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Why ophthalmic preparations ? • The eye is constantly exposed to the atmosphere, dust, pollutants, allergens, bacteria and foreign bodies. • Ophthalmic preparations are used to treat allergies, bacterial and I viral infections, glaucoma, and other eye conditions. School of Pharmacy, University of P...

Why ophthalmic preparations ? • The eye is constantly exposed to the atmosphere, dust, pollutants, allergens, bacteria and foreign bodies. • Ophthalmic preparations are used to treat allergies, bacterial and I viral infections, glaucoma, and other eye conditions. School of Pharmacy, University of Puerto Rico Definition: • Ophthalmic products are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device. The most commonly employed ophthalmic dosage forms are: The newest dosage forms for ophthalmic drug delivery are: Solutions, gels, suspensions, and gel-forming solutions, ointments. ocular inserts , intravitreal injections and implants. School of Pharmacy, University of Puerto Rico Ophthalmic delivery and role of dosage form Topical delivery • to the eye to treat surface or intraocular conditions, including bacterial, fungal, and viral infections of the eye or eyelids; allergic or infectious conjunctivitis or inflammation; elevated intraocular pressure and glaucoma; and dry eye due to inadequate production of fluids bathing the eye. Systemic delivery • To the eye to treat certain ophthalmic conditions, such as glaucoma, both systemic and topical treatments may be employed. School of Pharmacy, University of Puerto Rico Dynamics of lacrimal system and retention time of ophthalmic product • The normal volume of tear fluid in the cul-de-sac of the human eye is about 7 to 8 μL. • Non-blinking eye can accommodate a maximum of about 30 μL of fluid, Blinked eye can retain only about 10 μL. • The capacity of the eye to retain liquid and semisolid preparations is limited, therefore, topical applications are administered in small amounts: • liquids dropwise, and • ointments as a thin ribbon applied to the margin of the eyelid. • Larger volumes of liquid preparations may be used to flush or bathe the eye. School of Pharmacy, University of Puerto Rico • Excessive liquids, both normally produced and externally delivered, rapidly drain from the eye. • A single drop of an ophthalmic solution or suspension measures about 50 μL, so much of an administered drop may be lost. • The optimal volume to administer, based on eye capacity, is 5 to 10 μL. • Microliter-dosing medication droppers are not generally available for personal use, so, loss of instilled medication using standard eye droppers is a common occurrence. • The average dropper delivers about 25 to 50 μL/drop. School of Pharmacy, University of Puerto Rico • Because of the dynamics of the lacrimal system, the retention time of an ophthalmic solution on the eye surface is short, and the amount of drug absorbed is usually only a small fraction of the quantity administered. • e.g. after administration of pilocarpine ophthalmic solution, the solution is flushed out from the precorneal area within 1 to 2 minutes, resulting in the ocular absorption of less than 1% of the administered dose. • This necessitates repeated administration of the solution. School of Pharmacy, University of Puerto Rico Pharmacological categories of drugs for ophthalmic use • Anesthetics • Antimicrobials - antibiotics • Antifungals • Antivirals • Anti-inflammatory • Astringent • Beta-adrenergic blockers • Miotics • Vasoconstrictors School of Pharmacy, University of Puerto Rico Dosage forms for the eye • Solutions- most often used but relatively low duration of action, cover the eye globe, spread well • Suspensions- slightly longer duration of action as drug particles usually settle in the lower conjunctival sac and release the drug as the particles dissolve • Ointment- have even larger duration of action, spreads over the eye and into the conjunctival sac School of Pharmacy, University of Puerto Rico Dosage forms for the eye • Gels - are not as thick as ointment, used for dry eye conditions, eg. Lubricating gel in very dry eye condition where frequent use of artificial tears is ineffective • Gel forming solutions - increases ease of administration as solution followed by gel formation in the eye • Inserts - for sustained drug release School of Pharmacy, University of Puerto Rico How to deal with low retention time of ophthalmic products? • Formulations can be developed to achieve: • decreased frequency of dosing, • increased ocular retention time, and • greater bioavailability • Approach used is: to extend corneal contact time • gel systems, liposomes, polymeric drug carriers and ophthalmic suspensions and ointments can be employed. School of Pharmacy, University of Puerto Rico Advantages and disadvantages dosage forms • Ophthalmic suspensions and ophthalmic ointments have the advantage of staying longer in contact with the surface of the eye, so their dosage is lower than with the solutions. • Ophthalmic solutions are more used than suspensions and ointments because they do not affect visibility. • The inserts provide for the release of the medication in a controlled manner and for prolonged periods of time. School of Pharmacy, University of Puerto Rico Characteristics of ophthalmic products • Essentially