CN113018252A - Triamcinolone acetonide econazole cream and preparation method thereof - Google Patents

Triamcinolone acetonide econazole cream and preparation method thereof Download PDF

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CN113018252A
CN113018252A CN202110284768.6A CN202110284768A CN113018252A CN 113018252 A CN113018252 A CN 113018252A CN 202110284768 A CN202110284768 A CN 202110284768A CN 113018252 A CN113018252 A CN 113018252A
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triamcinolone acetonide
cream
percent
econazole
water
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CN113018252B (en
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王燕
钱伟钢
周建伟
胡朝新
杨涛
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SHANGHAI ZHAOHUI PHARMACEUTICAL CO Ltd
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SHANGHAI ZHAOHUI PHARMACEUTICAL CO Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to triamcinolone acetonide econazole cream and a preparation method thereof. The triamcinolone acetonide econazole cream contains 1.0-1.5% of sodium dodecyl sulfate by mass percent. The invention adopts the sodium dodecyl sulfate as the emulsifier of the triamcinolone acetonide econazole cream, limits the specific dosage, redesigns the prescription on the basis, ensures the stability of the triamcinolone acetonide econazole cream, and keeps the stable product properties and content after 6-month accelerated test and 24-month long-term stability test, thereby solving the clinical risk of unstable product quality and ensuring the safety and effectiveness of the product.

Description

Triamcinolone acetonide econazole cream and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to triamcinolone acetonide econazole cream and a preparation method thereof.
Background
The triamcinolone acetonide and econazole nitrate cream is a white cream and a compound preparation, has main active components of triamcinolone acetonide and econazole nitrate, is clinically used for fungal infection, eczema and the like of skin and mucous membrane, is a relatively common skin external application drug, and has huge market. The triamcinolone acetonide econazole cream preparation of various brands exists in the market, the quality is uneven, part of products are poor in stability and easy to discolor, the characters are changed in the storage period, and the content is reduced.
Patent application CN101239066A provides a prescription and a preparation process of triamcinolone acetonide econazole cream, but in actual sample trial, it is found that a sample prepared according to the prescription still has a stability problem, and has a color change problem of different degrees in the process of accelerating examination.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a triamcinolone acetonide econazole cream to solve the technical problem of poor stability of the triamcinolone acetonide econazole cream in the prior art.
The second purpose of the invention is to provide a preparation method of the triamcinolone acetonide econazole cream.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the triamcinolone acetonide econazole cream contains 1.0-1.5% of sodium dodecyl sulfate by mass percent.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream does not contain polyoxyethylene stearate and polyoxyethylene oleate.
When the sample stability of the existing triamcinolone acetonide econazole cream is researched, the problem of color change of different degrees exists in the process of accelerated research, the analysis may be that more peroxide impurities remain in the synthesis of polyoxyethylene-7-stearate and polyoxyethylene-5-oleate, and at present, substances such as polyoxyethylene-7-stearate and polyoxyethylene-5-oleate have no medical unified standard, and most of the substances execute the internal control standard of enterprises and cannot be unified, so that the difference between product batches is large, and the stability of the triamcinolone acetonide econazole cream is influenced finally.
According to the invention, a large amount of creative work discovers that the stability can be ensured by adopting the sodium dodecyl sulfate as the emulsifier and matching with the rest components in the triamcinolone acetonide econazole cream under the condition of a certain addition amount, and the problem of poor stability of the triamcinolone acetonide econazole cream is solved from the source.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream is mainly prepared from the following components in percentage by mass:
0.09-0.115 percent of triamcinolone acetonide, 0.9-1.1 percent of econazole nitrate, 7.5-8.5 percent of liquid paraffin, 11.5-12.5 percent of glycerol, 4.5-5.5 percent of hexadecanol, 3.5-4.5 percent of octadecanol, 1.0-1.5 percent of sodium dodecyl sulfate, 0.015-0.025 percent of antioxidant, 0.05-0.15 percent of disodium edetate, 0.15-0.25 percent of preservative and 65.86-70.795 percent of water.
In a specific embodiment of the present invention, the antioxidant comprises at least one of butylated hydroxyanisole, dibutyl hydroxytoluene and sodium bisulfite, and is preferably butylated hydroxyanisole.
