Patient centricity an important driver in topical development.
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 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 commercialised products and those in development, said 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. The big challenge is delivery, according to Dr Gregg J. Berdy, MD, voluntary associate professor of clinical ophthalmology in the John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences at Washington University School of Medicine and a physician with Ophthalmology Associates in St. Louis, Missouri, United States.
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 active pharmaceutical ingredient (API) and can reach the intended target within the eye—the surface, the anterior segment tissues (cornea, aqueous humour, iris, ciliary body, and lens), or the posterior segment tissues (vitreous humour, retina, and choroid)—providing the correct dosage.
One of the challenges with topical ophthalmic drugs is ensuring patient adherence. 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 Dr 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 or order, pickup and then take their prescriptions. Whether the reason may be price, pain or forgetfulness, adherence is a big challenge with self-administered treatments,” Dr Berdy said.
For this reason, Dr Berdy noted 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, the injectable treatment schedule may be every 3 months to 1 year, and patients do not need to worry about refilling prescriptions monthly 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 or 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 path a drug must take to effectively penetrate the target tissue.
In addition, the average eye drop is 40 to 50 μL, whereas the tear film capacity of the eye is only 7 μL, and the eye can only hold about 20 to 25 μL, according to Dr Berdy. This situation results in a waste of product and presents a significant delivery limitation, Rezak noted. 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 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 anatomic and physiologic 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,” said Rezak. “In addition to decreased patient adherence 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 continued.
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 Dr 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 the anterior chamber to be effective.
The first topical treatment for presbyopia was approved in 20213 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 advancing through the clinic.4
Bioadhesion is one way to widen topical applications
There are several candidates in development for the treatment of ocular posterior segment diseases including age-related macular degeneration, diabetic retinopathy, diabetic macular oedema, 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 with 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 said.
The best way to enhance drug delivery of ocular topicals, Lee continued, 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 said.
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 explained. 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 said.
Both small-molecule drugs and biologics can feasibly be delivered using these systems, Lee added. However, he noted 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 because of their large molecule size.
With respect to successful bioadhesive solutions, Rezak stressed 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 said.
LLS Health provides muco- and bioadhesive 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 studies5 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 said.
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 Dr 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 is 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,” Dr Berdy concluded.
This article was originally published on PharmTech.com.