CN105997896B - The injection freeze-dried powder and preparation method thereof for treating non-Hodgkin lymphoma - Google Patents
The injection freeze-dried powder and preparation method thereof for treating non-Hodgkin lymphoma Download PDFInfo
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- CN105997896B CN105997896B CN201610364343.5A CN201610364343A CN105997896B CN 105997896 B CN105997896 B CN 105997896B CN 201610364343 A CN201610364343 A CN 201610364343A CN 105997896 B CN105997896 B CN 105997896B
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- freeze
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- lactose
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- 238000002347 injection Methods 0.000 title claims abstract description 52
- 239000007924 injection Substances 0.000 title claims abstract description 52
- 239000000843 powder Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 title claims abstract description 12
- 229960004403 pixantrone Drugs 0.000 claims abstract description 31
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 claims abstract description 30
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 29
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 29
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000011976 maleic acid Substances 0.000 claims abstract description 28
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 25
- 239000008101 lactose Substances 0.000 claims abstract description 25
- 229930091371 Fructose Natural products 0.000 claims abstract description 22
- 239000005715 Fructose Substances 0.000 claims abstract description 22
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims abstract description 22
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 21
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 12
- 229960003194 meglumine Drugs 0.000 claims abstract description 12
- 239000000470 constituent Substances 0.000 claims abstract description 11
- 238000004108 freeze drying Methods 0.000 claims description 51
- 238000001035 drying Methods 0.000 claims description 46
- 238000002791 soaking Methods 0.000 claims description 43
- 238000007710 freezing Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000011049 filling Methods 0.000 claims description 24
- 239000008215 water for injection Substances 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 19
- 230000008014 freezing Effects 0.000 claims description 18
- 230000009191 jumping Effects 0.000 claims description 16
- 238000005192 partition Methods 0.000 claims description 16
- 239000011265 semifinished product Substances 0.000 claims description 16
- 238000005303 weighing Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- 239000003002 pH adjusting agent Substances 0.000 claims description 11
- 239000012530 fluid Substances 0.000 claims description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052796 boron Inorganic materials 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000012982 microporous membrane Substances 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 238000011179 visual inspection Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229940092714 benzenesulfonic acid Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000009472 formulation Methods 0.000 abstract description 4
- 229960001375 lactose Drugs 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 238000000859 sublimation Methods 0.000 description 4
- 230000008022 sublimation Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000000306 recurrent effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- SVAGFBGXEWPNJC-SPIKMXEPSA-N 6,9-bis(2-aminoethylamino)benzo[g]isoquinoline-5,10-dione;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN SVAGFBGXEWPNJC-SPIKMXEPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 244000050510 Cunninghamia lanceolata Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- CQSUGYIHVNGOSF-UHFFFAOYSA-N NCCNC=1N=C(C2=CC3=C(C=C2C=1)C=CC=C3)NCCN Chemical compound NCCNC=1N=C(C2=CC3=C(C=C2C=1)C=CC=C3)NCCN CQSUGYIHVNGOSF-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- AHIBWURJLGCHAY-UHFFFAOYSA-N [S].C1=CC=CC=C1 Chemical compound [S].C1=CC=CC=C1 AHIBWURJLGCHAY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- -1 phosphatide Chemical compound 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 208000009146 rhinoscleroma Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of injection freeze-dried powders and preparation method thereof for treating non-Hodgkin lymphoma, are mainly made of the meglumine of the active constituent maleic acid Pixantrone of 1 parts by weight, the lactose and fructose mixed accessories and 0.8~1.2 parts by weight of 4.0~6.0 parts by weight；In the mixed accessories of lactose and fructose, the weight ratio of lactose and fructose is 1:(1-2).Injection freeze-dried powder prepared by the present invention can effectively shorten the preparation time of preparation, reduce production cost, while invention formulation quality is stablized, and shape is good, no powder scattering.
Description
Technical field
The invention belongs to technical field of medicine preparation, and in particular to a kind of injection freeze-drying for treating non-Hodgkin lymphoma
Powder and preparation method thereof.
