CN102138909A - Asparaginase freeze-dried powder injection and preparation method thereof, as well as asparaginase solution - Google Patents
Asparaginase freeze-dried powder injection and preparation method thereof, as well as asparaginase solution Download PDFInfo
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- CN102138909A CN102138909A CN2011100813874A CN201110081387A CN102138909A CN 102138909 A CN102138909 A CN 102138909A CN 2011100813874 A CN2011100813874 A CN 2011100813874A CN 201110081387 A CN201110081387 A CN 201110081387A CN 102138909 A CN102138909 A CN 102138909A
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- asparaginase
- injection
- lyophilized injectable
- injectable powder
- solution
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- 229960003272 asparaginase Drugs 0.000 title claims abstract description 117
- 108010024976 Asparaginase Proteins 0.000 title claims abstract description 116
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 title claims abstract description 114
- 239000000843 powder Substances 0.000 title claims abstract description 80
- 239000000243 solution Substances 0.000 title claims abstract description 37
- 239000007924 injection Substances 0.000 title claims abstract description 21
- 238000002347 injection Methods 0.000 title claims abstract description 21
- 102000015790 Asparaginase Human genes 0.000 title claims abstract 26
- 238000002360 preparation method Methods 0.000 title claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000002736 nonionic surfactant Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000004094 surface-active agent Substances 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 40
- 239000008215 water for injection Substances 0.000 claims description 26
- 239000006166 lysate Substances 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 239000000872 buffer Substances 0.000 claims description 20
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 14
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 12
- 229930195725 Mannitol Natural products 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000000594 mannitol Substances 0.000 claims description 12
- 235000010355 mannitol Nutrition 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 229920001993 poloxamer 188 Polymers 0.000 claims description 12
- 229940044519 poloxamer 188 Drugs 0.000 claims description 12
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 9
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 9
- 235000019800 disodium phosphate Nutrition 0.000 claims description 9
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 9
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 9
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 9
- 239000011521 glass Substances 0.000 claims description 7
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 238000005303 weighing Methods 0.000 claims description 7
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 6
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 230000033228 biological regulation Effects 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 6
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- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 6
- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012982 microporous membrane Substances 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims 2
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 24
- 229940093181 glucose injection Drugs 0.000 abstract description 24
- 229940090044 injection Drugs 0.000 abstract description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 16
- 239000011780 sodium chloride Substances 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 2
- 239000006172 buffering agent Substances 0.000 abstract 3
- 239000012905 visible particle Substances 0.000 abstract 2
- 230000000638 stimulation Effects 0.000 abstract 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 90
- 238000012360 testing method Methods 0.000 description 37
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 11
- 239000008354 sodium chloride injection Substances 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- PLZNPHDJGFDNRM-UHFFFAOYSA-M O.[Na+].[O-][PH2]=O Chemical compound O.[Na+].[O-][PH2]=O PLZNPHDJGFDNRM-UHFFFAOYSA-M 0.000 description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 235000009582 asparagine Nutrition 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000008176 lyophilized powder Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
- 229960001230 asparagine Drugs 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 150000002411 histidines Chemical class 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 206010015150 Erythema Diseases 0.000 description 3
- 239000004201 L-cysteine Substances 0.000 description 3
- 235000013878 L-cysteine Nutrition 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 229940126680 traditional chinese medicines Drugs 0.000 description 3
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920001304 Solutol HS 15 Polymers 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001508 asparagines Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
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- 208000032839 leukemia Diseases 0.000 description 1
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- 229940080526 mannitol injection Drugs 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- QLFFCLRSMTUBEZ-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].[Na].OP(O)(O)=O QLFFCLRSMTUBEZ-UHFFFAOYSA-N 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an asparaginase freeze-dried powder injection. The injection comprises asparaginase, a buffering agent, a surfactant, medical auxiliary materials and 5% of injection water which is used as a solvent in a preparing process and less than the addition finally, wherein the surfactant is a nonionic surfactant; and the buffering agent and the nonionic surfactant are added into the formula, so that the situation that tiny visible particles exceed standard is prevented when the asparaginase is dissolved and transferred into an injection. The invention also discloses a dedicated solution for dissolving the asparaginase, wherein the solution solvent is the injection water, and the solute comprises the buffering agent and the surfactant. On the premise of not changing the conventional formula of the freeze-dried powder injection, when the freeze-dried powder is dissolved in the solution, and is transferred into sodium chloride or a glucose injection, the situation that tiny visible particles exceed standard is prevented, so that the stimulation to human bodies is reduced in use, and the clinical administration safety is improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of asparaginase lyophilized injectable powder and preparation method thereof, and the used solvent of a kind of asparaginase dissolving.
