WO2024027816A1 - 利福霉素-喹嗪酮偶联分子软膏剂及其制备方法 - Google Patents

利福霉素-喹嗪酮偶联分子软膏剂及其制备方法 Download PDF

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WO2024027816A1
WO2024027816A1 PCT/CN2023/111153 CN2023111153W WO2024027816A1 WO 2024027816 A1 WO2024027816 A1 WO 2024027816A1 CN 2023111153 W CN2023111153 W CN 2023111153W WO 2024027816 A1 WO2024027816 A1 WO 2024027816A1
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rifamycin
total mass
coupling molecule
quinolizinone
ointment
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PCT/CN2023/111153
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English (en)
French (fr)
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刘宇
宋婷
王唤
徐向毅
马振坤
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丹诺医药(苏州）有限公司
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Publication of WO2024027816A1 publication Critical patent/WO2024027816A1/zh

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application relates to the field of medical technology, and in particular to a rifamycin-quinozinone coupling molecule ointment and a preparation method thereof.
  • Rifamycin-quinolizinone coupling molecule is a multi-target drug, and its structural formula is shown as the following formula I:
  • the rifamycin-quinozinone coupling molecule has low solubility in water, is soluble in dichloromethane, polyethylene glycol 400 and dimethyl sulfoxide, and is almost insoluble in ethanol, methanol and ether; water solubility is pH-dependent. The solubility is maximum at pH 10, and the solubility is lower at low pH conditions.
  • rifamycin-quinozinone conjugate molecules may be oxidized and converted from phenolic to quinone form when exposed to air. Degradation will occur when the temperature exceeds 60°C. When stored dry, the main degradation product is the quinone structure. Oxidation or degradation of compounds may result in a reduction in the effective dose of the drug. Therefore, it is necessary to broaden the application prospects through a series of improvements or making certain specific preparations.
  • the purpose of this application is to provide a rifamycin-quinolizinone coupling molecule ointment that can improve the drug content of the preparation and the stability of the drug ingredients, and prevent the generation of oxidation products. Improve medication effectiveness and medication safety.
  • the purpose of this application is also to provide a preparation method of rifamycin-quinolizinone coupling molecule ointment, which can improve the drug content and stability of the product.
  • the present application provides a rifamycin-quinolizinone coupling molecule ointment, which is characterized in that the raw material components of the rifamycin-quinolizinone coupling molecule ointment include: Formula I
  • the compounds shown are rifamycin-quinozinone coupling molecules, polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, solubilizers and antioxidants;
  • the dosage of the rifamycin-quinozinone coupling molecule accounts for 0.05%-0.7% of the total mass
  • the dosage of the polyethylene glycol 400 accounts for 55%-0.7% of the total mass.
  • the amount of polyethylene glycol 3350 accounts for 25%-35% of the total mass
  • the amount of propylene glycol accounts for 8%-12% of the total mass
  • the amount of the solubilizer accounts for 0.1%- 1%.
  • the dosage of the antioxidant accounts for 0.3%-1% of the total mass.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.3% to 0.7% of the total mass.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.05% to 0.5% of the total mass.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.5% of the total mass.
  • the amount of polyethylene glycol 400 accounts for 55%-60% of the total mass.
  • the amount of polyethylene glycol 400 accounts for 56%-58% of the total mass.
  • the amount of polyethylene glycol 3350 accounts for 28%-33% of the total mass.
  • the amount of polyethylene glycol 3350 accounts for 30%-32% of the total mass.
  • the solubilizing agent is used in an amount of 0.3% to 0.7% of the total mass.
  • the solubilizing agent includes triethanolamine.
  • the antioxidant is used in an amount of 0.5% to 1% of the total mass.
  • the antioxidant includes one or a combination of vitamin C and vitamin E.
  • the amount of vitamin C and/or vitamin E accounts for 0.3%-0.5% of the total mass.
  • the raw material components of the rifamycin-quinolizinone coupling molecule ointment include: the compound rifamycin-quinolizinone coupling molecule represented by formula I, polyethylene glycol 400 , polyethylene glycol 3350, propylene glycol, solubilizer and antioxidant; based on the total mass percentage of 100%, the dosage of the rifamycin-quinolizinone coupling molecule accounts for 0.3%-0.7% of the total mass, The amount of polyethylene glycol 400 accounts for 55%-60% of the total mass, the amount of polyethylene glycol 3350 accounts for 28%-33% of the total mass, and the amount of propylene glycol accounts for 8%-60% of the total mass.
  • the solubilizing agent includes triethanolamine.
  • the antioxidant includes one or a combination of vitamin C and vitamin E.
  • the raw material components of the rifamycin-quinozinone coupling molecule ointment include: rifamycin-quinolin in an amount of about 0.5% of the total mass based on a total mass percentage of 100%.
  • polyethylene glycol 400 is used in an amount of 56%-58% of the total mass
  • polyethylene glycol 3350 is used in an amount of 30%-32% of the total mass
  • polyethylene glycol 3350 is used in an amount of about 10% of the total mass.
  • Propylene glycol, triethanolamine in an amount of 0.3%-0.7% of the total mass
  • vitamin C in an amount of 0.3%-0.5% of the total mass
  • vitamin E in an amount of 0.3%-0.5% of the total mass.
  • this application provides a method for preparing the rifamycin-quinolizinone coupling molecule ointment described in this application, including: combining polyethylene glycol 3350, propylene glycol, solubilizer, antioxidant and part of polyethylene glycol. Ethylene glycol 400 is heated and melted, and mixed to obtain a first mixture; the rifamycin-quinozinone coupling molecule and the remaining polyethylene glycol 400 are mixed and dissolved to obtain a first medicinal liquid; the first medicinal liquid and The first mixture is mixed to obtain a rifamycin-quinolizinone coupling molecule ointment.
  • the mixing and dissolving temperature is 50°C.
  • the mixing temperature is 50°C-53°C.
  • this application provides a method for preparing the rifamycin-quinolizinone coupling molecule ointment described in this application, including: combining polyethylene glycol 3350, propylene glycol, solubilizer, antioxidant and polyethylene glycol.
  • the alcohol 400 is heated and melted, and mixed to obtain a first mixture; the rifamycin-quinolizinone coupling molecule is mixed with the first mixture to obtain a rifamycin-quinolizinone coupling molecule ointment.
  • the heating and melting temperature is 70°C to 73°C.
  • the mixing temperature is 50°C.
  • Figure 1 shows the reaction equation for the oxidative degradation of rifamycin-quinolizinone coupled molecules to produce oxidative impurities.
  • Figure 2 shows the comparison results of electron microscopy with different solubilizer formulations.
  • Figure 3 shows the results of bacterial load in mice in Example 5 of the present invention.
  • the term "ointment preparation” generally refers to a homogeneous, semi-solid topical preparation prepared by mixing a drug with a greasy or water-soluble base. Because the dispersion state of the drug in the matrix is different, it can be divided into solution-type ointment and suspension-type ointment.
  • the solvent-type ointment is an ointment dosage form made by dissolving or co-dissolving the drug in the matrix or matrix components.
  • the suspension ointment is an ointment form in which fine powder of the drug is evenly dispersed in the matrix.
  • the ointment preparations provided in this application are usually used for external application and local treatment.
  • the drugs in the ointment preparations can exert systemic pharmacological or systemic effects after being absorbed through the skin. Therapeutic effect.
  • the base of an ointment dosage form serves as an excipient and drug carrier, which can have an important impact on the quality of the ointment and the release and absorption of the drug.
  • the bases of common ointment dosage forms in this field can be divided into oily bases, emulsion bases and water-soluble bases. Preparation methods and techniques suitable in this field can be used to obtain the ointment form required for the treatment method of the present application.
  • melting generally refers to the process of a first-order phase transition, which is accompanied by an increase in thermal enthalpy, entropy and volume; for example, when the temperature is increased, the kinetic energy of the thermal motion of molecules increases, leading to crystallization is destroyed, and the process in which a substance changes from a crystalline phase to a liquid phase can be called melting; for example, in this application, a substance that is solid at room temperature reaches its melting point when heated to a certain temperature.
