Ophthalmic Preparations - Lecture 6 PDF

Sterile Pharmaceutical Preparations Lecture 7 Lecture 6 Ophthalmic Preparations Presented by: Prof. Gihan Labib  ANATOMY OF THE EYE Anterior chamber: the space between the cornea and the iris, filled with the aqueous humor. Choroid: the...

Sterile Pharmaceutical Preparations Lecture 7 Lecture 6 Ophthalmic Preparations Presented by: Prof. Gihan Labib  ANATOMY OF THE EYE Anterior chamber: the space between the cornea and the iris, filled with the aqueous humor. Choroid: the vascular layer of the eye, containing connective tissue. Nutrition of the eye is dependent upon blood vessels in the choroid.. Cornea: the clear, dome-shaped tissue covering the front of the eye. Iris: the colored part of the eye that controls the amount of light that enters the eye by changing the size of the pupil. Pupil: the opening in the center of the iris. It changes in size as the amount of light changes. Lens: A crystalline structure located just behind the iris – it focuses light onto the retina. Retina: light-sensitive tissue that lines the back of the eye. It contains millions of photoreceptors that convert light rays into electrical impulses that are relayed to the brain via the optic nerve. Optic nerve: the nerve that transmits electrical impulses from the retina to the brain. Vitreous gel: a thick, transparent liquid that fills the center of the eye. It is mostly water and gives the eye its form and shape. Sterile Pharmaceutical Preparations Lecture 6 Ophthalmic preparations Are sterile products, essentially free from foreign particles; for instillation into the eye. Advantages of topical ophthalmic drug delivery:  Low systemic exposure to the drug.  Facilitates the drug absorption into the eye.  Avoid intestinal or hepatic first pass metabolism.  Ease of application & patient compliance. However , The bioavailability from eye drops is poor due to the pre-corneal loss factors. Only < 5% of the instilled dose is absorbed through the cornea & reaches the intraocular tissues. Sterile Pharmaceutical Preparations Lecture 6 Physiological Barriers to Ocular Drug Delivery ✓High turnover rate ✓Gel-like mucus layer ✓Tear pH (6.9-7.5) Frequent instillation ✓Sandwich-like structure Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Solutions Suspensions Liquid Dry powder for reconstitution In-situ gels (gel forming solution) Ointments Semi-solid Bioadhesive hydrogels Ocular inserts Solid Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Solutions ▪ Most common topical ophthalmic preparation. ▪ All ingredients are completely in solution and there is little physical interference with vision. ▪ Most common are aqueous solutions in water, oily solutions are rare. ▪ No co-solvants Disadvantage: ▪ The relative short contact time between the drug and the absorbing surface. ✓ Contact time and ocular bioavailability can be increased to some extent using viscosity imparting agent e.g. methyl cellulose, carbomer, polyvinyl alcohol, and natural polymers (hyaluronic acid, gellan gum). ✓ Optimum viscosity for drug retention and visual comfort: 15-25 cps. Ophthalmic solutions are also desirable where a rapid onset o action is required as they do not need to undergo dissolution. This would be the case or local anesthetics (e.g. lignocaine, proxymetacaine hydrochloride); ocular diagnostics (fluorescein sodium) and ocular preoperative drugs Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Suspensions Are dispersions of finely divided insoluble drugs in an aqueous vehicle containing suitable suspending agent. Oily suspensions are very rare. Suspending agents for ophthalmic suspension include; cellulose derivatives (e.g. CMC, HPMC), synthetic polymers (e.g. poloxamers, polyvinyl alcohol) Contact time and duration of action of suspensions > solution, due to the tendency of the particles to be retained in the cul-du-sac. Particle size of the suspended drug affects the surface area available for dissolution. Also, plays important part in the irritation potential of the formulation. Irritation causes excessive tearing and rapid drainage of the instilled dose. Particles should be < 10 μm to minimize irritation to the eye. Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Suspensions Difficulties in suspension preparations ? Dose uniformity always requires shaking to distribute suspended drug. Patient compliance !!! Polymorphism; a change in crystal structure may occur during storage, resulting in an increase or decrease in crystal size and changing the suspension characteristics, causing solubility changes and increase or decreased bioavailability. Sterile Pharmaceutical Preparations Lecture 6 Dry powder for reconstitution ▪ For unstable drugs in aqueous medium, e.g. acetylcholine. ▪ Prepared as sterile dry powders to be reconstituted into solution or suspension before use. ▪ Expiration date considered should be after reconstitution Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations In-situ gels Are viscous liquids that upon exposure to physiological conditions will shift to gel. Phase transition on the eye surface can be triggered by change in: 1. Temperature Some polymers change from sol to gel at the eye temperature (33 - 34°C), e.g. poloxamers. 2. pH Cellulose acetatephthalte (CAP) is a solution at pH 4.4 and undergo coagulation when pH is raised to 7.4 by the tear fluid. 