CN106038479A

CN106038479A - Fructus Cnidii microcapsule thermosensitive gel and preparation method and quality test method thereof

Info

Publication number: CN106038479A
Application number: CN201610588932.1A
Authority: CN
Inventors: 杨婧; 王蔚; 王锐; 葛鹏玲; 韩东卫; 孙娜
Original assignee: Heilongjiang University of Chinese Medicine
Current assignee: Heilongjiang University of Chinese Medicine
Priority date: 2016-07-25
Filing date: 2016-07-25
Publication date: 2016-10-26
Anticipated expiration: 2036-07-25
Also published as: CN106038479B

Abstract

The invention belongs to the field of medicines, particularly relates to a motion sickness treating Fructus Cnidii microcapsule thermosensitive gel medicine and a preparation method thereof and provides Fructus Cnidii microcapsule thermosensitive gel and a preparation method and a quality test method thereof. Fructus Cnidii dry extract is prepared by a pre-forming process, Fructus Cnidii porous microcapsules are prepared according to a porous microcapsule preparation process, and the Fructus Cnidii microcapsule thermosensitive gel is obtained finally according to a porous microcapsule preparation process. The invention further provides a fingerprint analysis method for the Fructus Cnidii microcapsule thermosensitive gel by high performance liquid chromatography, and the scientific method is provided for quality assessment and control of the Fructus Cnidii microcapsule thermosensitive gel.

Description

A kind of Fructus Cnidii microcapsule thermosensitive hydrogel and preparation method thereof and quality determining method

Technical field

The invention belongs to drug world, be specifically related to a kind of Fructus Cnidii microcapsule thermosensitive hydrogel medicine treating motion sickness and Preparation method.

Background technology

Fructus Cnidii is the dry mature fruit of samphire cnidium monnieri, and it is warm in nature, acrid in the mouth is bitter, slightly poisonous, returns kidney channel.Have Dampness is dispeled the wind, killing parasites for relieving itching, the function of warming the kidney to invigorate YANG.For pudendal pruritus leukorrhagia, eczema pruritus, wet spleen lumbago, impotence due to deficiency of the kidney, cold womb Infertile disease such as grade.Fructus Cnidii complex chemical composition, mainly contain tool bioactive coumarin kind compound, including osthole, Bergapton, isopimpinellin etc..

1, medicine allergic dermatitis

130 example drug sensitivity dermatitis patients, the application Fructus Kochiae, the Radix Astragali, Radix Glycyrrhizae, Fructus Cnidii are by Sun Zhenming

Guiding drug, coordinates other drug, the anaphylaxis skin causing medicine (such as serum preparation, penicillins, sulfa drugs etc.) Inflammation is treated, and have received good result, and cure rate reaches 92.5%, inefficiency only 1.8%.Prescription is: Radix Angelicae Sinensis, Flos Lonicerae, red Chinese herbaceous peony, the Radix Rehmanniae, Herba Patriniae, Fructus Cnidii, Cortex Sclerotii Poriae, each 15g of Radix Salviae Miltiorrhizae, Periostracum Cicadae, Fructus Arctii, Cortex Dictamni each 12g are Rhizoma Chuanxiong, Spica Prunellae, white Fructus Tribuli, Radix Glycyrrhizae, each 10g of Pericarpium Citri Reticulatae, Fructus Kochiae 30g, Radix Astragali 40g, Cortex Lycii 20g etc., add and subtract according to the state of an illness, after being administered orally, and medicine Residue local thermal washing.After taking 1～2 dose in treatment, subjective symptoms and sign substantially alleviate, and erythema, urticaria, gargalesthesia disappear completely Lose.More than 90% person, taking 2～10 doses can fully recover.

2, treatment eczema

Poplar is built new grade and uses self-control preparation Compound Fructus Cnidium liniment (each 60g of Fructus Cnidii, Radix Sophorae Flavescentis, the Fructus Kochiae, sulfur 20g, the Radix Stemonae 100g, zinc sulfate 17g, glycerol 33mL etc.) treatment infant eczema, obtain promising result.Treatment group external this product, soak is suffered from Place, 2 times/d, 1 15min, continuous 2 weeks, the control group corticosteroids hydrocortisone butyrate ointment was treated with method.Through statistics Analyzing, treatment group compares the two in terms of total effective rate without significant difference with matched group, but treatment group curative effect is more preferable.Li Jing etc. Having carried out the clinical observation on the therapeutic effect of Fructus Cnidii soup external curing 81 example dermatitis and eczema, result is satisfied.Author by Empirical formula Fructus Cnidii, The compositions such as Radix Clematidis, Radix Sophorae Flavescentis, Radix Angelicae Sinensis, adding decocting becomes decoction, uses gauze to soak medicinal liquid for dermatitis and eczema acute stage and applies ointment or plaster In affected part 30min, 1 time/d, continuous 3d, chronic phase then with ultrasound atomizer cold spray affected part, 1 time/d, continuous 7d.As a result, cure Rate 67.9%, improvement rate 28.4%, total effective rate 96.3%, inefficiency 3.7%.Author thinks that the method is simple, clinic Promote.

3, treatment urticaria

Kong Zhifeng etc. apply Fructus Cnidii injection for treating urticaria patient 41 example, through 1～2 courses for the treatment of, cure 32 examples, and take a turn for the better 8 examples, not More 1 example.Total effective rate is 97.56%.The fastest curative effect is 1 recovery from illness of injection, the most slowly for 21 recoveries from illness of injection.

4, treatment RVVC

Liu Jinli etc. inquire into and add the taste Fructus Cnidii lotion clinical effectiveness to women RVVC after treatment, Result is satisfactory.198 example patients are divided into 2 groups by author at random, observation group 100 example, matched group 98 example.Matched group fluconazol 150mg is administered orally once in a week, and treatment group adds on this basis with adding taste Fructus Cnidii lotion 125mL, warm water 250mL fumigation and wash method pudendum Vagina each 15～20min, the next day once, respectively treat 3 months for two groups.As a result, two groups of total effective rate comparing differences have statistics Meaning (P ＜ 0.05), treatment group curative effect is better than matched group.Author it is thus regarded that, add taste Fructus Cnidii lotion cloudy to recurrent pudendum Road candidiasis after treatment curative effect safety, reliably, can significantly increase cure rate, reduce Recurrent vulvovaginal beads mattress Palindromia rate.

