JP2021107332A - Oral pharmaceutical composition - Google Patents

Abstract

To provide an oral pharmaceutical composition having enhanced analgesic action of nabumetone.SOLUTION: In an oral pharmaceutical composition, a sedative, acetaminophen, and/or vitamin are used in combination, which can result in dramatically enhanced analgesic action of nabumetone.SELECTED DRAWING: None

Description

The present invention relates to an orally administered pharmaceutical composition containing nabumetone. More specifically, the present invention relates to an orally administered pharmaceutical composition in which the analgesic effect of nabumetone is enhanced.

Non-steroidal anti-inflammatory drugs such as nabumetone, diclofenac sodium, ibuprofen, and loxoprofen sodium have less concern about serious side effects as seen with steroidal anti-inflammatory drugs, and there are few restrictions on the amount and duration of use. It is widely used in oral pharmaceutical compositions for the purpose of analgesia, fever reduction, anti-inflammatory and the like. Among the non-steroidal anti-inflammatory drugs, nabumetone is metabolized in the liver and converted to the active form 6-methoxy-2-naphthylacetic acid, and the activated form has a higher inhibitory effect on cyclooxygenase 2 than cyclooxygenase 1. It is a steroidal anti-inflammatory drug. Among the non-steroidal anti-inflammatory drugs, nabumetone is known to be taken less frequently and have relatively few side effects.

Conventionally, various studies have been conducted on pharmaceutical formulations having enhanced analgesic action of steroidal anti-inflammatory agents. For example, Patent Document 1 discloses that the anti-inflammatory analgesic effect is enhanced by using menthols in combination with a phenylacetic acid derivative or salt such as nabumetone or diclofenac. Further, Patent Document 2 discloses that the analgesic effect is enhanced by the combined use of a propionic acid-based analgesic such as ibuprofen and two or more kinds of B vitamins. Has not been considered.

Japanese Unexamined Patent Publication No. 2003-286161 Japanese Unexamined Patent Publication No. 2008-247822

In recent years, there has been an increasing demand for enhanced drug efficacy in the pharmaceutical field, and there is a demand for the development of a technique for enhancing the analgesic action of nabumetone by a new formulation technology. Therefore, an object of the present invention is to provide an oral pharmaceutical composition having an enhanced analgesic effect of nabumetone.

The present inventor has conducted diligent studies to solve the above problems, and found that nabumetone analgesia when nabumetone is used in combination with a hypnotic sedative, acetaminophen, and / or vitamin in an oral pharmaceutical composition. We have found that the action can be dramatically enhanced. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following aspects.
Item 1. An oral pharmaceutical composition comprising (A) nabumetone and (B) at least one selected from the group consisting of hypnotic sedatives, acetaminophen, and vitamins.
Item 2. Item 2. The pharmaceutical composition for internal use according to Item 1, wherein the total amount of the component (B) is 0.1 to 1000 parts by weight per 100 parts by weight of the component (A).
Item 3. Item 2. The pharmaceutical composition for internal use according to Item 1 or 2, wherein the component (B) is at least one selected from the group consisting of bromovaleryl urea, acetaminophen, and vitamin B _2.
Item 4. Item 4. The pharmaceutical composition for internal use according to any one of Items 1 to 3, which is used for analgesic use.
Item 5. A way to enhance the analgesic effect of nabumetone
A method for enhancing an analgesic effect, which comprises a pharmaceutical composition for internal use, together with nabumetone, at least one selected from the group consisting of a hypnotic sedative, acetaminophen, and vitamins.

According to the oral pharmaceutical composition of the present invention, the analgesic effect of nabumetone can be dramatically enhanced by using nabumetone in combination with a hypnotic sedative, acetaminophen, and / or vitamin.

It is a figure which shows the result of having evaluated the analgesic effect by the acetic acid rising method in Test Example 1. It is a figure which shows the result of having evaluated the analgesic effect by the acetic acid rising method in Reference Test Example 1.

1. 1. Oral Pharmaceutical Composition The internal pharmaceutical composition of the present invention is selected from at least a group consisting of nabumetone (sometimes referred to as "component (A)"), a hypnotic sedative, acetaminophen, and vitamins. It is characterized by containing one type (sometimes referred to as "(B) component"). Hereinafter, the pharmaceutical composition for internal use of the present invention will be described in detail.

