Introduction
Mucosal adhesion as a new route of administration has gradually attracted the attention of the pharmaceutical industry in recent years. Chitosan is a polyaminopolysaccharide with mucoadhesive properties that enhances the retention time of the drug in the mucosa and thus its bioavailability. Chitosan is hydrophilic, contains functional amino groups and cationic charges. These properties make it an ideal delivery tool for macromolecular drugs, but its solubility in neutral or alkaline media is poor, limiting its use. .
The chitosan molecular group can be optimized by chemical modification, and studies have shown that the thiol group-containing polymer has higher adhesion characteristics. The thiol group-containing compound can be covalently bonded to the amino group through an amide bond, wherein the hydroxy acid group of the ligand (such as thioglycolic acid TGA) is mediated by a water-soluble carbodiimide, and is condensed by an amino group and a shell. Sugar coupling. TG-chitosan has better mucoadhesive properties, that is, the thiol group of the polymer forms a stronger covalent bond with the cysteine-rich glycoprotein subdomain of the mucus layer.
The mucoadhesive properties of polymers are affected by many factors, including the molecular weight, concentration and drying method of the polymer. For example, TG-chitosan obtained by lyophilization has better mucoadhesive properties than the organic solvent precipitated and dried. The addition of plasticizers to polymeric dosage forms also enhances toughness and flow and reduces brittleness.
In this paper, TG-chitosan xerogel was prepared by dialysis-lyophilization method and its characteristics as oral mucosal administration were evaluated.
experiment
In the preparation of TG-chitosan, 500 mg of chitosan was dissolved in 50 ml of 0.1 M HCl, an equivalent amount of 500 mg of thioglycolic acid was added, the pH was adjusted to 5 with 1 M NaOH, and 50 mM EDAC was added to activate the hydroxyl group of TGA. After continuous stirring and incubation for 4 h at room temperature, the obtained thiolated polymer was added to a 8-10 kD Spectra/Por Float-A-Lyzer G2 ready-to-use dialysis apparatus and dialyzed in different aqueous media to remove unbound TGA. The media sequence of multi-step dialysis was: dialysis for 8 h in 5 L 5 mmol/L HCl, dialysis for 2 h in 5 mmol/L HCl containing 1% NaCl for 8 h to prevent ionic reaction between cationic chitosan and anionic sulfhydryl ligand, and finally 5 L 5 mmol/L HCl was dialyzed for two 8 h in the dark. The product obtained by dialysis was used directly in the gel preparation or lyophilized and stored at 4 ° C for further analysis. The number of coupled thiol groups was determined using an Ellman reaction and a standard cysteine ​​HCl curve. The molecular weights of chitosan and TG-chitosan were monitored using gel permeation chromatography.
To the recovered dialysis gel, 10% of a glycerin plasticizer and a mannitol cryoprotectant were separately added, and 50% of BSA was loaded as a model protein drug. The gel containing 1% (w/v) TG-chitosan was continuously stirred at room temperature for 30 min to obtain a homogeneous mixture, which was stored at room temperature to remove bubbles.
TG-chitosan-BSA was transferred to a mold and lyophilized using an automated freeze-drying cycle with an annealing step. The lyophilized xerogel is placed on silica gel and placed in a desiccator to reduce water content and maintain protein stability.
The TG-chitosan gel was analyzed and identified by ATR-FTIR spectroscopy, CD spectroscopy, X-ray diffraction and scanning electron microscopy. At the same time, the drug loading efficiency, swelling degree, moisture content, in vitro mucoadhesive ability and drug dissolution degree of the gel were examined.
discuss
The sample obtained after lyophilization has complete structure and good performance, and all the indexes are within the acceptable range, indicating that the stable TG-chitosan xerogel which can be delivered by oral adhesion is successfully prepared in this experiment. The specifications of the drug-loaded xerogel containing plasticizer and cryoprotectant are affected by the annealing and thiolation processes, but do not affect the conformational stability of the protein. The test results also showed that the wet content, swelling degree, mucoadhesive properties and microstructure of the xerogel after lyophilization were affected by the thiolation process. The annealing step in the lyophilization cycle helps the dry gel to achieve the desired porous structure, thereby optimizing the hydration, mucoadhesion, and drug release index of the xerogel. Finally, the product is obtained as a product of high mechanical strength and can be stably stored for a long period of time. These results indicate that the novel lyophilized thiolated chitosan can be used for protein drug delivery by mucosal adhesion.
The editor compiles and introduces this article for communication purposes. Due to the limited level, please be aware of any inconvenience. For details, please refer to the original text.
Original: Ayensu I., Mitchell JC, Boateng JS, In vitro characterisation of chitosan based xegels for potential buccal delivery of proteins. Carbohydrate Polymers, 2012, 89: 935-941.
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