WO2004103362A1

WO2004103362A1 - Formulation of the total anhydrides of cantharidin for the treatment and prevention of severe acute respiratory syndrome infections and the preparation thereof

Info

Publication number: WO2004103362A1
Application number: PCT/CN2004/000450
Authority: WO
Inventors: Wei Wang
Original assignee: Wei Wang
Priority date: 2003-05-09
Filing date: 2004-05-08
Publication date: 2004-12-02
Also published as: CN1449752A

Abstract

A formulation of the total anhydrides of cantharidin for the treatment and prevention of Severe Acute Respiratory Syndrome, which is characterized in containing the total anhydrides of cantharidin as an effective ingredient as well as pharmaceutical acceptable essential oil or synthetic perfume as a solvent. Moreover the total anhydrides of cantharidin will be present in amount within the range of from 0.05 to 7 %. The preparation comprises the following steps: (1) add a measured amount of the total anhydides of cantharidin into the essential oil or the synthetic perfume, and stir to make the total anhydrides of cantharidin dissolved into essential oil at 40-160 °C and under normal pressure, the formulation of total anhydrides of cantharidin-essential oil is then obtained; (2) mix a measured amount of the formulation of total anhydrides of cantharidin-essential oil or synthetic perfume and pharmaceutical carrier or excipient, stir uniformly, and the desired pharmaceutical composition is obtained.

Description

Macular chelate anhydride preparation for treating and preventing atypical pneumonia infectious disease and preparation thereof

Technical field

The invention provides a cantharidin total acid anhydride preparation for resisting viral diseases such as atypical pneumonia (SARS) and bacterial diseases such as tubercle bacillus, and a series of antiviral antibacterial drugs prepared by using the preparation as a basic raw material of active ingredients. Background technique

Traditional Chinese medicine has long been documented for anti-tumor, anti-panting, and treatment of rabies bites. The present inventors started research on the animal test of chicken virus disease with the lipid solvent cantharidin as early as 1972, and carried out the clinical practice of using the lipid solvent cantharidin in the treatment of viral hepatitis in 1976, and achieved good therapeutic effects. To this end, the inventor published a report on "cantharidin-an antiviral antibiotic" in the 1980 issue of Nature Magazine. Then the present inventors successively obtained patents related to "preparation of cantharidin fat-soluble preparations" (patent numbers ZL 90106365.7 and ZL 931101573) and in 1991 the Ministry of Health of the People's Republic of China pointed out that the four new types of western medicine "antiviral drugs" "cantharidin cream" ".

Antiviral tests and a large number of long-term clinical trials have proven that cantharidin total acid anhydride is an active ingredient preparation that has a broad spectrum against hepatitis virus, HIV, influenza virus, a variety of viruses that cause common colds, tubercle bacilli, staphylococcus, etc. Very excellent antiviral and antibacterial effects. The original unmutated coronavirus, "is one of the main pathogens of the common cold", the "cantharidin cream" using the cantharidin total acid anhydride produced by the patent of ZL 90106365.7 has been clinically applied since 1991. Viral infections such as colds and tracheitis have significant curative effects.

The antiviral efficacy of cantharidin total acid anhydride fat-soluble preparations is much higher than that of non-lipid solvents, and it can achieve long-term application with non-toxic side effects. '.

However, the stable solubility of the total acid anhydride of cantharidin in animal and vegetable fats, which does not precipitate crystals at room temperature, is only 0.4-0.5¾o. Its fat-soluble preparation has a large dose, is greasy and uncomfortable, and has poor bioavailability. The cantharidin total acid anhydride is a solvent, which improves the efficacy of its antiviral preparation.

There are dozens of MELOIDAE insects, and their dry bodies contain about 1% of the total acid anhydride of cantharididae. According to the data before 1990, it can be concluded that the species of cantharidinidae only contains one kind of cantharidin ( Cantharidic anhydride). It is now known that in addition to cantharidin, it contains various types of cantharidic anhydride, such as hydroxyl cantharidic anhydride. The structure is slightly different from that of cantharidic anhydride, which is known to be the most abundant. Therefore, in this paper, a mixture of many kinds of acid anhydrides extracted and purified from the genus Kryptonia quinquefasciatus, etc., is referred to as the total acid anhydride of pupa.

