CN1709236A - Fat emulsion containing docetaxel and its preparing method - Google Patents
Fat emulsion containing docetaxel and its preparing method Download PDFInfo
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- CN1709236A CN1709236A CN 200510084055 CN200510084055A CN1709236A CN 1709236 A CN1709236 A CN 1709236A CN 200510084055 CN200510084055 CN 200510084055 CN 200510084055 A CN200510084055 A CN 200510084055A CN 1709236 A CN1709236 A CN 1709236A
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Abstract
The present invention relates to an infatmul containing docetaxel and its preparation method. Said preparation can be directly used for intravenous injection. At the same time of that it is used as medicine for curing tumor disease said preparation also can provide nutrients for patient. The weight volume concentration range of docetaxel contained by said preparation is 0.1-1.0 mg/ml, and its specification is that 1-500 mg of active component docetaxel is contained. Said infatmul composition includes docetaxel, vegetable oil, phospholipids and injection water, at the same time the components of glycerin and group emulsion, etc. can be added, in which the optimum group emulsion is poloxamer 188. Besides, said invention also provides the concrete steps of its preparation method and its application in preparation of medicine for resisting tumor.
Description
Technical field
The invention belongs to medical technical field, particularly, the present invention relates generally to a kind of lipomul that contains docetaxel and preparation method thereof, the invention still further relates to the purposes of this medicine at preparation medicine for treating tumor thing.
Background technology
Docetaxel is a kind of in the bearing taxanes, has antineoplastic action, recently, by the approval of U.S. food Drug Administration to treatment for cancer.Among relevant patent CN1293570A, the CN1490048A of docetaxel, CN1281373A, US5900419, the US5880133 description is arranged.Soup causes and waits the people to discover by force, docetaxel to late period cancer such as breast carcinoma, advanced ovarian cancer have good curative effect (Tang Zhiqiang. anti-cancer agent-docetaxel. Chinese Pharmaceutical Journal, 1999,34 (2:134)).
The docetaxel molecular formula is: C
43H
53NO
14
Structural formula is as follows:
Docetaxel belongs to bearing taxanes, and its independent medication oral administration biaavailability is 8% only, be made into ejection preparation and be improve one of its bioavailability means (Zhang Xuenong etc. foreign medical science pharmacy fascicle, 200229 (6), 321-325).The dissolubility of docetaxel in water is low especially, has seriously limited its use clinically.The docetaxel ejection preparation of clinical practice at present has freeze-dried powder and small-volume injection, said preparation will dissolve with normal saline or 5% glucose injection before intravenous drip, dilution could be used, not only using method is loaded down with trivial details, and may bring danger for the medication patient because of medicine dissolution or dilution generation secondary pollution.Contain group solvents such as tween 80 and ethanol in the small-volume injection component, tween 80 easily produces untoward reaction such as haemolysis and allergy, and prevent with other drugs such as needing to give in advance patient's oral dexamethasone before wanting, clinical application is extremely inconvenient, and drug safety is not high yet.
Most of tumor disease patient need to supplement the nutrients, and lipomul can provide required energy for the patient, is one of at present the most frequently used nutritional supplementation medicine in the drug application treatment.Purpose patient use that docetaxel carries out antineoplaston and when supplementing the nutrients, need separately with lipomul, progressively injection is used, clinical practice is extremely inconvenient.
Summary of the invention
The present invention seeks to overcome the prior art deficiency, provide a kind of and can be directly used in the docetaxel infusion solution that intravenous injection is used.
The invention provides a kind of injection that curative drug docetaxel and nutritional drugs fat milk directly can be used simultaneously, be docetaxel fat emulsion.
One of main contribution of the present invention is to have solved the low prior art deficiency of docetaxel dissolubility in water.Contribution of the present invention also is creatively curative drug docetaxel and the merging of nutritional drugs fat milk to be made a kind of pharmaceutical preparation, and the patient can also replenish desired nutritional in the treatment disease.
Do not contain tween 80 in the component of docetaxel fat emulsion of the present invention, increased the safety of this medicine.
Advantages such as that the docetaxel fat emulsion by preparation technology of the present invention preparation has is safe, good stability, toxic and side effects is low, curative effect is reliable.
