Abstract
A thermosensitive, mucoadhesive in-situ gel for clonazepam (CLZ) intranasal delivery was developed, which aimed to achieve prolonged in-situ residence and controlled drug release, overcoming problems associated with its oral or parenteral administration. Poloxamer was selected as a thermosensitive polymer and chitosan glutamate and sodium hyaluronate as mucoadhesive and permeation enhancer. Moreover, randomly methylated β-Cyclodextrin (RAMEB) was used to improve the low drug solubility. A screening DoE was applied for a systematic examination of the effect of varying the formulation components proportions on gelation temperature, gelation time and pH. Drug-loaded gels at different clonazepam-RAMEB concentrations were then prepared and characterized for gelation temperature, gelation time, gel strength, mucoadhesive strength, mucoadhesion time, and drug release properties. All formulations showed suitable gelation temperature (29–30.5 °C) and time (50–65 s), but the one with the highest drug-RAMEB concentration showed the best mucoadhesive strength, longest mucoadhesion time (6 h), and greatest release rate. Therefore, it was selected for cytotoxicity and permeation studies through Caco-2 cells, compared with an analogous formulation without RAMEB and a drug solution. Both gels were significantly more effective than the solution. However, RAMEB was essential not only to promote drug release, but also to reduce drug cytotoxicity and further improve its permeability.
Highlights
Epilepsy affects more than 50 million people worldwide [1], and benzodiazepines are still considered the mainstay in the treatment of epileptic acute repetitive seizures.Among the different benzodiazepines, clonazepam (CLZ) offers the advantage of longer duration of action [2], proving effective in the treatment of seizures, panic disorder and akathisia [3,4,5]
It is known that PLX gelation temperature increases with decreasing its concentration, and that combinations of PLX with other excipients may alter the dehydration of hydrophobic PPO blocks and the consequent micellization process, changing its sol-gel transition temperature and time necessary for gelling [23]
A screening design was carried out as a first step of this work, in order to investigate the effect of varying the relative percent of the gel formulation components on gelation temperature (Y1 ), gelation time (Y2 ), and pH (Y3 ), considered as the responses to be optimized, as well as to point out possible interactions among the components
Summary
Epilepsy affects more than 50 million people worldwide [1], and benzodiazepines are still considered the mainstay in the treatment of epileptic acute repetitive seizures. Clonazepam (CLZ) offers the advantage of longer duration of action [2], proving effective in the treatment of seizures, panic disorder and akathisia [3,4,5]. Oral or parenteral CLZ administration results in limited uptake across the blood–brain barrier [6]. Other pharmacological issues of this drug, such as high first-pass metabolism, need for long-term treatment, and repetitive dosing, make the development of innovative delivery systems exploiting alternative routes to the oral and parenteral ones desirable.
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