Nghiên cứu bào chế viên felodipin 5 mg giải phóng kéo dài theo cơ chế thẩm thấu tt tiếng anh

Ministry of Education and Training Ministry of National Defense VIETNAM MILITARY MEDICAL UNIVERSITY VU THI THANH HUYEN FORMULATION OF THE EXTENDED RELEASE OSMOTIC TABLETS CONTAINING mg FELODIPINE Speciality: PHARMACEUTICAL TECHNOLOGY AND PHARMACEUTICS Code: 72 02 02 ABSTRACT OF THESIS Hanoi - 2020 THE THESIS WAS COMPLETED AT VIETNAM MILITARY MEDICAL UNIVERSITY Full-name of supervisors: Prof Nguyen Thanh Hai, PhD Assoc Prof Nguyen Thi Kieu Anh, PhD Scientific reviewer 1: Assoc Prof Nguyen Thi Thanh Duyen, PhD Scientific reviewer 2: Assoc Prof Tran Viet Hung, PhD Scientific reviewer 3: Assoc Prof Trinh Nam Trung, PhD The thesis defense will take place before the Thesis Evaluation Committee of Vietnam Military Medical University at: hour date month year 2020 This thesis is available at: National Library of Vietnam Library of Vietnam Military Medical University ABBREVIATIONS IN THE ABSTRACT No Abbreviation Definition AUC Area under curve Cmax Maximum concentration FE Felodipin IS Internal standard MW Molecular weight MS Mass spectrometry NaCl Sodium chloride PEO Polyethylen oxyd PPOP Push - pull osmotic pump 10 RSD Relative Standard Deviation 11 SLS Sodium lauryl sulfat 12 Tmax Maximum time 13 UPLC Ultra performance liquid chromatography INTRODUCTION Felodipine (FE) is used in hypertension management with many advantages such as: Selective effect on the smooth muscle of arteries, which leads to antihypertension; no orthostatic hypotension, hence, safe and suitable for long-term use for the elderly; no risk of drug accumulation during prolonged treatment… However, FE is poorly water soluble and used with low dose Therefore, release rate of FE should be controlled to improve bioavailability Osmotically controlled release dosage formulations are widely used with many distinct and practical advantages such as: Suitable for most of the drugs, drug release can be controlled at a constant rate, drug release rate is not significantly affected by external physiological conditions The push - pull osmotic pump (PPOP) is an oral osmotically controlled release system that has been successfully developed to retard release of drugs possessing different aqueous solubility, especially poorly soluble drugs Therefore, FE is suitable for being prepared into PPOP in order to retard drug release for a long period of time This is a feasible method with a great significance for the pharmaceutical industry and clinical practice This study is performed to achieve the following objectives: To prepare extended release push - pull osmotic tablets containing mg felodipine in 10.000 tablets/batch successfully To propose standard criteria and stability of the prepared tablets To evaluate the bioequivalence of the prepared tablets in comparision with the reference tablets Felutam CR mg * Summary of new scientific contributions of the thesis The push - pull osmotic extended release tablets containing mg FE was successfully formulated and prepared with a batch scale of 10.000 tablets/batch with in vitro release profile extended up to 12 hours The bilayered core tablets containing FE in a formulation of polymeric, osmotic agent and other tablet excipients were prepared by double compression method, followed by semipermeable membrane coating with cellulose acetate One releasing orifice was drilled by laser on the drug side of tablets The osmotic tablets were coated with immediate release layer containing 10 % of FE content (0.5 mg) and HPMC 6cps to increase amount of release drug in the first hour The prepared tablets at a batch scale of 10.000 tablets/batch met standard criteria in terms of appearance, qualification, quantification,content uniformity and in vitro drug release The osmotic tablets were stable for 24 months in real conditions and months in accelerated conditions An Ultra Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method for the quantification of FE in human plasma was developed and validated The validated method was used for the bioequivalence study between the prepared push - pull osmotic extended release tablets containing mg FE and Felutam CR mg tablets as reference in 12 healthy human volunteers It could be concluded that the prepared osmotic tablets of FE are bioequivalent to Felutam CR mg - the marketed reference FE formulation in fasting condition The UPLC-MS/MS method could be applied to evaluate the in vivo bioavailability and bioequivalence of the other products containing FE The thesis has resolved the urgent demands Therefore, it has important scientific significance and practicality The results of the thesis reveal new contributions to the pharmaceutical technology and pharmaceutics fields The thesis constitutes as an useful scientific reference for