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 solution- medical 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 anti-inflammatoy 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 HCl’s. Antihistamines- emedastine difumarate, ketotifen fumarate, olopatadine HCl

Pharmaceutical Requirements

OSterility and PreservationO IsotonicityOBufferingOViscosityOOcular bioavailabilityOPackaging

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

OThe 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.

OEx: 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.

OLimitations: Chlorobutanol-cannot be autoclaved because it decomposes to HCL even in moderate heat.

OBenzalkonium 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 stableO Chemical and physical compatibility

with other formulation and packaging components

O Effectiveness.

ISOTONICITY VALUEO 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 VALUEO 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

OA 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:

OSolution with greater # of particles(ions or molecules has higher osmotic pressure than does a solution having fewer particles.

0.9 % NaCl SolutionO 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 non-physiologic fluids.

Hypotonic

OOsmotic 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

OOsmotic 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

OIn ophthalmic preparation the limit is:

O0.6% to 2% without any marked discomfort to the eye.

ISOTONICITY VALUE

OBoric acid- an alternative to 0.9% NaCl solution because it has the same osmotic pressure with 0.9% NaCl solution.

OThe concentration of Boric acid must be 1.9%

ISOTONICITY VALUE

Determinants in Isosmoticity(Directly

proportional):OOsmotic pressureOVapor pressureOBoiling and freezing point

(most used in determinig isosmoticity)

BUFFERINGO Purpose:

O Greater comfort to the eye.O To render stability to the formulationO To enhance the aqueous solubility of

drugO To enhance bioavailability of the drug

by favoring unionized molecular species.)

O To maximize preservative efficacy.

TEARSO 7.4 pH but varies.O Have some buffer capacity

Ophthalmic drugsO Weakly acidic and have weak buffer

capacity.O Tears’ buffering action neutralized

the ophthalmic preparation and prevents marked discomfort.

BUFFERINGO 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 bitartrate-acidic and overtax the tears’ buffer capacity.

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.

BUFFERING

ISOTONIC PHOSPHATE VEHICLE

OPrepared with 2 stocks solution.OContains:8 g monobasic sodium

phosphate per liter and the other 9.47 dibasic sodium phosphate per liter

ODrug 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 water at same temperature= 10 centipoise(cP)

O 1 poise= 100 centipoise(cP). O Poise or cP determination results in the

calculation of absolute viscosity.O Increasing temperature= decrease in

viscosity. O 15 to 25 cP=viscosity for ophthalmic

preparations.

VISCOSITY AND THICKENING AGENTS

OKinematic scale=convinient in solving viscosity.

OFormula:Kinematic Viscosity=absolute viscosity/ density

THICKENING AGENTSO 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

O1% solution of methylcellulose w/o medication is used as a tear replacement.

OCULAR BIOAVAILABILITYOImportant factor in the

effectiveness of an apllied ocular medication.

OFactors affecting ocular bioavailability:OProtein bindingODrug metabolismOLacrimal drainage

OProtein bound drugs- incapable of penetrating the corneal epithelium because of the size of protein-drug complex thus resulting to inabsorption of drug’s therapeutic effect because of the brief retention time of drug in the eyes,

OTears contain 0.6% to 2% protein including albumin and globulins.

Other factors…

OPhysiocochemical characteristics of the drug

OProduct formulation O Important because it is in these

factors that the effectivity of the ophthalmic preparation lies.

Additional Considerations

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.

O Ophthalmic solutions must be:O Sparkling clearO Free of all particulate matter

Additional Considerations

O Ophthalmic suspensions must be:O Finely subdividedO Micronized to prevent irritation/

scratchingO Suspended particles must not

associate into large particles upon storage

O Easily ad uniformly distributed upon shaking.