Electrosprayed 4-carboxybenzenesulfonamide-chitosan microspheres for acetazolamide delivery

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Abstract

4-Carboxybenzensulfonamide-chitosan (4-CBS-chitosan) microspheres were prepared by electrospraying with acetazolamide (ACZ) as a model drug. The obtained 4-CBS-chitosan microspheres with or without ACZ-loading were characterized by Fourier transform infrared spectroscopy, differential scanning colorimetry, scanning electron microscopy and particle size analyses. The crystalline form and the stability of ACZ in a basic solution was determined using X-ray single crystal analysis. 4-CBS-chitosan had 90% encapsulation efficiency for ACZ compared to 47% of encapsulation efficiency (EE) obtained from native chitosan, forming 3.1 μm diameter microspheres with a low polydispersity index (0.4). After an initial burst release (58% in 5 min), ACZ-loaded 4-CBS-chitosan gave a sustained release of ACZ (∼100% over 3 h) in simulated gastric fluid (0.1 N HCl; pH 1.2), which was better than that seen for the release from ACZ-loaded chitosan (44% over 1.5 h). Thus, 4-CBS-chitosan microspheres are a possible drug carrier in acidic conditions, such as at the gastric mucosal wall.

Introduction

Nowadays, the idea of using mucoadhesive micro-/nano-particles from natural biodegradable polymers represents a promising drug delivery system. Mucoadhesive polymers capable of attaching at the mucosal surfaces may prolong the residence time and improve the specific localization of target drug absorption [1].

Chitin ((1-4)-2-amino-2-deoxy-β-d-glucan) can be partly deacetylated to form chitosan, a mucoadhesive polysaccharide [2] that has increasingly been used in the pharmaceutical application and food industries, due to its non-toxic, biocompatible and enzymatic biodegradable nature plus its antimicrobial and mucoadhesive properties [3]. Chitosan microspheres are a potential carrier for the controlled release of drugs, such as antibiotics, antihypertensive agents, anticancer agents, proteins, peptide drugs and vaccines [4]. 4-Carboxybenzensulfonamide covalently linked with chitosan (4-CBS-chitosan) has been reported to reveal a stronger mucoadhesion to mucin type II and a higher swelling behavior than the corresponding unmodified chitosan [5]. Moreover, it was found to be non-toxic in vitro to the Vero, KB, MCF-7 and NCI-H187 cell lines in tissue culture, but showed potential antibacterial activity against Esherichia coli and Staphlyococcus aureus.

Therefore, it is of interest if 4-CBS-chitosan microspheres suitable for drug delivery could be easily synthesized. In this work electrospraying (ESI) was used to prepare 4-CBS-chitosan microspheres due to the advantage of ESI in that it typically provides a uniform particle size with a narrow size distribution, and it is a simple, fast one-step technique [6].

Acetazolamide (ACZ) is an inhibitor of carbonic anhydrase with a weak diuretic activity that is used for the symptomatic treatment of glaucoma, epilepsy, benign intracranial hypertension, altitude sickness and in the therapy of gastric and duodenal ulcers [7]. However, ACZ does not remain concentrated in the circulatory system but is diluted in various body fluids and is subsequently absorbed from mucosal tissues leading to systemic toxic side effects [8]. One potential strategy to reduce these side effects and increase the therapeutic treatment is the encapsulation of ACZ in a mucoadhesive polymer delivery system to keep the drug concentrated and slowly released into the target organ. However, ACZ has a low solubility in water and organic solvents, leading to a low effective bioavailability and so requiring specialized pharmaceutical formulations and specific evaluation of its bioactivity in each formulation. Moreover, it has very poor compression properties making tablet formation difficult [9]. To improve the solubility of ACZ, it can be dissolved in 0.1 N aqueous ammonia solutions, but the bioactivity of ACZ depends on the solution pH [10] and no reports about ACZ in a base condition are available. Therefore, in this work we also investigated the crystalline form and the stability of ACZ in a base condition, after being fabricated as ACZ loaded 4-CBS-chitosan microspheres, using X-ray single crystal analysis.

The aim of this work was to prepare ACZ-loaded 4-CBS-chitosan microspheres by ESI as a potential mucoadhesive carrier for the sustained release of ACZ at the gastric mucosal surface. Fourier transform infrared spectroscopy (FT-IR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM) analyses were used to characterize the microspheres.

Section snippets

Materials

Chitosan with an average molecular weight (Mw) of >500 kDa was provided by Bonafide Co., Ltd., Thailand. The degree of deacetylation of chitosan was determined to be 81% by 1H NMR. ACZ (99% purity), 4-CBS (99% purity), sodium tripolyphosphate (TPP) and 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (EDAC) were purchased from Aldrich Co., USA and used without purification. Cellulose dialysis tubing (Membrane Filtration Products Inc., USA) with a molecular weight cut-off of 12–14 kDa

Morphology and particle size

The characterization of 4-CBS covalently linked onto chitosan was determined by 1H NMR and FT-IR as previously reported [5]. The degree of 4-CBS substitution was determined to be 4.5% by 1H NMR.

ESI, with a flow rate of 2.5 mL/h, applied voltage of 15 kV, stirring rate of 400 rpm and 8 cm distance between the needle tip and negative electrode based on the reported information [13], was used to prepare the chitosan, 4-CBS-chitosan and their respective ACZ-loaded microspheres. The SEM images of the

Conclusions

Toward developing an effective drug delivery devices for the treatment of gastric and duodenal ulcers in the stomach; 4-CBS-chitosan microspheres were successful prepared by ESI to obtain microspheres with a relatively narrow size distribution (PDI of 0.46–0.60). 4-CBS-chitosan microspheres showed a 1.9-fold higher ACZ EE than that of pure chitosan, reaching an ∼90% EE, as well as an improved total amount (100%) and sustained level (∼3 h) of ACZ release in SGF.

Acknowledgements

The authors gratefully acknowledge the funding from the 90th Anniversary of Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund) to P.S.; Integrated Innovation Academic Center: IIAC Chulalongkorn University Centenary Academic Development Project (Ratchadaphiseksomphot Endowment Fund) to N.M. (RES560530064-FW). Thanks are also given to Dr. Robert Butcher of the PCU, Faculty of Science, Chulalongkorn University, for constructive comments and English corrections.

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