CN104274406B - A kind of injection tacrolimus fat emulsion and preparation method thereof - Google Patents
A kind of injection tacrolimus fat emulsion and preparation method thereof Download PDFInfo
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- CN104274406B CN104274406B CN201410571019.1A CN201410571019A CN104274406B CN 104274406 B CN104274406 B CN 104274406B CN 201410571019 A CN201410571019 A CN 201410571019A CN 104274406 B CN104274406 B CN 104274406B
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Abstract
The invention discloses a kind of injection tacrolimus fat emulsion, contain tacrolimus, injection oil-based solvent, surfactant, amphipathic nature block polymer, injection osmotic pressure regulator, antioxidant, stabilizer.In addition, the invention also discloses the preparation method of the fat emulsion.The present invention can be effectively increased the chemical stability of medicine, and in tacrolimus fat emulsion, most of drug distribution is in oil phase or oil-water interfaces, it is to avoid medicine and water directly contact；Medicament solubilization isolates medicine in oil phase, and the medication amount of water phase is few, greatly reduces the amount of drug hydrolysis, and the stability to medicine improves a lot.During drug moiety is wrapped in oil phase or interfacial film by injection tacrolimus fat emulsion system of the invention, it is to avoid the directly contact with body fluid, therefore reduce the issuable part of medicine itself and blood vessel irritation.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of injection tacrolimus fat emulsion and its preparation side
Method.
Background technology
Organ transplant is referred to as one of much progress of 20th century physianthropy three.Organ transplant is treated most as organ failure
Effective means afterwards, very big in the demand of China, nowadays the whole nation has 100 multiple hospitals and the 200 multidigit experts can be wrapped
25 kinds of allogeneic organ transplants such as kidney, liver, heart, pancreas, lung, marrow and cornea are included, Organ Transplantation Patients need
Lifelong after transplanting to take immunodepressant, immunodepressant is to Organ Transplantation Patients time-to-live, the holding good work(of transplant organ
The aspects such as energy all play an important role.Therefore immunodepressant has clinical value as the exploitation of organ transplant medication.
Tacrolimus (Tacrolimus, FK506, trade name Prograf) is Japanese Teng Ze (Fujisawa) drugmaker
A kind of 23 membered macrolide for being purified from the 9993rd plant of tunning of Tsukubaensis streptomycetes first for 1984 is new
Immunodepressant.Its molecular formula is C44H69NO12, molecular weight 804.02.White crystallization or crystalline powder, are soluble at room temperature
In methyl alcohol, ethanol, acetone, ethyl acetate, chloroform and ether, be slightly soluble in hexane, petroleum ether, it is water insoluble, its fusing point be 127~
129 DEG C, optical activity is -84.4 °.
Tacrolimus in addition to antifungic action, also with very strong immunosuppressive action, the tacrolimus mechanism of action
For：Tacrolimus is combined with endogenous cell inner recipient (cytosol binding protein FKBP12), forms immunophilin complex, and this is combined
Thing is competitively specifically combined with calmodulin and is suppressed calmodulin, effectively suppresses t cell activation, suppresses interleukin 8
The generation of -2 (IL-2) of element.The effect of the tacrolimus ciclosporin A (cyclosporine A, CsA) wider than application is high nearly by 100
Times.In the case of less than 1/100 Determination of Cyclosporin, also tool suppresses the reaction of heart xenotransplantaion thing, tacrolimus energy
It is enough effectively to prevent the rejection after organ transplant, and the rejection invalid to cyclosporine can be reversed.
The pharmaceutical preparation with tacrolimus as effective active components existing in the market has parenteral solution, capsule and ointment
Three kinds.Tacrolimus paste is used for non-specific dermatitis, and tacrolimus injection agent and tacrolimus capsules agent are used to prevent liver
Or the postoperative graft rejection of kidney transplant and treatment liver or kidney transplant it is postoperative apply other immunosuppressive drugs without
The graft rejection of method control.
Clinically, because disturbing factor suffered during tacrolimus body absorption is a lot, so substantially increasing
The dissolution rate of tacrolimus, tacrolimus oral administration preparation remains sizable individual difference, causes blood concentration
Fluctuation is very big；Tacrolimus injection agent be applied to can not receive to be administered orally or need to reach in a short time blood concentration higher,
The patient of rapid-onset.Therefore, tacrolimus injection agent is still that oral formulations cannot replace on clinical treatment.
At present clinically tacrolimus injection agent frequently with non-aqueous vehicle system, i.e.,：Tacrolimus is dissolved in polyoxy second
In the mixed solvent of alkene rilanit special and absolute ethyl alcohol.Crodaret has pharmacological activity and bad anti-
Should, toxic and side effect is often brought in clinical practice.And there is the risk of medicine precipitation in dilution in injection.Tacrolimus exists
It is unstable under alkalescence condition.
In view of above-mentioned characteristic, to make tacrolimus preferably play immunosuppressive action, exploitation is a kind of without with pharmacology
The surfactant of activity and the parenteral solution of organic reagent, and keep its stability tool to be of great significance.
Intravenous injection fatty emulsion is widely used recently as the carrier of poorly water soluble drugs.Its special reason
Change characteristic and hypotoxicity determines that it can be as the good carrier of fat-soluble medicine.Compare with conventional injection liquid phase, Fat Emulsion
Agent can reduce blood vessel irritation.Drug-loaded emulsion is dissolved in fat oil by by medicine, and through phosphatide emulsion dispersion in water
It is made after phase, is a kind of microparticle dispersion system encapsulated by immobilized artificial membrane so that fat oil is soft matrix, is had as pharmaceutical carrier
The advantages of improving drug solubility and stability.
The development and production of Japanese Teng Ze drugmakers and the injection of tacrolimus listed in states such as China, Japan, the U.S., its
The surfactant of use be Cremophor RH60 (Polyoxyl60Hydrogenated Castor Oil, below
Abbreviation HCO-60), HCO-60 containing 200mg in every milliliter of injection of tacrolimus.Korean Patent No.0177158 discloses one kind
Pharmaceutical solutions, the pharmaceutical solutions contains tacrolimus or its pharmaceutically acceptable salt, including rilanit special APEO
Pharmaceutically acceptable surfactant and pharmaceutically acceptable nonaqueous solvents.Korean Patent No.0206722 discloses one
Liquid composite is planted, said composition contains tacrolimus or its pharmaceutically acceptable salt；Selected from by egg yolk lecithin, soybean ovum
The pharmaceutically acceptable emulsifying agent that phosphatide and rilanit special APEO are constituted；With selected from by soybean oil and sesame oil
The pharmaceutically acceptable oil of the liquid carbon compound for being constituted.Korean laid-open No.2001-0006070 discloses a kind of medicine
With composition, the Pharmaceutical composition contains water-insoluble drug and two or more surfactants, at least one surface-active
Agent can dissolve other water-insoluble surfactants and water-insoluble drug.
A kind of injection of tacrolimus preparation of U.S. Publication, said preparation includes tacrolimus, the poly- hydrocarbon oxygen ester of castor oil
And nonaqueous solvents (35).In pharmacy, advocate to reduce the component or its content unrelated with therapeutic action as far as possible in pharmaceutical formulation, and
Reach similar or more preferable drug quality and clinical efficacy.The increase of any component unrelated with therapeutic action or its addition
Increase all can bring safety issue to Clinical practice.Kinds of surface is used from pharmacy angle analysis, data disclosed above
The invention of activating agent combination is not optimal invention, and the efficacy and saferry of its clinical practice not yet has correlative study data,
Its security is worth discussion.
Additionally, existing liquid composite be present, medicine can produce precipitation during term stores, and
With the reduction of medicament contg, its pharmaceutical stability will decline.Therefore, traditional liquid composite is not suitable for human body note
Penetrate and use preparation.
The content of the invention
The technical problems to be solved by the invention are for above-mentioned the deficiencies in the prior art, there is provided a kind of injection he
Ke Mosi fat emulsions.The fat emulsion can be effectively increased the chemical stability of medicine, most of in tacrolimus fat emulsion
Drug distribution is in oil phase or oil-water interfaces, it is to avoid medicine and water directly contact；Medicament solubilization isolates medicine, water phase in oil phase
Medication amount it is few, greatly reduce the amount of drug hydrolysis, the stability to medicine improves a lot；Injection tacrolimus fat
During drug moiety is wrapped in oil phase or interfacial film by fat emulsion system, it is to avoid directly contact with body fluid, therefore reduce medicine
Itself issuable part and blood vessel irritation.In addition, medicine is slowly discharged by oil phase, medicine can be avoided from existing
Due to adverse reaction that initial stage excessive concentration causes during injection.
In order to solve the above technical problems, the technical solution adopted by the present invention is：A kind of injection tacrolimus fat emulsion,
Characterized in that, containing tacrolimus 0.01g~10g in per 100mL injection tacrolimus fat emulsions, injection oiliness is molten
Agent 2g~20g, surfactant 0.5g~7g, amphipathic nature block polymer 0.1g~2g, injection osmotic pressure regulator 0.5g
~7g, 0~3g of antioxidant, stabilizer 0.1g~5g；The antioxidant is water soluble antioxidants and/or oil-soluble antioxidants.
Above-mentioned a kind of injection tacrolimus fat emulsion, it is characterised in that per 100mL injections tacrolimus fat
Contain tacrolimus 0.01g~5g, injection oil-based solvent 10g~20g, surfactant 1g~3g in emulsion, it is amphipathic embedding
Section copolymer 1 g~2g, injection osmotic pressure regulator 1g~4g, antioxidant 1g~2g, stabilizer 0.5g~2g.
Above-mentioned a kind of injection tacrolimus fat emulsion, it is characterised in that per 100mL injections tacrolimus fat
Contain tacrolimus 0.2g, injection oil-based solvent 20g, surfactant 2.05g, amphipathic nature block polymer in emulsion
1.4g, injection osmotic pressure regulator 2.5g, antioxidant 1.5g, stabilizer 0.8g.
Above-mentioned a kind of injection tacrolimus fat emulsion, it is characterised in that per 100mL injections tacrolimus fat
Also contain metal-chelator 0.001g~3g in emulsion, the metal-chelator is natrium adetate and/or sodium calcium edetate.
A kind of above-mentioned injection tacrolimus fat emulsion, it is characterised in that the injection tacrolimus Fat Emulsion
Also contain pH adjusting agent in agent, the consumption of pH adjusting agent is to make the pH value of injection tacrolimus fat emulsion be 4.0~9.0,
The pH adjusting agent is NaOH or hydrochloric acid.
Above-mentioned a kind of injection tacrolimus fat emulsion, it is characterised in that the injection oil-based solvent is castor-oil plant
Oil, corn oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm
Oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil in one or more；The table
Face activating agent is one or more in lecithin, sapn, tween, pluronic, enuatrol, oleic acid and deoxycholic aicd.
Above-mentioned a kind of injection tacrolimus fat emulsion, it is characterised in that in the amphipathic nature block polymer
Hydrophilic segment is polyethylene glycol, and hydrophobic segment is PLLA, dextrorotation PLA or PDLLA.
A kind of above-mentioned injection tacrolimus fat emulsion, it is characterised in that the viscosity average molecular weigh of the hydrophilic segment
It is 2000~10000, the viscosity average molecular weigh of hydrophobic segment is 8000~100000.
Above-mentioned a kind of injection tacrolimus fat emulsion, it is characterised in that the stabilizer is cholesterol and/or courage
Sterol sodium sulfovinate；The injection osmotic pressure regulator is in sodium chloride, glucose, mannitol, glycerine and sorbierite
Plant or several；The water soluble antioxidants are sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid and the Guang ammonia of L- half
One or more in acid, the oil-soluble antioxidants are vitamin E.
