CN1353972A - Asiaticoside antisticking film and its preparation method - Google Patents
Asiaticoside antisticking film and its preparation method Download PDFInfo
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- CN1353972A CN1353972A CN 00127464 CN00127464A CN1353972A CN 1353972 A CN1353972 A CN 1353972A CN 00127464 CN00127464 CN 00127464 CN 00127464 A CN00127464 A CN 00127464A CN 1353972 A CN1353972 A CN 1353972A
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Abstract
The present invention provides a asiaticoside antiadhesion film. It is a film preparation formed from centella total glycoside and sodium hyaluronate. The Chinese medicine centella total glycoside selected by said invention can effectively prevent postoperative adhesion and the sodium hyaluronate with excellent elasticity, lburication and osmosis is used as carrier skeleton. Said invention antiadhesion film can be better adhered on the opening of wound. Its therapeutic effect is good, and its cost is low. Said invention also provides its preparation method.
Description
The present invention relates to medical material, be specifically related to a kind of asiaticoside antisticking film and preparation method.
Adhesion is a common complication behind the surgical operation, its incidence rate is high, it is the operating difficult problem of long-term puzzlement, as intestinal adhesion incidence rate behind the abdominal surgery up to 80～90%, wherein have about 30% finally to develop into intestinal obstruction again, caused great misery to patient, therefore, how effectively to solve postoperative intestinal adhesion is the important topic of domestic and international in recent ten years surgery research, also carries out the searching and the research of tissue adhesion medicine when updating the surgical operation skill.
The clinical practice face broad of the anti medicine behind the surgical operation, thoracic surgery, abdomen surgery, gynecological surgery etc. all need have application.The U.S. once estimated with regard to the market that should be used as of its national surgery anti medicine: the adhesion that surgical operation causes just accounts for nearly 8,000,000 every year, and wherein only the operation financial burden of abdominal part adhesion is about 1.1 hundred million dollars every year.And China has 1,200,000,000 populations, and its market demand capacity will be more considerable.
The interrelated data report, it is skeleton that external existing many scholars begin one's study with the hyaluronic acid sodium, adopt the whole bag of tricks that the some drugs composition is combined with hyaluronic acid sodium in the hope of developing tissue adhesion medicine preferably, Genzyme ' s company as the U.S. is that raw material is developed into membrane with the hyaluronic acid sodium, according to recognizing from the parties concerned, this product is about to obtain the permission of U.S. F.D.A.; In addition, according to nearest U.S.'s surgical magazine, hyaluronic acid sodium combines the surgery made from CMC (being carboxymethyl cellulose) and has carried out preclinical study with biomembrane.Another traded commodity is called macromolecular material antiadhesion barrier GORE-TEX, and the film of a 6cm * 12cm is amounted to 2000 yuan of RMB.Therefore, to be that China is clinical medical press for the effective anti-tissue adhesion medicine of development and production.
It is very abundant that Herba Centellae originates in a plurality of other provinces and towns plant resourceses such as the Jiangsu, Zhejiang, Guangdong, Fujian, Guangxi of China.The accumulated snow general glycoside be the utilization modern separation technology from Chinese medicine Herba Centellae Centella asiatia (L.) Urban[Hydrocotyle asiatia L.] the purified active ingredients of plants of extraction separation, main Asiaticoside (asiaticoside) and the madecassoside (madecassoside) of containing, the chemical constitution of its composition is clear and definite, the modern pharmacology effect experiment confirms, it has following function: can promote wound healing, prevent adhesion, soften, dwindle so that avoid cicatrix, recover the level and smooth and elasticity of skin, functions such as desalination pigmentation.Its pharmacological action mechanism mainly is to activate the skin epithelial cell, promotes the formation of normal granulation tissue, and wound surface is healed rapidly; It has obvious inhibitory action to fibroblasts proliferation simultaneously, chaotic keloid hypertrophy is had suppress and mitigation, can prevent that adhesion from the formation of adhesion taking place and alleviating, to reach therapeutic purposes and effect preferably.It is widely used clinically, and the damaging adhesion that the wound that long-term do not heal ulcer of the lower limb, the operation etc. that the vein dysfunction is caused cause and hypertrophic cicatrix pimple, the inflammation of hindering face recovery back formation due to the factors such as adhesion of tendon, calcination cause, long-term skin ulcer and scleroderma and the amyloidosis cutis etc. that other factors produces all have notable therapeutic effect.