the modern formulations * The content and structure of the thesis The thesis consists of 139 pages including pages of introduction; 30 pages of overview; 28 pages of materials, equipments, objects and methods; 55 pages of results; 22 pages of discussion; pages of conclusions and proposals It owns 85 references (12 Vietnamese documents, 73 English documents) and 10 appendices Chapter OVERVIEW The overview contains information on all aspects of FE including its formula, physicochemical properties, quantification of FE in pharmaceutical dosage forms, pharmacokinetics, pharmacological effects, indications, dosages, extended release formulations and studies of FE; overview of oral osmosis systems, knowledge related to PPOP and studies of PPOP; overview of bioavailability and bioequivalence studies of preparations containing FE Chapter MATERIALS, EQUIPMENTS, SUBJECTS AND METHODS 2.1 Materials, equipments and study subjects - FE meets the US Pharmacopoeia standard The excipients and chemicals meet either the pharmacopoeia or manufacturer’s standards or analytical grade The equipments used in the study are appropriate for the preparation, test and evaluation of bioavailability - Reference product: Felutam CR mg tablets - the marketed products, Viet Nam Pharmaceuticals Vellpharm Ltd., Viet Nam; Lot number: 12 005; Expiry date: 07-2014 - 12 healthy male volunteers 18 - 55 years and Body Mass Index of 18 - 25 kg/m2 were included in the study Selection of subjects was based on inclusion and exclusion criteria as per the approved protocol 2.2 Methods 2.2.1 Preparation methods Osmotic pump tablets were prepared comprising of four main steps: Preparation of the bilayered core tablets, semi-permeable membrane coating, drilling the orifice, and fast-release coating - Preparation of the bilayered core tablets: The core tablets were prepared with powder direct compression technology Before tableting, FE and all excipients (except PEO, Avicel PH101) were ground in a mortar then filtered through appropriate sieve The ingredients for both layers were mixed separately and the bilayered core tablet compressed on an instrument tablet machine with a 9-mm standard concave punch Firstly, the drug layer mixture was fed into the cavity of the die as usual and compressed into a solid layer; the push layer mixture was then manually loaded into the cavity overlaying the drug layer after stopping the machine and compressed into a solid layer to form a bilayered tablet core The hardness of the obtained core tablets was adjusted to about 10  kP - Semi-permeable membrane coating: The core tablets were coated by film coating method with cellulose acetate as a semipermeable membrane, using polyethylene glycol as a plasticizer - Drilling the releasing orifice using a laser beam: The coated tablets were automatically drilled on the drug side by CO2-laser equipment (Epilog Helix) with a computer-based control for batch production - Fast release coating: The osmotic tablets were coated by film coating method with HPMC cps, the coating layer contained 0.5 mg of FE/tablet 2.2.2 Evaluation methods for some physicochemical properties, formulating basic criteria and stability study - Evaluation methods for some physicochemical properties of powder: Size particle distribution, apparent density, solubility, the content uniformity, interaction study was carried out by Differential Scanning calorimeter (DSC) and IR - Evaluation methods for core tablets: Hardness, quantitative assay - Evaluation methods for osmotic tablets: Thickness of the coat, diameter of the orifice, the content uniformity of fast release coating layer, quantitative assay, dissolution profile, effect of dissolution conditions on the release process - Formulating basic criteria for the extended release osmotic tablets of FE (according to USP 36 and Vietnamese Pharmacopoeia IV): Appearance, qualification, quantification,content uniformity and in vitro drug release - Stability studies: Stability studies were carried out with osmotic tablets from the optimal formulation batches of 10.0000 tablets at temperature and humidity in real conditions up to 24 months and in accelerated storage study for months The tablets were evaluated in terms of appearance, quantification and in vitro drug release 2.2.3 Bioequivalence study between the extended release tablets of mg felodipine and Felutam CR mg tablets as reference 2.2.3.1 Method development and validation of quantifying felodipine in plasma The estimation of FE in human plasma samples was carried out by a validated UPLC-MS/MS method, glibenclamid was used as internal standard (IS) - Sample preparation: FE was extracted from human plasma by a liquid/liquid procedure using diethylether - chloroform (7 : v/v) - Chromatographic conditions: + Stationary phase: RP 18 50 x 2.1 mm + 100 