CN102078301A - Taxotere nano preparation carried by albumin and phospholipid and method preparing same - Google Patents
Taxotere nano preparation carried by albumin and phospholipid and method preparing same Download PDFInfo
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Abstract
The invention provides a taxotere nano preparation with albumin and phospholipid acting as carriers and a preparation method thereof, which relate to an anticancer medicament preparation and preparation thereof and solve the problems that the taxotere medicament is poor in water solubility, has toxic and side effect, especially has high irritability and hemolysis, and can cause severe anaphylaxis symptoms when used in intravenous injection. The taxotere nano preparation comprises the following components in percentage by weight: docetaxel 1% to 15%, albumin of 10% to 43%, 10% to 43% of phospholipids, vitamin E about 1% to 10%, freeze-dried excipient about 1% to 20% and acid buffer salt about 1% to 15%, and is prepared by adding solvent in the compositions and using a high pressure homogenization method and a freeze-drying technology. In the taxotere nano preparation, auxiliaries and solvents which bring about an allergic reaction of a human body are not used, thereby eliminating the allergic reaction caused by solvents and Tween-80 accessories, greatly improving the safety of taxotere solid nano medicament preparation and patient medication compliance. By using the preparation method, the stability of pharmaceutical preparation is greatly improved, thereby being beneficial to storage and transportation of medicaments.
Description
Technical field
The present invention relates to antitumor drug and preparation thereof.Being specifically related to albumin and phospholipid is docetaxel solid nano preparation of carrier and preparation method thereof.
Background technology
Docetaxel has another name called Docetaxel, and English name docetaxel, its chemical name are [2aR-(2a α, 4 β, 4 α β, 6 β, 9 α, (aR ', β S '), 11 α, 12 α, 12a α, 12b α)]-β-[[(1,1-dimethyl ethyoxyl) carbonyl] amino]-alpha-carbonyl benzenpropanoic acid [12b-acetyl oxygen-12-benzoyl oxygen-2a, 3,4,4a, 5,6,9,10,11,12,12a, 12b-ten dihydros-4,6,11-trihydroxy-4a, 8,13,13-tetramethyl-5-oxo-7,11-methylene-1H-ring pentaene in the last of the ten Heavenly stems is benzo [1,2-b] oxa-fourth ring-9-yl also-[3,4]] ester.Molecular formula is C
43H
53NO
14, molecular weight is 807.89.Docetaxel is the taxanes antineoplastic agent, plays antitumor action by interference cell mitosis and the necessary microtubule network of karyostasis cell function.Docetaxel can combine with free tubulin, promotes that tubulin is assembled into stable microtubule, suppresses its depolymerization simultaneously, has caused losing the generation of microtubule fasolculus and the fixing of microtubule of normal function, thereby suppresses the mitosis of cell.Docetaxel and combining of microtubule do not change the number of precursor.This point is different with most of spindle drug toxicities of clinical practice at present.Docetaxel is by the former Rhone-Poulenc Rorer of France, the i.e. a kind of semi-synthetic antitumor drug of Sanofi-Aventis company exploitation now, April nineteen ninety-five is in Mexico's Initial Public Offering, and is present then get permission sale in more or less a hundred country, the world that comprises China and Europe, the United States, day etc.JIUYUE 27 good days, ten thousand spies (China) Investment Co., Ltd at first carried out the imported product registration in 2003, and specification is that 20mg/ props up.Injection docetaxel was listed China's medical insurance catalogue Class B kind in 2004 in.Docetaxel has at present obtained to be used for the treatment of now in each major country of the whole world that three kinds of the most common tumors of the world are the multiple indication of breast carcinoma, nonsmall-cell lung cancer and carcinoma of prostate, and is becoming one of the most frequently used or standard treatment of these cancer kinds treatments.Docetaxel also is widely used in the later stage clinical research of treatment gastric cancer, tumor of head and neck, the esophageal carcinoma, ovarian cancer etc., the treatment of these indications is expected to can obtain the America and Europe in the future ratifies.Being used for the treatment of gastric cancer, tumor of head and neck, the esophageal carcinoma, ovarian cancer and carcinoma of endometrium at Japanese docetaxel at present gets the Green Light.Malignant tumor is one of major disease that threatens the human life always.At present, on average there are every year 1500000 people to suffer from various tumors approximately, have every year 800000 people to die from malignant tumor approximately in China.So numerous tumor patients presses for antitumor drug safe, effective, low toxicity.Therefore, research and development antitumor drug efficient, low toxicity is particularly important.
