JPS62198621A - Carcinostatic assistant - Google Patents

Abstract

PURPOSE:To provide a carcinostatic assistant composed of extract of KAMI- SHOYOSAN or TOKAKU-SHOKITO which is a compounded Chinese herb drug for women's dizziness, having mitigated side effect of cisplatin such as renal disorder and useful as an assistant to promote effective and safe remedying effect of cisplatin. CONSTITUTION:The objective carcinostatic assistant for cisplatin is composed of an extract of KAMI-SHOYOSAN [composed of 3.0pts.(wt.) each of TOKI (root of Angelica acutiloba), SHAKUYAKU (root of Paeonia albiflora), BYAKUJUTSU (rhizome of Atractylodes japonica) and SAIKO (root of Bupleurum falcatum), 2.0pts. each of BOTANPI (root bark of Paeonia moutan) and SANSHISHI (fruit of Gardenia jasmioides), 1.5-2pts. of KANZO (root of Glycyrrhiza glabra var. glandulifera), 0.5-2pts. of SHOKYO (rhizome of Zingiber officinale) and 1.0pt. of HAKKA (leaf of Mentha arvensis)] or TOKAKU-SHOKITO [composed of 5pts. of TONIN (stone of Prunus persica), 4pts. of KEIHI (bark of Cinnamomum cassia), 1-3pts. of DAIO (rhizome of Rheum palmatum), 1pt. of dried sodium sulfate and 1.5pts. of KANZO]. The extract suppresses the increase of BUN value and creatinine value caused by cisplatin. It is preferably administered continuously even in the pausing period of the cisplatin administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a drug that reduces the side effects of cisplatin. More specifically, it consists of an extract of Kamishoyosan or Tokokujokito. This invention relates to a drug that reduces the side effects of cisplatin.

[Conventional technology]

Cisplatin [cissudiamindichloroplatinum (■
)] has been hailed as an effective anticancer agent for Minemaru tumor, prostate cancer, bladder cancer, ovarian cancer, and renal urethral tumor, but it has been recognized to cause kidney damage, pancreatic damage, gastrointestinal damage, etc. In particular, renal damage is significant, and this is a factor regulating the dosage of cisplatin (The American Journal
l of Medicine Volume 85 3
07-314, 1978).

[Problem that the invention seeks to solve]

As mentioned above, cisplatin has clinical drawbacks, so if a method to reduce the side effects of cisplatin can be developed, cancer treatment using cisplatin may become even more effective.6 The purpose of the present invention is to reduce the side effects of cisplatin. The object of the present invention is to provide a drug (hereinafter referred to as the drug of the present invention) that causes

[Means for solving problems]

As a result of examining the extracts of various Chinese herbal medicines, the present inventors found that extracts of Kami Shoyosan, which is conventionally used to treat blood symptoms in women, and Tokoku Jokito, which is used to treat blood symptoms in women. The inventors discovered that the extract satisfies the above objectives and completed the present invention.

In the present invention, the composition (weight ratio) of kamishochisan is 2
~4), Shiyaku (2~4), White T (2~4), Kyourei (2~
4), Saiko (2-4), Botanpi (1-3), Yamateko (1
~3), licorice (0,5~3).

They are student board (0,5~3), @load (1~2), and particularly preferred are Danggui (3,0), Xunyaku (3,0), and White*(
3゜0), Hagirei (3,0), Saiko (3,0), Botanpi (2,0).

Mountain shield (2,0), licorice (1,5~2), health care (0,5
〜2), @(1,0), and the composition (weight ratio) of Tokokujokito in the present invention is Momin (5), Cinnamon (4)
, large scales (1-3), dry sodium sulfate (1) and licorice (1,5).

In the present invention, Kamishoyosan or Tokokujokito is extracted with a solvent, and the extract may be used as it is or as a concentrated solution, but it is preferably a concentrated extract, and if necessary, a dried extract powder. It is preferable to use it as

The extraction is at a weight ratio of 5 to Kami Shoyosan or Tokoku Jokito.
~25 times, preferably 8 to 20 times as much extraction solvent is added, and this is usually heated at 80 to 100[deg.] C. for 30 minutes to 2 hours. The extraction solvent is water, a water-soluble organic solvent, or a mixed solvent thereof, and ethanol is preferable as the water-soluble organic solvent.

