CN105616361A - Preparation method of tinib drug alhumin nano preparation used for injection - Google Patents
Preparation method of tinib drug alhumin nano preparation used for injection Download PDFInfo
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Abstract
The invention belongs to the field of medicinal preparation, and relates to a preparation method of a tinib drug alhumin nano preparation used for injection. According to the preparation method, a tinib drug is dissolved in an oil phase; a mixture is prepared from the oil phase and a human serum albumin water phase; the mixture is delivered into a high pressure homogenizer for high shearing so as to obtain a nano preparation; organic solvents are removed via thin film evaporation; and a finished product is obtained via freeze drying. A solubilizer, an oil stabilizing agent, and a pH adjusting agent are added so as to ensure the stability of the nano particles, relatively small particle size, and narrow particle size distribution. Reproducibility of the preparation method is excellent; content of the tinib drug in the nano particles can be increased; corresponding sets of apparatus from laboratory scale to large-scale production scale of the adopted technologies are available; and industrial production application prospect is promising.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of injection preparation method for Buddhist nun's class medicine albumin nano preparation, slightly solubility is prepared into solubility injection albumin nano granular preparation for Buddhist nun's class medicine by this method, the method favorable reproducibility, the drug loading of nanoparticle can be greatly improved, strengthen its stability and safety, it is adaptable to industrialized production.
Background technology
Prior art discloses for Buddhist nun's class medicine is research and development in recent years the molecule targeted drug in clinical success application, such medicine is mainly used in the treatment of the cancers such as nonsmall-cell lung cancer, breast carcinoma, cancer of pancreas, renal carcinoma, melanoma, chronic myelocytic leukemia, it is mainly through selectively targeted and suppress the activity of tyrosine kinase to suppress tumor growth, and its antitumous effect is good. Wherein, imatinib listed in calendar year 2001, and clinical indication is chronic myelocytic leukemia, within 2002, was approved for treatment transitivity or the gastrointestinal malignant stromal tumors that cannot excise of performing the operation. Gefitinib is approved by the fda in the united states for, in May, 2003, the advanced Non-small cell lung that treatment chemotherapy is failed, and gets permission listing in March, 2005 in China. Lapatinib is researched and developed by GlaxoSmithKline PLC company, in 2007 by U.S. FDA approval listing, combines with capecitabine for treating late period or metastatic breast cancer. Erlotinib listed in 2004, is used for treating nonsmall-cell lung cancer, within 2007, expands indication to cancer of pancreas. What listed at present also has Dasatinib, Sutent, AMN107 etc. for Buddhist nun's class medicine. In addition, domestic the Suo Fan that has of new drug application is submitted to replace Buddhist nun, furan quinoline for Buddhist nun, Ah handkerchief for Buddhist nun to CFDA. 2009��2013 years, have 14 domestic pharmacy corporations and submitted the a kind new medicine clinic application for Buddhist nun's class medicine, relate to 23 kinds. For Buddhist nun's class medicine because its anticancer spectrum is wide, determined curative effect, it is increasingly becoming the line medication treating various cancers.
Although having many advantages for Buddhist nun's class medicine at anti-tumor aspect, but practical application also runs into a lot of difficulty. water (as gefitinib dissolubility in water only has 8.8 �� g/mL) mostly it is insoluble in for Buddhist nun's class medicine, oral administration biaavailability is relatively low (if AMN107 is 31%, ALS1306 < 20%), and the absorption of drug after oral administration is subject to medicining times, food and drug combination etc. affect, absorb variation (separately to take more daily 1 AUC such as Lapatinib and increase by 1 times greatly, with food with clothes, AUC increases by 3��4 times), cause oral administration of drugs dosage big (as pazopanib unit dosage form reaches 800mg, Lapatinib then reaches 1250mg), gastrointestinal side effect is serious. therefore, research and development are for the injection delivery systems of Buddhist nun's class medicine, and the limitation being expected to improve in its oral formulations Clinical practice is with not enough.
In recent years, the solubilising developing into insoluble drug of nanotechnology provides effective means, and wherein albumin nano granular receives significant attention because having the advantage of uniqueness. Human serum albumin (HSA) is most rich in protein in human plasma, has good aqueous solubility, stability, hypotoxicity and reduced immunogenicity. Utilize the space structure that albumin is unique, in the way of physically encapsulation or chemical bond coupling, medicine is loaded into wherein, the dissolubility of insoluble drug can be increased, significantly reduce drug toxicity, and owing to albuminous high initiative is absorbed by tumor cell, and the EPR effect of albumin nano granular, be all conducive to more effectively being delivered to medicine tumor locus, play pharmacologically active. Therefore, albumin nano preparation is possible not only to solubilising insoluble drug, it is also possible to realize the purpose of targeted medicine. 2005, paclitaxel albumin nano granular injection (the trade name Abraxane of Abraxis company of U.S. exploitation, triumphant element) obtain FDA approval listing, become the most successful story of albumin nano granular drug-supplying system, for the treatment of metastatic breast cancer, nonsmall-cell lung cancer, advanced pancreatic cancer etc., it it is the formulation for paclitaxel that curative effect is best clinically at present.
Chinese invention patent: 2012101304132 disclose about for Buddhist nun's class medicine albumin nano preparation. This research and utilization for the very high characteristic of Buddhist nun's class medicine and plasma protein binding rate (plasma protein binding rate such as Conmana > 98%, the plasma protein binding rate of Sorafenib is 99.5%), but its existence of practice display is following not enough, as, preparation method adopt magnetic agitation become breast, rotary evaporation to remove organic solvent, these methods are only suitable for the preparation of laboratory small lot, it is impossible to realize pilot-scale or industrialized production albumin nano preparation; Additionally, in order to the albumin nano granular particle diameter making preparation is little, (phospholipid consumption reaches 50��75% to add substantial amounts of phospholipid in this research, exceed albuminous consumption), phospholipid consumption is big, not only reduce drug loading (being only 2��5%) and the stability (having medicine to precipitate out for 3-6 days) of albumin nano granular, also the amount making the toxic product LYSOLECITHIN SUNLECITHIN A that its oxydrolysis produces increases, and increases the probability that the untoward reaction such as phlebitis, heating, pain, hemorrhage, allergy occur.