x 2.1 mm; 1.8 m + Column temperature: 40°C + Mobile phase: Methanol - isopropanol - acetonitrile ammonium acetate mM (45:35:10:10 v/v) + Flow rate: 0.2 mL/min + Injection volume: µL - Mass spectrometry conditions: Tandem mass spectrometry (MS/MS) was performed with a triple-quadruple mass spectrometer FE and glibenclamid were ionized via electrospray ionization (ESI) in positive ion mode The detection of the ions was performed in the selected reaction monitoring mode, monitoring the transition of the precursor ion at m/z 384.0 to the product ion at m/z 338.0 for FE, and the transition of the precursor ion at m/z 494.0 to the product ion at m/z 369.0 for glibenclamid - Method validation: The UPLC-MS/MS method for the quantification of FE in human plasma was validated using the various validation parameters such as: System suitability, specificity, matrix effect, linear range and calibration curves, precision, accuracy, the lower limit of quantification, recovery and stability studies 2.2.3.2 Bioequivalence study between the extended release tablets of mg felodipine and Felutam CR mg tablets as reference - Study design: The study design used was a randomised, 2period, 2-sequence crossover, single-dose bioequivalence study and the wash out period of days - Blood sampling: mL blood samples were withdrawn at following times: before drug administration (0) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 48 hours after drug administration - Determination of pharmacokinetic parameters and statistical analysis: + Cmax and AUC: The log-transformed pharmacokinetic parameters (Cmax, AUC0-t and AUC0-∞) of FE for test and reference formulation were subjected to analysis of variance (ANOVA) with the main effects of sequence, subject, treatment and period Bioequivalence is evaluated based on the 90% confidence intervals (CIs) The 90% CIs for the intra-individual geometric mean ratios (Test/Reference formulation) of log-transformed Cmax and AUC should be within the range 70 - 143% and 80 - 125%, respectively + Tmax were compared for test and reference using nonparametric Wilcoxon Signed Rank test The difference between Tmax values must not statistically significant 2.2.4 Data analysis and display of the results Kinetic model analysis of drug release was performed by MathCad software version 14.0.0.16 The statistical data analysis was performed using Microsoft Excel software version 2007 The research results are processed and shown in this thesis with the form of average value ± standard deviation (± SD), in which n is replicates and RSD % is relative standard deviation 18 more than 34.47 times blank response The recovery concentrations compared to the real values were from 83.89 to 112.93 % (in the range of 80 - 120 %) and RSD was 10.73 % (< 20 %) Thus, concentrations of 0.1 ng/ml met the requirements of lower limit of quantification of bioanalytical methods - Accuracy and precision: + Interday accuracy and precision: The UPLC-MS/MS method for the quantification of FE in human plasm had high accuracy from 86.41 % to 114.38 % (in the range of 85 % - 115 %) and 83.89 % 112.93 % (in the range of 80 % - 120 %) at the LLOQ with small RSD values (5.92 % - 10.73 %) Thus, the analytical method met the requirements of the interday accuracy and precision of bioanalytical methods + Intraday accuracy and precision: The UPLC-MS/MS method had high accuracy in the range of 85 % - 115 % and the repeatability with small RSD values were less than 15 % for different days Thus, the analytical method met the requirements of the interday accuracy and precision of bioanalytical methods Therefore, interday and intraday accuracy and precision met the requirements for bioanalytical procedures - Recovery: Extraction method gained high IS recovery rate (92.86 %) and high FE recovery rate (84.32 % - 86.81 %), good repeatability at various concentrations with small RSD < 15 % Thus, the sample preparation method has been developed to be suitable for extracting IS and FE from human plasma - Stability of the samples: The samples were stable after hours at room temperature, after freezing-thawing cycles, after storing at -35 ± C for 68 days and after 22 hours in auto-sampler 19 3.4.2 Bioequivalence study of the prepared extended release tablets of mg felodipine 3.4.2.1 Determination felodipine concentration in plasma for 12 volunteers of test and reference formulation The present bioequivalence study was conducted in 12 volunteers and the final evaluation was carried out on data obtained from 12 volunteers who completed the study according to protocol The mean plasma concentrations of FE versus time curves for test and reference formulation are shown in figure 3.20 Figure 3.20 Mean plasma concentration vs time curve for 12 volunteers of test and reference formulation 3.4.2.2 Bioequivalence