CN101856328B - Ketoconazole foaming agent and preparation method thereof - Google Patents
Ketoconazole foaming agent and preparation method thereof Download PDFInfo
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- CN101856328B CN101856328B CN 200910081689 CN200910081689A CN101856328B CN 101856328 B CN101856328 B CN 101856328B CN 200910081689 CN200910081689 CN 200910081689 CN 200910081689 A CN200910081689 A CN 200910081689A CN 101856328 B CN101856328 B CN 101856328B
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Abstract
The invention provides a ketoconazole foaming agent and a preparation method thereof, which are used for treating fungal infective diseases, such as seborrheic dermatitis and the like.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains ketoconazole, be used for the treatment of seborrheic dermatitis and local fungal infection, belong to the pharmaceutics field.
Background technology
Foam is widely used in cosmetic industry, and foam has obtained comparatively deep exploitation as a kind of new drug carrier at pharmaceutical industry in recent years.Its characteristics mainly are easy to use, and density is little, more easily are distributed in epidermis than other external preparation, do not stain, but can guarantee easily to wash the absorption of medicine or action time, and compliance is strong.
Ketoconazole is the antifungal drug of classics, goes on the market 20 for many years, and its efficacy and safety has obtained any widely.Developed successively lotion, gel, emulsifiable paste, oral tablet, suppository, capsule, vaginal tablet, shampoo etc. both at home and abroad, in July, 2007 drugs approved by FDA the ketoconazole foaming agent listing.Ketoconazole has been developed at present abroad 2% concentration foam (
StiefelLaboratories, Inc.).According to right
The investigation of product, we find that it has very significantly defective.Being mainly manifested in the employed ethanol of this product must carry out modification through some special reagents (such as the tert-butyl alcohol, strychnine sulfate etc.), and these modifier often have this stronger toxicity, are not easy control.Product has higher extremely strong danger, and the ethanol consumption is up to 58%, and employed propellant is propane, butane mixture, all is very easily to fire explosive article, and is unfavorable to production safety control, and cost is very high, and people's routine use is also brought very big hidden danger.
Summary of the invention
We find, can reach good foam effect by prescription of the present invention and preparation technology, and can avoid simultaneously
Many rough sledding of product.
The present invention provides a kind of pharmaceutical composition of topical, contains the ketoconazole of foam carrier, and compositions is preserved under pressure.This compositions can be used in seborrheic dermatitis or fungal infectious disease in the surface.
Preparation is during pharmaceutical composition of the present invention, and the concentration of ketoconazole is not crucial, he only with medicine in mixed solvent the dissolving situation and need situation relevant during clinical use.Ketoconazole in the ketoconazole drug level 1%～4% that often uses clinically at present, this concentration range can both be in the mixed solvent that is formed by ethanol and short chain multi-alcohol dissolve complete, can both successfully make foam and be applied to routine use.
Advantage of the present invention is mainly reflected in the simple possible of technique.Form mixed solvent by the ethanol in the compositions, propylene glycol or glycerol, the dissolving ketoconazole.The foam support composition such as octadecanol, hexadecanol etc., is added in the solution, dissolving safety.Its consumption can be adjusted according to the required state of foam, and general amount ranges is 0.3%～6%.Behind all the other component mix homogeneously, add in the ketoconazole alcoholic solution in the situation that stir.
The present invention can realize at ambient temperature, also can accelerate whole technical process by suitable heating (as more than 40 ℃), all can obtain desirable preparation effect.After the heating, the time of expending generally can be above 5 hours yet.
The semi-finished product of preparing by technique of the present invention are gel.Fill with to press propellant, the ejecta foam that is white in color after the metal bottle packing, this foam is soft fine and smooth, has certain intensity, and can be coated with rapidly evenly the foreign sense.
For the solute effect that guarantees that ketoconazole is good, the consumption of loss of quantity aliphatic alcohol should account for more than 2% of heavy total amount, preferably can have more than 5%.By experimental study, we find, the consumption of ethanol in foam can successfully ease down to below 40% of foam gross weight, and not affecting the molding effect of whole foam, best ethanol consumption wherein is 20%～35%, and the consumption of short chain fatty alcohol is surpassing 20% of foam gross mass, and be not higher than in 45% the situation, the molding effect of foam is better, and wherein best consumption is in 30%～35% scope.
