STERILE DOSAGE FORMS: OPHTHALMIC FORMULATIONS STERILE PRODUCTS PHT 434 COLLEGE OF PHARMACY STERILE DOSAGE FORMS: OPHTHALMIC FORMULATIONS Dr. shahid Jamil M.Pharm.Ph.D Contact info: shahidjamil07@gmail.com

OPHTHALMIC PREPARATIONS Ophthalmic preparations are sterile products essentially free from foreign particles; suitably compounded and packaged for instillation into the eye.

ANATOMY OF THE EYE The human eye has always been a difficult subject for topical administration of drugs. The basis of this difficulty can be found in the anatomical arrangement of the surface tissues and in the permeability of the cornea.

LACRIMAL GLAND ?

Cornea The front facing part of the boundary layer is clear and colorless and is called the cornea. The cornea contains no blood vessels but is richly supplied with nerve endings. The iris is the part of the eye that gives it color. It consists of muscular tissue that responds to surrounding light, making the pupil, or circular opening in the center of the iris, larger or smaller depending on the brightness of the light.

The lachrymal glands Secrete tears which is a clear watery fluid containing mineral salts, glucose, other low molecular weight organic compounds, and protein. Sebaceous glands on the margins of the eyelids secrete an oily fluid which spreads over the tear film, reducing the rate of evaporation from the exposed surfaces of the eye.

Drugs used in the eye: Miotics e.g. pilocarpine Hcl Mydriatics e.g. Atropine Anti-inflammatories e.g. corticosteroids Anti-infectives (antibiotics, antivirals and antibacterials) Anti-glucoma drugs e.g. pilocarpine Hcl Surgical adjuncts e.g. irrigating solutions Diagnostic drugs e.g. sodiumfluorescein Anesthetics e.g. tetracaine

DRUG PENETRATION INTO THE EYE One of the main problems associated with the treatment of ocular disease is the difficulty in achieving a sufficient concentration of the drug at the required site of action. When medicated ophthalmic preparations are administered systemically, the lack of vascularity in the cornea and the chambers of the eye and the relatively non-permeable nature of the capillaries in the retina and iris, limits diffusion of drug from the blood into the aqueous and vitreous humors.

DRUG PENETRATION INTO THE EYE It is therefore necessary to consider non-systemic means of delivering drugs to ocular targets. For the treatment of superficial eye diseases, such as conjunctivitis, topical application is the suitable route of administration When the intended site of action is within the globe of the eye, the ocular barrier presents problems for penetration of topically applied preparations.

Factors Influencing Drug Absorption From The Eye: Tear volume is 10-30 μl, therefore application of two drops 50 μl x 2 = (100 μl) of the preparation, results in expelling more than 70% of the dose from the eye by overflow. Drainage of the administered dose to the nasolacrimal system. The vascular systems of the conjunctiva and sclera tend to transport the penetrating drug away from the eye into the general circulation. Therefore, cornea is a more favorable route than the conjunctiva for the penetration of topically applied drugs into the interior of the eye.

FORMULATION OF OPHTHALMIC PRODUCTS Ophthalmic solutions are formulated to be sterile, isotonic and buffered for stability and comfort. The stability of a drug in ophthalmic product depends on the chemical nature of the drug substance, the product pH, method of preparation, solution additives, and the type of packaging.

FORMULATION OF OPHTHALMIC PRODUCTS Buffering and pH Adjustment: Ophthalmic solutions are formulated to be sterile, isotonic and buffered for stability and comfort. Ideally ophthalmic preparations should be formulated at a pH equivalent to the tear fluid value of pH 7.4 Practically this is seldom achieved that the large majorities of active ingredients used in ophthalmology are salts of weak bases and are most stable at acidic pH. For example drugs such as pilocarpine and physostigmine are both active and comfortable in the eye at a pH of 6.8 however loss in drug stability will occur in less than a year. On the other hand, at pH 5 both drugs are stable for several years.

FORMULATION OF OPHTHALMIC PRODUCTS Buffering and pH Adjustment: The optimum pH may be lower (ACIDIC) than comfortable pH, this effect may be minimized by adjusting the pH with a buffer of minimum capacity. Thus the buffer system selected should have pH for optimum stability and a capacity adequate to maintain pH within the stability range for the duration of the product shelf life.

