CN1242740C - Mitoxantrone or mitoxantrone hydrochloride liposome injection and its preparing process - Google Patents
Mitoxantrone or mitoxantrone hydrochloride liposome injection and its preparing process Download PDFInfo
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- CN1242740C CN1242740C CN 200410041612 CN200410041612A CN1242740C CN 1242740 C CN1242740 C CN 1242740C CN 200410041612 CN200410041612 CN 200410041612 CN 200410041612 A CN200410041612 A CN 200410041612A CN 1242740 C CN1242740 C CN 1242740C
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Abstract
The present invention discloses a mitoxantrone or mitoxantrone hydrochloride liposome injection and preparation technology thereof. The injection is composed of mitoxantrone or mitoxantrone hydrochloride, phospholipid, cholesterol, an antioxidant, organic acid, alkali, sugar, a buffering agent and injecting water. The preparation technology comprises the steps: preparing a lipid film, packing medicine, homogenizing a liposome, purifying or solidifying the liposome, setting volume, killing bacteria, separately charging and preserving the medicine, etc. The injection has the advantages of high stability, high packing efficiency, low cost and little toxic or side effect; the preparation technology is simple and feasible.
Description
Technical field
The present invention relates to the preparation of mitoxantrone or mitoxantrone hydrochloride, relate to a kind of mitoxantrone or liposome of mitoxantrone hydrochloric acid injection specifically, the invention still further relates to the preparation technology of this medicine.
Background technology
Mitoxantrone or mitoxantrone hydrochloride are anthracene nucleus antineoplastic antibiotic, and its mechanism of action mainly is that the mitoxantrone molecule enters nucleus and combines with DNA, thereby suppress the synthetic and mitosis of nucleic acid and cause cell death.Mitoxantrone or mitoxantrone hydrochloride are mainly used in malignant lymphoma, breast carcinoma and acute leukemia, and pulmonary carcinoma, melanoma, soft tissue sarcoma, multiple myeloma, hepatocarcinoma, colorectal cancer, renal carcinoma, carcinoma of prostate, carcinoma of endometrium, tumor of testis, ovarian cancer and incidence cancer are also had certain curative effect.
For doxorubicin hydrochloride, the long-term and short term toxicity of mitoxantrone or mitoxantrone hydrochloride is lower, but can produce bone marrow depression when accumulated dose strengthens, and causes leukocyte and thrombocytopenia.Clinically the toxic and side effects of Chu Xianing also have to feel sick, digestive tract reactions such as vomiting, loss of appetite, diarrhoea, also have toxic and side effects such as weak, alopecia, erythra, stomatitis to find in addition.Above-mentioned toxic and side effects makes the clinical practice of mitoxantrone or mitoxantrone hydrochloride be subjected to very big restriction.
Liposome (Liposome) is dispersed in phospholipid by Britain scholar Bangham and Standish at first and finds when carrying out electron microscopic observation in the water.Phospholipid is dispersed in and forms multilamellar vesicle, every layer of bilayer that is lipid in the water naturally; Separated by water between vesicle central authorities and each layer, bilayer thickness is about 4 nanometers.Afterwards, this bilayer folliculus with similar biofilm structure was called liposome.Liposome can be divided into multilamelar liposome and unilamelar liposome.Unilamelar liposome is divided into small unilamellar vesicle and large unilamellar vesicle again.What Bangham and Standish found at first is exactly multilamelar liposome, and they more easily prepare, and size is generally good 0.5-5 micron.Small unilamellar vesicle is spherical, and size is generally good 20-50 nanometer; Large unilamellar vesicle is of a size of the micron number magnitude.People such as Britain Lai Men began liposome is used for pharmaceutical carrier in 1971, the main mechanism of action is drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane, this microgranule has the class cellularity, enter the autoimmune function that is mainly activated body in the human body by reticuloendothelial system phagocytic, and the interior distribution of the body that changes encapsulated medicine, make the drug main will be liver, spleen, put aside in the histoorgan such as lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of the therapeutic dose and the reduction medicine of medicine.Liposome as pharmaceutical carrier mostly is large unilamellar vesicle at present, and particle diameter is generally between the 100-1000 nanometer.The seventies middle and late stage, people begin one's study liposome as the effective carrier of anthracycline anticancer drug, the end of the eighties, existing clinical experiment began to carry out, to American-European existing liposome medicament listing of the mid-90.When this type of medicine is wrapped in after specific liposome enters human body by intravenous injection again, the clinical experiment result shows that its toxic and side effects obviously reduces, the drug half-life significant prolongation, but its drug effect does not weaken on the contrary and is strengthened.
