JP6018891B2 - Antipyretic analgesic composition - Google Patents

Description

  The present invention relates to an antipyretic analgesic composition.

Loxoprofen is a non-steroidal drug having excellent antipyretic, analgesic and anti-inflammatory effects, and is formulated as an active ingredient of antipyretic analgesics. Generally, loxoprofen is a prodrug and is said to cause less gastric damage, but in fact, gastric damage has been reported in clinical settings. Furthermore, in order to improve the efficacy of loxoprofen, it has been proposed to use caffeine and allylisopropylacetylurea together. In this case, however, the gastric damage due to the loxoprofen tends to worsen.
It has been proposed to use an antacid as a means of suppressing gastric damage of loxoprofen (Patent Document 1). In addition, a loxoprofen-containing tablet using a small amount of magnesium aluminate metasilicate as an additive for preparation has been proposed (Patent Document 2).

JP 2006-52210 A JP-A-10-279476

  However, according to the study by the present inventors, depending on the type and amount of antacids combined with loxoprofen, problems such as worsening of gastric disorder, reduced analgesic effect of loxoprofen, and lowering of stability occur. At the same time, it became clear that there was a need to consider possible solutions.

  The present invention has been made in view of the above circumstances, and provides an antipyretic and analgesic composition excellent in effectiveness and stability, in which stomach injury caused by loxoprofen is suppressed.

  As a result of detailed examination of antacids suitable for antipyretic analgesics containing loxoprofen, the present inventors have selected aluminum antacids among antacids and formulated them with loxoprofen sodium hydrate in a specific ratio. As a result, it was found that an excellent antipyretic analgesic having high efficacy and gastric mucosal disorder inhibiting effect was obtained, and the present invention was completed.

The present invention has the following aspects.
[1] Loxoprofen sodium hydrate (A), an aluminum antacid (B) containing an aluminum atom and no magnesium atom in the molecule,
An antipyretic analgesic composition, wherein a mass ratio ((B) / (A)) of the aluminum-based antacid (B) to the loxoprofen sodium hydrate (A) is 1.1 to 1.9. .
[2] The antipyretic analgesic composition according to [1], wherein the loxoprofen sodium hydrate (A) is administered at a dose of 45 to 140 mg / dose.
[ 3 ] The aluminum-based antacid (B) is at least selected from the group consisting of aluminum hydroxide, aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitate, and aluminum glycinate. The antipyretic analgesic composition according to [1] or [2], which is one type.
[ 4 ] As described in any one of [1] to [3], further containing at least one (C) selected from caffeine and a salt thereof and any one or both of allylisopropylacetylurea (D). Antipyretic analgesic composition.
[ 5 ] The antipyretic analgesic composition according to any one of [1] to [ 4 ], which is a solid preparation.

  According to the present invention, it is possible to provide an antipyretic analgesic composition in which stomach injury caused by loxoprofen is suppressed and which is excellent in effectiveness and stability.

The antipyretic analgesic composition of the present invention includes loxoprofen sodium hydrate (A) (hereinafter also referred to as “component (A)”), an aluminum antacid containing an aluminum atom in the molecule and no magnesium atom ( B) (hereinafter also referred to as “component (B)”),
The mass ratio ((B) / (A)) of the component (B) to the component (A) is 1.1 to 1.9.

The antipyretic analgesic composition of the present invention comprises at least one (C) selected from caffeine and a salt thereof (hereinafter also referred to as “component (C)”) and allylisopropylacetylurea (D) (hereinafter referred to as “component (D)”. It is preferable to further contain one or both of the above.
Conventionally, the (C) component and (D) component in the combined system of the (A) component and the (C) component and / or the (D) component improve the antipyretic analgesic effect of the (A) component. It is known that there is a tendency to exacerbate. However, in the present invention, even when the component (B) is used in combination with the component (C) and / or the component (D) by using the component (B) so that (B) / (A) is within the above range. The gastric disorder can be suppressed. Therefore, the aspect which further contains any one or both of (C) component and (D) component in addition to (A) component and (B) component is an aspect with the remarkable usefulness of this invention.

