Ophthalmic Preparations: Introduction, absorption through eye, formulation considerations

-Lokesh Adhikari Department of Pharmaceutical Sciences,

H.N.B Garhwal University (A Central University)

Definition:

Three ways can do the instillation of the specialised dosage forms into the eyes: 1) topical (onto the external surface of the eye), 2) intraocular (administered inside) and 3) periocular (adjacent to the eye). Sometimes these formulations are also used in conjunction with an ophthalmic device. These are known as ophthalmic dosage forms.

Ophthalmic dosage forms can be of the semisolid or liquid type, including solutions, suspensions, and ointments. Gel, gel-forming solution, ocular insert, intravitreal injections and implants are few newly developed forms of ophthalmic drug delivery.

Examples:

Miotics, e.g. pilocarpine HCl
Mydriatics, e.g. Atropine
Cycloplegics, e.g. atropine

Anti-inflammatories, e.g. corticosteroids
- Anti-infectives (antibiotics, antivirals and antibacterials)
- Anti-glaucoma drugs, e.g. pilocarpine HCl
- Adjuncts, e.g. Irrigating solutions
- Diagnostic drugs, e.g. sodium fluorescein
- Anaesthetics, e.g. Tetracaine

Anatomy & Physiology of the eye

In the human eye, the protective outer layer is known as the sclera, also called “white of the eye” which helps in maintaining the shape of the eye.
The front transparent portion of the sclera is called the cornea. It passes the light into the eye. The cornea provides the focusing power of the eye with its sturdy refracting surface.
Another layer between the sclera and the retina is present, which is named as the choroids. Retina gets nourishment from the choroids, which contain the blood vessels.

The colourful portion of the eye, the iris, is made up of muscular tissues. Iris has a property to respond to the surrounding light subsequent opening of the pupil, which is present in the centre of the iris. The pupil changes its shape with the change in the brightness of the light.
A transparent, biconvex lens is encased in a thin transparent covering which refracts the incoming light. It also helps in focusing the light onto the retina.
The innermost layer in the eye is called the retina, which converts images into electrical impulses. These impulses are sent along the optic nerve to the brain. The brain interprets these impulses Into an image.
In the centre of the retina, the macula is located, which produces the sharpest vision. The lens divides the eyeball from inside into two fluid-filled sections.
At the back of the eye, a larger section is filled with vitreous humor, which is a colourless gelatinous mass called the.
A transparent, water-like material called aqueous humor is filled in the front of the eye.
The mucous membrane, conjunctiva, begins at the edge of the cornea and lines the inside surface of the eyelids and sclera, which serves to lubricate the eye.

Factors affecting drug availability:

Gravity, lachrymation, blinking, and tear turnover are some common factors which result in rapid solution drainage from the eye

The normal volume of tears = 7 ul, the blinking eye can accommodate a volume of up to 30 ul without spillage, the drop volume = 50 ul

As the drug solubility increases, the gradient increases, the driving force for drug entry into the aqueous humour increases.

Sterilization by heat can not be used for most ophthalmic products. The reason behind this is the instability of the active principle or polymers used to increase viscosity at high temperatures. Aseptic manufacturing, followed by aseptic filling-and-capping techniques in aseptic environments is the most suitable technique for the majority of ophthalmic products.

Ocular toxicity and irritation

the ocular toxicity and irritation of ophthalmic formulations are tested in albino rabbits. The observation of changes in the conjunctiva, the cornea or the iris is the basis of this testing.

For example, the USP test of plastic containers:

Containers are cleaned and sterilized as in the final packaged product.
- It is extracted by submersion in saline and cottonseed oil.
- The rabbit eye test is performed for topical ocular instillation of the extracts and samples.

Preservation and preservatives:

A multiple-dose eye solution requires product sterility and stability maintained during its use. This specific purpose is solved by using preservatives in the formulation. However, preservatives are not needed in the case of the unit-dose package. For the products with surgical applications, the use of preservatives is prohibited as the cells of the corneal endothelium can become damaged when gets contact with a high concentration of the preservative. It may result in clouding of the cornea and possible loss of vision. So, the sterility of the product should be maintained during the production, packaging to the application and sterile, unit-of-use containers are used to achieve the desired sterility.

Examples:

Category	Example	Properties
Cationic wetting agents	Benzalkonium chloride	0.01-0.1%
	Disodium edetate (EDTA)	Ability to render the resistant strains of PS aeruginosaMore sensitive to benzalkonium chloride
Organic mercurial	Phenylmercuric nitrate	0.002-0.004%
	phenylmercuric acetate	0.005-0.02%.
Esters of p-hydroxybenzoic acid	Methyl and propyl hydroxybenzoate	2 :1, 0.1% mixture
Alcohol Substitutes	Chlorobutanol	0.5%pH 5-6.
	Phenylethanol	0.5%

Foreign particles:

Similar to the parenteral products, foreign particles, fibres and filaments should not be present or within the limit in all the ophthalmic products. Bacteria proof filters (membrane filters, sintered glass filters) are applied to attain the desired clarity. in ophthalmic products. The particle size of the eye suspension should be in an ultrafine state of subdivision to minimize irritation. To avoid contamination within the products during the filtration, for every ophthalmic product, a separate filter should be used.

Viscosity:

Optimum viscosity is an essential character for any ophthalmic formulation which prolongs the contact time of the drug in the eye. To achieve the desired viscosity, we add one or more thickening agents in the ophthalmic preparations. Some of the commonly used viscosity enhancers are polyvinyl alcohol (1-4%), polyethylene glycol, methylcellulose, carboxymethylcellulose.

Desired properties an ideal thickening agent:

Easy to filter.
Easy to sterilize.
Compatible with other ingredients.
Must have requisite refractive index and clarity level.

Due to some possible adverse effects, in the formulation of eye drops and eye lotions that are required to be used during or after surgery on the interior of the eye, thickening agents are not included.

Tonicity:

Isotonicity with lachrymal secretions is very much desirable in all ophthalmic products to avoid discomfort and irritation. On average, an eye can only tolerate a range of tonicity equivalent to 0.5-2% solution of NaCl. To adjust tonicity, we prepare ophthalmic products with certain isotonic vehicles such as 1.9% boric acid, sodium acid phosphate buffer.

pH:

The pH of the product has a vital role in the therapeutic activity, solubility, stability and comfort to the patient. Tears have a pH of about 7.4. An eye can tolerate solutions of a wide pH range as eyes have a control system for pH. Alkaloid salt solutions are stable at pH 2-3 pH, which is irritant to the eye. The alkaloids get precipitated at pH above 7 and create several formulation problems. Benzalkonium chloride, polysorbate 20, polysorbate 80, dioctyl sodium succinate are some of the surfactants which are commonly used.

References

Banker, G. S., Siepmann, J., & Rhodes, C. (2002). Modern Pharmaceutics. CRC Press.
Indian Pharmacopoeia 2018. (2018). Indian Pharmacopoeia Commission.
Reddy, I. K. (1995). Ocular Theraputics and Drug Delivery. CRC Press.
Reynolds, L. A. (1993). Extemporaneous Ophthalmic Preparations. Applied Therapeutics.
Organization, W. H. (2006). The International Pharmacopoeia. World Health Organization.

Further Readings

Reynolds, L. A. (1993). Extemporaneous Ophthalmic Preparations. Applied Therapeutics.
Banker, G. S., Siepmann, J., & Rhodes, C.(2002). Modern Pharmaceutics. CRC Press.
Ghebre-Selassie, I. (1989). Pharmaceutical Pelletization Technology. Taylor & Francis.