Background technology
Asparaginase (following another name L-asparaginase, asparaginase, asparaginase etc. are also arranged) is a kind of medicine that tumor cell is had selective inhibitory, especially best to the curative effect of acute lymphoblastic leukemia (ALL), acute granulocyte type leukemia, acute monocytic leukemia, malignant lymphoma also there are certain curative effect.
Asparaginase (hereinafter to be referred as L-ASP) can be hydrolyzed to the asparagine in the serum Aspartic Acid and ammonia, and asparagine is cell synthetic protein and the necessary aminoacid of proliferate, normal cell has the function of self synthetic asparagine, but tumor cells such as acute leukemia do not have this function; Thereby when asparagine is sharply lacked, tumor cell also can not self synthesize because of can not obtain enough asparagines from blood, protein synthesis will occur and be subjected to obstacle, breed downtrod situation, tumor cell will considerable damage and the survival of can not growing thus.In addition, L-ASP also can disturb the synthetic of cell DNA, RNA, may act on cell G1 in proliferating cycle, is to suppress fissional cell cycle specific medicine of this phase.
At present, the injection asparaginase of domestic clinical use all adopts the freeze-dried powder dosage form, is mainly produced by companies such as Japanese Kyowa Hakkokogyo Co., Ltd, Mercks, based on the specification of every 5000 unit or 10000 units.This injection asparaginase lyophilized injectable powder is made up of asparaginase and mannitol.Should adopt suitable solvent to dissolve before injectable sterile powder uses, should be clarification, transparent solution after the dissolving.General sodium chloride injection or the glucose injection of adopting dissolved when asparaginase used.But in clinical use, find, having microgranule when the asparaginase diluent joins in sodium chloride or the glucose injection separates out, and mostly be 1mm above tiny protein floccule or protein particulate, cause visible foreign matters to exceed standard, increase the zest of transfusion, patient's life security is threatened human body.
In " Strait Pharmaceutical Journal " the 18th to the 19 page of disclosed document " stability study of L-asparaginase " of 2006 06 phases, relevant issues are studied, illustrate why L-ASP mixes and can saltout with the saliferous transfusion, consider that simultaneously 10% glucose injection (GS) sugar content is too high, clinical practice is not extensive, so the GS of selection 5% is as the best solvent of L-ASP, the concrete configuration method is as follows: 5% the sodium bicarbonate solution that adds 0.19mL in the glucose injection of the l 5% of every 100m is 7.5 to adjust the solvent pH value, prepare the L-ASP intravenous drip liquid with the glucose injection of adjusting pH value as solvent and lyophilized injectable powder, the transfusion that configures should be finished using in 4 hours, and the transfusion of failing in time to use answers low-temperature dark to preserve.
But because the pH value of 5% glucose injection of producing is uncertain, and " GS of every 100ml (5%) adds 5% the NaHCO of 0.19mL
3, adjusting the solvent pH value is 7.5 " the solvent configuration operation loaded down with trivial details, and be unfavorable for practical operation.We find by actual tests simultaneously, and are above-mentioned simple by NaHCO
3Regulate the method for the pH value of transfusion, still can not solve the separate out problem of asparaginase in transfusion.
Chinese patent literature CN100502944C(application number 200510102992.X) disclose a kind of asparaginase injection, it is mainly formed and is: the disodiumedetate (EDTA) of the L-cysteine of the asparaginase of 10-80mg, 2-30mmol/L, 10-30mmol/L phosphate buffer, 0.5-5mmol/L and the sodium chloride of 0.5%-2%; But the form of injection is inconvenient to store and transport, and the L-cysteine character instability in forming, and the time of guaranteeing the quality of injection is short, so there is defective in the injection of this kind prescription.
Summary of the invention
To be solved by this invention is that the asparaginase diluent is when joining in sodium chloride or the glucose injection, the problem that fine visible foreign matters exceeds standard, first purpose of the present invention for this reason provide a kind of clinical easy to use, redissolve rapidly, the asparaginase lyophilized injectable powder of good stability and preparation method thereof, second purpose of the present invention provide a kind of clinical easy to use, redissolve rapidly, the asparaginase dissolution solvent of good stability.
