JP2011116744A - Antipyretic analgesic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antipyretic analgesic composition highly safe with suppressing stomach disorders, excellent in effectiveness and improved in stability, ease of oral administration and productivity. <P>SOLUTION: The antipyretic analgesic composition contains (A) ibuprofen, (B) acetaminophen and (C) an aluminum-based antacid and has ≥0.75 blended mass ratio of the component (B) over the component (A) expressed by (B)/(A), and 0.3-1 blended mass ratio of the component (C) over the component (A) expressed by (C)/(A). <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an antipyretic analgesic composition that suppresses gastric disorders derived from ibuprofen and is excellent in stability.

  Ibuprofen has excellent antipyretic, analgesic and anti-inflammatory effects and is widely used as a non-steroidal drug, and various studies have been made. In particular, regarding the effectiveness, a combination with various other components has been studied as a means for improving the effect, and a combination of ibuprofen and an aniline derivative antipyretic analgesic such as acetaminophen (Patent Document 1). -3: Japanese Patent Application Laid-Open No. 56-97224, Japanese Patent Application Laid-Open No. 5-246845, Japanese Patent Application Laid-Open No. 5-148139) have been proposed.

  However, it has been pointed out that when ibuprofen is orally administered, stomach discomfort, stomach pain, nausea, etc. may occur, causing gastrointestinal disorders as side effects. For this purpose, antipyretic analgesics with excellent efficacy and reduced acute toxicity by combining ibuprofen with aniline derivative antipyretic analgesics for the purpose of suppressing gastrointestinal disorders due to oral administration of ibuprofen. (Patent Documents 1, 4, 5: JP-A-56-97224, JP-A-56-154416, JP-A-59-104315) and a technique used in combination with a salicylic acid drug (Patent Document 6: Japanese Laid-Open Patent Publication No. 61-134315) and a technique (Patent Document 7: Japanese Laid-Open Patent Publication No. 63-198620) used in combination with an antacid and / or a mucosa coating agent have been proposed. However, a method for suppressing gastrointestinal disorders of ibuprofen by a simpler method has been desired.

  The mechanism of action of ibuprofen-induced gastric damage is thought to be due to suppression of the production of prostaglandins (PG), which is responsible for the protective function of the stomach, and direct stimulation of gastric wall cells. Therefore, in order to dissolve ibuprofen quickly and shorten gastric residence time, to reduce gastric damage and reduce gastric damage, ibuprofen and acetaminophen are added to magnesium-based antacids. A technique (Patent Document 3: Japanese Patent Laid-Open No. Hei 5-148139) and the like that have both safety and effectiveness have been proposed. However, further suppression effect of gastric damage by ibuprofen has been desired.

JP-A-56-97224 JP-A-5-246845 JP-A-5-148139 JP-A-56-154416 JP 59-104315 A JP 61-134315 A JP 63-198620 A

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an antipyretic analgesic that suppresses gastric damage caused by ibuprofen, has excellent stability, and has improved dosage and manufacturability.

  As described above, antacids are one of the important means of suppressing ibuprofen gastric damage, but in order to raise the pH in the stomach to the dissolution zone of ibuprofen, a considerable amount of antacids, for example, It is a general understanding of those skilled in the art that an amount of about 300 mg (a single dose for humans) is required. On the other hand, when a large amount of antacid is blended, the amount of the preparation is increased and the dosage is significantly reduced. In addition, ibuprofen and antacids cause significant compounding changes, so that when antacids are present in large quantities, the stability is significantly reduced. The inventors of the present invention can suppress gastric damage caused by ibuprofen by combining a specific amount of acetaminophen and an aluminum antacid in combination with ibuprofen, and have excellent efficacy and stability of the preparation. Has been found to improve. Moreover, the above-mentioned gastric disorder suppression effect can be obtained even when the amount of antacid used is small, and the amount of antacid against ibuprofen can be reduced, resulting in further improvement in the stability of the formulation and The present inventors have found that an antipyretic analgesic composition having excellent properties and manufacturability can be obtained.

