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OPHTHALMIC PREPARATION. Dr. DEWI ISADIARTUTI, Apt., M.Si DEPARTEMEN FARMASETIKA FAKULTAS FARMASI UNIVERSITAS AIRLANGGA.

Ophthalmic preparation. Sterile dosage forms, liquid, semi-solid or solid preparations intended for administration upon the eyeball and/or to the conjunctiva or to be inserted in the conjunctival sac.

The major categories of drugs applied topically to the eye:.

ANATOMY OF THE EYE. Figure 6.1 Cross-section of tre anatomy of tre eye. referencegray,fW869 Comea Conjunctiva SUICUS circularis corneae (Adapted from http://educatjon.yarm.com•' Iris Sulcus circularis comeae Ciliary b)dy Posterior chamtv Lens Rectus lateralis Vitreous Nene sheath CDtic nerve Bcn:ty Zonular spaces Hyaloid canal Rectus medialis Sclera Retina Fovea centralis A. centralis retinae.

ANATOMY OF THE EYE. Conjunctiva Located at the side of the eye and joins on the cornea and eyelids The surface area is large (circa 18 cm2) Helps produce and maintain the tear film The permeability is greater than that of the cornea.

ANATOMY OF THE EYE. Cornea The cornea is composed of the three layer > epithelium: a multilayered ephithelium that is rich in lipids > stroma (central region): an aqueous matrix composed of collagen and keratocytes > endothelium: a lipid-rich, single-cellular epithelium that maintains corneal hydration b. The diffusion of drugs is controlled by the cornea via paracelluler routes c. Effectively absorbed of drug must be exhibit intermediate solubility in lipid and aquoes phase and must be of low molecular weight d. The cornea is non vascular and negatively charged.

ANATOMY OF THE EYE. Lacrimal fluid Secreted from glands The pH is 7.4 , good buffer capacity (presence carbonic acid, weak organic acid and protein) being able to neutralize unbuffered formulations ( pH 3.5 – 10.0 ) Isotonic with blood (0.9% w/w NaCl ), may be formulated within a range tonicity 0.7 -1.5 % w/w NaCl The rate turnover is ± 1 μ L/min and blinking is circa 15-20 times times/min. Function act to remove the therapeutic agent/formulation from the surface of the eye.

THE EYE MECHANISM AGAINST INFECTION. a. the eyelashes help to prevent small particles of dust entering the eye b. the blink reflex is initiated when objects are perceived to be travelling towards the eye c. the eye is continually washes by tear fluid which contains lysozyme (an antibacterial enzyme).

FACTORS AFFECTING BIOAVALABILITY. Degree of ionization Water/lipid solubility coefficient The ocular contact time.

. Tears R3NH R3N Epithelium R3NH R3N Lipid rich Cornea Stroma R3NH R3N Lipid poor Endothelium R3NH R3N Lipid rich Aqueous humour R3NH+ R3N Figure 6.2 Diagrammatic representation of the effect of ionisation (and hence PH) on drug absorption across the comea..

OPTHALMIC PRODUCTS. Eye drops Eye Lotion Eye ointment Contact lens solutions.

TYPES OF OPTHALMIC PRODUCTS. Liquid: eye drops (liquid, suspension, emulsion) and eye lotion Semisolid: ointment, creams and gel Solid: ocular inserts Parenteral products for sub conjunctival or intra ocular injection Liquid product for irrigation of the eye during surgical procedure.

REQUIREMENTS. Particulate matter Viscosity Tonicity pH Sterility Surface activity.

PARTICULATE MATTER. To ovoid irritation: eye drops in the form of solution do not contain particles → filtration particle size of eye drop suspensions is limited → the use of medicaments in the form of ultra-fine powders.

PARTICULATE MATTER. Particle size ( μ m) Particle limitation (per mL) ≥ 10 ≤ 50 ≥ 25 ≤ 5 > 50 Not allowed.

VISCOSITY. Normal capacity of conjunctival sac : 7 -10 μ l Maximum capacity : 30 μ L One drop : 50 μ l Tears viscosity: 1.3 – 5.9 cps (2.92 cps) Most of the drug will have disappeared from the conjunctival sac within 30 seconds and the total amount instilled will have disappeared within 20 -30 minutes Increasing the viscosity to 15 cP → ocular contact time ↑ → bioavailability ↑ Viscolizing agent used in ophthalmic preparations: MC, Hypromellose , PVA.

