Cai Thien Do Tan Bang Hptr1

Copyright

by

Dave Alan Miller

2007

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The Dissertation Committee for Dave Alan Miller Certifies that this is the approved

version of the following dissertation:

Improved Oral Absorption of Poorly Water-Soluble Drugs by

Advanced Solid Dispersion Systems

Committee:

James W. McGinity, Co-Supervisor

Robert O. Williams III, Co-Supervisor

Roger T. Bonnecaze

Alan B. Combs

Krishnendu Roy

Robert L. Talbert

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by

Dave Alan Miller, B.S.

Dissertation

Presented to the Faculty of the Graduate School of

The University of Texas at Austin

in Partial Fulfillment

of the Requirements

for the Degree of

Doctor of Philosophy

The University of Texas at Austin

December 2007

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UMI Number: 3291310

32913102008

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Dedication

To Mom, Dad, and Allison

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v

Acknowledgements

I would foremost like to thank my parents, Mark and Janie Miller for their love

and support throughout every stage of my life. My success in life has merely been a

reflection of your success as parents. I would like to give my deepest gratitude to my

girlfriend Allison Earle for providing the love I needed to see me through the past eight

years. You have made countless sacrifices so that I could achieve this success, and for

that I am forever grateful. I must also thank my sister and my nephew, Michelle and

Chase Pina, for all their love and support as well as providing much needed distractions

from the daily stresses of graduate school. I would also like to thank the Earle family for

their love, encouragement, and Sunday night dinners.

To my supervising professors, Drs. James W. McGinity and Robert O. Williams

III, I would like to extend my deepest gratitude for the opportunities you have given me

over the past four years. This has truly been a life enriching experience and I owe most of

that experience to the both of you. I would like to thank Dr. Jason McConville for being a

friend and mentor during my early years in graduate school. I would like to thank Jim

DiNunzio for all of his help over the past few months which has proven essential to the

completion of this dissertation. I would like to thank Wei Yang for the countless hours

she spent helping me with my in vivo studies. I would like to sincerely thank Chris

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vi

Brough, Mike Miller, and Gershon Yaniv for their support of the TKC project and for

taking the time to seriously consider the crazy ideas of a young graduate student.

A heartfelt thank you goes out to all of my friends down in the basement, past and

present, who have all helped and supported me along the way: Shawn Kucera, Dorothea

Sauer, Caroline Dietzsch, Mamoru Fukuda, Troy Purvis, Alan Watts, Justin Tolman,

Loni Coots, Sandra Schilling, Kirk Overhoff, Jason Vaughn, Michal Matteucci, Chris

Young, Weija Zheng, and Prapasri Sinswat. Thank you to the people at PharmaForm who

helped turn a summer internship into a lifelong carrier: John Koleng, Feng Zhang, Pann

Mahaguna, Michael Crowley, Frank Sherwood, Mark Mendoza, and Chris Lively. I

would also like to thank my mentor at Celanese, Jim Wann, for his encouraging words in

a time of despair and his guidance in helping me find a life after Celanese. I would like to

thank the College of Pharmacy Staff for making an overworked graduate student’s life a

little easier: Claudia McClelland, Yolanda Abasta, Mickie Sheppard, Joyce McClendon,

Jay Hamman, Jim Baker, and Steve Littlefield.

Finally, I would like to thank my extended Miller and Standefer families for your

praise and support. To know that I am making you all proud provides me with the

inspiration I need to keep going when I am ready to quit.

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vii



Publication No._____________

Dave Alan Miller, Ph.D.

The University of Texas at Austin, 2007

Supervisors: James W. McGinity and Robert O. Williams III

Current high-throughput molecular screening methods have resulted in a vast

increase in the proportion of new drugs which are poorly water-soluble. Since poor

water-solubility typically precludes efficacy of therapeutic molecules, there is a growing

need for advanced processing and formulational techniques to improve the dissolution

properties of poorly water-soluble drugs.

