CN115414321A - Beclomethasone dipropionate emulsifiable paste and preparation method thereof - Google Patents
Beclomethasone dipropionate emulsifiable paste 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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- 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 pharmaceutical preparations, and particularly relates to beclomethasone dipropionate emulsifiable paste and a preparation method thereof. The method comprises the following steps of oil phase melting: heating the oil-fat component and the preservative in water bath to melt, filtering, adding beclomethasone dipropionate, and uniformly mixing to obtain an oil phase; melting the water phase: dissolving the 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 emulsifier, and stirring to form paste. The beclomethasone dipropionate cream prepared by the invention has high stability, can promote the skin permeation capability of beclomethasone dipropionate, increase the skin retention amount, improve the local skin drug concentration, is beneficial to the drug treatment of local diseases and has small irritation and high safety.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical 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, localized psoriasis, cutaneous pruritus and the like. Beclomethasone dipropionate is a powerful glucocorticoid drug, has stronger anti-inflammatory effect than dexamethasone, triamcinolone acetonide, fluocinolone acetonide and triamcinolone, and has the effects of anti-inflammation, anti-allergy, itching relieving and cell mitosis resisting. Has strong fat solubility and good skin penetration effect, takes effect after being applied to the affected part for 30 minutes, and has long maintenance time. The external preparation is mainly absorbed through pilosebaceous glands and epidermis, has strong functions of contracting local capillaries and resisting inflammation, and does not cause side effects caused by adrenal cortex dysfunction.
At present, two dosage forms of beclomethasone dipropionate suspension and cream are available.
Chinese patent CN106539751A discloses beclomethasone dipropionate cream and a preparation method thereof, wherein the preparation method comprises the following steps: mixing stearic acid, glyceryl monostearate, white vaseline, octadecanol, simethicone and liquid paraffin, heating to 70-80 deg.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 the 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 the talcum powder, stirring for 40-50min, and then cooling to room temperature. Studies have shown that small amounts of vegetable residues present in peanut oil can lead to rancidity of the oil, and that secondly a substance called linoleic acid in peanut oil is susceptible to hydrolysis by interaction with atmospheric oxygen, forming low molecular weight aldehydes or ketones with a characteristic odor, which produce decomposition products that acidify the oil, so that the addition of peanut oil tends to exacerbate deterioration of the formulation, producing an unpleasant odor.
Disclosure of Invention
The invention overcomes the defects of the prior art, provides the beclomethasone dipropionate emulsifiable paste and the preparation method thereof, solves the problem that the beclomethasone dipropionate emulsifiable paste is easy to deteriorate, and provides the beclomethasone dipropionate emulsifiable paste which has high stability, strong skin permeability and small 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:
(1) Oil phase melting: heating the oil-fat components and the preservative in a water bath to melt, filtering, adding beclomethasone dipropionate, and uniformly mixing to obtain an oil phase;
(2) Melting the water phase: dissolving a water-soluble component in a buffer solution with pH =6.0-8.0, and heating in a water bath to melt the water-soluble component 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 emulsifier, and stirring to form paste.
Further, the method comprises the following steps:
(1) Melting an oil phase: heating the oleaginous components in water bath at 65-85 deg.C to melt, filtering, cooling to 35-45 deg.C in water bath, adding beclomethasone dipropionate, mixing, and performing ultrasonic treatment at 50-60 deg.C for 5-15min to obtain oil phase;
(2) Melting the water phase: dissolving the water soluble components in buffer solution with pH =6.0-8.0, heating in water bath at 55-65 deg.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 emulsifier, and stirring to form the ointment.
Wherein, the gradient temperature control step in the step (3) is as follows:
the first stage is as follows: stirring for 5-15min at water bath temperature of 50-60 deg.C;
and a second stage: stirring for 10-20min at water bath temperature of 30-40 deg.C;
and a third stage: stirring for 10-20min at water bath temperature of 40-55 deg.C;
a fourth stage: the temperature of the water bath is 20-30 ℃, and the stirring is carried out for 15-25min.
