Novel Ophthalmic Drug Delivery Approach: An Ophthalmic Inserts
Anjali Patel*, Dhara Patel, Nimisha Patel, Jayvadan Patel, Manish Patel, Anita Patel
Department of Pharmaceutics, Nootan Pharmacy College, Visnagar-384315,Gujarat, India,
*Corresponding Author E-mail: email@example.com
Ophthalmic drug delivery system is one of the most interesting and challenging approach facing the Pharmaceutical Scientist. The conventional ophthalmic drug delivery system like solution, suspension. Which shows poor bioavailability and therapeutic response because of rapid precorneal drug loss? Utilization of novel ophthalmic drug delivery system an ophthalmic inserts offers an advantage to prolonged drug residence time and a higher bioavailability with respect to conventional ophthalmic drug delivery system. Ocular inserts are sterile preparations, with a thin, multilayered, drug-impregnated, solid or semisolid consistency devices placed into cul-de-sac or conjunctiva sac. They are usually made up of polymeric vehicle containing drug. The therapeutic efficacy of an ocular drug can be greatly improved by prolonging its contact with the corneal surface. Newer ocular drug delivery systems are being explored to develop extended duration and controlled release strategy.
KEYWORDS: Ocular inserts, Swelling index, Solvent casting method, Bio-erosion, Semi synthetic polymer.
History of ocular inserts
The first solid medication (precursors of the present insoluble inserts) was used in the 19th century, which consisted of squares of dry filter paper, previously impregnated with dry solutions (e.g., atropine sulphate, pilocarpine hydrochloride). Small sections were cut and applied under eyelid. Later, lamellae, the precursors of the present soluble inserts, were developed.1
Ocular inserts are defined as preparations with a solid or semisolid consistency, whose size and shape are especially designed for ophthalmic application (i.e., rods or shields). These inserts are placed in the lower fornix and, less frequently, in the upper fornix or on the cornea. They are usually composed of a polymeric vehicle containing the drug and are mainly used for topical therapy.2 The figure 1 shows the schematic diagram of ocular inserts.
Ocular inserts offer several advantages 3, 4
· Increased ocular residence, hence a prolonged drug activity and a higher bioavailability with respect to standard vehicles;
· Possibility of releasing drugs at a slow, constant rate;
· Accurate dosing (contrary to eye drops that can be improperly instilled by the patient and are partially lost after administration, each insert can be made to contain a precise dose which is fully retained at the administration site);
· Reduction of systemic absorption (which occurs freely with eye drops via the naso-lacrimal duct and nasal mucosa);
· Better patient compliance, resulting from a reduced frequency of administration and a lower 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;
· Possibility of incorporating various novel chemical/technological approaches.
· Such as pro-drugs, mucoadhesives, permeation enhancers, microparticulates, salts acting as buffers, etc.
Disadvantages of ocular inserts:
The disadvantages of ocular inserts are as follows: 3, 4
a. A capital disadvantage of ocular inserts resides in their 'solidity', i.e., in the fact that they are felt by the (often oversensitive) patients as an extraneous body in the eye. This may constitute a formidable physical and psychological barrier to user acceptance and compliance.
b. 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,
c. The occasional inadvertent loss during sleep or while rubbing the eyes,
d. Their interference with vision, and
e. Difficult placement of the ocular inserts (and removal, for insoluble types).
Criteria for successful ocular insert 5 :
· Comfort and noninterference with vision
· Successful oxygen permeability
· Biocompatibility and stability
· Reproducibility of release kinetics
· Applicability to a variety of drugs
· Ease of sterility and nontoxicity
· Ease of handling ( insertion and removal)
· Ease of manufacture and low cost
Mechanism of drug release 6:
The mechanism of controlled drug release into the eye is as follows:
In the Diffusion mechanism, the drug is released continuously at a controlled rate through the membrane into the tear fluid. If the insert is formed of a solid non-erodible body with pores and dispersed drug. The release of drug can take place via diffusion through the pores. Controlled release can be further regulated by gradual dissolution of solid dispersed drug within this matrix as a result of inward diffusion of aqueous solution. In a soluble device, true dissolution occurs mainly through polymer swelling. In
swelling-controlled devices, the active agent is homogeneously dispersed in a glassy polymer. Since glassy \polymers are essentially drug-impermeable, no diffusion through the dry matrix occurs. When the insert is placed in the eye, water from the tear fluid begins to penetrate the matrix, then swelling and consequently polymer chain relaxation and drug diffusion take place. The dissolution of the matrix, which follows the swelling process, depends on polymer structure: linear amorphous polymers dissolve much faster than cross-linked or partially crystalline polymers. Release from these devices follows in general Fickian 'square root of time' kinetics; in some instances, however, known as case II transport, zero order kinetics has been observed.
