Abstract
Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.
Highlights
Sobrerol, developed in the 1970s as a mucolytic agent, is widely used to treat acute or chronic respiratory diseases caused by increased bronchial mucus and obstruction [1].The recommended dose of sobrerol was 400 mg daily for adults, the longest treatment period was 3 months with a daily dose of 600 mg, and the maximum daily dose was 900 mg for 10 consecutive days
Sobrerol IR pellets were formed in a matrix structure, and the drug loading was more than 70% by total weight
We successfully developed high-drug-loaded IR and SR pellets of sobrerol
Summary
The recommended dose of sobrerol was 400 mg daily for adults, the longest treatment period was 3 months with a daily dose of 600 mg, and the maximum daily dose was 900 mg for 10 consecutive days. Sobrerol is considered a relatively safe drug with no substantial side effects when administered under guidance [2,3,4]. In addition to respiratory diseases, sobrerol has recently been studied to treat multiple sclerosis, an autoimmune neurological disease [5]. The experimental autoimmune encephalomyelitis (EAE) animal model exhibiting inflammatory demyelination and axonal damage was adopted in the study on multiple sclerosis treatment [6,7], and sobrerol could effectively alleviate EAE symptoms at a dose of 100 mg/kg thrice daily, which is equivalent to the positive control dimethyl fumarate at a dose of 100 mg/kg twice daily. Dimethyl fumarate is the first-line oral drug currently used for treating multiple sclerosis, and its most common adverse events are flushing, diarrhea, abdominal pain, nausea, vomiting, and lymphocyte reduction [8,9]
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