CN101756908A - Hydroxyapatite micro-sphere with polyester coating and preparation method thereof - Google Patents
Hydroxyapatite micro-sphere with polyester coating and preparation method thereof Download PDFInfo
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- CN101756908A CN101756908A CN201010100143A CN201010100143A CN101756908A CN 101756908 A CN101756908 A CN 101756908A CN 201010100143 A CN201010100143 A CN 201010100143A CN 201010100143 A CN201010100143 A CN 201010100143A CN 101756908 A CN101756908 A CN 101756908A
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Abstract
The invention belongs to the technical field of medicine and discloses a hydroxyapatite micro-sphere with a biodegradable aliphatic polyester coating, the inside of the coated micro-sphere is the hydroxyapatite micro-sphere which is formed by gathering nano hydroxyapatite particles, and the surface or inside of the hydroxyapatite micro-sphere absorbs and is loaded with small molecular drugs. The biodegradable aliphatic polyester material is selected from polylactic acid or poly lactide, polyglycolic acid or poly glycolide, poly(lactic-co-glycolic acid) or poly(lactide-co-glycolide), polycaprolactone or lactide-caprolactone copolymer. The hydroxyapatite micro-sphere with the polyester coating can release drugs for more than three days, and burst release does not exist in the drug release process. The coated micro-sphere can be implanted into animals or human bodies by injection or implantation by an operation for treating various diseases.
Description
Technical field
The invention belongs to pharmaceutical field, relate to hydroxyapatite micro-sphere of polyester coating and preparation method thereof, be specifically related to a kind of be used to wrap year small-molecule drug and microsphere of realizing the long-time slow release of medicine and preparation method thereof.
Background technology
At present, the depot drug product transmission system is one of focus of pharmaceutical preparation research field.After the sustained-release preparation administration of common oral, injection or mucosa, the release of medicine and action time, generally in 1 day, the patch of some percutaneous dosing can stick for 1 week continuously, and its medicine continuous action time is longer.After the depot drug product transmission system is often referred in the pharmaceutical preparation implant into body body, medicine continues slowly to discharge, and brings into play long therapeutic effect, and its action time is sustainable more than 3 days usually, even can in half a year or one-year age, continue slowly to discharge medicine, bring into play the long-term treatment effect.Because the local high drug level that administration frequency significantly reduces, the undulatory property of vivo medicine concentration reduces and can realize implant site, the toxic and side effects of depot drug product transmission system is lower, the safety of patient's medication and compliance etc. are better.
The mode administration that depot drug product transmission system in the past adopts operation to implant more because pharmaceutical carrier (as silicone rubber) is not degraded, also needs operation once more to take out carrier behind the drug release.Progress along with drug preparation technique; recently the depot drug product transmission system of Chu Xianing adopts the preparation of microgranule suspendible, solution or gel type more; the mode administration that can utilize the syringe needle of suitable specification to implant with injector to inject; can be degraded or absorb in human body as carrier material; during administration and drug consumption all do not need operation after intact, the compliance of patient's medication is better.
At present, the existing injectable depot drug product transmission system of using comprises the preparation of form such as the suspension type injection, liposome, multivesicular liposome, microsphere, situ-gel of the insoluble salt of oily injection agent, medicine or ester, the wherein foremost product that has gone on the market is as first Injectable microspheres durative action preparation---the leuprorelin PLGA micro-balloon injection that Japanese Wu Tian company released in the nineties in last century, the cytarabine multivesicular liposome that Skypharm company releases
With morphine multivesicular liposome (DepoMorphine
TM) wait (Zheng Junmin etc. translate. the injectable sustained-release preparation. and Chemical Industry Press, 2005.).Although the drug release controllability of this class multiple-unit particle system of microsphere and multivesicular liposome is good, the low prominent system that performance is better than solution-type or gel-type such as release, the factor of cost of material aspect has greatly limited its application.For biodegradable microsphere, research at most, application safety and allowed to be used for the material of human body inner injecting and administering by a plurality of national statutory bodies such as FDA, have only aliphatic polyester series homopolymer and copolymer at present, and the used pharmaceutical adjunct of multivesicular liposome removes the used injection stage lipid of production conventional liposome, also must add the charged matrix material of suitable vast scale.
For now, but the price of the aliphatic polyester of hyoscine and matrix material is all quite expensive.For all injectable depot drug product transmission systems, reduce small-molecule drug, especially prominent the releasing of soluble small molecular medicine is the problem that this class pharmaceutical preparation is faced jointly, often cause drug release too slow again simultaneously but reduce prominent the releasing of medicine, promptly drug release is not exclusively or do not reach effective drug level in action time at expected drug.