Asiaticoside antisticking film is used for the treatment of the surgical operation posterior synechiae, its mechanism of action is to utilize asiaticoside antisticking film Chinese medicine ingredients Total Of Triterpenes can suppress granulation tissue fibroblasts proliferation in maturation process, thereby suppress and alleviated the hypertrophy of unordered keloid, arrive the therapeutic purposes of anti-tissue adhesion.
The objective of the invention is to use asiaticoside and design a kind of good effect, biological anti-stick film that cost is low.
The invention provides a kind of asiaticoside antisticking film, the membrane that it is made up of Total Of Triterpenes and hyaluronic acid sodium.
The present invention utilizes the hyaluronic acid sodium molecule to have good solid space framework, with its carrier framework as the effective ingredient asiaticoside, have better elastic, lubricity, permeability because of hyaluronic acid sodium simultaneously, so asiaticoside antisticking film can adhere to wound well, make local drug concentration keep higher level, and can delay pharmaceutical release time, better bring into play the anti-tissue adhesion's of Total Of Triterpenes effect.
Hyaluronic acid sodium (Sodium Hyaluronate) extensively is present in human organ and the animal organ.The hyaluronic acid sodium that extracts refining purification from cockscomb is a macromolecular polysaccharide, is alternately to be arranged in conjunction with the long-chain macromolecule material that constitutes by a part acetylglucosamine and a part glucuronic acid.The present invention utilizes hyaluronic acid sodium three-dimensional spatial structure and the good film-formable characteristic of plasticity, in asiaticoside antisticking film, with its as in pharmaceutically active ingredient carrier framework and make membrane, simultaneously also have better elastic, lubricity and excellent biological compatibility because of it, and can progressively be degraded and absorbed in vivo, be ideal filmogen.
The macromolecule medicine film that Total Of Triterpenes and hyaluronic acid sodium are formed, can be attached at wound, improve local drug concentration, delay drug release action time, better the performance Total Of Triterpenes is suppressed to fibroblast proliferation, anti-tissue adhesion's effect, thereby reaches the generation that effectively prevents surgical operation posterior synechiae complication.
Hyaluronic acid sodium can commercially availablely obtain, and quality standard is:
Molecular weight: be not less than 750,000
Content: greater than 90%
Protein content: less than 0.5%
Ultraviolet absorption value (1% aqueous solution): 280nm＜3.0,257nm＜2.0
pH：5.0～7.0
Antibacterial, thermal source: qualified
The specification requirement of asiaticoside antisticking film of the present invention is thickness 0.3-0.4 centimetre, the heavily about 300 ± 30mg of sheet (because of the hygroscopicity of hyaluronic acid sodium stronger, sheet weight is ± 10%), wherein the asiatic centella total salidroside content is not less than 78mg with the quantifier that closes of Asiaticoside and madecassoside.Membranous type can adjust according to clinical needs.
The main pharmacodynamics of asiaticoside antisticking film of the present invention is as follows through Ruijin Hospital Attached to Shanghai Medical Univ No.2 department of general surgery Shanghai digestion institute of Surgical Research result of study: one, test objective
This experiment is with rabbit row stomach operation, and it is back at the paries anterior gastricus otch in operation, the inboard attaching of incision of abdominal wall asiaticoside antisticking film is Asiaticoside-hyaluronic acid sodium (Asiaticosides-Sodium Hyaluronate, A-HA), hyaluronic acid sodium (Sodium Hyalruonate, HA) film prevents the effect of tissue adhesion with observation.Two, be subjected to the reagent thing
Title and lot number: A-HA film (990524) (every contains Total Of Triterpenes 100mg)
HA film (981026)
The unit of providing: develop by Shanghai Institute of Pharmaceutical Industry.
