CN102138909B - 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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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 freeze-dried powder injection and preparation method thereof, and the used solvent of a kind of asparaginase dissolving.
Background technology
Asparaginase (following another name ASP, 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 granulocytic 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 the tumor cells such as acute leukemia are without this function; Thereby when asparagine is sharply lacked, tumor cell also can not self synthesize because 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, take the specification of every 5000 units or 10000 units as main.This injection asparaginase freeze-dried powder injection is comprised 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 transfusion to the zest of human body, patients ' lives is threatened safely.
In " Strait Pharmaceutical Journal " the 18th to the 19 page of disclosed document " stability study of ASP " of 06 phase in 2006, 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 select 5% GS as the best solvent of L-ASP, the concrete configuration method is as follows: add 5% the sodium bicarbonate solution of 0.19mL to adjust the solvent pH value as 7.5 in the glucose injection of the l 5% of every 100m, 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
3The method of the pH value of regulating 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, its chief component is: the disodiumedetate (EDTA) of the asparaginase of 10-80mg, the Cys of 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 Cys character in forming is unstable, 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, for this reason the first purpose of the present invention provide a kind of clinical easy to use, redissolve rapidly, the asparaginase freeze-dried powder injection of good stability and preparation method thereof, the 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 the first purpose is: asparaginase freeze-dried powder injection of the present invention comprises asparaginase and mannitol, also comprises buffer agent, surfactant, and wherein surfactant is nonionic surfactant; In the process of the described asparaginase freeze-dried powder injection 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 freeze-dried powder injection, 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 freeze-dried powder injection of preparation, the pH value of solution is 7.1～7.5 before the lyophilizing.
The included buffer agent of above-mentioned asparaginase freeze-dried powder injection 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 freeze-dried powder injection is PLURONICS F87, Cremophor EL, Solutol HS15, polysorbas20 or Tween 80.
Calculate with respect to 10000 unit asparaginase in the above-mentioned asparaginase freeze-dried powder injection, 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 freeze-dried powder injection 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 is 7.1～7.5 again; 2. the asparaginase that adds recipe quantity in the solution that 1. obtains to step, mix homogeneously, regulating pH value with sodium hydroxide solution or hydrochloric acid is 7.1～7.5; 3. add water to the prescription regulation in the solution that 2. obtains to step, 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 by every bottle of 10000 unit asparaginase 3. step is obtained is sub-packed in the glass tube vial, partly jumps a queue to be placed on lyophilizing in the freezer dryer, and lid is rolled in final vacuum tamponade to be dried, labels, and namely gets lyophilized injectable powder, is kept under 2～8 ℃ of temperature.
The step of the preparation method of above-mentioned asparaginase freeze-dried powder injection 4. in, filtrate is sub-packed in when partly jumping a queue rear lyophilizing in the corresponding glass tube vial, 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 freeze-dried powder injection in 5%, thereby finish the lyophilizing program.
The technical scheme that realizes the present invention's the second purpose is: the solvent of asparaginase lysate of the present invention is 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 PLURONICS F87, Cremophor EL, Solutol HS15, polysorbas20 or Tween 80.
When above-mentioned asparaginase lysate used, with respect to per 10000 units asparaginase freeze-dried powder injection to be dissolved, the buffer agent in the used asparaginase lysate was 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 a small amount of sodium chloride injection or glucose injection are being injected this asparaginase freeze-dried powder injection 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; Reduce the zest to human body during use, improved clinical drug safety.(2) asparaginase freeze-dried powder injection of the present invention clinical easy to use, redissolve rapidly, good stability.(3) to prepare the technique 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 freeze-dried powder injection, asparaginase lysate of the present invention with recipe quantity injects this existing lyophilized injectable powder first, so that after 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 is the aspect graph after matched group is made lyophilized injectable powder, 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 freeze-dried powder injection)
The prescription of present embodiment asparaginase freeze-dried powder injection is as follows:
Asparaginase 1,000 ten thousand units, PLURONICS F87 (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 altogether 1000.
The preparation method of present embodiment asparaginase freeze-dried powder injection is as follows:
The two hypophosphite monohydrate sodium dihydrogens that will accurately take by weighing according to above-mentioned recipe quantity, PLURONICS F87 (F68) (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 again recipe quantity in the 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, partly jumping a queue is placed on lyophilizing in the freezer dryer, and lid is rolled in final vacuum tamponade to be dried, labels, and namely 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, then every asparaginase lyophilized powder is transferred in 500mL glucose injection or the sodium chloride injection first with the dissolving of 3～5mL sterilized water for injection, uses by normal mode.