Preferably, the gradient temperature control is as follows:
the first stage is as follows: stirring for 10min at water bath temperature of 55 deg.C;
and a second stage: stirring for 15min at the water bath temperature of 35 ℃;
and a third stage: stirring for 15min at the water bath temperature of 50 ℃;
a fourth stage: the water bath temperature is 25 ℃, and the stirring is carried out for 20min.
Furthermore, the beclomethasone dipropionate is micronized beclomethasone dipropionate, and the particle size is preferably 60-80 micrometers.
In particular, the emulsifier is added in the third stage of the gradient temperature control.
Further, the buffer solution is selected from one of a barbiturate-sodium chloride buffer solution, a phosphate buffer solution and a sodium citrate buffer solution, and is preferably the barbiturate-sodium chloride buffer solution.
Further, the barbiturate-sodium chloride buffer pH =7.8.
A second object of the present invention is to provide a beclomethasone dipropionate cream prepared by the above method, wherein:
the oleaginous component is one or more selected from glyceryl monostearate, stearyl alcohol, vaseline, stearic acid, stearyl alcohol, beeswax, cetyl alcohol, ceresin, and paraffin,
the water-soluble component is one or more selected from propylene glycol, glycerol and water,
the preservative is one or more selected from benzalkonium bromide, chlorhexidine acetate, sodium benzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate,
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 cream:
the oleaginous components include glyceryl monostearate, stearyl alcohol and vaseline,
the water-soluble component is selected from propylene glycol, 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:
preferably, the first and second liquid crystal display elements are,
compared with the prior art, the invention has the beneficial effects that:
(1) The invention optimizes the preparation process and formula, and provides the stable beclomethasone dipropionate emulsifiable paste by means of ultrasound, pH adjustment, temperature control and the like.
(2) The beclomethasone dipropionate emulsifiable paste can promote the skin permeability of beclomethasone dipropionate, increase the skin retention amount, particularly improve the local drug concentration of the skin, is beneficial to the drug treatment of local diseases and plays a curative effect, and has small irritation and high safety factor.
Detailed Description
In order to make the purpose and technical solutions of the present invention more clearly understood, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.
Example 1 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Melting an oil phase: heating the oil-fat components in water bath at 65 deg.C to melt, filtering, cooling to 35 deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and performing ultrasonic treatment at 50 deg.C for 5min to obtain oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbiturate-sodium chloride buffer solution with the pH =6.0, and heating in a water bath at 55 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 5min at water bath temperature of 50 deg.C; and a second stage: stirring for 10min at water bath temperature of 30 deg.C; and a third stage: adding emulsifier at 40 deg.C, and stirring for 10min; a fourth stage: stirring for 15min at 20 deg.C in water bath to obtain paste.
Example 2 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Melting an oil phase: heating the oleaginous components in water bath at 65-85 deg.C to melt, filtering, cooling to 45 deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and performing ultrasonic treatment at 60 deg.C for 15min to obtain oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbiturate-sodium chloride buffer solution with the pH =8.0, and heating in a water bath at 65 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 15min at water bath temperature of 60 deg.C; and a second stage: stirring for 20min at water bath temperature of 40 deg.C; and a third stage: adding emulsifier at 55 deg.C, and stirring for 20min; a fourth stage: stirring for 25min at water bath temperature of 30 deg.C to obtain paste.
