CN103284948A - Preparation and application of polymer composition loaded with sirolimus compound or its derivative - Google Patents
Preparation and application of polymer composition loaded with sirolimus compound or its derivative Download PDFInfo
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- CN103284948A CN103284948A CN 201310049051 CN201310049051A CN103284948A CN 103284948 A CN103284948 A CN 103284948A CN 201310049051 CN201310049051 CN 201310049051 CN 201310049051 A CN201310049051 A CN 201310049051A CN 103284948 A CN103284948 A CN 103284948A
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Abstract
The invention relates to a polymer composition loaded with a sirolimus compound or its derivative. The composition can have diversified forms. A necessary link includes preparing the sirolimus compound or its derivative and a polymer carrier into a micelle. Then according to needs, the micelle can be further prepared into a freeze-dried composition by a freeze-drying technology, or the micelle and other polymer and carrier can be prepared into a solid or semi-solid preparation. The polymer composition can be used for treating tumors, reducing rejection reactions after organ and tissue transplantation, promoting cell regeneration and repair, preventing excessive scar tissue growth after injury and preventing vascular restenosis and blood coagulation embolism, treating or inhibiting autoimmune diseases, and treating or inhibiting inflammation, etc.
Description
Invention field
The present invention relates to the preparation of a kind of Nano medication, and be starting material with this Nano medication, be used for oncotherapy, the anti-rejection of organ transplantation, the cicatrix reparation prevents that angiostenosis and blood coagulation thromboembolism from occurring, the application of aspects such as treatment or inhibition autoimmune disease, inflammation belongs to technical field of pharmaceuticals.
Background technology
1. the background of relevant sirolimus
Sirolimus is the inhibitive ability of immunity macrolide that is generated by moisture absorption streptomycete (Streptomyces hygroscopicus).The chemical name of sirolimus (also claiming rapamycin) is (3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 26R, 27R, 34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-, 16 hydrogen-9, the 27-dihydroxy-3-[(1R)-2-[(1S, 3R, 4R)-4-hydroxyl-3-methoxyl group cyclohexyl]-the 1-Methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido [2,1-c] [1,4] oxa-azepine hentriacotine-1,5,11,28,29 (4H, 6H, 31H)-five ketone.Its molecular formula is C
51H
79NO
13, molecular weight is 914.2, structural formula is:
Sirolimus is white to pale powder, water insoluble, but is dissolved in ethanol, methanol, chloroform, acetone and acetonitrile; Be up to now, find the potent immunosuppressant of toxicity minimum, can be used for oncotherapy clinically, the anti-rejection of organ transplantation, the cicatrix reparation prevents that angiostenosis and blood coagulation thromboembolism from occurring, treatment or inhibition autoimmune disease, inflammation etc.At present the sirolimus dosage form of using clinically have oral liquid, tablet (trade name:
) and injection (trade name:
).
Yet sirolimus belongs to the strong-hydrophobicity chemical compound, its oral formulations, oral after, enter the medication amount of blood flow seldom, bioavailability is low, only is 14% for oral solution, and unstable under the solution state; The sirolimus nanocrystal sheet of E1an company exploitation afterwards, its oral administration biaavailability also only brings up to 27%, can not keep steady blood drug level, and there are some researches show, and sirolimus is easy to be decomposed by enzyme after entering digestive tract.The sirolimus injection at renal cell carcinoma in late period (RCC) of Pfizer's research and development afterwards, it is the targeted drug of first treatment renal cell carcinoma, also be that unique specificity that goes through to go on the market suppresses the kinase whose medicine of mTOR, its injection contain dehydrated alcohol (39.5%, w/v), vitamin E (0.075%, w/v), Polyethylene Glycol (50.3%, w/v), anhydrous citric acid (0.0025%w/v).; The diluent of joining: Tween 80 (40.0%w/v), PEG400 (42.8%w/v), dehydrated alcohol (19.9%w/v)..A large amount of organic solvent dehydrated alcohol and surfactant polyethylene, Tween 80 etc. have been added in injection and the diluent.But Polyethylene Glycol, Tween 80 and ethanol have proved to have strong side reaction clinically, as allergy, haemolysis, nephrotoxicity, neurotoxicity and cardiac toxicity etc., may cause death when serious.And increase with dosage, toxic and side effects has the trend of increase, has therefore greatly limited the clinical practice of sirolimus.
Therefore, how can solve sirolimus chemical compound or derivatives thereof dissolubility in water, improve the bioavailability of rapamycin, reduce its side effect, have very important researching value and meaning.
