JP2020100610A - Oral pharmaceutical composition - Google Patents

Abstract

To provide an oral pharmaceutical composition having improved anti-inflammatory action.SOLUTION: In an oral pharmaceutical composition, use of nabumetone in combination with a specific nonsteroidal antiinflammatory agent can dramatically improve anti-inflammatory action. Specifically, the specific nonsteroidal antiinflammatory agent is salicylate, salicylate derivative, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, oxaprozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and/or salt thereof.SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical composition for oral administration containing nabumetone. More specifically, the present invention relates to a pharmaceutical composition for oral administration in which the anti-inflammatory effect of nabumetone is improved.

Nabumetone, diclofenac sodium, non-steroidal anti-inflammatory drug such as loxoprofen sodium, there is little concern of serious side effects as seen in steroidal anti-inflammatory drugs, because there are few restrictions such as the amount used and the period of use, antipyretic, It is widely used in internal-use pharmaceutical compositions for the purpose of analgesia, anti-inflammatory, etc.

On the other hand, in recent years, there has been a demand for improved drug efficacy in the pharmaceutical field, and it has been demanded to improve the anti-inflammatory effect even in a pharmaceutical composition using a nonsteroidal anti-inflammatory agent. Increasing the dose of non-steroidal anti-inflammatory drug leads to improvement of anti-inflammatory effect, but some non-steroidal anti-inflammatory drugs are accompanied by side effects such as gastric mucosal disorders, and increasing dose is not always effective. Not necessarily.

Therefore, various studies have hitherto been made on pharmaceutical formulations in which the anti-inflammatory action itself of steroidal anti-inflammatory agents is enhanced. For example, in Patent Document 1, by combining loxoprofen with caffeine, allylisopropylacetylurea, bromvalerylurea, acetaminophen and/or etenzamid, the anti-inflammatory action of loxoprofen is enhanced. Has been reported. However, the formulation technology disclosed in Patent Document 1 is not applicable to nonsteroidal anti-inflammatory agents other than loxoprofen.

On the other hand, nabumetone is a nonsteroidal anti-inflammatory drug that is metabolized in the liver and converted into the active form 6-methoxy-2-naphthylacetic acid, and the active form has a higher inhibitory effect on cyclooxygenase 2 than cyclooxygenase 1. .. Among non-steroidal anti-inflammatory agents, it is known that nabumetone is taken less frequently and has relatively few side effects, and a medicinal composition for oral administration containing nabumetone has been put to practical use. However, a technique capable of improving the anti-inflammatory effect in a preparation using nabumetone has not yet been sufficiently investigated.

Japanese Patent Laid-Open No. 11-139971

An object of the present invention is to provide a pharmaceutical composition for internal use that has an improved anti-inflammatory effect.

The present inventor has conducted extensive studies to solve the above problems, in a pharmaceutical composition for internal use, together with nabumetone, a specific nonsteroidal anti-inflammatory agent (specifically, salicylic acid, salicylic acid derivative, salicylamide, Ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, oxabrogin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and/or these It was found that the anti-inflammatory effect can be dramatically improved by using a combination thereof. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following modes.
Item 1. (A) Nabumetone, and
(B) salicylic acid, salicylic acid derivative, 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,
An orally-administered pharmaceutical composition containing:
Item 2. Item 2. The pharmaceutical composition for internal use according to Item 1, which contains the component (A) in an amount of 1 to 95% by weight.
Item 3. Item 3. The pharmaceutical composition for internal use according to Item 1 or 2, containing 0.03 to 3000 parts by weight of the component (B) per 100 parts by weight of the component (A).
Item 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 the anti-inflammatory effect in an internally administered pharmaceutical composition,
In the pharmaceutical composition for internal use, (A) together with nabumetone, (B) salicylic acid, salicylic acid derivative, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, A method for potentiating an anti-inflammatory effect, which comprises 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 internal-use pharmaceutical composition of the present invention, by combining nabumetone with a specific nonsteroidal anti-inflammatory agent, the anti-inflammatory effect is dramatically improved, and an excellent anti-inflammatory and analgesic effect is exhibited. be able to. Therefore, the pharmaceutical composition for internal use of the present invention can exhibit excellent effects in analgesia, antipyreticity, relief of common cold symptoms and the like.

FIG. 6 is a diagram showing the results of measuring the change over time in the edema rate for each group in Test Example 1. FIG. 3 is a diagram showing the results of measuring AUC (sum of edema rates) for each group in Test Example 1. It is a figure which shows the result of having measured the time-dependent change of the edema rate about each group in reference test example 1. In reference test example 1, it is a figure which shows the result of having measured AUC (sum of edema rate) about each group.

