Ocular Systems Flashcards
What are the different routes of ocular delivery
- Topical administration
- Systemic (parenteral) administration
- Oral administration
- Periocular & intravitreal administration
What are Physiological Barriers
- Cornea
- Sclera
- Tear production/Blinking
- Protein binding (up to 2%) & drug metabolism
What is the most popular route of administration
Eye-drops
Eye drops
- removal from the eye is rapid due to tear production and the blinking processes occurring simultaneously.
- The precorneal volume is about 7 μL, but volumes of up to 20 to 30 μL can be held in this area before spillage occurs.
- Volumes greater than this will simply spill out onto the cheek or will be rapidly lost
∴ less than 10 % (typically 1 % ), of the topically instilled dose into the eye actually permeates the cornea
Opthalmic Product Design Considerations
- Drug Candidate Selection
- Formulation Design Options
- Solutions, Water-Based Gels, Suspensions, & Ointments - Packaging Design Considerations
- Design Specifications and Critical Quality Parameters
Drug Candidate Selection - Physicochemical drug properties
- Solubility
- Lipophilicity,
- Molecular size and shape,
- Charge &
- Degree of ionisation.
Drug Candidate Selection - solubility transport across the cornea
For most topically applied drugs
1. Passive diffusion along the concentration gradient, either transcellularly or paracellularly, is the main permeation mechanism across the cornea.
2. Carrier-mediated active transport mechanism is also indicated.
Drug Candidate Selection - solubility Lipophilic vs hydrophobic
- Lipophilic drugs tend to favour the transcellular route,
- Hydrophilic drugs usually permeate via the paracellular route through intercellular spaces.
- Drugs possessing both lipophilic and hydrophilic properties permeate it most effectively.
- The optimal range for the octanol/buffer pH 7.4 distribution coefficient (log P) for corneal permeation is 2 to 3.
Drug Candidate Selection: Charge
- Unionised form usually permeates the lipid membranes more easily than the ionised form.
- Ionised/ unionised drug in the eye will depend on the
- pKa (of the drug) &
- pH (of both the eye-drop and the lachrymal fluid). - For ionisable drugs,
- the nature of the charge,
- degree of ionisation, will affect corneal permeability. - Corneal epithelium is negatively charged —- charged cationic drugs permeate more easily through the cornea than do anionic species.
Drug Candidate Selection: Molecular size
< 500 daltons
Drug Candidate Selection: Chemical form
- important for ocular bioavailability.
- Changing the salt can affect the solubility and lipophilicity of the drug.
What do prodrugs do
- increase Bioavailability, Solubility, Stability and Potency and to decrease systemic side-effects
Formulation Design Options: what do they depend on ?
- Drug property - solubility
- Target concentration
- Eye condition to be treated
Formulation Design Options: Solutions advantages
- Many therapeutic agents used in eye products are water- soluble compounds (or can be formulated as water-soluble salts)
- High solution concentration can be achieved
- Easier to manufacture &
- Potentially provide better dose uniformity & ocular bioavailability
Formulation Design Options: Solutions disadvantages
- Rapidly drained from the eye
Solution
- Inclusion of viscosity-increasing agents to increase the tear viscosity, which decreases drainage.
Examples:
- Hypromellose,
- Hydroxyethylcellulose,
- Polyvinyl alcohol, Povidone or Dextran
- High viscosity products may not be well tolerated in the eye Range of 10 to 25 cP
Formulation Design Options: Water-Based Gels
- Polymers that are liquid formulations upon administration, but gel on contact with the eye to provide extended retention times.
Examples:
- changes in temperature (e.g., poloxamers),
- changes in pH (e.g., cellulose acetate hydrogen phthalate latex) or
- changes in ionic strength in the tear film (e.g., low-acetyl gellan gum, GelriteTM)
Formulation Design Options: Water-Based Gels advantages
- ease of administration, improved patient compliance
Ex: in situ gelling preparation of timolol (Timoptic XE, Merck and Co., Inc.)
Formulation Design Options: Suspensions
considered for drugs that are poorly water soluble, or because of poor aqueous drug stability.
- Drug particle size must be < 10 μm to avoid irritation of the eye surface.
- Prolong the residence time of drug particles in the eye, allowing time for dissolution in the tears and an increase in ocular bioavailability
Formulation Design Options: Suspensions disadvantages
- May pose physical instability problems
- Ex: increase in particle size with time, difficulties in resuspension, homogeneity & dose uniformity - Possibilities of either degradation or morphological changes occurring during the sterilisation process exist and must be prevented
Formulation Design Options: Ointments
Eye ointments are sterile semi-solid preparations intended for application to the conjunctiva.
๏ Increased contact time & better bioavailability compared to solutions.
๏ Night-time application,
๏ Poor patients compliance - often cause blurred vision.
Formulation Design Options: Ointments Examples
- Water-free oleaginous eye ointment bases are composed of white petrolatum and liquid petrolatum (mineral oil) base formula.
- Like suspensions, ointments can be more difficult to manufacture in sterile form.
- Terminally sterilised or manufactured from sterile ingredients in an aseptic environment.
- Filtration through a suitable membrane or dry heat sterilisation is often used.
Packaging Design Considerations
- Materials are compatible with the formulation and ensure product stability
- Sterility of the product can be achieved & assured for the entire shelf-life
- Materials meet pharmacopoeial and regulatory standard requirements
- Containers should be tamper-evident &
- Pack design offers ease of administration to the patient.
Design Specifications & Critical Quality Parameters
- required to be sterile up to the point of use and must comply with the pharmacopoeial tests for sterility.
- Terminal sterilisation is the preferred method from a regulatory point of view, as opposed to aseptic manufacture
- Using established excipients in a topically applied formulation is to improve the chance of patient tolerability and patient compliance.
- Minimise ocular side-effects such as irritation, burning, stinging and blurring of vision.
- Product should be stable at room temperature over a shelf-life period of 2–3 years
Ocular Solutions: Choice of drug salt for use in Ocular Solutions
- determined by the solubility
- to increase the retention of therapeutic agents within the precorneal region the concentration of therapeutic agents in ocular solutions should be relatively high.
- certain drug salts results in greater pain/irritation.
Examples adrenaline (epinephrine)
- hydrochloride: Adrenaline hydrochloride, although relatively acidic (pH 2.5–4.5)
- borate: has low buffer capacity and lower acidity of this salt (pH 5.5–7.5)
- bitartrate salts Adrenaline bitartrate is the most acidic salt in solution (pH 3–4)