5, treatment vaginitis

Wang Xuehui uses Fructus Cnidii powder plus-minus treatment vaginitis 140 example, obtains promising result.Author is based on Fructus Cnidii powder Side, i.e. Fructus Cnidii, each 30g of Radix Sophorae Flavescentis, the Radix Stemonae, Alumen, the Fructus Kochiae, Cortex Phellodendri 15g, Fructus Zanthoxyli 10g.Plus-minus: vulvovaginal candida mycoderma Bacterium disease goes Fructus Zanthoxyli, trichomonal vaginitis to add Cortex Meliae 10g.Above-mentioned prescription is prepared as packed decoction respectively, every bag of 250mL, 1 time/ D, each 500mL, vaginadouche, 7d is 1 course for the treatment of, general treatment 1～2 courses for the treatment of.As a result, 98 examples of fully recovering 1 course for the treatment of, 2 Fully recover the course for the treatment of 34 examples, cure rate 87.1%, effective percentage 97.8%, invalid 2.2%.Li Yanmin uses Fructus Cnidii powder to add taste treatment vagina Scorching 100 examples, treated effect is 96%.Author is by Fructus Cnidii 30g, Cortex Phellodendri 15g, each 18g of Herba Artemisiae Scopariae, Rhizoma Smilacis Glabrae, Fructus Zanthoxyli, Alumen Each 6g, Periostracum Cicadae, each 12g of Herba Menthae, add water 1000mL, decocts 30min, extracting juice 500mL, and in demibain 1 time every night, before demibain, taking liquid is put In clean container, filling in vagina with sterilized cotton ball anchor line (string) dip in liquid medicine after demibain, morning next day takes out.Every 1 time/d, being used in conjunction 7d is 1 course for the treatment of, 100 example trichomonal vaginitis, colpitis mycotica and senile vaginitis total effective rate are 96% as a result.The red rosy clouds of official are used Fructus Cnidii lotion fumigation and wash method demibain treatment and nursing colpitis mycotica 50 example, obtain promising result.Two groups sleep the most every night before give 1 vagina drug applying of daktarin suppository, 1 time/d, observation group use self-control Fructus Cnidii lotion (Radix Angelicae Sinensis, Rhizoma Smilacis Glabrae, Fructus Cnidii, Radix Sophorae Flavescentis, Cortex Phellodendri, the Fructus Kochiae, the Radix Stemonae, Cortex Dictamni, Herba Artemisiae Scopariae, Pericarpium Zanthoxyli, Radix Gentianae, Folium Artemisiae Argyi, Borneolum Syntheticum etc., decoct through traditional Chinese medicine extracting machine and pack, Every bag of 150mL) 2 bags of 300mL, pour demibain basin dedicated into, add hot water to about 1000mL, first smoke with hot water, be down to 50 etc. water temperature DEG C～when 60 DEG C, dip in medicine with clean towel and clean affected part gently, advise patient to sit in leaching medicinal liquid when water temperature reaches 38 DEG C～42 DEG C, 20min/ time, 1 time/d, 4d is 1 course for the treatment of.Matched group uses 2% sodium bicarbonate vaginadouche, and 1 time/d, 7d is 1 course for the treatment of.Knot Really, observation group's total effective rate is 94.0%, and matched group is 82.0%, both differences statistically significant (P ＜ 0.05).Tian Tianmei Using therapy of combining Chinese and Western medicine senile vaginitis 63 example, result is satisfactory.113 example cases are randomly divided into two groups by author, Matched group uses diethylstilbestrol, norfloxacin to pulverize, after every daily 1:5000 potassium permanganate warm water washing vagina, by medicated powder Put into intravaginal.Treatment group, except with in addition to said medicine, adds dexamethasone 1.5mg, boric acid powder 0.5g, and Fructus Cnidii 2g vagina is given Medicine, coordinates XUEFU ZHUYU KOUFUYE treatment simultaneously, and two groups of equal 7d are 1 course for the treatment of.As a result, matched group cure rate is 56.0%, treatment Group cure rate 90.5%, two groups of total effective rates are 100%, but after two groups of case treatments, cure rate compares, and difference has statistics to anticipate Justice (P ＜ 0.05).Author it is thus regarded that, therapy of combining Chinese and Western medicine senile vaginitis, evident in efficacy, on clinic further Popularization and application.

6, treatment pudendal pruritus

Han Wei gives Fructus Cnidii powder plus-minus side washout treatment pudendal pruritus, obtains satisfactory result.Author is by Fructus Cnidii 30g, Fructus Zanthoxyli, the Radix Stemonae Each 10g, Radix Sophorae Flavescentis, Radix Gentianae, Cortex Phellodendri, each 15g of Herba Taraxaci, Fructus Kochiae 20g etc. is put and is given in earth pot, soaks 15min, first boils with high heat After boiling.10～15min are decocted again with slow fire.Decocting twice, filters medicinal liquid with gauze and puts temperature, demibain 15～20min after first fumigation and wash method, 2 times/d, 7d is 1 course for the treatment of.As a result, cure rate 70.0%, obvious effective rate 22.5%, inefficiency 6%, total effective rate is 92.5%.The party Method is to pudendum and pruritus of vagina, and the pruritus vulvae effect that reason causes including per vaginam inflammation, eczema, vulvar dystrophy etc. is good Good.

