Download Categorization

Ophthalmic Preparations
• Definition: They are specialized dosage forms
designed to be instilled onto the external
surface of the eye (topical), administered
inside (intraocular) or adjacent (periocular) to
the eye or used in conjunction with an
ophthalmic device
Categorization
• Solution/suspension into conjunctival sac
• Lotions for irrigating & cleansing eye surface
• Ointments/ creams/ gels for lid margin/
conjunctival sac
• Contact lenses sol facilitate wearing & care of
lenses
• Parenterals (intracorneal,intraviterous,
retrobulbar inj
• Solids in conjunctival sac release over long period
Drugs used in the eye:
•
•
•
•
•
•
•
•
•
•
•
Miotics e.g. pilocarpine Hcl
Mydriatics e.g. atropine
Cycloplegics e.g. atropine
Anti-inflammatories e.g. Corticosteroids, antihistamines
Anti-infectives (antibiotics, antivirals and antibacterials)
Anti-glucoma drugs e.g. pilocarpine Hcl, beta-blockers
Surgical adjuncts e.g. irrigating solutions
Diagnostic drugs e.g. sodiumfluorescein
Anesthetics e.g. tetracaine surgical procedurs
Astringent e.g. zinc sulphate
Diagnostic agents e.g fluorescein
Anatomy and Physiology of the Eye:
Formulation
•
•
•
•
A.I/s therapeutic effect
Vehicle ,usu aq./ can be oil (tetracycline HCl)
Antimicrobial preservative , maintain sterility
Adjuvants, adjust tonicity, viscosity, pH to
↑comfort in use & stability of A.I
• Suitable container for storage & use
• Most important sterility
Preservatives:
• Preservatives are included in multiple-dose eye solutions for
maintaining the product sterility during use.
• Preservatives not included in unit-dose package.
• The use of preservatives is prohibited in ophthalmic products that are
used at the of eye surgery because, if sufficient concentration of the
preservative is contacted with the corneal endothelium, the cells can
become damaged causing clouding of the cornea and possible loss of
vision.
So these products should be packaged in sterile, unit-of-use containers.
• The most common organism is Pseudomonas aeruginosa that grow in
the cornea and cause loss of vision.
Benzalkonium chloride
• Preservative of choice if not C/I for
incompatibility or sensitivity
• It is generally used in combination with 0.010.1% disodium edetate (EDTA). The chelating,
EDTA has the ability to render the resistant
strains of P.aeruginosa more sensitive to
benzalkonium chloride.
• Well-tolerated on the eye up to conc of
0.02%w/v, usu used at 0.01%w/v
• Stable to sterilization by autoclave
• Rapid bactericidal action G+ve/G-ve bacteria
working on cell envelop
• Active in the controlled aq. Environment & pH
values of ophthalmic products
• Activity is reduced in the presence of multivalent
cations as they compete w/ the antibacterial for
negatively charged sites on bacterial cell surface
• Reduced activity if heated w/ methylcellulose
or formulated with anionic & certain conc of
nonionic surfactants
• Incompatible w/ fluorescein ( large anion), &
nitrates
• It is sorbed from solutions through contact w/
rubber
• Its antibacterial activity is enhanced by
aromatic alcohols ( benzyl alcohol)
• Its surface activity may be used to enhance
the transcorneal passage of non-lipid-soluble
drugs such as carbacol
• It should not be used with local anesthetics as
anesthetics will abolish blink reflex &
preservative will result in drying & irritation of
the cornea.
