CN111658601A - Voriconazole external preparation and preparation method thereof - Google Patents
Voriconazole external preparation and preparation method thereof Download PDFInfo
- Publication number
- CN111658601A CN111658601A CN202010532576.8A CN202010532576A CN111658601A CN 111658601 A CN111658601 A CN 111658601A CN 202010532576 A CN202010532576 A CN 202010532576A CN 111658601 A CN111658601 A CN 111658601A
- Authority
- CN
- China
- Prior art keywords
- voriconazole
- preparation
- external preparation
- solubilizer
- external
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
The invention relates to an antifungal pharmaceutical preparation, in particular to a voriconazole external preparation and a preparation method thereof. The voriconazole external preparation at least comprises voriconazole, a matrix material and a solubilizer, wherein the solubilizer is an isopropyl ester or hydroxyl solvent. The invention provides a voriconazole external preparation, provides a voriconazole external antifungal preparation, can be more effectively used for affected parts, and solves the problems that voriconazole has poor stability in the preparation process of the voriconazole external preparation, and particularly, in a water state, voriconazole is easy to hydrolyze and generates inactive isomer impurities through the recombination of retro-aldol reaction products. In the research, the voriconazole has good solubility and stability in esters and alkane auxiliary materials, and particularly has obvious effect after isopropyl esters and hydroxyl solvents are added.
Description
Technical Field
The invention relates to an antifungal pharmaceutical preparation, in particular to a voriconazole external preparation and a preparation method thereof.
Background
The chemical name of voriconazole is: (2R,3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2, 4-triazol-1-yl) -2-butanol, formula: c16H14F3N5The molecular weight of O is: 349.3.
voriconazole is a second generation triazole antifungal drug, which overcomes the problems of the first generation antifungal drugs, such as fluconazole and itraconazole, of insufficient antibacterial spectrum, low bioavailability and drug resistance. It can be used for treating invasive aspergillosis, non-neutropenia and other candidemia of deep tissue in adults and children over 2 years old, esophageal candidiasis, and severe fungal infections caused by Fusarium oxysporum and Fusarium (including Fusarium solani).
Fungal infections of the skin can be clinically classified into superficial mycoses (the infected site is limited to the cuticle, hair, and nails), subcutaneous mycoses (infection of the dermis and subcutaneous tissue), and systemic mycoses (also called invasive mycoses) according to the infected site. The external preparation for superficial mycosis is mainly used, and the common medicines comprise: the external preparation comprises ketoconazole, ciclopirox, terbinafine and the like, wherein imidazole drugs represented by ketoconazole account for the largest proportion. Because of the hepatotoxicity of ketoconazole, its orally administered dosage forms were discontinued in europe, australia and china. In 2017, the prescription monitoring management is implemented by taking out the non-prescription medicines such as lotion and ointment related to ketoconazole from the non-prescription medicine catalogue.
The Voriconazole marketed preparation comprises freeze-dried powder injection for intravenous administration, tablets for oral administration and dry suspension, and has the trade name: vefend. Voriconazole is a fluconazole derivative, has a wider antibacterial spectrum and has a bactericidal effect on aspergillus; has antibacterial activity against Candida, Fusarium and Fusarium; diphase against cryptococcusFungi and the like also have good antibacterial activity. A study of Carrillo-Munoz et al showed: the in vitro bacteriostatic activity of fungi causing onychomycosis such as candida voriconazole, candida albicans and the like is better than that of terbinafine and itraconazole. Bueno J G et al[3]The antibacterial activity of voriconazole on dermatophytes (such as trichomonas rubescens, trichomonas digitalis and the like) causing onychomycosis is determined, the geometric mean value of MIC is 0.037-0.107g/mL, and the antibacterial activity is better. Its studies also show that: voriconazole also has high antifungal activity against other related dermatophytes. Muangkaew W et al, respectively carrying out in vitro bacteriostasis tests on fungi (including trichophyton, trichophyton rubrum, spore fungi and the like) with different antifungal agents for clinically common skin diseases. The results show that: the bacteriostatic effect of voriconazole on candida is better than that of fluconazole, itraconazole and terbinafine.