  • the process of becoming a liquid substance and acquiring some of the physical properties of a liquid can also be called melting.
  • Substances in a molten state may be in a liquid state, or they may be in a state where solid and liquid coexist.
  • mixing generally refers to the process of combining one or more compounds, cells, molecules, etc. in the same area. This can be done, for example, in a test tube, a petri dish or any container that allows mixing of one or more compounds, cells or molecules.
  • “about” or “approximately” may mean a range of up to 10% or 20% (i.e., ⁇ 10% or ⁇ 20%).
  • about 3 mg may include any amount between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
  • the term may mean up to one order of magnitude in value or up to 5 times the value.
  • the present application provides a rifamycin-quinolizinone coupling molecule ointment, which is characterized in that the raw material components of the rifamycin-quinolizinone coupling molecule ointment include: Formula I
  • the compound shown is rifamycin-quinolizinone coupling molecule, polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, solubilizer and antioxidant; based on the total mass percentage of 100%, the rifamycin
  • the dosage of prime-quinolizinone coupling molecules accounts for 0.05%-0.7% of the total mass
  • the dosage of polyethylene glycol 400 accounts for 55%-65% of the total mass
  • the dosage of polyethylene glycol 3350 accounts for 0.05%-0.7% of the total mass.
  • the amount of propylene glycol accounts for 8%-12% of the total mass
  • the amount of the solubilizer accounts for 0.1%-1% of the total mass
  • the amount of the antioxidant accounts for 10% of the
  • this application provides a method for preparing the rifamycin-quinolizinone coupling molecule ointment described in this application, including: combining polyethylene glycol 3350, propylene glycol, solubilizer, antioxidant and part of polyethylene glycol. Ethylene glycol 400 is heated and melted, and mixed to obtain a first mixture; the rifamycin-quinozinone coupling molecule and the remaining polyethylene glycol 400 are mixed and dissolved to obtain a first medicinal liquid; the first medicinal liquid and The first mixture is mixed to obtain a rifamycin-quinolizinone coupling molecule ointment.
  • this application provides a method for preparing the rifamycin-quinolizinone coupling molecule ointment described in this application, including: combining polyethylene glycol 3350, propylene glycol, solubilizer, antioxidant and polyethylene glycol.
  • the alcohol 400 is heated and melted, and mixed to obtain a first mixture; the rifamycin-quinolizinone coupling molecule is mixed with the first mixture to obtain a rifamycin-quinolizinone coupling molecule ointment.
  • Rifamycin-quinolinone coupling molecule is a multi-target compound composed of rifamycin and quinolone pharmacophore, and its structural formula is shown in Formula I,
  • RNA polymerase RNA polymerase
  • DNA gyrase DNA gyrase
  • topoisomerase IV RNA polymerase
  • This multi-target mechanism of action can produce technical effects that reduce the tendency of drug resistance.
  • Rifamycin-quinozinone coupling molecule raw materials are all prepared by Dannuo Pharmaceuticals.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.05% to 0.7% of the total mass.
  • the amount of the rifamycin-quinolizinone coupling molecule can account for about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, of the total mass.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.3% to 0.7% of the total mass.
  • the amount of the rifamycin-quinolizinone coupling molecule can account for about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, of the total mass. About 0.65% or about 0.7%.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.05% to 0.5% of the total mass.
  • the amount of the rifamycin-quinolizinone coupling molecule can account for about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, of the total mass.
  • the rifamycin-quinolizinone coupling molecule is used in an amount of 0.5% of the total mass.
  • Polyethylene glycol 400 and polyethylene glycol 3350 are Polyethylene glycol 400 and polyethylene glycol 3350.
  • the solubility of the rifamycin-quinozinone coupling molecule is relatively low.
  • this application provides an ointment that combines polyethylene glycol 400 and polyethylene glycol 3350. matrix.
  • the amount of polyethylene glycol 400 accounts for 55%-65% of the total mass.
  • the amount of polyethylene glycol 400 can account for about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63% of the total mass. %, about 64% or about 65%.
  • the amount of polyethylene glycol 400 accounts for 55%-60% of the total mass.
  • the amount of polyethylene glycol 400 may account for about 55%, about 56%, about 57%, about 58%, about 59% or about 60% of the total mass.
  • the amount of polyethylene glycol 400 accounts for 56%-58% of the total mass.
  • the amount of polyethylene glycol 400 can account for about 56%, about 56.1%, about 56.2%, about 56.3, about 56.4, about 56.5, about 56.6%, about 56.7%, about 56.8%, about 56.9%, about 57%, about 57.1%, about 57.2%, about 57.3, about 57.4, about 57.5, about 57.6%, about 57.7%, about 57.8%, about 57.9%, or about 58%.
  • the amount of polyethylene glycol 3350 accounts for 25%-35% of the total mass.
  • the amount of polyethylene glycol 3350 can account for about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33% of the total mass. %, about 34% or about 35%.
  • the amount of polyethylene glycol 3350 accounts for 28%-33% of the total mass.
  • the amount of polyethylene glycol 3350 may account for about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34% or about 35% of the total mass.
  • the amount of polyethylene glycol 3350 accounts for 30%-32% of the total mass.
  • the amount of polyethylene glycol 3350 can account for about 30%, about 30.1%, about 30.2%, about 30.3, about 30.4, about 30.5, about 30.6%, about 30.7%, about 30.8%, about 30.9%, about 31%, about 31.1%, about 31.2%, about 31.3, about 31.4, about 31.5, about 31.6%, about 31.7%, about 31.8%, about 31.9%, or about 32%.
  • the ointment of the present application not only considers the stability of the preparation formula, but also improves the hard application feel caused by the polyethylene glycol base by adding a certain proportion of propylene glycol, taking into account the patient or user experience.
  • the amount of propylene glycol accounts for 8% to 12% of the total mass.
  • the amount of propylene glycol may account for about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5% or about 12% of the total mass.
  • the amount of propylene glycol may account for about 10% of the total mass.
  • the solubilizing agent is used in an amount of 0.1% to 1% of the total mass.
  • the amount of the solubilizing agent may account for about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1%.
  • the solubilizing agent is used in an amount of 0.3% to 0.7% of the total mass.
  • the amount of the solubilizing agent may account for about 0.3%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.36%, about 0.37%, about 0.38%, about 0.39%, about 0.4%, about 0.41%, about 0.42%, about 0.43%, about 0.44%, about 0.45%, about 0.46%, about 0.47%, about 0.48%, about 0.49%, about 0.5%, about 0.51% , about 0.52%, about 0.53%, about 0.54%, about 0.55%, about 0.56%, about 0.57%, about 0.58%, about 0.59%, about 0.6%, about 0.61%, about 0.62%, about 0.63%, about 0.64%, about 0.65%, about 0.66%, about 0.67%, about 0.68%, about 0.69%, or about 0.7%.
  • the solubilizing agent may include triethanolamine.
  • the rifamycin-quinolizinone coupling molecule ointment described in the present application may contain about 0.3%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35% of the total mass.
  • the rifamycin-quinozinone coupling molecule ointment described in this application can also add antioxidants to improve its stability during storage and improve its oxidative degradation.
  • the antioxidant is used in an amount of 0.3% to 1% of the total mass.
  • the amount of the antioxidant can account for about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, About 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1%.
  • the antioxidant is used in an amount of 0.5% to 1% of the total mass.
  • the amount of the antioxidant can account for about 0.5%, about 0.51%, about 0.52%, about 0.53%, about 0.54%, about 0.55%, about 0.56%, about 0.57%, about 0.58%, About 0.59%, about 0.6%, about 0.61%, about 0.62%, about 0.63%, about 0.64%, about 0.65%, about 0.66%, about 0.67%, about 0.68%, about 0.69%, about 0.7%, about 0.71 %, about 0.72%, about 0.73%, about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about 0.79%, about 0.8%, about 0.81%, about 0.82%, about 0.83%, About 0.84%, about 0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, about 0.9%, about 0.91%, about 0.92%, about 0.93%, about 0.94%, about
  • the antioxidant includes one or a combination of vitamin C and vitamin E.
