DDS: Intraocular Flashcards
What is the principal route for local ophthalmic drug delivery?
topical application of solutions to the surface of the eye as drops: easy to apply and good patient acceptance
What are the limitations of eye drops to the surface to the eye?
- Significant barrier to solute flux provided by the corneal epithelium
- Precorneal drug loss that occurs by way of tear drainage and tear fluid turnover
- < 5% of a topically applied drug actually permeates the cornea and eventually reaches intraocular tissues
What are the problems associated with ophthalmic drug delivery?
- Dilution by the lacrimal fluid (tear), aided by the mixing action of the blinking reflex
- Low permeability of the corneal tissue. Low bioavailability (0.2-2%)
- Loss through the lacrimal duct or by rolling down the side of the face.
What is the physiology of the eye?
- Cornea is avascular and transparent
- Conjunctiva provides protection and lubrication
- Cornea is multilayered with lipophilic and hydrophilic properties
- Corneal epithelium is predominantly lipophilic –> 90% resistance to hydrophilic drug transport
- Cornea nourished by aqueous humour and cleansed/lubricated by mucus and tear fluid
> Vascular network around back of eye provides metabolic support to retina, ciliary body and iris
> These membranes also provide ‘blood-eye barrier’ or blood-retina barrier (BRB)
Retina: light sensitive region that links via the optic nerve to the visual cortex
Aqueous humour: clear aqueous fluid similar to blood plasma
- Iris controls intensity of light entering the eye
Define the following periocular disorders;
Blepharitis
Conjunctivitis
Dry eye
Trachoma
Keratitis
Cataract:
Fuchs Endothelial Dystrophy:
Keratoconus:
Iridocorneal Endothelial Syndrome:
Retinitis Pigmentosa
Macular Degeneration
Diabetic Macular Oedema
Blepharitis: common and often recurring inflammatory condition causing infection of the eyelids. Symptoms: red, swollen, crusty eyelids
Conjunctivitis: “pink eye” - inflammation of the conjunctiva, caused by allergenic response or bacterial infection. Symptoms: pain, burning, scratchiness, or itchiness may occur
Dry eye
Trachoma: contagious infection of Chlamydia trachomatis. Causes a roughening of the inner surface of the eyelids - leads to pain in the eyes, breakdown of the cornea and blindness.
Keratitis: inflammatory corneal disorder due to injury, infection. Symptoms: excessive tearing, pain, photophobia, gritty sensation, inflammation
Cataract: changes in the crystalline lens causing reduced transparency – commonly due to ageing
Fuchs Endothelial Dystrophy: slowly progressing oedema of the cornea – stroma becomes cloudy
Keratoconus: progressive thinning of the cornea – blurring and shortsightedness
Iridocorneal Endothelial Syndrome: changes to the endothelium, iris, swelling of the cornea and associated development of glaucoma •
Retinitis Pigmentosa: hereditary disease with degradation of photoreceptor cells
Macular Degeneration: leading cause of blindness in ageing population. Neovascularisation or ischemia affects the retina and retinal pigmented epithelium leading to severe vision loss
Diabetic Macular Oedema: retina inflamed and swollen, can detach
What are the negatives for the following drug delivery strategies for the ye:
A) systemic
B) eye drops
C) photodynamic therapy
D) injectable solutions
A)
- limited penetration
- high drug levels = toxic
B)
- limited pentetration (less than 1%)
- rapidly diluted
- tear washout
- poor patient compliance
C)
- limited applications
- repeat procedures
D)
- rapidly diluted
- repeat procedures
What are some of the duration of action of the ocular drug delivery systems?
Fprmulation strategies to improve drug solubility, increased loading and improved bioavailability. What are some of these strategies?
- Retention of drugs improved by viscosity enhancing (polymers such as cellulose derivatives, PVA, hyaluronic acid, dextran, gellan gum) or mucoadhesive agents (interfacial interaction of polymeric-based formulation with mucosal tissue)
- Drug transport improved by penetration enhancing compounds, pro-drugs e.g. latanoprost (Xalantan™)
> Ester prodrug that is absorbed well through the cornea and completely hydrolysed to the active latanoprost acid –> for management of glaucoma
Enhanced retention: sol-gel systems
Sol-gel phase transition systems can be designed to respond to? Provide three different reasons.
- Temperature: dosage transforms from liquid at room temperature to a mucoadhesive gel at the temperature of the eye, ~34 ºC.
- pH: sol-gel transformation takes place when the dosage responds to the pH environment of the tear film, mean pH = 7.4.
- Ion response: sol-gel transformation responds to ion concentration of the tear film
name of products: azasite, virgan, cytoryn
What are THREE examples of eye formulations
- Timolol-XE® –> non-selective beta adrenergic receptor blocking agent –> gel forming solution
- Azasite® –> azithromycin ophthalmic solution
- Betoptic S –> betaxolol hydrochloride –> cardioselective beta adrenergic receptor inhibtor –> opthalmic suspension
Enhanced retention: Ocular insert dosage forms –> preparations with a solid or semi-solid consistency, whose size and shape are specially designed for ophthalmic application. What are some key design considerations?
- Comfort
- Lack of expulsion during wear
- Ease of handling and insertion
- Noninterference with vision and oxygen permeability
- Reproducibility of release kinetics
- Applicability to a variety of drugs
- Sterility
- Stability
- Ease of manufacture
What are some properties of an erodible ocular insert? What happens if there is a missing insert?
