CN115414321B - Beclomethasone dipropionate cream and preparation method thereof - Google Patents
Beclomethasone dipropionate cream and preparation method thereof Download PDFInfo
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- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of medicinal preparations, and particularly relates to beclomethasone dipropionate emulsifiable paste and a preparation method thereof. The method comprises the following steps of melting an oil phase: heating the oleaginous component and the preservative in water bath to melt, filtering, adding beclomethasone dipropionate, and uniformly mixing to obtain an oil phase; melting an aqueous phase: dissolving water-soluble components in a buffer solution, and heating in a water bath to melt the water-soluble components to obtain a water phase; emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, adding the emulsifying agent, and stirring to obtain the ointment. The beclomethasone dipropionate emulsifiable paste prepared by the invention has high stability, can promote the skin permeation capacity of beclomethasone dipropionate, increase the skin retention, improve the local medicine concentration of skin, and is favorable for the medicine to treat local diseases to exert curative effect, small in irritation and high in safety.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to beclomethasone dipropionate emulsifiable paste and a preparation method thereof.
Background
Beclomethasone dipropionate is used for treating eczema, allergic dermatitis, neurodermatitis, lichen planus, discoid lupus erythematosus, palmoplantar pustulosis, contact dermatitis, limited psoriasis, skin pruritus and the like. Beclomethasone propionate is a powerful glucocorticoid drug, has anti-inflammatory effect compared with dexamethasone, triamcinolone acetonide, fluocinolone acetonide and is strong, and has anti-inflammatory, antiallergic, antipruritic and anti-cell mitosis effects. Has strong fat solubility, good skin penetration effect, and long maintenance time after being applied to affected part for 30 min. The external application mainly adopts the pilo sebaceous gland and epidermis to absorb, has stronger local capillary contraction and anti-inflammatory effects, and can not cause side effects caused by adrenal cortex dysfunction.
Currently, there are two dosage forms of beclomethasone dipropionate suspension and cream.
Chinese patent CN106539751a discloses a beclomethasone dipropionate cream and a preparation method thereof, which comprises the following steps: mixing stearic acid, glyceryl monostearate, white vaseline, stearyl alcohol, simethicone and liquid paraffin, heating to 70-80deg.C for melting, adding peanut oil after 20-30min, and stirring to obtain oil phase; heating purified water to 70-80 ℃, adding ethylparaben, sequentially adding glucose and sodium acetate after the ethylparaben is completely dissolved, adding glycerol and triethanolamine after the glucose and sodium acetate are completely dissolved, and uniformly stirring to obtain a water phase; slowly adding beclomethasone dipropionate into the oil phase, uniformly mixing, slowly adding the oil phase into the water phase, keeping the temperature at 70-80 ℃, adding talcum powder, stirring for 40-50min, and cooling to room temperature. Research shows that the presence of small amounts of vegetable residues in the peanut oil can lead to rancidity of the peanut oil, and that a substance called linoleic acid in the peanut oil is susceptible to interact with oxygen in the air to hydrolyze, forming small molecular aldehydes or ketones with a specific odor, which produce decomposition products to acidify the peanut oil, so that the addition of the peanut oil is susceptible to exacerbating the deterioration of the preparation and to produce a bad odor.
Disclosure of Invention
The beclomethasone dipropionate emulsifiable paste and the preparation method thereof solve the problem that beclomethasone dipropionate emulsifiable paste is easy to be degraded, and the beclomethasone dipropionate emulsifiable paste is high in stability, strong in skin permeation capacity and small in irritation.
Specifically, the technical scheme of the invention is as follows:
the invention provides a preparation method of beclomethasone dipropionate emulsifiable paste, which comprises the following steps of:
(1) And (3) oil phase melting: heating the oleaginous component and the preservative in water bath to melt, filtering, adding beclomethasone dipropionate, and uniformly mixing to obtain an oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in a buffer solution with pH=6.0-8.0, and heating in water bath to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, adding the emulsifying agent, and stirring to obtain the ointment.