Above-mentioned 2.0g filtrate is sub-packed in when partly jumping a queue rear lyophilizing in the corresponding glass tube vial, 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 freeze-dried powder injection 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 freeze-dried powder injection prescription except phosphoric acid disodium hydrogen and sodium dihydrogen phosphate; Also can directly in prescription, comprise sodium hydrogen phosphate and sodium dihydrogen phosphate), can also be replaced by sodium bicarbonate, glycinate, histidine salt or TRIS-HCl; Surfactant in the prescription also can be Cremophor EL (CAS number: 61791-12-6), Solutol HS15 (Solutol HS15, CAS number: 9004-99-3), other nonionic surfactant such as polysorbas20 or Tween 80 except PLURONICS F87; 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 freeze-dried powder injection 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, only have in other words a small amount of water for injection residual 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 again with after the sodium hydroxide reaction, make to add water to before the 2000g pH 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 that the water for injection of the same amount of only using in adding and the layoutprocedure in finished product, the pH value of the rear solution of dissolving are just consistent with pH before the lyophilizing or approaching; Finished product was used the water-soluble stability of injection again after but the pH value of the front solution of lyophilizing affected lyophilizing, and finished product was used the water-soluble stability of injection again after the 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 Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; The formula mannitol injection liquid specification is 50g:250mL, derives from Jiangsu Sihuan Biological Co., Ltd.; PLURONICS F87 (F68) derives from BASF China.
(embodiment 2 to embodiment 5, asparaginase freeze-dried powder injection)
The prescription of embodiment 2 to embodiment 5 asparaginase freeze-dried powder injections sees the following form 1.
Table 1
Embodiment 2 to embodiment 5 is according to each prescription in the upper table, and preparation method is identical with the preparation method of embodiment 1 asparaginase freeze-dried powder injection.
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 PLURONICS F87 (F68) 4.0g; The above-mentioned two hypophosphite monohydrate sodium dihydrogens that accurately take by weighing, PLURONICS F87 (F68) are added in the 300g water for injection after the dissolving, are that 7.1～7.5(present embodiment is 7.5 with the NaOH solution regulator solution pH value of 0.1mol/L); Then injecting water to the solution gross weight 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, namely 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 Cremophor EL, Solutol HS15 (Solutol HS15), polysorbas20 or Tween 80 except PLURONICS F87.
During clinical use, the lysate of respectively getting a commercially available asparaginase freeze-dried powder injection and preparing according to the method described above, after being transferred to lysate in the asparaginase freeze-dried powder injection 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 PLURONICS F87 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, then injecting water to the solution gross weight 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 stabilization-asparaginase freeze-dried powder injection)
In order to prove the reasonability of lyophilized injectable powder prescription of the present invention, we at first investigate the stability of dissolving rear transfusion, get each 5 of the asparaginase freeze-dried powder injections 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 as a result criterion such as following table 3, 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 less than about 1mm or protein particulate.
(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 rear test sample, have the smoke-like precipitation to float after rotating gently, jog i.e. lost person.
The precipitation of (5) cannot not shaking loosely: mean to be long placed in a small amount of deposit that rear protein solution 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 stabilization-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 freeze-dried powder injection 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 as a result criterion such as following table 3, testing result sees Table 6.The described commercially available asparaginase freeze-dried powder injection of present embodiment derives from Changzhou thousand red-face roleization Pharmacy stock Co., Ltd, and wherein except asparaginase, adjuvant is 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, the testing result of each sample 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 in the situation that has the asparaginase freeze-dried powder injection 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 freeze-dried powder injection)
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 in the rear transfusion visible foreign matters and detect; Detection method adopts " under two middle asparaginase items of Chinese pharmacopoeia and the method for describing in the appendix; Test specimen is from three batches of (lot number: S1-1, S1-2, S1-3) asparaginase freeze-dried powder injection 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 ℃)
Can find out that by above-mentioned experiment lyophilized injectable powder of the present invention was placed for 5 weeks under 40 ± 2 ℃ hot test condition, indices 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, the indices in last week or last January are compared with initial index substantially without significant change, illustrate 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 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, Cys, the HP-β-CD (not adding in the sample 1) that above-mentioned recipe quantity accurately takes by weighing and dissolve, the asparaginase mix homogeneously that adds again recipe quantity in the mentioned solution, 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, partly jumping a queue is placed on lyophilizing in the freezer dryer, and lid is rolled in the vacuum tamponade, namely gets the sample 1 of different prescriptions and sample 2 each 1000, 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; Cys is SILVER REAGENT purity, and lot number is 20100831, and molecular weight is 157.5, derives from Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; Two hypophosphite monohydrate sodium dihydrogens, disodium hydrogen phosphate dodecahydrate, sodium hydroxide are injection stage purity, derive from Solution on Chemical Reagents in Shanghai company of traditional Chinese medicines group; HP-β-CD is 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 stabilization 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), the 2mL that then 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 such as following table 16.
Table 16
Therefore by lyophilized powder outward appearance and stability test result as can be known, defective according to the lyophilized injectable powder of the formula preparation of asparaginase injection, can not be used for clinical use.
