Layered Silicate-Alginate Composite Particles for the pH-Mediated Release of Theophylline.

Uttom Nandi,Nichola J. Coleman,Andrew P. Mendham,Dennis Douroumis,Vivek Trivedi

doi:10.3390/ph13080182

Uttom Nandi, Nichola J. Coleman + Show 3 more

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https://doi.org/10.3390/ph13080182

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Abstract

Numerous natural and synthetic clay minerals have proven to be excellent drug carriers for high drug-loaded and sustained release formulations due to their considerable ion exchange, adsorption, and swelling capacities. Moreover, the synthetic smectite clays have added advantages in terms of compositional purity and controlled cation exchange capacity in comparison to natural clays. This study involves the intercalation of theophylline (TP) in a synthetic clay, Laponite® (LP), followed by the inclusion of the resulting intercalates into sodium alginate (SA) beads to achieve pH-controlled drug release. Maximum intercalated drug incorporation of 68 mg/g was obtained by ion exchange at pH 1.2 and confirmed by an increase in basal spacing of the clay from 12.9 to 15.5 Å. TP release from the binary LP-TP intercalates in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was found to be 40% and 70%, respectively. LP-TP particles were also incorporated in an SA matrix via polymer crosslinking using CaCl2(aq) to improve the pH selective release. The ternary polymer-clay-drug composite particles effectively prevented the release of TP at low pH in SGF and resulted in sustained release in SIF, with 40% dissolution within 120 min.

Highlights

Theophylline (TP), C7H8N4O2, is a methylxanthine derivative that has been in clinical use for more than 70 years [1]
It is a weak nonselective inhibitor of phosphodiesterase enzymes (PDEs), which prevents the breakdown of cyclic adenosine monophosphate and cyclic guanosine monophosphate, resulting in the relaxation of airway smooth muscles
These mechanisms, along with the interleukin-10 release promoted by TP, ameliorate the symptoms of asthma and chronic obstructive pulmonary disease (COPD) [4]

Summary

Introduction

Theophylline (TP), C7H8N4O2, is a methylxanthine derivative that has been in clinical use for more than 70 years [1]. TP is primarily used as a bronchodilator at high concentrations, but low dosages are known to provide an anti-inflammatory effect It is a weak nonselective inhibitor of phosphodiesterase enzymes (PDEs), which prevents the breakdown of cyclic adenosine monophosphate and cyclic guanosine monophosphate, resulting in the relaxation of airway smooth muscles. It is a potent adenosine receptor antagonist and treats bronchoconstriction caused by histamine release due to the actions of adenosine on the airway mast cells [2,3]. The therapeutic window of TP is narrow, usually 10–20 mg/L, below which the bronchodilation effect is minimal, and above 25 mg/L, any additional benefits outweigh potential side effects [5]. The maintenance of serum TP concentration within the therapeutic boundaries is absolutely crucial to the wellbeing of the patient

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