SPECIAL SOLUTIONS AND SUSPENSIONS

Ophthalmic Drug Delivery

O Preparations applied topically to the eye.
O Used to treat bacterial, viral & fungal

infections of the eyes or eyelids. O Used in treating allergic or infectious conjunctivitis and inflammation; elevated intraocular pressure and glaucoma as well as dry eyes due to insufficient fluid production for bathing the eyes.

Ophthalmic Drug Delivery

O 7 to 8 uL normal volume of tear fluid in

the cul-de-sac(conjunctival fornix) of the eye. O 30uL- eye that does not blink. O 10uL- eye that blink. O Topical applications and ointments are used in small amounts and liquid dropwise because the eyes cannot retain liquid and semisolid preparations.

Ophthalmic Drug Delivery

O 5 to 10 uL the optimal volume of

administration of ophthalmic preparations. O 25-50 uL the average dropper delivery . O Short retention time of preparations because of the dynamics of the lacrimal glands. O Absorption of drug is only a small fraction of the quantity administered.

Ophthalmic Drug Delivery

O Gel systems. Liposomes, polymeric drug

carriers , ophthalmic suspensions and ointments INCREASE ocular retention thus greater bioavailability is achived. O Ex: Pilocarpine Ophthalmic solutionmedical management of glaucoma,.

Pharmacologic Categories of Ophthalmic Drugs

O Anesthetics- employed to provide pain

relief preoperatively(before surgery), postoperatively(aftersurgery) for ophthalmic trauma, and ophthalmic examination.
O Ex: Tetracaine, cocaine and proparacaine

Pharmacologic Categories of Ophthalmic Drugs

O Antibiotic and antimicrobial agents- used

systemically and locally to combat ophthalmic infection.

O Ex: Topically applied Azithromycin,

Gentamicin Sulfate, Sodium Sulfacetamide, Ciprofloxacin HCL, ofloxacin, polymyxin B- bacitracin, Tobramycin.

Pharmacologic Categories of Ophthalmic Drugs

O Antifungal agents- for fungal infections

cause by fungal endophthalmitis and fungal keratitis.

O Ex: Amphotericin B, Natamycin,

Flucytosine

Pharmacologic Categories of Ophthalmic Drugs

O Anti-inflammatory agents-for treating

inflammation of the eyes, as allergic conjunctivitis.

O Ex: Fluorimetholone, Prednisone,

Dexamethasone salts( Topical antiinflammatoy steroidal agents) O Diclofenac, flurbiprofen, ketorolac, suprofen(NSAIDS)

Pharmacologic Categories of Ophthalmic Drugs

O Astringents- used in the treatment of

conjunctivitis.
O Ex: Zinc sulfate(astringent in ophthalmic

solutions)

Pharmacologic Categories of Ophthalmic Drugs

O Beta-adrenergic blocking agents- used

topically in the treatment of intraocular pressure and chronic open-angle glaucoma.

O Ex: Betaxolol HCl, Levobunolol HCl,

Metipranolol HCl, Timolol maleate.

Pharmacologic Categories of Ophthalmic Drugs

O Miotics- used in the treatment of

glaucoma, accommodative esotropia, convergent strabismus and for local treatment of myasthenia gravis.
O Ex: Pilocarpine, echothiophate iodide,

demecarium bromide, acetazolamide(oral), timolol(beta-blocker), apraclonidine HCl(alpha-adrenergic agent), dipivefrin HCl(sympathomimetics), bimatoprost, latanoprost, travoprost(Ester producing analog of prostaglandin)

Pharmacologic Categories of Ophthalmic Drugs

O Mydriatrics-examination of the fundus by

dilating the pupil. O Cycloplegics-mydriatrics having long duration of action.

O Ex: Scopolamine, homatropine,

cyclopentolate, phenylephrine, hydroxyamphetamine, and tropicamide.

