CN117999304A - Hydrophobic drug polymer micelle and preparation method thereof - Google Patents

Hydrophobic drug polymer micelle and preparation method thereof Download PDF

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CN117999304A
CN117999304A CN202280053105.6A CN202280053105A CN117999304A CN 117999304 A CN117999304 A CN 117999304A CN 202280053105 A CN202280053105 A CN 202280053105A CN 117999304 A CN117999304 A CN 117999304A
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polyethylene glycol
glycol monomethyl
monomethyl ether
polylactic acid
block copolymer
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史瑞文
卞祥
刘永东
鲍雪竹
宋田
刘艳红
李臻
任晋生
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Nanjing Zaiming Pharmaceutical Co ltd
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides

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Abstract

The polyethylene glycol monomethyl ether-polylactic acid segmented copolymer is a segmented copolymer formed by ring-opening polymerization of D, L-lactide and polyethylene glycol monomethyl ether, and the feeding mass ratio of the polyethylene glycol monomethyl ether to the D, L-lactide is 1:1.05-1.25. The freeze-dried preparation of the hydrophobic drug polymer micelle comprises a hydrophobic drug and the polyethylene glycol monomethyl ether-polylactic acid block copolymer, and has higher purity and reconstitution stability, and is more suitable for clinical use.

Description

Hydrophobic drug polymer micelle and preparation method thereof
The present disclosure claims priority from China patent application No. 202111033302.5, entitled "hydrophobic drug Polymer micelle and preparation method thereof", filed by China national intellectual property office on the 09 th year 2021 and 03 th day. The entire contents of the above-mentioned prior application are incorporated by reference into this disclosure.
Technical Field
The disclosure relates to the field of medicines, in particular to a hydrophobic drug polymer micelle freeze-dried preparation and a preparation method thereof.
Background
The taxane compounds are a large class of natural products obtained from plants, are important anticancer drugs used clinically, and greatly limit clinical application due to the very low solubility of the taxane drugs in water. Docetaxel (DTX), also known as docetaxel, has a molecular formula of C 43H 53NO 14 and a molecular weight of 807.88, is a taxane antitumor agent, which can bind to free tubulin, promote the assembly of tubulin into stable microtubules, inhibit depolymerization thereof, and cause the generation of bundles of microtubules and the fixation of microtubules, which lose normal functions, thereby inhibiting mitosis of cells, and exerting antitumor effects. However, docetaxel is difficult to be absorbed orally, and has the disadvantages of poor water solubility, short half-life, high toxicity and the like, and is usually administered by intravenous infusion in clinic. At present, docetaxel injection sold in domestic and foreign markets is prepared by dissolving docetaxel in tween-80, and the docetaxel is prepared by using a special solvent and diluted by using an isotonic solution in clinical application, so that the docetaxel injection is cumbersome to use and has strict operation requirements. The preparation contains a large amount of tween-80 which is easy to cause adverse reactions such as hemolysis, allergy and the like, and needs to be prevented and treated by medicines such as dexamethasone in advance, so that the clinical application is inconvenient and the safety is low. Paclitaxel is a taxane alcohol antitumor agent extracted from Taxus chinensis or Taxus chinensis, and is white crystal powder, insoluble in water, and easily soluble in organic solvents such as chloroform and acetone. The paclitaxel injection used clinically at present contains polyoxyethylated modified castor oil and absolute ethyl alcohol, and the polyoxyethylated modified castor oil and the absolute ethyl alcohol often cause strong side reactions, such as hypersensitivity reaction, hemolysis, nephrotoxicity, neurotoxicity, cardiotoxicity and the like, and can cause death in severe cases.
The nano-polymer micelle is a drug delivery system for insoluble drugs, which has been developed in recent years, and has a core-shell structure, wherein the core is a hydrophobic part, and the shell is a hydrophilic part. The polymer micelle can wrap the insoluble medicine on the core part to solubilize the insoluble medicine.
CN201410326208.2 discloses a docetaxel nano polymer micelle freeze-dried preparation and a preparation method thereof, wherein the docetaxel is coated by polyethylene glycol monomethyl ether-polylactic acid segmented copolymer prepared by using polyethylene glycol monomethyl ether and D, L-lactide with the feeding mass ratio of 1:0.99. The present disclosure is further optimized based on CN201410326208.2 to provide a hydrophobic drug polymer micelle lyophilized formulation with higher purity and reconstitution stability.
Disclosure of Invention
It is an object of the present disclosure to provide a hydrophobic drug polymer micelle lyophilized formulation with higher purity and reconstitution stability.
It is another object of the present disclosure to provide a method for preparing the hydrophobic drug polymer micelle freeze-dried formulation.
It is another object of the present disclosure to provide a polyethylene glycol monomethyl ether-polylactic acid block copolymer.