7, treatment psoriasis

Wang Jinhai etc. use self-control osthole patch treatment psoriasis vulgaris 296 example, obtain good result.Author uses and opens The method putting formula autologous control, left limb target skin lesion externally used compound flumetasone ointment, 2 times/

d；Right side limbs target skin lesion external osthole patch (containing 5% osthole), 1 time/d.Further consultation 1 time in every 2 weeks, sees continuously Examining 6 weeks is 1 course for the treatment of.Clinical test results shows, the overall clinical efficacy rate of osthole patch and Compound Flumetasone Ointment divides It is not 79.72% and 82.77%, illustrates that osthole patch obtains relatively satisfactory curative effect to curing psoriasis, with compound recipe flumetasone Ointment group compares without significant difference.But clinical observation finds osthole patch group antipruritic effect and Compound Flumetasone Ointment group Comparing difference statistically significant (P ＜ 0.05), Fructus Cnidii have preferable itching-relieving action.

8, treatment infertility

Yan Hengyi etc. use Fructus Cnidii, Fructus Schisandrae Chinensis, Radix Polygalae Chinese herbs decoction that ovulation rate treatment infertility is administered orally, and obtain and are satisfied with effect Really.The patient of 68 example infertility ovulation failures is divided into observation group 35 example by author immediately, to above-mentioned Chinese medicine ovulation treatment, Matched group 33 example is to clomiphene.As a result, observation group's endometrium substantially relatively matched group is thick (P ＜ 0.01), and pregnancy rate is the highest In matched group (P ＜ 0.05), abortion ratio is significantly lower than matched group (P ＜ 0.05), dominant follicle and ovulation rate two groups contrast (P ＜ 0.05) all there is significance.Therefore, author thinks that Fructus Cnidii, Fructus Schisandrae Chinensis, Radix Polygalae three taste Chinese medicine have rush endometrial growth, rush Entering follicular development and Effect of Ovulation, pregnancy rate is high, and pregnancy outcome is good, has clinical generalization value.

Motion sickness (motion sickness), i.e. motion sickness, motion sickness, air-sickness and due to shaking that a variety of causes causes Put, jolt, rotate, the general designation of the associated diseases such as accelerated motion.

There are many people in travelling, the dizziness, Nausea and vomiting, the pale complexion that cause because being in movement environment, are in a cold sweat Deng syndrome, " cinetosis " severe patient even occur arrhythmia, collapse, shock etc..This motion sickness symptom generally changes travelling The most all alleviate after mode or end tourism.

China is one of country that the world's " motion sickness " incidence rate is the highest, and it is dizzy that the people of 80% the most once lived through in various degree Dynamic reaction.This disease is currently without the way thoroughly cured, but selects effective anti-blooming medicine to can be good at alleviating misery.Base In the universality of " cinetosis ", people build up some tips the most gradually, such as suck Rhizoma Zingiberis, hear Pericarpium Citri Reticulatae, smear essential balm etc., but Effect is the most inconspicuous.

The Fructus Cnidii microcapsule thermosensitive hydrogel that the present invention provides has therapeutic effect very significantly for motion sickness, can be effective The effect of suppression gastrointestinal tract autonomic nervous dysfunction, the outbreak determined curative effect to preventing and treating motion sickness.

Aescin for injection is clinical commonly used drug, has infection, edema, increase intravenous tension, improves blood The effects such as liquid circulation and protection nerve, but it also has stronger stimulation to mucosa and muscular tissue, is administered orally at gastrointestinal tract Not absorbing, intramuscular injection easily causes tissue necrosis, is intended for venoclysis, but venoclysis is often because drug level is high, infusion is fast And vein is caused damage in various degree, the lighter has the irritations such as acid, fiber crops, swollen, pain, and severe one has phlebitic performance, goes out Existing topalgia, red, swollen and the change of vein bar rope sample, accessible scleroma.Venous extravasation not only brings misery to patient, too increases The difficulty of nursing staff's venipuncture, have impact on the seriality for the treatment of work.In order to improve rapidly patient's local conditions, preferably Making therapeutic scheme be smoothed out, inventor is constantly exploring the side preventing venous stimulation symptom clinical in research work always Method, in Practical experiments repeatedly, has been surprisingly found that and applies the outer method curative effect being coated with in Fructus Cnidii microcapsule thermosensitive hydrogel of the present invention local Significantly, follow-up carry out again the clinical experimental study of specification, obtain technical scheme.

Summary of the invention

It is an object of the invention to provide a kind of Fructus Cnidii microcapsule thermosensitive hydrogel medicine treating motion sickness.

It is a further object of the present invention to provide the preparation method of this Fructus Cnidii microcapsule thermosensitive hydrogel medicine.

The present invention also provides for the quality determining method of this Fructus Cnidii microcapsule thermosensitive hydrogel medicine.

Present invention also offers the pharmaceutical applications of this Fructus Cnidii microcapsule thermosensitive hydrogel medicine.

It is an object of the invention to be accomplished by:

A kind of Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine treating motion sickness, adopts and prepares with the following method:

(1) technique before molding: weigh Surfactant SDS, the constant volume that adds water, in volumetric flask, prepares dodecane Base metabisulfite solution, weighs Fructus Cnidii coarse powder, sodium dodecyl sulfate solution respectively, all loads round-bottomed flask, adds ethanol, adds Circumfluence distillation, united extraction medicinal liquid, filters, filtrate is concentrated and dry, obtain the dry cream of Fructus cnidii extract；

(2) preparation of porous microcapsule: take the dry cream of Fructus cnidii extract prepared by step (1), be dissolved in ethyl acetate, then add to it Enter liquid paraffin, ultrasonic mixing, obtain Fructus cnidii extract medicament mixed liquid, standby；Take gelatin, arabic gum is dissolved in distilled water In, mixing, make the mixed solution of arabic gum and gelatin, standby；Above-mentioned Fructus cnidii extract medicament mixed liquid is slowly added Enter in the mixed solution of arabic gum and gelatin, stir in tissue mashing machine, make O/W type Emulsion；Under 50 DEG C of water-baths, to Being slowly added dropwise acetic acid to pH in O/W type Emulsion is 4, stirs, and adds distilled water and is diluted, and continues stirring fast to ice bath Speed is cooled to 10 DEG C, adds glutaraldehyde solidification, and it is 7 that dropping NaOH solution is adjusted to pH, stands and treats that it settles, precipitum distilled water It is washed till without glutaraldehyde abnormal smells from the patient, filtration drying, obtains Fructus Cnidii porous microcapsule；

(3) prepared by microcapsule thermosensitive hydrogel: uses cold process to prepare gel solution, takes poloxamer188, PLURONICS F87, propylene glycol Joining in distilled water, stirring makes it be uniformly dispersed, and places, make gel the most swelling and obtain settled solution under the conditions of 4 DEG C, Under stirring, add Fructus Cnidii porous microcapsule prepared by step (2), stir, make Fructus Cnidii microcapsule thermosensitive hydrogel.

