DRUGS OCULAR DELIVERY SYSTEM

2. CONTENTS
 Introduction
 Physiology of the eye
 Precorneal disposition of pilocarpine
 Transcorneal permeation of pilocarpine
 Product development
 Packaging Design Considerations

3. INTRODUCTION
 Sterile products are essentially free from foreign
particles for instillation into the cul-de-sac.
 Ophthalmic preparations including eye drop
solutions(eg. antiglaucoma pilocarpine solution),
suspensions and ointments can be applied topically to
the cornea or instilled in the space between the eyeball
and lower eyelid.
 When drops of an aqueous solution are applied onto
the cornea, through which the drug must penetrate to
reach the interior part of the eye, the solution in the
drops is immediately diluted with tears and washes
away rapidly through the lachrymal apparatus.

4.  Only small fraction of instilled dose is absorbed
into target tissues(1.2% is available to the aqueous
humor).
 Higher the drug concentration in eye drop
solution,greater the amount of drug lost through
nasolacrimal drainage system.
The Ophthalmic Drug Delivery Systems (ODDS)
are desired to improve efficacy and minimization
of toxicity.

5. Following characteristics are required to optimize
ocular drug delivery system:
 Good corneal penetration.
 Prolong contact time with corneal tissue.
 Simplicity of instillation for the patient.
 Non irritative and comfortable form.

6. Factors influencing local drug
penetration into ocular tissue
Addition of methylcellulose and polyvinyl alcohol
increases drug penetration by increasing the
contact time with the cornea and altering corneal
epithelium.
 Lipid solubility:
Because of the lipid rich environment of the
epithelial cell membranes, higher lipid solubility
of the drug, more the penetration.
 Preservatives used in ocular preparations alter cell
membrane in the cornea and increase drug
permeability.e.g. benzylkonium and thiomersal.

7. Advantages of ocular drug delivery
system
1. Better compliance to the patient .
2. To provide controlled drug delivery.
3. To increase the ocular bioavailability of drug
by increasing the corneal contact time.
4. To provide targeting within the ocular globe
so as to prevent the loss to other ocular
tissues.
5. To provide comfort and to improve
therapeutic performance of drug.

8. STRUCTURE OF EYE

9. Physiology of the eye
 The protective outer layer of the eye, “white of the
eye” is called the sclera and it maintains the shape
of the eye.
 The front portion of the sclera, called the cornea,
is transparent and allows light to enter the eye.
 The choroid is the second layer of the eye and lies
between the sclera and the retina.
 The retina is the innermost layer in the eye.

10.  Cornea,lens and vitreous body are transparent
media,oxygen and nutrients are transported to
these by the aqueous humor.
 Cornea is covered by thin epithelial layer
continous with conjunctiva at the cornea sclerotic
junction and it is formed of crisscrossing layers of
collagen.
 The cornea is often the tissue through which drugs
in ophthalmic preparations reach the inside of the
eye.

11.  The eye is constantly cleansed and lubricated by
the lacrimal apparatus which consist of 4
structures:
 Lacrimal glands
 Lacrimal canals
 Lacrimal sac
 Nasolacrimal duct
 Normal volume of Lacrimal fluid = 7 µl
 Isotonic aqueous solution of bicarbonate and
sodium chloride(pH =7.4)

12.  Dilutes irritants or to wash the foreign bodies out
of the conjunctival sac.
 Contains lysozyme whose bacteriocidal activity
reduces the bacterial count in conjunctival sac.
 Volume of aqueous humor =300µl(fills anterior
chamber of the eye).
 Rate of drainage of aqueous humor is comparable
to rate of production thus maintaining constant
intraocular tension of 25-30 mm Hg.

13.  Absorption of drugs in the eye takes place either
through corneal or non‐corneal route.
 Maximum absorption takes place though the
cornea, which leads the drug into aqueous humor.
 Loss of the administered dose of drug takes place
through spillage and removal by the naso lacrimal
apparatus.
 The non corneal route involves the absorption
across the sclera and conjunctiva into the intra
ocular tissues.

14. Ocular delivery of pilocarpine
 Pilocarpine is obtained from leaflets of Pilocarpus
jaborandi and Pilocarpus microphyllus.
 It is preferred ocular hypotensive agent for
treatment of increased intraocular pressure.
 Pilocarpine eye drops has low intraocular drug
bioavailability and sideffects.
 Ocusert Pilo 20 and Ocusert Pilo 40(Ocusert
system) delivers pilocarpine at constant rate of 20
and 40 µg/hr for 7 days.

15. Precorneal disposition of
pilocarpine
 Precorneal barriers are the first barriers that slow
the penetration of an active ingredient into the eye
and consist of the tear film and the conjunctiva.
 Major portion of drug is drained within 5 min by
nasolacrimal drainage system(75%) until solution
volume returns to normal tear volume of 7.5µl.
 Nasolacrimal drainage dependent upon eye drop
instilled.
 Smaller the instillation,higher the intraocular
bioavailability of pilocarpine.

16.  Drug dose decreases very rapidly initially as a
result of nasolacrimal drainage but drug conc. very
slowly as a result of tear turnover and corneal and
conjunctival absorption.
 Eye drop size of 50-70µl is reduced to 5-10µl.
 More the instillation volume is reduced,greaterthe
intraocular bioavailability.

17. Transcorneal permeation of
pilocarpine
 Existence of transcorneal permeation barrier(located
at the outermost cell layer of the corneal epithelium)
varies in the magnitude of its permeability in relation
to solubility characteristics.
 Cornea is a membrane barrier containing both
lipophilic and hydrophilic layers,drugs possessing
both lipophilic and hydrophilic properties permeate it
most effectively.
 Transport of pilocarpine from cornea to anterior
chamber is controlled by corneal epithelium.

18. Lacrimal Lacrimal
fluid glands
Precorneal Epithelial Corneal
Stroma
Drug pool surface epithelium
epithelium
Aqueous
humor
Nasolacrimal Conjunctiva Metabolism Elimination
drainage system

19.  Instillation of pilocarpine eye drops the drug conc.
reached a peak level within 5 min in cornea and
within 20 min in aqueous humor.
 Corneal epithelium layer plays a dual role in
transcorneal permeation of pilocarpine both as
permeability barrier to transcorneal permeation
and a reservoir for prolonged release of drug to
underlying layers of cornea.

20. PRODUCT DEVELOPMENT
A. Environment factors includes:
o Sterility.
o Preservative efficacy.
o Freedom from foreign particulate matter.
o Separate entrance for personnel and equipment
should be provided through special designed
airlocks.
o Walls,ceilings and floors should be constructed of
materials that are hard,nonchipping,smooth.

21.  Class 100 conditions can be achieved by HEPA
filtered laminar airflow sources.
 Relative humidity is maintained between 40- 60%.
 Personnel must be trained in the proper mode of
gowning with sterile, nonshedding garments.

22. B. Manufacturing techniques:
 Aqueous ophthalmic solutions are manufactured
by dissolving the active ingredient into water and
then sterlizing this solution by heat or by filtration
through sterile membrame filter media.
 Methods of sterlization of packaging components
include exposure to heat,ethylene oxide gas and
gamma radiations.

23. C. Raw material includes:
Vehicles
Tonicity adjusting agents
Buffers
Surfactants
Stabilizers
Viscosity imparters

24.  Official purified water is used as vehicle for
ophthalmic drugs.
 Mucoadhesive polymers capable of retaining
mediation in precorneal area not only by viscosity
effects but by pysiochemical interaction with
mucin layer covering the corneal epithelium .
 The ointment vehicle is usually a mixture of
mineral oil and White petrolatum.
 Tonicity adjusting agents includes NaCl,KCl,Buffer
salts,dextrose,glycerin and propylene glycol.

25.  Range of .5-2% NaCl doesnot cause a marked pain
response.
 The stability of most commonly used ophthalmic
drugs is controlled by the pH of their environment.
 pH adjustment(pH=7.4) can influence the
comfort,safety and activity of the product.
 Use of surfactants is greatly restricted in formulating
ophthalmic solutions.
 Order of surfactants toxicity:
anionic>>cationic>>nonionic

26.  Antioxidants are principal stabilizers(Isoascorbic
acid,sodium bisulfite) used to decrease
decomposition of the active ingredient in
ophthalmics solutions.
 Preservatives use is prohibited but found safe and
effective with few compounds.eg.
Propyparaben,benzalkonium chloride.
 Methylcellulose,carbomers and polyvinyl
alcohol(viscosity imparters) increases drug
penetration by increasing the contact time with
the cornea and increases bioavailability.

27. D. Equipment:
 All tanks,valves,pumps and piping must be of the
best available grade of corrosion resistant stainless
steel.
 Stainless steel type 304 or 316 is preferable.
 Equipment will be placed in aseptic filling areas
such as filling and capping machine.

28. Packaging Design
Considerations
The choice of packaging for ophthalmic products
will depend on the type of dosage form whether it
is a liq. solution/suspension /semi-solid gel
/ointment.
The packaging design acceptance criteria must
ensure that the
 materials are compatible with the formulation and
ensure product stability.
 sterility of the product can be achieved and
assured for the entire shelf-life.

29.  Eyedrops are packaged almost in plastic dropper
bottles.
 Plastic bottle is made of low density
polyethylene(LPDE) which provides necessary
flexibility and inertness.
 The plastic resin are compatible with wide range of
drugs.
 The plastic resins must pass the USP biological
and chemical tests for suitability.

30. Reference
Chien, Y.W., In ocular Systemic Medications,
Fundamentals, Developmental Concepts and
Biomedical Assessments, Elsevier, New York, 226,
1985.

31. THANK
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