WO2003043623A1 - Compositions pharmaceutiques antivirales, antibacteriennes d'anhydride cantharidique et son procede de preparation - Google Patents

Compositions pharmaceutiques antivirales, antibacteriennes d'anhydride cantharidique et son procede de preparation Download PDF

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Publication number
WO2003043623A1
WO2003043623A1 PCT/CN2002/000839 CN0200839W WO03043623A1 WO 2003043623 A1 WO2003043623 A1 WO 2003043623A1 CN 0200839 W CN0200839 W CN 0200839W WO 03043623 A1 WO03043623 A1 WO 03043623A1
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Prior art keywords
anhydride
cantharidic
essential oil
preparation
cantharidic anhydride
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PCT/CN2002/000839
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English (en)
French (fr)
Inventor
Wei Wang
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Wei Wang
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Application filed by Wei Wang filed Critical Wei Wang
Priority to US10/496,561 priority Critical patent/US8003691B2/en
Priority to DE60231427T priority patent/DE60231427D1/de
Priority to AU2002349451A priority patent/AU2002349451A1/en
Priority to EP02782647A priority patent/EP1454624B1/en
Publication of WO2003043623A1 publication Critical patent/WO2003043623A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • A61P31/06Antibacterial agents for tuberculosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV

Definitions

  • the present invention provides an antiviral and antibacterial cantharidic anhydride pharmaceutical composition and a method for preparing the pharmaceutical composition.
  • the invention provides a pharmaceutical composition having antiviral and antibacterial effects, which is prepared by dissolving cantharidic acid essential oil preparation dissolved in essential oil or monomer essential oil as an effective component and a pharmaceutically acceptable carrier or excipient.
  • Antiviral tests and a large number of clinical trials have been conducted to prove that the pharmaceutical composition of the present invention has very excellent antibacterial and antiviral effects on diseases such as tuberculosis, staphylococcus, hepatitis virus, HIV, influenza virus and rotavirus infection. . Background technique
  • Cantharidic anhydride-cantharidin, hydroxycantharidin are highly toxic substances extracted from Chinese worms such as cantharidin and cyanine.
  • candida tsutsugamushi has a long history of antitumor effects in Chinese medicine.
  • Classical cantharimum plaster abroad is a foaming medicine made from cantharis powder supplemented with beeswax, rosin, tallow, etc.
  • the cantharidin powder in the paste is 25%.
  • most of the cantharitic anhydride has not been used in the ointment process. Dissolves, so this classic skin irritant is just a product of cantharidin powder.
  • cantharidic anhydride can be used as an anticancer drug
  • research on the pharmacology of cantharilic anhydride and its clinical application has developed rapidly.
  • organic solvents such as acetone, chloroform, and ether.
  • candida powder is usually treated with concentrated hydrochloric acid before extracting cantharidic anhydride with an organic solvent.
  • the purified cantharidic anhydride and hydroxycantharitic anhydride are purified and then prepared into pharmaceuticals, for example, cantharidin tablets (Shanghai Q / WS-1-566-80) and cantharidin injection (Shanghai Q WS-l-567-80).
  • cantharidic anhydride is an antiviral antibiotic.
  • the antibiotic effect of cantharidic anhydride in humans and animals is not obvious in ordinary non-lipid-soluble cantharidic anhydride preparations, while fat-soluble cantharidic anhydride shows Good results (Journal of Nature, 1980, Vol.3, No.6, p.458).
  • the preparation prepared by using fat-soluble cantharidic anhydride can have a special effect. This technology was reported in the inventor's early 1990 Chinese patent application (ZL 90106365.7).
  • the preparation of specific fat-soluble cantharidin acid liver preparations mainly uses the following steps:
  • the refined oils and fats can be vegetable oils such as soybean oil, corn oil, rapeseed oil, sunflower oil, sesame oil, and cocoa butter, and lanolin and tallow can also be used.
  • Natural worms contain cantharidinates such as cantharidate, indicating that this cantharidate can exert its biological anti-biotic effect in living cantharidia, and it is more soluble in body fluids than cantharidin.
  • cantharidate than cantharidic anhydride, has its special antibacterial and antiviral drugs.
  • cantharidate-containing antiviral preparations are convenient to use, and have anti-biotic effects on a variety of important bacteria and viruses, and have applicability to a wide range of medical prevention practices.
  • the agent has an antiviral effect similar to the lipid solvent cantharidic anhydride.
  • cantharidate preparations in some fields of treatment and prevention of diseases, fill the blank of preparations for which lipid solvent cantharidate cannot be applied.
  • the object of the present invention is to provide an antiviral and antibacterial pharmaceutical composition.
  • This pharmaceutical composition against tuberculosis Pathogenic microorganisms such as bacteria, staphylococcus, hepatitis virus, HIV, influenza virus and rotavirus have very good antibacterial and antiviral effects.
  • the present invention also provides an antiviral and antibacterial pharmaceutical composition for topical use.
  • Various topical preparations containing this pharmaceutical composition can be widely used for various disinfection and as health care products.
  • Another object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical composition.
  • an antiviral and antibacterial cantharidic anhydride pharmaceutical composition of the present invention contains cantharidic anhydride as an effective pharmaceutical ingredient, which is characterized in that the cantharitic anhydride is a cantharitic anhydride essential oil preparation dissolved in an essential oil, and the cantharitic anhydride
  • the essential oil preparation is formulated with a pharmaceutically acceptable carrier or excipient, and the cantharidic anhydride essential oil preparation contains cantharidic anhydride in an amount of 0.05% to 0.7% by weight.
  • the above-mentioned antiviral and antibacterial cantharidic acid pharmaceutical composition of the present invention can be used as a topical medicine, SP.
  • the cantharitic acid essential oil preparation is formulated with a pharmaceutically acceptable carrier or excipient, and the cantharitic acid essential oil Cantharidic anhydride is contained in the preparation in an amount of 0.05% to 0.7%.
  • the cantharidic acid essential oil pharmaceutical composition of the present invention has particularly good antibacterial and antiviral effects against bacteria such as Mycobacterium tuberculosis and various viruses.
  • cantharidic anhydride essential oil preparation is used as an active ingredient of the medicine.
  • the main reason is that cantharidic anhydride has a higher solubility in essential oils.
  • the solubility of cantharidic anhydride in water is about 0.003%, and in oils and fats. Solubility can reach 0.05% in oil and 0.7% in essential oil. ⁇ P.
  • the concentration of canthic anhydride in essential oil can be 14 times that in oil and more than 200 times in water.
  • Essential oil also known as essential oil, volatile oil or aromatic oil.
  • the main ingredients are terpenes, aromatics, alcohols, alcohols, ketones, ethers, esters and phenols.
