CN109662988A - The feedstock composition and preparation method for treating leucoderma - Google Patents

The feedstock composition and preparation method for treating leucoderma Download PDF

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CN109662988A
CN109662988A CN201910056485.9A CN201910056485A CN109662988A CN 109662988 A CN109662988 A CN 109662988A CN 201910056485 A CN201910056485 A CN 201910056485A CN 109662988 A CN109662988 A CN 109662988A
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parts
muskone
handed
leucoderma
ethyl alcohol
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王晰
马丽华
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Sino Pharmaceutical Chiral Technology (dalian) Co Ltd
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    • AHUMAN NECESSITIES
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    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Abstract

The present invention relates to a kind of feedstock compositions for treating leucoderma, it is characterised in that: composition includes the following raw material by weight: left-handed muskone: 30-60 parts, dalbergia heartwood oil: and 15-30 parts, ethyl alcohol: 10-20 parts, 1,2 propylene glycol: 5-10 parts.Composition of the invention is significant to leucoderma therapeutic effect, and efficient and cure rate is very high, and treatment cycle is short, without side-effects, does not recur;Left-handed muskone, dalbergia heartwood oil and 1,2-PD, ethyl alcohol have synergistic effect, can be improved the therapeutic effect of leucoderma.

Description

The feedstock composition and preparation method for treating leucoderma
Technical field
The present invention relates to a kind of medical formulations, more particularly to a kind of feedstock composition for treating leucoderma and preparation side Method.
Background technique
Leucoderma is a kind of common posteriority limitation or general hair property skin pigment depigmentation disease.Since the melanocyte of skin is thin Born of the same parents' defunctionalization and cause, but pathogenesis is not currently fully understood.Each position of disease whole body can occur, and be common in finger Back, wrist, forearm, face, neck and surrounding genital etc..Female genitalia can also occur, and young women is in the majority.According to incomplete system Meter, in the leucoderma patient of China about as many as 35,000,000-4,000 ten thousand.For this disease without obvious inducement, doctor trained in Western medicine thinks may be with TYR is unbalance and the factors such as hereditary, autoimmunity, endocrine and refreshing essence are related.Due to etiology unknown, treatment is also without preferably doing Method.Traditional Chinese medicine very early, has the record at treatment " white place ", and have second prescription to the understanding of this disease in " 52 Bingfang ".Sui " General Treatise on the Cause and Symptoms of Diseases " of Tang Shidai, Prescriptions Worth Thousand Gold for Emergencies begins to claim " leucoderma ", " leucoderma " or " white lump ", and points out that its interpretation of the cause, onset and process of an illness is " ailment said due to cold or exposure is won in skin, vim and vigour discord " in treatment method, then based on wind-dispelling.There are also " vitiligos " in later age doctor and medicine writings Name, to this disease observation, description specifically, treatment substantially from wind, it is wet, heat it is several in terms of start with, advocate " treating suitable morning " " doctor Zong Jinjian ".
Current existing treatment means are:
(1) hormone therapy
The technology is primarily adapted for use in progressive stage patients with vitiligo generalized.Oral or intramuscular injection hormone, can make to be in progress The leucoderma at initial stage tends towards stability, and clinically common drug includes Halometasone ointment, Momestasone furoate cream etc..
(2) phototherapy and photochemotherapy
Narrow wave ultraviolet light (NB-UVB) treatment topical type or general hair property leucoderma have certain effect.
(3) transplantation treatment
Suitable for stationary phase, the skin lesion a few days is few, and without scar diathesis person.Common method includes AUTOEPIDERMIC GRAFTING, micro- Small autografts transplantation, self culture melanocyte transplanting etc..
(4) vitamin D 3-derivatives therapy
Substantially there is the side effect for the treatment of in above-mentioned therapy pros and cons half-and-half, such as single photochemical therapy first-elected at present has and draws A possibility that causing cutaneum carcinoma, cataract can occur for a few patients, furthermore it may also occur that the secondary work such as toxic hepatitis, katzeniammer With long-term Corticosteroids can upset the metabolic system of patient.Grafting skin survival rate is lower, some cannot not only restore The normal skin tone of itself can aggravate disease instead, vitamin D 3-derivatives side effect include erythema, scorching hot, irritation and Allergy etc., since drug long-time service will affect blood calcium concentration, the patient with calcium phosphorus insufficiency of accommodation such as impaired renal function is not It is suitble to use or need periodic monitoring blood calcium index.
Therefore the healing of leucoderma or very difficult, mostly because its course for the treatment of is very long and also curative effect be not it is very definite, This disease is currently without good method, mainly based on some externally applied drugs, can also take orally some Chinese and western drugs or some auxiliary The drug helped.Western medicine therapy can be with some steroids ointment of external application or immune regulative drug and optical treatment.It generally deposits at present The problem of be it is unobvious to the therapeutic effect of leucoderma, cure rate is lower, and treatment time is long, and side effect is larger and easy to be multiple Hair.
Summary of the invention
It is a primary object of the present invention to provide a kind of feedstock composition for treating leucoderma and preparation process, to be solved Certainly the technical issues of is effectively to treat leucoderma, is responded well to treatment fast, without side-effects, do not allow after treatment it is easy to recur, thus more Suitable for practical.
The object of the invention to solve the technical problems adopts the following technical solutions to realize.It proposes according to the present invention A kind of feedstock composition for treating leucoderma, including following raw material and auxiliary material and step:
Left-handed muskone: 30-60 parts, dalbergia heartwood oil: 15-30 parts, ethyl alcohol: 10-20 parts, 1,2 propylene glycol: 5-10 parts.
The object of the invention to solve the technical problems also can be used following technical measures and further realize.
Preferably, the feedstock composition for the treatment of leucoderma above-mentioned, wherein the composition includes following original by weight Material:
Left-handed muskone: 30 parts, dalbergia heartwood oil: 15 parts, ethyl alcohol: 10 parts, 1,2 propylene glycol: 5 parts.