Advantage of the present invention also is embodied in the selection of propellant.This compositions selects 3%～20% scope interior non-dichlorodifluoromethan hydro carbons propellant tetrafluoroethane, Difluoroethane and fluorochloroparaffins isceon, dichlorodifluoromethane, dichlorotetra-fluoroethane etc. or their mixture all can make good foam.But consider that dichlorodifluoromethan hydro carbons propellant such as isceon etc. may produce heavy damage to earth atmospheric ozone layer, and do not advise adopting.Difluoroethane has and alkane or the similar character of paraffins mixture propellant such as propane, butane, and is highly inflammable and explosive.So best propellant is selected, and uses separately tetrafluoroethane, consumption is 5%～10%.
Make propellant with tetrafluoroethane, carry out safety anti-explosive test, result such as following table 1 to making foam (5).
Table 1 ketoconazole foaming agent safety anti-explosive result of the test
| 40℃ | 1h | 2h | 4h | 8h |
| Gas leakage (%) | 0 | 0 | 0 | 0 |
| Explosion (%) | 0 | 0 | 0 | 0 |
| Blast (%) | 0 | 0 | 0 | 0 |
| 50℃ | 1h | 2h | 4h | 8h |
| Gas leakage (%) | 0 | 0 | 0 | 0 |
| Explosion (%) | 0 | 0 | 0 | 0 |
| Blast (%) | 0 | 0 | 0 | 0 |
| 60℃ | 1h | 2h | 4h | 8h |
| Gas leakage (%) | 0 | 50 | 70 | 80 |
| Explosion (%) | 0 | 0 | 0 | 0 |
| Blast (%) | 0 | 0 | 0 | 0 |
Determine that by testing the present invention makes product and has good safety.Simultaneously, to the present invention make sample and
The foam of product ejection carries out inflammability test, found that
Product ejection foam very easily fires and the trend of initiatively igniting is arranged, and the sample that the present invention makes can't be lighted.
The neccessary composition that the present invention makes foam also comprises an amount of surfactant, we attempt with anionic, non-ionic surfactant Tween 60 grades prepare foam and have all obtained good foam-formed effect, and its amount ranges is 1%～10%.
When application the present invention preparation is used in the medicine of human body, can add as the case may be necessary additive.Studies show that, ketoconazole foam manufactured goods, under the condition of air, pH becomes sourer gradually with velocity variations faster open.We select to add the right mode of buffer salt and can address this problem well, and buffer salt is right to, tartaric acid and tartrate buffering to, boric acid and borate buffering to, carbonate buffering to, citric acid and citrate buffering to, acetic acid and acetate salt buffer to being selected from phosphoric acid and phosphate-buffered.
Certainly, can add an amount of compositions such as essence in the time of necessary, these then are not key factor concerning the preparation effect.Among the present invention, ethanol, propylene glycol or glycerol all have certain antisepsis, need not add separately antiseptic again.
In the process of development ketoconazole foaming agent, adopt highly effective liquid phase chromatographic system that sample is carried out assay and related substance detection.Adopt thermocycling, the physical stability of preparation is verified.To place 24 hours at 30 ℃ by the sample of this method preparation, and observe foam state, then 2～8 ℃ of placements of low temperature are 24 hours, return to 20 ℃, and the ejection foam state is observed in jolting, is a circulation.Continue to observe 15 circulations.The result shows, after 15 circulations are investigated and finished, still can keep normal character under the preparation recovery condition of storage, and the ejection foam state is good.And directly this product is heated to 40 ℃, 50 ℃, 60 ℃ sample, still very good in the foam-formed effect of condition of high temperature elder generation.
Sample by this method preparation, carry out 6 months study on the stability, and related substance in preparation and the crude drug is compared, find that the number of impurity on the basis of crude drug and amount all do not have to increase, the stability that formulation samples has very number is described, product can be kept good character.
