CN108392637B - Posaconazole liposome and preparation method thereof - Google Patents
Posaconazole liposome and preparation method thereof Download PDFInfo
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- CN108392637B CN108392637B CN201810287307.2A CN201810287307A CN108392637B CN 108392637 B CN108392637 B CN 108392637B CN 201810287307 A CN201810287307 A CN 201810287307A CN 108392637 B CN108392637 B CN 108392637B
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- posaconazole
- phospholipid
- liposome
- buffer solution
- freeze
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- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 189
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 188
- 239000002502 liposome Substances 0.000 title claims abstract description 148
- 238000002360 preparation method Methods 0.000 title abstract description 27
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 122
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 62
- 239000007853 buffer solution Substances 0.000 claims abstract description 61
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Abstract
The invention belongs to the technical field of pharmaceutical preparations. The invention discloses a posaconazole liposome, which is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein PEG modified phospholipid and/or charged phospholipid can be added; the invention also discloses a preparation method of the posaconazole liposome, which comprises the steps of preparing a phospholipid membrane, carrying out hydration incubation, carrying out high-pressure homogenization and carrying out freeze drying to obtain the posaconazole liposome. Compared with the traditional preparation formulation, the posaconazole liposome has the advantages of sustained release effect, reduced administration dosage, avoidance of drug accumulation in vivo after long-term administration, improvement of the bioavailability and intracellular treatment effect of posaconazole, increased targeting property, and reduction of drug toxicity and side effects; the preparation method of the saperconazole liposome has simple process and good reproducibility, and can realize industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to posaconazole liposome and a preparation method thereof.
Background
Fungi are eukaryotic microorganisms, and are classified into superficial and deep fungi according to the site of infection. Superficial fungal infections mainly attack the epidermis, hair, nails, etc., and can be cured by topical administration of ointments, lotions, etc. Deep fungi can cause infection of tissues such as internal organs, bones and the like, and are relatively harmful. With the wide application of high-efficiency and broad-spectrum antibiotics and the increasing number of AIDS patients, the incidence rate of invasive fungal infection is increasing, so that broad-spectrum, high-efficiency, low-toxicity and novel antifungal medicines become the key point of antifungal medicine research.
Clinically, the drugs for deep fungal infection are classified according to the mechanism of action: 1. affecting the fungal cell membrane: polyenes (amphotericin B, etc.), triazoles (itraconazole, voriconazole, posaconazole, fluconazole, etc.); 2. affecting the fungal cell wall: echinocandins (caspofungin, anidulafungin, etc.); 3. influence protein and nucleic acid synthesis: fluorocytosine. After general antifungal drugs are administered, the antifungal drugs have weak ability to enter cells due to inappropriate oil-water distribution coefficient, pH gradient, strong binding force between the drugs and protein, unfavorable activity transport mechanism and the like, and cannot play a role because the drugs are difficult to enter the cells, so that the antifungal drugs have difficulty in treating most intracellular infections and can increase the toxic and side effects of the drugs on human bodies. Therefore, the development and application of the novel antifungal preparation can effectively reduce the infection rate and the death rate of deep fungi of immunodeficiency patients such as HIV patients, acute leukemia patients receiving chemotherapy, patients receiving bone marrow transplantation and the like.
Posaconazole is a second-generation triazole antifungal drug, is a derivative of itraconazole, is suitable for treating deep fungal infections (such as invasive aspergillus, fusarium, yeast, mycobacterium and coccidioidomycosis), and is also suitable for patients 13 years old and over 13 years old with increased infection risks due to severe immunodeficiency. These patients include patients who develop Graft Versus Host Disease (GVHD) after receiving Hematopoietic Stem Cell Transplantation (HSCT) or hematological malignancies whose chemotherapy results in prolonged neutropenia. The mechanism of action of posaconazole is mainly to reduce the synthesis of ergosterol. Ergosterol is an essential substance in the process of fungal cell synthesis, is involved in the synthesis of some important proteins on the cell, and is an essential substance in fungal cells. When the posaconazole acts on fungal cells, the posaconazole competes with lanosterol 14 alpha-demethylase in the fungi to reduce the activity of the posaconazole, so that the cellular lanosterol is accumulated and the ergosterol is absent, and the cell membrane cannot be synthesized, thereby exerting the drug effect of the posaconazole.
