1. Eye, ear and nose
formulations
Dr Liesl Brown
Department of Pharmacy
University of Limpopo (Medunsa Campus)
Module 2.3: Respiratory system, ear and eye (2011)
2. Pre-reading required
Aulton, M.E. (Editor). Pharmaceutics: The Science of Dosage
Form Design. Latest Edition. London: Churchill Livingstone.
Chapter on solutions and chapter on nasal drug delivery.
Collett, B.M., Aulton, M.E. Pharmaceutical Practice. Latest
Edition. London: Churchill Livingstone. Chapter on ophthalmic
products.
Winfield, A.J., Richards, R.M.E. Pharmaceutical Practice. Latest
Edition. Edinburgh: Elsevier, Churchill Livingstone. Chapter on
ophthalmic products
3. Learning Objectives:
Identify the components of eye drops, eye ointments
and their special pharmaceutical needs;
Briefly discuss the clinical effects regarding the
formulation (not manufacture) of eye drops, such as
the use of preservatives and the effect of chronic use
of preservatives on the integrity of the cornea; and
Identify the target sites in the eye and delivery of drugs
to these sites as well as the design of a dosage form
that achieve the desired effect.
5. Examples of eye
preparations used for a local
effect
Eye drops Contact lens solutions
(solutions/suspensions) – facilitate wearing &
– AI (active ingredient) care
into conjuctival sac Parenteral products –
Eye lotions - for intracorneal,
irrigation & cleaning intravitreous or
eye surface retrobulbar injection
Eye ointments, Solid dosage forms -
creams & gels – AI to placed in conjunctival
lid margins and/or sac to release AI over
conjunctival sac prolonged period
6. Examples of drugs used in
eye preparations
Anaesthetics – e.g. topical Diagnostic agents – e.g.
& surgical procedures fluorescein – highlight
Anti-infectives – e.g. damage to epithelial tissue
antibacterials, antifungals, Miotics – e.g. pilocarpine –
antivirals constrict pupil & contract
Anti-inflammatories – e.g. ciliary muscle
corticosteroids, Mydriatics & cycloplegics –
antihistamines e.g. atropine – dilate pupil &
Antiglaucoma agents – paralyse ciliary muscle to
reduce intraocular pressure facilitate examination of
e.g. beta-blockers interior of the eye
Astringents – e.g. zinc
sulphate
7. Properties of eye drops
Sterile – NB! NB! NB! Isotonic with lachrymal
Free of foreign secretion
particles Hydrogen ion [ ]
should be suitable for
Free from irritating particular drug – ideally
effect not too far from neutrality
Contain suitable Chemically stable
preservative – to prevent
growth of micro organisms
which may accidentally be
introduced during use
8. Components used in eye
preparations
Adjuvants – adjust
Active ingredient(s) tonicity, viscosity or pH –
– desired therapeutic increase stability of AI
effect Suitable container
Vehicle - usually for administration –
aqueous, occasionally oil maintain prep in stable form
e.g. tetracycline & protect contamination
during preparation, storage &
hydrochloride use
Antimicrobial
preservative –
eliminate microbial
contamination during use
& maintain sterility
9. Antimicrobial preservatives
used in eye preparations
Multiple dose containers must contain preservatives
Capable of withstanding test of efficacy of preservatives (BP)
Sterility of drops maintained during use
Drops will not introduce contamination into eyes being treated
Must not adsorb onto the container
Efficacy must not be impaired by the pH of the solution /
interactions with other ingredients
IMPORTANT: Eye drops used during intraocular surgery should
not contain a preservative due to risk of damage to the internal
surfaces of the eye.
!! Preservative may enter the anterior chamber of the eye and
damage the corneal endothelium.
10. Antimicrobial preservatives
used in eye preparations :
Benzalkonium chloride
Preservative of choice Activity enhanced
Present in 70% of aromatic alcohols
commercially produced chelating agents e.g.
eye drops disodium edetate
Enhance transcorneal passage
Stable to autoclaving of non-lipid-soluble drugs e.g.
