CN101249095B - Preparation of emulsifiable paste for containing decoloring agent, tretinoin and skinniness steroids - Google Patents
Preparation of emulsifiable paste for containing decoloring agent, tretinoin and skinniness steroids Download PDFInfo
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- CN101249095B CN101249095B CN2007100928091A CN200710092809A CN101249095B CN 101249095 B CN101249095 B CN 101249095B CN 2007100928091 A CN2007100928091 A CN 2007100928091A CN 200710092809 A CN200710092809 A CN 200710092809A CN 101249095 B CN101249095 B CN 101249095B
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Abstract
The invention discloses a preparation method of cream containing decolorant, tretinoin and corticosteroids. The cream prepared by the method has good uniformity and stability. The method facilitates the quality control of the cream during the production and ensures the validity and safety of the cream product.
Description
Technical field:
The invention belongs to the preparation method field of pharmaceutical preparation, be specifically related to contain the preparation of the emulsifiable paste of hydroquinone, tretinoin, corticosteroid material and their derivants.
Technical background:
Chloasma also claims chloasma hepaticum, claims " butterfly spot " again, is a kind of common hyperpigmentation dermatoses, good sending out in facial solar radiation position, as buccal, forehead, upper lip, nose and chin.Chloasma is butterfly and distributes, and principal character is that the pigment symmetry is excessively calm, and out-of-shape, color are shallow to brown.
Chloasma pathogeny complexity, real pathogenic factor is still not fully aware of at present.It is generally acknowledged that chloasma is that a kind of microcirculation function that causes because of multiple reason in the body is unbalance, the metabolism of pigment disorder finds expression in facial a kind of chronic functional disease.The morbidity of this disease is slower, forms gradually, and what have just forms the speckle that is visible to the naked eye for the several years.Melanic generation is directly proportional with the activity of Tyrosinase, and the activity of Tyrosinase is high more, and the melanin of generation is just many more.Therefore human face's epidermis is the thinnest, and blood capillary is the abundantest, and when the physiological function disorder appearred in organ or internal organs, the formation of mottle will find expression in face.In addition, long-term ultraviolet radiation, the abuse of cosmetics, the endocrine disturbance, acid base imbalance also can cause the generation of chloasma in the body.
The crowd is based on the women in the chloasma morbidity, and the highest with women's sickness rate of marrying later.In China, the sickness rate of chloasma is about 10% according to statistics.Though chloasma is superficial, do not influence the health status of body yet, because it is long at face, greatly influenced appearance U.S. of women.Particularly along with social progress, the raising of economic civilization level, increasing women is considered as a most important link to appearance U.S.A, and chloasma has become and has perplexed most one of cosmetic problem of women, and its puzzlement degree is only second to obesity.
Hydroquinone claims hydroquinone again, is a kind of depigmenting agent of the most normal use, and adjustable being assigned in cream or the lotion is widely used in treatment chloasma, freckle and cutaneous pigmentation.Hydroquinone can suppress melanosome formation and promote its decomposition, and its decolouring mechanism is thought: (1) hydroquinone is more suitable than tyrosine itself as the substrate of tryrosinase (TYR), and its decolouring mechanism is relevant with competition TYR activity; (2) another viewpoint thinks that hydroquinone decolouring essence is the cytotoxicity of TYR mediation.The hydroquinone molecule is little, easily diffuses into chromatophorous melanosome, and as the inhibitor of tryrosinase, melanocyte capable of blocking generates one or more steps of approach.Simultaneously, hydroquinone makes cell membrane lipid generation peroxidating behind the virose semiquinone base of oxidized generation thing under the tryrosinase effect, and cell membrane is destructurized, causes cell death.The variable concentrations hydroquinone, the mechanism of its decolouring may be different, and to suppress cheese ammonia (sour enzyme) activity, high concentration mainly is a cytotoxicity during low concentration.So it is many clinically with 1.5%～4% concentration.＞5% concentration might cause the danger of irreversibility leukoderma.
Because hydroquinone unstable chemcial property, developed the esters derivative of hydroquinone now: the hydroquinone ester, hydroquinone ester character is more stable than hydroquinone, as hydroquinone monocarboxylic acid esters (Hydroquinone Monoester): as hydroquinone monoacetate, hydroquinone monoleate, hydroquinone monostearate, hydroquinone list valerate, hydroquinone list propanoic acid fat etc., hydroquinone double carboxy acid ester (hydroquinone diester) is as the two ethyl esters of hydroquinone, hydroquinone dioleic acid ester, the two hard fatty acid esters of hydroquinone, the two propanoic acid fat of hydroquinone etc.Its decolouring mechanism of the hydroquinone ester of variable concentrations may be different, based on the restraint of tyrosinase activity, mainly are cytotoxicity during high concentration during low concentration.Fatty acid chain carbon number＞3 of hydroquinone mono fattya nd ester o'clock have good stability; Carbon number＜8 o'clock are skin absorbs easily, can promptly be hydrolyzed in skin and discharge hydroquinone performance decolorization, and its hydrolysis rate increases with fatty acid chain and slows down.They can be considered the prodrug of hydroquinone.
Arbutin (Arbutin), be called vegetalitas hydroquinone glycocide (phytohydroquinone glueosidel) again, being a kind of natural existence form of hydroquinone, is the natural activity monomeric substance with decolorization from separating from the leaf of Ericaceae manzanita Folium Vaccinii vitis-idaeae.It suppresses melanin and forms by to the cytotoxic effect of melanocyte with to the obstruction mechanism of tryrosinase.This product also plays effects such as skin nutrition, skin care be wrinkle resistant except that the effect of the bright skin of Pear Power, give the care of skin with pure natural, and compare stable chemical performance with hydroquinone, cytotoxicity is little, and is safe in utilization, therefore, the primary raw material medicine that is considered to the 21 century freckle removing and whitening.
Arbutin also has antitussive, eliminates the phlegm, antiinflammatory, physiologically active such as antibiotic, thereby is used as uses such as antitussive medicine and urethra disinfectant, also uses as food supplement abroad, and certain clinical practice potentiality are arranged.
What traditional arbutin product used is β-arbutin, its chemistry 4-hydroxyphenyl-β by name-D-pyrans heteroside.And present Japanese scholar by research relatively, finds that the intensity of alpha-arbutin restraint of tyrosinase and safety are better than the present β-arbutin that is widely used just gradually greatly.Alpha-arbutin is the epimer of β-arbutin, its chemistry 4-hydroxyphenyl-α by name-D-pyranglucoside, and its oxygen glycosidic bond is compared just in time opposite in spatial direction with the direction of β-arbutin.Test shows that the intensity of alpha-arbutin restraint of tyrosinase is 10 times of β-arbutin, and is better than other active component of whitening at present, as adopting kojic acid that yeast cultivates and vitamin C etc.Alpha-arbutin is not seen the growth that suppresses cell under higher concentration, and effective inhibition has then appearred in the β-arbutin of same concentrations, and obviously alpha-arbutin has higher safety than β-arbutin.In a word, the effectiveness of alpha-arbutin and safety are all than β-arbutin height.
The source of alpha-arbutin and β-arbutin is different fully.β-arbutin can prepare by plant extract, culture plant cell and three kinds of methods of synthetic.And alpha-arbutin generally can only carry out sugared transfer reaction by the enzyme of different microorganisms, allows the hydroquinone of the glucose of a part and a part in conjunction with forming single alpha-arbutin.In preparation arbutin process, need utilize hydroquinone, thereby cause the situation of residual 0.2% hydroquinone of arbutin more.For encouraging the whitening and speckle dispelling skin care item to adopt arbutin,, the U.S. allowed 0.2% with interior residual volume so should listing the hydroquinone of using the forbidden zone in as functional additive.
Arbutin has been widely used in fields such as cosmetics, pharmacy at present.