Background technique
Non-Hodgkin lymphoma (Non-Hodgkin lymphoma, NHL) is one group originating from lymph node and other lymphs
The malignant tumour of tissue is a big type of lymthoma.Worldwide disease incidence is up to 20/,100,000.The inspection in the U.S., stream
Row disease learns the disease incidence of investigation and final result (surveillance epidemiology and end results, SEER)
Statistics indicate that male is more susceptible to suffer from NHL compared with women.Non-Hodgkin's B cell lymphoma is the main parting of NHL, accounts for about NHL's
85%.The average age that the U.S. is diagnosed to be non-Hodgkin's B cell lymphoma is 67 years old.The statistics of China shows that non-Hodgkin's B is thin
Born of the same parents' lymthoma can betide any age, but more with person between twenty and fifty with children.The morbidity and mortality of China's Coastal Areas are high
In interiorly, area that are fairly developed economically is higher than economically underdeveloped area, and age of onset curve peak was at 40 years old or so.
Pixantrone is a kind of anthraquinone series antineoplastic medicament, anti-tumor activity with higher and lower cardiac toxic, is faced
For treating more recurrents or refractory aggressive non-Hodgkin's B cell lymphoma on bed.
On 2 17th, 2012, European Union's approval pixantrone (trade name Pixuvri) can be used as a kind of monotherapy
More recurrents or refractory aggressive non-Hodgkin's B cell lymphoma adult patient, the first for becoming that European Union passes through is to this
Kind in the case of patient therapeutic regimen, and so far in world wide it is first for more recurrents and refractory aggressive it is non-
The monotherapy drug of Huo Qijin B cell lymphoma treatment.
Pixantrone exists usually in the form of maleic acid Pixantrone, maleic acid Pixantrone, and molecular formula is
C17H19N5O2.2C4H4O4, entitled bis- [(2- amino-ethyl) amino] benzo [g] isoquinolin -5, the 10- diketone two of 6,9- of chemistry
Maleate, structural formula are as follows:
Currently, the formulation patent about injection maleic acid Pixantrone is less, United States Patent (USP) US2006/0199831A1 is public
A kind of injection maleic acid Pixantrone of cloth and preparation method thereof, mainly by active constituent maleic acid Pixantrone and auxiliary material cream
Sugar, dextran and sodium chloride composition.
Chinese Patent Application No. 201210195910.0 discloses the Liposomal formulation and its system of a kind of maleic acid Pixantrone
Standby technique, said preparation are established substance by maleic acid Pixantrone, phosphatide, cholesterol and gradient and are prepared.The preparation process includes
It prepares blank liposome, gradient liposome, load drug.Preparation is simple, gained better stability of preparation, packet
Envelope rate is high, and the tumor-targeting of drug can be improved and reduce its toxic side effect.
It is mentioned in the injection maleic acid Pixantrone operation instructions that European EMA official website announces, injection maleic acid
Pixantrone is molten by active constituent maleic acid Pixantrone, sodium chloride, lactose monohydrate and pH adjusting agent hydrochloric acid solution, sodium hydroxide
Liquid composition.
But it is found in inventor's test, maleic acid Pixantrone injection freeze-dried powder lyophilization stage in freeze-drying process
Sublimation temperature it is too low, if improve temperature, will cause the generation of spray bottle phenomenon.Spray bottle is due to the drying stage temperature mistake that heats up
Height causes product upper and lower temperature difference excessive, the crystallization of lower part product not instead of from solid to gas distil, from solid, liquid to
Gas evaporation forms spray bottle.There is different appearances in this position up and down for also causing product, and top is uniform, loose, in spongy
Desirable appearance, and lower part then present scleroma and irregular hole, scrap of the product can be caused when serious.
The sublimation temperature in lyophilization stage is too low, and to cause the used time in lyophilization stage longer, increases the production of product
Cost, while very big inconvenience is brought to producers.
Summary of the invention
For current deficiency, the present invention provides a kind of injection freeze-dried powders for treating non-Hodgkin lymphoma, mainly
By the active constituent maleic acid Pixantrone of 1.0 parts by weight, the lactose of 4.0~6.0 parts by weight and fructose mixed accessories and 0.8~
The meglumine of 1.2 parts by weight forms；
Wherein in the mixed accessories of lactose and fructose, the weight ratio of lactose and fructose is 1:(1-2).
Injection freeze-dried powder provided by the invention, further preferably for by the active constituent maleic acid China fir of 1.0 parts by weight
Fine jade, the lactose of 5.0 parts by weight and fructose mixed accessories and the meglumine of 1.0 parts by weight form.
Wherein in the mixed accessories of lactose and fructose, the weight ratio of lactose and fructose is 1:1.5.
