CN1803204A - Absorbable biological medicinal membrane - Google Patents
Absorbable biological medicinal membrane Download PDFInfo
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- CN1803204A CN1803204A CN 200610020207 CN200610020207A CN1803204A CN 1803204 A CN1803204 A CN 1803204A CN 200610020207 CN200610020207 CN 200610020207 CN 200610020207 A CN200610020207 A CN 200610020207A CN 1803204 A CN1803204 A CN 1803204A
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- caprolactone
- lactide
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Abstract
The invention discloses an absorbable biological medicinal membrane, wherein the constituents include (by weight percent) caprolactone-lactide copolymer 10-95%, polylactide or/and lactide-glycolide copolymer 5-90%, wherein in the caprolactone-lactide copolymer, the content of caprolactone is 10-70%, the molecular weight of the copolymer is 50-1500 thousand, the molecular weight of polylactide or lactide-glycolide copolymer is 50-150 thousand, and 0.5-40% of biological adhesive can be charged.
Description
Technical field
The present invention relates to a kind of biological medicinal membrane that macromolecular material is made that absorbs, in particular, the present invention relates to a kind of biological medicinal membrane of making by the blend of caprolactone-lactide copolymer and polylactide etc.End the wound surface adhesion with the rear defence that operates, guide tissue regeneration, soft-tissue patch, artificial skin, dermis scaffold.
Background technology
The wound surface adhesion that prevents in the surgical operation is the problem of not fine solution always.The sequela that operation back tissue adhesion brings is: the operative site constant pain is several years; Operative site partly loses function, after the operation on tendon adhesion, limbs can't activity freely.The subject matter of existence such as the silicone oil of using clinically, transparent ester acid sodium, chitin glue is that anti-adhesion effects is poor at present, even does not have antiseized effect.This is that absorption in vivo is very fast because this class material all is fluid or semifluid shape, and the general 3-4 days time just absorbs fully, and anti is short action time, so often is difficult to reach comparatively ideal preventing adhesiving effect.
Playing the anti effect with the mechanical isolation principle of film is present a kind of development trend.U.S. ETHICON company develops INTERCEED fiber isolating membrane, and this film is to be made by the oxidation regeneration fiber, can absorb fully in 28 days in vivo.GENZYNE company develops the SEPRAFILM film, and it is mainly made by carboxymethyl cellulose, has tangible preventing adhesiving effect.But but above two kinds of absorbing films owing to all be that water-soluble cellulose is made, infiltration rate is fast, therefore must make very thick film (＞0.5mm) could keep the time that needs in vivo.
Chinese patent application number 001127837 discloses a kind of absorbable polylactic acid and has made Antiadhesive film, and this film is the water white transparency shape.Though certain preventing adhesiving effect is arranged, still there are some problems in using, reason is: 1) because the characteristic such as the vitrification point height of poly-lactic acid material itself, film fragility and hardness are bigger, in the degradation process, can form some bigger granules, sensation of pricking can be produced to tissue, inflammation can be produced; 2) to organizing not attaching property, alice can occur, and need to sew up.
Utilize 6-caprolactone and lactide modification by copolymerization (D.Cohn, and A.Hotovely Salomon, Volume26, Issue 15, and May 2005, Pages 2297-2305), the vitrification point of its copolymer material own is lower than room temperature, so this material can be made very softish film.But the film that uses this copolymeric material to make separately is too soft, and moulding processability is poor, and degradation time is uncontrollable, and is not easy to operate in the operation, therefore uses and is limited to.
United States Patent (USP) 5,085,629 disclose a kind ofly by L-lactide, 6-caprolactone, the synthetic terpolymer of lactide, are a kind of very softish materials, use this material separately or add barium sulfate to be used to make the absorbable endoureteral support.But use the film of this copolymeric material manufacturing easily to have above problem separately.
Chinese patent CN 113680C discloses the copolymer of 6-caprolactone-lactide-Acetic acid, hydroxy-, bimol. cyclic ester, but uses the film of this copolymeric material manufacturing easily still to have above problem separately.