<(A) component>
Loxoprofen sodium hydrate (A) is an active ingredient used as one of the main components of an antipyretic analgesic that has antipyretic analgesic action and suppresses symptoms such as fever and headache.
In the present invention, “loxoprofen sodium hydrate” refers to loxoprofen sodium dihydrate (16th revised Japanese Pharmacopoeia).
The content of the component (A) in the antipyretic analgesic composition of the present invention (the content as loxoprofen sodium hydrate) is such that (B) / (A) is within the range of 1.1 to 1.9. If it is, it will not specifically limit, It sets suitably according to a formulation form, a desired dose, etc. For example, when the preparation form is a solid preparation, the content of the component (A) is preferably 0.1 to 55% by mass with respect to the total mass (100% by mass) of the antipyretic analgesic composition, and 1.0 More preferably, it is -50 mass%. When the content of the component (A) is more than 55% by mass, when the antipyretic analgesic composition of the present invention is used as a solid preparation, production problems such as tableting troubles may occur, and the content is When the amount is less than 0.1% by mass, in the use of the antipyretic analgesic composition of the present invention, the dose of the antipyretic analgesic composition necessary for administering the predetermined amount of the component (A) is increased, so There is a possibility that trouble may occur.
In the use of the antipyretic analgesic composition of the present invention, the dose of the component (A) to a person is usually preferably 45 to 140 mg / dose, more preferably 60 to 115 mg / dose for an adult. Within the above range, an antipyretic analgesic composition that is safe for the human body and has excellent efficacy and suppressed side effects.

<(B) component>
The component (B), an aluminum antacid, is an alkaline compound that contains aluminum atoms in its molecule and no magnesium atoms. An alkaline compound means a compound that reacts with gastric juice and raises the pH. The component (B) may contain metal atoms other than aluminum and magnesium (for example, alkali metals such as sodium and potassium, silicon and the like) in addition to aluminum in the molecule.

Specific examples of the component (B) include aluminum hydroxide / sodium hydrogen carbonate coprecipitate (trade name: cumlite, manufactured by Kyowa Chemical Industry Co., Ltd.), aluminum glycinate (dihydroxyaluminum / amino acetate), hydroxide Examples include aluminum, aluminum hydroxide gel, dry aluminum hydroxide gel, and aluminum silicate.
As the component (B), aluminum hydroxide, aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide / sodium hydrogen carbonate coprecipitate and aluminum glycinate are preferable, and dry aluminum hydroxide gel and aluminum glycinate are particularly preferable. preferable. As these components (B), those listed in the Pharmaceutical Additives Encyclopedia 2007 (published by Yakuji Nippo) can be used.
(B) A component can be used individually by 1 type or in combination of 2 or more types.

Content of (B) component in the antipyretic analgesic composition of this invention is prescribed | regulated by mass ratio with content of (A) component. The mass ratio ((B) / (A)) of the component (B) to the component (A) is 1.1 to 1.9.
When (B) / (A) is 1.1 or more (the content of component (B) is 1.1 parts by mass or more with respect to 1 part by mass of component (A)), a sufficient gastric disorder inhibitory effect is obtained. It is done. When (B) / (A) is 1.9 or less (the content of component (B) is 1.9 parts by mass or less with respect to 1 part by mass of component (A)), together with the effectiveness of component (A) Storage stability is also good.

<(C) component>
(C) A component is at least 1 sort (s) chosen from caffeine and its salt.
(C) component has a function as an antipyretic analgesic auxiliary component.
Caffeine may be anhydrous caffeine or caffeine hydrate. Examples of caffeine salts include sodium caffeine benzoate.
As the component (C), caffeine (anhydrous caffeine, caffeine hydrate) is preferable, and anhydrous caffeine is particularly preferable.
(C) A component can be used individually by 1 type or in combination of 2 or more types.
Content of (C) component in the antipyretic analgesic composition of this invention is not specifically limited, It sets suitably according to a formulation form, desired dosage, etc. For example, when the dosage form is a solid preparation, the content of the component (C) is preferably 1 to 50% by mass, and 3 to 45% by mass with respect to the total mass (100% by mass) of the antipyretic analgesic composition. It is more preferable that When the content exceeds 50% by mass, production problems such as tableting problems may occur when the antipyretic analgesic composition of the present invention is used as a solid preparation, and the content is 0.1% by mass. If the amount is less than 1%, the use of the antipyretic analgesic composition of the present invention may increase the dose of the antipyretic analgesic composition necessary for administering an effective amount, possibly causing a problem in dosing and the like. . However, the content of the component (C) in the present invention is not limited to the above range, and the antipyretic analgesic necessary for administering the predetermined amount of the component (A) in the use of the antipyretic analgesic composition of the present invention. It can set suitably according to the desired dosage of (C) component when a composition is administered.
In the use of the antipyretic analgesic composition of the present invention, the dose of the component (C) to a person is usually preferably 5 to 250 mg / dose for an adult, more preferably 10 to 200 mg / dose, 20 More preferably, it is set to ˜150 mg / time. Effectiveness is sufficiently obtained by setting it to 5 mg / dose or more, and by setting it to 250 mg / dose or less, the occurrence of side effects can be suppressed and a safe analgesic can be obtained for the human body.
The content and dose of the component (C) are values in terms of anhydrous caffeine.

