Cornea penetrating

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]. 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

The most common means of administering drugs to the eye is by topical administration of agents capable of penetrating the cornea and targeting the appropriate tissue for either physiological or medicinal effect [159,160]. The trilaminar structure of the transparent avascular cornea has been described previously. The... 

K Morimoto, T Nakamura, K Morisaka. (1989). Effect of medium-chain fatty acid salts on penetration of a hydrophilic compound and a macromolecular compound across rabbit corneas. Arch Int Pharmacodyn 302 18-26. 

Swan, K.C. and White, N.G. (1972). Corneal permeability (1) factors affecting penetration of drugs into the cornea. Amer. J. Ophthalmol. 25 1043-1058. 

For in vitro toxicity studies and assessment of the barrier function, drug transport, cell physiology, and metabolism as well as the development of delivery systems, cell culture models provide powerful systems for scientific research. As the corneal epithelium is the main barrier for ocular penetration, various corneal epithelial cell cultures were established besides the corneal constructs that mimic the whole cornea and serve as reductionist models for the ocular barrier. In general, two types of cell culture models are available primary cell cultures and immortalized, continuous cell lines. 

The ocular membranes comprise the cornea (not vascularized) and the eonjuetiva (vascularized). The corneal epithelium consists of five or six layers of nonkeratinized squamous cells, and is considered to be the major pathway for ocular drug penetration [57]. 

Completely absorbed from the G1 tract penetrates cornea after ophthalmic administration (may be systemically absorbed). Protein binding greater than 99%. Widely distributed. Metabolized in the liver. Primarily excreted in urine. Minimally removed by hemodialysis. Half-life 1.2-2 hr. 

Acute injuries of the eyes, primarily from effects of blast and missiles, may occur from tear-gas weapons, such as pen guns. The lnmeulate effects of these Injuries include swelling and edema of the lids, with penetration of skin, conjunctiva, cornea, sclera, or globe by gunpowder and CN conjunctival ischemia and chemosls corneal edema, erosion, Inflammation, or ulceration and focal hemorrhage. 13,20... 

Josset, R, Meyer, M.C., Blomet, J. Penetration d un toxique dans le comee. Etude experimental et simulation [French]. [Penetration of a toxic agent into the cornea. Experimental study and simulation]. SMT 85, 25-33 (1986)... 

The first damages to tissues do not develop within the first seconds of contact with a corrosive. They progressively and quickly take place only when the penetration phase starts from the surface of the cornea toward the deeper layers. 

Finally, Chaps. 5 and 6 will develop the experimental results of the penetration of various corrosive compounds through the cornea, up to the anterior chamber, in the contact of the lens (see Sect. 5.1.6). 

The experimental simulation of a chemical bum (Figs. 3.84 and 3.85) is stated on a corrosive such as some IM soda in contact for 3 min with the semipermeable membrane representing the cornea. It favorably shows the time gained, thanks to a solution that physically and chemically helps the pH of the aqueous humor to get back to the safe zone. Here, the point is not only to show the mechanical draining effect at the surface of the membrane/comea (which quickly restores the pH to a normal value), but also to show how the internal decontamination of a corrosive is important and difficult. The internal decontamination will deal with the amount of corrosive that might have already penetrated into the anterior chamber of the eye. 

The cornea enables the penetration of rays of light inside the eye, thanks to completely particular optical capacities allied to its great fragility largely due to its distant origin within the aquatic species. We will see how the histology of the cornea helps to understand this permanent miracle. 

Transparency [5] is the essential property of the cornea because it enables the light rays to penetrate into the inside of the eye. It only starts to develop in the fourth month of fetal life until it is complete in the 6th month. Endangered in case of a severe eye bum, this critical function depends on different factors. 

In normal state, the cornea would be a too compact tissue for the vessels to penetrate it. 

We will see in Chap. 5, Physiopathology of the cornea and physiopathology of eye bums, that this corneal osmolarity must be considered as part of the immediate treatment of chemical bums. Moreover, we know that the osmolarity of a burnt cornea increases [6]. Thus, in this situation and differently to hypertonic products, the application of an iso- or hypotonic wash liquid (in comparison with a healthy cornea) like water or physiological saline onto the cornea will lead to an afflux of water into the cornea and facilitate the penetration of corrosives into the deep layers of the cornea. 

The penetration into the tissue follows the initial breakdown of the epithelial barrier. This results in an immediate and strong edema of the conjunctiva, known as chemosis, due to a water influx from the surrounding tissue, vascular leakage, tears, and applied fluids. The cornea itself loads up with ions to a measured osmolarity of 1,830 mOsmol/kg after a 1 mol NaOH bum for 30 s [24]. The penetration of strong alkali has been systematically tested on sodium hydroxide by means of evaluation of the anterior chamber pH. This pH change typically occurs within 2 min after exposure of the comeal surface. The change of the cornea... 

In any type of ocular bum and later on rinsing therapy, we have found that the speed of the penetration was roughly correlated to the concentration of the corrosive and the type of corrosive. This question is still scientifically open but estimations of penetration of sodium hydroxide are from about 5-8 pm/s depth propagation into the tissues, derived from measurements of Rihawi et al. on rabbit corneas [43]. Theoretical work on penetration characteristics of different chemicals have been published by Pospisil and Holzhuetter [44]. They have proved that, in first order estimation, the chemical properties like molecular size and shape, partition coefficients, and the type of interaction with the intrinsic membrane parameters determine the penetration characteristics. In very good estimations, they have shown that, for a various set of test substances, the penetration is almost exactly predicted by their modelization. 

For the contact time, the chemical agent physically migrates into tissue and can pass through the cornea in 90 s if 4% soda (1 N/pH = 14). Penetration is gradual and induces no immediate deleterious effect. As set out in Chap. 5, cells can survive for some time in contaminated medium. The shorter this time, the greater the chances of cell survival. 

After one minute, however, all the experimental studies have demonstrated the ineffectiveness and even harmfulness of eye rinsing with water or with the other isotonic solutes (isotonic to blood). In fact, these aqueous solutions dilute the chemical substance and facilitate the release of the active ions of the corrosive or irritating product. In addition, being hypo-osmolar to the cornea, aqueous solutions create flows from tissue surface to the inside, favoring the penetration of the chemical into ocular tissue (see Chaps. 5 Physiopathology and 6 Eye Rinsing Solutions ). 

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