Further, the method comprises the steps of:
(1) And (3) oil phase melting: heating the greasy component in water bath at 65-85deg.C to melt, filtering, cooling to 35-45deg.C in water bath, adding beclomethasone dipropionate, mixing, and ultrasonic treating at 50-60deg.C for 5-15min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in buffer solution with pH=6.0-8.0, heating in water bath at 55-65deg.C to melt to obtain water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, adding the emulsifying agent, and stirring to obtain the ointment.
Wherein, the gradient temperature control step in the step (3) is as follows:
the first stage: the water bath temperature is 50-60 ℃, and the stirring is carried out for 5-15min;
and a second stage: the water bath temperature is 30-40 ℃, and stirring is carried out for 10-20min;
and a third stage: the water bath temperature is 40-55 ℃, and stirring is carried out for 10-20min;
fourth stage: the water bath temperature is 20-30 ℃, and the stirring is carried out for 15-25min.
Preferably, the gradient temperature control is:
the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min;
and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min;
and a third stage: the water bath temperature is 50 ℃, and the stirring is carried out for 15min;
fourth stage: the water bath temperature is 25 ℃, and stirring is carried out for 20min.
Furthermore, the beclomethasone propionate is micronized beclomethasone propionate, and the particle size is preferably 60-80 microns.
In particular, the emulsifier is added in the third stage of gradient temperature control.
Further, the buffer solution is selected from one of barbital-sodium chloride buffer solution, phosphate buffer solution and sodium citrate buffer solution, and is preferably barbital-sodium chloride buffer solution.
Further, the barbital-sodium chloride buffer ph=7.8.
A second object of the present invention is to provide a beclomethasone dipropionate cream prepared by the above-mentioned method wherein:
the oleaginous component is one or more of glyceryl monostearate, stearyl alcohol, vaseline, stearic acid, stearyl alcohol, beeswax, cetyl alcohol, ceresin, and paraffin,
the water-soluble component is selected from one or more of propylene glycol, glycerol and water,
the preservative is one or more selected from benzalkonium bromide, chlorhexidine acetate, sodium benzoate, methylparaben, ethylparaben and propylparaben,
the emulsifier is one or more selected from sodium stearate, sodium oleate, sodium dodecyl sulfate, sodium hexadecyl sulfate, sulfated castor oil, polysorbate-80, methyl glucoside sesquistearate, and ergosterol.
Further, in the beclomethasone dipropionate emulsifiable paste:
the oleaginous component is glyceryl monostearate, stearyl alcohol and vaseline,
the water-soluble component is selected from propylene glycol and glycerol,
the preservative is sodium benzoate, and the preservative is sodium benzoate,
the emulsifier is methyl glucoside sesquistearate and ergosterol.
Preferably, the beclomethasone dipropionate cream comprises the following components in percentage by weight:
it is preferred that the composition is,
compared with the prior art, the invention has the beneficial effects that:
(1) The invention optimizes the preparation process and the formula, and provides stable beclomethasone dipropionate emulsifiable paste by means of ultrasound, pH adjustment, temperature control and the like.
(2) The beclomethasone dipropionate emulsifiable paste disclosed by the invention can promote the skin permeation capacity of beclomethasone dipropionate, increase the skin retention, especially can improve the local drug concentration of skin, is favorable for the drug to exert the curative effect on local diseases, and has the advantages of small irritation and high safety coefficient.
Detailed Description
The present invention will be further described with reference to examples for the purpose of making the objects and technical aspects of the present invention more apparent, but the scope of the present invention is not limited to these examples, which are only for explaining the present invention. It will be understood by those skilled in the art that variations or equivalent substitutions that do not depart from the spirit of the invention are intended to be included within the scope of the invention.
Example 1 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in a water bath at 65 ℃ to melt, filtering, cooling to 35 ℃ in the water bath, adding beclomethasone dipropionate with the particle size of 60-80 microns, uniformly mixing, and carrying out ultrasonic treatment at 50 ℃ for 5min to obtain an oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=6.0, and heating in water bath at 55 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 50 ℃, and the stirring is carried out for 5min; and a second stage: the water bath temperature is 30 ℃, and the stirring is carried out for 10min; and a third stage: adding the emulsifier into the water bath at the temperature of 40 ℃ and stirring for 10min; fourth stage: the water bath temperature is 20 ℃, and the mixture is stirred for 15min to form paste.