Chemical name of posaconazole: 4- [4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazol-1-ylmethyl) oxolan-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazol-3-one, having the formula:
posaconazole was successfully developed by the company pionship, and was marketed in 2005 in germany in the form of an oral suspension, trade name: NOXAFIL, later purchased by merck corporation, was marketed by the FDA with sequential approval of posaconazole oral delayed-release tablets and injections in 2013 and 2014. At present, only oral suspension is approved for use clinically in China. The three dosage forms of posaconazole on the market are all suitable for preventing and treating deep fungal infection, but due to the lipophilicity and high protein binding rate of posaconazole, the bioavailability of oral suspension after administration is low, the bioavailability of delayed release tablets and injection is improved, but the drug targeting is poor, in-vivo drug accumulation can be caused after long-term administration, and the injection has strong hepatotoxicity and side effects, particularly, sulfobutyl-betacyclodextrin is selected as an auxiliary material for increasing the solubility of posaconazole, and has certain nephrotoxicity.
That is, the existing posaconazole formulations have the following problems. The posaconazole oral liquid has low bioavailability; the bioavailability of the oral liquid and the delayed release tablet is greatly influenced by food after administration; the injection administration needs central vein administration, the operation is complex, and the adjuvant is sulfobutyl-beta-cyclodextrin, which has nephrotoxicity, high drug protein binding rate and poor targeting property, and the long-term administration can accumulate the drug in vivo and increase the toxic and side effects.
Disclosure of Invention
In order to solve the problems of the existing posaconazole preparation, the invention provides a posaconazole liposome;
the invention also provides a preparation method of the posaconazole liposome.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 3-10, wherein the weight ratio of cholesterol to phospholipid is 1: 3-8, 5-20 wt% of dry protective agent, 1-10 wt% of antioxidant and 1-10 wt% of hydration buffer.
The liposome is a cell-like lipid bilayer consisting of phospholipid and cholesterol, and the medicament is wrapped in the liposome or between phospholipid layers, so that the liposome has the advantages of slow release, targeting, medicament stability improvement, toxic or side effect reduction and the like. The liposome auxiliary materials are phospholipid and cholesterol, so that the liposome has good biocompatibility, no toxicity, no antigenicity and the like, and the drug toxicity is greatly reduced. After the liposome is injected and administered, the liposome is exogenous substances in vivo, and is quickly phagocytized by mononuclear cells or macrophages in blood to reach target sites such as liver, spleen, lung, bone marrow and the like with concentrated distribution of a reticuloendothelial system, so that intracellular infection which is difficult to treat by the traditional preparation is solved, and the therapeutic index of the medicament is improved. The patent also adopts PEG modified phospholipid to prepare posaconazole long-circulating liposome. The surface of the liposome is provided with a layer of PEG (polyethylene glycol) membrane with hydrophilic polyhydroxy group, so that the combination of posaconazole and conditioning components in plasma is reduced, and the stability of posaconazole in blood is improved; can also reduce the recognition and phagocytosis of mononuclear phagocyte in vivo, effectively prolong the circulation time of the drug in vivo, improve half-life, allow the liposome to have sufficient time to be permeated by tissues with strong capillary permeability such as inflammation parts, and increase the concentration of the drug in target tissues.
Preferably, the weight ratio of posaconazole to phospholipid is 1: 4-7; the weight ratio of cholesterol to phospholipids is 1: 4 to 7.
Preferably, the weight ratio of posaconazole to phospholipid is 1: 6; the weight ratio of cholesterol to phospholipids is 1: 6.
preferably, the lyoprotectant comprises 10 wt% of the total weight.
Preferably, the posaconazole liposome further contains at least one of PEG modified phospholipid or charged phospholipid; wherein the weight ratio of the PEG modified phospholipid to the posaconazole is 1: 0.5-3, wherein the weight ratio of the charged phospholipid to the posaconazole is 1: 0.5 to 3.
Preferably, the weight ratio of the PEG-modified phospholipid to posaconazole is 1: 2.
preferably, the PEG-modified phospholipid is at least one of distearoylphosphatidylethanolamine-polyethylene glycol 2000, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 5000, or dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000; the charged phospholipid is at least one of dilauroyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, distearoyl phosphatidyl glycerol, dimyristoyl phosphatidyl glycerol, dioleoyl phosphatidyl glycerol, dilauroyl phosphatidic acid, egg yolk phosphatidyl glycerol, dioleoyl phosphatidyl serine, dimyristoyl phosphatidic acid or distearoyl phosphatidic acid.
Preferably, the phospholipid is at least one of distearoylphosphatidylcholine, egg yolk phospholipid, soybean phospholipid, and hydrogenated soybean phospholipid.
Preferably, the antioxidant is at least one of alpha-tocopherol, sodium sulfite, sodium metabisulfite, L-cysteine, thiourea, ascorbyl palmitate or tert-butyl p-hydroxyanisole.
Preferably, the lyoprotectant is at least one of sucrose, lactose, mannitol, sorbitol, trehalose, glucose, or dextran.