2, the background of relevant oncotherapy
When a part of cell of health began growth out of hand, cancer had just produced, and cancer has diffusibility, can spread other position to health by blood flow and lymphsystem.Therefore treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy, and wherein operative treatment can not be removed the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.The cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth.Therefore how can improve the medicine aggregate concentration of tumor locus, reduce whole body or normal structure toxic reaction, become research direction and the focus of current entity tumor chemotherapy.
And the polymer composition of sirolimus or derivatives thereof of the present invention has following advantage: (1) nano-micelle form has higher drug loading,＞25%; Higher entrapment,＞98%; Suitable preparation method is arranged; Carrier material is biodegradable, and toxicity is lower; Suitable particle diameter (10～600nm) and form, can be used as foreign body by macrophage phagocytic, arrive reticuloendothelial system and distribute and concentrate on target sites such as liver, spleen, lung, bone marrow, lymph; To organ transplantation, especially liver transplantation has the concentration building-up effect.(2) arrive the drug-carrying nanometer particle of target site, can be different and have different drug release rates by the kind of carrier material or proportioning.Adjust carrier material kind or proportioning, can adjust the rate of release of medicine, (3) because the adhesiveness of drug-carrying nanometer particle and little particle diameter, the increase of anelasticity when namely being conducive to local application, the time of contact and the contact area that also are conducive to medicine and intestinal wall improve the bioavailability that drug oral absorbs.(4) can prevent medicine hydrolysis under the stomach acidity condition, and can reduce the chance that digestive enzyme such as medicine and pepsin contact greatly, thereby improve the stability of medicine in gastrointestinal tract.(5) drug-carrying nanometer particle can change the film operative mechanism, increases medicine to biomembranous permeability, is conducive to drug transdermal and absorbs and the interior drug effect performance of cell, improves oral administration biaavailability.
3, relevant cicatrix recovery technique background
Scar tissue formation, adhesion and angiostenosis are to adopt the abdominal part of classical opening and arthroscope/laparoscopy program, nerve, spinal column, blood vessel, chest or other types operation subject matter afterwards after the too much operation.Usually cause wound healing reaction fully and rapidly at body, produce through after the tissue that reproduces, repairs, part as the normal healing process of damaging forms scar tissue, but in some cases, normal agglutination also may cause too much scar tissue.And too much the generation of scar tissue is influence operation and healing result's subject matter.For example in eyes, operation back cicatrization can determine the consequence of performing the operation.Particularly in blinding disease glaucoma, adopt some anti-cicatrization systems to improve the operation for glaucoma result at present, but because severe complications, clinical application is limited.Other comprise adhesion release operation, angioplasty, spinal operation, vascular surgery and operation on heart etc. because too much scar tissue produces negative influence operation healing example.The effort that forefathers do for solution operation back cicatrization problem has the mitotic inhibitor that adopts high cell toxicity, for example anthracene nucleus element, daunorubicin, ametycin etc.The state of the art is to lack operation back and post-traumatic compound treatment, with the formation of remarkable minimizing scar tissue.
But sirolimus interference cell cycle G0 or the progress of G1 phase reduce cell proliferation, therefore can be used for reducing the too much scar tissue formation at operation or epidermal wound position.Although the purposes base of sirolimus reason is known, the compositions of neither one parcel sirolimus is successfully gone on the market for this purposes so far; Therefore research and development can make sirolimus easily be administered to wound site, can not omit any position of sufferer tissue, slowly discharge medicine, its slowly biodegradation of parcel substrate simultaneously, thus the pharmaceutical preparation or the compositions that effectively prevent too much scar tissue growth have very great economic worth and social meaning.
And the polymer composition of sirolimus or derivatives thereof of the present invention, can micellar conformation, directly local injection administration, perhaps with the nano-hydrogel state, evenly be applied in site of injury, medicine slowly is discharged into damage location from nanoparticle, gel, is absorbed by cell or tissue.
