JP6440959B2 - Pharmaceutical composition for pain insomnia - Google Patents

Description

  The present invention relates to a pharmaceutical composition for improving insomnia associated with pain.

  Of the insomnia associated with physical illness, night pain is often the cause. According to Gallap, 56 million people in the United States have a sleepless night because of pain. In Canada, 44% of patients with pain complain of insomnia. It is also experimentally known that pain causes insomnia, while it has been proven that insomnia affects pain (Non-patent Document 1).

  Conventionally, analgesics containing acetaminophen, etenzamide and allylisopropylacetylurea are known and have been taken during pain such as back pain, joint pain, headache, menstrual pain, but directly to insomnia caused by pain It is not known to be effective. In addition, it is known that acetaminophenone and allyl isopropyl acetylurea are combined with ibuprofen to sustain the action time of ibuprofen and synergistically improve antipyretic analgesic action, but also to insomnia caused by pain It is not known that there is a direct effect (Patent Document 1).

Pain Clinic vol.25 No.11p1467-1473 (November 2004)

JP-A-5-246845

  An object of the present invention is to provide a pharmaceutical composition effective for improving insomnia associated with pain for persons with pain (including mammals including humans). In particular, an object of the present invention is to provide a pharmaceutical composition effective in improving insomnia (sleep maintenance disorder) due to the inhibition of sleep duration due to pain.

  The present inventor has made extensive studies to solve the above-mentioned problems, and by combining acetaminophen, etenzamide and allylisopropylacetylurea, the above-mentioned problems can be solved, which is the intended purpose. It was found that insomnia associated with pain, particularly sleep maintenance disorder, can be significantly improved. In addition, as shown in the experimental examples to be described later, such an effect is not an effect obtained by simply improving pain using a pain relieving agent or a sedative, but three components of acetaminophen, etenzamide and allyl isopropyl acetyl urea. This is the first effect obtained by combining the two.

The present invention has been completed based on the above findings, and has the following embodiments.
Item 1. A pain insomnia-improving agent comprising acetaminophen, etenzamide and allylisopropylacetylurea.
Item 2. The pain insomnia improving agent according to Item 1, further comprising a processed valerian plant.
Item 3. Item 3. The pain insomnia improving agent according to item 1 or 2 which does not contain caffeine.
Item 4. Item 4. The pain insomnia improving agent according to any one of Items 1 to 3, comprising acetaminophen at a ratio of 100 to 500 mg per administration.
Item 5. Item 5. The pain insomnia improving agent according to any one of Items 1 to 4, comprising etezamide at a ratio of 0.2 to 6 parts by weight per 1 part by weight of acetaminophen.
Item 6. Item 6. The pain insomnia improving agent according to any one of Items 1 to 5, comprising allylisopropylacetylurea at a ratio of 0.04 to 1 part by weight per part by weight of acetaminophen.
Item 7. Item 7. The pain insomnia improving agent according to any one of Items 2 to 6, comprising 0.1 to 60 parts by weight of the processed valerian per 1 part by weight of acetaminophen.
Item 8. Item 8. The pain insomnia improving agent according to any one of Items 1 to 7, wherein the pain insomnia is a sleep maintenance disorder associated with pain.

  The pain insomnia-improving agent of the present invention is a pharmaceutical composition comprising three components of acetaminophen, etenzamide and allylisopropylacetylurea. According to the pain insomnia-improving agent, it is possible to significantly improve insomnia associated with pain, particularly sleep maintenance disorder in which sleep is not sustained by pain. Therefore, by administering the pain insomnia improving agent of the present invention to a patient whose sleep does not persist due to pain, it is possible to increase the sustainability of sleep and to improve mental and physical disorders due to insomnia.

(I) Pain insomnia improving agent The pain insomnia improving agent of the present invention is a pharmaceutical composition intended for patients (mammals including humans) whose symptoms are insomnia associated with pain. It comprises three components: aminophen, (B) etenzamide, and (C) allylisopropylacetylurea. In addition to these three components, (D) processed valerian can also be blended.

  Hereinafter, each of these components will be described.

