CN104274413A - Nanoparticles of camptothecin drugs and preparation method of nanoparticles - Google Patents
Nanoparticles of camptothecin drugs and preparation method of nanoparticles Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines and relates to hydroxycamptothecine nanoparticles and a preparation method of the nanoparticles. The nanoparticles of camptothecin drugs are prepared by adopting a solvent precipitation or/and high-pressure homogenization method; the prescription comprises hydroxycamptothecine and a stabilizer cholesterol-PEG which are in a ratio of 1 to (0.02-10); the drug loading capacity of the prepared nanoparticles of the camptothecin drugs can reach 98%; the minimum particle size can reach 115nm; the nanoparticles are stable in storage, have a good slow-release effect in vitro, and are free of initial burst release; the nanoparticles can effectively load various medicines comprising a camptothecin skeleton and compositions of the medicines; the prepared camptothecin nanosuspension is capable of significantly improving the in vivo circulating time in plasma after intravenous injection in comparison with a commercially available injection, is capable of improving in vivo tissue distribution of the drugs, displays a good antitumor effect and has a wide development prospect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to the nanoparticle of the stable camptothecine of a kind of cholesterol-PEG, its preparation method and application.
Background technology
Camptothecine comprises camptothecine, 10-hydroxycamptothecine, 7-ethyl-camptothecin, SN38,9-nitrocamptothecin etc., be insoluble drug, all have lactonic ring and good anti-tumor activity, wherein 10-hydroxycamptothecine (10-HCPT) clinical practice is the most extensive.10-HCPT (also referred to as HCPT) is one of first-line drug of clinical anticancer, and molecular formula is C
20h
16n
2o
5, molecular weight is 364.35, and have broad spectrum anticancer activity, nephrotoxicity is little, is widely used in the treatment of hepatocarcinoma, gastric cancer, tumor of head and neck, leukemia, bladder cancer etc.
HCPT poorly water-soluble, clinical normal being opened by its activated lactone ring makes sodium salt injection to use, and weak curative effect, strong toxicity, half-life are short, and need multiple dosing, patient's toleration is poor; Phenolic hydroxyl group simultaneously in structure exposes easily oxidized in atmosphere.The report of the existing preparation about hydroxy camptothecin, drug loading is lower (usual < 15%, rare > 25%) mostly, and the many existence of release in vitro are prominent releases phenomenon.
Nanoparticle is granule medicine being prepared into nanosized by diverse ways, comprises micelle, polymer nanoparticle, nano suspension etc.Owing to having larger surface area, drug-eluting speed and degree are all higher, and nanoparticle has become one of main method of the administration problem solving insoluble drug.Meanwhile, medicine is encapsulated in nanoparticle inside more, can isolate within a certain period of time, thus protect unstable medicine to a certain extent, delay metabolism after entering in body with external environment.Surface has the nanoparticle of PEG chain, can also avoid the conditioning of plasma protein after entering blood, and then is effectively lessly played long circulating action by the removing of the system of engulfing, and the medicine of encapsulating also thus prolong half-life can realize long-acting to a certain extent.If the particle diameter of nanoparticle less (within 300nm), also can due to EPR (enhanced permeation and retention) effect passive target tumor.Therefore, administration nano-drug administration system solves insoluble drug, the effective means of the especially clinical practice of insoluble anti-tumor medicament.
Nano suspension is the important branch of administration nano-drug administration system, is the microgranule by suitable technology, medicine being directly prepared into nanosized, and the drug-supplying system obtained by means of stabilizing agent carries out stablizing to it, be the one of nanoparticle.Compare with other administration nano-drug administration systems employing a large amount of adjuvant, nano suspension has many advantages: (1) in theory, nano suspension is the nanoparticle of intimate pure medicine, there is drug loading and medicine transmission efficiency to greatest extent, be particularly suitable for the oral of heavy dose of insoluble drug and drug administration by injection; (2) applied widely, no matter be the medicine being insoluble in water, or water, oil all indissoluble medicine, certain method all can be utilized to obtain corresponding nano suspension, and realize industrialized great production by relevant art.Nano suspension prescription composition is simple, technique simple, preparation fast, after dry, gained powder is prepared into the different dosage form such as oral, injection, external further as intermediate, is convenient for carrying, raising patient compliance.