Summary of the invention
It is an object of the invention to for prior art exist about nanoparticle drug loading relatively low (being only 2��5%), poor stability, phospholipid consumption big (reaching 50��75%) easily causes toxic and side effects, preparation technology is difficult to the shortcoming and defect such as industrialization, there is provided a kind of injection for the preparation method of Buddhist nun's class medicine albumin nano preparation, this preparation method can increase substantially the medicament contg (drug loading reaches as high as 20%) of described preparation, strengthen stability (nanosuspension room temperature can stablize 15 days) and the safety (reduce phospholipid consumption or adjust the kind of solubilizing agent) of nanoparticle, this method is suitable to industrialized production albumin nano grain.
The invention provides a kind of favorable reproducibility, particle diameter is little and the preparation method for Buddhist nun's class medicine albumin nano granular of be evenly distributed (particle diameter be 50��200nm, PDI < 0.2). The albumin nano granular of preparation can pass through 0.22 ��m of Filter Sterile and filter, and can this most important for carry out Bolos intravenous administration.
Instant invention overcomes the defect existed in prior art, as, human serum albumin in forming due to preparation cannot pass through conventional method (such as autoclaving) sterilizing, the solidification degeneration of albumen otherwise can be caused thus having influence on the particle diameter of preparation and internal targeting characteristic, if secondly containing phospholipid solubilizing agent in preparation composition, part phospholipid under the hot conditions of sterilizing also converted into LYSOLECITHIN SUNLECITHIN A, thus causing toxicity; Prepare particle diameter albumin nano preparation that is little and that be evenly distributed be particularly suited for drug administration by injection (such as intravenously administrable).
More specifically, a kind of injection provided by the invention is for the preparation method of Buddhist nun's class medicine albumin nano preparation, it is characterised in that it includes step:
(1) being dissolved in suitable organic solvent as oil phase using a certain amount of for Buddhist nun's class medicine, add injection human serum albumin's aqueous solution (adjustment optimum pH), high speed shear emulsifying obtains colostrum;
(2) colostrum is transferred quickly in high pressure homogenizer and carries out the process that homogenizes, control homogenization pressure and cycle period to obtain satisfactory nano-emulsion;
(3) it is transferred in membrane evaporator by nano-emulsion evaporating organic solvent;
(4) cross film and adjust albumin nano granular particle diameter, filtration sterilization simultaneously;
(5) collecting nanosuspension, add lyophilizing caffolding agent, lyophilization obtains replacing Buddhist nun's class medicine albumin nano granular, before use with suitable aqueous medium disperse can the liquid preparation of injection.
In the present invention, the mixture that the organic solvent described in step (1) is individually composed by the organic solvent immiscible with water or water-miscible organic solvent forms in addition; This solvent system can include but not limited to one or several combination of dichloromethane, chloroform, ethyl acetate, oxolane, methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-Methyl pyrrolidone.
In the present invention, replace the physicochemical property of Buddhist nun's medicine for difference, the oil phase of step (1) can add phospholipid solubilizing agent, including phospholipid natural, semi-synthetic, complete synthesis and functionalization derivant thereof; The consumption of phospholipid is reduced to 50% (w/w) below by the present invention, controls in 10��45% (w/w) scope, advantageously reduces the amount of phospholipid toxicity oxide LYSOLECITHIN SUNLECITHIN A, improves the safety of preparation;
In the present invention, in step (1), the Application Range of solubilizing agent can be significantly expanded, and described solubilizing agent is selected from one or more in the high-grade aliphatic ester of polyoxyethylene castor oil (CremophorEL), PLURONICS F87, Tween 80, polyethyleneglycol-12-hydroxy stearin (SolutolHS15), vitamin E polyethylene glycol succinic acid ester (TPGS), sodium cholate, NaTDC, sucrose; Wherein, the consumption of CremophorEL is the consumption of the high-grade aliphatic ester that consumption is 0.1��5% (w/w), sucrose that consumption is 0.05��5% (w/w), sodium cholate and NaTDC that consumption is 1��15% (w/w), TPGS that consumption is 0.1��5% (w/w), SolutolHS15 that consumption is 1��5% (w/w), Tween 80 of 1��15% (w/w), PLURONICS F87 is 1��15% (w/w); Different according to pharmaceutical properties, above-mentioned solubilizing agent can join in oil phase or in albuminous aqueous solution;
In order to increase albumin nano granular to the stability for Buddhist nun's class drug encapsulation, the oil phase of step of the present invention (1) can add oils stabilizer; Described oils stabilizer includes but not limited to one or several combination of soybean oil, Oleum Cocois, olive oil, Oleum Gossypii semen, Oleum sesami, oleic acid, medium chain triglyceride, tocopherol acetate; Stabilizer volume fraction in oil phase is 0��50% (v/v), it is preferred to 0��30% (v/v);
In order to increase albumin nano granular to the stability for Buddhist nun's class drug encapsulation, the present invention; In step (1), human serum albumin's aqueous solution need to add the pH value that pH adjusting agent adjustment is extremely suitable; Described pH adjusting agent includes but not limited to organic acid, organic base or mineral acid, inorganic base. Example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, citric acid, lactic acid, fumaric acid, tartaric acid, sorbic acid, succinic acid, maleic acid, ascorbic acid, oxalic acid, benzenesulfonic acid, glutamic acid, aspartic acid, sodium hydroxide, potassium hydroxide, triethanolamine, ammonia etc.; Regulate aqueous phase pH and range for 3��9, it is preferred to 4��7.