  • the antioxidant may be vitamin C, vitamin E, or a combination of vitamin C and vitamin E.
  • the rifamycin-quinolizinone coupling molecule ointment described in the present application may contain about 0.5%, about 0.51%, about 0.52%, about 0.53%, about 0.54%, about 0.55% of the total mass.
  • the amount of vitamin C and/or vitamin E accounts for 0.3%-0.5% of the total mass.
  • the amount of vitamin C can account for about 0.3%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.36%, about 0.37%, about 0.38%, about 0.39%, about 0.4%, about 0.41%, about 0.42%, about 0.43%, about 0.44%, about 0.45%, about 0.46%, about 0.47%, about 0.48%, about 0.49%, or about 0.5%
  • the amount of vitamin E can account for about 0.3%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.36%, about 0.37%, about 0.38%, about 0.39% of the total mass. , about 0.4%, about 0.41%, about 0.42%, about 0.43%, about 0.44%, about 0.45%, about 0.46%, about 0.47%, about 0.48%, about 0.49%, or
  • the preparation method of the rifamycin-quinolizinone coupling molecule ointment described in the present application includes heating and melting polyethylene glycol 3350, propylene glycol, solubilizer, antioxidant and polyethylene glycol 400 to obtain a first mixture , in this heating and melting process, part of the quantitative polyethylene glycol 400 can be added, or all of the quantitative polyethylene glycol 400 can be added.
  • the temperature of the heating and melting is not lower than 70°C.
  • the heating and melting temperature may be about 70°C, about 71°C, about 72°C, about 73°C or higher.
  • the preparation method described in the present application also includes mixing the rifamycin-quinolizinone coupling molecule with the first mixture containing all polyethylene glycol 400.
  • the temperature of the mixing step is not lower than 50 °C, for example, the temperature of the mixing step can be about 50°C, about 51°C, about 52°C, about 53°C or higher; alternatively, the preparation method described in the present application also includes adding rifamycin-quinolizinone
  • the coupling molecule is mixed and dissolved with the remaining polyethylene glycol 400 in the step of heating and melting to obtain the first mixture, and then mixed with the first mixture, and the mixing and dissolving as well as the polyethylene glycol 400 mixed with the first mixture are The temperature is not lower than 50°C.
  • the temperature at which the mixture is dissolved and mixed with the first mixture may be about 50°C, about 51°C, about 52°C, about 53°C or higher.
  • ointment As a relatively safe external preparation, ointment is a better choice because it is easy to use and targeted for skin and skin tissue infections.
  • Commonly used ointment bases include PEG400 (polyethylene glycol 400), etc. Since the solubility of the rifamycin-quinolizinone coupling molecule is relatively low, the base needs to be selected so that the base can better dissolve the drug. , to increase the drug content of the preparation.
  • the solubility of the rifamycin-quinolizinone coupling molecule in PEG400 at 40°C is greater than the preparation specification (specification 0.5%, i.e. 5mg/g), better than room temperature conditions, and significantly better than other matrices, such as propylene glycol. . Therefore, PEG400 is used as the main matrix.
  • Propylene glycol has a lower viscosity than PEG400, is miscible with PEG400, and can be melt-mixed with PEG3350, which can significantly improve the harder feel of polyethylene glycol hydrophilic ointment; 2. Propylene glycol As a commonly used moisturizer in external preparations, it can maintain the consistency of the ointment; 3. Propylene glycol has certain antibacterial properties.
  • the bases of the ointments are compared. The products of the embodiments of the present application can improve the situation in which the existing ointments are hard and waxy and have a bad application feel.
  • This embodiment provides a rifamycin-quinolizinone coupling molecule ointment.
  • the raw material components of the rifamycin-quinolizinone coupling molecule ointment include: 0.5% of the mass of rifamycin-quinozinone coupling molecule, 56%-58% of the total mass of polyethylene glycol 400, 30%-32% of the total mass of polyethylene glycol 3350 , the amount of propylene glycol accounts for 10% of the total mass, the amount of vitamin C accounts for 0-0.5% of the total mass, the amount of vitamin E accounts for 0-0.5% of the total mass, and the amount of BHT accounts for 0-0.5% of the total mass.
  • Rifamycin-quinolizinone coupling molecules may oxidatively degrade and produce oxidative impurities when exposed to air during the preparation process.
  • the reaction structure changes are shown in Figure 1; in order to reduce the For the oxidative degradation rate, the single or combined use and dosage of several antioxidants such as 2,6-di-tert-butyl-p-cresol (Butylated Hydroxytoluene, BHT), vitamin C, and vitamin E were investigated.
  • BHT butylated Hydroxytoluene
  • the ointment paste prepared in Example 2 was subjected to microscopic examination and comparison. The results are shown in Figure 2. It can be seen that the material of Formula 11 has a tendency of precipitation or aggregation of red API when stored at 2-8°C for 5 months. The content uniformity is qualified but the RSD is high (5.5%). It is possible that the API precipitates causing the content uniformity value to be unsatisfactory.
  • triethanolamine is added as a solubilizing agent in the embodiments of the present disclosure.
  • the rifamycin-quinozinone coupling molecular structure has one carboxylic acid and three phenolic hydroxyl groups that can provide H + .
  • Triethanolamine provides a lone pair of electrons and can form an ion pair complex with the organic acid rifamycin-quinolinone coupling molecule.
  • the ion pair complex has a lower lattice energy.
  • the rifamycin-quinolinone coupling molecule More easily soluble in solvents.
  • triethanolamine has a certain alkalinity.
  • triethanolamine it is initially planned to use triethanolamine to adjust the ointment to neutrality.
  • the acidity and alkalinity of the ointment can be examined.
  • the amount of triethanolamine added is preliminarily calculated from the amount of API and vitamin C.
  • triethanolamine provides a lone pair of electrons and is a Lewis base, which can form a salt with carboxylic acid or Lewis acid at room temperature without catalysis.
  • the direct pH measurement data are the data measured three times on the same batch of samples; the pH data (measured when diluted twice with pure water) are the pH data measured three times after the same centrifuge tube sample was diluted twice.
  • adding triethanolamine can adjust the pH of the ointment from weakly acidic to neutral.
  • This embodiment provides a rifamycin-quinolizinone coupling molecule ointment.
  • the raw material components of the rifamycin-quinolizinone coupling molecule ointment include: rifamycin-quinolizinone coupling molecule accounts for 0.5% of the mass, polyethylene glycol 400 accounts for 56% of the total mass, polyethylene glycol 3350 accounts for 32% of the total mass, and polyethylene glycol 3350 accounts for 32% of the total mass. 10% propylene glycol, 0.5% triethanolamine, 0.5% vitamin C, and 0.5% vitamin E.
  • PEG3350 polyethylene glycol 3350
  • PEG400 polyethylene glycol 400
  • the rifamycin-quinozinone coupling molecule ointment is all prepared by this method, and the difference is that the formula composition of each excipient is slightly different.
  • Staphylococcus aureus is one of the most common human bacterial pathogens, causing skin and soft tissue infections (SSTI), bacteremia, osteomyelitis, and other disseminated infections.
  • Penicillin-binding protein PBP2a is responsible for drug resistance in Staphylococcus aureus The main cause of sex.
  • PBP2a has poor binding ability to ⁇ -lactam antibiotics. In the presence of these antibiotics, it can maintain the stability of bacterial peptidoglycan, thereby causing bacteria to become resistant.
  • PBP2a-containing strains known as methicillin-resistant Staphylococcus aureus (MRSA), of which S.
  • aureus NRS 384 is one, have gained prominence in the United States for causing infections in health care settings, primarily on the skin. Related to soft tissue infections. Rifamycin-quinolizinone coupling molecule ointment is an ointment preparation to be tested prepared by Danno Pharmaceuticals (Suzhou) Co., Ltd. and is intended to be used for the treatment of Staphylococcus aureus infection. In this experiment, S. aureus NRS 384 was selected to establish a mouse skin infection model to evaluate the antibacterial activity of rifamycin-quinolizinone conjugated molecule ointment on the skin surface.