Summary of the invention
An object of the present invention is to provide that a kind of preparation method is easy, drug loading is high, stability is high, the nanoparticle of the anticancer therapeutic that can realize the inside and outside slow release of hydroxy camptothecin and other camptothecines, improve its distribution in vivo, strengthen.
A nanoparticle for camptothecine, is made up of camptothecine and stabilizing agent, and the mass ratio of medicine and stabilizing agent is 1: 0.02 ~ 10.
A nanoparticle for camptothecine, the stabilizing agent selected is cholesterol-poly(oxyethylene glycol) (chol-PEG).
Two of the object of the invention is the preparation method of the nanoparticle providing a kind of camptothecine, the present invention adopt be solvent deposition or solvent deposition associating high pressure homogenize method prepare nanoparticle, technical scheme is as follows:
(1) be dissolved in can in the organic solvent miscible with water for camptothecine and stabilizing agent;
(2) under ultrasonic or stirring condition, the organic solvent containing medicine and stabilizing agent is added to the water;
(3) reduce pressure rotary evaporation or dialysis removing organic solvent, or adding aqueous suspension after high speed centrifugation (can't detect nanoparticle to supernatant to exist) collecting precipitation;
(4) high pressure homogenize reduces particle diameter further if desired.
Above-mentioned preparation method, is characterized in that: the organic solvent described in step (1) is selected from the mixed system of the one or two or more in DMSO, DMF, methanol, ethanol, propanol, acetonitrile, isopropyl alcohol, PEG400, PEG600; Or above solvent and ethyl acetate, dichloromethane, chloroform equal the mixed system of the not miscible organic solvent of water, if mixed system can and water miscible while can drip dissolved substance and adjuvant very well.Medicine concentration is in organic solvent 0.001% ~ 20% (w/v), and the concentration of stabilizing agent is 0.001% ~ 50% (w/v); In step (2), the volume ratio of organic solvent and aqueous phase is 1: 2 ~ 100 (v/v); Step (3) high speed centrifugal condition is the centrifugal 1 ~ 60min of 2000 ~ 60000rpm, supernatant discarded, precipitates the ultrasonic redissolution that adds water; Step (4) high pressure homogenize condition is temperature 0 ~ 80 DEG C, pressure 500-4000bar, wherein ideal homogeneous condition be 25 DEG C, 2000 ~ 2500bar, >=10 circulations.
Step (3) and step (4) can also pass through the solidification further such as lyophilization, atomizing freeze drying or spraying dry, freeze drying protectant used can be one or both and two or more combinations in PVP, glucose, trehalose, maltose, galactose, mannitol, and preferred PVP is freeze drying protectant; The consumption of freeze drying protectant is the 10-200% of nanoparticle weight, the freeze drying protectant of the 20-50% of preferred nanoparticle weight.
When step (3) and step (4) are by lyophilization, atomizing freeze drying solidification; at some time (as Cholesterol-PEG600, suitable medicine carry ratio); even can any freeze drying protectant; direct lyophilizing, can be redeveloped into original nanometer disperse system after adding water.
Three of object of the present invention is to provide a kind of hydroxycamptothecin nano grain preparing the application in injection, and described injection comprises injection and aseptic powder injection.Hydroxycamptothecin nano grain Aqueous dispersions medium of the present invention by the isotonic system of D/W furnishing 5% glucose physiology of high concentration, can adapt to clinical practice.Hydroxycamptothecin nano grain lyophilized powder of the present invention can add appropriate aseptic medicinal 5% D/W dilution, is reconstructed into the dispersion for intravenously administrable, adapts to Clinical practice.
