CN101361771B - Compound paclitaxel-oleum fructus bruceae injection emulsion and preparation method thereof - Google Patents
Compound paclitaxel-oleum fructus bruceae injection emulsion and preparation method thereof Download PDFInfo
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- CN101361771B CN101361771B CN2008103048577A CN200810304857A CN101361771B CN 101361771 B CN101361771 B CN 101361771B CN 2008103048577 A CN2008103048577 A CN 2008103048577A CN 200810304857 A CN200810304857 A CN 200810304857A CN 101361771 B CN101361771 B CN 101361771B
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Abstract
The invention relates to a compound paclitaxel, namely oleum fructus bruceae emulsion for injection, and a preparation method thereof, which pertain to the field of medicine preparation, and aim at solving the technical problem of looking for a new paclitaxel emulsion for intravenous injection with large drug-loading rate, few side-effects and convenient drug administration and a preparation method thereof so as to meet the requirements of markets for the new medicine. Particularly, the new paclitaxel emulsion is prepared by the steps: after dissolving in ethanol, the paclitaxel is added with the oleum fructus bruceae to form a compound oil phase and then is prepared into the emulsion of oil-in-water type with accessories for injection, such as lecithin, water for injection and the like. In the invention, the paclitaxel is obtained by a plurality of screening experiments; the paclitaxel in the compound oil phase consisting of ethanol and the oleum fructus bruceae has very high solubility; an external water phase does not contain the paclitaxel, and therefore the emulsion of oil-in-water type prepared effectively prevents phlebitis caused by the external water phase, greatly reduces anaphylactic reaction and enhances the adaptability of patients. In addition, the preparation of the emulsion has simple prescription and does not produce sediment after being diluted; embolizing does not occur during intravenous injection, thus providing a new paclitaxel emulsion for intravenous injection in clinical treatment.
Description
Technical field
The present invention relates to a kind of compound paclitaxel-oleum fructus bruceae injection emulsion and preparation method thereof, belong to pharmaceutical field.
Background technology
Paclitaxel is to extract the diterpene-kind compound that obtains from the bark of taxaceae Chinese yew genus plants.It is a kind of novel microtubule stabilizer, has unique active anticancer, is thought the most important progress of chemotherapy of tumors over nearly 15～20 years by national cancer institute.As the second line treatment medicine of advanced ovarian cancer, get permission listing in more than 40 countries so far, and in the treatments such as vascular restenosis behind breast carcinoma, pulmonary carcinoma, leukemia, gastrointestinal cancer and the interventional therapy, shown challenging curative effect.
Though paclitaxel has good antineoplastic activity, paclitaxel is solvable in organic solvents such as methanol, ethanol and DMSO, and the dissolubility in water is less than 0.03mg/mL.The oral administration bioavailability is poor, can only pass through intravenous administration.The water-insoluble of paclitaxel brings very big difficulty for its intravenously administrable, has limited its clinical practice.Existing clinical formulation for paclitaxel commonly used is that the oil preparation (Cremophor EL) that is mixed and made at 1: 1 with polyoxyethylene castor oil and dehydrated alcohol is a paclitaxel Cremophor preparation, is diluted to administration concentration with normal saline or 5% glucose solution before the drug administration by injection.For solving this difficult problem, people add surfactant polyoxyethylene Oleum Ricini (Cremophor EL) in injection, and clinical application effect is better.But can cause multiple untoward reaction, as anaphylaxis, nephrotoxicity, neurotoxicity, cardiovascular toxicity etc.For avoiding severe anaphylactic reaction, clinically, often inject cortex alcohols (as dexamethasone) before the paclitaxel drug administration by injection in advance, diphenhydramine and bisfentidine (as cimetidine, ranitidine).But the use of these injections still can not effectively thoroughly prevent all patients' untoward reaction, still can cause behind the part patient infusion paclitaxel anaphylaxis [Kim SC.Kim DW.ShimYH.et al.In vivo evaluation of polymeric micellar paclitaxel formulation:toxicity and efficacy.J Controlled Release.2001.72 (123): 191.] taking place.
In recent years, in order to solve variety of issue such as the low and untoward reaction of the water solublity that occurs in the clinical practice, research worker is modified the paclitaxel structure or it is prepared into specific formulation, and wherein preparation is the focus and emphasis of research.At present, the new formulation research to paclitaxel comprises: microemulsion, micelle, prodrug, clathrate, liposome, microsphere, nanoparticle, magnetic vesicle, paste, gel, implant and drug releasing stent etc.These formulation for paclitaxel are having improvement in various degree aspect water solublity, stability and the bioavailability, but still do not have a kind of preparation can replace Cremophor EL fully.Therefore, be necessary further to develop the new formulation of paclitaxel.
