CN104306336A - Technology for preparing citric acid daunorubicin lipidosome injection liquid - Google Patents
Technology for preparing citric acid daunorubicin lipidosome injection liquid Download PDFInfo
- Publication number
- CN104306336A CN104306336A CN201410662764.7A CN201410662764A CN104306336A CN 104306336 A CN104306336 A CN 104306336A CN 201410662764 A CN201410662764 A CN 201410662764A CN 104306336 A CN104306336 A CN 104306336A
- Authority
- CN
- China
- Prior art keywords
- solution
- daunoxome
- sucrose
- blank liposome
- gained
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 title claims abstract description 68
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 title claims abstract description 68
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 238000002347 injection Methods 0.000 title claims abstract description 36
- 239000007924 injection Substances 0.000 title claims abstract description 36
- 238000005516 engineering process Methods 0.000 title claims abstract description 28
- 229960000975 daunorubicin Drugs 0.000 title claims abstract description 20
- 239000007788 liquid Substances 0.000 title abstract 2
- 239000000243 solution Substances 0.000 claims description 101
- 239000002502 liposome Substances 0.000 claims description 59
- 229930006000 Sucrose Natural products 0.000 claims description 50
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 50
- 239000005720 sucrose Substances 0.000 claims description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 229940107841 daunoxome Drugs 0.000 claims description 48
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 24
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 claims description 18
- 229960003109 daunorubicin hydrochloride Drugs 0.000 claims description 18
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 16
- 238000000502 dialysis Methods 0.000 claims description 16
- 239000004471 Glycine Substances 0.000 claims description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 13
- 229960005069 calcium Drugs 0.000 claims description 13
- 229910052791 calcium Inorganic materials 0.000 claims description 13
- 239000011575 calcium Substances 0.000 claims description 13
- 150000003445 sucroses Chemical class 0.000 claims description 13
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 8
- 235000012000 cholesterol Nutrition 0.000 claims description 8
- 239000006166 lysate Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 241000498254 Heterodera glycines Species 0.000 claims description 4
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 claims description 4
- 229940052299 calcium chloride dihydrate Drugs 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000011017 operating method Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 238000005538 encapsulation Methods 0.000 abstract 1
- 238000001125 extrusion Methods 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000012528 membrane Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229920000515 polycarbonate Polymers 0.000 description 6
- 239000004417 polycarbonate Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
The invention discloses a technology for preparing citric acid daunorubicin lipidosome injection liquid. According to the technology, the encapsulation efficiency of a final product is promoted to 97 percent or higher through the operation of preparing of blank lipidosome through multiple times of extrusion, gradient adjusting of the pH value and the like, the releasing rate and stability are good, the safety and effectiveness of the product are effectively improved, the safety of medicine use of a patient is improved, the compliance of medicine use of the patient is improved, and a treatment effect is obviously improved.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of preparation technology of DaunoXome injection.
Background technology
Daunorubicin is first generation anthracene nucleus antineoplastic antibiotic, is mainly used in various types of acute leukemia, does not orally absorb, can only intravenous administration, the form of its hydrochlorate conventional and citrate.
Liposome is the lipid microcapsule with aqueous phase kernel be made up of phospholipid bilayer.There is due to it features such as slow release, low toxicity and tissue-targeting, be often applied to many aspects such as bag medicine carrying thing, gene transfer at present.
DaunoXome injection is the product that Gilead company develops, and is encapsulated in liposome by citric acid daunorubicin and injects.Daunorubicin is encapsulated in after in liposome, not only can avoid cytophagous engulfing, daunorubicin distribution in the tissue can also be changed, increase its directionality to cancerous tumor cell, daunorubicin can be made optionally to kill and wound the breeding of cancerous cell or anticancer, and to normal biological cells and tissues harmless or inhibitory action.Therefore, be that the daunorubicin curative effect of carrier is improved with liposome, toxicity reduces, and immunoreation alleviates.
Daunorubicin liposome injection is so can have these advantages and have benefited from daunorubicin and can be good at being encapsulated in liposome, and envelop rate is the visualize of encapsulating degree.The envelop rate of current commercially available DaunoXome injection is 90%, and consider from the effective angle of safety of medicine, envelop rate still has larger room for promotion.
