OCULAR DRUG DELIVERY SYSTEM

PRESENTED BY: SOMNATH NAVGIRE M. PHARM II: (PHARMACEUTICS) DEPARTMENT OF PHARMACEUTICAL SCIENCES, RASHATRASANT TUKDOJI MAHARAJ NAGPUR UNIVERSITY,NAGPUR.

1

IDEAL OPHTHALMIC DELIVERY SYSTEM

Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritative and comfortable form

Appropriate rheological properties

OCULAR DRUG DELIVERY SYSTEMS

ADVANCED DELIVERY SYSTEMS

Scleral plugs Gene therapyStem cell

CONTROLLED DELIVERY SYSTEMS

Implants Hydrogels DendrimersIontophorosisPolymeric solutionPenetration enhancersContact lensesNano suspensionsMicro emulsionsCyclodextrinsPhase transition systemsMucoadhesive

PARTICULATE SYSTEMS

Nano particlesMicro particles

VESICULAR DELIVERY SYSTEMS

LiposomesNeosomesPharmacosomesdiscomes

RETRO METABOLIC DELIVERY SYSTEMS

Softdrug approachChemical delivery systems

SOLUTIONSGELS OINTMENTSSUSPENSIONSEYE DROPS

CONVENTIONAL DOSAGE FORMS

LIMITATIONS OF CONVENTIONAL DRUG DELIVERY

Rapid precorneal elimination

Solution drainage by gravity

Frequent instillation is necessary

Conjuctival absorption

ADVANTAGES OF AVANCED DUG DELIVERY

Sustained and/or controlled drug release Site-specific targeting Protect the drug from chemical or enzymatic hydrolysisIncreasing contact time and thus improving bioavailabilityBetter patient compliance.

4

Factors Affecting Intraocular Bioavailability:

1. Inflow & Outflow of Lacrimal fluids.

2. Efficient naso-lacrimal drainage.

3. Interaction of drug with proteins of Lacrimal fluid.

4. Dilution with tears.

5. Limited and poor corneal permeability

6. Metabolism

NOVEL OCULAR DRUG DELIVERY SYSTEM

OBJECTIVES : To prolong the pre ocular retention To reduce the frequency of administration To provide controlled, continuous drug delivery To avoid or minimize the initial drug concentration

peak in the aqueous humour To avoid periods of under-dosing that may occur

between eye drop instillation.

APPROACHES TO IMPROVE OCULAR DRUG DELIVERY

ENHANCEMENT OF BIOAVAILABILITY VISCOSITY IMPROVER Solution Viscosity Solution Drainage. Enhances viscosity of the formulation.

Slows elimination rate from the precorneal area and enhance contact time.

Generally hydrophilic polymers- e. Methyl cellulose, polyvinyl alcohols, polyacrylic acids, sodium carboxy methyl cellulose,carbomer is used

A minimum viscosity of 20 cst is needed for optimum corneal absorption.

USE OF PENETRATION ENHANCERS: Act by increasing corneal uptake by modifying the integrity of the corneal epithelium

Substances which increases the permeability characteristics of the cornea by modifying the integrity of corneal epithelium are known as penetration enhancers.

Modes of actions By increasing the permeability of the cell membrane.

Acting mainly on tight junctions.

Classification

Calcium chelators :

e.g. EDTA

Surfactants :

e.g. palmiloyl carnitine, sodium caprate, Sodium dodecyl sulphate

Bile acids and salts :

e.g. Sodium deoxycholate, Sodium taurodeoxycholate, Taurocholic acid

10

11

Preservatives :

e.g. Benzalkonium chloride

Glycosides :

e.g. saponins, Digitonon

Fatty acids :

e.g. Caprylic acid

Miscellaneous :

e.g. Azone, Cytochalasins

PRODRUGSProdrugs enhance corneal drug permeability through modification

of the hydrophilic or lipophilicity of the drug.

The method includes modification of chemical structure of the drug

molecule, thus making it selective, site specific and a safe ocular

drug delivery system.

Drugs with increased penetrability through prodrug formulations are

epinehrine, phenylephrine, timolol, pilocarpine

USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY

Polymereric mucoadhesive vehicle: Retained in the eye due to non-covalent bonding with conjuctival mucine.

Mucine is capable of picking of 40-80 times of weight of water.

Thus prolongs the residence time of drug in the conjuctival sac.

• Mucoadhesives contain the dosage form which remains adhered to cornea until the polymer is degraded or mucus replaces itself.

• Types-1. Naturally Occurring Mucoadhesives- Lectins, Fibronectins

2. Synthetic Mucoadhesives-PVA,Carbopol, carboxy methyl

cellulose, cross-linked polyacrylic acid

• Drugs incarporated in to this are pilocarpine, lidocaine, benzocaine and prednisolone acetate.

13

Mechanism of mucoadhesion

• The polymer undergoes swelling in water,

• Entanglement of the polymer chains with mucin on the epithelial surface.

• The un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin.

• The water-swellable yet water-insoluble systems are preferred

14

PHASE TRANSITION SYSTEM

PHASE TRANSITION SYSTEM

PHASE TRANSITION SYSTEM

POLYMERS MECHANISM

Lutrol FC – 127 and Poloxamer 407

Viscosity increased when their temperature raised to eye temperature.

Cellulose acetate phthalate latex

Coagulates when its native pH 4.5 raised by tear fluid to pH 7.4

Gelrite Forms clear gel in the presence of cations

PHASE TRANSITION SYSTEM

18

PARTICULATE SYSTEM FOR OCULAR DRUG DELIVERYNANOPARTICLES:

For water soluble drugs.

Size:10-1000nm

Drug is Dispersed, Encapsulated, or Absorbed

Produced by Emulsion Polymerization

• Chemical initiation, Gamma irradiation, Visible light.

Polymerization is carried out by :

Emulsifier stabilizes polymer particle

Polymer used are Biodegradable.

E.g. :- Nanoparticle of Pilocarpine enhances Mitotic response by 20-23%.

Advantages of nanoparticles• Sustained drug release and prolonged therapeutic activity• Site-specific targeting• Higher cellular permeability• Protect the drug from chemical or enzymatic hydrolysis• Efficient in crossing membrane barriers -blood retinal barrier • Act as an inert carrier for ophthalmic drugs• Poly alkyl cyano acrylate(PACA) nanoparticles and

nanocapsules improve corneal penetration of hydrophilic and lipophilic drugs.

• Poly- ԑ-caprolactone(PECL) nanocapsules increase ocular penetration of lipophilic drugs such as metipranolol,betaxolol.

20

VESICULAR SYSTEM FOR OCULAR DRUG DELIVERY

LIPOSOMES

22

• Vesicle composed of phospholipid bilayer enclosing aqueous compartment in alternate fashion.

• Biodegradable, Non-toxic in nature.• Types :1.MLV• 2.ULV-SUV(upto 100 nm)• LUV(more than 100 nm) • Polar drugs are incorporated in aqeous compartment while

lipophilic drugs are intercalated into the liposome membrane

• Phospholipids used- Phosphotidylcholine, Phosphotidic acid, Sphingomyline, Phosphotidyleserine,Cardiolipine

ADVANTAGES • Drugs delivered intact to various

body tissues.• Liposomes can be used for both

hydrophilic and hydrophobic drug.• Possibility of targeting and

decrease drug toxicity.• The size, charge and other

characteristics can be altered according to drug and desired tissue.

DISADVANTAGES OF LIPOSOMES• Their tendency to be uptaken by

RI system.• They need many modification

for drug delivery to special organs.

• Cost .

23

Degradation and Drug Release Of Liposomes

24

1. Endocytosis

2. Fusion

Niosomes are non-ionic surfactant based multilamellar(>0.05µm),small unilamellar(0.025-0.05µm) or large unilamellar vesicles(>0.1µm) in which an aqueous solution of solute(s) is entirely enclosed by a membrane resulted from organization of surfactant macromolecules as bilayers STRUCTURAL COMPONENTS USED• Surfactants (dialkyl polyoxy ethylene ether non ionic surfactant) • Cholesterol.

NEOSOMES

•ADVANTAGES: •The vesicle suspension being water based offers greater patient compliance over oil based systems•Since the structure of the niosome offers place to accommodate hydrophilic, lipophilic as well as ampiphilic drug moieties, they can be used for a variety of drugs.•The characteristics such as size, lamellarity etc. of the vesicle can be varied depending on the requirement.•The vesicles can act as a depot to release the drug slowly and offer a controlled release.•They are osmotically active and stable.•They increase the stability of the entrapped drug•Improves therapeutic performance of the drug by protecting it from the biological environment and restricting effects to target cells, thereby reducing the clearance of the drug.•DISADVANTAGES• Physical instability, Aggregation, Leaking of entrapped drug, Fusion,a

PHARMACOSOMES• The vesicle formation takesplace not only just by association of

phospholipids but also by amphiphilic molecular association• Since many drugs are also amphiphiles, they can form the

vesicles

Advantages: • Drug metabolism can be decreased• Controled release profile can be achieved

DISCOMES• Soluble surface active agents when added in critical amount to

vesicular dispersion leads to solubilization or breakdown of vesicles & translates them into mixed micellar systems

• e.g: Egg yolk phosphatidyl choline liposomes by the addition of non ionic surfactants of poly oxy ethylene cetyl ether till the lamellar and mixed lamellar coexist

• Advantages: • Minimal opacity imposes no hinderance to vision • Increased patient compliance• Zero order release can be easily attained

Advantages of vesicular systems

1. No difficulty of insertion as in the case of ocular inserts

2. No tissue irritation and damage as caused by penetration enhancers

3. Provide patient compliance as there is no difficulty of insertion as observed in the case of inserts

4. The vesicular carriers are biocompatable and have minimum side effects

5. Degradation products formed after the release of drugs are biocompatable

6. They prevent the metabolism of drugs from the enzymes present at tear/corneal epithelium interface

7. Provide a prolong and sustained release of drug

IONTOPHORESIS Iontophoresis is the process in which direct current drives ions into cells or tissues.

If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode.

Requires a mild electric current which is applied to enhance ionized drug penetration into tissue.

Ocular iontophoresis offers a drug delivery system that is fast, painless, safe, and results in the delivery of a high concentration of the drug to a specific site.

Ocular iontophoresis has gained significant interest recently due to its non-invasive nature of delivery to both anterior and posterior segment.

Iontophoretic application of antibiotics may enhance their

bactericidal activity and reduce the severity of disease

Can overcome the potential side effects associated with

intraocular injections and implants.

iontophoresis is useful for the treatment of bacterial keratitis.

Iontophoresis

CYCLODEXTRINS: Cyclodextrins (CDs) forming inclusion complexes with many guest

molecules. And aqueous solubility of hydrophobic drugs can be enhanced without changing their molecular structure and their intrinsic ability to permeate biological membranes.

They increase corneal permeation of drugs and increase ocular bioavailability of poorly water soluble drugs. Applied in the form of eye drops.

DENDRIMERS: These are macromolecular compounds made up of a series of

branches around a central core. Their nanosize, ease of preparation, functionalization and possibility to attach multiple surface groups provides suitable alternative vehicle for ophthalmic drug delivery.

This system can entrap both hydrophilic and lipophilic drugs into their structure.

MICROEMULSION

They can be easily prepared through emulsification method,

easily sterilized, and are more stable and have a high capacity for

dissolving drugs.

The presence of surfactants and co-surfactants in microemulsion

increase the dug molecules permeability, thereby increasing

bioavailability of drugs. they act as penetration enhancers to

facilitate corneal drug delivery

NANOSUSPENSIONS

It is consist of pure, hydrophobic drugs (poorly water soluble),

suspended in appropriate dispersion medium..

It offer advantages such as more residence time and avoidance of

the high tonicity created by water-soluble drugs, their performance

depends on the intrinsic solubility of the drug in lachrymal fluids

after administration. Thus, they controlled its release and increase

ocular bioavailability.

Ocular Control Release System: Ophthalmic Inserts

Definition:- Solid or Semisolid in nature,

- Placed in lower Fornix

- Composed of Polymeric vehicle containing drug.

Desired Criteria For Control Release Ocular Inserts.

Comfort Ease of handling

Reproducibility of release

kineticsSterility Stability Ease of mfg.

Advantages 1. Accurate dosing.

2. Absence of preservative.

3. Increase in shelf life due to

absence of water.

Limitations• 1. Perceived by patient as foreign body.• 2. Movement around the eye.• 3. Occasional loss during sleep or

while rubbing eyes.• 4. Interference with vision.• 5. Difficulty in placement & removal.

CONTROLLED RELEASE OCULAR DEVICES

INSERTS:

Ophthalmic inserts are solid devices intended to be placed in the conjunctival sac and to deliver the drug at a comparatively slow rate

Increased ocular permeation with respect to

standard vehicles, hence prolonged drug activity

and a higher drug bioavailability;

Accurate dosing -theoretically, all of the drug is

retained at the absorption site;

Capacity to provide, in some cases, a constant rate of drug release;

INSOLUBLE INSERTSOCUSERTS:

Flexible, oval inserts

Consists of a medicated core reservior prepared out of hydrogel polymer sandwiched between two sheets of transperant lipophilic,rate controlling polymer like ethylene/vinyl acetate copolymer membrane.

CONTACT LENS : The most widely used Material is poly-2-hydroxyethylmethacrylate.

Its copolymers with PVP are used to correct eyesight , hold and deliver drugs.

Controlled release can be obtained by binding the active ingredient via biodegradable covalent linkages.

SOLUBLE OCULAR INSERTS

LACRISERT:

It is a sterile ophthalmic insert use in treatment of dry eye syndrome.

The insert is composed of 5mg of HPC in rod-shaped form about 1.27

mm diameter by about 3.5 m long

MINIDISC:

It is made up of counter disc with convex front & concave back

surface in contact with eye ball.

Composition: silicon based pre polymer

Hydrophillic or hydrophobic.

• COLLAGEN SHIELDS • Collagen is the structural protein of bones, tendons, ligaments and• skin and comprises more than 25% of the total body protein in

mammals. Collagen shields have been used in animal model and in

humans (eg. Antibiotics, antiviral etc.,) or combination of these

drugs often produces higher drug concentration in the cornea and

aqueous humor when compared with eye drops and contact lens• They are manufactured from porcine scleral tissue, which bears a

collagen composition similar to that of hu man cornea. • They are hydrated before being placed on the eye and the drug is

loaded with the collagen shield simply by soaking it in the drug solution.

• They provide a layer of collagen solution that lubricates the eye.

INTRAOCULAR INJECTIONS

Micro needle used to deliver drug to posterior segment as an alternative to topical route.

It shows excellent in vitro penetration into sclera and rapid dissolution of coating solution after insertion. In-vivo drug level was found to be significantly higher than the levelobserved following topical drug administration.

To deliver anti-infective, corticosteroids and anesthetic product to achieve higher therapeutic condition intraocularly, FDA approved intraocular Injections includes miotics, viscoelastics, and anti-viral agents for intravitreal injection

INTRAOCULAR IMPLANTS

It employed to extend the release in ocular fluids and tissues particularly in the posterior segment. It may be biodegradable and non-biodegradable.

With implants, the delivery rate could be modulated by varying polymer composition.

Implants can be in the form of solid, semi-solid or particulate based delivery systems. These implants have been applied in the treatment of diseases affecting both anterior and posterior segments of the eye.

Implant containing gancyclovir or, anti-neoplastic agents is release drug over a 5 to 8 months.

RETROMETABOLIC DELIVERY SYSTEM

• Combination of SAR and SMR Retrometabolic drug design (RMDD)• Metabolic activation of inactive delivery forms: chemical delivery systems

CDS Drug

inactive active

Alkyl oxime datives oximes(enzymes located in iris-celiary body)

• Metabolic deactivation of specifically designed active species:soft drugs

SD Mi

Active inactive metabolites

hydrocartisone spirothiazolidine• RMDD represent novel, systemic approach to achieve these goles include

two distinct methods aimed to increase the therapeutic index SOFT DRUG design CHEMICAL DELIVERY SYSTEM design

The chemical delivery systems(CDSs)- chemical compounds – produced by synthetic chemical reaction(s) forming covalent bonds between the drug(D) and specifically designed ‘carrier ’ and other moieties. At least one chemical bond needs to be broken for active compound (D) to be released. The release of active compound from CDSs takes pace by enzymatic or hydrolytic cleavage.

The basic principle of retrometabolic drug design approaches is that the drug metabolism considerations should actually be involved at a very early stage of the design process- not as an after thought inorder to explain some of the behaviours of the drug

SAR+SMR=RETROMETABOLIC DRUG DELIVERY SYSTEM

Drug targeting by CDS’s1.enzymatic physical chemical based targeting2.site specific-enzyme activated targeting3.receptor based chemical targeting

Drug targeting by soft drugs1.soft drug analogs2.activated soft coompounds3.active metabolite type soft drugs4.controlled release of endogenous soft compounds5.Inactive metabolic approach

CONCLUSION The main efforts in ocular drug delivery is to prolong the residence time of

drugs

The development of ophthalmic drug delivery systems is easy because we can easily target the eye to treat ocular diseases

the eye has specific characteristics such as eye protecting mechanism, which make ocular delivery systems extremely difficult.

The most widely developed drug delivery system is represented by the conventional and non-conventional ophthalmic formulations to polymeric hydrogels, nanoparticle, nanosuspensions, microemulsions, iontophorosis and ocular inserts.

In future an ideal system should be able to achieve an effective drug concentration at the target tissue for an extended period of time, while minimizing systemic exposure and the system should be both comfortable and easy to use.

REFERENCES• Ophthalmic drug delivery system: Challenges and approaches

PB Patel, DH Shastri, PK Shelat, AK Shukla

Controlled drug delivery – Concepts and Advances, by S.P. Vyas and Roop K.

Khar, page no.: 383 – 410.

Ansel’s Pharmaceutical dosage forms and drug delivery systems, by Loyd V.

Allen, Nicholas G. Popovich and Howard c. Ansel page no.: 661 – 663.

Advances in Controlled and Novel drug delivery, edited by N.K. Jain, page no.:

219 – 223.

. http://www.pharmainfo.net/reviews/recent advances in opthalmic drug

delivery system.