The invention provides a polyethylene glycol monomethyl ether-polylactic acid block copolymer, which is a block copolymer formed by polymerizing D, L-lactide and polyethylene glycol monomethyl ether, wherein the feeding mass ratio of the polyethylene glycol monomethyl ether to the D, L-lactide is 1:1.05-1.25, and the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by the following method: (a) Adding polyethylene glycol monomethyl ether into a reactor, heating and melting under vacuum, and replacing with inert gas; (b) Adding D, L-lactide, replacing with inert gas, adding a metal catalyst, ensuring that the reactor is under negative pressure or under inert gas protection, and then heating to 125-150 ℃ for reaction; (c) Cooling after the reaction is finished, adding a first organic solvent for dissolution, adding a second organic solvent, filtering, and vacuum drying a filter cake to obtain the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
In some embodiments, the mass ratio of polyethylene glycol monomethyl ether to D, L-lactide is 1:1.1-1.2.
In some embodiments, the ratio of polyethylene glycol monomethyl ether to D, L-lactide is 1:1.1 by mass.
In some embodiments, the molecular weight of the polyethylene glycol monomethyl ether of step (a) is from 1000 to 20000, preferably from 1000 to 5000, more preferably from 1800 to 2200, even more preferably 2000.
In some embodiments, the polyethylene glycol monomethyl ether of step (a) is heated to 60 to 130 ℃ under vacuum.
In some embodiments, the metal catalyst of step (b) is stannous isooctanoate.
In some embodiments, the stannous isooctanoate comprises 0.05 to 0.5wt%, preferably 0.15 to 0.3wt% of the total mass of D, L-lactide and polyethylene glycol monomethyl ether.
In some embodiments, the step (b) reaction time is from 1 to 20 hours, preferably from 3 to 10 hours, more preferably from 4 to 6 hours.
In some embodiments, the first organic solvent of step (c) is one or more of acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, a short chain aliphatic alcohol, or ethyl acetate, preferably one or more of dichloromethane, chloroform, methanol, ethanol, isopropanol, more preferably dichloromethane; the amount of the first organic solvent to be used is 0.1 to 100 times by volume (L/kg), preferably 0.2 to 50 times by volume (L/kg), more preferably 0.5 to 20 times by volume (L/kg) based on the mass of polyethylene glycol monomethyl ether.
In some embodiments, the second organic solvent of step (c) is one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, n-heptane, cyclohexane, petroleum ether, preferably one or more of diethyl ether, isopropyl ether or methyl tert-butyl ether, more preferably diethyl ether; the second organic solvent is used in an amount of 1 to 100 times by volume (L/kg), preferably 10 to 50 times by volume (L/kg), more preferably 15 to 20 times by volume (L/kg) based on the total mass of the polyethylene glycol monomethyl ether.
In some embodiments, the step (b) further comprises the steps of adding a third organic solvent and activated carbon after the reaction is completed, stirring, filtering, and concentrating the filtrate under reduced pressure.
In some embodiments, the third organic solvent is one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, butyl acetate, butanone, toluene, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, short chain aliphatic alcohol, preferably one or more of dichloromethane, chloroform, methanol, ethanol, isopropanol, more preferably dichloromethane.
In some embodiments, the third organic solvent is used in an amount of 0.1 to 100 volumes (L/kg), preferably 0.2 to 50 volumes (L/kg), more preferably 0.5 to 20 volumes (L/kg) based on the mass of polyethylene glycol monomethyl ether.
In some embodiments, the activated carbon is used in an amount of 1 to 500wt%, preferably 5 to 200wt%, more preferably 5 to 75wt%, and even more preferably 20 to 50wt% of the total mass of D, L-lactide and polyethylene glycol monomethyl ether.
In some embodiments, the polyethylene glycol monomethyl ether-polylactic acid block copolymer has a metal tin ion content of 10ppm or less, preferably 1ppm or less, more preferably 0.1ppm or less.
In some embodiments, the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by the following method: (a) Adding polyethylene glycol monomethyl ether into a reactor, charging nitrogen, vacuumizing, heating, vacuum drying and replacing inert gas; (b) Adding D, L-lactide, filling nitrogen, vacuumizing, keeping the reactor in vacuum, replacing with inert gas, adding a metal catalyst under the protection of nitrogen, replacing with nitrogen, ensuring that the reactor is under negative pressure or inert gas protection, and then heating to 125-150 ℃ for reaction; (c) Cooling after the reaction is finished, adding a first organic solvent for dissolution, adding a second organic solvent, filtering, and vacuum drying a filter cake to obtain the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
Another aspect of the present disclosure provides a hydrophobic drug polymer micelle lyophilized formulation comprising a hydrophobic drug and the polyethylene glycol monomethyl ether-polylactic acid block copolymer described above.
In some embodiments, the mass ratio of the hydrophobic drug to the polyethylene glycol monomethyl ether-polylactic acid block copolymer is from 0.01 to 0.15:1, preferably from 0.02 to 0.12:1, more preferably from 0.03 to 0.10:1, even more preferably 0.04:0.96.
In some embodiments, the lyophilized formulation further comprises a stabilizer.