sterile • Usually topical • Oral and parenteral routes can also be used to treat ophthalmic conditions • There are no differences in doses for children and adults School of Pharmacy, University of Puerto Rico Special considerations in the preparation of ophthalmic products • Sterility – free of microorganisms • Isotonicity – concentration equal to/near to that of the tear (0.9% NaCl) • pH and Buffering – pH as close as possible to the tear drop (7) • Viscosity – thickness • Preservation – antimicrobial agents School of Pharmacy, University of Puerto Rico How to administer drops for ophthalmic use? How to administer eye drops: • Wash hands with soap and water • Shake the vial of eye drops well if necessary (suspension) • Put the head back a little by bending the neck slightly • Open your eyes and look up • Take the eyelid with your thumb and index your lower eyelid and stretch it slightly down so that it fits like a small pouch inside the lower eyelid. • Put the indicated drops in that space. • Release the eyelid and close the eyes. • Keep your eyes closed for a few moments. School of Pharmacy, University of Puerto Rico How to administer ointments for ophthalmic use? How to apply ointment and eye gel • Wash your hands thoroughly with soap and water. • Avoid that the tip of the tube rubs the eye or anything else; It is very important to keep the tube clean. • Hold the tube between the index finger and the thumb, and hold it close to the eyelid as much as possible, but without touching it. • Rest the other fingers of that hand on the face. • Tilt your head back slightly. • With the index finger of the other hand, pull the lower eyelid down to form a hole. • Press the tube to apply an ointment or gel in the hole formed by the lower eyelid. Remove the index finger from the lower eyelid. • Blink slowly; then gently close the eye for 1 or 2 minutes. • Remove excess ointment or gel from your eyelids and eyelashes with a tissue. Use another disposable handkerchief to clean the tip of the tube. • Replace the cap immediately and tighten it. • Wash your hands to eliminate any excess medication. • You may have blurred vision for a while after applying the eye ointment. Wait until you can see well before driving or doing any other activity that requires seeing clearly. School of Pharmacy, University of Puerto Rico How to administer drops and ointments for ophthalmic use? School of Pharmacy, University of Puerto Rico Recommendations when using Ophthalmic drops and ointments • Wash your hands well before and after putting the drops or the ointment. You can use disposable medical gloves, it is recommended to use them when you instil drops or apply ointments in the eyes of another person. Even if you use gloves, wash your hands afterwards. • Make sure the dropper or tube is clean and does not touch the eye, eyelid, eyelashes or other surface. This is to keep it free of bacteria. Droplets or ointments that are contaminated with bacteria can easily spread bacteria to the eyes and cause an infection. • If the dropper is separated from the bottle and touches the eye, you should not put the dropper back into the bottle. You should wash it well with hot water, wait for it to dry before putting it back inside the jar. • Do not use the drops or ointment of another person. • If you have an eye infection (conjunctivitis), you should not wear contact lenses while using eye drops or ointments unless your doctor has authorized it. School of Pharmacy, University of Puerto Rico Recommendations when using Ophthalmic drops and ointments • Sometimes the drops and ointments burn when they are instilled or applied for the first time in the eyes. The burning should disappear after a few minutes. • When instilling drops in the eye, it could get to feel its taste in the mouth, also that they come out through the nose. This may be normal and disappear. • Drops and ointments for the eyes can have side effects. They should be used exactly as indicated. • They should not be used any longer or in larger quantities than those indicated by the doctor or packaging. • Do not use an ophthalmic medication prescribed for one condition, to treat another different problem. • Between each dose, the drops or ointment should be stored as indicated. Some of these products require refrigeration. • You must not use expired ophthalmic products. School of Pharmacy, University of Puerto Rico Precautions and care • not to touch the dropper to the eye, eyelid, or any other surface • the dropper should not be rinsed or wiped off • the container cap should be tightly closed School of Pharmacy, University of Puerto Rico Patient counselling • In every case, the patient should be advised about: • • • • • the correct number of drops to instil, the frequency of application, the duration of treatment, proper storage of the medication, and usual side effects specific to the product. • Among the side effects encountered with the use of ophthalmic medication are: • transient stinging or burning, foreign body sensation, itching, tearing, decreased vision, margin crusting, and occasionally a bad (drug) taste. School of Pharmacy, University of Puerto Rico Patient counselling • This is a sterile solution. Contamination of the dropper or eye solution can lead to a serious eye infection. • If irritation persists or increases, discontinue