CN106389352A - Stable dianhydrogalactol lyophilized powder for injection - Google Patents
Stable dianhydrogalactol lyophilized powder for injection Download PDFInfo
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- CN106389352A CN106389352A CN201610620241.5A CN201610620241A CN106389352A CN 106389352 A CN106389352 A CN 106389352A CN 201610620241 A CN201610620241 A CN 201610620241A CN 106389352 A CN106389352 A CN 106389352A
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- 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
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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Abstract
The invention relates to stable dianhydrogalactol lyophilized powder for injection. The dianhydrogalactol lyophilized powder for injection provided by the invention is good in stability, and the quality effect of the dianhydrogalactol lyophilized powder for injection, after long-term preservation, is significantly better than that of the prior art.
Description
Technical field
The present invention relates to chemical drugs field is and in particular to a kind of stable injection dianhydrodulcitol freeze-dried powder.
Background technology
1.2；5.6 2 anhydrous dulcit (1.2；5.6-Dianhydrog alactito.DAD is hexitol kind anti-cancer drugs,
Also known as dianhydrodulcitol (C6H10O4), NSC-132313, dianhydrogalactitol, DAG.【Outer literary fame】
Dianhydrogalactitol.It is anticarcinogen 1, the converted product of 6- mitolactol, chronic granulocytes leukemia is had preferably recent
Curative effect, remission rate is 86%.Also there is certain curative effect to pulmonary carcinoma, multiple myeloma, nasopharyngeal carcinoma etc., effective to various pulmonary carcinoma
Rate, is only below chlormethine, ametycin and methotrexate, but toxicity is then lighter.
Dianhydrodulcitol has broad-spectrum anti-tumor activity to the transplanted tumor of animal.Clinical research proves to chronic granulocyte
Leukemia (slow grain) has preferable short term effect, and remission rate is 86.0%, and markedly fast, beautiful with the Myleran of document report and indigo
Red comparison, remission rate and Myleran are close and be higher than indirubin, but complete remission rate is less than Myleran.DAD effective compared with other two
Medicine is fast, and side effect is lighter than Myleran, with Myleran no crossing drug resistant, can promote the use of as inducer remission medicine.
In addition dianhydrodulcitol compares with to the medicine of pulmonary carcinoma and other pernicious breast tumor, is only second to nitrogen to the curative effect of adenocarcinoma
Mustard, ametycin and methotrexate and more above-mentioned two medicines of the toxicity such as bone marrow, digestive tract and Liver and kidney are light.To multiple myeloma
Effective percentage 55.6%, remaining clinical symptoms is improved, and osteodynia substantially mitigates, and also has certain curative effect to plasma cell multiple myeloma,
Thus have the value researching and developing further.
Existing injection dianhydrodulcitol (lyophilizing) statutory standards are not specified by water content, and Chinese Pharmacopoeia Commission issues
Injection dianhydrodulcitol (lyophilizing) publicity standard moisture must not be defined as with 2.0%, its moisture content requires relatively to close at《In
State's pharmacopeia》Injection (lyophilizing) kind of two is higher, and respectively providing moisture content in other variety and quality standards must not mistake
The following upper limit：Pantoprazole sodium for injection 4.0%, carboplatin for injection 3.0%, Somatostatin for injection 4.0%, injection cephalo
The western sodium of Buddhist nun 5.0%, cefoxitin sodium for injection 1.0%, ceftriaxone sodium for injection 8.0%～11.0%, injection benzyl penicillium sp
Element 5.0%～8.0%, the aseptic freeze-dried product of latamoxef sodium for injection 2.0%.By existing statutory standards or Chinese Pharmacopoeia Commission
Injection dianhydrodulcitol (lyophilizing) standard of publicity is detected, every detection of injection dianhydrodulcitol, including medicine
Moral character shape, acid-base value, clarity, relevant material (high performance liquid chromatography), content (high-efficient liquid phase technique), testing result is shown in
Steady quality in its expiration date of drug.
Through research, detected using new detection method to about material, find that before the deadline, injection spends water
The relevant material detection data of dulcitol (lyophilizing) is in fact and unstable, elapses over time, the content about material can be
Increase, this will affect the safety of medicine.
For existing injection dianhydrodulcitol freeze-dried powder about the unstable problem of material it is proposed that the present invention.
