Bioavailability ophthalmic formulations

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. 

Topical ocular drugs are generally administered in the form of eye drops. Ophthalmic formulations like solutions, suspensions, and ointments available in the market show drawbacks such as increased pre-corneal elimination, blurred vision, and high variability in efficiency. Actually, these conventional dosage forms suffer from the problems of poor ocular bioavailability, because of various anatomical and pathophysiological barriers prevailing in the eye. 

Suspension. If the drug is not sufficiently soluble, it can be formulated as a suspension. A suspension may also be desired to improve stability, bioavailability, or efficacy. The major topical ophthalmic suspensions are the steroid anti-inflammatory agents prednisolone acetate, dexamethasone, fluorometholone, and rimex-olone. Water-soluble salts of prednisolone phosphate and dexamethasone phosphate are available however, they have a lower steroid potency and are poorly absorbed. 

Given the considerable challenge of ocular drug delivery, i.e. short contact time and low drug bioavailability, mucoadhesives are attractive excipients in ophthalmic drug formulations. The presence of mucin in the eye allows bioadhesive polymers to thicken the tear film in the front of eye. 

Emulsions have been used for centuries for the oral administration of medical oils and vitamins and as dermatological vehicles. Recently, their application has been extended as drug carriers in the delivery and targeting of ophthalmic drags. An indomethacin emulsion has been reported to increase ocular bioavailability and efficacy compared to commercially available formulation in rabbits. 0.4% indomethacin emulsion showed 2.2 fold increase in the area under the anterior aqueous drag concentration/time curve compared to a 1% indomethacin suspension. The emulsion formulation also reduced ocular surface irritation caused by indomethacin Similar advantages have been shown for a pilocarpine emulsion which produced a prolonged therapeutic effect in comparison with pilocarpine hydrochloride eyedrops in man. It can be administered only twice a day, rather than four times daily for conventional formulation. 

According to Davies [174], topical ophthalmic suspensions have a number of limitations compared to solutions. They need to be adequately shaken before use to ensure correct dosing, a process which can result in poor patient compliance. In addition, they need to be sterilized, which may cause physical instability of the formulation. Furthermore, the amount of drug required to achieve only a moderate increase in bioavailability is very high, rendering suspensions expensive in terms of their production costs [175],... 

In contrast, low-methoxy (LM) pectins gel in the presence of divalent cations, especially calcium, by the egg box mechanism proposed for alginates. Moreover, calcium pectinate gels prepared at neutral pH are heat stable, whereas acidic pH gels are thermo-reversible. Gel strength depends on the extent of esterification (levels from 30% to 50% are optimal), the distribution of ester groups on the chain, and the average molecular weight. LM pectins have been used traditionally in antidiarrheal formulations with kaolin. HM pectins were evaluated in controlled release matrix formulations. Pectin microspheres were reported to improve ophthalmic bioavailability of piroxicam in rabbits compared with commercial piroxicam eye drops. ... 

An excipient is defined as a material that is deliberately incorporated into the formulation to aid some physicochemical process, for example for a tablet, integrity, dissolution, bioavailability or taste excipients are typically chosen from among many compounds without pharmacological properties (e.g. lactose), although there are examples where pharmacokinetics change with the excipient used. There are specialized examples of excipients, for example propellants are excipients that assist in the delivery of inhaled drugs to the respiratory tract. For intravenous infusions or ophthalmic products, the excipients are usually pH buffers or... 

Frequent instillation of solution or higher drug concentration is needed to achieve the desired therapeutic response. But this attempt is potentially dangerous if drug solution drained from the eye is systemically absorbed from the nasolacrimal duct. To increase precorneal residence time and ocular bioavailability, different ophthalmic delivery systems such as viscous solutions, ointments, gels, suspensions, or polymeric inserts are used. But because of blurred vision (e.g., ointments) or lack of patient compliance (e.g., inserts), these formulations have not been widely accepted. 

S.P. Eriksen, Physiological and formulation constraints on ocular drug bioavailability, in "Ophthalmic... 

In a very recent study, Lou et al. prepared a thermoresponsive in situ gel system based on Pluronic F127 and Pluronic F68 and containing curcumin-loaded albumin nanoparticles. The physicochemical properties of Cur-BSA-NPs-Gel showed temperature-responsive features. Thus, this formulation, which transforms into a gel when exposed to eye temperature, may be applied as eye drops. The sol-gel transition temperature depended on the Pluronic F127 and Pluronic F68 concentrations increases in Pluronic F127 content decreased the sol-gel transition temperature of the formulation, whereas increases in Pluronic F68 increased the sol-gel transition temperature. Cur-BSA-NPs-Gel could enhance the ophthalmic bioavailability of curcumin in rabbit eyes and remarkably reduce the administration frequency compared with other suspension formulations [32]. 

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