[(A) component]
The pharmaceutical composition for internal use of the present invention contains nabumetone as an analgesic ingredient. Nabumetone is a known non-steroidal anti-inflammatory drug also called 4- (6-methoxynaphthalene-2-yl) -2-butanone.

The content of the component (A) in the oral pharmaceutical composition of the present invention may be appropriately set according to the dosage form, dosage and the like, and is, for example, 1 to 90% by weight, preferably 5 to 80% by weight. Can be mentioned.

[(B) component]
The oral pharmaceutical composition of the present invention contains at least one selected from the group consisting of hypnotic sedatives, acetaminophen, and vitamins as a component that enhances the analgesic effect of nabumetone. By using these components (B) in combination with nabumetone, the analgesic effect of nabumetone can be dramatically enhanced.

Among the components (B), examples of hypnotic sedatives include bromovaleryl urea, allylisopropylacetylurea, triazolam, lylmazafone hydrochloride, lormetazepam, zopiclone, eszopiclone, zolpidem tartrate, brotizolam, estazolam, flunitrazepam, nitrazepam, and flurazepam hydrochloride. Examples include salt, quazepam, haloxazolam and the like. These hypnotic sedatives may be used alone or in combination of two or more. Among these hypnotic sedatives, bromovaleryl urea is preferably mentioned.

Among the components (B), acetaminophen is a known compound used as a non-steroidal anti-inflammatory drug in the pharmaceutical field.

Among the components (B), the vitamin may be any of vitamin B, vitamin A, vitamin C, vitamin D, vitamin E, and vitamin K.

_{Specific examples of vitamin B include vitamin B 2} such as riboflavin, riboflavin butyrate, and sodium riboflavine phosphate _{; vitamin B 1} such as thiamine hydrochloride, thiamine sulfate, bistiamine nitrate, thiamine disulfide, and thiamine disetyl sulfate ester salt; hydrochloric acid. _{Vitamin B 6} such as pyridoxin and pyridoxal phosphate _{; Vitamin B 12} such as cyanocobalamin, methylcobalamine, hydroxocobalamine acetate, hydroxocobalamine hydrochloride; niacin such as nicotinic acid and nicotinic acid amide; pantenol, pantothenic acid, calcium pantothenate, pantoten Pantothenic acids such as sodium acid acid; examples thereof include folic acid and biotin.

Specific examples of vitamin A include retinyl acetate, retinol palmitate, vitamin A oil, cod liver oil, and strong liver oil.

Specific examples of vitamin C include ascorbic acid, calcium ascorbic acid, sodium ascorbic acid, glucoside ascorbic acid, ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate and the like.

Specific examples of vitamin D include ergocalciferol and choleciferol.

Specific examples of vitamin E include tocopherol, tocopherol acetate, tocopherol succinate, and calcium tocopherol succinate.

Specific examples of vitamin K include phylloquinone, menaquinone, menadione, menadiol, 4-amino-2-methyl-1-naphthol and the like.

These vitamins may be used alone or in combination of two or more. Among these vitamins, vitamin B is preferable, vitamin B ₂ is more preferable, and riboflavin is more preferable.

These (B) components may be used alone or in combination of two or more.

Further, in the pharmaceutical composition for internal use of the present invention, the ratio of the component (A) to the component (B) is, for example, 0.1 to 1000 weight by weight of the total amount of the component (B) per 100 parts by weight of the component (A). The department is mentioned. From the viewpoint of further enhancing the analgesic effect of nabumetone, the preferable ratio of the component (A) to the component (B) for each type of the component (B) is as follows.
When the component (B) is a hypnotic sedative : per 100 parts by weight of nabumetone, the hypnotic sedative is preferably 1 to 1000 parts by weight, more preferably 5 to 500 parts by weight, still more preferably 10 to 100 parts by weight.
When the component (B) is acetaminophen : per 100 parts by weight of nabumetone, acetaminophen is preferably 1 to 1000 parts by weight, more preferably 10 to 100 parts by weight, still more preferably 30 to 200 parts by weight.
When the component (B) is a vitamin : per 100 parts by weight of nabumetone, the vitamin is preferably 0.1 to 100 parts by weight, more preferably 0.2 to 10 parts by weight, still more preferably 2 to 2.5 parts by weight. ..

