CN102008434A - Compound docetaxel ester microsphere injection and preparation method thereof - Google Patents
Compound docetaxel ester microsphere injection and preparation method thereof Download PDFInfo
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- CN102008434A CN102008434A CN2009101872340A CN200910187234A CN102008434A CN 102008434 A CN102008434 A CN 102008434A CN 2009101872340 A CN2009101872340 A CN 2009101872340A CN 200910187234 A CN200910187234 A CN 200910187234A CN 102008434 A CN102008434 A CN 102008434A
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Abstract
The invention discloses a compound docetaxel ester microsphere injection and a preparation method thereof, belonging to the technical field of medicines. The compound docetaxel ester microsphere injection is characterized by being prepared from the following raw materials in weight parts: 0.5 to 5 parts of docetaxel, 30-150 parts of Brucea javanica oil, 30-150 parts of middle-chain triglyceride, 10-30 parts of lecithin, 10-60 parts of polyethylene glycol surface active agents, 20-35 parts of glycerine and 700-950 parts of sterilized water for injection. The compound docetaxel ester microsphere injection of the invention is oil in water type microsphere preparation. The docetaxel as a main drug is coated in the Brucea javanica and middle-chain triglyceride compound oil phase of the oil in water type microsphere. The microsphere has a smaller grain diameter (which is lower than 100nm), and the preparation has better stability. The compound oil phase compositions play a cooperative anticancer role, and reduce the stimulation reaction of the injection and the side reactions such as hemolysis, allergy and the like. The invention has targeting function and increases the medicine effect.
Description
Technical field
The present invention relates to a kind of compound recipe Docetaxel lipid microsphere injection and preparation method, said preparation has good antitumaous effect, belongs to field of pharmaceutical technology.
Background technology
Docetaxel is the derivant of paclitaxel, is called docetaxel again, English Docetaxel by name, chemistry { 2aR-[2a α, 4 β, 4a β, 6 β, 9 α (α R by name
*, β s
*), 11 α, 12 α, 12a α, 12b α] }-β-{ [(1,1-dimethyl ethyoxyl) carbonyl] amino }-alpha-carbonyl benzenpropanoic acid [12b-acetyl oxygen-12-benzoyl oxygen-2a, 3,4,4a, 5,6,9,10,11,12,12a, 12b-ten dihydros-4,6,11-trihydroxy-4a, 8,13,13-tetramethyl-5-oxo-7,11-methylene-1H-ring pentaene in the last of the ten Heavenly stems is [3,4] benzo [1,2-b] oxa-fourth ring-9-yl also] ester.Taxanes substance has unique antitumaous effect mechanism, by inducing and promoting tubulin polymerization, assembling and stabilize microtubules effect, stop growth of tumour cell, evident in efficacy to ovarian cancer, breast carcinoma, incidence cancer, lung cancer in non-cellule type and carcinoma of prostate.From 1993 since U.S. listing, be clinical acceptance rapidly, becoming also is antitumor drug the most salable in the worldwide in history at present.The taxanes chemical constituent is water-soluble hardly, for this reason, from the eighties, people promptly are devoted to improve its water solublity, the water-soluble prodrug for preparing paclitaxel by structure of modification, and it can be discharged under physiological condition reaching anticancer purpose, but these prodrug are not enough because of stability, fail commercialization always.So the present clinical preparation of using as Taxolx (U.S.), Anzatxg (Australia) and home-made purple element, taxol etc., is polyoxyethylene castor oil (Cemophor EL)-dehydrated alcohol (50: the 50) oil solution of paclitaxel.Cemophor EL in the prescription has good solubilization to paclitaxel, but can cause histamine release in the body, anaphylaxis takes place, and can interact with igelite transfusion device commonly used, lixiviate goes out plasticizer phthalic acid class material (DEHP) wherein, causes toxicity.So, must use glass or polyethylene transfusion device instead, obey antihistaminic in advance and strengthen monitoring, inconvenience is arranged.For this reason, seek new solubilising system or solubilization method, preparation does not contain the intravenous injection of Cemophor EL, becomes a focus in the formulation for paclitaxel research.Docetaxel curative effect and safety all are greatly improved than paclitaxel, but still are insoluble in water, and injection adopts tween 80 and ethanol hydrotropy, and the hidden danger that preparation exists is bigger, occur irritated, haemolysis easily, and clinical side reaction is bigger.
