CN116650399A - Fusidic acid cream and preparation method thereof - Google Patents
Fusidic acid cream and preparation method thereof Download PDFInfo
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- CN116650399A CN116650399A CN202310391147.7A CN202310391147A CN116650399A CN 116650399 A CN116650399 A CN 116650399A CN 202310391147 A CN202310391147 A CN 202310391147A CN 116650399 A CN116650399 A CN 116650399A
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- fusidic acid
- cream
- acid cream
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- preservative
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- 229960004675 fusidic acid Drugs 0.000 title claims abstract description 85
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 title claims abstract description 85
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 239000006071 cream Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 239000012071 phase Substances 0.000 claims abstract description 36
- 239000003755 preservative agent Substances 0.000 claims abstract description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 28
- 230000002335 preservative effect Effects 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 20
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 16
- 239000008346 aqueous phase Substances 0.000 claims abstract description 14
- 239000011159 matrix material Substances 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- 235000011187 glycerol Nutrition 0.000 claims abstract description 12
- 239000008213 purified water Substances 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 36
- 238000002156 mixing Methods 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 13
- 229960000541 cetyl alcohol Drugs 0.000 claims description 9
- 229940057995 liquid paraffin Drugs 0.000 claims description 9
- 239000003871 white petrolatum Substances 0.000 claims description 9
- -1 hydroxyphenyl ester Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 6
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 6
- 229960002216 methylparaben Drugs 0.000 claims description 6
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 5
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 5
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 4
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 4
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 229950011392 sorbitan stearate Drugs 0.000 claims description 3
- 235000019271 petrolatum Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 11
- 238000005286 illumination Methods 0.000 abstract description 8
- 238000010257 thawing Methods 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 5
- 238000007710 freezing Methods 0.000 abstract description 3
- 230000008014 freezing Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 16
- 230000003078 antioxidant effect Effects 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000003814 drug Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 230000007774 longterm Effects 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 238000011835 investigation Methods 0.000 description 4
- 230000000813 microbial effect Effects 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 229950008882 polysorbate Drugs 0.000 description 3
- 239000004302 potassium sorbate Substances 0.000 description 3
- 235000010241 potassium sorbate Nutrition 0.000 description 3
- 229940069338 potassium sorbate Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 230000002906 microbiologic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010007247 Carbuncle Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010016936 Folliculitis Diseases 0.000 description 1
- 206010017553 Furuncle Diseases 0.000 description 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 206010034016 Paronychia Diseases 0.000 description 1
- 241000029132 Paronychia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 239000007957 coemulsifier Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000002557 hidradenitis Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
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Abstract
The application provides a fusidic acid cream preparation, which comprises an active ingredient fusidic acid, an aqueous phase part and an oil phase part, wherein the aqueous phase part comprises glycerin, a preservative and purified water; the oil phase part comprises an oily matrix and an emulsifying agent; further, in order to avoid the rise of impurities caused by the thermal instability of the auxiliary materials added with antioxidants, the cream does not contain antioxidants. The stability of the fusidic acid cream is superior to that of a commercial reference preparation, the stability of the fusidic acid cream can be kept under the conditions of high temperature, high humidity, low temperature, freezing and thawing and illumination, the maximum single impurity and total impurity content in the product are not obviously increased, and the quality is controllable. Meanwhile, the preparation process of the fusidic acid cream disclosed by the application is simple and easy for industrial production.
Description
Technical Field
The application belongs to the field of pharmaceutical preparations, and in particular relates to fusidic acid cream and a preparation method thereof.
Background
The fusidic acid cream (Fusidic Acid Cream) is an antibiotic-based external medicament for treating skin infections caused by staphylococci, streptococci, propionibacteria acnes, corynebacteria and other bacteria sensitive to fusidic acid. The main indications include: the composition is suitable for treating facial and head infections, such as impetigo, furuncle, carbuncle, paronychia, wound infection, sore, sweat gland inflammation, tinea rubra, folliculitis, and acne vulgaris.
The cream preparation is usually stored at a sealed normal temperature (10-30 ℃) and has poorer stability than other solid preparations, so that the cream preparation is easy to change in characteristics such as oil-water separation (demulsification), color change, peculiar smell and the like during daily transportation, storage and long-term clinical use, and the quality and the effective service life of the cream can be reduced. Meanwhile, the total amount of impurities in the fusidic acid cream is increased during long-term or high-temperature storage, the content of active ingredients is reduced, and the problems have adverse effects on the quality and stability of the fusidic acid cream. Therefore, there is a need for fusidic acid creams with stable properties and better quality for clinical use.