Above-mentioned Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine, preferentially adopts and prepares with the following method:

(1) technique before molding: weigh Surfactant SDS 1g, the constant volume that adds water in 100mL volumetric flask, preparation Mass fraction is the sodium dodecyl sulfate solution of 1%, weighs Fructus Cnidii rough segmentation 10g, sodium dodecyl sulfate solution respectively 10mL, all loads round-bottomed flask, adds 95% ethanol 60mL, heating and refluxing extraction 2 times, each 1.5h, united extraction medicinal liquid, mistake Filter, concentrates filtrate and dries, obtain the dry cream of Fructus cnidii extract；

(2) preparation of porous microcapsule: take Fructus cnidii extract dry cream 2g prepared by step (1), be dissolved in 1mL ethyl acetate, then Add 2mL liquid paraffin, ultrasonic mixing to it, obtain Fructus cnidii extract medicament mixed liquid, standby；Take gelatin 1g, arabic gum 1g is dissolved in 20mL distilled water, mixing, makes the mixed solution of arabic gum and gelatin, standby；By above-mentioned Fructus cnidii extract Medicament mixed liquid is slowly added in the mixed solution of arabic gum and gelatin, stirs 3 times, make O/W type in tissue mashing machine Emulsion；Under 50 DEG C of water-baths, being slowly added dropwise 5% acetic acid to pH is 4, stirs, and the distilled water adding system bulk 2 times amount enters Row dilution, continues stirring to ice bath and is cooled to rapidly 10 DEG C, adds glutaraldehyde solidification 1h, and dropping 10%NaOH solution is adjusted to pH Being 7, stand and treat that it settles, precipitum distilled water is washed till without glutaraldehyde abnormal smells from the patient, filtration drying, obtains Fructus Cnidii porous microcapsule；

(3) prepared by microcapsule thermosensitive hydrogel: uses cold process to prepare gel solution, takes the poloxamer of the poloxamer188 of 18g, 1g 188, during the propylene glycol of 15mL joins 100mL distilled water, stirring makes it be uniformly dispersed, and places 12h, make to coagulate under the conditions of 4 DEG C Glue is the most swelling and obtains settled solution, adds Fructus Cnidii porous microcapsule prepared by step (2), stirring, system under stirring Become Fructus Cnidii microcapsule thermosensitive hydrogel.

A kind of quality determining method of the Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine treating motion sickness, this Fructus Cnidii microcapsule temperature Quick gel medicine is adopted and is prepared with the following method:

(3) prepared by microcapsule thermosensitive hydrogel: uses cold process to prepare gel solution, takes poloxamer188, PLURONICS F87, propylene glycol Joining in distilled water, stirring makes it be uniformly dispersed, and places, make gel the most swelling and obtain settled solution under the conditions of 4 DEG C, Under stirring, add Fructus Cnidii porous microcapsule prepared by step (2), stir, make Fructus Cnidii microcapsule thermosensitive hydrogel；

Use following high-efficient liquid phase technique method that the Fructus Cnidii microcapsule thermosensitive hydrogel of above-mentioned preparation carries out the quality inspection of finger printing Surveying, method is as follows:

(1) chromatographic condition: chromatographic column Waters Xbridge C₁₈Post, flowing is with acetonitrile as mobile phase A, with water for flowing phase B, gradient elution: 0min to 12min, mobile phase A is linearly increasing to 30% from 15%, Mobile phase B from 85% linear decline to 70%, 12min to 45min, mobile phase A is linearly increasing to 80% from 30%, and Mobile phase B is from 70% linear decline to 20%, and 45min is extremely 55min, mobile phase A is maintained at 80%, and Mobile phase B is maintained at 20%, detects wavelength 203nm, flow velocity 1.0mL min^-1；Column temperature 30 DEG C, sampling volume 10 μ L；

(2) preparation of reference substance solution: precision weighs different pimpinellin reference substance, different bolt wing celery alcohol reference substance, diosmetin Reference substance, puts in measuring bottle, adds methanol and dissolves and be diluted to scale, to obtain final product；

(3) preparation of need testing solution: take Fructus Cnidii microcapsule thermosensitive hydrogel, accurately weighed, accurate addition methanol, weigh, ultrasonic Process, take out, let cool, mend weight, shake up, filter, take subsequent filtrate filter membrane, to obtain final product；

(4) measure: accurate absorption reference substance solution and need testing solution inject high performance liquid chromatograph, are measured.