Hydroxyapatite (Hydroxyapatite, HAP) be a kind of cheap, broad-spectrum biomaterial, synthesized first in 1871, nineteen sixty finds that it is the main inorganic composition of bone and tooth, the HAP pottery successfully is used for pulp-cap and hard tissue repair since 1971, and hydroxyapatite also is widely used at other industrial circles.Hydroxyapatite has good biocompatibility, chemical stability, degradable and absorbability, multiple drug molecule there is adsorption, hydroxyapatite and hydroxyapatite micro-sphere more and more are subjected to people and pay close attention in the drug delivery field, in recent years, there is report to carry albumen and polypeptide drug with its absorption bag, antibiotic, anti-inflammatory drug, analgesic, cancer therapy drug, somatomedin etc., make microsphere, implant, the local targeting of form such as support and bone cement or depot drug product transmission system (Matsumoto T, Okazaki M, Inoue M, Yamaguchi S, Kusunose T, Toyonaga T, Hamada Y, J.Takahashi.Hydroxyapatite particles as a controlled release carrier of protein.Biomaterials, 2004,25:3807-3812.Ginebra M P.Traykova T.Calcium phosphate cements as bone drug deliverysystems:Areview.J Controlled Release, 2006,113:102-110.).But, owing to pass through the characteristics of adsorption medicine carrying between hydroxyapatite-drug molecule, for water soluble drug, in human body in the physiological liquid, simple hydroxyapatite or hydroxyapatite micro-sphere are difficult to avoid the medicine rapid release and realize long-time slow release, are possible solution routes with polymer coating.The hydroxyapatite micro-sphere of existing report polymer coating is used for slow release (the rock-block field great waves of macromolecular drug, Zhang Zhi's honor, Gong Tao, Liu Shiwei, old another name for Sichuan Province. the preparation of insulin sustained-release oral drug-supplying system. the West China pharmaceutical journal, 2005,20 (2): 101-104.Boonsongrit Y.Sato K, Kondo A, Abe H, Naito M, Yoshimura M, Ichikawa H, Fukumori Y, Encapsulation of Protein-Loaded Hydroxyapatite Granules withPoly (lactic-co-glycolic acid) .J Ceram Soc Japan, 2007,115:745-747.), but for small-molecule drug (especially soluble small molecular medicine), medicine is prominent release and drug releasing rate between contradiction still exist.In addition, in the preparation process of the hydroxyapatite micro-sphere of the coating of above-mentioned bibliographical information, the consumption of coating polymer is higher, and resulting microsphere inside has a plurality of hydroxyapatite micro-spheres and is dispersed in structure in the polymer backbone, be not real coating structure, and particle diameter is bigger.The higher cost that must cause of the consumption of coating polymer is higher, and excessive particle diameter then is not suitable for injecting drug delivery implant.
Summary of the invention
The hydroxyapatite micro-sphere that the purpose of this invention is to provide a kind of polyester coating, to solve the prominent shortcoming such as release obviously of existing injectable sustained-release preparation cost height, small-molecule drug (especially soluble small molecular medicine), provide a kind of can be used for wrapping carry small-molecule drug and realize the microsphere of the long-time slow release of medicine and the pharmaceutical preparation of injectable administration thereof.
The present invention adopts the carrier material of the hydroxyapatite micro-sphere of biodegradable and absorption as the absorption medicine, and hydroxyapatite micro-sphere can be prepared by nano-hydroapatite particles by spray drying method.The surface of hydroxyapatite micro-sphere or inner absorption are loaded with suitable small-molecule drug, then with a kind of biodegradable and absorb and the medicinal aliphatic poly ester material coating medicine carrying hydroxyapatite micro-sphere at positions such as subcutaneous in statutory body allows implant into body, intramuscular or skeleton, according to the difference of art for coating condition, coating microsphere inside is only contained 1 medicine carrying hydroxyapatite micro-sphere or minority (as be less than coating microsphere sum 5%) medicine carrying hydroxyapatite micro-sphere is only arranged.The syringe needle that the hydroxyapatite micro-sphere of the polyester coating that particle diameter is suitable can pass through suitable specification also can be implanted in the human or animal body by operation heeling-in mode with the injection system administration.
Utilize the interaction between hydroxyapatite and the drug molecule, and coating membrane is to the retardation of drug diffusion, delay the release of medicine and reduce that medicine is prominent to be released, the small-molecule drug that coating microsphere bag carries slowly discharges the performance therapeutical effect in vivo, the biodegradation gradually of coating microsphere, corrosion and absorbed by body.Because hydroxyapatite and aliphatic polyester itself have excellent biological compatibility and safety, advantage such as biodegradation and bioresorbable, in conjunction with the dual sustained release effect of absorption-coating of the present invention, the hydroxyapatite micro-sphere of polyester coating of the present invention has the following advantages: the long-time slow releasing function of realizing small-molecule drug (especially soluble small molecular medicine), do not have that obvious medicine is prominent to be released, the injectable drug delivery implant, carrier can degrade in human body or absorb behind the drug release, significantly reduce cost, and obviously improve the safety of patient's medication and compliance etc.
Although the multiple biodegradable polymer that has of bibliographical information is expected to be used for the carrier material that human body is implanted into administration, comprise aliphatic polyester, poe, chitosan, the poly-nitrile etc. of seeing, but be proved safety at present and allowed the biodegradable polymers of implant into body to have only aliphatic polyester series by statutory body, comprise polylactic acid or polylactide (PLA), polyglycolic acid or poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA), lactic acid-ethanol copolymer or lactide-glycolide copolymer (PLGA), polycaprolactone (PCL) or lactide-caprolactone copolymer.The hydroxyapatite micro-sphere of polyester coating of the present invention, the weight ratio of coating polymer and medicine carrying hydroxyapatite micro-sphere should be less than 4, preferably less than 2.More than or equal to 4, resulting coating hydroxyapatite micro-sphere particle diameter is bigger, and each coating microsphere contains a plurality of hydroxyapatite micro-spheres as the weight ratio of coating polymer/medicine carrying hydroxyapatite micro-sphere.Obviously, along with polyester proportion in the microsphere increases, the character of the microsphere of this structure more approaches common polyester microsphere, and causes the cost of microsphere to increase.