Docetaxel belongs to Cytotoxic drugs, and the human immune system is had bigger nocuity, brings a lot of clinical safety problems thus.Therefore, when improving the Docetaxel curative effect, how to protect the human immune system, increase curative effect of medication, reduce drug toxicity and become medical science pharmacy circle research focus.In the anticancer treatment clinical course of China, there were many integrative therapies to combine, the example that cancer is successfully cured in the past.The method of this treatment mainly is to adopt Cytotoxic drugs to combine with Chinese medicine, utilizes Chinese medicine to improve human immunity, and auxiliary anticancer effect reaches and improves the cancer therapy drug curative effect, and reduces the toxicity purpose.In addition, medical research now finds that some chemical constituents and natural product have the cancerous cell of raising to the effect of chemotherapy cell toxicity medicament sensitivity, can improve the anticarcinogen drug effect.Therefore, if can find with paclitaxel and Docetaxel have the Synergistic anti-cancer effect, reduce toxic medicine simultaneously, will help the application of paclitaxel and Docetaxel.
At present the ejection preparation document and the patent report of relevant taxanes medicine are more, comprising a lot of Emulsions related with this patent and liposome document, patent.The prescription and the preparation method of paclitaxel emulsion have been described as 03134714.2 1 kinds of new paclitaxel used for intravenous injection preparations of Chinese patent, but this technology has been used surfactants such as Oleum Ricini, tween, owing to adopted Oleum Ricini hydrotropy scheme, bigger toxic and side effects is arranged, simultaneously not with reduce toxicity, technology contents that potentiation is relevant.200510084055.6 1 kinds of lipomul and preparation methoies that contain Docetaxel of Chinese patent have been described the Docetaxel method of preparing emulsion, this patent directly is dissolved in Docetaxel in the oil phase in its method of preparing emulsion, learn from technology in the past, Docetaxel listed oil in patent, as soybean oil, Oleum Sesami, dissolubility is less in the Semen Gossypii wet goods, only dissolve 0.1mg/mL or the like as soybean oil, therefore, medicine in the oil may be in precipitation state from Emulsion, to constitute security implication to clinical application, in addition, this patent does not relate to other active component shared to improve drug effect, reduce toxic technology contents.World patent WO2005065676 and WO2005065677, promptly name is called and contains dissolving or dispersion Docetaxel lipomul patent, the preparation method that is dissolved in the lipomul of paclitaxel in the oil and Docetaxel with dissolving or dispersity has been described, this patent disclosure be partially soluble in and be dispersed in Docetaxel in the oil, under the emulsifying agent effect, and then be prepared into the technology of lipomul, employed oil is soybean oil, Oleum Sesami, Semen Gossypii wet goods, also there are the problems referred to above in this patent, does not also relate to the technology contents with the common medication of other active component simultaneously.
Pei Kan has reported that employing tributyrin and tricaprylin are as oil phase among document Journal of Controlled Release 58 (1999) 271-278, under the effect of emulsifying agent phospholipid and tween 80, preparation paclitaxel lipomul, concentration can reach 0.75mg/mL and obtain effect preferably, but this Technology Need adds the surfactant tween 80, may therefore produce irritated, haemolysis, the document does not relate to the technology contents with the common medication of other active component yet, provided paclitaxel only molten 0.18mg/ml in soybean oil in the document, in the data of the molten 0.23mg/ml of Oleum Gossypii semen.Chinese patent 200410068134.3 1 kinds of paclitaxel used for intravenous injection Emulsion and preparation method have been described the preparation method of paclitaxel emulsion, this patent directly is dissolved in paclitaxel in the vegetable oil, because paclitaxel is lower than dissolubility in oil, paclitaxel should be suspended in the oil mostly, and after being prepared into Emulsion, medicine is very easily separated out after the clinical dilution, has drug safety hidden danger, and this patent does not relate to the technology of drug combination equally.It is oil phase that Chinese patent 200810304857.7 compound paclitaxels and Oleum Fructus Bruceae adopt Fel Anas domestica seed oil and ethanol, contains organic solvent, and certain toxicity is arranged.Chinese patent 200610045752.5 has been described compound paclitaxel and derivant Docetaxel lipomul and preparation method, this patent is by meeting the oil phase method, improved the dissolubility of paclitaxel at oil phase, and emphasized that anticancer Oleum Fructus Bruceae improves immunity, the effect of efficacy enhancing and toxicity reducing, but Emulsion belongs to the submicron emulsion scope, and particle diameter is in the 150-1000nm scope.Above-mentioned employing lipomul method all unavoidably adopts the final sterilization mode of pressure sterilizing, because Docetaxel drug degradation behind pressure sterilizing is serious, formulation content descends, so these technology much all exist principal agent Docetaxel or the unsettled shortcoming of its preparation.
