Oral pharmaceutical composition

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

Technical Field

[0001] The present invention relates to an oral pharmaceutical composition containing nabumetone. More specifically, the present invention relates to an oral pharmaceutical composition in which the analgesic effect of nabumetone is enhanced.

Background Art

[0002] Non-steroidal anti-inflammatory drugs such as nabumetone, diclofenac sodium, ibuprofen, and loxoprofen sodium have few concerns about serious side effects as seen in steroidal anti-inflammatory drugs, and have few restrictions on the dosage and duration of use, etc. Therefore, they are widely used in oral pharmaceutical compositions for the purpose of analgesia, antipyretic, anti-inflammatory, etc. Among non-steroidal anti-inflammatory drugs, nabumetone is metabolized in the liver and converted to the active form 6-methoxy-2-naphthylacetic acid, and the active form is a non-steroidal anti-inflammatory drug with a higher inhibitory effect on cyclooxygenase 2 than on cyclooxygenase 1. Among non-steroidal anti-inflammatory drugs, nabumetone is known to have fewer dosing times and relatively fewer side effects.

[0003] Conventionally, various studies have been conducted on formulation prescriptions for enhancing the analgesic effect of steroidal anti-inflammatory drugs. For example, Patent Document 1 discloses that the anti-inflammatory and analgesic effect is enhanced by combining phenylacetic acid derivatives or salts such as nabumetone and diclofenac with menthols. Further, Patent Document 2 discloses that the analgesic effect is enhanced by combining propionic acid-based analgesics such as ibuprofen with two or more types of vitamin Bs, but specific studies on formulations containing nabumetone have not been conducted.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] In recent years, in the pharmaceutical field, the demand for enhancing the drug efficacy has been increasing, and the development of a technology for enhancing the analgesic effect of nabumetone by a new formulation technology has been demanded. Therefore, an object of the present invention is to provide an oral pharmaceutical composition having an enhanced analgesic effect of nabumetone.

Means for Solving the Problems

[0006] The present inventors conducted intensive studies to solve the above problems, and as a result, found that when nabumetone is used in combination with a hypnotic sedative, acetaminophen, and / or a vitamin in an oral pharmaceutical composition, the analgesic effect of nabumetone can be remarkably enhanced. The present invention has been completed by further studies based on such findings.

[0007] That is, the present invention provides an invention in the following aspects. Item 1. An oral pharmaceutical composition containing (A) nabumetone and at least one selected from the group consisting of (B) a hypnotic sedative, acetaminophen, and a vitamin. Item 2. The oral pharmaceutical composition according to Item 1, wherein the component (B) is contained in a total amount of 0.1 to 1000 parts by weight per 100 parts by weight of the component (A). Item 3. The oral pharmaceutical composition according to Item 1 or 2, wherein the component (B) is at least one selected from the group consisting of bromovalerylurea, acetaminophen, and vitamin B2. Item 4. The oral pharmaceutical composition according to any one of Items 1 to 3, which is used for analgesic use. Item 5. A method for enhancing the analgesic effect of nabumetone, A method for enhancing the analgesic effect, which comprises formulating at least one selected from the group consisting of a hypnotic sedative, acetaminophen, and a vitamin together with nabumetone in an oral pharmaceutical composition.

Effects of the Invention

[0008] According to the oral pharmaceutical composition of the present invention, by combining nabumetone with a hypnotic sedative, acetaminophen, and / or a vitamin, the analgesic effect of nabumetone can be remarkably enhanced.

Brief Description of the Drawings

[0009]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0010] 1. Oral pharmaceutical composition The oral pharmaceutical composition of the present invention contains nabumetone (which may also be referred to as “component (A)”), and at least one selected from the group consisting of a hypnotic sedative, acetaminophen, and a vitamin (which may also be referred to as “component (B)”). Hereinafter, the oral pharmaceutical composition of the present invention will be described in detail.

