One of the exciting pharmaceutical opportunities afforded when exploring formulations for ocular applications is the direct visual observation and measurement of the consequences of dosage design on therapeutic activity. The disadvantages of treating such an intricate organ are often outweighed by the advantages of its accessibility and the prospect of monitoring a pharmacological benefit of therapeutic intervention. With investigation of impacts of environment and nutrition on ocular health, short-term observations are now replaced by long-term monitoring of the gradual and progressive changes over many years. While pathological conditions are still observable, such as deposits in the retina known as drusen, or changes in gross physiological state measured by visual acuity, or tissue and cellular structure and function by novel technologies such as OCT (285-289) and electroretino-grams (ERGs) (290,291), respectively, discovering underlying biochemical etiologies poses the same difficulties as that existing for internal organs and tissues. Conversely, observation of progressive structural and functional changes observed over years often provides a window into the state of not just ocular but systemic health.
Because the eye is unique in its demand for oxygen required to sustain its high rate of metabolism (214), and because whenever functioning its tissues are concurrently exposed to the stress of electromagnetic radiation, it should not be surprising that the retina is exquisitely sensitive to homeostatic balance, influenced by the state of systemic health (292). It had been suspected by physicians for some time and epidemiologists more recently that nutrition, and in particular certain essential nutrients, might retard progression of age-related disease, and in particular, age-related eye disease (293-295). However, it was not until a large trial [AREDS (Age-Related Eye Disease Study) trial] of extended duration was undertaken by the National Eye Institute (NEI), initiated about 1992 and extending beyond seven years, that there was clinical evidence for benefit of dietary modification through supplementation. The AREDS trial demonstrated unambiguous benefit of supplementation with five essential vitamins and minerals at high potency. The formulation consisted of P-carotene, vitamin C, vitamin E, zinc, and copper, either well-known antioxidants or enzyme cofactors of antioxidant enzymes.
In a series of papers in Archives of Ophthalmology and other journals, investigators described significant findings, perhaps the most noteworthy being that even with relatively late-stage intervention, individuals with the advanced dry form of AMD could delay progression of this insidious disease, which ultimately robs sight from a significant fraction of the elderly (296,297). In this segment of the population, physicians reported that over a five-year period there was about a 25% reduction in the rate of progression to advanced AMD, observed as neovascularization and hemorrhage or geographic atrophy. Because of the epidemiological significance from this recognized prophylaxis, as well as the sociological and economic implications for public policy, administration of high-potency nutrients has become the standard of care for subpopulations at risk of AMD (298). Because of extensive evaluations and dissections of the trial's statistics, numerous valuable observations have been made affecting prognosis and treatment (299,300). Safety of the formulation, an initial concern of some physicians based on the high potency of these nutrients relative to their dietary reference intakes (DRIs), has been allayed, though in a new trial, AREDS2, the required levels of those ingredients seemingly posing greatest risk, zinc and P-carotene, are being reevaluated. Genetic sampling has contributed to the understanding of the role of single nucleotide polymorphism (SNP) in complement factor H as a risk factor for AMD (301,302). While the AREDS trial did not support an effect on cognition or vascular function in the elderly, alternate studies of antioxidants have suggested the value of antioxidant nutrients that appear capable of influencing inflammatory states (300). Consequently, several ancillary studies have been incorporated into the AREDS2 trial. The rationale for these extensions of the study is supported by the observation that the decreased survival rates of AMD patients appears to be countered for those patients in particular arms of the AREDS trial, and that AMD patients' decrease in cognitive function appears correlated with the disease's visual impairment (303).
Because two essential carotenoids, the C40 xanthophylls lutein and zeaxanthin, are found concentrated in the retina with increased level in the macula (304), because these compounds are both antioxidants and absorbers of short-wavelength visible light (305), because of the risk engendered in exposure to blue light that can produce fluorescent excitation of A2E chromophores (a 2,4-bis retinoid pyridinyl ethanol salt) in lipofuscin (306,307), because epidemiological evidence suggesting reduced incidence of AMD for those individuals in the higher quintiles of these compounds in their diet, because of the protection observed from light damage by these two compounds in preclinical studies (304,308,309), because of demonstrable clinical benefit in delaying the effects of AMD on visual function from using xanthophyll supplementation (310,311), because of evidence for binding by specific retinal proteins of these xanthophylls (312), and because analysis of the AREDS population disclosed that there was a reduced likelihood of neovascular AMD, geographic atrophy, and large drusen for those individuals in the highest quintiles of lutein and zeaxanthin consumption (313), NEI has embarked on an extension of the AREDS trial, designated as AREDS2, in which the impact of these carotenoids on progression of AMD is being evaluated. Another class of lipid, the essential co-3 fatty acids, eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3), also is of interest. Because these antioxidants are abundant in photoreceptor disk membranes, are significant enough to be reprocessed by the RPE so they can be reused by the photoreceptors, are incorporated in neural membranes contributing to controlling their growth and function, are known to influence inflammatory responses by influencing arachidonic acid metabolism, and in epidemiological investigations appear to reduce the incidence of AMD, they also are being evaluated in this new trial (300,313). As evermore information, both basic and clinical, about the subtle nutritional requirements of the eye and its age dependence emerges, benefit from more complex formulations can be anticipated (314-317).
The linkage of the impact of these studies on dosage form, the influence of nutrient administration on compliance, and ultimately the effect on the health of patients is appreciated by a review of the types and timing of the administrations available. In the AREDS trial, supplementation was provided by four tablets, taken twice a day with meals. Relatively large tablet volumes were needed because, in addition to the high potency of the actives, high loads of excipients were required to confine lipophilic materials and avoid "bleed-through" and discoloration of the tablets, or the need to satisfy other tableting requirements (297). Specifically, in the original trial, a daily dose of AREDS antioxidants provided along with 69.6 mg of zinc as zinc oxide and 1.6 mg of copper as cupric oxide, 400 mg of vitamin E as DL-a-tocopheryl acetate and 28,640 IU (about 17.2 mg) of vitamin A as P-carotene. Because the latter two need to be provided as free-flowing powders, they are incorporated into the tablet as beadlets, conventionally made from gelatin or starch, whose amounts can be in excess of the nutrient. Another nutrient, also present at high levels, more than seven times the DRI, is the water-soluble and effective antioxidant vitamin C, at 452 mg/day. While vitamin C can be provided as a free-flowing crystalline powder of nearly 100% active nutrient, it also is well known to be sensitive to oxidation on prolonged exposure to air. For example, many vitamin C tablets once exposed to the atmosphere have been observed to discolor. For that reason, one class of additional excipient required for extending the shelf life to two years is a protective antioxidant, an ingredient more readily oxidized than any of the other effective antioxidants in the formulation! In a tablet formulation, several additional classes of excipient may be required to provide the appropriate flow and mixing characteristics of the blend, hardness, and fracture properties under compression and disintegration attributes following ingestion (318). Tablet coatings serve to impart good barrier characteristics contributing to product stability, lubricity to facilitate swallowing, and color to assist in tablet identification, providing consumer recognition (319).
While compliance with this regimen of four tablets per day was very high during the AREDS trial, that is, found to be better than 75% for 71% of the participants with very few lost to follow-up (<2.4%), later analysis of compliance for a broader spectrum of AMD patients, for tablets available in the marketplace, appears to dwindle (297). It is not clear whether this loss of compliance was driven by inconvenience of the dosage form, their cost, or simple and conventional attrition accompanying normal loss of discipline to the regimen. The consequence, nonetheless, is obvious, since any regimen less than the design deprives the patients of the high potency found effective. In part these failings can be addressed through redesign of the dosage form, which has been provided for the second-tier evaluation occurring in AREDS2, to be a softgel dosed as two softgels per day. And the composition of the precise AREDS multivitamin mineral formulation was slightly readjusted so that it more nearly approached the design composition indicated in the original descriptions of the trial, 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of P-carotene, 80 mg of zinc, and 2 mg of copper, a design intended to be compliant with USP requirements over the shelf life of the product. The new formulation provided for the AREDS2 trial, donated to the study by Alcon Research, Ltd., meets the current operative DSHEA legislation, as provided in the Federal Register and Code of Federal Regulations (CFR) (320). The softgel dosage form (321), with primary capsule fill excipient and carrier being oil in which the lipophilic vitamins are soluble, reduces posology by half. The oil barrier also serves to protect the ingredients from hydrolytic and oxidative instability. Because the new AREDS2 trial is so large, nominally 4000 participants, there is high probability that the results will be able to offer broad guidelines of essential nutrients, spanning vitamins, minerals, and lipids, capable of contributing to the reduction in rate of progression of AMD, and perhaps contributing to improved systemic health as measured by the impact of these nutrients on cardiovascular health and cognition. As the number, amounts, and diversity in properties of these nutrients increase to support good nutrition and maintenance of health, it is expected that new dosage forms will emerge to facilitate treatment and support compliance.
Was this article helpful?