Summary of the invention
Technical problem to be solved by this invention provides a kind of compound recipe Docetaxel lipid microsphere injection, it can reach the following effect of small particle diameter 100nm, physical stability is better, medicine carrying is difficult for leaking, can filtration sterilization, solved because pressure sterilizing causes the problem that preparation of Chinese medicine content descends.
The inventor is in aforementioned patent 200610045752.5, describe compound paclitaxel and derivant Docetaxel lipomul and preparation technology in detail, paclitaxel or Docetaxel with the synergism of Fructus Bruceae wet goods plants for anticancer oil under, anticancer effect has obtained reinforcement, simultaneously, compound oil mutual-assistance paclitaxel and Docetaxel dissolubility be improved, and wherein narrated Oleum Fructus Bruceae and formed effect behind the compound oil phase with soybean oil.The present invention continues to form compound recipe with Docetaxel and anticancer Oleum Fructus Bruceae on aforementioned patent 752 bases, but oil phase is compound with the same midchain oil of Oleum Fructus Bruceae (being called for short MCT), and emulsifying agent is with lecithin and Polyethylene Glycol-12-hydroxy stearic acid ester (solutol HS
15, be called for short HS
15) or polyethylene glycol 1000 vitamin E succinic acid ester (be called for short TPGS) compound, can reach the following effect of small particle diameter 100nm, physical stability is better, the antileakaging advantage of medicine carrying, can filtration sterilization, solved because pressure sterilizing causes the problem that preparation of Chinese medicine content descends.
The present invention discovers, anticancer Oleum Fructus Bruceae such as Oleum Fructus Bruceae are mainly based on the long-chain fat pinolenic acid, with midchain oil MCT composite after, not only having increased Docetaxel dissolubility in oil phase has promptly improved drug loading but also because a large amount of oleic existence have improved the physical stability of preparation greatly, the safety of clinical practice has further been improved.After lecithin and Polyethylene Glycol-12-hydroxy stearic acid ester or polyethylene glycol 1000 vitamin E succinic acid ester (being called for short TPGS) are composite, can improve the current potential of preparation, reduce particle diameter to 100nm, reach the effect (thermodynamic stable system) of nano-emulsion.More main is because the polyethylene glycols surfactant is the introducing of Polyethylene Glycol-12-hydroxy stearic acid ester or polyethylene glycol 1000 vitamin E succinic acid ester (being called for short TPGS), avoid medicine in blood, to be eliminated fast, can further strengthen the targeting effect of medicine.Clinicing aspect, compound recipe Emulsion Oleum Fructus Bruceae has the Synergistic anti-cancer effect with Docetaxel.
In order to solve the problems of the technologies described above, the present invention is achieved through the following technical solutions.
Compound recipe Docetaxel lipid microsphere injection, it is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: lecithin: polyethylene glycols surfactant: glycerol: sterilized water for injection=0.5～5: 30～150: 30～150: 10～30: 10～60: 20～35: 700～950.
Described compound recipe Docetaxel lipid microsphere injection is to be prepared from Docetaxel by the preferred weight portion rate by following raw material: Oleum Fructus Bruceae: midchain oil: lecithin: polyethylene glycols surfactant: glycerol: sterilized water for injection=1.0～2.0: 50～100: 50～100: 15～20: 15～20: 20～30: 700～950.
Described lecithin is soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
Described midchain oil is middle carbochain triglyceride.
