CN101129363A - FK506 topical application sustained release film patch of immunosuppressive agent for accelerating regeneration of nerve, method of producing the same and use of the same - Google Patents
FK506 topical application sustained release film patch of immunosuppressive agent for accelerating regeneration of nerve, method of producing the same and use of the same Download PDFInfo
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- CN101129363A CN101129363A CNA2007100752821A CN200710075282A CN101129363A CN 101129363 A CN101129363 A CN 101129363A CN A2007100752821 A CNA2007100752821 A CN A2007100752821A CN 200710075282 A CN200710075282 A CN 200710075282A CN 101129363 A CN101129363 A CN 101129363A
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Abstract
The invention discloses a slow release diaphragm and making method and application to do local usage of immune inhibitor FK506 to accelerate the regeneration of nerve, which is characterized by the following: the slow release diaphragm can be copolymer (PLGA) of decomposably biological macromolecular material-polylactic acid (PLA)[2] and polyglycolic acid (PGA), which is composed of immune inhibitor FK506 and slow release carrier. The making method of the slow release diaphragm comprises the following steps: a. reacting polylactic acid (PLA) [2] and polyglycolic acid (PGA) to produce the copolymer PLGA; b. blending the copolymer PLGA and FK506; adding the mixture into deionized water to dilute; removing organic solvent; stirring under indoor temperature to evaporate the solvent; freezing; drying; obtaining nanometer microball; c. using the nanometer microball into drug diaphragm to make local exterior drug to restore the peripheral nerve damage.
Description
[technical field]
The present invention relates to medicinal slow release agent, particularly relate to a kind of FK 506 topical application sustained release film patch of immunosuppressive agent that promotes neuranagenesis and its production and use.
[background technology]
The peripheral nerve injury reparation is a global problem, and peripheral nerve injury is a kind of high morbidity in China, and particularly the hands surgery relates to peripheral nerve injury through regular meeting.Because the speed of neuranagenesis is slow behind the peripheral nerve injury, cause the target organ of long-time denervation dysfunction to occur, cause such patient to reach sensual misery mentally, and bring serious sequela to the patient, all bring a series of adverse influences also for simultaneously individual and society, increased the weight of burden on society.
In the clinical position that nerve injury is repaired, the incidence rate of simple neurotmesis accounts for more than 90% around, and wherein great majority need directly to coincide to repair.At present to different times, different parts disconnected overtax one's nerves through the mechanical prosthesis method research and use comparative maturity, promote that the methods such as pharmacology, histochemistry, biology of neuranagenesis are being tried to explore among.Use existing several years history of research that immunosuppressant FK506 suppresses the immunologic rejection of allogeneic neural transplantation, relevant report is not then seen in neural regeneration both at home and abroad but application FK506 promotes directly to coincide.
People found through experiments, FK
506Promoting to have following function aspect the peripheral nerve regeneration: 1. suppress cell and humoral immunization, thereby suppress the destruction of lymphocytic infiltration, the inducibility of neuranagenesis is given full play to neuromechanism and neurocyte.2. suppress immunity, wound and inflammatory hyperplasia, regulate the local immunity microenvironment, for nerve fiber provides wide regeneration space.3. directly promote neuranagenesis by the activity that strengthens regenerating nerve fiber growth vertebra.4. owing to improved the partial embedded pressure of neural reparation and reduced immune complex the damage of blood vessel is promoted blood capillary regeneration further to promote the recovery of function of nervous system indirectly.5. there is the function of the cytokine of facilitation not have obvious influence to cytophagous phagocytic function in the local microenvironment and secretion to neuranagenesis in theory
[6]6. promote the propagation of Schwann cell and the formation of BunnerShi band.
In spare-part surgery, the using method of traditional FK506 is oral or injection, effective dose scope oral or injection FK506 is 0.05-0.30mg/kg/d, promptly be the adult of 60kg for average weight, its consumption can reach 3.0-18mg/d, the 1.5-2 that then requires to reach adult's dosage for the child doubly often needs lifelong medication.Only show as reactions such as mild hypertension, constipation, skin erythema during excessive application (consumption reaches 2-3 times of high limit).Therefore, how FK506 is used for the objective demand that the peripheral nerve injury reparation just becomes medical domain.
[summary of the invention]
The present invention is intended to address the above problem, and provide a kind of FK 506 topical application sustained release film patch of immunosuppressive agent that promotes neuranagenesis, make it can regulate neuranagenesis chamber local immunity microenvironment, suppressing cell hyperplasia (immunity and inflammatory hyperplasia) and collagen forms, improve neural anastomosis mouth local microenvironment and suppress the endo cell edema, thereby suppress neuromatous formation, the formation of neural outer adhesion and improve neural embedded pressure, aixs cylinder is regenerated smoothly, realize the axoplasm transportation smoothly, in time provide neural and self repair material, make local current reach threshold value and smooth, finally realize the recovery of nerve conduction function by anastomotic stoma.
The present invention also aims to provide the diaphragm-operated preparation method of described slow release to reach the topical application that nerve injury is around repaired.
For achieving the above object, the invention provides a kind of FK 506 topical application sustained release film patch of immunosuppressive agent that promotes neuranagenesis, this slow release diaphragm comprises inhibitor FK506, it is characterized in that, this slow release diaphragm is with in the immunosuppressant FK506 implantation slow release carrier and the flexible medicine film that forms.
Slow-released carrier is the degradable biological macromolecular material, the preferred polylactic acid of slow-released carrier (PLA)
[2]And the copolymer (PLGA) of polyglycolic acid (PGA), this copolymer is that molecular weight is methoxy poly (ethylene glycol)-polylactic acid di-block copolymer of 25000.
The particle diameter that the slow release diaphragm is made by immunosuppressant FK506 and slow-released carrier is that the nano microsphere of 544～545nm is formed, and immunosuppressant FK506 and slow-released carrier mixed in 1: 4 by weight percentage.
The present invention also provides described slow release diaphragm-operated preparation method, and this method comprises the steps:
A, with polylactic acid PLA
[2]Reaction generates copolymer p LGA with polyglycolic acid PGA;
B, the copolymer p LGA of 40mg is dissolved in 18ml 100% pure acetone, mix under ultrasonication with 10mg FK506 medicinal liquid, then above-mentioned mixed solution is slowly joined in the 50mL deionized water, ultrasonic emulsification 20～40 seconds, be diluted to 100mL with deionized water, rotary evaporation is removed organic solvent, at room temperature stirs volatilization solvent wherein, gets Nano microsphere after lyophilization;
C, the Nano microsphere that step (b) is obtained are made length: wide: the medicine film of the thick 1cm of being respectively * 1cm * 0.2cm includes 10～30mg FK506.
The present invention also provides this slow release diaphragm-operated purposes, the local topical medicine that this slow release diaphragm is repaired as peripheral nerve injury.
Contribution of the present invention is, by will increasing the medicament adjusting of specific part in the inhibitor FK506 implantation slow release carrier, make medicine more approach target cell, the drug level fluctuation is little, avoid systemic administration through the first pass effect of liver metabolism and can reduce medicine to systemic toxic side effect and can reach that perseverance is released, long lasting purpose, had not replaceable effect of other preparations.Slow-released carrier PLGA is biodegradable polymer, and its final catabolite is a lactic acid, has the favorable tissue compatibility.Use FK506 in the neural around repair process and can quicken a watt pathological process of reining in degeneration; promote the propagation and the secretory nerve trophic factors of Schwann cell; neuroprotective unit and the rudiment of promotion aixs cylinder; increase quality and quantity and the effective hypertrophy and autoimmune response that suppresses matter between nerve of axon regeneration; reduce the resistance of neuranagenesis, thereby reach ideal neuranagenesis quality and speed.
Slow release diaphragm of the present invention can be applicable to the clinical initiative that still belongs to that peripheral nerve injury is repaired at home and abroad.The present invention can be widely used in the intervention chemotherapy of bacillary osteomyelitis, malignant tumor etc., and technology is used reliable.As long as local application dose is controlled in strictness, can guarantee the safety and the reliability of clinical practice, and service time short (about 20 days).
[description of drawings]
Fig. 1 is for passing through field emission scanning electron microscope (F-SEM, JSM-6330F, Japan) the diaphragm-operated Nano microsphere shape appearance figure of the slow release of Guan Chaing.