Bactericidal carbachol
Activity reduced:
CAUTION: Do not use with
In the presence of local anaesthetics.
multivalent cations
(Mg2+, Ca2+)
When heated with The combination of the
methylcellulose anaesthetic abolishing the blink
Incompatible – fluorescein, reflex and the preservative
nitrates solubilising the outer oily
Sorbed by rubber protective layer of the precorneal
film results in drying of the eye
and irritation of the cornea
11. Chlorhexidine acetate /
gluconate (0.01% w/v)
Bactericide
Activity reduced – in presence of other
formulation ingredients
Activity enhanced – by aromatic alcohols &
disodium edetate
Stable – pH 5-6
Less stable to autoclaving
12. Chlorbutol (0.5% w/v)
Effective against
bacteria & fungi
Compatible – most
ophthalmic products
Disadvantage
volatility
absorption by plastic
containers
lack of stability at high
temp e.g. autoclaving
13. Phenyl mercuric salts
(0.001 – 0.04% w/v)
Active against CAUTION: do not
bacteria & fungi use in eyes for
Activity increased – prolonged time –
phenyl ethanol intraocular deposition
Activity decreased – of mercury
sodium edetate
Sorbs to rubber
15. Isotonic modifiers
Eye drops should be made iso-osmotic
with tissue fluid (lachrymal fluid) – to
avoid pain & irritation
Only added after all other additives have
been added – each ingredient will
contribute towards the overall osmotic
pressure of the solution
E.g. dextrose, sodium chloride
16. Viscosity enhancers
Gelling agents e.g. methylcellulose,
polyvinyl alcohol
Increasing viscosity – increase residence
time of drop in eye resulting in increased
penetration & therapeutic action of drug
17. Buffers (pH adjustment)
pH offering best stability during
preparation & storage
pH offering best therapeutic activity
Comfort of the patient – avoid irritation
Acidic solutions (e.g. pilocarpine HCl)
buffred to reduce stinging on installation
E.g. borate buffer, phosphate buffer,
citrate buffer
18. Antioxidants
Added to protect AI from oxidation e.g.
adrenaline, sulphacetamide, amethocaine, phenylephrine,
physostigmine
Physostigmine – antioxidant prevents
discoloration (cosmetic acceptability)
E.g. sodium metabisulphite, sodium
sulphite
19. Chelating agents
Heavy metals catalyse breakdown of AI
by oxidation
Chelating agents included to chelate
metal ions & enhance stability
Enhance antibacterial activity & chemical
stability
E.g. disodium edetate
20. Bioavailability of eye
drops
Active ingredients should have both hydrophilic
and lipophilic forms
At tear pH (7.4) they are able to penetrate the
outer lipid layer of the lipid-water-lipid sandwich
which constitutes the physiochemical structure
of the cornea
Once inside the epithelium the dissociated,
free drug will partially dissociate
The water-soluble dissociated moiety will then
traverse the middle aqueous stromal layer of
the cornea
21. Bioavailability of eye
drops
When the dissociated drug reaches the
junction of the stroma and the endothelium it
will again partially associate forming the lipid-
soluble moiety and thus cross the endothelium
Finally the drug will dissociate into its water-
soluble form and enter the aqueous humour
From here it can diffuse to the iris and the
ciliary body which are the sites of its
pharmacological action
22. Storage conditions
Consider storage temp & conditions at
time of formulation
Refrigerated storage (2-8˚C) can improve
stability of the active ingredient
E.g. chloramphenicol; neomycin,
epinephrine
23. Containers
Made of glass / plastic
Single dose / multiple dose (should not
contain >10 ml)
24. Properties of containers
Protect eye drop from - Internal surfaces treated
microbial contamination, during manufacturing to
moisture, air, light; reduce release of alkali
Material should not be when in contact with
shed/leached into the aqueous solution;
solution; Seal properly;
Formulation should not Rubber components
be sorbed by container should be treated with
Withstand autoclaving; preservative;
Comply with test for Comply with poisons
alkalinity of glass – glass regulation;
composition (neutral glass / soda Non-glass components
glass) –
should all be inert
25. Formulation of eye drops
1. Preparation of solution
Prepare vehicle containing preservative,
antioxidant, stabilizer, tonicity modifier, viscolizer
or buffer
Add active ingredient
Vehicle made up to volume
2. Clarification
No particulate matter left in solution
Make use of sintered glass filters/membrane filters
(0.45 – 1.2 µg pore size)
Clarified solution is then filled into final containers
Sealed and
Sterilized
26. Formulation of eye drops
3. Sterilization
Autoclaving - 115ºC for 30 min or 121ºfor 15 min
Heating – 98-100ºC for 30 min with benzalkonium chloride
/ect
Filtration – membrane filter 0.22 µg pore size into sterile
containers using strict aseptic technique (Grade A laminar
airflow conditions)
Dry heat sterilization - 160ºC for 2 hours – for non-aqueous
preparations e.g. liquid paraffin eye drops – silicone rubber
teats must be used
4. Cover with readily breakable seal e.g. viskring –
to distinguish between opened and unopened
containers
5. Labelling of container
27. Labeling requirements
Fully identify the Ensure correct use e.g.
