CN107303275A - Gefitinib liposome complex and preparation method thereof - Google Patents
Gefitinib liposome complex and preparation method thereof Download PDFInfo
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- CN107303275A CN107303275A CN201610255645.9A CN201610255645A CN107303275A CN 107303275 A CN107303275 A CN 107303275A CN 201610255645 A CN201610255645 A CN 201610255645A CN 107303275 A CN107303275 A CN 107303275A
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- Prior art keywords
- gefitinib
- lipid
- degrees celsius
- dppc
- liposome
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
Abstract
The present invention relates to a kind of Gefitinib liposome complex and preparation method thereof.The compound includes Gefitinib, lipid materials, buffer solution etc..The liposome complex includes one or more lipid materials, and the ratio with high active Gefitinib and lipid.The present invention can improve the envelop rate of Gefitinib liposome complex, with stability is good, targeting is high and the low feature of toxic side effect.Preparation method of the present invention is simple, workable, easily realizes industrialized production.
Description
Gefitinib-it is that one kind is used for relatively effective anticancer in cancer systematic treating.This chemotherapeutics is dynamic to experiment
The treatment of thing and human tumor model is highly effective, and the treatment that is particularly suitable for use in previously received chemotherapy or was unsuitable for the office of chemotherapy
Portion's late period or Metastatic Nsclc (NSCLC).
As other cancer chemotherapeutic agents, Gefitinib compound has toxicity.The main deficiency of Gefitinib compound is
Often occur skin adverse reaction, side effect of digestive tract, dysfunction of liver etc..Wherein, interstitial pneumonia is that Gefitinib is rare
The adverse reaction seen but can be fatal, fatal rate is higher.
Reduce Gefitinib toxicity of compound method, including combined chemotherapy, synthetic analogues (Fahmy et al.,
2016.2.11, Urol Int.；Xiaoqing Wu et al., 2010.6.1, Bioorg Med Chem.18 (11):3812–3822),
Immunotherapy and liposome embedded (Maruyama S et al., 2003Oct Gan To Kagaku Ryoho.30 (11):1773-
5.；Shao Yue, Chinese excellent MA theses 2015).Relative to the formulation of free form, including it is embedded in liposome
This antineoplastic of Gefitinib, while antitumor activity is kept, with low toxicity (Shao Yue, national best in 2015
Elegant master thesis).
But, because the water solubility of bioactivator is low, Gefitinib can somewhat dissolve in pH=1, work as pH>7
When, it can hardly dissolve, and the lipophile of Gefitinib is low, causes the ratio of bioactivator/lipid low, so being difficult to
Gefitinib is effectively embedded in liposome or peptide/lipid complex formation.
Liposome and composite of lipid comprising Gefitinib there is a further problem --- the stability of compound.Especially
The confining force for being the persistence of bioactivator effect and bioactivator in the liposome during storage is to generally acknowledge problem
(Freise et al., 1982；Gondal et al., 1993；Potkul et al., 1991Am J Obstet
Gynecol.164(2):652-658；Steerenberg et al., 1988；Sweiss et al., 1993).
Summary of the invention
The present invention describes a kind of new Gefitinib liposome complex embedded by lipid and preparation method thereof.This
The method of invention description is the new method to form this new Gefitinib liposome complex.
Among others, the present invention provides a kind of composition including liposome or peptide/lipid complex formation and Gefitinib, institute
State liposome and include one or more kinds of lipids, the wherein weight rate of Gefitinib and lipid is 1:50-1:1, or 1:30-
1:3, or 1:20-1:5.One or more kinds of lipids can include, for example 50-100mol%DPPC and 0-50mol% courages
Sterol, in another example 50-70mol%DPPC and 10-30mol% cholesterol
The present invention also provides a kind of preparation method of Gefitinib liposome complex simultaneously, comprises the following steps：(a) Ji Fei
Mixed for Buddhist nun's homogeneous phase solution with lipid solution；(b) (a) mixed solution is injected into water-bearing media and mixed；(c) in the first temperature
Under make the two formed mixture；Then under than first temperature lower second temperature form further mixture (d).Wherein walk
Suddenly (c) and (d) is effective to the envelop rate for improving Gefitinib.Step (c) is realized generally by heating, and is usually
Step (d) is realized by cooling down.In embodiment alternatively, circulate since cooling step, be transformed into heating step
Suddenly, two such step is repeated.Methods described include continuing to make step (c) and (d) repeat two or three or more follow
Ring.Gefitinib solution can be prepared by the way that Gefitinib is dissolved in into dimethyl sulfoxide (DMSO).Two palmityl phosphatidyls
Choline (DPPC) and cholesterol are dissolved in the organic solvent including absolute ethyl alcohol, form lipid solution.In all steps
(c) and after (d) completion, the preparation method of Gefitinib liposome complex may further include：(e) by through
The film for pinpointing selective power with molecular wt is filtered, and removes non-encapsulated Gefitinib, retain the liposome that needs or
Person's peptide/lipid complex formation.
