CN104274406A - Tacrolimus lipid emulsion for injection and preparation method thereof - Google Patents
Tacrolimus lipid emulsion for injection and preparation method thereof Download PDFInfo
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- CN104274406A CN104274406A CN201410571019.1A CN201410571019A CN104274406A CN 104274406 A CN104274406 A CN 104274406A CN 201410571019 A CN201410571019 A CN 201410571019A CN 104274406 A CN104274406 A CN 104274406A
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Abstract
The invention discloses a tacrolimus lipid emulsion for injection, and the tacrolimus lipid emulsion contains tacrolimus, an oily solvent for injection, a surfactant, amphiphilic block copolymers, an osmotic pressure regulator for injection, an antioxidant and a stabilizer. In addition, the invention also discloses a preparation method of the lipid emulsion. The tacrolimus lipid emulsion is capable of effectively increasing the chemical stability of the medicines; most of medicines in the tacrolimus lipid emulsion are distributed in an oil phase or an oil-water interface; and the medicines are prevented from directly contacting water, are solubilized into the oil phase, and are isolated, so that the medicine dosage of the water phase is reduced, the hydrolysis amount of the medicines is greatly reduced, and the stability on the medicines is greatly improved. The tacrolimus lipid emulsion for injection disclosed by the invention can be used for wrapping a part of medicines into the oil phase or an interfacial film, and preventing the medicines from directly contacting body fluid, so that the local and vascular stimulation which can be generated by the medicines is reduced.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of injection tacrolimus lipomul and preparation method thereof.
Background technology
Organ transplantation is called as one of 20th century physianthropy three much progress.The last effective means that organ transplantation is treated as organ failure, very large in the demand of China, nowadays national You100Duo Jia hospital and 200 multidigit experts can carry out comprising 25 kinds of allogeneic organ transplants such as kidney, liver, heart, pancreas, lung, bone marrow and cornea, Organ Transplantation Patients needs to take immunosuppressant all the life after the transfer, and immunosuppressant all plays an important role to aspects such as Organ Transplantation Patients time-to-live, maintenance transplant organ good function.Therefore immunosuppressant has clinical value as the exploitation of organ transplantation medication.
Tacrolimus (Tacrolimus, FK506, trade name Prograf) be the one 23 membered macrolide neotype immunosuppressant that Japanese Teng Ze (Fujisawa) drugmaker purifies for 1984 first from Tsukubaensis streptomycete the 9993rd strain tunning.Its molecular formula is C
44h
69nO
12, molecular weight 804.02.In white crystals or crystalline powder under room temperature, be soluble in methanol, ethanol, acetone, ethyl acetate, chloroform and ether, be slightly dissolved in hexane, petroleum ether, water insoluble, its fusing point is 127 ~ 129 DEG C, and optical rotation is-84.4 °.
Tacrolimus is except having antifungic action, also there is very strong immunosuppressive action, the tacrolimus mechanism of action is: tacrolimus and endogenous cell inner recipient (cytosol binding protein FKBP12) combine, form immunophilin complex, this complex is combined specifically with calmodulin competitively and suppresses calmodulin, suppressor T cell activates effectively, suppresses the generation of interleukin II (IL-2).The effect of tacrolimus is than applying high nearly 100 times of wider ciclosporin A (cyclosporine A, CsA).When lower than 1/100 Determination of Cyclosporin, also tool suppresses the reaction of heart xenotransplantaion thing, and tacrolimus effectively can prevent the rejection after organ transplantation, and can reverse the rejection invalid to ciclosporin.
Existing is in the market that the pharmaceutical preparation of effective active components has injection, capsule and ointment three kinds with tacrolimus.Tacrolimus paste is used for non-specific dermatitis, and tacrolimus injection agent and tacrolimus capsules agent are for preventing liver or the postoperative transplant rejection of renal transplantation and treatment liver or the uncontrollable transplant rejection of other immunosuppressive drugs of the postoperative application of renal transplantation.
Clinically, because interference factor suffered in tacrolimus body absorption process is a lot, so namely substantially increase the dissolution rate of tacrolimus, tacrolimus oral administration preparation still also exists sizable individual variation, causes the fluctuation of blood drug level very large; Tacrolimus injection agent is applicable to the patient that can not accept oral administration or need to reach in a short time higher blood drug level, rapid-onset.Therefore, tacrolimus injection agent remains on clinical treatment that oral formulations cannot replace.
Tacrolimus injection agent often adopts non-aqueous matchmaker system clinically at present, that is: be dissolved in by tacrolimus in the mixed solvent of polyoxyethylene hydrogenated Oleum Ricini and dehydrated alcohol.Polyoxyethylene hydrogenated Oleum Ricini also exists pharmacologically active and untoward reaction, and clinical practice often brings toxic and side effects.And there is the risk that medicine is separated out when diluting in injection.Tacrolimus is unstable in the basic conditions.
In view of above-mentioned characteristic, for making tacrolimus better play immunosuppressive action, developing a kind of not containing the injection of the surfactant and organic reagent with pharmacologically active, and keeping its stability tool to be of great significance.
Intravenous injection fatty emulsion, as the carrier of poorly water soluble drugs, is widely used recently.Its special physicochemical property and hypotoxicity determine it can as the good carrier of fat-soluble medicine.Compare with conventional injection liquid phase, lipomul can reduce blood vessel irritation.Drug-loaded emulsion is by being dissolved in fatty oil by medicine, and make after aqueous phase through phospholipid emulsion dispersion, be a kind ofly be soft substrate with fatty oil and the microparticulate system encapsulated by immobilized artificial membrane, have as pharmaceutical carrier and improve the advantage such as drug solubility and stability.