study of the prepared extended release tablets of mg felodipine Various pharmacokinetic parameters were evaluated during study are mention in Table 3.44 20 Table 3.44 Summary of pharmacokinetic parameters for 12 volunteers after the administration of felodipine test and reference formulations PK parameters Cmax  SD AUC0-t  SD AUC0-  SD Tmax  SD (ng/mL) (h.ng/mL) (h.ng/mL) Test 0.72 ± 0.27 6.66 ± 1.67 9.99 ± 3.63 5.50 ± 2.28 Reference 0.63 ± 0.12 6.16 ± 1.06 9.74 ± 3.72 5.67 ± 1.50 Formulation (h) (SD: Standard deviation) The 90% CIs for the geometric mean ratios of test/reference formulation were calculated for the AUC and C max parameters These results are shown in table 3.48 Table 3.48 The 90% CIs for the geometric mean ratios of the log-transformed Cmax and AUC Pharmacokinetic parameters Geometric mean Geometric mean 90% CIs (%) Test Reference ratio (%) Cmax (ng/mL) 0.689 0.622 110.77 88.29 - 138.97 AUC0-t (ng.h/mL) 6.439 6.055 106.33 95.40 - 118.51 AUC0- (ng.h/mL) 9.378 9.198 101.96 85.20 - 122.02 The 90% CIs for mean C max and AUC of test/ reference individual ratios were within the accepted bioequivalence range Non-parametric analysis by the Wilcoxon Signed Rank test showed no statistically significant difference between the Tmax values of both formulations with p > 0.05 Hence, we could conclude that: The extended release push-pull osmotic tablets containing mg of FE is bioequivalent to Felutam CR mg - the marketed FE reference formulation in fasting condition Chapter DISCUSSION 21 4.1 Preparation extended release push-pull osmotic tablets of felodipine 4.1.1 Design dosage form PPOP is the most practical way to prepare poorly soluble drugs into osmotic system Specifically designed to deliver poorly soluble drugs, PPOP consists of a bilayered core surrounded by a semipermeable membrane with a laser-drilled releasing orifice The polymeric nature of the drug layer allows the drug to be dissolved and released at a constant rate until drug release completion, especially with a low dose The drug release mechanism allows the drug to be delivered independently of external physiological conditions FE is poorly water soluble and used with a low dose Therefore, FE is suitable for preparing into PPOP in order to control the release behavior and absorption of FE, reduce fluctuations in the plasma concentration and increase the drug bioavailability 4.1.2 Preparation of bilayered core tablets The optimal formulation was mainly affected by the compositions of the core tablets The primary components of PPOP are osmotic agent, dispersed excipient and swelling agent The osmotic agents play an important role in controlling drug release rate The osmotic agents act as a channeling agent for penetration of water in drug layer and push layer, resulting in accelerating the expansion of PEO and push drug out via the releasing orifice The commonly used osmotic agent in PPOP is NaCl Using NaCl in the tablet core composition can guarantee stable and sustained drug release The NaCl content and location are therefore important parameters to properly balance the hydration kinetics between both 22 the drug and the push layers and thereby, efficiently deliver the drug The absence of NaCl or a reduced proportion of NaCl in the drug layer caused poor hydration, the slow expansion of PEO resulting in long lag time (Tlag lasted about hours) and slower drug release rate This result can be explained by the fact that the swelling of the drug layer is responsible for the initial drug fraction delivered through the orifice The absence of NaCl in the push layer resulted in the drug release profile is not much affected However, drug release was not complete and the linearity was compromised in the absence of osmotic agent in the push layer of the osmotic tablets Lactose is another osmotic agent in PPOP formulation of FE These osmotic agents are essential components of osmotic tablets, responsible for maintaining an effective concentration gradient through the membrane and act as a driving force for attracting water and help in maintaining an uniform drug distribution in the hydrated system Therefore, drug release profile from optimized formulation could controlled in a zero order kinetic PEO is the most commonly used polymer in PPOP These polymers are hydrophilic with good water solubility, low toxicity, and high swelling capacity Both polymers in the drug and the push layers are preferably PEOs because of their singular swelling kinetic as well as their good flowability and compressibility properties The developed formulation containing low molecular weight PEO (200.000) as the dispersing agent in the drug layer to improve FE solubility and better drug dispersion and high molecular weight PEO (5.000.000) as swelling agent in the push layer In contact with physiologic