The quality determining method of above-mentioned Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine, this Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine is adopted Prepare with the following method:

(3) prepared by microcapsule thermosensitive hydrogel: uses cold process to prepare gel solution, takes the poloxamer of the poloxamer188 of 18g, 1g 188, during the propylene glycol of 15mL joins 100mL distilled water, stirring makes it be uniformly dispersed, and places 12h, make to coagulate under the conditions of 4 DEG C Glue is the most swelling and obtains settled solution, adds Fructus Cnidii porous microcapsule prepared by step (2), stirring, system under stirring Become Fructus Cnidii microcapsule thermosensitive hydrogel；

Preferably employ following high-efficient liquid phase technique method and the Fructus Cnidii microcapsule thermosensitive hydrogel of above-mentioned preparation is carried out the matter of finger printing Amount detection, method is as follows:

(2) preparation of reference substance solution: precision weighs different pimpinellin reference substance 4.13mg, different bolt wing celery alcohol reference substance 4.21mg, diosmetin reference substance 2.15mg, put in 10mL measuring bottle, adds methanol and dissolves and be diluted to scale, to obtain final product；

(3) preparation of need testing solution: take Fructus Cnidii microcapsule thermosensitive hydrogel 0.5g, accurately weighed, the accurate methanol 25mL that adds, title Weight, supersound process 30min, take out, let cool, mend weight, shake up, filter, take subsequent filtrate and cross 0.45 μm filter membrane, to obtain final product；

(4) measure: accurate absorption reference substance solution and each 10 μ L of need testing solution inject high performance liquid chromatographs, are measured.

A kind of Fructus Cnidii microcapsule thermosensitive hydrogel agent application in preparation treatment motion sickness medicine, this Fructus Cnidii microcapsule is temperature sensitive Gel medicine is adopted and is prepared with the following method:

A kind of Fructus Cnidii microcapsule thermosensitive hydrogel agent is at the venous injury medicine caused by preparation protective inoculation aescine Application in thing, this Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine adopts and prepares with the following method:

A kind of Fructus Cnidii microcapsule thermosensitive hydrogel agent application in preparation treatment sexual impotence medicine, this Fructus Cnidii microcapsule is temperature sensitive solidifying Colloid medicine is adopted and is prepared with the following method:

A kind of Fructus Cnidii microcapsule thermosensitive hydrogel agent application in preparation treatment eczema medicine, this Fructus Cnidii microcapsule is temperature sensitive solidifying Colloid medicine is adopted and is prepared with the following method:

Technique effect by the following experimentation checking present invention:

Experiment one: the experimentation of inventive gel Drug therapy motion sickness

Inventor creates inventive gel medicine, and dog has carried out treating the experimentation of motion sickness.

1 materials and methods

1.1 experiment material

1.1.1 laboratory animal

Domestic healthy dogs 6, male and female half and half, body weight 5～6kg, regular grade, Heilongjiang University of Chinese Medicine's Experimental Animal Center carry Supply.

1.1.2 medicine

Medicine of the present invention (Fructus Cnidii microcapsule thermosensitive hydrogel): prescription: dry Fructus Cnidii rough segmentation 10g.Preparation method: (1) molding Front technique: weigh Surfactant SDS 1g, the constant volume that adds water is in 100mL volumetric flask, and preparation mass fraction is The sodium dodecyl sulfate solution of 1%, weighs Fructus Cnidii rough segmentation 10g, sodium dodecyl sulfate solution 10mL respectively, all loads circle End flask, adds 95% ethanol 60mL, heating and refluxing extraction 2 times, each 1.5h, united extraction medicinal liquid, filters, filtrate concentrated Dry, obtain the dry cream of Fructus cnidii extract；

Drugs compared (osthole gel): prescription: osthole 0.5g；Preparation method: weigh 0.15g Acritamer 940, Uniformly dispense in suitable quantity of water, put the most swelling overnight；Measure ethanol and 0.5mL laurocapram, be separately added into the most also Stirring, dropping triethanolamine regulation pH to 6～8 makes into gel；Weigh osthole 0.5g to add in above-mentioned substrate, fill Divide and stir evenly, obtain 10g white osthole gel.(detailed preparation method refers to: Lou Ying, Zhao Hua, Hu Jinhong. orthogonal experiment Optimize formula [J] pharmaceutical services of osthole gel and study .2016.16 (1): 52)

1.1.3 equipment

Rotatory stimulation device, is pressed report (Crampton GH, the Lucot such as Crampton by pharmaceutical college of Heilongjiang University of Chinese Medicine JB. A stimulator for labo ratory studies of motion sickness in cars [J].Aviat Space Environ Med, 1985,56:462.) imitated form.This device rotates wheel diameter 1.2m, is furnished with the dynamic of transparent ventilation Thing case and rotating speed control knob.According to rotating speed and the diameter that rotates wheel, (i.e. induced movement disease is sent out can to calculate the size of angular acceleration The quantity of stimulus made).

1.2 method

1.2.1 animal screening

During experiment, by chainless for experimental dog the cattle container inserting rotary apparatus, turn clockwise around trunnion axis, with 70 ° (s)^2-1Angular acceleration accelerates 4.5s, reaches maximal rate 315 ° (s)^-1After at the uniform velocity rotate 3s, immediately with 126 ° (s)^2-1Angle subtracts Speed reduction, until rotating stopping is 1 cycle, so circulation carry out inducing motion sickness (Jiang Zhenglin. ginger is to motion Sick rat blood feritin, angiotensin, the impact [J] of aldosterone level. China's nautical medicine and hyperbar medical journal, 2001,8 (1): 16).

Rotate and start in half an hour after, if stream birth or symptoms of emesis person occurs in selected dog, be i.e. considered sensitive to this test, As this experimental dog, totally 6, marker number the most respectively, adaptability is raised 2 weeks routinely.

1.2.2 own control test

Carry out inventive gel medication therapy groups (observation group) experiment for 1st time.Every dog is tested in front half an hour in starting, and shaves except umbilicus Portion, by hair, cleans umbilicus with 75% ethanol cotton balls, repastes and smears inventive gel agent 2g, and then dog is put by external adhesive plaster sealing Rotating in cattle container, determination experiment starts to animal stream birth or the duration of symptoms of emesis, and record respectively occur.

After experiment terminates, instant clean umbilical part inventive gel agent, raise 10 days the most routinely, then carry out the 2nd reality Test.

