OCULAR DRUG DELIVERY (OCUSERT)

K. A. Noufal Ahamad, Vimal Mathew

National College of Pharmacy, Manassery, Calicut

Cite this: K. A. Noufal Ahamad, Vimal Mathew, "OCULAR DRUG DELIVERY (OCUSERT)", B. Pharm Projects and Review Articles, Vol. 1, pp. 992-1023, 2006. (http://farmacists.blogspot.in/)

 

INTRODUCTION

OPHTHALMIC PREPARATION

Ophthalmic preparations are the sterile product, meant for the instillation in to the eye in the space between the eyelid and the eyeball. These products must be isotonic with lachrymal secretion to avoid discomforts and irritations. The pH should be controlled up to 7.4 to avoid irritations. Vehicles in the preparation must have good wetting ability to penetrate cornea and other tissues. Ophthalmic products include: -

• Solution
• Suspension
• Ointment

Solution

These are the sterile aqueous solutions used for washing of eyes. The eye solutions are supplied in concentrated form and are required to be diluted with warm water immediately before use. They are usually applied with a clean eye- bath or sterilized fabric dressing and a large volume of solution is allowed to flow quickly over the eye

E.g.: - Sodium chloride eye lotion B.P.C

- Sodium bicarbonate eye lotion

Suspension

Eye suspensions are not commonly used, as compared to eye drops. They are prepared only in those cases, when the drug is insoluble in the desired vehicle or unstable in liquid form they are also used to produce the sustained action of the preparation. The particle size of the suspension should be fine to avoid irritation. The preparation shaken thoroughly before use in order to distribute the drug particles uniformly

E.g.: - Pilocarpien suspension

- Nitroglycerin suspension

Ointment

Eye ointments are sterile preparations meant for application to the eye. These are prepared under aseptic conditions and packed in sterile collapsible tubes, which keep the preparation sterile until whole of it is consumed. The ointments have longer contact time with eye and produce sustained action. It has greater storage stability. The application of ointment producing film over the eye and blurring vision may occur.

E.g.: - Atropine eye ointment B.P

- Chloramphenicol eye ointment

CONTROLLED DELIVERY SYSTEM

Controlled delivery system is the one, which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. Targeted drug delivery system is the one, which delivers the drug only to its site of action and not to the non-target organs or tissues. These agents are formulated to produce maximum stability activity and bioavailability.

In eye drugs are released and dissolved in lachrymal secretions. The rate of drug release is controlled by its permeation through a membrane wall. The active agents are homogeneously through out a rate controlling polymer matrix and the rate of drug release is controlled by diffusion through the polymer matrix

Theoretically, Fick's law of diffusion governs controlled release of drugs. It depends molecular weight of drugs, aqueous solubility of drugs, partitions coefficient of drugs, drugs stability drug pKa and ionization.

Controlled delivery system has an important advantages is drug with not serious side effect.

RELEVANT ANATOMY AND PHYSIOLOGY OF THE EYE

HUMAN EYE

The accessory structures of the eye are the eyelids, eyelashes, eyebrows, the lachrymal apparatus and extrinsic eye muscles. The diameter of eye is 23mm.

Eye lid

The upper and lover eyelids, shade the eyes during sleep, protect the eyes from excessive light and foreign objects and spread lubricating secretion over the eyeballs. Each eyelid consists of epidermis subcutaneous tissue, fibers of orbicularis oculi muscle, a tarsal plate, tarsal glands and conjunctiva.

Eye lashes and eye brows:

The eyelashes, which project from the border of each eyelid. The eyebrows, which arch transversely above the upper eyelid, help protect the eyeballs from foreign objects, perspiration and the direct rays of the sun.

The lachrymal apparatus:

The lachrymal apparatus is group of stutters that produces and drains lachrymal fluid. The tears pass medially over the anterior of the eyeball to enter two small opining called lachrymal puncta.

Extrinsic eye muscles:

Six extrinsic eye muscles move each eye:

• Superior rectus

• Inferior rectus
  • Lateral rectus
  • Medial rectus
  • Superior oblique
  • Inferior oblique

Fig. 1. Cross-sectional view of the eye

ANATOMY OF EYEBALL

The adult eyeball measures about 23mm in diameter. Of its surface area, only the anterior one-six is exposed; the remainder is recessed and protected by the orbit, into which it fits. Anatomically, the walls of the eyeball consists of three layers:

• Fibrous tunic
• Vascular tunic
• Retina

Fibrous
tunic:

It is the superficial coat of the eyeball, is vascular and consists of anterior cornea and posterior sclera.