In some embodiments, the stabilizer is one or more of citric acid, hydrochloric acid, sorbic acid, lactic acid, tartaric acid, malic acid, phosphoric acid, acetic acid, adipic acid, fumaric acid, preferably one or more of citric acid, tartaric acid, fumaric acid, more preferably citric acid.
In some embodiments, the mass ratio of the hydrophobic drug to the stabilizer is 1:0.00125 to 0.25, preferably 1:0.005 to 0.25, more preferably 1:0.0125 to 0.125.
In some embodiments, the hydrophobic drug is selected from the group consisting of taxanes.
In some embodiments, the hydrophobic drug is selected from docetaxel or paclitaxel.
In some embodiments, the hydrophobic drug is selected from docetaxel.
In some embodiments, the lyophilized formulation comprises the following components in the following proportions:
The disclosure also provides a preparation method of the hydrophobic drug polymer micelle freeze-dried preparation, which comprises the following steps:
(1) Dissolving the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer and the hydrophobic drug in an organic solvent, removing the organic solvent by rotary evaporation to obtain a gel-like drug film, and then adding water into the drug film to dissolve and disperse the drug film to obtain a micelle solution;
(2) Filtering, sterilizing and freeze-drying the micelle solution prepared in the step (1) to obtain the hydrophobic drug polymer micelle freeze-dried preparation.
In some embodiments, step (1) is to dissolve the polyethylene glycol monomethyl ether-polylactic acid block copolymer, the stabilizer and the hydrophobic drug in an organic solvent, remove the organic solvent by rotary evaporation to obtain a gel-like drug film, and then add water into the drug film to dissolve and disperse the drug film, thereby preparing a micelle solution.
In some embodiments, the organic solvent in step (1) is selected from any one or more of acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, short chain fatty alcohol, ethyl acetate, preferably any one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, more preferably methanol.
In some embodiments, the amount of organic solvent used in step (1) is from 0.5 to 12ml of organic solvent, preferably from 3 to 12ml of organic solvent, per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer.
In some embodiments, in step (1), water is added to the drug film in an amount of 2 to 40ml of water per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer, preferably 10 to 20ml of water per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer, more preferably 10 to 15ml of water per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer.
In some embodiments, in step (2), the conditions for removing the organic solvent by rotary evaporation are: the rotation speed is 10-150 rpm, the temperature is 20-80 ℃ and the time is 1-4 h.
In another aspect, the disclosure provides use of the hydrophobic drug polymer micelle freeze-dried formulation described above in the preparation of a medicament for preventing or treating cancer.
The hydrophobic drug polymer micelle freeze-dried preparation provided by the disclosure has higher purity and reconstitution stability, and is more suitable for clinical use.
Definition and description of terms
Unless defined otherwise by the present disclosure, scientific and technical terms related to the present disclosure should have meanings understood by one of ordinary skill in the art.
Polyethylene glycol monomethyl ether may be abbreviated mPEG or mPEG.
The polyethylene glycol monomethyl ether-polylactic acid block copolymer, also known as polyethylene glycol monomethyl ether-polylactide block copolymer, may be abbreviated as MPEG-PDLLA or mPEG-PDLLA.
The metallic tin ion refers to stannous ion or tin ion, or a mixture of the stannous ion and the tin ion.
The short chain fatty alcohol means a fatty alcohol having 1 to 6 carbon atoms. May be a monohydric, dihydric or polyhydric alcohol. Including but not limited to: methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, n-pentanol, isopentanol, n-hexanol, isohexanol, 1, 2-propanediol, glycerol or 1, 3-butanediol. Preferably methanol, ethanol or isopropanol.
Drawings
FIG. 1 is a 1 HNMR chart of a polyethylene glycol monomethyl ether-polylactic acid block copolymer.
Fig. 2 is a transmission electron microscope image of a docetaxel polymer micelle freeze-dried formulation.
Detailed Description
The present disclosure is further described below in conjunction with specific embodiments, and advantages and features of the present disclosure will become apparent as the description proceeds. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The disclosed embodiments are merely exemplary and do not constitute any limitation on the scope of the present disclosure. It will be understood by those skilled in the art that various changes and substitutions may be made in the details and form of the technical solutions of the present disclosure without departing from the spirit and scope of the present disclosure, but these changes and substitutions fall within the scope of the present disclosure.
The molecular weight and distribution of polyethylene glycol monomethyl ether-polylactic acid block copolymer, and related substances, particle size and span of docetaxel polymer micelle lyophilized formulation were examined according to the following methods:
(1) Molecular weight and distribution detection method
1 HNMR takes 0.5-1.0 mL of deuterated chloroform 10-20% (g/mL) of 1% tetramethylsilane, scans from 0ppm to 10ppm, and quantifies by a direct comparison method, and the specific method is as follows: 3.6ppm is the peak of CH in polylactic acid, 5.1ppm is the peak of CH2 in polyethylene glycol monomethyl ether, and the peak area and the number of hydrogen have the following relationship: polyethylene glycol monomethyl ether molecular weight 2000, l/g=2m/4n, m=2000/44=45.5, the composition and molecular weight of the copolymer can be determined.