At present, existing abroad docetaxel injection listing, commodity are called docetaxel; Its concrete preparation specification has two kinds of 20mg/0.5ml and 80mg/2ml, and conventional recommended dose scheme is 1 time 1 hour venoclysis 75mg/m of per 3 weeks
2Domestic also have a docetaxel injection preparation that comprises Hengrui Medicine Co., Ltd., Jiangsu Prov..But docetaxel poorly water-soluble.Because docetaxel is water insoluble, slightly is dissolved in ethanol, promptly separate out the docetaxel precipitation behind the thin up.Be the preparation injection docetaxel, commercially available docetaxel injection or Docetaxel for Injection all are to be solvent with the tween 80 of high concentration and 1: 1 ratio of ethanol, add the concentrated solution that the ethanol preparation of (in the packing capsule subsidiary again 1) 13% forms, the Docetaxel for Injection commercially available by the regulation of Chinese Pharmacopoeia is actually solution type injection agent.Tween 80 is the surfactant of using always, and tween 80 has serious toxic and side effects, and particularly high anaphylaxis and hemolytic are used for intravenous injection, can cause severe anaphylactic reaction, comprise anaphylactoid reaction symptoms such as shock, dyspnea, hypotension, angioedema, rubella.These untoward reaction can be very serious in people's clinical trial, and dead report is arranged.So the conventional enforcement of clinical application pretreatment: treat preceding 1 day beginning oral dexamethasone 8mg from docetaxel, every day 2 times, serve on 3～5 days.Even like this, some patients still can be irritated, and 6.5% patient can produce irritated edema.5% patient can have to stop using because of allergy.In order to remind doctor and patient to recognize the seriousness of this poison of drug side reaction, the allergy shock side reaction to this product in the drug products description of the U.S. is added with the grave warning term; And the tween 80 stickiness is big, also makes troubles for clinical application.In addition, though tween 80 can increase the dissolubility of docetaxel, at the docetaxel poor stability of solution state, effect duration is short; Subsidiary 1 13% ethanol had so both increased production cost in the packing capsule, made troubles for again patient's use.Therefore, press for the dosage form that changes docetaxel, eliminate anaphylaxis that causes by solvents such as tween 80s and the toxic and side effects that reduces docetaxel self.Chinese scholars has been done multiple trial to this, study comprising derivant and preparation to docetaxel.Chinese patent C08F283/06 gets up to constitute the prodrug of docetaxel with Polyethylene Glycol and docetaxel keyed jointing, has increased the water solublity of docetaxel; Chinese patent A61K31/337 adopts hyaluronic acid, glucose or mannitol, ethanol, propylene glycol, non-ionic surface active agent etc. to prepare the injection of docetaxel.
Summary of the invention
The present invention is in order to solve the problem of existing docetaxel medicine poorly water-soluble.Docetaxel injection or Docetaxel for Injection all are to be solvent with the tween 80 of high concentration and 1: 1 ratio of ethanol, and tween 80 has serious toxic and side effects, particularly high anaphylaxis and hemolytic, be used for intravenous injection, can cause severe anaphylactic reaction, comprise the problem of anaphylactoid reaction symptoms such as shock, dyspnea, hypotension, angioedema, rubella.The invention provides a kind of is docetaxel nanometer preparation of carrier and preparation method thereof with albumin and phospholipid.The concrete technical scheme that addresses this problem is as follows:
Of the present invention is the docetaxel nanometer preparation of carrier with albumin and phospholipid, is made up of docetaxel, albumin, phospholipid, vitamin E, freeze-dried excipient and acidic buffer salt by weight percentage.Docetaxel is 1～15% by weight percentage, albumin is 10～43%, phospholipid is 10～43%, vitamin E is 1～10%, freeze-dried excipient be 1～20% and acidic buffer salt be 1～15% to form, add organic solvent, adopt high pressure homogenization and cryodesiccated preparation technology to prepare the powder formulation of 100～700 nanometers.