Vascular tunic:

The vascular tunic or uvea is the middle layer of the eye ball and has three parts:

• Choroids
• Ciliary body
• Iris

• Choroids, which is the posterior portion of the vascular tunic. It provides nutrients to the posterior surface of the retina.
• In the anterior portion of the vascular tunic, the choroids become ciliary body.
• The iris, the colored portion of the eyeball, is shaped like a flattened donut. It is suspended between the cornea and the lance and is attached at its outer margin to the ciliary prose's
  
  
  
  
  Retina
  
  
  
  The third and inner coat of the eyeball, the retina, lines the posterior three-quarters of the eyeball and is the beginning of the visual pathway. The surface of the retina is the only place in the body where blood vessels can be viewed directly.
  
  
  
  
  .
  Fig 2. Structural detail of the retina.
  
  
  
  

  Lance:

  
  

  Behind the pupil and iris, within the cavity of the eyeball, it's the lance. It is enclosed by a clear connective tissue capsule and held in position by encircling zonular fibers, which attach to the celery processes. The lance helps focus images on the retina to facilitate clear vision.

  
  

  Cornea:

  
  
  The cornea is a transparent coat that covers the colored iris. Its outer surface consists of nonkeratinized-stratified squamous epithelium. The middle coat of the cornea consist of collagen fibers and fibroblasts, and the inner surface is simple squamous epithelium
  
  
  
  
  Fig. 3. Corneal cross-section
  
  
  
  

  INTERIOR OF THE EYEBALL
  

  
  

  The lance divides the interior of the eyeball in to two cavities: -

  • Anterior cavities

  • Posterior cavities
    

  
  
  The chambers of the anterior cavities are killed with aqueous humor. The humor continually filters out of the bred capillaries in the ciliary process. It then flows forward between the iris and the lens, through the pupil, and into the anterior chamber. From the anterior chamber, aqueous humor drains into the scleral venous sinus and then into the blood. Normally, aqueous humor is completely about every 90minuts.
  
  
  The pressure in the eye, called intraocular pressure, is produced mainly by the aqueous humor by the vitreous body; normally it is about 16mmHg. The interaocular pressure maintains the shape of the eyeball and prevents the eyeball from collapsing.
  
  
  The second, and larger, cavity of the eyeball is the vitreous chamber, which lies between the lens and the retina. Within the vitreous chamber is the vitreous body, a jelly like substance that contributes to intraocular pressure. It holds the retina flush against the choroids, so that the retina provides an even surface for the reception of clear images. Unlike the aqueous humor, the vitreous body does not undergo constant replacement. It is formed during embryonic life and is not replaced thereatter. The vitreous body also contains phagocytic cells that remove debris, keeping this part of the eye clear for unobstructed vision.
  
  

  DISTRIBUTION AND DISPOSITION OF DRUGS

  
  
  Physiological barriers to diffusion and productive absorption of topically applied drug exit in precorneal and corneal space. The precorneal constraints responsible for poor ocular bioavailability of conventional ophthalmic dosage forms are solution drainage, lacrimation, tear dilution, tear turnover and conjunctival absorption. Drug solution drainage away from the precorneal area has been shown to be most significant factor in reducing the contact time of the drug with the cornea and consequently ocular bioavailability of topical dosage forms. The instilled dose leaves the precorneal area within 2 minutes of instillation in humans. The drainage allows the drug to be absorbed across the nasal mucosa into the systemic circulation. The conjunctiva also possesses a relatively large surface area, 5times the surface of cornea making the loss significant. Both the conjuctival and nasal mucosa have been indicated as the main potential sites for systemic absorption of topically applied drugs.
  
  
  
  
  
  
  
  
  Drug particle size
  
  
  
  
  PH Tonicity
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  Fig 4. Distributon Disposition of Drug
  
  
  
  
  Metabolism in the precorneal area has been shown to account for the further loss of the drugs. The low fraction of the applied dose further undergoes rapid elimination from the intraocular tissues and loss through the canal of Schlemn or via absorption through the ciliary body or suprachoroid into episcleral space. Binding of drugs to protein also contributes to the loss of drugs through the precorneal parallel elimination loss pathway. The tears contain both free and bound drug, which is rapidly drained from the front of the eye.
  
