CN106692031A - Implant capable of releasing doxorubicin continuously for long term, and preparation method thereof - Google Patents
Implant capable of releasing doxorubicin continuously for long term, and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an implant capable of releasing doxorubicin continuously for a long term, and a preparation method thereof. The implant is composed of doxorubicin hydrochloride, a glycolide-lactide copolymer, and polyethylene glycol. According to the preparation method, melting method is adopted to prepare the cylindrical implant with a diameter ranging from 0.3 to 1.6mm and a length ranging from 0.8 to 5mm; in in-vivo test, 5 to 21% of the coated drug is released in one day, 25 to 51% of the coated drug is released in 5 days, 35 to 63% of the coated drug is released in 10 days, and 80 to 100% of the coated drug is released in 30 days. The surface of the implant is smooth; the implant can be implanted in tumor, or tumor surrounding tissue, or administration places using a drug implanting needle via percutaneous puncture; the implant is suitable for treatment of solid tumor; the preparation process is simple; quality control is convenient to realize; cost is low; no pollution is caused; and the preparation method is convenient for industrialization.
Description
Technical field
The present invention relates to a kind of adriamycin sustained-release implant and preparation method thereof, composition, shape, size, intensity, Release Performance and the preparation method of adriamycin sustained-release implant are related in particular to, belong to technical field of pharmaceuticals.
Background technology
Adriamycin is a kind of broad-spectrum anti-cancer drug, with very strong Pycnorus cinnabarius, can be done directly on DNA, inserts DNA double coiled strand, unties the latter, changes the template property of DNA, suppresses archaeal dna polymerase so as to suppress DNA synthesis, also suppresses RNA synthesis.In addition, adriamycin has the function of forming super oxygen base free radical, and play the role of the membrane structure and function of special destruction cell, as a kind of cycle non-specific anticancer chemotherapeutic agent, there is effect to each phase cell, it is adaptable to acute leukemia, malignant lymphoma, breast cancer, lung bronchogenic carcinoma, oophoroma, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing sarcoma, the nephroblastoma, neuroblastoma, carcinoma of urinary bladder, thyroid cancer, prostate cancer, G. cephalantha, carcinoma of testis, stomach cancer, liver cancer etc..
Adriamycin is a kind of concentration, time dependence medicine, and the time of maintenance active drug concentration is more long, and curative effect is better；Peak drug levels are higher in blood, and general toxicity is bigger.
In early days, adriamycin is intravenous injection administration, and residence time is short in vivo for medicine, and curative effect is relatively low, and because blood peak concentration of drug is high, toxic and side effect is serious, such as serious cardiac toxic, bone marrow suppression, canker sore.
Be lifting curative effect, reduce the toxic and side effect of whole body, be administered with drip-feed mode, the intravenous infusion time be dozens of minutes by 96 hours, extension medicine run time in blood reduces blood peak concentration of drug, as a result shows：The intravenous infusion time is more long, and curative effect is better, and the toxicity of whole body is smaller.Because medicine is through hemoperfusion whole body, there is no targeting, normal cell is also killed while tumour cell is killed, still there is certain toxicity to whole body, and administration is difficult.
In the recent period, Evacet injection is developed, when using, is diluted with 5% Glucose Liquid, removed slowly in drip-feed 30~60 minutes, medicine body, long half time was up to 55 hours, and internal residence time is long, curative effect has been lifted, and convenient drug administration, but general toxicity is still present.
In order that adriamycin is concentrated for a long time to act on tumor area to obtain more preferable curative effect, medicine is greatly lowered or avoided simultaneously to the toxicity of whole body, people develop adriamycin sustained-release implant, when using, by delivery device or operation implantation tumour area, implant discharges adriamycin for a long time in tumor locus, make that tumor area concentration is high, long action time, curative effect is lifted, while blood concentration is extremely low, systemic adverse reactions are minimum.
The adriamycin implant researched and developed already has non-degradable type and the class of degradation-type two, non-degradable type is the adriamycin implant being made for auxiliary material with non-degradable material (such as hydroxyapatite, silicon rubber, polyacrylate, polyvinyl acetate), this kind of implant release regulation and control are easy, steady quality, but auxiliary material is non-degradable, some adverse reactions are produced after implantation human body, using being restricted, research and development are gradually decreased；Degradation-type is the adriamycin implant being made for auxiliary material with degradation material (such as PLA, glycolide-lactide copolymer, poly- second lactone, shitosan, gelatin), this kind of implant release is difficult to control to, preservation condition requirement is high, but it is nontoxic small-molecule substance that auxiliary material is degradable, toxic and side effect is not produced after implantation human body, using wide model, paid attention to by people, research and development increasingly increase, wherein most practical, the most popular one kind of adriamycin implant with glycolide-lactide copolymer (PLGA) as auxiliary material.
PLGA good biocompatibilities, are first degraded to endogenous material glycolic, lactic acid in vivo, and the latter participates in metabolism in vivo, is degraded to carbon dioxide and water, harmless.In addition, its intensity, hardness, degradation speed and the controling power to medicine can be adjusted by changing molecular structure, molecular weight, the molecular weight distribution etc. of PLGA, it is the good high-quality medicinal materials of security, it is well received after the launch such as the DUROS-leuprolide being made of PLGA, dexamethasone implant.