Usually, after filtering the extract, the drug of the present invention can be obtained by conventional concentration means such as vacuum concentration, and if necessary further conventional drying means such as vacuum drying, spray drying or freeze drying.

The drug of the present invention obtained as described above is in the form of an extract or a dry powder. These can be used in combination with cisplatin as is, but if necessary, conventional excipients, disintegrants, etc. may be added and used in a conventional manner.

It can also be used in the form of capsules, granules, single tablets of fine granules, or powders.

Cisplatin is administered in three ways: once a day for 5 consecutive days, followed by 2 weeks of rest, once a week, or once every 3 weeks. (Refer to Japanese Pharmaceutical Collection, 8th edition, pp. 350-351, edited by Japan Information Center, Yakuji Jihosha, 1984), the drug of the present invention is orally administered each time cisplatin is administered, but administration of cisplatin as described above It is desirable to continue administering the drug of the present invention every day even during the rest period.The dosage of the drug of the present invention varies depending on the patient's disease condition, age and body weight, but usually,
0.3 to 10 per day for adults as dry extract powder
g is administered orally at once or in 2-3 divided doses.

〔Effect of the invention〕

The effect of the drug of the present invention on the nephrotoxicity of cisplatin was investigated in rats using serum urea nitrogen level (BUFl value) and serum creatinine level as indicators. Results 1. The drug of the present invention increased the BUN value caused by cisplatin. It was also found that the increase in creatinine levels was suppressed. Furthermore, when the effect of the drug of the present invention on pancreatic damage caused by cisplatin was examined, it was found that the drug of the present invention suppresses the decrease in pancreatic 11 caused by cisplatin. Furthermore, it was found that the drug of the present invention also suppresses weight loss caused by cisplatin (see Test Example 1).

Furthermore, the drug of the present invention was found to alleviate the lethal toxicity of cisplatin when used in combination with cisplatin (see Test Example 2); however, the drug of the present invention did not have a negative effect on the anticancer effect of cisplatin (test example 2). (see Example 3), and the toxicity of the drug itself of the present invention is low (see Test Example 4).
.

The various test results described below demonstrate that the drug of the present invention alleviates the side effects of cisplatin and can be used effectively and safely in cancer treatment with cisplatin.

Hereinafter, the effects of the present invention will be explained in detail by giving test examples.

Test Example 1 (Effect of reducing side effects) (1) Test materials (a) Animals used: Wistar male rats (7 withdrawals, 1 body weight 170-200 g, 6 animals per group) (b) Test drug (dose) a: Cisplatin (1 Dose per dose is 2 kg/kg
) A: Dry extract powder of Kamishoyosan of Example 1 (dose per dose is 1000 mg/kg) a+A: Cisplatin and dry extract powder of Kamishoyosan of Example 1 (combined use of both).

The dose per dose is 2 mg/kg for the former, and 10 mg/kg for the latter.
0OB/kg) B: Toukokujokito dry extract powder of Example 2 (dosage per dose is 1000 mg/kg) a+B: Cisplatin and Tokokujokito dry extract powder of Example 2 (both (2) Test method Test drug a, test drug A, and test drug B each alone, or test drug a and test drug A. or test drug a and test drug B were administered to rats 5 times every 24 hours. When test drug a was administered alone, test drug a dissolved in physiological saline (II degree G, 4 g/5 dl) was injected into the tail vein five times every 24 hours. If test drug A or test drug B is administered alone, 0
．． Each test drug suspended in a 5 (W/V)% sodium carboxymethyl cellulose aqueous solution (concentration rooms/mu) was orally administered 5 times every 24 hours.

Combination of test drug a and test drug A or test drug a and test drug B
When used in combination, dissolve in physiological saline (concentrated [0.4 g
/5fl) Immediately after injecting test drug a into the tail vein,
Test drug A or test drug B suspended in a 0.5 (W/V)% carboxymethyl cellulose sodium aqueous solution (concentration 100g/aQ) was orally administered, and this combination administration was
Repeated 5 times every 4 hours.