Injection freeze-dried powder provided by the invention, pH value range is 6.1~6.7 after the injection freeze-dried powder redissolves,
Preferably 6.4.
Injection freeze-dried powder provided by the invention, the pH adjusting agent are hydrochloric acid, acetic acid, phosphoric acid, citric acid, benzene sulphur
One of acid, maleic acid are either several.
Injection freeze-dried powder provided by the invention, preparation method mainly comprise the steps that
1) lactose and fructose mixed accessories for, weighing formula ratio, which are dissolved in, to be accounted for total volume 20%~40% and penetrates in water, is stirred
It mixes uniformly mixed；
2) maleic acid Pixantrone and meglumine for, weighing formula ratio, which are dissolved into, accounts for 30%~50% water for injection of total volume
In, it is uniformly mixed；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted to 6.1~6.7 with suitable pH adjusting agent, is settled to total amount with water for injection, is stirred
It is even；
5) medical fluid, is propped up into the filling neutral boron silica glass pipe in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane
In injection bottle processed, freeze-drying, visual inspection is got product；
Wherein active constituent maleic acid Pixantrone is 6.0~12.0mg/ml preparing the concentration in solution.
Injection freeze-dried powder provided by the invention, preparation method mainly comprise the steps that
1) lactose and fructose mixed accessories for, weighing formula ratio, which are dissolved in, to be accounted for total volume 30% and penetrates in water, is stirred
Uniformly；
2) maleic acid Pixantrone and meglumine for, weighing formula ratio, which are dissolved into, to be accounted in 40% water for injection of total volume, stirring
It is uniformly mixed；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted to 6.1~6.7 with suitable pH adjusting agent, is settled to total amount with water for injection, is stirred
It is even；
5) medical fluid, is propped up into the filling neutral boron silica glass pipe in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane
In injection bottle processed, freeze-drying, visual inspection is got product；
Wherein active constituent maleic acid Pixantrone is 8.0mg/ml, 10.0mg/ml preparing the concentration in solution.
Injection freeze-dried powder provided by the invention, described freeze-drying method point or less three phases carry out:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature, pre-freezing temperature range is between -58~-52 DEG C, and temperature fall time used time about 60~120min, soaking time is about
120~180min；
2), the lyophilization stage: when the vacuum degree in drying box reaches 80mTorr~120mTorr, temperature is risen to-
14.0~-10.0 DEG C, used time about 60~120min, soaking time about 540min~660min；
3), the re-dry stage: 30~40 DEG C, used time about 90~150min are raised the temperature to, by the vacuum in drying box
Degree is evacuated to ultimate vacuum, and soaking time about 240~360min obtains injection freeze-dried powder.
Injection freeze-dried powder provided by the invention, the freeze-drying method further select following three phases into
Row:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature, pre-freezing temperature is -55 DEG C, temperature fall time 90min, and the pre-freeze time is 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Temperature is risen to -12 DEG C；Used time
90min；Soaking time is 600min；
3), the re-dry stage: 35 DEG C are raised the temperature to, used time 120min；Vacuum degree in drying box is evacuated to the limit
Vacuum, soaking time 300min obtain injection freeze-dried powder.
Inventor has carried out a large amount of test to the selection of auxiliary material in the injection freeze-dried powder recipe development stage, sends out in test
It is existing, using single excipient (for example, a certain type in a certain type, oligosaccharide in monosaccharide, certain in polyalcohol are a kind of
Type or sodium chloride etc.) for injection freeze-dried powder sublimation temperature influence and it is little, and use oligosaccharide in lactose and monosaccharide
In the mixed accessories that are configured to according to certain component of fructose for improve the lyophilization temperature in lyophilization stage have it is larger
Improvement.Meglumine is an ideal ion balance pair, it is generally the case that for improving the dissolubility and bioavilability of drug
There is good improvement result.It is used in combination by meglumine and lactose, fructose mixed accessories, inventor is in prefreezing
The beam stage is it has been observed that the crystal form of formation is larger and loose after medical fluid jelly is real, convenient for the liter of lyophilization stage water vapour
China；Meanwhile the sublimation temperature for improving the lyophilization stage will not cause crystalline solid to melt, and greatly shorten the distillation of product
Drying time；It is found in test by the investigation to each stage, the stability of product is more conducive in pH value 6.1~6.7.
Above-mentioned injection freeze-dried powder of the present invention has the advantage that injection freeze-dried powder prepared by the present invention can be with
The effective preparation time for shortening preparation reduces production cost, while invention formulation quality is stablized, and shape is good, no powder
Volume scattering.