The inventors have discovered through various experimental studies that artificially synthesized edible aromatic substances and natural essential oils The total anhydride solubility can reach 4 to 7%. The solubility of total acid anhydride in animal and vegetable oils is only 0.4-0.5%. The difference between the two is usually more than ten times. The significance of this discovery is that using synthetic perfume and natural essential oils as solvents for the total acid anhydride of cantharidin can be made into a superior antiviral preparation than the lipid solvent cantharidium total anhydride. It has also been experimentally proven that a drug made by dissolving the total anhydride of cantharidin with synthetic flavors and essential oils has a significantly higher anti-pathogenic effect than the original fat-soluble cantharidin total anhydride preparation. This agent not only significantly improves the efficacy of various viral infections. Moreover, it is also superior to remifen and streptavidin for the treatment of tuberculosis.

SARS is a severe infectious disease. According to the World Health Organization, the SARS vaccine will not be released on the market in two to three years. Therefore, there is an urgent need for a drug that can effectively treat and prevent SARS. Summary of the Invention

The main object of the present invention is to provide a cantharidin total acid anhydride preparation for preventing and treating viruses such as SARS and bacterial diseases such as tuberculosis, and a systemic medicament made from such preparations, which is effective against SARS, influenza, cold and other viral diseases. It has very excellent preventive and therapeutic effects; the topically effective drug made by this preparation is used in skin and mucous membranes, and it is a disinfection and health care product that has no damage to human tissue cells and can inactivate pathogenic microorganisms.

Another object of the present invention is to provide a method for preparing a cantharidin total acid anhydride preparation, and a method for preparing a specific medicine using this preparation as an effective ingredient.

In the above-mentioned patent applications (ZL 90106365.7 and ZL 93110157.3) and the application number 01140066.8 proposed by the inventors, the total acid anhydride of cantharis tinctorius has been refined and described, and these techniques can be used in the present invention. use.

The above-mentioned invention patent application No. 01140066.8 has the outstanding feature that the natural acid oil or the essential oil monomers isolated from the natural oil are used to dissolve the total acid anhydride of cantharidii, thereby achieving a significant increase in the antibiotic effect of the total acid anhydride of cantharidium.

In addition, most artificial fragrances are based on the chemical structure of natural fragrance monomers isolated from essential oils and natural animal fragrances, and are biomimetically synthesized single-component pure aromatic substances.

Synthetic fragrances and their essential oils are similar in toxicity to those permitted in foods. Compared with natural essential oils, synthetic fragrances have the obvious advantages of single ingredients, low incidence of allergies, easy preparation in large quantities, and lower prices than essential oils.

The essential oils or synthetic fragrances referred to in the present invention are essential oils or synthetic fragrances which can be used as medicines, and essential oils or synthetic fragrances which are of low toxicity and can be used in cosmetics. Essential oils or synthetic fragrances include terpenes, aromatics, alcohols, ketones, aldehydes, ethers, esters, and phenols. For example, L-carvone, p-methoxyphenylbutanone, phenethyl alcohol, benzyl alcohol, gamma nonolactone, threonyl acetate, benzyl benzoate, DL muskone, citronone, benzyl isovalerate , Strawberry aldehyde, ethyl cyclohexyl, butyl cyclohexyl, etc. are all excellent raw materials. Pure lemon smelt and carvone isolated from natural essential oils also have the same medicinal applicability as synthetic flavors, and are also excellent medicinal cantharid total anhydride solvents of the present invention.

The cantharidin total anhydride preparation for treating and preventing the SARS infectious disease of the present invention is characterized by containing the cantharidin total anhydride anhydride as an active ingredient and dissolving the cantharidin total anhydride anhydride preparation in an essential oil or a synthetic perfume. In the above formulation, the total weight of the cantharidin total anhydride can reach 7%. .

