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Overcoming Challenges in Ophthalmic Formulations through Polymer Selection

Ophthalmic drugs are delivered to the eye to treat chronic diseases such as dry eye and acute conditions such as inflammation and infections.

The market for drugs administered to the eye is growing, in large part, due to our aging population and the increased prevalence of eye-related conditions such as diabetic retinopathy and macular degeneration. In addition, increased screen time, partially due to the pandemic, has negatively impacted eye health in both adults and pediatric populations.

In this technical article, we discuss:

How Can Ophthalmic Drugs be Administered?

Ophthalmic drugs can be delivered to the eye via intravitreal injection, subconjuctival injection, subretinal injection and topical administration. Topical ophthalmic formulations, which are non-invasive and have minimum side effects, can take the form of solutions, emulsions, suspensions, gels, in-situ gels, ointments, and inserts.

Challenges of Ophthalmic Drug Delivery

When compared to other administration routes, those intended for the eye present distinct delivery challenges, and the relatively low ocular bioavailability drives the need for novel approaches to improve delivery of the desired concentration, at the site of action, at a controlled rate. In addition, formulators must pay attention to several factors including:

  • Tonicity
  • pH
  • Stability
  • Viscosity
  • Sterility

Ophthalmic drugs also have very specific regulatory requirements. The United States Food and Drug Administration (FDA) considers ophthalmic formulations designed for administration as eye drops to be drug–device combination products. This makes the regulatory compliance requirements much more complex than those for “standalone” drugs. Since 2008, the FDA has posted 28 product-specific bioequivalence recommendations (PSRs) for ophthalmic drug products.1 These recommendations describe bioequivalence studies (clinical, pharmacokinetic, and in vitro) that can be conducted for developing generic ophthalmic drugs and generating evidence needed to support Abbreviated New Drug Application (ANDA) approvals.

Benefits of Polymers for Ophthalmic Formulations

Excipients play an important role in ophthalmic dosage forms, having a direct impact on critical process parameters and critical quality attributes. Polymers are an important part of the formulation toolbox and offer several benefits for ophthalmic dosage forms. They can:

  • Increase contact time with the target tissue by enhancing viscosity
  • Reduce drainage of the solution, helping to enhance efficacy of the drug
  • Act as a solubilizer and crystallization inhibitor
  • Enhance drug efficacy
  • Improve formulation stability
  • Provide lubricant activity
  • Sustain drug release

In addition to selecting the right polymer for the formulation, aspects related to preparing the polymer solution, sterilization, and interaction with other excipients in the final formulation must be considered.

Considerations for Polymer Selection for Ophthalmic Formulations

Excipients play an important role in ophthalmic dosage forms, having a direct impact on critical process parameters and critical quality attributes. Given their contribution to a successful dosage form, selection of the right polymer is a critical first step.

Types of Polymers

A variety of polymers can be used in ophthalmic formulations including those of natural, synthetic, and semi-synthetic origins.

Natural polymers such as gellan, xanthan, guar gum, and hyaluronic acid are relatively inconsistent in terms of viscosity and have the potential for a higher microbial load as compared to semi-synthetic and synthetic polymers. Control over the microbial load can be challenging for an ophthalmic formulation as there is a stringent limit to what is allowed.

Semi-synthetic polymers have a higher probability of batch-to-batch variation and broader range of viscosity compared to synthetic polymers, which can impact performance. Examples include hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), and hydroxyethyl cellulose (HEC).

The advantages of synthetic polymers include high batch-to-batch consistency and a narrow range of viscosity which helps to deliver a reproducible performance. Examples of synthetic polymers are polyvinyl alcohol (PVA), carbomer and polyvinyl pyrrolidone (PVP).

Polymer Compatibility with Sterilization Methods and Final Formulation

In addition to selecting the right polymer for the formulation, aspects related to preparing the polymer solution, sterilization, and interaction with other excipients in the final formulation should be considered.

Preparation of bulk-quantity polymer solutions for scale-up or commercial manufacturing can be time-consuming. For some polymers, heating is required for dissolution, and this necessitates use of jacketed vessels as well as additional time needed for heat-up of the solvent and cool-down of the polymer solution. If the polymer is not properly dissolved, the final concentration will be impacted. Also, in this process step the polymer choice is very important: if a polymer of insufficient quality and purity is used, insoluble impurities may be encountered in the polymer solution. Removal of these undissolved particles is mandatory to meet the quality expectations for ophthalmic preparations such as the pharmacopeial requirement for particle-free eye drops.

After preparing the polymer solution, it must be sterilized. Selection of the sterilization method, which can include steam or filtration, is critical as it must be compatible with the polymer solution. The method should not have an impact on the critical quality attributes of the polymer such as viscosity or the molecular weight.
Preparation of the final formulation can also present challenges. The potential for interaction of the polymers with other excipients throughout the shelf life and any impact on stability must be understood.

Conclusion

As the demand for drugs administered via the eye continue to increase, new excipients are needed to address their unique delivery challenges. Polymers are a class of excipients that should be considered by formulators to help overcome a wide range of obstacles for these types of medications.

PVA specifically offers important benefits and meets all the essential requirements to be used in ophthalmic preparations.

References

1.
Ophthalmology Management, Volume: 20, Issue: Balancing Cost & Care in 2017 November 2016, page(s): 8, 9.
2.
Trott M, Driscoll R, Iraldo E, Pardhan S. 2022. Changes and correlates of screen time in adults and children during the COVID-19 pandemic: A systematic review and meta-analysis. eClinicalMedicine. 48101452. https://doi.org/10.1016/j.eclinm.2022.101452
3.
2022. Certain Ophthalmic Products: Policy Regarding Compliance With 21 CFR Part 4 Guidance for Industry. [Internet]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/certain-ophthalmic-products-policy-regarding-compliance-21-cfr-part-4-guidance-industry
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