Ophthalmic Preparations

Ophthalmic Preparations

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Ophthalmic preparationsDefinition: Pharmaceutical preparations that applied topically to the eye to treat surface (topical), or intraocular conditions, including bacterial, fungal, and viral infections of the eye or eyelids; allergic or infectious conjunctivitis or inflammation; elevated intraocular pressure and glaucoma; and dry eye due to inadequate production of fluidsbathing the eye. In treating certain ophthalmic conditions, such as glaucoma, both systemic drug use and topical treatments may be employed.

2 Ophthalmic preparationsThe most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments. these preparations when instilled into the eye are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage.

The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts , intravitreal injections and implants.

3 PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGSAnesthetics: Topical anesthetics, such as tetracaine, cocaine, and proparacaine, are employed to provide pain relief preoperatively, postoperatively, for ophthalmic trauma, and during ophthalmic examination.

Antibiotic and antimicrobial agents: Used systemically and locally to combat ophthalmic infection. Among the agents used topically are azithromycin, gentamicin sulfate, sodium sulfacetamide, ciprofl oxacin hydrochloride, ofloxacin, polymyxin B-bacitracin,and tobramycin.

Antifungal agents: Among the agents used topically against fungal endophthalmitis and fungal keratitis are amphotericin B, natamycin, and flucytosine.

Anti-infl ammatory agents: Used to treat inflammation of the eye, as allergic conjunctivitis.Among the topical anti-inflammatory steroidal agents are fl uorometholone, prednisolone, and dexamethasone salts. Nonsteroidal anti-infl ammatory agents include diclofenac f lurbiprofen,ketorolac, 4 PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGS Antiviral agents: Used against viral infections, as that caused by herpes simplex virus. Among the antiviral agents used topically are trifluridine, ganciclovir, and vidarabine.

Astringents: Used in the treatment of conjunctivitis. Zinc sulfate is a commonly used astringent in ophthalmic solutions.

Beta-adrenergic blocking agents: Agents such as betaxolol hydrochloride, levobunolol, and timolol maleate are used topically in the treatment of intraocular pressure and chronic open-angle glaucoma.

5 PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGSMiotics and other glaucoma agents: Miotics are used in the treatment of glaucoma, accommodative esotropia, convergent strabismus,and for local treatment of myasthenia gravis. Among the miotics are pilocarpine, echothiophate iodide, and demecarium bromide.

Protectants and artifi cial tears: Solutions employed as artifi cial tears or as contact lens fluids to lubricate the eye contain agents such as carboxymethyl cellulose, methylcellulose,hydroxypropyl methylcellulose, and polyvinyl alcohol.

Mydriatics and cycloplegics: Mydriatics allow examination of the fundus by dilating the pupil. Mydriatics having a long duration of action are termed cycloplegics. Among themydriatics and cycloplegics are atropine, scopolamine, homatropine, cyclopentolate, phenylephrine, hydroxyamphetamine, and tropicamide.

6 PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGSVasoconstrictors and ocular decongestants: applied topically to the mucous membranes of the eye cause transient constriction of the conjunctival blood vessels. They are intended to soothe, refresh, and remove redness due to minor eye irritation. Among the vasoconstrictors used topically are naphazoline, and oxymetazoline.

Antihistamines, such as emedastine difumarate, ketotifen fumarate,and olopatadine hydrochloride, are included in some products to provide relief of itching due to pollen, ragweed, and animal dander.7Anatomy and Physiology of the Eye:

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PHARMACEUTICAL REQUIREMENTS:9SterilityPreservationIsotonicity valueBufferingViscosity And Thickening Agents

PHARMACEUTICAL REQUIREMENTS:10A. SterilityIdeally, all ophthalmic products should be terminally sterilized in the final packaging.

Only a few ophthalmic drugs formulated in simple aqueous vehicles are stable to normal autoclaving temperatures and times (121C for 20-30 min).

As an alternative, bacterial filters may be used. Although bacterial filters work with a high degree of efficiency, they are not as reliable as the autoclave.

However, because final product testing is used to validate the absence of microbes, sterility may be ensured by either method.

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11One advantage of filtration is the retention of all particulate matter (microbial, dust, fiber), the removal of which has substantial importance in the manufacture and use of ophthalmic solutions.

B. Preservation and preservativesTo maintain sterility during use, antimicrobial preservatives generally are included in ophthalmic formulations; an exception is for preparations to be used during surgery or in the treatment of traumatized eyes because some preservatives irritate the eye. These preservative-free preparations are packaged in single-use containers.During preformulation studies antimicrobial preservatives must demonstrate stability, chemical and physical compatibility with other formulation and packaging components, and effectiveness at the concentration employed.