For guarantee syringeability good in the drug administration by injection process (be suspendible have the preparation of microsphere can be smoothly syringe needle by certain specification) and the safety and the nonirritant of administration, the size of the microsphere of injection drug delivery implant should have certain requirement.The hydroxyapatite micro-sphere of polyester coating of the present invention, its mean diameter are preferably between the 5-50 micron between the 1-200 micron, and syringeability is good.
Hydroxyapatite surface has a large amount of adsorption sites, pass through the ionic interaction physical absorption between common dissociated medicine and the adsorption site in hydroxyapatite surface, hydroxyapatite micro-sphere has the characteristics of porous, high-specific surface area, also adsorbable non-dissociative type small-molecule drugs.Hydroxyapatite is as the carrier material of drug delivery, be more suitable for water miscible dissociative type medicine, can be used to bag and carry polytype small-molecule drug, comprise: antibiotics, the local anaesthesia medicine, the small peptide medicine, antitumor drug etc., as: doxycycline, minocycline, gentamycin, metronidazole, amikacin, tobramycin, ganciclovir, bupivacaine, lignocaine, bulleyaconitine A, lappaconitine, morphine, leuprorelin, goserelin, the brain peptide, octreotide, enkephalin, cytarabine, fluorouracil, cisplatin, methotrexate, bleomycin, cucurbitacin, Ang Danxiqiong, Ge Laxiqiong, risperidone, the original shape of the first-class medicine of huperzine or its hydrochlorate, sulfate, the form of salt such as acetate.
According to different treatment needs, the medicine that the injectable sustained-release preparation requires continues release time not to be waited, and needs about 7 days as periodontal pocket treatment, and postoperative analgesia needs 3-5 days, other treatment needs more than 15 days mostly, and long may requiring continues to discharge medicine in half a year even 1 year.The hydroxyapatite micro-sphere of polyester coating of the present invention, the lasting release time of medicine is more than 3 days, can change the type of polyester material of coating and the thickness adjusted drug release rate and the lasting release time of coating, it is slow that general coating thickness increases drug release, and the drug release rate when lactic acid-ethanol copolymer is coating material is that coating material is compared slowly with co-glycolic acid.Because the adsorption of drug molecule and hydroxyapatite, and the retardation of coating membrane, the medicine of the hydroxyapatite micro-sphere of polyester coating is prominent release not obvious, the medicine of accumulative total release in general 0-12 hour is no more than 30% of microsphere contained drug total amount, and drug release is complete, can obtain relative stable blood concentration.
The preparation of the hydroxyapatite micro-sphere of polyester coating of the present invention can be adopted following method and step.
Method one:
1. get the suitable commercially available hydroxyapatite micro-sphere of particle diameter or prepare the spray-dried preparation hydroxyapatite micro-sphere of nano-hydroapatite particles with chemical precipitation method, behind the purification, add the drug solution of suitable concentration according to the requirement of pharmaceutical properties and drug loading, make medicine be adsorbed on the surface of hydroxyapatite micro-sphere and inner;
2. after medicine absorption reaches balance, filter or the centrifugalize microsphere medicine of flush away microsphere surface, drying;
3. adopt fluid drying technology, fluidized coating technology, spray drying technology, or other preparation techniques get the hydroxyapatite micro-sphere of polyester coating at medicine carrying hydroxyapatite micro-sphere appearance bread one deck aliphatic polyester clothing film, airtight, the low tempertaure storage in dry back.
Method two:
1. prepare nano-hydroapatite particles with chemical precipitation method, behind the purification, add the drug solution of suitable concentration according to the requirement of pharmaceutical properties and drug loading, make medicine be adsorbed on the surface of hydroapatite particles, spray-dried preparation medicine carrying hydroxyapatite micro-sphere;
2. adopt fluid drying technology, fluidized coating technology, spray drying technology, or other preparation techniques get the hydroxyapatite micro-sphere of coating at medicine carrying hydroxyapatite micro-sphere appearance bread one layer of polymeric clothing film, airtight, the low tempertaure storage in dry back.
For the hydroxyapatite micro-sphere of realizing polyester coating of the present invention can be applied to clinical treatment safe ready; have good stability with quality controllable; need be used other pharmaceutical necessitieses and make the appropriate drug preparation; as cryodesiccated injectable microsphere preparation; these pharmaceutical necessitieses are conventionally known to one of skill in the art, comprise suspending agent, isoosmotic adjusting agent, stabilizing agent, freeze drying protectant etc.Aseptic is one of the most important prescription of ejection preparation, and the hydroxyapatite micro-sphere preparation for polyester coating of the present invention can adopt sterile working's processes, also can adopt terminal sterilization technology such as radiation sterilization to realize aseptic requirement.
The hydroxyapatite micro-sphere of polyester coating of the present invention and pharmaceutical preparation thereof can be adopted multiple route of administration, as injection in the periodontal pocket, subcutaneous injection, intramuscular injection, and also can be by the mode administration of operation heeling-in; In clinical treatment, be widely used, as be used for the bone reparation, the postoperative analgesia, tell in the town of chemicotherapy, and diseases such as treatment periodontal disease, senile dementia, malignant tumor also can be used for Animal diseases treatment or prevention.
