CN110507612A - Mono methoxy polyethylene glycol-widow's chitosan amphotericin B micella and its preparation based on the modification of alfa- linolenic acid - Google Patents
Mono methoxy polyethylene glycol-widow's chitosan amphotericin B micella and its preparation based on the modification of alfa- linolenic acid Download PDFInfo
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- CN110507612A CN110507612A CN201910835482.5A CN201910835482A CN110507612A CN 110507612 A CN110507612 A CN 110507612A CN 201910835482 A CN201910835482 A CN 201910835482A CN 110507612 A CN110507612 A CN 110507612A
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- amphotericin
- alfa
- polyethylene glycol
- chitosan
- mono methoxy
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- 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
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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
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- 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
- A61P31/10—Antimycotics
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Abstract
Master of the present invention to be protected is carrier micelle and its preparation process composed by alfa- linolenic acid modification mono methoxy polyethylene glycol-widow's chitosan and amphotericin B.Its preparation process are as follows: it is carrier material that alfa- linolenic acid, which modifies mono methoxy polyethylene glycol-widow's chitosan polymer, mixes with a certain proportion of amphotericin B, after being dissolved in dimethyl sulfoxide, is prepared for amphotericin B carrier micelle using dialysis.
Description
Technical field
Mono methoxy polyethylene glycol-widow's chitosan that carrier is the modification of alfa- linolenic acid is prepared the present invention relates to a kind of
Carrier micelle of amphotericin B and preparation method thereof.
Background technique
Amphotericin B is polyene antifungal drug (structure is as follows), is mainly used for serious fungal infections, is treatment
The first-line drug of Systemic fungal infections.But a variety of toxicities including existing comprising renal toxicity.Acute renal failure be its most
Serious complication, the renal damage including the loss of potassium magnesium, renal tubular acidosis, the forfeiture of urine concentrating function etc.
It is common kidney toxic side effect relevant to amphotericin B medication, it can also cause Fanconi syndrome.
Other than serious toxic side effect, amphotericin B there is also it is water-soluble it is low, pharmacokinetic property is poor, hemolytic is high etc.
Drawback.Therefore, domestic and international researcher develops several formulations, to solve the above problems.The conventional formulation of amphotericin B is two
Property mycin B deoxycholic acid salt injection, amphotericin B water solubility can be improved, but toxic side effect does not improve.1996, the U.S.
FDA ratifies the aqueous colloidal dispersion listing of equimolar amphotericin B and cholesterine sulfuric acid composition, and it is related that there are dose-limiting infusions
Toxicity, dosage are up to 3-4 mg/kg/ days.1997, FDA ratified with soy phosphatidylcholine, distearyl phosphatide
Acyl glycerol and cholesterol are the AM Bison of principal component, and renal toxicity reduces, but at high price, are limited its application.Cause
This, is badly in need of developing a kind of relative low price, toxicity be lower, activating agent pharmacokinetic property makes moderate progress novel two
Property mycin B carrying medicine.
Polyethylene glycols amphiphilic polymer can be self-assembly of the micella with nucleocapsid structure in water: kernel is parent
Water segment occurs intermolecular interaction with lipophilic drugs, realizes drug containing in kernel；Shell is hydrophilic poly- second
With water aquation occurs for glycol, to improve the water solubility of drug.Meanwhile the polyethylene glycol for being covered in micellar surface can subtract
Few interaction such as micella and internal plasma protein, the phagocytosis of reduction macrophage system, so as to improve drug bioavilability or
Pharmacokinetic property.
Water-soluble widow's chitosan is the low-molecular weight chitoglycan containing 2-20 chitosan monomer, has and is easy to by organism
The characteristics of cellular uptake, has poly- electrical.Alfa- linolenic acid be lipophilicity polyunsaturated fatty acid class compound, have antibacterial,
The multiple biological activities such as antimycotic, anticancer, anti-inflammatory.Few chitosan is connected with polyethylene glycol, and repairs through lipophilicity alfa- linolenic acid
Decorations, can form amphiphilic polymer.The polymer can be self-assembled into micella: polyethylene glycol, few chitosan etc. are close in the micella
Surface distribution, few chitosan segment can occur electrostatic interaction with elecrtonegativity fungal cell, the fungal cell of drug promoted to absorb；Two
Property mycin B contains the functional groups such as amino, carboxyl, hydroxyl and lipophilic polyene structure, can be with the few chitosan in micella, parent
The interaction such as lipid alfa- linolenic acid, that realizes amphotericin B contains and assembles reduction, improves its hemolytic, renal toxicity etc.