Example 3 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Oil phase melting: heating the oil-fat components in water bath at 70 deg.C to melt, filtering, cooling to 40 deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and performing ultrasonic treatment at 55 deg.C for 10min to obtain oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbital-sodium chloride buffer solution with the 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 an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at the water bath temperature of 55 ℃; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Example 4 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Oil phase melting: heating the oil-fat components in water bath at 70 deg.C to melt, filtering, cooling to 40 deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and performing ultrasonic treatment at 55 deg.C for 10min to obtain oil phase;
(2) Melting the water phase: dissolving a water-soluble component in a phosphate buffer solution with pH =7.6, and heating in a water bath at 60 ℃ to melt the water-soluble component to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Example 5 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Oil phase melting: heating the oil-fat components in a water bath at 70 ℃ to melt, filtering, cooling in the water bath to 40 ℃, adding beclomethasone dipropionate with the particle size of 60-80 microns, uniformly mixing, and performing ultrasonic treatment at 55 ℃ for 10min to obtain an oil phase;
(2) Melting the water phase: dissolving a water-soluble component in a citrate buffer solution with pH =7.6, and heating in a water bath at 60 ℃ to melt the water-soluble component to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Comparative example 1 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Oil phase melting: heating the oil-fat components in a water bath at 70 ℃ to melt, filtering, cooling in the water bath to 40 ℃, adding beclomethasone dipropionate with the particle size of 60-80 microns, uniformly mixing, and performing ultrasonic treatment at 55 ℃ for 10min to obtain an oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbiturate-sodium chloride buffer solution with the 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 an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Comparative example 2 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Melting an oil phase: heating the oil-fat components in a water bath at 70 ℃ to melt, filtering, cooling in the water bath to 40 ℃, adding beclomethasone dipropionate with the particle size of more than 100 microns, uniformly mixing, and performing ultrasonic treatment at 55 ℃ for 5-15min to obtain an oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbital-sodium chloride buffer solution with the pH =7.8, and heating in a water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
The first stage is as follows: stirring for 5-15min at water bath temperature of 50-60 deg.C;
and a second stage: stirring for 10-20min at water bath temperature of 30-40 deg.C;
and a third stage: stirring for 10-20min at water bath temperature of 40-55 deg.C;
a fourth stage: the temperature of the water bath is 20-30 ℃, and the stirring is carried out for 15-25min.
Comparative example 3 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Oil phase melting: heating the oil-fat components in water bath at 70 deg.C to melt, filtering, cooling in water bath to 40 deg.C, adding beclomethasone dipropionate with particle size of 60-80 μm, and mixing to obtain oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbiturate-sodium chloride buffer solution with the 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 an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Comparative example 4 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Melting an oil phase: heating the oil-fat components in a water bath at 70 ℃ to melt, filtering, cooling in the water bath to 40 ℃, adding beclomethasone dipropionate with the particle size of 60-80 microns, uniformly mixing, and performing ultrasonic treatment at 55 ℃ for 10min to obtain an oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbital-sodium chloride buffer solution with pH =5.5, heating in a water bath at 60 ℃ to melt the water-soluble components to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: adding emulsifier at 50 deg.C, and stirring for 15min; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Comparative example 5 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Melting an oil phase: heating the oil-fat components in water bath at 70 deg.C to melt, filtering, cooling to 40 deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and performing ultrasonic treatment at 55 deg.C for 10min to obtain oil phase;
(2) Melting the water phase: dissolving a water-soluble component in a buffer solution with pH =7.6, and heating in a water bath at 60 ℃ to melt the water-soluble component to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: adding emulsifier at 55 deg.C, and stirring for 10min; and a second stage: stirring for 15min at the water bath temperature of 35 ℃; and a third stage: stirring for 15min at the water bath temperature of 50 ℃; a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Comparative example 6 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Melting an oil phase: heating the oil-fat components in a water bath at 70 ℃ to melt, filtering, cooling in the water bath to 40 ℃, adding beclomethasone dipropionate with the particle size of 60-80 microns, uniformly mixing, and performing ultrasonic treatment at 55 ℃ for 10min to obtain an oil phase;
(2) Melting the water phase: dissolving a water-soluble component in a buffer solution with pH =7.6, and heating in a water bath at 60 ℃ to melt the water-soluble component to obtain a water phase;
(3) Emulsification: mixing an oil phase and a water phase, controlling the temperature in a gradient water bath, and performing a first stage: stirring for 10min at water bath temperature of 55 deg.C; and a second stage: adding emulsifier at 35 deg.C, and stirring for 15min; and a fourth stage: stirring for 20min at 25 deg.C in water bath to obtain paste.
Comparative example 7 beclomethasone dipropionate and preparation method thereof
The formula is as follows:
the preparation method comprises the following steps:
(1) Oil phase melting: heating the oil-fat components in water bath at 70 deg.C to melt, filtering, cooling to 40 deg.C in water bath, adding beclomethasone dipropionate with particle size of 60-80 μm, mixing, and performing ultrasonic treatment at 55 deg.C for 10min to obtain oil phase;
(2) Melting the water phase: dissolving the water-soluble components in a barbital-sodium chloride buffer solution with the 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, adding emulsifier, maintaining at 60 deg.C, stirring for 30min, and cooling to obtain paste.
