CN112716894A - Biotin-modified pluronic F127-oligochitosan-based honokiol micelle and preparation thereof - Google Patents

Biotin-modified pluronic F127-oligochitosan-based honokiol micelle and preparation thereof Download PDF

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CN112716894A
CN112716894A CN202011505696.5A CN202011505696A CN112716894A CN 112716894 A CN112716894 A CN 112716894A CN 202011505696 A CN202011505696 A CN 202011505696A CN 112716894 A CN112716894 A CN 112716894A
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honokiol
pluronic
biotin
drug
micelle
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朱力
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University of Jinan
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The invention mainly protects a drug-loaded micelle consisting of biotin-modified pluronic F127-chitosan oligosaccharide and honokiol and a preparation process thereof. The manufacturing process comprises the following steps: the biotin-modified pluronic F127-chitosan oligomer is used as a carrier material, is mixed with a certain proportion of honokiol, is dissolved in dimethyl sulfoxide, and is prepared into the honokiol drug-loaded micelle by a dialysis method.

Description

Biotin-modified pluronic F127-oligochitosan-based honokiol micelle and preparation thereof
Technical Field
The invention relates to a honokiol drug-loaded micelle of pluronic F127-chitosan modified by biotin as a carrier and a preparation method thereof.
Background
Honokiol (structure shown below) is a biphenol compound extracted from root bark of cortex Magnolia officinalis, and research shows that honokiol has various biological effects, including muscle relaxation, antiinflammatory, antioxidant activity, and multiple protective effects on hepatotoxicity, neurotoxicity, thrombosis and angiopathy. But the low selectivity and poor solubility limit the clinical application of the compound as an antitumor drug.
Figure RE-GDA0002992750980000011
A great number of scientific researches report that honokiol has various biological activities of resisting bacteria, viruses, oxidation, inflammation, tumors, angiogenesis, spasm and depression and the like. However, the structure of honokiol contains phenolic groups, which has poor stability and is easy to be oxidized. And due to poor water solubility, the protein is also subjected to an efflux function mediated by P glycoprotein (P-gp) in cell transportation. These reasons all result in low bioavailability of honokiol, thereby limiting the development of honokiol into patent drugs. Nearly half of the new drugs or compounds obtained by combinatorial chemistry and high throughput screening are eliminated in the new drug development phase due to their low solubility in gastrointestinal fluids and inability to reach therapeutic concentrations for oral absorption. Therefore, there is an urgent need to develop a novel drug-loaded preparation of honokiol with relatively low price, improved solubility and improved bioavailability.
The pluronic F127 amphiphilic polymer can be self-assembled in water to form micelle 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 covered on the micelle surface can reduce the interaction between the micelle and plasma protein in vivo and reduce the phagocytosis of the macrophagy system, thereby improving the bioavailability or pharmacokinetic property of the medicament.
The water-soluble oligo-chitosan is low-molecular-weight chitosan containing 2-20 chitosan monomers, has the characteristic of easy uptake by organism cells, and has polyelectrostatic property. Biotin is a water-soluble vitamin, plays an important role in the process of synthesizing vitamin C, and is also an indispensable substance for the normal metabolism of fats and proteins. The chitosan oligosaccharide is connected with Pluronic F127 and modified by water-soluble biotin to form an amphiphilic polymer. The polymer can self-assemble into a micelle: the Pluronic F127, the chitosan oligosaccharide and the like are distributed on the near surface of the micelle, and the chitosan oligosaccharide chain segment can generate electrostatic interaction with electronegative fungal cells to promote the fungal cell uptake of the medicine; the honokiol contains functional groups such as aromatic rings, phenolic hydroxyl groups, lipophilic olefin structures and the like, and can generate interaction with the chitosan oligosaccharide in micelles, thereby realizing entrapment of the honokiol, improving the water solubility of the honokiol and the like.
Disclosure of Invention
The invention aims to provide a preparation process and a formula of honokiol drug-loaded micelles to improve the solubility of honokiol and improve the bioavailability of honokiol. The prepared preparation can be used as a dosage form for intravenous administration or oral administration.
The honokiol drug-loaded micelle is a sustained-release drug-loaded micelle. The weight ratio of the water-soluble biotin-modified pluronic F127-chitosan oligosaccharide polymer to honokiol is as follows: 1 part of honokiol and 5-10 parts of biotin-modified pluronic F127-chitosan oligomer.
The preparation method of the honokiol drug-loaded micelle comprises the following steps: dissolving the pluronic F127-chitosan oligomer and honokiol modified by biotin according to the formula ratio in an organic solvent, performing ultrasonic assisted dissolution, dialyzing at room temperature, and filtering by using a microporous filter membrane to remove the non-entrapped honokiol to prepare a micellar solution.
The biotin-modified pluronic F127-chitosan oligosaccharide structure related to the invention is as follows:
Figure RE-GDA0002992750980000021
the molecular weight of the selected pluronic F127 in the biotin-modified pluronic F127-chitosan oligosaccharide polymer is 13000, the molar ratio of the pluronic F127 to biotin is 1: 1-1: 2, and the molecular weight of the selected chitosan oligosaccharide is 1000-5000.
The organic solvent selected in the method is dimethyl sulfoxide.
Detailed Description
The structure of the biotin-modified pluronic F127-chitosan oligomer is as follows:
Figure RE-GDA0002992750980000031
the honokiol micelle is a colloid drug delivery system and is characterized in that the honokiol micelle is composed of honokiol and biotin-modified pluronic F127-chitosan oligomer and does not contain other auxiliary agents.
The weight ratio of the biotin-modified pluronic F127-chitosan oligomer to honokiol is as follows: 1 part of honokiol and 5-10 parts of biotin-modified pluronic F127-chitosan oligomer.
The molecular weight of the selected pluronic F127 in the biotin-modified pluronic F127-chitosan oligosaccharide polymer is 13000, the molecular weight of the chitosan oligosaccharide is 1000-5000, and the molar ratio of the pluronic F127 to biotin is 1: 2.
Example 1
Dissolving biotin-modified pluronic F127-oligochitosan polymer (70mg) and honokiol (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with a microporous filter membrane to remove the unencapsulated honokiol, and preparing into a micellar solution with an encapsulation rate of 72.25% and a drug loading rate of 9.36%.
Example 2
Dissolving the biniotin-modified pluronic F127-oligochitosan polymer (70mg) and honokiol (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with a microporous filter membrane to remove the unencapsulated honokiol, and preparing into a micellar solution with the encapsulation rate of 82.27% and the drug loading rate of 10.52%.
Example 3
Dissolving biotin-modified pluronic F127-oligochitosan polymer (100mg) and honokiol (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with a microporous filter membrane to remove the unencapsulated honokiol, and preparing into a micellar solution with the encapsulation rate of 77.26% and the drug loading rate of 7.17%.
Example 4
Dissolving the biniotin-modified pluronic F127-oligochitosan polymer (100mg) and honokiol (10mg) in dimethyl sulfoxide, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with a microporous filter membrane to remove the unencapsulated honokiol, and preparing into a micellar solution with an encapsulation rate of 75.27% and a drug loading rate of 7.00%.