  • cinnamon oil containing 85-90% cinnamaldehyde, a small amount of cinnamic acid, benzoic acid and coumarin, has a sweet and spicy flavor, similar to cinnamaldehyde, with a slightly woody aroma and is used in food.
  • Citronella oil the main ingredient is citronellal (35
  • the above-mentioned characteristics of essential oils are used. 1. Higher solubility in cantharidic anhydride, which can increase the content of active ingredients in the pharmaceutical composition; 2. Most of the essential oils are edible, that is, the edibles commonly used in the invention are edible Essential oils without any side effects on the human body; 3. Essential oils are soluble in alcohols such as ethanol and glycerol, and ethanol or glycerin is soluble in water. Therefore, cantharidic anhydride essential oil preparations can be formulated into water-soluble topical pharmaceutical compositions. Can effectively exert the antiviral and antibacterial effects of cantharidic anhydride.
  • essential oils having a boiling point higher than 100 ° C, and preferably higher than 160 ° C are mainly used when preparing cantharidic anhydride essential oil preparations, preferably under heating conditions. Therefore, essential oils with higher boiling points are less volatile during the preparation.
  • the cantharidic anhydride essential oil preparation is formulated at a low level, such as 50-100 ° C, as long as the boiling point of the refined sleeve is higher than 100 ° C, it can be effectively applied. Therefore, in the present invention, most commonly used edible essential oils can be used to formulate cantharidic anhydride essential oil preparations.
  • the preparation method of the antiviral and antibacterial pharmaceutical composition provided by the present invention comprises the following steps:
  • Cantharidic anhydride is added to the refined essential oil in a metered manner, and the cantharitic anhydride is dissolved in the essential oil at a temperature of 40-160 ° C under stirring to prepare cantharidic anhydride essential oil preparation;
  • the prepared cantharidic anhydride essential oil preparation is mixed with a pharmaceutically acceptable carrier or excipient according to a metered amount and stirred to prepare a pharmaceutical composition.
  • the preparation method of cantharidic anhydride used in the present invention can be prepared according to the method used in the aforementioned patent 90106365. Specifically, the preparation of cantharidic anhydride includes ⁇
  • the preparation method is characterized in that the organic solvent is acetone, methylene chloride, chloroform, or ether.
  • the larvae powder is prepared by crushing and drying the larvae 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 method for preparing a pharmaceutical composition.
  • the above-mentioned pharmaceutically acceptable carriers or excipients can be performed according to the dosage form of the prepared pharmaceutical composition with reference to conventional pharmaceutical processes, and the present invention is not particularly limited thereto.
  • the inventors made a lot of research on the antiviral and antibacterial effects of cantharidine anhydride and found that the medium containing 0.01 ppm cantharidine concentration can completely inactivate pathogens such as Mycobacterium tuberculosis and staphylococcus (the minimum inactivated virus concentration of cantharidin is 0.000132) ppm), there are data reports that the minimum inhibitory concentration of tuberculosis is streptomycin is 10ppm, rifampicin is 25ppm, the above test shows that cantharidic anhydride has stronger antibacterial effect on tuberculosis, staphylococcus, etc., has clinical Trial value.
  • the essential oil-soluble cantharidine preparation of the present invention has been used to treat tuberculosis and tuberculous pleurisy, and has achieved a clinical effect that is significantly superior to the combined use of antimimetic drugs such as remiphon, streptomycin, and rifampicin.
  • antimimetic drugs such as remiphon, streptomycin, and rifampicin.
  • there is no toxic side effect of liver and hematopoietic system of anti-TB drugs which is twice as fast as the other patients' anti-TB drugs. .
  • chloramphenicol eye drops and erythromycin eye ointment are commonly used for bacterial conjunctivitis.
  • the application of the essential oil-soluble eye drops and eye ointment (containing 3-6 ppm of canthic anhydride) of the present invention has an effective rate of 99%, and the symptoms are relieved within 1 to 2 hours after treatment, and the treatment is cured within 1-3 days.
  • the curative effect is significantly better than erythromycin, chloramphenicol, etc.
  • Antibacterial eye ointment, eye drops are significantly better than erythromycin, chloramphenicol, etc.
  • the essential oil-soluble cantharidic acid cream of the present invention is applied to the palate for 2-3 hours to relieve pain, and most bloated subsides within 2-3 days.
  • cantharidic anhydride pharmaceutical compositions made from essential oil-soluble cantharidic anhydride preparations have significantly improved clinical efficacy, and because the amount of the medicament can be reduced, it is convenient to use, and can be used for safety without adverse effects.
  • the essential oil is used as a solvent of cantharidic anhydride, and the amount of the essential oil is not large.
  • the non-toxic side reaction essential oil is selected, and the prepared preparation does not cause adverse reactions due to the addition of the essential oil.
  • peppermint oil, peppermint oil, and food additives stipulate that "the amount is limited to production needs.”
  • the doses of sweet orange oil, spearmint oil, carvone, and limonene commonly used in the preparations of the present invention are far lower than those prescribed by the United Nations Food Regulatory Commission Dosage of food additives.
  • essential oils are easier to absorb in the skin than oils.
  • the use of essential oils as solvents enhances the permeability of the agent and increases the bioavailability of cantharidic anhydride, while essential oil-soluble agents also easily penetrate the outer membrane of bacterial viruses, which improves the efficacy of cantharidic anhydride. .
  • Some essential oils are excreted through the lungs, which is conducive to enhancing the efficacy of cantharidine in treating tuberculosis.
  • a variety of essential oils are easily soluble in vegetable oils and can be used with vegetable oils to make particularly effective creams and ointments.
  • Some essential oils are easily soluble in glycerol.
  • Cantharidic anhydride is first dissolved in essential oils and then used as a preparation for sexual organs with glycerol, which has become an excellent preparation for controlling HBV AIDS infection.
  • the cantharidic anhydride essential oil preparation of the present invention can be performed according to the technique disclosed by the inventor in the early stage (patent application number 91110970.6).
  • the specific preparation process is as follows:
  • the solid phase candida powder dregs enters the extraction tank, and the candida powder dregs are impregnated with concentrated hydrochloric acid and acetone solution, the immersion time is more than 24 hours, and repeated diafiltration with acetone to separate the organic phase into the second separator, and the residue discharge;
  • the cantharidic anhydride is repeatedly washed with petroleum ether, and then repeatedly heated and dissolved with a solvent such as acetone, ethanol and the like, and the crystals 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 cantharidic anhydride more than 99%). The crystals enter the preparation kettle;
  • the cantharidic anhydride essential oil preparation prepared by the above process can be prepared into various cantharidic anhydride pharmaceutical compositions by adding other auxiliary materials (carriers or excipients) in a certain proportion.
  • the preparation process is carried out in a pharmaceutical kettle, and the preparation conditions and processes are further illustrated by the following examples.