The technical scheme that realizes the present invention's first purpose is: asparaginase lyophilized injectable powder of the present invention comprises asparaginase and mannitol, also comprises buffer agent, surfactant, and wherein surfactant is a nonionic surfactant; In the process of the described asparaginase lyophilized injectable powder of preparation, have as solvent and finally be less than 5% water for injection of addition.
Calculate with respect to 10000 unit asparaginase in the above-mentioned asparaginase lyophilized injectable powder, mannitol is 40～100mg, and buffer agent is 3～15mg, and nonionic surfactant is 2～8mg; The water for injection that is used as solvent in the preparation process is 0.8～2.4g.
In the process of the above-mentioned asparaginase lyophilized injectable powder of preparation, the pH value of solution is 7.1～7.5 before the lyophilizing.
The included buffer agent of above-mentioned asparaginase lyophilized injectable powder is sodium bicarbonate, glycinate, histidine salt or TRIS-HCl, or the phosphate buffer of sodium dihydrogen phosphate and sodium hydrogen phosphate composition.
The included nonionic surfactant of above-mentioned asparaginase lyophilized injectable powder is poloxamer 188, polyoxyethylene ether (35) Oleum Ricini, polyglycol distearate 15, polysorbas20 or Tween 80.
Calculate with respect to 10000 unit asparaginase in the above-mentioned asparaginase lyophilized injectable powder, mannitol is 40～80mg, and the addition of all the other compositions is buffer agent 4～6mg, nonionic surfactant 4～6mg; Be used as the water for injection 1.4～2.4g of solvent in the preparation process.
The preparation method of above-mentioned asparaginase lyophilized injectable powder has following steps: 1. will add in the water for injection that is chilled in advance below 10 ℃ according to mannitol, buffer agent, the nonionic surfactant that recipe quantity accurately takes by weighing and dissolve, adding the sodium hydrate regulator solution pH value again is 7.1～7.5; 2. the asparaginase that in the solution that 1. step obtains, adds recipe quantity, mix homogeneously, regulating pH value with sodium hydroxide solution or hydrochloric acid is 7.1～7.5; 3. adding water to prescription regulation in the solution that 2. step obtains, the solution that adds behind the water is 0.22 with the aperture
The filtering with microporous membrane degerming and obtain filtrate; 4. the filtrate that 3. step is obtained by every bottle 10000 unit asparaginase is sub-packed in the glass tube vial, and the false add plug is placed on lyophilizing in the freezer dryer, and lid is rolled in final vacuum tamponade to be dried, labels, and promptly gets lyophilized injectable powder, is kept under 2～8 ℃ of temperature.
The step of the preparation method of above-mentioned asparaginase lyophilized injectable powder 4. in, when filtrate is sub-packed in the corresponding glass tube vial behind the false add plug lyophilizing, pre-freeze keeps 120min, evacuation after-25 ℃, in 660min, sublime up into 0 ℃, insulation 270min, and in 150min, be warming up to 25 ℃, insulation 240min, to the moisture of asparaginase lyophilized injectable powder in 5%, thereby finish the lyophilizing program.
The technical scheme that realizes the present invention's second purpose is: the solvent of asparaginase lysate of the present invention is a water for injection, and solute comprises buffer agent and nonionic surfactant; Described buffer agent is sodium bicarbonate, glycinate, histidine salt or TRIS-HCl, or the phosphate buffer of sodium dihydrogen phosphate and sodium hydrogen phosphate composition; Described nonionic surfactant is poloxamer 188, polyoxyethylene ether (35) Oleum Ricini, polyglycol distearate 15, polysorbas20 or Tween 80.
When above-mentioned asparaginase lysate uses, treat dissolved asparaginase lyophilized injectable powder with respect to per 10000 units, the buffer agent in the used asparaginase lysate is 3～15mg, and nonionic surfactant is 2～8mg, and aqueous solvent is 1～15g.