Content of the invention
It is an object of the invention to provide a kind of stable injection dianhydrodulcitol freeze-dried powder, its moisture is
Less than 1.5%.
Preferably：Described moisture is less than 1%.
Preferably：Described moisture is 0.01%-1.4%.
Preferably：Described moisture is 0.02%-1.3%.
Preferably：Described moisture is 0.03%-1.2%.
Preferably：Described moisture is 0.04%-1.1%.
Preferably：Described moisture is 0.05%-1.0%.
Preferably：Described moisture is 0.08%-0.9%.
Preferably：Described moisture is 0.1%-0.8%.
Preferably：Described moisture is 0.15%-0.7%.
Preferably：Described moisture is 0.2%-0.6%.
Preferably：：Described moisture is 0., 05-0.6%..
Preferably：：Described moisture is 0., 05-0.2%.
It is a further object of the present invention to provide a kind of preparation method of stable injection dianhydrodulcitol freeze-dried powder, its
It is characterised by comprising the following steps：
Weigh dianhydrodulcitol, add the water for injection of 15-40 times amount fully to dissolve, stir evenly, be settled to water for injection
Gross weight is 20-45 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Lyophilizing.Weigh dianhydrodulcitol,
The water for injection adding 15-40 times amount fully dissolves, and stirs evenly, is dianhydrodulcitol weight with water for injection constant volume ad pond om
20-45 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Lyophilizing.
Wherein, plus water for injection fully dissolve, constant volume when temperature be preferably less than 20 DEG C.As 20 DEG C, 19 DEG C, 18 DEG C,
17℃、16℃、15℃、14℃、13℃、12℃、11℃、10℃、9℃、8℃、7℃、6℃、5℃、4℃、3℃、2℃、1℃.
Wherein, lyophilizing operating procedure is：Pre-freeze, distillation, parsing.
Wherein, during lyophilizing, pre-freezing temperature is -20 DEG C～-60 DEG C, and the time is 30-300min.If pre-freezing temperature can be -20
℃、-21℃、-22℃、-23℃、-24℃、-25℃、-26℃、-27℃、-28℃、-29℃、-30℃、-31℃、-32℃、-
33℃、-34℃、-35℃、-36℃、-37℃、-38℃、-39℃、-40℃、-41℃、-42℃、-43℃、-44℃、-45
℃、-46℃、-47℃、-48℃、-49℃、-50℃、-51℃、-52℃、-53℃、-54℃、-55℃、-56℃、-57℃、-
58℃、-59℃、-60℃.As the time can for 30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,
46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、
71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、
96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、
116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、
135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、
154、155、156、157、158、159、160、161、162、163、164、165、166、167、168、169、170、171、172、
173、174、175、176、177、178、179、180、181、182、183、184、185、186、187、188、189、190、191、
192、193、194、195、196、197、198、199、200、201、202、203、204、205、206、207、208、209、210、
211、212、213、214、215、216、217、218、219、220、221、222、223、224、225、226、227、228、229、
230、231、232、233、234、235、236、237、238、239、240、241、242、243、244、245、246、247、248、
249、250、251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、
268、269、270、271、272、273、274、275、276、277、278、279、280、281、282、283、284、285、286、
287、288、289、290、291、292、293、294、295、296、297、298、299、300min.
Wherein, during lyophilizing, sublimation temperature is -20 DEG C～0 DEG C, and the time is 30-3000min, and pressure is 10-60pa.As temperature
Can be；-20℃、-19℃、-18℃、-17℃、-16℃、-15℃、-14℃、-13℃、-12℃、-11℃、-10℃、-9℃、-
8℃、-7℃、-6℃、--5℃、-4℃、-3℃、-2℃、-1℃、0℃.As the time can for 30,31,32,33,34,35,36,
37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、
62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、
87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、
109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、
128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、
147、148、149、150、151、152、153、154、155、156、157、158、159、160、161、162、163、164、165、
166、167、168、169、170、171、172、173、174、175、176、177、178、179、180、181、182、183、184、
185、186、187、188、189、190、191、192、193、194、195、196、197、198、199、200、201、202、203、
204、205、206、207、208、209、210、211、212、213、214、215、216、217、218、219、220、221、222、
223、224、225、226、227、228、229、230、231、232、233、234、235、236、237、238、239、240、241、
242、243、244、245、246、247、248、249、250、251、252、253、254、255、256、257、258、259、260、
261、262、263、264、265、266、267、268、269、270、271、272、273、274、275、276、277、278、279、
280、281、282、283、284、284、285、286、287、288、289、290、291、292、293、294、295、296、297、
298、299、300min.As pressure can for 10pa, 11pa, 12pa, 13pa, 14pa, 15pa, 16pa, 17pa, 18pa, 19pa,
20pa、21pa、22pa、23pa、24pa、25pa、26pa、27pa、28pa、29pa、30pa、31pa、32pa、33pa、34pa、
35pa、36pa、37pa、38pa、39pa、40pa、41pa、42pa、43pa、44pa、45pa、46pa、47pa、48pa、49pa、
50pa、51pa、52pa、53pa、54pa、55pa、56pa、57pa、58pa、59pa、60pa.