Carry out the experiment of osthole gel controls group for 2nd time.Every dog is tested in front half an hour in starting, and shaves except umbilical part quilt Hair, cleans umbilicus with 75% ethanol cotton balls, repastes and smear osthole gel 2g, and then dog is placed in by external adhesive plaster sealing Rotating in cattle container, determination experiment starts to animal stream birth or the duration of symptoms of emesis, and record respectively occur.

2 results

Laboratory observation group occurs after acceptance identical rotatory stimulation amount that with matched group the duration of vomiting or sialorrhea is shown in Table 1-1.Observe Group induction dog produces the time relatively matched group of sialorrhea or symptoms of emesis and is obviously prolonged, and through paired t-test, two groups of differences have the most notable Property (P < 0.01, t=4.9035), prompting observation group curative effect be substantially better than matched group.

There is vomiting or the time (min) of sialorrhea in two groups of experimental dogs of table 1-1

3 discuss and conclusion

This experiment by under the conditions of identical rotatory stimulation amount, the time of comparative observation group and the vomiting of matched group inducing nausea, Time is the longest, and animal is the strongest to the toleration of rotatory stimulation, shows that curative effect is the best.Result shows, Fructus Cnidii microcapsule temperature of the present invention Quick gel has the effect of higher suppression gastrointestinal tract autonomic nervous dysfunction compared with osthole gel, sends out preventing and treating motion sickness Make determined curative effect.This also absolutely proves, unique preparation method that the present invention provides, and the effect considerably improving medicine is treated Effect.

Modern medicine study is thought, umbilicus is in embryo development procedure, and at the last Guan Bi of stomach wall, its horny layer of epidermis is Thin, barrier function is the most weak, subcutaneous fat-free layer, and nervus vasculairs enrich, beneficially drug absorption, therefore umbilical part has treated reliably Theoretical foundation.The research that inventor combines modern Transdermal absorption mechanism is theoretical, by the approach of umbilical region administration, makes active drug fast Speed absorbed into serum and play optimum curative effect.Its curative effect is strongly, rapidly, persistently.Compared with traditional Therapeutic Method, inventive gel Medicine also has easy to use, has no side effect, and the old children advantage such as the most preferably, therefore has wide Prospect of R & D.

Experiment two: Fructus Cnidii microcapsule thermosensitive hydrogel exterior coating treatment aescin for injection of the present invention causes the effect of venous extravasation Fruit is observed

1. data and method

1.1 physical data

The patient that 28 example venoclysis aescin for injection cause venous extravasation is randomly divided into experimental group and matched group each 14 Example.

Experimental group man's 7 examples, female 7 example；20 years old age～55 years old；Severe venous extravasation 7 example, moderate venous extravasation 5 example, slightly Venous extravasation 2 example.

Matched group man's 7 examples, female 7 example；21 years old age～55 years old；Severe venous extravasation 7 example, moderate venous extravasation 6 example, slightly Venous extravasation 1 example.

All use 7 number sword-shaped needles, choose thicker vein.Two groups of patient genders, age, sick kind, injection aescine Outside sodium (Beijing Sihuankebao Pharmaceutical Co., Ltd. produce, authentication code: traditional Chinese medicines quasi-word H20044036) dosage and usage, vein Ooze degree comparing difference not statistically significant (P > 0.05), there is comparability.

1.2 method

1.2.1 Therapeutic Method

Fructus Cnidii microcapsule thermosensitive hydrogel of the present invention it is coated with (with reference to this outside the position of swelling, the pain of exosmosing to experimental group venous patient Prepared by the embodiment 1 spoken frankly in bright book detailed description of the invention), medication thickness 3mm～5mm, does not massage, every day 1 time, 09:00 Outer painting, uses 3d continuously, need not wrap up.The lighter's medication thickness can be thinner.

To matched group patient with thin Rhizoma Solani tuber osi 72h outer proper after hot water soak.

1.2.2 efficacy assessment standard

Cure: after treatment 72h, pain substantially disappears, without touching a tender spot, without swelling, normal skin color.

Effective: after treatment, in 72h, pain disappears, swelling is disappeared, and skin is that dark red vitta rope disappears or deliquescing.

Effective: pain relief in 72h after treatment, swelling alleviates, and skin is that dark red vitta rope reduces.

Invalid: it is unchanged that curative effect terminates rear symptom and sign.

Cure+effective+it is effectively total effective.

2. result

Two groups of patient effectiveness comparison example (%) of table 2-1

Note: two groups of therapeutic effect compare, P < 0.05.

3. discuss and conclusion

Aescin for injection can fully suppress the release of prostaglandin E in vivo, improves thyroliberin content in blood, fall The activity of low adenosine phosphatase, stablizing of protection cell membrane, improve intravenous tension, maintain the normal permeability of blood capillary, Improve microcirculation, improve the oxygen-derived free radicals damage to neurocyte, Inflammatory substances can be suppressed, eliminate cellular edema, also to marrow god Through the protected effect of reperfusion injury, alleviate histologic lesion.Most patients blood vessel local after venoclysis 3d～5d has , i.e. there is symptom the same day to medicaments insensitive person medication in the irritations such as sour, numb, swollen, pain, and at transfusion vein centered by Above, spreading to the left and right, local skin is rubescent, scorching hot and has tenderness, and vein is hardening, elasticity loss, and even tube wall is inaccessible, and vein collapses Falling into, during limb activity, pain increases the weight of, it is impossible to continues venous transfusion, and is easy to block syringe needle, increases the misery of patient, the most very Easily cause venous extravasation, cause the red and swollen pain in local acutely, also increase nursing staff and puncture the difficulty of vein, also have impact on simultaneously The seriality for the treatment of work.Clinical with nursery work, use and outside Fructus Cnidii microcapsule thermosensitive hydrogel of the present invention, be coated with local treatment Method, the venous injury caused by protective inoculation aescine, pain, swelling disappear fast, and this method effect is obvious, carries simultaneously The high success rate of nursing staff's puncture vessel.Its main cause is that Fructus Cnidii microcapsule thermosensitive hydrogel of the present invention can prevent shallow table blood Bolt is formed, and accelerates cell regeneration, promotes to absorb, and stops the development of local inflammation and accelerates the absorption of hematoma, can relax and rapidly Ease the pain.And external application Rhizoma Solani tuber osi is in process of clinical application after hot water soak, hot water is easy to cool, and easily soaks bed Single, quilt cover, and the Rhizoma Solani tuber osi external application of stripping and slicing easily drops, it has not been convenient to, and effect is undesirable.

