CN113750034A - Ear temperature-sensitive gel and preparation method thereof - Google Patents

Ear temperature-sensitive gel and preparation method thereof Download PDF

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CN113750034A
CN113750034A CN202010506353.4A CN202010506353A CN113750034A CN 113750034 A CN113750034 A CN 113750034A CN 202010506353 A CN202010506353 A CN 202010506353A CN 113750034 A CN113750034 A CN 113750034A
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voriconazole
sensitive gel
temperature
poloxamer
ear temperature
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阳国平
李维
曾韵
王震宇
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Third Xiangya Hospital of Central South University
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Abstract

The invention discloses an ear temperature-sensitive gel and a preparation method thereof, wherein the ear temperature-sensitive gel comprises the following raw materials in parts by mass: 0.2-3% of voriconazole clathrate, 40718-20% of poloxamer, 1882-8% of poloxamer and 50-79% of water. The preparation method comprises the steps of dropwise adding an ethanol solution of voriconazole into a sulfobutyl-beta-cyclodextrin sodium solution to prepare a voriconazole cyclodextrin inclusion compound, then adding poloxamer 407 and poloxamer 188 into water for swelling to prepare a blank gel matrix, and then adding the voriconazole cyclodextrin inclusion compound solution, or adding poloxamer 407, poloxamer 188 and voriconazole cyclodextrin inclusion compound into water for swelling to obtain the product. The ear canal temperature-sensitive gel drug has good slow release effect, can effectively reduce the administration times and prolong the action time of the drug, has small irritation and high safety, and can obviously improve the medication compliance of patients.

Description

Ear temperature-sensitive gel and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, relates to an ear temperature-sensitive gel and a preparation method thereof, and particularly relates to an ear temperature-sensitive gel containing voriconazole sulfobutyl-beta-cyclodextrin sodium and a preparation method thereof.
Background
External auditory canal mycosis (called as otitis externa mycotica) is a common disease of an auditory canal caused by conditional pathogenic fungal infection invading the external auditory canal or the internal part of the external auditory canal, causes subacute or chronic inflammatory lesion of the external auditory canal, can cause earache, ear itch and purulence in the ear of a patient, and can be combined with bacterial infection to cause repeated attack and long-term treatment. Common pathogenic bacteria of the external auditory canal mycosis include yeasts, candida, blastomyces, aspergillus, mucor, actinomycetes, penicillium and the like, wherein the most common pathogenic bacteria are aspergillus, such as aspergillus fumigatus, aspergillus niger, aspergillus flavus and the like. The treatment period of the auricularia mycosis is long, and the auricularia mycosis is easy to relapse. And the occurrence of the mycosis of the external auditory canal not only has geographic factors, but also changes along with the change of time and seasons. The incidence of diseases is high in subtropical regions, tropical regions and rainy seasons. The infection is not sex-related, and the number of children is small. Mycosis of the external auditory canal has been reported to occur in approximately 9% of ear diseases in north america, which, although not fatal, can affect the normal life of patients and often requires long-term treatment and follow-up.
At present, the clinical treatment means aiming at the external auditory canal mycosis is to treat local antifungal medicines after the external auditory canal is primarily cleaned, and the common treatment method is to drip boric acid alcohol and salicylic acid alcohol on the ear, so that the inflammation diminishing and itching relieving effects of the alcohol are strong, but the irritation of the alcohol to the human body is large, and the patient can feel burning pain and stabbing pain during use, so that the compliance of the patient is poor. The external auditory canal is smeared with antifungal ointment to treat diseases, but because the external auditory canal is physiologically bent and narrow, the drugs are difficult to be uniformly distributed at all parts of the external auditory canal, and meanwhile, the ointment can not be cleaned and updated in time, so that the treatment effect is influenced. The doctor administration operation increases the inconvenience and treatment cost of patients, and the patients can have poor treatment effect due to self administration; the fluconazole solution is also adopted for ear drop treatment clinically, and doctors usually prepare fluconazole sodium chloride solution or fluconazole aqueous solution temporarily, but the method has good treatment effect, needs temporary preparation and is difficult to store.
The common treatment drugs for the ear canal mycosis are antifungal drugs, such as triazole drugs like voriconazole, itraconazole, clotrimazole and the like, the common administration modes are intravenous injection and oral administration, and no special preparation for the otomycosis appears in China at present. The current market has less preparations for treating the otomycosis, and because the external auditory canal of a human body has a special structure, some common administration operations are quite troublesome, and the common preparation of the auditory canal is ear drops. However, with the increasing of the fungal diseases, the traditional treatment methods cannot meet the clinical requirements, and the development of the preparation for treating the fungal diseases is urgent.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the ear temperature-sensitive gel which has good drug slow-release effect, can obviously reduce the administration times, prolongs the action time of the drug, has little or no irritation and high safety and can obviously improve the drug compliance of patients and the preparation method thereof.
