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Ophthalmic dosage forms

Types and characteristics

1) Liquid preparations: (eye drops and eye lotion)


2) Semisolid dosage forms: (ointment creams and gels) applied to the margin of the
eyelid or in the conjunctival sac.
3) Solid dosage form: applied to the eye surface to produce modified release dosage
form

4) Device for surgical implantation: to give prolonged release action.


5) Parentral products: (intracorneal, intravetireous)
6) Liquid for irrigation: used during surgical operations.

All ophthalmic products are required to be sterile and free from particulate matter.
They could be presented as single use or multiple use containers.
In multidose container preservative should be added.

Most liquid ophthalmic products are prepared using aqueous vehicles


Semisolid dosage forms may be based on paraffin or water in oil emulsions.
Solid modified-release products have the drug enclosed within a diffusion membrane or
as hydrophilic gels
Eye drops
BP defines eye drops as sterile aqueous or oily solution or suspension of one or more
active ingredients intended for installation into the eye.
Most therapeutic agents used are water soluble or can be formulated as water soluble
salts.

Basic drugs are used as hydrochloric or sulfate or nitrate salt. Acidic drugs are used as
sodium salt.
Oily eye drops are seldom used and should be prepared in sterile oil ex: oily drops of
pilocarpine.
The therapeutic activity of the drug in eye drops may be affected by the pH value but
for stability reason the pH must be kept low.

Drop size and bioavailability of eye formulations

1- The decrease in drop size to 20 or less decreases the drainage rate and increases the
residence time and bioavailability.
Practically there is difficulty in design safe eye droppers that will deliver volumes as
small as 5 or 10 µl.
Following installation of even a small drop, normal lachrymation will immediately
begin to dilute and wash away the drug.

2-The second technique is to increase the concentration of drug in each drop.


but the drug may have limited solubility
and even if it is dissolved, the high concentration used may result in unacceptable
systemic side effects following the drainage of any excess drop volume.

3) An alternative approach is to increase the contact time in the eye by:


a) Formulation of suspension
b) Use drug carrier particles.
c) increase the viscosity of the eye solution
Viscosity more than 10-20 CP has no advantage or no further increase in bioavailability.
Ex: HPMC, PVA, PVP, dextran and macrogol.
Mucoadhesive polymers (hyaluronic acid or carbomer) are more effective.

Problems associated with viscosity enhancing agents


a) Change in pH can affect the activity of viscosity enhancing agent.
b) Cellulose derivatives coagulated on heat sterilization but usually go back into
solution shaken while cooling
c) Products of high viscosity are not always well tolerated in the eye and form a deposit
or crust on eyelid.
d) They do not mix readily with tears and may interfere with drug diffusion.

Suspension

Why suspensions are used?


lack of availability of soluble forms of the drug.
stability problems associated with soluble form.
Ex.: corticosteroids eye drops
to prolong residence time and enhance bioavailability.

Suspension particles usually produce irritation and increase the rate of lachrymation
and blinking.
So the particle size of suspension particles should be very small.
Drugs with p.s. less than 10 µm are rapidly removed from the eye as are drugs in
solution.

A potential problem associated with ophthalmic suspension is the possibility of a change


in P.S. during storage. The suspension should be shaken before use.
Eye lotions

Used in large volume to mechanically remove foreign materials.


It is important to control pH than in eye drops because of large volume administered.
It can be used to impregnate eye dressings.
Each container is used one time and not require to add preservative.
Ex. Sodium bicarbonate eye lotion used in emergency treatment of acid burns of the eye
and is known as Factory eye drops no. 2.
Eye ointments

It is sterile semi-solid preparation of homogenous appearance intended for application


to the conjunctiva.
The ointment base is paraffin base has melting point close to body temp.
This base is nonirritating and inert can be used as anhydrous medium for delivery of
moisture sensitive drugs.

Mixture of petrolatum and liquid petrolatum (mineral oil) is used as ointment base.
Addition of drug to ointment base could be by:
direct solution in oily basis (water soluble)
incorporation of very finely powdered drug into the base (insoluble)

Incorporation of aqueous phase drug into the ointment may require the addition of
hydrous wool fat or aliphatic alc. to increase its emulsifying capacity.
Addition of aqueous phase into the eye ointment may necessitate the addition of
buffering agents and antioxidant.

Antimicrobial is essential in multidose container.


After preparation of ointment it is filled into previously sterilized tin or plastic tubes.
The tubes hold 3.5 gm oint. and fitted with narrow gauge tips which permit the
expulsion of narrow bands of ointment.

Advantage: Increase ocular contact time


Disadvantage: Blurred vision
Ocular inserts

Ex. Ocusert system by Alza


It is designed to provide release of medication at predetermined, predictable rate.

It has dimension of 13.4 by 5.7 mm and 0.3 mm thickness, it is flexible.


It is multilayer structure consisting of a drug-containing core surrounded by polymer
membrane through which the drug diffuse at a constant rate.
The rate of diffusion is controlled by:
polymer composition
membrane thickness
solubility of the drug

Advantage:
1) Decrease the frequency of administration
2) Ensure night time medication
3) Enhance patient compliance

The device is sterile and not containing preservative.


It can release the drug over 7 days.
Ex. Pilocarpine inserts in glaucoma therapy.
Gels

It is water soluble based gels


Ex. 1) Pluronic F127 or poloxamer gel
2) Carbomer gel
3) Gellan gum or gelrite.
Increase the contact time of drug with the eye.
Injections

Injected intraoccularly or subconjunctivally.


It can be formulated as injection solution or dry powder for reconstitution

Formulation of ophthalmic products

pH and buffering capacity

Buffers are used in ophthalmic to:


Reduce discomfort, assure drug stability, control therapeutic activity.
Human tears pH is about 7.2 with good buffering capacity.
Solution of pH 3.5-10.5 can be usually tolerated with little discomfort.

The buffer capacity should be high enough to avoid change in pH during storage, and
low enough to significantly change the pH of the tear film within eyes.

Ex: borate ,phosphate, and citrate.


Most of drugs used in the eye are salts or weak organic bases and are stable at acid pH
values.
The degree of ionization is affected by pH ,as it approaches neutrality, the concentration
of the unionized organic base is increased.
The free base is lipid soluble and will penetrate the cornea more rapidly than the
ionized form of the drug.
Tonicity of the eye drops

Tears have tonicity equivalent to 0.9% solution of sod. chloride.


Eye can tolerate a variety of isotonicities, 0.7% to 1.5% sod chloride.
Use glucose, glycerol or boric acid, or pot chloride to adjust isotonicity.

Tonicity should be adjusted to avoid eye irritation.


Hypotonic solution should be avoided.
Hypertonic solution sometimes is unavoidable due to high conc. of drug.

Antioxidant
Ascorbic acid, acetylcysteine
The use of plastic dropper bottles which could permeable to gases increases oxidative
deterioration during storage of eye drops
Wetting and spreading agents

SAA disturb the integrity of tear film and are not often included in eye formulations
except in the form of antimicrobial preservatives.
It also may be included in suspension formulation to facilitate dispersion of the powder.
Nonionic SAA is preferred than anionic and cationic compounds.
Macrogol used as artificial tear to facilitate spreading over the eye surface.
Dextran and PVA are also used.

Preservatives
Added to prevent the growth of microorganism accidentally introduce during use in
multidose container.
Product used in traumatized eye or during surgery should not contain preservative.

Benzalkonium chloride , most commonly used at conc. 0.01-0.02%.


Advantages: non-volatile- stable in autoclaving, active against wide range of gm +ve
and gm –ve bacteria.
Disadvantages: its activity is reduced in presence of methylcellulose, magnesium and
calcium.

Incompatible with nitrates.


Unsuitable for eye drops containing local anesthetics because benzalkonium chloride
remove the protective oily layer from precorneal film due to its detergent effect.
L.A. abolish the blinking reflex which help the formation of oily layer.
So the eye will suffer from irritation and may be ulceration.

Chlorhexidine
It is bisbiguanide bactericide effective in 0.01% against most bacteria.
Used more extensively in contact lens solutions.
It is cationic agent dose not have surface activity as benzalkonium chloride.
It is not stable in autoclave

Organic mercurial compound


Phenylmercuric acetate (0.002%), thiomersal (0.05%)
Disadvantages
If used over prolonged period of time it can results in intraocular deposition of mercury
and allergy.

Chlorbutol
Substituted alc., active against most bacteria and fungi.
Well tolerated by eye and compatible with most drugs used in ophthalmic.
It is volatile and can be lost during storage in plastic containers.
It is only stable in acidic solutions.
It can withstand sterilization.

All the previously mentioned preservatives are ineffective against some strains of
Pseudomonas aeruginosa.
The organism that can invade an abraded cornea causes ulceration and blindness.
Only mixture of 0.01% benzalkonium chloride and 1000 USP units of polymyxin B
sulfate is effective against this bacteria.

In some ophthalmic preparation a mixture of benzalkonium chloride (0.015) and


disodium ethylenediaminetetraacetated (0.01-0.1%) is employed.
The chelating agent renders the resistant strains of Pseudomonas Aeruginosa more
sensitive to the bezalkonium chloride.