JPH0840916A - Onset preventive and therapeutic agent for verruca consisting mainly of 3-oxygermylpropionic acid compound - Google Patents

Abstract

PURPOSE:To obtain an onset preventive and therapeutic agent for verruca esp. due to the immune system, consisting mainly of a 3-oxygermylpropionic acid eight-member-based polymer having specific three-dimensional structure. CONSTITUTION:This onset preventive and therapeutic agent for verruca consists mainly of a 3-oxygermylpropionic acid eight-member-based polymer expressed by a three-dimensional structure of the formula {R is CH2CH2C00H; (m) is the weight-average polymerization degree reduced from the weight-average molecular weight of propagermanium propyl ester, being 137 + or -84 [an average of 137 + or - standard deviation (3sigma)]}. The minimum constituent of the polymer is (O1/2)3GeCH2CH2COOH, its experimental formula being C6H10Ge2O7. It is preferable that this medicinal agent be used as an activated composition prepared so as to contain 0.005-50wt.% of an activated and stabilized carrier (e.g. lactose, sucrose, albumin) based on 0.005-5wt.% of the main ingredient.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preventive and therapeutic agent for the onset of warts, which is mainly composed of a 3-oxygermylpropionic acid 8-membered polymer having the following three-dimensional structure.

[0002]

Embedded image (In the formula, R is —CH ₂ CH ₂ COOH, m is a weight average polymerization degree converted from the weight average molecular weight of propagermanium propyl ester, and represents 137 ± 84 [average value 137 ± standard error (3б)]) Unit (O _1/2 ) ₃ GeCH ₂ CH ₂ COOH Empirical formula C ₆ H ₁₀ Ge ₂ O ₇

Preferably, the compound has a dosage form comprising a saccharide or a cellulose macromolecule as a carrier for stabilizing action and activation, and hydroxypropylcellulose, as a carrier for stabilizing activation of 3-oxygermylpropionic acid.
The present invention relates to a preventive and therapeutic agent for the onset of warts, which is an action-activating composition comprising 0.005 to 50% by weight of an action-activating and stabilizing carrier with respect to weight%.

[0004]

2. Description of the Related Art 3-Oxygermylpropionic acid is a compound that has received a great deal of attention in recent years from the viewpoint of its pharmacological activity because it has complex polymerizability and has various uses, and its antiviral action has been reported. . (Patent publication 53, 1973 53800
Further, carboxyethyl germanium cesoxide has been known as Ge132 for a long time, and its 12-membered ring structure has been reported. {J.Am.Chem.Soc.98 (25) 8287 (1976
However, there are problems that these compounds have different activities depending on the synthetic lots, have poor storability, and the activity decreases due to the operation of preparations.

The present inventors have proceeded with formulation studies to maintain the original pharmacological activity of 3-oxygermylpropionic acid and to maintain stable pharmacological activity, and also examined the action / activity status after ingestion into the living body. As a result, we discovered various substances as stabilizers of 3-oxygermylpropionic acid
In particular, we have also found a substance that enhances the activity of saccharides (1986, No. 65819) (Patent Publication No. 190714, Showa 60).

[0006]

[Problems to be Passed by Invention] Regarding carboxyethyl germanium cesoxide, J. Am. Chem. Soc. 98
The structure was identified in (25) 8287 (1976). Patent publication Showa 57
No. 53800 describes the possibility of the presence of various substances for 3-oxygermylpropionic acid compounds.
All of these substances had the above-mentioned problems.

The present inventor has published a patent publication No. 53800 in 1982 in order to solve various problems in activity due to the difference in the synthetic operation and physicochemical operation of 3-oxygermylpropionic acid.
As a result of pursuing various publicly known compounds including the compounds described in No. 3, the existence of substances having various three-dimensional structures was confirmed. In addition, as a result of screening the pharmacological action according to the three-dimensional structure, several stereo-structures were found in the compound that the present inventors thought to be represented by [(O _1/2 ) ₃ GeCH ₂ CH ₂ COOH] _n. Body (s ~ w ~
It was discovered that c) was present and there was a difference in activity, and among these, the drug with the highest activity was provided.

[0008]

[Means and Actions for Solving Problems] The present invention is shown in Table 1.
~ 2 has the physicochemical properties described. (In the table, the substance of the present invention is described as 8-membered SK818, Table 1 shows the results of molecular weight measurement by the light scattering method, Table 2 shows the lattice constants obtained by powder X-ray diffraction, and Table 3 shows known germanium compounds. (12
The physical property comparison data with Ge 132) is shown.

