Preparation, characterization and in vivo evaluation of the orally disintegrating mini-tablet formulations containing atomoxetine hydrochloride in the treatment of attention deficit and hyperactivity with the quality by design (QBD) system

"Attention Deficit Hyperactivity Disorder" (ADHD), which is characterized by problems in attention, concentration, mobility and impulse control, is one of the most common psychiatric disorders of childhood. Individuals with ADHD are much more likely to have psychiatric disorders such as antisocial personality disorder and alcohol-substance use disorders compared to normal individuals. They are exposed to academic risks, such as under-performing or being expelled from school; They are exposed to social risks such as frequent accidents, causing accidents, frequent divorce, early pregnancy, low job success or unemployment. Therefore, the diagnosis and treatment of ADHD is gaining great importance day by day. In current drug therapy for ADHD treatment, two different groups draw attention, mainly central nervous system stimulants (methylphenidate, dexmethylphenidate, amphetamine and dextroamphetamine) and selective noradrenaline reuptake inhibitors (atomoxetine, venlafaxine). Atomoxetine (ATO), a selective noradrenaline reuptake inhibitor, is the first non-stimulant active substance approved by the FDA because it stands out as an important alternative in the treatment of ADHD. ATO is preferred in the first place, especially if the patient with ADHD is accompanied by substance use, tic and anxiety disorders. Studies show that; Early diagnosis and treatment of ADHD in childhood facilitates the treatment and may lead to the disappearance of the previously mentioned social and psychological problems in later ages. Therefore, it was preferred to study a pediatric drug form of ATO in our study. Pediatric patients differ greatly from adult patients in several aspects of pharmacotherapy, including route of drug administration, drug-related toxicity, and taste characteristics. ATO has a capsule form on the pharmaceutical market. However, in our study, the orally disintegrating mini tablet formulations for ATO were found to be the best ones to be used for pediatric purposes because they disintegrate within 1 minute when placed in the mouth on the tongue, do not require water for swallowing during travel, can be used easily in pediatric patients with swallowing difficulties, and have high patient compliance. was considered to be the appropriate dosage form. For this purpose, inclusion complexes of ATO with beta cyclodextrin (β-CD) were prepared in order to mask the bitter taste of the active substance and increase its solubility. DSC, IR analyzes, light and electron microscopy images of the prepared complexes were determined. By using the prepared ATO-β-CD inclusion complexes, ODMT formulations were prepared by direct compression method with 25 mg ATO in each tablet. Weight deviation, friability, diameter-thickness measurement, disintegration time, dissolution rate, wetting time, wetting percentage and stability properties of prepared ODMTs were determined. Experimental design method, which is the first step of design and quality, was used in the optimization of both ATO-β-CD inclusion complexes and ODMTs. In the preparation of ODMTs, the ATO-β-CD inclusion complex and superdisintegrant, as well as other ODMT components, were selected considering that ODMTs will be used for pediatric purposes. It has been proven by the taste test with E-tongue that the optimized ODMTs have a faster dissolution and disintegration time of the active substance than the capsule form available in the market and the bitter taste of the active substance is suppressed. As a result of all these controls, it was determined that the ATO-β-CD complex is applicable for pediatric purposes, thanks to its formulation as ODMT. In addition, in vivo animal studies performed on experimental animals with hyperactivity with nicotine administration seem promising, but it is thought that it would be appropriate to increase the number of subjects and extend the treatment period to an advanced level.