Example 2 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 65-85deg.C to melt, filtering, cooling to 45deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasonic treating at 60deg.C for 15min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=8.0, and heating in water bath at 65 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 60 ℃, and the stirring is carried out for 15min; and a second stage: the water bath temperature is 40 ℃, and stirring is carried out for 20min; and a third stage: adding the emulsifier into the water bath at the temperature of 55 ℃ and stirring for 20min; fourth stage: the water bath temperature is 30 ℃, and the mixture is stirred for 25 minutes to form paste.
Example 3 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=7.6, and heating in water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Example 4 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in phosphate buffer solution with pH=7.6, and heating in water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Example 5 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in citrate buffer solution with pH=7.6, heating in water bath at 60deg.C to melt to obtain water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Comparative example 1 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=7.6, and heating in water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Comparative example 2 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of more than 100 μm, mixing, and ultrasonic treating at 55deg.C for 5-15min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=7.8, and heating in water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
The first stage: the water bath temperature is 50-60 ℃, and the stirring is carried out for 5-15min;
and a second stage: the water bath temperature is 30-40 ℃, and stirring is carried out for 10-20min;
and a third stage: the water bath temperature is 40-55 ℃, and stirring is carried out for 10-20min;
fourth stage: the water bath temperature is 20-30 ℃, and the stirring is carried out for 15-25min.
Comparative example 3 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous component in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, and mixing to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=7.6, and heating in water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Comparative example 4 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in a barbital-sodium chloride buffer solution with pH=5.5, and heating in a water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: adding the emulsifier into the water bath at the temperature of 50 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Comparative example 5 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in a buffer solution with pH=7.6, and heating in a water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: adding the emulsifier into the water bath at the temperature of 55 ℃ and stirring for 10min; and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min; and a third stage: the water bath temperature is 50 ℃, and the stirring is carried out for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Comparative example 6 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in a buffer solution with pH=7.6, and heating in a water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, and in the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min; and a second stage: adding the emulsifier into the water bath at the temperature of 35 ℃ and stirring for 15min; fourth stage: the water bath temperature is 25 ℃, and the mixture is stirred for 20 minutes to form paste.
Comparative example 7 beclomethasone dipropionate and preparation method thereof
The formula comprises the following components:
the preparation method comprises the following steps:
(1) And (3) oil phase melting: heating the oleaginous components in water bath at 70deg.C to melt, filtering, cooling to 40deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and ultrasound at 55deg.C for 10min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in barbital-sodium chloride buffer solution with pH=7.6, and heating in water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing the oil phase and the water phase, adding the emulsifying agent, maintaining the temperature at 60 ℃, stirring for 30min, and cooling to obtain the ointment.
Verification embodiment
1. Stability test of beclomethasone dipropionate cream
According to the commercial package, the acceleration test is carried out under the conditions of 40+/-2 ℃ and 75+/-5% relative humidity, and the samples are respectively sampled and analyzed for 0, 3 and 6 months, and the properties, uniformity, content, granularity, related substances, layering phenomenon and the like are checked.
1. Appearance shape
The color is required to be uniform and consistent, the texture is fine, rancidity, abnormal odor, discoloration and hardening are avoided, and the phenomena of oil-water separation, layering and flatulence are avoided.
2. Related substances
The test was performed by thin layer chromatography (general rule 0502).
Test solution: the product was taken, dissolved in chloroform-methanol (9:1) and diluted to a solution containing about 3mg per 1 ml.
Control solution: 1ml of the sample solution is precisely measured, placed in a 50ml measuring flask, diluted to the scale with chloroform-methanol (9:1) and shaken well.
Chromatographic conditions: the method adopts a silica gel G thin layer plate and adopts dichloroethane-methanol-water (95:5:0.2) as developing agent.