4, the relevant anti-rejection of organ transplantation
Rapamycin (RAPA) is a kind of novel macrolide immunosuppressants.Rapamycin is by different cytokine receptor disabling signal conduction, and blocking-up T lymphocyte and other cells are by the process of G1 phase to the S phase, thus the performance immunosuppressive effect.From clinical practice, rapamycin has good anti-repulsive interaction, and with immunosuppressant such as Ciclosporin A (CsA) and FK506 good synergism is arranged, and is a kind of good effect, low toxicity, the neotype immunosuppressant of no nephrotoxicity.1999, the advantage that FDA's approval rapamycin is compared calcineurin inhibitors as immunosuppressant for the renal transplantation rapamycin was lower Toxicity of Kidney.Prolonged application transfers the organ transplantation patient of calcium inhibitors of phosphatases can tend to develop into impaired renal function, even chronic renal failure, uses rapamycin then can avoid.Rapamycin is particularly useful for carrying out because of hemolytic uremic syndrome the patient of renal transplantation, if use calcineurin inhibitors then may cause this palindromia.Rapamycin can use separately, also can share with calcineurin inhibitors, as tacrolimus or mycophenolate.Rapamycin may exist wound healing obstacle and thrombocytopenic side effect; Therefore, some organ transplantation centers can't be used rapamycin immediately after transplant operation, but several weeks or several months just begin to use after surgery.But there are same problem in rapamycin and tacrolimus, are exactly to have added a large amount of organic solvent dehydrated alcohol and surfactant polyethylene etc. in its injection and the diluent.Polyethylene Glycol and ethanol have proved to have strong side reaction clinically, as allergy, haemolysis, nephrotoxicity, neurotoxicity and cardiac toxicity etc., may cause death when serious.And increase with dosage, toxic and side effects has the trend of increase, has therefore greatly limited the clinical practice of sirolimus.
And the polymer composition of sirolimus or derivatives thereof of the present invention has following advantage: (1) nano-micelle form has higher drug loading,＞25%; Higher entrapment,＞98%; Suitable preparation method is arranged; Carrier material is biodegradable, and toxicity is lower; Suitable particle diameter (10～600nm) and form, can concentrate target sites such as being distributed in liver, spleen, lung, bone marrow, lymph than regular solution; To organ transplantation, especially liver, renal transplantation have the concentration building-up effect.(2) arrive the drug-carrying nanometer particle of target site, can be different and have different drug release rates by the kind of carrier material or proportioning.Adjust carrier material kind or proportioning, can adjust the rate of release of medicine, discharge medicine for a long time; The patient need take medicine for a long time after the organ transplantation, and this invention can obviously improve patient's compliance, improves curative effect.
5, angiostenosis and blood coagulation embolotherapy background
The disease of the blood circulation that the angiemphraxis of many people be dispersed throughout heart and other major organs causes, in this crowd, some more serious angiemphraxis regular meetings cause hypertension, ischemic injury, apoplexy or myocardial infarction.Atherosclerosis can limit or hinder artery blood flow, is the main cause that causes cardiac ischemia.Percutaneous is a medical surgery through the chamber coronary angioplasty, its objective is the increase artery blood flow.Percutaneous is the main therapy of coronary stricture through the chamber coronary angioplasty, more and more uses this therapy to be because it has higher relatively success rate and the characteristics little with respect to the coronary bypass surgery operation wound.Percutaneous through the chamber coronary angioplasty be confined to can occur the unexpected obturation of blood vessel immediately and in ensuing operation, engender vascular restenosis with postoperative.Restenosis is the chronic sympton of saphenous vein bypass grafting postoperative patient in addition.Acute inaccessible machine-processed many factors that comprise, and can cause because of the fibrin of damaged part in vessel sealing and/or platelet deposition and the blood vessel of newly opening.
Percutaneous restenosis behind the coronary angioplasty of chamber is a slow pathological process that is caused by vascular injury, comprises the release of thrombosis, inflammation, somatomedin and cytokine, and cell proliferation, cell migration and extracellular matrix synthetic all can cause restenosis.At present, support is proved to be and can be effectively be used for alleviating restenosis, yet though simple support has improved percutaneous, through the angiographic success rate of chamber coronary angioplasty, but still can not eliminate the incidence rate of restenosis.And the stent drug coating shows and is conducive to reduce support and implants the subacute thrombosis in back.The damage that multiple bracket coating and compositions have been in the news and have caused for pachyhymenia in prevention and the treatment.
The polymer composition of sirolimus or derivatives thereof of the present invention, can the nano-micelle form or the hydrogel form of loading nano-micelle be applied in support, can play medicine and discharge for a long time, delay intrastent restenotic lesions.
