O slideshow foi denunciado.
Utilizamos seu perfil e dados de atividades no LinkedIn para personalizar e exibir anúncios mais relevantes. Altere suas preferências de anúncios quando desejar.

Formulation and development of antihypertensive immediate release tablets

Formulation and Development of Antihypertensive Immediate Release Tablets

  • Entre para ver os comentários

Formulation and development of antihypertensive immediate release tablets

  1. 1. Formul 1 Formulation and Development of Antihypertensive Immediate Release Tablets Presented By: Anvita Jadhav M. Pharm (IP)
  2. 2. Introduction ∂ Tablet is the most popular among all dosage forms. ∂ Immediate release tablets are those which rapidly disintegrate and get dissolved to release the medicaments very quickly. ∂ The basic approach used in development immediate release tablets is the use of superdisintegrants. Dosage Form: Immediate Release Tablet • Dose precision • Compactness • Ease of administration • Rapid dissolution • Quick onset of action • Ease of shipping etc. Advantages 2
  3. 3. Diuretics, ACE inhibitors, Angiotensin-II receptor antagonists, Calcium channel blockers, β adrenergic blockers, β + α adrenergic blockers, α adrenergic blockers, Central sympatholytics & Vasodilators Clinical classification of hypertension Category Systolic (mm Hg) Diastolic (mm Hg) Optimal < 120 < 80 Normal < 130 < 85 High normal 130 – 139 85 – 89 Hypertension mild (stage 1) 140 – 159 90 – 99 moderate (stage 2) 160 – 179 100 – 109 severe (stage 3) 180 – 209 110 – 119 very severe (stage 4) ≥ 180 ≥ 110 Very common disorder, particularly past middle age. WHO – ISH guidelines have defined hypertension to be ≥140 mm Hg systolic and ≥90 mm Hg diastolic. Globally, complications of hypertension account for 9.4 million deaths worldwide every year. Hypertension 3
  4. 4. Combination Therapy • Almost 70% of hypertensive patients do not reach the recommended treatment target of <140/90 mmHg with monotherapy, therefore combination therapy necessary to achieve these targets with minimal adverse effects. Advantages Combination of 2 agents at low doses gives greater blood pressure reductions than higher dose of 1 drug Fewer adverse effects Blockade of several pathways that increase blood pressure Prompt blood pressure control Effects beyond their antihypertensive actions Double Combination • CCB + ARB/ACEI • CCB + β blocker • Diuretic+ ARB/ACEI • Diuretic + β blocker • β blocker + ARB/ACEI Triple Combination • CCB+ ARB + Diuretic • CCB+ RI + Diuretic 4
  5. 5. Ca++ L – type Ca++ channel ↑ Arterial vasodilation ↓ BP 5 Angiotensin II AT1 ↓ Vasoconstriction ↓ BP Calcium Channel Blocker BCS Class I Drug A Angiotensin Receptor Blocker BCS Class II Dru g B Additive BP lowering 10 mg 160 mg
  6. 6. 6 6 Literature Review Preformulatio n studies Innovator Characterization Formulation & developme nt of IR tablets Evaluation of blend and tablets Stability Studies Optimization Trials Conclusio n Plan of work Aim & Objectives To formulate, develop and optimize immediate release tablets of combination of drug A and drug B for the treatment of hypertension. To match the dissolution profile of formulation with the innovator’s product.