Japan's Teng Ze drugmaker development and production the injection of tacrolimus gone on the market in the state such as China, Japan, the U.S., its surfactant adopted is Cremophor RH60 (Polyoxyl60Hydrogenated Castor Oil, hereinafter referred to as HCO-60), containing 200mg HCO-60 in every milliliter of injection of tacrolimus.Korean Patent No.0177158 discloses a kind of pharmaceutical solutions, and this pharmaceutical solutions contains tacrolimus or its pharmaceutically acceptable salt, the pharmaceutically acceptable surfactant comprising castor oil hydrogenated polyoxyethylene ether and pharmaceutically acceptable nonaqueous solvent.Korean Patent No.0206722 discloses a kind of liquid composite, and said composition contains tacrolimus or its pharmaceutically acceptable salt; Be selected from the pharmaceutically acceptable emulsifying agent be made up of Ovum Gallus domesticus Flavus lecithin, soybean lecithin and castor oil hydrogenated polyoxyethylene ether; With the pharmaceutically acceptable oil being selected from the liquid carbon compound be made up of soybean oil and Oleum sesami.Korean laid-open No.2001-0006070 discloses a kind of Pharmaceutical composition, and this Pharmaceutical composition contains water-insoluble drug and two or more surfactants, and at least one surfactant can dissolve other water-insoluble surfactant and water-insoluble drug.
The U.S. discloses a kind of injection of tacrolimus preparation, and said preparation comprises tacrolimus, Oleum Ricini gathers hydrocarbon oxygen ester (35) and nonaqueous solvent.On pharmaceutics, advocate to reduce the component irrelevant with therapeutical effect or its content in pharmaceutical formulation as far as possible, and reach similar or better drug quality and clinical efficacy.Any increase of component of haveing nothing to do with therapeutical effect or the increase of its addition all can bring safety issue to Clinical practice.From pharmaceutics angle analysis, the invention adopting kinds of surface activating agent to combine in above open source information is not all best invention, and the efficacy and saferry of its clinical practice not yet has correlational study data, and its safety is worth discussion.
In addition, there are some problems in existing liquid composite, and medicine can produce precipitation in the process stored term, and along with the reduction of medicament contg, its pharmaceutical stability will decline.Therefore, traditional liquid composite is unsuitable for being used as human injection's preparation.
Summary of the invention
Technical problem to be solved by this invention is for above-mentioned the deficiencies in the prior art, provides a kind of injection tacrolimus lipomul.This lipomul effectively can increase the chemical stability of medicine, and in tacrolimus lipomul, most of drug distribution, at oil phase or oil-water interfaces, avoids medicine directly to contact with water; Medicament solubilization is in oil phase, and isolate medicine, the medication amount of aqueous phase is few, greatly reduces the amount of drug hydrolysis, improves a lot to the stability of medicine; Drug moiety is wrapped in oil phase or interfacial film by injection tacrolimus lipomul system, avoids and contacts with the direct of body fluid, because this reducing the issuable local of medicine self and blood vessel irritation.In addition, medicine is by slow releasing in oil phase in vivo, can avoid the untoward reaction that medicine causes due to initial stage excessive concentration when injecting.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of injection tacrolimus lipomul, it is characterized in that, containing tacrolimus 0.01g ~ 10g in every 100mL injection tacrolimus lipomul, injection oil-based solvent 2g ~ 20g, surfactant 0.5g ~ 7g, amphipathic nature block polymer 0.1g ~ 2g, injection osmotic pressure regulator 0.5g ~ 7g, antioxidant 0 ~ 3g, stabilizing agent 0.1g ~ 5g; Described antioxidant is water soluble antioxidants and/or oil-soluble antioxidants.
Above-mentioned a kind of injection tacrolimus lipomul, it is characterized in that, containing tacrolimus 0.01g ~ 5g in every 100mL injection tacrolimus lipomul, injection oil-based solvent 10g ~ 20g, surfactant 1g ~ 3g, amphipathic nature block polymer 1g ~ 2g, injection osmotic pressure regulator 1g ~ 4g, antioxidant 1g ~ 2g, stabilizing agent 0.5g ~ 2g.
Above-mentioned a kind of injection tacrolimus lipomul, it is characterized in that, containing tacrolimus 0.2g in every 100mL injection tacrolimus lipomul, injection oil-based solvent 20g, surfactant 2.05g, amphipathic nature block polymer 1.4g, injection osmotic pressure regulator 2.5g, antioxidant 1.5g, stabilizing agent 0.8g.
Above-mentioned a kind of injection tacrolimus lipomul, is characterized in that, also containing metal-chelator 0.001g ~ 3g in every 100mL injection tacrolimus lipomul, described metal-chelator is disodium edetate and/or sodium calcium edetate.
Above-mentioned a kind of injection tacrolimus lipomul, it is characterized in that, also containing pH adjusting agent in described injection tacrolimus lipomul, the consumption of pH adjusting agent is make the pH value of injection tacrolimus lipomul be 4.0 ~ 9.0, and described pH adjusting agent is sodium hydroxide or hydrochloric acid.
Above-mentioned a kind of injection tacrolimus lipomul, it is characterized in that, described injection oil-based solvent is one or more in Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, Oleum Curcumae and Rhizoma Chuanxiong oil; Described surfactant is one or more in lecithin, span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid.
Above-mentioned a kind of injection tacrolimus lipomul, it is characterized in that, the hydrophilic segment in described amphipathic nature block polymer is Polyethylene Glycol, and hydrophobic segment is Poly-L-lactic acid, dextrorotation polylactic acid or PDLLA.
Above-mentioned a kind of injection tacrolimus lipomul, it is characterized in that, the viscosity-average molecular weight of described hydrophilic segment is 2000 ~ 10000, the viscosity-average molecular weight of hydrophobic segment is 8000 ~ 100000.
Above-mentioned a kind of injection tacrolimus lipomul, is characterized in that, described stabilizing agent is cholesterol and/or cholesterol sulfate sodium; Described injection osmotic pressure regulator is one or more in sodium chloride, glucose, mannitol, glycerol and sorbitol; Described water soluble antioxidants is one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid and Cys, and described oil-soluble antioxidants is vitamin E.
In addition, present invention also offers a kind of method preparing above-mentioned injection tacrolimus lipomul, it is characterized in that, the method comprises the following steps:
Step one, tacrolimus, oil-soluble antioxidants and stabilizing agent are added in injection oil-based solvent, be stir under the condition of 50 DEG C ~ 80 DEG C in temperature, obtain oil phase;
Step 2, injection osmotic pressure regulator, surfactant, amphipathic nature block polymer, metal-chelator and water soluble antioxidants are added in water for injection, be stirred to described raw material under the condition of 50 DEG C ~ 80 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, oil phase described in step one is added in aqueous phase described in step 2 or aqueous phase described in step 2 is added in oil phase described in step one, then stir 2min ~ 8min with 6000rpm ~ 20000rpm, obtain colostrum;
Step 4, by pH adjusting agent, the pH value of colostrum described in step 3 is adjusted to 4.0 ~ 9.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 20 DEG C ~ 60 DEG C, with 300bar ~ 1200bar pressure homogenizing 4 ~ 12 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 4.0 ~ 9.0;
Step 5, with high-pressure steam sterilizing pan, sterilizing is carried out to the whole breast after adjust ph in step 4, obtain injection tacrolimus lipomul.
The present invention compared with prior art has the following advantages:
1, injection tacrolimus lipomul of the present invention effectively can increase the chemical stability of medicine, and in tacrolimus lipomul, most of drug distribution, at oil phase or oil-water interfaces, avoids medicine directly to contact with water; Medicament solubilization is in oil phase, and isolation medicine, the medication amount of aqueous phase is few, greatly reduces the amount of drug hydrolysis, improves a lot to the stability of medicine.
3, drug moiety is wrapped in oil phase or interfacial film by injection tacrolimus lipomul system of the present invention, avoids and contacts with the direct of body fluid, because this reducing the issuable local of medicine self and blood vessel irritation.In addition, medicine is by slow releasing in oil phase in vivo, can avoid the untoward reaction that medicine causes due to initial stage excessive concentration when injecting.
4, injection tacrolimus lipomul of the present invention adopts surfactant and the composite physical stability improving preparation of amphipathic nature block polymer.Hydrophobic part in amphipathic nature block polymer can be inserted in oil phase whole or in part, and hydrophilic segment is freely unfolded in aqueous phase, effectively prevents the gathering between emulsion droplet, improves the stability of preparation.
5, the stabilizing agent in injection tacrolimus lipomul of the present invention is cholesterol and/or cholesterol sulfate sodium, stabilizing agent can regulate the mobility of fat milk interfacial film, there is good membrane stabilizing action, the Emulsion adding stabilizing agent can not only stand high temperature hot pressing sterilizing, and room temperature or low temperature are placed stable, medicine is not easily separated out.
6, the pharmaceutical pack of tacrolimus more than 90% to be wrapped in the lipid core of fat milk inner in the present invention, and all the other drug distribution are in oil-water interfacial film, and slow down drug degradation, improve the physical and chemical stability of pharmaceutical preparation, extends medicine action time in vivo.
7, significantly reduce when showing as injection after tacrolimus lipomul administrated by injection of the present invention the zest of blood vessel, preparation shows as good chemical physical stability in storage process, without the Seepage of medicine.
8, it is high that the injection tacrolimus lipomul that prepared by the present invention has envelop rate, and the advantage such as have good stability, and is a kind of effective intravenous injection medication, has wide DEVELOPMENT PROSPECT.
Below in conjunction with drawings and Examples, technical scheme of the present invention is described in further detail.
Accompanying drawing explanation
Fig. 1 is the Drug-time curve after the injection tacrolimus lipomul administration of commercially available injection of tacrolimus and the embodiment of the present invention 1 preparation.
Particle size distribution when Fig. 2 is the injection tacrolimus lipomul zero of the embodiment of the present invention 1 preparation.
Detailed description of the invention
Embodiment 1
The injection tacrolimus lipomul of the present embodiment, containing tacrolimus 0.2g in every 100mL injection tacrolimus lipomul, soybean oil 10g, MCT Oil 10g, lecithin (Ovum Gallus domesticus Flavus lecithin) 2g, oleic acid 0.05g, (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides PLLA-PEG, wherein the viscosity-average molecular weight of Polyethylene Glycol is 2000, the viscosity-average molecular weight of Poly-L-lactic acid is 14000) 1.4g, glycerol 2.5g, vitamin E 1.5g, cholesterol 0.8g, disodium edetate 0.02g, hydrochloric acid (consumption is make the pH value of injection tacrolimus lipomul be 6.0), surplus is water for injection.
The preparation method of the injection tacrolimus lipomul of the present embodiment is:
Step one, tacrolimus, vitamin E and cholesterol are added in the mixed solvent of soybean oil and MCT Oil, be stir under the condition of 70 DEG C in temperature, obtain oil phase;
Step 2, glycerol, lecithin, oleic acid, PLLA-PEG and disodium edetate are added in water for injection, be stirred to described raw material under the condition of 70 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, oil phase described in step one is added in aqueous phase described in step 2, then stir 5min with 10000rpm, obtain colostrum;
Step 4, with sodium hydroxide, the pH value of colostrum described in step 3 is adjusted to 6.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 40 DEG C, with 800bar pressure homogenizing 8 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 6.0;
Step 5, carry out sterilizing with high-pressure steam sterilizing pan to the whole breast after adjust ph in step 4, sterilising conditions is 103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus lipomul.
Embodiment 2
The present embodiment is identical with embodiment 1, wherein difference is: described injection oil-based solvent is Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, one in Oleum Curcumae and Rhizoma Chuanxiong oil or more than three kinds, or be Oleum Ricini, Semen Maydis oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, two kinds in Oleum Curcumae and Rhizoma Chuanxiong oil, or be Oleum Ricini, Semen Maydis oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, the mixture of a kind of and soybean oil in Oleum Curcumae and Rhizoma Chuanxiong oil, described surfactant is one in lecithin, span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid or more than three kinds, or be two kinds in span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid, or be the mixture of a kind of and lecithin in span, tween, pluronic, enuatrol and deoxycholic acid, described injection osmotic pressure regulator is sodium chloride, glucose, mannitol or sorbitol, or is at least two kinds in sodium chloride, glucose, mannitol, glycerol and sorbitol, described antioxidant is sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid or Cys, or is at least two kinds in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, Cys and vitamin E, described stabilizing agent is cholesterol sulfate sodium, or cholesterol and cholesterol sulfate sodium, described metal-chelator is sodium calcium edetate, or disodium edetate and sodium calcium edetate.
Embodiment 3
The injection tacrolimus lipomul of the present embodiment, containing tacrolimus 0.01g in every 100mL injection tacrolimus lipomul, Oleum Fructus Bruceae 10g, lecithin (Ovum Gallus domesticus Flavus lecithin) 0.5g, enuatrol 0.1g, Tween 80 0.4g, (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides dextrorotation PLEG, wherein the viscosity-average molecular weight of Polyethylene Glycol is 5000, the viscosity-average molecular weight of Poly-L-lactic acid is 8000) 1g, glycerol 1g, ascorbic acid 1g, cholesterol sulfate sodium 0.5g, sodium calcium edetate 0.01g, sodium hydroxide (consumption is make the pH value of injection tacrolimus lipomul be 9.0), surplus is water for injection.
The preparation method of the injection tacrolimus lipomul of the present embodiment is:
Step one, tacrolimus and cholesterol sulfate sodium are added in Oleum Fructus Bruceae, be stir under the condition of 50 DEG C in temperature, obtain oil phase;
Step 2, glycerol, lecithin, enuatrol, Tween 80, dextrorotation PLEG, sodium calcium edetate and ascorbic acid are added in water for injection, be stirred to described raw material under the condition of 50 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, aqueous phase described in step 2 is added in oil phase described in step one, then stir 8min with 6000rpm, obtain colostrum;
Step 4, with sodium hydroxide, the pH value of colostrum described in step 3 is adjusted to 9.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 20 DEG C, with 1200bar pressure homogenizing 12 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 9.0;
Step 5, carry out sterilizing with high-pressure steam sterilizing pan to the whole breast after adjust ph in step 4, sterilising conditions is 103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus lipomul.
Embodiment 4
The present embodiment is identical with embodiment 3, wherein difference is: described injection oil-based solvent is Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, Oleum Curcumae or Rhizoma Chuanxiong oil, or be Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, at least two kinds in Oleum Curcumae and Rhizoma Chuanxiong oil, described surfactant be one in lecithin, span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid, more than two kinds or four kinds, or be three kinds in span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid, or be two kinds in span, pluronic, enuatrol, oleic acid and deoxycholic acid with the mixture of lecithin, or be the mixture of a kind of and lecithin in span, pluronic, oleic acid and deoxycholic acid and tween, described injection osmotic pressure regulator is sodium chloride, glucose, mannitol or sorbitol, or is two or more in sodium chloride, glucose, glycerol, mannitol and sorbitol, described antioxidant is sodium sulfite, sodium pyrosulfite, sodium sulfite, Cys or vitamin E, or is at least two kinds in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, Cys and vitamin E, described stabilizing agent is cholesterol, or cholesterol and cholesterol sulfate sodium, described metal-chelator is disodium edetate, or disodium edetate and sodium calcium edetate.
Embodiment 5
The injection tacrolimus lipomul of the present embodiment, containing tacrolimus 5g in every 100mL injection tacrolimus lipomul, soybean oil 20g, lecithin (Ovum Gallus domesticus Flavus lecithin) 3g, (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides PDLLA polyethyleneglycol block copolymer, wherein the viscosity-average molecular weight of Polyethylene Glycol is 5000, the viscosity-average molecular weight of PDLLA is 100000) 2g, sodium chloride 1g, sorbitol 1g, glycerol 2g, Cys 1g, vitamin E 1g, cholesterol 1g, cholesterol sulfate sodium 1g, disodium edetate 0.5g, sodium calcium edetate 0.5g, hydrochloric acid (consumption is make the pH value of injection tacrolimus lipomul be 4.0), surplus is water for injection.
The preparation method of the injection tacrolimus lipomul of the present embodiment is:
Step one, tacrolimus, vitamin E, cholesterol and cholesterol sulfate sodium are added in soybean oil, be stir under the condition of 80 DEG C in temperature, obtain oil phase;
Step 2, sorbitol, glycerol, lecithin, PDLLA polyethyleneglycol block copolymer, disodium edetate, sodium calcium edetate and Cys are added in water for injection, be be stirred to described raw material under the condition of 80 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, oil phase described in step one is added in aqueous phase described in step 2, then stir 2min with 20000rpm, obtain colostrum;
Step 4, with hydrochloric acid, the pH value of colostrum described in step 3 is adjusted to 4.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 60 DEG C, with 300bar pressure homogenizing 4 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 4.0;
Step 5, carry out sterilizing with high-pressure steam sterilizing pan to the whole breast after adjust ph in step 4, sterilising conditions is 103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus lipomul.
Embodiment 6
The present embodiment is identical with embodiment 5, wherein difference is: described injection oil-based solvent is Oleum Ricini, Semen Maydis oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, one or more in Oleum Curcumae and Rhizoma Chuanxiong oil, or be Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, at least two kinds in Oleum Curcumae and Rhizoma Chuanxiong oil, described surfactant is span, tween, pluronic, enuatrol, oleic acid or deoxycholic acid, or is at least two kinds in lecithin, span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid, described injection osmotic pressure regulator be one in sodium chloride, glucose, mannitol, glycerol and sorbitol, two kinds, four kinds or five kinds, or be three kinds in glucose, mannitol, glycerol and sorbitol, or be two kinds in glucose, mannitol and sorbitol with the mixture of sodium chloride, or be sodium chloride, glucose and mannitol, described antioxidant is one in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, vitamin E and Cys or more than three kinds, or be two kinds in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid and Cys, or be the mixture of a kind of and vitamin E in sodium sulfite, sodium pyrosulfite, sodium sulfite and ascorbic acid, described stabilizing agent is cholesterol or cholesterol sulfate sodium, described metal-chelator is disodium edetate or sodium calcium edetate.
Embodiment 7
The injection tacrolimus lipomul of the present embodiment, containing tacrolimus 0.5g in every 100mL injection tacrolimus lipomul, Oleum Ricini 0.5g, MCT Oil 0.5g, Petiolus Trachycarpi oil 0.8g, Oleum Curcumae 0.2g, pluronic 0.2g, deoxycholic acid 0.3g, (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides PDLLA polyethyleneglycol block copolymer, wherein the viscosity-average molecular weight of Polyethylene Glycol is 10000, the viscosity-average molecular weight of PDLLA is 50000) 0.1g, glucose 0.5g, cholesterol sulfate sodium 0.1g, disodium edetate 0.001g, sodium hydroxide (consumption is make the pH value of injection tacrolimus lipomul be 8.0), surplus is water for injection.
The preparation method of the injection tacrolimus lipomul of the present embodiment is:
Step one, tacrolimus and cholesterol sulfate sodium are added in the mixed solvent of Oleum Ricini, MCT Oil, Petiolus Trachycarpi oil and Oleum Curcumae, be stir under the condition of 60 DEG C in temperature, obtain oil phase;
Step 2, glucose, pluronic, deoxycholic acid, PDLLA polyethyleneglycol block copolymer and disodium edetate are added in water for injection, be stirred to described raw material under the condition of 60 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, aqueous phase described in step 2 adds in oil phase described in step one, then stirs 4min with 12000rpm, obtains colostrum;
Step 4, by pH adjusting agent, the pH value of colostrum described in step 3 is adjusted to 8.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 30 DEG C, with 1000bar pressure homogenizing 6 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 8.0;
Step 5, carry out sterilizing with high-pressure steam sterilizing pan to the whole breast after adjust ph in step 4, sterilising conditions is 103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus lipomul.
Embodiment 8
The present embodiment is identical with embodiment 7, and wherein difference is: described injection oil-based solvent is Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, one in Oleum Curcumae and Rhizoma Chuanxiong oil, two kinds, more than three kinds or five kinds, or be Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, four kinds in Oleum Curcumae and Rhizoma Chuanxiong oil, or be Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, three kinds in Oleum Curcumae and Rhizoma Chuanxiong oil with the mixture of Oleum Ricini, or be Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Fructus Bruceae, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, two kinds in Oleum Curcumae and Rhizoma Chuanxiong oil with the mixture of Oleum Ricini and MCT Oil, or be Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Fructus Bruceae, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, two kinds and Oleum Ricini in Oleum Bulbus Allii and Rhizoma Chuanxiong oil, the mixture of MCT Oil and Oleum Curcumae, described surfactant is one in lecithin, span, tween, enuatrol, oleic acid and deoxycholic acid or more than three kinds, or is the mixture of a kind of and F68 in lecithin, span, tween, enuatrol and oleic acid, described injection osmotic pressure regulator is sodium chloride, mannitol, glycerol and sorbitol, or is at least two kinds in sodium chloride, glucose, mannitol, glycerol and sorbitol, described stabilizing agent is cholesterol, or cholesterol and cholesterol sulfate sodium, described metal-chelator is sodium calcium edetate, or is disodium edetate and sodium calcium edetate.
Embodiment 9
The injection tacrolimus lipomul of the present embodiment, containing tacrolimus 10g in every 100mL injection tacrolimus lipomul, MCT Oil 20g, lecithin (Ovum Gallus domesticus Flavus lecithin) 5g, enuatrol 2g, (Changchun Applied Chemistry Research Inst., Chinese Academy of Sciences provides PLLA-PEG, wherein the viscosity-average molecular weight of Polyethylene Glycol is 5000, the viscosity-average molecular weight of Poly-L-lactic acid is 20000) 2g, mannitol 2g, glycerol 3g, sorbitol 2g, sodium pyrosulfite 2g, vitamin E 1g, cholesterol 5g, sodium calcium edetate 3g, sodium hydroxide (consumption is make the pH value of injection tacrolimus lipomul be 9.0), surplus is water for injection.
The preparation method of the injection tacrolimus lipomul of the present embodiment is:
Step one, tacrolimus, vitamin E and cholesterol are added in injection oil-based solvent, be stir under the condition of 50 DEG C in temperature, obtain oil phase;
Step 2, mannitol, glycerol, sorbitol, lecithin, enuatrol, PLLA-PEG, sodium calcium edetate and sodium pyrosulfite are added in water for injection, be be stirred to described raw material under the condition of 50 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, oil phase described in step one is added in aqueous phase described in step 2 or aqueous phase described in step 2 is added in oil phase described in step one, then stir 8min with 6000rpm, obtain colostrum;
Step 4, by pH adjusting agent, the pH value of colostrum described in step 3 is adjusted to 9.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 60 DEG C, with 500bar pressure homogenizing 8 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 9.0;
Step 5, carry out sterilizing with high-pressure steam sterilizing pan to the whole breast after adjust ph in step 4, sterilising conditions is 103.4kPa, 121 DEG C of sterilizing 10min, obtains injection tacrolimus lipomul.
Embodiment 10
The present embodiment is identical with embodiment 9, wherein difference is: described injection oil-based solvent is Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, Oleum Curcumae or Rhizoma Chuanxiong oil, or be Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, at least two kinds in Oleum Curcumae and Rhizoma Chuanxiong oil, described surfactant is one in lecithin, span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid or more than three kinds, or be two kinds in span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid, or be the mixture of a kind of and lecithin in span, tween, pluronic, oleic acid and deoxycholic acid, described injection osmotic pressure regulator be one in sodium chloride, glucose, mannitol, glycerol and sorbitol, two kinds, four kinds or five kinds, or be three kinds in sodium chloride, glucose, mannitol and glycerol, or be the mixture of in sodium chloride, glucose and mannitol two kinds and sorbitol, or be sodium chloride, glycerol and sorbitol, or be glucose, glycerol and sorbitol, described antioxidant is one in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, Cys and vitamin E or more than three kinds, or be two kinds in sodium sulfite, sodium sulfite, ascorbic acid, Cys and vitamin E, or be the mixture of a kind of and sodium pyrosulfite in sodium sulfite, sodium sulfite, ascorbic acid and vitamin E, described stabilizing agent is cholesterol or cholesterol and cholesterol sulfate sodium, described metal-chelator is disodium edetate or disodium edetate and sodium calcium edetate.
The properties of injection tacrolimus lipomul of the present invention is investigated:
One, vascular stimulation test
Get healthy rabbits 15, be divided into 5 groups at random, often organize 3.5 groups of left ears of rabbit all inject sodium chloride injection, and auris dextra injects the injection tacrolimus lipomul of the embodiment of the present invention 1,3,5,7 and 9 respectively, administration every day 1 time, for three days on end.During administration, perusal administration every day local vascular is with or without thrombosis, and surrounding tissue is with or without inflammatory reactions such as red and swollen congestion.Administration terminates rear execution, and ear tissue is taken off at centripetal direction 3cm place of self administration of medication place, fix with 10% formalin, paraffin embedding, film-making, dyeing, light Microscopic observation vascular machine tissue morphology change.
Table 1 vascular stimulation result of the test
Histological findings shows: administration group rabbit ear edge venous blood tube wall is complete, smooth.Have no endothelial injury, without pathological changes such as thrombosis and peripheral tissue edema, cell infiltration, inflammation and necrosis.Administration group compares without significant difference with negative control group, shows that prepared injection tacrolimus fat milk has no obvious stimulation to family's rabbit ear blood vessel.
Two, animal sensitivity test
Get body weight 250g ~ 350g healthy guinea pig 42, be divided into 7 groups at random, 0.9% sodium chloride injection is injected for one group as negative control group, per injection dosage is 0.5mL/, 10% egg albumin solution is injected for one group as positive controls, per injection dosage is 0.1mL/, injects the injection tacrolimus lipomul of the embodiment of the present invention 1,3,5,7 and 9 respectively for all the other five groups as test sample group, and per injection dosage is 0.5mL/.Injection system and number of times: the next day lumbar injection once, altogether inject three times.Then negative control group, positive controls and each confession examination group intravenous injection 0.9% sodium chloride injection, 10% egg albumin solution and each need testing solution respectively on the 14th after final injection, administration volume is only 1mL/, excites.After injection in 15 minutes, whether the Cavia porcellus observing liquid medicine injection there is anaphylaxis.If any two or more person in the phenomenons such as perpendicular hair, dyspnea or cough 3 sound, or there is the one of the phenomenons such as tic, collapse or death, be then judged to the positive (having anaphylaxis).The results are shown in Table 2.
Table 2 Hypersensitive tests result (n=6)
As can be seen from Table 2, often organize each 6 Cavia porcelluss in 15 minutes after injection tacrolimus lipomul twice intravenously administrable that negative control group and the present invention prepare and all do not occur anaphylaxis, after positive control solution twice intravenously administrable, in 1 minute, 6 Cavia porcelluss all occur that cough, respiration inhibition, tic are until death.Result shows: systemic anaphylaxis does not appear in the injection tacrolimus lipomul hypersensitive test that the embodiment of the present invention 1,3,5,7 and 9 prepares under this experimental condition.
Three, animal hemolytic test
The preparation of 2% red cell suspension: get fresh Sanguis Leporis seu oryctolagi 10mL, be placed in beaker, use Glass rod mild agitation, except defibrinating after several minutes, taking out blood, adding 5 times amount normal saline, shake up, the centrifugal 5min of 2500rpm/min, abandoning supernatant; The erythrocyte of precipitation is again with the cleaning of commensurability normal saline, and centrifugal, cyclic washing like this 3 ~ 4 times, to supernatant becomes water white transparency.The erythrocyte normal saline washed is become 2% red cell suspension, for subsequent use.
Experimental design: get clean tube 7, number respectively, adds each liquid in following table successively, it is blank pipe that 6th pipe does not add test liquid, and the 7th effective distilled water replaces physiological water, shakes up, whether be placed in 37 DEG C of water-baths, observing respectively at 0.5h, 1h, 2h, 3h, 4h has haemolysis to occur.
Result criterion: full haemolysis: the clear and bright redness of solution, remains without erythrocyte at the bottom of pipe; Part haemolysis: solution is clear and bright or brown, has a small amount of erythrocyte to remain at the bottom of pipe; Without haemolysis: erythrocyte all sinks, supernatant liquid achromatism and clarity; Coagulation: not haemolysis, erythrocyte is coagulation bottom test tube, and after jolting, cell can not disperse.
The hemolytic test result of the injection tacrolimus lipomul of table 3 embodiment of the present invention 1
Note: +++ complete hemolysis; ++ part haemolysis; + coagulation; , also there is not coagulation in-not haemolysis
Result of the test shows: the injection tacrolimus lipomul that the embodiment of the present invention 1 prepares did not cause haemolysis or agglutination in 4 hours.
Adopt said method to carry out the test of animal hemolytic to injection tacrolimus lipomul prepared by the embodiment of the present invention 3,5,7 and 9, in 4 hours, all do not cause haemolysis or agglutination.
Four, rat Internal pharmacokinetics experiment
By 12 Wistar kind male rats, body weight (200 ± 20) g, is divided into two groups: R group and A group at random, often organizes 6, fasting one night before experiment.R group is matched group, the commercially available injection of tacrolimus of tail vein injection (Prograf); A group is tested group, in injection tacrolimus lipomul (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 gets blood 0.5mL, puts in the 1.5mL point end centrifuge tube of heparinization in advance, measures drug level after process with LC-MS/MS.
Every pharmacokinetic parameters (n=6) that table 4 adopts statistical moment method to calculate
Note: a represents p<0.05;
Statistical software (SPSS, version11.5) is adopted to carry out one-tailed t-test analysis to every pharmacokinetic parameters that two kinds of preparations are main.Relatively two groups of data, if when obtaining p<0.05, illustrate that two groups of data have significant difference.As shown in Table 4, TLE and Prograf compares, except AUC, and other pharmacokinetic parameters there are no significant difference.
By TLE in Fig. 1 (injection tacrolimus lipomul prepared by the embodiment of the present invention 1), compared with Prograf (commercially available injection of tacrolimus), the two Internal pharmacokinetics behavior is very similar.Show that prepared preparation is similar to commercially available injection, under the prerequisite not changing pharmacokinetics behavior, serve the effect improving drug solubility, increase medicine stability.
Five, accelerated stability test
Because injection tacrolimus lipomul is thermodynamic unstable system, belong to heat sensitive dosage form.According to the explanation of Chinese Pharmacopoeia version crude drug in 2010 and pharmaceutical preparation stability test guideline, the injection tacrolimus lipomul embodiment of the present invention 1 prepared is placed 6 months under the condition of 25 ± 2 DEG C, investigates the change of physical and chemical stability.
Table 5 accelerated stability test result
| 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, it is good that the injection tacrolimus lipomul that prepared by the embodiment of the present invention 1 accelerates outward appearance, physical stability and chemical stability after 6 months under the condition of 25 ± 2 DEG C.
Adopt said method to carry out accelerated stability test to injection tacrolimus lipomul prepared by the embodiment of the present invention 3,5,7 and 9, under the condition of 25 ± 2 DEG C, accelerate outward appearance, physical stability and chemical stability after 6 months good.
Six, long-term stable experiment
The injection tacrolimus lipomul embodiment of the present invention 1 prepared is placed 12 months under the condition of 6 ± 2 DEG C, investigates the change of physical and chemical stability.The embodiment of the present invention 1 prepare injection tacrolimus lipomul zero time particle size distribution as shown in Figure 2, mean diameter is at about 200nm.
Table 6 long-term stable experiment result
| 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 lipomul that prepared by the embodiment of the present invention 1 still meets quality standard regulation in the assay of 6 ± 2 DEG C of long term tests, 12 months every inspection target.
Adopt said method long-term stable experiment is carried out to injection tacrolimus lipomul prepared by the embodiment of the present invention 3,5,7 and 9,6 ± 2 DEG C of long term tests after 12 months outward appearance, physical stability and chemical stability good.
To sum up, injection tacrolimus lipomul of the present invention still meets quality standard regulation in the assay through 25 ± 2 DEG C of accelerated tests 6 months and 6 ± 2 DEG C of long term tests, 12 months every inspection target, can ensure the steady quality of preparation at duration of storage.
The above; it is only preferred embodiment of the present invention; not the present invention is imposed any restrictions, every above embodiment is done according to the technology of the present invention essence any simple modification, change and equivalent structure change, all still belong in the protection domain of technical solution of the present invention.
Claims (10)
1. an injection tacrolimus lipomul, it is characterized in that, containing tacrolimus 0.01g ~ 10g in every 100mL injection tacrolimus lipomul, injection oil-based solvent 2g ~ 20g, surfactant 0.5g ~ 7g, amphipathic nature block polymer 0.1g ~ 2g, injection osmotic pressure regulator 0.5g ~ 7g, antioxidant 0 ~ 3g, stabilizing agent 0.1g ~ 5g; Described antioxidant is water soluble antioxidants and/or oil-soluble antioxidants.
2. a kind of injection tacrolimus lipomul according to claim 1, it is characterized in that, containing tacrolimus 0.01g ~ 5g in every 100mL injection tacrolimus lipomul, injection oil-based solvent 10g ~ 20g, surfactant 1g ~ 3g, amphipathic nature block polymer 1g ~ 2g, injection osmotic pressure regulator 1g ~ 4g, antioxidant 1g ~ 2g, stabilizing agent 0.5g ~ 2g.
3. a kind of injection tacrolimus lipomul according to claim 2, it is characterized in that, containing tacrolimus 0.2g in every 100mL injection tacrolimus lipomul, injection oil-based solvent 20g, surfactant 2.05g, amphipathic nature block polymer 1.4g, injection osmotic pressure regulator 2.5g, antioxidant 1.5g, stabilizing agent 0.8g.
4. a kind of injection tacrolimus lipomul according to claim 1,2 or 3, it is characterized in that, also containing metal-chelator 0.001g ~ 3g in every 100mL injection tacrolimus lipomul, described metal-chelator is disodium edetate and/or sodium calcium edetate.
5. a kind of injection tacrolimus lipomul according to claim 4, it is characterized in that, also containing pH adjusting agent in described injection tacrolimus lipomul, the consumption of pH adjusting agent is make the pH value of injection tacrolimus lipomul be 4.0 ~ 9.0, and described pH adjusting agent is sodium hydroxide or hydrochloric acid.
6. a kind of injection tacrolimus lipomul according to claim 1,2 or 3, it is characterized in that, described injection oil-based solvent is one or more in Oleum Ricini, Semen Maydis oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, safflower oil, MCT Oil, Oleum Fructus Bruceae, Petiolus Trachycarpi oil, Oleum Helianthi, Fructrs Hippophae seed oil, Radix Angelicae Sinensis oil, Fructus Zanthoxyli oil, Oleum Bulbus Allii, Oleum Curcumae and Rhizoma Chuanxiong oil; Described surfactant is one or more in lecithin, span, tween, pluronic, enuatrol, oleic acid and deoxycholic acid.
7. a kind of injection tacrolimus lipomul according to claim 1,2 or 3, it is characterized in that, the hydrophilic segment in described amphipathic nature block polymer is Polyethylene Glycol, and hydrophobic segment is Poly-L-lactic acid, dextrorotation polylactic acid or PDLLA.
8. a kind of injection tacrolimus lipomul according to claim 7, is characterized in that, the viscosity-average molecular weight of described hydrophilic segment is 2000 ~ 10000, and the viscosity-average molecular weight of hydrophobic segment is 8000 ~ 100000.
9. a kind of injection tacrolimus lipomul according to claim 1,2 or 3, is characterized in that, described stabilizing agent is cholesterol and/or cholesterol sulfate sodium; Described injection osmotic pressure regulator is one or more in sodium chloride, glucose, mannitol, glycerol and sorbitol; Described water soluble antioxidants is one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid and Cys, and described oil-soluble antioxidants is vitamin E.
10. prepare a method for injection tacrolimus lipomul as claimed in claim 5, it is characterized in that, the method comprises the following steps:
Step one, tacrolimus, oil-soluble antioxidants and stabilizing agent are added in injection oil-based solvent, be stir under the condition of 50 DEG C ~ 80 DEG C in temperature, obtain oil phase;
Step 2, injection osmotic pressure regulator, surfactant, amphipathic nature block polymer, metal-chelator and water soluble antioxidants are added in water for injection, be stirred to described raw material under the condition of 50 DEG C ~ 80 DEG C all to dissolve in temperature, obtain aqueous phase;
Step 3, utilize high-speed tissue mashing machine, oil phase described in step one is added in aqueous phase described in step 2 or aqueous phase described in step 2 is added in oil phase described in step one, then stir 2min ~ 8min with 6000rpm ~ 20000rpm, obtain colostrum;
Step 4, by pH adjusting agent, the pH value of colostrum described in step 3 is adjusted to 4.0 ~ 9.0, then water for injection standardize solution is used, colostrum after standardize solution is transferred in high pressure homogenizer, controlling homogenizing temperature is 20 DEG C ~ 60 DEG C, with 300bar ~ 1200bar pressure homogenizing 4 ~ 12 times, obtain whole breast, then by pH adjusting agent, the pH value of described breast is eventually adjusted to 4.0 ~ 9.0;
Step 5, with high-pressure steam sterilizing pan, sterilizing is carried out to the whole breast after adjust ph in step 4, obtain injection tacrolimus lipomul.
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| CN108721702A (en) * | 2018-06-29 | 2018-11-02 | 江西理工大学 | A kind of preparation method of magnesium/l-lactic acid Composite Bone holder |
| CN115137713A (en) * | 2021-03-29 | 2022-10-04 | 北京新领先医药科技发展有限公司 | Amphotericin B atomization inhalation preparation and preparation method thereof |
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| WO2012011192A1 (en) * | 2010-07-23 | 2012-01-26 | マルホ株式会社 | Tacrolimus-containing oil-in-water type creamy composition |
| CN102302447B (en) * | 2011-09-09 | 2013-04-24 | 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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| CN108721702A (en) * | 2018-06-29 | 2018-11-02 | 江西理工大学 | A kind of preparation method of magnesium/l-lactic acid Composite Bone holder |
| CN115137713A (en) * | 2021-03-29 | 2022-10-04 | 北京新领先医药科技发展有限公司 | Amphotericin B atomization inhalation preparation and preparation method thereof |
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