WO2024041083A1 - 一种抗真菌溶液及其制备方法和应用 - Google Patents

一种抗真菌溶液及其制备方法和应用 Download PDF

Info

Publication number
WO2024041083A1
WO2024041083A1 PCT/CN2023/098300 CN2023098300W WO2024041083A1 WO 2024041083 A1 WO2024041083 A1 WO 2024041083A1 CN 2023098300 W CN2023098300 W CN 2023098300W WO 2024041083 A1 WO2024041083 A1 WO 2024041083A1
Authority
WO
WIPO (PCT)
Prior art keywords
antifungal
ionic liquid
present
antifungal solution
preparation
Prior art date
Application number
PCT/CN2023/098300
Other languages
English (en)
French (fr)
Inventor
武喜营
朱全刚
陈中建
沈敏
台宗光
喻琴
戚建平
吴伟
Original Assignee
上海市皮肤病医院
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 上海市皮肤病医院 filed Critical 上海市皮肤病医院
Publication of WO2024041083A1 publication Critical patent/WO2024041083A1/zh

Links

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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to an antifungal solution and its preparation method and application.
  • Tinea dermatophytosis is a common superficial fungal infectious skin disease that is widespread around the world.
  • the most common pathogen of superficial fungal infection is dermatophytes, which have a high prevalence and are prone to recurrence (Yu et al., Mycoses 2020, 63, 1235-1243).
  • ringworm is not fatal, patients experience disproportionate itching, pain, and emotional distress, and their quality of life is significantly reduced.
  • Skin tinea can be treated with topical medications, oral medications, or a combination of both. Since systemic administration of some drugs can cause side effects such as pain, allergic reactions, and hepatotoxicity, topical administration is currently used clinically to treat diseases (Shirsand et al., Int J Pharm Investig 2012, 2, 201-207). In recent years, topical imidazole antifungal drugs that act on fungal cell membranes have made certain progress in the treatment of tinea pedis. Common products include miconazole cream, 2% ketoconazole cream, clotrimazole cream, Bifonazole cream, 1% luliconazole cream, etc.
  • the object of the present invention is to provide an antifungal solution and its preparation method and application.
  • the antifungal solution provided by the present invention can reduce the dosage of medicine and at the same time improve the therapeutic effect of tinea skin.
  • the invention provides an antifungal solution, and the preparation raw materials include antifungal drugs and solvents;
  • the mass ratio of the antifungal drug to the solvent is (0.1 ⁇ 1): (18 ⁇ 318);
  • the solvents include ionic liquids, alcoholic organic solvents and water.
  • the mass ratio of the ionic liquid, alcoholic organic solvent and water is (15 ⁇ 68): (3 ⁇ 30): (0.1 ⁇ 220).
  • the antifungal drugs include imidazole antifungal drugs.
  • the imidazole antifungal drug includes miconazole, ketoconazole, clotrimazole, bifonazole or luliconazole.
  • the ionic liquid includes choline ionic liquid.
  • the choline-based ionic liquid includes aromatic acid choline-based ionic liquid.
  • the alcoholic organic solvent includes one or more of ethanol, propylene glycol and polyethylene glycol.
  • the present invention also provides a method for preparing the antifungal solution described in the above technical solution, which is characterized in that it includes the following steps:
  • the mixture is mixed with water to obtain the antifungal solution.
  • the heating temperature is 60-90°C and the heating time is 1-2 hours.
  • the present invention also provides the use of the antifungal solution described in the above technical solution or the antifungal solution obtained by the preparation method described in the above technical solution in the preparation of antidermatophytes.
  • the invention provides an antifungal solution.
  • the preparation raw materials include antifungal drugs and solvents; the mass ratio of the antifungal drugs to the solvent is (0.1 ⁇ 1): (18 ⁇ 318); the solvent includes Ionic liquids, alcoholic organic solvents and water.
  • ionic liquids have superior solubility, skin penetration-promoting properties and antifungal effects; water can not only dissolve anions through hydrogen bonds, but also dissolve aromatic rings present in some cations, destroying the polarity of the original ionic liquids Network, forming smaller soluble ion groups, greatly increasing the miscibility window; alcoholic organic solvents can form latent solvents with ionic liquids and water, which helps miscibility.
  • the antifungal solution provided by the invention can ensure that the drugs in the system are maintained in a dissolved state, improves bioavailability, and can ensure better therapeutic effects at a reduced dose. According to the example data, it can be seen that the antifungal solution provided by the present invention has Reducing the dosage of antibacterial drugs simultaneously improves the therapeutic effect of skin tinea, reduces the recurrence rate, and overcomes the technical problem of high dosage of external imidazole antifungal drugs but unsatisfactory efficacy.
  • Figure 1 shows the cumulative amount of drug in the skin treated with ketoconazole antifungal solution of different concentrations in Test Example 1;
  • Figure 2 is the flow chart of Test Example 3 Reporting Guidelines for Randomized Controlled Trials (CONSORT);
  • Figure 3 shows the clinical symptom scores of patients in the KCZ-ILs group and the control group at each visit in Test Example 3.
  • the invention provides an antifungal solution, including an antifungal drug and a solvent;
  • the invention provides an antifungal solution, and the preparation raw materials include antifungal drugs and solvents;
  • the mass ratio of the antifungal drug to the solvent is (0.1 ⁇ 1): (18 ⁇ 318);
  • the solvents include ionic liquids, alcoholic organic solvents and water.
  • the mass ratio of the antifungal drug to the solvent is (0.1 ⁇ 1): (18 ⁇ 318), preferably (0.2 ⁇ 0.8): (60 ⁇ 260), more preferably ( 0.3 ⁇ 0.6): (100 ⁇ 200).
  • the mass ratio of the ionic liquid, alcoholic organic solvent and water is preferably (15 ⁇ 68): (3 ⁇ 30): (0.1 ⁇ 220), more preferably (20 ⁇ 60): (10 ⁇ 28): (20 ⁇ 180); most preferably (25 ⁇ 40): (15 ⁇ 25): (30 ⁇ 100).