fluids, water diffuses through the semi-permeable membrane and hydrates the polymers of both the drug and the push 23 layers leading to the formation of a drug dispersion in the drug layer and swelling of the push layer The hydrodynamic pressure generated by the swelling of PEO forces the drug dispersion through the releasing orifice at a constant rate until drug release completion An appropriate concentration of PEO in both layers will results in the increase of drug release rate and release of the drug in a zero order release profile The study results proved that the developed formulation could release over 90 % FE after 12 hours and release profile was controlled in a zero order kinetic for prolonged period of - 10 hours 4.1.3 Semi-permeable membrane coating As water can only get into the interior of the osmotic pump through the membrane, the composition and thickness of the semipermeable membrane therefore has a signifcant impact on the drug release Cellulose acetate is a widely used polymer as the semipermeable membrane for osmotic systems, along with polyethylene glycol with a dual functionality of plasticizer and pore former to increase the flexibility and control the membrane permeability The thesis used cellulose acetate pre-mixed with polyethylene glycol in a ratio of 9: under the trade name Opadry® CA Using Opadry® CA has many advantages: Easy to dissolve in acetone, no need to add plasticizer, good film quality, uniformity, smooth surface and easy to dry Semi-permeable membrane thickness is an important parameter that controls the rate of penetration of water into the system Therefore, the coating thickness had signifcant influence on the FE release performance The appropriate coating thickness can help to achieve the desired drug release profile The thickness of the 24 membrane is diffcult to measure, but was reflected by the increased weight after coating Drug release was found to be inversely proportional to the membrane thickness The higher coating weight gain led to a longer lag time and slower drug release rate due to the lower rate of water passing through the semi-permeable membrane All of the osmotic tablets were semi-permeable membrane coated with %, 8.5 % 10 % additional weights (by weight of core tablet) that had the release profiles in the zero-order model with different drug release rate without broken membrane Thus, using Opadry® CA can prepare flexible semi-permeable membrane with good drug release controlling, stable water absorption rate through membrane The developed osmotic tablets were semi-permeable membrane coated with weight gain 8.5 % is the most optimal because of achieving the desired drug release rate, good appearance, shortening coating time, saving coating material 4.1.4 Drilling the releasing orifice Laser drilling is one of the most commonly used techniques to create delivery orifice in the osmotic tablets This technology is well established for producing sub-millimeter size hole in tablets It offers excellent reliability characteristics at low costs It is possible to control the releasing orifice size by varying the laser power, firing duration (pulse time), thickness of the membrane and the dimensions of the beam at the membrane Epilog Helix laser drilling is a cuttingedge, compact, easy-to-operate device The study results showed that using CO2 laser beam with 25% of the device capacity is able to obtain a high homogeneous releasing orifice The size of releasing orifice must be optimized in order to control the drug release from osmotic systems Results of the 25 dissolution test of the osmotic tablets with varying releasing orifice diameters (0.6 mm, 0.8 mm and 1.0 mm) showed that the orifice diameter did not significantly affect Tlag but significantly affected the drug release rate The larger the releasing orifice diameter was, the faster the drug release took place The release orifice size of 0.8 mm was chosen to develope PPOP for FE because of the longest release period and the longest linear range on the drug release profile 4.1.5 Scaled-up preparation process of the extended release felodipine tablets The preparation process of the extended release osmotic tablets of FE was built and scaled-up at a batch scale of 10.000 tablets/batch with suitable key parameters Triple batches of optimal formulation were prepared by the same process The results showed that the prepared core tablets of triple batches met the requirements of appearance, hardness, mass uniformity and content uniformity These standards were significantly different between the core tablets of triple batches Thus, it is concluded that the formulation and preparation method was appropriate, the process of preparing the core tablets was stable The core tablets of triple batches met the requirements for the next stages After semi-permeable