  • the CFU counting results of the inoculum solution are as follows: the actual measured concentration of the inoculum solution is 3.85E+09CFU/mL, and the inoculation volume of each mouse is 3.85E+07CFU.
  • This study used S. aureus NRS 384 to construct a stable mouse skin infection model and evaluate the antibacterial activity of rifamycin-quinolizinone conjugated molecule ointment on the skin surface.
  • the results showed that the rifamycin-quinolizinone coupling molecule ointment can effectively reduce the bacterial load on the skin of mice and exhibit dose-dependent bactericidal activity.

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Abstract

一种利福霉素-喹嗪酮偶联分子软膏剂。所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：以质量百分比总和为100％计，利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.7％，聚乙二醇400的用量占总质量的55％-65％、聚乙二醇3350的用量占总质量的25％-35％、丙二醇的用量占总质量的8％-12％、增溶剂的用量占总质量的0.1％-1％、抗氧剂的用量占总质量的0.3％-1％。该利福霉素-喹嗪酮偶联分子软膏剂能够提升制剂的药物含量及药物成分的稳定性，提升用药效果及用户感受。

Description

利福霉素-喹嗪酮偶联分子软膏剂及其制备方法 技术领域
本申请涉及医药技术领域，尤其涉及一种利福霉素-喹嗪酮偶联分子软膏剂及其制备方法。
背景技术
利福霉素-喹嗪酮偶联分子是一种多靶点药物，其结构式如下式I所示：
其是由利福霉素和喹诺酮药效团组成，能够有效治疗细菌感染。利福霉素-喹嗪酮偶联分子水中溶解度低，可溶于二氯甲烷、聚乙二醇400和二甲基亚砜，几乎不溶于乙醇、甲醇和乙醚；水溶性呈pH依赖性，在pH 10溶解度最大，低pH条件下溶解度较低。此外，利福霉素-喹嗪酮偶联分子暴露在空气中可能被氧化，从酚转化成醌的形式。而温度超过60℃时会出现降解。干燥保存时，主要降解产物为醌式结构。化合物的氧化或降解可能造成药物有效剂量的降低。故需要通过一系列的改进或制成某些特定的制剂来拓宽应用前景。
发明内容
鉴于上述现有技术存在的缺陷，本申请的目的是提供一种利福霉素-喹嗪酮偶联分子软膏剂，能够提升制剂的药物含量及药物成分的稳定性，防止氧化产物的产生，提升用药效果，提高用药安全性。
本申请的目的还在于提供一种利福霉素-喹嗪酮偶联分子软膏剂的制备方法，能够提升产品的药物含量及产品的稳定性。
本申请的目的通过以下技术方案得以实现：
一方面，本申请提供一种利福霉素-喹嗪酮偶联分子软膏剂，其特征在于，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：式Ⅰ所示的化合物利福霉素-喹嗪酮偶联分子、聚乙二醇400、聚乙二醇3350、丙二醇、增溶剂和抗氧剂；
以质量百分比总和为100％计，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.7％，所述聚乙二醇400的用量占总质量的55％-65％、所述聚乙二醇3350的用量占总质量的25％-35％、所述丙二醇的用量占总质量的8％-12％、所述增溶剂的用量占总质量的0.1％-1％、所述抗氧剂的用量占总质量的0.3％-1％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.3％-0.7％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.5％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.5％。
在一些实施方案中，所述聚乙二醇400的用量占总质量的55％-60％。
在一些实施方案中，所述聚乙二醇400的用量占总质量的56％-58％。
在一些实施方案中，所述聚乙二醇3350的用量占总质量的28％-33％。
在一些实施方案中，所述聚乙二醇3350的用量占总质量的30％-32％。
在一些实施方案中，所述增溶剂的用量占总质量的0.3％-0.7％。
在一些实施方案中，所述增溶剂包括三乙醇胺。
在一些实施方案中，所述抗氧剂的用量占总质量的0.5％-1％。
在一些实施方案中，所述抗氧剂包括维生素C、维生素E中的一种或几种的组合。
在一些实施方案中，所述维生素C和/或所述维生素E的用量占总质量的0.3％-0.5％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：式Ⅰ所示的化合物利福霉素-喹嗪酮偶联分子、聚乙二醇400、聚乙二醇3350、丙二醇、增溶剂和抗氧剂；以质量百分比总和为100％计，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.3％-0.7％，所述聚乙二醇400的用量占总质量的55％-60％、所述聚乙二醇3350的用量占总质量的28％-33％、所述丙二醇的用量占总质量的8％-12％、所述增溶剂的用量占总质量的0.1％-1％、所述抗氧剂的用量占总质量的0.5％-1％。上述的利福霉素-喹嗪酮偶联分子软膏剂中，优选的，所述增溶剂包括三乙醇胺。上述的利福霉素-喹嗪酮偶联分子软膏剂中，优选的，所述抗氧剂包括维生素C、维生素E中的一种或几种的组合。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：以质量百分比总和为100％计，用量占总质量的约0.5％的利福霉素-喹嗪酮偶联分子，用量占总质量的56％-58％的聚乙二醇400、用量占总质量的30％-32％的聚乙二醇3350、用量占总质量的约10％的丙二醇、用量占总质量的0.3％-0.7％的三乙醇胺、用量占总质量的0.3％-0.5％的维生素C、用量占总质量的0.3％-0.5％的维生素E。
另一方面，本申请提供本申请所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法，包括：将聚乙二醇3350、丙二醇、增溶剂、抗氧剂及部分的聚乙二醇400加热熔融，混合得到第一混合物；将利福霉素-喹嗪酮偶联分子与剩余部分的聚乙二醇400混合溶解得到第一药液；将所述第一药液与所述第一混合物混合，得到利福霉素-喹嗪酮偶联分子软膏剂。
在一些实施方案中，在所述将利福霉素-喹嗪酮偶联分子与剩余部分的聚乙二醇400混合溶解得到第一药液的步骤中，混合溶解的温度为50℃。
在一些实施方案中，在将所述第一药液与所述第一混合物混合的步骤中，混合的温度为50℃-53℃。
另一方面，本申请提供本申请所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法，包括：将聚乙二醇3350、丙二醇、增溶剂、抗氧剂及聚乙二醇400加热熔融，混合得到第一混合物；将利福霉素-喹嗪酮偶联分子与所述第一混合物混合，得到利福霉素-喹嗪酮偶联分子软膏剂。
在一些实施方案中，所述加热熔融的温度为70℃-73℃。
在一些实施方案中，在所述将利福霉素-喹嗪酮偶联分子与所述第一混合物混合的步骤中，混合的温度为50℃。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：
图1显示的是利福霉素-喹嗪酮偶联分子氧化降解产生氧化杂质的反应式。
图2显示的是添加不同增溶剂配方的电子显微镜镜检对比结果。
图3显示的是本发明实施例5小鼠荷菌量结果图。
具体实施方式
为了对本发明申请的技术特征、目的和有益效果有更加清楚的理解，现对本发明申请的技术方案进行以下详细说明，但不能理解为对本发明的可实施范围的限定。下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