The liposome product of succeeding in developing in the world at present and going on the market has the Doxil of U.S. Alza Pharmaceuticals pharmaceuticals development
And Caelyx
, be mainly used in treatment recurrent ovarian carcinoma Kaposi ' the s sarcoma relevant with AIDS; (Elan Pharmaceuticals Inc.) is mainly used in the Myocet that treats breast carcinoma in U.S. Yi Lan pharmaceuticals
TMAmBisome and DaunoXome that U.S. Gilead produces, its pharmacy activity component is respectively amphotericin B and daunorubicin.Doxil
, Caelyx
And Myocet
TMPharmacy activity component all be amycin or doxorubicin hydrochloride, wherein Doxil
And Caelyx
Be the utilization " stealth " (stealth) technology doxorubicin hydrochloride is wrapped in the liposome microgranule, simultaneously superscribe Polyethylene Glycol (PEG) again with its circulating half-life in vivo of further prolongation at each liposome microparticle surfaces, their half-life can reach 55 hours.The success of the APHOIS company of the U.S. has made Liposomal formulation with paclitaxel (paclitaxel) and camptothecine insoluble drugs such as (camptothecin) and has been used for the treatment of breast carcinoma in addition.But up to the present, also there is not the liposome product of mitoxantrone on market, to sell in the world.The mitoxantrone that the present invention relates to or the preparation of mitoxantrone hydrochloride have not only been replenished the blank that China developed and produced the mitoxantrone Liposomal formulation voluntarily, and will make China be in the first place in the world on the research and development of this product and production technology.
Summary of the invention:
The purpose of this invention is to provide a kind of good stability, encapsulation ratio height, cost is low, toxic and side effects is few mitoxantrone or liposome of mitoxantrone hydrochloric acid injection.
Another object of the present invention provides the preparation technology of this injection.
Technical scheme of the present invention is the characteristic according to liposome, select for use specific phospholipid to prepare the bilayer lipid membrane of parcel mitoxantrone or mitoxantrone, also add cholesterol and free radical scavenger vitamin E in the prescription and increase the stability of liposomal mitoxantrone, adopt the pH gradient method to promote the medicine parcel, the medicine encapsulation ratio is up to more than 95%, and mitoxantrone is discharged into the intravital speed of people after controlling said preparation and be injected into human body by special processing technique from liposome, has reduced the toxic and side effects of mitoxantrone hydrochloride and its drug effect is increased.Liposome mainly is made up of natural and/or synthetic phospholipid, and these phospholipid can be divided into three major types, promptly neutral phospholipid, and positively charged phospholipid and electronegative phospholipid, liposome preparation of the present invention is mainly selected neutral lecithin for use.In addition, also add cholesterol in the prescription, it solidifies liposome bimolecular tunic, thereby reduces the generation of free radical, has reduced oxidation level, and liposome stability is significantly strengthened.The molar ratio of cholesterol and neutral phospholipid is 0.1: 1-1: 1.Simultaneously for the further phospholipid of formation liposome and the chemical degradation of liposome institute packaging medicine of reducing, also having added vitamin E in the prescription. vitamin E is a kind of effective anti-oxidants, is considered to by bringing into play its antioxidation with the oxygen molecule of reaction of phospholipid peroxylradicals and quencher singlet state with to bilayer (as the flowability of restriction lipoid layer molecule) equimolecular mechanism that sorts of phospholipid.The molar ratio of vitamin E and phospholipid is 0.001: 1-0.1: 1.Existing result of study shows that the hydrolysis of lecithin, saturated soybean phospholipid and phosphatidyl glycerol ester etc. all is subjected to the influence of pH value, and hydrolyzate can make the pH value decline of liposome suspension, the further hydrolysis of acceleration liposome.These phospholipid compositions are all the most stable when pH 6.5, hydrolysis rate constant minimum.Therefore, the present invention is after being wrapped in mitoxantrone or mitoxantrone hydrochloride in the blank liposome effectively, again mitoxantrone or liposome of mitoxantrone hydrochloric acid are placed the Liposomal dispersion that adds buffer agent, further strengthened the stability of mitoxantrone or liposome of mitoxantrone hydrochloric acid.
