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.
Mechanism
of ocular absorption
1. Non corneal absorption:
· penetration across sclera and conjunctiva into intraocular tissue
· non productive because penetrated drug is absorbed by general circulation
2. corneal absorption :
·
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.
Factor
affecting 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
•
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
·
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
•
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.
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.
NIOSOMES AND 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.
·
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. CONTROL
RELEASE 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
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.
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.
·
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.
·
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.
·
4-5mm in diameter.
·
Composition : Silicon based polymer.
·
Drug release upto170 hr. 62
PARTICULATES
(NANOPARTICLES AND MICROPARTICLES)
·
Nanoparticle- <1 micrometre Microparticle-
>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.
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