Summary of the invention
For overcoming above-mentioned shortcoming, the present invention adopts the mode of absorbable polymer and caprolactone-lactide copolymer blend to material modification, and, improve the adhesiveness of material by adding a certain amount of adhesive agent.Biological medicinal membrane by material of the present invention is made can be absorbed fully by human body, and degradation speed can be regulated by the variation of component ratio, and adhesiveness is good, need not sew up, and is easy to operate in the operation.
Consisting of of biological medicinal membrane of the present invention: by weight percentage:
Caprolactone-lactide copolymer 10%～95%,
Polylactide is or/and lactide-glycolide copolymer 5%～90%,
Wherein, in caprolactone-lactide copolymer, the caprolactone weight percentage is 10%-70%, and the molecular weight of copolymer is 5～1,500,000; The molecular weight of polylactide or lactide-glycolide copolymer is 5～1,500,000; The lactide here can be the L type, also can be the DL type.
The molecular weight of caprolactone-lactide copolymer, polylactide, lactide-glycolide copolymer is viscosity-average molecular weight (Mn), with Ubbelohde viscometer 25 ℃ of intrinsic viscositys ([η]) that record polymer in oxolane, the following formula of reuse calculates viscosity-average molecular weight earlier:
[η]＝1.04×10
-4Mn
0.75
Biological medicinal membrane of the present invention can also add bioadhesive polymer, as: the sanlose of water-soluble anionic type, alginic acid, hyaluronic acid, pectin, xanthan gum, polyacrylic acid, chitosan-EDTA complex; Cationic chitosan, polylysine; Nonionic polyethers, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose.
Add the amount of bioadhesive polymer in the biological medicinal membrane of the present invention, be 0.5～40% of material gross weight.
In the biological medicinal membrane of the present invention, caprolactone-lactide copolymer, mainly synthetic by experiment, wherein, caprolactone monomer can be 6-caprolactone, ε-alkyl caprolactone, described alkyl is the alkyl of C1-C4, i.e. ε-methyl caprolactone, ε-ethyl caprolactone, ε-propyl group (or isopropyl) caprolactone and ε-butyl (or isobutyl group) caprolactone; Lactide monomer is L-lactide, DL-lactide or L-lactide and DL-lactide mixture; The ratio of its caprolactone and lactide, the one, according to the flexibility, the 2nd of material requested,, regulate the ratio that feeds intake and reach according to the degradation speed of the concrete purposes of material.
In the biological medicinal membrane of the present invention, with polylactide or/and Acetic acid, hydroxy-, bimol. cyclic ester-lactide join in caprolactone-lactide copolymer, mainly improve caprolactone-lactide copolymer too softness cause in the operation not easy to operate, the processing and forming difficulty of film, problem such as degradation time is uncontrollable.After the blend, the hardness of material improves, and the film molding is easy, and the fabrication yield height is convenient to operation technique during use.
In the biological medicinal membrane of the present invention, add bioadhesive polymer, mainly increase the hydrophilic of material, help and the attaching of organizing, do not need to sew up.
The molding of biological medicinal membrane of the present invention can be adopted conventional film technique, as The tape casting, solvent evaporation film forming, extrudes, calendering, blowing film forming, and lyophilization, film forming etc. is separated.
Biological medicinal membrane of the present invention compared with prior art has following advantages:
1) material therefor is a kind of good biocompatibility, can degrade voluntarily, and degradation speed can reach by regulating copolymer or blend ratio.
2) material therefor is an intermingling material, and blending and modifying is simpler than synthetic copolymer technology, and its material property is more easy to control as soft durometer.
3) add bioadhesive polymer, increased the material hydrophilic, help and the attaching of organizing, do not need sutured.
Biological medicinal membrane of the present invention can be used for surgical operation and prevent the wound surface adhesion, guide tissue regeneration, soft group of sticking patch, artificial skin, dermis scaffold etc.Can also sneak into the medicine of anti-inflammatory.
The specific embodiment
The invention will be further described below in conjunction with embodiment.