use immediately. • Generally, eye makeup should be avoided while using eye solutions. • You may want to use a mirror when applying the drops, or it may be much easier to have someone help you instil your eye drops. School of Pharmacy, University of Puerto Rico Pharmaceutical requirements • The preparation of solutions and suspensions for ophthalmic use requires special consideration with regard to: • • • • • • • • clarity sterility and preservation, isotonicity, pH and buffering, antioxidation viscosity, ocular bioavailability, Packaging and storage School of Pharmacy, University of Puerto Rico 2 Clarity • Ophthalmic solutions must be free from foreign particles. Filtration is usually used to remove these particles and to achieve clarity of the solution. • Polysorbate 20 and Polysorbate 80 (1.0 %) can be used to achieve clarity. School of Pharmacy, University of Puerto Rico 3 Sterility • Ophthalmic solutions and suspensions must be sterilized for safe use. • Most ophthalmic products, however cannot be sterilized by heat due to the active principle or polymers used to increase viscosity are not stable to heat. • Most ophthalmic products are aseptically manufactured and filled into previously sterilized containers in aseptic environments using aseptic filling-and-capping techniques. School of Pharmacy, University of Puerto Rico 4 • It is a regulatory requirement that preparations intended or ophthalmic use, including those for cleansing the eyes, must be sterile at the time of filling and closing in a sealed container. Ocular infections are extremely dangerous and can rapidly lead to the loss o vision. Eye-cups, droppers and all other dispensers should also be sterile and regulated if packaged with the drug product. • For ophthalmic preparations, terminal sterilization of products in their original containers should be adopted wherever possible. If the product cannot withstand terminal sterilization then filtration under aseptic conditions should be considered, usually performed using a filter pore size o 0.22 μm or less. • The raw materials used or aseptic manufacture should be sterile, wherever possible, or should meet a low specified bioburden control limit. • Ophthalmic preparations must be labelled with duration of use once opened. School of Pharmacy, University of Puerto Rico 5 Advantage of filtration: the retention of all particulate matter (microbial, dust, fiber), the removal of which is importance in the manufacture and use of ophthalmic solutions. School of Pharmacy, University of Puerto Rico Sterile filter having pore size 0.45 µ or 0.2 µ 6 Examples of sterilizing filters. Sterilization by filtration. The preparation of a sterile solution by passage through a syringe affixed with a microbial filter. School of Pharmacy, University of Puerto Rico 7 Preservation • Preservatives are included in multiple-dose eye solutions for maintaining the product sterility during use. • Preservatives are not included in unit-dose package. • The use of preservatives is prohibited in ophthalmic products that are used at the time of eye surgery because: • Some preservatives irritate the eye • If sufficient concentration of the preservative is contacted with the corneal endothelium, the cells can become damaged causing clouding of the cornea and possible loss of vision. • So these products should be packaged in sterile, single use containers. School of Pharmacy, University of Puerto Rico 8 Ideal requirements of preservatives Antimicrobial preservatives must demonstrate: • • • • Stability, Chemical and physical compatibility with other formulation Chemical and physical compatibility with packaging components, effectiveness at the concentration employed. School of Pharmacy, University of Puerto Rico 10 Examples of preservatives 1. Cationic wetting agents: • Benzalkonium chloride (0.01%) • generally used in combination with 0.010.1% disodium edetate (EDTA). 2. Organic mercurials • Phenylmercuric nitrate: 0.002-0.004% • phenylmercuric acetate: 0.005-0.02%. 3. Esters of p-hydroxybenzoic acid: • Mixture of 0.1% of both methyl and propyl hydroxybenzoate (2:1) 4. Alcohol substitutes: • Chlorobutanol (0.5%). Effective only at pH 5-6. • Phenylethanol (0.5%) School of Pharmacy, University of Puerto Rico 11 Preservation: limitations/important facts o All preservatives have drug incompatibilities and a compounder must ensure that the chosen preservative is compatible with all components in the ophthalmic dosage form. o All ocular injections must be prepared without preservatives, which can be toxic to the eye's internal structures, especially when injected. School of Pharmacy, University of Puerto Rico 12 Preservation: limitations/important facts • Chlorobutanol can not be sterilized in an autoclave because it decomposes in hydrochloric acid even under moderate heat conditions. This degradation makes a product susceptible to microbial growth and may alter its pH and therefore affect the stability and/or physiological activity of the therapeutic ingredient. • At concentrations tolerated by the eye, most of the preservatives mentioned are not effective against some strains of Pseudomonas aeruginosa. (This microorganism can invade a abraded/lacerated cornea (corneal laceration= deep cut on the cornea) and cause ulceration and even blindness.) • Combination of benzalkonium chloride (0.01%) with either polymyxin B sulfate (1,000 USP U/ml) or EDTA (disodium ethylenediaminetetraacetate) (0.01% to 0.1%) are effective against most Pseudomonas strains. • EDTA, commonly used as a chelating agent for metals, makes strains of P. aeruginosa more sensitive to benzalkonium chloride. School of Pharmacy, University of Puerto Rico 13 Preservation: limitations/important facts • Thiomersal is the alternative preservative to Benzalkonium chloride and can be used by soft contact lens wearers. • It is bacteriostatic and fungistatic at neutral and alkaline pHs, but bactericidal at acidic pH levels. • It is stable at room temperature, but is light sensitive. School of Pharmacy, University of Puerto Rico 14 Isotonicity • Body fluids, including blood and tears, have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride. Thus, a 0.9% sodium chloride solution is said to be isotonic, or having an osmotic pressure equal to that of physiologic fluids. • Solutions with a lower osmotic pressure than body fluids or a 0.9% sodium chloride solution are commonly called hypotonic, whereas solutions having a greater osmotic pressure are termed hypertonic. School of Pharmacy, University of Puerto Rico 15 • Human tears are isotonic and very similar to 0.9% sodium chloride solution. • So, tonicity is an important consideration for ophthalmic preparations. However, the eye can tolerate tonicity 0.6-2.0 % without marked discomfort. • Common tonicity adjusting agents are: sodium chloride, boric acid, dextrose. • Pharmacists can use sodium chloride equivalent method to calculate the quantity of solute that must be added to render the hypotonic solution of a drug isotonic. School of Pharmacy, University of Puerto Rico 16 What happens if solution is hypo- or hyper- tonic? • Theoretically, a hypertonic solution added to the body system will have a tendency to draw water from the tissues of the body towards the solution in an effort to dilute and establish a balance of concentration. • In the bloodstream, a hypertonic injection can cause the creation (contraction) of blood cells. • In the eye, the solution can draw water to the site of topical application. • Conversely, a hypotonic solution can induce red blood cell hemolysis or passage of water from the site of an ophthalmic application through the tissues of the eye. School of Pharmacy, University of Puerto Rico 19 Buffering and pH adjustment Why pH adjustment for ophthalmic solutions ? • To provide greater comfort to the eye, • to render the formulation more stable, • to enhance the aqueous solubility of the drug, • to enhance the drug’s bioavailability (i.e., by favoring unionized molecular species), and • to maximize preservative efficacy. School of Pharmacy, University of Puerto Rico 35 • Most ophthalmic drugs used are weakly acidic and have only weak buffer capacity. • Normally, the buffering action of the tears neutralizes the ophthalmic solution and thereby prevents marked discomfort. • For maximum comfort, an ophthalmic solution should have the same pH as the tears. However, this is not pharmaceutically possible, because at pH 7.4 many drugs are insoluble in water. • Ophthalmic solutions are generally buffered at pH of maximum stability of drug(s) they contain. School of Pharmacy, University of Puerto Rico 36 Stabilizers and antioxidants • Stabilizers are ingredients added to a formula to decrease the rate of decomposition of the active ingredients. • Antioxidants are the principal stabilizers added to some ophthalmic solutions, primarily those containing epinephrine and other drugs prone to oxidation. • Some examples of antioxidants used in ophthalmic preparations are: • Sodium sulfite (0.1% concentration, Na2SO3) • Sodium bisulfite (0.1% concentration, NaHSO3) • Sodium metasulfite (0.1% concentration, Na2S2O3) School of Pharmacy, University of Puerto Rico 39 Viscosity and thickening agents • Viscous ophthalmic solutions remain for longer period in the eye and allow more time for drug absorption and effect. • For this reason, viscosity enhancing agents are added in formulations. • Viscosity for ophthalmic solutions is considered optimal in the range of 15 to 25 cP. • e.g. Methyl cellulose-0.25% (if 4000 cP grade is used), 1% (if 25 cP is used) Additive Usual Max. Conc. (%) Hydroxyethylcellulose 0.8 Hydroxypropylmethylcellul ose 1.0 Methylcellulose 2.0 Polyvinly alcohol 1.4 Polyvinylpyrrolodine 1.7 School of Pharmacy, University of Puerto Rico 40 Ocular bioavailability • Physiologic factors that can affect a drug’s ocular bioavailability include: • protein binding, • drug metabolism, and • lacrimal drainage. • Protein bound drugs are incapable of penetrating the corneal epithelium because of the size of the protein–drug complex. • Tears contain enzymes (e.g., lysozyme) capable of metabolic degradation of drug substances. • Ophthalmic suspensions, gels, and ointments mix with lacrimal fluids less readily than do low-viscosity solutions, so less lacrimal drainage and so remain longer in the culde-sac, enhancing drug activity. School of Pharmacy, University of Puerto Rico 41 Quality control Checking parameters by compounding pharmacist: • Appearance and clarity • Sterility: (checking sample for microbial growth on agar plate/send for laboratory testing) • pH • Volume/weight School of Pharmacy, University of Puerto Rico 45