JPH05221857A - Compounded antipyretic analgesic agent - Google Patents

Abstract

PURPOSE:To provide the compounded antipyretic analgesic agent eliminating defects such as the easy generation of gastrointestinal injuries, having an excellent analgesic activity and having high safety. CONSTITUTION:A compounded antipyretic analgesic agent comprises a mixture of dichlofenac or its salt (e.g. Na salt) and an aniline derivative antipyretic analgesic agent (e.g. acetoaminophen). The ingredients are compounded in a weight ratio of the dichlofenac sodium salt : aniline derivative antipyretic analgesic agent of 1:0.1-100, especially 1:1-60. The addition of a caffeine and a vitamin B1 derivative (e.g. dibenzoylthiamine, fursulthiamine or benfotiamine to the compounded antipyretic analgesic agent in amounts of 1-100wt.% and 0.2-20wt.%, respectively, based on the total amount of both the ingredients further enhances the analgesic action and durability of the agent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel compounded antipyretic analgesic, more specifically a combination of diclofenac sodium and an aniline derivative antipyretic analgesic, and diclofenac sodium, an aniline derivative antipyretic analgesic, caffeine and vitamin B. _{The present} invention relates to a compound antipyretic analgesic comprising a combination of _one derivative.

[0002]

2. Description of the Related Art Conventionally, many compound antipyretic analgesics have been marketed, and headache, toothache, post-extraction pain, sore throat, earache, arthralgia, neuralgia, low back pain, muscle pain, bruising pain, sprain pain,
It is widely used for analgesia such as menstrual pain, traumatic pain, etc., or fever when fever and fever. However, in recent years, the safety of compounded antipyretic analgesics has come to be strictly required. Therefore, the components of the antipyretic analgesic that can be compounded are limited, and aniline derivative-based acetaminophen, lactylphenetidine, and salicylic acid are limited. At present, derivative-type aspirin, aspirin aluminum, sazapyrine, etenzamid, salicylamide, sodium salicylate and the like are used in combination.
However, salicylic acid derivative-based antipyretic analgesics have a drawback that they are likely to cause gastrointestinal disorders, and compounded antipyretic analgesics containing such agents are not always sufficiently satisfactory.

[0003]

SUMMARY OF THE INVENTION Therefore, the object of the present invention is to eliminate the drawbacks of the conventional compounded antipyretic analgesics, such as easy occurrence of gastrointestinal disorders, and to provide an excellent analgesic action and a highly safe compounded antipyretic analgesic. To develop a drug.

[0004]

The present invention eliminates these drawbacks by combining various antipyretic analgesic and anti-inflammatory agents.
It is characterized by exhibiting excellent effects in terms of effectiveness and safety.

[0005]

[Action and Example] Diclofenac sodium (Chemical name:
2- (2,6-dichloro-anilino) phenylacetic acid sodium salt) is a non-steroidal anti-inflammatory drug with excellent antipyretic,
It is known to have analgesic and anti-inflammatory effects. It has been found that when such diclofenac sodium is combined with an existing antipyretic analgesic, an aniline derivative antipyretic analgesic such as acetaminophen, a remarkable synergistic effect exceeding additive effects is found. For example, in terms of analgesic activity, diclofenac sodium and acetaminophen were mixed at an ED ₅₀ amount ratio of 3/4: 1/4, 1/2: 1/2, 1
In the three kinds of combinations which were blended so as to be / 4: 3/4, the theoretical values of 1.20, 1.14 and 1.
A high synergistic effect that a 41-fold analgesic effect was obtained was exhibited. Furthermore, the problem of gastrointestinal disorders was solved by incorporating diclofenac sodium into the aniline derivative antipyretic analgesic instead of the salicylic acid derivative antipyretic analgesic.

As a result of intensive studies to further improve it, when diclofenacnalium was combined with an aniline derivative antipyretic analgesic, and when caffeine and a vitamin B ₁ derivative were further added, diclofenacnatoum was added. The present inventors have completed the present invention by surprisingly finding that the pain threshold value can be further increased in the analgesic effect test, as compared with the case where two components of the aniline derivative antipyretic analgesic are blended. That is, the present invention relates to a combined antipyretic analgesic comprising diclofenac sodium and an aniline derivative antipyretic analgesic, and diclofenac sodium, an aniline derivative antipyretic analgesic, caffeine and a vitamin B ₁ derivative.

The antipyretic analgesic of the present invention is particularly effective mainly when used as an analgesic. Examples of the aniline derivative antipyretic analgesic to be used include acetaminophen and lactylphenedine, and acetaminophen is preferable from the viewpoint of synergistic effect and toxicity in combination with diclofenac sodium.

The proportion of diclofenac sodium and the aniline derivative antipyretic analgesic is preferably 0.1 to 100 parts, particularly 1 to 60 parts for the former 1 part (part by weight, the same hereinafter). When the ratio of the diclofenac sodium and the aniline derivative antipyretic analgesic is out of the above range, the synergistic effect described above cannot be remarkably exhibited.