Summary of the invention
The object of this invention is to provide a kind of preparation technology of DaunoXome injection, the envelop rate of the DaunoXome injection that this technique prepares more than 97%, and has good stability.
In order to realize object of the present invention, inventor provide following technical scheme.
The preparation technology of DaunoXome injection, comprises following operating procedure:
A. citric acid soln is prepared
Compound concentration is 8.64%, pH value is the citric acid soln of 5.0, for subsequent use;
B. blank liposome is prepared
Under 68-72 DEG C of condition, distearoyl phosphatidylcholine 37.65 weight portion, cholesterol 9 weight portion, dehydrated alcohol 42 parts by volume are mixed with steps A gained citric acid soln 258 parts by volume, stirs 1 hour, obtain lipoid lysate, for subsequent use;
Under 68-72 DEG C of condition, lipoid lysate is placed in the extruding of nanometer extruder and prepares blank liposome, it is first the film of 0.2 μm with aperture, under the condition of squeeze pressure 450-600Psi, be repeatedly squeezed to blank liposome mean diameter is 200-220nm, then be the film of 0.1 μm with aperture, the mean diameter being repeatedly squeezed to blank liposome under the condition of squeeze pressure 200-300Psi is 120-130nm, be the film of 0.05 μm again with aperture, the mean diameter being repeatedly squeezed to blank liposome under the condition of squeeze pressure 120-150Psi is 55-62nm, final gained blank liposome is preserved under being placed in 4 DEG C of conditions, for subsequent use,
C. sucrose solution is prepared
Compound concentration is 8.5%, pH value is the sucrose solution of 5.0, for subsequent use;
D. blank liposome dialysis
Under 4 DEG C of conditions, the blank liposome prepared by step B is sealed in bag filter, is placed in step C gained sucrose solution dialysis 4 hours, so repeats, dialyse 3 times altogether, change sucrose solution at every turn;
After dialysis, regulate the pH value to 8.0 of blank liposome, for subsequent use;
E. daunorubicin hydrochloride solution is prepared
Take daunorubicin hydrochloride 2.4 weight portion, be dissolved in 90 parts by volume step C gained sucrose solutions, adjust ph to 8.0 subsequently, finally add step C gained sucrose solution again and be settled to 100 parts by volume, obtain daunorubicin hydrochloride solution, for subsequent use;
F. sucrose solution is prepared
Compound concentration is 8.5%, pH value is the sucrose solution of 8.0, for subsequent use;
G. DaunoXome solution is prepared
Under 68-72 DEG C of condition, the daunorubicin hydrochloride solution that blank liposome after being dialysed by step D gained, step e obtain and the mixing of 200 parts by volume step F gained sucrose solutions, when to be stirred to pH value be 5.6-6.0, stop stirring, obtain DaunoXome solution, be cooled to room temperature, for subsequent use;
H. glycine chlorinated sucrose calcium buffer is prepared
Containing 7.6g sucrose, 0.376g glycine, 0.028 calcium chloride dihydrate in every 100ml, pH value is 5.8;
I. DaunoXome injection is prepared
In step G gained DaunoXome solution, add the concentration that glycine chlorinated sucrose calcium buffer is diluted to daunorubicin is 2mg/ml, gained DaunoXome dilute solution carries out aseptic filtration through 0.2 μm of film, namely obtains DaunoXome injection.
The preparation technology of above-mentioned DaunoXome injection, prepares citric acid soln described in steps A, and the NaOH solution adjust ph using 1mol/L is 5.0.
The preparation technology of above-mentioned DaunoXome injection, prepares sucrose solution described in step C, and the HCl solution adjust ph using 1mol/L is 5.0.
The preparation technology of above-mentioned DaunoXome injection, blank liposome dialysis described in step D, uses the NaOH solution of 1mol/L to regulate the pH value to 8.0 of blank liposome.
The preparation technology of above-mentioned DaunoXome injection, prepares daunorubicin hydrochloride solution described in step e, use the NaOH solution adjust ph to 8.0 of 0.1mol/L.
The preparation technology of above-mentioned DaunoXome injection, prepares sucrose solution described in step F, and the NaOH solution adjust ph using 2mol/L is 8.0.
The preparation technology of above-mentioned DaunoXome injection, prepares glycine chlorinated sucrose calcium buffer described in step H, the hydrochloric acid solution adjust ph using 2mol/L is 5.8.