American scholar Brent D. Weinberg etc. with ADMh be effective medicine, PLGA (glycolides:Lactide=50:50) be slow-release material, sodium chloride be pore-foaming agent, adriamycin implant is made of pressure sintering, diameter 1.5mm, 8mm long, it is 65%, sodium chloride 21.5%, adriamycin 13.5% containing PLGA, in implantation rabbit liver knurl body (knurl strain is XV2, Tumor diameter about 8mm), implant periphery is at concentrations up to 1000 μ g/g, and to external diffusion, 4 days treatment group tumors areas are 0.17 ± 0.06 cm2, control group is 0.31 ± 0.08 cm2, p=
0.048；8 days treatment group tumors areas are 0.14 ± 0.04 cm2, control group is 1.8 ± 0.8 cm2, p=
0.025, implant tumor killing effect significantly { [1] Brent D. Weinberg, Hua Ai, Elvin Blanco, et al. Antitumor efficacy and local distribution of
doxorubicin via intratumoral delivery from polymer millirods[J].
Journal of Biomedical Materials Research Part A DOI 10.1002/jbm.a, Published
online 21 November 2006 in Wiley InterScience (www.interscience.wiley.com).
DOI:10.1002/jbm.a.30914 }.The implant sustained release about 4 days (internal 4 days releases 87.2 ± 1.5%, 8 day after 87.2 ± 2.3%, 4 days release do not have change), action time is short, offer limited effectiveness.
American scholar Ronnie Ortiz etc. have made systematic research to the composition of adriamycin PLGA implants and the relation of release, with ADMh as effective medicine, PLGA as slow-release material, acetone is as solvent, the sequence of implants of the mm of diameter 0.8,8 mm long is developed into solvent method, the molecular weight of PLGA used is respectively 7.9,9.4,33 and 54kDa, it is uncapped less than 10 kD, higher molecular weight it is ester terminated, the content of the implant ADMh being made is respectively 10%, 20% and 30%, and external 7 days release characteristics have 4 kinds：(1) quick release：During ADMh content 30%, release more than 80% in 1 day, release in 1~2 day is complete；(2) it is serious prominent release, release time is short, drug release is incomplete：During ADMh content 20%：Release more than 60% in 1 day, sustained release 2 days~7 days, releasing degree is about 75%；(3) rate of release is small, release time is short, releasing degree is low：During ADMh content 10%, release in 1 day is less than 4%, and release stops release after 1 day~2 days, and releasing degree is about 5%.(4) drug release amount is small, discharge discontinuous, secondary release：PLGA molecular weight is less than 10
The implant of KDa, ADMh content 10%, release in the 1st day is less than 4%, stops releasing 2 days~4 days, discharges again, { [the 2] (Ronnie of releasing degree 17%~40%
Ortiz, Jessie L-S. Au , Ze Lu ,et al.Biodegradable
Intraprostatic Doxorubicin Implants[J]. The AAPS Journal 2007; 9 (2)
Article 27 (http://www.aapsj.org) }.The rapid release that these implants have, have it is prominent release serious, some release is too slow, and some releasing degrees are low, the secondary release having, and without the property long lasting for release adriamycin, implantation tumour area can not for a long time be administered killing tumour cell, offer limited effectiveness.
To overcome the deficiencies in the prior art, the present invention provides a kind of implant of the adriamycin of release for a long time and preparation method thereof, solve the problems, such as existing adriamycin PLGA implants can not for a long time, it is uniform or than it is more uniform, discharge adriamycin completely or more completely, for clinic provides safe and high quality adriamycin implant, behind implant implantation knurl area, release adriamycin is until discharge complete, tumor locus concentration is high, long action time, evident in efficacy for a long time；Blood concentration is extremely low simultaneously, and general toxicity significantly declines；It is administered once, tens of days effectively, are particularly suited for the treatment of entity tumor.
The content of the invention
Technical scheme：A kind of implant (implant hereinafter referred to as of the present invention) for discharging adriamycin for a long time, it is characterized in that, the Solid Releasing Fresh-keeping Agent of the slow release adriamycin being made up of ADMh, PLGA, polyethylene glycol, the PLGA, its glycolide is 15 with the mol ratio of lactide:85~85:15, preferably 15:85、25:75、50:50 or 75:25, most preferably 25:75 or 50:50, viscosity is 0.22 dl/g~1.23 dl/g, most preferably preferably 0.29 dl/g~0.86 dl/g, 0.32 dl/g~0.56 dl/g；The molecular weight of the polyethylene glycol is 2300~8500, preferably 3000~6500, most preferably 3350,4000,4500,5000 or 6000；Each component content (percentage by weight) is as follows：
ADMh：9%~36%, preferably 12%~28%, most preferably 15%~24%；
Polyethylene glycol：4.5%~9.5%, preferable amount 5%~8%, most preferably 5.5%~7.5%；
PLGA：Surplus, i.e. 100%- ADMhs content-polyethyleneglycol content.
Implant of the present invention is shaped as cylinder, diameter 0.3mm~1.6mm, preferably 0.8mm~5mm long, diameter 0.6mm~1.2mm, 1.2mm~4mm long, most preferred diameters 0.7mm, 0.8mm or 0.9mm, 2 mm, 3mm or 4mm long；Compression strength 41MPa~65MPa, can be implanted into focal zone with medicine pin percutaneous puncture is planted.
The implant of the present invention drug release in 5%~21%, 5 days of drug release in 1 day drug release in 25%~51%, 10 days drug release 80%~100% in 35%~63%, 30 days in vivo.
The preparation method of implant of the present invention is melt molding method, is comprised the following steps：
(1) difference low-temperature grinding adriamycin, PLGA, polyethylene glycol, cross 120 mesh medicines sieve respectively, are made 3 kinds of fine powders；
(2) fine powder of (1) is uniformly mixed according to a ratio, is made mixed powder；
(3) it is vacuum dried by the mixed powder of (2) below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes mixed powder reclaimed water and volatile component content less than 0.1%, dry mixed powder is obtained；
(4) the dry mixed powder of (3) is melted 3~12 minutes at a temperature of 90 DEG C~140 DEG C, injection in-mold molding, cooling, the demoulding obtain final product the implant for discharging adriamycin for a long time.
