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Файл:Ординатура / Офтальмология / Английские материалы / Drug Product Development for the Back of the Eye_Kompella, Edelhauser_2011.pdf
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- •Drug Product Development for the Back of the Eye
- •Preface
- •Contents
- •Contributors
- •1.1 Introduction
- •1.2 A Strategic Overview of Drug Delivery Systems
- •1.3 Specific Approaches to Drug Delivery for the Posterior Segment
- •1.3.1 The Influence of Physicochemical Properties on Drug Delivery and Pharmacokinetics
- •1.3.2 The Chosen Route of Administration
- •1.3.3 Location of the Target Tissue
- •1.3.4 Potency of the Drug
- •1.3.5 Need for Continuous or Pulsatile Delivery
- •1.3.6 Duration of Drug Delivery Necessary to Induce and Maintain Efficacy
- •1.3.7 Type of Drug Delivery System Selected
- •1.3.8 Pharmacokinetic (PK) Properties of the Drug
- •1.3.9 Local and Systemic Toxicity of the Drug and its Metabolites
- •1.3.10 Previous Ocular Use of Excipients
- •1.3.11 Development and Strategic Team Input
- •References
- •2.1 Introduction
- •2.2 Posterior Segment as a Sampling Site
- •2.3 Principle of Microdialysis
- •2.3.1 Extraction Efficiency/Recovery
- •2.4.1 Anesthetized Animal Models
- •2.4.2 Conscious Animal Model
- •2.5 Vitreal Pharmacokinetics in Animals Other than Rabbits
- •2.6 Summary
- •References
- •3.1 Commercial Fluorophotometer
- •3.2 Normal Human Subject and Rabbit Ocular Fluorescence
- •3.3 Fluorophotometry Applications
- •3.3.1 Tear Turnover Rate (%/min)
- •3.3.2 Corneal Epithelial Cell Layer Permeability Methodologies
- •3.3.3 Eye Bath Technique
- •3.3.4 Single Drop Technique to Measure Epithelial Permeability
- •3.3.5 Eye Bath Technique to Measure Epithelial Permeability
- •3.4 Clinical Applications of Fluorophotometry
- •3.5.1 Transscleral Pathways
- •3.5.2 Suprachoroidal Injection
- •3.6 Retrobulbar Fluorescein Injection
- •3.7 Intravenous Fluorescein Injection In Vivo
- •3.8 Ocular Uptake of Fluorescein from Topical Eye Drops
- •References
- •4.1 Introduction
- •4.1.1 Role of the Blood-Retinal Barrier as a Dynamic Interface
- •4.1.2 Potential Approach of Blood-Retinal Barrier-Targeted Systemic Drug Delivery to the Retina
- •4.2.1 Amino Acid-Mimetic Drugs
- •4.2.2 Monocarboxylic Drugs
- •4.2.3 Nucleoside Analogs
- •4.2.4 Folate Analogs
- •4.2.5 Organic Cationic Drugs
- •4.2.6 Opioid Peptides and Peptidomimetic Drugs
- •4.2.7 Antioxidants
- •4.2.7.1 Vitamin C
- •4.2.7.2 Vitamin E
- •4.2.7.3 Cystine
- •4.2.8 Miscellaneous Protective Compounds
- •4.2.8.1 Creatine
- •4.2.8.2 Taurine
- •4.3.1 Organic Anion Transporter 3 (OAT3, SLC22A8)
- •4.3.3 P-Glycoprotein (ABCB1)
- •4.3.4 Multidrug Resistance-Associated Proteins (ABCCs)
- •4.3.6 ABCAs
- •4.4 Conclusions and Perspectives
- •References
- •5.1 Introduction
- •5.2 Drug Distribution
- •5.2.1 Drug Distribution from the Anterior Ocular Surface to the Posterior Segment
- •5.2.2 Studies of Trans-Corneal and Periocular Drug Delivery to the Retina
- •5.2.2.1 The Uvea-Scleral Route
- •5.3 Eye Drops for Posterior Segment Diseases in the Clinic
- •5.4 Summary
- •References
- •6.1 Introduction
- •6.2 Vitreous Anatomy
- •6.2.1 The Inner Limiting Membrane