Wherein, during lyophilizing, parsing-desiccation temperature is 0-60 DEG C, and the time is 30-500min, and pressure is 10-60pa.As temperature
Can be；0℃、1℃、2℃、3℃、4℃、5℃、6℃、7℃、8℃、9℃、10℃、11℃、12℃、13℃、14℃、15℃、16
℃、17℃、18℃、19℃、20℃、21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃、30℃、31
℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃、46
℃、47℃、48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃、56℃、57℃、58℃、59℃、60℃.As when
Between can for 30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,
53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、
78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、
102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、
121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、
140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、
159、160、161、162、163、164、165、166、167、168、169、170、171、172、173、174、175、176、177、
178、179、180、181、182、183、184、185、186、187、188、189、190、191、192、193、194、195、196、
197、198、199、200、201、202、203、204、205、206、207、208、209、210、211、212、213、214、215、
216、217、218、219、220、221、222、223、224、225、226、227、228、229、230、231、232、233、234、
235、236、237、238、239、240、241、242、243、244、245、246、247、248、249、250、251、252、253、
254、255、256、257、258、259、260、261、262、263、264、265、266、267、268、269、270、271、272、
273、274、275、276、277、278、279、280、281、282、283、284、284、285、286、287、288、289、290、
291、292、293、294、295、296、297、298、299、300、301、302、303、304、305、306、307、308、309、
310、311、312、313、314、315、316、317、318、319、320、321、322、323、324、325、326、327、328、
329、330、331、332、333、334、335、336、337、338、339、340、341、342、343、344、345、346、347、
348、349、350、351、352、353、354、355、356、357、358、359、360、361、362、363、364、365、366、
367、368、369、370、371、372、373、374、375、376、377、378、379、380、381、382、383、384、385、
386、387、388、389、390、391、392、393、394、395、396、397、398、399、400、401、402、403、404、
405、406、407、408、409、410、411、412、413、414、415、416、417、418、419、420、421、422、423、
424、425、426、427、428、429、430、431、432、433、434、435、436、437、438、439、440、441、442、
443、444、445、446、447、448、449、450、451、452、453、454、455、456、457、458、459、460、461、
462、463、464、465、466、467、468、469、470、471、472、473、474、475、476、477、478、479、480、
481、482、483、484、485、486、487、488、489、490、491、492、493、494、495、496、497、498、499、
500min.As pressure can for 10pa, 11pa, 12pa, 13pa, 14pa, 15pa, 16pa, 17pa, 18pa, 19pa, 20pa, 21pa,
22pa、23pa、24pa、25pa、26pa、27pa、28pa、29pa、30pa、31pa、32pa、33pa、34pa、35pa、36pa、
37pa、38pa、39pa、40pa、41pa、42pa、43pa、44pa、45pa、46pa、47pa、48pa、49pa、50pa、51pa、
52pa、53pa、54pa、55pa、56pa、57pa、58pa、59pa、60pa.
Specific embodiment：
1st, weigh：100.0g dianhydrodulcitol is weighed on balance.
2nd, prepare：Add the water for injection of dulcitol weight 15-40 times in ingredients pot, add raw material and fully dissolve,
Stir evenly below 20 DEG C, be settled to 20-45 times of dulcitol weight with water for injection.
3rd, filter：Medicinal liquid is carried out in aseptic filtration fill storage tank.
