Tear fluid

To remain safe and efficacious on the eye, contact lenses must maintain clear and wetted surfaces, provide an adequate supply of atmospheric oxygen to and adequate expulsion of carbon dioxide from the cornea, allow adequate flow of the eye s tear fluid, and avoid excessive abrasion of the ocular surface or eyeflds, all under a variety of environmental conditions. The clinical performance of a contact lens is controlled by the nature of the lens material the lens design the method and quaUty of manufacture the lens parameters or specifications prescribed by the practitioner and the cleaning, disinfection, and wearing procedures used by the patient. 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

The collagen shield, fabricated from procine scleral tissue, is a spherical contact lens-shaped film whose thickness can be made to vary from 0.027 to 0,071 mm. It has a diameter of 14.5 mm and a base curve of 9 mm. Once the shield is hydrated by tear fluid and begins to dissolve, it softens and conforms to the corneal surface. Dissolution rates can be varied from 2 to as long as 72 hr by exposing the shields to ultraviolet radiation in order to achieve varying degrees of crosslinking. 

The ocular surface and the tear-secreting glands of the eye are now known to function as an integrated unit. This unit refreshes the tear supply and clears used tears. An autonomic neural reflex loop stimulates secretion of tear fluid and proteins by the lacrimal glands. The sensitivity of the ocular surface decreases as aqueous tear production and tear clearance decreases. This results in a decrease in sensory-stimulated reflex tearing which exacerbates dry eye.29,30 Over time, wearing contact lenses also desensitizes the cornea by constant stimulation.12... 

Gel-Forming Solutions. One disadvantage of solutions is their relatively short residence time in the eye. This has been overcome to some degree by the development of solutions that are liquid in the container and thus can be instilled as eyedrops but gel on contact with the tear fluid and provide increased contact time with the possibility of improved drug absorption and increased duration of therapeutic effect. 

In addition to stability effects, pH adjustment can influence comfort, safety, and activity of the product. Comfort can be described as the subjective response of the patient after instillation of the product in the cul-de-sac (i.e., whether it may cause a pain response such as stinging or burning). Eye irritation is normally accompanied by an increase in tear fluid secretion (a defense mechanism) to aid in the restoration of normal physiological conditions. Accordingly in addition to the discomfort encountered, products that produce irritation will tend to be flushed from the eye, and hence a more rapid loss of medication may occur with a probable reduction in the therapeutic response [15]. 

A number of ocular surface disorders collectively termed as Dry Eye Syndromes have also been associated with the conjunctiva. For example, a deficiency and/or imbalance in compositions of the tear film is often found on the ocular surface during keratoconjunctivitis sicca. Since the conjunctiva plays a direct role in the maintenance of the tear fluid stability via secretion of mucin [1] by its resident goblet cells [4] and basal fluid secretion driven by electro-osmotic gradients across the tissue [3], the conjunctiva is a well deserved, but not intensively studied, target of interest in research efforts aimed against combating Dry Eye Syndromes. 

An immunoassay using immobilized antibodies was described by Phillips and Chmielinska (14). By means of this approach the determination of the immunosuppressant cyclosporin A (CsA) in tear fluid was obtained using UV detection. Although the detection limit is sufficient using only immu-noaffinity capillary electrophoresis, overlapping signals can be avoided. A set of tear samples was quantified. Immunoaffinity CE was able to detect... 

Alkyl monoesters of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) are bioerodible acidic polymers that are used to control drug release. In biological fluids with poor buffering capacity, drug release from the polymers and their dissolution are slowed owing to the lower pH on the polymer surface. We studied whether the release of timolol from matrices of monoisopropyl ester of PVM-MA in vitro and in vivo in rabbits eyes could be affected by disodium phosphate in the matrices. Addition of disodium phosphate to the matrices doubled the release rate of timolol in vitro, but it did not affect the bulk pH of the dissolution medium. On the basis of the timolol concentrations in the tear fluid and in systemic circulation, disodium phosphate seems to accelerate drug release in vivo also. Disodium phosphate probably affects the rate of dmg release by increasing the microenvironmental pH on the polymer surface. 

The aim of this study was to find out whether it is possible to affect the dissolution of monoisopropyl ester of PVM-MA and drug release form the polymer in vivo in tear fluid by adding basic salts to the matrices. Timolol maleate was used as the drug. 

Matrices of monoisopropyl ester of PVM-MA were carefully applied in the lower conjunctival sac of rabbits. Inserts did not cause any irritation in rabbit eyes. Plasma and tear fluid samples were collected at different times during a period of 8 h. Blood samples were taken from the cannulated ear artery. Plasma was separated by centrifuging (2000 g, 4min) and kept at -20°C until analysed. Tear fluid samples (1 pi) were collected with microcapillaries at 30, 120, 240 and 480 min after application of the matrices. Tear fluid samples were diluted in 5 ml of phosphate buffer. 

Timolol concentration in plasma and tear fluid samples was measured using a modified radioreceptor assay [7]. In the assay, displacement of a P-antagonist, (-)-3H-CGP-12177, from 0-receptors of rat reticulocyte membranes by timolol was measured. Rat reticulocyte membranes were obtained as described by Wellstein el al. [7]. 

Timolol concentration in tear fluid samples was measured in the same way, but 200 pi of the diluted tear fluid in phosphate buffer were used instead of 180 pi plasma. After incubation, bound and free radioligand were separated by vacuum filtration through Whatman GF/F glass fibre filters. Filters were washed three times with 10 ml ice-cold 310 mOsm phosphate buffer, dried and counted for retained radioactivity in 5 ml of Lipoluma-Lumasolve-water (10 1 0.2) mixture using... 

The concentration profiles in tear fluid (Fig. 4) resemble the profiles in plasma (Fig. 3). Compared with unbuffered matrix (cmax=45,2 9.4pg/ml) administration of timolol in polymer matrix with disodium phosphate resulted in a higher peak (91.5 13.7 pg/ml) in tear fluid (Fig. 4). With the unbuffered matrices, the peak levels of timolol in tear fluid were seen much later than with buffered matrices (Fig. 4). 

Timolol concentrations in the tear fluid and plasma suggest that compared with unbuffered matrices timolol is released more rapidly from the isopropyl ester of PVM-MA matrices with disodium phosphate in vivo. During the experiment, the buffered matrices also dissolved more rapidly in the tear fluid than the unbuffered matrices. 

In vivo results correspond quite well to those of the in vitro experiments although the effect of a basic additive seems to be greater in vivo. It is possible to increase the dissolution rate of PVM-MA esters in tear fluid by adding disodium phosphate or possibly other basic salts to the matrices. With basic additives it may be possible to modify drug release and polymer dissolution also in the case of other polyacids. 

Fig. 4—Timolol concentration (pg/ml) in tear fluid after application of one buffered ( ) or unbuffered ( ) matrix in each eye of a rabbit. Means SEM of 11-18 eyes are shown.

Nondegradable polymers are also useful as matrices for ocular implants. This application requires the polymer to be hydrophilic, to minimize local tissue irritation. Need for ocular implants stems from the challenges posed to conventional ocular medicines (i.e., eye drops) such as rapid dilution, tear washout, poor patient compliance, and limited bioavailability. Ocular implants from hydrophilic polymer matrices that provide localized sustained release may overcome the above limitations. The first polymeric sustained release product to reach the market was Ocusert , a pilocarpin sustained release ocular implant developed by Alza. Ocusert has the drug reservoir as a thin disc of pilocarpine-alginate complex sandwiched between two transparent discs of microporous membrane fabricated from ethylene-vinyl acetate copolymer. The microporous membranes permit the tear fluid to penetrate into the drug reservoir compartment to dissolve pilocarpine from the complex. Pilocarpine molecules are then released at a constant rate of 20 or 40 pg/hr for a four- to seven-day management of glaucoma. 

Pflugfelder, S.C., et al. 2000. Detection of sialomucin complex (MUC4) in human ocular surface epithelium and tear fluid. Invest Ophthalmol Vis Sci 41 1316. 

After ocular instillation, aqueous eye drop solutions and suspensions mix with the tear fluid and are dispersed over the eye surface. The greater part of the applied drug... 

The anterior surface of the eye is constantly rinsed by tear fluid secreted at a flow rate of about 1 pL/min by the main lachrymal gland of the lachrymal apparatus. Tears eventually drain into the nasal cavity through the nasolachrymal ducts. Tear fluid contains mucin, lysozyme, lactoferrin, prealbumin, and serum proteins. It functions as an antibacterial lubricant and aids in draining out foreign substances. The normal volume of tear fluid is 5 to 10 xL.66... 

Apart from physical barriers, topical drug delivery to eye is also affected by the volume, viscosity, pH, tonicity of vehicle, and type of drug. Constant drainage by tear fluid minimizes topical drug absorption and increases systemic absorption. As a result, only about 5 percent of total dose is effectively absorbed through the intraocular route,... 

Thygesen, J.E.M., Bach, B., Molliave, L., Pedersen, O.F., Prause, J.U. and Skov, P. (1987) Tear fluid electrolytes and albumin in persons under environmental stress. Environmental Research, 43, 60-5. 

B. L. Schulz, D. Oxley, N. H. Packer, and H. G. Karlsson, Identification of two highly si-alylated human tear-fluid DMBT1 isoforms The major high-molecular-mass glycoproteins in human tears, Biochem. J., 366 (2002) 511-520. 

Alexeev V, Das S, Finegold DN, Grabowski J, Somayajula K, Asher SA. Photonic crystal glucose sensing material for non-invasive monitoring of glucose in tear fluid. Clinical Chemistry 2004, 50, 2352-2366. 

Contact lenses are attractive formats for fluorescence-based sensing, as they are optically transparent, easily accessible, and are sufficiently inexpensive to be disposable. A handheld device for patients to self-test has been developed to excite and measure fluorescence from lenses (Figure 10.9) and some limited clinical trials have been performed.143 144 However, the efficacy of using tear fluid to manage diabetes... 

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