Described albumin adopts human serum albumin, bovine serum albumin or passes through the resulting albumin of biotechnology.But be not limited to above-mentioned listed.
Described phospholipid adopts soybean phospholipid, egg yolk fat or synthetic phospholipid.But be not limited to above-mentioned listed.
Described freeze-dried excipient adopts sucrose, lactose, maltose, mannitol or trehalose.But be not limited to above-mentioned listed.
Described acidic buffer salt adopts hydrochloric acid, citric acid, phosphoric acid, lactic acid or acetic acid.But be not limited to above-mentioned listed.
Described organic solvent adopts ethanol or chloroform.But be not limited to above-mentioned listed.
The preparation method of docetaxel nanometer preparation that with albumin and phospholipid is carrier is as follows:
Step 1, get that docetaxel is 1～15% by weight percentage, phospholipid be 10～43% and vitamin E be 1～10%, add the organic solvent of 10～43ml, ultrasonic dissolution is made organic facies;
Step 2, by weight percentage get albumin be 10～43% and acidic buffer salt be 1～15%, add the water for injection of 100～1000ml, be mixed with aqueous solution, the pH value of solution is 6.7 (regulating with HCl),
Step 3, the organic facies of step 1 is joined in the aqueous solution of step 2, under high speed shear, be prepared into colostrum;
Step 4, the colostrum that step 3 is prepared into are handled on high pressure homogenizer, under low pressure 30～40 MPas, handle once earlier, under high pressure 130～150 MPas, handle twice then, with the nano-emulsion of above-mentioned processing and 1～20% aqueous solution freeze-dried excipient mixing by weight percentage, the pH value of aqueous solution is 6.7;
Step 5, employing Rotary Evaporators are removed the intravital organic solvent of step 4 mixing liquid, to remove the liquid concentration of organic solvent to 500ml, with 0.22 μ m microporous filter membrane aseptic filtration, get the nanoemulsions sample and carry out particle size determination with laser particle analyzer, particle diameter is normal distribution, particle diameter is 10nm～100nm, and the nanoemulsions branch installs in the lyophilizing bottle;
Step 6, the unsealed lyophilizing bottle of step 5 packing is put into freeze drying box, the temperature in the freeze drying box be-38 ℃～-42 ℃, keeps 10～12 hours, then freeze drying box is carried out application of vacuum, makes the interior vacuum of case less than 100 * 10
-3Mbar, kept 45～50 hours by-38 ℃～-42 ℃ again,-33 ℃～-37 ℃ kept 20～24 hours, and-28 ℃～-32 ℃ kept 10～14 hours, and-25 ℃～-27 ℃ kept 10～14 hours,-18 ℃～-22 ℃ kept 5～7 hours,-8 ℃～-12 ℃ kept 5～7 hours, and-3 ℃～-7 ℃ kept 3～7 hours, and 0 ℃ kept 4～6 hours, 2～6 ℃ keep encapsulation after 3～5 hours, promptly make docetaxel nanometer preparation of the present invention.
The present invention makes nano particle preparations with docetaxel, and nanoparticle is a kind of novel drug-loading system, and its particle diameter in the scope of hundreds of nanometer, is a kind of ideal intravenous pharmaceutical carrier usually.Medicine can dissolve or be wrapped in the nanoparticle, is particularly suitable for bag and carries fat-soluble medicine, can solve the solubility problem of the medicine such as the docetaxel of poorly water-soluble.Owing to do not use easy adjuvant hypersensitive and solvent such as tween 80, product of the present invention does not have the anaphylaxis that adjuvant or solvent bring, so need not carry out the antiallergic pretreatment in the administration front and back, has significantly increased the compliance of patient's medication.This novel form has been subjected to increasing concern.The nanometer formulation that has abroad gone on the market has treatment breast cancer medicines paclitaxel (Abraxane), immunosuppressant sirolimus (Rapamune) and Bendectin aprepitant (Emend) at present.In addition, the nanometer formulation of budesonide, busulfan, insulin, FENOBRATE top grade medicine has entered the I clinical trial phase stage, and Thymectacin and a kind of cytokine inhibitor also enter the II phase respectively, the I/II clinical trial phase stage.
