Pharmaceutics 2 & 3 2 & 3 Unit 7 2015 / second
semester
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Ophthalmic preparations Definition: 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. 3
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Ophthalmic preparations The 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. 4
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PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGS Anesthetics:
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, 5
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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. 6
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PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGS Miotics 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. 7
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PHARMACOLOGIC CATEGORIES OF OPHTHALMIC DRUGS Vasoconstrictors
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. 8
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Anatomy and Physiology of the Eye: 9
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PHARMACEUTICAL REQUIREMENTS: 10 A.Sterility B.Preservation
C.Isotonicity value D.Buffering E.Viscosity And Thickening
Agents
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PHARMACEUTICAL REQUIREMENTS: 11 A. Sterility - Ideally, 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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12 One 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.
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B. Preservation and preservatives To 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. 13
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14 Among 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%.
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15 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.
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16 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.
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C. ISOTONICITY VALUE Body 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.
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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.
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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.
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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.
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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.
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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.
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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):
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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.
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Simple isosmotic solutions, then, may be calculated by this
general formula:
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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
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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.
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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 = 36mg Thus, 270 36 mg = 234 mg of sodium
chloride required.
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BUFFERING The pH of an ophthalmic preparation may be adjusted
and buffered for one or more of the following purposes : (a) for
greater comfort tothe eye, (b) to render the formulation more
stable, (c) to enhance the aqueous solubility of the drug, (d) to
enhance the drugs bioavailability (i.e., by favoring unionized
molecular species), (e) to maximize preservative efficacy.
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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.
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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.
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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.
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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.
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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.
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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.
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Classification of ocular drug delivery systems -Solutions -
Suspensions - Powders for reconstitution - Sol to gel systems
-Ointments - Gels - Ocular inserts 39
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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 irritative and comfortable
form Appropriate rheological properties 40
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A. Topical Eye drops: 41
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1- Solutions - Ophthalmic solutions are sterile solutions,
essentially free from foreign particles, suitably compounded and
packaged for instillation into the eye. 42
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Disadvantages 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 drug 4- the necessity of using preservatives. 43
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2- suspensions 44
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3- Powders for Reconstitution 45
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4- Gel-Forming Solutions 46
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Packaging 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 weight - lower cost The plastic bottle and
dispensing tip is made of low- density polyethylene (LDPE) resin,
which provides the necessary flexibility and inertness. 48
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A special plastic ophthalmic package made of polypropylene is
introduced. The bottle is filled then sterilized by steam under
pressure at 121c. 49
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The glass bottle is made sterile by dry-heat or steam autoclave
sterilization. Amber glass is used for light-sensitive products.
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B. 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.
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*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. 52
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It 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. 53
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Packaging 54
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How to Use Eye Ointments and Gels Properly? 55
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C. 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 composition - The
membrane thickness - The solubility of the drug 56
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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. 57
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e.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. 58 C. Solid Dosage Forms: Ocular Inserts
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59 Advantages 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 place
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D. 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-free 2- strict control of particulate matter 3- compatible
with sensitive internal tissues 4- packaged as preservative-free
single dosage 60
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1- Irrigating Solutions It is a balanced salt solution was
developed for hydration and clarity of the cornea during surgery.
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