Ocular drug delivery system - NDDS - B.PHARMA Introduction, intra ocular barriers and methods to overcome –Preliminary study, ocular formulations and ocuserts

1. OCULAR DRUG DELIVERY SYSTEM
NDDS
B.PHARMA SEMESTER 7
Jsmasipharmacy.blogspot.com
Introduction, intra ocular barriers and methods to overcome –Preliminary study, ocular
formulations and ocuserts
Ocular administration of the drug is primarily associated with need to treat ophthalmic disease
Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain vicinity of
front of the eye for prolong period of the time.
Mechanismof ocular absorption
1. Non cornealabsorption:
 penetration across sclera and conjunctiva into intraocular tissue
 non productive because penetrated drug is absorbed by general circulation
2. cornealabsorption :
 outer epithelium : rate limiting barrier , with pore size 60a only access to small
ionic and lipophilic molecule
 trans cellular transport between corneal epithelium and stroma.
Factoraffecting intraocular bioavailability
 inflow and outflow of laominal fluids
 efficient naso-lacrimal drainage
 intraction of drug with proteins of lacrimal fluid
 dilution with tears
 corneal barriers
 active ion transport at cornea
BARRIERS IN OCULAR ABSORPTION
Precorneal Constraints It include –
• Solution drainage
• Lacrimation
• Tear dilution

2. • Tear turnover
• Conjunctival absorption
Corneal constraints
• Cornea as rate limiting barrier
• Anatomy of cornea
1.Outer- Epithelium(lipophilic),
2.Middle- Stroma(hydrophilic),
3.Inner- Endothelium(lipophilic)
opthalmic dosage forms
ophthalmic preparation are starile products essentially free from forign particles , suitably
compounded and paekaged for instillation in to eye.
Following dosage form have been developed to ophthalmic drugs.
1. Conventional : solution , suspention , emulsion , ointment , insert , gels
2. Vesicular : liposomes , niosomes , discomes , pharmacosomes
3. Particulate : microparticals , nanoparticals
4. Control release : implants , hydrogels,dendrimers,iontoporesis,collagen shieid ,
polymeric solutions, contact lenses , cyclodexrin , microneedle , microimulsion , nano
suspension
5. Advanced : sclera plugs , gene delivery , Si RNA , STEM cell , ECT
ADVANTAGE
 They are easily administered by the nurse
 They are easily administered by the patient himself.
 They have the quick absorption and effect.
 less visual and systemic side effects.
 better patient compliance.
DISADVANTAGE
 The very short time the solution stays at the eye surface.
 Its poor bioavailability.
 The instability of the dissolved drug.
 The necessity of using preservative.
IDEAL CHARACTERISTICS
 Sterility
 Isotonicity
 Buffer/pH adjustment

3.  Less drainage tendency
 Minimum protein binding
A. CONVENTIONAL
1.Eye Drops:
• Drugs which are active at eye or eye surface are widely administered in the form of
Solutions, Emulsion and Suspension.
• Various properties of eye drops like hydrogen ion concentration, osmolality, viscosity
and instilled volume can influence retention of a solution in the eye.
• Less than 5 % of the dose is absorbed after topical administration into the eye.
• The dose is mostly absorbed to the systemic blood circulation via the conjunctival and
nasal blood vessels.
2. SOLUTIONS
2.1ADVANTAGE-
• Ease of bulk scale manufacturing
• High pt. Aceptibility
• Drug product efficacy
• Stability
• Cost effectiveness
3.EMULSION
• A Fine dispersion of minute droplets of one liquid into another liquid in which it is
generally not soluble or misceble.
• Emulsion are of 2 types-
• 1.Oil in Water- use in ophthal bcoz of less irritance nd better tolerance
• 2. Water in Oil Eg.- Difluprednate 0.05% , Difluprednate 0.05% + Moxifloxacin 0.5% ,
E/d Cyclosporin is Emulsion
• Eg.- Fluribrophen axetil + Castor oil have better bioavailability and less irritation
• Eg,- Chitosan coating and HPMC coating of indomethacin increase precorneal residence
time
3.1 Advantage of emulsion