product state: “Shake the bottle”
Specify storage for eye suspensions
conditions: cool place Do not use more than 30
/protect from light days after first opening
Expiry date Keep out of reach of
Warning label children
indicated: “Not to be
taken”
Specify volume
28. Formulation of eye lotions
- Uses -
Cleaning of external surfaces of the eye
Help remove a non-impacted foreign
body
Clean away conjunctival discharge
Very simple – most consist of sterile
normal saline
Are not formulated to deliver the active
ingredient to the eye
29. Formulation of eye lotions
- Requirements -
Sterile Lotions for surgical &
Usually containing first-aid procedures
no preservatives No antimicrobial
preservatives
Isotonic with
Single-use containers
lachrymal fluid
Supplied in coloured
Large volume - not
fluted bottles
greater than 200 ml
Sealed to exclude
Non-irritant to
microorganisms
ocular tissue
30. Formulation of eye lotions
- Labeling requirements -
Title identifying the product
“Sterile until opened”
“Not to be taken”
“Use once and discard the remaining solution”
Expiry date
Preserved eye lotions
“Avoid contamination of contents during use”
“Discard remaining solutions not more than 4 weeks
after first opening”
31. Formulation of eye
ointments
Advantages: Disadvantages:
Provide greater total Temporarily
drug bioavailability interfering with vision
than liquids
However, takes a
longer time to reach
peak absorption
32. Formulation of eye ointments
- Requirements -
Sterile
Suitable antimicrobial preservatives – BP
states chlorbutol / the parabens / organic
mercurials to be used
Antioxidants
Stabilizers
Free from particulate matter (<25 µm)
33. Formulation of eye lotions
- Components -
Liquid paraffin 1 part
Wool fat 1 part – to facilitate incorporation of
water
Yellow soft paraffin 8 parts
Hard paraffin as required – to produce
required consistency in hot climates
34. Formulation of eye
ointments - Containers -
Small sterilized collapsible tubes – made of
metal / suitable plastic
Must not contain more than 5 g of
preparation
Fitted / provided with nozzle – to facilitate
application to eye & surrounds without allowing
contamination of contents
Suitably sealed – to prevent microbial
contamination
35. Formulation of eye
ointments - Preparation -
Aseptic techniques – all apparatus clean &
sterile
Finely powdered active ingredient / sterilized
concentrated solution incorporated into sterile
ointment base
Filled into sterile containers
Sealed – to exclude microorganisms
Screw cap cover with readily breakable seal
Sometimes sterilized in final containers –
ionising radiation
36. Formulation of eye
ointments - Labeling -
Names and % of active ingredients
Contain an expiry date
Storage conditions – not >25˚C
Name & [ ] antimicrobial preservative /
other substance added
Statement to effect that contents are
sterile - proving the container has not
been opened
40. Ear preparations
- Formulation aspects -
No special difficulties
Solutions of drugs in
water (purified water/boiled & cooled water)
diluted alcohol (alcohol/water mixtures)
glycerol
propylene alcohol
Apparatus & containers – should be
thoroughly cleaned & rinsed before use
Eye dropper bottles may be used
41. Ear preparations
- Containers -
Small glass or plastic containers – with a
dropper
42. Ear preparations
- Labeling -
“For external use only” and “Not to be
taken” in addition to any special
directions
46. Nasal preparations
- Uses / Examples -
Active agents for local use:
Antibiotics
Anti-inflammatory
Decongestants
47. Nasal preparations
- Dosage forms -
Dosage forms should be designed in
order for drugs to be:
deposited in the anterior (back) part of nasal
cavity as it is:
better absorbed there
nasal residence time increased
48. Nasal preparations
- Dosage forms -
Liquid formulation
Usually aqueous solutions - (simple to develop)
Have a lower microbiological & chemical stability -
requiring the use of various preservatives (disadv:
can cause irritation/ciliotoxicity)
Nose drops – simplest way of nasal drug
administration, but its cheapness & convenience
are outweighed by the inaccuracy of dosing
volume and likelihood of too-rapid clearance by
the nose liquid running straight into oesophagus
This is improved by unit-dose packs
49. Nasal preparations
- Dosage forms – (cont.)
