EP0427781A1 - Ozonides de terpenes et leurs applications medicales - Google Patents

Ozonides de terpenes et leurs applications medicales

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Publication number
EP0427781A1
EP0427781A1 EP89909317A EP89909317A EP0427781A1 EP 0427781 A1 EP0427781 A1 EP 0427781A1 EP 89909317 A EP89909317 A EP 89909317A EP 89909317 A EP89909317 A EP 89909317A EP 0427781 A1 EP0427781 A1 EP 0427781A1
Authority
EP
European Patent Office
Prior art keywords
terpene
ozonide
ozonides
medicament
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP89909317A
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German (de)
English (en)
Other versions
EP0427781A4 (en
Inventor
Stephen Herman
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Individual
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Individual
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Publication date
Application filed by Individual filed Critical Individual
Publication of EP0427781A1 publication Critical patent/EP0427781A1/fr
Publication of EP0427781A4 publication Critical patent/EP0427781A4/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C07D323/02—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to ozonides of terpene hydrocarbons. More particularly, it relates to formation of terpene trioxyacyclopentanes and pharmaceutical preparations including these compounds for treating or preventing medical conditions. It also relates to methods for preparing certain ozonized terpenes, and to the ozonides prepared by those methods. Procedures for preparing ozonides of oil-soluble compounds are known in the art, being disclosed, for example, in U.S. patent No. 925,590 to Neel, U.S. Patent No. 2,083,572 to McKee, and U.S. Patent No. 4,451,480 to De Villez.
  • Neel discloses the use of ozonides of terpenes and other ozonides for inhalation therapy, because it was believed to have a therapeutic effect for consumption and asthma. No specific terpene ozonides are disclosed. Although the Neel patent application was filed in 1902, ther-e have apparently been no supporting data reported in the intervening years that corroborate the utility theorized by Neel. Knox, U.S. Patent No. 1,210,949 discloses ozonation of castor oil in order to produce a laxative. Ozonation of the oil was believed to reduce its toxicity and create a germicidal effect.
  • Chicken pox (Herpes zoster) is a common childhood disease, for which no vaccine is currently known. Lesions of chicken pox cause itching, and may lead to permanent disfigurement, if scratched. Since the disease strikes mainly children, who are unable to resist scratching, the need exists for compositions that can anti-pruritically treat chicken pox lesions to minimize disfigurement caused by the disease.
  • External fungal infections such as athletes foot and onychomycosis (fungal infections of the nails) , afflict a large portion of the human population. Similar fungal infections afflict a large percentage of the animal population. Current treatments for external fungal infections are irritating to sensitive individuals, and not always effective.
  • onychomycosis is difficult to treat, and its incidence appears to be on the rise with the advent of acrylic and other adhesively-mounted artificial nails. Therefore, a need exists for a relatively non-irritating, effective treatment for these infections.
  • Indolent neoplasms of the skin also afflict a large portion of the human and animal population.
  • Current over-the-counter medications are not always effective, and the only effective therapy in some instances is to have the neoplasms frozen or burned off, necessitating a doctor's visit.
  • Steroidal medications are currently in widespread use to relieve the discomforts of bee stings, insect bites, and other der atoses, such as those caused by psoriasis and those caused by poison oak or poison ivy.
  • Sexually transmitted diseases including herpes, syphilis, gonorrhea and AIDS, are endemic in today's society.
  • Condoms are currently the most effective means of preventing the transmission of these diseases.
  • condoms are not 100% effective.
  • a terpene also known as an isoprenoid, is any of a class of products having a structural relationship to isoprene:
  • the ozonized terpenes contain up to 50% oxygen by weight.
  • the invention also provides methods for producing the terpene ozonides.
  • the terpene ozonides may be produced according to the equation:
  • the terpene ozonides may also be produced through inverse ozonolysis procedure described by Y.N. Yurev et al in J. Org. Chem. U.S.S.R. 2, 5 (1975).
  • the invention in addition, provides pharmaceutical compositions containing the above novel compounds and a pharmaceutically acceptable carrier.
  • these compositions are in dosage form comprising a clinically effective amount of the active compound.
  • the pharmaceutical composition is comprised of a compound of the invention in a stable emulsion for injection.
  • the pharmaceutical composition is comprised of a compound of the invention in a composition suitable for topical application.
  • the pharmaceutical composition is in the form of a vaginal cream, foam, or suppository.
  • the invention further, provides novel methods of treatment and prevention of a wide variety of medical conditions in humans and other mammals by the application of the above pharmaceutical compositions.
  • Topical application of compounds of the present invention has at least some effectiveness against a wide range of medical conditions. These include, but are not limited to use in treating acne; dermatitis; bacterial infections; fungal infections; viral infections, including those of the herpes type such as herpes simplex, chicken pox (herpes zoster) , and genital herpes; the treatment of insect and animal stings and dermatoses caused by poisonous plants and other irritants and allergens; and treatment of indolent neoplasms of the skin, such as warts or moles.
  • herpes type such as herpes simplex, chicken pox (herpes zoster) , and genital herpes
  • the treatment of insect and animal stings and dermatoses caused by poisonous plants and other irritants and allergens and treatment of indolent neoplasms of the skin, such as warts or moles.
  • Terpene hydrocarbons are also known as isoprenoids, because they may generally be constructed from isoprene units. Terpene hydrocarbons are usually exact multiples of C5H 8 . Terpenes are classified according to the number of isoprene units of which they are composed, as shown in Table 1. Table 1
  • examples of terpenes which may prove especially effective, when used in the method of the preferred embodiment, include limonene, citronella, alpha-carotene, beta-carotene , Vitamin A, linalool, linalyl acetate, and squalene.
  • Other compounds which are believed to make pharmacologically active terpene ozonides in accordance with the present invention include geraniol, limonene, alpha-pinene, loganin, cymene, farnesanes, eudesmanes, acoranes, cedranes, chamigranes, caryophyllanes, illudanes, humulenes, himachalenes, longifolanes, perhydroazulenes, quaianes, quaianolides, and germacranes- Still other compounds which are believed to make pharmacologically active terpene ozonides in accordance with the present invention include labdanes, clerodanes, abietic acid, phyllocladene, giberellins, ophiobolin A, re igeranic acid, gasgardic acid, lanosterol, euphol, oleanane, ursane, lupe
  • Ozonides of terpenes have three oxygen atoms replacing the double bonds at sites of unsaturation, creating a trioxyacyclopentane.