Description of drawings
Fig. 1 is respectively the microphotograph of coating microsphere prepared under the condition of 8 (prescription 1 among the embodiment 1, left figure) and 2 (prescription 4 among the embodiment 1, right figure) for PLGA/ hydroxyapatite micro-sphere ratio.
Fig. 2 is the cumulative in vitro drug release discharge curve of hydroxyapatite micro-sphere that is loaded with the PLGA coating of doxycycline hydrochloride.
■-hydroxyapatite micro-sphere,-PLGA/ hydroxyapatite micro-sphere=2.7, Δ-PLGA/ hydroxyapatite micro-sphere=1.0, ◇-PLGA/ hydroxyapatite micro-sphere=0.5, zero-PLGA/ hydroxyapatite micro-sphere=0.25, ●-PLGA microsphere.
The weight ratio of PLGA and hydroxyapatite micro-sphere has a significant effect to drug release rate, and the PLGA proportion is big more, and then coating thickness is big more, and drug release is slow.
Fig. 3 is the cumulative in vitro drug release discharge curve of hydroxyapatite micro-sphere that is loaded with the different size PLGA coating of doxycycline hydrochloride.
□-LG/GA＝50/50，IV＝0.28dl/g；○-LG/GA＝50/50，IV＝0.60dl/g；△-LG/GA＝75/25，IV＝0.60dl/g。
Wherein, LA/GA refers to the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester among the PLGA, and IV is the sign viscosity of commodity PLGA, and the viscosity of the big more then PLGA of IV solution is big more, and molecular weight is high more; The weight ratio of PLGA and hydroxyapatite micro-sphere is less than 2.7.
Fig. 4 is an accumulation drug release discharge curve in the body after hydroxyapatite micro-sphere (zero) the mouse subcutaneous injection administration of the hydroxyapatite micro-sphere (■) that is loaded with doxycycline hydrochloride and PLGA coating.
Fig. 5 is blood drug level-time graph in the body after hydroxyapatite micro-sphere (zero) the mouse subcutaneous injection administration of the hydroxyapatite micro-sphere (■) that is loaded with doxycycline hydrochloride and PLGA coating.
Fig. 6 is the cumulative in vitro drug release discharge curve of the polyester coating hydroxyapatite micro-sphere that is loaded with octreotide acetate (), Cucurbitacin B (zero), bulleyaconitine A (△), hydrochloric acid Ang Danxiqiong (◇), hydrochloric acid risperidone (■) and huperzine A (●) respectively.
The specific embodiment
The present invention will contrast specific embodiment hereinafter and carry out more detailed explanation, but it is restricted to it will be appreciated by persons skilled in the art that these specific embodiments do not have.
Embodiment 1: lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere that is loaded with doxycycline hydrochloride
The general preparation process of hydroxyapatite micro-sphere of PLGA coating that intra-liquid desiccation method preparation is loaded with doxycycline hydrochloride is as follows:
1. absorption method prepares the medicine carrying hydroxyapatite micro-sphere: get an amount of blank hydroxyapatite micro-sphere, add finite concentration doxycycline hydrochloride solution, 50 rev/mins-120 rev/mins speed constant temperature (0-60 ℃) vibration mixed 1-12 hour, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, clean 3 times with small amount of deionized water, lyophilization gets the medicine carrying hydroxyapatite micro-sphere.
2. use PLGA coating medicine carrying hydroxyapatite micro-sphere: the concentration that adds proper volume in above-mentioned medicine carrying hydroxyapatite micro-sphere dry powder is that the PLGA solution of 0-100 mg/ml (can be used dichloromethane, chloroform, ethyl acetate, oxolane, organic solvents such as acetonitrile, or one or more mixed solvent dissolving PLGA wherein), stirring is uniformly dispersed microsphere in organic facies, it is added dropwise to contains 0%-5% (concentration) stabilizing agent (as polyvinyl alcohol, PVA) in the aqueous solution (as water, buffer, simulated body fluid etc.), continual and steady mechanical agitation 4-8 hour volatilization organic solvent under 0 ℃ of-60 ℃ of constant temperature, isolated by filtration coating microsphere, clean repeatedly 3 times with small amount of deionized water, drying under reduced pressure, the hydroxyapatite micro-sphere of PLGA coating.
By above-mentioned preparation method, use the PLGA of different size respectively, and the weight ratio of different PLGA/ medicine carrying hydroxyapatite micro-spheres prepares the coating microsphere, concrete preparation condition is as follows, and prescription is formed as table 1.
Get 50 gram hydroxyapatite micro-spheres, adding concentration is 7000 milliliters of 1 mg/ml doxycycline hydrochloride aqueous solutions, 100 rev/mins of rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, clean 3 times with small amount of deionized water, lyophilization gets the medicine carrying hydroxyapatite micro-sphere.26.5 milligrams of the hydrochloric doxycycline of the exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, adding 20 ml concns is the PLGA dichloromethane solution of 40 mg/ml, high speed machine mixes, and must consolidate/oil (S/O) type suspension, and it is added dropwise in the aqueous solution of 200 milliliter of 2.5% polyvinyl alcohol (PVA), 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PLGA coating.
