CN103751788A - Composite sustained-release preparation, as well as preparation method and application thereof - Google Patents
Composite sustained-release preparation, as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN103751788A CN103751788A CN201310711544.4A CN201310711544A CN103751788A CN 103751788 A CN103751788 A CN 103751788A CN 201310711544 A CN201310711544 A CN 201310711544A CN 103751788 A CN103751788 A CN 103751788A
- Authority
- CN
- China
- Prior art keywords
- pdlla
- preparation
- lactide
- hours
- degrees celsius
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a composite sustained-release preparation, as well as a preparation method and application thereof. The preparation comprises polylactic acid and 5-fluorouracil, and is prepared by immersing a membrane of 30*440mm, made from polylactic acid in 1mg of 5-fluorouacil. According to the preparation method, the 5-Fu and PDLLA (polylactic acid) are compounded, the biodegradation rate of the composite material is remarkably lower than a single PDLLA material, and the degrading speed is lowered.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of composite slow release agent its preparation method and application, specifically, relate to a kind of PDLLA/5-Fu composite slow release agent its preparation method and application.
Background technology
In glaucomatous filtration surgery, postoperative failed reason is due to the formation that filters road cicatrix mostly.How to avoid the formation of postoperative scar, become the key that improves success rate of operation.The current formation for anti-postoperative scar, researcheres have done a large amount of research, the wherein application of bioamnion in the application of anti-synulotic medicine in art and art, its effectiveness has obtained clinical confirmation, but the side effect of antiscaring drugs has also brought some postoperative complication, its valid density is also difficult to control; And the Antiscarring effect of bioamnion is limited, it still causes cicatrix formation after absorbing, causes the failure of operation.Domestic and international many experts adopt distinct methods to filter the formation of passage paralysis trace to reduce for this reason, as used, suppress synulotic medicine, at present conventionally clinically there are 5-fluorouracil, mitomycin, tissue-type plasminogen activator, encircle mycin A etc., though these medicines can delay cicatrization, because its toxic and side effects easily causes more complication.In operation, use on the other hand implant, as SK glue, amniotic membrane, collagem membrane etc., can mechanical isolation scleral flap and sclera bed, avoid or reduce fiber adhesion, keep filtering passage unobstructed.But with regard to implant, its Main Function is to maintain by mechanical support effect the Deep Layer of Sclera lacuna that operation forms, and unrestraint filters passage proliferation function, and curative effect time is short.The implants such as while amniotic membrane, scleral strip, anterior capsule may cause the side effect such as immunological rejection, and therefore its application is subject to certain limitation.
At present, one of Main Means that glaucoma filtration surgery improves curative effect is in the world exactly the improvement of embedded material.Select the biopolymer functional material that biocompatibility is good, ophthalmic degraded is slow, have certain fibroblast growth effect that is suppressed to.Or grafting suppresses synulotic medicine on the basis of this embedded material, thereby effectively reduce the cicatrization of avascular filtering bleb, improve success rate of operation.The 5-fluorouracil medicine that can suppress significantly avascular filtering bleb fibrocyte propagation that this experimental selection is commonly used clinically.By being carried out chemical modification, and carry out covalence graft with PDLLA.Prepare polylactic acid grafting 5-Fu medicine carrying diaphragm, reach the object of medicament slow release.
Polylactic acid PDLLA (Polylactide) is the polymer that the more class of Recent study has good biocompatibility and biological degradability.Poly-light acetic acid (the self-reinforced poly glyeolide of self-reinforcing of external development, SR-PGA), self-reinforcing poly (l-lactic acid) (self-reinforced poly levolcte, SR-PLLA) and non-enhancing poly (l-lactic acid) (PLL-A) are in clinical use.But PGA degraded is very fast, and complication is many, PLLA degraded is slow, can retain for a long time in vivo.
Polylactic acid is owing to having good biocompatibility, degradability, and its final catabolite is carbon dioxide and water, by the normal metabolism of body, is excreted.Nontoxic to human body, non-stimulated, be applied at present in multiple slow releasing pharmaceutical.
Summary of the invention
The object of the invention is to overcome the defect that above-mentioned technology exists, a kind of composite slow release agent its preparation method and application are provided.
Its concrete technical scheme is:
A kind of composite slow release agent, its composition comprises polylactic acid and 5-fluorouracil, and the 5-fluorouracil that described composite slow release agent is made the diaphragm immersion 1mg of 30 × 440mm by polylactic acid obtains.
