CN103565743A - Tranexamic acid skin externally applied nano-preparation, as well as preparation method and use thereof - Google Patents
Tranexamic acid skin externally applied nano-preparation, as well as preparation method and use thereof Download PDFInfo
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Abstract
The invention relates to a tranexamic acid skin externally applied nano-preparation, as well as a preparation method and a use thereof. The nano-preparation is prepared from tranexamic acid, medicated oil, an emulsifier, pharmaceutical additives, a thickener and pure water. The tranexamic acid skin externally applied nano-preparation provided by the invention has good physiological skin compatibility and can effectively promote the percutaneous absorption of tranexamic acid, improve the effect of preventing or treating pigmentation of the tranexamic acid and avoid toxicity and side effects, which are caused by systemic administration of the tranexamic acid.
Description
Technical field
The invention belongs to chemical pharmacy field, more particularly, relate to tranexamic acid external preparation for skin nanometer formulation and its production and use.Tranexamic acid external preparation for skin nanometer formulation of the present invention has the good skin physiology compatibility, can effectively promote the percutaneous of tranexamic acid to absorb, and improves tranexamic acid prevention or treats Pigmented effect, the toxic and side effects of avoiding tranexamic acid systemic administration to cause.
Background technology
Tranexamic acid also claims tranamic acid, tranamic acid, and chemical name is trans-4-(aminomethyl) naphthenic acid, molecular formula: C
8h
15nO
2, molecular weight: 157.21, there is following chemical constitution:
Tranexamic acid is a kind of anti-fibrinolytic hemorrhage.Because tranexamic acid is similar to the tyrosine part-structure of participating in melanin metabolism, there is a carboxyl, contestable restraint of tyrosinase and then reduce melanic formation, has good curative effect to pigmentation, if the clinical total effective rate of chloasma is 82.3%.But the existing preparation of tranexamic acid is tablet and injection, has the shortcomings such as dosage is large, zest is strong, the course for the treatment of is long, and general medication also causes the untoward reaction such as gastrointestinal reaction, central nervous system symptom, had a strong impact on its clinical practice.
Preparation for external application to skin can directly act on target site, avoids first pass effect of hepar, increases medicine at the local concentration of site of action, reduces the untoward reaction of medicine when better bringing into play curative effect; Preparation for external application to skin can also reduce administration number of times, avoids unnecessary a large amount of administrations; In addition, preparation for external application to skin also has advantages of that patient's compliance is high.But tranexamic acid polarity is strong, aqueous solution transdermal capability is poor, directly tranexamic acid is made to the performance that simple preparation for external application to skin has a strong impact on its curative effect.
At present, there is no the tranexamic acid preparation for external application to skin of development voluntarily, have been reported the simple combination of tranexamic acid and other Multiple components (Chinese patent CN99800921.0, Chinese patent CN200580031837, Chinese patent CN201110122382.1), in order to reach whitening or prevention pigmentation, but this composition is more complicated, mechanism is indefinite, and skin is had to certain zest and damaging, belongs to cosmetic field more.
Therefore, the present invention is according to the composition of keratodermatitis (lipoid, protein, water), and the matrix material with good biocompatibility of take has been prepared tranexamic acid nanometer formulation as matrix design, as preparation for external application to skin.Said preparation can be realized by the fusion of matrix material and cell membrane the deep layer of tranexamic acid and transport; The particle wherein with nanoscale also can increase drug percutaneous permeability by nano effect, increases its curative effect; Local application has greatly reduced its untoward reaction simultaneously.Therefore tranexamic acid preparation for external application to skin according to the present invention has a good application prospect.
Summary of the invention
An object of the present invention is to provide a kind of tranexamic acid external preparation for skin nanometer formulation, it can prevent or treat cutaneous pigmentation effectively, has the advantages that curative effect is high, toxicity is low.
Another object of the present invention is to provide the preparation method of above-mentioned tranexamic acid external preparation for skin nanometer formulation.
A further object of the present invention is to provide the purposes of above-mentioned tranexamic acid external preparation for skin nanometer formulation.