Accordingly, the present invention provides the following antipyretic analgesic composition.
[1]. It contains (A) ibuprofen, (B) acetaminophen, and (C) an aluminum antacid, and the blending mass ratio of the component (B) to the component (A) represented by (B) / (A) is 0. An antipyretic analgesic composition having a blending mass ratio of the component (C) to the component (A) represented by (C) / (A) of 0.3 to 1 or more.
[2]. The antipyretic analgesic composition according to [1], wherein the component (C) is aluminum hydroxide.
[3]. The antipyretic analgesic composition according to [1] or [2], which is a solid preparation in which the components (A), (B) and (C) are mixed.

  ADVANTAGE OF THE INVENTION According to this invention, the antipyretic analgesic composition which suppressed the gastric disorder | damage | failure by ibuprofen, and was excellent in the effective pharmaceutical characteristic and stability of a formulation can be provided. Furthermore, according to the present invention, it is possible to provide an antipyretic analgesic composition that achieves both the ingestibility and the pharmaceutical properties of manufacturability (which can be produced even with a single layer tablet or the like without requiring any special device). it can.

  The antipyretic analgesic composition of the present invention comprises (A) ibuprofen, (B) acetaminophen, and (C) an aluminum-based antacid, which is represented by (B) / (A) component (A) ( B) The blending mass ratio of the component is 0.75 or more, and the blending mass ratio of the (C) component to the (A) component represented by (C) / (A) is 0.3 to 1. .

(A) Ibuprofen The component (A) ibuprofen is one of antipyretic analgesic components, and is a drug used as one of the main components of an antipyretic analgesic that suppresses symptoms such as fever and headache. In the present invention, ibuprofen (2- (4-isobutylphenyl) propionic acid) and pharmaceutically acceptable salts thereof can be used. The amount of component (A) is usually 0.1 to 55% by mass in the composition, preferably 1.0 to 50% by mass, more preferably 10 to 45% by mass, and 12 to 36% by mass. % Is more preferable. If the amount is too large, it may lead to tableting troubles and the like, and if the amount is too small, the dosage increases and the dosage may be hindered. Moreover, it is preferable that the dosage with respect to a person is normally 130-200 mg / time in an adult. Effectiveness is sufficiently obtained at 130 mg / dose or more, and by setting it to 200 mg / dose or less, the occurrence of side effects can be suppressed, and an antipyretic analgesic safe for the human body can be obtained.

(B) Acetaminophen (B) The acetaminophen component is also an antipyretic analgesic component, and is a drug used as one of the main components of an antipyretic analgesic that suppresses symptoms such as fever and headache. In the present invention, by blending a specific amount of acetaminophen with ibuprofen, gastric disorders derived from ibuprofen can be suppressed, and the effectiveness can be improved. As the component (B), acetaminophen (N- (4-hydroxyphenyl) acetamide) and salts thereof can be used. (B) As a compounding quantity of a component, the compounding mass ratio of the (B) component with respect to the (A) component represented by (B) / (A) is 0.75 or more, and 0.75-2 are preferable, More preferably, it is 1-2. By setting the blending mass ratio of acetaminophen to 0.75 or more, the effect of suppressing gastric damage by ibuprofen is improved, and the action tends to be enhanced as the blending ratio of acetaminophen increases. When the ratio is less than 0.75, this effect is insufficient. When the ratio exceeds 2, the gastric disorder tends to be reduced, but the dose may increase and the dosage may be deteriorated. . In addition, the effectiveness of ibuprofen is improved by combining any amount of acetaminophen with ibuprofen, but a significant synergistic effect is observed when the blending mass ratio of acetaminophen to ibuprofen is 0.5 or more. By setting the ratio to 1: 0.75 to 2, particularly 1: 1, the synergistic effect is maximized. In addition, although the compounding quantity of the composition of (B) component depends on the said compounding ratio, it is 11-55 mass% normally, and 14-45 mass% is preferable.

(C) Aluminum-based antacids An antacid is an alkaline agent that has the effect of neutralizing stomach acid and raising the pH. The antipyretic analgesic composition of the present invention requires an aluminum antacid. The aluminum-based antacid referred to in the present invention refers to a compound that substantially contains only aluminum as a polyvalent metal that forms a salt in the molecule. “Substantially containing only aluminum” means that other polyvalent metals mixed in the production method and production environment are allowed within the range that does not impair the effects of the present invention. It means mass% or less, preferably 5 mass% or less.

  Specific examples of the aluminum-based antacid used in the present invention include the following. Examples include cumulite, dihydroxyaluminum / aminoacetate (aluminum glycinate), aluminum hydroxide (aluminum hydroxide gel, dry aluminum hydroxide gel, etc.), aluminum silicate, synthetic aluminum silicate, aluminum glycinate, etc. It can use individually or in combination of 2 or more types as appropriate. Among these, aluminum hydroxide, aluminum glycinate, and cumulite are preferable, and aluminum hydroxide is more preferable.

  The blending amount of the component (C) is such that the blending mass ratio of the component (C) to the component (A) represented by (C) / (A) is 0.3 to 1, preferably 0.5 to 0.00. 8. When the compounding ratio of the component (C) is less than 0.3, the gastric disorder suppressing effect is lowered, whereas when the compounding ratio exceeds 1, the stability is lowered. In general, gastric damage caused by ibuprofen is considered to be caused by solid undissolved ibuprofen staying in the stomach and directly contacting the stomach wall. When administered concurrently with ibuprofen, antacids neutralize the acid in the stomach due to its antacid effect, and improve the solubility by setting the pH in the stomach to be higher than the pKa of ibuprofen, so that solid ibuprofen and In order to reduce the chance of contact with the stomach wall, it is considered to have an effect of suppressing stomach damage. Therefore, it was considered that a sufficient amount of an antacid that raises the pH in the stomach is necessary for the above effect. On the other hand, in this invention, even when it mix | blends a small amount by using an aluminum type | system | group antacid, it has an effect which suppresses a stomach disorder. Moreover, since the compounding quantity of an antacid can be made into a small quantity, even if it uses with ibuprofen, stability is favorable and it is excellent also in ingestibility and manufacturability. In addition, although the compounding quantity of the composition of (C) component depends on the said compounding ratio, it is usually 3 to 33 mass%, and 6 to 26 mass% is preferable.

  In the present invention, an antacid other than the aluminum-based antacid of component (C) can be blended within a range that does not impair the effects of the present invention. Examples of other antacids include magnesium oxide, magnesium silicate, magnesium carbonate, magnesium hydroxide, synthetic hydrotalcite, magnesium aluminate metasilicate, calcium carbonate, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, and the like. The compounding amount of the antacid other than the component (C) is the molar ratio of the metal [M] other than aluminum in the compounded antacid and aluminum [Al] ([M] / [ Al]) is preferably within a range of less than 1, more preferably less than 0.6, even more preferably less than 0.3, and particularly preferably 0. By making this molar ratio less than 1, the inhibitory effect of gastric disorder is more exhibited, and the stability of the preparation becomes particularly good.

  In the antipyretic analgesic composition of the present invention, optional components other than the above components can be blended within a range not impairing the effects of the present invention. Optional ingredients include binders, excipients, lubricants, fragrances, flavoring agents (sweeteners, acidulants, etc.), pigments, stabilizers, coating agents, plasticizers, hiding agents, etc. An appropriate amount can be used alone or in appropriate combination of two or more.

  Specifically, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be used as the binder. As the excipient, lactose, corn starch, talc, crystalline cellulose (such as Theolas), powdered sugar, mannitol, light anhydrous silicic acid, L-cysteine and the like can be used. Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester. Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like. Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like. As the acidulant, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used. As the coating agent, hydroxypropylmethylcellulose, polyvinyl alcohol, carboxymethylcellulose, etc. (trade name: Opadry, Nippon Colorcon, etc.) can be used. As the plasticizer, polyethylene glycol or the like can be used. As the concealing agent, titanium oxide, talc, or the like can be used.

  Since the antipyretic analgesic composition of the present invention can be made into a solid preparation and is excellent in stability even when mixed with ibuprofen, it is a composition in which the components (A), (B) and (C) are mixed or uniformly mixed. be able to. As the solid preparation, the components (A) to (C) and optional components are mixed as necessary, and the mixture is filled in a tableting machine and tableted to obtain a tablet. Moreover, it can also granulate with a granulator and can also be used as a granule and a fine granule. In particular, in the case of a tablet, it is possible to make a single layer tablet or the like, and even when it is a multilayer tablet, the components (A), (B) and (C) can be blended in the same layer.

