Twice-pulsed Controlled-release Capsule Of Dexmethylphenidate Hydrochloride: Formulation Design, Release Mechanism And In Vivo Evaluation

Attention-deficit/hyperactivity disorder(ADHD) is an impairing neurobehavioral condition, clinically characterized by inattention, hyperactivity, and impulsivity. It’s estimated to have a worldwide prevalence rate of 5.29% in children and 4.4% in adults. ADHD primarily occurs in childhood, although the symptoms persist to adulthood in 46–66% of cases. ADHD severely interferences an individual’s academic and psychosocial functioning, affects their occupational advancement and development of successful family and peer relationships, and eventually results in social life skill deficits and inferiority.MPH is the most commonly used drugs for the treatment of ADHD,which is a kind of central nervous system stimulant used in the treatment of children with ADHD. Its role is of inhibiting reuptake of norepinephrine and dopamine, So the concentration of dopamine and norepinephrine increased in the synaptic cleft. MPH is a racemic mixture of d- and l- isomers of Methylphenidate hydrochloride, While l-isomers are rapidly metabolismed through hepatic first pass metabolism effect, by contrast it’s easier for d-isomers to access to central nervous system. Dexmethylphenidate which has been in clinical use for the treatment of ADHD for several years. The half-life of immediate-release(IR) dexmethylphenidate is only 2–3 hours so multiple daily dosing is required to provide adequate drug coverage. For convenience, compliance and to avoid drug diversion problems, a long-acting formulation requiring administration only once daily is desirable. This long-acting formulation is given once daily, allows administration of the medication in the morning and, omits the children’s need for a midday dose at school, thereby avoiding potential problems of embarrassment or psychological illness for the child.Dexmethylphenidate XR capsules [Focalin® XR] have a bimodal release profile, which are equivalent to take two doses dexmethylphenidate immediate release formulations given 4 hours apart and overcomes problems associated with the short duration and adverse reaction of immediate-release formulations, which require multiple daily doses. There are equal amounts of immediate release beads and enteric-coated, delayed-release beads in each capsule. Following a single capsule, the first dexmethylphenidate peak plasma concentration is reached at 1.5 hours, and a second peak is reached at 6.5 hours after drug administration. A single extended–release dose of 20 mg is bioequivalent to two doses of dexmethylphenidate immediate release formulations 10 mg given 4 hours apart.This article took Focalin® XR as reference preparation to carry out the key technologies research about the twice-pulsed release system. On the bases of it, double pulse controlled-release methylphenidate hydrochloride capsule was studied in this paper. The first pulse was obtained through drug-containing immediate release part, yet second pulse by enteric-coated drug-containing pellets. These enteric-coated pellets deliver the drug to small intestine of action at the right time and release the drug in the intestine rapidly after a predetermined lag time to give an effective therapeutic drug concentration. There existed a lag-time between twice-pulesd drug release which in the morning and in the afternoon respectively, thereby reduced patient dosing frequency and increased patient compliance. In an attempt to achieve this time-delayed and pulsed-release goal, researchers have overcoated extended release core pellets with functional coating materials. An interesting option is to use blends of different types of well-known polymers: by simply varying the polymer:polymer blend ratio to get different film coating properties eventually and provide broad spectra of drug release patterns. The objective of the study was to optimize the formulation consisting of Eudragit® RS as a sustained release polymer in combination with Eudragit® L as the p H-dependent polymers(in terms of their ratio and coating level) for coating of d-MPH pellets to achieve time-delayed delivery of this drug.Durg-containing pellets were prepared by bottom-spray fluidized bed technology, Optimized proeessing conditions were obtained after the study of formulation factors and proeessing factors. The pellets produced were of good sphericity, and good reproducibility. The average yield of drug-containing pellets was up to 90%. Similarly extended release pellets were prepared by bottom-spray fluidized bed technology. Pellets were covered with the blends of Eudragit® RS(water insoluble) and Eudragit® L(p H-sensitive) polymers. In the stomach(at low p H), both polymers are insoluble, whereas in the intestine(at high p H), the p H-sensitive component might leach out of the polymeric film, resulting in dynamic changes in the physicochemical properties of the coatings so then increase in drug permeability of the film coating. The optimized results were verified by produceted three batchs sample. To determine content and dissolution of d-MPH high performance liquid chromatography method was developed. Changing dissolution medium simulating gastro-intestinal p H values was used for cumulative release testing. The optimal coating levels were thus determined at 25%.The above two kinds of pellets were filled into capsules at the equal dose, forming tested preparation. Among them, immediate-release pellets content d-MPH 6.5%; extended-release pellets content d-MPH 5% which were prepared with equal parts of Eudragit® RS and Eudragit® L as sustained-release coating material. Extended-release capsule Focalin® XR on sale was reference preparation. To determine the plasma concentration of d-MPH capsules a LC/MS method was established. To observe the pharmacokinetic characteristics, an animal pharmacokinetic studies was carried in Beagle dog by administrating tested preparation. The plasma concentration had bi-modal plasma concentration-time profile as the same as Focalin® XR: Tmax1=0.75 h,Tmax2=3.33 h,Cmax1=0.59ng/ml,Cmax2=1.18ng/ml.Vitro experiment results showed that: the first pulse dose release completely within 5 min in dissolution medium of 0.01 M HCl; the second pulse dose release completely about 1.5h, the lag time interval the pulse is about 3.5h, Its release in vitro conformed to zero-order process. Optimized proeessing conditions were of good reproducibility. Vivo experiment results showed that: the equal-dose twice-pulsed extended release capsules show a twice-pulsed release characteristic in vivo of Beagle dogs.Polymer blends as coating materials in controlled drug delivery systems is coupled with a higher complexity of the mechanisms compared to dosage forms coated with only one type of polymer. Dosage forms coated with different polymer blend ratio, comparison with experimental results allowed for a better understanding of the involved mass transport phenomena in the investigated systems, in particular with respect to the importance of drug diffusion through the intact polymeric film coatings versus drug diffusion and/or convection through water-filled cracks.In sum, the equal-dose twice-pulsed d-MPH extended release capsule researehed and producted according this paper, the proeess is stable and reproducible and have a stable product quality; Pharmacokinetic studies indicate the pellets will have a perfect release characteristics of twice-pulse; the methods to analysis in vitro of d-MPH extended release capsule were precise and reliable; stability data of stess testing ang accelerated testing revealed that d-MPH extended release capsule were stable; The obtained new insight on how the coated dosage forms control drug release can be very helpful during device optimization and improve the safety of the respective medical treatments; the twice-pulsed d-MPH extended release capsule was feasible and could fulfill the specific needs of clinical therapy.