JPH06199674A - Medicine related to treatment and prevention for opportunistic infectious disease - Google Patents

Abstract

PURPOSE:To obtain an inhibitor against rise in infection sensibility useful for opportunistic infectious disease, etc., having excellent safety, antiviral action and recovering effect on phylaxis ability, comprising KANZOBUSHITOU as an active ingredient. CONSTITUTION:The objective inhibitor against rise in infection sensibility, for example, comprises KANZOBUSHITOU in the blending ratio of 2.0-3.0 root of Glycyrrhiza glabra, 2.0-5.0 bark of Cinnamonum cassia, 2.0-9.0 JYUTSU and 0.3-2.0 tuber of Aconitum carmichaeli as an active ingredient. The content of the active ingredient in the preparation is preferably 0.1-0.5mugs/g base in the case of external preparation and the dose of the active ingredient is preferably 3-15g daily.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug useful for opportunistic infections, and more particularly to an agent for suppressing infection susceptibility increase containing Kanzobushito as an active ingredient.

[0002]

2. Description of the Related Art Infectious diseases are said to have undergone major changes in recent years. Classic infectious diseases are overshadowed by intractable infectious diseases that depend on the patient's resistance to infection. That is, it is an opportunistic infectious disease that occurs based on the factors on the patient side. For example, the herpes simplex type I viruses that represent the causative pathogen of opportunistic infections and their diseases are shown in Table 1 below, and although the causative pathogens are the same, many of the diseases are serious. Table 1

As described above, an opportunistic infection is a condition in which an infection is usually caused by a microorganism showing almost no pathogenicity because the infection protective ability of the patient is lowered due to some cause (increased susceptibility to infection). for that reason,
For the treatment of opportunistic infections, a drug having an effect of recovering the infection protective ability and an antimicrobial agent effective for the pathogenic agent are used. In particular, drugs that have a protective effect on the recovery of infection are essential as essential treatments for opportunistic infections.
It is emphasized.

[0004] However, in opportunistic infections, it is difficult to identify the causative pathogen from the clinical disease image because the clinical disease image is similar although it is not rare that there are multiple causative pathogens. It is difficult to select an antimicrobial agent useful for treating infectious diseases. Even if an antimicrobial agent is selected appropriately, it cannot be an essential treatment for opportunistic infections if the infection resistance of the patient does not recover during treatment, but because the patient's general condition is poor, infection protection is not possible. In many cases, administration of a drug having an activity-recovering effect adversely induces a decrease in infection defense ability, and there is no medicinal drug that can be safely administered to treat or prevent opportunistic infections.

Therefore, it has been desired to develop a drug which can be safely used for patients with opportunistic infections and which has a remarkable antimicrobial effect or an effect of recovering the infection protective ability.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that kanzo-bushi-to has excellent antiviral activity and suppresses the increase in infection susceptibility. The present invention was found out and the present invention was completed.

[0007] That is, the present invention is an infection susceptibility suppressor containing kanzobushito (hereinafter referred to as the active ingredient of the present invention) as an active ingredient. The term "infection susceptibility suppressor" as used in the present invention refers to a drug that has an effect of improving a state in which the infection defense ability of a patient is lowered due to some cause (increase in infection susceptibility), and is essentially Useful for treatment.

Kanzobushito, which is the active ingredient of the present invention, is described in the classical Chinese herbal formula (Kinbyo, etc.), and although there are some differences, the compounding range of crude drugs is generally as follows.

[Keishibushi-to] Licorice 2.0-3.0 Keishi 2.0-5.0 Shu 2.0-9.0 Fuzi 0.3-2.0

The active ingredient of the present invention may be prepared by combining the above-mentioned formulation of kanzo-bushi-to as it is or an extract thereof as an active ingredient and combining it with a known pharmaceutical carrier.

Examples of the extract include various aqueous solvent extracts, and it is preferable to use the water extract. As a specific example of adjusting the extract, 1 part of the above-mentioned mixture of kanzo-bushi-to
Examples include a method of extracting with 0 times the amount of hot water and filtering the obtained extract. This extract can be dried if necessary and used as a dry powder.

Specific examples of the active ingredients of the present invention will be shown and described in detail.

Specific Example 1 2.0 g of licorice, 6.0 g of soy sauce, 3.5 g of katsushi and 1.0 g of adjunct herbs (kanzobushito: 12.5 g)
5 g of purified water was added, and the mixture was heated and extracted at 100 ° C for 1 hour. The obtained extract is filtered and then spray-dried.
1 g of dry extract powder was obtained.

Concrete Example 2 25 g of a mixed crude drug (kanzo-bushi-to: 2.5 kg) of 400 g of licorice, 1200 g of soy sauce, 700 g of Keishi and 200 g of apricot
Add 1 liter of purified water and heat it to 100 ° C.
Time extracted. The obtained extract was centrifuged and the residue was separated to obtain a solution.

