Preparation and Drug Release Mechanism of Time Controlled Explosive Pulsatile Tablets with Ethylcellulose Coating

Abstract

Core tip:

The development of pharmacology in the decade revealed the biological rhythm of the occurrence and development of certain diseases, usually the circadian rhythm. Therefore, chronopharmacological drug delivery is of great significance in the prevention and treatment of diseases having onset rhythm inconvenient to take drug. An easy-to-prepared, time-controlled explosive metoprolol tartaric pulsatile tablet was developed in order to provide patients with timed therapy of effective blood drug concentration at the optimal time. The formulation and process were optimized using single factor experiments and orthogonal experiments. In addition, the swelling and water absorption rate of tablet and the mechanical properties of the coating film were measured to further reveal its release mechanism. The results showed that the strong tensile strength of coating film and the weak flexibility of EC film resulted in a shell-type exploding rupture of the coating film followed by the pulsatile fast release of drug when the swelling force of core tablet caused by water uptake was high enough. Both the swelling capacity of core tablets and the thickness of coating film together controlled the lag time of drug release. The prepared time-controlled explosive pulsatile tablets with ethylcellulose coating thereafter are expected to be used for the delivery of therapeutic agents for chronotherapy by adjusting the lag time of drug release to match the different high attack rhythm of the exact diseases.

Abstract:

Background The time rhythm of human body is associated with the occurrence and development of many diseases, and it also affects the efficacy and pharmacokinetic characteristics of the corresponding therapeutic drugs. Therefore, the chronopharmacological drug delivery system has potential applications.

Aim In this work, it is proposed to develop a kind of pulsatile release tablet of simple structure and preparing process, thus to provide an alternative drug delivery system for therapeutic agents used in treatment of diseases of typical onset biorhythm at period inconvenient to take drug.

Methods Metoprolol tartrate (MT), a drug widely used clinically to treat cardiovascular diseases was selected as a model drug for developing pulsatile tablets of time-controlled explosive system (TES). The MT pulsatile tablets were ethyl cellulose (EC) coating tablets produced by pan coating process, and the core tablets were prepared by direct compression. The formulation and process was optimized by single factor test and orthogonal design. Also, the pulsatile release mechanism of the tablets was discussed through investigating the water absorption and swelling capacity of tablets as well as the mechanical properties of EC free film.

Results A kind of pulsatile tablets of MT were developed with a drug release lag time around 7 h and a fast release of drug after lag time. When the swelling force of core tablet caused by water uptake was high enough over the tensile strength of EC coating film, the MT pulsatile tablets demonstrated a shell-type exploding rupture due to the great rigidity and weak flexibility of EC film, and then a fast pulsatile release of drug was observed. Both the swelling capacity of core tablet and the thickness of coating film together controlled the lag time of drug release. The lag time showed a good linear relationship with the thickness of coating film (r = 0.9984, P < 0.01). The sort and amount of fillers and disintegrants dominated the release behaviour after lag time.

Conclusion The developed MT pulsatile tablets can exert a timely release of drug before peak onset period of hypertension and angina pectoris early in the morning after drug taking around 22:00 P.M the night before. The good linear relationship between lag time and coating thickness enabled the pulsatile tablets to be used for delivery of other therapeutic agents of similar chronotherapy demand by adjusting the coating thickness to achieve the appropriate lag time of drug release to match the different high attack rhythm of the exact diseases.