Table 2 ketoconazole foaming agent stability test result
| Condition of storage and time | Character | Related substance (%) | Content (%) |
| Place January for 40 ℃ | White foam | 0.65 | 99.07 |
| Place February for 40 ℃ | White foam | 0.65 | 99.13 |
| Place March for 40 ℃ | White foam | 0.61 | 98.27 |
| Place June for 40 ℃ | White foam | 0.59 | 98.75 |
| Place March for 25 ℃ | White foam | 0.67 | 99.07 |
| Place June for 25 ℃ | White foam | 0.67 | 98.91 |
Take 8 of New Zealand's white big ear rabbits as experimental animal, female dual-purpose, be divided at random 2 groups, carry out the test of medicine-feeding part skin and eye irritation, result of the test shows that ketoconazole foaming agent administration treated animal hematology and blood biochemical are learned index and matched group compares no significant difference, prompting ketoconazole dermatologic does not cause animal allergy and haemolysis, and the minimal irritation that produces is compared slighter with the shampoo of this product, unguentum, and has restorability.By observing the local excitation response situation that produces behind rabbit intact skin and the damaged skin multiple-contact ketoconazole foaming agent, find ketoconazole foaming agent to the rabbit skin histology without the obvious stimulation effect.
Get 40 of healthy male guinea pigs, be divided at random vehicle group, ketoconazole foaming agent group, positive controls, observe whether to cause allergic reaction after exciting, conclusion confirm ketoconazole foaming agent to Cavia porcellus without the effect of active sensitization of skin.
To sum up, the present invention can be with simpler, safety, but method is prepared the good long term storage of physical behavior, ketoconazole foaming agent safely and effectively cheaply.
The specific embodiment
Following embodiment only is to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1
| Composition | Consumption (g) |
| Ketoconazole | 2 |
| Dehydrated alcohol | 21 |
| Propylene glycol | 34.5 |
| Octadecanol | 1 |
| Polysorbate60 | 3 |
| Citric acid/potassium citrate buffer | 0.5 |
| Water | 28 |
| Tetrafluoroethane | 10 |
Take by weighing dehydrated alcohol, mixed with propylene glycol evenly as solvent, keep 50～60 ℃ of temperature, for subsequent use.
With octadecanol, add, 60 ℃ of stirrings make dissolve complete, keep 50～60 ℃ of temperature, and are for subsequent use.
Take by weighing ketoconazole, add in the above solvent, make dissolve complete, make pure phase.
Take by weighing in polysorbate60, the citrate buffer adding prescription water gaging, make dissolve complete, make water.
Keep 50～60 ℃ of temperature, water slowly adds pure phase.
Keep temperature 50 C, stirred 30 minutes, stopped heating continues stirring until approximately 40 ℃.Fill, sealing, gland.
Fill propellant.
Citrate buffer compound method: get 10% liquor kalii citratis, use 10% citric acid soln, regulate pH value to 7.0.
Embodiment 2
| Composition | Consumption (g) |
| Ketoconazole | 2 |
| Dehydrated alcohol | 25 |
| Propylene glycol | 30 |
| Hexadecanol | 0.5 |
| Polysorbate60 | 2 |
| Citric acid/potassium citrate buffer | 0.5 |
| Water | 30 |
| Difluoroethane | 10 |
Take by weighing dehydrated alcohol, mixed with propylene glycol evenly as solvent, keep 40 ℃ of temperature, for subsequent use.
With octadecanol, add, 60 ℃ of stirrings make dissolve complete, keep 40 ℃ of temperature, and are for subsequent use.
Take by weighing ketoconazole, add in the above solvent, make dissolve complete, make pure phase.
Take by weighing in polysorbate60, the citrate buffer adding prescription water gaging, make dissolve complete, make water.
Keep 40 ℃ of temperature, water slowly adds pure phase.
Keep 40 ℃ of temperature, stirred 1 hour.
Fill, sealing, gland.
Fill propellant.
Citrate buffer compound method: with embodiment 1.
The sample no significant difference that the sample state that is prepared into by embodiment 2 methods and embodiment 1 are prepared into.
Embodiment 3
| Composition | Consumption (g) |
| Ketoconazole | 2 |
| Dehydrated alcohol | 35 |
| Glycerol | 20 |
| Hexadecanol | 2 |
| Polysorbate60 | 3 |
| Citric acid/potassium citrate buffer | 0.5 |
| Water | 27.5 |
| Tetrafluoroethane | 10 |
Take by weighing dehydrated alcohol, mixed with propylene glycol evenly as solvent, keep 40 ℃ of temperature, for subsequent use.
With octadecanol, add, 60 ℃ of stirrings make dissolve complete, keep 40 ℃ of temperature, and are for subsequent use.
Take by weighing ketoconazole, add in the above solvent, make dissolve complete, make pure phase.
Take by weighing in polysorbate60, the citrate buffer adding prescription water gaging, make dissolve complete, make water.
Keep 40 ℃ of temperature, water slowly adds pure phase.
