CN100457096C - An elemene formulation and preparation method thereof - Google Patents
An elemene formulation and preparation method thereof Download PDFInfo
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- CN100457096C CN100457096C CNB2005101177086A CN200510117708A CN100457096C CN 100457096 C CN100457096 C CN 100457096C CN B2005101177086 A CNB2005101177086 A CN B2005101177086A CN 200510117708 A CN200510117708 A CN 200510117708A CN 100457096 C CN100457096 C CN 100457096C
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Abstract
The invention relates to an elemene preparation having antiviral and anticancer actions and process for preparation, wherein the raw materials include elemene, polyethylene glycol 400, Tween 80, ethanol, polyoxyethylene castor oil 40, and water for injection. the preparation has good stability, no irritant odor, and substantial curative effects. The preparation can be administrated through injection or oral channel.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, particularly relate to a kind of elemene formulation and preparation method thereof with antiviral, antitumaous effect.Said preparation can be by injection, oral administration.
Background technology
Elemene is the effective ingredient from zingiberaceous plant Rhizoma Curcumae Curcuma phaeocalis Valeton. or Guangxi zedoary Curcumakwangsiensis S.GLee et C.F. or warm Rhizoma Curcumae Curcuma Wenyujin Y.H.chen et C.Ling or other plant extraction, English Elemene by name, chemical name: 1-methyl isophthalic acid-vinyl-2,4 diisopropenyl cyclohexane extraction, molecular formula: C
15H
24Contain multiple isomer in the elemene, mainly contain α-elemene, beta-elemene, γ-elemene, δ-elemene, curcumene, Flos Caryophylli alkene.Extract purified method about elemene, more bibliographical information has been arranged, as among Chinese patent CN1060038 and the Chinese patent CN1200266 description being arranged all.
Elemi olefinic volatile oil is liposoluble constituent, is insoluble in water, and has the strong impulse abnormal smells from the patient.Pharmacological testing proves: elemene has the obvious suppression effect to multiple animal transplanting tumor; Animal experiment all shows with clinical trial: demonstrate the effect that significantly kills and wounds and suppress growth of tumour cell when elemene directly contacts with tumor cell.
Dalian medical science institute in 1996 and Jingang Pharmaceutical Co., Ltd., Dalian's joint research and development be used for the treatment of ascites pleural fluid tumor disease ' elemene emulsion injection ' list marketings such as (local applications).Because determined curative effect, side effect such as no bone marrow depression are applied clinically very soon.Clinical practice for many years proves: this medicine is very effective to treatment tumor of cervix, lymphoma, skin carcinoma, the carotid artery injection for curing cerebral tumor, femoral arteriography treatment hepatocarcinoma.
The production technology of Elemenum Emulsion injection is the liposome production technology, the adjuvant that uses is soybean phospholipid, cholesterol, it has as undesirable, the newborn grain granule of the targeting distribution of carrier inhomogeneous, easily layering, preparation stability are poor, storage and traffic condition special (promptly producing breakdown of emulsion below 4 ℃) etc., if be applied to the human vein injection, can produce phlebitis, pain etc., bring misery to the patient, therefore, can not be used for the intravenous injection of human body.
Calendar year 2001 Dalian medical science institute and Jingang Pharmaceutical Co., Ltd., Dalian's joint research and development be used for the treatment of esophageal carcinoma, gastric cancer ' the oral breast of elemene ' beginning list marketing, the treatment digestive tract tumor all receive good curative effect.But this Emulsion also exists, and inhomogeneous, the easy layering of breast grain granule, preparation stability are poor, storage and the special defectives such as (promptly producing breakdown of emulsion below 4 ℃) of traffic condition.
In addition, because elemi olefinic volatile oil, has special penetrating odor, domestic present employing liposome production technology can only reach 85% to the encapsulation ratio that elemene wraps up, can't effectively cover the penetrating odor of elemene, and can make elemene be free on (generation floating oil phenomenon) in the solution, cause when clinical practice, therefore the patient can't take, and has limited the clinical expansion and the application of product.
At present, do not have as yet in the prior art a kind of good stability of report, have no irritating odor can be used for intravenous elemene formulation.
Summary of the invention
Purpose of the present invention be exactly overcome poor stability that existing elemene pharmaceutical preparation exists, penetrating odor arranged, defective such as easily have side effects, adopt specific supplementary product compatibility, make elemene formulation, thereby solved the problems referred to above, a kind of good stability be provided, had no irritating odor, evident in efficacy, can be used for intravenous elemene formulation.
An object of the present invention is to provide a kind of elemene formulation.
Another object of the present invention provides the preparation method of described elemene formulation.
The objective of the invention is to be achieved through the following technical solutions:
A kind of elemene formulation, by the weight of said preparation, it comprises:
Elemene 0.5-10%,
PEG400 5-20%,
Tween 80 5-25%,
Ethanol 5-25%
Polyoxyethylene castor oil-40 10-25%,
Water for injection 30-70%.
The term elemene of the present invention meaning is meant α-elemene, beta-elemene, γ-elemene, δ-elemene and curcumene, Flos Caryophylli alkene monomer or its mixture arbitrarily.By the weight of elemene formulation of the present invention, the content of elemene is 0.5-10%, preferred 0.5-5%, more preferably 1-2%.
The PEG400 that the present invention is used, by the weight of elemene formulation of the present invention, its content is 5-20%, preferred 5-15%, more preferably 5-10%.PEG400 can play the effect of solubilising, makes preparation have fine solubility.
The Tween 80 that the present invention is used, by the weight of elemene formulation of the present invention, its content is 5-25%, preferred 5-15%, more preferably 5-10%.Tween (Tween) 80 is a chain structure, one end of chain has hydrophobic (oleophylic) group of nonpolar or low pole, the other end then has strong polar hydrophilic (oleophobic) group, add medicinal tween (Tween) 80, can reduce molecular surface tension force, play emulsifying, dispersive effect, improve the dissolving and the drug compatibility of preparation.
The polyoxyethylene castor oil-40 that the present invention is used, by the weight of elemene formulation of the present invention, its content is 10-25%, preferred 10-20%, more preferably 10-15%.Polyoxyethylene castor oil-40 is class non-ionic surface active agents, has higher H LB value (14-16), be efficient solubilizing agents, can effectively reduce surface tension, oily matter is evenly dispersed in the true solution that forms stable transparent in the water, it is dispersed in elemene the aqueous solution that forms stable transparent in the water in the present invention as solubilizing agent.
The ethanol that the present invention is used, by the weight of elemene formulation of the present invention, its content is 5-25%, preferred 5-20%, more preferably 5-15%.Alcohol at normal temperature is down liquid, has the extensive compatibility with all kinds of solvents, is good solvent, and it can fully dissolve elemene, so that be dissolved in the polyoxyethylene castor oil-40.
Water for injection of the present invention, by the weight of elemene formulation of the present invention, its content is 30-70%, preferred 40-60%, more preferably 50-60%.
A kind of elemene formulation of the present invention also can contain the pH regulator agent, such as alkali or acid, and preferred sodium hydroxide or hydrochloric acid.
The present invention adopts specific ratio to carry out compatibility by selecting adjuvants such as polyoxyethylene castor oil-40, PEG400, Tween 80 and ethanol, makes elemene that good dissolubility be arranged, and said preparation is stable, and no floating oil phenomenon has no irritating odor.In said preparation, polyoxyethylene castor oil-40 interacts with the elemene molecular energy, forms the class clathrate, makes elemene have rust inhibition, has reduced zest, has prolonged the medicine holdup time in vivo, has improved curative effect.
Elemene formulation of the present invention can obtain by following preparation method:
Take by weighing each raw material according to quantity, elemene and polyoxyethylene castor oil-40 are mixed and heated to 50-60 ℃, add PEG400 and Tween 80, be stirred well to clear and brightly fully, add ethanol again, after stirring, add and be preheated to 50-60 ℃ water for injection, high-speed stirred is used filtering with microporous membrane to clear and bright, and embedding is in ampoule, fill nitrogen, sealing by fusing, steam sterilization, promptly.
The aperture of used microporous filter membrane is 0.01-1 μ m in the preparation method of the present invention, preferred 0.22 μ m.
Preparation method of the present invention is simple, cost is low, adjuvant is easy to get, adjuvant is the adjuvant with medicinal standard of domestic and international extensive use, product quality is easy to control, the problem of the encapsulation ratio that the liposome production technology wraps up elemene and phenomenon that elemene is free on (generation floating oil) in the emulsion solution have been avoided, solve the oral breast of elemene and can't effectively cover the penetrating odor of elemene, cause that therefore the patient can't take when clinical practice, limited the clinical expansion of product and the defective of application.Preparation method of the present invention is not only applicable to elemene, and is applicable to α-elemene, beta-elemene, γ-elemene, δ-elemene and curcumene, Flos Caryophylli alkene monomer or its mixture arbitrarily.
Elemene formulation of the present invention dosage form be water preparation, can make dosage forms such as oral liquid, liquid drugs injection, transfusion, can be used to injection, oral, external, enlarged the indication scope, reduced zest, made the patient can continuous use, life-time service this product, functions such as blood phase, liver,spleen,kidney are had no effect, help clinical application.Elemene formulation of the present invention does not have specific (special) requirements for storage and traffic condition, has avoided that existing elemene emulsion exists that breast inhomogeneous, an easy layering of granule, preparation stability are poor, storage and the special unfavorable factors such as (promptly producing breakdown of emulsion below 4 ℃) of traffic condition; (hemolytic test, sensitivity test, blood vessel irritation test) proves through safety testing, can be applied to the intravenous injection of human body fully, solved the intravenous defective that the Elemenum Emulsion injection can not be used for human body.Elemene formulation of the present invention can be used for antiviral, antineoplastic treatment.
The specific embodiment
Below adopt embodiment to specify elemene formulation of the present invention and preparation method thereof.
Embodiment 1
Get elemene 10 grams that meet China " national drug standards ws-048 (x-040) 96 ", polyoxyethylene castor oil-40 200 gram is mixed and heated to 50-60 ℃, adding Polyethylene Glycol-400 100 gram, tween 80 150 grams are stirred well to clear and bright fully, add ethanol 130ml again, after stirring, add and be preheated to 50-60 ℃ water for injection 1000ml, high-speed stirred is to clear and bright, and with 0.22 μ m filtering with microporous membrane, embedding is in ampoule, fill nitrogen, sealing by fusing, steam sterilization 30 minutes, promptly.
Embodiment 2
Raw materials used with embodiment 1, take by weighing elemene 20 grams according to quantity, polyoxyethylene castor oil-40 200 gram, be mixed and heated to 50-60 ℃, adding Polyethylene Glycol-400 100 gram, tween 80 150 grams are stirred well to clear and bright fully, add ethanol 130ml again, after stirring, adding is preheated to 50-60 ℃ water for injection 1000ml, and high-speed stirred is to clear and bright, with 0.22 μ m filtering with microporous membrane, embedding is filled nitrogen in ampoule, sealing by fusing, steam sterilization 30 minutes, promptly.
Embodiment 3
Raw materials used with embodiment 1, take by weighing elemene 10 grams according to quantity, polyoxyethylene castor oil-40 250 gram, be mixed and heated to 50-60 ℃, adding Polyethylene Glycol-400 150 gram, tween 80 200 grams are stirred well to clear and bright fully, add ethanol 230ml again, after stirring, adding is preheated to 50-60 ℃ water for injection 1000ml, and high-speed stirred is to clear and bright, with 0.22 μ m filtering with microporous membrane, embedding is filled nitrogen in ampoule, sealing by fusing, steam sterilization 30 minutes, promptly.
Embodiment 4
Raw materials used with embodiment 1, take by weighing beta-elemene 50 grams that meet China " national drug standards ws-048 (x-040) 96 " according to quantity, polyoxyethylene castor oil-40 500 gram, be mixed and heated to 50-60 ℃, adding Polyethylene Glycol-400 200 gram, tween 80 300 grams are stirred well to clear and bright fully, add ethanol 300ml again, after stirring, adding is preheated to 50-60 ℃ water for injection 1000ml, and high-speed stirred is to clear and bright, with 0.22 μ m filtering with microporous membrane, embedding is filled nitrogen in ampoule, sealing by fusing, steam sterilization 30 minutes, promptly.
Embodiment 5
Raw materials used with embodiment 1, take by weighing beta-elemene 100 grams that meet China " national drug standards ws-048 (x-040) 96 " according to quantity, polyoxyethylene castor oil-40 500 gram, be mixed and heated to 50-60 ℃, adding Polyethylene Glycol-400 200 gram, tween 80 200 grams are stirred well to clear and bright fully, add ethanol 200ml again, after stirring, adding is preheated to 50-60 ℃ water for injection 1000ml, and high-speed stirred is to clear and bright, with 0.22 μ m filtering with microporous membrane, embedding is filled nitrogen in ampoule, sealing by fusing, steam sterilization 30 minutes, promptly.
Embodiment 6
Raw materials used with embodiment 1, take by weighing beta-elemene 30 grams that meet China " national drug standards ws-048 (x-040) 96 " according to quantity, polyoxyethylene castor oil-40 200 gram, be mixed and heated to 50-60 ℃, adding Polyethylene Glycol-400 100 gram, tween 80 150 grams are stirred well to clear and bright fully, add ethanol 130ml again, after stirring, adding is preheated to 50-60 ℃ water for injection 1000ml, and high-speed stirred is to clear and bright, with 0.22 μ m filtering with microporous membrane, embedding is filled nitrogen in ampoule, sealing by fusing, steam sterilization 30 minutes, promptly.
The effect of elemene formulation of the present invention below is described by experiment:
The safety testing of elemene formulation of the present invention
Elemene injection of the present invention is made into debita spissitudo with 5% glucose injection, presses the administration of clinical equivalent amount;
1. experiment purpose:
Check elemene injection intravenous drip of the present invention to have or not blood vessel irritation, allergy, hemolytic reaction, to determine whether this medicine can be used for intravenously administrable.
2. be subjected to reagent thing and reagent
Title: the embodiment of the invention 1 elemene injection
Specification: 10mL/ props up
Other reagent:
1% fresh albumen, matching while using (1ml Ovum Gallus domesticus album adds normal saline to 100ml)
Commercially available elemene injection: 10ml/ props up, Shanghai and xanthate industry Co., Ltd, lot number: 0210118;
5% glucose injection: Zhiying Pharmaceutical Factory, Shenyang, lot number: 00081003;
Prepared by the reagent thing:, to get appropriate amount of drug and add 5% glucose injection and be made into desired concn according to different tests.
Table 1, rabbit blood vessel irritation experiment dosage
3. animal subject
Mice, body weight 19～22g, male and female dual-purpose;
Cavia porcellus, body weight 250～350g, male;
Rabbit, the big ear of New Zealand is white, body weight 1.8～2.5kg, male and female dual-purpose;
Animal origin: animal housing of Shenyang Pharmaceutical University provides, the quality certification number: No. (2000) 042, distant real kinoplaszm word
4. route of administration
Intravenous injection is similar in appearance to clinical vein instillation approach
5. experimental technique and result:
5.1 blood vessel irritation experiment
Get 9 of 2.0～2.5kg rabbit, be divided into 3 groups at random, 3/group, the male and female dual-purpose.The glucose diluent of experimental group ear vein injection elemene injection of the present invention (4 → 500ml) 1ml/kg, quiet notes speed 10ml/5 minute; Another organizes same method, with the diluent of the commercially available elemene injection of speed injection isometric(al) (4 → 500ml) 1ml/kg are made positive controls; The 3rd group of same method, with fast quiet notes 5% glucose 8ml/kg, once a day, 3d altogether.Perusal injection place reaches the vascular reaction away from injection place after the last administration, and marks according to table 4 standard, and the result shows, 1) elemene injection of the present invention has slight zest to the intravascular injection position, no abnormality seen beyond the injection place 1cm must be divided into 0.67 fen, shows slight zest; 2) matched group has a routine injection site that minimal irritation is arranged, and must be divided into 0.33 fen; 3) injection place of glucose blank group has an example slightly rubescent, must be divided into 0.33 fen.Above-mentioned three kinds of medicines there is no unusually in injection part 1cm down to basal part of the ear portion, must be divided into 0 fen.
Table 4, blood vessel irritation perusal standards of grading
Criterion as a result :≤0.5 nonirritant ,≤2.5 minimal irritation ,≤4.5 moderate stimulations ,≤6.0 heavy zests
5.2 allergic experiment
Get 18 of male guinea pigs, be divided into 3 groups at random, 6 every group.Be experimental group, guinea pig intraperitoneal injection elemene injection 0.5ml/ of the present invention only, the next day once, totally three times; Positive controls is with capacity 1% fresh albumens such as method injections, and blank group is with capacity 5% glucose injections such as method injections.After the first administration 14 days every group get 3, experimental group intravenous injection elemene injection 1.0ml/ of the present invention only, intravenous injection 5% glucose injection and 1% fresh albumen 1.0ml/ be only respectively for blank group and positive controls.Observe animal after the administration immediately and have or not anaphylactic reactions such as sneeze, retch or cough, perpendicular hair, tic, dyspnea, gatism, shock or death.Observed 1 hour, and the results are shown in Table 5.Elemene injection intravenous injection of the present invention does not have irritated reaction, and allergic symptom all appears in each group of Ovum Gallus domesticus album.
The hypersensitive test of table 5. elemene injection
(-) do not have irritated reaction; (+) has anaphylaxis
5.3 external hemolytic test
The rabbit ear edge vein exploitating blood, bamboo let stirs and defibrinates, and is centrifugal with normal saline washing back, for several times until the supernatant redfree, is made into 2.0% erythrocyte suspension with normal saline by volume then and is for experiment repeatedly.
Get 7 in test tube for every group, each manages medicinal liquid and the erythrocyte suspension that adds different volumes respectively by shown in each table, and pipe 6 not dosings add normal saline and make blank, manages 7 adding distil waters and does complete haemolysis contrast.After shaking up gently, each pipe is put in 37 ℃ of water-baths and is placed, and has or not haemolysis respectively at 30 minutes, 1 hour, 2 hours and perusal in 3 hours, the record result.After last is observed,, observe to have or not and precipitate and agglutination phenomenon, the results are shown in Table 6～8 each test tube shake well.The elemene injection of the present invention of clinical consumption is not seen hemolytic reaction, and high concentration elemene injection 3.5mg/ml2～5 pipes all produce obvious haemolysis, are diluted to 0.875mg/ml and promptly do not produce haemolysis; The normal saline group is not seen haemolysis, and the then complete hemolysis of distilled water group produces red clear solution.
4 of table 6. elemene injections are diluted to the external hemolytic test of 100ml
Judge: the no haemolysis of (-) expression, no coagulation, no precipitation;
(±) expression has slight hemolysis, the solution layering, and the upper strata is blush;
(+) expression haemolysis, solution is not stratified, and is red transparent.
4 of table 7. elemene injections are diluted to the external hemolytic test of 250ml
Judge: the no haemolysis of (-) expression, no coagulation, no precipitation;
(+) expression haemolysis, solution is not stratified, and is red transparent;
4 of table 8. elemene injections are diluted to the external hemolytic test of 500ml
Judge: the no haemolysis of (-) expression, no coagulation, no precipitation;
(+) expression haemolysis, solution is not stratified, and is red transparent;
6. experimental result:
6.1 elemene injection Cavia porcellus hypersensitive test is the result be negative;
6.2 the administration of elemene injection clinical application concentration rabbit vein, injection place blood vessel has minimal irritation, and pathological examination also has minimal irritation, does not have obvious irritation away from injection place blood vessel;
6.3 elemene injection 0.87mg/ml, 0.28mg/ml injecting fluid do not have haemolysis outward, elemene injection 3.5mg/ml injecting fluid has obvious haemolysis outward.
Sum up: elemene injection is made into debita spissitudo with 5% glucose injection, presses the administration of clinical equivalent amount; The no obvious blood vessel irritation of rabbit vein instillation; External hemolytic test is not seen haemolysis and haemagglutination test; Cavia porcellus does not see type by the Cmax intravenous injection.Rat does not see passive cutaneous anaphylaxis, PCA.
Conclusion: elemene injection of the present invention can instil for clinical vein and try out administration.
Claims (8)
1. elemene formulation, by the weight of said preparation, it comprises:
Elemene 0.5-5%,
PEG400 5-15%,
Tween 80 5-15%,
Ethanol 5-20%
Polyoxyethylene castor oil-40 10-20%,
Water for injection 40-60%.
2. according to the elemene formulation of claim 1, by the weight of said preparation, it comprises:
Elemene 1-2%,
PEG400 5-10%,
Tween 80 5-10%,
Ethanol 5-15%,
Polyoxyethylene castor oil-40 10-15%,
Water for injection 50-60%.
3. according to the elemene formulation of claim 2, it also can contain the pH regulator agent.
4. according to the elemene formulation of claim 3, described pH regulator agent is sodium hydroxide or hydrochloric acid.
5. according to each described elemene formulation of claim 1-4, wherein said elemene is α-elemene, beta-elemene, γ-elemene, δ-elemene and curcumene, Flos Caryophylli alkene monomer or its mixture arbitrarily.
6. according to the elemene formulation of claim 5, it is oral liquid, liquid drugs injection, transfusion dosage form.
7. according to the elemene formulation of claim 6, it is used for antiviral or antitumor.
8. according to the preparation method of each described elemene formulation of claim 1-5, it may further comprise the steps: take by weighing each raw material according to quantity, elemene and polyoxyethylene castor oil-40 are mixed and heated to 50-60 ℃, add PEG400 and Tween 80, be stirred well to clear and brightly fully, add ethanol again, after stirring, adding is preheated to 50-60 ℃ water for injection, and high-speed stirred is to clear and bright, use filtering with microporous membrane, embedding is filled nitrogen in ampoule, sealing by fusing, steam sterilization, promptly.
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| CN112315901B (en) * | 2019-07-17 | 2022-10-25 | 四川弘合生物科技有限公司 | Concentrated solution for injection and preparation method thereof |
| 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 |
| CN111135143B (en) * | 2020-01-19 | 2021-12-14 | 齐鲁工业大学 | Beta-elemene self-microemulsion and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1244389A (en) * | 1998-08-12 | 2000-02-16 | 大连科宇药业科技开发有限公司 | Elemi olefine injecta and its preparation |
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| CN1244389A (en) * | 1998-08-12 | 2000-02-16 | 大连科宇药业科技开发有限公司 | Elemi olefine injecta and its preparation |
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