1.3.8  Pharmacokinetic (PK) Properties of the Drug

Obviously, when designing a drug delivery system, it is critical that PK studies be conducted to help determine the optimal route of administration. What is not so obvious is that it is important that the animal test eyes be analyzed in quadrants, so that the true distribution of the drug can be revealed. If the target is the macula, then a “punch-out” around the target will provide far more information than simple quadrant analysis.

For example, a drug formulation may analyze at “effective” concentrations, after topical application, if the whole retina is analyzed. However, since there may be a tenfold difference between concentrations in the anterior portion of the retina and concentrations at the macula, the actual target may be getting a subeffective dose.

1.3.9  Local and Systemic Toxicity of the Drug and its Metabolites

As discussed earlier, the design of a drug delivery system should take into account the toxicity of the drug and/or its metabolites at the proposed site of administration; for a variety of reasons, a drug might appear to be toxic in the sub-Tenon’s region while not in the vitreous or vice versa. The researcher needs to be cautious about applying toxicology results from one dosage form to another. For example, a drug solution injected into the vitreous might be quite toxic while a drug delivery device delivering the same total amount of drug may not be because it controls the peaks and valleys of the drug’s vitreal concentration.

1.3.10  Previous Ocular Use of Excipients

When designing a drug delivery system, it is always best to use excipients that have already been used at the site of administration, preferably at the concentration previously used. For example, 0.25% magnesium stearate is used in the preparation of the solid dosage form in Vitrasert and has a proven safety track record. It would be unwise to use a different tablet lubricant without reasonable justification for abandoning magnesium stearate.

However, the number of excipients safely used for dosage forms in the vitreous, sub-Tenon’s space, or other sites of ophthalmic administration is severely limited. Consequently, the next best strategy is to use excipients shown safe for injection. If previously identified injectable excipients do not meet the formulator’s need, then excipients previously used topically in the eye may be the next best choice. The surface of the eye is quite sensitive, so a chemical that is safe for topical administration has a fair chance of being suitable for in-eye purposes.

Excipients, which have GRAS status (i.e., Generally Recognized As Safe), should be tried next; regulatory agencies generally will look kindly on the use of

GRAS excipients. However, the burden of proof of safety is still higher than those excipients already proven to be safe in the eye or by injection. Indeed, GRAS materials, used in ophthalmic tissues, are not always as safe as the name implies. The researcher should particularly watch out for materials which may form peroxides or formaldehyde on standing.

All of the above are superior choices to using a totally new excipient; regulatory agencies will likely require a new excipient to be studied as if it was a drug; a drug delivery system which includes such a chemical might be considered to be delivering two drugs instead of one…..and, the requirements of a dual drug system can be expensive in both time and money.

1.3.11  Development and Strategic Team Input

Even though it is quite common for a single researcher to publish on a “new” ophthalmic drug delivery system, most of such “inventions” are not commercially viable. As a rule, to be commercially viable, drug delivery systems require the contributions of specialists in many different fields.

While the capabilities of a novel drug delivery system are being explored by the researcher, it is prudent to get feedback from other functions. R&D planning involving multiple functions is essential to designing a successful drug delivery formulation or device. The typical R&D team should include a representative from the pharmaceutics, regulatory, process development, chemistry, microbiology, packaging, legal, safety, toxicology, clinical and quality assurance functions. If the system is a device, an engineer may be needed on the team.

Drug delivery devices will be considered both a drug and a device by the FDA and possibly, other regulatory agencies. As a consequence, the device will need to meet both device and drug laws. Aside, from its main function of developing a plan with action steps and timelines, the development team will help make key decisions related to the drug delivery system. Are the drug and excipients safe? How is the drug distributed to various tissues from the site of administration and what are the kinetics involved? What is the rate of elimination of the drug and its metabolites? How will the product be sterilized? What is the long-term stability of the product? Are there endotoxins in the product? What type of packaging should be used? What standards must the new device meet? What raw material assays are necessary? What are the release and final product assays? What are the risks associated with the proposed product (risk assessment)?

The team will shape a development plan, which will include a detailed clinical study proposal. The regulatory function will take the plan to regulatory agencies for review and feedback. The plan and possibly the system itself may be modified based upon the regulatory response.

In addition to a development team, a strategic team is quite useful in designing a drug delivery system. While the development team deals with a current drug delivery system, the strategic team deals with future products. This team generally has a