DEFINITIONS: Ophthalmic preparation or eye preparation: they are sterile liquid, semi-solids, or solid preparations that, may contain one or more active pharmaceutical; ingredients that are Applied to eye.
EYE DROPS: They are sterile water and oily solutions, emulsions or suspensions of one or more active ingredients meant for instillation into eyes with suitable dropper.
Ophthalmic Ointments: They are sterile, greasy, semi-solid preparations that are applied to the conjunctiva or the eyelids.
EYE LOTION: They are sterile aqueous solutions applied to an eye bath for washing of the eyes.
INTRODUCTION: Ophthalmic preparations or eye preparations are sterile liquid, semisolid or solid preparation that may contain one or more active pharmaceutical ingredients that are applied to eye. The ophthalmic preparations are instilled in between eye lids and eye balls.
TYPES OF OPHTHALMIC PREPARATIONS
Ophthalmic preparations are available in different forms such as;
Ophthalmic or eye solution
FORMULATION OF OPHTHALMIC DOSAGE FORM
All Ophthalmic preparation must be sterile and free from foreign particles, fibers and filaments.
The raw materials, in-process intermediates and drug substance are the potential sources of contamination.
Most ophthalmic products are sterilised by septic filtration through a 0.22 micro meter filter.
Ophthalmic products should be iso-tonic with lachrymal secretions to avoid discomfort and irritation.
When the tonicity of ophthalmic solution is equal to 0.9% w/v of sodium chloride solution, then it will be isotonic.
The eye can tolerate a range of tonicity from 0.5-2% Nacl.
There are various isotonic vehicles which are used to prepare ophthalmic products like 1.9% w/v boric acid, sodium acid phosphate buffer.
To prolong the contact time of the drug in the eye, various thicking agents are added in the ophthalmic preparations.
Some examples of thicking agents are polyvinyl alcohol (1-4%), polyethylene glycol, methyl cellulose, carboxy methyl cellulose.
These agents enhance the viscosity of the preparation.An ideal thicking agent should be easy to filter, easy to sterilise, compatible with other ingredients.
Thicking agents are avoided in the formulation of eye drops and lotions that are used during or after surgery due to some potential adverse effects on the inside of the eye.
Tears have a pH of about 7.4.
The pH has has major role in therapeutic activity, solubility, stability, and comfort to the patient.
The eye can tolerate solution with wide range of pH but they should not be strongly buffered.
For example: alkaloid salt solutions are stable at pH 2-3 but this pH is irritant to eye.
The vehicles used in ophthalmic preparations must have good wetting ability.
This property increases penetration into cornea and other tissues.
Hence some surfactants or wetting agents are added in ophthalmic products.
Examples of wetting agents are Benzalkonium chloride, polysorbate 20, polysorbate 80, dioctyl sodium sulpho succinate etc.
The surfactant should not cause any damage to the tissue of eye.
Eye drops are sterile water and oily solutions, emulations, or suspensions of one or more active ingredients meant for instillation into eye with suitable dropper.
Ophthalmic drops should be sterile.
They should be free from particles when examined under suitable conditions of visibility.
Water for injections should be used in the manufacture of aqueous ophthalmic drops.
They should have neutral pH.
COMPONENTS USED IN FORMULATION OF EYE DROPS
- Active ingredients
- Thickening agents
- Tonicity modifier
They are incorporated in eye drops to produce pharmacological effect.
BUFFERS: The control of pH of Ocular formulations are important determinants which influence the stability of the therapeutic agents, the ocular acceptability of the formulation and the absorption of the drug through the cornea. Ideally the pH of the ocular solution should be controlled at 7.4 pH. The pH of the formulation should be the one that optimizes the chemical stability of the therapeutic agent. Example boric acid, sodium acid phosphate, sodium citrate.
PRESERVATIVES: Ocular formulations are sterile but they should contain preservatives to avoid microbial contamination. Example: benzalkonium chloride and benzethonium chloride, Mixtures of methyl and propyl esters of parahydroxybenzoic acid (typically at a a combined concentration of 0.2% w/v), chlorobutanol, and phenylethylalcohol.
ANTIOXIDANTS: They are included in some ophthalmic preparation, primarily those containing epinephrine, and other oxidizable drugs. Example: sodium bisulphite or met bisulphite are used in concentration up to 0.3%.
THICKENING AGENTS: They are added to increase the viscosity of eye drops so that contact time of drugs in the eye can be prolonged. Examples: methyl cellulose, carboxy methyl cellulose, polyvinyl alcohol and polyethylene glycol.
Tonicity modifier: The tonicity of eye drops should be isotonic with lachrymal secretion. Common tonicity adjusting ingredients are Nacl, KCl, buffer salt, dextrose, glycerine, propylene glycol and mannitol.
Vehicles: In ophthalmic preparation generally purified water USP are used as a solvent which may be obtained by reverse osmosis, deionization and distillation process. Mineral oil, vegetable oil such as sesame oil, castor oil, are also used in extemporaneous compounding.
Surfactant: Example: Benzthonium chloride, polysorbate-20 .etc.
Example: physostigmine eye drops
|1||Physostigmine Sulphate||0.5 grams|
|2||Sodium Metabisuphite||0.2 grams|
|3||Benzalkonium Chloride||0.02 ml|
|4||Purified water||Up to 100 ml|
PREPARATION OF EYE DROPS
The steps involved in the preparation of eye drops involves the following:
- Preparation of the solution.
- Clarification and Filling.
(1) Preparation of the solution: The various adjuvants (preservative, antioxidants, stabiliser, tonicity modifier, viscosity modifier or buffer) are dissolved in vehicle.
Then the active ingredients is added and then vehicle is added to make the volume.
(2) Clarification and Filling: Sintered glass filters or membrane filters of 0.45-1.2 micron pore size are used for this purpose. The clarified solution is either filled directly into the final containers which are sealed prior to heat sterilisation or filled into a suitable container prior to filtration sterilisation.
(3) Sterilization: Ophthalmic preparations are sterilised by;
- Autoclave at 115 Degree Celsius for 30 minutes or 121 Degree Celsius for 15 minutes.
- Heating at 98-100 Degree Celsius for 30 minutes together with either benzalkonium chloride 0.01% w/v or thiomersal 0.01% w/v.
- Filtration through a membrane filter having a 0.22 micron pore size into sterile containers using strict aseptic technique. Filling should betake place under Grade A laminar airflow conditions. The filter assembly is sterilized by autoclaving before use.
- Dry heat sterilization at 160 Degree Celsius for 2 hours is employed for non-aqueous preparations such as liquid paraffin eye drops. Silicon rubber tests must be used
The following information should be mentioned on the label clearly.
Name and concentration of medicament.
Name and concentration of antimicrobial agents.
Date after which the p[products is not intended to be used.
Discard the contents at a specified time after opening (about one month).
If only discomfort or irritation discontinue use of eye drop.
For External use only.
Ophthalmic drops are supplied in multi dose container that allow successive drops of the preparations to be administered.
The container should be fitted with a tamper-evident device. Dropper supplied separately should also comply with the Test for sterility.
Traditionally Glass bottles with rubbers teat dropper were used but now a days plastic bottles (LDPE) are widely used.
Ophthalmic drops may also be provided in suitable single dose container that will maintain the sterility of the contents.
The single dose container consists of a disposable, pliable, tube like applicator made from polypropylene by ultrasonic sealing.
IT has a nozzle protected by a cap.
IT is generally enclosed in a heat sealed envelope.
Ophthalmic preparation are sterile, greasy, semi-solid preparation that are applied to the conjunctiva or the eye lids.
The drugs enter the eyes through the cornea by simple diffusion.
They are formulated from non-aqueous bases, e.g soft paraffin, liquid paraffin, and wool fat.
They are suitable for use at bed time.
The ointment base should be non-irritant to the eye.
Ophthalmic ointment should be homogeneous.
Eye ointment offer the advantage of longer contact time and greater total drug bio-availability.
But its disadvantage is it interferes with vision and their use is usually limited to bedtime instillation.
Formulation of Eye Ointment
|1||Atropine Sulphate||0.1 grams|
|2||Wool Fat||1 grams|
|3||Liquid Paraffin||1 ml|
|4||Yellow Soft Paraffin||Up to 8 grams|
Yellow paraffin preferred over white paraffin because white paraffin is prepared by bleaching with oxidising agents and acids.
Some of the bleaching agent may remain sticking to the base even after careful washing, which when used in the eyes may lead to irritation.
Wool fat is used to ensure specific emulsification of the solution and help in absorption of active ingredients.
Liquid paraffin is used to reduce viscosity of base which helps to expel the content from tube easily.
These ingredients produce a transparent, lubricating and moistening film on the surface of the eyeball.
METHOD OF PREPARATION
Preparation of the base: melt wool fat, yellow soft paraffin on a water bath and then add liquid paraffin.
Filter through coarse filter paper (e.g. Whatman 54) placed in a heated funnel.
It is sterilised at 160 Degree Celsius for 2 hours.
Add medicament’s with eye ointment base and then pack in the sterile container.
There are two methods of incorporating the medicaments.
The whole procedure should be under aseptic conditions.
CASE 1: If medicament is water soluble then it is dissolved in minimum volume of purified water.
The solution is then sterilised by autoclaving or filtration and gradually incorporated in the previously melted sterile base which is stirred until cold.
CASE 2: In case of insoluble medicaments, the medicament’s is finely powdered & triturated with a small quantity of the melted, previously sterilised base.
The mixture is then incorporated with the remainder of the melted base.
Eye ointment should be packed in small, sterilised collapsible metal (aluminium) or plastic (polyvinyl chloride) tubes fitted with a tamper-evident applicator.
Collapsible metal tubes out with a powerful jet of filtered, dust free air.
Certain proprietary formulations of eye ointment are available in single dose container.
These take the form of an elongated, flexible gelatin capsule with one end constricted, and are opened by cutting off the constriction end with sterile scissors.
The British pharmacopoeia Codex requires that the label on the tube should state that the content are sterile provided that the container has not been opened.
Eye ointment should be stored in a cool place.
Eye lotions are sterile aqueous solution applied to an eye bath for washing of the eyes.
The large volume of fluid to flow quickly over the eye.
Eye lotion should be isotonic and ISO-osmotic to tears.
The prepared lotions should not be stored for more than two days.
Example Sodium chloride (Na-Cl) eye lotion B.P.C.
|1||Sodium chloride||9 grams|
|2||Purified Water to Produce||1000 ml|
METHOD OF PREPARATION:
Dissolve sodium chloride in purified water.
The final volume is made by adding more of purified water.
Filter it through sintered glass filter grade 4.
Transfer the eye lotion to bottle and seal it.
Sterilisation is done by autoclave.
Label and dispense the bottle.
Amber coloured screw capped fluted bottles are used to pack eye lotion.
The container is labelled “For External Use Only”.
EVALUATION OF OPHTHALMIC PREPARATIONS:
(1) STERILITY: The ingredients that meet the sterility requirements described should be used.
The container for ophthalmic preparation should be sterile at the time of filling and closing.
Ophthalmic semi-solids should be free from anaerobic bacteria and fungi.
Sterility tests are therefore performed by the;
(a). MEMBRANE FILRATION TECHNIQUE: A solution of test products (1%) is prepared in isopropyl myristate and allowed to penetrate through cellulose nitrate filter with pore size less than 0.45 Micro meter.
The membrane is then washed three times with 100 ml of sterile diluting solution and rinse it with fluid and then transfer aseptically into fluid thioglycolate (FTG) and soybean-casein digest medium (SBCD).
The membrane is finally incubated for 14 Days.
Growth on FTG medium indicates the presence of anaerobic and aerobic bacteria.
Soybean casein digest medium indicates fungi and aerobic bacteria.
Absence of any growth in both these media establishes the sterility of the product.
(b). DIRECT-INOCULATION METHOD:
1 part of the product is diluted with 10 parts of sterile diluting and rinsing fluid with the help of an emulsifying agent.
Incubated in fluid thioglycolate (FTG) and soybean-casein digest medium (SBCD) media for 14 D
(2) UNIFORMITY OF DOSAGE UNITS:
This test is applicable to dosage forms packed in single unit containers.
It includes both the mass of the dosage form and the content of the drug substance in the dosage form.
The test can be performed by either content uniformity or weight variation.
(3) CLARITY TEST:
Ophthalmic solutions should be free from foreign particles.
This is done by visual inspection under proper light or by instruments (such as light scattering or video image projection).
(4) LEAKAGE TEST:
This test is done for ophthalmic ointment to evaluate the intact-nature of the ointment tube and its seal.
10 sealed container are selected and their exterior surface are cleaned.
They are horizontally placed over absorbent blotting paper in an oven kept at 60 +-3 for 8 hours.
The test passes if leakage is not observed from any tube.
If leakage is observed the test is repeated with an additional 20 tubes.
The test passes if not more than 1 tube shows leakage out of 30 tubes.
(5)PRESENCE OF METAL PARTICLES:
This test is required only for ophthalmic ointments.
The presence of metal particle will irritate the corneal or conjunctiva surface of the eye.
It is performed using 10 ointment tubes.
The content from each tube is completely withdraw onto a clean 60 mm diameter petri dish having flat bottom.
The lid is closed and the product is heated at 85 C for 2 hours.
Once the product is melted and distributed uniformly, it is cooled to room temperature.
Remove the lid after solidification.
The bottom surface is then viewed through an optical microscope at 30 times magnification.
The viewing surface is illuminated using an external light source positioned at 45 C on the top.
The entire bottom surface of the ointment is examined and the number of particles 50 micro meter or above are counted using a calibrated eyepiece micrometer.
The USP recommends that the number of such particles in 10 tubes should not exceed 50, with not more than 8 particles in any individual tube.
(6) CONTAINER CLOSURE INTEGRITY:
The packing system should be closed or sealed in such a manner as to prevent contamination or loss of contents and should provide evidence of being tamper-proof.
a. Viscosity: This is not a compendial test.
Generally the viscosity is measured by different instruments such as capillary viscometer methods, Rotational Rheometer methods, and rolling ball viscometer method.
b. Resuspendibility / Redispersability:
In case of ophthalmic suspension consideration must be given to establishing good physical stability of a suspension.
The particles should not produce a cake at the bottom of the container.
They must re-dispersed readily at the time of use to achieve dosage uniformity.
c. Drop Size:
For ophthalmic drug products dispersed as drops, drop sizes may typically range from 20 to 70 micro litres.
However, the drop size for any individual product should be controlled and maintained throughout the product shelf life.
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