JPH0597665A - Antimalarial agent - Google Patents

Abstract

PURPOSE:To obtain an antimalarial agent containing 15-deoxyspergualin or its pharmacologically permissible salt as an active ingredient. CONSTITUTION:Treating effects of 15-deoxyspergualin on a malaria model using mouse are examined. By administration with 15-deoxyspergualin, infection of malaria protozoan is prevented and curing or like prolonging effect is recognized. The antimalarial agent containing the compound as an active ingredient is useful, because the compound is low in toxicity and high in safety.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an antimalarial agent containing 15-deoxyspergualin as an active ingredient.

[0002]

2. Description of the Related Art At present, typical antimalarial agents for malaria patients include quinine, chloroquine and primaquine. Further, 15-deoxyspagarin is a derivative of spagarin isolated from a bacterium belonging to the genus Bacillus and is known to have antitumor activity and immunosuppressive activity. (JP-A-58-62152, JP-A-61-1)
29119).

[0003]

The antimalarial agents currently used are highly toxic and may cause sequelae in some cases, and due to the occurrence of drug-resistant malaria, etc., they are novel and highly safe anti-malarial agents. Development of a malaria drug is earnestly desired.

[0004]

[Means for Solving the Problems] The present inventors have conducted diligent research to develop a new type of drug for treating malaria.
The present invention was completed by finding that 15-deoxyspergualin has the ability to prevent infection with malaria parasites. That is, the present invention relates to an antimalarial agent containing 15-deoxyspergualin and a pharmacologically acceptable salt thereof as an active ingredient. 15-deoxyspergualin has the structural formula (I) and is known in the art (Japanese Patent Laid-Open No. 58-6215).
It can be manufactured in 2).

[0005]

[Chemical 1]

The compound of formula (I) forms a salt with an acid, and the acid for forming the salt may be either an inorganic acid or an organic acid as long as it is pharmacologically acceptable. As the inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like are preferable,
Examples of organic acids include acetic acid, propionic acid, succinic acid,
Fumaric acid, maleic acid, malic acid, tartaric acid, glutaric acid, citric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, aspartic acid and glutamic acid are preferable.

When the compound is used as an antimalarial agent, it is administered alone or in admixture with an excipient or carrier as an injection, an oral preparation, a suppository or the like. As the excipient and carrier, those which are pharmaceutically acceptable are selected,
The type and composition depend on the administration route and administration method. For example, water, alcohols or soybean oil, animal oil and vegetable oil such as peanut oil, sesame oil, mineral oil or synthetic oil is used as the liquid carrier, and lactose, malt-containing oil as the solid carrier.
Sugars such as sugar and sucrose, amino acids, cellulose derivatives such as hydroxypropyl cellulose and organic acid salts such as magnesium stearate are used.

Excipients used for injection are mannitol,
Maltose, dextran, lactose, cyclodextrin, chondroitin sulfate, gelatin, human serum albumin, but maltose, lactose, chondroitin sulfate,
Gelatin and human serum albumin are preferred. A lyophilized preparation together with these excipients, and a suitable solvent for injection at the time of administration, such as sterile water, physiological saline, glucose solution,
The electrolyte solution can also be administered by dissolving it in a liquid for intravenous administration such as an amino acid solution.

The pH of the composition of the present invention is
An acid, an alkali, or an appropriate amount of a buffer may be added for the purpose of adjustment. The pH at which 15-deoxyspergualin is stably present in an aqueous solution is about 5 or less, and it is better to adjust the pH to 2-5, preferably 3-5 when preparing a drug solution for freeze-drying.

The content of the compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1
Is about 98% by weight. For example, in the case of an injection solution, it is usually 0.
The active ingredient may be contained in an amount of 1 to 30% by weight, preferably 1 to 10% by weight. For oral administration,
It is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with the solid carrier or liquid carrier. Capsules, tablets, granules and powders generally contain 5-100% by weight, preferably 25-98% by weight, of the active ingredient.

The dose is determined according to the age, body weight, condition of the patient, purpose of treatment, etc., but the therapeutic dose is generally 1 to 100 mg / kg for parenteral administration, 5 to 500 mg / kg for oral administration.
・ It is a day. The compound is characterized by relatively low toxicity and low toxicity accumulation after continuous administration. 50 when the present compound is administered once intraperitoneally to mice
The% lethal dose LD ₅₀ is 25 to ₅₀ mg / kg.

[0012]

The effect of 15-deoxyspergualin on the malaria model in mice is shown as a test example. Test Example Therapeutic effect on malaria model in mice Experimental method Bals / Plasmodium berghei
Inoculated into C mice, the infection rate of protozoa to mouse red blood cells is 2%
Alternatively, the administration of 15-deoxyspergaline hydrochloride was started after reaching 5%. The mice were divided into 3 groups, non-drug administration group, 15-deoxyspergaline hydrochloride 2.5 mg / kg
And 5.0 mg / kg administration group were intraperitoneally administered continuously for 6 days, and then the variation of protozoal infection rate of mouse erythrocytes and the life prolongation period were examined with time.

[0013]

[Results] Untreated mice continued to increase in protozoal infection rate and died. On the other hand, mice that started administration of 15-deoxyspergaline from the time when the erythrocyte protozoal infection rate increased to 2% were treated with 5 days of administration at both doses of 2.5 mg / kg and 5.0 mg / kg. The erythrocyte protozoal infection rate dropped to 0% in the eye, which led to healing. On the other hand, the red blood cell infection rate is 5
The group of mice that started drug administration after the
Although the dose of g / kg was effective, the infection rate of protozoa decreased to 0% and it was cured, but in the administration group of 2.5 mg / kg, the growth of protozoa was blocked,
A life extension effect was recognized.

[0014]

INDUSTRIAL APPLICABILITY 15-Deoxyspergualin has an excellent inhibitory effect against malaria parasite, has low toxicity and high safety, and is therefore useful as an active ingredient of an antimalarial agent.

[0015]

EXAMPLES Examples of the present invention will be specifically shown below, but the present invention is not limited thereto. Example 1 Injection 15-deoxyspergualin hydrochloride 10 parts by weight, lactose 20
Parts by weight, 1N-hydrochloric acid (suitable amount) and distilled water for injection (suitable amount)
To obtain 500 parts by weight of a chemical solution adjusted to pH 4.0. This adjusted chemical solution is sterilized and filtered with a membrane filter, then dispensed into a glass container for injection and freeze-dried. After the completion of freeze-drying, a lyophilized injectable preparation containing 100 mg of 15-deoxyspergualine hydrochloride in one vial is obtained.

Example 2 Granules 50 parts by weight of hydrochloride of 15-deoxyspergualine, lactose 6
00 parts, 330 parts of crystalline cellulose and 20 parts of hydroxypropyl cellulose were mixed well, compressed using a roll type compressor (Roller Compactor®), and crushed to obtain 16 mesh. Sieve to fit between 60 mesh,
It was made into granules.

Example 3 Tablets 30 parts by weight of hydrochloride of 15-deoxyspergualin, 120 parts of crystalline lactose, 147 parts of crystalline cellulose and 3 parts of magnesium stearate were tabletted with a V-type mixer to give 300 mg of one tablet.
To obtain a tablet.

Claims (1)

[Claims] 1. An antimalarial agent comprising 15-deoxyspergualin and a pharmacologically acceptable salt thereof as an active ingredient.