In order to solve the technical problems, the invention adopts the following technical scheme.
Figure BDA0002526689150000021
The voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
The ear temperature-sensitive gel preferably further comprises auxiliary materials, wherein the auxiliary materials comprise one or more of a preservative, a wetting agent, a transdermal agent and an adhesive.
Preferably, the preservative comprises one or more of sodium benzoate, benzalkonium bromide, lysozyme and ethylparaben, the wetting agent comprises glycerol and/or propylene glycol, the transdermal agent comprises azone and/or menthol, and the adhesive comprises hydroxypropyl methylcellulose and/or chitosan.
Preferably, the temperature-sensitive gel for ears is prepared from 0.05-0.5% of preservative, 5-10% of wetting agent, 5-10% of transdermal agent and 0.5-2% of adhesive by mass.
The sum of the mass fractions of all the raw materials of the ear temperature-sensitive gel is 100 percent.
As a general technical concept, the invention also provides a preparation method of the ear temperature-sensitive gel, which comprises the following steps:
dissolving voriconazole cyclodextrin inclusion compound in water to obtain voriconazole cyclodextrin inclusion compound solution, wherein the voriconazole cyclodextrin inclusion compound is mainly prepared from sulfobutyl-beta-cyclodextrin sodium solution and voriconazole ethanol solution; adding poloxamer 407 and poloxamer 188 into water, uniformly dispersing, and swelling at 4 +/-1 ℃ for 24-48 h to obtain a blank gel matrix; and adding the voriconazole cyclodextrin inclusion compound solution into the blank gel matrix, and uniformly mixing to obtain the ear temperature-sensitive gel.
Preferably, in the preparation method of the ear temperature-sensitive gel, the voriconazole cyclodextrin inclusion compound accounts for 0.2-3% by mass, the poloxamer 407 accounts for 18-20%, the poloxamer 188 accounts for 2-8%, and the total amount of water accounts for 50-79%.
Preferably, the preparation method of the ear temperature-sensitive gel further comprises adding auxiliary materials into the blank gel matrix, wherein the auxiliary materials comprise one or more of preservatives, wetting agents, transdermal agents and adhesives.
In the preparation method of the ear temperature-sensitive gel, preferably, the preservative comprises one or more of sodium benzoate, benzalkonium bromide, lysozyme and ethylparaben, the wetting agent comprises glycerol and/or propylene glycol, the transdermal agent comprises azone and/or menthol, and the adhesive comprises hydroxypropyl methylcellulose and/or chitosan.
Preferably, in the preparation method of the ear temperature-sensitive gel, the preservative is 0.05-0.5%, the wetting agent is 5-10%, the transdermal agent is 5-10%, and the adhesive agent is 0.5-2% by mass.
As a general technical concept, the invention also provides a preparation method of the ear temperature-sensitive gel, which comprises the following steps:
adding poloxamer 407, poloxamer 188 and voriconazole cyclodextrin inclusion compound into water, uniformly dispersing, and swelling for 24-48 h at 4 +/-1 ℃ to obtain the ear temperature-sensitive gel, wherein the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
Preferably, in the preparation method of the ear temperature-sensitive gel, the voriconazole cyclodextrin inclusion compound accounts for 0.2-3% by mass, the poloxamer 407 accounts for 18-20%, the poloxamer 188 accounts for 2-8%, and the water accounts for 50-79%.
Preferably, the preparation method of the ear temperature-sensitive gel further comprises adding auxiliary materials into the water, wherein the auxiliary materials comprise one or more of a preservative, a wetting agent, a transdermal agent and an adhesive.
In the preparation method of the ear temperature-sensitive gel, preferably, the preservative comprises one or more of sodium benzoate, benzalkonium bromide, lysozyme and ethylparaben, the wetting agent comprises glycerol and/or propylene glycol, the transdermal agent comprises azone and/or menthol, and the adhesive comprises hydroxypropyl methylcellulose and/or chitosan.
Preferably, in the preparation method of the ear temperature-sensitive gel, the preservative is 0.05-0.5%, the wetting agent is 5-10%, the transdermal agent is 5-10%, and the adhesive agent is 0.5-2% by mass.