To sum up, how can solve sirolimus chemical compound or derivatives thereof dissolubility in water, make its convenience, safety, effective when clinical practice, cause many people's attention.For example, CN200510105774.1, CN101532662B, US8053444B2, US6004973, US6197781, US2003/000835 all adopts solid dispersion technology to prepare the sirolimus preparation, but the dissolubility of sirolimus also only increases, all can not steadily discharge, not solve the narrow problem of sirolimus treatment window, and rigidly connect closely to release and sell reference preparation nanocrystalline external release, so its bioavailability can not surpass 27%, does not fundamentally solve the low problem of bioavailability.CN1919194A adopts and ciclosporin soft capsule similar techniques-self emulsifying technology, the fluid composition that has prepared sirolimus, though improved oral administration biaavailability, the gastrointestinal upset that a large amount of surfactants brings is very important, and its side effect also greatly improves.CN101032463A has adopted organic solvent to add cosolvent polyvinylpyrrolidone or hydroxypropyl beta cyclodextrin, nicotiamide prepares the sirolimus injection, but it is very prudent in the use of intravenous injection for polyvinylpyrrolidone or hydroxypropyl beta cyclodextrin, nicotiamide clinically, because its many-sided safety issue such as haemolysis are not generally approved of and are used in human body.CN 101129361 A " sirolimus lipidosome freeze-dried acanthopanax powder and preparation technology thereof " adopt liposome, and the liposome turbid liquor of or ultrasonic dispersing technology system even by the high pressure breast, lyophilizing again, its envelop rate reaches 96%, and particle diameter also has only 50～250nm, for the bioavailability of sirolimus preparation, stable aspect very big improvement is arranged, but liposome cost height, preparation technology needs special installation, and uses the organic solvent of Nitrosamines, and safety, cost are not very desirable.CN101365447 A " pharmaceutical composition that contains nanoparticle that is used for the treatment of restenotic lesions " adopts catheter perfusion that the forms such as nanoparticle, Nano capsule, liposome or nanotube contain sirolimus are applied in topical remedy's perfusion to coronary arterial wall, can effectively prevent the in-stent restenosis problem.But its nanoparticle, liposome, nanotube can not be secured in the support for a long time, and particle diameter is bigger, is unfavorable for cytophagy.And the nano-micelle that we research and develop is miscible in hydrogel, and the nano-hydrogel of preparing can effectively evenly be coated support position everywhere, reach permanent and slowly discharge medicine, and carrier can slowly be degraded, and does not have any potential safety hazard.For the cicatrix reparation, CN101094650A, CN101014299A has reported and has adopted biodegradable polymer carrier, dissolves by organic solvent, medicine is dissolved in the solution of carrier and solvent, the organic solvent that then volatilizees, medicine is dispersed in the carrier material, and its principle is identical with solid dispersion technology, though medicine can slowly discharge from carrier, medicine is not easy to enter blood, cell tissue; Its effect is unsatisfactory.
Summary of the invention
At the deficiencies in the prior art, technical problem to be solved by this invention provide a kind of load sirolimus chemical compound or and the polymer composition of derivant, be used for improving the dissolubility of sirolimus or derivatives thereof, improve its bioavailability, and reduce toxic and side effects; Improve it at the drug level of target organ, in the hope of better bringing into play curative effect.
The compositions that the present invention is used for load sirolimus chemical compound or derivatives thereof polymer can have variform, it can be the slow release nanometer micelle that exists with liquid form, also can be by the powder behind the slow release nanometer micelle freeze-drying, or based on nano-micelle, the gel that is prepared from, ointment, emulsifiable paste, solid preparation (tablet, capsule, granule) etc.It is made by biodegradable macromolecular material and sirolimus chemical compound and derivant thereof.The said composition system can control drug release effectively, and wherein biodegradable macromolecular material then can be degraded voluntarily, formed nano-micelle form, and its particle diameter is between 10nm-600nm, and drug loading is up to 40%, and envelop rate is more than 99%.According to the EPR effect, the nano-micelle of sirolimus chemical compound and derivant thereof can effectively penetrate the damaged endotheliocyte of tumor and enter tumor tissues, and owing to removing obstacles and high concentration, accumulate in tumor tissues for a long time, reach the effect of passive target administration; In order to guarantee the stable of sample, further injectable powder is made in lyophilizing, is used for the treatment of multiple solid tumor, comprises sarcoma and cancer, for example star-like glucagonoma, carcinoma of prostate, breast carcinoma, small cell lung cancer and ovarian cancer; Adult T-cell leukemia/lymphoma etc.; Or according to arriving organ-tissue, adjust size, be used for the anti-rejection of organ transplantation and the treatment of autoimmune disease; The for example alloplast of kidney, heart, liver, lung, bone marrow, pancreas, cornea, small intestinal and skin, and valvular xenograft; Treatment or inhibition host versus graft disease, treatment; Or according to disease type, treatment needs, route of administration needs, and the nano-micelle of sirolimus chemical compound and derivant thereof can be prepared into various dosage forms such as ointment, gel etc. and be used for suppressing autoimmune disease, as lupus, rheumatoid arthritis, diabetes, myasthenia gravis and multiple sclerosis; Treatment or inflammation-inhibiting, for example psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel, pneumonia (comprising asthma, chronic obstructive pulmonary disease, emphysema, acute respiratory distress syndrome, bronchitis etc.), uveitis etc.; Or based on the nano-micelle of sirolimus chemical compound and derivant thereof, be prepared into gel coat, more effectively prevention of restenosis; Make hydrogel, with the collosol state topical, enter human body after, under the body temperature condition, become gel, slowly discharge medicine, be used for to repair scar tissue, the anti-rejection of organ transplantation etc.