Claims (6)
1. an asparaginase freeze-dried powder injection comprises asparaginase and mannitol, it is characterized in that: also comprise buffer agent, surfactant, wherein surfactant is nonionic surfactant; In the process of the described asparaginase freeze-dried powder injection of preparation, have as solvent and finally be less than 5% water for injection of addition; Calculate with respect to 10000 unit asparaginase, mannitol is 40～100mg, and buffer agent is 3～15mg, and 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; The pH value of solution is adjusted to 7.1～7.5 by NaOH solution before the preparation process lyophilizing; Wherein said 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 PLURONICS F87, Cremophor EL, Solutol HS15, polysorbas20 or Tween 80.
2. asparaginase freeze-dried powder injection according to claim 1, it 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.
3. the preparation method of an asparaginase freeze-dried powder injection as claimed in claim 1 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 is 7.1～7.5 again;
2. the asparaginase that adds recipe quantity in the solution that 1. obtains to step, mix homogeneously, regulating pH value with sodium hydroxide solution or hydrochloric acid is 7.1～7.5;
3. add water to the prescription regulation in the solution that 2. obtains to step, the solution that adds behind the water is that the filtering with microporous membrane degerming of 0.20～0.25 μ m obtains filtrate with the aperture;
4. the filtrate that by every bottle of 10000 unit asparaginase 3. step is obtained is sub-packed in the glass tube vial, partly jumps a queue to be placed on lyophilizing in the freezer dryer, and lid is rolled in final vacuum tamponade to be dried, labels, and namely gets lyophilized injectable powder, is kept under 2～8 ℃ of temperature.
4. the preparation method of asparaginase freeze-dried powder injection according to claim 3, it is characterized in that: step 4. in, filtrate is sub-packed in when partly jumping a queue rear lyophilizing in the corresponding glass tube vial, 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 freeze-dried powder injection in 5%, thereby finish the lyophilizing program.
5. asparaginase lysate, it is characterized in that: the solvent of lysate is 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 PLURONICS F87, Cremophor EL, Solutol HS15, polysorbas20 or Tween 80; Wherein comprise buffer agent 3～15mg in the lysate of every 5.0g, nonionic surfactant 2～8mg; The pH value of lysate is adjusted to 7.1～7.5 by NaOH solution.
6. asparaginase lysate according to claim 5, it is characterized in that: during use with respect to per 10000 units asparaginase freeze-dried powder injection to be dissolved, buffer agent in the used asparaginase lysate is 3～15mg, nonionic surfactant is 2～8mg, and the solvent injection water is 1～15g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| EP3463308A4 (en) * | 2016-06-01 | 2019-12-18 | Servier IP UK Limited | Formulations of polyalkylene oxide-asparaginase and methods of making and using the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102631328A (en) * | 2012-05-04 | 2012-08-15 | 常州千红生化制药股份有限公司 | Recombinant human antithrombosis protein lyophilized powder injection and preparation method thereof |
| EP3197291A1 (en) * | 2014-07-04 | 2017-08-02 | West Systems S.r.l | Method and composition to reduce the formation of acrylamide in fresh or pre-fried foods to be subjected to heat treatment |
| 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 |
| CN106310244A (en) * | 2016-08-19 | 2017-01-11 | 广州白云山明兴制药有限公司 | Freeze-drying process of asparaginase for injection |
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| CN1748790A (en) * | 2005-09-16 | 2006-03-22 | 北京双鹭药业股份有限公司 | Asparaginase injection its preparing method and use |
| CN1925845A (en) * | 2004-03-01 | 2007-03-07 | 大不列颠药品有限公司 | Powdered compositions of sensitive active materials in an at least partially amorphous state |
| CN101063118B (en) * | 2007-04-18 | 2010-09-08 | 常州千红生化制药股份有限公司 | Method for purification of L-asparaginyl amine enzyme |
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| CN1925845A (en) * | 2004-03-01 | 2007-03-07 | 大不列颠药品有限公司 | Powdered compositions of sensitive active materials in an at least partially amorphous state |
| CN1748790A (en) * | 2005-09-16 | 2006-03-22 | 北京双鹭药业股份有限公司 | Asparaginase injection its preparing method and use |
| CN101063118B (en) * | 2007-04-18 | 2010-09-08 | 常州千红生化制药股份有限公司 | Method for purification of L-asparaginyl amine enzyme |
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| EP3463308A4 (en) * | 2016-06-01 | 2019-12-18 | Servier IP UK Limited | Formulations of polyalkylene oxide-asparaginase and methods of making and using the same |
| EP4019007A1 (en) * | 2016-06-01 | 2022-06-29 | Servier IP UK Limited | Formulations of polyalkylene oxide-asparaginase and methods of making and using the same |
| JP7109427B2 (en) | 2016-06-01 | 2022-07-29 | セルヴィエ アイピー ユーケー リミテッド | Formulations of polyalkylene oxide-asparaginase and methods of making and using the same |
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