CN110200920A - A kind of reduction sensitive medicaments composition and its preparation and application - Google Patents
A kind of reduction sensitive medicaments composition and its preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of reduction sensitive medicaments composition and its preparations and application, the pharmaceutical composition is the nano particle (according to circumstances further including acceptable auxiliary agent in pharmacodynamics) of double-thio nalka acid glycerol phosphocholine of alkyl two and drug composition, with the sensitive fast degradation of reduction, not only stability is good, long circulating, has the function of that targeting disintegrates and quickly releases the drug.The reduction sensitive medicaments composition passes through film dispersion method, reverse phase evaporation, freeze-drying, ultrasonic dispersion, spray drying process, film extrusion or high pressure homogenization method preparation, simple process.The reduction sensitive medicaments composition is used to prepare anti-tumor drug, antiviral drugs, antibacterials.
Description
Technical field
The present invention is a kind of reduction sensitive medicaments composition and its preparation and application, is related to pharmaceutical technology field.
Background technique
Nano particle is a kind of important pharmaceutical carrier, including liposome, solid lipid nano granule, nano-micelle etc., can
With the various drugs of loaded control release.Hydrophobic drug is usually in the lipid of nano particle.The nano particle of carrying medicament is in vivo
In cyclic process, drug is easy to leak out from nano particle, influences the performance of drug effect.
Large hydrophilic molecular such as polyethylene glycol is covered in surface of liposome, when can extend the circulation of liposome in blood
Between, also referred to as stealthy nano particle slows down the leakage of drug.Stealthy nano particle not only has the long circulating time, but also can be with
Enhance osmotic effect using tumour capillary, improves the cancer target effect of drug, improve antitumous effect.But due to
Circulation time is too long, and is easy to cause nano particle to deposit in brothers part, such as the most common administration mode of Doxorubicin is
Drug administration by injection is loaded by nano particle, but deposition of the Doxorubicin long circulating nano particle at brothers position often results in brothers
Disease.Therefore, drug-loading nanoparticles especially long circulating nano particle recycles in blood is conducive to reach tumor locus, but swollen
Tumor position needs drug release of quickly disintegrating, that is, requires certain cancer target degradation.
Inflammatory tissue, tumor tissues especially tumour cell glutathion inside concentration are much higher than normal tissue, micro- using its
Environment can promote the prodrugs containing cystine linkage or long circulating phospholipid molecule to be broken, and realize release and the active drug of drug
The raising of concentration.But the reduction sensitivity nano particle of forefathers' report generallys use normal long chain fatty acids phosphatide, cystine linkage
Fracture be not easy that nano particle is made thoroughly to disintegrate.
It is accordingly required in particular to invent a kind of existing assembling ability, and have the function of restoring sensitive targeted disruption phosphatide,
The nano particle of assembling quickly releases the drug because of sensitive thoroughly disintegrate of reduction, the defect for overcoming the drug release of long circulating nano particle too slow.
Anthracene nucleus medicament such as Doxorubicin etc. is a kind of important anti-tumor drug, but usually has cardiac toxic, marrow
Toxicity etc..Its toxicity can be reduced to a certain degree by being carried in liposome, but be easily leaked out, and be released the drug too fast.Using polyethylene glycol
The nanoparticle vector of macromolecular phosphatide building can extend pharmaceutical release time, but too long circulation time leads to nano particle
It is easy to cause brothers sick in brothers' site deposition.It is accordingly required in particular to invent a kind of tumor locus microenvironment response quickly degradation
Drug release method prevents from leaking, but is easy and fast to the drug delivery system of drug release in tumor locus.
Summary of the invention
Technical problem: the purpose of the present invention is to provide a kind of reduction sensitive medicaments composition and its preparations and application, should
Pharmaceutical composition is that the nano particle that double-thio nalka acid glycerol phosphocholine of alkyl two and drug form (is according to circumstances gone back
Including auxiliary agent acceptable in pharmacodynamics), have and restores sensitive fast degradation；It provides simultaneously a kind of based on the pharmaceutical composition
Preparation method and its preparing anti-tumor drug, antiviral drugs, the application in antibacterials.
Technical solution: the present invention provides a kind of reduction sensitive medicaments composition, which is to receive
Rice grain, including double-thio nalka acid glycerol phosphocholine of alkyl two and drug.
Wherein:
The reduction sensitive medicaments composition further includes acceptable auxiliary agent in pharmacodynamics.
The reduction sensitive medicaments composition is in nano particle, and nano particle is liposome, solid lipid nano granule
Or micella, and grain diameter is 10~1000nm.
The general structure of the double-thio nalka acid glycerol phosphocholine of alkyl two is as follows:
In formula, m is 2~10 positive integer, and n is 7~15 positive integer.
The drug is anti-tumor drug, antiviral drugs or antibacterials.
The anti-tumor drug is taxol, Docetaxel, Cabazitaxel, camptothecine, hydroxycamptothecin, 7- second
Base -10-hydroxycamptothecine, Irinotecan, topotecan, Lurtotecan, Belotecan, 7- methylol camptothecine, vincristine,
Vinorelbine, Ansamycin, rapamycin, cytarabine, Etoposide, mitoxantrone, Doxorubicin, zorubicin, table are soft
Than star, idarubicin, Sha bar than one of star, tamoxifen, triptolide, rice lumbering peptide, ursolic acid or platinum medicine.
The platinum medicine includes cis-platinum, carboplatin, oxaliplatin, Nedaplatin, Lobaplatin or cis--bis- trans--R of neodecanoic acid-,
R-1,2- cyclohexyl diamine closes platinum (II).
The antibacterials are amphotericin B, gentamicin, nystatin, Fluconazole, amikacin, levofloxacin
One of star or econazole nitrate.
Antiviral drugs is Ribavirin or Aldoforwe ester.
Acceptable auxiliary agent is that phosphatide, glyceride, fatty acid, tween, poloxamer or gallbladder are solid in the pharmacodynamics
One of alcohol is a variety of.
