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Title: Formulation Development and Evaluation of Loxoprofen Sodium Pellets and its Pharmacokinetic Studies
Authors: Farooq, Muhammad
Keywords: Biological & Medical Sciences
Issue Date: 2020
Publisher: University of Karachi, Karachi.
Abstract: The use of pellets as multiple unit dosage form has been extensive in recent years, increasing its importance due to numerous biopharmaceutical and technological advantages over traditional monolithic dosage form. Pellet as a dosage form offers better flow properties, narrow size distribution, less friability, easy coating and excellent packing characteristics. Pellets can be matrix or coated for enhancement of flow and mixing properties that ultimately reduces segregation and enhancing the physical and chemical properties of fine powder. Pelletization technique employed in the formulation of spherical beads or pellets with diameter ranges from 0.5-2 mm. Extrusion-spheronization is a multistage procedure for attaining uniform size pellets. Pellets produced by extrusion-spheronization have intrinsic tendency for sustained release of active ingredients. This method is especially beneficial for producing dense granules for sustained release oral dosage form pellets including minimum amount of excipients. Extrusion-Spheronization technique is superior as compare to other techniques due to simplicity, fast processing and high efficacy. Loxoprofen sodium is non-steroidal anti-inflammatory drug (NSAID) and inhibits prostaglandin biosynthesis by effecting cyclooxygenase enzyme. After oral administration, absorbed as a free acid form in GIT and then converted into active trans-alcohol metabolites (trans-OH). The objectives of this study were to prepare (i) immediate Loxoprofen sodium core pellets (ii) sustained release coated and matrix pellets of Loxoprofen sodium by Extrusion Spheronization technique. IR core pellets were formulated by using different ratio of Lactose, glyceryl mono stearate (GMS) and avicel pH 101. Sustained release coated pellets were prepared by application of Ethyl cellulose (10cps), Eudragit RS100 and Eudragit RL100 coat on Loxoprofen sodium core pellets by varying concentration of polymeric coatings. Sustained release matrix pellets were formulated by using Eudragit RSPO, Eudragit RLPO, glyceryl mono stearate (GMS), Avicel pH 101 and lactose in different ratio. Drug core, coated and matrix pellets were evaluated for flow properties, friability, swelling index, drug content and in-vitro drug release in 0.1N HCl (pH 1.2) and phosphate buffer (pH 6.8 and 7.4). Drug release rate was determined using model dependent approaches such as zero order, first order, Higuchi, Hixson-Crowell and Korsemeyer-Peppas models and model independent approach xxvii i.e. f2 similarity factor. Fourier Transform Infra-Red Spectroscopy (FTIR), Thermogravimetric analysis (TGA) and X-ray Diffraction (XRD) techniques were used to access the drug-excipient compatibility of pellets. The shape of pellets were analyzed using digital stereomicroscope and aspect ratio, sphericity, perimeter, area and ferret diameter were calculated by applying image analysis software (Image J1.47v, USA). Surface morphology, smoothness, sphericity and cross section of pellets were also characterised by Scanning electron microscope (SEM). A simple, sensitive and accurate high-performance liquid chromatographic (HPLC) method for effective and specific analysis of Loxoprofen (LXP) in the mobile phase and human plasma was developed and validated. Effective chromatographic separation was attained on a Mediterranea Sea C18 column (250×4.6mm, 5um) containing mobile phase of acetonitrile and 0.01 M NaH2PO4 buffer (55: 45) by adjusting pH 6.5 with sodium dihydrogen phosphate buffer. The flow rate of was 1ml /min and Loxoprofen was detected at 222 nm. The method was validated for linearity, lower limit of quantification (LLOQ), lower limit of detection (LOD), stability, inter-day and intra-day precision and accuracy in mobile phase and human plasma. The pharmacokinetic study was conducted for assessment of bioequivalence between optimized sustained release coated pellet (F4) as test formulation and immediate release marketed tablet as reference. This study was single centred, single dose, open labelled, two treatment, two sequence, two period’s randomized crossover with one-week washout period in fasted and fed state after 10 hours overnight fasting. Five ml blood samples were withdrawn in heparinized tube at 0, 0.5,1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h post dose for immediate marketed tablet and 0, 0.5,1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 14 and 24 h post dose for sustained release pellets in fasted and fed conditions. After centrifugation, Plasma was separated and 100µl deproteinized sample was injected by using above HPLC method. Pharmacokinetic and in vivo bioequivalence parameters including maximum drug concentration in plasma (Cmax), time for maximum drug concentration in plasma (tmax), mean residence time (MRT), half-life (t1/2) and area under the plasma concentration curve (AUC) were evaluated through non compartmental model by using Kinetica version 5.0 (Thermo electron corp, USA). Statistical analysis was