A preparation method for composite slow release agent, comprises the following steps:
(1) adopt ring-opening polymerisation method by D synthesis of lactide from lactic acid, then form polylactic acid by lactide ring-opening polymerisation.Under the effect of catalyst, catalyst is zinc oxide, by the mass fraction of 1500ml, is the three-neck flask that 85% DL lactic acid and appropriate zinc oxide are placed in 3000ml, slowly heated and stirred, when temperature reaches 98 degrees Celsius, starts to reduce pressure with water pump, continue heating, after to be drained off completing, the receiving bottle of distilled water is taken off, connect receiving bottle, with oil pump decompression, heat up rapidly, maintain more than 140 degrees Celsius, steam the crude product of flaxen lactide, about 600g.Wherein dehydration temperaturre is 140 degrees Celsius, and dewatering time is 2 hours, and depolymerization temperature is 230 degrees Celsius, and the time is 2 hours;
(2) room temperature is under 22 ℃, 40% humidity, to being housed, the ampulla of lactide is evacuated 5 hours with oil pump, by stannous octoate (food additive of U.S. FFD approval) and the ratio wiring solution-forming of chloroform in 2: 1, pour in the ampulla of vacuum, lactide is mixed homogeneously with solution, continue evacuation approximately 3 hours, solvent chloroform is volatilized totally, alcohol blast burner tube sealing in evacuation, ampulla after tube sealing is put into silicone oil, 140 degrees Celsius of silicone oil temperature, polymerization 48 hours;
(3) take domestic DL lactic acid as raw material, prepare PDLLA (molecular weight 2.0x105), preparation condition is under 22 ℃, 40% humidity, take ethyl acetate as solvent, adding respectively 95% molecular weight is 2.0 × 105PDLLA, 5%5-Fu1mg adopts solvent evaporation method to prepare PDLLA/5-Fu composite membrane, size is the thin film of 3 × 4mm, and after subpackage, oxirane disinfection is standby.
Composite slow release agent of the present invention is the application in the postoperative cicatrix medicine of glaucoma process in preparation.
Compared with prior art, beneficial effect of the present invention is: the present invention adopt 5-Fu and PDLLA compound after, the biological degradation rate of composite is starkly lower than simple PDLLA material, degradation speed slows down.May be due to: in (1) composite, have equally distributed 5-Fu granule, similar a kind of physical barriers, the entering and the rate of release of catabolite of the degraded media such as hydrone that can slow down; (2) 5-Fu dissolubility in acid medium improves, forming alkalescence environment (can react with acid degradation product, reduced autocatalytic effect and the generation speed thereof of material internal acid degradation product, also to material, pH value decline around has certain cushioning effect.5-Fu and PDLLA are compound, and rear degradation speed slows down, and only a small amount of catabolite slowly discharges, and can not cause that a large amount of inflammatory cells gather, and biocompatibility improves.After 5-Fu and PDLLA are compound, make Antiscarring effect more lasting, thereby can effectively suppress the formation of cicatricial phase cicatrix, and this point is to use merely PDLLA not available.The degradation speed of composite slows down, the strength maintenance time that can improve material on the one hand, and also can avoid on the other hand a large amount of catabolites in a short time to discharge, cause the gathering of inflammatory cell, thereby can improve the biocompatibility of material.Therefore, after 5-Fu and PDLLA are compound, can obviously improve material initial strength, the degradation speed that slows down, improves strength maintenance time and biocompatibility, reaches the slow releasing function of medicine, in the formation of anti-cicatrix effectively of cicatrization phase, thereby improve the success rate of operation, and its safety is higher, the pair damage of avoiding the toxic action of high concentration anti-scar drug thing to bring for tissue.
Accompanying drawing explanation
Fig. 1 is that each group of histopathology changes (hematoxylin-eosin staining, × 40) respectively organize White Rabbit limbus of corneae pathology and change observation: wherein matched group: comparatively common with lymphocyte, fibrocyte, apocyte, filter road healing inaccessible, between conjunctiva and sclera, heal, and (Fig. 1 a) to occur more inflammatory cell; PDLLA/5-Fu group: visible fibroblast proliferation and collagen fiber form all few compared with the first two experimental group amount, lymphocyte 1-2/H, two-layer scleral flap separately, filters gap, road visible, and subconjunctival tissue is loose, and (Fig. 1 is b); PDLLA group: have as seen a few fibres hyperplasia, a small amount of collagen fiber form, a little lymphocyte, two-layer scleral flap separately, filters gap, road visible, subconjunctival tissue loosen (Fig. 1 c, d).
The specific embodiment
Below in conjunction with the drawings and specific embodiments, technical scheme of the present invention is described in more detail.
