37 results about "Posaconazole" patented technology

The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug, wherein the patient is treated with posaconazole. In some embodiments, the patient stops posaconazole treatment, waits for at least 2 days, and then is treated with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 2-42 days after stopping posaconazole. In some embodiments, the patient is treated with a reduced dose of the CYP3A4 substrate drug for about 2-42 days.

The invention provides a posaconazole ethosome and a preparation method thereof, posaconazole is encapsulated in ethosome, and the posaconazole ethosome is composed of the following components by weight: 0.1-5% of posaconazole, 0.1-5% of posaconazole, 0.1-5% of posaconazole, 0.1-5% of posaconazole, and the balance of ethanol. 1-8% of phospholipid; 0%-0.5% of cholesterol; 20%-45% of ethanol; 0-0.1% of an antioxidant; 0%-0.5% of a nonionic surfactant; and 40.9 to 78.9 percent of water. The invention has the characteristics of high encapsulation efficiency, uniform particle size distribution and no irritation to skin. And the ethosome can load both water-soluble drugs and fat-soluble drugs, and has the advantages of simple composition, high encapsulation efficiency, uniform particle size distribution, no skin irritation, simple preparation and the like.

The invention relates to the technical field of medical examination, and discloses a method for rapidly measuring the blood concentration of posaconazole and application of the method. According to the method for rapidly determining the blood concentration of posaconazole and the application of the method, compared with chromatography in the prior art, the adopted mobile phase is relatively single, the configuration time of the mobile phase is saved, and meanwhile, the fluctuation of a detection result caused by the configuration of the mobile phase is reduced to the greatest extent; the stability of the method is further enhanced; meanwhile, compared with other liquid chromatography methods, the detection method has the advantages that the single-needle sample injection time is short, the reagent preparation is simple, no endogenous and common exogenous substance interference exists around the target peak of posaconazole, and the like, and the detection efficiency and the accuracy of the detection result are improved.

A gastro-resistant high-strength unit dosage form includes a solid solution prepared by hot-melt extrusion, whereby the solid solution contains 300 mg posaconazole and an enteric polymer in a specific weight ratio. The unit dosage form may be a capsule or an optionally film-coated tablet.

The present invention relates to the technical field of drug intermediate synthesis, and particularly relates to a preparation method of posaconazole starting material SM3. CeCl3·7H2O and sodium borohydride are added to compound POS-1 for an asymmetric reduction reaction to obtain compound POS-2. Compound POS-2 reacts with 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to obtain compound POS-3. Hydrazine hydrate attacks from the back of compound POS-3 with a larger steric hindrance to undergo an SN2 reaction to obtain a stereoselectively specific compound POS-4. Compound POS-4 then reacts with ethyl formate and forms a salt with oxalic acid to obtain the product posaconazole starting material SM3. By means of asymmetric reduction of carbonyl groups and selective nucleophilic substitution, the present invention effectively avoids the chiral resolution step, thereby reducing the content of isomeric impurities. The prepared product not only has a high ee value, but also the yield is significantly improved, thereby greatly reducing the production cost.

The invention relates to application of azole drugs in preparation of antifungal drugs, and belongs to the technical field of research and development of antifungal drugs. According to the application of the glycyrrhetinic acid combined with the azoles in preparation of the antifungal drugs, the glycyrrhetinic acid combined with the itraconazole, the voriconazole and the posaconazole shows a good synergistic effect or antagonistic effect on aspergillus, ectobottle dermatitis, candida and cryptococcus neoformans, and the application of the glycyrrhetinic acid combined with the itraconazole, the voriconazole and the posaconazole in preparation of the antifungal drugs is disclosed. And a research and development direction is provided for preparing medicines for resisting aspergillus, ectobottle dermatitis, candida and cryptococcus neoformans.

The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug, wherein the patient is treated with posaconazole. In some embodiments, the patient stops posaconazole treatment, waits for at least 3 days, and then is treated with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 3-42 days after stopping posaconazole. In some embodiments, the patient is treated with a reduced dose of the CYP3A4 substrate drug for about 3-42 days.

The application discloses application of gynostemma pentaphyllum saponin H combined with azole drugs in preparation of antifungal drugs and the antifungal drugs, and relates to the technical field of antifungal drugs. It is found through systematic in-vitro drug sensitivity test that natural product gynostemma pentaphyllum saponin H combined with specific azole antifungal drugs (especially posaconazole POS) can produce significant synergistic antifungal effect, especially for clinical thorny aspergillus, candida, new cryptococcus and dark fungi. The combination strategy can significantly reduce the minimum inhibitory concentration of azole drugs, reverse drug resistance, and is effective for multi-drug resistant strains (such as candida auris). The application provides an efficient and low-toxicity new combination drug scheme for overcoming the increasingly serious fungal drug resistance problem.