The advantage of nanoparticle of the present invention is: (1) prescription is simple, minimum can only containing medicine and stabilizing agent cholesterol-PEG; (2) drug loading can up to 98% simultaneously mean diameter can be less than 200nm, there is very high medicine transmission efficiency, easily realize the passive target to tumor simultaneously; (3) release in vitro is prominent releases, even if the high drug load more than 90% does not observe significantly to dash forward yet release phenomenon; (4) freeze drying protectant consumption is few, even if up under the drug loading of 90%, DO weight 25% freeze drying protectant can realize lyophilizing after the reconstruction that adds water; (5) (10-98%) adjustment in the scope that drug loading can be very wide more as required, when low drug loading, nanoparticle exists with the form of micelle.
Nanoparticle of the present invention proves through rat Pharmacokinetic experiments, long circulating and slow release successful, and plasma A UC comparatively injection significantly improves, apparent half-life significant prolongation.
Nanoparticle of the present invention proves through tumor-bearing mice experiment, can improve the distribution of medicine, largely achieve the passive target to tumor, contributes to improving drug effect, reduces toxic and side effects.
Nanoparticle of the present invention proves through tumor-bearing mice effect experiment, shows the antitumor drug effect that more commercially available camptothecine injection is much better, is a kind of up-and-coming drug delivery system for oncotherapy.
Nanoparticle technique of the present invention is simple, and composition is simple, is easy to production control, has wide industrialization prospect.
Accompanying drawing explanation
Fig. 1 is the average particle size distribution figure in embodiment 1 before and after hydroxycamptothecin nano grain high pressure homogenize
Fig. 2 is the stereoscan photograph (× 19000) in embodiment 1
Fig. 3 is transmission electron microscope photo (× 19000) in embodiment 1
Fig. 4 is that X-powder diffraction spectrum in embodiment 1 (is followed successively by hydroxycamptothecin nano grain, the former medicine of hydroxy camptothecin and stabilizing agent chol-PEG from top to bottom
600physical mixture, the former medicine of hydroxy camptothecin)
Fig. 5 is the In-vitro release curves of hydroxy camptothecin in PBS (n=3) in embodiment 1
Fig. 6 is the In-vitro release curves of hydroxy camptothecin in water (n=3) in embodiment 1
Fig. 7 is the relation curve (n=8) of serum level and time variations in embodiment 1
Fig. 8 is tumor-bearing mice body weight change curve (n=6) in time in embodiment 1
detailed description of the invention
Several embodiments of the present invention will be described below, but content of the present invention is not limited to this completely.
Embodiment 1
Take hydroxy camptothecin 25mg, Chol-PEG
6002.5mg is dissolved in 1mL DMF, be heated to 80 DEG C, be injected into rapidly in the 5mL water of 4 DEG C, inject complete, 250Hz, 4 DEG C of ultrasonic 30min, the centrifugal 1h of 14000rpm, abandon supernatant (remove DMF), be deposited in 60 DEG C, the ultrasonic 15min of 250Hz is dispersed in 5mL water again, 25 DEG C, namely 2000bar, 12 circulation high pressure homogenize obtain nanoparticle, mean diameter is 115.0nm (Fig. 1), and polydispersity index (PDI) is 0.168.
Redissolve after preserving 60 days by direct for the not lyophilizing of hydroxycamptothecin nano grain 4 DEG C, particle diameter 117.3nm, has good stability.Not with after protective agent lyophilizing in 4 DEG C of preservations, redissolve after half a year, particle diameter is 120.6nm, and long-time stability are good again.
