CN103565743B - Tranexamic acid external preparation for skin nanometer formulation and its production and use - Google Patents
Tranexamic acid external preparation for skin nanometer formulation and its production and use Download PDFInfo
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- CN103565743B CN103565743B CN201310303855.7A CN201310303855A CN103565743B CN 103565743 B CN103565743 B CN 103565743B CN 201310303855 A CN201310303855 A CN 201310303855A CN 103565743 B CN103565743 B CN 103565743B
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- Prior art keywords
- skin
- tranexamic acid
- external preparation
- nanometer formulation
- mixture
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Landscapes
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- Cosmetics (AREA)
Abstract
The present invention relates to a kind of tranexamic acid external preparation for skin nanometer formulation and its production and use, this nanometer formulation is formulated by tranexamic acid, medicinal oil, emulsifying agent, medical additive, thickening agent, pure water。The tranexamic acid nanometer formulation of the present invention has the good skin physiology compatibility, can effectively facilitate the percutaneous absorbtion of tranexamic acid, improves tranexamic acid prevention or treats Pigmented effect, it is to avoid the toxic and side effects that tranexamic acid systemic administration causes。
Description
Technical field
The invention belongs to chemical pharmacy field, more particularly, it relates to tranexamic acid external preparation for skin nanometer formulation and its production and use。The tranexamic acid external preparation for skin nanometer formulation of the present invention has the good skin physiology compatibility, can effectively facilitate the percutaneous absorbtion of tranexamic acid, improves tranexamic acid prevention or treats Pigmented effect, it is to avoid the toxic and side effects that tranexamic acid systemic administration causes。
Background technology
Tranexamic acid is also referred to as tranamic acid, tranamic acid, and chemical name is trans-4-(aminomethyl) naphthenic acid, molecular formula: C8H15NO2, molecular weight: 157.21, there is following chemical constitution:
Tranexamic acid is a kind of anti-fibrinolytic hemorrhage。Owing to tranexamic acid is similar to the tyrosine moieties structure participating in melanin metabolism, having a carboxyl, contestable suppresses tryrosinase and then reduces melanic formation, and pigmentation has good curative effect, and the overall clinical efficacy rate such as chloasma is 82.3%。But the existing preparation of tranexamic acid is tablet and injection, have that dosage is big, zest strong, the course for the treatment of shortcoming such as length, and general medication also results in the untoward reaction such as gastrointestinal reaction, central nervous system symptom, has had a strong impact on its clinical practice。
Preparation for external application to skin can be done directly on target site, it is to avoid first pass effect of hepar, increases the medicine local concentration at site of action, reduces the untoward reaction of medicine while better playing curative effect；Preparation for external application to skin can also reduce administration number of times, it is to avoid unnecessary a large amount of administrations；It addition, preparation for external application to skin also has the advantage that patient's compliance is high。But tranexamic acid polarity is strong, and aqueous solution transdermal capability is poor, tranexamic acid is directly made simple preparation for external application to skin and has a strong impact on the performance of its curative effect。
At present, there is no the tranexamic acid preparation for external application to skin developed voluntarily, have been reported the simple combination (Chinese patent CN99800921.0, Chinese patent CN200580031837, Chinese patent CN201110122382.1) of tranexamic acid Yu other Multiple components, in order to reach whitening or prevention pigmentation, but this composition is more complicated, mechanism is indefinite, skin has certain zest and damaging, belongs to cosmetic field more。
Therefore, the present invention composition (lipoid, protein, water) according to keratodermatitis, it is prepared for tranexamic acid nanometer formulation with the matrix material with good biocompatibility for matrix design, as preparation for external application to skin。Said preparation can realize the deep layer transhipment of tranexamic acid by the fusion of matrix material Yu cell membrane；The particle wherein with nanoscale increases drug percutaneous permeability also by nano effect, increases its curative effect；Local application greatly reduces its untoward reaction simultaneously。Therefore the tranexamic acid preparation for external application to skin according to the present invention has a good application prospect。