VISCOSITY. Ideally viscosity-modifying agent: Easily filtered all eye drop solution are filtered during the manufacturing process (using 0.8 µm-filter) or filtration sterilization (0.2 µm-filter) Easily sterilized Sterilisation of eye drop: filtration or by heat Heat steralisation : viscosity-modifying agent must be chemically and physically stable Compatible with other components interaction between preservative and the viscosity modifying agent interaction between API and the viscosity modifying agent.

TONICITY. Tonicity tears approximately equivalent to 0.9 % w/w Na Cl solution Osmolaritas 290-310 mOsm kg -1 Eye can tolerate solutions having tonicity range equivalent to 0.6 -2.0 % w/w Na Cl solution Hypotonic solution can cause temporary oedema of the cornea → impaired vision Hypertonic solution can produce discomfort due to inability of the tears to adequately or rapidly dilute the solution.

pH. Ideally the pH of the ocular solution shouid be controlled at 7.4 (pH of tear fluid) Tears have a great capacity to buffer solutions → solution varying in pH from 3.5 – 10.5 may be instilled without discomfort Buffer may be used to maintain the pH ex. Borate buffer ( pH range 6.8 -9.1) Phosphate buffer (pH range 4.5 – 8.5) Citrate buffer (pH range 2.5 – 6.5).

Buffer & pH adjustment. pH affects: 1. to render the formulation more stable 2. The comfort, safety and activity of the product 3. To enhance aqueous solubility of the drug 4. To enhance the drug bioavailability 5. To maximize preservative efficacy.

Effect temperature & pH. Table 6.1 The effect of temperature and pH on the stability (half-life) of pilocarpine and atropine Drug Atropine Pilocarpine Temperature (oc) 121 121 25 25 121 121 25 25 6.8 5 6.8 5 6.8 5 6.8 5 Half-life 1 hour 60 hours 2 years 130 years 34 minutes 24 hours 66 days Several years.

STERILITY. Ophthalmic preparation must be sterile Pseudomonas aeruginosa → serious infection cause complete loss of eye sight in 24 – 28 hrs. The selected sterilization method is adjusted to formulation and the dosage form a. autoclave b. oven c. filtration d. radiation/gas Preservative is needed to maintain sterility of multiple ophthalmic preparation.

PRESERVATIVE. Ophthalmic preparation intended for multiple use must contain antimicrobial preservative The preservative should be active against a wide range of organism (bacteria and fungi), be capable of withstanding the test efficacy of antimicrobial preservatives Its activity should not be affected by the pH solution into which it is introduce Eye drops supplied for use during intraocular surgery should not contain preservatives → preservative will enter the anterior chamber of the eye and damage the corneal endothelium. Preservatives used in eye preparation: 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%..

PRESERVATIVE. preservatives must demonstrate stability, chemical and physical compatibility with other formulation and packaging components, and effectiveness at the concentration employed. Phenylmercuric salts → deposited in the lens of the eye (termed mercurialentis ) when formulated in preparations that are designed for chronic usage, e.g. for the treatment of glaucoma. Thimerosal is not associated with this problem Chlorobutanol cannot be autoclaved → decomposes to hydrochloric acid even in moderate heat: → a. product susceptible to microbial growth b. alter its pH c. affect the stability and/or physiologic activity of the therapeutic ingredient. benzalkonium chloride (0.01%) + polymyxin B sulfate (1,000 USP U/ mL) or benzalkonium chloride (0.01%) + disodium ethylenediaminetetraacetate (0.01% to 0.1%) are effective against most strains of Pseudomonas.

SURFACE ACTIVITY. The use of surfactants affect the ability of penetration and absorbtion of active ingredients The use of surfactant: 1. As preservative 2. Decrease the surface tension between eye medication and cornea 3. Increase mixing between drugs and lacrimal fluid, increase contact of active ingredients with the cornea and conjunctiva thus increasing penetration and absorption of active ingredients 4. May not increase tear drainage, should not be irritant and damage cornea..

STABILIZER ANTIOXIDANT. Several drugs oxidize on exposure to air with loss potency Autooxidations catalyzed by light and trace metals - replace by inert gas such as nitrogen - inclusion of a chelating agent ( e.g 0.02 % w/v Na EDTA ~ BAC ↓ 0.004 % w/v) - protection of light - antioxidants.