The phosphatide includes lecithin, synthetic phospholipid.
The phosphatide includes targeting phosphatide.
The phosphatide includes glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol and glycerol disterate phosphatidyl second
Hydramine-polyethylene glycol-folic acid.
The present invention also provides a kind of preparation method for restoring sensitive medicaments composition, the reduction sensitive medicaments composition is logical
Cross film dispersion method, reverse phase evaporation, freeze-drying, ultrasonic dispersion, spray drying process, film extrusion or high-pressure homogeneous
Method preparation.
The present invention also provides a kind of application for restoring sensitive medicaments composition, which is applied to
The preparation of anti-tumor agents, antiviral agent, antimicrobial agent.
Wherein:
The medicament is liquid preparation, solid pharmaceutical preparation, semisolid preparation, capsule, granule or gelling agent.
The medicament can be administered in a unit, and administration route can be enteron aisle or non-bowel, such as oral, muscle,
Subcutaneously, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc..
From the point of view of external degradation speed, pharmaceutical composition performance of the invention restores sensitive fast degradation.
The utility model has the advantages that compared with prior art, the present invention having the advantage that
Reduction sensitive medicaments composition of the present invention is nano particle, has and restores sensitive fast degradation, in inflammation
In the presence of disease, tumor locus or tumour cell middle and high concentration glutathione, the double-thio nalka acid glycerol phosphoric acid of alkyl two
The cystine linkage fast fracture of choline, liposome disintegration, rapid delivery of pharmaceuticals play drug effect；
Reduction sensitive medicaments composition of the present invention, not only stability is good, long circulating, but also in tumor locus because of reduction
Microenvironment responds and has the function of targeting and disintegrate and quickly drug release；
Reduction sensitive medicaments composition of the present invention can be non-using simple process, such as membrane process, high pressure homogenization method
It often easily prepares, 10~1000 nanometers of particle diameter；
Reduction sensitive medicaments composition of the present invention is liposome, solid lipid nano granule or micella；
The anti-tumor agents that reduction sensitive medicaments composition of the present invention is prepared, have excellent antitumor work
Property；
Reduction sensitive medicaments composition of the invention can be used as liquid preparation, solid pharmaceutical preparation, semisolid preparation, sterilizing system
Agent and sterile preparation.
Detailed description of the invention
Fig. 1 is Doxorubicin (DOX) reduction response liposome transmission electron microscope picture；
Fig. 2 is the Electron microscope figure of two thio phospholipid liposome DOX/12-SS3-LLP liposome different conditions, wherein scheming a
For two thio phospholipid liposome 12-SS3-LLP transmission electron microscope pictures (insertion figure is freezing transmission electron microscope picture), figure b is two thio phosphorus
Rouge liposome 12-SS3-LLP is through dithiothreitol (DTT) treated transmission electron microscope picture；
Fig. 3 is to load the reduction sensitive liposome of DOX bent containing the release in (or being free of) dithiothreitol (DTT) DTT medium
Line；
Fig. 4 is to be imitated using the extracorporeal anti-tumor of A549 cell model and MCF-7 cell model evaluation reduction sensitive liposome
The schematic diagram of fruit, wherein figure a is the signal for evaluating the extracorporeal anti-tumor effect of reduction sensitive liposome using A549 cell model
Figure, figure b are the schematic diagram that the extracorporeal anti-tumor effect of reduction sensitive liposome is evaluated using MCF-7 cell model；
Fig. 5 is the internal antitumous effect and toxicity schematic diagram for loading the reduction sensitive liposome of Doxorubicin, wherein scheming a
For tumor volume change, b is schemed for mouse weight variation, figure c is tumor weight.
Specific embodiment
Further details of the technical solution of the present invention with embodiment with reference to the accompanying drawings of the specification.
Reduction sensitive medicaments composition of the invention, the reduction sensitive medicaments composition are nano particle, including double-nalka
The thio nalka acid glycerol phosphocholine of base two and drug.
Wherein:
The reduction sensitive medicaments composition further includes acceptable auxiliary agent in pharmacodynamics.
The reduction sensitive medicaments composition is nano particle, and partial size is 10~1000nm, and nano particle can be
Liposome, solid lipid nano granule or micella；
Double-thio nalka acid glycerol the phosphocholine of alkyl two has the following structure:
In formula, m is 2~10 positive integer, and n is 7~15 positive integer.
The drug is anti-tumor drug, antiviral drugs, antibacterials.
The anti-tumor drug is following one of which: taxol, Docetaxel, Cabazitaxel, camptothecine, hydroxyl happiness
Set alkali, 7-Ethyl-10-hydroxycamptothecin, Irinotecan, topotecan, Lurtotecan, Belotecan, 7- methylol camptothecine,
Vincristine, vinorelbine, Ansamycin, rapamycin, cytarabine, Etoposide, mitoxantrone, Doxorubicin, assistant are soft
Than star, epirubicin, idarubicin, Sha bar than star, tamoxifen, triptolide, rice lumbering peptide, ursolic acid, platinum medicine.
The platinum medicine includes cis-platinum, carboplatin, oxaliplatin, Nedaplatin, Lobaplatin or cis--bis- trans--R of neodecanoic acid-,
R-1,2- cyclohexyl diamine closes platinum (II).
The antibacterials are following one of which: amphotericin B, gentamicin, nystatin, Fluconazole, A meter Ka
Star, lavo-ofloxacin or econazole nitrate.
The antiviral drugs is Ribavirin or Aldoforwe ester.
Acceptable auxiliary agent is that phosphatide, glyceride, fatty acid, tween, poloxamer or gallbladder are solid in the pharmacodynamics
One of alcohol is a variety of.
The phosphatide includes lecithin, synthetic phospholipid.
The phosphatide includes targeting phosphatide.
The phosphatide includes glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol and glycerol disterate phosphatidyl second
Hydramine-polyethylene glycol-folic acid.
A kind of preparation method restoring sensitive medicaments composition, passes through film dispersion method, reverse phase evaporation, freeze-drying
Method, ultrasonic dispersion, spray drying process, film extrusion or high pressure homogenization method preparation.