Another preparation method of implant of the present invention is melt extrusion method, is comprised the following steps：
(1) difference low-temperature grinding adriamycin, PLGA, polyethylene glycol, cross 120 mesh medicines sieve respectively, are made 3 kinds of fine powders；
(2) fine powder of (1) is uniformly mixed according to a ratio, is made mixed powder；
(3) it is vacuum dried by the mixed powder of (2) below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes mixed powder reclaimed water and volatile component content less than 0.1%, dry mixed powder is obtained；
(4) the dry mixed powder extruding machine melting of (3) is extruded into cylinder material strip, after cooling, cylinder is cut into cutter, obtain final product the implant for discharging adriamycin for a long time.
The application method of implant of the present invention：According to the concrete condition of patient, method used below can be used：
(1) for being reluctant operation or inoperable tumor patient, intra-tumor or tumour periphery are implanted into medicine pin percutaneous puncture is planted, or implantation needs the position of administration, is allowed to kill tumour cell for a long time, suppresses tumour growth；
(2) for the tumour that can not be extractd in operation, intra-tumor or tumour periphery are implanted into by operation, or implantation needs the position of administration, is allowed to kill tumour cell for a long time, suppresses tumour growth；
(3) knurl bed is implanted into for the tumour of surgical removal, in art, the tumour cell of residual, prevention of tumor recurrence is killed.
Invention description：
The present invention is a kind of implant and preparation method thereof of the adriamycin of release for a long time, to make, to more fully understanding having invented, to be further elaborated：
1 implant composition of the present invention：It is made up of ADMh, PLGA and polyethylene glycol, each component effect is with requirement：
(1) ADMh：Antitumor active ingredient, can directly kill tumour cell, and drug of choice grade hydrochloric acid adriamycin, the content (percentage by weight) in implant is 9%~36%, preferably 12%~28%, most preferably 15%~24%.Content is too low, it is difficult to discharge, too high levels, and release is difficult to control.
(2)
PLGA：It is major auxiliary burden, assigns shape, hardness and the intensity of implant, controls rate of release of ADMh etc..PLGA is good biocompatibility, degradable high-quality medicinal materials, and endogenous material lactic acid, glycolic are degraded to after medicine has been released in vivo, and the latter participates in being metabolized as carbon dioxide and water in vivo, harmless.
The composition of PLGA had both influenceed intensity, Release Properties, stability, storing condition and the application of implant with inherent viscosity, the manufacturing technique of implant is influenceed again, and lactide content is too high in PLGA molecules, and fusing point is high, degraded is slow, difficulty increase is prepared, range of application is limited；PLGA viscosity is too low, and degraded is fast, stability is poor, causes the difficult control of implant quality, stability poor, preservation, transport difficult；Viscosity is too high, and difficulty of processing is big, and degraded is slow, using limited.
The glycolide of PLGA used by implant of the present invention elects 15 as with the mol ratio of lactide:85~85:15, preferably 15:85、25:75、50:50 or 75:25, most preferably 25:75 or 50:50；PLGA viscosity elects 0.22 dl/g~1.23 dl/g, most preferably preferably 0.29 dl/g~0.86 dl/g, 0.32 dl/g~0.56 dl/g as.
(3) polyethylene glycol：It is secondary auxiliary material, effect has：1. reduce the prominent of implant to release, shorten or eliminates the stagnant of implant and release the time, the drug release feature of regulation implant；2. toughness, intensity, the surface flatness of implant are improved, improves the quality of implant；3. the mobility and processability of implant material are improved.
Polyethylene glycol to implant it is prominent release, it is stagnant release, the molecular weight and consumption of the regulating effect of the rule that releases the drug etc. and polyethylene glycol it is closely related, molecular weight polyethylene glycol within the specific limits, when consumption is suitable, early stage release can be reduced, can eliminate again it is stagnant release the phase, make implant have for a long time release medicine until the property that discharges completely.
The molecular weight of polyethylene glycol used by implant of the present invention is chosen as 2300~8500, preferably 3000~6500, most preferably 3350,4000,4500,5000 or 6000；Polyethylene glycol consumption (percentage by weight) is 4.5%~9.5%, preferable amount 5%~8%, most preferably 5.5%~7.5%；Consumption is too low, and early stage burst size increases, and the impact that implants is excessive, is easily caused local necrosis；Consumption is too high, and early stage release is too low, and implanting can make tumour cell produce acquired resistance effect, and discharge to produce after certain medicine and new stagnant release the phase, it is impossible to persistently release medicine completely, in addition, the too high hardness and rigidity for also reducing implant of consumption, causes plant medicine pin to use difficult.
In order to more fully understand effect of the polyethylene glycol in implant of the present invention, illustrate further below：
Be effective medicine with ADMh, with different molecular composition, different viscosities PLGA as auxiliary material, release characteristics of the adriamycin implant in pure water prepared by fusion method in 3 classes below occurring, as shown in Figure 1：
1st class, quick-releasing type：When ADMh content is high, release more than 80% in the 1st day, release in 1 day~2 days is complete, such as Fig. 1 release profiles A, and prominent to release especially severe, drug release time is especially short.
2nd class, quick release-stagnant releases (drug releasing rate is minimum or stops release)-release type again：When ADMh content is medium, early stage release is fast, stagnant to release a couple of days~tens of days after release 2 days~5 days, then discharges again to complete, and such as Fig. 1 release profiles B, drug release time is short, and stagnant to release the phase long.