Tonicity Adjustment: Tonicity refers to the osmotic pressure exerted by salts in aqueous solution. An ophthalmic solution is considered isotonic when its tonicity is equal to that of 0.9% sodium chloride solution. The eye can usually tolerate solutions equivalent to a range of 0.5 to 1.8% sodium chloride. If the osmotic pressure of the drug at the desired concentration exceeds that of the tear fluid, nothing can be done since the solution is hypertonic. For hypotonic solutions tonicity-adjusting ingredients usually used include sodium chloride, potassium chloride, buffer salts, dextrose, glycerin and propylene glycol.

Viscosity Adjustment: Viscosity increasing agents are used to prolong contact time in the eye and thus enhance drug absorption and activity. Substances such as methyl cellulose, PVA and hydroxy propyl methyl cellulose are frequently added to increase viscosity. Viscosity increase up to the 25-50 cps improve contact time in the eye.

Antioxidants Surfactants Antioxidant, specifically sodium bisulfite or metabisulfite is permitted in concentrations up to 0.3% particularly in solutions containing epinephrine salts used as stabilizer to minimize oxidation of epinephrine. Surfactants The use of surfactants in ophthalmic preparations is similarly limited. Nonionic surfactants, the least toxic class of such compounds, are used in low concentrations particularly in steroid suspensions and as aids in achieving solution clarity.

Preservatives The choice of preservative is limited to those safe and effective products. These are benzalkonium chloride, chlorobutanol, phenylmercuric nitrate and acetate, methyl and propyl paraben, phenylethanol, chlorhexidine and various combinations of these chemicals.

C.Preservation and preservatives: Why Preservatives ?

Ideal ophthalmic delivery system: Following characteristics are required to optimize ocular drug delivery system: Good corneal penetration. Prolong contact time with corneal tissue. Simplicity of instillation for the patient. Non irrittative and comfortable form Appropriate rheological properties

CLASSIFICATION OF OCULAR DRUG DELIVERY SYSTEMS: Ointments Gels Topical eye drops: Solutions - Suspensions - Powders for reconstitution - Sol to gel systems - Ocular inserts

Ophthalmic Solutions: TYPES OF OPHTHALMIC PRODUCTS Ophthalmic Solutions: This is the most common means of administering a drug to the eye in which all ingredients are completely in solution, uniformity is not a problem and there little physical interference with vision. The principle disadvantage of solutions is the low contact time between the medication and absorbing surfaces. Contact time may be increased to some extent by the inclusion of a viscosity increasing agent such as methyl cellulose.

Ophthalmic Solutions: The selection of the appropriate AND common salt forms used are the hydrochloride, sulfate, nitrate, and phosphate to avoid the discomfort reactions. Salicylate, hydrobromide, and bitartarate salts are also used for drugs that are acidic such as sulfonamides. The hydrochloride salts combines better stability and acceptable patient tolerance. Hence, epinephrine hydrochloride was the salt of choice for its ophthalmic solution.

Ophthalmic Suspensions: Suspensions are dispersions of finely divided, insoluble drug substances in an aqueous vehicle containing suitable suspending and dispersing agents. The following are the most important points to be taken in consideration for opthalmic suspensions: a- Particle Size b- Intrinsic Solubility and Dissolution Rate c- Polymorphism

a- Particle Size: Because of a tendency of particles to be retained in the cul-de-sac, the contact time and duration of action of a suspension probably exceeds that of a solution. Each of these actions is a function of particle size; with solubility rate favored by small size and retention by a large size. Thus optimum activity should result from optimum particle size (90% less than 10 µm)

b- Intrinsic Solubility and Dissolution Rate The intrinsic solubility determines the amount of drug actually in solution and available for immediate absorption upon instillation of the dose. As the intrinsic solubility of the drug increases, the concentration of the drug in the saturated solution surrounding the suspended drug particle also increases.

c- Polymorphism: Polymorphism is the ability of a substance to exist in several different crystalline forms. A change in crystal structure may occur during storage resulting in increase (or decrease) in crystal size and alteration in the suspension characteristics, causing solubility changes reflected in increased or decreased bioavailability.

3. Powders for Reconstitution Several ophthalmic drugs are prepared as sterile powders for reconstitution before dispensing to the patient. These include chloramphenicol, epinephrine, and colistin sulfate. The sterile powder is usually manufactured by lyophilization and is packaged separately from the diluent, and a sterile dropper assembly is provided. In powder form, these drugs have a much longer shelf life than that of their solution forms.