Specification: circle, diameter 4.5cm, thick 0.2～0.3cm.Three, animal
New zealand white rabbit (providing) by Shanghai City Dong Jing breeding feed lot
Body weight: average 2.5 kilograms
Number of animals: 36 (female, hero half and half)
The animal grouping
Matched group: N=12
A-HA film group: N=12
HA film group: N=12 four, test method and step
Rabbit after chlore-ammonia ketone vein paralysis, the abdominal part median incision, otch is about 6cm, makes the 2cm otch in paries anterior gastricus flesh layer after entering the chamber, sews up the incision then.The administration group uses A-HA, HA film (half sheet) to place on the paries anterior gastricus otch respectively, sews up incision of abdominal wall then.Matched group is done identical operation, not administration, layer-by-layer suture otch.Five, experimental observation
Experimental rabbit is normally taken food in the hands second day after operation, drinking-water.Every treated animal is the dead also situation of anatomic observation abdominal incision, paries anterior gastricus wound healing and adhesion outside perform the operation 4 weeks of back and 8 weeks, and does the pathology inspection.
To the split pole standard grading of adhesion degree, adhesion is divided into the 0-4 level by both at home and abroad;
0 grade: no adhesion
1 grade: indivedual loose, the adhesion of thin transparent lamellar
2 grades: patchy adhesion, but the adhesion strap does not have blood vessel, can passivity separate.
3 grades: adhesion is more obvious, in a small amount of blood vessel is arranged, need the separation of sharp property
4 grades: adhesion is tight, and boundary disappears between tissue
Dissect the back and judge the adhesion grade, and by 0,1,2,3,4 grade of adhesion level 0,1,2,3,4 minute respectively, record.
Get matched group and experimental group stomach wound site tissue, do the pathology inspection.Six, result of the test 1, matched group
12 rabbits of matched group, 3 rabbits are dead midway.Through 4 weeks and 8 all anatomic observations, see that all incision of abdominal wall and gastric wall incision have adhesion in various degree.Wherein severe adhesion (3 grades or 4 grades) accounts for 55.5% (n=5), and its incision of abdominal wall has adhesive band, gastric wall incision and omentum majus adhesion.Moderate adhesion (2 grades) accounts for 11.1% (n=5).No adhesion or slight adhesion (0 grade or 1 grade) account for 33.3% (n=3).2, Asiaticoside-hyaluronic acid sodium (A-HA) film group
12 rabbits of A-HA film group, 4 weeks of operation back dissected with 8 weeks.See that gastric wall incision and omentum majus moderate adhesion (2 grades) account for 8.3% (n=1).Slight adhesion (1 grade) accounts for 33.35 (n=4).The all smooth no adhesion of incision of abdominal wall and gastric wall incision (0 grade) accounts for 58.3% (n=7).3, glass wort glycoside (HA) film group
12 of HA film group rabbits, wherein 1 rabbit is dead midway.Dissection has a rabbit to see that adhesion is more obvious, and the incision of abdominal wall inboard sees that the adhesion band forms (3 grades) and accounts for 9.0% (n=1).The moderate adhesion, gastric wall incision and omentum majus adhesion (1 grade) account for 27.2% (n=3).No adhesion, abdominal part and gastric wall incision all smooth (0 grade) account for 45.5%.
The pathological examination operative site of matched group, A-HA film group, HA film group is organized and all is inflammatory reaction, and other does not see pathological change.Seven, discuss
Tissue adhesion is the complication that easily produces behind the surgical operation.In recent years, all carried out the research of anti-postoperative intestinal adhesion both at home and abroad.The antiadhesion barrier of this experimental applications Shanghai Institute of Pharmaceutical Industry development uses behind the outer operation of rabbit, observes the effect of its anti-surgical adhesions.
Experimental result show operation back use anti-stick film after (promptly after operation with the film horizontal at the operation tissue), the tissue adhesion incidence rate obviously reduces (seeing Table one).