The cantharidin total anhydride preparation of the present invention is an active ingredient, which is formulated with a pharmaceutically acceptable excipient and has a systemic effect. The total cantharidin total anhydride content is 0.2-0.6% of the weight of the drug. ; A locally effective drug formulated, wherein the total anhydride content of cantharidin is 1 to 8 ppm by weight of the drug.

The systemic medicinal medicament prepared by using the cantharidin total acid anhydride preparation of the present invention as an active ingredient has an ideal antibacterial effect on infectious diseases caused by viruses such as SARS and bacteria such as tuberculosis.

The preparation method for treating and preventing SARS disease provided by the present invention comprises the following steps:

(1) Adding cantharidin total acid anhydride to the refined essential oil or synthetic fragrance by metering, and stirring at 40-160 ° C under normal pressure to dissolve cantharidium total acid anhydride in essential oil or synthetic fragrance to prepare cantharidium total acid anhydride preparation;

(2) The prepared cantharid total acid anhydride essential oil or synthetic flavor preparation is mixed with a pharmaceutically acceptable carrier or excipient according to a metering amount, and stirred to prepare a pharmaceutical composition.

In addition, the preparation method of cantharidin total acid anhydride in the present invention can be prepared according to the method adopted in the aforementioned patent 90106365. Specifically, the preparation of cantharid total anhydride includes:

(1) impregnating cantharidium powder with an organic solvent, and extracting the effective components from the cantharidium hydrangea to the organic phase;

(2) After the cantharidin powder which has been extracted with an organic solvent is dried, and then impregnated with concentrated hydrochloric acid and an organic solvent, the concentrated hydrochloric acid can convert the cantharidin salt into the total anhydride of cantharidium, and the organic solvent can dissolve the total anhydride of cantharidium in the organic phase;

(3) After separating the cantharid total anhydride and cantharidin oil from the organic phase, petroleum ether is added, and the cantharidin oil is extracted to separate the cantharid total anhydride from the cantharidin oil. 2) The total isolated anhydrides of cantharidin are combined.

In addition, in the above preparation of cantharid total acid anhydride, the preparation method is characterized in that the organic solvent is acetone, chloroform, dichloromethane, trichloromethane or diethyl ether.

In addition, in order to avoid the volatilization of the active ingredients in the leafworm, the leafworm powder is prepared by crushing and drying the leafworm at a temperature below 55 ° C.

In the cantharidin total acid anhydride essential oil preparation prepared above, various antiviral and antibacterial pharmaceutical compositions of the present invention can be prepared by adding a pharmaceutically acceptable carrier or an excipient according to a conventional pharmaceutical composition preparation method. The above pharmaceutically acceptable carriers or excipients can be prepared according to the dosage form of the prepared pharmaceutical composition and with reference to conventional pharmaceutical processes. The invention is not particularly limited in this regard.

The topical medicine prepared by using the cantharid total anhydride preparation of the present invention as an active ingredient can inactivate viruses attached to the body surface of the nasal cavity, conjunctival sac, pharynx and other parts, and can prevent SARS, influenza and other infectious diseases without damage. Preventive medicine for skin and mucous membrane that adheres to the tissue surface for a long time and exerts antiviral effect. In addition, it has been proved in practice that the local medicine prepared by the present invention for treating and preventing the SARS infectious disease cantharius total anhydride preparation, eye drops, eye drops, eye ointment, is used to treat epidemic infectious viral "red eye disease" It also has extremely obvious effects.

The cantharidin total anhydride preparation for treating and preventing SARS infectious diseases of the present invention has the following characteristics: 1. The same synthetic fragrance and essential oil, the higher the cantharidin total anhydride, 4 to 7%. The solubility can increase the effective ingredient content of the preparation, so that the amount of the finished preparation is relatively reduced, and it is convenient to use; 2. The amount of the synthetic flavor used is lower than the allowable amount of food additives, and no toxic side effects are caused by the synthetic flavor being added to the drug. Reaction; 3. Essential oils or synthetic fragrances can be absorbed through the skin smoothly, with higher discharge in the respiratory tract, which can increase the bioavailability of total acid anhydride in cantharidin; especially in the application of preventive treatment of SARS, it can increase the bioavailability of drugs in the lung. 4. The topical medicinal preparations are made of ethanol, glycerol, propylene glycol essential oils or synthetic flavors, and are made into water-soluble topical medicinal preparations for nasal, eye, pharynx and SARS prevention. There are no adverse reactions; 5. The synthetic fragrance has a single ingredient, and the various preparations can be smoothly analyzed for qualitative and quantitative analysis.

