CN102846547A - Gemcitabine or its salt liposome and preparation method thereof - Google Patents
Gemcitabine or its salt liposome and preparation method thereof Download PDFInfo
- Publication number
- CN102846547A CN102846547A CN2012102606197A CN201210260619A CN102846547A CN 102846547 A CN102846547 A CN 102846547A CN 2012102606197 A CN2012102606197 A CN 2012102606197A CN 201210260619 A CN201210260619 A CN 201210260619A CN 102846547 A CN102846547 A CN 102846547A
- Authority
- CN
- China
- Prior art keywords
- gemcitabine
- salt
- liposome
- phospholipid
- emulsifying agent
- 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.)
- Granted
Links
Abstract
The invention relates to gemcitabine or its salt liposome and a preparation method thereof; the liposome comprises gemcitabine or its salts, phospholipid, cholesterol and an emulsifier; the average particle size of gemcitabine or its salts is 10 nm-100 nm. The liposome has higher entrapment efficiency and stability, lower side-effect, and better curative effect.
Description
Technical field
The present invention relates to a kind of gemcitabine or its salt new formulation and preparation method thereof, specifically relate to liposome of gemcitabine or its salt and preparation method thereof.
Background technology
Gemcitabine is a kind of Difluoronucleosides class antimetabolite anticarcinogen that destroys cellular replication, it is the water-soluble analogues of cytosine deoxyriboside, a kind of substitute of substrate of inhibition to ribonucleotide reductase, this kind of enzyme is at DNA in the synthetic and repair process, is vital to the generation of needed Deoxydization nucleotide.Have that antitumor spectra is wide, mechanism of action is unique, with other chemotherapeutics without crossing drug resistant and toxic reaction without characteristics such as stacks.
Gemcitabine is the good substrates of thymine deoxyriboside kinase phosphorylation in cell as a kind of prodrug, changes into following metabolite under the effect of enzyme: gemcitabine monophosphate (dFdCMP), gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP) wherein dFdCDP and dFdCTP are activated product.DFdCDP suppresses ribonucleotide reductase, thereby has reduced the amount (especially dCTP) of the required Deoxydization nucleotide of the synthetic reparation of DNA, and low-level dCTP has reversed the normal negative feedback inhibition of deoxidation glycosides kinases, cause dFdCTP more to gather.Simultaneously dFdCDP has suppressed deoxidation born of the same parents ammonia enzyme that dCTP induces to the deamination of dFdCMP, and dFdCTP directly suppresses deoxycytidine and takes off enzyme, thereby make more dFdCMP change into the deamination of active metabolite dFdCMP, and dFdCTP directly suppresses deoxycytidine deaminase, thereby make more dFdCMP change into active metabolite dFdCDP, dFd-CTP dFdCTP then enters the DNA chain with dCTP competition combination, be inserted into the site of deoxycytidine in the DNA chain, and permission guanosine and its pairing, the gemcitabine molecule just " is sheltered " by this guanosine and is made it avoid the reparation that removes of exoribonuclease, then the DNA chain is synthetic stops, and then dna break, cell death.
Confirm that now gemcitabine is remarkable to multiple treatment of solid tumors effect, especially to nonsmall-cell lung cancer, cancer of pancreas and breast carcinoma, single drug or unite other cancer therapy drug and all obtain very high curative effect.Gemcitabine is short (between 32～94min) in the intracellular half-life, must heavy dose of (recommended dose be 1000mg/m2), the during continuous intravenous infusion administration keeps its effective medicinal concentration and to the toxicity of cancerous cell, but this toxicity simultaneously normal tissue also works, and this dose-limiting toxicity affects clinical efficacy.In addition, the inorganizable specificity of gemcitabine, the whole body toxic and side effects is large; Internal metabolism is rapid, and plasma half-life is short; The shortcomings such as drug resistance of tumor.
Therefore, it is stronger to seek a kind of target-oriented drug that can make, and the medication that toxic and side effects is less is emphasis and the difficult point of current research.The medicine-carried nano particles that contains active drug is a kind of novel slow-released system, can change conventional administering mode, and extremely wide prospect is arranged, it is the study hotspot in medicine and pharmacology field in recent years, the nanometer medicine in entering body after, medicine slowly discharges in the target area, to alleviate the untoward reaction of medicine.