Also the following technical solution is employed for the object of the invention to solve the technical problems to realize.It proposes according to the present invention A kind of feedstock composition for treating leucoderma preparation method, comprising the following steps:
Step 1: heating water bath, prepares ethyl alcohol and 1,1,2 propylene glycol will be added in the mixed liquor of 2 propylene glycol in triangular flask: 5-10 parts, ethyl alcohol: 10-20 parts, less than 45 DEG C, stirring 15min~20min is cooled to room temperature spare thermosol temperature;
Step 2: heating water bath, is added left-handed muskone 30-60 parts in another flat conical flask, heat up 30 DEG C At~35 DEG C, it is added dalbergia heartwood oil 20-30 parts and continuously stirs holding heat of solution 30min;Obtain left-handed muskone and dalbergia wood oil mixture;
Step 3: ethyl alcohol and 1 is added when measuring in bottle the temperature of left-handed muskone and dalbergia heartwood oil mixed liquor less than 35 DEG C, The mixed liquor of 2 propylene glycol, heating keep 40 DEG C~45 DEG C stirring heat of solution 30min~35min, are cooled to room temperature and combination is made Object.
Drug introduction:
Left-handed muskone
English name;L-MUSCONE
MF;C16H30O
MW;238.42
CAS#541-91-3
PSA:17.07000
LogP:5.27650
Physico-chemical property:
Density: 0.843g/cm3
Boiling point: 130 DEG C (0.5mmHg)
Flash-point: 145.3 DEG C
Boiling range (DEG C): 329.5 DEG C of at 760mmHg
Refractive index: 1.436
Specific rotation;- 11~-14
Vapour pressure: 25 ° of 0.000176mmHg at
C13C NMR:Predict (shellfish chemical network of rubbing) is as shown in Figure 1.
Left-handed muskone is bioactive ingredients and aromatic core in natural musk, is biologically active single right Body drug is reflected, can be extracted, artificial synthesized can also be obtained at present, pharmacological effect property through steam distillation method with natural musk It is clear, it can satisfy experiment condition and the quality analysis of reproducibility.
The left-handed expansible coronary artery of muskone increases coronary blood flow, plays promoting blood circulation, channels and collaterals, saturating flesh are opened in detumescence, analgesic The effect of bone, it is interior control apoplexy, middle gas, middle evil and infantile convulsion, control stable damage and the diseases such as sore outside and famous.
Left-handed muskone has optical activity, and subcutaneous injection will increase the superoxide dismutase SOD of subcutaneous free radical resisting Content reduces peroxide malonaldehyde (MDA) content, and mitigating ischemia symptom improves skin histology microcirculation.Ethyl alcohol, 1, 2 propylene glycol, which combine system, has collaboration to promote infiltration effect raw medicine, to the two-sided application of the lesion of persistent ailment, skin of the clinical observation to affected area Skin recovery has good therapeutic effect.Hemorheology index to leucoderma case the study found that the hematocrit of patient, Whole blood viscosity and whole blood reduced viscosity pole are apparently higher than normal controls group, show that the Blood denseness of patient increases, cause Blood flow is unsmooth, forms syndrome of blood stasis described in Chinese medicine.Recent studies shows that the main component of natural musk is left-handed Moschus Ketone, which has, has one's ideas straightened out, wards off dirty, promoting blood circulation, dissipating bind and powdered medicine ' Tongluosan ' stasis of blood effect, can expand local vascular, improve microcirculation.Left-handed Moschus Ketone13C NMR spectra is as shown in Figure 1.
Have been reported that Liao Cuilin, Zhu Guangdou etc. treat leucoderma, research theory collection with raceme muskone (dl-muscone) In in melanocyte in skin reduce or lack caused by depigmentation;Although dl- muskone treatment leucoderma has been described, It is the left-handed muskone subcutaneous injection joint composition topical application and narrow wave ultraviolet light (NB-UVB) irradiation treatment of native configurations The application that the traditional Chinese and western medicine of leucoderma combines has no that example is reported.
FDA thinks;" when stereoisomer is when can biologically distinguish, they seem to be different drugs ", dl- Muscone is a pair of of enantiomer, is to be made of respectively a pair of of enantiomer of R- (-) and S- (+) configuration, is that can biologically distinguish Raceme mixture, medicine of S- (+) configuration in chiral environment in the dl-muscone mapping structure body of domestic listing at present Whether have an apparent conversion for dynamics, the pharmacokinetics behavior of the isomers whether with another enantiomer therein Behavior is identical, there is no final conclusion, it is different classes of that thinking of the present invention, which is according to after a pair of of Chiral Separation in dl-muscone, Drug and realize purposes of the invention.Although dl-muscone has similar structure with L-muscone and seems similar medicine Effect, but in chiral environment it is two entirely different drugs;L-muscone is with optical activation is naturally occurring Object, pharmacokinetics is absorbed in vivo, is distributed, being metabolized and absolute bioavailability will be substantially better than the former;Its poison is secondary Effect can also be significantly less than the former.
Dalbergia heartwood oil
English name: Olibanum Gum
MF:C32H48O5
MW:512.72100
CAS:8050-07-5
Specific rotation :+3 °~+37 °
Fig. 3 is dalbergia heartwood oil molecular structural formula.
Dalbergia heartwood oil is mentioned by leguminous plant dalbergia wood santol, for colourless or yellowish oily liquids, has face cream and faint The lemonish smell of class, principal component β-heerabolene, trans--β-farnesene, trans--nerolidol etc. are nature and flavor temperature, pungent, have The promoting flow of qi and blood circulation dissipates the stasis of blood, and analgesic therapy of stopping blooding, sending down abnormally ascending wards off dirty effect;" this is through meeting original " record drop smells good, and color is red, enters blood system and declines, Energy promoting circulation of blood broken stasis of blood, can stop blooding analgesic therapy;Chinese medicine effect of dalbergia heartwood oil: regulating qi-flowing for relieving pain, promoting blood circulation to remove blood stasis, doctor trained in Western medicine pharmacology: drop blood is viscous, drops blood Rouge improves microcirculation.