3. Electrolyte composition Gellan gum, in aqueous solution forms clear gel in the presence of mono or divalent cations found in the tear fluids. Advantage: ✓ Accurate and precise dosing compared to already gelled formulations ✓ Promote precorneal retention. Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Ointments ▪ Most ophthalmic ointments are prepared with a base of white petrolatum and mineral oil, often with anhydrous lanoline. ▪ The selected base must be; non-irritant to the eye, permits drug diffusion and free of any particulate contamination. Advantages: ✓ Longer contact time and greater total drug bioavailability Disadvantages: Interfere with vision (use is limited to bedtime instillation) and eye drops used during the day. Inaccurate dosing. Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Bioadhesive hydrogels Semisolid preparations which can provide a localized delivery of an active agent to the eye using bioadhesive polymers. These polymers can extend ocular contact time thus, improve the ocular bioavailability. Bioadhesive polymers form strong non-covalent bonds with mucin covering the ocular surface, e.g. CMC, carbopol, sodium alginate Sterile Pharmaceutical Preparations Lecture 6 Types of ophthalmic preparations Ocular inserts ▪ Solid ophthalmic dosage form, as thin disks or small cylinders made of polymeric material to be instilled into the lower or upper conjunctival cul-du-sac. ▪ The main objective of the ophthalmic inserts is to increase the contact time between the preparation and the conjunctival tissue, to ensure a sustained drug release suited for topical or systemic treatment. ▪ Their long persistence in pre-ocular area can result in greater drug bioavailability compared to liquid and semisolid formulations. Advantages of ocular inserts: ✓Increased ocular residence time hence a higher bioavailability. ✓Possibility of sustained drug releasing at a slow constant rate. ✓Accurate dosing (each insert contains a precise dose). ✓Reduction of systemic absorption (occurs with eye drops via the nasolacrimal duct). ✓Better patient compliance, due to reduced frequency of administration. Sterile Pharmaceutical Preparations Lecture 6 Ocular inserts Types of ocular inserts Insoluble Soluble Biodegradable Designed to be placed in Offer the advantage of Made of biodegradable the cul-du-sac for sustained being totally soluble and polymers, drug release over a dissolves within 1h, so they e.g. poly-orthoesters and prolonged period of time, do not need to be removed poly-orthocarbonates. then should be removed. from the site of application. e.g. pilocarpine ocusert e.g. Lacrisert® for dry eye (release pilocarpine at syndrome. steady rate for 7 days for treatment of glaucoma). Sterile Pharmaceutical Preparations Lecture 6 Characteristics of ophthalmic preparations Sterility Clarity pH Tonicity Viscosity Sterile Pharmaceutical Preparations Lecture 6 Characteristics of ophthalmic preparations Sterility: ✓ All ophthalmic preparations should be sterile. ✓ Preservatives are included in multi-dose liquid and semisolid preparations to maintain the sterility of the opened product during the life-time of use. Clarity: Ophthalmic solutions should be free of foreign particles. This is achieved by; ✓ Filtration, ✓ Preparation of ophthalmics in laminar air flow hoods, ✓ Filtration equipment, containers and closures must b clean and well rinsed so that not to contribute particles to the solution. Sterile Pharmaceutical Preparations Lecture 6 Characteristics of ophthalmic preparations pH: An ideal ophthalmic preparation should be prepared at pH equivalent to tear fluid value i.e. 7.4. However, Most ophthalmic drugs are salts of weak bases and are most stable at an acidic pH; e.g. suspensions of insoluble corticosteroids, (more stable at acidic pH). Buffer system with an adequate buffer capacity is used to maintain pH in the stable range for the product. Sterile Pharmaceutical Preparations Lecture 6 Characteristics of ophthalmic preparations pH: In general, an acidic pH will cause minimum if the overall pH of the tears reverts stinging or discomfort upon instillation, rapidly to 7.4 after instillation. If the buffer capacity resists adjustment Stinging and discomfort will result. by tear fluid and the overall eye pH remain acidic, for a long period of time; Thus, Buffer capacity should be minimized as possible to allow the tear pH to be disrupted only momentarily Sterile Pharmaceutical Preparations Lecture 6 Characteristics of ophthalmic preparations Tonicity: ▪ An ophthalmic solution is isotonic when its tonicity is equivalent to that of 0.9% sodium chloride solution. ▪ The eye can tolerate tonicity variation ranging from 0.5 - 1.8% sodium chloride concentration. Viscosity: ▪ The USP permits the use of viscosity imparting agents to prolong the ocular contact time by decreasing the drainage rate and thus increase the drug absorption and bioavailability. ▪ Increasing the viscosity up to 15 – 25 cp range has improved significantly the ocular contact time. ▪ Increasing the viscosity beyond 50 cp is not recommended Sterile Pharmaceutical Preparations Lecture 6 Drug Components of ophthalmic Vehicle preparations Additives  Sterile Pharmaceutical Preparations Lecture 6 Vehicle ✓ For liquid ophthalmic preparations: Aqueous Non-aqueous  Water for injection is not required in ophthalmic  Oils are used for eye drops sensitive to drops. moisture.  