The solvent used in the present invention is 70-120 ° C essential oil or synthetic perfume. A solvent with a boiling point above 160 ° C is preferred. Higher boiling solvents are less volatile, odorless, and stable. However, as long as the edible essential oils and fragrances whose boiling point is higher than 70 ° C can be effectively used. The technology of the present invention will be further described in detail through the following embodiments. Of course, the present invention is not limited to these embodiments. detailed description

Example 1. Preparation of cantharid total anhydride preparation

The cantharidin total acid anhydride preparation of the present invention can be performed according to the technology disclosed by the inventor in the early stage (patent application number

91110970.6). The specific preparation process is as follows:

(1) pulverizing and drying the cantha in a pulverizer at a temperature lower than 55 ° C to obtain a dried cantha powder;

(2) The cantharis powder enters the extraction tank with an organic solvent, such as acetone, and is immersed for more than 24 hours and repeatedly diafiltration to separate the organic phase into the first separator and the solid phase into the extraction tank;

(3) The solid phase candida powder residue enters the extraction tank, and the candida powder residue is impregnated with concentrated hydrochloric acid and acetone solution, the immersion time is more than 24 hours, and repeated diafiltration with acetone, the organic phase is separated and entered into the second separator, the residue Discharge; (4) In the first separator, the total acid anhydride and cantharidin oil in the organic phase of the above (2) are removed from the organic solvent. Separation in acetone, acetone recovery, cantharidin total anhydride and cantharidin oil enter the third separator;

(5) In the third separator, petroleum ether is added to dissolve cantharidin oil. In this separator, the cantharidium total anhydride is separated from the cantharidium oil, the cantharidin oil is discharged, and the cantharidin total acid anhydride enters the refining tank;

(6) The organic phase is separated from the inorganic phase (unreacted concentrated hydrochloric acid and the salt formed after the reaction) in the second separator. After the inorganic phase is discharged, the organic solvent acetone is separated from the total acid anhydride of cantharidin and the total acid of cantharidin. Enter the refined tank;

(7) In the refining tank, the cantharidin total anhydride is repeatedly washed with petroleum ether, and then repeatedly heated and dissolved with a solvent such as acetone, ethanol, etc., and the crystallisation can be obtained by cooling and crystallization. Finally, the crystals are repeatedly heated and dissolved with an appropriate amount of acetone, and the crystals are cooled for more than two times to obtain pure crystals (containing more than 99% of the total acid anhydride of cantharidin). The crystals enter the preparation kettle;

(8) Refining and sterilizing synthetic flavors or essential oils such as sweet orange oil, peppermint oil, spearmint oil; limonene, carvone, etc .;

(9) In the preparation kettle, the total acid anhydride of cantharidin and the essential oil or synthetic flavor are added at a certain ratio at a temperature of 40-180 ° C under normal pressure stirring to dissolve the total acid anhydride of the cantharidin in the essential oil or synthetic flavor. When the temperature reaches about 90 ° C, the total acid anhydride of cantharidis can be quickly dissolved in essential oils or synthetic fragrances, and the dissolution rate of the increased temperature can no longer be significantly accelerated with the increase of temperature. In the production process, the optimal heating dissolution temperature is 88-98 ° C, and the dissolution process can be completed within 30 minutes. After the preparation process of (1) to (9) above, a preparation containing total candidum anhydride of 0.26-0.7% of essential oil anhydride or synthetic flavor can be obtained.

The cantharidin total anhydride anhydride preparation prepared by the above process can be prepared into various cantharidin total anhydride anhydride pharmaceutical compositions by adding other excipients (carriers or excipients) in a certain proportion. The preparation process is performed in a pharmaceutical kettle, and the preparation conditions and processes are further illustrated by the following examples.

