Luận án tiến sĩ nghiên cứu bào chế viên nifedipin giải phóng kéo dài theo cơ chế

MINISTRY OF MINISTRY OF EDUCATION AND TRAINING NATIONAL DEFENSE MILITARY MEDICAL UNIVERSITY TRAN QUANG TRUNG A STUDY ON THE PREPARATION OF OSMOTIC PUMP TABLETS OF NIFEDIPINE PHARMACEUTICAL DOCTORAL THESIS HANOI – YEAR 2021 MINISTRY OF MINISTRY OF EDUCATION AND TRAINING NATIONAL DEFENSE MILITARY MEDICAL UNIVERSITY TRAN QUANG TRUNG A STUDY ON THE PREPARATION OF OSMOTIC PUMP TABLETS OF NIFEDIPINE Speciality: PHARMACEUTICAL TECHNOLOGY AND PHARMACEUTICS Code: 9720202 PHARMACEUTICAL DOCTORAL THESIS FULL NAME OF SUPERVISOR: 1. Trinh Van Lau 2. Nguyen Thanh Hai HANOI – YEAR 2021 ACKNOWLEDGEMENT I would like to express deep gratitude to my advisors, Assoc. Trinh Van Lau and Prof.

Nguyen Thanh Hai for their enthusiastic guidance and wholehearted help throughout the course of this thesis. I would also like to express my sincere thanks to Assoc.Trinh Nam Trung, all my colleagues and technicians from Pharmaceutical Training Institute under the Military Medical University for their enthusiastic help and extending the facilities to complete this research work. I would extend my sincere thanks to Prof. Pham Thi Minh Hue and lecturers, technicians of the Pharmaceutics Department of Hanoi University of Pharmacy for their help and facilitation.

I would like to thank the VNU University of Medicine and Pharmacy, National Institute of Pharmaceutical Technology, Institute of Biomedicine and Pharmacy, National Institute of Drug Quality Control, Hanoi Quality Control Center of Drug, Cosmetic and Food, Colorcon Vietnam company limited, Traphaco Joint Stock Company, and Pharmaceutical Corporation Ha Tay for the help and extending the facilities to complete this work. I would like to thank the Board of Directors of Military Medicine University, Prof. Nguyen Linh Toan, Dr. Dao Hong Duong, and the experts of the Postgraduate Training Department for their interest and help during the course of study and research.

I would extend my special thanks to my family members, friends, and colleagues for their constant encouragement and for extending the facilities to complete this research work. Hanoi, day month year, 2021 Tran Quang Trung COMMITMENT I here by declare that this is my own research work. The data and results stated in the thesis are true and have not been published by anyone in any project. Author TRAN QUANG TRUNG TABLE OF CONTENTS Acknowledgement Commitment Table of contents List of abbreviations List of tables List of figures INTRODUCTION.REVIEW OF LITERATURE.

OVERVIEW OF NIFEDIPINE. Physical and chemical properties. Some preparations containing nifedipine on the Vietnamese market 6 1. Some studies on the extended-release drug delivery system containing nifedipine 7 1.

PUSH-PULL OSMOTIC PUMP EXTENDED-RELEASE DRUG DELIVERY SYSTEM. Structure and mechanism of drug release. Advantages and disadvantages. EVALUATE THE BIOAVAILABILITY AND BIOEQUIVALENCE OF PRODUCT CONTAINING NIFEDIPINE.

In vitro drug release studies. In vivo bioavailability studies. MATERIALS AND METHODS. Equipment and tools.

Reference and test product. Study location and duration of implementation. Formulation development studies. Validation of preparation process of push – pull osmotic pump tablets of 30 mg nifedipine with a batch scale of 2,000 tablets 48 2.

Quality control methods. Stability study methods. Bioavailability study of extended-release nifedipine tablets in experimental dogs 56 2. DEVELOPMENT AND VALIDATION OF HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD FOR THE DETERMINATION OF NIFEDIPINE.

FORMULATION DEVELOPMENT STUDY. Assessment of the drug - excipients interaction. Stability study of nifedipine to the light in mediums. In vitro dissolution study of the reference product.

FORMULATION OF PUSH-PULL OSMOTIC PUMP TABLETS OF NIFEDIPINE. Formulation of core tablets. Formulation of osmotic coating. Effect of the release orifice size on the drug release.

