CN103830181A - Docetaxel freeze-dried lipidosome and preparation method thereof - Google Patents
Docetaxel freeze-dried lipidosome and preparation method thereof Download PDFInfo
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- CN103830181A CN103830181A CN201210489755.3A CN201210489755A CN103830181A CN 103830181 A CN103830181 A CN 103830181A CN 201210489755 A CN201210489755 A CN 201210489755A CN 103830181 A CN103830181 A CN 103830181A
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Abstract
The invention belongs to the field of medical technology, and discloses a docetaxel freeze-dried lipidosome and a preparation method thereof. Docetaxel is included by cyclodextrin to improve the solubility, and then the docetaxel freeze-dried lipidosome is prepared by a film dispersion method and a freeze thawing method. The docetaxel freeze-dried lipidosome consists of 0.5-2.0% of cyclodextrin-included docetaxel, 2-65% of natural phospholipid, 0.1-20.0% of cholesterol and derivative thereof, 15-80% of freeze-drying protection agent and appropriate buffer salt. In the invention, the lipidosome prepared by repeated freeze thawing has relatively small particle size and high encapsulation rate while the water solubility of docetaxel and the stability of lipidosome are improved by cyclodextrin coating, and the prepared freeze-dried lipidosome is convenient to store and transport.
Description
one, technical field:
The invention belongs to field of pharmaceutical preparations, relate to a kind of property anticarcinogen docetaxel lyophilization dry liposome hard to tolerate of meter and preparation method thereof.
two, background technology:
Docetaxel (docetaxel, Docetaxel, commodity are called Taxotere, taxotere) be antitumor drug of new generation, it and paclitaxel (paclitaxel, commodity are called Taxol) belong to taxanes together, structural formula as shown in Figure 1, is the taxanes cancer therapy drug of FDA approval.Docetaxel can be by the non-activity compound extracting in European yew (Taxusbaccata, European yew) needle, then obtains through semi-synthetic.Docetaxel is developed by French Rhone-Poulenc Rorer, and as the chemotherapeutics of breast carcinoma, nonsmall-cell lung cancer, Fig. 1 be shown in chemical structural formula, its mechanism of action is the formation that promotes microtubule, stop the decomposition of tubulin, thereby blocking-up cell mitogen impels apoptosis.Docetaxel and combination chemotherapy thereof are applied to the treatment of the kinds of tumors such as breast carcinoma, nonsmall-cell lung cancer, cancer of pancreas, soft tissue sarcoma, head and neck cancer, gastric cancer, ovarian cancer and carcinoma of prostate clinically more and more.
Docetaxel is as the common medicine of cancer therapy drug, and its independent medication oral administration biaavailability is only 8%, and being made into ejection preparation is one of means that improve its bioavailability.Because docetaxel is insoluble in water, docetaxel injection is mainly formulated with tween 80 and ethanol etc. at present, and commodity are called taxotere (Taxotere
).Although Tween 80 toxicity is relatively little, but in I clinical trial phase, still there is serious allergy, because tween 80 easily produces the untoward reaction such as haemolysis and allergy, therefore before use docetaxel injection, toxicity and the untoward reaction such as the severe allergy that must use Claritin to help alleviate to produce due to the use of docetaxel, usually bring misery to patient, directly affected the use of this medicine.In addition, as cytotoxicity antitumor drug, the general toxicity of docetaxel, particularly easily causes the immune system toxicity such as neutrophilic granulocytopenia, has caused great infringement to patient's body and mind, has greatly limited its clinical practice.Therefore, develop new injection docetaxel type and have great importance, be both at home and abroad all devoted to study low toxicity, eutherapeutic docetaxel novel form, increases the dissolubility of medicine, avoids the use of Tween 80 simultaneously.
Administration nano-drug administration system (nanoparticle drug delivery system, NDDS) be the focus of the outer research of Present Domestic, show good application prospect realizing the aspect such as the bioavailability of targeting administration, sustained-release administration, raising insoluble drug and polypeptide drugs, reduction adverse effect.The more docetaxel nanometer preparation of research mainly contains liposome (liposome), microemulsion (microemulsion), solid lipid nanoparticle (solid lipid nanoparticles at present, SLN), nano-lipid carrier (nanostructured lipid carrier, NLC), polymer nanoparticle (polymeric nanoparticles), micellar system (micellar system) etc.
To be nineteen sixty-five be at first dispersed in water discovery while carrying out electron microscopic observation by British scholar Bangham and Standish by phospholipid to liposome (liposome).Liposomal lipid plastid is made up of phospholipid and cholesterol, has similar biomembranous bilayer structure.Liposome belongs to a kind of novel form of targeting drug delivery system, it can be large by toxic and side effects, poor stability in blood, degraded is fast, it is in nano level liposome microgranule that water-fast drug powder or solution are embedded in diameter, this microgranule can see through vascular endothelial cell gap, body foci position and arrive lesions position, and the interior distribution of the body that changes encapsulated medicine, make it pile up and discharge in focus portion, make the drug main will be liver, spleen, in the histoorgan such as lung and bone marrow, put aside, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine, to reach the object of targeted delivery of drugs.Current novel targeted liposome comprises pro-liposome, long circulating liposomes, immunoliposome etc.Docetaxel, with after liposome, can overcome the untoward reaction that in normal injection agent, Tween 80 produces, and Polyethylene Glycol (PEG) is modified the rear prolong drug holdup time in vivo, improves drug effect, also can increase the stability of medicine.
At present, the method of preparing liposome is more, conventional have that membrane process, reverse phase evaporation, ultrasound wave disperse, solvent injection method and multi-emulsion method etc., these methods are commonly referred to as Passive loading method, in the time preparing pastille liposome, first medicine is soluble in the aqueous phase or organic facies in, then prepare pastille liposome by suitable method, this method is suitable for fat-soluble strong medicine, and gained liposome has higher envelop rate.And pH gradient method, ammonium sulphate gradient is commonly referred to as active loading method.Below simply introduce the method for several Passive loadings:
1, film dispersion method: at first by reports such as Bangham, be the most original but be the preparation method of the most widely used liposome of fundamental sum up to now.The lipoid such as phospholipid and cholesterol and fat-soluble medicine are dissolved in to organic solvent, then this solution is placed in to a large round-bottomed flask, rotating pressure-decreasing evaporate to dryness again, phospholipid can form the very thin film of one deck on flask inwall, then add a certain amount of buffer solution, fully vibration flask comes off lipid film aquation, can obtain liposome.This method can obtain higher envelop rate to water soluble drug, but liposome particle diameter is between 0. 2～5 μ m, can process or make liposome pass through the polycarbonate membrane of fixing particle diameter by extruding by ultrasonoscope, reduce to a certain extent the particle diameter of liposome.
2, ultrasonic dispersion: phospholipid, cholesterol are dissolved in organic solvent together with medicine to be encapsulated, and after mix homogeneously, rotary evaporation is removed organic solvent, and remaining solution, again through ultrasonic Treatment, is separated and obtain liposome.Supercritical ultrasonics technology can be divided into two kinds " water-bath supercritical ultrasonics technology and probe supercritical ultrasonics technologies ", and this law is to prepare the common method of small liposome, but ultrasound wave easily causes the degradation problem of medicine.
3, freeze-drying: liposome turbid liquor is easily assembled at lay up period, fusion and drug leakage, and phospholipid is oxidizable, hydrolysis, is difficult to meet the requirement of pharmaceutical preparation stability.The reported first such as Vanleberghe in 1978 adopt freeze-drying to improve the bin stability of liposome.At present, this method has become one of more promising method of improving Liposomal formulation long-time stability.Liposome lyophilization comprises pre-freeze, preliminarily dried and 3 processes of redrying.Freeze-dried lipidosome can be directly as solid dosage forms, and as spray uses, also available water or other solvation are reconstructed into liposome turbid liquor and use, but the processes such as pre-freeze, dry and rehydration are all unfavorable for the stable of liposome structure and function.As added suitable freeze drying protectant before lyophilizing, adopt suitable technique, can greatly alleviate and even eliminate the destruction of freeze-drying process to liposome, after rehydration, the form of liposome, particle diameter and envelop rate etc. are all without significant change.Monosaccharide, disaccharide, oligosaccharide, polysaccharide, polyhydric alcohol and other water-soluble high-molecular substances can be used as lipidosome freeze-dried protective agent, and wherein disaccharide is that most study is also the most effective, and conventional have trehalose, maltose, sucrose and a lactose.This law is suitable for the preparation of thermosensitive type prodrug liposome, but cost is higher.Chen Jianmings etc., taking soybean phospholipid as film material, taking mannitol as freeze drying protectant, adopt lyophilization to prepare vitamin A precursor liposome, and after rehydration, mean diameter is 0. 615 1 μ m, envelop rate 98. 5%.In woods, side waits employing lyophilization to prepare podophyllotoxin body liposome, and after rehydration, mean diameter is 1. 451 μ m, envelop rate 72. 3%, and still this method still exists weak point, and for example after liposome rehydration, particle size distribution is even not.
4, freeze-thaw method: first preparation is encapsulated with the liposome of medicine, then freezing.In quick freezing process, due to the formation of ice crystal, the liposome membrane forming is broken, the lamella of ice crystal and broken film exist simultaneously, this state labile, in slow melting process, the mutual fusion of adipose membrane exposing forms liposome again.Find by research, the envelop rate of liposome prepared by freeze-thaw method is the highest, but particle diameter maximum.Multigelation can improve the envelop rate of liposome, and Wang Jiansong has prepared Azithromycin liposome, and experiment is found, repeat after freeze thawing through 3 times, the envelop rate of Azithromycin liposome is increased to 78% from 61.4%, but is increased to 4 times when number of freezing and thawing, and envelop rate changes very little.This preparation method is suitable for relatively large production, especially the most applicable to unsettled medicine.
5, multi-emulsion method: phospholipid is dissolved in organic solvent by the 1st step, add the solution of medicine to be encapsulated, emulsifying obtains W/O colostrum, and the 2nd step joins colostrum in the water of 10 times of volumes mixes, emulsifying obtains W/O/W emulsion, then removes at a certain temperature organic solvent and can obtain liposome.The envelop rate that Kim makes liposome with emulsion process is higher, but particle diameter is larger.Tomoko etc. find by research, the temperature of the removal process of the 2nd step emulsion process and organic solvent has larger impact to the particle diameter of liposome, lower temperature is conducive to reduce the particle diameter of liposome, and can make particle diameter by control temperature is 400 nm, and envelop rate reaches 90% liposome.
6, injection method: lipoids and fat-soluble medicine are dissolved in to (oil phase) in organic solvent, then oil phase average rate are expelled in water (containing water-soluble medicine), stir and wave most organic solvent, the more newborn even or ultrasonic liposome that obtains.Can be divided into alcohol injection and ether injection according to the difference of solvent.Alcohol injection has been avoided with an organic solvent, and Ding Liyan has prepared sparfloxacin by Ethanol Method, finds to inject and can make the liposome with higher envelop rate at a slow speed by research, and its envelop rate is 47%.Liposome prepared by ether injection is mostly unilamelar liposome, the particle diameter overwhelming majority is below 2 μ m, temperature lower (40 DEG C) in operating process, therefore, the method is applicable to have better dissolubility in ether and to thermally labile medicine, by regulating the concentration of different phospholipid in ether, can obtain the uniform liposome turbid liquor of different-grain diameter and particle size distribution simultaneously.
7, reverse phase evaporation: proposed by Szoka at first, general method for making is that the film materials such as phospholipid are dissolved in organic solvent, and sonic oscillation in short-term, until form stable W/O emulsion, then reduction vaporization is removed organic solvent, reach after colloidal state, drip buffer, rotary evaporation comes off the gel on wall, then under reduced pressure continue evaporation, make aqueous suspension, remove the medicine not wrapping into, obtain large unilamellar liposome liposome.This method can be wrapped up larger water capacity, is generally applicable to seal water soluble drug, macromole bioactive substance etc.
8, supercritical methanol technology: traditional method for preparing lipidosome, must use the organic solvents such as chloroform, ether, methanol, this is all harmful to environment and human body.Supercritical carbon dioxide is the reaction medium of a kind of nontoxic, inertia and environmental sound.Yan Bin etc. have prepared cefazolin sodium lipidosome by supercritical methanol technology, and a certain amount of lecithin is dissolved in ethanol and joins to obtain lecithin alcoholic solution, put into and add autoclave together with cefazolin sodium sodium solution, and autoclave is put into water bath with thermostatic control, pass into CO
2.Under its above-critical state, hatch 30min, prepare liposome.Adopt supercritical CO
2the standby envelop rate of legal system is high, particle diameter is little, and stability strengthens.
three, summary of the invention:
The object of the invention is to prepare that a kind of particle diameter is less, envelop rate is high, the lyophilized formulations of the much higher Xi Tasai liposome of stability, be convenient to transport and storage simultaneously.