Mitoxantrone or mitoxantrone hydrochloride can adopt " ion gradient method " to be wrapping in the blank liposome, and its difference by ion concentration inside and outside the liposome bimolecular lipid layer makes that medicine is easier to be wrapping in the liposome, and these ions comprise Na
+, K
+, Li
+, NH
4 +, H
+Deng, use H
+The time method be known as " pH gradient method ".The present invention will adopt in " ion gradient method " effect preferably " pH gradient method " wrap up mitoxantrone or mitoxantrone hydrochloride.This method makes liposome outer mitoxantrone or mitoxantrone hydrochloride more easily enter in the liposome by the pH difference of regulating the liposome internal and external environment, and intravital mitoxantrone of lipid or mitoxantrone hydrochloride are difficult for being discharged into outside the liposome, thereby make the medicine encapsulation ratio very high, generally can reach more than 95%.The pH value in the liquid phase environment increases the medicine encapsulation ratio to concrete measure outside the liposome lipid duplicature by mitoxantrone or mitoxantrone hydrochloride are regulated with ground caustic foam or aqueous alkali when being wrapping to liposome, medicine is in the acidic aqueous solution that the liposome bilayer lipid membrane wrapped up, and acidic aqueous solution is by the organic acid preparation of 0.01M-0.5M.The granularity of liposome and the uniformity can all grain be fully machine-processed by high pressure, also can reach the blank liposome suspension pushes through respective aperture under pressure microporous membrane by extrusion equipment.Behind packaging medicine, then mitoxantrone or liposome of mitoxantrone hydrochloric acid are placed and Liposomal dispersion like the Human Physiology environmental classes by the dialysis Filtration.
The preparation of blank liposome can be adopted film dispersion method (TFV), and also available reverse phase evaporation (REV), alcohol injection prepare.Exact temperature is different and different with the liposome component in the preparation process.Added buffer agent for increasing its stability between the storage life in the dispersion liquid of finished product mitoxantrone or liposome of mitoxantrone hydrochloric acid.
Purpose of the present invention can be come for realizing by following measure:
The lipidosome injection of a kind of mitoxantrone or mitoxantrone hydrochloride, the composition of raw materials of every 1000ml preparation is:
Mitoxantrone or mitoxantrone hydrochloride 500mg-2.5g
Phosphatidase 15 00mg-25g
Cholesterol 25mg-14.3g
Antioxidant 0.28mg-1.6g
Organic acid 30mg-30g
Alkali 25mg-42g
Sugar 28g-150g
Buffer agent 1g-100g
Water for injection is settled to 1000ml
Satisfy simultaneously: the molar ratio of mitoxantrone or mitoxantrone hydrochloride and phospholipid is 0.05: 1-0.5: 1, and the molar ratio of cholesterol and neutral phospholipid is 0.1: 1-1: 1.
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, wherein phospholipid can be Ovum Gallus domesticus Flavus lecithin (EPC), hydrogenated yolk lecithin (HEPC), two stearic acid lecithin (DSPC), soybean lecithin (soy PC), hydrogenated soy phosphatidyl choline (HSPC), two palmitic acid lecithin (DPPC) or two nutmeg acid lecithin (DMPC).
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, wherein antioxidant can be a vitamin E, the molar ratio of vitamin E and phospholipid is 0.001: 1-0.1: 1.
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, wherein organic acid can be citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or galacturonic acid.
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, wherein alkali can be calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium phosphate, dibastic sodium phosphate, sodium hydroxide.
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, wherein sugar is lactose, maltose, sucrose, glucose, trehalose or cotton white sugar.
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, wherein buffer agent can be glycine, histidine or trometamol.
The lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride, its dosage form can be injection, lyophilized powder.