58 days after the final administration, the rats were weighed, blood was collected, and the pancreas was removed.
b) Lung weight change rate.

(c) Increase rate of serum urea nitrogen level (BUN value), and (
d) The rate of increase in serum creatinine level was determined.

(b) Body weight change rate (%): The body weight of the rat immediately before administration of the test drug* (Xg) and the body fr (Yg) of the rat 5 days after the final administration of each test drug were weighed, and the body weight of the rats in each test drug administration group was measured. The rate of change was determined using the formula below.

(b) Rate of change in weight of tiles Ii1 (%): Extracted pancreas tl (Xg) of rats in the test drug-free group and removed tiles ll of rats in each test drug-administered group! The weight (Yg) of each was weighed and determined by the following formula.

(c) BUN value increase rate (%): Blood was collected from the femoral artery of rats in each test drug administration group or in a test drug non-administration group at 3000 rpm at room temperature. Centrifuge for 5 minutes,
Test serum was obtained. The BIJN value in this test serum was measured using a urea nitrogen measurement kit (Urea NB-Test Wako) based on the urease-indophenol method. That is, - Take 20μ of the above test serum into a test tube, add 1 volume of coloring reagent A (urease solution to p
Solution diluted with 20 volumes of H7,0 phosphate buffer) 2, Od
was added, mixed well, and heated at 37°C for 15 minutes. 2. Add coloring test solution B (liquid containing sodium hypochlorite and sodium hydroxide) to this. Add Omfi and mix well 37
A test solution was prepared by heating at ℃ for 10 minutes. On the other hand, an aqueous solution with a urea content of 5 g/d or distilled water was added at 2 O
A standard solution and a blind solution were prepared in the same manner as in the preparation of the above test solutions using a blind test using a spectrophotometer. Using the liquid as a control, the absorbance of the test solution and standard solution in 570 n intestines was measured, and the BUN value in the test serum was determined by the following formula.

As described above, the BUN value (BUNc) in the serum of rats in the drug-free group and the BtlN in the serum of rats in the drug-administered group.
After determining the value (BUNt), the increase in the BUN value was determined using the following formula.

(d) Creatinine, rate of increase (%): Take 0.5 aQ of the test serum obtained when measuring the BUN value, and
Using a creatinine measurement kit (Creatinine-test Wako) based on the I1n-Wu method,
/1 was measured. In other words, the test serum in the test tube is 0
．． 5d Protein removal test solution (tungstic acid-sulfuric acid solution) 3
．． Add Od while stirring and leave it at room temperature for 10 minutes.
Centrifuged at 000 rpm for 10 minutes. Obtained supernatant 2
．． Take OaQ in another test tube and add picric acid test solution i, o aQ and 0.75N NaOH solution 1. A test solution was prepared by adding Od and leaving it for 20 minutes at the same temperature. On the other hand, apart from this, creatinine solution (concentration 10
mg/dl) or distilled water was placed in a test tube and treated in the same manner as in the preparation of the test solution described above to prepare a standard solution and a blind solution, respectively. Within 30 minutes after preparing the test solution, standard solution, and blind solution, measure the absorbance of each of the test solution and standard solution at 520n using a spectrophotometer using the blind solution as a control. The creatinine value (mg/d) in serum was determined.

After determining the serum creatinine value (Cc) of the rats in the drug-free group and the serum creatinine value (Ct) in 1 m serum of the rats in the drug-administered group as described above, the rate of increase in creatinine value was calculated using the following formula.

(3) Test results Shown in Table 1.

As shown in the results of Tests (a) to (d) above in Table 1, the drug of the present invention clearly reduces the side effects caused by cisplatin.