99 of healthy Japan large ear rabbits, body weight 2.0-2.5k g, male and female half and half.Be divided at random 3 groups: 1) PDLLA group; 2) PDLLA/5-Fu enters group; 3) matched group.During experiment, first carry out animal surgery.By the Japan large ear rabbit after sub-cage rearing 7d, intramuscular injection ketamine (1ml/kg) adds promethazine (1ml/kg) anesthesia.Rabbit is got ventral decubitus and is fixed on operating-table, the conventional preserved skin of surgical operation, sterilization, drape.All laboratory animals are all selected right eye, preoperative give art eye ofloxacin order water day 6 eye dripping three days, in art, give tobramycin normal saline washing conjunctival sac, from 10 o'clock to 2 o'clock position along limbus of corneae, open bulbar conjunctiva, separate subconjunctival tissue, in the scleral flap of 12 o'clock of top position take limbus of corneae as 1/2 scleral thickness of substrate 3 × 4mm size, trabecular tissue and the deep layer cornea tissue of excision 1.5 × 1.5mm size, wipe out iris tissue, implant is placed in to below scleral valve, sew up scleral flap and conjunctival flap, subconjunctival injection dexamethasone 2.5mg, tobramycin dexamethasone eye ointment is coated with eye, eye pad applies eye, art finishes.
Its animation of clinical follow, wound healing situation, after surveying 1 day, 3 days, 7 days, 15 days, 30 days, the intraocular pressure of 90 days, and in postoperative 30 days, within 90 days, row UBM checked.
Pathological examination: the injection of the auricular vein in rabbit air 30mL was lethal in postoperative 8 weeks,, separated along socket of the eye wall through incision of skin along margo orbitalis, and reserve part eyelid, retains complete conjunctiva, cuts off extraocular muscles and optic nerve, takes out eyeball.Clean with normal saline flushing, it is fixing that eyeball tissue is put into 40g/L paraformaldehyde, makes specimen, then the section of specimen Line Continuity is made to pathological section, hematoxylin-eosin staining.Avascular filtering bleb situation and avascular filtering bleb situation around under low power Microscopic observation conjunctiva, neutrophil cell, fibroblast and lymphocyte in high power Microscopic observation scleral flap tissue.
The standards of grading of avascular filtering bleb: the height of avascular filtering bleb is divided into 0～4 point, the range size of avascular filtering bleb is divided into 0～12 point, by the range size of corneoscleral junction, divides, and both are added as are less than 2 and are divided into non-functional avascular filtering bleb, are greater than 2 points of persons for filtration bleb.
Simple PDLLA material degradation is very fast, and after 5-Fu and PDLLA are compound, the biological degradation rate of composite is starkly lower than simple PDLLA material, and degradation speed slows down.May be due to: in (1) composite, have equally distributed 5-Fu granule, similar a kind of physical barriers, the entering and the rate of release of catabolite of the degraded media such as hydrone that can slow down; (2) 5-Fu dissolubility in acid medium improves, forming alkalescence environment (can react with acid degradation product, reduced autocatalytic effect and the generation speed thereof of material internal acid degradation product, also to material, pH value decline around has certain cushioning effect.5-Fu and PDLLA are compound, and rear degradation speed slows down, and only a small amount of catabolite slowly discharges, and can not cause that a large amount of inflammatory cells gather, and biocompatibility improves, to the healing process unrestraint effect of conjunctival flap.After 5-Fu and PDLLA are compound, make Antiscarring effect more lasting, thereby in the formation that effectively suppresses cicatricial phase cicatrix, and this point is that simple PDLLA is not available.The degradation speed of composite slows down, and the strength maintenance time that can improve material on the one hand, also can avoid on the other hand a large amount of catabolites in a short time to discharge, thereby can improve the biocompatibility of material.Therefore, after 5-Fu and PDLLA are compound, can obviously improve material initial strength, the degradation speed that slows down, improves strength maintenance time and biocompatibility, reaches the slow releasing function of medicine, in the formation of anti-cicatrix effectively of cicatrization phase, thereby improve the success rate of operation, and its safety is higher, the pair damage of avoiding the toxic action of high concentration anti-scar drug thing to bring for tissue.
Between group, compare:
Cornea situation: respectively organize the postoperative slight corneal opacity that all has, disappeared in postoperative 1 week, compare between two zero difference between each group.
Anterior chamber's situation: respectively organize the generation of the bad complication such as the postoperative anterior chamber of being showed no shoals, disappearance, compare between two zero difference between each group.
Bleeding: have 6 generations hyphema in various degree in the operation of 24, but absorb in postoperative 3d, compare between two zero difference.