4. • Improve residence time
• Drug corneal permeation increase
• Sustain drug release
4. SUSPENSION
• Disperssion of finely divided insoluble API in an aqueous solvent consisting of suitable
suspending and dispersing agent
• Its activity is particle size dependent. So if size is optimum then optimal activity is
achieved.
• Suspension must be resuspended by shaking to provide accurate dosage.
• Eg.- Tobramycin 0.3% + Dexa 0.1% (but have high viscosity)
• Tobra 0.3% + Dexa 0.05% (TobraDex ST) have very low settling rate
• Moxi 0.5% + Prednisolone 1%
• Prednisolone 1%
• Nepafenac 0.1% eye drop is suspension
• Natamycin
• Brinzolamode
5. GELS
• Eg.- pilocarpine 4% gel
• Eg.- several artificial tear preparations are formulated as ophthalmic gels
• Eg.- treatment with Timolol 0.5% gel once daily in the morning acheives intraocular
pressure level equal to twice daily solution
6. OINTMENTS
 Mixture of semisolid and solid hydrocarbons (parrfins) that have melting point at ocular
temp. (340 c).
 When applied to inferior conjuctival sac, ointments melt quickly and the excess spread
out onto the lid margin, lashes, skin of lids.
 It has a therapeutic effect for 6hr.
 This method may be of practical value in paediatric and geriartic age group.
 Early formulations of ointment contained waxy grades of petroleum or unwashed lanolin
which interfered with corneal wound healing.
 Newer ointments not contain these but should be used cautiously in ulcer with
impending perforation. And should not be used in any surgical wound in which there is a
question of wound integrity, such as when difficulty is experienced maintaining the Ant.
Chamber at surgery.

5. B. VESICULAR SYSTEM
 Vesicular drug delivery system can be defined as highly ordered assemblies consisting of
one or more concentric bilayers formed as a result of self-assembling of amphiphilic
building blocks in presence of water.
 Vesicular drug delivery systems are particularly important for targeted delivery of drugs
because of their ability to localize the activity of drug at the site or organ of action
thereby lowering its concentration at the other sites in body.
VESICULAR SYSTEM TYPES
 LIPOSOMES
 NIOSOMES
 DISCOSOMES
 PHARMACOSOMES
1. LIPOSOMES
 Liposomes are biocompatible and biodegradable lipid vesicles made up of natural lipids
and about 25–10 000 nm in diameter.
 They are having an intimate contact with the corneal and conjunctival surfaces which is
desirable for drugs that are poorly absorbed, the drugs with low partition coefficient, poor
solubility or those with medium to high molecular weights and thus increases the
probability of ocular drug absorption.
2. NIOSOMESAND DISCOMES
 The major limitations of liposomes are chemical instability, oxidative degradation of
phospholipids, cost and purity of natural phospholipids.
 To avoid this niosomes are developed as they are chemically stable as compared to
liposomes and can entrap both hydrophobic and hydrophilic drugs.
 They are non toxic and do not require special handling techniques.
 Niosomes are nonionic surfactant vesicles that have potential applications in the delivery
of hydrophobic or amphiphilic drugs. Discomes may act as potential drug delivery
carriers as they released drug in a sustained manner at the ocular site.
 Discosomes are giant niosomes (about 20 um size) containing poly- 24- oxy ethylene
cholesteryl ether or otherwise known as Solulan 24. Pharmacosomes: This term is used
for pure drug vesicles formed by the amphiphilic drugs.
 The amphiphilic prodrug is converted to pharmacosomes on dilution with water.

6.  Niosomes are microscopic lamellar structures, which are formed on the admixture of
non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with
subsequent hydration in aqueous media.
 Structurally, niosomes are similar to liposomes, in that they are also made up of a
bilayer. However, the bilayer in the case of niosomes is made up of non- ionic surface
active agents rather than phospholipids as seen in the case of liposomes.
.C. CONTROLRELEASE SYSTEM
 IMPLANTS
 IONTOPHORESIS
 DENDRIMER
 MICROEMULSION
 NANOSUSPENSION
 MICRONEEDLE
 MUCOADHESIVE POLYMER
 INSERTS
.1. IMPLANTS
 Implants help in circumventing multiple introcular injection and associated
complications.
 Implants use for drug delivery in posterior ocular tissue
 For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants are effective
drug delivery system. Earlier non biodegradable polymers were used but they needed
surgical procedures for insertion and removal.
 Presently biodegradable polymers such as Poly Lactic Acid (PLA) are safe and effective
to deliver drugs in the vitreous cavity and show no toxic signs
 Eg. Of Implants-
 NONBIODEGRADABLE-
o VITRASERT- controlled release of ganciclovir for t/t of CMV retinitis.
o RETISERT- release of Fluocinolone acetonide for t/t of chronic uveitis of post.
Segment.
 BIODEGRADABLE-
o SURODEX- release Dexamethasone for controle of postop inflamation.
o OZURDEX- for t/t of Macular Edema

7. 2. IONTOPHORESIS
 In Iontophoresis direct current drives ions into cells or tissues. For iontophoresis the ions
of importance should be charged molecules of the drug.
 Positively charged of drug are driven into the tissues at the anode and vice versa.
 Ocular iontophoresis delivery is not only fast, painless and safe but it can also deliver
high concentration of the drug to a specific site.
 Types of iontophoresis- 1. transcorneal 2. transscleral
3. DENDRIMER
 Dendrimer are nanosized, highly branched, star shaped polymerise system
 Its highly branched structure allow incorporation of wide range of drugs (Hydrophobic
and Hydrophilic )
 Dendrimers can successfully used for different routes of drug administration and have
better water-solubility, bioavailability and biocompatibility.
4. MICROEMULSION
 Microemulsion is dispersion of water and oil stabilized using surfactant and co-
surfactant to reduce interfacial tension and usually characterized by small droplet size
(100 nm), higher thermodynamic stability and clear appearance.
 Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are
critical parameters which can affect stability of the system
5. NANOSUSPENSION
 Nanosuspensions have emerged as a promising strategy for the efficient delivery of
hydrophobic drugs because they enhanced not only the rate and extent of ophthalmic
drug absorption but also the intensity of drug action with significant extended duration of
drug effect.
 For commercial preparation of nanosuspensions, techniques like media milling and high-
pressure homogenization have been used.
6. MICRONEEDLE
 Microneedle had shown prominent in vitro penetration into sclera and rapid dissolution of
coating solution after insertion while in vivo drug level was found to be significantly
higher than the level observed following topical drug administration like pilocarpine
 Microneedle is minimum invasive mode to deliver in posterior ocular tissue.
 Penetrate only 100 um of sclera so deposite drug into sclera or into suprachoroid space.

8. 7. MUCOADHESIVE POLYMER
 In this dosage form adhere to the precorneal mucus and residue in the eye until the
polymer dissolve or mucin replace itself.
 These are in early phase of research.
 They are basically macromolecular hydrocolloids with plentiful hydrophilic functional
groups, such as hydroxyl, carboxyl, amide and sulphate having capability for
establishing electrostatic interactions.
 Some mucoadhesives are- carboxymethycellulose. Carbopol, polymethymethacrylate,
acrylic acid, polycarbophil, sodium alginate. A mucoadhesive drug formulation for the
treatment of glaucoma was developed using a highly potent beta blocker drug,
levobetaxolol (LB) hydrochloride and partially neutralized poly acrylic acid (PAA).
8. INSERTS
 The ocular insert represents a significant advancement in the therapy of eye disease.
Ocular inserts are defined as sterile, thin, multilayered, drug-impregnated, solid or
semisolid consistency devices placed into the cul-de-sac or conjuctival sac, whose size
and shape are especially designed for ophthalmic application.
8.1 Ocular Inserts as an Ocular Sustained Release Drug Delivery System
 The main objective of the ophthalmic inserts is to increase the contact time between the
preparation and the conjunctival tissue, to ensure a sustained release suited for topical or
systemic treatment.
 The advantages of ocular inserts over the traditional ophthalmic preparation can be
summarized as follows-
8.2 ADVANTAGE
 Increased ocular residence, hence, prolonged drug activity and higher bioavailability
with respect to standard vehicles.
 Release of drugs at a slow, constant rate
 Accurate dosing (insert contains a precise dose, which is fully retained at the
administration site).
 Reduction of systemic absorption.
 Better patient compliance, due to reduced frequency of administration and less incidence
of visual and systemic side-effects.
 Possibility of targeting internal ocular tissues through non- corneal (conjunctival scleral)
routes.
 Increased shelf life with respect to aqueous solutions.
 Exclusion of preservatives, thus reducing the risk of sensitivity reactions.

9.  Incorporation of various novel chemical / technological approaches, such as pro-drugs,
mucoadhesives, permeation enhancers, micro particulates, salts acting as a buffer.
8.3 Disadvantage
 A major disadvantage of ocular inserts resides in their ‘solidity’, that is, they are felt by
the (often oversensitive) patients as an extraneous body in the eye. This may constitute a
difficult physical and psychological barrier to patient compliance.
 Their movement around the eye, in rare instances, the simple removal is made more
difficult by unwanted migration of the insert to the upper fornix.
 The occasional unintentional loss during sleep or while rubbing the eyes.
 Their interference with vision.
 Difficulty in placement of the ocular inserts
A) Insoluble inserts-
1. Diffusional Inserts :
 Central reservoir of drug enclosed in Semi permeable or microporous membrane for
diffusion of drug.
 Diffusion is controlled by Lacrimal Fluid penetrating through it.
 Release follows : Zero Order Kinetics.
 e.g. Ocusert®:
 20-40µg/hr for 7day
 Annular ring : Impregnated with Ti02 : For Visibility 5
2) Osmotic inserts
 A central part surrounded by a peripheral part
 Central part-single reservoir or two distinct compartments.
 Peripheral part- an insoluble semi permeable polymer.
 The tear fluid diffuse and induces dissolution.
 Solubilized deposits generate a hydrostatic pressure.
 Drug is then released through these aperture
3) Contact Lens :
 Presoaked Hydrophilic lens.
 Drug Release : within 1st 30 Min.
 Alternate approach : incorporate drug either as soln or suspension .e.g. Pilocarpine.
 Release rate is up to : 180 hr.

10.  Use in treatment of Bullous keratopathy, Dry eye syndrome, corneal condition requiring
protection such as traumatic corneal abrasion or erosions.
B) Soluble Inserts
1.SODI: Soluble Ocular Drug Insert.
 Small water soluble made of soluble synthetic polymers.
 Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate.
 Weight 15-16 mg. In 10-15 sec Softens; In 10-15 min. turns in Viscous Liquids; After
30-60min. Becomes Polymeric Solution.
Advantages of SODI
 Single SODI application : replaces 4-12 eye drops Instillation, or 3-6 application of
Ointments.
 Once a day treatment of Glaucoma.
2.The corneal collagen shield
 A disposable, short-term therapeutic bandage lens for the cornea.
 It conforms to the shape of the eye, protects the corneal surface, and provides
lubrication as it dissolves.
 The shields are derived from bovine collagen and are 14.5 mm in diameter.
 Sterilized by gamma irradiation.
 Disadvantages 1. It is not optically clear. 2. The collagen shield causes some discomfort.
 Clinical uses 1. Wound healing. 2. Treatment of dry eye. 58
C) Biodegradable inserts
1.Lacrisert:
 Sterile, Rod Shaped device.
 Composition: HPC.
 Weight:5mg,
 Dimension:Diameter:12.5mm, Length:3.5mm
 Use:-Dry eye treatment.
2.Minidisc:
 It is made up of counter disc with Convex front & Concave back surface in contact with
eye ball.

11.  4-5mm in diameter.
 Composition : Silicon based polymer.
 Drug release upto170 hr. 62
PARTICULATES(NANOPARTICLESAND
MICROPARTICLES)
 Nanoparticle- <1 micrometre - >1 micrometre
 The maximum size limit for microparticles for ophthalmic administration is about 5-10
micrometer above which a scratching feeling in the eye can result upon ocular
instillation.
 That is why micro and nanoparticles are promising drug carriers for ophthalmic
application.
 Nanopaticles are produced by emulsion polymerisation.
 Polyalkylcyanoacrylate are most commonly used ophthalmic nanoparicles.
 Many antiglaucoma drugs loaded onto nanoparicles for testing efficacy.