Ophthalmic Preparations Sterile, aqueous or oily preparations (solution, lotions, ointment, gels etc), designed for application into the eye either for the treatment or symptomatic relief or diagnosis or as adjuvant to surgical procedure.

Ocular Drug Absorption Absorption routes Corneal Absorption Drug Installation Dilution in tear fluid Diffusion from mucin layer Corneal Penetration Transfer from cornea to Aqueous humor Non-Corneal Absorption Involves penetration across Sclera & Conjunctiva e.g. Gentamicin, Prostaglandin F2, Timolol mealeate

Ocular Drug Availability Barriers Pre-corneal Barriers Drainage Lacrimation Tear dilution Tear Turnover Conjunctival absorption

Ocular Drug Availability Barriers Post-corneal barriers Enzymatic degradation Absorption by ciliary body

Formulation Active Ingredients Pilocarpine, carbachol, betaxolol, Echotiophate ect (Anti-glaucoma Drugs) Atropine, Scopolamine, Cyclopentolate, tropicamide (Miotics) Dexamethasone, Prednisolone, hydrocortisone, Medrysone (corticosteriods)

Particle Size Eyes are sensitive to particle size of 20 µm or more. The desired particle size of a suspended drugs is 5 – 10 µm or less

ADDITIVES Preservatives Multi dose formulation require preservation because when pressure of bottle is released, the suck back of unreleased drop or air may lead to contamination

ADDITIVES Benzalkonium Chloride Preservatives: Combined with Di Sodium EDTA Most effective & Rapid Acting No degradation at hot storage temperature Absorption to package components & surfactant Not effective against P. aeruginose strain (resistant)

Preservatives Organic Mercural More effective in neutral or alkaline pH Weak and slow activity Banned in several countries

Preservatives Chlorobutanol Relatively safe then mercurals Slow activity 30% activity is loss when sterilized at 121 ͦC for 20 minutes at pH 5 Hydrolytic decomposition, produce HCl decrease pH Permeate through polyolefin plastic containers

Preservatives Methyl & Propyl Paraben Effectively prevent mold growth Low aqueous solubility Bind to nonionic surfactants & large polymers May cause burning sensation in eye Permeate through polyolefin plastic containers

Preservatives Other preservatives used are; Polyaminopropyl biguanide Phenyl ethyl alcohol Chlorhexadine Polyquat

Penetration enhancers Azone (laurocaprum) Very small concentration is required (0.1%) Corneal absorption of hydrophilic drugs are increased by at least 20 folds e.g. Prednisolone & Bunolol. Inhibit absorption of lipophilic drugs e.g. flurbiprofen Other such agents are; Hexamethylene lauramide, hexamethylene octamide, decylmethyl sulfoxide

Buffering Agents Bicarbonate Phosphate Carbonate Citrate Borate in concentration range of 50 – 200 milimolar For targeted pH range of 7.4 ± 0.1 (buffer system chosen should have pka close to target pH to get maximum buffer capacity)

(concentration up to 0.3%) Stabilizers Sodium metabisulphate Sodium bisulphate Acetylcysteine Ascorbic acid Sodium thiosulphate Disodium edetate (concentration up to 0.3%)

Degree of ocular irritation Surfactants Polysorbate 80 Polysorbate 20 Tyloxapol Polyoxyethylene Poloxamers (concentration 0.1 – 0.2 %) Degree of ocular irritation Nonionic Cationic Anionic

Viscosity Increasing Agents Acrylicacid polymers (carbomers) Methylcellulose Hydroxypropylmethyl cellulose (HPMC) Hoxyethyl cellulose (HEC) Polyvinyl Acetate (PVA) function: Increase contact time Increase bioavailability Lubricating effect

Isotonicity adjusting agent 0.9% NaCl w/v Mannitol

TYPICAL FORMULA 1% Prednisolone acetate Ophthalmic Suspension Prednisolone Acetate (micronized) 1.0 % Benzalkonium chloride 0.01% Disodium edetate q.s. Phosphate Buffer q.s. HPMC q.s. Polysorbate 80 q.s. Sodium Chloride q.s. Sodium hydroxide q.s. Purified Water q.s. 100 ml

Sterilization Stream sterilization (121 ͦͦC) Gas sterilization (Ethylene oxide) Ionization radiation (UV, Gama) Filtration (0.22 µ filter)

Ocular Toxicity Draize test: The procedure involves applying 0.5mL or 0.5g of a test substance to the eye of a restrained, conscious albino rates, and leaving it for four hours. The animals are observed for up to 14 days, for signs of redness, swelling, discharge, ulceration, hemorrhaging, cloudiness, or blindness in the tested eye.

Packaging material Low density polyethylene Polystyrene Polypropylene Type I Glass (highest hydrolytic resistance, transparent) For Ointment Collapsible tubes of tin or aluminum are used suitable for cap making

Ointments Sterile semi-sold preparations of homogenous appearance intended for application to conjunctives. B.P

Base for Ointments; Paraffin base, having melting point close to body temperature non-irritant Chemically inert Anhydrous medium for delivery of moisture sensitive drugs. For addition aqueous solutions Hydrous Wool Fat or aliphatic alcohol are added to the base to increase its emulsifying capacity.

GELS Substantially dilute cross linked system which exhibits no flow when in steady state. Dispersion of molecules or particles within liquid in which the solid is the continuous phase and the liquid is the discontinuous phase.

Gelling agents Polyacrylic acid compound Hypromellose Carbomer Gellar gum

Formulated Product Stability Studies Finished product stability is tested according to International Conference on harmonization (ICH) guidelines i.e. Q1A (R2) Stability Testing of New Drug Substances and Products.