In cosmetics,, desalinate, dispel freckle, chloasma, melanin pigmentation, acne and the senile plaque of skin gradually to the efficient whitening and speckle dispelling of skin energy.Characteristics are nonirritant, sensitization, and ultraviolet radiation is had safety and stability, with each component of cosmetics excellent compatibility are arranged, help realizing whitening, speckle dispelling, preserve moisture, softness, wrinkle removal, anti-inflammatory effect.The 90's of 20th century are at first released as the cosmetics whitening agent by Japanese Shiseido Co., Ltd., U.S. CTFA is written into U.S.'s cosmetics component compilation with the name of " Arbutusextarct ", and developed country is almost monopolized by arbutin in whitening and skin-protecting market at present.
Present β-arbutin adds consumption and is about 3% in cosmetics.Less than this amount to the inhibitory action of the catalytic activity of tryrosinase in the skin a little less than, whitening effect is not obvious.Can obviously suppress or thereby damaging cells growth produces cytotoxicity greater than this content, allow the normal skin decolouring, and its cytotoxicity presents dose-effect relationship, so the consumption of β-arbutin and its safety there are certain relation.
Alpha-arbutin is as up-to-date beauty treatment brightening agent, and world-famous brand is just brought into use.Peutaharm had released the new viable skin brightening agent that contains alpha-arbutin in 2002, and Japanese Shiseido has also been released the serial cosmetics that contains the alpha-arbutin composition.Find that after deliberation alpha-arbutin has a significant effect to the formed cicatrix of ultraviolet burn, its chemical property is also more stable than β-arbutin effect, can join more easily in the various bright skin cosmetics of whitening.PH value is the most stable between 3.5-6.5, and recommending addition is between 0.2%～5%, can be used in all prescriptions.
Tretinoin is the metabolic intermediate of vitamin A, mainly influences the growth of bone and promotes metabolism effects such as epithelial hyperplasia, differentiation, cutin dissolving.Be used for the treatment of diseases such as acne vulgaris, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, follicular keratosis, squamous cell carcinoma and melanoma.By promoting effects such as metabolism such as epithelial hyperplasia, differentiation, cutin dissolving, make pigment slowly be distributed to keratinocyte, hinder the pigment transhipment, quicken epithelium and upgrade, quicken pigment and disappear.UVB in the sunlight and UVA can strengthen the oncogenic function of tretinoin.These act in the pigmentation mice and are confirmed; Melanin pigmentation can not avoid 0.05% tretinoin to see the enhanced effect of photic cancer ability.Although the carcinogenesis of tretinoin is confirmed obviously that at human body the patient should avoid being exposed in the sunlight, perhaps other artificial ultraviolet during external hydrogen dimension fluorine emulsifiable paste as far as possible.Tretinoin is a kind of teratogen, orally may cause EF death, changes fetal development, cause congenital malformation, and significantly neural disappearance, but the human data confirms as yet.Tretinoin can oral or external, and oral 10mg/ time, 2～3 times/day.External, 0.05%～0.1% cream or ointment.Embrocate the part, 1～2 time/day.
Tretinoin (Tretinoin) claim retinoic acid again, and it can suppress epidermis cell hyperkeratosis, cell proliferation, has antineoplastic action; Can also suppress smegma, reduce or the removing skin surface pathogenic bacterium relevant, to reduce the inflammatory reaction of acne with acne; But resisting age of skin makes skin tender, and wrinkle reduces, and excessively calm color element goes down; Can suppress epidermal hyperplasia, regulate immunologic function.Be used for the treatment of diseases such as acne, chloasma, psoriasis, abnormal cutaneous keratinization, photoaging dermatoses, cutaneous tumor.
The outer time spent of glucocorticoid, be usually used in eczema (particularly infantile eczema), neurodermatitis, skin pruritus, contact dermatitis, psoriasis, discoid lupus erythematosus, lichen planus, external otitis, solar dermatitis etc. as hydrocortisone, cortisone, prednisone, meticortelone, methyl meticortelone, omcilon, dexamethasone, betamethasone, fluocinonide etc.Prove effective rapidly, use low concentration (0.025%) that obvious curative effects is promptly arranged as potent glucocorticoids such as fluocinonides.Fluocinonide influences melanocyte secretion melanocyte by reducing secretory function.Glucocorticoid since fat-soluble good, fusing point is lower, this medicines part of a lot of externals can absorb through skin.After stopping the external glucocorticoid, can produce reversible because of the insufficient inhibitory action of glucose 17-hydroxy-11-dehydrocorticosterone to hypothalamus-hypophysis-hypothalamic pituitary adrenal axis (HPA).During the external glucocorticoid treatment, absorb symptoms such as to produce cotton-padded mattress syndrome, high sugar, glycosuria through system.If it is very obvious that hpa axis suppresses, should stop using.Generally speaking, stop the external glucocorticoid, can recover the function of hpa axis.
Many at present clinically compound preparations, for example prescription of hydroquinone+tretinoin and derivant+corticosteroid thereof with hydroquinone.Its formula concentration commonly used has: 1. 4% hydroquinone and 0.05% betamethasone; 2. 2% hydroquinone adds 0.05% tretinoin and adds 0.05% dexamethasone; 3. 1.5% hydroquinone adds 0.1% tretinoin and adds 0.1% dexamethasone; 4. hydroquinone 4% adds retinoic acid 0.05% and adds fluocinolone acetonide 0.01% (listing).Tretinoin can promote epidermis cell upgrade to assist hydroquinone to penetrate epidermis in the compound preparation, but concentration slightly Da Yi make skin rubefaction.It is synthetic that 17-hydroxy-11-dehydrocorticosterone suppresses melanocyte by the metabolic activity that reduces epidermis cell, prevents the stimulation of hydroquinone, tretinoin and derivant thereof in addition.
U.S. Pat 5,656,672 disclose a kind of preparation method of using retinal as the water-in-oil emulsion of active component.This emulsion comprises: comprise the organic solvent (for example aliphatic aliphatic alcohol) of at least a retinal and the oil phase of optional lipotropy additive; The water of the hydrophilic additive that comprises water and choose wantonly; Reagent with emulsifying water in oil phase.Oil phase and water are independent preparations, and water is joined in the oil phase, add subsequently to comprise retinol and its solvent mutually.
U.S. Pat 5,660,837 disclose a kind of preparation method of pharmaceutical preparation of oil-in-water emulsion form.The step of this method comprises: at room temperature add stable emulsifying surface activity medicine and optimum conventional surfactants in oil-water two-phase system; Make stable emulsifying surface activity medicine in balance at the interface; Adding can be given the reagent of final preparation isotonicity; And carry out homogenize by high pressure technique.
U.S. Pat 5,976,555 disclose skin care compositions and methods.Oil-in-water emulsion substrate comprises: retinoid (retinoid); The mixture of the Polyethylene Glycol ethers of the general or octadecanol of cetearyl alcohol (ceteary alcobol) and cetearyl alcohol sugar; Spermol, octadecanol and its mixture; Light, exsiccant absorbable oil; With a large amount of (substantive) softening agent oils or paraffin.
U.S. Pat 6,080,393 disclose a kind of skin care compositions and methods: comprise the oil-in-water emulsion that contains the retinoid for the treatment of effective dose; Wherein oil phase comprises the oil-soluble Hangzhoupro oxygen agent of one or more oils and at least a effective dose; And wherein said composition comprises corticosteroid.
U.S. Pat 2003033876, a kind of skin care compositions and methods is disclosed: the oil-in-water emulsifiable paste that includes tretinoin, hydroquinone, fluocinonide, be used for the treatment of the cutaneous pigmentation disease, its preparation method is at a certain temperature, and tretinoin, fluocinonide, hydroquinone are directly added successively.According to the emulsifiable paste that the method and the experiment condition of this patent are prepared, its tretinoin and fluocinonide content uniformity are not ideal enough, thereby can not judge whether tretinoin and fluocinonide are enough stablized.
Chinese patent CN200510081635 discloses one group of compositions of mainly treating acne, this disclosure of the Invention one group of compositions of mainly treating a skin ulcer.It contains adapalene and/or Aloe and/or propolis.In description its preparation technology have a step with the adapalene of recipe quantity (crossing 120 mesh sieves in advance) and PEG-400 in appropriate containers, grind even, stand-by.The emulsifiable paste of preparing according to the method and the experiment condition of this patent though the content uniformity of its tretinoin is slightly better than US2003033876, but still not ideal enough, and has added and grinding step has been arranged, the expense that wastes time and energy energy.