In a particular embodiment of the invention, the preservative comprises at least one of benzoic acid, sorbic acid and benzyl alcohol, preferably benzoic acid.
In a specific embodiment of the present invention, the amount of the sodium lauryl sulfate is 1.1% to 1.4%, preferably 1.2% to 1.3%.
The invention adopts the sodium dodecyl sulfate as the emulsifier of the triamcinolone acetonide econazole cream, limits the specific dosage, redesigns the prescription on the basis, ensures the stability of the triamcinolone acetonide econazole cream, and keeps the stable product properties and content after the accelerated test of 6 months and the long-term stability test of 24 months.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream is mainly prepared from the following components in percentage by mass:
0.095-0.11% of triamcinolone acetonide, 0.95-1.05% of econazole nitrate, 7.8-8.2% of liquid paraffin, 11.8-12.2% of glycerol, 4.8-5.2% of hexadecanol, 3.8-4.2% of octadecanol, 1.2-1.3% of sodium dodecyl sulfate, 0.018-0.022% of antioxidant, 0.08-0.12% of disodium edetate, 0.18-0.22% of preservative and 67.378-69.277% of water.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream is prepared from the following components in percentage by mass:
0.1% of triamcinolone acetonide, 1% of econazole nitrate, 8% of liquid paraffin, 12% of glycerol, 5% of hexadecanol, 4% of octadecanol, 1.2% of sodium dodecyl sulfate, 0.02% of butyl hydroxy anisole, 0.1% of disodium edetate, 0.2% of benzoic acid and 68.38% of water.
In practice, the water is purified water.
The invention also provides a preparation method of the triamcinolone acetonide econazole cream, which comprises the following steps:
uniformly mixing the sodium dodecyl sulfate and the water phase material to obtain a water phase; and mixing the water phase and the oil phase for emulsification, and then mixing with the triamcinolone acetonide and the econazole nitrate.
Wherein the water phase material includes glycerol, water, and edetate disodium.
In a specific embodiment of the present invention, the preparation method comprises the steps of:
(a) the glycerin, the water, the edetate disodium and the sodium dodecyl sulfate are uniformly mixed according to a proportion to obtain a water phase; mixing the liquid paraffin, cetyl alcohol, stearyl alcohol, antioxidant such as butyl hydroxy anisol, and antiseptic such as benzoic acid at a certain proportion to obtain oil phase;
(b) transferring the oil phase into a vacuum emulsifying pot by utilizing vacuum, transferring the water phase into the oil phase in the vacuum emulsifying pot at a constant speed within 15-20 min, carrying out heat preservation homogenizing emulsification at 82-85 ℃ for 20-30 min after the two phases are transferred, and then cooling;
(c) and cooling to 60-65 ℃, adding triamcinolone acetonide and econazole nitrate, stirring and homogenizing for 20-30 min, cooling to 35-40 ℃, and discharging.
In a specific embodiment of the present invention, in the step (a), the preparation method of the aqueous phase comprises: mixing the glycerol with water, adding edetate disodium under the stirring and heating state, continuously heating to the temperature of more than 88 ℃, adding sodium dodecyl sulfate, and then stirring for 10-15 min to obtain the water phase. Wherein the temperature corresponding to the continuous heating to above 88 ℃ can be 90-95 ℃.
In a specific embodiment of the present invention, in the step (a), the preparation method of the oil phase comprises: mixing the liquid paraffin, cetyl alcohol and stearyl alcohol, heating for melting, adding antioxidant such as butyl hydroxy anisole, and antiseptic such as benzoic acid, and mixing to obtain the oil phase.
In actual operation, the temperature of the prepared oil phase is ensured to be more than or equal to 88 ℃ for standby.
In a specific embodiment of the present invention, the time for transferring the oil phase into the vacuum emulsification pot is 5-8 min.
Through the intensive research on the oil phase transfer time and the water phase transfer time, the invention adopts the specific water phase transfer time and the oil phase transfer time, particularly the water phase transfer time, so that the combination stability of the oil phase and the water phase can be further improved, and the separation phenomenon between the oil phase and the water phase and the like can be avoided. If the water phase transfer time is too short, the formed cream has large size of emulsion drops in the microcosmic state, the cream is not fine and smooth enough, and the emulsion breaking phenomenon can be generated along with the time; however, if the water phase transfer time is too long, the production efficiency cannot be guaranteed.