Docetaxel fat emulsion of the present invention comprises following component, but the present invention never only limits to described formation of this component and ratio range
Docetaxel 0.1-1kg
Injection vegetable oil 100-500kg
Injection phospholipid 10-30kg
Water for injection adds to 1000L
In the component of the invention described above docetaxel fat emulsion, vegetable oil is selected from soybean oil, Oleum Sesami, Oleum Gossypii semen, Radix Oenotherae erythrosepalae oil, perilla oil, Oleum Hippophae, safflower oil, Semen Lini oil, Semen Maydis oil, Oleum Vitis viniferae, sand sagebrush seed oil, stings in the vegetable oil such as fruit oil, Palmic acid one or more, wherein preferred soybean oil clearly.
In the component of the invention described above docetaxel fat emulsion, preferred soybean phospholipid of phospholipid or lecithin.
In the component of docetaxel fat emulsion of the present invention, can add the suitable Emulsion that helps, wherein help among the preferred poloxamer of Emulsion, Polyethylene Glycol, arabic gum, saponin and the agar one or more.
In the component of docetaxel fat emulsion of the present invention, help Emulsion optimum selection poloxamer 188.
The bulking value concentration range of docetaxel is 0.1-1.0mg/ml in the docetaxel fat emulsion of the present invention.
The preferred 0.1mg/ml of bulking value concentration, 0.2mg/ml, 0.5mg/ml, 0.8mg/ml or the 1.0mg/ml of docetaxel in the docetaxel fat emulsion of the present invention.
The bulking value concentration range of injection vegetable oil is 100-500mg/ml in the docetaxel fat emulsion of the present invention.
The preferred 100mg/ml of bulking value concentration, 150mg/ml, 200mg/ml or the 300mg/ml of injection vegetable oil in the docetaxel fat emulsion of the present invention.
The bulking value concentration range of injection phospholipid is 10-30mg/ml in the docetaxel fat emulsion of the present invention.
The preferred 12mg/ml of bulking value concentration, 15mg/ml or the 20mg/ml of injection phospholipid in the docetaxel fat emulsion of the present invention.
In the docetaxel fat emulsion component of the present invention, can also add an amount of glycerol, wherein contained glycerol bulking value concentration range is 15-27.5mg/ml.
In the docetaxel fat emulsion of the present invention, preferred 16.7mg/ml of glycerol bulking value concentration or 22mg/ml.
Docetaxel fat emulsion of the present invention, the above drug specifications of its pharmaceutics is for containing active constituent docetaxel 1-500mg.Preferably contain active constituent docetaxel 20mg, 50mg, 80mg, 100mg or 200mg.
Docetaxel fat emulsion of the present invention is made by following method:
One, gets the raw materials ready: prepare various raw materials, adjuvant and other components.
Two, dosing: following step is all carried out under the condition of nitrogen protection
1. preparation oil phase: docetaxel is joined in the injection vegetable oil, stirs,, solution temperature is heated to 60-85 ℃ to the docetaxel dissolving, be incubated standby, must solution 1., be oil phase.
2. preparation water: water for injection joined at a high speed organizes in the pulper, add injection phospholipid, stirred the companion 5-10 minute, solution temperature is heated to 60-85 ℃, be incubated standby, must solution 2., be water.
3. prepare thick emulsion: 2. aqueous phase solution is joined at a high speed organize in the pulper, 1. oil-phase solution is joined the aqueous phase that is stirring lentamente, keeping solution temperature is 60-85 ℃, stirred the companion 5-10 minute, adding water for injection to overall solution volume then is ormal weight, regulates pH value to 5-8.5 with sodium hydroxide solution, continues to stir 15 minutes, get solution 3., be thick emulsion.
4. preparation fats emulsion: use two step homogenize machines.
I. temperature is cooled to 50-70 ℃ solution 3. (thick emulsion) join in the two step homogenize machines, the first step is regulated homogenize pressure 13-18MPa, second step joint homogenize pressure 50-60Mpa, so with thick emulsion repeatedly homogenize particle diameter is qualified (measures with enumerator to breast grain, most of breast grain particle diameters should be about 0.5 μ m, and in the breast grain sum of particle diameter greater than 0.5 μ m, particle diameter must not cross 3% greater than the breast grain number of 1 μ m, and must not detect the breast grain of particle diameter greater than 5 μ m), get solution 4.;
II. regulate two steps homogenize machine homogenize pressure to 13-18MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 20-35 ℃ rapidly, must solution 5., be fats emulsion.
Three, fill: under the condition of nitrogen protection, 5. solution be filled in the infusion bottle gland.
