CN110193014B - Laquinimod micelle freeze-dried preparation for injection, preparation method thereof and laquinimod injection - Google Patents
Laquinimod micelle freeze-dried preparation for injection, preparation method thereof and laquinimod injection Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a laquinimod micelle freeze-dried preparation for injection, a preparation method thereof and a laquinimod injection. The invention uses micelle formed by amphiphilic block polymer to wrap laquinimod in molecular or amorphous or microcrystalline form, and then embeds beta-cyclodextrin derivative into the hydrophilic shell of the micelle, and uses freeze-drying technology to prepare freeze-dried preparation, the micelle form and particle size of the freeze-dried micelle powder preparation can not be changed after rehydration, the freeze-dried micelle preparation is stored as sterile freeze-dried powder, which not only can obviously improve the storage stability of the laquinimod-carrying micelle, but also can ensure that the freeze-dried micelle can not generate precipitation after being redissolved and diluted by physiological saline or glucose solution during application, can keep the state of clear solution for a long time, reduces unsafe factors of clinical medication, has higher drug loading capacity and better stability, can be clinically used for intramuscular or intravenous injection, has simple preparation method and good reproducibility, and is easy to realize large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a laquinimod micelle freeze-dried preparation for injection, a preparation method thereof and a laquinimod injection.
Background
Laquinimod is chemically named N-ethyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide (CAS number 248281-84-7), has a melting point of 275 ℃, is poorly soluble in water, and has the following chemical structure:
laquinimod, an oral immunomodulator, has demonstrated therapeutic utility in a variety of experimental inflammatory/autoimmune animal models, such as Experimental Autoimmune Encephalomyelitis (EAE), animal models for Multiple Sclerosis (MS), Dextran Sodium Sulfate (DSS) induced colitis for inflammatory bowel disease, non-obese diabetic (NOD) mice for type I diabetes (IDDM), Experimental Autoimmune Neuritis (EAN) for Guillain-barre syndrome (Guillain-barre syndrome), Systemic Lupus Erythematosus (SLE), lupus nephritis, lupus arthritis, Crohn's disease, and rheumatoid arthritis. Laquinimod is an immunomodulatory drug that has been shown to be orally effective for the treatment of multiple sclerosis by phase ii clinical trials. Compared with other medicines for treating multiple sclerosis such as interferon and mitoxantrone, laquinimod has the advantages of convenient use, weak adverse reaction and the like.
The laquinimod takes an oral solid preparation as a clinical application preparation, has high lipid solubility and rapid absorption, and the oral bioavailability can reach 82-95%. However, laquinimod has low solubility in water, only 10 μ g/mL, and is difficult to prepare into a rapid-acting solution injection, so that the clinical application of laquinimod is limited. To increase its water solubility, U.S. patent No. 6077851 discloses the synthesis of laquinimod and the preparation of its sodium salt. In addition, chinese patent (patent publication No. CN 104955522A) discloses that laquinimod, meglumine, choline hydroxide, and L-lysine are prepared into laquinimod amine salt to improve its solubility in water, but this process is cumbersome and requires purification treatment such as recrystallization.
The amphiphilic block polymer molecule has a hydrophobic chain segment and a hydrophilic chain segment, can be spontaneously assembled into micelles in water, has good solubilization effect on insoluble drugs, and becomes a common auxiliary material for the insoluble drug injection formula. Genex-PM is a nano micelle preparation with a shell-core structure, which is prepared by taking amphiphilic block polymer mPEG2000-PLA1750 as a carrier and solubilizing paclitaxel, and is currently on the market in Korea. But the polymer micelle preparation has the defects of poor drug loading stability, poor freeze-drying rehydration performance and the like in clinical application. Although the mixed micelle prepared by PEG-PLA/Vitamino E-TPGS in Chinese patent (patent publication No. CN 104997758A) can ensure that the drug loading of paclitaxel is up to 35% (w/w), the defects of form change, drug crystal precipitation and the like still exist after the mixed micelle is freeze-dried into powder.
Disclosure of Invention
The invention aims to provide a laquinimod micelle freeze-dried preparation for injection, a preparation method thereof and a laquinimod injection, and the micelle preparation can overcome the defects that the existing laquinimod is poor in water solubility and difficult to prepare into a solution injection, and provides a quick-acting preparation for the treatment of clinical diseases.
The technical scheme adopted by the invention is as follows: a laquinimod micelle freeze-dried preparation for injection comprises freeze-dried powder consisting of amphiphilic polyethylene glycol block polymer, laquinimod and beta-cyclodextrin derivative.
