WO1998046553A1 - Beta-elemene, method to prepare the same and uses thereof - Google Patents
Beta-elemene, method to prepare the same and uses thereof Download PDFInfo
- Publication number
- WO1998046553A1 WO1998046553A1 PCT/US1998/007341 US9807341W WO9846553A1 WO 1998046553 A1 WO1998046553 A1 WO 1998046553A1 US 9807341 W US9807341 W US 9807341W WO 9846553 A1 WO9846553 A1 WO 9846553A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- elemene
- beta
- composition
- producing
- fraction
- Prior art date
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
- B01D3/009—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping in combination with chemical reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C7/00—Purification; Separation; Use of additives
- C07C7/04—Purification; Separation; Use of additives by distillation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
Definitions
- Beta-elemene is a chemical compound that can be extracted from numerous plants.
- Curcuma Wenyuj in Chen et C. Ling, Curcuma aromatia, and Curcuma longa linn (all belonging to Ziniberaceae) are resources for elemene extraction in China. They grow in tropical areas around the world. In China they are found primarily in Guangdong, Sichuan Fujian, Guangxi and Zhejiang provinces. More than 50 different plants have been found to contain beta-elemene, such as Radix Inulae, Radix Ginseng, E. Wenyuj in chen et C. Ling and others.
- Beta-elemene can be extracted from the essential oil contained in plants. In China, about 40 different essences were found to contain more than 1% beta-elemene. Higher concentrations are found in the essential oil produced from Magnolia sieboldii, Citrus junos leaves and Aglaia odorata flower and particularly, G. Cymbopogon winterianus Jowitt .
- Cymbopogon winterianus Jowitt is one of the major plant resources for essential oil production in China.
- the essential oil contains 1.63-5.21% of beta-elemene and the byproduct of essence extraction i.e. crude product, contains as much as 80% beta-elemene.
- Beta-elemene has the chemical name:
- Beta-elemene is found in elemene in the various extracts, along with gamma and delta elemene, which are chemical isomers of the beta-elemene.
- the extracts contain other compounds as well and it is very difficult to isolate beta- elemene from these other compounds using routine isolation techniques .
- Elemene at various concentrations with other ingredients appears in applications as diverse as a mosquito repellent (see US Patent 5,66,781), burn treatment (see US
- Patent 5,558,914 and 5,384,125 and treatment for Herpes Simplex (see US Patent 5,385,733).
- concentration % in a sample is the volume of beta-elemene divided by the total volume of the sample, multiplied by 100.
- the beta-elemene was extracted by chromatography .
- elemene has not only the ability to manage malignant chest and abdominal ascites, but also had beneficial effects on brain tumors (neuroglioma) , liver and esophageal cancer.
- the elemene has apparent anti -cancer activity on mouse Ehrlich Ascites Carcinoma (EAC) and mouse leukemia P388, L 1210 , ARS and rat YAS etc. From the Chinese phase I, II and III clinical trials, it was proved that the elemene exhibits some control over cancerous chest and abdominal ascites and surface tumors. The total effect rate was about 69%. It should be noted that 27% of the cerebral carcinoma patients reached CR level with a combination of the elemene and local chemotherapy in the expanded clinical trials.
- the research conducted demonstrated that the beta-elemene component of elemene had significant anti -tumor characteristics and that the primary mechanism was the induction of apoptosis in the tumor cells.
- BBB brain-blood barrier
- This invention relates generally to compositions of beta- elemene and method of producing higher concentration than previously possible, produced at reasonable cost using abundant plant sources; pharmaceuticals containing beta- elemene and application of the pharmaceuticals to treat various malignant diseases.
- indications for the pharmaceutical composition of beta-elemene at the present time are mainly for malignant disorders it is an object of the invention to provide a method for applying the pharmaceutical to treat various malignancies, especially neuroglioma and solid tumors.
- beta-elemene monomer as a component of elemene with a strong anti -tumor activity
- a further object of the invention is to provide a beta- elemene composition of high concentration (96.4-97.2%).
- a composition with highly concentrated effective content and minimum impurities is required in many countries with high pharmaceutical standards which are not usually met by simple extracts since the norms apply to pure substances. Until now it has not been possible to prepare such high concentrations of beta-elemene from the plant sources.
- Another advantage of the highly concentrated bete-elemene is the reduced amount that must be dosed to be effective.
- beta-elemene is the further removal of inactive substances.
- the extensive removal of inactive accompanying substances enhances the safety of the pharmaceutical, since the simpler composition of the active component concentrate facilitates a more precise analytical determination of the main components and detection of potential impurities.
- the present invention is the use and preparation of beta- elemene that is characterized by a purity of more than 96%.
- the invention involves the preparation methods and the composition of an anti-cancer drug, especially with the preparation methods and the composition of an anti-cancer drug in which the beta-elemene is the effective ingredient.
- This invention provides a composition of 96.4-97.2% beta- elemene .
- the other ingredients are gamma-elemene 0.5 % elemenol 0.8-1.2%
- This invention provides a composition of at least 96.4% beta-elemene .
- This invention provides the above compositions having components extracted from a group of over 40 plants known to have useful levels of beta-elemene.
- This invention provides an injectable formulation containing the above compositions.
- the injectable formulation may then be administered to the subject via different routes, such as intravenous injection, intramuscular injection, intradermal injection, peritoneal injection and injection into solid tumor .
- This invention provides the above compositions that can be added into cream, ointments or presence in raw materials to prepare the same .
- This invention provides a method for obtaining a beta- elemene composition using a distillation tower to separate the crude material into fractions, the tower being specifically constructed (the precision distillation tower) to produce beta-elemene at a concentration of 96.4-97.2% and at very low cost .
- the precision distillation tower to be used is designed and manufactured specifically for this purpose.
- a tower has a height of 1.4 meters, a tower diameter of 6 cm and the tower interior is fitted with as many 3 3 mm hollow 120 mesh stainless steel cylinders as can be fit within it.
- the number of plates within the tower is 40.
- This invention utilizes at least one of the following as the source of the plant material:
- Aglaia odorata leaves Yibin geranium leaves, Kunmin geranium leaves, Litchi chenensis cinnamomifolium, dry Lauris nobilis, Citrus limona leaves, Vitis vinifera grape leaves, Clausena lansium leaves, Fortunella margarita leaves, Fortunella oborata, C. Wenyuj in Chen, and Magnolia sieboldi .
- This invention provides for a method comprising the following steps:
- Zhangzhou Aglaia odorata flower Fuzhou Aglaia odorata flower, Chunging Aglaia odorata flower, Chunging Aglaia odorata leaves, Zhangzhou Aglaia odorata leaves, Yibin geranium leaves, Kunmin geranium leaves, Litchi chenensis cinnamomifolium, dry Lauris nobilis, Citrus limona leaves, Vitis vinifera grape leaves, Clausena lansium leaves, Fortunella margarita leaves, Fortunella oborata, C. Wenyuj in Chen, and Magnolia sieboldi.
- the beta-elemene composition produced in step (D) is further concentrated by a second fractionation comprising the following additional step: (E) loading the composition comprising about 95% beta- elemene into the tower to separate into fractions; and collecting the fraction with the highest concentration of beta-elemene, thereby producing a composition of beta-elemene with a concentration of 96.4-97.2%.
- the harvest rate is about 60%.
- this invention provides for the method of obtaining beta-elemene from its plant sources comprising the steps of:
- the precision distillation tower has a height of 1.4 meters and a diameter of 6 cm.
- the tower cavity is fitted with as many hollow 3 mm X 3 mm 120 mesh stainless steel cylinders as can be fit inside.
- the number of plates within the tower is 40;
- fractionation can be repeated further, using these same steps.
- the final product from the precision distillation contains: beta-elemene 96.4-97.2% copane 1.3-1.7%
- Beta- and gamma elemene have similar structure and anti- cancer activities.
- the beta-elemene can be used in any pharmaceutically suitable carrier.
- pharmaceutically suitable carriers means any of the standard pharmaceutical carriers.
- suitable carriers are well known in the art and may include, but not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, phosphate buffered saline containing Polysorb 80, water, emulsions such as oil/water emulsion, and various type of wetting agents.
- Other carriers may also include sterile solutions, tablets, coated tablets, and capsules.
- Such carriers typically contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
- excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients.
- Such carriers may also include flavor and color additives or other ingredients.
- Compositions comprising such carriers are formulated by well known conventional methods .
- Ascites carcinoma intra-peritoneal injection of the beta-elemene has a stable therapeutic effect on EAC and S 180 ascites cancer.
- the life prolongation rates are 85-310% and 90-321% respectively.
- the life prolongation rate for hepatic ascites carcinoma is 103-224%.
- (B) Solid tumor The beta-elemene injection has some inhibition effect on S 180 solid tumor. The inhibition rate is 33-59%. The inhibition rate for hepatic solid tumor is 10-30%.
- Murine leukemia L 1210 The beta-elemene injection has obvious therapeutic effect on L 1210 leukemia. The life prolongation rate was 47-286%.
- beta-elemene has beneficial effects on the treatment of ascites carcinoma, solid tumor, neuroglioma, murine leukemia etc. with no obvious side effects observed. They further conclude that beta-elemene was suitable for development as a national (China) class I new drug for human cancerous ascites, neuroglioma and solid tumor, and for research in its use to be continued.
- Patient I (Hospitalization #3106) A 25 year old female Patient had headache, right side arm and leg weakness and hemiplegia. She was diagnosed by CT scan as having a thalamic glioblastoma . The tumor size was 3.8 x 5.3 x 4 cm. The patient was hospitalized for surgery in July 1995. 80% of the tumor was excised, but it grew back to the full size within two weeks after the operation. A beta-elemene emulsive injection was employed through 600 ml cervical artery intubation and 400 ml intravenous drip alternately once per day. The growth of the tumor was quickly controlled, but on CT scan there was no apparent reduction in tumor size. The patients symptoms improved and she survived for 11 months with the tumor.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Analytical Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Water Supply & Treatment (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU71115/98A AU7111598A (en) | 1997-04-14 | 1998-04-13 | Beta-elemene, method to prepare the same and uses thereof |
US09/402,744 US6464839B1 (en) | 1997-04-14 | 1998-04-13 | Beta-elemene, method to prepare the same and uses thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN97103910 | 1997-04-14 | ||
CN97103910.0 | 1997-04-14 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/402,744 A-371-Of-International US6464839B1 (en) | 1997-04-14 | 1998-04-13 | Beta-elemene, method to prepare the same and uses thereof |
US10/270,098 Continuation US20030216605A1 (en) | 1997-04-14 | 2002-10-11 | Beta-elemene, method to prepare the same and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998046553A1 true WO1998046553A1 (en) | 1998-10-22 |
Family
ID=5166977
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/007341 WO1998046553A1 (en) | 1997-04-14 | 1998-04-13 | Beta-elemene, method to prepare the same and uses thereof |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU7111598A (en) |
WO (1) | WO1998046553A1 (en) |
-
1998
- 1998-04-13 WO PCT/US1998/007341 patent/WO1998046553A1/en active Application Filing
- 1998-04-13 AU AU71115/98A patent/AU7111598A/en not_active Abandoned
Non-Patent Citations (4)
Title |
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ANJANEYULU V., HARI BABU B.: "TWO NEW NORLOBANE DITERPENES FROM A SOFT CORAL LOBOPHYTUM PAUCIFLORUM OF THE INDIAN OCEAN.", INDIAN JOURNAL OF CHEMISTRY, JODHPUR, IN, vol. 32B., no. 11., 1 January 1993 (1993-01-01), IN, pages 1198/1199., XP002911362 * |
AZZOUZ M. A., REINECCIUS G. A., MOSHONAS M. G.: "COMPARISON BETWEEN COLD-PRESSED AND DISTILLED LIME OILS THROUGH THE APPLICATION OF GAS CHROMATOGRAPHY AND MASS SPECTROMETRY.", JOURNAL OF FOOD SCIENCE, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 41., 1 January 1976 (1976-01-01), US, pages 324 - 328., XP002911360, ISSN: 0022-1147, DOI: 10.1111/j.1365-2621.1976.tb00610.x * |
HIROI M., ET AL.: "SESQUITERPENOIDS IN THE LEAF OIL OF CAMPHOR TREES. II. SESQUITERPENOIDS OF SAFROLE TREES AND SESQUITERPENE TREES.", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, CHEMICAL SOCIETY OF JAPAN, TOKYO., JP, vol. 40., no. 11., 1 November 1967 (1967-11-01), JP, pages 2689 - 2690., XP002911359, ISSN: 0009-2673 * |
JUSHENG H.: "ELEMENE IN THE TREATMENT OF PRIMARY BRAIN TUMORS.", INTERNATIONAL CANCER CONGRESS, XX, XX, vol. 02., 1 January 1994 (1994-01-01), XX, pages 877 - 879., XP002911361 * |
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Publication number | Publication date |
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AU7111598A (en) | 1998-11-11 |
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