In addition, present invention also offers a kind of method for preparing above-mentioned injection tacrolimus fat emulsion, its feature
It is that the method is comprised the following steps：
Step one, by tacrolimus, oil-soluble antioxidants and stabilizer add injection oil-based solvent in, temperature be 50
DEG C~80 DEG C under conditions of stir, obtain oil phase；
Step 2, by injection osmotic pressure regulator, surfactant, amphipathic nature block polymer, metal-chelator and
Water soluble antioxidants are added in water for injection, are stirred to the raw material under conditions of being 50 DEG C~80 DEG C in temperature and all dissolved,
Obtain water phase；
Step 3, using high-speed tissue mashing machine, oil phase described in step one is added described in step 2 in water phase or
Be added to water described in step 2 described in step one in oil phase by person, then with 6000rpm~20000rpm stirring 2min~
8min, obtains colostrum；
Step 4, the pH value of colostrum described in step 3 is adjusted to 4.0~9.0 with pH adjusting agent, then use injection
Water constant volume, the colostrum after constant volume is transferred in high pressure homogenizer, controls homogenizing temperature for 20 DEG C~60 DEG C, with 300bar~
1200bar pressure homogeneous 4~12 times, obtains whole breast, then adjusted to 4.0~9.0 the pH value of the breast eventually with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, obtain injection
Tacrolimus fat emulsion.
The present invention has advantages below compared with prior art：
1st, injection tacrolimus fat emulsion of the invention can be effectively increased the chemical stability of medicine, tacrolimus fat
In fat emulsion, most of drug distribution is in oil phase or oil-water interfaces, it is to avoid medicine and water directly contact；Medicament solubilization is in oil phase
In, isolate medicine, the medication amount of water phase is few, greatly reduces the amount of drug hydrolysis, and the stability to medicine improves a lot.
3rd, during drug moiety is wrapped in oil phase or interfacial film by injection tacrolimus fat emulsion system of the invention, it is to avoid
Directly contact with body fluid, therefore reduce the issuable part of medicine itself and blood vessel irritation.In addition, medicine is in body
It is inside slowly to be discharged by oil phase, the adverse reaction that medicine can be avoided to cause due to initial stage excessive concentration in injection.
4th, injection tacrolimus fat emulsion of the invention is compounded using surfactant and amphipathic nature block polymer
To improve the physical stability of preparation.Hydrophobic part in amphipathic nature block polymer can whole or in part be inserted into oil phase
In, hydrophilic segment is freely unfolded in water phase, effectively prevents the aggregation between emulsion droplet, improves the stability of preparation.
5th, the stabilizer in injection tacrolimus fat emulsion of the invention is cholesterol and/or cholesterol sulfate
Sodium, stabilizer can adjust the mobility of Fat Emulsion interfacial film, there is good membrane stabilizing action, add the emulsion of stabilizer not only
High temperature hot pressing sterilizing is amenable to, and normal temperature or low temperature place stabilization, and medicine is difficult to separate out.
6th, be wrapped in the medicine of tacrolimus more than 90% inside the lipid core of Fat Emulsion by the present invention, remaining medicine point
It is distributed in oil-water interfacial film, slows down drug degradation, improve the physical and chemical stability of pharmaceutical preparation, extends medicine in vivo
Action time.
Excitant when injection the 7th, will be shown as after tacrolimus fat emulsion administrated by injection of the invention to blood vessel shows
Writing reduces, and preparation shows as preferable chemical physical stability in storage process, the Seepage without medicine.
8th, injection tacrolimus fat emulsion prepared by the present invention has envelop rate high, the advantages of having good stability, is
A kind of effective intravenous injection medication, with wide DEVELOPMENT PROSPECT.
With reference to the accompanying drawings and examples, technical scheme is described in further detail.
Brief description of the drawings
Fig. 1 be the injection tacrolimus fat emulsion for preparing of commercially available injection of tacrolimus and the embodiment of the present invention 1 to
Drug-time curve after medicine.
Particle diameter distribution when Fig. 2 is the injection tacrolimus fat emulsion zero of the preparation of the embodiment of the present invention 1.
Specific embodiment
Embodiment 1
The injection tacrolimus fat emulsion of the present embodiment, contains in every 100mL injection tacrolimus fat emulsions
Tacrolimus 0.2g, soybean oil 10g, MCT Oil 10g, lecithin (egg yolk lecithin) 2g, oleic acid 0.05g,
(Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides PLLA-PEG, and wherein polyethylene glycol is viscous equal
Molecular weight is 2000, and the viscosity average molecular weigh of PLLA is 14000) 1.4g, glycerine 2.5g, vitamin E 1.5g, cholesterol
0.8g, natrium adetate 0.02g, hydrochloric acid (consumption be make injection tacrolimus fat emulsion pH value be 6.0), balance of note
Penetrate and use water.
The preparation method of the injection tacrolimus fat emulsion of the present embodiment is：
Step one, the mixing that tacrolimus, vitamin E and cholesterol are added soybean oil and MCT Oil
In solvent, stirred under conditions of being 70 DEG C in temperature, obtain oil phase；
Step 2, glycerine, lecithin, oleic acid, PLLA-PEG and natrium adetate are added
Enter in water for injection, stirred to the raw material under conditions of being 70 DEG C in temperature and all dissolved, obtain water phase；
Step 3, using high-speed tissue mashing machine, oil phase described in step one is added described in step 2 in water phase, so
5min is stirred with 10000rpm afterwards, colostrum is obtained；
Step 4, the pH value of colostrum described in step 3 is adjusted to 6.0 with NaOH, it is then fixed with water for injection
Hold, the colostrum after constant volume is transferred in high pressure homogenizer, it is 40 DEG C control homogenizing temperature, with 800bar pressure homogeneous 8 times, is obtained
To whole breast, then the pH value of the breast eventually is adjusted to 6.0 with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, sterilising conditions are
103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus fat emulsion.
