Development of a Cyclodextrin-Based Nasal Delivery System for Lorazepam

• Published in: Drug development and industrial pharmacy Vol. 34; no. 8; pp. 817 - 826
• Main Authors: Jug, Mario, Be irevi -La an, M.
• Format: Journal Article
• Language: English
• Published: Colchester Informa UK Ltd 01.01.2008; Taylor & Francis
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Administration, Intranasal; beta-Cyclodextrins - chemistry; Biological and medical sciences; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical - methods; Drug Delivery Systems; Excipients - chemistry; General pharmacology; Humans; hydroxypropyl-β-cyclodextrin; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - chemistry; Hypnotics and Sedatives - pharmacokinetics; lorazepam; Lorazepam - administration & dosage; Lorazepam - chemistry; Lorazepam - pharmacokinetics; Medical sciences; mucoadhesion; nasal delivery; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Solubility; Spectroscopy, Fourier Transform Infrared; Delivery system; Bioadhesion; Pharmaceutical technology; Psychotropic; Mucosa; Hypnotic; hydroxypropyl-β-cyclodextrin; Intranasal administration; nasal delivery; Cyclodextrin; Tranquillizer; mucoadhesion; Benzodiazepine derivatives; Lorazepam; Sedative; Inclusion compound
• ISSN: 0363-9045; 1520-5762
• DOI: 10.1080/03639040801926063

A new drug delivery system containing hydroxypropyl-β-cyclodextrin (HP-β-CD) and a mucoadhesive polymer was developed with the aim to overcome the limitations connected with the nasal application of drugs with low water solubility. Lorazepam, free or as cyclodextrin inclusion complex, was loaded into mucoadhesive microparticles by spray drying, using hydroxypropylmethyl cellulose (HPMC), carbomer, and HPMC carbomer interpolymer complex (IPC) as mucoadhesive components. Differential scanning calorimetry (DSC) indicated the presence of drug crystalline areas in microparticles loaded with free lorazepam, whereas in those loaded with HP-β-CD inclusion complex, the drug was amorphous. Zeta potential measurement revealed that the polymer was the main component on the surface of the microparticles. The swelling rate and mucoadhesive properties of the microparticles were determined by the polymer type used in formulation. IPC- and carbomer-based microparticles showed superior swelling rate and mucoadhesion compared with the HPMC-based microparticles (p < .05). Drug loading into the polymer matrix decreased the swelling rate as well as the mucoadhesive properties of microparticles (p < .05), whereas the presence of HP-β-CD in the matrix did not induce any additional reduction of those parameters (p > .05). The in vitro dissolution studies demonstrated that the microparticles containing the lorazepam inclusion complex displayed 1.8-2.5 times faster drug release compared with those containing free lorazepam. The change in the drug release rate could be connected with improved drug solubility inside the polymer matrix due to inclusion complex formation, as well as to the reduction in crystallinity following complexation, as confirmed by DSC studies.