Example 2. Preparation of cantharidin total anhydride cream

According to the following ingredients-cantharidin total anhydride 0.66-0.92g

Essential oil or synthetic flavor 200- 260g

Ointment base (stearyl alcohol or stearic acid) 15-25g

Emulsifier (Tween or Span) 60— 80g

Preservatives

Distilled water

Made into 2000g cream The cantharidin total acid anhydride preparation prepared in Example 1 is heated to 60-70 ° C, and other auxiliary materials are dissolved and heated to 66-72 ° C, water is heated to about 70 ° C, and the water phase is put into the oil phase. The colloid mill or the high-speed stirrer is sufficiently emulsified to obtain the antiviral therapeutic agent of the present invention for preventing and treating SARS.

Example 3 Preparation of Cantharidin Total Anhydride Intravenous Emulsion

Refined pure cantharidin total anhydride 0.08—O.lg

Refined synthetic, semi-synthetic spices (such as carvone) 18-22g

Refined vegetable oil (such as sesame oil) 60—80g

Emulsifier (soybean phospholipid or other emulsifier for injection) 6-12g

The rest is 1000ml of water for injection

In the preparation kettle, the water for quantitative injection and the emulsifier are made into an emulsifier dispersion under a stream of nitrogen. The cantharidin total acid anhydride preparation prepared in Example 1 is put into a colloid mill, milled at 60-70 ° F, and then made in a milk homogenizer. Highly homogeneous, fully emulsified emulsion, and then sterilized to obtain an injection. The production process requires operation in a nitrogen stream.

Example 4 Cantharidin Total Anhydride Enteric-Coated Tablets ''

According to the following ingredients:

Cantharidii total anhydride 0.06—O.lg

Essential oil or synthetic flavor 20-30g

Antioxidant 0.06— 0.09g

Other excipients

1000g in total 300g

In the preparation kettle, add quantitative excipients to make excipient blank tablets. Then, at 20-50 ° C, in a rotating sugar-coated pan, the cantharidin total acid anhydride preparation prepared in Example 1 is slowly and uniformly penetrated into the blank tablets. Get ready to coat.

Example 5.Cantharid Total Anhydride Eye Cream

Its composition is-Total Canine Anhydride 3-9mg

Essential oil or synthetic flavor (such as phenethyl alcohol) 0.6- 2.0g

Animal and vegetable fats and oils 700—860 _g

Other bases (such as lanolin or beeswax)

Antioxidant 0.1-6.0g

1000g

Put sterilized fat and other ointment bases in the preparation kettle, and prepare the cantharid total anhydride preparation prepared in Example 1, Put it into the preparation kettle and continue to stir for 2 hours under the temperature of 66-76 ° C to make it completely homogeneous. Filter off the impurities and reduce to room temperature.

Example 6 Cantharid Total Anhydride Eye Drops

Its composition is-total cantharidin acid 3-9mg

Synthetic fragrance (such as benzyl isoformate) 0.6- 2.0g

Antioxidant 0.2- 6.0g

Vegetable oil (such as peanut oil) to 1000g

1000g

In addition to general ophthalmic anti-infective applications, eye drops can be maintained for 1 to 3 hours at a time to prevent SARS virus from infecting the eyes and entering the body through the eyes.

Example 7.Cantharid Total Anhydride Nasopharyngeal Spray

Its composition is:

