Formulation and Evaluation of Controlled Release Matrices of Selected Propionic Acid Derivatives

Abstract

Ibuprofen and Ketoprofen are propionic acid derivatives and belong to the non-steroidal anti-inflammatory group of drugs. These are also used as analgesics, antipyretics and as adjuncts in steroid therapy, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal injury and for systematic relief of dysmenorrhea. Due to their short half-life, dosage frequency, patient non-compliance and side effects such as gastrointestinal disturbance, peptic ulceration and gastrointestinal bleeding, they are considered to be good candidates for formulation into controlled release dosage forms. Optimization of a drug substance through the determination and/or definition of some physical and chemical properties are mandatory in the development of stable, effective, safe and reproducible dosage form. Therefore, during our pre-formulation work, our efforts encompassed the detailed study of parameters such as optical rotation, melting point, percentage purity, particle size, size distribution, solubility at different temperatures and pH, IR spectra for conformation, λ max determination, micromeritics properties determination of model drugs, polymers and excipients used in this research work and interaction conformation studies of drugs with polymers and co-excipients, using DSC and FT-IR. During this studies attention was also focused on some contributing approaches to improve the dissolution rates of Ibuprofen and Ketoprofen, which are sparingly soluble drugs. For this purpose solid dispersions of Ibuprofen and Ketoprofen were prepared by solvent evaporation technique, using Glucosamine HCl as dispersion carrier. The drug-carrier interactions were investigated through SEM, DSC, FT-IR and X-ray diffraction analysis. The influence of proportional amount of the carrier on the dissolution rate of Ibuprofen and Ketoprofen were also investigated. The results obtained did not show any chemical decomposition or well defined interaction between drugs and carrier, indicating a good compatibility among them. The solid dispersions with Glucosamine HCl demonstrated a marked increase in the dissolution rate and solubility of Ibuprofen and Ketoprofen. The enhancement in the dissolution rate and solubility of Ibuprofen and Ketoprofen could be attributed to several factors such as improved wettability, local solubilization, conversion from crystalline form to amorphous form and drugs particle size reduction. In Part-1 of my research work conducted at Drug Delivery Research Centre, Faculty of Pharmacy, Gomal University, D. I. Khan, Pakistan, directly compressed controlled release matrix tablets, using granular Ethocel ® standard premium and Ethocel ® standard FP premium were designed, prepared and evaluated in-vitro, in the first instance, followed by in vivo evaluation of the best products. Physicochemical assessment of the formulated tablets was performed, using different physicochemical, dimensional and quality control tests such as weight variation, thickness and diameter, hardness test, friability test, content uniformity, disintegration and dissolution testing. Results for all these tests were found within acceptable range and tablets meet the pharmacotechnical requirments. The effect of different viscosity grades of Ethocel ® on the tablets Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page ivCR Matrices of Propionic Acid Derivatives By: A.Wahab characteristics, drug release rates, release patterns and release kinetics were investigated. Ethocel ® with lower viscosity grades showed good compressibility, resulting in harder tablets. Particle size and amount of polymer used were found to be the determining factors in controlling the release rates of Ibuprofen and Ketoprofen from the tablets. The mechanism of drug release from the tablets seemed to be changeable from formulation to formulation, depending on the amount of Ethocel ® and/ particle size of the polymer used. Our research also focused on the effect of partial replacement of primary excipient (lactose) by various co-excipients such as hydroxypropylmethylcellulose (HPMC), starch and corboxymethylcellulose (CMC) on the release rate and mechanism of drugs release from the matrix tablets. All of the co-excipients used enhanced the release rates to different extent. In-vitro studies revealed that tablet formulations containing polymer Ehocel ® standard 7 FP premium, at D: P ratio 10: 3 were the best amongst the formulations for both drugs (Ibuprofen and Ketoprofen) because they provided better release patterns with optimum amount of the drugs released in 24 hours; and due to their prolonged release rates with either zero or near to zero-order release kinetics. The optimized Ibuprofen and Ketoprofen matrix tablets formulations were further used for in-vitro and in-vivo bioavailability-bioequivalence and stabilities studies as compared to the comparative studies with SR Ibuprofen and Ketoprofen available in market and stability studies. Stability studies were performed for the optimized formulation for one year in ambient and accelerated condition and the tablets were re- evaluated physicochemicaly at different interval of time. The results obtained showed maximum stability for one year. The comparative in-vitro dissolution studies showed prolonged release rate of test formulations as 87.66% and 95.4% of Ibuprofen and Ketoprofen were release after 24 hours, respectively, while all of the drugs were released from the market SR formulations well before 24 hours. In-vivo studies of the optimized tablets were conducted; using HPLC based modified methods for analysis of Ibuprofen and Ketoprofen in rabbit‟s plasma. Measured plasma concentrations of the drugs were used in calculation of pharmacokinetic parameters including T max , C max , AUC 0-t , MRT 0-t , t 1/2 , Vd, Vdss, Kel and Cl total for the CR test tablets and reference SR tables of Ibuprofen and Ketoprofen, using PK WinNolin software. Significantly prolonged T max , t 1/2 and MRT 0-t of the test CR matrix tablets of model drugs indicate smooth and extended absorption phase of the drugs under investigation. As compared to reference SR tablet formulations the test CR tablets showed better and linear in-vitro and in-vivo correlation. In Part 2 nd of my research work conducted at the at University of KENT, UK, Nanoparticles were also developed of the model drugs (Ibuprofen, Ibuprofen sodium salt and Ketoprofen), which were evaluated for their capability prolonging the drug Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page vCR Matrices of Propionic Acid Derivatives By: A.Wahab realse, using a novel functionalized biodegradable polymers PGA (poly glycerol adipate) and its acylated derivatives, such as 40% C-18 PGA and 100% C-18 PGA by interfacial deposition method. Before development of nanoparticles, different techniques such as DSC and FT-IR were used for determination of drug-polymer interactions. After development of nanoparticles different physicochemical characteristics were determined, such as zeta potential, particle size, polydispersity index and in-vitro drug release study was conducted for 17 days. These polymers are able to self-assemble into well-defined particles of relatively small size and high homogeneity with an ability to entrap Ibuprofen, Ibuprofen sodium salt and Ketoprofen with high efficiency.