Four, sterilization: the infusion bottle after the above-mentioned fill at 110-120 ℃ of flowing steam sterilization 15-30 minute, is promptly obtained docetaxel fat emulsion of the present invention.
Unless the 517th page of described plant equipment of version " pharmaceutics " in 1984 that specified otherwise, the high speed of the present invention's record organize pulper and two step homogenize machines to adopt Nanjing pharmaceutics teaching and research group of pharmaceutical college to write.
In above-mentioned preparation technology's dosing step, during the preparation water, can add an amount of Emulsion that helps, concrete steps are: the preparation water: water for injection is joined at a high speed organize in the pulper, add injection phospholipid, add and help Emulsion, stirred the companion 5-10 minute, solution temperature is heated to 60-85 ℃, be incubated standby, get solution 2., be water.
In above-mentioned preparation technology's dosing step, during the preparation water, can add an amount of glycerol, concrete steps are: the preparation water: organize in the pulper joining in the water for injection at a high speed, add glycerol, add injection phospholipid, stirred the companion 5-10 minute, solution temperature is heated to 60-85 ℃, be incubated standby, get solution 2., be water.
In above-mentioned preparation technology's dosing step, also injection phospholipid can be joined and be prepared into oil phase in the vegetable oil, concrete steps are as follows:
1. preparation oil phase: the injection vegetable oil joined at a high speed organize in the pulper, add docetaxel, be stirred to the docetaxel dissolving, add injection phospholipid, stir the companion, solution temperature is heated to 60-85 ℃, be incubated standbyly, get solution 1., be oil phase to dissolving.
2. preparation water: get water for injection, be heated to 60-85 ℃, be incubated standby, solution 2., be water.
All the other steps are constant.
In above-mentioned preparation technology's dosing step, when preparation water and oil phase, preferred 68 ℃ of solution temperature.
In above-mentioned preparation technology's dosing step, when preparing thick emulsion, preferred 56 ℃ of solution temperature.
In above-mentioned preparation technology's dosing step, when preparing thick emulsion, regulate back solution pH value preferred 5,6 or 7.
In above-mentioned preparation technology's dosing step, during the preparation fats emulsion, in the 1st step, two step homogenize machine homogenize pressure optimums are: low pressure 15MPa and high pressure 58MPa.
In above-mentioned preparation technology's dosing step, preparation is during fats emulsion, and in the II step, it is 25 ℃ that the solution that homogenize is gone out is cooled to optimum temperature value rapidly.
In the above-mentioned preparation docetaxel fat emulsion technology of the present invention fill step, filled with solution can be gone into vial, plastic bottle, plastic bag, the above other any packaging material of saying of ampoule and pharmaceutics.
That docetaxel fat emulsion of the present invention has is safe, good stability, drug effect advantages of higher, for the ease of understanding, carries out following blood vessel irritation test, study on the stability test and pharmacodynamics test, and result of the test will illustrate advantage of the present invention.
The preparation test products is pressed group component and is prepared raw material, adjuvant and other components.
Docetaxel 0.1kg
Injection soybean oil 15kg
Injection lecithin 1.2kg
Water for injection adds to 100L
Following step is all carried out under the nitrogen protection condition.Docetaxel is joined in the injection soybean oil, stirs,, solution temperature is heated to 68 ℃ to the docetaxel dissolving, be incubated standby, must solution 1.; Organize in the pulper at a high speed joining in the water for injection, add injection lecithin, stirred the companion 8 minutes, solution temperature is heated to 68 ℃, be incubated standby, must solution 2.; 2. solution joined high speed organizes in the pulper, with solution 1. join lentamente the solution that stirring 2. in, keeping solution temperature is 68 ℃, stirred the companion 8 minutes, adding water for injection to overall solution volume then is 100L, regulate pH value to 7 with sodium hydroxide solution, continue to stir 15 minutes, get solution 3.; Temperature is cooled to 68 ℃ solution 3. joins in the two step homogenize machines, the first step is regulated homogenize pressure 15MPa, second step joint homogenize pressure 58Mpa, so homogenize is qualified to breast grain particle diameter repeatedly with thick emulsion, solution 4.; Regulate two step homogenize machine homogenize pressure to 15MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 25 ℃ rapidly, must solution 5.; 5. solution be filled in the infusion bottle gland; Infusion bottle after the fill 115 ℃ of flowing steam sterilizations 22 minutes, is promptly obtained docetaxel fat emulsion of the present invention, leave and take said preparation and carry out following experiment.
