JPS58152821A - Blended drug - Google Patents

Abstract

PURPOSE:A blended drug for reducing and suppressing disorders of digestive tube as side effects, obtained by blending a compound for drug active ingredient with a water-soluble alginate. CONSTITUTION:A compound (e.g., aspirin, phenylbutazone, indomethacin, mefenamic acid, reserpine, cortisone, etc.) for drug active ingredient causing disorders of digestive tube as side effects such as gastric erosion, hemorrhage, ulcer, etc. is blended with a water-soluble alginate (e.g., sodium alginate, potassium alginate, ammonium alginate, amine alginate, etc.). The water-soluble alginate is preferably used in the form of an aqueous solution, its concentration is 2- 10w/v% and its pH is about 7. Only side effects can be reduced and lowered without lowering the medical effect of the compound for active ingredient of its own.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a new compounded drug, more specifically, a drug that causes gastrointestinal disorders as a side effect, by incorporating water-soluble salts of alf-sialic acid, thereby completely eliminating the original pharmacological action of the drug. The present invention relates to a combination drug that does not cause any deterioration but rather improves the health of the patient, and also significantly reduces or suppresses side effects.

BACKGROUND OF THE INVENTION Conventionally, there are many drugs that are mainly orally administered that cause gastrointestinal disorders as side effects. For example, aspirin is an antipyretic analgesic, which is one of the most frequently used medicines, phenylbutaline, indomethacin, mefenamic acid, etc. are anti-inflammatory agents, antihypertensive agents, and mefenamic acid.
Corchiline, which is used as an analgesic and a steroid, has excellent medicinal efficacy, but is known to cause side effects such as gastrointestinal disorders, such as gastric erosion, bleeding, and ulcers. It is being Therefore, when using second class drugs, it is necessary to carefully manage the dosage by fully considering the balance between the original medicinal efficacy and the above-mentioned side effects.

In particular, aspirin, which is one of the representative drugs known to induce gastric ulcers, is often accompanied by peptic ulcers in clinical use. Its most common sites are the lesser curvature of the stomach and the antrum of the pylorus, and its mechanism of occurrence is thought to be direct damage to the gastric mucosa. Asdilin is also known to have a phototransmissive effect on gastric juice secretion and an effect on promoting the propensity for birth, and is also well known as a drug that experimentally induces ulcers. Therefore, when applying the various pharmaceuticals mentioned above, there is a need for measures to prevent and attenuate gastrointestinal problems such as acute gastritis bleeding, erosions, and ulcers that may be caused.Currently, measures are being taken to eliminate such problems. is the same as nothing.

The object of the present invention is to successfully solve the above problems and provide a new combination drug that can be applied extremely safely without side effects.

That is, the present invention relates to a combination drug characterized in that a water-soluble salt of alinic acid is added to a drug that causes gastrointestinal disorders as a side effect.

In the process of intensive research into various drugs conventionally used in the pharmaceutical field, the present inventors discovered Al-4:JFIR sodium, which has long been used as a pharmaceutical raw material, bulking laxative, plasma expander, etc. It has been found that water-soluble salts of alinic acid have gastrointestinal mucosal-preserving and gastrointestinal hemostatic effects and are useful as therapeutic agents for peptic ulcers. When used in combination with pharmaceuticals such as aspirin, it was discovered that only the side effects occurred without any reduction in the original efficacy of secondary drugs. The present invention was completed based on this new knowledge.

The compounded medicine of the present invention must contain water-soluble salts of Alf:/# together with its active ingredient compound, and based on this, the action of the active ingredient compound can be enhanced without reducing the original medicinal efficacy of the active ingredient compound. It can be significantly reduced or prevented. Examples of the water-soluble salts of alinic acid used here include storium salts, potassium salts, anthinium salts, and amine salts of alinic acid. The above-mentioned alinic acid is a polysaccharide belonging to the polysaccharide D:/acid (D-machinic acid and L - talonic acid), and is usually purified as a sodium salt after extraction with a dilute alkaline solution from the above MSs. The Al 4
:i# Sodium has low toxicity and guaranteed safety, as its use has been recognized in the pharmaceutical field. The average molecular weight of the water-soluble alinic acid salts is usually in the range of about 60,000 to 250,000. This average molecular weight was determined by eluting the Al4:Jm salt in 0.1# hydrochloric acid, measuring the flow rate in seconds using an Ostwald viscometer, and calculating the intrinsic viscosity. A 21F/V% aqueous solution of an alinic acid water-soluble salt having the above average molecular weight is usually prepared using a B-type viscometer (0-9-2,
The viscosity is in the range of about 5 to 150Q liters (2 minutes, 20 DEG C.), and an alinate having a viscosity within this range is suitably used in the present invention and can produce the desired effect.