According to an aspect of the present invention, but provide the polymer composition of a kind of load sirolimus chemical compound and derivant thereof, it comprises the block copolymer of biodegradable hydrophilic polyglycol component and hydrophobic biodegradable component, and wherein said hydrophobicity component is the biodegradable polymer that is selected from following group: polylactic acid, poly-(6-caprolactone), polyglycolic acid, poly-(lactic acid-ethanol) and their mixture.Polymer of the present invention can prepare by ring-opening polymerization, for example, by as (A) PEG of hydrophilic component with form AB type diblock copolymer as hydrophobicity component (B) and can have methoxyl group on the end group and prepare at the PEG that the other end has a hydroxyl by using.BAB type triblock copolymer can all be that the PEG of hydroxyl prepares on two end groups by using.The dissolubility of micelle in water can be regulated by the ratio of controlling new aqueous component and hydrophobicity component; CN 101023919A, CN101002729A, though CN101002730A also uses block copolymer and loads sirolimus chemical compound or derivatives thereof, but its selected materials molecular weight, block ratio, preparation method difference, cause the preparation state difference prepared, patent report be microsphere, and patent of the present invention is to reach Nano grade, clearly dramatic difference can appear in effect in vivo, bioavailability, absorbing state.And the weight average molecular weight of the hydrophilic component of water solublity amphiphilic block copolymer of the present invention and hydrophobicity component is respectively 2000-3400 dalton and 500-4000 dalton.
Polymer composition micellar conformation of the present invention, can adopt following any one method preparation:
Method one: solvent evaporation method
A, polymer and sirolimus chemical compound or derivatives thereof are dissolved in organic solvent, then remove organic solvent fast, add water at 40～80 ℃, be self-assembled into nano-micelle;
Method two: direct lyophilization
A, with polymer and sirolimus chemical compound or derivatives thereof be dissolved in the tert-butyl alcohol or with the mixture of other solvent, obtain settled solution, carry out pre-freeze, then make lyophilized formulations according to the lyophilization processing method, add water at 40～80 ℃, be self-assembled into nano-micelle.
In the said method, used organic solvent is one or more the mixed solvent in ethanol, propylene glycol, the tert-butyl alcohol, acetonitrile, dichloromethane, acetone, trifluoroethanol or the hexafluoroisopropanol.Especially preferentially select to allow in the tert-butyl alcohol and the pharmacy organic solvent ethanol of use, can effectively reduce environmental pollution on the one hand, residual organic solvent ethanol, the tert-butyl alcohol are in process of clinical application on the other hand, and other toxicity solvents are compared in safety such as acetonitrile, dichloromethane etc. improve a lot.
Gained micelle particle diameter is 10nm-600nm, and drug loading generally can reach 2-40%, envelop rate at least 98%.Selection process is handled and can be made particle diameter reach 10nm-400nm, and the clinical practice of being more convenient for can realize high concentration, accumulate in tumor tissues for a long time, or arrives the effect in the predetermined administration tissue.
For guaranteeing the polymer micelle composition stability of formulation, to be convenient to store and transportation, the inventor has been made into lyophilized formulations.This lyophilized powder adds the injection water will form slow release automatically under the condition of giving heat nanoscale micelle before clinical use.The back particle diameter that redissolves still remains on 10nm-400nm, or even 10nm-100nm, has embodied good solubility and stability.
The polymer composition of sirolimus chemical compound or derivatives thereof of the present invention can be prepared into various forms according to clinical application, so that use.
Description of drawings
Fig. 1 is the character photo after A sirolimus micelle, B lyophilized formulations, the redissolution of C sirolimus lyophilized formulations.
Fig. 2 is sirolimus micelle transmission electron microscope photo.
Fig. 3 is that mouse body giving drugs into nose after sirolimus nano-micelle and the administration of commercially available product injection is for curve
Fig. 4 is the mouse body inner tissue scattergram after sirolimus nano-micelle and the administration of commercially available product injection
Fig. 5 is sirolimus nano-micelle and commercially available product injection oncotherapy figure
Fig. 6 is sirolimus nano-hydrogel two states-collosol state and gel state
Fig. 7 be mouse behind the abdominal cavity tumor resection, in the injecting body, become gel, through 60 days degradeds test
The specific embodiment
Following embodiment only is used for enumerating some aspect of the present invention, implements the present invention to help those skilled in the art, and they also limit scope of the present invention never in any form.