The blood vessel irritation test is investigated:
Get 6 of body weight 2.1-2.5kg healthy rabbits, benefit people pharmaceutical factory provides by Shandong, and the male and female dual-purpose is divided into two groups, i.e. medicine group and matched group at random.Rabbit is placed in the holder, medicine group rabbit left side auricular vein instillation docetaxel fat emulsion 15ml/kg of the present invention, the matched group rabbit left side auricular vein 0.9% normal saline 15ml/kg that instils, drip velocity is 20 (1ml) min, every morning instils once, be equivalent to be grown up 3.6 times of each consumption (500ml) of 60kg, for three days on end, observe the auricular vein reaction of a rabbit left side, 24h is with the animal sacrificed by exsanguination after the last administration, take off left ear, carry out tissue slice inspection (routine paraffin wax section, dyeing, light microscopy checking is also taken pictures), the position of drawing materials is the entad end distance inserting needle position 1～4cm at inserting needle position, divide 1～2.5cm and 2.5～4cm two-stage nitration to draw materials, result of the test is, observe after reaching administration during each the instillation, local excitation reactions such as the red and swollen heat of left auricular vein, histopathological examination matched group and medication group skin are not seen in perusal, the subcutaneous tissue form is normal, the auricular vein vascular endothelial cell is arranged normal, do not see that level increases, no mural thrombus in the change of arrangement disorder, tube chamber, no cell infiltration, tube wall does not have and thickens, and does not see obvious degeneration around the tube wall, morphological change such as necrosis and inflammation.
Result of the test shows that intravenous drip docetaxel fat emulsion of the present invention has no stimulation to the rabbit auricular vein, illustrates that this product safety is good.
The study on the stability test:
Docetaxel fat emulsion room temperature of the present invention was placed 1 year, observed outward appearance, detection pH value, breast grain and free fatty, (detection method is seen two ones the 6th of Drug Standard of Ministry of Public Health of the Peoples Republic of China, 1998, and 117-119) result is as follows:
| Time (moon) | Outward appearance | The breast grain | Free fatty | PH value |
| ??0 | Qualified | Qualified | Up to specification | ??7.2 |
| ??1 | Qualified | Qualified | Up to specification | ??7.3 |
| ??2 | Qualified | Qualified | Up to specification | ??7.1 |
| ??3 | Qualified | Qualified | Up to specification | ??7.0 |
| ??6 | Qualified | Qualified | Up to specification | ??6.9 |
| ??9 | Qualified | Qualified | Up to specification | ??6.8 |
| ??12 | Qualified | Qualified | Up to specification | ??6.8 |
The study on the stability result of the test shows: docetaxel fat emulsion outward appearance of the present invention, breast grain, free fatty and pH value are all qualified, show that this product was placed to stablize in 1 year, illustrate that the present invention has advantages of higher stability.
Pharmacodynamics test:
Get 20 of the male Kunming mouses of 18-22g, be divided into test group and matched group at random, every group each 10,1.5 * 106 S180 cells of 20 right side of mice axillary fossa subcutaneous injections.Test group after planting tumor, the next day lumbar injection medicine 10mg/kg of the present invention, the normal saline of matched group injection equivalent, successive administration 8 days, the last administration was put to death animal after 24 hours, and dissected the tumor piece and weigh, and calculated tumour inhibiting rate, result such as following table:
Tumour inhibiting rate (%)=(the average tumor of the average tumor weight-test group of matched group is heavy)/average tumor of matched group heavy * 100%
Medicine of the present invention is to the inhibitory action (ip) of mice S180
| Group | Dosage (mg/kg) | Animal number of elements (beginning/end) | Average tumor weight (g, X ± SD) | Tumour inhibiting rate (%) | ? ??P |
| Matched group | ??- | ??10/10 | ??2.32±0.83 | ??- | ??- |
| Test group | ??10 | ??10/10 | ??1.13±0.76 | ??51.3 | ??＜0.01 |
Results of pharmacodynamic test shows that medicine of the present invention is inhibited to mice S180, illustrates that medicine of the present invention has the drug action of treatment tumor disease aspect.
After docetaxel is prepared into lipomul, can plays and reduce docetaxel toxicity, improve stability, promote the effect of docetaxel drug effect.Evidence docetaxel fat breast of the present invention stability is high, safety is good, is applicable to the treatment to tumor disease.