Described polyethylene glycols surfactant is Polyethylene Glycol-12-hydroxy stearic acid ester (solutolHS
15, be called for short HS
15) or polyethylene glycol 1000 vitamin E succinic acid ester (being called for short TPGS) or their mixture
The preparation method of described compound recipe Docetaxel lipid microsphere injection is got Oleum Fructus Bruceae, midchain oil, polyethylene glycols surfactant, lecithin respectively by above-mentioned weight ratio and is made misciblely, forms compound oil phase; Get Docetaxel by above-mentioned weight ratio and be added in the above-mentioned compound oil phase heating for dissolving; Get glycerol and 55-65 ℃ of sterilized water for injection by above-mentioned weight ratio, to the glycerol that above-mentioned compound oil is added to sterilized water for injection and gets by above-mentioned weight ratio, high speed shear homogenizing 2～5 minutes forms colostrum; Then, use high pressure homogenizer, under the pressure of 20～100MPa, logical N
2Protection; through 4～6 circulations, form the lipoid microsphere of homogeneous, the lipoid microsphere for preparing at first uses the microporous filter membrane pressure filtration of 0.35-0.55 μ m; re-use the filtering with microporous membrane degerming of 0.22 μ m, 100 ℃ of auxiliary sterilizations 20-40 minute of flowing steam after the packing.
The content assaying method of paclitaxel lipomul of the present invention mainly adopts high performance liquid chromatography, method is that to get compound recipe Docetaxel lipid microsphere injection an amount of, the dehydrated alcohol breakdown of emulsion and be settled to an amount of concentration after as need testing solution, sample introduction 10 μ l, chromatographic condition: C18 post, mobile phase acetonitrile: methanol: water=26: 45: 29 (volume ratio), detect wavelength 232nm, external standard method is calculated content.
Docetaxel lipoid microsphere particle size determination method of the present invention is got this product 0.1ml, adds purified water (being 0.22 μ ml membrane filtration with the aperture in advance) and is diluted to 5000 times, and mixing as test liquid, adopts Ma Erwen Nano-ZS 90 particle size analyzers to measure.
Advantage of the present invention and effect are as follows:
Docetaxel is insoluble in water, clinical parenterai administration difficulty, at this situation, the invention provides a kind of technology that Docetaxel is written into lipoid microsphere, this technology adopts midchain oil and Oleum Fructus Bruceae to be re-dubbed oil phase, lecithin and polyethylene glycols surfactant are formed emulsifying agent, can reach the effect of nanoscale lipoid microsphere, the polymeric microspheres stabilize raising.Change interior distribution of body of Docetaxel, the circulation time of principal agent in blood increased, improved the drug distribution in the target tissue, utilize anticancer Oleum Fructus Bruceae to increase cancerous cell, improve anticancer effect, adopt paclitaxel and the bigger midchain oil of Docetaxel dissolubility are mixed with anticancer Oleum Fructus Bruceae Docetaxel sensitivity, form compound oil phase, the dissolubility of medicine is improved, increase the drug loading of preparation, be more convenient for clinical practice.After oil phase and the water preparation, under natural lecithin and emulsifying agent Polyethylene Glycol-12-hydroxy stearic acid ester or polyethylene glycol 1000 vitamin E succinic acid ester combined effect, use glycerol or other isoosmotic adjusting agent (sugar alcohols) to regulate osmotic pressure, can prepare the fat micro sphere preparation of formation particle diameter below 100nm.Docetaxel is dissolved in the oil phase of oil-in-water lipoid microsphere, aqueous phase does not contain Docetaxel and other anticancer oil-phase components, avoided the preparation envelop rate to descend after the clinical dilution and caused medicine to be separated out, further improved technology stability, this is different from technology in the past.The microsphere Chinese medicine can slowly release medicine from oil phase, have slow release and targeting.Said preparation does not contain poisonous hydrotropy composition, and as tween 80, Semen Ricini wet goods, side reactions such as haemolysis, allergy and blood vessel irritation will alleviate; Simultaneously, because outer aqueous phase does not contain the Docetaxel composition, will effectively reduce owing to drug-induced phlebitis, probability hypersensitive strengthens patient's compliance.In addition, lipoid microsphere reduces the generation of whole body side reaction because the targeting effect can reduce the drug level of outer target area, has improved patient's life quality.
Preparation method of the present invention does not adopt violent autoclaving, makes filtration sterilization become possibility, has avoided Docetaxel because of the medicament contg that pressure sterilizing causes descends, and improves Docetaxel preparation technology's stability.