Keep 40 ℃ of temperature, stirred 1 hour.
Fill, sealing, gland.
Fill propellant.
Citrate buffer compound method: with embodiment 1.
Embodiment 4
The product of above example 3 is detected according to the quality standard of working out, and the result is as follows:
Claims (7)
1. medicinal foam of ketoconazole, formed by principal agent ketoconazole and foam carrier, it is characterized in that, described carrier comprises mixture, tetrafluoroethane, foam support composition, surfactant and water and the buffer salt of ethanol and a kind of short chain polyhydric alcohol, forms with following ratio:
Wherein, described short chain polyhydric alcohol is propylene glycol and glycerol, and described surfactant is polysorbate60, polysorbate65, Tween 80 and polyoxyethylene castor oil.
2. the medicinal foam of ketoconazole as claimed in claim 1, the amount that the consumption of the organic solvent ethanol in its foam carrier accounts for total composition is 10%～40% (w/w), the polyhydric alcohol consumption accounts for 20%～45% (w/w) of total composition.
3. the medicinal foam of ketoconazole as claimed in claim 1, the consumption of the organic solvent ethanol in its foam carrier is 20%～30% (w/w), the consumption of polyhydric alcohol is 30%～40% (w/w).
4. the medicinal foam of ketoconazole as claimed in claim 1, wherein said foam support composition comprises octadecanol, hexadecanol, triethanolamine, diethanolamine, paraffin, Cera Flava, cocoa butter, Oleum Linderae, oleum sapii.
5. the medicinal foam of ketoconazole as claimed in claim 1, the consumption of wherein said tetrafluoroethane is 5%～10% (w/w).
6. the medicinal foam of ketoconazole as claimed in claim 1, the consumption of wherein said water is 20%～40% (w/w).
7. the medicinal foam of ketoconazole as claimed in claim 1, wherein said buffer salt comprises phosphate, acetate, citrate, carbonate, borate, tartrate.
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| CN 200910081689 CN101856328B (en) | 2009-04-09 | 2009-04-09 | Ketoconazole foaming agent and preparation method thereof |
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| CN 200910081689 CN101856328B (en) | 2009-04-09 | 2009-04-09 | Ketoconazole foaming agent and preparation method thereof |
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| CN101856328B true CN101856328B (en) | 2013-01-30 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525885B (en) * | 2011-11-21 | 2017-06-27 | 程雪翔 | A kind of Ketoconazole gel and preparation method thereof |
| CN104490782B (en) * | 2015-01-20 | 2017-04-12 | 北京康蒂尼药业有限公司 | Temperature control foaming agent for external use, making method thereof and application thereof |
| CN105770237B (en) * | 2016-04-22 | 2018-01-26 | 广东红珊瑚药业有限公司 | It is a kind of that there is antipruritic, anti-inflammatory effect foaming agent and preparation method thereof |
| CN107137352B (en) * | 2017-05-31 | 2020-05-22 | 北京兴源联合医药科技有限公司 | Novel foaming agent |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10117501A1 (en) * | 2001-04-07 | 2002-10-17 | Cognis Deutschland Gmbh | Washing composition, useful in cosmetic and/or pharmaceutical preparations such as hair shampoos and foam baths, comprises an alkyl or alkenyl oligoglycoside, an anionic surfactant and a mineral oil |
| CN101342369A (en) * | 2008-08-20 | 2009-01-14 | 周小萍 | Safety environment-friendly type medicinal propellant |
-
2009
- 2009-04-09 CN CN 200910081689 patent/CN101856328B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10117501A1 (en) * | 2001-04-07 | 2002-10-17 | Cognis Deutschland Gmbh | Washing composition, useful in cosmetic and/or pharmaceutical preparations such as hair shampoos and foam baths, comprises an alkyl or alkenyl oligoglycoside, an anionic surfactant and a mineral oil |
| CN101342369A (en) * | 2008-08-20 | 2009-01-14 | 周小萍 | Safety environment-friendly type medicinal propellant |
Non-Patent Citations (2)
| Title |
|---|
| 孙延萍等.酮康唑洗剂致接触性皮炎1例.《中国药师》.2000,第3卷(第6期),第356页. * |
| 施仲香等.脂溢性皮炎研究进展.《中国麻风皮肤病杂志》.2006,第22卷(第6期),第489-491页. * |
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| CN101856328A (en) | 2010-10-13 |
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