术语定义
在本申请中，术语“软膏制剂”通常是指药物和油脂性或水溶性基质混合制成的均匀的半固体外用制剂。其因为药物在所述基质中的分散状态不同可分为溶液型软膏剂和混悬型软膏剂，其中溶剂型软膏剂为药物溶解或共溶于基质或基质组分中而制成的软膏剂型，而混悬型软膏剂为药物细粉均匀分散于基质中而制成的软膏剂型。本申请所提供的软膏制剂通常用于外用和局部治疗，在某些实施方案中，软膏制剂中的药物(例如，本申请所述的式I化合物)经透皮吸收后可发挥全身的药理或治疗作用。在某些实施方案中，软膏剂型的基质作为赋形剂和药物载体，可对软膏剂的质量和药物的释放与吸收产生重要影响。本领域常见的软膏剂型的基质可分为油脂性基质、乳剂基质和水溶性基质。可采用本领域适合的制备方法和工艺获得本申请治疗方法所需要的软膏剂型。
在本申请中，术语“熔融”通常是指一级相转变的过程，其伴随着热焓、熵和体积的增大；例如，温度升高时，分子的热运动的动能增大，导致结晶被破坏，物质由晶相转变为液相的过程可称为熔融；例如在本申请中，常温下为固体的物质在加热到一定温度下达到熔点 变为液态物质而具有了液体的某些物理性质的过程，也可称为熔融。熔融状态下的物质可能处于液态，也可能处于固液共存的状态。
在本申请中，术语“混合”通常是指将在相同的区域中一种或多种化合物、细胞、分子等组合在一起的过程。这可以例如在试管、培养皿或允许混合一种或多种化合物、细胞或分子的任意容器中进行。
本申请中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值，每一个数字的数值有可能会出现例如±1％，±2％，或±5％等差异。术语“约”或“大约”则通常由本领域普通技术人员确定的针对特定值的可接受误差范围内，其部分取决于怎样测量或确定该值，即，测量系统的限制。例如，“约”或“大约”可意指按照本领域的实践在1或超过1个标准偏差内。或者，“约”或“大约”可意指至多10％或20％的范围(即，±10％或±20％)。例如，约3mg可包括2.7mg和3.3mg之间(对于10％)或2.4mg和3.6mg之间(对于20％)的任何数量。此外，特别是关于生物学系统或过程，该术语可意指至多一个数量级的值或至多5倍的值。当具体的值或组合物在本说明书和所附权利要求书中提供时，除了另外说明，“约”或“大约”的含义应假定在对于该具体的值或组合物可接受的误差范围内。
发明详述
一方面，本申请提供一种利福霉素-喹嗪酮偶联分子软膏剂，其特征在于，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：式Ⅰ所示的化合物利福霉素-喹嗪酮偶联分子、聚乙二醇400、聚乙二醇3350、丙二醇、增溶剂和抗氧剂；以质量百分比总和为100％计，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.7％，所述聚乙二醇400的用量占总质量的55％-65％、所述聚乙二醇3350的用量占总质量的25％-35％、所述丙二醇的用量占总质量的8％-12％、所述增溶剂的用量占总质量的0.1％-1％、所述抗氧剂的用量占总质量的0.3％-1％。
另一方面，本申请提供本申请所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法，包括：将聚乙二醇3350、丙二醇、增溶剂、抗氧剂及部分的聚乙二醇400加热熔融，混合得到第一混合物；将利福霉素-喹嗪酮偶联分子与剩余部分的聚乙二醇400混合溶解得到第一药液；将所述第一药液与所述第一混合物混合，得到利福霉素-喹嗪酮偶联分子软膏剂。
另一方面，本申请提供本申请所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法，包括：将聚乙二醇3350、丙二醇、增溶剂、抗氧剂及聚乙二醇400加热熔融，混合得到第一混合物；将利福霉素-喹嗪酮偶联分子与所述第一混合物混合，得到利福霉素-喹嗪酮偶联分子软膏剂。
利福霉素-喹嗪酮偶联分子
利福霉素-喹嗪酮偶联分子(API)是一种多靶点化合物，由利福霉素和喹诺酮药效团组成，其结构式如式Ⅰ所示，
其对葡萄球菌、链球菌和肺炎球菌等细菌具有活性，其外用制剂可用于治疗皮肤感染。该药物作用于三个不同靶点，包括RNA聚合酶、DNA旋转酶和拓扑异构酶IV。这种多靶点作用机制能够产生降低耐药倾向的技术效果。利福霉素-喹嗪酮偶联分子原料药均为丹诺医药制备。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.7％。例如，所述利福霉素-喹嗪酮偶联分子的用量可占总质量的约0.05％、约0.06％、约0.07％、约0.08％、约0.09％、约0.1％、约0.15％、约0.2％、约0.25％、约0.3％、约0.35％、约0.4％、约0.45％、约0.5％、约0.55％、约0.6％、约0.65％或约0.7％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.3％-0.7％。例如，所述利福霉素-喹嗪酮偶联分子的用量可占总质量的约0.3％、约0.35％、约0.4％、约0.45％、约0.5％、约0.55％、约0.6％、约0.65％或约0.7％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.5％。例如，所述利福霉素-喹嗪酮偶联分子的用量可占总质量的约0.05％、约0.06％、约0.07％、约0.08％、约0.09％、约0.1％、约0.15％、约0.2％、约0.25％、约0.3％、约0.35％、约0.4％、约0.45％、或约0.5％。
在一些实施方案中，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.5％。
聚乙二醇400和聚乙二醇3350
利福霉素-喹嗪酮偶联分子的溶解性比较低，本申请为了获得具有合适含药量和稳定性的软膏剂，提供了聚乙二醇400和聚乙二醇3350组合的软膏剂基质。
在一些实施方案中，所述聚乙二醇400的用量占总质量的55％-65％。例如，所述聚乙二醇400的用量可占总质量的约55％、约56％、约57％、约58％、约59％、约60％、约61％、约62％、约63％、约64％或约65％。
在一些实施方案中，所述聚乙二醇400的用量占总质量的55％-60％。例如，所述聚乙二醇400的用量可占总质量的约55％、约56％、约57％、约58％、约59％或约60％。
在一些实施方案中，所述聚乙二醇400的用量占总质量的56％-58％。例如，所述聚乙二醇400的用量可占总质量的约56％、约56.1％、约56.2％、约56.3、约56.4、约56.5、约56.6％、约56.7％、约56.8％、约56.9％、约57％、约57.1％、约57.2％、约57.3、约57.4、约57.5、约57.6％、约57.7％、约57.8％、约57.9％或约58％。
在一些实施方案中，所述聚乙二醇3350的用量占总质量的25％-35％。例如，所述聚乙二醇3350的用量可占总质量的约25％、约26％、约27％、约28％、约29％、约30％、约31％、约32％、约33％、约34％或约35％。
在一些实施方案中，所述聚乙二醇3350的用量占总质量的28％-33％。例如，所述聚乙二醇3350的用量可占总质量的约28％、约29％、约30％、约31％、约32％、约33％、约34％或约35％。
在一些实施方案中，所述聚乙二醇3350的用量占总质量的30％-32％。例如，所述聚乙二醇3350的用量可占总质量的约30％、约30.1％、约30.2％、约30.3、约30.4、约30.5、约30.6％、约30.7％、约30.8％、约30.9％、约31％、约31.1％、约31.2％、约31.3、约31.4、约31.5、约31.6％、约31.7％、约31.8％、约31.9％或约32％。
丙二醇
本申请的软膏剂不单单考虑了制剂配方的稳定性，还通过添加一定比例的丙二醇以改善聚乙二醇类基质带来的偏硬的涂抹感，兼顾了患者或使用者的使用体验。在一些实施方案中，所述丙二醇的用量占总质量的8％-12％。例如，所述丙二醇的用量可占总质量的约8％、约8.5％、约9％、约9.5％、约10％、约10.5％、约11％、约11.5％或约12％。具体地，所述丙二醇的用量可占总质量的约10％。
增溶剂
为解决利福霉素-喹嗪酮偶联分子的低溶解性以及其可能带来的API析出或聚集的不利 趋势，本申请的软膏剂组分中还添加了适当的增溶剂。在一些实施方案中，所述增溶剂的用量占总质量的0.1％-1％。例如，所述增溶剂的用量可占总质量的约0.1％、约0.15％、约0.2％、约0.25％、约0.3％、约0.35％、约0.4％、约0.45％、约0.5％、约0.55％、约0.6％、约0.65％、约0.7％、约0.75％、约0.8％、约0.85％、约0.9％、约0.95％或约1％。
