JPH11199486A - Vitamin b2-containing medicine composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine composition having strongly immunopoterntiative actions and infection protecting actions, useful as a preventive/therapeutic agent for mastitis, septic shock, eukopoenia, etc. SOLUTION: This medium composition comprises vitamin B2 (preferably riboflavin, riboflavin tetrabutyrate, sodium riboflavin phosphate, flavin mononucleotide or flavin adenine dinucleotide) and m-cresol. The dose of vitamin B2 is preferably 1-25 mg based on 1 kg weight. In the case of administering the composition as an injection, the amount of m-cresol is preferably 0.05-0.25 W/V%, based on the total volume of the injection. The administration form of the medicine composition is preferably an injection and the composition can be administered by intramuscular injection, intravenous injection, subcutaneous injection, etc. In the case of the injection, the injection can be formulated with a surfactant such as Tween 80 or the like, an emulsifying agent such as gum arabic, a soothing agent such as benzyl alcohol or the like, if required.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing vitamin B2, and more particularly to an immunostimulatory / infective protective agent containing vitamin B2.

[0002]

2. Description of the Related Art Vitamin B2 is generally known as riboflavin, riboflavin butyrate, sodium riboflavin phosphate and the like. In particular, sodium riboflavin phosphate is widely used because of its good water solubility and excellent absorption. These are presumed to be involved in vitamin B2 deficiency or metabolic disorders such as stomatitis, retinal inflammation, acute / chronic eczema, and conjunctivitis as components of nutritional supplements when intake from the diet is insufficient, such as in wasting diseases. It is used as a component of preventive and therapeutic agents for diseases that are caused. In addition, flavin mononucleotide and flavin adenine dinucleotide, which are riboflavin derivatives existing in the living body, play a central role in oxidative degradation of sugars, lipids and amino acids, and in electron transport systems of mitochondria and microsomes. More recently, vitamin B2 has been found to be useful as an immunostimulatory / infective protective agent (Japanese Patent Application Laid-Open No. 5-201864, Japanese Patent Application No. 9-91352).

[0003]

Problems to be Solved by the Invention
The immunostimulatory / infection protective agent disclosed in Japanese Patent Publication No. 4 has an effect of suppressing the lethality of mice due to Escherichia coli infection, but it is necessary to administer vitamin B2 at a high level of 100 mg / kg. However, in general, vitamin B2 has low water solubility, and vitamin B2 in existing vitamin B2 injections.
The two concentrations are low. Even riboflavin sodium phosphate, which is considered to have relatively good water solubility, has a concentration of about 1 to 2% in an injection. When such a vitamin B2 is used for a large animal, particularly in the case of administration of an injection, the amount of the injection solution becomes large, which burdens both the administering doctor, veterinarian, patient, and test animal. In view of the above background, there is a need to provide a vitamin B2-containing drug capable of exhibiting a strong immunostimulatory and protective action with a smaller dose.

[0004]

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies with the aim of providing a more powerful infection protective agent. As a result, surprisingly, among the substances used as preservatives for injections, vitamin B2 injections containing metacresol, in particular, showed a lethal dose of mice infected with lethal E. coli. The present inventors have found that they significantly and significantly suppress the vitamin B2 injection and the vitamin B2 injection containing other preservatives, and completed the present invention.

[0005] That is, the present invention is a pharmaceutical composition comprising vitamin B2 and meta-cresol, and by providing vitamin B2 and meta-cresol, provides a pharmaceutical composition having a stronger immunostimulatory and protective action against infection. can do. This is the purpose of the present invention.

[0006] Meta-cresol is also called metamethylphenol or metahydroxytoluene, and is a substance having extremely excellent biodegradability, and has been conventionally used mainly as a preservative in pharmaceuticals. Meta-cresol in the present invention, when administered as an injection, sufficiently produces the desired action / effect at a compounding ratio suitable as a pharmaceutical, but preferably 0.001 to 0.5 W / V%, more preferably per total volume of the injection solution. 0.01-0.4W / V%, more preferably 0.05-0.25W / V%
It is.

[0007] The present invention is also an immunostimulatory / infective protective agent comprising vitamin B2 and meta-cresol. Immunostimulation here refers to the immune function of humans, livestock, poultry, etc.
It means to increase the infection defense function. Therefore, the immunostimulatory / infection protective agent according to the present invention is useful as a preventive / therapeutic agent for various diseases by enhancing the immune function / infective protective function. For example, various infectious diseases such as bacterial infections such as mastitis and septic shock, viral infections such as parvo infection, cancer, organ transplantation, leukopenia, rheumatoid arthritis, autoimmune disease, bronchial bronchial disease asthma,
It can be used as an effective prophylactic / therapeutic agent for malnutrition, surgery, aging disease and the like.

As the vitamin B2 in the present specification, specifically, for example, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, flavin mononucleotide, flavin adenine dinucleotide and the like can be used, and preferably riboflavin, riboflavin butyrate, It is sodium riboflavin phosphate, more preferably sodium riboflavin phosphate.