In preparation technology of the present invention, weight portion is corresponding with the unit of parts by volume, and corresponding relation is a gram corresponding milliliter, by that analogy.
Described in step D, the process of blank liposome dialysis is static dialysis, within 4 hours, reaches capacity, and can dialyse completely after 3 times.Being suspended vertically in sucrose solution by the bag filter that blank liposome is housed during dialysis to make dialysis more abundant.
Prepare in the process of DaunoXome solution described in step G, after solution mixing, to be stirred to pH value be 5.6-6.0, under this condition the envelop rate of finished product and release better, too high or too low envelop rate and the release that all can affect finished product of pH value.
The glycine chlorinated sucrose calcium buffer prepared described in step H, buffer under this ratio condition can dilute dense liposome solutions on the one hand, final products can be made on the other hand to be in a more stable environment, play the effect of buffering.
The water used in preparation technology of the present invention is sterilized water for injection.
The DaunoXome injection that preparation technology of the present invention obtains, containing daunorubicin 50mg, distearoyl phosphatidylcholine 376.5mg, cholesterol 90mg, sucrose 2125mg, glycine 94mg, calcium chloride 7mg in every 25ml, wherein, the mol ratio of daunorubicin, distearoyl phosphatidylcholine, cholesterol is 1:10:5.The best envelop rate and release and the most stable state can be obtained under this ratio condition.
Preparation technology of the present invention is regulated by the gradient of each material solution pH value, the mixing of materials that pH value is 8.0 the most at last prepares DaunoXome injection, each operating procedure complements each other, and finally realizes finished product envelop rate and reaches more than 97%.
The DaunoXome injection obtained according to preparation technology of the present invention, envelop rate, more than 97%, release, to have good stability, and safety and the effectiveness of product are promoted significantly, the compliance of patient can be improved, and then improve the effect for the treatment of.
Detailed description of the invention
Below in conjunction with specific embodiment, content of the present invention is further described in detail.
Embodiment 1
A. citric acid soln is prepared
Accurately weighed 43.2g citric acid, pours in 450ml water and dissolves, to be dissolved completely after, regulate solution ph to 5.0 with the NaOH of 1mol/L, add water and be settled to 500ml, obtain that concentration is 8.64%, pH value is the citric acid soln of 5.0, for subsequent use;
B. blank liposome is prepared
Accurately weighed distearoyl phosphatidylcholine 37.65g, cholesterol 9g, under 68-72 DEG C of condition, mix distearoyl phosphatidylcholine, cholesterol with 42ml dehydrated alcohol, 258ml citric acid soln, stirs 1 hour, obtain lipoid lysate, for subsequent use;
Under 68-72 DEG C of condition, lipoid lysate is placed in the extruding of nanometer extruder and prepares blank liposome, it is first the polycarbonate membrane of 0.2 μm with aperture, repeatedly 5 times are extruded under the condition of squeeze pressure 450Psi, the mean diameter detecting blank liposome is 220nm, then be the polycarbonate membrane of 0.1 μm with aperture, repeatedly 5 times are extruded under the condition of squeeze pressure 200Psi, the mean diameter detecting blank liposome is 130nm, be the polycarbonate membrane of 0.05 μm again with aperture, repeatedly 5 times are extruded under the condition of squeeze pressure 120Psi, the mean diameter detecting blank liposome is 62nm, gained blank liposome is preserved under being placed in 4 DEG C of conditions, for subsequent use,
C. sucrose solution is prepared
Taking sucrose 0.85kg, be settled to 10 liters, is 5.0 by the HCl solution adjust ph of 1mol/L, obtains that concentration is 8.5%, pH value is the sucrose solution of 5.0, for subsequent use;
D. blank liposome dialysis
Step B gained blank liposome is loaded in bag filter, in 4 DEG C of isoperibols, 3L step C gained sucrose solution is poured in the beaker of 5L, then the bag filter vertical suspension of blank liposomes liquid solution being housed in beaker, start magnetic agitation simultaneously, dialyse 4 hours.Repetition like this, dialyses 3 times altogether, the sucrose solution at every turn more renewed;