  
  Due to potential drug loss from the front of the apparent absorption rate constant is due to both corneal absorption and precorneal loss. Drug absorption rate constants are in the range of contrast to the preconeal loss constant, which is usually 1-2 order higher. Actually corneal permeability to drugs is quit low and thus the reason for the early maximum level of the drug has to do with the enormous loss of drug from the front of the eye. The epithelium is composed of five to six layers where as the endothelium is one cell thick. The stroma represents about 90% of thickness of the cornea. It contains 76-80% of water while the remainders consist of collagen fibrils. Drugs gain access into the eye by simple passive diffusion. The epithelium is the predominant rate limiting barrier for hydrophilic drugs whereas the stroma is rate limiting for most of the lipophilic drugs. Recent studies suggest that the noncorneal route of absorption involving penetration across the sclera and conjuctiva may be significant for drug molecules with poor corneal permeability.
  
  
  The existing ocular drug delivery systems are thus fairly primitive and inefficient. However, the design of ocular systems is undergoing gradual transition from an empirical to rational basis. Interest in the broad areas of ocular drug delivery has increased in recent years due to an increased understanding of a number of ocular physiological process and pathological condition. The focus of this review is the approaches made towards optimization of ocular delivery systems. Attempts have been towards:
  
  
  1- Improving ocular contact time
  2- enhancing corneal permeability
  3-enhancing site specificity
  
  
  TOPICAL DOSAGE FORMS
  
  
  Solution
  
  
  They are sterile aqueous preparations instilled in to the eye with a dropper and free from foreign particles. They usually contain drugs having antiseptic, anaesthetic, anti-inflammatory, mydriatic or meiotic properties
  
  

  Suspension
  

  
  
  They are prepared only in those cases, when the drug is insoluble in the desired vehicle or unstable in liquid form. They are also used to produce the sustained action of the preparation. Commonly used for the treatment of inflammatory disease.
  
  
  Ointment:
  
  
  
  Eye ointments are sterile preparations. These are prepared under aseptic conditions and packed in sterile collapsible tubes which keep the preparation sterile until whole of it is consumed
  
  
  
  TOPICALLY INSTILLED DRUG
  
  
  The insert unit is designed to provide for the release of medication at predetermine and predictable rates permitting the elimination of frequent dosing by the patient, ensuring night time medication and providing a better meaning of passion complaints. The insert is flexible and is multi layered stretchers consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug defuses at constant rate. The rate of drug diffusion is controlled by the polymer composition, the membrane thickness and the solubility of the drug. They are sterile and do not contain preservatives. They are act as tear dilution and washout.
  
  
  PRESERVATIVES
  
  
  A suitable preservative is needed to preserve drug against bacterial growth. Preservatives selected should be affective against a wide range of microorganism.
  -
  E.g.: Benzalkonium chloride
  Thimerosal , Chlorobutanol
  
  
  
  

  REQUIREMENTS OF CONTROLLED OCULAR DELIVERY SYSTEM

  
  
  • To overcome the side effect of pulsed dosing produced by conventional system
  • To provide sustained and controlled drug delivery
  • To increase the ocular bioavailablity of drug by increasing corneal contact time
  • To provide targeting with in the ocular globe so as to prevent the loss of other ocular diseases
  • To provide comfort and complaints to the patient and yet improve therapeutic performance of the drug over conventional systems
  • To provide the better housing of the delivery system in the eye so as the loss to other tissues besides cornea is prevented
  
  
  
  
  
  
  Two major approaches are being undertaken to improve topical delivery of drugs, which are,
  
  
  • Approaches to prolong the contact time of drug with corneal surface
  • Approaches to enhance corneal permeability either by mild or transient structural alterations of corneal epithelium or by modification of chemical structure of the drug molecules
  
  

  FORMULATIONS

  
  
  The recent formulation trends that are currently being explored include Polymeric solutions, phase transition system, mucoadhesive/biodhesive dosage forms, collagen shields, peudolatices, ocular penetration enhancers, ocular Iontophoresin and various ocular
  
  
  1-Polymeric Solution: -
  
  
  The addition of polymers like methylcellulose, polyvinyl alcohol, hydroxypropyle cellulose and polyvinyl pyrrolidone to the eye drop solution increases the corneal penetrations of drug. This is presumably due to on increases tear viscosity, which decreases the other wise rapid initial drainage rate, increases the corneal contact time and thus sustains to some extant the initial tear concentration of the drug.
  
  
  2-Phase Transition Systems: -
  
  
  These are liquid dosage forms which shift to the gel or solid phase when instilled in the cul-de-sac. Polymers that are normally used are Lutrol FC-127and poloxamer 407 whose viscosity increases when its temperature raised to 37° C. cellulose acetate phthalate too coagulates when its native pH of 4.5 is raised by tear fluid to pH 7.4. Gelrite a new phase transition systems are evaluated by Mazuel and frieteyre, 1987 a low acetyl gum which gels clearly in the presence of sodium ions in tears. The concentration of sodium ion in tears, 2.6 g/L, was particularly suited to cause gelation of the material when topically instilled into the conjunctival sac. These polymers are serve as good sustained release material for ophthalmic use but the surface active properties and low pH of CAP, however limits their use. It has excellent ocular tolerence, low toxicity per os and it can be formulated as isotonic neutral solution, all this making it a safe excipient for the ocular route. It presents the practical advantage over other polymers of withstanding sterilization by autoclaving.
  
  
  
  
  3-Mucoadhesive/Bioadhesive Dosage Forms: -
  
  
  Any polymer solution/suspension placed in the eye first encounters mucin at the cornea and conjunctival surface. Bioadhesive/Mucoadhesive systems can be either polymeric solution or microparticle suspensions.They are retained in the cul-de-sac through adhesive bonds established with the mucins or the epithelium thus increasing the corneal contact time. However water-soluble polymers face the disadvantage of having a short half-life. Muchoadhesive polymers are usually macromolecular hydrocolloids with numerous hydrophilic functional groups. These groups are, carboxyl, hydroxyl, amide and sulphate. They establish electrostatic and hydrophobic interactions and hydrogen bonding with the underlying surface. A good bioadhesive should exhibit a near zero contact angle to allow maximalcontact with the mucin coat. The structural factors like chain flexibility and molecular weight also influence the bioadhesion. To diffuse and penetrate into mucin layer, flexibility in chain of polymer is required. The entanglement with mucin coat increases the adhesive strength of polymer. Generally, an increase in molecular weight to a critical value, increases the bioadhesiveness. pH and ionic strength of dosage forms also affect the bioadhesion performance
  
  
  4-Collagen Shields: -.
  
  
  Collagen corneal bandages in the shape of a contact lens an alternative to soft contact lenses. For drug delivery, the shields are rehydrated in a water solution of the drug, whereby the drug is absorbed by the protein matrix and is released once the shield dissolves in the eye. Water-soluble drug is incorporated at the time of manufacture. The simplicity of use and the convenience afforded by shields make them an attractive delivery device.Crosslinking of collagen corneal shield affects ofloxacin bjoavailability. As the dissolution times for the cross linked collagen shield are longer than those of the non-cross-linked type, they serve as drug reservoirs. Therefore, cross-linked collagen shields might be useful ocular drug delivery devices because they can allow drug concentrations to achieve higher levels in the cornea and aqueous humor. Some drawbacks of these devices are: application of shield requires to anaesthetize the cornea and they often produce some discomfort and interfere with vision.
  
  
  
  
  
  
  5-Pseudolatices: -
  
  
  Organic solution of polymer is dispersed in an aqueous phase to form a o/w type emulsion subsequently using appropiate means, i.e. by applying vacuum, or by using controlled temperature. Water is removed partially to an extent that residual water is sufficient enough to keep polymeric phase discrete and dispersed. Such dispersions are referred to a pseudolatices which on application leave an intact non invasive continuous polymer film which reserves drug. The drug from such systems is released slowly over a prolonged period if time ensuring better ocular availability and patient compliance by avoiding frequent instillation of preparation.
  
  
  6-Ocular Penetration Enhancers: -
  
  
  Penetration enhancers like actin filament inhibitors, surfactants, bile salts, chelators and organic compounds have been used to increase the bioavailability of topically applied peptides and proteins which ate otherwise poorly absorbed due to unfavorable molecular size, charge, hydrophilic as well as their susceptibility to degradation by peptidases in the eye.
  
  
  7-Ocular Iontophoresis: -
  
  
  Iontophoresis is the process in which the direct current derives ions into cell or tissues. Antibiotics, antifungals, Anesthetic agents and adrenergic agents have been tried by this method
  
  
  
  
  EXAMPLES OF OCULAR DRUG DELIVERY SYSTEMS
  
  

  Ocusert by Alza

  
  
  
  Pilocarpine, a parasympathomimetic agent for glaucoma
  
  Act on target organs in the iris, ciliary body and trabecular meshwork
  Copolymer
  :
  Ethylene-vinylacetate
  Carrier for pilocarpine : alginic acid in the core of Ocusert
  White annular border : EVA membrane with titanium dioxide (pigment) (easy for patient to visualize)
  
  

  Lacrisert by Merck:

  
  
  Patients with dry eyes (keratitis sicca)
  A substitute for artificial tears
  Placed in the conjunctival sac and softens within 1 h and completely dissolves within 14 to 18 h
  Stabilize and thicken the precorneal tear film and prolong the tear film break-up time
  
  
  
  
  
  

  Ophthalmic gel for pilocarpine:

  
  
  Poloxamer 407 (low viscosity, optical clearity, mucomimetic property)
  
  
  Ophthalmic prodrug:
  
  
  Dipivalylepinephrine (Dipivefrin)
  Lipophilic :- increase in corneal absorption
  Esterase within cornea and aqueous humor
  
  
  
  
  Fig 5. Ocusert ocular therapeutic systems are thin, flexible wafers placed under the eyelid to provide a week's dosage of pilocarpine in the treatment of glaucoma. Ocuset system cause less blurring of vision than pilocarpine eye drops, which must be used 4 times daily
  
  
  
  
  
  
  
  
  Fig 6. Schematic diagram of the Occusert
  
  
  
  
  Continuous delivery system based upon the osmotic property:
  
  
  Thin flat layer, contoured three-dimensional unit
  Conform to the supratarsal space of the upper cul-de-sac
  Delivery of diethylcarbamazine in ocular onchocerciasis
  
  
  Topically applied peptides
  
  
  These preparations are entered via the blood vessels in the congunctival mucosa. Prolonged the action by increasing the viscosity of the preparation. These formulations prevent the peptidase-mediated degradation of peptide in the corneal epithelium.
  Eg: [D-ala2] met - enkephalinamide
  
  
  
  
  
  

  CONCLUSION AND FUTURE OUTLOOK

  
  
  
  
  Advantages of the ocular routes of administration
  
  
  • Rapid absorption
  • Ease of administration
  • Good local tolerance
  
  
  Ocular indication of controlled-release systems
  
  
  Short, topical ocular half-life
  e.g., heparin for ligneous disease
  Small, topical ocular, therapeutic index
  e.g., pilocarpine for chronic open-angle glaucoma , possibly nucleside, antiviral
  Systemic side effects
  e.g., timolol for glaucoma and cyclosporin A for graft rejection
  
  
  Need for combination therapy
  e.g., cromoglycate and corticosteroid for asthma and allergies
  The need for a predetermined profile of drug delivery over a prolonged period of days, weeks, or months
  e.g., acute corneal infections, acute-becoming chronic inflammation, and corneal graft rejection episodes
  Long-continued low dosage for therapy or prophylaxis
  e.g., for prevention of corneal graft rejection, prevention of recrudescence of inflammation, and prevention of, or recurrence of, herpetic disease.
  
  
  
  
  The technologies described here represent small fraction of the development of drug delivery systems and few of them are still at experiment level. The need for research into drug delivery systems extends beyond ways to administer new pharmaceutical therapies. The safety and efficacy of current systems can be improved if their delivery rate, biodegradation, and site-specific targeting can be predicted, monitored, and controlled. Which the help of rapid advances in biotechnology, chemistry, and chemical engineering, it will be possible for researchers to obtain drug delivery systems with minimum side effects and maximum effectiveness.
  
  
  
  
  REFERENCES
  
  

1. Ocular drug delivery SA. Menqi and S. G. Deshpande
2. A Literature seminar on control drug delivery system Dipali Chaudhari, University of Alabama
3. Chien. Y. W edited, Novel drug delivery system, second edition, Marcel Dekker, New York
4. Charsden, M. and R. Langer editors, Biodegradable Polymers as drug delivery system, Marcel Dekker, New York
5. Domb and A. J edited polymeric Sife – specific pharmacotherapy, John Wiley and sons, , New York
6. Pharmaceutics 2 R.M Metha Published by Vallabh Prakashan
7. www.pharmaarticles@gmail.com
8. www.appspharmscitech@vnict.com
9. www.boas.org
10. www.drugdel.com

www.devicelink.com

Cite this: K. A. Noufal Ahamad, Vimal Mathew, "OCULAR DRUG DELIVERY (OCUSERT)", B. Pharm Projects and Review Articles, Vol. 1, pp. 992-1023, 2006. (http://farmacists.blogspot.in/)