CN102743343B - Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product - Google Patents
Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product Download PDFInfo
- Publication number
- CN102743343B CN102743343B CN201210157512.XA CN201210157512A CN102743343B CN 102743343 B CN102743343 B CN 102743343B CN 201210157512 A CN201210157512 A CN 201210157512A CN 102743343 B CN102743343 B CN 102743343B
- Authority
- CN
- China
- Prior art keywords
- decitabine
- preparation
- solution
- adjuvant solution
- compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention belongs to the field of medicines, especially relates to the field of decitabine preparation, and more especially relates to a decitabine composition, a preparation method of the decitabine composition, an application thereof in a medicinal lyophilized preparation, a medicinal lyophilized preparation product, and a preparation method of the medicinal lyophilized preparation product. The invention aims at providing a decitabine composition and a preparation method thereof. With the decitabine composition, the dissolving speed of decitabine in a preparation process is increased, the stability of a decitabine preparation product is improved, and no organic solvent residue is left in the preparation product. According to the invention, micronized decitabine is adopted as a raw material, and potassium dihydrogen phosphate and sodium hydroxide are adopted as auxiliary materials. With an ultrasonic material dissolving method, the main medicine is dissolved into an emulsion, such that the use of the organic solvent is avoided, and the residue of the organic solvent in the medicine preparation product is avoided. Therefore, the safety of the preparation in clinical application is greatly improved. Also, during a lyophilized preparation production process, lyophilization equipment is prevented from being damaged by the organic solvent.
Description
technical field
The invention belongs to field of medicaments, particularly relate to the preparation field of decitabine, more specifically relate to decitabine composition and method of making the same and its application, finished product and preparation method in medicinal lyophilized formulations.
background technology
Decitabine (Decitabine), chemistry 4-amino-1-(2-deoxidation-β-D-erythro-ribofuranose) by name-1,3,5-triazines-2 (1H)-one, CAS 2353-33-5, is a kind of nucleoside analog.Decitabine belongs to dnmt rna inhibitor, and its mechanism of action is to be directly combined with DNA and to suppress dnmt rna after decitabine phosphorylation, causes DNA hypomethylation and cell differentiation apoptosis.Under external decitabine inhibition DNA methylation concentration, do not cause that DNA synthesizes inhibition, decitabine, at the hypomethylation of tumor cell induction, may recover normal function after strictly controlling cell differentiation and breeding.
Decitabine was synthesized first in 1964, by SuperGen company, was researched and developed and was listed a company by MGI PHARMA, and trade name Dacogen, is injection, specification 50mg.In April, 2006 and May are by European EMEA and U.S. FDA approval listing, within 2008, obtain state food Drug Administration office (SFDA) approval, exempt from clinical trial and directly go on the market, be mainly used in treating the rare disease of constitutional and Secondary cases myelodysplastic syndrome (MDS).
Decitabine is slightly water-soluble, and the dissolubility in water is lower.Decitabine stability in aqueous solution is very poor, very easily degrades, and is converted into the isomers form of non-activity.When decitabine aqueous solution is placed at ambient temperature, related substance increases sharply, so must prepare and preserve by low temperature in the preparation process of decitabine, and will shorten the standing time before fill as far as possible.So critical process prepared by decitabine preparation is to accelerate the dissolution velocity of decitabine raw material in aqueous solution, and reduce the standing time of aqueous solution state as far as possible.
Slow in order to solve decitabine dissolving dissolution velocity, and in order to improve stability of solution, existing known technology has proposed the multiple technical scheme addressing this problem, adopt first utilized organic solvent dissolution by decitabine more, with the preparation technology of the miscible formation preparation of water aqueous solution, utilize this preparation technology to prepare decitabine freeze-dry preparation and can bring many-sided problem and potential safety hazard again.First the introducing of organic solvent can cause and in finished product preparation, contain more organic solvent residual, and organic solvent is very large to human toxicity, can cause a series of health toxicity; Secondly, before lyophilizing, in formulation soln, contain organic solvent, can cause larger infringement to freeze-drier, and in freeze-drying process, can cause principal agent to be taken out of with organic solvent, affect the mouldability of pharmaceutical preparation.
Thereby United States Patent (USP) 2006128653 is mentioned and utilized cyclodextrin to reduce after decitabine parcel and the contacting of water environment, and this preparation technology is not only loaded down with trivial details, and cyclodextrin has the side effect of haemolysis and nephrotoxicity, and clinical safety risk is higher; Chinese patent CN101966157 provides a kind of preparation technology of decitabine sustained-release micro-spheres, adopts variety carrier material in this technique, and has used multiple organic solvent, according to the unstability of raw material, has more unsafe factor in clinical use.
The technique that the patents such as Chinese patent CN101361718, CN102106831, CN10231922 provide multiple decitabine freeze-dry preparation to prepare, but all used organic solvent, consumption from 0.3 ~ 4.0% to 5 ~ 80% is not etc., the use of organic solvent brings great side effect and health to poison to human body, is unwell to clinical safety and uses.Chinese patent CN101623267 provides the sterilized powder of a kind of decitabine and other adjuvant direct packaging, but because decitabine dissolves difficulty in water, during clinical use, can not dissolve in time, causes and uses difficulty.
Chinese patent CN101843592 provides a kind of preparation method of decitabine freeze-dried powder pin, in this preparation technology not with an organic solvent, but in preparation process, used active carbon to carry out carbonization treatment, but our test of many times finds that active carbon has larger adsorption for principal agent decitabine, reduce drug content, affected quality; In addition the routine that it adopts is dissolved the method for principal agent, under production permit condition, can not dissolve raw material completely at all.Although patent CN101637458 does not adopt organic solvent, in order to improve the dissolubility of decitabine, simultaneously in order to reach formulation soln concentration, the adjuvants such as extra glucose or lactose are introduced in this invention, have increased the security risks of preparation.
summary of the invention
The object of the present invention is to provide a kind of new decitabine compositions, and preparation method thereof and the application in lyophilized formulations, finished product and preparation method, thereby meet simultaneously, accelerate the dissolving speed of decitabine in preparation process, improve decitabine preparation finished product stability, the multiple requirement such as in preparation finished product organic solvent-free is residual.
In order to realize foregoing invention object, the invention discloses following technical scheme:
Decitabine compositions, the micronization ground decitabine of take is principal agent, the adjuvant solution that potassium dihydrogen phosphate and sodium hydroxide form of take is the emulsus compositions that lysate forms.
Described micronization ground decitabine particle diameter is 10 ~ 50 μ m.
In described adjuvant solution, the concentration of sodium dihydrogen phosphate is 0.06mol/L ~ 0.08mol/L, and the concentration of sodium hydroxide is 0.03 mol/L ~ 0.05 mol/L.
And further, the invention provides a kind of method of decitabine compositions, comprise the following steps:
A) by crude drug decitabine micronization processes;
B) by the potassium dihydrogen phosphate of recipe quantity and dissolution of sodium hydroxide in aqueous solution, obtain adjuvant solution;
C) by the adjuvant solution cooling obtaining in step b, measure the adjuvant solution of 20 ~ 50 times of crude drug weight to be mixed, add the crude drug obtaining in step a, low temperature water-bath is ultrasonic, to homogeneous emulsus, obtains.
In described step c, the adjuvant solution obtaining in step b is cooled to 2 ~ 8 ℃.
In described step c, under the temperature conditions of 2 ~ 8 ℃, low temperature water-bath is ultrasonic.
It is raw material that decitabine preparation novel preparation process provided by the invention adopts micronized decitabine, take potassium dihydrogen phosphate and sodium hydroxide as adjuvant, adopt the method for ultrasonic dissolution raw material first principal agent to be dissolved and becomes emulsus, directly take decitabine and compare as raw material with traditional, greatly shortened the preparation preparation time, reduce the time of contact of decitabine and water, effectively reduced the degraded that decitabine particularly occurs in preparation process in water, improved product quality.
Meanwhile, as the application of the disclosed decitabine compositions of the present invention, the present invention further discloses the application of decitabine compositions in the medicinal lyophilized formulations of preparation.
The invention also discloses the lyophilized formulations that contains decitabine compositions disclosed in this invention simultaneously.