calculated through Latin square design by using two-way analysis of variance (ANOVA) for crossover study and standard 90% confidence interval (Cl) of ratio test/ reference formulation. Micromeritic studies of core, coated and matrix sustained release pellets demonstrated excellent compressibility and flow properties of all formulations. The friability of all xxviii formulated pellets was less than 1% that confirms higher mechanical strength of pellets. The maximum value of swelling index was shown in uncoated core pellets F1 (20%) and ethyl cellulose coated pellets F2 showed 16%. The immediate release drug core pellets (F1) released 100% drug in 2 hr in acidic medium pH 1.2 (0.1N HCl) and followed first order release. Minimum drug release was found in an acidic medium which was sustained in a basic medium at a higher concentration of polymer coated formulations of Ethyl cellulose (15%), Eudragit RS100 (10%) and Eudragit RL100 (10%). The matrix pellet formulations exhibited minimum drug release at high concentration of polymeric content in acidic medium. Matrix formulation containing polymers Eudragit RLPO and Eudragit RSPO revealed sustained release effect by releasing 80% drug at phosphate buffer pH 7.4 in 12 hours. Coated formulations F2, F4 and F5 followed first order and formulations F3, F6, F7 and F8 exhibited Higuchi release kinetics while all matrix formulations followed zero order release at pH 6.8 and Higuchi release model at pH 7.4. Uncoated drug core pellets (F1) exhibited polymer erosion and relaxation with super case II transport. Non-Fickian diffusion behavior (Anomalous release) was observed by all coated and matrix formulations. Drug excipients compatibility studies confirmed that there was no interaction between drug and polymers during formulation process. Results of Image analysis and Scanning Electron Microscopy (SEM) indicated formation of smooth surface and spherical pellets. Calibration ranged curve from 0.1ppm to 10 ppm with a coefficient of relation value (R2=0.999) by using a linear regression method and lower limit of quantification was 0.1ppm. The current method showed inter-day and intra-day accuracy and precision within the range of ±10%. Percentage RSD was less than 5 % and analytical recovery was more than 90%, which confirmed the reliability of method and found appropriate for assessment of Loxoprofen sodium in pharmacokinetic and bioequivalence studies. The time versus drug plasma concentration was used for the evaluation of pharmacokinetics and bioequivalence studies using Kinetica version 5.1. Pharmacokinetic and bioequivalence studies of reference (Roxonin) and optimized SR coated pellet test formulation (F4) exhibited mean AUClast values 24.54 ± 0.13 µg/ml×h and 27.70 ± 0.088 µg/ml×h while AUCtotal values were 24.57 ± 0.12 µg/ml×h and 27.74 ± 0.18 µg/ml×h for reference and test formulations in fasting condition. The calculated Cmax and Tmax values were 8.74 ± 0.538 µg/ml, 1.50 ± 0.056 and 5.04 ± 0.0212 µg/ml, 6.01 ± 0.192, respectively. Bioequivalence results showed 90% confidence intervals (Cl) of AUClast was 99.99% (99.71-100.28%) and AUCtotal was 99.96% (99.52-100.40%) which were within range (85-125). xxix The effect of food was also observed on sustained release coated pellets. Optimized sustained release coated pellets (F4) in fast state was selected as reference formulation and same formulation in fed state was coded as test formulation. The calculated Cmax values were 5.06 ± 0.212 and 4.81 ± 0.057 for reference (fasted) and test (fed), respectively. The mean AUClast values were 27.74 ± 0.18 µg/ml×h and 29.75 ± 0.736 µg/ml×h while AUCtotal values were 27.76 ± 0.180 µg/ml×h and 29.77 ± 0.736 µg/ml×h for reference (fasted) and test formulations (fed), respectively. Bioequivalence results showed 90% confidence intervals (Cl) of Cmax was 100% (98.63-101.37), for AUClast was 100% (98.86-101.14%) and for AUCtotal these values were 100% (98.60-101.41%) within range (85-125) for reference (fasted) and test (fed) formulations. However, tmax is non-significant in bioequivalence studies. According to ICH guidelines, accelerated stability was performed under the condition of 40 ±2 °C and 75±5 RH. The assay of three batches of optimized coated (F4) and matrix pellets (F12) was within acceptable limit. Shelf life of formulations was calculated by using R Gui software and its exhibit 12 months for coated SR pellets (F4) and 10 months for matrix SR pellets (F12). The research project was effectively completed, achieving the goals of the formulation of immediate release core pellets and subsequently development of sustained release polymeric coated and matrix pellets formulation. According to pharmaco-economic point of view, this study discriminates cost effective elements and patient compliance in a significant way. This study open the new perspectives of formulation development and optimization of pellet formulation, HPLC method development and validation in mobile phase and plasma, pharmacokinetic and bioequivalence study of optimized formulated SR coated pellets and marketed IR formulation on healthy human volunteers in fasted and fed conditions
Gov't Doc #: 21308
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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