Ophthalmic Drug Delivery PDF

4.4 Ophthalmic Drug Delivery Ophthalmic drug delivery primarily involves applying drugs to the eyes, with eye drops being the most common method. While designed for local effects, some drugs applied to the eye can enter systemic circulation. Indications for Topical Ophthal...

4.4 Ophthalmic Drug Delivery Ophthalmic drug delivery primarily involves applying drugs to the eyes, with eye drops being the most common method. While designed for local effects, some drugs applied to the eye can enter systemic circulation. Indications for Topical Ophthalmic Products Topical ophthalmic products are commonly used for a range of conditions: Glaucoma: Treatment of increased intraocular pressure. Infections: Antibacterial, antiviral, and antifungal products for primarily external eye infections. Inflammatory Conditions: Corticosteroids and NSAIDs for external and internal inflammation. Dry Eye: Over-the-counter (OTC) and medicated eye drops. Alternative Delivery Methods Intraocular Injection: Directly into the eye for faster, higher, and more deeply distributed ocular drug levels, particularly to reach the retina. Subconjunctival Injection: Injection into the conjunctiva, similar to a subcutaneous injection. Topically applied drugs typically do not reach the retina in adequate concentrations. Anatomy and Physiology of the Eye Understanding the eye's structure is crucial for comprehending drug delivery. Eye Wall Layers The eye wall consists of three concentric layers: 1. Outermost Layer: Conjunctiva and sclera (white part of the eye). ○ The cornea, a transparent layer, is the primary site for drug penetration into the eyeball. 2. Middle Layer: Uveal tract, comprising the choroid, ciliary body, and iris. ○ The uveal tract is an important target for many ophthalmic drugs. 3. Innermost Layer: Retina (back of the eye). ○ Topically applied drugs typically struggle to reach the retina in sufficient concentrations. Humors of the Eye  The inside of the eye is divided by the lens into two humors: ○ Aqueous Humor: Located in front of the lens. ○ Vitreous Humor: Located behind the lens. Segments of the Eye The eye is also divided into anterior and posterior segments: ○ Anterior Segment: In front of the lens, contains the aqueous humor. ○ Posterior Segment: Behind the lens, contains the vitreous humor. Chambers of the Aqueous Humor The iris divides the aqueous humor (in the anterior segment) into: ○ Anterior Chamber: In front of the iris. ○ Posterior Chamber: Behind the iris. The aqueous humor is continuously produced by the ciliary bodies and flows from the posterior chamber to the anterior chamber, exiting through the pupil and draining into systemic circulation via the canal of Schlemm. Surrounding Structures Conjunctiva: Thin, transparent, vascularized mucous membrane extending from the edge of the cornea across the sclera and the inner surface of the eyelids, forming conjunctival sacs. ○ Eye drops are typically instilled into these conjunctival sacs. Lacrimal Gland: Produces tears, which play a crucial role in removing foreign material. ○ Tears flow through the puncta (small openings) into the lacrimal canaliculi, then to the lacrimal sac, and finally drain into the nasal cavity via the lacrimal duct. Nasolacrimal Apparatus This drainage system removes tears: ○ Tears drain through the canaliculi, lacrimal sac, and into the nasal cavity via the lacrimal duct. ○ From the nasal cavity, tears are transported to the nasopharynx and eventually swallowed. Excessive tearing can overflow from the nasal cavity. Tear Drainage Mechanism Tear drainage relies on gravity and a pumping mechanism facilitated by blinking.  ○ Blinking (about 15-20 times per minute) helps pump tears through the nasolacrimal apparatus into the nasal cavity. Target Areas for Topical Ophthalmics Topical ophthalmic drugs primarily target: Preocular Structures: Conjunctiva and eyelids, often for infections or inflammatory conditions. Corneal Tissues: For treating corneal issues such as infections or pain. ○ The cornea is highly sensitive due to numerous nerve endings. Tissues and Receptors in the Anterior Segment: Includes iris muscles, ciliary epithelium, and ciliary muscle. Challenges Reaching the Posterior Segment Reaching tissues in the posterior segment (e.g., the retina) with topically applied drugs is highly unlikely due to various barriers. Drug Absorption and Distribution Transcorneal Absorption The primary route for topical ophthalmics to reach intraocular tissues is transcorneal absorption (through the cornea). ○ While drug passage can occur through the sclera (white of the eye), absorption through the cornea dominates. Corneal Structure The cornea is a complex, optically transparent tissue covered by a tear film. Tear Film Layers The tear film comprises three crucial layers: 1. Mucoid Layer: Promotes adhesion of the aqueous tear fluid and keeps the cornea wettable. ○ The eyeball is a mucous membrane that needs to stay moist. 