  • the antifungal drugs preferably include imidazole antifungal drugs; the imidazole antifungal drugs preferably include miconazole, ketoconazole, clotrimazole, bifonazole or luliconazole, and more preferably include Miconazole, ketoconazole, or bifonazole.
  • the antifungal drug acts on fungal cell membranes to kill fungi.
  • the ionic liquid preferably includes choline ionic liquid, and more preferably includes aromatic acid choline ionic liquid; the aromatic acid choline ionic liquid preferably includes caffeic acid choline, gallic acid choline and enene.
  • the choline acids; the choline acid preferably includes choline geranate and/or choline 2,4-pentadienoate.
  • the functions of the ionic liquid are dissolving ability, skin penetration-promoting performance and antifungal effect.
  • the alcoholic organic solvent preferably includes one or more of ethanol, propylene glycol and polyethylene glycol, and more preferably includes ethanol and/or propylene glycol.
  • the present invention does not have any special restrictions on the proportion of the above-mentioned specific substances, and they can be mixed in any proportion.
  • the function of the alcoholic organic solvent is to form a latent solvent with the ionic liquid and water, so that the drug can achieve maximum solubility in the mixed solvent.
  • the function of the water is to form an ionic liquid aqueous solution system with the ionic liquid, which can not only dissolve anions through hydrogen bonds, but also dissolve the aromatic rings present in some cations, destroying the original ionic liquid polar network and forming a more Small soluble ion groups greatly increase the miscibility window.
  • the antifungal solution is preferably used externally, specifically preferably: after cleaning and drying the affected area, the antifungal solution is fully applied to the affected area.
  • the frequency of use of the antifungal solution is preferably once a day in the morning and evening; the use period is preferably 4 weeks.
  • the antifungal solution provided by the invention can ensure that the drugs in the system are maintained in a dissolved state, improves bioavailability, and can ensure better therapeutic effects at a reduced dose.
  • the antifungal solution provided by this application is comprehensive and quick-acting in improving skin lesion area, scales, keratinization and itching, and solves the problem of single treatment of existing formulas.
  • the antifungal solution provided by this application is easy to use, has a light and thin texture, is safe, and has high patient compliance.
  • the present invention also provides a method for preparing the antifungal solution described in the above technical solution, which includes the following steps:
  • the mixture is mixed with water to obtain the antifungal solution.
  • the antifungal drugs, alcoholic organic solvents and ionic liquids are mixed and heated to obtain a mixed liquid.
  • the present invention does not have any special limitations on the mixing, and a process well known to those skilled in the art can be used.
  • the heating temperature is preferably 60-90°C, more preferably 70-70°C; the heating time is preferably 1-2h, more preferably 1.5h.
  • the present invention does not have any special limitations on the heating method, and a process well known to those skilled in the art can be used.
  • the function of the heating is to cause a hydrogen atom transfer reaction to occur between ions in the solution, so that the ions and solvent molecules form a complex, and the energy released offsets the crystal lattice energy of the salt to dissolve it; at the same time, heating further Promote the loosening of the structure of ionic liquids, reduce intra- and intermolecular interactions, and reduce the lattice energy of ionic liquids, thus promoting the formation of heterogeneous microstructures and liquid morphologies; and, ionic liquids with longer terminal alkyl chains exhibit liquid crystalline Properties: After heating, it enters an isotropic state and is easily miscible.
  • the present invention preferably also includes sequentially allowing the mixed liquid to stand and separate solid-liquid.
  • the standing temperature is preferably 20 to 40°C, more preferably 22 to 30°C, and most preferably 24 to 26°C;
  • the time is preferably 4 to 48 hours, more preferably 8 to 36 hours, and most preferably It is 12 ⁇ 24h.
  • the solid-liquid separation process is preferably centrifugation; the centrifugal speed is preferably 5,000 to 20,000 rpm, more preferably 8,000 to 18,000 rpm, and most preferably 10,000 to 15,000 rpm;
  • the centrifugation time is preferably 2 to 15 min, more preferably The time is 4 to 10 minutes, and the most preferred time is 5 to 7 minutes.
  • the purpose of the standing and centrifugation is to separate the solid-liquid mixture into a clear mixed solution if the drug precipitates.
  • the mixed solution is mixed with water to obtain the antifungal solution.
  • the volume ratio of the mixed liquid to water is preferably 1: (0.005-60), more preferably 1: (1-50), and most preferably 1: (5-30).
  • the present invention does not have any special limitations on the mixing method, and a process well known to those skilled in the art can be used.
  • the preparation method of the antifungal solution provided by the invention has simple steps, can reduce costs, and is suitable for industrial production.
  • the present invention also provides the use of the antifungal solution described in the above technical solution or the antifungal solution obtained by the preparation method described in the above technical solution in the preparation of antidermatophytes.
  • the skin tinea is preferably tinea pedis, more preferably tinea pedis.
  • the present invention does not have any special limitations on the application method, and it is sufficient to adopt processes well known to those skilled in the art.
  • the resulting mixture was mixed with water at a volume ratio of 1:7 to obtain an antifungal solution containing 2.21 wt% ketoconazole.
  • the resulting mixed solution was mixed with water at a volume ratio of 1:3, 1:6, 1:12, 1:24 and 1:48 to obtain ketoconazole-containing antifungal solutions KCZ-ILs, 1/2KCZ-ILs, 1/4KCZ-ILs, 1/8KCZ-ILs and 1/16KCZ-ILs.
