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OPHTHALMIC DRUG DELIVERY SYSTEMS: A REVIEW


Ayush Garg*, Nisha Sharma, Alka Agarwal and Indrajeet Singhvi

Pacific College of Pharmacy, Udaipur, Rajasthan, India


ABSTRACT

Products to be instilled into the eye, while not parenteral by definition, have many similar and often identical characteristics. The formulation of stable, therapeutically active ophthalmic preparations requires high purity of ingredients as well as freedom from chemical, physical (particles), and microbial contaminants. These preparations usually require buffers to stabilize the pH of the product, additives to render it isotonic or nearly so, and stabilizers such as antioxidants for the particular ingredients. Those ophthalmics used in larger quantities, such as eye irrigants, or in the case of devices such as contact lenses, are usually relatively uncomplicated solutions similar to large volume parenteral. One characteristic critical for ophthalmics is their freedom from pyrogens since pyrogens are not absorbed systemically from the eye: however, insofar as pyrogens are indicative of a microbiologically clean process, they should not be present.

Keywords: Ophthalmic, Eye drops, Eye emulsion, Contact lenses, Ocuserts

INTRODUCTION

Eye is a unique and very valuable organ .This is considered a window hinge. There are many eye diseases that can affect the body and loss of vision as well. They are classified as a traditional and new drug development system. The bioavailability of ophthalmic drug is, however poor due to efficient protective mechanisms of the eye. Blinking baseline and reflex lachrymation, and drainage remove rapidly foreign substances, including drugs from the substances of the eye. There are many eye aliments which affected to eye and one can loss the eye sight also.

These are classified as conventional and non – conventional (newer) drug delivery system. These preparations when instilled into the ocular cavity due to tear flow and lachrymal nasal drainage. Only a small amount is available for its therapeutic effect resulting in frequent dosing. So overcome to these formulation such as in – situ gel, nanoparticle, liposomes, nanosuspensions, microemulsion, intophoresis and ocular inserts have been developed in last three decades increase the bioavailability of the drug as a sustained and controlled manner1.

Advantages of ocular drug delivery system

  1. Increased accurate dosing to overcome the side effects of pulsed dosing produced by conventional systems.
  2. To provide sustained and controlled drug delivery.
  3. To increase the ocular bioavailability of drug by increasing the corneal contact time. This can be achieved by effective adherence to corneal surface.
  4. To provide targeting within the ocular globe so as to prevent the loss to other ocular tissues.
  5. To provide comfort, better compliance to the patient and to improve therapeutic performance of drug.
  6. To provide better housing of delivery system.

Limitations of ophthalmic drug delivery system

  1. Dosage form cannot be terminated during emergency.
  2. Interference with vision.
  3. Difficulty in placement and removal.
  4. Occasional loss during sleep or while rubbing eyes.

Anatomy and physiology of the eye: –

The eye is a spherical structure with a wall consisting of three layers; the outer sclera, the middle choroid layer, cilliary body and iris and the inner nervous tissue layer retina (figure 1). The sclera is tough fibrous coating that protects the inner layers. It is white except for the transparent area at the front, the cornea which allow light to enter the eye. The choroid layer, situated inside the sclera, contains many blood vessels and is modified at the front of the eye as pigmented iris. The iris is the colored part of the eye (in shades of blue, green, brown, hazel, or grey).

Figure 1:- The structure of eye.

The cornea is a strong clear transparent bulge located at the front of the eye that conveys images to the black of the eyes. The front surface of the adult cornea has a radius of approximately 8mm that covers about one – sixth of the total surface of the eye ball. It is a vascular tissue to which nutrient and oxygen are supplied via bathing with lachrymal fluid and aqueous humor as well as from blood vessels those lines the junction between the cornea and sclera (in figure 1). The cornea is the main path permeation of drug into the eye. It is composed of five layers: epithelium, Bowman’s layer, stroma, Descemet’s membrane and endothelium. The epithelium consists of 5-6 layers of cells. The corneal thickness is 0.5-0.7 mm and it is thicker in the central region. Lipophilic drug prefer the transcellular route and hydrophilic drug penetrates primarily through the paracellular pathway which involves passive or altered diffusion through intercellular spaces.  Lipophilic drug prefer the transcellular route and hydrophilic drug penetrates primarily through the paracellular pathway which involves passive or altered diffusion through intercellular spaces.

For most topically applied drugs, passive diffusion along their concentration gradient, either transcellulary or paracellularly, is the main permeation mechanism across the cornea7.

Figure 2:- Schematic diagram of naso-lachrymation drainage system

Figure 3:- Schematic illustration of the ocular disposition of topically applied formulations

Figure 3:- Schematic presentation of the ocular structure with the routes of drug kinetics illustrated

  1. It consist of three parts; the secretory system, the distributive system and the excretory system. The secretory portion is composed of the lachrymal gland that secreted tears are spread over the ocular surface by the eyelids during blinking.
  2. The execratory parts consist of the Nasolachrymal drainage system consist of the lachrymal puncta, the superior, inferior and common canaliculi; the lachrymal sac and the naso-lachrymal papilla (figure 2).

It is thought that tears are largely absorbed by the mucous membrane that lines duct and the lachrymal sac; only a small amount reaches the nasal passage (figure 3 & 4).

CLASSIFICATION OF OPHTHALMIC DRUG DELIVERY SYSTEM

  1. Conventional drug delivery system-

  1. Non conventional or newer or novel ophthalmic drug delivery system-

 

Conventional ophthalmic drug delivery system

Eye drops –

Eye drops are sterile aqueous or oily solutions or suspensions of drugs that are instilled into the eye with a dropper (figure 3). They are used both for diagnostic and therapeutic purposes and contain drugs which are act on the anterior segment of the eye:  cornea, conjunctiva and anterior uvea. They also contain drugs used in the treatment of glaucoma, local anaesthetics, miotic and mydriatics.

The eye lashes help to prevent small dust particles to enter into the eye. The blink reflex is initiated when objects are perceived to be travelling towards the eye.

Essential characteristics of eye drops-

  1. They should be sterile.
  2. They should be iso – osmotic with lachrymal secretions.
  3. They should be free from foreign particles.
  4. They should have neutral ph.
  5. They should be preserved with a suitable bactericide.
  6. They should remain stable during its storage.

 

Figure 3: Eye Drops Formulation of eye drops

The eye drops are prepared in following stages.  These stages are as under:

Preparation of bactericidal and fungicidal vehicle:  The aqueous or oily vehicle is used in the preparation of eye-drops. The aqueous vehicle may support bacterial or fungal growth, so one of the following bactericide may be used to preserve the eye-drops:-

  • Phenyl mercuric nitrate/acetate 002%
  • Benzalkonium chloride 01%
  • Chlorhexidine acetate 01%
  • Chlorobutanol 5%
  • Thiomersal  1%

Preparation of solution of medicament(s) and adjuvants: The Medicament(s) are dissolved in the aqueous vehicle containing suitable Antimicrobial agent. The adjuvants are also dissolved in the vehicle at this stage to form a stable preparation.

Clarification: The eye-drops are clarified by passing the solution through Membrane filter having pore size of 0.8 µm. The clarified solution is immediately transferred into  final containers and sealed to exclude microorganism.

Sterilization:  The eye-drops are sterilized by autoclaving or heating with bactericide at    98-1000 C for 30 minutes or filtration through bacteria proof filter.

Containers: The eye-drops should be packed in neutral glass containers or in a suitable plastic container. The bottle must conform to limit test for alkalinity of glass. It has two polypropylene screw caps one for attaching a silicon rubber teat to the container and the other for covering the teat.

Labeling: Eye-drops should be labeled ‘For External Use Only’ along with storage conditions to maintain full activity.

Adjuvants used in the preparation of eye-drops:

The following adjuvants are used in the preparation of eye drops:-

  1. Thickening agent: The thickening agents, such as, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyethylene glycols are used to increase the viscosity of eye-drops. It will also help to prolong the contact time of the drug in the eye.
  1. Buffers: Buffers are added to adjust and maintain the pH of the eye-drops. The pH of the eye drop is adjusted to maintain chemical stability to reduce discomfort and to improve clinical response. The buffers used in eye drop formulations are: borate buffer (boric acid/borax), phosphate buffer (sodium acid phosphate/ sodium phosphate) and citrate buffer (citric acid/ sodium citrate).
  1. Wetting agents: these are used for proper penetration of eye-drops into the cornea of the eye. Polysorbate 20 and polysorbate 80 are used as wetting agent
  1. Isotonicity adjustment substances: Eye-drops are made isotonic with the lachrymal secretion with the help of various buffers and other solutions.

Example: Prepare and dispense 100 ml of atropine eye-drops B.P.C.

Rx

Atropine sulphate                                 1.0 gm

Phenyl mercuric nitrate                        50.0 ml

Solution (0.002%)

Purified water, add up to                      100 ml

Direction                                       To be used as directed.

 

  • Eye lotions –

These are the sterile aqueous solutions used for washing of the eyes (figure 4). The eye lotions 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 sterilised fabric dressing and a large volume of solution is allowed to flow quickly over the eye.

Eye lotions should be isotonic and free from foreign particles to avoid Irritation to the eye. The drugs used for preparing eye solutions include sodium chloride, sodium bicarbonate, boric acid, borax or zinc sulphate.

Figure 4:- Eye lotions

Formulation of eye-lotions: –

Eye lotions are simple solution. They are iso-osmotic with tears because they cause much greater dilution of the lachrymal fluid and hence, are more likely to cause discomfort if not adjusted. The eye lotions should be sterile because the large volume is used to remove the irritant from the eye. The eye lotions are sterilized by autoclaving or by passing through bacteria proof filters

Example: Prepare and dispense 100 ml of sodium chloride eye solution B.P.C

Rx

Sodium chloride                                  0.9 g

Purified water to produce                   100 ml

 

Storage:

Eye lotions are supplied in amber colored screw fluted bottles. The containers must be labeled clearly “FOR EXTERNAL USE ONLY” and avoid contamination during use add discard any unused part after 24 hrs.

  • Eye ointments

It is a sterile preparation 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 (figure 5).

Formulation of eye ointments: –

The ointment base selected for an eye ointment must be non-irritating to the eye. The eye ointment base should melt near to the body temperature, so as to permit the diffusion of the drug through the lachrymal secretions of the eye.

Yellow soft paraffin                           80 g

Liquid paraffin                                    10 g

Wool fat                                              10 g

 

Figure 5:- Eye ointments

Containers-

Eye ointments must be supplied in collapsible tubes which may be made of metal or suitable plastic. The capacity of the collapsible tube should not exceed 5 g, fitted with a nozzle of suitable shape to facilitate application of the eye ointment without contamination.

Labeling

In addition to the general labeling requirements, the label on the container or on the sealed outer package enclosing an eye ointment should indicate that the contents are sterile provided that the container has not been opened.

Storage-

Eye ointment should be stored in a cool place.

 

  • Eye suspension –

Eye suspensions (figure 6) 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.

Essential characteristics of eye suspensions –

  1. They should be sterile.
  2. They should have desired viscosity.
  3. They should be isotonic.
  4. They should be packed in a suitable container, so that it can be easily instilled into the

Figure 6:- Eye suspensions  

  • Contact lens solution –  Contact lenses are usually made from polymethyl methacrylate which is a hard hydrophobic plastic (figure 7).

Figure 7:- Contact lens

 

Hard contact lensesHard contact lenses generally use of two solutions:-

  1. 1. Wetting solutions –

It is used primarily for treating the lenses before insertion. Due to its hydrophobic nature, polymethyl methacrylate is poorly wetted by the lachrymal fluid of the eye. The contact lens solution is required to be used daily for years together.

 

The formulation of contact lens solution may contain: –

 

  • Wetting agent: polyvinyl alcohols and polysorbate 80 (0.5%) are commonly used wetting agents.
  • Antimicrobial agents: Benzalkonium chloride (0.004%) Chlorhexidine acetate (0.005% – 0.006%) and Chlorobutanol (0.3% – 0.4%).
  • Isotonicity adjuster:g. sodium chloride.
  • Buffering agent:g. boric acid / borax.
  • Thickening agent: polyvinyl alcohols or cellulose derivative are commonly used as thickening agent.

 

  1. Storage solutions –

It is used for overnight cleansing, soaking and storage. The contact lenses after its removal from the eye are cleaned with wetting solution and rinsed with purified water. Then they are stored in a storage solution to prevent dehydration.

Soft contact lenses – These are soft flexible type lenses. Certain medicaments from the eye drops and preservative from wetting and storage solutions are strongly absorbed by the soft contact lenses. For cleaning, soft contact lenses are heated in 0.9% sodium chloride solutions. The wetting and storage solution used for hard contact lenses should not be used.

Containers –

Contact lens solution is packed in containers designed to minimize the chances of accidental microbial containers of the products. Many multi dose preparations are stored in plastic container with inbuilt droppers which prevent the return of used or excess solutions to the containers. [6]

Novel drug delivery system –

Requirements of controlled ocular delivery system –

  • To overcome the side effects of pulsed dosing produced by conventional system.
  • To provide sustained and controlled drug delivery system
  • To increase the ocular bioavailability of drug by increasing corneal contact time
  • To provide the better housing of the delivery system in the eye so as the loss to other tissues besides cornea is prevented.

Artificial tear insert

A rod shaped pellet of hydroxyl propyl cellulose without preservative is commercially available (figure 8). This device is designed as a sustained release artificial tear for the treatment of dry eye disorders. It was developed by Merck, sharp and Dohme in 1981.

Figure 8:- Artificial tear insert.    

Flourescein filter paper strip –

Sodium flourescein and rose Bengal dyes are commercially available as drug          impregnated filter paper strips. These dyes are used diagnostically to disclose corneal          injuries and infections such as herpes simplex and dry eye disorders (figure 9).

Figure 9:- Flourescein filter paper strip 

Microemulsion –

Due to their intrinsic properties and specific structures, micro-emulsions are a promising   dosage form for the natural defense of the eye. Indeed, because they are prepared by nexpensive processes through auto emulsification or supply of energy and can be easily sterilized, they are stable and have a high capacity of dissolving the drugs (figure 10).

The in vivo results and preliminary studies on healthy volunteers have shown a delayed effect and an increase in the bioavailability of the drug.

Figure 10:- Micro-emulsions 

Ocular inserts –

These are solid dosage form and can overcome the disadvantage reported with traditional ophthalmic systems like aqueous solutions, suspensions and ointments. The ocular inserts maintain an effective drug concentration in the target tissues.

A number of ocular inserts were prepared utilizing different techniques to make soluble, erodible, non-erodible and hydrogel inserts (figure 11).

 Figure 11:- Ocular inserts

Collagen shield –

Collagen shields (figure 12) are designed to be inserted in a physician’s office: they often produce some discomfort and interference with vision. Shields are not individually fit for each patient, as are soft contact lenses and therefore, comfort may be problematic and expulsion of the shield may occur 8.

Figure 12:- Collagen Shield 

TESTING OF OCULAR DRUG DELIVERY SYSTEM 

Sterility testing:-

After sterilization, the test for sterility is the most reliable method for determining whether or not the particular lot of material is sterile.

Principle –

The test is based on the principle that if bacteria or fungi are placed in a medium which provides nutritive material and water, and kept at a favourable temperature, the organism will grow and their presence can be indicated by turbidity in the clear medium.

Steps involved in sterility testing:-

  • Selection of the sample size.
  • Selection of the quantity of product to be used.
  • Method of testing.
  • Observation and results.  

Selection of the sample size

Sample must be representative of the whole of the bulk material and lot of final containers. Though mixing is required, while taking the sample from the bulk material, the random sampling is taken from the final containers.

Selection of the quantity of product to be used

Selection of the quantity of product to be used for sterility testing depends mainly on the volume or weight in the container. The minimum sample to be used in each culture medium in the test for sterility.

Methods of testing –

Test for sterility may be carried out by –

  1. Membrane filtration method :-

The method is preferred in following cases –

  • Oily or oily preparations.
  • An ointment that can be put into solutions.
  • A non bacteriostatic solid not readily soluble in culture medium.
  • A soluble powder or a liquid that possesses bacteriostatic and fungi static
  • Liquid products where the volume in a container is 100 ml or more.

 

  1. Direct inoculation method : –In this method the specified quantity of sample under test is drawn aseptically from the container and transferred into a vessel of culture medium. Mix the liquid with the medium and incubate for not less than 14 days. Observe the growth of microorganism in the medium.

Observation and results – The culture medium is examined during and at end of incubation to find out if there is any microbial growth.

The following observations are possible: –

  • No evidence of growth; hence the preparation being examined passes the test for sterility.
  • There is evidence of growth. If no evidence of microbial growth is then found, the preparation being examined passes the test for sterility.
  • There is evidence of microbial growth. So, isolate and identify the organism. In case there is evidence of growth of any microorganisms in the second re – test, the preparation being examined fails the tests for sterility.
  • Particulate matter monitoring:-

All the parenteral products must be sterile, free from pyrogen and particulate matter. Particulate matter is defined as unwanted mobile insoluble matter other than gas bubbles present in the given product. The limit test for particulate matter is prescribed in I.P.1996. injectable solution in containers that are labeled as containing 100 ml or more of a single dose large volume injection intended for administration by intravenous infusion comply with limits of particulate matter, as shown in table 1.[6]  

Table 1:- Permitted limits of particulate matter as prescribed in I.P. 

Particle size in um                                                                           Maximum number of

(equal to or large than)                                                                     particles per ml

10                                                                                                         50

25                                                                                                          5

50                                                                                                         Nil

Conclusion

Drug delivery to targeted ocular tissues has been a major challenge to ocular scientist for decades. Administration of drug solutions as topical drop with conventional formulations was associated with certain drawbacks which initiated the introduction of different carrier system for ocular delivery. Tremendous efforts are being put into ocular research toward the development of safe and patient compliant novel drug delivery strategies. Currently researches are thriving hard to improve in vivo performance of conventional for mutations. Drugs molecules are being encapsulated into nanosized carrier systems or devices and are being delivered by invasive/ non invasive or minimally invasive mode of drug administration.

However, there is still need of developing a carrier system which could reach      targeted ocular tissue, including back of the eye tissues, post non – invasive mode of drug administration. With the current pace of ocular research and effort being made and put in, it is expected to result in a topical drop formulation that retains high pre-corneal residence time, avoids non specific drug tissues accumulation and deliver therapeutic drug levels into targeted ocular tissue ( both anterior and posterior).

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