JP7769741B2 - Oral pharmaceutical composition - Google Patents

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.

Non-steroidal anti-inflammatory drugs such as nabumetone, diclofenac sodium, ibuprofen, and loxoprofen sodium are less likely to cause serious side effects like those seen with steroidal anti-inflammatory drugs, and there are fewer restrictions on dosage and duration of use. Therefore, they are widely used in oral pharmaceutical compositions for analgesia, antipyresis, anti-inflammation, etc. Among non-steroidal anti-inflammatory drugs, nabumetone is metabolized in the liver and converted to its active form, 6-methoxy-2-naphthylacetic acid, and this activated form is a non-steroidal anti-inflammatory drug with a stronger inhibitory effect on cyclooxygenase 2 than cyclooxygenase 1. Among non-steroidal anti-inflammatory drugs, nabumetone is known to require less frequent administration and to have relatively few side effects.

Various studies have been conducted on pharmaceutical formulations that enhance the analgesic effects of steroidal anti-inflammatory drugs. 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. Furthermore, Patent Document 2 discloses that the analgesic effects are enhanced by combining a propionic acid analgesic such as ibuprofen with two or more types of B vitamins, but no specific studies have been conducted on formulations containing nabumetone.

Japanese Patent Application Laid-Open No. 2003-286161 Japanese Patent Application Laid-Open No. 2008-247822

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

The present inventors conducted extensive research to solve the above-mentioned problems and discovered that the analgesic effect of nabumetone can be dramatically enhanced by combining nabumetone with synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon, and/or cinnamon extract 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. A pharmaceutical composition for oral administration comprising (A) nabumetone and (B) at least one member selected from the group consisting of synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon bark, and cinnamon bark extract.
Item 2. The pharmaceutical composition for internal use according to Item 1, comprising 0.1 to 6,000 parts by weight of the total amount of component (B) per 100 parts by weight of component (A) (provided that, when component (B) is cinnamon bark or cinnamon bark extract, the amount is calculated as the crude drug).
Item 3. The oral pharmaceutical composition according to Item 1 or 2, wherein the component (B) is synthetic hydrotalcite.
Item 4. The oral pharmaceutical composition 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:
A method for enhancing analgesic effect, comprising blending nabumetone and at least one member selected from the group consisting of synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon, and cinnamon extract into 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 synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon, and/or cinnamon extract.

FIG. 1 shows the results of evaluating the analgesic effect by the acetic acid writhing method in Test Example 1. FIG. 1 shows the results of evaluation of 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 is characterized by containing nabumetone (hereinafter sometimes referred to as "ingredient (A)") and at least one selected from the group consisting of synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon, and cinnamon extract (hereinafter sometimes referred to as "ingredient (B)"). The oral pharmaceutical composition of the present invention is described in detail below.

[Component (A)]
The oral 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 oral pharmaceutical composition of the present invention may be appropriately determined depending on the dosage form, dosage amount, etc., but may be, for example, 1 to 90% by weight, preferably 5 to 80% by weight.

[(B) component]
The oral pharmaceutical composition of the present invention contains at least one component selected from the group consisting of synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon, and cinnamon extract as a component that enhances the analgesic effect of nabumetone. By using this component (B) in combination with nabumetone, the analgesic effect of nabumetone can be dramatically enhanced.

Of the (B) components, synthetic hydrotalcite and magnesium carbonate are well-known inorganic compounds used in the pharmaceutical field as antacids, etc.

Among the components (B), aldioxa is a well-known inorganic compound used in the pharmaceutical field as a gastric mucosa protective agent, etc.

Of the (B) components, cinnamon is the dried bark of Cinnamon Bark (Cinnamon) of the Lauraceae family and other plants of the same genus, and is a well-known ingredient used as a herbal medicine. The cinnamon used in the present invention may be in the form of crushed, shredded, powdered, or dried versions of these, but powdered form (cinnamon powder) is preferred.

Of the (B) components, cinnamon extract is an extract obtained by extracting cinnamon bark as the extraction raw material, and can be obtained by known extraction methods. Examples of extraction solvents used in the extraction process for cinnamon bark extract include polar solvents such as water (including hot water); lower alcohols such as ethanol; polyhydric alcohols such as 1,3-butylene glycol; and mixtures of these. Water, ethanol, 1,3-butylene glycol, or a mixture of these solvents is preferred. The extraction method used in the production of cinnamon bark extract is not particularly limited, and any common extraction method used in the production of herbal extracts can be used. Examples include immersing the raw herbal medicine in the extraction solvent by cold or hot infusion, with stirring as needed; percolation; and steam distillation. The resulting extract can be filtered or centrifuged to remove solids, if necessary, to recover the herbal extract. The liquid extract obtained by the above extraction process may be used as is, or, if necessary, the cinnamon bark extract may be used as a concentrated liquid (soft extract) or dried product (dry extract) after removing some or all of the solvent. Furthermore, these concentrated liquids (soft extracts) or dried products (dry extracts) may be further purified, or may be dissolved or suspended in an appropriate solvent before use.

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

In addition, in the oral pharmaceutical composition of the present invention, the ratio of component (A) to component (B) can be, for example, 0.1 to 6,000 parts by weight of the total amount of component (B) per 100 parts by weight of component (A). When component (B) is cinnamon bark and/or cinnamon bark extract, the ratio is calculated based on the crude drug equivalent amount of cinnamon bark and/or cinnamon bark extract. "Equivalent amount of crude drug" refers to the weight (dry weight) of the herb required to obtain that amount of ingredient. In the case of cinnamon itself, the weight of the cinnamon bark to be blended is the crude drug equivalent amount, and in the case of cinnamon extract, the dry weight of cinnamon bark required to obtain the amount of cinnamon extract to be blended is the crude drug equivalent amount.

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 synthetic hydrotalcite : the amount of synthetic hydrotalcite is preferably 0.1 to 6,000 parts by weight, more preferably 1 to 3,000 parts by weight, and even more preferably 10 to 1,000 parts by weight per 100 parts by weight of nabumetone.
When component (B) is magnesium carbonate : the amount of magnesium carbonate is preferably 0.1 to 3,000 parts by weight, more preferably 1 to 1,000 parts by weight, and even more preferably 10 to 500 parts by weight per 100 parts by weight of nabumetone.
When component (B) is aldioxa : the amount of aldioxa is preferably 0.1 to 1,000 parts by weight, more preferably 1 to 500 parts by weight, and even more preferably 1 to 100 parts by weight per 100 parts by weight of nabumetone.
When component (B) is cinnamon bark and/or cinnamon bark extract : the amount of cinnamon bark and/or cinnamon bark extract is preferably 0.1 to 6,000 parts by weight, more preferably 1 to 3,000 parts by weight, and even more preferably 30 to 1,000 parts by weight, in terms of crude drug 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 depending on the type, dosage form, and dosage of component (B) used, within the range corresponding to the ratio of component (A) to component (B) described above, but may be, for example, 0.1 to 95% by weight.

The preferred contents of components (A) and (B) for each type of component (B) are as follows:
When component (B) is synthetic hydrotalcite : 5 to 99% by weight of component (A) and 1 to 95% by weight of synthetic hydrotalcite, preferably 10 to 50% by weight of component (A) and 50 to 90% by weight of synthetic hydrotalcite, and more preferably 15 to 30% by weight of component (A) and 70 to 85% by weight of synthetic hydrotalcite.
When component (B) is magnesium carbonate : 5 to 99% by weight of component (A) and 1 to 95% by weight of magnesium carbonate, preferably 20 to 70% by weight of component (A) and 30 to 80% by weight of magnesium carbonate, and more preferably 25 to 35% by weight of component (A) and 65 to 75% by weight of magnesium carbonate.
When component (B) is aldioxa : 5 to 99% by weight of component (A) and 1 to 95% by weight of aldioxa, preferably 50 to 95% by weight of component (A) and 5 to 50% by weight of aldioxa, more preferably 60 to 70% by weight of component (A) and 30 to 40% by weight of aldioxa.
When the (B) component is cinnamon bark and/or cinnamon bark extract : the (A) component is 5 to 95% by weight and the cinnamon bark and/or cinnamon bark extract is 5 to 95% by weight in terms of the crude drug, preferably the (A) component is 13 to 65% by weight and the cinnamon bark and/or cinnamon bark extract is 35 to 87% by weight in terms of the crude drug, more preferably the (A) component is 10 to 20% by weight and the cinnamon bark and/or cinnamon bark extract is 80 to 90% by weight in terms of the crude drug.

[Other ingredients]
The oral 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 include vitamins, anti-inflammatory analgesics other than nabumetone, intestinal motility improvers, digestive agents, antispasmodics, mucosal repair agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives and hypnotics, 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. The content of these pharmacological ingredients may be appropriately determined depending on the type of pharmacological ingredient used, the dosage form of the oral pharmaceutical composition, etc.

The pharmaceutical composition of the present invention may contain pharmaceutically acceptable bases and additives, as necessary, to prepare the composition into the 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, flavoring agents, fragrances, powders, thickeners, dyes, and chelating agents. These bases and additives may be used alone or in combination of two or more. The amount of these bases and additives may be appropriately determined depending on the type of added ingredient used and the dosage form of the oral pharmaceutical composition.

[Dosage form]
The dosage form of the oral 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, component (A), component (B), and optionally other pharmacological ingredients, bases, and additives may be formulated according to conventional formulation techniques used in the pharmaceutical field.

[Dosage/Dosage]
The oral pharmaceutical composition of the present invention has an enhanced analgesic effect and can exert an excellent analgesic effect, and can therefore be used for purposes such as relieving pain from headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, neuralgia, muscle pain, stiff shoulder pain, earache, pain from bruises, bone fractures, sprains, pain from trauma, etc.; 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 recipient, etc. For example, the daily dose of nabumetone may be approximately 200 to 1600 mg, preferably approximately 400 to 1000 mg, taken once a day, or may be divided into multiple doses depending on the recipient'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 nabumetone and at least one member selected from the group consisting of synthetic hydrotalcite, magnesium carbonate, aldioxa, cinnamon bark, and cinnamon bark extract into an oral pharmaceutical composition.

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

The present invention will be explained in more detail below using 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 (7 to 11 mice per group) consisting of a control group and test groups (Examples 1 to 4 and Comparative Example 1). The mice in each group were kept for 1 week to allow them to acclimate, and then the test was carried out under the following conditions.

Control group: After fasting for approximately 16 hours, mice were orally administered 10 ml/kg (mouse body weight) of an aqueous solution containing 0.1 wt% carboxymethylcellulose (control solution). Fifty minutes after administration of the control solution, 20 ml/kg (mouse body weight) of a 0.6 wt% aqueous acetic acid solution was intraperitoneally administered. The number of times the mice writhed (stretched their hind limbs) for 10 minutes after administration of the acetic acid solution was counted.

After fasting for approximately 16 hours, the test group was orally administered a test solution containing the components shown in Table 1 added to the control solution at a predetermined dose at 10 ml/kg (mouse body weight). 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 mice writhed (stretched their hind limbs) for 10 minutes starting 10 minutes after administration of the aqueous acetic acid solution was counted.

The results are shown in Figure 1. As a result, when nabumetone was used in combination with magnesium carbonate, aldioxa, synthetic hydrotalcite, or cinnamon powder (Examples 1 to 4), 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 at the prescribed doses, and the number of writhing behaviors was determined. Diclofenac sodium is a phenylacetic acid-based non-steroidal 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 magnesium carbonate, aldioxa, synthetic hydrotalcite, or cinnamon powder (Reference Examples 2 to 5), the number of writhing behaviors tended to be equal to 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 diclofenac sodium in combination with magnesium carbonate, aldioxa, synthetic hydrotalcite, or cinnamon powder is a unique effect observed when nabumetone is selected as the non-steroidal anti-inflammatory agent.

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

Claims (4)

An oral pharmaceutical composition containing (A) nabumetone and (B) aldioxa. The oral pharmaceutical composition according to claim 1, comprising a total amount of 0.1 to 6,000 parts by weight of component (B) per 100 parts by weight of component (A). The oral pharmaceutical composition according to claim 1 or 2, 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 aldioxa together with nabumetone into an oral pharmaceutical composition.