  • the drug contents determined by HPLC were 4.72mg/g, 2.36mg/g, 1.18mg/g, 0.59mg/g and 0.30mg/g respectively.
  • the resulting mixed solution was mixed with water at a volume ratio of 1:3, 1:6, and 1:12 to obtain bifonazole-containing antifungal solutions BIF-ILs, 1/2BIF-ILs, and 1/4BIF-ILs.
  • the drug contents determined by HPLC were 5.98mg/g, 2.99mg/g and 1.50mg/g respectively.
  • mice Add the antifungal solutions KCZ-ILs, 1/2KCZ-ILs, 1/4KCZ-ILs, 1/8KCZ-ILs and 1/16KCZ-ILs obtained in Example 2 to the isolated rat skin diffusion pool respectively for 6 hours. , remove the skin and clean it, cut the skin into pieces and soak it in 50% methanol solution, leave it overnight, centrifuge to obtain the supernatant containing the drug, and measure the drug content in the skin by HPLC.
  • Control group The experimental procedures were the same as above, except that the antifungal solution was replaced with an equal amount of commercially available 2% ketoconazole cream.
  • the accumulation amount in the skin of the KCZ-ILs and 1/2KCZ-ILs groups is more than twice that of the 2% ketoconazole cream in the control group.
  • the effect of the 1/4KCZ-ILs group is equivalent to that of the control group.
  • the /8KCZ-ILs and 1/16KCZ-ILs groups were not as effective as the control group. Therefore, a ketoconazole antifungal solution with a concentration above 1.18 mg/g, that is, a ketoconazole antifungal solution with a concentration greater than 0.118%, can achieve a cumulative amount of skin drugs exceeding that of the commercially available 2% ketoconazole cream.
  • Rat experiments were used to test the accumulation of bifonazole in the skin in antifungal solutions of different concentrations:
  • Control group The experimental procedures are the same as above, the only difference is that the antifungal solution is replaced with an equivalent amount of commercially available 1% bifonazole cream.
  • the test results showed that the accumulation amount in the skin of the BIF-ILs group (3.78 ⁇ 0.09 ⁇ g/cm 2 ) was twice that of the control group (1.85 ⁇ 0.19 ⁇ g/cm 2 ), and the effect of the 1/2 BIF-ILs group (1.89 ⁇ 0.13 ⁇ g/cm 2 ) is equivalent to the control group bifonazole cream. Therefore, with a bifonazole antifungal solution with a concentration of 2.99 mg/g or above, that is, a bifonazole antifungal solution with a concentration greater than 0.299%, the cumulative amount of skin drugs that can be achieved can exceed the commercially available 1% bifonazole cream.
  • the cases were selected from tinea pedis patients who visited the general dermatology outpatient clinic of Shanghai Dermatology Hospital from August 2021 to November 2021. According to the clinical diagnostic criteria, 36 patients with tinea pedis who were positive for fungal microscopy in the skin lesions were divided into the experimental group (KCZ-ILs group, 18 cases, 17 completed the trial) and the control group ( Ketoconazole cream group, 18 cases, 16 cases completed the trial), aged 20 to 65 years old.
  • ketoconazole cream (10g: 0.2g or 20mg/g, Xi'an Janssen Pharmaceutical Co., Ltd., national drug approval number H20043171).
  • Clinical TSS recordings and mycological analysis of skin samples were performed at weeks 0 (baseline), 1, 2, 3, 4, and 8 (endpoint). TSS and mycological results were recorded at weekly follow-up visits for the first 4 weeks. Four weeks after drug withdrawal, patients were followed for disease recurrence.
  • the main efficacy indicator is the clinical effectiveness rate after 4 weeks of treatment, where clinical effectiveness is defined as the patient's mycological results being negative and the total clinical symptom score (TSS) decreasing by at least 60% from the baseline.
  • Secondary efficacy endpoints used to assess disease recurrence included the proportion of clinical responders at week 8 and fungal recurrence rates at weeks 2, 3, 4, and 8. Additionally, changes in TSS, mycological eradication rates, and compliance were analyzed at each visit. Through physical examination, vital signs, and adverse events, especially irritations such as erythema, scaling, papules, and blisters, to assess safety.
  • TSS 1Total symptom score
  • the efficacy is evaluated based on the total clinical symptom score (TSS) and fungal examination results, and is divided into cured, markedly effective, effective and ineffective.
  • TSS total clinical symptom score
  • TSS 100%, clinical symptoms disappear, skin lesions completely subside, and fungal microscopy is negative;
  • TSS total clinical symptom score
  • the clinical symptom scores of patients in the KCZ-ILs group and the control group at each visit are shown in Figure 3.
  • KCZ-ILs significantly improved the skin lesion area, scale, keratosis and itching, while Tends to reduce scaly symptoms.
  • KCZ-ILs (KCZ, 4.72 mg/g) is significantly better than (KCZ, 20mg/g). Furthermore, KCZ-ILs were well tolerated without any adverse events, whereas one patient in the control group reported transient mild erythema. In conclusion, ILs loaded with only 1/4 KCZ dose of the control formulation showed better efficacy and safety in the treatment of tinea pedis, which creates new opportunities for the treatment of skin diseases caused by fungal infections and is worthy of clinical application.
  • the antifungal solution provided by the present invention improves the therapeutic effect of skin tinea while reducing the dosage of drugs.
  • the antifungal solution provided by this application is comprehensive and quick-acting in improving skin lesion area, scales, keratinization and itching, and solves the problem of single treatment of existing formulas.
  • the antifungal solution provided by this application is easy to use, has a light and thin texture, is safe, and has high patient compliance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明属于医药技术领域，具体涉及一种抗真菌溶液及其制备方法和应用。本发明提供了一种抗真菌溶液，制备原料包括抗真菌药物和溶剂；所述抗真菌药物的质量与所述溶剂的质量比为(0.1～1)：(18～318)；所述溶剂包括离子液体、醇类有机溶剂和水。在本发明中，离子液体具有优越的溶解能力、皮肤促渗性能和抗真菌效果；水可以破坏原离子液体的极性网络，形成更小的可溶性离子团，使混溶性窗口大大增加；醇类有机溶剂能够与离子液体和水形成潜溶剂，起到帮助混溶的效果。本发明提供的抗真菌溶液能够保证体系中药物维持在溶解状态，提高了生物利用度高，可以保证在降低剂量的情况下获得更好的治疗效果。