The amphiphilic polyethylene glycol block polymer is any one or a mixture of a block copolymer (mPEG-PLA) of polyethylene glycol monomethyl ether and polylactic acid, Solutol HS-15 and vitamin E polyethylene glycol 1000 succinate (TPGS).
The beta-cyclodextrin derivative is any one or a mixture of more than one of beta-cyclodextrin, hydroxypropyl beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin.
The mass ratio of the amphiphilic polyethylene glycol block polymer to the laquinimod and the beta-cyclodextrin derivative is 100: 1-20: 100 to 500.
The laquinimod micelle for injection has a core-shell structure, the hydrophobic chain segment of the amphiphilic polyethylene glycol block polymer is wrapped by the molecular or amorphous or microcrystalline dispersed laquinimod to form the inner core of the micelle, and the beta-cyclodextrin derivative is embedded into the hydrophilic PEG chain segment to form the shell of the micelle. The mass ratio of polyethylene glycol monomethyl ether to polylactic acid in mPEG-PLA is 1: (0.2-5), and the more preferable mass ratio is 1: (0.2 to 3); the molecular weight of the polyethylene glycol monomethyl ether is 2000-10000 Da, and the molecular weight is more preferably 2000-6000 Da; the molecular weight of the polylactic acid is 1000-20000 Da, and the molecular weight is more preferably 1000-15000 Da.
The chain length of the polyethylene glycol in the TPGS is 500-5000 Da, and the chain length is more preferably 100-4000 Da.
The preparation method of the laquinimod micelle freeze-dried preparation for injection comprises the following steps:
(1) uniformly mixing laquinimod and amphiphilic polyethylene glycol block polymer with an organic solvent to obtain a basic drug solution;
(2) removing the organic solvent in the basic drug solution to obtain a material-drug transparent film matrix;
(3) dissolving beta-cyclodextrin derivative in water for injection, adding the above material-medicinal transparent film matrix, and controlling temperature at 30-60 deg.CoC, hydrating the carrier material for self-assembly, and then filtering the carrier material to remove the drug which is not entrapped, so as to obtain a drug-containing micelle solution;
(4) freeze-drying the drug-containing micelle solution to obtain the laquinimod micelle freeze-dried preparation for injection.
The organic solvent is any one of acetone, diethyl ether, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane and chloroform.
The control conditions of the freeze drying are as follows: pre-freezing the medicinal micelle solution at minus 60 to minus 30 ℃ for 2 to 8 hours, then carrying out primary drying at minus 30 to 40 ℃ for 12 to 56 hours, and then carrying out secondary drying at 20 to 40 ℃ for 2 to 8 hours, wherein the time of the whole freeze-drying curve is 20 to 60 hours.
A laquinimod injection preparation comprises the laquinimod micelle freeze-dried preparation for injection.
The laquinimod injection preparation is obtained by diluting the laquinimod micelle freeze-dried preparation for injection with physiological saline or glucose solution before use.
The invention uses micelle formed by amphiphilic block polymer to wrap laquinimod in molecular or amorphous or microcrystalline form, then embeds beta-cyclodextrin derivative into the hydrophilic shell of the micelle, and prepares injectable freeze-drying preparation by using freeze-drying technology, and the micelle form and particle size of the micelle freeze-dried powder preparation can not be changed after rehydration. The laquinimod micelle freeze-dried preparation is stored as sterile freeze-dried powder, so that the storage stability of the laquinimod-carrying micelle can be obviously improved, the laquinimod-carrying micelle freeze-dried preparation can be redissolved and diluted by using normal saline or glucose solution during application without generating precipitate, the state of a clear solution is kept for a long time, and unsafe factors of clinical medication are reduced. The laquinimod micelle injection provided by the invention has higher drug loading capacity and better stability, can be clinically used for intramuscular injection or intravenous injection, and has the advantages of simple preparation method, good reproducibility and easy realization of large-scale production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 is a DSC analysis chart of laquinimod micelle lyophilized powder prepared in group 2 of example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
Example 1 preparation of laquinimod-loaded nanomicelles
Weighing laquinimod and amphiphilic polyethylene glycol block polymer into a 200mL round-bottom flask according to the formula shown in the table 1, adding an organic solvent with the formula amount, dissolving together to prepare a basic drug solution, placing the basic drug solution in a water bath at 40 ℃ for rotary evaporation to remove the organic solvent to obtain a polymer-drug transparent film, and further drying the polymer-drug transparent film overnight in a vacuum dryer to prepare a dry polymer-drug transparent film; dissolving the beta-cyclodextrin derivative with the formula amount in 100mL of water for injection in water bath at 40 ℃ to prepare a water phase; adding the water phase into the material-drug transparent film, magnetically stirring to make the polymer-drug film fall off, controlling the temperature of water area at 30-60 ℃ to make the polymer-drug film hydrated and dissolved, and filtering with 0.22 μm filter membrane to remove the drug which is not carried in the polymer-drug film to obtain the drug-containing micelle solution. Pouring the prepared drug-containing micelle solution into a surface dish with a certain volume, placing the surface dish into a freeze dryer, pre-freezing the drug-containing micelle solution for 2-8 h at-60 to-30 ℃, performing primary drying for 12-56 h at-30 to 40 ℃, and performing secondary drying for 2-8 h at 20-40 ℃ to obtain a white collapse-free loose solid.