Specific embodiment
Embodiment 1:
Formula
Preparation process
1) lactose and fructose for, weighing formula ratio are dissolved in the water for injection of 300ml, are uniformly mixed；
2) maleic acid Pixantrone and meglumine for, weighing formula ratio are dissolved into the water for injection of 400ml, are stirred
It is even；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted with suitable pH adjusting agent, total amount is settled to water for injection, is uniformly mixed；
5) medical fluid, is propped up into the filling neutral boron silica glass pipe in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane
In injection bottle processed, freeze-drying, visual inspection is got product.Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -55 DEG C, temperature fall time 90min, soaking time 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -12 DEG C；With
When 90min；Soaking time 600min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 300min obtains injection freeze-dried powder.
Embodiment 2:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -54 DEG C, temperature fall time 70min, soaking time 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 80mTorr；Main drying temperature is risen to -10 DEG C；With
When 80min；Soaking time 600min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 240min obtains injection freeze-dried powder.
Embodiment 3:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -57 DEG C, temperature fall time 120min, soaking time 160min；
2), the lyophilization stage: the vacuum degree in drying box reaches 110mTorr；Main drying temperature is risen to -10 DEG C；With
When 60min；Soaking time 540min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 240min obtains injection freeze-dried powder.
Embodiment 4:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -52 DEG C, temperature fall time 60min, soaking time 180min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -13 DEG C；With
When 80min；Soaking time 620min；
3) re-dry temperature, the re-dry stage: is increased to 38 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 330min obtains injection freeze-dried powder.
Embodiment 5:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -57 DEG C, temperature fall time 100min, soaking time 120min；
2), the lyophilization stage: the vacuum degree in drying box reaches 120mTorr；Main drying temperature is risen to -10 DEG C；With
When 100min；Soaking time 640min；
3) re-dry temperature, the re-dry stage: is increased to 30 DEG C；Used time 140min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 280min obtains injection freeze-dried powder.
Embodiment 6:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -55 DEG C, temperature fall time 100min, soaking time 160min；
2), the lyophilization stage: the vacuum degree in drying box reaches 80mTorr；Main drying temperature is risen to -10 DEG C；With
When 80min；Soaking time 600min；
3) re-dry temperature, the re-dry stage: is increased to 40 DEG C；Used time 130min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 300min obtains injection freeze-dried powder.
Embodiment 7:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -54 DEG C, temperature fall time 70min, soaking time 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -10 DEG C；With
When 120min；Soaking time 660min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 240min obtains injection freeze-dried powder.
Embodiment 8:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -54 DEG C, temperature fall time 70min, soaking time 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 120mTorr；Main drying temperature is risen to -14 DEG C；With
When 80min；Soaking time 600min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 240min obtains injection freeze-dried powder.
Embodiment 9:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -52 DEG C, temperature fall time 90min, soaking time 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -10 DEG C；With
When 80min；Soaking time 600min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 240min obtains injection freeze-dried powder.
Embodiment 10:
Formula
Preparation process: with embodiment 1.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -53 DEG C, temperature fall time 100min, soaking time 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 110mTorr；Main drying temperature is risen to -10 DEG C；With
When 80min；Soaking time 600min；
3) re-dry temperature, the re-dry stage: is increased to 35 DEG C；Used time 120min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 240min obtains injection freeze-dried powder.
Comparative example 1:
Formula
Preparation process: with embodiment 1.
Comparative example 2:
Formula
Preparation process: with embodiment 1.
Comparative example 3:
Formula
Preparation process: with embodiment 1.
Comparative example 4:
Formula
Preparation process: with embodiment 1.
Comparative example 5:
Formula
Preparation process
1) sodium chloride and lactose for, weighing formula ratio are dissolved in the water for injection of 300ml, are uniformly mixed；
2) maleic acid Pixantrone for, weighing formula ratio is dissolved into 400ml water for injection, is uniformly mixed；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted with suitable pH adjusting agent, total amount is settled to water for injection, is uniformly mixed；
5) medical fluid, is propped up into the filling neutral boron silica glass pipe in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane
In injection bottle processed, freeze-drying, visual inspection is got product.
Freeze-drying curve: with embodiment 1.