Summary of the invention
It is an object of the present invention to provide a kind of tranexamic acid external preparation for skin nanometer formulation, it can effectively prevent or treat cutaneous pigmentation, has curative effect height, a feature that toxicity is low。
The preparation method that it is a further object to provide above-mentioned tranexamic acid external preparation for skin nanometer formulation。
It is also another object of the present invention to provide the purposes of above-mentioned tranexamic acid external preparation for skin nanometer formulation。
According to the first aspect of the invention, it is provided that 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, selected from vegetable oil, medium chain triglyceride, isopropyl myristate and mixture thereof。Described medium chain triglyceride refers to the triglyceride formed by glycerine esterification by the medium-chain fatty acid forming carbochain containing 6～12 carbon atoms, and typical medium chain triglyceride is such as saturated Trivent OCG or the triglyceride of saturated tricaprin or the mixing of saturated caprylic-capric acid。Preferably, can be used for the medicinal oil of the present invention to include: 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 mixture thereof。
In the present invention, described emulsifying agent is the pharmaceutic adjuvant that other material can be made to become emulsified state。Conventional emulsifying agent is surfactant, and its Main Function is by adsorbing on oil-water interface, thus reduce interface energy to form one layer of protecting film with some strength at liquid bead surface simultaneously。Such as, the emulsifying agent that can be used in nanometer formulation of the present invention includes: nonionic or anion emulsifier, such as, Tween 80, polysorbate60, Mai Ze 52, tristerin, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, lecithin (such as soybean lecithin, Ovum Gallus domesticus Flavus lecithin), polyglycol distearate, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine, double; two Semen Myristicae phospholipid acid cholines etc. or its mixture。In the present invention, it is preferred that emulsifying agent is selected from polyoxyethylene castor oil, Tween 80, Ovum Gallus domesticus Flavus lecithin, Solutol HS15 (SolutolHS15) and mixture thereof。
In the present invention, described thickening agent is selected from carbomer, hyaluronic acid, polyvidone, tragakanta, cellulose compound (such as sodium carboxymethyl cellulose, hydroxypropylcellulose, hypromellose) and mixture thereof, it is preferable that selected from carbomer, hyaluronic acid, carboxymethyl cellulose chlorins compound (such as sodium carboxymethyl cellulose) and mixture thereof。In the present invention, described thickening agent uses in form of an aqueous solutions, and the concentration range of its aqueous solution can be preferably 0.1%～10%。
In the present invention, described medical additive is one or more in osmotic pressure regulator, pH adjusting agent, antioxidant and preservative。
In the present invention, described osmotic pressure regulator is for regulating the osmotic pressure of preparation, its kind is not limited, as long as osmotic pressure is within the scope of 200～600mOsmol after can making preparation diluent 3 times, it is preferably selected from glucose, sodium chloride, potassium chloride, propylene glycol, glycerol, mannitol, sucrose, sorbitol and mixture thereof, is more preferably selected from glucose, glycerol, sodium chloride and mixture thereof。
In the present invention, described antioxidant is for delaying or preventing the oxidation of readily oxidizable substance in preparation, its kind is not limited, as long as having antioxidation, it is preferably selected from Butylated hydroxyanisole (BHA), dibenzylatiooluene (BHT), propylgallate (PG), tert-butyl hydroquinone (TBHQ), the polyatomic phenol materials such as dilauryl thiodipropionate, vitamin E (VE), D-sodium ascorbate, Ascorbyl Palmitate, sulphite, L-cysteine hydrochloride, conventional antioxidant and the mixture thereof such as sulfur glycerol, it is more preferably selected from vitamin E, D-sodium ascorbate, dibenzylatiooluene and mixture thereof。