The voriconazole oral administration and injection has long clinical application time, and the safety is superior to the imidazole antifungal drugs represented by ketoconazole. The in vitro bacteriostatic activity test shows that: it has good bacteriostatic activity on fungi causing skin infection, and may be a safe and effective means for treating intractable infection (such as onychomycosis) or skin fungal infection of immunodeficiency patients. The voriconazole is not easy to directly aim at an affected part when the voriconazole is orally taken or injected for superficial fungal infection, and the voriconazole can be directly aimed at the affected part if the voriconazole is prepared into an external preparation, so that the voriconazole can be more effectively treated.
However, voriconazole is poor in stability, and particularly, in an aqueous solution state, voriconazole is easily hydrolyzed, and inactive isomer impurities are generated through recombination of a retro-aldol reaction product. Therefore, voriconazole is difficult to be prepared into aqueous ointment, injection and eye drops with long-term stability. Furthermore, voriconazole has a log d of 1.8, is a semi-polar compound, is poorly soluble, has a solubility of only 0.65mg/ml in aqueous solution, and cannot be solubilized by conventional solubilization methods such as oils, surfactants, or water-miscible co-solvents.
Disclosure of Invention
The invention aims to provide a voriconazole external preparation which can be directly applied to an affected part and is used for treating superficial fungal infection, solves the problems that voriconazole is poor in solubility and unstable in water, and has good stability and solubility and high intracutaneous distribution.
The invention also aims to provide a preparation method of the voriconazole external preparation.
In order to solve the problems existing in the background technology, the invention adopts the following technical scheme:
voriconazole external preparation, comprising at least voriconazole, matrix material and solubilizer, wherein the solubilizer is isopropyl ester or hydrocarbon solvent.
Preferably, the isopropyl ester is diisopropyl adipate.
Preferably, the hydroxyl solvent is hexadecane.
Preferably, the matrix material is one or more of tetradecanol, hexadecanol, octadecanol and their mixtures, emulsifying wax, microcrystalline wax, paraffin or liquid paraffin, vaseline, mineral oil, beeswax, lanolin, and lanolin alcohols.
The voriconazole external preparation comprises, by weight, 0.3% -3% of voriconazole, 67% -94% of a matrix material and 5% -30% of a solubilizer.
The invention also discloses a preparation method of the voriconazole external preparation, which comprises the following steps:
(1) adding voriconazole raw material into solubilizer, stirring and dissolving;
(2) melting the matrix material for later use;
(3) mixing and stirring to obtain the product.
The invention provides a voriconazole external preparation, provides a voriconazole external antifungal preparation, can be more effectively used for affected parts, and solves the problems that voriconazole has poor stability in the preparation process of the voriconazole external preparation, and particularly, in a water state, voriconazole is easy to hydrolyze and generates inactive isomer impurities through the recombination of retro-aldol reaction products. In the research, the voriconazole has good solubility and stability in esters and alkane auxiliary materials, and particularly has obvious effect after isopropyl esters and hydroxyl solvents are added.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1: preparation of voriconazole ointment
Prescription:
the preparation process comprises the following steps:
(1) weighing a prescription amount of solubilizer in a beaker, heating in water bath at 60 ℃, adding and stirring the prescription amount of voriconazole to completely dissolve the voriconazole as far as possible, and keeping the temperature for later use;
(2) heating in water bath at 60 deg.C, melting the matrix, and keeping the temperature for use;
(3) mixing: slowly pouring the medicine solution obtained in the step (1) into the melted matrix under the stirring state, and uniformly stirring. Cooling at room temperature to obtain the final product.
Example 2: solubility experiments of voriconazole in different solvents;
solubility of voriconazole in different solvents:
from the above table, voriconazole has the greatest solubility in diisopropyl adipate.
