Defense Date

5-12-2011

Graduation Date

2011

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmaceutics

School

School of Pharmacy

Committee Chair

Moji C. Adeyeye, Wilson Meng

Committee Member

Aleem Gangjee

Committee Member

Ira S. Buckner

Committee Member

Raman Venkataramanan

Keywords

Antiretroviral, Bioequivalence, Clinical trial, Fixed-dose combination, Overencapsulation, Roller compaction

Abstract

This dissertation was designed to develop and assess bioavailability/ bioequivalence of age-appropriate fixed-dose combination granules of lamivudine/zidovudine/nevirapine as reconstitutable suspension for pediatrics for use in pediatric patients. The granules were developed via roller compaction process to improve granule flow characteristics, minimize segregation of the multi-component active pharmaceutical ingredients, and avoid introducing moisture into the formulation and thereby improve the stability of the product. Optimization of the roller compaction process for the roll pressure and the ratio of the horizontal feed screw speed to the roll speed showed that these parameters had minimal effect on granule quality. Subsequently, a replicated 32 factorial design was utilized to optimize the levels of the suspending agent (Avicel RC 591) and the anticaking agent (Aerosil 200). Modeling of the formulation viscosity through multiple regression analysis showed that the viscosity was a quadratic function of the concentration of Avicel RC 591. An assessment of the stability of the granules for reconstitution under International Conference on Harmonization stability conditions at 40 oC/75 %RH and 30 oC/65 %RH indicated the granule formulation to be stable with an estimated shelf-life of not less than 6 months. Similarly, the evaluation of the chemical stability of the reconstituted suspension at 30 oC/65 %RH showed the suspension to be stable for several weeks.

A clinical batch of the granules for reconstitution manufactured under Good Manufacturing Practices was tested for bioavailability and bioequivalence in a clinical study. A randomized single dose two-way complete crossover design in 24 healthy adult cohorts was performed, and the plasma samples from the subjects were analyzed by HPLC with UV detection. Non-compartmental pharmacokinetic analysis was performed to obtain the Cmax, AUCo-t, and AUCo-inf utilizing WinNonlin software. Analysis of variance of the formulation, period, sequence, and subject effects established the absence of any significant effects due to these parameters. Application of the two one-sided statistical tests using the Anderson-Hauck method showed that the 90 % confidence interval for the ratio of test/reference for various pharmacokinetic parameters was within 82.6 - 124.5 % bioequivalence limits for all the three drugs. This confirms that the fixed-dose combination granule for reconstitution was bioequivalent to the simultaneously administered single-entity reference products.

Format

PDF

Language

English

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