CN1158084C - Long-ncting heparin intraocular slow-released system - Google Patents
Long-ncting heparin intraocular slow-released system Download PDFInfo
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- CN1158084C CN1158084C CNB021024782A CN02102478A CN1158084C CN 1158084 C CN1158084 C CN 1158084C CN B021024782 A CNB021024782 A CN B021024782A CN 02102478 A CN02102478 A CN 02102478A CN 1158084 C CN1158084 C CN 1158084C
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Abstract
The present invention provides a long-acting heparin intraocular slow-released system which comprises heparin and a medicinal carrier, wherein the weight ratio of the heparin to the medicinal carrier is from 0.1:0.9 to 0.9:0.1. The medicinal carrier is a synthetic biodegradation type high molecular material and a natural biodegradation high molecular material or a blend of a synthetic biodegradation type high molecular material and a natural biodegradation high molecular material. The medicine release period of the long-acting heparin intraocular slow-released system of the present invention is from one week to one year. The present invention can be used to inhibit the generation of antithrombin, and the proliferation and the chemiotaxis of mechanocytes, prevents fibrinogen from being converted to insoluble fibrin, reduces postoperative cellulose exudation and prevents rear capsule opacification. Consequently, the occurrence of after-cataracts is inhibited.
Description
Technical field
The present invention relates to a kind of body and be implanted into pharmaceutical preparation, specially refer to a kind of with the long-ncting heparin intraocular slow-released system of Biodegradable macromolecular material as pharmaceutical carrier.
Background technology
Along with the development of micro-operative technique, the modern day cataract capsule extracts the clinical practice of operation and ultrasonic emulsification extraction associating artificial intraocular lenses implant surgery outward, make large quantities of because of the blind patient of cataract again heavily to have seen light.Yet the after cataract in postoperative late period (be called for short the back and send out barrier) still seriously affects patient's vision, becomes main post-operative complication.The incidence rate that barrier is sent out in the back because of patient age, sickly plant differently and different with modus operandi, the incidence rate of the postoperative 2-5 that generally is grown up is 50%, child's incidence rate can be up to 100%.Therefore, the important subject that becomes current ophthalmic industry of barrier is sent out in the control back.
For back the barrier that the cataract extraction postoperative forms because of epithelial hyperplasia, most common therapeutic method be perform the operation again or Nd:YAG laser after cystitomy.Though this modus operandi is generally believed to have lower risk, artificial intraocular lenses's damage, off normal might take place, intraocular pressure raises, cystoid macular edema, and severe complications such as detachment of retina; The shortcoming that this method also exists laser apparatus to cost an arm and a leg, be difficult for to promote in addition, postoperative still might recur and infant can not partner treatment.In improvement artificial intraocular lenses's shape with when improving surgical technic, people also are devoted to adopt immunosuppressant to suppress the research of proliferation of lens epithelial cells in recent years.The immunosuppressant that is adopted has antimetabolites such as daunorubicin, colchicine, 5-fluorouracil, but since they to the effect of lens epithelial cell do not have specificity, within the eye toxic and side effects incidence rate big, that cause corneal endothelium damage and retinal necrosis is high and be restricted on using.
Heparin is a kind ofly to be with anionic acidity to gather the mucopolysaccharide natural polymer, is that one group of molecular weight is that 3000-30000 dalton, mean molecule quantity are 15000 daltonian poly-mucopolysaccharide mixture.Heparin is soluble in water, has strong elecrtonegativity in aqueous solution, can be combined into polyelectrolyte with some cationes.Heparin is traditional anticoagulation medicine, can be converted into insoluble fibrin with reversible generation, the prevention Fibrinogen that combines to suppress antithrombase of Antithrombin III (AT-III), therefore has the dual function of anticoagulation and blood fat reducing in vivo.Heparin can combine, suppress fibroblasts proliferation with multiple somatomedin within the eye and chemotactic, the postoperative fiber disposition of minimizing are oozed out, thereby prevents that back capsule muddiness from suppressing the back and sending out the generation that hinders.Heparin is sent out the application facet that hinders and mainly contained following three kinds of route of administration after inhibition at present: (1) handles artificial plane of crystal (HSM-IOL) with heparin; (2) with containing the anterior chamber irrigating solution of the solution of heparin as pioneering operation; (3) as the heparin eye drop.These three kinds of route of administration all can suppress the generation of back capsule muddiness to a certain extent, but all exist because heparin is soluble in water, retention time is short within the eye for medicine, and the drug level instability makes can't bring into play optimum medicine efficacy, and bioavailability is poor; And the shortcoming that may cause side effect generations such as intraocular hemorrhage.