In a specific embodiment of the invention, in the step (b), the stirring speed of the vacuum emulsifying pot is 15-20 r/min when the water phase is transferred and the oil phase is transferred.
The invention further ensures the uniformity and stability of the product by adopting specific conditions of stirring, emulsification, homogenization and the like.
In a specific embodiment of the present invention, in the step (b), the conditions of the homogeneous emulsification include: the stirring speed is 20-45 r/min, the vacuum pressure is-0.02-0.03 MPa, and the homogenizing speed is 1500-2800 r/min.
In a specific embodiment of the present invention, in the step (b), during the temperature reduction, the vacuum pressure is controlled to be-0.03 to-0.05 MPa.
In a specific embodiment of the present invention, in the step (c), the stirring and homogenizing conditions include: the stirring speed is 20-45 r/min, the homogenizing speed is 1500-2800 r/min, and the vacuum pressure is-0.03 to-0.05 MPa.
In a specific embodiment of the invention, in the process of cooling to 35-40 ℃, the vacuum pressure is-0.04 to-0.06 MPa.
In the specific embodiment of the invention, the material is discharged at a stirring speed of 10-20 r/min.
In practice, the above steps (b) and (c) are carried out in a vacuum emulsifying pot.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the invention, by improving the prescription of the triamcinolone acetonide econazole cream, the clinical risk of unstable product quality is solved, and the safety and effectiveness of the product are ensured;
(2) the preparation method further improves the product quality, is suitable for large-scale industrial production, and has great application value.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following detailed description, but those skilled in the art will understand that the following described examples are some, not all, of the examples of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The triamcinolone acetonide econazole cream contains 1.0-1.5% of sodium dodecyl sulfate by mass percent.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream does not contain polyoxyethylene stearate and polyoxyethylene oleate.
Among them, polyoxyethylene stearate includes, but is not limited to, polyoxyethylene-7-stearate; polyoxyethylene oleate includes, but is not limited to, polyoxyethylene-5-oleate.
According to the invention, a large amount of creative work discovers that the stability can be ensured by adopting the sodium dodecyl sulfate as the emulsifier and matching with the rest components in the triamcinolone acetonide econazole cream under the condition of a certain addition amount, and the problem of poor stability of the triamcinolone acetonide econazole cream is solved from the source. In addition, it is found through research that the addition amount of sodium dodecyl sulfate as an emulsifier is in the above range, and the emulsification, stability, production efficiency and the like can be ensured at the same time. When the content of the sodium dodecyl sulfate exceeds 1.5%, the production process needs longer defoaming time, and the production efficiency is greatly influenced.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream does not contain span series and tween series emulsifiers.
The invention discovers, through research, that when span or tween series are adopted as the emulsifying agent of the triamcinolone acetonide econazole cream, the span or tween series can cause the discoloration of the product in different degrees during the stability period.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream is mainly prepared from the following components in percentage by mass:
0.09-0.115 percent of triamcinolone acetonide, 0.9-1.1 percent of econazole nitrate, 7.5-8.5 percent of liquid paraffin, 11.5-12.5 percent of glycerol, 4.5-5.5 percent of hexadecanol, 3.5-4.5 percent of octadecanol, 1.0-1.5 percent of sodium dodecyl sulfate, 0.015-0.025 percent of antioxidant, 0.05-0.15 percent of disodium edetate, 0.15-0.25 percent of preservative and 65.86-70.795 percent of water.
In a specific embodiment of the present invention, the antioxidant comprises at least one of butylated hydroxyanisole, dibutyl hydroxytoluene and sodium bisulfite, and is preferably butylated hydroxyanisole.
In a particular embodiment of the invention, the preservative comprises at least one of benzoic acid, sorbic acid and benzyl alcohol, preferably benzoic acid.
In a specific embodiment of the present invention, the amount of the sodium lauryl sulfate is 1.1% to 1.4%, preferably 1.2% to 1.3%.
