CN111012741B - Fluconazole ear drops and preparation method thereof - Google Patents
Fluconazole ear drops and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of ear drops preparation, and particularly relates to a fluconazole ear drop and a preparation method thereof. The fluconazole ear drops are prepared from the components of fluconazole, hydroxypropyl methyl cellulose, propylene glycol, benzalkonium bromide, amino acid and the like through the steps of step-by-step dissolution, stirring, filtering and the like, the prepared ear drops have good sterilization and anti-inflammation effects, the side effect is small, the ear drops are modified fluconazole ear drops with good performance, the preparation method is simple, and the preparation method is suitable for industrial popularization and application.
Description
Technical Field
The invention belongs to the technical field of ear drops preparation, and particularly relates to a fluconazole ear drop and a preparation method thereof.
Background
Mycosis of external auditory canal, also called as ear mycosis, is a condition pathogenic fungus invaded into external auditory canal or external auditory canal, and subacute or chronic inflammatory lesion of external auditory canal caused by reproduction under proper condition, and can be combined with bacterial infection. . Subacute or chronic inflammatory diseases of the skin of the external auditory canal can occur at any age. Fungus infection of external auditory canal can cause itching or odd itching and stuffy feeling in ear in early stage, and a small amount of watery secretion exists; if the desquamated epithelium and hyphae form a crust together due to inflammation and block the external auditory canal or cover the surface of the tympanic membrane, hearing loss and tinnitus may occur, manifested as discomfort, distending pain or itching of the external auditory canal, obstruction of the external auditory canal, and auditory disturbance. If bacterial infection is present, swelling, pain and purulence of the external auditory canal may occur. Seriously affecting the life of the patient. Currently, therapeutic approaches rely primarily on the rational application of antifungal drugs. For the treatment of external auditory canal mycosis, a safe and effective external medicine for treating ear fungal infection is lacking clinically at present.
The common ear drops comprise 3-5% of sodium bicarbonate glycerin ear drop, 3% of hydrogen peroxide ear drop, 2% of phenol glycerin ear drop, 25% of chloramphenicol ear drop, 0.3% of ofloxacin ear drop, 3% of procymidone ear drop, thymol alcohol ear drop and tympanum anesthetic. Different drugs are different in symptoms, and are reflected in the aspects of cerumen softening, crust skin diminishing, inflammation diminishing, sterilization, pain relieving, swelling diminishing and the like.
Chinese patent application 200910016125.2 discloses a compound fluconazole ointment and a preparation method thereof, wherein the compound fluconazole ointment consists of fluconazole, neomycin sulfate, vaseline, lanolin, liquid paraffin, stearic acid, span-80, span-85, tween-80, sorbic acid, A-200, A-380, glycerol, DMF, ethyl acetate and distilled water. The nystatin in the otofural is replaced by fluconazole which is a new generation triazole medicine, and the fluconazole is combined with neomycin sulfate to treat deep fungal infection.
Chinese patent application 201010011454.0 discloses a drop for treating otitis externa mycotica and a preparation method thereof. Relates to a compound ear drop for treating otitis externa mycotica, in particular to an ear drop for treating otitis externa mycotica. The preparation is prepared from the following substances: 3-30g of fluconazole, 5-50g of tinidazole, 3-30g of menthol, 800g of glycerol 100, 30-200ml of ethanol, 5-100ml of 1mol/L sodium hydroxide solution and distilled water to 1000 ml. In the preparation process, because the tinidazole is slightly soluble in water and needs to be heated in a water bath to be dissolved, the fluconazole and the menthol are easily dissolved in the ethanol and are dissolved by the ethanol.
In the prior art, although the traditional Chinese medicine composition has a certain effect on the external auditory canal mycosis, the effect is not ideal, or the treatment effect is slow, and certain adverse reactions exist, which are mainly reflected in gastrointestinal tract reactions, abnormal liver functions, dizziness, headache and other symptoms. Therefore, the development of the ear drop with small side effect and good sterilization, anti-inflammation and other effects has important significance.