[0009]

[Table 1]

[0010]

[Table 2]

[0011]

[Table 3]

When the 3-oxygermylpropionic acid according to the present invention is actually administered to humans, the substance of the present invention is 0.005%.
~ 5% by weight of the activity-activated stabilizing carrier 0.005-50
It is preferably used as an action-activating composition prepared so as to contain 100% by weight, and particularly provided as a preventive and therapeutic agent for the onset of warts caused by the immune system.

As the action-activating / stabilizing carrier, saccharides such as lactose, sucrose and dextran are used as the cellulosic polymeric substance, hydroxypropyl cellulose, and the natural polymeric substance are albumin and the like. . In addition, a mixture of drugs with a high direct therapeutic effect commonly used for these (antiviral agents for viral hepatitis, antiallergic agents for allergic diseases, anticancer agents for cancer) is mixed. It can also be made into a formulation, and in this case, the toxicity of drugs having a high direct therapeutic effect is reduced and an effective therapeutic effect can be expected.

(Dosage Form and Dosage) The 3-oxygermylpropionic acid according to the present invention can be used in a usual formulation form, but it can be made enteric according to the characteristics of the drug to be incorporated. . The dose of the drug of the present invention when administered to humans depends on the dosage form, age of the patient, etc., but is within the range of 1 to 1500 mg, and is 150 mg / day for oral administration to an adult (body weight 50 kg). Is preferred.

[0015]

EXAMPLES The present invention will be described in more detail below with reference to production examples of the substance of the present invention, pharmacological test examples, and formulation examples.

Preparation Example 252 g (1 mol) of 3-trichlorogermylpropionic acid was dissolved in 2 liters of ethyl alcohol, and 1.5 liters of water was added over several hours while keeping the solution temperature at 20 ° C. To do. After standing overnight, the crystals were collected by suction filtration, washed with acetone, and dried under reduced pressure to obtain a 3-oxygermylpropionic acid polymer with a yield of 90%. The molecular weight of the obtained compound of the present invention was measured by a light scattering method, and the lattice constant was determined by powder X-ray diffraction. The results are as shown in Tables 1-2.

Composition Production Example The substance 2 of the present invention was kneaded with 1 of hydroxypropyl cellulose using ethanol as a wetting agent, and dried at a temperature of 50 ° C. or lower to obtain a powdery or granular composition.

Formulation Example Tablet A compressed tablet was prepared according to the following formulation. 3-Oxygermylpropionic acid polymer 10.0 Lactose 159.2 CMC-Na 8.0 Light anhydrous silicic acid 2.0 Magnesium stearate 1.8 180.0 mg

Pharmacological and Pharmacological Test Example 1 (Comparative Utility of the Substances of the Present Invention with Known Substances) a) Purpose Carboxyethylgelmanium sesquioxide which is known for its action on the antibody-producing ability of cancer-bearing mice.
(Ge132).

B) Procedure 2 × 10 ⁶ Sarcoma-180 cells were subcutaneously transplanted to 7-week-old BALB / c mice, and 9 days after the transplantation, the compound of the present invention and Ge1 were used.
32 was administered at a dose of 0.3, 1, 3, 10 and 30 mg / kg / day for 5 consecutive days. Sheep red blood cells (SRBC) 2 × 10 ^{8 on the} day after the final administration
Individuals were sensitized by intravenous injection, and 4 days after the sensitization, the spleen was removed and the number of anti-SRBC IgM-PFC in splenocytes was measured.

C) Results and Discussion Table 4 shows the test results for the antibody-producing ability of the compound of the present invention and Ge132. The compound of the present invention significantly enhanced the number of PFCs decreased by tumor-bearing at 0.3 mg / kg or more, and reached the maximum at 1-3 mg / kg. A significant potentiating effect was observed up to 10 mg / kg. With Ge132, only a significant effect was observed at 30 mg / kg. As described above, it is considered that the compound of the present invention enhances the antibody-producing ability that is decreased in tumor-bearing, and is 100 times more useful than the known substance Ge132.

[0022]

[Table 4]

Pharmacological and Pharmacological Test Example 2 (Preventive and therapeutic effects on warts) a) Purpose The effect on the induction of papilloma and its formation by SHOPPAPIROMA VIRUS (SPV) is examined using a rabbit (Japanese white).