DEVELOPMENT AND VALIDATION OF THE PREPARATION PROCESS OF PUSH-PULL OSMOTIC PUMP TABLETS OF NIFEDIPINE WITH A BATCH SCALE OF 2,000 TABLETS. Description of the preparation process of push-pull osmotic pump tablets of 30 mg nifedipine with a batch scale of 2,000 tablets 90 3. Validation of the preparation process of push-pull osmotic pump tablets of 30 mg nifedipine with a batch scale of 2,000 tablets 92 3. ESTABLISHING THE QUALITY STANDARD AND EVALUATING THE STABILITY OF PUSH-PULL OSMOTIC PUMP NIFEDIPINE TABLETS.

Establishing the quality standards of push-pull osmotic pump tablets of nifedipine 102 3. Stability study of push-pull osmotic pump tablets of nifedipine 104 3. BIOAVAILABILITY STUDY OF PUSH – PULL OSMOTIC PUMP TABLETS OF NIFEDIPINE. In vitro equivalence study.

Validation of UPLC-MS/MS method for the determination of nifedipine in dog plasma 108 3. Bioavailability study of push-pull osmotic pump tablets of 30 mg nifedipine in experimental dogs 123 CHAPTER 4. Selecting the extended-release type. Formulation of push-pull osmotic pump tablets of nifedipine.

Development of the preparation process of extended-release nifedipine tablets 151 4. ESTABLISHING THE QUALITY STANDARD AND INITIAL EVALUATING THE STABILITY OF EXTENDED-RELEASE TABLETS CONTAINING 30 MG NIFEDIPINE. Establishing the quality standards. Evaluating the stability of extended-release nifedipine tablets.

INITIAL ASSESSMENT OF BIOAVAILABILITY. Development and validation of UPLC-MS/MS method for the determination of nifedipine in dog plasma 156 4. Bioavailability study of extended-release tablets of 30 mg nifedipine 161 CONCLUSION. 169 LIST OF APPENDICES LIST OF ABBREVIATIONS Number Abbreviations Full written section 1 ACN Acetonitrile 2 OSP Osmotic pressure 3 AUC Area Under the Curve – time 4 AUMC Area under the first moment curve (Or the curve of concentration*time versus time) 5 BCS Biopharmaceutical Classification System 6 CA Cellulose acetat 7 CV Coefficient of Variation 8 API Active Pharmaceutical Ingredient 9 PK Pharmacokinetics 10 VNP Vietnamese Pharmacopoeia 11 DSC Differential scanning calorimetry 12 EC Ethyl cellulose 13 EOP Elementary Osmotic Pump 14 EtOH Ethanol 15 EtOAc Ethylacetat 16 FDA Food and Drug Administration 17 FTIR Fourie Transform Infrared 18 GC Gas chromatography 19 GLI Glibenclamide 20 ER Extended-release 21 CR Controlled-release 22 PR Pulsatile release 23 HPLC High performance liquid chromatography 24 SDN Solid dispersions 25 HPTLC High performance thin layer chromatography 26 HPMC Hydroxy propyl methyl celulose 27 HQC High quality control sample 28 IPA Isopropyl alcohol 29 IS Internal standard 30 w/w Weight/weight 31 SMW Weight gains of semipermeable membrane 32 MW Molecular weight 33 BDS Bulk density 34 TDS Tapped density 35 AVW Average weight 36 LC Liquid chromatography Number Abbreviations Full written section 37 LLOQ Lower limit of quantification 38 LOD Limit of detection 39 LOQ Limit of quantification 40 LQC Low quality control sample 41 MCC Microcrystalline cellulose 42 MeOH Methanol 43 MOTS Monolithic osmotic tablet system 44 MQC Medium quality control sample 45 MS Mass Spectrometry 46 MRT Mean residence time 47 NIF Nifedipine 48 PEG Polyethylen glycol 49 PEO Polyethylen Oxid 50 PPOP Push – Pull Osmotic Pump 51 PVP Polyvinyl Pyrrolidon 52 RSD Relative standard deviation 53 SCMC Sodium carboxymethylcellulose 54 SD Standard deviation 55 SEOP Swellable elementary osmotic pump 56 SEM Scanning electron microscopy 57 BA Bioavailability 58 SLS Sodium lauryl sulfat 59 SOTS Sandwiched osmotic tablet system 60 SSG Sodium starch glycolat 61 UDE Undesirable effects 62 BE Bioequivalent 63 Tlag Lag time 64 UPLC-MS/MS Ultra performance liquid chromatography with tandem mass spectrometric detection 65 USP The United States Pharmacopoeia 66 v/v Volume/volume 67 WHO World Health Organisation LIST OF TABLES Table no.