In addition, for the cancer therapy drug docetaxel, selecting another major reason of nanoparticle is its good biocompatibility, internally there is the biological target tropism at positions such as rete cutaneum shape system, tumor, can and can reduce the toxic and side effects of medicine by the intravital esterase biological of machine degraded back slow releasing pharmaceutical, behind the material degradation easily by the body removing etc.Adopt the nanoparticle of nanotechnology preparation, can arrive cancerous cell and act on cancerous cell inside and outside micromolecule or genetic stew by highly selective, fully shown its superiority.Nano-particle enters behind the blood circulation often by macrophage phagocytic, is enriched in liver, spleen, lung, bone marrow, lymph node etc., and these organs and tissue are the natural target organs of drug-carrying nanometer particle.Wherein be distributed in liver (60%～90%), spleen (2%～10%), lung (3%～10%).Therefore, people often utilize these characteristics of Nano medication to treat tumor.But the retention time of nanoparticle slow release antitumor drug prolong drug in tumor, tumor growth slows down; With free drug mutually specific energy prolong the time-to-live of laboratory animal.Animal experiment study shows, after daunorubicin paracyanogen base propylene alkane ester nanoparticles is carried in intravenous injection, the liver Kupffer Cell is engulfed a large amount of nanoparticles, become a kind of effective drug storage warehouse, the nanoparticle of degraded constantly discharges free medicine to the liver tumor tissue, the phagocyte that is activated simultaneously also discharges cytotoxic factor, has improved the curative effect of medicine potentially.The amycin glucan complex is sealed and is made the chitosan/nanometer particle after vein is annotated people's tumor-bearing mice, prolong drug plasma half-life not only, and can keep effect by enhanced infiltration, make medicine be enriched to tumor tissues, and can slowly discharge medicine and prolong drug effect.In addition, adopt amycin paracyanogen base propylene alkane ester nanoparticles to studies show that the drug resistance of cancerous cell is greatly reduced, and drug effect specific ionization amycin increases by 10 times.A kind of antimicrobial agents---clofazimine just under study for action, that be used for the treatment of the infection of HIV sufferers mycobacterium avium.This medicine is because low, toxicity of dissolubility and side effect are bigger, and application is restricted.Use for the experimental mouse intravenous injection of inoculation pathogenic bacteria after being made into nanometer formulation, result after 1 week of medication shows, compare with isodose clofazimine liposome group, though two kinds of preparations do not have significant difference on the curative effect to the experimental mouse pulmonary infection, the gradient of infection of nanometer formulation group experimental mouse liver and spleen is starkly lower than clofazimine liposome group.Find that simultaneously to behind the experimental mouse injection clofazimine nanometer formulation two hours, the concentration of medicine in liver was 1.62 times of its Liposomal formulation.The tissue distribution data show that also the medicine of nanoparticle is more suitable for targeting in RE matter system.
Of the present invention is the docetaxel nanometer preparation and the preparation method of carrier with albumin and phospholipid, do not adopt the adjuvant and the solvent that human body are produced harm, eliminate the anaphylaxis that causes by adjuvants such as tween 80s, improved the safety of docetaxel solid nano-medicine preparation and the compliance of patient's medication greatly; The Docetaxel for Injection nanoparticle is to preserve with the solid state after the lyophilizing, faces with before adding the injection water and disperses the back to use, and therefore, the stability of docetaxel improves greatly, also helps the storage and the transportation of medicine simultaneously; The good biocompatibility of Docetaxel for Injection nanometer formulation, internally there is passive biological target tropism at positions such as rete cutaneum shape system, tumor, can arrive cancerous cell and act on cancerous cell inside and outside micromolecule or genetic stew by highly selective, fully shown the advantage of potential advantage for its antitumor action.Method of the present invention adopts high pressure homogenization and Freeze Drying Technique, can carry out suitability for industrialized production.