Molecular weight of copolymer= (1+weight ratio of pdlla/MPEG) ×2000
Wherein: l is the integral area of the composite peak at 5.1ppm and represents the methine of the polylactide;
g is the integral area of the composite peak at 3.6ppm and represents the methylene group of the polyoxyethylene;
m is the polymerization degree of the oxyethylene in the structural formula of the copolymer;
n is the degree of polymerization of D, L-lactide in the structural formula of the copolymer.
GPC was measured by high performance liquid chromatography (rule < 0512 >) in the fourth edition of Chinese pharmacopoeia 2020.
The chromatographic conditions adopt gel chromatographic columns; differential refraction detection; tetrahydrofuran is the mobile phase; the flow rate was 1.0mL/min and the column temperature was 40 ℃.
The determination method is to take a proper amount of the product, add tetrahydrofuran to prepare 1% solution, suck 20 mu L, inject into a liquid chromatograph, use polystyrene standard substance as standard sample, and treat the data by GPC software.
(2) The related substance detection method comprises the following steps:
Chromatographic conditions:
Mobile phase a: water and its preparation method
Mobile phase B: acetonitrile
Gradient elution was performed as follows:
A diluent: acetonitrile-water-glacial acetic acid (100:100:0.1)
Chromatographic column: octadecylsilane chemically bonded silica as filler (4.6X105 mm,5 μm)
Column temperature: 35 ℃;
detection wavelength: 230nm;
Flow rate: 1.0mL/min;
Sample injection volume: 20. Mu.L.
Test solution: taking 1 bottle of docetaxel polymer micelle freeze-dried preparation, adding a proper amount of diluent for dissolving and transferring into a 50ml measuring flask, washing the penicillin bottle with the proper amount of diluent for at least 3 times, transferring all the penicillin bottle into the measuring flask, adding the diluent for dilution to a scale, and shaking uniformly;
control solution: precisely measuring 1ml of the sample, placing in a 100ml measuring flask, adding diluent to scale, and shaking.
Auxiliary material solution: precisely weighing appropriate amount of polyethylene glycol monomethyl ether-polylactic acid block copolymer (MPEG-PDLLA), adding diluent, dissolving, and diluting to obtain solution containing 9.6mg per 1 ml.
Sensitivity solution: taking a proper amount of docetaxel reference substance, precisely weighing, adding a diluent for dissolving and diluting to prepare a solution containing about 0.2 mug in each 1ml.
System applicability solution: taking a proper amount of docetaxel identification reference substance, precisely weighing, adding a diluent for dissolving and diluting to prepare a solution containing about 0.4mg per 1ml.
System applicability requirements: in the system applicability solution chromatogram, the separation degree of docetaxel peak and impurity B, C, D is required to meet the requirement. In the sensitivity solution chromatogram, the signal to noise ratio of docetaxel peak height should be greater than 10.
The analysis process comprises the following steps: the measurement is carried out by high performance liquid chromatography (four general rules of Chinese pharmacopoeia 2020 edition < 0512 >). Precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms.
The calculation formula is as follows:
total impurity (%) = Σ% individual impurity
Wherein:
Area of impurity peak in A SPL sample solution
Main peak area in A STD control solution
F correction factor
Judgment standard: the impurity content is calculated according to the main component self-contrast method multiplied by correction factor (1.0) except that the auxiliary material peak is subtracted from the chromatogram of the sample solution. Peaks smaller than 0.05 times the main peak area of the control solution in the chromatogram of the test solution are ignored.
(3) Particle size and span detection method: taking docetaxel polymer micelle freeze-dried preparation, adding 20mL of 0.9% sodium chloride injection to prepare a solution, and measuring according to the guiding principle of the microparticle preparation (the rule of the fourth edition of Chinese pharmacopoeia 2020 edition is less than 9014 >) and the particle size and particle size distribution measurement method (the rule of the fourth edition of Chinese pharmacopoeia 2020 edition is less than 0982 > the third method).
EXAMPLE 1 preparation of polyethylene glycol monomethyl ether-polylactic acid Block copolymer
Adding 4.50kg of polyethylene glycol monomethyl ether (2000) into a reaction kettle under the protection of nitrogen, charging nitrogen, vacuumizing, heating to 120 ℃, continuously heating and keeping vacuum when all molten, drying for 2 hours, replacing with nitrogen, adding 4.95kg of D, L-lactide under the protection of nitrogen, charging nitrogen, vacuumizing, and keeping vacuum in the reaction kettle; stirring uniformly and then replacing nitrogen. Heating to 140 ℃, adding 18.000g of stannous iso-octoate under the protection of nitrogen, replacing the stannous iso-octoate with nitrogen, and heating to 140+/-5 ℃ under the protection of nitrogen for reaction for 5 hours. After the reaction, the temperature of the product is reduced to 40 ℃, 36L of dichloromethane and 4.50kg of active carbon are added, the mixture is stirred and decolorized for 1h, the mixture is filtered, and the filtrate is concentrated to dryness under reduced pressure.
Adding 4.5L of dichloromethane, adding 90L of cold anhydrous diethyl ether under stirring, standing after stirring for 30min, filtering, refining the filter cake twice according to the operation process, and vacuum drying to obtain 6.204kg of polyethylene glycol monomethyl ether-polylactic acid segmented copolymer, wherein the yield is 65.65%. The resulting copolymer was characterized by nuclear magnetic resonance and the results are shown in FIG. 1. Molecular weight 3647, gpc analysis result: polydisperse coefficient pd=1.2.
Examples 2 to 4 preparation of polyethylene glycol monomethyl ether-polylactic acid Block copolymer
The same procedure as in example 1 was conducted except that the following feeding was used to prepare a polyethylene glycol monomethyl ether-polylactic acid block copolymer. Detecting the content of D, L-lactide in the prepared polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
EXAMPLE 5 preparation of polyethylene glycol monomethyl ether-polylactic acid Block copolymer
Under the protection of nitrogen, 20g of polyethylene glycol monomethyl ether (2000) is added into a reaction bottle, nitrogen is filled, vacuum is pumped, the reaction bottle is kept under vacuum, the reaction bottle is heated to 120 ℃, the reaction bottle is heated to be completely molten, the heating is continued, the vacuum is kept, and the reaction bottle is replaced by nitrogen after being dried for 2 hours. Adding 22g of weighed D, L-lactide under the protection of nitrogen, filling nitrogen, and vacuumizing to keep vacuum in a reaction bottle; stirring uniformly and then replacing nitrogen. Heating to 135 ℃, adding 0.08g of stannous iso-octoate under the protection of nitrogen, replacing nitrogen, protecting nitrogen, and heating to 140 ℃ for reaction for 5 hours. After the reaction, the temperature of the product was reduced to 40℃and 160ml of methylene chloride and 10g of activated carbon were added thereto, followed by stirring for 1 hour and filtration. The filtrate was concentrated to dryness under reduced pressure. The contents of the rotary evaporator were transferred to a reaction flask with 20ml of methylene chloride, 400ml of cold anhydrous diethyl ether was added with stirring, and after stirring for 30min, the mixture was allowed to stand and filtered. The filter cake was refined twice more according to the above procedure, and vacuum-dried to obtain 32g of polyethylene glycol monomethyl ether-polylactic acid block copolymer. The D, L-lactide content was 0.07%. GPC analysis results: polydisperse coefficient pd=1.11. Inductively coupled plasma mass spectrometry ICPMS detects the metal tin ion content, resulting in: the metal tin ion content was 0.042ppm.
Example 6 preparation of polyethylene glycol monomethyl ether-polylactic acid Block copolymer
Under the protection of nitrogen, 20g of polyethylene glycol monomethyl ether (2000) is added into a reaction bottle, nitrogen is filled, vacuum is pumped, the reaction bottle is kept under vacuum, the reaction bottle is heated to 120 ℃, the reaction bottle is heated to be completely molten, the heating is continued, the vacuum is kept, and the reaction bottle is replaced by nitrogen after being dried for 2 hours. Adding 22g of weighed D, L-lactide under the protection of nitrogen, filling nitrogen, and vacuumizing to keep vacuum in a reaction bottle; stirring uniformly and then replacing nitrogen. Heating to 135 ℃, adding 0.08g of stannous iso-octoate under the protection of nitrogen, and heating to 140 ℃ for reaction for 5h. After the reaction, the temperature of the product was reduced to 40 ℃, 160ml of dichloromethane and 20g of activated carbon were added, stirred for 1 hour, and filtered. The filtrate was concentrated to dryness under reduced pressure. The contents of the rotary evaporator were transferred to a reaction flask with 20ml of methylene chloride, 400ml of cold anhydrous diethyl ether was added with stirring, and after stirring for 30min, the mixture was allowed to stand and filtered. The filter cake was refined twice more according to the above procedure, and vacuum-dried to obtain 32g of polyethylene glycol monomethyl ether-polylactic acid block copolymer. Inductively coupled plasma mass spectrometry ICPMS detects metal tin ion content, detection result: the content of metallic tin ions was 0.06ppm.
