Eye, ear and nose formaulations

1. Eye, ear and nose
for mulations
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.

4. T he eye

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
 Hydrogen ion [ ]
particles
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
& protect contamination
e.g. tetracycline 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
 Incompatible – fluorescein, blink reflex and the
nitrates preservative solubilising the
 Sorbed by rubber outer oily 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

14. Thiomersal
(0.005 – 0.01% w/v)
 Bacteriostatic &
fungistatic

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

37. T he ear

38. Ear preparations
(aka otic/aural products)
Uses / examples:
 Active agents for local use
 Antibiotic – treat infections
 Antifungal agents – polysorbate, gentian violet,
nystatin
 Anti-inflammatory
 Antiseptics
 Cleansing solutions
 Wax softeners

39. Ear preparations
- Dosage forms -
 Drops
 Sprays
 Washes

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

43. T he nose

44. Nasal preparations
 Benefits of nasal administration:
 Convenient
 Useful area for absorbing drugs
 Good systemic blood supply

45. Nasal preparations
- Properties -
 Effective
 Acceptable safety and stability
(chemical & microbiological)
 Acceptable to patient – ensure
compliance

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. Phar maceutical Car e
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
1.
drops -
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 A d u lt
side with the ear upward.
 Gently pull the lobe to expose the
ear canal. C h ild
 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.
1 cm
 Apply the amount of drops
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