In the two preparation methods of the ear temperature-sensitive gel, preferably, the voriconazole cyclodextrin inclusion compound is mainly prepared by the following steps: adding sulfobutyl-beta-cyclodextrin sodium into water, heating to be completely dissolved, wherein the heating temperature is 30-50 ℃ to obtain sulfobutyl-beta-cyclodextrin sodium solution, dissolving voriconazole in ethanol to obtain ethanol solution of voriconazole, dropwise adding the ethanol solution of voriconazole into the sulfobutyl-beta-cyclodextrin sodium solution, wherein the ratio of the total mass of voriconazole to the mass of the sulfobutyl-beta-cyclodextrin sodium is 1: 10-30, stirring at the rotating speed of 100-400 r/min for 1-5 h after dropwise adding, and the stirring temperature is 30-50 ℃ to perform inclusion, filtering, and drying the filtrate to obtain voriconazole cyclodextrin inclusion compound; wherein the mass-volume ratio of voriconazole to ethanol is 0.1-0.2 g: 1-3 mL, and the ethanol is ethanol solution or absolute ethanol.
In the two methods for preparing the ear temperature-sensitive gel, the ear temperature-sensitive gel preferably has a gelling temperature of 30-36 ℃.
In the two methods for preparing the ear temperature-sensitive gel, preferably, the species against which the ear temperature-sensitive gel is directed include one or more of candida, aspergillus and trichoderma.
Compared with the prior art, the invention has the advantages that:
(1) the ear temperature-sensitive gel (also called ear temperature-sensitive hydrogel) disclosed by the invention has excellent drug slow-release effect and antibacterial effect by adopting voriconazole cyclodextrin inclusion compound, poloxamer 407 and poloxamer 188 as main raw materials and cooperating with a formula. The ear temperature-sensitive gel has the gelation temperature of 30-36 ℃, is in a flowable liquid state at normal temperature, can be quickly converted into gel when contacting human auditory canals, has strong operability, can realize uniform coverage of the drugs in the human auditory canals, realizes proper drug slow release effect, effectively reduces the administration times, prolongs the drug action time, improves the drug compliance of patients, and reduces the complicated administration operation. The ear temperature-sensitive gel does not involve any toxic substances such as organic chemical solvents and the like in the conversion process, and has good safety.
The invention mainly adopts poloxamer 407 to control the gelling temperature of the ear temperature-sensitive gel, and adopts poloxamer 188 to finely adjust the gelling temperature. When the poloxamer 407 is 18% -20% and the poloxamer 188 is 2% -8%, the gelling temperature can be controlled between 30 ℃ and 36 ℃. The influence of poloxamer 407 on the gelling temperature of the temperature-sensitive gel is large, the influence of the change of the content of the temperature-sensitive gel on the temperature is large, the influence of poloxamer 188 on the gelling temperature of the temperature-sensitive gel is small, and the change of the content of the temperature-sensitive gel can cause small-amplitude change of the temperature.
(2) In the preparation method, the voriconazole cyclodextrin inclusion compound, the poloxamer 407 and the poloxamer 188 are mainly adopted for synergistic interaction, so that the stability, the water solubility and the safety of the medicine are obviously improved, particularly, the release rate of the medicine is effectively controlled, the absorption effect is better, and the irritation to the skin is reduced. The temperature-sensitive gel is prepared by adopting a cold dissolution method, the voriconazole cyclodextrin inclusion compound, the poloxamer 407 and the poloxamer 188 are mixed at room temperature, and the mixture is swelled in a low-temperature environment, so that the influence of high temperature on medicines and other auxiliary materials is avoided, and the stability and the safety of the medicines are improved. Meanwhile, the voriconazole cyclodextrin inclusion compound can effectively improve the slow release effect, is easy to dissolve in water, and reduces the use of organic solvent ethanol, thereby reducing the irritation of the preparation to the skin.
(3) In the process of preparing the voriconazole cyclodextrin inclusion compound, the ethanol solution of voriconazole is added into the sulfobutyl-beta-cyclodextrin sodium solution in a dropwise manner, so that the voriconazole and cyclodextrin are included more fully, the inclusion rate is improved, the ratio of the total mass of voriconazole to the mass of sulfobutyl-beta-cyclodextrin sodium is controlled to be 1: 10-30, the voriconazole and cyclodextrin are stirred for 1 h-5 h at the rotating speed of 100 r/min-400 r/min, the inclusion temperature is 30-50 ℃, the invention takes the aqueous solution as the inclusion solvent and adopts absolute ethanol as the organic solvent, the evaporation is easy, the materials are easy to obtain, the process is simple, the prepared voriconazole cyclodextrin inclusion compound has small irritation to human bodies, is safe and nontoxic, the solubility of the voriconazole cyclodextrin inclusion compound in the temperature-sensitive gel solution is higher, the medicine can be uniformly distributed in the solution, the curative effect is enhanced, and more particularly, the voriconazole cyclodextrin inclusion compound can obviously prolong the drug slow-release time in the temperature-sensitive gel, achieve better slow-release effect, reduce the irritation to the skin and improve the absorption of voriconazole.