Further, the invention also discloses the preparation method of the above-mentioned lyophilized formulations that contains decitabine compositions, comprise the following steps:
I. by crude drug decitabine micronization processes;
Ii. the potassium dihydrogen phosphate of recipe quantity and sodium hydroxide are added in the water for injection of full dose 60% ~ 90% volume, stirring and dissolving, obtains adjuvant solution;
Iii. the adjuvant solution obtaining in step (2) is cooled to 2 ~ 8 ℃, measure the adjuvant solution of 20 ~ 50 times of crude drug weight to be mixed, the crude drug decitabine that adds the micronization processes that step (1) obtains, at the temperature conditions of 2 ~ 8 ℃, bend down tepidarium ultrasonic, be homogeneous emulsus to solution;
Iv. the emulsus decitabine compositions obtaining in step (3) is added in remaining adjuvant solution gradually, stirs, to dissolving completely, mend water for injection to full dose, stir, obtain the front formulation soln of lyophilizing;
V. detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations.
Technical scheme disclosed in this invention, adopts the method for ultrasonic dissolution raw material first principal agent to be dissolved and becomes emulsus, and then adds in adjuvant solution entirely moltenly, obtains formulation soln.The formulation soln obtaining according to this technique, has not only greatly shortened principal agent and has not contained the dissolution time in the water of organic solvent, and effectively prevented the degraded of decitabine, and the stability that obtains the decitabine freeze-dry preparation that does not contain organic solvent after lyophilizing is better.
In sum, adopt after technical scheme disclosed in this invention, avoided the use of organic solvent, thereby prevent residual in pharmaceutical preparation finished product of organic solvent, greatly improved the safety of preparation in clinical use; Also avoided simultaneously in lyophilized formulations is produced, the damage of organic solvent to freeze-drier, preparation technology's simple possible of transformation, has reduced production cost, is applicable to industrialization and produces.
the specific embodiment
Below by specific embodiment, the present invention is described, in following embodiment, the various process and methods of not describing in detail are conventional methods as known in the art.Should correct understanding: embodiments of the invention are to say for the present invention is described, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple transformation of the present invention is also belonged to protection scope of the present invention.
In the present invention, micronization ground decitabine is to adopt micronization technology conventional in current field of medicaments to obtain, different according to the requirement of further preparation, can use the ripe micronization technology such as powder beater, jet mill to obtain.
In following examples, the testing conditions of the high performance liquid chromatography that adopts is:
Chromatographic column: octadecylsilane chemically bonded silica is packed column (250 mm * 4.6 mm, 5 μ m);
Mobile phase: 0.03mol/L potassium dihydrogen phosphate (regulating pH value with 4mol/L sodium hydroxide solution is 6.8);
Detect wavelength: 220nm;
Flow velocity: 2ml/min;
Column temperature: 15 ℃ ± 2 ℃;
Sample size: 5 μ l.
Embodiment 1
(1) preparation of the open method sample of the present invention
A) measure the water for injection of 50 ℃ of 60ml, add potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, stirring and dissolving, obtains adjuvant solution;
B) adjuvant solution is cooled to 2 ~ 8 ℃, measures the adjuvant solution of 10ml, the micronization particle diameter that adds recipe quantity is 50 μ m decitabine raw material 0.5g, and it is ultrasonic that 2 ~ 8 ℃ of conditions bend down tepidarium, and in the time of ultrasonic approximately 4 minutes, solution becomes the milky solution of homogeneous;
C) principal agent milky solution is added in adjuvant solution, be stirred to principal agent and dissolve completely, mend water for injection to 100ml full dose, stir, obtain the front formulation soln of lyophilizing;
D) detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product detects to obtain its content 100.1% through high performance liquid chromatography, and total impurities is 0.79%, and maximum single assorted 0.32%
(2) preparation of control formulation (referenced patent CN101637458 public technology)
Measure the water for injection of 80ml room temperature, add potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, stirring and dissolving, obtains adjuvant concentrated solution; Adjuvant solution is cooled to 2 ~ 8 ℃, what add recipe quantity does not pass through micronization processes decitabine 0.5g, mechanical agitation under cryogenic conditions (500rpm) 3 hours, principal agent does not dissolve yet completely, final solution is muddy, mends water for injection to full dose, filters fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product content is determined as 67.8%, and related substance total impurities is 3.28%, and maximum single assorted 2.31%.
Embodiment 2
(1) preparation of the open method sample of the present invention
A) measure the water for injection of 60 ℃ of 80ml, add potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, stirring and dissolving, obtains adjuvant solution;
B) adjuvant solution is cooled to 2 ~ 8 ℃, measures the adjuvant solution of 20ml, the micronization particle diameter that adds recipe quantity is 50 μ m decitabine raw material 0.5g, and low temperature water-bath is ultrasonic, and during ultrasonic about 3min, solution becomes the milky solution of homogeneous;
C) principal agent milky solution is added in adjuvant solution, be stirred to principal agent and dissolve completely, mend water for injection to 100ml full dose, stir, obtain the front formulation soln of lyophilizing;
D) detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product detects to obtain its content 100.2% through high performance liquid chromatography, and total impurities is 0.59%, and maximum single assorted 0.26%.Content and related substance detection method are with embodiment 1.
(2) preparation of control formulation (referenced patent CN101637458 public technology)
Measure the water for injection of 60ml room temperature, add potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, stirring and dissolving, obtains adjuvant solution; Adjuvant solution is cooled to 2 ~ 8 ℃, add and do not pass through micronization processes decitabine 0.5g, mechanical agitation under cryogenic conditions (500rpm) 3 hours, principal agent does not dissolve yet completely, and final solution is muddy, mends water for injection to full dose, after filtration, add active carbon to stir, filter de-carbon, fill lyophilizing, obtains final lyophilized formulations finished product.
Before lyophilizing, before formulation soln decarburization, assay is 65.4%, and after decarburization, content 52.3%, and lyophilizing finished product related substance total impurities is 4.04%, and maximum list mixes 2.65%, and this technique can not meet basic manufacturing technique requirent.
Finished product detects to obtain its content 100.1% through high performance liquid chromatography, and total impurities is 0.74%, and maximum single assorted 0.35%.
Embodiment 3
(1) preparation of the open method sample of the present invention
A) measure the water for injection of 50 ℃ of 90ml, add potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, stirring and dissolving, obtains adjuvant solution;
B) adjuvant solution is cooled to 2 ~ 8 ℃, measures the adjuvant solution of 25ml, the micronization particle diameter that adds recipe quantity is 10 μ m decitabine raw material 0.5g, and it is ultrasonic that 2 ~ 8 ℃ of conditions bend down tepidarium, and in the time of ultrasonic approximately 2 minutes, solution becomes the milky solution of homogeneous;
C) principal agent milky solution is added in adjuvant solution, be stirred to principal agent and dissolve completely, mend water for injection to 100ml full dose, stir, obtain the front formulation soln of lyophilizing;
D) detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product detects to obtain its content 100.0% through high performance liquid chromatography, and total impurities is 0.49%, and maximum list mixes 0.23%, and without organic residue, content and related substance detection method are with embodiment 1.
(2) preparation of control formulation (referenced patent CN102319222 public technology)
Measure the water for injection of 60ml room temperature, add potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, stirring and dissolving, obtains adjuvant concentrated solution; Adjuvant solution is cooled to 2 ~ 8 ℃, takes and do not pass through micronization processes decitabine 0.5g, add the dehydrated alcohol of 1ml to be uniformly dispersed, then principal agent alcoholic solution is added in the adjuvant solution of 2 ~ 8 ℃, stir about 4 ~ 5min principal agent dissolves completely, filters, fill lyophilizing, obtains final lyophilizing finished product.
Before intermediate decarburization, assay is 99.8%, and lyophilizing finished product related substance total impurities is 0.87%, and maximum list mixes 0.46%, organic residue 0.45%, and Determination of Residual Organic Solvents checks according to the method in 2010 editions appendix of Chinese Pharmacopoeia.
Embodiment 4
(1) preparation of the open method sample of the present invention
1, the water for injection that measures 50 ℃ of 60ml, adds potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, and stirring and dissolving, obtains adjuvant solution;
2, adjuvant solution is cooled to 2 ~ 8 ℃, measures the adjuvant solution of 20ml, the micronization particle diameter that adds recipe quantity is 40 μ m decitabine raw material 0.5g, and it is ultrasonic that 2 ~ 8 ℃ of conditions bend down tepidarium, and in the time of ultrasonic approximately 5 minutes, solution becomes the milky solution of homogeneous;
3, principal agent milky solution is added in adjuvant solution, be stirred to principal agent and dissolve completely, mend water for injection to 100ml full dose, stir, obtain the front formulation soln of lyophilizing;
4, detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product detects to such an extent that its content is 99.8% through high performance liquid chromatography, and total impurities is 0.69%, and maximum list mixes 0.37%, and content and related substance detection method are with embodiment 1.