Assay: sucking 5 μl of each of the test solution and the control solution, respectively spotting on the same thin layer plate, spreading, air drying, drying at 105deg.C for 10min, cooling, spraying with alkaline tetrazolium blue test solution, and immediately inspecting.
Limit: the sample solution, such as the impurity-developing spot, must not be more than 2, and its color must not be darker than the main spot of the control solution.
3. Beclomethasone dipropionate content
The measurement was performed by high performance liquid chromatography (general rule 0512).
Internal standard solution: methyltestosterone was taken, dissolved in the mobile phase and diluted to a solution of about 0.12mg per 1 ml.
Test solution: taking about 12.5mg of the product, precisely weighing, placing into a 100ml measuring flask, adding 74ml of methanol to dissolve, diluting with water to scale, and shaking; precisely measuring 10ml of the solution and 5ml of the internal standard solution, placing the solution and the 5ml of the internal standard solution into a 50ml measuring flask, diluting to a scale by using a mobile phase, and shaking uniformly.
Control solution: taking about 12.5mg of beclomethasone dipropionate reference substance, precisely weighing, placing into a 100ml measuring flask, adding 74ml of methanol to dissolve, diluting with water to scale, and shaking; precisely measuring 10ml of the solution and 5ml of the internal standard solution, placing the solution and the 5ml of the internal standard solution into a 50ml measuring flask, diluting to a scale by using a mobile phase, and shaking uniformly.
Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; methanol-water (74:26) was used as mobile phase; the detection wavelength is 240nm; the sample volume was 20. Mu.l.
System applicability requirements: the theoretical plate number is not lower than 2500 calculated by the beclomethasone dipropionate peak, and the separation degree between the beclomethasone propionate peak and the internal standard substance peak is larger than 4.0.
Assay: precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. Calculated as peak area by internal standard method.
Table 1 evaluation of stability of beclomethasone dipropionate cream for each example, comparative example
As shown in Table 1, the beclomethasone dipropionate emulsifiable paste prepared by the invention has high stability, and an acceleration test shows that the beclomethasone dipropionate emulsifiable paste has stable appearance, uniform emulsifiable paste, stable content, low related substances and no layering phenomenon.
2. Comparative test of transdermal penetration of beclomethasone dipropionate cream
Experimental animals: SD rats, SPF grade, 180-220g, experimental animal license number: SYXK 2018 0008, supplied by runan pharmaceutical group inc, was adapted for one week prior to the experiment.
Preparation of ex vivo mouse skin: dehairing the rats by using 8% sodium sulfide solution, cleaning, raising the animals for 24 hours, taking abdominal skin after neck breakage and sacrifice, removing subcutaneous fat, repeatedly cleaning by using normal saline, and sucking surface water by using filter paper for later use.
Fixing the treated abdominal skin of rat between the supply tank and the receiving tank by using a transdermal instrument, wherein the stratum corneum faces the supply tank, and the effective transdermal area is 1.92cm 2 . The same doses of example 1, example 2, example 3, comparative example 1, comparative example 4, comparative example 5 beclomethasone dipropionate cream and commercially available beclomethasone dipropionate cream (Tianjin, pharmaceutical Co., ltd.) were respectively supplied to the pools; the receiver was 20% ethanol/pH 7.4 phosphate buffer, sampled at 1,2,4,6,8, 10, 12, 24h and supplemented with the corresponding volumes of receiver. The sample was filtered through a 0.22 μm microporous membrane, and the content of beclomethasone dipropionate as an active ingredient in the receiving solution was measured, and the cumulative permeation of each example was calculated according to the formula.
Wherein V is the total volume of the receiving liquid, cn is the drug concentration (mug/mL) measured at the nth sampling point, C is the drug concentration (mug/mL) measured at the ith sampling point, V is the sampling volume, A is the diffusion penetration area (cm) 2 )。
After the in vitro transdermal test was terminated, the rat skin was removed from the diffusion cell, the surface was washed with water, the cotton was wiped dry, sheared, 5mL of pH7.4 phosphate buffer was added, homogenized, 5000 r.min -1 Centrifuging for 5min, collecting supernatant, filtering with 0.22 μm filter membrane, collecting filtrate, and measuring beclomethasone dipropionate content in skin by high performance liquid chromatography.
