JP7584882B2 - Internal 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 anti-inflammatory effect of nabumetone is improved.

Non-steroidal anti-inflammatory drugs such as nabumetone, diclofenac sodium, ibuprofen, and loxoprofen sodium are less likely to cause serious side effects as seen with steroidal anti-inflammatory drugs, and there are fewer restrictions on the dosage and duration of use, so they are widely used in internal pharmaceutical compositions for the purposes of antipyresis, analgesia, anti-inflammation, etc.

On the other hand, in recent years, there has been a demand in the pharmaceutical field for improved efficacy, and there is a demand for improved anti-inflammatory effects in pharmaceutical compositions that use non-steroidal anti-inflammatory agents. Increasing the dose of a non-steroidal anti-inflammatory agent leads to improved anti-inflammatory effects, but some non-steroidal anti-inflammatory agents are accompanied by side effects such as gastric mucosal damage, and increasing the dose is not necessarily effective.

Therefore, various studies have been conducted on formulations that enhance the anti-inflammatory effect of steroidal anti-inflammatory agents. For example, Patent Document 1 reports that the anti-inflammatory effect of loxoprofen is enhanced by combining loxoprofen with caffeine, allylisopropylacetylurea, bromvalerylurea, acetaminophens, and/or ethenzamide. However, the formulation technology disclosed in Patent Document 1 is not applicable to other non-steroidal anti-inflammatory agents.

On the other hand, nabumetone is metabolized in the liver and converted to the active form 6-methoxy-2-naphthylacetic acid, and this activated form is a nonsteroidal anti-inflammatory drug that has a stronger inhibitory effect on cyclooxygenase 2 than on cyclooxygenase 1. Among nonsteroidal anti-inflammatory drugs, nabumetone is known to require less administration and to have relatively few side effects, and oral pharmaceutical compositions containing nabumetone have been put to practical use. However, formulation technology that can improve the anti-inflammatory effect of nabumetone has not yet been fully investigated.

JP 11-139971 A

The present invention aims to provide an oral pharmaceutical composition that improves the anti-inflammatory effect of nabumetone.

The present inventors have conducted extensive research to solve the above problems and have found that the anti-inflammatory effect of nabumetone can be dramatically improved by combining liquorice, cinnamon bark, moutan tree, valerian, Japanese pepper, ginger, Zithium Root, Mallotus japonicus, Corydalis rotundifolia, and/or extracts thereof with nabumetone in an internal 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) Nabumetone, and
(B) at least one selected from the group consisting of licorice, cinnamon bark, moutan tree, valerian, Japanese pepper, ginger, jiru, Mallotus japonicus, Corydalis rotundifolia, and extracts thereof;
A pharmaceutical composition for internal use comprising:
Item 2. The pharmaceutical composition for internal use according to Item 1, comprising 1 to 90% by weight of the component (A).
Item 3. The pharmaceutical composition for internal use according to Item 1 or 2, comprising the component (B) in an amount equivalent to a daily dose of 400 to 12,000 mg in terms of the amount of the original herbal drug.
Item 4. The pharmaceutical composition for internal use according to any one of Items 1 to 3, comprising 1 to 6,000 parts by weight of the component (B) per 100 parts by weight of the component (A), calculated as the amount of the raw herbal medicine.
Item 5. The pharmaceutical composition for internal use according to any one of Items 1 to 4, wherein the component (B) is licorice and/or licorice extract.
Item 6. A method for enhancing the anti-inflammatory effect of nabumetone, comprising:
A method for enhancing anti-inflammatory action, comprising blending nabumetone with at least one member selected from the group consisting of licorice, cinnamon bark, moutan peel, valerian, Japanese pepper, ginger, Zithium Root, Mallotus japonicus, Corydalis rotundifolia, and extracts thereof, in an internal pharmaceutical composition.

According to the internal pharmaceutical composition of the present invention, the anti-inflammatory effect of nabumetone is dramatically improved by combining it with a specific herbal medicine such as licorice and/or its extract, and an excellent anti-inflammatory and analgesic effect can be exhibited. Therefore, the internal pharmaceutical composition of the present invention is highly effective in analgesia, antipyresis, and easing cold symptoms, etc.