A kind of application restoring sensitive medicaments composition, the reduction sensitive medicaments composition are applied to anti-tumor agents, resist
The preparation of viral agent, antimicrobial agent.
Wherein:
The medicament is liquid preparation, solid pharmaceutical preparation, semisolid preparation, capsule, granule or gelling agent.
The medicament that pharmaceutical composition is prepared into can be administered in a unit, administration route can be enteron aisle or non-bowel,
Such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.
From the point of view of external degradation speed, pharmaceutical composition performance of the invention restores sensitive fast degradation.
From the point of view of pharmacy in vitro screening, the present invention restores sensitive medicaments composition and shows good anti-inflammatory, anti-tumor activity.
The preparation method of reduction sensitive medicaments composition of the present invention, is by double-thio nalka acid glycerol of alkyl two
Acceptable auxiliary agent passes through film dispersion method, reverse phase evaporation, freeze-drying, ultrasound in phosphocholine, drug and pharmacodynamics
The preparation of the methods of wavelength-division arching pushing, spray drying process, film extrusion or high pressure homogenization method.
It is following that the present invention is further illustrated by embodiment, but the present invention is not limited to following embodiments.
In embodiment, the phosphatide cpd and structural formula that following code name indicates are as follows:
8-SS3-PC is bis--n-octyl dithiopropionic acid choline glycerophosphatide,
10-SS3-PC is bis--positive decyl dithiopropionic acid choline glycerophosphatide,
12-SS3-PC is bis--dodecyl dithiopropionic acid choline glycerophosphatide,
14-SS3-PC is bis--n-tetradecane base dithiopropionic acid choline glycerophosphatide,
16-SS3-PC is bis--n-hexadecyl dithiopropionic acid choline glycerophosphatide.
10-SS6-PC is bis--the thio n-caproic acid choline glycerophosphatide of n-decane base two
8-SS11-PC is bis--the thio n-undecane acid glycerol phosphocholine of normal octane base two
14-SS6-PC is bis--the thio caproic acid choline glycerophosphatide of n-tetradecane base two
Embodiment 1
A kind of reduction sensitive medicaments composition, the pharmaceutical composition are Doxorubicin (DOX) reduction response liposome, are
Granular and partial size be 110 nanometers, including double-dodecyl dithiopropionic acid choline glycerophosphatide, Doxorubicin, cholesterol and
Distearoyl Phosphatidylcholine DSPC.
Preparation method is as follows:
It will double-dodecyl dithiopropionic acid choline glycerophosphatide 12-SS3-PC 0.5mmol, distearoylphosphatidyl
Choline DSPC 0.5mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slowly rotate dry, nitrogen
Air-blowing is swept 10 minutes, forms thin film in eggplant-shape bottle inner wall；20ml ammonium sulfate, 60 DEG C of skinnings, 200nm filter membrane mistake is added
Filter, obtains liposome solutions；Liposome solutions are dialysed with semi-permeable membrane, the ammonium sulfate outside liposome are removed, by Doxorubicin salt
Hydrochlorate 0.1mmol is added in liposome solutions, is incubated at 50 DEG C；It is heavy that Doxorubicin enters formation sulfate gel in liposome
Product obtains Doxorubicin reduction response liposome in liposome interior.
Use laser particle analyzer measurement liposome average grain diameter for 110nm, transmission electron microscope measures the form of nano particle, shows
Show spherical structure (Fig. 1)；Elaioplast nanometer particle solution is lyophilized, powdered nanoparticles particle is obtained.
The Doxorubicin reduction response liposome that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 2
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are taxol reduction response liposome, are
Graininess and partial size are 108 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, taxol, two palmitinic acids
Phosphatidyl choline, cholesterol.
Preparation method is as follows:
Taxol 0.1mmol, double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 1.0mmol, two
Palmitinic acid phosphatidyl choline 1.0mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, 60 DEG C of slowly rotations
It is evaporated, nitrogen purges 10 minutes, forms thin film in eggplant-shape bottle inner wall, 20ml PBS (pH 7.4) solution is added, 60 DEG C are risen
Film, 200nm membrane filtration, obtains elaioplast nanometer particle.
Average grain diameter is measured using laser particle analyzer, is 108nm, transmission electron microscope measures the form of nano particle, shows ball
Shape structure；Taxol is restored into response elaioplast nanometer particle solution freeze-drying, obtains powdered nanoparticles particle.
The taxol reduction response liposome that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 3
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are Docetaxel reduction response lipid
Body is graininess and partial size is 112 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, Docetaxel
With auxiliary agent lecithin and cholesterol.
Preparation method is as follows:
Docetaxel 0.1mmol, double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.2
Mmol, lecithin 0.7mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slow
Slow revolving is dry, and nitrogen purges 10 minutes, forms thin film in eggplant-shape bottle inner wall；Addition 20ml PBS (pH 7.4) solution, 60
DEG C skinning, 200nm membrane filtration obtain elaioplast nanometer particle solution.
The Docetaxel reduction response liposome that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 4
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are taxol reduction response stealthy liposome
Body is graininess and partial size is 120 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, taxol and two
Stearoylphosphatidylcholine DSPC, distearoylphosphatidylethanolamine-polyethylene glycol and cholesterol.
Preparation method is as follows:
Taxol 0.1mmol, double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, two
Stearoylphosphatidylcholine (DSPC) 0.5mmol, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG2000, PEG
Molecular weight 2000) 0.1mmol, cholesterol 0.3mmol, chloroform 20ml add in eggplant-shape bottle and dissolve, 60 DEG C slowly revolving it is dry,
Nitrogen purges 10 minutes, forms thin film in eggplant-shape bottle inner wall；Addition 20ml PBS (pH 7.4) solution, 60 DEG C of skinnings,
200nm membrane filtration obtains elaioplast nanometer particle solution；Elaioplast nanometer particle solution is lyophilized, powdered nanoparticles are obtained
Grain.
