cork skin is peeled off and dried as it is or vertically divided and evenly stirred with lime is used. Ginger powder is powdered ginger according to a conventional method, and ginger extract is obtained by extracting ginger or ginger powder with a solvent such as water or ethanol, and concentrating and drying as necessary. It is a thing. The blending amount of ginger in the warming agent of the present invention is 100 to 1000 mg, preferably 100 to 500 mg, more preferably 100 to 300 mg in terms of crude drug equivalent as the daily dose for an adult.

The cinnamon tree includes the cinnamon tree (Cinnamomum cassia), a plant belonging to the genus Cinnamomum cassia, or its cognate, the cinnamon tree (Cinnamomum verum). , Cinnamon tree, cinnamon powder, cinnamon extract, etc. are exemplified. As the cinnamon, for example, the cinnamon bark of the trunk and branches is used as it is, or the periderm is slightly removed. The cinnamon powder is a powder of cinnamon powder by a conventional method, and the cinnamon extract is a cinnamon or cinnamon powder extracted with a solvent such as water or ethanol, and concentrated and dried as necessary. The amount of cinnamon compounded in the warming agent of the present invention is 100 to 1000 mg, preferably 200 to 600 mg, and more preferably 300 to 500 mg in terms of crude drug equivalent as the daily dose for adults.

In addition to the above-mentioned propionic acid-based non-steroidal anti-inflammatory drugs, ginger and cinnamon, the warming-imparting agent of the present invention further comprises excipients, binders, disintegrants and lichens commonly used in the pharmaceutical field. Formulations such as agents are formulated by adding additives.

Examples of the excipient include lactose, starch, corn starch, pregelatinized starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, refined sucrose, sugar alcohols, and light anhydrous silicic acid. Calcium silicate, titanium oxide, precipitated calcium carbonate and the like can be mentioned. One or more of these excipients can be used.

Examples of the binder include gelatin, gum arabic powder, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / Acrylic acid derivatives such as polyethylene glycol graft copolymer, pullulan, dextrin, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, and methacrylic acid copolymer, cellac, carboxyvinyl polymer, sodium carboxymethyl starch, carboxymethyl ethyl cellulose, cellulose acetate and the like can be mentioned. .. One or more of these binders can be used.

Examples of the disintegrant include croscarmellose sodium, crospovidone, cross-linked insolvable polyvinylpyrrolidone, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, potato starch, corn starch, pregelatinized starch and the like. Be done. One or more of these disintegrants can be used.

Examples of the lubricant include talc, stearic acid, magnesium stearate, sucrose fatty acid esters, polyethylene glycol and the like. One or more of these lubricants can be used.

The dosage form of the warming agent of the present invention is not particularly limited, and in addition to tablets, caplets, hard capsules, soft capsules, orally disintegrating tablets, chewable tablets, fine granules, granules, and dry syrups. Examples thereof include oral solid preparations and oral solutions. Further, if necessary, a film coating or sugar coating may be applied to obtain a coating preparation of the above preparation. These can be produced according to the usual formulation method.

In addition to the warmth-imparting agents obtained as described above, antihistamines, antiallergic agents, antitussive expectorants, central nervous system stimulants, antacids, vitamins, crude drugs (excluding ginger and ginger), if necessary. ) And the like can be blended to produce the antipyretic analgesic composition of the present invention.

Examples of antihistamines or antiallergic agents include azerastin hydrochloride, alimemazine tartrate, isotipendyl hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, evastin, emedastin fumarate, oxatomide, carbinoxamine diphenyldisulfonate, carpi. Noxamine maleate, cremastine fumarate, chlorpheniramine maleate, d-chlorpheniramine maleate, diphenhydramine hydrochloride, dipheterol phosphate, diphenyldisulfonate carbinoxamine, diphenylpyraline hydrochloride, diphenylpyraline Theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetilidine hydrochloride, triprolidine hydrochloride hydrate, tryperenamine hydrochloride, tonzilamine hydrochloride, hexofenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine Examples thereof include methylene disalicylate, bepotastine besilate, homochlorocyclidine hydrochloride, mequitazine, metodilazine hydrochloride, and mebuhydrolinnapadisylate. These may be added by 1 type or a mixture of 2 or more types.