Pharmacologic Categories of Ophthalmic Drugs

O Protectants and artificial tears- for

lubrication.
O Ex: Carboxymethyl cellulose,

methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol

Pharmacologic Categories of Ophthalmic Drugs

O Vasoconstrictors and Ocular

decongestants-applied topically to the mucous membrane of the eye causing transient constriction of the conjunctial blood vessels. O Employed to soothe, refresh and remove redness due to minor irritation. O Ex: Naphazoline, oxymetazoline, tetrahydrozoline HCls. Antihistaminesemedastine difumarate, ketotifen fumarate, olopatadine HCl

Pharmaceutical Requirements
O Sterility and Preservation
O Isotonicity O Buffering

O Viscosity
O Ocular bioavailability O Packaging

Sterelity and Preservation

O Ophthalmics sterilized by autoclaving at

121 degrees Celcius for 15 minutes. O Alternative is bacterial filters, but they are not as reliable as the autoclave.

Advantage of Filtration
O The retention of all particulate

matter(microbial, dust, fiber), the removal is of importance to the industry.

Sterelity and Preservation

O Antimicrobial preservatives- to maintain

sterility; exception is during surgery or in the treatment of traumatized eyes because it can cause irritation. O Preservative- free preparations- packed in single-use containers.

O Ex: Benzalkonium chloride(0.004%-

0.01%), Benzethonium chloride(0.01%), Chlorobutanol(0.5%), Phenylmercuric acetate(0.004%), Thimerosal (0.005%- 0.01%) ineffective against Pseudomonas aeruginosa which can cause ulceration and blindness. O Limitations: Chlorobutanol-cannot be autoclaved because it decomposes to HCL even in moderate heat.

O Benzalkonium chloride(0.01%)

+ polymyxin B sulfate or aminetetraacetate(0.01% to 0.1%) effective against most strains of Pseudomonas.

Sterelity and Preservation

O During preformulation studies
O stable O Chemical and physical compatibility with

other formulation and packaging components O Effectiveness.

ISOTONICITY VALUE
O Osmosis occurs if a solution is placed

behind a semipermeable membrane that alows only the solvent molecules and not the solute molecules. O Osmotic pressure is responsible in a solution-filled membrane that has a higher solute concentration than its own and the solvent is trying to reach equilibrium.

ISOTONICITY VALUE
O Solute is not electrolyte= concentration of

solution depends solely on the # of molecules present.

O Solute is a electrolyte= depend not only

on the # of molecules present but also on their ionization degree.

ISOTONICITY VALUE
O A highly ionized chemical will

contribute a greater # of particles to the solution than will the same amount of a poorly ionized substance the effect is:
O Solution with greater # of

particles(ions or molecules has higher osmotic pressure than does a solution having fewer particles.

0.9 % NaCl Solution

O Body fluids including blood ad tears.
O Considered to be isosmotic or having an

osmotic pressure equal to that of body fluids. O Isotonic is the equal tone while isosmotic is the comparison of 2 physiologic or nonphysiologic fluids.

Hypotonic
O Osmotic pressure lower than 0.9

NaCl solution. O It may induce hemolysis(bursting/swelling) of RBC or water passage from the site of ophthalmic application through the tissue of the eye.

Hypertonic
O Osmotic pressure greater than 0.9%

NaCl solution.
O It can cause crenation or cell

shrinking; in the eye, it can draw water toward the site of topical application

ISOTONICITY LEVEL LIMIT

O In ophthalmic preparation the

limit is:
O0.6% to 2% without any

marked discomfort to the eye.

ISOTONICITY VALUE
O Boric acid- an alternative to 0.9%

NaCl solution because it has the same osmotic pressure with 0.9% NaCl solution.
O The concentration of Boric acid

must be 1.9%

ISOTONICITY VALUE
Determinants in Isosmoticity(Directly proportional):
O Osmotic pressure
O Vapor pressure O Boiling and freezing point (most

used in determinig isosmoticity)

BUFFERING
O Purpose:
O Greater comfort to the eye. O To render stability to the formulation O To enhance the aqueous solubility of drug O To enhance bioavailability of the drug by

favoring unionized molecular species.) O To maximize preservative efficacy.

TEARS
O 7.4 pH but varies.
O Have some buffer capacity

Ophthalmic drugs
O Weakly acidic and have weak buffer

capacity. O Tears buffering action neutralized the ophthalmic preparation and prevents marked discomfort.

BUFFERING
O Eye more comfortable with pH higher than

7(basic) than pH lower than 7 (acidic). O Ophthalmic solution- should have same pH as the tears(7.4 pH) but it is impossible because many drugs are insoluble in water at 7.4 pH. O Pilocarpine HCl & Epinephrine bitartrateacidic and overtax the tears buffer capacity.

BUFFERING
O Drugs used in ophthalmic solutions are

most active therapeutically at pH levels that favors the undissociated molecule but the pH that permits greatest activity may also be the pH at which the drug is least stable thus a COMPROMISE pH is selected maintained by buffers to permit the greatest activity while maintaining stability. O Isotonic phosphate vehicle- employed in extemporaneous compounding of ophthalmic solution at desired pH.

ISOTONIC PHOSPHATE VEHICLE

O Prepared with 2 stocks solution.
O Contains:8 g monobasic sodium

phosphate per liter and the other 9.47 dibasic sodium phosphate per liter O Drug substances into the isotonic phosphate vehicle= SOLUTION BECOMES SLIGHTLY HYPERTONIC.

VISCOSITY AND THICKENING AGENTS

O Viscosity- property of liquid to flow. It is

defined in terms of the force required to move one plane surface past another under specified conditions when the space between is filled by the liquid in question. O All viscosities are expressed in terms of the viscosity of pure water at 20 degrees Celcius which is 1.0087 centipoise(cP). O Fluidity- the opposite of viscosity.

VISCOSITY AND THICKENING AGENTS

O Liquid material 10 times as viscous as
O

O
O

water at same temperature= 10 centipoise(cP) 1 poise= 100 centipoise(cP). Poise or cP determination results in the calculation of absolute viscosity. Increasing temperature= decrease in viscosity. 15 to 25 cP=viscosity for ophthalmic preparations.

VISCOSITY AND THICKENING AGENTS

O Kinematic scale=convinient

in solving viscosity. O Formula:

Kinematic Viscosity=absolute viscosity/ density

THICKENING AGENTS
O Added to increase the viscosity and aid in

maintaining the drug in contact with the tissues to enhance therapeutic effectiveness. O Ex; Methylcellulose of 4,000 cP used in 0.25%; 25-cP type at 15 concentration.
Hydroxypropyl methylcellulose, polyvinyl alcohol.

VISCOSITY AND THICKENING AGENTS

O 1% solution of methylcellulose

w/o medication is used as a tear replacement.

OCULAR BIOAVAILABILITY
O Important factor in the

effectiveness of an apllied ocular medication. O Factors affecting ocular bioavailability:

O Protein binding

O Drug metabolism
O Lacrimal drainage

O Protein bound drugs- incapable of

penetrating the corneal epithelium because of the size of protein-drug complex thus resulting to inabsorption of drugs therapeutic effect because of the brief retention time of drug in the eyes,
O Tears contain 0.6% to 2% protein

including albumin and globulins.

Other factors
O Physiocochemical characteristics of

the drug O Product formulation O Important because it is in these factors that the effectivity of the ophthalmic preparation lies.

Additional Considerations
O Ophthalmic solutions must be:
O Sparkling clear O Free of all particulate matter

O The formulation of ophthalmic suspension

is used when extended corneal contact time is desired or when the medicinal agent is insoluble or unstable in aqueous vehicle.

Additional Considerations
O Ophthalmic suspensions must be:
O Finely subdivided O Micronized to prevent irritation/

scratching O Suspended particles must not associate into large particles upon storage O Easily ad uniformly distributed upon shaking.