ABSTRACT
The aim of this study was to formulate salbutamol sulfate (SS), a model drug, as mucoadhesive in situ gelling inserts having a high potential as nasal drug delivery system bypassing the first-pass metabolism. In situ gelling inserts, each containing 1.4% SS and 2% gel-forming polymer, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium (CMC Na), sodium alginate (AL), and chitosan (CH) were prepared. The inserts were investigated for their different physicochemical properties. The weight of inserts was 16-27 mg, drug content was 3.9-4.2 mg, thickness ranged between 15 and 28 µm and surface pH was 5-7. Cumulative drug released from the inserts exhibited extended release for more than 10 h following the decreasing order: CH>AL>CMC Na>HPMC. The drug release from CMC Na and AL inserts followed zero-order kinetics while HPMC and CH inserts exhibited non-Fickian diffusion mechanism. The inserts exhibited different water uptake (7-23%) with the smallest values for CH. Differential scanning calorimetry study pointed out possible interaction of SS and oppositely charged anionic polymers (CMC Na and AL). The mucoadhesive in situ gelling inserts exhibited satisfactory mucoadhesive and extended drug release characteristics. The inserts could be used for nasal delivery of SS over about 12 h; bypassing the hepatic first-pass metabolism without potential irritation.
Subject(s)
Albuterol/chemistry , Bronchodilator Agents/chemistry , Drug Carriers , Polymers/chemistry , Adhesiveness , Administration, Intranasal , Albuterol/administration & dosage , Alginates/chemistry , Bronchodilator Agents/administration & dosage , Calorimetry, Differential Scanning , Carboxymethylcellulose Sodium/chemistry , Chemistry, Pharmaceutical , Chitosan/chemistry , Delayed-Action Preparations , Diffusion , Gels , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Hypromellose Derivatives , Kinetics , Methylcellulose/analogs & derivatives , Methylcellulose/chemistry , Mucins/chemistry , Solubility , Surface Properties , Technology, Pharmaceutical/methodsABSTRACT
OBJECTIVES: The objectives of this study were to assess the bioavailability of an optimized mephenamic acid (MFA) microspheres (test) against a Ponstan® capsule (reference) in healthy volunteers, and to establish a correlation with in vitro parameters. SUBJECTS AND METHODS: Four subjects received the test and reference (250 mg MFA each) in a randomized crossover design, separated by a 1-week washout period. The drug was analyzed in plasma by a specific high-performance liquid chromatographic method. The relevant pharmacokinetic parameters [maximum plasma concentration (C(max)), time of peak concentration (T(max)), area under plasma concentration-time curves from 0 to 12 h (AUC(0-12)) and area under plasma concentration-time curves from zero to ∞ (AUC(0-)∞)] were calculated from the plasma drug concentration-time data. RESULTS: The test product exhibited faster absorption (T(max) of 1.87 ± 0.482 vs. 2.14 ± 0.20 h; C(max) of 5.91 ± 0.604 vs. 3.58 ± 0.671 µg/ml) when compared to the reference. The relative bioavailability of the test compared to the reference capsule was 172%. Good correlations were established between the in vitro 90% dissolution (T90) and each of the AUC(0-12) and T(max), as well as between the percentage of drug released and plasma concentrations. CONCLUSION: The formulation of MFA microsphere with polyethylene glycol improved the dissolution rate and bioavailability of MFA, as evidenced by a higher C(max), AUC(0-12) and AUC(0-)∞, and shorter T(max) values. Good correlations between T90 and both AUC(0-12) and T(max) as well as between the percentage of drug released and plasma concentrations were achieved.