Table one adhesion hierarchical statistics table
| Rabbit number | Matched group (level) | A-HA organizes (level) | HA organizes (level) | ||||
| All around | Eight weeks | All around | Eight weeks | All around | |||
| ??I | ??1 | ????3 | ????0 | ????0 | |||
| ??2 | ????4 | ????0 | ????0 | ||||
| ??3 | Dead | ????0 | ????1 | ||||
| ??4 | ????4 | ????0 | ??0 | ||||
| ??5 | Dead | ????0 | ??2 | ||||
| ??6 | Dead | ????1 | Dead | ||||
| ??II | ??1 | ????3 | ????0 | ????0 | |||
| ??2 | ????2 | ????0 | ????0 | ||||
| ??3 | ????3 | ????1 | ????1 | ||||
| ??4 | ????1 | ????2 | ????1 | ||||
| ??5 | ????1 | ????1 | ????3 | ||||
| ??6 | ????1 | ????1 | ????2 | ||||
The adhesion that can alleviate wound site to stomach wall, coat of the stomach medicine film.Learn the difference (P＜0.01) that processing matched group and administration group have significance by statistics.Wherein with A-HA film more effective (seeing Table two).
Table two adhesion progression percentage rate
| Progression | Matched group | The A-HA group | The HA group | |||
| Number of animals | ????％ | Number of animals | ????％ | Number of animals | ????％ | |
| ???0 | ????0 | ????7 | ????58.3 | ????5 | ????45.5 | |
| ???1 | ????3 | ????33.3 | ????4 | ????33.3 | ????3 | ????27.2 |
| ???2 | ????1 | ????11.1 | ????1 | ????8.3 | ????2 | ????18.2 |
| ???3 | ????3 | ????33.3 | ????0 | ????1 | ????9.0 | |
| ???4 | ????2 | ????22.2 | ????0 | ????0 | ||
| Add up to | ????9 | ????12 | ????11 | |||
Total Of Triterpenes is the active compound from plant extract, has been widely used in clinically abroad, and it can be suppressed to fibrocellular hypertrophy.Hyaluronic acid sodium is the biopolymer polysaccharide, be present in tissue, in machine, can progressively be degraded and absorb, in the asiaticoside antisticking film with its carrier as the effective ingredients in plant Total Of Triterpenes, the messenger drug film can be attached at wound, improve the wound local drug concentration, can delay pharmaceutical release time again, the two prevents the effect of tissue adhesion in conjunction with performance.Effect experiment shows that asiaticoside antisticking film is that an effective anti-postoperative is an adhesion agent, and clinical verification can be further carried out in hope.
The animal acute toxicity of asiaticoside antisticking film of the present invention, toxicity chamber result of the test is as follows through Shanghai Institute of Pharmaceutical Industry: one, experiment purpose
Measure the maximum tolerated dose of asiaticoside antisticking coating solution intraperitoneal injection of mice.Two, tried thing
Title: asiaticoside antisticking film, lot number are 990524, the heavy 300mg of sheet, and every asiatic centella total salidroside content is 100mg.
The preparation of sample: the Cmax that asiaticoside antisticking film can be prepared is 10mg/ml.Get two of asiatic centella total antisticking films, be cut into fragment after, be mixed with the solution of final volume 20ml with normal saline.Three, animal
Healthy Kunming mouse (quality certification number is provided by the court's Animal House: Shanghai is moving closes the card word No. 116)
Body weight: 18-22 gram
Number of animals: 20 (female, male half and half) four, route of administration and dosages
Use lumbar injection, the maximum administration capacity of every mice is 0.6ml/20g.Five, test method
Select 20 of healthy qualified kunming mices for use, female, male half and half.Every mouse peritoneal injection asiaticoside antisticking coating solution, the administration capacity is the 0.6ml/20g body weight.At once observe the reaction of animals situation after the administration, observed continuously 7 days, record toxic reaction symptom and dead distribution situation, and before administration, after the administration, take by weighing the body weight of mice when 24 hours, 48 hours, 72 hours and off-test.Six, experimental result:
Reaction of animals situation: do not observe any toxic reaction symptom, none routine animal dead of viewing duration.
Body weight: before the administration, after the administration when 25 hours, 48 hours, 72 hours and off-test the average weight of mice be respectively 18.7 ± 0.7,22.4 ± 1.2,23.4 ± 1.6,23.8 ± 2.2,24.9 ± 1.9.Seven, conclusion
The LD of mouse peritoneal injection asiaticoside antisticking coating solution
50Value is greater than 300mg/kg.