在一些实施方案中，所述增溶剂的用量占总质量的0.3％-0.7％。例如，所述增溶剂的用量可占总质量的约0.3％、约0.31％、约0.32％、约0.33％、约0.34％、约0.35％、约0.36％、约0.37％、约0.38％、约0.39％、约0.4％、约0.41％、约0.42％、约0.43％、约0.44％、约0.45％、约0.46％、约0.47％、约0.48％、约0.49％、约0.5％、约0.51％、约0.52％、约0.53％、约0.54％、约0.55％、约0.56％、约0.57％、约0.58％、约0.59％、约0.6％、约0.61％、约0.62％、约0.63％、约0.64％、约0.65％、约0.66％、约0.67％、约0.68％、约0.69％或约0.7％。
在一些实施方案中，所述增溶剂可包括三乙醇胺。例如，本申请所述的利福霉素-喹嗪酮偶联分子软膏剂可包含用量占总质量的约0.3％、约0.31％、约0.32％、约0.33％、约0.34％、约0.35％、约0.36％、约0.37％、约0.38％、约0.39％、约0.4％、约0.41％、约0.42％、约0.43％、约0.44％、约0.45％、约0.46％、约0.47％、约0.48％、约0.49％、约0.5％、约0.51％、约0.52％、约0.53％、约0.54％、约0.55％、约0.56％、约0.57％、约0.58％、约0.59％、约0.6％、约0.61％、约0.62％、约0.63％、约0.64％、约0.65％、约0.66％、约0.67％、约0.68％、约0.69％或约0.7％的三乙醇胺。
抗氧剂
本申请所述的利福霉素-喹嗪酮偶联分子软膏剂还可通过添加抗氧剂以提高其在贮存过程中的稳定性，改善其氧化降解的情况。在一些实施方案中，所述抗氧剂的用量占总质量的0.3％-1％。例如，所述抗氧剂的用量可占总质量的约0.3％、约0.35％、约0.4％、约0.45％、约0.5％、约0.55％、约0.6％、约0.65％、约0.7％、约0.75％、约0.8％、约0.85％、约0.9％、约0.95％或约1％。
在一些实施方案中，所述抗氧剂的用量占总质量的0.5％-1％。例如，所述抗氧剂的用量可占总质量的约0.5％、约0.51％、约0.52％、约0.53％、约0.54％、约0.55％、约0.56％、约0.57％、约0.58％、约0.59％、约0.6％、约0.61％、约0.62％、约0.63％、约0.64％、约0.65％、约0.66％、约0.67％、约0.68％、约0.69％、约0.7％、约0.71％、约0.72％、约0.73％、约0.74％、约0.75％、约0.76％、约0.77％、约0.78％、约0.79％、约0.8％、约0.81％、约0.82％、约0.83％、约0.84％、约0.85％、约0.86％、约0.87％、约0.88％、约0.89％、约0.9％、约 0.91％、约0.92％、约0.93％、约0.94％、约0.95％、约0.96％、约0.97％、约0.98％、约0.99％或约1％。
在一些实施方案中，所述抗氧剂包括维生素C、维生素E中的一种或几种的组合。例如，所述抗氧剂可以是维生素C、维生素E或者维生素C与维生素E的组合形式。例如，本申请所述的利福霉素-喹嗪酮偶联分子软膏剂可包含用量占总质量的约0.5％、约0.51％、约0.52％、约0.53％、约0.54％、约0.55％、约0.56％、约0.57％、约0.58％、约0.59％、约0.6％、约0.61％、约0.62％、约0.63％、约0.64％、约0.65％、约0.66％、约0.67％、约0.68％、约0.69％、约0.7％、约0.71％、约0.72％、约0.73％、约0.74％、约0.75％、约0.76％、约0.77％、约0.78％、约0.79％、约0.8％、约0.81％、约0.82％、约0.83％、约0.84％、约0.85％、约0.86％、约0.87％、约0.88％、约0.89％、约0.9％、约0.91％、约0.92％、约0.93％、约0.94％、约0.95％、约0.96％、约0.97％、约0.98％、约0.99％或约1％的维生素C、维生素E或者维生素C与维生素E的组合。
在一些实施方案中，所述维生素C和/或所述维生素E的用量占总质量的0.3％-0.5％。例如，所述维生素C的用量可占总质量的约0.3％、约0.31％、约0.32％、约0.33％、约0.34％、约0.35％、约0.36％、约0.37％、约0.38％、约0.39％、约0.4％、约0.41％、约0.42％、约0.43％、约0.44％、约0.45％、约0.46％、约0.47％、约0.48％、约0.49％或约0.5％，和/或所述维生素E的用量可占总质量的约0.3％、约0.31％、约0.32％、约0.33％、约0.34％、约0.35％、约0.36％、约0.37％、约0.38％、约0.39％、约0.4％、约0.41％、约0.42％、约0.43％、约0.44％、约0.45％、约0.46％、约0.47％、约0.48％、约0.49％或约0.5％。
软膏剂的制备方法
本申请所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法包括将聚乙二醇3350、丙二醇、增溶剂、抗氧剂和聚乙二醇400加热熔融以获得第一混合物，该加热熔融过程可加入定量聚乙二醇400的一部分，也可加入定量聚乙二醇400的全部，在某些情形下，所述加热熔融的温度不低于70℃。例如，所述加热熔融的温度可以是约70℃、约71℃、约72℃、约73℃或者更高。本申请所述的制备方法还包括将利福霉素-喹嗪酮偶联分子与包含全部聚乙二醇400的第一混合物混合，在某些情形下，该混合步骤的温度不低于50℃，例如，该混合步骤的温度可以是约50℃、约51℃、约52℃、约53℃或者更高；或者，本申请所述的制备方法还包括将利福霉素-喹嗪酮偶联分子与所述加热熔融获得第一混合物的步骤中剩余的聚乙二醇400混合溶解后再与所述第一混合物混合，且所述混合溶解以及与所述第一混合物混合的 的温度均不低于50℃，例如，所述混合溶解以及与所述第一混合物混合的温度可以是约50℃、约51℃、约52℃、约53℃或者更高。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的软膏剂及其制备方法和用途等，而不用于限制本申请发明的范围。
实施例
实施例1
软膏剂基质选择
软膏剂作为一种较为安全的外用制剂，其使用方便、靶向性地针对皮肤和皮肤组织感染，是一种较好的选择。常用的软膏剂的基质如PEG400(即聚乙二醇400)等，鉴于利福霉素-喹嗪酮偶联分子的溶解性比较低，故基质需要进行选择，使得基质能够较好地溶解药物，提升制剂的含药量。
实验步骤：将约340mg API分别逐步缓慢加入约5g PEG400(40℃水浴)，磁力搅拌溶解。橙红色混合物逐渐粘稠，搅拌不动，逐步添加约7g PEG400，继续搅拌20分钟。分成两份：一份40℃水浴，一份冷却至室温。两份均用PES水膜(13mm，0.45μm)过滤，得滤液送检含量。
将约400mg API分别逐步缓慢加入约5g丙二醇(40℃水浴)，搅拌溶解。橙红色混合物逐渐粘稠，搅拌不动，逐步添加约7g PEG400，继续搅拌20分钟。分成两份：一份40℃水浴，一份冷却至室温。两份均用PES水膜(13mm，0.45μm)过滤，得滤液送检含量。
测试4份滤液中的药物含量。如下表1所示。
表1 API在基质中的溶解度
由上表可见，利福霉素-喹嗪酮偶联分子在PEG400中40℃的溶解度大于制剂规格(规格0.5％，即5mg/g)，优于室温条件，明显优于其他基质，如丙二醇。故采用PEG400作为主要基质。
如PEG400作为单一软膏剂的基质时，软膏剂偏硬，涂布感受不佳。经过多次试验，在基质中加入不同比例的丙二醇，获得以下配方，进行对比测试。配方组成如下表2所示：
表2 不同基质配方考察
实验步骤：按配方量称量各辅料，采用一锅煮法，各批次辅料不分先后一次性投入，65-73℃水浴加热，磁力搅拌，熔融前缓慢搅拌，熔融后1500rpm搅拌10分钟后，室温800rpm搅拌冷却至凝固。
将上述不同比例的基质配方放置2-8℃冰箱过夜，第二天取出恢复至室温，分别观察产品外观及显微镜图，并体验涂抹感。通过对比发现，配方1、配方2、配方3呈现蜡状，尤其配方3呈现蜡状固液分离，而配方4、配方5、配方6、配方7则呈现雪花状并逐渐稀薄；相应的7个配方的涂抹感也从能够涂抹到容易涂抹均匀转变。显微镜显示，配方4、配方5的基质分布相对更均匀，更适合作为基质。
