JPH04139128A - Antiviral composition - Google Patents

Abstract

PURPOSE:To provide the title composition having markedly high synergistic effect, comprising (+)9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl]guanidine or its salt and acyclovir or its salt. CONSTITUTION:The objective novel antiviral composition having selective and synergistic antiviral activity, comprising (A) (+)9-[(1R,2R,3S)-2,3-bis(hydroxy) cyclobutyl]guanidine of formula I or its pharmaceutically permissible salt and (B) 9-(2-hydroxyethoxymethyl)guanine of formula II (acyclovir) or its pharmaceutically permissible salt. The present composition is relatively high in synergistic effect, also being low in toxicity.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field] The present invention relates to novel antiviral compositions having selective and synergistic antiviral activity.

[Conventional technology]

Herpes type 1 and type 2 viruses cause encephalitis, herpesvirus infections of the cornea, lips, and genitals in infants and adults, and cause serious illness, especially in young children.

In recent years, the herpesvirus group (herpesvi)
rus group) is known to cause serious infections.

Currently, for diseases caused by these herpesviruses,
9-(2-Hydroxyethoxymethyl)guanine (hereinafter referred to as acyclovir or ACV) is used in boat fishing. Recently, the combination of acyclovir and bromovinyldeoxyuridine (BVDU) (Japanese Patent Application Laid-open No. 6O-12
0814) and the combination of acyclovir with a polynucleotide reductase inhibitor (Japanese Unexamined Patent Publication No. 2-45423).

[Invention or problem to be solved]

However, there are no satisfactory results in terms of efficacy or side effects. Therefore, it is desired to develop antiviral agents that are more effective and less toxic.

[Means to solve problems]

As a result of various studies, the inventors found that (a) Structural formula (■): (+) -9-((IR,2R,3S) -
2゜3-bis(hydroxymethyl)cyclobutylcoguanine (hereinafter referred to as carbocyclic oxetanosine G or C)
-0XT-G) or a pharmacologically acceptable salt thereof; and (b) an antiviral composition having the structural formula shown in the following or a pharmacologically acceptable salt thereof; It has been found that these compounds can be used as anti-herpesvirus compositions because they have a synergistic effect that is significantly superior to that of each agent alone.

The present invention was completed based on the above findings. All the compounds used in the present invention are known compounds; for example, acyclovir is currently commercially available as an antiviral agent, and is available from Proc, Natl, Acad.

Sci, Vol. 74, p. 5716 (1977), and carbocyclic oxetanosine G is a known compound disclosed in JP-A-1-269073.

In the present invention, the ratio of component (a): carbocyclic oxetanosine G (C-0XT-G) to component (b), acyclovir (ACV) may vary depending on the type of virus, or may be 20:1 by weight. ~1:200, preferably about 10:1~1:100.

Oxetanosine G, acyclovir and carbocyclic oxetanosine G may form a salt with an acid, or the acid that forms a salt may be any pharmacologically acceptable acid, such as hydrochloric acid, sulfuric acid, phosphorus, etc. Acids are preferred. It is also possible to form a sodium or potassium adduct by using an alkaline solution such as sodium hydroxide or potassium hydroxide.

The antiviral composition of the present invention is usually mixed with excipients or carriers and administered as an injection, oral preparation, or halved solution. Excipients and carriers are selected from those that are pharmaceutically acceptable, and their types and compositions are determined by the route and method of administration. For example, water, alcohol, animal or vegetable oils such as soybean oil, peanut oil, rubber oil, mineral oil, or synthetic oils are used as liquid carriers. As solid carriers, saccharides such as maltose and shufucose, organic acid salts of amino acids such as hydroxyprobyl cellulose, cellulose derivatives, and magnesium stearate are used. In the case of injections, physiological saline, various buffer solutions, saccharide solutions such as glucose, inositol, and mannitol, and glycols such as ethyl glycol and polyethylene gelicol are generally preferred. In addition, it is made into a lyophilized preparation together with excipients of sugars such as inositol, mannitol, glucose, mannose, maltose, and shufucose, and amino acids such as phenylalanine, and is then administered in a suitable solvent for injection, such as sterile water or physiological saline. It can also be administered by dissolving it in a liquid for intravenous administration such as water, glucose solution, electrolyte solution, amino acid, or the like.