Avascular filtering bleb situation: 3 groups of avascular filtering blebs relatively have no difference (P > 0.05) in 1 week after surgery.But avascular filtering bleb all carrying out property dwindles, and with matched group, dwindles obviously.Matched group and experimental group more variant (P < 0.05) after postoperative 2 weeks.The avascular filtering bleb of postoperative 4 weeks matched groups becomes non-functional, and experimental group postoperative 8 weeks is still functional avascular filtering bleb.Postoperative each observing time point, between PDLLA/5-Fu group and PDLLA group and matched group group, compare, there is significant difference (P < 0.05), and between PDLLA group and PDLLA/5-Fu group, compare zero difference (P > 0.05), in Table 1.
The average 2.50kPa of the preoperative intraocular pressure of change of perioperatively intraocular pressure, postoperative 2 groups of 1 week intraocular pressures obviously reduce, postoperative and preoperative comparison, all there were significant differences (P < 0.01).2 weeks after surgery intraocular pressures of matched group obviously raise, and apparently higher than experimental group, in Table 2.
The performance appraisal result of avascular filtering bleb after table 1 operation
Between PDLLA/5-Fu group and PDLLA group and matched group group, relatively, there is significant difference (P < 0.05), and compare zero difference (P > 0.05) between PDLLA group and PDLLA/5-Fu group
The change of table 2 perioperatively intraocular pressure
A:P < 0.05, b:P < 0.01, vs. matched group; C:P < 0.05, d:P < 0.01, vs is preoperative.
Each group White Rabbit limbus of corneae pathology change to be observed:
Matched group: comparatively common with lymphocyte, fibrocyte, apocyte, filter road healing inaccessible, between conjunctiva and sclera, heal, and (Fig. 1 is a) to occur more inflammatory cell.
PDLLA/5-Fu group: visible fibroblast proliferation and collagen fiber form all few compared with the first two experimental group amount, 1～2/H of lymphocyte, two-layer scleral flap separately, filters gap, road visible, and subconjunctival tissue is loose, and (Fig. 1 is b).
PDLLA group: have as seen a few fibres hyperplasia, a small amount of collagen fiber form, a little lymphocyte, two-layer scleral flap separately, filters gap, road visible, subconjunctival tissue loosen (Fig. 1 c, d).
The above; it is only the preferably specific embodiment of the present invention; protection scope of the present invention is not limited to this; any be familiar with those skilled in the art the present invention disclose technical scope in, the simple change of the technical scheme that can obtain apparently or equivalence replace all fall within the scope of protection of the present invention.
Claims (3)
1. a composite slow release agent, is characterized in that, its composition comprises polylactic acid and 5-fluorouracil, and the diaphragm immersion 1mg5-fluorouracil that described composite slow release agent is made 30 × 440mm by polylactic acid obtains.
2. a preparation method for composite slow release agent, is characterized in that, comprises the following steps:
(1) adopt ring-opening polymerisation method by DL synthesis of lactide from lactic acid, by lactide ring-opening polymerisation, form polylactic acid again, under the effect of catalyst, catalyst is zinc oxide, by the mass fraction of 1500ml, it is the three-neck flask that 85% DL lactic acid and appropriate zinc oxide are placed in 3000ml, slowly heated and stirred, when temperature reaches 98 degrees Celsius, start to reduce pressure with water pump, continue heating, after to be drained off completing, the receiving bottle of distilled water is taken off, connect receiving bottle, reduce pressure with oil pump, heat up rapidly, maintain more than 140 degrees Celsius, steam the crude product 600g of flaxen lactide, wherein dehydration temperaturre is 140 degrees Celsius, dewatering time is 2 hours, depolymerization temperature is 230 degrees Celsius, time is 2 hours,
(2) room temperature is under 22 ℃, 40% humidity, to being housed, the ampulla of lactide is evacuated 5 hours with oil pump, ratio wiring solution-forming by stannous octoate and chloroform in 2: 1, pours in the ampulla of vacuum, and lactide is mixed homogeneously with solution, continue evacuation approximately 3 hours, solvent chloroform is volatilized totally, and alcohol blast burner tube sealing in evacuation, puts into silicone oil by the ampulla after tube sealing, 140 degrees Celsius of silicone oil temperature, polymerization 48 hours;
(3) take domestic DL lactic acid as raw material, prepare PDLLA molecular weight 2.0 × 10
5, preparation condition is under 22 ℃, 40% humidity, and take ethyl acetate as solvent, adding respectively 95% molecular weight is 2.0 × 10
5pDLLA, 5%5-Fu1mg adopts solvent evaporation method to prepare PDLLA/5-FU composite membrane, the thin film that size is 3 × 4mm, after subpackage, oxirane disinfection is standby.