3rd class, slow release-stagnant releases-type is released again：When ADMh content is low, release less than 4% in the 1st day after release 2 days~5 days, stops releasing a couple of days~tens of days, then discharges again to complete, and release profiles C in such as Fig. 1, rate of release is too small, and stagnant to release the phase long.
Above-mentioned 1st class PLGA contents are few, weak to ADMh control, cause medicine to discharge rapidly, and drug release time is especially short；3rd class PLGA contents are more, it is strong to ADMh control, and adriamycin is anthracyclines, complex structure, molecular weight is big (580 Da), space geometry size is big, the a small amount of not controlled or controlled weak ADMh of dyskinesia, it is difficult to dissolution, only implant surface can be with dissolution, cause to discharge it is stagnant after a small amount of medicine release, the later stage discharges caused by being PLGA degradeds, implant short texture again.Between the 1st class and the 3rd class, ADMh part is controlled 2nd class PLGA contents by PLGA, and not controlled part discharges rapidly, controlled components be difficult to dissolution cause it is stagnant release, it is PLGA degradeds that the later stage discharges again, caused by implant short texture.All implants are without release adriamycin for a long time until the complete property of release.
The major defect of above-mentioned adriamycin implant be have it is long it is stagnant release the phase, to obtain the implant for discharging adriamycin for a long time, it is important to eliminate it is stagnant release the phase, while reducing early stage burst size.
Research finds：(1) retarding agent of water-insoluble is added in above-mentioned adriamycin implant, can reduce early stage release, but can not eliminate it is stagnant release the phase, also increasing for having stagnant releases the phase；(2) pore-foaming agent of water-soluble low-molecular is added in adriamycin implant, then early stage release aggravation.Both measures can not all obtain the implant for discharging medicine for a long time.
Further study show that：Polyethylene glycol is added in adriamycin implant, situations below occurs：
1. when molecular weight polyethylene glycol is low, dosage is more, prominent to release more serious, and discharges faster, similar with other soluble small molecular pore-foaming agent effects are added.
2. when molecular weight polyethylene glycol is 2300~10000, the release of implant early stage waits the various changes of generation with stagnant releasing：
Early stage burst size increases with the increase of polyethylene glycol amount, and after reaching an extreme value, the increase with polyethylene glycol amount reduces on the contrary, for example：When molecular weight polyethylene glycol is 3350, the implant containing 4% polyethylene glycol, early stage rate of release is than without the fast of polyethylene glycol, release profiles E is higher than release profiles D in such as Fig. 2；Implant containing 6% polyethylene glycol, early stage rate of release is than without the slow of polyethylene glycol, release profiles F is less than release profiles D in such as Fig. 2.
It is stagnant to release the phase and be gradually shortened with the increase of polyethylene glycol amount until disappear, then with the increase of polyethylene glycol amount, then occur new stagnant releasing the phase in release higher.For example：Implant containing 6% polyethylene glycol, the stagnant phase of releasing disappears, release profiles F in such as Fig. 2；And contain the implant of 10% polyethylene glycol, then formd in release higher it is stagnant release the phase, release profiles G in such as Fig. 2.
Polyethylene glycol the early stage burst size with regulation implant, is reduced or eliminated and stagnant release the phase, formed and new stagnant release the effect that phase etc. releases at 2300~10000.
The mechanism of action of the polyethylene glycol in implant：1. when molecular weight polyethylene glycol is low, dissolved because high-hydrophilic medicine around is obtained moisture, spread, because self-molecules present amount is low, good water solubility, meets water dissolves and to external diffusion, produces hole, for medicine provides diffusion admittance, double action promotes the release of medicine, causes to dash forward and releases increase, and release is accelerated；2. when molecular weight polyethylene glycol is high, top layer polyethylene glycol water absorption and swelling forms gel, medicine around is obtained moisture and is dissolved, spreads, and produces release acceleration effect, on the other hand, gel hinders covered medicine to external diffusion again, produces retarding effect, polyethyleneglycol content hour, gel overlay is few, retarding effect is small, and acceleration effect is big, and causing early stage to discharge increases；As the increase of polyethylene glycol amount, gel increase, the medicine for being covered increases, and retarding effect increase, acceleration effect reduces, and causes early stage to discharge and reduces.Polyethylene glycol inside implant absorbs water to form gel, implant is caused to expand, internal structure is loose, and after certain hour, the polyethylene glycol of gel state gradually dissolves, further loose internal structure, the outside diffusional resistance of medicine reduces, while implant internal moisture increases, promotes internal drug dissolving, diffusion, multiple action promotes the release of internal drug, so as to shorten or eliminate the stagnant of medicine release the phase.
2 implant shapes of the present invention：It is cylinder, diameter 0.3mm~1.6mm, preferably 0.8mm~5mm long, diameter 0.6mm~1.2mm, 1.2mm~4mm long, most preferred diameters 0.7mm, 0.8mm or 0.9mm, 2 mm, 3mm or 4mm long；Compression strength 41MPa~65MPa, can be implanted into focal zone with medicine pin percutaneous puncture is planted.
Implant shape elect as cylinder be easy to plant medicine pin use；Size is directed to use with and manufacture, size is smaller, can be smaller with the plant medicine pin of minor diameter, the wound to patient when using, but manufacture is more difficult to, it is oversized, it is necessary to use larger-diameter plant medicine pin, wound is big, clinical practice is taken into account with manufacture difficulty or ease, above-mentioned suitable size is selected, the implant can be used in operation, can also used in No operation.
3
Release in implant body of the present invention：The drug release in 10%~21%, 5 days of drug release in the 1 day drug release 80%~100% in 35%~63%, 30 days of drug release in 25%~51%, 10 days.