Specific embodiment
In order to understand better and to implement the present invention, the specific embodiment of the invention is explained, but the present invention never only limits to this
Embodiment 1
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.1kg
Injection soybean oil 30kg
Injection lecithin 1.2kg
Water for injection adds to 100L
Following step is all carried out under the nitrogen protection condition.The 0.1kg docetaxel is joined in the 30kg injection soybean oil, stirs,, solution temperature is heated to 68 ℃ to the docetaxel dissolving, be incubated standby, must solution 1.; Organize in the pulper at a high speed joining in the 100L water for injection, add 1.2kg injection lecithin, stirred the companion 8 minutes, solution temperature is heated to 68 ℃, be incubated standby, must solution 2.; 2. solution joined high speed organizes in the pulper, with solution 1. join lentamente the solution that stirring 2. in, keeping solution temperature is 68 ℃, stirred the companion 8 minutes, adding water for injection to overall solution volume then is 100L, regulate pH value to 7 with sodium hydroxide solution, continue to stir 15 minutes, get solution 3.; Temperature is cooled to 68 ℃ solution 3. joins in the two step homogenize machines, the first step is regulated homogenize pressure 15MPa, second step joint homogenize pressure 58Mpa, so homogenize is qualified to breast grain particle diameter repeatedly with thick emulsion, solution 4.; Regulate two step homogenize machine homogenize pressure to 15MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 25 ℃ rapidly, must solution 5.; 5. solution be filled in the infusion bottle gland; Infusion bottle after the fill 115 ℃ of flowing steam sterilizations 22 minutes, is promptly obtained docetaxel fat emulsion of the present invention.
Embodiment 2
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.01kg
Injection soybean oil 15kg
Injection lecithin 1.0kg
Water for injection adds to 100L
Other step promptly obtains docetaxel fat emulsion of the present invention with embodiment 1.
Embodiment 3
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.05kg
Injection soybean oil 20kg
Injection soybean phospholipid 2.0kg
Water for injection adds to 100L
Other step promptly obtains docetaxel fat emulsion of the present invention with embodiment 1.
Embodiment 4
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.1kg
Injection soybean oil 20kg
Injection lecithin 2.0kg
Glycerol 1.67kg
Water for injection adds to 100L
Following step is all carried out under the nitrogen protection condition.The 0.1kg docetaxel is joined in the 20kg injection soybean oil, stirs,, solution temperature is heated to 68 ℃ to the docetaxel dissolving, be incubated standby, must solution 1.; Organize in the pulper at a high speed joining in the 100L water for injection, add glycerol 1.67kg, add injection lecithin 2.0kg, stirred the companion 10 minutes, solution temperature is heated to 68 ℃, be incubated standbyly, get solution 2.; 2. solution joined high speed organizes in the pulper, with solution 1. join lentamente the solution that stirring 2. in, keeping solution temperature is 68 ℃, stirred the companion 8 minutes, adding water for injection to overall solution volume then is 100L, regulate pH value to 6 with sodium hydroxide solution, continue to stir 15 minutes, get solution 3.; Temperature is cooled to 68 ℃ solution 3. joins in the two step homogenize machines, the first step is regulated homogenize pressure 15MPa, second step joint homogenize pressure 58Mpa, so homogenize is qualified to breast grain particle diameter repeatedly with thick emulsion, solution 4.; Regulate two step homogenize machine homogenize pressure to 15MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 20 ℃ rapidly, must solution 5.; 5. solution be filled in the infusion bottle gland; Infusion bottle after the fill 110 ℃ of flowing steam sterilizations 30 minutes, is promptly obtained docetaxel fat emulsion of the present invention.
Embodiment 5
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.02kg
Injection soybean oil 20kg
Injection soybean phospholipid 2.0kg
Glycerol 2.2kg
Water for injection adds to 100L
Other step promptly obtains docetaxel fat emulsion of the present invention with embodiment 4.