membrane coating and the releasing orifice drilling, the prepared osmotic tablets of triple batches meet the requirements of appearance, qualification, quantification, content uniformity and in vitro drug release Therefore, the results indicated that the preparation process of the extended release osmotic tablets of mg FE has strengths for industrial scale producting 4.2 Formulating basic criteria and stability studies for the 26 extended release osmotic tablets of felodipine 4.2.1 Formulating basic criteria The basic criteria for extended release osmotic tablets of FE was developed in accordance with the Vietnamese Pharmacopoeia IV, USP 36 and general criteria of extended release tablets The basic criteria was built in accordance with the process of preparing the bilayered osmotic tablets with the double compression method and was characterized as the 12 hour extended release tablets The standard criteria of the extended release tablets of FE prepared at a batch scale of 10.000 tablets/batch were proposed in terms of appearance, qualification, quantification,content uniformity and in vitro drug release 4.2.2 Stability studies The DSC thermograms of pure FE, physical mixtures of FE and PEO 200.000 indicating that there is no possible interaction between FE and PEO 200.000 The prepared tablets at a batch scale of 10.000 tablets/batch were stable for 24 months in real conditions and months in accelerated conditions The tablets are predicted up to 24 months of stability 4.3 Bioequivalence study of the prepared extended release tablets of mg felodipine 4.3.1 Method development and validation of quantifying felodipine in human plasma A UPLC-MS/MS method for the quantification of FE in human plasma was developed and validated according to the requirements laid down in international regulatory guidelines The UPLC system 27 used particle size of 1.8 μm resulting in better chromatographic resolution, performs more sensitive analysis, consumes less time, reduces solvent consumption and has high analysis speed Under these conditions chromatographic detection of FE and IS was highly sensitive Chromatographic conditions and mass spectrometry conditions were optimised for the estimation of FE, which provided a well defined separation between the drug, IS and endogenous components without interference from the human plasma matrix Glibenclamide is relatively stable, can run both negative and positive ions, extracted by many various processes The results showed that glibenclamide was well extracted by diethyl ether chloroform, stable response, unaffected by matrix The UPLC-MS/MS method was developed and validated using the various validation parameters such as: System suitability, specificity, matrix effect, linear range and calibration curves, precision, accuracy, the lower limit of quantification, recovery and stability studies The method validation results showed that the UPLC-MS/MS method had enough sensitivity, specificity, small lower limit of quantification (0.1 ng/mL), good linearity over wide concentration range linear range (0.1 - 20.0 ng/mL) with a correlation coefficient r = 0.9987, high accuracy (96.84 % - 104.59 %), the intra-day and inter-day repeatabilities with small RSD values (6.40% - 11.95%), good recovery from the plasma matrix and stability under all storage conditions short run time (2 minutes for each sample) and the samples were stable for long period (68 days in –35  °C) The validation parameters of the UPLC-MS/MS method fulfilled the requirements of the biological analysis method Therefore, the validated method could be applied to the FE 28 estimation in human plasma for bioavailability and pharmacokinetic studies of pharmaceutical dosage forms containing FE 4.3.2 Bioequivalence study of the prepared extended release tablets of mg felodipine The bioequivalence study design used was a randomised, 2period, 2-sequence crossover, single-dose bioequivalence study The wash out period of days was sufficient to avoid any carrying over effects The experimental design is scientific to reduce interfered factors that influenced bioequivalence results The study selected Felutam CR 5mg tablets as reference product because of the same mechanism of PPOP and this product has produced franchises and been marketed regularly in Vietnam The reference tablets were tested with the same dose of mg as the test tablets Results of variance analysis showed that the differences between individuals affecting AUC were statistically significant with p < 0.05, indicating a difference in the extent of absorption between individuals Therefore, it is necessary to increase the number of volunteers in the bioavailability study of extended release FE preparations in order to minimize variability and allow the detection of differences between study drugs Therefore, the