(1) be used for the treatment of tumor, organ transplantation (intravenously administrable):
Sirolimus chemical compound or derivatives thereof can be prepared into nano-micelle with polymer support, make aseptic freeze-dried powder, before the clinical use, with normal saline or glucose solution it be redissolved, vein input human body.
Embodiment 1
Respectively with 100mg methoxy poly (ethylene glycol)-poly-(6-caprolactone) copolymer (MPEG
2000-PCL
2000) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, organic solvent is removed in decompression fast, then adds the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, the filtrate lyophilizing obtains sample.
Embodiment 2
Respectively with 100mg methoxy poly (ethylene glycol)-copolymer of poly lactic acid (MPEG
2000-PLA
1700) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, the decompression remove organic solvent fast, then add the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, the filtrate lyophilizing, obtain sample, see Fig. 1, nano micellar solution transmission electron microscope collection of illustrative plates is seen Fig. 2.
12 SD rats are divided into two groups at random, 6 every group, are respectively Temsirolimus micelle sirolimus nano-micelle group and Temsirolimus injection
Sirolimus injection group.Two groups of laboratory animals are distinguished tail vein injection sirolimus nano-micelle and sirolimus injection, after administration 0.083,0.5,1,2,4,6,8,10,12, the 24h docking gets blood, blood sample is in the centrifugal 5min of 10000rpm, get upper plasma 100 μ l, measure the content of sirolimus in the blood, its medicine is seen Fig. 3 for curve.The result shows, Isodose, and behind the sirolimus nano-micelle intravenously administrable, medicine is distributed to from blood plasma in each tissue fast, and blood vessel injury is reduced.
Tissue distribution research: 30 Kunming mouses are divided into two groups at random, 15 every group, are respectively Temsirolimus micelle sirolimus nano-micelle group and Temsirolimus injection
Sirolimus injection group.Two groups of laboratory animals respectively the tail vein injection same doses (Temsirolimus micelle) nano-micelle group and (Temsirolimus injection,
The sirolimus injection after administration 0.5,2,6,12, the disconnected neck of 24h puts to death mice, is cored, tissues such as liver, spleen, lung, kidney, takes by weighing the heart, liver, spleen, lung, the about 0.05g of each tissue of kidney respectively, adds the 0.25ml normal saline, homogenate.Draw 0.25ml tissue homogenate assay determination sirolimus concentration.In tissue homogenate, add levonorgestrel (29.4 μ g/ml) 50 μ l, vortex mixing 30s.Add extractant ethyl acetate-normal hexane (40: 60) 750 μ l, 2000rpm vortex mixing 5min, the centrifugal 10min of 12000rpm.Draw supernatant and dry up in 40 ℃ of nitrogen, residue redissolves with 50 μ l methanol, vortex mixing 1min, and the centrifugal 5min of 16000rpm, 20 μ l sample introductions are analyzed, and measure the content of sirolimus in each tissue sample.Measurement result is seen Fig. 4, the result shows that sirolimus nano-micelle (Temsirolimus micelle) is at kidney, liver, tumor locus, than normal injection tangible medicine congregational rate is arranged all, this is undoubtedly gratifying effect for kidney, liver transplantation and oncotherapy.
The antitumous effect trial test:
Get the Balb/c mice, 6-8 week, 20 ± 5g, female entirely, raised 4-6 days before using, to conform; Get well-grown Mus source breast carcinoma 4T1 cell, by cell counting, adjusting cell concentration with normal saline is 2 * 10
6/ ml, every the subcutaneous place's inoculation of healthy Balb/C mice 0.1ml contains 2 * 10
5Individual cell, about four days of inoculation back can be laid one's hand on and Subcutaneous tumor, can observe tumor and obviously generate in seven days.When treating seven days left and right sides, with vernier caliper measurement tumor major diameter a and minor axis d, with formula vol=d
2* a/2 calculates gross tumor volume.
Vol: gross tumor volume,
A: the major diameter of tumor,
D: the minor axis of tumor;
Treat gross tumor volume length to 20～100mm
3, 10 Balb/C mices are divided into 2 groups at random; Every group 5: (A) sirolimus nano-micelle group (B) sirolimus injection group; Two groups equal 0,3,6,9, was administered once in 12 days, and the set time administration is administered five times altogether; Put to death all mices in the 13rd day for the treatment of, solution cuts tumor tissues, and photo is seen Fig. 5.The result shows that the nano-micelle group has the effect of obvious suppression tumor growth than sirolimus injection group.