According to a first aspect of the invention, provide a kind of tranexamic acid external preparation for skin nanometer formulation, it is mixed by following raw materials by weight:
Preferably, the invention provides a kind of tranexamic acid external preparation for skin nanometer formulation, it is mixed by following raw materials by weight:
In the present invention, described medicinal oil is acceptable oils in pharmacy, is selected from vegetable oil, medium chain triglyceride, isopropyl myristate and composition thereof.Described medium chain triglyceride refers to the triglyceride being formed by glycerine esterification by containing medium-chain fatty acid that 6～12 carbon atoms form carbochain, typical medium chain triglyceride be for example saturated Trivent OCG or saturated tricaprin or saturated sad-triglyceride of capric acid mixing.Preferably, can be used for medicinal oil of the present invention comprises: soybean oil, Oleum Camelliae, Oleum sesami, fish oil, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, Oleum Ricini, Oleum Cocois, Miglyol 812N, isopropyl myristate etc. or its mixture, be more preferably selected from soybean oil, Miglyol 812N, Oleum Ricini, olive oil and composition thereof.
In the present invention, described emulsifying agent is for can make other material become the pharmaceutic adjuvant of emulsified state.Conventional emulsifying agent is surfactant, and its Main Function is by adsorbing on oil-water interface, thereby reduce interface energy, forms the protecting film that one deck has some strength at liquid bead surface simultaneously.For example, the emulsifying agent can be used in nanometer formulation of the present invention comprises: nonionic or anion emulsifier, for example, Tween 80, polysorbate60, Mai Ze 52, tristerin, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, lecithin (as soybean lecithin, Ovum Gallus domesticus Flavus lecithin), polyglycol distearate, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine, two Semen Myristicae phospholipid acid cholines etc. or its mixture.In the present invention, preferred emulsifying agent is selected from polyoxyethylene castor oil, Tween 80, Ovum Gallus domesticus Flavus lecithin, Solutol HS15 (Solutol HS15) and composition thereof.
In the present invention, described thickening agent is selected from carbomer, hyaluronic acid, polyvidone, tragakanta, cellulose compound (as sodium carboxymethyl cellulose, hyprolose, hypromellose) and composition thereof, is preferably selected from carbomer, hyaluronic acid, carboxymethyl cellulose chlorins compound (as sodium carboxymethyl cellulose) and composition thereof.In the present invention, described thickening agent is used with the form of aqueous solution, and the concentration range of its aqueous solution can be preferably 0.1%～10%.
In the present invention, described medical additive is to be selected from one or more in osmotic pressure regulator, pH adjusting agent, antioxidant and antiseptic.
In the present invention, described osmotic pressure regulator is for regulating the osmotic pressure of preparation, to the not restriction of its kind, as long as osmotic pressure is within the scope of 200～600mOsmol after can making preparation dilute 3 times, be preferably selected from glucose, sodium chloride, potassium chloride, propylene glycol, glycerol, mannitol, sucrose, sorbitol and composition thereof, be more preferably selected from glucose, glycerol, sodium chloride and composition thereof.
In the present invention, described antioxidant is for delaying or prevent the oxidation of preparation readily oxidizable substance, to the not restriction of its kind, as long as there is antioxidation, be preferably selected from Butylated hydroxyanisole (BHA), dibenzylatiooluene (BHT), propyl gallate (PG), tert-butyl hydroquinone (TBHQ), the polyatomic phenol materials such as dilauryl thiodipropionate, vitamin E (VE), D-sodium ascorbate, Ascorbyl Palmitate, sulphite, Cys hydrochlorate, conventional antioxidant such as sulfur glycerol and composition thereof, more preferably be selected from vitamin E, D-sodium ascorbate, dibenzylatiooluene and composition thereof.
In the present invention, described antiseptic is putrid and deteriorated for the preparation that postpones growth of microorganism or chemical change and cause, to the not restriction of its kind, as long as it is corrupt to suppress medicine, be preferably selected from Common Preservatives such as Nipagin ester antiseptic (as methyl hydroxybenzoate, propylparaben), benzoic acid and sodium benzoate, sorbic acid and salt thereof, benzalkonium bromide, chlorhexidine acetate and composition thereof, more preferably Nipagin ester antiseptic, benzalkonium bromide, sorbic acid and salt thereof.