In the present invention, described preservative is putrid and deteriorated for the preparation postponing growth of microorganism or chemical change causes, its kind is not limited, as long as medicine corruption can be suppressed, it is preferably selected from Common Preservatives and the mixture thereof such as Nipagin ester preservative (such as methyl hydroxybenzoate, propylparaben), benzoic acid and sodium benzoate, sorbic acid and salt, benzalkonium bromide, chlorhexidine acetate, more preferably Nipagin ester preservative, benzalkonium bromide, sorbic acid and salt thereof。
In the present invention, described pH adjusting agent is for regulating the pH value of preparation, its kind is not limited, as long as the pH value of scalable preparation is to required scope, it is preferably selected from hydrochloric acid, sodium hydroxide, trometamol and all kinds of buffer salt system (such 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, preventing skin irritation from angularly considering, the pH of the tranexamic acid external preparation for skin nanometer formulation of the present invention generally can be 4.0～8.0, and is preferably 5.0～7.0。
According to the second aspect of the invention, it is provided that the preparation method of above-mentioned tranexamic acid external preparation for skin nanometer formulation, it comprises the following steps:
1) being dissolved in pure water by tranexamic acid and the water-soluble substances in emulsifying agent, medical additive, under 20～80 DEG C of conditions, stirring and dissolving makes its mix homogeneously, obtains aqueous phase；
2) by medicinal oil and the oil soluble material in emulsifying agent, medical additive, under 30～80 DEG C of conditions, stirring makes its mix homogeneously, obtains oil phase；
3) by described oil phase, aqueous phase mixing, high shear or high pressure homogenizer is adopted to prepare nanometer microemulsion under 20～80 DEG C of conditions；
4) by gained nanometer microemulsion with aqueous thickener solution by a certain percentage (proportion of nanometer microemulsion and aqueous thickener solution is preferably 9:1～6:4(w/w), more preferably ratio is 7:3(w/w)) it is mixed and stirred for uniformly, regulate pH value to 4.0～8.0(preferably 5.0～7.0) in scope, obtain tranexamic acid external preparation for skin nanometer formulation。
The tranexamic acid preparation for external application to skin of the present invention has the absorbability of excellence。For guaranteeing that it is absorbed by skin preferably, the mean diameter of the tranexamic acid external preparation for skin nanometer formulation of the present invention should less than 0.5 μm, and 90% particle-size accumulation value should less than 0.8 μm；Preferably, mean diameter should less than 0.3 μm, and 90% particle-size accumulation value should less than 0.5 μm；Most preferably, mean diameter should less than 0.15 μm, and 90% particle-size accumulation value should less than 0.3 μm。
The advantage of tranexamic acid external preparation for skin nanometer formulation of the present invention is in that: (1) composition (lipoid, protein, water) according to keratodermatitis, with there is good biocompatibility matrix material for matrix composition tranexamic acid external preparation for skin nanometer formulation, said preparation can by the fusion of matrix material Yu cell membrane realize tranexamic acid deep layer transhipment；(2) particle in tranexamic acid external preparation for skin nanometer formulation with nanoscale increases the percutaneous permeability of tranexamic acid also by nano effect, and then increases its curative effect；(3) tranexamic acid external preparation for skin nanometer formulation greatly reduces the untoward reaction of its systemic administration by local application。Therefore the tranexamic acid preparation for external application to skin according to the present invention has a good application prospect。
According to the third aspect of the present invention, it is provided that above-mentioned tranexamic acid external preparation for skin nanometer formulation is for preparing prevention or treatment mottle and chloasma, suppression tyrosinase activity, reduce reactive black pigment cell's quantity, reducing the purposes that melanin activity is formed and/or improves the dim heavy medicine of local skin。
The 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, suppression tyrosinase activity, reduce reactive black pigment cell's quantity, reduce melanin activity and form and improve local skin dim heavy。
Accompanying drawing explanation