(A) Acetaminophen Acetaminophen (N- [4-hydroxyphenyl] acetamide) is a compound having a central antipyretic analgesic action. The analgesic effect of acetaminophen is due to an increase in the threshold of pain in the thalamus and cerebral cortex, and the antipyretic effect is due to the movement of body water and the perspiration due to the expansion of peripheral blood vessels. Will not be affected.

  The mixing ratio of acetaminophen in the pain insomnia improving agent of the present invention can be appropriately set from the range of usually 1 to 40% by weight, preferably 10 to 30% by weight.

(B) Etenzamide Ethenzaamide (2-Ethoxybenzamide) is a salicylic acid antipyretic analgesic and anti-inflammatory agent, which is known to be included in commercially available headaches and general cold medicines to suppress headache, toothache, menstrual pain and fever. ing.

  The blending ratio of etenzaamide in the pain insomnia improving agent of the present invention can be appropriately set in the range of usually 1 to 40% by weight, preferably 15 to 35% by weight.

(C) Allyl isopropyl acetyl urea Allyl isopropyl acetyl urea (2-Isopropyl-4-pentenoylurea) is a kind of sedative component and has an action of calming tension, school style and irritability.

  The blending ratio of allylisopropylacetylurea in the pain insomnia improving agent of the present invention can be appropriately set from the range of usually 0.1 to 10% by weight, preferably 1 to 10% by weight, more preferably 5 to 10% by weight. %.

(D) Processed valerian plant valerian plant (Valeriana) is a plant belonging to the genus Valeriana and has a mild sedative effect, and has been used as a plant that suppresses the height of nerves since ancient Greek times. At present, extracts of roots, rhizomes and leaves of valerian are used as sedatives, mainly for the purpose of improving mental stress, as sedatives and insomnia-improving drugs.

  As a plant belonging to the genus Valeriana used as a raw material of the processed valerian plant of the present invention, Valeriana fauriei Briquet (Valeriana fauriei), Valeriana fauriei forma (Ezo) Valerian), Valeriana officinalis (valerian valerian) can be mentioned (in the present invention, these are collectively referred to as “valerian”).

  The processed valerian plant targeted by the present invention is a crushing process, a drying process, a heating process, an extraction process, a solid-liquid process using all or part of the valerian plant (plant) (for example, roots, rhizomes, leaves, etc.) as raw materials. Processes such as separation treatment, concentration treatment, and / or membrane treatment are applied. More specifically, as a processed valerian product, for example, a processed product (including either coarse powder or fine powder) obtained by drying and pulverizing a raw plant body (all or a part) of valerian (hereinafter referred to as “valerian powder”) )), An extract obtained by extracting a raw or dry product of valerian plant (all or a part) with a solvent, a dried product (dried extract), and a powder dry extract obtained by pulverizing the extract. (These are collectively referred to as “valerian extract”). Preferred is a processed product of roots and rhizomes of valerian root, and among them, valerian powder which is obtained by dry crushing roots and rhizomes of valerian roots and powdered.

  In addition, the above-mentioned valerian extract is a colander plant (all or part), as it is or as necessary, dried, shredded, crushed, pressed or boiled, with cold water, hot water or an organic solvent, Or it can acquire by extracting with extraction solvents, such as a liquid mixture of water and an organic solvent. Examples of the organic solvent used for this extraction include methanol, ethanol, isopropanol, propylene glycol, 1,3-butylene glycol, acetone (above, polar solvent), ethyl acetate, chloroform, pentane, hexane, heptane, etc. (above, Nonpolar solvents) may be used alone or in combination of two or more.

  Among the extraction solvents, a polar solvent is preferable, and among them, water; lower alcohols such as methanol, ethanol, and isopropanol; or a mixed solution of water and these lower alcohols can be given.

  Further, the extraction temperature is preferably room temperature (25 ± 5 ° C.) or higher, and although the extraction temperature differs depending on the solvent used, for example, a range of room temperature to about 100 ° C. can be mentioned. More specifically, for example, when water is used as the extraction solvent, it is preferably about 50 to 100 ° C, more preferably about 80 to 100 ° C. When an organic solvent such as a lower alcohol or a mixture of an organic solvent and water is used as the extraction solvent, for example, the extraction temperature is preferably in the range of room temperature to 80 ° C, more preferably about 40 to 80 ° C. Can be mentioned.