In the Osmosis mechanism, 7 the insert comprises a transverse impermeable elastic membrane dividing the interior of the insert into a first compartment and a second compartment; the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is bounded by an impermeable material and the elastic membrane. There is a drug release aperture in the impermeable wall of the insert. The first compartment contains a solute which cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form. When the insert is placed in the aqueous environment of the eye, water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the second compartment so that the drug is forced through the drug release aperture.
In the bioerosion mechanism, the configuration of the body of the insert is constituted from a matrix of bioerodible material in which the drug is dispersed. Contact of the insert with tear fluid results in controlled sustained release of the drug by bioerosion of the matrix. The drug may be dispersed uniformly throughout the matrix but it is believed a more controlled release is obtained if the drug is superficially concentrated in the matrix. In truly erodible or E-type devices, the rate of drug release is controlled by a chemical or enzymatic hydrolytic reaction that leads to polymer solubilization, or degradation to smaller, water-soluble molecules. These polymers, as specified by Heller, 8 may undergo bulk or surface hydrolysis. Erodible inserts undergoing surface hydrolysis can display zero order release kinetics; provided that the devices maintain a constant surface geometry and that the drug is poorly water-soluble.
Figure 1: Schematic diagram of ocular inserts Advantages of ocular inserts
Classification of ocular inserts 9:
1) Insoluble ocular inserts
a) Diffusion based
b) Osmotic based
c) Soft contact lenses
2) Soluble ocular inserts
3) Bioerodible ocular inserts
The following figure 2 shows the classification of ocular inserts.
1. Insoluble ocular inserts
The insoluble inserts have been classified into three groups:-
a) Diffusion systems
b) Osmotic systems
c) Hydrophilic contact lenses.
The first two classes include a reservoir in contact with the inner surface of the rate controller and supplying drug thereto. The reservoir contains a liquid, a gel, a colloid, a semisolid, a solid matrix or a carrier-containing drug homogeneously or heterogeneously dispersed or dissolved therein.10 Carriers can be made of hydrophobic, hydrophilic, organic, inorganic, naturally occurring or synthetic material.
The third class including the contact lenses. The insoluble of these devices is their main disadvantages, since they have to be removed after use.
a) Diffusion inserts :
The diffusion systems are compared of a central reservoir of drug enclosed in specially designed semi permeable or micro porous membranes, which allow the drug to diffuse the reservoir at a precisely determined rate. The drug release from such a system is controlled by the lachrymal fluid permeating through the membrane until a sufficient internal pressure is reached to drive the drug out of the reservoir. The drug delivery rate is controlled by diffusion through the membrane, which one can be Controlled. 11 The components of the diffusional inserts are given in table 1.
Table1:Componentsof diffusional inserts
Glycerine, ethylene glycol, propylene glycol, water, methyl cellulose mixed with water, sodium alginate, poly (vinylpyrrolidone), polyox ethylene stearate.
Polycarbonates, polyvinyl chloride, polysulfones, cellulose esters, cross-linked poly (ethyl oxide), cross-linked polyvinylpyrrolidone, and cross-linked polyvinyl alcohol.
b) Osmotic inserts
The osmotic inserts are generally compared of a central part surrounded by a peripheral part. 12 The first central part can be composed of a single reservoir or of two distinct compartments.
In first case, it is composed of a drug with or without an additional osmotic solute dispersed through a polymeric matrix, so that the drug is surrounded by the polymer as discrete small deposits. In the second case, the drug and the osmotic solutes are placed in two separate compartments, the drug reservoir being surrounded by an elastic impermeable membrane and the osmotic solute reservoir by a semi permeable membrane. The second peripheral part of these osmotic inserts comprises in all cases a covering film made of an insoluble semi permeable polymer .The tear fluid diffuse into peripheral deposits through the semi permeable polymeric membrane wets them and induces their dissolution. The solubilized deposits generate a hydrostatic pressure against the polymer matrix causing its rupture under the form of apertures. Drug is then released through these apertures from the deposits near the surface of the device which is against the eye, by the sole hydrostatic pressure. This corresponds to the osmotic part characterized by zero order drug release profile. The table 2 shows the components of osmotic inserts.
c) Soft contact lenses:
These are shaped structure made up of a covalently cross-linked hydrophilic or hydrophobic polymer that forms a three-dimensional network or matrix capable of retaining water, aqueous solution or solid components . When a hydrophilic contact lens is soaked in a drug solution, it absorbs the drug, but does not give a delivery as precise as that provided by other non-soluble ophthalmic systems. The drug release from such a system is generally very rapid at the beginning and then declines exponentially with time. The release rate can be decreased by incorporating the drug homogeneously during the manufacture or by adding a hydrophobic component. Contact lenses have certainly good prospects as ophthalmic drug delivery systems.
Figure 2: Classification of ocular insert
Table 2: Components of osmotic inserts
Water permeable matrix
Ethylene- vinyl esters copolymers, Divers- plasticized polyvinyl chloride (PVC), polyethylene, cross-linked polyvinylpyorrolidone (PVP)
Cellulose acetate derivatives, Divers- Ethyl vinyl acetate (EVA), polyesters of acrylic and methacrylic acids (Eudragit).
Inorganic- magnesium sulfate, sodium chloride, potassium phosphate dibasic sodium carbonate and sodium sulfate.
Organic- calcium lactate, magnesium succinate and tartaric acid.
Carbohydrates- Sorbitol, mannitol, glucose and sucrose.
2. Soluble ocular inserts:
These soluble inserts offer the advantage of being entirely soluble so that they do not need to be removed from their site of application, thus limiting the intervention to insertion only.They can be broadly divided into two types, the first one being based on natural polymers and the other on synthetic or semi-synthetic polymers.
A. Natural polymer:
The first type of soluble inserts is based on natural polymer.13 Natural polymer used to produce soluble ophthalmic inserts is preferably collagen. The therapeutic agent is preferably absorbed by soaking the insert in a solution containing the drug, drying, and re-hydrating it before use on the eye. The amount of drug loaded will depend on the amount of binding agent present, the concentration of the drug solution into which the composite is soaked as well as the duration of the soaking. As the collagen dissolves, the drug is gradually released from the interstics between the collagen molecules.
B. Synthetic and semi-synthetic polymer;
The second type of soluble insert is usually based on semi-synthetic polymers (e.g., cellulose derivatives) or on synthetic polymers such as polyvinyl alcohol. A decrease of release rate can be obtained by using Eudragit, a polymer normally used for enteric coating, as a coating agent of the insert. Saettone et al. 14 have observed in rabbits that Eudragit coated inserts containing pilocarpine induced a miotic effect of a longer duration, compared to the corresponding uncoated ones. However, the inherent problems encountered with these soluble inserts are the rapid penetration of the lachrymal fluid into the device, the blurred vision caused by the solubilization of insert components and the risk of expulsion due to the initial dry and glassy consistency of the device. Ethyl cellulose, a hydrophobic polymer, can be used to decrease the deformation of the insert and thus to prevent blurred vision. The soluble inserts offer the additional advantage of being of a generally simple design, of being based on products well adapted for ophthalmic use and easily processed by conventional methods. The main advantage is decreased release rate, but still controlled by diffusion. The table 3 shows the components of soluble inserts containing synthetic polymer.
Table 3: Components of soluble inserts containing synthetic polymers
Soluble synthetic polymers
Cellulose derivatives- Hydroxypropylmethylcellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
Divers- Polyvinyl alcohol, ethylene vinyl acetate copolymer.
Plastisizer- Polyethylene glycol, glycerin, propylene glycol.
Enteric coated polymer- Cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate.
Complexing agent- Polyvinyl pyrrolidone.
Bioadhesives- Polyacrylic acids.
3. Bioerodible ocular inserts 15:
This type of device is fabricated from bio- erodible or bio- degradable polymer of hydrogel or non hydro gel type. The mechanism of drug release in this system is dependent on rate of erosion or rate of degradation. Several erodible type of ocuserts have been prepared using polymer like carboxymethyl cellulose, poly vinyl alcohol, collagen etc. Containing drug like pilocarpine, gentamicin etc in the form of disc and wafers. Some of the products are also marketed recently as,
Ű Soluble ocular drug insert, (SODI)
Ű Ocular therapeutic system or (minidisk)
Ű Corneal collagen shield
· It is sterile rod shaped device made of hydroxypropyl cellulose without any preservative. i.e. used for the treatment of dry eye syndrome.
· It weighs 5 mg and measures 1.27 mm in diameter with a length of 3.5 mm.
· It is inserted into the inferior fornix where it imbibes water from conjunctiva and forms a hydrophilic film which stabilizes the tear film and hydrates and lubricates the cornea.
· Day long relief from dry eye syndrome has been reported from a single insert placed in the eye early in the morning.
Replacement of 4 times an hr regimen by once or twice daily regimen is the benefit achieved by this dosage forms.
Soluble ocular drug insert (SODI) :
· The insert is small oval wafer.
· It is in the form of sterile thin film of oval shaped Weighing 15-16 mg .
· After introduction into the inferior cul-de-sac where wetted by tear film, it soften in 10-15 seconds and assumes the curved configuration of globe.
· During the following 10-15 min. the film is turn into viscous polymer mass, thereafter in 30-60 min it becomes a polymer solution.
Single SODI application has been reported to replace 4-12 drops instillation or 3-6 applications of ointment before treatment of glaucoma and trachoma.
Ocular therapeutic system (minidisk) :
· Consist of countered disc with a convex front and concave back surface in contact with eyeball.
· It is like a miniature contact lenses with a diameter of 4-5mm.
· The major component of it is silicone based prepolymer.
· The OTS can be hydrophilic or hydrophobic to permit extended release of both water soluble and insoluble drugs.
Corneal collagen shield:
Prepared by molding collagen mixed with the drug into a contact lens configuration is dehydrated and sterilized by gamma radiation and packed. Drugs like antibiotics, steroids have been reported (Bloomfield, 1978).
The biodegradable inserts are composed of homogeneous dispersion of a drug included or not into a hydrophobic coating which is substantially impermeable to the drug. They are made of the so-called biodegradable polymers. Successful biodegradable materials for ophthalmic use are the poly (orthoesters) and poly (orthocarbonates). The release of the drug from such a system is the consequence of the contact of the device with the tear fluid inducing a superficial diversion of the matrix.
Method of preparation of ocular inserts 16;
1. Solvent casting method:
In this method using different ratios of drug and polymer a no. of batches are prepared. The polymer is dissolved in distilled water. A plasticizer is added to this solution under stirring conditions. The weighed amount of drug was added to above solution and stirred to get a uniform dispersion. After proper mixing the casting solution was poured in clean glass petridish and covered with an inverted funnel to allow slow and uniform evaporation at room temperature for 48 h. The dried films thus obtained were cut by cork borer into circular pieces of definite size containing drug. The ocular inserts were then stored in an airtight container (desiccator) under ambient condition .
2. Glass substrate technique:
Drug reservoir film: 1% w/w polymer for example chitosan was soaked in 1%v/v Acetic acid solution for 24hrs, to get a clear solution of chitosan in acetic acid solution. The solution was filtered through a muslin cloth to remove undissolved portion of the polymer (chitin). Required quantity of drug-β CD complex was added and vortexed for 15minutes to dissolve the complex in chitosan solution. 1%w/v propylene glycol (plasticizer) was added to it and mixed well with stirrer. The viscous solution was kept aside for 30 minutes for complete expulsion of air bubbles. The rate controlling films were prepared. The films were casted by pouring solution into the center of leveled glass mould and allowing it to dry at room temperature for 24hrs. After drying, films were cut into ocuserts of desired size so that each contains equal quantity of the drug. Then, the matrix was sandwiched between the rate controlling membranes using non-toxic, nonirritating, water insoluble gum. They were wrapped in aluminium foil separately and stored in a desiccator.
3. Melt extrusion technique:
Drug for example acyclovir and the polymer were sieved through 60#, weighed and blended geometrically. The plasticizer was added and blended. The blend was then charged to the barrel of Melt Flow Rate apparatus and extruded. The extrudate was cut into appropriate size and packed in polyethylene lined aluminium foil, heat sealed and sterilized by gamma radiation (2.5 Mrad for 4 h) .
Evaluation of ocular inserts 5, 15, 17, 18:
1. Thickness of ocular inserts
2. Weight variation test
3. Surface pH determination
4. Drug content uniformity
5. Swelling index
6. Folding endurance
7. Tensile Strength
9. In vitro drug release
10. In vivo drug release
11. Accelerated Stability study
12. Ocular irritation test
1. Thickness of ocular inserts:
Thickness of the inserts is measured using dead weight thickness gauge. After initial settings, the foot is lifted with the help of the lifting lever fixed on the side of the dial gauge. Insert is placed on the anvil such that the area where the thickness is to be measured lies below the foot. Readings of the dial gauge are recorded after gentle lowering of foot.
2. Weight variation test:
Inserts from each batch are randomly selected and weighed individually on electronic balance. Mean weight of inserts of each formulation is recorded.
3. Surface pH determination:
Inserts are left to swell for 5 h on agar plate prepared by dissolving 2% (w/v) agar in warm simulated tear fluid (STF; sodium chloride: 0.670 g, sodium bicarbonate: 0.200 g, calcium chloride. 2H 2 O: 0.008 g, and purified water q. s. 100 g) of pH 7.4 under stirring and then pouring the solution into Petri dish till gelling at room temperature. After the time of soaking, the pH of the wet surface is measured by placing the electrode in contact with the surface of the insert.
4. Drug content uniformity:
Uniformity of the drug content is determined by assaying the individual inserts. Each insert is grounded in a glass pestle mortar and STF is added to make a suspension. The suspension so obtained is filtered and the filtrate is assayed spectrophotometrically.
5. Swelling index:
Swelling of the polymer depends on the concentration of the polymer, ionic strength, and the presence of water. To determine the swelling index of prepared ocular inserts (n = 3), initial weight of insert is taken, and then placed in agar gel plate (2% w/v agar in STF, pH 7.4) and incubated at 37șC ± 1șC. For 5 h, insert is removed from plate after every 1 h, surface water is removed with help of filter paper, and insert is reweighed.
% swelling index = [wt − wo/wo] Χ 100
Where, wt = weight of swollen insert after time t,
wo= original weight of insert at zero time
6. Folding endurance:
Folding Endurance of the film was determined by repeatedly folding the inserts at the same place till it breaks. The ocuserts was folded in the center, between finger and thumb and then opened. This was one folding. The number of times, the film could be folded at the same place without breaking gave the value of folding endurance.
7. Tensile strength:
Ocular insert with good tensile strength would resist tearing due to stress generated by the blinking of eye. The insert was cut into strips. The apparatus consist of a base plate with pulley aligned on it. One aluminium clip was fixed on one end of the base plate to which the insert was clipped. The other end of the insert was clipped to movable aluminium clip. A thread was tied to movable clip and passed over the pulley to which the small pan was attached to hold weights. The weights were gradually added to the pan till the insert was broken. The weight necessary to break the insert was noted as break force.
Apparatus consist of a wooden stand of 11cm height and top area of 16 x16cm.A small pan was fixed horizontally on one end of the 2mm thick iron rod whose other end is reduced to sharp point. A hole of 0.2cm diameter was made at the centre of the top area of wooden stand for supporting the pan rod. An electric circuit was made through battery in such a way that the bulb lights up only when circuit is completed through the contact of the metal plate and sharp end of the rod. The insert was placed between metal plate and short end of rod. The weights were gradually added to the pan at an interval of 10 seconds and for the stabilization of force till the bulb was glown. The final weight was considered as measure of hardness.
9. In vitro drug release:
In-vitro release studies are carried out using a bi-chamber donor-receiver compartment model design made by using a transparent and regenerated cellulose type of semi-permeable membrane. It is tied at one end of an open cylinder, which acts as the donor compartment. The ocular insert is placed inside the donor compartment. The semi permeable membrane is used to create ocular in vivo conditions, like a corneal epithelial barrier, which simulates the tear volume; 0.7 m1 of distilled water is placed in a donar compartment and maintained at the same level throughout the study. The surface of the membrane is in contact with the reservoir compartment containing 25 ml of phosphate buffer having a pH of 7.4. It is stirred continuously using a magnetic stirrer. Samples of 1 ml are withdrawn from the receptor compartment at periodic intervals and replaced with an equal volume of distilled water. The withdrawn sample is analyzed at 246 nm against the reference standard using a pH 7.4 phosphate buffer as a blank on a UV / visible spectrophotometer.
10. In vivo drug release:
The inserts are sterilized by using UV radiation before in-vivo study. Inserts are taken in a Petri dish along with 100 mg of pure drug, which are spread to a thin layer. This Petri dish along with polyethylene bags and forceps are place in UV sterilization chamber (hood). The inserts and other materials are exposing to UV radiation for one hour. After sterilization, inserts are transferee into polyethylene bag with the help of forceps inside the sterilization chamber itself. The pure drugs which are sterilized along with inserts are analyzing for potency by UV spectrophotometer after suitable dilution with pH 7.4 phosphate buffer. The male albino rabbits, weigh between 2.5-3.0 kg are require for the experiment. The animals are house on individual cages and customized to laboratory conditions for 1 day. Receive free access to food and water.
The ocular inserts containing drug are taken for in-vivo study which are previously sterilize on the day of the experiment and are place into the lower conjunctivas cul-de-sac. The inserts are inserting into 7 eyes at same time and each one eye of seven rabbits is serving as control. Ocular inserts are removing carefully at 2, 4, 6, 8, 10, 12 and 24 hours and analyze for drug content as dilution mention in drug content uniformity. The drug remaining is subtracted from the initial drug content of inserts which will give the amount of drug release in the rabbit eye. Observation for any fall out of the inserts is also recording throughout the experiment. After one week of wash period the experiment is repeating for two times as before.
11. Accelerated stability study:
The accelerated stability studies are carries out to predict the breakdown that may occur over prolong periods of storage at normal shelf condition. The films of the formulation are taken in a separate Petri dish and are keep at three different temperatures 400C, 500C and 600C and the period for break down or degradation of the ocular inserts is check. When ocular inserts show degradation the time in days is note and subject to determine the drug content of each individual film using the drug content uniformity procedure.
12. Ocular irritation test:
The potential ocular irritation and/or damaging effects of the ocusert under test were evaluated by observing them for any redness, inflammation (or) increased tear production. Formulation was tested on five rabbits by placing the inserts in the cul-de-sac of the left eye. Both eyes of the rabbits under test were examined for any signs of irritation before treatment and were observed up to 12 h.
The main efforts in ocular drug drug delivery during the past two decades has been on the design of systems to increase the residence time of topically applied drugs in conjuctival sac. Various new approaches like ocular inserts, collagen shield, in-situ activated gel formation, non-corneal route of ocular drug penetration, and nanoparticle-based polymeric solutions and gels are being developed by the pharmaceutical scientists. The advantages gained by ocular inserts are many for the treatment of eye-related problems, but only few gain commercial acceptance.
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Received on 12.04.2012 Modified on 20.05.2012
Accepted on 24.05.2012 © RJPT All right reserved