Examples of the caffeine used in the present invention include caffeine, anhydrous caffeine, sodium benzoate caffeine, etc., and caffeine is particularly preferable. The blending ratio of the caffeine and the vitamin B ₁ derivative is preferably 1 to 100% by weight and 0.2 to 20% by weight, respectively, with respect to the total amount of the diclofenac sodium and the aniline derivative antipyretic analgesic.

The antipyretic analgesic of the present invention may further contain sedative hypnotics, antacids, mild herbs, vitamins, auxiliary agents such as amino acids.

The compound antipyretic analgesic of the present invention is effective for headache, toothache, pain after tooth extraction, analgesia for menstrual pain and chills, antipyreticity at the time of fever and the like. The daily dose for an adult is usually about 500 to 2000 mg in terms of the total amount of diclofenactodium, an aniline derivative antipyretic analgesic, caffeine and vitamin B ₁ , and the administration method is oral administration.

The antipyretic analgesics of the present invention are tablets, granules,
It is used as a preparation of various oral administration dosage forms such as fine granules, hard capsules, soft capsules, solutions, syrups, and dispersants. The preparation of such a formulation is carried out according to a conventional method, for example, as an excipient, starch, partially pregelatinized starch,
Carmellose sodium, lactose, crystalline cellulose, magnesium stearate, talc, etc., as a suspending agent, polysorbate 80, polyoxyethylene hydrogenated castor oil,
Pluronics are used. As the corrigent, sucrose, glucose, sodium saccharin, sorbitol,
Citric acid, aspartame, etc. are used.

Next, the compound antipyretic analgesic of the present invention will be described with reference to examples, but the present invention is not limited to these examples. Example 1 (Analgesic action) The analgesic action of the compound antipyretic analgesic of the present invention was examined. In each of the following experiments, a group of 10 ddY male mice (weight 20 to 24 g) and Wist were used as experimental animals.
A group of male ar rats (body weight 70 to 100 g) was used. The test drug was used by suspending it in a 0.2% sodium carboxymethylcellulose aqueous solution at the time of use, and this suspension was orally administered at a rate of 0.1 ml with a body weight of 10 g. Fifty
The ED _50, which is the% effective dose, was calculated by the Probit method. (1) Combination of diclofenac sodium and acetaminophen (a) Acetic acid stretching method First, ED ₅₀ was determined for each of diclofenac sodium and acetaminophen alone. That is, the animals were fasted for about 4 hours, and 30 minutes after oral administration of the test drug,
0.7% acetic acid (diluted with physiological saline) solution 0.1 ml / 1
0 g was injected intraperitoneally. Ten times after the injection, the number of stretchings (abdominal pain symptoms showing pain) was measured for 10 minutes, and animals that were suppressed to less than half of the average number of stretchings (about 40/10 minutes) in the control group were selected. The effective rate was calculated based on the all or none judgment method which is considered to have an analgesic effect. The results are shown in Table 1.

[0014]

[Table 1]

Next, diclofenac sodium and acetaminophen were mixed in an ED ₅₀ amount ratio of 3/4: 1/4, 1/2: 1/2, 1 as shown in Table 2 from the results of Table 1.
/ 4: The effective rate was determined in the same manner as described above for the three types of compounding agent formulations combined so as to be 3/4. as a result,
As shown in Table 3, measured values (ED ₅₀ ) of each compounding agent
Is 24.7 mg / kg, 45.8 mg / kg and 52.
It was 6 mg / kg. The theoretical values (ED ₅₀ ) are 29.7 m / kg, 52.1 mg / kg and 74.4, respectively.
It was mg / kg. FIG. 1 shows the measured data plotted by the Gaddum plotting method. As shown in the figure, the combination effect is synergistic because it is located closer to the origin side than the line connecting the single ED _50s in the three types of combination agents, and in particular, 1/4 of the ED ₅₀ amount of diclofenac sodium and acetamino acid. It can be seen that there is the most remarkable synergistic effect in the combination in which phen is mixed at a ratio of 3/4 of the ED ₅₀ amount.

[0016]

[Table 2]

[0017]

[Table 3]

(2) Combination of diclofenac sodium, acetaminophen, caffeine and dibenzoylthiamine As shown in Table 4, diclofenac sodium and acetaminophen having an ED ₅₀ amount ratio of 3/4: 1/4.
(I), 1/2: 1/2 (II), 1/4: 3/4 (I
The compounding effect was examined by combining caffeine and dibenzoylthiamine with each of the three formulations formulated so as to be II). That is, the drug group A of I was 5.5 mg / kg of diclofenac sodium + acetaminophen 24.2 mg / kg, and the drug group B of I was 5.5 mg of diclofenac sodium / kg + acetaminophen 24.
2 mg / kg + caffeine 15 mg / kg + dibenzoylthiamine 2 mg / kg, C drug group II is diclofenac sodium 3.7 mg / kg + acetaminophen 4
8.4 mg / kg, II drug group D was 3.7 mg / kg of diclofenac sodium + 48.4 acetaminophen.
mg / kg + caffeine 15 mg / kg + dibenzoylthiamine 2 mg / kg, the E drug group of III is diclofenac sodium 1.8 mg / kg + acetaminophen 7
2.6 mg / kg, III F drug group is diclofenac sodium 1.8 mg / kg + acetaminophen 72.
The compounding amounts of 6 mg / kg + caffeine 15 mg / kg + dibenzoylthiamine 2 mg / kg were administered respectively.
On the other hand, the IV G drug group was treated with 0.
Only an aqueous solution of 2% sodium carboxymethyl cellulose was administered.