Embodiment 3
Respectively with 100mg polycaprolactone-polyethylene glycol-polycaprolactone copolymer (PCL
800-PEG
2000-PCL
800) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, organic solvent is removed in decompression fast, then adds the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, the filtrate lyophilizing obtains sample.
Embodiment 4
Respectively with 100mg polylactic acid-polyglycol-copolymer of poly lactic acid (PLA
1000-PEG
2000-PLA
1000) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, organic solvent is removed in decompression fast, then adds the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, the filtrate lyophilizing obtains sample.
(2) be used for the treatment of tumor, organ transplantation, cicatrix reparation (topical):
Respectively with 100mg methoxy poly (ethylene glycol)-poly-(6-caprolactone) copolymer (MPEG
2000-PCL
1500) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, organic solvent is removed in decompression fast, then adds the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, filtrate for later use.Get an amount of polycaprolactone-polyethylene glycol-polycaprolactone copolymer (PCL
1100-PEG
1000-PCL
1100), add above-mentioned solution, be prepared into collosol state and see Fig. 6, inject or be applied to the tumor operation rear, or the operative site after the organ transplantation, will under the body temperature condition, become gel state.
Fig. 7 be mouse behind the abdominal cavity tumor resection, in the injecting body after, become gel, the degradeds test through 60 days.
Embodiment 6
Respectively with 100mg polycaprolactone-polyethylene glycol-polycaprolactone copolymer (PCL
850-PEG
2000-PCL
850) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, organic solvent is removed in decompression fast, then adds the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, filtrate for later use.Get an amount of polycaprolactone-polyethylene glycol-polycaprolactone copolymer (PCL
1100-PEG
1000-PCL
1100), add above-mentioned solution, be prepared into collosol state, inject or be applied to operation back tumor locus, or the operative site after the organ transplantation, under the effect of body temperature, become gel.
Embodiment 7
The emulsifiable paste prescription:
A, respectively with 100mg polycaprolactone-polyethylene glycol-polycaprolactone copolymer (PCL
850-PEG
2000-P CL
850) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, the decompression remove organic solvent fast, then add the 5ml distilled water of preheating, under stirring condition, 60 ℃ of bunchys then add recipe quantity distilled water, nipalgin.
B, with the recipe quantity liquid paraffin, white vaseline, stearic acid, glyceryl monostearate, Cera Flava place the 250ml beaker, after 80 ℃ of heating in the water-bath are dissolved, mix homogeneously, insulation is placed in water-bath, then water is added in the above-mentioned fuel tank, and the limit edged stirs, to the semi-solid that is creamy white, namely get emulsifiable paste.
During clinical use, emulsifiable paste can be applied to the operative site after the organ transplantation, or be used for the treatment of autoimmune disease, as lupus, rheumatoid arthritis, psoriasis, dermatitis, eczema, seborrhea, uveitis or be used for postoperative cicatrix reparation etc.
(3) angiostenosis and blood coagulation thromboembolism:
Embodiment 8
Respectively with 100mg polylactic acid-polyglycol-copolymer of poly lactic acid (PLA
850-PEG
2000-PLA
850) and the 15mg sirolimus be dissolved in the 3ml dehydrated alcohol, organic solvent is removed in decompression fast, then adds the 5ml water for injection of preheating, under stirring condition, 60 ℃ of bunchys are crossed 0.22 μ m filter membrane, filtrate for later use.Get an amount of polyvinyl alcohol, add above-mentioned solution, be prepared into collosol state, be applied in intravascular stent or the medication coat.
Claims (10)
1. the polymer composition of a load sirolimus or derivatives thereof, it comprises the polymer support of being made up of the block copolymer of possess hydrophilic property component (A) and hydrophobic biodegradable component (B), wherein said hydrophilic component is Polyethylene Glycol or methoxy poly (ethylene glycol), and the hydrophobicity component is to be selected from following biodegradable polymer: polylactic acid, poly-(6-caprolactone), polyglycolic acid, poly-(lactic acid-ethanol) and their mixture.
2. the polymer composition of the described sirolimus or derivatives thereof of claim 1, wherein the sirolimus derivant is CCI-779 (for sirolimus), (the hydroxyl usefulness-OR1 on the cyclohexyl ring of sirolimus replaces the derivant that O-replaces, be hydroxyalkyl at this R1, the hydroxyl alkoxyalkyl, the acyl aminoalkyl, aminoalkyl), 40-O-(2-hydroxyl) ethyl-sirolimus, 40-O-(3-hydroxyl)-propyl group-sirolimus, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl-sirolimus and 40-O-(2-acetylamino ethyl)-propyl group-sirolimus, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl-sirolimus and 40-O-(2-acetylamino ethyl)-sirolimus, wherein preferred sirolimus, CCI-779 (for sirolimus), 40-O-(2-hydroxyl) ethyl-sirolimus etc.