The present invention has positive effect: (1) lyophilized injectable powder of the present invention is included in buffer agent and the nonionic surfactant that adds in the prescription, thereby small amount of sodium chloride injection or glucose injection are being injected this asparaginase lyophilized injectable powder and after obtaining containing the mixed system of asparaginase, when transferring to this mixed system in sodium chloride or the glucose injection again, the situation that fine visible foreign matters exceeds standard can not appear; Reduced zest during use, improved clinical drug safety human body.(2) asparaginase lyophilized injectable powder of the present invention clinical easy to use, redissolve rapidly, good stability.(3) to prepare the technology of asparaginase freeze-dried powder simple in the present invention, and production cost is low, is fit to industrialized great production.(4) asparaginase lysate of the present invention, be used for existing asparaginase lyophilized injectable powder, asparaginase lysate of the present invention with recipe quantity injects this existing lyophilized injectable powder earlier, after feasible asparaginase wherein is dissolved in wherein, when transferring in sodium chloride or the glucose injection, the situation that fine visible foreign matters exceeds standard can not appear equally.
Description of drawings
Fig. 1 is the aspect graph of lyophilized injectable powder of the present invention.
Fig. 2 makes aspect graph behind the lyophilized injectable powder for matched group, and wherein (a) figure is the aspect graph after matched group 1 is made lyophilized injectable powder, and (b) figure is the aspect graph after matched group 2 is made lyophilized injectable powder.
The specific embodiment
(embodiment 1, asparaginase lyophilized injectable powder)
The prescription of present embodiment asparaginase lyophilized injectable powder is as follows:
Asparaginase 1,000 ten thousand units, poloxamer 188(F68) 4.0g, mannitol (20%w/v) 300g, two hypophosphite monohydrate sodium dihydrogens, 6.24 grams, 0.1mol/L the NaOH aqueous solution pH of regulation system (an amount of be 7.5 ± 0.2), water for injection adds to 2000g, makes 1000 altogether.
The preparation method of present embodiment asparaginase lyophilized injectable powder is as follows:
Two hypophosphite monohydrate sodium dihydrogens, the poloxamer 188(F68 that will accurately take by weighing according to above-mentioned recipe quantity) (CAS number: 9003-11-6), mannitol (20%w/v) adds 300g and be chilled in advance in the water for injection below 10 ℃ after the dissolving, be 7.3～7.5 with the NaOH regulator solution pH value of 0.1mol/L; The asparaginase mix homogeneously that adds recipe quantity again in above-mentioned solution is that 7.3 ± 0.2(present embodiment is 7.5 with the NaOH solution of 0.1mol/L or the HCl adjusting pH value of 0.1 mol/L); Add water to 2000g, solution is with 0.22
The filtering with microporous membrane degerming; By every bottle of 2.0g filtrate is sub-packed in the glass tube vial, the false add plug is placed on lyophilizing in the freezer dryer, and lid is rolled in final vacuum tamponade to be dried, labels, and promptly gets 1000 of lyophilized injectable powders, be kept under 2～8 ℃ of temperature, and as sample S1.
See Fig. 1, be depicted as five lyophilized injectable powders randomly drawing that make according to the present embodiment prescription, the perusal character is white lyophilizing block, and " its outward appearance is the regulation of white lyophilizing block or powder under two injection asparaginase of Chinese pharmacopoeia item to meet version in 2010.
When prepared asparaginase lyophilized powder uses, dissolve in the following way:
During clinical use, every asparaginase lyophilized powder is transferred in 500mL glucose injection or the sodium chloride injection, by the normal mode use then earlier with the dissolving of 3～5mL sterilized water for injection.
When above-mentioned 2.0g filtrate is sub-packed in the corresponding glass tube vial behind the false add plug lyophilizing, pre-freeze is after-25 ℃, keep 120min, evacuation sublimes up into 0 ℃ in 660min, insulation 270min, and in 150min, be warming up to 25 ℃, insulation 240min, to the moisture of asparaginase lyophilized injectable powder in 5%, thereby finish the lyophilizing program.
(sodium hydrogen phosphate of present embodiment is to obtain through sodium dihydrogen phosphate and sodium hydroxide reaction to buffer agent in the above-mentioned asparaginase lyophilized injectable powder prescription except that phosphoric acid disodium hydrogen and sodium dihydrogen phosphate; Also can directly in prescription, comprise sodium hydrogen phosphate and sodium dihydrogen phosphate), can also replace by sodium bicarbonate, glycinate, histidine salt or TRIS-HCl; Surfactant in the prescription also can be polyoxyethylene ether (35) Oleum Ricini (CAS number: 61791-12-6), polyglycol distearate 15 (Solutol HS15, CAS number: 9004-99-3), other nonionic surfactant such as polysorbas20 or Tween 80 except that poloxamer 188; A large amount of orthogonal tests show that above-mentioned adjuvant has good Stabilization to the injection asparaginase.