  7. 7. Literature Review • Books, research article, review articles, scientific journals and patents etc. 7
  8. 8. 888 Preformulation Studies
  9. 9. 999 Physicochemical Properties of Drug A Properties Details Description White to off white powder, light and temperature sensitive Molecular Weight 567.1 g/mol Solubility Freely soluble in methanol, sparingly soluble in anhydrous ethanol, slightly soluble in water and 2 - propanol Partition Coefficient 2.22 Melting point 198°C – 202°C Hygroscopicity Non Hygroscopic
  10. 10. 10101010101010 UV Spectrum of Drug A ƛmax = 236 nm
  11. 11. 111111111111 Infrared Spectrum of Drug A
  12. 12. 1212121212 Properties Details Description White to off white powder Molecular Weight 435.5 g/mol Solubility Freely soluble in methanol and anhydrous ethanol, sparingly soluble in methylene chloride, insoluble in water Partition Coefficient 5.8 Melting point 116°C - 117°C Hygroscopicity Hygroscopic Physicochemical Properties of Drug B
  13. 13. 13131313 UV Spectrum of Drug B ƛmax = 250 nm
  14. 14. 141414 Infrared Spectrum of Drug B
  15. 15. 1515 Bulk Density 0.317 g/ml Tapped Density 0.435g/ml Compressibility Index 27.12 Hausner’s Ratio 1.37 Angle of Repose 45.15⁰ Particle Size Distribution D90 45.20µm D50 12.09µm D10 2.18µm Bulk Density 0.408 g/ml Tapped Density 0.671g/ml Compressibility Index 39.19 Hausner’s Ratio 1.64 Angle of Repose 66.01⁰ Particle Size Distribution D90 35.30 µm D50 10.13 µm D10 1.91 µm Drug A Drug B Bulk Characterization
  16. 16. 16 Saturation Solubility mg/ml Media Drug A Drug B 0.1N HCl 3.53 0.08 0.01N HCl 4.19 0.09 0.001N HCl 4.33 0.12 pH 4.5 Phosphate Buffer 2.06 2.94 pH 6.8 Phosphate Buffer 4.14 4.55 pH 7.5 Phosphate Buffer 1.96 4.69 Water 2.81 0.21 Saturation Solubility Study
  17. 17. 171717 Ratio of Drug: Excipient Lactose (anhydrous) MCC 112 Croscarmellose Sodium Colloidal Silicon Dioxide Magnesium Stearate Opadry Yellow All Excipients Drug A 1: 10 1: 10 1: 2 1: 0.2 1: 0.1 1: 0.8 1: 15 Drug B 1:1 1:1 1: 0.2 1: 0.1 1: 0.1 1: 0.1 1: 1.5 Drug A + Drug B 1: 16: 16 1: 16: 16 1: 16: 3 1: 16: 1.5 1: 16: 1.5 1: 16: 1.5 1: 16: 20 Schedule for withdrawal of vials Condition Time points Initial 0th day 40°C±2°C/75%±5% RH (Open Vials) 15 Days and 1 Month 40°C±2°C/75%±5% RH (Closed Vials) 15 Days and 1 Month 25°C±2°C/60%±5% RH (Open Vials) 15 Days and 1 Month 25°C±2°C/60%±5% RH (Closed Vials) 15 Days and 1 Month Analysis results confirmed that excipients used are compatible with both drugs. Drug - Excipients Compatibility Studies
  18. 18. 1818 Innovator Characterization
  19. 19. 19 Physical Characterization of Innovator Description Yellow colored, oval shaped, film coated tablets Strength (Drug A) 10 mg Strength (Drug B) 160 mg Individual Tablet Weight (mg) 330.1, 328.0, 327.8, 329.9, 331.0 Disintegration time 1 min 02 sec to 1 min 10 sec Hardness (N) 185, 185, 181, 175 & 172 Tablet Dimensions (mm) Length 13.24, 13.25, 13.27, 13.24 & 13.25 Breadth 5.11, 5.12, 5.12, 5.13. & 5.11 Thickness 4.49, 4.50, 4.51, 4.48 & 4.51
  20. 20. 2020 Multimedia Dissolution Profile of Drug A Time (min) % Drug Release pH 6.8 Phosphate Buffer 0.1 N HCl pH 4.5 Phosphate Buffer 0 0 0 0 10 68 60 35 15 76 70 45 20 80 75 54 30 86 80 57 45 90 84 63 60 95 90 68 0 20 40 60 80 100 0 10 20 30 40 50 60 %DrugRelease Time (min) pH 6.8 Phosphate Buffer 0.1 N HCl pH 4.5 Phosphate Buffer