  • terpene ozonides In the preparation of terpene ozonides, the particular desired terpene starting material is first obtained. A large and representative number of such terpenes are disclosed in the literature and/or are commercially available. (Many terpenes are essential oils that have been isolated from various parts of plants or wood by steam distillation or extraction.)
  • ozone In the ozonide synthesis, ozone is passed through the terpene under conditions that provide for intimate contact between the terpene starting material and the ozone, such as thin film procedures, sparging, gas entrainment procedures, and the like. On a small scale, for example, the terpene is placed in a vented vessel, and ozone is sparged through the material until the reaction is complete.
  • the ozone may advantageously be generated with any of the commercially-available ozone generators.
  • Such devices include corona discharge tubes through which oxygen gas may be passed.
  • oxygen gas passing through an ozone generator will typically leave the device_ as from 2% to 6% O 3 (ozone), with the remainder O 2 .
  • This ozone mixture may then be sparged through the terpene at ambient temperature and pressure until the reaction is complete. Completion may be judged by analyzing the gas exiting the ozonation chamber for ozone.
  • reaction may be followed by observing the weight gain of the material undergoing the reaction, by observing changes in physical characteristics (such as conversion from a liquid form to a soft paste) , or by simply calculating the quantity of ozone needed to fully ozonate the material and stopping the reaction when a slight excess of ozone has passed through the reaction chamber. Because the reaction is exothermic, its progress may also be followed by monitoring the heat evolved by the reaction medium, and stopping the flow of ozone when the mixture ceases to generate heat.
  • the terpene When the terpene is normally a solid, such as ⁇ - carotene, it may be ' solubilized in any suitable saturated nonaqueous solvent system prior to ozonation. With all of the terpene ozonides, it is desirable to exclude water, lower alcohols, nucleophilic peroxides, and proton donors from the reaction mixture and from the final composition, in order to prevent premature hydrolysis of the trioxolane ring.
  • the compounds of the present invention are • formulated into pharmaceutical preparations.
  • These pharmaceutical preparations include one or more of the terpene ozonides of the present invention, and may further include other pharmaceutically active ingredients.
  • any of the well-known pharmaceutically-acceptable carriers or excipients may be combined with the compounds of the present invention in a well-known manner.
  • Suitable diluents include, for example, polyethylene glycol, isporopyl myristate, and mineral oil.
  • the pharmaceutical composition may be in any form suitable for topical use, such as an ointment, gel, or cream. Conventional coloring, fragrance and preserving agents may also be provided.
  • the excellent weight to oxygen ratio of some of the terpene ozonides renders them especially effective in treating many medical conditions.
  • the present invention is capable of releasing large amounts of oxygen, up to 30% of the weight of the compound. This is because terpenes are highly unsaturated compounds. Ozonization of these compounds results in the addition of three oxygen atoms at each site of unsaturation.
  • the terpene ozonides of the present invention appear to have significant unexpected pharmacological properties that are different in kind or quality from those of unrelated ozonides disclosed in the prior art.
  • the effective dosage of the compounds of .the present invention appears to be much lower than would be expected in light of the prior art, suggesting that the compounds have unexpectedly high efficacy. While the compounds may be used neat (and, indeed, some of them form pharmaceutically elegant creams or ointments, e.g., linalyl ozonide and linalool ozonide) , the effective concentration for most topical applications can be as little as 0.01%, by weight. However, the compositions more preferably contain from about 0.5% or 1% to about 10% or 20% by weight active ingredient. Topical compositions containing about 2% or 3% of active ingredient appear to be particularly effective.
  • compositions may similarly contain from about 0.01% to about 99% active ingredient, by weight.
  • Preferred systemic compositions contain from about 0.05% to about 20% active ingredient, by weight.
  • the toxicity of the terpene ozonides appears to be surprisingly low, in both topical and systemic use.
  • Our preliminary data suggest that the LD 50 for a representative compound, linalool ozonide, is about 3000 mg/kg in mice.
  • terpene ozonides of the present invention when applied topically in suitable pharmacological compositions, are effective for treatment of bacterial, viral, and fungal infections.
  • topical administration of the terpene ozonides of the present invention in a suitable composition having from about 0.1% to about 50% active ingredient by weight, preferably about 0.5% to about 20% by weight, is effective to minimize the extent and severity of Herpes simplex, genital herpes, and chicken pox lesions, when applied on incipient eruptions.
  • vaginal administration of a composition containing the terpene ozonides of the present invention, in a suitable vaginal carrier such as a suppository, cream, gel, or foam
  • a suitable vaginal carrier such as a suppository, cream, gel, or foam
  • topical administration of the terpene ozonides of the present invention in a suitable composition having from about 0.01% to about 99% or 100% active ingredient, by weight, preferably from about 0.1% to about 25% by weight, is effective in treating fungal infections of the skin and nails, such as athlete's foot and onychomycosis. Similar compositions appear to have a shrinking effect on indolent neoplasms, including warts and moles. Compositions having from about 0.01% to about 50% active ingredient, preferably about 0.1% to about 20%, are non-irritating to acne affected skin, and have exhibited a strong anti-comedonal effect when used topically on affected areas.
  • compositions deliver nascent oxygen to kill anaerobic bacteria such as P . acne when the ozonides undergo hydrolysis.
  • ozonolysis fragments such as ketones or carboxylic acids
  • topical application of the terpene ozonides of the present invention is effective in ameliorating the severity of sunburn and facilitating the healing process. Similar reduction of pain, inflammation, and blistering, and an increase in the speed of the healing process has been observed when the composition of the present invention is applied to first and second degree thermal burns on a mammal. Based on the demonstrated antiviral, antifungal, and antibacterial properties of the present compositions in vi tro , and the relatively non-irritating properties of the terpene ozonides, it is further believed that topical administration of the compounds of the present invention can decrease the probability of transmission of sexually transmitted diseases.
  • the previously described vaginal compositions may be used alone or in conjunction with a condom to decrease the risk of infection.
  • the active ingredient may further advantageously be formulated into a lubricating composition of known type.
  • topical administration of terpene ozonides in a topical preparation as previously described exhibits significant efficacy in the treatment of most dermatoses, including psoriasis and those dermatoses caused by bee stings, insect bites, poison plants such as poison oak, poison ivy, and stinging nettle, diaper rash, hives, and other reactions for which antihistamine or steroidal medications are commonly prescribed.