Some parameters of each step of the preparation method of above-mentioned asparaginase lyophilized injectable powder can suitably be adjusted, as the water for injection of lytic activity material and adjuvant the present embodiment ormal weight 40%～120% between all allow; The ormal weight of filtrate fill also can change according to the unit of the asparaginase of packing, such as fill 1g filtrate in every bottle, then comprises asparaginase 5000 units in every bottle.
The lyophilized injectable powder of present embodiment preparation, in finished product, do not comprise the water for injection in the layoutprocedure, have only a spot of water for injection residual in other words in the finished product because since the particularity of the preparation method of present embodiment removed in freeze-drying process as the water for injection of solvent; But because the performance of finished product is closely related with solvent and consumption thereof, so the amount that is used as the water for injection that solvent also finally removes in the preparation process need be controlled in certain scope.
Sodium hydrogen phosphate when present embodiment prepares in the prescription is dissolved in water for injection, form phosphate buffer with sodium hydroxide reaction back again, make to add water to before the 2000g solution pH value between 7.1～7.5, add water to and limit that the pH value of solution is 7～8 before the lyophilizing behind the 2000g; What certainly can understand is, only in finished product, add with layoutprocedure in the water for injection of the same amount used, the pH value of dissolving back solution is just consistent or approaching with solution pH value before the lyophilizing; Finished product was used the dissolved stability of water for injection again after but the pH value of solution influenced lyophilizing before the lyophilizing, and finished product was used the dissolved stability of water for injection again after buffer agent in the prescription and consumption thereof had then guaranteed lyophilizing.
Present embodiment is according to prescription, and used asparaginase derives from Changzhou thousand red-face roleization Pharmacy stock Co., Ltd; Two hypophosphite monohydrate sodium dihydrogens, sodium hydroxide derive from Shanghai chemical reagents corporation of traditional Chinese medicines group; The formula mannitol injection liquid specification is 50g:250mL, derives from Jiangsu Sihuan Biological Co., Ltd.; Poloxamer 188(F68) derives from BASF China.
(embodiment 2 to embodiment 5, asparaginase lyophilized injectable powder)
The prescription of embodiment 2 to embodiment 5 asparaginase lyophilized injectable powders sees the following form 1.
Table 1
Embodiment 2 to embodiment 5 is according to each prescription in the last table, and preparation method is identical with the preparation method of embodiment 1 asparaginase lyophilized injectable powder.
The lyophilized injectable powder that makes according to prescription and the preparation method of embodiment 2 to embodiment 5 is successively as sample S2, S3, S4, S5.
(embodiment 6, asparaginase lysate)
The collocation method of the asparaginase lysate of present embodiment is as follows:
At first accurately take by weighing two hypophosphite monohydrate sodium dihydrogen 6.24g, surfactant poloxamer 188(F68) 4.0g; With above-mentioned two hypophosphite monohydrate sodium dihydrogens, the poloxamer 188(F68 that accurately takes by weighing) add in the 300g water for injection after the dissolving, be that 7.1～7.5(present embodiment is 7.5 with the NaOH solution regulator solution pH value of 0.1mol/L); Adding injection water to solution gross weight then is 5000g, and gained solution is with 0.22
The filtering with microporous membrane degerming; By every bottle of 5.0g filtrate is sub-packed in the ampoule, jumps a queue and roll lid, label, promptly get 1000 of dedicated solvents, room temperature is preserved, and as sample S6.
The buffer system of present embodiment asparaginase lysate is made of sodium hydrogen phosphate and sodium dihydrogen phosphate, and sodium hydrogen phosphate wherein is to be obtained by sodium dihydrogen phosphate and sodium hydroxide reaction; Except above-mentioned phosphate buffer, buffer agent also can be selected any one among sodium bicarbonate, glycinate, histidine salt or the TRIS-HCl.
The surfactant of present embodiment also can be other nonionic surfactant such as polyoxyethylene ether (35) Oleum Ricini, polyglycol distearate 15 (Solutol HS15), polysorbas20 or Tween 80 except that poloxamer 188.
During clinical use, the lysate of respectively getting a commercially available asparaginase lyophilized injectable powder and preparing according to the method described above, after being transferred to lysate in the asparaginase lyophilized injectable powder bottle with syringe, rocking concussion dissolves lyophilized powder fully, then solution is transferred at last in 500mL glucose injection or the sodium chloride injection, uses by normal mode.