Cantharidin total anhydride 0.48— 1.6mg

Synthetic perfume (such as threonyl acetate) 3-6g

Propylene glycol 10-20g

Glycerin 50- 180g

Antioxidants

Preservatives

Water for injection up to 1000ml

1000ml

The cantharidin total acid anhydride preparation prepared in Example 1 was put into propylene glycol glycerol, stirred at 66-76 ° C for 8 minutes, poured into water for injection, and stirred for 8 minutes. The preparation can rapidly inactivate a variety of respiratory and enteric viruses, and the nasal spray has significant effects in preventing influenza and colds. After the water of this preparation is volatilized, the concentration of the dissolved cantharidin total acid anhydride in the completely miscible solution of the three components of glycerol, rediol, and synthetic flavor is higher than that of the drug resistance that has been performed by tissue culture technology in the past. Viral test results of adenovirus, syncytial virus, polio virus, coxsackie virus B ₅ virus minimum inactivated virus cantharidin total drug anhydride concentration of 2 to 60,000 times, water content of this preparation cantharidin The total acid anhydride drug concentration can also reach 1 to 20,000 times the concentration of inactivated viral drugs in the above-mentioned antiviral experiments. Therefore, this nasopharyngeal spray is a special effective inactivated viral drug to prevent SARS infection, and it is sprayed once an hour, continuously Systemic and local adverse reactions did not occur for several weeks and months. This spray can be sprayed into the eyes or into a mask On. This preparation can also be divided into eye drops for use as eye drops.

Example 8 Cantharidin Total Anhydride Refreshing Cleanser

Its composition is:

Cantharidin total anhydride 1.2- 4.8mg

Synthetic fragrance (such as phenylethanol) 6-9g

Glycerin 160- 600g

Antioxidants

Preservatives

Other excipients

Water for injection up to 1000ml

Made into 1000ml

Glycerol was added to the preparation kettle, and the cantharid total anhydride preparation prepared in Example 1 was also put into the preparation kettle, stirred at 62-66 ° C for 30 minutes, and then distilled water and other auxiliary materials were added at 62-66 ° C. Stir for another 30 minutes. After cooling, it will become slightly sticky. According to the antiviral test results of the cantharidin total acid anhydride against HIV and other viruses, the concentration of the cantharidin total acid anhydride drug in the preparation has exceeded thousands to tens of thousands of times of the minimum inactivated virus of various viruses. The drug can completely reach the concentration of inactivated pathogens such as HIV, B, and C in the sexual organs, which can make people refreshing and prevent sexually transmitted pathogenic microorganisms.

Example 9 Cantharidin Total Anhydride Disinfection Wipes

Its composition is-total canine anhydride 1.2- 2.4mg

Synthetic fragrances (such as threonyl acetate) 3-4 _g

Glycerin 260— 300g

Antioxidant 2— 8g

Fresh Angelica and Other Skin Care Herbal Liquid 600ml

Add distilled water to 2000ml

Made into 2000ml

Put other auxiliary materials of glycerin in the preparation kettle, and then add the cantharid total acid anhydride preparation prepared in Example 1. After stirring at 62-66 ° C for 30 minutes, put in distilled water and stir at 62-66 ° C for another 30 minutes. The wipe liquid is obtained by soaking the wet wipe liquid in a weight ratio. When there is no hand-washing condition, this wipe can prevent the infection of SARS and other virus bacteria. This hand towel can also be used for disinfection after washing hands. Over time, this product does not damage the skin. However, the effect of this preparation is significantly reduced in a metal ion environment.

Example 10 Preparation of preparation solution of canine total anhydride anhydride inactivated pathogenic microorganism vaccine

Its composition is-Total canine anhydride 0.6- 6000mg

Synthetic fragrance (such as phenylethanol) 6—6000g

Other excipients

Add distilled water to 1000kg

1000kg of vaccine preparation solution for inactivated microorganisms.

After a small test, determine the concentration of the inactivated drug of the pathogenic microbial cantharidii, the total acid anhydride of the prepared vaccine, and then use a certain concentration of antibiotic to inactivate the microbial vaccine preparation solution. In a closed condition at 30-38 ° C, inactivate different cultivated varieties Live extracellular virus; or bacteria, prepared as a nasal spray or injectable antibiotic inactivated vaccine. According to public information from the World Health Organization, it will take 2-3 years for the SARA vaccine to reach the market. With the method of the present invention, the vaccine can be put on the market within 3 months. At present, this type of antibiotic-inactivated vaccine is only a kind of total acid such as cantharidium, which has a strong killing effect on organisms other than the insects of the family Asteraceae Produced. Antibiotics inactivate pathogens, and vaccines made of them, have the possibility of having many important advantages over inactivated vaccines by physicochemical methods.

Claims

Rights request

A cantharidin total acid anhydride preparation for treating and preventing atypical pneumonia, which is characterized by containing the cantharidin total acid anhydride as an active ingredient and an essential oil or a synthetic perfume which can be used as a medicine as a solvent.