Examples of the antitussive sputum are ambroxol hydrochloride, allocramide hydrochloride, tipepidin citrate, cloperastine hydrochloride, cloperastin fendizoate, codeine phosphate hydrate, dihydrocodein phosphate hydrate, dibunato sodium, etc. Tipepidin hibenzate, dextrometholphan hydrobromide, dextrometholphan phenolphthaline salt, pentoxyberinquinate, dimemorphan phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride Salts, dl-methylephedrine saccharin salt, guayphenesin, potassium guayacol sulfonate, potassium cresolsulfonate, bromhexine hydrochloride, L-carbocysteine, L-ethylcysteine hydrochloride, veradonna total alkaloid, isopropamide iodide, epradinone hydrochloride, etc. Be done. These may be added by 1 type or a mixture of 2 or more types.

Examples of the central nervous system stimulant include sodium caffeine benzoate, anhydrous caffeine, and caffeine hydrate. These may be added by 1 type or a mixture of 2 or more types.

Examples of the antioxidant include glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, dry aluminum hydroxide gel, and aluminum hydroxide.・ Sodium hydrogen carbonate co-precipitate, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitate, magnesium hydroxide / potassium aluminum sulfate co-precipitate, magnesium carbonate, aluminon metasilicate Examples thereof include magnesium acid. These may be added by 1 type or a mixture of 2 or more types.

Examples of the vitamin include vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives, and their salts. These may be added alone or in admixture of two or more.

Herbal medicines include Maou, Nantenjitsu, Ohi, Onji, Kanzo, Kikyo, Shazenshi, Shazensou, Sexan, Senega, Baimo, Uiko, Oubaku, Ouren, Kajutsu, Kamitsure, Gentiana, Goou, Beast, Shajin, Sojutsu, Chouji, Chinpi. , Byakujutsu, Jiryu, Chikusetsu carrot, Carrot, Kakkonto, Kakkonto Kakikyo, Keishito, Kasosan, Saiko Keishito, Shosaikoto, Shoseiryuto, Bakumondoto, Hangekobokuto, Maoto And so on. These may be added by 1 type or a mixture of 2 or more types. However, it is preferable not to add licorice because it may cause pseudoaldosteronism whose main symptoms are hypertension, swelling, potassium loss and the like. In addition, it is preferable to mix only ginger and cinnamon as crude drugs.

The antipyretic analgesic composition of the present invention is further formulated into various dosage forms by adding additives generally used in the formulation field, if necessary. The types of additives that can be used and the dosage forms that can be taken are the same as those for the warming sensation imparting agent.

The antipyretic and analgesic composition of the present invention obtained as described above is excellent in antipyretic effect and can give a feeling of warming the body such as a feeling of warmth and warmth, and reduces chills and cold limbs associated with fever. In addition, since it can alleviate the feeling of weakness during fever reduction, it is suitable as a medicine for colds and the like. In particular, since a feeling of warmth is immediately felt after administration and lasts for a certain period of time, administration in the early stage of fever can reduce or prevent chills and cold feeling of limbs due to an increase in body temperature.

Next, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited to these Examples and the like.

Example 1
Preparation of anti-fever analgesic composition containing ibuprofen, gypsum and caffeine 450 g of ibuprofen, 200 g of ginger powder, 400 g of caffeine powder, 7.5 g of chlorpheniramine maleate, 24 g of dihydrocodeine phosphate, 60 g of dl-methylephedrine hydrochloride , 75 g of anhydrous caffeine, 70 g of lactose, 150 g of low-substituted hydroxypropyl cellulose, and 849.5 g of crystalline cellulose are added with 675 g of Japanese Pharmacopoeia, wet granulated by a conventional method, dried and sized, and granulated powder. Got To 2391 g of this granulated powder, 34.5 g of talc and 34.5 g of magnesium stearate were added and mixed uniformly to obtain a powder for tableting. This tableting powder is compression-molded, and then a mixed coating solution of hypromellose, talc, titanium oxide, and macrogol is prepared and made into a film-coated tablet by a conventional method. In 6 tablets (daily dose for adults), 450 mg of ibuprofen is prepared. , 200 mg of ginger powder and 400 mg of talc powder were obtained (Product 1 of the present invention).

Comparison example 1
In place of ginger powder and ginger powder, 24 g of thiamine nitrified product and 300 g of ascorbic acid were used, and 450 mg of ibuprofen was added to 6 tablets (daily dose for adults) in the same manner as in Example 1 except that the total amount was corrected with crystalline cellulose. A tablet containing the substance was obtained (Comparative Product 1).