The invention discloses an in-vitro dissolution method of a posaconazole enteric-coated tablet, which is characterized in that a Tween-80 (TWEEN-80) surfactant is added into a dissolution medium, so that the solubility of the posaconazole enteric-coated tablet in a phosphate buffer solution is remarkably improved, the phenomenon that a solution in a dissolution cup is not uniform is solved, the jump point phenomenon of a dissolution curve is eliminated, and the dissolution rate of the posaconazole enteric-coated tablet is improved. When a phosphate buffer solution added with a certain amount of surfactant is used as a dissolution medium, the accumulated dissolution amount at each time point is stable, the dissolution curve is smooth, the detection result is accurate and reliable, the repeatability and predictability of the dissolution test are remarkably improved, and a more reliable detection method is provided for the initial stage of drug research and development and quality control.

The invention relates to an ophthalmic antifungal phospholipid complex solution containing posaconazole. The ophthalmic antifungal phospholipid complex solution comprises at least one of an anionic phospholipid complex solution, a neutral phospholipid complex solution and a cationic phospholipid complex solution, when the solution is an anionic phospholipid complex solution, the posaconazole, phospholipid, beta-sitosterol, a hydrated buffer solution and an organic solvent are mixed according to a ratio of 10 mg of posaconazole, 20-200 mg of phospholipid, 20-120 mg of beta-sitosterol, 5-20 mL of the hydrated buffer solution and 1-20 mL of the organic solvent; when the solution is a neutral phospholipid complex solution, the posaconazole and phospholipid complex solution is prepared from the following components in proportion: 10 mg of posaconazole, 17.5 to 170 mg of phospholipid, 20 to 120 mg of beta-sitosterol, 2.5 to 30 mg of DSPE-PEG2000, 5 to 20 mL of hydrated buffer solution and 1 to 20 mL of organic solvent; when the solution is a cationic phospholipid complex solution, the following components are proportioned: 10 mg of posaconazole, 17.5 to 170 mg of phospholipid, 20 to 120 mg of beta-sitosterol, 2.5 to 30 mg of DSPE-PEG2000, 20 to 70 mg of a cationic material, 5 to 20 mL of a hydration buffer solution and 1 to 20 mL of an organic solvent. The penetrating power of the phospholipid complex solution in cornea can be remarkably improved, and the effect of treating fungal keratitis is remarkable.

The present invention provides a preparation method of a posaconazole intermediate. In this method, 3-pentanone is used as the starting material, and the posaconazole intermediate is prepared through an asymmetric catalytic oxidation reaction, a substitution reaction and an asymmetric reductive amination reaction. The product obtained by this method has high purity and good yield. The preparation method has fewer steps, the raw materials are cheap and easily available, the operation is simple, the total yield is high, and it is more suitable for industrial production.

The invention discloses a preparation method of a posaconazole key intermediate diol olefin compound, which comprises the following steps: dissolving a compound 1 in an organic solvent A, adding a mixed solution of an additive and an organic solvent B, alkali a and trioxymethylene, continuing to react, and treating to obtain a compound 2; dissolving the obtained compound 2 in an organic solvent C, adding a reducing agent, and performing heating reflux reaction to obtain a compound I; the synthesis route is as follows: the reaction process is simple, the raw materials are simple and easy to obtain, harsh reaction conditions are not needed, the route is simple and convenient, the reaction operation is simple, and the drug development potential is achieved.

The disclosure generally relates to cocrystals of posaconazole and a coformer. The disclosure further relates to pharmaceutical compositions comprising the cocrystals, as well as methods of making the cocrystals, and methods of treating or preventing fungal, yeast, or dermatophyte infections using the cocrystals.

The invention discloses a carbonyl reductase mutant and application of the carbonyl reductase mutant in synthesis of a posaconazole intermediate. The mutant protein is a non-natural protein, and the mutant protein can significantly improve the activity of catalyzing reduction of carbonyl in (S)-2-benzyloxy-3-pentanone to generate R-configuration alcohol. When the carbonyl reductase mutant strain with improved activity is applied to the production process of a posaconazole intermediate, 100-200 g / L of a substrate can be completely converted, and (2S, 3R)-2-benzyloxy-3-pentanol is generated.

The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug, wherein the patient is treated with posaconazole. In some embodiments, the patient stops posaconazole treatment, waits for at least 3 days, and then is treated with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 3-42 days after stopping posaconazole. In some embodiments, the patient is treated with a reduced dose of the CYP3A4 substrate drug for about 3-42 days.