Preferably, the hydration buffer solution is at least one of phosphate buffer solution, citrate buffer solution, carbonate buffer solution, borate buffer solution, acetate buffer solution or ammonium chloride solution, and the pH value is 2-11.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and removing the organic solvent to obtain a phospholipid membrane;
b) pouring the hydration buffer solution into the phospholipid membrane, adding the freeze-drying protective agent, and vibrating and stirring to obtain a hydration solution;
c) and homogenizing the hydration solution under high pressure to obtain the posaconazole liposome.
d) And (3) freeze-drying the prepared posaconazole liposome.
Preferably, in step a, the organic solvent is removed by a membrane separation method, a spray drying method or a vacuum drying method.
Preferably, the organic solvent is removed by a spray drying method in the step a, the pressure of nitrogen is 0.3Mpa, the temperature is 35 ℃, and after the liquid spraying is finished, the drying is continued for 10 to 30 minutes.
Preferably, in step a, the organic solvent is at least one of dichloromethane, chloroform, methanol and acetone.
Preferably, in step a, the organic solvent is at least one of dichloromethane and methanol.
Preferably, in the step b, the pH value of the hydration buffer solution is 5-8, the treatment temperature of the oscillation stirring is 30-80 ℃, and the treatment time of the oscillation stirring is 20-120 minutes.
Preferably, the rotation speed of the step b during the oscillating and stirring treatment is 200-600 rpm, and the treatment time is 20-40 minutes.
Preferably, the treatment temperature of the shaking and stirring in the step b is 37 ℃.
Preferably, in step c, the high-pressure homogenization method is an ultrasonic method, a high-pressure micro-jet method or a pressure extrusion method, and the particle size of the liposome is controlled within the range of 50-200 nm.
Preferably, in the step c, the homogenization method adopts a high-pressure micro-jet method, and the pressure is 10000-24000 psi.
Preferably, in step c, the homogenization method is a high-pressure microfluidization method, and the pressure is 15000-20000 psi.
Preferably, in step c, the homogenization method is a high-pressure microfluidization method, and the pressure is 16000 psi.
Preferably, in step c, the liposome has a particle size of 100 nm.
Preferably, in the step c, the homogenizing method adopts a pressure extrusion method, the particle size of an extrusion film is 80-500 nm, and the solution after extrusion is subjected to aseptic packaging.
Preferably, in step c, the homogenization method is a pressure extrusion method, the pressure of extrusion gas is 0.4MPa, the particle size of an extrusion film is 100nm, and the solution is subjected to aseptic subpackaging after extrusion.
Preferably, the posaconazole liposome is directly stored in a nitrogen-filled manner or is frozen and dried to prepare the posaconazole liposome freeze-dried powder.
Therefore, the invention has the following beneficial effects:
(1) compared with the traditional preparation formulation, the posaconazole liposome has the advantages of sustained release effect, reduced administration dosage, avoidance of drug accumulation in vivo after long-term administration, improvement of the bioavailability and intracellular treatment effect of posaconazole, increased targeting property, and reduction of drug toxicity and side effects;
(2) the preparation method of the saperconazole liposome has simple process and good reproducibility, and can realize industrial production.
Drawings
Figure 1 is a particle size distribution plot of posaconazole liposome of example 7;
figure 2 is the particle size distribution plot of posaconazole liposome of example 11;
FIG. 3 is a posaconazole liposome dissolution profile;
FIG. 4 is a scanning electron micrograph of posaconazole long-circulating liposomes;
FIG. 5 is a transmission electron microscope image of posaconazole long-circulating liposome frozen;
FIG. 6 is a set of curves of concentration of posaconazole in blood and between tissues in mice with time;
wherein a is a blood drug concentration-time curve, b is a heart drug concentration-time curve, c is a liver drug concentration-time curve, d is a spleen drug concentration-time curve, e is a lung drug concentration-time curve, and f is a kidney drug concentration-time curve.
Detailed Description
The technical solution of the present invention will be further described with reference to the following embodiments.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the present invention, all the equipments and materials are commercially available or commonly used in the industry, and the methods in the following examples are conventional in the art unless otherwise specified.