Regarding the content of the component (B) in the pharmaceutical composition for internal use of the present invention, the type and dosage form of the component (B) to be used within the range corresponding to the ratio of the component (A) and the component (B) described above. , And may be appropriately set according to the dose and the like, and examples thereof include 0.1 to 90% by weight.

The suitable contents of the component (A) and the component (B) for each type of the component (B) are as follows.
When the component (B) is a hypnotic sedative : the component (A) is 1-95% by weight and the hypnotic sedative is 5-99% by weight, preferably the component (A) is 30-90% by weight and the hypnotic sedative. 10 to 70% by weight, more preferably 50 to 60% by weight of component (A) and 40 to 50% by weight of hypnotic sedative.
When the component (B) is acetaminophen : the component (A) is 1 to 95% by weight and acetaminophen is 5 to 99% by weight, preferably the component (A) is 30 to 70% by weight and acetaminophen is. 30-70% by weight, more preferably 45-55% by weight of component (A) and 45-55% by weight of acetaminophen.
When the component (B) is a vitamin : the component (A) is 5 to 99.99% by weight and the vitamin is 0.01 to 95% by weight, preferably the component (A) is 50 to 99.9% by weight and the vitamin is. 0.1 to 10% by weight, more preferably 70 to 99% by weight of the component (A) and 1 to 2% by weight of vitamins.

[Other ingredients]
The pharmaceutical composition for internal use of the present invention may contain other pharmacological components in addition to the above-mentioned components, if necessary. The types of such pharmacological components are not particularly limited, but for example, anti-inflammatory analgesics other than nabumetone and acetaminophen, intestinal motility improving agents, digestive agents, antispasmodics, mucosal repair agents, astringent agents, antiemetic agents, antitussive agents, etc. Examples include antispasmodics, anti-inflammatory enzyme agents, antihistamines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, crude drugs, crude drug extracts, caffeines, menthols, polyphenols, etc. .. These pharmacological components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the dosage form of the pharmaceutical composition for internal use, and the like.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable base, additives and the like, if necessary, in order to prepare a desired dosage form. Such bases and additives include, for example, excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers. Agents, suspending agents, pressure-sensitive agents, coating agents, brighteners, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols Types, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents and the like. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately set according to the type of additive component to be used, the dosage form of the pharmaceutical composition for internal use, and the like.

[Dosage form]
The dosage form of the pharmaceutical composition for internal use of the present invention is not particularly limited, and may be any of a solid-state preparation, a semi-solid-state preparation, and a liquid-state preparation.

Specific examples of the solid-state preparation include tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup) and the like. Specific examples of the semi-solid preparation include a jelly agent and the like. Specific examples of the liquid preparation include liquid preparations, suspension preparations, syrup preparations and the like.

Among these dosage forms, a solid-state preparation is preferable.

In order to prepare the pharmaceutical composition for internal use of the present invention in the above-mentioned dosage form, the component (A), the component (B), and other pharmacological components, the base, and the additive added as needed are used. , It may be formulated according to the usual formulation method adopted in the pharmaceutical field.

[Dosage and administration]
Since the oral pharmaceutical composition of the present invention can exert an excellent analgesic effect, for example, headache, menstrual pain (physiological pain) / toothache, post-extraction pain, sore throat, lower back pain, joint pain, nerve pain, muscle pain, etc. It can be used for the purpose of relieving pain such as stiff shoulder pain, ear pain, bruising pain, fracture pain, sore throat, and traumatic pain; relieving fever during cold and fever; and alleviating sensation symptoms.

The dose of the pharmaceutical composition for internal use of the present invention may be appropriately set according to the degree of symptoms, the age of the user, and the like. For example, the daily dose of nabumetone is about 200 to 1600 mg, preferably 400. The dose may be about 1000 mg once a day, and may be divided into a plurality of doses depending on the age and symptoms.