As in the various embodiments, the sodium lauryl sulfate may be used in an amount of 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, etc., preferably 1.2%.
The invention adopts the sodium dodecyl sulfate as the emulsifier of the triamcinolone acetonide econazole cream, limits the specific dosage, redesigns the prescription on the basis, ensures the stability of the triamcinolone acetonide econazole cream, and keeps the stable product properties and content after the accelerated test of 6 months and the long-term stability test of 24 months.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream is mainly prepared from the following components in percentage by mass:
0.095-0.11% of triamcinolone acetonide, 0.95-1.05% of econazole nitrate, 7.8-8.2% of liquid paraffin, 11.8-12.2% of glycerol, 4.8-5.2% of hexadecanol, 3.8-4.2% of octadecanol, 1.2-1.3% of sodium dodecyl sulfate, 0.018-0.022% of antioxidant, 0.08-0.12% of disodium edetate, 0.18-0.22% of preservative and 67.378-69.277% of water.
In a specific embodiment of the invention, the triamcinolone acetonide econazole cream is prepared from the following components in percentage by mass:
0.1% of triamcinolone acetonide, 1% of econazole nitrate, 8% of liquid paraffin, 12% of glycerol, 5% of hexadecanol, 4% of octadecanol, 1.2% of sodium dodecyl sulfate, 0.02% of butyl hydroxy anisole, 0.1% of disodium edetate, 0.2% of benzoic acid and 68.38% of water.
In practice, the water is purified water.
The invention also provides a preparation method of the triamcinolone acetonide econazole cream, which comprises the following steps:
uniformly mixing the sodium dodecyl sulfate and the water phase material to obtain a water phase; and mixing the water phase and the oil phase for emulsification, and then mixing with the triamcinolone acetonide and the econazole nitrate.
Wherein the water phase material includes glycerol, water, and edetate disodium.
In a specific embodiment of the present invention, the preparation method comprises the steps of:
(a) the glycerin, the water, the edetate disodium and the sodium dodecyl sulfate are uniformly mixed according to a proportion to obtain a water phase; mixing the liquid paraffin, cetyl alcohol, stearyl alcohol, antioxidant such as butyl hydroxy anisol, and antiseptic such as benzoic acid at a certain proportion to obtain oil phase;
(b) transferring the oil phase into a vacuum emulsifying pot by utilizing vacuum, transferring the water phase into the oil phase in the vacuum emulsifying pot at a constant speed within 15-20 min, carrying out heat preservation homogenizing emulsification at 82-85 ℃ for 20-30 min after the two phases are transferred, and then cooling;
(c) and cooling to 60-65 ℃, adding triamcinolone acetonide and econazole nitrate, stirring and homogenizing for 20-30 min, cooling to 35-40 ℃, and discharging.
In a specific embodiment of the present invention, in the step (a), the preparation method of the aqueous phase comprises: mixing the glycerol with water, adding edetate disodium under the stirring and heating state, continuously heating to the temperature of more than 88 ℃, adding sodium dodecyl sulfate, and then stirring for 10-15 min to obtain the water phase.
In a specific embodiment of the present invention, in the step (a), the preparation method of the oil phase comprises: mixing the liquid paraffin, cetyl alcohol and stearyl alcohol, heating for melting, adding antioxidant such as butyl hydroxy anisole, and antiseptic such as benzoic acid, and mixing to obtain the oil phase.
In actual operation, the temperature of the prepared oil phase is ensured to be more than or equal to 88 ℃ for standby.
In a specific embodiment of the invention, in the step (b), the stirring speed of the vacuum emulsifying pot is 15-20 r/min when the water phase is transferred and the oil phase is transferred.
In a specific embodiment of the present invention, in the step (b), the conditions of the homogeneous emulsification include: the stirring speed is 20-45 r/min, the vacuum pressure is-0.02-0.03 MPa, and the homogenizing speed is 1500-2800 r/min.
In a specific embodiment of the present invention, in the step (b), during the temperature reduction, the vacuum pressure is controlled to be-0.03 to-0.05 MPa.
In a specific embodiment of the present invention, in the step (c), the stirring and homogenizing conditions include: the stirring speed is 20-45 r/min, the homogenizing speed is 1500-2800 r/min, and the vacuum pressure is-0.03 to-0.05 MPa.
