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PMY2006 > Ocular Systems > Flashcards

Ocular Systems Flashcards

1
Q

What are the different routes of ocular delivery

A
  • Topical administration
  • Systemic (parenteral) administration
  • Oral administration
  • Periocular & intravitreal administration
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2
Q

What are Physiological Barriers

A
  • Cornea
  • Sclera
  • Tear production/Blinking
  • Protein binding (up to 2%) & drug metabolism
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3
Q

What is the most popular route of administration

A

Eye-drops

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4
Q

Eye drops

A
  • 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
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5
Q

Opthalmic Product Design Considerations

A
  • Drug Candidate Selection
  • Formulation Design Options
    - Solutions, Water-Based Gels, Suspensions, & Ointments
  • Packaging Design Considerations
  • Design Specifications and Critical Quality Parameters
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6
Q

Drug Candidate Selection - Physicochemical drug properties

A
  • Solubility
  • Lipophilicity,
  • Molecular size and shape,
  • Charge &
  • Degree of ionisation.
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7
Q

Drug Candidate Selection - solubility transport across the cornea

A

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.

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8
Q

Drug Candidate Selection - solubility Lipophilic vs hydrophobic

A
  • 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.
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9
Q

Drug Candidate Selection: Charge

A
  • 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.
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10
Q

Drug Candidate Selection: Molecular size

A

< 500 daltons

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11
Q

Drug Candidate Selection: Chemical form

A
  • important for ocular bioavailability.
  • Changing the salt can affect the solubility and lipophilicity of the drug.
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12
Q

What do prodrugs do

A
  • increase Bioavailability, Solubility, Stability and Potency and to decrease systemic side-effects
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13
Q

Formulation Design Options: what do they depend on ?

A
  • Drug property - solubility
  • Target concentration
  • Eye condition to be treated
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14
Q

Formulation Design Options: Solutions advantages

A
  • 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
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15
Q

Formulation Design Options: Solutions disadvantages

A
  • 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

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16
Q

Formulation Design Options: Water-Based Gels

A
  • 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)

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17
Q

Formulation Design Options: Water-Based Gels advantages

A
  • ease of administration, improved patient compliance
    Ex: in situ gelling preparation of timolol (Timoptic XE, Merck and Co., Inc.)
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18
Q

Formulation Design Options: Suspensions

A

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

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19
Q

Formulation Design Options: Suspensions disadvantages

A
  • 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
20
Q

Formulation Design Options: Ointments

A

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.

21
Q

Formulation Design Options: Ointments Examples

A
  • 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.
22
Q

Packaging Design Considerations

A
  • 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.
23
Q

Design Specifications & Critical Quality Parameters

A
  • 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
24
Q

Ocular Solutions: Choice of drug salt for use in Ocular Solutions

A
  • 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)

25
Q

Manipulation of Formulation pH

A
  • Eye can tolerate eye preparations formulated over a range of pH values : 3.5 - 9.0
  • pH 7.4 is preferred
  • antimicrobial preservative, parabens, is inactive at alkaline pH and more active as the pH becomes more acid.
  • Acrylic acid polymers (carbomer)/ CarbopolTM resins are sensitive to pH
    - low viscosity in the dosing solutions, the pH is typically in the 4 to 5 range.
    - When placed in the eye, the immediate increase in pH causes a rapid gellation, which results in an increase residence time and bioavailability
26
Q

Manipulation of Formulation pH: acidic pH adjustments

A
  • acetic acid/sodium acetate
  • citric acid/sodium citrate
27
Q

Manipulation of Formulation pH: alkaline-buffered solutions

A
  • phosphate
  • borate buffers
28
Q

Osmolarity

A
  • Ophthalmic products instilled into the eye may be tolerated over a fairly wide range of tonicity —- 0.5–1.5 %
    NaCl equivalents 0.9% w/v NaCl
  • Hypotonic ophthalmic solutions or suspensions:
    - NaCl,
    - KCl,
    - dextrose,
    - glycerol
    - buffering salts.
29
Q

Vehicle Viscosity

A
  • Increased in vehicle viscosity —> the residence time in the eye
  • High viscosity —> Not well tolerated in the eye
    -Drug diffusion - inhibited the residence time in the eye,
    - Administration - difficult