(embodiment 7 to embodiment 10, asparaginase lysate)
The prescription of the lysate of embodiment 7 to embodiment 10 sees the following form 2:
Table 2
When the lysate of the various embodiments described above disposes, recipe quantity according to table 2 accurately takes by weighing poloxamer 188 and two hypophosphite monohydrate sodium dihydrogens, after being dissolved in 300g water for injection, NaOH solution regulator solution pH value with 0.1mol/L is 7.1～7.5, adding injection water to solution gross weight then is 5000g, and operation afterwards is identical with embodiment 6.
The lysate that makes according to prescription and the preparation method of embodiment 7 to embodiment 10 is as sample S7, S8, S9, S10.
(test example 1, asparaginase transfusion stability-asparaginase lyophilized injectable powder)
In order to prove the reasonability of lyophilized injectable powder prescription of the present invention, we at first investigate the stability of dissolving the back transfusion, get each 5 of the asparaginase lyophilized injectable powders of embodiment 1～5 preparation, respectively with the dissolving of 5mL water for injection, the 2mL that then extracts respectively wherein is injected in the 100mL transfusion (glucose injection or sodium chloride injection), mix homogeneously, then according to 2010 editions " two appendix IX of Chinese pharmacopoeia H visible foreign matters inspection technique mensuration, respectively 1,3, on the clarity test instrument, transfusion is observed after 6 hours, wherein observation index and criterion such as following table 3 as a result, testing result see Table 4 and table 5.
Table 3 observation index and criterion as a result
Explanation about trickle visible foreign matters in the table 3:
(1) white point: mean the white object that to differentiate plane or corner angle.
(2) tiny protein floccule or protein particulate: mean translucent flocculent deposit or protein particulate less than about 1mm.
(3) a small amount of floccule or protein particulate: mean in regulation in the review time protein floccule or the protein particulate of difficult counting.
(4) negligible deposition thing: mean the small deposit that leaves standstill in the test sample of back, have the smoke-like precipitation to float after rotating gently, the promptly lost person of jog.
(5) shake the precipitation of not loosing: mean a small amount of deposit that postpone protein solution of a specified duration occurs, can not disperse disappearance person after shaking gently.
Visible foreign matters measurement result in table 4 glucose injection
Visible foreign matters measurement result in table 5 sodium chloride injection
By the measurement result of table 4 and table 5 as can be known, when asparaginase diluent of the present invention joins in sodium chloride or the glucose injection under the room temperature, the problem that does not exist visible foreign matters to exceed standard.
(test example 2, asparaginase transfusion stability-asparaginase lysate)
In order to prove the feasibility of asparaginase lysate of the present invention, after the lysate dissolved freeze-dried powder, stability to the transfusion of asparaginase is investigated, get each 5 of the asparaginase lysates of embodiment 6～10 preparation, extract respectively and inject commercially available asparaginase lyophilized injectable powder bottle, rock after concussion dissolves fully, the 2mL that extracts respectively wherein is injected in the 100mL transfusion (glucose injection or sodium chloride injection), mix homogeneously, then according to 2010 editions " two appendix IX of Chinese pharmacopoeia H visible foreign matters inspection technique mensuration, respectively 1,3, on the clarity test instrument, transfusion is observed after 6 hours, wherein observation index and criterion such as following table 3 as a result, testing result sees Table 6.The described commercially available asparaginase lyophilized injectable powder of present embodiment derives from Changzhou thousand red-face roleization Pharmacy stock Co., Ltd, and wherein except that asparaginase, adjuvant is a mannitol.
Visible foreign matters measurement result in table 6 glucose injection
In addition, according to above-mentioned detection method, after extraction 2mL wherein is injected in the 100mL sodium chloride injection respectively, each test result of samples and its coming to the same thing in glucose injection.
By the measurement result of table 6 and the testing result in the sodium chloride injection as can be known, do not changing under the situation that has asparaginase lyophilized injectable powder prescription under the room temperature, after being dissolved in lyophilized injectable powder wherein, when transferring in sodium chloride or the glucose injection, the situation that fine visible foreign matters exceeds standard can not appear equally.