The implant initial stage a little dashes forward and releases, and then discharges medicine for a long time until discharging completely, behind such implant implantation knurl area, drug concentration high can be formed in tumor area in short time, valid density is then maintained for a long time, effective acting time is long, treatment intensity is big, can lift curative effect；Enter blood dose simultaneously few, general toxicity can be made significantly to decline；Effective time be administered once up to tens of days.
4 implant preparation methods of the present invention：Fusion method.
The method for preparing implant as auxiliary material with ADMh as active ingredient, with PLGA, polyethylene glycol has pressing, solvent method, microballoon method, microencapsulation, fusion method etc., and because of ADMh good water solubility, pressing is unable to control release speed；Solvent method uses organic solution, complex process, there is pollution and potential safety hazard, and industrial problems are more；Microballoon method is big with microencapsulation complex process, difficulty, and quality is difficult to control to, and industrializes extremely difficult；Fusion method is strong to the release control of medicine, process is simple, pollution-free, easily realization industrialization, most Development volue.The present invention selects fusion method, it is therefore an objective to effectively control implant quality, simplify production process, reduce pollution to environment, reduce production cost, be easy to industrialization, fusion method of the invention is divided into melt molding method and melt extrusion method, and preparation process is described below：
(1) melt molding method, comprises the following steps：
1. distinguish low-temperature grinding adriamycin, PLGA, polyethylene glycol, 120 mesh medicines sieve is crossed respectively, be made 3 kinds of fine powders；
2. fine powder 1. is uniformly mixed according to a ratio, is made mixed powder；
3. it is vacuum dried by mixed powder 2. below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes the volatile component contents such as mixed powder reclaimed water less than 0.1%, obtains dry mixed powder；
4. dry mixed powder 3. is melted 3~12 minutes at a temperature of 90 DEG C~140 DEG C, injection in-mold molding, cooling, the demoulding, sterilizing obtain final product the implant for discharging adriamycin for a long time.
(2) melt extrusion method, comprises the following steps：
1. distinguish low-temperature grinding adriamycin, PLGA, polyethylene glycol, 120 mesh medicines sieve is crossed respectively, be made 3 kinds of fine powders；
2. fine powder 1. is uniformly mixed according to a ratio, is made mixed powder；
3. it is vacuum dried by mixed powder 2. below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes the volatile component contents such as mixed powder reclaimed water less than 0.1%, obtains dry mixed powder；
4. dry mixed powder extruding machine melting 3. is extruded into cylinder material strip, after cooling, cylinder is cut into cutter, sterilized, obtain final product the implant for discharging adriamycin for a long time.
Beneficial effect of the present invention
The advantage of 1 implant of the present invention is：
(1) surface is smooth, good toughness, intensity are high, with when planting medicine pin and being administered, does not block needle tubing, not fragmentation.
(2)
Medicine is discharged for a long time, until discharging completely, effective time is long, fully, action intensity is big for drug utilization.
Implant of the present invention contain in right amount, the polyethylene glycol of higher molecular weight, it has the function such as lubrication, plasticising, toughness reinforcing, enhancing so that implant surface is smooth, good toughness, intensity are high；It meets water and gradually forms hydrogel, surface polyethylene glycol forms the drug diffusion that hydrogel reduces surface after implant enters human body, serious dashing forward is avoided to release, internal polyethylene glycol forms loose implant structure during hydrogel, promote internal drug dissolving diffusion, cause the implant initial stage to be dashed forward on a small quantity to release, then discharge medicine for a long time until release (release the drug 10%~21%, 5 days the drug release 80%~100% in 35%~63%, 30 days of drug release in 25%~51%, 10 days that releases the drug for internal 1 day) completely；Behind implantation knurl area, can make to form drug concentration high in the short time of tumor area, and maintain valid density for a long time, effective acting time is long, and action intensity is big, can be obviously improved curative effect；Blood concentration is extremely low simultaneously, and general toxicity can be greatly lowered；Tens of days be administered once effectively, clinical administration is more convenient.
And existing adriamycin implant does not contain the material of plasticising, toughness reinforcing, enhancing, lubricating function so that implant processing difficulties, rough surface, frangible, it is difficult to used with medicine pin is planted.
It is important that existing implant can not completely discharge adriamycin for a long time, action time is short, and drug utilization is low, and release characteristics are following several：
(1) release the drug rapid, action time is short：Half-life period only has 4 hours[1], release in 1~2 day is completely [2]；
(2) dash forward and release serious, drug release time is short, releasing degree is low：Release more than 40% in 1 day, discharges 2~7 days, and releasing degree is less than 75%[2]；
(3) discharged slow, medicine effect can not be played:Release in 1 day is less than 4%, is less than 6% within 2~5 days[2]。
Compared with the prior art, implant of the present invention has substantive distinguishing features and marked improvement.
2
Implant preparation method of the present invention is fusion method, and advantage is：
(1) any medium such as organic solvent is not used, three-waste free discharge is environment-friendly, on human body without influence, security is good；
(2) process is simple, equipment requirement are low, easy to operate, and implant quality controllability is good；
(3) with short production cycle, yield is big, low cost, easily realizes industrialization.
Preparation process is：
1. distinguish low-temperature grinding adriamycin, PLGA, polyethylene glycol, 120 mesh medicines sieve is crossed respectively, be made 3 kinds of fine powders；
2. fine powder 1. is uniformly mixed according to a ratio, is made mixed powder；
3. it is vacuum dried by mixed powder 2. below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes the volatile component contents such as mixed powder reclaimed water less than 0.1%, obtains dry mixed powder；
4. dry mixed powder 3. is melted 3~12 minutes at a temperature of 90 DEG C~140 DEG C, injection in-mold molding, cooling, the demoulding, sterilizing obtain final product the implant for discharging adriamycin for a long time.