2. The cantharidin total acid anhydride preparation according to claim 1, wherein the cantharidin total acid anhydride content is 0.05 to 7% _{0. 3} .

3. A method for preparing a cantharidin total anhydride preparation for treating and preventing atypical pneumonia according to claim 1, according to the following steps:

(1) Adding cantharid total acid anhydride to the refined essential oil or synthetic perfume, and stirring at 40-160 ° C under normal pressure to dissolve cantharid total acid anhydride in the essential oil to prepare cantharid total acid anhydride essential oil preparation;

4. A medicine for treating and preventing atypical pneumonia, which is characterized by containing cantharidin total anhydride as an active ingredient and can be used as a medicine for essential oil or synthetic flavor as a solvent, and can be used as a medicine Add auxiliary ingredients.

5. The medicament according to claim 4, characterized in that it is a cantharidin total acid anhydride cream formulated according to the following ingredients,

Cantharid total anhydride 0.66— 0.92g

Essential oil or synthetic flavor 200- 260g

Ointment base (stearyl alcohol or stearic acid) 15-25g

Emulsifier (Tween or Span) 60— 80g

Preservative

Distilled water

Made into 2000g cream.

6. The medicament according to claim 4, characterized in that it is an intravenous injection of cantharidin total anhydride prepared according to the following ingredients,

Refined pure cantharidin total anhydride 0.08—O.lg

Refined synthetic, semi-synthetic spices (such as carvone) 18-22g

Refined vegetable oil (such as sesame oil) 60—80g Emulsifier (soybean phospholipid or other emulsifier for injection) 6-12g

The rest is the total water for injection 1000mL

7. The medicament according to claim 4, characterized in that the cantharidin total acid anhydride enteric-coated tablets are formulated according to the following ingredients,

Cantharidii total anhydride 0.06-0.1 g

Essential oil or synthetic flavor 20-30g

Antioxidant 0.06— 0.09g

Other accessories

A total of 300 g is made into 1,000 tablets.

8. The medicament according to claim 4, characterized in that it is a total cantharidin acid which is prepared according to the following ingredients

Essential oil or synthetic flavor (such as phenethyl alcohol) 0.6- 2.0g

Animal and vegetable fats 700—860g

Other bases (such as lanolin or beeswax)

Antioxidant 0.1-6.0g

1000g of medicine.

9. The medicament according to claim 4, characterized in that the cantharidin total acid anhydride nasopharyngeal spray formulated according to the following ingredients,

Cantharidin total anhydride 0.48— 1.6mg

Synthetic perfume (such as threonyl acetate) 3-6g

Propylene glycol 10-20g

Glycerin 50- 180g

Antioxidants

Preservatives

Water for injection up to 1000ml

Made into 1000ml of medicine.

The medicament according to claim 4, characterized in that the cantharidin total acid anhydride refreshing cleanser is formulated according to the following ingredients,

Cantharidine total anhydride 1.2— 4.8mg Synthetic fragrance (such as phenylethanol) 6-9g

Glycerin 160- 600g

Antioxidant

Preservative

Other accessories

Water for injection up to 1000ml

Made into 1000ml.

The medicament according to claim 4, characterized in that the cantharidin total anhydride anhydride wipes are formulated according to the following ingredients,

Cantharidin total anhydride 1.2— 2.4mg

Synthetic fragrance (such as threonyl acetate) 3-4g

Glycerin 260— 300g

Antioxidant 2— 8g

Fresh Angelica and Other Skin Care Herbal Liquid 600ml

Add distilled water to 2000ml

Made into 2000ml.

The medicament according to claim 4, characterized in that it is a preparation solution of cantharidin total acid anhydride antibiotic inactivated pathogenic microorganism vaccine prepared according to the following ingredients,

Cantharidii total anhydride 0.6- 6000mg

Synthetic fragrance (such as phenylethanol, etc.) 6— 6000g

Other accessories

Add distilled water to 1000kg

1000kg of vaccine preparation solution for inactivated microorganisms.