- •6.3 The Vitreous As a Drug Reservoir
- •6.4 Flow Processes in the Vitreous
- •6.4.1 Flow Patterns
- •6.4.2 Injection and Hydrostatic Effects
- •6.4.3 Diffusion
- •6.4.4 Convective Flow
- •6.5 Clearance Pathways from the Vitreous Compartment
- •6.5.1 Charge and Collagen Interaction
- •6.5.2 Aqueous Clearance
- •6.5.3 Retinal Clearance
- •6.6 Transfer Through the Vitreoretinal Border
- •6.6.1 The Role of the Blood–Retinal Barrier
- •6.6.1.1 Amino Acid Transport
- •6.6.1.2 P-Glycoprotein
- •6.6.1.3 Organic Cationic Transporters
- •6.6.1.4 Organic Anion Transporters
- •6.6.1.5 Other Transporters
- •6.7 The Ageing Vitreous
- •6.7.1 Underlying Mechanisms of Vitreous Degeneration
- •6.7.2 Physical Changes Involved in the Ageing Vitreous
- •6.7.2.1 Pre-Clinical Model of Ageing Vitreous
- •6.7.2.2 Effects of Vitreous Liquefaction on Intravitreal Drug Delivery
- •6.7.3 Vitrectomised Eyes
- •6.7.3.1 Intravitreal Drug Distribution and Clearance in Silicone Oil
- •6.7.4 Role of Ocular Movements in Disordered Vitreous
- •6.8 Concluding Remarks
- •References
- •7.1 Introduction
- •7.2 Drug Delivery to Posterior Segment Ocular Tissues
- •7.3 Scleral Structure and Drug Delivery
- •7.4 Scleral Permeability: Initial Studies
- •7.5 Sustained-Release Delivery In Vitro
- •7.6 In Vivo Studies
- •7.7 Conclusions and Future Directions
- •References
- •8.1 Introduction
- •8.2 Background
- •8.3 Posterior Segment Delivery
- •8.4 Transscleral and Intrascleral Drug Delivery
- •8.5 Suprachoroidal Drug Delivery
- •8.6 Summary
- •References
- •9.1 Introduction
- •9.2 Nonbiodegradable Ocular Drug Delivery Systems
- •9.2.1 Retisert
- •9.2.2 Ocusert
- •9.2.3 Vitrasert
- •9.2.4 I-vation
- •9.2.5 Iluvien
- •9.2.6 Nonbiodegradable Matrix Implants
- •9.2.6.2 Punctal Plugs
- •9.3 Medical Applications for Biodegradable Polymers
- •9.3.3 Poly(Ortho Esters)
- •9.3.4 Polyanhydrides
- •9.5.1 Ozurdex™
- •9.5.2 Surodex
- •9.5.3 Verisome
- •9.5.4 Lacrisert
- •9.6.1 Poly(Lactic Acid)-Based Implants
- •9.6.2 PLGA-Based Implants
- •9.6.5 Poly(Ortho Ester)-Based Implants
- •9.6.6 Polyanhydride-Based Implants
- •9.6.7 Other Biodegradable Polymer-Based Implants
- •9.7 Conclusions
- •References
- •10.1 Introduction
- •10.2 Manufacturing of Microparticles
- •10.3 Characterization of Microparticles
- •10.3.1 Morphological Characterization of Microparticles
- •10.3.2 Particle Size Analysis and Distribution
- •10.3.3 Infrared Absorption Spectrophotometry (IR)
- •10.3.4 Differential Scanning Calorimetry (DSC)
- •10.3.5 X-Ray Diffraction
- •10.3.6 Gel Permeation Chromatography (GPC)
- •10.3.7 Determination of Drug Loading Efficiency
- •10.3.8 “In Vitro” Release Studies
- •10.3.8.1 Additives in Microspheres
- •10.4 Sterilization of Microparticles
- •10.5 Calculation of the Dose of Microparticles for Injection
- •10.6 Injectability Studies
- •10.7 In Vivo Studies
- •10.7.1 In Vivo Injection of Microparticles
- •10.7.2 Ocular Disposition and Cellular Uptake
- •10.7.3 Tolerance of Microparticles
- •10.7.4 In Vivo Degradation of PLA and PLGA Microparticles
- •10.8 In Vitro and In Vivo Correlation
- •10.9 Microparticles for the Treatment of Posterior Segment Diseases. Animal Models and Human Studies
- •10.9.1 Proliferative Vitreoretinopathy (PVR)
- •10.9.2 Uveitis
- •10.9.3 Age-Related Macular Degeneration (AMD)
- •10.9.4 Diabetic Retinopathy
- •10.9.5 Macular edema
- •10.9.6 Acute Retinal Necrosis (ARN)
- •10.9.7 Cytomegalovirus (CMV) Retinitis
- •10.9.8 Choroidal Neovascularization
- •10.9.9 Diseases Affecting the Optic Nerve
- •10.9.11 Microparticles in Retinal Repair
- •10.10 Conclusions
- •References
- •11.1 Introduction
- •11.2 Nanoparticles
- •11.2.1 Polymer Nanoparticles
- •11.2.2 Liposomes and Lipid Nanoparticles
- •11.2.3 Micelles
- •11.2.4 Protein Nanoparticles
- •11.2.5 Carbohydrate Nanoparticles
- •11.2.6 Dendrimers
- •11.2.7 Combination Nanosystems
- •11.3 Using Nanotechnology to Improve Ocular Therapeutics
- •11.3.1 Improving Patient Compliance
- •11.3.2 Increasing Drug Retention and Sustained Release
- •11.3.3 Increasing Permeability and Tissue Partitioning
- •11.3.4 Targeting Nanotherapies
- •11.3.5 Intracellular Trafficking
- •11.4 Alternative Approaches to Improve Ocular Therapeutics
- •11.5 Conclusion
- •References
- •12.1 Introduction
- •12.2 Hydrogel Technology
- •12.6 Future Directions
- •References
- •13.1 Introduction
- •13.2 General Design Considerations
- •13.2.1 Administration Site
- •13.2.2 Body Design
- •13.2.3 Port Design
- •13.2.4 Vacuum and Pressure
- •13.2.5 Flushing and Fluid Replacement
- •13.2.5.1 Active Pumps
- •13.2.5.2 Passive Systems
- •13.2.5.3 Solid Refill
- •13.2.6 Contamination Potential
- •13.3 Historical Influences
- •13.3.1 Infusion Pumps
- •13.3.2 Glaucoma Drainage Devices
- •13.3.3 Pioneering of Refill Procedure in the Eye
- •13.4 Ophthalmic Refillable Devices
- •13.4.1 Invasiveness and Refilling Frequency
- •13.4.2 Intravitreal Delivery Through the Pars Plana
- •13.4.3 Episcleral Implantation for Trans-Scleral Delivery
- •13.4.4 Subretinal and Suprachoroidal Implantation
- •13.4.5 Lens Capsule Delivery
- •13.5 Conclusions
- •References
- •14.1 Introduction
- •14.2 Current Methods of Drug Delivery to the Eye
- •14.3 Improved Methods of Drug Delivery to the Eye Using Microneedles
- •14.3.1 Intrastromal Delivery to the Cornea Using Coated Microneedles
- •14.3.3 Suprachoroidal Delivery Using Hollow Microneedles
- •14.4 Microneedle Types and Other Applications
- •14.4.1 Poke and Apply
- •14.4.2 Coat and Poke
- •14.4.3 Poke and Release
- •14.4.4 Poke and Flow
- •14.5 Discussion
- •14.6 Conclusion
- •References
- •15.1 Introduction
- •15.1.1 General Mechanisms of Iontophoretic Drug Delivery
- •15.1.2 The Shunt Pathway
- •15.1.3 The Flip–Flop Gating Mechanism
- •15.1.4 Electro-Osmosis
- •15.2 Ocular Drug Delivery: The Past and the Future
- •15.3 Ophthalmic Applications of Iontophoresis
- •15.3.1 Transconjunctival Iontophoresis
- •15.3.1.1 Transconjunctival Iontophoresis of Antimitotics
- •15.3.1.2 Transconjunctival Iontophoresis of Anesthetics
- •15.3.2 Transcorneal Iontophoresis
- •15.3.2.1 Transcorneal of Fluorescein Iontophoresis for Aqueous Humor Dynamic Studies
- •15.3.2.2 Transcorneal Iontophoresis of Antibiotics
- •15.3.2.3 Transcorneal Iontophoresis of Antiviral Drugs
- •15.3.2.4 Other Drugs for Transcorneal Iontophoresis
- •15.3.2.5 Is Transcorneal Iontophoresis Safe?
- •15.4 Transscleral Iontophoresis
- •15.4.1 Transscleral Iontophoresis of Antibiotics
- •15.4.2 Transscleral Iontophoresis of Antiviral Drugs
- •15.4.3 Transscleral Iontophoresis of Anti-Inflammatory Drugs
- •15.4.3.1 Aspirin
- •15.4.3.2 Glucocorticoids
- •15.4.3.3 Transscleral Iontophoresis of Carboplatin
- •15.4.3.4 Is Transscleral Iontophoresis Safe?
- •15.4.3.5 Transscleral Iontophoresis for High Molecular Weight Compounds and Proteins
- •15.4.3.6 Clinical Application of Transscleral Iontophoresis
- •15.5 Applications of Iontophoresis to Ocular Gene Therapy
- •15.6 Future Developments
- •References
- •16.1 Introduction
- •16.2 Background
- •16.2.1 Intravitreal Injections
- •16.2.2 Impact of Genetics
- •16.3 Better Tools for Delivery and Treatment
- •16.3.1 Barriers to Success
- •16.3.2 Physics-Based Approaches
- •16.3.2.1 Physical Methods to Deliver Drugs to a Target Cell in the Posterior Segment
- •16.3.2.2 History of Electrical Fields in Medicine
- •16.3.2.3 Safety Concerns with Electric Fields
- •16.3.2.4 Definitions of Electric Field Methods
- •16.3.2.5 Advantages of Electric Fields for DNA Transfection vs. Viral Mediated DNA Delivery
- •16.3.2.6 Problems of In Vivo Electric Field Applications
- •16.3.2.7 Possible Strategies to Improve Electric Field-Mediated Drug Delivery
- •16.3.3 Experiences with Iontophoresis
- •16.3.3.1 Examples of Iontophoresis
- •16.3.3.2 Summary of the Strengths and Weaknesses of Iontophoresis
- •16.3.4 Experiences with Electroporation
- •16.3.4.1 Examples of Electroporation in Living Animals
- •16.3.4.2 Strengths and Weaknesses of Electroporation
- •16.4 Outstanding Issues in Electric Fields for the Delivery of Drugs
- •16.5 Summary
- •References
- •17.1 Introduction
- •17.2 Routes of Protein Administration
- •17.2.1 Topical
- •17.2.2 Intracameral
- •17.2.3 Intravitreal
- •17.2.4 Periocular (Transscleral)
- •17.2.5 Suprachoroidal
- •17.2.6 Subretinal
- •17.2.7 Systemic
- •17.3 Advantages and Challenges of Protein Delivery
- •17.4 Current Development Strategies
- •17.4.1 Pure Protein
- •17.4.2 PEGylation
- •17.4.4 Liposomes
- •17.4.5 Stem Cells
- •17.4.6 Implants
- •17.5 Case Studies
- •17.6 Ophthalmic Protein Formulation Development
- •17.6.1 Protein Biosynthesis
- •17.6.2 Preformulation Studies
- •17.6.3 Selection of Excipients
- •17.6.4 Optimization of Process Variables
- •17.7 Specifications and Regulatory Guidelines
- •17.8 Conclusions
- •References
- •18.1 Need for Suspension Development for the Back of the Eye
- •18.2 Background
- •18.3 Development of Drug Suspensions Intended for the Back of the Eye
- •18.3.1 Drug Suspensions
- •18.3.1.1 Physical Pharmacy Principles that Explain the Stability and Formulation of Suspensions
- •18.3.1.2 Formulation Methodology
- •18.3.1.3 Manufacturing Process
- •18.3.2 Factors To Be Considered in Suspension Development for the Back of the Eye
- •18.3.2.1 Formulation Development and Evaluation
- •18.3.2.2 In Situ Forming Suspensions, Selection of Drug Form for Suspension, and Polymeric Microparticle Suspension
- •18.3.2.3 Clinical Studies on Safety
- •18.4 Conclusions
- •References
- •19.1 Introduction
- •19.2 Drug Product Approval Process
- •19.3 Considerations for Back of the Eye Treatments
- •19.4 Adaptive Trial Design
- •19.5 Drug-Device Combinations
- •19.6 Product Summary Basis of Approval Reviews
- •19.6.1 OZURDEX™
- •19.6.2 LUCENTIS™
- •19.7 Summary
- •References
- •20.1 Background
- •20.2 FDA Endpoints
- •20.3 Endpoints for Neovascular Age-Related Macular Degeneration (Table 20.1)
- •20.4 FDA Guidelines for Other Retinal Diseases
- •20.5 Endpoint for Geographic Atrophy
- •20.6 Endpoint for Retinal Vein Occlusion
- •20.7 Future Endpoints
- •References
- •21.1 Introduction
- •21.2 Ocular Physiology and Pathology
- •21.2.1 Ocular Inflammation
- •21.2.2 Neovascularization
- •21.2.3 Degeneration
- •21.3 Current Therapies for Key Back of the Eye Disorders
- •21.3.1 Age-Related Macular Degeneration
- •21.3.1.1 Pathophysiology
- •21.3.1.2 Therapeutics Either in Current Use or in Clinical Trials
- •21.3.1.3 Current Research Focused on Identifying New Targets
- •21.3.2 Diabetic Retinopathy
- •21.3.2.1 Pathophysiology
- •21.3.2.2 Therapeutics Either in Current Use or in Clinical Trials
- •21.3.3 Retinopathy of Prematurity
- •21.3.3.1 Pathophysiology
- •21.3.3.2 Therapeutics Either in Current Use and in Clinical Trials
- •21.3.4 Degenerative Conditions
- •21.3.4.1 Pathophysiology
- •21.3.4.2 Therapeutics Either in Current Use or in Clinical Trials
- •21.3.5 Opportunistic Infections
- •21.3.5.1 Pathophysiology
- •21.3.5.2 Therapeutics Either in Current Use or in Clinical Trials
- •21.3.6 Autoimmune Disease
- •21.3.6.1 Pathophysiology
- •21.3.6.2 Therapeutics Either in Current Use or in Clinical Trials
- •21.4 Conclusion
- •References
- •22.1 Bile Acids as Anti-Apoptotic Neuroprotectants
- •22.3 Potential Need for Local Delivery of Bile Acids as Neuroprotectants
- •22.4 Preliminary Studies of Ocular Delivery of Bile Acids
- •22.5 Conclusion
- •References
- •Index
192 |
S.S. Lee et al. |
ophthalmic delivery device. It consists of pilocarpine and alginic acid contained within a reservoir enclosed by two release-controlling membranes made of EVA copolymer surrounded by a ring to aid in positioning and placement (Conway 2008; Ghate and Edelhauser 2006). While this product represented a major innovation in ophthalmic drug delivery technology, its use was limited by complications associated with device insertion and removal and the later development of more effective topical antiglaucoma medications for lowering intraocular pressure (Conway 2008; Kearns and Williams 2009).
9.2.3 Vitrasert
Vitrasert® (Bausch and Lomb, Inc., Rochester, NY, USA) is a nonbiodegradable polymeric intravitreal ganciclovir implant developed for the treatment of cytomegalovirus retinitis. Ganciclovir is encapsulated within a reservoir, encased by a PVA/EVA membrane, and diffuses out according to zero-order release kinetics when fluid enters the device and creates a saturated solution (Yasukawa et al. 2006). The device provides sustained release of ganciclovir for 5–8 months and achieves higher intraocular drug concentrations as compared with systemic administration. The ganciclovir implant is ideal for cytomegalovirus retinitis lesions that pose an immediate risk to vision, and combination treatment with oral valganciclovir can be used to prevent second-eye involvement (Kedhar and Jabs 2007).
9.2.4 I-vation
I-vation™ (SurModics, Inc., Eden Prairie, MN) is a nonbiodegradable intra-vitreal implant consisting of a nonferrous metal alloy helix coated with a triamcinolone acetonide-containing polymer, similar to the design of drug-eluting cardiovascular stents (Kearns and Williams 2009). The device has a sharpened tip, which is used to make the incision for implantation, and its helical shape maximizes the surface area for drug coating and enables secure anchoring to the pars plana/sclera (Conway 2008). The polymers used to manufacture the device are a proprietary blend of polybutyl methacrylate (PBMA) and PVA, the ratio of which can be customized to vary the drug delivery rate (1–3 mg/day) and corresponding duration of delivery (6–24 months) (Kiernan and Mieler 2009). I-vation had been under investigation for the treatment of diabetic macular edema, but early trials evaluating the device reported the incidence of intraocular pressure elevation, conjunctival hemorrhage lenticular opacities, and endophthalmitis, and one phase 2 trial (clinicaltrials.gov study ID NCT00692614) was halted prematurely in 2008 (Kiernan and Mieler 2009).
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