CONTENTS CHAPTER-1 1.1.3 Role of leukotrienes in asthma...

CONTENTS

CHAPTER-1Introduction Page No1.1 1.1 Bronchial Asthma 1

1.1.1 Patho physiology of Asthma 1

1.1.2 Asthma types 2

1.1.3 Role of leukotrienes in asthma pathophysiology 2

1.2 Role of inclusion complexes in orally disintegrating tablets 2

1.2.1 Advantages of Inclusion complexes 3

1.2.2 Mechanisms involved in the increased dissolution

rates of Inclusion complexes

4

1.2.3 Carriers for Inclusion complexes 4

1.2.4 Ideal requirements of the carrier 4

1.3 Taste abatement by ion exchange resins 4

1.3.1 Factor affecting Resinate Performance 5

1.3.2 Properties of ion exchange resin 5

1.3.3 Applications of Ion Exchange Resins 5

1.4 Orally disintegrating drug delivery System 5

1.4.1 Advantages of orally disintegrating drug delivery

system

6

1.4.2 Limitations 6

1.4.3 Unsuitable Drug Characteristics 6

1.4.4 Role of superdisintegrants in orally disintegrating

tablets

7

1.4.5 Direct Compression Technique in orally disintegrating

Tablets

7

1.4.6 Excipients used in ODT formulations 7

1.4.6.1 Bulking materials 7

1.4.6.2 Emulsifying Agents 8

1.4.6.3 Superdisintegrants 8

1.4.6.4 Binders and Adhesives 8

1.4.6.5 Lubricants 8

1.4.6.6 Flavors and Sweeteners 9

1.4.7 Approaches for orally disintegrating tablets 9

1.5. Chronobiology and Chronotherapeutics 9

1.5.1 Chronopathology 10

1.5.2 Chronopharmacology 10

1.5.3 Chronokinetics 11

1.5.4 Chronodynamics 11

1.5.5 Pulsatile drug delivery 11

1.5.6 Conditions that demand PDDS 11

1.5.7 Various approaches of PDDS 12

1.5.8 Press coated pulsatile drug delivery 12

1.5.9 Role of hydrophyllic and hydrophobic polymers in

press coated compartment of PCPT

13

CHAPTER-2LITERATURE SURVEY

2.1 Literature review 15-19

2.2 Drug profiles

2.2.1 Drug profile of Montelukast sodium 20

2.2.2 Drug profile of Zafirlukast 21

2.2.3 Drug profile of Levocetirizine Dihydrochloride 22

2.3 Excipients Profile 23-42

CHAPTER-3THEORETICAL ANALYSIS

3.1 Taste masking by formation of inclusion complexes 43

3.1.1 Cyclodextrin complexation 43

3.1.2 Benefits after complexation 44

3.2 Ion exchange resin 44

3.2.1 Drug release from ion exchange resin depends upon

two factors

45

3.2.2 Resinate Preparation and Evaluation 46

3.3 Role of inclusion complexes in orally disintegrating tablets 47

3.4 Role of superdisintegrants in orally disintegrating tablets 47

3.5 Role of effervescent agents in orally disintegrating tablets 47

3.5.1 Mechanism of the penetration enhancement 48

3.6 Direct compression technique in orally disintegrating

tablets

49

3.7 Evaluation of orally disintegrating tablets 49

3.7.1 Crushing Strength 49

3.7.2 Friability of tablet 49

3.7.3 Wetting time 50

3.7.4 Modified disintegration test 50

3.7.5 Moisture uptake studies 51

3.7.6 Dissolution test 51

3.8 Similarity Factor 52

3.8.1 Definition of similarity factor 52

3.8.2 Equation for calculation of similarity factor 52

3.9 Dissolution Efficiency 53

3.10 Assessment of Pharmacokinetic Parameters Following

Extravascular Administration

54

3.10.1 Peak plasma concentration (Cmax) 54

3.10.2 Peak time (Tmax) 54

3.10.3 Area under curve(AUC) 55

3.10.4 Elimination rate constant 55

3.10.5 Elimination Half- life 56

3.10.6 Absorption rate constant 56

3.10.6.1 The Method of Residuals 56

CHAPTER - 4EXPERIMENTAL INVESTIGATIONS

4.1 Materials and methods

list of materials’ used

58

4.2 List of Instruments Used 59

4.3. Development of Analytical Methods 60

4.3. 1 Analytical method for Estimation of Montelukast

sodium

60

4.3.2 Analytical method for Estimation of Levocetirizine

dihydrochloride

61

4.3.3 Analytical method for Estimation of Zafirlukast 62

4.4 Solubility studies 62

4.4.1 Solubility studies of Montelukast sodium 62

4.4.2 Solubility studies of Levocetrizine Dihydrochloride 63

4.4.3 Solubility studies of Zafirlukast 64

4.5 Preformulation studies 64

4.6 Drug - Excipient interaction study 65

4.7 Taste Masking of Montelukast sodium by Inclusion Complex

Array with Beta-Cyclodextrin

65

4.7.1 Preparation of Inclusion Complexes of Montelukast

sodium with β cyclodextrin using Kneaded system

66

4.7.2 Compatibility analysis 66

4.7.3 Determination of drug content in the complexes 67

4.7.4 In vitro drug release 68

4.7.5 Taste evaluation of Montelukast sodium- β-

cyclodextrin complexes

68

4.8 Preparation and Evaluation of Taste Masked complexes of

Levocetirizine Di Hydrochloride - Resin (Kyron - T114)

69

4.8.1 Preparation of Levocetirizine-resin complexes 69

4.8.2 Selection of Resin 69

4.8.3 Effect of Resin Activation 70

4.8.4 Effect of Levocetirizine : Kyron T - 114 ratio on drug

loading

70

4.8.5 Effect of volume of Distilled water on drug loading 71

4.8.6 Effect of Kyron T-114 pH on Drug loading 71

4.8.7 Effect of Temperature on Drug loading 72

4.8.8 Effect of soaking time of Resin on drug loading 72

4.8.9 Effect of Stirring time on drug loading 72

4.8.10 Molecular properties of drug resin complex 73

4.8.11 Estimation of drug content from DRC in 0.1N HCl 73

4.8.12 In vitro release of Levocetrizine from the DRC in 0.1N

HCl

73

4.8.13 Taste evaluation 74

4.9 Preparation and Evaluation of Inclusion Complexes

of Zafirlukast with γ- cyclodextrin

74

4.9.1 Phase solubility studies 74

4.9.2 Preparation of Inclusion complex of Zafirlukast with γ-

cyclodextrin

75

4.9.3 Drug content analysis 76

4.9.4 In vitro dissolution studies for inclusion complexes 76


4.10. Development of Orally Disintegrating Tablets

of Montelukast sodium

77

4.10.1. Optimization of diluents and superdisintegrants 77

4.10.2. Formulation of Orally Disintegrating Tablets by

direct compression

79

4.10.3. Evaluation of Orally Disintegrating Tablets 79

4.10.3.1 In-Vitro Dissolution Testing 79

4.10.3.2 In-Vitro Dissolution kinetic parameters for Orally

Disintegrating Tablets of Montelukast sodium

80

4.10.4 Comparative study of Final formulation with market

product

80

4.10.4.1 One way – ANOVA 80

4.10.5 Stability Studies 81

4.11. Development of Orally Disintegrating Tablets of Montelukast

plus Levocetirizine

81

4.11.1 Formulation of Orally Disintegrating Tablets of

Montelukast sodium plus Levocetrizine

82

4.11.2. Evaluation of Orally Disintegrating Tablets 82

4.11.2.2 In vitro disintegration time 82

4.11.2.3 Wetting time 83

4.11.3 Dissolution rate studies 83

4.11.4 In-Vitro Dissolution kinetic parameters for Orally

Disintegrating Tablets of Montelukast sodium with

Levocetrizine

83


product

84

4.11.5.1 Student t- test (Unpaired) 84

4.11.5.2 Fit Factor Test (f1andf2) 85

4.11.6. Stability Studies 85

4.12 Preparation and Evaluation of Montelukast sodium

Chewable Tablets by Different Techniques

85

4.12.1 Manufacturing methods 85-87

4.12.2 Evaluation of Tablets 88


4.12.4 Taste Evaluation 89

4.12.5 Comparison of dissolution profile of final with market

product

89

4.12.6. In–vitro Dissolution kinetic parameters for all

chewable Tablet formulations of Montelukast sodium

89

4.12.7. Fit factor test 89

4.12.8 Stability study 90

4.13 Formulation and Evaluation of Orally Disintegrating Tablets

of Zafirlukast

90

4.13.1 Selection and optimization of direct Compressible

diluents

90

4.13.2 Selection and optimization of superdisintegrants 91

4.13.3 Preparation of blends and tablets 91

4.13.4 Evaluation of blend 91

4.13.5 Dissolution studies 92

4.13.6 Optimization of Effervescent agents 93

4.13.7 Preparation of blends and tablets 93