The invention starts from a formula and a preparation process, researches the improvement of the fluconazole ear drop, and enables the external ear drop to be used for treating the external auditory canal mycosis so as to reduce the dosage of toxic and side effect components, improve the curative effect, and reduce the occurrence of adverse reactions and drug resistance of fungi.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide fluconazole ear drops which are simple in preparation method, and the prepared ear drops can achieve better bacteriostasis and anti-inflammation effects and are small in side effect.
In order to achieve the purpose, the invention provides the following technical scheme:
the fluconazole ear drops comprise the following components in percentage by mass: 0.2-0.6% of fluconazole, 0.1-1.0% of hydroxypropyl methyl cellulose, 2-10% of propylene glycol, 0.003-0.01% of benzalkonium bromide, 1-5% of amino acid and the balance of water.
Preferably, the fluconazole ear drops comprise the following components in percentage by mass: 0.2-0.5% of fluconazole, 0.3-0.8% of hydroxypropyl methyl cellulose, 5-8% of propylene glycol, 0.005-0.01% of benzalkonium bromide, 2-5% of amino acid and the balance of water.
Preferably, the fluconazole ear drop further comprises the following components: n-octyl acetate, ethanol and water.
Preferably, the fluconazole ear drops comprise the following components in percentage by mass: 0.2-0.6% of fluconazole, 0.1-1.0% of hydroxypropyl methyl cellulose, 2-10% of propylene glycol, 0.003-0.01% of benzalkonium bromide, 1-5% of amino acid, 0.3-1% of n-octyl acetate, 10-30% of ethanol and the balance of water.
Preferably, the fluconazole ear drops comprise the following components in percentage by mass: 0.2-0.5% of fluconazole, 0.3-0.8% of hydroxypropyl methyl cellulose, 5-8% of propylene glycol, 0.005-0.01% of benzalkonium bromide, 2-5% of amino acid, 0.3-0.5% of n-octyl acetate, 15-20% of ethanol and the balance of water.
Preferably, the amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 1-2: 1.
Preferably, the water is water for injection.
Another object of the present invention is to provide a method for preparing fluconazole ear drops, which comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water, and stirring to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, stirring for dissolving, adding water, stirring, performing ultrasonic treatment, and adjusting the pH value to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH, adding water, stirring, and performing ultrasound treatment to obtain crude ear drop;
(4) filtering the crude product to obtain a semi-finished product, and performing quality inspection, subpackaging and sterilization to obtain the fluconazole ear drop.
Preferably, in the step (1), the water is added at the temperature of 40-60 ℃;
preferably, in the step (2), the stirring and dissolving are carried out at the temperature of 40-70 ℃, preferably 50 ℃;
preferably, in step (2), the pH value is 4-6, preferably 4-5;
preferably, in step (3), the pH value is 4-6, preferably 4-5;
preferably, in the step (4), the crude product is filtered by a microporous filter membrane or a filter element;
preferably, the size of the microporous filter membrane or the filter element is 0.1-1.0 μm;
preferably, the size of the microporous filter membrane or the filter element is 0.22 μm or 0.8 μm;
preferably, the filtration is carried out twice, with 0.22 μm and 0.8 μm filter elements or membranes, respectively;
preferably, the step (2) further comprises adding ethanol and n-octyl acetate, wherein the adding mode of the ethanol and the n-octyl acetate is as follows: after adding water, ethanol is added while stirring, and then n-octyl acetate is added.
Preferably, the preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection, stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution, and stirring to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol and polyethylene glycol, stirring for dissolving, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment, and adjusting the pH value to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH, adding water, stirring, and performing ultrasound treatment to obtain crude ear drop;
(4) filtering the crude product to obtain a semi-finished product, and performing quality inspection, subpackaging and sterilization to obtain the fluconazole ear drop.
Preferably, in the step (2), the frequency of the ultrasonic wave is 80-100HZ, and the time of the ultrasonic wave is 20-40 min;
preferably, in the step (3), the frequency of the ultrasonic treatment is 100-120HZ, and the time of the ultrasonic treatment is 30-60 min;
preferably, in step (3), the addition amount of the polyethylene glycol is 0.01-0.05% of the total amount of the ear drop, and the molecular weight is 200-.
Compared with the prior art, the invention has the advantages that:
(1) the ear drop solves the problem of single effect of the ear drop in the prior art, has better sterilization and bacteriostasis effects and small side effect, and is an ear drop with excellent performance;
(2) the addition of the amino acid can promote the bacteriostatic effect of the fluconazole ear drop, can be used for otitis media, otitis externa, suppurative otitis media, tympanitis and the like caused by sensitive bacteria, and reduces the toxic and side effects of the ear drop; the amino acid used in the invention is a mixture of alanyl glutamine and glycine, and compared with single component or other kinds of amino acids, the antibacterial effect of the fluconazole ear drops can be better promoted, and the toxic and side effects are reduced;
(3) the n-octyl acetate and the fluconazole added in the method have better synergistic effect, and have no side effect on human body under the action of enhancing the sterilization and anti-inflammation of the fluconazole;
(4) the pH value of the system is controlled within the range of 4-6, and the system has better stability; on one hand, under the condition, the components have better synergistic effect and better bacteriostatic effect; secondly, the pH value is too small or too large, so that the hydrolysis of the n-octyl acetate in the ear drops is promoted, the stability of the components of the ear drops is not facilitated, and the drug effect of the ear drops is further influenced;
(5) the polyethylene glycol 200-400 is added in the preparation process, so that the dissolving performance of n-octyl acetate in the solution preparation process can be improved, the effective action of the n-octyl acetate in the solution can be further promoted, and meanwhile, the final system of the ear drop has better dispersing performance;
(6) the preparation method is simple and feasible, and is suitable for industrial production and popularization.
Detailed Description
Example 1
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.2% of fluconazole, 0.3% of hydroxypropyl methyl cellulose, 5% of propylene glycol, 0.005% of benzalkonium bromide, 5% of amino acid, 0.3% of n-octyl acetate, 20% of ethanol and the balance of water.
The amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 2: 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 50 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 300) accounting for 0.02% of the total mass of the ear drops, stirring and dissolving at the temperature of 50 ℃, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment (the frequency is 80HZ and the time is 40min), and adjusting the pH value to 5 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 5, adding water, stirring, and performing ultrasonic treatment (frequency of 100HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with filter element with size of 0.22 μm and 0.8 μm respectively to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Example 2
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.5% of fluconazole, 0.8% of hydroxypropyl methyl cellulose, 8% of propylene glycol, 0.01% of benzalkonium bromide, 2% of amino acid, 0.5% of n-octyl acetate, 15% of ethanol and the balance of water.
The amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 1: 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water at 40 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 200) accounting for 0.05% of the total mass of the ear drops, stirring and dissolving at 40 ℃, adding water, adding ethanol and n-octyl acetate while stirring, and regulating the pH value to 4 by ultrasound (the frequency is 100HZ and the time is 20min) to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 4, adding water, stirring, and performing ultrasonic treatment (frequency of 120HZ for 60min) to obtain crude product of ear drop;
(4) filtering the crude product with 0.1 μm microporous membrane to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Example 3
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.2% of fluconazole, 0.1% of hydroxypropyl methyl cellulose, 2% of propylene glycol, 0.01% of benzalkonium bromide, 5% of amino acid, 1% of n-octyl acetate, 30% of ethanol and the balance of water.
The amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 1: 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 60 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 400) accounting for 0.01% of the total mass of the ear drops, stirring and dissolving at 70 ℃, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment (the frequency is 80HZ, and the ultrasonic treatment time is 20min), and adjusting the pH value to 6 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 6, adding water, stirring, and performing ultrasonic treatment (frequency of 120HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with a filter element with the size of 1.0 μm to obtain a semi-finished product, and performing quality inspection, subpackaging and sterilization to obtain the fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Example 4
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.6% of fluconazole, 1.0% of hydroxypropyl methyl cellulose, 10% of propylene glycol, 0.003% of benzalkonium bromide, 1% of amino acid, 0.3% of n-octyl acetate, 10% of ethanol and the balance of water.
The amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 1: 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 60 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 200-;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 6, adding water, stirring, and performing ultrasonic treatment (frequency of 120HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with a filter element with the size of 1.0 μm to obtain a semi-finished product, and performing quality inspection, subpackaging and sterilization to obtain the fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Comparative example 1
The difference compared to example 1 is that the amino acid consists only of alanylglutamine.
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.2% fluconazole, 0.3% hydroxypropyl methylcellulose, 5% propylene glycol, 0.005% benzalkonium bromide, 5% amino acids (alanyl glutamine only), 0.3% n-octyl acetate, 20% ethanol, and the balance water.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 50 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 300) accounting for 0.02% of the total mass of the ear drops, stirring and dissolving at the temperature of 50 ℃, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment (the frequency is 80HZ and the time is 40min), and adjusting the pH value to 5 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 5, adding water, stirring, and performing ultrasonic treatment (frequency of 100HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with filter element with size of 0.22 μm and 0.8 μm respectively to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Comparative example 2
The difference compared to example 1 is that n-octyl acetate was replaced with ethyl acetate.
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.2% fluconazole, 0.3% hydroxypropyl methyl cellulose, 5% propylene glycol, 0.005% benzalkonium bromide, 5% amino acid, 0.3% hexyl acetate, 20% ethanol and the balance of water.
The amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 2: 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 50 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 300) accounting for 0.02% of the total mass of the ear drops, stirring and dissolving at the temperature of 50 ℃, adding water, adding ethanol while stirring, adding ethyl acetate, performing ultrasonic treatment (the frequency is 80HZ, the time is 40min), and adjusting the pH value to 5 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 5, adding water, stirring, and performing ultrasonic treatment (frequency of 100HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with filter element with size of 0.22 μm and 0.8 μm respectively to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Comparative example 3
The difference compared to example 1 is the difference in the pH during the preparation.
An ear drop of fluconazole has the same composition as example 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 50 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 300) accounting for 0.02% of the total mass of the ear drops, stirring and dissolving at the temperature of 50 ℃, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment (the frequency is 80HZ and the time is 40min), and adjusting the pH value to 8 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 8, adding water, stirring, and performing ultrasonic treatment (frequency of 100HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with filter element with size of 0.22 μm and 0.8 μm respectively to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Comparative example 4
The difference compared to example 1 is that no amino acid is present.
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.2% of fluconazole, 0.3% of hydroxypropyl methyl cellulose, 5% of propylene glycol, 0.005% of benzalkonium bromide, 0.3% of n-octyl acetate, 20% of ethanol and the balance of water.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose, adding water for injection at 50 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 300) accounting for 0.02% of the total mass of the ear drops, stirring and dissolving at the temperature of 50 ℃, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment (the frequency is 80HZ and the time is 40min), and adjusting the pH value to 5 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 5, adding water, stirring, and performing ultrasonic treatment (frequency of 100HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with filter element with size of 0.22 μm and 0.8 μm respectively to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Comparative example 5
The difference compared to example 1 is the difference in the molecular weight of the polyethylene glycol used in the preparation.
A fluconazole ear drop, which is calculated by the mass percent,
the fluconazole ear drop comprises the following components: 0.2% of fluconazole, 0.3% of hydroxypropyl methyl cellulose, 5% of propylene glycol, 0.005% of benzalkonium bromide, 5% of amino acid, 0.3% of n-octyl acetate, 20% of ethanol and the balance of water.
The amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 2: 1.
The preparation method of the fluconazole ear drop comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water for injection at 50 ℃, and stirring until the hydroxypropyl methylcellulose is uniformly dispersed to a transparent solution to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol, adding polyethylene glycol (M is 600) accounting for 0.02% of the total mass of the ear drops, stirring and dissolving at the temperature of 50 ℃, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment (the frequency is 80HZ and the time is 40min), and adjusting the pH value to 5 to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH to 5, adding water, stirring, and performing ultrasonic treatment (frequency of 100HZ for 30min) to obtain crude product of ear drop;
(4) filtering the crude product with filter element with size of 0.22 μm and 0.8 μm respectively to obtain semi-finished product, quality testing, packaging, and sterilizing to obtain fluconazole ear drop.
Wherein the water is water for injection, and the water added in the steps (1), (2) and (3) is 1/3 of the formula amount respectively.
Examples of effects
(I) bacteriostatic test
Inoculating each strain to be tested into sterilized glucose broth, culturing for 18-24h at 37 deg.C, and adjusting to 10 final concentration with sterile physiological saline6-108CFU·mL-1(colony unit) as a suspension of test bacteria
The 9 ear drops prepared in examples 1-4 and comparative examples 1-5 were subjected to bacteriostatic tests, and the bacteriostatic test method for each ear drop (group) was as follows:
determination of the minimum inhibitory concentration: taking 8 test tubes, adding 0.5mL of sterilized hydrolyzed casein liquid culture medium into the test tubes, respectively adding 10, 20, 30, 40, 50 and 60 mu L of ear drops into the first 6 test tubes of each group, respectively adding 50 mu L of corresponding test bacteria liquid into each group, and fully and uniformly mixing; no liquid medicine and no bacterial liquid are added into the 8 th tube of each group as negative control; no liquid medicine is added into the 9 th tube of each group, the tubes are placed in a 37 th incubator as a positive control and cultured for 24h, the growth of bacteria in each tube is detected by a spectrophotometer method, and the lowest dosage without the bacterial growth phenomenon is used as the minimum inhibitory concentration of the medicine to the bacteria.
TABLE 1 antibacterial Effect (μ L)
| Test group | Staphylococcus aureus | Haemophilus influenzae | Hemolytic streptococcus | Pneumoniae |
| Example 1 | 20 | 30 | 10 | 30 |
| Example 2 | 20 | 30 | 10 | 30 |
| Example 3 | 20 | 30 | 10 | 30 |
| Example 4 | 20 | 30 | 10 | 30 |
| Comparative example 1 | 30 | 40 | 20 | 40 |
| Comparative example 2 | 50 | 60 | 50 | 60 |
| Comparative example 3 | 30 | 40 | 30 | 40 |
| Comparative example 4 | 40 | 50 | 40 | 50 |
| Comparative example 5 | 30 | 40 | 30 | 40 |
Therefore, the ear drops provided by the invention have better antibacterial effect; and the components and the preparation method in the preparation process have great influence on the antibacterial effect.
(II) toxicity test
100 Kunming mice are taken, half of the mice are fed and observed for 1d without abnormality, after hunger (fasting without water prohibition) is carried out for 12h, 10 groups are divided into 10 groups at random according to the weight, the 10 groups are respectively a control group (provided with clear water as a control), examples 1-4 and comparative examples 1-5, each group is provided with 10 mice, each group is respectively administered with subcutaneous injection according to the dose of 2.0g/kg, and various reaction conditions of the nervous system, the respiratory system, the cardiovascular system, the gastrointestinal system, the genitourinary system, the movement and the like of the mice are closely observed after administration. After continuously observing for 14d, recording the toxic reaction condition and death number of each system of the animal in detail, and carrying out necropsy on dead mice in time; and (5) counting the death rate of the mice and the toxicity reaction of the mice without death after the drug.
TABLE 2 toxicity test
In the experiments of examples 1 to 4, dead mice were necropsied, and no abnormal change was observed in the organs such as heart, liver, spleen, lung, and kidney of the animals by visual observation. The non-dead mice were essentially normal 24h after dosing in terms of foraging, spontaneous activity and mental status.
Therefore, the ear drops provided by the invention have small toxic and side effects; and the components and the preparation method in the preparation process have great influence on the toxic and side effects of the traditional Chinese medicine.
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (3)
1. The fluconazole ear drop is characterized by comprising the following components in percentage by mass: 0.2-0.6% of fluconazole, 0.1-1.0% of hydroxypropyl methyl cellulose, 2-10% of propylene glycol, 0.003-0.01% of benzalkonium bromide, 1-5% of amino acid, 0.3-1% of n-octyl acetate, 10-30% of ethanol, 0.01-0.05% of polyethylene glycol and the balance of water; the molecular weight of the polyethylene glycol is 200-400;
the amino acid is a mixture of alanyl glutamine and glycine, and the mass ratio of the alanyl glutamine to the glycine is 1-2: 1.
2. The method for preparing fluconazole ear drops as set forth in claim 1, wherein the method for preparing fluconazole ear drops comprises the following steps:
(1) weighing hydroxypropyl methylcellulose and amino acid, adding water, and stirring to obtain a solution A;
(2) weighing fluconazole, adding propylene glycol and polyethylene glycol, stirring for dissolving, adding water, adding ethanol and n-octyl acetate while stirring, performing ultrasonic treatment, and adjusting the pH value to obtain a solution B;
(3) adding the solution A into the solution B, adding benzalkonium bromide, stirring, adjusting pH, adding water, stirring, and performing ultrasound treatment to obtain crude ear drop;
(4) filtering the crude product to obtain a semi-finished product, and performing quality inspection, subpackaging and sterilization to obtain the fluconazole ear drop.
3. The process for preparing an ear drop of fluconazole as claimed in claim 2, wherein,
in the step (2), the ultrasonic frequency is 80-100HZ, and the ultrasonic time is 20-40 min;
in the step (3), the frequency of the ultrasonic wave is 100-120HZ, and the time of the ultrasonic wave is 30-60 min.
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| CN102018667A (en) * | 2010-10-29 | 2011-04-20 | 杭州雷布科技有限公司 | Imidazoles antifungal skin wiping agent and preparation method thereof |
| CN107854427A (en) * | 2017-11-09 | 2018-03-30 | 广州博济医药生物技术股份有限公司 | A kind of Fluconazole auristilla and preparation method thereof |
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| CN102018667A (en) * | 2010-10-29 | 2011-04-20 | 杭州雷布科技有限公司 | Imidazoles antifungal skin wiping agent and preparation method thereof |
| CN107854427A (en) * | 2017-11-09 | 2018-03-30 | 广州博济医药生物技术股份有限公司 | A kind of Fluconazole auristilla and preparation method thereof |
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Address after: 510670 Building 2, 3, 4 and 5, No. 62, Nanxiang 1st Road, Science City, Huangpu District, Guangzhou, Guangdong Province Patentee after: Boji Pharmaceutical Technology Co.,Ltd. Address before: 510640 room 701, 1933 Huaguan Road, Tianhe District, Guangzhou City, Guangdong Province Patentee before: GUANGZHOU BOJI MEDICAL BIOTECHNOLOGY Co.,Ltd. |
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Denomination of invention: Fluconazole ear drops and its preparation method Effective date of registration: 20221027 Granted publication date: 20210608 Pledgee: Bank of China Limited Guangzhou Development Zone Branch Pledgor: Boji Pharmaceutical Technology Co.,Ltd. Registration number: Y2022980019865 |