Implant Design for Ophthalmic Delivery: The place of materials and fabrication methods

Size: px

Start display at page:

Download "Implant Design for Ophthalmic Delivery: The place of materials and fabrication methods"

Carol Burke
5 years ago
Views:

1 Implant Design for Ophthalmic Delivery: The place of materials and fabrication methods Clive G Wilson, Strathclyde Institute of Pharmacy & Biomedical Sciences

2 World demographics

3 Glaucoma Numbers on the Rise! The leading cause of irreversible blindness worldwide Impact of Glaucoma in Africa Egypt 3

Glaucoma The disease Glaucoma was recognised by the Greeks. It arose from observing the pupil area. Glaucomatous eyes have a greyish-blue/green color (In Greek Glaukos means light green ).

4 Glaucoma The disease Glaucoma was recognised by the Greeks. It arose from observing the pupil area. Glaucomatous eyes have a greyish-blue/green color (In Greek Glaukos means light green ). During an attack of acute glaucoma, intra-ocular pressure rises and the retinal blood supply is compromised Treatment is to reduce secretion of aqueous humour and maintain the outflow Mainstay drugs are carbonic anhydrase inhibitors, beta blockers especially timolol, alpha-1 agonists such as bromonidine and prostaglandins including latanoprost and bimatoprost.

5 Amount of drug

6 Reservoir formed close to target

7 S&N Soluble PVA flag containing pilocarpine base

8 Scleral absorption and NODS 1 minute C G Wilson OcT

9 5 minutes 300s

10 600s 10 minutes

11 INCREASE IN BIOAVAILABILITY WHEN PILOCARPINE IS DELIVERED AS THE FREE BASE

12 Access to posterior tissues from the anterior surfaces is difficult Turnover of aqueous humour Tear loss Bekkerman et al., 2014 J Ophthal. Article ID , 5 pages, doi: /2014/ Convective flow allows drugs to be eliminated either through the anterior chamber or the posterior retina

13 Human vitreous of a 9- month-old child dissected of the sclera, choroid, and retina, is still attached to the anterior segment. Although the specimen is situated on a surgical towel in room air, the vitreous maintains its shape, because in youth the vitreous body is nearly entirely gel. From Sebag 2002 Courtesy Rad Tzekov

14 Dark-Field Illumination system Schematic diagram of dark-field illumination system for the study of vitreous structure. The dissected specimen is mounted and immersed in a Lucite chamber containing a physiologic solution. From Sebag 1991 Courtesy Rad Tzekov

15 The ageing eye 33 week 88y 59y 6y Seebag J (1987)

16 The ageing Human eye

18 Simple Diffusion medium? Pour vitreous into a glass cuvette and add 100 µl 10 µ fluorescent beads with a syringe..

19 10 µm particles in PBS (control) 2 hours 3 hours 5 hours After injection Needle out 30 mins 1 hour

20 Collagenase (10mg/mL)-treated vitreous repeat II 1.5 hours 2 hours 3 hours 5 hours After injection Needle out 30 mins 1 hour

21 3D structure of the human vitreous body (according to Jongebloed & Worst 1987)

22 Fluorescent intensity of FD 150kDa Plot generated using Matlab (based on HRA images) Means (n=3) ± s.d.

23 The Product Ozurdex Allergan, Inc. Ozurdex Applicator Ozurdex implanted in anterior chamber 23

24 Application 24

25 Challenge Possible Causes of Swelling/Deformation? Processing Parameters Formulation Parameters New Polymers Polymer Modification PDLLA PGA PCA Fibrin Collagen PLA PPZ Hyaluronate PHA PHB PCL Cellulose Chitin Starch PAA PES The Chemistry 25

26 What causes Swelling? Water Poly (Lactide Co- Glycolide) Water Glycolide Lactide Source of Hydrophilicity? Concept 1: Capping would decrease hydrophilicity 26

27 Endcapping Glycolide Lactide - R - R - OH End Capping - R NH2 R = (C 2~4 - C 12~16 ) Physicochemical Properties Mechanical Thermal Degradation Release Hydrophillicity Profiles Properties Rate 27

28 Heat Flow into polymer Heat flow into polymer Heat flow into polymer Heat flow into polymer What causes Deformation? Heating a Crystalline Solid Heating an Amorphous Polymer solid Increase in temperature and energy absorbed liquid Amorphous state Glassy state (hard, rigid, brittle) Rubbery state (flexible) Rubbery solid Tm Tm Tg Tg Temperature Temperature Temperature Temperature

29 Endcapping Challenges 3. Optimization Two Parameters Tg Hydrophilicity 29

30 Change in Mass (%) Change In Mass (%) Effect of Dodecyl Ester Endcap (Ch3) Swelling Studies - DVS Cycle 1 Sorp Cycle 1 Desorp Cycle 2 Sorp Cycle 2 Desorp Target RH (%) Target RH (%) Sorption-Desorption curves for Non endcapped PLGA 15k Sorption-Desorption curves for PLGA 15k D (E) Non-endcapped PLGA showed obvious hysteresis when compared to its endcapped counterpart indicating that water was absorbed into rather than adsorbed onto the surface of the film

31 Effect of Dodecyl Ester Endcap (Ch3) Water Diffusion Studies M t /M inf R² = R² = K 15k DD E K Time (sec) M t /M inf Polymer Diffusion Coefficient 15 K- OH 1.95E K-D[E] 2.29E-11 t 10X

32 % Swelling Decrease Effect of Molecular Weight (Ch3) % Tg Increase H Bond Molecular Weight (Mw 10 3 ) Chain entanglement

Cummulative Release (%w/w) Group I: Effect of Endcapping on brimonidine base release Group I: Effect of Endcapping (Acid vs Amide vs Ester) on 1% BFB Loaded 15k PLGA implants

33 Cummulative Release (%w/w) Group I: Effect of Endcapping on brimonidine base release Group I: Effect of Endcapping (Acid vs Amide vs Ester) on 1% BFB Loaded 15k PLGA implants k-Dd-E-1%BFB 15K-C-E-1%BFB 15K-OH-1%BFB Sample SEM 80 15k-Dd-A-1%BFB 70 15k-OH-1% BFB k-Dd-E-1% BFB k-Dd-A-1% BFB Time (day) 33

34 % water uptake Water Uptake comparison of ester and amide substitution on 15 dodecyl endcapped polymer K-OH 15K-Dd-E 15K-Dd-A Time (day)

Outcomes: Ms Mariam Badawi Chemical modification of the PLGAspecifically endcapping with amide or ester groups alters the swelling and thermal properties of the families of polymers For a given

35 Outcomes: Ms Mariam Badawi Chemical modification of the PLGAspecifically endcapping with amide or ester groups alters the swelling and thermal properties of the families of polymers For a given motif, we were able to construct relationships across molecular weights of the endcapped polymers to predict drug release Next stage of the work is larger scale production of selected polymers for further study.

36 It s all done with colleagues Allergan Irvine,

Issued: 02/07/06 Spring 2006 Due: 02/16/06 10 points/problem

Problem Set 1 solutions 20.462J/3.962J Issued: 02/07/06 Spring 2006 Due: 02/16/06 10 points/problem 1. Listed in the table below are chemical and schematic structures of poly(l-lactide) and a number of