[0011] [Component (A)] The oral pharmaceutical composition of the present invention contains nabumetone as an analgesic component. Nabumetone is a known non- steroidal anti-inflammatory agent also called 4-(6-methoxynaphthalen-2-yl)-2-butanone.

[0012] Regarding the content of component (A) in the oral pharmaceutical composition of the present invention, it may be appropriately set according to the dosage form, dosage, etc., but for example, 1 to 90% by weight, preferably 5 to 80% by weight can be mentioned.

[0013] [Component (B)]​The oral pharmaceutical composition of the present invention contains at least one selected from the group consisting of hypnotics, acetaminophen, and vitamins as a component for enhancing the analgesic effect of nabumetone. By using these component (B) in combination with nabumetone, the analgesic effect of nabumetone can be enhanced dramatically.

[0014] Among the component (B), examples of the hypnotic include bromovaleryl urea, allylisopropyl acetyl urea, triazolam, lormetazepam hydrochloride, lorazepam, zopiclone, eszopiclone, zolpidem tartrate, brotizolam, estazolam, flunitrazepam, nitrazepam, flurazepam hydrochloride, quazepam, haloxazolam and the like. These hypnotics may be used alone or in combination of two or more. Among these hypnotics, bromovaleryl urea is preferably mentioned.

[0015] Among the component (B), acetaminophen is a known compound used as a non-steroidal anti-inflammatory drug in the pharmaceutical field.

[0016] Among the component (B), the vitamin may be any of vitamin B, vitamin A, vitamin C, vitamin D , vitamin E, and vitamin K.

[0017] Specific examples of vitamin B include vitamin B2 such as riboflavin, riboflavin butyrate, sodium riboflavin phosphate; vitamin B1 such as thiamine hydrochloride, thiamine sulfate, bisthiamine nitrate, thiamine disulfide, cetyl thiamine disulfate; vitamin B6 such as pyridoxine hydrochloride, pyridoxal phosphate; vitamin B 12 such as cyanocobalamin, methylcobalamin, hydroxocobalamin acetate, hydroxocobalamin hydrochloride; niacin such as nicotinic acid, nicotinamide; pantothenic acids such as panthenol, pantothenic acid, calcium pantothenate, sodium pantothenate; folic acid, biotin and the like.​

[0018] As vitamin A, specifically, retinol acetate, retinol palmitate, vitamin A oil, fish liver oil, cod liver oil, etc. can be mentioned.

[0019] As vitamin C, specifically, ascorbic acid, calcium ascorbate, sodium ascorbate, ascorbyl glucoside, ascorbyl phosphate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, etc. can be mentioned.

[0020] As vitamin D, specifically, ergocalciferol, cholecalciferol, etc. can be mentioned.

[0021] As vitamin E, specifically, tocopherol, tocopherol acetate, tocopherol succinate, calcium tocopherol succinate, etc. can be mentioned.

[0022] As vitamin K, specifically, phylloquinone, menaquinone, menadione, menadiol, 4-amino-2-methyl-1-naphthol, etc. can be mentioned.

[0023] These vitamins may be used alone or in combination of two or more. Among these vitamins, vitamin B is preferably used, and vitamin B2 is more preferably used. More preferably, riboflavin can be mentioned.

[0024] These (B) components may be used alone or in combination of two or more. Also, in the oral pharmaceutical composition of the present invention, as the ratio of the (A) component to the (B) component, for example, per 100 parts by weight of the (A) component, the total amount of the (B) component is 0.1 to 1000 parts by weight. From the viewpoint of further enhancing the analgesic action of nabumetone, the preferred ratios of the (A) component to the (B) component for each type of the (B) component are as follows.

[0025] (B) component is a hypnotic sedative : Per 100 parts by weight of nabumetone, the hypnotic and sedative agent 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. (B) component 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. (B) component 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.

[0026] Regarding the content of component (B) in the oral pharmaceutical composition of the present invention, within the range according to the ratio of component (A) and component (B) described above, it may be appropriately set according to the type, dosage form, dosage, etc. of component (B) to be used. For example, 0.1 to 90% by weight can be mentioned.

[0027] The preferred contents of component (A) and component (B) for each type of component (B) are as follows. (B) component is a hypnotic sedative : Component (A) is 1 to 95% by weight and the hypnotic and sedative agent is 5 to 99% by weight, preferably component (A) is 30 to 90% by weight and the hypnotic and sedative agent is 10 to 70% by weight, more preferably component (A) is 50 to 60% by weight and the hypnotic and sedative agent is 40 to 50% by weight. (B) component is acetaminophen : Component (A) is 1 to 95% by weight and acetaminophen is 5 to 99% by weight, preferably component (A) is 30 to 70% by weight and acetaminophen is 30 to 70% by weight, more preferably component (A) is 45 to 55% by weight and acetaminophen is 45 to 55% by weight. (B) component is a vitamin : Component (A) is 5 to 99.99% by weight and the vitamin is 0.01 to 95% by weight, preferably component (A) is 50 to 99.9% by weight and the vitamin is 0.1 to 10 % by weight, more preferably, the component (A) is 70 to 99% by weight and the vitamin is 1 to 2% by weight.

[0028] [Other contained components] In addition to the components described above, the oral pharmaceutical composition of the present invention may contain other pharmacological components as necessary. The types of such pharmacological components are not particularly limited. For example, anti-inflammatory and analgesic agents other than nabumetone and acetaminophen, intestinal motility improvers, digestive agents, antispasmodics, mucosal repair agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzyme agents, antihistamines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, crude drugs, crude drug extracts, caffeine, menthol, polyphenols, etc. may be mentioned. These pharmacological components may be used alone or in combination of two or more. Also, the content of these pharmacological components may be appropriately set according to the type of pharmacological component used and the dosage form of the oral pharmaceutical composition.

[0029] In order to prepare the pharmaceutical composition of the present invention into a desired dosage form, pharmaceutically acceptable bases, additives, etc. may be contained as necessary. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, tonicity agents, plasticizers, dispersants, emulsifiers, solubilizing agents, wetting agents, stabilizers, suspending agents, adhesives, coating agents, gloss agents, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, ultraviolet ray preventives, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents, etc. These bases and additives may be used alone or in combination of two or more. Also, the content of these bases and additives may be appropriately set according to the type of additive component used and the dosage form of the oral pharmaceutical composition.

[0030] [Dosage form] The dosage form of the oral pharmaceutical composition of the present invention is not particularly limited and may be any of solid preparations, semi-solid preparations, or liquid preparations.

[0031] Examples of solid preparations include tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrups), and the like. Examples of semi-solid preparations include jelly preparations and the like. Examples of liquid preparations include solutions, suspensions, syrup preparations, and the like.

[0032] Among these dosage forms, solid preparations are preferably used.

[0033] To prepare the oral pharmaceutical composition of the present invention into the above dosage forms, components (A), (B), and other pharmacological components, bases, and additives added as necessary can be used, and formulation can be carried out according to the usual formulation methods employed in the pharmaceutical field.

[0034] [Dosage and Administration] Since the oral pharmaceutical composition of the present invention can exhibit an excellent analgesic effect, for example, it can be used for the purposes of analgesia for headache, menstrual pain (dysmenorrhea), toothache, pain after tooth extraction, sore throat, low back pain, joint pain, neuralgia, muscle pain, stiff shoulder pain, earache, contusion pain, fracture pain, gout pain, trauma pain, etc.; antipyretic effect during chills and fever; and relief of cold symptoms.

[0035] Regarding the dosage of the oral pharmaceutical composition of the present invention, it may be appropriately set according to the degree of symptoms, age of the user, etc. For example, the daily dosage of nabumetone is about 200 to 1600 mg, preferably about 400 to 1000 mg, and it may be taken once a day, or may be taken in multiple divided doses depending on age and symptoms.

[0036] 2. Method for enhancing analgesic effect The present invention further provides a method for enhancing the analgesic action of nabumetone, which is characterized in that at least one selected from the group consisting of a sedative, acetaminophen, and a vitamin is formulated together with nabumetone in an oral pharmaceutical composition.

[0037] In the method for enhancing the analgesic effect, the types of components used, the compounding amounts, the dosage forms of the oral pharmaceutical compositions, etc. are as described in the column of "1. Oral pharmaceutical composition" above.

Examples

[0038] Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[0039] Test Example 1: Evaluation test of analgesic effect Six-week-old male mice (Slc: ddy, Japan SLC Inc.) were divided into six groups (13 to 15 mice per group) of a control group and test groups (Examples 1 to 3 and Comparative Example 1). After breeding and acclimating the mice in each group for one week, the tests were conducted under the following conditions.

[0040] · Control group After fasting for about 16 hours, an aqueous solution containing 0.1% by weight of carboxymethyl cellulose (control solution) was orally administered at 10 ml / kg (mouse body weight). Fifty minutes after the administration of the control solution, an aqueous solution of 0.6% by weight acetic acid was intraperitoneally administered at 20 ml / kg (mouse body weight). The number of rising behaviors (movements of stretching the hind legs) of the mice for 10 minutes starting 10 minutes after the administration of the acetic acid aqueous solution was measured.

[0041] · Test group After fasting for about 16 hours, a test solution obtained by adding the components shown in Table 1 to the control solution so as to have a predetermined dosage was orally administered at 10 ml / kg (mouse body weight). Fifty minutes after the administration of the test solution, an aqueous solution of 0.6% by weight acetic acid was intraperitoneally administered at 20 ml / kg (mouse body weight). The number of rising behaviors (movements of stretching the hind legs) of the mice for 10 minutes starting 10 minutes after the administration of the acetic acid aqueous solution was measured.

[0042]

Table 1

[0043] The results are shown in Figure 1. As a result, when nabumetone was used in combination with acetaminophen, bromovalerylurea, or riboflavin (Examples 1 to 3), the number of rising behaviors was significantly reduced compared to the case of nabumetone alone (Comparative Example 1), and it was confirmed that the analgesic effect of nabumetone was significantly enhanced.

[0044] Reference Test Example 1: Evaluation test of analgesic effect 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 so as to have a predetermined dosage, and the number of rising behaviors was determined. In this test, 7 to 10 mice were used per group. Diclofenac sodium is a phenylacetic acid-based non-steroidal anti-inflammatory drug similar to nabumetone.

[0045]

Table 2

[0046] The results are shown in Figure 2. As a result, when diclofenac sodium was used in combination with acetaminophen, bromovalerylurea, or riboflavin (Reference Examples 2 to 4), the number of rising behaviors tended to be equal to or more than that in the case of diclofenac sodium alone (Reference Example 1). That is, from the results of this test, it was confirmed that the enhancement of the analgesic effect by using nabumetone and acetaminophen, bromovalerylurea, or riboflavin is a specific effect observed when nabumetone is selected as a non-steroidal anti-inflammatory drug.

[0047] Formulation example Tablets having the compositions shown in Tables 3 to 5 were prepared. In Tables 3 to 5, the unit of the content of each contained component is the daily dosage (mg). A dramatic improvement in the analgesic effect of nabumetone can be expected from these tablets.

[0048]

Table 3

[0049]

Table 4

[0050]

Table 5

Claims

1. (A) Nabumetone, and (B) vitamin B ２ An oral pharmaceutical composition containing the same.

2. The oral pharmaceutical composition according to claim 1, containing 0.1 to 1000 parts by weight of the component (B) in total per 100 parts by weight of the component (A).

3. The oral pharmaceutical composition according to claim 1 or 2, wherein the component (B) is riboflavin.

4. The oral pharmaceutical composition according to any one of claims 1 to 3, which is used for analgesic use.

5. A method for enhancing the analgesic effect of nabumetone, comprising A method for enhancing analgesic effect, wherein vitamin B is formulated together with nabumetone in an oral pharmaceutical composition. ２ ​

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