In Chapter 2, particle engineering and hot-melt extrusion (HME) were utilized to

produce advanced solid dispersion systems that improved the dissolution properties of a

poorly water-soluble drug, itraconazole (ITZ), in acidic media. A subsequent in vivo

study revealed a substantial absorption improvement with these formulations over

crystalline ITZ; however, a pH switch dissolution test indicated limited intestinal

absorption due to ITZ precipitation at neutral pH.

Polymeric carriers that promote supersaturation of ITZ following an acidic to

neural pH switch were investigated in Chapter 2. It was discovered that high molecular

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viii

weight polymers with hydrogen bond donor sites are the optimal stabilizers of ITZ in

neutral pH solution. An in vivo study revealed that stabilization of supersaturated ITZ

following acidic-to-neutral pH transition resulted in substantially improved absorption.

A targeted intestinal delivery system with sustained supersaturation of ITZ in

neutral pH media was developed in Chapter 4. Carbopol® 974P at two different

formulation concentrations was evaluated as a stabilizing additive to a pH-dependant,

enteric release system for ITZ. It was hypothesized that Carbopol® 974P would prolong

ITZ supersaturation in the small intestine thus providing greater absorption with less

variability. An in vitro pH switch dissolution analysis proved the stabilizing effects of the

Carbopol® additive on supersaturated ITZ in neutral pH. In vivo studies demonstrated

that the Carbopol additive provided an additional mechanism for ITZ absorption that

contributed to 5 and 3-fold improvements in absorption over the best performing solid

dispersion formulations from Chapters 2 and 3, respectively.

The final chapter introduced a novel, thermal process for the production of

amorphous solid dispersion systems, known as thermokinetic compounding (TKC). This

process was utilized to produce amorphous compositions of high-melting point drugs in

both thermally stable and temperature sensitive polymers without the need for processing

aids representing a significant advancement to solid dispersion manufacturing.

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Table of Contents

List of Tables ....................................................................................................... xiii

List of Figures ...................................................................................................... xvi

Chapter 1: Solid Dispersion Technologies: Improving Oral Drug Therapies .........1 1.1 Introduction...............................................................................................1

1.1.1 Overview of solid dispersion technologies ...................................3 1.2 Contributions of solid dispersion technologies to oral drug therapies......7

1.2.1 Treatment of cardiovascular disorders..........................................7 1.2.2 Pain management ........................................................................16 1.2.3 Cancer therapy ............................................................................23 1.2.4 HIV treatment .............................................................................28 1.2.5 Anti-biotic treatments .................................................................34 1.2.6 Immunosuppression ....................................................................40 1.2.7 Other drug treatments .................................................................43

1.3 Concluding Remarks...............................................................................46 1.4 References...............................................................................................50 1.5 Dissertation Objectives and Outline .......................................................60

Chapter 2: Hot-Melt Extrusion for Enhanced Delivery of Drug Particles.............64 2.1 Abstract ...................................................................................................64 2.2 Introduction.............................................................................................65 2.3 Materials and Methods............................................................................69

2.3.1 Production of ITZ-PVP and ITZ-HPMC micronized particles..70 2.3.2 Hot-melt extrusion of micronized particles ................................71 2.3.3 Differential scanning calorimetry ...............................................71 2.3.4 X-Ray diffraction ........................................................................72 2.3.5 Scanning electron microscopy ....................................................72 2.3.6 Dissolution testing .....................................................................73 2.3.7 Oral dosing of rats.......................................................................75

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2.3.8 Plasma extraction and chromatographic analysis .......................75 2.3.9 Pharmacokinetic analysis............................................................76

2.4 Results and Discussion ...........................................................................77 2.4.1 Evaluation of micronized particle properties before and after hot-

melt extrusion..............................................................................77 2.4.2 Evaluation of dissolution performance at sink conditions..........81 2.4.3 Evaluation of supersaturation dissolution performance..............82 2.4.4 Evaluation of supersaturation performance with a pH change ...84 2.4.5 Evaluation of in vivo performance .............................................86

2.5 Conclusions.............................................................................................88 2.6 Acknowledgements.................................................................................88 2.7 References...............................................................................................89

Chapter 3: Enhanced In Vivo Absorption of Itraconazole via Stabilization of Supersaturation Following Acidic-to-Neutral pH Transition .......................96 3.1 Abstract ...................................................................................................96 3.2 Introduction.............................................................................................97 3.3 Materials ...............................................................................................101 3.4 Methods.................................................................................................102

3.4.1 Hot-melt Extrusion (HME).......................................................102 3.4.2 Differential Scanning Calorimetry (DSC) ................................103 3.4.3 Dissolution Testing ...................................................................103 3.4.4 In Vivo Studies .........................................................................105 3.4.5 Plasma Extraction and Chromatographic Analysis...................105 3.4.6 Pharmacokinetic Analysis.........................................................106

3.5 Results and Discussion .........................................................................107 3.5.1 Rationale for Polymer Carrier Selection...................................107 3.5.2 DSC Analysis of HME Processed ITZ-Polymer Formulations 110

3.5.2.1 Immediate Release Formulations..................................110 3.5.2.2 Enteric Release Formulations .......................................111

3.5.3 Dissolution Testing with pH Change........................................113 3.5.3.1 Immediate Release Polymers........................................113

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3.5.3.2 Enteric Release Polymers .............................................119 3.5.4 In Vivo Absorption Analysis ....................................................122

3.6 Conclusions...........................................................................................126 3.7 References.............................................................................................128

Chapter 4: Targeted Intestinal Delivery of Supersaturated Itraconazole for Improved In Vivo Absorption .....................................................................................135 4.1 Abstract .................................................................................................135 4.2 Introduction...........................................................................................136 4.3 Materials ...............................................................................................140 4.4 Methods.................................................................................................140

4.4.1 Hot-Melt Extrusion (HME).......................................................140 4.4.2 Differential Scanning Calorimetry (DSC) ................................141 4.4.3 Energy Dispersing X-ray Spectroscopy (EDS).........................142 4.4.4 Dissolution Testing ...................................................................142 4.4.5 In Vivo Studies .........................................................................144 4.4.6 Plasma Extraction and Chromatographic Analysis...................144 4.4.7 Pharmacokinetic Analysis.........................................................145

4.5 Results and discussion ..........................................................................146 4.5.1 DSC Analysis of HME Processed Formulations ......................146 4.5.2 Analysis of Drug Distribution by EDS .....................................149 4.5.3 Dissolution Analysis with pH Switch .......................................150 4.5.4 In Vivo ITZ Absorption Analysis .............................................154

4.6 Conclusions...........................................................................................159 4.7 Acknowledgements...............................................................................160 4.8 References.............................................................................................161

Chapter 5: Thermokinetic Compounding: A Novel Technology for the Production of Pharmaceutical Solid Dispersions...............................................................165 5.1 Abstract .................................................................................................165 5.2 Introduction...........................................................................................166 5.3 Materials ...............................................................................................174 5.4 Methods.................................................................................................174

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5.4.1 Thermokinetic Compounding ...................................................174 5.4.2 HPLC Analysis .........................................................................176 5.4.3 Hot-Melt Extrusion (HME).......................................................176 5.4.4 Differential Scanning Calorimetry (DSC) ................................177 5.4.5 Dissolution Testing ...................................................................178

5.5 Results and discussion ..........................................................................178 5.5.1 Analysis of Drug Degradation in TKC Processed Compositions178 5.5.2 DSC Analysis of TKC Processed Compositions with Thermally

Stable Polymers ........................................................................180

5.5.3 Dissolution Testing of TKC Processed KTZ in Methocel™ E50 and Kollidon® 30 .............................................................................184

5.5.4 Production of Solid Dispersion Systems by TKC with a Thermolabile Polymeric Carrier ...............................................186

5.6 Conclusions...........................................................................................189 5.7 Acknowledgements...............................................................................190 5.8 References.............................................................................................191

Tables...................................................................................................................198

Figures..................................................................................................................213

Appendices...........................................................................................................249 Appendix A: Raw Data from Figures Presented in Chapter 2....................249 Appendix B: Raw Data from Figures Presented in Chapter 3 ....................253 Appendix C: Raw Data from Figures Presented in Chapter 4 ....................256 Appendix D: Raw Data from Figures Presented in Chapter 5....................258

Bibliography ........................................................................................................259

Vita .....................................................................................................................286

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List of Tables

Table 1.1: Mean Pharmacokinetic Parameters and Relative Bioavailabilities

for the Three Formulation Approaches ........................................................198

Table 1.2: Pharmacokinetic parameters of ABT-963 after oral dosing of 50 mg

ABT-963 in capsules and PEG solution in fasted dogs................................199

Table 1.3: Pharmacokinetics Data of the Solid Dispersions and Cyclodextrin

Complexes with Lonidamine (Lon) ...............................................................200

Table 1.4: Pharmacokinetic parameters of CGP 70726 incorporated in

Eudragit L100-55 pH-sensitive particles after oral administration

to dogs; Mean6S.E.M. (n=4) .........................................................................201

Table 1.5: Pharmacokinetic parameters (±S.D.) of itraconazole and

hydroxyitraconazole after oral administration of four different

formulations in healthy humans.....................................................................202

Table 1.6: Pharmacokinetic Parameters of CyA After Oral Administration of

CyA Solid Dispersion and Sandimmun Neoral® to Wistar Rats ..................203

Table 2.1: Area under the supersaturation dissolution curve values for acid,

pH change, and adjusted pH change for the micronized particle

extrudate (MPE) formulations. ......................................................................204

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Table 2.2: Pharmacokinetic parameters calculated using non-compartmental

analysis in Win-Nonlin of rats dosed with micronized particle

extrudate (MPE) compositions and crystalline ITZ.......................................205

Table 3.1: Hot-melt extrusion processing parameters for each investigated

composition....................................................................................................206

Table 3.2: Area Under Dissolution Curve (AUDC) values for the acid phase,

neutral phase and total dissolution test for each composition. Each

composition contains 33% ITZ by weight. ....................................................207

Table 3.3: Pharmacokinetic data from the in vivo absorption study with the

ITZ:Methocel™ E50 and ITZ:EUDRAGIT® L100-55 HME

processed amorphous solid dispersion formulations. ....................................208

Table 4.1: Formulation summary for HME processed ITZ:EUDRAGIT® L

100-55 amorphous solid dispersions with Carbopol® 974P

additives .........................................................................................................209

Table 4.2: Area under the dissolution curve (AUDC) values for the acid phase,

neutral phase and total dissolution test for the EUDRAGIT® L

100-55, 20% Carbopol® 974P, and 40% Carbopol® 974P

formulations ................................................................................................. 210

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Table 4.3: Pharmacokinetic data from the in vivo absorption study with the

20% Carbopol® 974P additive formulation and the 40%

Carbopol® 974P additive formulation......................................................... 211

Table 5.1: Operating parameters of the thermokinetic compounding process

for each processed batch ................................................................................212

Table A.1: Raw data presented in Figure 2.4.................................................................. 249




Table B.1: Raw data presented in Figure 3.4.................................................................. 253



Table C.1: Raw data presented in Figure 4.4.................................................................. 256

Table C.2: Raw data presented in Figure 4.5.................................................................. 257

Table D.1: Raw data presented in Figure 5.5.................................................................. 258

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List of Figures

Figure 1.1: Plasma concentration vs. time curve of FNB after oral

administration of (■) pH-sensitive self-assemblies of PEG-b-

P(nBA17-co-MAA17), (●) Lipidil MicroR and (∆) FNB powder

to fasted Sprague–Dawley rats at a dose of 7.5 mg/kg.

MeanFSEM for n =6. ..................................................................................213

Figure 1.2: Results of the pharmacokinetic study with 18 healthy male subjects.

Comparison of the R103757 100-mg melt extrudate tablet, the

100-mg bead capsule, and the 100mg GTS capsule under (a)

fasting and (b) fed conditions. ....................................................................214

Figure 1.3: Geometric mean ibuprofen plasma concentrations following single

oral administration of a 400-mg ibuprofen extrudate (square),

lysinate (triangle), and regular (diamond) tablet under fed (filled)

and fasted (open) conditions, respectively..................................................215

Figure 1.4: Plasma concentration of ABT-963 following oral administration of

PEG solution and capsule formulations to fasted dogs...............................216

Figure 1.5: In vitro dissolution in 0.1N HCl of (a)physical mixture containing

crystalline ritonavir–PEG at 10:90, and amorphous ritonavir in

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PEG solid dispersions at concentrations of (b) 10%, (c) 20%, and

(d) 30% (w/w). Dissolution was determined by the USP I method

(50 rpm, 378C).The data for20%dispersion is an average of two

runs; others are three runs. ..........................................................................217

Figure 1.6: Mean plasma concentration–time profiles of ritonavir after a single

oral dose to beagle dogs. Ritonavir was administered in (a) the

crystalline form or the amorphous in PEG solid dispersions at

concentrations of (b) 10%, (c) 20%, and (d) 30% (w/w)............................218

Figure 1.7: Dissolution behavior of albendazole from solid dispersions in

media of pH 1.2 - 6.5: , physical mixture; , solid dispersion

with hydroxypropylmethylcellulose and hydroxypropyl

methylcellulose phthalate; , solid dispersion with

hydroxypropyl methylcellulose; , solid dispersion with

hydroxypropyl methylcellulose phthalate...................................................219

Figure 1.8: Mean plasma concentrations of albendazole sulphoxide after oral

administration of physical mixture ( , ) and solid dispersion

( , ) to normal acidity rabbits (A) and to low acidity rabbits (B)

at a dose of 5 mg/kg. Each point represents the mean ± standard

error of results from five rabbits. ................................................................220

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Figure 1.9: Mean griseofulvin plasma concentration-time profile following oral

administration to rats (± S.D., n = 4). ( ) Control; ( ) Spray-

dried; ( ) Spraydried + Poloxamer 407. ...................................................221

Figure 1.10: Blood concentration of tacrolimus after oral administration of

SDF with HPMC to beagle dogs. ( ) SDF of tacrolimus with

HPMC; ( ) tacrolimus crystalline powders. Values are expressed

as the mean with a vertical bar showing S.E. of six animals. Each

dosage form was administered at the dose of 1mg as tacrolimus. ..............222

Figure 1.11: Oral Bioavailability of Danazol in a Mouse Model for the SFL

Composition (Danazol:PVP-K15 1:1) (■), EPAS Composition

(Danazol:PVP-K15 1:1) (♦), Physical Mixture (Danazol:PVP-K15

1:1) (*), and Commercially Available Danazol (▲). .................................223

Figure 2.1: DSC thermograms of (a) ITZ-HPMC micronized particles (b) ITZ-

PVP micronized particles (c) ITZ-HPMC micronized particle

extrudates, (d) ITZ-PVP micronized particle extrudates (e)

extrudate formulation with bulk crystalline ITZ (f) bulk

crystalline ITZ (g) poloxamer 407:PEO (7:3) placebo extrudate.

The samples were heated from 20 to 200 ºC in open aluminum

pans at a heating rate of 10 ºC/min under nitrogen purge...........................224

Figure 2.2: X-ray diffraction patterns of (a) poloxamer 407:PEO (7:3) placebo

extrudate (b) extrudate formulation with crystalline ITZ (c) ITZ-

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HPMC micronized particle extrudates (d) ITZ-PVP micronized

particle extrudates (e) bulk crystalline ITZ (f) ITZ-PVP

micronized particles and (g) ITZ-HPMC micronized particles.

The arrows indicate peaks due to crystalline ITZ present in the

extrudate formulation containing crystalline ITZ. ......................................225

Figure 2.3: SEM images of (a) ITZ-HPMC micronized particles (b) a typical

cross section of the ITZ-HPMC micronized particle extrudates (c)

ITZ-PVP micronized particles (d) close-up view of a typical ITZ-

PVP micronized particle within the polymer matrix of the

extrudate......................................................................................................226

Figure 2.4: Dissolution testing at sink conditions of the micronized particle and

micronized particle extrudate formulations and bulk crystalline

ITZ. Approximatly 5 mg of ITZ was present in each vessel (n=6).

Testing was conducted in 900 mL of 0.1N HCl at 37 ºC and a

paddle speed of 50 rpm. ..............................................................................227

Figure 2.5: Supersaturation dissolution testing of the ITZ-HPMC and ITZ-PVP

micronized particle extrudate formulations. Approximately 100

mg of ITZ was added to each dissolution vessel (n=6). Testing

was conducted in 900 mL of 0.1N HCl at 37 ºC and a paddle

speed of 50 rpm...........................................................................................228

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Figure 2.6: Supersaturation dissolution testing of the ITZ-HPMC and ITZ-PVP

micronized particle extrudate formulations by a pH change

method according to the USP 29 specifications for the Method A

enteric test. Approximately 100 mg of ITZ was added to each

dissolution vessel (n=6). Testing was conducted for 2 hours in

750 mL of 0.1N HCl followed by pH adjustment with 250 mL of

0.2M sodium phosphate tribasic at 37 ºC and a paddle speed of 50

rpm. .............................................................................................................229

Figure 2.7: Plasma ITZ concentration versus time from oral dosing of the ITZ-

HPMC micronized particle extrudate, ITZ-PVP micronized

particle extrudate, and bulk crystalline ITZ. The dosing was done

by oral gavage in the amount of 30 mg/kg per subject (n=3). ....................230

Figure 3.1: DSC analysis of: (a) HME processed ITZ:Methocel™ E5 (1:2), (b)

HME processed ITZ:Methocel™ E50 (1:2), (c) HME processed

ITZ:Kollidon® 90 (1:2), (d) HME processed ITZ:Kollidon® 12

(1:2), (e) ITZ:Kollidon® 90 (1:2) physical mixture, (f)

ITZ:Methocel™ E50 (1:2) physical mixture, and (g) crystalline

ITZ. .............................................................................................................231

Figure 3.2: DSC analysis of: (a) EUDRAGIT® L 100-55 powder, (b) glassy

ITZ, (c) placebo (HME processed EUDRAGIT® L 100-55 with

20% TEC based on polymer mass), (d) HME processed

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ITZ:[EUDRAGIT® L100-55 w/ 20% TEC] (1:2), and (e) physical

mixture of ITZ:[EUDRAGIT® L100-55 w/ 20% TEC] (1:2)....................232

Figure 3.3: DSC analysis of: (a) HP-55 powder, (b) HP-55S powder, (c)

placebo (HME processed HP-55S w/ 20% TEC based on dry

polymer mass), (d) glassy ITZ, (e) HME processed ITZ:[HP-55

w/ 20% TEC] (1:2), (f) HME processed ITZ:[HP-55S w/ 20%

TEC] (1:2), and (g) physical mixture of ITZ:[HP-55S w/ 20%

TEC] (1:2)...................................................................................................233

Figure 3.4: Supersaturation dissolution testing of the ITZ-IR polymer HME

processed compositions by pH modulation method. Each

dissolution vessel (n = 3) contained 180 mg of the formulation (60

mg ITZ equivalent) corresponding to 20 times the saturation

solubility of ITZ in the acid phase. Testing was conducted for 2 hr

in 750 mL of 0.1 N HCl followed by pH adjustment 6.8 ± 0.5

with 250 mL of 0.2 M tribasic sodium phosphate solution. .......................234

Figure 3.5: Supersaturation dissolution testing of the ITZ-enteric polymer

HME processed compositions by pH modulation method. Each

dissolution vessel (n = 3) contained 180 mg of the formulation (60

mg ITZ equivalent) corresponding to 20 times the saturation

solubility of ITZ in the acid phase. Testing was conducted for 2 hr

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in 750 mL of 0.1 N HCl followed by pH adjustment 6.8 ± 0.5

with 250 mL of 0.2 M tribasic sodium phosphate solution. ......................235

Figure 3.6: Plasma ITZ concentration versus time from oral dosing of (A)

HME processed ITZ:Methocel™ E50 (1:2) and (B) HME

processed ITZ:[EUDRAGIT® L 100-55 w/ 20% TEC] (1:2). The

dose was administered by oral gavage in the amount of 30 mg

ITZ/kg per subject (n = 4)...........................................................................236

Figure 4.1: DSC analysis of: (a) HME processed active 20% Carbopol® 974P

additive formulation (b) HME processed placebo 20% Carbopol®

974P additive formulation (c) EUDRAGIT® L 100-55 powder (d)

Carbopol® 974P powder (e) amorphous ITZ (f) physical mixture

of the active 20% Carbopol® 974P additive formulation...........................237

Figure 4.2: DSC analysis of: (a) HME processed active 40% Carbopol® 974P

additive formulation (b) HME processed placebo 40% Carbopol®

974P additive formulation (c) EUDRAGIT® L 100-55 powder (d)

Carbopol® 974P powder (e) amorphous ITZ (f) physical mixture

of the active 20% Carbopol® 974P additive formulation...........................238

Figure 4.3: EDS Mapping of ITZ:EUDRAGIT® L 100-55 (1:2) (Top) and 40%

Carbopol® 974P additive (Bottom) formulations. Red = Cl,

Green = N, Yellow = Overlap of Cl and N. Note that nitrogen

shown in EDS images outside of the sample are due to small

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amounts of nitrogen adsorbed on the copper film. (Color images

available online.).........................................................................................239

Figure 4.4: Supersaturation dissolution testing of the 20% Carbopol® 974P

additive formulation, the 40% Carbopol® 974P additive

formulation, as well as an all EUDRAGT® L 100-55 carrier

system by pH switch method. Each dissolution vessel contained

180 mg of the formulation (60 mg ITZ equivalent) corresponding

to 20 times the saturation solubility of ITZ in the acid phase.

Testing was conducted for 2 hr in 750 mL of 0.1 N HCl followed

by pH adjustment to 6.8 ± 0.5 with 250 mL of 0.2 M tribasic

sodium phosphate solution..........................................................................240

Figure 4.5: Plasma ITZ concentration versus time from oral dosing of (A) 20%

Carbopol® 974P additive formulation and (B) 40% Carbopol®

974P additive formulation. The doses were administered by oral

gavage in the amount of 30 mg TZ/kg body weight per subject in

rats (n = 4)...................................................................................................241

Figure 5.1: HPLC analysis of ACM:EUDRAGIT® L 100-55 (1:2) TKC

processed material as compared to an ACM standard injection. ................242

Figure 5.2: HPLC analysis of KTZ:Kollidon® 30 (1:2) TKC processed

material in comparison to a KTZ standard injection and the

Kollidon® 30 polymer alone. .....................................................................243

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