Note: mPEGm -PLAn (w) m is the mPEG molecular weight, n is the PLA continuous molecular weight, and w is the weight of mPEG-PLA used in the preparation; PEGiTPGS (j) i is the PEG molecular weight and j is the weight of the PEG-TPGS used in the formulation set; laq is laquinimod; DCM is dichloromethane; SBE-beta-CD is yellow butyl ether-beta-CD; HP-beta-CD is hydroxypropyl-beta-CD; PLA is polylactic acid (molecular weight 8000 Da).
Comparative example 1 preparation of CremophorEL solubilized laquinimod injection
Weighing 10mg of laquinimod and 500mg of polyoxyethylene hydrogenated castor oil (cremophor EL) into a beaker, slowly adding 5mL of ethanol and 5mL of water for injection respectively, and stirring to dissolve to prepare a 1mg/mL clear solution for dilution stability comparison study.
Comparative example 2 Tween-80 solubilized laquinimod micelle lyophilized formulation
Weighing 10mg of laquinimod and 500mg of Tween-80 into a beaker, slowly adding 5mL of water for injection, stirring and dissolving to prepare a 1mg/mL clear solution, adding 200mg of HP-beta-CD powder for dissolving, and freeze-drying to prepare a Tween-80 solubilized laquinimod micelle freeze-dried preparation for the redissolution comparison study of freeze-dried substances.
Comparative example 3 lyophilized formulation of laquinimod phospholipid Complex
Weighing 10mg of laquinimod and 500mg of phospholipid into a beaker, slowly adding 5mL of water for injection and 5mL of tert-butyl alcohol respectively, stirring and dissolving to prepare a 1mg/mL clear solution, adding 200mg of HP-beta-CD powder for dissolving, and freeze-drying to prepare the lyophilized preparation of the laquinimod phospholipid complex for the redissolution contrast study of the lyophilized product.
The following is a test analysis for the above examples and comparative examples:
1. detection of drug content in laquinimod micelle freeze-dried powder preparation
Precisely weighing 100mg of each group of freeze-dried powder in example 1, adding the freeze-dried powder into a 100mL volumetric flask, adding 80mL of acetonitrile, performing ultrasonic treatment for 15min to dissolve and destroy laquinimod micelles, fixing the volume of the acetonitrile to a scale, filtering with a 0.8-micron microporous membrane, and taking 20 mu L of filtrate to perform HPLC (high performance liquid chromatography) to detect the content of laquinimod in the freeze-dried substance. The HPLC detection conditions are as follows: eclipse XDB-C18 column (250 mm. times.4.6 mm, 5 μm) with mobile phase: acetonitrile-water (70: 30, v/v); the flow rate is 1.0 mL/min, the detection wavelength is 254 nm, and the column temperature is 25 ℃. According to the actual amount of the tested drug and the actual adding amount of the amphiphilic polyethylene glycol block polymer and the beta-cyclodextrin derivative during preparation of the preparation, the weight ratio of the amphiphilic polyethylene glycol block polymer to the drug to the stabilizer in the laquinimod micelle lyophilized powder preparation in the table 1 is calculated.
2. Double solubility of laquinimod micelle lyophilized preparation
Weighing the quimod micelle freeze-dried powder of each group in the example 1 and 100mg 2 parts of the freeze-dried preparation obtained in the comparative examples 1-3 into a penicillin bottle, respectively adding 2mL of physiological saline injection and glucose injection, shaking the mixture in a shaking table at room temperature, and observing the rehydration of the freeze-dried substance within 2 min; after the above-mentioned quinimod micelle freeze-dried powder is dissolved, DLS measures micelle particle size, HPLC measures supernatant drug concentration after 3000rpm centrifugation, continue to add the above-mentioned solvent to dilute 100 times, after placing in 37 ℃ water bath shaking table and shaking for 2h, DLS measures micelle particle size, HPLC measures supernatant drug concentration after 3000rpm centrifugation, the result is as shown in Table 2.