3. the polymer composition of the described sirolimus or derivatives thereof of claim 1, the block copolymer of wherein said hydrophilic component (A) and hydrophobic biodegradable component (B) is A-B, A-B-A or B-A-B type block copolymer, and the hydrophilic component of amphiphilic block copolymer and the weight average molecular weight of hydrophobicity component are respectively 2000-3400 dalton and 500-4000 dalton.
4. the polymer composition of the described sirolimus or derivatives thereof of claim 1, the hydrophobicity component of wherein said water solublity amphiphilic block copolymer is polylactic acid, poly-(6-caprolactone), polyglycolic acid, poly-(lactic acid-ethanol) and their mixture, preferred polylactic acid and poly-(6-caprolactone), preferred especially following copolymer: MPEG
2000-PCL
2000, MPEG
2000-PLA
1700, PCL
850-PEG
2000-PCL
850, PLA
850-PEG
2000-PLA
850
5. the polymer composition of the described sirolimus or derivatives thereof of claim 1, it is characterized in that sirolimus or derivatives thereof and polymer support are prepared into the micelle kenel, then can further adopt freeze drying technology to make freeze-dried composition as required, or micelle and other polymer, carrier solid or the semi-solid preparation made.
6. the described polymer composition with the sirolimus or derivatives thereof of claim 1, its micelle particle diameter is 10nm-600nm, and drug loading is 2-40%, and envelop rate is more than 98%.
7. a preparation method for preparing the described polymer composition with the sirolimus or derivatives thereof of claim 1 adopts the solvent evaporation method preparation, may further comprise the steps:
Polymer and sirolimus chemical compound or derivatives thereof are dissolved in organic solvent, then remove organic solvent fast, add water at 40～80 ℃, be self-assembled into nano-micelle, then add the excipient lyophilizing, make lyophilized formulations.
8. a preparation method for preparing the described polymer composition with the sirolimus or derivatives thereof of claim 1 adopts direct lyophilization preparation, may further comprise the steps:
With polymer and sirolimus chemical compound or derivatives thereof be dissolved in the tert-butyl alcohol or with the mixture of other solvent, obtain settled solution, carry out pre-freeze, then make lyophilized formulations according to the lyophilization processing method, be dissolved in water, be self-assembled into nano-micelle.
9. according to claim 7 or 8 described preparation of compositions methods, wherein used organic solvent is one or more the mixed solvent in ethanol, propylene glycol, the tert-butyl alcohol, acetonitrile, dichloromethane, acetone, trifluoroethanol or the hexafluoroisopropanol; The ethanol of permission to use in organic solvent preferred tertiary butanols and the pharmacy.
The polymer composition of load sirolimus or derivatives thereof for the preparation of the treatment tumor; After organ, the tissue transplantation, reduce rejection, promote cell regeneration and reparation; For preventing the too much scar tissue growth in damage back and preventing vascular restenosis and the appearance of blood coagulation thromboembolism; Be used for the treatment of or suppress autoimmune disease; Be used for the treatment of or the inflammation-inhibiting medicine in application.
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| CN 201310049051 CN103284948A (en) | 2012-02-29 | 2013-02-07 | Preparation and application of polymer composition loaded with sirolimus compound or its derivative |
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| CN201210048986 | 2012-02-29 | ||
| CN 201310049051 CN103284948A (en) | 2012-02-29 | 2013-02-07 | Preparation and application of polymer composition loaded with sirolimus compound or its derivative |
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| CN114939110A (en) * | 2021-02-10 | 2022-08-26 | 上海交通大学医学院附属第九人民医院 | Sirolimus drug-loaded microsphere, preparation method and application |
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| CN108619094A (en) * | 2018-06-15 | 2018-10-09 | 四川省人民医院 | A kind of nanometer formulation and preparation method thereof of anticancer natural product gambogicacid |
| CN109406650A (en) * | 2018-10-25 | 2019-03-01 | 美康生物科技股份有限公司 | Kit and detection method for four kinds of immunosuppressant drug concentrations in Accurate Determining people's whole blood |
| CN114939110A (en) * | 2021-02-10 | 2022-08-26 | 上海交通大学医学院附属第九人民医院 | Sirolimus drug-loaded microsphere, preparation method and application |
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