In sum, comparing with external application Rhizoma Solani tuber osi after hot water soak, Fructus Cnidii microcapsule thermosensitive hydrogel of the present invention is simple to operate Convenient, retention time is long, and comfort level is good, has cooling sensation, particularly summer, and curative effect is high, and safely and effectively, patient is acceptant.

Experiment three: the HPLC finger printing research of Fructus Cnidii microcapsule thermosensitive hydrogel

High-efficient liquid phase technique is used to set up the fingerprint analysis method of Fructus Cnidii microcapsule thermosensitive hydrogel, for evaluating and controlling Fructus Cnidii The quality of microcapsule thermosensitive hydrogel provides the method for science.

1 material

1.1 instrument

Waters2695-2998 type high performance liquid chromatograph (U.S.)；PDA detector, quaternary gradient pump,

Software is Empower2 data processing software system；KQ5200DE type numerical control ultrasonic cleaner (Kunshan). METTLERXS205DU electronic balance (Switzerland).

1.2 reagent

Fructus Cnidii microcapsule thermosensitive hydrogel, prepares with reference to the embodiment 1 in description of the invention detailed description of the invention, is shown in Table by 10 batches 3-1.The different pimpinellin of reference substance, different bolt wing celery alcohol, diosmetin are purchased from China pharmaceutical biological product calibrating academy.Acetonitrile For chromatographically pure, liquid phase water is Watson distilled water, and remaining reagent is analytical pure.

Table 3-1 Fructus Cnidii microcapsule thermosensitive hydrogel test sample lot number

2 methods and result

2.1 chromatographic condition

Chromatographic column Waters Xbridge C₁₈(4.6mm × 250mm, 5 μm) post, flowing, with acetonitrile as mobile phase A, with water is Mobile phase B, carries out gradient elution by table 3-2, detects wavelength 203nm, flow velocity 1.0mL min^-1；Column temperature 30 DEG C, sampling volume 10 μL。

Table 3-2 flows phase elution requirement

The preparation of 2.2 reference substance solution

Precision weighs different pimpinellin reference substance 4.13mg, different bolt wing celery alcohol reference substance 4.21mg, diosmetin reference substance 2.15mg, puts in 10mL measuring bottle, adds methanol and dissolves and be diluted to scale, to obtain final product.

The preparation of 2.3 need testing solutions

Take above-mentioned S1～S10 Fructus Cnidii microcapsule thermosensitive hydrogel about 0.5g, accurately weighed, accurate addition methanol 25mL, weigh, super Sonication 30min, takes out, lets cool, and mends weight, shakes up, and filters, takes subsequent filtrate and cross 0.45 μm filter membrane, to obtain final product.

2.4 methodological study

2.4.1 replica test

Taking same sample lots, precision weighs 6 parts respectively, according to 2.3 lower section legal system available test sample solutions, respectively sample introductions, with 4 Number different pimpinellin in peak is with reference to peak, calculates the relative retention time of 1～No. 18 total fingerprint peaks and relative peak area RSD ＜ 3%, is all higher than 0.99 by the similarity of each chromatographic fingerprinting of similarity evaluation computed in software simultaneously, shows that method repeats Property is good.

2.4.2 precision test

Take same need testing solution in replica test, continuous sample introduction 5 times, with No. 4 different pimpinellins in peak for reference to peak, calculate The RSD of the relative retention time and relative peak area that go out 1～No. 18 total fingerprint peaks is respectively less than 3%, simultaneously soft with similarity evaluation Part calculates the similarity of each chromatographic fingerprinting and is all higher than 0.99, shows instrument stabilizer, and precision is good.

2.4.3 stability test

Take same need testing solution in replica test, respectively 0,4,8,12,24h sample introductions, with No. 4 different pimpinellins in peak be With reference to peak, the RSD of the relative retention time and relative peak area that calculate 1～No. 18 total fingerprint peaks is respectively less than 3%, uses simultaneously The similarity of each chromatographic fingerprinting of similarity evaluation computed in software is all higher than 0.99, shows that need testing solution is stable in 24h.

The foundation of 2.5 finger printing

Accurate draw 2.2 under reference substance solution and 2.3 under each 10 μ L of need testing solution of preparation, inject high-efficient liquid phase color Spectrometer, obtains 10 lot number Fructus Cnidii microcapsule thermosensitive hydrogel HPLC finger printing, and result is shown in Fig. 1.

By the comparison with reference substance, confirming that No. 3 peaks are diosmetin, No. 4 peaks are different pimpinellin, and No. 7 peaks are different Bolt wing celery alcohol, wherein No. 4 peak different pimpinellin peak areas are more greatly and more stable, therefore select this peak for reference to peak.By 10 batches of Serpentiss Machine tool microcapsule thermosensitive hydrogel finger printing imports the chromatographic fingerprints of Chinese materia medica similarity evaluation system using committee of pharmacopeia to recommend System (A version), carries out chromatographic peak coupling, and matching result is shown in that Fig. 2, gained reference fingerprint are shown in Fig. 3.

With No. 4 different pimpinellins in peak as reference, after removing solvent peak, determine that 18 total peaks are for constituting Fructus Cnidii microcapsule The characteristic peak of thermosensitive hydrogel finger printing, sample has a relative retention time at peak and relative peak area be listed in respectively table 3-3 and Table 3-4.10 batches of Fructus Cnidii microcapsule thermosensitive hydrogel are respectively 0.968 with reference fingerprint Similarity Measure result, and 0.999, 0.998,0.998,0.997,0.990,0.990,0.999,0.999,0.998.