Huang Lesong, Chunxia WANG, Chen Zhi very waits " targeting of gemcitabine poly-alkyl-alfa-cyanoacrylate nanoparticles in mouse brain distributes " (Journal of Chinese Hospital Pharmacy, 2008,28(16): 1332), and Huang Lesong, Chunxia WANG, Chen Zhi very wait " the gemcitabine poly-alkyl-alfa-cyanoacrylate nanoparticles is on the impact of mouse brain Glioma Model research " (China Dispensary, 2009,20(19): introduced a kind of nanoparticle of gemcitabine 1457) and on the impact of animal.Huang Junqin, and Kong Liwen " the mensuration character of the preparation of gemcitabine hydrochloride liposome and content and envelop rate " (Chinese antibiotic magazine, 2010,35(1): 30) introduced a kind of preparation and content assaying method of gemcitabine liposome.CN101444485B discloses a kind of gemcitabine liposome, and this liposome comprises gemcitabine, phospholipid, cholesterol, but the envelop rate of this liposome and dispersibility all perform poor, and stability and the bioavailability of medicine all had adverse effect.CN101926779A discloses a kind of gemcitabine solid lipid nanospheres and preparation method thereof, and said preparation still exists entrapment efficiency not high, and the not good problem of stability, stores about 3 months medicines Partial digestion namely occurs.Although the research of the liposome of some drugs or nanometer medicine has obtained greater advance even obtained application in clinical.But because the difference of physical and chemical properties of drugs and pharmacological action, the technology that liposome or nanometer medicine are used in the gemcitabine field does not obtain to break through yet.
From the achievement of present research, the poor problem of gemcitabine liposome existence and stability of existing method preparation, and gemcitabine main side effects-blood system bone marrow depression, platelet and neutrophilic granulocyte this problem that descends lacks deep research in the formulation art of gemcitabine always.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, provide a kind of and can improve entrapment efficiency, minimizing side effect, and the gemcitabine of better efficacy or its liposome of salt.
Gemcitabine provided by the invention or its liposome of salt comprise gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent, and the mean diameter of described gemcitabine or its salt is 10nm-100nm.
Preferably, described gemcitabine is hydrochlorate, and the mean diameter of gemcitabine hydrochloride is 50-80nm.
Preferably, the weight ratio of phospholipid, cholesterol is 1-8:1 in the described liposome; Take gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent gross weight as 100%, wherein emulsifying agent weight accounts for 10%-20%.
Preferred, the weight ratio of described phospholipid and cholesterol is 6:1; Take gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent gross weight as 100%, wherein emulsifying agent weight accounts for 10%-15%.
Preferably, described phospholipid is selected from lecithin, fabaceous lecithin or its mixture; Described emulsifying agent is selected from propylene glycol, polyoxyethylene hydrogenated Oleum Ricini acid esters, polysorbate, Triton X-100 or triethanolamine.
Preferably, described phospholipid is selected from fabaceous lecithin, and described emulsifying agent is selected from propylene glycol and polyoxyethylene hydrogenated Oleum Ricini acid esters.
Another object of the present invention also is to provide a kind of method for preparing described gemcitabine or its liposome of salt, comprises the steps:
A) preparation gemcitabine or its saline solution are used the high pressure homogenizer homogenize;
B) phospholipid, cholesterol and emulsifying agent are dissolved in an amount of ether, add gemcitabine or its saline solution, ultrasonic, make Emulsion;
C) boil off ether, ultrasonic, cross 0.1 μ m microporous filter membrane.
Preferably, the concentration of described gemcitabine or its saline solution is 15-25mg/ml.
Preferred, the concentration of described gemcitabine or its saline solution is 20mg/ml.
Preparation of the present invention has been opened up the new way of gemcitabine or its salt administration, by prescription research, established stable preparation prescription, improved the envelop rate of medicine, reduce medicine toxic and side effects in use, had better curative effect with respect to present clinical injection commonly used.
The specific embodiment
In order more specifically to describe this invention, further specify this invention below in conjunction with specific embodiment, but content of the present invention is not limited to specific embodiment.
Embodiment one
Preparation method:
The preparation of step 1, gemcitabine hydrochloride aqueous solution.Under inert gas shielding; gemcitabine hydrochloride 10g is joined among the water for injection 500ml; stir 20min 40 ℃ of water bath with thermostatic control high speeds, mixed solution is transferred to homogenize 20min in the high pressure homogenizer, join to such an extent that concentration is the Jixitabing hydrochloride solution of 20mg/ml.