Object of the present invention can be achieved through the following technical solutions.
The lyophilized formulations of docetaxel liposome of the present invention, contains following composition in every 100g docetaxel liposome lyophilized formulations:
Cyclodextrin inclusion compound docetaxel 0.5-2.0g
Natural phospholipid 2.0-65.0g
Vitamin E 2.0-20.0g
Cholesterol and derivant 0.1-20.0g thereof
Freeze drying protectant 15.0-80.0g
Buffer 0.01-1.00g
Docetaxel liposome sterile freeze-drying preparation of the present invention makes according to following method:
The docetaxel, natural phosphatidyl choline, vitamin E, cholesterol and the derivant thereof that take the cyclodextrin inclusion compound of above-mentioned amount are dissolved in appropriate organic solvent fully dissolves, by mixture reduction vaporization on Rotary Evaporators, remove organic solvent, lipid is evenly distributed in round-bottomed flask inner surface, with a small amount of buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle, by the 0.22 μ m filter membrane granulate depyrogenation that pressurizeed, divide and be filled to room temperature thawing after refrigerator freezing in ampoule, repeat after 3 times lyophilization and get final product.
The preparation of docetaxel lyophilization dry liposome comprises following detailed step:
(1) docetaxel, natural phosphatidyl choline, vitamin E, cholesterol and the derivant thereof that take cyclodextrin inclusion compound are dissolved in eggplant-shape bottle, add in appropriate organic solvent and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(2) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent.
(3) adopt water for injection to prepare the buffer salt solution that contains freeze drying protectant, regulate between pH5.5-7.5, with a small amount of buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(4) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(5) ampoule is placed in to room temperature after refrigerator freezing and melts, repeat 3 times;
(6) lyophilization obtains docetaxel lyophilization dry liposome.
What in the present invention, in docetaxel lyophilization dry liposome, docetaxel adopted is its cyclodextrin clathrate, preparation method is to take appropriate docetaxel and cyclodextrin and derivant thereof to be dissolved in appropriate solvent, and constant temperature stirs, solvent evaporated under reduced pressure, after suitably processing, be drying to obtain.Described suitable processing method comprises that reduction vaporization is to solvent-free, pulverizes dry; Reduction vaporization is appropriate to solvent residue, to refrigerator overnight crystallize, filtration drying; Reduction vaporization is appropriate to solvent residue, to the slow crystallize of room temperature, filtration drying.Wherein, in the docetaxel of cyclodextrin inclusion compound, the ratio of cyclodextrin and docetaxel is 10:1-1:1, preferably 6:1-4:1; Cyclodextrin is selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, methyl-β-cyclodextrin, hydroxypropyl first group-beta-cyclodextrin, one chlorotriazine-beta-schardinger dextrin-, 2,6-DM-β-CD.
Described docetaxel lyophilization dry liposome, it is characterized in that natural phospholipid be selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin, in one or more.Cholesterol and derivant thereof are selected from one or more in cholesterol, hydrocholesterol, D-straight glucose cholesterol.Buffer is selected from the one in phosphate, acetate, succinate, citrate, histidine and glycinate.Freeze drying protectant is selected from one or more in maltose, mannitol, galactose, lactose, glucose sugar, sucrose, trehalose.
Docetaxel lyophilization dry liposome in the present invention, the method for employing is the combination of film dispersion method and freeze-thaw method, wherein the method for multigelation is that after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times.
Final products are lyophilized formulations, are convenient to store and transport, and its cryodesiccated method is the pre-freeze temperature of-45 DEG C, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and saves backup.
four, brief description of the drawings
The structural formula of Fig. 1, docetaxel;
five, detailed description of the invention:
Embodiment 1
Docetaxel 0.5g
Beta-schardinger dextrin-2.0g
Ovum Gallus domesticus Flavus lecithin 15.0g
Vitamin E 2.5g
Cholesterol 2.0g
Mannitol 30.0g
Glycinate buffer 0.3g
(1) prepare the docetaxel of dextrin enclose: take 1.0g docetaxel and 4.0g beta-schardinger dextrin-is dissolved in appropriate chloroform: in ethanol (2:1) mixed solvent, constant temperature stirs 5-6h, reduction vaporization, pulverizing is drying to obtain.