The invention discloses posaconazole fatty acid ester, posaconazole fatty acid ester fat emulsion and a preparation method of the posaconazole fatty acid ester fat emulsion, and belongs to the technical field of pharmaceutical preparations. The solubility of the posaconazole fatty acid ester provided by the invention in the oil for injection is remarkably improved, and the posaconazole fatty acid ester can be effectively applied to subsequent preparation of the posaconazole fatty acid ester fat emulsion. Meanwhile, by selecting components in a proper mass percentage range for mutual cooperation, the obtained posaconazole fatty acid ester fat emulsion is small in average particle size, and the pH value and the osmotic pressure are close to those of human plasma, so that the posaconazole fatty acid ester fat emulsion has excellent intravenous injection safety and can be effectively applied to preparation of antifungal injection. In addition, the preparation methods of the posaconazole fatty acid ester and the posaconazole fatty acid ester fat emulsion provided by the invention are simple to operate and beneficial to actual large-scale production.

The present invention discloses a carbonyl reductase mutant and its application in the synthesis of posaconazole intermediates. The mutant protein is a non-natural protein and has significantly improved catalysis ( S )-2-benzyloxy-3-pentanone is reduced to form R The carbonyl reductase mutant strain with enhanced activity in the present invention is applied to the production process of posaconazole intermediates, and 100-200 g / L substrate can be completely converted to produce (2 S ,3 R )-2-benzyloxy-3-pentanol.

This invention provides a method for inhibiting the growth of a pathogenic mold by contacting the pathogenic mold with a synergistically effective amount of an NK1 antagonisfand an antifungal agent. This invention also provides a method for inhibiting the growth of a mammalian fungal pathogen by contacting the mammalian fungal pathogen with a synergistically effective amount of posaconazole and rolapitant. In some aspects, the mammalian fungal pathogen is a species of Candida (e.g., C. glabrata, C. auris, C. albicans, C. dubliniensis, or C. parapsilosis). Aspergillus, Cryptococcus, Mucor, orRhizopus. In addition, A surface disinfectant comprising a synergistic amount of an NK1 antagonist and an antifungal agent in admixture with a carrier or excipient.

One embodiment of the present invention provides a posaconazole-containing solid dispersion that suppresses the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration of a posaconazole-containing formulation. Alternatively, one embodiment of the present invention provides a posaconazole-containing formulation in which the delayed dissolution of posaconazole during the storage period after manufacturing or the period until administration is suppressed. [Solution] A posaconazole-containing solid dispersion according to one embodiment of the present invention comprises posaconazole, hypromellose acetate succinate, and hydroxypropyl cellulose having a viscosity of 6 mPa·s or more and 10 mPa·s or less in a 2% aqueous solution at 20°C and an average molecular weight of 140,000.

The invention relates to a hybridoma cell strain secreting an isavuconazole monoclonal antibody and application of the hybridoma cell strain, and belongs to the technical field of immunodetection. The monoclonal antibody secreted by the hybridoma cell strain has good sensitivity and specificity to the isavuconazole, the IC50 value of the monoclonal antibody to the isavuconazole is 13.317 ng / mL, and the IC50 value of the monoclonal antibody to the structural analogue of the isavuconazole is 13.317 ng / mL. According to the present invention, the low-concentration isavuconazole, such as fluconazole, ketoconazole, posaconazole, clotrimazole, miconazole, econazole, voriconazole, bifenconazole, luliconazole and sertaconazole, does not have the cross reaction, and the cross reaction rate is less than 1%, such that the low-concentration isavuconazole can be accurately detected.

The present disclosure relates to an in situ ready-to-use injection formulation of posaconazole free of cyclodextrin and derivatives of cyclodextrin, which can be formulated in situ as a nanosuspension injection of posaconazole by a simple dilution operation during clinical use. The formulation has no adverse effects on the renal function of patients, no extreme pH, and low vascular irritation, and can be administrated without the need for central venous cannulation during clinical use. The present disclosure also relates to a method for preparing the formulation and the use of the formulation in the treatment and prevention of fungal infections.

The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation method of a posaconazole starting material SM3. CeCl3. 7H2O and sodium borohydride are added into a compound POS-1 for an asymmetric reduction reaction to obtain a compound POS-2, the compound POS-2 reacts with 3, 5-bis (trifluoromethyl) benzene sulfonyl chloride to obtain a compound POS-3, hydrazine hydrate attacks from the back side of the compound POS-3 with large steric hindrance, an SN2 reaction is carried out to obtain a compound POS-4 with specific stereoselectivity, the compound POS-4 reacts with ethyl formate, and the compound POS-4 reacts with ethyl formate to obtain a compound POS-3 with specific stereoselectivity. And salifying with oxalic acid to obtain the initial raw material SM3 of the product posaconazole. According to the method, the chiral resolution step is effectively avoided in the modes of asymmetric carbonyl reduction and selective nucleophilic substitution, so that the content of isomer impurities is reduced, the prepared product is high in ee value, the yield is also remarkably improved, and the production cost is greatly reduced.

