Ophthalmic Drug Delivery Study Guide PDF

4.5 Ophthalmic Drug Delivery Study Guide The main goal of ophthalmic products is to treat the eye, not to be absorbed systemically. However, systemic absorption can occur. The clinical significance of this absorption varies based on factors like drug potency and strength....

4.5 Ophthalmic Drug Delivery Study Guide The main goal of ophthalmic products is to treat the eye, not to be absorbed systemically. However, systemic absorption can occur. The clinical significance of this absorption varies based on factors like drug potency and strength. There are several pathways for drugs to enter systemic circulation, including: ○ Nasolacrimal Drainage: This is a major pathway where drops entering the puncta drain through the nasolacrimal system into the nasal cavity. ○ Absorption in Nasal Structures: Once in the nasal cavity, absorption can occur in the nasal cavity itself, the nasopharynx, the lacrimal sac, and even the cheeks through mixing with saliva. ○ GI Tract Absorption: Drugs reaching the nasopharynx can be swallowed, leading to absorption in the gastrointestinal tract. ○ Conjunctival Absorption: The conjunctiva, with its rich blood supply, is more permeable than the cornea and offers a large surface area for drug absorption. ○ Absorption via Trabecular Meshwork: Drugs entering the eye can drain through the trabecular meshwork and subsequently enter the bloodstream. Over 50% of an instilled ophthalmic dose can be systemically absorbed. Except for drugs absorbed via the GI tract, the absorbed drug bypasses the hepatic first-pass effect. Key considerations in designing topical ophthalmic dosage forms include sterility, pH, osmolarity, and viscosity. Sterility is paramount for ophthalmic products , similar to injectable drugs, as contamination can lead to serious consequences, including blindness. ○ Pseudomonas aeruginosa is a particularly dangerous organism that can cause corneal ulcers, potentially leading to blindness. ○ Sterility testing is mandatory for commercially manufactured ophthalmics. Antimicrobial preservatives are required in all multi-dose eye drops to maintain sterility. Single-use eye drops do not require preservatives.  ○ Benzalkonium Chloride (BAK) is the most common preservative due to its effectiveness, especially against Pseudomonas aeruginosa. BAK, being a surfactant, can enhance corneal penetration but also carries a risk of corneal epithelium damage at high concentrations. ○ Alternatives to BAK include: Polyquad (polyquaternium 1), which is considered less sensitizing and does not penetrate the cornea well. Thimerosal, a mercury-based preservative with a long history of use, but its use has declined due to hypersensitivity concerns. Oxidizing agents, like sodium perborate, are newer preservatives that act by oxidizing microbes. The ideal pH of an ophthalmic product should match that of the tear film (around 6.6-7.8). pH values outside this range can cause irritation, tearing, and blinking, leading to drug removal from the eye surface. ○ Buffers are included in formulations to adjust pH for stability, solubility, and patient comfort. Common buffers include acetate, phosphate, citrate, and borate. Similar to pH, maintaining isotonicity (osmolarity similar to tears, approximately 300 mOsm/kg) is crucial for patient comfort. Deviations from this range can irritate the eye, prompting tearing and blinking, which remove the drug. ○ While most products aim for isotonicity, some are intentionally hypertonic. For instance, 5% sodium chloride is used to treat corneal edema by drawing fluid away from the cornea. ○ Tonicity modifiers, such as sodium chloride, mannitol, and dextrose, are added to adjust osmolarity. Viscosity plays a role in ophthalmic formulations by influencing residence time and drug diffusion. ○ Increased viscosity can prolong contact time and reduce drainage rate, potentially enhancing bioavailability. However, excessive viscosity can irritate the eye, hinder drug diffusion, and cause blurred vision. ○ Common viscosity modifiers include glycerin, cellulose derivatives, polyvinyl alcohol, polyethylene glycols (PEGs), and carbomers. ○ Cellulose derivatives and polyvinyl alcohol are frequently used in lubricating eye drops or artificial tears. ○ High viscosity agents can cause transient blurring and crust formation upon drying. Liquid ophthalmics, primarily solutions, are the most common type. Other forms include suspensions and emulsions. ○ Solution formulations involve dissolving the drug and excipients, followed by sterilization. Sterilization methods include heat or filtration through a 0.2 micron membrane filter. ○ Suspensions contain finely micronized drug particles (typically less than 10 microns) to minimize irritation and promote rapid dissolution. They are used for poorly soluble drugs or to enhance drug stability.  Suspensions cannot be filter sterilized as this would remove the drug particles. Instead, sterile drug crystals are aseptically mixed with a sterile vehicle. Suspensions, though not providing a depot effect, mix less rapidly with tears and can reside in the conjunctival sac, allowing for prolonged drug release. ○ Emulsions are less common and are employed for lipophilic drugs. The drug is dissolved in the oil phase, and surfactants are used for emulsification and stabilization. Common excipients in ophthalmic products: ○ Antioxidants: Sodium metabisulfite and its related sulfites are frequently used. Consider patient sensitivity to sulfites. ○ Chelating Agents: EDTA sodium is commonly included, serving dual roles: limiting oxidation by chelating metal ions and enhancing the activity of BAK against Pseudomonas aeruginosa. ○ Surfactants: Polysorbate 80 and tyloxapol are examples. They function as wetting agents in suspensions, emulsifiers in emulsions, and spreading agents to enhance drop coverage on the eye surface. Most liquid ophthalmics are packaged in dropper bottles called droppers. These are typically sterilized and come in various standard volumes. Semisolid ophthalmics include ointments and gels. ○ Ointments, often petrolatum-based, provide prolonged contact time due to their slow clearance rate (0.5% per minute). Mineral oil is often added to reduce the viscosity of petrolatum. Sterilization of the ointment base can be achieved through heat and sterile filtration. Ointments are frequently used post-surgery, for instance, antibiotic ointments like bacitracin to prevent infection. The major disadvantage is blurred vision, which can last longer than with viscous drops. ○ Gels, formulated using gelling agents like carbomers and cellulose derivatives, also offer prolonged contact time. Examples include products like Timoptic-XE, a gel-forming solution that increases contact time and allows for once-daily dosing. Administration of Ophthalmic Products: ○ General guidelines for eye drop administration: Thoroughly wash hands. Shake suspensions well before use. Tilt head back and create a pouch by pulling down the lower eyelid. Instill one drop into the conjunctival sac. Gently close the eye and keep it closed for 30 seconds. Avoid blinking. Applying gentle pressure to the inner corner of the eye for 30 seconds can minimize nasolacrimal drainage and systemic absorption, taste, and drainage.  Avoid rubbing, wiping, or squeezing the eye. Replace the cap without touching the dropper tip. ○ Additional tips: Wait at least 5 minutes before applying another drop, whether of the same or a different medication. If using fast-acting and long-acting formulations together, apply the fast-acting one first, followed by the long-acting one after at least 5 minutes. Apply eye drops at least 10 minutes before eye ointments. Unless directed otherwise, remove contact lenses before instilling eye drops. Store eye drops according to product instructions, as some may require refrigeration. Monitor for signs of contamination and discard multi-dose products within 30 days of opening. ○ Instructions for eye ointment administration: Wash hands thoroughly. Hold the tube securely and tilt head back. Pull down the lower eyelid to create a pouch and gently squeeze a ribbon of ointment into the conjunctival sac. Close the eye for 1-2 minutes and roll the eyeball in all directions to distribute the ointment. Wipe away excess ointment and replace the cap without touching the tip. Warn the patient about potential blurred vision.