The left-handed muskone of the present invention and being used in combination for dalbergia heartwood oil are combined with good synergistic effect with phototherapy, can effectively protect Shield phototherapy Irradiation on Skin is burnt.Also it can avoid for laser means treatment leucoderma is used alone especially in sensitivity Mucous membrane in addition to skin lesion also often shine in single laser by involvement on the inside of the leucoderma at position such as lip, labia, glans penis and foreskin Penetrate bring side effect;Left-handed muskone and dalbergia heartwood oil are the compounds respectively containing one and four carbonyl, general carbon-based Compound wavelength photoreceptor is in UVA and visible-range, and wavelength period is to absorb purple light color to be also referred to as black light area, using narrow wave UVB The theory of phototherapy thinks;Leucoderma is the depigmentation spot due to caused by being reduced melanocyte in skin or missing.Using photochemical The target for learning the narrow spectrum UVB irradiation of therapy is activation tyrosinase activity, promotees melanin and is formed.Pigmentation effect is also known as blackspot Effect, it refers to that ultraviolet radioactive penetrates skin deep part, and quasi- melanin substance existing for there, which is oxidized to form melanin, makes skin Blackening, ultraviolet radioactive continue to irradiate, and the melanin being continuously generated will form pigmentation.
Composition molecule can in visible-range after left-handed muskone being subcutaneously injected and composition crust smears drug Luminous energy is absorbed, molecule becomes excitation state by ground state, and photolysis (Norrish) reaction of carbonyls, carbonyl occur for molecule Covalent bond between adjacent carbon atom is elongated, reduction, is broken, and generates primary group of free radicals, causes radical UV curing system, fragrance Ketone compounds usually pass through hydrogen and extract initiated polymerization.The response feature of dalbergia heartwood oil alkene also all occurs in functional group C=C Reaction with alkene most of on C-H has the disconnection of double bond and forms two new singly-bounds.Left-handed muskone and dalbergia heartwood oil group Daily illumination rate of polymerization can also be improved by closing object.This may be more advantageous to generation excitation state due to compound, increase and generated Free base unit weight, function similarly to the effect of fragrant ketone photoinitiator.UV curing system is generally low pole environment, Left-handed Moschus one compositions induction natural lighting is also particularly advantageous to the formation of free radical and the reaction of the pigmentation effect in later period.
Light-initiated chemical reaction with and subsequent polymerization reaction in play a leading role is free radical intermediate, this is also Using the more extensive reason of the light-initiated reference of compound free radical " and cation light initiator is under photoreactivation, molecule To excitation state, series of decomposition reaction can occur for molecule, generate super strong proton acid or lewis acid, the activity as cationic polymerization It plants and initiated polymerization.Aromatics carbonyls near ultraviolet band maximum absorbing wavelength in 380~420nm, and inhale Strong, peak width is received, hydrogen-taking capacity is strong.And it is this under the conditions of photosensitive absorption also have certain protection to corium and cuticula and make With.
The EtOH and PG of 75% concentration combine system and left-handed muskone and dalbergia heartwood oil high proportion are solvable, 1,2 propylene glycol Hydrophily by penetrate into polarity channel formed savings, dissolution cuticula a- albumen and therewith formed hydrogen bond promote skin hydration drop Low channel resistance.Ethyl alcohol is amphiphilic solvent, can swellable hydrophilic albumen can also extract lipoids, ethyl alcohol and 1,2 propylene glycol connection It closes using drug can be increased in the distribution coefficient and diffusion coefficient of each phase and film two sides, increases infiltration rate, left-handed Moschus Ketone is the chemical structure efficiency relationship that R- (-) configuration macrocyclic ketone has similar Stratum corneum lipids, and double bond structure forms asymmetry Space effectively influences the lipid structure in space between cells, enhances the mobility of lipoids, thus can also promote lipophilic drugs Transdermal operating, EtOH combines system with PG can be effectively by the hydrophilic and oleophilic channel of skin multilayer to the dissolution and delivery of main ingredient Therapeutic effect is played to leucoderma lesion.
By above-mentioned technical proposal, the feedstock composition and preparation method of present invention treatment leucoderma at least have following excellent Point:
1, composition of the invention is significant to leucoderma therapeutic effect, and cure rate is very high, and treatment cycle is short, no secondary work With not recurring;Left-handed muskone, dalbergia heartwood oil and 1,2-PD, ethyl alcohol have synergistic effect, can be improved the treatment of leucoderma Effect.The present invention can make drug distribution uniform using needle-free transdermal disperse injection technique, increase the disperse diffusion of medical fluid and inhale It produces effects fruit, medical fluid is diffused into hickie subcutaneous tissue with mist, is evenly distributed, and targeting is strong, is conducive to the absorption of drug, is improved Therapeutic effect does not leave callosity.
2, synergistic effect is stored using the absorption that spread compositions and the left-handed muskone of injection increase optics energy when phototherapy, it is right The formation of free radical and the reaction of the pigmentation in later period are particularly advantageous.
3, two taste medicine prescription raw materials are simple, and type is few, and left-handed muskone is the androsterone hormone like substance of native configurations It is that cytochrome P 450 Enzyme inducer has resuscitation with aromatics, clearing and activating the channels and collaterals, swelling and pain relieving and anti-inflammatory effect, dalbergia heartwood oil is also one Its ingredient of the hydrocarbon of kind native configurations accounts for about many plant colors of 90% this kind of compounds of crude oil based on terpenes Element plays important role in photosynthesis.Terpenes has two or more double bonds, it is also that atmospheric reaction is living Property very strong hydrocarbon, two kinds of raw materials all have the optical activity property of native configurations, and are all single-activity enantiomer, Single medicine effect targeting mechanism is clear.The indication of two medicine drug combinations is: playing clearing and activating the channels and collaterals, swelling and pain relieving, antibacterial anti-inflammatory Enter blood system with dalbergia heartwood oil and decline, promoting circulation of blood broken stasis of blood dissipates the synergistic effect of the stasis of blood, to heighten the effect of a treatment, postpones or reduce going out for drug resistance It is existing;The combined use of two medicines can expand clearing and activating the channels and collaterals, promoting circulation of blood broken stasis of blood range;Reduce antagonism or toxicity.It is generally acknowledged that: two kinds of medicines It manages similar single-activity enantiomer to be used in combination and antagonism phenomenon occurs and only accounts for 3%~5%, ailment said due to cold or exposure is won in skin Skin, two medicine of leucoderma of vim and vigour discord obtains synergistic effect chance after being used in combination increase;It is opposite to be better than individually with left-handed musk deer Ketone musk or dalbergia heartwood oil issuable mechanism of drug resistance when being raw material;Such as: inactivator changes target, changes logical, forced-ventilated etc. that increase antagonism existing As, thus have the function of good synergy.
4, preparation process provided by the present invention is simple to operation;Realize two kinds of optical activities in composition again simultaneously Single enantiomer combination without side-effects;Both drug safety is improved, human skin absorption, main ingredient medicine target in preparation are also easy to Clear to the mechanism of action, major ingredient and auxiliary material physicochemical property chemical can quantify, and curative effect specificity is clear, provide for treatment leucoderma One more effective approach.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention, And can be implemented in accordance with the contents of the specification, it with presently preferred embodiments of the present invention and is described in detail with the accompanying drawings as follows below It states.
Detailed description of the invention
Fig. 1 is left-handed muskone molecular formula of the invention.
Fig. 2 is injection thin layer of transparent plastic sheet grid coral
Fig. 3 is dalbergia heartwood oil molecular structural formula
Specific embodiment
It is of the invention to reach the technical means and efficacy that predetermined goal of the invention is taken further to illustrate, below in conjunction with Attached drawing and preferred embodiment, to it is proposed according to the present invention treatment leucoderma feedstock composition and preparation process its specific implementation Mode, feature and its effect, detailed description is as follows.In the following description, different " embodiment " or " embodiment " refers to not It must be the same embodiment.In addition, the special characteristic or feature in one or more embodiments can be combined by any suitable form.
Following embodiment material therefor, method and instrument, without specified otherwise, be this field conventional material, method and Instrument, those of ordinary skill in the art can be obtained by commercial channel.
Composition auxiliary material is described below in the present invention:
Ethyl alcohol
English name: Ethanol
Chemical formula: C2H6O
Molecular weight: 46.07
Density;0.789(20℃)
Boiling point: 78.3 DEG C
Fusing point: -114.1 DEG C of EINECSCC
1,2 propylene glycol
Product English name: 1,2-Propanediol;
Molecular formula: C3H8O2
Molecular weight: 76.09
Relative density: (20/20 DEG C) 1.0381
Appearance: colourless moisture absorption thick liquid, it is almost tasteless odorless.
Boiling point: 188.2
Fusing point: -59 DEG C.
Embodiment 1
Composition includes the following raw material by weight:
Left-handed muskone: 30 parts, dalbergia heartwood oil: 15 parts, ethyl alcohol: 10 parts, 1,2 propylene glycol: 5 parts.By above-mentioned raw materials according to such as Lower step preparation,
Step 1: heating water bath, ethyl alcohol and 1 are prepared, the mixed liquor of 2 propylene glycol is added 1,2 the third two simultaneously in triangular flask Alcohol: 5 parts, ethyl alcohol: 10 parts, 40 DEG C~45 DEG C of thermosol temperature continuously stir 15min~20min be cooled to room temperature it is spare;
Step 2: heating water bath, 30 parts of left-handed muskone are added in flat conical flask, heat up 55 DEG C~65 DEG C, stir It mixes and keeps heat of solution 20min-30min;
Step 3: water-bath cools down, left-handed muskone bath temperature is down to 30 DEG C~35 DEG C, and measure left-handed muskone When temperature is less than 30 DEG C, 15 parts of dalbergia heartwood oil are added, continues to stir 15min~20min, rear that ethyl alcohol and 1 is added, 2 propylene glycol are mixed Liquid is closed, stirring heats 40 DEG C~45 DEG C, keeps heat of solution 30min~35min, composition is made to room temperature after cooling.Character To be colourless to pale yellow transparent oily liquids.
Embodiment 2
Composition includes the following raw material by weight: take left-handed muskone: 60 parts, and dalbergia heartwood oil: 30 parts, ethyl alcohol: 20 parts, 1, 2 propylene glycol: 10 parts.Above-mentioned raw materials are prepared in accordance with the following steps,
Step 1: heating water bath, ethyl alcohol and 1 are prepared, 2 mixed with propylene glycol liquid are added 1,2 propylene glycol in triangular flask: 10 Part, ethyl alcohol is added after stirring 10min in thermosol temperature 45 C: 20 parts, continue to stir 15min~20min be cooled to room temperature it is spare;
Step 2: heating water bath, 60 parts of left-handed muskone are added in another flat conical flask, heat up 55-65 DEG C, stir It mixes and keeps heat of solution 30Min;
Step 3: water-bath cools down, left-handed muskone bath temperature is down to 30 DEG C~35 DEG C, and measure left-handed muskone When temperature is less than 30 DEG C, 30 parts of dalbergia heartwood oil are added, continues to stir 15min~20min, adds ethyl alcohol and 1,2 propylene glycol are mixed Liquid is closed, stirring keeps 40 DEG C~45 DEG C temperature, and composition is made to room temperature after cooling in heat of solution 30min~35Min.
Embodiment 3
Composition includes the following raw material by weight: take left-handed muskone: 45 parts, and dalbergia heartwood oil: 25 parts, ethyl alcohol: 15 parts, 1, 2 propylene glycol: 8 parts.Above-mentioned raw materials are prepared as follows,
Step 1: heating water bath, prepares ethyl alcohol and 1,1,2 propylene glycol are added in the mixed liquor of 2 propylene glycol in triangular flask: 8 parts, thermosol temperature is added ethyl alcohol after stirring 10min: 15 parts, continuing stirring 15min~20min and be cooled to room temperature less than 45 DEG C It is spare;
Step 2: heating water bath, 45 parts of left-handed muskone are added in flat conical flask, heat up 55-65 DEG C, stirring Keep heat of solution 30min;
Step 3: water-bath cools down, left-handed muskone bath temperature is down to 30 DEG C~35 DEG C, and measure left-handed muskone When temperature is less than 30 DEG C, 25 parts of dalbergia heartwood oil are added, continues to stir 15min~20min, adds ethyl alcohol and 1,2 propylene glycol are mixed Liquid is closed, stirring keeps 40 DEG C~45 DEG C temperature, and composition is made to room temperature after cooling in heat of solution 30min~35Min.
