Jl

0 50 100 150 200 250 Average velocity (m s-1)

Figure 9.31 Average % delivery of mannitol by jet injection through a 152 um diameter nozzle into human (•) and porcine (■) skin. The error bars shown are one standard deviation (n = 5-19 for each human skin data point). The magnitude of the delivery into human skin is higher than into porcine skin.

Reproduced from J. Shramm and S. Mitragotri, Pharm. Res., 19, 1673-1679 (2002).

delivery is then possibly due to either or both of skin 'failure' and possibly flow through the skin.15 The theoretical maximum velocity (v) of the jet is related to the pressure (P) in the nozzle and the density (p) of the liquid by v=(7r but the velocity is affected by diameter of the orifice and is reduced by turbulence and friction. Figure 9.31 shows the percentage delivery of mannitol into the skin as a function of the average velocity of the jet.15

9.6 Medication of the eye and the eye as a route for systemic delivery

The eye is not, of course, a general route for the administration of drugs to the body, although it has been explored for the systemic delivery of peptides and proteins such as insulin. It is considered here because absorption of drugs does occur from medication applied to the eye, producing sometimes toxic systemic effects, although often the desired local effect is on the eye or its component parts. We will consider the factors affecting drug absorption from the eye, and those properties of formulations that affect drug performance. A wide range of drug types are placed in the eye, including antimicrobials, antihistamines, decongestants, mydriatics, miotics and cycloplegic agents.

Drugs are usually applied to the eye in the form of drops or ointments for local action. The absorbing surface is the cornea. Drug absorbed by the conjuctiva enters the systemic circulation. It is useful to consider some of the properties of the absorbing surfaces and their environment.

The eye (Fig. 9.32) has two barrier systems: a blood-aqueous barrier and a blood-vitreous barrier. The former is composed of the ciliary epithelium, the epithelium of the posterior surface of the iris, and blood vessels within the iris. Solutes and drugs enter the aqueous humour at the ciliary epithelium and at blood vessels. Many substances are transported out of the vitreous humour at the retinal surface. Solutes also leave the vitreous humour by diffusing to the aqueous humour of the posterior chamber.

Figure 9.32 is a diagrammatic representation of those parts of the eye involved in drug absorption. The cornea and the conjuctiva are covered with a thin fluid film, the tear film, which protects the cornea from dehydration and infection. Cleansed corneal epithelium is hydrophobic, physiological saline forming a contact angle of about 50° with it, and it has, in this clean condition, a critical surface tension of 28 mN m_1. The aqueous phase of tear fluid is spread by blinking.

Tears

Tears comprise inorganic electrolytes - sodium, potassium and some calcium ions, chloride and hydrogencarbonate counterions - as well as glucose. The macromolecular components include some albumin, globulins and lysozyme. Lipids which form a monolayer over the tear

Figure 9.32 Diagrams of parts of the eye of importance in medication: the superior and inferior punctae are the drainage ports for solutions and tear fluids, and medicaments can drain via the canaliculi into the nasolacrimal duct and then to the nasal cavity, from whose surfaces absorption can occur.

Modified from J. R. Robinson (ed.), Ophthalmic Drug Delivery Systems, American Pharmaceutical Association, Washington DC, 1980.

Figure 9.32 Diagrams of parts of the eye of importance in medication: the superior and inferior punctae are the drainage ports for solutions and tear fluids, and medicaments can drain via the canaliculi into the nasolacrimal duct and then to the nasal cavity, from whose surfaces absorption can occur.

Modified from J. R. Robinson (ed.), Ophthalmic Drug Delivery Systems, American Pharmaceutical Association, Washington DC, 1980.

fluid surface derive from the Meibomian glands which open on to the edges of the upper and lower lids. This secretion consists mainly of cholesteryl esters with low melting points (35°C) due to the predominance of double bonds and branched-chain structures. This fluid lies on the surface of the cornea (Fig. 9.33) and its importance in formulation lies in the possibility that components of formulations or drugs themselves can so alter the properties of the corneal surface, or interact with components of the tear fluid, that tear coverage of the eye is disrupted. When this occurs the so-called dry-eye syndrome (xerophthalmia) may arise, characterised by the premature break-up of the tear layer resulting in dry spots on the corneal surface.

9.6.2 Absorption of drugs applied to the eye

The cornea, which is the main barrier to absorption, consists of three parts: the epithelium, the stroma and the endothelium. Both the endothelium and the epithelium have a high lipid content and, as with most membranes, they are penetrated by drugs in their unionised lipid-soluble forms. The stroma lying between these two structures has a high water content, however, and thus drugs which have to negotiate the corneal barrier successfully must be both lipid-soluble and water-soluble to some extent (Fig. 9.33).

Tears have some buffering capacity so, as we noted before, the pH-partition hypothesis has to be applied with some circumspection. The acid neutralising power of the tears when 0.1 cm3 of a 1% solution of a drug is instilled into the eye is approximately equivalent to 10 ^L of a 0.01 mol dm 3 strong base. The pH for either maximum solubility (see Chapter 5) or maximum stability (see Chapter 4) of a drug may well be below the optimum in relation to acceptability and activity. Under these conditions it is possible to use a buffer with a low buffering capacity to maintain a low pH adequate to prevent change in pH due to alkalinity of glass or carbon dioxide ingress from the air. When such drops are instilled into the eye the tears will participate in a fairly rapid return to normal pH.

In agreement with the pH-partition hypothesis, raising the pH from 5 to 8 results in a two- to threefold increase in the amount of pilocarpine reaching the anterior chamber. It is also found, however, that glycerol penetration increases to the same extent (Fig. 9.34). The clue to why this should be so lies in the effect of the buffer solutions on lacrimation. Increased tear flow reduces the concentration

Layer of adsorbed lipid

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