CN1084187C - Method for preparing anti-cancer medicine using beta-elemene as main effective ingredient, and components of the medicine - Google Patents
Method for preparing anti-cancer medicine using beta-elemene as main effective ingredient, and components of the medicine Download PDFInfo
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- CN1084187C CN1084187C CN98106848A CN98106848A CN1084187C CN 1084187 C CN1084187 C CN 1084187C CN 98106848 A CN98106848 A CN 98106848A CN 98106848 A CN98106848 A CN 98106848A CN 1084187 C CN1084187 C CN 1084187C
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Abstract
The present invention relates to an anticancer medicine which is composed that lemongrass is used as a main raw material, and anticarcinogen, namely beta-elemene, is extracted from lemongrass used as a main component. In the preparing method for the anticancer medicine, secondary fractionation in a precise fractionation tower is carried out to separate beta-elemene with a purity of 96.4% from lemongrass oil. Lemongrasses is plentiful and cheap, and contains much beta-elemene. The method has the characteristics of simple process, high efficiency, low cost and no pollution. Pharmacodynamic tests prove that the medicine has obvious action for curing animal transplantation tumors and gliomas, such as EAC, S180, L1210, etc., and has low toxic and side effect; the medicine is an ideal medicine for curing carcinomatous hydrothorax and ascites, gliomas and carcinomatous solid tumors.
Description
The present invention relates to a kind of preparation method and composition thereof of cancer therapy drug, particularly a kind of with cancer therapy drug preparation method and the composition thereof of beta-elemene as active ingredient.
The PTS elemene obtains national two kind new medicine certificates in December, 1993, the elemene anticancer research meeting of the assessment of results that hold by State Scientific and Technological Commission's tissue, medicine office of country in February, 1994.Elemene can be from various plants extraction separation and getting, for example one of most important source is that plant RADIX CURCUMAE (C.Wenyujin chen et C.ling) rhizome from China's special product is commonly called as a kind of chemical compound that extracts the volatile oil of warm Rhizoma Curcumae, it is the Elemene vinyl chemical compound, be main component with the beta-elemene wherein, contain δ-elemene and γ-elemene simultaneously.Elemene is the effective site of extracting from plant, and non-single component or monomer, chemical isomerization body wherein are difficult to separate.
Recently, pharmacodynamic experiment proves that elemene is separated from Zedoary turmeric oil, verified it have cancer resistance.It not only has the pernicious breast of good control, seroperitoneum, treatment superficial tumor, the characteristics that toxic and side effects is low, and when enlarging application, find that it all has certain curative effect to cerebroma, hepatocarcinoma, digestive tract tumor etc.As two kind new medicines, it is reasonable to produce 2 years proof process routes as a trial, and constant product quality is fit to industrialness production.Above-mentioned plant RADIX CURCUMAE and other two kind of plant Rhizoma Curcumae and Rhizoma Curcumae Longae belong to the zingiberaceous plant monoid, originate in torrid areas, the world, and provinces such as Guangdong, Sichuan, Fujian, Guangxi, Zhejiang are mainly originated in China.A main antitumaous effect is beta-elemene in the elemene, beta-elemene, its latin name β-Elemenum, English name β-elemene, chemistry 1-methyl isophthalic acid-vinyl-2 by name, 4-diisopropenyl cyclohexane extraction, beta-elemene still is in conceptual phase, though the report of beta-elemene was once arranged in the past, all should be elemene (isomer mixture) through examining, elemene is all used in all experiments, rather than single beta-elemene.At present, have in many kind of plant and contain beta-elemene, as: 50 various plants such as RADIX CURCUMAE, Rhizoma Acori Calami, Radix Inulae, the Radix Linderae, Radix Ginseng.Relevant department's preliminary survey shows that containing the essence of beta-elemene more than 1% just has nearly 40 kinds in China, wherein content is higher and from the gas chromatogram elution curve, segregative just have 7 kinds, as: Tiannu Magnolia oil, Eriocheir sinensis petitgrain oil, sieve strand leaf oil, oil of aglaia odorate and Caulis et Folium piperis wet goods, but above-mentioned resource does not include rich reality, and cost is also higher.Elemene formulation is to mice ehrlich carcinoma (EAC), mouse leukemia (P
388, L
1210), reticulocyte cell tumor ARS, and rat yoshida sarcoma ascitic type polyoma such as (YAS) spectrum all has tangible active anticancer.I, II, III phase clinical practice confirms it to carcinous breast, ascites, superficial tumor all has the better controlled effect, and total effective rate is more than 69%.What be worth proposition is to adopt regional chemotherapeutic treatment cerebroma to have 27% patient to reach recovery level fully when enlarging clinical practice.Another characteristics of this medicine are that toxic and side effects is slight, to the bone marrow unrestraint, do not influence body's immunological function, and blood phase, liver, renal function are not all influenced.But also not having a kind of method beta-elemene can be extract separately as cancer therapy drug at present uses.