  • Administration of the ozonides of .the present invention in lieu of steroidal medications is sometimes equally effective; however, side effects are considerably reduced, making terpene ozonide therapy the more desirable treatment.
  • the invention contemplates combination therapy in some instances.
  • compositions of the present invention may further include an effective amount of an antihistamine or a corticosteroid.
  • an antihistamine or a corticosteroid are well known, and effective dosages for the various antihistamines and corticosteroids have been established.
  • the effective topical concentrations of these ingredients will generally be toward the lower end of the effective range in which they are presently used alone.
  • the present invention also includes systemic and localized injection of the compositions disclosed herein, including intravascular, intramuscular, subcutaneous, intraperitoneal, and other injection techniques. Such injection may be used for treatment of viral, -fungal, and bacterial infection. We have also discovered that localized injection of a terpene ozonide of the present invention into a tumor has an anti-neoplastic effect.
  • the present invention further includes other suitable pharmacological preparations of terpene ozonides including: medicinal douches, eardrops, eyedrops, throat sprays, dental preparations for topical sores, mouthwashes, armpit deodorants, disinfectant/germicidals, and contact lens sterilization solutions.
  • suitable pharmacological preparations of terpene ozonides including: medicinal douches, eardrops, eyedrops, throat sprays, dental preparations for topical sores, mouthwashes, armpit deodorants, disinfectant/germicidals, and contact lens sterilization solutions.
  • EXAMPLE 1 Preparation of squalene ozonide.
  • Squalene is ozonized by preparing a solution of 10 g squalene in 100 ml hexane. Ozone gas (4% in oxygen, from- a corona discharge ozone generator) , is bubbled through this solution via a glass sparger at the rate of 5000 cc/min. The reaction is exothermic, and the reaction temperature is kept within the range of 0°C to 35°C, preferably 20°C to 25°C, and more preferably, 22°C to 24°C, using a cool water bath. The resulting product is the ozonide of beta carotene, and has a 98% weight gain over squalene. EXAMPLE 2 - Preparation of linalool ozonide.
  • the ozonide of linalool is prepared by bubbling ozone (4% in oxygen, from a corona discharge ozone generator) through 100 ml neat linalool via a glass sparger.
  • the reaction is exothermic, and the reaction temperature is kept within the range of 0°C to 35 ⁇ C, preferably 20 ⁇ C to 25 ⁇ C, and more preferably, 22°C to 24°C, using a cool water bath.
  • the resulting product is the ozonide of linalool, and has a 31% weight gain over linalool.
  • EXAMPLE 3 Preparation of Linalyl Acetate Ozonide
  • the ozonide of linalyl acetate was prepared by bubbling ozone (4% in oxygen, from a corona discharge ozone generator) through 5 ml neat linanyl acetate at the rate of 5000 cc/min.
  • the reaction mixture was cooled in a water bath, and after 20 minutes, the evolution of heat ceased, indicating completion of the ozonation process.
  • the resulting material had no odor, and was soluble in polyethylene glycol, isopropyl myristate, and mineral oil.
  • EXAMPLE 4 A vaginal suppository for treatment of vaginitis
  • EXAMPLE 6 A topical cream effective against acne 2.5% w/v Ozonide of linalool
  • EXAMPLE 7 A lubricant for condoms effective against the transmission of STDs
  • EXAMPLE 8 An injectable composition effective against vervucae 25 mg/ml ozonide of linalyl acetate from Example 3 balance Polyethylene glycol m.w. 200
  • Example 5 The composition of Example 5 is applied topically to only a portion of the skin surface of a severely sunburned patient in a single application, two hours after the exposure to sunlight.
  • the treated area exhibits slight reddening, but no peeling or blistering. Only minor disco fort is apparent.
  • the untreated area in contrast, becomes red, blistered, and painful.
  • Example 5 The composition of Example 5 is topically applied to a portion of the lesions on a child suffering from chicken pox. Within 1 hour, the treated lesions are significantly reduced with little or no self-induced trauma from scratching. The untreated lesions are unchanged in size, and show the effects of trauma from scratching. EXAMPLE 11 - Test for efficacy of treatment of swollen joints
  • Patients at a sports medicine clinic complaining of swollen knees are divided into three groups: groups A, B and C.
  • the patients in group A receive an injection of the composition of Example 8 into the swollen knee.
  • the patients in group B receive an injection of a placebo, the composition without active ingredient.
  • the patients in group C receive an injection of a corticosteroidal medication.
  • Within 12 hours the swelling in the knees of the patients in group A is significantly reduced. No change is reported in the knees of # the patients of group B.
  • the swelling in the knees of the patients of group C is also reduced, however, a significant percentage of the patients suffer inflammatory reactions.
  • the suppository of Example 4 is administered intra-vaginally to one group of patients suffering from yeast infections of the vagina.
  • a second group of such patients receive a suppository without the active ingredient of Example 4.
  • a third group receives a suppository containing the drug clotrimazole, a commonly used drug for treatment of fungal infections of the vagina. Every 24 hours the process is repeated.
  • the patients of the first group have no reddening of the vagina and within 7 days, a yeast culture produces negative results.
  • the second group of patients continues to complain of itching and other common complaints of fungal infections.
  • a yeast assay is positive.
  • a yeast assay is negative; however, a number of these patients complain of irritation and in those patients, a significant reddening of the vagina is present.
  • a culture of E. coli was harvested with sterile saline using sterile swabs. The number of Colony Forming Units (CFUs) per ml in the suspension was determined by Standard Plate Count Method.
  • CFUs Colony Forming Units
  • a working suspension of E. coli with approximately 1.0 X 10 7 CFUs/0.1 ml was then prepared.
  • Four aliquots of 1 ml each of test ointment containing 1.0% ozonide of linalool were removed and placed in separate sterile screw-capped tubes. Each sample was inoculated with 0.1 ml of the working suspension of E. coli to yield a final concentration of approximately 1 X 10 6 CFUs/1 ml of the product.
  • Example 14 Primary skin irritation test of ozonide of linalool
  • test material residue was removed with 70% isopropyl alcohol. An evaluation was also made at 72 hours after application. The reactions were scored according to the methods described in the Federal Hazardous Substances Act.
  • the test solution had a Primary Irritation Index (PII) of 1.0. According to FHSA regulations, a material with a PII of less than 5.00 is generally not considered a primary irritant to the skin.
  • PII Primary Irritation Index
  • the eyes were examined with a pen light and re-examined with UV light following fluorescein staining of the cornea. Under the conditions of this test, the test solution was considered a non-irritant to ocular tissues of the rabbit.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Rheumatology (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

