EYE DROPS

Definition: Aqueous or oily solutions or suspensions for instilling into the conjuctival sac.

Eye drops are used as

ü  Anaesthetics,

ü  Anti-inflammatory agents

ü  Antiseptics

ü  Diagnostic agents

ü  Miotics

ü  Mydriatics

ü  Artificial tears

Consideration of certain factors in the formulation of eye drops

Sterility:

Eye is well protected by the tough epithelium of the cornea (the transparent disc in front of the eye ball) and by the tears.

The tears contain lysozyme, an antibacterial enzyme

Tears wash the contaminants in to nasal cavity via the lachrymal duct

Accidental or surgical damage to the cornea provides an invasion route which has low resistance to microbial attack and therefore, may become badly ulcerated.

Eye infections are caused by:

Staphylococcus aureus

Proteus vulgaris

Bacillus subtilis

Fungi (Asperigillus fumigatus)

Certain Adenoviruses

The most dangerous organism is Pseudomonas aeruginosa

Pseudomonas aeruginosa can grow and multiply in simple salt solutions, poorly stored distilled and water

Pseudomonas aeruginosa produces severe corneal ulceration and blindness.

Hence, eye drops must comply sterility tests.

Foreign particles:

Foreign particles cause discomfort, may abrade the corneal epithelium facilitating invasion of pathogenic microorganisms.

Microporous plastic membrane filter (pore size 0.8µm) is used to separate foreign particles.

Medicaments in suspensions, 90% of the particles does not exceed 5 µm and no particle is more than 50 µm.

Pain and irritation:

Solutions of unfavourable osmotic pressure pH certain medicaments and preservatives cause pain and irritation.

The lachrymal fluid is iso-osmotic with blood plasma and with 0.9% NaCl solution. 

Eye drops if iso-osmotic with tears, do not cause any discomfort, but more attention is given to pH and selection of medicament and preservative.

Eye drops with NaCl concentrations ranging from 0.5 to 2.0% are well tolerated.

Tears (pH 7.4) have buffering capacity due to the presence of carbonic acid, weak organic acids and protein. Hence, pH of unbuffered (3.5 to 10.5) solutions are neutralized.

Normal volume of eye drops instilled is 1 -2 drops (0.05 to 0.1ml).

Considerable discomfort may be caused by

Very acid drugs like adrenaline acid tartrate and pilocarpine hydrochloride and highly buffered solutions (particularly acid pH).

Local anesthetic, amethocaine also causes discomfort.

Viscosity

Thickening agents are added to eye drops to prolong the contact with the eye and for easy administration.0.5 to 1.0% solutions of Methyl cellulose 4500 and Hypromellose 4500 and polyvinyl alcohol (1.4%) and providone are used as are used as thickening agents.

Eye drop thickeners should be

Easy to filter: products with PVA are easy to filter

Easy to sterilize cellulose derivatives precipitate on heating. PVA does not present this problem.

Compatible with other ingredients:

Cellulose derivatives are incompatible with certain antimicrobial preservatives like chlorocresol, phenol, resorcinol, tannic acid and acridines

Methyl cellulose is compatible with phenyl mercuric nitrate 0.002%.

Methyl cellulose and hypromellose are compatible with Benzalkonium Chloride 0.02%.

Thickening agents are not included in drops or lotions for use during or after surgery because of adverse effects on the interior of the eye.

Antimicrobial activity

Eye drop preservative must be:

• Rapidly effective against a wide range of bacteria (including Pseudomonas aeruginosa) and fungi.
• A preservative should be capable of sterilizing the solution within one hour of adding a large inoculum of a test organism.
• Stable during sterilization and storage.
• Compatible with medicaments, stabilizers and thickeners.

Phenyl mercuric nitrate or Acetate 0.002%w/v

v  Effective against wide range of bacteria and fungi.

v  Slow action against Pseudomonas aeruginosa

Disadvantages:

Incompatibility with Halides:

Precipitation with may occur with hydrobromides of hyoscine and homatropine but no precipitation with amethocaine hydrochloride.

Strong absorption by rubber

Rubber teats of rubber closures may absorb preservatives.

Mercurialentis

These preservatives may deposit mercury in eye, on using for long periods in the treatment of glaucoma with pilocarpine hydrochloride and physostigmine sulphate.

Benzalkonium chloride

Rapidly active against bacteria.

Chelating agents (EDTA) removes calcium and magnesium ions from cell membrane of Pseudomonas aeruginosa and increase the permeability of Benzalkonium chloride.

Incompatible with:

v  Anionic medicaments such as soluble sulphonamides and fluorescien.

v  Nitrates and salicylates.

v  High concentrations of non-ionic compounds (more than 5% of methyl cellulose and hypromellose).

Less effective below pH 5

Chlorhexidine acetate 0.01%w/v

Most effective against gram positive bacteria.

Inactive against spores.

Susceptibility against Proteus and Pseudomonas species increases in the presence of EDTA.

Anti microbial efficiency reduces in the presence of organic matter.

Hydroxyl benzoates 0.02%

Chlorocresol 0.05%w/v: Efficiency increases in acid solutions.

Chlorbutol 0.5%w/v

Stable in solutions of pH less than 6.

Unstable in alkaline solutions.

Thiomersal 0.01%w/v

It may be used instead of phenyl mercuric nitrate or acetatein Sulphacetamide Eye-Drops.

Chemical stabilization

pH adjustment: The pH of the eye drops is adjusted for three reasons

To reduce discomfort: strongly buffered solutions resist the buffering action of tears (a phosphate buffer of pH 5 is painful), hence the buffering capacity of eyedrops must be low.

To maintain chemical stability

The majority of eyedrop medicaments are salts of strong acids and weak organic bases, hence thy are more stable at a pH of 3 to 5.

a)      atropine sulphate

at pH 5, at 120⁰C:  60hrs- for loss of 50% activity.

At pH 6.8, 120⁰C:  1hr for loss of 50% activity.

b)      1% amethocaine hydrochloride

At pH 5.6, in autoclaving for 30 minutes at 115⁰C:loss of 3% activity.

At pH 4,  in autoclaving for 30 minutes at 115⁰C:loss of 1% activity

To improve clinical response

A controlled pH should provide a balance between therapeutic activity, chemical stability and comfort. Acidic solutions are more stable but cause discomfort. Neutral or slightly alkaline solutions do not cause any discomfort, but instable.

Boric acid vehicle: boric acid 1.9%; Phenyl mercuric nitrate or Acetate 0.001%w/v; pH 4.7. It provides a balance between therapeutic activity, chemical stability and comfort.

Special boric acid vehicle: Boric acid vehicle containing 0.1% sodium sulphite.

Isotonic phosphate vehicle: various ratios of Na₂HPO₄ : NaH₂PO_{4 :} NaCl

Preparation of eye drops

1. Preparation of bactericidal or fungicidal vehicle
2. Solution of medicament and adjunct
3. Clarification
4. sterilization

Preparation of bactericidal or fungicidal vehicle

Phenyl mercuric nitrate or Acetate are incompatible with aluminum and strongly absorbed by rubber

Solutions of Phenyl mercuric salts lose potency in polythene containers

Phenyl mercuric nitrate tend to deposit mercury on storage.

Chlorhexidine acetate slightly degrades in autoclaving and is inactivated by cork.

Benzalkonium chloride is absorbed by PVC.

All these solutions require protection from light.

Dissolution of medicaments and adjuncts

Chloramphenicol eye drops: the antibiotic is more soluble in borax boric acid vehicle (pH 7)

Heating assists the dissolution of preservative. But the solution must be cooled before dissolving antibiotic.

Clarification:

Microporous plastic membrane filter (0.8micrometers: Millipore AA grade)

Sterilization:

Heating in an autoclave

Maintaining at 98 – 100⁰C for 30 minutes in the presence of a bactericide for the drugs like ch;loramphenicol, cocaine hydrochloride, neomycin sulphate and physostigmine sulphate in an electrically heated anodized aluminum water bath.

Filtration: filters should retain Pseudomonas aeruginosa (1.5 x 5µ)

Millipore GS type: 0.22µ ± 0.02 µ; HA type: 0.45 µ ± 0.02 µ

Filter diameters: 13mm (suitable for few 10ml portions), 25mm (suitable for 100-1000ml), 90mm (few liters). A pressure difference of 1.3 to 1.7 bars preferred.