In the present invention, described pH adjusting agent is for regulating the pH value of preparation, to the not restriction of its kind, as long as the pH value of scalable preparation is to required scope, be preferably selected from hydrochloric acid, sodium hydroxide, trometamol and all kinds of buffer salt system (as acetic acid-sodium acetate, citric acid-sodium citrate, citric acid-sodium citrate, phosphate etc.), more preferably sodium hydroxide, phosphate or trometamol.
From the stability of preparation, prevent that skin irritation equal angles from considering, the pH of tranexamic acid external preparation for skin nanometer formulation of the present invention can be 4.0～8.0 conventionally, and is preferably 5.0～7.0.
According to a second aspect of the invention, provide the preparation method of above-mentioned tranexamic acid external preparation for skin nanometer formulation, it comprises the following steps:
1) tranexamic acid and the water-soluble substances being selected from emulsifying agent, medical additive are dissolved in pure water, under 20～80 ℃ of conditions, stirring and dissolving makes its mix homogeneously, obtains water;
2) by medicinal oil and be selected from the oil soluble material in emulsifying agent, medical additive, under 30～80 ℃ of conditions, stir and make its mix homogeneously, obtain oil phase;
3) described oil phase, water are mixed, adopt high shear or high pressure homogenizer to prepare nanometer microemulsion under 20～80 ℃ of conditions;
4) by gained nanometer microemulsion and aqueous thickener solution (proportion of nanometer microemulsion and aqueous thickener solution is preferably 9:1～6:4(w/w) by a certain percentage, more preferably ratio is 7:3(w/w)) mix and stir, regulate pH value to 4.0～8.0(preferably 5.0～7.0) in scope, obtain tranexamic acid external preparation for skin nanometer formulation.
Tranexamic acid preparation for external application to skin of the present invention has excellent absorbability.For guaranteeing that skin absorbs preferably to it, the mean diameter of tranexamic acid external preparation for skin nanometer formulation of the present invention should be no more than 0.5 μ m, and 90% particle diameter accumulated value should be no more than 0.8 μ m; Preferably, mean diameter should be no more than 0.3 μ m, and 90% particle diameter accumulated value should be no more than 0.5 μ m; Most preferably, mean diameter should be no more than 0.15 μ m, and 90% particle diameter accumulated value should be no more than 0.3 μ m.
The advantage of tranexamic acid external preparation for skin nanometer formulation of the present invention is: (1) is according to the composition of keratodermatitis (lipoid, protein, water), the matrix material with good biocompatibility of take is matrix composition tranexamic acid external preparation for skin nanometer formulation, and said preparation can be realized by the fusion of matrix material and cell membrane the deep layer of tranexamic acid and transport; (2) particle that has nanoscale in tranexamic acid external preparation for skin nanometer formulation also can increase by nano effect the percutaneous permeability of tranexamic acid, and then increases its curative effect; (3) tranexamic acid external preparation for skin nanometer formulation has greatly reduced the untoward reaction of its systemic administration by local application.Therefore tranexamic acid preparation for external application to skin according to the present invention has a good application prospect.
According to a third aspect of the present invention, provide above-mentioned tranexamic acid external preparation for skin nanometer formulation active for the preparation of prevention or treatment mottle and chloasma, restraint of tyrosinase, reduce reactive black pigment cell quantity, reduce the active purposes that forms and/or improve the dim heavy medicine of local skin of melanin.
Tranexamic acid external preparation for skin nanometer formulation of the present invention has prevention or treats Pigmented effect, can be used for treating mottle and chloasma, restraint of tyrosinase active, reduce reactive black pigment cell quantity, reducing melanin, active to form and improve local skin dim heavy.
Accompanying drawing explanation
Fig. 1 shows according to the tranexamic acid external preparation for skin nanometer formulation isolated skin of Preparation Example 1 of the present invention and 2 preparations to organize Franz diffusion to investigate the curve chart (n=3) of result.
Fig. 2 shows according to the tranexamic acid external preparation for skin nanometer formulation isolated skins of Preparation Example 1 of the present invention and 2 preparations to organize Franz diffusion to investigate 6h enlarged drawing (n=3) before result.