(or dry mixed powder extruding machine melting 3. is extruded into cylinder material strip, and after cooling, cylinder is cut into cutter, sterilize, obtain final product the implant for discharging adriamycin for a long time.)
And the preparation method of existing adriamycin PLGA implants has pressure sintering[1] 、 [3], solvent method[2], major defect has：
(1) dichloromethane is used[1] 、 [3], acetone[2]Make solvent Deng the inflammable organic matter of poisonous and harmful, pollute environment, be detrimental to health, process or reclaim difficult big, cost increase.
(2)
Material heated time is long, and implant quality is difficult to control to that (PLGA microballoons, adriamycin-NaCl mixtures press 2 hours at 90 DEG C[1] 、 [3], heated time is long, and PLGA thermal degradations are more, and implant stability is poor, and quality is difficult to control to)；
(3) complex process, equipment is more, operating difficulties (with emulsification, freezing etc. method prepare PLGA microballoons, with neutralize, washing, again neutralisation prepare ADMh-sodium chloride mixed powder, prepare implant with pressure sintering[1] 、 [3])；
Pressure sintering[1][3]Preparation process is：
1. PLGA is dissolved with dichloromethane, the PLGA solution of 100mg/L is obtained；
2. above-mentioned PLGA solution 1. is added and is emulsified in the aqueous solution that polyvinyl alcohol content is 1%, PLGA emulsions are obtained；
3. by above-mentioned emulsion evaporative removal dichloromethane 2., suspension is obtained；
4. the above-mentioned suspension 3. of centrifugation, collects microballoon；
5. washing, the above-mentioned microballoon 4. of freeze-drying, the PLGA microballoons of 4 μm of screened prepared particle diameter；
6. with NaOH and ADMh solution is to pH=9.0, and adriamycin is precipitated；
7. above-mentioned adriamycin 6. is washed；
8. the above-mentioned adriamycin 7. of resuspension, plus hydrochloric acid is adjusted to pH=3.0, obtains adriamycin acid solution；
9. by the above-mentioned concentration of adriamycin acid solution, lyophilized, prepared adriamycin-NaCl mixtures fine powder (adriamycin percetage by weight is that 38.5%, NaCl is 61.5%) 8.,
10. it is above-mentioned PLGA microballoons 65% (weight portion) 5. is uniform with above-mentioned (weight portion) mixed grinding of adriamycin-NaCl mixtures fine powder 35% 9., uniform mixed powder is obtained；
(11) above-mentioned mixed powder 10. is loaded in teflon tube；
(12) the mixed powder in above-mentioned teflon tube (11) is pushed 2 hours for 90 DEG C in temperature with stainless steel pistons rod, obtain micro- rod；
(13) above-mentioned micro- rod (12) is taken out from teflon tube, adriamycin implant is obtained.
{ [3] Feng Qian, Agata Szymanski, Jinming Gao.Fabrication and
characterization of controlled release poly(D,L-lactide-co-glycolide)
Millirods [J] 2001 John Wiley ＆ Sons, Inc.512-522. }
Solvent method[2]Preparation process is：
1. PLGA is dissolved in acetone, is made PLGA acetone solns；
2. ADMh is added in above-mentioned solution 1., is well mixed, mixture is obtained；
3. the part acetone in above-mentioned mixture 2. is removed, paste mixture is obtained；
4. above-mentioned paste mixture 3. is injected into silica gel rubber pipe；
5. the cylindrical rod in above-mentioned silicone rubber tube 4. is dried, room temperature is cooled to, in preservation under vacuum；
6. cylindrical rod is taken out from above-mentioned silicone rubber tube 5., is sterilized, obtain final product adriamycin implant, diameter 0.8mm, 8mm long.
Compared with prior art, the inventive method has marked improvement.
Implant of the present invention is used for clinic, can give difficult patient following benefit：
(1) for being reluctant operation or inoperable tumor patient, such as Old patients with tumor, the tumor patient performed the operation, the patient that has tumour is unable on the organ of surgical removal, with planting medicine pin percutaneous puncture by implant implantation tumour or tumour periphery, or implantation needs the position of administration, then release adriamycin kills tumour cell to implant for a long time, and tumour growth is suppressed for a long time；
(2) tumour for that can not be extractd in operation, find that the tumour at some positions can not be extractd in such as performing the operation, can be by performing the operation in implant implantation tumour or tumour periphery, or implantation needs the position of administration, implant then kills tumour cell, suppresses tumour growth for a long time；
(3) for the tumour of surgical removal, implant is implanted into knurl bed in art, implant is then instant and kills the tumour cell of residual for a long time, prevention of tumor recurrence.
Figure of description
Accompanying drawing is briefly described：
Fig. 1 is the relation of adriamycin implant vitro release and release time, and abscissa represents release time, and unit is day, and ordinate represents release, is represented with percentage (%)；Figure inner curve A, B, C represent respectively the vitro release (%) of adriamycin implant A, B, C and release time (my god) relation, the percentage by weight of the hydrochloric adriamycins of adriamycin implant A, B, C is respectively 30%, 20% and 10%.
Fig. 2 is the relation of adriamycin implant vitro release and polyethyleneglycol content in implant, and abscissa represents time release time, and unit is day；Ordinate represents release, is represented with percentage (%)；Figure inner curve D, E, F, G represent adriamycin implant D, E, F, G vitro release and the relation of release time respectively, and the percentage by weight of adriamycin implant D, E, F, G containing polyethylene glycol is respectively 0%, 4%, 6% and 10%.
Fig. 3 is the relation of adriamycin implant F release and Implantation Time in rats'liver, and abscissa represents the time in implantation liver, and unit is day；Ordinate represents release in liver, is represented with percentage (%).