Preservatives are included in multiple-dose eye solutions for maintaining the product sterility during use.

The most common organism is Pseudomonas aeruginosa that grow in the cornea and cause loss of vision.

1213Among the antimicrobial preservatives used in ophthalmic solutions and suspensions:

benzalkonium chloride, 0.004% to 0.01%; benzethonium chloride, 0.01%; chlorobutanol,0.5%; phenylmercuric acetate, 0.004%; phenylmercuric nitrite, 0.004%; and, thimerosal, 0.005%to 0.01%.

14 Certain preservatives have limitations; for example, chlorobutanol cannot be autoclaved because it decomposes to hydrochloric acid even in moderate heat, rendering a product susceptible to microbial growth and could alter its pH and thereby affect the stability and/or physiologic activity of the therapeutic ingredient.

15 In concentrations tolerated by the eye, all of the aforementioned preservative agents are ineffective against some strains of Pseudomonas aeruginosa, which can invade an abraded cornea and cause ulceration and even blindness.

However, preservative mixtures of benzalkonium chloride (0.01%) and either polymyxin B sulfate(1,000 USP U/mL) or disodium ethylenediaminetetraacetate EDTA (0.01% to 0.1%) are effective against most strains of Pseudomonas.

EDTA , which is commonly employed as a chelating agent for metals, renders strains of P. aeruginosa more sensitive to benzalkonium chloride.C. ISOTONICITY VALUEBody fluids, including blood and tears, have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride. Thus, a 0.9% sodium chloride solution is said to be isosmotic , or having an osmotic pressure equal to that of physiologic fluids.

Solutions with a lower osmotic pressure than body fluids or a 0.9% sodium chloride solution are commonly called hypotonic, whereas solutions having a greater osmotic pressure are termed hypertonic.

Theoretically, a hypertonic solution added to the bodys system will have a tendency to draw water from the body tissues toward the solution in an effort to dilute and establish a concentration equilibrium. In the blood stream, a hypertonic injection can cause crenation (shrinking) of blood cells; in the eye, the solution can draw water toward the site of the topical application.

Conversely, a hypotonic solution may induce hemolysis of red blood cells or passage of water from the site of an ophthalmic application through the tissues of the eye.

In practice, the isotonicity limits of an ophthalmic solution in terms of sodium chloride or its osmotic equivalent may range from 0.6% to 2.0% without marked discomfort to the eye.

Sodium chloride itself does not have to be used to establish a solutions osmotic pressure.

Boric acid in a concentration of 1.9% produces the same osmotic pressure as does 0.9% sodium chloride.

All of an ophthalmic solutions solutes, including the active and inactive ingredients, contribute to the osmotic pressure of a solution.The calculations necessary to prepare isosmotic solutions may be made in terms of data relating to the colligative properties of solutions Like osmotic pressure, the other colligative properties of solutions, namely, vapor pressure, boiling point, and freezing point, depend on the number of particles in solution. These properties, therefore, are related, and a change in any one of them will be accompanied by corresponding changes in the others. Although any one of these properties may be used to determine isosmoticity, a comparison of freezing points between the solutions in question is most used.When 1 g molecular weight of a nonelectrolyte, such as boric acid, is dissolved in 1,000 g of water, the freezing point of the solution is about 1.86C below the freezing point of pure water. By simple proportion, therefore, the weight may be calculated for any nonelectrolyte to be dissolved in each 1,000 g of water to prepare a solution isosmotic with lachrymal fl uid and blood serum, which have freezing points of 0.52C.Boric acid, for example, has a molecular weight of 61.8, so 61.8 g in 1,000 g of water should produce a freezing point of 1.86C. Therefore:

Hence, 17.3 g of boric acid in 1,000 g of water theoretically should produce a solution isosmotic with tears and blood.

The calculation employed to prepare a solution isosmotic with tears or blood when using electrolytes is different from the calculation for a nonelectrolyte.

Since osmotic pressure is a cogitative property depends on the number of particles, substances that dissociate have an effect that increases with the degree of dissociation; the greater the dissociation, the smaller the quantity required to produce a given osmotic pressure.

