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FY2016 Regulatory Science Report: Ophthalmic Products

This section contains only new information from FY2016. For background scientific information and outcomes from previous years on this research topic, please refer to the FY15 Regulatory Science Research Report on Ophthalmic Products.


To date, OGD has funded 10 external grants and contracts focusing on ophthalmic products. There are 8 projects that focus on development of in vitro release and physical characterization methodologies that can be used to detect differences in product performance resulting from various manufacturing processes and to predict in vivo performance. Two projects focus on physicologically-based pharmacokinetic (PBPK) modeling and simulation approaches to predict the effect of formulation-related factors on ophthalmic drug absorption, distribution, and clearance in various eye tissues. Knowledge gleaned from these projects will help FDA determine BE methods for ophthalmic products and help industries develop generic products.


Dissolution and Physicochemical Characterization of Ophthalmic Ointments
Ointment drug products have been used clinically for the treatment of locally occurring eye conditions, such as infections and inflammation. These formulations, while often composed of just two or three ingredients, can exhibit complex physciochemical characteristics that are challenging to correlate with drug product performance. In addition, in vitro methods designed to evaluate quality and performance of ointment drug products intended for ocular drug delivery have not been well developed. Currently, FDA has funded two research grants addressing ophthalmic ointment drug products: 1U01FD005177-01 and 1U01FD005174-01. The objectives of these research grants are to 1) investigate dissolution methods for ophthalmic ointment drug products and to analyze their capability of detecting manufacturing differences, predicting in vivo performance, and evaluate method robustness, and 2) evaluate how differences in manufacturing affect physicochemical characteristics of ophthalmic ointments. While these research grants are still ongoing, initial findings suggest that differences in manufacturing can alter rheological properties across ointment formulations, while largely not affecting the particle size distribution of the API. In addition, excipient source can influence the rheology of ointment formulations. Lastly, both differences in manufacturing and excipient source can impact drug release rates from ointment formulations.

Dissolution and Physicochemical Characterization of Ophthalmic Suspensions and Emulsions
Q1/Q2 (compositionally equivalent) ophthalmic suspension formulations were manufactured using indomethacin. The manufacturing method was varied to produce particles that varied in size and viscosity. A flow through dissolution device was designed so that the suspension (50 µl) is injected in the upper compartment, and the samples are withdrawn from the lower compartment under a filter membrane. The upper compartment was static while sink conditions prevailed in the lower compartment with flow. In vivo experiments were carried out in albino rabbits. Suspensions were instilled into the eyes and drug concentrations were determined at various times until four hours from the lacrimal fluid, cornea and aqueous humour using LC/MS. Computational models were built to simulate drug dissolution in the flow device and pharmacokinetic processes in the rabbit eyes. The dissolution rates increased with decreasing particle size and the dissolution lasted about two hours for indomethacin. In vivo rabbit experiments revealed differences in the indomethacin suspension behavior: smaller particle size resulted in higher ocular bioavailability and peak concentrations of indomethacin in aqueous humour, while lowering of viscosity resulted in reduced concentration in the cornea and aqueous humour. Computational models were successfully built and simulation results were compared with the in vivo experiments using dissolution rates from flow device experiments as drug input rates.

In addition, Q1/Q2 ophthalmic emulsion formulations were manufactured using difluprednate. The manufacturing method was varied to produce globules that varied in size. In vitro release of Durezol® and the test formulations were investigated by dialysis method, gel chromatography and microdialysis. The dialysis method using a CE 20kD membrane could differentiate the release profiles of some test formulations. Further work on optimization of the microdialysis method is ongoing.

Prediction of intravitreal drug delivery of porous silicon particles
For many diseases of the eye such as choroidal neovascularization (CNV) in age-related macular degeneration (ARMD) or proliferative viteoretinopathy (PVR), sustained release therapeutic agents are delivered via intravitreal injection for treatment times varying between 0.25-3 years. The eye poses a particular challenge for delivery systems because of the sensitive foreign object response of ocular tissues. Porous silicon is an optimal material for many biological applications because of its excellent biocompatibility, degradability and versatile surface chemistry. In this project with the University of California - San Diego, objective is to design an in vitro setup that can mimic the eye to test these delivery systems and discriminate between similar formulations (such as generics). The most significant findings to date with characteristic figures and graphs are included below:

1.       A flow cell to be used in the in vitro dissolution device has been designed to prevent leakage and maintain the pressure. In addition, the quartz window provides the visualization and enable the imaging measurement. Figure 1 depicts the features of the flow cell and figure 2 is the picture of the whole in vitro dissolution study setup.