Chlorhexidine acetate / gluconate
• Cationic biguanide bactericide
• Antibacterial activity in aq soln similar to benzalkonium
Cl
• Activity reduced in presence of other formulation
ingredents
• Activity against G-ve bacteria is enhanced by presence
of aromatic alcohols + di-Na edetate
• Activity antagonized by multivalent cations
• Stability is greatest at pH 5-6, less stable to autoclaving
than benzalkonium Cl
• Well tolerated by the eye but allergic rxns may occur
Chlorbutol
• Chlorinated alcohol used at 0.5% w/v
• Compatible with most ophthalmic
preparations
• Disadvantages: volatility, absorption by plastic
containers, lack of stability at high temp
Phenylmercuric salts
• They are slowly active over a wide pH range
against bacteria & fungi
• Activity increased by phenylethanol
• Activity decreased by di-Na-edetate
• Marked absorption by rubber
• Not used if there is a suitable alternative
• The organic mercurial's should not be used in eye
drops which require prolonged usage as it can
lead to IO deposition of mercury
Thiomersal
• Organic mercurial
• Bacteriostatic, fungistatic action
• allergy
Tonicity
• Eye drops are to be made isotonic with the
lacrimal fluid (equivalent to 0.9% NaCl)
• Eye can tolerate small volumes of eye drops
with tonicity range equivalent to 0.7-1.5% w/v
NaCl.
• Common tonicity adjusting agents: NaCl, KCl,
buffer salts, glycerin, propylene glycol,
mannitol
Isotonicity
Lacrimal fluid is isotonic with blood having an isotonicity value
Corresponding to that of 0.9% Nacl solution
• How many grams of NaCl should be used in
compounding the following prescription?
Pilocarpine nitrate 0.3 g
Sodium chloride
q.s
Purified water ad 30 ml
Make isotonic sol.
For the eye
Note : Pilocarpine nitrate NaCl equivalent 0.23
Viscosity enhancers:
(to retard the rate of
setting of particles)
Disadvantages: 1- produce blurring vision as when dry form
a dry film on the eye lids
2- make filteration more difficult
pH Adjustment and Buffers:
• pH adjustment is very important as pH affects:
1- to render the formulation more stable
2- The comfort, safety and activity of the product.
Eye irritation
increase in tear fluid secretion
Rapid loss of medication.
3- to enhance aqueous solubility of the drug.
4- to enhance the drug bioavailability
5- to maximize preservative efficacy
Examples: boric acid/borax, phosphate buffer, citrate buffer
pH Adjustment and Buffers:
pH & buffer
Antioxidants
• To protect A.I from oxidation (adrenaline,
proxymetacaine, sulphacetamide,
phenylephrine)
• Na metabisulphite (preferred at acid pH & has
antimicrobial activity & enhances activity of
phenylmercuric nitrate) & Na sulphite
(preferred at basic pH) are used at 0.1% w/v .
Stable at soln protected from light
Chelating agents
• Such as di-Na-edetate are added to chelate
heavy metal traces so enhance stability
• It is also useful to enhance antibacterial
activity & chemical stability at conc up to 0.1%
Bioavailability
• Most A.I are salts of weak bases
• To penetrate the cornea the bases need to be
at alkaline pH (unionized)
• At tear pH they are able to penetrate the
outer lipid layer of the lipid-water-lipid
structure of the cornea
• Inside the epithelium it will partially dissociate
• So the water soluble moiety will traverse the
middle aq stromal layer of the cornea
• When it reaches the junction of the stroma &
the endothelium it will again partially
associate forming the lipid soluble moiety so it
crosses the endothelium
• Finally the drug dissociates into its water
soluble form & enter aq humor
• Then it can diffuse to the iris & the cillary
body (site of action
• Most effective penetration of lipophilichydrophilic-lipophilic corneal membrane is by
A.I having both hydrophilic & lipophilic forms
• Ex. Highly water soluble steroid phosphate
ester have poor corneal penetration, but the
less water soluble , more lipophilic steroid has
much better corneal penetration
Storage conditions
• To minimize degradation of eye drops storage
temp & conditions must be considered at time
of formulation.
• The stability of several eye drops is improved
by refrigerated storage (2-8C) ex.