For obtaining more excellent particle size distribution, the present invention; The volume ratio of oil phase and aqueous phase is controlled within the scope of 1:5��1:1000 by step (1), it is preferred to 1:10��1:100; It is 1:1��1:50 for Buddhist nun's class medicine and albuminous mass ratio, it is preferred to 1:4��1:20.
For preventing human serum albumin from inactivating in preparation process, the present invention; The rotating speed of the high speed shear emulsifying described in step (1) is 5000��30000r/min, it is preferred to 10000��20000r/min; Mixing time is 1��20min, it is preferred to 3��10min; For providing the instrument of high shear forces to include high-shear mixer, high-shear mixer and similar devices.
In step of the present invention (2), the temperature of high pressure homogenizer homogenizing controls in the temperature range of-10��30 DEG C, and high pressure homogenize pressure is 5000��30000psi, it is preferred to 10000��25000psi; Cycle-index is 2��40 cycles, it is preferred to 5��25 cycles;
In order to adapt to scale up test or the big needs produced, the vaporizer removing organic solvent described in step of the present invention (3) is membrane evaporator, wherein, the vacuum ranges of thin film evaporation is 5000��20000Pa, feeding temperature is 35��80 DEG C, flow is 200��500mL/min, and scraper plate rotating speed is 100��400r/min, and vaporization chamber temperature is 35��80 DEG C;
The albumin nano preparation prepared in step of the present invention (4) can pass through 0.22 ��m of microporous filter membrane one or many and filter the particle diameter to adjust nanoparticle, and degerming; The film material of described microporous filter membrane is selected from one or more in politef (PTFE), polyether sulfone (water system PES), mixed cellulose ester (water system MCE), nylon 6 (PA-6), nylon66 fiber (PA-66) and Kynoar (PVDF), it is preferred to polyether sulfone and Kynoar;
Lyophilizing caffolding agent described in step of the present invention (5) is selected from one or more in sucrose, lactose, glucose, mannitol, trehalose, maltose, erythrose, fructose, chitosan, dextran, xylitol, citric acid and sodium chloride, and consumption is 1%��20% (w/v).
What the present invention was suitable for includes but not limited to imatinib (Imatinib) for Buddhist nun's class medicine, gefitinib (Gefitinib), Conmana (Icotinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Dasatinib (Dasatinib), AMN107 (Nilotinib), Sorafenib (Sorafenib), Axitinib (Axitinib), Sutent (Sunitinib), bosutinib (Bosutinib), Wei Luofeini (Vemurafenib), pazopanib (Pazopanib), ZD6474 (Vandetanib), Ponatinib (ponatinib), Afatinib (afatinib), Rui Gefeini (regorafenib), card is rich for Buddhist nun (cabozantinib), Crizotinib (crizotinib), Da Lafeini (dabrafenib), Sibutramine Hydrochloride replaces Buddhist nun (trametinib), Tandutinib (Tandutinib), Telatinib (Telatinib), multidimensional replaces Buddhist nun (Dovitinib), Masitinib (Masatinib), Mubritinib (Mubritinib), expelling pathogens by strengthening vital QI replaces Buddhist nun (Tofacitinib), Canertinib (Canertinib), his imatinib (tamatinib), Ba Fei replaces Buddhist nun (Bafetinib), good fortune he for Buddhist nun (Fostamatinib), Suo Fan replaces Buddhist nun (Sulfatinib), furan quinoline replaces Buddhist nun (Fruquintinib), method rice replaces Buddhist nun, extra large that replaces Buddhist nun (Henatinib), fluorine imatinib (Flumatinib), ALS1306 (Allitinib), general quinoline replaces Buddhist nun (Puquitinib), AZD2171 (Cediranib), for pyrrole method Buddhist nun (Tipifarnib), Luo Nafani (Lonafarnib), PTK787 (Vatalanib), Mo Tesaini (Motesanib), Bu Linibu (Brivanib), one or more of lestaurtinib (Lestaurtinib).
The Buddhist nun's albuminoid nanometer formulation particle diameter that replaces prepared by preparation method of the present invention is 50��200nm, and envelop rate is 50��95%, and drug loading brings up to 5��20%, and organic solvent residual meets the requirements. Obtained freeze-drying powder can quickly redissolve after adding aqueous medium, and particle diameter does not significantly increase, and at room temperature placement all can remain stable for for 15 days.
The present invention is compared with the preparation method of prior art, and it has the prominent advantages that:
1. utilize high pressure homogenization technique to prepare albumin nano granular, significantly expand the range of choice of solubilizing agent in prescription, significantly reduce phospholipid solubilizing agent consumption in prescription simultaneously, add the stability of nanometer formulation and the safety of application.
2. by regulating the pH value of aqueous phase, adding the ratio of oils stabilizer, the composition of adjustment oil phase, adjustment oil phase and aqueous phase, it is thus achieved that more excellent particle size distribution and the drug loading of Geng Gao.
3. compared to rotary evaporation except organic solvent, the advantage that thin film evaporation has heat transfer efficiency height, evaporite ratio surface area is big, evaporation rate is fast, residence time of material is short, it is particularly suitable for this kind of evaporation to hot more sensitive nanoparticle of albumin.
4. the technology that the present invention adopts has corresponding from laboratory scale to the big necessary instrument produced, and is suitable for industrialized production for Buddhist nun's class medicine albumin nano granular.