In addition, in the present invention, as the active pharmaceutical ingredient compound to which the water-soluble alinic acid salts are blended, any compound that causes gastrointestinal disorders as a side effect can be used. Typical examples thereof include aspirin, phenylbutaric, indomethacin, mefenamic acid, reserpine, and cotiline.

The amounts of the Al 4:J acid water-soluble salts and the above-mentioned active ingredient compounds in the compounded drug of the present invention are appropriately determined depending on the type of the secondary compound, the formulation form of the obtained drug, the route of administration, the method of administration, etc. Ru. Generally, the water-soluble salts of alinic acid are most preferably used in the form of an aqueous solution, and in this case, considering its water solubility, the concentration is about 2 to 101 F/V%, preferably about 3 to 81 F/V%. It is better. An aqueous solution having a concentration in this range usually has a pH of around 7, which is preferable for practical purposes, but if desired, pH adjustment can be carried out using a conventional pH adjusting agent such as sodium chloride or hydrochloric acid. Therefore, the alinate used does not need to have all its carbo+syl groups neutralized (100% neutralized), but only about 50% or more, which is particularly advantageous for practical use. In order to maintain H6 to H8, the degree of neutralization is preferably about 70% or more. In the above, the active ingredient compound is preferably dissolved or dispersed or suspended in an aqueous Al4:imm aqueous salt solution,
In particular, when dispersing or suspending the above, Al 4:im water-soluble #
Since 1tII itself also acts as a suspending agent, an M suspension suitable for use can be easily obtained without using any other suspending agent. The amount of the active ingredient compound may be the same as the amount in the general form in which they are usually used,
In general, the concentration may be set to 0.01 W/V% or more, preferably Q, and about 95 W/V% or more in the case of the above-mentioned aqueous solution line. When using, for example, aspirin as the active ingredient compound, it is preferred that the compound is contained in an amount of about 0.5 to 1.51 per 1 unit form suitable for administration;
It is preferable that phenylptalis be contained in about 50 to 200 capes, and that indomethacin be contained in about 25 η. In particular, the present invention has the advantage that even if the second active ingredient compound is administered in a fairly large amount, the side effects caused by the compound can be significantly reduced, and it can be used safely and effectively.

The compounded pharmaceuticals of the present invention are generally administered orally, but the administration method is not particularly limited thereto, and can be administered by the administration method normally applied to the active pharmaceutical ingredient compound. Further, the compounded pharmaceutical of the present invention may be prepared in the form of a solid agent such as a dry syrup, powder, fine granule, granule, tablet, etc., and may be administered by an appropriate administration route. Preparation into each of these forms can be carried out according to conventional methods, and at that time, various commonly used pharmaceutical carriers such as excipients, diluents, fillers, extenders, binders, disintegrants, wetting agents, surface Active agents, tonicity agents,
Solubilizing agents, buffering agents, soothing agents, coloring agents, preservatives, etc.
Similar to known pharmaceuticals of this type, flavorings, sweeteners, etc. can be added.

The dosage of the compounded drug of the present invention thus prepared can be determined as appropriate depending on the symptoms, age, weight, sex, etc. of the patient to whom it is applied, as well as the dosage form and route of administration of the compounded drug. For example, when administered orally in the form of an aqueous liquid, approximately 5 to 1 of the liquid is administered per patient once a day.
Approximately 20 to 100 ml is preferably administered. This administration may also generally be carried out several times (3 to 5 times) per day.

The compounded medicine of the present invention is effective in preventing and treating various diseases in view of the original medicinal effects of the active ingredient compounds contained therein.

Examples of prescriptions for the pharmaceuticals of the present invention are listed below.

Formulation Example 1 Dissolve 50F of sodium alinate C (average molecular weight approximately 160,000, the same shall apply hereinafter) in 11 parts of purified water, add finely ground aspirin 20F to this, and disperse with a hot water bath to prepare an aqueous solution. Obtain an invented combination drug (antipyretic analgesic). This is suitable for administering approximately 50 m of the drug per 16 patients.