B) Operation Female rabbits (Japanese white breed, weight 2-2.5 kg) in groups of 5
Used as an animal. A solution obtained by homogenizing papilloma tissue to 20% (W / V) with phosphate buffered saline at pH 7.2 was used as the infectious virus solution, and the SPV solution was applied to the shaved skin of each rabbit at 4% per bird. Inoculation was carried out by the site scarification method.
The inoculation site was 20 × 20 mm. The volume of papilloma was calculated from major axis x minor axis x height. The compound of the present invention is a capsule
Orally administered at doses of 0.3, 1, 3, 10 and 30 mg / kg / day,
The administration schedule was the day of virus inoculation and twice a week for 10 weeks.

C) Results and Discussion Table 5 shows the papilloma formation (volume) at 5 and 10 weeks after SPV inoculation and the papilloma formation inhibitory action of the compound of the present invention. The papilloma volume was the average volume of papilloma at 4 points in each rabbit. The compound of the present invention is 1 to 30 at 5 weeks after virus inoculation.
Papilloma formation was significantly suppressed at mg / kg. At the 10th week, the inhibitory effect became even stronger, and the 1-3mg / kg inhibitory rate was maximized. In particular, in the 1 mg / kg group, some individuals had almost regressed papilloma. Further, the compound of the present invention has a maximum dose (30 mg / k
No weight loss was observed in g).

[0026]

[Table 5] Effect of the compound of the present invention on the formation of the Papu's tumor induced by the Shope papilloma virus Papilloma volume 5 weeks 10 weeks Untreated group 7.7 ± 0.9 13.8 ± 1.5 Compound of the present invention 0.3 mg / kg 5.5 ± 0.9 5.4 ± 0.9 ** 1 3.3 ± 0.5 ** 2.4 ± 0.5 *** 3 2.1 ± 0.6 *** 2.8 ± 0.7 *** 10 3.2 ± 0.3 ** 4.0 ± 0.4 *** 30 4.5 ± 0.9 * 7.9 ± 1.3 * Each value is 7 The average value ± standard error of the animals is shown. Significant difference from untreated group: * p <0.05, ** p <0.01, *** p <0.001

Clinical Trials (Effects of Treatment of Adolescent Flat Warts) a) Objective In adolescent flat warts caused by human papillomavirus infection, immunity is involved in the onset and healing process. Therefore, the therapeutic effect was examined for the usefulness of the compound of the present invention that activates the immunopotency of the host.

B) Operation Twenty patients with adolescent flat warts were given 10 mg of the compound of the present invention three times a day after each meal. As a general rule, the administration period was 12 weeks, but for patients with complete eruption of the eruption during the administration period, the administration was discontinued at that time and a comprehensive evaluation was conducted by the judgment of the attending physician.

C) Treatment Results Table 6 shows the treatment results 12 weeks after the administration of the compound of the present invention. A high efficacy rate was obtained by administering the compound of the present invention.
No significant side effects were observed during the administration period of the compound of the present invention.

[0030]

[Table 6] Therapeutic effect of adolescent flat warts by the compound of the present invention Healing 13 cases (65%) Remission 5 (25%) No change 1 Hatred 0 Dropout 1

[0031]

According to the present invention, the minimum structural unit (O _1/2 ) ₃ G
eCH ₂ CH ₂ COOH, empirical formula _C 6 _H 10 _Ge 2 _{O 7}
It is composed of an 8-membered organogermanium compound as a main component, which is a preventive and therapeutic agent for the onset of warts, and is particularly effective against warts caused by viral infection.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiro Ishiwatari 35, Higashi Sotobori-cho, Higashi-ku, Nagoya-shi Sanwa Chemical Research Institute Co., Ltd.

Claims (1)

[Claims] 1. A preventive and therapeutic agent for the onset of warts, which comprises a 3-oxygermylpropionic acid 8-membered polymer represented by the following three-dimensional structure as a main component. (In the formula, R is —CH ₂ CH ₂ COOH, m is a weight average polymerization degree converted from the weight average molecular weight of propagermanium propyl ester, and represents 137 ± 84 [average value 137 ± standard error (3б)]) Unit (O _1/2 ) ₃ GeCH ₂ CH ₂ COOH Empirical formula C ₆ H ₁₀ Ge ₂ O ₇