  More specifically, when preparing a tablet, the following method is mentioned, for example. (A) A powder mixture of ibuprofen and (B) acetaminophen and, if necessary, excipients such as low-substituted hydroxypropylcellulose, corn starch, mannitol, lactose, etc., are charged into a granulator, An aqueous cellulose solution is sprayed and granulated, and (C) an antacid is mixed with the resulting granulated product. In this case, excipients such as low-substituted hydroxypropylcellulose, corn starch, mannitol, and lactose, and lubricants such as magnesium stearate may be mixed. Tablets can be obtained by tableting the resulting mixture with a tableting machine. The obtained tablet can be coated with a coating agent containing polyvinyl alcohol or the like to form a coated tablet.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, the amount of each component is an amount converted into a pure component.

[Examples 1-15, Comparative Examples 1-14]
Each component was mixed with the components and blending ratios shown in Tables 1 to 5 to prepare a composition, and the inhibitory effect on gastric damage was evaluated according to the following method. Moreover, the tablet was prepared by the following method and stability was evaluated.

<Evaluation of gastric disorder suppression effect>
The components of the composition and mass ratio of each Example and Comparative Example were administered to rats as a suspension, and after 4 hours, the stomach was removed to evaluate gastric damage. The details of the experimental method are as follows.
(1) Animals SD male rats were preliminarily raised at 5 weeks of age for 1 week, and fasted overnight (20 to 24 hours, water ad libitum), and then subjected to the test. Ten animals were used for each example and comparative example.
(2) Sample (suspension)
The sample was prepared so that the dose of the sample to rats was 10 mL / kg and the dose of ibuprofen was 130 mg / kg.
The preparation of the sample is the following method in Example 1, and in other examples, the mass ratio of ibuprofen 650 mg acetaminophen and antacid is Table 1-5, and gum arabic is 5 w / mL%. As appropriate, it was prepared.
i) 650 mg of ibuprofen, 650 mg of acetaminophen, 200 mg of dry aluminum hydroxide gel and 2.5 g of gum arabic were weighed and mixed in a mortar.
ii) Purified water was added to the mixed powder and suspended therein to make 50 mL.

(3) Sample administration The sample was administered at a dose of 10 mL / kg.
Specifically, a suspension of an amount (rat weight 200 g: 2 mL) that was measured in advance (rat weight 200 g: 2 mL) was placed in a disposable syringe equipped with an oral administration sonde for rats and was forcibly administered orally. Fasting continued after oral administration.
(4) Evaluation of gastric damage 1) Four hours after oral administration, the stomach was removed under ether anesthesia. Immediately after gastrectomy, 10 mL of physiological saline was injected into the stomach with a sonde, and placed in a 1% by mass formalin solution for 1 hour or longer and fixed.
2) After fixing with formalin, open the large bay of the stomach, rinse the contents with physiological saline, spread the stomach on a filter paper and paste it, and measure the total length of ulcers (mm) (n = 10) did. The result evaluated according to the following score is written together in Tables 1-5.
Grade ◎: Less than 10 mm ○: Less than 20 mm Δ: Less than 40 mm x: 40 mm or more

<Stability>
According to the blending mass ratios shown in Tables 1 to 5, fluidized bed construction of 500 g of ibuprofen and acetaminophen powder and 100 g of low-substituted hydroxypropylcellulose (L-HPC · LH31, manufactured by Shin-Etsu Chemical Co., Ltd.) A granulator (MP-01, manufactured by POWREC Co., Ltd.) was charged, and 600 g of a 6% by weight aqueous solution of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was sprayed and granulated.
The granulated powder is sieved with a 750 μm sieve, 500 g of the antacid is mixed with an antacid corresponding to the blending ratio, 100 g of low-substituted hydroxypropylcellulose, and 0.5% by mass of magnesium stearate (extra) And a tablet containing 65 mg of ibuprofen was prepared using a rotary tableting machine (Clean Press 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.). The composition of the tablet of Example 1 (1 tablet) is shown below. In other examples, 65 mg of ibuprofen, 59 mg of low-substituted hydroxypropyl cellulose, 9.36 mg of hydroxypropyl cellulose, and 0.5% by mass of magnesium stearate (extra) are fixed, and the mass ratio of acetaminophen and antacid is expressed. It adjusted suitably in the quantity used as 1-5.