The taxol reduction response liposome that the embodiment is prepared is applied to prepare anti-tumor agents.
For the ease of control, the common hidden liposome of taxol is prepared, preparation method is same as above, except being replaced with equimolar DSPC
Outside for 14-SS3-PC.
Embodiment 5
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are Doxorubicin reduction response stealthy liposome
Body is graininess and partial size is 116 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, Doxorubicin and
Auxiliary agent cholesterol and Distearoyl Phosphatidylcholine DSPC.
Preparation method are as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, distearoylphosphatidyl gallbladder
Alkali (DSPC) 0.5mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slowly rotate dry, nitrogen
Air-blowing is swept 10 minutes, forms thin film in eggplant-shape bottle inner wall；20ml ammonium sulfate, 60 DEG C of skinnings, 200nm filter membrane mistake is added
Filter.It obtains liposome solutions to be dialysed with semi-permeable membrane, removes the ammonium sulfate outside liposome.By Doxorubicin hydrochloride 0.1mmol
It is added in liposome solutions, is incubated under 50 degrees Celsius.Doxorubicin enters formation sulfate gel in liposome and is deposited on rouge
Inside plastid；Then, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG2000) 0.1mmol and liposome is added
It is incubated for altogether in solution 30 minutes, obtains Doxorubicin reduction response hidden liposome, elaioplast nanometer particle solution is lyophilized, is obtained
To powdered nanoparticles particle.
The Doxorubicin reduction response hidden liposome that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 6
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are cytarabine liposome, are graininess
And partial size is 130 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, cytarabine.
Preparation method is as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, two palmityl phosphatidyls are sweet
It is molten that oily 1.0mmol, cholesterol 0.2mmol, olein 0.3mmol are placed in 3mL chloroform-ether (volume ratio 1: 1) mixing
It in agent, is stirred, obtains suspension.Cytarabine hydrochloride aqueous solution 2mL (concentration 0.1M) is added in above-mentioned suspension,
10000rpm high-speed stirred is at colostrum.Colostrum 1mL is taken to be rapidly injected molten containing 4% glucose of mass fraction and the mixing of 40mM lysine
In liquid 10mL, vortex oscillation is shaken in 37 DEG C of water-baths, with normal saline dilution to 10mL, obtains liposome turbid liquor at emulsion.
10mL physiological saline is added, 3000rpm is centrifuged 5min, discards supernatant liquid, is precipitated 3 times with brine.Precipitating uses physiology
Salt water dilutes the cytarabine multivesicular liposome that concentration 5mM is made.
The cytarabine liposome particle that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 7
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are irinotecan liposome, are
Graininess and partial size are 120 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, cytarabine cholesterol,
Glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000) and Distearoyl Phosphatidylcholine (DSPC).
Preparation method is as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, distearoylphosphatidyl gallbladder
Alkali (DSPC) 1.0mmol, cholesterol 0.2mmol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000)
0.1mmol is dissolved in appropriate 2mL dehydrated alcohol, is added dropwise in the sucrose octasulfate triethylamine solution that temperature is 60 DEG C,
Stir 10min；Vacuum rotary steam removes ethyl alcohol, crosses 0.2 μm of filter membrane homogenizing.Blank liposome suspension is dialysed with PBS, is removed outer
Sucrose octasulfate triethylamine in water phase, obtains blank liposome；It draws blank liposome respectively and Irinotecan drug is molten
Liquid is incubated under 60 DEG C of water bath conditions and carries medicine 30min, obtains irinotecan liposome.
The irinotecan liposome particle that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 8
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are liposomal vincristine body, are
Graininess and partial size are 132 nanometers, including double-n-hexadecyl dithiopropionic acid choline glycerophosphatide, vincristine, gallbladder are solid
Alcohol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000, PEG molecular weight 2000) and distearyl phosphorus
Phosphatidylcholine (DSPC).
Preparation method is as follows:
Vincristine 0.1mmol, double-n-hexadecyl dithiopropionic acid choline glycerophosphatide 16-SS3-PC 0.5mmol,
Distearoyl Phosphatidylcholine (DSPC) 2.0mmol, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG2000)
0.1mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slowly rotate dry, nitrogen purging 10
Minute, thin film is formed in eggplant-shape bottle inner wall.20ml PBS (pH 7.4) solution, 60 DEG C of skinnings, 200nm filter membrane mistake is added
Filter, obtains elaioplast nanometer particle solution.
The liposomal vincristine body particle that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 9
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are mitoxantrone liposome, are
Graininess and partial size are 120 nanometers, including double-n-hexadecyl dithiopropionic acid choline glycerophosphatide, mitoxantrone and drug effect
Acceptable auxiliary agent cholesterol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000) and two hard on
Acyl phosphatidyl choline (DSPC).
Preparation method is as follows:
Mitoxantrone 0.1mmol, double-n-hexadecyl dithiopropionic acid choline glycerophosphatide 16-SS3-PC 0.5mmol,
Distearoyl Phosphatidylcholine (DSPC) 2.5mmol, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG2000)
0.1mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slowly rotate dry, nitrogen purging 10
Minute, thin film is formed in eggplant-shape bottle inner wall.20ml PBS (pH 7.4) solution, 60 DEG C of skinnings, 200nm filter membrane mistake is added
Filter, obtains elaioplast nanometer particle solution.
The mitoxantrone liposome particles that the embodiment is prepared are applied to prepare anti-tumor agents.
Embodiment 10
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are AM Bison, are
Graininess and partial size are 136 nanometers, including double-thio n-caproic acid choline glycerophosphatide of n-decane base two, amphotericin B, gallbladder are solid
Alcohol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000) and Distearoyl Phosphatidylcholine (DSPC).