  The method for preparing such an extract is not particularly limited, and can be performed according to a conventional method. As an example, 2 to 500 parts by weight, preferably 50 to 200 parts by weight of water, an organic solvent or a mixture thereof are added to 1 part by weight of a dry pulverized product of a valerian plant (all or part), and extracted. Depending on the type of solvent, extraction is performed for about 1 to 300 minutes, preferably about 10 to 90 minutes with stirring at the above temperature, and then the liquid and solid are separated by a solid-liquid separation method such as filtration or centrifugation. The method of isolate | separating and acquiring a liquid as an extract can be mentioned.

  The extract thus obtained may be prepared as a dried product (dry extract, powder dry extract). As a method of drying the extract to obtain a dry extract, a method of removing the extraction solvent by distillation under reduced pressure or the like, a method of removing the extraction solvent by performing a drying treatment such as vacuum drying or freeze drying, dry spray or spraying, etc. A drying process etc. can be mentioned. The dry powder extract can be prepared by pulverizing the dry extract obtained above, and can also be prepared by subjecting the extract to a dry spray or spray drying treatment.

  In addition, as a processed valerian can be prepared by processing as described above using the collected valerian butter, for example, a processed product (dried product) obtained by crushing or pulverizing valerian, for example, is commercially available, This can also be used as a raw material.

  When using a processed valerian plant, the blending ratio of the processed valerian plant in the pain insomnia improving agent of the present invention can be appropriately set from the range of usually 0.5 to 30% by weight in terms of dry weight, preferably Is 5 to 30% by weight, more preferably 5 to 20% by weight.

(E) Form of pain insomnia improving agent and other components to be blended therein The pain insomnia improving agent of the present invention can be prepared in various preparation forms for oral administration. Such preparation forms include, for example, solid oral preparations such as tablets, pills, powders (powder), granules (fine granules), and capsules (hard capsules, soft capsules); The form of liquid oral administration preparations, such as a drink, can be mentioned. Preferred are solid oral preparations such as tablets, powders (powder), and granules (fine granules).

  The pain insomnia-improving agent of the present invention can be formulated with various additives according to each formulation form when preparing the above-described formulation form within the range that does not interfere with the effects of the present invention. For example, excipients, binders, disintegrants, stabilizers, surfactants, plasticizers, lubricants, buffers, sweeteners, flavoring agents, antioxidants, coating agents (including sugar coatings), wetting Agent, wetting agent, filler, antifoaming agent, cooling agent, binder, coloring agent, flavoring agent, tonicity agent, softening agent, emulsifier, thickening agent, foaming agent, pH adjusting agent, dispersion An agent, a disintegrating aid, a fragrance, a moisture-proofing agent, a preservative, a solubilizing aid, a solvent, a fluidizing agent, a bulking agent and the like can be blended. Examples of such additives are described in the Pharmaceutical Additives Dictionary and the like.

  Moreover, the pain insomnia improving agent of this invention can also mix | blend the following auxiliary | assistant ingredients and a medicinal ingredient in the range which does not prevent the effect of this invention.

[Auxiliary ingredients]
Passiflora extract, hop extract, crategus extract, butterfly extract, carrot extract, cypress extract, cinnamon extract, kouca extract, saishin extract, mint extract, flounder extract, sanso nin extract, bucurium extract, ogi extract, ryukotsu, borei, gypsum, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin E, Folic acid, Niacin, Benfotiamine, Octothiamine, Panthetin, Theanine, Inositol, Tryptophan, Tyrosine, Phenylalanine, Arginine, Aspartic acid, Tranexamic acid, Calcium lactate, Ribaol , Taurine, γ-oryzanol, carnitine chloride, γ-aminobutyric acid.

