Lecture 5

Ocular Controlled Dosage

Forms

By
Dr/ Ahmed Shawky Srag El-Din
Lecturer of Pharmaceutics and Industrial
pharmacy
 Introduction
Dosage form Advantages Disadvantages
Solutions Convenience - Rapid precorneal elimination -Drug loss by drainage
- Non sustained release
Suspension Patient compliance Depend on drug properties
Best for slowly dissolved drug
Emulsion Prolong release - Blurred vision - Patients Noncompliance
- Possible oil entrapment
Ointment Flexibility in drug choice - Sticking on eye lids - Blurred vision
Improve drug stability - Poor Patients compliance
- Drug choice limited by partition coefficient

Role of polymers
-Improve the ocular contact time - increase solution viscosity - reduce solution drainage
➢ Hydrophilic polymer: ethyl acetate, polyvinyl acetate and poly acrylic acid
➢ Hydrophobic polymer: glycerin monostearate, nylon and polyvinyl chloride.
 Type of Ocular Controlled Drug Delivery System
A) Non- Erodible inserts include: 1- Ocusert 2- contact lenses.
B) Erodible inserts include 1- lacrisert 2- Soluble ocular drug inserts (SODI) 3- minidisc
C) Nanoparticles
D) Liposomes

Advantages of Ocular-Controlled Drug Delivery Systems

1- Increase ocular residence (improve bioavailability)
2- Prolong drug release (better efficacy)
3- Less visual & systemic side effects
4- Increase shelf life
5- Accurate dosing
6- Exclusion of preservatives
7- Reduction of systemic side effects
8- Reduction of the number of administration
9- Better patient compliance

Ideal characteristics of Ocular-Controlled Drug Delivery Systems

1- Sterility 2- Isotonicity 3- pH adjusted
4- less drainage tendency 5- Minimum protein binding
 A) Non- Erodible inserts

1- Ocusert
Sterile insoluble ophthalmic insert that prolong residence time of drug with a controlled release
manner and less affected by nasolacrimal drainage so minimize the required number of
applications. It is placed in the inferior cul-de-sac between the sclera and the eyelid.
Ocuserts are commercially available for (Pilocarpine) in two different release rates for 7 days as;
Ocusert P-20, which delivers a dose of 20 µg/hr. Ocusert P-40, which delivers a dose of 40 µg/hr.
Part Material
Drug reservoir (central core ) pilocarpine
Carrier material Alginic acid
Rate controller (semi-permeable membranes) Ethylene vinyl acetate copolymers (EVA)
Delivery portal Copolymer membrane (housing)
Annular ring of the membrane impregnated with titanium dioxide that form white border for visibility in
handling of ethylene vinyl acetate
Diffusion is controlled by lacrimal fluid
penetrating through it.
Release follows: Zero-order kinetics
• Properties of an ideal Ocuserts:
a) Comfort
b) Ease of Handling and Insertion
c) Not interfere with vision and oxygen
permeability.
d) Stable, and inert
e) Applicable to a variety of drugs
f) Permeable enough to permit the
passage of water and oxygen.
g) Ease of Manufacture
 • Advantages of Ocusert
• Increase ocular residence
• Exclusion of preservatives
• Accurate dosing
• Ocusert only expose patient to 1/8 amount of drug compared with drops which reduce side effects
and toxicity
• Provide continuous round the clock control of intraocular pressure
• More patient compliance (dose once per week)
• Disadvantages of Ocusert
• Expensive
• Foreign body sensation
• Its retention in eye for 7 days (check periodically )
• Replacement of contaminated unit with a fresh one
• Some patients find positioning the ocusert in the eye to be challenging.
 • 2. Contact Lenses
• Circular shaped

• Dyes may be added during polymerization

• Drug release depends on : Amount of drug,

Soaking time, and Drug concentration in soaking
solution

❖ Uses:
A) For vision correction.
B) Therapeutic soft contact lenses used to aid in
corneal wound healing in patients with infectious
corneal ulcers (keratitis).
C) Pre-soaked hydrophilic contact lenses in ocular
drugs are used for ocular extremely rapid release drug
delivery as antibiotics, anti-glaucoma agents, and
polypeptides.
 1- Hard contact lenses: (PMMA).
▪ Termed hard because they are made of hydrophobic rigid plastic resin, Polymethyl meth-acrylate.
▪ To prevent epithelial tissue from damage, a solution are used that wet the surface of the lens to
provide a cushioning layer between the corneal epithelium and the inner surface of the lens.
❖ Advantages:
- Provide durability and clear crisp vision for the patient.
- Easy to handle during insertion and removal.
- Resist absorption of disinfectant, surfactant and contaminants.
❖ Disadvantages:
-impermeable to oxygen and moisture which will lead to respiration and to patient discomfort.
- Require an adjustment period and may become dislodged in the eye.
2- Rigid Gas Permeable contact lenses (RGP):
- Like PMMA but are oxygen permeable.
❖ Advantages: The same as PMMA, with some more extra advantages such as:
• a) Permit the transmission of oxygen through the lens more than hard lenses.
• b) The newer " super-permeable RGP lenses used for extended wear.
• Disadvantages: same as PMMA
 • 3- Soft contact lenses:
▪ Made of a hydrophilic transparent, hydroxyl ethyl meth-acrylate (HEMA), that contain 30 and 80%
water. Types:
a) Daily wear lenses: must be removed and cleaned at night before bedtime.
b) Disposable soft lenses: These are simply discarded and replaced with a new pair after week's wear,
so it does not need cleaning and disinfection..
c) Extended-wear lenses: for continuous wear, up to 30 days.