Description

一种抗真菌溶液及其制备方法和应用 技术领域
本发明属于医药技术领域，具体涉及一种抗真菌溶液及其制备方法和应用。
背景技术
皮肤癣是一种常见的浅部真菌感染性皮肤病，在世界范围内广泛存在。浅部真菌感染最常见的病原体是皮肤真菌，其患病率很高且易复发(Yu et al.,Mycoses 2020,63,1235-1243)。尽管皮肤癣并不致命，但患者有不成比例的瘙痒、疼痛和情绪困扰，生活质量大大下降。
皮肤癣的治疗可采用外用药、口服药或二者联合用药。由于部分药物全身用药会产生疼痛、过敏反应和肝毒性等副作用，目前临床上多采用局部用药进行疾病的治疗(Shirsand et al.,Int J Pharm Investig 2012,2,201-207)。近些年来，作用于真菌细胞膜的外用咪唑类抗真菌药物在治疗足癣方面取得了一定的进展，其常见产品包括咪康唑乳膏、2％酮康唑乳膏、克霉唑乳膏、联苯苄唑乳膏、1％卢立康唑乳膏等(Crawford,BMJ clinical evidence 2009,7,1712；中国手癣和足癣诊疗指南工作组,中国真菌学杂志2022,17,89-93)。遗憾的是，研究发现，外用咪唑类药物虽然比安慰剂对治疗真菌性皮肤感染更有效，但其治愈率并不确定；而且，没有足够的证据表明不同上述药物的治疗效果有差异(Crawford,BMJ clinical evidence 2009,7,1712)。现有皮肤癣治疗产品疗效不理想的原因与药物剂量和剂型密切相关。首先，由于药物本身对皮肤有刺激性，浓度过高会引发不良反应甚至蓄积性中毒，重者致命，而浓度过低又导致其在病灶部位无法达到有效治疗浓度从而难以有效发挥其抗菌作用(Deng et al.,Mater.Sci.Eng.C Mater.Biol.Appl.2017,78,296-304；Jacobs et al.,Drug Deliv.2016,23,631-641)。上述问题极大限制了咪唑类抗真菌药物的应用和推广。
发明内容
本发明的目的在于提供一种抗真菌溶液及其制备方法和应用，本发明提供的抗真菌溶液在降低药物用药剂量的同时提高了皮肤癣的治疗效果。
为了实现上述目的，本发明提供如下技术方案：
本发明提供了一种抗真菌溶液，制备原料包括抗真菌药物和溶剂；
所述抗真菌药物的质量与所述溶剂的质量比为(0.1～1)：(18～318)；
所述溶剂包括离子液体、醇类有机溶剂和水。
优选地，所述离子液体、醇类有机溶剂和水的质量比为(15～68)：(3～30)：(0.1～220)。
优选地，所述抗真菌药物包括咪唑类抗真菌药物。
优选地，所述咪唑类抗真菌药物包括咪康唑、酮康唑、克霉唑、联苯苄唑或卢立康唑。
优选地，所述离子液体包括胆碱类离子液体。
优选地，所述胆碱类离子液体包括芳香酸胆碱类离子液体。
优选地，所述醇类有机溶剂包括乙醇、丙二醇和聚乙二醇中的一种或多种。
本发明还提供了上述技术方案所述抗真菌溶液的制备方法，其特征在于，包括以下步骤：
将抗真菌药物、醇类有机溶剂和离子液体进行混合，加热，得到混合液；
将所述混合液与水混合，得到所述抗真菌溶液。
优选地，所述加热的温度为60～90℃，时间为1～2h。
本发明还提供了上述技术方案所述的抗真菌溶液或上述技术方案所述制备方法得到的抗真菌溶液在制备抗皮肤癣药物中的应用。
本发明提供了一种抗真菌溶液，制备原料包括抗真菌药物和溶剂；所述抗真菌药物的质量与所述溶剂的质量比为(0.1～1)：(18～318)；所述溶剂包括离子液体、醇类有机溶剂和水。在本发明中，离子液体具有优越的溶解能力、皮肤促渗性能和抗真菌效果；水既可以通过氢键溶解阴离子，也可以溶解一些阳离子中存在的芳香环，破坏了原离子液体的极性网络，形成更小的可溶性离子团，使混溶性窗口大大增加；醇类有机溶剂能够与离子液体和水形成潜溶剂，起到帮助混溶的效果。本发明提供的抗真菌溶液能够保证体系中药物维持在溶解状态，提高了生物利用度高，可以保证在降低剂量的情况下获得更好的治疗效果。根据实施例数据可见，本发明提供的抗真菌溶液在 降低抗菌药物用药剂量的同时提高了皮肤癣的治疗效果，并且降低了复发率，克服了外用咪唑类抗真菌药物用药剂量高，疗效却不理想的技术问题。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为测试例1不同浓度酮康唑抗真菌溶液处理下药物在皮肤内的累积量；
图2为测试例3随机对照试验报告指南(CONSORT)流程图；
图3为测试例3中KCZ-ILs组和对照组患者每次就诊时的临床症状评分。
具体实施方式
本发明提供了一种抗真菌溶液，包括抗真菌药物和溶剂；
本发明提供了一种抗真菌溶液，制备原料包括抗真菌药物和溶剂；
所述抗真菌药物的质量与所述溶剂的质量比为(0.1～1)：(18～318)；
所述溶剂包括离子液体、醇类有机溶剂和水。
在本发明中，如无特殊说明，所有原料组分均为本领域技术人员熟知的市售产品。
在本发明中，所述抗真菌药物的质量与所述溶剂的质量比为(0.1～1)：(18～318)，优选为(0.2～0.8)：(60～260)，更优选为(0.3～0.6)：(100～200)。
在本发明中，所述离子液体、醇类有机溶剂和水的质量比优选为(15～68)：(3～30)：(0.1～220)，更优选为(20～60)：(10～28)：(20～180)；最优选为(25～40)：(15～25)：(30～100)。
在本发明中，所述抗真菌药物优选包括咪唑类抗真菌药物；所述咪唑类抗真菌药物优选包括咪康唑、酮康唑、克霉唑、联苯苄唑或卢立康唑，更优选包括咪康唑、酮康唑或联苯苄唑。