Squeezed bottles
Better absorption – directing formulation
into the anterior part of the cavity –
covering a large part of nasal mucosa
Subject to contamination – “suck-back”
action as external material can be drawn
into the container as pressure on it is
released
50. Nasal preparations
- Dosage forms – (cont.)
Metered-dose pump system
Greater control over dosing
Deliver solutions, suspensions, emulsions – predetermined
volume of 25 – 200 μL – offering deposition over large area
Have control over size and localisation of dose by changing
various factors
E.g. Cone angle (angle at which spray leaves nozzle) will affect where
formulation is deposited
e.g. small angle (35º) deposited towards back of nasal cavity;
larger angle (90º) will go to the front nasal area
Optimum particle size – for deposition in nasal cavity is 10
μm
Particulate formulations e.g. those that have a longer
residence time than liquids are removed more slowly by
mucociliary clearance, hence their nasal deposition time is
longer
51. Nasal preparations
- Strategies to improve drug
bioavailability -
Improve nasal residence time
Enhance nasal absorption
Modify drug structure to change
physiochemical properties
52. Nasal preparations
- Physico-chemical factors
affecting drug absorption -
Size of drug molecule
Charge of drug molecule
Degree of hydrophilicity/lipophilicity
53. Nasal preparations
- Formulation aspects -
Formulated as small volume solutions in an aqueous
vehicle (oils no longer used for nasal administration)
Increase nasal residence time by adding viscosity
increasing agents (e.g. methylcellulose, hydroxypropylmethylcellulose,
polyacrylic acid [Carbopol])
delay mucociliary clearance - which acts to remove foreign
bodies from the nasal mucosa as quickly as possible (does not
necessarily increase absorption)
Absorption enhancers – should not damage or
permanently change epithelial cells e.g. bile salts,
cyclodextrins
54. Nasal preparations
- Formulation aspects -
Absorption enhancers – should not damage or
permanently change epithelial cells e.g. bile salts,
cyclodextrins
Modifying drug structure – more favourable
physiochemical properties
Isotonic with nasal secretions (adjusting pH 5.5 –
6.5) – use salts e.g. NaCl - nasal mucous has low
buffering capacity – to prevent damage to the ciliary
transport in the nose
Antioxidants e.g. butylated hydroxytoluene
Solubilising agents e.g. glycerol derivatives
Antimicrobial preservatives e.g. benzalkonium chloride
Humectants to minimise irritation e.g. glycerol
55. Nasal preparations
- Containers -
Drops:
Amber, ribbed hexagonal glass bottle fitted
with rubber teat & dropper
Nasal solutions:
Flexible plastic bottles which deliver a fine
spray when squeezed
Plain glass bottle with pump spray or
dropper
56. Pharmaceutical Care
Eye preparations
Ear preparations (drops)
Nose preparations (drops/sprays)
57. Learning Objective:
Describe the steps in counselling a
patient on correct eye drop/ointment use,
including storage and disposal
58. Eye preparations
- Installation of eye drops -
1. Wash your hands.
2. Do not touch the dropper opening.
3. Look upward.
4. Pull the lower eyelid down to make a
„gutter'.
5. Bring the dropper as close to the 'gutter'
as possible without touching it or the
eye.
6. Apply the prescribed amount of drops in
the 'gutter'.
7. Close the eye for about two minutes.
Do not shut the eye too tight.
8. Excess fluid can be removed with a
tissue.
9. If more than one kind of eye-drop is
used wait at least five minutes before
applying the next drops.
10. Eye-drops may cause a burning feeling
but this should not last for more than a
few minutes. If it does last longer
consult a doctor or pharmacist.
59. Eye preparations
- Installation of eye drops
into the eye of a minor -
1. Let the child lie back with head straight.
2. The child's eyes should be closed.
3. Drip the amount of drops prescribed
into the corner of the eye.