Drawings
FIG. 1 is a gel erosion curve of an ear temperature-sensitive gel prepared in example 1 of the present invention and a control voriconazole temperature-sensitive gel.
Fig. 2 is a drug release curve of the ear temperature-sensitive gel prepared in example 1 of the present invention and a control voriconazole temperature-sensitive gel.
Detailed Description
The invention is further described below with reference to the drawings and specific preferred embodiments of the description, without thereby limiting the scope of protection of the invention.
The materials and equipment used in the following examples are commercially available.
Example 1:
the ear temperature-sensitive gel comprises the following components in percentage by mass:
Figure BDA0002526689150000051
the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
The preparation method of the ear temperature-sensitive gel of the embodiment comprises the following steps:
(1) 2.0g of sulfobutyl-beta-cyclodextrin sodium is precisely weighed and dissolved in 20mL of water, and the solution is heated to 50 ℃ until the solution is completely dissolved. Precisely weighing 0.1g of voriconazole, dissolving the voriconazole in 1mL of ethanol solution with volume fraction of 95%, slowly dropping the ethanol solution of voriconazole into the aqueous solution of sulfobutyl-beta-cyclodextrin sodium, stirring at the speed of 100r/min at 50 ℃ for 3h, filtering while hot, drying and evaporating the filtrate to obtain the voriconazole cyclodextrin inclusion compound.
(2) Adding voriconazole cyclodextrin inclusion compound into partial deionized water, wherein the partial deionized water accounts for 10 wt% of the total amount of the raw materials, and stirring and dissolving to obtain voriconazole cyclodextrin inclusion compound solution. Adding poloxamer 407 and poloxamer 188 into another part of deionized water, wherein the other part of deionized water accounts for 56.9 wt% of the total amount of the raw materials, uniformly dispersing, and swelling at 4 ℃ for 24h to obtain a blank gel matrix. Adding the voriconazole cyclodextrin inclusion compound solution, propylene glycol and sodium benzoate into the blank gel matrix, and stirring to uniformly disperse the voriconazole cyclodextrin inclusion compound solution, the propylene glycol and the sodium benzoate to obtain the ear temperature-sensitive gel.
Example 2:
the ear temperature-sensitive gel comprises the following components in percentage by mass:
Figure BDA0002526689150000052
Figure BDA0002526689150000061
the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
The preparation method of the ear temperature-sensitive gel of the embodiment comprises the following steps:
(1) 1.5g of sulfobutyl-beta-cyclodextrin sodium is precisely weighed and dissolved in 20mL of water, and the solution is heated to 40 ℃ until the solution is completely dissolved. Precisely weighing 0.1g of voriconazole, dissolving in 1mL of ethanol solution with volume fraction of 95%, then dropwise adding into sulfobutyl-beta-cyclodextrin sodium water solution, stirring at the rotation speed of 200r/min at 40 ℃ for inclusion for 4h, filtering while hot, and freeze-drying the filtrate for more than 24h to obtain the voriconazole cyclodextrin inclusion compound.
(2) Adding voriconazole cyclodextrin inclusion compound into partial deionized water, wherein the partial deionized water accounts for 10 wt% of the total amount of the raw materials, and stirring and dissolving to obtain voriconazole cyclodextrin inclusion compound solution. Adding poloxamer 407 and poloxamer 188 into another part of deionized water, wherein the other part of deionized water accounts for 58.3 wt% of the total amount of the raw materials, uniformly dispersing, and swelling at 4 ℃ for 24h to obtain a blank gel matrix; adding the voriconazole cyclodextrin inclusion compound solution, hydroxypropyl methylcellulose and propylene glycol into the blank gel matrix, and uniformly mixing to obtain the ear temperature-sensitive gel.
Example 3:
the ear temperature-sensitive gel comprises the following components in percentage by mass:
Figure BDA0002526689150000062
the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
The preparation method of the ear temperature-sensitive gel of the embodiment comprises the following steps:
(1) precisely weighing 2.0g of sulfobutyl-beta-cyclodextrin sodium, dissolving in 30mL of water, heating to 40 ℃, and completely dissolving; precisely weighing 0.1g of voriconazole, dissolving in 1mL of ethanol solution with volume fraction of 95%, then dropwise adding in sulfobutyl-beta-cyclodextrin sodium water solution, stirring at 40 ℃ for inclusion for 3h at 400r/min, filtering while hot, and freeze-drying the filtrate for 48h to obtain the voriconazole cyclodextrin inclusion compound.