The particle diameter of the coating microsphere of the PLGA of table 1. usefulness different size and the weight ratio preparation of different PLGA/ medicine carrying hydroxyapatite micro-spheres
Wherein, prescription 1, prescription 2 and 3 the outer aqueous phase solvent of writing out a prescription are water; The outer aqueous phase solvent of other prescriptions is a simulated body fluid.
When the weight ratio of PLGA/ medicine carrying hydroxyapatite micro-sphere more than or equal to 4 the time (prescription 1 and prescription 2), resulting coating hydroxyapatite micro-sphere particle diameter is bigger, and each coating microsphere contains a plurality of hydroxyapatite micro-spheres.Other prescription gained coating microspheres, the particle diameter (11.4 ± 5.3 microns) of hydroxyapatite micro-sphere relatively increases seldom before its mean diameter and the coating, examine under a microscope in visible each microsphere only to contain 1, or a few hydroxyapatite micro-sphere.Microphotograph by prescription 1 and prescription 4 prepared coating microspheres is seen accompanying drawing 1.
Embodiment 2: the vitro drug release character that is loaded with lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere of doxycycline hydrochloride
The vitro drug release experimental technique is as follows: the precision weighing medicine carrying microballoons is an amount of, place 10 milliliters of tool plug plastic test tubes, add release medium (pure water) 4 milliliters, place (25 ℃ of water bath with thermostatic control shaking tables, 120 rev/mins) in, took out centrifugal (8000 rev/mins respectively at 0.25 day, 0.5 day, 1 day, 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days and 7 days, 5min) get supernatant 3mL, add pure water 3mL.Get supernatant determined by ultraviolet spectrophotometry medicament contg, calculate doxycycline hydrochloride cumulative release amount.
Do not write out a prescription 3 among coating hydroxyapatite micro-sphere, the embodiment 1, prescription 5, prescription 6 and write out a prescription 7, and see accompanying drawing 2 with the cumulative in vitro drug release discharge curve of the PLGA microsphere of method preparation.The cumulative in vitro drug release discharge curve of the hydroxyapatite micro-sphere of different size PLGA coating relatively see accompanying drawing 3.
The weight ratio of PLGA and hydroxyapatite micro-sphere has a significant effect to drug release rate, and the PLGA proportion is big more, and then coating thickness is big more, and drug release is slow.Hydroxyapatite micro-sphere is tangible rapid release, and 8 hours release percentage rate reaches 60%, and drug slow discharges subsequently.There is significantly prominent releasing in the PLGA microsphere, and it is about 10% to discharge percentage rate in 12 hours, and release rate slowly increases subsequently, and burst size almost no longer increases after 72 hours.And the hydroxyapatite micro-sphere of PLGA coating all occurs significantly dashing forward releasing phenomenon, discharges medicine with approaching constant speed after 8 hours.
The sign viscosity of PLGA is also influential to the slow release of medicine, and the viscosity of the big more then PLGA of IV solution is big more, and molecular weight is high more, and drug release is slow.
Embodiment 3: preparation and the drug disposition releasing properties and the blood drug level-time graph of injection that is loaded with lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere of doxycycline hydrochloride
Get the coating and the microsphere that carries doxycycline hydrochloride of coating not, the gamma-radiation radiation sterilization.In sterile cabinet, the coating microsphere of sterilizing is scattered in respectively in the 0.5% sodium carboxymethyl cellulose aqueous solution for injection of sterilization, mixing gets the doxycycline hydrochloride micro-balloon injection.
Get about 0.2 milliliter of micro-balloon injection, the administration of mouse back subcutaneous injection with 1 milliliter of syringe.Respectively at 2 hours, 6 hours, 12 hours, 24 hours and 48 hours (unentrapped medicine hydroxyapatite micro-sphere) after the administration and 0.5 day, 1 day, 2 days, 3 days, 4 days and 5 days (coating medicine carrying hydroxyapatite micro-sphere), mouse orbit is got blood, whole blood places 8000 rev/mins of centrifuge tubes that contain heparin centrifugal 10 minutes, get upper plasma, refrigerator is freezing standby; Disconnected neck is put to death mice, cuts off skin of back, can be observed the microsphere that is wrapped, and it is separated with the skin passivity, puts in 5 milliliters of tool plug centrifuge tubes, and refrigerator is freezing standby.With blood plasma and microsphere handle respectively extract medicine after, measure with high performance liquid chromatography, calculate blood plasma Chinese medicine concentration and remain in the dose that does not discharge in the microsphere.
Be loaded with the hydroxyapatite micro-sphere of doxycycline hydrochloride and PLGA coating the administration of hydroxyapatite micro-sphere mouse subcutaneous injection after, accumulation drug release discharge curve is seen accompanying drawing 4 in the body, blood drug level-time graph is seen accompanying drawing 5 in the body.
Compare with hydroxyapatite micro-sphere, after the hydroxyapatite micro-sphere mouse subcutaneous injection administration of PLGA coating, drug disposition discharges and is bright slow, and blood drug level is more steady.
Embodiment 4: lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere that is loaded with octreotide acetate
Get 10 gram hydroxyapatite micro-spheres, adding concentration is 100 milliliters of 2 mg/ml octreotide acetate aqueous solutions, 100 rev/mins of rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, clean 3 times with small amount of deionized water, lyophilization gets the medicine carrying hydroxyapatite micro-sphere.The exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram contains 12.7 milligrams of octreotide acetates.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, add the PLGA that 20 ml concns are 10 mg/ml (LA/GA=50/50, IV=0.28dl/l) dichloromethane solution mixes, get S/O type suspension, it is added dropwise in the PBS solution of 300 milliliter of 2.5% polyvinyl alcohol (PVA), and 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PLGA coating.