<(D) component>
The component (D) is allyl isopropyl acetyl urea.
(D) component has a function as an antipyretic analgesic auxiliary component like (C) component.
Content of (D) component in the antipyretic analgesic composition of this invention is not specifically limited, It sets suitably according to a formulation form, desired dosage, etc. For example, when the preparation form is a solid preparation, the content of the component (D) is preferably 1 to 50% by mass, and 3 to 40% by mass with respect to the total mass (100% by mass) of the antipyretic analgesic composition. It is more preferable that When the content exceeds 50% by mass, production problems such as tableting troubles may occur in the antipyretic analgesic composition solid preparation of the present invention, and the content is 0.1% by mass. If the amount is less than that, the use of the antipyretic analgesic composition of the present invention may increase the dose of the antipyretic analgesic composition necessary to administer an effective amount, possibly causing a problem in dosing and the like. However, the content of the component (D) in the present invention is not limited to the above range, and the antipyretic analgesic necessary for administering the predetermined amount of the component (A) in the use of the antipyretic analgesic composition of the present invention. It can set suitably according to the desired dosage of (D) component when a composition is administered.
In the use of the antipyretic analgesic composition of the present invention, the dose of the component (D) to a person is usually preferably 5 to 120 mg / time for an adult, more preferably 10 to 100 mg / time, More preferably, it is -80 mg / time. Efficacy is sufficiently obtained at 5 mg / dose or more, and by setting it to 120 mg / dose or less, the occurrence of side effects can be suppressed and a safe analgesic can be obtained for the human body.

<Optional component>
The antipyretic analgesic composition of the present invention may further contain an antacid other than the component (A) as long as the effects of the present invention are not impaired.
The other antacids can be appropriately selected from those known as antacids. For example, magnesium aluminate metasilicate, synthetic hydrotalcite, magnesium carbonate, magnesium oxide, calcium carbonate, aminoacetic acid, and a combination thereof. Examples include sediments.
However, when an antacid containing a magnesium atom in the molecule (magnesium-based antacid) is used, the content is aluminum in the entire antacid (total of component (A) and other antacids). The amount is preferably such that the molar ratio of magnesium atoms to atoms is less than 1. If the molar ratio exceeds 1, the gastric disorder inhibitory effect may be reduced.
The molar ratio of magnesium atoms to aluminum atoms in the entire antacid is more preferably less than 0.6, even more preferably less than 0.3, and most preferably 0 (aluminum only). That is, it is most preferable that the antipyretic analgesic composition of the present invention does not contain a magnesium-based antacid.

In the solid internal medicine composition of the present invention, if necessary, other drugs other than the components (A) to (D) and other antacids can be blended.
Examples of the other drugs include
Antipyretic / analgesic / anti-inflammatory drugs (for example, aspirin, sodium salicylate, ethenamide, salicylamide, salicylic acid such as sazapyrine, aniline drugs such as acetaminophen, fenamic acid drugs such as flufenamic acid, mefenamic acid, diclofenac sodium, indomethacin Arylacetic drugs such as phenylbutazone, pyrazolidine drugs such as oxyphenylbutazone, pyrimidine drugs such as bucolome, oxicam drugs such as piroxicam, pilin drugs such as sulpyrine, isopropylantipyrine, etc.);
Antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, clemastine fumarate, carbinoxamine maleate, etc.);
Antitussives (eg, dextromethorphan hydrobromide, dihydrocodine phosphate, codine phosphate, tipepidine hibenzate, cloperastine hydrochloride, benzonate, etc.);
Expectorants (eg noscapine hydrochloride, bromhexine hydrochloride, potassium guaiacol sulfonate, guaifenesin, etc.);
Mucosal lysates such as L-cysteine hydrochloride, L-methylcysteine hydrochloride, acetylcysteine;
Mucus repair agents such as carbocysteine;
Anti-inflammatory enzyme agents such as lysozyme chloride;
Anti-inflammatory agents such as glycyrrhizic acid;
Hypnotic sedatives such as allylisopropylacetylurea;
Mucus lubricants such as ambroxol hydrochloride;
Antifungal agents such as terbinafine hydrochloride;
Bronchodilators or asthma drugs (eg, pseudoephedrine, ephedrine hydrochloride, methylephedrine hydrochloride, terbutaline hydrochloride, isoproterenol, salbutamol, β-adrenergic receptor stimulants such as terbutaline, xanthine drugs such as theophylline, aminophylline, proxyphylline, etc. , Cromoglycic acid, etc.);
Examples include amino acids; crude drugs; vitamins (fat-soluble vitamins such as vitamins A, D, E, K, and U; water-soluble vitamins such as vitamins B, C, and P);
These other drugs can be used alone or in combination of two or more.
The content of the other drug in the antipyretic analgesic composition of the present invention is set at an appropriate prescription amount in view of effectiveness and safety depending on the intended use of the pharmaceutical preparation.

In the antipyretic analgesic composition of the present invention, optional components other than those described above can be blended within a range not impairing the effects of the present invention. Examples of the optional component include a binder, an excipient, a lubricant, a fragrance, a corrigent (such as a sweetener and a sour agent), a pigment, a stabilizer, a coating agent, a plasticizer, and a masking agent. An appropriate amount can be used alone or in combination of two or more.
As the binder, for example, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, pullulan, dextrin and the like can be used.
Examples of excipients that can be used include low-substituted hydroxypropylcellulose, corn starch, lactose, talc, crystalline cellulose (such as Theolas), sugar alcohols such as powdered sugar and mannitol, light anhydrous silicic acid, and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester, sodium stearyl fumarate and the like. Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
As the acidulant, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.
As the coating agent, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, carboxymethylcellulose, ethylcellulose and the like (trade names: Opadry, Nippon Colorcon, etc.) can be used.
As the plasticizer, for example, polyethylene glycol, triacetin and the like can be used.
As the concealing agent, for example, titanium oxide, talc and the like can be used.

The antipyretic analgesic composition of the present invention is excellent in effectiveness (antipyretic analgesic action) as an antipyretic analgesic composition, and is less likely to cause gastric damage due to the component (A). The antipyretic analgesic composition of the present invention is also excellent in stability. For example, when a solid preparation containing the antipyretic analgesic composition is stored in a high temperature and high humidity environment, changes in appearance such as discoloration hardly occur. .
Among the antacids, by selecting the component (B) and combining it with the component (A) in a specific ratio, it is possible to improve the effectiveness as well as to suppress gastric damage, and to obtain an excellent antipyretic analgesic composition. This is a novel finding that has not been known so far. Further, by using the component (B) as an antacid, a mass ratio to the component (A) is a low antacid ratio of 1.9 or less, and in addition to the above effects, an effect of improving storage stability can be obtained. This is also a new finding.
In addition, since the component (A) has the property of being extremely soluble in water, it is not usually necessary to adjust the stomach to a dissolution pH range like ibuprofen, which is hardly soluble, and thus a large amount of antacid is not blended. Both are considered to exhibit sufficient medicinal effects. However, when a magnesium-based antacid was used in place of the component (B) of the present application, the tendency of worsening gastric damage was observed with the ratio of the antacid of the present application.

Since the antipyretic analgesic composition of the present invention is excellent in stability even when loxoprofen sodium hydrate and an antacid are mixed, an antipyretic analgesic preparation in which the components (A) and (B) are mixed or uniformly mixed may be used. it can.
The antipyretic analgesic composition of the present invention is usually a granule (powder, granule, enteric granule, etc.), tablet (plain tablet, sugar-coated tablet, coated tablet, enteric tablet, orally disintegrating tablet, chewable tablet, effervescent tablet, etc. ) And other solid preparations, oral liquid preparations, syrups, oral jelly preparations, troches, gum preparations and the like.
The preparation form of the antipyretic analgesic composition of the present invention is preferably a solid preparation such as a granule or a tablet.
The method for making the antipyretic analgesic composition of the present invention into a preparation form is not particularly limited, and can be carried out by a conventional method according to the preparation form. For example, the blended components of the antipyretic analgesic composition of the present invention (components (A) and (B) and optional components as necessary) are mixed as they are, or granulation or coating is applied to some or all of the blended components. Thereafter, the mixture is mixed to produce a granular mixture, which can be used as a granule (granule, fine granule, powder). Further, the granular mixture can be tableted and further coated as necessary to obtain tablets.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

<< Examples 1-48, Comparative Examples 1-19 >>
The antipyretic analgesic compositions having the compositions shown in Tables 1 to 8 were evaluated for efficacy (blood concentration or analgesic effect), gastric disorder inhibitory effect, or stability according to the following method. The results are shown in Tables 1-8.

<Blood concentration (rat)>
In this evaluation, a suspension containing an antipyretic analgesic composition was prepared according to the following procedure, and this was orally administered to rats as a sample. After 15 minutes, the blood concentration of loxoprofen was measured.

(1) Animals:
Wistar male rats, 6 weeks old, were preliminarily raised for 1 week, fasted overnight (18-24 hours, water ad libitum), and then subjected to the test.

(2) Sample:
Based on the composition ratios shown in Tables 1 and 2, the sample dose is 10 mL / kg and the loxoprofen sodium hydrate dose is 6.8 mg / kg. A suspension was prepared. The preparation procedure of each sample is shown below.
As a control sample, a suspension of loxoprofen sodium hydrate alone was prepared.
Each sample was mixed with 5 W / V% gum arabic as a dispersant.

[Sample preparation]
The sample of Example 1 was prepared by the following procedure.
Loxoprofen sodium hydrate 68.1 mg, dry aluminum hydroxide gel 75 mg, and gum arabic 5 g were weighed and mixed in a mortar, and purified water was added to the resulting mixture to suspend it to 100 mL.
Other samples were prepared in the same procedure. That is, the amount (mg) shown in Tables 1 and 2 of each component shown in Tables 1 and 2 was weighed and mixed in a mortar, and purified water was added to the resulting mixture and suspended to make 100 mL.

(3) Sample administration:
The sample of each example and the control sample were each administered so that the amount of the sample per unit weight of the rat was 10 mL / kg. Specifically, a sample or a control sample (for example, 2 mL if the rat body weight is 200 g), which is measured in advance, is placed in a disposable syringe equipped with an oral administration sonde for rats, Forced oral administration. Fasting continued after oral administration. For each case, 5 rats were used (n = 5).

(4) Blood sampling and blood concentration measurement:
Rats were fixed under isoflurane anesthesia, and 0.3 mL of blood was collected from the jugular vein (15 minutes after sample administration). The collected blood was treated with heparin and then plasma was collected. The amount of loxoprofen was measured by high performance liquid chromatography (HPLC) per 20 μL of plasma.

(5) Evaluation:
The average value of the blood concentration of each group (n = 5) was calculated, and the relative blood concentration of each group when the blood concentration when the control sample (loxoprofen sodium hydrate only) was administered was taken as 100 The concentration was determined and evaluated according to the following criteria.
+: The relative blood concentration is 110 or more.
±: The relative blood concentration is 90 or more and less than 110.
-: The relative blood concentration is less than 90.

<Analgesic effect (Landal Celit method: rat)>
In this evaluation, a suspension containing an antipyretic analgesic composition was prepared according to the following procedure, and this was used as a sample for administration to a rat inflamed in the right hind leg, and the pain threshold after 2 hours was measured.

(1) Animals:
Wistar male rats were preliminarily raised at 5 weeks of age for 1 week and fasted overnight (18-24 hours, water ad libitum) before being subjected to the test.
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 i of about 60 to 120 were selected and used for the test.

(2) Sample:
Based on the composition ratios shown in Tables 3 to 6 and 8, so that the dose of the sample per unit mass of the rat is 10 mL / kg and the dose of loxoprofen sodium hydrate is 6.8 mg / kg. A suspension was prepared. The preparation procedure of each sample is shown below.
A sample containing no drug was prepared and used as a control (control sample).
Further, as a comparative sample, a suspension of loxoprofen sodium hydrate alone was prepared (the dose of loxoprofen was the same as that of each sample described above).
Each sample was mixed with 5 W / V% gum arabic as a dispersant.

[Sample preparation]
The sample of Example 10 was prepared by the following procedure.
Loxoprofen sodium hydrate 68.1 mg, anhydrous caffeine 80 mg, dry aluminum hydroxide gel 75 mg, and gum arabic 5 g are weighed and mixed in a mortar. The resulting mixture is suspended by adding purified water to 100 mL. did.
Other samples were prepared in the same procedure. That is, weigh out the amounts (mg) shown in Tables 3 to 6 and 8 of each component shown in Tables 3 to 6 and 8, respectively, mix them in a mortar, add purified water to the resulting mixture and suspend it, and add 100 mL. It was.

(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 sample of each example, the control sample, and the comparative sample were each administered so that the amount of the sample per unit weight of the rat was 10 mL / kg. Specifically, a sample (for example, 2 mL if the rat body weight is 200 g) is taken in a disposable syringe equipped with a rat oral administration sonde and is administered by oral gavage. did. Fasting continued after oral administration. For each sample, control sample, and comparative sample, 5 rats were used (n = 5).

(5) Pain threshold measurement and suppression rate calculation:
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 of sample administration group or comparative sample administration group) − (average pain threshold ii of control sample administration group)] / [(average pain threshold i of control sample administration group) − (average of control sample administration group) Pain threshold ii)] × 100

(6) Evaluation:
The average value of the inhibition rate (%) of each group (n = 5) was calculated, and the relative rate of each sample administration group when the inhibition rate of the comparative sample (loxoprofen sodium hydrate only) administration group was taken as 100. The inhibition rate was calculated and evaluated according to the following criteria.
+++: The relative inhibition rate is 115% or more.
++: The relative inhibition rate is 110% or more and less than 115%.
+: The relative inhibition rate is 105% or more and less than 110%.
±: The relative inhibition rate is 90% or more and less than 105%.
-: The relative inhibition rate is less than 90%.

<Stomach damage suppression effect>
In this evaluation, a suspension containing an antipyretic analgesic composition was prepared by the following procedure, and this was administered to a rat as a sample. After 4 hours, the stomach was removed to evaluate gastric damage.

(1) Animals:
SD male rats were preliminarily kept at 5 weeks of age for 1 week and fasted overnight (18-24 hours, water was ad libitum), and then subjected to the test.

(2) Sample:
Based on the composition ratios shown in Tables 1 to 8, the sample is suspended so that the dose of the sample per unit mass of the rat is 10 mL / kg and the dose of loxoprofen sodium hydrate is 68.1 mg / kg. A suspension was prepared. The preparation procedure of each sample is shown below.
As a comparative sample, a suspension of loxoprofen sodium hydrate alone was prepared.
Each sample was mixed with 5 W / V% gum arabic as a dispersant.

[Sample preparation]
The sample of Example 1 was prepared by the following procedure.
Loxoprofen sodium hydrate 681 mg, dry aluminum hydroxide gel 750 mg, and gum arabic 5 g were weighed and mixed in a mortar. Purified water was added to the resulting mixture to suspend it to 100 mL.
Other samples were prepared in the same procedure. That is, 10 times the amount (mg) shown in Tables 1 to 8 of each component shown in Tables 1 to 8 was weighed out, mixed in a mortar, purified water was added to the resulting mixture and suspended, and 100 mL It was.

(3) Sample administration:
The sample of each example and the comparative sample were each administered so that the amount of the sample per unit weight of the rat was 10 mL / kg. Specifically, a sample (for example, 2 mL if the rat body weight is 200 g) is taken in a disposable syringe equipped with a rat oral administration sonde and is administered by oral gavage. did. Fasting continued after oral administration. For each sample and each comparative sample, 5 rats were used (n = 5).

(4) Gastric disorder evaluation:
Four hours after oral administration, the stomach was removed under isoflurane 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.
After fixing with formalin, open the large bay of the stomach, flush the contents with physiological saline, spread the stomach on the filter paper and paste it, and measure the total length of ulcers (mm) (n = 5) .

(5) Evaluation:
When the average value of the ulcer length (mm) of each group (n = 5) is calculated, and the ulcer length of the comparison sample administration group (when only loxoprofen sodium hydrate is administered) is 100 The relative ulcer length of each sample administration group was determined and evaluated according to the following criteria. The larger the score, the more gastric disorder is suppressed.
5: Relative ulcer length is less than 5.
4: The relative ulcer length is 5 or more and less than 10.
3: The length of the relative ulcer is 10 or more and less than 15.
2: The relative ulcer length is 15 or more and less than 20.
1: The relative ulcer length is 20 or more and less than 30.
0: The relative ulcer length is 30 or more.

<Stability>
In this evaluation, a tablet containing an antipyretic analgesic composition was prepared by the following procedure, and the stability was evaluated using this as a sample.