Test Example 2 (alleviation of lethal toxicity) (1) Test materials (a) Test animals e ICR male mice (6 withdrawals, weight 26-29 g, 10 mice per group) (b) Test drug (dose) a: Cisplatin ( Dose per dose 6rag/kg
) A: Kami Shoyosan dried extract powder of Example 1 (dosage per dose is 1100 h/kg) a+A: Cisplatin and Kami Shoyosan dry extract powder of Example 1 (both used together, projection area per dose) The former is 6 B/kg, the latter is 100
0 + sg/kg) B: Tokokujokito dry extract powder of Example 2 (dosage 91000 mg/kg per time) a+B: Cisplatin and Tokokujokito dry extract powder of Example 2 (combined use of both, 1 The dosage per dose is 6 IIg/kg for the former and 1 for the latter.
000mg/kg) (2) Test method Test drug a, test drug A, and test drug B each alone, or in combination with test drug a and test drug A, or in combination with test drug a and test drug B. Mice were dosed 5 times every 24 hours. When administering test drug a alone, test drug a dissolved in physiological saline (B actual 0.8 mg/J) was administered at 24
It was injected into the tail vein five times at each hour. Test drug A
Or, if test drug B is administered alone, 0.
Each test drug suspended in a 5 (W/V)% carboxymethylcellulose sodium aqueous solution (100 mg/pkg) was orally administered 5 times every 24 hours. When using test drug a and test drug A together or test drug a and test drug B, dissolve in physiological saline (concentration 0.8 mg/aQ).
) Immediately after injecting test drug a into the tail vein, 0.5 (
Test drug A or test drug B suspended in sodium carboxymethylcellulose (w/v) (9B degree, 100 mg/J) was orally administered, and this combined administration was repeated 5 times every 24 days. Thereafter, the number of surviving mice was observed for 8 days, and the survival rate was reached at every 0 count from the end of administration [1].

(3) Test results Shown in Table 2.

Table 2 As shown in Table 2, the drug of the present invention, when used together with cisplatin [■, when dried, alleviates the lethal toxicity of cisplatin.] Test Example 3 (Influence on anticancer effect) (1) Test materials (a) Animals used I ICR male mouse (5i thick).

Body weight: 23-26g6-/group 10 animals) (B) Cancer cells used: Sarcoma-100 (Sareo) Test drug (dose) a: Cisplatin (dose per dose is 0.5 mg/
kg) B + A: Cisplatin and the Kakami Shoyosan Dando Extract Powder of Example 1 (combined use of both, for one administration,
The former is 0.5 mg/kg.

(latter 1000 mg/kg) a+B: Cisplatin and Tokokujokito dry extract powder of Example 2 (both used in combination, dosage per dose is 0.5 mg/kg of the former, 10 mg/kg of the latter)
(00 mg/kg) (2) Test method Mice were inoculated subcutaneously into the right inguinal area with i and xio'i cancer cells per mouse. Thereafter, test drug alc alone or test drug a and test drug A were administered 5 times every 24 hours.
or test drug a and test drug B were administered to mice in combination. When administering test drug a alone,
Test drug a dissolved in physiological saline (concentration 0.05 mg/d) was intraperitoneally administered 5 times every 24 hours. Combination of test drug a and test drug A, or test drug a and test drug B
When used in combination with a 0.5 (W/V) sodium carboxymethyl cellulose aqueous solution, immediately after administering the test drug dissolved in physiological saline in the same manner as above intraperitoneally (
Concentration; 100 mg/+IQ) Test drug A or test drug B was orally administered, and this combined administration was repeated 5 times every 24 hours.

On day 8, 14 days after cancer cell inoculation, each tumor was excised and weighed. After calculating the average tumor weight (wt) in each test drug administration group and the average tumor weight (Wc) in the test drug non-administration group,
The anti-tumor rate was determined using the formula below and is shown in Table 3 of the Gai (3) test results.

Table 3 As shown by the test results, the drug of the present invention does not adversely affect the anticancer effect of cisplatin.

Test Example 4 (Acute Toxicity Test. LD50) (1) Test Materials and Test Methods Kamisho'Jt powdered dried extract powder of Example 1 or Example 2
Tokokujokito dry extract powder was suspended in a 0.5 (W/V) 96 carboxymethyl cellulose strium aqueous solution (concentration 1000 mg/d) and added to ddY male mice (6
The drug was orally administered to 10 animals (group weight: 26-29 g), and the number of deaths was observed for up to 2 weeks after administration.

(2) Test results Even when 10 g/kg of each of the above dry extract powders was administered, no deaths were observed.1 The LD50 value of the drug of the present invention was Log/
kg is E.

From the results of Test Examples 1 to 4 above, it is clear that the drug of the present invention can be an effective and highly safe agent for reducing the side effects of cisplatin.

〔Example〕

Next, the present invention will be explained with reference to Examples.

Example 1 Manufacture of seasoned dried extract powder Danggu, Xunyaku,
3.0 kg each of Baifu Hua, Chai Ling, and Chai Hu, 2.0 kg each of Mudanpi and Yamateko, 1-5 kg of licorice, 0.5 kg of Seikyu
Water 2201 was added to a mixed herbal medicine consisting of 1.0 kg of thin powder and extracted by heating at about 100° C. for 1 hour. Filter the extract, and the filtrate is about 20! After concentrating to L under reduced pressure, it was spray-dried to obtain 4.1 kg of dry extract powder.

Example 2 Production of dried extract powder of Tokokujokito Tojin5. Ok
g, cinnamon 4.0 kg, rhubarb 3.0 kg, dry sodium sulfate 1. 145 g of water was added to a mixed herbal medicine consisting of 1.5 kg of licorice and 1.5 kg of licorice, and the mixture was extracted by heating at approximately 0.00" O for 1 hour. The extract was filtered, the filtrate was concentrated under reduced pressure to approximately 15 fL, and then dried by spray drying. 2.5 kg of extract powder was obtained.

Example 3 Production of fine granules of seasoned Shoyosan extract ■ Herbal medicine (dry extract powder of Example 1) 4.10911 parts Milk M O, 14 parts by weight Corn starch 1, 30 superposition 14 Silicic anhydride 0.37 parts by weight Magnesium stearate 0.09 parts by weight 7 The above ingredients were thoroughly mixed, the mixture was made into a plate using a compression molding machine, the mixture was ground into granules using an oscillator, and the particles were sieved to give 883 tags of the active ingredient in 1 g. A fine granule containing the following ingredients was obtained.

Example 4 Production of Tokokujokito extract fine granules 1] Main ingredient (dry extract powder of Example 2) 2.50 parts by weight Milk JI O, 20 parts by weight White sugar 1.50@41 Part corn starch 1. 30 parts by weight Silicic anhydride 0.45 parts by weight Magnesium stearate 0.05 parts by weight Using the above recipe and performing the same operation as in Example 3, 41 parts of the crude drug in 1 g. Fine granules containing +mg were obtained.

Example 5 Manufacture of Kamimi Shoyosan Extract Degradant] Main ingredient (dried extract powder of Example 1) 3.00 @ 1 part lactose
1.00 parts by weight Corn starch 0.501 titm Synthetic aluminum silicate 0.20 parts by weight Calcium carboxymethyl cellulose 0.25 parts by weight Magnesium stearate 0.05 parts by weight The above components were thoroughly mixed, and the mixture was passed through a tablet machine. 1k
'300 A+H tablet, 180% of active ingredient in 10%
Tablets containing tg were obtained.

Example 6 Manufacture of Tokokujokito extract tablets.1. Tablets containing 180 mg of the dry extract powder of Example 2 were obtained.

Example 7 Production of Kami Shoyosan Extract Capsules] Main ingredient (dried extract powder of Example 1) 3.34 parts by weight Synthetic aluminum silicate 0.18 parts by weight Magnesium stearate o, os Part by weight 1 amount of the above Mix each component thoroughly and fill 3 Htg of this mixture into capsules, each capsule containing 334 taz of herbal medicine.
Capsules containing the following were obtained.

Example 8 Production of Tokokujokito Extract Capsules The same formulation and procedure as in Example 7 were followed except that the dried extract powder of Example 2 was used instead of the dried extract powder of Example 1 as the main ingredient. A capsule preparation containing 334 ieg of the dry extract powder of Example 2 in one capsule was obtained.

Claims (1)

[Claims] Cisplatin side effect reducer made from extract of Kamishoyosan or Tokokujokito