  21. 21. 212121 Multimedia Dissolution Profile of Drug B Time (min) % Drug Release pH 6.8 Phosphate Buffer pH 4.5 Phosphate Buffer 0.1 N HCl 0 0 0 0 10 75 42 8 15 87 50 10 20 95 57 12 30 97 63 14 45 98 72 19 60 100 85 25 0 20 40 60 80 100 0 10 20 30 40 50 60 %DrugRelease Time (min) pH 6.8 Phosphate Buffer pH 4.5 Phosphate Buffer 0.1 N HCl
  22. 22. 222222 Formulation & Development
  23. 23. 23232323 Process Selection Direct Compressio n Poor flow properties of Drug B Not Suitable Wet Granulation Drug A is susceptible to thermal degradation Not Suitable Dry Granulation Slugging Roller Compaction Suitable
  24. 24. 2424242424 Excipients Selection Diluent Lactose (anhydrous) SuperTab 21 AN Disintegrant Croscarmellose Sodium Ac-Di-Sol Glidant Colloidal Silicon Dioxide Aerosil 200 Lubricant Magnesium Stearate Coating Agent Opadry Yellow Diluent Microcrystalline Cellulose Pharmacel 112
  25. 25. 25252525 Ingredients %w/w Intragranular Drug A 4.33 Drug B 50 Lactose (anhydrous) 40.42 Croscarmellose sodium 4 Colloidal silicon dioxide 0.5 Magnesium stearate 0.5 Extragranular Magnesium stearate 0.25 Slugging parameters Specifications Punch size and description 18 mm, circular punches having plain surface on upper and lower punch. Average weight About 1500 mg Hardness 70 ± 10 N Compression parameters Specifications Punch size and description 13.1 x 5.1, Oval shaped punches having plain surface on upper and lower punch. Average weight 320 ± 16 mg Thickness 4.5 ± 0.3 mm Hardness 120 – 150 N Disintegration time NMT 1 min Trial 1 Dry Granulation (Slugging)
  26. 26. 2626262626 Slugs obtained were not uniform. Hard slugs were obtained The flow of lubricated blend was very poor Fine particles were more than granules. Sticking was observed while compression. The slugging process was not feasible for the product.
  27. 27. 2727272727 Ingredients %w/w Intragranular Drug A 4.33 Drug B 50 Lactose (anhydrous) 39.67 Croscarmellose sodium 4 Colloidal silicon dioxide 0.5 Magnesium stearate 0.5 Extragranular Colloidal silicon dioxide 0.5 Magnesium stearate 0.5 Coating Opadry Yellow 2.5 Trial 2 Dry Granulation (Roller Compaction) Roller compaction parameters Cycle 1 2 Roller pressure (Ton) 6.1 0.5 Roller speed/rotations (RPM) 2.4 10 Flake/Ribbon thickness (mm) 2 2 Coating parameters Inlet temperature 51⁰C - 54⁰C Exhaust temperature 40⁰C - 45⁰C Product bed temperature 35⁰C - 40⁰C Pan RPM 6 Pump Speed 3 – 6
  28. 28. 282828282828 Feasible process Flakes obtained were easy to screen Hard granules, Poor flow During compression process tablet weight uniformity was difficult to maintain. Due to poor flow acceptance value of content uniformity of drug A was more than 15, hence it is not satisfactory. f2 (drug A) = 28 & f2 (drug B) = 31
  29. 29. 292929292929 T3 T4 Ingredients %w/w Intragranular Drug A 4.33 4.33 Drug B 50 50 Lactose (anhydrous) 27.76 26.91 Croscarmellose sodium 3 4 Colloidal silicon dioxide 0.5 0.5 Magnesium stearate 0.5 0.5 Extragranular Lactose (anhydrous) 11.90 10.76 Croscarmellose sodium 1 2 Colloidal silicon dioxide 0.5 0.5 Magnesium stearate 0.5 0.5 Coating Opadry Yellow 2.5 2.5 Trial 3 and 4 Roller compaction parameters Cycle 1 2 Roller pressure (Ton) 4.0 0.5 Roller speed/rotations (RPM) 3.3 10 Flake/Ribbon thickness (mm) 2 2
  30. 30. 30303030303030 Trial 3 • Soft granules • Passable flow • Acceptance value of content uniformity of drug A was below 15 • f2 (drug A) = 35 • f2 (drug B) = 45 Trial 4 • DT was lowered by few seconds • f2 (drug A) = 40 • f2 (drug B) = 64 • Physical binding of drug A during compaction process.
  31. 31. 3131313131313131 T5 T6 Ingredients %w/w %w/w Intragranular Drug B 50 50 Lactose (anhydrous) 26.91 26.91 Croscarmellose sodium 4 4 Colloidal silicon dioxide 0.5 0.5 Magnesium stearate 0.5 0.5 Extragranular Drug A 4.33 4.33 MCC 112 10.76 10.76 Croscarmellose sodium 2 2 Colloidal silicon dioxide 0.5 0.5 Magnesium stearate 0.5 0.5 Coating Opadry Yellow 2.5 2.5 Trial 5 and 6 • Extragranular addition of Drug A • Extragranular addition of MCC 112 instead of Lactose (anhydrous)
  32. 32. 32323232323232 Drug A release was comparable with innovator Multimedia dissolution was comparable Weight uniformity Results were reproducibl e Multimedia dissolution was comparable Formula & process finalized Trial 5 Trial 6
  33. 33. 333333333333333333 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A Innovator T2 T3 T4 T5 T6 0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug B Innovator T2 T3 T4 T5 T6 Comparative Dissolution Profiles (Dissolution Media= pH 4.5 Phosphate Buffer)
  34. 34. 34343434343434343434 Comparative Dissolution Profiles (Dissolution Media= pH 6.8 Phosphate Buffer) 0 20 40 60 80 100 120 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A Innovator T5 T6 0 20 40 60 80 100 120 0 10 20 30 40 50 60%DrugRelease Time (min) Drug B Innovator T5 T6
  35. 35. 3535353535353535353535 Comparative Dissolution Profiles (Dissolution Media= 0.1 N HCl) 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A Innovator T5 T6 0 5 10 15 20 25 30 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug B Innovator T5 T6
  36. 36. 363636363636363636363636 Evaluation of Lubricated Blend Compressibility Index Hausner’s Ratio Angle of Repose Flow Character T1 32.45 1.46 56.21⁰ Very Poor T2 27.58 1.40 48.55⁰ Poor T3 24.12 1.31 46.78⁰ Passable T4 23.15 1.30 40.89⁰ Passable T5 19.61 1.24 39.23⁰ Fair T6 19.61 1.24 37.34⁰ Fair
  37. 37. 37373737373737373737373737 Evaluation of Tablets Assay % Uniformity of Dosage Units (Acceptance Value) Drug A Drug B Drug A Drug B T2 100.1 98.2 15.3 10.2 T3 102.3 100.2 10.2 6.7 T4 98.1 99.6 8.7 4.6 T5 102.8 99.3 5.8 2.3 T6 99.7 100.2 4.1 2.7
  38. 38. 38383838383838383838383838 Manufacturing Process Dispensing Sifting All other ing#12 mesh Mg. stearate #60 mesh Blending (DCB) All other ing 10 min,16 RPM Lubrication (DCB) Mg. Stearate 5 min,16 RPM Compaction Cycle1Flakes #16 mesh Cycle 2 Flakes #25mesh Blending (DCB) Granules + Extragranular material (# 40 mesh) 10 min,16 RPM Lubrication (DCB) Mg. Stearate #60 mesh 5 min,16 RPM Compression Coating 10 % Opadry Yellow 2.5 % Weight Gain
  39. 39. 39393939393939393939 Process Parameters Compression Film Coating Roller Compacti on Inlet Temperature 54⁰C Exhaust Temperature 40⁰C Bed Temperature 35 - 40⁰C Pan RPM 6 Pump Speed 5 Average weight 320 mg ± 16 mg Thickness 4.50 mm ± 0.3 mm Hardness 120 N ± 10 N Disintegration time NMT 1 min Cycle Roller pressure (Ton) Roller speed (RPM) 1 4.0 3.3 2 0.5 10.0
  40. 40. Stability Studies 40
  41. 41. 41 Two reproducible batches 1 Month & 3 Months 40°C ± 2°C/ 75%RH ± 5% RH & 30°C ± 2°C/65% RH ± 5% RH PVC/PVDC blister ICH Q1A (R2)
  42. 42. 42 Trial 7 Parameters Specifications Initial 40°C/75% RH 30°C/65% RH 1 Month 3 Months 1 Month 3 Months Appearance Yellow colored, oval shaped, film coated tablets - NC NC NC NC DT (secs) About 1 min 53 – 63 60 – 70 59 – 72 59 – 67 52 – 60 Assay % Drug A 90.0% - 110.0% 100.6 100.1 99.9 100.0 98.4 Drug B 97.3 101.2 96.2 99.9 97.9 % Drug release (at 30 min) Drug A NLT 75% in 30 min 93 89 91 92 91 Drug B NLT 80% in 30 min 96 98 97 97 99
  43. 43. 43 Trial 8 Parameters Specifications Initial 40°C/75% RH 30°C/65% RH 1 Month 3 Months 1 Month 3 Months Appearance Yellow colored, oval shaped, film coated tablets - NC NC NC NC DT (secs) About 1 min 51 – 62 62 – 73 63 – 67 58 – 67 62 – 69 Assay % Drug A 90.0% - 110.0% 99.6 97.2 97.6 98.9 97.3 Drug B 100.7 98.2 99.3 100.4 99.6 % Drug release (at 30 min) Drug A NLT 75% in 30 min 90 94 93 91 92 Drug B NLT 80% in 30 min 90 90 90 90 90
  44. 44. 4444 Optimization Trials
  45. 45. 45 Optimization Formula Optimization Quantity of Super Disintegrant Quantity of Lubricant Process Optimization Compaction Roller Pressure Cycle 1 Cycle 2 Blending Blending Time Pre- lubrication Lubrication Compression Hardness
  46. 46. 464646 Current Level Higher Level Lower Level Intragranular 4 % 5 % 3 % Extragranular 2 % 3 % 1 % DT Secs (core tablets) 24 – 30 19 – 23 38 – 45 DT Secs (coated tablets) 59 – 67 49 – 58 77 – 82 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 %DrugReleae Time (min) Drug A T6 Higher level Lower level 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 %DrugRlease Time (min) Drug B T6 Higher level Lower level Optimization Trial 1 Quantity of Super Disintegrant
  47. 47. 474747 Current level Higher level Lower level Intragranular 0.5 % 0.75 % 0.25% Extragranular 0.5 % 0.75 % 0.25 % DT Secs (core tablets) 24 – 30 27 – 32 22 – 27 DT Secs (coated tablets) 59 – 67 54 – 69 58 – 63 Optimization Trial 2 Quantity of Lubricant 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A T6 Higher level Lower level 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug B T6 Higher level Lower level
  48. 48. 484848 Current level Higher level Lower level Roller Pressure 4.0 Ton 6.0 Ton 2.0 Ton PSD Cumulative % Retained on# 60 mesh 59 67 - Optimization Trial 3 Roller Pressure (Cycle 1) 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A T6 Higher level 0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug B T6 Higher level
  49. 49. 494949 Current level Higher level Lower level Roller Pressure 0.5 Ton 0.8 Ton 0.2 Ton PSD Cumulative % Retained on# 60 mesh 61 63 59 Optimization Trial 4 Roller Pressure (Cycle 2) 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A T6 Higher level Lower level 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug B T6 Higher level Lower level
  50. 50. 505050 TL TC TR ML MC MR BL BC BR Sampling Positions Optimization Trial 5 Pre-lubrication blending time Current level Higher level Lower level Blending Time 10 min 13 min 7 min Blend uniformity (Drug A) Mean 98.18 95.74 93.97 Relative standard deviation 2.2% 1.9% 4.34%
  51. 51. 515151 Optimization Trial 6 Lubrication blending time Current level Higher level Lower level Blending Time 10 min 13 min 7 min Bulk density 0.5 0.5 0.512 Tapped density 0.652 0.645 0.625 Particle size distribution Cumulative % retained on mesh no. 60 57 61 60 Blend uniformity (Drug A) Mean 99.18 94.74 96.97 Relative standard deviation 1.5% 2.7% 3.0%
  52. 52. 525252 Current level Higher level Lower level Hardness 120 ± 10 N 150 ± 10 N 90 ± 10 N DT Secs (core tablets) 24 – 30 41 – 52 20 – 25 DT Secs (coated tablets) 59 – 67 77 – 83 45 – 50 Friability % 0.02 0.01 0.18 Optimization Trial 7 Hardness 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug A T6 Higher level Lower level 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 %DrugRelease Time (min) Drug B T6 Higher level Lower level