Prescription Example 2 Sodium alkoshichia is finely ground, and finely ground aspirin 10F is added to the resulting 251, mixed well, and filled into a bottle to obtain the combination drug of the present invention (antipyretic analgesic) in the form of a dry syrup. This is 3.5g of Yosaki and 50g of purified water.
It is suitable for mixing and shaking well.

Formulation Example 3 Al 4: 0.4 f of finely powdered phenylbutaline is added to Jm sodium powder 51 and mixed uniformly, and the mixture is filled into a bottle to obtain a combination pharmaceutical of the present invention (anti-inflammatory agent) in the form of a dry syrup. This is suitable for mixing with 100 sJ of Yozaki Seisei Water and shaking and administering 501 d of the mixture at a time, 2 times a day.

Prescription Example 2.5 f of thorium powder brewed in Alfon is thoroughly mixed with 25 caps of finely powdered isidomethacin, and the mixture is filled into a bottle to obtain the combination drug of the present invention (anti-inflammatory agent) in the form of a dry syrup. This is suitable for use by shaking the mixture in 50 seconds of purified water and dispersing it.

Examples of tests conducted on the compounded pharmaceuticals of the present invention are listed below.

A test for platelet aggregation When bleeding occurs, platelets in the blood first adhere, aggregate, and metamorphose to form a platelet thrombus, which then stops the bleeding.

Therefore, platelets play an important role in preventing bleeding from gastric lesions. It is said that the above platelet aggregation does not occur at fiH5.9 or lower (F, t').

arttn, zt, at, ctutratntzrat
oyy, H, 3B-43 <1978)]. It has also been reported that platelet aggregation caused by ADP and the like does not occur in the presence of aspirin [Yamanaka Manabu, "Platelets", p. 137, published by Kagaku Hyoronsha, 1979]. However, the present inventors found that in the presence of water-soluble salts such as in the combination drug of the present invention, platelet aggregation was observed even under the above-mentioned low conditions and in the presence of aspirin, and hemostasis was achieved. In other words, the above-mentioned treatment was applied to gastrointestinal bleeding caused by aspirin. This test clarified the above facts and clarified that the combination drug of the present invention significantly suppresses the side effects of aspirin (gastrointestinal bleeding).

This test was conducted using the following method. That is, citrated rat blood was centrifuged (IIOGXIO) to obtain platelet-rich blood l! Obtain (PRP). its 0.25- to 0.01
#Asdirin 0.05- and 0.05 ml of aqueous solutions of 5-modified sodium perosinate were added, and the aggregated PRP knee was observed under a microscope. As a control, the same test was repeated using a physiological saline solution instead of the above sodium alphosinate aqueous solution.

As a result of the above test, platelet aggregation was observed when a L4:ifm sodium aqueous solution was used regardless of the presence of aspirin, but when a physiological saline solution was used as a control, platelet aggregation was observed due to the presence of asdirin. > No platelet aggregation was observed.

<Effect on ulcers> This test reveals that the effects of gastrointestinal disorder (ulcer development) caused by asdirin administration are significantly suppressed by the combination drug of the present invention. . The following drugs were used as the pharmaceuticals of the present invention.

That is, a 5% sodium acetate aqueous solution prepared according to Formulation Example 1 and asdirin were dispersed at a concentration of 4 W/V to obtain a pharmaceutical composition of the present invention in the form of a suspension. This product is stable and can be observed to precipitate if left for a short time.Also, if left for a long time, some precipitation may occur, but the precipitate is easily redispersed by shaking and becomes a uniform powder.
It was possible to return to the 111ilt11 format.

2.5s/(
Asdilin (200 q/#) was administered to rats for 5 days, and then the rats were sacrificed, the stomach was removed, and an incision was made along the greater curvature to determine the ulcer index. The coefficient is the entity − mold mirror (
It was determined by measuring the ulcer length W) at a magnification of 6.3 times. As a control, aspirin was added to purified water at 4W/V%.
Suspend at a concentration of 2.5 m (200 MI
/#) was used immediately to repeat the same test. The results obtained by testing 8 rats in each group are shown in Table 1 below. From Table 1 above, the result of the significance test (T-test) was 1%.
There was clearly a significant difference in the risk ratio between the two groups, and it was found that the induction of gastrointestinal disorders (ulcer formation) was clearly suppressed by administration of the combination pharmaceutical of the present invention.

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Claims (1)

[Claims] ■ A combination drug characterized by adding water-soluble salts of acyic acid to a drug that causes gastrointestinal disorders as a side effect.