Compound oil of the present invention is except having dissolving paclitaxel and the effect of derivant Docetaxel, have concurrently and improve immunity, living Pseudobulbus Bletillae (Rhizoma Bletillae) antitumaous effect, can the inverse cancer cell drug resistance, thereby has a potentiation, form compound preparation with principal agent, bring into play antitumaous effect jointly, compare with independent medication, when having improved anticancer therapeutic, reduced the toxicity of taxanes medicine.
Table 1. Docetaxel is dissolubility in different oil phases
Docetaxel has higher dissolubility in this patent oil phase as can be seen from the above table, thereby guarantees that drug ingredient does not leak.
Table 2. the present invention and aforementioned patent 200610045752.5 microspherulite diameters are relatively
Description of drawings
The distribution of Fig. 1 Docetaxel (DOC) in different tissues
The specific embodiment
Below description by the specific embodiment the present invention is described in further detail, but this is not to be limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within the scope of the present invention.
Embodiment 1:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: egg yolk lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: glycerol: sterilized water for injection=0.5: 30: 30: 10: 10: 20: 700.
Polyethylene Glycol-12-hydroxy stearic acid ester of 10g refine yolk lecithin (German Lipoid company) and 10g is distributed in the compound oil phase of 30g injection stage Oleum Fructus Bruceae and 30g midchain oil composition, taking by weighing Docetaxel 0.5g by above-mentioned weight ratio precision joins in the above-mentioned oil phase, make dissolving, add 700g about 55-65 ℃ sterilized water for injection and 20g glycerol, with 20000rpm, homogenizing 5 minutes forms colostrum, colostrum is joined in the high pressure homogenizer (Italian Niro-Soavi) logical N
2Protection, initial pressure is 20～30MPa, circulates 2 minutes, rises to 80～100Mpa then, circulates 6 times, forms the lipoid microsphere of homogeneous, emits homogenized milk; In hundred grades of cleaning shops, employing microporous filter membrane equipment is crossed 0.35-0.55 μ m filter membrane, crosses 0.22 μ m filter membrane degerming, packing, and the auxiliary sterilization in 30 minutes of 100 ℃ of flowing steams had both got product of the present invention.After testing, contain Docetaxel 0.45mg/mL, mean diameter 85nm.Wherein courage oil is the seed oil of plant Fructus Bruceae.
Embodiment 2:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: soybean lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: glycerol: sterilized water for injection=5: 150: 150: 30: 60: 35: 950.
Polyethylene Glycol-12-hydroxy stearic acid ester of the refining soybean lecithin of 30g (German Lipoid company) and 60g is distributed to takes by weighing Docetaxel 5g by above-mentioned weight ratio precision in the compound oil phase of 150g injection stage Oleum Fructus Bruceae and 150g midchain oil composition and join in the above-mentioned oil phase, make dissolving, add about 60 ℃ of sterilizeds water for injection of 950g and 35g glycerol, with 20000rpm, homogenizing 2-4 minute, form colostrum, colostrum is joined in the high pressure homogenizer (Italian Niro-Soavi), logical N
2Protection, initial pressure is 30～40MPa, circulates 2 minutes, rises to 60～90Mpa then, circulates 4 or 5 times, forms the lipoid microsphere of homogeneous, emits homogenized milk; In hundred grades of cleaning shops, employing microporous filter membrane equipment is crossed 0.45 μ m filter membrane, crosses 0.22 μ m filter membrane degerming, packing, and the auxiliary sterilization in 40 minutes of 100 ℃ of flowing steams had both got product of the present invention.
Through liquid chromatogram measuring, contain Docetaxel 3.8mg/mL, mean diameter 80nm.
Embodiment 3:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: polyethylene glycol 1000 vitamin E succinic acid ester: glycerol: sterilized water for injection=2: 50: 50: 15: 7: 8: 20: 800.
Its preparation method is as follows:
With 15g lecithin (German lipoid company) and the Polyethylene Glycol-12-hydroxy stearic acid ester of 7g and the polyethylene glycol 1000 vitamin E succinic acid ester of 8g: be distributed to and take by weighing Docetaxel 2g by above-mentioned weight ratio precision in the compound oil phase of 50g injection stage Oleum Fructus Bruceae and 50 midchain oils composition and join in the above-mentioned oil phase, make dissolving, add about 60 ℃ of sterilizeds water for injection of 800g and 20g glycerol, with 20000rpm, homogenizing 2-4 minute, form colostrum, colostrum is joined in the high pressure homogenizer (Italian Niro-Soavi) logical N
2Protection, initial pressure is 30～40MPa, circulates 2 minutes, rises to 60～90Mpa then, circulates 4 or 5 times, forms the lipoid microsphere of homogeneous, emits homogenized milk; In hundred grades of cleaning shops, employing microporous filter membrane equipment is crossed 0.45 μ m filter membrane, crosses 0.22 μ m filter membrane degerming, packing, and the auxiliary sterilization in 40 minutes of 100 ℃ of flowing steams had both got product of the present invention.
