ABSTRACT
Background The time rhythm of human body is associated with the occurrence and development of manydiseases, and it also affects the efficacy and pharmacokinetic characteristics of the corresponding therapeuticdrugs. 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 preparingprocess, thus to provide an alternative drug delivery system for therapeutic agents used in treatment of diseasesof typical onset biorhythm at period inconvenient to take drug.Methods Metoprolol tartrate (MT), a drug widely used clinically to treat cardiovascular diseases was selected asa model drug for developing pulsatile tablets of time-controlled explosive system (TES). The MT pulsatile tabletswere ethyl cellulose (EC) coating tablets produced by pan coating process, and the core tablets were preparedby 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 absorptionand 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 fastrelease of drug after lag time. When the swelling force of core tablet caused by water uptake was high enoughover the tensile strength of EC coating film, the MT pulsatile tablets demonstrated a shell-type exploding rupturedue 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 drugrelease. 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 ofhypertension and angina pectoris early in the morning after drug taking around 22:00 P.M the night before. Thegood linear relationship between lag time and coating thickness enabled the pulsatile tablets to be used fordelivery of other therapeutic agents of similar chronotherapy demand by adjusting the coating thickness toachieve the appropriate 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 manydiseases. Kinds of diseases of particular onset biorhythm provided the room for the development ofchronopharmacological drug delivery systems.Aim In this work, the drug release and pharmacokinetics behavior of metoprolol tartrate (MT) pulsatile tabletdeveloped in our lab was investigated to figure out its feasibility of convenient drug taking to exert effectivechronotherapy for cardiovascular diseases like hypertension and angina pectoris.Methods The in vitro release behavior of MT pulsatile tablets was investigated by using basket method. Theappearance and morphology of MT pulsatile tablets during drug release was observed by naked eye and scanning electronic microscope, respectively. In vivo pharmacokinetics performance was studied in NewZealand rabbits.Results The lag time of MT pulsatile tablets was approximately 7 h in vitro, and a fast release was observedthereafter, with more than 90% releasing within 10 min. The pharmacokinetics study in rabbits demonstrateda perfect consistence in the absorption lag time of 7.04 ± 0.29 h in vivo. Compared with the marketedconventional tablet, the MT pulsatile tablet showed a bioequivalence in absorption extent with a relativebioavailability of 110.04%, but not in absorption rate.Conclusion The designed lag time of 7 hours enabled the MT pulsatile tablets to achieve effectivechronotherapy for cardiovascular diseases like hypertension and angina pectoris with a high attack rhythmaround 4:00-6:00 A.M by giving medicine conveniently around 22:00 P.M. the night before.
ABSTRACT
Background Apocynin (4-hydroxy-3-methoxyacetophenone), an important active ingredient contained in root ofPicrorhiza kurroa Royle, has been widely investigated as an antioxidative and anti-inflammatory agent in kinds ofdisease models, and exerted certain efficacy deserving further research. However, little was known about thedisposal process of apocynin in vivo, which is important information required in drug research and development.Aim In this work, a tissue distribution study of apocynin was performed in Sprague-Dawley (SD) male rats to helpfurther understanding well the disposition of apocynin in vivo.Methods A simple HPLC-UV method was developed for measurement of apocynin concentration in rat tissues. Amixture of water-methanol (47:53, v/v) was used as solvent system, the flow rate was 1 mL/min, and the detectedwavelength was 279 nm. The method was validated and applied to the tissue distribution study of a single bolusintravenous administration of apocynin in SD male rats.Results The developed HPLC-UV method showed good specificity, precision, accuracy and extraction recovery. Thegood linearity was achieved within 0.8-32 μg/mL in tissues including heart, liver, spleen, lung, kidney and brain. Thelower limit of quantification (LLOQ) was 0.8 μg/mL. The method was well used in the study of tissue distribution ofapocynin. The results demonstrated that apocynin was distributed fast into the tested tissues and reached peakconcentration at 5 min after injection. Apocynin was mainly distributed in liver, kidney and lung within 15 minutesafter administration, and eliminated from the tissues with no sample be detected more than 2 h after dose