CN115068423A - Clarithromone foaming agent and preparation method thereof - Google Patents

Clarithromone foaming agent and preparation method thereof Download PDF

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Publication number
CN115068423A
CN115068423A CN202110267507.3A CN202110267507A CN115068423A CN 115068423 A CN115068423 A CN 115068423A CN 202110267507 A CN202110267507 A CN 202110267507A CN 115068423 A CN115068423 A CN 115068423A
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clarithromone
foam
claritone
percent
alcohol
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孙克
鲍毅
阎晓文
冯大林
单瑞平
桂盼
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Zhejiang Wansheng Pharmaceutical Co ltd
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Zhejiang Wansheng 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • 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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia

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  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

The invention discloses a Claritone foaming agent and a preparation method thereof, and the Claritone foaming agent comprises a Claritone liquid medicine, wherein the Claritone liquid medicine comprises Claritone, ethanol, a transdermal enhancer, a foam framework, an emulsifier, an antioxidant, a pH regulator and purified water. The Claritone foaming agent can be stored stably for a long time, and is safe, effective and simple in production process.

Description

Clarithromone foaming agent and preparation method thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a Claritone foaming agent composition and a preparation method thereof.
Background
Clascoterone (also known as CB-03-01) is a local Androgen Receptor (AR) inhibitor, has the chemical name of 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3, 20-dione, and has the following structural formula:
Figure BDA0002972783490000011
8 months of 2020, 1.0% of the carambone cream was first approved in the united states for topical treatment of acne vulgaris in patients aged 12 or older than 12 years. A 7.5% cladribone emulsion for genetic hair loss will initiate a phase II clinical study in women at quarter 4 of 2020 and a phase III clinical study in men at quarter 1 of 2020.
However, the existing external cream or lotion of the crassone has the defects of greasy coating, difficult uniform coating and influence on the beauty of the face, and is not beneficial to the application of the skin with hair areas, so the invention develops a novel crassone foaming agent aiming at the defects.
Disclosure of Invention
The invention aims to provide a Claritone foaming agent and a preparation method of the Claritone foaming agent.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a Claritone foaming agent which comprises a Claritone liquid medicine, wherein the Claritone liquid medicine comprises the following components in percentage by weight:
1 to 7.5 percent of Claritone
45 to 50 percent of ethanol
5 to 10 percent of transdermal enhancer
5 to 13 percent of foam framework
1 to 5 percent of emulsifier
0.1 to 0.5 percent of antioxidant
0.9 to 1.5 percent of PH regulator
The balance being purified water.
Preferably, the Claritone foaming agent further comprises a propellant, and 8-10 parts by weight of the propellant is added to every hundred parts by weight of the Claritone liquid medicine.
Preferably, the transdermal enhancer is one or more selected from glycerol, polyethylene glycol and propylene glycol.
Preferably, the foam skeleton is higher fatty alcohol, and the higher fatty alcohol is selected from one or more of octadecanol, hexadecanol, tetradecanol and docosanol.
Preferably, the emulsifier is one or more selected from glycerin monostearate, phosphatide, sodium dodecyl sulfate, polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, poloxamer 124, poloxamer 188 and poloxamer 182.
Preferably, the antioxidant is selected from one or more of 2, 6-di-tert-butyl-p-cresol, dibutyl hydroxy toluene, ascorbic acid, calcium ascorbate, ascorbyl palmitate, butyl hydroxy anisol and thiodipropionic acid.
Preferably, the PH regulator is one or more selected from phosphate buffer, acetate buffer, lactic acid buffer, and citric acid buffer.
Preferably, the propellant is selected from alkane or halogenated alkane, and the alkane or halogenated alkane is selected from one or more of tetrafluoroethane, heptafluoropropane, butane, propane and isobutane.
In another aspect, the invention provides a preparation method of the Claritone foaming agent, which comprises the following steps:
preparing an alcohol phase: mixing the Clarithromone, the foam framework, the emulsifier, the antioxidant and the ethanol, heating and dissolving until the mixture is clear, and keeping the temperature at 60 ℃ for later use;
preparation of an aqueous phase: mixing purified water, skin penetration enhancer and pH regulator, heating to dissolve until clear, and keeping the temperature at 60 deg.C;
total mixing: adding the water phase into the alcohol phase, stirring and cooling to 50 ℃;
filling and sealing and inflating: filling the medicinal liquid into medicinal aerosol canister, capping, and charging propellant.
In another aspect, the invention provides the use of a Clarithromone foam formulation as described above in the manufacture of a medicament for the treatment of acne and alopecia.
The positive progress effects of the invention are as follows:
1. the Clarithromone foaming agent is more convenient to use, can be sprayed out by pressing a valve when in use, has low density, is more easily distributed on the epidermis compared with emulsifiable paste and emulsion, and is more beneficial to uniform dispersion of the medicine after being smeared.
2. The Clarithromone foaming agent disclosed by the invention has the advantages of quick foam breakage, is more advantageous when being applied to skin with hair areas, is easy to enter a cuticle layer through hair, and is more convenient to use compared with other preparations.
3. The Claritone foaming agent disclosed by the invention is light in weight, high in safety, free of obvious stimulation and free of influence on patient compliance after long-term use.
4. The Clarithromone foaming agent has the advantages of simple and convenient production process, simple and easily obtained components, good uniformity, high stability, small impurity growth and suitability for industrial production.
Detailed Description