Specific embodiment：
Following examples are only further illustrated to of the invention, it is impossible to be interpreted as the limitation any to the present invention.
Embodiment 1 Adriamycin implant A, B, C
(1) prescription, is shown in Table 1.
The adriamycin implant A of table 1, B, component C and weight ratio
(2) prepare
1. the material of upper table 1 is crushed respectively, 120 mesh medicines sieve is crossed respectively, and ADMh fine powder, PLGA fine powders is obtained；
2. fine powder 1. is matched by upper table 1 well mixed, is respectively prepared implant A, B, C mixed powder；
3. mixed powder 2. is dried in vacuum drying chamber under 22 DEG C of temperature, pressure 9KPa, makes mixed powder reclaimed water and volatile component content less than 0.1%, be obtained and dry implant A, B, C mixed powder；
4. every kind of dry mixed powder 3. is put in rustless steel container respectively and is melted 9 minutes at a temperature of 110 DEG C, shaping, cooling, the demoulding in injection mould (die throat diameter 0.9mm, 4mm long), sterilizing, adriamycin implant A, B, C is obtained, implant is red cylinder, diameter 0.9mm, 4mm long, compressive resistance 47MPa.
Embodiment 2 Adriamycin implant D, E, F, G
(1) prescription, is shown in Table 2.
Adriamycin implant D, E, F, G component of table 2 and weight ratio
(2) prepare
1. the material of upper table 2 is crushed respectively, 120 mesh medicines sieve is crossed respectively, and ADMh fine powder, PLGA fine powders is obtained；
2. fine powder 1. is matched by upper table 2 well mixed, is respectively prepared implant D, E, F, G mixed powder；
3. mixed powder 2. is dried in vacuum drying chamber under 26 DEG C of temperature, pressure 11KPa, makes mixed powder reclaimed water and volatile component content less than 0.1%, be obtained and dry implant D, E, F, G mixed powder；
4. 3. every kind of dried into implant mixed powder respectively and is put in rustless steel container and melted 9 minutes at a temperature of 130 DEG C, shaping, cooling, the demoulding, sterilizing in injection mould (die throat diameter 0.9mm, 4mm long), adriamycin implant D, E, F, G is obtained, implant is red cylinder, diameter 0.9mm, 4mm long, compressive resistance 49MPa.
Embodiment 3 Vitro release is tested
(1) spectrophotometry adriamycin implant A, B, C, D, E, F, G content is used；
(2) 3 adriamycin implant A are taken, difference precise weighing, respectively it is put into 1 10mL cleaning tool plug test tube, 5mL purified waters (pH=7.0) is added in every test tube, and it is immersed in the water implant particle, it is put into the water bath inside holding of (37 ± 0.5) DEG C, as adriamycin implant A release in vitro devices.
（3）Make the release in vitro device of adriamycin implant B, C, D, E, F, G with legal system.
（4）Every invisible spectro whole liquid are taken out respectively daily, while adding the fresh purified water of same volume, and are put into the water bath inside holding of (37 ± 0.5) DEG C；
（5）Detect the amount of the ADMh for taking out liquid daily respectively with AAS, release is calculated according to input amount and burst size, as a result see Fig. 1,2.
Fig. 1 shows：1. when ADMh content 30%, release more than 80% in the 1st day, release in 1 day~2 days is complete, sees Fig. 1 release profiles A, and prominent to release especially severe, drug release time is especially short；2. when ADMh content 20%, release more than 30% in the 1st day discharges 6 days, stagnant to release 12 days, then discharges again to complete, sees Fig. 1 release profiles B, and prominent to release serious, drug release time is short, and stagnant to release the phase long;3. when ADMh content 10%, release less than 4% in the 1st day discharges 5 days, stagnant to release 13 days, then discharges again to complete, and release profiles C in such as Fig. 1, rate of release is too small, and stagnant to release the phase long.
Fig. 2 shows：Influence of the polyethylene glycol (molecular weight is 3350) to adriamycin implant release is extremely complex：1. when polyethyleneglycol content is 4%, the initial stage burst size of adriamycin implant is improve, early stage release is fast, stagnant to release phase disappearance, completely, release profiles E is higher than D to insoluble drug release in Fig. 2；2. when polyethyleneglycol content is 6%, the prominent amount of releasing of adriamycin implant is reduced, stagnant to release phase disappearance, insoluble drug release is more uniform until discharging completely, release profiles F early stages are less than D in Fig. 2, and the later stage is higher than D；3. when polyethyleneglycol content is 10%, be substantially reduced the prominent amount of releasing of adriamycin implant, when the more uniform release of medicine is to 85%, formed it is new it is stagnant release the phase, medicine can not persistently release master and discharge complete, and release profiles G early stages are less than D in Fig. 2, and the later stage is higher than D, but less than F.
Embodiment 4 Internal dissolution test
Wista rats 30 are taken, after every rat anesthesia, is cut open the belly, 1 adriamycin implant F for having weighed is implanted into liver with medicine pin is planted, close abdomen, sterilization, conventinal breeding；It is each when the 1st, 3,5,7,10,15,20,25,30,35 days after planting medicine to put to death rat 3, take out the residual implant in every rat, the surplus of ADMh in high performance liquid chromatography detection residual implant, release is calculated according to implantation dose and residual drug, adriamycin implant F in rats'liver release (%) and the time of implanting (my god) relation be shown in Table 3 and Fig. 3.
The adriamycin implant F of table 3 in the rats'liver release (/ %) and time in implantation liver (my god) relation
Table 3 shows with Fig. 3：Adriamycin implant F 1 day release (14.6 ± 2.5) %, 5 days release (35.8 ± 1.9) %, 10 days release (53.8 ± 2.7) %, 30 days release (93.5 ± 1.6) % in rat body, initial stage has certain dashing forward to release, and continues 35 days release adriamycins until release 98.7%.
