CN100376249C - Liposome of doxorubicin and prepration method and application - Google Patents
Liposome of doxorubicin and prepration method and application Download PDFInfo
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- CN100376249C CN100376249C CNB2004100970447A CN200410097044A CN100376249C CN 100376249 C CN100376249 C CN 100376249C CN B2004100970447 A CNB2004100970447 A CN B2004100970447A CN 200410097044 A CN200410097044 A CN 200410097044A CN 100376249 C CN100376249 C CN 100376249C
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 24
- 229960004679 doxorubicin Drugs 0.000 title claims abstract description 17
- 239000002502 liposome Substances 0.000 title claims description 28
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 18
- -1 doxorubicin lipid Chemical class 0.000 claims abstract description 4
- 241000124008 Mammalia Species 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 12
- 201000002528 pancreatic cancer Diseases 0.000 claims description 12
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- 150000001298 alcohols Chemical class 0.000 claims description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 4
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 238000001125 extrusion Methods 0.000 claims description 4
- 239000006194 liquid suspension Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 description 21
- 241000700159 Rattus Species 0.000 description 20
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 19
- 229940103064 lipodox Drugs 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000003814 drug Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229960005039 almitrine Drugs 0.000 description 3
- LWKZCNVWFBSPKH-FVLLGJNOSA-N almitrine-raubasine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1.C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C=2N=C(NCC=C)N=C(NCC=C)N=2)CC1 LWKZCNVWFBSPKH-FVLLGJNOSA-N 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 229940115080 doxil Drugs 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 240000000111 Saccharum officinarum Species 0.000 description 2
- 235000007201 Saccharum officinarum Nutrition 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 238000011694 lewis rat Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000012489 doughnuts Nutrition 0.000 description 1
- 229940042317 doxorubicin liposome Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
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- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The present invention provides a doxorubicin lipid composition for treating pancreas cancers of mammals and a preparing method thereof.
Description
Technical field
The present invention makes the method for Mycocet pharmaceutical composition about doxorubicin (doxorubicin) liposome drug combination, and is used for the treatment of the purposes of pancreatic cancer.
Background technology
In 2003, in the U.S., about 30,000 patients died from pancreatic cancer, and diagnosed out about 30,700 new cases, made pancreatic cancer become one of ten greatly common causes with the mortality rate of related to cancer.For many patients, operation, radiation cure, and chemotherapy selects for the treatment of continuity life and/or mitigation symptoms, but seldom cure (Cancer Facts and Figures, AmericanCancer Society 2003).
Compare with non-liposome medicament, liposome medicament, can quite successfully arrive primary tumor and suppress its transfer, and demonstrate stronger therapeutic effect to the animal and the mankind in intravenous injection, and slighter side effect.The most widely one of liposome medicament of development is doxorubicin (doxorubicin) liposome.In Taiwan, the modal brand of this medicine power by name gets (Lipo-Dox makes and sells by Dongyang Pharmaceutical Industry Co., Ltd., Taiwan is exclusive), and similar products, is known as the duxil (Doxil ) in the U.S..Mycocet usually is used for the treatment of specific cancer, for example breast carcinoma, ovarian cancer, and a kind of malignant tumor that is called the Ka Boxishi relevant with AIDS (Kaposi ' s) malignant tumor.
For pharmaceuticals industry, the preparation liposome medicament is difficult.Many methods that are used to prepare liposome and/or liposome medicament are disclosed, for example Szoka professor's invention.
Grant Francis C.Szoka, Jr. United States Patent (USP) the 5th, 077,057,5,277,914 and 5,549, disclose a kind of method that is used to prepare liposome suspension No. 910, this liposome has the particle size that is defined and is encapsulated with a useful chemical compound, and the dissolubility of this chemical compound in water, alcohols or halogenated hydrocarbon is not good.The suitable lipid system of chemical compound that this dissolubility is not good and capacity is dissolved in the non-protonic solvent of DMSO (dimethyl sulfoxide) for example, words if necessary, the lower alcohols (for example ethanol) that can comprise a meltage, and follow mixture through pushing or being injected in the aqueous solution that stirs.The liposome suspension of gained can or concentrate words if necessary through dialysis.Extruding can utilize injection tube, porous disc or any other to have about 0.05mm to carry out to the appropriate device of about 5mm bore hole size.In the embodiment 2 of these three United States Patent (USP)s, doxorubicin system is dissolved among the DMSO, and interpolation contains lecithin acyl glycerol (EPG): lecithin phatidylcholine (EPC): in the alcoholic solution of cholesterol (Chol) (7: 3: 6).Lipid system is by with lipid-doxorubicin mixture, under 30 ℃, is injected to an aqueous phase of being made up of 140mM NaCl-10mM Tris-HCl (pH 4.0).With the liposome suspension dialysis, and by the tubing string chromatography, will be through liposomal encapsulated doxorubicin and not entrapped separating substances.The particle diameter of the liposome of gained is 277nm, and 41.2% doxorubicin is encapsulated in the liposome particles.
Yet preceding method can't be eliminated some problem, the homogeneity of for example keeping of toxic organic solvent, aseptic condition, and liposome and quality, so preceding method is not suitable for extensive manufacturing.
Known techniques has disclosed a kind of method of utilizing Mycocet treatment pancreatic cancer, " assessment Kang Lisi (CAELYX; Mycocet, duxil (Doxil)) studies at the toleration of the treatment pancreatic cancer that can't excise and the II phase of effect " (Ann Oncol.2001 Oct for example; 12 (10): 1399-402).Yet this research obtains the conclusion that CAELYX (Mycocet, duxil (Doxil )) does not see objective reaction.Yet can't treat this disease the course of treatment of being used effectively.
The present invention also provides the method for utilizing Mycocet treatment pancreatic cancer except the method for preparing Mycocet that is suitable for the industry manufacturing is provided.In order to assess effect, research is through reaching tumor size and the time-to-live without the rat that has the pancreas tumor that crosses the Mycocet dispensing.
All above-mentioned document and patents, and hereinafter mentioned document are incorporated in this description for your guidance all in full.
Summary of the invention
Therefore, an object of the present invention is to provide Mycocet pharmaceutical composition and use this compositions to treat pancreatic cancer effectively.
On the one hand, the invention provides the mammiferous method that a kind of treatment suffers from pancreatic cancer, comprise the step that the Mycocet pharmaceutical composition of effective dose is gone up in the dispensing treatment.
On the other hand, the invention provides a kind of method of making the Mycocet pharmaceutical composition.
Description of drawings
Fig. 1 demonstration power get (Lipo-Dox ) to the rat that has AR42J pancreas tumor in the effect aspect the gross tumor volume; And
Fig. 2 demonstration power get (Lipo-Dox ) to the rat that has AR42J pancreas tumor in the effect aspect the time-to-live.
The specific embodiment
The detailed description of the present invention's preferred embodiment
The invention provides a kind of method of making Mycocet, comprise following step: (a) under about 55-65 ℃, provide the premix that comprises following chemical compound: 40-70% DSPC (DSPC), 10-35% cholesterol, and the premix/alcohol solution of a 15-30% methoxyl group-Polyethylene Glycol-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE (mPEG-DSPE) and an alcohols solvent, wherein the weight of this premix is about 1: 5 with the ratio of the volume of alcohols solvent, described alcohols is preferably lower alcohol, for example methanol, ethanol and propanol; (b) with premix/alcohol solution and 0.2-0.8N ammonium sulfate (preferred 0.2N ammonium sulfate), with about 1: the volume ratio of 2-10 is mixed, to form a mixture; (c) under 50-70 ℃, be preferably under 60 ℃, make the hole extrusion process of the mixture of step (b) gained, to form a preformed liposome liquid suspension through the aperture of 0.05-0.45 μ m; (d) at room temperature, utilize 5 weight % to 15 weight % aqueous sucrose solutions, this preformed liposome liquid suspension of dialysing obtains liposome suspension with activation; And (e) under 55-65 ℃, be preferably under 60 ℃, doxorubicin is mixed from this liposome suspension that aqueous sucrose solution obtained with step (d).
When with prior art method relatively the time, the present invention can under low pressure carry out under (about 40 to 140psi), but obtains higher productive rate (about 2 to 10L/min), and it is than carrying out under about 100 to 200psi and productive rate is that 1 to 5L/min prior art method is good.
The applicant has been denomination of invention on July 7th, 2003 with " liposome suspension manufacture method and product thereof ", submit application for a patent for invention in the continent, application number is 03178458.5, the power that wherein described in detail gets the preparation method and the composition of (Lipo-Dox), and the content of this application is also as a part of the present invention.
Utilize power to get (Lipo-Dox ), treat the rat that suffers from pancreatic cancer in the mode of intravenous injection (I.V.), dosage is 10mg/kg.The results are shown in the following explanation.
After process normal saline solution or power got (Lipo-Dox ) dispensing, the change of body weight, tumor size and time-to-live was shown in table 1 and 2.
It is that relative tumour volume was along with the change of time after 10mg/kg normal saline solution (matched group) or power got (Lipo-Dox ) that Fig. 1 is presented at dispensing dosage.Treatment is the 0th day and beginning in the 13rd day after tumor is implanted rat.Rat is in the time of the 0th, 3,7 and 10 day, utilizes normal saline solution or power to get (Lipo-Dox ) and (10mg/kg) treats.Measure tumor according to specified natural law.With V
t/ V
0Exponential representation relative tumour volume, wherein V
tBe the gross tumor volume of specified natural law, and V
0Same tumor size during for the treatment beginning.
It is after 10mg/kg normal saline solution (matched group) or power get (Lipo-Dox ) that Fig. 2 is presented at dispensing dosage, the time-to-live of rat.Treatment is the 0th day and beginning in the 13rd day after tumor is implanted rat.Rat is in the time of the 0th, 3,7 and 10 day, utilizes normal saline solution or power to get (Lipo-Dox ) and (10mg/kg) treats.
After table 1 gets (Lipo-Dox ) treatment in process or without exertin, the change body weight (g) of body weight
| Numbering | Before the injection | After the |
||||||
| 3 |
7 |
10 |
14 |
17 |
21 |
24 days | ||
| The normal saline solution group | ||||||||
| 303 308 | 180 180 | 180 180 | 220 240 | 230 225 | Dead 240 | Dead | Dead | Dead |
| Power gets (LIPODOX) group | ||||||||
| 304 305 311 | 170 180 160 | 180 190 170 | 170 180 170 | 120 120 120 | 110 110 110 | 110 110 110 | 110 110 110 | 110 110 110 |
After table 2 gets (Lipo-Dox ) treatment in process or without exertin, the change of gross tumor volume and time-to-live
| Numbering | Before the injection | Gross tumor volume (mm 3) | Reduce or increase % | Reaction | Time-to-live (d) | ||
| After the |
|||||||
| 3 |
7 |
10 days | |||||
| The normal saline solution group | |||||||
| 303 308 | 397.55 595.73 | 2771.72 3934.75 | 6885.52 7601.64 | 11258.26 12050.18 | Increase by 391.92% and increase by 291.11% | Bad | 13 15 |
| Power gets (L *Po-Dox ) group | |||||||
| 304 305 311 | 774.04 785.7 727.59 | 1195.91 671.62 1139.37 | 318.21 338.2 397.89 | 0 0 0 | Reduce 100% and reduce by 100% minimizing 100% | Good good | 26 27 27 |
Annotate: in table 1 and table 2, two repetition matched groups with same concentrations are represented in numbering in the normal saline solution group " 303 " and " 308 ", three the repeated experiments groups identical with content are formed in numbering during power must be organized " 304 ", " 305 " and " 311 " representative
When intravenous injection in the 0th, 3,7 and 10 day, the AR43J pancreas tumor that power gets (Lipo-Dox ) antagonism subcutaneous (s.c.) implantation is highly effective.Under the dosage of 10mg/kg, all animals are all cured, and the survival rate of the rat through treating presents increase (referring to Fig. 1 and Fig. 2).After via four dispensings of intravenous injection normal saline solution, the body weight of rat stably increases, yet the body weight of utilizing power to get the rat of (Lipo-Dox ) treatment presents decline up to 33.33 percentage ratios.This result can obtain following conclusion: the dispensing that power gets (Lipo-Dox ) is effective Therapeutic Method of pancreatic cancer.
Embodiment
Following embodiment illustrates preparation, characteristic description and uses the present invention's method for compositions.These embodiment are not intended to limit the present invention's scope.
Embodiment 1
Mycocet (doxorubicin (doxorubicin) pharmaceutical composition, Power gets the preparation of (Lipo-Dox )
The PEG-2000-DSPE (available from Genzyine Co., the U.S.) of 16.8 grams, the cholesterol (available from NOF Co., Japan) of 27.4 grams and the DSPC (available from NOF Co., Japan) of 38.2 grams are added in 600 milliliters of interior ethanol of glass container.Under 60 ℃, make the mixture good mixing.When stirring the mixture constantly and mixture maintained 60 ℃, the ammonium sulfate solution of 4 liters of 0.2N is added in the mixture.Under this temperature, ethanol is all evaporations almost.Mixture is carried out the hole extrusion process, use 1.5 liters filter membrane (available from Toyo Kaisha, Ltd., Japan).The hole extrusion process comprises:
(1) uses first filter membrane (142 millimeters, 0.1 micron), mixture is filtered 10 times; And
(2) use second filter membrane (142 millimeters, 0.05 micron), mixture is refiltered 10 times.
Squeeze pressure remains on 3 to 10 kilograms/square centimeter, and flow velocity is about 2 to 10 liters/minute.Collect 4500 milliliters of filtrates and then utilize the sucrose solution of 30 liter of 9 weight % to dialyse with 30KD doughnut (A/G Technology, UFP-30-C-6A, 30,000NM, 4800 square centimeters).Residual ethanol is removed by dialysis.About 3000 milliliters of the volume of collected solution, and collected solution is not for containing alcoholic acid liposome suspension.
3000 milliliters liposome suspension of manufacturing is added in the glass container that contains 8000 milligrams of doxorubicin hydrochlorates (red powder), then add previously prepared 200 milliliters of sugarcane powder solution (histidine-sugarcane powder solution) that contain the histidine of 0.8-1.2N (preferred 0.9N) constantly, the concentration of sugarcane powder solution is 0.9 weight %.Mixture is placed 60 ℃ water-bath and stirred 30 minutes, then be cooled to about 35 ℃, utilize 9% sucrose solution to be diluted to 4 liters, and good mixing.
Product is packaged in the little phial of aseptic glass that is used for as injectable formulation, and said preparation comprises 2.0 milligrams of doxorubicin hydrochlorate/milliliters.
Embodiment 2 preparation AR42J cell suspending liquids
Derivative type and for the AR42J cell strain (ATCC, CRL 1492) of the rat pancreas tumor of azaserine initiation available from ATCC.Under 37 ℃ and under the humidity environment of 95% oxygen and 5% carbon dioxide, with the AR42J cell culture in Ham ' s F-12K (Gibco BRL) culture medium, this culture medium contains the L-glutaminate of 20% tire bovine albumin, 2mM, and the sodium bicarbonate of 1.5 grams per liters.Cell is routinely with 1 * 10
6Concentration is cultivated in the T-flask.By main cultivation, utilize trypsin-EDTA (Gibco BRL) to collect by cell, and under 1000rpm centrifuge cell suspension 10 minutes, and be adjusted to 1 * 10
7Cells/ml.Use trypan blue (Trypan blue) to assess the vitality of AR42J pancreas tumor cell.
Use 5 lewis rat (Lewis rats can be provided by the Taiwan national science) to experimentize, every heavily about 160 grams of rat are to 180 grams, and all about 3 weeks of all rat are big.Food and water are unrestrictedly supplied with.Animal is taken care of and utilizes program to guide (Guide for the Care and Use ofLaboratoryAnimals from the Institute of Nuclear Energy Research) according to the treatment and the utilization of the laboratory animal of atomic energy research committee.In 0.1 milliliter of culture medium, and subcutaneous injection is to the right lower extremity of rat with 1,000,000 AR42J cell suspensions.After implanting for two weeks, by formula: length (millimeter) * width
2(millimeter
2)/2, the estimation gross tumor volume.V
t/ V
0Exponential representation relative tumour volume, wherein V
tBe the gross tumor volume of measuring at specified natural law, and V
0Be same tumor size when measuring beginning.
Embodiment 4 dispensing power get the therapeutic effect of (LiDo-Dox )
The rat that will have AR42J pancreas tumor is divided into two groups, and wherein two rat are matched group, and other three for power get (Lipo-Dox ) group.Give this rat of two groups respectively feeding normal saline solution or power get (Lipo-Dox ), dosage is 5 to 15 milligrams/kilogram, is preferably 10 milligrams/kilogram), secondary (on Wednesday and Saturday) weekly, intravenous injection is four times altogether.After dispensing, need to observe carefully immediately, for example gross tumor volume, body weight, energy degree, and the hair situation that drops, and monitoring is until there not being the rat survival.
Though the present invention illustrates together with the best specific embodiment of what is called that should be appreciated that, the present invention is not limited to above-mentioned specific embodiment, and be intended to contain and be included in the present invention's spirit of wide explanation and any different improvement in the scope.
Claims (4)
1. Mycocet is used for the treatment of application in the pharmaceutical composition of pancreatic cancer of mammal in preparation, and wherein this Mycocet utilizes following method preparation:
(a) with a lower alcohols solvent with comprise following chemical compound: 40-70% DSPC, 10-35% cholesterol, and the premix of 15-30% methoxyl group-Polyethylene Glycol-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE combination, to form the alcohol solution of a premix, wherein the weight of premix is about 1: 5 with the ratio of the volume of this lower alcohols solvent;
(b) with the alcohol solution and the 0.2-0.8N ammonium sulfate of premix, with 1: the 2-10 volume ratio is mixed, to form a mixture;
(c) making the mixture of step (b) gained is the hole extrusion process of 0.05-0.45 μ m through the aperture, to form a preformed liposome liquid suspension;
(d) at room temperature, utilize 5 weight % to 15 weight % aqueous sucrose solutions, this preformed liposome liquid suspension of dialysing obtains to contain the liposome suspension of the liposome particles of suspension with activation; And
(e) doxorubicin is mixed with this liposome suspension that step (d) is obtained.
2. application as claimed in claim 1, wherein this pharmaceutical composition is an injection.
3. application as claimed in claim 2, wherein this pharmaceutical composition comprises the doxorubicin hydrochlorate of 2.0 mg/ml.
4. application as claimed in claim 1, wherein this lower alcohols solvent is selected from the group that methanol, ethanol and propanol are formed.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100970447A CN100376249C (en) | 2004-12-21 | 2004-12-21 | Liposome of doxorubicin and prepration method and application |
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| CNB2004100970447A CN100376249C (en) | 2004-12-21 | 2004-12-21 | Liposome of doxorubicin and prepration method and application |
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|---|---|
| CN1795867A CN1795867A (en) | 2006-07-05 |
| CN100376249C true CN100376249C (en) | 2008-03-26 |
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| CNB2004100970447A Expired - Fee Related CN100376249C (en) | 2004-12-21 | 2004-12-21 | Liposome of doxorubicin and prepration method and application |
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| CN101897667B (en) * | 2009-05-26 | 2012-01-25 | 石药集团中奇制药技术（石家庄）有限公司 | Doxorubicin hydrochloride liposome injection and preparation technology thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4927571A (en) * | 1987-05-18 | 1990-05-22 | Liposome Technology, Inc. | Preparation of injectable doxorubicin/liposome suspension |
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2004
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4927571A (en) * | 1987-05-18 | 1990-05-22 | Liposome Technology, Inc. | Preparation of injectable doxorubicin/liposome suspension |
Non-Patent Citations (1)
| Title |
|---|
| A phase-II study of liposomal doxorubicin and docetaxel inpatients with advanced pancreatic cancer. Syrigos KN et al.Anticancer Research,Vol.22(6B) . 2002 * |
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Assignee: SHANGHAI XUDONG HAIPU PHARMACEUTICAL Co.,Ltd. Assignor: TTY BIOPHARM Co.,Ltd. Contract fulfillment period: 2009.8.1 to 2015.7.31 Contract record no.: 2009990001047 Denomination of invention: Liposome of doxorubicin and prepration method and application Granted publication date: 20080326 License type: Exclusive license Record date: 20090923 |
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