Excipients for Ophthalmic Drug Delivery:
Existing & Emerging Technologies to Tackle the Unique Challenges of Drug Delivery to the Eye
Part 2 of 4: Solubility Enhancers
The safety, quality, and consistency of pharmaceutical excipients in ophthalmic drug products are tightly controlled by the FDA and EMA. For companies developing ophthalmic, formulation development often starts with an evaluation of the excipient databases that identifies excipients previously used in approved products. For example, the FDA maintains the Inactive Ingredient Database (IID), which identifies the specific dosage forms, maximum potency, and maximum daily exposure of excipients used in approved pharmaceuticals. The IID has gaps and is not update in real time—any ophthalmic drug developer should work with a formulator who is experienced in navigating its complexities.
Callan Pharma Services specializes in maximizing an excipient’s impact on the safety and efficacy of an API. In this 4-part series we’ll review those excipients already used in approved ophthalmic pharmaceuticals, and discuss emerging technologies being developed to tackle unsolved challenges. In this Part 2, we’ll discuss Solubility Enhancers.
Part 2: Solubility Enhancers
Whether an ophthalmic pharmaceutical is injected or delivered topically to the eye, it must have some appreciable solubility in water to be delivered safely and effectively. For those active ingredients that are not inherently water soluble, a solubility enhancer excipient is required. These excipients complex with the drug to shepherd it into the aqueous environment of biological tissues, increasing bioavailability, and in some cases, modulating pharmacokinetics.
Since the majority of drugs used to treat ocular impairments are lipophilic, and thus poorly water-soluble, solubility enhancer excipients make it possible for the delivery of these drugs. The types of solubility enhancer excipients utilized in pharmaceuticals are diverse, and can be sub-divided into:
- Solvents – these excipients can be water soluble or not, but all form stable mixtures between the drug, the solubility enhancer, and the ocular tissue they are administered to. Subtypes include:
- Co-solvents – these are excipients combined water (the other solvent) to form aqueous solutions that dissolve hydrophobic drugs. Examples include poly(ethylene) glycols (e.g., PEG 300 or 400), glycerin, and in low concentrations, even ethanol.
- Lipid-based – these excipients are typically poorly water soluble themselves, which means they are predominantly used in complex dosage forms. For ointments, mineral oil is often used, while emulsions employ castor oil.
- Controlled Release Agents – these solubility enhancers form complexes matrixes with the drug. This can allow for diffusion of the drug out over time or release can be initiated via degradation of the matrix itself.
- Polysaccharides – the most common member is the cyclic hydroxypropyl-β-cyclodextrin (HPβCD) which can interact and change the permeability of the cornea. Hyaluronate, guar gum, and xanthan gum are also examples of polysaccharides used.
- Synthetic Polymers – the future of ocular drug delivery is this growing category. Poly(lactic-co-glycolic acid) (PLGA) is the classic example, while ethylene-vinyl acetate (EVA), which is well known in other routes of administration, is gaining traction in ocular drug delivery. Even the well-established PEGs can also act as a controlled release agent under certain conditions in ophthalmic drug formulations.
- Surfactants & Emulsifiers – grouped together as there is considerable overlap between excipients that can be called a surfactant and an emulsifier. These excipients can function to lower the surface tension between two phases, such as an oil-water or a drug-water interface thus improving aqueous solubility. They are used in a variety of dosage forms, from complex emulsions to standard solution eye drops. Categorized as:
- Non-ionic– the most common category for ophthalmic due to their versatility in various dosage forms and high tolerability. Ethoxylated sorbitans (polysorbate 20 and 80), the PPO-PEO polymers (poloxamer 188 and 407), and the poly aryl tyloxapol are all used in ophthalmic drug formulations. The stearic acid esters major types: including, glyceryl monostearate, polyoxyl 15 hydroxystearate (Kolliphor® HS 15), and polyoxyl 40 stearate (Myrj™ 52).
- Cationic – not as well tolerated as the non-ionic surfactants but can find applications in ophthalmic formulations. Cetalkonium chloride is used as a stabilizer and solubilizer in emulsions. Benzalkonium chloride is added as a preservative rather than a solubilizer but is a surfactant with solubilizing properties.
Emerging Technologies: New Technology for Ophthalmic Injectables
Although the list of solubility enhancers is extensive, for approved ophthalmic products, the majority have only been used in topicals. Development of ophthalmic injectables is surging as more drug developers are targeting the posterior segment of the eye. There is a growing need for new technologies to meet the drug delivery challenges of these drug candidates. Cutting edge solubility enhancers that have found clinical success in non-ocular parenteral routes of administration are a possible solution. Lubrizol’s Apisolex™ is one such innovative solubility enhancer with tremendous potential for ophthalmic injectables. This clinically used, GMP-validated polyamino acid excipient is a non-immunogenic alternative to the PEG-based excipients which can increase the solubility of BCS class II and IV APIs by 50,000-fold. Apisolex™ is one of many new technologies that should help in the delivery of poorly water soluble APIs which target ocular indications.