  53. 53. 535353 The compatibility studies showed that the excipients used in the formulation have no interaction with the drug. The tablets of drug A and drug B were developed successfully. Dissolution profile was found to be almost similar to the reference product. The finalized batch was found to be stable during stability studies. Optimization trials were carried out successfully Future Scope Pilot plant studies Rework if necessary Development of different strength with the same drugs. Conclusion
  54. 54. 54 • S. B. Jadhav, Vaishali Kadam and Vishal G. Rathod, Immediate Release Drug Delivery System: A Review, World Journal of Pharmacy and Pharmaceutical Sciences, Pg. No. 545 – 558, 3(6), 2014. • Kishor Salunke, Kiran Wale, Ishwar Gundecha, Mahesh Balsane, Priya Pande and Snehal Hase, Immediate Drug Release Dosage Form: A Review, American Journal of Pharmatech Research, Pg. No. 190 – 212, 4(1), 2014. • Shailesh K. Singh and Venkatesh Naini, Dosage Forms: Non-Parenterals, Encyclopedia of Pharmaceutical Technology, Informa Healthcare USA, Pg. No. 988 – 1000, 3rd Edition, Vol. 2, 2007. • Gilbert S. Banker and Neil R. Anderson, Chapter 11 – Tablets, Section III – Pharmaceutical Dosage forms, The Theory and Practice of Industrial Pharmacy, Lea and Febiger, Pg. No. 293 – 345, 3rd Edition, 1987. • Larry L. Augsburger, Albert W. Brzeczko, Umang Shah and Huijeong Ashley Hahm, Super Disintegrants: Characterization and Function, Encyclopedia of Pharmaceutical Technology, Informa Healthcare USA, Pg. No. 3553 – 3566, 3rd Edition, Vol. 6, 2007. • Larry L. Augsburger and Mark J. Zellhofer, Tablet Formulation, Encyclopedia of Pharmaceutical Technology, Informa Healthcare USA, Pg. No. 3641 – 3651, 3rd Edition, Vol. 6, 2007. • Norman Anthony Armstrong, Tablet Manufacture, Encyclopedia of Pharmaceutical Technology, Informa Healthcare USA, Pg. No. 3653 – 3671, 3rd Edition, Vol. 6, 2007. • R. W. Miller, Roller Compaction Technology, Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Pg. No. 99 – 150, Vol. 81, 1997. References
  55. 55. • James A. Seitz, Shashi P. Mehta and James L. Yeager, Chapter 12 – Tablet Coating, Section III – Pharmaceutical Dosage forms, The Theory and Practice of Industrial Pharmacy, Lea and Febiger, Pg. No. 346, 3rd Edition, 1987. • Linda A. Felton, Film Coating of Oral Solid Dosage Forms, Encyclopedia of Pharmaceutical Technology, Informa Healthcare USA, Pg. No. 1729 – 1734, 3rd Edition, Vol. 3, 2007. • K. D. Tripathi, Chapter 40 Antihypertensive Drugs, Essentials of Medical Pharmacology, Jaypee Brothers Medical Publishers Pvt. Ltd., Pg. No. 539 – 554, 6th Edition, 2010. • Harsh Mohan, Chapter 20 The Kidneys and Lower Urinary Tract, Textbook of Pathology, Jaypee Brothers Medical Publishers Pvt. Ltd., Pg. No. 708 – 711, 5th Edition, 2006. • Suzanne Oparil, M. Amin Zaman, and David A. Calhoun, Pathogenesis of Hypertension, Annals of Internal Medicine, Pg. No. 761 – 776, 139, 2003. • Section 2 Hypertension: The Basic Fact, A Global Brief on Hypertension, World Health Organization, Pg. No. 16 – 19, 2013. • Alberto F. Rubio-Guerra, David Castro-Serna, Cesar I. Elizalde Barrera and Luz M. Ramos-Brizuela, Current Concepts in Combination Therapy for The Treatment of Hypertension: Combined Calcium Channel Blockers and RAAS Inhibitors, Integrated Blood Pressure Control, Pg. No. 55 – 62, 2, 2009. • Xinhuan Wan, Panqin Ma and Xiangrong Zhang, A Promising Choice in Hypertension Treatment: Fixed-dose Combinations, Asian Journal of Pharmaceutical Sciences, Pg.No. 1 – 7, 9, 2014. 55
  56. 56. 56 Acknowledgements Almighty God My Family Dr. Milind J. Bhitre Vidya & Pradnya
  57. 57. 57

×