Through liquid chromatogram measuring, contain Docetaxel 2mg/mL, particle diameter 100nm breast grain is greater than 90%.
Embodiment 4:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: Ovum Gallus domesticus Flavus lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: glycerol: sterilized water for injection=1: 50: 50: 15: 15: 25: 900.
Its preparation method is with embodiment 1.
Through liquid chromatogram measuring, contain paclitaxel 0.7mg/mL, particle diameter 67nm breast grain is greater than 90%.
Embodiment 5:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: soybean lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: polyethylene glycol 1000 vitamin E succinic acid ester: glycerol: sterilized water for injection=2: 100: 100: 20: 5: 15: 25: 700.
Its preparation method is with embodiment 1.
Through liquid chromatogram measuring, contain Docetaxel 1.9mg/ml, particle diameter 92nm breast grain is greater than 90%.
Embodiment 6:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: Ovum Gallus domesticus Flavus lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: glycerol: sterilized water for injection=2: 50: 50: 15: 15: 25: 800.
Its preparation method is with embodiment 1.
Through liquid chromatogram measuring, contain Docetaxel 2.0mg/mL, particle diameter 105nm breast grain is greater than 90%.
Embodiment 7:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: soybean lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: glycerol: sterilized water for injection=2: 75: 75: 15: 15: 25: 900.
Its preparation method is with embodiment 1.Through liquid chromatogram measuring, contain Docetaxel 1.47mg/mL, particle diameter 60nm breast grain is greater than 90%.
Embodiment 8:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: Ovum Gallus domesticus Flavus lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: glycerol: sterilized water for injection=3: 60: 60: 20: 20: 27: 900.
Its preparation method is with embodiment 1.Through liquid chromatogram measuring, contain Docetaxel 2.47mg/mL, particle diameter 40nm breast grain is greater than 90%.
Embodiment 9:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: Ovum Gallus domesticus Flavus lecithin: polyethylene glycol 1000 vitamin E succinic acid ester: glycerol: sterilized water for injection=3: 50: 50: 20: 15: 27: 900.
Its preparation method is with embodiment 1.Through liquid chromatogram measuring, contain Docetaxel 2.6mg/mL, mean diameter is 96nm.
Embodiment 10:
Compound recipe Docetaxel lipid microsphere injection of the present invention is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: Ovum Gallus domesticus Flavus lecithin: Polyethylene Glycol-12-hydroxy stearic acid ester: polyethylene glycol 1000 vitamin E succinic acid ester: glycerol: sterilized water for injection=2: 70: 70: 20: 15: 15: 27: 900.
Its preparation method is with embodiment 1.Through liquid chromatogram measuring, contain Docetaxel 1.7mg/mL, particle diameter 60nm breast grain is greater than 90%.
Embodiment 11:
Compound recipe Docetaxel lipoid microsphere is to murine sarcoma S
180The growth inhibited effect
Get 50 of the Kunming kind white mice of body weight 18g～22g, every group 10, be respectively blank group (control) and give normal saline, Docetaxel injection group (S-DOC), Docetaxel lipoid microsphere group (E-DOC) (making), Docetaxel fat milk group (patent 752 by embodiment 3 methods, E-752), positive control drug cyclophosphamide Injection (S-CL) group, route of administration is tail vein injection.Get 8-10 days sarcoma S of aseptic absorption inoculation
180The mouse ascites that goes down to posterity is diluted to 5 * 10 with normal saline
6The tumor cell suspension of/mL, every mice right fore axillary fossa subcutaneous vaccination 0.2mL.Each treated animal gives the corresponding dosage medicine respectively in inoculation back 1,3,5d.Observe spirit, the activity situation of mice every day.Mice is respectively organized in execution in the 14th day, weighs, and strips the tumor piece and claims tumor heavy, calculates tumor control rate.