PLGA coating hydroxyapatite micro-sphere envelop rate is 72.9%, and mean diameter is 16.7 μ m, and the method for pressing among the embodiment 2 is measured release, and the drug release percentage rate reached more than 90% in 5 days, and cumulative in vitro drug release discharge curve is seen accompanying drawing 6.
Embodiment 5: lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere that is loaded with Cucurbitacin B
Get 5 gram hydroxyapatite micro-spheres, adding concentration is 20 milliliters of 10.0 mg/ml Cucurbitacin B methanol, and 100 rev/mins of rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, vacuum drying gets the medicine carrying hydroxyapatite micro-sphere.30.5 milligrams of the exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram sulfur acid Cucurbitacin Bs.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, add the PLGA that 20 ml concns are 10 mg/ml (LA/GA=50/50, IV=0.28dl/l) dichloromethane solution mixes, get S/O type suspension, it is added dropwise in the PBS solution of 300 milliliter of 2.5% polyvinyl alcohol (PVA), and 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PLGA coating.
PLGA coating hydroxyapatite micro-sphere envelop rate is 75.3%, and mean diameter is 16.5 μ m, and the method for pressing among the embodiment 2 is measured release, and the drug release percentage rate reached 70.2% in 7 days, and cumulative in vitro drug release discharge curve is seen accompanying drawing 6.
Embodiment 6: polycaprolactone (PCL) the coating hydroxyapatite micro-sphere that is loaded with bulleyaconitine A
Get 10 gram hydroxyapatite micro-spheres, add concentration and be 50 milliliters of the alcoholic solution of 5.0 mg/ml bulleyaconitine As, 100 rev/mins of rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, use the small amount of ethanol rinse, vacuum drying gets the medicine carrying hydroxyapatite micro-sphere.The exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram contains 18.4 milligrams of bulleyaconitine As.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, add the PCL that 20 ml concns are 20 mg/ml (production of BPI company) dichloromethane solution, mix, get S/O type suspension, it is added dropwise in the PBS solution of 300 milliliter of 2.5% polyvinyl alcohol (PVA), 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PCL coating.
PCL coating hydroxyapatite micro-sphere envelop rate is 92.5%, and mean diameter is 18.9 μ m, and the method for pressing among the embodiment 2 is measured release, and the drug release percentage rate reached 74.1% in 7 days, and cumulative in vitro drug release discharge curve is seen accompanying drawing 6.
Embodiment 7: lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere that is loaded with Ang Danxiqiong
Get 50 gram hydroxyapatite micro-spheres, adding concentration is 2000 milliliters of 10.0 mg/ml hydrochloric acid Ang Danxiqiong aqueous solutions, 100 rev/mins of rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, clean 3 times with small amount of deionized water, lyophilization gets the medicine carrying hydroxyapatite micro-sphere.178.9 milligrams of the hydrochloric Ang Danxiqiong of the exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, add the PLGA that 20 ml concns are 40 mg/ml (LA/GA=50/50, IV=0.28dl/l) dichloromethane solution mixes, get S/O type suspension, it is added dropwise in the PBS solution of 300 milliliter of 2.5% polyvinyl alcohol (PVA), and 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PLGA coating.
PLGA coating hydroxyapatite micro-sphere envelop rate is 67.5%, mean diameter is 17.2 μ m, and the method for pressing among the embodiment 2 is measured release, makes release medium with the buffer of pH6.8, the drug release percentage rate reached 80.3% in 7 days, and cumulative in vitro drug release discharge curve is seen accompanying drawing 6.
Embodiment 8: polylactic acid (PLA) the coating hydroxyapatite micro-sphere that is loaded with risperidone
Get 50 gram hydroxyapatite micro-spheres, adding concentration is 1000 milliliters of 4 mg/ml hydrochloric acid risperidone aqueous solutions, 100 commentaries on classics part rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, clean 3 times with small amount of deionized water, lyophilization gets the medicine carrying hydroxyapatite micro-sphere.43.6 milligrams of the hydrochloric risperidones of the exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, add the PLA that 20 ml concns are 20 mg/ml (IV=0.28dl/l) dichloromethane solution, mix, get S/O type suspension, it is added dropwise in the PBS solution of 300 milliliter of 2.5% polyvinyl alcohol (PVA), 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PLA coating.PLA coating hydroxyapatite micro-sphere envelop rate is 81.5%, mean diameter is 18.4 μ m, press the method among the embodiment 2, respectively at 0.25 day, 0.5 day, 1 day, 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days and 15 days sampling and measuring releases, the drug release percentage rate reached 93.7% in 15 days, and cumulative in vitro drug release discharge curve is seen accompanying drawing 6.
Embodiment 9: lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere that is loaded with huperzine A
Get 5 gram hydroxyapatite micro-spheres, adding concentration is 25 milliliters of 6.0 mg/ml huperzine A alcoholic solution, 100 rev/mins of rotating speeds, 25 ℃ of constant temperature vibrations mixed 12 hours, medicine is adsorbed on the hydroxyapatite micro-sphere, filter and collect microsphere, clean 3 times with small amount of ethanol, lyophilization gets the medicine carrying hydroxyapatite micro-sphere.The exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram contains 21.3 milligrams of huperzine As.
Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.8 gram, add the PLGA that 20 ml concns are 40 mg/ml (LA/GA=25/75, IV=0.28dl/l) dichloromethane solution mixes, get S/O type suspension, it is added dropwise in the PBS solution of 300 milliliter of 2.5% polyvinyl alcohol (PVA), and 25 ℃ of following constant temperature stirred 6 hours, the volatilization organic solvent, the isolated by filtration microsphere, small amount of deionized water is cleaned 3 times repeatedly, drying under reduced pressure, the hydroxyapatite micro-sphere of PLGA coating.
PLGA coating hydroxyapatite micro-sphere envelop rate is 85.6%, mean diameter is 19.2 μ m, the method of pressing among the embodiment 2 is measured release, buffer with pH5.6 is made release medium, respectively at 0.25 day, 0.5 day, 1 day, 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days and 15 days sampling and measuring releases, the drug release percentage rate reached 73.8% in 15 days, and cumulative in vitro drug release discharge curve is seen accompanying drawing 6.
Embodiment 10: lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere that is loaded with doxycycline hydrochloride
The preparation method of PLGA coating hydroxyapatite micro-sphere comprises the following steps:
1. the preparation of hydroxyapatite micro-sphere: chemical precipitation method routinely prepares nano-hydroapatite particles.With 250 milliliters of (NH
4)
2HPO
4Solution (0.3 mol, solution 1) and 250 milliliters of Ca (NO
3)
24H
2O solution (0.5 mol, solution 2), being adjusted to pH with ammonia respectively is in the 10-11 scope.Solution 1 is slowly added in the solution 2 (Ca/P is 1.67 in the system).Stirred 2 hours, and left standstill, ageing 24 hours.The gained white precipitate is with deionized water wash 3 times, treat the nano-hydroapatite particles sedimentation after, the water on the upper strata of inclining adds water to 1/2 of original volume.Regulate 120 ℃ of spray dryer inlet temperatures, 83 ℃ of outlet temperatures, feed flow flow velocity 1.2 ml/min, spray drying gets hydroxyapatite micro-sphere, and mean diameter is 8.2 μ m.
2. absorption method prepares the medicine carrying hydroxyapatite micro-sphere and with PLGA coating medicine carrying hydroxyapatite micro-sphere: by the method medicine carrying described in the embodiment 1, prepare the medicine carrying hydroxyapatite micro-sphere of PLGA coating by the condition of prescription 6 among the embodiment 1, mean diameter be the coating medicine carrying hydroxyapatite micro-sphere of 10.7 μ m.
Embodiment 11: be loaded with the preparation method of lactic acid-ethanol copolymer (PLGA) the coating hydroxyapatite micro-sphere PLGA coating hydroxyapatite micro-sphere of doxycycline hydrochloride, comprise the following steps:
1. the preparation of hydroxyapatite micro-sphere: the chemical precipitation method by embodiment 5 total described routines prepares nano-hydroapatite particles.With 100 milliliters of (NH
4)
2HPO
4Solution (0.3 mol, solution 1) and 100 milliliters of Ca (NO
3)
24H
2O solution (0.5 mol, solution 2), being adjusted to pH with ammonia respectively is in the 10-11 scope.Solution 1 is slowly added in the solution 2 (Ca/P is 1.67 in the system).Stirred 2 hours, and left standstill, ageing 24 hours.The gained white precipitate is with deionized water wash 3 times, treat the nano-hydroapatite particles sedimentation after, the water on the upper strata of inclining adds water to 1/2 of original volume, adds doxycycline hydrochloride 5 grams, room temperature condition stirred 2 hours down.Regulate 120 ℃ of spray dryer inlet temperatures, 83 ℃ of outlet temperatures, feed flow flow velocity 1.2 ml/min, spray drying gets the medicine carrying hydroxyapatite micro-sphere, mean diameter is 8.7 μ m, 28.1 milligrams of the hydrochloric doxycycline of the exsiccant medicine carrying hydroxyapatite micro-sphere of every after measured gram.
2. absorption method prepares the medicine carrying hydroxyapatite micro-sphere and with PLGA coating medicine carrying hydroxyapatite micro-sphere: by the method medicine carrying described in the embodiment 1, prepare the medicine carrying hydroxyapatite micro-sphere of PLGA coating by the condition of prescription 6 among the embodiment 1, mean diameter be the coating medicine carrying hydroxyapatite micro-sphere of 11.4 μ m.
Embodiment 12: carry the lidocaine hydrochloride hydroxyapatite micro-sphere with the spray drying method coating
Press the method preparation described in the embodiment 4 and carry the bupivacaine hydrochloride hydroxyapatite micro-sphere.Get the exsiccant medicine carrying hydroxyapatite micro-sphere of 0.5 gram, adding 40 ml concns is the PLGA ethyl acetate solution of 25 mg/ml, mixes, and gets S/O type suspension.
Regulate 65 ℃ of spray dryer inlet temperatures, 0 ℃ of outlet temperature, feed flow flow velocity 2.0 ml/min, spray drying, reclaim organic solvent, get the coating hydroxyapatite micro-sphere, mean diameter is 17.9 μ m, only there is a hydroxyapatite micro-sphere most coating hydroxyapatite micro-spheres inside, and minority contains a plurality of hydroxyapatite micro-spheres.