(2) Adding poloxamer 407 and poloxamer 188 into part of deionized water, wherein the part of deionized water accounts for 50 wt% of the total amount of the raw materials, uniformly dispersing, adding voriconazole cyclodextrin inclusion compound, glycerol and lysozyme, finally adding deionized water until the total mass fraction is 100%, stirring to uniformly disperse, and swelling for 24h at 4 ℃ to obtain the ear temperature-sensitive gel.
Example 4:
the ear temperature-sensitive gel comprises the following components in percentage by mass:
Figure BDA0002526689150000071
the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
The preparation method of the ear temperature-sensitive gel of the embodiment comprises the following steps:
(1) precisely weighing 1.6g of sulfobutyl-beta-cyclodextrin sodium, dissolving in 20mL of water, heating to 40 ℃, and completely dissolving; precisely weighing 0.1g of voriconazole, dissolving in 1mL of ethanol solution with volume fraction of 95%, dropwise adding into sulfobutyl-beta-cyclodextrin sodium water solution, stirring at the speed of 300r/min at 40 ℃ for inclusion for 1.5h, filtering while hot, and evaporating filtrate to dryness to obtain the voriconazole cyclodextrin inclusion compound.
(2) Adding voriconazole cyclodextrin inclusion compound into partial deionized water, wherein the partial deionized water accounts for 10 wt% of the total amount of the raw materials, and stirring and dissolving to obtain voriconazole cyclodextrin inclusion compound solution. Adding poloxamer 407 and poloxamer 188 into another part of deionized water, wherein the other part of deionized water accounts for 68 wt% of the total amount of the raw materials, uniformly dispersing, and swelling at 4 ℃ for 48h to obtain a blank gel matrix. Adding the voriconazole cyclodextrin inclusion compound solution, lysozyme and chitosan into the blank gel matrix, and stirring to uniformly disperse the gel matrix to obtain the ear temperature-sensitive gel.
The performance of the ear temperature-sensitive gels obtained in the examples was examined as follows:
1. gel temperature and gel time measurements of the products of the examples
The detection method of the gelling temperature comprises the following steps: the test tube inversion method is adopted for determination, 2g of ear temperature-sensitive gel (solution state) is weighed and injected into the test tube, the test tube is placed in a water bath which is continuously and slowly heated at 0.1 ℃, and the test is carried out by a thermometer with the accuracy of 0.1 ℃. The viscosity of the gel solution increases with increasing temperature, the temperature at which the gel solution completely gels and no longer flows when the tube is inverted is the gelling temperature of the formulation, the time from which the solution changes to gel is recorded as the gelling time, and the average is taken in triplicate for each example. The results are shown in Table 1.
And (4) conclusion: the gelation temperature of all the embodiments meets the preparation requirement, namely the gel is in a solution state at room temperature (25 ℃), can be converted into gel at the temperature of a human body, can be gelled in a short and proper time, avoids the inconvenience of administration caused by rapid gelation, and can cause the outflow of temperature-sensitive gel and the leakage of drugs caused by slow gelation.
TABLE 1 gelation temperature and gelation time of temperature-sensitive gels for ears of each example
Reagent Gelation temperature (. degree.C.) Gel time(s)
Example 1 33.5 100
Example 2 31.2 92
Example 3 30.5 88
Example 4 35.8 112
2. High performance liquid chromatography for detecting content uniformity of voriconazole
Chromatographic conditions are as follows: a chromatographic column: thermos
Mobile phase: methanol and water 60: 40
Detection wavelength: 256nm
Column temperature: at room temperature
Flow rate: 1.0mL/min
Sample introduction amount: 20 μ L
The content determination method comprises the following steps: accurately weighing 1.0g of the ear temperature-sensitive gel into a 10mL volumetric flask, diluting the ear temperature-sensitive gel to corresponding scales by using pure methanol, fully and uniformly oscillating, taking 100 mu L of solution, adding 900 mu L of 50% methanol, uniformly oscillating, carrying out sample injection analysis, substituting peak area into a voriconazole standard curve for calculation to obtain the concentration of the ear temperature-sensitive gel, and inspecting the concentration of a sample and the actual measured concentration. The preparation method is the same as that of example 1 except that the voriconazole cyclodextrin inclusion compound solution is replaced by an ethanol solution of voriconazole, and the results are shown in table 2. In each embodiment, the three average measured contents of the ear temperature-sensitive gel are relatively close, the drug labeled amount is between 95% and 115%, the three average measured contents of the voriconazole temperature-sensitive gel are relatively large in difference, the RSD value of the voriconazole temperature-sensitive gel is 21.29%, and the RSD value of the ear temperature-sensitive gel is far lower than 21.29%, which shows that the ear temperature-sensitive gel provided by the invention is uniform in drug distribution, and the voriconazole temperature-sensitive gel is non-uniform in drug distribution.