1. Pharmaceutical composition for internal use The pharmaceutical composition for internal use of the present invention is nabumetone (hereinafter sometimes referred to as “(A) component”) and salicylic acid, salicylic acid derivative, salicylamide, ibuprofen, acetaminophen, lactyl. At least selected from the group consisting of phenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lonoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof. It is characterized by containing one kind (hereinafter sometimes referred to as “(B) component”). Hereinafter, the pharmaceutical composition for internal use of the present invention will be described in detail.

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

The content of the component (A) in the external pharmaceutical composition of the present invention may be appropriately set depending on the dosage form, dose, etc., for example, 1 to 95% by weight, preferably 2 to 90% by weight, More preferably, it is 2 to 70% by weight.

[(B) component]
The oral pharmaceutical composition of the present invention, as the component (B), salicylic acid, salicylic acid derivative, 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) together with nabumetone, the anti-inflammatory effect can be dramatically improved.

Specific examples of the salicylic acid derivative of the component (B) include ethenamide, choline salicylate, acetylsalicylic acid, and sazapyrine.

Among the components (B), examples of the salt form component 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 internal-use pharmaceutical composition of the present invention, as the component (B), salicylic acid, salicylic acid derivative, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, Oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and one of these salts may be selected and used alone, or two or more of these may be used. You may use it in combination.

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

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

More specifically, as the component (B), salicylic acid, salicylic acid derivative, salicylamide, and / or if these salts are used, the content of the component (B) in the oral pharmaceutical composition 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. In the case of using ibuprofen as the component (B), the content of the 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.

Further, in the pharmaceutical composition for internal use of the present invention, the ratio of the component (A) and the component (B) may be within the range according to the respective contents, and is not particularly limited, but, for example, (A) The component (B) is used in an amount of 0.03 to 3000 parts by weight, preferably 0.05 to 3000 parts by weight, and more preferably 0.05 to 750 parts by weight, per 100 parts by weight of the component.

More specifically, when salicylic acid, a salicylic acid derivative, salicylamide, and/or a salt thereof is used as the component (B), the component (B) is preferably used per 100 parts by weight of the 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. When ibuprofen is used as the component (B), the component (B) is preferably 3 to 500 parts by weight, more preferably 5 to 500 parts by weight, particularly preferably 5 to 500 parts by weight, per 100 parts by weight of the component (A). Preferably, it is 5 to 125 parts by weight.

[Other ingredients]
The pharmaceutical composition for oral administration of the present invention may contain other pharmacological components, if necessary, in addition to the components described above. The type of such a pharmacological component is not particularly limited, but examples thereof include vitamins, anti-inflammatory analgesics other than the components (A) and (B), intestinal motility improvers, antacids, gastric mucosa protective agents, digestion. Agents, antispasmodics, mucosal repair agents, astringents, antiemetics, antitussives, expectorants, antiphlogistic enzymes, sedative hypnotics, antihistamines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pumps Inhibitors, crude drugs, caffeines, menthols, polyphenols and the like can be mentioned. These pharmacological components may be used alone or in combination of two or more. Further, the content of these pharmacological components may be appropriately set according to the type of the pharmacological components used, the dosage form of the internal pharmaceutical composition, and the like.

The pharmaceutical composition of the present invention may contain pharmaceutically acceptable bases, additives and the like, if necessary, in order to prepare a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers. Agents, suspending agents, adhesives, coating agents, brightening agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols Examples thereof include polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, antiseptics, corrigents, fragrances, powders, thickeners, dyes and chelating agents. These bases and additives may be used alone or in combination of two or more. Further, 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.

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

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

Among these dosage forms, a solid preparation is preferable.

To prepare the pharmaceutical composition for oral administration of the present invention in the above-mentioned dosage form, using (A) component, (B) component, and other pharmacological components optionally added, a base, and an additive. Formulation may be carried out according to the usual formulation methods adopted in the pharmaceutical field.

[Usage/Dose]
The pharmaceutical composition for internal use of the present invention has an improved anti-inflammatory effect and can exhibit an excellent anti-inflammatory and analgesic effect, and therefore, for example, headache, menstrual pain (menstrual pain)/toothache, pain after tooth extraction, sore throat, Use for the purpose of analgesia such as low back pain, arthralgia, neuralgia, muscle pain, stiff neck pain, ear pain, contusion pain, fracture pain, sprain pain, traumatic pain, etc.; relieving fever during chills and fever; relieving common cold symptoms. You can

The dose 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 recipient, etc., for example, the daily dose of nabumetone is about 200 to 1600 mg, preferably 400. It may be taken once per day in an amount of about 1000 mg, and may be taken in multiple doses depending on age and symptoms.

2. Method for enhancing anti-inflammatory effect The present invention is further a method for enhancing anti-inflammatory effect, in a pharmaceutical composition for internal use, (A) together with nabumetone, (B) salicylic acid, salicylic acid derivative, salicylamide, ibuprofen, aceto. From aminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, felbinibuirophen, oxabrogin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof. There is provided a method for enhancing anti-inflammatory action, which comprises blending at least one selected from the group consisting of:

In the anti-inflammatory effect enhancing method, the types and amounts of the components used, the dosage form of the pharmaceutical composition for internal use, and the like are as described in the section “1. Pharmaceutical composition for internal use”.

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

Test Example 1: Evaluation test of anti-inflammatory effect A male rat (Slc:Wister(SPF), Japan SLC, Inc.) of 5 weeks was treated with a control group and a test group (Examples 1 and 2 and Comparative Example 1). It was divided into a total of 4 groups (3 groups, 6 animals per group). The rats in each group were bred for 1 week to acclimatize and then tested under the following conditions.

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

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

The hind footpad volume of the rat was measured using a digital limb volume measuring device using water (“Digital Plethysmometer LE7500”, Panlab, SLU). From the measured hind footpad volume, the edema rate (%) and AUC (sum of edema rate) (%·time) were calculated according to the following formulas. The edema rate and AUC were calculated for each individual, and the average value in each group was obtained. Note that AUC was also statistically analyzed by the Student's t-test.

Table 2 shows the changes over time in the edema rate and the AUC measurement results. In addition, the results of measuring changes in the edema rate over time are shown in FIG. 1, and the results of AUC measurement are shown in FIG. As a result, in the control group, the edema rate and AUC were high, and inflammation was induced by carrageenin administration. On the other hand, when nabumetone was administered alone (Comparative Example 1), the edema rate and AUC could be reduced to some extent as compared with the control group. On the other hand, when ethenzamid or ibuprofen was administered together with nabumetone (Examples 1 and 2), the edema rate and AUC were markedly lower than those 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, a test was carried out in the same manner as in Test example 1 except that the components shown in Table 3 were administered so as to give a predetermined dose, and the edema ratio And AUC were determined. Diclofenac sodium is a phenylacetate non-steroidal anti-inflammatory drug similar to nabumetone.

Table 4 shows the changes over time in the edema rate and the AUC measurement results. Further, the results of measuring changes in the edema rate over time are shown in FIG. 3, and the results of AUC measurement are shown in FIG. 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 those of diclofenac sodium alone (Reference Example 1). In addition, when diclofenac sodium and ethenzamid were used in combination (Reference Example 2), the edema rate and AUC tended to be higher than those in the case of diclofenac sodium alone (Reference Example 1). That is, from the results of this test, it was confirmed that the improvement of the anti-inflammatory effect observed in Examples 1 and 2 was a unique effect obtained by using nabumetone in combination with etenzamid or ibuprofen.

Formulation Example Tablets (formulation examples 1-36, 38, 39, and 41-44) and granules (formulation examples 37 and 40) having the compositions shown in Tables 5-7 were prepared. In Tables 5 to 7, the unit of the content of each contained component is the daily dose (mg). These granules and tablets can be expected to have a dramatically improved anti-inflammatory effect.

Claims (5)

(A) Nabumetone, and
(B) salicylic acid, salicylic acid derivative, 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,
An orally-administered pharmaceutical composition containing: The pharmaceutical composition for internal use according to claim 1, which comprises 1 to 95% by weight of the component (A). The pharmaceutical composition for internal use according to claim 1 or 2, containing 0.03 to 3000 parts by weight of the component (B) per 100 parts by weight of the component (A). The pharmaceutical composition for internal use according to any one of claims 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. A method for enhancing the anti-inflammatory effect in an internally administered pharmaceutical composition,
In the pharmaceutical composition for internal use, (A) together with nabumetone, (B) salicylic acid, salicylic acid derivative, salicylamide, ibuprofen, acetaminophen, lactylphenetidine, diflunisal, mefenamic acid, flurbiprofen, naproxen, pranoprofen, A method for potentiating an anti-inflammatory effect, which comprises adding at least one selected from the group consisting of oxabrozin, loxoprofen, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam, celecoxib, valdecoxib, parecoxib, and salts thereof.