Embodiment 5
1, the water for injection that measures 50 ℃ of 80ml, adds potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, and stirring and dissolving, obtains adjuvant solution;
2, adjuvant solution is cooled to 2 ~ 8 ℃, measures the adjuvant solution of 20ml, the micronization particle diameter that adds recipe quantity is 30 μ m decitabine raw material 0.5g, and it is ultrasonic that 2 ~ 8 ℃ of conditions bend down tepidarium, and in the time of ultrasonic approximately 4 minutes, solution becomes the milky solution of homogeneous;
3, principal agent milky solution is added in adjuvant solution, be stirred to principal agent and dissolve completely, mend water for injection to 100ml full dose, stir, obtain the front formulation soln of lyophilizing;
4, detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product detects to such an extent that its content is 99.9% through high performance liquid chromatography, and total impurities is 0.64%, and maximum list mixes 0.32%, and content and related substance detection method are with embodiment 1.
Embodiment 6
1, the water for injection that measures 50 ℃ of 80ml, adds potassium dihydrogen phosphate 0.68g, sodium hydroxide 0.116g, and stirring and dissolving, obtains adjuvant solution;
2, adjuvant solution is cooled to 2 ~ 8 ℃, measures the adjuvant solution of 20ml, the micronization particle diameter that adds recipe quantity is 20 μ m decitabine raw material 0.5g, and it is ultrasonic that 2 ~ 8 ℃ of conditions bend down tepidarium, and in the time of ultrasonic approximately 3 minutes, solution becomes the milky solution of homogeneous;
3, principal agent milky solution is added in adjuvant solution, be stirred to principal agent and dissolve completely, mend water for injection to 100ml full dose, stir, obtain the front formulation soln of lyophilizing;
4, detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations finished product.
Finished product detects to such an extent that its content is 99.9% through high performance liquid chromatography, and total impurities is 0.62%, and maximum list mixes 0.28%, and content and related substance detection method are with embodiment 1.
Embodiment 7 different-grain diameter raw materials are prepared lyophilized formulations contrast
The structural formula of related catabolite II is as follows below:
Decitabine preparation process in reference example 3 of the present invention, after use micronization, different-grain diameter and not micronized decitabine raw material carry out the preparation of lyophilizing sample, and material dissolution process and lyophilizing finished product are carried out to the detection of content and related substance.Experimental result is in Table 1:
Table 1 different-grain diameter and not micronization ground Xi Tabin raw material are prepared sample contrast
By the above mensuration to the dissolving of different-grain diameter and not micronized decitabine raw material and lyophilizing finished product related substance, we can learn that the raw material of 10 ~ 50 μ m particle diameters not only dissolves rapidly, preparation process is simple possible more, the related substance of finished product remains on reduced levels, and not micronized decitabine is quite difficult in course of dissolution, due to can not be whole break up, form milky solution, so finished product content is low, related substance because of preparation time compared with long increases obvious.
Embodiment 8 study on the stability
The sample obtaining in embodiment in the present invention 3 is carried out at 2 ~ 8 ℃ and 25 ℃ to stability of solution investigation, at the temperature of 2 ~ 8 ℃, 4 ℃ representative, so using in the present embodiment 4 ℃ as experimental temperature, represents the effect of 2 ~ 8 ℃.Experimental result is in Table 2:
2 ~ 8 ℃ and 25 ℃ stabilities of solution of table 2 are investigated result
Conclusion: investigating data according to 2 ~ 8 ℃ and 25 ℃ of stabilities of solution can learn, the sample of preparing by the present invention (catabolite II < 1.5%, always assorted < 3%) under far below control limit, stable in properties.