2. Tear Fluid: A solution of inorganic electrolytes, proteins (including enzymes and immunoglobulins), and glucose. 3. Outer Lipid Layer: Composed of wax and cholesterol esters that reduce tear fluid evaporation. Role of Tear Film in Drug Delivery The drug concentration in the tear film drives passive diffusion through the cornea. Passive diffusion is the dominant mechanism for corneal permeation. Corneal Layers The cornea has three main layers relevant to drug absorption: 1. Epithelium: Outermost layer, primarily lipophilic. 2. Stroma: Middle layer, primarily hydrophilic and composed of collagen fibers. 3. Endothelium: Innermost layer, a single cell layer. Corneal Epithelium as a Barrier The corneal epithelium, continuous with the conjunctiva but with varying thickness (5-6 layers at the center to 8-10 layers at the periphery), is the main barrier for drug passage through the cornea. Squamous cells with tight junctions on the surface, uniquely possessing microvilli that increase surface area and potentially aid absorption. Being primarily lipophilic, the epithelium favors the penetration of lipophilic drugs. The unionized form of a drug penetrates better than the ionized form. Enzymes present in the epithelium (esterases, peptidases, and proteases) can metabolize some drugs. Stroma and Endothelium The stroma, composed of collagen fibers and mostly water, acts as a hydrophilic barrier. However, lipophilic drugs that have passed the epithelium generally pass through the stroma without major issues. The endothelium, a single cell layer, is more permeable than the epithelium (about 200 times) and poses a lesser barrier to drug penetration. Factors Influencing Transcorneal Absorption Lipophilicity and Ionization: Drugs with a moderate octanol-water partition coefficient (balancing lipophilicity and hydrophilicity) and a favorable ionization state at physiological pH are best absorbed. Concentration Gradient: A higher drug concentration in the tear film results in faster penetration due to passive diffusion. Epithelial Integrity: Damaged epithelium enhances drug absorption. Time to Peak Concentration: It takes approximately 20-60 minutes for a topically applied drug to reach peak concentrations in the aqueous humor.  Overall Efficiency: Typically, less than 5% of an instilled eye drop dose crosses the cornea. Drug Loss Before Corneal Penetration Several factors contribute to drug loss before it can reach the aqueous humor: Spillage: The lower conjunctival sac can only accommodate approximately 30 microliters. Any excess volume spills over. Blinking: Blinking increases spillage and promotes drug removal through the nasolacrimal apparatus. ○ Blinking reduces the residual volume to about 10 microliters. Nasolacrimal Drainage: Drugs forced through the puncta by blinking and gravity are removed via the nasolacrimal drainage system, eventually being swallowed. Multiple Drops: Administering multiple drops consecutively can lead to significant loss of the second drop. Drug Fate After Corneal Penetration Distribution and Elimination Drugs that cross the cornea primarily reach the aqueous humor in the anterior chamber. The drug concentration in the anterior chamber is significantly lower than the applied concentration due to previous losses. Reaching the posterior segment is generally insignificant, limiting the treatment of posterior segment conditions with topicals. Protein Binding and Metabolism Some lipophilic drugs can bind to melanin in the iris, which can slow drug effects or act as a depot for sustained release. Drugs may also bind to proteins in tears. Ophthalmic metabolism can occur, with enzymes in the aqueous humor metabolizing certain drugs. ○ Prodrugs are designed to be activated by enzymes in the eye. Examples include dipivalyl epinephrine (converted to epinephrine) and latanoprost (converted to prostaglandin F2α). Drugs primarily exit the eye by following the aqueous humor turnover, exiting through the canal of Schlemm or entering uveal blood vessels and systemic circulation.