Transcript Ophthalmic Preparations

Pharmaceutics 2 & 3
3&2 ‫صيدالنيات‬
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.
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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.
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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,
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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.
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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.
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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.
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Anatomy and Physiology of the Eye:
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PHARMACEUTICAL REQUIREMENTS:
A.
B.
C.
D.
E.
Sterility
Preservation
Isotonicity value
Buffering
Viscosity And Thickening Agents
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PHARMACEUTICAL REQUIREMENTS:
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 (121°C for 20-30 min).
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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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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.
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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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• 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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• 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.
 Theoretically, a hypertonic solution added to the
body’s 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
solution’s 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 solution’s 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 1.86°C 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 −0.52°C.
 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 −1.86°C. 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 = 36mg
 Thus, 270 − 36 mg = 234 mg of sodium chloride required.
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 drug’s bioavailability (i.e., by favoring
unionized molecular species),
(e) 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
bitartrate—are 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,
homatropinem salts, which show instability in the vehicle.
and
 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
-Ointments
- Suspensions
- Gels
- Ocular inserts
- Powders for
reconstitution
- Sol to gel systems
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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
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A. Topical Eye drops:
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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.
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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.
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2- suspensions
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3- Powders for Reconstitution
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4- Gel-Forming Solutions
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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.
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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 121°c.
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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.
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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.
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 Packaging
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How to Use Eye Ointments and Gels Properly?
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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
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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.
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C. Solid Dosage Forms: Ocular Inserts
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.
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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
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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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2- Intraocular Injections
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3- Intravitral Implant
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