Fig. 1 shows the curve chart (n=3) that result is investigated in the tranexamic acid external preparation for skin nanometer formulation isolated skin tissue Franz diffusion of preparation embodiment 1 and 2 preparation according to the present invention。
Fig. 2 be show according to the present invention preparation embodiment 1 and 2 preparation tranexamic acid external preparation for skin nanometer formulation isolated skin tissue Franz diffusion investigation result before 6h enlarged drawing (n=3)。
Fig. 3 shows the curve chart (n=3) that the tranexamic acid external preparation for skin nanometer formulation isolated skin tissue infiltration of preparation embodiment 1 and 2 preparation according to the present invention investigates result。
Detailed description of the invention
Below in conjunction with specific embodiment, and it is described in further detail the present invention with reference to data。Should be understood that these embodiments present invention solely for the purpose of illustration, it is intended to the concrete formula composition of the present invention, preparation method and function thereof and effect be described, but not the scope being intended to limit the present invention in any manner。
In the examples below, the various processes not being described in detail and method are conventional methods as known in the art。
In the present invention, agents useful for same, the source of equipment and trade name, all indicate when occurring first, identical reagent used is if no special instructions, all identical with the content indicated first thereafter。Wherein, tranexamic acid crude drug is purchased from Dongting Lake, Hunan pharmaceutcal corporation, Ltd。
Preparation embodiment
Preparation embodiment 1
Prescription 1:
Preparation method:
1. weigh recipe quantity tranexamic acid, glycerol (Ziguang Guhan Amino-acid Co., Ltd., Shantou's manufacture) is dissolved in pure water, adopt magnetic agitation (IKA company manufactures when 70 ± 10 ° of C, model: RETBasicC) in 300rpm stir about 10min, it is completely dissolved to obtain aqueous phase to tranexamic acid。
2. the ethyl hydroxybenzoate (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture) of recipe quantity, soybean oil (Tieling Beiya Medical Oil Co., Ltd.'s manufacture) are weighed, it is preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, polyoxyethylene castor oil (BASF Corp. of Germany's manufacture of recipe quantity is added after completing dissolving to ethyl hydroxybenzoate, trade name: CremophorEL) and VE(DSM vitamin (Shanghai) Co., Ltd. manufacture), continue stirring and make solution mix homogeneously obtain oil phase。
3. by oil phase, aqueous phase in 70 ± 10 ° of C water-baths, high shear machine (IKA company manufactures, model T25digital) is sheared 10min and is formed colostrum。
4. by this colostrum by high pressure homogenizer (ATSEngineeringInc. manufactures, model: AH100D), adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains tranexamic acid concentration nanometer microemulsion。
5. nanometer microemulsion and (Lubrizol company of the U.S. manufacture of 1% carbomer will be concentrated, model: 980NF) aqueous thickener solution is in 7:3(w/w) it is slowly stirred mixing under ratio room temperature condition, nanometer microemulsion is carried out thickening, regulate pH to 5.0～7.0 with NaOH, 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 (PolydispersityIndex, PI) 0.069。
Preparation embodiment 2
Prescription 2:
Preparation method:
1. weigh recipe quantity tranexamic acid, glycerol, D-sodium ascorbate (manufacture of Chemical Co., Ltd. of traditional Chinese medicines group) are dissolved in pure water, adopt when 70 ± 10 ° of C magnetic agitation to stir in 300rpm and about mix 10min, are completely dissolved to obtain aqueous phase to tranexamic acid。
2. the propylparaben (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture) of recipe quantity, Miglyol 812N (Tieling Beiya Medical Oil Co., Ltd.'s manufacture), Ovum Gallus domesticus Flavus lecithin (Japan mound manufactures) are weighed than company, it is preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, make each material dissolve to obtain oil phase。
3. by oil phase, aqueous phase in 70 ± 10 ° of C water-baths, high shear machine is sheared 10min and is formed colostrum。
4. by this colostrum by high pressure homogenizer, adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains tranexamic acid concentration nanometer microemulsion。
5. nanometer microemulsion and (Co., Ltd. of SHIN-ETSU HANTOTAI of the Japan manufacture of 2% hydroxypropylcellulose will be concentrated, model: HPC-H) thickened aqueous solutions liquid is in 7:3(w/w) it is slowly stirred mixing under ratio room temperature condition, nanometer microemulsion is carried out thickening, regulate pH to 5.0～7.0 with sodium dihydrogen phosphate, 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 (PolydispersityIndex, PI) 0.130。
Preparation embodiment 3
Prescription 3:
Preparation method:
1. weigh recipe quantity tranexamic acid, glycerol, benzalkonium bromide (Taicang Pharmaceutical Factory manufacture) are dissolved in pure water, adopt when 70 ± 10 ° of C magnetic agitation in 300rpm stir about 10min, are completely dissolved to obtain aqueous phase to tranexamic acid。
The dibenzylatiooluene (offer of Beijing Feng Lijingqiu commerce and trade company limited) of recipe quantity, Oleum Ricini (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture), Tween 80 (manufacture of Shanghai Shen Yu medication chemistry company limited) are 2. provided, it is preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, make each material dissolve to obtain oil phase。
3. by oil phase, aqueous phase in 70 ± 10 ° of C water-baths, high shear machine is sheared 10min and is formed colostrum。
4. by this colostrum by high pressure homogenizer, adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains tranexamic acid concentration nanometer microemulsion。
5. will concentration nanometer microemulsion and 1% hyaluronic acid (Furuida Biochemical Co., Ltd., Shandong's manufacture) aqueous thickener solution in 7:3(w/w) be slowly stirred mixing under ratio room temperature condition, nanometer microemulsion is carried out thickening, with sodium hydroxide molten adjustment 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 (PolydispersityIndex, PI) 0.100。
Preparation embodiment 4
Prescription 4:
Preparation method:
1. weigh recipe quantity tranexamic acid, SolutolHS15(BASF Corp. of Germany manufactures), sodium chloride (Jiangsu Province diligent pharmaceutcal corporation, Ltd manufacture), sorbic acid (Hunan Er-kang Pharmaceutical Co., Ltd.'s manufacture) be dissolved in pure water, magnetic agitation is adopted to stir 10min in 300rpm when 70 ± 10 ° of C, to being completely dissolved to obtain aqueous phase。
2. weigh the olive oil (Xi'an rehabilitation Pharmaceuticals Ltd of Zao Lutang Pharmaceutical group) of recipe quantity, VE, be preheated to 70 ± 10 ° of C, adopt magnetic agitation in 300rpm stir about 10min, make each material dissolve to obtain oil phase。
3. by oil phase, aqueous phase in 70 ± 10 ° of C water-baths, high shear machine is sheared 10min and is formed colostrum。
4. by this colostrum by high pressure homogenizer, adjustment pressure is 700～1200bar, circulates and within 5～15 weeks, obtains tranexamic acid concentration nanometer formulation。
5. will concentration nanometer formulation and 2% sodium carboxymethyl cellulose (Anhui Shanhe Medical Accessary Material Co., Ltd.'s manufacture) aqueous thickener solution in 7:3(w/w) be slowly stirred mixing under ratio room temperature condition, nanometer formulation is carried out thickening, regulate pH to 5.0～7.0 with citric acid-sodium citrate aqueous solution, 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 (PolydispersityIndex, PI) 0.060。
EXPERIMENTAL EXAMPLE
EXPERIMENTAL EXAMPLE 1
According to Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline, adopt and with the following method tranexamic acid external preparation for skin nanometer formulation is carried out skin irritation investigation。
Experimental technique: take the tranexamic acid external preparation for skin nanometer formulation of tested material 0.5g(above-mentioned preparation embodiment 1 preparation) it is directly coated at the plucked skin (animal: rabbit in side, source: Shanghai institute of materia medica Experimental Animal Center) on, then cover with two layers of gauze (2.5cm × 2.5cm) and one layer of cellophane or the like, then fixed with nonirritant adhesive plaster and binder；Opposite side coating blank formulation (, with preparation embodiment 1, prescription composition is except without all the other same preparation embodiments 1 except tranexamic acid for preparation method) compares。Stick 4 hours。After sticking end, remove tested material and with warm water or nonirritant solvent cleaned medicine-feeding part。Multiple dosing irritation test should continuously at same regional administration, and each administration time is identical, and sticking the time limit is 4 days。
Result is observed: observe dermoreaction under available light or full spectrum light。Skin erythema and edema are marked by the standards of grading provided by table 1。
Observe after every time removing medicine 1h and before again sticking and whether record erythema and edema, coating part have pigmentation, petechia, pachylosis or epidermatic atrophy situation and time of origin thereof and regression time, and erythema and edema are marked。After last sticks, removing after medicine 30-60 minute, 24 hours, 48 hours and perusal in 72 hours record coating part with or without the situation such as erythema and edema。
Evaluation of result:
Multiple dosing irritation test, first calculates each group of integral mean value of point each observing time, then calculates and observe animal integral mean value every day every in the time limit, carry out stimulus intensity evaluation by table 2。
Table 1 skin wound repair standards of grading
Table 2 skin irritation intensity evaluation standard
Rabbit zest investigates result in Table 3 and table 4。
Table 3 blank formulation rabbit irritant experiment result (n=4)
Table 4 tranexamic acid external preparation for skin nanometer formulation administration group rabbit irritant experiment result (n=4)
Whole experimentation has not been observed the situations such as pigmentation, petechia, pachylosis or epidermatic atrophy。From result, obtained ammonia first ring external preparation for skin nanometer formulation nonirritant, safety is good。
EXPERIMENTAL EXAMPLE 2
Select formula preparation tranexamic acid external preparation for skin nanometer formulation described in above-mentioned preparation embodiment 1 and preparation embodiment 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: Shanghai institute of materia medica Experimental Animal Center), after removing the tissues such as fat, muscle, mucosa, is clipped in the middle of improved Franz diffusing cells method, 32 DEG C of water-baths。Supply pool gives 0.5ml and investigates preparation: prescription 1, 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 take sample 0.5ml from reception tank, mend 0.5ml normal saline simultaneously。Take off skin histology after 24h, clean up, weigh, add 3ml normal saline homogenate, centrifugal, take supernatant and measure medicament contg with HPLC。Experimental result is shown in Fig. 1 and Fig. 2。
Ex vivo Permeation experimental technique: take neonate rat skin of back, after removing the tissues such as fat, muscle, mucosa, is laid in culture dish, 32 DEG C of water-baths。Skin keratin aspect gives to investigate preparation respectively: prescription 1, prescription 2 (maintenance 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 3ml normal saline homogenate, centrifugal, take supernatant and measure medicament contg with HPLC。Experimental result is shown in Fig. 3。
From Fig. 1, Fig. 2 and Fig. 3, the in vitro diffusion/permeability of neonate rat skin of back is totally presented the trend continuing to spread by above-mentioned two prescription, it was shown that good according to the tranexamic acid external preparation for skin nanometer formulation transdermal effect of the present invention。
EXPERIMENTAL EXAMPLE 3
Select the tranexamic acid external preparation for skin nanometer formulation of formula preparation described in above-mentioned preparation embodiment 1 and preparation embodiment 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: taking female mice (animal: Kunming mouse, source: Shanghai institute of materia medica Experimental Animal Center) 50, body weight 25～35g, with 10%Na2S(Chemical Reagent Co., Ltd., Sinopharm Group) aqueous solution sloughs hair on the right side of back, expose skin 1 piece, area is about 1.5cm × 1.5cm, with progesterone injection (Shanghai General Pharmaceutical Co., ltd. of 0.4%, specification 1ml:20mg) by 0.02g/kg dosage in mouse hind leg intramuscular injection, inject weekly 6d, continuous 4 weeks, lose hair or feathers weekly once。Normal group presses 0.02g/kg dosage in mouse hind leg intramuscular injection sterilized water for injection。
Animal administration and Indexs measure: take above-mentioned animal pattern, be randomly divided into 5 groups, often group 10。Normal group, model group, prescription 1, prescription 2, hydroquinone cream positive controls (Shanghai Changhai Hospital, specification 20g:0.4g)。Tranexamic acid preparation for external application to skin therapeutic component not in mice modeling local skin on same day medication, 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, time and the course for the treatment of with tranexamic acid preparation for external application to skin treatment group in modeling the same day。After medication 30 days, record cast animal medicine-feeding part cutaneous pigmentation state, cervical dislocation puts to death mice, back unhairing, takes rapidly the skin histology at coating position, with ice-cold normal saline flushing, remove blood, filter paper blots, and cuts skin 0.5g, puts in 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；It is centrifuged 15 minutes with 3500r/min rotating speed again, takes supernatant。Adopting xanthine oxidase, by SOD(superoxide dismutase) test kit (Bioengineering Research Institute is built up in Nanjing) detects description method and measures the SOD value in supernatant；Adopting thiobarbituricacidα-method, by MDA(malonaldehyde) test kit (Bioengineering Research Institute is built up in Nanjing) detects description method and measures the MDA value in supernatant。
After mice partial smearing tranexamic acid preparation for external application to skin, SOD enzyme activity in Skin tissue fluid, the measurement result of MDA and pigmentation state are in Table 5。
Mice skin tissue SOD, MDA assay (x ± s) respectively organized by table 5
Remarks: compare * P < 0.05, * * P < 0.01, x with model group: meansigma methods, s: standard deviation
As seen from Table 5: the indices of normal group, compared with model group, has pole significant difference (P < 0.01), illustrate that it is successful for replicating chloasma mouse model。In model group mice skin tissue, SOD enzyme activity content is substantially less than normal group, and after treating, in positive group, prescription 1 group, 2 groups of mice skin tissue of prescription, SOD enzyme activity content substantially increases, and positive group, prescription 1 group are respectively provided with significant difference (P < 0.05) with prescription 2 groups compared with model group。In addition, in model group mice skin tissue, content of propylene glycol is significantly higher than normal group (P < 0.01), and after treating, in positive group, prescription 1 group, 2 groups of mice skin tissue of prescription, mda content substantially reduces, and positive group, prescription 1 group are respectively provided with significant difference (P < 0.05) with prescription 2 groups compared with model group。Again, substantially there is pigmentation phenomenon in model group mouse skin, and positive group, prescription 1 group and 2 groups of pigments of prescription are all significantly desalinated。
The above results shows, the tranexamic acid preparation for external application to skin of the present invention can improve SOD enzyme activity and reduction mda content in local skin tissue, significantly improves the pigmentation situation of skin, compares with positive control hydroquinone group and there was no significant difference。Visible, the tranexamic acid preparation for external application to skin of the present invention can significantly improve pigmentation, and chloasma has obvious therapeutical effect。
Claims (15)
1. a tranexamic acid external preparation for skin nanometer formulation, it is mixed by following raw materials by weight:
Wherein, described medicinal oil is selected from vegetable oil, medium chain triglyceride, isopropyl myristate and mixture thereof,
Described medical additive is one or more in osmotic pressure regulator, pH adjusting agent, antioxidant and preservative, and described preservative is selected from Nipagin ester, benzoic acid and sodium benzoate, sorbic acid and salt, benzalkonium bromide, chlorhexidine acetate and mixture thereof,
Described thickening agent is selected from carbomer, hyaluronic acid, polyvidone, tragakanta, cellulose compound and mixture thereof,
The mean diameter of described tranexamic acid external preparation for skin nanometer formulation is less than 0.3 μm, and 90% particle-size accumulation value is less than 0.5 μm。
2. a tranexamic acid external preparation for skin nanometer formulation, it is mixed by following raw materials by weight:
Wherein, described medicinal oil is selected from vegetable oil, medium chain triglyceride, isopropyl myristate and mixture thereof,
Described medical additive is one or more in osmotic pressure regulator, pH adjusting agent, antioxidant and preservative, and described preservative is selected from Nipagin ester, benzoic acid and sodium benzoate, sorbic acid and salt, benzalkonium bromide, chlorhexidine acetate and mixture thereof,
Described thickening agent is selected from carbomer, hyaluronic acid, polyvidone, tragakanta, cellulose compound and mixture thereof,
The mean diameter of described tranexamic acid external preparation for skin nanometer formulation is less than 0.3 μm, and 90% particle-size accumulation value is less than 0.5 μm。
3. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described medicinal oil is selected from soybean oil, Oleum Camelliae, Oleum sesami, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, Oleum Ricini, Oleum Cocois, Miglyol 812N, isopropyl myristate and mixture 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, double; two Semen Myristicae phospholipid acid choline and mixture thereof。
5. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described emulsifying agent is selected from polyoxyethylene castor oil, Tween 80, Ovum Gallus domesticus Flavus lecithin, SolutolHS15 and mixture thereof。
6. tranexamic acid external preparation for skin nanometer formulation according to claim 1 and 2, wherein, described thickening agent is selected from carbomer, hyaluronic acid, carboxymethyl cellulose chlorins compound and mixture thereof。
7. 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 mixture thereof；
Described antioxidant is selected from Butylated hydroxyanisole, dibenzylatiooluene, propylgallate, tert-butyl hydroquinone, dilauryl thiodipropionate, vitamin E, D-sodium ascorbate, Ascorbyl Palmitate, sulphite, L-cysteine hydrochloride, sulfur glycerol and mixture thereof；
Described preservative is selected from Nipagin ester, sorbic acid and salt, benzalkonium bromide and mixture 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。
8. 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。
9. 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 5.0～7.0。
10. 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 less than 0.15 μm, and 90% particle-size accumulation value is less than 0.3 μm。
11. 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) being dissolved in pure water by tranexamic acid and the water-soluble substances in emulsifying agent, medical additive, under 20～80 DEG C of conditions, stirring and dissolving makes its mix homogeneously, obtains aqueous phase；
2) by medicinal oil and the oil soluble material in emulsifying agent, medical additive, under 30～80 DEG C of conditions, stirring makes its mix homogeneously, obtains oil phase；
3) by described oil phase, aqueous phase mixing, high shear or high pressure homogenizer is adopted to prepare nanometer microemulsion under 20～80 DEG C of conditions；
4) being mixed with aqueous thickener solution by gained nanometer microemulsion, wherein, the proportion of nanometer microemulsion and aqueous thickener solution is 9:1～6:4, and stirs, and regulates pH value to 4.0～8.0 scopes, obtains tranexamic acid external preparation for skin nanometer formulation。
12. method according to claim 11, wherein, step 4) in, the ratio of nanometer microemulsion and aqueous thickener solution is 7:3。
13. method according to claim 11, wherein, step 4) in, regulate pH value to 5.0～7.0 scopes。
14. the tranexamic acid external preparation for skin nanometer formulation described in claim 1 or 2 is for preparing prevention or treatment mottle, suppress tyrosinase activity, reduce reactive black pigment cell's quantity, reducing the purposes that melanin is formed and/or improves the dim heavy medicine of local skin。
15. purposes according to claim 14, wherein, described mottle is chloasma。
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| EP4349414A3 (en) | 2014-12-23 | 2024-06-19 | Dyve Biosciences, Inc. | Methods and formulations for transdermal administration |
| EP3681479B1 (en) | 2017-09-15 | 2024-01-31 | Dyve Biosciences, Inc. | Sodium bicarbonate for use in the treatment of gout and related disorders |
| US10980757B2 (en) | 2018-09-06 | 2021-04-20 | RTU Pharma SA | Ready-to-use tranexamic acid intravenous solution |
| CN111840417A (en) * | 2019-04-30 | 2020-10-30 | 成都铜雀台医学美容医院有限公司 | Injection for treating chloasma, preparation method and application thereof |
| CN112472809B (en) * | 2019-09-12 | 2022-08-19 | 中科微针（北京）科技有限公司 | Composition for fading color spots, microneedle patch containing composition and preparation method of microneedle patch |
| CN113116826A (en) * | 2021-04-20 | 2021-07-16 | 河北医科大学 | A topical carbamazepine nanometer preparation and its preparation method |
| CN113244437A (en) * | 2021-06-15 | 2021-08-13 | 福州大学 | Preparation method and application of bionic multifunctional composite sponge dressing |
| CN113662932A (en) * | 2021-08-30 | 2021-11-19 | 杭州拾珍医疗器械有限公司 | Novel nano tranexamic acid targeting preparation and preparation method thereof |
| US11642324B1 (en) | 2022-03-01 | 2023-05-09 | Bio 54, Llc | Topical tranexamic acid compositions and methods of use thereof |
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| CN116284814A (en) * | 2023-01-17 | 2023-06-23 | 杭州三式化妆品有限公司 | Supermolecule tranexamic acid glycolate ion salt and preparation method and application thereof |
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