Therapeutic Vehicles: The Familiar and the New

How do you administer therapy to an organ designed to reject invaders?

By Agustin Gonzalez, OD

Topical formulations account for the majority of ophthalmic pharmaceutical products due to their ease of application, noninvasive mode of delivery, and access to target tissues. From solutions to suspensions to emulsions,1 there is great variability in the vehicles and formulations in topical therapeutics. A look at topical vehicles for drug delivery is relevant to understanding the effects of these drugs on ocular tissues.

TO THE POINT

Topical ophthalmic preparations lose efficacy due to tear turnover, nasolacrimal drainage, reflex blinking, and ocular static and dynamic barriers. Novel methods of delivery hold great promise for eye care professionals and patients.

The eye is designed to prevent any foreign substance from entering. Achieving efficacy with topical ophthalmic preparations has proven to be a challenge due to obstacles such as tear turnover, nasolacrimal drainage, reflex blinking, and ocular static and dynamic barriers. These factors affect drug concentration and efficacy in both the anterior and posterior segments. The formulations and vehicles employed in delivery of drugs to ocular tissues influence the bioavailability of those drugs.

SOLUTIONS

Ophthalmic formulations include solutions, suspensions, and emulsions.1 Solutions are liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents.2-4 Topical ophthalmic solutions provide a convenient and noninvasive method of application of drugs onto the surface of the eye. There is an immediate rise in bioavailability due to increased permeability after drop application, but this quickly declines in proportion to the concentration of the drug.

Additives can be included to promote penetration, bioavailability, and contact time. These include benzalkonium chloride (also called BAK), permeability enhancers, viscosity enhancers, and cyclodextrin.5 These excipients can often cause local toxicity. Because of this, efforts have been made to create topical ophthalmic emulsions, suspensions, and ointments in new formulations to address problems in permeability, bioavailability, and contact time without the side effects of eye irritation, redness, inflammation, changes in vision, and instability in storage.1

EMULSIONS

Emulsions are preparations in which finely dispersed globules of an active ingredient are distributed in an immiscible solvent. In an emulsion, one liquid (called the dispersed phase) is mixed with another (the continuous phase). When the two phases consist of a combination of an aqueous and an oleaginous liquid, emulsions can be either water-in-oil (W/O) or oil-in-water (O/W) preparations. Each of these has advantages and disadvantages regarding drug delivery.4 W/O emulsions provide longer contact times, whereas O/W emulsions allow easier tissue penetration.2 In ophthalmic emulsions, O/W emulsions are more common, mainly because they cause less irritation than W/O emulsions.

Emulsions with lipid additives promote the bioavailability of some drugs, such as azithromycin. The addition of derivatized drugs and mucoadhesive polymers has also been used in attempts to reduce eye irritation, improve drug effects, and promote eye residence time. Therefore, emulsions can often provide the advantages of improving residence time, improving corneal permeability, achieving sustained release, and, ultimately, improving drug bioavailability.1,3

SUSPENSIONS

In a suspension, finely dispersed drug particles are distributed in an aqueous dispersing medium in which the drug is poorly miscible, forming suspensoids in the medium.2 Suspensions provide improved contact time and duration of action, as they are retained in the conjunctival fornix after administration. Some drugs are also more stable in suspension.2 Suspensions may have small or large suspensoids, and each has different advantages. Small suspensoids provide increased absorption, and large suspensoids provide longer residence time, although they also slow drug dissolution.1 The drawbacks of suspensions include eye irritation and stability problems such as caking, which renders the drug incapable of redispersion.2,4

OINTMENTS

Ointments are semisolid preparations intended for external use on the mucous surface of the eye. Different bases may be used depending on the purpose of the ointment, including oleaginous, absorption, water-removable, and water-soluble bases.2,4 In topical ophthalmic preparations, ointments comprise a mixture of a semisolid ingredient and a solid hydrocarbon, usually paraffin, to have a melting point that matches the physiologic ocular temperature of 34°C. Compatibility of the material with the ocular tissue also dictates the choice of the hydrocarbon. The advantages of ointments are improved bioavailability and sustained release of the drug into the tissue; disadvantages include ocular irritation, redness, inflammation, and visual disturbances.1

XANTHAN GUM AND POLYCARBOPHILS

Some recently developed medications use novel vehicles such as xanthan gum and polycarbophil. Xanthan gums are naturally occurring biopolymers that are used in some formulations to form topical gels. They have potential benefits for promoting wound healing and repairing posttraumatic eye abrasions and epithelial defects in the corneum.6 According to Kocatürk et al, a combined eye gel containing xanthan gum and hyaluronic acid accelerated wound healing, due to the high polysaccharide content of the gel, and promoted increased hydration.7

Xanthan gum is used to increase the viscosity of topical ophthalmic solutions, promoting increased contact time and allowing sustained release of the drug.1,8 An additional benefit of xanthan gums in ophthalmic preparations is the potential for safe and sustained delivery of the drug.9,10 Malhotra et al supported this claim, demonstrating that the addition of xanthan gum to an ophthalmic preparation containing voriconazole improved the antifungal activity of voriconazole compared with other viscosity modifiers. Xanthan gum provided the maximum precorneal residence time, making it an effective additive to the vehicle of this ophthalmic preparation.11

Polycarbophils are the newest, safest, and most exciting technology for topical drug delivery. These mucoadhesive vehicles promote longer corneal contact times, improving drug bioavailability. The polycarbophil forms a polymeric matrix that stabilizes the drug and delivers drug molecules over time. It reduces clearance from the eye surface and alters tight cellular junctions, promoting paracellular drug permeability and delivery. Several studies have employed polycarbophils as vehicles for ophthalmic use.1,12-14 Despite altering the corneal epithelium to promote drug permeability, the polycarbophils caused no damage to the corneal epithelium in these studies, suggesting that they are safe for use in ophthalmic drug delivery.1,12,13,14

Shaikh et al, reviewing mucoadhesive drug delivery systems, explained theories regarding the mode of action of these materials. The wetting theory holds that adhesion is an embedding process wherein the attached adhesive agent must overcome any surface tension on the interface. The electrostatic theory states that mucoadhesion is the result of an electrical double layer at the interface, and a series of attractive forces is responsible for maintaining contact. The diffusion theory states that the combination of polymeric chains of the bioadhesive to the glycoprotein mucin chains form semipermanent bonds. The fracture theory states that mucoadhesion is achieved when a certain level of strength is required to separate the two joined surfaces in an interface.15

Polycarbophils have shown great potential as mucoadhesives. Hornof et al demonstrated that a polycarbophil-cysteine excipient enhanced the permeability of sodium fluorescein and dexamethasone by more than twofold.14 They attributed the increased permeability to the promotion of paracellular diffusion by the substances, with sodium fluorescein used as a marker for corneal permeability.14

Similar findings were reported regarding the polycarbophils in DuraSite (InSite Vision) in a study of the drug azithromycin with DuraSite as the vehicle. Not only was there an increase in permeability, but the polycarbophils in DuraSite also allowed increased stability of azithromycin on the corneal surface and maintained therapeutic levels of the drug for at least 24 hours.12

Sensoy et al incorporated polycarbophils in a mixture for coating sulfacetamide sodium microspheres to increase their bioadhesive properties in the treatment of ocular keratitis. They found that a 2:1 polymer-to-drug ratio was the most suitable for ocular application. The microspheres of sulfacetamide sodium showed greater efficacy compared with sulfacetamide sodium alone. The data suggest that polycarbophil delivery has great potential to improve drug delivery, bioavailability, and efficacy.16

BUT WHAT’S NEXT?

There is no question that drug delivery to the eye has changed and will continue to do so. It is an exciting time in eye care, as the number of pharmaceutical formulations with innovative delivery vehicles, including polycarbophils, will most likely expand in the next few years. We can expect topical formulations promoting better delivery to target tissues to emerge. With topical formulations the most common way to manage most ocular surface and anterior chamber conditions, our clinical conversations will expand beyond the active ingredient and include vehicles of delivery. n

1. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: An overview. World J Pharmacol. 2013;2(2):47-64.

2. Allen LV, Ansel HC, Popovich, NG. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 9th Ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

3. Liang H, Brignole-Baudouin F, Rabinovich-Guilatt L, et al. Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits. Mol Vis. 2008;14:204-216.

4. Lang J, et al. Remington: The Science and Practice of Pharmacy. 21st Ed. Philadelphia: Lippincott Williams & Wilkins; 2009.

5. Sasaki H, Yamamura K, Mukai T, et al. Enhancement of ocular drug penetration. Crit Rev Ther Drug Carrier Syst. 1999;16:85-146.

6. Faraldi F, Papa V, Santoro D, et al. A new eye gel containing hyaluronic acid and xanthan gum for the management of post-traumatic corneal abrasions. Clin Ophthalmol. 2012;6:727-731.

7. Kocatürk T, Gençgönül A, Balica F, et al. Combined eye gel containing sodium hyaluronate and xanthan gum for the treatment of the corneal epithelial defect after pterygium surgery. Clin Ophthalmol. 2015;9:1463-1466.

8. Baranowski P, Karolewicz B, Gajda M, Pluta J. Ophthalmic drug dosage forms: characterisation and research methods. Scientific World Journal. 2014;18:861904.

9. Pahuja P, Arora S, Pawar P. Ocular drug delivery system: a reference to natural polymers. Expert Opin Drug Deliv. 2012;9(7):837-861.

10. Bhowmik M, Kumari P, Sarkar G, et al. Effect of xanthan gum and guar gum on in situ gelling ophthalmic drug delivery system based on poloxamer-407. Int J Biol Macromol. 2013;62:117-123.

11. Malhotra S, Khare A, Grover K, et al. Design and evaluation of voriconazole eye drops for the treatment of fungal keratitis. J Pharm (Cairo). 2014;490595.

12. DuraSite Core Technology. Insite Vision. www.insitevision.com/durasite.html. Accessed April 27, 2017.

13. Kompella UB, Kadam RS, Lee VH. Recent advances in ophthalmic drug delivery. Ther Deliv. 2010;1(3):435-456.

14. Hornof MD, Bernkop-Schnürch A. In vitro evaluation of the permeability enhancing effect of polycarbophil-cysteine conjugates on the cornea of rabbits. J Pharm Sci. 2002;91(12):2588-2592.

15. Shaikh R, Raj Singh TR, Garland MJ, et al. Mucoadhesive drug delivery systems. J Pharm Bioallied Sci. 2011;3:89-100.

16. Sensoy D, Cevher E, Sarici A, et al. Bioadhesive sulfacetamide sodium microspheres: evaluation of their effectiveness in the treatment of bacterial keratitis caused by Staphylococcus aureus and Pseudomonas aeruginosa in a rabbit model. Eur J Pharm Biopharm. 2009;72(3):487-495.

Agustin L. Gonzalez, OD, FAAO
• optometric glaucoma specialist and therapeutic optometrist, Eye & Vision, Richardson, Texas
• financial interest: none disclosed
ag@txeyedr.com