Verification examples
1. Stability test of beclomethasone dipropionate cream
According to the market package, the accelerated test is carried out under the conditions of 40 ℃ plus or minus 2 ℃ and 75 percent plus or minus 5 percent of relative humidity, and the samples are respectively sampled and analyzed at 0, 3 and 6 months to check the properties, uniformity, content, granularity, related substances, layering phenomena and the like.
1. Appearance shape
The color and luster are required to be uniform and consistent, the texture is fine and smooth, rancidity, foreign odor, color change and hardening are avoided, and the phenomena of oil-water separation, layering and flatulence are avoided.
2. Related substances
The test was carried out by thin layer chromatography (general 0502).
Test solution: taking the product, adding chloroform-methanol (9: 1) to dissolve and dilute to prepare a solution containing about 3mg per 1 ml.
Control solution: precisely measuring 1ml of the test solution, placing the test solution in a 50ml measuring flask, diluting the test solution to a scale with chloroform-methanol (9: 1), and shaking up.
Chromatographic conditions are as follows: adopts silica gel G thin layer plate and dichloroethane-methanol-water (95: 5: 0.2) as developing agent.
The determination method comprises the following steps: sucking test solution and control solution 5 μ l each, dispensing on the same thin layer plate, spreading, air drying, drying at 105 deg.C for 10min, cooling, spraying alkaline tetrazolium blue test solution, and immediately inspecting.
Limitation: the test solution should not show more than 2 spots with impurities, and the color should not be darker than the main spot of the control solution.
3. Beclomethasone dipropionate content
Measuring by high performance liquid chromatography (general rule 0512).
Internal standard solution: methyltestosterone is dissolved in mobile phase and diluted to make a solution containing about 0.12mg per 1 ml.
Test solution: weighing about 12.5mg of the product, accurately weighing, placing in a 100ml measuring flask, adding 74ml of methanol for dissolving, diluting with water to scale, and shaking; precisely measuring 10ml of the solution and 5ml of the internal standard solution, placing the solution in a 50ml measuring flask, diluting the solution to a scale mark by using a mobile phase, and shaking up.
Control solution: taking beclomethasone dipropionate reference substance of about 12.5mg, precisely weighing, placing in a 100ml measuring flask, adding 74ml of methanol for dissolving, diluting with water to scale, and shaking up; precisely measuring 10ml of the solution and 5ml of the internal standard solution, placing the solution in a 50ml measuring flask, diluting the solution to a scale mark by using a mobile phase, and shaking up.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-water (74: 26) is used as a mobile phase; the detection wavelength is 240nm; the injection volume was 20. Mu.l.
System applicability requirements: the number of theoretical plates is not less than 2500 calculated according to the beclomethasone dipropionate peak, and the separation degree between the beclomethasone dipropionate peak and the internal standard substance peak is more than 4.0.
The determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram. Calculated as peak area by internal standard method.
TABLE 1 stability evaluation of beclomethasone dipropionate creams in the examples and comparative examples
As shown in Table 1, the beclomethasone dipropionate cream prepared by the invention has high stability, and an accelerated test shows that the beclomethasone dipropionate cream has stable appearance and character, uniform cream, stable content, low related substances and no layering phenomenon.
2. Comparative test for transdermal permeability of beclomethasone dipropionate cream
Experimental animals: SD rat, SPF grade, 180-220g, laboratory animal license number: SYXK (U) 2018 0008, provided by the pharmaceutical group of Lunan, inc., was acclimatized for one week prior to the experiment.
Preparation of in vitro rat skin: depilating rat with 8% sodium sulfide solution, cleaning, feeding animal for 24 hr, killing neck, taking abdominal skin, removing subcutaneous fat, repeatedly cleaning with normal saline, and absorbing surface water with filter paper.