Embodiment 6
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.08kg
Injection soybean oil 20kg
Injection soybean phospholipid 2.0kg
Glycerol 1.67kg
Water for injection adds to 100L
Following step is all carried out under the nitrogen protection condition.The 0.08kg docetaxel is joined in the 20kg injection soybean oil, stirs,, solution temperature is heated to 68 ℃ to the docetaxel dissolving, be incubated standby, must solution 1.; Organize in the pulper at a high speed joining in the 100L water for injection, add glycerol 1.67kg, add injection soybean phospholipid 2.0kg, stirred the companion 10 minutes, solution temperature is heated to 68 ℃, be incubated standbyly, get solution 2.; 2. solution joined high speed organizes in the pulper, with solution 1. join lentamente the solution that stirring 2. in, keeping solution temperature is 68 ℃, stirred the companion 8 minutes, adding water for injection to overall solution volume then is 100L, regulate pH value to 7 with sodium hydroxide solution, continue to stir 15 minutes, get solution 3.; Temperature is cooled to 68 ℃ solution 3. joins in the two step homogenize machines, the first step is regulated homogenize pressure 13MPa, second step joint homogenize pressure 60Mpa, so homogenize is qualified to breast grain particle diameter repeatedly with thick emulsion, solution 4.; Regulate two step homogenize machine homogenize pressure to 13MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 25 ℃ rapidly, must solution 5.; 5. solution be filled in the infusion bottle gland; Infusion bottle after the fill 115 ℃ of flowing steam sterilizations 22 minutes, is promptly obtained docetaxel fat emulsion of the present invention.
Embodiment 7
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.1kg
Injection soybean oil 30kg
Injection soybean phospholipid 2.0kg
Poloxamer 188 0.05kg
Water for injection adds to 100L
Following step is all carried out under the nitrogen protection condition.The 0.1kg docetaxel is joined in the 30kg injection soybean oil, stirs,, solution temperature is heated to 68 ℃ to the docetaxel dissolving, be incubated standby, must solution 1.; Organize in the pulper at a high speed joining in the 100L water for injection, add 0.05kg poloxamer 188, add injection soybean phospholipid 2.0kg, stirred the companion 10 minutes, solution temperature is heated to 68 ℃, be incubated standbyly, get solution 2.; 2. solution joined high speed organizes in the pulper, with solution 1. join lentamente the solution that stirring 2. in, keeping solution temperature is 68 ℃, stirred the companion 8 minutes, adding water for injection to overall solution volume then is 100L, regulate pH value to 7 with sodium hydroxide solution, continue to stir 15 minutes, get solution 3.; Temperature is cooled to 68 ℃ solution 3. joins in the two step homogenize machines, the first step is regulated homogenize pressure 13MPa, second step joint homogenize pressure 60Mpa, so homogenize is qualified to breast grain particle diameter repeatedly with thick emulsion, solution 4.; Regulate two step homogenize machine homogenize pressure to 13MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 25 ℃ rapidly, must solution 5.; 5. solution be filled in the infusion bottle gland; Infusion bottle after the fill 115 ℃ of flowing steam sterilizations 22 minutes, is promptly obtained docetaxel fat emulsion of the present invention.
Embodiment 7
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.1kg
Injection soybean oil 30kg
Injection lecithin 2.0kg
Poloxamer 188 0.1kg
Water for injection adds to 100L
Other step promptly obtains docetaxel fat emulsion of the present invention with embodiment 7.
Embodiment 8
Press group component and prepare raw material, adjuvant and other components
Docetaxel 0.1kg
Injection soybean oil 30kg
Injection lecithin 2.0kg
Poloxamer 188 0.05kg
Glycerol 2.2kg
Water for injection adds to 100L
Following step is all carried out under the nitrogen protection condition.The 0.1kg docetaxel is joined in the 30kg injection soybean oil, stirs,, solution temperature is heated to 68 ℃ to the docetaxel dissolving, be incubated standby, must solution 1.; Organize in the pulper at a high speed joining in the 100L water for injection, add glycerol 2.2kg, add 0.05kg poloxamer 188, add injection lecithin 2.0kg, stirred the companion 10 minutes, solution temperature is heated to 68 ℃, be incubated standbyly, get solution 2.; 2. solution joined high speed organizes in the pulper, with solution 1. join lentamente the solution that stirring 2. in, keeping solution temperature is 68 ℃, stirred the companion 8 minutes, adding water for injection to overall solution volume then is 100L, regulate pH value to 7 with sodium hydroxide solution, continue to stir 15 minutes, get solution 3.; Temperature is cooled to 68 ℃ solution 3. joins in the two step homogenize machines, the first step is regulated homogenize pressure 15MPa, second step joint homogenize pressure 58Mpa, so homogenize is qualified to breast grain particle diameter repeatedly with thick emulsion, solution 4.; Regulate two step homogenize machine homogenize pressure to 15MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 35 ℃ rapidly, must solution 5.; 5. solution be filled in the infusion bottle gland; Infusion bottle after the fill 115 ℃ of flowing steam sterilizations 22 minutes, is promptly obtained docetaxel fat emulsion of the present invention.