After dialysis, regulate the pH value to 8.0 of blank liposome by the NaOH solution of 1mol/L, for subsequent use;
E. daunorubicin hydrochloride solution is prepared
Accurately weighed 2.4g daunorubicin hydrochloride in safety operation cabinet, is dissolved in 90ml step C gained sucrose solution, after dissolving completely, by the NaOH solution adjust ph to 8.0 of 0.1mol/L, finally adding step C gained sucrose solution is again settled to 100ml, obtains daunorubicin hydrochloride solution, for subsequent use;
F. sucrose solution is prepared
Take sucrose 25.5g, the water adding 250ml dissolves, and is 8.0 by the NaOH solution adjust ph of 2mol/L, then adds water and be settled to 300ml, obtains that concentration is 8.5%, pH value is the sucrose solution of 8.0, for subsequent use;
G. DaunoXome solution is prepared
Under 68-72 DEG C of condition, the daunorubicin hydrochloride solution that blank liposome, step e after being dialysed by step D gained obtain and the mixing of 200ml step F gained sucrose solution, when to be stirred to pH value be 5.6, stop stirring, obtain DaunoXome solution, be cooled to room temperature, for subsequent use;
H. glycine chlorinated sucrose calcium buffer is prepared
Taking sucrose 76g, glycine 3.76g, calcium chloride dihydrate 0.28g, be settled to 1000ml, is 5.8 by the HCl solution adjust ph of 2mol/L, obtains glycine chlorinated sucrose calcium buffer, for subsequent use;
I. DaunoXome injection is prepared
The assay of daunorubicin is carried out by efficient liquid phase, external standard method is adopted to carry out calculating the content of daunorubicin in liposome solutions, for 4.56mg/ml, the volume of step G gained DaunoXome solution is 600ml, add glycine chlorinated sucrose calcium buffer 640ml wherein, obtain the liposome solutions that daunorubicin concentration is 2mg/ml, carry out aseptic filtration through the PES sterilised membrane filter of 0.2 μm, namely obtain DaunoXome injection.
Inflated with nitrogen divides and is filled in cillin bottle, gland, packaging, labeling, warehouse-in.
Embodiment 2
A. citric acid soln is prepared
Accurately weighed 43.2g citric acid, pours in 450ml water and dissolves, to be dissolved completely after, regulate solution ph to 5.0 with the NaOH of 1mol/L, add water and be settled to 500ml, obtain that concentration is 8.64%, pH value is the citric acid soln of 5.0, for subsequent use;
B. blank liposome is prepared
Accurately weighed distearoyl phosphatidylcholine 37.65g, cholesterol 9g, under 68-72 DEG C of condition, mix distearoyl phosphatidylcholine, cholesterol with 42ml dehydrated alcohol, 258ml citric acid soln, stirs 1 hour, obtain lipoid lysate, for subsequent use;
Under 68-72 DEG C of condition, lipoid lysate is placed in the extruding of nanometer extruder and prepares blank liposome, it is first the polycarbonate membrane of 0.2 μm with aperture, repeatedly 5 times are extruded under the condition of squeeze pressure 600Psi, the mean diameter detecting blank liposome is 200nm, then be the polycarbonate membrane of 0.1 μm with aperture, repeatedly 5 times are extruded under the condition of squeeze pressure 300Psi, the mean diameter detecting blank liposome is 120nm, be the polycarbonate membrane of 0.05 μm again with aperture, repeatedly 5 times are extruded under the condition of squeeze pressure 150Psi, the mean diameter detecting blank liposome is 55nm, gained blank liposome is preserved under being placed in 4 DEG C of conditions, for subsequent use,
C. sucrose solution is prepared
Taking sucrose 0.85kg, add water and be settled to 10 liters, is 5.0 by the HCl solution adjust ph of 1mol/L, obtains that concentration is 8.5%, pH value is the sucrose solution of 5.0, for subsequent use;
D. blank liposome dialysis
Step B gained blank liposome is loaded in bag filter, in 4 DEG C of isoperibols, 3L step C gained sucrose solution is poured in the beaker of 5L, then the bag filter vertical suspension of blank liposomes liquid solution being housed in beaker, start magnetic agitation simultaneously, dialyse 4 hours.Repetition like this, dialyses 3 times altogether, the sucrose solution at every turn more renewed;
After dialysis, regulate the pH value to 8.0 of blank liposome by the NaOH solution of 1mol/L, for subsequent use;