Embodiment 4
Composition includes the following raw material by weight: left-handed muskone: 56 parts, dalbergia heartwood oil: and 28 parts, ethyl alcohol: 19 parts, 1,2 Propylene glycol: 9 parts.Above-mentioned raw materials are prepared in accordance with the following steps,
Step 1: heating water bath, ethyl alcohol and 1 are prepared, 1,2 propylene glycol are added: 9 in triangular flask by the mixed liquor of 2 propylene glycol Part, ethyl alcohol is added after stirring 10min in thermosol temperature 45 C: 19 parts, continue to stir 15min~20min be cooled to room temperature it is spare;
Step 2: heating water bath, 56 parts of left-handed muskone are added in another flat conical flask, heat up 55-65 DEG C, even Continuous stirring, keeps heat of solution 30Min;
Step 3: water-bath cools down, left-handed muskone bath temperature is down to 30 DEG C, 28 parts of dalbergia heartwood oil is added, continues to stir 15min~20min, adds ethyl alcohol and 1, the mixed liquor of 2 propylene glycol, stirring, keeps 45 DEG C of temperature, and heat of solution 30min~ Composition is made to room temperature after cooling in 35min.
Embodiment is finish on this.
Reference examples 1
Composition includes the following raw material by weight: dalbergia heartwood oil: 28 parts, ethyl alcohol: and 19 parts, by above-mentioned raw materials according to following step Rapid preparation.
Heating water bath prepares the mixed liquor of ethyl alcohol and dalbergia heartwood oil, addition dalbergia heartwood oil in triangular flask: 28 parts;Ethyl alcohol: 19 parts; 35 DEG C of thermosol temperature, composition is made to room temperature after stirring 15min~20min is cooling
Reference examples 2
Composition includes the following raw material by weight: dalbergia heartwood oil: 25 parts, ethyl alcohol: and 15 parts, 1,2 propylene glycol: 8 parts.It will be above-mentioned Raw material is prepared as follows,
Heating water bath, prepares ethyl alcohol and 1, the mixed liquor of 2 propylene glycol, is added 1,2 propylene glycol simultaneously in triangular flask: 8 Part, ethyl alcohol: 15 parts, thermosol temperature less than 45 DEG C, stir water-bath after 10min be added when being cooled to less than 35 DEG C 25 parts of dalbergia heartwood oil after Continuous stirring 15min~20min, which is cooled to room temperature, is made composition;
Reference examples 3
Composition includes the following raw material by weight: take left-handed muskone: 1 part, and dalbergia heartwood oil: 30 parts, ethyl alcohol: 20 parts, 1,2 Propylene glycol: 10 parts.Above-mentioned raw materials are prepared in accordance with the following steps,
Step 1: heating water bath, ethyl alcohol and 1 are prepared, 2 mixed with propylene glycol liquid are added 1,2 propylene glycol in triangular flask: 10 Part, ethyl alcohol is added after stirring 10min in thermosol temperature 45 C: 20 parts, continue to stir 15min~20min be cooled to room temperature it is spare;
Step 2: heating water bath, 1 part of left-handed muskone is added in another flat conical flask, heats up 55-65 DEG C, stir It mixes and keeps heat of solution 20min;
Step 3: water-bath cools down, left-handed muskone bath temperature is down to 30 DEG C~35 DEG C, and measure left-handed muskone When temperature is less than 35 DEG C, 30 parts of dalbergia heartwood oil are added, continues to stir 15min~20min, adds ethyl alcohol and 1,2 propylene glycol are mixed Liquid is closed, 30 DEG C~35 DEG C temperature are kept, heat of solution 30min~35min is stirred, composition is made to room temperature after cooling.
Reference examples 4
Composition includes the following raw material by weight: taking left-handed muskone: 30 parts, dalbergia heartwood oil: 15 parts, above-mentioned raw materials being pressed It is prepared according to following steps,
30 parts of left-handed muskone are added in flat conical flask heating water bath, heat up 55-65 DEG C, and stirring keeps thermosol Solve 20min;When water-bath cools down and measures the temperature of left-handed muskone less than 35 DEG C, 15 parts of dalbergia heartwood oil are added, continues to stir 15min Composition is made to room temperature after~20min is cooling
Embodiment
Phototherapy three are irradiated using smearing+NB-UVB on lesion subcutaneous injection+lesion skin to patients with vitiligo in the present invention Use in conjunction therapeutic scheme.
The left-handed muskone of injection stage needs purification process;Purification process such as following: take left-handed muskone 100g (in it is micro- Know and write the production of drug chiral technology (Dalian) Co., Ltd), chemical purity 98%, water-bath is heated up to 50 DEG C of stand-by, three mouthfuls of connections Round bottom cucurbit and relief pipe, stirring rod, tripod are equal to above water-bath, and 75% ethyl alcohol 100g of precision weighing first pours into L- Ethyl alcohol is added after muscone to be placed in another triangular flask, is poured into round bottom cucurbit after being sufficiently mixed uniformly, water-bath is heated up to 60 DEG C~65 DEG C, the distillation of 0.06Mpa vacuum decompression keeps fraction 40Min~50Min, is cooled to room temperature precision weighing, obtains 99% left-handed muskone about 97g after purification.Character is colourless to pale yellow transparent oily liquids.The left-handed muskone oil of injection Agent preparation should meet " chemicals injection main technique requirements (tentative) " (medicine examines center 2008) specification, quality index According to " preparation of Chinese Pharmacopoeia 2005 version (two) oil for injection solution standard, preparation process further include left-handed after refining Muskone 150 DEG C hot air sterilization 1-2 hours, and let cool to the conventional inlines such as suitable temperature operate;Sterility test is according to nothing Method (Ⅹ III B of annex) under bacterium inspection technique item checks that clarity test should meet specification regulation
Specific treatment implementation method are as follows: using the transdermal disperse technology in Needleless injection, leucoderma affected part is carried out subcutaneous Left-handed muskone is injected, the point hole of the grid mark provided according to attached drawing 2 is injected weekly twice, and per injection amount is 0.006ml~0.009ml/cm2, while leucoderma affected part is smeared with composition, smears weekly secondary, applying amount is 0.02ml~0.03ml/cm2, smear after 1 day to carried out at the leucoderma of patient joint NB-UVB irradiate, 2 times a week according to It penetrates, subcutaneous injection and phototherapy were performed separately (interim date is smearing day) every 2 days;It is applied to injection and phototherapy blank day implements, 2 times a week;Since minimum hickie amount;4 weeks as a treatment course, and first course for the treatment of starts to take effect, and continuously treats 6 courses for the treatment of, most 2 courses for the treatment of are consolidation afterwards.(specific Joint Implementation chronological order is referring to table 4;Irradiation time reference table 5;NB-UVB radiation instrument For commercially available conventional plain edition.)