Claims (21)
1. a docetaxel infusion solution wherein contains the active component docetaxel.
2. a docetaxel fat emulsion wherein contains the active component docetaxel.
3. docetaxel fat emulsion according to claim 2 is characterized in that this lipomul is made up of active component docetaxel, injection vegetable oil, injection phospholipid and water for injection.
4. docetaxel fat emulsion according to claim 3 is characterized in that its injection vegetable oil that contains is selected from injection, Oleum Sesami, Oleum Gossypii semen, Radix Oenotherae erythrosepalae oil, perilla oil, Oleum Hippophae, safflower oil, Semen Lini oil, Semen Maydis oil, Oleum Vitis viniferae, sand sagebrush seed oil, stings in the vegetable oil such as fruit oil, Palmic acid one or more clearly.
5. docetaxel fat emulsion according to claim 4 is characterized in that the injection vegetable oil is the injection soybean oil, and injection phospholipid is injection soybean phospholipid or injection lecithin.
6. docetaxel fat emulsion according to claim 5 is characterized in that the bulking value concentration range of docetaxel in the described lipomul is 0.1-1.0mg/ml.
7. docetaxel fat emulsion according to claim 6, the bulking value concentration that it is characterized in that docetaxel in the described lipomul is 0.1mg/ml, 0.2mg/ml, 0.5mg/ml, 0.8mg/ml or 1.0mg/ml.
8. docetaxel fat emulsion according to claim 5 is characterized in that the bulking value concentration range of injection vegetable oil in the described lipomul is 100-500mg/ml.
9. docetaxel fat emulsion according to claim 8, the bulking value concentration that it is characterized in that injection vegetable oil in the described lipomul is 100mg/ml, 150mg/ml, 200mg/ml and 300mg/ml.
10. docetaxel fat emulsion according to claim 5 is characterized in that the bulking value concentration range of injection phospholipid in the described lipomul is 10-30mg/ml.
11. docetaxel fat emulsion according to claim 10, the bulking value concentration that it is characterized in that injection phospholipid in the described lipomul is 12mg/ml, 15mg/ml or 20mg/ml.
12. docetaxel fat emulsion according to claim 5 is characterized in that containing in the component glycerol, the glycerol bulking value concentration range that contains is 15-27.5mg/ml.
13. docetaxel fat emulsion according to claim 12 is characterized in that the glycerol bulking value concentration that contains is 16.7mg/ml or 22mg/ml.
14. docetaxel fat emulsion according to claim 5 is characterized in that containing the suitable Emulsion that helps in the component, wherein helps Emulsion to be selected among poloxamer, Polyethylene Glycol, arabic gum, saponin and the agar one or more.
15. docetaxel fat emulsion according to claim 14 is characterized in that the Emulsion that helps that is contained is poloxamer 188.
16. docetaxel fat emulsion according to claim 5 is characterized in that the above drug specifications of its pharmaceutics is for containing active constituent docetaxel 1-500mg.
17. docetaxel fat emulsion according to claim 16 is characterized in that the above drug specifications of its pharmaceutics is for containing active constituent docetaxel 20mg, 50mg, 80mg, 100mg or 200mg.
18. the preparation method of a docetaxel fat emulsion comprises the following steps:
One, gets the raw materials ready: prepare various raw materials, adjuvant and other components.
Two, dosing: following step is all carried out under the condition of nitrogen protection
1. preparation oil phase: docetaxel is joined in the injection vegetable oil, stirs,, solution temperature is heated to 60-85 ℃ to the docetaxel dissolving, be incubated standby, must solution 1., be oil phase.
2. preparation water: organize in the pulper joining in the water for injection at a high speed, add injection phospholipid, stirred the companion 5-10 minute, solution temperature is heated to 60-85 ℃, be incubated standby, must solution 2., be water.
3. prepare thick emulsion: 2. aqueous phase solution is joined at a high speed organize in the pulper, 1. oil-phase solution is joined the aqueous phase that is stirring lentamente, keeping solution temperature is 60-85 ℃, stirred the companion 5-10 minute, adding water for injection to overall solution volume then is ormal weight, regulates pH value to 5-8.5 with sodium hydroxide solution, continues to stir 15 minutes, get solution 3., be thick emulsion.
4. preparation fats emulsion: use two step homogenize machines.