The purpose of this invention is to provide a kind of with the preparation method and the composition thereof of beta-elemene as the anti-cancer medicament raw material of active ingredient, this anti-cancer medicament raw material is based on Herba Cymbopogonis Citrari, aboundresources, cheap, contain beta-elemene amount height and can supply suitability for industrialized production.
The object of the present invention is achieved like this: a kind of with the preparation method of beta-elemene as the effective antitumor medicine, it is characterized in that in the precision fractionation tower, carrying out the secondary fractional distillation with the raw material of citronella oil as the extraction beta-elemene.
Described secondary fractional distillation is all carried out under certain condition, and vacuum is 2-5mmHg (pressure 10
-2-10
-0.5Pa); Temperature range is 86-93 ℃; The fractional distillation ratio is 4: 1 or 5: 1; About 10 hours of response time.
The described fractional distillation first time is: coarse fodder is placed described precision fractionation tower still, heat fractional distillation, according to described condition, have three warm area fractions; 86-88 ℃, 89-90 ℃ and 91-93 ℃, beta-elemene mainly are in 89-90 ℃ the fraction, receive 89-90 ℃ fraction.
The described fractional distillation second time is: get 89-90 ℃ the distillate that fractional distillation for the first time obtains, condition is with fractional distillation for the first time, receives three kinds warm area fraction: 86-88 ℃, 89-90 ℃ and 91-93 ℃ in fractional distillation process, collects 89-90 ℃ fraction.
Residual oil recycles as coarse fodder at the bottom of in the described secondary fractional distillation process 86-88 ℃ and 91-93 ℃ of fraction and the fractionated still of secondary, repeats described secondary fractional distillation.Because whole extraction fractional distillation process is to carry out in hermetic container, can not pollute environment.
Described precision fractionation tower is the equipment that extracts beta-elemene that is specifically designed to, the high 1.4m of rectifying column wherein, and diameter 6cm, interior dress is a filler with 120 order rustless steel net volumes, 3 * 3mm hollow cylinder, number of plates N=40.
A kind of with method for preparing with the cancer therapy drug of beta-elemene as active ingredient, it is characterized in that described cancer therapy drug is made up of beta-elemene and the γ-elemene that obtains simultaneously and impurity.
Impurity in the described medicine is mainly elemol, flaw in a piece of jade crust alkene and different furan Ji alkene.
Each composition relative amount percentage ratio in the described medicine is:
Beta-elemene: more than 96.4%
γ-elemene: 0.5%
Elemol: 0.8-1.2%
Flaw in a piece of jade crust alkene: 1.3-1.7%
Different furan Ji alkene: 0.2%.
Beneficial effect of the present invention is:
1, anti-cancer medicament raw material of the present invention, based on Herba Cymbopogonis Citrari, this plant resources is abundant, cheap, contain beta-elemene amount height, be convenient to extract, and the isomer γ-elemene of beta-elemene and beta-elemene structural similarity, act on similarly, antitumaous effect is all arranged.Pharmacodynamic experiment proves that cancer therapy drug of the present invention has tangible anti-animal EAC, S
180, L
1210Deng transplanted tumor and gliomatous effect, its toxic and side effects is low, and effect is obvious, is the medicine of a kind of ideal cancer resistance ascites, glioma brain tumour and carcinous solid tumor.