Embodiment 2
The present embodiment is same as Example 1, and wherein difference is：The injection oil-based solvent is castor oil, jade
Rice bran oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm oil, certain herbaceous plants with big flowers
Flower seed oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil in one kind or more than three kinds, Huo Zhewei
Castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm oil,
Two kinds in sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil, or be castor oil, jade
Rice bran oil, sesame oil, cottonseed oil, peanut oil, safflower oil, brucea fruit oil, palm oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, flower
A kind of mixture with soybean oil in green pepper oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil；The surfactant is lecithin, department
One kind in disk, tween, pluronic, enuatrol, oleic acid and deoxycholic aicd or more than three kinds, or be sapn, tween, Pu Lang
Two kinds in Ni Ke, enuatrol, oleic acid and deoxycholic aicd, or be sapn, tween, pluronic, enuatrol and deoxycholic aicd
In a kind of mixture with lecithin；The injection osmotic pressure regulator is sodium chloride, glucose, mannitol or sorb
Alcohol, or be at least two in sodium chloride, glucose, mannitol, glycerine and sorbierite；The antioxidant be sodium sulfite,
Sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid or Cys, or be sodium sulfite, sodium pyrosulfite, bisulfite
In sodium, ascorbic acid, Cys and vitamin E at least two；The stabilizer is cholesterol sulfate sodium, or courage is solid
Alcohol and cholesterol sulfate sodium；The metal-chelator is sodium calcium edetate, or natrium adetate and sodium calcium edetate.
Embodiment 3
The injection tacrolimus fat emulsion of the present embodiment, contains in every 100mL injection tacrolimus fat emulsions
Tacrolimus 0.01g, brucea fruit oil 10g, lecithin (egg yolk lecithin) 0.5g, enuatrol 0.1g, Tween 80 0.4g, dextrorotation gather
(Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides lactic acid polyethyleneglycol block copolymer, wherein the viscosity average molecular weigh of polyethylene glycol
It is 5000, the viscosity average molecular weigh of PLLA is 8000) 1g, glycerine 1g, ascorbic acid 1g, cholesterol sulfate sodium 0.5g,
Sodium calcium edetate 0.01g, NaOH (consumption be make injection tacrolimus fat emulsion pH value be 9.0), balance of note
Penetrate and use water.
The preparation method of the injection tacrolimus fat emulsion of the present embodiment is：
Step one, tacrolimus and cholesterol sulfate sodium adds brucea fruit oil, under conditions of being 50 DEG C in temperature
Stir, obtain oil phase；
Step 2, by glycerine, lecithin, enuatrol, Tween 80, dextrorotation PLEG, according to ground
Sour sodium calcium and ascorbic acid are added in water for injection, are stirred to the raw material under conditions of being 50 DEG C in temperature and all dissolved, and are obtained
To water phase；
Step 3, using high-speed tissue mashing machine, water described in step 2 is added to described in step one in oil phase, so
8min is stirred with 6000rpm afterwards, colostrum is obtained；
Step 4, the pH value of colostrum described in step 3 is adjusted to 9.0 with NaOH, it is then fixed with water for injection
Hold, the colostrum after constant volume is transferred in high pressure homogenizer, it is 20 DEG C control homogenizing temperature, with 1200bar pressure homogeneous 12 times,
Whole breast is obtained, then is adjusted to 9.0 the pH value of the breast eventually with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, sterilising conditions are
103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus fat emulsion.
Embodiment 4
The present embodiment is same as Example 3, and wherein difference is：The injection oil-based solvent is castor oil, jade
Rice bran oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, palm oil, sunflower oil, sand
Spine seed oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric or rhizome of chuanxiong oil, or for castor oil, corn oil, soybean oil, sesame oil,
Cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm oil, sunflower oil, Seabuckthorm Seed Oil, when
Return at least two in oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil；The surfactant is lecithin, sapn, tells
One kind in temperature, pluronic, enuatrol, oleic acid and deoxycholic aicd, two kinds or more than four kinds, or be sapn, tween, Pu Lang
Three kinds in Ni Ke, enuatrol, oleic acid and deoxycholic aicd, or be sapn, pluronic, enuatrol, oleic acid and deoxycholic aicd
In two kinds with the mixture of lecithin, or for a kind of and lecithin in sapn, pluronic, oleic acid and deoxycholic aicd and
The mixture of tween；The injection osmotic pressure regulator is sodium chloride, glucose, mannitol or sorbierite, or is chlorination
It is two or more in sodium, glucose, glycerine, mannitol and sorbierite；The antioxidant is sodium sulfite, sodium pyrosulfite, Asia
Niter cake, Cys or vitamin E, or be sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid, L-
In cysteine and vitamin E at least two；The stabilizer is cholesterol, or cholesterol and cholesterol sulfate sodium；Institute
Metal-chelator is stated for natrium adetate, or natrium adetate and sodium calcium edetate.
Embodiment 5
The injection tacrolimus fat emulsion of the present embodiment, contains in every 100mL injection tacrolimus fat emulsions
Tacrolimus 5g, soybean oil 20g, lecithin (egg yolk lecithin) 3g, the PDLLA polyethyleneglycol block copolymer (Chinese Academy of Sciences
Changchun applied chemistry study is provided, and wherein the viscosity average molecular weigh of polyethylene glycol is 5000, the viscosity average molecular weigh of PDLLA
For 100000) 2g, sodium chloride 1g, sorbierite 1g, glycerine 2g, Cys 1g, vitamin E 1g, cholesterol 1g, cholesterol
Sodium sulfovinate 1g, natrium adetate 0.5g, sodium calcium edetate 0.5g, (consumption is to make injection tacrolimus fat emulsion to hydrochloric acid
PH value for 4.0), balance of water for injection.
The preparation method of the injection tacrolimus fat emulsion of the present embodiment is：
Step one, by tacrolimus, vitamin E, cholesterol and cholesterol sulfate sodium add soybean oil in, be in temperature
Stirred under conditions of 80 DEG C, obtain oil phase；
Step 2, by sorbierite, glycerine, lecithin, PDLLA polyethyleneglycol block copolymer, natrium adetate,
Sodium calcium edetate and Cys are added in water for injection, stir all molten to the raw material under conditions of being 80 DEG C in temperature
Solution, obtains water phase；
Step 3, using high-speed tissue mashing machine, oil phase described in step one is added described in step 2 in water phase, so
2min is stirred with 20000rpm afterwards, colostrum is obtained；
Step 4, the pH value of colostrum described in step 3 is adjusted to 4.0 with hydrochloric acid, then use water for injection constant volume, will
Colostrum after constant volume is transferred in high pressure homogenizer, controls homogenizing temperature for 60 DEG C, with 300bar pressure homogeneous 4 times, obtains end
Breast, then adjusted to 4.0 the pH value of the breast eventually with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, sterilising conditions are
103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus fat emulsion.