For ease of understanding, the present invention below will be set forth more specifically by drawings and Examples. All include in protection scope of the present invention it is important to note that the following examples are merely to illustrate present invention, any pro forma change or correction.
Accompanying drawing explanation
The particle diameter that Fig. 1 is the nanoparticle adopting patent 2012101304132 method and this patent method to prepare in the embodiment of the present invention 3 changes over figure.
Fig. 2 be the embodiment of the present invention 5 dried frozen aquatic products and redissolve after cosmetic variation.
Fig. 3 is the stereoscan photograph of the embodiment of the present invention 6.
Fig. 4 is the In-vitro release curves of the embodiment of the present invention 15.
Fig. 5 is the cellular uptake photo of the albumin nano granular of the embodiment of the present invention 16.
Fig. 6 is that the albumin nano granular carrying Axitinib in the embodiment of the present invention 17 induces the apoptotic Fluirescence observation of 786-O and streaming quantitatively to scheme.
Fig. 7 is that after giving each preparation of Erlotinib in the embodiment of the present invention 18, HCC827 tumor volume changes over
Curve.
Detailed description of the invention
Embodiment 1: the parameter of high pressure homogenize is for preparing the impact of albumin nano granular particle diameter
Weigh a certain amount of Conmana and polyoxyethylene castor oil is dissolved in the mixed solvent of chloroform and ethanol as oil phase, join in human serum albumin's aqueous solution, the volume ratio controlling oil phase and aqueous phase is 1:20��1:80, and Conmana and albuminous mass ratio are 1:5��1:10. Utilize high-shearing dispersion emulsifying machine emulsifying (rotating speed: 5000r/min, shear time: 10min) form colostrum, it is quickly transferred in high pressure homogenizer, according to condition homogenizing each in table 1, gained nano-emulsion removes organic solvent by thin film evaporation, must carry Conmana albumin nano granular suspension.
From table 1, after high pressure homogenize pressure brings up to 15000psi from 5000psi, nanoparticle particle diameter is substantially reduced, and continues to increase homogenization pressure, and particle diameter gradually balances. Nanoparticle particle diameter also increases with homogenisation cycle number of times and constantly reduces, and after homogenizing circulates more than 8, change of size is little.
The impact on nanoparticle particle diameter of the table 1 high pressure homogenize parameter
Embodiment 2: the inventive method and patent 2012101304132 method prepare nanoparticle needed for phospholipid amount ratio relatively
Being dissolved in dichloromethane using the hydrogenated soya phosphatide of Sorafenib and different proportion as oil phase, add human serum albumin's aqueous solution that pH is 4��7, controlling oil/water phase volume ratio is 1:50��1:100, and Sorafenib and albuminous mass ratio are 1:5��1:12. Being respectively adopted the albumin nano granular of the inventive method and patent 2012101304132 method preparation load Sorafenib, and measure its particle diameter, result is in Table 2.
The consumption of the hydrogenated soya phosphatide impact on nanoparticle particle diameter in table 2 prescription
Visible, using hydrogenated soya phosphatide as solubilizing agent, when its consumption is relatively low, adopt albumin nano granular particle diameter prepared by patent 2012101304132 method bigger, only after solubilizing agent consumption is more than 60%, the mean diameter of nanoparticle is<200nm, but particle size distribution is still wider (PDI>0.3). And adopting this patent method to prepare, solubilizing agent ratio can obtain preferably particle diameter and distribution (PDI<0.2) below 40%.
Embodiment 3: the nanoparticle stability that the inventive method is prepared with patent 2012101304132 method compares
It is respectively adopted the albumin nano granular that the inventive method prepares the load Conmana of embodiment 1 with patent 2012101304132 method. Two kinds of Conmana albumin nano granular suspensions are placed in room temperature, observed its outward appearance respectively at 0,3,6,9,12,15 days and measure particle diameter (accompanying drawing 1). As a result, adopt load Conmana albumin nano granular suspension prepared by patent 2012101304132 method to occur that obvious medicine precipitated out when the 3rd��6 day, and particle diameter reaches a ��m rank. And adopt nanoparticle suspension stability prepared by the inventive method better, and do not observe the layering of obvious suspension or precipitation in 15 days, when 15 days, the particle diameter of nanoparticle has increased slightly, and is about 200nm.
Embodiment 4: the nanoparticle safety that the inventive method is prepared with patent 2012101304132 method is compared
Being respectively adopted the albumin nano granular that the inventive method prepares the load Sorafenib of embodiment 2 with patent 2012101304132 method, both are about 150nm by particle diameter. Taking Balb/c mice, male and female half and half, often group 6, respectively two kinds of Sorafenib albumin nano granulars of tail vein injection, dosage is 30mg/kg, within one week, injects twice, continuously injection two weeks, is administered for the last time and terminates rear 24h eye socket and take blood and carry out blood routine examination. Result is as shown in table 3:
Table 3 Mouse Blood conventional analysis
aP < 0.05, there were significant differences with normal saline group,bP < 0.05, there were significant differences to prepare nanoparticle group with this method
Result shows, after adopting Sorafenib albumin nano granular mice prepared by patent 2012101304132 method to inject two weeks continuously, cause the significance change of more hematological indices, reduce including erythrocyte, illustrate that blood system is had bigger toxicity by it, cause mice anemia. And leukocyte reduces, neutrophilic granulocyte significantly raises and lymphocyte reduces, illustrate that mouse immune system is also had bigger toxicity by this nanoparticle. And not causing obvious Hematological changes after nanoparticle mice intravenous prepared by this method, it was shown that its safety is better. Speculating that reason is probably: 1) the nanoparticle drug loading prepared by patent 2012101304132 method is relatively low, under identical dosage, the nanoparticle amount being expelled in Mouse Blood is many, owing to human serum albumin is foreign protein for mice, it is easy to cause immune repulsion; 2) according to embodiment 2, as prepared the particle diameter nanoparticle at about 150nm, consumption need to be added by the preparation of patent 2012101304132 method and reach the hydrogenated soya phosphatide of 80%, and this patent method only needs the consumption of about 20%, therefore greatly reduce hydrogenated soya phosphatide oxydrolysis in preparation process and produce the amount of LYSOLECITHIN SUNLECITHIN A, thus improve the safety of nanoparticle application.
Embodiment 5: the formulation and technology of Dasatinib albumin nano granular
A certain amount of Dasatinib is dissolved in chloroform as oil phase, another preparation human serum albumin's aqueous solution, add PLURONICS F87 as solubilizing agent so that it is the consumption in prescription is 1��5% (w/w), regulating aqueous phase pH is 3��6. By oil, aqueous phase mixing, controlling oil/water phase volume ratio is 1:50��1:500, and Dasatinib and albuminous mass ratio are 1:5��1:10. High cut disperse emulsification obtains the colostrum of O/W, colostrum is transferred quickly in high pressure homogenizer, in 15000��20000psi when, homogenizing 6��15 circulates to obtain nano-emulsion, thin film evaporation is adopted to remove chloroform, gained nanoparticle suspension filters through 0.22 ��m of polyvinylidene fluoride microporous filtering film, remove big particle, add the glucose of 5��10% (w/v) as lyophilizing caffolding agent, it is sub-packed in after dissolving in cillin bottle, lyophilization 48h, obtains Dasatinib albumin nano granular powder (accompanying drawing 2). Gained powder can redissolve rapidly after adding normal saline, and its particle diameter is 100��150nm, and the drug loading of Dasatinib is 8��15%, envelop rate > 80%.
The vacuum ranges of wherein said thin film evaporation is 5000��15000Pa, feeding temperature is 35��50 DEG C, and flow velocity is 200��300mL/min, and scraper plate rotating speed is 100��200r/min, and vaporization chamber temperature is 35��50 DEG C.
Embodiment 6: prepare Erlotinib albumin nano granular
A certain amount of Erlotinib is dissolved in the double solvents of dichloromethane and ethanol as oil phase, the another human serum albumin's aqueous solution preparing suitable concentration, regulating its pH is 3��7, oil phase and aqueous phase are mixed that (controlling oil/water phase volume ratio is 1:10��1:50, Erlotinib and albuminous mass ratio are 1:3��1:15), in 10000r/min emulsification pretreatment 10min, obtain colostrum. It is transferred quickly in high pressure homogenizer, homogenizing 8��15 circulation when 12000��18000psi, the nano-emulsion obtained removes organic solvent by thin film evaporation, Erlotinib albumin nano granular must be carried, scanning electron microscopic observation its outward appearance relatively rounding, monodispersity are well as shown in Figure 3), particle diameter is 70��150nm, and envelop rate is 65��90%, drug loading is 6��20%, and organic solvent residual meets regulation.
The vacuum ranges of wherein said thin film evaporation is 5000��10000Pa, feeding temperature is 40��60 DEG C, and flow velocity is 200��300mL/min, and scraper plate rotating speed is 100��200r/min, and vaporization chamber temperature is 40��60 DEG C.
Embodiment 7: prepare gefitinib albumin nano granular
Weigh a certain amount of gefitinib and be dissolved in chloroform, add after stabilizer oleic acid 20��40% (v/v) of oil phase (volume account for) mixing as oil phase, oil phase is joined in human serum albumin's aqueous solution (pH is 4��8), controlling oil/water phase volume ratio is 1:10��1:30, gefitinib and albuminous mass ratio are 1:3��1:10, and high-shear emulsifying forms colostrum. It is transferred quickly in high pressure homogenizer, homogenizing 10��25 circulation when 15000��25000psi, gained nano-emulsion thin film evaporation removes chloroform, cross 0.22 ��m of polyether sulfone (PES) microporous filter membrane and adjust particle diameter, gefitinib albumin nano granular must be carried, its particle diameter is 120��200nm, and drug loading is 9��20%.
Embodiment 8: prepare Sutent albumin nano granular
Weigh a certain amount of Sutent to be dissolved in 20mL ethyl acetate as oil phase; Separately being dissolved in 5L tri-distilled water using human serum albumin as aqueous phase, regulating aqueous phase pH is 3��6, by oil, aqueous phase mixing, utilizes high-shearing dispersion emulsifying machine emulsifying (rotating speed: 15000r/min, shear time: 5min), forms colostrum. Being quickly transferred in high pressure homogenizer, when 10000��15000psi, homogenizing 8��15 circulation, obtains nano-emulsion and removes ethyl acetate by thin film evaporation, must carry Sutent albumin nano granular suspension, and recording particle diameter is 100��160nm. Nanoparticle suspension passes through the microporous filter membrane of 0.22 ��m, and its turbidity and granular size are without significant change, and yield reaches more than 90%.
The vacuum ranges of wherein said thin film evaporation is 10000��15000Pa, feeding temperature is 50��80 DEG C, and flow is 300��500ml/min, and scraper plate rotating speed is 250��400r/min, and vaporization chamber temperature is 50��80 DEG C.