Embodiment 2
Take hydroxy camptothecin 25mg, Chol-PEG
10002.5mg is dissolved in 1mL DMF, be heated to 80 DEG C, be injected into rapidly in the 5mL water of 4 DEG C, inject complete, 250Hz, 4 DEG C of centrifugal 1h of ultrasonic 30min, 14000rpm, be deposited in 60 DEG C, the ultrasonic 15min of 250Hz be dispersed in 5mL water again, 25 DEG C, namely 2000bar, 12 circulation high pressure homogenize obtain nanoparticle, mean diameter is 126.0nm.
Embodiment 3
7-ethyl is claimed to get hydroxy camptothecin 25mg, Chol-PEG
20002.5mg is dissolved in 1mL DMF, be heated to 80 DEG C, be injected into rapidly in the 5mL water of 4 DEG C, inject complete, 250Hz, 4 DEG C of centrifugal 1h of ultrasonic 30min, 14000rpm, abandon supernatant (removing DMF), be deposited in 60 DEG C, the ultrasonic 15min of 250Hz is dispersed in 5mL water again, 25 DEG C, namely 2000bar, 12 circulation high pressure homogenize obtain nanoparticle, mean diameter is 131.0nm.
Embodiment 4
Take 9-nitro camptothecine 12.5mg, camptothecine 12.5mg, Chol-PEG
500010mg is dissolved in 1mL DMF-EtOH (4: 1, v/v) in, be heated to 50 DEG C, be injected in the 5mL water of 4 DEG C, 250Hz, 4 DEG C of centrifugal 1h of ultrasonic 30min, 14000rpm, abandon supernatant (removing DMF), be deposited in 60 DEG C, the ultrasonic 15min of 250Hz is dispersed in 5mL water again, mean diameter is 167.0nm.
Embodiment 5
Take camptothecine 5mg, hydroxy camptothecin 10mg, SN38 10mg, Chol-PEG
500015mg is dissolved in 1mL DMF-acetone (4: 1), be heated to 40 DEG C, drop in the 5mL water of 4 DEG C, inject complete, 250Hz, 4 DEG C of centrifugal 1h of ultrasonic 30min, 14000rpm, abandon supernatant (removing DMF), be deposited in 60 DEG C, the ultrasonic 15min of 250Hz is dispersed in 5mL water again, mean diameter is 179.0nm.
Embodiment 6
The nanoparticle lyophilizing of preparation 5mg/mL concentration, after coated with gold 6min, taken pictures by scanning electron microscopic observation, accelerating potential is 30mV (Fig. 2); The suspensoid of preparation 5mg/mL concentration, draws 6 μ L and drips on 300 object copper mesh, naturally dry in air, and rear use 0.1% phosphotungstic acid dyeing 10min, observes the form (Fig. 3) of particle under transmission electron microscope.
Embodiment 7
X-powder x ray diffraction collection of illustrative plates is shown in Fig. 4, sample measurement parameter: Cu target pipe irradiates,
, 40kV, 100mA, walk wide: 0.01 °, sweep limits: 3-70 °, and result known hydroxycamptothecin nano grain Chinese medicine exists with crystalline forms.
Embodiment 8
The extracorporeal releasing experiment of hydroxycamptothecin nano grain
Scheme: experiment adopts Bag filter method to carry out extracorporeal releasing experiment to hydroxycamptothecin nano grain, contrasts with commercially available carboxylic acid type alkyl camptothecine injection (Injections) simultaneously.Get each 1mL of above sample (pastille 200 μ g) in bag filter (MWCO=3500), be placed in 100mL release medium respectively, in 37 DEG C, constant temperature stirs under 100rpm condition, each time point gets the outer liquid HPLC survey of 1mL release medicament contg wherein, supplements the isopyknic release medium of isothermal simultaneously, calculates Accumulation dissolution, release medium adopts PBS buffer salt or the pure water of 0.1mol/L, pH7.4, same sample parallel laboratory test 3 parts.
Result: nanoparticle significantly enhances the slow release effect of medicine, equal energy slow release 72h (Fig. 5 and Fig. 6) in water or PBS medium, release behavior is close to Zero order release.
Embodiment 9
Hydroxycamptothecin nano grain pharmacokinetic
Laboratory animal: healthy SD rat 16, male, body weight 200 ~ 220g.
Dosage regimen: be divided into two groups at random.Before administration, fasting 12h, freely drinks water.With the dosage of 5mg/kg respectively intravenous injection give hydroxycamptothecin nano grain and commercially available injection.
Sample collecting: after administration 5,15,30,60,120,240,480, get blood 0.5mL, 5000rpm centrifuging and taking supernatant blood plasma after 720min eye socket; Get the blood plasma 200 μ L that collects in EP pipe, add glacial acetic acid 20 μ L, transform 3h (carboxylic acid type is changed into lactone type) in dark place; Add ethyl acetate 1mL, the centrifugal 10min of vortex oscillation 1min, 10000rpm; Get supernatant, nitrogen dries up; Residue adds methanol 200 μ L ultrasonic dissolution, crosses 0.22 μm of syringe filter, gets 20 μ L and detect with HPLC.
Result: mean blood plasma concentration data Phoenix WinNonlin (version6.1) matching, calculate pharmacokinetic parameter, pharmacokinetic parameter is as following table (n=8, mean ± commercially available injection of SD, * P < 0.01vs.):
Embodiment 10
Hydroxycamptothecin nano grain is at H22 tumor-bearing mice distribution in vivo
The foundation of animal model: after mouse H22 hepatoma carcinoma cell frozen for recovery, go down to posterity under being inoculated in 5 ICR male mice abdominal cavities.According to sterile working's program, putting to death mice after 7 days, take out the ascites containing H22 cell, is 1 × 10 by physiological saline solution adjustment tumor cell suspension concentration
6individual/mL is for subsequent use.The H22 cell (1 × 10 of the ICR male mice right oxter injection 0.2mL in 6 week age
6/ mL) normal saline suspension, tumor growth was to the 7th day, and volume is greater than 100mm
3, 80 mices screening tumor size relatively consistent are tested.
Dosage regimen: get tumor-bearing mice 80, be divided into commercially available injection and nanoparticle 2 groups at random, before administration, fasting 12h, freely drinks water, according to the administration of 8mg/kg dosage tail vein injection.
Sample collecting: after administration 0.5,1,4,8,24h pluck eyeball get blood after de-cervical vertebra put to death mice; Core, liver, spleen, lung, kidney, brain and tumor tissues, normal saline cleans floating blood, and filter paper blots; Each tissue adds 3 times of quality normal saline tissue homogenates after weighing; Centrifugal, get each tissue homogenate 200 μ L and add glacial acetic acid 20 μ L dark place conversion 3h, add ethyl acetate 1mL, the centrifugal 10min of vortex oscillation 1min, 10000rpm; Get supernatant, nitrogen dries up, and residue adds methanol 200 μ L ultrasonic dissolution, crosses 0.22 μm of syringe filter, gets 20 μ L and detect with HPLC.Each parameter Phoenix WinNonlin (version 6.1) the Fitting Calculation.Be calculated as follows parameter according to the following formula: relative organization uptake ratio (R
e), peak concentration ratio (C
e), targeting efficiency (T
e), to assess the Targeting Effect of HCPT nanoparticle to tumor tissues.
In formula, AUC
i: the area under the drug-time curve of different tissues; N:HCPT nanometer suspension; I:HCPT injection.
Result: the more commercially available injection group of the distribution of nanoparticle group in each tissue significantly increases, the AUC especially in liver, lung, spleen, tumor
0-24hbe respectively 192.35,393.40,141.67,64.21 times of injection group.Hydroxycamptothecin nano grain and the distributed constant of commercially available injection in each tissue are as following table:
Ra＝AUC(NSps)/AUC(Inj)?Rb＝MRT(NSps)/MRT(Inj)?Rc＝C
max(NSps)/C
max(Inj)
Embodiment 11
Hydroxycamptothecin nano grain is at the antitumor drug efficacy study of H22 tumor-bearing mice
The foundation of animal model: with identical in embodiment 10.
Dosage regimen: the tumor-bearing mice screened is divided into 3 groups at random, often organize 8, except normal diet, tail vein injection administration, is administered once for every 3 days, tests 7 days.Blank group gives normal saline, and injection group is according to the commercially available injection of dosage tail vein injection of 5mg/kg, and nanoparticle group is according to the dosage tail vein injection nanoparticle of 5mg/kg.
Inspection target: at 9 o'clock in morning every day weighed Mouse Weight to 10 o'clock with electronic scale.After experiment terminates, de-cervical vertebra puts to death mice, and complete stripping swelling of the axilla tumor tissue is weighed, and calculates tumour inhibiting rate (%)=(the average tumor weight of 1-treatment group average tumor weight/normal saline group) × 100%.
Result: the Mouse Weight change curve of nanoparticle group is similar to normal saline group, shows that this treatment group does not show toxicity (figure) to mice.Under same dosage, nanoparticle shows remarkable antineoplaston, and the more commercially available injection of tumor control rate (89.83%vs.30.56%) has and shows property and strengthen, P < 0.01.Show chol-PEG
600being the effective stabilizing agent of one of the nanoparticle of antitumor drug hydroxy camptothecin, is a kind of up-and-coming drug delivery system for oncotherapy.Nanoparticle and injection to the tumour inhibiting rate of H22 tumor-bearing mice as following table (n=8, mean ± SD):
Claims (17)
1. a nanoparticle for camptothecine, is characterized in that: described nanoparticle is made up of camptothecine and stabilizing agent, and the mass ratio of medicine and stabilizing agent is 1: 0.02 ~ 10.
2. the nanoparticle of camptothecine according to claim 1, is characterized in that: described stabilizing agent is cholesterol-PEG, and its structure is shown below, and wherein R can be OH, OCH
3, OCH
2cH
3, COOH, NH
2; Wherein the molecular weight of PEG can from 200-10000, preferred molecular weight 400-5000, more preferably molecular weight 600-2000.
。
3. according to the nanoparticle of the camptothecine described in claim 1 to 2, it is characterized in that: described camptothecine, be camptothecine or the derivant with camptothecin backbone, comprise camptothecine, 10-hydroxycamptothecine, 7-ethyl-camptothecin, SN38,9-nitrocamptothecin etc.
4. the nanoparticle of the camptothecine according to claims 1 to 3, is characterized in that: described camptothecine, can be the compositions of the one or two or more medicine in the camptothecine described in claim 4.
5. the nanoparticle of the camptothecine as described in Claims 1-4, is characterized in that drug loading reaches as high as 98%, particle diameter 10-1000nm, and preferred mean diameter is at 20-200nm.
6. according to the nanoparticle of the camptothecine described in claim 1 to 5, it is characterized in that: described nanoparticle includes but not limited to nano suspension, nanocrystalline, nanoparticle, Micelle-like Nano-structure of Two etc., but does not comprise the liposome and vesicle with interior aqueous phase.
7. the nanoparticle of the camptothecine as described in claim 1 to 6, is characterized in that camptothecine is wherein exist with lactone type substantially.
8. the nanoparticle of the camptothecine as described in claim 1 to 7, is characterized in that medicine wherein has good slow releasing function, does not dash forward and releases.
9. according to the nanoparticle of the camptothecine described in claim 1 to 8, it is characterized in that: adopt one or both combinations in anti-solvent method, high pressure homogenization method to prepare.
10. the nanoparticle of camptothecine according to claim 9, is characterized in that, preparation method comprises the following steps:
(1) be dissolved in can in the organic solvent miscible with water for camptothecine and stabilizing agent;
(2) under ultrasonic or stirring condition, the organic solvent containing medicine and stabilizing agent is added to the water;
(3) reduce pressure rotary evaporation or dialysis removing organic solvent, or adding aqueous suspension after high speed centrifugation (can't detect nanoparticle to supernatant to exist) collecting precipitation;
(4) high pressure homogenize reduces particle diameter further if desired.