Tumour inhibiting rate I (%)=(the average tumor of the average tumor weight/matched group of 1-administration group is heavy) * 100%
Table 3. compound recipe Docetaxel lipoid microsphere is to mice transplantability S
180The shadow of sarcoma growth
*P＜0.05，
**P＜0.01
Each administration group is to murine sarcoma S
180Growth the obvious suppression effect is all arranged, but the tumor control rate of Emulsion and lipoid microsphere group is significantly higher than the injection group, relatively Emulsion and lipoid microsphere group separately, the latter's effect is better than the former.
Embodiment 12:
Compound recipe Docetaxel fat micro sphere preparation irritation test by the embodiment of the invention 4 preparations:
1, hank 24 of year healthy rabbit, the male and female dual-purpose, body weight 2.0～2.5kg, random packet is given normal saline for first group, and second group is commercially available Docetaxel injection, and the 3rd group is compound recipe Docetaxel fat micro sphere preparation.Through the auricular vein administration, 20mL/, 1mL/ branch constant speed pushes, and two hours after administration is put to death animal, gets the injection site, and 10% formalin solution is fixed, paraffin embedding, and H.E. dyeing, simple microscope is observed the injection site blood vessel down, and blood capillary is to the reaction of medicine.
2, hank 24 of year rabbit, the male and female dual-purpose, body weight 2.0～2.5kg, random packet, first group is normal saline, and second group is commercially available Docetaxel injection, and the 3rd group is compound recipe Docetaxel fat micro sphere preparation.Be administered once through auricular vein every day, 20mL/ only, 1mL/ branch constant speed pushes, one week of successive administration, 2 hours execution animals after the administration in the 7th day, get the injection site, 10% formalin solution is fixed, paraffin embedding, H.E. dyeing, simple microscope is observed the injection site blood vessel, and blood capillary is to the reaction of medicine.
The result, there is 1 routine neutrophil to adhere to and soak in compound recipe Docetaxel fat micro sphere preparation 8 examples to blood vessel wall, and have 4 routine neutrophils to adhere to and soak in commercially available Docetaxel injection 8 examples to blood vessel wall, both all have in various degree between the matter edema.
There are 5 examples all to have mixed thrombus in commercially available Docetaxel injection 8 examples.Has only the slight hyaline thrombus of 1 example in compound recipe Docetaxel fat micro sphere preparation 8 examples.The two all has inflammatory reaction around in various degree venous endothelial swelling, the capillary tube, but compound recipe Docetaxel fat micro sphere preparation significantly is lighter than commercially available Docetaxel injection.
Embodiment 13:
Pharmacokinetics and tissue distribution experiment
Get 99 of healthy Kunming mouses, be divided into 3 groups (n=3) at random; The commercially available injection solution group of DOC-(DOC-S), by 752 patent workings example Emulsion group (DOC-E1, mean diameter 200nm), the compound recipe Docetaxel lipoid microsphere that this patent lipoid microsphere E2 group (DOC-E2, mean diameter 92nm) (by embodiment of the invention 5) is equipped with).Mice is overnight fasting before experiment, all by 50mg/kg, and respectively at after the administration 0,1min, 5min, 15min, 30min, 1h, 1.5h, 2h, 8,12,24h eye socket vein is got the about 0.5mL of blood and is placed the 1.5mL centrifuge tube that scribbles heparin, centrifuging and taking blood plasma, protein precipitation extracts medicine, with acetonitrile-methanol-water is mobile phase, and liquid phase method detects the blood plasma Chinese medicine, and external standard method is calculated drug level.
Adopt pharmacokinetics software (DAS2.0, chief editors such as Sun Ruiyuan), utilize non-compartment model to calculate pharmacokinetic parameters.
The pharmacokinetic parameter (n=3) of table 4. injection and different-grain diameter Emulsion blood plasma Chinese medicine behind tail vein injection
By pharmacokinetic parameter as can be known, compare with solution-type, the half-life of Emulsion group and lipoid microsphere group all increases to some extent, but the lipoid microsphere group is more obvious, the AUC data show that particle diameter reduces (100nm is following) and helps slowing down the removing of medicine in blood, has increased the circulation time of medicine in blood, so the MRT and the V maximum of lipoid microsphere group, and the CL minimum.