TABLE 2 cumulative penetration and skin hold-up of beclomethasone dipropionate cream
Table 2 shows that the cumulative penetration of the beclomethasone dipropionate cream of the present invention is about 2 times that of the commercial beclomethasone dipropionate cream and that the retention in the skin is about 2 times that of the commercial beclomethasone propionate cream. The beclomethasone dipropionate emulsifiable paste disclosed by the invention can promote the skin permeation capacity of beclomethasone dipropionate, increase the skin retention, especially can improve the local drug concentration of skin, and is favorable for the drug treatment of local diseases to exert curative effects.
3. Beclomethasone dipropionate cream irritation test
The test for intact skin and broken skin irritation was performed using physiological saline as a negative control and the beclomethasone dipropionate cream of examples 1,2, and 3 and commercial beclomethasone dipropionate cream as test agents.
Experimental animals: common grade new zealand rabbit, experimental animal license number: SYXK 2018 0008, supplied by runan pharmaceutical group inc, was adapted for one week prior to the experiment.
1. Test of intact skin irritation
Complete skin irritation test method: several common grade New Zealand rabbits were taken, and each half of the male and female rabbits were randomly divided into a negative control group, 5 groups of beclomethasone dipropionate cream and commercially available beclomethasone dipropionate cream of examples 1,2 and 3, and 6 groups each. The middle of the back was dehaired 24 hours before the test, with the range of dehairing each being about 5cm by 5cm. Test was performed by examining the skin-removed intact person prior to administration. Physiological saline examples 1,2 and 3 of beclomethasone dipropionate cream and commercial beclomethasone dipropionate cream are respectively coated on dehaired skin of a new zealand rabbit after grouping, single administration is carried out, continuous coating and administration are carried out for 8 hours, skin reaction is observed under natural light, whether skin red and swelling are taken as an investigation index, and skin local reaction conditions of 0h, 12h, 24h, 48h and 72h after administration are observed. The results were as follows:
TABLE 3 beclomethasone dipropionate cream complete skin irritation test
2. Broken skin irritation test
18 New Zealand rabbits were taken, and each half of the female and male rabbits were randomly divided into a negative control group, 5 groups of beclomethasone dipropionate cream and commercially available beclomethasone dipropionate cream of examples 1,2 and 3, and 6 groups each. The middle of the back was dehaired 24 hours before the test, with the range of dehairing each being about 5cm by 5cm. The skin was then developed with a dense bleeding spot by abrasion at the dehairing site with the sterilized 400 # fine sand paper, and immediately, physiological saline, the beclomethasone propionate cream of examples 1,2, and 3, and the commercially available beclomethasone propionate cream were applied to the skin abrasion sites of the new zealand rabbits, respectively, in a single administration, and a continuous application for 8 days. The skin reaction was observed under natural light.
The results show that 3/6 animals of the commercially available beclomethasone dipropionate cream group New Zealand rabbits showed slight erythema at Day 1, 4/6 animals showed moderate erythema at Day 3, 6/6 animals showed crusting, 6/6 animals showed rough skin and desquamation, and gradually lightened after 7 d. Example 3 beclomethasone dipropionate cream group New Zealand rabbits showed 1/6 of the animals at Day 1 had a slight erythema, which gradually abated after 3d, to a 7d erythema resolution after the last dose. Example 1 beclomethasone dipropionate cream group, example 2 beclomethasone dipropionate cream group, new Zealand rabbits of negative control group did not see erythema and edema.
The test result shows that the beclomethasone dipropionate cream product has small skin irritation, can improve the life quality of patients when being applied to local skin allergy, and has wide product market application value.
