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WO2004103362A1 - Formulation contenant le total d'anhydrides de cantharidine pour le traitement et la prevention du syndrome respiratoire aigu severe (sras), et preparation de cette formulation - Google Patents

Formulation contenant le total d'anhydrides de cantharidine pour le traitement et la prevention du syndrome respiratoire aigu severe (sras), et preparation de cette formulation Download PDF

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Publication number
WO2004103362A1
WO2004103362A1 PCT/CN2004/000450 CN2004000450W WO2004103362A1 WO 2004103362 A1 WO2004103362 A1 WO 2004103362A1 CN 2004000450 W CN2004000450 W CN 2004000450W WO 2004103362 A1 WO2004103362 A1 WO 2004103362A1
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WO
WIPO (PCT)
Prior art keywords
cantharidin
total
anhydride
preparation
acid anhydride
Prior art date
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Ceased
Application number
PCT/CN2004/000450
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English (en)
Chinese (zh)
Inventor
Wei Wang
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Individual
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Individual
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Publication of WO2004103362A1 publication Critical patent/WO2004103362A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • the preparation of cantharid total anhydride includes:
  • 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;
  • the preparation method is characterized in that the organic solvent is acetone, chloroform, dichloromethane, trichloromethane or diethyl ether.
  • the leafworm powder is prepared by crushing and drying the leafworm at a temperature below 55 ° C.
  • 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.
  • 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 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.
  • 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.
  • the edible essential oils and fragrances whose boiling point is higher than 70 ° C can be effectively used.
  • 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
  • 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;
  • an organic solvent such as acetone
  • 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;
  • 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.
  • Ointment base (stearyl alcohol or stearic acid) 15-25g
  • Emulsifier (Tween or Span) 60— 80g
  • Example 2 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.
  • 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
  • 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.
  • composition is-Total Canine Anhydride 3-9mg
  • Synthetic perfume (such as threonyl acetate) 3-6g
  • 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.
  • 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.
  • 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.
  • composition is-total canine anhydride 1.2- 2.4mg
  • composition is-Total canine anhydride 0.6- 6000mg
  • Synthetic fragrance (such as phenylethanol) 6—6000g
  • 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.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Botany (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation contenant leccc total d'anhydrides de cantharidine pour le traitement et la prévention du SRAS. Cette formulation se caractérise en ce qu'elle contient, comme principe actif, le total d'anhydrides de cantharidine, ainsi que, comme solvant, une huile essentielle ou un parfum synthétique pharmaceutiquement acceptable. En outre, le total d'anhydrides de cantharidine est présent dans cette formulation en une quantité comprise entre 0,05 et 7‰. L'invention concerne également une préparation comprenant les étapes suivantes : (1) addition d'une dose du total d'anhydrides de cantharidine à l'huile essentielle ou au parfum synthétique, et agitation pour faire dissoudre le total d'anhydrides de cantharidine dans l'huile essentielle ou dans le parfum synthétique à une température de 40-160 °C et sous une pression normale, cela dans le but d'obtenir la formulation constituée du total d'anhydrides de cantharidine et d'huile essentielle ou de parfum synthétique ; (2) mélange d'une dose de la formulation obtenue à l'étape (1) avec un excipient pharmaceutique et agitation pour l'obtention d'un mélange uniforme, cela dans le but d'obtenir la composition pharmaceutique désirée.
PCT/CN2004/000450 2003-05-09 2004-05-08 Formulation contenant le total d'anhydrides de cantharidine pour le traitement et la prevention du syndrome respiratoire aigu severe (sras), et preparation de cette formulation Ceased WO2004103362A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN03123500.X 2003-05-09
CN03123500A CN1449752A (zh) 2003-05-09 2003-05-09 用于治疗和预防非典型肺炎传染病的斑蝥总酸酐制剂及其制备

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WO2004103362A1 true WO2004103362A1 (fr) 2004-12-02

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PCT/CN2004/000450 Ceased WO2004103362A1 (fr) 2003-05-09 2004-05-08 Formulation contenant le total d'anhydrides de cantharidine pour le traitement et la prevention du syndrome respiratoire aigu severe (sras), et preparation de cette formulation

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021238836A1 (fr) * 2020-05-25 2021-12-02 甘肃芫美药业有限公司 Préparation antivirale et antibactérienne de cantharidine, son procédé de préparation, et son utilisation pour prévenir et traiter une nouvelle infection à coronavirus
CN111568897A (zh) * 2020-05-25 2020-08-25 甘肃芫美药业有限公司 一种斑蝥素抗病毒、抗菌制剂、其制备方法及用作预防和治疗新冠病毒感染

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1059338A (zh) * 1990-08-29 1992-03-11 王日卫 斑蝥素脂溶性制剂的制备
CN1073096A (zh) * 1991-12-10 1993-06-16 王日卫 斑蝥素脂溶性制剂的制备
CN1091953A (zh) * 1993-03-10 1994-09-14 王曰卫 斑蝥酸盐抗病毒制剂及其制备

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1059338A (zh) * 1990-08-29 1992-03-11 王日卫 斑蝥素脂溶性制剂的制备
CN1073096A (zh) * 1991-12-10 1993-06-16 王日卫 斑蝥素脂溶性制剂的制备
CN1091953A (zh) * 1993-03-10 1994-09-14 王曰卫 斑蝥酸盐抗病毒制剂及其制备

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PHARMACEUTICAL ANALYSIS JOURNAL, vol. 20, no. 5, 31 October 2000 (2000-10-31), pages 324 - 325 *

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