It is a kind of novel medicament preparation that body is implanted into drug sustained release system, has the influence that is not subjected to body fluid flushing, dilution, and dosage is few, and can slowly discharge the characteristics of medicine for a long time in vivo; Particularly, can reach good medication effect to the position of drug absorption difficulty.The appearance of drug sustained release system just is being subjected to global attracting attention.Yet because the problem of pharmaceutical carrier never solves, therefore up to now, the heparin body with long-term release function is implanted into preparation and can't comes out.
Body is implanted into drug sustained release system and mainly is grouped into by medicine and two kinds of one-tenth of pharmaceutical carrier; pharmaceutical carrier plays protection and control rate to the release of medicine, thereby reaches effect (Jani P., the J.Pharm.Pharmacol. that can discharge for a long time in vivo; 1990,41:821).Pharmaceutical carrier must have certain permeability to medicine, do not interact with medicine, in addition, because pharmaceutical preparation is to implant for a long time to carry out drug release, therefore pharmaceutical preparation must have the good biocompatibility of body, body is not produced effects such as inflammation, stimulation, sensitization.The drug carrier material that can satisfy these conditions can be divided into biologically inert macromolecule and Biodegradable macromolecular material two classes again.Silicone rubber, polyurethane etc. all are the biologically inert macromolecular materials of being used widely at medical domain, has excellent biological compatibility, be applied to preparing cardiac valve interventional therapy intubate etc., also be used to simultaneously the pharmaceutical carrier of slow releasing pharmaceutical such as long acting contraceptive.Yet with this class bio-inert material during as pharmaceutical carrier, though can keep the long-term slow release effect of medicine, and can not produce the problem of biocompatibility such as inflammation, stimulation and sensitization to body, but owing to increase along with time, the continuous minimizing of content of dispersion in the medicament, drug releasing rate and burst size also can constantly descend, so the release dosage of medicine can't guarantee constant drug dose in time in continuous minimizing; Because the biologically inert of these materials can not change in vivo, therefore after drug release is intact, also must in body, take out again, in addition in order to avoid stay in the body and to exert an adverse impact as foreign body.
Another kind of is Biodegradable polymer drug carrier.Biodegradable polymer drug carrier is in drug release, because the effect of intravital physiological environment (body temperature, body fluid, enzyme etc.), carrier material is also constantly degraded, molecular weight diminishes, it is loose that structure becomes, so that finally be degraded to micromolecule or monomer, absorbed or metabolism by body, therefore be pharmaceutical carrier with such material, the taking-up of after drug release is intact, can performing the operation again.In addition, because material is along with degraded, structure becomes loose and makes that medicine is easier therefrom to be discharged, thereby the trend that release amount of medicine is increased is arranged.When because the minimizing of the caused drug release dosage of minimizing of content of dispersion when consistent with the amount of the release amount of medicine increase that causes by degraded, just can realize the constant release of medicine, this be when being pharmaceutical carrier with the biologically inert macromolecule the drug release behavior (Wang Shenguo that can not realize, chemistry circular 1997,2:45).
Summary of the invention
The purpose of this invention is to provide one and long-ncting heparin intraocular slow-released system, this heparin slow releasing preparation is implanted under the conjunctiva or back room the same period in crystalline lens extraction operation process, therefore not only can avoid heparin easily to meet water-soluble go out and the short defective of retention time within the eye, and have once implant permanently effective, and the advantage that drug level is stable, bioavailability is high.
For achieving the above object, the present invention adopts the sustained release carrier of water-insoluble Biodegradable macromolecule as water-soluble heparin, and heparin is carried out embedding and the heparin slow-released system (HEP DDS, Heparin Drug Delivery System) made.
