Aiming for Improved Efficacy and Patient Compliance for Topical Ophthalmics

Drug delivery to the human eye is a rapidly growing area in the pharmaceutical industry, but it is also one of the most challenging. The inherent structure and physiology of the eye make it difficult for drugs to reach the site of action and persist over time. Despite these constraints, ocular therapies continue to garner significant interest due to growing patient need, according to Ashley Rezak, Global Market Manager for Topical Drug Delivery at Lubrizol Life Science Health (LLS Health). Drug product developers are actively seeking options for overcoming these barriers and effectively delivering ophthalmic drugs.

Ocular injectable products in particular are experiencing strong growth with the development of gene and other advanced therapies. Even so, topicals (mostly liquids including solutions and suspensions, but also semi-solids) remain the most prominent dosage form for ophthalmic commercialized products and those in development, says Dr. Robert Lee, President of LLS Health’s CDMO Division.

Topicals are appealing due to their ease of administration, non-invasive nature, and ability to be administered at the site of action, all of which make them attractive to treat eye diseases such as conjunctivitis, glaucoma, and dry eye, among many others. The big challenge is delivery, according to Gregg J. Berdy, MD, voluntary associate professor of clinical ophthalmology in the Department of Ophthalmology at Washington University School of Medicine and a physician with Ophthalmology Associates of St. Louis, Missouri.

Formulations must be stable and homogeneous and designed such that when a drop leaves the medication container and hits the surface of the eye, it has the appropriate concentration of API and can reach the intended target within the eye—the surface, the anterior segment tissues (cornea, aqueous humor, iris, ciliary body, and lens), or the posterior segment tissues (vitreous humor, retina, and choroid)—providing the correct dosage.

Patient centricity an important driver in topical development

One of the challenges with topical ophthalmic drugs is ensuring patient compliance. Topical drugs are easy for patients to apply themselves, but there is no way to ensure that patients do so at the proper frequency, according to Berdy.

“Studies have shown that patients don’t generally take medicines more than twice per day, so it can be difficult to get them to apply ophthalmic drugs as often as needed in some cases. In addition, refill rates for many basic drugs are well below 50%. There is no way to guarantee medication adherence, which requires that patients buy/order, pickup, and then take their prescriptions. Whether the reason may be price, pain, or forgetfulness, compliance is a big challenge with self-administered treatments,” Berdy explains.

For this reason, Berdy notes that physicians often prefer intraocular injectable drugs that can be administered in the office. With these medications, proper dosing is assured. In many cases, he adds that the injectable treatment schedule may be every three months to one year, and patients don’t need to worry about refilling prescriptions on a monthly basis for a prolonged period. Furthermore, there is no worry of accidental harm to the ocular surface while patients apply topical solutions.

Given the benefits and concerns associated with topicals, it is not surprising that much research has focused on developing topical ophthalmic drug products that are easier to use, more comfortable, and specifically reduce the frequency of administration. Such efforts include developing sustained/extended release and increasing the bioavailability of the active drug substances in formulations.

Natural barriers create delivery challenges

Frequent dosing requirements for topical ophthalmic drugs can be attributed to the fact that typically only approximately 5% of the of the administered drug substance in a standard eye drop is absorbed at
the site of action, according to Rezak. There are several reasons why this issue exists. Primarily, she observes, it is due to the tricky path a drug must take to effectively penetrate the target tissue.

In addition, the average eye drop is 40–50 μL, whereas the tear film capacity of the eye is only 7 μL, and the eye can only hold about 20–25 μL, according to Berdy. This situation results in a large waste of product and presents a significant delivery limitation, Rezak notes. Furthermore, the little liquid that does remain is subjected to innate solution drainage and blinking, making it difficult to keep a topical drug product in place long enough to be absorbed.

Given that there are significant protective barriers and mechanisms on the ocular surface and achieving relevant drug concentrations in various parts of the eye is so challenging, it is crucial to understand the pharmacokinetics of any topical ophthalmic drug (1). Part of this knowledge must include the ability to correlate data generated in animal models—often rabbits because of anatomical and physiological similarities—to humans (2).

As a result, some suggest that successful topical ophthalmic drugs for the treatment of diseases of the anterior and posterior segments of the eye must be highly potent and administered only to the eye, avoiding delivery of the topical dose to systemic circulation (1).

“Without incorporating differentiated ingredients or technologies that help overcome these challenges, frequent administration of the drug product is required to maintain an effective drug level,” says Rezak. “In addition to decreased patient compliance due to the added inconvenience of more frequent administrations, toxicity and overdosing can become an issue, as can the increased cost if dealing with an expensive API,” she continues.

Early products focus on outer eye conditions

Most topical ophthalmic drugs are formulated as liquids delivered as drops to the eye. These drugs generally treat issues involving the eye surface or anterior segment tissues, including both acute problems (conjunctivitis, keratitis, iritis) and chronic conditions (dry eye syndrome, glaucoma).

Eye drops have also been formulated to treat surface abrasions and infections and to prevent swelling of the retina following surgery, according to Berdy. The most common use of eye drops today, he observes, is for the treatment of glaucoma. These treatments take many forms, but all must reach the cornea and penetrate into the anterior chamber to be effective.