The results in table 2 show that the polyethylene glycol amphiphilic polymer entraps the micelle prepared from laquinimod, and then the micelle is lyophilized with a beta-cyclodextrin stabilizer to obtain lyophilized powder of laquinimod micelle. When the mass ratio of the amphiphilic polyethylene glycol block polymer to the laquinimod and the beta-cyclodextrin derivative in the laquinimod micelle freeze-dried powder is 100: 1-20: when the amount is 100-500 hours, the freeze-dried substance can be quickly rehydrated and dissolved to form a clear solution, meanwhile, no drug is precipitated and separated out from the diluted drug-loaded micelle, and the particle size of the micelle is not obviously changed. In contrast, laquinimod micelle freeze-dried powder prepared by adding no stabilizer or only mannitol or hydroxyethyl starch as a stabilizer has the phenomenon of slow rehydration or drug precipitation after rehydration, and the particle size of the drug-loaded micelle after dilution has larger change. In comparative examples 1-3, the laquinimod freeze-dried powder preparation prepared by respectively coating the materials of Cremophor EL, Tween-80 and phospholipid has the problem of redissolution and agglomeration or particle generation. In the Cremophor EL solubilized laquinimod solution, drug crystals are precipitated in the dilution process, so that the concentration of the drug in the supernatant after dilution is remarkably reduced.
The maximum drug concentration of the lyophilized preparation after reconstitution depends on the drug content in the lyophilized powder preparation and the rehydration property of the lyophilized powder preparation, and as can be seen from table 2, when the mass ratio of the amphiphilic polyethylene glycol block polymer in the laquinimod micelle lyophilized powder, the laquinimod and the β -cyclodextrin derivative is 100: 1-20: at 100-500 days, the maximum drug concentration of the re-dissolved lyophilized powder is milligram, and the solubility of laquinimod in water is only 10 mug/mL, so that the amphiphilic polyethylene glycol block polymer and the beta-cyclodextrin derivative can enable the injection of laquinimod to have higher drug concentration, and the target drug dosage can be selected according to clinical needs. Wherein, the maximum drug concentration after the reconstitution of the group 7 and the group 13 exceeds 3.5 mg/mL, and has obvious advantages compared with the drug concentration of other groups.
1. Stability of laquinimod micelle lyophilized formulation
And (3) taking three parts of 100mg laquinimod micelle freeze-dried powder, respectively placing the three parts at-20 ℃, 4 ℃ and 25 ℃ for 60 days, adding 2mL physiological saline for injection and redissolution, observing the redissolution state of the laquinimod micelle freeze-dried powder, and observing the micelle particle size after redissolution and the drug concentration of supernatant after centrifugation, wherein the results are shown in Table 3. As can be seen from the table, when the ratio of the mass of the amphiphilic polyethylene glycol block polymer, laquinimod and β -cyclodextrin derivative is 100: 1-20: after the laquinimod micelle freeze-dried powder is placed for 60 days at 3 temperatures for 100-500 hours, the laquinimod micelle freeze-dried powder can be quickly rehydrated and dissolved to form a clear solution, and the concentration of the drug is not obviously changed. In contrast, when laquinimod micelle freeze-dried powder prepared without adding a stabilizer or only adding mannitol or hydroxyethyl starch as a stabilizer is placed at 4 ℃ and 25 ℃ for 60 days, agglomeration occurs, and the phenomenon of drug precipitation is separated out after slow rehydration or rehydration.
1. Characterization of particle size and morphology of laquinimod micelle
A dynamic light scattering laser particle size analyzer (DLS) is used for measuring the particle size and the Zeta potential of the nano-micelle, a polymer nano-micelle aqueous solution is diluted properly, the laser wavelength is fixed to be 632.8 nm and the scattering angle is 90 degrees under the normal temperature condition, and an ICOMPTM 380 particle size analyzer is used for measuring the particle size and the Zeta potential; detecting the nano micelle shape by a Transmission Electron Microscope (TEM), dropping the double-drug-loaded nano micelle on a copper mesh paved with a carbon film, sucking redundant liquid from the edge of the copper mesh by using non-fiber filter paper, dropping 2% phosphotungstic acid for dyeing, naturally airing for 2 days, and placing in the TEM to inspect and take pictures at 100 kV accelerating voltage. The results show that the particle size, the particle size distribution and the micelle form of the laquinimod micelle are not obviously changed before and after freeze-drying, and the laquinimod micelle has good rehydration performance.