Fig. 3 shows the curve chart (n=3) of investigating result according to the tranexamic acid external preparation for skin nanometer formulation isolated skin tissue infiltration of Preparation Example 1 of the present invention and 2 preparations.
The specific embodiment
Below in conjunction with specific embodiment, and comparable data is described in further detail the present invention.Should be understood that these embodiment just in order to demonstrate the invention, are intended to illustrate concrete formula composition of the present invention, preparation method and function and effect, but not limit the scope of the invention by any way.
In following examples, various processes and the method do not described in detail are conventional methods as known in the art.
In the present invention, the source of agents useful for same, equipment and trade name are all indicated when occurring first, and identical reagent used is if no special instructions, all identical with the content of indicating first thereafter.Wherein, tranexamic acid crude drug is purchased from Dongting Lake, Hunan pharmaceutcal corporation, Ltd.
Preparation Example
Preparation Example 1
Prescription 1:
Preparation method:
1. take recipe quantity tranexamic acid, glycerol (Ziguang Guhan Amino-acid Co., Ltd., Shantou's manufacture) is dissolved in pure water, (IKA company manufactures under 70 ± 10 ° of C conditions, to adopt magnetic agitation, model: RET Basic C) in 300rpm stir about 10min, dissolve to obtain water completely to tranexamic acid.
2. take ethyl hydroxybenzoate (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture), the soybean oil (Tieling Beiya Medical Oil Co., Ltd.'s manufacture) of recipe quantity, be preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, to the polyoxyethylene castor oil that adds recipe quantity after ethyl hydroxybenzoate completes dissolving, (German BASF AG manufactures, trade name: Cremophor EL) and VE(DSM vitamin (Shanghai) Co., Ltd. manufacture), continue to stir and make solution mix homogeneously obtain oil phase.
3. by oil phase, water in 70 ± 10 ° of C water-baths, high shear machine (IKA company manufacture, model T25digital) is sheared 10min and is formed colostrum.
4. by this colostrum, by high pressure homogenizer, (ATS Engineering Inc. manufactures, and model: AH100D), adjustment pressure is 700～1200bar circulates and within 5～15 weeks, obtains the concentrated nanometer microemulsion of tranexamic acid.
5. (U.S. Lubrizol company manufactures will to concentrate nanometer microemulsion and 1% carbomer, model: 980NF) aqueous thickener solution is in 7:3(w/w) slow stirring and evenly mixing under ratio room temperature condition, nanometer microemulsion is carried out to thickening, with NaOH, regulate pH to 5.0～7.0, obtain tranexamic acid external preparation for skin nanometer formulation.
The mean diameter of obtained tranexamic acid external preparation for skin nanometer formulation is 105.0nm, and polydispersity coefficient is (Polydispersity Index, PI) 0.069.
Preparation Example 2
Prescription 2:
Preparation method:
1. take recipe quantity tranexamic acid, glycerol, D-sodium ascorbate (manufacture of Chemical Co., Ltd. of traditional Chinese medicines group) and be dissolved in pure water, under 70 ± 10 ° of C conditions, adopt magnetic agitation to stir and approximately mix 10min in 300rpm, dissolve to obtain water completely to tranexamic acid.
2. take the propylparaben (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture), Miglyol 812N (Tieling Beiya Medical Oil Co., Ltd.'s manufacture), Ovum Gallus domesticus Flavus lecithin (Japanese Qiu Bi company manufacture) of recipe quantity, be preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, make each substance dissolves obtain oil phase.
3. by oil phase, water in 70 ± 10 ° of C water-baths, high shear machine is sheared 10min and is formed colostrum.
4. this colostrum is passed through to high pressure homogenizer, adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains the concentrated nanometer microemulsion of tranexamic acid.
5. (Co., Ltd. of Japanese SHIN-ETSU HANTOTAI manufactures will to concentrate nanometer microemulsion and 2% hyprolose, model: HPC-H) viscous water solution liquid is in 7:3(w/w) slow stirring and evenly mixing under ratio room temperature condition, nanometer microemulsion is carried out to thickening, with sodium dihydrogen phosphate, regulate pH to 5.0～7.0, obtain tranexamic acid external preparation for skin nanometer formulation.