[specific embodiment]
The FK 506 topical application sustained release film patch of immunosuppressive agent of promotion neuranagenesis of the present invention is with in the immunosuppressant FK506 implantation slow release carrier and the flexible medicine film that forms, be used in the spare-part surgery operation in the local use of the specific part of health, so that peripheral nerve injury obtains repairing and regeneration.FK506 wherein is a kind of known immunosuppressant, is generally used for oral or injection.Described slow-released carrier adopts the degradable biological macromolecular material, preferred polylactic acid (PLA) in this example
[2]And the copolymer (PLGA) of polyglycolic acid (PGA), this copolymer is methoxy poly (ethylene glycol)-polylactic acid di-block copolymer, its molecular weight is 25000.
This slow release diaphragm is a kind of compositions of nano level microsphere, is mixed by 1: 4 (percentage by weight) by immunosuppressant FK506 and above-mentioned slow-released carrier, and the particle diameter of microsphere is 544～545nm, and its microscopic pattern as shown in Figure 1.
Slow release diaphragm of the present invention prepares as follows:
A, with polylactic acid PLA
[2]Reaction generates methoxy poly (ethylene glycol)-polylactic acid di-block copolymer PLGA with polyglycolic acid PGA;
B, 40mg copolymer p LGA is dissolved in 18mL 100% pure acetone, mix under ultrasonication with 10mg FK506 medicinal liquid, then above-mentioned mixed solution is slowly joined in the 50mL deionized water, ultrasonic emulsification 30 seconds, be diluted to 100mL with deionized water, rotary evaporation is removed organic solvent, at room temperature continues to stir volatilization solvent wherein 4 hours, gets Nano microsphere after lyophilization;
C, the FK506 Nano microsphere that step (b) is obtained are made length: wide: the medicine film of the thick 1cm of being respectively * 1cm * 0.2cm, include 20mg FK506, and the medicine of making is softer membranously, but embowment.
Whole process of preparation adopts the sterile working.
Vitro drug release test: prepared diaphragm is placed normal saline, keep 37 ℃, vibration, sampling regularly, adopt chromatography to detect the concentration of solution Chinese medicine, come the degradation speed of control material by the ratio of PLA and PGA among the PLGA of regulating, reach the drug releasing rate of 1mg/day, and kept 20 days.
The local topical medicine that slow release diaphragm of the present invention is repaired as peripheral nerve injury.
The diaphragm-operated using method of this slow release is as follows: to the disconnected nerve of hindering of emergency treatment appear as routine and mirror under accurate para-position, adopts outer embrane method with the identical nerve of 9-0 noinvasive suture ends-end.Thoroughly the hemostasis back with sterile gauze wipe away do neural around wound surface, the release membranes sheet is surrounded on around the neural anastomosis mouth.Conventional nerve of repairing other damaged tissue and will repairing with soft tissues such as fascias and membrane covered are also separated skin suture afterwards with the tissue of other reparation.Conventional 4 weeks of plaster slab external fixation of postoperative also register respectively and follow up a case by regular visits to.
In clinical practice, choose (in 4 months) rasceta of same time period 5cm incision to the elbow and cause median nerve or the disconnected case of hindering of ulnar nerve emergency treatment totally 16 examples and be divided into experimental group and matched group, every group 8 example in conjunction with patient's wish and average packet principle.Wherein male 13 examples, women 3 examples.Experimental group is for using slow release diaphragm group of the present invention, and matched group is not for containing the PLGA macromolecular material slow release diaphragm group of FK506, wherein every group of median nerve and disconnected each 4 example of hindering of ulnar nerve.Two groups of case postoperatives are following up a case by regular visits to through 1 week-2 year all.1-4 week short-term is observed no abnormal reaction, and wound healing is good; 1-3 month follow-up observation healing process of tendons is good, and the B ultrasonic monitoring is shown and all carried out function exercise as scheduled by identical vascular patency.3-12 month follow-up observation, experimental group and the matched group recovery of all feeling, experimental group sensory recovery speed average out to 3.1mm/d, obvious 1.7mm/d faster than matched group, and experimental group hyperesthesia degree is lighter, on average continues 2-4 week, and on average lasting 4-8 week of matched group and degree are heavier; 10 weeks of postoperative begin to follow up a case by regular visits to electromyogram, and 14 weeks of experimental group can be drawn newborn current potential, on average shift to an earlier date for 4 weeks than matched group.Organize local observation of tenolysis operation of 3 examples, matched group 5 examples in the time of 3-6 month by experiment, see that the experimental group neuroma is not obvious, the anastomotic stoma local nerve is soft and do not have obvious adhesion with surrounding tissue; The healing of experimental group tendon and other soft tissue is excellent than matched group, and cicatrization is lighter.12-24 month follow-up observation in late period, seeing has 7 examples to recover good in experimental group 8 examples, and sensory recovery is complete, and lopsided complete obiteration is wherein received the abduction function in disconnected thumb opposing function of hindering of median nerve and the disconnected little finger of toe of hindering of ulnar nerve and is all recovered good; 4 examples do not reach above-mentioned recovery effects yet and matched group recovers preferably.