通过试验可以看出，选用丙二醇的优点在于：1、丙二醇比PEG400黏度低，且与PEG400互溶，与PEG3350可熔融混合，可显著改善聚乙二醇亲水性软膏较硬的感官；2、丙二醇作为外用制剂常用保湿剂可保持软膏稠度；3、丙二醇具有一定抑菌性。本申请的实施例中，对于软膏剂的基质进行对比，本申请的实施例的产品能够改善现有软膏剂呈偏硬的蜡状，涂抹感不好的情况。
实施例2
氧化剂及其用量的选择
本实施例提供了一种利福霉素-喹嗪酮偶联分子软膏剂，以质量百分比计，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：用量占总质量的0.5％的利福霉素-喹嗪酮偶联分子，用量占总质量的56％-58％的聚乙二醇400、用量占总质量的30％-32％的聚乙二醇3350、用量占总质量的10％的丙二醇、用量占总质量的0-0.5％的维生素C、用量占总质量的0-0.5％的维生素E、用量占总质量的0-0.5％的BHT。
本实施例的利福霉素-喹嗪酮偶联分子软膏剂是通过如下方法制备得到的：
将聚乙二醇3350、丙二醇、抗氧剂及聚乙二醇400加入容器中，70-73℃水浴中加热熔 融，以1000rmp的转速缓慢机械搅拌至澄清溶液后，继续搅拌10分钟，混合得到第一混合物；在50-53℃水浴下，将利福霉素-喹嗪酮偶联分子与所述第一混合物混合，以1000rpm机械搅拌15分钟左右至肉眼观察无利福霉素-喹嗪酮偶联分子粉末；继续搅拌，冷却至40-43℃，得到利福霉素-喹嗪酮偶联分子软膏剂。
配方8-12所述利福霉素-喹嗪酮偶联分子软膏剂均以此方法进行制备，区别在于每种辅料的配方组成稍有不同。
利福霉素-喹嗪酮偶联分子在制备过程中暴露于空气可能会氧化降解产生氧化杂质，其反应结构变化如图1所示；为了降低利福霉素-喹嗪酮偶联分子的氧化降解速率，考察了2,6-二叔丁基对甲酚(Butylated Hydroxytoluene，BHT)、维生素C、维生素E等几种抗氧剂单一使用或联合使用的情况及其用量。配方见表3所示。
表3 不同抗氧剂配方考察
根据上表的配方组成，进行了利福霉素-喹嗪酮偶联分子软膏剂的制备，并对其有关物质进行了考察，结果如下表4所示：
表4 抗氧剂考察有关物质结果

由上表可见，配方8室温放置7天，氧化杂质由0.37％增长至3.55％，总杂质也明显增加，说明BHT未能降低氧化杂质的降解。而抗氧剂VC(VC均为维生素C简称)的加入可以明显提高配方的稳定性，氧化降解情况得到明显改善，其中配方11的氧化杂质和总杂质增长最小，证明0.5％VC+0.5％VE(VE均为维生素E简称)的抗氧剂组合对改善配方稳定性有较好影响。本申请的实施例中，通过对抗氧剂的种类和比例进行对比，本申请的实施例的产品能够改善现有软膏剂氧化杂质的降解，配方稳定性不高的情况。
实施例3
增溶剂筛选与考察
对实施例2中制备的软膏剂膏体进行镜检对比，结果如图2所示，可以看到配方11物料在2-8℃储存5个月时有红色API析出或聚集趋势。含量均匀度合格但是RSD偏高(5.5％)，可能API析出导致含量均匀度数值不理想。
基于API本身溶解度不太理想的情况，本公开的实施例中加入三乙醇胺作为增溶剂。利福霉素-喹嗪酮偶联分子结构中有一个羧酸、三个酚羟基可提供H+。三乙醇胺提供孤对电子可与有机酸利福霉素-喹嗪酮偶联分子形成离子对复合物，离子对复合物具有更低的晶格能，利福霉素-喹嗪酮偶联分子更易溶解于溶剂中。同时三乙醇胺具有一定碱性，软膏初步拟定用三乙醇胺调节乳膏至中性。可考察软膏的酸碱性。三乙醇胺加入量由API和维生素C加入量初步计算得出。理论上三乙醇胺提供孤对电子，为路易斯碱，在常温无催化条件下可与羧酸或路易斯酸成盐。反应式为N-(CH2CH2OH)3+HCOOH＝HCOO-+[HN-(CH2CH2OH)3]+。假设软膏中1mol维生素C提供1mol H+，API结构中有一个羧酸、三个酚羟基可提供H+。以100g软膏为例，中和配方中0.5g维生素C需要0.4235g三乙醇胺，中和API中一个羧酸和三个酚羟基提供的H+需要0.26g三乙醇胺，则理论上三乙醇胺添加量应低于0.4235g+0.26g＝0.6835g，基于此，设置三乙醇胺配方添加量梯度，0.3％，0.5％，0.7％。
在配方11基础上，分别加入0.3％、0.5％、0.7％的三乙醇胺得到配方13-15，考察不同配 方软膏pH、有关物质和性状的影响。
表5 配方pH考察
备注：
1、纯水稀释手工振摇至目测均匀。
2、pH直接测数据为同批样品3次测得的数据；pH(纯水稀释两倍测)数据为同离心管样品稀释两倍后3次测的pH数据。
从上表可以看出，加入三乙醇胺可将软膏pH由弱酸性调节到中性。
表6 不同三乙醇胺加入量配方稳定性结果
酸降解杂质，其结构是如下式所示：从各批次稳定性结果可以看出，三乙醇胺0.3％、0.5％、0.7％的添加量，2-8℃存放3个月，总杂1.32％、1.12％、1.02％，相比仅加抗氧剂配方11总杂1.69％(表7)，化学稳定性有改善；而且从表6中可以看出，3批次的5℃、3个月均无API析出聚集，物理稳定性有改善，增溶效果体现。
实施例4
利福霉素-喹嗪酮偶联分子软膏剂的制备
本实施例提供了一种利福霉素-喹嗪酮偶联分子软膏剂，以质量百分比计，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：用量占总质量的0.5％的利福霉素-喹嗪酮偶联分子，用量占总质量的56％的聚乙二醇400、用量占总质量的32％的聚乙二醇3350、用量占总质量的10％的丙二醇、用量占总质量的0.5％的三乙醇胺、用量占总质量的0.5％的维生素C、用量占总质量的0.5％的维生素E。
本实施例的利福霉素-喹嗪酮偶联分子软膏剂是通过如下方法制备得到的：
将聚乙二醇3350(简称PEG3350)、丙二醇、增溶剂、抗氧剂及聚乙二醇400(简称PEG400)加入容器中，70-73℃水浴中加热熔融，以1000rmp的转速缓慢机械搅拌至澄清溶液后，继续搅拌10分钟，混合得到第一混合物；
在50-53℃水浴下，将利福霉素-喹嗪酮偶联分子与所述第一混合物混合，以1000rpm机械搅拌15分钟左右至肉眼观察无利福霉素-喹嗪酮偶联分子粉末；继续搅拌，冷却至40-43℃，得到利福霉素-喹嗪酮偶联分子软膏剂。
所述利福霉素-喹嗪酮偶联分子软膏剂均以此方法进行制备，区别在于每种辅料的配方组成稍有不同。
实施例5
利福霉素-喹嗪酮偶联分子软膏在皮肤表面的抗菌活性测试
金黄色葡萄球菌(S.aureus)是最常见的人类细菌病原菌之一，可引起皮肤和软组织感染(SSTI)、菌血症、骨髓炎和其他播散性感染。青霉素结合蛋白PBP2a是金黄色葡萄球菌耐药 性产生的主要原因。PBP2a与β-内酰胺类抗生素结合能力较差，在该类抗生素存在的情况下，能维持菌体肽聚糖的稳定，从而使细菌产生耐药。含有PBP2a的菌株，被称为耐甲氧西林金黄色葡萄球菌(MRSA)，S.aureus NRS 384就是其中一株，在美国因其在医疗保健环境中引起感染而引人注目，它主要与皮肤和软组织感染有关。利福霉素-喹嗪酮偶联分子软膏为丹诺医药(苏州)有限公司制备的待测软膏制剂，拟用于金黄色葡萄球菌感染的治疗。本实验选择S.aureus NRS 384建立小鼠皮肤感染模型以评估利福霉素-喹嗪酮偶联分子软膏在皮肤表面的抗菌活性。
实验设计：本实验共设立6组，分别为：空白软膏组、百多邦软膏组、利福霉素-喹嗪酮偶联分子软膏的低、中、高三个剂量组。每组8只动物，具体的分组情况见表7。
表7 给药方案
实验结果：
1)接种菌液计数结果：
接种菌液CFU计数结果如下：接种液实测浓度为3.85E+09CFU/mL，每只小鼠接种量为3.85E+07CFU。
表8 接种剂量
2)小鼠皮肤荷菌量计数结果：
表9 皮肤荷菌量计数结果

注：***与模型组比，p<0.001，具极显著性差异；*与模型组比，0.01<p<0.05，具显著差
异；采用one-way ANOVA分析方法。
本次药效实验结果显示，空白软膏组皮肤载菌量为9.154±0.273lg，使用S.aureus NRS 384可构建稳定的皮肤感染模型(表9，图3)。与空白软膏组相比，经30mg/小鼠的百多邦软膏(2％莫匹罗星)治疗，小鼠皮肤载菌量下降了2.119个Log，具有良好的杀菌作用；分别经0.5％、0.05％和0.005％利福霉素-喹嗪酮偶联分子软膏治疗的动物，皮肤载菌量下降幅度为4.718个Log、3.100个Log和1.063个Log，高剂量组0.5％和0.05％的利福霉素-喹嗪酮偶联分子软膏在该皮肤感染模型中展现出良好的杀菌效果，与空白软膏组动物相比具极显著差异。
实验结论：
本研究使用S.aureus NRS 384构建稳定的小鼠皮肤感染模型，评估利福霉素-喹嗪酮偶联分子软膏剂在皮肤表面的抗菌活性。结果显示，利福霉素-喹嗪酮偶联分子软膏能有效的降低小鼠皮肤载菌量，呈现出剂量依赖性的杀菌活性。