I. temperature is cooled to 50-70 ℃ solution 3. (thick emulsion) join in the two step homogenize machines, the first step is regulated homogenize pressure 13-18MPa, second step joint homogenize pressure 50-60Mpa, so with thick emulsion repeatedly homogenize particle diameter is qualified (measures with enumerator to breast grain, most of breast grain particle diameters should be about 0.5 μ m, and in the breast grain sum of particle diameter greater than 0.5 μ m, particle diameter must not cross 3% greater than the breast grain number of 1 μ m, and must not detect the breast grain of particle diameter greater than 5 μ m), get solution 4.;
II. regulate two steps homogenize machine homogenize pressure to 13-18MPa, with solution 4. again homogenize once, the solution that homogenize is gone out is cooled to 20-35 ℃ rapidly, must solution 5., be fats emulsion.
Three, fill: under the condition of nitrogen protection, 5. solution be filled in the infusion bottle gland.
Four, sterilization: the infusion bottle after the above-mentioned fill at 110-120 ℃ of flowing steam sterilization 15-30 minute, is promptly obtained docetaxel fat emulsion of the present invention.
19., it is characterized in that in the dosing step that when preparation water and oil phase, solution temperature is 68 ℃ according to docetaxel fat emulsion preparation method according to claim 18; When preparing thick emulsion, solution temperature is 56 ℃, and regulating back solution pH value is 5,6 and 7.
20., it is characterized in that in the dosing step that during the preparation fats emulsion, two step homogenize machine homogenize force value are among the step I: low pressure 15MPa and high pressure 58MPa according to docetaxel fat emulsion preparation method according to claim 18; In the Step II, the solution that homogenize is gone out is cooled to 25 ℃ rapidly.
21. purposes that contains the lipomul of docetaxel at preparation treatment tumor disease medicine.
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| CN 200510084055 CN1709236A (en) | 2005-07-18 | 2005-07-18 | Fat emulsion containing docetaxel and its preparing method |
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| CN 200510084055 CN1709236A (en) | 2005-07-18 | 2005-07-18 | Fat emulsion containing docetaxel and its preparing method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857222B (en) * | 2006-06-05 | 2010-05-12 | 中国医药研究开发中心有限公司 | Submicron docetaxel emulsion for intravenous injection and its preparing process |
| CN101244053B (en) * | 2007-02-16 | 2010-12-08 | 石药集团中奇制药技术（石家庄）有限公司 | Novel dispersed system with docetaxel as main component |
| CN101330912B (en) * | 2006-02-20 | 2010-12-22 | 北京世纪博康医药科技有限公司 | Pharmaceutical composition of docetaxel, preparation method and purpose |
| CN102784105A (en) * | 2012-08-07 | 2012-11-21 | 郑州大学 | RLT polypeptide-mediated docetaxel tumor targeting submicroemulsion and preparation method thereof |
| CN111888332A (en) * | 2020-06-19 | 2020-11-06 | 杭州师范大学 | Cabazitaxel flexible emulsion and preparation method thereof |
| CN114129519A (en) * | 2021-10-18 | 2022-03-04 | 湖北一半天制药有限公司 | Docetaxel nano fat emulsion injection and preparation method thereof |
-
2005
- 2005-07-18 CN CN 200510084055 patent/CN1709236A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101330912B (en) * | 2006-02-20 | 2010-12-22 | 北京世纪博康医药科技有限公司 | Pharmaceutical composition of docetaxel, preparation method and purpose |
| CN1857222B (en) * | 2006-06-05 | 2010-05-12 | 中国医药研究开发中心有限公司 | Submicron docetaxel emulsion for intravenous injection and its preparing process |
| CN101244053B (en) * | 2007-02-16 | 2010-12-08 | 石药集团中奇制药技术（石家庄）有限公司 | Novel dispersed system with docetaxel as main component |
| CN102784105A (en) * | 2012-08-07 | 2012-11-21 | 郑州大学 | RLT polypeptide-mediated docetaxel tumor targeting submicroemulsion and preparation method thereof |
| CN111888332A (en) * | 2020-06-19 | 2020-11-06 | 杭州师范大学 | Cabazitaxel flexible emulsion and preparation method thereof |
| CN111888332B (en) * | 2020-06-19 | 2023-07-25 | 杭州师范大学 | Flexible cabazitaxel emulsion and preparation method thereof |
| CN114129519A (en) * | 2021-10-18 | 2022-03-04 | 湖北一半天制药有限公司 | Docetaxel nano fat emulsion injection and preparation method thereof |
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