The preparation method of the lipidosome injection of described mitoxantrone or mitoxantrone hydrochloride comprises the following step:
1) preparation lipid membrane: select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in chloroform or the chloroform-methanol mixed solvent according to prescription; With Rotary Evaporators solvent decompression in the solution is removed, form lipid membrane;
2) preparation contains the liposome suspension of mitoxantrone or mitoxantrone hydrochloride:
A. prepare the mitoxantrone organic acid soln of 0.01M-0.5M, come the aquation lipid membrane with the mitoxantrone acid solution, hydration temperature generally between 40 ℃-70 ℃, gets the mitoxantrone liposome suspension;
B. prepare the aqueous alkali of 0.1M-2.0M or prepare the ground caustic end, regulate the mitoxantrone liposome suspension with aqueous alkali or ground caustic end and be incubated a period of time down to alkalescence and at 40 ℃-70 ℃;
3) homogenize liposome: parcel back fully is equipped with liposome to the required particle diameter and the uniformity with the equal grain mechanism of high pressure, also can reach the blank liposome suspension pushes through respective aperture under pressure microporous membrane by extrusion equipment, the particle diameter of liposome is controlled at 50-300nm, and the liposome particle diameter and the uniformity can detect with multi-angle nanoparticle analyzer;
4) preparation mitoxantrone or liposome of mitoxantrone hydrochloric acid: compound concentration is the sugar aqueous solution of 3%-15% and adds buffer agent by weight percentage, is adjusted to pH5-pH7, gets the dispersion liquid of liposome, and the content of buffer agent is 0.2%-10%; Adopt the dispersion liquid of liposome to wash the liposome that contains mitoxantrone or mitoxantrone hydrochloride then, utilize the dialysis Filtration to make mitoxantrone or the outer solution of liposome of mitoxantrone hydrochloric acid be replaced into the dispersion liquid of the liposome of pH5-pH7, make mitoxantrone or liposome of mitoxantrone hydrochloric acid be dispersed in sugar aqueous solution like the Human Physiology environmental classes in, mitoxantrone or liposome of mitoxantrone hydrochloric acid;
5) standardize solution, degerming, packing, preservation: use the water for injection standardize solution; With gained mitoxantrone or the micro-pore-film filtration degerming of liposome of mitoxantrone hydrochloric acid suspension, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Advantage of the present invention:
The particle diameter of liposomal lipid plastid of the present invention is between 50nm-300nm, and the medicine encapsulation ratio can reach more than 95%, and non-parcel mitoxantrone or mitoxantrone hydrochloride content are few, are generally less than 5%.Simultaneously, prescription adds cholesterol and antioxidant vitamin E, makes the stability of mitoxantrone or liposome of mitoxantrone hydrochloric acid improve greatly.In addition; since in the production process of liposome acid hydrochloride salt crucial equal grain step can by high pressure efficiently all a grain machine finish; and said preparation also can be made freeze-dried formulation by lyophilizing and preserves; this not only makes the stability of mitoxantrone or liposome of mitoxantrone hydrochloric acid further improve, and makes the suitability for industrialized production of said preparation become possibility.The one year stability experiment result of lyophilized powder of the present invention under 2 ℃-8 ℃ shows its mean diameter rate of change less than 10%, and the rate of change of medicine encapsulation ratio has shown the stability of mitoxantrone of the present invention or liposome of mitoxantrone hydrochloric acid preparation excellence less than 5%.
Domestic raw material has been adopted in the preparation of mitoxantrone or liposome of mitoxantrone hydrochloric acid preparation, greatly reduces its production cost, makes China cancer patient can bear this drug effect height and the low PTS of toxic and side effects.
Pharmacodynamic experiment result of the present invention:
1) toxic and side effects experiment
Mitoxantrone liposome (L-MITOX) preparation is pressed example 4 preparations, and concentration is 1.0mg/ml, and traditional mitoxantrone hydrochloride (F-MITOX) preparation is dissolved in the physiological saline solution preparation by mitoxantrone hydrochloride, and concentration is 1.0mg/ml.L-MITOX and F-MITOX are gone in the mice body by mouse tail vein injection respectively.Toxicity test shows that mice is 10mg/Kg to the maximum drug resistance dosage (MTD) of F-MITOX, and the maximum drug resistance dosage (MTD) of L-MITOX significantly is increased to 30mg/Kg.In 10mg/Kg dosage group, the reduction of the mice body weight of injection L-MITOX in two weeks is less than 3%, and mice body weight body weight continuous decrease after injection of injection F-MITOX reaches 30% body weight minimizing in the 12nd day.
Experimental result shows that the toxic and side effects of mitoxantrone liposome is starkly lower than traditional mitoxantrone hydrochloride.
2) the mitoxantrone liposome is to the effect experiment of leukemia L1210 cell
Leukemia L1210 cell is injected in the mice body by mouse tail vein.The concentration of being injected by example 1 preparation by mouse tail vein after 24 hours is the liposomal mitoxantrone (L-MITOX) of 1.0mg/ml.Mice in control group is injected traditional mitoxantrone hydrochloride (F-MITOX) that the concentration that is dissolved in physiological saline solution is 1.0mg/ml under similarity condition.Use the L-MITOX and the F-MITOX:5mg/Kg of three kinds of various dose in the experiment, 10mg/Kg and 20mg/Kg, experiment periods is 60 days.