The mean diameter of obtained tranexamic acid external preparation for skin nanometer formulation is 99.2nm, and polydispersity coefficient is (Polydispersity Index, PI) 0.130.
Preparation Example 3
Prescription 3:
Preparation method:
1. take recipe quantity tranexamic acid, glycerol, benzalkonium bromide (Taicang Pharmaceutical Factory manufacture) and be dissolved in pure water, under 70 ± 10 ° of C conditions, adopt magnetic agitation in 300rpm stir about 10min, dissolve to obtain water completely to tranexamic acid.
2. take dibenzylatiooluene (Beijing Feng Lijingqiu commerce and trade company limited provides), Oleum Ricini (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture), the Tween 80 (manufacture of Shanghai Shen Yu medication chemistry company limited) of recipe quantity, be preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, make each substance dissolves obtain oil phase.
3. by oil phase, water in 70 ± 10 ° of C water-baths, high shear machine is sheared 10min and is formed colostrum.
4. this colostrum is passed through to high pressure homogenizer, adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains the concentrated nanometer microemulsion of tranexamic acid.
5. will concentrate nanometer microemulsion and 1% hyaluronic acid (Furuida Biochemical Co., Ltd., Shandong's manufacture) aqueous thickener solution in 7:3(w/w) slow stirring and evenly mixing under ratio room temperature condition, nanometer microemulsion is carried out to thickening, with the molten adjusting of sodium hydroxide pH to 5.0～7.0, obtain tranexamic acid external preparation for skin nanometer formulation.
The mean diameter of obtained tranexamic acid external preparation for skin nanometer formulation is 90.1nm, and polydispersity coefficient is (Polydispersity Index, PI) 0.100.
Preparation Example 4
Prescription 4:
Preparation method:
1. taking recipe quantity tranexamic acid, Solutol HS15(Germany BASF AG manufactures), sodium chloride (the diligent pharmaceutcal corporation, Ltd in Jiangsu Province manufactures), sorbic acid (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture) is dissolved in pure water, under 70 ± 10 ° of C conditions, adopt magnetic agitation to stir 10min in 300rpm, to dissolving to obtain water completely.
2. the olive oil (rehabilitation medicine company limited of Xi'an Zao Lutang Pharmaceutical group), the VE that take recipe quantity, be preheated to 70 ± 10 ° of C, adopts magnetic agitation in 300rpm stir about 10min, makes each substance dissolves obtain oil phase.
3. by oil phase, water in 70 ± 10 ° of C water-baths, high shear machine is sheared 10min and is formed colostrum.
4. this colostrum is passed through to high pressure homogenizer, adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains the concentrated nanometer formulation of tranexamic acid.
5. will concentrate nanometer formulation and 2% sodium carboxymethyl cellulose (Anhui Shanhe Medical Accessary Material Co., Ltd.'s manufacture) aqueous thickener solution in 7:3(w/w) slow stirring and evenly mixing under ratio room temperature condition, nanometer formulation is carried out to thickening, with citric acid-sodium citrate aqueous solution, regulate pH to 5.0～7.0, obtain tranexamic acid external preparation for skin nanometer formulation.
The mean diameter of obtained tranexamic acid external preparation for skin nanometer formulation is 115.6nm, and polydispersity coefficient is (Polydispersity Index, PI) 0.060.
EXPERIMENTAL EXAMPLE
EXPERIMENTAL EXAMPLE 1
According to chemicals zest, anaphylaxis and hemolytic investigative technique guideline, adopt with the following method tranexamic acid external preparation for skin nanometer formulation is carried out to skin irritation investigation.
Experimental technique: the tranexamic acid external preparation for skin nanometer formulation of getting above-mentioned Preparation Example 1 preparation of tested material 0.5g() directly coat the plucked skin (animal: rabbit of a side, source: institute of materia medica, Shanghai Experimental Animal Center), then use two layers of gauze (2.5cm * 2.5cm) and one deck cellophane or analog to cover, then fixed with nonirritant adhesive plaster and binder; Opposite side be coated with blank preparation (preparation method is with Preparation Example 1, prescription form except not containing tranexamic acid all the other with Preparation Example 1) compare.Stick 4 hours.Stick after end, remove tested material and with warm water or nonirritant solvent cleaned medicine-feeding part.Multiple dosing irritation test should be continuously in the administration of same position, and each administration time is identical, and sticking the time limit is 4 days.
Result is observed: under available light or full gloss spectrum light, observe dermoreaction.The standards of grading that provide by table 1 are marked to skin erythema and edema.
Each remove medicine 1h after and again stick before observe and record erythema and edema, whether coating part has pigmentation, petechia, pachylosis or epidermatic atrophy situation and time of origin and regression time, and erythema and edema is marked.After last sticks, 30-60 minute, 24 hours, 48 hours and perusal in 72 hours record coating part and have or not the situations such as erythema and edema after removing medicine.
Evaluation of result:
Multiple dosing irritation test, first calculates to put and respectively organizes integral mean value each observing time, then calculates and observes every animal integral mean value interior every day in time limit, by table 2, carries out stimulus intensity evaluation.
Table 1 skin irritation reaction standards of grading
Table 2 skin irritation intensity evaluation standard
Rabbit zest is investigated and be the results are shown in Table 3 and table 4.
The blank preparation rabbit of table 3 irritant experiment result (n=4)
Table 4 tranexamic acid external preparation for skin nanometer formulation administration group rabbit irritant experiment result (n=4)
The situations such as pigmentation, petechia, pachylosis or epidermatic atrophy in whole experimentation, have not been observed.From result, prepared ammonia first ring external preparation for skin nanometer formulation nonirritant, safety is good.
EXPERIMENTAL EXAMPLE 2
Select the nanometer formulation of formula preparation tranexamic acid external preparation for skin described in above-mentioned Preparation Example 1 and Preparation Example 2, investigate its in vitro diffusion/permeability to neonate rat skin of back.
In vitro diffusion experiment method: neonate rat skin of back (animal: SD rat, source: institute of materia medica, Shanghai Experimental Animal Center), remove after the tissues such as fat, muscle, mucosa, be clipped in the middle of improved Franz diffusing cells method 32 ℃ of water-baths.Supply pool gives 0.5ml and investigates preparation: write out a prescription 1, write out a prescription 2; Reception tank dress 2ml normal saline, stirrer stirs.In time point 0.5,1,1.5,2.0,4.0,6.0,8.0,20.0,24.0h from reception tank sample thief 0.5ml, mend 0.5ml normal saline simultaneously.After 24h, take off skin histology, clean up, weigh, add the homogenate of 3ml normal saline, centrifugal, get supernatant and measure medicament contg with HPLC.Experimental result is shown in Fig. 1 and Fig. 2.
In vitro permeability test method: get neonate rat skin of back, remove after the tissues such as fat, muscle, mucosa, be laid in culture dish 32 ℃ of water-baths.Skin keratin aspect is investigated respectively preparation: write out a prescription 1, write out a prescription 2 (keep preparation/be organized in same mass ratio); In time point 1.0,2.0,6.0,8.0h, take out tissue, clean up, weigh, add the homogenate of 3ml normal saline, centrifugal, get supernatant and measure medicament contg with HPLC.Experimental result is shown in Fig. 3.
From Fig. 1, Fig. 2 and Fig. 3, above-mentioned two prescriptions totally present the trend that continues diffusion to the in vitro diffusion/permeability of neonate rat skin of back, show that tranexamic acid external preparation for skin nanometer formulation transdermal effect according to the present invention is good.
EXPERIMENTAL EXAMPLE 3
Select the tranexamic acid external preparation for skin nanometer formulation of formula preparation described in above-mentioned Preparation Example 1 and Preparation Example 2, investigate its curative effect to chloasma in chloasma experimental animal model.
Details are as follows for experimental technique:
The foundation of mice chloasma animal model: get female mice (animal: Kunming mouse, source: institute of materia medica, Shanghai Experimental Animal Center) 50, body weight 25～35g, with 10%Na
2s(Chemical Reagent Co., Ltd., Sinopharm Group) aqueous solution is sloughed right side, back hair, expose 1 of skin, about 1.5cm * the 1.5cm of area, progesterone injection (Shanghai General Pharmaceutical Co., ltd. with 0.4%, specification 1ml:20mg) press 0.02g/kg dosage in mouse hind leg intramuscular injection, inject weekly 6d, continuous 4 weeks, depilation once weekly.Normal group is pressed 0.02g/kg dosage in mouse hind leg intramuscular injection sterilized water for injection.