4. Keep the head straight.
5. Remove excess fluid.
60. Eye preparations
-Installation of eye ointment-
1. Wash your hands.
2. Do not touch anything with the tip
of the tube.
3. Tilt the head backwards a little.
4. Take the tube in one hand, and
pull down the lower eyelid with the
other hand, to make a 'gutter'.
5. Bring the tip of the tube as close to
the 'gutter' as possible.
6. Apply the amount of ointment
prescribed.
7. Close the eye for two minutes.
8. Remove excess ointment with a
tissue.
9. Clean the tip of the tube with
another tissue.
61. Counseling aspects, storage
and disposal of eye
preparations
Preparations use for the eye should be sterile
Keep opened eye drops for 30 days only, then discard / return to your
pharmacist for proper disposal
Never touch eye lashes or eye with eye dropper / opening of eye
ointment container, as this may lead to repeated reinfection
Never share eye drops/ointment - eye drops or ointments should never
be administrated to different patients from the same container
When multidose containers or fluorescein are used, special care
should be taken to avoid contamination. Corneal abrasions are natural
portals to infection, and as Pseudomonas aeroginosa grows in
fluorescein, this agent has often been implicated in introducing
infection.
Single dose containers are more expensive, but are preferred for their
safety
Wash your hands before and after application of ophthalmic agent
62. Counseling aspects, storage
and disposal of eye
preparations (cont.)
Keep drops/ointment at room temperature unless otherwise advised /
indicated
General OTC ophthalmic agents shouldn't be used for more than 3
days without a doctors supervision
When using drops - apply to uncovered eye early and frequently at
least hourly
When using ointments - apply under the eye pad for ulcers and injuries
to the eye. Apply at night.
When applying sulphur drugs -never use if the eye has excessive pus,
as the pus inactivates its action
When using steroids, care should be exercised in their use as they are
extremely dangerous in herpetic infections and injuries caused by
cellulose
Antiallergic agents (e.g. antihistamines) have generally little effect
topically, and may be used prophylactically
When using wetting agents - apply only to dry eyes
63. Ear preparations
- Installation of ear drops -
Warm the ear-drops by keeping
them in the hand or the armpit for
several minutes. Do not use hot
water tap, no temperature control!
Tilt head sideways or lie on one Adult
side with the ear upward.
Gently pull the lobe to expose the
ear canal. Child
Apply the amount of drops
prescribed.
Wait five minutes before turning to
the other ear.
Use cotton wool to close the ear
canal after applying the drops
ONLY if the manufacturer explicitly
recommends this.
Ear-drops should not burn or sting
longer than a few minutes.
64. Nose preparations
- Installation of nose drops -
Blow the nose.
Sit down and tilt head
backward strongly or lie down
with a pillow under the
shoulders; keep head straight.
Insert the dropper one
centimetre into the nostril. cm
Apply the amount of drops 1
prescribed and remove the
dropper.
Immediately afterward tilt head
forward strongly (head
between knees).
Sit up after a few seconds, the
drops will then drip into the
pharynx.
Repeat the procedure for the
other nostril, if necessary.
Rinse the dropper with boiled
water.
65. Nose preparations
- Installation of nasal spray -
Blow the nose.
Sit with the head slightly tiled
forward.
Shake the spray.
Insert the tip in one nostril.
Close the other nostril and mouth.
Spray by squeezing the vial (flask,
container) and sniff slowly.
Remove the tip from the nose and
bend the head forward strongly
(head between the knees).
Sit up after a few seconds; the
spray will drip down the pharynx.
Breathe through the mouth.
Repeat the procedure for the other
nostril, if necessary.
Rinse the tip with boiled water.
66. References
Alton, M.E. (Editor). Pharmaceutics: The Science of Dosage Form
Design. Latest edition. London: Churchill Livingstone. Chapters
on Solutions / Nasal Drug Delivery
Collett, B.M., Alton, M.E. Pharmaceutical Practice. Latest edition.
London: Churchill Livingstone, Chapter on Ophthalmic products
Winfield, A.J., Richards, R.M.E. Pharmaceutical Practice. Latest
Edition. Edinburgh: Elsevier, Churchill Livingstone. Chapter on
Ophthalmic Products