(2) docetaxel, Ovum Gallus domesticus Flavus lecithin, vitamin E, cholesterol that take recipe quantity cyclodextrin inclusion compound are in eggplant-shape bottle, add in the appropriate tert-butyl alcohol and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(3) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent.
(4) adopt water for injection to prepare the glycinate buffer salt solution of the freeze drying protectant that contains mannitol, regulate between pH5.5-7.5, with the jolting of a small amount of glycinate buffer, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(5) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(6) after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times;
(7) ampoule is placed in to the pre-freeze temperature of-45 DEG C, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and saves backup.
Embodiment 2
Docetaxel 0.5g
Beta-schardinger dextrin-2.0g
Soybean lecithin 15.0g
Vitamin E 2.5g
Hydrocholesterol 2.0g
Mannitol 30.0g
Phosphate buffer 0.3g
(1) prepare the docetaxel of dextrin enclose: take 1.0g docetaxel and 4.0g beta-schardinger dextrin-is dissolved in appropriate chloroform: in ethanol (2:1) mixed solvent, constant temperature stirs 5-6h, and reduction vaporization is appropriate to solvent residue, to refrigerator overnight crystallize, filtration drying and get final product.
(2) docetaxel, soybean lecithin, vitamin E, hydrocholesterol that take recipe quantity cyclodextrin inclusion compound are in eggplant-shape bottle, add in appropriate ethanol and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(3) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent.
(4) adopt water for injection to prepare the phosphate buffered saline of the freeze drying protectant that contains mannitol, regulate between pH5.5-7.5, with a small amount of phosphate buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(5) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(6) after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times;
(7) ampoule is placed in to the pre-freeze temperature of-45 DEG C, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and saves backup.
Embodiment 3
Docetaxel 0.5g
Hydroxypropyl first group-beta-cyclodextrin 2.5g
Ovum Gallus domesticus Flavus lecithin 15.0g
Vitamin E 2.5g
Cholesterol 2.0g
Maltose 12.0g
Mannitol 18.0g
Acetate buffer 0.3g
(1) prepare the docetaxel of dextrin enclose: take 1.0g docetaxel and 5.0g hydroxypropyl first group-beta-cyclodextrin is dissolved in appropriate chloroform: in ethanol (2:1) mixed solvent, constant temperature stirs 5-6h, reduction vaporization, appropriate to solvent residue, to the slow crystallize of room temperature, crystallize completely after filtration drying and get final product.
(2) docetaxel, Ovum Gallus domesticus Flavus lecithin, vitamin E, cholesterol that take recipe quantity cyclodextrin inclusion compound are in eggplant-shape bottle, add in the appropriate tert-butyl alcohol and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(3) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent.
(4) adopt water for injection to prepare the acetate salt buffer saline solution of the freeze drying protectant that contains maltose and mannitol, regulate between pH5.5-7.5, with a small amount of acetate buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(5) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(6) after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times;
(7) ampoule is placed in to the pre-freeze temperature of-45 DEG C, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and saves backup.
Embodiment 4
Docetaxel 0.5g
Hydroxypropyl first group-beta-cyclodextrin 3.0 g
Ovum Gallus domesticus Flavus lecithin 15.0g
Vitamin E 2.5g
Cholesterol 2.0g
Glucose 12.0g
Mannitol 18.0g
Citrate buffer 0.3g
(1) prepare the docetaxel of dextrin enclose: take 1.0g docetaxel and 6.0g hydroxypropyl first group-beta-cyclodextrin is dissolved in appropriate chloroform: in ethanol (2:1) mixed solvent, constant temperature stirs 5-6h, reduction vaporization, appropriate to solvent residue, to refrigerator overnight crystallize, filtration drying and get final product.
(2) docetaxel, Ovum Gallus domesticus Flavus lecithin, vitamin E, cholesterol that take recipe quantity cyclodextrin inclusion compound are in eggplant-shape bottle, add in appropriate ethanol and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(3) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent.
(4) adopt water for injection to prepare the citrate buffer salt solution of the freeze drying protectant that contains glucose and mannitol, regulate between pH5.5-7.5, with a small amount of citrate buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(5) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(6) after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times;
(7) ampoule is placed in to the pre-freeze temperature of-45 DEG C, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and saves backup.
Implement grain 5
Docetaxel 0.5g
Beta-schardinger dextrin-2.5g
Soybean lecithin 15.0g
Vitamin E 2.5g
Hydrocholesterol 2.0g
Maltose 12.0g
Mannitol 18.0g
Phosphate buffer 0.3g
(1) prepare the docetaxel of dextrin enclose: take 1.0g docetaxel and 5.0g beta-schardinger dextrin-is dissolved in appropriate chloroform: in ethanol (2:1) mixed solvent, constant temperature stirs 5-6h, and reduction vaporization is appropriate to solvent residue, to refrigerator overnight crystallize, filtration drying and get final product.
(2) docetaxel, soybean lecithin, vitamin E, hydrocholesterol that take recipe quantity cyclodextrin inclusion compound are in eggplant-shape bottle, add in the appropriate tert-butyl alcohol and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(3) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent.
(4) adopt water for injection to prepare the phosphate buffered saline of the freeze drying protectant that contains maltose and mannitol, regulate between pH5.5-7.5, with a small amount of phosphate buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(5) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(6) after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times;
(7) ampoule is placed in to the pre-freeze temperature of-45 DEG C, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and preserves standby.
Claims (10)
1. a lyophilized formulations for docetaxel liposome, is characterized in that containing in every 1000g docetaxel liposome lyophilized formulations following composition:
Cyclodextrin inclusion compound docetaxel 0.5-2.0g
Natural phospholipid 2.0-65.0g
Vitamin E 2.0-20.0g
Cholesterol and derivant 0.1-20.0g thereof
Freeze drying protectant 15.0-80.0g
Buffer 0.01-1.00g
This docetaxel liposome sterile freeze-drying preparation makes according to following method:
The docetaxel, natural phosphatidyl choline, vitamin E, cholesterol and the derivant thereof that take the cyclodextrin inclusion compound of above-mentioned amount are dissolved in appropriate organic solvent fully dissolves, by mixture reduction vaporization on Rotary Evaporators, remove organic solvent, lipid is evenly distributed in round-bottomed flask inner surface, with a small amount of phosphate buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle, by the 0.22 μ m filter membrane depyrogenation that pressurizeed, divide and be filled to room temperature thawing after refrigerator freezing in ampoule, repeat after 3 times lyophilization and get final product.
2. a kind of docetaxel lyophilization dry liposome preparation as claimed in claim 1, is characterized in that preparation method comprises the steps:
(1) docetaxel, natural phosphatidyl choline, vitamin E, cholesterol and the derivant thereof that take cyclodextrin inclusion compound are dissolved in eggplant-shape bottle, add in appropriate organic solvent and fully dissolve, by mixture reduction vaporization (temperature is adjusted to 40 DEG C) on Rotary Evaporators, remove organic solvent, lipid soln is just formed one deck thin film very uniformly, and shape is evenly distributed in eggplant-shape bottle inner surface;
(2) eggplant-shape bottle is placed in drying baker by taking off in evaporimeter, drying baker is vacuum, spends the night and eliminates solvent;
(3) adopt water for injection to prepare the buffer salt solution that contains freeze drying protectant, regulate between pH5.5-7.5, with a small amount of buffer jolting, make the abundant hydration of lipid film swelling, obtain the evenly white suspension without white particle;
(4) by white suspension successively by the 0.8 μ m that pressurizeed, 0.45 μ m and 0.22 μ m filter membrane depyrogenation, point be filled in ampoule;
(5) ampoule is placed in to room temperature after refrigerator freezing and melts, repeat 3 times;
(6) lyophilization obtains docetaxel lyophilization dry liposome.
3. a kind of docetaxel lyophilization dry liposome as claimed in claim 1, the docetaxel preparation method that it is characterized in that cyclodextrin inclusion compound is to take appropriate docetaxel and cyclodextrin and derivant thereof to be dissolved in appropriate solvent, and constant temperature stirs, solvent evaporated under reduced pressure, after suitably processing, be drying to obtain.
4. the docetaxel of cyclodextrin inclusion compound as claimed in claim 3, its feature comprises that in suitable processing method reduction vaporization is to solvent-free, pulverizes dry; Reduction vaporization is appropriate to solvent residue, to refrigerator overnight crystallize, filtration drying; Reduction vaporization is appropriate to solvent residue, to the slow crystallize of room temperature, filtration drying; The docetaxel of cyclodextrin inclusion compound as claimed in claim 3, the ratio that it is characterized in that cyclodextrin and docetaxel is 10:1-1:1, preferably 6:1-4:1.
5. the docetaxel of cyclodextrin inclusion compound as claimed in claim 3, is characterized in that cyclodextrin is selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, methyl-β-cyclodextrin, hydroxypropyl first group-beta-cyclodextrin, one chlorotriazine-beta-schardinger dextrin-, 2,6-DM-β-CD.
6. a kind of docetaxel lyophilization dry liposome as claimed in claim 1, is characterized in that natural phospholipid is selected from one or more in Ovum Gallus domesticus Flavus lecithin, soybean lecithin.
7. a kind of docetaxel lyophilization dry liposome as claimed in claim 1, is characterized in that cholesterol and derivant thereof are selected from one or more in cholesterol, hydrocholesterol, D-straight glucose cholesterol.
8. a kind of docetaxel lyophilization dry liposome as claimed in claim 1, is characterized in that buffer is selected from the one in phosphate, acetate, succinate, citrate, histidine and glycinate.
9. a kind of docetaxel lyophilization dry liposome as claimed in claim 1, is characterized in that freeze drying protectant is selected from one or more in maltose, mannitol, galactose, lactose, glucose sugar, sucrose, trehalose.
10. a kind of docetaxel lyophilization dry liposome as claimed in claim 1, the method that it is characterized in that multigelation is that after ampoule being placed in to-80 DEG C of refrigerator freezings, room temperature is melted, and repeats 3 times; A kind of docetaxel lyophilization dry liposome as claimed in claim 1, its feature is the pre-freeze temperature of-45 DEG C in cryodesiccated method, then carries out 4h insulation; The 1st time baking temperature is-30 DEG C, carries out the insulation of 30h; Secondary baking temperature is 25 DEG C, then carries out 10h insulation, can obtain Docetaxel for Injection liposome, is placed in 4 DEG C of environment and saves backup.
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| CN104174036A (en) * | 2014-08-29 | 2014-12-03 | 国家纳米科学中心 | Nano-micelle capable of realizing integration of diagnosis and treatment, as well as preparation method and application of nano-micelle |
| CN105943502A (en) * | 2016-06-16 | 2016-09-21 | 安徽医科大学 | Lipidosome medicine carrying method |
| CN107296959A (en) * | 2016-04-13 | 2017-10-27 | 沈阳药科大学 | The cyclodextrin inclusion compound and preparation and use of resibufogenin |
| CN113425689A (en) * | 2021-08-06 | 2021-09-24 | 江西杏林白马药业股份有限公司 | A nanometer preparation of Pithecellobium clypearia extract and its preparation method |
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| CN1813679A (en) * | 2005-11-30 | 2006-08-09 | 上海医药(集团)有限公司 | Taxane liposome lyophilized composition and its preparing method |
| CN1883466A (en) * | 2005-06-22 | 2006-12-27 | 广州威尔曼新药开发中心有限公司 | Preparation process of paclitaxel injection |
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| CN1883466A (en) * | 2005-06-22 | 2006-12-27 | 广州威尔曼新药开发中心有限公司 | Preparation process of paclitaxel injection |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104174036A (en) * | 2014-08-29 | 2014-12-03 | 国家纳米科学中心 | Nano-micelle capable of realizing integration of diagnosis and treatment, as well as preparation method and application of nano-micelle |
| CN107296959A (en) * | 2016-04-13 | 2017-10-27 | 沈阳药科大学 | The cyclodextrin inclusion compound and preparation and use of resibufogenin |
| CN105943502A (en) * | 2016-06-16 | 2016-09-21 | 安徽医科大学 | Lipidosome medicine carrying method |
| CN113425689A (en) * | 2021-08-06 | 2021-09-24 | 江西杏林白马药业股份有限公司 | A nanometer preparation of Pithecellobium clypearia extract and its preparation method |
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