Heparin slow-released system of the present invention comprises medicine and pharmaceutical carrier, and the two is 0.1 by weight: 0.9-0.9: 0.1.Described pharmaceutical carrier be have excellent biological compatibility, have certain intensity, the synthesising biological degradation-type macromolecular material of consistency and elasticity, natural biological degradation-type macromolecular material or synthesising biological degradation-type macromolecular material be pharmaceutical carrier with the blend of natural biodegradated polymer materal.Drug sustained release system can keep certain intensity, elasticity and shape before drug release is intact, thereby and can be absorbed or excrete by natural degradation under the physiological condition in vivo by metabolism, therefore neither can become foreign body body is produced stimulation, can not make body produce foreign body reaction yet, therefore not need to go again second operation that it is taken out.Above-mentioned synthesising biological degradation-type macromolecular material can be the aliphatic polyester family macromolecule, they can be poly (l-lactic acid) (PLLA), poly-DL-lactic acid (PDLLA), copolymerization (L-lactic acid/DL-lactic acid) (PLLA-co-PDLLA), polyglycolic acid (PGA), copolymerization (lactic acid/glycolic) (PLGA), polycaprolactone (PCL), (glycolic/lactic acid/caprolactone) terpolymer (PGLC), polycaprolactone/polyether block copolymer (PCE), polycaprolactone/polyethers/polylactic acid terpolymer (PCEL), and other polyhydroxy acid (PHA).Above-mentioned natural biological degradation-type macromolecular material can be chitosan, gelatin, or their blend.
Described pharmaceutical carrier can be membranaceous, lamellar, granular, block, strip.It also can be the spongy body by above-mentioned synthetic or natural biological degradation-type macromolecular material by the high molecular adhesive-bonded fabric of above-mentioned natural or synthetic Biodegradable.The size of above-mentioned pharmaceutical carrier pore structure and density are controlled by the method for the method of controlling solution evaporation speed or control pore dosage or by the method for control Density.
Described heparin slow-released system can be an atresia, or has the pore structure that is interconnected, and its pore size is 10 nanometers-500 micron.
Heparin slow-released system of the present invention is the long-ncting heparin slow-released system, and the release cycle is week to one year; It is few to have dosage, and can slowly discharge the characteristics of medicine for a long time within the eye; For the position of drug absorption difficulty, can reach good medication effect.Can be used for the generation that ophthalmology suppresses antithrombase, stop Fibrinogen to be converted into insoluble fibrin, the effect of anticoagulation and blood fat reducing.Combine, suppress fibroblasts proliferation and chemotactic with multiple somatomedin within the eye, reduce postoperative fibroid and ooze out, thereby prevent that back capsule muddiness from suppressing the generation that barrier is sent out in the back.
The specific embodiment
Embodiment 1,
Copolymerization (lactic acid/glycolic) is (molecular weight 110,000) 5 parts (PLGA), and with adding 15 parts in heparin powder after 20 parts of dissolvings of dichloromethane, the politef mould is injected in the back that stirs, and the control air velocity makes the dichloromethane volatilization.After treating bone dry, this copolymerization (lactic acid/glycolic) drug sustained release system that contains heparin is taken off from the politef mould, in the room temperature vacuum drying oven, keep 48 hours to eliminate solvent fully, to obtain thickness be 2 millimeters, be the lamellar medicament of 10 nanometer small structures, and the reuse aperture is that to be washed into thick be that 2 millimeters, diameter are 2 millimeters heparin slow-released system preparation to 2 millimeters punch die.With this heparin slow-released system preparation with 24 hours sterilizations of epoxyethane fumigation, place the back room of 1 week implanting lagophthalmos when phacectomy is implemented to lagophthalmos in the back again.
The perusal of postoperative and local histopathological examination result show: the reaction of back room NIP; Vitreous chamber and retina do not see that pathologic changes; Cornea, posterior lens capsule film transparency and reaction of iris are normal: find no corneal edema, iris new vessels, atrophy or downright bad phenomenon, do not see the generation of the downright bad phenomenon of tissue degeneratiaon, and the posterior lens capsule film keeps transparent; Intraocular pressure is also normal, the perioperatively no change.In addition, there are not obvious inflammatory cell infiltration, inorganization degeneration and downright bad performance from iris, the cornea at the indicated position, heparin slow-releasing system place of local organization pathological examination result, and the angle, room at position, heparin slow-released system place do not have obvious difference with normal room corner structure, proves that the ophthalmic biocompatibility of heparin slow-released system is good.