Further, the sample by open method obtains in the embodiment of the present invention 3, control sample and the former sample that grinds are carried out to 40 ℃ of acceleration investigations, concrete stability result is in Table 3:
40 ℃ of acceleration experiment study on the stability results of table 3
The disclosed technological means of the present invention program is not limited only to the disclosed technological means of above-mentioned technological means, also comprises the technical scheme being comprised of above technical characterictic combination in any.
The above is the specific embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Claims (5)
1. decitabine compositions, is characterized in that described decitabine compositions is to take micronized decitabine as principal agent, and the adjuvant solution that potassium dihydrogen phosphate and sodium hydroxide form of take is the emulsus compositions that lysate forms; Described micronized decitabine particle diameter is 10 ~ 50 μ m; In described adjuvant solution, the concentration of potassium dihydrogen phosphate is 0.06mol/L ~ 0.08mol/L, and the concentration of sodium hydroxide is 0.03 mol/L ~ 0.05 mol/L;
Described decitabine compositions is prepared by following steps:
(a) by crude drug decitabine micronization processes;
(b) by the potassium dihydrogen phosphate of recipe quantity and dissolution of sodium hydroxide in aqueous solution, obtain adjuvant solution;
(c) the adjuvant solution obtaining in step b is cooled to 2～8 ℃, measures the adjuvant solution of 20 ~ 50 times of crude drug weight to be mixed, add the crude drug obtaining in step a, 2～8 ℃ of low temperature water-baths are ultrasonic, to homogeneous emulsus, obtain.
2. a method of preparing decitabine compositions as claimed in claim 1, is characterized in that being comprised of following steps:
(a) by crude drug decitabine micronization processes;
(b) by the potassium dihydrogen phosphate of recipe quantity and dissolution of sodium hydroxide in aqueous solution, obtain adjuvant solution;
(c) the adjuvant solution obtaining in step b is cooled to 2～8 ℃, measures the adjuvant solution of 20 ~ 50 times of crude drug weight to be mixed, add the crude drug obtaining in step a, 2～8 ℃ of low temperature water-baths are ultrasonic, to homogeneous emulsus, obtain.
3. the application of decitabine compositions claimed in claim 1 in the medicinal lyophilized formulations of preparation.
4. take the lyophilized formulations that decitabine compositions claimed in claim 1 is intermediate for one kind.
5. a preparation method for the lyophilized formulations that the decitabine compositions claimed in claim 1 of take is intermediate, is characterized in that being comprised of following steps:
(1) by crude drug decitabine micronization processes;
(2) potassium dihydrogen phosphate of recipe quantity and sodium hydroxide are added in the water for injection of full dose 60% ~ 90% volume, stirring and dissolving, obtains adjuvant solution;
(3) the adjuvant solution obtaining in step (2) is cooled to 2 ~ 8 ℃, measure the adjuvant solution of 20 ~ 50 times of crude drug weight to be mixed, the crude drug decitabine that adds the micronization processes that step (1) obtains, at the temperature conditions of 2 ~ 8 ℃, bend down tepidarium ultrasonic, be homogeneous emulsus to solution;
(4) the emulsus decitabine compositions obtaining in step (3) is added in remaining adjuvant solution gradually, stirs, to dissolving completely, mend water for injection to full dose, stir, obtain the front formulation soln of lyophilizing;
(5) detect intermediate qualified after, fill, lyophilizing, obtains final lyophilized formulations.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210157512.XA CN102743343B (en) | 2012-05-21 | 2012-05-21 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210157512.XA CN102743343B (en) | 2012-05-21 | 2012-05-21 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102743343A CN102743343A (en) | 2012-10-24 |
| CN102743343B true CN102743343B (en) | 2014-04-16 |
Family
ID=47024080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210157512.XA Active CN102743343B (en) | 2012-05-21 | 2012-05-21 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102743343B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104887632B (en) * | 2015-05-25 | 2017-10-24 | 连云港杰瑞药业有限公司 | A kind of preparation method of decitabine freeze-dried preparation and products thereof |