Thus the dissociation factor, commonly symbolized by the letter i, must be included in the proportion when we seek to determine the strength of an isosmotic solution of sodium chloride (molecular weight, 58.5):If we assume that sodium chloride in weak solutions is about 80% dissociated, each 100 molecules yield 180 particles, or 1.8 times as many particles as are yielded by 100 molecules of a nonelectrolyte. This dissociation factor, commonly symbolized by the letter i, must be included in the proportion when we seek to determine the strength of an isosmotic solution of sodium chloride (molecular weight, 58.5):

Therefore, 9.09 g of sodium chloride in 1,000 g of water should make a solution isosmotic with blood or lacrimal fl uid. As indicated previously, 0.9% (w/v) sodium chloride solution is taken to be isosmotic (and isotonic) with the body fl uids.

Simple isosmotic solutions, then, may be calculated by this general formula:

Although the i value has not been determined for every medicinal agent that might be named, the following values may be generally used:

Since 0.9% sodium chloride is considered to be isosmotic and isotonic with tears, other medicinal substances are compared with regard to their sodium chloride equivalency. An often usedrule states

Using the drug atropine sulfate as an example: Molecular weight of sodium chloride = 58.5; i = 1.8 Molecular weight of atropine sulfate = 695; i = 2.6

x = 0.12 g of sodium chloride represented by 1 g of atropine sulfate Thus, the sodium chloride equivalent for atropine sulfate is 0.12 g. To put it one way, 1.0 g of atropine sulfate equals the tonic effect of 0.12 g of sodium chloride. To put it another way, atropine sulfate is 12% as effective as an equal weight of sodium chloride in contributing to tonicity.

For instance, consider the following prescription:

To make the 30 mL isotonic with sodium chloride, 30 mL 0.9% = 0.27 g or 270 mg of sodium chloride would be required. However, because 300 mg of atropine sulfate is to be present, its contribution to tonicity must be taken into consideration.The sodium chloride equivalent of atropine sulfate is 0.12. Thus, its contribution is calculated as follows: 0.12 300mg = 36mgThus, 270 36 mg = 234 mg of sodium chloride required.

BUFFERINGThe pH of an ophthalmic preparation may be adjusted and buffered for one or more of the following purposes : for greater comfort tothe eye, to render the formulation more stable, to enhance the aqueous solubility of the drug,to enhance the drugs bioavailability (i.e., by favoring unionized molecular species),to maximize preservative efficacy.

The pH of normal tears is considered to be about 7.4, but it varies; for example, it is more acidic in contact lens wearers .

Tears have some buffer capacity. The introduction of a medicated solution into the eye stimulates the flow of tears, which attempts to neutralize any excess hydrogen or hydroxyl ions introduced with the solution. Most drugs used ophthalmically are weakly acidic and have only weak buffer capacity.Normally, the buffering action of the tears neutralizes the ophthalmic solution and thereby prevents marked discomfort.

The eye apparently can tolerate a greater deviation from physiologic pH toward alkalinity (and less discomfort) than toward the acidic range .

For maximum comfort, an ophthalmic solution should have the same pH as the tears. However, this is not pharmaceutically possible, because at pH 7.4 many drugs are insoluble in water. A few drugs notably pilocarpine hydrochloride and epinephrine bitartrateare quite acid and overtax the buffer capacity of the tears.Most drugs, including many used in ophthalmic solutions, are most active therapeutically at pH levels that favor the Undissociated molecule , However, the pH that permits greatest activity may also be the pH at which the drug is least stable. For this reason, a compromise pH is generally selected for a solution and maintained by buffers to permit the greatest activity while maintaining stability.

An isotonic phosphate vehicle prepared at the desired pH and adjusted for tonicity may be employed in the extemporaneous compounding of solutions. The desired solution is prepared with two stock solutions, one containing 8 g of monobasic sodium phosphate (NaH2PO4) per liter, and the other containing 9.47 g of dibasic sodium phosphate (Na2HPO4) per liter, the weights being on an anhydrous basis.

The vehicles listed in Table 17.3 are satisfactory for many ophthalmic drugs, excepting pilocarpine, eucatropine, scopolamine, and homatropinem salts, which show instability in the vehicle.

The vehicle is used effectively as the diluent for ophthalmic drugs already in isotonic solution . When drug substances are added directly to the isotonic phosphate vehicle, the solution becomes slightly hypertonic.

Generally, this provides no discomfort to the patient. However, if such a solution is not desired, the appropriate adjustment can be made through calculated dilution of the vehicle with purified water.

VISCOSITY AND THICKENING AGENTS

In the preparation of ophthalmic solutions, a suitable grade of methylcellulose or other thickening agent is frequently added to increase the viscosity and thereby aid in maintaining the drug in contact with the tissues to enhance therapeutic effectiveness.