在本发明中，所述抗真菌药物作用于真菌细胞膜以起到杀灭真菌的功效。
在本发明中，所述离子液体优选包括胆碱类离子液体，更优选包括芳香酸胆碱类离子液体；所述芳香酸胆碱类离子液体优选包括咖啡酸胆碱、没食子酸胆碱和烯酸类胆碱中的一种或多种；所述烯酸类胆碱优选包括垅牛儿酸胆碱和/或2,4-戊二烯酸胆碱。当所述离子液体为上述具体选择中的两种以上时，本发明对上述具体物质的配比没有任何特殊的限定，按任意配比进行混合即可。
在本发明中，所述离子液体的作用是发挥溶解能力、皮肤促渗性能和抗真菌效果。
在本发明中，所述醇类有机溶剂优选包括乙醇、丙二醇和聚乙二醇中的一种或多种，更优选包括乙醇和/或丙二醇。当所述醇类有机溶剂为上述具体选择中的两种以上时，本发明对上述具体物质的配比没有任何特殊的限定，按任意配比进行混合即可。
在本发明中，所述醇类有机溶剂的作用是与离子液体和水形成潜溶剂，使药物在混合溶媒中达到最大溶解度。
在本发明中，所述水的作用是与离子液体形成离子液体水溶液体系，既可以通过氢键溶解阴离子，也可以溶解一些阳离子中存在的芳香环，破坏了原离子液体极性网络，形成更小的可溶性离子团，使混溶性窗口大大增加。
在本发明中，所述抗真菌溶液的使用方式优选为外用，具体优选为：清洗患处并擦干后，以抗真菌溶液全面涂擦患处。在本发明中，所述抗真菌溶液的使用频次优选为每日早晚各用一次；使用周期优选为4周。
本发明提供的抗真菌溶液能够保证体系中药物维持在溶解状态，提高了生物利用度高，可以保证在降低剂量的情况下获得更好的治疗效果。同时，本申请提供的抗真菌溶液在皮损面积、鳞屑、角化和瘙痒的改善方面具有综合性和速效性，解决了现有配方的治疗单一性问题。并且，本申请提供的抗真菌溶液使用方便，质地轻薄，安全性好，患者依从性高。
本发明还提供了上述技术方案所述抗真菌溶液的制备方法，包括以下步骤：
将抗真菌药物、醇类有机溶剂和离子液体进行混合，加热，得到混合液；
将所述混合液与水混合，得到所述抗真菌溶液。
本发明将所述抗真菌药物、醇类有机溶剂和离子液体进行混合，加热，得到混合液。本发明对所述混合没有任何特殊的限定，采用本领域技术人员熟知的过程即可。在本发明中，所述加热的温度优选为60～90℃，更优选为70～70℃；时间优选为1～2h，更优选为1.5h。本发明对所述加热的方式没有任何特殊的限定，采用本领域技术人员熟知的过程即可。
在本发明中，所述加热的作用是使溶液中离子间发生氢原子转移反应，使离子和溶剂分子形成络合物，其释放的能量抵消盐的晶格能使其溶解；同时，加热进一步促进离子液体结构松散，减少分子内和分子间相互作用，降低离子液体的晶格能，从而促进异质微结构及液体形态的形成；并且，具有较长末端烷基链的离子液体表现出液晶性质，加热后进入各向同性状态，易于混溶。
得到混合液后，本发明还优选包括将所述混合液依次进行静置和固液分离。在本发明中，所述静置的温度优选为20～40℃，更优选为22～30℃，最优选为24～26℃；时间优选为4～48h，更优选为8～36h，最优选为12～24h。在本发明中，所述固液分离的过程优选为离心；所述离心的转速优选为5000～20000rpm，更优选为8000～18000rpm，最优选为10000～15000rpm；时间优选为2～15min，更优选为4～10min，最优选为5～7min。
在本发明中，所述静置以及离心的作用是若药物发生析出，则对其进行固液分离，得到澄清的混合液。
本发明将所述混合液与水混合，得到所述抗真菌溶液。在本发明中，所述混合液与水的体积比优选为1：(0.005～60)，更优选为1：(1～50)，最优选为1：(5～30)。本发明对所述混合的方式没有任何特殊的限定，采用本领域技术人员熟知的过程即可。
本发明提供的抗真菌溶液的制备方法步骤简单，能够降低成本，适于工业化生产。
本发明还提供了上述技术方案所述的抗真菌溶液或上述技术方案所述制备方法得到的抗真菌溶液在制备抗皮肤癣药物中的应用。
在本发明中，所述皮肤癣优选为手足癣，更优选为足癣。本发明对所述应用的方式没有任何特殊的限定，采用本领域技术人员熟知的过程即可。
为了进一步说明本发明，下面结合附图和实施例对本发明提供的抗真菌溶液及其制备方法和应用进行详细地描述，但不能将它们理解为对本发明保护范围的限定。
实施例1
将0.5g酮康唑、15g丙二醇和34g咖啡酸胆碱混合，置于60℃条件下加热2h，得到混合液；
将所得混合液，于24℃条件下放置12h后在转速为10000rpm条件下离心5min，得到混合液和沉淀；
将所得混合液与水按照1:7的体积比混合，得到含酮康唑2.21wt％的抗真菌溶液。
实施例2
将0.5g酮康唑、15g丙二醇和34g垅牛儿酸胆碱混合，置于90℃条件下加热1h，得到混合液；
将所得混合液，于24℃条件下放置12h后在转速为10000rpm条件下离心5min，得到混合液和沉淀；
将所得混合液与水按照1:3、1:6、1:12、1:24和1:48的体积比混合，得到含酮康唑的抗真菌溶液KCZ-ILs、1/2KCZ-ILs、1/4KCZ-ILs、1/8KCZ-ILs和1/16KCZ-ILs。HPLC测定药物含量分别为4.72mg/g、2.36mg/g、1.18mg/g、0.59mg/g和0.30mg/g。
实施例3
将0.5g联苯苄唑、20g丙二醇和56g没食子酸胆碱混合，置于60℃条件下加热2h，得到混合液；
将所得混合液，于24℃条件下放置24h后在转速为10000rpm条件下离心5min，得到混合液和沉淀；