This solution was subjected to aseptic clarification filtration with a 0.3 μm membrane filter (manufactured by Toyo Roshi Kaisha, Ltd.). The obtained filtrate was ultrafiltered using a diafilter G-10T (manufactured by Bio Engineering Co., Ltd .: molecular weight cut off 10,000). For this ultrafiltration, a membrane with a diameter of 152 mm was set on the lower surface of a container with an internal volume of 2.0 l and the pressure was 3 kg / cm ^2.
Then, as the liquid in the container was concentrated, about 2 l of purified water was added. As a result, 21 l of ultrafiltrate was obtained.

Next, the experimental examples will be described to explain that the active ingredient of the present invention has antiviral activity and inhibitory effect on increase in infection susceptibility.

The present invention was previously reported in [FASEB Journal 6 A19.
81 (1992)] Inhibition cell activity induced in a model of increased susceptibility to infection (burn mouse) and interleukin-4 production related to the expression of the activity, mortality rate due to herpes simplex virus type I infection, and virus proliferation after infection as indicators. The effects of the active ingredient of the present invention, the contra suppressor cells induced by the active ingredient of the present invention, or the culture solution thereof were examined.

Experiment 1 Anti-herpes action in an infection susceptibility increase model (burn mouse) Preparation of burn mouse BALB / c (or C57BL / 6) mice of 7 weeks old were pentoparbital (intraperitoneal administration; 0.8 mg / 20)
g) was anesthetized. The hair was shaved from the base of the thigh of the mouse to the armpit using a hair clipper, and a third degree burn (total table about 3
0% / 20g mouse). Asbestos wire mesh (2
X 3 cm) was brought into close contact with the exposed part of the skin, and made using a gas burner. Immediately after the burn, 3 ml of physiological saline was intraperitoneally administered to prepare a hypoimmune disease model (burn mouse). In addition, as a control group, mice subjected to the same treatment as the above treatment except the burn operation were used.

Method for Measuring Contra suppressor Cell Activity The suppressive cell activity and its inhibitory cell activity (contra suppressor cell activity) induced in burned mice were measured by mixed lymphocyte reaction (MLR). That is, 96
Splenic mononuclear cells (SMNC) (reactive cells, 1 × 1) obtained from BALB / c mice using a round-bottomed microplate.
0 ⁵ cells / hole) and SM obtained from C57BL / 6 mice
NCs (stimulated cells, 1 × 10 ⁵ cells / well) were cultured with the following cells or cell culture medium for 5 days. Before culturing, cells other than the reaction cells were mitomycin C solution (20 μg
/ Ml) at 37 ° C for 30 minutes. 24 hours before the end of 5 days of culture, ³ H-thymidine (0.5 μCi /
Hole) was added, and the amount of ³ H-thymidine incorporated into the reaction cells was measured by a liquid scintillation counter to evaluate the contra suppressor cell activity induced by the administration of the active ingredient of the present invention against the suppressor cell activity.

[Cells added to MLR or culture medium thereof] (A) SMNC obtained from a normal mouse. (B) Suppressed cells: SMNC obtained from burned mice. (C) Contra suppressor cells: SMNC obtained from burned mice intraperitoneally administered with the active ingredient of the present invention (5 mg / kg) 2 days before, 1 day after and 4 days after burn. (D) Contra suppressor cell culture medium: suppressor cells (B) and SMNCs obtained from normal mice orally administered with the active ingredient of the present invention 1 day, 3 days and 5 days before extraction.
A culture solution (4 times diluted) obtained by culturing (1 × 10 ⁶ cells) for 48 hours. (E) Contra suppressor cell culture medium: suppressor cells (B) and SMNCs obtained from normal mice orally administered with the active ingredient of the present invention 1 day, 3 days and 5 days before extraction.
A culture solution (2-fold dilution) obtained by culturing (1 × 10 ⁶ cells) for 48 hours. (F) Mouse rIL-4 (recombinant interleukin-4: 50 U / ml) (G) Mouse rIL-4 (recombinant interleukin-4: 50 U / ml) and 1 day before extraction, 3
A culture solution (4-fold dilution) obtained by culturing for 48 hours SMNC (1 × 10 ⁶ cells) obtained from a normal mouse to which the active ingredient of the present invention was orally administered on the day before and 5 days before. (H) Mouse rIL-4 (recombinant interleukin-4: 50 U / ml) and 1 day before extraction, 3
A culture solution (2-fold dilution) obtained by culturing for 48 hours SMNC (1 × 10 ⁶ cells) obtained from a normal mouse to which the active ingredient of the present invention was orally administered 5 days and 5 days before. The results are shown in FIGS.