Animals administer and index detect: get above-mentioned animal pattern, be divided at random 5 groups, 10 every group.Normal group, model group, prescription 1, write out a prescription 2, hydroquinone cream positive controls (Shanghai Changhai Hospital, specification 20g:0.4g).Tranexamic acid preparation for external application to skin treatment group is respectively at the medication of mice modeling local skin on the same day, every day 1 time, 6 times weekly, continuous use 30 days.Normal group and model group give distilled water partial smearing in the corresponding time; Hydroquinone cream positive drug control group started local application in modeling the same day, and time and the course for the treatment of are with tranexamic acid preparation for external application to skin treatment group.After medication 30 days, record cast animals administer position cutaneous pigmentation state, mice is put to death in cervical vertebra dislocation, back unhairing, gets rapidly the skin histology at coating position, with ice-cold normal saline flushing, remove blood, filter paper blots, and cuts skin 0.5g, puts into the beaker of the pre-cold saline of 2.0ml, shred tissue, pour into again in test tube, with high speed disperser homogenate twice, each 10 seconds; With 3500r/min rotating speed centrifugal 15 minutes again, get supernatant.Adopting xanthine oxidase, by SOD(superoxide dismutase) test kit (Bioengineering Research Institute is built up in Nanjing) detects the SOD value in description method mensuration supernatant; Adopting thiobarbituricacidα-method, by MDA(malonaldehyde) test kit (Bioengineering Research Institute is built up in Nanjing) detects the MDA value in description method mensuration supernatant.
After mice partial smearing tranexamic acid preparation for external application to skin, in Skin tissue fluid, the measurement result of SOD enzymatic activity, MDA and pigmentation state are in Table 5.
Table 5 Ge Zu mouse skin tissue SOD, MDA assay (x ± s)
Remarks: compare * P<0.05, * * P<0.01, x: meansigma methods, s: standard deviation with model group
As seen from Table 5: the indices of normal group is compared with model group, there is utmost point significant difference (P<0.01), illustrate that it is successful copying chloasma mouse model.In model group mouse skin tissue, SOD enzymatic activity content is significantly lower than normal group, and after treatment, in positive group, write out a prescription 1 group, the 2 groups of mouse skin tissues of writing out a prescription, SOD enzymatic activity content obviously increases, and positive group, writing out a prescription 1 group all has significant difference (P<0.05) with writing out a prescription 2 groups to compare with model group.In addition, in model group mouse skin tissue, content of propylene glycol is significantly higher than normal group (P<0.01), and after treatment, in positive group, write out a prescription 1 group, the 2 groups of mouse skin tissues of writing out a prescription, mda content obviously reduces, and positive group, writing out a prescription 1 group all has significant difference (P<0.05) with writing out a prescription 2 groups to compare with model group.Again, obviously there is pigmentation phenomenon in model group mouse skin, and positive group, write out a prescription 1 group and all significantly desalinations of 2 groups of pigments of writing out a prescription.
The above results shows, tranexamic acid preparation for external application to skin of the present invention can improve in local skin tissue SOD enzymatic activity and reduce mda content, significantly improves the pigmentation situation of skin, with positive control hydroquinone group there was no significant difference relatively.Visible, tranexamic acid preparation for external application to skin of the present invention can significantly improve pigmentation, and chloasma is had to obvious therapeutical effect.
Claims (10)
1. a tranexamic acid external preparation for skin nanometer formulation, it is mixed by following raw materials by weight:
Wherein, described medical additive is to be selected from one or more in osmotic pressure regulator, pH adjusting agent, antioxidant and antiseptic.
2. tranexamic acid external preparation for skin nanometer formulation according to claim 1, it is mixed by following raw materials by weight:
Wherein, described medical additive is to be selected from one or more in osmotic pressure regulator, pH adjusting agent, antioxidant and antiseptic.
3. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described medicinal oil is selected from vegetable oil, medium chain triglyceride, isopropyl myristate and composition thereof; Be preferably selected from soybean oil, Oleum Camelliae, Oleum sesami, fish oil, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, Oleum Ricini, Oleum Cocois, Miglyol 812N, isopropyl myristate and composition thereof; More preferably be selected from soybean oil, Miglyol 812N, Oleum Ricini, olive oil and composition thereof.
4. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described emulsifying agent is selected from Tween 80, polysorbate60, Mai Ze 52, tristerin, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, lecithin, polyglycol distearate, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine, two Semen Myristicae phospholipid acid cholines and composition thereof; Be preferably selected from polyoxyethylene castor oil, Tween 80, Ovum Gallus domesticus Flavus lecithin, Solutol HS15 and composition thereof.
5. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described thickening agent is selected from carbomer, hyaluronic acid, polyvidone, tragakanta, cellulose compound and composition thereof; Be preferably selected from carbomer, hyaluronic acid, carboxymethyl cellulose chlorins compound and composition thereof.
6. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described osmotic pressure regulator is selected from glucose, sodium chloride, potassium chloride, propylene glycol, glycerol, mannitol, sucrose, sorbitol and composition thereof, is more preferably selected from glucose, glycerol, sodium chloride and composition thereof;
Described antioxidant is selected from Butylated hydroxyanisole, dibenzylatiooluene, propyl gallate, tert-butyl hydroquinone, dilauryl thiodipropionate, vitamin E, D-sodium ascorbate, Ascorbyl Palmitate, sulphite, Cys hydrochlorate, sulfur glycerol and composition thereof, is preferably selected from vitamin E, D-sodium ascorbate, dibenzylatiooluene and composition thereof;
Described antiseptic is selected from Nipagin ester, benzoic acid and sodium benzoate, sorbic acid and salt thereof, benzalkonium bromide, chlorhexidine acetate and composition thereof, is preferably selected from Nipagin ester, sorbic acid and salt thereof, benzalkonium bromide and composition thereof; Or
Described pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, trometamol, acetic acid-sodium acetate, citric acid-sodium citrate, citric acid-sodium citrate and phosphate, is preferably selected from sodium hydroxide, phosphate and trometamol.
7. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, the pH of described tranexamic acid external preparation for skin nanometer formulation is 4.0～8.0, is preferably 5.0～7.0.
8. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, the mean diameter of described tranexamic acid external preparation for skin nanometer formulation is no more than 0.5 μ m, and 90% particle diameter accumulated value is no more than 0.8 μ m; Preferably, mean diameter is no more than 0.3 μ m, and 90% particle diameter accumulated value is no more than 0.5 μ m; Most preferably, mean diameter is no more than 0.15 μ m, and 90% particle diameter accumulated value is no more than 0.3 μ m.
9. the preparation method of the tranexamic acid external preparation for skin nanometer formulation described in claim 1 or 2, it comprises the following steps:
1) tranexamic acid and the water-soluble substances being selected from emulsifying agent, medical additive are dissolved in pure water, under 20～80 ℃ of conditions, stirring and dissolving makes its mix homogeneously, obtains water;
2) by medicinal oil and be selected from the oil soluble material in emulsifying agent, medical additive, under 30～80 ℃ of conditions, stir and make its mix homogeneously, obtain oil phase;
3) described oil phase, water are mixed, adopt high shear or high pressure homogenizer to prepare nanometer microemulsion under 20～80 ℃ of conditions;
4) gained nanometer microemulsion is mixed (wherein with aqueous thickener solution, the proportion of nanometer microemulsion and aqueous thickener solution is preferably 9:1～6:4, more preferably ratio is 7:3) and stir, regulate pH value to 4.0～8.0(preferably 5.0～7.0) in scope, obtain tranexamic acid external preparation for skin nanometer formulation.
Tranexamic acid external preparation for skin nanometer formulation claimed in claim 1 active for the preparation of prevention or treatment mottle and chloasma, restraint of tyrosinase, reduce reactive black pigment cell quantity, reduce the active purposes that forms and/or improve the dim heavy medicine of local skin of melanin.
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