Figure 1. Flow cell design for In vitro dissolution study (Courtesy of Dr. Michael Sailor, UCSD)

Figure 1Figure 2. In vitro dissolution experiment setup (Courtesy of Dr. Michael Sailor, UCSD)

Figure 2

2.       Release experiments with two commercially available drug products (Kenalog 40 and Triesence) have been conducted under different flow rates and different hyaluronic acid concentrations to mimick the vitreous. Typical static release conditions, which are commonly performed in literature, were considered to be inadequate for mimicking the release of therapeutics in vivo and a flow rate of 5 μL/min was used to mimic the in vivo condition. Figure 3 is the cumulative release profiles of those two drug products under different conditions and figure 4 shows the calculated half-lives of the two drug products based on in vitro release results (the red horizontal line is the in vivo half-life value from literature).

Figure 3. Cumulative release of (a) Kenalog40 and (b) Triesence under different flow conditions (Courtesy of Dr. Michael Sailor, UCSD)

Figure 3

Figure 4. Calculated half-life values from (c) Ke-nalog40 and (d) Triesence (Courtesy of Dr. Michael Sailor, UCSD)

Figure 43.   The fabrication procedure for the proposed drug loaded porous silicon microparticles has been optimized as shown in Figure 5. In vivo studies are currently underway.

Figure 5. Scheme of the fabrication process of porous silicon microparticles (Courtesy of Dr. Michael Sailor, UCSD)

Figure 5

ORS staff facilitating research in this area

  • Bryan Newman, Stephanie Choi, Yan Wang, Darby Kozak, Yuan Zou, Peter Petrochenko

Projects and Collaborators

  • In Vitro-In Vivo Correlation of Ocular Implants
    • Site PI: Uday Kompella
    • Grant #: 1U01FD004929-01
  • Evaluation and Development of Dissolution Testing Methods for Semisolid Ocular Drug Products
    • Site PI: Diane Burgess
    • Grant #: 1U01FD005177-01
  • Dissolution Methods for Predicting Bioequivalence of Ocular Semi-Solid Formulations
    • Site PI: Xiuling Lu
    • Grant #: 1U01FD005174-01
  • Modeling of the vitreous for in vitro prediction of drug delivery of porous silicon particles and episcleral plaques
    • Site PI: Michael Sailor
    • Grant #: 1U01FD005173-01
  • Topical Ophthalmic Suspensions: New Methods for Bioequivalence Assessment
    • Site PI: Arto Urtti
    • Grant #: 1U01FD005180-01
  • Dissolution Methods for Topical Ocular Emulsions
    • Site PI: Srinath Palakurthi
    • Grant #: 1U01FD005184-01
  • PBPK Modeling and Simulation for Ocular Dosage Forms
    • Site PI: Michael Bolger
    • Grant #: 1U01FD005211-01
  • An integrated multiscale-multiphysics modeling and simulation of ocular drug delivery with whole-body pharmacokinetic response
    • Site PI: Kay Sun
    • Grant #: 1U01FD005219-01
  • Pulsatile microdialysis for in vitro release of ophthalmic emulsions (New)
    • Site PI: Robert Bellatone
    • Contract #: HHSF223201610105C

Publications and Presentations

  • Matter, B., Ghaffari, A., Bourne, D., Wang, Y., Choi, S., Kompella, U.B. Dexamethasone Degradation During In Vitro Release from an Intravitreal Implant. ARVO Seattle, WA (May 1-5, 2016) B0188
  • Design and Validation of an Intraocular In Vitro Simulator. J. Wang, T. Kumeria, M. Sailor, D. Warther, CRS Seattle, WA (July 17-20, 2016)
  • Silicon-Based Nanomaterials for Ocular Drug Delivery. M. Sailor, J. Wang, T. Kumeria, L. Cheng, H. Hou, W. Freeman. CRS Seattle, WA (July 17-20, 2016)
  • An Update on FDA’s Research Program for Ophthalmic Generic Products. S. Choi, CRS, Seattle, WA (July 17-20, 2016)
  • Alternative Approaches to Demonstrate Bioequivalence of Ophthalmic Products and the Role of Regulatory Science. S. Choi, AAPS Pre-conference workshop on Locally acting drug products: Bioequivalence Challenges and Opportunities, Denver, CO (November 11-12, 2016)
  • Manufacturing Differences on Physicochemical and In Vitro Release Characteristics of Semisolid Ophthalmic Ointments. Quanying Bao, Jie Shen, Bryan Newman, Yan Wang, Stephanie Choi, Diane J Burgess. AAPS Denver, CO (November 13-17, 2016)
  • Impact of Excipient Sources on In Vitro Drug Release Characteristics of Semisolid Ophthalmic Ointments. Quanying Bao, Jie Shen, Bryan Newman, Yan Wang, Stephanie Choi, Diane J. Burgess. AAPS Denver, CO (November 13-17, 2016)
  • Toward Development of Sensitive In Vitro Drug Release Methods for Difluprednate Ophthalmic Emulsion. Mahendra, H, et al. AAPS Denver, CO (November 13-17, 2016) 33T0200
  • Physical Formulation Features and Ocular Absorption from Topical Suspensions: Toward Mechanistic Understanding. Toropainen, E., et al. AAPS Denver, CO (November 13-17, 2016) 05T0430



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