The specific embodiment
The specific embodiment one: present embodiment is made up of docetaxel, albumin, phospholipid, vitamin E, freeze-dried excipient and acidic buffer salt by weight percentage, docetaxel is 1～15% by weight percentage, albumin is 10～43%, phospholipid is 10～43%, vitamin E is 1～10%, freeze-dried excipient be 1～20% and acidic buffer salt be 1～15% to form, add organic solvent, adopt high pressure homogenization and cryodesiccated preparation technology to prepare the solid powder preparation of 100～700 nanometers.
The specific embodiment two: the difference of the present embodiment and the specific embodiment one is by weight percentage that docetaxel is 8%, albumin 30%, phospholipid are 30%, vitamin E is 5%, freeze-dried excipient be 15% and acidic buffer salt 12% form, add the ethanol of 35ml, adopt high pressure homogenization and cryodesiccated preparation technology to prepare the powder formulation of 100～700 nanometers.
The specific embodiment three: the described albumin of present embodiment adopts human serum albumin, bovine serum albumin or passes through the resulting albumin of biotechnology.But be not limited to above-mentioned listed.
The specific embodiment four: the described phospholipid of this enforcement formula adopts soybean phospholipid, egg yolk lecithin or synthetic phospholipid.But be not limited to above-mentioned listed.
The specific embodiment five: the described freeze-dried excipient of present embodiment adopts sucrose, lactose, maltose, mannitol or trehalose.But be not limited to above-mentioned listed.
The specific embodiment six: present embodiment is that the preparation method of docetaxel nanometer preparation of carrier is as follows with albumin and phospholipid:
Step 1, get that docetaxel is 1～15% by weight percentage, phospholipid be 10～43% and vitamin E be 1～10%, add the organic solvent of 10～43ml, ultrasonic dissolution is made organic facies;
Step 2, by weight percentage get albumin be 10～43% and acidic buffer salt be 1～15%, add the water for injection of 100～1000ml, be mixed with aqueous solution, the pH value of solution is 6.7 (regulating with HCl),
Step 3, the organic facies of step 1 is joined in the aqueous solution of step 2, under high speed shear, be prepared into colostrum;
Step 4, the colostrum that step 3 is prepared into are handled on high pressure homogenizer, under low pressure 30～40 MPas, handle once earlier, under high pressure 130～150 MPas, handle twice then, with the nano-emulsion of above-mentioned processing and 1～20% aqueous solution freeze-dried excipient mixing by weight percentage, the pH value of aqueous solution is 6.7;
Step 5, employing Rotary Evaporators are removed the intravital organic solvent of step 4 mixing liquid, to remove the liquid concentration of organic solvent to 500ml, with 0.22 μ m microporous filter membrane aseptic filtration, get the nanoemulsions sample and carry out particle size determination with laser particle analyzer, particle diameter is normal distribution, particle diameter is 10nm～100nm, and the nanoemulsions branch installs in the lyophilizing bottle;
Step 6, the unsealed lyophilizing bottle of step 5 packing is put into freeze drying box, the temperature in the freeze drying box be-38 ℃～-42 ℃, keeps 10～12 hours, then freeze drying box is carried out application of vacuum, makes the interior vacuum of case less than 100 * 10
-3Mbar, kept 45～50 hours by-38 ℃～-42 ℃ again,-33 ℃～-37 ℃ kept 20～24 hours, and-28 ℃～-32 ℃ kept 10～14 hours, and-25 ℃～-27 ℃ kept 10～14 hours,-18 ℃～-22 ℃ kept 5～7 hours,-8 ℃～-12 ℃ kept 5～7 hours, and-3 ℃～-7 ℃ kept 3～7 hours, and 0 ℃ kept 4～6 hours, 2～6 ℃ keep encapsulating after 3～5 hours, promptly make the bottled preparation of docetaxel nanometer of the present invention.
The specific embodiment seven: the difference of the present embodiment and the specific embodiment six is to get by weight percentage in the step 1 8% docetaxel, 30% soybean phospholipid and 5% vitamin E, adds the chloroform of 35ml, ultrasonicly makes dissolving, makes organic facies; Get in the step 2 in the aqueous solution that above-mentioned organic facies joins 800ml, this solution contains and comprises the acidic buffer salt organic facies material, that account for total solid material 12% and 30% albumin, the pH value of solution is 6.7, regulates with HCl, is prepared into colostrum after high speed shear; The colostrum that step 3 is prepared into is handled on high pressure homogenizer, under low pressure 35 MPas, handle once earlier, handle twice then under high pressure 140 MPas, with the nano-emulsion of above-mentioned processing and 15% aqueous solution freeze-dried excipient mixing by weight percentage, the pH value of aqueous solution is 6.7; Temperature in the step 5 in the freeze drying box is-40 ℃, keeps 12 hours, then freeze drying box is carried out application of vacuum, makes the interior vacuum of case less than 100 * 10
-3Mbar, kept 48 hours by-40 ℃ again,-35 ℃ kept 24 hours, and-30 ℃ kept 12 hours, and-25 ℃ kept 12 hours,-20 ℃ kept 6 hours,-10 ℃ kept 6 hours, and-5 ℃ kept 5 hours, and 0 ℃ kept 5 hours, 4 ℃ keep lyophilizing end encapsulation after 4 hours, promptly make docetaxel nanometer preparation of the present invention.
Redissolve with 0.9%NaCl solution during use, the back particle diameter that redissolves is normal distribution, and size is 100～700nm.
The specific embodiment eight: the described organic solvent of present embodiment adopts ethanol or chloroform.
Claims (9)
1. with albumin and phospholipid the docetaxel nanometer preparation of carrier, form by docetaxel, albumin, phospholipid, vitamin E, freeze-dried excipient and acidic buffer salt by weight percentage, it is characterized in that by weight percentage that docetaxel is 1～15%, albumin is 10～43%, phospholipid is 10～43%, vitamin E is 1～10%, freeze-dried excipient be 1～20% and acidic buffer salt be 1～15% to form, add organic solvent, adopt high pressure homogenization and cryodesiccated preparation technology to prepare the powder formulation of 100～700 nanometers.
2. according to claim 1 is the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that by weight percentage that docetaxel is 8%, albumin 30%, phospholipid are 30%, vitamin E is 5%, freeze-dried excipient be 15% and acidic buffer salt 12% form, add the ethanol of 35ml, adopt high pressure homogenization and cryodesiccated preparation technology to prepare the powder formulation of 100～700 nanometers.
3. according to claim 1 is the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that described albumin adopts human serum albumin, bovine serum albumin or passes through the resulting albumin of biotechnology.
4. according to claim 1 is the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that described phospholipid adopts soybean phospholipid, egg yolk lecithin or synthetic phospholipid.
5. according to claim 1 is the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that described freeze-dried excipient adopts sucrose, lactose, maltose, mannitol or trehalose.
6. according to claim 1 is the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that described acidic buffer salt adopts hydrochloric acid, citric acid, phosphoric acid, lactic acid or acetic acid.
7. according to claim 1 is the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that described organic solvent adopts ethanol or chloroform.
8. claim 1 is described is the preparation method of the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that the step of this method is as follows:
Step 1, get that docetaxel is 1～15% by weight percentage, phospholipid be 10～43% and vitamin E be 1～10%, add the organic solvent of 10～43ml, ultrasonic dissolution is made organic facies;
Step 2, by weight percentage get albumin be 10～43% and acidic buffer salt be 1～15%, add the water for injection of 100～1000ml, be mixed with aqueous solution, the pH value of solution is 6.7, adopts HCl to regulate,
Step 3, the organic facies of step 1 is joined in the aqueous solution of step 2, under high speed shear, be prepared into colostrum;
Step 4, the colostrum that step 3 is prepared into are handled on high pressure homogenizer, under low pressure 30～40 MPas, handle once earlier, under high pressure 130～150 MPas, handle twice then, with nano-emulsion after the above-mentioned processing and 1～20% aqueous solution freeze-dried excipient mixing by weight percentage, the pH value of aqueous solution is 6.7;
Step 5, employing Rotary Evaporators are removed the intravital organic solvent of step 4 mixing liquid, to remove the liquid concentration of organic solvent to 500ml, with 0.22 μ m microporous filter membrane aseptic filtration, get the nanoemulsions sample and carry out particle size determination with laser particle analyzer, particle diameter is normal distribution, particle diameter is 10nm～100nm, and the nanoemulsions branch installs in the lyophilizing bottle;
Step 6, the unsealed lyophilizing bottle of step 5 packing is put into freeze drying box, the temperature in the freeze drying box be-38 ℃～-42 ℃, keeps 10～12 hours, then freeze drying box is carried out application of vacuum, makes the interior vacuum of case less than 100 * 10
-3Mbar, kept 45～50 hours by-38 ℃～-42 ℃ again,-33 ℃～-37 ℃ kept 20～24 hours, and-28 ℃～-32 ℃ kept 10～14 hours, and-25 ℃～-27 ℃ kept 10～14 hours,-18 ℃～-22 ℃ kept 5～7 hours,-8 ℃～-12 ℃ kept 5～7 hours, and-3 ℃～-7 ℃ kept 3～7 hours, and 0 ℃ kept 4～6 hours, 2～6 ℃ keep encapsulation after 3～5 hours, promptly make docetaxel nanometer preparation of the present invention.