∴ 10 to 25 cP, using an appropriate viscosity-enhancing agent

30
Q

Stabilisers/antioxidants

A
  • Drugs that are susceptible to oxidative degradation —> antioxidants and/or chelating agents
  • plastic bottles, which allow gases to permeate through the container, will be particularly susceptible to oxidative degradation
  • commonly used antioxidants in liquid ophthalmic products:
    - sodium metabisulphite,
    - sodium sulphite,
    - ascorbic acid acetylcysteine,
    - 8-hydroxyquinoline
    - antipyrine.
31
Q

Antimicrobial Preservatives

A
  • Manufactured sterile: free of microorganisms , once opened the sterility of the multi-dose must be maintained during its use.
  • discarded after 4 weeks
  • limited number of regulatory approved antimicrobial preservatives which can be used in ophthalmic products
    - Effective at the optimal formulation pH
    - Stable to processing,
    - possibly heat sterilisation
    - Stable over the product shelf-life
    - Does not interact with other components in the formulation/packing material
32
Q

Packing Considerations: autoclaving

A
  • manufactured & packaged in the final container under clean conditions. Sterilisation may then be performed using moist-heat sterilisation.
33
Q

Packing Considerations: filtration

A
  • thermolabile — filtration through an appropriate filter (circa 1μm), followed by sterilisation filtration (0.22-μm filter) and packaging (both under aseptic conditions)
34
Q

Packing Considerations: Production under aseptic conditions

A
  • dispersion of the sterile therapeutic agent into the sterile vehicle & packaging (both under aseptic conditions)
35
Q

Drug and Excipient Interactions

A

physical or chemical incompatibilities occurring due to number of components in the formulation
↓
Unstable product
↓
Accelerated stress stability testing of the final product, with all the components added, should establish whether there are any compatibility problems between the drug, excipients and packaging.

36
Q

Types of Contact Lenses

A
  • Hard
  • Semi-Hard/ Semi-flexible Lens
  • Soft Lens
  • Soft continuous wear Lens
37
Q

Types of Contact Lenses: Hard Lens

A
  • Made from hydrophobic polymer such as poly(methyl methacrylate) (PMMA)
  • Absorb 1-2% water
  • Cheap
  • Long-lasting
  • Give excellent vision correction
  • Comfort and tolerance levels quite low
38
Q

Types of Contact Lenses: semi- hard

A
  • Made from hydrophobic gas-permeable polymer such as cellulose acetate butyrate (CAB)
  • Low water content
  • Semi-flexible
  • Long-lasting
  • Give good vision correction
  • Permit passage of oxygen through lens to cornea
39
Q

Types of Contact Lenses: soft lends

A
  • Made from hydrophilic polymer such as poly(hydroxyethyl methacrylate) (pHEMA)
  • Contain 50-80% water
  • Flexible
  • Used for 1 day – 1 month
  • Give good vision correction
  • Comfort and tolerance levels very high
40
Q

Types of Contact Lenses: soft lends continues wear

A
  • Made from hybrid hydrogel-silicone material
  • Lower water content than hydrogel lens (~33%)
  • Flexible
  • Long-lasting (1 month)
  • Give good vision correction
  • Require no cleaning or periodic cleaning
  • Permit passage of oxygen through lens to cornea
41
Q

Formulation of a Contact Lens Solution

A
  • Viscosity increasers – comfort, convenience
  • Surfactants – wetting, cleaning
  • Inorganic salts – isotonicity, pH, lens stability, buffering
  • Preservative systems – efficacy, compatibility
  • Potentiators – sequestering agents such as disodium edetate
42
Q

Contacts: Functions Carried Out by Solutions Soaking

A
  • Disinfects lens and maintains hydrated state
    - Preservative, NaEDTA, buffering agents, NaCl
43
Q

Contacts: Functions Carried Out by Solutions: (Re)wetting

A
  • Hydrates lens, should cope with chance contamination, lubricates/cushions between lens and eyelid
    - Preservative, NaEDTA, buffering agents, NaCl, wetting agents (such as polyvinylacetate), viscosity
    enhancers
44
Q

Contacts: Functions Carried Out by Solutions: Cleaning

A
  • Removes ocular debris, protein deposits, dust particles and bacteria, should cope with chance contamination
    - Preservative, NaEDTA, buffering agents, NaCl, cleaning agent (surfactant and/or enzyme product)
45
Q

Contacts: Functions Carried Out by Solutions: Multifunction

A
  • Can combine all functions for lens care - wetting, cleaning, soaking, rinsing and rewetting in one product

PMY2006 (12 decks)

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