In a specific embodiment of the invention, in the process of cooling to 35-40 ℃, the vacuum pressure is-0.04 to-0.06 MPa.
In the specific embodiment of the invention, the material is discharged at a stirring speed of 10-20 r/min.
In practice, the above steps (b) and (c) are carried out in a vacuum emulsifying pot. Specifically, the method comprises the following steps:
(b) transferring the oil phase into a vacuum emulsifying pot, starting the emulsifying pot and stirring, wherein the stirring speed is 15-20 r/min; then, transferring all the water phase into the vacuum emulsifying pot at a constant speed within 15-20 min, controlling the temperature of the vacuum emulsifying pot to be 82-85 ℃ after the transfer is finished, and emulsifying for 20-30 min under the conditions of stirring rotating speed of 20-45 r/min, vacuum pressure of-0.02-0.03 MPa and homogenizing rotating speed of 1500-2800 r/min; then starting cooling water of the emulsifying pot for cooling, and keeping the pressure of the cooling water at 0.1-0.2 MPa and regulating and controlling the vacuum pressure in the emulsifying pot at-0.03-0.05 MPa in the cooling process;
(c) when the temperature of the emulsifying pot is reduced to 60-65 ℃, opening the pot cover, adding triamcinolone acetonide and econazole nitrate, covering the pot cover, starting stirring, wherein the stirring speed is 20-45 r/min, starting homogenizing, the homogenizing speed is 1500-2800 r/min, the vacuum pressure is gradually controlled to be-0.03 to-0.05 MPa, stirring and homogenizing for 20-30 min, cooling while stirring, the vacuum pressure is controlled to be-0.04 to-0.06 MPa, cooling to 35-40 ℃, starting compressed air to extrude the materials at the stirring speed of 10-20 r/min, weighing, and finishing discharging.
Further, after the materials are pressed out, filling is carried out. Specifically, a full-automatic hose filling and end sealing machine can be used for filling, and the filling amount is checked once per hour to obtain the triamcinolone acetonide econazole cream.
Example 1
The embodiment provides a preparation method of triamcinolone acetonide econazole cream, which comprises the following steps:
(1) weighing each component according to the prescription amount for later use; wherein, the 200kg prescription dose of the triamcinolone acetonide econazole cream comprises the following raw materials and auxiliary materials:
0.20kg of triamcinolone acetonide, 2.00kg of econazole nitrate, 16.00kg of liquid paraffin, 24.00kg of glycerin, 10.00kg of hexadecanol, 8.00kg of octadecanol, 2.40kg of sodium dodecyl sulfate, 0.04kg of butyl hydroxy anisole, 0.20kg of edetate disodium, 0.40kg of benzoic acid and 136.76kg of purified water.
(2) Preparing an aqueous phase: adding weighed and rechecked glycerol and purified water into a water phase pot, heating while stirring, adding edetate disodium, continuously heating to 90 ℃, then adding sodium dodecyl sulfate, and stirring for 10-15 min until dissolution to obtain a water phase for later use.
(3) Preparing an oil phase: adding weighed and rechecked liquid paraffin, cetyl alcohol and stearyl alcohol into an oil phase pot, heating to melt, adding butyl hydroxy anisole and benzoic acid, melting and uniformly mixing to obtain an oil phase, and ensuring that the temperature of the oil phase pot is more than or equal to 88 ℃ for later use.