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 licorice, cinnamon bark, moutan peel, valerian, Japanese pepper, ginger, Zithium Root, Mallotus japonicus, Corydalis rotundifolia, and extracts thereof (hereinafter sometimes referred to as "ingredient (B)"). The oral pharmaceutical composition of the present invention will be described in detail below.

[Component (A)]
The internal pharmaceutical composition of the present invention contains nabumetone as an anti-inflammatory and 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 topical pharmaceutical composition of the present invention may be appropriately set depending on the dosage form, dosage amount, etc., but may be, for example, 1 to 90% by weight, preferably 1.5 to 90% by weight, and more preferably 8 to 70% by weight.

[Component (B)]
The pharmaceutical composition for internal use of the present invention contains at least one selected from the group consisting of licorice, cinnamon bark, moutan pea, valerian, Japanese pepper, ginger, Zithroat, Mallotus japonicus, Corydalis rotundifolia, and extracts thereof as an ingredient for enhancing the anti-inflammatory effect. By using these ingredients (B) in combination with nabumetone, the anti-inflammatory effect of nabumetone can be dramatically improved.

Licorice is the root and/or rhizome of a plant of the genus Licorice in the family Fabaceae, and is a well-known ingredient used as a herbal medicine. The licorice used in the present invention may be in the form of crushed material, shredded material, or a dried product thereof.

Cinnamon is the dried bark of Cinnamon bark 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 material, shredded material, or a dried form of either of these.

Peony root is the bark of the Peony family, a well-known ingredient used as a herbal medicine. The Peony root used in the present invention may be crushed, shredded, or dried.

Valerian is the root of the Valeriana officinalis plant of the family Valeriana, and is a well-known ingredient used as a herbal medicine. The Valerian used in the present invention may be in the form of crushed material, shredded material, or a dried product thereof.

Zanthoxylum nigricans is the pericarp of Zanthoxylum nigricans, a member of the Rutaceae family, and is a well-known ingredient used as a herbal medicine. The Zanthoxylum nigricans used in the present invention may be in the form of crushed or shredded material, or a dried form of either of these.

Zingiber officinale is the rhizome of Zingiberaceae, and is a well-known ingredient used as a herbal medicine. The ginger used in the present invention may be crushed, shredded, or dried.

Jiryu is the whole or internal parts of Pheretima aspergillum Perrier or other closely related animals, and is a well-known ingredient used as a herbal medicine. The jiryu used in the present invention may be in the form of crushed material, shredded material, or dried products thereof.

Mallotus japonicus is the bark of Mallotus japonicus, a tree of the Euphorbiaceae family, and is a well-known ingredient used as a herbal medicine. The Mallotus japonicus used in the present invention may be in the form of crushed material, shredded material, or a dried product thereof.

Corydalis rotundifolia is the tuber of Corydalis rotundifolia, a plant of the Fumaceae family, and is a well-known ingredient used as a herbal medicine. The Corydalis rotundifolia used in the present invention may be in the form of crushed material, shredded material, or dried material thereof.

Herbal extracts made from these herbal medicines can be obtained by extraction processing using known methods.

The extraction solvents used in the extraction process of these herbal extracts 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, with water, ethanol, 1,3-butylene glycol, or mixtures of these being preferred.

The extraction method used in the production of these herbal extracts is not particularly limited, and may be any common extraction method used in the production of herbal extracts. Examples include a method in which the raw herbal medicine is immersed in an extraction solvent by cold immersion, hot immersion, etc., and stirred as necessary; a percolation method; and a steam distillation method. The herbal extract can be recovered by removing solid matter from the obtained extract by filtration or centrifugation as necessary.

In the pharmaceutical composition for internal use of the present invention, the liquid extract obtained by the above extraction process may be used as it is, or, if necessary, a concentrated liquid (soft extract) or a dried product (dry extract) may be used after removing a part or all of the solvent. In addition, these concentrated liquids (soft extracts) or dried products (dry extracts) may be subjected to further purification processes, or may be dissolved or suspended in an appropriate solvent before use.