The following examples and experimental examples are intended to further illustrate the present invention and should not be construed as limiting the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The raw materials and auxiliary materials in the examples can be obtained commercially. The Clarithromone used in the invention is prepared according to the method disclosed in Chinese patent CN 02815719.2.
Example 1: clarasidone foam (1%) preparation
The weight ratio of each component of the Claritone foaming agent (1%) is shown in Table 1:
table 1: the dosage of each component of the Claritone foaming agent (1 percent)
Figure BDA0002972783490000031
Figure BDA0002972783490000041
(1) Preparing an alcohol phase: mixing the clarasidone, the octadecanol, the hexadecanol, the polysorbate 80, the dibutyl hydroxy toluene and the absolute ethyl alcohol, heating and dissolving the mixture, and keeping the temperature at 60 ℃ for standby.
(2) Preparation of an aqueous phase: mixing purified water, glycerol, and citric acid, heating to dissolve, and keeping at 60 deg.C.
(3) Total mixing: and adding the water phase into the alcohol phase, stirring for 5 minutes, and cooling to 50 ℃ under stirring to obtain the cral-ketone liquid medicine.
(4) Filling and sealing and inflating: filling the liquid medicine into a medicinal aerosol can, pressing a cover, and mixing the liquid medicine and the propellant according to the weight ratio of 100: 8 charging propellant heptafluoropropane.
The samples were tested and the results are shown in table 2.
Table 2: claritone foaming agent (1%) test results
Inspection item Test standard Test results
Traits The liquid medicine should be white-like foam when sprayed Off-white foam
Chemical identification Should be positive or negative Positive reaction
Safety explosion-proof test No explosion and air leakage Without blasting and leakingQi (Qi)
pH value 4.0～4.5 4.2
Related substances Should not be more than 2.0% 0.5
Leakage rate Should comply with the regulations Compliance with regulations
Injection rate Should not be less than 3 g/s 3.9 g/s
Total volume of ejection Should not be less than 85% of the marked amount 95％
Limit of microorganism Should comply with the regulations Compliance with regulations
Content (wt.) The marked amount is 90 to 110 percent 100.5％
The test result shows that the properties, related substances, contents and the like of the foam agent all meet the quality requirements of the foam agent.
Example 2: clarasidone foam (7.5%) preparation
The weight ratio of each component of the krasone foaming agent (7.5%) is shown in Table 3:
table 3: claritone foaming agent (7.5%) using amount of each component
Components Proportioning
Clarithromone 7.5％
Octadecanol 7％
Cetyl alcohol 6％
Polysorbate 80 3％
Dibutylhydroxytoluene 0.5％
Citric acid 1.5％
Anhydrous ethanol 50％
Glycerol 8％
Purified water 16.5％
Total of 100％
Tetrafluoroethane 8％
(1) Preparing an alcohol phase: mixing the clarasidone, the octadecanol, the hexadecanol, the polysorbate 80, the dibutyl hydroxy toluene and the absolute ethyl alcohol, heating and dissolving the mixture, and keeping the temperature at 60 ℃ for standby.
(2) Preparation of an aqueous phase: mixing purified water, glycerol and citric acid, heating to dissolve, and keeping at 60 deg.C.
(3) Total mixing: adding the water phase into the alcohol phase, stirring for 5 minutes, and cooling to 50 ℃.
(4) Filling and sealing and inflating: filling the liquid medicine into a medicinal aerosol can, pressing a cover, and mixing the liquid medicine and the propellant according to the weight ratio of 100: 8 filling propellant tetrafluoroethane.
The samples were tested and the results are shown in table 4.
Table 4: claritone foaming agent (7.5%) test results
Figure BDA0002972783490000051
Figure BDA0002972783490000061
The test result shows that the properties, related substances, contents and the like of the foam agent all meet the quality requirements of the foam agent.
Example 3: clastone foam stability study
Samples of the crabanone foam prepared according to example 1 were tested for stability at 30 ℃ for 6 months and the results are shown in Table 5.
Table 5: clarasidone foam stability results
Figure BDA0002972783490000062
The test result shows that the content and the impurities do not change greatly, which indicates that the Claritone foaming agent has good stability and the product can maintain good properties.
Example 4: clastone foamer irritation test
Samples of the Claritone foam prepared in example 1 were tested for irritation and the following were examined: 16 rabbits (New Zealand rabbits, from Hill Hangzhou, Hangzhou Co-Ltd.) qualified for quarantine were assigned to 4 groups, including a test sample intact skin group, a test sample damaged skin group, a blank matrix control intact skin group and a blank matrix control damaged skin group, each group including 4 rabbits, and each rabbit was male and female. The animals in each group are compared with the animals on the left and right sides of the same body, the test sets the administration frequency and period as 1 time of administration per day, 4 hours of application, 28 days of continuous administration and 0.5 ml/side/skin allergy test, and the test period is 1 time of observation per day. The observation contents comprise the symptoms of appearance, physical signs, skin, behavior activity, gland secretion, respiration, eyes, ears, nose, anus, fecal characters, limbs and the like, and the result shows that the Claritone foaming agent has no obvious stimulation.
Example 5: clarasidone foam test
A sample of the Clarithromone foam prepared according to example 1 was placed in a measuring cylinder, placed in a water bath at 28 ℃, 30 ℃, 33 ℃, 35 ℃, 40 ℃ and observed for defoaming time, the results are shown in Table 6.
Table 6: krastone foam agent defoaming time result
Figure BDA0002972783490000071
The test results showed that the jet was a white fine foam, not flowing, not defoaming below about 30 ℃. When the temperature is higher than 30 ℃, the foam is gradually defoamed into colorless to light yellow clear solution, and when the temperature is higher than 33 ℃, the foam can be eliminated within one minute.
In conclusion, the invention can prepare a sample of the foam of the carat ketone, which has stable physical shape, long-term stable storage, safety, effectiveness, quick foam rupture, easy penetration of the drug into the cuticle through the hair, and quicker and more uniform dispersion than other preparations, by a simple, safe and low-cost method.

