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Ocular Drug Delivery System by KaRaM-C
Ocular Drug Delivery System by KaRaM-C
Ocular Drug Delivery System by KaRaM-C
CONTENTS
I. INTRODUCTION
II. ANATOMY OF THE EYE
III. MECHANISMS AND BARRIARS FOR OCULAR DRUG
ABSORPTION
IV. CONVENTIONAL OCULAR FORMULATIONS
V. RECENT OCULAR DRUG DELIVERY FORMULATIONS
1. OCULAR PENETRATION ENHANCERS
2. MUCOADHESIVE DOSAGE FORMS
3. COLLAGEN SHIELDS
4. DENDRIMERS
4. 1. General Chemical Structure
4. 2. Physical Properties
4. 3. Applications In Ocular Drug Delivery
5. IN SITU-FORMING HYDROGELS
5. 1. Introduction
5. 2. Temperature Induced Gelation
5. 3. Ph Induced Gelation
5. 4. Osmotically Induced Gelation
5. 5. Performance Of ‘In-Situ’ Gelling Hydrogels
6. MICRO AND NANO PARTICLES
6. 1. Methods Of Preparation Of Nanoparticles
6. 2. Polymers Used In The Preparation Of Nanoparticles
7. IONTOPHORESIS
7. 1. Introduction
7. 2. Design Of Iontophoresis Devices
7. 3. Approaches Of Iontophoretic Delivery
VI. REFERENCES
Ocular administration of the drug is primarily related with the treatment of ophthalmic
diseases, not for gaining systemic action.
Ophthalmic drug delivery is one of the most interesting and challenging endeavours
facing the pharmaceutical scientist. The anatomy, physiology, and biochemistry of the eye
render this organ highly impervious to foreign substances. A significant challenge to the
formulator is to circumvent the protective barriers of the eye without causing permanent
tissue damage. Development of newer, more sensitive diagnostic techniques and novel
therapeutic agents continue to provide ocular delivery systems with high therapeutic efficacy.
Major classes of the drugs that are administered through ocular route are Miotics,
Mydriatics/Cycloplegics, Anti-inflammatories, Anti-infectives, Surgical adjuvants,
Diagnostics etc.
Historically, the bulk of the research has been aimed at delivery to the anterior
segment tissues, but whenever an ophthalmic drug is applied topically to the anterior segment
of the eye, only a small amount (5%) actually penetrates the cornea and reaches the internal
anterior tissue of the eyes. Rapid and efficient drainage by the nasolacrimal apparatus,
noncorneal absorption, and the relative impermeability of the cornea to both hydrophilic and
hydrophobic molecules, all account for such poor ocular bioavailability. The various
approaches that have been attempted to increase the bioavailability and the duration of the
therapeutic action of ocular drugs can be divided into two categories. The first one is based
on the use of sustained drug delivery systems, which provide the controlled and continuous
delivery of ophthalmic drugs, such as implants, inserts, and colloids. The second involves
maximizing corneal drug absorption and minimizing precorneal drug loss through viscosity
and penetration enhancers, prodrugs, and colloids.
Drug delivery to the posterior eye, where 40% of main ocular diseases are located, is
another great challenge in ophthalmology. Only recently has research been directed at
delivery to the tissues of the posterior globe.
Three layers
3. Inner Layer: Retina which is an extension of central nervous system (optic nerve)
Fluid system:-
1. Aqueous humor
2. Vitreous humor.
Topical delivery into the cul-de-sac is, by far, the most common route of ocular drug
delivery. Adsorption from this site may be corneal or noncorneal. The so called noncorneal
route of absorption involves penetration across the sclera and conjunctiva into the intraocular
tissues. This mechanism of absorption is usually nonproductive, as drug penetrating the
surface of the eye beyond the corneal-scleral limbus is taken up by the local capillary beds
and removed to the general circulation2. This noncorneal absorption in general precludes
entry into the aqueous humor.