E. daunorubicin hydrochloride solution is prepared
Accurately weighed 2.4g daunorubicin hydrochloride in safety operation cabinet, is dissolved in 90ml step C gained sucrose solution, after dissolving completely, by the NaOH solution adjust ph to 8.0 of 0.1mol/L, finally adding step C gained sucrose solution is again settled to 100ml, obtains daunorubicin hydrochloride solution, for subsequent use;
F. sucrose solution is prepared
Take sucrose 25.5g, the water adding 250ml dissolves, and is 8.0 by the NaOH solution adjust ph of 2mol/L, then adds water and be settled to 300ml, obtains that concentration is 8.5%, pH value is the sucrose solution of 8.0, for subsequent use;
G. DaunoXome solution is prepared
Under 68-72 DEG C of condition, the daunorubicin hydrochloride solution that blank liposome, step e after being dialysed by step D gained obtain and the mixing of 200ml step F gained sucrose solution, when to be stirred to pH value be 6.0, stop stirring, obtain DaunoXome solution, be cooled to room temperature, for subsequent use;
H. glycine chlorinated sucrose calcium buffer is prepared
Taking sucrose 76g, glycine 3.76g, calcium chloride dihydrate 0.28g, be settled to 1000ml, is 5.8 by the HCl solution adjust ph of 2mol/L, obtains glycine chlorinated sucrose calcium buffer, for subsequent use;
I. DaunoXome injection is prepared
The assay of daunorubicin is carried out by efficient liquid phase, external standard method is adopted to carry out calculating the content of daunorubicin in liposome solutions, for 4.68mg/ml, the volume of step G gained DaunoXome solution is 600ml, add glycine chlorinated sucrose calcium buffer 804ml wherein, obtain the liposome solutions that daunorubicin concentration is 2mg/ml, carry out aseptic filtration through the PES sterilised membrane filter of 0.2 μm, namely obtain DaunoXome injection.
Inflated with nitrogen divides and is filled in cillin bottle, gland, packaging, labeling, warehouse-in.
Embodiment 3
Inventor has carried out quality testing to obtaining DaunoXome injection according to preparation technology of the present invention, and investigates its stability, and concrete outcome is in table 1.
Accelerate stability conditions in June: T=25 DEG C, RH=60%
Table 1
As can be seen from Table 1, the DaunoXome injection envelop rate obtained according to preparation technology of the present invention more than 97%, accelerated test after 6 months envelop rate there is not obvious change, more than 95%, other Testing index is all stable, illustrates that product stability is good.Compared to the envelop rate of commercially available prod 90%, quality has obvious lifting.
Claims (7)
1. the preparation technology of DaunoXome injection, is characterized in that, comprises following operating procedure:
A. citric acid soln is prepared
Compound concentration is 8.64%, pH value is the citric acid soln of 5.0, for subsequent use;
B. blank liposome is prepared
Under 68-72 DEG C of condition, distearoyl phosphatidylcholine 37.65 weight portion, cholesterol 9 weight portion, dehydrated alcohol 42 parts by volume are mixed with steps A gained citric acid soln 258 parts by volume, stirs 1 hour, obtain lipoid lysate, for subsequent use;
Under 68-72 DEG C of condition, lipoid lysate is placed in the extruding of nanometer extruder and prepares blank liposome, it is first the film of 0.2 μm with aperture, under the condition of squeeze pressure 450-600Psi, be repeatedly squeezed to blank liposome mean diameter is 200-220nm, then be the film of 0.1 μm with aperture, the mean diameter being repeatedly squeezed to blank liposome under the condition of squeeze pressure 200-300Psi is 120-130nm, be the film of 0.05 μm again with aperture, the mean diameter being repeatedly squeezed to blank liposome under the condition of squeeze pressure 120-150Psi is 55-62nm, final gained blank liposome is preserved under being placed in 4 DEG C of conditions, for subsequent use,
C. sucrose solution is prepared
Compound concentration is 8.5%, pH value is the sucrose solution of 5.0, for subsequent use;
D. blank liposome dialysis
Under 4 DEG C of conditions, the blank liposome prepared by step B is sealed in bag filter, is placed in step C gained sucrose solution dialysis 4 hours, so repeats, dialyse 3 times altogether, change sucrose solution at every turn;