Experimental example 3: compatibility
Voriconazole is dissolved in the following solvents to prepare approximately saturated drug-containing solution. The drug-containing solution was left under accelerated conditions (40 ℃ C./75% RH), taken out 7 days later, and the following liquid chromatography conditions were used to detect the relevant substances.
| Sample introduction volume | 20μL |
| Flow rate of flow | 1.0mL/min |
| Column temperature | 35℃ |
| Detection wavelength | UV 256nm |
| Run time | 30min |
| Buffer solution | 1.9g/L of aqueous ammonium formate solution, the pH being adjusted to 4.0 with formic acid |
| Mobile phase | Buffer acetonitrile methanol 55:15:30 |
| Chromatographic column | Waters Nova-pak C18 3.9×150mm,4μm |
The results are shown in the following table:
and (4) conclusion: after the voriconazole is accelerated for 7 days in different solvents, detection shows that the voriconazole has better compatibility and stability in diisopropyl oxalate and hexadecane and is not easy to degrade.
Example 4: stability test:
voriconazole ointments obtained in the first, second and third prescriptions of example 1 were allowed to stand under accelerated conditions for 7 days, and then subjected to appearance and related substance testing.
And (4) conclusion: the voriconazole ointment obtained in example 1 showed no significant increase in total impurities after 7 days of acceleration, showing better compatibility.
Example 5: in vitro skin permeability tests were used to evaluate the in vitro transdermal permeability of the different formulations.
The experimental process comprises the following steps:
(1) taking out the frozen pigskin, and unfreezing the pigskin in 0.9% of normal saline at room temperature; after thawing, shaving the pigskin on the pigskin surface by using an electric hair clipper, and cutting subcutaneous adipose tissues by using an operation for later use;
(2) spreading experimental skin in a receiving room of a Franz vertical diffusion cell, and trimming edges by adopting surgical scissors, wherein the margin of the edges is not less than 5 mm; and after trimming is finished, clamping by using a clamp. And precisely weighing the whole set of diffusion cell.
(3) A 1ml syringe is adopted, the front part of the syringe is cut off by a utility knife, the front end is opened, so that a sample is conveniently sucked and extruded, and the influence of extrusion stress on the performance of a sample to be tested is reduced; absorbing about 0.2-0.3ml of sample with the device, and uniformly applying on skin surface (sample addition amount is about 300 mg); weighing the weight of the diffusion cell after sample adding, and deducting the weight before sample adding to obtain the weight of the sample; after the application of sample, adopt the sealing film to seal, avoid the sample dry in the experimentation.
(4) Taking phosphate buffer solution with pH of 7.2 as a receiving medium, and testing at the temperature of 32 +/-1 ℃;
(5) after 6 hours, the stratum corneum and epidermis were extracted, respectively. Extracting with extraction medium, and determining the concentration of the medicine.
Claims (6)
1. Voriconazole external preparation, comprising at least voriconazole, matrix material and solubilizer, wherein the solubilizer is isopropyl ester or hydroxyl solvent.
2. The voriconazole external preparation according to claim 1, wherein the isopropyl ester is diisopropyl adipate.
3. The voriconazole external preparation according to claim 1, wherein the hydroxylic solvent is hexadecane.
4. The voriconazole external preparation according to claim 1, wherein the matrix material is one or more of tetradecanol, hexadecanol, octadecanol and their mixture, emulsifying wax, microcrystalline wax, paraffin or liquid paraffin, vaseline, mineral oil, beeswax, lanolin alcohol.
5. The voriconazole external preparation according to any one of claims 1 to 4, comprising, by weight, 0.3% to 3% voriconazole, 67% to 94% matrix material, and 5% to 30% solubilizer.