❖ Advantages:
1- Can be wear for longer periods of time. 2- Little adaptation time associated with them.
3- Visual adjustment easier when switching from contact lenses to eyeglasses.
4- The increased amount of water in lenses improves its permeability to oxygen.
❖ Disadvantages:
1- Provide a slight reduction in quality of vision and have a shorter life span.
2- They are extremely fragile; the wearer must ensure that the lenses not dry out.
 ❖ Care of contact lenses
• 1- Cleaning to remove lipids from the lens; Using surfactants, nonionic detergent, wetting agent,
and chelating agent which emulsify accumulated oils, lipids and inorganic compounds.
• 2- Cleaning to remove proteins deposits; papain and pancreatin, in a solution of 3% H2O2 can
cause the hydrolysis of protein to peptides and amino acids which can be easily removed.
• 3- Disinfection to kill microorganisms;
▪ Disinfection can be achieved by two methods:-
A) Thermal (using heat): The lenses are placed into a specially designed heating unit with saline
solution, at a minimum of 80 C for 10 min.
B) Chemical (no heat): Using of H2O2 is sufficient to kill microorganisms.
N.B.; To prevent eye irritation from residual peroxide after disinfection, the lens must be treated with
neutralizing agents, as; enzyme catalase or sodium thiosulfate.
4- Rinsing with 0.9% saline solution to remove the cleaning solution, dust, salts, and tobacco
smoke.
5- Storage the lens while not in use: The lens must be soaked in isotonic saline (0.9%), with neutral
pH contain sufficient concentration of disinfecting agent, usually 0.01% benzalkonium chloride and
0.01% sodium edentate to kill surface bacteria.
 ❖ Lenses-Drugs Contraindications
1- Oral medications which are excreted in tear fluid or discolor tears.
• Examples: - Rifampicin (orange-colored tear). - Sulfasalazine (yellow-colored tear).
2- Oral or topical drugs cause ocular side effects.
Examples: - Drugs with anti-cholinergic effects, as antihistamines, and antidepressants, decrease tear
secretion and may cause lens damage.
3- Medicines, that promote excessive lacrimation: It may antagonize the wear of lens. Ex: Reserpine.
4- Medicines, which are prescribed for ocular or eye lid edema may be contraindicated with lens
wear. Examples: Hydrochlorothiazide, chlorthalidone.
 • B) Erodible inserts
• The solid inserts adsorb the aqueous tear fluid and gradually erode or disintegrate. The drug is slowly
leached from the hydrophilic matrix.
• 1- Lacriserts
• Sterile rod-shaped devices made up of propyl cellulose without any preservative.
• Used for treatment of dry eye syndrome - Inserted into the inferior fornix.
• It weight 5 mg and measure 1.27 mm in diameter with a length of 3.5 mm
• 2- Soluble ocular drug inserts (SODI)
• Small sterile oval thin film.
• Composition: acryl amide, vinyl pyrrolidine and ethyl acrylate.
• Weight: 15-16 mg Used for treatment of glaucoma and trachoma.
• Advantages : single SODI replaces 4-12 eye drops or 3-6 application of ointments.
• 3- mini disc
• Diameter of 4-5 mm. - made up of silicone based prepolymer
• Minidisc can be hydrophilic or hydrophobic to permit extend release of both water soluble and
insoluble drugs
 Packaging of ocular preparations
▪ Eye drops are frequently packaged in multiple dose containers ranging from 4 to 60 ml.
▪ Packaging components must offer ease of administration and maintenance of sterility of the product
for its entire shelf life.
▪ Ophthalmic formulations are usually dispensed in a glass dropper bottle with the dropper either
inserted or packaged separately.
▪ Ophthalmic solutions used for special cases such as surgery or traumatized eye must be dispensed in
single-use containers.
1. Glass packages: Glass packages consist of following components:
• a) Glass bottle: used for packaging products that is not compatible with plastics.
• b) Dropper: A glass or plastic dropper is placed directly into the glass bottle or is packaged in a
separate sterile blister packet.
• c) Closures: Made of plastic material.
• d) Caps: Made of aluminum or plastic.
• 2- Plastic containers: Plastic containers must not contain any material that can be extracted into the
formulation.
• 3-Droptainers: Droptainers are plastic containers that dispense a drop of medication when inverted
and gently squeezed. They consist of a plastic bottle, dispenser tip, and cap.
 QC of Parenteral and Ophthalmic Dosage Forms
• In-vitro evaluation
• 1- Sterility Test:
A) Direct inoculation method
B) membrane Filtration method (2 media soya bean-Casein digest medium (20-25 °C),
Fluid Thioglycolate medium (30-35 °C) 7 days
• 2- Pyrogen free test. (rabbits)
• 3-Clarity Test: visual inspection or instrumental method (free from particulate matter)
• 4-Leakage Test
• 5- metal particles in Ophthalmic preparation
• 6- Assay
• 7- pH (pH meter)
• 8- Viscosity: (15-25 cps) using Brookfield viscometer
• 9- Stability: accelerated stability study and freez thaw method
• 10- Drug/preservative content (HPLC and UV)
 QC of Parenteral and Ophthalmic Dosage Forms
• 11- Drug carrier compatibility study (FTIR, DSC, and XRD)
• 12- Drug release
• 13- Swelling (inserts) : % Swelling index = (Weight of swollen insert after time t – original
weight of insert) / original weight of insert x 100
• In-vivo evaluation:
• Eye irritancy test: - Draize irritancy test (rabbits observe signs 14 day)
• - modified friedenwald and Draize method
• Trans-corneal study (rabbits)
• In-vivo release evaluation of inserts (rabbits)
• In-vivo performance (rabbits)
 Evaluation of Advance ocular dosage forms
• 1- Thickness of the film:
• Measured by dial caliper at different points and the mean value is calculated.
• 2- Drug content uniformity:
• The cast film cut at different places and tested for drug
• 3- Uniformity of weight
• 4- Percentage moisture absorption
• Ocular film are weighed and placed in a desiccator containing 100 ml of saturated solution of
aluminum chloride and 79.5% humidity was maintained.
• After 3 days the ocular films are reweighed, and the percentage moisture absorbed is calculated.
• 5- Percentage moisture loss
• Ocular films are weighed and kept in a desiccator containing anhydrous calcium chloride.
• After 3 days the ocular films are reweighed, and the percentage moisture loss is calculated
 In- vitro Evaluation of ocular dosage form for drug release
• Bottle method
• Dosage forms are placed in bottle containing dissolution medium maintained at specified temperature
and pH.
• The bottle is then shaken, and sample of medium is taken at appropriate interval and analyzed for drug
content.
• Diffusion method
• Drug solution is placed in the donor compartment and buffer medium is placed in between donor and
receptor compartment
• Drug diffused in receptor compartment is measured at various time intervals.
• Modified rotating basket method
• Dosage form is placed in a basket assembly connected to stirrer.
• The assembly is lowered into jacketed beaker containing buffer medium and temperature 37 C
• Samples are taken at appropriate time intervals and analyzed for drug content
• Modified rotating paddle apparatus
• Dosage form is placed in a diffusion cell which is placed in the flask of rotating paddle apparatus
• The buffer medium is placed in the flask and paddle is rotated at 50 rpm
• The entire unit is maintained at 37 c
• Samples are taken at appropriate time intervals and analyzed for drug content
 In- vivo Evaluation of ocular dosage form for drug release