After dialysis, regulate the pH value to 8.0 of blank liposome, for subsequent use;
E. daunorubicin hydrochloride solution is prepared
Take daunorubicin hydrochloride 2.4 weight portion, be dissolved in 90 parts by volume step C gained sucrose solutions, adjust ph to 8.0 subsequently, finally add step C gained sucrose solution again and be settled to 100 parts by volume, obtain daunorubicin hydrochloride solution, for subsequent use;
F. sucrose solution is prepared
Compound concentration is 8.5%, pH value is the sucrose solution of 8.0, for subsequent use;
G. DaunoXome solution is prepared
Under 68-72 DEG C of condition, the daunorubicin hydrochloride solution that blank liposome after being dialysed by step D gained, step e obtain and the mixing of 200 parts by volume step F gained sucrose solutions, when to be stirred to pH value be 5.6-6.0, stop stirring, obtain DaunoXome solution, be cooled to room temperature, for subsequent use;
H. glycine chlorinated sucrose calcium buffer is prepared
Containing 7.6g sucrose, 0.376g glycine, 0.028 calcium chloride dihydrate in every 100ml, pH value is 5.8;
I. DaunoXome injection is prepared
In step G gained DaunoXome solution, add the concentration that glycine chlorinated sucrose calcium buffer is diluted to daunorubicin is 2mg/ml, gained DaunoXome dilute solution carries out aseptic filtration through 0.2 μm of film, namely obtains DaunoXome injection.
2. the preparation technology of DaunoXome injection according to claim 1, is characterized in that, prepare citric acid soln described in steps A, and the NaOH solution adjust ph using 1mol/L is 5.0.
3. the preparation technology of DaunoXome injection according to claim 1, is characterized in that, prepare sucrose solution described in step C, and the HCl solution adjust ph using 1mol/L is 5.0.
4. the preparation technology of DaunoXome injection according to claim 1, is characterized in that, blank liposome dialysis described in step D, uses the NaOH solution of 1mol/L to regulate the pH value to 8.0 of blank liposome.
5. the preparation technology of DaunoXome injection according to claim 1, is characterized in that, prepares daunorubicin hydrochloride solution described in step e, uses the NaOH solution adjust ph to 8.0 of 0.1mol/L.
6. the preparation technology of DaunoXome injection according to claim 1, is characterized in that, prepare sucrose solution described in step F, and the NaOH solution adjust ph using 2mol/L is 8.0.
7. the preparation technology of DaunoXome injection according to claim 1, is characterized in that, prepares glycine chlorinated sucrose calcium buffer described in step H, and the HCl solution adjust ph using 2mol/L is 5.8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410662764.7A CN104306336B (en) | 2014-11-18 | 2014-11-18 | The preparation technology of DaunoXome parenteral solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410662764.7A CN104306336B (en) | 2014-11-18 | 2014-11-18 | The preparation technology of DaunoXome parenteral solution |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104306336A true CN104306336A (en) | 2015-01-28 |
| CN104306336B CN104306336B (en) | 2016-08-24 |
Family
ID=52361754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410662764.7A Active CN104306336B (en) | 2014-11-18 | 2014-11-18 | The preparation technology of DaunoXome parenteral solution |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104306336B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626100A (en) * | 2004-08-12 | 2005-06-15 | 常州太平洋药物研究所有限公司 | Injection of liposome of daunorubicin or hydrochloric daunorubicin and preparationmethod |
| CN101190188A (en) * | 2006-11-30 | 2008-06-04 | 北京天衡药物研究院 | Anthracene nucleus medicinal liposome injection and preparation method |
| CN102018672A (en) * | 2010-11-29 | 2011-04-20 | 广州朗圣药业有限公司 | Freeze-dried liposome composition of water-soluble medicament and preparation method thereof |
| WO2014083058A1 (en) * | 2012-11-30 | 2014-06-05 | Boehringer Ingelheim International Gmbh | Combination therapy with volasertib |
-
2014
- 2014-11-18 CN CN201410662764.7A patent/CN104306336B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626100A (en) * | 2004-08-12 | 2005-06-15 | 常州太平洋药物研究所有限公司 | Injection of liposome of daunorubicin or hydrochloric daunorubicin and preparationmethod |
| CN101190188A (en) * | 2006-11-30 | 2008-06-04 | 北京天衡药物研究院 | Anthracene nucleus medicinal liposome injection and preparation method |
