JP7229012B2 - Pharmaceutical composition for internal use - Google Patents

Description

The present invention relates to an internal pharmaceutical composition containing nabumetone. More particularly, the present invention relates to an internal pharmaceutical composition with improved anti-inflammatory action of nabumetone.

Non-steroidal anti-inflammatory agents such as nabumetone, diclofenac sodium, loxoprofen sodium, etc. have fewer concerns about serious side effects than those seen with steroidal anti-inflammatory agents. It is widely used in internal pharmaceutical compositions for analgesia, anti-inflammation and the like.

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

Therefore, conventionally, various investigations have been made on formulations of steroidal anti-inflammatory agents that enhance the anti-inflammatory action itself. For example, Patent Document 1 discloses that the anti-inflammatory action of loxoprofens is enhanced by the combined use of loxoprofens and caffeines, allylisopropylacetylurea, bromvalerylurea, acetaminophens and/or ethenzamide. has been reported. However, the formulation technology disclosed in Patent Document 1 is not applicable to non-steroidal anti-inflammatory agents other than loxoprofen.

On the other hand, nabumetone is a non-steroidal anti-inflammatory drug that is metabolized in the liver and converted to its active form, 6-methoxy-2-naphthylacetic acid, which has a higher inhibitory effect on cyclooxygenase-2 than on cyclooxygenase-1. . Among non-steroidal anti-inflammatory agents, nabumetone is known to be taken less frequently and has relatively few side effects, and an oral pharmaceutical composition containing nabumetone has been put into practical use. However, in preparations using nabumetone, sufficient studies have not yet been conducted on techniques that can improve the anti-inflammatory effect.

JP-A-11-139971

An object of the present invention is to provide a pharmaceutical composition for internal use with improved anti-inflammatory action.

As a result of intensive studies to solve the above problems, the present inventor found that nabumetone and a specific non-steroidal anti-inflammatory agent (specifically, salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, oxabrozine, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and/or these It was found that the anti-inflammatory effect can be dramatically improved when used in combination with a salt of The present invention has been completed through further studies based on such findings.

That is, the present invention provides inventions in the following aspects.
Section 1. (A) nabumetone, and
(B) salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam , at least one selected from the group consisting of celecoxib, valdecoxib, parecoxib, and salts thereof;
A pharmaceutical composition for internal use containing
Section 2. Item 2. The pharmaceutical composition for internal use according to Item 1, comprising 1 to 95% by weight of component (A).
Item 3. Item 3. The pharmaceutical composition for internal use according to Item 1 or 2, comprising 0.03 to 3000 parts by weight of component (B) per 100 parts by weight of component (A).
Section 4. Item 4. The pharmaceutical composition for internal use according to any one of Items 1 to 3, wherein the component (B) is at least one selected from the group consisting of salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen and salts thereof.
Item 5. A method for enhancing anti-inflammatory action in an internal pharmaceutical composition, comprising:
(B) salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, A method for enhancing anti-inflammatory activity, comprising adding at least one selected from the group consisting of oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof.

According to the pharmaceutical composition for internal use of the present invention, the combined use of nabumetone and a specific non-steroidal anti-inflammatory agent dramatically improves the anti-inflammatory action and exhibits excellent anti-inflammatory and analgesic action. be able to. Therefore, the pharmaceutical composition for internal use of the present invention can exhibit remarkable effects in analgesia, antipyretic, alleviation of cold symptoms, and the like.

1 is a diagram showing the results of measuring changes over time in the edema rate for each group in Test Example 1. FIG. 1 is a diagram showing the results of measuring AUC (total edema rate) for each group in Test Example 1. FIG. 1 is a diagram showing the results of measurement of changes in edema rate over time for each group in Reference Test Example 1. FIG. 1 is a diagram showing the results of measuring AUC (total edema rate) for each group in Reference Test Example 1. FIG.

1. Pharmaceutical Composition for Internal Use The pharmaceutical composition for internal use of the present invention comprises nabumetone (hereinafter sometimes referred to as "ingredient (A)"), salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, acetaminophen and lactyl. At least selected from the group consisting of phenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, oxabrozine, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof It is characterized by containing one type (hereinafter sometimes referred to as "component (B)"). The pharmaceutical composition for internal use of the present invention is described in detail below.

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

The content of component (A) in the topical pharmaceutical composition of the present invention may be appropriately set according to the dosage form, dosage, etc. More preferably 2 to 70% by weight.

[(B) component]
The pharmaceutical composition for internal use of the present invention contains, as component (B), salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, It contains at least one selected from the group consisting of oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof. By using these components (B) in combination with nabumetone, the anti-inflammatory action can be dramatically improved.

Specific examples of salicylic acid derivatives of component (B) include ethenzamide, choline salicylate, acetylsalicylic acid, and sazapyrin.

Examples of component (B) in the form of salts include alkali metal salts of salicylic acid such as sodium salicylate and potassium salicylate; alkali metal salts of acetylsalicylic acid such as sodium acetylsalicylate and potassium acetylsalicylate; .

In the pharmaceutical composition for internal use of the present invention, as component (B), salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, One of oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof may be selected and used alone, or two or more of these may be used. May be used in combination.

Among these components (B), salicylic acid, salicylic acid derivatives, salicylic acid, ibuprofen, and salts thereof are preferred from the viewpoint of more effectively improving the anti-inflammatory action; salicylic acid derivatives and salicylic acid are more preferred. Derivative salts, ibuprofen; particularly preferred are ethenzamide and ibuprofen.

The content of component (B) in the pharmaceutical composition for internal use of the present invention may be appropriately set according to the type of component (B) used, daily dosage, dosage form, dosage, etc. For example, 0.01 to 95% by weight, preferably 0.1 to 90% by weight, more preferably 0.2 to 80% by weight.

More specifically, if salicylic acid, a salicylic acid derivative, salicylamide, and/or a salt thereof is used as component (B), the content of component (B) in the pharmaceutical composition for internal use of the present invention is preferably 4 to 95% by weight, more preferably 4 to 90% by weight, and particularly preferably 5 to 90% by weight. When ibuprofen is used as component (B), the content of component (B) in the pharmaceutical composition for internal use of the present invention is preferably 1 to 85% by weight, more preferably 2 to 85% by weight. %, particularly preferably 2 to 80% by weight.

In addition, in the pharmaceutical composition for internal use of the present invention, the ratio of the components (A) and (B) is not particularly limited as long as it is within the range corresponding to the respective contents. 0.03 to 3,000 parts by weight, preferably 0.05 to 3,000 parts by weight, and more preferably 0.05 to 750 parts by weight of component (B) per 100 parts by weight of component.

More specifically, when using salicylic acid, a salicylic acid derivative, salicylamide, and/or a salt thereof as component (B), component (B) is preferably used per 100 parts by weight of component (A). is 6 to 3000 parts by weight, more preferably 10 to 3000 parts by weight, particularly preferably 10 to 750 parts by weight. In addition, when ibuprofen is used as component (B), component (B) is preferably 3 to 500 parts by weight, more preferably 5 to 500 parts by weight, particularly 5 to 125 parts by weight are preferred.

[Other ingredients]
The pharmaceutical composition for internal use of the present invention may contain other pharmacological ingredients in addition to the ingredients described above, if necessary. The types of such pharmacological ingredients are not particularly limited, but for example, vitamins, anti-inflammatory analgesics other than ingredients (A) and (B), intestinal motility improving agents, antacids, gastric mucosa protective agents, digestive antispasmodic, mucosal repair agent, astringent, antiemetic, antitussive, expectorant, antiphlogistic enzyme, sedative hypnotic, antihistamine, cardiac diuretic, antibacterial, vasoconstrictor, vasodilator, local anesthetic, proton pump inhibitors, herbal medicines, caffeines, menthols, polyphenols and the like. These pharmacological ingredients may be used singly or in combination of two or more. In addition, the content of these pharmacological ingredients may be appropriately set according to the type of pharmacological ingredient used, the dosage form of the internal pharmaceutical composition, and the like.

The pharmaceutical composition of the present invention may, if necessary, contain pharmaceutically acceptable bases, additives and the like in order to prepare a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, tonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, agents, 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 inhibitors, preservatives, corrigents, fragrances, powders, thickeners, pigments, chelating agents and the like. These bases and additives may be used singly or in combination of two or more. In addition, the contents of these bases and additives may be appropriately set according to the type of additive components 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 a solid formulation, a semi-solid formulation, or a liquid formulation.

Specific examples of solid preparations include tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup), and the like. Specific examples of semi-solid formulations include jelly agents and the like. Specific examples of liquid preparations include solutions, suspensions, syrups and the like.

Among these dosage forms, solid preparations are preferred.

In order to prepare the internal pharmaceutical composition of the present invention in the above dosage form, the components (A), (B), and optionally other pharmacological components, bases, and additives are used. , it may be formulated according to a general formulation technique employed in the pharmaceutical field.

[Dosage and administration]
The pharmaceutical composition for internal use of the present invention has an improved anti-inflammatory action and can exhibit excellent anti-inflammatory and analgesic effects. Low back pain, arthralgia, neuralgia, muscle pain, stiff shoulder pain, earache, bruise pain, bone fracture pain, sprain pain, trauma pain, etc.; alleviation of fever during chills and fever; alleviation of cold symptoms, etc. can be done.

The dosage 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 patient, etc. It may be taken in an amount of about 1000 mg once a day, or it may be taken in multiple doses depending on age and symptoms.

2. Method for Enhancing Anti-inflammatory Action The present invention further relates to a method for enhancing anti-inflammatory action, wherein (A) nabumetone and (B) salicylic acid, salicylic acid derivatives, salicylamide, ibuprofen, and acetone are added to a pharmaceutical composition for internal use. Aminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, felbinibirofen, oxabrozine, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof Provided is a method for enhancing anti-inflammatory action, characterized by blending at least one selected from the group consisting of:

In the method for enhancing anti-inflammatory action, the types and amounts of ingredients used, dosage form of the internal use pharmaceutical composition, etc. are as described in the above-mentioned "1. Internal use pharmaceutical composition".

EXAMPLES The present invention will be specifically described below by way of examples, but the present invention is not limited to these examples.

Test Example 1: Evaluation test of anti-inflammatory effect 5-week-old male rats (Slc:Wister (SPF), Japan SLC Co., Ltd.) were treated as a control group and a test group (Examples 1 and 2, and Comparative Example 1). They were divided into a total of 4 groups (6 animals per group), 3 groups). After the rats of each group were bred for one week and acclimatized, the test was conducted under the following conditions.

- Control group At the start of the test (-1 hr), water for injection (distilled water) was orally administered to 10 ml/kg (rat body weight). One hour after the start of the test (0 hr), 0.1 ml/head of physiological saline containing 1% by weight of carrageenan was subcutaneously administered to the hind foot pads of the rats to induce edema due to inflammation. Hind paw volume was measured at the beginning of the test (-1 hr) (before administration of water for injection), and further hind paw volume was measured every hour from 1 hour (1 hr) to 5 hours (5 hrs) after administration of carrageenan. Plantar volume was measured.

・Test group At the start of the test (-1 hr), the test solution obtained by adding the components shown in Table 1 to water for injection (distilled water) at a predetermined dosage was added to the rat at a dose of 10 ml / kg (rat body weight). was orally administered to One hour after the start of the test (0 hr), a physiological saline solution containing 1% by weight of carrageenan was subcutaneously administered to the hind foot pads of the rats at a dose of 0.1 ml/head. Hind paw volume was measured at the beginning of the test (−1 hr) (before administration of the test solution), and further hind paw volume was measured every hour from 1 hour (1 hr) to 5 hours (5 hrs) after administration of carrageenan. Plantar volume was measured.

Hind paw volumes of rats were measured using a water-based digital plethysmometer (“Digital Plethysmometer LE7500”, Panlab, SLU). The edema rate (%) and AUC (total edema rate) (%/time) were calculated from the measured hind leg paw volume according to the following formula. The edema rate and AUC were calculated for each individual, and the average values for each group were obtained. AUC was also statistically analyzed by student's t-test.

Table 2 shows the changes in edema rate over time and the results of AUC measurements. FIG. 1 shows the results of measuring changes in edema rate over time, and FIG. 2 shows the results of AUC measurements. As a result, in the control group, the edema rate and AUC were high, and inflammation was induced by administration of carrageenan. On the other hand, when nabumetone alone was administered (Comparative Example 1), the edema rate and AUC could be reduced to some extent compared to the control group. In contrast, when ethenzamide or ibuprofen was administered together with nabumetone (Examples 1 and 2), the edema rate and AUC were markedly lower than in the control group, and the anti-inflammatory effect was dramatically improved. Was.

Reference Test Example 1: Evaluation test of anti-inflammatory action As a test group, the test was performed in the same manner as in Test Example 1 except that the components shown in Table 3 were administered in predetermined dosages, and the edema rate was evaluated. and AUC were determined. Diclofenac sodium, like nabumetone, is a phenylacetic acid non-steroidal anti-inflammatory drug.

Table 4 shows the changes in edema rate over time and the results of AUC measurements. FIG. 3 shows the results of measuring changes in the edema rate over time, and FIG. 4 shows the results of measuring AUC. As a result, when diclofenac sodium was used in combination with ibuprofen (Reference Example 3), the edema rate and AUC were almost the same as when diclofenac sodium was used alone (Reference Example 1). Further, when diclofenac sodium and ethenzamide were used in combination (Reference Example 2), the edema rate and AUC tended to be higher than when diclofenac sodium was used alone (Reference Example 1). That is, from the results of this test, it was confirmed that the improvement in anti-inflammatory action observed in Examples 1 and 2 is a unique effect obtained by the combined use of nabumetone and ethenzamide or ibuprofen.

Preparation Examples Tablets (Formulation Examples 1 to 36, 38, 39, and 41 to 44) and granules (Formulation Examples 37 and 40) having compositions shown in Tables 5 to 7 were prepared. In Tables 5 to 7, the unit for the content of each ingredient is the dose (mg) per day. These granules and tablets are expected to have dramatically improved anti-inflammatory action.

Claims (4)

(A) nabumetone, and
(B) at least one selected from the group consisting of ethenzamide and ibuprofen ;
A pharmaceutical composition for internal use containing The pharmaceutical composition for internal use according to claim 1, comprising 1 to 95% by weight of component (A). 3. The pharmaceutical composition for internal use according to claim 1, comprising 0.03 to 3000 parts by weight of component (B) per 100 parts by weight of component (A). A method for enhancing anti-inflammatory action in an internal pharmaceutical composition, comprising:
A method for enhancing an anti-inflammatory action, comprising adding (A) nabumetone and (B) at least one selected from the group consisting of ethenzamide and ibuprofen to a pharmaceutical composition for internal use.

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