Claims (20)

  1. 一种利福霉素-喹嗪酮偶联分子软膏剂，其特征在于，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：
    式Ⅰ所示的化合物利福霉素-喹嗪酮偶联分子、聚乙二醇400、聚乙二醇3350、丙二醇、增溶剂和抗氧剂；
    以质量百分比总和为100％计，所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.7％，所述聚乙二醇400的用量占总质量的55％-65％、所述聚乙二醇3350的用量占总质量的25％-35％、所述丙二醇的用量占总质量的8％-12％、所述增溶剂的用量占总质量的0.1％-1％、所述抗氧剂的用量占总质量的0.3％-1％。
  2. 根据权利要求1所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.3％-0.7％。
  3. 根据权利要求1所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.05％-0.5％。
  4. 根据权利要求1-3中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述利福霉素-喹嗪酮偶联分子的用量占总质量的0.5％。
  5. 根据权利要求1-4中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述聚乙二醇400的用量占总质量的55％-60％。
  6. 根据权利要求1-5中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述聚乙二醇400的用量占总质量的56％-58％。
  7. 根据权利要求1-6中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述聚乙二醇3350的用量占总质量的28％-33％。
  8. 根据权利要求1-7中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述聚乙二醇3350的用量占总质量的30％-32％。
  9. 根据权利要求1-8中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述增溶剂的用量占总质量的0.3％-0.7％。
  10. 根据权利要求1-9中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述增溶剂包括三乙醇胺。
  11. 根据权利要求1-10中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述抗氧剂的用量占总质量的0.5％-1％。
  12. 根据权利要求1-11中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述抗氧剂包括维生素C、维生素E中的一种或几种的组合。
  13. 根据权利要求12所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于：所述维生素C和/或所述维生素E的用量占总质量的0.3％-0.5％。
  14. 根据权利要求1-13中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂，其特征在于，以质量百分比总和为100％计，所述利福霉素-喹嗪酮偶联分子软膏剂的原料组分包括：用量占总质量的0.5％的利福霉素-喹嗪酮偶联分子，用量占总质量的56％-58％的聚乙二醇400、用量占总质量的30％-32％的聚乙二醇3350、用量占总质量的10％的丙二醇、用量占总质量的0.3％-0.7％的三乙醇胺、用量占总质量的0.3％-0.5％的维生素C、用量占总质量的0.3％-0.5％的维生素E。
  15. 权利要求1-14中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法，包括：
    将聚乙二醇3350、丙二醇、增溶剂、抗氧剂及部分的聚乙二醇400加热熔融，混合得到第一混合物；
    将利福霉素-喹嗪酮偶联分子与剩余部分的聚乙二醇400混合溶解得到第一药液；
    将所述第一药液与所述第一混合物混合，得到利福霉素-喹嗪酮偶联分子软膏剂。
  16. 根据权利要求15所述的制备方法，其特征在于：在所述将利福霉素-喹嗪酮偶联分子与剩余部分的聚乙二醇400混合溶解得到第一药液的步骤中，混合溶解的温度为50℃。
  17. 根据权利要求15所述的制备方法，其特征在于：在将所述第一药液与所述第一混合物混合的步骤中，混合的温度为50℃-53℃。
  18. 权利要求1-14中任一项所述的利福霉素-喹嗪酮偶联分子软膏剂的制备方法，包括：
    将聚乙二醇3350、丙二醇、增溶剂、抗氧剂及聚乙二醇400加热熔融，混合得到第一混合 物；
    将利福霉素-喹嗪酮偶联分子与所述第一混合物混合，得到利福霉素-喹嗪酮偶联分子软膏剂。
  19. 根据权利要求15或18所述的制备方法，其特征在于：所述加热熔融的温度为70℃-73℃。
  20. 根据权利要求18所述的制备方法，其特征在于：在所述将利福霉素-喹嗪酮偶联分子与所述第一混合物混合的步骤中，混合的温度为50℃。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031572A (zh) * 2004-07-22 2007-09-05 坎布里制药公司 (r/s)利福霉素衍生物，它们的制备和药物组合物
CN109453166A (zh) * 2018-10-16 2019-03-12 丹诺医药(苏州）有限公司 一种利福霉素-喹嗪酮偶联分子的固体分散体及其应用
CN109464673A (zh) * 2019-01-08 2019-03-15 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其盐的应用和制剂
CN109529045A (zh) * 2019-01-08 2019-03-29 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其药学上可接受的盐的应用
CN115501230A (zh) * 2022-08-05 2022-12-23 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子软膏剂及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7858607B2 (en) * 2003-03-14 2010-12-28 Mamchur Stephen A System for use by compounding pharmacists to produce hormone replacement medicine customized for each consumer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031572A (zh) * 2004-07-22 2007-09-05 坎布里制药公司 (r/s)利福霉素衍生物，它们的制备和药物组合物
CN101065385A (zh) * 2004-07-22 2007-10-31 坎布里制药公司 治疗微生物感染的利福霉素衍生物
CN109453166A (zh) * 2018-10-16 2019-03-12 丹诺医药(苏州）有限公司 一种利福霉素-喹嗪酮偶联分子的固体分散体及其应用
CN109464673A (zh) * 2019-01-08 2019-03-15 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其盐的应用和制剂
CN109529045A (zh) * 2019-01-08 2019-03-29 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其药学上可接受的盐的应用
CN115501230A (zh) * 2022-08-05 2022-12-23 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子软膏剂及其制备方法

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