Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis

https://doi.org/10.1016/j.ijantimicag.2005.07.012Get rights and content

Abstract

Pharmacokinetic and chemotherapeutic studies have been carried out with aerosolised alginate nanoparticles encapsulating isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA). The nanoparticles were prepared by cation-induced gelification of alginate and were 235.5 ± 0 nm in size, with drug encapsulation efficiencies of 70–90% for INH and PZA and 80–90% for RIF. The majority of particles (80.5%) were in the respirable range, with mass median aerodynamic diameter of 1.1 ± 0.4 μm and geometric standard deviation of 1.71 ± 0.1 μm. The relative bioavailabilities of all drugs encapsulated in alginate nanoparticles were significantly higher compared with oral free drugs. All drugs were detected in organs (lungs, liver and spleen) above the minimum inhibitory concentration until 15 days post nebulisation, whilst free drugs stayed up to day 1. The chemotherapeutic efficacy of three doses of drug-loaded alginate nanoparticles nebulised 15 days apart was comparable with 45 daily doses of oral free drugs. Thus, inhalable alginate nanoparticles can serve as an ideal carrier for the controlled release of antitubercular drugs.

Introduction

The failure of antitubercular chemotherapy is mainly due to patient non compliance [1], which is attributed to the requirement of multidrug administration daily or several times a week for at least 6 months. Although attempts to improve patient non compliance by applying modified drug delivery systems for antimycobacterial agents are encouraging [2], higher polymer consumption [3], lower drug entrapment [4], higher cost, use of toxic substances and organic solvents during preparation [5], [6], and surgical requirements [7] are all drawbacks associated with these drug delivery systems. Moreover, these particulate systems (liposomes, microparticles and nanoparticles) used as drug carriers are rapidly taken up from the blood by mononuclear phagocytes, especially by the Kupffer cells in the liver, which is a drawback to gaining access to other target sites in the body, e.g. the lungs [8]. In addition, the high frequency of pulmonary tuberculosis demands the development of novel drug delivery approaches that enhance the bioavailability of drugs at the level of lungs. In recent years, one of the best ways to achieve higher drug levels in the lungs has been the development of new formulations (nanoparticle-based) that are directly delivered to the lungs via the aerosol route [9]. The present study was planned with an aim of developing a natural polymer-based inhalable drug delivery system to overcome the limitations associated with various drug delivery systems. Sodium alginate, a natural polymer (β-d-mannuronic acid and α-l-guluronic acid) with properties such as an aqueous matrix environment, high gel porosity and biocompatibility, and approved by the US Food and Drug Administration (FDA) for oral use [10], [11], was used to prepare nanoparticles encapsulating three antitubercular drugs (ATDs). Alginate nanoparticles containing isoniazid (INH), pyrazinamide (PZA) and rifampicin (RIF) were developed and characterised, and pharmacokinetic and pharmacodynamic evaluation was carried out via the aerosol route in guinea pigs.

Section snippets

Chemicals

Sodium alginate (medium viscosity, 3500 cps for a 2% w/v solution), chitosan (minimum 85% deacetylated), INH, RIF and PZA were obtained from Sigma Chemical Co. (St Louis, MO). Middlebrook 7H10 agar was obtained from Difco (Detroit, MI). All other reagents were of analytical grade obtained from standard companies.

Animals

Guinea pigs of either sex, weighing 250–350 g, were obtained from Haryana Agricultural University, Hisar, India. Animals were housed in animal isolators (NU 605-600E, Series 6; NuAire

Statistical analysis

The pharmacokinetic data, including bioavailability, were analysed by Student's unpaired t-test, and CFU data were analysed by analysis of variance (ANOVA) to compare the control and treated groups.

Physicochemical characterisation of alginate nanoparticles

Alginate nanoparticles had an average size of 235.5 ± 0 nm, with a polydispersity index of 0.439. Drug encapsulation efficiency was observed to be 80–90% for RIF and 70–90% for INH and PZA. The drug loading capacity of alginate nanoparticles was 586–654 mg, 480–600 mg and 468–576 mg for RIF, INH and PZA, respectively, per 100 mg of alginate.

Aerodynamic characterisation of nebulised alginate nanoparticles

Aerodynamic characterisation revealed that nearly 80.5% of nebulised alginate nanoparticle droplets were in the size range 0.4–2.1 μm (respirable range), with a

Discussion

To overcome the daily dosing problem of tuberculous therapy, the application of drug delivery systems is a novel strategy [16]. Alginate nanoparticles are a drug delivery system bearing the benefits of sustained release properties of nanoparticles, but also carry additional advantages, including the least use of organic solvents, no involvement of toxic molecules, least use of equipment, and reduced reticuloendothelial system uptake due to the stealth nature of alginate [8]. The present study

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