TABLE 2 uniformity of drug content in ear temperature-sensitive gels of each example
Figure BDA0002526689150000081
Figure BDA0002526689150000091
3. In vitro release degree examination of ear temperature-sensitive gel
A membraneless dissolution method is adopted, a clean penicillin bottle is weighed, the weight of the penicillin bottle is recorded, 5.0g of ear temperature-sensitive gel prepared in example 1 and voriconazole temperature-sensitive gel are precisely weighed and placed in the penicillin bottle, and the weight of the gel is recorded. And (3) placing the penicillin bottle into a constant-temperature heating water bath kettle at 37 ℃ to be kept at the constant temperature until the penicillin bottle is completely gelled. 2.00mL of 37 ℃ PBS buffer (pH 7.4) was added, the mixture was shaken at 37 ℃ and the buffer medium was removed every 30min, vials were quickly wiped dry and weighed, and then 2.00mL of 37 ℃ PBS buffer (pH 7.4) was added and the procedure was repeated until the gel was completely dissolved. The difference of the total weight of the adjacent time points is the erosion amount of the temperature-sensitive gel in the period.
Diluting the PBS buffer solution taken out each time to 10mL by using 50% methanol, filtering by using a 0.45-micrometer filter membrane, analyzing by sample injection according to chromatographic conditions, determining the concentration of voriconazole (the voriconazole cyclodextrin inclusion compound is physical inclusion, does not influence the chemical structure of the voriconazole, only detects the voriconazole in a liquid phase), namely the release amount of voriconazole at adjacent time points, and calculating the accumulated release amount of the temperature-sensitive gel drug.
As shown in the figures 1 and 2, the ear temperature-sensitive gel prolongs the gel erosion time, improves the drug release rate, and ensures that the drug accumulated release reaches more than 90% in 6 hours, thereby indicating that the ear temperature-sensitive gel is an excellent drug release platform carrier. The release time of the voriconazole temperature-sensitive gel is only about 3 hours, the release time of the ear temperature-sensitive gel drug reaches more than 6 hours, and meanwhile, the dissolution curve of the graph 1 and the release curve of the graph 2 can show that compared with the voriconazole temperature-sensitive gel, the curve of the ear temperature-sensitive gel prepared by the invention is more gentle and tends to be linear, and the curve accords with a zero-order kinetic equation, so that the release rate of the ear temperature-sensitive gel drug in vitro does not change along with the time, the fixed release amount of the drug in a certain time can be ensured, and a better slow release effect can be achieved.
4. In vitro bacteriostasis experiment of ear temperature-sensitive gel
In vitro bacteriostatic experiment: the in vitro bacteriostatic test was performed by the drug sensitive paper strip method and compared with sterile pure water (blank control). The test results are shown in table 3, wherein the larger the mean value of the inhibition zone is, the better the inhibition effect is.
TABLE 3 mean zone of inhibition for each example and sterile pure water in vitro bacteriostasis test
Unit: millimeter (mm)
Figure BDA0002526689150000101
5. Animal ear canal irritation and safety test
The preparation of example 1 was selected as a formulation, and ear canal irritation and safety tests were performed on domestic rabbits, and 15 adult new zealand white rabbits that were healthy and free of abnormalities by ear canal examination were randomly divided into three groups of 5 animals, namely, a normal saline group (negative control group), a voriconazole ethanol solution group (positive control group), and an ear temperature-sensitive gel group (administration group). The corresponding medicine is dropped on two ears of New Zealand rabbit by syringe, 1-2 drops each time, 2 times daily, and 7 days are continuously administered. The change of the ear canals of the rabbits, such as whether the animals are red and swollen, hyperemia, swelling and the like, is observed and recorded every day, and the conditions of the animals after administration, whether the animals have restlessness, nose scratching and the like, are observed. The results are shown in Table 4.
TABLE 4 safety results of local administration to rabbit ears
Physiological saline group Voriconazole ethanol solution group The ear temperature-sensitive gel group of the invention
Red swelling and pain 0 2 0
Congestion of blood 0 1 0
Behavioral abnormalities 0 0 0
Total score 0 3 0
The normal saline group and the ear temperature-sensitive gel group have no irritation to rabbit ear skin, and have no adverse reactions such as red swelling, congestion and abnormal behaviors, while the voriconazole ethanol solution group has red swelling and congestion phenomena and has certain irritation to rabbits.