Among the (B) ingredients, herbal extracts (especially dried extracts) are preferably used because the active ingredients are concentrated, the amount of the preparation can be reduced, and it is easy to formulate them into the desired dosage form.

In the pharmaceutical composition for internal use of the present invention, component (B) may be one selected from licorice, cinnamon bark, moutan pea, valerian, Japanese pepper, ginger, zirconium, Mallotus japonicus, Corydalis rotundifolia, and extracts thereof, and used alone, or two or more of these may be used in combination.

Of these (B) components, licorice and licorice extract are preferred from the viewpoint of improving the anti-inflammatory effect of nabumetone.

The content of component (B) in the internal pharmaceutical composition of the present invention may be appropriately determined depending on the type of component (B) used, the daily dose, dosage form, administration amount, etc. The daily dose is 400 to 12,000 mg, preferably 1,000 to 10,000 mg, calculated as the amount of raw herbal medicine.

In the present invention, the "equivalent amount of raw herbal medicine" is the weight (dry weight) of the herbal medicine required to obtain the amount of the ingredient. In the case of the herbal medicine itself, the weight of the herbal medicine to be mixed is the equivalent amount of raw herbal medicine, and in the case of a herbal medicine extract, the dry weight of the herbal medicine required to obtain the amount of the herbal medicine extract to be mixed is the equivalent amount of raw herbal medicine.

In addition, in the internal pharmaceutical composition of the present invention, the ratio of component (A) to component (B) is not particularly limited as long as it is within the range corresponding to the above-mentioned respective contents, but for example, the amount of component (B) is 1 to 6,000 parts by weight, preferably 2 to 6,000 parts by weight, calculated as the raw herbal drug, per 100 parts by weight of component (A).

[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 vitamins, anti-inflammatory analgesics other than nabumetone, intestinal motility improvers, antacids, gastric mucosa protectors, digestive agents, antispasmodics, mucosa repair agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, 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 depending on 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 has an improved anti-inflammatory effect and can exhibit excellent anti-inflammatory and 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 a day, or may be taken in multiple divided doses depending on the user's age and symptoms.

2. Method for enhancing anti-inflammatory effect The present invention further provides a method for enhancing the anti-inflammatory effect of nabumetone, which comprises blending, together with nabumetone, at least one member selected from the group consisting of licorice, cinnamon bark, moutan peel, valerian, Japanese pepper, ginger, Zithium Root, Mallotus japonicus, Corydalis rotundifolia, and extracts thereof, into an internal pharmaceutical composition.

In the method for enhancing anti-inflammatory action, 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 anti-inflammatory effect Five-week-old male rats (Slc:Wister (SPF), Japan SLC Co., Ltd.) were divided into four groups (six rats per group): a normal group, a control group, and a test group (Example 1 and Comparative Example 1). After the rats in each group were kept for one week to acclimate, a test was carried out under the following conditions.

Normal group: At the start of the test (-1 hr), 10 ml of water for injection (distilled water) was orally administered to the rats per kg (rat body weight), and no carrageenan was administered thereafter. The volume of the hind paw was measured at the start of the test (-1 hr) (before administration of the water for injection), and then every hour from 2 hours (1 hr) to 6 hours (5 hrs) after the start of the test.

Control group: At the start of the test (-1 hr), 10 ml/kg (rat body weight) of water for injection (distilled water) was orally administered to the rats. One hour (0 hr) after the start of the test, 0.1 ml/head of saline containing 1% by weight of carrageenin was subcutaneously administered to the rats' hind paws to induce edema due to inflammation. The volume of the hind paws was measured at the start of the test (-1 hr) (before administration of the water for injection), and was measured every hour from 1 hr to 5 hr after carrageenin administration.

Test group: At the start of the test (-1 hr), the test solution was orally administered to rats at a dose of 10 ml/kg (rat body weight) by adding the components shown in Table 1 to water for injection (distilled water) to obtain the prescribed dose. One hour (0 hr) after the start of the test, physiological saline containing 1% by weight of carrageenin was subcutaneously administered to the rats' hind footpad at 0.1 ml/head. The hind footpad volume was measured at the start of the test (-1 hr) (before administration of the test solution), and further measured every hour from 1 hour (1 hr) to 5 hours (5 hrs) after carrageenin administration.