Embodiment 6
The present embodiment is same as Example 5, and wherein difference is：The injection oil-based solvent is castor oil, jade
Rice bran oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm oil, sunflower oil,
One or more in Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil, or are castor oil, corn
Oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm oil, sunflower
In seed oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil at least two；The surfactant
It is sapn, tween, pluronic, enuatrol, oleic acid or deoxycholic aicd, or is lecithin, sapn, tween, pluronic, oil
In sour sodium, oleic acid and deoxycholic aicd at least two；The injection osmotic pressure regulator be sodium chloride, glucose, mannitol,
One kind in glycerine and sorbierite, two kinds, four kinds or five kinds, or be three in glucose, mannitol, glycerine and sorbierite
Kind, or be two kinds in glucose, mannitol and sorbierite and the mixture of sodium chloride, or for sodium chloride, glucose and
Mannitol；The antioxidant is sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid, vitamin E and the Guang ammonia of L- half
One kind in acid or more than three kinds, or be sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid and the Guang ammonia of L- half
Two kinds in acid, or for sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite and ascorbic acid in it is a kind of with vitamin E
Mixture；The stabilizer is cholesterol or cholesterol sulfate sodium；The metal-chelator is natrium adetate or edetic acid(EDTA)
Sodium calcium.
Embodiment 7
The injection tacrolimus fat emulsion of the present embodiment, contains in every 100mL injection tacrolimus fat emulsions
Tacrolimus 0.5g, castor oil 0.5g, MCT Oil 0.5g, palm oil 0.8g, oil of zedoary turmeric 0.2g, pluronic
0.2g, deoxycholic aicd 0.3g, PDLLA polyethyleneglycol block copolymer (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides,
Wherein the viscosity average molecular weigh of polyethylene glycol is 10000, and the viscosity average molecular weigh of PDLLA is 50000) 0.1g, glucose
0.5g, cholesterol sulfate sodium 0.1g, natrium adetate 0.001g, (consumption is to make injection tacrolimus fat to NaOH
The pH value of emulsion is 8.0) balance of water for injection.
The preparation method of the injection tacrolimus fat emulsion of the present embodiment is：
Step one, tacrolimus and cholesterol sulfate sodium are added into castor oil, MCT Oil, palm oil
In the mixed solvent of oil of zedoary turmeric, stirred under conditions of being 60 DEG C in temperature, obtain oil phase；
Step 2, by glucose, pluronic, deoxycholic aicd, PDLLA polyethyleneglycol block copolymer and according to ground
Acid disodium is added in water for injection, is stirred to the raw material under conditions of being 60 DEG C in temperature and all dissolved, and obtains water phase；
Step 3, using high-speed tissue mashing machine, water described in step 2 is added to described in step one in oil phase, then
4min is stirred with 12000rpm, colostrum is obtained；
Step 4, the pH value of colostrum described in step 3 is adjusted to 8.0 with pH adjusting agent, it is then fixed with water for injection
Hold, the colostrum after constant volume is transferred in high pressure homogenizer, it is 30 DEG C control homogenizing temperature, with 1000bar pressure homogeneous 6 times,
Whole breast is obtained, then is adjusted to 8.0 the pH value of the breast eventually with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, sterilising conditions are
103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus fat emulsion.
Embodiment 8
The present embodiment is same as Example 7, and wherein difference is：The injection oil-based solvent is castor oil, jade
Rice bran oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm oil, certain herbaceous plants with big flowers
One kind in flower seed oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil, two kinds, three kinds or five kinds with
On, or be corn oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, Java brucea
Four kinds in oil, palm oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil, or
It is corn oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, brucea fruit oil, palm oil, sunflower oil, seabuckthorn seeds
Three kinds in oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil with the mixture of castor oil, or for corn oil,
Soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, brucea fruit oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil,
Two kinds in garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil with castor oil and the mixture of MCT Oil, or be corn
Oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, brucea fruit oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Chinese prickly ash
Two kinds in oil, garlic oil and rhizome of chuanxiong oil with the mixture of castor oil, MCT Oil and oil of zedoary turmeric；The surface
Activating agent is one kind or more than three kinds in lecithin, sapn, tween, enuatrol, oleic acid and deoxycholic aicd, or is lecithin
A kind of mixture of the and F68 in fat, sapn, tween, enuatrol and oleic acid；The injection osmotic pressure regulator is
Sodium chloride, mannitol, glycerine and sorbierite, or for sodium chloride, glucose, mannitol, glycerine and sorbierite at least two
Kind；The stabilizer is cholesterol, or cholesterol and cholesterol sulfate sodium；The metal-chelator is sodium calcium edetate, or
Person is natrium adetate and sodium calcium edetate.
Embodiment 9
The injection tacrolimus fat emulsion of the present embodiment, contains in every 100mL injection tacrolimus fat emulsions
Tacrolimus 10g, MCT Oil 20g, lecithin (egg yolk lecithin) 5g, enuatrol 2g, PLLA gather
Ethylene glycol block copolymer (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides, and wherein the viscosity average molecular weigh of polyethylene glycol is 5000,
The viscosity average molecular weigh of PLLA is 20000) 2g, mannitol 2g, glycerine 3g, sorbierite 2g, sodium pyrosulfite 2g, vitamin
E 1g, cholesterol 5g, sodium calcium edetate 3g, (consumption is that the pH value for making injection tacrolimus fat emulsion is to NaOH
9.0), balance of water for injection.
The preparation method of the injection tacrolimus fat emulsion of the present embodiment is：
Step one, by tacrolimus, vitamin E and cholesterol add injection oil-based solvent in, be 50 DEG C in temperature
Under the conditions of stir, obtain oil phase；
Step 2, by mannitol, glycerine, sorbierite, lecithin, enuatrol, PLLA polyethylene glycol block copolymerization
Thing, sodium calcium edetate and sodium pyrosulfite are added in water for injection, stir complete to the raw material under conditions of being 50 DEG C in temperature
Portion dissolves, and obtains water phase；
Step 3, using high-speed tissue mashing machine, oil phase described in step one is added described in step 2 in water phase or
Be added to water described in step 2 described in step one in oil phase by person, then stirs 8min with 6000rpm, obtains colostrum；
Step 4, the pH value of colostrum described in step 3 is adjusted to 9.0 with pH adjusting agent, it is then fixed with water for injection
Hold, the colostrum after constant volume is transferred in high pressure homogenizer, it is 60 DEG C control homogenizing temperature, with 500bar pressure homogeneous 8 times, is obtained
To whole breast, then the pH value of the breast eventually is adjusted to 9.0 with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, sterilising conditions are
103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus fat emulsion.