9. according to claim 8 is the preparation method of the docetaxel nanometer preparation of carrier with albumin and phospholipid, it is characterized in that getting by weight percentage in the step 1 8% docetaxel, 30% soybean phospholipid and 5% vitamin E, the ethanol that adds 35ml, ultrasonicly make dissolving, make organic facies; Get in the step 2 in the aqueous solution that above-mentioned organic facies joins 800ml, this solution contains and comprises that the organic facies material accounts for the acidic buffer salt of total solid material 12% and 30% albumin, the pH value of solution is 6.7, regulates with HCl, is prepared into colostrum after high speed shear; The colostrum that step 3 is prepared into is handled on high pressure homogenizer, under low pressure 35 MPas, handle once earlier, handle twice then under high pressure 140 MPas, with nano-emulsion after the above-mentioned processing and 15% aqueous solution freeze-dried excipient mixing by weight percentage, the pH value of aqueous solution is 6.7; Temperature in the step 5 in the freeze drying box is-40 ℃, keeps 12 hours, then freeze drying box is carried out application of vacuum, makes the interior vacuum of case less than 100 * 10
-3Mbar, kept 48 hours by-40 ℃ again,-35 ℃ kept 24 hours, and-30 ℃ kept 12 hours, and-25 ℃ kept 12 hours,-20 ℃ kept 6 hours,-10 ℃ kept 6 hours, and-5 ℃ kept 5 hours, and 0 ℃ kept 5 hours, 4 ℃ keep lyophilizing end encapsulation after 4 hours, promptly make docetaxel nanometer preparation of the present invention.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552174A (en) * | 2011-11-18 | 2012-07-11 | 中山大学 | Preparation method of polypeptide/proteinic drug nanoparticle with high drug loading and high encapsulation efficiency |
| CN102626393A (en) * | 2011-10-17 | 2012-08-08 | 复旦大学 | Albumin nanometer particle preparation for soluble injection and preparation method of albumin nanometer particle preparation |
| CN103751107A (en) * | 2013-12-18 | 2014-04-30 | 清华大学深圳研究生院 | Nano-particle containing docetaxel and vitamin E TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) and preparation method thereof |
| CN105616361A (en) * | 2014-10-30 | 2016-06-01 | 复旦大学 | Preparation method of tinib drug alhumin nano preparation used for injection |
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2009
- 2009-11-30 CN CN200910073294XA patent/CN102078301A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626393A (en) * | 2011-10-17 | 2012-08-08 | 复旦大学 | Albumin nanometer particle preparation for soluble injection and preparation method of albumin nanometer particle preparation |
| CN102626393B (en) * | 2011-10-17 | 2015-10-28 | 复旦大学 | A kind of solubility injection albumin nano granular preparation and preparation method thereof |
| CN102552174A (en) * | 2011-11-18 | 2012-07-11 | 中山大学 | Preparation method of polypeptide/proteinic drug nanoparticle with high drug loading and high encapsulation efficiency |
| CN103751107A (en) * | 2013-12-18 | 2014-04-30 | 清华大学深圳研究生院 | Nano-particle containing docetaxel and vitamin E TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) and preparation method thereof |
| CN105616361A (en) * | 2014-10-30 | 2016-06-01 | 复旦大学 | Preparation method of tinib drug alhumin nano preparation used for injection |
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