Embodiment 9: prepare Lapatinib albumin nano granular
Lapatinib and lecithin are dissolved in the double solvents of chloroform and ethanol as oil phase, lecithin consumption in prescription is 10��45% (w/w), oil phase is joined in human serum albumin's aqueous solution that pH is 4��8, controlling oil/water phase volume ratio is 1:20��1:60, Lapatinib and albuminous mass ratio are 1:5��1:15, utilize high-shearing dispersion emulsifying machine emulsifying (rotating speed: 10000r/min, shear time: 5min), form colostrum; Transfer in high pressure homogenizer, homogenizing 6��18 circulation when 15000��25000psi, obtain nano-emulsion and remove organic solvent by film evaporation method, gained nanoparticle suspension is crossed 0.22 ��m of microporous filter membrane and is adjusted particle diameter, it is sub-packed in cillin bottle after adding the trehalose dissolving of 10��20% (w/v), lyophilization 48h, obtains Lapatinib albumin nano granular powder. The particle diameter recording nanoparticle after normal saline redissolves is 100��160nm, envelop rate > 75%.
The vacuum ranges of wherein said thin film evaporation is 10000��20000Pa, feeding temperature is 50��70 DEG C, and flow is 300��400mL/min, and scraper plate rotating speed is 200��300r/min, and vaporization chamber temperature is 50��70 DEG C.
Embodiment 10: prepare imatinib albumin nano granular
Weigh a certain amount of imatinib and be dissolved in dichloromethane as oil phase; Add in human serum albumin's aqueous solution that pH is 5��9, controlling oil/water phase volume ratio is 1:20��1:50, imatinib and albuminous mass ratio are 1:8��1:16, adopt high-shearing dispersion emulsifying machine emulsifying (rotating speed: 15000r/min, shear time: 5min), form O/W colostrum; Transferring in high pressure homogenizer, when 15000��25000psi, homogenizing 6��12 circulation, obtains nano-emulsion and removes organic solvent by thin film evaporation, must carry the albumin nano granular of imatinib, and its particle diameter is 90��150nm, and drug loading is 5��10%.
Embodiment 11: preparation Wei Luofeini albumin nano granular
Wei Luofeini is dissolved in the double solvents of dichloromethane and ethanol as oil phase; Another preparation human serum albumin's aqueous solution, adds Tween 80 as solubilizing agent so that it is the consumption in prescription is 0.1��5% (w/w), and regulating aqueous phase pH is 4��7. By oil, aqueous phase mixing, control oil/water phase volume ratio and be 1:80��1:800, Wei Luofeini and albuminous mass ratio is 1:8��1:20, adopt high-shearing dispersion emulsifying machine emulsifying (rotating speed: 10000r/min, shear time: 8min), form colostrum; Transferring in high pressure homogenizer, when 10000��20000psi, homogenizing 10��25 circulation, obtains nano-emulsion and removes organic solvent by thin film evaporation, the albumin nano granular of Wei Luofeini must be carried, its particle diameter is 100��180nm, and drug loading is 5��10%, and envelop rate reaches 70��80%.
The vacuum ranges of wherein said thin film evaporation is 10000��20000Pa, feeding temperature is 35��65 DEG C, and flow is 200��400mL/min, and scraper plate rotating speed is 150��250r/min, and vaporization chamber temperature is 35��65 DEG C.
Embodiment 12: prepare pazopanib albumin nano granular
Weigh 5g pazopanib and be dissolved in chloroform, add stabilizer soybean oil 10��30% (v/v) of oil phase (volume account for) mixing as oil phase, oil phase is joined in human serum albumin's aqueous solution that pH is 3��6, controlling oil/water phase volume ratio is 1:100��1:200, pazopanib and albuminous mass ratio are 1:5��1:20, high cut disperse emulsification obtains colostrum, colostrum is transferred quickly in high pressure homogenizer, homogenizing 6��16 circulation in 15000��30000psi when, the nano-emulsion obtained removes organic solvent by thin film evaporation, the albumin nano granular of pazopanib must be carried, its particle diameter is 50��150nm, by disposable for the nanoparticle suspension polyethersulfone millipore filter filtration sterilization by 0.22 ��m, yield reaches 85%.
Embodiment 13: the formulation and technology of AMN107 albumin nano granular and repeatability checking
Weigh 10g AMN107 to be dissolved in the double solvents of chloroform and medium chain triglyceride as oil phase, join in human serum albumin's aqueous solution that pH is 4��7, the volume ratio controlling oil phase and aqueous phase is 1:20��1:60, and AMN107 and albuminous mass ratio are 1:5��1:12. Adopt high-shearing dispersion emulsifying machine emulsifying (rotating speed: 10000r/min, shear time: 15min) form colostrum, it is quickly transferred in high pressure homogenizer, when 15000��25000psi, homogenizing 12��20 circulation, obtains nano-emulsion and removes chloroform by thin film evaporation, degerming through 0.22 ��m of filtering with microporous membrane, after adding the dissolving of lyophilizing caffolding agent mannitol, it is sub-packed in cillin bottle, lyophilization 48h, obtain AMN107 albumin nano granular powder. Adopting above-mentioned condition to prepare three batches continuously, measure particle diameter and the drug loading of nanoparticle, result is as shown in table 4, it is seen that the preparation technology favorable reproducibility of nanoparticle.
4 three batches of AMN107 albumin nano granular measurement results of table
Embodiment 14: prepare Axitinib albumin nano granular
Weigh a certain amount of Axitinib to be dissolved in 20mL dichloromethane as oil phase; Separately human serum albumin and vitamin E polyethylene glycol succinic acid ester (TPGS) being dissolved in 10L tri-distilled water, making TPGS consumption in prescription is 0.05��5% (w/w), and regulating aqueous phase pH is 3��6. Oil phase and aqueous phase are mixed, high shear dispersion forms colostrum, rapidly colostrum is transferred in high pressure homogenizer, homogenizing 8��15 circulation when 15000��20000psi, obtains nano-emulsion and removes dichloromethane by thin film evaporation, and the microporous filter membrane crossing 0.22 ��m removes big particle, after adding the dissolving of lyophilizing caffolding agent sucrose, it is sub-packed in cillin bottle, lyophilization 48h, obtain Axitinib albumin nano granular powder. The particle diameter recording nanoparticle after redissolving that adds water is 100��160nm, envelop rate > 80%, organic solvent residual meets regulation.