[Medicinal ingredients]
Bromovaleryl urea, hesperidin and derivatives thereof and salts thereof, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum, aluminum hydroxide gel, magnesium carbonate, magnesium aluminate metasilicate. Also, earth dragon, licorice, peony, button pi, salamander, ginger, chimpi or these extracts.

  The pain insomnia-improving agent of the present invention can also contain caffeine (including anhydrous caffeine) as another component, but as shown in the experimental examples (Examples 1 and 2) described later, the cafe Since inn tends to interfere with sleep sustainability, it is preferable not to mix in if possible.

(F) Preparation method and use method of pain insomnia improving agent The pain insomnia improving agent of the present invention is described in the above components (A) to (C) or (A) to (D), and further, if necessary, (E). It can be prepared by mixing at least one component and formulating it by a well-known method according to the formulation form described above.

  The amount of (A) acetaminophen contained per administration of the pain insomnia-improving agent is usually in the range of 100 to 500 mg, preferably 150 to 500, for example, when administered to an adult having an average body weight of 40 to 60 kg. 500 mg, more preferably 200 to 400 mg can be mentioned. The amount of (B) etenzamide contained per administration of the pain insomnia improving agent is 0.2 to 6 parts by weight with respect to the amount of acetaminophen contained in the pain insomnia improving agent (1 part by weight). , Preferably 0.5 to 4 parts by weight, more preferably 0.75 to 4 parts by weight, specifically in the range of 50 to 800 mg, preferably 100 to 600 mg, More preferably, 200-400 mg can be mentioned. Furthermore, the amount of (C) allylisopropylacetylurea contained per administration of the pain insomnia improving agent is 0.04 with respect to the amount of acetaminophen (1 part by weight) contained in the pain insomnia improving agent. To 1 part by weight, preferably 0.1 to 0.8 part by weight, more preferably 0.2 to 0.5 part by weight, specifically 20 to 100 mg. A range, preferably 30 to 80 mg, more preferably 30 to 70 mg can be mentioned.

  In addition, when (D) valerian processed product is used in combination with the above components (A) to (C), the amount of (D) valerian processed product contained in a single administration of the pain insomnia improving agent is 0.1 to 60 parts by weight, preferably 0.2 to 30 parts by weight, more preferably 0.5 to 20 parts by weight, and still more preferably 0 to the amount (1 part by weight) of the acetaminophen contained in It can be adjusted to a ratio of 5 to 10 parts by weight, specifically, usually in the range of 60 to 6000 mg, preferably 150 to 2000 mg, more preferably 200 to 1500 mg.

  The pain insomnia-improving agent of the present invention is usually used in such a mode that it is taken orally 30 minutes to 1 hour before going to bed. When the single dose is converted into the amount of acetaminophen contained in the pain insomnia-improving agent, as described above, in the case of an adult having an average body weight of 40 to 60 kg, usually in the range of 100 to 500 mg, preferably 150 to 500 mg, More preferably, 200-400 mg can be mentioned.

  Hereinafter, the present invention will be specifically described based on experimental examples and examples. However, the present invention is not limited by these.

Experimental Example 1 Sleep Sustainability Evaluation Test (1) Test Method (1-1) Animals Used and Breeding Conditions Five 4-week-old ICR (SPF) male mice are housed in cages on the floor and kept on pellet feed . The breeding environment is 23 ± 3 ° C, relative humidity is 50 ± 10%, lighting is 12 hours (8: 00-20: 00), and feed and water (tap water) are freely consumed and acclimatized for about 7 days. It was. Eight groups of mice were prepared as the administration groups of Examples 1 to 3 and Comparative Examples 1 to 5 described in Table 1, and experiments were conducted with 10 mice in each group.

(1-2) Test drug and dose The ingredients described in Table 1 were mixed so as to have the ratio described in the table to prepare a combination drug. Subsequently, the obtained compounding agent (sample) was ground and mixed with 1 ml of physiological saline, and orally administered to the mouse using a stomach tube. Loxoprofen, ibuprofen, acetaminophen, and etenzaamide used in each formulation are all compounds having an analgesic action, and when the analgesic effects are arranged in order of strength, “loxoprofen>ibuprofen>acetaminophen> ethenzamid”.