research results showed that the validated method and bioequivalence study design was appropriately developed to assess bioavailability for the prepared extended release tablets of FE Initially, it could be concluded the prepared osmotic tablets containing mg of FE is bioequivalent to Felutam CR mg - the marketed FE reference formulation in fasting condition 29 CONCLUSIONS The extended release push - pull osmotic tablets of mg felodipine was preparated - PPOP for FE was successfully formulated, which can obtain an extended in vitro release profile over a 12-hour period The bilayered push - pull osmotic tablets of mg FE were prepared by double compression method Then, the core tablets were semipermeable membrane coated with cellulose acetate and one releasing orifice was drilled by laser on the drug side of tablets The developed formulation containing low molecular weight PEO (200.000) as the primary component in the drug layer and high molecular weight PEO (5.000.000) as swelling agent in the push layer The developed formulation consists of 49.75% (w/w) low molecular weight PEO (200.000 Da) as the primary component in the drug layer; 45.00% (w/w) high molecular weight PEO (5.000.000 Da) as a swelling agent in the push layer; 8.29% and 4.62% (w/w) NaCl as osmotic agent in both drug and push layers, respectively; which was semipermeable membrane coated with weight gain 8.5 % and drilled the release orifice of 0.8 mm, then coated immediate release layer containing 10 % of FE content (0.5 mg) with HPMC 6cps to increase amount of release drug in the first hour The research results showed that the developed osmotic tablets can immediate release over 10 % content of FE in the first hour, followed by drug releasing for prolonged period of - 10 hours in a zero order kinetic - The preparation process of the extended release osmotic tablets of FE was built and scaled-up at a batch scale of 10.000 tablets/batch with suitable key parameters 30 The standard criteria and stability of prepared tablets containing mg felodipine were proposed and evaluated - The standard criteria of the extended release tablets prepared at a batch scale of 10.000 tablets/batch were proposed in terms of appearance, qualification, quantification,content uniformity and in vitro drug release - The prepared tablets at a batch scale of 10.000 tablets/batch were stable for 24 months in real conditions and months in accelerated conditions The tablets are predicted up to 24 months of stability A bioequivalence study of the prepared extended release push pull osmotic tablets containing mg felodipine was evaluated - The UPLC-MS/MS method has been developed and evaluated with sensitivity, specificity and accuracy to quantify the concentration of FE in human plasma enough to meet the requirements of the biological analysis method - A bioequivalence study between the prepared extended release osmotic tablets containing mg FE and Felutam CR mg tablets as reference was carried out in 12 healthy human volunteers The 90% confidence intervals for the intra-individual mean ratios of logtransformed (Cmax, AUC0-t and AUC0-∞) for test and reference formulations were 88,29 - 138,97%; 95,40 - 118,51% and 85,20 122,02%, respectively All of these values were found within the accepted bioequivalence ranges The difference between T max values of two formulations was not statistically significant Hence, the prepared osmotic tablets containing mg of FE is bioequivalent to Felutam CR mg - the marketed FE reference formulation in fasting condition 31 PROPOSALS In order to be applicable to practical production, further research needs to be carried out on pilot production with a larger scale using industrial equipments AUTHOR'S PUBLICATIONS Vũ Thị Thanh Huyền, Nguyễn Thanh Hải, Phạm Thị Minh Huệ (2018) Xây dựng công thức bào chế viên felodipin giải phóng kéo dài theo chế bơm thẩm thấu kéo - đẩy Tạp chí Y Dược học Quân sự, tập 43, số 2, tr 15 - 23 Vu Thi Thanh Huyen, Pham Thi Minh Hue, Nguyen Thi Kieu Anh, Ta Manh Hung, Nguyen Thanh Hai (2018) Bioequivalence study of extended release push-pull osmotic tablets containing mg of felodipine Journal of Military Pharmaco-medicine, vol 43, N03, pp 101 - 107 ... After hours: 42 - 68 % After hours:  75 % 17,21  1,30 57 ,90  3,13 90 ,57  2,13 16,34  2, 45 55, 63  2,41 92,63  2 ,51 16, 45  2,64 55 , 35  2,41 93,34  2 ,54 3.3.2 Stability studies 3.3.2.1 Appearance... actual average drug content in the fast release coating is 0. 454 mg Therefore, it is necessary to increase the FE content up to 0 .55 mg/ tablet to compensate for the loss weight during coating 3.3... 3. 15) Figure 3. 15 Percentage of felodipine released from the test and the reference (Felutam CR) 3.2 Scaled-up preparation process of extended release push pull osmotic tablets containing mg felodipine