Example 1
The posaconazole liposome is prepared from posaconazole, phospholipid, PEG modified phospholipid, charged phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 3-10, wherein the weight ratio of cholesterol to phospholipid is 1: 3-8, the freeze-drying protective agent accounts for 5-20 wt% of the total weight, the antioxidant accounts for 1-10 wt% of the total weight, the hydration buffer accounts for 1-10 wt% of the total weight, and the weight ratio of the PEG modified phospholipid to the posaconazole is 1: 0.5-3, wherein the weight ratio of the charged phospholipid to the posaconazole is 1: 0.5 to 3;
the phospholipid is yolk phospholipid, the antioxidant is a mixture of alpha-tocopherol and sodium sulfite, the freeze-drying protective agent is a mixture of sorbitol and trehalose, the hydration buffer is a mixed buffer of a citrate buffer and a carbonate buffer, and the PEG modified phospholipid is a mixture of distearoylphosphatidylethanolamine-polyethylene glycol 2000 and dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 5000; the charged phospholipid is a mixture of dilauroyl phosphatidyl glycerol and dimyristoyl phosphatidyl glycerol.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and then removing the organic solvent to obtain a phospholipid membrane; removing the organic solvent by a thin film dispersion method; the organic solvent is dichloromethane;
b) pouring the hydration buffer solution into the phospholipid membrane, oscillating and stirring to obtain a hydration solution, and adding a freeze-drying protective agent; the pH value of the hydration buffer solution is 5, the processing temperature of the oscillation stirring is 30 ℃, the rotating speed is 200rpm, and the processing time of the oscillation stirring is 20 minutes;
c) homogenizing the hydrated solution under high pressure to obtain posaconazole liposome; the homogenizing method is an ultrasonic method, and the particle size of the liposome is controlled within the range of 50-200 nm;
the posaconazole liposomes in this example were stored directly by filling nitrogen.
Example 2
The posaconazole liposome is prepared from posaconazole, phospholipid, PEG modified phospholipid, charged phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 3-10, wherein the weight ratio of cholesterol to phospholipid is 1: 3-8, the freeze-drying protective agent accounts for 5-20 wt% of the total weight, the antioxidant accounts for 1-10 wt% of the total weight, the hydration buffer accounts for 1-10 wt% of the total weight, and the weight ratio of the PEG modified phospholipid to the posaconazole is 1: 0.5-3, wherein the weight ratio of the charged phospholipid to the posaconazole is 1: 0.5 to 3;
the phospholipid is soybean phospholipid, the antioxidant is a mixture of sodium metabisulfite and sodium sulfite, the freeze-drying protective agent is a mixture of mannitol and sucrose, the hydration buffer is a mixed buffer of a carbonate buffer and a borate buffer, and the PEG modified phospholipid is dipalmitoyl phosphatidylethanolamine-methoxypolyethylene glycol 5000; the charged phospholipid is a mixture of dipalmitoyl phosphatidyl glycerol and dioleoyl phosphatidyl glycerol.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and then removing the organic solvent to obtain a phospholipid membrane; removing organic solvent by spray drying method under nitrogen pressure of 0.3Mpa and temperature of 35 deg.C, and continuously drying for 20min after liquid spraying is finished; the organic solvent is dichloromethane;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 6, the processing temperature of the oscillation stirring is 37 ℃, the rotating speed is 400rpm, and the processing time of the oscillation stirring is 40 minutes;
c) homogenizing the hydrated solution under high pressure to obtain posaconazole liposome; the high-pressure homogenizing method is a high-pressure micro-jet method, the particle size of the liposome is controlled within the range of 50-200 nm, the high-pressure micro-jet method is adopted in the homogenizing method, and the pressure is 16000 psi;
the posaconazole liposomes in this example were stored directly by filling nitrogen.
Example 3
The posaconazole liposome is prepared from posaconazole, phospholipid, PEG modified phospholipid, charged phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 3-10, wherein the weight ratio of cholesterol to phospholipid is 1: 3-8, the freeze-drying protective agent accounts for 5-20 wt% of the total weight, the antioxidant accounts for 1-10 wt% of the total weight, the hydration buffer accounts for 1-10 wt% of the total weight, and the weight ratio of the PEG modified phospholipid to the posaconazole is 1: 0.5-3, wherein the weight ratio of the charged phospholipid to the posaconazole is 1: 0.5 to 3;
the phospholipid is soybean phospholipid, the antioxidant is a mixture of L-cysteine, ascorbyl palmitate and tert-butyl p-hydroxyanisole, the freeze-drying protective agent is a mixture of glucose and dextran, the hydration buffer is a mixed buffer of citrate buffer and acetate buffer, the PEG modified phospholipid is dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000, and the charged phospholipid is a mixture of distearoylphosphatidylglycerol, egg yolk phosphatidylglycerol, dimyristoylphosphatidic acid and distearoylphosphatidic acid.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and then removing the organic solvent to obtain a phospholipid membrane; removing the organic solvent by a vacuum drying method; the organic solvent is acetone;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 8, the processing temperature of the oscillation stirring is 80 ℃, the rotating speed is 600rpm, and the processing time of the oscillation stirring is 120 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenizing method is a pressure extrusion method, and the particle size of the liposome is controlled within the range of 50-200 nm; the homogenizing method adopts a pressure extrusion method, the pressure of extrusion gas is 0.4MPa, the grain diameter of an extrusion film is 300nm, and the solution after extrusion is subjected to aseptic subpackage;
the posaconazole liposomes in this example were stored directly by filling nitrogen.
Example 4
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 6, the weight ratio of cholesterol to phospholipid is 1: 6, the cryoprotectant accounts for 5 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the antioxidant is L-cysteine, the freeze-drying protective agent is glucose, and the hydration buffer solution is phosphate buffer solution.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and removing the organic solvent by adopting a vacuum drying method to prepare the phospholipid membrane; the organic solvent is dichloromethane;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 7, the processing temperature of the oscillation stirring is 60 ℃, the rotating speed is 400rpm, and the processing time of the oscillation stirring is 70 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenization method is an ultrasonic method.
The posaconazole liposome in the embodiment is subjected to freeze drying to prepare the posaconazole liposome freeze-dried powder.
Example 5
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 6, the weight ratio of cholesterol to phospholipid is 1: 6, the cryoprotectant accounts for 5 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the antioxidant is thiourea, the freeze-drying protective agent is sorbitol, and the hydration buffer solution is phosphate buffer solution.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and removing the organic solvent by adopting a vacuum drying method to prepare the phospholipid membrane; the organic solvent is dichloromethane;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 7, the processing temperature of the oscillation stirring is 60 ℃, the rotating speed is 400rpm, and the processing time of the oscillation stirring is 70 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenization process was a high pressure microfluidization process at 15000 psi.
The posaconazole liposome in the embodiment is subjected to freeze drying to prepare the posaconazole liposome freeze-dried powder.
Example 6
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 6, the weight ratio of cholesterol to phospholipid is 1: 6, the cryoprotectant accounts for 5 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the antioxidant is ascorbyl palmitate, the freeze-drying protective agent is trehalose, and the hydration buffer is phosphate buffer.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and removing the organic solvent by adopting a vacuum drying method to prepare the phospholipid membrane; the organic solvent is dichloromethane;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 7, the processing temperature of the oscillation stirring is 60 ℃, the rotating speed is 400rpm, and the processing time of the oscillation stirring is 70 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenizing method adopts pressure extrusion method, the pressure of extrusion gas is 0.4MPa, the particle diameter of extrusion film is 80nm, continuous extrusion is carried out for 3 times, and the solution is aseptically packaged after extrusion.
The posaconazole liposome in the embodiment is subjected to freeze drying to prepare the posaconazole liposome freeze-dried powder.
Example 7
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 6, the weight ratio of cholesterol to phospholipid is 1: 6, the cryoprotectant accounts for 10 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the antioxidant is sodium metabisulfite, the freeze-drying protective agent is sucrose, and the hydration buffer solution is phosphate buffer solution.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and then removing the organic solvent to obtain a phospholipid membrane; the organic solvent adopts dichloromethane, and the spray drying method is adopted to remove the organic solvent, the pressure of nitrogen is 0.3Mpa, the temperature is 35 ℃, and after the liquid is sprayed, the drying is continued for 15 minutes;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 5-8, the processing temperature of the oscillation stirring is 60 ℃, the rotating speed is 200-600 rpm, and the processing time of the oscillation stirring is 20-120 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenization method was a high pressure microfluidics method with a gas pressure of 16000 psi.
The posaconazole liposome in the embodiment is subjected to freeze drying to prepare the posaconazole liposome freeze-dried powder.
Example 8
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 6, the weight ratio of cholesterol to phospholipid is 1: 6, the cryoprotectant accounts for 10 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the antioxidant is sodium sulfite, the freeze-drying protective agent is mannitol, and the hydration buffer solution is borate buffer solution.
The preparation method of posaconazole liposome in this example was the same as in example 7.
Example 9
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 6, the weight ratio of cholesterol to phospholipid is 1: 6, the cryoprotectant accounts for 10 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the antioxidant is alpha-tocopherol, the freeze-drying protective agent is sucrose, and the hydration buffer solution is acetate buffer solution.
The preparation method of posaconazole liposome in this example was the same as in example 7.
Example 10
The posaconazole liposome is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 5, the weight ratio of cholesterol to phospholipid is 1: 6.25, the lyoprotectant comprises 10 wt% of the total weight of the lyoprotectant, 1 wt% of the total weight of the antioxidant and 5 wt% of the total weight of the hydration buffer;
the phospholipid is distearyl phosphatidylcholine, the antioxidant is ascorbyl palmitate, the freeze-drying protective agent is sucrose, and the hydration buffer solution is citrate buffer solution.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and then removing the organic solvent to obtain a phospholipid membrane; removing the organic solvent by adopting dichloromethane as the organic solvent and adopting a spray drying method, wherein the pressure of nitrogen is 0.3Mpa, the temperature is 35 ℃, and after the liquid is sprayed, continuously drying for 10-30 minutes;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 5-8, the processing temperature of the oscillation stirring is 60 ℃, the rotating speed is 200-600 rpm, and the processing time of the oscillation stirring is 20-120 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenization method is a high-pressure micro-jet method, the pressure is 16000psi, and the circulation is carried out for 5 times.
The posaconazole liposome in the embodiment is subjected to freeze drying to prepare the posaconazole liposome freeze-dried powder.
Example 11
The posaconazole liposome is prepared from posaconazole, phospholipid, PEG modified phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 4, the weight ratio of cholesterol to phospholipid is 1: 4, the weight ratio of the PEG modified phospholipid to the posaconazole is 1: 2, the cryoprotectant accounts for 10 wt% of the total weight, the antioxidant accounts for 1 wt% of the total weight, and the hydration buffer accounts for 5 wt% of the total weight;
the phospholipid is hydrogenated soybean phospholipid, the PEG modified phospholipid is distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, the antioxidant is ascorbyl palmitate, the freeze-drying protective agent is sucrose, and the hydration buffer solution is phosphate buffer solution.
A preparation method of posaconazole liposome comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and then removing the organic solvent to obtain a phospholipid membrane; the organic solvent adopts dichloromethane, and the spray drying method is adopted to remove the organic solvent at the same time, the pressure of nitrogen is 0.3Mpa, the temperature is 35 ℃, and after the liquid spraying is finished, the drying is continued for 10-30 minutes;
b) adding the phospholipid membrane and the freeze-drying protective agent into a hydration buffer solution, and oscillating and stirring to obtain a hydration solution; the pH value of the hydration buffer solution is 5-8, the processing temperature of the oscillation stirring is 60 ℃, the rotating speed is 200-600 rpm, and the processing time of the oscillation stirring is 20-120 minutes;
c) homogenizing the hydration solution to prepare posaconazole liposome; the homogenizing method adopts a pressure extrusion method, the pressure of extrusion gas is 0.4MPa, the particle size of an extrusion film is 100nm, and the solution after extrusion is subjected to aseptic subpackage.
The posaconazole liposome in the embodiment is subjected to freeze drying to prepare the posaconazole liposome freeze-dried powder.
The method for detecting the physicochemical indexes of the posaconazole liposome comprises the following steps:
1. particle size distribution: taking a proper amount of posaconazole liposome, adding purified water to dilute the posaconazole liposome to a proper concentration, determining the particle size and the distribution of the posaconazole liposome by using a Zetasizer Nano ZS90 nanometer particle size analyzer (Marvin), and observing the posaconazole liposome by using a scanning electron microscope and a freezing transmission electron microscope;
2. encapsulation efficiency: taking 0.5ml of liposome solution, carrying out G50 sephadex column chromatography, and taking phosphate buffer as eluent to separate free drugs and liposome. Collecting the liposome effluent liquid to a 25ml volumetric flask, and fixing the volume to the scale with water to obtain a liquid I. And (3) taking 0.5ml of liposome solution into a 25ml volumetric flask, and directly metering the volume to the scale with water to obtain a solution II. Precisely sucking the liquids I and II respectively 2ml to 10ml volumetric flasks, adding 10% Triton-X100 ethanol solution 1ml for demulsification, adding water to constant volume to scale, and measuring the drug concentration C by HPLCⅠ、CⅡAnd (3) chromatographic column: octadecylsilane chemically bonded silica, mobile phase: 0.05% aqueous phosphoric acid solution-acetonitrile (30: 70), flow rate: 1.0ml/min, detection wavelength: 260nm, column temperature: 30 ℃, sample introduction: 10ul, calculating the encapsulation efficiency,
in vitro release rate: precisely absorbing a proper amount of posaconazole liposome injection (prepared by the posaconazole liposome freeze-dried powder in the embodiments 7 and 11) and a proper amount of posaconazole solution with the same concentration, placing the posaconazole liposome injection and the posaconazole solution in a pretreated dialysis bag, fixing the posaconazole liposome injection in a stirring paddle, placing the posaconazole liposome injection in a dissolution cup filled with 200ml of phosphate buffer (pH 6.8) and containing 0.3% of lauryl sodium sulfate, stirring the posaconazole liposome injection at the temperature of 37 ℃ and the rotating speed of 100rpm, regularly sampling 3ml of the posaconazole liposome injection, filtering. Detecting the concentration of the drug in the filtrate by HPLC, detecting the drug in the same encapsulation rate by the detection method, and calculating the accumulative release rate of the liposome.
Physicochemical indexes of posaconazole liposome:
1. the particle size and entrapment efficiency of posaconazole liposomes of the examples are shown in table 1;
table 1: examples 1-11 particle size and encapsulation efficiency of posaconazole liposomes
Liposome particle size is an important parameter for evaluating liposomes. The particle size of the final product can significantly affect its in vivo behavior, which in turn affects the therapeutic efficacy and toxicity of the encapsulated drug. After intravenous administration, the chance that the liposome leaves the blood vessel and enters the intercellular substance is small, because the particle size of the liposome is generally controlled to be 50-200 nm, the normal endothelial cell gap is less than 10nm, only the cell gaps of inflammatory parts or tumor cells and the like are larger (more than 200nm), the liposome with less than 200nm easily penetrates into the inflammatory parts, the drug concentration of the inflammatory parts is increased, and the targeting property is improved.
The posaconazole liposome can be prepared in the embodiments of the embodiments, and the particle size of the liposome can be well controlled by adopting an ultrasonic method, a high-pressure micro-jet method and a high-pressure extrusion method; the particle size range of the posaconazole liposome is controlled to be 50-200 nm, and the average particle size in the embodiment is about 100 nm.
In particular, the particle size distribution of the posaconazole liposome obtained in the two examples is determined according to the example 7 and the example 11, and as shown in fig. 1 and fig. 2, it can be seen that the particle sizes of the posaconazole liposome prepared in the two examples are mainly concentrated around 100nm, and all the particle sizes fall within the range of 50-200 nm, so that the requirements are met; meanwhile, as can be seen from fig. 4 and 5, the posaconazole liposome has uniform particles and concentrated particle size distribution.
2. In the above examples, examples 4 to 11 finally obtained a freeze-dried preparation by freeze-drying posaconazole liposome, and the average particle size of posaconazole liposome in the above examples and the average particle size of the re-dissolved freeze-dried preparation were detected and compared, and the results are shown in table 2;
table 2: examples 4-11 Pre-and post-lyophilization average particle sizes of posaconazole liposomes
From the above data, the particle size of posaconazole liposome did not change significantly after reconstitution of the lyophilized preparation.
3. Cumulative release rate of posaconazole liposome:
the release rates of the injection prepared in example 7 and the injection prepared in example 11 and the posaconazole solution with the same concentration were continuously tested, and the release rate curves are respectively shown in fig. 3.
As can be seen from FIG. 3, the posaconazole solution reaches more than 90% within 2 hours, while the posaconazole liposome reaches 80% within 24 hours, and the posaconazole liposome reaches more than 95% within 48 hours.
The posaconazole liposome has a good slow release function and a high drug release rate.
Secondly, researching pharmacokinetics and tissue targeting of the posaconazole long-circulating liposome in vivo:
healthy Kunming mice were selected and randomly divided into two groups of 4 mice per session. The drug is administered by tail vein injection, the dose is 15mg/kg, the drug is fasted for 12h before administration, the drug is freely drunk, the first group is a posaconazole solution group, and the second group is a posaconazole long-circulating liposome group (the posaconazole liposome freeze-dried powder prepared in example 11 is adopted). At 0h before administration, 5min, 15min, 30min, 45min, 1,2,4, 6, 8, 12, 24h after administration, respectively taking blood, immediately killing, and taking heart, liver, spleen, lung, and kidney tissues. Placing whole blood in a heparinized centrifugal tube, centrifuging at 3000rpm for 20min, taking supernatant, and measuring the concentration of posaconazole in plasma by using HPLC; animal organs were homogenized by adding 1ml of physiological saline, centrifuged, and the supernatant was collected and the concentration of posaconazole in each tissue was determined by HPLC.
The in vivo targeting property of the posaconazole long-circulating liposome is evaluated by adopting targeting parameters such as relative uptake rate (re), total targeting efficiency (Te) and peak concentration ratio (Ce). Re AUCL/AUCQ, Te AUC tissue/AUC total, Ce CmaxL/CmaxQ, wherein L represents posaconazole long-circulating liposomes and Q represents posaconazole solution.
The in vivo targeting results of posaconazole long-circulating liposomes and solution mice are shown in table 3;
table 3: posaconazole long-circulating liposome and targeting result in solution mice
By combining the table 3 and the figure 6, according to the results of the blood concentration of the mice, the elimination time of the posaconazole long-circulating liposome in vivo is prolonged, the sustained-release long-acting effect is achieved, and the bioavailability of the drug is improved. According to the experimental result of tissue distribution in mice, after posaconazole is prepared into the growth cycle liposome, the in vivo targeting is obviously changed: the relative uptake rate re of the liver is the maximum and reaches 5.97, which indicates that the liposome has obvious targeting on the liver; the total targeting rate in the liver is also increased from 25.32% to 42.01%. Meanwhile, relative uptake rates of spleen and lung with more macrophages are up to 2.79 and 3.99, which shows that the liposome has stronger targeting to an endothelial reticulum system; the total target rate of the heart is from 5% to 0.05%, and the total target rate of the kidney is from 5.97% to 0.03%, which shows that the toxicity of the long-circulating liposome to the heart and the kidney is reduced, and the damage of the medicament to the heart and the kidney is reduced.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (9)
1. A posaconazole liposome, which is characterized in that: the compound is prepared from posaconazole, phospholipid, cholesterol, a freeze-drying protective agent, an antioxidant and a hydration buffer solution, wherein the weight ratio of posaconazole to phospholipid is 1: 3-10, wherein the weight ratio of cholesterol to phospholipid is 1: 3-8, the freeze-drying protective agent accounts for 5-20 wt% of the total weight, the antioxidant accounts for 1-10 wt% of the total weight, and the hydration buffer agent accounts for 1-10 wt% of the total weight;
wherein the phospholipid also contains at least one of PEG modified phospholipid or charged phospholipid; wherein the weight ratio of the PEG modified phospholipid to the posaconazole is 1: 0.5-3, wherein the weight ratio of the charged phospholipid to the posaconazole is 1: 0.5 to 3;
the particle size of the posaconazole liposome is 103.1-125.1 nm.
2. The posaconazole liposome of claim 1, wherein:
the PEG modified phospholipid is at least one of distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, dipalmitoyl phosphatidyl ethanolamine-methoxy polyethylene glycol 5000 or dipalmitoyl phosphatidyl ethanolamine-methoxy polyethylene glycol 2000;
the charged phospholipid is at least one of dilauroyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, distearoyl phosphatidyl glycerol, dimyristoyl phosphatidyl glycerol, dioleoyl phosphatidyl glycerol, dilauroyl phosphatidic acid, egg yolk phosphatidyl glycerol, dioleoyl phosphatidyl serine, dimyristoyl phosphatidic acid or distearoyl phosphatidic acid.
3. The posaconazole liposome according to claim 1 or 2, wherein:
the phospholipid is at least one of distearoyl phosphatidylcholine, egg yolk phospholipid, soybean phospholipid or hydrogenated soybean phospholipid.
4. The posaconazole liposome according to claim 1 or 2, wherein:
the antioxidant is at least one of alpha-tocopherol, sodium sulfite, sodium metabisulfite, L-cysteine, thiourea, ascorbyl palmitate or tert-butyl p-hydroxyanisole.
5. The posaconazole liposome according to claim 1 or 2, wherein:
the freeze-drying protective agent is at least one of sucrose, lactose, mannitol, sorbitol, trehalose, glucose or dextran;
the hydration buffer solution is at least one of phosphate buffer solution, citrate buffer solution, carbonate buffer solution, borate buffer solution, acetate buffer solution or ammonium chloride solution, and the pH value is 2-11.
6. A method for preparing posaconazole liposomes according to claim 1 or 2, which comprises the following steps:
a) dissolving the components except the antioxidant, the freeze-drying protective agent and the hydration buffer solution in an organic solvent, uniformly mixing, and removing the organic solvent to obtain a phospholipid membrane;
b) pouring the hydration buffer solution into the phospholipid membrane, oscillating and stirring, and adding the freeze-drying protective agent to prepare hydration solution;
c) homogenizing the hydration solution to prepare posaconazole liposome;
d) and (3) freeze-drying the prepared posaconazole liposome.
7. The method for preparing posaconazole liposome according to claim 6, wherein:
in the step a, the organic solvent is removed by adopting a film separation method, a spray drying method or a vacuum drying method.
8. The method for preparing posaconazole liposome according to claim 6, wherein:
in the step b, the pH value of the hydration buffer solution is 5-8, the treatment temperature of the oscillation stirring is 30-80 ℃, and the treatment time of the oscillation stirring is 20-120 minutes.
9. The method for preparing posaconazole liposome according to claim 6, wherein:
in the step c, the homogenizing method is an ultrasonic method, a high-pressure micro-jet method or a pressure extrusion method.
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| CN1969830A (en) * | 2006-12-01 | 2007-05-30 | 哈尔滨医科大学 | Itraconazole liposome and preparation process thereof |
| CN102369198A (en) * | 2008-09-08 | 2012-03-07 | N·吴 | Triazole antifungal agents |
| CN105055317A (en) * | 2015-08-28 | 2015-11-18 | 四川大学 | Doxorubicin and itraconazole common carrier nano-liposome and preparing method thereof |
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| CN1969830A (en) * | 2006-12-01 | 2007-05-30 | 哈尔滨医科大学 | Itraconazole liposome and preparation process thereof |
| CN102369198A (en) * | 2008-09-08 | 2012-03-07 | N·吴 | Triazole antifungal agents |
| CN105055317A (en) * | 2015-08-28 | 2015-11-18 | 四川大学 | Doxorubicin and itraconazole common carrier nano-liposome and preparing method thereof |
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