Ocular drug delivery administration routes

Consequently, frequent instillation of eye drops is required, resulting in pulsed administration and patient noncompliance. Clearly, the main prerequisite for absorption of drugs into the eye is good corneal penetration and prolonged contact time with the corneal epithelium. Many intrinsic barriers, such as the cornea barrier, blood-aqueous barrier (BAB), and blood-retinal barrier (BRB), restrict ocular drug delivery (Figure 51.2). The barriers related to topical drug administration route are as follows. 

Different ocular drug delivery routes are schematically shown in Fig. 21.2. For a thorough review on this field, several articles are available [7—13]. Topical or systemic administration of drugs is preferred over all other delivery methods since these techniques are cost-effective, non-invasive and easy to administer. However, systemic delivery is extremely inefficient for ocular drugs due to the separation of ocular tissues from the systemic circulation of the body [14,15]. A study has shown that systemic administration of a radiolabeled protein to healthy rats led to the accumulation of high radioactivity in blood, liver, and spleen, but no radioactivity could be detected in the ocular tissues [16]. 

Due to the lack of activity after oral administration for most peptides and proteins, administration by injection or infusion - that is, by intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration - is frequently the preferred route of delivery for these drug products. In addition, other non-oral administration pathways have been utilized, including nasal, buccal, rectal, vaginal, transder-mal, ocular, or pulmonary drug delivery. Some of these delivery pathways will be discussed in the following sections in the order of the increasing biopharmaceutic challenges to obtain adequate systemic exposure. 

Several types of CDD systems have been designed based on various mechanisms of drug release (Table I). These mechanisms are dependent on the required site of drug delivery, the physicochemical properties of the drug and also of the delivery vehicle (13), Modes of administration can be oral, sublingual, transdermal, rectal, intrauterine, ocular, or parenteral (intramuscular, peritoneal, and subcutaneous routes of injection). 

It has to be clear that, once diluted and injected (or administered in ocular and other routes), the emulsion stability and fate are determined by three measurable parameters. The first is the partition coefficient of each emulsion component (including added drugs and agents) between the emulsion assembly and the medium. To some extent this partition coefficient is related to oil-water and/or octanol-water partition coefficients. For example, it was well demonstrated that per component of which logP is lower than 8, the stability upon intravenous (IV) injection is questionable [42,138], The other two parameters are kQff, a kinetic parameter which describes the desorption rate of an emulsion component from the assembly, and kc, the rate of clearance of the emulsion from the site of administration. This approach is useful to decide if and what application a drug delivery system will have a chance to perform well [89],... 

The lack of activity after oral administration for most peptides and proteins resulted in the past besides parenteral application into the utilization of nonoral administration pathways, for example, nasal, buccal, rectal, vaginal, percutaneous, ocular, or pulmonary drug delivery [27]. Drug delivery via these administration routes, however, is also frequently accompanied by presystemic degradation processes. Bioavailability of numerous peptides and proteins is, for example, markedly reduced after subcutaneous or intramuscular administration compared to their intravenous administration. The pharma-cokinetically derived apparent absorption rate constant is thus the combination of absorption into the systemic circulation and presystemic degradation at the absorption... 

Solid lipid nanoparticles have been investigated in many different administration routes parenteral, oral, (trans)dermal, ocular d64,i97 pulmonary.Furthermore, cationic SLN formulations were used to complex DNA for cell transfection. In the following chapter, selected studies are summarized with respect to a parenteral, oral and dermal administration as well as for gene delivery to illustrate the versatility of solid lipid nanoparticle formulations in drug delivery. 

As previously mentioned, systemic delivery is limited because of the isolation of ocular tissues from the systemic circulation thus, topical delivery is often the preferred administration route owing to ease of access and patient compliance, particularly when treating infections of the anterior segment such as keratitis sicca, conjunctivitis, or blepharitis and diseases such as glaucoma or uveitis that require the drug to be diffused across the corneal barrier [19,20]. However, drainage, lacrimation and tear dilution, tear turnover, conjunctival absorption, and the corneal epithelium all limit corneal drug penetration [21,22]. 

Mucoadhesive drug delivery systems are comprised of administration of drug across the mucosal membrane using a mucoadhesive/bioadhesive polymer through various noninvasive routes such as peroral, ocular, buccal, nasal, stomach, intestinal, colon, vaginal, rectal, cervical or vulval. The drug delivery systems, which have made use of chitosan as a carrier for administration through various routes, have been represented in Table 2.2. 

The use of ttaditional disperse systems, e.g., macroemulsions, in the pharmaceutical industry has been limited due to manufacturing complexity and stability problems [117]. The characteristic properties of nano-emulsions (kinetic stability, small and controlled droplet size, etc.) make them interesting systems for pharmaceutical applications. Indeed, nano-emulsions are used as drug delivery systems for administration through various systemic routes. There are numerous publications on nano-emulsions as drug delivery systems for parenteral [17,18,28,29,118-124], oral [25,125-129], and topical administration, which includes the administration of formulations to the external surfaces of the body skin [32,130,131] and to the body cavities nasal [30,132] as weU as ocular administration [31,133-136]. Moreover, many patents concerning pharmaceutical applications of nano-emulsions have been registered [17,18,25,137-145]. An application of nano-emulsions in this field has been in the development of vaccines [33,146-147]. 

The conventional concentration of benzalkonium chloride in eyedrops is 0.01%, with a range of 0.004-0.02% [111]. While uptake of benzalkonium chloride itself into ocular tissues is limited [113], even lower concentrations of benzalkonium chloride have been reported to enhance corneal penetration of other compounds including therapeutic agents [93,112,114]. The differential effect of this preservative on the cornea compared to the conjunctiva can be exploited to target a drug for corneal absorption and delivery to the posterior segment of the eye [115]. Its use has been proposed as a means of delivering systemic doses by an ocular route of administration [116]. 

It has been shown in a number of studies that the incorporation of drug in o/w nanosized emulsions significantly increased the absorption of the drug when compared with the equivalent aqueous solution administered orally [132-135], However, the use of emulsions for oral application is limited since other attractive alternatives, such as self-emulsifying oil delivery systems, which are much less sensitive and easy to manufacture, are available [136,137], Thus the potential of nanosized emulsions after administration with parenteral and traditional nonparenteral topical routes such as ocular, percutaneous, and nasal is covered in this section. 

One of the key pieces to development of a successful drug product is the ability to deliver the drug to the site of action with minimal discomfort or inconvenience to the patient. For small molecule therapeutics, there is a wide range of options available for drug administration. Delivery via injection (IV, IM, and SC), oral, nasal, ocular, transmucosal (buccal, vaginal, and rectal), and transdermal routes is possible with small molecule drugs. However, the size of proteins and the complexity of their structures severely limit the routes of administration available to proteins. 

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