2. Differential scanning calorimetry analysis of laquinimod micelle lyophilized preparation
And (3) analyzing the existing state of the medicament by Differential Scanning Calorimetry (DSC), and performing DSC analysis on a proper amount of free medicament powder, amphiphilic polymer powder, a blank nano micelle freeze-dried powder, a physical mixture of the free medicament and the medicament-loaded nano micelle freeze-dried powder, wherein the initial temperature is 20 ℃, the heating speed is 2 ℃/min, and the final temperature is 250 ℃. The DSC analysis result of the laquinimod micelle lyophilized powder prepared in group 2 in example 1 is shown in fig. 1, and the crystalline peak of laquinimod disappears at 207 ℃, which indicates that laquinimod in the micelle lyophilized powder is dispersed in the micelle core in the form of molecules, amorphous form or microcrystal.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (7)
1. The laquinimod micelle freeze-dried preparation for injection is characterized by comprising freeze-dried powder consisting of an amphiphilic polyethylene glycol block polymer, laquinimod and a stabilizer, wherein the stabilizer is beta-cyclodextrin or a beta-cyclodextrin derivative;
the amphiphilic polyethylene glycol block polymer is mPEG-PLA, and the mass ratio of mPEG-PLA, laquinimod and stabilizer is 100: 1-20: 100 to 500 parts;
or the amphiphilic polyethylene glycol block polymer is TPGS, and the mass ratio of TPGS to laquinimod to the stabilizer is 100: 1-4.8: 200 of a carrier;
or the amphiphilic polyethylene glycol block polymer is a combination of mPEG-PLA and TPGS, the combination of mPEG-PLA and TPGS has a mass ratio of laquinimod to stabilizer of 100:16.5: 100;
or the amphiphilic polyethylene glycol block polymer is a combination of mPEG-PLA and solutol HS-15, the combination of mPEG-PLA and solutol HS-15, and the mass ratio of laquinimod to the stabilizer is 100:0.1: 400.
2. The laquinimod micelle lyophilized formulation for injection according to claim 1, wherein: the beta-cyclodextrin derivative is any one or a mixture of hydroxypropyl beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin.
3. The preparation method of laquinimod micelle freeze-dried preparation for injection according to claim 1 or 2, characterized by comprising the steps of:
(1) uniformly mixing laquinimod and amphiphilic polyethylene glycol block polymer with an organic solvent to obtain a basic drug solution;
(2) removing the organic solvent in the basic drug solution to obtain a material-drug transparent film matrix;
(3) dissolving a stabilizer in water for injection, adding the material-drug transparent film matrix, controlling the temperature to be 30-60 ℃ to enable the carrier material to be hydrated and self-assembled, and then filtering a membrane to remove the unencapsulated drug to obtain a drug-containing micelle solution;
(4) freeze-drying the drug-containing micelle solution to obtain the laquinimod micelle freeze-dried preparation for injection.
4. The preparation method of the laquinimod micelle freeze-dried preparation for injection according to claim 3, wherein: the organic solvent is any one of acetone, diethyl ether, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane and chloroform.
5. The preparation method of the laquinimod micelle freeze-dried preparation for injection according to claim 3, wherein: the control conditions of the freeze drying are as follows: pre-freezing the drug-containing micelle solution at minus 60 to minus 30 ℃ for 2 to 8 hours, then carrying out primary drying at minus 30 to 40 ℃ for 12 to 56 hours, and then carrying out secondary drying at 20 to 40 ℃ for 2 to 8 hours, wherein the time of the whole freeze-drying curve is 20 to 60 hours.
6. A laquinimod injectable formulation, characterized by: the laquinimod micelle lyophilized formulation for injection comprising according to claim 1 or 2.
7. The laquinimod injectable formulation according to claim 6, wherein: the laquinimod micelle lyophilized formulation for injection according to claim 1 or 2, which is obtained by diluting with physiological saline or glucose solution just before use.
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| WO2007146248A2 (en) * | 2006-06-12 | 2007-12-21 | Teva Pharmaceutical Industries, Ltd. | Stable laquinimod preparations |
| CN102091025B (en) * | 2009-12-14 | 2012-07-11 | 中国科学院化学研究所 | Anti-tumor injectable hydrogel as well as preparation method and application thereof |
| CN101766821B (en) * | 2010-01-05 | 2012-03-21 | 浙江大学 | Application of polymer based on beta-cyclodextrin |
| CA2980730A1 (en) * | 2015-03-23 | 2016-09-29 | The Brigham And Women's Hospital, Inc. | Tolerogenic nanoparticles for treating diabetes mellitus |
| US20170028013A1 (en) * | 2015-07-30 | 2017-02-02 | Teva Pharmaceutical Industries, Ltd. | Combination formulation of laquinimod and glatiramer acetate with amino acids |
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