The total content of both component (a) and component (b) acyclovir in the formulation varies depending on the formulation, and is usually 0.1 to 100% by weight, preferably 1 to 90% by weight. For example, in the case of injections, it is usually 0.1 to 5
It may contain 6% by weight of components (a) and (b). When administered orally, it is used in the form of tablets, capsules, powders, granules, liquids, dry capsules, etc. together with the solid carrier or liquid carrier. In the case of capsules, tablets, granules and powders, the total content of both is generally about 3 to 100% by weight, preferably 5 to 90% by weight, with the balance being carrier.

The dosage is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., and the therapeutic amount is generally 1 to 50 m
g/kg (total amount of both is the same)/day, and oral administration is 5 to 50 mg/kg/day.

Next, examples of formulations of the present invention will be shown.

Formulation Example 1 Purified water was added to 250 parts by weight of each of carbocyclic oxetanosine G and acyclovir to adjust the pH to 13 to 14. The total amount was dissolved to 2000 parts, and then sterilized and filtered using a Millipore filter GS type. 2 g of this filtrate was placed in a 10-bar vial and lyophilized to obtain a lyophilized injection containing 50 mg each of carbocyclic oxetanosine G and acyclovir per vial.

Formulation Example 2 Granules 50 parts by weight each of carbocyclic oxetanosine G and acyclovir, 600 parts of lactose, 330 parts of crystalline cellulose
1 part and 20 parts of hydrocoxib 0-pill cellulose were mixed well, compressed using a coal-type compressor (roller compactor-11), crushed, and sieved to obtain granules between 16 mesh and 60 mesh. .

Formulation Example 3 Tablets: 50 parts by weight each of carbocyclic oxetanosine G and acyclovir, 120 parts of crystalline lactose, 1 part of crystalline cellulose
47 parts of magnesium stearate and 3 parts of magnesium stearate were compressed into tablets using a V-type mixer to obtain 300 mg tablets (each containing about 50 mg).

Next, a test example of the combined effect of the composition of the present invention on suppressing the growth of herpes simplex type 1 and type 2 viruses will be explained in more detail.

(1) Method for measuring growth inhibition effect Eagle's minimal medium (MEM-) containing 10% newborn calf serum
C310) to create a monolayer cell culture of green monkey kidney cells (vero cells) in a 24-well microplate,
Herpes simplex type 1 (H3V-1) or type 2 (H3V-1)
-2) 50PFU10. in//well was inoculated. After adsorption for 1 hour at 37°C, cells of each formula were washed with phosphate buffered saline (PBS) and serially diluted with C-0X.
0.5% including T-G or ACV alone or in combination
Layer methylcellulose-containing MEM-C32 and hold at 37°
Cultured for 12 days. After discarding the overlay medium and fixing the cells with formalin, they were stained with crystal leaf fluid and the number of plaques for each type was counted. The percentage (% value) of the number of plaques at each drug concentration with respect to the number of control (no drug added) plaques was calculated, and a graph of the % value against the drug concentration was created by measuring the 50% plaque inhibitory concentration (ICso).

(2) Results Table 1 0XT-G in H3V-1 (VR-3)
and ACV. Table 2: Synergistic effects of C-0XT-G and ACV in combination on H3V-1 (VW-268) As is clear from the above results, the combination of components (a) and (b) In some cases, the calculated inhibition rate was 50% at a dose of 28 to 39%, indicating that a significant additive effect was achieved by combined use.

Patent applicant: Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] (1) Structural formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (+)9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)silocbutyl]guanine or its Pharmacologically acceptable salts and ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) Contains 9-(2-hydroxyethoxymethyl)guanine (aciclovir) or its pharmacologically acceptable salts. Featured antiviral composition