Chinese patent application CN1634021A discloses with a kind of oil for injection and has dissolved paclitaxel and be prepared into the Emulsion that meets the intravenous injection requirement with pharmaceutic adjuvants such as suitable emulsifying agents.Wherein oil for injection is to be selected from soybean oil, fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, hot capric acid glycerol vinegar or to invite one or more mixture in the core oil.This patent directly is dissolved in paclitaxel in the vegetable oil, because taxol lower dissolubility in oil, paclitaxel should be suspended in the oil mostly, is in free state, be prepared into Emulsion after, be easy to form precipitation during clinical practice after the dilution.
Chinese patent application CN 101006997A discloses a kind of compound paclitaxel and derivative docetaxel fat emulsion, said preparation is that principal agent paclitaxel or docetaxel are wrapped in the compound oil phase of oil-in-water microsphere, and this compound oil phase adopts the bigger solubilising liposoluble constituent plant volatile oil of paclitaxel and docetaxel dissolubility or three butanoic acid glycerol are cruel or three caprylins mix with vegetable oil.
Oleum Fructus Bruceae is to extract the fatty oil that obtains from the dry mature fruit of quassia Fructus Bruceae, is the pharmacological screening index with external ascites cells Yihong staining, finds that the oleic acid in the Oleum Fructus Bruceae has very strong active anticancer.So far, do not see that compound oil phase that paclitaxel, Oleum Fructus Bruceae and ethanol forms prepares the report of injectable emulsion with injection supplementary material.
Summary of the invention
The objective of the invention is to seek that a kind of drug loading is big, side effect is little, the new paclitaxel emulsion for intravenous injection of convenient drug administration and preparation method thereof, to satisfy on the market demand to this kind new drug.
Technical scheme of the present invention: compound paclitaxel-oleum fructus bruceae injection emulsion of the present invention is dissolved in by paclitaxel and adds Oleum Fructus Bruceae behind the ethanol and form compound oil phase, again the compound recipe Emulsion that is prepared into injection supplementary material such as lecithin, waters for injection.
Wherein, paclitaxel: ethanol: Oleum Fructus Bruceae: lecithin: the weight proportion of water for injection=0.01～10: 1～20: 5～50: 1～30: 600～1000.
Preferably: paclitaxel: ethanol: Oleum Fructus Bruceae: lecithin: the weight proportion of water for injection=0.05～5: 2～10: 10～30: 5～20: 600～800.
Further preferably: paclitaxel: ethanol: Oleum Fructus Bruceae: lecithin: the weight proportion of water for injection=0.1～2: 4～12: 10～20: 5～15: 600～700.
Wherein said lecithin is soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
The preparation method of compound paclitaxel-oleum fructus bruceae injection emulsion of the present invention is:
Paclitaxel is dissolved in the ethanol, Oleum Fructus Bruceae is added in the alcoholic solution of paclitaxel, mix homogeneously forms oil phase, lecithin is scattered in obtain water in the water for injection, and water and oil phase are mixed, and stirs with the high-speed homogenization machine and gets colostrum in 5-10 minute; The Emulsion that makes is placed the high pressure dispersing emulsification machine, and under the pressure of 80～100MPa, emulsifying 3～5 times obtains the Emulsion of homogeneous.Gained Emulsion is with the filtering with microporous membrane of 0.45 μ m, after the packing in 115 ℃ of autoclavings 30 minutes.
The feature of gained compound preparation of the present invention is the oil-in-water emulsion that contains anti-cancer medicine paclitaxel and Oleum Fructus Bruceae, and this Emulsion particle diameter is less than 1000nm, and content of taxol is 0.5～10 mg/g.
The content high-performance liquid chromatogram determination of paclitaxel in the compound paclitaxel-oleum fructus bruceae injection emulsion of the present invention; Particle diameter is measured with the dynamic laser light scattering experimental instrument.
Advantage of the present invention:
Obtain paclitaxel through a large amount of screening experiment, the dissolubility of paclitaxel is very big in the compound oil phase that ethanol and Oleum Fructus Bruceae are formed, be prepared into oil-in-water emulsion, outer aqueous phase does not contain the paclitaxel composition, effectively reduce because drug-induced phlebitis, anaphylaxis reduces greatly, strengthens patient's compliance.And preparation prescription of the present invention is simple, does not produce precipitation after the dilution, and intravenous injection thromboembolism can not take place.Provide for clinical that a kind of drug loading is big, side effect is little, the new paclitaxel emulsion for intravenous injection of convenient drug administration.