将所得混合液与水按照1:3、1:6、1:12的体积比混合，得到含联苯苄唑的抗真菌溶液BIF-ILs、1/2BIF-ILs和1/4BIF-ILs。HPLC测定药物含量分别为5.98mg/g、2.99mg/g和1.50mg/g。
应用例1
周某，女，41岁，患有糜烂性足癣1年，反复发作，苦不堪言。经实施 例3提供的抗真菌溶液1/2BIF-ILs治疗，每日2次涂抹于患病处，一周后皮损面积明显减小、鳞屑、角化和瘙痒症状均减轻；用药四周后足癣临床症状消除，1年多来未再复发。
应用例2
王某，男，50岁，患有角化性足癣长达5年，反复用药，疗效不佳。经实施例3提供的抗真菌溶液1/2BIF-ILs治疗，每日2次涂抹于患病处，一周后皮损面积减小、鳞屑和角化明显减轻，瘙痒症状无；用药四周后临床评价显效；继续用药2周，临床症状基本消除，半年多来未再复发。
测试例1
采用大鼠实验检验不同浓度抗真菌溶液中酮康唑在皮肤内的累积量：
实验组：将实施例2所得抗真菌溶液KCZ-ILs、1/2KCZ-ILs、1/4KCZ-ILs、1/8KCZ-ILs和1/16KCZ-ILs，分别加入离体大鼠皮肤扩散池6h后，取下皮肤清洗干净，将皮肤剪碎后浸泡于50％甲醇溶液中，放置过夜，离心得到含有药物的上清液，经HPLC测定皮肤内药物含量。
对照组：实验步骤同上，区别仅在于，将抗真菌溶液替换为等量的市售2％酮康唑乳膏。
检测结果如图1所示。
由图1可见，KCZ-ILs和1/2KCZ-ILs组在皮肤内的蓄积量是对照组2％酮康唑乳膏的2倍以上，1/4KCZ-ILs组的效果与对照组相当，1/8KCZ-ILs和1/16KCZ-ILs组效果不如对照组。因此，浓度为1.18mg/g以上，即浓度大于0.118％的酮康唑抗真菌溶液，所能达到的皮肤药物累计量即可超过市售2％酮康唑乳膏。
测试例2
采用大鼠实验检验不同浓度抗真菌溶液中联苯苄唑在皮肤内的累积量：
实验组：将实施例2所得抗真菌溶液BIF-ILs和1/2BIF-ILs和1/4BIF-ILs，分别加入离体大鼠皮肤扩散池6h后，取下皮肤清洗干净，将皮肤剪碎后浸泡于50％甲醇溶液中，放置过夜，离心得到含有药物的上清液，经HPLC测定皮肤内药物含量。
对照组：实验步骤同上，区别仅在于，将抗真菌溶液替换为等量的市售 1％联苯苄唑乳膏。
测试结果表明，BIF-ILs组在皮肤内的蓄积量(3.78±0.09μg/cm2)是对照组(1.85±0.19μg/cm2)的2倍，1/2BIF-ILs组的效果(1.89±0.13μg/cm2)与对照组联苯苄唑乳膏相当。因此，浓度为2.99mg/g以上，即浓度大于0.299％的联苯苄唑抗真菌溶液，所能达到的皮肤药物累计量即可超过市售1％联苯苄唑乳膏。
测试例3
(1)临床资料
病例均选自2021年8月至2021年11月在上海市皮肤病医院普通皮肤科门诊就诊的足癣患者。根据临床诊断标准将皮损部位真菌镜检阳性符合入组的36例足癣患者，按照简单排序随机化法分为试验组(KCZ-ILs组，18例，17例完成试验)与对照组(酮康唑乳膏组，18例，16例完成试验)，年龄20～65岁。
(2)药物
实验组：实施例2所得酮康唑抗真菌溶液KCZ-ILs。
对照组：酮康唑乳膏(10g:0.2g即20mg/g，西安杨森制药有限公司，国药准字H20043171)。
(3)治疗方法
将患处清洗干净，保持干燥舒适，然后取药物适量涂于患处，每日2次，连续使用4周。
(4)观察指标及疗效评定标准
临床TSS记录和皮肤样本的真菌学分析，分别在第0周(基线)、1、2、3、4和8周(终点)进行。在前4周的每周随访中记录TSS和真菌学结果。在停药4周后，对患者进行随访以了解疾病的复发情况。主要疗效指标是在治疗4周后临床有效率，其中临床有效定义为患者真菌学结果为阴性，临床症状总积分(Total symptom score,TSS)较基线下降至少60％。用于评估疾病复发的次要疗效指标包括第8周的临床有效者比例和第2、3、4和8周的真菌复发率。此外，每次访问还分析了TSS的变化、真菌学根除率和依从性。通过体格检查、生命体征和不良事件，特别是红斑、脱皮、丘疹和水疱等刺 激反应来评估安全性。
①临床症状总积分(Total symptom score,TSS)指标与标准
根据皮损面积、浸渍程度、糜烂面积、渗出程度、鳞屑、角化和瘙痒的评分合计临床症状总积分(Total symptom score,TSS)，每个症状的严重程度被分为4个等级(0＝无症状到3＝症状最严重)，标准如表1。
表1.临床症状评分标准
②真菌学检查
从感染部位收集皮肤刮片，并进行真菌学检测，用氢氧化钾(KOH)检测来代表真菌学结果。
③疗效评定指标与标准
根据临床症状总积分(Total symptom score,TSS)及真菌检查结果进行疗效评价，分为痊愈、显效、有效和无效。
痊愈：TSS＝100％，临床症状消失，皮损完全消退，真菌镜检阴性；
显效：60％≤TSS≤99％，症状明显缓解，真菌镜检阴性或极少量菌丝；
有效：20％≤TSS≤59％，症状减轻，真菌镜检可阳性。
无效：TSS＜20％，症状无明显改变，真菌镜检阳性。
④安全性评定指标
观察患者治疗过程中的不良反应发生情况，尤其关注皮肤局部刺激反应。
(5)受试者资料分析
共有39例患者接受了筛选，其中36例符合纳入和排除标准。3例患者在研究期间因更换工作或不守时而失访。在33例完整的可评估患者中，17例接受KCZ-ILs治疗，16例接受治疗。参与者的CONSORT图如图2所示。治疗结束时，KCZ-ILs组和组对试验方案的依从率分别为96.4％和98.4％。
表2基线时患者的人口统计学和临床特征


*并发症：高血压(n＝2，每组1例)、糖尿病(n＝1，KCZ-ILs组)或
两者兼有(n＝1，对照组)。
由表2可知，试验组17例，男9例，女8例，年龄31～59岁，临床症状总积分(Total symptom score,TSS)为8.76±2.14；对照组男8例，女8例，年龄32～59岁，TSS为9.44±3.18。少数患者(4/33，12％)合并高血压(2/33，6％)、糖尿病(1/33，3％)或两者兼有(1/33，3％)。除体重指数外，两组患者基线时的特征差异无统计学意义(P>0.05)。
(6)临床症状总积分(TSS)
治疗4周后KCZ-ILs组的TSS变化为-4.94(±2.51)[p<0.001]，组为-4.44(±2.34)[p<0.001]。仅治疗一周后症状开始改善，且效果持续整个研究期。两组间TSS差异有统计学意义(F＝58.58，P<0.001)，主要表现在第2周和第3周。KCZ-ILs组和对照组患者每次就诊时的临床症状评分如图3所示。
由图3可见，KCZ-ILs在皮损面积、鳞屑、角化和瘙痒方面有显著改善，而倾向于减轻鳞屑症状。
(7)真菌清除率
表3真菌学结果


a：KCZ-ILS组与对照组的差异。
b：KCZ-ILS组或对照组与基线相比的差异。
c：阴性转阳性的病人比例为新的阳性病例在前一阶段的阴性病例总
数中的占比。
由表3可知，KCZ-ILs组的治疗效果随时间而增强，治疗结束时，仅4例阳性患者，真菌清除率达76.47％。组1～3周的真菌清除率为50.00％(8/16例)，第4周为56.25％(9/16例)。在整个试验期间，KCZ-ILs有6例(35.29％)真菌阴性病例转为阳性，相比之下，对照组16例真菌阴性病例中有11例(68.75％)转为阳性。
(8)总体疗效
表4两组在第4周和第8周的总体疗效

由表4可知，在KCZ-ILs组中，大约53％的患者有效，41％的患者显效，6％的患者完全治愈，而对照组的无效、有效、显效和完全治愈的患者分别为19％、56％、19％和6％。主要疗效结果是临床有效(治愈和显效)的比例。治疗结束时，KCZ-ILs组临床有效率为47.06％，而组仅为25.00％，4周时KCZ-ILs组疗效优于KCZ-ILS组，差异有统计学意义(P＝0.010)。治疗结束后4周，KCZ-ILs组的临床有效率为41.17％，而对照组为31.25％。
(9)不良反应
试验组患者未出现不良反应，对照组出现1例(6.25％)，症状主要为涂抹药物一周后皮损处出现一过性轻微红斑，不影响其继续治疗及疗效判定。两组不良反应差异无统计学意义。
该项临床试验评估了一种包载酮康唑的抗真菌溶液治疗足癣患者的疗效和安全性。KCZ-ILs(KCZ，4.72mg/g)在临床改善和预防复发方面均明显优于(KCZ，20mg/g)。此外，KCZ-ILs的耐受性很好，没有任何不良事件，而对照组中有一名患者报告了一过性轻度红斑。总之，仅加载对照制剂1/4KCZ剂量的ILs在治疗足癣方面显示出更好的疗效和安全性，这为治疗由真菌感染引起的皮肤病创造了新的机会，值得临床应用。
根据上述实施例可知，本发明提供的抗真菌溶液在降低药物用药剂量的同时提高了皮肤癣的治疗效果。同时，本申请提供的抗真菌溶液在皮损面积、鳞屑、角化和瘙痒的改善方面具有综合性和速效性，解决了现有配方的治疗单一性问题。并且，本申请提供的抗真菌溶液使用方便，质地轻薄，安全性好，患者依从性高。
尽管上述实施例对本发明做出了详尽的描述，但它仅仅是本发明一部分实施例，而不是全部实施例，还可以根据本实施例在不经创造性前提下获得其他实施例，这些实施例都属于本发明保护范围。

Claims (10)

  1. 一种抗真菌溶液，其特征在于，制备原料包括抗真菌药物和溶剂；
    所述抗真菌药物的质量与所述溶剂的质量比为(0.1～1)：(18～318)；
    所述溶剂包括离子液体、醇类有机溶剂和水。
  2. 根据权利要求1所述的抗真菌溶液，其特征在于，所述离子液体、醇类有机溶剂和水的质量比为(15～68)：(3～30)：(0.1～220)。
  3. 根据权利要求1所述的抗真菌溶液，其特征在于，所述抗真菌药物包括咪唑类抗真菌药物。
  4. 根据权利要求3所述的抗真菌溶液，其特征在于，所述咪唑类抗真菌药物包括咪康唑、酮康唑、克霉唑、联苯苄唑或卢立康唑。
  5. 根据权利要求1～4任一项所述的抗真菌溶液，其特征在于，所述离子液体包括胆碱类离子液体。
  6. 根据权利要求5所述的抗真菌溶液，其特征在于，所述胆碱类离子液体包括芳香酸胆碱类离子液体。
  7. 根据权利要求1～4任一项所述的抗真菌溶液，其特征在于，所述醇类有机溶剂包括乙醇、丙二醇和聚乙二醇中的一种或多种。
  8. 权利要求1～7任一项所述抗真菌溶液的制备方法，其特征在于，包括以下步骤：
    将抗真菌药物、醇类有机溶剂和离子液体进行混合，加热，得到混合液；
    将所述混合液与水混合，得到所述抗真菌溶液。
  9. 根据权利要求8所述的制备方法，其特征在于，所述加热的温度为60～90℃，时间为1～2h。
  10. 权利要求1～7任一项所述的抗真菌溶液或权利要求8或9所述制备方法得到的抗真菌溶液在制备抗皮肤癣药物中的应用。
PCT/CN2023/098300 2022-08-24 2023-06-05 一种抗真菌溶液及其制备方法和应用 WO2024041083A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211021087.1A CN115671285B (zh) 2022-08-24 2022-08-24 一种抗真菌溶液及其制备方法和应用
CN202211021087.1 2022-08-24