The preparation of embodiment 1 6-caprolactone-DL-lactide copolymer:
6-caprolactone (Sigma company) and DL-lactide (self-control) that dehydration and purification is handled respectively 50 restrain the reaction bulb that places 500ml, add 0.02% stannous octoate catalyst (Sigma company) again, reaction is 6 hours under vacuum condition and under 150 ℃, obtain elastic polymer, with this polymer dissolution in acetone, precipitate in ethanol, precipitate drying in vacuum desiccator promptly obtained elastomeric material in 48 hours.The molecular weight of product is 530,000, measures through nuclear-magnetism C13 spectrum, and the 6-caprolactone unit accounts for 43.6% in 6-caprolactone-lactide copolymer.The measuring vitrification point is 3 ℃.
The DL-lactide can be replaced with the L-lactide in the above-mentioned experiment, or the mixture of DL-lactide and L-lactide, and experiment condition is basic identical, synthetic corresponding copolymer.
Embodiment 2
6-caprolactone 60 grams and DL-lactide 40 that dehydration and purification is handled restrain the reaction bulb that places 500ml, add 0.01% stannous octoate catalyst again, reaction is 6 hours under vacuum condition and under 150 ℃, obtain elastic polymer, with this polymer dissolution in acetone, precipitate in ethanol, precipitate drying in vacuum desiccator promptly obtained elastomeric material in 48 hours.The molecular weight of product is 1,130,000, measures through nuclear-magnetism C13 spectrum, and the 6-caprolactone unit accounts for 39.1% in 6-caprolactone-lactide copolymer.The measuring vitrification point is 2 ℃.
The DL-lactide can be replaced with the L-lactide in the above-mentioned experiment, or the mixture of DL-lactide and L-lactide, and experiment condition is basic identical, synthetic corresponding copolymer.
The preparation of embodiment 3 ε-alkyl caprolactone-DL-lactide copolymer:
ε-methyl caprolactone (Sigma company) and DL-lactide that dehydration and purification is handled respectively 50 restrain the reaction bulb that places 500ml, add 0.01% stannous octoate catalyst again, reaction is 7 hours under vacuum condition and under 150 ℃, obtain elastic polymer, with this polymer dissolution in acetone, precipitate in ethanol, precipitate drying in vacuum desiccator promptly obtained elastomeric material in 48 hours.The molecular weight of product is 360,000, measures through nuclear-magnetism C13 spectrum, and ε in ε-alkyl caprolactone-lactide copolymer-alkyl caprolactone units accounts for 36.6%.The measuring vitrification point is 5.5 ℃.
ε-ethyl caprolactone, ε-propyl group (or isopropyl) caprolactone and ε-butyl (or isobutyl group) caprolactone are synthetic by identical method with the DL-lactide copolymer.
The DL-lactide can be replaced with the L-lactide in the above-mentioned experiment, or the mixture of DL-lactide and L-lactide, and experiment condition is basic identical, synthetic corresponding copolymer.
Embodiment 4
Acetic acid, hydroxy-, bimol. cyclic ester 30 grams and DL-lactide 70 that dehydration and purification is handled restrain the reaction bulb that places 500ml, add 0.01% stannous octoate catalyst again, reaction is 6 hours under vacuum condition and under 150 ℃, obtain copolymer, this copolymer is dissolved in the acetone, precipitate in ethanol, precipitate drying in vacuum desiccator promptly obtained elastomeric material in 48 hours.The molecular weight of product is 230,000, measures through nuclear-magnetism C13 spectrum, and glycolide units accounts for 31.6% in the glycolide-lactide copolymer.The measuring vitrification point is 56 ℃.
The glycolide-lactide copolymer ratio is regulated in the above-mentioned experiment, can change monomeric rate of charge, obtains synthetic corresponding copolymer, and experiment condition is basic identical.
Embodiment 5
Press 6-caprolactone-DL-lactide copolymer 50 grams of embodiment 1 preparation, (press the preparation of embodiment 4 similar approach with the DL-polylactide, molecular weight is 250,000, vitrification point is 52 ℃) 50 grams are by the blend of solution dissolution method, solvent for use is an acetone, casting film-forming, the vitrification point of measuring film are 8 ℃.
