Seeing the Value of Nano

The global population is aging and increasing numbers of patients are suffering from chronic eye conditions such as dry eye disease and allergic conjunctivitis. These conditions are typically treated with topical medications, which offer a number of advantages over systemic therapies; topical ophthalmic delivery is a relatively noninvasive route and side effects can be minimized. Systemic therapy, in contrast, requires a relatively high circulating drug concentration to achieve a therapeutically effective dose in the eye (1).

To meet the needs of patients and allow more ophthalmic therapies to reach the market, it is vital that the industry overcome several key obstacles. One is the low bioavailability of topical ophthalmic therapies. First, high tear-fluid turnover rate and nasolacrimal drainage rapidly removes fluid from the eye – along with any topically applied drug particles. Second, the eye possesses a number of specialized physiological barriers, such as the corneal epithelia, which are designed to effectively prevent toxic chemicals from penetrating the eye. Unfortunately, this also hinders therapeutic agents (2). A trend toward more complex – and, consequently, more hydrophobic – drug molecules further exacerbates the issue (3).Drug molecules with higher molecular weights often suffer from poor solubility, leading to poor bioavailability and absorption in the body.

Put simply, ophthalmic formulations require a higher precorneal residence time and enhanced drug penetration to enhance drug bioavailability. To this end, novel drug delivery technologies based on cyclodextrins, prodrugs, colloidal systems (such as nanoparticles, liposomes, and nanomicelles) and nanocrystals have been the subject of extensive research.

For example, solubility enhancer cyclodextrin derivatives – which have a hydrophilic surface and a hollow hydrophobic core – have proven an effective means of improving the permeability of active ingredients in certain cases, increasing retention time on the ocular surface. The poorly soluble API is entrapped within the β-cyclodextrins to allow them to be carried across biological membranes. In addition to enhancing efficacy and bioavailability, this approach also reduces inflammation – a significant patient benefit (1). Cyclodextrins’ chief drawbacks, however, are their complexity and high cost. Because the API is loaded into the cavities of cyclodextrin molecules, it can also be difficult to achieve very high drug loads (4).

The prodrug approach, meanwhile, involves modifying the physicochemical properties of the drug to achieve one or more objectives, which can include increasing solubility. The drug is then converted into its therapeutically active, less soluble form by cellular enzymes once it reaches the corneal tissue (1). This can successfully improve the bioavailability of poorly soluble APIs. However, formulation of ocular prodrugs is a challenging task, because they should exhibit optimum chemical stability as well as the ability to be converted by enzymes into the parent drug after administration at the desired pace. As a result, this approach can only be applied in some cases (5).

Colloidal nanocarriers have achieved some success in facilitating sustained and controlled drug release, protecting drugs from ocular enzymes and overcoming ocular barriers for poorly soluble drugs. As such, they can help reduce the frequency of dosing, increase precorneal residence time, and improve tissue concentrations for better pharmacological action (1).

Another exciting approach is the use of API nanocrystals. This involves reducing the size of API particles to between 10 and 1,000 nm to increase their surface area and interaction with solvent particles, thereby dramatically enhancing solubility. Nanocrystal-based formulations have been explored for ocular drug delivery and found successful in achieving increased retention time, bioavailability, and permeability of drugs in the eye. Compared with other nanocarriers, nanocrystals have high drug loading, which helps efficiently transport drugs into cells; they can also show increased adhesion to cell membranes, which can increase residence time in the ocular sac. Nanocrystal production requires fewer processing steps and generates fewer physical and chemical stability concerns than other nanocarriers. Because of the simplicity in formulating nanocrystals and their applicability to a wide variety of drugs, there are already products on the market leveraging nanocrystals for oral and injectable drugs, such as Triglide (fenofibrate) and Ritalin (methylphenidate) (6).

The latest innovations in technology further spotlight the use of nanocrystals for ophthalmic drugs. For instance, using scalable nanoparticle engineering approaches such as controlled expansion of supercritical solutions, drug particle size can be reduced uniformly without damaging their inherent chemical properties. The subsequent upsurge in surface area can enable poorly soluble particles to be dissolved, held in suspension, or formulated for a variety of other form factors depending on the desired route of administration. In my view, this approach is well suited to very poorly soluble APIs, offering the potential to enhance penetration into tissues – including the eye.

Overall, by directly reducing the size of API particles, advances in nanoparticle engineering open up exciting possibilities across the board, from ophthalmic to oral and beyond.