EXAMPLE 7 preparation of polyethylene glycol monomethyl ether-polylactic acid Block copolymer
150G of polyethylene glycol monomethyl ether (2000) is added into a reaction bottle under the protection of nitrogen, nitrogen is filled, vacuum is pumped, the reaction bottle is kept under vacuum, the reaction bottle is heated to 120 ℃, the reaction bottle is heated to be completely molten, the heating is continued, the vacuum is kept, and the reaction bottle is replaced by nitrogen after being dried for 2 hours. Adding 165g of weighed D, L-lactide under the protection of nitrogen, charging nitrogen, and vacuumizing to keep the vacuum in the reaction product; stirring uniformly and then replacing nitrogen. Heating to 135 ℃, adding 0.6g of stannous iso-octoate under the protection of nitrogen, replacing nitrogen, protecting nitrogen, and heating to 140 ℃ for reaction for 5 hours. After the reaction, the temperature of the product is reduced to 40 ℃, 150ml of dichloromethane is added for dissolution, 3000ml of cold absolute ethyl ether is added under stirring, and after stirring for 30min, the mixture is kept stand and filtered. The filter cake was refined twice more according to the above procedure, and vacuum-dried to obtain 224g of polyethylene glycol monomethyl ether-polylactic acid block copolymer. Inductively coupled plasma mass spectrometry ICPMS detects the metal tin ion content, resulting in: the metallic tin ion content was 350ppm.
Example 8 preparation of docetaxel Polymer micelle freeze-dried preparation
The formula comprises the following components:
The preparation process comprises the following steps: (1) The polyethylene glycol monomethyl ether-polylactic acid block copolymer prepared in the example 1 with the prescription amount is weighed, added into 50% of methanol with the prescription amount for ultrasonic treatment until the mixture is completely dissolved, and a methanol solution is obtained.
(2) Adding the prescribed amount of citric acid into the methanol solution for dissolution, adding the prescribed amount of docetaxel and the residual methanol after the dissolution is completed, continuing to dissolve, filtering, and performing rotary evaporation on the filtrate for at least 1h at the temperature of 50-60 ℃ and the rpm of 80-120 rpm to obtain the docetaxel polymer gel film.
(3) Adding 15kg of water for injection at about 50-60 ℃ into a round bottom rotary steaming bottle filled with docetaxel polymer medicine membrane, placing into a rotary oscillator for hydration, placing the round bottom flask into cold water for cooling when the water is completely hydrated, and obtaining docetaxel polymer micelle solution. Sterilizing, filtering, filling in a penicillin bottle, and freeze-drying to obtain the docetaxel polymer micelle freeze-dried preparation. Each bottle contains 20mg of docetaxel.
Taking a small amount of docetaxel polymer micelle freeze-dried preparation, and detecting by a transmission electron microscope after redissolving. The results are shown in FIG. 2, which shows that the sample is approximately spherical and that micelles have formed.
And taking a small amount of docetaxel polymer micelle freeze-dried preparation, and detecting the particle size and span, wherein the particle size is 22nm and the span is 0.73.
Example 9 encapsulation efficiency test
Samples prepared in example 8 were taken, dissolved in physiological saline to a concentration of 1mg/ml, and then left at room temperature (25.+ -. 2 ℃ C.) to examine the encapsulation efficiency at various time points.
Control solution (containing docetaxel about 0.2 mg/ml): precisely weighing 10mg of docetaxel reference substance in a 50ml measuring flask, adding a diluent for dissolution, diluting to a scale, and shaking uniformly to obtain a reference substance solution for content measurement.
Test stock solution (containing docetaxel 1 mg/ml): taking 5 bottles of the product (each bottle contains 20mg of docetaxel), adding 20ml of 0.9% sodium chloride injection respectively, and mixing by vortex for 10 minutes to obtain a stock solution of the test product. Three portions were arranged in parallel.
Solution before centrifugation: taking 4ml of the sample stock solution, centrifuging for 10 minutes by 10000G centrifugal force, precisely measuring 2.0ml of supernatant, placing in a 10ml measuring flask, diluting to a scale with a diluent, shaking uniformly, and taking the solution as a centrifuged solution.
The HPLC chromatographic conditions were: ODS is used as filler, 0.043mol/L ammonium acetate aqueous solution-acetonitrile (45:55) is used as mobile phase, and the detection wavelength is 230nm.
The detection results of encapsulation efficiency of docetaxel polymer micelle freeze-dried preparation at different times after reconstitution are shown as follows:
the result shows that the docetaxel polymer micelle freeze-dried preparation has excellent encapsulation efficiency, and the encapsulation efficiency after 24 hours of redissolution is not lower than 95%.
Examples 10-12 preparation of docetaxel Polymer micelle lyophilized preparation
Docetaxel polymer micelles were prepared in the following amounts, and related substances (total impurities) were examined.
(1) Preparation of polyethylene glycol monomethyl ether-polylactic acid block copolymer
Adding polyethylene glycol monomethyl ether (2000) into a reaction bottle, charging nitrogen, vacuumizing, keeping vacuum in the reaction bottle, heating to 100-120 ℃, and continuously heating for 2h and keeping vacuum when all the materials are melted; adding D, L-lactide after nitrogen replacement, filling nitrogen, and vacuumizing to keep vacuum in the reaction product; after nitrogen substitution, 0.18 percent by weight of stannous octoate is added according to the weight of the materials in a reaction bottle, nitrogen substitution and nitrogen protection are carried out, the mixture is heated to 140 ℃ for reaction for 5 hours, after the reactants are cooled to room temperature, the product is dissolved by methylene dichloride with the volume being equal to 0.5 times of the weight of the reactants, cold anhydrous diethyl ether with the volume being equal to 10 times of the weight of the reactants is immediately added for precipitation under stirring, and after stirring for 30 minutes, the mixture is stood and filtered. And refining the filter cake twice according to the operation process, and vacuum drying the product to obtain the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
(2) Docetaxel polymer micelles were prepared in the amounts shown in the above table according to the preparation method in example 8.