FIG. 1

FIG. 2

FIG. 3

From the results of FIGS. 1 to 3, the active ingredient of the present invention,
The contra suppressor cells and the cell culture solution thereof induced by the active ingredient of the present invention have an inhibitory effect on the production of interleukin-4, which is closely related to the suppressor cells and the expression thereof which are significantly induced in the infection susceptibility increase model. It was confirmed.

Experimental Example 2 Effect on HSV-1 infection Mortality due to viral infection 2 hours before burn injury, (I) physiological saline, (J) 1 day, 3 days and 5 days before extraction, the active ingredient of the present invention (50 mg / Kg) was orally administered to normal mice, and SMNC (contra suppressor cells: 1 ×)
A culture solution (0.5 ml / mouse) obtained by culturing the contra suppressor cells (F) for 48 hours for 10 ⁷ to 1 × 10 ⁸ cells / mouse and / or (K) was intravenously administered to the mouse. Next, HS burns 24 hours later
V-1 (herpes simplex type 1 virus: 10 LD ₅₀ ) was intraperitoneally administered and infected. HSV-1 administered is 3 × 1
Equivalent to 0 ³ PFU / kg. The effect of the contra suppressor cells was evaluated by the survival rate. The results are shown in Figs.
Shown in.

FIG. 4

FIG. 5

From the results of FIGS. 4 to 5, the active ingredient of the present invention,
It was confirmed that the contra suppressor cells and the cell culture solution thereof induced by the active ingredient of the present invention have the action of reducing the mortality rate.

Intraspleen virus titer One day, three days and five days before intraperitoneal infection of mice with HSV-1 (equivalent to 10 LD ₅₀ ), the active ingredient of the present invention (5
0 mg / kg) was intraperitoneally administered. The spleen tissue of the infected mouse was disrupted with a homogenizer and suspended in a serum-free culture medium at 10%. The ultrasonic treatment (maximum: 10 minutes) and the freeze-thaw treatment were repeated 3 times and centrifuged at 3000 rpm for 10 minutes to obtain a virus test solution. The test solution was serially diluted 10-fold in the same medium, and the virus titer was determined as Vero cells (V
The effect on the virus growth of the active ingredient of the present invention was calculated by the plaque method using ero Cell) and compared with that of the control group. Results are shown in FIG.

FIG. 6

From the results shown in FIG. 6, it was confirmed that the active ingredient of the present invention suppresses the growth of virus.

As is clear from the above results, it was confirmed that the active ingredient of the present invention has an excellent antiviral effect and an inhibitory effect on the increase in infection susceptibility. Therefore,
Kanzobushito, which is an active ingredient of the present invention, is useful as an antiviral agent.

Since the effective ingredient of the present invention, kanzo-bushi-to, has a long history as a Chinese medicine and its safety has been confirmed, it can be safely used. For example, for mice and rats, the limit dose is 15 g /
It is extremely safe, as evidenced by the fact that no cases of death were observed after oral administration of kg.

Next, the formulation of the active ingredient of the present invention will be described.

The dosage form of the active ingredient of the present invention is not particularly limited and may be appropriately selected and used as necessary. Oral preparations such as tablets, capsules, granules, fine granules and powders, suppositories, It can be used as a parenteral preparation such as an injection and an external preparation.

In order to exert the intended effect, it depends on the age, body weight and degree of disease of the patient, but usually 3 to 15 g as the weight of the active ingredient of the present invention is divided into several times a day in adults. Seems to be appropriate.

The active ingredient of the present invention includes tablets, capsules,
Oral preparations such as granules are produced by a conventional method using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a surfactant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The active ingredient of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

On the other hand, parenteral preparations are manufactured by a conventional method,
For example, when manufacturing external preparations such as ointments, lotions, and liniments, as a carrier (base), liquid paraffin, isoper, petrolatum, silicone oil, higher aliphatic alcohols (palmityl alcohol, oleyl alcohol) ), Higher fatty acids (myristic acid, stearic acid), fatty acid esters (microcrystalline wax, isopropyl myristate, etc.), lanolin, plastibase (mixture of liquid paraffin and polyethylene), polyethylene glycol, water etc. Is. In addition, if necessary, emulsifiers (fatty acid monoglyceride, sorbitan fatty acid ester, polyoxyethylene lauryl ether, etc.), wetting agents (glycerin, propylene glycol, sorbit, etc.), preservatives (methyl or propyl paraoxybenzoate, etc.), antioxidants Agent (BH
A), pH adjusting agent (citric acid, etc.), suspending agent (CMC)
Etc.) and other drugs (pruritus, analgesics, etc.) can be added. The above-mentioned external medicines include those intended for percutaneous absorption.