The invention relates to an in-situ ready-to-use posaconazole injection preparation free of cyclodextrin and derivatives thereof. According to the injection preparation, a nanosuspension injection of posaconazole can be prepared in situ through simple dilution operation in the clinical use process. The preparation has no influence on the renal function of a patient, has no extreme pH value, has low irritation to blood vessels, and can be applied without a central venous cannula in the clinical use process. The invention also relates to a method for preparing the preparation and application of the preparation in preparation of a medicament for treating and preventing fungal infection.

The present disclosure relates to a method for preparing a compound as an intermediate for synthesizing the drug posaconazole and the intermediate compounds prepared thereby. The method for preparing a compound of Formula I provided in the present disclosure comprises: firstly reacting 4-(2,4-difluorophenyl)pent-4-enoate or its reduction product 4-(2,4-difluorophenyl)pent-4-enal as a starting material with formaldehyde or paraformaldehyde in the presence of a chiral catalyst, and then subjecting the reaction product to a characteristic oxidation, an esterification, a halogenation and cyclization reaction, finally a hydrolysis and an acid treatment. The preparation method of the present disclosure has advantages such as mild reaction conditions, simple reaction process, and high overall yield and high purity of target products, and thus is suitable for industrial production.

The present disclosure provides a liquid composition comprising posaconazole, and a preparation method and use thereof. The liquid composition comprises posaconazole, a cyclodextrin, a dilution stabilizer, an antioxidant, and an acidic pH regulator. The dilution stabilizer comprises hydroxypropyl cellulose and / or hydroxypropyl methylcellulose, and the cyclodextrin is present in an amount of 25% to 45% (w / v), based on the total volume of the liquid composition. The liquid composition can increase an oral bioavailability of posaconazole, mitigate an impact of food on bioavailability of posaconazole, and improve patient compliance.

The application provides a synthesis method of posaconazole halogenated cyclic intermediate, which comprises the following steps: carrying out halogenation reaction on a raw material intermediate shown in formula (1) and a halogenating reagent in an organic solvent in the presence of an acidic substance, so as to obtain a posaconazole halogenated cyclic intermediate shown in formula (2). The application also provides a synthesis method of posaconazole. The synthesis method provided by the application activates the halogenating reagent by using a cheap acidic substance and carries out the halogenation reaction under low-temperature conditions, so that the target product has the advantages of high yield, high diastereoselectivity and the like, the process is simple and convenient to operate, post-treatment is simple, the synthesis efficiency is obviously improved, the synthesis cost is reduced, the synthesis method provided by the application has great potential for industrialized production, has strong industrial practicability, and has important significance for expanding the production and application of posaconazole.

The application discloses a synthesis method of a high-chirality purity posaconazole mother ring and belongs to the technical field of medicine preparation. In the application, sodium borohydride is used to reduce (R)-3-[(3S,5R)-5-(2,4-difluorobenzene)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone containing isomers to an intermediate alcohol, the hydroxyl group of the intermediate alcohol is protected, then the intermediate alcohol is beaten in acetonitrile and filtered to obtain an intermediate; then the intermediate is reacted with sodium triazole to obtain a triazole substituent; finally, the triazole substituent is deprotected into a hydroxyl group, and then p-toluenesulfonyl chloride is added to react, so that the high-chirality posaconazole mother ring is obtained. Compared with the existing preparation technology, the synthesis method provided by the application is simple in operation, high in product yield, low in by-products and high in purity.

This invention discloses a novel use of posaconazole to enhance the immune response in the immunotherapy of breast cancer. Specifically, this invention provides a drug combination comprising posaconazole and a PD-L1 inhibitor. The effects of this invention are: (1) using posaconazole to prepare a drug for treating breast cancer, especially triple-negative breast cancer (TNBC), achieving "repurposing of an old drug"; (2) clarifying its core mechanism of action, clarifying that the anti-tumor effect of clinically commonly used doses of posaconazole depends on the host immune system, rather than traditional direct cytotoxicity, specifically by inhibiting CYP11A1 and other related enzymes in the tumor, thereby reducing immunosuppressive steroid hormones, providing a new drug and target for tumor immunotherapy; (3) providing a technical solution for the combined treatment of posaconazole and PD-L1 inhibitors (such as anti-PD-L1 antibodies), further enhancing anti-tumor immunity and improving the treatment effect of TNBC.

The application relates to the application of azole drugs in the preparation of antifungal drugs and belongs to the technical field of antifungal drug research and development. The application of glycyrrhetic acid combined with azole drugs in the preparation of antifungal drugs discloses that glycyrrhetic acid combined with itraconazole, voriconazole and posaconazole shows good synergistic effect or antagonistic effect on aspergillus, exophiala dermatiditis, candida and new cryptococcus, and provides a research and development direction for preparing drugs for resisting aspergillus, exophiala dermatiditis, candida and new cryptococcus.