Top several patents has all been mentioned the preparation method of emulsifiable paste, but just contain the emulsifiable paste of hydroquinones, tretinoin, cortical steroid material and their derivant, operation by experiment, find its preparation method and imperfection, they all have shortcomings such as the uneven and/or preparation effort of the content of tretinoin and corticosteroid material, have a strong impact on the quality control of production process emulsifiable paste, and the emulsifiable paste that adopts the present invention to prepare can improve these shortcomings greatly, more helps the quality control of product.
Summary of the invention
The invention provides a kind of preparation method of preparation of the emulsifiable paste that contains depigmenting agent, tretinoin, corticosteroid material and their derivants, this method comprises following process:
(a), form water with water and at least a hydrophilic compound;
(b) at least two kinds of hydrophobic compounds are mixed, form nonaqueous phase;
(c) water and nonaqueous phase are mixed, form biphase mixture;
(d) add at least a emulsifying agent in biphase mixture, make blank emulsifiable paste;
(e) antioxidant, tretinoin and cortical steroid material or their derivant are joined in the Polyethylene Glycol, be dissolving or/and homogeneously dispersed state, and then join in the blank emulsifiable paste of (d), homogenize obtains mixture;
(f) antioxidant and depigmenting agent or derivatives thereof are joined in the mixture of step (e), stir, obtain emulsifiable paste.
The emulsifiable paste that method of the present invention obtains is compared finer and smoother with the emulsifiable paste that the existing method that emulsifying agent is joined the preparation ointment in water or the nonaqueous phase obtains.Concerning being used for anti-Pigmented emulsifiable paste, tretinoin, cortical steroid content of material are very low, and, tretinoin, cortical steroid meet light, thermally labile because being insoluble to oil phase, aqueous phase substrate and the tretinoin material of common preparation emulsifiable paste, in the preparation, stability and content uniformity, become the key of investigating preparation method: if adopt tretinoin and the direct addition method of cortical steroid to prepare emulsifiable paste, temperature is too low, content uniformity is bad, temperature is too high, and stability is bad.For this reason, the present invention in experiment, adopted with tretinoin be dissolved in, cortical steroid is dispersed in the polyethylene glycols solution, thereby realized the emulsifiable paste that obtains under lower temperature, the content of its tretinoin, cortical steroid material has better homogeneity and stability.
Emulsifiable paste by the inventive method preparation can be to be used for the treatment of any dermatosis.Can will resist a skin ulcer, anticancer disease, antibiotic, anti-inflammatory agent, hormone, antifungal and analgesic activities agent to cover in the preparation method of the present invention.
The example of corticosteroid is fluocinonide (fluocinolone acetonide), and the example of keratolytic is a tretinoin, and the example of depigmenting agent is hydroquinone, hydroquinone list valerate, hydroquinone diacetate, Arbutin.
In specific embodiment, emulsifiable paste of the present invention comprises hydroquinone, tretinoin and fluocinonide.
In a specific embodiment, the present invention also provides a kind of ointment, and it comprises inactive ingredients butylated hydroxytoluene, hexadecanol, octadecanol, citric acid, glycerol, PEG400, Magnesiumaluminumsilicate, methyl hydroxybenzoate, propylparaben, pure water, sodium pyrosulfite and stearic acid.
In a specific embodiment, ointment is to comprise fluocinonide, hydroquinone, tretinoin and its combination carrier as active component.It is with standard depigmenting agent hydroquinone and tretinoin and the partial Pharmaceutical composition that can be used as the anti-cutaneous pigmentation of the corticosteroid coupling that independent preparation uses.
In other three specific embodiments, ointment is to comprise fluocinonide, tretinoin and hydroquinone list valerate respectively; Fluocinonide, tretinoin and hydroquinone diacetate; Fluocinonide, tretinoin and Arbutin; Its combination is as the carrier of active component.It is with depigmenting agent and tretinoin and the partial Pharmaceutical composition that can be used as the anti-cutaneous pigmentation of the corticosteroid coupling that independent preparation uses.
An advantage of the inventive method is that by preparation method of the present invention, the content uniformity of tretinoin and fluocinonide will be much better than the method for reporting in the past.
Another advantage of the inventive method is, comprises that by the control component tretinoin, hydroquinone add fashionable temperature, and adds antioxidant, makes ointment can not change dark yellow or brown into, thereby forms the more desirable product of color.
Emulsifiable paste is that water and oil phase component form Emulsion by emulsification, is the dosage form of semi-solid paste at normal temperatures.Usually add emulsifying agent or surfactant and some auxiliary emulsifiers,, form stable Emulsion to promote the mixing of water and oil phase.Can add some chemical compounds in addition as effects such as antioxidant, antiseptic.
Substrate and adjuvant that the preparation emulsifiable paste is selected for use generally are known in this area, representative instance comprises hexadecanol, octadecanol, stearic acid, lanoline, paraffin, liquid paraffin, glycerol, ethanol, EDTA, parabens, zinc oxide, titanium dioxide, benzoic acid, hydroxy methocel, dimethyl sulfoxine, Polyethylene Glycol, citric acid.
The present invention relates to a kind of method of emulsifiable paste matrix for preparing as the excipient of one or more pharmacologically active agents that is used for the dermatological purposes.Method of the present invention comprises the adding and the blended concrete sequencing of ointment component.Oil phase or hydrophilic component are comprised that water mixes, can utilize heating to promote dissolving and dissolubility, with preparation solution.Oil phase or hydrophobic components are mixed respectively, can utilize heating to promote to mix and homogenize.
With hydrophilic solution and mixing of lipophile solution and allotment, then, in the good mixture of whole mediations, add one or more emulsifying agent then, prepare blank emulsifiable paste.One or more forms of pharmacologically active agents is dissolved in the Polyethylene Glycol, joins then in the blank emulsifiable paste, to prepare dermatological ointment of the present invention.
The temperature of heating lipophile and hydrophilic solution will be enough to promote the acquisition of homogeneous phase solution.Usually, the lower elevated temperature that preferably has longer incorporation time.
According to method of the present invention, at the hydrophilic chemical compound described in the step (a), be known in the art, for materials such as certain hydrophilic thickening agent, wetting agent, coemulsifier are arranged.
Hydrophilic thickening agent comprises hydroxy methocel, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, carbomer, silicon dioxide, silicone rubber, aluminium-magnesium silicate etc., preferred aluminium-magnesium silicate, silicon dioxide; Wetting agent comprises monohydric alcohol and polyhydric alcohol, for example, and ethanol, isopropyl alcohol, propylene glycol, glycerol, Sorbitol, 2 one methyl cellosolves, diethylene glycol, ethylene glycol, hexanediol, mannitol propylene glycol; Ethers is diethyl or dipropyl ether for example; Polyethylene glycols and methoxyl group polyethylene glycol oxide class; Molecular weight is 200 to 20,00 Polyethylene Glycol; The polyoxyethylene glycerol class; Polyethylene glycol oxide; Sorbitol; With diacetyl stearyl ether etc., preferably glycerine; Coemulsifier is the material that emulsification is had certain help, therefore, every emulsifying agent all can be used as coemulsifier, and some thickening agents are because increase emulsifiable paste viscosity, stablized emulsification, so also can be used as coemulsifier, as aluminium-magnesium silicate, silicon dioxide, silicone oil etc., preferred aluminium-magnesium silicate.Polyethylene Glycol for another example, has thickening, auxiliary emulsification again at its existing certain moisture-keeping function, and therefore, above-mentioned classification just mainly acts on the classification of being done by it, and does not mean that absolute qualification.
Hydrophilic chemical compound of the present invention also includes certain hydrophilic antiseptic, as Buddhist nun's methyl ester, Buddhist nun's ethyl ester, benzyl alcohol, benzoic acid, dichloro benzyl alcohol, geramine, bromo geramine etc., and preferred Buddhist nun's methyl ester.