Sterile purified water meeting USP standards may  e.g. Tetracycline HCl antibiotic (stable be obtained by distillation or reverse osmosis. only few days in aqueous solutions).  Should be of highest purity, since oils are liable to rancidity.  Common vegetable oil for ocular use include: olive oil, castor oil and sesame oil. ✓ For semisolid ophthalmic preparations:  White petrolatum and its combination with liquid petrolatum to obtain proper consistency is commonly used. Sterile Pharmaceutical Preparations Lecture 6 Additives ▪ Few inactive ingredients are permitted in ophthalmic preparations. ▪ The choice of a particular ingredient and its concentration is based on; physical, chemical compatibility and biochemical compatibility with the sensitive and delicate ocular tissues. ▪ The possible systemic effect due to nasolacrimal drainage must be considered. Tonicity adjusting agent: Precise adjustment of the tonicity of ophthalmic products to be isotonic, should be considered to increase the patient compliance. Common tonicity adjusting agents include: NaCl, KCl, dextrose and mannitol. Antioxidants: Used as a stabilizer to minimize oxidation of oxidizable drugs, e.g. epinephrine. Common antioxidants for ophthalmic preparations are: Sodium bisulphite or metasulphite (up to 0.3% concentration).  Sterile Pharmaceutical Preparations Lecture 6 Viscosity imparting agents: HPMC, methyl cellulose and polyvinyl alcohol (PVA) are commonly used in ophthalmic preparations to enhance viscosity. Surfactants: Surfactant toxicity is ordered as follows; anionic >> cationic > nonionic Both non-ionic and cationic surfactants can be included in ophthalmic preparations. Non-ionic surfactants Cationic surfactants Least toxic to ocular tissues. Used in most ophthalmic solutions and Used in low concentrations in steroid suspensions as antimicrobial preservative. suspensions to aid dispersion, or in e.g. benzalkonium chloride (0.005 – solutions to improve clarity. 0.02%). e.g.Tween 20 and 80, tyloxapol. The used concentration is limited by Disadvantage: can bind with toxicity. antimicrobial preservatives and inactivate Disadvantage: can be inactivated by them. macromolecules of opposite charge. Sterile Pharmaceutical Preparations Lecture 6 Preservatives: Are intended to be used in multi-dose ophthalmic preparations, not for single-dose preparations. Few preservatives are suitable candidates for ophthalmic preparations. ▪ Benzalkonium chloride(0.005 – 0.02%). Most common preservative (~65% of commercial products). Limitation: Being a cationic SAA of high molecular weight, it is not compatible with anionic compounds. Incompatible with salicylates and nitrates. Can be inactivated with high molecular weight non-ionic compounds. ▪ Organic mercurial e.g. phenyl mercuric nitrate or acetate (0.002 – 0.004%) Used instead of benzalkonium chloride as a preservative for salicylates and nitrates Limitation: Permanent yellowish brown discoloration of the lens was reported, due to mercury deposits upon frequent use of phenyl mercuric nitrate (0.004%). Sterile Pharmaceutical Preparations Lecture 6 ▪ Parahydroxy benzoic acid ester; e.g. methylparaben, propylparaben Used in a mixture; methylparaben (0.1 – 0.2%), propylparaben (0.04%) Limitation: Not efficient ophthalmic preservatives. Cause stinging and irritation. ▪ Chlorobutanol Effective against (Gram +) and (Gram –) bacteria in addition to some fungi Used in 0.5% concentration Highly compatible with other ingredients Sterile Pharmaceutical Preparations Lecture 6 Packaging of liquid ophthalmic preparations ✓ The most convenient is ”glass container” accompanied by a “glass dropper”. ✓ Formed of USP type I glass. Bottles should be well rinsed with sterile distilled water and sterilized by autoclaving. Droppers should be sterilized and packed in blister pack. ✓ Now limited to drugs with stability problems in plastic; e.g. products sensitive to oxygen or contain permeable components. Almost completely replaced by low density polyethylene dropper unit called “Drop-Tainer®” Sterile Pharmaceutical Preparations Lecture 6 Advantages of Drop-Tainer®: ✓ Easy use by patients. ✓ Low weight. ✓ Low cost. ✓ Decreased contamination potential; thus, low antimicrobial concentration can be used. Sterile Pharmaceutical Preparations Lecture 6 Limitations of low- density polyethylene: If drug is light sensitive e.g. epinephrine, an additional Permeable to light and air package protection must be involved; Adding opacifying agent e.g. titanium dioxide. Using opaque sleeves over the container. Place the bottle in cardboard cartoon. Volatile material may permeate from solution, Permeation may be overcome by using e.g. chlorobutanol preservative secondary package as blister of non- permeable material e.g. aluminum foil. Label glue and ink may permeate through it. May leach extraneous substances e.g. antioxidants from plastic to the solution. Sterile Pharmaceutical Preparations Lecture 6 Packaging of semisolid ophthalmic preparations In metal tubes, with ophthalmic tips. Sterilized by autoclaving or by ethylene oxide. Metal tubes may be lined with epoxy or vinyl plastic in case of metal reactivity or incompatibility.