The currently marketed fusidic acid creams are improved in stability and bacteriostatic ability by adding antioxidants (e.g. butylhydroxytoluene, butylhydroxyanisole, EDTA, etc.) and preservatives (e.g. chlorocresol, potassium sorbate, benzoic acid); if the antibacterial effect of the preservative is weak, the antibacterial effect is improved by further adding an antibacterial synergist. Common antioxidants such as butyl hydroxy anisole, butyl hydroxy toluene and the like belong to synthetic antioxidants, have poor thermal stability and are extremely volatile and invalid at the temperature of more than 70 ℃. The range of applications for such synthetic oxidants has been gradually narrowed in recent years.
The parahydroxybenzoate preservative, namely the nipagin antibacterial preservative, has the advantages of low toxicity, no odor, no smell, stability, difficult decomposition at high temperature and good antibacterial activity in the pH range of 4-8. Due to the formation of the phenolate anion, the bacteriostatic effect can be increased along with the decrease of the pH value, and the antibacterial agent has a strong inhibition effect on gram-negative bacteria, gram-positive bacteria, yeasts and moulds.
Patent CN104758242 a discloses a sodium fusidate ointment pharmaceutical composition and a preparation method thereof, comprising sodium fusidate, ointment base, emulsifying agent and antioxidant, wherein the preservative is not contained; patent CN 107224426A discloses a topical cream composition containing fusidic acid, comprising fusidic acid as main drug, oil phase solvent, emulsifier, co-emulsifier, antioxidant, thickener, aqueous phase solvent, hydrolysis stabilizer, wherein no preservative is contained; both ointment drugs contained antioxidants sufficient to demonstrate the important role of antioxidants in stability of fusidic acid cream formulations.
Patent CN104706579 a discloses an ophthalmic solution of fusidic acid and a process for its preparation, comprising fusidic acid, a thickener, an osmotic pressure regulator, a preservative, a metal ion chelating agent, a PH regulator, water for injection, which does not contain an antioxidant. Because the eye drops are directly applied to eyeballs, strict quality requirements on PH value, osmotic pressure, viscosity and aseptic preservation are met, and the eye drops are easy to be polluted by tears and microorganisms in the storage and application process even though preservatives are added, the use time of the eye drops after being started is not longer than four weeks in the pharmacopoeia general rule. The fusidic acid cream preparation is directly used on the surface of skin, and is in an environment of air exposure and illumination for a long time, so that the requirements of long-time use and storage are met, and the requirements on oxidation resistance and corrosion resistance of the product in the preparation process are strict, thereby increasing the complexity of the preparation prescription and the production process. Currently, there is no report in patent literature of a fusidic acid cream formulation without an antioxidant, which contains both an antioxidant and a preservative in the fusidic acid cream product sold.
Disclosure of Invention
In order to solve the quality and stability problems of the fusidic acid cream, and avoid the increase of impurities caused by the thermal instability of the antioxidant added in auxiliary materials, the application provides the fusidic acid cream without the antioxidant, which has better quality stability than the commercial product (risidian), has better antiseptic and antioxidant effects, and can still keep the stability of paste properties and active ingredients under different environments (temperature, humidity and illumination); meanwhile, the application also provides a preparation method of the fusidic acid cream, which is simple in process and easy for industrial production. In order to achieve the above purpose, the present application adopts the following technical scheme:
a fusidic acid cream comprising the active ingredient fusidic acid, an aqueous phase portion and an oil phase portion; the aqueous phase portion comprises glycerin, a preservative and purified water; the oil phase part comprises an oily matrix and an emulsifying agent; further, the cream does not contain an antioxidant.
In one embodiment of the application, the preservative is a hydroxyphenyl ester preservative; further, the hydroxyphenyl ester preservative is methylparaben or ethylparaben.
In one embodiment of the present application, the emulsifier is selected from one or more of polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan stearate, and polyoxyethylene sorbitan monooleate.
In one embodiment of the present application, the oil phase base comprises white petrolatum, liquid paraffin and cetyl alcohol.