When water and at least a hydrophilic compound are formed water, should note making hydrophilic chemical compound fully dissolving, aquation or be uniformly dispersed.The concrete state of hydrophilic chemical compound in water is by this Substance Properties decision.
At the hydrophobic compound described in the step (b), be known in the art, as vaseline class substrate, hydrocarbon base, fat and miscella substrate, silicone substrate and absorption bases.Vaseline class substrate: comprise vaseline, hard paraffin and liquid paraffin, ceresine and microwax.This class substrate can form the oil film of one deck exquisiteness at skin surface, prevents the evaporation of moisture, helps cuticular aquation, and generally speaking vaseline class substrate does not have physiologically active, but proves recently and also contain the material that trace can make cell effect in the vaseline.The vaseline that Huang, white two kinds of colors are arranged, white vaseline are to be made through bleaching by Yellow Vaselin.Hard paraffin and microwax chemical property are similar to Yellow Vaselin, just do not have liquid component.In preparation industry, vaseline softening extremely important must make vaseline softening when the pumping of mixing, grinding and material, patient's embrocating action and also can make substrate softening when using the local topical preparation.Under the effect of shearing force, the denseness of vaseline reduces, and this is because the three dimensional structure of substrate is destroyed.In order to change the denseness of vaseline, generally can add for example low-molecular-weight polyisobutylene of liquid paraffin, lanoline and some polymer.Dilute vaseline with liquid paraffin, the degree of its rheological parameters and dilution is linear.The different material of human is arranged, and for example: oil, wax, lanoline, multiple emulsion l surfactant, emulsion solution wait and dilute vaseline and carry out ftheoloqical measurements, and the estimation of the parameter of result and user matches.
Hydrocarbon base often share multiple substrate: be made up of cera alba, hard paraffin, Alcohol Cetylicuset Stearylicus and vaseline as paraffin Ointment substrate.Ceresine is a kind of mineral Wax, mainly by C
35~ C
55Saturated hydrocarbons is formed.International market commodity Ceresin is the mixture of ceresine and hard paraffin.Ceresine and commodity Ceresin contain oily substance in matrix structure, but can not separate.International market commodity Plastibase (Jelene is produced by Shi Guibao company) is a series of hydrocarbon mixture, wherein contains liquid paraffin and hard paraffin (molecular weight is 1300), and the major part of liquid paraffin is in the gap of skeleton.This product softness, lubricated, evenly, be neutral, colourless, tasteless, nonirritant, no anaphylaxis, similar gels, its fusing point is at 90 ~ 91 ℃, can both keep ideal denseness for 15 ~ 60 ℃ in temperature, be very stable substrate, be suitable for various prescription designs, under body temperature, can combine closely, lubricious sense is arranged but not have greasy feeling, very easily flush away with skin.This product and medicine be difficult for to produce incompatibility, can make substrate become softer but mix with Mentholum and wintergreen oil.Its method for making is as follows: when temperature is higher, adds in the mineral oil with low molecular weight polyethylene, and then hurried cooling.Polyethylene is the bigger hydrocarbon polymer of molecular weight, in certain molecular weight ranges, though the structure of molecule is a fluid state, but the semi-solid preparation substrate that typical skin is used.This construction features helps medicine and discharge (with the vaseline contrast) from this type of substrate.
Fat and miscella substrate: ointment base also contains mixed vegetable oil sometimes, generally has: saturated and unsaturated fatty acid, and single, two or triglyceride.Usually used vegetable oil comprises Oleum Arachidis hypogaeae semen, Oleum sesami, olive oil, Oleum Gossypii semen, almond oil, Semen Maydis oil, peach kernel oil.These oily denseness are relevant with the iodine value and the degree of unsaturation of glyceride.This class oil is met situations such as light, air, high temperature, easily oxidative degradation.Trace metal ion often plays catalytic action to oxidation reaction.Therefore with above-mentioned oils and fats during as substrate, generally to add a spot of antioxidant, for example butyl-hydroxy-methylbenzene (BHT), butyl-BHA (BHA), do not have the stone propyl propionate (or to add chelating agen, as EDTA), but should notice that antioxidant can cause incompatibility, can make some patients that anaphylaxis takes place.In a word, vegetable oil and animal oil have two big shortcomings, and the first is oxidation very easily, and it two is that water absorption is limited, therefore at present at skin with seldom using in the topical formulations.
Silicone substrate, silicone has similar physical property to hydrocarbon base, and most important chemical compound is that (or claim dimethyl polysiloxane, Dimethylpolysiloxanes), its flowability is fine, and the basic structure formula is CH for dimethicone
3[Si (CH
3)
2O] Si (CH
3)
2, in each construction unit, methyl all links to each other with silicon atom with oxygen atom.The consistency range broad of silicone, viscosity commonly used in ointment are at 50-1, and 000 centistoke has excellent water-proof function, and surface tension is very little, and to oxygen or thermally-stabilised, the main preparation protectiveness emulsifiable paste that is used as protects skin to avoid the invasion and attack of water solublity stimulus object.In emulsifiable paste, lotion and ointment, contain 10% ~ 30% dimethicone, can prevent and treat diaper rash and decubital ulcer.It is best to add 30% dimethicone protective effect in vaseline.In addition, methyl phenyl silicone oil (methyl phenyl polysiloxane, the commodity of international market are called DowCorning DC556) dissolves in 95% ethanol, and is better with the compatibility of organic substance.
Absorption bases: absorption bases has hydrophilic (suction) property, can absorb moisture and form W/O emulsion-type substrate and still keep its semi-solid state.Generally speaking, this type of substrate all is anhydrous substrate, can absorb the moisture of itself several times of amount.By alkyl and can be with alkyl miscible and material that have polar group form, can play W/O emulsion-type emulsifying agent.Its polar group can be carboxyl, sulfonic group, carboxyl or ether.The representative substrate of absorption bases has separator, cholesterol, lanosterol and other steroid, acetyl steroid or the esters of polyhydric alcohol (as span) of lanoline, lanoline.Below introduce lanoline and derivative eater thereof and related compound:
Anhydrous lanolin extracts purification, anhydrous smectic material from sheep's wool, mainly be made up of the fatty acid ester of cholesterol, lanosterol, aliphatic alcohol etc.This type of substrate water absorbing capacity is strong, and the water that can absorb two times of weight forms W/O Emulsion.Its emulsifying property is by high-molecular weight hydroxy acid diester, but also the someone claims lanoline to mix with alcohols material, can better keep its water absorption.
Several derivants of lanoline all can keep the inherent characteristics of lanoline, and other advantage is arranged.Liquid lanolin is the fractionated aqueous ester mixture of lanoline, is not clamminess on skin.Lanoline and reacting ethylene oxide can generate polyoxyethylene deriv liquid or solid, for example water miscible lanoline.Hydrogenated lanolin viscosity is not good, and water absorbing capacity is bigger by 50% than lanoline.Agnolin is to add 3 parts of water by 7 parts of lanolines to mix.
Lanonol is by after the lanoline saponification, and the part that will contain pure and mild cholesterol is separated and got.Contain and be less than 30% cholesterol, 10% ~ 13% isocholesterin also contains other steroid and triterpene alcohol; Can add 500 ~ 1000ppm butyl-BHA or butyl-hydroxy-methylbenzene as antioxidant.Lanonol is the good emulsifying agent, by its W/O Emulsion of making can be with storage blackening or produce bad smell at hot weather.In vaseline, add 5% lanonol, can absorb triple water, and Emulsion can not destroy by weak acid, add 16/18 mixed alcohols and can further make Emulsion stable.As the simple Ointment of British Pharmacopoeia, be by lanoline, hard paraffin, 16/18 mixed alcohols, white or Yellow Vaselin is formed, and this substrate such as can absorb at the water of weight.
Absorption bases such as lanonol or simple Ointment can form the oil layer of similar hydrocarbon base on skin surface, but comparatively speaking, its ability outline that suppresses moisture loss is weaker, but, the W/O ointment made from absorption bases can make horny layer aquation better, prolongs the time of skin absorbs moisture.