A small amount of the docetaxel polymer micelle freeze-dried preparation prepared in examples 10 to 12 was taken and the related substances (total impurities) were measured. The results are shown in the following Table
Investigation project Example 10 Example 11 Example 12
Related substances (Total impurities) 0.43％ 0.28％ 0.26％
From the test results, the preparation with the feeding mass ratio of the MPEG to the D, L-lactide of 1:1.1 and the feeding mass ratio of the L-lactide of 1:1.2 is obviously reduced relative to the preparation with the feeding mass ratio of the MPEG to the D, L-lactide of 1:1.0.

Claims (27)

  1. The polyethylene glycol monomethyl ether-polylactic acid block copolymer is a block copolymer formed by polymerizing D, L-lactide and polyethylene glycol monomethyl ether, wherein the feeding mass ratio of the polyethylene glycol monomethyl ether to the D, L-lactide is 1:1.05-1.25, and the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by the following method: (a) Adding polyethylene glycol monomethyl ether into a reactor, heating and melting under vacuum, and replacing with inert gas; (b) Adding D, L-lactide, replacing with inert gas, adding a metal catalyst, ensuring that the reactor is under negative pressure or under inert gas protection, and then heating to 125-150 ℃ for reaction; (c) Cooling after the reaction is finished, adding a first organic solvent for dissolution, adding a second organic solvent, filtering, and vacuum drying a filter cake to obtain the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
  2. The polyethylene glycol monomethyl ether-polylactic acid block copolymer according to claim 1, wherein the feeding mass ratio of polyethylene glycol monomethyl ether to D, L-lactide is 1:1.1-1.2, preferably 1:1.1.
  3. The polyethylene glycol monomethyl ether-polylactic acid block copolymer according to claim 1, wherein the molecular weight of the polyethylene glycol monomethyl ether of step (a) is 1000 to 20000, preferably 1000 to 5000, more preferably 1800 to 2200, even more preferably 2000.
  4. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the polyethylene glycol monomethyl ether of step (a) is heated to 60-130 ℃ under vacuum.
  5. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the metal catalyst of step (b) is stannous isooctanoate.
  6. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 5, wherein the stannous iso-octoate is 0.05 to 0.5wt%, preferably 0.15 to 0.3wt%, of the total mass of D, L-lactide and polyethylene glycol monomethyl ether.
  7. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the reaction time of step (b) is 1 to 20 hours, preferably 3 to 10 hours, more preferably 4 to 6 hours.
  8. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the first organic solvent of step (c) is one or more of acetonitrile, acetone, methylene chloride, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, a short chain aliphatic alcohol, or ethyl acetate, preferably one or more of methylene chloride, chloroform, methanol, ethanol, isopropanol, more preferably methylene chloride; the amount of the first organic solvent to be used is 0.1 to 100 times by volume (L/kg), preferably 0.2 to 50 times by volume (L/kg), more preferably 0.5 to 20 times by volume (L/kg) based on the mass of polyethylene glycol monomethyl ether.
  9. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the second organic solvent of step (c) is one or more of diethyl ether, isopropyl ether, methyl t-butyl ether, n-heptane, cyclohexane, petroleum ether, preferably one or more of diethyl ether, isopropyl ether or methyl t-butyl ether, more preferably diethyl ether; the second organic solvent is used in an amount of 1 to 100 times by volume (L/kg), preferably 10 to 50 times by volume (L/kg), more preferably 15 to 20 times by volume (L/kg) based on the total mass of the polyethylene glycol monomethyl ether.
  10. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the step (b) further comprises the steps of adding a third organic solvent and activated carbon after the completion of the reaction, stirring, filtering, and concentrating the filtrate under reduced pressure.
  11. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 10, wherein the third organic solvent is one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, butyl acetate, butanone, toluene, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, short-chain aliphatic alcohol, preferably one or more of dichloromethane, chloroform, methanol, ethanol, isopropanol, more preferably dichloromethane; the third organic solvent is used in an amount of 0.1 to 100 times by volume (L/kg), preferably 0.2 to 50 times by volume (L/kg), more preferably 0.5 to 20 times by volume (L/kg) based on the mass of polyethylene glycol monomethyl ether.
  12. The polyethylene glycol monomethyl ether-polylactic acid block copolymer according to claim 10, wherein the activated carbon is used in an amount of 1 to 500wt%, preferably 5 to 200wt%, more preferably 5 to 75wt%, still more preferably 20 to 50wt%, based on the total mass of D, L-lactide and polyethylene glycol monomethyl ether.