In one embodiment of the application, the fusidic acid cream comprises per 100 parts by weight the following components: 1.0 to 3.0 parts of fusidic acid, 25.0 to 35.0 parts of oily matrix, 4.0 to 6.0 parts of emulsifier, 8.0 to 12.0 parts of glycerol, 0.1 to 0.3 parts of preservative and 50.0 to 55.0 parts of purified water.
Further, the oily matrix comprises the following components in parts by weight: 4.0 to 10.0 portions of white vaseline, 10.0 to 15.0 portions of liquid paraffin and 10.0 to 15.0 portions of cetyl alcohol.
In one embodiment of the application, the cream is further adjusted to a pH in the range of 4.0 to 6.5 using hydrochloric acid or sodium hydroxide.
The application also provides a preparation method of the fusidic acid cream, which specifically comprises the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding preservative and glycerin, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating the oily matrix and the emulsifier to melt to obtain an oil phase part, and preserving heat at 70-75 ℃ for later use;
(3) Total mixing: mixing the water phase part and the oil phase part uniformly, adding active ingredients, and stirring and mixing uniformly to obtain a total mixture;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
Further, the above preparation method of fusidic acid cream, wherein the step (3) further comprises a process of adding a proper amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to 4.0-6.5.
The beneficial effects of the application are as follows:
the fusidic acid cream preparation does not contain an antioxidant, and the fusidic acid cream preparation with stable property and controllable quality can be obtained by the mutual matching of the polysorbate emulsifier and the hydroxyphenyl preservative; tests show that the stability of the fusidic acid cream is superior to that of a commercial reference preparation, the fusidic acid cream can keep stable properties under the conditions of high temperature, high humidity, low temperature, freezing and thawing and illumination, and the maximum single impurity and total impurity content in the product are not obviously increased. Meanwhile, the preparation process of the fusidic acid cream disclosed by the application is simple and easy for industrial production.
Detailed Description
The technical scheme of the present application will be further described with reference to specific examples, but the present application is not limited thereto.
Example 1
The preparation method comprises the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding methylparaben and glycerin, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating up an oily matrix (white vaseline, liquid paraffin and cetyl alcohol) and polyoxyethylene sorbitan monopalmitate to melt to obtain an oil phase, and preserving heat at 70-75 ℃ for later use;
(3) Total mixing: mixing the oil phase part and the water phase part uniformly, adding the fusidic acid main drug, and stirring and mixing uniformly to obtain a total mixture; further adding a proper amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to 4.0-6.5;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
Example 2
The preparation method comprises the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding methylparaben and glycerin, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating up oily matrix (white vaseline, liquid paraffin, cetyl alcohol) and polyoxyethylene sorbitan stearate to melt to obtain oil phase, and keeping the temperature at 70-75 ℃ for later use;
(3) Total mixing: mixing the oil phase part and the water phase part uniformly, adding the fusidic acid main drug, and stirring and mixing uniformly to obtain a total mixture; further adding a proper amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to 4.0-6.5;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
Example 3
The preparation method comprises the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding ethylparaben and glycerol, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating up oily matrix (white vaseline, liquid paraffin, cetyl alcohol) and polyoxyethylene sorbitan monooleate to melt to obtain oil phase, and keeping the temperature at 70-75 ℃ for later use;
(3) Total mixing: mixing the oil phase part and the water phase part uniformly, adding the fusidic acid main drug, and stirring and mixing uniformly to obtain a total mixture; further adding a proper amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to 4.0-6.5;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
Example 4
The preparation method comprises the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding ethylparaben and glycerol, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating up oily matrix (white vaseline, liquid paraffin, cetyl alcohol) and polyoxyethylene sorbitan monopalmitate to melt to obtain oil phase, and keeping the temperature at 70-75 ℃ for later use;
(3) Total mixing: mixing the oil phase part and the water phase part uniformly, adding the fusidic acid main drug, and stirring and mixing uniformly to obtain a total mixture; further adding a proper amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to 4.0-6.5;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
Example 5
The preparation method comprises the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding methylparaben and glycerin, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating up oily matrix (white vaseline, liquid paraffin, cetyl alcohol) and polyoxyethylene sorbitan monopalmitate to melt to obtain oil phase, and keeping the temperature at 70-75 ℃ for later use;
(3) Total mixing: mixing the oil phase part and the water phase part uniformly, adding the fusidic acid main drug, and stirring and mixing uniformly to obtain a total mixture; further adding a proper amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to 4.0-6.5;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
Comparative example
To examine the effect of polysorbate emulsifiers and hydroxyphenyl preservatives on stability of fusidic acid cream formulations, fusidic acid creams of comparative examples 1-5 were prepared according to the following table formulation formulas, and the comparative example preparation method was similar to the preparation method of example 1. Wherein the preservative of comparative example 1 is potassium sorbate; control 2 without the preservative methylparaben; control 3 the emulsifier was sodium dodecyl sulfate; comparative example 4 the emulsifier was glycerol monostearate; comparative example 5 the antioxidant butyl hydroxy anisol was added; reference formulation (commercial product risidian) which differs from i.m. fusidic acid cream in that the reference formulation contains an antioxidant and the preservative is potassium sorbate.