In the mice of injection L-MITOX, the mouse death rate of 10mg/Kg and 20mg/Kg dosage group is zero, and average survival period was above 60 days.The mouse death rate of 5mg/Kg dosage group is 100%, about 15 days of average survival period.
In the mice of injection F-MITOX, 5mg/Kg, the mouse death rate of 10mg/kg and 20mg/Kg dosage group is 100%.About 12 days of the average survival period of mice of 5mg/kg dosage group; About 15 days of the average survival period of mice of 10mg/Kg dosage group; About 10 days of the average survival period of mice of 20mg/Kg dosage group.
Above-mentioned effect experiment result shows that liposomal mitoxantrone not only has the obvious treatment effect to the L1210 leukemia, and toxic and side effects obviously alleviates, and curative effect is better than traditional mitoxantrone greatly.And liposomal mitoxantrone preparation of the present invention can obviously increase medicine in the intake of sick body and strengthen its antineoplastic treatment function.
The specific embodiment
By the following examples the present invention is further illustrated, embodiment is not a limitation of the present invention.
Embodiment 1
Preparation prescription (1000ml capacity):
Mitoxantrone 500mg
Two nutmeg acid lecithins (DMPC) 6g
Cholesterol 1.3g
Vitamin E 7.8mg
Citric acid 1150mg
Natrium carbonicum calcinatum 800mg
Sucrose 90g
Histidine 5g
Water for injection is settled to desired volume
Preparation process is as follows:
Select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in the chloroform according to prescription; With Rotary Evaporators chloroform decompression in the solution is removed, form lipid membrane; The citric acid solution of preparation 50mM also adds the mitoxantrone of formula ratio, comes the aquation lipid membrane with the citric acid solution of gained mitoxantrone, and generally between 60 ℃-65 ℃, hydration time is 15-30 minute to hydration temperature; Regulate the pH to 7.2+0.2 of gained mitoxantrone liposome suspension with the Carbon Dioxide sodium water solution of 0.5M, insulation 10-30 minute between 60 ℃-65 ℃ then; Wrapping up complete back is 100nm with machine-processed liposome to the mean diameter fully of the equal grain of high pressure, and the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer; Preparation 9% aqueous sucrose solution also adds 0.5% histidine, Liposomal dispersion; Adopt the Liposomal dispersion washing to contain the liposome of mitoxantrone, utilizing the dialysis Filtration to make the outer solution of mitoxantrone liposome be replaced into pH is 7.0 ± 0.2 Liposomal dispersion, with water for injection standardize solution and the concentration that is adjusted to mitoxantrone is 1.0mg/ml solution, with of the micro-pore-film filtration degerming of mitoxantrone liposome suspension with 0.22 micron pore size, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Embodiment 2
Preparation prescription (1000ml capacity):
Mitoxantrone 1000mg
Two nutmeg acid lecithins (DMPC) 12g
Cholesterol 2.5g
Vitamin E 15mg
Citric acid 2300mg
Natrium carbonicum calcinatum 1600mg
Sucrose 90g
Histidine 5g
Water for injection is settled to desired volume
Preparation process is as follows:
Select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in the chloroform according to prescription; With Rotary Evaporators chloroform decompression in the solution is removed, form lipid membrane; The citric acid solution of preparation 50mM also adds the mitoxantrone of formula ratio, comes the aquation lipid membrane with the citric acid solution of gained mitoxantrone, and generally between 60 ℃-65 ℃, hydration time is 15-30 minute to hydration temperature; Regulate pH to 7.2 ± 0.2 of gained mitoxantrone liposome suspension with the Carbon Dioxide sodium water solution of 0.5M, insulation 10-30 minute between 60 ℃-65 ℃ then; Wrapping up complete back is 80nm with machine-processed liposome to the mean diameter fully of the equal grain of high pressure, and the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer; Preparation 9% aqueous sucrose solution also adds 0.5% histidine, Liposomal dispersion; Adopt the Liposomal dispersion washing to contain the liposome of mitoxantrone, utilizing the dialysis Filtration to make the outer solution of mitoxantrone liposome be replaced into pH is 7.0 ± 0.2 Liposomal dispersion, with water for injection standardize solution and the concentration that is adjusted to mitoxantrone is 1.0mg/ml solution, with of the micro-pore-film filtration degerming of mitoxantrone liposome suspension with 0.22 micron pore size, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Embodiment 3