In addition, in 8 weeks after the heparin slow-released system is implanted, kept certain density heparin in the aqueous humor, this heparin delivery system can take out in the 8 weeks back complete obiteration of implanting again always.
Embodiment 2,
With heparin copolymerization (lactic acid/glycolic) drug sustained release system of embodiment 1, but implant under the conjunctiva of lagophthalmos, any bad biological respinse is not seen in 8 all postheparin slow-released systems complete obiterations as a result.。
Embodiment 3,
Press method and the step of embodiment 1, but adopt 7 parts of 7 parts of poly-DL-lactic acid (PDLLA) (molecular weight 60,000), 20 parts of dichloromethane and heparin, make diameter and be 2 millimeters medicine rod, obtaining diameter and be 2 millimeters, pore structure is the medicine rod of 10 nanometers, keeps 48 hours to be cut into the heparin slow-released system of 2 millimeters long after eliminating solvent fully again in the room temperature vacuum drying oven.With 24 hours sterilizations of epoxyethane fumigation, place the 1 week back anterior chamber that implants lagophthalmos with embodiment 1 method again.The perusal of postoperative and local histopathological examination result show, the heparin slow-released system has good ophthalmic biocompatibility, heparin can be kept finite concentration in after the implantation 10 week in aqueous humor, and 14 all postheparin slow-released systems complete obiterations can be taken out again.
Embodiment 4,
Press method and the step of embodiment 1, but adopting (by Chinese invention patent application number 99105984.0 methods preparations) 10 parts of (glycolic/lactic acid/caprolactone) terpolymers (PGLC) (molecular weight 80,000), 18 parts of dichloromethane and 9 parts of heparin, making each length of side is 10 millimeters block, and maintenance 48 hours is to be cut into 2 millimeters square heparin slow-released systems again after eliminating solvent fully in the room temperature vacuum drying oven.With this heparin slow-released system with 24 hours sterilizations of epoxyethane fumigation, again place 1 week the back implant the back room of lagophthalmos with embodiment 1 method.
The perusal of postoperative and local histopathological examination result show, the heparin slow-released system has good ophthalmic biocompatibility, heparin can be kept finite concentration in after the implantation 10 week in aqueous humor, and 10 all postheparin slow-released systems complete obiterations can be taken out again.
Embodiment 5,
With embodiment 1 same procedure and step, but adopt (press Chinese invention patent ZL92113100.3 method preparation) polycaprolactone/polyether block copolymer (PCE) (molecular weight 80,000) to prepare, obtaining the pore structure size is the heparin slow-released system of 10 nanometers, with 24 hours sterilizations of epoxyethane fumigation, again place 1 week the back implant under the conjunctiva of lagophthalmos.
The perusal of postoperative and local histopathological examination result show that the heparin slow-released system has good ophthalmic biocompatibility, heparin can be kept finite concentration in 1 year after the implantation in aqueous humor, the complete obiteration of 1 year postheparin slow-released system can be taken out again.
Embodiment 6,
With embodiment 1 same procedure and step, but adopt (press Chinese invention patent application number 98102212X method preparation) polycaprolactone/polyethers/polylactic acid terpolymer (PCEL) (molecular weight 90,000) to prepare, obtaining the pore structure size is the heparin slow-released system of 50 nanometers, with 24 hours sterilizations of epoxyethane fumigation, again place 1 week the back implant the back room of lagophthalmos.
The perusal of postoperative and local histopathological examination result show that the heparin slow-released system has good ophthalmic biocompatibility, heparin can be kept finite concentration in after the implantation 30 week in aqueous humor, 40 all postheparin slow-releasing systems complete obiterations can be taken out again.
Embodiment 7,
With embodiment 2 same procedure and step, press method and the step of embodiment 4, but adopt the poly (l-lactic acid) (PLLA) (molecular weight 60,000) (95% weight) and the mixture of chitin (5% weight) to prepare, obtain the pore structure size and be 15 microns heparin slow-released system, with 24 hours sterilizations of epoxyethane fumigation, again place 1 week the back implant the back room of lagophthalmos.