Chloramphenicol eye drops
Containers for eye drops
• They should protect the eye drop from
microbial contamination, moisture & air
• Container material should not be shed or
leached into solution, neither should any of
the eye drop formulation be sorbed by the
container
• It should withstand sterilization method used
if the product is to be sterilized in final
container
• Containers may be glass, plastic & may be
single or multiple dose
Single dose containers
• The minims is single dose eye drop container
• Container sealed at its base & has a nozzle
with a screw cap
• Sterilized by autoclaving in an outer heatsealed pouch with peel-off paper backing
Plastic bottle
• Most commercially prepared eye drops are
supplied in plastic dropper bottles
• The bottles are made from polyethylene or
polypropylene & are sterilized by ionizing
radiation prior to filling with sterile
formulation under aseptic conditions
Glass bottles
• Most extemporaneously prepared eye drops
are supplied in amber partially ribbed glass
bottle bottle
• Made from neutral /soda glass which had the
inetrnal surface treated during manufacture to
reduce release of alkali when in contact with
sol
• Neutral can be autoclaved more than once
• Soda autoclaved once
• Teat made from synthetic or natural rubber
• Natural withstand autoclaving at 115⁰C for 30
min but not the high temp of dry heat
sterilization
• Silicone rubber will withstand dry heat
sterilization & are suitable for use with oily
eye drops . They are permeable to water
vapor (susp become cake)
• So aq eye drops having rubber teat have shelf
life of 3 months whichcan be lengthened by
supplying the sterile eye drop in bottle with an
ordinary screw cap together with a separately
wrapped & sterilized silicone rubber dropper
• Teats & caps are used once only\
• All components are thoroughly washed with
filtered distilled or deionized water dried &
stored in a clean area until required
• Rubber teats sorb preservatives &
antioxidants during autoclaving & storage
• Studies are to be done individually to
counteract this loss
Preparation of eye drops
•
•
•
•
Preparation involves
Preparation of the solution
Clarification
Filling & sterilization
Preparation of the solution
• The aq eye drop vehicle containing any
necessary preservatives, antioxidant,
stabilizer, tonicity modifier, viscosity enhancer
or buffer should be prepared first
• Then A.I is added & vehicle made up to vol.
Clarification
• They should be free from particulate matter & BP
has stringent requirement for their absence
• Sintered glass filter or membrane filter of 0.451.2 µm pore size are suitable
• The clarified sol is either filled directly into the
final container which are sealed prior to heat
sterilization or filled into a suitable container to
filtration sterilization
• Clarified vehicle is used to prepare eye drops
susp. Which are filled into final container &
sealed prior to sterilization
Sterilization
• Autoclaving at 115⁰C for 30 min or 121⁰C for
15 min
• Heating at 98-100⁰C for 30 min together with
either benzalkonium Cl or phenylmercuric
acetate or nitrate or thiomersal. This method
is described in BP but is no longer a
pharmacopeial recommendation method
• Filtration through a membrane filter having 0.22
µm pore size into sterile container using strict
aseptic technique
• Dry heat sterilization at 160⁰C for 2 hours
employed for non-aqueous preparation, Silicone
rubber teat must be used
• Immediately following sterilization the eye
containers must be covered with a readily
breakable seal to distinguish btw opened &
unopened containers
How to Use Eye Ointments and Gels
Properly?
Formulation of eye lotions
• eye lotions used to assist in the cleaning of the
external surface of the eye.
• Remove non-impacted foreign body or clean
away conjunctival discharge
• For surgical use in surgical or 1st aid procedure
should not contain antimicrobial preservative
& should be in single-use container
• Preparation is very simple, most common
consist of NS
•
•
•
•
•
•
Requirements
Sterile & usu containing no preservative
Isotonic w/ lacrimal fluid
Neutral pH
Large vol. but not greater than 200ml
Non-irritant to occular tissue
Labels include
• Title identifying the product & conc of
contents
• Sterile until open
• Not to be taken
• Use once & discard the remaining solution
• Expiray date
• Preserved eye lotions would need additional
label
• Avoid contamination of contents during use
• Discard remaining solutions not more than 4
weeks after 1st opening
• Lotions should be supplied in coloured fluted
bottles & sealed to exclude MO