• In- vivo study

• The dosage form is applied to one eye of animal and the other eye serve as
control
• Then the dosage form is removed carefully at regular time interval and are
analyzed for drug content
• The drug remaining is subtracted from the initial drug content which will give
the amount of drug absorbed in the eye of animal at particular time
• After one week of washed period the experiment was repeated for two times as
before
 Clean area Classification
• Cleanrooms are classified according to the number and size of particles permitted per volume of air.
• For the manufacture of sterile pharmaceutical preparations, four grades of clean areas are
distinguished as follows:
• Grade A: The local zone for high-risk operations, e.g. filling and making aseptic connections.
Normally such conditions are achieved by using a unidirectional airflow workstation. The uniformity
and effectiveness of the unidirectional airflow should be demonstrated by undertaking airflow
visualization tests.
• Grade B: In aseptic preparation and filling, this is the background environment for the Grade A zone.
• Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile
products or carrying out activities during which the product is not directly exposed (i.e. aseptic
connection with aseptic connectors and operations in a closed system).
 Air Classification System
Grade At rest In operation Maximum number
Maximum number of particles permitted per m3 of viable micro-
organism per m3
0.5-5 µm > 5 µm 0.5-5 µm > 5 µm
A 3 500 0 3 500 0 Less than 1
B 3 500 0 350 000 2 000 5
C 350 000 2 000 3 500 000 20 000 100
D 3 500 000 20 000 Not defined Not defined 500
Iso classification system
 British standard classification

Class Maximum particles/m3

≥ 0.5 µm ≥ 1 µm ≥ 5 µm ≥ 10 µm ≥ 25 µm
Class 1 3000 0 0 0
Class 2 300 000 2000 30
Class 3 1000 000 20 000 4 000 300
Class 4 200 000 40 000 4000