Toxic side effect.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation process and formula of a kind of amphotericin B carrier micelle, with
The aggregation for reducing amphotericin B, improves the toxic side effects such as the renal toxicity of amphotericin B.Obtained preparation can be given as vein
Medicine or the dosage form of oral administration.
Amphotericin B carrier micelle according to the present invention is sustained release carrier micelle.The modification of lipophilicity alfa- linolenic acid
Mono methoxy polyethylene glycol-widow's chitosan polymer and anphotericin weight ratio are as follows: 1 part of amphotericin B, alfa- linolenic acid
The mono methoxy polyethylene glycol of modification -5-20 parts of widow's chitosan polymer.
Amphotericin B carrier micelle the preparation method is as follows:
Mono methoxy polyethylene glycol-widow's chitosan polymer and amphotericin B that the alfa- linolenic acid of formula ratio is modified are dissolved in
In organic solvent, ultrasonic dissolution assisting is dialysed under room temperature, and filtering with microporous membrane removes the amphotericin B of unentrapped, and micella is made
Solution.
Mono methoxy polyethylene glycol-widow's chitosan structure of the modification of alfa- linolenic acid involved in the present invention is as follows:
Selected mono methoxy polyethylene glycol point in mono methoxy polyethylene glycol-widow's chitosan polymer of alfa- linolenic acid modification
Son amount is 2000, and mono methoxy polyethylene glycol and the linolenic molar ratio of alfa- are 1:1-1:5, selected widow's molecular weight of chitosan
It is 1000.
Selected organic solvent is dimethyl sulfoxide in the above method.
Detailed description of the invention
The transmission electron microscope photo (13000 times of amplification) of Fig. 1 amphotericin B micella of the present invention.
Specific embodiment:
Mono methoxy polyethylene glycol-widow's chitosan polymer structure of alfa- linolenic acid modification is as follows:
。
Amphotericin B micella of the invention is a kind of colloidal drug delivery system, it is characterised in that be by amphotericin B and
The mono methoxy polyethylene glycol of alfa- linolenic acid modification-widow's chitosan polymer composition, does not contain other auxiliary agents.
Mono methoxy polyethylene glycol-widow's chitosan polymer and amphotericin B weight ratio of alfa- linolenic acid modification
Are as follows: 1 part of amphotericin B, mono methoxy polyethylene glycol -5-20 parts of widow's chitosan polymer of alfa- linolenic acid modification.
The selected poly- second two of mono methoxy in mono methoxy polyethylene glycol-widow's chitosan polymer of alfa- linolenic acid modification
Alcohol molecular weight is 2000, and the molecular weight of few chitosan is 1000, and mono methoxy polyethylene glycol is with the linolenic molar ratio of alfa-
1:1-1:5。
Embodiment 1
Mono methoxy polyethylene glycol-widow's the chitosan polymer (200 mg) and amphotericin B that single alfa- linolenic acid is modified
(10 mg) is dissolved in dimethyl sulfoxide, and ultrasonic dissolution assisting is dialysed under room temperature, and the both sexes that filtering with microporous membrane removes unentrapped are mould
Micellar solution, encapsulation rate 71.15%, drugloading rate 3.43% is made in plain B.
Embodiment 2
Mono methoxy polyethylene glycol-widow's the chitosan polymer (70 mg) and amphotericin B (10 that double alfa- linolenic acids are modified
Mg it) being dissolved in dimethyl sulfoxide, ultrasonic dissolution assisting is dialysed under room temperature, and filtering with microporous membrane removes the amphotericin B of unentrapped,
Micellar solution, encapsulation rate 82.27%, drugloading rate 10.52% is made.
Embodiment 3
Mono methoxy polyethylene glycol-widow's the chitosan polymer (120 mg) and amphotericin B that five alfa- linolenic acids are modified
(10 mg) is dissolved in dimethyl sulfoxide, and ultrasonic dissolution assisting is dialysed under room temperature, and the both sexes that filtering with microporous membrane removes unentrapped are mould
Micellar solution, encapsulation rate 54%, drugloading rate 4.3% is made in plain B.