The perusal of postoperative and local histopathological examination result show that the heparin slow-released system has good ophthalmic biocompatibility, heparin can be kept finite concentration in after the implantation 50 week in aqueous humor, the complete obiteration of 1 year postheparin slow-released system can be taken out again.
Embodiment 8,
Method and step with embodiment 6, but adopt the poly-DL-lactic acid (PDLLA) (molecular weight 60,000) (95% weight) and the mixture of collagen (5% weight) to prepare, obtain the pore structure size and be 10 microns heparin slow-released system, with 24 hours sterilizations of epoxyethane fumigation, again place 1 week the back implant the back room of lagophthalmos.
The perusal of postoperative and local histopathological examination result show that the heparin slow-released system has good ophthalmic biocompatibility, heparin can be kept finite concentration in after the implantation 20 week in aqueous humor, 20 all postheparin slow-released systems complete obiterations can be taken out again.
Reference examples 1:
With polyurethane be carrier, method for making, consumption and the step by example 3 prepares the heparin slow-released system fully.Postoperative perusal and local histopathological examination show that the heparin slow-released system has good ophthalmic biocompatibility, and it is finite concentration at aqueous humor that 15 after the implantation can be kept heparin in week, also detect in the aqueous humor during by six months less than there being heparin to exist.But 1 year preparation of postoperative still is present among the anterior chamber, and external form, size and intensity no change, the taking-up of therefore must performing the operation again.
Reference examples 2:
10 of lens extraction rats, postoperative 5% heparin eye drop eye drip, every day 3 times.50% a back barrier takes place after 3 months.
Claims (7)
1, a kind of long-ncting heparin intraocular slow-released system comprises heparin and pharmaceutical carrier, it is characterized in that, the weight ratio of heparin and pharmaceutical carrier is 0.1: 0.9-0.9: 0.1; Described pharmaceutical carrier is synthesising biological degradation-type macromolecular material, natural biological degradation-type macromolecular material or their blend.
According to the described long-ncting heparin intraocular slow-released system of claim 1, it is characterized in that 2, described synthesising biological degraded macromolecular material is the aliphatic polyester family macromolecule, described natural biological degraded macromolecular material is chitosan and/or gelatin.
According to the described long-ncting heparin intraocular slow-released system of claim 2, it is characterized in that 3, described aliphatic polyester family macromolecule is polyhydroxy acid (PHA).
4, according to the described long-ncting heparin intraocular slow-released system of claim 2, it is characterized in that described aliphatic polyester family macromolecule is poly (l-lactic acid), poly-DL-lactic acid, copolymerization (L-lactic acid/DL-lactic acid), polyglycolic acid, copolymerization (lactic acid/glycolic), polycaprolactone, (glycolic/bladder acid/caprolactone) terpolymer, polycaprolactone/polyether block copolymer and/or polycaprolactone/polyethers/polylactic acid terpolymer.
According to the described long-ncting heparin intraocular slow-released system of claim 1, it is characterized in that 5, described long-ncting heparin slow-released system has the pore structure that is interconnected, its aperture is 10 nanometers-500 micron.
According to the described long-ncting heparin intraocular slow-released system of claim 1, it is characterized in that 6, described pharmaceutical carrier is membranaceous, lamellar, granular, block or strip.
7, according to claim 1,2,3 or 4 described long-ncting heparin intraocular slow-released systems, it is characterized in that, described carrier is the high molecular adhesive-bonded fabric of above-mentioned natural or synthetic Biodegradable, or by above-mentioned synthetic or spongy body that natural biological degradation-type macromolecular material is made.
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| CNB021024782A CN1158084C (en) | 2002-01-22 | 2002-01-22 | Long-ncting heparin intraocular slow-released system |
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| CNB021024782A CN1158084C (en) | 2002-01-22 | 2002-01-22 | Long-ncting heparin intraocular slow-released system |
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| CN1433775A CN1433775A (en) | 2003-08-06 |
| CN1158084C true CN1158084C (en) | 2004-07-21 |
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| CN101259098B (en) * | 2008-04-25 | 2010-06-09 | 山东省眼科研究所 | Long-acting low molecule heparin intraocular sustained-release system |
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