The rat hind paw volume was measured using a digital paw volume measuring device ("Digital Plethysmometer LE7500", Panlab, SLU) with water. From the measured hind paw volume, the edema rate (%) and AUC (sum of edema rates) (% x time) were calculated according to the following formula. The edema rate and AUC were calculated for each individual, and the average value for each group was calculated.

The results are shown in Table 2. In the control group, the edema rate and AUC were high, and carrageenan administration induced inflammation. When nabumetone was administered alone (Comparative Example 1), the edema rate and AUC were reduced to a certain extent compared to the control group. In contrast, when liquorice extract was administered together with nabumetone (Example 1), the edema rate and AUC were significantly lower than in the control group, and the anti-inflammatory effect was dramatically improved.

Reference Test Example 1: Evaluation test of anti-inflammatory effect The test was conducted in the same manner as in Test Example 1, except that the test groups were administered the components shown in Table 3 in the prescribed doses, and the edema rate and AUC were determined. Diclofenac sodium is a phenylacetic acid-based nonsteroidal anti-inflammatory drug, the same as nabumetone.

The results are shown in Table 4. As a result, when diclofenac sodium was used in combination with licorice extract (Reference Example 2), the edema rate tended to be higher and the AUC increased compared to when diclofenac sodium was used alone (Reference Example 1). In other words, the anti-inflammatory effect was reduced. In other words, the results of this test confirmed that the improvement in anti-inflammatory effect by using licorice extract is a unique effect observed when nabumetone is selected as the non-steroidal anti-inflammatory agent.

Granules (Formulation Examples 1 to 4, and 8 to 10) and tablets (Formulation Examples 5 to 7, and 11 to 30) were prepared having the compositions shown in Formulation Examples Tables 5 and 6. The units of the content of each ingredient in Tables 5 and 6 are the daily dose (mg). These granules and tablets are expected to dramatically improve the anti-inflammatory effect of nabumetone.

The dosage forms, etc. of the herbal medicines shown in Tables 5 and 6 are as follows:
・Licorice powder : Powdered herbal medicine
・Cinnamon powder : Powdered herbal medicine
・Peony root powder : Powdered herbal medicine
・Valeriana powder : Powdered herbal medicine
・Zanthoxylum powder : Powdered herbal medicine
・Ginger powder : Herbal powder
・Jiryu Powder: Powdered herbal medicine
Mallotus japonicus powder : Powdered herbal medicine
・Corydalis powder : Powdered herbal medicine
Licorice extract powder : dried extract, extraction solvent is water, 5 times concentrated extract in terms of raw herbal medicine
・Cinnamon extract powder : dried extract, extraction solvent is water, 22 times concentrated extract in terms of raw herbal medicine
・Ginger extract powder : dried extract, 5 times concentrated extract in terms of raw herbal medicine
・Jiryu Extract Powder : Dried extract, extraction solvent is 30% ethanol aqueous solution, 5 times concentrated extract in terms of raw herbal medicine
Mallotus japonicus extract powder : dried extract, extraction solvent is water, 10 times concentrated extract in terms of raw herbal medicine

Claims (5)

(A) Nabumetone, and
(B) licorice and/or licorice extract,
An internal medicinal composition containing the above (excluding medicinal compositions containing peony root and/or its extract) . The pharmaceutical composition for internal use according to claim 1, which contains 1 to 90% by weight of the component (A). The pharmaceutical composition for internal use according to claim 1 or 2, containing the component (B) in an amount equivalent to a daily dose of 400 to 12,000 mg in raw drug form. The pharmaceutical composition for internal use according to any one of claims 1 to 3, which contains 1 to 6,000 parts by weight of the component (B) calculated as the amount of raw herbal medicine per 100 parts by weight of the component (A). 1. A method for enhancing the anti-inflammatory effect of nabumetone, comprising:
A method for enhancing anti-inflammatory effect, comprising blending liquorice and/or liquorice extract together with nabumetone in an oral pharmaceutical composition.