Recent studies, suggest that the noncorneal route of absorption may be significant for
poorly cornea-permeable drugs; however, corneal absorption represents the major mechanism
of absorption for most therapeutic entities. The anatomical structures of the cornea exert
unique differential solubility requirements for drug candidates. In terms of transcorneal flux
of drugs, the cornea can be viewed as a trilaminate structure consisting of three major
diffusional barriers: epithelium, stroma, and endothelium. The epithelium and endothelium
contain on the order of 100-fold the amount of lipid material per unit mass of the stroma3.
Depending on the physiochemical properties of the drug entity, the diffusional resistance
offered by these tissues varies greatly4, 5. The outermost layer, the epithelium, represents the
rate-limiting barrier for trans-corneal diffusion of most hydrophilic drugs. The epithelium is
composed of five to seven cell layers. The basement cells are columnar in nature, allowing
for minimal paracellular transport. Corneal surface epithelial intracellular pore size has been
estimated to be about 60 A˚ 6. Small ionic and hydrophilic molecules appear to gain access to
the anterior chamber through these pores7; however, for most drugs, paracellular transport is
precluded by the interjectional complexes.
Sandwiched between the corneal epithelium and endothelium is the stroma (substantia
propia). The stroma constitutes 85–90% of the total corneal mass and is composed of mainly
of hydrated collagen8. The stroma exerts a diffusional barrier to highly lipophilic drugs owing
to its hydrophilic nature. There are no tight junction complexes in the stroma, and
paracellular transport through this tissue is possible.
The endothelium is lipoidal in nature; however, it does not offer a significant barrier
to the transcorneal diffusion of most drugs. Endothelial permeability depends solely on
molecular weight and not on the charge of hydrophilic nature of the compound9, 10.
Transcellular transport across the corneal epithelium and stroma is the major mechanism of
ocular absorption of topically applied ophthalmic pharmaceuticals.
Formulations:
3. Collagen Shields
4. Dendrimers
5. In Situ-Forming Hydrogels
7. Iontophoresis
After topical instillation of an eye drop, the drug is subject 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.
The principal functions of the mucus layer are lubrication and protection of the underlying
epithelial cells from dehydration and other challenges. The mechanism of mucoadhesion is
simply a physical entanglement. The polymer undergoes swelling in water, which permits
entanglement of the polymer chains with mucin on the epithelial surface of the tissue16. The
un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin
molecule.
Number of factors can affect the performance of mucoadhesives such as polymer’s adhesion
property, swelling characterisation, hydration time, molecular weight, degree of cross linking,
pH, mucin turn over, extent of drug incorporation, etc.
Clinical studies
demonstrated that the
collagen shield is easy to use
in the ophthalmologist’s
office, prevents delay in
beginning therapy, and
maintains therapeutic
concentrations of drug in the eye without the need for frequent topical instillation of drops17.
The safety of collagen for human use is evidenced by its diverse uses and biomedical
applications. In medicine, collagen has been used in cardiovascular surgery, plastic surgery,
orthopedics, urology, neurosurgery, and ophthalmology. The major medical application of
collagen is catgut suture In the manufacture of corneal collagen shields, the ability to control
the amount of cross-linking in the collagen subunits by exposure to ultraviolet (UV) light is
an important physicochemical property, because the amount of cross-linking is related to the
dissolution time of the shield on the cornea18, 19.
The collagen shield is designed to be 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. Although collagen shields produce some discomfort and interfere
with vision, corneal collagen shields could become a commonly employed technological
improvement in ophthalmic drug delivery20.
Tomalia et al.22 developed the first dendrimer, named the StarburstTM polyamidoamine
(PAMAM) dendrimer because of its dendritic branches and controlled starburst growth. This
macromolecule is built on an ammonia core with extending branches of alternating methyl
acrylate and ethylene diamine molecules23. The cascade is continued by adding methyl
acrylate moieties onto the reactive ends of the ethylene diamine molecules and then ethylene
diamine moieties onto the methyl acrylate. Each addition creates another branched layer,
referred to as a generation. Each generation causes an exponential increase in the surface
reactive sites that may have functional implications24. The critical molecular design
parameters of size, shape, surface chemistry, flexibility, and topology can be carefully
regulated to create the complex molecule. In addition, the dendrimer possesses a remarkably
cell like construction consisting of a low-density core and modifiable internal and external
surfaces, making it a perfect container or scaffolding for drugs, DNA, and protein.
Dendrimers show great promise for a variety of uses such as drug and gene delivery systems,
imaging agents, diagnostic kits, tumour therapy, industrial catalysts, and sensors.
Hudde et al.27 reported the efficiency of gene transfer to the corneal endothelium using
PAMAM dendrimers in an ex vivo model. The dendrimer was complexed with a plasmid
containing a reporter gene, β-galactosidase, in a ratio of 18 : 1 and incubated with a quarter of
a full-thickness rabbit cornea. The expression of β-galactosidase was assessed after 3 days: 6–
10% of the endothelial cells were stained blue 24.
Dendrimer therapy could also correct hereditary diseases such as lattice corneal dystrophy by
introducing the normal gene (i.e., transforming growth factor, β-induced gene) into the
endothelial cells so a functioning protein could be expressed.
Diseases of the retina include retinitis pigmentosa and macular degeneration; both result in
blindness due to the death of retinal cells. Drugs applied to the cornea usually do not reach
the back of the eye. Therefore, direct injection of the drugs into the vitreous is required to
target the retina. While this method provides adequate drug levels, it is not without significant
risk of retinal detachment, endophthalmitis, vitreal hemorrhage, and/or cellular toxicity28, 29,
30
. The use of dendrimers to deliver drugs and gene therapy to this area of the eye has great
potential.
5.1. Introduction
In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the
ocular cul-desac to form visco-elastic gel and this provides a response to environmental
changes. In the past few years, an impressive number of novel temperature, pH, and ion
induced in situ-forming systems have been reported for sustain ophthalmic drug delivery.
Each system has its own advantages and drawbacks. The choice of a particular hydrogel
depends on its intrinsic properties and envisaged therapeutic use. This review includes
various temperature, pH, and ion induced in situ-forming polymeric systems used to achieve
prolonged contact time of drugs with the cornea and increase their bioavailability31.
The most common way to improve drug retention on the corneal surface is undoubtedly by
using polymers to increase solution viscosity. Hydrogels are polymers endowed with an
ability to swell in water or aqueous solvents and induce a liquid–gel transition. Currently, two
groups of hydrogels are distinguished, namely preformed and in situ forming gels. Preformed
hydrogels can be defined as simple viscous solutions which do not undergo any modifications
after administration. In situ forming gels are formulations, applied as solutions, sols, or
suspensions, that undergo gelation after instillation due to physic-chemical, changes inherent
to the eye32.
In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the
ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental
changes33.
Three methods have been employed to cause phase transition on the surface: change in
temperature34, pH35, and electrolyte composition36.
These hydrogels are liquid at room temperature (20–25 °C) and undergo gelation when in
contact with body fluids (35– 37 °C), due to an increase in temperature37. For example
Poloxamers, cellulose derivatives, and xyloglucan.
5.2.1. Poloxamer
PEO-PPO-PEO (Poloxamer).
The Poloxamer series covers a range of liquids, pastes, and solids They are formed by central
hydrophobic part (polyoxypropylene) surrounded by hydrophilic part (ethylene oxide).
Depending on the ratio and the distribution along the chain of the hydrophobic and
hydrophilic subunits, several molecular weights are available, leading to different gelation
At room temperature (< 25 °C), the solution behaves as a mobile viscous liquid, which is
transformed into a semisolid transparent gel at body temperature (37 °C). At room
temperature (b25 °C), the solution behaves as a mobile viscous liquid, which is transformed
into a semisolid transparent gel at body temperature (37 °C). Preliminary toxicity data
indicate that this copolymer is well tolerated. Poloxamer formulation generally increased
drug residence time at application sites, resulting in improved bioavailability and efficacy39.
Potential drawbacks of Poloxamer gels include their weak mechanical strength, rapid erosion
(i.e. dissolution from the surface), and the nonbiodegradability of PEO-PPO-PEO, which
prevents the use of high molecular weight polymers that cannot be eliminated by renal
excretion.
Most natural polymer aqueous solutions form a gel phase when their temperature is lowered.
Classic examples of natural polymers exhibiting a sol–gel transition include gelatin and
carrageenan.
At elevated temperatures, these polymers adopt a random coil conformation in solution. Upon
cooling, a continuous network is formed by partial helix formation40.
5.3.1. Pseudolatexes
Some Prerequisites necessary for an optimal formulation of ophthalmic pseudo latex are
listed below:
The choice of this polymer was determined by the compatibility of the polymer with the
active compound, the ability of the CAP latex to be a free-running solution at pH 4.2 and a
gel at 7.2, and finally, the latex stability at relatively low pH which is a prerequisite to
ensuring the stability of pilocarpine.
5.3.3. Carbomer
Carbopol® 934 is a synthetic polymer composed of 62% of carboxyl groups with a high
molecular weight (approximately 3×106) formed by repeating units of acrylic acid, cross-
In this method, gelling of the solution instilled is triggered by change in the ionic strength44.
5.4.1. Gelrite
5.4.2. Alginates
Alginate with a high guluronic acid content will improve the gelling properties and reduce the
total polymer to be introduced into the eye. The alginate forms 3-dimensional ionotropic
hydrogel matrices, generally by the preferential interaction of calcium ions with the G
moieties resulting in the formation of inhomogeneous gel. Calcium-crosslinked alginate gels
have shown good mechanical properties even when prepared from relatively low solution
concentrations of the polymer, 0.5% w/v, and they can physically entrap a whole array of
molecules, and sustain their release.
In fact, an enhanced viscosity induces an increase in ocular contact time by reducing the
drainage rate and, as a consequence, improves the overall bioavailability of an instilled
solution47. below a certain viscosity, there is no real improvement of bioavailability, and
upon this limit there is no further increase of the residence contact time and blinking becomes
painful48.
Systemic absorption can be minimized by reducing the instilled volume50, controlling drug
release51, pro-drug derivatization52 and adding vasoconstrictive agents53. The occlusion of the
puncta54 by applying prolonged pressure or enhancing the formulation's viscosity can also be
an alternative.
Erodible systems have an inherent advantage over other systems in that the self-eroding
process of the hydrolysable polymer obviates the need for their removal or retrieval after the
drug is delivered. Upon the administration of particle suspension in the eyes, particles reside
at the delivery site and the drug is released from the polymer matrix through diffusion,
erosion, ion exchange, or combinations thereof58.
Nanoparticles, when formulated properly, provide controlled drug release and prolonged
therapeutic effect. To achieve these characteristics, particles must be retained in the cul-de-
sac after topical administration, and the entrapped drug must be released from the particles at
an appropriate rate. The utility of nanoparticles as an ocular drug delivery system may
depend on (a) optimizing lipophilic-hydrophilic properties of the polymer-drug system, (b)
optimizing rates of biodegradation in the precorneal pocket, and (c) increasing retention
efficiency in the precorneal pocket. It is highly desirable to formulate the particles with
In this process monomers are dissolved in the aqueous phase and within emulsifier micelles.
Additional monomers may be present as monomer droplets stabilized by emulsifier
molecules. Initiation of polymerization takes place in the aqueous phase when the dissolved
monomer molecules are hit by a starter molecule or by high-energy radiation62, 63.
Polymerization and chain growth is maintained by further monomer molecules, which
originate from the aqueous phase, the emulsifier micelles, or the monomer droplets. The
monomer droplets and the emulsifier micelles therefore act mainly as reservoirs for the
monomers or for the emulsifier, which later stabilize the polymer particles after phase
separation and prevent coagulation. Also, to prevent excessively rapid polymerization and
promote the formation of nanoparticles, emulsion polymerization is carried out at an acidic
pH (pH is 1–2)64. The drugs may be added before, during, or after polymerization and
formation of particles.
Gurny et al.69 were the first to use this process for the production of polylactic acid
nanoparticles containing testosterone. In this method, the polymer of interest is dissolved in
an organic solvent, suspended in a suitable water or oil medium, after which the solvent is
extracted from the droplets. The particles obtained after solvent evaporation are recovered by
filtration, centrifugation, or lyophilization. In general, the diameter of the particles depends
on the size of the microdroplets that are formed in the emulsion before evaporation of the
solvent. Chiang et al. used the solvent evaporation technique with an oil-in-oil emulsion to
prepare polylactide-co-glycolide microspheres of 5-fluorouracil for ocular delivery70.
Microspheres containing cyclosporin A have been prepared with a mixture of 50 : 50
polylactic and polyglycolic acid polymers using the solvent evaporation process. The
polymer and drug mixture was dissolved in a mixture of chloroform and acetone, emulsified
in an aqueous solution of polyvinyl alcohol, and stirred for 24 hours to evaporate the organic
solvent and yield the microparticle dispersion71.
De Campos et al. developed chitosan nanoparticles using the ionic gelation technique72.
Nanoparticles were obtained upon the addition of sodium tripolyphosphate aqueous solution
to an aqueous polymer solution of chitosan under magnetic stirring at room temperature. The
formation of nanoparticles was a result of the interaction between the negative groups of the
tripolyphosphate and the positively charged amino groups of chitosan. In this technique, drug
in an acetonitrile-water mixture can be incorporated either into chitosan solution or the
tripolyphosphate solution.
6.1.6. Nano-precipitation
Fessi et al. 73 developed nanoparticles using this method. In this technique a polymer and a
specified quantity of drug is dissolved in acetonitrile. The organic phase is then added
dropwise to the aqueous phase and stirred magnetically at room temperature until complete
evaporation of the organic phase takes place. Drug-free nanoparticles may be prepared using
the same procedure by simply omitting the drug.
A successful nanoparticulate system may be one that has a high loading capacity, thus
reducing the quantity of carrier required for administration. The drug can be either adsorbed
onto the surface of performed particles or incorporated into the nanospheres during the
polymerization process. Concerning the loading capacity of nanoparticles, it has been found
that both the nature and quantities of the monomer used influences the absorption capacity of
the carrier. Generally, the longer the chain length, the higher is the affinity of the drug to the
polymer.
7.1. Introduction
Iontophoresis is the use of a direct electrical current to drive topically applied ionized
substances into or through a tissue75. Iontophoresis is based on the physical principle that ions
with the same charge repel (electro-repulsion) and ions with opposite charge attract (electro-
osmosis).
Iontophoresis usually employs low voltage (10V or less) to supply a continuous direct current
of 0.5mA/cm2 or less. These basic operational guidelines have enabled iontophoresis to be
used to enhance drug delivery in a wide variety of conditions. Iontophoresis causes increased
transport of ionized substances into or through a tissue by application of an external electric
current.
When iontophoresis is used therapeutically, the ions of importance are charged molecules of
the drug or other bioactive substances. The ionized substances are driven into the tissues by
electro-repulsion at either the anode (if they carry a positive charge) or the cathode (if they
carry a negative charge) 76.
Iontophoretic devices vary in complexity, but the basic design is a unit with a power source
(either a battery or an on-line unit with a voltage regulator), a milliampere meter to measure
the current, a rheostat to control the amount of current flowing through the system, and two
electrodes. Platinum is the material of choice for the electrodes, since it releases almost no
ions, undergoes degradation at a slow rate, and is nontoxic.
A variety of iontophoretic
apparatuses exist for use in ocular
iontophoresis. They mainly
consist of either an eyecup or an
applicator probe. Figure shows a
diagram of ocular iontophoresis
of a positively charged drug in a
rabbit. The eyecup, with an
internal diameter of about 1 cm,
is placed over the cornea and
filled with the drug solution. A
metal electrode that is connected
to a direct current power supply is
submerged in the solution in the eyecup without making contact with the surface of the eye.
The ground electrode, connected to the other terminal of the power supply, is attached to the
ear of the rabbit via wet (0.9% NaCl) gauze to ensure a good connection. With the hand-held
applicator probe, the metal (platinum) electrode extends into the eyecup that is filled with the
drug solution. The eyecup is placed against the eye and is held in place throughout the entire
That delivers a high concentration of drug to the anterior segment of the eye such as cornea,
aqueous humour, ciliary body, and lens.
That can produce significantly high and sustained drug concentration in the vitreous humour
and retina.
VI. REFERENCES
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