2, the equipment for preparing material of beta-elemene cancer therapy drug provided by the invention and method, this method technology is simple, cost is low, pollution-free.
The invention will be further described below in conjunction with drawings and Examples.
Fig. 1 is a cancer therapy drug preparation method flow chart of the present invention.
Cancer therapy drug preparation method of the present invention is to extract beta-elemene from the Herba Cymbopogonis Citrari quintessence oil.Now, about more than 2,000 tons of Chinese Fragrant Rhizoma Imperatae quintessence oil annual production is one of large quintessence oil of Chinese exports, accounts for 50% of present international quintessence oil market lemongrass oil volume of trade, and this quintessence oil contains beta-elemene 1.63-5.21%.Especially the side-product after lemongrass oil extracts essence, promptly the content of beta-elemene is higher in the coarse fodder, can reach 80%.This coarse fodder can provide low price by the spice chemical plant of processing citronella oil.Experimental results show that: utilize the precision fractionation method can make the beta-elemene of purity more than 96.4%, major impurity has been studied clear, and its cost is cheap, and toxic and side effects is humble, has obvious antineoplastic.Especially cancerous ascites pleural fluid, glioma brain tumour, solid tumor there are positive effect, belong to a kind new medicine.
The present invention adopts the fractional method of precision fractionation tower still to produce beta-elemene first, is to place precision fractionation tower still to carry out repeatedly precision fractionation raw oil.The precision fractionation tower is exclusively used in beta-elemene production.The precision fractionation tower that the present invention is used, the high 1.4m of rectifying column wherein, diameter 6cm, interior dress is a filler with 120 order rustless steel net volumes, 3 * 3mm hollow cylinder, number of plates n=40.
The condition of extraction separation: vacuum is not less than 2mmHg (pressure 10
-2Pa), generally adopt 2-5mmHg (pressure 10
-2-10
-0.5Pa); Temperature range is 86-93 ℃; The fractional distillation ratio was controlled at 4: 1 or 5: 1; About 10 hours of response time; But repeatable operation 2-3 time.
Extract fractionated method: the secondary fractionating process, concrete steps are:
Coarse fodder (containing beta-elemene more than 80%) is got in fractional distillation for the first time, joins in the precision fractionation tower still; According to above-mentioned condition, enter three warm area fractions; 86-88 ℃, 89-90 ℃ and 91-93 ℃, beta-elemene mainly are in 89-90 ℃ the fraction, receive three kinds of warm area fractions.89-90 ℃ fraction wherein, yield is 63% of an inventory, purity is about 95%.
95% the distillate first time is got purity and is in fractional distillation for the second time, carries out fractional distillation second time purification, and condition is the same, three kinds warm area fraction: 86-88 ℃ of reception in fractional distillation process, 89-90 ℃ and 91-93 ℃.Collect 89-90 ℃ fraction, yield 60%, beta-elemene purity is more than 96.4%.
If Residual oil at the bottom of 86-88 ℃ in twice fractional distillation process and 91-93 ℃ of fraction and the fractionated still of secondary is recycled, beta-elemene 89-90 ℃ fraction total recovery can reach 45%.With the said equipment and method, after carrying out the secondary fractional distillation and purifying, the purity of beta-elemene can reach more than 96.4%.Whole extraction fractional distillation process is to carry out in hermetic container, can not pollute environment.
The present invention carries out Analysis and Identification according to the technical standard of following provisions:
Refractive index n
25=1.4911 relative densities 0.8813
Specific optical rotation [a]
25196 ℃-219 ℃ of=13.47 boiling ranges
Elementary analysis: theoretical value measured value value of calculation
C 88.24 88.12
H 11.76 11.70 C
15H
24
Do through infrared spectrum, ultraviolet spectra, gas chromatogram, mass spectrum and gas chromatograph-mass spectrometer and nuclear magnetic resonance, NMR
1H,
13C, DEPT, evaluations such as COSY spectrum meet the structure of beta-elemene.