The preferred hexadecanol of hydrophobic compound, octadecanol, stearic acid or their any mixture described in the above-mentioned steps (b).
The described hydrophobic compound of this step also includes the antiseptic of certain hydrophobic compound, as Buddhist nun's methyl ester, Buddhist nun's ethyl ester, Buddhist nun's propyl ester, Buddhist nun's butyl ester, benzyl alcohol, benzoic acid, dichloro benzyl alcohol etc., and preferred Buddhist nun's propyl ester.
Step (c) is mixed water and nonaqueous phase, forms biphase mixture; This step can join oil phase with water, also oil phase can be joined water, but add the time, should keep certain temperature, this temperature should be higher than room temperature, lyophobic dust in the oil phase is not cooled off separate out, and generally is controlled at 50 ℃～100 ℃.
The described emulsifying agent of step (d) can be nonionic surfactant, cationic surface active agent, anionic surfactant, amphoteric surfactant.
Nonionic surfactant comprises: the monostearate sorbitan ester, tristerin, polysorbate, the poly alkyl alcohol ethene derivatives, fatty alcohol-polyoxyethylene ether, the C12-C18 aliphatic alcohol, ester and its ether, the aliphatic aliphatic alcohol is spermol or octadecanol or both mixture for example, aliphatic alcohol oxyethylation or bound to polyglycerol, the macrogol ester of fatty acid is polyglycol distearate for example, fatty acid esters of sorbitan oxyethylation or non-oxyethylation with trade name Tweens or Spans sale, the fatty acid ester of sucrose, the aliphatic ester derivatives of glucose is the methyl glucosamine sesquistearate for example, Arlacel 165 and Myrj52, aliphatic alcohol with 10 to 20 carbon atoms, aliphatic alcohol with 2 to 20 moles of ethylene oxide or expoxy propane condensation with 10 to 20 carbon atoms, the alkyl phenol that in alkyl chain, has 6 to 12 carbon atoms with 2 to 20 moles ethylene oxide condensation, the single fat acid and the 21 fatty vinegars of oxirane, the single fat acid and the 21 fatty vinegars of ethylene glycol, wherein fatty acid part comprises 10 to 20 carbon atoms, diethylene glycol, molecular weight is 200 to 6000 Polyethylene Glycol, molecular weight is 200 to 3000 propylene glycol, glycerol, Sorbitol, anhydro sorbitol, the polyethylene glycol oxide Sorbitol, polyethylene glycol oxide anhydro sorbitol and hydrophilic wax ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene fatty acid vinegar, the polyethylene glycol oxide sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene glycol fatty acid ester and polyol fatty acid ester.
The example of cationic emulsifier comprises various ammonium salt class emulsifying agents: triethanolamine, diethylamine, ethylenediamine, Dodecyl trimethyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, Tetradecyl Trimethyl Ammonium Bromide, hexadecyltrimethylammonium chloride, cetyl trimethyl ammonium bromide, octadecyl trimethyl ammonium chloride, the octadecyl trimethylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, tetramethyl ammonium chloride, 4 bromide, Methanaminium, N,N,N-trimethyl-, fluoride, tetramethyl-ammonium iodide, the tetramethyl ammonium hydrogen sulfate, the tetramethyl ammonium acetate, tetraethylammonium chloride, tetraethylammonium bromide, tetraethyl ammonium fluoride, tetraethyl ammonium iodide, the tetraethyl ammonium hydrogen sulfate, the tetraethyl ammonium acetate, 4-propyl ammonium chloride, 4-propyl bromide, the tetrapropyl ammonium fluoride, the tetrapropyl ammonium iodide, the tetrapropyl ammonium hydrogen sulfate, the tetrapropyl ammonium acetate, tetrabutylammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, the tetrabutylammonium acetate ammonium, the phenyl trimethyl ammonium chloride, the phenyl trimethylammonium bromide, trioctylphosphine methyl ammonium bromide, three nonyl ammonio methacrylates, three nonyl methyl ammonium bromide, three-cetyl ammonio methacrylate, tri-n-octyl methyl ammonium chloride, two eight alkyl-dimethyl ammonium chlorides, two dodecyl dimethyl ammonium chloride, methyl tripropyl ammonium chloride, methyltributylammonichloride chloride, methyl trioctylphosphine ammonium chloride, the butyl trimethyl ammonium chloride. the two alkyl-dimethyl based quaternary ammonium salts of different chain length.
The preferred triethanolamine of mentioned emulsifier.
Join in the biphase mixture at emulsifying agent, when making blank emulsifiable paste, should keep certain temperature, actual temp is generally remained between 48 ℃～80 ℃ by the fusing point decision of hydrophobic compound in the oil phase.When the blank emulsifiable paste of preparation, can use paddling process, high speed homogenization method, because the emulsion droplet of high speed homogenization method preparation is thin, mixing is more even, thus be main emulsifying means generally with the high speed homogenization method, auxiliary with paddling process.
Step (e) joins antioxidant, tretinoin and cortical steroid material or their derivant in the Polyethylene Glycol, is dissolving or/and homogeneously dispersed state, and then joins in (d), and homogenize obtains mixture; Antioxidant such as sodium sulfite, sodium sulfite, sodium pyrosulfite, potassium sulfite, vitamin C, two uncle's fourth hydroxy-methylbenzene phenol (BHT), tocopherol, Tocopheryl derivatives, as tocopheryl acetate, cysteine, glycine, gallic acid, gallic acid-derivate, as progallin A, propyl ester, glutathion, thioglycerol, tartaric acid, succinic acid, malic acid, citric acid, sodium citrate, ethylenediaminetetraacetic acid, sodium ethylene diamine tetracetate.In this step, preferred two uncle's fourth hydroxy-methylbenzene phenol (BHT) and citric acid.
The adding sequencing of antioxidant, tretinoin and cortical steroid material is unrestricted in this step, can earlier antioxidant be joined in the Polyethylene Glycol stir, ultrasonic, homogenizing is dissolved in antioxidant or is scattered in the Polyethylene Glycol, adds tretinoin and cortical steroid material or their derivant again; Also antioxidant, tretinoin and cortical steroid material or their derivant can be joined stirring, ultrasonic, homogenizing in the PEG400 simultaneously.A tretinoin can dissolve in 250 parts of Macrogol 200s or PEG400 or Macrogol 600 fully, the cortical steroid material can well-proportionedly be scattered in Macrogol 200 or PEG400 or the Macrogol 600 because crystal is very thin.
Step (f) joins antioxidant and depigmenting agent or derivatives thereof in the mixture of step (e), stirs, and obtains emulsifiable paste.
This step should be noted that the temperature when control adds antioxidant and depigmenting agent or derivatives thereof, for hydroquinone, because hydroquinone is subjected to thermally labile, so the temperature that adds is difficult for above 55 ℃, for hydroquinone list valerate, hydroquinone diacetate, Arbutin, though they are stablized than hydroquinone, adding temperature had better not be above 60 ℃.Antioxidant can be prior to depigmenting agent, or adds simultaneously, and antioxidant comprises the antioxidant kind of being mentioned in the step (e), preferred sodium pyrosulfite.
This invention also comprises can add some excipient; As spice, menthol for example; Opacifier is zinc oxide for example, Magnesiumaluminumsilicate and titanium dioxide; Softening agent; Coloring agent; Penetration enhancers or the like.
When adding spice, because spice all is that certain volatile material is arranged, so be preferably in the whole latter stage of preparation emulsifiable paste, temperature adds when dropping to below 40 ℃ again.Opacifier, softening agent, coloring agent, penetration enhancers can add in any step of the present invention.
Penetration enhancers can be interpreted as it: a kind of improve skin for the permeability of one or more activating agent so that material that can the transdermal application activating agent.The all cpds that is used to improve percutaneous permeability is known in this area.For example, the inferior maple (DMSO) of diformazan, dimethyl methyl ether amine (DMF) and N, N one dimethyl acetic acid amine (DMA), the inferior vitriol of decyl methyl, isopropyl myristate, oleic acid, Polyethylene Glycol mono laurate vinegar and 1 monobasic azepan one 2 ketone.