Publications (1)

Publication Number Publication Date
WO2024041083A1 true WO2024041083A1 (zh) 2024-02-29

Family

ID=85060599

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/098300 WO2024041083A1 (zh) 2022-08-24 2023-06-05 一种抗真菌溶液及其制备方法和应用

Country Status (2)

Country Link
CN (1) CN115671285B (zh)
WO (1) WO2024041083A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115671285B (zh) * 2022-08-24 2024-01-05 上海市皮肤病医院 一种抗真菌溶液及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0396184A2 (en) * 1989-05-03 1990-11-07 Janssen Pharmaceutica N.V. Use of ketoconazole and a retinoid for the treatment of acne vulgaris
US20210353565A1 (en) * 2020-05-12 2021-11-18 President And Fellows Of Harvard College Antifungal prophylaxis for cornea
CN115671285A (zh) * 2022-08-24 2023-02-03 上海市皮肤病医院 一种抗真菌溶液及其制备方法和应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101273971A (zh) * 2008-05-09 2008-10-01 绍兴文理学院 抗真菌药物的醇质体制剂及其制备方法
CN101396360B (zh) * 2008-10-16 2011-02-02 山东京卫制药有限公司 一种用于治疗皮肤或头皮浅部真菌感染的药物洗剂及其制备方法
CN102018667B (zh) * 2010-10-29 2012-08-08 杭州雷布科技有限公司 一种咪唑类抗真菌皮肤擦拭剂及其制备方法
ES2908345T3 (es) * 2013-11-03 2022-04-28 Univ California Líquidos iónicos para la administración transdérmica de medicamentos
CN103638062B (zh) * 2013-12-23 2016-04-13 四川农业大学 一种抗皮肤癣菌的浇泼剂及其制备方法
CN112587593B (zh) * 2020-11-17 2022-05-10 中山大学 一种治疗痤疮的组合物及其制备方法
CN112831074B (zh) * 2021-02-03 2023-07-07 哈尔滨工业大学（深圳） 一种天然离子液体保鲜膜的制备方法与应用
CN114642733B (zh) * 2022-03-02 2023-08-22 中山大学 一种治疗雄激素源性脱发的组合物及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0396184A2 (en) * 1989-05-03 1990-11-07 Janssen Pharmaceutica N.V. Use of ketoconazole and a retinoid for the treatment of acne vulgaris
US20210353565A1 (en) * 2020-05-12 2021-11-18 President And Fellows Of Harvard College Antifungal prophylaxis for cornea
CN115671285A (zh) * 2022-08-24 2023-02-03 上海市皮肤病医院 一种抗真菌溶液及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI, XIAODAN ET AL.: "Applications of Choline-Based Ionic Liquids in Drug Delivery", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 612, 9 December 2021 (2021-12-09), XP086907053, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2021.121366 *
WU, XIYING ET AL.: "Ionic Liquids Containing Ketoconazole Improving Topical Treatment of T. Interdigitale Infection by Synergistic Action", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 589, 3 September 2020 (2020-09-03), XP086309104, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2020.119842 *

Also Published As

Publication number Publication date
CN115671285B (zh) 2024-01-05
CN115671285A (zh) 2023-02-03

Similar Documents

Publication Publication Date Title
WO2024041083A1 (zh) 一种抗真菌溶液及其制备方法和应用
AU2022205208A1 (en) Use of oxygenated cholesterol sulfates (OCS) to treat inflammatory skin disease and skin lesions
CA3094445A1 (en) Ionic liquid compositions for treatment of rosacea
CN108057018B (zh) 秋水仙碱外用组合物及其制备方法
WO2014118040A1 (en) Extract from indigo tinctoria for the topical treatment and prophylaxis of skin disorders
CN102379879B (zh) 一种含有利拉萘酯和糠酸莫米松的局部应用复方药物组合物
CN104117066B (zh) 外敷用抗甲状腺软膏的制备方法
US20120225143A1 (en) Cold sore formulation and related method of manufacture
TWI630921B (zh) 含埃克替尼的皮膚外用藥物組合物及其應用
MX2011009935A (es) Crema medicinal para dermatitis del pañal y un proceso para hacerla.
RU2496476C1 (ru) Средство наружной терапии для больных атопическим дерматитом
JP2012232969A (ja) 抗疣贅医薬組成物及び疣贅を処置するための方法
CN114712375B (zh) 一种羟基白桦酸化合物在制备皮肤病药物中的应用
CN102319229A (zh) 一种制备双氯芬酸钠透皮贴片的方法
CN112020352A (zh) 用于痤疮的大麻素给药方案
CN102389514B (zh) 一种治疗日光性皮炎的外用擦剂及制备方法
CN103735494B (zh) 治疗蚊虫叮咬的外用止痒乳膏及其制备方法
CN113713000B (zh) 用于治疗疮痈、烧烫伤和痤疮的主药成分组合物、缓控释药物制剂及其制备方法和应用
JP2010047518A (ja) 鼻閉抑制剤
CN105560248A (zh) 一种治疗真菌感染的药物组合物及其制备方法和应用
CN105288016B (zh) 一种防治膝骨关节炎外用中药乳剂及其制备方法
BR102016006307B1 (pt) Processo para obtenção de extrato de brassica oleracea var. capitata, composição à base de folhas de brassica oleracea var. capitata, processo de fabricação de emulsão, gel e pomada cicatrizante à partir de brassica oleracea var. capitata, e respectivos usos
Miao et al. Analysis of dosage form of traditional Chinese medicine
CA3232028A1 (en) Gel composition for preventing or treating atopic dermatitis
RU2608457C2 (ru) Способ лечения кандидозного глоссита

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23856175

Country of ref document: EP

Kind code of ref document: A1