1.3  Specific Approaches to Drug Delivery for the Posterior Segment

partition coefficient, PKa, ion pairing, particle size, drug stability, molecular size, and polymorphic forms are very important characteristics, which govern a drug’s ability to reach the targeted receptor. Consequently, it is helpful to understand these parameters in order to develop a stable drug delivery vehicle and to select the optimal site of administration.

A drug that is highly water soluble will be difficult to deliver in a controlled dosage manner. Moreover, highly water soluble drugs will generally have low permeability through lipophilic tissue and, consequently, would be unlikely to penetrate target tissues such as the retina and choroid in effective concentration. Typically, water-soluble drugs are rapidly eliminated and have short half-lives.

On the other hand, highly lipophilic drugs are difficult to dissolve in the aqueous biological environment. A poorly water-soluble drug typically will have low tissue permeability because diffusion is dependent upon the concentration of drug in solution. Formulations which include a pharmaceutical aid for the dissolution of such a drug (surfactants, cyclodextrins, etc.) may increase tissue concentration but would decrease duration of delivery. Moreover, unless the solubility-enhancing excipients travel with the drug into the tissue, the drug may precipitate within cells and may disrupt vital functions. And, even if the drug and solubilizing excipients are injected directly into the tissue (e.g., vitreous), the excipients may be diluted and the drug will then likely precipitate; in this case, the excipients would be eliminated much faster than the drug.

On the positive side of highly lipophilic drugs, an intravitreal injection of a suspension – or a formulation which precipitates in vivo – may create a reservoir for prolonged release of a drug; for example, triamcinolone acetonide suspension injected into the vitreous may deliver an effective dose of the steroid for months. However, it should be noted that, just because drug particles settle in the vitreous, does not necessarily mean that the drug will be available to reach its target; the drug may be unavailable to targets for a number of reasons such as endocytosis by nontarget tissue(s), low solubility, drug degradation, or metabolism.

While it is more likely that an extremely lipophilic drug would be effective than a highly water soluble drug, it is best to consider that both species will be difficult to formulate. If a promising drug is at either of these solubility extremes, it may be wise to evaluate a prodrug approach, in parallel, or instead, of devoting enormous resources in an effort to develop a viable formulation.

At least equally important as a drug’s solubility, the drug’s partition coefficient plays a vital role in passive diffusion; the hydrophobic/hydrophilic balance of drug molecules usually determines the degree in which a pharmaceutical will be taken up by tissues. A drug solution injected into the vitreous will diffuse in a concentration dependent manner (assuming that the drug remains in solution). In most cases, flow and ocular pressure will be only minor contributors to vitreal drug distribution; an intravitreal injection of a solution at the pars plana will distribute in declining gradients throughout the vitreous to reach the macular at roughly 1/10th the concentration of the injected formulation (Missel 2002).

From its local concentration in the vitreous, a drug diffuses into the retina depending on a number of factors, which include the drug’s concentration in solution,

its ability to partition between tissues, its bioelimination rate, and the drug’s stability. From the retinal tissue, the drug will travel to the choroid and then to the sclera. It should be kept in mind that the Bruch’s membrane is between the retina and choroid and can serve as a barrier to drugs. However, in ARMD, this barrier is typically disrupted by choroidal vessels, which modify the architecture of the retina. Consequently, drugs may more readily permeate the choroid after an intravitreal administration to a patient with macular degeneration.

Drugs may be delivered to the choroid and retina from a subTenons site of administration. The sclera appears to be rather “porous” to drugs. Assuming the drug is sufficiently liposoluble, it will also penetrate the choroidal tissue and then enter the retina. The Bruch’s membrane may serve as a barrier between the choroid and the retina but, again, in ARMD this may be disrupted. Some drug will be eliminated by the choroidal blood vessels.

It is likely that the partition coefficient also plays an important role in a drug migrating posteriorly after topical ocular administration (Tamilvanan et al. 2006). Very few drugs reach the back of the eye in effective concentration by this path because there is substantial dilution of a drug by tear fluid, followed by precorneal drainage. Also, there are numerous physiological barriers which block the drug from reaching posterior tissue (Short 2008).

One possible route around these barriers may be by trans-limbal/intrascleral migration (Ottiger et al. 2009). A topical formulation for treating a blinding disease would be a very important discovery because it would be both noninvasive and patient friendly.

PKa is another important factor in drug permeation of lipophilic tissue (e.g., retina and choroid); generally, drugs, which are unionized at physiological pH, have a better opportunity to reach the target tissue than ionized drugs; however, there may be exceptions to this rule (Brechue and Maren 1993). Also, ion-pairing may assist ionized drugs to penetrate tissue by decreasing the overall charge.

Particle size also may play an important role in drug distribution. Formulations with smaller particle size have a greater net surface area than identical formulations with larger particle size. Generally, because of the higher surface area, the drug divided in smaller particles will dissolve at a faster rate than if the drug was in larger particles. Therefore, small-particle formulations would normally be expected to deliver a higher solubilized concentration of drug in vivo, in a shorter period of time.

Formulations with smaller drug particles might stay suspended in the vitreous longer than larger ones; this would give the drug an opportunity to spread more evenly and to more readily penetrate the retina either by localized dissolution followed by diffusion or by endocytosis. However, if the particles remain suspended in the vitreous too long or settle on the retina in large concentration, they may impair vision and cause temporary blindness for days or weeks. Alternatively, if a formulation with small particles settle and unite to form a mass in the vitreous, the formulation may have nearly identical properties as one with larger particles. Similarly, large particle suspensions injected into the sub-Tenon’s space might be expected to have a longer duration than smaller particles of the same drug. But, here too, the smaller particles might form a mass and behave much like the larger particles.

Or, macrophages might carry away the smaller particles, while ignoring the larger ones, resulting in a higher concentration of drug in the target tissues and longer duration with latter formulation. In contrast, drugs, which inhibit macrophage digestion, may produce the opposite results.

Drug molecule size is another physicochemical property that can play a role in tissue distribution. In the vitreous, molecules with a higher molecular weight (e.g., oligonucleotides, polypeptides, proteins) generally have a longer half-life than smaller drug molecules. However, lipophilicity, dose, and solubility also play important roles in vitreal half-life of a drug (Dias and Mitra 2000; Durairaj et al. 2009). Molecules, both small and large (285–69,000 Da) readily diffuse through the sclera (Maurice and Polgar 1977; Geroski et al. 2001). In contrast, the retinal pigment endothelium (RPE)-choroid barrier is about 10–100 times less permeable to large molecules than the sclera (Pitkänen et al. 2005).

Polymorphism is another physicochemical property which can be important to drug delivery. Polymorphs may differ in filterability, solubility, dissolution rate, chemical and physical stability, melting point, color, refractive index, enthalpy, density, viscosity, bioavailability, and many other properties (Llinàs et al. 2007).

The importance of understanding the polymorphic forms of a drug and their stability cannot be understated. In 1998 – 2 years after launch – Abbott Labs discovered that several lots of Ritonavir capsules failed the QC dissolution testing. Microscopy and X-ray powder diffraction indicated that a new polymorph had formed and that the new material was more thermodynamically stable and had greatly reduced solubility compared to the original crystal form (Bauer et al. 2001). Abbott lost hundreds of millions of dollars in the expense of a major recall, in lost revenues, and in R&D efforts to reintroduce the drug. But this change was more than just a costly and embarrassing problem; some AIDS patients may have been given the nondissolving dosage form, while others, due to the recall, were deprived of this life-extending therapy altogether.

Polymorphism is a potential problem with all types of dosage forms, including ophthalmic formulations and drug delivery systems. For example, after completing a phase I/II clinical study of an intravitreal suspension of a steroid, an ophthalmic drug company belatedly discovered that there were three polymorphs of the drug in the raw material: the mix was 80% “alpha”, 15% “beta,” and 5% “gamma” polymorphs. Immediately critical questions arose: Would future raw material lots always contain the same ratio of polymorphic forms? Did the ratio between the polymorphic forms change during manufacture, storage, and/or distribution? If the ratio of polymorphs changes under any of these conditions, would the formulation’s efficacy, stability, and safety observations be reproducible in the future?

These are some of the questions that regulatory authorities would ask, with the highly likely outcome that the information generated in the clinical study would be deemed worthless, causing the loss of time to market and millions of dollars. Fortunately, in this particular case, further investigation showed that the suspension’s processing steps had converted the beta and gamma crystal forms in the raw material to the alpha polymorph. The final clinical suspension was composed of 100% of the alpha form; it also was quite fortuitous that the formulation remained