(4) Emulsification: transferring the oil phase obtained in the step (3) into a vacuum emulsifying pot within 6min, starting the emulsifying pot for stirring during transferring, wherein the stirring speed is 15 r/min; then, the water phase is completely transferred into the vacuum emulsifying pot at a constant speed within 15min, after the transfer is finished, the temperature of the vacuum emulsifying pot is controlled to be 84-85 ℃, and the water phase is emulsified for 25min under the conditions that the stirring rotating speed is 30r/min, the vacuum pressure is-0.02 to-0.03 MPa and the rotating speed of a homogenizer is 2500 r/min; then starting cooling water of the emulsifying pot for cooling, and keeping the pressure of the cooling water at 0.1-0.2 MPa and regulating and controlling the vacuum pressure in the emulsifying pot at-0.03-0.05 MPa in the cooling process; when the temperature is reduced to about 65 ℃, opening the cover of the vacuum emulsifying pot, adding the weighed and rechecked triamcinolone acetonide and econazole nitrate, covering the cover of the vacuum emulsifying pot, opening the stirring at the stirring speed of 40r/min, starting the homogenization, controlling the rotation speed of the homogenizer at 2500r/min, gradually controlling the vacuum pressure at-0.03 to-0.05 MPa, stirring and homogenizing for 30min, and ensuring that the materials are fully wet. Then cooling while stirring, controlling the vacuum pressure at-0.04 to-0.06 MPa, cooling to 40 ℃, starting compressed air to extrude the material under the condition that the stirring speed is 15r/min, and weighing.
(5) Filling: filling by using a full-automatic hose filling and end sealing machine according to the specification requirement, and checking the filling amount once per hour to obtain the triamcinolone acetonide econazole cream.
Example 2
This example refers to the preparation of example 1, with the only difference that: the amount of sodium lauryl sulfate was 2.00kg and the amount of purified water was 137.16 kg.
Example 3
This example refers to the preparation of example 1, with the only difference that: the amount of sodium lauryl sulfate was 3.00kg and the amount of purified water was 136.16 kg.
Comparative example 1
Comparative example 1 the preparation process of example 1 was referenced, with the following differences: sodium dodecyl sulfate was replaced with 6.4kg tween 80, corresponding to a purified water dose of 132.76 kg.
Comparative example 2
Comparative example 2 the preparation process of example 1 was referenced, with the following differences: sodium lauryl sulfate was replaced with 12kg span 20, corresponding to purified water usage of 127.16 kg.
Comparative example 3
Comparative example 3 the preparation process of example 1 was referenced, with the following differences: sodium lauryl sulfate was replaced with 24kg polyoxyethylene-7-stearate and 6kg polyoxyethylene-5-oleate, corresponding to a purified water dose of 109.16 kg.
Experimental example 1
For comparative illustration of the stability of the triamcinolone acetonide econazole cream of the present invention, 3 sets of triamcinolone acetonide econazole cream products, examples 1-1#, examples 1-2#, and examples 1-3# were prepared in parallel according to the preparation method of example 1, and the indexes of the triamcinolone acetonide econazole cream products, examples 1-1#, examples 1-2#, and examples 1-3# were examined, and the results are as follows.
The examination method comprises the following steps: the stability characters, contents and microbial limits of the triamcinolone acetonide econazole cream product in 0 month, 6 months and 24 months are detected.
The content detection method comprises the following steps: measuring by high performance liquid chromatography (general rule 0512).
Chromatographic conditions and system applicability test: using octyl silane bonded silica gel as a filling agent; the mobile phase A is: dissolving 0.94g of sodium hexanesulfonate in acetonitrile-isopropanol-water-85% phosphoric acid (140: 720: 1) and diluting to 1000 mL; the mobile phase B is as follows: dissolving 0.94g sodium hexanesulfonate in methanol-water-85% phosphoric acid (900: 100: 1), and diluting to 1000mL to obtain mobile phase B; gradient elution was performed as in table 1 below; the column temperature was 40 ℃; the detection wavelength was 227 nm. The separation degree of the triamcinolone acetonide peak and the econazole nitrate peak is in accordance with the requirement.
The determination method comprises the following steps: taking about 1.25g of a corresponding product, precisely weighing, placing in a 25mL measuring flask, adding 2mL of tetrahydrofuran, shaking for 1 minute to dissolve triamcinolone acetonide and econazole nitrate, diluting with methanol to a scale, shaking up, filtering, taking a subsequent filtrate as a sample solution, precisely measuring 10 mu L of the subsequent filtrate, injecting into a liquid chromatograph, and recording a chromatogram; precisely weighing about 15.6mg of triamcinolone acetonide reference substance, placing into a 25mL measuring flask, adding methanol to dissolve and dilute to scale, and shaking up to obtain triamcinolone acetonide reference substance solution; precisely weighing about 12.5mg of econazole nitrate as a reference substance, placing the reference substance in a 25mL measuring flask, precisely adding 2mL of triamcinolone acetonide reference substance solution and 2mL of tetrahydrofuran, diluting with methanol to scale, shaking up, measuring by the same method, and calculating by peak area according to an external standard method to obtain the final product.
TABLE 1 gradient elution procedure
Time (minutes) Mobile phase A (%) Mobile phase B (%)
0 100 0
25 0 100
35 100 0
45 100 0
Microbial limit detection methods reference: the four parts of the appendix 1105, 1106 of the chinese pharmacopoeia 2020 edition.
The test results of 6 months accelerated (30 + -2 deg.C, relative humidity 65% + -5%) and 24 months long (25 + -2 deg.C, relative humidity 60 + -10%) are shown in tables 2-4.
TABLE 2 examination results of corresponding indexes of three groups of triamcinolone acetonide and econazole cream products in 0 month
Figure BDA0002979989050000131
TABLE 3 three sets of data on the accelerated 6 month stability of triamcinolone acetonide econazole cream products
Figure BDA0002979989050000132
Figure BDA0002979989050000141
TABLE 4 Long-term 24-month stability data for three groups of triamcinolone acetonide econazole cream products
Figure BDA0002979989050000142
From the test results in tables 2 to 4, it can be seen that all indexes of 3 groups of triamcinolone acetonide econazole cream products prepared by the components and the method in the embodiment 1 of the invention meet the standard specification, the stability test characters, contents and microbial limits in 0 month, 6 months and 24 months after acceleration all meet the product quality standard, the production process is controllable, and the requirements of large-scale continuous and stable production are met.
Experimental example 2
In order to illustrate the performance difference between the triamcinolone acetonide econazole cream and the triamcinolone acetonide econazole cream prepared by other formulas or preparation methods in a comparative way, the triamcinolone acetonide econazole cream products prepared in examples 1 to 3 and comparative examples 1 to 3 are subjected to accelerated test investigation (30 +/-2 ℃, relative humidity 65% +/-5%), appearance properties of the products in an accelerated process are observed, and test results are shown in table 5.
TABLE 5 stability test results for different triamcinolone acetonide econazole creams products
Frequency of Example 1 Example 2 Example 3 Comparative example 1 Comparative example 2 Comparative example 3
Accelerating for 1 month White cream White cream White cream White cream White cream White cream
Accelerated for 2 months White cream White cream White cream White cream White cream White cream
Accelerated for 3 months White cream White cream White cream White cream Yellowish cream Yellowish cream
Accelerated for 6 months White cream White cream White cream Yellowish cream Yellowish cream Yellow cream
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. The triamcinolone acetonide econazole cream is characterized by comprising 1.0-1.5% of sodium dodecyl sulfate by mass percent.
2. The triamcinolone acetonide econazole cream of claim 1, wherein the triamcinolone acetonide econazole cream is free of polyoxyethylene stearate and polyoxyethylene oleate.
3. The triamcinolone acetonide econazole cream of claim 1, which is prepared from the following components in percentage by mass:
0.09-0.115 percent of triamcinolone acetonide, 0.9-1.1 percent of econazole nitrate, 7.5-8.5 percent of liquid paraffin, 11.5-12.5 percent of glycerol, 4.5-5.5 percent of hexadecanol, 3.5-4.5 percent of octadecanol, 1.0-1.5 percent of sodium dodecyl sulfate, 0.015-0.025 percent of antioxidant, 0.05-0.15 percent of edetate disodium, 0.15-0.25 percent of preservative and 65.86-70.795 percent of water;
preferably, the antioxidant comprises at least one of butylated hydroxyanisole, butylated hydroxytoluene and sodium bisulfite;
preferably, the preservative comprises at least one of benzoic acid, sorbic acid and benzyl alcohol.
4. The triamcinolone acetonide econazole cream of claim 1, which is prepared from the following components in percentage by mass:
0.095-0.11% of triamcinolone acetonide, 0.95-1.05% of econazole nitrate, 7.8-8.2% of liquid paraffin, 11.8-12.2% of glycerol, 4.8-5.2% of hexadecanol, 3.8-4.2% of octadecanol, 1.2-1.3% of sodium dodecyl sulfate, 0.018-0.022% of antioxidant, 0.08-0.12% of disodium edetate, 0.18-0.22% of preservative and 67.378-69.277% of water.
