List of Symbols and Abbreviations LIST OF SYMBOLS AND ABBREVIATIONS λ max : Absorption Maxima AZT : Azithromycin Dihydrate ANOVA : Analysis of Variance BI : Bleeding Index CBL : Carbopol cm : Centimeter cps : Centipoises CAL : Clinical Attachment Level CD4 : Cluster Differenciation 4 Conc. : Concentration 60 Co : Cobalt 60 o C : Degree Centigrade F : Degree Farenheit DNA : Deoxyribose Nucleic Acid DSC : Differential Scanning Calorimetry DMF : Dimethyl Formamide DDS : Drug Delivery System eg : Example FT-IR : Fourier Transform Infrared Spectroscopy FDA : Food and Drug Administration GI : Gastro Intestinal GIT : Gastro Intestinal Tract GP : Glycerophosphate GI : Gingival Index g : Gram/s g/cm 3 : Gram per cubic centimeter h : Hour/s HEC : Hydroxy Ethyl Cellulose HPMC : Hydroxy Propyl Methyl Cellulose IM : Intra Muscular IV : Intra Venous Kg : Kilogram I
List of Symbols and Abbreviations KGray : Kilo Gray lt : Litre LCST : Lower Critical Solution Temperature LVET : Low Volume Eye Test µg : Microgram μm : Micrometer mg : Milligram ml : Milliliter min : Minutes MTX : Methotrexate Sodium M : Molarity nm : Nano Meter % : Percent PF-127 : Pluronic F-127 PF-68 : Pluronic F-68 PI : Plaque Index PCL : Polycarbophil PEO : Poly Ethylene Oxide PPO : Poly Propylene Oxide PPD : Probing Pocket Depth RH : Relative Humidity RA : Rheumatoid Arthritis RNA : Ribose Nucleic Acid rpm : Rotations per minute SEM : Scanning Electron Microscopy sec : Seconds S.D. : Standard Deviation SC : Subcutaneous UV : Ultra Violet UCST : Upper Critical Solution Temperature w/v : Weight/volume WHO : World Health Organization yr : Year/s II
LIST OF TABLES List of Tables Sl. Table Title of the Table Page 1 3.01 LCSTs of several typical thermosensitive polymers 15 2 3.02 Therapeutic uses, dosage and administration of Methotrexate 3 3.03 Patents related to in situ 78 4 4.01 5 4.02 6 4.03 7 4.04 8 4.05 9 4.06 Standard plot data of Azithromycin dihydrate in 0.1 N HCl solution Standard plot data of Pilocarpine hydrochloride in simulated lachrymal fluid Standard plot data of Methotrexate in ph 7.4 phosphate buffer Standard plot data of Losartan potassium in ph 1.2 hydrochloric acid buffer Formulation chart of Azithromycin dihydrate in situ Formulation chart of pilocarpine hydrochloride in situ 10 4.07 Formulation chart of Methotrexate sodium in situ 95 11 4.08 Formulation chart of Losartan potassium floating in situ 12 4.09 Parameters for diffusion study Static method 106 13 4.10 Parameters for diffusion study Dynamic method 107 14 4.11 Criteria for clinical parameters and their ratings 114 15 4.12 Ocular parameters and their scorings - Draize Test 117 16 5.01 17 5.02 18 5.03 19 5.04 FT-IR spectral data of azithromycin dihydrate and in situ gel A8 Characteristics of prepared Azithromycin dihydrate in situ In vitro release data of Azithromycin dihydrate in situ Model fitting data for prepared Azithromycin in situ III 59 86 88 90 92 93 94 96 124 130 134 137
Sl. List of Tables Table Title of the Table Page Results of clinical parameters studied for 20 5.05 21 5.06 22 6.01 23 6.02 24 6.03 25 6.04 26 6.05 27 6.06 28 6.07 29 7.01 30 7.02 Azithromycin dihydrate in situ in human patients with chronic periodontitis Stability study data of optimized Azithromycin dihydrate in situ gel (A8) FT-IR spectral data of Pilocarpine hydrochloride and in situ gel P5 Characteristics of prepared Pilocarpine hydrochloride in situ ph & observations during Isotonicity test (Pilocarpine in situ ) In vitro release data of Pilocarpine hydrochloride in situ Model fitting data for prepared Pilocarpine hydrochloride in situ Scoring of P5 for various ocular parameters during ocular irritation study Stability study data of Pilocarpine hydrochloride in situ gel (P5) FT-IR spectral data of methotrexate pure drug and in situ gel M4 Gelation temperature of Methotrexate sodium in situ 31 7.03 Gelation time of Methotrexate sodium in situ 183 32 7.04 Drug content values for Methotrexate sodium in situ 140 144 150 155 157 161 164 166 171 177 181 184 33 7.05 Observed viscosity values for Methotrexate sodium in situ 187 34 7.06 Syringeability time for Methotrexate in situ 189 35 7.07 In vitro drug diffusion data of Methotrexate sodium in situ by Static Method (M2-M7) 191 IV
List of Tables Sl. Table Title of the Table Page In vitro drug diffusion data of Methotrexate sodium in 36 7.08 192 situ by Static Method (M8-M13) 37 7.09 38 7.10 39 7.11 40 7.12 41 7.13 In vitro drug diffusion data of Methotrexate sodium in situ by Dynamic Method (M2-M7) In vitro drug diffusion data of Methotrexate sodium in situ by Dynamic Method (M8-M13) In vitro diffusion data of Methotrexate sodium in situ (static & dynamic) Calculated t & tabulated t values of Methotrexate sodium in situ Data obtained from Peppas model fitting for Methotrexate in situ 42 7.14 Stability data of Methotrexate in situ 207 43 8.01 Measured ph values of Losartan potassium in situ 210 44 8.02 45 8.03 46 8.04 47 8.05 48 8.06 49 8.07 50 8.08 FT-IR spectral data of pure Losartan potassium and formulation L4 DSC thermograms data of pure Losartan potassium and Formulation L4 Characteristics of prepared Losartan potassium floating in situ Characteristics of prepared Losartan potassium floating in situ In vitro release data of Losartan potassium from floating in situ (L1 to L6) In vitro release data of Losartan potassium from floating in situ (L7 to L12) Data of various parameters of model fitting for in vitro release of Losartan potassium from in situ 51 8.09 Stability data of Losartan potassium in situ 233 196 197 202 204 206 211 213 222 224 226 226 231 V
List of Figures Sl. Figure 1 3.01 2 3.02 3 3.03 4 3.04 5 3.05 6 3.06 7 3.07 8 3.08 9 3.09 10 3.10 11 3.11 12 3.12 13 3.13 LIST OF FIGURES Title of the Figure Schematic illustration showing the different types of responses of intelligent polymer systems to environmental stimuli. Schematic representation of sol-to-gel transition in stimuli-sensitive polymers Mechanism of in situ physical gelation driven by hydrophobic interactions Tissue locations applicable for in situ gel-based drug delivery systems Schematic of relative ionic hydrogel swelling as a function of ph Schematic representation of glucose-sensitive swelling changes in a poly(gema) Con A hydrogel Schematic representation of antigen responsive swelling changes in a Antibody immobilized polymer chain Drug concentration at site of therapeutic action after delivery as conventional injection and as a temporal controlled release system Drug delivery from an ideal distribution controlled release system. Schematic representation of normal tooth structure and periodontal pocket The plaque-bacteria association with tooth surface and periodontal tissues Schematic localization of an intragastric floating system in the stomach Picturisation of various gastro retentive formulations location in the Stomach 14 4.01 UV Spectra of Azithromycin dihydrate in 0.1 N HCl 85 15 4.02 Standard plot of Azithromycin dihydrate in 0.1N HCl solution VI Page 13 13 15 17 18 21 22 25 26 33 33 47 48 86
Sl. Figure 16 4.03 17 4.04 18 4.05 19 4.06 20 4.07 21 4.08 Title of the Figure List of Figures UV spectrum of Pilocarpine Hydrochloride in simulated lachrymal fluid Standard Graph of Pilocarpine Hydrochloride in simulated lachrymal fluid UV spectrum of Methotrexate sodium in ph 7.4 phosphate buffer Standard plot of Methotrexate Sodium in ph 7.4 phosphate buffer UV spectrum of Losartan Potassium in ph 1.2 hydrochloric acid buffer Standard plot of Losartan potassium in ph 1.2 hydrochloric acid buffer VII Page 22 4.09 Apparatus for testing syringeability time 104 23 4.10 Apparatus for diffusion testing by static method 107 24 4.11 25 4.12 26 5.01 27 5.02 28 5.03 29 5.04 30 5.05 31 5.06 32 5.07 Placement of Azithromycin dihydrate in situ gel in periodontal pocket Measurement of pocket depth (Metallic wire of acrylic template is taken as reference) Sterility test for aerobic bacteria in nutrient Agar media A = Control, B = Test Sterility test for aerobic bacteria in nutrient broth media A = Control, B = Test Sterility test for anaerobic bacteria in fluid thioglycollate media A = Control, B = Test FT-IR spectra of Azithromycin dihydrate and in situ gel A8 Viscosity of formulations A4 and A8 as a function of temperature Sigma plot of viscosity, gelation temperature and syringeability time In vitro drug release profile of Azithromycin dihydrate from in situ (A1-A4) 87 88 89 90 91 92 115 115 123 123 123 125 129 131 135
Sl. Figure 33 5.08 Title of the Figure List of Figures In vitro drug release profile of Azithromycin dihydrate from in situ (A5-A8) VIII Page 34 5.09 Periodontal pack given after placement of in situ gel 141 35 5.10 36 5.11 37 5.12 38 5.13 39 5.14 40 5.15 41 6.01 42 6.02 43 6.03 Baseline measurement of pocket depth at test site (Group A) Baseline measurement of pocket depth at control site (Group B) Measurement of pocket depth after 3 months at test site (Group A) Measurement of pocket depth after 3 months at test site (Group B) Drug content in Azithromycin dihydrate in situ when stored at 5 ± 3 C for 12 months Drug content in Azithromycin dihydrate in situ when stored at 25 ± 2 C & 60 ± 5 % RH for 6 months Sterility test for aerobic and anaerobic bacteria in fluid thioglycollate media. A = Test, B = Control, C= Gram ve control & D = Gram +ve bacteria control Sterility test for fungi in soybean casein digest media. A = Control, B = Test, C = Fungi control FT-IR spectra of Pilocarpine hydrochloride and in situ gel P5 44 6.04 Blood cells with marketed product [Pilocar Drops] 158 45 6.05 Blood cells with Pilocarpine hydrochloride in situ 158 46 6.06 47 6.07 In vitro drug release profile of Pilocarpine hydrochloride from in situ (P1-P3) In vitro drug release profile of Pilocarpine hydrochloride from in situ (P4-P6) 48 6.08 Rabbits used for ocular irritation studies 167 49 6.09 rmal rabbit eye (Before instillation) 167 50 6.10 Instillation of Pilocarpine in situ gel at test site (right eye) 135 141 142 142 143 145 145 149 149 151 162 162 168
List of Figures Sl. Figure Title of the Figure Page 51 6.11 Instillation of normal saline at control site (left eye) 168 52 6.12 53 6.13 54 6.14 55 6.15 56 6.16 Observation of eye after instillation of Pilocarpine in situ gel Pilocarpine in situ gel retained at the test site after 6 hours Pilocarpine in situ gel retained at the test site after 12 hours %Drug content in Pilocarpine hydrochloride in situ when stored at 5 ± 3 C for 12months % Drug content in Pilocarpine hydrochloride in situ when stored at 25 ± 2 C & 60 ± 5 % RH for 6 months 57 7.01 Sterility test for aerobic bacteria in Nutrient broth media 176 58 7.02 59 7.03 60 7.04 Sterility test for anaerobic bacteria in fluid thioglycollate media FT-IR spectra of Methotrexate pure drug and in situ gel M4 Gelation temperature of Methotrexate sodium in situ 61 7.05 Gelation time of Methotrexate sodium in situ 183 169 169 170 172 172 176 178 181 62 7.06 Percentage drug content in Methotrexate sodium in situ 185 63 7.07 Viscosity profile of Methotrexate sodium in situ 188 64 7.08 Syringeability time for Methotrexate sodium in situ 190 65 7.09 66 7.10 67 7.11 68 7.12 situ by static method (M2-M4) situ by static method (M5-M7) situ by static method (M8-M10) situ by static method (M9-M13) 193 193 194 194 IX
List of Figures Sl. Figure 69 7.13 70 7.14 71 7.15 72 7.16 73 7.17 74 7.18 75 7.19 76 8.01 77 8.02 78 8.03 79 8.04 80 8.05 81 8.06 82 8.07 83 8.08 84 8.09 Title of the Figure In vitro drug diffusion data of Methotrexate sodium in situ by dynamic method (M2-M4) situ by dynamic method (M5-M7) situ by dynamic method (M8-M10) situ by dynamic method (M11-M13) In vitro diffusion of Methotrexate sodium in situ by static and dynamic methods % Drug content in Methotrexate sodium in situ when stored at 5 ± 3 C for 12 months % Drug content in Methotrexate sodium in situ when stored at 25 ± 2 C & 60 ± 5 % RH for 6 months FT-IR spectra of pure Losartan potassium and formulation L4 DSC thermograms of pure Losartan potassium and Fomrulation L4 Effect of gellan gum on gelation time & floating lag time Effect of HPMC on gelation time & floating Lag time Effect of calcium carbonate on gelation time & floating lag time Photograph showing the appearance of gellan gel (L4) formed in ph 1.2 In vitro drug release profile from Losartan potassium in situ (L1-L4) In vitro drug release profile from Losartan potassium in situ (L5-L8) In vitro drug release profile from Losartan potassium in situ (L9-L12) Page 198 198 199 199 202 208 208 212 213 217 218 220 221 227 227 228 X
List of Figures Sl. Figure 85 8.10 86 8.11 87 8.12 Title of the Figure % Drug content in Losartan potassium in situ when stored at 25±2 C/60±5% RH for 12 months % Drug content in Losartan potassium in situ when stored at 30±2 C/65 ± 5 % RH for 12 months % Drug content in Losartan potassium in situ when stored at 40±2 C/75 ± 5 % RH for 6 months Page 233 234 234 XI
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