CN112716895A - Andrographolide drug-loaded micelle of Pluronic F127 modified based on phenylbutyric acid and preparation method thereof - Google Patents

Andrographolide drug-loaded micelle of Pluronic F127 modified based on phenylbutyric acid and preparation method thereof Download PDF

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CN112716895A
CN112716895A CN202011505706.5A CN202011505706A CN112716895A CN 112716895 A CN112716895 A CN 112716895A CN 202011505706 A CN202011505706 A CN 202011505706A CN 112716895 A CN112716895 A CN 112716895A
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andrographolide
pluronic
phenylbutyric acid
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loaded micelle
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朱力
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University of Jinan
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Abstract

The invention mainly protects a drug-loaded micelle consisting of phenylbutyric acid modified pluronic F127 and andrographolide and a preparation process thereof. The preparation process comprises the following steps: the phenylbutyric acid modified pluronic F127 triblock copolymer is used as a carrier, is mixed with andrographolide in a certain proportion, is dissolved in dimethyl sulfoxide, and is prepared into the andrographolide drug-loaded micelle through a dialysis method.

Description

Andrographolide drug-loaded micelle of Pluronic F127 modified based on phenylbutyric acid and preparation method thereof
Technical Field
The invention relates to an andrographolide drug-loaded micelle with a prenex F127 modified by phenylbutyric acid as a carrier and a preparation method thereof.
Background
Andrographolide (structure shown below) is a diterpenoid compound extracted from plant herba Andrographitis, has effects of diminishing inflammation, resisting bacteria, protecting liver, promoting bile flow, clearing heat, detoxicating, resisting virus infection, resisting cardiovascular disease, and resisting tumor, and is known as "traditional Chinese medicine antibiotic", and belongs to BCS II class medicine. However, andrographolide has strong hydrophobicity, poor oral absorption, slow in vivo absorption and low bioavailability, thereby affecting the curative effect.
Figure RE-GDA0002992751310000011
Andrographolide is extracted from natural dicotyledonous plant andrographis paniculata, has the functions of resisting tumor, infection, regulating immune system, resisting virus, bacteria, fungi, protozoa and other activity, and has obvious effect of preventing and controlling opportunistic infection. The diterpenoid lactone compound belongs to a diterpenoid lactone compound, has no similar compatibility with water and can not react, and generally can only be taken by adopting an oral administration mode. In order to further improve the bioavailability of andrographolide, researches on new carriers and new formulations of andrographolide are gradually carried out in recent years. However, almost half of them are eliminated in the development stage of new drugs because their solubility is low and their concentration required for treatment cannot be reached. Therefore, there is an urgent need to develop a novel andrographolide drug-carrying preparation with relatively low price, improved solubility and improved bioavailability.
Pluronic F127 amphiphilic polymers can self-assemble in water to form micelles with a core-shell structure: the inner core is a lipophilic chain segment, and the lipophilic drug are subjected to intermolecular interaction to realize the entrapment of the drug in the inner core; the shell is a hydrophilic chain segment, and hydration with water occurs, so that the water solubility of the medicine is improved. Meanwhile, the pluronic F127 covering the micelle surface can reduce the interaction between the micelle and plasma protein in vivo and reduce phagocytosis of a macrophagy system, thereby improving the bioavailability or pharmacokinetic property of the medicament.
Phenylbutyric acid, an approved drug by the U.S. FDA for uric acid cycle disorder, is now under investigation for its treatment of a variety of diseases including insulin resistance, cystic fibrosis, and maple syrup urine disease, wherein the drug has been studied in phase ii clinical trials for the treatment of brain tumors. Pluronic F127 is modified with phenylbutyric acid to form an amphiphilic polymer. The polymer can self-assemble into a micelle: the Polyoxyethylene (PEO) hydrophilic segment of pluronic F127 is present at the near surface of the micelle, and the polyoxypropylene (PPO) hydrophobic segment thereof is present in the inner core of the micelle; the andrographolide contains functional groups such as olefinic bond and cyclic lactone, and can generate interaction force with hydrophobic chain segments and phenylbutyric acid in the micelle, so that entrapment of the andrographolide is realized, water solubility of the andrographolide is improved, and the like.
Disclosure of Invention
The invention aims to provide a preparation process and a formula of andrographolide drug-loaded micelles to improve the solubility of andrographolide and improve the bioavailability of andrographolide. The prepared preparation can be used as a dosage form for intravenous administration or oral administration.
The andrographolide drug-loaded micelle is a sustained-release drug-loaded micelle. The weight ratio of the water-soluble phenylbutyric acid modified pluronic F127 polymer to the andrographolide is as follows: 1 part of andrographolide and 10-20 parts of phenylbutyric acid modified pluronic F127 polymer.
The preparation method of the andrographolide drug-loaded micelle comprises the following steps: dissolving the phenylbutyric acid modified pluronic F127 polymer and andrographolide in the formula amount in an organic solvent, performing ultrasonic assisted dissolution, dialyzing at room temperature, and filtering with a microporous filter membrane to remove unencapsulated andrographolide, thereby preparing a micellar solution.
The structure of the phenylbutyric acid modified pluronic F127 related to the invention is as follows:
Figure RE-GDA0002992751310000021
the molecular weight of the selected pluronic F127 in the phenylbutyric acid modified pluronic F127 polymer is 13000, the molar ratio of the pluronic F127 to the phenylbutyric acid is 1: 16, and the molecular weight of the selected poly (isobutylene-alt-maleic anhydride) is 6000.
The organic solvent selected in the method is dimethyl sulfoxide.
Detailed Description
The phenylbutyric acid modified pluronic F127 polymer has the following structure:
Figure RE-GDA0002992751310000031
the andrographolide micelle is a colloid drug delivery system and is characterized in that the andrographolide micelle is composed of andrographolide and phenylbutyric acid modified pluronic F127 polymer and does not contain other auxiliary agents.
The weight ratio of phenylbutyric acid modified pluronic F127 polymer to andrographolide was: 1 part of andrographolide and 10-20 parts of phenylbutyric acid modified pluronic F127 polymer.
The molecular weight of the selected pluronic F127 in the phenylbutyric acid modified pluronic F127 polymer is 13000, the molecular weight of poly (isobutylene-alt-maleic anhydride) is 6000, and the molar ratio of the pluronic F127 to the phenylbutyric acid is 1: 2.
Example 1
Dissolving phenylbutyric acid-modified Pluronic F127 polymer (200mg) and andrographolide (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with microporous membrane to remove unencapsulated andrographolide, and making into micellar solution with encapsulation rate of 74.55% and drug loading rate of 3.44%.
Example 2
Dissolving phenylbutyric acid modified pluronic F127 polymer (150mg) and andrographolide (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with microporous membrane to remove unencapsulated andrographolide, and making into micellar solution with encapsulation rate of 88.27% and drug loading rate of 5.28%.
Example 3
Dissolving phenylbutyric acid modified pluronic F127 polymer (100mg) and andrographolide (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with a microporous filter membrane to remove unencapsulated andrographolide, and making into micellar solution with an encapsulation rate of 64.41% and a drug loading rate of 6.02%.