Stability investigation test
According to the stability test guiding principle (four general rules 9001 of Chinese pharmacopoeia 2020 edition) and the chemical drug (bulk drug and preparation) stability research technical guiding principle, the influence factor test and uniformity stability test are carried out on the fusidic acid cream preparation. The samples examined were fusidic acid creams of examples 1-5, comparative examples 1-5 and the reference formulation (commercially available risdine).
1. Influence factor investigation
High temperature 40 ℃ tape wrapping material test: 3 samples were taken, placed in an incubator at 40℃for 30 days, sampled 1 sample each for 5 days, 10 days and 30 days, and the properties were observed and examined for the relevant substances.
And (3) illumination belt packing material test: 3 samples are taken, placed in an illumination box, placed for 30 days under the conditions of illumination of 5000Lux and ultraviolet energy of 0.9W/m < 2 >, sampled for 1 sample respectively for 5 days, 10 days and 30 days, and the properties are observed and related substances are detected.
High wet tape wrapping test: 3 samples were taken, placed in a RH92.5% desiccator for 30 days, 1 sample was taken for 5 days, 10 days and 30 days, and the properties were observed and examined for the relevant substances.
Low temperature belt wrapping test: taking 3 samples each, standing at 2-8deg.C for 2 days, inspecting at 40deg.C for 2 days, sampling 1 sample, observing properties, and detecting related substances. This is one cycle, for a total of 3 cycles.
Freezing and thawing belt packing material test: taking 3 samples, standing at-20 to-10 ℃ for 2 days, then inspecting at 40 ℃ for 2 days, sampling 1 sample, observing the properties and detecting related substances. This is one cycle, for a total of 3 cycles.
TABLE 1 summary of test property results of factor (high temperature, high humidity, light) affecting fusidic acid cream samples
Table 2 summary of results of related substances (%) of the test of factors (high temperature, high humidity, light) affecting the sample of fusidic acid cream
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TABLE 3 Table 3 results summary of test Properties of factor (Low temperature, freeze thawing) affecting samples of fusidic acid creams
Table 4 summary of results of related substances (%) of the factor (low temperature, freeze thawing) test on sample of fusidic acid cream
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The stability investigation test results show that the fusidic acid creams of examples 1-5 have no obvious change in properties after high temperature, high humidity, illumination, low temperature and freeze thawing, and the maximum single impurity and total impurity are not obviously increased; the demulsification phenomenon occurs after long-time high temperature, high humidity and freeze thawing in comparative examples 3-4; comparative examples 1-5 showed significantly higher maximum single and total impurities at high temperature, high humidity, light, low temperature and freeze thawing, and significantly higher maximum single and total impurities for the commercial reference formulations, and examples 1-5 of the present application showed better performance than the commercial reference formulations.
Taken together, it can be seen that the stability of the fusidic acid creams of examples 1-5 was significantly better than the fusidic acid creams of comparative examples 1-5, and than the commercial reference formulation risdine, under different environmental conditions; thus, it can be demonstrated that the combination of the polysorbate emulsifier and the hydroxyphenyl preservative can provide a stable and controllable quality formulation of fusidic acid cream without the addition of an antioxidant.
2. Uniformity inspection
Long-term test: taking fusidic acid cream samples of examples 1-5 and comparative examples 1-5 and a reference preparation, namely risdine, under the condition of accelerating (40 ℃ +/-2 ℃ and 75% +/-5% RH), standing for 6 months; sampling at 0 month and 6 months respectively, and detecting the content of active ingredients in the neck, middle and tail of the tube of the fusidic acid cream, wherein the limit of the content of the active ingredients is required to be 95.0% -105.0%.