Claims (8)
1. a FK 506 topical application sustained release film patch of immunosuppressive agent that promotes neuranagenesis comprises inhibitor FK506, it is characterized in that, this slow release diaphragm is with in the immunosuppressant FK506 implantation slow release carrier and the flexible medicine film that forms.
2. the FK 506 topical application sustained release film patch of immunosuppressive agent of promotion neuranagenesis as claimed in claim 1 is characterized in that, described slow-released carrier is the degradable biological macromolecular material.
3. the immunosuppressant FK506 slow release diaphragm of promotion neuranagenesis as claimed in claim 2 is characterized in that, described slow-released carrier is polylactic acid (PLA)
[2]And the copolymer (PLGA) of polyglycolic acid (PGA).
4. the FK 506 topical application sustained release film patch of immunosuppressive agent of promotion neuranagenesis as claimed in claim 3 is characterized in that, described copolymer (PLGA) is that molecular weight is methoxy poly (ethylene glycol)-polylactic acid di-block copolymer of 25000.
5. the FK 506 topical application sustained release film patch of immunosuppressive agent of promotion neuranagenesis as claimed in claim 1 is characterized in that, the particle diameter that this slow release diaphragm is made by immunosuppressant FK506 and slow-released carrier is that the nano microsphere of 544～545nm is formed.
6. the FK 506 topical application sustained release film patch of immunosuppressive agent of promotion neuranagenesis as claimed in claim 5 is characterized in that, described immunosuppressant FK506 and slow-released carrier mixed in 1: 4 by weight percentage.
7. the diaphragm-operated preparation method of slow release according to claim 1 is characterized in that this method comprises the steps:
A, with polylactic acid (PLA)
[2]And polyglycolic acid (PGA) reaction generates copolymer (PLGA);
B, the copolymer p LGA of 40mg is dissolved in 18ml 100% pure acetone, mix under ultrasonication with 10mg FK506 medicinal liquid, then above-mentioned mixed solution is slowly joined in the 50mL deionized water, ultrasonic emulsification 20～40 seconds, be diluted to 100mL with deionized water, rotary evaporation is removed organic solvent, at room temperature stirs volatilization solvent wherein, gets Nano microsphere after lyophilization;
C, the Nano microsphere that step (b) is obtained are made length: wide: the medicine film of the thick 1cm of being respectively * 1cm * 0.2cm includes the medicine film of 10～30mg FK506.
8. the described slow release diaphragm of claim 1 is as the local topical medicine of peripheral nerve injury reparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100752821A CN101129363B (en) | 2007-07-24 | 2007-07-24 | FK506 topical application sustained release film patch of immunosuppressive agent for accelerating regeneration of nerve, method of producing the same and use of the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100752821A CN101129363B (en) | 2007-07-24 | 2007-07-24 | FK506 topical application sustained release film patch of immunosuppressive agent for accelerating regeneration of nerve, method of producing the same and use of the same |
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| Publication Number | Publication Date |
|---|---|
| CN101129363A true CN101129363A (en) | 2008-02-27 |
| CN101129363B CN101129363B (en) | 2012-12-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2007100752821A Expired - Fee Related CN101129363B (en) | 2007-07-24 | 2007-07-24 | FK506 topical application sustained release film patch of immunosuppressive agent for accelerating regeneration of nerve, method of producing the same and use of the same |
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| CN1579396A (en) * | 2004-05-19 | 2005-02-16 | 山东省眼科研究所 | Slow-releasing medicine inplanted in eye and use thereof |
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