Measurement minimal phototoxic dose is needed before NB-UVB irradiation treatment, and using sub- phototoxic dose as initial illumination amount.Transdermal disperse skill Thin layer of transparent plastic sheet band grid of holes coral is chosen in art, is punched on the grid coral crosspoint using commercial punch, by the net Ge Shan is attached at leucoderma, by hole site injection drug, each hole site 0.006ml~0.009ml/cm of injection volume2, every 4 Lattice are 1cm2.Above-mentioned Needleless injection drug distribution is uniform, increases disperse and the assimilation effect of medical fluid, and medical fluid is diffused into mist It in hickie subcutaneous tissue, is evenly distributed, targeting is strong, is conducive to the absorption of drug, improves therapeutic effect and does not leave callosity.
Composition toxicologic study
Implement according to " Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline " method, evaluation criterion It is calculated by table 1;
1 Chemical induced irritation of table, anaphylaxis and hemolytic evaluation
Skin allergy experiment:
Test group: 30 5 week old of cavy, weight 250-350g, half male and half female animal selection: are selected.In to tested preceding 24 Hour takes off guinea pig back diamond wool, the every side of unhairing range about 3cm × 3cm.
Experimental group 2 drug of composition embodiment, 75% alcohol of control group.Positive sensitizer: 2,4- dinitro-chlorine generation (Liaoning chemical reagent work produces benzene, lot number: 170321190320), with sesame oil is configured to 1% sensitization concentration and 0.1% excitation dense Spend medical fluid.
Experimental group: cavy is randomly divided into 3 groups, every group 10 (half male and half female) by weight, gender.1st group to experiment Drug, the 2nd group is given 75% alcohol, and the 3rd group to positive sensitizer.
Sensitization contact: it takes experimental drug .2ml to be coated in hair removal section on the left of cavy, is put into animal house after to be dried.7th day and 14th day, in kind respectively repeat secondary 8.2nd group is same as above with the 3rd group of medication.
Experimental result:
It is observed after first group of 7 days, 14 days tested day and tested example and does not occur erythema or oedema, also do not occurred Other symptoms.Sensitization rate is O.
There is erythema in observation after second group of 7 days, 14 days tested day and tested example or oedema is 3 total, does not go out Existing other symptoms, sensitization rate are 30%.
There are erythema or oedema 6 in observation when 7 days tested days of third group, severe occurs after 14 days and tested example Oedema 1, moderate erythema 1, Severe edema symptom 2, sensitization rate is 100%
Acute toxicity test:
30 5 week old of SD big white mouse are chosen, are divided into 2 groups by male and female, upper one day is tired at the bilateral skin shaving of big white mouse back Meter coating 0.08ml/cm2The composition of embodiment 1, observation in 7-14 days is not as a result, find that the poison of whole body or local skin is secondary anti- It answers, appetite and daily routines behavior are normal.
Long term toxicity test: choosing above-mentioned test group SD big white mouse, divides three groups, first group, second group uses anxious poison test Mouse group, third group male and female are random, at this group of white mouse back skin shaving on smear the composition of embodiment 2, continuously smear six A month, third group applying amount was respectively 10 times of clinical treatment amount, 20 times, 30 times, and first during test, two, three groups of white mouse are equal The toxicity of whole body or local skin erythema or oedema is not found.
The composition compatibility of embodiment 2 be highest usage amount be prepared into finish, respectively under the conditions of as described above Embodiment 1 carries out the hypersensitive test of skin, anxious malicious and long-term poison test, as a result identical.
It follows that the feedstock composition for the treatment of leucoderma provided by the invention does not generate allergy to skin and poison is secondary anti- It answers.
The test of animal delayed type hypersensitivity, DTH and subcutaneous injection test (omission) are by the left-handed muskone poison of following documents evidence Reason research confirms:
(1), the effect natural musk ketone or muscone's ketone of Central nervous system have centainly the conditioned reflex of animal Influence, and change with dosage.As low dose of (0.002mg/kg) to the conditioned reflex of big white mouse food movement without significant shadow It rings;Median dose (0.01~0.05mg/kg) can make positive conditioned reflex prolongation of latency or reaction disappear, and differentiation phase improves, There is individual animal differentiation phase to be suppressed;When large dosage of (1mg/kg) then most animals be in intoxicating phenomenon, show as positive item The reaction of part reflection is irregular or disappears, and differentiation phase is suppressed.
(2), toxicity
Mouse vein infuses muskone emulsion, LD50 172mg/kg.The LD50 of intraperitoneal injection is 270~290mg/kg. Sub-acute toxicity test: muskone 56mg/kg intraperitoneal injection, one time a day, total 20d can be such that Rat Erythrocytes reduce, leucocyte Increase visually observes, and liver, spleen increase compared with control group, and edge thickness is pure, has no that recovery is normal after being discontinued 1 week.Dog intramuscular injection is artificial Muskone injection 400mg/kg or 800mg/kg, continuously inject 14d, and as a result: all dog foods are intended to increase, freedom of movement.Injection Phenomena such as non-show in position, swollen, heat and lump.Liver and kidney function and blood are mutually also had no significant effect.Each internal organs of microscopy do not find different Often variation.Every 1.2g of monkey, the continuous 2d that injects is also without any toxic reaction." Baidupedia "
https://www.chemicalbook.com/ProductChemicalPropertiesCB1378768. htm
Clinical test
Case clinical diagnosis and criterion of therapeutical effect are according to " leucoderma clinical classification and criterion of therapeutical effect (2003) revise original text "
Criterion of therapeutical effect
Recovery from illness: hickie all subsides, and restores normal skin tone.
Effective: hickie partial remission or diminution, the area for restoring normal skin tone account for skin lesion area >=50%.
It improves: hickie partial remission or diminution.
Invalid: the regeneration of hickie non-pigment or range expand.
Case selection 40: dividing experimental group and control group each 20.