The relative retention time at the total peak of 10 batches of Fructus Cnidii microcapsule thermosensitive hydrogel of table 3-3

10 batches of Fructus Cnidii microcapsule thermosensitive hydrogel of table 3-4 have the relative peak area at peak

3 discuss

Extraction solvent, detection wavelength, flow phase system are investigated by experiment.Once water, 50% methanol, methanol conduct were used Extraction solvent, result is not good enough with water and 50% methanol need testing solution peak shape as Extraction solvent, and separating degree is the highest, makees with methanol Preferable for Extraction solvent gained chromatographic peak peak shape, therefore use methanol as Extraction solvent.

Use diode array detector that collection of illustrative plates has been carried out full wavelength scanner, result chromatographic peak information under 203nm Relatively horn of plenty, therefore select 203nm as measuring wavelength.

Flowing phase condition optimizing time test methanol-water, 2 kinds of flow phase system of acetonitrile-water respectively, finally choose acetonitrile- Water is as flowing phase, and chromatographic peak peak shape is preferable with this understanding.

Fructus Cnidii microcapsule thermosensitive hydrogel is determined for comparison peak with different pimpinellin, different bolt wing celery alcohol, diosmetin 18 total peaks, and obtain the comparison collection of illustrative plates of 10 batches of Fructus Cnidii microcapsule thermosensitive hydrogel and each batch sample by Similarity Measure software With the similarity compareed between collection of illustrative plates, result is all higher than 0.9, shows the stable preparation process of Fructus Cnidii microcapsule thermosensitive hydrogel.Right It is provided that more comprehensively quality control information according to collection of illustrative plates, can be as the quality control and evaluation side of Fructus Cnidii microcapsule thermosensitive hydrogel One of method.

Accompanying drawing explanation:

Fig. 1: Fructus Cnidii microcapsule thermosensitive hydrogel HPLC

Fig. 2: 10 batch sample coupling chromatographs

Fig. 3: reference substance finger printing

Detailed description of the invention:

Embodiment 1: Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine

Adopt and prepare with the following method:

Fructus Cnidii is Umbelliferae Cnidium Cusson plant cnidium monnieriCnidium monnieri (L.) Cuss. [Selinum monnieri L.]Dry mature fruit.

Although moreover, it will be appreciated that this specification is been described by according to embodiment, but the most each embodiment only wraps Containing an independent technical scheme, this narrating mode of description is only that for clarity sake those skilled in the art should Description can also be formed those skilled in the art through appropriately combined as an entirety, the technical scheme in each embodiment May be appreciated other embodiments.

Claims

1. the Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine treating motion sickness, it is characterised in that adopt and prepare with the following method:

Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine the most according to claim 1, it is characterised in that adopt and make with the following method Standby:

(2) preparation of porous microcapsule: take Fructus cnidii extract dry cream 2g prepared by step (1), be dissolved in 1mL ethyl acetate, then Add 2mL liquid paraffin, ultrasonic mixing to it, obtain Fructus cnidii extract medicament mixed liquid, standby；Take gelatin 1g, arabic gum 1g is dissolved in 40mL distilled water, mixing, makes the mixed solution of arabic gum and gelatin, standby；By above-mentioned Fructus cnidii extract Medicament mixed liquid is slowly added in the mixed solution of arabic gum and gelatin, stirs 3 times, make O/W type in tissue mashing machine Emulsion；Under 50 DEG C of water-baths, being slowly added dropwise 5% acetic acid to pH is 4, stirs, and the distilled water adding system bulk 2 times amount enters Row dilution, continues stirring to ice bath and is cooled to rapidly 10 DEG C, adds glutaraldehyde solidification 1h, and dropping 10%NaOH solution is adjusted to pH Being 7, stand and treat that it settles, precipitum distilled water is washed till without glutaraldehyde abnormal smells from the patient, filtration drying, obtains Fructus Cnidii porous microcapsule；

3. treating a quality determining method for the Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine of motion sickness, this Fructus Cnidii microcapsule is temperature sensitive Gel medicine is adopted and is prepared with the following method:

It is characterized in that, use following high-efficient liquid phase technique method that its finger printing carries out quality testing:

The quality determining method of Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine the most according to claim 3, this Fructus Cnidii microcapsule Thermosensitive hydrogel agent medicine is adopted and is prepared with the following method:

5. the application treated in motion sickness medicine is being prepared in a Fructus Cnidii microcapsule thermosensitive hydrogel agent, it is characterised in that this cnidium monnieri Sub-microcapsule thermosensitive hydrogel agent medicine is adopted and is prepared with the following method:

(1) technique before molding: weigh Surfactant SDS 1g, the constant volume that adds water, in 100mL volumetric flask, is joined Mass fraction processed is the sodium dodecyl sulfate solution of 1%, weighs Fructus Cnidii rough segmentation 10g, sodium dodecyl sulfate solution respectively 10mL, all loads round-bottomed flask, adds 95% ethanol 60mL, heating and refluxing extraction 2 times, each 1.5h, united extraction medicinal liquid, mistake Filter, concentrates filtrate and dries, obtain the dry cream of Fructus cnidii extract；

6. a Fructus Cnidii microcapsule thermosensitive hydrogel agent is at the venous injury medicine caused by preparation protective inoculation aescine In application, it is characterised in that this Fructus Cnidii microcapsule thermosensitive hydrogel agent medicine is adopted and is prepared with the following method:

7. the application treated in sexual impotence medicine is being prepared in a Fructus Cnidii microcapsule thermosensitive hydrogel agent, it is characterised in that this Fructus Cnidii Microcapsule thermosensitive hydrogel agent medicine is adopted and is prepared with the following method:

8. the application treated in eczema medicine is being prepared in a Fructus Cnidii microcapsule thermosensitive hydrogel agent, it is characterised in that this Fructus Cnidii Microcapsule thermosensitive hydrogel agent medicine is adopted and is prepared with the following method: