CN100337631C - Fluorouracil injecting emulsion and production thereof - Google Patents
Fluorouracil injecting emulsion and production thereof Download PDFInfo
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- CN100337631C CN100337631C CNB2005100203204A CN200510020320A CN100337631C CN 100337631 C CN100337631 C CN 100337631C CN B2005100203204 A CNB2005100203204 A CN B2005100203204A CN 200510020320 A CN200510020320 A CN 200510020320A CN 100337631 C CN100337631 C CN 100337631C
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Abstract
The present invention discloses a fluorouracil injection emulsion. 1000 ml of injection is prepared from the following components with the proportion by weight: 1.0 to 10.0g of fluorouracil, 50 to 300g of vegetable oil for injection, and/or 1.0 to 10.0g of polysaccharide, 5 to 20g of emulsifying agent, 20 to 60g of isoosmotic adjusting agent and water for injection which is added to reach 1000 ml. The preparation method comprises the processing steps of dissolving, heating, uniform mixture, emulsifying, cooling, filling, sterilization, etc. The present invention has the advantages of few therapeutic dose, small toxic reaction and stimulation, good therapeutic effect, high safety and reliability, and drug effect continuity, targeting, slow release and trophism. The injection emulsion can provide patients with energy, is used for treatment simultaneously and has obvious active treatment action on alimentary tract cancers, such as colon cancers, rectum cancers and stomach cancers, mammary cancers, primary liver cancers, etc.
Description
Technical field
The present invention relates to Emulsion of a kind of injection and preparation method thereof, especially relate to a kind of fluorouracil injecting emulsion that is used for the treatment of cancers such as alimentary tract cancer (as colon cancer, rectal cancer, gastric cancer), breast carcinoma, primary hepatocarcinoma and preparation method thereof.
Background technology
Fluorouracil also claims 5-fluorouracil (5-FU), by Switzerland Roche company, the exploitation of U.S. Adria company, goes on the market in Switzerland first in June, 1956.The domestic time of registration first is 1989.It is as the DNA anti-malignant-tumor agent of synthesis stage, be mainly used in digestive tract cancer and breast carcinoma, be the drug of first choice of treatment gastric cancer, also be the drug of first choice of therapeutic alliance digestive tract tumor, and ovarian cancer, cervical cancer, chorionic epithelioma, bladder cancer are also had certain curative effect.Yet this medicine side effect is big, and untoward reaction has: gastrointestinal reaction, bone marrow depression, alopecia and functional disorder etc.For avoid or alleviate its untoward reaction as far as possible, make it have targeting or slow releasing function, there are many scholars to carry out dosage form research to this medicine.(progress of domestic 5-fluorouracil dosage form is seen Chinese Pharmaceutical 2003; 12 (4): 72～73).Roughly situation is as follows for it:
1, tablet, capsule and water soluble parenteral solution thereof, its dosage are big, and (the each 0.3g of tablet, every day three times, injection concentration was 2.5% little liquid drugs injection, every 125mg and 250mg, each 0.5～0.7g, 2～3 times weekly; Transfusion is 1%:250ml, and 2.5g is generally 15mg/Kg), toxic reaction is serious.
2, assistant meter parcel, matrix tablet, millimicro ball, microemulsion, fibroin protein film, controlled release implant, pharmacosomes have carried out certain research to these, because adjuvant, process conditions etc. are immature, and equal suitability for industrialized production not.
3, emulsion, the red grade of book is an emulsifying agent with tween 80 and Span-80, has reported the development of emulsion, because tween 80 and Span-80 can not intravenously administrables, can only be oral, its dosage is bigger, has certain toxic reaction.
4, liposome (oral liquid and injection) has compound fluorouracil oral liquid and compound fluorouracil injection, during oral administration, absorbs irregularly, and bioavailability is low, and taking dose is still bigger; Though injected dose is less, more satisfactory, it contains a large amount of tween 80s, and it has certain haemolysis and changes the effect of biofilm structure, be unfavorable for the patient, and the zest of polyvidon quinoline is bigger.Therefore, up to the present, the oral and injection type of above-mentioned these routines of fluorouracil all can not be considered to be best suited for patient's desirable dosage form.
Summary of the invention
The present invention be intended to overcome above-mentioned dosage form toxic reaction and taking dose all bigger, bioavailability is low, and drug effect can not reach the big problem of zest lastingly, provides a kind of toxic reaction and zest little, effective drug duration is long, and has the fluorouracil injecting emulsion of the low dosage of persistence and targeting.This injectable emulsion can also reach the effect of supplying with patient's energy, thereby improve patient's life quality effectively when being used for the treatment of.
The present invention also provides the preparation method of this injectable emulsion simultaneously.
The present invention realizes the object of the invention by implementing following technical scheme.
A kind of fluorouracil injecting emulsion, it comprises active component fluorouracil and medicinal organic adjuvant solvent, it is characterized in that: it is to be mixed with 1000 milliliters of injection by following weight proportion:
Fluorouracil 1.0～10.0g
Injection vegetable oil 50～300g
And/or polysaccharide 1.0～10.0g
Emulsifying agent 5～20g
Isoosmotic adjusting agent 20～60g
Water for injection adds to 1000ml
The optimization formula of above-mentioned injectable emulsion is: be mixed with 1000 milliliters of injection by following weight proportion:
Fluorouracil 3.6～6.0g
Injection vegetable oil 100～200g
And/or polysaccharide 3.0～8.0g
Emulsifying agent 10～15g
Isoosmotic adjusting agent 22.5～55g
Water for injection adds to 1000ml
Also can add membrane stabilizer in the described injectable emulsion, as oleic acid or oleic oil.
Also can add antioxidant vitamin E etc. in the described injectable emulsion.
Described injection vegetable oil is selected from a kind of in soybean oil, safflower oil, Semen Maydis oil, olive oil, the Semen Sesami wet goods vegetative grease.
Described emulsifying agent is selected at least a in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cholesterol, the poloxamer (Poloxamer) etc. for use.
Described isoosmotic adjusting agent is selected a kind of in glycerol, xylitol, sorbitol, the fructose etc. for use.
Described polysaccharide is meant ginseng polysaccharide, lentinan, astragalus polysaccharides, Radix Angelicae Sinensis polysaccharide etc., and it belongs to the composition that can add or not add in the injectable emulsion of the present invention.
Described injectable emulsion is made by following three kinds of methods, and its processing step is as follows:
Method one: by above-mentioned weight proportion, fluorouracil, emulsifying agent are dissolved in the injection vegetable oil, and/or polysaccharide, isoosmotic adjusting agent are dissolved in the water for injection, be heated to 40～90 ℃ respectively, mixing, first dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets 1000ml finished product injectable emulsion.
Method two: by above-mentioned weight proportion, fluorouracil and/or polysaccharide, isoosmotic adjusting agent are dissolved in the water for injection, emulsifying agent is dissolved in the vegetable oil, be heated to 40～90 ℃ respectively, mixing, first dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets 1000ml finished product injectable emulsion.
Method three: by above-mentioned weight proportion, emulsifying agent and/or polysaccharide are dissolved in the isoosmotic adjusting agent, be heated to 40～90 ℃, earlier with tissue mashing machine after 8000～12000 rev/mins of stirrings disperse for three times, add fluorouracil and injection vegetable oil again, under same speed conditions, stir and carry out emulsifying for three times and disperse, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets 1000ml finished product injectable emulsion.
Route of administration of the present invention mainly adopts the intravenous injection mode.
The invention has the advantages that:
1, injectable emulsion of the present invention be with lipomul as carrier, and under as cooperations such as soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cholesterol, can replace the Tweens composition in its lipidosome injection fully as emulsifying agent.
2, owing to soybean oil, Flos Carthami wet goods composition as oil phase, and all nontoxic as the compositions such as phospholipid of emulsifying agent to human body, and its clinical application is for many years, and is safe and reliable, and can be the metabolism of human body institute, therefore can increase the stability of fluorouracil satisfactorily.
3, after fluorouracil is made into Emulsion, the directionality of lymph and the harmonicity of cancerous cell have been increased, so increase in the abundance of reticuloendothelial system, tumor body and brain, and prolong action time in vivo, thereby improved curative effect, reduced dosage, alleviated toxic and side effects.
4, in injectable emulsion, add polysaccharide, the effect that promotes body's immunity is not only arranged, but also the side effect that can alleviate fluorouracil.
5, owing to compositions such as injection soybean oil and/or soybean lecithin have used as fat milk transfusion, therefore injectable emulsion of the present invention is when giving to treat, can also play the dual function of supplying with patient's energy, especially very important to hepatocarcinoma patient, positive role has been played in the raising of medical effect and medical level.
6, the present invention has tangible active treatment effect to cancers such as alimentary tract cancer (as colon cancer, rectal cancer, gastric cancer), breast carcinoma, primary hepatocarcinoma.
The specific embodiment
Embodiment 1
Fluorouracil 4.0g, ginseng polysaccharide 4.0g, glycerol 22.5g are dissolved in the water for injection, refining soybean lecithin 12.0g is dissolved in the refined soybean oil, is heated to 55 ℃ respectively, mixing, earlier in tissue mashing machine's mid score emulsifying, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets fluorouracil injecting emulsion.This technology is the prescription of 1000ml, and production can enlarge, and needs nitrogen protection in the production process.
Embodiment 2
Fluorouracil 1.0g, sorbitol 25.0g are dissolved in the water for injection, and refining cholesterin 8g is dissolved in the refined maize oil, is heated to 40 ℃ respectively, mixing, earlier in tissue mashing machine's mid score emulsifying, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets fluorouracil injecting emulsion.
Embodiment 3
Fluorouracil 10.0g, astragalus polysaccharides 10.0g, xylitol 55.5g are dissolved in the water for injection, refining poloxamer 15.0g is dissolved in the refining Oleum sesami, is heated to 80 ℃ respectively, mixing, earlier in tissue mashing machine's mid score emulsifying, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets fluorouracil injecting emulsion.
Embodiment 4
With fluorouracil 3.0g, refine yolk lecithin 10.0g is dissolved in the refining safflower oil of 100g, and Radix Angelicae Sinensis polysaccharide 8.0g, fructose 20.0g are dissolved in the water for injection, be heated to 60 ℃ respectively, mixing, first dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water and cool off to 1000ml, fill, sterilization promptly gets fluorouracil injecting emulsion.
Embodiment 5
With fluorouracil 4.0g, refining soybean lecithin 15.0g is dissolved in the 100.0g refined soybean oil, and lentinan 4.5g, glucose 50.0g are dissolved in the water for injection, be heated to 55 ℃ respectively, mixing, first dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water and cool off to 1000ml, fill, sterilization promptly gets fluorouracil injecting emulsion.
Embodiment 6
With Ovum Gallus domesticus Flavus lecithin 6.0g, be dissolved in the solution that contains xylitol 50.0g, be heated to 75 ℃, earlier with tissue mashing machine after 8000～12000 rev/mins of stirrings disperse for three times, oil solution with fluorouracil and refined soybean oil 50.0g adds again, under same speed conditions, stir and carry out emulsifying for three times and disperse, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets fluorouracil injecting emulsion.
Embodiment 7
With soybean lecithin 15.0g, lentinan 6.0g is dissolved in the solution that contains sorbitol 40.0g, be heated to 85 ℃, earlier with tissue mashing machine after 8000～12000 rev/mins of stirrings disperse for three times, oil solution with fluorouracil and refining olive oil 100.0g adds again, under same speed conditions, stir and carry out emulsifying for three times and disperse, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill, sterilization promptly gets fluorouracil injecting emulsion.
Embodiment 7 contrast tests
| The oral breast of fluorouracil | The fluorouracil lipidosome injection | Fluorouracil injecting emulsion | |
| Stability | Layering is relatively poor | Layering is relatively poor | Not stratified, stable |
| Breast grain particle diameter | Wider range, the regulation | ≤ 15um, wider range | ＜1um accounts for more than 95% |
| Targeting and slow-releasing | Do not have | Have | Have |
| The haemolysis tendency | Have | Have | Do not have |
| The zest tendency | Have | Have | Do not have |
| Trophism | Do not have | Do not have | Have |
Result of the test shows that injectable emulsion stability of the present invention is better, and breast grain particle diameter is less, stipulates tighter, safe.Owing to do not contain tween 80 and polyvidon class material, obviously reduced the toxicity and the zest of medicine.Simultaneously, injectable emulsion of the present invention also has targeting, slow-releasing and trophism.
Claims (5)
1, a kind of fluorouracil injecting emulsion, it comprises active component fluorouracil and medicinal organic adjuvant solvent, it is characterized in that: it is to be mixed with 1000 milliliters of injection by following weight proportion:
Fluorouracil 1.0～10.0g
Injection vegetable oil 50～300g
Emulsifying agent 5～20g
Isoosmotic adjusting agent 20～60g
And/or polysaccharide 1.0～10.0g
Water for injection adds to 1000ml;
Described injection vegetable oil is selected from a kind of in soybean oil, safflower oil, Semen Maydis oil, olive oil or the Oleum sesami vegetative grease;
Described emulsifying agent is selected at least a in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cholesterol, the poloxamer for use;
Described isoosmotic adjusting agent is selected a kind of in glycerol, xylitol, sorbitol or the fructose for use;
Described polysaccharide is meant ginseng polysaccharide, lentinan, astragalus polysaccharides or Radix Angelicae Sinensis polysaccharide.
2, injection emulsion according to claim 1 is characterized in that: be mixed with 1000 milliliters of injection by following weight proportion:
Fluorouracil 3.6～6.0g
Injection vegetable oil 100～200g
Emulsifying agent 10～15g
Isoosmotic adjusting agent 22.5～55g
And/or polysaccharide 3.0～8.0g
Water for injection adds to 1000ml.
3, the preparation method of a kind of fluorouracil injecting emulsion according to claim 1 and 2, it is characterized in that: processing step is as follows: by claim 1 or 2 described weight proportions, fluorouracil, emulsifying agent are dissolved in the injection vegetable oil, and/or polysaccharide, isoosmotic adjusting agent are dissolved in the water for injection, be heated to 40～90 ℃ respectively, mixing, elder generation's dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter, add the injection water to 1000ml, cooling, fill, sterilization promptly gets 1000ml finished product injectable emulsion.
4, the preparation method of a kind of fluorouracil injecting emulsion according to claim 1 and 2, it is characterized in that: processing step is as follows: by claim 1 or 2 described weight proportions, fluorouracil and/or polysaccharide, isoosmotic adjusting agent are dissolved in the water for injection, emulsifying agent is dissolved in the vegetable oil, be heated to 40～90 ℃ respectively, mixing, elder generation's dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter, add the injection water to 1000ml, cooling, fill, sterilization promptly gets 1000ml finished product injectable emulsion.
5, the preparation method of a kind of fluorouracil injecting emulsion according to claim 1 and 2, it is characterized in that: processing step is as follows: by claim 1 or 2 described weight proportions, with emulsifying agent, and/or polysaccharide is dissolved in the isoosmotic adjusting agent, be heated to 40～90 ℃, earlier with tissue mashing machine after 8000～12000 rev/mins of stirrings disperse for three times, add fluorouracil and injection vegetable oil again, under same speed conditions, stir and carry out the emulsifying dispersion for three times, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter, add the injection water to 1000ml, cooling, fill, sterilization promptly gets 1000ml finished product injectable emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100203204A CN100337631C (en) | 2005-02-03 | 2005-02-03 | Fluorouracil injecting emulsion and production thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100203204A CN100337631C (en) | 2005-02-03 | 2005-02-03 | Fluorouracil injecting emulsion and production thereof |
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| CN1679578A CN1679578A (en) | 2005-10-12 |
| CN100337631C true CN100337631C (en) | 2007-09-19 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101322687B (en) * | 2008-07-30 | 2010-06-02 | 海南灵康制药有限公司 | preparation of adenosine cyclophosphate oil emulsion for vein |
| CN101940548B (en) * | 2010-06-21 | 2011-09-28 | 湖南中和制药有限公司 | Oral fluorouracil emulsion and preparation method thereof |
| CN114272259A (en) * | 2021-06-15 | 2022-04-05 | 海南卓泰制药有限公司 | Fluorouracil injection and preparation method thereof |
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Non-Patent Citations (5)
| Title |
|---|
| 5-氟尿嘧啶复乳的制备和质量控制 肖斌等，中国药房，第10卷第6期 1999 * |
| 中药多糖的免疫调节及抗肿瘤作用 李杰等，中国兽医杂志，第11期 2004 * |
| 乳剂给药系统药物的靶向输送与释放 董泽民，中国医药工业杂志，第26卷第12期 1995 * |
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