[Sample preparation]
The sample (tablet) of Example 1 was prepared by the following procedure.
Loxoprofen sodium hydrate 82.3 g, crystalline cellulose (Theorus PH-101, Asahi Kasei) 36.3 g (corresponding to 30 mg in one tablet), lactose (Pharmacatose 100M, DMV) 145.1 g (corresponding to 120 mg in one tablet), After mixing 36.3 g of low-substituted hydroxypropylcellulose (LH-21, Shin-Etsu Chemical Co., Ltd.) (corresponding to 30 mg in one tablet) with a high speed mixer (Fukae Powtech), an appropriate amount of water was added and granulated. The granulated product was dried at 60 ° C. with a dryer.
The obtained dried product is sieved (No. 18, JP), and 250 g thereof is added with (B) component or the antacid of the comparative example in an amount that gives a predetermined mass ratio with respect to (A) component (for example, In Example 1, dry aluminum hydroxide gel (75.4 g) was added and mixed. Next, 1.6 g of magnesium stearate (0.5% by mass relative to other powders) was added and mixed for 1 minute.
The obtained mixed powder was tableted with a rotary tableting machine (Clean Press 12HUK, Kikusui Seisakusho) to prepare tablets containing 68.1 mg of loxoprofen sodium hydrate per tablet.

  Other samples were prepared in the same procedure. That is, the addition amount of each component was adjusted according to the composition ratios shown in Tables 1, 2, and 8. The excipient was used in the same amount as in Example 1, and tablets were produced in the same manner. In Examples 46 to 48, anhydrous caffeine and allylisopropylacetylurea were mixed with loxoprofen sodium hydrate and granulated, and the subsequent steps were similarly performed to produce tablets.

[Preparation of Samples of Examples 4 to 6 and Comparative Examples 6 to 9]
Instead of the dry aluminum hydroxide gel, aluminum glycinate was used in the same manner as the sample of Example 1 except that the mass ratio of the component (A) to the component (B) was used in the amount shown in Table 2. Prepared.

(2) Evaluation:
The tablet produced above was stored in a petri dish covered with medicine-wrapped paper under 50 ° C. and 75% RH conditions, the appearance change after 2 days was observed, and the stability was evaluated according to the following criteria.
A: No discoloration at all.
○: Almost no discoloration.
Δ: Slightly discolored.
X: There is considerable discoloration.

As shown in the above results, the antipyretic analgesic compositions of Examples 1 to 45 obtained excellent results in any of effectiveness (blood concentration or analgesic effect), gastric disorder suppressing effect, and stability.
On the other hand, Comparative Examples 1, 6, 10, 11, 12, and 13 in which the mass ratio of (B) / (A) was less than 1.1 did not have the effect of suppressing gastric damage. In particular, even if the component (B) is included, the comparative examples 1 and 6 in which the mass ratio of (B) / (A) is less than 1.1 are inferior in effectiveness (blood concentration) to those in Examples 1 to 6. It was. Comparative Examples 2-5 and 7-9 with (B) / (A) exceeding 1.9 were less stable than Examples 1-6. Moreover, the tendency for effectiveness (blood concentration) to fall was seen, so that the mass ratio of (B) / (A) became large.
In Comparative Examples 14 to 19 using an antacid other than the component (B), the gastric disorder suppressing effect is obtained even when the mass ratio of the antacid / (A) is 1.10 or 2.94. There wasn't.

Claims (5)

Loxoprofen sodium hydrate (A), an aluminum antacid (B) containing an aluminum atom in the molecule and no magnesium atom,
An antipyretic analgesic composition, wherein a mass ratio ((B) / (A)) of the aluminum-based antacid (B) to the loxoprofen sodium hydrate (A) is 1.1 to 1.9. . The antipyretic analgesic composition according to claim 1, wherein the loxoprofen sodium hydrate (A) is administered at a dose of 45 to 140 mg / dose. The aluminum-based antacid (B) is at least one selected from the group consisting of aluminum hydroxide, aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitate, and aluminum glycinate. The antipyretic analgesic composition according to claim 1 or 2 . The antipyretic analgesic composition according to any one of claims 1 to 3, further comprising at least one selected from caffeine and a salt thereof (C) and allylisopropylacetylurea (D) or both. The antipyretic analgesic composition according to any one of claims 1 to 4 , which is a solid preparation.