The dose of vitamin B2 according to the present invention is
0.1 to 100 mg per kg of body weight, preferably 0.5 to 50
mg, more preferably 1 to 25 mg. Vitamin B
No. 2 is a drug listed in the Japanese Pharmacopoeia and has no serious toxicity under normal use. In addition, metacresol is also allowed to be added up to 0.5% in the case of injection,
There is no particular toxicity problem.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The mode of administration of the pharmaceutical composition or the immunostimulatory / infective protective agent according to the present invention is not particularly limited, and may be injections, suppositories, granules, capsules and the like. it can. Particularly preferred are injections, intramuscular injection,
It can be administered by intravenous injection, subcutaneous injection or the like.

For the preparation of pharmaceutical preparations, commonly used excipients, binders, lubricants, surfactants, pH adjusters, preservatives, antioxidants and, if necessary, stabilizers and absorption enhancers are used. Can be formulated by a conventional method.

In the case of an injection, Tween 80 and polyoxyl stearate 4 may be used as necessary, for example, as a surfactant.
0, sorbitan sesquioleate, glycerin monostearate, lauromacrogol, etc .; gum arabic, tragacanth, sodium alginate, etc. as emulsifiers; benzyl alcohol, chlorobutanol, etc. as soothing agents; citric acid, acetic acid, tartaric acid, succinic acid as stabilizers Components such as a buffer such as an acid, propylene glycol, diethylin, sulfite, ascorbic acid, and Rongalite can be added.

[0013] The method for producing the pharmaceutical composition of the present invention as an injection is not particularly limited, and can be based on a commonly used apparatus and method. For example, when sodium riboflavin phosphate is used as vitamin B2, sodium riboflavin phosphate and an isotonic agent are dissolved in water, meta-cresol is added, and then, if necessary, various additives such as sodium citrate are added. It can be manufactured by adjusting the pH to 4.5 to 7.0 by adding sodium hydroxide as a pH adjuster, and performing sterilization by filtering or heating.

Hereinafter, the effects of the pharmaceutical composition according to the present specification will be described in detail by test examples, but the present invention is not limited to these examples.

[Test Examples] Inhibitory effect on mouse lethality : First, injections (Control, control examples, samples 1 to 6) having eight kinds of compositions having a pH of 6.3 shown in Table 1 were prepared. At this time, the injection solution was sterilized by heating at 105 ° C. for 60 minutes. Next, 0.05 ml of each injection (25 mg / k
g) was intravenously administered to 10 SLC: ICR male mice (5-6 weeks of age, 25-30 g of body weight) for each sample.
Four hours later, clinically derived E. coli (4.0 × 10 ⁷ CFU / mouse, 0.2m
l) was inoculated subcutaneously into all mice. Determined the survival rate from the survival number of infected 4 days, a significant difference for the Control was determined by x ² test. The results are shown in Table 2, where "*"
And “**” represent p <0.05 and p in the x ² test, respectively.
<0.01

[0016]

[Table 1]

[0017]

[Table 2]

[0018]

In the above test examples, the pharmaceutical composition according to the present invention (sample 5) showed that the lethality of mice infected with a lethal dose of Escherichia coli was stronger and significantly greater than that of a vitamin B2 alone preparation (control example). Suppressed. In other words, the action of vitamin B2 was enhanced by adding meta-cresol. According to the present invention, an immunostimulatory / infective protective agent having stronger activity than conventional vitamin B2 injection can be provided, and the same effect can be exerted even in a low dose. The immunostimulatory / infection protective agent according to the present invention comprises:
It is useful as a prophylactic / therapeutic agent for various diseases that can be prevented or treated by enhancing immune function, such as various infectious diseases. The injection consisting of vitamin B2 and meta-cresol used in the above test examples was produced by the method shown in the following examples.

[0019]

[Example] Riboflavin phosphate 5.02g, meta-cresol
0.1 g was dissolved in 80 ml of water for injection, 1% sodium hydroxide was added to adjust the pH to 6.3, and the total amount was adjusted to 100 ml with water for injection. After filling into a 20 ml vial, the mixture was sterilized by heating at 105 ° C. for 60 minutes to obtain a target injection. .

Claims (7)

[Claims] (1) a pharmaceutical composition comprising vitamin B2 and meta-cresol; 2. An immunostimulatory / infective protective agent comprising vitamin B2 and meta-cresol. 3. The immunostimulatory / infective protective agent according to claim 2, wherein the vitamin B2 is riboflavin, riboflavin butyrate, sodium riboflavin phosphate, flavin mononucleotide or flavin adenine dinucleotide. 4. The immunostimulatory / infective protective agent according to claim 2, wherein the composition is an injection. 5. A preventive / therapeutic agent for mastitis comprising vitamin B2 and metacresol. 6. A preventive / therapeutic agent for septic shock comprising vitamin B2 and metacresol. 7. A prophylactic / therapeutic agent for leukopenia comprising vitamin B2 and meta-cresol.