(test example 3, asparaginase shelf stability---asparaginase lyophilized injectable powder)
This test example is investigated appearance character, pH value, visible foreign matters, activity, purity, the transfusion of sample sample under hot test, accelerated test and long term test condition and is observed; Wherein high spot reviews activity index, purity, deposit that visible foreign matters detects in the back transfusion; Detection method adopts that " two middle asparaginase items of Chinese pharmacopoeia down and the method for describing in the appendix; Test specimen is from three batches of (lot number: S1-1, S1-2, S1-3) asparaginase lyophilized injectable powder samples of embodiment 1 preparation of commercially available back.
The hot test condition is 40 ± 2 ℃/RH60 ± 5%, and testing result is as follows:
Table 7 S1-1 hot test
Table 8 S1-2 hot test
Table 9 S1-3 hot test
The accelerated test condition is 25 ± 2 ℃/RH 60 ± 5%, and testing result is as follows:
Table 10 S1-1 accelerated test
Table 11 S1-2 accelerated test
Table 12 S1-3 accelerated test
The long term test condition is 5 ± 3 ℃, and testing result is as follows:
Table 13 S1-1 long term test
Table 14 S1-2 long term test
Table 15 S1-3 long term test (5 ± 3 ℃)
By above-mentioned experiment as can be seen, lyophilized injectable powder of the present invention was placed for 5 weeks under 40 ± 2 ℃ hot test condition, and every index is stable, and stable in infusion process; In 25 ± 2 ℃ of accelerated test Decembers, index is stable, and stable in infusion process; In 5 ± 3 ℃ of long term test Decembers, index is stable, and stable in infusion process; Especially three tests, every index in last week or last January is compared with initial index does not have significant change substantially, illustrates that thus the prescription of lyophilized injectable powder of the present invention has excellent stability, clinical trial safety.
(reference examples 1)
This reference examples is according to Chinese patent literature CN100502944C(application number 200510102992.X) prescription of disclosed a kind of asparaginase injection, prepare lyophilized injectable powder, and investigate the appearance character and the stability of prepared lyophilized powder.
Wherein the prescription of this reference examples (in 1000) is as follows:
Conventional preparation method according to lyophilized injectable powder in the pharmaceuticals industry, to add in the water for injection according to disodium hydrogen phosphate dodecahydrate, two hypophosphite monohydrate sodium dihydrogens, L-cysteine, the HP-(not adding in the sample 1) that above-mentioned recipe quantity accurately takes by weighing and dissolve, the asparaginase mix homogeneously that in above-mentioned solution, adds recipe quantity again, add water to recipe quantity, solution is with 0.22
The filtering with microporous membrane degerming; Filtrate is sub-packed in the glass tube vial of respective volume specification by the prescription ormal weight, the false add plug is placed on lyophilizing in the freezer dryer, and lid is rolled in the vacuum tamponade, promptly get respectively 1000 in the sample 1 of different prescriptions and sample 2, is kept under-20 ℃ of temperature.
The purity of this reference examples agents useful for same and source are as follows: used asparaginase derives from Changzhou thousand red-face roleization Pharmacy stock Co., Ltd; The L-cysteine is a SILVER REAGENT purity, and lot number is 20100831, and molecular weight is 157.5, derives from Shanghai chemical reagents corporation of traditional Chinese medicines group; Two hypophosphite monohydrate sodium dihydrogens, disodium hydrogen phosphate dodecahydrate, sodium hydroxide are injection stage purity, derive from Shanghai chemical reagents corporation of traditional Chinese medicines group; HP-is a SILVER REAGENT, derives from auspicious this in Kunshan and digests worker's raw material company limited.
See Fig. 2, wherein (a) figure makes aspect graph behind the lyophilized injectable powder according to the prescription of matched group 1, and (b) figure makes aspect graph behind the lyophilized injectable powder according to the prescription of matched group 2; By we see among the figure, the outward appearance of the lyophilized injectable powder that makes does not obviously meet the pharmacopeia regulation of " white lyophilizing block ", there is no need to carry out other stability tests.
But we have still investigated the transfusion stability of matched group 1 and matched group 2, get matched group 1 and matched group 2 sample each 5, with the dissolving of 5mL water for injection (once dissolving), then the 2mL that extracts wherein respectively is injected into (secondary dissolving) in 100mL glucose injection or the sodium chloride injection, mix homogeneously, then according to 2010 editions " two appendix IX of Chinese pharmacopoeia H visible foreign matters inspection technique mensuration, on the clarity test instrument transfusion is being observed after 1,3,6 hour respectively, observation index and result judge as following table 16.