Preparation method is as follows:
Amphotericin B 0.5mmol, double-thio n-caproic acid choline glycerophosphatide 10-SS6-PC of n-decane base two
0.5mmol, Distearoyl Phosphatidylcholine (DSPC) 5.0mmol, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-
PEG2000) 0.3mmol, cholesterol 1.0mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slowly rotate dry, nitrogen
Air-blowing is swept 10 minutes, forms thin film in eggplant-shape bottle inner wall.20ml PBS (pH 7.4) solution, 60 DEG C of skinnings, 200nm is added
Membrane filtration obtains elaioplast nanometer particle solution.
The AM Bison particle that the embodiment is prepared is applied to preparation antimicrobial agent.
Embodiment 11
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are liposomal amikacin, are
Graininess and partial size are 142 nanometers, including double-thio n-undecane acid glycerol phosphocholine of normal octane base two, amikacin, gallbladder
Sterol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG4000, PEG molecular weight 4000) and distearyl
Phosphatidyl choline (DSPC).
Preparation method is as follows:
Amikacin 0.1mmol, double-thio n-undecane acid glycerol phosphocholine 8-SS11-PC of normal octane base two
0.5mmol, Distearoyl Phosphatidylcholine DSPC 0.5mmol, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-
PEG2000) 0.1mmol, cholesterol 0.3mmol, chloroform 20ml are added in eggplant-shape bottle and are dissolved, and 60 DEG C slowly rotate dry, nitrogen
Air-blowing is swept 10 minutes, forms thin film in eggplant-shape bottle inner wall.20ml PBS (pH 7.4) solution, 60 DEG C of skinnings, 200nm is added
Membrane filtration obtains elaioplast nanometer particle solution.
The liposomal amikacin particle that the embodiment is prepared is applied to preparation antimicrobial agent.
Embodiment 12
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are cisplatin liposome, are particle
Shape and partial size are 110 nanometers, including double-thio caproic acid choline glycerophosphatide of n-tetradecane base two, cis-platinum, lecithin, cholesterol.
Its preparation step is as follows:
Double-thio caproic acid choline glycerophosphatide 14-SS6-PC of n-tetradecane base two, lecithin, cholesterol, DSPE-
In eggplant type bottle the dissolution of 15m L chloroform is added, revolving removes dechlorination in 45 DEG C of water-baths in PEG2000 (molar ratio 2:2:2:0.3)
It is imitative, one layer of phospholipid membrane is formed in bottle wall；Residual solvent is removed in vacuum, and is purged with nitrogen.After forming immobilized artificial membrane, 9m L is added
Normal saline solution containing 9.0mg cis-platinum shakes aquation 1h in 37 DEG C of constant temperature oscillators；After the completion of aquation, vortex oscillation
5min, ultrasonic 10min obtain multilamellar liposome suspension.Liposome turbid liquor is successively pressed through 450nm, 220nm polycarbonate
Filter membrane each 5 times；It obtains average grain diameter 110nm or so, be distributed uniform cis-platinum hidden liposome.
The cisplatin liposome particle that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 13
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are topotecan liposome, are
Graininess and partial size are 120 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, Irinotecan, gallbladder are solid
Alcohol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000) and Distearoyl Phosphatidylcholine (DSPC).
Preparation method is as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, DSPC 0.5mmol, gallbladder
Sterol 0.2mmol, DSPE-PEG2000 0.1mmol are dissolved in appropriate 2mL dehydrated alcohol, and being added dropwise to temperature is 60 DEG C
In sucrose octasulfate triethylamine solution, 10min is stirred；Vacuum rotary steam removes ethyl alcohol, crosses 0.2 μm of filter membrane homogenizing；By blank rouge
Plastid suspension is dialysed with PBS, is removed the sucrose octasulfate triethylamine in outer aqueous phase, is obtained blank liposome；It draws respectively
Blank liposome and topotecan drug solution are incubated under 60 DEG C of water bath conditions and carry medicine 30min, obtain Irinotecan lipid
Body.
The topotecan liposome particles that the embodiment is prepared are applied to prepare anti-tumor agents.
Embodiment 14
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are that Doxorubicin reduction is sensitive hidden
Shape liposome series particle, including the serial (double-n-octyl two thio third of double-thio nalka acid glycerol phosphocholine of alkyl two
Acid glycerol phosphocholine 8-SS3-PC, double-positive decyl dithiopropionic acid choline glycerophosphatide 10-SS3-PC, double-dodecyl
Dithiopropionic acid choline glycerophosphatide 12-SS3-PC, double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC,
Double-n-hexadecyl dithiopropionic acid choline glycerophosphatide 16-SS3-PC), Doxorubicin, cholesterol, glycerol disterate phosphorus
Acyl ethanol amine-polyethylene glycol (DSPE-PEG2000).
Doxorubicin restores the preparation of sensitive stealthy liposome series:
Serial (double-n-octyl dithiopropionic acid the choline glycerophosphatide of double-thio nalka acid glycerol phosphocholine of alkyl two
8-SS3-PC, double-positive decyl dithiopropionic acid choline glycerophosphatide 10-SS3-PC, double-dodecyl dithiopropionic acid glycerol
Phosphocholine 12-SS3-PC, double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC, double-n-hexadecyl
Dithiopropionic acid choline glycerophosphatide 16-SS3-PC) 0.9mmol, with Distearoyl Phosphatidylethanolamine polyethylene glycol DSPE-
20ml ammonium sulfate is added in PEG2000 0.1mmol, cholesterol 0.3mmol and chloroform 20ml mixing, 60 DEG C of rotation solvent evaporateds
Solution, 60 DEG C of skinnings, and be homogenized with ultrasound, 200nm membrane filtration obtains restoring sensitive hidden liposome serial nano particle molten
Liquid is denoted as 8-SS3-LLP, 10-SS3-LLP, 12-SS3-LLP, 14-SS3-LLP, 16-SS3-LLP respectively.
Above-mentioned liposome serial solution is dialysed with semi-permeable membrane, removes the ammonium sulfate outside liposome；By Doxorubicin hydrochloric acid
Salt 0.1mmol is added in liposome solutions, 50 DEG C of incubations；Doxorubicin enters formation sulfate gel in liposome and is deposited on
Liposome interior obtains Doxorubicin reduction response stealthy liposome series, is denoted as DOX/8-SS3-LLP, DOX/10- respectively
SS3-LLP、DOX/12-SS3-LLP、DOX/14-SS3-LLP、DOX/16-SS3-LLP。
The preparation method of the common hidden liposome of Doxorubicin (being denoted as DOX/LP) is same as above, and is removed and is substituted with equimolar DSPC
Outside 14-SS3-PC.
Using the content of Doxorubicin in ultraviolet spectroscopy measurement liposome solutions, Doxorubicin drug-loading efficiency is calculated
(EE%) and drugloading rate (DL%), the results are shown in Table 1.
Liposome particles average diameter and surface potential are measured using dynamic laser light scattering method (DLS), the results are shown in Table
1.As can be seen that two thio phosphatide long circulating liposome sizes are 100 rans, surface is negatively charged, illustrates that liposome has
There is stability.
DOX/12- is observed in transmission electron microscope (TEM, JEOL) and freezing transmission electron microscope (Tecnai G2F20 200kV, FEI)
The structure of SS3-LLP liposome, as a result such as Fig. 2 a.As can be seen that liposome is in regular spherical structure, diameter is measured less than DLS
Liposome hydration kinetics diameter.Freezing transmission electron microscope shows that two thio phospholipid liposome 12-SS3-LLP are in typical single chamber
Liposome structure, about 5 nanometers of double Lipid Layer Thickness (small figure is inserted into Fig. 2 a).
The characterization of the load thio phosphatide hidden liposome of medicine two of table 1.
Embodiment 15
DOX/12-SS3-LLP restores the cracking of sensitive hidden liposome
Degradation experiment uses reducing environment in DTT solution analogue body.The thio phosphatide hidden liposome of the two of embodiment 14
DOX/12-SS3-LLP (10 μ g/mL) 2mL and dithiothreitol (DTT) aqueous solution (DTT, concentration 10mmol/L) 0.5mL are incubated altogether at room temperature
It educates 1 hour.Changed with transmission electron microscope observing liposome structure, as a result sees Fig. 2 b.
It is thoroughly disintegrated under DTT effect by liposome it can be seen from Fig. 2 b, becomes fragment.Obviously, two thio phosphatide are also
It is cracked into Non-amphiphilic molecule under the conditions of originality, liposome is caused thoroughly to be disintegrated.This two thio phosphatide cracking process follows length
Thoroughly disintegration and quickly abundant drug release are advantageous ring grease plastid reduction sensitivity.
Embodiment 16
Taxol reduction response hidden liposome external degradation Drug Releasing Test
Taxol reduction response hidden liposome nano particle prepared by embodiment 4 is dissolved in 10mL PBS solution, is divided into 2
Part, the PBS buffer solution 0.5mL (GSH concentration 50mmol) of glutathione (GSH) is added in a copy of it, and PBS buffering is added in another
Liquid 0.5mL.Reference substance is to load the common long circulating liposome (DOX/LP) of identical molar content taxol (except sour with distearyl
Choline glycerophosphatide DSPC substitutes 14-SS3-PC, and other 2 component ratios and method are same as Example 4).Placement and incubator
In be incubated at 37 DEG C, with the content of high performance liquid chromatography detection taxol (Agilent 1100LC, Zorbax reverse phase C18 column,
150 × 4.6mm, 5 μm, sample volume 20 μ L, 25 DEG C of column temperature, Detection wavelength 254nm；Gradient elution: 2-90% buffer solution B/A, stream
Fast 1.0mL/min, buffer solution A: the deionized water of 0.1% trifluoroacetic acid TFA, buffer solution B: the acetonitrile of 0.1%TFA), it calculates purple
The burst size of China fir alcohol.
The result shows that the taxol that the taxol reduction response stealthy liposome liquid solution of GSH processing releases after 3 hours
Reach the 82% of total amount；Taxol is released behind taxol reduction response stealthy liposome liquid solution 3 hours without GSH processing
Only the 11% of total amount.The taxol discharged behind paclitaxel loaded common long circulating liposome 3 hours is the 9% of total amount.Institute
With taxol reduction response hidden liposome has reduction-sensitive, the quick release taxol raw medicine under GSH effect, release
Speed is far faster than common long circulating liposome.
Embodiment 17
Doxorubicin reduction response hidden liposome external degradation Drug Releasing Test
Doxorubicin reduction response stealthy liposome liquid solution series DOX/8-SS3-LLP, DOX/10- prepared by embodiment 14
Each 2mL of SS3-LLP, DOX/12-SS3-LLP, DOX/14-SS3-LLP, DOX/16-SS3-LLP (DOX concentration 0.1mg/mL) adds
Enter in bag filter (MWCO 8000).Dissolution medium is the PBS buffer solution containing (or being free of) 10mM dithiothreitol dithio DTT.
Bag filter immerses in dissolution medium together with liposome, and system maintains 37 DEG C of constant temperature；Point sampling 1mL degradation in different times is situated between
Matter, while the new dissolution medium of 1mL is supplemented, the DOX concentration of each sample uses UV spectrophotometer measuring, and calculates final
Release rate.
As a result as shown in figure 3, comparing with the common hidden liposome (DOX/LP, embodiment 14) of load DOX, DOX is loaded
Reduction sensitive long circulating liposomes high release rate, cumulative release in 24 hours are presented in the dissolution medium of the DTT containing 10mM
Amount is up to 80% or so；In contrast, in the dissolution medium of no DTT, the accumulation of the sensitive hidden liposome of reduction of DOX is loaded
Burst size can only achieve 10%-20%, it can be seen that, there is the reduction sensitivity hidden liposome for loading DOX apparent reduction to ring
Ying Xing, and quick release goes out the DOX drug loaded.