Trial example 1
Antipyretic effect test A yeast-induced fever model was created by subcutaneously administering a baker's yeast physiological saline suspension to the back of the neck of a 7-week-old male SD rat under isoflurane anesthesia, and the rectal temperature after administration of the test substance was measured. Then, the change in body temperature was examined.
A 20% (w / v) baker's yeast saline solution, which is an inducer, was subcutaneously administered to the back of the neck at a rate of 10 mL / kg under isoflurane anesthesia. 14 hours after yeast administration, the rectal temperature and body weight of the induced animals were measured, and 5 animals were divided into 3 groups using the rectal temperature as an index.
After grouping, the test substance or solvent (0.5% (w / v) aqueous solution of sodium carboxymethyl cellulose (CMC)) was orally administered by gavage, and the rectal temperature was measured 1, 2, 4 and 6 hours later, and immediately before administration ( The difference from the rectal temperature (0 hours) was calculated. The results are shown in FIG.

The test substance was administered according to the following group composition.
Ibuprofen and herbal medicine combination group:
Ibuprofen 75 mg / kg, dihydrocodeine phosphate 4 mg / kg, dl-methylephedrine hydrochloride 10 mg / kg, dried ginger extract 6.7 mg / kg, dried kei extract 4.8 mg / kg, anhydrous caffeine 12.5 mg / kg And chlorphenylamine maleate was suspended in a 0.5% CMC aqueous solution at a dose of 1.25 mg / kg and administered.
Ibuprofen alone group:
0.5% at doses of ibuprofen 75 mg / kg, dihydrocodeine phosphate 4 mg / kg, dl-methylephedrine hydrochloride 10 mg / kg, anhydrous caffeine 12.5 mg / kg and chlorpheniramine maleate 1.25 mg / kg It was suspended in a CMC aqueous solution and administered.

In this study, it was confirmed that the antipyretic effect of the examples was enhanced by the combined use of ibuprofen and herbal medicines as compared with the administration of ibuprofen alone. That is, it was clear that the combination drug of ibuprofen, cinnamon and ginger had an excellent antipyretic effect.

Trial example 2
Warmness imparting test For healthy adults, the degree of body sensitivity of fever after taking the preparation of the product 1 of the present invention or the preparation product 1 was compared. After lunch, 5 subjects took 2 tablets of the product 1 of the present invention (daily dose (6 tablets): ibuprofen 450 mg, ginger powder 200 mg, cinnamon powder 400 mg) or 2 tablets of the comparative product 1 (daily dose). Ibuprofen (450 mg) was taken as (6 tablets), and 0.5, 1, 1.5, and 2 hours later, the body sensitivity of fever was evaluated based on the following criteria. The results are shown in Table 1.
(Standard)
+: Obviously fever ±: Fever-: No change

Although there are individual time differences in the sensation of fever after taking the product of the present invention, the sensation of fever was clearly observed 0.5 to 1.5 hours after taking the product. On the other hand, with the comparative product, the experience of fever could not be obtained in all hours. Originally, ibuprofen is classified as an antipyretic analgesic and has an antipyretic effect. However, it was clarified that by blending ginger and cinnamon, a pleasant warmth can be obtained even though the heat is reduced due to the influence of ibuprofen.

The warming sensation-imparting agent of the present invention exhibits an excellent heat-reducing effect and imparts a warming sensation such as a warm feeling and a warm feeling, and is unpleasant such as chills during fever, peripheral cold feeling and weakness during fever reduction. Since the symptoms can be alleviated or alleviated, it can be used as a medicine for colds.

Claims (6)

A warming agent characterized by containing ibuprofen and only ginger and cinnamon as crude drugs. The warmth-imparting agent according to claim 1, wherein the compounding amount per day for an adult is 20 to 2000 mg of ibuprofen, 100 to 1000 mg of ginger, and 100 to 1000 mg of cinnamon. The warmth-imparting agent according to claim 1 or 2, which has a chills-reducing effect during fever. The warming sensation-imparting agent according to claim 1 or 2, which has a peripheral cooling sensation reducing effect at the time of fever. The warmth-imparting agent according to claim 1 or 2, which has a weakness-relieving effect at the time of fever reduction. An antipyretic analgesic composition containing the warming agent according to claim 1 or 2 ( excluding those containing crude drugs other than ginger and cinnamon ).

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