- No need to remove upon completion of therapy
- Often made of collagen or chitosan
- Hydrolytic degradation, rather than enzymatic degradation, is preferred
- Variability of patients’ tear turnover and variable interpatient insert degradation
Missing insert
> patient doesn’t know if there is a missing insert, could be fully dissolved or insert fallen out.
> potential under and over dosing
What is an example of ocular insert?
ACRISERT (hydroxypropyl cellulose ophthalmic insert) is a sterile, translucent, rod-shaped, water soluble, preservative-free, slow-release, lubricant which is placed into the inferior cul-de-sac of the eye
- One insert per day provides continuous lubrication
What are some advantages and disadvantages of non-erodible ocular insert?
Advantages
- A patient knows if the non-erodible insert is lost and needs to be replaced
- More consistent control of drug release
- Drug-polymer physicochemical interactions manipulation allows controlled release.
Disadvantages
- Possibility of discomfort and irritation.
- Have to be removed at completion of therapy - inconvenience
What is a pilocarpine ocular insert (ocusert)? What is the reservoir? What is the white annual border made of to make it easier for patient to visualize?
- Membrane-controlled reservoir system
- Pilocarpine is sandwiched in between two ethylene-vinyl acetate membranes
- Alginic acid matrix serves as a reservoir for pilocarpine
- White annular border made of ethylene-vinyl acetate copolymer with titanium dioxide (pigment) that makes it easier for the patient to visualize
Where is the pilocarpine ocusert placed? How does it exert its effects? What is the release rate?
The ocusert is placed in the cul-de-sac where it will float with the tears
- The tear fluid penetrates the microporous membrane, dissolving the pilocarpine
- The pilocarpine will diffuse from the device (zero order release) and exert its pharmacological effect
> The release rate of pilocarpine is in the range of 20 or 40 µg/h for up to seven days
What is needed to overcome the blood-retina barrier?
To achieve sufficient concentration of drug delivered to the back of the eye, medications are frequently administered systemically at very high doses
What happens when injectable drug solutions are injected directly into the back of the eye? What are examples of these drugs?
Quickly removed by the eye’s natural circulatory process. Thus, injectable solutions rapidly lose their therapeutic benefit, often necessitating frequent injections.
Wet macular degeneration: anti-VEGFs eg Ranibizumab (Lucentis®), Aflibercept (Eylea®), Bevacizumab (Avastin®).
Define the following sites and methods for intraocular drug delivery;
A) Scleral plug
B) Subconjunctival implant
C) Supra choroidal implant
D) Suprascleral injection
E) Intravitreal implant
F) Intravitreal injection
A)
- a device that penetrates the sclera at the Pars Plana where it releases its payload in a controlled manner
B)
- inserted between the conjunctiva and sclera at sites away from the Pars Plana, for controlled and sustained drug delivery
C)
- a device placed between the sclera and choroid, capable of sustained drug delivery
D)
- an injection under the sclera, suitable for medium term therapy
E)
- sustained drug delivery device intruding directly into the vitreous humour for long term controlled drug delivery
F)
- drug injection directly into the vitreous humour. Repeat injections are often required
What are the advantages of implants?
- An alternative to repeated injections because they increase half-life of the drug and may help to minimize peak plasma level; they might improve patient acceptance and compliance
- Stabilization of the drug
- The non-biodegradable implants are more controllable delivery profile and longer periods of drug release than biodegradable ones
- The biodegradable implants do not need to be removed
What are the disadvantages of implants?
- Side effects: the insertion of these devices is invasive and with associated ocular complications (retinal detachment and intravitreal hemorrhage for intravitreal implant)
- The non-biodegradable require surgery to harvest the device once is depleted of the drug (risk of ocular complications)
- The biodegradable implants have a final uncontrollable ‘burst’ in their drug release profile
What are the examples of intraoccular implants?
What are the advantages and disadvantages of microparticles, nanoparticles and liposomes
Advantages
- stabilization of the drug
- Increase half-life of drugs (the frequency of injections diminishes)
- Decrease peak concentration resulting in decreasing the toxicity (micro and nanoparticles minimize ‘BURST’ in their drug delivery profile because the dose volume is limited)
- Localized delivery of drug (RPE cells)
- Improved patient compliance and convenience
Disadvantages
- Side effects: risk associated with injections and vitreous clouding
What are the advantages and disadvantages of cell encapsulation?
Advantages
- Long-lasting and continuous expression of the given protein –> avoid repeated injections
- Delivery directly to the target site (limiting toxicity)
- Easy retrieval of the implant when desired (making the treatment reversible)
- Improve patient compliance
Disadvantages
- invasive method with the complications related to the surgical insertion and removal
- patient acceptance to be seen
What are the advantages and disadvantages of iontophoresis?
> iontophoresis: applicator placed on the conjunctiva –> the drug resides in the applicator and is propelled through the conjunctiva and sclera during the periods of electrical stimulation
Advantages
- Non-invasive method and easy to use
- May combine with other drug delivery systems
- Ability of modulate dosage (less risk of toxicity)
- Good drug penetration to anterior and posterior segment of the eye
- Good acceptance by patients
- A broad applicability to deliver a broad range of drugs or genes to treat several ophthalmic diseases in the posterior segment of the eye
Disadvantages
- No sustained half-life: requires repeated administrations
- Side effects: mild pain in some cases, but no risk of infections or ulcerations
- Risk of low patient compliance because frequent administration that may be needed
Summary of Ocular Delivery Systems