| CN107260690A (en) * | 2017-06-22 | 2017-10-20 | 江苏豪森药业集团有限公司 | Lyophilized formulations of Decitabine and preparation method thereof |
| CN109498581B (en) * | 2018-12-29 | 2020-05-05 | 健进制药有限公司 | Decitabine freeze-dried powder injection for injection and production process thereof |
| CN112870171B (en) * | 2020-12-31 | 2023-03-28 | 海南葫芦娃药业集团股份有限公司 | Freeze-drying method of azithromycin for injection |
| CN112618496A (en) * | 2020-12-31 | 2021-04-09 | 海南葫芦娃药业集团股份有限公司 | Preparation method of azithromycin freeze-dried powder injection for injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612131A (en) * | 2009-07-17 | 2009-12-30 | 郑州大学 | 2-methoxyestradiol nanosuspension frozen powder and preparation method thereof |
| CN101637458A (en) * | 2009-08-19 | 2010-02-03 | 北京满格医药科技有限公司 | Preparation method of stable decitabine freeze-dried preparation |
| CN101843592A (en) * | 2009-03-27 | 2010-09-29 | 北京本草天源药物研究院 | Preparation method of decitabine freeze-dried powder injection |
-
2012
- 2012-05-21 CN CN201210157512.XA patent/CN102743343B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843592A (en) * | 2009-03-27 | 2010-09-29 | 北京本草天源药物研究院 | Preparation method of decitabine freeze-dried powder injection |
| CN101612131A (en) * | 2009-07-17 | 2009-12-30 | 郑州大学 | 2-methoxyestradiol nanosuspension frozen powder and preparation method thereof |
| CN101637458A (en) * | 2009-08-19 | 2010-02-03 | 北京满格医药科技有限公司 | Preparation method of stable decitabine freeze-dried preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102743343A (en) | 2012-10-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102743343B (en) | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product | |
| CN102133199B (en) | Doxofylline lyophilized preparation for injection and preparation method thereof | |
| CN102614118B (en) | Preparation method for epirubicin hydrochloride preparation for injection and preparation | |
| CN103251565A (en) | Voriconazole freeze-dried powder injection for injection and preparation method thereof | |
| CN101744807A (en) | Epigallocatechin-3-gallate pharmaceutical composition and freeze-dried powder injection thereof | |
| CN104414983B (en) | A kind of injection fosaprepitant dimeglumine sterile lyophilized powder and its preparation process | |
| CN104306329A (en) | Bromhexine hydrochloride injection and preparation method and application thereof | |
| CN102525963B (en) | Netilmicin sulfate lyophiled powder injection and preparation method thereof | |
| CN104434786A (en) | Stable bromhexine hydrochloride sodium chloride injection composition | |
| CN103446068B (en) | Bortezomib freeze-dried composition and preparation method thereof | |
| CN103006586B (en) | Epirubicin hydrochloride lyophilized injectable powder and preparation method thereof | |
| CN107496361A (en) | A kind of thyme essential oil solid dispersions and preparation method thereof | |
| CN110812334A (en) | Voriconazole pharmaceutical composition for injection and preparation method thereof | |
| CN104257615A (en) | Dezocine freeze-dried pharmaceutical composition and preparation method thereof | |
| WO2012103802A1 (en) | Liquid medicinal composition containing echinocandin antifungal agent micafungin | |
| CN105315444B (en) | The purification process of injection poly glycol monomethyl ether polylactic acid amphiphilic block copolymer | |
| CN102784382A (en) | Argatroban drug composition and preparation method and application of argatroban drug composition | |
| CN106265536A (en) | Bortezomib pharmaceutical composition and preparation method thereof | |
| CN103040855B (en) | Pharmaceutical composition of fludarabine phosphate and preparation method thereof | |
| CN101890022B (en) | Cefoperazone sodium and tazobactam sodium medicament composition liposome injection | |
| CN106860404A (en) | A kind of sildenafil citrate taste masking resin complexes and its application | |
| CN102743342B (en) | Sodium fusidate lyophilized composition for injection | |
| CN103845295A (en) | Palonosetron preparation for injection and preparation method thereof | |
| CN102475687A (en) | Decitabine freeze-dry powder injection solution | |
| CN103735522B (en) | A kind of Yanhuning freeze dried powder for injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 211112 No. 699, Kejian Road, Nanjing Jiangning Science Park, Nanjing, Jiangsu Province Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 No. 699, Kejian Road, Nanjing Jiangning Science Park, Nanjing, Jiangsu Province Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |
|
| CP01 | Change in the name or title of a patent holder |