5. The triamcinolone acetonide econazole cream of claim 1, which is prepared from the following components in percentage by mass:
0.1% of triamcinolone acetonide, 1% of econazole nitrate, 8% of liquid paraffin, 12% of glycerol, 5% of hexadecanol, 4% of octadecanol, 1.2% of sodium dodecyl sulfate, 0.02% of butyl hydroxy anisole, 0.1% of disodium edetate, 0.2% of benzoic acid and 68.38% of water.
6. The method for preparing the triamcinolone acetonide econazole cream of any one of claims 1 to 5, comprising the steps of:
uniformly mixing the sodium dodecyl sulfate and the water phase material to obtain a water phase; and mixing the water phase and the oil phase for emulsification, and then mixing with the triamcinolone acetonide and the econazole nitrate.
7. The preparation method of the triamcinolone acetonide econazole cream as claimed in claim 6, comprising the following steps:
(a) mixing glycerol, water, edetate disodium and sodium dodecyl sulfate uniformly according to a proportion to obtain the water phase; uniformly mixing liquid paraffin, cetyl alcohol, stearyl alcohol, an antioxidant and a preservative in proportion to obtain the oil phase;
(b) transferring the oil phase to a vacuum emulsifying pot by using vacuum, transferring the water phase to the oil phase at a constant speed within 15-20 min, then carrying out heat preservation homogenizing emulsification at 82-85 ℃ for 20-30 min, and then cooling;
(c) and cooling to 60-65 ℃, adding triamcinolone acetonide and econazole nitrate, stirring and homogenizing for 20-30 min, cooling to 35-40 ℃, and discharging.
8. The method for preparing the triamcinolone acetonide econazole cream as claimed in claim 7, wherein in step (a), the method for preparing the aqueous phase comprises: mixing the glycerol with water, adding edetate disodium under the stirring and heating state, continuously heating to the temperature of more than 88 ℃, adding sodium dodecyl sulfate, and then stirring for 10-15 min to obtain the water phase;
in step (a), the preparation method of the oil phase comprises the following steps: and mixing the liquid paraffin, the hexadecanol and the octadecanol, heating and melting, and then adding the antioxidant and the preservative to melt and mix uniformly to obtain the oil phase.
9. The preparation method of the triamcinolone acetonide econazole cream as claimed in claim 7, wherein in the step (b), the stirring speed of the vacuum emulsifying pot is 15-20 r/min when the water phase is transferred and the oil phase is transferred;
preferably, in step (b), the conditions for the homogeneous emulsification include: the stirring speed is 20-45 r/min, the vacuum pressure is-0.02 to-0.03 MPa, and the homogenizing speed is 1500-2800 r/min;
preferably, in the step (b), the vacuum pressure is controlled to be-0.03 to-0.05 MPa in the temperature reduction process.
10. The method for preparing the triamcinolone acetonide econazole cream as claimed in claim 7, wherein the stirring homogenization conditions in step (c) comprise: the stirring speed is 20-45 r/min, the homogenizing speed is 1500-2800 r/min, and the vacuum pressure is-0.03 to-0.05 MPa;
preferably, the vacuum pressure is-0.04 to-0.06 MPa in the process of cooling to 35-40 ℃.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110118220A1 (en) * 2009-11-13 2011-05-19 Fibonacci Biological Medicine, LLC Composition of bifonazole and its use
CN103751100A (en) * 2013-11-28 2014-04-30 郑州韩都药业集团有限公司 Acyclovir emulsifiable paste
CN107260656A (en) * 2016-04-08 2017-10-20 湖北人福成田药业有限公司 Desonide cream and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110118220A1 (en) * 2009-11-13 2011-05-19 Fibonacci Biological Medicine, LLC Composition of bifonazole and its use
CN103751100A (en) * 2013-11-28 2014-04-30 郑州韩都药业集团有限公司 Acyclovir emulsifiable paste
CN107260656A (en) * 2016-04-08 2017-10-20 湖北人福成田药业有限公司 Desonide cream and preparation method thereof

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