11., according to the preparation method of the nanoparticle of the camptothecine described in claim 9 to 10, is characterized in that: the organic solvent described in step (1) is selected from the mixed system of the one or two or more in DMSO, DMF, methanol, ethanol, propanol, acetonitrile, isopropyl alcohol, PEG400, PEG600; Or above solvent and ethyl acetate, dichloromethane, chloroform equal the mixed system of the not miscible organic solvent of water, if mixed system can and water miscible while can drip dissolved substance and adjuvant very well.Medicine concentration is in organic solvent 0.001% ~ 20% (w/v), and the concentration of stabilizing agent is 0.001% ~ 50% (w/v); In step (2), the volume ratio of organic solvent and aqueous phase is 1: 2 ~ 100 (v/v); Step (3) high speed centrifugal condition is the centrifugal 1 ~ 60min of 2000 ~ 60000rpm, supernatant discarded, precipitates the ultrasonic redissolution that adds water; Step (4) high pressure homogenize condition is temperature 0 ~ 80 DEG C, pressure 500-4000bar, wherein ideal homogeneous condition be 25 DEG C, 2000 ~ 2500bar, >=10 circulations.
12. according to the preparation method of the nanoparticle of the camptothecine described in claim 9 to 11, it is characterized in that: step (3) and step (4) can also pass through the solidification further such as lyophilization, atomizing freeze drying or spraying dry, freeze drying protectant used can be one or both and two or more combinations in PVP, glucose, trehalose, maltose, galactose, mannitol, and preferred PVP is freeze drying protectant; The consumption of freeze drying protectant is the 10-200% of nanoparticle weight, the freeze drying protectant of the 20-50% of preferred nanoparticle weight.
13. according to the preparation method of the nanoparticle of the camptothecine described in claim 9 to 11; be further characterized in that: when step (3) and step (4) are by lyophilization, atomizing freeze drying solidification; at some time (as Cholesterol-PEG600, suitable medicine carry ratio); even can any freeze drying protectant; direct lyophilizing, can be redeveloped into original nanometer disperse system after adding water.
14. according to the nanoparticle of the camptothecine described in claim 1 to 13, and can be used for preparing injection, described injection comprises injection and aseptic powder injection; Aqueous dispersions medium by the isotonic system of D/W furnishing 5% glucose physiology of high concentration, can adapt to clinical practice; Hydroxycamptothecin nano grain lyophilized powder of the present invention can add appropriate aseptic medicinal 5% D/W dilution, is reconstructed into the dispersion for intravenously administrable, adapts to Clinical practice.
The nanoparticle of 15. camptothecines as described in claim 1 to 14, after it is characterized in that drug administration by injection, the lower area of blood concentration-time curve (AUC) of better drug level, longer plasma half-life and Geng Gao can be obtained compared with conventional injection agent, and in liver, lung, drug distribution (AUC) that tumor tissues is higher.
The nanoparticle of 16. camptothecines as described in claim 1 to 14, after it is characterized in that administration, can obtain the comparatively better antitumous effect of conventional injection agent.
The nanoparticle of 17. camptothecines as described in claim 1 to 16, is characterized in that: cholesterol-PEG is absolutely necessary core stable agent; For improving the character of drug-carrying nanometer particle further, can also add has on other medicaments that the various adjuvant of acceptable is as nonessential auxiliary stabilizer, and these adjuvants include but not limited to PCL-PEG, phospholipid, polyvinyl alcohol etc.
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| CN110665003A (en) * | 2019-08-20 | 2020-01-10 | 聊城大学 | Double-drug-loading carrier-free nanoparticle and preparation method thereof |
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