3. composite slow release agent claimed in claim 1 application in the postoperative cicatrix medicine of glaucoma process in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310711544.4A CN103751788A (en) | 2013-12-17 | 2013-12-17 | Composite sustained-release preparation, as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310711544.4A CN103751788A (en) | 2013-12-17 | 2013-12-17 | Composite sustained-release preparation, as well as preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103751788A true CN103751788A (en) | 2014-04-30 |
Family
ID=50519211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310711544.4A Pending CN103751788A (en) | 2013-12-17 | 2013-12-17 | Composite sustained-release preparation, as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103751788A (en) |
-
2013
- 2013-12-17 CN CN201310711544.4A patent/CN103751788A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| LI-JUN CUI ET AL.: ""Subconjunctival sustained release 5-fluorouracil for glaucoma filtration surgery"", 《ACTA PHARMACOLOGICA SINICA》 * |
| LI-JUN CUI ET AL.: ""Subconjunctival sustained release 5-fluorouracil for glaucoma filtration surgery"", 《ACTA PHARMACOLOGICA SINICA》, vol. 29, no. 9, 30 September 2008 (2008-09-30), pages 1021 - 1028 * |
| 宋杰: ""生物可降解聚乳酸（PDLLA）的合成及性能表征"", 《中国优秀硕士学位论文全文数据库》 * |
| 黄福龙等: ""HA/PDLLA复合材料的制备及其降解性能研究"", 《无机材料学报》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lai et al. | Ocular biocompatibility of carbodiimide cross-linked hyaluronic acid hydrogels for cell sheet delivery carriers | |
| CN101357242B (en) | Structure for modulating intraocular pressure | |
| CN101522133B (en) | Implantable optical system, method for developing it and applications | |
| Rosentreter et al. | Capsule excision and Ologen™ implantation for revision after glaucoma drainage device surgery | |
| US20230321145A1 (en) | Compositions and methods of treating dry eye syndrome and other traumatized non-keratinized epithelial surfaces | |
| Leszczynski et al. | In vivo biocompatibility assessment of (PTFE–PVDF–PP) terpolymer-based membrane with potential application for glaucoma treatment | |
| CN101269220B (en) | Rapamycin eye-in implantation type medicine release system with bletilla striata glue as carrier | |
| Yang et al. | Feasibility study of chitosan as intravitreous tamponade material | |
| Huang et al. | Anterior lens capsule: biomechanical properties and biomedical engineering perspectives | |
| Andreev et al. | A new collagen scaffold for the improvement of corneal biomechanical properties in a rabbit model | |
| Xeroudaki et al. | A double-crosslinked nanocellulose-reinforced dexamethasone-loaded collagen hydrogel for corneal application and sustained anti-inflammatory activity | |
| CN110314252A (en) | Collagen Implant is preparing the purposes in operation for glaucoma auxiliary reconstruction | |
| WO2020050779A1 (en) | Hydrogels with tunable electrostatic properties | |
| CN107115299B (en) | Rapamycin nano micelle eye drops and preparation method thereof | |
| CN103751788A (en) | Composite sustained-release preparation, as well as preparation method and application thereof | |
| Xu et al. | EFFICACY, SAFETY, AND BIODEGRADATION OF A DEGRADABLE SCLERAL BUCKLE OF CHITOSAN–GELATIN POLYMER IN RABBITS | |
| CN112263570A (en) | Infiltration type medicine composite amnion and preparation method and use method thereof | |
| Zhang et al. | Use of 5‐Fluorouracil‐Soaked Bioamniotic Membranes in Trabeculectomy for Primary Open‐Angle Glaucoma: A Retrospective Analysis | |
| Muir et al. | Air, methylcellulose, sodium hyaluronate and the corneal endothelium. Endothelial protective agents | |
| Bao et al. | Effect of an MG132-sustained drug delivery capsular ring on the inhibition of posterior capsule opacification in a rabbit model | |
| CN111001010A (en) | External eye operation flushing fluid and preparation method thereof | |
| CN1175900C (en) | Preparation for eyes | |
| Song et al. | Long-term study of corneal stroma and endothelium on structure and cells after genipin treatment of rabbit corneas | |
| Zheng et al. | Recent Advances in Ocular Therapy by Hydrogel Biomaterials | |
| US20230201031A1 (en) | Dissolvable medical device for promoting healing of wounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140430 |