Claims (5)
1. A method for preparing beclomethasone dipropionate cream, which is characterized by comprising the following steps of:
(1) And (3) oil phase melting: heating the oleaginous components and the preservative in water bath at 65-85deg.C to melt, filtering, cooling to 35-45deg.C in water bath, adding beclomethasone dipropionate, mixing, and ultrasonic treating at 50-60deg.C for 5-15min to obtain oil phase;
(2) Melting an aqueous phase: dissolving water-soluble components in buffer solution with pH=6.0-8.0, heating in water bath at 55-65deg.C to melt to obtain water phase;
(3) Emulsification: mixing the oil phase and the water phase, controlling the temperature in a gradient water bath, adding an emulsifying agent, and stirring to form paste;
the gradient temperature control in the step (3) is as follows:
the first stage: the water bath temperature is 50-60 ℃, and the stirring is carried out for 5-15min;
and a second stage: the water bath temperature is 30-40 ℃, and stirring is carried out for 10-20min;
and a third stage: the water bath temperature is 40-55 ℃, and stirring is carried out for 10-20min;
fourth stage: the water bath temperature is 20-30 ℃, and stirring is carried out for 15-25min;
the emulsifier is added in the third stage of gradient temperature control;
the beclomethasone dipropionate cream comprises the following components in parts by weight:
0.05-1 part of beclomethasone dipropionate;
the oleaginous component comprises 60-90 parts of glyceryl monostearate, 40-80 parts of stearyl alcohol and 30-70 parts of Vaseline;
the water-soluble component comprises 50-80 parts of propylene glycol and 40-74 parts of glycerol;
the preservative is sodium benzoate 0.5-2 parts;
the emulsifier is methyl glucoside sesquistearate 0.5-2 parts and ergosterol 0.5-2 parts;
the beclomethasone propionate is micronized beclomethasone propionate, and the particle size of the beclomethasone propionate is 60-80 microns;
the buffer solution is selected from one of barbital-sodium chloride buffer solution, phosphate buffer solution and sodium citrate buffer solution.
2. The method according to claim 1, wherein the gradient temperature control in the step (3) is:
the first stage: the water bath temperature is 55 ℃, and the stirring is carried out for 10min;
and a second stage: the water bath temperature is 35 ℃, and the stirring is carried out for 15min;
and a third stage: the water bath temperature is 50 ℃, and the stirring is carried out for 15min;
fourth stage: the water bath temperature is 25 ℃, and stirring is carried out for 20min.
3. The method of claim 1, wherein the buffer solution is a barbital-sodium chloride buffer solution.
4. A method according to claim 3, wherein the barbital-sodium chloride buffer pH = 7.6.
5. The method according to claim 1, wherein the beclomethasone dipropionate cream comprises the following components in parts by weight:
beclomethasone dipropionate 0.075 parts
Glycerin monostearate 70 parts
Stearyl alcohol 50 parts
60 parts of Vaseline
60 parts of propylene glycol
55 parts of glycerol
Sodium benzoate 1 part
Methyl glucoside sesquistearate 0.8 part
0.8 parts of ergosterol.
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| CN100560056C (en) * | 2007-01-12 | 2009-11-18 | 上海交通大学医学院附属第九人民医院 | A kind of compound all-trans retinoic acid cream and its production and application |
| WO2012017383A1 (en) * | 2010-08-02 | 2012-02-09 | Sulur Subramaniam Vanangamudi | A medicinal fusidic acid cream made using sodium fusidate and incorporating biopolymer, beclomethasone dipropionate, terbinafine hydrochloride and a process to make it |
| CN103705441B (en) * | 2012-10-08 | 2017-06-23 | 天津金耀集团有限公司 | A kind of Beclomethasone dipropionate emulsifiable paste |
| CN106063778A (en) * | 2015-04-21 | 2016-11-02 | 北京化工大学 | A kind of preparation method of beclometasone transparent aqueous phase Nanodispersion |
| CN106539751A (en) * | 2017-01-17 | 2017-03-29 | 景德镇牧堂陶瓷科技有限公司 | A kind of Beclomethasone dipropionate emulsifiable paste and preparation method thereof |
| CN113063886A (en) * | 2021-03-22 | 2021-07-02 | 广州白云山医药集团股份有限公司白云山何济公制药厂 | Content determination method of mometasone furoate cream |
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