The formulation content of the active ingredient of the present invention varies depending on the dosage form, the age of the patient and the condition of the affected part in order to exert the intended effect.
~ 5 μg / base g is suitable, 0.1-0.5 μg /
Base g is preferred.

Next, the present invention will be described in more detail by showing Examples of the preparation of the active ingredient of the present invention, but the present invention is not limited thereto.

Example 1 Corn starch 21 g Crystalline cellulose 10 g Carboxymethyl cellulose calcium 7 g Light anhydrous silicic acid 1 g Magnesium stearate 1 g Ganzo-bushi-to obtained in Example 1 160 g Total 200 g According to the above formulation, It was compression-molded with a tablet machine to obtain 200 mg tablets. This tablet contains 160 mg of kanzo-bushi-to obtained in Example 1, and 20 to 80 tablets for adults are divided into several times and taken.

Example 2 Corn starch 29 g Magnesium stearate 2 g Carboxymethyl cellulose calcium 8 g Light anhydrous silicic acid 1 g Kanzo-bushi-to obtained in Example 1 160 g Total 200 g According to the above formulation, After compression molding, it was crushed by a crusher and sieved to obtain granules. 1 g of this granule contains 800 mg of kanzo-bushi-to obtained in Example 2, and 4 to 18 times a day for adults.
Take g in several divided doses.

Example 3 Corn starch 19 g Light anhydrous silicic acid 1 g Kanzo-bushi- to obtained in Example 1 180 g Total 200 g According to the above formulation, were mixed uniformly to 200 mg.
Was filled in a No. 2 capsule. One capsule of this capsule contains 20 mg of kanzo-bushito obtained in Example 3, and 20 to 80 capsules per day for adults are to be taken in several divided doses.

Example 4 300 g of alanine (containing no heat-generating substance) was added to 20 l of licorice-bushi-to obtained in Example 2, dissolved and freeze-dried. This lyophilized product was dispensed into 900 vials to obtain an injection. 1 vial of this injection contains lyophilized product 406
It contained mg and was easily dissolved in 10 ml of purified water. In addition, the injectable solution after dissolution had a transmittance of 92% (550 nm) and passed the test method for pyrogenic substances of the Japanese Pharmacopoeia.

Example 5 Kanzo-fuzi-to obtained in Example 1 0.05 g isopropyl myristate 5 g Plastibase 94.95 g The above components (1) to (4) were mixed and gradually added to the mixture while stirring to homogenize it to obtain an oily ointment. .

Example 6 Kanzo-fuzi-to obtained in Example 1 0.05 g Isopropyl myristate 5.95 g Isopropyl myristate 10 g Vaseline 66 g Liquid paraffin 5 g Microcrystalline wax 13 g The above ingredients were dissolved by heating and mixed in advance. Was added at 45 to 50 ° C., and the mixture was stirred and homogenized until solidified to give an oily ointment.

Example 7 Kanzo-fuzi-to obtained in Example 1 0.05 g Polyethylene glycol (400) 11.95 g Polyethylene glycol (400) 12 g Polyethylene glycol (4000) 76 g The above ingredients were dissolved at 70 ° C. Was mixed in advance at 50 ° C., and the mixture was stirred and homogenized until solidified to obtain a hydrophilic ointment. For hydrophilic ointment, add Calbol 9
34 can be blended.

Example 8 Kanzo-fuzi-to obtained in Example 1 0.01 g isopropyl myristate 5.99 g stearic acid 19 g cetyl alcohol 4 g polyoxyethylene lauryl ether 2 g glycerin monostearate 0.5 g propylene glycol 4 g citric acid 0 0.05 g Methyl paraoxybenzoate 0.05 g ◆ Paraoxybenzoic acid 0.05 g The above ~ was dissolved at 80 ° C, and ~ ◆ containing 64.35 g of distilled water heated and dissolved at 85 ° C was added, and further heated and dissolved. Was added at 55 ° C, and the mixture was stirred and homogenized to give a cream.

Example 9 Kanzobushito obtained in Example 1 0.001 g propylene glycol 12 g polyoxyethylene lauryl ether 1 g isostearic acid 1 g octyldodecanol 4 g glycerin 3 g citric acid 0.075 g The above components are dissolved at 40 ° C. Then, 78.924 g of distilled water was added thereto with stirring to form a lotion.

Example 10 Kanzobushito obtained in Example 1, 0.05 g Hydrocortisone acetate 0.5 g Diphenhydramine 0.5 g White petrolatum 4.85 g White petrolatum 95 The above ingredients were dissolved by heating and mixed homogeneously. As an ointment.

Claims (1)

[Claims] 1. An infection susceptibility elevation inhibitor containing kanzobushito as an active ingredient.