The specific embodiment
Embodiment 1 oil phase screening test
The foundation of screening is paclitaxel to be dissolved in add vegetable oil or surfactant behind the ethanol, investigates the dissolubility of paclitaxel, select to the paclitaxel dissolubility preferably oil phase create conditions for successfully preparing the injection paclitaxel.
Concrete screening process is as follows:
Take by weighing 5 parts of 20mg paclitaxels, add 0.5g ethanol respectively, the supersound process dissolving; In paclitaxel solution, add each 1g of soybean oil, Oleum Fructus Bruceae, Semen Maydis oil, Oleum Gossypii semen and olive oil respectively, mix, in supersound process on the ultrasound wave after 30 minutes, centrifugal 10 minutes of 10000rpm, discard precipitation, the content of taxol high-performance liquid chromatogram determination the results are shown in table 1 in the supernatant.
Table 1
| Vegetable oil | Soybean oil | Oleum Fructus Bruceae | Semen Maydis oil | Oleum Gossypii semen | Olive oil |
| Concentration (mg/ml) | 2.7 | 13.2 | 3.4 | 5.1 | 6.3 |
Test shows, do not add various oil contents in the paclitaxel alcoholic solution after, except Oleum Fructus Bruceae, other oil all produces precipitation in various degree.Therefore, the present invention selects paclitaxel is dissolved in and adds Oleum Fructus Bruceae behind the ethanol and obtain oil phase through handling, and further prepares Emulsion.
Embodiment 2 preparations contain the compound paclitaxel-oleum fructus bruceae injection emulsion of paclitaxel 0.7mg/g
Take by weighing the 480mg paclitaxel, add 8g ethanol, after the supersound process dissolving, add 13g Oleum Fructus Bruceae, stir oil phase; The refining soybean lecithin of 10g is scattered in must water in the 300g water for injection.Above two liquid are mixed, transfer in the high-speed homogenization machine, add 350g water for injection, with 20000rpm mixings homogenizing 10 minutes, the formation colostrum.Colostrum is transferred in the high pressure dispersing emulsification machine, under the nitrogen protection 80～100MPa circulation 4 times, with the filtering with microporous membrane of Emulsion with 0.45 μ m, packing, 115 ℃ of autoclavings 30 minutes.The breast grain of this Emulsion particle diameter between 100～1000nm accounts for 94%, and the high-performance liquid chromatogram determination content of taxol is 0.68mg/g.
Embodiment 3 preparations contain the compound paclitaxel-oleum fructus bruceae injection emulsion of paclitaxel 1mg/g
Take by weighing the 800mg paclitaxel, add 10g ethanol, after the supersound process dissolving, add 10g Oleum Fructus Bruceae, stir oil phase; The refining soybean lecithin of 10g is scattered in must water in the 300g water for injection.Above two liquid are mixed, transfer in the high-speed homogenization machine, add 470g water for injection, with 20000rpm mixings homogenizing 10 minutes, the formation colostrum.Colostrum is transferred in the high pressure dispersing emulsification machine, under the nitrogen protection 80～100MPa circulation 4 times, with the filtering with microporous membrane of Emulsion with 0.45 μ m, packing, 115 ℃ of autoclavings 30 minutes.The breast grain of this Emulsion particle diameter between 100～1000nm accounts for 97%, and the high-performance liquid chromatogram determination content of taxol is 0.96mg/g.