Fixing the treated abdominal skin of rat between the supply pool and the receiving pool by using a transdermal analyzer, wherein the stratum corneum faces the supply pool, and the effective transdermal area is 1.92cm 2 . The beclomethasone dipropionate cream of example 1, example 2, example 3, comparative example 1, comparative example 4 and comparative example 5 and the commercially available beclomethasone dipropionate cream (Tianjin. Pharmaceutical Co., ltd.) were supplied to the tanks at the same doses, respectively; the receiving solution was 20% ethanol/pH7.4 phosphate buffer, and samples were taken at 1,2,4,6,8, 10, 12, and 24h, and the corresponding volume of receiving solution was replenished. The sample is filtered by a 0.22 mu m microporous filter membrane, the content of the effective component beclomethasone dipropionate in the receiving solution is measured, and the cumulative permeation amount of each embodiment is calculated according to a formula.
Wherein V is the total volume of the receiving solution, cn is the concentration of the drug measured at the nth sampling point (μ g/mL), C is the concentration of the drug measured at the ith sampling point (μ g/mL), V is the sampling volume, and A is the diffusion permeation 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, cotton was wiped dry, sheared, 5mL of phosphate buffer pH7.4 was added, homogenized and 5000 r.min -1 Centrifuging for 5min, collecting supernatant, filtering with 0.22 μm filter membrane, collecting filtrate, and measuring content of beclomethasone dipropionate in skin by high performance liquid chromatography, i.e. skin retention.
TABLE 2 cumulative permeation and skin Retention of beclomethasone dipropionate cream
Table 2 shows that the cumulative permeation of the beclomethasone dipropionate cream of the present invention is about 2 times that of the commercially available beclomethasone dipropionate cream, and the retention in the skin is 2 times that of the commercially available beclomethasone dipropionate cream. The beclomethasone dipropionate emulsifiable paste is shown to be capable of promoting the skin permeability of beclomethasone dipropionate, increasing the skin retention amount, particularly improving the local drug concentration of the skin, and being beneficial to the drug treatment of local diseases to exert curative effect.
3. Beclomethasone dipropionate cream irritation test
Complete skin tests and broken skin irritation tests were performed using normal saline as a negative control, and beclomethasone propionate creams of examples 1,2, and 3 and a commercially available beclomethasone propionate cream as test drugs.
Experimental animals: common grade New Zealand rabbits, laboratory animal license number: SYXK (U) 2018 0008, provided by the pharmaceutical group of Lunan, inc., was acclimatized for one week prior to the experiment.
1. Intact skin irritation test
Intact skin irritation test method: a plurality of common-grade New Zealand rabbits with half of each sex are taken and randomly divided into 5 groups of a negative control group, beclomethasone dipropionate emulsifiable paste of examples 1,2 and 3 and a commercially available beclomethasone dipropionate emulsifiable paste, and each group comprises 6 rabbits. In the middle of the back, 24 hours before the test, the hair removal range is about 5cm multiplied by 5cm each. The test is carried out by examining the unhaired skin without damage prior to dosing. The beclomethasone dipropionate creams of the examples 1,2 and 3 of the physiological saline and the beclomethasone dipropionate cream sold on the market are respectively coated on the grouped depilated skin of the New Zealand rabbit, the single administration is carried out, the application and the administration are continuously carried out for 8 hours, the skin reaction is observed under the natural light, whether the skin is red and swollen or not is taken as an investigation index, and the skin local reaction conditions of 0h, 12h, 24h, 48h and 72h after the administration are observed. The results were as follows:
TABLE 3 complete skin irritation test of beclomethasone dipropionate cream
2. Damaged skin irritation test
18 New Zealand rabbits, each half of male and female, were randomly divided into 5 groups, 6 in each group, of a negative control group, beclomethasone dipropionate creams of examples 1,2 and 3 and a commercially available beclomethasone dipropionate cream. The middle of the back faded 24 hours before the test, the range of fading was about 5cm x 5cm each. Then, no. 400 fine sandpaper subjected to disinfection treatment is used for causing abrasion at the hair-removed part, so that dense bleeding points appear on the skin, physiological saline, beclomethasone dipropionate emulsifiable pastes of examples 1,2 and 3 and a commercially available beclomethasone dipropionate emulsifiable paste are immediately coated on the grouped skin-abraded part of the New Zealand rabbit respectively by taking blood seepage as a degree, and the medicine is administered once and continuously for 8 days. The skin reaction was observed under natural light.