Preparation method of the present invention can also be applicable to the preparation of the emulsifiable paste of other all kinds of active components, as any known cytostatic agent, softening keratin agent, antibiotic and antimicrobial, NSAID (non-steroidal anti-inflammatory drug), local anesthetic, cortex steroidal class medicine, skin treating medicine etc.
Cytostatic agent comprises alkylating agent, enzyme inhibitor, hyperplastic inhibitory agent, DNA synthetic inhibitor, lytic agent, DNA intercalator, metabolic antagonist or the like.Reagent as illustration comprises steroid, taxol, ionomycin (ionomycin), Rhizoma Dysosmae Versipellis second is glycoside again, nitroso ureas is Asia urea nitrogen mustard (BCNU) slightly for example, daunorubicin (daunoxubicin), actinomycin D, meclorethamine, busulfan, CCNU, Me-CCNU, chlorambucil, actinomycin C (cactinomycin), carzinophillin, the fast quinoline of 6-chlorine, the fast quinoline of sulfur, fluorouracil, hydroxyurea, thioquanine, campothecin, mitomycin, hexamethylene nitrous arteries and veins (CCNU), methyl cyclohexane nitrous arteries and veins (Me-CCNU), speckle huge legendary turtle element, camptothecine, carboplatin, ricin, the Rhodopseudomonas extracellular toxin, interferon, interleukin, tumor necrosis factor, vincristin, the mitotane melphalan, methchlorethamine, plicamycin, the pyridine of diamidogen nitre mouth bifurcation, the cry of certain animals of talking endlessly of ammonia first, nogalamycin, streptonigrin, streptozotocin, ftorafur, pyrrolidinomethyl tetracycline (tetramin), testolactone demecolcine and D actinomycin D.Spendable other chemical compound comprises: cyclosporin, peace mouthful bifurcation pyridine, camostat mesilate, camptothecine, enocitabine, etoposide, daunorubicin, epirubicin hydrochlorate, fludarabine, flutamide, fotemustine, darubicin hydrochlorate, ionomycin, mitoxantrone hydrochlorate, nilutamide, taxol, Toremifene Citrate, vinorelbine.
Suitable softening keratin agent comprises salicylic acid, salicylic derivant, for example 5 one decoyl salicylic acid; Retinoid, for example retinoic acid and their derivant (for example, cis and trans), retinol, axerophthal, acetic acid retinal, palm fibre are put sour retinal or its mixture; Salicylic acid and its derivant; The aminoacid of sulfur-bearing and its derivant and salt; The D of sulfur-bearing and L aminoacid and its derivant and salt, specifically N one acetate derivant, for example N one acetyl group one L one cysteine, thioctic acid, mercaptan, hydroxyacetic acid.
Antibiotic and antimicrobial be benzoyl peroxide for example, Azelaic Acid, phenyl phenol, phenoxypropanol, the phenoxy group isopropyl alcohol, tetracycline, penicillin, cephamycin, clindamycin, erythromycin, amphotericin, ciclopirox olamine, bifonazole, mupirocin, nystatin, griseofulvin, clotrimazole, miconazole, ketoconazole, econazole, fluconazol, terbinafine, abafungin, metronidazole, tinidazole, arteannuin, artesunate, dihydroartemisinine, flavonoid, the anthraquinone class, the salt of terpenoid and its derivant.
The example of spendable NSAID (non-steroidal anti-inflammatory drug) comprises the salicylic acid derivant in the present invention, amino benzenes derivates, the arylpropionic acid analog derivative, indole derivatives, the fenamic acids derivant, the heterocyclic aryl phenylacetic acid derivative, former times the health compounds, comprising: aspirin, sodium salicylate, acetaminophen, ibuprofen, naproxen, fenoprofen, fenbufen, ketoprofen, indoprofen, the pirprofen sweet smell, carprofen, oxaprozin, pranoprofen, sulfur uh Luo Fen, suprofen, alminoprofen, Tai Pufen acid, fluprofen, the bucloxic acid, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, Tolmetin, diclofenac, oxygen former times health, piroxicam, tenoxicam, Phenylbutazone, nabumetone.
The example of spendable local anesthetic comprises in the present invention: benzocaine, lignocaine, marcaine, chloroprocaine, etidocaine, Carbocainum, tetracaine, dyclonine, hexylcaine, procaine, 2.beta.-carbomethoxy-3.beta.-benzoxytropane, ketamine, Pramoxine, ropivacaine and its officinal salt.
Spendable cortex steroidal class comprises that the halogenation corticosteroid is normally known in topical preparation of the present invention, and has commercially available.Example comprises cortisone, and hydrocortisone and its derivant comprise the deoxidation cortisone, fludrocortisone acetate, flurandrenolide acetonide, medroxyprogesterone; Prednisone, andrographolide and its derivant comprise amcinafal, the benzoate of betamethasone, valerate and dipropionate, chlorine prednisone acetas, descinolone (descinalone) acetonide, ciclesonide, dexamethasone, dichlorisone acetas, ground fuprednate butyl ester, flucloronide, aniprime, flunisolide acetas, fluocinolone acetonide, fluocinonide, fluocortolone, fluorine first deoxidation prednisolone, fluprednisolone valerate, meprednisone, methyl prednisolone, Dilar acetas, the acetas of andrographolide, butylacetic acid vinegar and phosphoric acid ester sodium, fluorine hydroxyl prednisolone acetonide, triamcinolone hexacetonide, diacetate or ester, hydrocortisone butyrate, the aniprime pivalate, halcininide and CBP.
The example of spendable in the present invention skin treating medicine comprises calcipotriol, crotamiton, resorcin, allantoin, methoxsalen, coal tar.
The inert component in dermatological preparation of the present invention and the consumption of activating agent are normally known in the art.Those skilled in the art can know the concrete consumption of component by inference and obtain emulsifiable paste of the present invention.The concrete consumption of employed any component is not very crucial, and the mensuration that is known in the art of the precision of use amount or the precision of compound method.
The specific embodiment mode
Following embodiment is used to further specify the present invention, but does not limit the scope of the invention.
Embodiment 1:
At first the stearic acids of 64.0 16/18 mixed alcohols that restrain, 48.0 grams, the glycerol of 40.0 grams, the propyl hydroxybenzoate (claiming Buddhist nun's propyl ester again) of 0.16 gram are mixed post-heating to the 75 ℃ uniform oil phase of one-tenth;
Second step was mixed and heated to 75 ℃ with the aluminium-magnesium silicate of 24.0 grams, the distilled water of 484 grams, the methyl hydroxybenzoate (claiming Buddhist nun's methyl ester again) of 1.44 grams, stirred about 2 hours, made the abundant aquation of aluminium-magnesium silicate become the water of colloid sample;
The 3rd step joined aqueous phase with oil phase, added the triethanolamine of 3.6 grams while stirring, became milky white emulsion with Fu Luke high-shear homogenizer homogenizing then, and lasting stirring is cooled to 60 ℃ and becomes emulsifiable paste matrix;
The 4th step under the lucifuge operation, joined 0.4 BHT that restrains, 0.4 gram citric acid, 0.4 gram tretinoin, 0.08 gram fluocinonide in the PEG400 of 100.0 grams, and stirring and dissolving one-tenth does not have yellow short grained yellow suspendible liquid;
The 5th step under lucifuge operation, joined yellow suspendible liquid in the emulsifiable paste matrix, while stirring high speed homogenization and naturally cool to 50 ℃ and become faint yellow emulsifiable pastes;
The 6th step under lucifuge operation, with the hydroquinone of the sodium pyrosulfite of 1.6 grams and 32.0 grams join previous step make in the faint yellow emulsifiable paste, stir to put and be chilled to room temperature and promptly make emulsifiable paste.