Table 2, experimental group case
Table 3, control group case
Name/gender Age The course of disease Clinical diagnosis Serial number
All XX, male 40 5 Vulgaris;General hair, progressive stage 1
Grandson XX male 29 4 Vulgaris;General hair, progressive stage 2
Liu X male 55 4 Vulgaris;Limitation, stationary phase 3
Neat X male 33 3 Vulgaris;Limitation, progressive stage 4
XX female Xu 29 2 Vulgaris;General hair, progressive stage 5
Liu XX male 37 2 Vulgaris limitation progressive stage 6
Grandson X male 49 6 Vulgaris;Limitation, stationary phase 7
XX female Lee 55 5 Vulgaris acra stationary phase 8
Flourish XX male 42 4 Segmental pattern imperfection hickie progressive stage 9
Chu XX male 49 2 Vulgaris;Being dispersed in property, progressive stage 10
Yellow XX male 43 3 Segmental pattern imperfection hickie progressive stage 11
Open XX male 45 2 Segmental pattern imperfection hickie progressive stage 12
Open X male 31 1 Vulgaris limitation progressive stage 13
King XX male 36 2 Vulgaris acra stationary phase 14
Zhu XX male 29 3 Vulgaris;Limitation, stationary phase 15
Grandson XX female 40 3 Vulgaris;General hair, progressive stage 16
Open XX male 43 3 Vulgaris acra stationary phase 17
Lee XX male 50 4 Segmental pattern imperfection hickie progressive stage 18
XX female Lee 41 7 Vulgaris;Limitation, stationary phase 19
King XX female 19 2 Vulgaris;General hair, progressive stage 20
It is one group 8 groups total to experimental group and control every 5 people of group selection according to diagnosis typing,
1 parting of experimental group is vulgaris general hair property progressive stage;2 parting of experimental group is vulgaris limitation stationary phase;Experiment Group 3 and the random parting of experimental group 4;
Control group is 1-1,2-2,3-3, and totally 4 component types are identical with experimental group by 4-4.
Test result: experimental group and the curative effect of control group are shown in Table 6;
4 therapeutic scheme schedule of table
Monday Tuesday Wednesday Thursday Friday Saturday Sunday
Injection It smears NB-UVB Injection It smears NB-UVB It recuperates day
5 phototherapy irradiation time length table of table
Irradiate number Facial (S) Trunk (S) Brothers (S)
1st day 6 6 6
4th day 8 8 8
7th day 11 11 11
10th day 13 13 13
13rd day 16 16 16
16th day 20 20 20
19th day 25 25 25
22nd day 32 32 32
25th day 41 41 41
28th day 51 55 55
31st day 51 65 65
34th day 51 76 76
37th day 51 90 90
40th day 51 120 120
The N days The quantity of illumination < 52s The quantity of illumination < 180s The quantity of illumination < 220s
Experimental group 1: specific therapeutic scheme is implemented according to table 4,5 method of table.Using the transdermal disperse technology in Needleless injection The leucoderma affected part of patient is carried out left-handed muskone is subcutaneously injected, per injection amount is 0.006ml~0.009ml/cm2, together When smeared with finish prepared by the composition of embodiment 1 at the leucoderma of patient, applying amount is 0.02ml~0.03ml/ cm2, furthermore to joint NB-UVB irradiation (narrow wave ultraviolet light) is carried out at the leucoderma of patient, irradiate, since minimum hickie amount; 4 weeks as a treatment course, and first course for the treatment of starts to take effect, and continuously treats 6 courses for the treatment of, and last 2 courses for the treatment of are consolidation.
Experimental group 2: specific implementation method is identical as 1 method of experimental group;Simultaneously at the leucoderma of patient with embodiment 2 The finish of composition preparation is smeared, and applying amount is 0.02ml~0.03ml/cm2, furthermore carried out at the leucoderma of patient Joint NB-UVB irradiates (narrow wave ultraviolet light), since minimum hickie amount;4 weeks as a treatment course, and first course for the treatment of starts to see Effect, continuously treats 6 courses for the treatment of, and last 2 courses for the treatment of are consolidation.
Experimental group 3;Specific implementation method is identical as 1 method of experimental group;Simultaneously at the leucoderma of patient with embodiment 3 The finish of composition preparation is smeared, and applying amount is 0.02ml~0.03ml/cm2, furthermore carried out at the leucoderma of patient Joint NB-UVB irradiates (narrow wave ultraviolet light), irradiation, since minimum hickie amount;4 weeks as a treatment course, and first course for the treatment of starts It takes effect, continuously treats 6 courses for the treatment of, last 2 courses for the treatment of are consolidation.
Experimental group 4;Specific implementation method is identical as 1 method of experimental group;Simultaneously at the leucoderma of patient with embodiment 4 The finish of composition preparation is smeared, and applying amount is 0.02ml~0.03ml/cm2, furthermore carried out at the leucoderma of patient Joint NB-UVB irradiates (narrow wave ultraviolet light), irradiation, since minimum hickie amount;4 weeks as a treatment course, and first course for the treatment of starts It takes effect, continuously treats 6 courses for the treatment of, last 2 courses for the treatment of are consolidation.
Control group 1-1:
Specific implementation method are as follows: it is smeared with composition prepared by reference examples 1 at the leucoderma of patient, it is secondary weekly, it applies The amount of smearing is 0.02ml~0.03ml/cm2, furthermore to carried out at the leucoderma of patient joint NB-UVB irradiation (narrow wave ultraviolet light), It irradiates 2 times a week, since minimum hickie amount;4 weeks as a treatment course, continuously treats 6 courses for the treatment of, and last 2 courses for the treatment of are to consolidate Phase.
Control group 2-2:
Specific implementation method are as follows: it is smeared with composition prepared by reference examples 2 at the leucoderma of patient, it is secondary weekly, it applies The amount of smearing is 0.02ml~0.03ml/cm2, furthermore to carried out at the leucoderma of patient joint NB-UVB irradiation (narrow wave ultraviolet light), It irradiates 2 times a week, since minimum hickie amount;4 weeks as a treatment course, continuously treats 6 courses for the treatment of, and last 2 courses for the treatment of are to consolidate Phase.
Control group 3-3:
Specific implementation method are as follows: smeared with the composition of reference examples 3 at the leucoderma of patient, secondary weekly, applying amount For 0.02ml~0.03ml/cm2, furthermore to joint NB-UVB irradiation (narrow wave ultraviolet light) is carried out at the leucoderma of patient, weekly 2 irradiations, since minimum hickie amount;4 weeks as a treatment course, continuously treats 6 courses for the treatment of, and last 2 courses for the treatment of are consolidation.
Control group 4-4:
Specific implementation method are as follows: smeared with the composition of reference examples 4 at the leucoderma of patient, secondary weekly, applying amount For 0.02ml~0.03ml/cm2, subcutaneously infused using leucoderma affected part of the transdermal disperse technology in Needleless injection to patient Left-handed muskone is penetrated, per injection amount is 0.006ml~0.009ml/cm2, 4 weeks are as a treatment course, 6 courses for the treatment of are continuously treated, Last 2 courses for the treatment of are consolidation.
6 experimental group of table and control group test result
Experimental group and control group compare with otherness (P < 0.05)
By treatment group 1-4, control group (1-1)-(4-4) comparison in table 6 it is found that the effective percentage of experimental group 1-4 100%, cure rate reaches 75%, without side-effects, and does not recur, and injects left-handed muskone and feedstock composition of the invention is combined to apply It smears and NB-UVB irradiation can effectively treat leucoderma, therapeutic effect is significant, and cure rate is high, and the therapeutic effect of experimental group 1-4 is bright It is aobvious to be better than control group (1-1)-(4-4).By experimental group 1 it is found that left-handed muskone is as monarch drug in a prescription compared with the prescription of control group 1-1 There is remarkable effect to the therapeutic effect of leucoderma, by the usage amount and treatment of the left-handed muskone compared with control group 2-2 of experimental group 2 Effect has causalnexus;Know that the left-handed muskone of subcutaneous injection influences final result compared with control group 3-3 by experimental group 3;By The EtOH known to compared with control group 4-4 of experimental group 4, PG system play an important role to the rush infiltration of raw medicine.
In summary: 1, experimental group 1-4 and control group (1-1)-(4-4) although effectively comparison rate difference be only 30%, It cures comparison rate difference and is but up to 45%, side effect and recurrence comparison rate are 0 to 3 and 0 to 2.
2, experimental group 1-4 is in treatment phase;First course for the treatment of starts to take effect, and sends out when treating the period in the first course for the treatment of latter stage Duration of an exhibition lesion Edge-stopping continues to expand, and there are unconspicuous kermesinus colour of skin color difference, continual cure 2 treatments in stationary phase lesion edge Occurs the irregular spot of crineous at journey period Growth period and the skin lesion of stationary phase, 2 course for the treatment of hickie edges of continual cure are presented The dotted similar normal skin tone of some dispersions, minimum day shift start to be gradually reduced, and brown-black element is got over after 2 courses for the treatment of of continual cure Carry out more and color burn, pore also more and more intensively eventually connects in flakes, and skin lesion memory phenomenon is obvious, visually observes new skin Still there is color difference with normal skin;Electronic Speculum observes new fur hole and dermatoglyph is no different with normal skin.After 2 courses for the treatment of of after treatment Skin color difference disappears substantially, visually with normal skin tone no significant difference.
Composition of the invention is significant to leucoderma therapeutic effect, and cure rate is very high, and without side-effects, treatment cycle is short not Recurrence.
Qing Dynasty's Wang Qingren points out in one book of errors in Medicine Corrected, and leucoderma is that " blood stasis in flesh side, emphasizing in the treatment should be with Based on blood circulation, help with the product of promoting the dispersing function of the lung promoting the circulation of qi.Cutaneous lesions damage reason is different, and recovery mechanism is more complicated, restores item Part is influenced by the comprehensive factor in many inside and outsides, especially for this recalcitrant dermal illness of leucoderma, pathogenesis It there is no the final conclusion generally acknowledged from gene angle at present;Solve the problems, such as that, there are theoretic missing, we are setting from cause of disease source Basic point when the meter present invention is started with from external condition form, is injected to the two-sided application of pars affecta skin to lesion point, enhancing The targeting of drug creates a polynary Curing circumstance in conjunction with phototherapy method;It is found in the screening of numerous traditional Chinese medicinal material raw materials It is in other Chinese medicines on the basic function " microcirculation " of the promoting blood circulation of left-handed muskone and dalbergia heartwood oil needed for skin rejuvenation The outstanding figure position of material.,
According to the medicament composing prescription of the application and comparative example clinical data it is found that for patients with vitiligo, left-handed muskone Subcutaneous point injection is smeared with composition and the therapy of combing traditional Chinese and Western medicine leucoderma of NB-UVB phototherapy may be that one kind can be long-term Using and safely and effectively therapeutic choice.
The above described is only a preferred embodiment of the present invention, be not intended to limit the present invention in any form, according to According to technical spirit any simple modification, equivalent change and modification to the above embodiments of the invention, this hair is still fallen within In the range of bright technical solution.

Claims (3)

1. a kind of feedstock composition for treating leucoderma, it is characterised in that: composition includes the following raw material by weight:
Left-handed muskone: 30-60 parts, dalbergia heartwood oil: 15-30 parts, ethyl alcohol: 10-20 parts, 1,2 propylene glycol: 5-10 parts.
2. the feedstock composition for the treatment of leucoderma according to claim 1, which is characterized in that composition includes by weight The following raw material:
Left-handed muskone: 30 parts, dalbergia heartwood oil: 15 parts, ethyl alcohol: 10 parts, 1,2 propylene glycol: 5 parts.
3. a kind of preparation method for the feedstock composition for treating leucoderma, which comprises the following steps:
Step 1: heating water bath, prepares ethyl alcohol and 1,1,2 propylene glycol: 5-10 will be added in the mixed liquor of 2 propylene glycol in triangular flask Part, ethyl alcohol: 10-20 parts, less than 45 DEG C, stirring 15min~20min is cooled to room temperature spare thermosol temperature;
Step 2: heating water bath, is added left-handed muskone 30-60 parts, temperature rises to 30-35 in another flat conical flask DEG C when, be added dalbergia heartwood oil 20-30 part continuously stir holding heat of solution 30min;Obtain left-handed muskone and dalbergia wood oil mixture;
Step 3: water-bath is kept for 30 DEG C~35 DEG C, the temperature of left-handed muskone and dalbergia heartwood oil mixed liquor in bottle is measured less than 35 DEG C When be added ethyl alcohol and 1, the mixed liquor of 2 propylene glycol, heating keep 40 DEG C~45 DEG C stirring heat of solution 30min~35min, be cooled to Composition is made in room temperature, and character is colourless to pale yellow transparent oily liquids.
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CN105982882A (en) * 2015-02-03 2016-10-05 中微知著药物手性技术(大连)有限公司 External-use medicine prepared from optically active material composition and used for treating haemorrhoids and preparation technology of external-use medicine

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