Viscosity for ophthalmic solutions is considered optimal in the range of 15 to 25 cP.Generally, methylcellulose of 4,000 cP is used in concentrations of 0.25% and the 25-cP type at 1% concentration.

Hydroxypropyl methylcellulose and polyvinyl alcohol are also used as thickeners in ophthalmic solutions.

Occasionally, a 1% solution of methylcellulose without medication is used as a tear replacement.

Classification of ocular drug delivery systems

Solutions

- Suspensions

- Powders for reconstitution

- Sol to gel systems

Ointments

Gels - Ocular inserts

38Ideal 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 irritative and comfortable form Appropriate rheological properties39A. Topical Eye drops:40

1- Solutions- Ophthalmic solutions are sterile solutions, essentially free from foreign particles, suitably compounded and packaged for instillation into the eye.

41Disadvantages of eye solutions:

1-The very short time the solution stays at the eye surface.The retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration and the instilled volume.

2- its poor bioavailability (a major portion i.e. 75% is lost via nasolacrimal drainage)3- the instability of the dissolved drug4- the necessity of using preservatives.

422- suspensions

433- Powders for Reconstitution

444- Gel-Forming Solutions

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46Packaging Ophthalmic Solutions And Suspensions

Although a few commercial ophthalmic solutions and suspensions are packaged in small glass bottles with separate glass or plastic droppers, most are packaged in soft plastic containers witha fixed built-in dropper The main advantage of the soft plastic containers are: convenience of use by the patient decreased contamination potential lower weightlower cost

The plastic bottle and dispensing tip is made of low-density polyethylene (LDPE) resin, which provides the necessary flexibility and inertness.

47A special plastic ophthalmic package made of polypropylene is introduced. The bottle is filled then sterilized by steam under pressure at 121c.

48The glass bottle is made sterile by dry-heat or steam autoclave sterilization.Amber glass is used for light-sensitive products.

49B. Semisolid Dosage Forms Ophthalmic Ointments and Gels:

Formulation:

Ointments are used as vehicles for antibiotics, sulfonamides, antifungals and anti-inflammatories.Petrolatum vehicle used as an ocular lubricant to treat dry eye syndromes.50

*Gels have increased residence time and enhanced bioavailability than eye drops.N.B. Emulsion bases should not be used in the eye owing to ocular irritation produced by the soaps and surfactants used to form the Emulsion.

51It is suitable for moisture sensitive drugs and has longer contact time than drops.Chlorobutanol and methyl- and propylparaben are the most commonly used preservatives in ophthalmic ointments.

52Packaging

53How to Use Eye Ointments and Gels Properly?

54C. Solid Dosage Forms: Ocular Inserts

Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate.The rate of drug diffusion is controlled by:The polymer compositionThe membrane thicknessThe solubility of the drug

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Advantages:Increasing contact time and improving bioavailability.Providing a prolong drug release and thus a better efficacy.Reduction of adverse effects.Reduction of the number administrations and thus better patient compliance.

56e.g. The Ocusert Pilo-20 and Pilo-40 Ocular system Designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release pilocarpine continuously at a steady rate for 7 days for treatment of glucoma.

consists of (a) a drug reservoir, pilocarpine (free base), and a carrier material, alginic acid: (b) a rate controller ethylene vinyl acetate (EVA) copolymer membrane.

57C. Solid Dosage Forms: Ocular Inserts

58Advantages of pilocarpine ocuserts over drops :

The ocusert exposes the patient to a lower amount of the drug leading to reduced side effects The ocusert provide a continuous control of the intra-ocular pressure The ocusert is administered only once per week & this will imporve patient compliance The ocusert contain no preservative so they will be suitable for patients sensitive to preservatives in opthalmic solutions

Disadvantages of pilocarpine ocuserts:

They are more expensive than drops It may be inconvenient for the patient to retain the ocusert in the eye for the full 7 days The ocusert must be checked periodically by the patient to see that the unit is still in placeD. Intraocular Dosage Forms

They are Ophthalmic products that introduced into the interior structures of the eye primarily during ocular surgery.

Requirements for formulation:1- sterile and pyrogen-free2- strict control of particulate matter3- compatible with sensitive internal tissues4- packaged as preservative-free single dosage

591- Irrigating Solutions

It is a balanced salt solution was developed for hydration and clarity of the cornea during surgery.

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2- Intraocular Injections

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3- Intravitral Implant

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