6. Preliminary therapeutic effect experiment of animal
Selecting the example 1 as a formulation, carrying out a preliminary curative effect experiment on rabbits infected with auditory canals, selecting adult New Zealand white rabbits which are healthy and qualified and have no abnormity after auditory canal examination, numbering and recording, injecting bacterial liquid along the edge of rabbit ears by using an injector to the center, respectively injecting aspergillus and candida albicans, wherein the injection amount of each fungus is 0.25 mL/ear, injecting the fungus once a day, continuously injecting the fungus for 3d, and after 5d, taking secretion of the auditory canals of the rabbits to carry out fungus culture examination, wherein the two fungi which have positive results are the success of molding, randomly dividing the two fungi into three groups, and each group comprises 10 fungi, namely a physiological saline group (a negative control group), a voriconazole ethanol solution group (a positive control group) and a temperature-sensitive gel group (an administration group). Saline group dosing (negative control group): 4 times/d, 1-2 times/d, 7 days of continuous administration. Voriconazole ethanol solution group administration dose (positive control group): 4 times/d, 1-2 times/d, 7 days of continuous administration. Administration dose of ear temperature-sensitive gel group (administration group): 2 times/d, 1-2 times/d, 7 days of continuous administration. After the fifth day of administration, the ear canal secretions were cultured with fungi every day, and the therapeutic effect was observed. The results are shown in Table 5.
TABLE 5 cure rate and inefficiency in different experimental groups
Figure BDA0002526689150000111
The standard for evaluating the therapeutic effect is as follows:
and (3) healing: the symptom signs disappear completely;
and (3) relieving: the symptoms and signs are reduced earlier;
and (4) invalidation: signs of symptoms were not improved prior to treatment.
From the results, the ear temperature-sensitive gel prepared by the invention has the advantages of rapid and efficient antifungal effect, excellent drug slow-release effect, reduced administration times, small irritation to auditory canals, rapid effect and high curative effect.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make many possible variations and modifications to the disclosed embodiments, or equivalent modifications, without departing from the spirit and scope of the invention, using the methods and techniques disclosed above. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention are still within the scope of the protection of the technical solution of the present invention.

Claims (10)

1. The ear temperature-sensitive gel is characterized by comprising the following raw materials in percentage by mass:
Figure FDA0002526689140000011
the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
2. The ear temperature-sensitive gel according to claim 1, further comprising an adjuvant, wherein the adjuvant comprises one or more of a preservative, a wetting agent, a transdermal agent, and an adhesive.
3. The ear temperature-sensitive gel according to claim 2, wherein the preservative comprises one or more of sodium benzoate, benzalkonium bromide, lysozyme and ethylparaben, the humectant comprises glycerol and/or propylene glycol, the transdermal agent comprises azone and/or menthol, the adhesive comprises hydroxypropylmethyl cellulose and/or chitosan; according to the mass fraction, the preservative is 0.05-0.5%, the wetting agent is 5-10%, the transdermal agent is 5-10%, and the adhesive agent is 0.5-2%.
4. A preparation method of the ear temperature-sensitive gel is characterized by comprising the following steps:
dissolving voriconazole cyclodextrin inclusion compound in water to obtain voriconazole cyclodextrin inclusion compound solution, wherein the voriconazole cyclodextrin inclusion compound is mainly prepared from sulfobutyl-beta-cyclodextrin sodium solution and voriconazole ethanol solution; adding poloxamer 407 and poloxamer 188 into water, uniformly dispersing, and swelling at 4 +/-1 ℃ for 24-48 h to obtain a blank gel matrix; and adding the voriconazole cyclodextrin inclusion compound solution into the blank gel matrix, and uniformly mixing to obtain the ear temperature-sensitive gel.
5. The preparation method of the ear temperature-sensitive gel according to claim 4, wherein the voriconazole cyclodextrin inclusion compound is 0.2-3%, the poloxamer 407 is 18-20%, the poloxamer 188 is 2-8%, and the total amount of water is 50-79% by mass.
6. The preparation method of the ear temperature-sensitive gel according to claim 5, further comprising adding an adjuvant to the blank gel matrix, wherein the adjuvant comprises one or more of a preservative, a wetting agent, a transdermal agent and an adhesive; the preservative comprises one or more of sodium benzoate, benzalkonium bromide, lysozyme and ethylparaben, the wetting agent comprises glycerol and/or propylene glycol, the transdermal agent comprises azone and/or menthol, and the adhesive comprises hydroxypropyl methylcellulose and/or chitosan; according to the mass fraction, the preservative is 0.05-0.5%, the wetting agent is 5-10%, the transdermal agent is 5-10%, and the adhesive agent is 0.5-2%.
7. A preparation method of the ear temperature-sensitive gel is characterized by comprising the following steps:
adding poloxamer 407, poloxamer 188 and voriconazole cyclodextrin inclusion compound into water, uniformly dispersing, and swelling for 24-48 h at 4 +/-1 ℃ to obtain the ear temperature-sensitive gel, wherein the voriconazole cyclodextrin inclusion compound is mainly prepared from a sulfobutyl-beta-cyclodextrin sodium solution and an ethanol solution of voriconazole.
8. The preparation method of the ear temperature-sensitive gel according to claim 7, wherein the voriconazole cyclodextrin inclusion compound is 0.2-3%, the poloxamer 407 is 18-20%, the poloxamer 188 is 2-8%, and the water is 50-79% by mass.
9. The method for preparing the ear temperature-sensitive gel according to claim 8, further comprising adding an adjuvant to the water, wherein the adjuvant comprises one or more of a preservative, a wetting agent, a transdermal agent and an adhesive; the preservative comprises one or more of sodium benzoate, benzalkonium bromide, lysozyme and ethylparaben, the wetting agent comprises glycerol and/or propylene glycol, the transdermal agent comprises azone and/or menthol, and the adhesive comprises hydroxypropyl methylcellulose and/or chitosan; according to the mass fraction, the preservative is 0.05-0.5%, the wetting agent is 5-10%, the transdermal agent is 5-10%, and the adhesive agent is 0.5-2%.
10. The preparation method of the ear temperature-sensitive gel according to any one of claims 4 to 9, wherein the voriconazole cyclodextrin inclusion compound is mainly prepared by the following steps: adding sulfobutyl-beta-cyclodextrin sodium into water, heating to be completely dissolved, wherein the heating temperature is 30-50 ℃ to obtain sulfobutyl-beta-cyclodextrin sodium solution, dissolving voriconazole in ethanol to obtain ethanol solution of voriconazole, dropwise adding the ethanol solution of voriconazole into the sulfobutyl-beta-cyclodextrin sodium solution, wherein the ratio of the total mass of voriconazole to the mass of the sulfobutyl-beta-cyclodextrin sodium is 1: 10-30, stirring at the rotating speed of 100-400 r/min for 1-5 h after dropwise adding, and the stirring temperature is 30-50 ℃ to perform inclusion, filtering, and drying the filtrate to obtain voriconazole cyclodextrin inclusion compound; wherein the mass-volume ratio of voriconazole to ethanol is 0.1-0.2 g: 1-3 mL, and the ethanol is ethanol solution or absolute ethanol;
and/or the gelation temperature of the ear temperature-sensitive gel is 30-36 ℃, and the strain targeted by the ear temperature-sensitive gel comprises one or more of candida, aspergillus and trichoderma.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116570558A (en) * 2023-06-21 2023-08-11 广州仁恒医药科技股份有限公司 Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof
CN118178683A (en) * 2024-05-15 2024-06-14 云南中医药大学 Spanish gel, and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632803B1 (en) * 1997-06-21 2003-10-14 Pfizer Inc Pharmaceutical formulations containing voriconazole
CN102525885A (en) * 2011-11-21 2012-07-04 程雪翔 Ketoconazole gel and preparation method thereof
CN108567782A (en) * 2018-07-05 2018-09-25 江苏先声药业有限公司 A kind of posaconazole externally-applied medicinal composition, preparation method and the usage
CN113662914A (en) * 2021-08-25 2021-11-19 兆科药业（合肥）有限公司 Eye gel containing voriconazole and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632803B1 (en) * 1997-06-21 2003-10-14 Pfizer Inc Pharmaceutical formulations containing voriconazole
CN102525885A (en) * 2011-11-21 2012-07-04 程雪翔 Ketoconazole gel and preparation method thereof
CN108567782A (en) * 2018-07-05 2018-09-25 江苏先声药业有限公司 A kind of posaconazole externally-applied medicinal composition, preparation method and the usage
CN113662914A (en) * 2021-08-25 2021-11-19 兆科药业（合肥）有限公司 Eye gel containing voriconazole and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANJEEVANI SHEKHAR DESHKAR等: "Formulation and development of thermosensitive cyclodextrin-based in situ gel of voriconazole for vaginal delivery", 《JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY》, vol. 49, pages 277 - 285 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116570558A (en) * 2023-06-21 2023-08-11 广州仁恒医药科技股份有限公司 Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof
CN116570558B (en) * 2023-06-21 2023-12-26 广州仁恒医药科技股份有限公司 Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof
CN118178683A (en) * 2024-05-15 2024-06-14 云南中医药大学 Spanish gel, and preparation method and application thereof

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