6. The method for preparing voriconazole external preparation according to claim 5, comprising the steps of:
(1) adding voriconazole raw material into solubilizer, stirring and dissolving;
(2) melting the matrix material for later use;
(3) mixing and stirring to obtain the product.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010532576.8A CN111658601A (en) | 2020-06-12 | 2020-06-12 | Voriconazole external preparation and preparation method thereof |
| PCT/CN2020/096728 WO2021248532A1 (en) | 2020-06-12 | 2020-06-18 | Voriconazole preparation for external use and preparation method therefor |
| CN202110532279.8A CN114344245A (en) | 2020-06-12 | 2021-05-14 | Voriconazole external preparation and preparation method thereof |
| PCT/CN2021/098224 WO2021249288A1 (en) | 2020-06-12 | 2021-06-04 | Voriconazole external preparation and preparation method therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010532576.8A CN111658601A (en) | 2020-06-12 | 2020-06-12 | Voriconazole external preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111658601A true CN111658601A (en) | 2020-09-15 |
Family
ID=72387290
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010532576.8A Pending CN111658601A (en) | 2020-06-12 | 2020-06-12 | Voriconazole external preparation and preparation method thereof |
| CN202110532279.8A Pending CN114344245A (en) | 2020-06-12 | 2021-05-14 | Voriconazole external preparation and preparation method thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110532279.8A Pending CN114344245A (en) | 2020-06-12 | 2021-05-14 | Voriconazole external preparation and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN111658601A (en) |
| WO (1) | WO2021248532A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021249288A1 (en) * | 2020-06-12 | 2021-12-16 | 海南普利制药股份有限公司 | Voriconazole external preparation and preparation method therefor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090175810A1 (en) * | 2008-01-03 | 2009-07-09 | Gareth Winckle | Compositions and methods for treating diseases of the nail |
| BRPI0914863A2 (en) * | 2008-06-06 | 2017-05-30 | Glenmark Pharmaceuticals Ltd | stable topical formulation and use thereof |
| WO2012092527A1 (en) * | 2010-12-29 | 2012-07-05 | Strategic Science & Technologies, Llc | Delivery of treatments transdermally for fungal infections and other indications |
-
2020
- 2020-06-12 CN CN202010532576.8A patent/CN111658601A/en active Pending
- 2020-06-18 WO PCT/CN2020/096728 patent/WO2021248532A1/en active Application Filing
-
2021
- 2021-05-14 CN CN202110532279.8A patent/CN114344245A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021249288A1 (en) * | 2020-06-12 | 2021-12-16 | 海南普利制药股份有限公司 | Voriconazole external preparation and preparation method therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114344245A (en) | 2022-04-15 |
| WO2021248532A1 (en) | 2021-12-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2423128C2 (en) | Pharmaceutical composition for external application | |
| EP2191825B1 (en) | Agent for fungal dermatitis | |
| KR20140074883A (en) | Gel compositions of oxymetazoline and methods of use | |
| JPWO2009031643A1 (en) | Antifungal composition | |
| US9072660B2 (en) | Topical itraconazole formulations and uses thereof | |
| KR20100099191A (en) | Pre-surgical treatment | |
| WO2010124175A1 (en) | Stable topical compositions for 1,2,4-thiadiazole derivatives | |
| EP2948134B1 (en) | Compositions for transdermal delivery of mtor inhibitors | |
| KR20070024543A (en) | Antifungal drug delivery | |
| US20210401989A1 (en) | Semi-solid, oil-based pharmaceutical compositions containing pirfenidone for application in tissue repair | |
| JP2018516989A (en) | Topical formulations for the delivery of hedgehog inhibitory compounds and uses thereof | |
| US9040573B2 (en) | Anti-fungal agent | |
| CN111658601A (en) | Voriconazole external preparation and preparation method thereof | |
| TWI630921B (en) | A pharmaceutical composition for skin external use comprising icotinib and the application thereof. | |
| KR20150016984A (en) | O/w-emulsion-type topical pharmaceutical compositions containing a retinoid | |
| WO2021249288A1 (en) | Voriconazole external preparation and preparation method therefor | |
| WO2011061155A1 (en) | Antifungal formulations and their use | |
| KR101690765B1 (en) | Transdermal formulation comprising antifungal agent | |
| CN114028262A (en) | Preparation method and application of azelaic acid ionic salt/eutectic cyclodextrin inclusion compound liposome | |
| KR101733189B1 (en) | Composition for promotion of growing nail or toenail | |
| WO2014017411A1 (en) | External preparation for treating trichophytosis unguium | |
| EP3666254A2 (en) | Pharmaceutical composition containing (r)-n-[1-(3,5-difluoro-4-methansulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide | |
| Banyal et al. | EMULGEL: An Enormous Approach for Topical Delivery of Hydrophobic Drugs | |
| RU2576612C2 (en) | Transdermally absorbable medicinal product | |
| CN111249223B (en) | Propranolol hydrochloride cubic liquid crystal gel and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200915 |
|
| WD01 | Invention patent application deemed withdrawn after publication |