  • Cantharidic acid cream has the following ingredients:
  • Other ointment bases stearic acid, stearyl alcohol, cetyl alcohol, beeswax, chlorinated vegetable oil monostearate, etc. 15-25g
  • Emulsifier (Tween, Span, Maybelin, Pingping plus 0 or Soy phospholipid) 6-20g
  • Example 3 Preparation of Cantharidic Acid Enteric Coated Tablets
  • Canthic anhydride enteric-coated tablets are as follows:
  • Cantharidic anhydride emulsion for intravenous injection is based on the following ingredients-pure cantharitic anhydride 0.08—O.lg
  • Refined monomer essential oil for example, lemon thin 16-20g
  • Emulsifier (soybean lecithin or emulsifier for injection) 6-12g
  • a certain amount of water for injection, an emulsifier, and glycerin were made into a soy phospholipid dispersion under a stream of nitrogen.
  • the cantharidic anhydride essential oil preparation prepared in the above Example 1 was put into a colloid mill and milk homogenizer to make it highly uniform.
  • the fully emulsified emulsion is then sterilized to obtain an injection emulsion.
  • the preparation process of the injection emulsion is run in a nitrogen stream.
  • Example 1 the cantharidic acid If essential oil preparation prepared in the above Example 1 can also be prepared into cantharidic acid injection, coating agent, smearing agent, patch, rubber plaster, oral emulsion, capsule , Enteric capsules, soft capsules, gelatin pills, dense pills, etc.
  • cantharidic acid essential oil preparation prepared in the above Example 1 can also be made into a hygienic disinfectant for local pharmacological treatment and prevention of bacterial and viral diseases.
  • it can be made into-
  • composition is-Cantharidic anhydride 0.0003-0.03g
  • ointment bases such as stearyl alcohol beeswax
  • the cantharidic anhydride essential oil preparation prepared in the above Example 1 was put into sterilized oils and fats and other bases.
  • the eye ointment was prepared by the same method as the above ointment, and the effect of this kind of eye ointment on conjunctival bacterial and viral infections It is particularly superior to the existing antibacterial and antiviral eye medicines.
  • composition is-Cantharidic anhydride 0.0003-0.03g
  • Glycerin Also use propylene glycol, sorbitol, polyethylene glycol in whole or in part
  • Glycerin and other auxiliary materials are added to the pharmaceutical kettle, and the cantharidic anhydride essential oil preparation prepared in the above Example 1 is put into the preparation kettle 10, stirred at 66-76 ° C for 30-60 minutes, and then distilled water and spices are added. , Stir at 66-76 ° C for another 10-20 minutes. After cooling, it will become a slightly viscous liquid.
  • the preparation can completely inactivate its HIV, HBV, and many kinds of germs when used in the sex organs, make people refreshing, and prevent sexual transmission of the above-mentioned pathogenic microorganisms. Since the concentration of cantharidic anhydride drug of this agent has exceeded the minimum inactivated virus concentration more than ten thousand times, and it has no adverse effects on human organs, it is an ideal preventive agent for sexually transmitted diseases.
  • Essential oil (such as ⁇ -phenylethanol) 3.6— 9.6g
  • the wet tissue medicine solution is soaked in the wet tissue paper in a weight ratio, and the wet tissue paper soaked in the medicine solution is packaged in a small plastic bag.
  • the concentration of cantharidic acid drug of this wet wipe can reach more than 30,000 times the minimum inactivated virus concentration of cantharitic acid after water evaporation, which can kill the skin and the superficial wounds of the skin and the virus and bacteria, and also achieve emollient The function of skin care and cleaning the skin. In traveling or in the field, you can use this disinfection wipe to wash your face and hands. In case of trauma, you can also use this towel to cover the wound. This wipe is an ideal travel health care product on airplanes and trains.
  • Example 6 A cantharilic acid pharmaceutical composition made from cantharidic anhydride essential oil preparation, and a treatment experiment for tuberculosis and hepatitis virus infection diseases
  • Example 2 the agent of Example 2 is used to treat tuberculous pleurisy.
  • the pleural effusion does not absorb water at its own rate, and the rate of body temperature and blood sedimentation to normal is significantly faster than the combined effect of remifen and streptomycin rifampicin. , And non-toxic side effects.
  • the specific clinical experiment was performed according to the following procedure.
  • Example 2 For the tuberculosis patients in the treatment group, the cream made in Example 2 was used for 90 consecutive days to observe the clinical treatment effect. In addition, both the control group ( ⁇ ) and the treatment group were creamed on the chest and back of the patients three times a day with 2 g each time. The results of the above three treatments are shown in Tables 1 to 3 below. Comparison of the efficacy of three treatments for invasive pulmonary tuberculosis
  • the pharmaceutical composition of the present invention is also used to clinically implement the curative effect of hepatitis, especially hepatitis E and hepatitis C.
  • the experiment was also performed by three groups simultaneously.
  • Control group (1) ⁇ Traditional Chinese medicine decoction was used for treatment.
  • control group ( ⁇ ) was treated with fat-soluble cantharidic acid cream.
  • Table 5 lists the results of clinical experiments on the treatment of epidemic acute viral conjunctivitis-red eye disease with fat-soluble cantharidic anhydride ophthalmic oil and cantharidic anhydride ophthalmic oil of the essential oil adjuvant prepared by the present invention, respectively. Table 5 Comparison of the efficacy of fat-soluble cantharidic anhydride ophthalmic oil and essential oil-dissolved cantharidic anhydride ophthalmic oil in the treatment of acute viral conjunctivitis
  • the cantharidic anhydride pharmaceutical composition of the present invention has broad-spectrum antiviral and antibacterial properties that are good for viral or bacterial diseases. In particular, it has a very good therapeutic effect on the treatment of tuberculosis, viral hepatitis, and viral enteritis.

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Description

一种抗病毒、 抗菌的斑蝥酸酐药物组合物及其制备方法 发明领域
本发明提供一种抗病毒、 抗菌的斑蝥酸酐药物组合物以及制备该药物组合物的方 法。 具体地说, 是提供一种以溶解于精油或单体精油的、 斑蝥酸酐精油制剂为有效成 分与可药用载体或赋形剂配制而成的具有抗病毒和抗菌作用的药物组合物。 已经进行 的抗病毒试验及大量临床试验证明, 本发明的药物组合物对结核杆菌、 葡萄球菌、 肝 炎病毒、 艾滋病毒、 流感病毒及轮状病毒等感染的疾病具有非常优异的抗菌、 抗病毒 作用。 背景技术
斑蝥酸酐一斑蝥素、 羟基斑蝥素, 是由中药斑蝥、 芫菁等虫体中提取的有剧毒性 物质。 斑蝥虫作为药物, 在我国医学上很早就有抗肿瘤作用的记载。 国外古典的斑蝥 硬膏是由斑蝥粉辅以蜂蜡、 松香、 牛脂等所制成的发泡药, 该膏中斑蝥粉 25 % , 经过 溶解度计算及试验观察斑蝥酸酐在制膏过程中大部分没有被溶解, 因此这一古典的皮 肤剌激药只是斑蝥粉的制成品。 近几年来, 特别是发现了斑蝥酸酐可以作为抗癌药以 后, 对斑蝥酸酐的药理及在医学临床上应用的研究迅速地发展起来。 目前制备斑蝥酸 酐所采用的方法, 是利用有机溶剂, 例如丙酮、 氯仿、 乙醚等从斑蝥粉中抽提。 为促 使斑蝥酸镁转化成斑蝥酸酐而增加收率, 所以通常在用有机溶剂抽提斑蝥酸酐前, 都 要用浓盐酸处理斑蝥粉。 所得斑蝥酸酐、 羟基斑蝥酸酐经提纯后, 再制备成药剂, 例 如, 斑蝥素片 (沪 Q/WS-1-566-80)及斑蝥素注射液(沪 Q WS-l-567-80)。
近年医学上又发现斑蝥酸酐是一种抗病毒抗生素, 但是斑蝥酸酐在人和动物体内 的这种抗生药效, 通常的非脂溶性斑蝥酸酐制剂反应并不明显, 而脂溶性斑蝥酸酐却 显示出良好的效果(自然杂志 1980年 3卷 6期 458页)。特别是对病毒性肝炎等病毒 感染的治疗。 利用脂溶性斑蝥酸酐所制备的制剂可起到特效的作用。 这一技术在本发 明人早期的 1990年申请中国专利 (ZL 90106365.7) 中给予报导。 具体的脂溶性斑蝥 酸肝制剂的制备主要采用下列步骤:
1. 首先用有机溶剂, 例如丙酮、 二氯甲烷、 三氯甲烷、 乙醚等浸渍斑蝥粉, 将 斑蝥中的斑蝥油和斑蝥酸酐的成份抽提到有机相;
2- 经过有机溶剂抽提过的斑蝥粉干燥后, 再用浓盐酸和丙酮溶液进行浸渍, 浓 盐酸可将斑蝥酸盐转化成斑蝥酸酐, 丙酮可将斑蝥酸酐溶解进有机相;
3. 将上述有机相中斑蝥酸酐和斑蝥油从该有机相分离出后, 加入石油醚, 将斑 蝥油抽提出, 而使斑蝥酸酐与斑蝥油分离, 得到的斑蝥酸酐与上述 2分离的斑蝥酸酐 合并。
4.在精制油脂中加入一定量斑蝥油并按计量加入斑蝥酸酐,在 80— 120°C温度下, 常压搅拌下加热, 制得脂溶性斑蝥酸酐中间制剂。
上述精制油脂可采用豆油、 玉米油、菜籽油、 葵花籽油、 麻油、 可可脂等植物油, 也可采用羊毛脂牛脂等。
上述专利技术的含斑蝥酸酐脂溶剂的药物有优良适用价值, 但是, 不足之处是药 剂品种适用范围受脂溶剂药剂性质的限制, 比如脂溶剂制成注射剂, 其制剂工艺及临 床运用都不够简便易行。
另一方面, 在昆虫斑蝥等虫体中, 作为有效成分斑蝥酸酐中, 有约三分之一是以 斑蝥酸镁的盐类形式存在, 因此在传统中药中, 运用斑蝥虫体作为内服药, 其药效也 包括斑蝥酸镁的作用。 斑蝥酸盐较易溶于水, 制成药剂工艺和应用都有简便宜行的一 面。 但是从斑蝥虫体中直接提取并制成纯品的斑蝥酸镁等斑蝥酸盐, 提纯方法复杂, 收率低, 远远没有先提纯斑蝥酸酐, 然后再半合成制成纯品斑蝥酸盐的方法简便、 节 省、 易行、 适用。 天然虫体中含有斑蝥酸镁等斑蝥酸盐, 说明这种的斑蝥酸盐, 在活 体的斑蝥虫体中, 发挥其生物学抗生作用, 并且与斑蝥酸酐比较, 有其易溶于其体液 的优点, 因此斑蝥酸盐, 比斑蝥酸酐是有其特长的抗菌抗病毒药物。
另外, 含斑蝥酸盐的抗病毒制剂 (药剂), 使用方便, 且对多种重要细菌和多种 病毒具有的抗生作用, 有宽广的医疗预防实践的适用性, 数种斑蝥酸盐制成的药剂, 有相似于脂溶剂斑蝥酸酐的抗病毒药效。 而斑蝥酸盐的制剂, 在某些治疗和预防疾病 的领域, 填补了脂溶剂斑蝥酸酐药剂无法应用的制剂的空白。
上述这一种技术在本发明人的另一专利中 (ZL931101573 ) 给予详细的报导。 但 是斑蝥酸盐的药剂制备工艺较繁、 对设备要求较高, 因此, 制备成本较高。
另外, 如上所述, 虽然斑蝥酸酐具有抗病毒作用, 但是, 尚没有斑蝥酸酐具有抗 结核杆菌等细菌的抗菌作用的报导。 发明内容
本发明的目的是提供一种抗病毒、 抗菌的药物组合物。 这种药物组合物对结核杆 菌、 葡萄球菌、 肝炎病毒、 艾滋病毒、 流感病毒以及轮状病毒等病原微生物具有非常 优异的抗菌和抗病毒作用。 另外, 本发明也提供一种用于局部使用的抗病毒、 抗菌的 药物组合物。 含有这种药物组合物的各种局部用制剂可广泛用于各种消毒和作为卫生 保健用品。
本发明的另一目的是提供上述药物组合物的制备方法。
为了实现上述目的, 本发明的一种抗病毒、 抗菌的斑蝥酸酐药物组合物, 含有斑 蝥酸酐作为有效药物成分, 其特征在于所述斑蝥酸酐为溶解于精油的斑蝥酸酐精油制 剂, 将该斑蝥酸酐精油制剂与可药用载体或赋形剂配制而成, 并且该斑蝥酸酐精油制 剂中含有斑蝥酸酐的重量为 0.05 %— 0.7%。
另外, 本发明上述抗病毒、 抗菌的斑蝥酸酐药物组合物可以用于作局部使用的药 物, SP, 将该斑蝥酸酐精油制剂与可药用载体或赋形剂配制而成, 并且该斑蝥酸酐精 油制剂中含有斑蝥酸酐的量为 0.05 %— 0.7%。
还有, 本发明的斑蝥酸酐精油药物组合物, 对抗结核杆菌等细菌及多种病毒具有 特别良好的抗菌抗病毒药效。
在本发明的药物组合物, 作为药物的有效成分是采用斑蝥酸酐精油制剂, 其主要 原因在于斑蝥酸酐在精油中有较高的溶解度,例如,斑蝥酸酐在水中的溶解度约为 0.003 %, 在油脂中的溶解度能达到 0.05%, 而在精油中可达到 0.7%, §Ρ, 精油中斑蝥酸酐 的浓度可以为油脂中的 14倍, 而为水中的 200多倍。
精油, 又称香精油、 挥发油或芳香油。 具有一定香气并有挥发性的植物性油状液 体。 是植物的花、 叶、 茎、 根或全草经蒸镏而得的产品。 也可用压榨、 提取或吸附等 方法制得。 其品种很多。 主要成分是萜烯烃类、 芳香烃类、 醇类、 醒类、 酮类、 醚类、 酯类和酚类等。 例如肉桂油, 含 85— 90%肉桂醛, 少量肉桂酸、 苯甲酸及香豆素等, 具甜辛香味, 类似桂醛, 稍带木香香韵, 用于食品。 香茅油, 主要成分是香茅醛(35
—50% )和香叶醇 (35-45 % ), 香气甜美、 圆厚, 稍带柠檬香, 广泛用于皂类及家庭 用品的加香。 精油能溶于乙醇等有机溶剂, 大多数不溶或微溶于水。
因此, 在本发明中利用精油的上述特点, 1.对斑蝥酸酐有较高的溶解性, 可提高 药物组合物中有效成分的含量; 2.精油大多可食用, 即本发明釆用常用可食用的精油, 对人体无任何副作用; 3.精油能溶于乙醇、 甘油等醇类, 而乙醇或甘油又能溶于水, 因此可将斑蝥酸酐精油制剂, 配制成溶水性局部使用药物组合物, 能有效地发挥斑蝥 酸酐的抗病毒、 抗菌的功效。 另外, 在本发明中采用沸点高于 100°C, 而最好高于 160°C的精油, 主要是在配 制斑蝥酸酐精油制剂时, 最好在加热条件下进行。 所以沸点较高的精油在制备中不易 挥发。 当配制斑蝥酸酐精油制剂在较低, 例如 50— 100Ό时, 只要精袖的沸点高于 100 °C都可有效地应用。 因此, 在本发明中, 大多数常用的食用精油都可用于配制斑蝥酸 酐精油制剂。
本发明提供的抗病毒、 抗菌的药物组合物的制备方法, 按下述步骤:
( 1 )在精制精油中按计量加入斑蝥酸酐, 于 40— 160°C温度下, 常压下搅拌使斑 蝥酸酐溶解于精油制得斑蝥酸酐精油制剂;
(2) 把所制斑蝥酸酐精油制剂与可药用载体或赋形剂按计量混合, 搅拌均匀调 制成药物组合物。
另外, 在本发明中所用斑蝥酸酐的制备方法, 可按照上述专利 90106365所釆用 的方法制备。 具体地说, 斑蝥酸酐的制备包括-
( 1 )用有机溶剂浸渍斑蝥粉, 把斑蝥中有效成分提取到有机相;
(2) 经过有机溶剂抽提过的斑蝥粉干燥后, 再用浓盐酸和有机溶剂进行浸渍, 浓盐酸可将斑蝥酸盐转化成斑蝥酸酐, 有机溶剂可将斑蝥酸酐溶解进有机相;
(3 )将上述有机相中斑蝥酸酐和斑蝥油从该有机相分离出后, 加入石油醚, 将 斑蝥油抽提出, 而使斑蝥酸酐与斑蝥油分离, 得到的斑蝥酸酐与上述(2)分离的斑蝥 酸酐合并。
另外, 在上述制备斑蝥酸酐中, 所述的制备方法, 其特征在于所述有机溶剂釆用 丙酮、 二氯甲垸、 三氯甲烷或乙醚。
并且, 为了避免斑蝥虫中有效成分的挥发, 斑蝥粉是在低于 55Ό条件下粉碎和干 燥斑蝥虫制得的。
在上述制备的斑蝥酸酐精油制剂中, 可按常规药物组合物的配制方法, 加入可药 用载体或赋形剂即可配制成本发明的各种抗病毒、 抗菌的药物组合物。 对于上述可药 用载体或赋形剂均可按所制药物组合物的剂型, 参照常规制药工艺进行, 本发明对此 并无任何特别地限定。
本发明人对斑蝥酸酐的抗病毒、 抗菌作用作了大量的研究发现含 O.Olppm斑蝥酸 酐浓度的培养基已可完全灭活结核杆菌和葡萄球菌等病菌 (斑蝥酸酐最低灭活病毒浓 度为 0.000132ppm), 有资料报道对结核菌最低抑菌浓度链霉素为 10ppm、 利福平为 25ppm, 上述试验说明斑蝥酸酐对结核杆菌、 葡萄球菌等有更强的抗菌作用, 有临床 试用价值。
多年来应用本发明精油溶性斑蝥酸酐制剂, 治疗肺结核和结核性胸膜炎, 取得显 著优于雷米丰、 链霉素、 利福平等抗结核药联合应用的临床疗效。 而且没有利福平等 抗结核药的肝和造血系统毒副反应, 比其他抗结核药自觉症状和血沉等恢复正常的速 度快一倍。 .
另外, 细菌性结膜炎常用氯霉素眼药水、 红霉素眼药膏。 但应用本发明精油溶性 眼药水、 眼药膏 (含斑蝥酸酐 3— 6ppm)有效率 99% , 用药后 1一 2小时症状减轻 1— 3天治愈, 疗效显著优于红霉素、 氯霉素等抗菌眼药膏、 眼药水。
还有, 应用本发明精油溶性斑蝥酸酐乳膏涂在疖上 2— 3小时止痛, 多数疖肿 2— 3天消退。
临床试验证明, 用精油溶性斑蝥酸酐制剂制成的斑蝥酸酐药物组合物, 临床药效 显著提高, 而且由于药剂的量可减少, 使用方便, 可达到安全无不良反应的特效应用。
另外, 本发明把精油当作斑蝥酸酐的溶剂, 其精油用量不大, 选择无毒副反应的 精油, 制成的制剂不因添加精油而出现不良反应。 例如薄荷油、 薄荷素油, 食品添加 剂规定 "用量以生产需要为限", 本发明制剂中常用的甜橙油、 留兰香油、 香芹酮、 柠 檬烯等的剂量, 远低于联合国食品法规委员会规定的食品添加剂的剂量。
多数精油比油脂更容易在皮肤吸收, 用精油作溶剂使药剂渗透性增强而提高斑蝥 酸酐的生物利用度, 而精油溶性药剂也易渗入细菌病毒的外膜内, 而提髙斑蝥酸酐的 药效。 精油有的经肺排出体外, 有利于提高斑蝥酸酐治疗肺结核药剂药效的发挥。 多 种精油易溶于植物油, 可与植物油共同制成特别有效的乳膏软膏。 有的精油易溶于甘 油, 斑蝥酸酐先溶于精油中, 然后与甘油等制成性器官应用的制剂, 成为控制乙丙肝 病毒艾滋病毒性传染的优良制剂。
下面通过实施例对本发明的技术给予进一步详细的说明, 当然本发明不限于这些 实施例。 具体实施方式
实施例 1斑蝥酸酐精油制剂的制备
本发明斑蝥酸酐精油制剂, 可按本发明人早期公开的技术进行 (专利申请号 91110970.6)。 具体制备过程如下:
( 1 )在粉碎器内将斑蝥在低于 55°C条件下进行干燥粉碎, 得到干燥的斑蝥粉; (2)斑蝥粉进入浸提罐, 用有机溶剂, 例如丙酮进行浸渍, 浸泡 24小时以上并 反复多次渗滤, 分离出有机相进入第 1分离器, 固相进入浸提罐;
(3 ) 固相斑蝥粉渣进入浸提罐, 用浓盐酸和丙酮溶液浸渍斑蝥粉渣, 浸渍时间 在 24小时以上, 并用丙酮反复多次渗滤, 分离出有机相进入第 2分离器, 残渣排出;
(4)在第 1分离器内, 将上述(2) 的有机相中斑蝥酸酐及斑蝥油从有机溶剂丙 酮中分离, 丙酮回收, 斑蝥酸酐及斑蝥油进入第 3分离器;
(5)在第 3 分离器内, 加入石油醚, 可将斑蝥油溶解, 在该分离器中, 将斑蝥 酸酐与斑蝥油分离, 斑蝥油排出, 斑蝥酸酐进入精制罐内;
(6)在第 2分离器内将有机相与无机相 (没反应的浓盐酸及反应后生成的盐) 分离, 无机相排出后, 再将有机溶剂丙酮与斑蝥酸酐分离、 斑蝥酸酐进入精制罐内;
(7)在精制罐内, 将斑蝥酸酐反复用石油醚清洗, 然后用丙酮、 乙醇等溶剂反 复加热溶解, 冷却结晶, 可得到斑蝥酸酐结晶。 最后再对结晶体用适量丙酮反复加温 溶解, 冷却结晶二次以上, 即可得到纯晶体(含斑蝥酸酐 99%以上)。 该晶体进入制剂 釜;
(8)将精油例如甜橙油、薄荷素油、留兰香油;单体精油例如柠檬)希、香芹酮…… 进行精制灭菌, 精制后的精油进入制剂釜;
(9)在制剂釜内, 将斑蝥酸酐和精油按一定比例投入后在 40— 180Ό温度下, 常 压搅拌下加热则可使斑蝥酸酐溶解在精油中, 当温度达到 90Ό左右时, 斑蝥酸酐在精 油中可被迅速溶解, 再提高温度其溶解速度, 已不能随温度的增加而显著加快。 在生 产过程中, 最佳的加热溶解温度是 88— 98°C, 在 30分钟内可完成溶解过程。 经过上 述 ( 1 ) - (9) 的制备过程即得含有斑蝥酸酐 0.26— 0.7%的精油溶解的斑蝥酸酐精油 制剂。
上述过程制备的斑蝥酸酐精油制剂, 按一定比例加入其它辅料(载体或赋形剂) 可制备成各种斑蝥酸酐药物组合物。 制备过程在制药釜中进行, 制备条件和过程通过 下述实施例给予进一步说明。
实施例 2斑蝥酸酐乳膏的制备
斑蝥酸酐乳膏按下列成份:
斑蝥酸酐 0.15—0.25g
精油 40— 50g
植物油 15— 20g 其它软膏基质(硬脂酸、 硬脂醇、 鲸蜡醇、 蜂蜡、 氯化植物油单硬脂酸甘油脂等) 15— 25g
乳化剂 (吐温、 司盘、 乳百灵、 平平加 0或豆磷脂) 6-20g
抑菌剂 适量
其余蒸馏水 总量 250g
在制药釜内, 将乳化剂, 蒸馏水制成乳化剂分散液, 其它软膏基质熔于上述实施 例 1制备的斑蝥酸酐精油制剂中, 在 60— 80°C下胶体磨研磨成乳状物, 冷至室温。 即 实施例 3斑蝥酸酐肠溶衣片的制备
斑蝥酸酐肠溶衣片按下列成份:
斑蝥酸酐 0.06— O.lg
精油 20— 30g
植物油 8— 10g
抗氧剂 0.06— 0.09g
其他辅料 适量
300g (1000片)
在制药釜中, 加入一定量辅料搅拌均勾先制成辅料片剂, 然后按上述实施例 1制 备的斑蝥酸酐精油制剂在 40~60°C温度下, 均匀渗入片剂中、 包衣, 即得。
实施例 4斑蝥酸野静脉注射乳剂的制备
斑蝥酸酐静脉注射用乳剂按下列成份- 纯品斑蝥酸酐 0.08— O.lg
精制单体精油 (例如, 柠檬稀) 16— 20g
精制植物油 80— 100g
乳化剂 (注射用豆磷脂或其乳化剂) 6— 12g
丙三醇 0— 20g
其余为注射用水 总量 1000ml
在制药釜中将一定量注射用水, 乳化剂, 甘油在氮气流下制成豆磷脂分散液, 将 上述实施例 1 制备的斑蝥酸酐精油制剂, 投入用胶体磨和乳匀机, 制成高度均匀, 充 分乳化的乳剂, 再经灭菌处理, 得注射乳剂, 注射乳剂制备过程, 在氮气流中运行。
实施例 5斑蝥酸酐滴丸的制备 斑蝥酸酐滴丸按下列成份:
斑蝥酸酐 0.06— O.lg
精油 22— 32g
植物油 10— 12g
抗氧剂 0.06— 0.09g
其他辅料 适量
总量 300g ( 1000丸)
在制药釜中投入植物油和其他辅助, 然后投入上述实施例 1制备的斑蝥酸酐精油 制剂, 在 66— 76°C搅拌 30— 60分钟, 制成滴丸油液。 然后用滴丸机滴制成胶丸干燥 分装即得。
除实施例 1-5之外, 用上述实施例 1制成的斑蝥酸 If精油制剂, 还可制备成- 斑蝥酸酐注射液、 涂膜剂、 涂抹剂、 贴片、 橡皮硬膏、 口服乳液、 胶囊、 肠溶胶囊、 软胶囊、 胶丸、 密丸等。
此外, 上述实施例 1制备的斑蝥酸酐精油制剂, 也可制成局部药效的治疗和预防 细菌、 病毒性疾病的卫生消毒药剂, 例如可制成-
1. 斑蝥酸酐软膏
其组成为- 斑蝥酸酐 0.0003— 0.03g
精油 6— 12g
油脂 460— 520g
其它软膏基质(例如十八酸十八醇蜂蜡) 适量
抗氧剂 0.2— 8g
制成 600g
在制药釜内加入灭菌油脂、 其它软膏基质, 将上述实施例 1制备的斑蝥酸酑精油 制剂投入制药釜内, 保持温度在 66— 76Ό不断搅拌 1一 2小时, 使完全均匀, 滤去残 渣降至室温分装即得。 其抗菌抗病毒效果突出, 可完全防止烧伤、 外伤和外科缝合创 口的感染, 并且止痛效果优良, 二度浇伤涂后 30分钟就可完全止痛。
2. 斑蝥酸酐眼膏
其组成为:
斑蝥酸酐 0.0002— 0.02g 精油 2— 8g
油脂 460— 520g
其它基质(例如羊毛脂、 蜂蜡、 液状石蜡) 适量
抗氧剂 0.1— 8g
制成 600g
将上述实施例 1制备的斑蝥酸酐精油制剂, 投入灭菌油脂和其它基质中, 在制药 釜内, 用上述制软膏同样方法制成眼膏, 该种眼膏治疗结膜的细菌和病毒感染的疗效, 特别突出的优于现有各种抗菌抗病毒眼药。
3. 斑蝥酸酐爽洁露
其组成为- 斑蝥酸酐 0.0003— 0.03g
精油 3— 9g
抗氧剂 0.1— 0.9g
甘油 (也可全部或部分应用丙二醇、 山梨醇、 聚乙二醇)适量
其他辅料香料 适量
蒸馏水 适量
制成 900g
在制药釜内加入甘油、 其他辅料, 再将上述实施例 1制备的斑蝥酸酐精油制剂, 投入制剂釜 10内, 在 66— 76°C温度条件搅拌 30— 60分钟, 然后投入蒸熘水、 香料, 66— 76°C温度条件下再搅拌 10~20分钟, 冷后成为略粘稠液状, 即得爽洁露。 该制剂 用于性器官可完全灭活其艾滋病毒、 乙丙肝病毒、 多种病菌, 使人爽洁畅快, 又可预 防上述病原微生物的性传染。 由于该药剂的斑蝥酸酐药物浓度已超过最低灭活病毒浓 度万倍以上, 又对人体器官毫无不良作用, 因而是一种十分理想的性传染病预防药剂。
4. 斑蝥酸酐护肤消毒湿巾
其药液组成为:
斑蝥酸酐 0.00036— 0.036g
精油 (例如 β苯乙醇) 3.6— 9.6g
抗氧剂 2— 12g
甘油 适量
其他辅料、 香料 适量 蒸馏水、 护肤中药液 适量
制成 900g
在制剂釜中投入甘油、 其他辅料, 然后投入上述实施例 1制备的斑蝥酸酐精油制 剂, 保持 66— 76Ό搅拌 30— 60分钟。 投入蒸馏水、 香料, 在 66— 76 °C搅拌 10— 20分 钟即得护肤消毒湿巾药液。
将湿巾药液按重量比例浸湿湿巾纸, 再将浸过药液的湿巾纸用小塑袋封装即得。 这种湿巾的斑蝥酸酐药物浓度, 在水份蒸发后可达到斑蝥酸酐最低灭活病毒浓度 的 3万倍以上, 可杀灭皮肤以及皮肤表浅创口上的病毒和细菌, 也同时达到润肤护肤 清洁皮肤的作用, 在旅游或野外, 可用本消毒湿巾擦洗脸手, 遇有外伤也可用该巾应 急包盖伤口, 该湿巾是飞机、 火车上十分理想的旅行卫生保健用品。
运用相似于上述方法, 还可制成精油溶性的橡皮膏、 气雾剂、 目艮药油、 烧伤药油、 烧伤喷剂、 消毒喷剂、 栓剂、 滴眼液、 滴耳液、 滴鼻液、 口腔消毒液等精油溶性斑蝥 酸酐局部药效的制剂。
实施例 6斑蝥酸酐精油制剂制成的斑蝥酸酐药物组合物, 进行的结核杆菌、 肝炎 病毒感染疾病的治疗实验
结核病的疗程, 国内卫生行政部门现在已将结核病用雷米丰等药联合应用的 "化 疗"疗程延长到 "标准化疗"为 18— 24个月, "短程化疗"为 6— 9个月。 说明目前抗 结核药的疗效已经下降, 而必须长期治疗, 上述长期联合用药毒副反应率已达 70— 80 %。 患者在 1一 2年用药期, 主要因毒付反应无法参加家庭和社会劳动。 但是利用本发 明斑蝥酸酐精油为主要辅料的药剂的大量临床实验, 已证明其疗效理想。 例如用上述 实施例 2 的药剂治疗结核性胸膜炎, 其胸水的不抽水自行吸收速度, 体温、 血沉降至 正常的速度都显著的快于雷米丰、 链霉素利福平联用的疗效速度、 而且无毒副反应。 具体临床实验按下述过程进行。
1. X寸对照组(I) 的肺结核患者, 使用常规雷米丰、 链霉素利福平进行联合治疗, 连续用药 180天, 观察临床治疗效果。
2. 对对照组 (Π) 的肺结核患者, 使用脂溶性斑蝥酸酐乳膏 (制备过程参照实施 例 2, 在制备中用油脂代替精油, 并使投入药剂的斑蝥酸酐含有量与下述治疗组相同), 连续用药 90天, 观察临床治疗效果。
3. 对治疗组的肺结核患者, 使用实施例 2所制乳膏, 连续用药 90天, 观察临床 治疗效果。 另外, 对对照组 (π)及治疗组均采用乳膏涂抹患者胸部和背部, 每日三次, 每 次用药 2g。 上述三种疗法用药的结果如下表 1至表 3所示。 三种疗法治疗浸润型肺结核疗效对比表
Figure imgf000012_0001
三种疗法治疗结核性胸膜炎疗效对比表
项目 病 食欲不振乏力 体温血沉 不抽积液 不抽积液 CT 备注 例 等症状消失时 降至正常 CT 或超 或超声波 X 数 间 时间 声波见胸 光确诊胸液 分组 (平均天) (平均天) 液减少 全吸收
(平均天) (平均天)
对照组 (I) 30 因药物毒副反 59.6 42.3 66.6 连续用药 应此二种症状 90天 用 60%以上的
人不恢复
对照组 (Π) 20 13.2 24.6 24.6 38.2 连续用药
90天 治疗组 22 9.9 14.6 14.6 31.6 连续用药
90天 表 3 治疗浸润型肺结核、 结核性胸膜炎、 三种疗法三个月用药期间毒副反应发生率对 比表
Figure imgf000013_0001
另外, 又用本发明的药物组合物对肝炎, 特别是甲戊肝、 乙丙肝的疗效进行临床 实施。 实验同样由三组同时进行。
1. 对照组(1),·采用传统中药煎剂进行治疗。
2. 对照组(Π), 采用脂溶性斑蝥酸酐乳膏进行治疗。
3. 治疗组, 采用实施例 2所制斑蝥酸酐乳膏进行治疗。
在上述对照组 (Π)及治疗组, 如上述治疗结核病患者相同, 采用等量的斑蝥酸 酐有效剂量, 给药方法也相同, 对三组的治疗结果列于表 4。 表 4 脂溶性斑蝥酸野乳膏、 精油溶解的斑蝥酸酐乳膏治疗急性甲戊肝、 乙丙肝的疗效 对比表
项目 食欲不振压油乏力等 症状完全 化验 GPT 病例 症状显著好转 消失 ALT黄疽恢 分组 (平均天) (平均天) 复正常
(平均天)
对照组 (I) 甲戊肝组 6.8 31.8 36.3 16 乙丙肝组 21.2 38.6 56.6 20 对照组 (II) 甲戊肝组 3.6 12.6 21.1 20 乙丙肝组 11.2 22.3 32.3 22 治疗组 甲戊肝组 2.6 10.8 16.2 26 乙丙肝组 8.3 19.6 28.2 26 另外, 表 5列出分别用脂溶性斑蝥酸酐眼药油及本发明所制精油辅料的斑蝥酸酐 眼药油, 治疗流行性急性病毒性结膜炎一红眼病的临床实验结果。 表 5 脂溶性斑蝥酸酐眼药油、 精油溶解的斑蝥酸酐眼药油治疗急性病毒性结膜炎疗效 对比表
Figure imgf000014_0001
实施例 7斑蝥酸酐精油制剂进行的 "利用组织培养技术"实施的斑蝥酸酐抗病毒实 斑蝥酸酐抗病毒试液
其组成为
斑蝥酸酐 O.lg
精油 (与甘油完全互溶的品种) 30g
甘油 适量
蒸馏水 适量
制成 1000g 本斑蝥酸酐精油溶解的抗病毒试液含斑蝥酸酐为 lOOppm, 按组织培养技术方案的 要求需要各组不同药物浓度培养再用水将上述抗病毒试液用水进行稀释用该抗病毒试 液试验的为实验组; 用水直接溶解并稀释斑蝥酸酐的试验组为对照组, 实验结果如下 表 6。 表 6斑蝥酸酐精油溶制剂与斑蝥酸酑水溶液 8种病毒抗病毒实验对照表
Figure imgf000015_0001
由上述大量的临床实验结果可以看到, 本发明的斑蝥酸酐药物组合物具有对病毒 性或病菌性疾病良好的广谱抗病毒性和抗病菌性。 特别是对治疗结核病及病毒性肝炎、 病毒性肠炎等有十分良好的治疗效果。

Claims

权 利 要 求
1. 一种抗病毒、 抗菌的斑蝥酸酐药物组合物, 含有斑蝥酸酐作为有效药物成分, 其特征在于所述斑蝥酸酐为溶解于精油或单体精油的斑蝥酸酐精油制剂, 将该斑蝥酸 酐精油制剂与可药用载体或赋形剂配制而成, 并且该斑蝥酸酐精油制剂中含有斑蝥酸 酐的重量为 0.05%— 0.7%。
2. 一种外用局部使用的抗病毒、 抗菌的斑蝥酸酐药物组合物, 含有斑蝥酸酐作 为有效药物成分, 其特征在于所述斑蝥酸酐为溶解于精油或单体精油的斑蝥酸酐精油 制剂, 将该斑蝥酸酐精油制剂与可药用载体或赋形剂配制而成, .并且该斑蝥酸酐精油 制剂中含有斑蝥酸酐的重量为 0.05 %— 0.7%。
3. —种抗结核杆菌的斑蝥酸酐药物组合物, 其特征在于含有斑蝥酸酐作为有效 药物成分, 所述斑蝥酸酐为溶解于精油或单体精油的斑蝥酸酐精油制剂, 将该斑蝥酸 酐精油制剂与可药用载体或赋形剂配制而成, 并且该斑蝥酸酐精油制剂中含有斑蝥酸 酐的重量为 0.05%— 0.7%。
4. 一种抗肝炎病毒、 肠炎病毒的斑蝥酸酐药物组合物, 其特征在于含有斑蝥酸 酐作为有效药物成分, 所述斑蝥酸酐为溶解于精油或单体精油的斑蝥酸酐精油制剂, 将该斑蝥酸酐精油制剂与可药用载体或赋形剂配制而成, 并且该斑蝥酸酐精油制剂中 含有斑蝥酸酐的重量为 0.05 %— 0.7%。
5. 根据权利要求 1一 4所述的斑蝥酸酐药物组合物, 其特征在于所述精油为沸点 100°C以上的可食用精油或单体精油。
6. 一种权利要求 1一 4所述的斑蝥酸酐药物组合物的制备方法, 按下述步骤:
( 1 )在精制精油或单体精油中按计量加入斑蝥酸酐, 于 40— 160Ό温度下, 常压 下搅拌使斑蝥酸酐溶解于精油制得斑蝥酸酐精油制剂;
(2)把所制斑蝥酸酐精油制剂与可药用载体或赋形剂按计量混合, 搅拌均匀调 制成药物组合物。
7. 根据权利要求 6所述的制备方法, 其特征在于所述的斑蝥酸酐按下述步骤制 .
( 1 )用有机溶剂浸渍斑蝥粉, 把斑蝥中有效成分提取到有机相;
(2)经过有机溶剂抽提过的斑蝥粉干燥后, 再用浓盐酸和有机溶剂进行浸渍, 浓盐酸可将斑蝥酸盐转化成斑蝥酸酐, 有机溶剂可将斑蝥酸酐溶解进有机相; (3 ) 将上述有机相中斑蝥酸酐和斑蝥油从该有机相分离出后, 加入石油醚, 将 斑蝥油抽提出, 而使斑蝥酸酐与斑蝥油分离, 得到的斑蝥酸酐与上述 (2) 分离的斑蝥 酸酐合并。
8. 根据权利要求 7所述的制备方法, 其特征在于所述有机溶剂采用丙酮、 二氯 甲垸、 三氯甲烷或乙醚。
9. 根据权利要求 7所述的制备方法, 其特征在于斑蝥粉是在低于 55Ό条件下粉 碎和干燥斑蝥虫制得的。
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