Embodiment 4 preparations contain the compound paclitaxel-oleum fructus bruceae injection emulsion of paclitaxel 2mg/g
Take by weighing the 800mg paclitaxel, add 12g ethanol, after the supersound process dissolving, add 15g Oleum Fructus Bruceae, stir oil phase; The refining soybean lecithin of 13g is scattered in must water in the 250g water for injection.Above two liquid are mixed, transfer in the high-speed homogenization machine, add 110g water for injection, with 20000rpm mixings homogenizing 10 minutes, the formation colostrum.Colostrum is transferred in the high pressure dispersing emulsification machine, under the nitrogen protection 80～100MPa circulation 4 times, with the filtering with microporous membrane of Emulsion with 0.45 μ m, packing, 115 ℃ of autoclavings 30 minutes.The breast grain of this Emulsion particle diameter between 100～1000nm accounts for 92%, and the high-performance liquid chromatogram determination content of taxol is 1.91mg/g
Embodiment 5 preparations contain the compound paclitaxel-oleum fructus bruceae injection emulsion of paclitaxel 5mg/g
Take by weighing the 500mg paclitaxel, add 10g ethanol, after the supersound process dissolving, add 15g Oleum Fructus Bruceae, stir oil phase; The refining soybean lecithin of 10g is scattered in must water in the 65g water for injection.Above two liquid are mixed, transfer in the high-speed homogenization machine, with 20000rpm mixings homogenizing 10 minutes, the formation colostrum.Colostrum is transferred in the high pressure dispersing emulsification machine, under the nitrogen protection 80～100MPa circulation 4 times, with the filtering with microporous membrane of Emulsion with 0.45 μ m, packing, 115 ℃ of autoclavings 30 minutes.The breast grain of this Emulsion particle diameter between 100～1000nm accounts for 92%, and the high-performance liquid chromatogram determination content of taxol is 4.85mg/g).
Embodiment 6 preparations contain the compound paclitaxel-oleum fructus bruceae injection emulsion of paclitaxel 8mg/g
Take by weighing the 800mg paclitaxel, add 10g ethanol, after the supersound process dissolving, add 20g Oleum Fructus Bruceae, stir oil phase; The refining soybean lecithin of 10g is scattered in must water in the 40g water for injection.Above two liquid are mixed, transfer in the high-speed homogenization machine, with 20000rpm mixings homogenizing 10 minutes, the formation colostrum.Colostrum is transferred in the high pressure dispersing emulsification machine, under the nitrogen protection 80～100MPa circulation 4 times, with the filtering with microporous membrane of Emulsion with 0.45 μ m, packing, 115 ℃ of autoclavings 30 minutes.The breast grain of this Emulsion particle diameter between 100～1000nm accounts for 90%, and the high-performance liquid chromatogram determination content of taxol is 7.46mg/g).
The reference substance that below test example adopts is commercially available paclitaxel injection, and ChongQing LaiMei Pharmacy Co., Ltd provides, and lot number is 080402.
Test example one irritation test
1, healthy rabbits is 30, male and female half and half, and body weight 2.5 ± 0.2kg divides three groups at random, gives normal saline for first group, and second group is commercially available paclitaxel injection, and the 3rd group is the compound paclitaxel-oleum fructus bruceae injection emulsion of embodiment 3 preparations.Through the auricular vein administration, 20ml/, the 1ml/min constant speed pushes, and puts to death animal in two hours behind the medicine, gets the capable pathological section H.E. dyeing in injection site, and simple microscope is observed the injection site blood vessel down, and blood capillary is to the reaction of medicine.
2, healthy rabbits is 30, male and female half and half, and body weight 2.5 ± 0.2kg divides three groups at random, gives normal saline for first group, and second group is commercially available paclitaxel injection, and the 3rd group is the compound paclitaxel fat emulsion injection of embodiment 3 preparations.Every day, auricular vein was administered once, 20ml/ only, the 1ml/min constant speed pushes, one week of successive administration, put to death animal in 2 hours behind the 7th day medicine, it is liquid-solid fixed to get injection site 10% Fu Erduolin, paraffin embedding, H.E. dyeing, simple microscope is observed the injection site blood vessel down, and blood capillary is to the reaction of medicine.
The result shows, there are 3 routine neutrophils to adhere to and soak in compound paclitaxel fat emulsion injection 10 examples of the present invention to blood vessel wall, and have 4 routine neutrophils to adhere to and soak in commercially available paclitaxel injection 10 examples to blood vessel wall, both all have in various degree between the matter edema.There are 7 examples all to have mixed thrombus in commercially available paclitaxel injection 10 examples.Thrombosis does not appear in compound paclitaxel emulsion injection 10 examples of the present invention.The two all has inflammatory reaction around in various degree venous endothelial swelling, the capillary tube, but compound paclitaxel emulsion injection of the present invention significantly is lighter than commercially available paclitaxel injection.
Test example two acute hypersensitive tests
Get 20 of Cavia porcelluss, be divided into 2 groups at random, male and female half and half.Being subjected to the reagent thing is commercially available paclitaxel injection and by the compound paclitaxel-oleum fructus bruceae injection emulsion of embodiment 5 preparation, according to the intramuscular injection of 4mg/kg dose delivery, injection volume is 0.5ml respectively, and the next day injects, continuous 3 times, the toxic and side effects of observing Cavia porcellus behavior and appearance.