Claims (6)
1. a kind of amphotericin B carrier micelle, it is characterised in that: it is the poly- second two of mono methoxy modified by alfa- linolenic acid
Alcohol-widow's chitosan and amphotericin B are made, weight ratio are as follows: and 1 part of amphotericin B, the mono methoxy of alfa- linolenic acid modification
5-20 parts of polyethylene glycol-polyethylenimine；Preparation method: the polymer of formula ratio and amphotericin B are dissolved in organic solvent
In, ultrasonic dissolution assisting is dialysed under room temperature, and filtering with microporous membrane removes the amphotericin B of unentrapped, and micellar solution is made.
2. the mono methoxy of amphotericin B carrier micelle described in claim 1, related alfa- linolenic acid modification is poly-
Ethylene glycol-widow's chitosan structure is as follows:
。
3. amphotericin B carrier micelle as stated in claim 2, corresponding to the modification of alfa- linolenic acid mono methoxy
Polyethylene glycol-widow's chitosan is characterized in that: mono methoxy polyethylene glycol is 1:1-1:5 with the linolenic molar ratio of alfa-.
4. amphotericin B carrier micelle as stated in claim 2, corresponding to the modification of alfa- linolenic acid mono methoxy
Polyethylene glycol-widow's chitosan is characterized in that: selected mono methoxy polyethylene glycol molecular weight is 2000.
5. amphotericin B carrier micelle as stated in claim 2, corresponding to the modification of alfa- linolenic acid mono methoxy
Polyethylene glycol-widow's chitosan is characterized in that: selected few molecular weight of chitosan is 1000.
6. amphotericin B carrier micelle described in claim 1, organic solvent described in preparation method is dimethyl sulfoxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019104492370 | 2019-05-28 | ||
| CN201910449237 | 2019-05-28 |
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| CN110507612A true CN110507612A (en) | 2019-11-29 |
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| CN201910835482.5A Withdrawn CN110507612A (en) | 2019-05-28 | 2019-09-05 | Mono methoxy polyethylene glycol-widow's chitosan amphotericin B micella and its preparation based on the modification of alfa- linolenic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112716894A (en) * | 2020-12-18 | 2021-04-30 | 济南大学 | Biotin-modified pluronic F127-oligochitosan-based honokiol micelle and preparation thereof |
| CN112999152A (en) * | 2021-02-26 | 2021-06-22 | 遵义医科大学附属医院 | Targeting polymer micelle modified based on GEBP11, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005118672A1 (en) * | 2004-06-02 | 2005-12-15 | The Governors Of The University Of Alberta | Polymer based nano-carriers for the solubilization and delivery of hydrophobic drugs |
| CN102614105A (en) * | 2011-01-28 | 2012-08-01 | 复旦大学 | Brain targeted amphotericin B (AmB) polymer micelle administration system |
| CN103479576A (en) * | 2013-09-27 | 2014-01-01 | 华南理工大学 | Adriamycin-wrapped polyethyleneimine-polyethylene glycol-creatine copolymer micelle and preparation method thereof |
-
2019
- 2019-09-05 CN CN201910835482.5A patent/CN110507612A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005118672A1 (en) * | 2004-06-02 | 2005-12-15 | The Governors Of The University Of Alberta | Polymer based nano-carriers for the solubilization and delivery of hydrophobic drugs |
| CN102614105A (en) * | 2011-01-28 | 2012-08-01 | 复旦大学 | Brain targeted amphotericin B (AmB) polymer micelle administration system |
| CN103479576A (en) * | 2013-09-27 | 2014-01-01 | 华南理工大学 | Adriamycin-wrapped polyethyleneimine-polyethylene glycol-creatine copolymer micelle and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| SONG ET AL.: "Linolenic acid-modified methoxy poly (ethylene glycol)-oligochitosan conjugate micelles for encapsulation of amphotericin B", 《CARBOHYDRATE POLYMERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112716894A (en) * | 2020-12-18 | 2021-04-30 | 济南大学 | Biotin-modified pluronic F127-oligochitosan-based honokiol micelle and preparation thereof |
| CN112999152A (en) * | 2021-02-26 | 2021-06-22 | 遵义医科大学附属医院 | Targeting polymer micelle modified based on GEBP11, and preparation method and application thereof |
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