2. Method for enhancing analgesic action The present invention is a method for further enhancing the analgesic action of nabumetone, which is selected from the group consisting of a sedative, acetaminophen, and vitamin in an oral pharmaceutical composition together with nabumetone. Provided is a method for enhancing an analgesic action, which comprises blending one kind.

The types of ingredients used in the method for enhancing the analgesic action, the blending amount, the dosage form of the pharmaceutical composition for internal use, and the like are as described in the column of "1. Pharmaceutical composition for internal use".

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.

Test Example 1: Evaluation test of analgesic effect 6-week-old male mice (Slc: ddy, Nippon SLC Co., Ltd.) were used in 6 groups (per group) of a control group and a test group (Examples 1 to 3 and Comparative Example 1). 13 to 15 animals). After the mice in each group were bred for 1 week and acclimatized, the test was conducted under the following conditions.

-Control group After fasting for about 16 hours, an aqueous solution (control solution) containing 0.1% by weight of carboxymethyl cellulose was orally administered so as to be 10 ml / kg (mouse body weight). Fifty minutes after the administration of the control solution, a 0.6 wt% acetic acid aqueous solution was intraperitoneally administered to 20 ml / kg (mouse body weight). The number of mouse rising behaviors (exercises to stretch the hind limbs) for 10 minutes after 10 minutes of administration of the acetic acid aqueous solution was measured.

-After fasting for about 16 hours in the test group, the test solution in which the components shown in Table 1 were added to the control solution at a predetermined dose was orally administered at a rate of 10 ml / kg (mouse body weight). Fifty minutes after the administration of the test solution, a 0.6 wt% acetic acid aqueous solution was intraperitoneally administered to 20 ml / kg (mouse body weight). The number of mouse rising behaviors (exercises to stretch the hind limbs) for 10 minutes after 10 minutes of administration of the acetic acid aqueous solution was measured.

The results are shown in FIG. As a result, when nabumetone was used in combination with acetaminophen, bromovaleryl urea, or riboflavin (Examples 1 to 3), the number of rising actions was significantly reduced as compared with the case of nabumetone alone (Comparative Example 1). It was confirmed that the analgesic effect of nabumetone was significantly enhanced.

Reference Test Example 1: Evaluation of analgesic action As a test group, a test was conducted in the same manner as in Test Example 1 except that the components shown in Table 2 were administered at a predetermined dose, and the rising behavior was determined. I asked for the number of times. In this test, 7 to 10 mice per group were used. Diclofenac sodium is the same phenylacetic acid-based non-steroidal anti-inflammatory drug as nabumetone.

The results are shown in FIG. As a result, when diclofenac sodium was used in combination with acetaminophen, bromovaleryl urea, or riboflavin (Reference Examples 2 to 4), the number of rising actions was the same as when diclofenac sodium was used alone (Reference Example 1). Or there was a tendency to increase. That is, from the results of this test, the enhancement of the analgesic effect by using nabumetone and acetaminophen, bromovaleryl urea, or riboflavin is a peculiar effect observed when nabumetone is selected as a non-steroidal anti-inflammatory drug. It was confirmed that there was.

Examples of pharmaceuticals Tablets having the compositions shown in Tables 3 to 5 were prepared. In Tables 3 to 5, the unit of the content of each component is the daily dose (mg). These tablets can be expected to dramatically improve the analgesic effect of nabumetone.

Claims (5)

An oral pharmaceutical composition comprising (A) nabumetone and (B) at least one selected from the group consisting of hypnotic sedatives, acetaminophen, and vitamins. The pharmaceutical composition for internal use according to claim 1, wherein the total amount of the component (B) is 0.1 to 1000 parts by weight per 100 parts by weight of the component (A). The oral pharmaceutical composition according to claim 1 or 2, wherein the component (B) is at least one selected from the group consisting of bromovaleryl urea, acetaminophen, and vitamin B _2. The pharmaceutical composition for internal use according to any one of claims 1 to 3, which is used for analgesic use. A way to enhance the analgesic effect of nabumetone
A method for enhancing an analgesic effect, which comprises a pharmaceutical composition for internal use, together with nabumetone, at least one selected from the group consisting of a hypnotic sedative, acetaminophen, and vitamins.

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