As a result, 3 grades of anaphylaxiss appear in commercially available paclitaxel injection group, as repeatedly grabbing nose, tremble, and sneeze, perpendicular hair is twitched, dyspnea, gatism appears in 2 examples, 3 death; 1 grade of symptoms of allergic appears in compound paclitaxel-oleum fructus bruceae injection emulsion of the present invention, perpendicular hair occurs, and the sneeze phenomenon does not have the phenomena of mortality.Therefore, the anaphylaxis of the more commercially available paclitaxel emulsion of compound paclitaxel-oleum fructus bruceae injection emulsion of the present invention is light.
Test antitumor test in the routine trisome
The Mice Bearing Lewis Lung Cancer tissue that will be in the growth animated period is made thin suspension, and it is subcutaneous to be inoculated in the right side of mice armpit, and about 2～2.5 * 10
6Cell/, inoculate 24 hours and divide cage, tail intravenously administrable at random.Dosage regimen is: commercially available paclitaxel injection group, press the compound paclitaxel-oleum fructus bruceae injection emulsion of embodiment 6 preparations, and the blank group was administered once totally 4 times in per two days; Put to death animal in 48 hours after the drug withdrawal, claim tumor heavy, it is heavy that average tumor is respectively organized in calculating, presses formula and obtain inhibition rate of tumor growth and carry out the T check.
Inhibition rate of tumor growth=average tumor of blank group heavily treatment is organized the average tumor weight * 100% of average tumor weight/blank, the results are shown in Table 2.
Table 2
| The sample group | Dosage ml/kg | Number of animals (only) | Heavy X ± the SD (g) of tumor | Suppression ratio % |
| Blank group | 15 | 2.6±0.25 | ||
| Commercially available paclitaxel injection group | 10 | 15 | 1.06±0.23 | 59 |
| Compound paclitaxel-oleum fructus bruceae injection emulsion | 10 | 15 | 0.55±0.18 | 79 |
The result shows: compound paclitaxel-oleum fructus bruceae injection emulsion tumour inhibiting rate of the present invention significantly is better than the paclitaxel injection group, and the animal state is good.
Claims (6)
1. compound paclitaxel-oleum fructus bruceae injection emulsion is characterized in that it is dissolved in by paclitaxel and adds Oleum Fructus Bruceae behind the ethanol and form compound oil phase, again the oil-in-water emulsion that forms with lecithin, water for injection mix homogeneously.
2. according to the described compound paclitaxel-oleum fructus bruceae injection emulsion of claim 1, it is characterized in that: content of taxol is 0.5～10mg/g in this Emulsion.
3. according to the described compound paclitaxel-oleum fructus bruceae injection emulsion of claim 1, it is characterized in that:
Paclitaxel: ethanol: Oleum Fructus Bruceae: lecithin: the weight proportion of water for injection=0.01～10: 1～20: 5～50: 1～30: 600～1000.
4. according to the described compound paclitaxel-oleum fructus bruceae injection emulsion of claim 3, it is characterized in that:
Paclitaxel: ethanol: Oleum Fructus Bruceae: lecithin: the weight proportion of water for injection=0.05～5: 2～15: 10～30: 5～20: 600～800.
5. according to the described compound paclitaxel-oleum fructus bruceae injection emulsion of claim 4, it is characterized in that:
Paclitaxel: ethanol: Oleum Fructus Bruceae: lecithin: the weight proportion of water for injection=0.1～2: 4～12: 10～20: 5～15: 600～700.
6. prepare the method for each described compound paclitaxel-oleum fructus bruceae injection emulsion of claim 3～5, it comprises the steps:
A, prepare raw material by above-mentioned weight ratio;
B, paclitaxel is dissolved in the ethanol, adds the Oleum Fructus Bruceae mix homogeneously, form oil phase;
C, lecithin is scattered in obtains water in the water for injection;
D, water and oil phase are mixed, with the high-speed homogenization machine stirred 5-10 minute colostrum; The Emulsion that makes is placed the high pressure dispersing emulsification machine, under the pressure of 80～100MPa, emulsifying 3～5 times, with the filtering with microporous membrane of 0.45 μ m, after the packing in 115 ℃ of autoclavings 30 minutes promptly.
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| CN101204390A (en) * | 2006-12-21 | 2008-06-25 | 北京京卫燕康药物研究所有限公司 | Paclitaxel mainline menstruum and application programme thereof |
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| CN100998867A (en) * | 2007-01-09 | 2007-07-18 | 重庆太极医药研究院 | Anticancer Chinese medicine compound nanometer emulsion and its preparation method |
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