Applications of Sustained Release Delivery Systems in Ocular Disease

Size: px

Start display at page:

Download "Applications of Sustained Release Delivery Systems in Ocular Disease"

Shonda Sullivan
5 years ago
Views:

1 Applications of Sustained Release Delivery Systems in Ocular Disease Formulation and Delivery Systems For Peptide and Protein 2012 December 5, 2012 Christopher A. Rhodes, Ph.D. Principal, Christopher A Rhodes & Associates, LLC Biopharmaceutical Consulting Practice chris.rhodes45@gmail.com

2 Content Market Overview Unmet Needs in Glaucoma and Retinal Disease Emerging Treatments 2

Know Your Technology Options, Technical and Market Constraints

gram Physicochemical properties Delivery System Process complexity

Device complexity Ease of use / acceptance Cost per unit

3 Know Your Technology Options, Technical and Market Constraints Molecule Efficacy / side effects Continuous or pulsatile Cost per gram Physicochemical properties Delivery System Process complexity Bioavailability Cost per unit Compatibility with molecule Device Device complexity Ease of use / acceptance Cost per unit Formulation compatibility Biology & Chemistry PK & Formulation Device & Handling 3

4 Ocular Delivery Techniques and Challenges 4

5 Market Overview All Ocular Indications Global sales in billions of USD, market share 4.1, 28% 1.9, 13% 1.7, 12% 5.3, 37% 1.4, 10% Glaucoma Allergy/inflammation/infection Retinal disorders Dry eye Others IMS Health % of Ocular Products are Topical 5

6 Top Ocular Pharmaceutical Products Company Indication World sales (millions of USD) Lucentis Genentech (Roche) Wet AMD 1,785 Xalatan Pfizer Glaucoma 1,524 Travatan Alcon Glaucoma 565 Patanol/Pataday Alcon Allergy 511 Restasis Allergan Dry Eye 480 Cosopt Merck Glaucoma 462 Lumigan Allergan Glaucoma 433 Alphagan Allergan Glaucoma 337 Azopt Alcon Glaucoma 269 Vigamox Alcon Infection 252 Tobradex Alcon Inflammation 240 Hyalein Santen Dry Eye 209 IMS Health

7 The Eye and Its Many Chambers Aqueous Humor Anterior (Front of Eye) Posterior (Back of Eye) 7

8 Glaucoma Treatments (Front of the Eye) Majority are topical drops Treat symptomatic increase in intraocular pressure (aqueous humor) Delivery Systems Primary focus on moving multiple daily drops to once per day Inserts in development for once per week administration Unmet Need for Delivery Systems Once every three months injection Subconjunctival injection depot Patients see the doctor once every three months 8

9 Glaucoma Delivery System Opportunities Sustained Release Depot System PLGA or other polymer implant or microparticle Primarily small molecules Polymer inserts Physician administered therapy Glaucoma physicians not yet comfortable with injection Must be a simple injection Delivery Constraints Injection site is conjunctiva Safety first must not cause inflammation or tolerability issues Volume of injection is preferably 50 microliters 100 to 200 microliters may be tolerated 27 guage needle or better 9

10 Back of the Eye Diseases Diseases of the Retina, Vitreous, and Macula VITREOUS 10

11 Back of the Eye Drug Delivery Approaches 11

12 Back of the Eye Diseases Diseases of the Retina, Vitreous, and Macula Age related macular degeneration Retinitis pigmentosa Diabetic retinopathies Neural changes induced by glaucoma Age-Related Macular Degeneration (AMD) Leading cause of severe vision loss in people over 50 20/200 or worse visual acuity Most people have dry form no treatment available Wet form is less common but treatment exists Laser photocoagulation therapy Pharmacotherapies 12

Back of the Eye Diseases Dry AMD Cells of macula breakdown Drusen deposits Death of RPE and photoreceptor cells Blurry or spotty loss of clear, straight ahead vision 90% of cases Wet AMD Abnormal

13 Back of the Eye Diseases Dry AMD Cells of macula breakdown Drusen deposits Death of RPE and photoreceptor cells Blurry or spotty loss of clear, straight ahead vision 90% of cases Wet AMD Abnormal blood vessels grow - neovascularization Leak fluid and blood scarring macula Straight ahead vision can be distorted or lost in a short period of time 10% of cases 90% of legal blindness 13

14 Imaging Techniques for Early Detection Drusen Normal Dry AMD Wet AMD Symptoms Wet AMD 14

15 AMD Treatment Options Growing Rapidly (Preclinical, Clinical, Approved) BA Zarbin and PJ Rosenfeld, RETINA 30: ,

16 Targets for Drug Development Steps in AMD Pathogenesis Oxidative damage Lipofuscin accumulation Chronic inflammation Mutations in the complement pathway Noncomplement mutations that influence chronic inflammation and/or oxidative damage Steps in Neovascularization Angiogenic factor production Factor release Binding of factors to extracellular receptors Endothelial cell activation and basement membrane degradation Endothelial cell proliferation Directed endothelial cell migration Extracellular matrix remodeling Tube formation Vascular stabilization BA Zarbin and PJ Rosenfeld, RETINA 30: ,

17 Properties of Biologics in Systemic Disease 100 Antibodies 100 SC or IV Dose (mg) 10 Proteins 10 Plasma Half-life (hrs) 1 Peptides Molecular Weight (kda) 17

18 Pharmacokinetics in the Eye Anterior chamber Posterior chamber Fig. 1. Schematic presentation of the ocular structure with the routes of drug kinetics illustrated. The numbers refer to following processes: 1) transcorneal permeation from the lacrimal fluid into the anterior chamber, 2) non-corneal drug permeation across the conjunctiva and sclera into the anterior uvea, 3) drug distribution from the blood stream via blood-aqueous barrier into the anterior chamber, 4) elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and Sclemm's canal, 5) drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier, 6) drug distribution from the blood into the posterior eye across the blood-retina barrier, 7) intravitreal drug administration, 8) drug elimination from the vitreous via posterior route across the blood-retina barrier, and 9) drug elimination from the vitreous via anterior route to the posterior chamber. A Urtti, Advanced Drug Delivery Reviews 58 (2006)

19 Local Intravitreal Injection Reduces Dose by Fold Increases Half-life in the Vitreous by 3 5 Fold Ocular Dose (mg) Peptides Proteins Antibodies Intravitreal Half-life (hrs) Molecular Weight (kda) 19

20 Pharmacokinetics in the Eye Vitreous Large hydrophilic and charged molecules active transport mechanisms Often slower elimination than systemic circulation Peculiarities for Development Cannot sample ocular tissues in humans, only plasma Exposure response relationships and tissue distribution in animals critical Plasma levels guide human studies based on models from animals 20

21 Ranibizumab Pharmacokinetics in the Eye [Lucentis approved for AMD, DME, RVO] Intravitreal half-life 3.5 days Intravenous half-life 15 hours Gaudreault et al., IOVS (2)

22 Current and Future Drugs for Choroidal Neovascularization antibody oligo peptide Kuno and Fujii, Drugs Aging (2)

23 Current and Future Drugs for Macular Edema antibody oligo peptide Kuno and Fujii, Drugs Aging (2)

24 Current and Future Drugs for AMD antibody oligo peptide other Kuno and Fujii, Drugs Aging (2)

25 Antibodies Ranibizumab (Lucentis) Aflibercept (Eylea) 25

26 Oligonucleotides, Aptamers, sirna Pegaptanib (Macugen) 26

27 Peptides POT-4 analogue of Compstatin 27

28 Back of The Eye Treatments Majority today are implants of small molecules Emerging therapies are once per month intravitreal injections of proteins Delivery Systems for Peptides and Proteins Reduce monthly injection frequency Reduce doctors visits and improve therapy Unmet Need for Delivery Systems Intravitreal injection depot for once every 4 to 6 months 28

29 Back of the Eye Delivery System Opportunities Sustained Release Depot System PLGA or other polymer implant or microparticle Systems designed for Proteins and Peptides Maintaining stability is key Physician administered therapy Retinal physicians very comfortable with injection Must be a simple injection Delivery Constraints Injection site is vitreous cavity Safety first must not cause inflammation or tolerability issues Volume of injection is preferably 50 microliters 100 microliters may be tolerated 27 guage needle or better 29

30 Primary Routes of Ocular Administration Anterior chamber Topical drops Implants with drug that diffuses to front of eye Posterior chamber Direct injection into vitreous Implants with drug that diffuses to vitreous, choroid B Short, Toxicol Pathol 2008, 36 (1)

Ophthalmic VEGF Inhibitors. Eylea (aflibercept), Macugen (pegaptanib) Description

Ophthalmic VEGF Inhibitors. Eylea (aflibercept), Macugen (pegaptanib) Description Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 Subject: Ophthalmic VEGF Inhibitors Page: 1 of 5 Last Review Date: September 20, 2018 Ophthalmic VEGF Inhibitors