Of ophthalmic formulations

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

Due to the wide variety of ophthalmic formulation types available, it was not possible to cover all aspects of every formulation type in detail. However, there should be sufficient guidance and practical examples in this chapter to give the preformulation or formulation scientist a good understanding of the subject, and to provide some direction in their endeavours to develop a new ophthalmic product. It is hoped that some of the possible pitfalls mentioned will be avoided along the way. 

This new type of ophthalmic formulations has to possess well defined properties in order to meet biopharmaceutical requirements such as be capable of delivering the effective ocular drug concentrations along an extended period of time (without inducing systemic side effects), user friendly, and exempt of side effects such as blurring, irritation, or foreign-body sensation. 

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. 

Figure 14 SEC chromatogram of carboxymethylcellulose in an ophthalmic formulation. The horizontal axis is elution time in minutes and the vertical axis is DRI response in arbitrary units.

Although usually considered to be inactive ingredients in ophthalmic formulations added because they impart viscosity, many of these polymers function as ocular lubricants. They are marketed as the active ingredients in OTC ocular lubricants used to provide relief from dry eye conditions. The regulatory requirements for these OTC products are found in the FDA Code of Federal Regulations (21CFR349.12), and their formulations are presented in the Twelfth Edition of the APhA Handbook of Nonprescription Drugs. 

The pH dependence of dorzolamide solubility was also determined between pH 4.0 and 7.0, using acetate, citrate, and phosphate buffer solutions to set the desired pH. These data are collected in Table 2 (also plotted in Figure 4), and show a maximum solubility of approximately 40 mg/mL at pH 5.6. The equilibrium solubility decreases to approximately 13 mg/mL at pH 6 and 4 mg/mL at pH 7.0. These data indicate that in order to have a stable 2% solution for an ophthalmic formulation, the solution pH should be maintained below 5.8. At pH values exceeding 5.8, precipitation of the free base could occur. 

Flurbiprofen is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. 

The efficacy of flurbiprofen at dosages of 200-400 mg/d is comparable to that of aspirin and other NSAIDs in clinical trials for patients with rheumatoid arthritis, ankylosing spondylitis, gout, and osteoarthritis. It is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously has been found to be effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. 

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. 

Presoaked lenses are considered a more efficient and reliable delivery system. However, the soaking of lenses in ophthalmic formulations to incorporate the drag into the lens may cause toxicity to corneal epithelium because preservatives, such as benzalkonium chloride, have a great affinity for the hydrophilic contact lens material and are concentrated in the contact lens. Contact lens for sensitive wearers may also cause foreign-body sensation, blurring and decreased oxygen tension on the corneal surface resulting from occlusion by contact lens. 

Selection of an appropriate base for an ointment or cream formulation depends on the type of activity desired (e.g., topical or percutaneous absorption), compatibility with other components, physicochemical and microbial stability of the product, ease of manufacture, pourability and spreadability of the formulation, duration of contact, chances of hypersensitivity reactions, and ease of washing from the site of application. In addition, bases that are used in ophthalmic preparations should be nonirritating and should soften at body temperatures. White petrolatum and liquid petrolatum are generally used in ophthalmic preparations. Table 1 summarizes... 

Conventional eye drops currently account for more than 90% of the marketed ophthalmic formulations [1], However, after instillation of an eye drop, typically less than 5% of the applied drug penetrates the cornea and reaches the intraocular... 

Osmotic Pressure The osmolality of the lacrimal fluid is mainly dependent on the number of ions dissolved in the aqueous layer of the tear film and normally ranges between 310 and 350mOsm/kg [44], When an ophthalmic solution is instilled into the eye, it mixes with the tear fluid, resulting in an osmotic pressure that is dependent on the osmolality of the tears as well as that of the formulation and the amount of the formulation instilled. In general, hypotonic solutions are better tolerated by... 

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],... 

Ocular inserts probably represent one of the oldest ophthalmic formulation approaches. In 1948 the British Pharmacopoeia described an atropine-in-gelatin wafer and ever since then numerous systems have been developed applying various polymers and different release principals. However, the difficulty of insertion by the patient, foreign-body sensation, and inadvertent loss of inserts from the eye make these systems less popular, especially among the elderly. Furthermore, the high cost involved in manufacture prevented the insert market from taking off [197],... 

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