[0019]

[Table 4] (A) Acetic acid stretching method The acetic acid stretching method was performed according to the method described above. However, as a method for determining the effect, the method of suppressing the number of stretching times was used here. As shown in Table 5, at each of the compounding ratios, a stronger inhibition rate was observed when caffeine and dibenzoylthiamine were added, and in particular, the ratio of II: 1/2: 1/2 (that is, diclofenac sodium 3.7 mg / kg and acetoacetate). Aminophen 4
8.4 mg / kg, C drug group), a strong analgesic effect was observed in the D drug group containing 15 mg / kg of caffeine, which has no analgesic activity, and 2 mg / kg of dibenzoylthiamine. ..

[0020]

[Table 5]

(B) Randall-Serit method Since the enhancement of the analgesic effect was observed by the acetic acid stretching method using mice, the animal species was changed next, and the pain threshold (g) and the action in rats were evaluated by the Randall-Serit method. I investigated the duration. That is, 0.1 ml of 10% dry yeast suspension was previously injected subcutaneously in the left footpad of a rat to induce inflammation. After 3 hours, an animal with a decreased pain threshold width was selected and the test drug was orally administered, and thereafter, the pain threshold of the inflamed paw (left paw) was measured every 4 hours until 4 hours later. The results are shown in Table 6, FIG. 2, FIG. 3 and FIG. As is clear from FIG. 3, the D drug group in which caffeine and dibenzoylthiamine were mixed in the ED ₅₀ amount ratio of diclofenac sodium and acetaminophen of 1/2: 1/2, compared with the C drug group, had a pain threshold value. Was found to be increased, and the duration of action was further extended.

[0022]

[Table 6]

Example 2 (Preparation Method of Preparation) Tablets containing the following ingredients in 2 tablets were prepared by a conventional method. Component Diclofenac sodium 15 mg Acetaminophen 150 mg Caffeine 60 mg Dibenzoylthiamine 8 mg Carboxymethylcellulose calcium 45 mg Hydroxypropylcellulose 45 mg Crystalline cellulose 40 mg Lactose 64.8 mg Silicon dioxide 30 mg Magnesium stearate 2.2 mg Hydroxypropylmethylcellulose 2910 9m
g Titanium oxide 1 mg

Example 3 (Preparation Method of Preparation) A granule containing the following components in one package (500 mg) was prepared by a conventional method. Component Diclofenac sodium 15 mg Acetaminophen 150 mg Caffeine 60 mg Dibenzoylthiamine 8 mg Hydroxypropyl cellulose 97 mg Crystalline cellulose 54 mg Lactose 85 mg Silicon dioxide 30 mg Magnesium stearate 1 mg

[Brief description of drawings]

FIG. 1 is a diagram illustrating a compounding effect (Table 3) of three combinations of diclofenac sodium and acetaminophen by an acetic acid stretching method by a Gaddum drawing method.

FIG. 2 is a drug group A by the Randall-Serit method, B
Changes over time in pain thresholds of the drug group and the G drug group (control group) (Table 6)
And I) and IV) of FIG.

FIG. 3 is a C drug group by the Randall-Serit method, D
Changes over time in pain thresholds of the drug group and the G drug group (control group) (Table 6)
II and IV) of FIG.

FIG. 4 shows E drug group, F by Randall-Serit method.
Changes over time in pain thresholds of the drug group and the G drug group (control group) (Table 6)
III and IV) of FIG.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display area A61K 31:51 7252-4C 31:52) 7252-4C

Claims (8)

[Claims] 1. A compound antipyretic analgesic comprising a combination of diclofenac or a salt thereof and an aniline derivative antipyretic analgesic. 2. The compound antipyretic analgesic according to claim 1, wherein the aniline derivative antipyretic analgesic is acetaminophen. 3. The compound antipyretic analgesic according to claim 1, wherein 0.1 to 100 parts by weight of the aniline derivative-based antipyretic analgesic is compounded with 1 part by weight of diclofenac sodium. 4. A caffeine compound and a vitamin B ₁ derivative are blended in an amount of 1 to 100% by weight and 0.2 to 20% by weight, respectively, with respect to the total amount of diclofenac sodium and an aniline derivative antipyretic analgesic. Range first
The compound antipyretic analgesic according to item 2, 2 or 3. 5. The compound antipyretic analgesic according to claim 4, wherein the vitamin B ₁ derivatives are dibenzoylthiamine. 6. The compound antipyretic analgesic according to claim 4, wherein the vitamin B ₁ derivative is fursultiamine. 7. The compound antipyretic analgesic according to claim 4, wherein the vitamin B ₁ derivative is benfotiamine. 8. The compound antipyretic analgesic according to claim 1, 2, 3, 4, 5, 6 or 7, wherein the caffeine is caffeine. ..