The sampling test results are shown in the following table 5, so that the poor uniformity of the content of the active ingredients of the fusidic acid creams of comparative examples 1-5 is obvious, and the requirement of the specified content limit is not met; the uniformity of the active ingredient content of the fusidic acid creams of examples 1-5 is significantly better than that of comparative examples 1-5, which are within the required range of the content limit, and the uniformity of the active ingredient content is better than that of the commercial reference formulation.
TABLE 5 results of long-term test of content uniformity stability of fusidic acid cream samples
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3. Microbial limit investigation
Long-term test: taking fusidic acid cream samples of examples 1-5 and comparative examples 1-5 and a reference preparation, namely risdine, under the condition of accelerating (40 ℃ +/-2 ℃ and 75% +/-5% RH), standing for 6 months; samples were taken at 0 and 6 months, respectively, and the microbial limit in the cream was examined. The results of the microbial limit detection are shown in table 6 below, and it can be seen that: the microbiological limits of examples 1-5 and comparative examples 3-5 were satisfactory, whereas the microbiological limits were unsatisfactory after 6 months of acceleration of comparative examples 1 and 2 (both without the preservative hydroxypropyl methyl ester), thus demonstrating the necessity of adding hydroxypropyl ester preservative to the fusidic acid cream formulation of the present application.
TABLE 6 microbial limit stability long-term test results for samples of fusidic acid cream
The foregoing description of the preferred embodiments of the application is not intended to limit the application to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the application are intended to be included within the scope of the application.
Claims (10)
1. A fusidic acid cream characterized in that the cream comprises the active ingredient fusidic acid, an aqueous phase portion and an oil phase portion; the aqueous phase portion comprises glycerin, a preservative and purified water; the oil phase part comprises an oily matrix and an emulsifying agent; the cream does not contain antioxidants.
2. The fusidic acid cream of claim 1, wherein the preservative is a hydroxyphenyl ester preservative.
3. The fusidic acid cream of claim 2, wherein the hydroxyphenyl ester preservative is methylparaben or ethylparaben.
4. The fusidic acid cream according to claim 1, wherein the emulsifier is selected from one or more of polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan stearate, polyoxyethylene sorbitan monooleate.
5. The fusidic acid cream of claim 1, wherein the oily base comprises white petrolatum, liquid paraffin and cetyl alcohol.
6. The fusidic acid cream according to claim 1, wherein per 100 parts by weight of fusidic acid cream comprises the following components in parts by weight: 1.0 to 3.0 parts of fusidic acid, 25.0 to 35.0 parts of oily matrix, 4.0 to 6.0 parts of emulsifier, 8.0 to 12.0 parts of glycerol, 0.1 to 0.3 parts of preservative and 50.0 to 55.0 parts of purified water.
7. The fusidic acid cream according to claim 6, wherein the oily base is a component of the following parts by weight: 4.0 to 10.0 portions of white vaseline, 10.0 to 15.0 portions of liquid paraffin and 10.0 to 15.0 portions of cetyl alcohol.
8. The fusidic acid cream according to claim 1, wherein the cream is further adjusted to a pH ranging from 4.0 to 6.5 using hydrochloric acid or sodium hydroxide.
9. A process for the preparation of fusidic acid cream according to any one of claims 1-8, characterized in that it comprises in particular the following steps:
(1) Aqueous phase preparation: heating purified water to 70-75 ℃, adding preservative and glycerin, stirring and mixing uniformly, and preserving heat for later use;
(2) Preparing an oil phase part: heating the oily matrix and the emulsifier to melt to obtain an oil phase part, and preserving heat at 70-75 ℃ for later use;
(3) Total mixing: mixing the water phase part and the oil phase part uniformly, adding active ingredients, and stirring and mixing uniformly to obtain a total mixture;
(4) And (3) cooling: cooling the total mixture to normal temperature to obtain the fusidic acid cream.
10. The method of preparing fusidic acid cream according to claim 9, wherein the step (3) further comprises a process of adjusting the pH of the total mixture to a range of 4.0-6.5 by adding an appropriate amount of hydrochloric acid or sodium hydroxide.
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