The comparative example 1:
According to U.S. Pat 2003033876, prepared the emulsifiable paste that contains hydroquinone, tretinoin, fluocinonide:
At first the water, 15.0 with about 344.8 grams restrains Magnesiumaluminumsilicates and 0.2 gram Yoshinox BHT merging, and mixes the formation water down at 75-80 ℃.Scraping stirring with fixed speed side mixes.Obtain the water of suspension.
Second step, the hexadecanol of about 20.0 grams, stearic acid, 20.0 octadecanol that restrain, the methyl glucoside bull's eye oxidative ethanes (methyl gluceth-10) of 25.0 grams, the methyl parahydroxybenzoate of 0.9 gram, the propyl p-hydroxybenzoate of 0.1 gram and the glycerol of 20.0 grams of 15.0 grams are mixed with middling speed under about 75-80 ℃, form nonaqueous phase.Mix with middling speed.The nonaqueous phase that obtains is a suspension.Then, nonaqueous phase is joined aqueous phase, and the two-phase mixture that merges is cooled to about 70 ℃, then add the Arlacel of about 17.5 grams
165,0.25 gram retinoic acid and 0.05 gram fluocinolone acetonide, and in cooling procedure, stir.When mixture is reached 60 ℃, under mixing and cooling, add the 0.25g citric acid.When temperature reaches 55 ℃, under mixing and cooling, add the 20.0g hydroquinone.When temperature reaches about 50 ℃, continuing under the cooling mixture usefulness Fu Luke high-shear homogenizer homogenize.When mixture reaches 45 ℃, under stirring and cooling, add the sodium pyrosulfite of 1.0g.Mix in agitator with fixed speed.Obtain faint yellow ointment.
The comparative example 2:
According to Chinese patent CN200510081635, prepared the emulsifiable paste that contains adapalene, adapalene is the derivant of tretinoin,
On physicochemical property and tretinoin seemingly, so we prepare the tretinoin emulsifiable paste according to the method for CN200510081635:
Prescription:
Tretinoin 0.1%
EDTA 0.5％
Liquid paraffin 15%
Glyceryl monostearate 10%
Sodium laurylsulfate 10%
Stearyl alcohol 8%
Glycerol 10%
PEG one 400 8%
Methyl hydroxybenzoate 0.25%
Propylparaben 0.15%
Pure water 38%
Preparation technology:
1. with the tretinoin of recipe quantity (crossing 120 mesh sieves in advance), PEG-400 in appropriate containers, grind evenly, stand-by.Be called 1 phase.
2. the EDTA of recipe quantity, sodium laurylsulfate, glycerol, methyl hydroxybenzoate, propylparaben are added in the pure water of recipe quantity, be heated to 80 ℃ of dissolvings after, 2 phases.
3. after liquid paraffin, glycerol monostearate vinegar, the stearyl alcohol of recipe quantity being heated to 80 ℃ of dissolvings, 3 phases.
4. will handle well 2 be added to 3 mutually in, homogenizing 10 minutes.Be added to 1 when treating that temperature is reduced to 50 ℃ of left and right sides, stirring at low speed is after 1 hour, semi-finished product.
The comparative example 3:
According to Chinese patent CN200510081635, prepared the emulsifiable paste that contains tretinoin:
Prescription:
Tretinoin 0.1%
EDTA 0.5％
Liquid paraffin 15%
Glyceryl monostearate 10%
Sodium laurylsulfate 10%
Stearyl alcohol 8%
Glycerol 10%
PEG one 400 10%
Methyl hydroxybenzoate 0.25%
Propylparaben 0.15%
Pure water 36%
Preparation technology:
2. with the tretinoin of recipe quantity (crossing 120 mesh sieves in advance), PEG-400 in appropriate containers, grind evenly, stand-by.Be called 1 phase.
2. the EDTA of recipe quantity, sodium laurylsulfate, glycerol, methyl hydroxybenzoate, propylparaben are added in the pure water of recipe quantity, be heated to 80 ℃ of dissolvings after, 2 phases.
3. after liquid paraffin, glycerol monostearate vinegar, the stearyl alcohol of recipe quantity being heated to 80 ℃ of dissolvings, 3 phases.
4. will handle well 2 be added to 3 mutually in, homogenizing 10 minutes.Be added to 1 when treating that temperature is reduced to 50 ℃ of left and right sides, stirring at low speed is after 1 hour, semi-finished product.
With the content of the sample of high-performance liquid chromatogram determination embodiment 1, comparative example 1, comparative example 2, comparative example 3 preparations, respectively get 6 parts, calculate RSD (relative standard deviation), the results are shown in Table 1
Table 1
Check embodiment 1 and comparative example's 1 related substances is investigated stability, the results are shown in Table 2
Table 2
From the data of above-mentioned table 1 and table 2 as can be seen, with the emulsifiable paste of embodiment 1 method preparation be better than aspect the content uniformity by U.S. Pat 2003033876 preparations comparative example 1, by the comparative example 2 and the comparative example 3 of Chinese patent CN200510081635 preparation.Content uniformity is an important indicator of reflection drug quality, and the content uniformity of the tretinoin among tretinoin among the comparative example 1 and fluocinonide, comparative example 2 and the comparative example 3 is bad, therefore can not carry out quality control effectively.To place temperature by the sample of the present invention preparation is that 40 ± 2 ℃, humidity are to place 6 months under the condition of RH 75 ± 5%, the results are shown in Table 3:
Table 3
As can be seen from Table 3, placing temperature by the sample of method of the present invention preparation is that 40 ± 2 ℃, humidity are that to place under the condition of RH75 ± 5% after 6 months be stable.
Embodiment 2:
At first with 16/18 mixed alcohols of 64.0 grams, the stearic acid of 48.0 grams, the glycerol of 40.0 grams, propyl hydroxybenzoate mixing post-heating to the 75 ℃ uniform oil phase of one-tenth of 0.16 gram;
Second step was mixed and heated to 75 ℃ with the aluminium-magnesium silicate of 24.0 grams, the distilled water of 484 grams, the methyl hydroxybenzoate of 1.44 grams, stirred about 2 hours, made the abundant aquation of aluminium-magnesium silicate become the water of colloid sample;
The 3rd step joined aqueous phase with oil phase, added the triethanolamine of 3.6 grams while stirring, became milky white emulsion with the Fu Luke high speed homogenization then, and lasting stirring is cooled to 60 ℃ and becomes emulsifiable paste matrix;
The 4th step under the lucifuge operation, joined 0.4 BHT that restrains, 0.4 gram citric acid, 0.4 gram tretinoin, 0.08 gram fluocinonide in the PEG400 of 100.0 grams, and stirring and dissolving one-tenth does not have yellow short grained yellow suspendible liquid;
The 5th step under lucifuge operation, joined yellow suspendible liquid in the emulsifiable paste matrix, while stirring high speed homogenization and naturally cool to 50 ℃ and become faint yellow emulsifiable pastes;
The 6th step, under lucifuge operation, with the hydroquinone list valerates of the sodium pyrosulfite of 1.6 grams and 32.0 grams join previous step make in the faint yellow emulsifiable paste, stir to put and be chilled to room temperature and promptly make emulsifiable paste.
Content, uniformity of dosage units, the related substances of check embodiment 2 are investigated stability, the results are shown in Table 4
Table 4
As can be seen from the above table, fine aspect the uniform content degree with the emulsifiable paste of embodiment 2 methods preparation.On stability, the hydroquinone list valerate of embodiment 2 is more stable than the hydroquinone of embodiment 1.