The tissue distribution experiment
The same pharmacokinetics of dosage regimen, eye socket is put to death mice after getting blood, takes out the heart, liver, spleen, lung, kidney, brain is cleaned with normal saline, and filter paper blots, and-20 ℃ of the backs of weighing are freezing, treat homogenate.Handle tissue, protein precipitation extracts medicine, and liquid phase method detection of drugs peak area calculates the in-house drug level of each time point according to standard curve, and further is converted to contained medication amount in every gram tissue, the results are shown in Figure 1.
By the tissue distribution result as can be known, the Emulsion group has changed the medicine distribution of each tissue in vivo.Compare with solution, behind the mouse mainline Emulsion, medicine is liver, spleen, distribution in the lung obviously increases, at the heart, distributing in the kidney reduces, but the distribution of lipoid microsphere group in lung obviously increases, illustrate that particle diameter reduces, the clearance rate of medicine reduces, and has prolonged the circulation time of medicine in blood, has therefore also increased the distribution in target organ (lung).
Claims (5)
1. compound recipe Docetaxel lipid microsphere injection, it is characterized in that it is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: lecithin: polyethylene glycols surfactant: glycerol: sterilized water for injection=0.5～5: 30～150: 30～150: 10～30: 10～60: 20～35: 700～950.
2. compound recipe Docetaxel lipid microsphere injection according to claim 1, it is characterized in that it is to count ratio by following raw materials in parts by weight to be prepared from Docetaxel: Oleum Fructus Bruceae: midchain oil: lecithin: polyethylene glycols surfactant: glycerol: sterilized water for injection=1.0～2.0: 50～100: 50～100: 15～20: 15～20: 20～30: 700～950.
3. compound recipe Docetaxel lipid microsphere injection according to claim 1 and 2 is characterized in that described lecithin is soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
4. compound recipe Docetaxel lipid microsphere injection according to claim 1 and 2 is characterized in that described polyethylene glycols surfactant is Polyethylene Glycol-12-hydroxy stearic acid ester (solutolHS
15, be called for short HS
15) or polyethylene glycol 1000 vitamin E succinic acid ester (being called for short TPGS), perhaps their mixture.
5. the preparation method of the described compound recipe Docetaxel of claim 1 lipid microsphere injection is characterized in that getting Oleum Fructus Bruceae, midchain oil, polyethylene glycols surfactant, lecithin respectively by above-mentioned weight ratio makes misciblely, forms compound oil phase; Get Docetaxel by above-mentioned weight ratio and be added in the above-mentioned compound oil phase heating for dissolving; Get glycerol and 55-65 ℃ of sterilized water for injection by above-mentioned weight ratio, to the glycerol that above-mentioned compound oil is added to sterilized water for injection and gets by above-mentioned weight ratio, high speed shear homogenizing 2～5 minutes forms colostrum; Then, use high pressure homogenizer, under the pressure of 20～100MPa, logical N
2Protection; through 4～6 circulations, form the lipoid microsphere of homogeneous, the lipoid microsphere for preparing at first uses the microporous filter membrane pressure filtration of 0.35-0.55 μ m; re-use the filtering with microporous membrane degerming of 0.22 μ m, 100 ℃ of auxiliary sterilizations 20-40 minute of flowing steam after the packing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104606135A (en) * | 2015-01-22 | 2015-05-13 | 李宏 | Docetaxel-containing composition and preparation method thereof |
| WO2016177346A1 (en) * | 2015-05-06 | 2016-11-10 | 江苏天士力帝益药业有限公司 | Cabazitaxel fat emulsion injection, and preparation method and use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101006997B (en) * | 2006-01-26 | 2011-07-20 | 董英杰 | Compound taxol and its derivative docetaxel fat emulsion and preparation method |
| CN101011355B (en) * | 2006-02-01 | 2013-01-02 | 陈献 | Vitamin e succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104606135A (en) * | 2015-01-22 | 2015-05-13 | 李宏 | Docetaxel-containing composition and preparation method thereof |
| WO2016177346A1 (en) * | 2015-05-06 | 2016-11-10 | 江苏天士力帝益药业有限公司 | Cabazitaxel fat emulsion injection, and preparation method and use thereof |
| CN107530281A (en) * | 2015-05-06 | 2018-01-02 | 江苏天士力帝益药业有限公司 | A kind of Cabazitaxel Fat Emulsion Injection and its production and use |
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