Comparative example 6:
Formula
Preparation process
1) sodium chloride and lactose for, weighing formula ratio are dissolved in the water for injection of 300ml, are uniformly mixed；
2) maleic acid Pixantrone for, weighing formula ratio is dissolved into 400ml water for injection, is uniformly mixed；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted with suitable pH adjusting agent, total amount is settled to water for injection, is uniformly mixed；
5) medical fluid, is propped up into the filling neutral boron silica glass pipe in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane
In injection bottle processed, freeze-drying, visual inspection is got product.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -45 DEG C, temperature fall time 180min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -30 DEG C；With
When 180min；Soaking time 2400min；
3) re-dry temperature, the re-dry stage: is increased to 30 DEG C；Used time 600min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 480min obtains injection freeze-dried powder.
Comparative example 7:
Formula
Preparation process
1) sodium chloride and lactose for, weighing formula ratio are dissolved in the water for injection of 300ml, are uniformly mixed；
2) maleic acid Pixantrone for, weighing formula ratio is dissolved into 400ml water for injection, is uniformly mixed；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted with suitable pH adjusting agent, total amount is settled to water for injection, is uniformly mixed；
5) medical fluid, is propped up into the filling neutral boron silica glass pipe in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane
In injection bottle processed, freeze-drying, visual inspection is got product.
Freeze-drying curve:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled down
To pre-freezing temperature；Pre-freezing temperature is -45 DEG C, temperature fall time 180min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -0 DEG C；With
When 360min；Soaking time 1800min；
3) re-dry temperature, the re-dry stage: is increased to 30 DEG C；Used time 180min；Vacuum degree in drying box is taken out
To ultimate vacuum, soaking time 480min obtains injection freeze-dried powder.
Verify embodiment
1), preparation manufacturing parameter is investigated
The embodiment of the present invention 1~10 and 1~7 gained finished product preparation of comparative example are subjected to appearance character, yield, freeze-drying
The investigation to go wrong in time and freeze-drying process, test result are shown in Table 1
1 Examples 1 to 10 of table and comparison 1~7 finished product preparation influence factor experiment investigation result of patent
According to the experimental results: preparation high income made from the embodiment of the present invention 1~10, the used time, short be substantially better than compared in fact
Example 1~7 is applied, although comparative example 6 is consistent with Examples 1 to 10 in terms of yield and freeze-drying situation, the used time is obviously grown
In Examples 1 to 10.
2), long term test is investigated
The embodiment of the present invention 1 and 4 gained finished product preparation of comparative example are placed in 2-8 DEG C of refrigerator, respectively at the 0th, 12,
24, its appearance character, pH value, moisture, the variation in relation to substance and content are investigated in sampling in 36 months, and test result is shown in Table 2.
2 embodiment 1 of table investigates result with 4 finished product preparation long term test of comparative example
From experiment investigate result: appearance character of the embodiment of the present invention, pH value, moisture, in relation to substance and content etc. respectively
Item index meets regulation, and the present invention is worth the popularization of actual production.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (8)
1. a kind of injection freeze-dried powder for treating non-Hodgkin lymphoma, which is characterized in that by the active constituent Malaysia of 1 parts by weight
Sour pixantrone, the lactose of 4.0~6.0 parts by weight and fructose mixed accessories and the meglumine of 0.8~1.2 parts by weight form；
Wherein in the mixed accessories of lactose and fructose, the weight ratio of lactose and fructose is 1:(1-2)；
PH value range is 6.1~6.7 after the injection freeze-dried powder redissolves.
2. injection freeze-dried powder according to claim 1, which is characterized in that mainly by the active constituent Malaysia of 1 parts by weight
Sour pixantrone, the lactose of 5.0 parts by weight and fructose mixed accessories and the meglumine of 1.0 parts by weight form；
Wherein in the mixed accessories of lactose and fructose, the weight ratio of lactose and fructose is 1:1.5.
3. injection freeze-dried powder according to claim 1, which is characterized in that pH value after the injection freeze-dried powder redissolves
Range is 6.4.
4. injection freeze-dried powder according to claim 3, which is characterized in that pH adjusting agent be hydrochloric acid, acetic acid, phosphoric acid,
One of citric acid, benzene sulfonic acid, maleic acid are either several.
5. the preparation method of injection freeze-dried powder according to any one of claims 1 to 4, which is characterized in that mainly include
Following steps:
1) lactose and fructose mixed accessories for, weighing formula ratio, which are dissolved in, to be accounted for total volume 20%~40% and penetrates in water, and stirring is mixed
It closes uniform；
2) maleic acid Pixantrone and meglumine for, weighing formula ratio, which are dissolved into, to be accounted in 30%~50% water for injection of total volume, is stirred
It mixes uniformly mixed；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted to 6.1~6.7 with suitable pH adjusting agent, is settled to total amount with water for injection, is stirred
It is even；
5) medical fluid, is propped up the filling neutral boron silica glass control in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane to infuse
It penetrates in agent bottle, is freeze-dried, visual inspection is got product；
Wherein active constituent maleic acid Pixantrone is 6.0~12.0mg/ml preparing the concentration in solution.
6. preparation method according to claim 5, which is characterized in that mainly comprise the steps that
1) lactose and fructose mixed accessories for, weighing formula ratio, which are dissolved in, to be accounted for total volume 30% and penetrates in water, is uniformly mixed；
2) maleic acid Pixantrone and meglumine for, weighing formula ratio, which are dissolved into, to be accounted in 40% water for injection of total volume, is stirred
Uniformly；
3), 2) solution in is slowly added into 1), is uniformly mixed；
4) pH value, is adjusted to 6.1~6.7 with suitable pH adjusting agent, is settled to total amount with water for injection, is uniformly mixed；
5) medical fluid, is propped up the filling neutral boron silica glass control in 15ml according to 5ml/ after 0.22 μm of filtering with microporous membrane to infuse
It penetrates in agent bottle, is freeze-dried, visual inspection is got product；
Wherein active constituent maleic acid Pixantrone is 8.0~10.0mg/ml preparing the concentration in solution.
7. preparation method according to claim 5 or 6, which is characterized in that described freeze-drying step point or less three
Stage carries out:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled to pre-
Freeze temperature, pre-freezing temperature range be -58~-52 DEG C between, 60~120min of temperature fall time used time, soaking time 120~
180min；
2) when the vacuum degree in drying box reaches 80mTorr~120mTorr, temperature, the lyophilization stage: is risen to -14.0
~-10.0 DEG C, 60~120min of used time, soaking time 540min~660min；
3), the re-dry stage: raising the temperature to 30~40 DEG C, and the vacuum degree in drying box is evacuated to by 90~150min of used time
Ultimate vacuum, 240~360min of soaking time obtain injection freeze-dried powder.
8. preparation method according to claim 7, which is characterized in that described freeze-drying method point or less three phases
It carries out:
1), the pre-freeze stage: semi-finished product that are filling and partly jumping a queue are placed on the partition being lyophilized in cabinet and carry out pre-freeze, are cooled to pre-
Freeze temperature, pre-freezing temperature is -55 DEG C, temperature fall time 90min, and the pre-freeze time is 150min；
2), the lyophilization stage: the vacuum degree in drying box reaches 100mTorr；Temperature is risen to -12 DEG C；Used time 90min；It protects
The warm time is 600min；
3), the re-dry stage: 35 DEG C are raised the temperature to, used time 120min；Vacuum degree in drying box is evacuated to ultimate vacuum,
Soaking time is 300min, obtains injection freeze-dried powder.
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| WO2003097101A1 (en) * | 2002-05-16 | 2003-11-27 | Cell Therapeutics Europe S.R.L. | Injectable pharmaceutical compositions of an anthracenedione derivative with anti-tumoral activity |
| CN103479578A (en) * | 2012-06-14 | 2014-01-01 | 沈阳药科大学 | Pixantrone maleate liposome preparation and preparation process thereof |
| CN105596295A (en) * | 2016-01-25 | 2016-05-25 | 北京博恩特药业有限公司 | Maleic acid pixantrone liposomal and preparing method thereof |
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2016
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|---|---|---|---|---|
| CN1382039A (en) * | 1999-10-22 | 2002-11-27 | 诺威斯药物有限公司 | Liposome formulation of 6,9-bis-[(2-aminoethyl)-amino]benzo[g]isoquinoline-5, 10-dione dimaleate |
| WO2003097101A1 (en) * | 2002-05-16 | 2003-11-27 | Cell Therapeutics Europe S.R.L. | Injectable pharmaceutical compositions of an anthracenedione derivative with anti-tumoral activity |
| CN103479578A (en) * | 2012-06-14 | 2014-01-01 | 沈阳药科大学 | Pixantrone maleate liposome preparation and preparation process thereof |
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