Each product has an expiration date for the reconstituted solution and proper storage condition which should be explained to the patient and methods of usage. The sterile powders may contain inert bulking agents, as mannitol. Sometimes, potassium acetate is used as a co-drying agent to improve stability of the moisture sensitive drugs.

4- Ophthalmic Ointments Advantages: Longer contact time and greater total drug bioavailability with slower onset and time to peak absorption. Disadvantages: Ointments will interfere with vision unless use is limited to bedtime instillation.

Special precautions must be taken in the preparation of ophthalmic ointments: They are manufactured from sterilized ingredients under aseptic conditions and meet the requirements of the official sterility tests. Ophthalmic ointments must contain a suitable substance or mixture of substances to prevent growth of, or to destroy microorganisms accidentally introduced when the container is opened during use.

The base must be non-irritating to the eye, permit diffusion of the drug throughout the secretions bathing the eye and retain the activity of the medicament for a reasonable period of time, under proper storage conditions. Most ophthalmic ointments are prepared with paraffin bases of yellow petrolatum and mineral oil. The medicinal agent is added to the ointment base either as a solution or as a micronized powder. The finished ointment must be free from large particles.

Water-based gels are used to increase the viscosity and hence the residence time of eye drops. Several types of gelling agent have been investigated for use in eye products include- polyacrylic acid compounds, hypromellose, and carbomer. Anhydrous but water-miscible ocular bases have also been made using macrogol-based formulations.

Ophthalmic solutions intended for intraocular use are relatively recent additions to the ophthalmologist. Surgical procedures such as cataract removal require two types of intraocular solutions. During the surgery, the operating site is frequently rinsed with an irrigating solution (Ringer's Solution containing glutathione, bicarbonate and adenosine are being used over a period of hours during surgery and are available in volumes ranging from 15 to 500 ml). Late in the surgical procedure, carbachol is used as miotic solution to constrict the iris.

Drugs can be administered to the eye by intra-ocular (intra-corneal or intra-vitreous) or sub-conjunctival injection. Preparations may be formulated as injection solutions or as sterile powders for reconstitution before use.

8. Ocular Inserts: Ocular inserts have been developed in which the drug is delivered based on diffusional mechanisms. Such a device delivers an ophthalmic drug at constant known rate, minimizing side effect by avoiding excessive absorption peaks. The delivery of pilocarpine by such a device is a well-known commercial product (Ocusert Alza).

Contact lenses are optical and/or therapeutic ophthalmic devices. They are four main types: Hard-rigid hydrophobic Rigid hydrophilic Flexible hydrophobic Soft-flexible hydrophilic They require great care and considerable skill to formulate.

Typical Support Products Major Characteristics Chemical Classification Lens Type Wetting solutions Soaking solutions Cleaning solutions Combinations Artificial tears Negligible gas permeability, low water content, medium wettability PMMA (polymethylmethacrylate) Hard rigid, hydrophobic Disinfecting solutions low gas permeability, High water content, good wettability HEMA (hydroxyethyl methylmethacrylate) Soft-flexible, hydrophilic Good gas permeability Poor wettability Silicone rubber Flexible hydrophobic Good wettability Silicone vinylpyrollidone Rewetting solutions CAB (cellulose acetate butyrate) Rigid hydrophilic

The most important solutions for contact lenses are: Wetting solutions, Cleaning solution, Disinfecting systems, Soaking solutions Artificial tears.

OPHTHALMIC PREPARATIONS PACKAGING OF OPHTHALMIC PREPARATIONS Ophthalmic solutions are packaged either in polyethylene "drop-tainers" or in glass dropper bottles. The polyethylene containers are sterilized with ethylene oxide, whereas glass dropper assemblies can be wrapped and autoclaved.

OPHTHALMIC PREPARATIONS APPLICATION OF OPHTHALMIC PREPARATIONS Wash hands before each use. Shake well and remove the screw cap. Invert the bottle and hold the bottle between your thumb and middle finger, with the tips of the fingers pointing towards you.

APPLICATION ….. Tilt your head back and position the bottle above the affected eye. DO NOT TOUCH THE EYE WITH THE TIP OF THE DROPPER With the opposite hand, place a finger under the eye. Gently pull down until a "V" pocket is made between your eye and lower lid. With the hand holding the bottle, place your index finger on the bottom and push it to dispense one drop.

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