Embodiment 3:
At first with 16/18 mixed alcohols of 64.0 grams, the stearic acid of 48.0 grams, the glycerol of 40.0 grams, propyl hydroxybenzoate mixing post-heating to the 75 ℃ uniform oil phase of one-tenth of 0.16 gram;
Second step was mixed and heated to 75 ℃ with the aluminium-magnesium silicate of 24.0 grams, the distilled water of 484 grams, the methyl hydroxybenzoate of 1.44 grams, stirred about 2 hours, made the abundant aquation of aluminium-magnesium silicate become the water of colloid sample;
The 3rd step joined aqueous phase with oil phase, added the triethanolamine of 3.6 grams while stirring, became milky white emulsion with the Fu Luke high speed homogenization then, and lasting stirring is cooled to 60 ℃ and becomes emulsifiable paste matrix;
The 4th step under the lucifuge operation, joined 0.4 BHT that restrains, 0.4 gram citric acid, 0.4 gram tretinoin, 0.08 gram fluocinonide in the PEG400 of 100.0 grams, and stirring and dissolving one-tenth does not have yellow short grained yellow suspendible liquid;
The 5th step under lucifuge operation, joined yellow suspendible liquid in the emulsifiable paste matrix, while stirring high speed homogenization and naturally cool to 50 ℃ and become faint yellow emulsifiable pastes;
The 6th step, under lucifuge operation, with the hydroquinone diacetates of the sodium pyrosulfite of 1.6 grams and 32.0 grams join previous step make in the faint yellow emulsifiable paste, stir to put and be chilled to room temperature and promptly make emulsifiable paste.
Content, uniformity of dosage units, the related substances of check embodiment 3 are investigated stability, the results are shown in Table 5
Table 5
As can be seen from the above table, fine aspect the uniform content degree with the emulsifiable paste of embodiment 3 methods preparation.On stability, the hydroquinone diacetate of embodiment 3 is more stable than the hydroquinone of embodiment one.
Embodiment 4:
At first with 16/18 mixed alcohols of 64.0 grams, the stearic acid of 48.0 grams, the glycerol of 40.0 grams, propyl hydroxybenzoate mixing post-heating to the 75 ℃ uniform oil phase of one-tenth of 0.16 gram;
Second step was mixed and heated to 75 ℃ with the aluminium-magnesium silicate of 24.0 grams, the distilled water of 500 grams, the methyl hydroxybenzoate of 1.44 grams, stirred about 2 hours, made the abundant aquation of aluminium-magnesium silicate become the water of colloid sample;
The 3rd step joined aqueous phase with oil phase, added the triethanolamine of 3.6 grams while stirring, became milky white emulsion with the Fu Luke high speed homogenization then, and lasting stirring is cooled to 60 ℃ and becomes emulsifiable paste matrix;
The 4th step under the lucifuge operation, joined 0.4 BHT that restrains, 0.4 gram citric acid, 0.4 gram tretinoin, 0.08 gram fluocinonide in the PEG400 of 100.0 grams, and stirring and dissolving one-tenth does not have yellow short grained yellow suspendible liquid;
The 5th step under lucifuge operation, joined yellow suspendible liquid in the emulsifiable paste matrix, while stirring high speed homogenization and naturally cool to 50 ℃ and become faint yellow emulsifiable pastes;
The 6th step, under lucifuge operation, with the Arbutins of the sodium pyrosulfite of 1.6 grams and 16.0 grams join previous step make in the faint yellow emulsifiable paste, stir to put and be chilled to room temperature and promptly make emulsifiable paste.
Content, uniformity of dosage units, the related substances of check embodiment 4 are investigated stability, the results are shown in Table 6
Table 6
As can be seen from Table 6, fine aspect the uniform content degree with the emulsifiable paste of embodiment 4 methods preparation.On stability, the Arbutin of embodiment 4 is more stable than the hydroquinone of embodiment 1.
Claims (5)
1. preparation method that contains the emulsifiable paste of depigmenting agent, tretinoin, corticosteroid, this method comprises:
(a) water and hydrophilic compounds aluminium-magnesium silicate are mixed, form water;
(b) with the mixing of hydrophobic compound hexadecanol, stearic acid and octadecanol, form nonaqueous phase;
(c) water and nonaqueous phase are mixed, form biphase mixture;
(d) add the emulsifying agent triethanolamine in biphase mixture, make blank emulsifiable paste;
(e) antioxidant, tretinoin and corticosteroid material fluocinonide are joined in the PEG400, be dissolving or/and homogeneously dispersed state, and then join in (d), homogenize obtains mixture;
(f) antioxidant and depigmenting agent are joined in the mixture of step (e), stir, obtain emulsifiable paste, wherein, depigmenting agent is selected from hydroquinone, hydroquinone list valerate, hydroquinone diacetate and Arbutin.
2. the described method of claim 1, wherein, step (c) is carried out being higher than under the temperature of room temperature.
3. the described method of claim 1, wherein said antioxidant comprises following at least a: sodium sulfite, sodium sulfite, sodium pyrosulfite, potassium sulfite, vitamin C, two uncle's fourth hydroxy-methylbenzene phenol (BHT), tocopherol, tocopheryl acetate, cysteine, glycine, gallic acid, progallin A or propyl ester, glutathion, thioglycerol, tartaric acid, succinic acid, malic acid, citric acid, sodium citrate, ethylenediaminetetraacetic acid, sodium ethylene diamine tetracetate.
4. the described method of claim 2, described antioxidant is selected from two uncle's fourth hydroxy-methylbenzene phenol (BHT), citric acid, sodium pyrosulfite.
5. the described method of claim 1, said depigmenting agent is a hydroquinone.
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| GB201104766D0 (en) * | 2011-03-22 | 2011-05-04 | Givaudan Sa | Compositions |
| CN103099778B (en) * | 2012-10-08 | 2015-10-07 | 天津金耀集团有限公司 | The externally-applied medicinal composition of a kind of fluocinolone acetonide and ester thereof |
| CN106474052B (en) * | 2016-12-16 | 2019-10-25 | 重庆华邦制药有限公司 | Alclometasone diproionate emulsifiable paste and preparation method thereof |
| CN110025493A (en) * | 2019-03-01 | 2019-07-19 | 浙江孚诺医药股份有限公司 | A kind of Topical skin care composition and its preparation process without preservative |
| CN112336688B (en) * | 2020-08-14 | 2023-03-17 | 广东人人康药业有限公司 | Oil-in-water type compound hydroquinone emulsion as well as preparation method and application thereof |
| CN113413363B (en) * | 2021-08-12 | 2022-07-05 | 福元药业有限公司 | Desonide cream and preparation method thereof |
| CN114949169A (en) * | 2022-06-29 | 2022-08-30 | 九江高科制药技术有限公司 | Giant salamander polypeptide/carboxymethyl chitosan composite cream and preparation method thereof |
| CN115004982B (en) * | 2022-07-22 | 2023-06-09 | 威海智洁环保技术有限公司 | Low-carbon environment-friendly efficient saline-alkali soil restoration method based on radiation refrigeration |
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| US3856934A (en) * | 1970-06-24 | 1974-12-24 | A Kligman | Skin depigmentation |
| CN1226819A (en) * | 1996-03-01 | 1999-08-25 | 庄臣消费者有限公司 | Topical compositions comprising an oil-in-water emulsion and retinoid |
| CN1538833A (en) * | 2000-11-22 | 2004-10-20 | Mild cosmetic composition with stabilized retinoids | |
| CN1726017A (en) * | 2002-12-12 | 2006-01-25 | 盖尔德马研究及发展公司 | Aqueous-alcoholic depigmenting gel containing a phenolic derivative and a retinoid |
| CN1738587A (en) * | 2002-10-25 | 2006-02-22 | 希尔皮肤医药公司 | Topical skin care composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3856934A (en) * | 1970-06-24 | 1974-12-24 | A Kligman | Skin depigmentation |
| CN1226819A (en) * | 1996-03-01 | 1999-08-25 | 庄臣消费者有限公司 | Topical compositions comprising an oil-in-water emulsion and retinoid |
| CN1538833A (en) * | 2000-11-22 | 2004-10-20 | Mild cosmetic composition with stabilized retinoids | |
| CN1738587A (en) * | 2002-10-25 | 2006-02-22 | 希尔皮肤医药公司 | Topical skin care composition |
| CN1726017A (en) * | 2002-12-12 | 2006-01-25 | 盖尔德马研究及发展公司 | Aqueous-alcoholic depigmenting gel containing a phenolic derivative and a retinoid |
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| CN101249095A (en) | 2008-08-27 |
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