Claims (10)

1. The Claritone foaming agent is characterized by comprising a Claritone liquid medicine, wherein the Claritone liquid medicine comprises the following components in percentage by weight:
1 to 7.5 percent of Claritone
45 to 50 percent of ethanol
5 to 10 percent of transdermal enhancer
5 to 13 percent of foam framework
1 to 5 percent of emulsifier
0.1 to 0.5 percent of antioxidant
0.9 to 1.5 percent of PH regulator
The balance being purified water.
2. The Clarithromone foam formulation as claimed in claim 1, wherein the Clarithromone foam formulation further comprises a propellant, and 8-10 parts by weight of propellant is added per hundred parts by weight of Clarithromone solution.
3. The Clarithromone foam formulation as claimed in claim 1, wherein the skin penetration enhancer is selected from one or more of glycerol, polyethylene glycol, and propylene glycol.
4. The Clarithromone foaming agent as claimed in claim 1, wherein the foam skeleton is higher fatty alcohol, and the higher fatty alcohol is one or more selected from stearyl alcohol, cetyl alcohol, cetostearyl alcohol, tetradecanol, and behenyl alcohol.
5. The krasone foam of claim 1, wherein the emulsifier is selected from one or more of glyceryl mono-, distearate, phospholipids, sodium lauryl sulfate, polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, poloxamer 124, poloxamer 188, and poloxamer 182.
6. The cladribone foam formulation according to claim 1 wherein the antioxidant is selected from one or more of 2, 6-di-tert-butyl-p-cresol, dibutylhydroxytoluene, ascorbic acid, calcium ascorbate, ascorbyl palmitate, butylhydroxyanisole, thiodipropionic acid.
7. The cladribone foam formulation according to claim 1 wherein the PH modifier is selected from one or more of phosphate buffer, acetate buffer, lactic buffer, citric buffer.
8. The Clarithromone foam formulation as claimed in claim 2, wherein the propellant is selected from alkanes or halogenated alkanes selected from one or more of tetrafluoroethane, heptafluoropropane, butane, propane, isobutane.
9. A process for preparing a Clarithromone foam formulation as claimed in claim 2, comprising the steps of:
preparing an alcohol phase: mixing the Clarithromone, the foam framework, the emulsifier, the antioxidant and the ethanol, heating and dissolving until the mixture is clear, and keeping the temperature at 60 ℃ for later use;
preparation of an aqueous phase: mixing purified water, skin penetration enhancer and pH regulator, heating to dissolve until clear, and keeping the temperature at 60 deg.C;
total mixing: adding the water phase into the alcohol phase, stirring and cooling to 50 ℃;
filling and sealing and inflating: filling the medicinal liquid into medicinal aerosol canister, capping, and charging propellant.
10. Use of a clarithrone foam formulation according to any of claims 1-9 in the manufacture of a medicament for treating acne and alopecia.
CN202110267507.3A 2021-03-12 2021-03-12 Clarithromone foaming agent and preparation method thereof Pending CN115068423A (en)

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