Embodiment 18
Tumor cell in vitro killing experiments
In embodiment 14 load DOX reduction sensitivity hidden liposome (DOX/8-SS3-LLP, DOX/10-SS3-LLP,
DOX/12-SS3-LLP, DOX/14-SS3-LLP, DOX/16-SS3-LLP) extracorporeal anti-tumor effect assessment using A549 and
Two kinds of cell models of MCF-7.A549 and MCF-7 cell is inoculated in 96 well culture plates with the density of 10000 cells/wells；If
0.001,0.01,0.1,1 and 10 μ g/mL, five concentration gradients are set, incubation time is 24 hours；After incubation, inhales and abandon every hole
In culture medium, 20 μ L of MTT solution is added, 37 degrees Celsius are incubated for 4 hours.Then, the MTT solution abandoned in every hole is inhaled, is added
150 μ L of DMSO solution；Finally, the absorbance (OD) in every hole is read at 490nm wavelength using microplate reader.It is calculated according to formula thin
Cytoactive (cell viability).
ODdrugRepresent the OD value for being incubated for the hole of drug, ODcontrolBe no drug only the OD value in the hole of hatch culture medium,
ODblankIt is the OD value for only adding the hole of DMSO.
As a result see Fig. 4, compared with DOX/LP (embodiment 14), DOX/8-SS3-LLP, DOX/10-SS3-LLP, DOX/12-
SS3-LLP, DOX/14-SS3-LLP have the effect of relatively stronger killing cell.DOX is free drug, with most fast thin
Born of the same parents absorb speed, thus often show stronger killing cell effect.
Experimental example 19
Anti-tumor experiment in animal body
The preparation of nude mice model: mouse selects 2 monthly ages, 15-20 grams of female BAl BIc/c mouse.The MCF-7 for collecting culture is thin
Born of the same parents' suspension, concentration are 1 × 107A/ml it is subcutaneous to be inoculated in armpit on the right side of nude mouse with every 0.1ml, until tumour mean size
0.1 cubic centimetre.
Grouping and administration: transplanted tumor in nude mice vernier caliper measurement transplantable tumor diameter, tumour growth to 75mm3When by animal
Random grouping, experimental animal totally 20, random point 5 groups.Meanwhile each group nude mice starts tail vein injection administration, dosage regimen is shown in
Group and dosage regimen use the method for measurement knurl footpath, the anti-tumor effect of dynamic observation given the test agent.Gross tumor volume (TV)
Calculation formula are as follows: TV=1/2 × a × b2(formula 3-2), wherein a, b respectively indicate length and width.
Group and dosage regimen: dosage 5mg/kg.
Blank group: physiological saline, intravenous injection, injection is primary every three days, volume 0.2ml, and continuous 3 weeks.
Control group: Doxorubicin is dissolved in physiological saline group, and intravenous injection, injection is primary every three days, volume 0.2ml, even
It is 3 weeks continuous.Normal load Doxorubicin DOX hidden liposome group (embodiment 14), intravenous injection, injection is primary every three days, volume
For 0.2ml, continuous 3 weeks.
Medicine group: DOX/12-SS3-LLP group (embodiment 14)；DOX/16-SS3-LLP group (embodiment 14).Vein note
It penetrates, injection is primary every three days, volume 0.2ml, and continuous 3 weeks.
During the experiment, the weight and tumor size of mouse every two days records are primary.After administration 21 days, all groups
Mouse is condemned to death, and tumour is separated and record of weighing, and as a result sees Fig. 5.
Compared with blank group, control group, DOX/12-SS3-LLP group and DOX/16-SS3-LLP group show obviously to drop
The effect of low gross tumor volume and weight illustrates there is preferably inhibition tumor growth effect (Fig. 5 a and 5c).Wherein, DOX/16-
SS3-LLP effect is best, has the function of inhibition tumour growth more better than DOX/12-SS3-LLP.Change from mouse weight bent
Line (Fig. 5 b) shows apparent toxic side effect it is found that the weight of Doxorubicin physiological saline group is minimum；Restore sensitive long-circulation fat
The weight of plastid group is higher, and display toxicity is unobvious.
Embodiment 20
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are that taxol reduction response solid lipid is received
The grain of rice, partial size 132nm, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, taxol, stearic acid, Bo Luosha
Nurse Poloxamer188.
Preparation method is as follows:
Taxol 0.1g, palmitinic acid 5.0g, lecithin 2.0g mixing, are heated to 80 DEG C and are slowly dissolved, 20ml PBS is added
(pH 7.4) contains double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5g and poloxamer
In Poloxamer188 0.5g aqueous solution, high-speed stirred is high pressure homogenizer mean value 3 times, cooling, obtains solid lipid nano granule.
Average grain diameter is measured using laser particle analyzer, is 132nm, transmission electron microscope measures the form of nano particle, shows ball
Shape structure.
Embodiment 21
A kind of reduction sensitive medicaments composition, the reduction sensitive medicaments composition are that taxol restores response nano micella,
Partial size is 120nm, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, taxol, tricaprylin, tween
80。
Preparation method is as follows:
Docetaxel 0.1mmol, double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC
1.0mmol, it dipalmitoylphosphatidylcholine 1.0mmol, Capmul MCM C8 2.0mmol, tricaprylin 1.0mmol, spits
80 0.3mmol of temperature are heated to 60 DEG C and are slowly dissolved, addition 20ml PBS (pH 7.4) solution, high-speed stirred, and high pressure homogenizer is equal
Value 3 times, obtain nano-micelle.
Average grain diameter is measured using laser particle analyzer, is 120nm, transmission electron microscope measures the form of nano particle, shows ball
Shape structure.
Embodiment 22
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are rice lumbering peptidoliposome, are
Graininess and partial size are 132nm, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, rice lumbering peptide, cholesterol,
Glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000) and Distearoyl Phosphatidylcholine (DSPC).
Preparation method is as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, DSPC 0.5mmol, gallbladder
Sterol 0.2mmol, DSPE-PEG2000 0.1mmol, rice lumbering peptide 0.1mmol are dissolved in 5mL methylene chloride, are added to 250mL
In eggplant-shape bottle, rotary evaporation removes solvent, and 5mL physiological saline aquation is added；Ultrasonic treatment 5 minutes crosses 0.2 μm of filter membrane homogenizing,
Rice lumbering peptidoliposome nano particle is obtained, the average diameter that laser particle analyzer measures nanoparticle is 132nm.
