Title of Thesis

Development And Evaluation Of Extended Release Matrix Tablets Of Risperidone, Olanzapine And Prochlorperazine Maleate (antipsychotic Drugs)

Author(s)

Amir Badshah

Abstract
Antipsychotic drugs are widely used in the short term management of acute psychotic, manic and psycho depressive disorders and long period treatment of chronic psychotic disorders, including schizophrenia,psycho effective disorders and delusional disorders.However, these drugs produce serious side effects ranging from the most troublesome (Intense sedation, dry mouth and somnolence) to dangerous (Parkinsonism, dyskinesia and akathesia).The management of these side effects has become an important part of treatment plans as the frequency and intensity of the side effects play a major role in the effectiveness and tolerability of a particular antipsychotic agent.Non-compliance to antipsychotic medication is the primary issue directly linked to long term clinical outcomes.
The development of modified drug delivery systems (MDDSs) have improved patient compliance, reduced side effects and optimized the dosage schedule without compromising their therapeutic efficacy. As a result of reduction in side effects of antipsychotics, some MDDSs have been developed. In this respect, Quetiapinefumarate (Seroquel XR®) and Paliperidone (Invega®) extended release tablets of antipsychotic drugs are offering improved treatment and tolerability profiles.
As oral route for administration of drug is mostly preferred and tablet is the most popular dosage form, therefore, extended release tablets of risperidone, olanzapine and prochloperazine maleate were developed. Binary mixtures of the commonly recommended Methocel®K100 LV-CR (hydrophilic) and Ethocel® Standard 7FP Premium (hydrophobic) were used to prepare tablets by flow bound dry granulation-slugging method. Combination of the two polymers successfully extended the release period up to 24 hours.The release period was extended regularly as the amount of Ethocel® Standard 7FP Premium was sequentially increased from 30% to 60%. The inclusion of Methocel®K100 LV-CR helped in maintaining drugs knotted in its viscous gel layer, while presence of Ethocel® caused slow hydration & erosion of the matrices leading to extended drug release period.
pH independent drug release with zero order kinetics was an important achievement in the present study. Hardness of tablets did not influence the release
kinetics.The two polymers played a role of functional copartners.The matrix tablets containing 30% Methocel® and 60% Ethocel® (F3) with 12kg hardness were selected for further studies.The optimized matrix tablets of the model drugs exhibited an acceptable level of stability under accelerated storage conditions.
Bioavailability studies of the optimized tablets of risperidone, olanzapine and prochlorperazine were conducted in rabbit’s serum using HPLC based validated methods. Measured serum concentrations of the drugs were used in calculation of the various pharmacokinetic parameters, including peak concentration (Cmax), peak time (Tmax), area under curve up to 24 hours (AUC0–24), area under curve up to infinite time (AUC0-inf), mean residence time (MRT0-48), half life (t1/2), volume of distribution (Vd), elimination rate constant (Kel) and total clearance (Cltotal) for the Test-extended release and Reference-conventional tablets using PK WinNonlin software. Optimum levels of the drugs serum concentrations (Cmax) from the Test tablets were observed as compared to Reference tablets. Significantly prolonged peak time (tmax) of the Test tablets indicated smooth and extended absorption phase of the drugs.
A good correlation between the In-vitro drug release and In-vivo drug absorption was achieved in case of each model drug The area under curves (AUCs) of Test extended release tablets and Reference-conventional tablets were not significantly different (p < 0.05), indicating their bioequivalence. The bioavailability data generated in the present study indicated that the absorption of risperidone, olanzapine and prochlorperazine maleate from gastro intestinal tract (GIT) were dependent on their release rate. A good level of In-vitro In-vivo correlation of the all three drugs showed successful use of the dissolution process, binary mixtures of the model polymers and rabbits as model animals. Further studies on binary mixtures of the Methocel® and Ethocel® may ensure their utility in formulation of extended release tablets of other similarly low dose water insoluble drugs. Extensive preclinical studies and clinical trials of the presently developed tablet formulations need to be conducted to determine improvement in safety profiles of the model drugs.

1

1.1 Drug delivery systems
1.2 Drug dissolution and release mechanisms
1.3 Model polymers used for extending drug release period ...
1.4 Other factors affecting drug release
1.5 Model drugs
1.6 Motivation behind the current work
1.7 Objectives, hypothesis and aims

2.1 Animals, materials and equipments
2.2 General Methods

3.1 Introduction
3.2 Materials and methods
3.3 Results
3.4 Discussion
3.5 Conclusion

4.1 Introduction
4.2 Materials and methods
4.3 Results
4.4 Discussion
4.5 Conclusion

5.1 Introduction
5.2 Materials and methods
5.3 Results
5.4 Discussion
5.5 Conclusion