The first topical treatment for presbyopia (age-related hardening of the lens) was approved in 2021 (3), and several other candidates are in development. These drugs function by modulating the size of
the pupil or changing the thickness of the optical lens. There are also several new treatments for dry eye disease currently advancing through the clinic (4).

Bioadhesion one way to widen topical applications

Despite the challenges to treating diseases at the back of the eye with topical drugs, there are several candidates in development for the treatment of ocular posterior segment diseases including age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, and optic neuropathy glaucoma disease (1).

“The back of the eye is regarded as one of the most difficult areas to effectively treat. Compared to the anterior portion, the posterior segment generally cannot be accessed via a topical route due to the natural impermeability of the eye exterior and the distance a drug would have to travel to reach the site of action, which is usually the retina. However, the industry is making great strides in the area of exploring topicals to treat both anterior and posterior diseases of the eye,” Lee contends.

The best way to enhance drug delivery of ocular topicals, Lee continues, is by prolonging a drug’s residence time on the surface of the eye. “For eye drops, the key is thus muco- or bioadhesion,” he states.

Bioadhesion is commonly defined as the adherence between two surfaces, at least one of which is biological. In the case of topical ophthalmic delivery, the surface of the liquid drug product and the front of the eye are the relevant interfaces, Lee explains. Bioadhesion can be introduced in a formulation via a variety of ingredients and delivery systems.

There are some drug product developers working on advanced delivery systems to instill bioadhesive properties, such as those utilizing solid-lipid nanoparticles, micelles, and liposomes, according to Lee. “Some of these approaches are very promising, and it is exciting to see so much innovation in the ophthalmic space,” he says.

Both small-molecule drugs and biologics can feasibly be delivered using these systems, Lee adds. He does note, however, that the specific active ingredient must be evaluated in the given system to assess suitability, and biologics are often much more challenging to deliver topically due to their large molecule size.

With respect to successful bioadhesive solutions, Rezak stresses that one of the most effective and well-established methods to impart muco- or bioadhesion to a formulation is through strategic excipient selection. “There are many polymers a formulator could select for establishing bioadhesion in a formulation, such as carbomers, carboxymethylcellulose, polycarbophil, and sodium alginate, to name a few,” she comments.

LLS Health provides muco- and bio-adhesive excipients designed to increase the effectiveness of ophthalmic topical therapies. They have unique functionalities that impact the mucoadhesive product profile and come in multiple grades so that profiles can be fine-tuned for the individual needs of different products, according to Rezak. “LLS Health has conducted studies (5) that show formulations containing its Carbopol polymers and Noveon polycarbophil excipients display significantly longer product retention at the target site than those containing alternative polymers,” she says.

Other innovative delivery solutions

In addition to the use of excipients to improve bioadhesion, other innovative approaches to improving the performance of topical ophthalmic drugs are being investigated. Two primary approaches include decreasing the particle size to allow greater penetration through the mucous barrier in the eye and the use of hydrophilic coatings to increase API solubility and bioavailability, particularly for hydrophobic drug substances, according to Berdy.

Some specific examples include nanospheres, nanocapsules, nanomicelles, nanovesicles, dendrimers, in situ gels, and microneedles (2). In situ gels are applied as solutions but once in the eye form a gel in the target tissue in response to a specific stimulus (pH, temperature, or solvent change, ultraviolet irradiation, the presence of specific ions or molecules, etc.) The application of physical or electrical forces (iontophoresis and sonophoresis) to enhance API penetration are also under investigation. Extracellular vesicles, biological particles including exosomes, ectosomes, microvesicles, microparticles, oncosomes, and apoptotic bodies, are also being explored as delivery vehicles in topical ophthalmic drug formulations.

“Every major company in the ophthalmic drug sector is developing topical formulations aimed at a wide range of diseases from those more traditionally treated with drops to disorders of the posterior of the eye. They are exploring both novel compounds and new delivery technologies that will enable both greater efficacy and improved ease of use and comfort for patients,” Berdy concludes.

References

1. del Amo, E. M. Topical Ophthalmic Administration: Can a Drug Instilled onto the Ocular Surface Exert an Effect at the Back of the Eye? Front. Drug. Deliv. 8 Sept. 2022. https://doi.org/10.3389/fddev.2022.954771.
2. Lixiang Wang, L; Zhou, M. B.; and Zhang, H.The Emerging Role of Topical Ocular Drugs to Target the Posterior Eye. Ophthalmol Ther. 2021 Sep; 10(3): 465–494. doi: 10.1007/s40123-021-00365-y
3. Staff, First Presbyopia Drop Approved. Review of Ophthalmology. 10 Dec. 2021.
4. Novack, G.D. Eyes on New Product Development: Long-Acting Ocular Drug Delivery Technologies Addressing Unmet Needs in Ophthalmology. Journal of Ocular Pharmacology and Therapeutics, 2022. 38 (6). https://doi.org/10.1089/jop.2022.29093.gdn
5. Lubrizol Life Science. Mucoadhesive Polymers in Pharmaceutical Formulations. Technical Brief. 2021.

Article details

Pharmaceutical Technology
Vol. 47, No. 2
February 2023
Pages: 18–19

Citation

When referring to this article, please cite it as Challener, C.A. Aiming for Improved Efficacy and Patient Compliance for Topical Ophthalmics. Pharmaceutical Technology 2023 47 (2) pp. 18–19.