Embodiment 5 Pharmacodynamics test
Take the vigorous SGC-7901 tumor tissues of production and be cut into 1.5mm3Left and right, aseptically, it is inoculated in 12 nude mouses (BALB/CA, 18~22g, female, 6 week old) armpit is subcutaneous, control group and implant group are divided at random within the 6th day, control group is not treated, implant group only measures (in terms of ADMh) by adriamycin implant F embedment nude mouse rind gall knots edge on the 6th day by 0.06mg/ after inoculation, inoculation is dissected after 36 days and claims knurl weight, is calculated as follows inhibition rate of tumor growth：
Inhibiting rate=100% × (control group knurl weight-implant group knurl weight)/control group knurl weight
As a result：Adriamycin implant F is 83.2% to the tumour inhibiting rate of people's stomach knurl SGC-7901.
Embodiment 6 Adriamycin implant treats the single tumour of late period cancer
Later period of hepatocarcinoma, through multiple PTCA or and STENTS, liver's recurrence growth 5.4cm × 4.7cm tumours, under B ultrasonic guiding, plant medicine pin percutaneous puncture and adriamycin implant F are implanted into knurl with No. 12, dosage (in terms of ADMh) 200mg, the functions such as physiological and biochemical index no abnormality seen during treatment, liver, kidney, heart, lung are normal, adverse reaction do not occur, after January, CT machine checks：Intra-tumor necrosis 86%.
Embodiment 7 Adriamycin implant treatment advanced liver cancer multiple tumour
Later period of hepatocarcinoma, through multiple PTCA or and STENTS, liver's recurrence 3, tumour of growth, size is respectively 5.3cm × 4.2cm, 6.3cm × 5.8cm and 7.9cm × 6.4cm；Under B ultrasonic guiding, medicine pin percutaneous puncture being planted with No. 12, adriamycin implant F is implanted into knurl week, the 4 points of administrations of each knurl week point, 3 tumours are administered total amount (in terms of ADMh) 340mg, the functions such as physiological and biochemical index change without exception during treatment, liver, kidney, heart, lung are normal, adverse reaction do not occur, after January, CT machine checks：The knurl Zhou Jun of 3 tumours has different degrees of necrosis, tumor mass reduction.
Claims (4)
1. it is a kind of for a long time discharge adriamycin implant, it is characterized in that, the Solid Releasing Fresh-keeping Agent of the slow Slow release being made up of ADMh, glycolide-lactide copolymer, polyethylene glycol, content of the ADMh in Solid Releasing Fresh-keeping Agent is 9%~36% (weight ratio), preferably 12%~28%, most preferably 15%~24%；The glycolide-lactide copolymer, its glycolide is 15 with the mol ratio of lactide:85~85:15, preferably 15:85、25:75、50:50 or 75:25, most preferably 25:75 or 50:50, viscosity is 0.22 dl/g~1.23 dl/g, most preferably preferably 0.29 dl/g~0.86 dl/g, 0.32 dl/g~0.56 dl/g；The molecular weight of the polyethylene glycol is 2300~8500, it is preferred that 3000~6500, most preferably 3350,4000,4500,5000 or 6000, the content in Solid Releasing Fresh-keeping Agent are 4.5%~9.5% (weight ratio), it is preferred that 5%~8%, most preferably 5.5%~7.5%；The Solid Releasing Fresh-keeping Agent drug release in 5%~21%, 5 days of drug release in 1 day drug release in 25%~51%, 10 days drug release 80%~100% in 35%~63%, 30 days in vivo.
2. according to claim 1 it is a kind of for a long time discharge adriamycin implant, it is characterized in that, the implant is shaped as cylinder, diameter 0.3mm~1.6mm, 0.8mm~5mm long, preferably diameter 0.6mm~1.2mm, 1.2mm~4mm long, most preferred diameters 0.7mm, 0.8mm or 0.9mm, 2 mm, 3mm or 4mm long；Compression strength 41MPa~65MPa, can be implanted into focal zone with medicine pin percutaneous puncture is planted.
3. it is a kind of for a long time discharge adriamycin implant preparation method, it is characterized in that, comprise the following steps：
(1) difference low-temperature grinding adriamycin, glycolide-lactide copolymer, polyethylene glycol, cross 120 mesh medicines sieve respectively, are made three kinds of fine powders；
(2) three kinds of fine powders of (1) are uniformly mixed according to a ratio, are made mixed powder；
(3) it is vacuum dried by the mixed powder of (2) below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes mixed powder reclaimed water and volatile component content less than 0.1%, obtains dry mixed powder；
(4) mixed powder of (3) is melted 3~12 minutes at a temperature of 90 DEG C~140 DEG C, injection in-mold molding, cooling, the demoulding, sterilizing are obtained a kind of implant for discharging adriamycin for a long time.
4. it is a kind of for a long time discharge adriamycin implant preparation method, it is characterized in that, comprise the following steps：
(1) difference low-temperature grinding adriamycin, glycolide-lactide copolymer, polyethylene glycol, cross 120 mesh medicines sieve respectively, are made three kinds of fine powders；
(2) three kinds of fine powders of (1) are uniformly mixed according to a ratio, are made mixed powder；
(3) it is vacuum dried by the mixed powder of (2) below 20 DEG C of temperature, under pressure 2KPa~15KPa, makes mixed powder reclaimed water and volatile component content less than 0.1%, obtains dry mixed powder；
(4) the mixed powder extruding machine melting of (3) is extruded into cylinder material strip, after cooling, cylinder is cut into cutter, sterilized, a kind of implant for discharging adriamycin for a long time is obtained.
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