Can obtain a kind of with the cancer therapy drug of beta-elemene as active ingredient with said method, it is made up of beta-elemene and impurity γ-elemene, elemol, flaw in a piece of jade crust alkene and different furan Ji alkene, and each composition relative amount percentage ratio is: beta-elemene: more than 96.4%; Flaw in a piece of jade crust alkene: 1.3-1.7%; Elemol: 0.8-1.2%; γ-elemene: 0.5%; Different furan Ji alkene: 0.2%.
Preparation is as follows as the specific implementation method of the cancer therapy drug of active ingredient with beta-elemene:
1, get coarse fodder, promptly citronella oil (the spice chemical plant provides) by-product 2000g (containing beta-elemene more than 80%) places precision fractionation tower still to heat fractional distillation, and the fractional distillation ratio was controlled at 5: 1, and (pressure is 10 to vacuum 2mmHg
-2Pa);
2, the temperature range of heating is I:86-88 ℃, II 89-90 ℃, and III 91-93 ℃, receive 89-90 ℃ warm area fraction, yield 65%, purity 95% obtains fraction products one time;
3, will be 95% citronella oil 2000g through a fraction products purity, and carry out the secondary fractional distillation, condition and method receive 89-90 ℃ fraction with fractional distillation for the first time, and yield is 60%, and purity is more than 96.4%.
86-88 ℃ fraction that a fractional distillation is received and 91-93 ℃ fraction (two kinds of fractions) and through residue at the bottom of the still after the secondary fractional distillation, recirculation uses and carries out fractional distillation, and method and condition are the same, collect 89-90 ℃ fraction, and yield is 20%.
Final beta-elemene and the impurity thereof that gets precision fractionation, contain: beta-elemene is more than 96.4%; Flaw in a piece of jade crust alkene 1.3-1.7%; Elemol 0.8-1.2%; γ-elemene 0.5%; Different furan Ji alkene 0.2%.Wherein the isomer γ-elemene of beta-elemene and beta-elemene structural similarity act on similarly, and antitumaous effect is all arranged.
Above-mentioned raw materials can be prepared into preparation:
Described production method is:
1, beta-elemene, phospholipid and cholesterol are mixed together are heated to 80 ℃, clear and bright to melting;
2, biphosphate is received and phosphoric acid hydrogen two is received and is dissolved in water reheat to 80 ℃;
3, the mixture that the 1st, 2 steps were obtained is respectively put into the emulsifying of high speed dispersing emulsification machine together to emulsion injection;
4, emulsion injection is passed through G
4Hang down and melt the funnel filtration, carry out the granularity inspection then;
5, the injection embedding after will checking is carried out sterilizing to finished product in 40 minutes at 100 ℃ high temperature.
Be prepared into the beta-elemene anti-tumor agent by said process.
It is as follows to carry out animal pharmacodynamics result of study according to the beta-elemene cancer therapy drug of above-mentioned process route preparation:
1, cancer ascites: the injection of lumbar injection beta-elemene all has stable curative effect to EAC and S-180 ehrlich ascites carcinoma, and its increase in life span is respectively 85-310%, 90-321%.Increase in life span to the hepatic ascites cancer is 103-224%.
2, solid tumor: the beta-elemene injection also has certain inhibition to the S-180 solid tumor, and its suppression ratio is 33-59%, to the suppression ratio of liver-cancer solid tumor between 10-30%.
3, mouse leukemia L
1210: the beta-elemene injection is to L
1210Significantly curative effect is arranged, and its increase in life span is 47-286%.
4, glioma: the pharmacodynamic experiment that carries out glioma brain tumour with mice scrotum embrane method (SRC) shows, tumour inhibiting rate 50-70%.
5, γ-elemene is to mice ehrlich carcinoma and mouse leukemia L
1210Life prolong and to be about 111%, need further finish but study in great detail.
6, beta-elemene does not have the side effect of common antitumor drug such as reaction such as bone marrow depression, leukopenia.
The inventor thinks through experimentation: beta-elemene has tangible cancer resistance ascites pleural fluid, solid tumor, mouse leukemia L
1210, effects such as glioma brain tumour, non-evident effect.Be fit to develop a kind new medicine of treatment human cancerous ascites pleural fluid, glioma brain tumour and solid tumor.The antitumaous effect of γ-elemene should further be studied.
The clinical practice of beta-elemene
Under special circumstances, two Patients with Brain Tumors beta-elemene injection for treating are arranged, all obtain significant clinical efficacy.
Example 1, king * *, woman, 25 years old, admission number 3016.The excuse pain, upper right weakness of the lower extremities, hemiplegia is diagnosed as the thalamus glioblastoma multiforme through CT, and tumor body size is 3.8 * 5.3 * 4cm.The operation of being admitted to hospital July nineteen ninety-five, excision 4/5.Postoperative two all tumor bodies are long has used the beta-elemene injection in this case to the preceding size of art, and employing carotid artery intubate and intravenous drip replace the method for administration, once a day, each carotid artery intubate 600ml, intravenous drip 400ml, the tumor body is very fast controlled.Through the CT check, the tumor body dwindles not obvious.Sign takes a turn for the better, band tumor existence 11 months.
The high mountain * *, woman, 65 years old, admission number 3679.Because of pulmonary carcinoma with headache, it is unstable to walk, vomiting.Be diagnosed as pulmonary carcinoma through CT and accompany multiple vertigo to move, right cerebellar neoplasm body 2.8 * 4.0 * 3.1cm, left basal ganglia region 0.5 * 1.5 * 1.6cm.Because of being lung cancer with brain metastasis, primary tumor is in pulmonary, and is older, the operation difficulty, and be admitted to hospital in mid-November, 1996, estimates to be no more than one month life cycle.Adopt the beta-elemene injection for treating after being admitted to hospital, method and dosage are the same.Sb.'s illness took a favorable turn.Headache alleviates, and vomiting disappears, and carries out the CT check mid-December, and the tumor body dwindles.In March, 1997 is because of transfers such as pulmonary carcinoma lymph node, rib, left forearm pathologisch Bruch.Patient requires to leave hospital.Life prolongs four wheat harvesting periods.
All in the treatment of tumor branch of the attached Second Academy of Dalian Medical Univ, case record is kept at this institute to above-mentioned two cases.
Claims (7)
1, a kind of is the preparation method of the cancer therapy drug of active ingredient with the beta-elemene, it is characterized in that, as the raw material that extracts beta-elemene, carries out the secondary fractional distillation with citronella oil in precision fractionation is steamed.
2, method according to claim 1 is characterized in that, the fractionated condition of carrying out of described secondary is as follows:
Vacuum is 2～5mmHg;
Temperature range is 86～93 ℃;
The fractional distillation ratio is 4: 1 or 5: 1;
10 hours response time.
3, method according to claim 1 is characterized in that, the fractionated condition of carrying out of described secondary is as follows:
Vacuum is 2mmHg;
The fractional distillation ratio is 4: 1 or 5: 1;
10 hours response time;
4, according to claim 1 or 3 described methods, it is characterized in that, the fractional distillation first time in the described secondary fractional distillation is to place described precision fractionation tower to heat fractional distillation coarse fodder, have three warm area fractions: 86～88 ℃, 89～90 ℃ and 91～93 ℃, beta-elemene mainly is in 89～90 ℃ the fraction, receives 89～90 ℃ fraction;
5, method according to claim 4, it is characterized in that, the fractional distillation second time in the described secondary fractional distillation is: get 89～90 ℃ the distillate that fractional distillation for the first time obtains and carry out fractional distillation again, in fractional distillation process, receive three kinds of warm area fractions: 86～88 ℃, 89～90 ℃ and 91～93 ℃, collect 89～90 ℃ fraction.
6, method according to claim 5 is characterized in that, with the described first time and for the second time at the bottom of 86～88 ℃ in the fractional distillation process and 91～93 ℃ of fractions and the fractionated still of secondary Residual oil recycle as coarse fodder, repeat described secondary fractional distillation.