| CN102018672A (en) * | 2010-11-29 | 2011-04-20 | 广州朗圣药业有限公司 | Freeze-dried liposome composition of water-soluble medicament and preparation method thereof |
| WO2014083058A1 (en) * | 2012-11-30 | 2014-06-05 | Boehringer Ingelheim International Gmbh | Combination therapy with volasertib |
Non-Patent Citations (1)
| Title |
|---|
| 高琨等: "柔红霉素脂质体的制备", 《第四军医大学学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104306336B (en) | 2016-08-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104337851B (en) | The preparation method of brucea fruit oil nano structured lipid carrier and its freeze-dried powder | |
| CN102349998A (en) | Hydrophobic anticancer medicinal preparation on basis of exosome | |
| CN107982239A (en) | Hydrophobic drug crystal is the aspherical micro-capsule of albumen base and preparation method of template | |
| CN102716082B (en) | Cefoxitin sodium liposome injection | |
| Kaur et al. | Development of nanoemulsion based gel loaded with phytoconstituents for the treatment of urinary tract infection and in vivo biodistribution studies | |
| WO2019080193A1 (en) | Liposome encapsulating free astaxanthin and preparation method therefor | |
| CN102772802A (en) | Oleanolic acid nanoliposome modified by chitosan and polyethylene glycol and preparation method thereof | |
| CN104161745A (en) | Method for preparing nanometer iron citrate liposome | |
| CN105456193A (en) | EGCC liposome preparation and preparation method thereof | |
| CN102366410B (en) | Argatroban liposome injection | |
| Starýchová et al. | In vitro liberation of indomethacin from chitosan gels containing microemulsion in different dissolution mediums | |
| WO2018072644A1 (en) | Lipid nanoparticle film material composition | |
| CN107737043A (en) | A kind of self-assembled nanometer compound, preparation method and application that Tea Polyphenols is loaded based on hyaluronic acid | |
| CN104306336A (en) | Technology for preparing citric acid daunorubicin lipidosome injection liquid | |
| CN103637993A (en) | Monodisperse nano cefquinome sulfate liposome preparation and preparation method thereof | |
| CN104546706A (en) | Emulsion injection containing dexibuprofen and preparation method of emulsion injection | |
| Xin et al. | Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug | |
| CN103536537B (en) | A kind of preparation method of Lung targeting medicine gefitinib PLGA microsphere | |
| Nagao et al. | Preparation of Cubosomes with improved colloidal and structural stability using a Gemini surfactant | |
| CN101978952A (en) | Method for preparing berberine hydrochloride liposome preparation | |
| CN101401790A (en) | Lavo-ofloxacin liposome and preparation method thereof | |
| CN113521005A (en) | Nanometer lipid particle carrier for delivering resveratrol drug and preparation method and application thereof | |
| Wang et al. | Preparation and properties of semi-self-assembled lipopeptide vesicles | |
| CN105030673A (en) | Novel Asulacrine liposome with high drug-loading rate for preventing drug leakage | |
| CN103356507A (en) | Preparation method of all-trans tretinoin solid lipid nanoparticles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of daunorubicin citrate liposome injection Effective date of registration: 20210318 Granted publication date: 20160824 Pledgee: Nanhu sub branch of Bank of Cangzhou Co.,Ltd. Pledgor: HEBEI TIANCHENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2021990000241 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220601 Granted publication date: 20160824 Pledgee: Nanhu sub branch of Bank of Cangzhou Co.,Ltd. Pledgor: HEBEI TIANCHENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2021990000241 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation process of daunorubicin citrate liposome injection Effective date of registration: 20230201 Granted publication date: 20160824 Pledgee: China Construction Bank Corporation Cangzhou Development Zone Sub-branch Pledgor: HEBEI TIANCHENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2023110000049 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Granted publication date: 20160824 Pledgee: China Construction Bank Corporation Cangzhou Development Zone Sub-branch Pledgor: HEBEI TIANCHENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2023110000049 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |