CN113440483B - Terbinafine hydrochloride spray for dogs and preparation method thereof - Google Patents
Terbinafine hydrochloride spray for dogs and preparation method thereof Download PDFInfo
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- CN113440483B CN113440483B CN202110743082.9A CN202110743082A CN113440483B CN 113440483 B CN113440483 B CN 113440483B CN 202110743082 A CN202110743082 A CN 202110743082A CN 113440483 B CN113440483 B CN 113440483B
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- terbinafine hydrochloride
- dogs
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- spray
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Abstract
The invention discloses a terbinafine hydrochloride spray for dogs, which is prepared from the following raw materials in percentage by mass: terbinafine hydrochloride 0.5-3%, polyoxyethylene stearate 1-5%, polyoxyethylene alkyl ether 1-6%, propylene glycol 15-50%, pH regulator 0.05-0.15%, and purified water in balance. Correspondingly, the invention also provides a preparation method of the terbinafine hydrochloride spray for dogs. The invention has the advantages of convenient use, safety, effectiveness, good stability and low cost.
Description
Technical Field
The invention relates to the technical field of animal medicine, in particular to a terbinafine hydrochloride spray for dogs and a preparation method thereof.
Background
The allylamine antifungal terbinafine hydrochloride (hereinafter referred to as TH) has bactericidal effect by inhibiting the activity of squalene epoxidase to reduce the synthesis of ergosterol. Can be used for treating dermatomycosis of dog caused by infection of dermatophyte (Trichophyton rubrum, trichophyton mentagrophytes, etc.), aspergillus, and Microsporum canis. Has stronger bactericidal or bacteriostatic action, has stronger activity on dermatophyte and aspergillus than ketoconazole, itraconazole, clotrimazole, griseofulvin and the like, and has broad-spectrum antifungal activity. Terbinafine is highly hydrophobic, lipophilic and lipophilic, enters into skin horny layer in short time, can be fully combined with affected part, and is accumulated in skin deep layer, even if stopping administration, it can still continuously exert potency, and is beneficial to dermatophyte treatment. Can cure most of canine fungal skin diseases by external application, and has the advantages of low recurrence rate, little side effect and high safety.
At present, terbinafine has no clinically approved preparation in domestic and foreign pet fungal dermatosis, and the research and development of the patent are beneficial to the clinical application of the terbinafine in pet fungal dermatosis. At present, patents in the aspect of human medicine such as CN101467960, CN102988276A, CN109260141A, CN111067883A and the like are cream preparations which are adhered to the skin after being smeared, and because different pets and human beings have irregular movement, dirt is easily adhered after being smeared, and the clinical application is not convenient enough. The pharmacokinetic data of TH oral administration found in research literature data (Balfour and Faulds, 1992) show that the accumulation amount of TH oral administration is only 1/25 to 1/12 of the stratum corneum in the dermis layer of the skin epidermis, and the pharmacokinetic study test designed by (Wanglong, 2017) proves that TH oral administration has incomplete absorption and low absolute bioavailability. Therefore, the tablets for oral administration also have limitations in their therapeutic effects.
Solves the problem of solubility of TH and uses the TH as a spray, thereby being safe and effective and being convenient to use. Patent invention CN110638757 has studied to invent a TH spray, but it is an ethanol spray, and pet dermatomycosis is often accompanied with damaged skin with focus. Some irritant response may be elicited. Patent CN109453116A discloses an ethanol-free preparation, but the auxiliary material Kolliphorh HS15 used in the preparation is expensive, and the production investment cost is large according to the dosage.
Therefore, the development of the veterinary antifungal spray which is convenient to use, safe, effective and low in cost becomes an urgent technical problem to be solved.
Disclosure of Invention
The invention aims to solve the technical problem of providing a terbinafine hydrochloride spray for dogs, which is convenient to use, safe, effective, good in stability and low in cost.
The technical problem to be solved by the invention is to provide a preparation method of the terbinafine hydrochloride spray for dogs, which is simple, strong in implementation and low in cost, and the prepared finished product is convenient to use, safe, effective and good in stability.
In order to achieve the technical effect, the invention provides a terbinafine hydrochloride spray for dogs, which is prepared from the following raw materials in percentage by mass:
terbinafine hydrochloride 0.5-3%, polyoxyethylene stearate 1-5%, polyoxyethylene alkyl ether 1-6%, propylene glycol 15-50%, pH regulator 0.05-0.15%, and purified water in balance.
As an improvement of the above scheme, the mass ratio of the polyoxyethylene stearate to the polyoxyethylene alkyl ether is 1:0.5 to 1.5.
As a modification of the above scheme, the polyoxyethylene stearate is 15-hydroxystearic acid polyethylene glycol ester prepared by reacting ethylene oxide and 12-hydroxystearic acid, wherein the amount of the ethylene oxide is 15mol, and the amount of the 12-hydroxystearic acid is 1mol.
As an improvement of the scheme, the pH regulator is any one or more of sodium citrate, sodium acetate, ammonium acetate, sodium tartrate and ethylenediamine.
Correspondingly, the invention also provides a preparation method of the terbinafine hydrochloride spray for dogs, which comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, heating to 50-65 ℃ and completely melting to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), maintaining the temperature at 55-65 ℃, and stirring for 20-40min to stabilize micelle formation to obtain a mixture D;
(5) And (4) finally, adding the pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring, filtering by using a membrane, subpackaging and storing to obtain a finished product.
As an improvement of the scheme, the heating temperature of the step (3) is 55-62 ℃; the temperature of the step (4) is maintained in the range of 58-62 ℃.
As an improvement of the scheme, the terbinafine hydrochloride spray for dogs comprises the following raw materials in percentage by mass:
terbinafine hydrochloride 0.5-3%, polyoxyethylene stearate 1-5%, polyoxyethylene alkyl ether 1-6%, propylene glycol 15-50%, pH regulator 0.05-0.15%, and purified water in balance.
As an improvement of the above scheme, the mass ratio of the polyoxyethylene stearate to the polyoxyethylene alkyl ether is 1:0.5 to 1.5.
As a modification of the above scheme, the polyoxyethylene stearate is 15-hydroxystearic acid polyethylene glycol ester prepared by reacting ethylene oxide and 12-hydroxystearic acid, wherein the ethylene oxide is used in an amount of 15mol, and the 12-hydroxystearic acid is used in an amount of 1mol.
As an improvement of the scheme, the pH regulator is any one or more of sodium citrate, sodium acetate, ammonium acetate, sodium tartrate and ethylenediamine.
The implementation of the invention has the following beneficial effects:
1. the terbinafine hydrochloride spray for dogs comprises terbinafine hydrochloride, polyoxyethylene stearate, polyoxyethylene alkyl ether, propylene glycol, a pH regulator and purified water, fully utilizes physicochemical properties of raw materials and auxiliary materials, and enables the auxiliary material to generate a synergistic effect by compounding, thereby reducing the production cost and simultaneously considering the stability of the preparation, and the spray is convenient to use, safe and effective. In addition, after the composition consisting of the polyoxyethylene alkyl ether and the polyoxyethylene stearate is compounded, compared with the single use of the polyoxyethylene alkyl ether and the polyoxyethylene stearate, the solubility of the composition is improved, and the dosage of polyoxyethylene stearate is reduced, so that the cost is reduced. In addition, the invention replaces ethanol with propylene glycol, has lower irritation to wounds caused by fungal dermatosis, and is safe and reliable.
2. The invention relates to a preparation method of terbinafine hydrochloride spray for dogs, which creatively uses polyoxyethylene stearate and polyoxyethylene alkyl ether as a compound mixture, and after the compound mixture system is heated to a certain critical temperature, terbinafine hydrochloride is added and the critical temperature is maintained to be fully stirred, a complex of the polyoxyethylene stearate and the polyoxyethylene alkyl ether and the terbinafine hydrochloride form micelle in aqueous solution, and the complex plays a role in solubilization and can wrap the medicine in the micelle to be isolated from oxygen, so that secondary amine groups which are easily oxidized and degraded by the terbinafine hydrochloride are protected, and the stability of the preparation is improved. Therefore, the preparation method of the invention has the advantages of simple method, strong implementation and low cost, and the prepared finished product has the advantages of convenient use, safety, effectiveness and good stability.
Drawings
Fig. 1 is a schematic diagram of the preparation method of terbinafine hydrochloride spray for dogs in the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail below.
Referring to fig. 1, the invention provides a terbinafine hydrochloride spray for dogs, which is prepared from the following raw materials in percentage by mass:
terbinafine hydrochloride 0.5-3%, polyoxyethylene stearate 1-5%, polyoxyethylene alkyl ether 1-6%, propylene glycol 15-50%, pH regulator 0.05-0.15%, and purified water in balance.
Preferably, the terbinafine hydrochloride spray for dogs is prepared from the following raw materials in percentage by mass:
terbinafine hydrochloride 0.5-2%, polyoxyethylene stearate 1-3%, polyoxyethylene alkyl ether 1-3%, propylene glycol 20-40%, pH regulator 0.05-0.15%, and purified water in balance.
Terbinafine Hydrochloride (TH) is an allylamine drug with broad-spectrum antifungal activity, can specifically interfere early biosynthesis of fungal ergosterol, and can inhibit squalene epoxidase of fungi with high selectivity, so that squalene epoxidation reaction is hindered in the process of forming fungal cell membranes, thereby achieving the effect of killing or inhibiting fungi.
Terbinafine Hydrochloride (TH) is readily soluble in methanol (640.75 mg/ml), chloroform (656.9 mg/ml), dichloromethane (312.6), absolute ethanol (204 mg/ml), propylene glycol, isopropanol, slightly soluble in distilled water (8 ug/ml). Ethanol and propylene glycol are preferably used as the solvent for TH in view of the physicochemical properties of the dissolution characteristics thereof in combination with the safety of use of the solvent, and propylene glycol is selected as the water-miscible co-solvent because propylene glycol is less irritating to the skin and exposure to infection, and propylene glycol is safer to produce than ethanol. Generally, the TH can be completely melted when the content of the propylene glycol reaches 15-20%, but the low-temperature stability is poor and the color is not clear and bright when the freeze-thaw test is carried out on the TH, so that the invention adds a compound of polyoxyethylene stearate and polyoxyethylene alkyl ether as a solubilizer.
The polyoxyethylene stearate has no unstable double bonds in the chemical structure, and forms a micelle in aqueous solution, so that the medicament can be wrapped in the micelle and isolated from oxygen when the polyoxyethylene stearate has a solubilizing effect, and the position of the medicament which is easily oxidized is protected, thereby improving the stability of the preparation.
Polyoxyethylene alkyl ether, namely Alkylphenol Polyoxyethylene (APEO), is an important polyoxyethylene type nonionic surfactant and has the characteristics of stable property, acid and alkali resistance, low cost and the like.
After the composition consisting of the polyoxyethylene alkyl ether and the polyoxyethylene stearate is compounded, compared with the single use of the polyoxyethylene alkyl ether and the polyoxyethylene stearate, the solubilizing capability of the system is improved, the problem of the solubility of the terbinafine hydrochloride in water is solved, the clinical medication route of the medicine for pets is expanded, and the dosage of the polyoxyethylene stearate is reduced, so that the cost is reduced.
In the prior art, the combination of polyoxyethylene castor oil and polyoxyethylene alkyl ether is used, but when the combination is applied to the preparation of the type, because the polyoxyethylene castor oil is a mixture, and unreacted castor oil is unsaturated fat, the hydroxy oxidation and ester group are easy to hydrolyze, the stability is poor, and the prepared preparation has poor stability at high temperature.
Preferably, the mass ratio of the polyoxyethylene stearate to the polyoxyethylene alkyl ether is 1: 0.5-1.5, the ratio of the two is in the range, the mixture is beneficial to reducing the Critical Micelle Concentration (CMC), and has better dissolution increasing effect on insoluble drugs. More preferably, the mass ratio of the polyoxyethylene stearate to the polyoxyethylene alkyl ether is 1:1.
preferably, the polyoxyethylene stearate is 15-hydroxystearic acid polyethylene glycol ester prepared by reacting ethylene oxide and 12-hydroxystearic acid, wherein the amount of the ethylene oxide is 15mol, and the amount of the 12-hydroxystearic acid is 1mol. Compared with other similar polyoxyethylene stearate substances, the polyoxyethylene stearate has better thermal stability and less side effect on a use object, can be melted into liquid at the temperature of more than 30 ℃, and is convenient and easy to operate and use.
Specifically, the stearic acid polyoxyethylene ester substance is HS-15; the polyoxyethylene alkyl ether substance is CE-1000, but is not limited thereto.
In the solubilizer compound used in the invention, HS-15 not only has strong solubilizing capability, but also is beneficial to adjusting the pH value of the spray to the physiological pH value of animals, and CE-1000 has high safety, so that the spray is suitable for local medicinal preparations and cosmetics, shows more excellent solubilizing capability than single medicines after being compounded with HS-15, and greatly improves the stability of the preparation.
Preferably, the pH regulator is any one or more of sodium citrate, sodium acetate, ammonium acetate, sodium tartrate and ethylenediamine. More preferably, the pH regulator is any one or more of sodium citrate, sodium acetate and ethylenediamine. Most preferably, the pH regulator is 0.05-0.15% of sodium citrate, which can ensure that the pH value of the preparation is between 3.8-4.2, and if the pH value exceeds the range, terbinafine hydrochloride is easy to precipitate under the low temperature condition.
Furthermore, the polyoxyethylene stearate applied by the invention has no unstable double bonds in chemical structure and stable property. However, it was found that, when polyoxyethylene stearate and polyoxyethylene alkyl ether were simply mixed according to a conventional method, there was no significant difference from the case where terbinafine was dissolved by polyoxyethylene stearate alone. The inventor unexpectedly finds that after the compound mixture system is heated to a certain critical temperature, the terbinafine hydrochloride is added and the critical temperature is maintained to be fully stirred, so that the polyoxyethylene stearate and polyoxyethylene alkyl ether compound and the terbinafine hydrochloride form micelles in an aqueous solution, the compound plays a role in solubilization, and meanwhile, the medicament can be wrapped in the micelles and isolated from oxygen, so that secondary amine groups of the terbinafine hydrochloride, which are easily oxidized and degraded, are protected, and the stability of the preparation is improved.
Preferably, the formulation method is as follows:
firstly, mixing purified water and propylene glycol according to a ratio, and uniformly stirring; then adding terbinafine hydrochloride, and stirring uniformly; taking polyoxyethylene stearate and polyoxyethylene alkyl ether in a batching pot, heating until the polyoxyethylene stearate and the polyoxyethylene alkyl ether are completely melted, and then adding the mixture into the water solution containing terbinafine hydrochloride and propylene glycol; and finally adding a pH regulator, and fully stirring until the pH regulator is dissolved.
More preferably, the preparation method is as follows:
firstly, mixing purified water and propylene glycol according to a ratio, and uniformly stirring; then adding terbinafine hydrochloride, and stirring uniformly; taking polyoxyethylene stearate and polyoxyethylene alkyl ether, heating to 55-62 ℃ for complete melting, adding the mixture into a terbinafine hydrochloride-containing propylene glycol aqueous solution, and stirring for 20-40min while maintaining the temperature within the range of 58-62 ℃ to ensure that a micelle forms stably; and finally adding a pH regulator, and fully stirring until the pH regulator is dissolved.
In conclusion, the terbinafine hydrochloride spray for dogs comprises terbinafine hydrochloride, polyoxyethylene stearate, polyoxyethylene alkyl ether, propylene glycol, a pH regulator and purified water, fully utilizes physicochemical properties of raw materials and auxiliary materials, and enables the auxiliary material to generate a synergistic effect by compounding so as to reduce the production cost and simultaneously give consideration to the stability of the preparation, and is convenient to use, safe and effective.
Correspondingly, as shown in fig. 1, the invention also provides a preparation method of terbinafine hydrochloride spray for dogs, which comprises the following steps:
s101, mixing purified water and propylene glycol according to the proportion, and uniformly stirring to obtain a mixture A.
S102, adding terbinafine hydrochloride into the mixture A, and uniformly stirring to obtain a mixture B.
Terbinafine hydrochloride is a hydrophobic substance, and is added into propylene glycol aqueous solution to facilitate wetting in water and suspending therein.
S103, putting polyoxyethylene stearate and polyoxyethylene alkyl ether in a batching pot, heating to 50-65 ℃ for complete melting, and obtaining a mixture C.
In the present invention, when polyoxyethylene stearate and polyoxyethylene alkyl ether are simply mixed according to a conventional method, it is found that there is no significant difference from the case where terbinafine is dissolved by polyoxyethylene stearate alone. However, in the invention, after the compound mixture system is heated to a certain critical temperature, the compound mixture system is added into propylene glycol aqueous solution containing terbinafine hydrochloride, the critical temperature is maintained and the mixture is fully stirred, the polyoxyethylene stearate and polyoxyethylene alkyl ether compound and terbinafine hydrochloride form micelle in the aqueous solution, the compound and terbinafine hydrochloride play a role in solubilization, and the medicament can be wrapped in the micelle and isolated from oxygen, so that secondary amine groups which are easily oxidized and degraded by terbinafine hydrochloride are protected, and the stability of the preparation is improved. The invention needs to control the melting temperature of polyoxyethylene stearate and polyoxyethylene alkyl ether, and the melting temperature is in the range of 50-65 ℃. When the temperature reaches 50 ℃, hydrogen bonds between polyoxyethylene of polyoxyethylene stearate and water molecules are opened, so that the hydration action of the polyoxyethylene stearate is weakened, the system is easy to form micelles, the aggregation number is increased continuously, and otherwise the effect cannot be achieved. When the temperature exceeds 65 ℃, polyoxyethylene stearate in the system is clouded and precipitated, and the solution becomes milky white. The temperature is reduced to 55-65 ℃, and the solution is clear and bright. The heating temperature in step S101 is more preferably 55 to 62 ℃.
The polyoxyethylene stearate has no unstable double bonds in the chemical structure, and forms a micelle in aqueous solution, so that the medicament can be wrapped in the micelle and isolated from oxygen when the polyoxyethylene stearate has a solubilizing effect, and the position of the medicament which is easily oxidized is protected, thereby improving the stability of the preparation.
Polyoxyethylene alkyl ether, namely Alkylphenol Polyoxyethylene (APEO), is an important polyoxyethylene type nonionic surfactant and has the characteristics of stable property, acid and alkali resistance, low cost and the like.
After the composition consisting of the polyoxyethylene alkyl ether and the polyoxyethylene stearate is compounded, compared with the single use of the polyoxyethylene alkyl ether and the polyoxyethylene stearate, the solubilizing capability of the system is improved, the problem of the solubility of the terbinafine hydrochloride in water is solved, the clinical medication route of the medicine for pets is expanded, and the dosage of the polyoxyethylene stearate is reduced, so that the cost is reduced.
S104, adding the mixture C into the mixture B, and stirring for 20-40min at the temperature of 55-65 ℃ to ensure that a micelle forms stably to obtain a mixture D;
at the temperature, the compound of polyoxyethylene stearate and polyoxyethylene alkyl ether and the medicament form a micelle in aqueous solution, and the micelle plays a role in solubilization and can wrap the medicament in the micelle to be isolated from oxygen, so that secondary amine groups which are easily oxidized and degraded by the medicament are protected, and the stability of the preparation is improved.
And S105, finally, adding the pH regulator into the mixture D, fully stirring until the pH regulator is dissolved, stirring, filtering by using a filter membrane, subpackaging and storing to obtain a finished product.
Preferably, the pH regulator is any one or more of sodium citrate, sodium acetate, ammonium acetate, sodium tartrate and ethylenediamine. More preferably, the pH regulator is any one or more of sodium citrate, sodium acetate and ethylenediamine. Most preferably, the pH regulator is sodium citrate with the concentration of between.05 and 0.15 percent.
The invention will be further illustrated with reference to the following specific examples
Example 1
The formula (I) is as follows: terbinafine hydrochloride 0.5g, polyoxyethylene stearate 1g, polyoxyethylene alkyl ether 1g, propylene glycol 15g, pH regulator 0.05g, and purified water in balance to 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, heating to 50 ℃ to completely melt to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), maintaining the temperature at 55 ℃, and stirring for 20min to stabilize micelle formation to obtain a mixture D;
(5) And (5) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring and filtering the mixture by a membrane, subpackaging and storing to obtain a finished product.
Example 2
The formula (I) is as follows: terbinafine hydrochloride 1g, polyoxyethylene stearate 2g, polyoxyethylene alkyl ether 2g, propylene glycol 20g, pH regulator 0.05g, and purified water in balance to a constant volume of 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, heating to 55 ℃ to completely melt to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), maintaining the temperature at 55 ℃, and stirring for 30min to stabilize micelle formation to obtain a mixture D;
(5) And (5) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring and filtering the mixture by a membrane, subpackaging and storing to obtain a finished product.
Example 3
The formula (I) is as follows: terbinafine hydrochloride 2g, polyoxyethylene stearate 3g, polyoxyethylene alkyl ether 3g, propylene glycol 30g, pH regulator 0.1g, and purified water in balance to 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) And (3) putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, heating to 65 ℃ to completely melt to obtain a mixture C.
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), and maintaining the temperature at 65 ℃ and stirring for 40min to stabilize the micelle formation to obtain a mixture D.
(5) And (4) finally, adding the pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring, filtering by using a membrane, subpackaging and storing to obtain a finished product.
Example 4
The formula (I) is as follows: terbinafine hydrochloride 1g, polyoxyethylene stearate 3g, polyoxyethylene alkyl ether 3g, propylene glycol 40g, pH regulator 0.1g, and purified water in balance to 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the (1), and uniformly stirring to obtain a mixture B;
(3) And putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, and heating to 58 ℃ to completely melt to obtain a mixture C.
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), maintaining the temperature, and stirring for 20-40min at 58 ℃ to stabilize the micelle formation, thereby obtaining a mixture D.
(5) And (4) finally, adding the pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring, filtering by using a membrane, subpackaging and storing to obtain a finished product.
Example 5
The formula (I) is as follows: terbinafine hydrochloride 3g, polyoxyethylene stearate 5g, polyoxyethylene alkyl ether 6g, propylene glycol 50g, pH regulator 0.15g, and purified water in balance to 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, heating to 60 ℃ to completely melt to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), maintaining the temperature at 60 ℃, and stirring for 20-40min to stabilize micelle formation to obtain a mixture D;
(5) And (5) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring and filtering the mixture by a membrane, subpackaging and storing to obtain a finished product.
Comparative example 1
The formula (I) is as follows: terbinafine hydrochloride 1g, polyoxyethylene stearate 2g, polyoxyethylene alkyl ether 2g, propylene glycol 20g, pH regulator 0.05g, and purified water in balance to a constant volume of 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into (1), and uniformly stirring to obtain a mixture B;
(3) And (3) putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a mixing pot, heating to 40 ℃, and melting and uniformly mixing to obtain a mixture C.
(4) And (3) adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), finally adding a pH regulator, fully stirring until the mixture is dissolved, stirring, filtering by a membrane, subpackaging, and storing to obtain a finished product.
Comparative example 2
The formula (I) is as follows: 1g of terbinafine hydrochloride, 4g of polyoxyethylene castor oil, 2g of polyoxyethylene alkyl ether, 20g of propylene glycol, 0.05g of pH regulator and the balance of purified water, wherein the volume is up to 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether into a mixing pot, heating to 40 ℃ and completely melting to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), and stirring for 30min at 55 ℃ to obtain a mixture D.
(5) And (4) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the mixture is dissolved, stirring, filtering by using a membrane, subpackaging and storing to obtain a finished product.
Comparative example 3
The formula (I) is as follows: 1g of terbinafine hydrochloride, 4g of polyoxyethylene alkyl ether, 20g of propylene glycol, 0.15g of pH regulator and the balance of purified water to a constant volume of 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene alkyl ether into a batching pot, heating to 40 ℃ to completely melt to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), and stirring for 30min at 55 ℃ to obtain a mixture D.
(5) And (4) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the mixture is dissolved, stirring, filtering by using a membrane, subpackaging and storing to obtain a finished product.
Comparative example 4
The formula (I) is as follows: 1g of terbinafine hydrochloride, 4g of polyoxyethylene castor oil, 20g of propylene glycol, 0.05g of pH regulator and the balance of purified water, wherein the volume is 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene castor oil into a mixing pot, heating to 30 ℃ to completely melt to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), and stirring for 30min at 55 ℃ to obtain a mixture D.
(5) And (4) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the mixture is dissolved, stirring, filtering by using a membrane, subpackaging and storing to obtain a finished product.
Comparative example 5
The formula (I) is as follows: 1g of terbinafine hydrochloride, 4g of polyoxyethylene stearate, 20g of propylene glycol, 0.05g of pH regulator and the balance of purified water to a constant volume of 100mL.
(II) the preparation method comprises the following steps:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into the step (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene stearate in a batching pot, heating to 40 ℃ to completely melt to obtain a mixture C;
(4) And (3) adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), finally adding a pH regulator, fully stirring until the mixture is dissolved, stirring and filtering the mixture by a membrane, subpackaging and storing to obtain a finished product. Examples 1-5 and comparative examples 1-5 were compared experimentally and the results were as follows:
(I) TH solubility test
(1) And (3) according to a formula table in the table 1, dissolving TH in the aqueous solution of each solubilizer and propylene glycol respectively, stirring and melting completely according to the preparation conditions, and then fixing the volume to 100mL. Storing at 4 deg.C and-20 deg.C respectively, standing for 0 day, sampling at 1, 2, and 3 days, and observing dissolution of TH after re-melting. The properties of each solution were observed.
Table 1 formula table
It should be noted that examples 1 to 5 refer to examples 1 to 5, and comparative examples 1 to 5 refer to comparative examples 1 to 5.
(2) And (3) recording an experimental result: as is clear from the observation of the solubility in 1, 2 and 3 days, the low-temperature stability at 4 ℃ was good and no precipitates were formed in each of the examples except comparative example 3. Only examples 1-5 at-20 ℃ and comparative example 5 remained colorless and clear under the conditions of three repeated freeze-thaw cycles.
(II) investigation of high-temperature stability of TH spray
(1) TH spray prepared in examples 1-5 is subjected to high temperature influence factor test, and the high temperature test is selected to be carried out at 60 ℃ to examine the properties, related substances and contents of the sample. The specific test conditions and methods are shown in table 2 below for the high temperature investigation conditions:
TABLE 2 high temperature investigation conditions
(2) And (3) recording an experimental result:
the results of the high temperature tests are shown in tables 3-12, which are as follows:
table 3 example 1 high temperature test investigation results
Table 4 example 2 results of high temperature test investigation
Table 5 example 3 results of high temperature test investigation
Table 6 example 4 results of high temperature test investigation
TABLE 7 EXAMPLE 5 high temperature test investigation results
Table 8 comparative example 1 high temperature test investigation results
TABLE 9 investigation of comparative example 2 high temperature test
TABLE 10 investigation results of comparative example 3 high temperature test
TABLE 11 results of investigation of comparative example 4 high temperature test
TABLE 12 results of investigation of comparative example 5 high temperature test
The test results show that the properties and the pH value of the samples in the examples 1 to 5 are not obviously changed after being placed for 10 days under the condition of a high-temperature test (60 ℃), the maximum single impurity rise of related substances is less than 0.23%, the total impurity rise is less than 0.45%, and the TH content is reduced by less than 1.09%.
Comparative examples 2-4 were left at 60 ℃ for 10 days, and the samples had no significant change in properties and pH, with maximum single impurity rise of the related substances > 0.42%, total impurity rise > 0.91%, and TH content reduction > 3.03%.
Comparative examples 1 and 5 were left at high temperature (60 ℃) for 10 days, and the properties and pH of the samples did not change significantly, with the maximum single impurity rise of the related substances > 0.23%, the total impurity rise > 0.5%, and the TH content reduction > 2.05%.
As is clear from the comparison between examples 1 to 5 and comparative examples 2 to 4, the ratio of the former to the latter related substances tends to increase after 10 days at high temperature, and the TH content of comparative examples 1 to 5 decreases by about 3 times or more as much as that of examples 1 to 5. In contrast, in comparative examples 1 and 5, the TH content was reduced by about 2 times compared with examples 1 to 5, and the relevant substances were slightly higher than the latter. Thus, examples 1-5 are more stable under high temperature conditions than comparative examples 1-5. (III) eye irritation test of New Zealand rabbits with a single administration of TH spray
The terbinafine hydrochloride spray for dogs obtained in example 2 was subjected to a single eye irritation test as follows:
(1) Due to the sensitivity of the canine eye area, ophthalmic drugs and test drugs that may contact the eye should be considered for eye irritation testing. To see if the test drug is damaging to the eyes of the target animal. The test is used for dripping the TH spray into the New Zealand rabbit canthus, observing the irritant reaction of the test object to the rabbit canthus and providing reference for evaluating the safety of clinical use. Referring to the technical guidelines for research on drug irritation, allergy and hemolysis (2014, 05), rabbits were generally selected for eye irritation test animals, with at least 3 animals per group. To examine eye irritancy of different sexes at the same time, 3 new zealand rabbits, male and female, respectively, were used for the test.
(2) The test selects new zealand rabbits which are qualified in adaptability observation and are qualified in binocular examination (no eye irritation symptom, corneal defect and conjunctival injury) by using 0.5% fluorescein sodium, an eye lamp and a magnifying glass, randomly groups the new zealand rabbits according to weight and sex, generally sets a test object group and a negative control group (self-consubstantial control administration of the left eye and the right eye) with half male and half female.
Dripping 0.1 mL/side of the test substance or the control substance, slightly closing the eyelid for about 10s, and not flushing. The left rabbit eye is given the test substance and the right rabbit eye is given the same volume of 0.9% sodium chloride injection, in the order of administration right side to left side. Single administration.
Detailed observations are made once before and 0.5-1, 2, 4, 24, 48, 72 hours after administration; eye irritation reaction examination is carried out by adopting an eye lamp, observation of cornea, red membrane and conjunctiva is carried out by adopting a magnifying glass, and fluorescein sodium staining examination is carried out in the whole observation process; and the stimulation intensity at each observation time point was evaluated against the guidelines. If no obvious abnormality is detected 72 hours after the administration, the test can be ended. If there is obvious abnormality, the material is obtained by the dissection examination of half of the animals, and the material is obtained by the dissection examination of the rest half of the animals 14 days after the last administration. And finally, carrying out comprehensive judgment according to the examination results of visual observation and histopathology.
Description of the drawings: the day of first administration was defined as day 1 of the experiment.
(3) Eye abnormalities should be recorded for each examination, and the score and average score calculated according to table 13. The degree of stimulation was judged according to table 14.
TABLE 13 evaluation tables for respective observation time points
TABLE 14 evaluation criteria for eye irritation
From the above tables 13 and 14, it can be seen that the TH spray of the present invention is non-irritating to the eyes of rabbits. However, it was found that the right eye test group was opened 5 to 10 seconds later than the left eye negative control group after closing the eyelids during the administration. The medicine is shown to have certain irritability to eyes of New Zealand rabbits, but is not enough to cause irritability change.
(IV) skin irritation test of New Zealand rabbits by multiple TH spray administration
The terbinafine hydrochloride spray for dogs obtained in example 2 was subjected to eye irritation tests for a plurality of times, which were as follows:
(1) The test studies the skin irritation test of the TH spray to preliminarily know whether the TH spray can cause irritation reactions such as congestion, tissue degeneration, necrosis and the like after being applied to the skin.
Referring to the technical guidance of research on drug irritation, anaphylaxis and hemolysis (2014, 05), rabbits are usually selected as skin irritation test animals, and the number of the rabbits in each group is not less than 4. The TH spray is applied to New Zealand rabbits through skin for 1 time/day and is continuously applied for 14 days, and the local irritation reaction and the degree of the tested object to normal skin and damaged skin are observed, so that reference information is provided for evaluating the safety of clinical use. The animal has rich background information at home and abroad, and is favorable for comparing results with results of other test samples.
(2) The test uses the preparation to be clinically used for testing, according to the test purpose and the test design requirement, the test comprises a normal skin group, a damaged skin group and a negative control group of a tested product, the administration concentration is the concentration (10 mg/mL and TH) to be clinically used, the administration volume is 0.5 mL/side, and the administration is carried out 1 time per day. See table 15 for specific dosage design.
Table 15 toxicity test dose design table
Note: 10mg/ml calculated by C21H25N & HCL;
approximately 24 hours before administration, the two sides of the spine of the rabbit are dehaired, the range of dehairing on each side is approximately 3cm multiplied by 3cm, whether the skin in the dehaired area is intact is checked, and if damage or abnormal conditions exist, the area should be avoided, and the shaved area is selected again. The skin group is damaged, and the hair-removed areas on the left and right sides are marked with a "well" shape by using syringe needles and the epidermis layer is limited to be damaged.
0.5ml of the test substance or control substance is applied evenly and carefully to the left or right depilated skin of about 2.5cm by 2.5cm to ensure that the test substance or control substance is not lost, and after application, two layers of gauze (2.5 cm by 2.5 cm) and one layer of adhesive bandage are applied to the application site and fixed with non-irritating tape or bandage. The application time is at least 4 hours per day, the fixture and cover are removed, and the remaining test or control is gently wiped away with warm water and absorbent cotton.
Description of the drawings: the day of first administration was defined as day 1 of the experiment.
Observation and scoring time: observing the skin irritation response of the tested part before administration and about 1 hour after removing the tested substance or the reference substance every day, 0.5-1, 24, 48 and 72 hours after the last administration, and scoring the skin irritation response according to the skin irritation response scoring standard of table 16;
the observation period is as follows: 72 hours after the last dose.
TABLE 16 evaluation criteria for skin irritation intensity
(3) According to relevant regulations and skin irritation scoring tables of 'research technical guidelines on irritation, allergy and hemolysis of chemical drugs', a scoring method of taking mode by using a plurality of people participating in scoring is adopted 0.5-24 h after the last administration, so that experimental data is more convincing.
Table 17 complete skin group daily score report
Table 18 daily rating report for broken skin group
And (4) counting the erythema and edema integral of each rabbit every day, and dividing the erythema and edema integral by the number of the rabbits to be tested and the administration period to obtain the average integral of each rabbit every day. The results of the calculation of table 17 above show that the TH spray is non-irritating to the skin of new zealand rabbits according to the evaluation criteria of table 16, with a test complete skin group rating of 0.218 per day per rabbit and a test damaged skin group rating of 0.22 per day per rabbit. However, the data at days 1, 2, and 3 in table 18 show that the test article group has a score of 0.83 to 0.33, which gradually decreases as the skin heals. Care is therefore still taken to avoid use on broken skin during clinical administration.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (9)
1. The terbinafine hydrochloride spray for dogs is characterized by being prepared from the following raw materials in percentage by mass:
terbinafine hydrochloride 0.5-3%, polyoxyethylene stearate 1-5%, polyoxyethylene alkyl ether 1-6%, propylene glycol 15-50%, pH regulator 0.05-0.15%, and purified water in balance;
the terbinafine hydrochloride spray for dogs is prepared by the following method:
(1) Mixing purified water and propylene glycol according to a ratio, and uniformly stirring to obtain a mixture A;
(2) Adding terbinafine hydrochloride into (1), and uniformly stirring to obtain a mixture B;
(3) Putting polyoxyethylene stearate and polyoxyethylene alkyl ether into a batching pot, heating to 50-65 ℃ and completely melting to obtain a mixture C;
(4) Adding the mixture C obtained in the step (3) into the mixture B obtained in the step (2), maintaining the temperature at 55-65 ℃, and stirring for 20-40min to stabilize micelle formation to obtain a mixture D;
(5) And (5) finally, adding a pH regulator into the mixture D obtained in the step (4), fully stirring until the pH regulator is dissolved, stirring and filtering the mixture by a membrane, subpackaging and storing to obtain a finished product.
2. The terbinafine hydrochloride spray for dogs of claim 1, wherein the mass ratio of polyoxyethylene stearate to polyoxyethylene alkyl ether is 1:0.5 to 1.5.
3. The terbinafine hydrochloride spray for dogs of claim 1, wherein said polyoxyethylene stearate is polyethylene glycol 15-hydroxystearate prepared by reacting ethylene oxide with 12-hydroxystearic acid, said ethylene oxide being used in an amount of 15mol, said 12-hydroxystearic acid being used in an amount of 1mol.
4. The terbinafine hydrochloride spray for dogs of claim 1, wherein the pH adjusting agent is any one or more of sodium citrate, sodium acetate, ammonium acetate, sodium tartrate, ethylenediamine.
5. The method of preparing terbinafine hydrochloride spray for dogs as claimed in claim 1, wherein the heating temperature in step (3) is 55-62 ℃; the temperature of the step (4) is maintained in the range of 58-62 ℃.
6. The method for preparing terbinafine hydrochloride spray for dogs as claimed in claim 1, wherein the terbinafine hydrochloride spray for dogs comprises the following raw materials by mass percent:
terbinafine hydrochloride 0.5-3%, polyoxyethylene stearate 1-5%, polyoxyethylene alkyl ether 1-6%, propylene glycol 15-50%, pH regulator 0.05-0.15%, and purified water in balance.
7. The method for preparing terbinafine hydrochloride spray for dogs as claimed in claim 1, wherein the mass ratio of polyoxyethylene stearate to polyoxyethylene alkyl ether is 1:0.5 to 1.5.
8. The method of preparing terbinafine hydrochloride spray for dogs as claimed in claim 1, wherein said polyoxyethylene stearate is 15-hydroxystearic acid polyethylene glycol ester prepared by reacting ethylene oxide with 12-hydroxystearic acid, said ethylene oxide is used in an amount of 15mol, and said 12-hydroxystearic acid is used in an amount of 1mol.
9. The method for preparing terbinafine hydrochloride spray for dogs as claimed in claim 1, wherein the pH regulator is any one or more of sodium citrate, sodium acetate, ammonium acetate, sodium tartrate and ethylenediamine.
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| CN105012235B (en) * | 2015-07-31 | 2017-12-05 | 河南省眼科研究所 | A kind of ophthalmically acceptable antimycotic nano micellar solution containing terbinafine HCl |
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