Claims (9)
1. the hydroxyapatite micro-sphere of a polyester coating, it is characterized by: the inside of coating microsphere is for being assembled the hydroxyapatite micro-sphere that constitutes by nano-hydroapatite particles, the surface of hydroxyapatite micro-sphere or inner absorption are loaded with small-molecule drug, the hydroxyapatite micro-sphere polyester coating of medicine carrying, coating microsphere inside only contain 1 medicine carrying hydroxyapatite micro-sphere or the medicine carrying hydroxyapatite micro-sphere that is less than coating microsphere sum 5% are only arranged; The weight ratio of polyester and medicine carrying hydroxyapatite micro-sphere is less than 4.
2. the hydroxyapatite micro-sphere of polyester coating according to claim 1, it is characterized by: described polyester coating is biodegradable aliphatic poly ester material, is selected from polylactic acid or polylactide, polyglycolic acid or poly-Acetic acid, hydroxy-, bimol. cyclic ester, lactic acid-ethanol copolymer or lactide-glycolide copolymer, polycaprolactone and lactide-caprolactone copolymer.
3. the hydroxyapatite micro-sphere of polyester coating according to claim 1, it is characterized by: the weight ratio of polyester and medicine carrying hydroxyapatite micro-sphere is less than 2.
4. according to the hydroxyapatite micro-sphere of each described polyester coating among the claim 1-3, it is characterized in that: the mean diameter of described microsphere is between the 1-200 micron.
5. the hydroxyapatite micro-sphere of polyester coating according to claim 4, it is characterized in that: the mean diameter of described microsphere is between the 5-50 micron.
6. the hydroxyapatite micro-sphere of polyester coating according to claim 1, it is characterized by: described small-molecule drug is selected from antibiotics, local anaesthesia medicine, small peptide medicine, antitumor drug, anti-emetic and antipsychotic drug.
7. the hydroxyapatite micro-sphere of polyester coating according to claim 6, it is characterized by described small-molecule drug and be selected from doxycycline, minocycline, gentamycin, metronidazole, amikacin, tobramycin, ganciclovir, bupivacaine, lignocaine, bulleyaconitine A, lappaconitine, morphine, leuprorelin, goserelin, the brain peptide, octreotide, enkephalin, cytarabine, fluorouracil, cisplatin, methotrexate, bleomycin, cucurbitacin, Ang Danxiqiong, Ge Laxiqiong, risperidone, huperzine A, and hydrochlorate, sulfate, acetate, or the form of the salt of other types.
8. the preparation method of the hydroxyapatite micro-sphere of each described polyester coating of claim 1-7 is characterized by and comprises following steps:
1. get the suitable commercially available hydroxyapatite micro-sphere of particle diameter or prepare the spray-dried preparation hydroxyapatite micro-sphere of nano-hydroapatite particles with chemical precipitation method, behind the purification, add the drug solution of suitable concentration according to the requirement of pharmaceutical properties and drug loading, make medicine be adsorbed on the surface of hydroxyapatite micro-sphere and inner;
2. after medicine absorption reaches balance, filter or the centrifugalize microsphere medicine of flush away microsphere surface, drying;
3. adopt fluid drying technology, fluidized coating technology, spray drying technology, or other preparation techniques get the hydroxyapatite micro-sphere of coating at medicine carrying hydroxyapatite micro-sphere appearance bread one layer of polymeric clothing film, airtight, the low tempertaure storage in dry back.
9. the preparation method of the hydroxyapatite micro-sphere of each described polyester coating of claim 1-7 is characterized by and comprises following steps:
1. prepare nano-hydroapatite particles with chemical precipitation method, behind the purification, add the drug solution of suitable concentration according to the requirement of pharmaceutical properties and drug loading, make medicine be adsorbed on the surface of hydroapatite particles, spray-dried preparation medicine carrying hydroxyapatite micro-sphere;
2. adopt fluid drying technology, fluidized coating technology, spray drying technology, or other preparation techniques get the hydroxyapatite micro-sphere of coating at medicine carrying hydroxyapatite micro-sphere appearance bread one layer of polymeric clothing film, airtight, the low tempertaure storage in dry back.
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| CN104109684A (en) * | 2014-06-19 | 2014-10-22 | 中山大学附属第一医院 | Functionalized nano hydroxyapatite gene delivery material, preparation method, and applications thereof |
| CN104383594A (en) * | 2014-11-10 | 2015-03-04 | 苏州蔻美新材料有限公司 | Preparation method of polybutylene succinate/hydroxyapatite composite biological ceramic material |
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| CN107823626A (en) * | 2017-12-04 | 2018-03-23 | 安徽金太阳生化药业有限公司 | A kind of preparation method of compound cerebroprotin hydrolysate piece |
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| CN105496943B (en) * | 2015-12-16 | 2018-11-27 | 白艳洁 | Nanometer hydroxyapatite-PGE2-PLGA-MSs hydridization gel in place and preparation method thereof |
| CN105963773A (en) * | 2016-04-28 | 2016-09-28 | 南京凤源新材料科技有限公司 | Preparation method of polylactide acid glycolic acid copolymer-hydroxylapatite composite microspheres |
| CN106822066B (en) * | 2017-03-31 | 2019-10-01 | 上海交通大学医学院附属第九人民医院 | Minocycline sustained release preparation |
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