  13. The polyethylene glycol monomethyl ether-polylactic acid block copolymer according to claim 10, wherein the polyethylene glycol monomethyl ether-polylactic acid block copolymer has a metal tin ion content of 10ppm or less, preferably 1ppm or less, more preferably 0.1ppm or less.
  14. The polyethylene glycol monomethyl ether-polylactic acid block copolymer of claim 1, wherein the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by the following method: (a) Adding polyethylene glycol monomethyl ether into a reactor, charging nitrogen, vacuumizing, heating, vacuum drying and replacing inert gas; (b) Adding D, L-lactide, filling nitrogen, vacuumizing, keeping the reactor in vacuum, replacing with inert gas, adding a metal catalyst under the protection of nitrogen, replacing with nitrogen, ensuring that the reactor is under negative pressure or inert gas protection, and then heating to 125-150 ℃ for reaction; (c) Cooling after the reaction is finished, adding a first organic solvent for dissolution, adding a second organic solvent, filtering, and vacuum drying a filter cake to obtain the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
  15. A lyophilized formulation of a hydrophobic drug polymer micelle, wherein the lyophilized formulation comprises a hydrophobic drug and the polyethylene glycol monomethyl ether-polylactic acid block copolymer of any one of claims 1-14.
  16. The hydrophobic drug polymer micelle lyophilized formulation according to claim 15, wherein the mass ratio of the hydrophobic drug to polyethylene glycol monomethyl ether-polylactic acid block copolymer is 0.01-0.15:1, preferably 0.02-0.12:1, more preferably 0.03-0.10:1, even more preferably 0.04:0.96.
  17. The hydrophobic drug polymer micelle lyophilized formulation of claim 15, wherein the lyophilized formulation further comprises a stabilizer.
  18. The hydrophobic drug polymer micelle lyophilized formulation according to claim 17, wherein the stabilizer is one or more of citric acid, hydrochloric acid, sorbic acid, lactic acid, tartaric acid, malic acid, phosphoric acid, acetic acid, adipic acid, fumaric acid, preferably one or more of citric acid, tartaric acid, fumaric acid, more preferably citric acid.
  19. The hydrophobic drug polymer micelle lyophilized formulation of claim 17, wherein the mass ratio of hydrophobic drug to stabilizer is 1:0.00125 to 0.25, preferably 1:0.005 to 0.25, more preferably 1:0.0125 to 0.125.
  20. The hydrophobic drug polymer micelle lyophilized formulation according to claim 15, wherein the hydrophobic drug is selected from taxane compounds, preferably the hydrophobic drug is selected from docetaxel or paclitaxel, more preferably the hydrophobic drug is selected from docetaxel.
  21. The hydrophobic drug polymer micelle lyophilized formulation of claim 15, wherein the lyophilized formulation comprises the following components in the ratio:
  22. The method for preparing the hydrophobic drug polymer micelle freeze-dried preparation according to any one of claims 15 to 21, comprising the following steps: (1) Dissolving the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer and the hydrophobic drug in an organic solvent, rotationally evaporating to remove the organic solvent to obtain a gel-like drug film, and then adding water into the drug film to dissolve and disperse the drug film to obtain a micelle solution; (2) Filtering, sterilizing and freeze-drying the micelle solution prepared in the step (1) to obtain the hydrophobic drug polymer micelle freeze-dried preparation.
  23. The preparation method according to claim 22, wherein step (1) is to dissolve the polyethylene glycol monomethyl ether-polylactic acid block copolymer, the stabilizer and the hydrophobic drug according to any one of claims 1 to 14 in an organic solvent, remove the organic solvent by rotary evaporation to obtain a gel-like drug film, and then dissolve and disperse the drug film by adding water to the drug film to obtain a micelle solution.
  24. The preparation method according to claim 22 or 23, wherein the organic solvent in step (1) is selected from any one or more of acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, short-chain aliphatic alcohol, ethyl acetate, preferably any one or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, more preferably methanol; the dosage of the organic solvent in the step (1) is 0.5-12 ml of the organic solvent, preferably 3-12 ml of the organic solvent, is added into each gram of polyethylene glycol monomethyl ether polylactic acid block copolymer.
  25. The preparation method according to claim 22 or 23, wherein the amount of water added to the drug film in step (1) is 2 to 40ml of water per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer, preferably 10 to 20ml of water per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer, more preferably 10 to 15ml of water per gram of polyethylene glycol monomethyl ether polylactic acid block copolymer.
  26. The production method according to claim 22 or 23, wherein, in the step (2), the condition for removing the organic solvent by rotary evaporation is: the rotation speed is 10-150 rpm, the temperature is 20-80 ℃ and the time is 1-4 h.
  27. Use of a hydrophobic drug polymer micelle lyophilized formulation according to any one of claims 15 to 21 in the manufacture of a medicament for the prevention or treatment of cancer.
CN202280053105.6A 2021-09-03 2022-09-02 Hydrophobic drug polymer micelle and preparation method thereof Pending CN117999304A (en)

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