Table 16
Therefore as can be known by lyophilized powder outward appearance and stability test result, defective according to the lyophilized injectable powder of the prescription preparation of asparaginase injection, can not be used for clinical use.
Claims (10)
1. an asparaginase lyophilized injectable powder comprises asparaginase and mannitol, it is characterized in that: also comprise buffer agent, surfactant, wherein surfactant is a nonionic surfactant; In the process of the described asparaginase lyophilized injectable powder of preparation, have as solvent and finally be less than 5% water for injection of addition.
2. asparaginase lyophilized injectable powder according to claim 1, it is characterized in that: calculate with respect to 10000 unit asparaginase, mannitol is 40～100mg, buffer agent is 3～15mg, nonionic surfactant is 2～8mg, and the addition that is used as the water for injection of solvent in the preparation process is 0.8～2.4g.
3. asparaginase lyophilized injectable powder according to claim 2 is characterized in that: in the process of the described asparaginase lyophilized injectable powder of preparation, the pH value of solution is 7.1～7.5 before the lyophilizing.
4. asparaginase lyophilized injectable powder according to claim 2 is characterized in that: described buffer agent is sodium bicarbonate, glycinate, histidine salt or TRIS-HCl, or the phosphate buffer of sodium dihydrogen phosphate and sodium hydrogen phosphate composition.
5. asparaginase lyophilized injectable powder according to claim 2 is characterized in that: described nonionic surfactant is poloxamer 188, polyoxyethylene ether (35) Oleum Ricini, polyglycol distearate 15, polysorbas20 or Tween 80.
6. asparaginase lyophilized injectable powder according to claim 2 is characterized in that: calculate with respect to 10000 unit asparaginase, mannitol is 40～80mg, and buffer agent is 4～6mg, and nonionic surfactant is 4～6mg; Be used as the water for injection 1.4～2.4g of solvent in the preparation process.
7. the preparation method of an asparaginase lyophilized injectable powder as claimed in claim 2 is characterized in that having following steps:
1. will add in the water for injection that is chilled in advance below 10 ℃ according to mannitol, buffer agent and the nonionic surfactant that recipe quantity accurately takes by weighing and dissolve, adding the sodium hydrate regulator solution pH value again is 7.1～7.5;
2. the asparaginase that in the solution that 1. step obtains, adds recipe quantity, mix homogeneously, regulating pH value with sodium hydroxide solution or hydrochloric acid is 7.1～7.5;
3. adding water to prescription regulation in the solution that 2. step obtains, the solution that adds behind the water is 0.20～0.25 with the aperture
The filtering with microporous membrane degerming and obtain filtrate;
4. the filtrate that 3. step is obtained by every bottle 10000 unit asparaginase is sub-packed in the glass tube vial, and the false add plug is placed on lyophilizing in the freezer dryer, and lid is rolled in final vacuum tamponade to be dried, labels, and promptly gets lyophilized injectable powder, is kept under 2～8 ℃ of temperature.
8. the preparation method of asparaginase lyophilized injectable powder according to claim 7, it is characterized in that: step 4. in, when filtrate was sub-packed in the corresponding glass tube vial behind the false add plug lyophilizing, pre-freeze was after-25 ℃, keep 120min, evacuation sublimes up into 0 ℃ in 660min, insulation 270min, and in 150min, be warming up to 25 ℃, insulation 240min, to the moisture of asparaginase lyophilized injectable powder in 5%, thereby finish the lyophilizing program.
9. asparaginase lysate, it is characterized in that: the solvent of lysate is a water for injection, and solute comprises buffer agent and nonionic surfactant; Described buffer agent is sodium bicarbonate, glycinate, histidine salt or TRIS-HCl, or the phosphate buffer of sodium dihydrogen phosphate and sodium hydrogen phosphate composition; Described nonionic surfactant is poloxamer 188, polyoxyethylene ether (35) Oleum Ricini, polyglycol distearate 15, polysorbas20 or Tween 80.
10. asparaginase lysate according to claim 9, it is characterized in that: treat dissolved asparaginase lyophilized injectable powder with respect to per 10000 units during use, buffer agent in the used asparaginase lysate is 3～15mg, nonionic surfactant is 2～8mg, and the solvent injection water is 1～15g.
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| CN107693796B (en) * | 2016-06-22 | 2020-12-22 | 江苏众红生物工程创药研究院有限公司 | PEG (polyethylene glycol) site-directed modified asparaginase injection |
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