Ophthalmic drug delivery system

1. Ophthalmic Products
Dr. Prashant L. Pingale
Associate Professor, Dept. of Pharmaceutics
GES’s Sir Dr. M. S. Gosavi College of Pharm. Edu. & Research,
Nashik-422005, INDIA

2. Contact lens and lens care products
General Requirements
Ocular penetration enhancers
Approaches in recent ocular drug delivery system
Various conventional ocular formulations
Mechanisms & barriers for ocular drug absorption
Diagram shows various parts of eyes
Introduction, advantages & disadvantagesC
O
N
T
E
N
T
S
2

3.  Sterile, isotonic products that may be in the form of solutions,
suspensions, ointments or any novel drug delivery system,
administered topically, subconjunctival or as intraocular injection.
 For ailments of the eye, topical administration is usually preferred
over systemic administration, before reaching the anatomical
barrier of the cornea, any drug molecule administered by the
ocular route has to cross the precorneal barriers.
3
Introduction

4. Introduction
 They are specialized dosage forms designed to be instilled onto
the external surface of the eye (topical), administered inside
(intraocular) or adjacent (periocular) to the eye or used in
conjunction with an ophthalmic device.
 The most commonly employed ophthalmic dosage forms are
solutions, suspensions, and ointments. But these preparations
when instilled into the eye are rapidly drained away from the
ocular cavity due to tear flow and lacrimal nasal drainage.
 The newest dosage forms for: gels, gel-forming solutions,
ocular inserts, intravitreal injections and implants.
4

5. Drugs used in the eye
 Miotics e.g. pilocarpine HCl
 Mydriatics e.g. atropine
 Cycloplegics e.g. atropine
 Anti-inflammatory e.g. corticosteroids
 Anti - infectives e.g. antibiotics, antivirals and antibacterials)
 Anti-glucoma drugs e.g. pilocarpine Hcl
 Surgical adjuncts e.g. irrigating solutions
 Diagnostic drugs e.g. sodiumfluorescein
 Anaesthetics e.g. tetracaine
5

6. Characteristics required ocular drug delivery
system
 Good corneal penetration.
 Prolong contact time with corneal tissue.
 Simplicity of instillation for the patient.
 Non irritative and comfortable form (viscous solution
should not provoke lachrymal secretion and reflex
blinking)
 Appropriate rheological properties and concentrations
of the viscous system
6

7. Anatomy & Physiology of Eye
Ciliary body
Lens
Cornea
Iris
Anterior
chamber Posterior
chamber
7

8. Anatomy & Physiology of Eye
 The sclera: The protective outer layer of the eye, referred to as
the “white of the eye” and it maintains the shape of the eye.
 The cornea: The front portion of the sclera, is transparent and
allows light to enter the eye. The cornea is a powerful refracting
surface, providing much of the eye's focusing power.
 The choroid is the second layer of the eye and lies between the
sclera and the retina. It contains the blood vessels that provide
nourishment to the outer layers of the retina.
8

9. Anatomy & Physiology of Eye
 The iris is the part of the eye that gives it color. It consists of muscular
tissue that responds to surrounding light, making the pupil, or circular
opening in the center of the iris, larger or smaller depending on the
brightness of the light.
 The lens is a transparent, biconvex structure, encased in a thin
transparent covering. The function of the lens is to refract and focus
incoming light onto the retina.
 The retina is the innermost layer in the eye. It converts images into
electrical impulses that are sent along the optic nerve to the brain where
the images are interpreted.
9

10. Anatomy & Physiology of Eye
 The inside of the eyeball is divided by the lens into two fluid-filled
sections.
 The larger section at the back of the eye is filled with a colorless
gelatinous mass called the vitreous humor.
 The smaller section in the front contains a clear, water-like material
called aqueous humor.
 The conjunctiva is a mucous membrane that begins at the edge of the
cornea and lines the inside surface of the eyelids and sclera, which
serves to lubricate the eye.
10

11. General requirements and considerations
 Safety
 Ocular toxicity & irritation
 Preservation & Preservatives
11

12. Safety
▪ Ideally, all ophthalmic products would be terminally sterilized in the final
packaging.
▪ Only few ophthalmic drugs formulated in simple aq. vehicles are stable to
normal autoclaving tempt. & times (121°C for 20-30 min).
▪ Such heat-resistant drugs may be packaged in glass or other heat-
deformation-resistant packaging and thus can be sterilized in this manner.
▪ Most ophthalmic products, however cannot be heat sterilized due to the
active principle or polymers used to increase viscosity are not stable to
heat.
12

13. Safety
▪ Most ophthalmic products are aseptically manufactured and filled
into previously sterilized containers in aseptic environments using
aseptic filling-and-capping techniques.
13

14. Ocular toxicity and irritation
- Albino rabbits are used to test the ocular toxicity and irritation of
ophthalmic formulations.
- The procedure based on the examination of the conjunctiva, the cornea
or the iris.
- E.g. USP procedure for plastic containers:
1- Containers are cleaned and sterilized as in the final packaged product.
2- Extracted by submersion in saline and cottonseed oil.
3- Topical ocular instillation of the extracts and blanks in rabbits is
completed and ocular changes examined.
14

15. Preservation and preservatives
 Preservatives are included in multiple-dose eye solutions for
maintaining the product sterility during use.
 Preservatives not included in unit-dose package.
 The use of preservatives is prohibited in ophthalmic products that are
used at the of eye surgery because, if sufficient concentration of the
preservative is contacted with the corneal endothelium, the cells can
become damaged causing clouding of the cornea and possible loss of
vision.
 So these products should be packaged in sterile, unit-of-use
containers.
 The most common organism is Pseudomonas aeruginosa that grow in
the cornea and cause loss of vision.
15

16. Preservation and preservatives
16

17. Preservation and preservatives
Cationic wetting agents:
▪ Benzalkonium chloride (0.01%)
▪ It is generally used in combination with 0.01-0.1%
disodium edetate (EDTA). The chelating, EDTA has
the ability to render the resistant strains of PS
aeruginosa more sensitive to benzalkonium chloride.
Organic mercurials:
▪ Phenylmercuric nitrate 0.002-0.004%
▪ Phenylmercuric acetate 0.005-0.02%.
17

18. Preservation and preservatives
Esters of p-hydroxybenzoic acid:
▪ Mixture of 0.1% of both methyl and propyl hydroxybenzoate
(2 :1)
Alcohol Substitutes:
▪ Chlorobutanol (0.5%). Effective only at pH 5-6.
▪ Phenylethanol (0.5%)
18

19. Absorption of drugs in the eye
Factors affecting drug availability:
Rapid solution drainage by gravity, induced lachrymation,
blinking reflex, and normal tear turnover:
- The normal volume of tears = 7 μl, the blinking eye can
accommodate a volume of up to 30 μl without spillage, the
drop volume = 50 μl
19

20. Lacrimal nasal drainage
20

21. Absorption of drugs in the eye
▪ Superficial absorption of drug into the conjunctiva and sclera and
rapid removal by the peripheral blood flow:
▪ Low corneal permeability (act as lipid barrier)
▪ In general:
▪ Transport of hydrophilic and macromolecular drugs occurs through
scleral route
▪ Lipophilic agents of low molecular weight follow transcorneal
transport by passive diffusion and obey
▪ Fick’s first law of diffusion:
J = - D . d Cm / dx
21

22. Corneal absorption
J = The flux rate across the membrane
D = diffusion coefficient
- The diffusion coefficient, as the molecular size of the drug
Cm = concentration gradient
- As the drug solubility, the gradient, the driving force for drug entry into
the aqueous humor.
- The drug should have dual solubility (oil and water soluble) to traverse
the corneal epithelium (lipid barrier) then the aqueous humour.
22

23. Corneal absorption
23

24. Novel approaches in ocular DDS
 In situ forming gels
 Liposomes
 Nanoparticles
 Inserts
 Implantable systems
24
• Minidisc
• Soft contact lenses
• Niosomes
• Pharmacosomes
• Collagen shields

25. In situ forming gels
 The progress has been made in gel technology lip the
development of in-situ forming gel.
 They are liquid upon instillation and undergo phase transition in
the ocular cul-de-sac to form viscoelastic gel.
 This provides a response to environmental changes.
 Three methods have been employed to cause phase transition in
the eye surface.
 These are change in pH, change in temperature and ion
activation.
25

26. Change in pH
In this method gelling of the solution is triggered by a
change in the pH.
CAP latex cross linked polyacrylic acid and derivatives
such as carbomers are used.
They are low viscosity polymeric dispersion in water
which undergoes spontaneous coagulation and gelation
after instillation in the conjunctival cul-de-sac.
26

27. Change in Temperature
 In this method gelling of the solution is triggered by
change in the temperature.
 Sustained drug delivery can be achieved by the use of a
polymer that changes from solution to gel at the
temperature of the eye.
 But disadvantage of this is characterized by high
polymer concentration (25% Poloxamers).
 Methyl cellulose and smart hydrogels are other
examples.
27

28. Ionic strength
 In this method gelling of the solution Instilled Is triggered
by change in the Ionic strength.
 Example Is Gelrite.
 Gelrite is a polysaccharide, low acetyl gellan gum, which
forms a clear gel in the presence of mono or divalent
cations.
 The concentration of sodium in human tears is 2.6 g/l is
particularly suitable to cause gelation of the material
when topically installed into the conjunctival sac.
28

29. Liposomes
 'Lipos' meaning fat and 'Soma' meaning body
 artificially prepared vesicles made of lipid bilayer.
 can be filled with drugs, and used to deliver drugs for cancer
and other diseases.
 can be prepared by disrupting biological membranes, for
example by sonication.
 can be composed of naturally-derived phospholipids with
mixed lipid chains (like egg phosphatidylethanolamine) or other
surfactants.
29

30. Liposomes
 The use of liposomes as a topically administered ocular drug
delivery system began in the early stage of research into
ophthalmic drug delivery.
 But the results were favorable for lipophilic drugs and not for-
hydrophilic drugs.
 Liposomes must be suitable for ocular DD provided, they had an
affinity for, and were able to bind to, ocular surfaces, and release
contents at optimal rates.
 The addition of stearylamine to a liposomal preparation enhanced
the corneal absorption of dexamethyl valerate.
30

31. Liposomes
 The corneal epithelium is thinly coated with negatively charged
mucin to which the positive surface charge of the liposome may
absorb more strongly.
 Coating with bioadhesive polymers to liposomes, prolong the
precomea retention of liposomes.
 Carbopol 1342-coated pilocarpine containing liposomes were
shown to produce a longer duration of action.
 Liposomal preparation of acetazolamide, hydrocortisone and
tropicamide are studied.
 Coating the lipueme with bioadhesive polymers Ilka carbopal
increased the corneal retention followed by sustained action
Cyclosporin applied topically to the eye in the olive oil crops in a
liposome encapsulated form and in a cellophane shield showed
slow releasing property.
31

32. Nanoparticles
a small object that behaves as a whole unit in terms of its
transport and properties. It is further classified according to
size: in terms of diameter, fine particles cover a range between
100 and 2500 nanometers.
provide SR and prolonged therapeutic activity.
when retained in cul-de-sac after topical administration &
entrapped drug must be released from particles at an
appropriate rate.
enhance particle retention, it is desirable to fabricate the
particles with bioadhesive materials.
32

33. Nanoparticles
 Biodegradation is also a highly desirable property for the
fabrication of nanoparticles.
 Most commonly used polymers are venous poly (alkyl
cyanoacrylates), poly S- caprolactone and PLGA, which undergo
hydrolysis in tears.
 Coating of nanoparticles with bioadhesive polymers improves the
bioavailability. Chitosan coated nanocapsules improve the
bioavailability.
 Nanoparticles as an ophthalmic drug delivery have been
demonstrated for both hydrophilic and hydrophobic drugs.
33

34. Inserts
34

35. Classification of Patented Ocular Inserts
Insoluble
inserts
Soluble
inserts
Bioerodible
inserts
35

36. Classification of Patented Ocular Inserts
1) Insoluble inserts
a) Diffusion based
b) Osmotic based
c) Soft contact lenses
2) Soluble inserts
3) Bioerodible inserts
36

37. Characteristics of inserts
1) Ease of handling and insertion
2) Lack of expulsion during wear
3) Reproducibility of release kinetics (Zero-order drug delivery)
4) Applicability to variety of drugs
5) Non-interference with vision and oxygen permeability
6) Sterility
7) Stability
8) Ease of manufacture
37

38. Inserts
Solid inserts were introduced into the market 60 years ago.
The first solid insert was described in 1948 in BP.
It was an atropine containing gelatin wafer and in 1980's
numerous systems were developed using various polymers &
different drug release principles for controlled drug release.
Insoluble inserts are polymeric systems into which the drug is
incorporated as a solution or dispersion.
Ophthalmic inserts (ocuserts): alginate salts, PVP, modified
collagen and HPC.
Ocufit is a silicone elastomer based matrix that allows for the
CR of an active ingredient over, a period of at least 2 weeks.
38

39. Inserts
 Soluble inserts consists of all monolytic polymeric devices
that at the end of their release, the device dissolve or erode.
 Soluble ophthalmic drug inserts is a soluble copolymer of
acrylarnide, N-vinyl pyrrolidone and ethyl acrylate.
 It is a sterile thin film or wafer of oval shape.
 The system soften in 10-15 sec after introduction in to the
upper conjuctival sac, gradually dissolves within 1 h, while
releasing the drug.
 A soluble insert containing gentamycin sulphate and
dexamethasone phosphate has been developed.
 Pilocarpine Insert for glaucoma is also available.
39

40. Inserts
But these systems have the drawback that that blurred
vision while the polymer is dissolving.
Water soluble bioadhesive component in its formulation has
been developed to decrease the risk of expulsion and
ensure prolonged residence in the eye, combined with
controlled drug release.
They are bioadhesive ophthalmic drug inserts.
A system based on gentamycin obtained by extrusion of a
mixture of polymers, showing a release timer of about 72 h
has been reported.
Due to difficulty with self-insertion, foreign body sensation,
only few insert products are listed and pharmaceutical
manufacturers are not actively developing inserts for
commercialization.
40

41. Implantable systems
 The poly lactic acid and its copolymers with glycolic acid
have been used extensively as implants.
 An ocular implant for delivering ganciclovir for the treatment
of cytomegalo virus has also been developed.
 This delivers drug directly to the retina for over 5 months.
 These systems are less popular as they require minor
surgery.
41

42. Minidisc
 Minidisc is a controlled release monolithic matrix type
device consisting of a contoured disc with a convex front
and a concave back surface.
 The principle component is A (1) bis (4-methacryloxybutyl)-
polydimethyI siloxane.
 They can be made hydrophilic and hydrophobic to permit
extended release of bath water soluble and water insoluble
drugs.
42

43. Soft contact lenses
 The most widely used Material is poly-2-hydrosyethyl -
methacrylate.
 Its copolymers with PVP are used both to correct eyesight
and hold and deliver drugs.
 Controlled release can be obtained by binding the active
ingredient via biodegradable covalent linkages.
43

44. Niosomes
 Niosomes are reported as successful ophthalmic carriers.
 Discoidal niosomes of timolol maleate have been reported
to be promising systems for the controlled ocular
administration of water soluble drugs.
 The disc shape provides for a better fit in the cul-de-sac of
the eye and then large size may prevent release their
drainage into the systemic pool.
44

45. Pharmacosomes
 They are the vesicles formed by the amphiphilic drugs.
 Any drug possessing a free carboxyl group or an active
hydrogen atom (-OH, -NH2) can be esterifies to the hydroxyl
group of a lipid molecule, thus generating an amphiphilic
prodrug.
 These are converted to pharmacosomes on dilution with
water.
 They show greater stability, facilitated transport across the
cornea and a controlled release profile.
45

46. Collagen shields
 Manufactured from porcine scleral tissue, which bears a
collagen composition similar to that of human cornea.
 Hydrated before being placed on eye and drug is loaded
with the collagen shield simply by soaking it in drug
solution.
 Provide a layer of collagen solution that lubricates the eye.
 Collagen shields presoaked in tobramycin were used to
treat Pseudomonas aeruginosa infected cornea excoriation.
 Shield are not fully transparent & thus reduce visual activity.
 Are appropriate delivery systems for both hydrophilic and
hydrophobic drugs with poor penetration properties.
46

47. Viscosity improver
Used to prolong precorneal residence time and to improve
bioavailability, attempts were made to increase the viscosity
of the formulation
Examples are hydrophilic polymers such as cellulose,
polyalcohol and polyacrylic acid.
Na+ CMC: mucoadhesion polymers good adhesive strength.
The effects of polyacrylic acid and polyacrylamide based
hydrogels are tested on miotic response of pilocarpine.
47

48. Viscosity improver
 Carbomer were used in liquid and semisolid formulations as
suspending or viscosity increasing agents. Formulations
including creams, gels and ointments were used as ophthalmic
products.
 Polysaccharide such as xanthan gum was found to increase the
viscosity.
 Polycarbophil is water insoluble cross linked polyacrylic acid
helps in the retention of DDS in the eye due to the formation of
hydrogel bonds and mucoadhesive strength.
48

49. OCULAR PENETRATION ENHANCERS
 Purpose: After topical instillation of product, the drug is subjected
to a number of very efficient elimination mechanisms such as
drainage, binding to proteins, normal tear turnover, induced tear
production and non-productive absorption via the conjunctiva.
 So drug absorption is virtually complete in 90 sec. due to the rapid
removal of drug from the precorneal area & also the cornea is
poorly permeable to both hydrophilic & hydrophobic compounds.
 As a result, only approx. 10% or less of the topically applied dose
can be absorbed into the anterior segment of the eye
49

50. Penetration enhancers: characteristics
Absorbing-enhancing action should be immediate &
unidirectional, & the duration should be specific and
predictable.
Immediate recovery of the tissue after removing the
absorption enhancers.
No systemic and local effect associated with the enhancers.
Enhancers should be physically and chemically compatible
with a wide range of drugs and excipients.
50

51. Example of penetration enhancers
Class Examples
Surfactant Spans 20, 40, 85. Tweens 20, 40, 81.
Bile acids Deoxycholic acid, Taurocholic acid Taurodeoxycholic acid,
Urodeoxycholic acid Taurorsodeoxycholic acid
Fatty acid Capric acid
Preservatives Benzalkonium chloride, Chlorhexidine digluconate, Benzyl
alcohol, Chlorbutanol 2-Phenylethanol, Propyl paraben
Chelating agent EDTA
Others Alpha-cyclodextrin, Hexamethylene Lauramide,
Hexamethylene Octanamide, Decylmethylsulfoxide
Saponin.
51

52. Penetration enhancers : mechanisms
Altering membrane structure & enhancing transcellular
transport by extracting membrane components and/or
increasing fluidity.
Enhancing paracellular transport: Chelating calcium ions
leads to opening of tight junctions; Inducing high osmotic
pressure that transiently opens tight junctions; Introducing
agents to disrupt the structure of tight junctions.
Altering mucus structure and rheology so that this diffusion
barrier is weakened.
Modifying the physical properties of drug-enhancer entity.
Inhibiting enzyme activity.
52

53. Evaluation of ocular drug delivery systems
➢ In – vitro evaluation methods
➢ In – vivo evaluation methods
➢ In vitro – in vivo correlation
53

54. In – vitro evaluation methods
 Bottle method
 In this method, dosage forms are placed in the culture bottles
containing phosphate buffer at pH 7.4. The culture bottles are
shaken in a thermostatic water bath at 37°C. A sample of
medium is taken out at appropriate intervals and analyzed for
drug contents.
 Diffusion method
 An appropriate simulator apparatus is used in this method. Drug
solution is placed in the donor compartment and buffer medium
is placed in the receptor compartment. An artificial membrane or
goat cornea is placed in between donor and receptor
compartment. Drug diffused in receptor compartment is
measured at various time intervals.
54

55. In – vitro evaluation methods
 Modified rotating basket method
 In this method, dosage form is placed in a basket assembly
connected to a stirrer. The assembly is lowered into a jacketed
beaker containing buffer medium. The temperature of system
is maintained at 37°C. A sample of medium is taken out at
appropriate time intervals and analyzed for drug content.
 Modified rotating paddle apparatus
 In this method, diffusion cells (those that are used for analysis
of semi-solid formulations) are 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+0.5° C. Aliquots of samples are removed at appropriate
time intervals and analyzed for drug content.
55

56. In – vitro evaluation methods
 Flow through devices
 There are limitations to the official dissolution testing
apparatus concerning maintenance of sink condition for drugs
that saturate rapidly in large volumes of medium.
 The in-homogenicity of the solution in the rotating basket and
poor reproducibility led to enhanced use of flow through
devices.
 A constant fluid circulation apparatus is used as a flow through
device.
 The apparatus consist of a glass dissolution cell, a continuous
duty oscillating pump, a water bath and a reservoir.
56

57. In – vitro evaluation methods
 The dosage form is placed in the reservoir of the dissolution
medium.
 The whole assembly is maintained at the temperature of 37°C.
 The dissolution medium is circulated through the apparatus.
 Sampling of medium is done at various time intervals and
analyzed for drug content.
 Ali and Sharma had fabricated flow through cell for the
determination of in- vitro release of drug from ocular inserts.
 Sultana et al. modified the same apparatus by introducing
jacketed flask and eye.
57

58. In – vivo evaluation methods
 The controlled ocular drug delivery systems can be evaluated for
its PK & PD profiles.
 The main objective of the PK studies is to determine the drug
release from the dosage form to the eye.
 Rabbit is used as an experimental animal because of a number of
anatomical and physiological ocular similarities and also due to
larger size of the eye.
 PK studies are performed by measuring drug concentration in
various eye tissues e.g. lens, cornea, iris, ciliary body, retina
sclera, aqueous and vitreous humour in rabbits.
 The intraocular pressure of the eye is measured with a tonometer.
 Ocular PK studies can also be carried out by tear fluid sampling,
which is a non-invasive technique.
58

59. In – vivo evaluation methods
 Usually, disposible glass capillaries of 1ml capacity are used for
sampling.
 The samples are collected from the marginal tear strip of the rabbits.
 The capillary force fills the tube rapidly and the small volume collected
does not interfere with the ocular pharmacokinetics.
 Extreme care must be taken to avoid any corneal contact and possible
induced lacrimation.
 To withdraw aqueous humour, rabbits are anaesthetized with ketamine
and aqueous humour about 200 ml is withdrawn from the anterior
chamber using 1ml syringe with 26 guage needle.
 Vitreous samples are also obtained with 20 gauge needle.
 The entire cornea, lens, and iris-ciliary body are also removed and
analyzed for the drug content.
59

60. In vitro – in vivo correlation
 In establishing a good in-vitro-in-vivo correlation, one has to
consider not only the pharmaceutics aspects of the controlled
release drug delivery systems but also the biopharmaceutics and
pharmacokinetics of the therapeutic agent in the body after its
delivery from a drug delivery system, as well as the
pharmacodynamics of the therapeutic agent at the site of drug
actions.
60

61. Questions from the topic
 What do you know about Ocular drug delivery system? What are the
advantages of ODDS?
 With neat labeled diagram show various parts of eyes. Write a note
on Mechanisms and barriers for ocular drug absorption.
 What are various conventional ocular formulations?
 What are the approaches in recent ocular drug delivery system?
Write a short note on ocular inserts, nanoparticles & liposomes.
 Write a note on microspheres and nanoparticles drug delivery
system used as ocular drug delivery system.
 Write a note on:
 In situ-forming hydrogels
 Iontophoresis as an ocular drug delivery system.
 Write a note on ocular penetration enhancers.
61

62. 62