4th, fill：Often bottled amount as required carries out fill bottling, for example, can carry out fill according to 1.2g/ bottle.
5th, lyophilizing：After the medicinal liquid bottle having filled partly is jumped a queue, put into lyophilizing in lyophilizing cabinet and obtain final product.
A kind of preparation method of injection dianhydrodulcitol freeze-dried powder that the present invention provides has advantages below：The application
Injection dianhydrodulcitol freeze-dried powder product quality stable, even more than significant period of time effect duration before the deadline
Interior improved detection method is tested, and product stability is fabulous.
Specific embodiment
Further illustrate the present invention below by embodiment.It should be understood that embodiments of the invention are for illustrating
The present invention rather than limitation of the present invention.Broadly fall into the present invention according to the simple modifications that the essence of the present invention is carried out to the present invention
Claimed scope.Unless otherwise stated, the percent of the amount of alcohol in the present invention is percentage by volume, and v/v represents solution
Volume ratio.
Embodiment 1：
Weigh dianhydrodulcitol, add the water for injection of 40 times of weight of dulcitol, fully dissolve at 20 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 45 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -20 DEG C, and is incubated 300 minutes；Start
Evacuation, when vacuum reaches 18pa, starts and heats up, and when shelf temperature is to 0 DEG C, is incubated 900 minutes；Vacuum is maintained
18pa, continues temperature and rises to 40 DEG C, be incubated 180 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, moisture
Measurement result is 1.00%.
Embodiment 2：
Weigh dianhydrodulcitol, add the water for injection of 28 times of weight of dulcitol, fully dissolve at 10 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 30 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -40 DEG C, and is incubated 180 minutes；Start
Evacuation, when vacuum reaches 25pa, starts and heats up, and when shelf temperature is to -2 DEG C, is incubated 2800 minutes；Vacuum is maintained
In 25pa, continue temperature and rise to 30 DEG C, be incubated 240 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, water
Measurement result is divided to be 0.03%.
Embodiment 3：
Weigh dianhydrodulcitol, add the water for injection of 15 times of weight of dulcitol, fully dissolve at 10 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 30 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -60 DEG C, and is incubated 30 minutes；Start to take out
Vacuum, when vacuum reaches 15pa, starts and heats up, and when shelf temperature is to -2 DEG C, is incubated 720 minutes；Vacuum is maintained
15pa, continues temperature and rises to 35 DEG C, be incubated 280 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, moisture
Measurement result is 1.20%.
Embodiment 4：
Weigh dianhydrodulcitol, add the water for injection of 15 times of weight of dulcitol, fully dissolve at 15 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 20 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -60 DEG C, and is incubated 150 minutes；Start
Evacuation, when vacuum reaches 30pa, starts and heats up, and when shelf temperature is to -20 DEG C, is incubated 3000 minutes；Vacuum is tieed up
Hold in 30pa, continue temperature and rise to 20 DEG C, be incubated 500 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations,
Determination of water result is 0.01%.
Embodiment 5：
Weigh dianhydrodulcitol, add the water for injection of 15 times of weight of dulcitol, fully dissolve at 17 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 30 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -20 DEG C, and is incubated 30 minutes；Start to take out
Vacuum, when vacuum reaches 15pa, starts and heats up, and when shelf temperature is to -2 DEG C, is incubated 900 minutes；Vacuum is maintained
15pa, continues temperature and rises to 30 DEG C, be incubated 320 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, moisture
Measurement result is 1.10%.
Embodiment 6：
Weigh dianhydrodulcitol, add the water for injection of 20 times of weight of dulcitol, fully dissolve at 8 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 30 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -30 DEG C, and is incubated 240 minutes；Start to take out very
Sky, when vacuum reaches 25pa, starts and heats up, and when shelf temperature is to -5 DEG C, is incubated 1800 minutes；Vacuum is maintained
25pa, continues temperature and rises to 30 DEG C, be incubated 120 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, moisture
Measurement result is 0.05%.
Embodiment 7：
Weigh dianhydrodulcitol, add the water for injection of 18 times of weight of dulcitol, fully dissolve at 15 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 36 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -45 DEG C, and is incubated 150 minutes；Start
Evacuation, when vacuum reaches 10pa, starts and heats up, and when shelf temperature is to 0 DEG C, is incubated 1200 minutes；Vacuum is maintained
In 10pa, continue temperature and rise to 35 DEG C, be incubated 280 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, water
Measurement result is divided to be 1.30%.
Embodiment 8：
Weigh dianhydrodulcitol, add the water for injection of 15 times of weight of dulcitol, fully dissolve at 7 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 40 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -50 DEG C, and is incubated 260 minutes；Start to take out very
Sky, when vacuum reaches 45pa, starts and heats up, and when shelf temperature is to -15 DEG C, is incubated 1500 minutes；Vacuum is reduced simultaneously
Maintain 20pa, continue temperature and rise to 50 DEG C, be incubated 360 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilizing system
Agent, determination of water result is 0.02%.
Embodiment 9：
Weigh dianhydrodulcitol, add the water for injection of 20 times of weight of dulcitol, fully dissolve at 5 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 35 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -50 DEG C, and is incubated 90 minutes；Start to take out very
Sky, when vacuum reaches 20pa, starts and heats up, and when shelf temperature is to -6 DEG C, is incubated 660 minutes；Vacuum is reduced and ties up
Hold in 11pa, continue temperature and rise to 0 DEG C, be incubated 30 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, water
Measurement result is divided to be 1.43%.
Embodiment 10：
Weigh dianhydrodulcitol, add the water for injection of 16 times of weight of dulcitol, fully dissolve at 12 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 32 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -36 DEG C, and is incubated 250 minutes；Start
Evacuation, when vacuum reaches 15pa, starts and heats up, and when shelf temperature is to -5 DEG C, is incubated 2400 minutes；Vacuum is increased
And maintain 40pa, continue temperature and rise to 60 DEG C, be incubated 500 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilizing
Preparation, determination of water result is 0.04%.
Embodiment 11：
Weigh dianhydrodulcitol, add the water for injection of 30 times of weight of dulcitol, fully dissolve at 4 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 40 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -28 DEG C, and is incubated 150 minutes；Start to take out very
Sky, when vacuum reaches 35pa, starts and heats up, and when shelf temperature is to -4 DEG C, is incubated 3000 minutes；Vacuum is reduced and ties up
Hold in 25pa, continue temperature and rise to 55 DEG C, be incubated 200 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations,
Determination of water result is 0.20%.
Embodiment 12：
Weigh dianhydrodulcitol, add the water for injection of 30 times of weight of dulcitol, fully dissolve at 6 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 40 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -27 DEG C, and is incubated 240 minutes；Start to take out very
Sky, when vacuum reaches 20pa, starts and heats up, and when shelf temperature is to -2 DEG C, is incubated 2000 minutes；Vacuum is reduced and ties up
Hold in 20pa, continue temperature and rise to 35 DEG C, be incubated 200 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations,
Determination of water result is 0.33%.
Embodiment 13：
Weigh dianhydrodulcitol, add the water for injection of 35 times of weight of dulcitol, fully dissolve at 10 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 45 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -22 DEG C, and is incubated 90 minutes；Start to take out
Vacuum, when vacuum reaches 10pa, starts and heats up, and when shelf temperature is to -7 DEG C, is incubated 2100 minutes；By vacuum increase simultaneously
Maintain 35pa, continue temperature and rise to 28 DEG C, be incubated 200 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilizing system
Agent, determination of water result is 0.60%.
Embodiment 14：
Weigh dianhydrodulcitol, add the water for injection of 20 times of weight of dulcitol, fully dissolve at 8 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 40 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -20 DEG C, and is incubated 260 minutes；Start to take out very
Sky, when vacuum reaches 25pa, starts and heats up, and when shelf temperature is to -5 DEG C, is incubated 760 minutes；Vacuum is increased and ties up
Hold in 25pa, continue temperature and rise to 20 DEG C, be incubated 130 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations,
Determination of water result is 0.84%.
Comparative example 1：
Weigh dianhydrodulcitol, add the water for injection of 15 times of weight of dulcitol, fully dissolve at 10 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 28 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -10 DEG C, and is incubated 250 minutes；Start
Evacuation, when vacuum reaches 10pa, starts and heats up, and when shelf temperature is to -2 DEG C, is incubated 500 minutes；Vacuum is maintained
In 10pa, continue temperature and rise to 30 DEG C, be incubated 300 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, water
Measurement result is divided to be 1.63%.
Comparative example 2：
Weigh dianhydrodulcitol, add the water for injection of 16 times of weight of dulcitol, fully dissolve at 8 DEG C, stir evenly, with note
Penetrate be dianhydrodulcitol weight with water constant volume ad pond om 36 times；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put in lyophilizing cabinet,
With per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -10 DEG C, and is incubated 320 minutes；Start to take out very
Sky, when vacuum reaches 8pa, starts and heats up, and when shelf temperature is to 0 DEG C, is incubated 1000 minutes；Vacuum is maintained 8pa,
Continue temperature and rise to 35 DEG C, be incubated 240 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, determination of water
Result is 1.58%.
Comparative example 3：
Weigh dianhydrodulcitol, add the water for injection of 15 times of weight of dulcitol, fully dissolve at 15 DEG C, stir evenly, use
Water for injection constant volume ad pond om is 34 times of dianhydrodulcitol weight；Medicinal liquid aseptic filtration, fill, partly jump a queue；Put lyophilizing cabinet
In, with per hour 25 DEG C -35 DEG C of speed, the shelf temperature of freezer dryer is down to -8 DEG C, and is incubated 320 minutes；Start to take out
Vacuum, when vacuum reaches 6pa, starts and heats up, and when shelf temperature is to 0 DEG C, is incubated 900 minutes；Vacuum is maintained
6pa, continues temperature and rises to 40 DEG C, be incubated 180 minutes；Tamponade, outlet, obtain final product injection dianhydrodulcitol lyophilized formulations, moisture
Measurement result is 1.71%.
Above 17 batch samples are concurrently placed in 2～8 DEG C of constant-humidity constant-temperature case and deposit for a long time 24 months, sample detection sample
Redissolve and measure content and relevant material, result such as following table：
Although, above used general explanation, specific embodiment and test, the present invention made retouch in detail
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Scope.
Claims (9)
1. a kind of stable injection dianhydrodulcitol freeze-dried powder it is characterised in that：Its moisture is less than 1.5%.
2. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Its moisture is 1.0%
Below.
3. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Described moisture is
0.01%-1.4%.
4. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Described moisture is
0.02%-1.3%.
5. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Described moisture is
0.03%-1.2%.
6. injection dianhydrodulcitol freeze-dried powder as claimed in claim 4 it is characterised in that：Described moisture is
0.04%-1.1%.
7. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Described moisture is
0.05%-1.0%.
8. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Described moisture is 0.,
05-0.6%..
9. injection dianhydrodulcitol freeze-dried powder as claimed in claim 1 it is characterised in that：Described moisture is 0.,
05-0.2%.
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| CN201510451880 | 2015-07-29 | ||
| CN2015104518809 | 2015-07-29 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444490A (en) * | 2007-11-26 | 2009-06-03 | 天津市金圭谷木糖醇有限公司 | Injection preparation containing anhydrogalactitol and preparation method thereof |
| CN101450100A (en) * | 2007-11-28 | 2009-06-10 | 天津金世制药有限公司 | Medicine composition for treating urgent and chronic myelocytic leukemiaia |
| WO2013012135A1 (en) * | 2011-07-15 | 2013-01-24 | Boryung Pharmaceutical Co., Ltd | Pre-freeze dried azacitidine preparation, freeze dried azacitidine preparation and method of manufacturing the same |
-
2016
- 2016-07-29 CN CN201610620241.5A patent/CN106389352B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444490A (en) * | 2007-11-26 | 2009-06-03 | 天津市金圭谷木糖醇有限公司 | Injection preparation containing anhydrogalactitol and preparation method thereof |
| CN101450100A (en) * | 2007-11-28 | 2009-06-10 | 天津金世制药有限公司 | Medicine composition for treating urgent and chronic myelocytic leukemiaia |
| WO2013012135A1 (en) * | 2011-07-15 | 2013-01-24 | Boryung Pharmaceutical Co., Ltd | Pre-freeze dried azacitidine preparation, freeze dried azacitidine preparation and method of manufacturing the same |
Non-Patent Citations (1)
| Title |
|---|
| 韩丽: "《实用中药制剂新技术》", 30 November 2002, 化学工业出版社 * |
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