Tablet (1 tablet) composition (Example 1)
(Mg)
Ibuprofen 65
Acetaminophen 65
Dry aluminum hydroxide gel 19.5
Low-substituted hydroxypropylcellulose 59 (26 + 33)
Hydroxypropylcellulose 9.36
Total 217.86
Magnesium stearate 0.5% by mass (extra)

The tablet prepared above was stored in a petri dish at 50 ° C. and 75% RH, and the appearance change after 2 days was observed. The result evaluated according to the following score is written together in Tables 1-5.
Rating ◎: No discoloration ○: Almost no discoloration △: Some discoloration ×: Very discoloration

<Effectiveness (Landal Celit method)>
The effectiveness (Landhal celite method) was evaluated for Examples 2 and 11, Comparative Example 13 and ibuprofen alone.
The components of the composition ratio of each example are administered as a suspension to a rat inflamed in the right hind leg, and the pain threshold after 2 hours is measured. The details of the experimental method are as follows.
(1) Animals SD male male rats were preliminarily raised at 5 weeks of age for 1 week, and fasted overnight (17 to 20 hours, water was freely consumed), and then subjected to the test. Ten animals were used for each example.
Moreover, the animal measured the pain threshold value 3 times in 2 days as training before a test. Furthermore, the pain threshold value was measured before the onset of inflammation (pain threshold value i), and animals having a pain threshold value of about 60 to 120 were selected and subjected to the test.
(2) Sample A sample is prepared so that the dose of the sample to the rat is 10 mL / kg and the dose of ibuprofen is 13 mg / kg.
The preparation of the sample is the following method in Example 2, and other examples are 65 mg of ibuprofen, an amount in which the mass ratio of acetaminophen and antacid is Tables 1 to 4, and 5% by weight of gum arabic. It prepared suitably so that it might become.
i) 65 mg of ibuprofen, 65 mg of acetaminophen, 35 mg of dry aluminum hydroxide gel and 2.5 g of gum arabic were weighed and mixed in a mortar.
ii) Purified water was added to and suspended in the mixed powder to obtain 50 mL of suspension.
(3) Inflammation 4 g of brewer's yeast was made 20 g with physiological saline and dispersed. 0.1 mL of this solution was subcutaneously administered to the rat right hind paw.
Two hours after the onset of inflammation, the pain threshold of the right hind leg of the inflamed rat was measured with a pain threshold measurement device.

(4) Sample administration The suspension was administered at a dose of 10 mL / kg. A sample containing no drug (including only gum arabic) was prepared and used as a control.
After measuring the pain threshold value 2 hours after the onset of inflammation, a suspension of an amount (for example, rat body weight 200 g: 2 mL) according to the previously measured weight of the rat was attached to the rat oral administration sonde. It was taken into a disposable syringe and administered by gavage. Fasting continued after oral administration.
(5) Pain threshold evaluation One hour after oral administration of the sample, the pain threshold value of the right hind leg of a rat inflamed with a pain threshold value measuring apparatus was measured (pain threshold value ii). From the obtained results, the inhibition rate was calculated by the following formula.
Suppression rate (%) =
[(Average pain threshold ii) − (Average pain threshold ii of control group)] / [(Average pain threshold i of control group) − (Average pain threshold ii of control group)] × 100
Pain threshold i: Measurement of pain threshold before inflammation Inhibition rate of Example 2: 85.4%
Inhibition rate of Example 11: 58.7%
Inhibition rate of Comparative Example 13: 43.5%
Inhibition rate of ibuprofen alone: 37.8%
From the above results, it was shown that Examples 2 and 11 have high effectiveness.

Claims (3)

  It contains (A) ibuprofen, (B) acetaminophen, and (C) an aluminum antacid, and the blending mass ratio of the component (B) to the component (A) represented by (B) / (A) is 0. An antipyretic analgesic composition having a blending mass ratio of the component (C) to the component (A) represented by (C) / (A) of 0.3 to 1 or more.   The antipyretic analgesic composition according to claim 1, wherein the component (C) is aluminum hydroxide.   The antipyretic analgesic composition according to claim 1 or 2, wherein the composition is a solid preparation in which the components (A), (B) and (C) are mixed.