Embodiment 10
The present embodiment is same as Example 9, and wherein difference is：The injection oil-based solvent is castor oil, jade
Rice bran oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, brucea fruit oil, palm oil, sunflower oil, Seabuckthorm Seed Oil, when
Return oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric or rhizome of chuanxiong oil, or be castor oil, corn oil, soybean oil, sesame oil, cottonseed oil, flower
Oil generation, safflower oil, MCT Oil, brucea fruit oil, palm oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Chinese prickly ash
In oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil at least two；The surfactant is lecithin, sapn, tween, Pu Langni
Gram, the one kind in enuatrol, oleic acid and deoxycholic aicd or more than three kinds, or be sapn, tween, pluronic, enuatrol, oil
Two kinds in acid and deoxycholic aicd, or be the one kind and lecithin in sapn, tween, pluronic, oleic acid and deoxycholic aicd
Mixture；The injection osmotic pressure regulator is one kind, two in sodium chloride, glucose, mannitol, glycerine and sorbierite
Kind, four kinds or five kinds, or be three kinds in sodium chloride, glucose, mannitol and glycerine, or for sodium chloride, glucose and
Two kinds in mannitol and the mixture of sorbierite, or be sodium chloride, glycerine and sorbierite, or for glucose, glycerine and
Sorbierite；The antioxidant is sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid, Cys and vitamin
One kind in E or more than three kinds, or in sodium sulfite, sodium hydrogensulfite, ascorbic acid, Cys and vitamin E
Two kinds, or for sodium sulfite, sodium hydrogensulfite, ascorbic acid and vitamin E in a kind of mixing with sodium pyrosulfite
Thing；The stabilizer is cholesterol or cholesterol and cholesterol sulfate sodium；The metal-chelator be natrium adetate or according to
Ground acid disodium and sodium calcium edetate.
Properties to injection tacrolimus fat emulsion of the invention are investigated：
First, vascular stimulation test
Healthy rabbits 15 are taken, 5 groups, every group 3 are randomly divided into.5 groups of left ears of rabbit inject sodium chloride injection, auris dextra
The injection tacrolimus fat emulsion of the embodiment of the present invention 1,3,5,7 and 9 is injected respectively, is administered once daily, for three days on end.Give
Visually observe administration local vascular whether there is thrombosis daily during medicine, surrounding tissue whether there is the inflammatory reactions such as red and swollen extravasated blood.Give
Medicine is put to death after terminating, and ear tissue is removed at centripetal direction 3cm at self administration of medication, with 10% formalin fix, FFPE, system
Piece, dyeing, light Microscopic observation vascular machine tissue morphology change.
The vascular stimulation result of the test of table 1
Histological findings show：Administration group rabbit auricular vein vascular wall is complete, smooth.Endothelial injuries are had no, without blood
The pathological change such as bolt formation and peripheral tissue edema, cell infiltration, inflammation and necrosis.Administration group compares nothing with negative control group
Significant difference, shows that prepared injection tacrolimus Fat Emulsion has no obvious stimulation to rabbit ear blood vessel.
2nd, animal sensitivity test
Body weight 250g~350g healthy guinea pigs 42 are taken, 7 groups are randomly divided into, one group is injected 0.9% as negative control group
Sodium chloride injection, per injection dosage is 0.5mL/, and one group is injected 10% egg albumin solution as positive controls, often
Secondary injection dosage is 0.1mL/, remaining the five groups injections for injecting the embodiment of the present invention 1,3,5,7 and 9 respectively as test sample group
Tacrolimus fat emulsion is used, per injection dosage is 0.5mL/.Injection system and number of times：The next day intraperitoneal injection once, altogether
Injection three times.Then negative control group, positive controls and each confession examination group on the 14th are injected intravenously respectively after final injection
0.9% sodium chloride injection, 10% egg albumin solution and each need testing solution, administered volume are 1mL/ only, are excited.
After injection in 15 minutes, whether the cavy for observing liquid medicine injection there is allergic reaction.If any perpendicular hair, expiratory dyspnea or cough 3
Two or more person in the phenomenons such as sound, or have the one of the phenomenons such as tic, collapse or death, then being judged to the positive (had
Quick reaction).The results are shown in Table 2.
The Hypersensitive tests result of table 2 (n=6)
From Table 2, it can be seen that the injection tacrolimus fat emulsion two that negative control group and the present invention are prepared
Every group of each 6 cavy does not occur allergic reaction in 15 minutes after secondary intravenously administrable, and positive control solution is twice 1 point after intravenously administrable
All there is cough, respiration inhibition, twitch until dead in 6 cavys in clock.Result shows：The present invention is real under this experimental condition
Apply the injection tacrolimus fat emulsion hypersensitive test that example 1,3,5,7 and 9 prepares and systemic anaphylaxis do not occur.
3rd, animal hemolytic experiment
The preparation of 2% red cell suspension：New fresh rabbit blood 10mL is taken, is placed in beaker, use glass bar mild agitation, several minutes
Afterwards except defibrinating, blood is taken out, add 5 times of amount physiological saline, shaken up, 2500rpm/min centrifugation 5min, supernatant discarded
Liquid；The red blood cell of precipitation is cleaned with the physiological saline of same amount again, centrifugation, such cyclic washing 3~4 times, to supernatant into colourless
Untill transparent.The red blood cell normal saline that will have been washed is standby into 2% red cell suspension.
Experimental design：Clean tube 7 is taken, is numbered respectively, sequentially add each liquid in following table, the 6th pipe is not added with test liquid and is
Blank pipe, the 7th effective distilled water replaces physiological water, shakes up, and is placed in 37 DEG C of water-baths, respectively at 0.5h, 1h, 2h, 3h, 4h
See whether haemolysis.
Result judgement standard：Full haemolysis：The clear and bright red of solution, ttom of pipe is remained without red blood cell；Part haemolysis：Solution it is clear and bright or
Brown, ttom of pipe has a small amount of red blood cell to remain；Without haemolysis：Red blood cell all sinks, supernatant liquid achromatism and clarity；Aggegation：Not haemolysis,
In the aggegation of test tube bottom, cell can not disperse red blood cell after shaking.
The hemolytic test result of the injection tacrolimus fat emulsion of the embodiment of the present invention 1 of table 3
Note：+++ complete hemolysis；++ part haemolysis；+ aggegation；, also there is no aggegation in-not haemolysis
Result of the test shows：The injection tacrolimus fat emulsion that the embodiment of the present invention 1 is prepared in 4 hours not
Cause haemolysis or agglutinating reaction.
The injection tacrolimus fat emulsion prepared to the embodiment of the present invention 3,5,7 and 9 using the above method enters action
Thing hemolytic is tested, and does not cause haemolysis or agglutinating reaction in 4 hours.
4th, rat Internal pharmacokinetics experiment
12 Wistar kind male rats, body weight (200 ± 20) g are randomly divided into two groups：R groups and A groups, every group 6,
The night of fasting one before experiment.R groups are control group, the commercially available injection of tacrolimus of tail vein injection (Prograf)；A groups are tested group,
In injection tacrolimus fat emulsion (TLE) prepared by the tail vein injection embodiment of the present invention 1, respectively at 5min after administration,
15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h eye socket take blood 0.5mL, put the 1.5mL points bottom centrifugation examination of advance test tube of hepari
Guan Zhong, drug concentration is determined after treatment with LC-MS/MS.
Every pharmacokinetic parameters (n=6) that table 4 is calculated using statistics Moment Methods
Note：A represents p<0.05；
One side is carried out to two kinds of main every pharmacokinetic parameters of preparation using statistical software (SPSS, version11.5)
T- check analyses.Compare two groups of data, if obtaining p<When 0.05, illustrate that two groups of data have significant difference.As shown in Table 4,
TLE compared with Prograf, in addition to AUC, other pharmacokinetic parameters there are no significant difference.
By TLE in Fig. 1 (embodiment of the present invention 1 prepare injection tacrolimus fat emulsion) and Prograf (it is commercially available he
Ke Mosi parenteral solutions) compare, the two Internal pharmacokinetics behavior is much like.Show that prepared preparation is similar to commercially available parenteral solution,
On the premise of pharmacokinetic behavior is not changed, the effect for serve and improve drug solubility, increasing medicine stability.
5th, accelerated stability test
Because injection tacrolimus fat emulsion is thermodynamic unstable system, belong to thermo-responsive formulation.According to
Chinese Pharmacopoeia version bulk drug in 2010 and the explanation of pharmaceutical preparation stability test guideline, prepared by the embodiment of the present invention 1
Injection tacrolimus fat emulsion placed 6 months under conditions of 25 ± 2 DEG C, investigate physical and chemical stability change.
The accelerated stability test result of table 5
| Time (moon) | PH value | Particle diameter (nm) | Zeta-potential (mv) | Envelop rate (%) | Content (%) |
| 0 | 6.18 | 204.1±62.4 | -36.67 | 92.36 | 104 |
| 1 | 6.19 | 206.9±75.8 | -37.44 | 91.15 | 102 |
| 2 | 6.15 | 203.3±61.5 | -36.33 | 90.07 | 103 |
| 3 | 6.12 | 210.7±59.3 | -36.39 | 89.33 | 101 |
| 6 | 6.07 | 209.6±60.6 | -36.98 | 89.30 | 99 |
As can be seen from Table 5, the injection tacrolimus fat emulsion that prepared by the embodiment of the present invention 1 is at 25 ± 2 DEG C
Under the conditions of accelerate 6 months after outward appearance, physical stability and chemical stability it is good.
Injection tacrolimus fat emulsion prepared by the embodiment of the present invention 3,5,7 and 9 is added using the above method
Fast stability test, outward appearance, physical stability and chemical stability are good after accelerating 6 months under conditions of 25 ± 2 DEG C.
6th, long-term stable experiment
Injection tacrolimus fat emulsion prepared by the embodiment of the present invention 1 places 12 under conditions of 6 ± 2 DEG C
Month, investigate the change of physical and chemical stability.Particle diameter during injection tacrolimus fat emulsion zero prepared by the embodiment of the present invention 1
Distribution is as shown in Fig. 2 average grain diameter is in 200nm or so.
The long-term stable experiment result of table 6
| Time (moon) | PH value | Particle diameter (nm) | Zeta-potential (mv) | Envelop rate (%) | Content (%) |
| 0 | 6.18 | 204.1±63.3 | -39.67 | 92.36 | 104 |
| 3 | 6.14 | 206.7±74.7 | -38.37 | 90.98 | 102 |
| 6 | 6.11 | 203.3±62.2 | -38.54 | 91.32 | 103 |
| 9 | 6.17 | 203.0±59.5 | -39.63 | 90.17 | 100 |
| 12 | 6.15 | 203.3±60.4 | -38.28 | 90.12 | 98 |
As can be seen from Table 6, the injection tacrolimus fat emulsion that prepared by the embodiment of the present invention 1 is long-term at 6 ± 2 DEG C
12 months assays of every inspection target of experiment still conform to quality standard regulation.
It is long to injection tacrolimus fat emulsion prepared by the embodiment of the present invention 3,5,7 and 9 using the above method
Phase stability test, outward appearance, physical stability and chemical stability are good after 6 ± 2 DEG C of long term tests 12 months.
To sum up, injection tacrolimus fat emulsion of the invention is long through 25 ± 2 DEG C of accelerated tests 6 months and 6 ± 2 DEG C
Phase tests 12 months assays of every inspection target and still conforms to quality standard regulation, it is ensured that preparation is in storage period
Steady quality.
The above, is only presently preferred embodiments of the present invention, and not the present invention is imposed any restrictions, every according to the present invention
Any simple modification, change and equivalent structure change that technical spirit is made to above example, still fall within skill of the present invention
In the protection domain of art scheme.
Claims (6)
1. a kind of injection tacrolimus fat emulsion, it is characterised in that contain in per 100mL injection tacrolimus fat emulsions
There are tacrolimus 0.01g~10g, injection oil-based solvent 2g~20g, surfactant 0.5g~7g, amphiphilic block
Thing 0.1g~2g, injection osmotic pressure regulator 0.5g~7g, 0~3g of antioxidant, stabilizer 0.1g~5g；The antioxidant is
Water soluble antioxidants and/or oil-soluble antioxidants；Also contain metal-chelator in per 100mL injection tacrolimus fat emulsions
0.001g~3g, the metal-chelator is natrium adetate and/or sodium calcium edetate；In the amphipathic nature block polymer
Hydrophilic segment is polyethylene glycol, and hydrophobic segment is PLLA, dextrorotation PLA or PDLLA；The stabilizer is courage
Sterol and/or cholesterol sulfate sodium；The injection osmotic pressure regulator is sodium chloride, glucose, mannitol, glycerine and mountain
One or more in pears alcohol；The water soluble antioxidants are sodium sulfite, sodium pyrosulfite, sodium hydrogensulfite, ascorbic acid
With one or more in Cys, the oil-soluble antioxidants are vitamin E；The injection oil-based solvent is castor-oil plant
Oil, corn oil, soybean oil, sesame oil, cottonseed oil, peanut oil, safflower oil, MCT Oil, brucea fruit oil, palm
Oil, sunflower oil, Seabuckthorm Seed Oil, Angelica oil, Zanthoxylum essential oil, garlic oil, oil of zedoary turmeric and rhizome of chuanxiong oil in one or more；The table
Face activating agent is one or more in lecithin, sapn, tween, pluronic, enuatrol, oleic acid and deoxycholic aicd.
2. a kind of injection tacrolimus fat emulsion according to claim 1, it is characterised in that per 100mL injections
Containing tacrolimus 0.01g~5g in tacrolimus fat emulsion, injection oil-based solvent 10g~20g, surfactant 1g~
3g, amphipathic nature block polymer 1g~2g, injection osmotic pressure regulator 1g~4g, antioxidant 1g~2g, stabilizer 0.5g~
2g。
3. a kind of injection tacrolimus fat emulsion according to claim 2, it is characterised in that per 100mL injections
Contain tacrolimus 0.2g, injection oil-based solvent 20g, surfactant 2.05g in tacrolimus fat emulsion, it is amphipathic embedding
Section copolymer 1 .4g, injection osmotic pressure regulator 2.5g, antioxidant 1.5g, stabilizer 0.8g.
4. a kind of injection tacrolimus fat emulsion according to claim 1,2 or 3, it is characterised in that its feature exists
In, pH adjusting agent is also contained in the injection tacrolimus fat emulsion, the consumption of pH adjusting agent is to make injection Ta Kemo
The pH value for taking charge of fat emulsion is 4.0~9.0, and the pH adjusting agent is NaOH or hydrochloric acid.
5. a kind of injection tacrolimus fat emulsion according to claim 1,2 or 3, it is characterised in that described hydrophilic
The viscosity average molecular weigh of segment is 2000~10000, and the viscosity average molecular weigh of hydrophobic segment is 8000~100000.
6. a kind of method for preparing injection tacrolimus fat emulsion as claimed in claim 4, it is characterised in that the method
Comprise the following steps：
Step one, by tacrolimus, oil-soluble antioxidants and stabilizer add injection oil-based solvent in, temperature be 50 DEG C~
Stirred under conditions of 80 DEG C, obtain oil phase；
Step 2, by injection osmotic pressure regulator, surfactant, amphipathic nature block polymer, metal-chelator and water-soluble
Property antioxidant add water for injection in, temperature be 50 DEG C~80 DEG C under conditions of stir to raw material all dissolve, obtain water phase；
Step 3, using high-speed tissue mashing machine, oil phase described in step one is added described in step 2 in water phase or will
Water described in step 2 is added to described in step one in oil phase, then stirs 2min~8min with 6000rpm~20000rpm,
Obtain colostrum；
Step 4, the pH value of colostrum described in step 3 is adjusted to 4.0~9.0 with pH adjusting agent, it is then fixed with water for injection
Hold, the colostrum after constant volume is transferred in high pressure homogenizer, control homogenizing temperature be 20 DEG C~60 DEG C, with 300bar~
1200bar pressure homogeneous 4~12 times, obtains whole breast, then adjusted to 4.0~9.0 the pH value of the breast eventually with pH adjusting agent；
Step 5, with high-pressure steam sterilizing pan in step 4 adjust pH value after whole breast sterilize, obtain injection he gram
Do not take charge of fat emulsion.
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|---|---|---|---|---|
| CN101653413A (en) * | 2009-09-25 | 2010-02-24 | 宋洪涛 | Tacrolimus ophthalmic emulsion and its preparation method |
| CN102302447A (en) * | 2011-09-09 | 2012-01-04 | 沈阳药科大学 | Novel taxol lipid microsphere injection and preparation method thereof |
| CN102335140A (en) * | 2011-10-12 | 2012-02-01 | 沈阳药科大学 | Disulfiram lipid microsphere preparation for injection for treating tumor and preparation method thereof |
| EP2596788A1 (en) * | 2010-07-23 | 2013-05-29 | Maruho Co., Ltd. | Tacrolimus-containing oil-in-water type creamy composition |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101653413A (en) * | 2009-09-25 | 2010-02-24 | 宋洪涛 | Tacrolimus ophthalmic emulsion and its preparation method |
| EP2596788A1 (en) * | 2010-07-23 | 2013-05-29 | Maruho Co., Ltd. | Tacrolimus-containing oil-in-water type creamy composition |
| CN102302447A (en) * | 2011-09-09 | 2012-01-04 | 沈阳药科大学 | Novel taxol lipid microsphere injection and preparation method thereof |
| CN102335140A (en) * | 2011-10-12 | 2012-02-01 | 沈阳药科大学 | Disulfiram lipid microsphere preparation for injection for treating tumor and preparation method thereof |
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