The rice lumbering peptidoliposome particle that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 23
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are triptolide liposome,
For graininess and partial size is 150nm, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, triptolide, gallbladder are solid
Alcohol, DSPE-PEG2000, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol-folic acid (DSPE-PEG2000-FA) and two are hard
Acyl phosphatidyl choline (DSPC).
Preparation method is as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, DSPC 0.5mmol, gallbladder
Sterol 0.2mmol, DSPE-PEG2000 0.1mmol, DSPE-PEG2000-FA 0.02mmol, triptolide 0.05mmol
It is dissolved in 5mL methylene chloride, is added in 250mL eggplant-shape bottle, rotary evaporation removes solvent, and 5mL physiological saline aquation is added；It is super
Sonication 5 minutes, 0.2 μm of filter membrane homogenizing is crossed, the triptolide elaioplast nanometer particle with targeting folacin receptor is obtained, swashs
The average diameter of light particle size instrument nanoparticle is 150nm.
The triptolide elaioplast nanometer particle that the embodiment is prepared is applied to prepare anti-tumor agents.
Embodiment 24
A kind of reduction sensitive medicaments composition, the reduction sensitive liposome pharmaceutical composition are tamoxifen liposome, are
Graininess and partial size are 142 nanometers, including double-n-tetradecane base dithiopropionic acid choline glycerophosphatide, tamoxifen, gallbladder are solid
Alcohol, glycerol disterate phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG2000) and Distearoyl Phosphatidylcholine (DSPC).
Preparation method is as follows:
Double-n-tetradecane base dithiopropionic acid choline glycerophosphatide 14-SS3-PC 0.5mmol, DSPC 0.5mmol, gallbladder
Sterol 0.2mmol, DSPE-PEG2000 0.1mmol, tamoxifen 0.05mmol are dissolved in 10mL ether, are added to 250mL eggplant
In shape bottle, rotary evaporation removes solvent, and 5mL physiological saline aquation is added；Ultrasonic treatment 5 minutes is crossed 0.2 μm of filter membrane homogenizing, is obtained
To tamoxifen elaioplast nanometer particle, the average diameter that laser particle analyzer measures nanoparticle is 142 nanometers.
The tamoxifen liposome particles that the embodiment is prepared are applied to prepare anti-tumor agents.
Above-described embodiment is only the preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill of the art
For personnel, without departing from the principle of the present invention, several improvement and equivalent replacement can also be made, these are to the present invention
Claim improve with the technical solution after equivalent replacement, each fall within protection scope of the present invention.
Claims (10)
1. a kind of reduction sensitive medicaments composition, it is characterised in that: the pharmaceutical composition is nano particle, including double-alkyl
Two thio nalka acid glycerol phosphocholines and drug.
2. a kind of reduction sensitive medicaments composition as described in claim 1, it is characterised in that: the reduction sensitive medicaments group
Closing object further includes acceptable auxiliary agent in pharmacodynamics.
3. a kind of reduction sensitive medicaments composition as described in claim 1, it is characterised in that: the reduction sensitive medicaments group
Close object be nano particle in, nano particle be liposome, solid lipid nano granule or micella, and grain diameter be 10~
1000nm。
4. a kind of reduction sensitive medicaments composition as described in claim 1, it is characterised in that: double-two sulphur of alkyl
It is as follows for the general structure of nalka acid glycerol phosphocholine:
In formula, m is 2~10 positive integer, and n is 7~15 positive integer.
5. a kind of reduction sensitive medicaments composition as described in claim 1, it is characterised in that: the drug is anti-swollen
Tumor medicine, antiviral drugs or antibacterials.
6. a kind of reduction sensitive medicaments composition as claimed in claim 5, it is characterised in that: the anti-tumor drug is purple
China fir alcohol, Docetaxel, Cabazitaxel, camptothecine, hydroxycamptothecin, 7-Ethyl-10-hydroxycamptothecin, Irinotecan, topology
For health, Lurtotecan, Belotecan, 7- methylol camptothecine, vincristine, vinorelbine, Ansamycin, rapamycin, Ah
Sugared cytidine, Etoposide, mitoxantrone, Doxorubicin, zorubicin, epirubicin, idarubicin, Sha bar are than star, tamoxifen
One of sweet smell, triptolide, rice lumbering peptide, ursolic acid or platinum medicine；Wherein the platinum medicine include cis-platinum, carboplatin,
Oxaliplatin, Nedaplatin, Lobaplatin or cis--bis- trans--R of neodecanoic acid-, R-1,2- cyclohexyl diamine close platinum (II).
7. a kind of reduction sensitive medicaments composition as claimed in claim 5, it is characterised in that: the antibacterials are both sexes
One of mycin B, gentamicin, nystatin, Fluconazole, amikacin, lavo-ofloxacin or econazole nitrate；It is described
Antiviral drugs be Ribavirin or Aldoforwe ester.
8. a kind of reduction sensitive medicaments composition as claimed in claim 2, it is characterised in that: be subjected in the pharmacodynamics
Auxiliary agent be one of phosphatide, glyceride, fatty acid, tween, poloxamer or cholesterol or a variety of.
9. a kind of preparation method of the reduction sensitive medicaments composition as described in claim 1~8, it is characterised in that: the reduction
Sensitive medicaments composition passes through film dispersion method, reverse phase evaporation, freeze-drying, ultrasonic dispersion, spray drying process, film
Extrusion or high pressure homogenization method preparation.
10. a kind of application of the reduction sensitive medicaments composition as described in claim 1~8 is any, it is characterised in that: the reduction
Sensitive medicaments composition is applied to the preparation of anti-tumor agents, antiviral agent or antimicrobial agent, and the anti-tumor agents,
Antiviral agent or antimicrobial agent are liquid preparation, solid pharmaceutical preparation, semisolid preparation, capsule, granule or gelling agent.
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