Step 2, the soybean phospholipid that takes by weighing recipe quantity, cholesterol and propylene glycol are dissolved in the middle of an amount of ether, under stirring the gemcitabine aqueous solution in the step 1 are joined in the mentioned solution, and be ultrasonic, and 50 ℃ of decompression rotary evaporations eliminate ether.
Step 3, ultrasonic is crossed 0.1 μ m microporous filter membrane.
Embodiment two
Preparation method:
Propylene glycol replaces with the triethanolamine in prescription, and all the other each components and content, preparation method are identical with embodiment one.
Embodiment three
Preparation method:
Propylene glycol replaces with the polyoxyethylene hydrogenated Oleum Ricini acid esters in prescription, and all the other each components and content, preparation method are identical with embodiment one.
Embodiment four
Preparation method:
Compare with embodiment three, difference is that each constituent content is different in the prescription, and preparation method is identical with embodiment one.
Embodiment five
Preparation method:
Prescription form and each constituent content identical with embodiment three, the homogenize time changes into the 10min preparation method in the high pressure homogenizer except in the step 1 mixed solution being transferred to, all the other steps are all identical with embodiment one.
Embodiment six
Preparation method:
Prescription form and each constituent content identical with embodiment three, the homogenize time changes into the 40min preparation method in the high pressure homogenizer except in the step 1 mixed solution being transferred to, all the other steps are all identical with embodiment one.
The mensuration of experimental example one envelop rate
Adopt dialysis to measure the envelop rate of gemcitabine hydrochloride liposome.Get the gemcitabine hydrochloride liposome 1ml that each embodiment makes and place the bag filter of having processed, bag filter is immersed among the ammonium sulfate dialysis solution 100ml that concentration is 200mmol/L, place on the magnetic stirring apparatus and stir, regularly change dialysis solution, after 12 hours content taking-up in the bag filter is placed the 10ml measuring bottle, add the alcoholic solution 1ml breakdown of emulsion of 5% polyoxyethylene nonylphenol ether, water is settled to scale.Get respectively each 20 μ l of mentioned solution, the sample introduction analysis calculates the amount W that wraps up gemcitabine in the gemcitabine hydrochloride liposome
BagAnd W
Always, according to formula envelop rate=(W
Bag/ W
Always) * 100% calculates the envelop rate of gemcitabine hydrochloride liposome, and result of calculation is as shown in the table:
* emulsifier content refers to take gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent gross weight as 100%, the percentage by weight that emulsifying agent is shared.
Conclusion can be found out from experimental result, and gemcitabine hydrochloride liposome encapsulation effect of the present invention performance is excellent, and especially embodiment's three seals best results.
Experimental example two
Experiment purpose
Estimate preparation HH-GT-003(embodiment 3 samples of the present invention), HH-GT-005(embodiment 5 samples), HH-GT-006(embodiment 6 samples) to the curative effect of Non-small cell lung carcinoma A549 Nude Mice.
Tested medicine
Reference substance: gemcitabine hydrochloride injection (gemzar, Lilly Co., Eli.)
Test sample: HH-GT-003, HH-GT-005, HH-GT-00, offering sample unit is Jiangsu Haosen Pharmaceutical Co., Ltd;
Laboratory animal
The BALB/cA-nude nude mouse, ♀, age in 5-6 week is available from Shanghai Slac Experimental Animal Co., Ltd.; The quality certification number: SCXK(Shanghai) 2011-0005; Feeding environment: SPF level.
Experimental procedure:
Nude mouse subcutaneous vaccination Non-small cell lung carcinoma A549 cell treats that tumor growth is to 100-300mm
3After, with animal random packet (d0).Concrete dosage regimen sees Table 1.Survey weekly the tumor volume 2-3 time, claim Mus heavy, record data.Gross tumor volume (V) computing formula is:
V=1/2 * a * b
2Wherein a, b represent respectively length and width.
Experimental result
Table 1. intravenous injection HH-GT-003, HH-GT-005, HH-GT-006 are to the curative effect of Non-small cell lung carcinoma A549 Nude Mice
D0: minute cage administration time; Dn: after the 1st administration 18 days.* P＜0.01vs contrast
Conclusion
Judge that with data such as relative tumour volume (RTV), relative tumor proliferation rate T/C (%) HH-GT-003, HH-GT-005 all obviously suppress the growth of pulmonary carcinoma A549/ATCC, the HH-GT-003 curative effect is best.Growth also has good inhibitory action to HH-GT-006 to A549.
Claims (9)
1. a gemcitabine or its liposome of salt comprise gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent, and the mean diameter of described gemcitabine or its salt is 10nm-100nm.
2. gemcitabine according to claim 1 or its liposome of salt is characterized in that, described gemcitabine is hydrochlorate, and the mean diameter of gemcitabine hydrochloride is 50-80nm.
3. gemcitabine according to claim 2 or its liposome of salt is characterized in that, the weight ratio of phospholipid, cholesterol is 1-8:1 in the described liposome; Take gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent gross weight as 100%, wherein emulsifying agent weight accounts for 10%-20%.
4. gemcitabine according to claim 2 or its liposome of salt is characterized in that, the weight ratio of phospholipid and cholesterol is 6:1 in the described liposome; Take gemcitabine or its salt, phospholipid, cholesterol and emulsifying agent gross weight as 100%, wherein emulsifying agent weight accounts for 10%-15%.
5. gemcitabine according to claim 1 or its liposome of salt is characterized in that, described phospholipid is selected from lecithin, fabaceous lecithin or its mixture; Described emulsifying agent is selected from propylene glycol, polyoxyethylene hydrogenated Oleum Ricini acid esters, polysorbate, Triton X-100 or triethanolamine.
6. gemcitabine according to claim 1 or its liposome of salt is characterized in that, described phospholipid is selected from fabaceous lecithin, and described emulsifying agent is selected from propylene glycol and polyoxyethylene hydrogenated Oleum Ricini acid esters.
7. a method for preparing the described gemcitabine of claim 1-6 any one or its liposome of salt comprises the steps:
A) preparation gemcitabine or its saline solution are used the high pressure homogenizer homogenize;
B) phospholipid, cholesterol and emulsifying agent are dissolved in an amount of ether, add gemcitabine or its saline solution, ultrasonic, make Emulsion;
C) boil off ether, use the hydration medium eluting, ultrasonic, cross 0.1 μ m microporous filter membrane.
8. preparation method according to claim 7 is characterized in that, the concentration of described gemcitabine or its saline solution is 15-25mg/ml.
9. preparation method according to claim 7 is characterized in that, the concentration of described gemcitabine or its saline solution is 20mg/ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210260619.7A CN102846547B (en) | 2012-07-26 | 2012-07-26 | Gemcitabine or its salt liposome and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210260619.7A CN102846547B (en) | 2012-07-26 | 2012-07-26 | Gemcitabine or its salt liposome and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102846547A true CN102846547A (en) | 2013-01-02 |
| CN102846547B CN102846547B (en) | 2014-03-19 |
Family
ID=47393802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210260619.7A Active CN102846547B (en) | 2012-07-26 | 2012-07-26 | Gemcitabine or its salt liposome and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102846547B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474067A (en) * | 2016-11-24 | 2017-03-08 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of polyethyleneglycol modified gemcitabine or its liposome of salt and its preparation method and application |
| CN111035616A (en) * | 2019-12-30 | 2020-04-21 | 上海景峰制药有限公司 | Gemcitabine liposome and preparation method and application thereof |
| CN112898277A (en) * | 2019-11-19 | 2021-06-04 | 扬子江药业集团有限公司 | Preparation method of afatinib intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004017944A1 (en) * | 2002-08-23 | 2004-03-04 | Neopharm, Inc. | Liposomal gemcitabine compositions for better drug delivery |
| CN101444485A (en) * | 2008-12-25 | 2009-06-03 | 中国医药集团总公司四川抗菌素工业研究所 | Gemcitabine liposome and preparation method thereof |
| CN101926779A (en) * | 2010-08-19 | 2010-12-29 | 苏州特瑞药业有限公司 | Gemcitabine solid lipid nanospheres, preparation method thereof and use thereof |
-
2012
- 2012-07-26 CN CN201210260619.7A patent/CN102846547B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004017944A1 (en) * | 2002-08-23 | 2004-03-04 | Neopharm, Inc. | Liposomal gemcitabine compositions for better drug delivery |
| CN101444485A (en) * | 2008-12-25 | 2009-06-03 | 中国医药集团总公司四川抗菌素工业研究所 | Gemcitabine liposome and preparation method thereof |
| CN101926779A (en) * | 2010-08-19 | 2010-12-29 | 苏州特瑞药业有限公司 | Gemcitabine solid lipid nanospheres, preparation method thereof and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 黄君勤等: "盐酸吉西他滨脂质体的制备及含量和包封率的测定学性质", 《中国抗生素杂志》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474067A (en) * | 2016-11-24 | 2017-03-08 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of polyethyleneglycol modified gemcitabine or its liposome of salt and its preparation method and application |
| CN106474067B (en) * | 2016-11-24 | 2019-12-27 | 中国医药集团总公司四川抗菌素工业研究所 | Polyethylene glycol modified gemcitabine or salt liposome thereof |
| CN112898277A (en) * | 2019-11-19 | 2021-06-04 | 扬子江药业集团有限公司 | Preparation method of afatinib intermediate |
| CN112898277B (en) * | 2019-11-19 | 2022-04-22 | 扬子江药业集团有限公司 | Preparation method of afatinib intermediate |
| CN111035616A (en) * | 2019-12-30 | 2020-04-21 | 上海景峰制药有限公司 | Gemcitabine liposome and preparation method and application thereof |
| CN111035616B (en) * | 2019-12-30 | 2022-03-22 | 上海景峰制药有限公司 | Gemcitabine liposome and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102846547B (en) | 2014-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tomoda et al. | Preparation and properties of inhalable nanocomposite particles for treatment of lung cancer | |
| US20170088430A1 (en) | Application of silicon dioxide aerogel as nano-drug carrying system in pharmacy | |
| EP2123260A1 (en) | Liposome formulation and process for preparation thereof | |
| CN105338973A (en) | Treatment of cancer using coenzyme q10 combination therapies | |
| CN103976954A (en) | Drug-carrying liposome co-modified by folic acid and TAT peptide and preparation method thereof | |
| CN102784109B (en) | Taxane medicines albumin nanoparticle preparation for injection and preparation method thereof | |
| CN107530291A (en) | Double heavy duty liposomal pharmaceutical preparations | |
| CN109528654B (en) | Irinotecan hydrochloride and adriamycin hydrochloride co-carried liposome and preparation method thereof | |
| CN102784107B (en) | Gemcitabine or salt liposome thereof, and preparation method and application thereof | |
| CN102357074B (en) | Anti-tumor multi-medicine resistant targeted liposome | |
| CN102846547B (en) | Gemcitabine or its salt liposome and preparation method thereof | |
| CN102600077B (en) | Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof | |
| CN107260680B (en) | Dasatinib liposome preparation and preparation method thereof | |
| CN103181896A (en) | Liposome preparation comprising berbamine medicine, and preparation method thereof | |
| WO2015172712A1 (en) | Pharmaceutical composition for injection with synergistic effect of vitamin c and antitumour drugs | |
| EP3041477B1 (en) | Dendrogenin a and antineoplastic agents for the treatment of chemosensitive or chemoresistant tumors | |
| CN103181897B (en) | Gefitinib liposome preparation and preparation method thereof | |
| CN113840608B (en) | Use of CDK4/6 inhibitors in combination with VEGFR inhibitors for the preparation of a medicament for the treatment of tumors | |
| CN102614126B (en) | Thermosensitive liposome and its application | |
| Chang et al. | Nanostructured lipid carrier co-delivering paclitaxel and doxorubicin restrains the proliferation and promotes apoptosis of glioma stem cells via regulating PI3K/Akt/mTOR signaling | |
| CN106389437A (en) | Application of low-dose sildenafil as antitumor drug | |
| CN103989624A (en) | Irinotecan hydrochloride composition and preparation method thereof | |
| CN106265624A (en) | The treatment pharmaceutical composition of breast carcinoma, drug delivery system and preparation method thereof | |
| CN112237586A (en) | Application of rhizoma paridis saponin and sorafenib in preparation of anti-tumor combined medicine | |
| CN105796495A (en) | Irinotecan hydrochloride liposome pharmaceutical composition 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20130102 Assignee: LIANYUNGANG HENGYUN MEDICAL TECHNOLOGY Co.,Ltd. Assignor: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Contract record no.: 2015990000701 Denomination of invention: Gemcitabine or its salt liposome and preparation method thereof Granted publication date: 20140319 License type: Exclusive License Record date: 20150730 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |