Index

A

ABC transporters. See ATP-binding cassette (ABC) transporters

Abraxane®, 263 Absolute recovery, 25

Acute retinal necrosis (ARN), 253–254, 497 Acyclovir (ACV), 40, 370

ADAMTS protein, 518

Advanced glycation end-products (AGE), 521 Aflibercept®, 513

Ageing vitreous physical changes

anterior–posterior direction, 144–146 intravitreal drug delivery, vitreous

liquefaction, 146–148 liquid volume, 144–146 pre-clinical model, 146

vitreous degeneration, underlying mechanisms, 143–144

Age-related macular degeneration (AMD) anti-inflammatory therapeutics, 512–513 clinical trials

AREDS formulation, 508 dry and wet AMD, 509–510

photodynamic therapy, 508, 511 microparticles, 252

newer antiangiogenic targets pigment epithelial growth factor,

514–515 squalamine, 515

VEGF receptor, 515–516 new target identification

ECM components, 517–519 integrins, 516–517

matrix metalloproteinases, 517 NSAIDs, 519–520

rapamycin, 519 TG100572, 519 Tie2 signaling, 519

pathophysiology, 507–508 photoreceptor survival, neurotrophic

factors, 514

protein drug delivery, 409–410 VEGF signaling

aflibercept, 513 bevacizumab, 512 bevasiranib, 512–513 pegaptanib, 511 ranibizumab, 511–512

Albumin nanoparticles, 263, 272–275 AMD. See Age-related macular degeneration

(AMD)

Amino acid-mimetic drugs, 92–94

Amino acid transport, vitreous humour, 140 Aminoglycosides, 540

AMP-activated protein kinase (AMPK), 528 Anatomic endpoint, 488

ANCHOR trial, 487 Angiopoietin (Ang), 504–505 Angiotensin II inhibition, 530

Anti-apoptotic neuroprotectants, 563–564 Antibiotics, transcorneal iontophoresis

ciprofloxacin hydrochloride, 369 fungal keratitis, 369–370 gentamycin, 367

miconazole, 369–370 quinolone, 369 tobramycin, 367, 369

Anti-inflammatory drugs, 531 Antioxidants, 97–99 Aqueous clearance, 137–138

Aqueous humor turnover, 66–68

578

ARMD. See Age-related macular degeneration (AMD)

ARN. See Acute retinal necrosis (ARN) Arrestin, 516

Aspirin, 379 Atenolol, 113–114

ATP-binding cassette (ABC) transporters, 100–101

Autofluorescence, 50–52, 78–82 Autoimmune disease

lymphocyte activation, 541–542 signal transduction inhibition

CD28 signaling, 542 corticosteroids, 542

DNA synthesis inhibitor, 542–543 TCR signaling, 542

TNF blockade, 543 Azathioprine, 542

AZdU. See 3'-Azido–2,'3'-dideoxyuridine (AZdU)

3'-Azido–2,'3'-dideoxyuridine (AZdU), 24–25 AZT. See Zidovudine (AZT)

B

Bartonella, 540 N–4-(Benzoylaminophenylsulfonyl glycine)

(BAPSG), 522

Bevacizumab (Avastin®), 182, 428, 434, 512 Bevasiranib, 512–513

Bile acids, 563–570

Biodegradable ocular drug delivery systems biodegradable polymers (see

Biodegradable polymers) dexamethasone, 208, 210 implants, 208–210

examples, 214–216 microsomes, 223 nanocapsules, 223 nanoparticles, 223 PLA nanoparticles, 224

PLGA-based implants, 216–219 poly(e-caprolactone)-and

poly(glycolide-co-lactide-co- caprolactone)-based implants, 220–221

polyanhydride-based implants, 222 poly(lactic acid)-based implants,

214, 216

poly(ortho ester)-based implants, 221 poly(D,L-lactic-co-glycolic acid)/

poly(L-lactide-co–1, 3-trimethylene carbonate)-based composite implants, 220

scleral and vitreal implants, 222–223

Index

Lacrisert®, 214 nonbiodegradable systems (see

Nonbiodegradable ocular drug delivery systems)

Ozurdex™, 208, 211–213 Surodex™, 213 Verisome™, 213

Biodegradable polymers chemical structure, 195–196 microneedles, 357

nonocular biomedical application bioabsorbable sutures, 205–206

drug delivery systems manufacture, 206 examples, 203–204

history, 203 safety, 207–208 stents, 207

timeline for biodegradable drug delivery system, 203, 205

tissue engineering, 207 poly(e-caprolactone) (PCL), 201 poly(ortho esters) (POE), 202 polyanhydrides (PAH), 202–203 polyglycolic acid (PGA), 197–198 polylactic acid (PLA), 196–197 polylactic-co-glycolic acid (PLGA), 197–201

Blood ocular berries (BOB), 28–29 Blood–retinal barrier (BRB)

efflux transporters ABCAs, 103

ATP-binding cassette (ABC) transporters, 100–101

breast cancer resistance protein (BCRP/ ABCG2/MXR/ABCP), 103

multidrug resistance-associated proteins (ABCCs), 102–103

organic anion transporter 3 (OAT3, SLC22A8), 101

organic anion transporting polypeptides (OATPs, SLCO, SLC21A), 101–102

P-glycoprotein (ABCB1), 102 influx transporters/receptors

amino acid-mimetic drugs, 92–94 antioxidants, 97–99

creatine, 99 expression, 88–92 folate analogs, 95–96

monocarboxylic drugs, 94 nucleoside analogs, 94–95

opioid peptides and peptidomimetic drugs, 97

organic cationic drugs, 96–97 taurine, 100

potential approach, systemic drug delivery to retina, 88–89

Index

role of, 87–88

transport systems, inner and outer, 87 vitreous, 140–143

BOB. See Blood ocular berries (BOB) Branch retinal vein occlusion (BRVO), 479–481 BRB. See Blood–retinal barrier (BRB) Breast cancer resistance protein (BCRP), 103 Brimonidine, 117

Bruch’s membrane, 6

b-subunit of rod photoreceptor cGMPphosphodiesterase (b-PDE), 385

C

Caking, 454–455

Carbohydrate nanoparticles, 275–276 Carboplatin, 381 Carboxyfluorescein, 56

Carboxy methylcellulose (CMC), 461 CD36 protein, 518

CD28 signaling, 542

Centers for Biologics Evaluation and Research (CBER), 477–479

Centers for Drug Evaluation and Research (CDER), 477–479

Central retinal vein occlusion (CRVO), 480, 481 Chaperone proteins, 506–507

Chemokines, 505

Chitosan nanoparticles, 263, 275–276 Choroidal blood flow, 176

Choroidal neovascularization, 254 Cidofovir, 537

Ciliary neurotrophic factor (CNTF), 191, 429–430, 432, 509

Ciprofloxacin hydrochloride, 369 Clearance pathways

aqueous clearance, 137–138

charge and collagen interaction, 136–137 posterior and retina, 136

retinal clearance, 138–139 Clinical endpoints

FDA endpoints, 486 future endpoints, 490–492 geographic atrophy, 489

neovascular age-related macular degeneration, 486–487

retinal vein occlusion, 489–490 14C-mannitol subconjunctival injection, 415 CMV. See Cytomegalovirus (CMV) retinitis Coat and poke microneedle strategy, 350–351,

353–355 Coenzyme Q10, 535

Combination nanosystems, 278

Corneal epithelial cell layer permeability methodologies, 54–55

579

Cornea treatment, 334–339 Corticosteroids, 542 Creatine, 99

Cyclooxygenase 2 (COX 2), 519–520 Cyclosporin-A (CSA), 542

Cystine, 99

Cytomegalovirus (CMV) retinitis, 253–254, 537

D

Degenerative retinal disease clinical trials

cell-based therapy, 533, 535 nutritional supplements, 535 synthetic neuroprotective compounds,

535–536 pathophysiology

elevated intraocular pressure, 533 retinitis pigmentosa, 532–533

Demopressin, 353 Dendrimers, 276–278

Dendritic guanidilyated translocator (DPT), 277–278

Derjaguin and Landau, Verwey and Overbeek (DLVO) theory, 455–457

Dexamethasone, 208, 210, 489

Allergan Inc., 479–480 anti-inflammatory agent, 480 clinical development program, 481 nonclinical safety program, 480–481 ocular and systemic safety, 481

Diabetic macular edema (DME) antiangiogenic therapeutics, 524, 528 anti-inflammatory therapeutics, 529 clinical trials, 525–526 corticosteroids, 524

intracellular signal transduction modulator, 528–529

retinal detachment inhibition, 529 Diabetic retinopathy, 253

clinical trials, 527 pathophysiology

diabetic macular edema, 523 endogenous antiangiogenic proteins, 523 glycation, 521

obesity, 521

pigment epithelial growth factor (PEDF), 523

plasminogen activator inhibitor–1, 522–523

polyol accumulation, 521–522 proliferative diabetic retinopathy, 523–524 type I and type 2 diabetes, 520 vascular endothelial growth factor

(VEGF), 523

580

Diabetic retinopathy (cont.) therapeutics

angiotensin II inhibition, 530 anti-inflammatory drugs, 531 intracellular signal transduction

modulator, 529–530 somatostatin, 530

Differential scanning calorimetry (DSC), 238 Dipalmitoylphoshatidylcholine (DPPC),

263, 267–268

DME. See Diabetic macular edema DOPAC, in vitro recovery of, 25, 26 Doxil®, 263

DPPC. See Dipalmitoylphoshatidylcholine (DPPC)

DPT. See Dendritic guanidilyated translocator (DPT)

Drug and gene therapy barriers, 393–394 genetics, AMD, 393 intravitreal injections, 392

physics-based approaches (see Electric field mediated drug delivery)

Drug delivery approaches biopharmaceutical and pharmaceutical

pipelines, 3 continuous/pulsatile delivery, 13 drug potency, 12–13

induce and maintain efficacy, 13–14 local and systemic toxicity, 15 pharmacokinetics (PKs)

drug properties, 15 physicochemical properties, 4–7

planned obsolescence, 4 previous ocular use, 16 route of administration, 8–11 short-term therapies, 2 strategic team input, 16–17

target tissue, location of, 11–12 type of, 14–15

Drug delivery systems biodegradable polymers

(see Biodegradable ocular drug delivery systems)

electric field (see Electric field mediated drug delivery)

hydrogel technology (see Hydrogels) intrascleral drug delivery (see Intrascleral

drug delivery) microparticles (see Microparticles) nonbiodegradable ocular system

(see Nonbiodegradable ocular drug delivery systems)

protein (see Protein drug delivery)

Index

retinal drug delivery (see Retinal drug delivery)

suprachoroidal drug delivery, 177–183 targeted delivery (see Targeted drug

delivery)

topical drug delivery (see Topical drug delivery)

trans-corneal and periocular drug delivery, 116–118

transscleral drug delivery (see Transscleral drug delivery)

Drug loading efficiency determination, 239 Drug product approval process

adaptive trial design, 477–478 BRIC countries, 471–472 CMC section, 473–474 dexamethasone

Allergan Inc., 479–480 anti-inflammatory agent, 480 clinical development program, 481 nonclinical safety program, 480–481 ocular and systemic safety, 481

drug-device combinations, 478 Ex-US sites, 472

good clinical practice, 475–476 good laboratory practices, 475 International Conference on

Harmonization, 471

Investigational New Drug Application, 472 nonclinical pharmacokinetic studies, 475 nonclinical toxicology study, 474–475 phase II clinical trials, 472–473

phase III clinical trials, 473 ranibizumab, 481–482 sterile products, 474

US Food and Drug Administration, 471, 473 Drugs delivered structure, back of eye, 118 Drugs elimination routes, 23

Drug suspensions, 499–450 administration route, 453 advantages, 453 classification, 453

composition and dosage, 453, 454 definition, 453

formulation development and evaluation sterilization and pyrogenicity, 462–463 surfactants, 461–462

syringeability, 463–464 tonicity, 462

triamcinolone acetonide particle size, 461 viscosity, 462

formulation methodology, 458–459 ingredients, 453

manufacturing process, 460

Index

safety, 465–466

in situ forming suspensions advantage, 464–465 polymeric microparticles, 465 preparation, 465

stability and formulation dispersed material settling, 458 DLVO theory, 455–457

drug wettability, 454–455 Ostwald ripening, 458 sedimentation avoidance, 455

two-phase system, 452–453

E

Elastomer formations, 310

Electric field mediated drug delivery electroendosmosis, 396 electrophoresis, 395–396 electroporation, 396–397 electrostimulation, 396

history, 394–395 iontophoresis, 396

rDNA transfection vs. viral mediated DNA delivery, 397

safety concerns and issues, 395, 405–406 in vivo method, 397–399

Electroendosmosis, 396 Electro-osmosis, 364 Electrophoresis, 395–396 Electroporation, 396–397

advantages, 403–404 disadvantages, 405 living animals, 401–406

Electrostimulation, 396

Emulsion-solvent evaporation method, 265–266 Endogenous antiangiogenic proteins, 523 Endothelial cell layer permeability, 66–68 Endothelial precursor cells (EPC), 533 Endothelin–1 (ET–1), 506

Episcleral implantation, trans-scleral delivery, 319–322, 324

Episcleral implanted MEMS-controlled refillable drug delivery pump, 318, 321

Epithelial permeability

eye bath technique, 54, 62–63 single drop technique, 54, 56–62

Erythropoietin (EPO), 531–532 ESBA105, 412–413

ETDRS chart, 486

Experimental autoimmune uveitis (EAU), 497, 498

Eye bath application, 63

581

Eye bath technique, 54–56, 62–63

Eyegate II Delivery System, 366

F

FDA endpoints, 485–489 Fibroblast growth factor–2, 504 First-pass effect, 8

Flip-flop gating mechanism, 363–364 Flocculation, 458–464

Fluocinolone acetonide (FA), 501 Fluorophotometry. See also Pharmacokinetic

assessment, fluorophotometry applications

corneal epithelial cell layer permeability methodologies, 54–55

epithelial permeability, eye bath technique, 62–63

epithelial permeability, single drop technique, 56–62

eye bath technique, 55–56

tear turnover rate (%/min), 53–54 bell-shaped fluorescence curve, 48, 49 choroidal–retinal structure, 48, 49 clinical applications, 63–68

ocular structures, 48, 50 retina, 47–48

5-Fluorouracil, transconjunctival iontophoresis, 366

Flushing and fluid replacement, refillable devices

active pumps, 311 passive pumps, 311–312 solid refill, 312

Folate analogs, 95–96 Fomivirsen, 537 Foscarnet, 537

Fungal keratitis, 369–370

G

Ganciclovir (GCV), 39, 41, 537 Ganciclovir-loaded albumin, 272–273 GCV. See Ganciclovir (GCV)

Gel permeation chromatography (GPC), 239 Gelrite™, 412

Gene delivery, 283 Gentamycin, 367 Geographic atrophy, 489, 491

Glass microneedles, 340, 342, 356 Glaucoma drainage devices, 313–314 Glucocorticoids, 379–380 Glycylsarcosine, 34

Good Clinical Practice (GCP), 475–476

582

Good Laboratory Practices (GLP), 475 GPC. See Gel permeation chromatography

(GPC)

H

Herpes simplex virus 1 (HSV–1), 371 Hollow microneedles, 339–350, 355–357

Human serum albumin nanoparticles, 273–274 Hyaluronidase, 530

Hydrogels

design, characterization, and optimization, 293–295

further developments, 300–301 intravitreally administered type, 295–296 subconjunctivally administered type,

296–300 technology, 292–293

transscleral drug delivery, 296 Hydrostatic effects, 133–134

I

Idebenone, 535 Iluvien™, 193, 284

Implants, 187–190, 193–194, 204–206, 214–224, 284–286, 295–297, 426–427

Indomethacin-loaded micelles, 271–272 Infrared absorption (IR) spectrophotometry, 238 Inner limiting membrane, 127–130

In situ forming drug suspensions advantage, 464–465 polymeric microparticles, 465 preparation, 465

International Conference on Harmonization (ICH), 471

Intracameral injections, 414–415 Intracellular signal transduction modulator,

529–530 Intracorneal anterior spots, 307

Intraocular inflammation and infection after cataract surgery, 255

Intrascleral drug delivery

posterior segment delivery, 175, 176 suprachoroidal drug delivery, 177–183,

345–350

targeted drug delivery, 340–345 and transscleral diffusion, 175–176

Intravenous fluorescein injection in vivo, 75–78 Intravitreal (IVT) delivery through pars plana,

316–321

Intravitreal (IVT) drug distribution and clearance, silicone oil, 149–150

Intravitreal (IVT) injections, 392, 415–416

Index

Intravitreally administered hydrogels, 295–296 Intravitreal (IVT) pharmacokinetic parameters,

28–31 Inulin, 113–114

In vitro permeability and release, 166–169 Iontophoresis, 396

advantages, 400

animal studies, manganese ions, 399 disadvantages, 400

iodide iontophoresis, 399–400 I-vation®, 192

K

Kenalog suspensions, 465–466

L

Lacrisert®, 214

Laser photocoagulation, 410 Lens capsule delivery, 326

Leukemia inhibitory factor (LIF), 536 Lidocaine, transconjunctival iontophoresis, 366 Liposomal delivery devices, 269

Liposomes and lipids dipalmitoylphoshatidylcholine (DPPC),

263, 267–268

laser irradiation-triggered release, 270 liposomal delivery devices, 269 liposomal formulations, 269–270 nanostructured lipid carriers, 270 nonviral vectors, 268–269 reticuloendothelial system (RES), 268 solid lipid nanoparticles, 270 STEALTH liposomes, 268

Local and systemic toxicity, 15 Local drug delivery, 121–122, 174 Lucentis®, 9, 279, 481–482 Lumitect®, 193

Luveniq™, 8

Lymphocyte activation, 541–542

M

Macugen®, 9 Macular edema, 253

MCTs. See Monocarboxylate transporters (MCTs)

Mecamylamine, 119–120 Medidur®, 332 Memantine, 120 Micelles

drug pharmacokinetics, 272 formation, 270

Index

indomethacin-loaded micelles, 271–272 polyethyleneglycol (PEG), 271 structure, 270–271

Miconazole, 369–370 Microcannulation system, 178 Microdialysis. See also Vitreal

pharmacokinetics, microdialysis posterior segment

anesthetized animal models, 27–37 conscious animal model, 37–41 rats model, 42–43

sampling site for, 22–23 principle of

constant flow rate, 23–24

extraction efficiency/recovery, 24–27 molecular weight cut off (MWCO), 24

Microneedles. See also Targeted drug delivery coated and hollow microneedles,

intrascleral delivery, 339–345 coated microneedles, intrastromal delivery,

334–339

hollow microneedles, suprachoroidal delivery, 345–350

types and applications

biodegradable polymer microneedles, 357

coat and poke, 350–351, 353–355 hollow microneedles, 357

human cadevar sclera after uncoated microneedles, 355

pinpoint delivery, 356 poke and apply, 350–353

poke and flow, 350–351, 355–356 Microparticles

additives, 240–242 administration routes, 234 characterization

differential scanning calorimetry (DSC), 238

drug loading efficiency determination, 239

gel permeation chromatography (GPC), 239

infrared absorption (IR) spectrophotometry, 238

“in vitro” release studies, 240–242 morphological, 237

particle size analysis and distribution, 237

X-ray diffraction, 238–239 dose calculation, 245 injectability studies, 245 manufacturing

coacervation (phase separation), 235

583

solvent extraction/evaporation, microsphere preparation, 235–237

spray drying, 235

posterior segment diseases treatment acute retinal necrosis (ARN), 253–254 age-related macular degeneration

(AMD), 252

choroidal neovascularization, 254 cytomegalovirus (CMV) retinitis,

253–254

diabetic retinopathy, 253

diseases affecting optic nerve, 255 intraocular inflammation and infection

after cataract surgery, 255 macular edema, 253

proliferative vitreoretinopathy (PVR), 250–251

retinal repair, 255–256 uveitis, 251–252

sterilization, 242–244 structure, 234–235

in vitro and in vivo correlation, 249 in vivo studies

degradation of PLA and PLGA, 248–249 injection of microparticles, 246

ocular disposition and cellular uptake, 246–247

tolerance, 247–248 Microparticle suspension, 465 Microplasmin, 515 Microsomes, 223

Monocarboxylate transporters (MCTs), 94 Monocarboxylic drugs, 93

MRP4. See Multidrug resistance-associated protein 4 (MRP4)

Multidrug resistance-associated protein 4 (MRP4), 102–103

Mycophenolate mofetil (MMF), 543

N

Nanocapsules, 223

Nanoparticles. See also Nanotechnology biodegradable ocular drug delivery

systems, 223 carbohydrates, 275–276 combination nanosystems, 278 dendrimers, 276–278

gene delivery, 283 liposomes and lipids

dipalmitoylphoshatidylcholine (DPPC), 263, 267–268

laser irradiation-triggered release, 270 liposomal delivery devices, 269

584

Nanoparticles (cont.)

liposomal formulations, 269–270 nanostructured lipid carriers, 270 nonviral vectors, 268–269 reticuloendothelial system (RES), 268 solid lipid nanoparticles, 270 STEALTH liposomes, 268

materials under investigation, 262–263 micelles

drug pharmacokinetics, 272 formation, 270

indomethacin-loaded micelles, 271–272 polyethyleneglycol (PEG), 271 structure, 270–271

vs. microparticles, 284 PLA, 223

polymer

complexity of preparation, 265–266 dialysis method, 267 emulsion-solvent evaporation method,

265–266

nonviral vectors, 264–265 PLA and PLGA, 264, 282–283 structural changes, 265

protein

ganciclovir-loaded albumin, 272–273 human serum albumin nanoparticles,

273–274

surface charge, 274–275 surface functionalization, 280–281

Nanostructured lipid carriers, 270 Nanotechnology. See also Nanoparticles

drug delivery, 285

drug retention and sustained release, 279–280

intracellular trafficking, 282–283 nanotherapies, 281–282

patient compliance improvement, 279 permeability and tissue partitioning,

280–281

Necrotizing herpetic retinopathy (NHR), 537 Neovascularization, 410

Ang1 and Ang2, 504–505 chemokines, 505

fibroblast growth factor–2, 504 intracellular signaling molecule, 505 plasminogen, 503, 504

PLCg and PI3K, 502, 503 receptor system, 505

Neuroprotectants, 567–569 Neuroprotectin D1 (NPD1), 535 Neuroprotection, 120, 255, 567 Neuroretina, 121

New chemical entity (NCE), 475

Index

Nonbiodegradable ocular drug delivery systems Iluvien®, 193

implant-type devices, 188 I-vation®, 192

matrix implants Lumitect®, 193 punctal plugs, 193–194

Ocusert®, 189, 192 reservoir-type devices, 188 Retisert®, 189

Vitrasert®, 192 Nucleoside analogs, 94–95

O

OAT3. See Organic anion transporter 3 (OAT3) OATPs. See Organic anion transporting

polypeptides (OATPs)

OATs. See Organic anion transporters (OATs) OCTs. See Organic cation transporters (OCTs) Ocular disease

bile acids, 563–564 neuroprotectants, 567–569 ocular delivery, 569–570

TUDCA/UDCA, systemic treatment, 564–566

Ocular disposition and cellular uptake, 246–247 Ocular drug delivery, 364–366, 372, 411 Ocular fluorescence, 50–52

Ocular inflammation

acute phase proteins, 499

age-related macular degeneration, 498 complement system, 498 degeneration

apoptosis, 506 glaucoma, 506 neuron cell death, 505

protein misfolding, 506–507 drusen components, 498–499 glucocorticoids, 499–501 macrophages and neutrophils, 495–496 neovascularization, VEGF

Ang1 and Ang2, 504–505 chemokines, 505

fibroblast growth factor–2, 504 intracellular signaling molecule, 505 plasminogen, 503, 504

PLCg and PI3K, 502, 503 receptor system, 505

uveitis, 497 Ocular iontophoresis

controlled Coulomb iontophoresis, 365 corneal scarring and tissue damage, 365 degree of variability, 365

Index

drug penetration, 364–365 electro-osmosis, 364

Eyegate II Delivery System, 366 flip-flop gating mechanism, 363–364 future aspects, 385–386

ocular gene therapy, 384–385 shunt pathway, 363 therapeutic applications, 365 transconjunctival, 366 transcorneal iontophoresis

adrenergic agents, 371 antibiotics, 367–370 antiviral drugs, 370 corneal lesions, 371 corneal lesions, rabbit, 371 L-NAME, 371

transscleral iontophoresis (see Transscleral iontophoresis)

Ocular movements, role, 151–152

Ocular pharmacokinetics, ganciclovir (GCV), 39

Ocular posterior segment drug delivery, 291. See also Hydrogels

Ocular TB, 540

Ocular toxocariasis, 540 Ocular toxoplasmosis, 537, 540

OcuPhor transscleral probe, 372, 374 Ocusert®, 189, 192

OGTA. See Oregon green labeled triamcinolone (OGTA)

Ophthalmic protein formulation development clinical trials, 431

excipients selection antioxidants, 437

buffer ingredients, 435, 437 preservatives, 437 stabilizing agents, 437 surfactants, 437

growth factors, 432

macromolecule formulations, 433, 434 preformulation studies, 433, 435, 436 process variables optimization,

437–438

protein biosynthesis, 433 Opioid peptides, 97

Optic nerve diseases, 255

Oregon green labeled triamcinolone (OGTA), 168–169

Organic anion transporter 3 (OAT3), 101 Organic anion transporters (OATs), 142 Organic anion transporting polypeptides

(OATPs), 101–102, 568 Organic cation transporters (OCTs), 96–97,

141–142

585

Ostwald ripening, 458

Ozurdex™, 9, 208, 211–213, 284, 332, 479–481

P

PAH. See Polyanhydrides (PAH) PAMAM. See Polyamido amine (PAMAM)

dendrimers

Patient compliance, 279–280, 306 Pazopanib, 515

PCL. See Poly(e-caprolactone) (PCL) PDR. See Progressive diabetic retinopathy PEG. See Polyethyleneglycol (PEG) Pegaptanib (Macugen®), 281, 427–428, 434 PEGylation, 423–424

PEI-DNA. See Polyethylenimineamine DNA (PEI-DNA) nanocomplexes

Peptidomimetic drugs, 97 Periocular injections, 165, 416–417

Periocular route, 22, 112–113, 116, 411, 421 Permeability, 53–54, 56–63, 66–68, 163–166,

280–281, 362

PGA. See Polyglycolic acid (PGA) P-glycoprotein, 102

vitreous humour, 141 Pharmacokinetic assessment,

fluorophotometry applications, 53–63

bell-shaped fluorescence curve, 48, 49 choroidal-retinal structure, 48, 49 clinical applications, 63–68

human subject and rabbit ocular fluorescence, 50–52

intravenous fluorescein injection in vivo, 75–78

ocular structures, 48, 50 retina, 47–48

retrobulbar fluorescein injection, 69–75 topical eye drops, fluorescein, 78, 82 transscleral pathways, 68, 69

Pharmacokinetic parameters, ganciclovir (GCV), 39

Phosphatidyl inositol–3-kinase (PI3K), 502 Photodynamic therapy (PDT), 508, 511 Pigment epithelium derived factor (PEDF), 430 Pilocarpine, 354

Pinpoint delivery, 356

PLA. See Polylactic acid (PLA) Plasminogen activator inhibitor–1 (PAI–1),

522–523

Plasminogen, angiogenesis, 503, 504

PLGA. See Polylactic-co-glycolic acid (PLGA) PLGA-based implants, 216–219

POE. See Poly(ortho esters) (POE)

586

Poke and apply microneedle strategy, 350–353 Poke and flow microneedle strategy, 350–351,

355–356

Poke and release microneedle strategy, 355 Poly(e-caprolactone) (PCL), 201

Poly (lactic acid) (PLA), 424–425 Poly(ortho esters) (POE), 202 Polyamido amine (PAMAM) dendrimers,

276–277 Poly(e-caprolactone)-and poly(glycolide-co-

lactide-co-caprolactone)-based implants, 220–221

Polyanhydride-based implants, 222 Polyanhydrides (PAH), 202–203 Poly(lactic acid)-based implants, 214, 216 Poly(ortho ester)-based implants, 221 Polyethyleneglycol (PEG), 271 Polyethylenimineamine DNA (PEI-DNA)

nanocomplexes, 283 Polyglycolic acid (PGA), 197–198 Polylactic acid (PLA)

biodegradable polymers, 196–197 nanoparticles, 224, 266, 280, 425

Polylactic-co-glycolic acid (PLGA) biodegradable polymers, 197–201 nanoparticles, 263, 264, 266, 282

Poly (D,L-lactideco-glycolide) (PLGA) matrix, 480, 481

Polymer-based drug delivery systems dexamethasone, 208, 210 implants, 208–210

Lacrisertr®, 214 Ozurdex™, 208, 211–213 Surodex™, 213 Verisome™, 213

Polymer microneedle array, 354–355 Polymer nanoparticles

complexity of preparation, 265–266 dialysis method, 267 emulsion-solvent evaporation method,

265–266

nonviral vectors, 264–265 PLA and PLGA, 264, 282–283 structural changes, 265

Polyol accumulation, 521–522 Poly(D,L-lactic-co-glycolic acid)/poly(L-

lactide-co–1, 3-trimethylene carbonate)-based composite implants, 220

Posterior segment delivery, 175, 176 Posterior segment diseases treatment

acute retinal necrosis (ARN), 253–254 age-related macular degeneration

(AMD), 252

Index

choroidal neovascularization, 254 cytomegalovirus (CMV) retinitis, 253–254 diabetic retinopathy, 253

diseases, 174

diseases affecting optic nerve, 255 intraocular inflammation and infection

after cataract surgery, 255 macular edema, 253

proliferative vitreoretinopathy (PVR), 250–251

retinal repair, 255–256 uveitis, 251–252

Posterior segment ocular tissues, transscleral drug delivery, 160–162

Posterior vitreous detachment (PVD), 130 Posurdex®, 9, 332

Progressive diabetic retinopathy (PDR) clinical trials, 527

vitreous hemorrhage, 530

Proliferative vitreoretinopathy (PVR), 250–251 Propanolol, 113–114

Prostate-specific membrane antigen (PSMA), 281

Protein drug delivery. See also Ophthalmic protein formulation development

advantages and challenges, 419, 422 age-related macular degeneration, 409–410 anti-VEGF drug discovery, 410–411 developmental strategy

implants, 426–427 liposomes, 425

micro-and nano-particles, 424–425 PEGylation, 423–424

pure protein, 422 stem cells, 425–426

intracameral injections, 414–415 intravitreal injections, 415–416 macromolecule administration routes,

420–421 neovascularization, 410 periocular injections, 416–417 product specification

identity test, 439 potency assays, 440 purity, 439–440

regulatory guidelines, 440–441 retinal degenerative disease, 431 subretinal injections, 417–418 suprachoroidal route, 417 systemic route, 418–419 topical administration

ESBA105, 412–414 Gelrite™, 412 insulin, 414

Index

rapid drug clearance, 412 therapeutic effects, 414 vasostatin, 413–414

vascular endothelial growth factor bevacizumab, 428

ciliary neurotrophic factor, 429–430 pegaptanib, 427–428

ranibizumab, 428–429 VEGF Trap-Eye, 429

Protein nanoparticles ganciclovir-loaded albumin, 272–273 human serum albumin nanoparticles,

273–274

surface charge, 274–275

Pseudomonas aeruginosa keratitis, tobramycin, 367, 369

PSMA. See Prostate-specific membrane antigen (PSMA)

Punctal plugs, 193–194

PVD. See Posterior vitreous detachment (PVD) PVR. See Proliferative vitreoretinopathy (PVR)

Q

Quinidine, 35

Quinolone, 369

R

Ranibizumab (Lucentis®), 410, 428–429, 511–512

Refillable devices

capsule ring device prototype, 326 design considerations

administration site, 307–308 body design, 309 contamination potential, 312

flushing and fluid replacement, 311–312 port design, 309–310

vacuum and pressure, 310–311 drug amount, 307, 308

episcleral band design, 322–323 episcleral exoplant design, 324 episcleral implantation, trans-scleral

delivery, 319–322, 324 episcleral-placed silicone device, 320, 322 episcleral reservoir design, 325

history

glaucoma drainage devices, 313–314 infusion pumps, 313

refill procedure, 314–315 intravitreal delivery through pars plana,

316–321

invasiveness and refilling frequency, 315–316

587

lens capsule delivery, 326

minimum refill chamber volumes, 307, 308 nanotechnology, 284–285

pars plana implanted device, 316–318 ported controlled release, 317–319

silicone episcleral implanted device, 314–315 subretinal and suprachoroidal implantation,

324–325

visually accessible intraocular locations, 307–308

Reticuloendothelial system (RES), 268 Retinal and vitreal ganciclovir (GCV), 34, 35 Retinal clearance, 138–139

Retinal degeneration, 418, 566

Retinal disease, 22, 86, 97, 186, 291, 295, 487–489, 534, 564–566

Retinal drug delivery blood–retinal barrier (BRB)

efflux transporters, 100–103

influx transporters/receptors, 89–100 potential approach, 88–89

role, 87–88 vitreous

ageing, 143–152 anatomy, 126–130

blood–retinal barrier (BRB) role, 140–143 clearance pathways, 135–139

drug reservoir, 130 flow processes, 131–135

Retinal ganglion cell (RGC) injury, 533 Retinal pigment epithelial (RPE) cells, 87–88 Retinal progenitor cells (RPC), 426

Retinal repair, 255–256

Retinal vascular endothelial cells (RVEC), 87–88

Retinal vein occlusion, clinical endpoints, 489–490

Retinopathy of prematurity (ROP) clinical trials, 532 pathophysiology, 531–532

Retisert®, 9, 189, 284, 332

Retrobulbar fluorescein injection, 69–75 Retrodialysis, 26, 40

RPE cells. See Retinal pigment epithelial (RPE) cells

RPE-choroid, 121

RVEC. See Retinal vascular endothelial cells (RVEC)

S

Safety of suspensions, 452, 465 Scleral and vitreal implants, 222–223 Scleral permeability, 163–165

588

Scleral structure, 162–163 Sclera treatment, 339–345 Sedimentation, 148, 455

Single drop technique, epithelial permeability, 54, 56–62

Sodium fluorescein, 53–55, 66, 67, 73–76, 79, 81

Solid lipid nanoparticles, 270 Somatostatin, 530

Specific transport systems, 23

Spectral domain optical coherence tomography (SD-OCT), 490–491

STEALTH liposomes, 268 Sterilization, microparticles, 242–244 Stern layer, drug suspension, 455 Subconjunctival injections, 414–415

Subconjunctivally administered hydrogels, 296–300

Subretinal and suprachoroidal implantation, 324–325

Subretinal injections, 417–418 Sub-Tenon, 3, 10, 285

Suprachoroidal drug delivery, 177–183. See also Intrascleral drug delivery

Suprachoroidal injection, 68–69, 417 Surodex™, 213

Surrogate endpoint, 487–488

Suspension formulation, 450, 461, 463, 465 Suspension manufacturing, 454, 466 Sustained-release delivery in vitro,

165–166

SynchroMed implantable infusion pump, 313 Syphilis, 540

Syringeability, drug suspensions, 463–464

T

Targeted drug delivery intrascleral delivery

fluorescein-labeled bovine serum albumin (BSA) delivery, 340–341

hollow glass microneedle vs. standard 30-gauge needle, 340, 342

hollow microneedles, 340

human cadaver sclera cross-sections, 340–341

microparticle suspensions, 344–345 nanoparticles delivery, 343–344 pressure effect on fluid delivery,

341–343

solid-coated microneedles, 340 sulforhodamine solution delivery and

spread, 340, 342

Index

intrastromal delivery

fluorescein concentration profiles, 337–338

microneedle insertion scenarios, 334–335 porcine cornea cross-section after

microneedle insertion, 336–337 pupil diameter changes, 339

solid, coated microneedle, 336 microneedle types and other applications

biodegradable polymer microneedles, 357 coat and poke, 350–351, 353–355 hollow microneedles, 357

human cadevar sclera after uncoated microneedle, 355

pinpoint delivery, 356 poke and apply, 350–353

poke and flow, 350–351, 355–356 poke and release, 355

suprachoroidal delivery

infusion pressure and microneedle length, 348

intraocular pressure (IOP), 350 normal ocular tissue, 346 particle size effect on particle

distribution, 349

particle suspensions delivery, 346–348 periocular tissues anatomy, 345–346 sclera–choroid interface, 346

Targeting nanotherapies, 281–282 Taurine, 100

Tauroursodeoxycholic acid (TUDCA), 563–566

T cell receptor (TCR), 541 Thrombospondin–1 (TSP–1), 517–518 Timolol, 113–114

Tissue partitioning, 563–570 Tobramycin, 367, 369 Topical drug delivery

anterior ocular surface to posterior segment, 114–116

posterior segment diseases, eye drops, 118–121

routes of drug penetration, 112–113 trans-corneal and periocular drug delivery,

116–118 Toxocariasis, 540

Toxoplasma gondii, 537, 540 Transconjunctival iontophoresis, 366 Trans-corneal and periocular drug delivery,

116–118 Transcorneal iontophoresis

adrenergic agents, 371 antibiotics, 367–370

Index

antiviral drugs, 370 corneal lesions, rabbit, 371 L-NAME, 371

Transporters

ATP-binding cassette (ABC) transporters, 100–101

efflux transporters, 100–103

influx transporters/receptors, 89–100 monocarboxylate transporters (MCTs), 94 organic cation transporters (OCTs), 96–97,

141–142 Transscleral diffusion, 175–176 Transscleral drug delivery, 296

in vitro permeability and release, 166–169

posterior segment ocular tissues, 160–162

scleral permeability, 163–165 scleral structure, 162–163 sustained-release delivery in vitro,

165–166 Transscleral iontophoresis

anti-inflammatory drugs aspirin, 379 carboplatin, 381

glucocorticoids, 379–380 lesions, 381–382

clinical application, 382–384 drug penetration routes, 372, 373 high drug concentration, 372 high molecular weight compounds

and proteins, 382 iontophoretic prototypes, 372, 373 MRI technology, 372, 373, 375 OcuPhor transscleral probe, 372, 374 optis transscleral probe, 372, 374

Transscleral pathways, 68, 69 Trans-vitreous route, 112–113, 116–117 Triamcinolone acetonide (TA), 461,

465, 501 Triesence™, 9 Trivaris™, 9

TUDCA. See Tauroursodeoxycholic acid (TUDCA)

U

UDCA. See Ursodeoxycholic acid (UDCA) Urokinase plasminogen activator (uPA),

503, 504 Ursodeoxycholic acid (UDCA),

563–570

Uvea-scleral route, 112–113, 117–118

589

Uveitis, 251–252 bacterial targets, 540 parasitic targets

ocular toxocariasis, 540 ocular toxoplasmosis, 537, 540

pathophysiology, 536–537 viral targets, 537

V

Valganciclovir, 537 Varicella zoster virus, 537

Vascular endothelial growth factor (VEGF) Trap-Eye™, 429

Vasostatin, 413–414

Verapamil, 34–35

Verisome™, 213

Vidarabine monophosphate (Ara-AMP), 370 Vitamin A, 535

Vitamin C, 98 Vitamin E, 98–99

Vitrasert®, 9, 12, 192, 332 Vitreal chamber, 28, 38

Vitreal pharmacokinetics, microdialysis posterior segment

anesthetized animal models, 27–37 conscious animal model, 37–41 rats model, 42–43

sampling site for, 22–23 principle

constant flow rate, 23–24 extraction efficiency/recovery,

24–27 Vitrectomised eyes, 148–150 Vitreous fluorescein, 68–69 Vitreous humor

ageing

ocular movements, role, 151–152 physical changes, 144–147 vitrectomised eyes, 148–151 vitreous degeneration, underlying

mechanisms of, 143–144 anatomy, 125–130 blood–retinal barrier (BRB) role

amino acid transport, 140 fluorescein and fluorescein

monoglucuronide, 142–143 organic anion transporters (OAT), 142 organic cationic transporters (OCT),

141–142 P-glycoprotein, 141

clearance pathways

aqueous clearance, 137–138