The vacuum ranges of wherein said thin film evaporation is 10000��15000Pa, feeding temperature is 35��60 DEG C, and flow is 300��500mL/min, and scraper plate rotating speed is 250��400r/min, and vaporization chamber temperature is 35��60 DEG C.
Embodiment 15: the release in vitro of albumin nano granular
Albumin nano granular prepared by embodiment 1��14 and corresponding free drug are separately added in bag filter swelling in advance, both drug level are identical, tighten bag mouth, be respectively put into equipped with 100mL blood plasma, PBS (pH5.0), PBS (pH7.4) three kinds of release medium container in (ensure drug release carry out under sink conditions), 37 DEG C of constant temperature oscillators vibrate, timing sampling, HPLC method is adopted to measure the concentration replacing Buddhist nun's class medicine in release medium, calculate cumulative release percentage rate, and draw release profiles.
As a result, bag filter is to the free release for Buddhist nun's class medicine almost without speed limit effect, and in 12h, the cumulative release of each free drug is more than 80%; And drug-carrying nanometer particle rate of release in three kinds of release medium is slowly steady accordingly. Accompanying drawing 4 is the release profiles of embodiment 7. Visible, albumin nano granular 5d cumulative release percentage rate in three kinds of media of load gefitinib is about 60%, illustrates that albumin nano granular has good slowly releasing effect.
Embodiment 16: the cellular uptake test of albumin nano granular
By human breast cancer cell SKBr3 by 2 �� 104The concentration in individual/hole is inoculated in 24 orifice plates, cultivates 24h, and then every hole is separately added into the albumin nano granular suspension of a certain amount of load fluorescent probe Coumarin-6, hatches certain time, the picked-up to albumin nano granular of the fluorescence microscope qualitative observation SKBr3 cell.
Result is as it is shown in figure 5, SKBr3 cell can effectively absorb albumin nano granular, and cell is to the picked-up presentative time of albumin nano granular and concentration dependent.
Embodiment 17: the albumin nano granular induction 786-O Change of Apoptosis in Renal Cancer Cells test of load Axitinib
By the 786-O cell of exponential phase by 5 �� 104The density in individual/hole is inoculated in 12 orifice plates, and every hole is separately added into certain density Axitinib solution or the albumin nano granular suspension of load Axitinib, hatches 24h, simultaneously to add 786-O cell that blank RMPI1640 culture medium hatches as negative control. After hatching end, PBS washing, paraformaldehyde are fixed, and then carry out nuclear targeting with Hoechst33342, the metamorphosis of observation of cell core under fluorescence microscope; Or use 0.25% trypsin digestion cell, collect, washing, resuspended, with reference to the operation of AnnexinV-FITC cell apoptosis detection kit, flow cytometer quantitative assay.
Result is as shown in Figure 6, nucleus after solution group and the process of nanoparticle group is accordion, the nuclear chromatin high degree of coagulation of part, marginalisation, illustrate that two kinds of preparations of Axitinib have all had been turned on the apoptosis program of 786-O cell, and existing part cell is in apoptotic late period. Streaming quantitative assay apoptosis result is identical with fluorescence Qualitative observations: compared with negative control, and the cell that two preparations process is in the cell of apoptosis early stage, late period and death and significantly increases (p < 0.05); And compared to solution group, nanoparticle group is in apoptosis early stage cell after processing is more.
Embodiment 18: load Erlotinib albumin nano granular is for the therapeutic effect of nonsmall-cell lung cancer
By the Non-small cell lung carcinoma HCC827 cell of exponential phase, resuspended into about 1 �� 10 with PBS after digestion8/ mL cell suspension, is inoculated in the 4 week old male Balb/c right axil of nude mice subcutaneous, every inoculation 0.1mL cancer cell suspension.
Tumor-bearing mice is randomly divided into 6 groups, often group 10, is administered according to below scheme respectively, after administration every 2 days with the major diameter of vernier caliper measurement group nude mouse tumor and minor axis, calculate gross tumor volume according to formula: gross tumor volume=(minor axis2�� major diameter)/2, draw tumor volume and change over curve.
The dosage regimen of each experimental group of table 5
Fig. 7 is the tumor growth curve of each group, which show the gross tumor volume of each administration group and be all significantly smaller than matched group (p < 0.05) after treating 20 days, show that oral Erlotinib, intravenous injection Erlotinib solution or albumin nano granular all can effectively suppress the growth of the nonsmall-cell lung cancer of heterotopic transplantation, wherein, the tumor killing effect of Erlotinib albumin nano granular low dose group (2.5mg/kg) is similar to the tumor killing effect of oral Erlotinib suspensoid (25mg/kg), and there was no significant difference; And the middle and high dosage group of nanoparticle tumor mass reduction after being administered 16 days, it was shown that it has better tumor killing effect; Test result indicate that, the Buddhist nun's class medicine albumin nano granular that replaces obtained by the present invention has better anticancer effect than the oral formulations of existing Clinical practice.
Claims (15)
1. the preparation method that an injection replaces Buddhist nun's class medicine albumin nano preparation, it is characterised in that it includes step,
(1) being dissolved in suitable organic solvent as oil phase using a certain amount of for Buddhist nun's class medicine, add injection human serum albumin's aqueous solution, regulate optimum pH, high speed shear emulsifying obtains colostrum;
(2) colostrum is transferred in high pressure homogenizer and carries out the process that homogenizes, control homogenization pressure and cycle period obtains satisfactory nano-emulsion;
(3) it is transferred in membrane evaporator by nano-emulsion evaporating organic solvent;
(4) cross film and adjust albumin nano granular particle diameter, filtration sterilization simultaneously;
(5) collecting nanosuspension, add lyophilizing caffolding agent, lyophilization obtains replacing Buddhist nun's class medicine albumin nano granular; The liquid preparation of injection is disperseed to obtain before use with aqueous medium.
2. the method according to claim l, it is characterized in that, described is selected from imatinib for Buddhist nun's class medicine, gefitinib, Conmana, Erlotinib, Lapatinib, Dasatinib, AMN107, Sorafenib, Axitinib, Sutent, bosutinib, Wei Luofeini, pazopanib, ZD6474, Ponatinib, Afatinib, Rui Gefeini, card is rich for Buddhist nun, Crizotinib, Da Lafeini, Sibutramine Hydrochloride replaces Buddhist nun, Tandutinib, Telatinib, multidimensional replaces Buddhist nun, Masitinib, Mubritinib, expelling pathogens by strengthening vital QI replaces Buddhist nun, Canertinib, his imatinib, Ba Fei replaces Buddhist nun, good fortune he for Buddhist nun, Suo Fan replaces Buddhist nun, furan quinoline replaces Buddhist nun, method rice replaces Buddhist nun, extra large that replaces Buddhist nun, fluorine imatinib, ALS1306, general quinoline replaces Buddhist nun, AZD2171, for pyrrole method Buddhist nun, Luo Nafani, PTK787, Mo Tesaini, one or several combination of Bu Linibu or lestaurtinib.
3. the method according to claim l, it is characterised in that the mixture that described organic solvent is individually composed by the organic solvent immiscible with water or water-miscible organic solvent forms in addition; This solvent system is selected from one or several combination of dichloromethane, chloroform, ethyl acetate, oxolane, methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-Methyl pyrrolidone.
4. the method according to claim l, it is characterized in that, in described oil phase and/or aqueous phase add solubilizing agent, including phospholipid, polyoxyethylene castor oil (CremophorEL), PLURONICS F87, Tween 80, polyethyleneglycol-12-hydroxy stearin (SolutolHS15), vitamin E polyethylene glycol succinic acid ester (TPGS), sodium cholate, NaTDC, sucrose high-grade aliphatic ester in one or more.
5. method according to claim 4, it is characterised in that described phospholipid solubilizing agent includes phospholipid natural, semi-synthetic, complete synthesis and functionalization derivant thereof, its consumption is 10��45% (w/w); The consumption of CremophorEL is 1��15% (w/w); Wherein, the consumption of PLURONICS F87 is 1��5% (w/w); The consumption of Tween 80 is 0.1��5% (w/w); The consumption of SolutolHS15 is 1��15% (w/w); The consumption of TPGS is 0.05��5% (w/w); The consumption of sodium cholate and NaTDC is 0.1��5% (w/w); The consumption of the high-grade aliphatic ester of sucrose is 1��15% (w/w).
6. the method according to claim l, it is characterised in that in described oil phase add oils stabilizer, selected from soybean oil, Oleum Cocois, olive oil, Oleum Gossypii semen, Oleum sesami, oleic acid, medium chain triglyceride, tocopherol acetate one or several combination; Described stabilizer volume fraction in oil phase is 0��50% (v/v).
7. the method according to claim l, it is characterised in that described human serum albumin's aqueous solution adds pH adjusting agent and regulates to suitable pH value; Described pH adjusting agent is selected from organic acid, organic base or mineral acid, inorganic base. Example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, citric acid, lactic acid, fumaric acid, tartaric acid, sorbic acid, succinic acid, maleic acid, ascorbic acid, oxalic acid, benzenesulfonic acid, glutamic acid, aspartic acid, sodium hydroxide, potassium hydroxide, triethanolamine or ammonia; Regulate aqueous phase pH and range for 3��9.
8. the method according to claim l, it is characterised in that the volume ratio of described oil phase and aqueous phase should control within the scope of 1:5��1:1000.
9. the method according to claim l, it is characterised in that described should control within the scope of 1:1��1:50 for Buddhist nun's class medicine and albuminous mass ratio.
10. the method according to claim l, it is characterised in that it is 5000��30000r/min that the rotating speed of colostrum is prepared in described high speed shear emulsifying; Mixing time is 1��20min.
11. the method according to claim l, it is characterised in that the temperature of described high pressure homogenizer homogenizing controls in the temperature range of-10��30 DEG C, high pressure homogenize pressure is 5000��30000psi; Cycle-index is 2��40 cycles.
12. the method according to claim l, it is characterized in that, the vaporizer of described removing organic solvent is membrane evaporator, wherein, the vacuum ranges of thin film evaporation is 5000��20000Pa, and feeding temperature is 35��80 DEG C, and flow is 200��500mL/min, scraper plate rotating speed is 100��400r/min, and vaporization chamber temperature is 35��80 DEG C.
13. the method according to claim l, it is characterised in that described albumin nano preparation filters the particle diameter to adjust nanoparticle by 0.22 ��m of microporous filter membrane one or many, and degerming.
14. method according to claim 13, it is characterized in that, the film material of described microporous filter membrane is selected from one or more in politef (PTFE), polyether sulfone (water system PES), mixed cellulose ester (water system MCE), nylon 6 (PA-6), nylon66 fiber (PA-66) or Kynoar (PVDF).
15. the method according to claim l, it is characterized in that, described lyophilizing caffolding agent is selected from one or more in sucrose, lactose, glucose, mannitol, trehalose, maltose, erythrose, fructose, chitosan, dextran, xylitol, citric acid or sodium chloride, and consumption is 1%��20% (w/v).
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