Claims (6)

1. A honokiol medicine carrying micelle is characterized in that: the drug-loaded micelle consisting of biotin-modified pluronic F127-oligochitosan and honokiol comprises the following components in percentage by weight: 1 part of honokiol, 5-10 parts of biotin-modified pluronic F127-chitosan oligosaccharide; the preparation method comprises the following steps: dissolving the polymer and honokiol in the formula ratio in an organic solvent, performing ultrasonic assisted dissolution, dialyzing at room temperature, filtering with a microporous filter membrane to remove the unencapsulated honokiol, and preparing into a micellar solution.
2. The honokiol drug-loaded micelle of claim 1, wherein the biotin-modified pluronic F127-chitosan oligosaccharide is of the following structure:
Figure FDA0002844883610000011
3. the honokiol drug-loaded micelle of claim 2, wherein the biotin-modified pluronic F127-oligochitosan is characterized by: the molar ratio of the pluronic F127 to the biotin is 1: 1-1: 2.
4. The honokiol drug-loaded micelle of claim 2, wherein the corresponding pluronic F127-chitosan oligosaccharide is characterized by: the chosen pluronic F127 molecular weight was 13000.
5. The honokiol drug-loaded micelle of claim 2, wherein the corresponding pluronic F127-chitosan oligosaccharide is characterized by: the molecular weight of the selected chitosan oligosaccharide is 1000-5000.
6. The honokiol drug-loaded micelle of claim 1, wherein the organic solvent is dimethyl sulfoxide.
CN202011505696.5A 2020-12-18 2020-12-18 Biotin-modified pluronic F127-oligochitosan-based honokiol micelle and preparation thereof Pending CN112716894A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110507612A (en) * 2019-05-28 2019-11-29 济南大学 Mono methoxy polyethylene glycol-widow's chitosan amphotericin B micella and its preparation based on the modification of alfa- linolenic acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110507612A (en) * 2019-05-28 2019-11-29 济南大学 Mono methoxy polyethylene glycol-widow's chitosan amphotericin B micella and its preparation based on the modification of alfa- linolenic acid

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANNAPINA RUSSO ET AL.: ""Biotin-targeted Pluronic1 P123/F127 mixed micelles delivering", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 *
ZHIMEI SONG ET AL.: ""Oligochitosan-pluronic 127 conjugate for delivery of honokiol"", 《ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY》 *
孙少平 等: "《高分子材料在纳米给药系统中的应用》", 31 August 2017 *

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