Table name Page no. Some preparations containing nifedipine. List of materials and chemicals used in the study. List of equipment for preparation and production.

List of equipment and tools for evaluation. Parameters of mass spectrometry detector for qualitative and quantitative analysis of nifedipine and internal standard glibenclamide. Model of testing the drugs on experimental dogs. Results of the column analysis validation.

Mobile phase investigation results. Results of investigating the ratio of mobile phase components MeOH: H2O. Results of testing the system suitability. Results of method precision.

Results of intermediate precision. Results of accuracy test. Decomposition of nifedipine in pH 7. Decomposition of nifedipine in the pH 1.5% sodium lauryl sulfate.

Proportion (%) of nifedipine released from the reference tablet. Tablet samples of different polymers in the drug layer and push layer. The drug layer formulation of the osmotic nifedipine tablets with the different content ratios of sodium chloride. The push layer formulation of osmotic nifedipine tablets with the different content ratios of sodium chloride.

Table name Page no. The coating formulation of tablets with the different content ratios of plasticizer to cellulose acetate. The coating formulation of tablets with the content ratio of plasticizer to cellulose acetate of 10%. The formulation of a batch of 2,000 tablets.

The particle size distribution of NIF raw material powder. The nifedipine content uniformity when dry blending the drug layer in a batch scale of 2,000 tablets. The density of the push layer powder after dry blending in a batch scale of 2,000 tablets. Loss on drying of the drug layer granules with different drying times in a batch scale of 2,000 tablets.

Loss on drying of the push layer granules with different drying times in a batch scale of 2,000 tablets. The particle size distribution of the drug layer granules after final blending in a batch scale of 2,000 tablets. Properties of the drug layer granules after final blending in a batch scale of 2,000 tablets. The particle size distribution of the push layer granules after final blending in a batch scale of 2,000 tablets.

Properties of the push layer granules after final blending in a batch scale of 2,000 tablets. Properties of tablets at all the stages with tableting speed 1 (2.5 rpm) in a batch scale of 2,000 tablets. Properties of tablets at all the stages with tableting speed 2 (5 rpm) in a batch scale of 2,000 tablets. Properties of tablets at all the stages with tableting speed 3 (10 rpm) in a batch scale of 2,000 tablets.

Table name Page no. The effect of some parameters of the coating process on the uniformity of coating weight. Investigation results of the parameters for drilling the drug release orifice. Granule properties of the push and the drug layers in a batch scale of 2,000 tablets.

Properties of core tablet and osmotic tablet in a batch scale of 2,000 tablets. he mass uniformity of three batches of the coated tablets. The dissolution results of three study batches. Nifedipine content (%) of the three study batches.

Several quality standards which proposed for the extended-release tablet containing 30 mg nifedipine. Nifedipine content (%) of three batches stored under the accelerated conditions. Nifedipine content (%) of three batches stored under the real conditions. Impurity content (%) of three batches stored under the accelerated conditions for three months.

Impurity content (%) of three batches stored under the accelerated conditions for six months. Impurity content (%) of three batches stored under the real conditions for twelve months. Percentage of nifedipine released from the test product and the reference product in three dissolution media. Test results of the UPLC-MS/MS system suitability.

Effect of blank samples at the retention time of nifedipine and internal standard of glibenclamide. Table name Page no. Accuracy of standard samples. The peak area response of zero samples compared with the LLOQ sample.

The determination results of the LLOQ value of the method. The investigation results of accuracy and intra-day precision. The investigation results of accuracy and inter-day precision. The investigation results of recovery percentage of NIF and GLI.

The evaluation results of matrix effect. The evaluation results of carry-over. The stability of the working solutions of internal standard. The stability of plasma samples after three freeze-thaw cycles.

The stability of plasma samples at room temperature for 5 hours. The stability of the post-process samples in auto-sampler. The long-term stability of plasma samples. Nifedipine concentration in dog plasma after taking a single dose of the test product (T).

Nifedipine concentration in dog plasma after taking a single dose of Adalat LA 30 mg reference product (R). The pharmacokinetic parameters of the test product. The pharmacokinetic parameters of the reference product. The analysis of variance with the dependent variable of ln[Cmax].

The analysis of variance with the dependent variable of ln[AUC0-∞]. The analysis of variance with the dependent variable of ln[MRT]. The comparison of Tmax value as per the non-parametric statistical method. 131 LIST OF FIGURES Figure no.

Figure name Page no. Structure of push-pull osmotic pump. Mechanism of drug release from a push pull osmotic pump. Preparation process flow diagram for extended-release nifedipine tablets.