Claims (5)

1. An andrographolide drug-loaded micelle is characterized in that: the drug-loaded micelle composed of phenylbutyric acid modified pluronic F127 and andrographolide comprises the following components in percentage by weight: 1 part of andrographolide, 12710-20 parts of phenylbutyric acid modified pluronic F; the preparation method comprises the following steps: dissolving the polymer and andrographolide in the formula ratio in an organic solvent, performing ultrasonic assisted dissolution, dialyzing at room temperature, and filtering with a microporous filter membrane to remove unencapsulated andrographolide, thereby preparing a micellar solution.
2. The andrographolide drug-loaded micelle of claim 1, wherein the phenylbutyric acid modified pluronic F127 is as follows:
Figure FDA0002844885410000011
3. the andrographolide-loaded micelle of claim 2, wherein the phenylbutyric acid-modified pluronic F127 is characterized in that: the molar ratio of pluronic F127 to phenylbutyric acid was 1: 2.
4. The andrographolide loaded micelle of claim 2, wherein the corresponding pluronic F127 is characterized by: the chosen pluronic F127 molecular weight was 13000.
5. The andrographolide-loaded micelle of claim 1, wherein the organic solvent is dimethyl sulfoxide.
CN202011505706.5A 2020-12-18 2020-12-18 Andrographolide drug-loaded micelle of Pluronic F127 modified based on phenylbutyric acid and preparation method thereof Withdrawn CN112716895A (en)

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Publication number Priority date Publication date Assignee Title
EP0586524A1 (en) * 1991-06-03 1994-03-16 Holmes Michael John Improvements in or relating to contrast agents.
US20030082238A1 (en) * 1999-02-12 2003-05-01 Babich John W. Matrices for drug delivery and methods for making and using the same
US20080138310A1 (en) * 2006-12-11 2008-06-12 Alcon Manufacturing, Ltd. Use of PEO-PBO block copolymers in ophthalmic compositions
CN101732724A (en) * 2010-01-07 2010-06-16 浙江大学 Composite micelle carrying anti-tumor medicine and preparation method thereof
CN102626518A (en) * 2012-05-09 2012-08-08 中国药科大学 Preparation and application of insoluble drug-entrapped poloxamer/amphiphilic polysaccharide mixed micelle
CN103006539A (en) * 2012-12-14 2013-04-03 沈阳药科大学 Polymeric micelle medicine composition and preparation method thereof
CN104415029A (en) * 2013-08-20 2015-03-18 苏州雷纳药物研发有限公司 Andrographolide polymer micelle, preparation method and medicinal application thereof
WO2019125130A1 (en) * 2017-12-20 2019-06-27 Leyva Gomez Gerardo Biopolymer of chitosan and poloxamer 407, obtained by means of gamma irradiation, which exhibits physicochemical and biological properties for the healing of wounds

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0586524A1 (en) * 1991-06-03 1994-03-16 Holmes Michael John Improvements in or relating to contrast agents.
US20030082238A1 (en) * 1999-02-12 2003-05-01 Babich John W. Matrices for drug delivery and methods for making and using the same
US20080138310A1 (en) * 2006-12-11 2008-06-12 Alcon Manufacturing, Ltd. Use of PEO-PBO block copolymers in ophthalmic compositions
CN101732724A (en) * 2010-01-07 2010-06-16 浙江大学 Composite micelle carrying anti-tumor medicine and preparation method thereof
CN102626518A (en) * 2012-05-09 2012-08-08 中国药科大学 Preparation and application of insoluble drug-entrapped poloxamer/amphiphilic polysaccharide mixed micelle
CN103006539A (en) * 2012-12-14 2013-04-03 沈阳药科大学 Polymeric micelle medicine composition and preparation method thereof
CN104415029A (en) * 2013-08-20 2015-03-18 苏州雷纳药物研发有限公司 Andrographolide polymer micelle, preparation method and medicinal application thereof
WO2019125130A1 (en) * 2017-12-20 2019-06-27 Leyva Gomez Gerardo Biopolymer of chitosan and poloxamer 407, obtained by means of gamma irradiation, which exhibits physicochemical and biological properties for the healing of wounds

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Title
RUNLIANG FENG等: "Phenylboronic acid-functionalized F127-oligochitosan conjugate micelles for doxorubicin encapsulation", 《J BIOMED MATER RES.》 *

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