Preparation prescription (1000ml capacity):
Mitoxantrone 1000mg
Hydrogenated soy phosphatidyl choline (HSPC) 13.9g
Cholesterol 2.5g
Vitamin E 15mg
Citric acid 2300mg
Natrium carbonicum calcinatum 1600mg
Sucrose 90g
Histidine 5g
Water for injection is settled to desired volume
Preparation process is as follows:
Select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in the chloroform according to prescription; With Rotary Evaporators chloroform decompression in the solution is removed, form lipid membrane; The citric acid solution of preparation 50mM also adds the mitoxantrone of formula ratio, comes the aquation lipid membrane with the citric acid solution of gained mitoxantrone, and generally between 60 ℃-65 ℃, hydration time is 30-60 minute to hydration temperature; Regulate pH to 7.2 ± 0.2 of gained mitoxantrone liposome suspension with the Carbon Dioxide sodium water solution of 0.5M, insulation 10-30 minute between 60 ℃-65 ℃ then; Wrapping up complete back is 100nm with machine-processed liposome to the mean diameter fully of the equal grain of high pressure, and the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer; Preparation 9% aqueous sucrose solution also adds 0.5% histidine, Liposomal dispersion; Adopt the Liposomal dispersion washing to contain the liposome of mitoxantrone, utilizing the dialysis Filtration to make the outer solution of mitoxantrone liposome be replaced into pH is 7.0 ± 0.2 Liposomal dispersion, with water for injection standardize solution and the concentration that is adjusted to mitoxantrone is 1.0mg/ml solution, with of the micro-pore-film filtration degerming of mitoxantrone liposome suspension with 0.22 micron pore size, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Embodiment 4
Preparation prescription (1000ml capacity):
Mitoxantrone 1000mg
Two palmitic acid lecithin (DPPC) 13g
Cholesterol 2.5g
Vitamin E 15mg
Citric acid 2300mg
Sodium hydroxide 1200mg
Sucrose 90g
Histidine 5g
Water for injection is settled to desired volume
Preparation process is as follows:
Select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in the chloroform according to prescription; With Rotary Evaporators chloroform decompression in the solution is removed, form lipid membrane; The citric acid solution of preparation 50mM also adds the mitoxantrone of formula ratio, comes the aquation lipid membrane with the citric acid solution of gained mitoxantrone, and generally between 60 ℃-65 ℃, hydration time is 30-60 minute to hydration temperature; Regulate pH to 7.2 ± 0.2 of gained mitoxantrone liposome suspension with the sodium hydrate aqueous solution of 1.0M, insulation 10-30 minute between 60 ℃-65 ℃ then; Wrapping up complete back is 100nm with machine-processed liposome to the mean diameter fully of the equal grain of high pressure, and the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer; Preparation 9% aqueous sucrose solution also adds 0.5% histidine, Liposomal dispersion; Adopt the Liposomal dispersion washing to contain the liposome of mitoxantrone, utilizing the dialysis Filtration to make the outer solution of mitoxantrone liposome be replaced into pH is 7.0 ± 0.2 Liposomal dispersion, with water for injection standardize solution and the concentration that is adjusted to mitoxantrone is 1.0mg/ml solution, with of the micro-pore-film filtration degerming of mitoxantrone liposome suspension with 0.22 micron pore size, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Embodiment 5
Preparation prescription (1000ml capacity):
Mitoxantrone 1000mg
Two stearic acid lecithin (DSPC) 14g
Cholesterol 2.5g
Vitamin E 15mg
Citric acid 2300mg
Natrium carbonicum calcinatum 1600mg
Sucrose 90g
Histidine 5g
Water for injection is settled to desired volume
Preparation process is as follows:
Select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in the chloroform according to prescription; With Rotary Evaporators chloroform decompression in the solution is removed, form lipid membrane; The citric acid solution of preparation 50mM also adds the mitoxantrone of formula ratio, comes the aquation lipid membrane with the citric acid solution of gained mitoxantrone, and generally between 60 ℃-65 ℃, hydration time is 30-60 minute to hydration temperature; Regulate pH to 7.2 ± 0.2 of gained mitoxantrone liposome suspension with the Carbon Dioxide sodium water solution of 0.5M, insulation 10-30 minute between 60 ℃-65 ℃ then; Wrapping up complete back is 88nm with machine-processed liposome to the mean diameter fully of the equal grain of high pressure, and the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer; Preparation 9% aqueous sucrose solution also adds 0.5% histidine, Liposomal dispersion; Adopt the Liposomal dispersion washing to contain the liposome of mitoxantrone, utilizing the dialysis Filtration to make the outer solution of mitoxantrone liposome be replaced into pH is 7.0 ± 0.2 Liposomal dispersion, with water for injection standardize solution and the concentration that is adjusted to mitoxantrone is 1.0mg/ml solution, with of the micro-pore-film filtration degerming of mitoxantrone liposome suspension with 0.22 micron pore size, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Embodiment 6
Preparation prescription (1000ml capacity):
Mitoxantrone 2500mg
Two stearic acid lecithin (DSPC) 35g
Cholesterol 6.3g
Vitamin E 38mg
Citric acid 5800mg
Natrium carbonicum calcinatum 4000mg
Sucrose 90g
Histidine 5g
Water for injection is settled to desired volume
Preparation process is as follows:
Select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in the chloroform according to prescription; With Rotary Evaporators chloroform decompression in the solution is removed, form lipid membrane; The citric acid solution of preparation 50mM also adds the mitoxantrone of formula ratio, comes the aquation lipid membrane with the citric acid solution of gained mitoxantrone, and generally between 60 ℃-65 ℃, hydration time is 30-60 minute to hydration temperature; Regulate pH to 7.2 ± 0.2 of gained mitoxantrone liposome suspension with the Carbon Dioxide sodium water solution of 0.5M, insulation 10-30 minute between 60 ℃-65 ℃ then; Wrapping up complete back is 110nm with machine-processed liposome to the mean diameter fully of the equal grain of high pressure, and the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer; Preparation 9% aqueous sucrose solution also adds 0.5% histidine, Liposomal dispersion; Adopt the Liposomal dispersion washing to contain the liposome of mitoxantrone, utilizing the dialysis Filtration to make the outer solution of mitoxantrone liposome be replaced into pH is 7.0 ± 0.2 Liposomal dispersion, with water for injection standardize solution and the concentration that is adjusted to mitoxantrone is 1.0mg/ml solution, with of the micro-pore-film filtration degerming of mitoxantrone liposome suspension with 0.22 micron pore size, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
Claims (9)
1, the lipidosome injection of a kind of mitoxantrone or mitoxantrone hydrochloride is characterized in that the composition of raw materials of every 1000ml preparation is:
Mitoxantrone or mitoxantrone hydrochloride 500mg-2.5g
Phosphatidase 15 00mg-25g
Cholesterol 25mg-14.3g
Antioxidant 0.28mg-1.6g
Organic acid 30mg-30g
Alkali 25mg-42g
Sugar 28g-150g
Buffer agent 1g-100g
Water for injection is settled to 1000ml
Satisfy simultaneously: the molar ratio of mitoxantrone or mitoxantrone hydrochloride and phospholipid is 0.05: 1-0.5: 1, and the molar ratio of cholesterol and phospholipid is 0.1: 1-1: 1.
2, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that phospholipid is selected from Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, two palmitic acid lecithin or two nutmeg acid lecithin.
3, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that antioxidant is a vitamin E, and the molar ratio of vitamin E and phospholipid is 0.001: 1-0.1: 1.
4, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that organic acid is citric acid, succinic acid, acetic acid, oxalic acid, Fructus Vitis viniferae acid, lactobionic acid, glucuronic acid or galacturonic acid.
5, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that alkali is calcium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium phosphate, dibastic sodium phosphate or sodium hydroxide.
6, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that sugar is lactose, maltose, sucrose, glucose, trehalose or cotton white sugar.
7, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that buffer agent is glycine, histidine or trometamol.
8, the lipidosome injection of mitoxantrone according to claim 1 or mitoxantrone hydrochloride is characterized in that its dosage form is injection, lyophilized powder.
9, the preparation method of the lipidosome injection of described mitoxantrone of claim 1 or mitoxantrone hydrochloride is characterized in that comprising the following step:
1) preparation lipid membrane: select for use phospholipid, cholesterol and vitamin E to be dissolved in mix homogeneously in chloroform or the chloroform-methanol mixed solvent according to prescription; With Rotary Evaporators solvent decompression in the solution is removed, form lipid membrane;
2) preparation contains the liposome suspension of mitoxantrone or mitoxantrone hydrochloride:
A. prepare the mitoxantrone organic acid soln of 0.01M-0.5M, come the aquation lipid membrane with the mitoxantrone acid solution, hydration temperature generally between 40 ℃-70 ℃, gets the mitoxantrone liposome suspension;
B. prepare the aqueous alkali of 0.1M-2.0M or prepare the ground caustic end, regulate the mitoxantrone liposome suspension with aqueous alkali or ground caustic end and be incubated a period of time down to alkalescence and at 40 ℃-70 ℃;
3) homogenize liposome: parcel back fully is equipped with liposome to the required particle diameter and the uniformity with the equal grain mechanism of high pressure, also can reach the blank liposome suspension pushes through respective aperture under pressure microporous membrane by extrusion equipment, the particle diameter of liposome is controlled at 50-300nm, and the liposome particle diameter and the uniformity can detect with multi-angle nanoparticle analyzer;
4) preparation mitoxantrone or liposome of mitoxantrone hydrochloric acid: compound concentration is the sugar aqueous solution of 3%-15% and adds buffer agent by weight percentage, is adjusted to pH5-pH7, gets the dispersion liquid of liposome, and the content of buffer agent is 0.2%-10%; Adopt the dispersion liquid of liposome to wash the liposome that contains mitoxantrone or mitoxantrone hydrochloride then, utilize the dialysis Filtration to make mitoxantrone or the outer solution of liposome of mitoxantrone hydrochloric acid be replaced into the dispersion liquid of the liposome of pH5-pH7, make mitoxantrone or liposome of mitoxantrone hydrochloric acid be dispersed in sugar aqueous solution like the Human Physiology environmental classes in, mitoxantrone or liposome of mitoxantrone hydrochloric acid;
5) standardize solution, degerming, packing, preservation: use the water for injection standardize solution; With gained mitoxantrone or the micro-pore-film filtration degerming of liposome of mitoxantrone hydrochloric acid suspension, packing gets product, and finished product can preserve under 2 ℃-8 ℃ or lyophilizing is saved to use.
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| CN 200410041612 CN1242740C (en) | 2004-08-05 | 2004-08-05 | Mitoxantrone or mitoxantrone hydrochloride liposome injection and its preparing process |
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| CN 200410041612 CN1242740C (en) | 2004-08-05 | 2004-08-05 | Mitoxantrone or mitoxantrone hydrochloride liposome injection and its preparing process |
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| CN1242740C true CN1242740C (en) | 2006-02-22 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10028913B2 (en) | 2006-12-29 | 2018-07-24 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd | Liposomal pharmaceutical preparation and method for manufacturing the same |
| EP3643299A4 (en) * | 2017-06-23 | 2021-03-17 | Shenzhen China Resources Jiuchuang Medical and Pharmaceutical Co., Ltd | Biological self-assembled nanocrystal injection having lymphatic targeting function and preparation method |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244039B (en) * | 2008-03-20 | 2012-09-12 | 江苏先声药物研究有限公司 | Novel method for preparing indissoluble medicaments liposome preparations |
| CN101912363A (en) * | 2010-07-29 | 2010-12-15 | 蔡海德 | Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine |
| KR20190067172A (en) * | 2016-09-09 | 2019-06-14 | 아이리시스, 인크. | Liposome cancer composition |
| WO2021180184A1 (en) * | 2020-03-12 | 2021-09-16 | 石药集团中奇制药技术（石家庄）有限公司 | Use of mitoxantrone hydrochloride liposomes |
| CN114601791B (en) * | 2020-12-08 | 2023-09-19 | 成都倍特药业股份有限公司 | Mitoxantrone hydrochloride liquid preparation and preparation method thereof |
| CN114748457A (en) * | 2022-04-11 | 2022-07-15 | 中国医学科学院医学生物学研究所 | Pharmaceutical composition for treating cervical cancer and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10028913B2 (en) | 2006-12-29 | 2018-07-24 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd | Liposomal pharmaceutical preparation and method for manufacturing the same |
| EP3643299A4 (en) * | 2017-06-23 | 2021-03-17 | Shenzhen China Resources Jiuchuang Medical and Pharmaceutical Co., Ltd | Biological self-assembled nanocrystal injection having lymphatic targeting function and preparation method |
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| CN1602844A (en) | 2005-04-06 |
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