The results show that the commercial beclomethasone dipropionate cream group of New Zealand rabbits showed mild erythema in 3/6 of the animals at Day 1, moderate erythema in 4/6 of the animals at Day 3, scabbing in 6/6 of the animals, rough skin and desquamation in 6/6 of the animals, and gradual reduction after 7 days. Example 3 beclomethasone dipropionate cream group New Zealand rabbits showed mild erythema in 1/6 of the animals at Day 1, gradually decreasing after 3 days until the erythema subsided at 7 days after the last dose. EXAMPLE 1 beclomethasone dipropionate cream group, EXAMPLE 2 beclomethasone dipropionate cream group, and New Zealand rabbits as a negative control group did not show erythema and edema.
The test result shows that the beclomethasone dipropionate cream product has small irritation to the skin, can improve the life quality of patients when being applied to local skin allergy, and has wide product market application value.
Claims (10)
1. A preparation method of beclomethasone dipropionate cream is characterized by comprising the following steps:
(1) Melting an oil phase: heating the oil-fat component and the preservative in water bath to melt, filtering, adding beclomethasone dipropionate, and uniformly mixing to obtain an oil phase;
(2) Melting the water phase: dissolving a water-soluble component in a buffer solution with pH =6.0-8.0, and heating in a water bath to melt the water-soluble component 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 emulsifier, and stirring to form paste.
2. Method according to claim 1, characterized in that it comprises the following steps:
(1) Oil phase melting: heating the oleaginous components in water bath at 65-85 deg.C to melt, filtering, cooling to 35-45 deg.C in water bath, adding beclomethasone dipropionate, mixing, and performing ultrasonic treatment at 50-60 deg.C for 5-15min to obtain oil phase;
(2) Melting the water phase: dissolving the water soluble components in buffer solution with pH =6.0-8.0, heating in water bath at 55-65 deg.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 emulsifier, and stirring to form paste.
3. The method according to claim 1 or 2, wherein the temperature gradient in step (3) is as follows:
the first stage is as follows: stirring for 5-15min at water bath temperature of 50-60 deg.C;
and a second stage: stirring for 10-20min at water bath temperature of 30-40 deg.C;
and a third stage: stirring for 10-20min at water bath temperature of 40-55 deg.C;
a fourth stage: the temperature of the water bath is 20-30 ℃, and the stirring is carried out for 15-25min.
Preferably, the gradient temperature control is as follows:
the first stage is as follows: stirring for 10min at water bath temperature of 55 deg.C;
and a second stage: stirring for 15min at the water bath temperature of 35 ℃;
and a third stage: stirring for 15min at the water bath temperature of 50 ℃;
a fourth stage: the water bath temperature is 25 ℃, and the stirring is carried out for 20min.
4. The method according to claim 1, wherein the beclomethasone dipropionate is micronized beclomethasone dipropionate, preferably having a particle size of 60-80 μm.
5. The method of claim 3, wherein the emulsifier is added during the third stage of the gradient temperature control.
6. The method according to claim 1, wherein the buffer solution is selected from one of a barbiturate-sodium chloride buffer solution, a phosphate buffer solution, a sodium citrate buffer solution, preferably a barbiturate-sodium chloride buffer solution.
7. The method of claim 6, wherein the barbiturate-sodium chloride buffer pH =7.8.
8. A beclomethasone dipropionate cream prepared by the method of claim 1,
the oleaginous component is selected from one or more of glyceryl monostearate, stearyl alcohol, vaseline, stearic acid, stearyl alcohol, beeswax, cetyl alcohol, ceresin wax, and paraffin,
the water-soluble component is one or more selected from propylene glycol, glycerol and water,
the preservative is selected from one or more of benzalkonium bromide, chlorhexidine acetate, sodium benzoate, methyl hydroxybenzoate, ethylparaben and propyl hydroxybenzoate,
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.
9. The beclomethasone dipropionate cream according to claim 8,
the oleaginous components are glyceryl monostearate, octadecanol and vaseline,
the water-soluble component is selected from propylene glycol, glycerol,
the preservative is sodium benzoate, and the preservative is sodium benzoate,
the emulsifier is methyl glucoside sesquistearate and ergosterol.
10. The beclomethasone dipropionate cream according to claim 9, characterized in that the components are calculated by weight ratio as:
preferably, the first and second liquid crystal display elements are,
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