Documents and materials 1:
" external medicine " plant amedica fascicle was reprinted Fitoterapia.-1997 in 1998 the 13rd the 5th phases of volume, and 68 (5) .-413-416. study report: the pharmacology of Herba Centellae extract and toxicologic study.Now that the synopsis of relevant acute toxicity aspect is as follows:
Tried thing: (CAE, 1mg CAE is equivalent to 5.95mg to Herba Centellae 70% ethanol extraction
Dry crude drug)
Laboratory animal: rat
Result of the test: LD
50Greater than 675mg/kg.
Documents and materials 2:
British patent 1,123,288 bibliographical informations: the acute toxicity and the long term toxicity test that from the plant Herba Centellae, separate the effective ingredient madecassoside that obtains.Now that the synopsis of relevant acute toxicity aspect is as follows:
1, madecassoside (C
48H
78O
20, Madecassoside) obtain from Herba Centellae CentellaAsitica (L.) Urban extraction, separation.
2, the acute toxicity test of madecassoside
Tried thing: the pure product of madecassoside
Laboratory animal: mice (about 20 grams of body weight), rat (about 120 grams of body weight)
Dosage: 3g/kg, 5g/kg (choose the medicament of giving of two high dose group in the trial test
Amount, 20 animals of each dosage group)
Route of administration: oral and subcutaneous injection
Observing time: 14 days
Conclusion: none example of (1) all experimental group animals is dead
(2) because the toxicity of medicine is too low, can't try to achieve the median lethal dose(LD 50) of medicine
(LD
50)
The animal long term toxicity of asiaticoside antisticking film of the present invention:
Asiaticoside antisticking film belongs to disposable administration as the intraperitoneal medication of anti-surgical operation posterior synechiae, and containing Total Of Triterpenes in the every medicine film is 100mg, and wherein effective ingredient Asiaticoside and the hydroxyl total content of avenging careless glycoside is not less than 78mg.
The absorption test result shows in the mouse peritoneal of asiaticoside antisticking film: can reach absorption fully in four days, and animal acute toxicity test LD
50Greater than 300mg/kg, by illustrating down about the long term toxicity test item in National Drug Administration's " specification requirement of study of tcm new drug ", application exempts to do the long-term toxicity test for animals of asiaticoside antisticking film.
Another order of the present invention has provided a kind of preparation method of asiaticoside antisticking film, this method is to take by weighing Total Of Triterpenes and hyaluronic acid sodium respectively by recipe quantity, after the dissolving, mixes two kinds of solution respectively, with phosphoric acid after liquid, normal saline solution adjusting pH and ionic strength, volume is sub-packed in the film tool of required form in accordance with regulations, lyophilisation, system film molding, plastic packaging behind diaphragm places aseptic, the apyrogenic disposable plate, deposit in 5～8 ℃, dry lucifuge environment.
The present invention selects to prevent effectively that the Chinese medicine ingredients Total Of Triterpenes of tissue adhesion from combining with the biomacromolecule material hyaluronic acid sodium with good space framework and film property, make biological anti-stick film, its good effect, the cost of raw material is relatively low, and the market demand is wide, thereby asiaticoside antisticking film has good development prospect.
Example 1, prescription:
Total Of Triterpenes 100.0 grams
Hyaluronic acid sodium 90.0 grams
Buffer phosphate buffer (P.B.S)
An amount of compound method of normal saline solution:
Take by weighing the hyaluronic acid sodium of 100 gram Total Of Triterpenes and corresponding amount respectively, respectively with behind the physiological saline solution, and it is miscible by a certain percentage, regulating pH6.5 volume in accordance with regulations with phosphate buffer is sub-packed in the film tool, lyophilisation, make 1000 chip sizes and be about diameter 6cm, thickness is the 0.3-0.4cm membrane.Diaphragm after the film forming places plastic packaging behind aseptic, the apyrogenic disposable plate.Example 2, prescription:
Total Of Triterpenes 100.0 grams
Hyaluronic acid sodium 50.0 grams
Other components and operation are all with example 1.Example 3, prescription:
Total Of Triterpenes 100.0 grams
Hyaluronic acid sodium 110.0 grams
Other components and operation are all with example 1.Example 4, prescription:
Total Of Triterpenes 100.0 grams
Hyaluronic acid sodium 100.0 grams
Other components and operation are all with example 1.Example 5, prescription:
Total Of Triterpenes 50.0 grams
Hyaluronic acid sodium 100.0 grams
Other components and operation are all with example 1.Example 6, prescription:
Total Of Triterpenes 100.0 grams
Hyaluronic acid sodium 100.0 grams
Normal saline
Operation substitutes phosphate buffer with example 1 with normal saline.Example 7, prescription:
Total Of Triterpenes 50.0 grams
Hyaluronic acid sodium 100.0 grams
Other are with example 6.Example 8, prescription:
Total Of Triterpenes 100.0 grams
Hyaluronic acid sodium 50.0 grams
Other are with example 6.
Claims (2)
1, a kind of asiaticoside antisticking film is characterized in that the membrane that this antiadhesion barrier is made up of Total Of Triterpenes and hyaluronic acid sodium.
2, a kind of preparation method of a kind of asiaticoside antisticking film as claimed in claim 1, it is characterized in that this method is to take by weighing Total Of Triterpenes and hyaluronic acid sodium respectively by recipe quantity, respectively with after the dissolving of doubly measuring, mix two kinds of solution, after regulating pH and ionic strength with phosphoric acid towards liquid, normal saline solution, volume is sub-packed in the film tool of required form in accordance with regulations, lyophilisation, the molding of system film, plastic packaging behind diaphragm places aseptic, the apyrogenic disposable plate, deposit in 5～8 ℃, dry lucifuge environment.
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| CNB001274643A CN1137681C (en) | 2000-11-21 | 2000-11-21 | Asiaticoside antisticking film and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001274643A CN1137681C (en) | 2000-11-21 | 2000-11-21 | Asiaticoside antisticking film and its preparation method |
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| Publication Number | Publication Date |
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| CN1353972A true CN1353972A (en) | 2002-06-19 |
| CN1137681C CN1137681C (en) | 2004-02-11 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100333804C (en) * | 2003-04-18 | 2007-08-29 | 上海建华精细生物制品有限公司 | Sodium hyaluronate anti-adhesion film, and its prepn. method |
| EP1925310A1 (en) | 2006-11-24 | 2008-05-28 | Development Center For Biotechnology | Plant extracts from genera Plectranthus and Centella for treating skin disorders and enhancing healing of wounds for diabetics patients |
| CN1788730B (en) * | 2004-12-13 | 2010-05-05 | 上海医药工业研究院 | Gel containing centella general glycoside and sodium hyaluronate for preparing drop and spray agent |
| US10758584B2 (en) | 2016-07-17 | 2020-09-01 | Oneness Biotech Co. LTD | Topical formulation for promoting wound healing |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8449924B2 (en) | 2007-08-29 | 2013-05-28 | Development Center For Biotechnology | Process for the preparation of plant extracts for treating skin disorders and enhancing healing of wounds |
-
2000
- 2000-11-21 CN CNB001274643A patent/CN1137681C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100333804C (en) * | 2003-04-18 | 2007-08-29 | 上海建华精细生物制品有限公司 | Sodium hyaluronate anti-adhesion film, and its prepn. method |
| CN1788730B (en) * | 2004-12-13 | 2010-05-05 | 上海医药工业研究院 | Gel containing centella general glycoside and sodium hyaluronate for preparing drop and spray agent |
| EP1925310A1 (en) | 2006-11-24 | 2008-05-28 | Development Center For Biotechnology | Plant extracts from genera Plectranthus and Centella for treating skin disorders and enhancing healing of wounds for diabetics patients |
| US10758584B2 (en) | 2016-07-17 | 2020-09-01 | Oneness Biotech Co. LTD | Topical formulation for promoting wound healing |
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|---|---|
| CN1137681C (en) | 2004-02-11 |
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