L'invention concerne des ozonides de terpènes dont on a découvert qu'ils sont pharmacologiquement actifs lorsqu'on les prépare selon la présente invention, ils comprennent: limonène, citronelle, alpha-carotène, bêta-carotène, vitamine A, linalol, linalyle acétate, ou squalène. D'autres composés dont on a découvert qu'ils constituent des ozonides de terpènes pharmacologiquement actifs selon la présente invention comprennent: géraniol, limonène, alpha-pinène, loganine, cymène, farnésanes, eudesmanes, acoranes, cédranes, chamigranes, caryophyllanes, illudanes, humulènes, himachalènes, longifolanes, perhydroazulènes, quaianes, quaianolides, ou germacranes. D'autres composés dont on a découvert qu'ils constituent aussi des ozonides de terpènes pharmacologiquement actifs selon la présente invention comprennent: labdanes, clérodanes, acide abiétique, phyllocladène, gibérellines, ophioboline A, acide rétigéranique, acide gasgardique, lanostérol, euphol, oléanane, ursane, lupéol, hydroxyhopanone, lupanes, ou hopanes. D'autres composés de terpènes particuliers dont on a découvert qu'ils constituent des ozonides de terpènes pharmacologiquement actifs, lorsqu'on les prépare selon la présente invention, comprennent: B-sélinène, zingibène, camphène, sabinène, ocimène, myrcène, nérol, citral A, citral B, farnésol, bisabolène, phytol, et hormone de cécropia. L'invention concerne aussi un procédé de production d'ozonides de terpènes. Elle concerne en outre des préparations pharmaceutiques utilisant ces compositions, ainsi que des procédés de traitement médical utilisant lesdites préparations pharmaceutiques.
EP19890909317 1988-06-24 1989-06-16 Ozonides of terpenes and their medical uses Pending EP0427781A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21137888A 1988-06-24 1988-06-24
US211378 1988-06-24

Publications (2)

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EP0427781A1 true EP0427781A1 (fr) 1991-05-22
EP0427781A4 EP0427781A4 (en) 1991-08-21

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EP (1) EP0427781A4 (fr)
JP (1) JPH04502145A (fr)
AU (1) AU4058689A (fr)
CA (1) CA1338083C (fr)
WO (1) WO1989012626A1 (fr)

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CA2566180A1 (fr) * 2004-05-10 2005-11-24 Robert F. Hofmann Utilisation d'une formulation therapeutique oxydative ciblee dans le traitement du cancer
JPWO2008001553A1 (ja) * 2006-06-28 2009-11-26 株式会社Ｅｒｃテクノロジー オゾン化界面活性剤
JP2011507969A (ja) * 2007-12-27 2011-03-10 タイラテック， インク． 相乗的抗寄生虫組成物とスクリーニング方法
KR101698051B1 (ko) * 2016-01-13 2017-01-20 아주대학교산학협력단 로가닌 또는 이의 유도체를 유효성분으로 함유하는 여성 갱년기 증후군 예방, 개선 또는 치료용 조성물
CN108210490A (zh) * 2018-04-10 2018-06-29 武汉大学 一种雌激素受体下调剂的应用

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Also Published As

Publication number Publication date
WO1989012626A1 (fr) 1989-12-28
EP0427781A4 (en) 1991-08-21
CA1338083C (fr) 1996-02-27
JPH04502145A (ja) 1992-04-16
AU4058689A (en) 1990-01-12

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