7, method according to claim 1 is characterized in that, described precision fractionation tower is to be specifically designed to the equipment that extracts beta-elemene, the high 1.4m of rectifying column wherein, diameter 6cm, interior dress is a filler with 120 order rustless steel net volumes, 3 * 3mm hollow cylinder, number of plates N=40.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98106848A CN1084187C (en) | 1997-04-14 | 1998-04-13 | Method for preparing anti-cancer medicine using beta-elemene as main effective ingredient, and components of the medicine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97103910 | 1997-04-14 | ||
| CN97103910.0 | 1997-04-14 | ||
| CN98106848A CN1084187C (en) | 1997-04-14 | 1998-04-13 | Method for preparing anti-cancer medicine using beta-elemene as main effective ingredient, and components of the medicine |
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| CN1084187C true CN1084187C (en) | 2002-05-08 |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101306182B (en) * | 2002-04-17 | 2011-11-23 | 谢恬 | Elemene vein emulsion injection and preparation method thereof |
| CN101306183B (en) * | 2002-04-17 | 2011-06-29 | 谢恬 | Common turmeric extract fat emulsion injection and its preparation method and use |
| CN100374106C (en) * | 2002-09-18 | 2008-03-12 | 中国远大国际集团有限公司 | High nurity elemene anti-cancer medicine and its preparing method |
| JP2008505893A (en) * | 2004-07-07 | 2008-02-28 | ロング レンジ インターナショナル ユーエスエー リミテッド，インコーポレイテッド | Synthesis of Minus Beta Element, Minus Beta Elemental, Minus Beta Elementenol, Minus Beta Fluorinated Elementene and Their Analogues, Intermediates and Drugs |
| CN1981749B (en) * | 2005-12-13 | 2012-12-05 | 石药集团远大(大连)制药有限公司 | Use of beta-elemene for inhibiting cerebrovascular endothelial cell |
| CN1970054B (en) * | 2006-11-29 | 2010-05-12 | 王喜文 | Method for extracting anticancer extract from citronella oil, composition and use thereof |
| CN101810593B (en) | 2010-05-10 | 2012-07-18 | 谢恬 | Elemene sustained-release tablets |
| CN102992940B (en) * | 2012-12-19 | 2015-03-11 | 石药集团远大(大连)制药有限公司 | Method for extracting delta-elemene |
| CN110903156A (en) * | 2019-11-18 | 2020-03-24 | 贵州景诚制药有限公司 | Method for separating and purifying β -elemene, gamma-elemene and delta-elemene |
| JP2023504821A (en) * | 2019-12-03 | 2023-02-07 | 四川弘合生物科技有限公司 | Pharmaceutical composition containing elemen, method of preparation thereof, and use thereof |
-
1998
- 1998-04-13 CN CN98106848A patent/CN1084187C/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| 中国肿瘤临床，23(60) 1996.1.1 钱军等"抗癌新药-揽香烯的药理及临床" * |
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| TR01 | Transfer of patent right |
Effective date of registration: 20130620 Address after: 116000 No. 19, independence street, Zhongshan District, Liaoning, Dalian Patentee after: Dalian ambitious building Ltd. Address before: 116000 No. 19, independence street, Zhongshan District, Liaoning, Dalian Patentee before: CSPC YUANDA (DALIAN) PHARMACEUTICAL CO.,LTD. |
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| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 116000 No. 19, independence street, Zhongshan District, Liaoning, Dalian Patentee after: CSPC YUANDA (DALIAN) PHARMACEUTICAL CO.,LTD. Address before: 116000 No. 19, independence street, Zhongshan District, Liaoning, Dalian Patentee before: Dalian ambitious building Ltd. |
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| CI01 | Publication of corrected invention patent application |
Correction item: Change of the name or address of the patent holder Correct: Revocation of the alteration of the name of the patent holder False: Change of the name of the patent holder Number: 43 Volume: 31 |
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| ERR | Gazette correction | ||
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Granted publication date: 20020508 |
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| CX01 | Expiry of patent term |