Embodiment 6
Press 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 1 preparation, (molecular weight is 230,000 with embodiment 4 preparation lactide-glycolide copolymers, vitrification point is 56 ℃) 10 grams are by the dissolution method blend, solvent for use is an acetone, solvent evaporates film forming, the vitrification point of measuring film are 8 ℃.
Embodiment 7
Press 6-caprolactone-DL-lactide copolymer 9 grams of embodiment 1 preparation, (press the preparation of embodiment 4 similar approach with the poly-propyl ester-glycolide copolymer of handing over, molecular weight 320,000, vitrification point is 58 ℃) 21 grams are by the dissolution method blend, solvent for use is an acetone, solvent evaporates film forming, the vitrification point of measuring film are 17 ℃.
Embodiment 8
Press 6-caprolactone-DL-lactide copolymer 48 grams of embodiment 1 preparation, with DL-polylactide molecular weight be 250,000,48 grams, carboxymethyl cellulose 4 grams of the anionic of aqueous solution, by the dissolution method blend, casting film-forming, the vitrification point of measuring film is 16 ℃.
Embodiment 9
Press 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 1 preparation, with DL-polylactide (molecular weight is 250,000) 10 grams, cationic chitosan 4 grams, by the dissolution method blend, solvent evaporates film forming, the vitrification point of measuring film are 8 ℃.
Embodiment 10
Press methyl 6-caprolactone-DL-lactide copolymer 15 grams of embodiment 3 preparations, with DL-polylactide (molecular weight is 250,000) 15 grams, cationic chitosan 4 grams are by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 8 ℃.
Embodiment 11
Press 6-caprolactone-DL-lactide copolymer 21 grams of embodiment 2 preparations, with poly-propyl ester-glycolide copolymer (molecular weight is 230,000) 9 grams of handing over, solvent evaporates film forming, the vitrification point of measuring film are 4 ℃.
Embodiment 12
Press 6-caprolactone-DL-lactide copolymer 9 grams of embodiment 2 preparations, with poly-propyl ester-glycolide copolymer (molecular weight is 230,000) 21 grams of handing over, solvent evaporates film forming, the vitrification point of measuring film are 9 ℃.
Embodiment 13
Press 6-caprolactone-DL-lactide copolymer 9 grams of embodiment 2 preparations, with DL-polylactide (molecular weight is 1,360,000, and vitrification point is 61 ℃) 21 grams, solvent evaporates film forming, the vitrification point of measuring film are 11 ℃.
Embodiment 14
Press methyl 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 3 preparations, with DL-polylactide (molecular weight is 250,000) 40 grams, by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 15 ℃.
Embodiment 15
Press methyl 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 3 preparations, with copolymer (molecular weight is 250,000) 40 grams of DL-polylactide-co-glycolide, by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 19 ℃.
Embodiment 15
Press methyl 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 3 preparations, with copolymer (molecular weight is 250,000) 40 grams of DL-polylactide-co-glycolide, by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 19 ℃.
Embodiment 16
Press methyl 6-caprolactone-DL-lactide copolymer 8 grams of embodiment 3 preparations, with copolymer (molecular weight is 250,000) 36 grams of DL-polylactide-co-glycolide, cationic chitosan 6 grams are by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 13 ℃.
Embodiment 17
Press methyl 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 3 preparations, copolymer (molecular weight is 250,000) 36 grams with the DL-polylactide-co-glycolide, carboxymethyl cellulose 4 grams of the anionic of aqueous solution, by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 13 ℃.
Embodiment 18
Press methyl 6-caprolactone-DL-lactide copolymer 10 grams of embodiment 3 preparations, with DL-polylactide (molecular weight is 250,000) 36 grams, carboxymethyl cellulose 4 grams of the anionic of aqueous solution are by the dissolution method blend, freeze-drying film forming, the vitrification point of measuring film are 13 ℃.
The degraded situation of absorbable biological medicinal membrane of the present invention, row are as table 1.
The degraded situation of table 1 absorbable biological medicinal membrane
| Sample | Hot strength (MPa) | Extension at break (%) | Vitrification point (℃) | Half time (week) that needs of molecular weight degradation * |
| Embodiment 6 | 5.5 | 158 | 8 | 3 |
| Embodiment 7 | 5.0 | 149 | 17 | 1 |
| Embodiment 8 | 10.8 | 87 | 16 | 3 |
| Embodiment 9 | 6.0 | 123 | 6 | 2 |
| Embodiment 10 | 6.7 | 110 | 8 | 2 |
| Embodiment 11 | 4.1 | 220 | 4 | 1 |
| Embodiment 12 | 12.0 | 108 | 9 | 2 |
| Embodiment 13 | 38.5 | 115 | 11 | 5 |
* in 37 ℃ phosphate buffer solution, test
Claims (6)
1. absorbable biological medicinal membrane, it is characterized in that: it consists of (by weight percentage):
Caprolactone-lactide copolymer 10%～95%,
Polylactide is or/and lactide-glycolide copolymer 5%～90%,
Wherein, in caprolactone-lactide copolymer, the caprolactone weight percentage is 10%-70%, and the molecular weight of copolymer is 5～1,500,000; The molecular weight of polylactide or lactide-glycolide copolymer is 5～1,500,000.
2. absorbable biological medicinal membrane according to claim 1 is characterized in that: the caprolactone in wherein said caprolactone-lactide copolymer is 6-caprolactone, ε-alkyl caprolactone.
3. absorbable biological medicinal membrane according to claim 2, it is characterized in that: described alkyl is the alkyl of C1-C4, and ε-alkyl caprolactone is ε-methyl caprolactone, ε-ethyl caprolactone, ε-propyl group caprolactone, ε-isopropyl caprolactone, ε-butyl caprolactone, ε-isobutyl group caprolactone.
4. absorbable biological medicinal membrane according to claim 1 is characterized in that: the lactide in wherein said caprolactone-lactide copolymer is L-lactide, DL-lactide, or L-lactide and DL-lactide mixture.
5. according to the described arbitrary absorbable biological medicinal membrane of claim 1～4, it is characterized in that: this absorbable biological medicinal membrane also can add bioadhesive polymer, as: the sanlose of water-soluble anionic type, alginic acid, hyaluronic acid, pectin, xanthan gum, polyacrylic acid, chitosan-EDTA complex; Cationic chitosan, polylysine; Nonionic polyethers, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose.
6. absorbable biological medicinal membrane according to claim 5 is characterized in that: the amount of bioadhesive polymer is 0.5%～40% of a material gross weight.
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| CN 200610020207 CN1803204A (en) | 2006-01-23 | 2006-01-23 | Absorbable biological medicinal membrane |
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| CN 200610020207 CN1803204A (en) | 2006-01-23 | 2006-01-23 | Absorbable biological medicinal membrane |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104403286A (en) * | 2014-11-25 | 2015-03-11 | 苏州市贝克生物科技有限公司 | Medical pectin/polylactic acid composite film and preparation method thereof |
| CN107095728A (en) * | 2017-05-19 | 2017-08-29 | 东莞颠覆产品设计有限公司 | Carried stent in tube chamber |
| CN112521734A (en) * | 2020-10-14 | 2021-03-19 | 浙江中在医疗科技有限公司 | Degradable medical elastomer material and application thereof |
-
2006
- 2006-01-23 CN CN 200610020207 patent/CN1803204A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104403286A (en) * | 2014-11-25 | 2015-03-11 | 苏州市贝克生物科技有限公司 | Medical pectin/polylactic acid composite film and preparation method thereof |
| CN107095728A (en) * | 2017-05-19 | 2017-08-29 | 东莞颠覆产品设计有限公司 | Carried stent in tube chamber |
| CN112521734A (en) * | 2020-10-14 | 2021-03-19 | 浙江中在医疗科技有限公司 | Degradable medical elastomer material and application thereof |
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