  Only 1 ml of physiological saline was orally administered to the administration group (non-treatment group) of Comparative Example 1. The dose to the mouse was adjusted according to the body weight of the mouse used in the test, assuming that the prescription amount shown in Table 1 was “mg (dose) / kg (mouse weight)”. This is an administration method widely used as a single-dose drug administration test.

(1-3) Test method [Evaluation test of pain insomnia improvement effect]
Each test drug (Examples 1 to 3, Comparative Examples 1 to 5) was orally administered to each group of mice. Immediately thereafter, a 1% aqueous solution of carrageenan, a pain-causing substance, was subcutaneously administered to the hind footpad. Thirty minutes later, pentobarbital (PB) was injected intraperitoneally at a rate of 45 mg / kg, and the forward reflex was measured. The time from the disappearance of the positive reflex to the recovery of the normal reflex was measured and evaluated as “sleep duration”.

[Evaluation test of analgesic effect]
In parallel with the above, the analgesic effect was evaluated by the acetic acid rising method. Specifically, after the intraperitoneal administration of acetic acid, which is a pain substance, the number of risings observed during 30 minutes was measured. The analgesic effect was calculated according to the following formula, compared with the number of risings of mice (non-treated group) administered with only physiological saline (Comparative Example 1).

(2) Test results The results are shown in Table 1.

  As can be seen from the comparison between Comparative Examples 1 and 2, the pain was suppressed by 96.9% by administering loxoprofen, which is an analgesic agent, and the sleep time was changed from 646 seconds (Comparative Example 1) to 1561 seconds in the untreated group. (Comparative Example 2). However, the prescription example (Comparative Example 4) which has only about 60% of the analgesic effect has a significantly longer sleep time of 2210 seconds, which indicates that the analgesic effect is not directly linked to the extension of the sleep time. Moreover, even when allyl isopropyl acetyl urea having a sedative action was administered, no analgesic effect was obtained, and the sleeping time was not prolonged so much (Comparative Example 5). The prescription (Comparative Example 3) in which allyl isopropyl acetyl urea is used in combination with ibuprofen, which has a known analgesic effect, and caffeic anhydride, which has a known effect of enhancing the analgesic effect of ibuprofen, is added to the above comparative example. Compared to 2, 4 and 5, although the sleep time was slightly longer at 2540 seconds, there was no significant difference from the sleep time in Comparative Example 4 in which acetaminophen and etenzamid were used in combination.

  On the other hand, as shown in the results of Example 1, by using together acetaminophen and etenzamide, which are the formulations of Comparative Example 4, and allylisopropylacetylurea, which is the formulation of Comparative Example 5, Sleep time was extended (6727 seconds) beyond prediction from the result of 5. In addition, it was confirmed that the effect was enhanced by further using a processed valerian product (Example 2). In addition, as described above, anhydrous caffeine is generally known to have an action of enhancing the analgesic effect of an analgesic, but as shown in Example 3, when used in combination with acetaminophen, etenzamide and allylisopropylacetylurea, Although the analgesic effect was improved, the sleep persistence tended to decrease slightly. From this, in the present invention, it is considered preferable not to add anhydrous caffeine.

As shown above, insomnia associated with 疼 pain (sleep maintenance insomnia) is a disorder not be improved only removes the pain, nor can be any combination of analgesic and sedative effectively improved. In contrast, according to the present invention, acetaminophen, combined use of three components of ethenzamide and allylisopropylacetylurea, and by combining these further valerian workpiece, insomnia (sleep maintenance disorders associated with such 疼 pain ) Can be effectively improved.

Formulation Examples 1-8
According to the formulation shown in Table 2 (one adult dose), a pain insomnia improving agent (tablet) was produced by a conventional method.

Claims (3)

  A pain insomnia-improving agent comprising acetaminophen, etenzamide and allylisopropylacetylurea.   Furthermore, the pain insomnia improving agent of Claim 1 containing the processed valerian.   The pain insomnia improving agent according to claim 1 or 2, which does not contain caffeine.