Invention further provides the Gefitinib liposome complex prepared according to the inventive method and compound of the present invention
Reagent combination.The formula includes pharmaceutically acceptable carrier or diluent, suitable for patient is sucked or injected to
Prescription formula.
Brief description of the drawings
Fig. 1 shows Gefitinib liposome complex and Gefitinib active compound according to the present invention in three kinds of lung carcinoma cells
Inhibiting tumor cell activity.
The content of the invention
The present invention includes a kind of Gefitinib liposome complex of new peptide/lipid complex formation, wherein Gefitinib and lipid
Ratio is very high.Gefitinib and the weight rate of lipid are 1 in the present invention:1 to 1:Between 30.Most preferably, Ji Fei is replaced
The weight rate of Buddhist nun and lipid is 1:5 to 1:Between 10.
The preparation method of Gefitinib liposome complex includes mixing Gefitinib with lipid solution and making its mixture
One or more circulation is carried out at two kinds of single temperature.The formation Gefitinib lipid bluk recombination of this method can be passed through
Thing.
The preparation method for the pulmonary administration induction type Gefitinib liposome that the present invention is described includes following feature：Ji non-is replaced
Buddhist nun is dissolved in DMSO, and fat material is dissolved in the organic solvent miscible with water such as absolute ethyl alcohol, methanol, and the two is mixed and stirred
Lower physiological saline, isotonic glucose solution or the phosphate buffer solution (PBS) being preheated to more than fat material phase transition temperature of injecting is mixed to obtain
To liposome solutions；Using ultrafiltration, dialysing or crossing the free Gefitinib of the methods such as Sephadex posts removing produces Gefitinib fat
Plastid solution.
As routine test can be determined, in some cases, the suitable temperature used in method can be with using in method
Lipid mixtures and change.
The Gefitinib liposome complex of preparation has high medicine and lipid ratio.Formula goes for sucking or noted
Penetrate.
For the present invention lipid can be synthesis, semi-synthetic or naturally occurring lipid, including phosphatide, dimension life
Plain E, sterol, aliphatic acid, glycolipid, anion resin, cationic lipid.The phosphatide can include lecithin (EPC), phosphorus
Phosphatidyl glycerol (EPG), phosphatidylinositols (EPI), phosphatidylserine (EPS), phosphatidyl-ethanolamine (EPE),
With phosphatidic acid (EPA)：Soybean homologue, soybean lecithin (SPC)：SPG, SPS, SPI, SPE and SPA：Hydrogen
The ovum and soybean homologue (such as HEPC, HSPC) of change, the lecithin monoethanolamine of stearic acid (sterically) amendment, courage
Steroid derivatives, carotenoid, other are bonded the lecithin constituted by fat, and the ester on 2 and 3 by containing 12-26
The glycerine of individual carbon atom chain with contain the main base for Bu Tong including choline, glycerine, inose, serine, monoethanolamine on 1
The glycerine composition of group, and corresponding lecithin resin acid.These fatty acid chains can be saturation or undersaturated, and phosphatide can be by
The Fatty acid compositions of different length and saturation degree.Especially, the composition of formula can include DPPC, the lung table of naturally occurring
The main component of face activating agent.Other examples include dimyristoylphosphatidycholine (DMPC) and two myristoyl phosphatidyls
Glycerine (DMPG) and DPPC (DPPC) and two palmitic acid phosphatidyl glycerols (DPPG) and distearyl
Phosphatidyl choline (DSPC) and DSPG (DSPG), dioleoyl phospholipid acyl-choline (PSPC) and
Palmitostearate glycerine (PSPG), triacylglycerol, seranide, diacylglycerol, sphingol, such as sphingomyelins and single-oil
Single acyl phosphatide of acyl-phosphatidyl ethanolamine (MOPE).
Result of the test is transparent to show that out during the formation of liposome capsule and Gefitinib is contained.As a result further show
Show, because Gefitinib concentration ratio solubility limit is much higher, so the physical state of Gefitinib be solid-state or with lipid knot
Close.As a result freezing is not needed during further showing, but being cooled to the temperature on freezing temperature can produce
More preferable effect.As a result 3-4 cooling and the embedding effect of heat cycles and the embedding effect class of 6 circulations are further shown
Seemingly, 3-4 Temperature Treatment circulated of its explanation, which is enough to realize that priority is other, contains.
As a result it show further while embedding Gefitinib efficiency is improved, this technique can be amplified.Therefore,
The present invention further provides be 200mLS or more or 800LS or more (appropriate for supplying suitable for whole administration
A small amount of increase) method.In the case of every other condition all identicals, it is believed that production larger volume is generally than small-scale
Easily reach increased effect.If such volume is suitable to administration, volume can be reduced to be adapted to storage.
As a result it show further, due to minimal leakage, the Gefitinib liposome being prepared by the method for the present invention
Compound can keep being embedded in more than 1 year.The unique further confirmation of formula shows that Gefitinib is contained in liposome
In structure and be difficult leakage.
Embodiment
Embodiment 1
20mg Gefitinibs are dissolved in 1.0ml DMSO, by 100mg DPPCs
(DPPC) it is dissolved in 40mg cholesterol in 1.0ml absolute ethyl alcohols, 65 is preheated to respectively, and is expelled to and is preheated to 65
20ml normal saline solutions in；Slow cooling is to 5, and reheating is warming up to 65, repeats falling-rising temperature 3 times, then drops
Warm to room temperature, obtain Gefitinib liposome complex.Free Gefitinib is removed using dialysis process and produces Gefitinib lipid
Nanocrystal composition solution.It is 90% to remove envelop rate before free drug.
Embodiment 2
10mg Gefitinibs are dissolved in 1.0ml DMSO, 40mg hydrogenated soy phosphatidyl cholines (HSPC) and 27
Mg cholesterol is dissolved in 1.0ml absolute ethyl alcohols, and it is molten to inject the isotonic glucose of 5ml 50 under magnetic stirring after the two mixing
Liquid；0 is cooled to, then is slowly heated and is warming up to 50, falling-rising temperature is repeated 2 times, drops to and liposome solutions are obtained after room temperature.
Dialysis removes free Gefitinib and produces Gefitinib liposome solutions in isotonic glucose solution.Remove envelop rate before free drug
For 82%.
Embodiment 3
30mg Gefitinibs are dissolved in 1.0ml DMSO, 130mg egg yolk lecithins (Egg PC) and 50mg
Cholesterol is dissolved in 1.0ml ethanol, and it is slow for 6.8PBS phosphate to inject 15ml 40pH under magnetic stirring after the two mixing
Rush solution；0 is cooled to, then is slowly heated and is warming up to 40, falling-rising temperature is repeated 4 times, drops to after room temperature that to obtain liposome molten
Liquid.Dialysis removes free Gefitinib and produces Gefitinib liposome solutions in isotonic glucose solution.Remove and wrapped before free drug
Envelope rate is 85%.
Although the present invention only describes preferred embodiment emphatically, it is however possible to use the preferred equipment and method of change,
And can attempt to carry out using the method different from method described herein, this is aobvious and easy for the general staff of this area
See.Therefore, present invention resides in all modifications in the spirit and scope of the claims below.
Claims (17)
1. a kind of Gefitinib liposome complex, including liposome or peptide/lipid complex formation and Gefitinib embedded therein,
The liposome or peptide/lipid complex formation include one or more lipid materials, and the weight rate of wherein Gefitinib and lipid is
1:50-1:1；It is preferred that 1:30-1:3；More preferably 1:20-1:5.
2. composition according to claim 1, one or more of which lipid includes egg yolk lecithin, soybean lecithin
Fat, hydrogenated soy phosphatidyl choline, DPPC (DPPC), dimyristoyl phosphatidyl choline, distearyl
Phosphatidyl choline, DOPC, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL etc..
3. composition according to claim 1, wherein lipid include：Vitamin E, cholesterol and cholesterol derivative
Deng.
4. composition according to claim 1, wherein the medicine embedded is not limited to Gefitinib, in addition to her horse is replaced
How Buddhist nun, Tarceva, Dasatinib, Sutent, Sorafenib, AMN107, Afatinib, Conmana, card replace
Buddhist nun etc..
5. composition according to claim 2, one or more of which lipid includes DPPC
(DPPC)。
6. composition according to claim 3, one or more of which lipid includes cholesterol.
7. composition according to claim 5, one or more of which lipid includes 50-100 moles of %DPPC and 0-
50 moles of % cholesterol；Or 50-70 moles of %DPPC and 10-30 moles of % cholesterol..
8. a kind of method for preparing Gefitinib liposome complex, including following key step：
(a) Gefitinib homogeneous phase solution is mixed with lipid solution；
(b) (a) mixed solution is injected into water-bearing media and mixed；
(c) the two is made to form mixture at the first temperature；With
(d) then further mixture is formed under the second temperature lower than the first temperature.
Wherein step (c) and (d) are effective to the envelop rate for improving Gefitinib.
9. method according to claim 8, further comprise continuing making step (c) and (d) repeat altogether two or more
Circulation, or preferably total of three or more multi cycle, to improve the envelop rate of Gefitinib.
10. method according to claim 8, wherein Gefitinib are dissolved into one or more including dimethyl sulfoxide (DMSO)
(DMSO) in solvent, Gefitinib homogeneous phase solution is formed.Wherein DPPC (DPPC) and cholesterol are molten
Solution forms lipid solution in one or more organic solvents including absolute ethyl alcohol.
11. method according to claim 8, water-bearing media includes water, physiological saline, phosphate buffer solution
(PBS), isotonic glucose solution one or more combination.
12. the temperature range of method according to claim 9, wherein step (c) formation mixture is included in 5 degrees Celsius
To 70 degrees Celsius；Or at 15 degrees Celsius to 65 degrees Celsius；Or at 30 degrees Celsius to 65 degrees Celsius.
13. the temperature range of method according to claim 9, wherein step (d) formation mixture is included in subzero 20
Degree Celsius to 25 degrees Celsius；Or at subzero 10 degrees Celsius to 20 degrees Celsius；Or it is Celsius to 10 at subzero 5 degrees Celsius
Degree.
14. the temperature difference that method according to claim 9, wherein step (c) and (d) are used is taken the photograph for 25
Family name's degree is more.
15. method according to claim 8, after further comprising that all steps (c) and (d) are completed：
(e) by being filtered through the film that selection function is pinpointed with molecular weight, to remove non-encapsulated Gefitinib medicine,
Retain the liposome complex needed.
16. a kind of composition including described in claim 1 and the pharmaceutically pharmaceutical formulation of acceptable carrier or diluent.
17. a kind of composition including described in claim 1, it is adaptable to the pharmaceutical formulation that patient sucks or injected.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610255645.9A CN107303275A (en) | 2016-04-22 | 2016-04-22 | Gefitinib liposome complex and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610255645.9A CN107303275A (en) | 2016-04-22 | 2016-04-22 | Gefitinib liposome complex and preparation method thereof |
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| Publication Number | Publication Date |
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Family
ID=60152000
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610255645.9A Pending CN107303275A (en) | 2016-04-22 | 2016-04-22 | Gefitinib liposome complex and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1681478A (en) * | 2002-08-02 | 2005-10-12 | 川塞夫有限公司 | Platinum aggregates and process for producing the same |
| CN101056620A (en) * | 2004-11-08 | 2007-10-17 | 特兰萨夫公司 | Methods of treating cancer with lipid-based platinum compound formulations administered intraperitoneally |
| CN101244039A (en) * | 2008-03-20 | 2008-08-20 | 江苏先声药物研究有限公司 | Novel method for preparing indissoluble medicaments liposome preparations |
| CN103181897A (en) * | 2011-12-30 | 2013-07-03 | 沈阳药科大学 | Gefitinib liposome preparation and preparation method thereof |
-
2016
- 2016-04-22 CN CN201610255645.9A patent/CN107303275A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1681478A (en) * | 2002-08-02 | 2005-10-12 | 川塞夫有限公司 | Platinum aggregates and process for producing the same |
| CN101056620A (en) * | 2004-11-08 | 2007-10-17 | 特兰萨夫公司 | Methods of treating cancer with lipid-based platinum compound formulations administered intraperitoneally |
| CN101244039A (en) * | 2008-03-20 | 2008-08-20 | 江苏先声药物研究有限公司 | Novel method for preparing indissoluble medicaments liposome preparations |
| CN103181897A (en) * | 2011-12-30 | 2013-07-03 | 沈阳药科大学 | Gefitinib liposome preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 何琳等: ""吉非替尼脂质体的制备及含量测定"", 《沈阳药科大学学报》 * |
| 王宇等: ""吉非替尼脂质体的处方工艺优化"", 《沈阳药科大学学报》 * |
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Effective date of registration: 20220126 Address after: 510005 floor 5, building 4C, phase II, standard industrial unit, No. 9, helix 4th Road, International Biological Island, Guangzhou, Guangdong Applicant after: Enkang Pharmaceutical Technology (Guangzhou) Co.,Ltd. Applicant after: Foshan Yingte Pharmaceutical Technology Co., Ltd Address before: 510000 unit 214-25, second floor, office area, No. 1, helix 4th Road, Guangzhou International Biological Island, Guangzhou, Guangdong Province Applicant before: INTELGEN (GUANGZHOU) Ltd. Applicant before: Foshan Yingte Pharmaceutical Technology Co., Ltd |