JP2024055991A - 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 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.

Nonsteroidal anti-inflammatory agents such as nabumetone, diclofenac sodium, ibuprofen, and loxoprofen sodium are less likely to cause serious side effects as seen with steroidal anti-inflammatory agents, and are less restricted in terms of dosage and duration of use, and are therefore widely used in oral pharmaceutical compositions for the purposes of analgesia, antipyresis, anti-inflammation, etc. Among nonsteroidal anti-inflammatory agents, nabumetone is metabolized in the liver and converted to its active form, 6-methoxy-2-naphthylacetic acid, and this activated form is a nonsteroidal anti-inflammatory agent that has a higher inhibitory effect on cyclooxygenase 2 than on cyclooxygenase 1. Among nonsteroidal anti-inflammatory agents, nabumetone is known to be taken less frequently and to have relatively few side effects.

Various studies have been conducted on pharmaceutical formulations that enhance the analgesic effect of steroidal anti-inflammatory agents. For example, Patent Document 1 discloses that the anti-inflammatory and analgesic effects are enhanced by combining a phenylacetic acid derivative or salt such as nabumetone or diclofenac with a menthol. Patent Document 2 discloses that the analgesic effect is enhanced by combining a propionic acid analgesic such as ibuprofen with two or more types of vitamin B, but no specific studies have been conducted on formulations containing nabumetone.

JP 2003-286161 A JP 2008-247822 A

In recent years, there has been an increasing demand in the pharmaceutical field for enhanced efficacy, and there is a need to develop a technology to enhance the analgesic effect of nabumetone using new formulation technology. Therefore, the present invention aims to provide an oral pharmaceutical composition that enhances the analgesic effect of nabumetone.

The inventors have conducted extensive research to solve the above problems and have found that the analgesic effect of nabumetone can be dramatically enhanced by combining it with a sedative hypnotic, acetaminophen, and/or vitamins in an oral pharmaceutical composition. The present invention was completed based on this finding and through further research.

That is, the present invention provides the following aspects.
Item 1. An oral pharmaceutical composition comprising (A) nabumetone and (B) at least one member selected from the group consisting of hypnotics and sedatives, acetaminophen, and vitamins.
Item 2. The pharmaceutical composition for internal use according to Item 1, comprising a total amount of 0.1 to 1000 parts by weight of the component (B) per 100 parts by weight of the component (A).
Item 3. 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 bromovalerylurea, acetaminophen, and vitamin _B2 .
Item 4. The pharmaceutical composition for internal use according to any one of Items 1 to 3, which is used for analgesic purposes.
Item 5. A method for enhancing the analgesic effect of nabumetone, comprising the steps of:
A method for enhancing analgesic effect, comprising blending nabumetone together with at least one selected from the group consisting of hypnotics and sedatives, acetaminophen, and vitamins in an oral pharmaceutical composition.

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

FIG. 2 is a graph showing the results of evaluating the analgesic effect by the acetic acid writhing method in Test Example 1. FIG. 2 is a graph showing the results of evaluating the analgesic effect by the acetic acid writhing method in Reference Test Example 1.

1. Oral Pharmaceutical Composition The oral pharmaceutical composition of the present invention comprises nabumetone (sometimes referred to as "ingredient (A)") and
The oral pharmaceutical composition of the present invention is characterized by containing at least one selected from the group consisting of hypnotics, sedatives, acetaminophen, and vitamins (sometimes referred to as "ingredient (B)"). The oral pharmaceutical composition of the present invention is described in detail below.

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

The content of component (A) in the internal pharmaceutical composition of the present invention may be appropriately determined depending on the dosage form, dosage amount, etc., and may be, for example, 1 to 90% by weight, preferably 5 to 80% by weight.

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

Among the (B) components, examples of the hypnotic sedative include bromovalerylurea, allylisopropylacetylurea, triazolam, rilmazafone hydrochloride, lormetazepam, zopiclone, eszopiclone, zolpidem tartrate, brotizolam, estazolam, flunitrazepam, nitrazepam, flurazepam hydrochloride, quazepam, and haloxazolam. These hypnotic sedatives may be used alone or in combination of two or more. Among these hypnotic sedatives, bromovalerylurea is preferred.

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

(B) Vitamins included in the ingredients are vitamin B, vitamin A, vitamin C, and vitamin D.
, vitamin E, and vitamin K.

Specific examples of vitamin B include vitamin _B2 such as riboflavin, riboflavin butyrate, and riboflavin sodium phosphate; vitamin _B1 such as thiamine hydrochloride, thiamine sulfate, bisthiamine nitrate, thiamine disulfide, and thiamine dicetyl sulfate; vitamin _B6 such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin _B12 such as cyanocobalamin, methylcobalamin, hydroxocobalamin acetate, and hydroxocobalamin hydrochloride; niacin such as nicotinic acid and nicotinamide; pantothenic acids such as panthenol, pantothenic acid, calcium pantothenate, and sodium pantothenate; folic acid, biotin, etc.

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

Specific examples of vitamin C include ascorbic acid, calcium ascorbate, sodium ascorbate, ascorbyl glucoside, ascorbyl phosphate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, etc.

Specific examples of vitamin D include ergocalciferol and cholecalciferol.

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

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

These vitamins may be used alone or in combination of two or more. Among these vitamins, vitamin B is preferred, and vitamin _B2 is more preferred.
and more preferably riboflavin.

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

In the oral pharmaceutical composition of the present invention, the ratio of component (A) to component (B) may be, for example, 0.1 to 1000 parts by weight of the total amount of component (B) per 100 parts by weight of component (A). From the viewpoint of further enhancing the analgesic effect of nabumetone, the preferred ratio of component (A) to component (B) for each type of component (B) is as follows:
When component (B) is a hypnotic sedative : the amount of the hypnotic sedative is preferably 1 to 1,000 parts by weight, more preferably 5 to 500 parts by weight, and even more preferably 10 to 100 parts by weight, per 100 parts by weight of nabumetone.
When component (B) is acetaminophen : the amount of acetaminophen is preferably 1 to 1,000 parts by weight, more preferably 10 to 100 parts by weight, and even more preferably 30 to 200 parts by weight, per 100 parts by weight of nabumetone.
When component (B) is a vitamin : the vitamin is preferably 0.1 to 100 parts by weight, more preferably 0.2 to 10 parts by weight, and even more preferably 2 to 2.5 parts by weight per 100 parts by weight of nabumetone.

The content of component (B) in the oral pharmaceutical composition of the present invention may be set appropriately according to the type, dosage form, and dosage of component (B) used within the range corresponding to the ratio of components (A) and (B) described above, and may be, for example, 0.1 to 90% by weight.

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

[Other ingredients]
The internal pharmaceutical composition of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned ingredients. The types of such pharmacological ingredients are not particularly limited, and examples thereof include anti-inflammatory analgesics other than nabumetone and acetaminophen, intestinal motility improvers, digestive agents, antispasmodics, mucosal repair agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, antihistamines, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, herbal medicines, herbal extracts, caffeines, menthols, polyphenols, etc. These pharmacological ingredients may be used alone or in combination of two or more kinds. The content of these pharmacological ingredients may be appropriately set according to the type of pharmacological ingredient used and the dosage form of the internal pharmaceutical composition.

The pharmaceutical composition of the present invention may contain pharma- ceutically acceptable bases and additives, etc., as necessary, in order to prepare the pharmaceutical composition into a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, flavorings, fragrances, powders, thickeners, dyes, chelating agents, etc. 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 used and the dosage form of the pharmaceutical composition for internal use.

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

Specific examples of solid preparations include tablets, pills, capsules (soft capsules, hard capsules), powders, and granules (including dry syrups).Specific examples of semi-solid preparations include jellies.Specific examples of liquid preparations include solutions, suspensions, and syrups.

Among these dosage forms, solid formulations are preferred.

To prepare the oral pharmaceutical composition of the present invention in the above dosage form, the composition may be formulated according to the usual formulation methods used in the pharmaceutical field using component (A), component (B), and other pharmacological ingredients, bases, and additives that are added as necessary.

[Dosage and Administration]
The internal pharmaceutical composition of the present invention can exhibit excellent analgesic effects and can therefore be used for purposes such as relieving pain from headaches, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, neuralgia, muscle pain, stiff shoulders, earache, bruises, fractures, sprains, and trauma; reducing fever during chills and fever; and alleviating cold symptoms.

The dosage of the oral pharmaceutical composition of the present invention may be appropriately determined depending on the severity of symptoms, the age of the user, etc. For example, the dosage of nabumetone per day is about 200 to 1600 mg, preferably about 400 to 1000 mg, and may be taken once per day, or may be taken in multiple divided doses depending on the user's age and symptoms.

2. Method for enhancing analgesic effect The present invention further provides a method for enhancing the analgesic effect of nabumetone, which comprises blending at least one member selected from the group consisting of a sedative, acetaminophen, and a vitamin together with nabumetone in an oral pharmaceutical composition.

In the method for enhancing analgesic effect, the types of ingredients used, the amounts of ingredients used, the dosage form of the oral pharmaceutical composition, etc. are as described in the above section "1. Oral pharmaceutical composition."

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Test Example 1: Evaluation test of analgesic effect Six-week-old male mice (Slc:ddy, Japan SLC Co., Ltd.) were divided into 6 groups (13 to 15 mice per group) of a control group and test groups (Examples 1 to 3 and Comparative Example 1). Each group of mice was kept for 1 week for acclimatization, and then the test was carried out under the following conditions.

Control group: After fasting for about 16 hours, an aqueous solution containing 0.1% by weight of carboxymethylcellulose (control solution) was orally administered at 10 ml/kg (mouse body weight). 50 minutes after administration of the control solution, an aqueous solution of 0.6% by weight of acetic acid was intraperitoneally administered at 20 ml/kg (mouse body weight). The number of times the mouse writhed (stretched hind limbs) occurred for 10 minutes starting 10 minutes after administration of the aqueous solution of acetic acid was counted.

Test group: After fasting for about 16 hours, a test solution was orally administered to the control solution at 10 ml/kg (mouse body weight) in which the components shown in Table 1 were added to give a prescribed dose. 50 minutes after administration of the test solution, a 0.6 wt% aqueous acetic acid solution was intraperitoneally administered at 20 ml/kg (mouse body weight). The number of times the mouse writhed (stretched hind legs) occurred was counted for 10 minutes starting 10 minutes after administration of the aqueous acetic acid solution.

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 writhing behaviors was significantly reduced compared to when nabumetone was used alone (Comparative Example 1), confirming that the analgesic effect of nabumetone was significantly enhanced.

Reference Test Example 1: Evaluation test of analgesic effect The test was conducted in the same manner as in Test Example 1, except that the test groups were administered with the components shown in Table 2 in the prescribed doses, and the number of writhing behaviors was calculated. This test was conducted using 7 to 10 mice per group. Diclofenac sodium is a phenylacetic acid-based nonsteroidal anti-inflammatory drug, the same as nabumetone.

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 writhing behaviors tended to be equal or greater than when diclofenac sodium was used alone (Reference Example 1). In other words, the results of this test confirmed that the enhanced analgesic effect achieved by using nabumetone in combination with acetaminophen, bromovalerylurea, or riboflavin is a unique effect observed when nabumetone is selected as a nonsteroidal anti-inflammatory agent.

Tablets having the compositions shown in Formulation Examples Tables 3 to 5 were prepared. The units of the content of each ingredient in Tables 3 to 5 are the daily dose (mg). These tablets are expected to dramatically improve the analgesic effect of nabumetone.

Claims (5)

1. A pharmaceutical composition for oral administration comprising (A) nabumetone and (B) vitamin _B2 . The pharmaceutical composition for internal use according to claim 1, which contains 0.1 to 1000 parts by weight of the component (B) in total per 100 parts by weight of the component (A). The pharmaceutical composition for internal use according to claim 1 or 2, wherein the component (B) is riboflavin. The pharmaceutical composition for internal use according to any one of claims 1 to 3, which is used for analgesic purposes. 1. A method for enhancing the analgesic effect of nabumetone, comprising:
A method for enhancing analgesic effect by incorporating vitamin _B2 together with nabumetone into an oral pharmaceutical composition.