4.13.8 Effect of effervescent agents on dissolution profile of

Orally Disintegrating Tablets of Zafirlukast

93

4.13.9 In– vitro Dissolution kinetic parameters for all Orally

Disintegrating formulations of Zafirlukast

93


product

94

4.13.10.1 Student t- test (Unpaired): 94

4.13.10.2 Fit Factor Test (f1andf2) 94


4.14 Development of core tablets of Zafirlukast for Pulsatile drug

delivery

95

4.14.1 Development of Press coated tablets for Pulsatile

drug delivery

95

4.14.1.2 Viscosity measurement of selected polymers 95

4.14.1.3 Formulation of barrier layer 95

4.14.2 Preparation of press-coated tablets 96

4.14.3 Evaluation of press-coated tablets 97

4.14.4 Swelling index 97

4.14.5 Dissolution rate studies 97

4.14.6 Stability Studies 98

4.15 In-vivo Studies 99

4.15.1 In-vivo pharmacokinetic and bioavailability evaluation

of selected orally disintegrating tablets of Montelukast

sodium

99

4.15.2 Experimental design 99

4.15.3 In- vivo study protocol 100

4.15.4 Determination of various pharmacokinetic

parameters

101

4.15.4.1 Determination of Cmax and Tmax 101

4.15.4.2 Determination of Elimination rate constant (Kel) and

biological half-life (t1/2)

101

4.15.4.3 Determination of residual concentration (Cr) and

rate of absorption (Ka) with method of residuals

102

4.15.4.4 Estimation of area under curve (AUC) 102

4.15.5 Chromatographic conditions for Montelukast 103

4.15.6 In-vivo pharmacokinetic and bioavailability evaluation

of selected Zafirlukast formulations

105

4.15.7 Experimental design 106

4.15.8 In-vivo study protocol 106

4.15.9 Determination of various pharmacokinetic

parameters

108

4.15.9.1 Determination of Cmax and Tmax108

4.15.9.2 Determination of Elimination rate constant (Kel)

and biological half-life (t1/2)

108

4.15.9.3 Determination of residual concentration (Cr) and 108

rate of absorption (Ka) with method of residuals

4.15.9.4 Estimation of Area under curve (AUC)109

4.15.10 Chromatographic conditions for Zafirlukast 109

CHAPTER – 5EXPERIMENTAL RESULTS

5.1 Development of Analytical Methods 112

5.1.1 Analytical method for Estimation of Montelukast

sodium

112

5.1.2 Analytical method for Estimation of Levoceterizine

Dihydrochloride

113

5.1.3 Analytical method for Estimation of Zafirlukast 114

5.2 Solubility Studies 115

5.2.1 Solubility Studies of Montelukast sodium 115

5.2.2. Solubility studies of Levocetirizine Dihydrochloride 115

5.2. 3 Solubility studies of Zafirlukast 115


5.3.1 Preformulation studies Montelukast sodium 116

5.3.2 Preformulation studies of Levocetirizine

Dihydrochloride

117

5.3.3 Preformulation studies Zafirlukast 118

5.4 Drug – Excipient interaction study 119-121

5.5 Preparation of Inclusion Complexes of Montelukast sodium

with β Cyclodextrin

121


5.5.2 Determination of drug content in the complexes of

Montelukast sodium with β-CD

123

5.5.3 In-vitro drug release 124

5.5.4 Taste evaluation of Montelukast sodium and β-CD 125

complexes


Levocetirizine Di Hydrochloride – Resin (Kyron - T114)

complexes

126

5.6.1 Selection of Resin 126

5.6.2 Effect of Resin Activation 126

5.6.3 Effect of Levocetirizine - Kyron T - 114 ratio on

loading

126

5.6.4 Effect of volume of Distilled water on drug loading 127

5.6.5 Effect of Kyron T-114 pH on Drug loading 127

5.6.6 Effect of Temperature on Drug loading 128

5.6.7 Effect of soaking time of Resin on drug loading 128

5.6.8 Effect of Stirring time on drug loading 129

5.6.9 Molecular properties of drug resin complex

Characterization of Levocetirizine-Kyron T114 complex

130

5.6.10 Estimation of drug content from DRC in 0.1N HCl 131

5.6.11 In-vitro dissolution study of Drug release from DRC

In vitro release of Levocetirizine from the Drug-Resin

complex in 0.1N HCl

131

5.6.12 Taste evaluation 132

5.7 Preparation and Evaluation Inclusion Complexes

of Zafirlukast with γ- cyclodextrin

132

5.7.1 Phase solubility studies 132

5.7.2 Preparation of Inclusion complex of Zafirlukast with

γ – Cyclodextrin and Drug content analysis

133

5.7.3 In vitro dissolution studies 133


5.8 Development of Orally Disintegrating Tablets of

Montelukast sodium

135

5.8.1. Optimization of Diluents 135

5.8.2. Optimization of Superdisintegrants 136

5.8.3. Evaluation of Orally Disintegrating Tablets of

Montelukast sodium

137

5.8.4. Dissolution profile of Orally Disintegrating Tablets of

Montelukast sodium

138

5.8.5. In –vitro Dissolution kinetic parameters for all Orally

Disintegrating Tablet formulations of Montelukast sodium

139


product

141

5.8.6.1 ANOVA for Disintegration Time 141

5.8.6.2 Fit factor test (f1 and f2) 144



Montelukast plus Levocetrizine

146

5.9.1 Evaluation of Orally Disintegrating Tablets of


146


Montelukast sodium with Levocetrizine

147


Disintegrating Tablet formulations of Montelukast sodium

with Levocetrizine

149


product

149

5.9.4.1 Student t- test for Disintegration Time 152



5.10 Formulation and Evaluation of Montelukast sodium


154

5.10 .1 Evaluation of Tablets 154


5.10.3 Taste Evaluation 156

5.10.4 Comparison of Dissolution Profiles of Montelukast

chewable tablet Final with Marketed formulation

156

5.10.5. In –vitro Dissolution kinetic parameters of

Montelukast chewable tablets

157

5.10.6. Fit factor test (f1 and f2) 159

5.10.7. Stability study 160


of Zafirlukast

160

5.11.1 Selection and optimization of direct compressible

diluents

160

5.11.2 Selection and optimization of superdisintegrants 161


Zafirlukast

161


Disintegrating Tablet formulations of Zafirlukast

162

5.11 .5 Selection and optimization of Effervescent agents 163

5.11.6. Effect of effervescent agents on dissolution profile of

Orally Disintegrating Tablets of Zafirlukast

164

5.11.7. Effect of effervescent agents on In –vitro Dissolution

kinetic parameters for all Orally Disintegrating formulations

of Zafirlukast

165


product

169

5.11.8.1 Comparision of dissolution profile of Final

formulation (E9) with control and Marketed product

(Zuvair)

169

5.11.8.2 Student t – test for Disintegration Time 170


5.11.9 Stability studies for finalized formulation Orally

Disintegrating Tablets of Zafirlukast

171

5.12 Development and Optimization of core and press coated tablets of

Zafirlukast

172

5.12.1. Evaluation of directly compressible blends of barrier

layer and press coated tablets of Zafirlukast

172

5.12.2. Dissolution profiles of press coated tablets 173

5.12.3. First order plots of press coated tablets 179

5.12.4. In-vitro release kinetic parameters for press coated

tablets

180

5.13 In –Vivo Studies 182

5.13.1 Plasma concentrations of Montelukast sodium 182

5.13.2 Determination of Residual concentrations of

Montelukast sodium

184

5.13.3 Estimation of Pharmacokinetic parameters of

Montelukast sodium

188

5.13.4 Plasma concentrations of Zafirlukast 188

5.13.5 Determination of Residual concentrations of

Zafirlukast

190

5.13.6 Estimation of Pharmacokinetic parameters of

Zafirlukast

194

CHAPTER - 6DISCUSSION OF RESULTS

6.1 Development of Analytical Methods 195

6.2 Solubility Studies 196


6.4. Drug – Excipient Compatibility study 197

6.5 Determination of drug content in the complexes of

Montelukast sodium with β-CD

198

6.6 In-vitro drug release 198

6.7 Taste evaluation of Montelukast sodium and β-CD

complexes

199


Levocetirizine Di Hydrochloride – Resin (Kyron - T114)

199-202

6.9 Preparation and Evaluation Inclusion Complexes of

Zafirlukast with γ- cyclodextrin

203-204

6.10. Development of Orally Disintegrating Tablets of

Montelukast sodium

205-208



208-209

6.12 Formulation and Evaluation of Montelukast sodium


210-211


of Zafirlukast

212-215

6.14 Development and Optimization of core and press coated

tablets of Zafirlukast for pulsatile drug delivery

216-218

6.15 In –Vivo Studies 218-220

CHAPTER - 7

SUMMARY 221-229

CONCLUSION 230-240

RECOMMENDATIONS 241-243

CHAPTER – 8

BIBLIOGRAPHY 244-253

CHAPTER –9

APPENDICES

9.1 Publications of Research Scholar 254

9.2 Presentations of Research Scholar 254

CONTENTS CHAPTER-1 1.1.3 Role of leukotrienes in asthma...

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