Ophthalmic Preparation 2021

Ophthalmic Preparation

Kittichote Worachotekamjorn

Learning Objectives

1. Types of eye preps
2. Factors affecting eye preparations

3. Methods of sterilization and steps of
preparing eye products

4. Preservatives used
5. Tonicity calculation
6. Role of buffer and viscosity inducing agents
7. How to maintain eye products’ stability
8. Eye Containers
9. Precautions in eye products’ use

Preparation for the eye

•Eye drop

aqueous/oily solutions/suspension

Instilling into the conjunctival sac
•Eye lotion

aqueous solutions used undiluted for
bathing the eye
•Contact lens solution

aqueous solutions for lubricating,
cleaning and hydrating contact lens

Preparation for the eye

•Eye Ointment

ointments for placing in the conjunctival
sac/applying to the margin of the eyelid
•Membrane insert

a device consisting of a drug-containing core
surround by a flexible copolymer membrane
through which the drug diffuses
•Soluble ocular insert

small rod-shaped, water soluble solid of
hydrophilic polymer (i.e. HPC) that can hold an
identified amount of a drug

Preparation for the eye

• Implantable Drug Delivery System

• Ophthalmic Injections

About the eye

• low capacity

• low retention time

• effective dose

• eye disease ……..Eye preparation
(main route)

Ophthalmic Drug

1. Anti-inflammatory
Prednisolone, Dexamethasone

2. Anti-microbial (topical & systemic)
Gentamicin, tetracycline, sulfacetamide,

polymyxin B, bacitracin, chloramphenicol
3. Anti-viral

Vidarabine
4. Astringent …….. zinc



Ophthalmic Drug

5. - adrenergic block
Timolol maleate

6. Local anesthetics
cocaine, benoxinate

7. Miotics
pilocarpine

8. Mydriatrics …….. atropine,
scopolamine



Ophthalmic Drug

9. Topical protectant / thickener/ artificial
tear

MC, HPMC
10. Vasoconstrictors

naphazoline HCl, oxymetazoline HCl,
tetrahydrozoline HCl
11. Antihistamine
Antazoline HCl
12. NSAIDs …….. Diclofenac sodium





Requirements for
Ophthalmic Preparation

~ Other Sterile products
1. Products must be sterile
2. Free from visible particles
3. For ophthalmic injection,

product must be free from
pyrogen

Considerations in preparing

ophthalmic products

I. STERILITY

- most important requirement

- contaminated eye drops have
caused serious damage

- corneal epithelium & tear are natural
protectant of eye

- Accidental/surgical damage to
cornea provides invasive route to
underlying non-invasive tissue

Considerations in preparing

ophthalmic products

I. STERILITY

-the most dangerous organism is
Pseudomonas aeruginosa

-it can grow and multiply in simple salt
solution (i.e. many eyedrops) and in poorly
stored distilled and DI water

-it produces severe corneal ulceration

(blindness and loss of the eye)

-its invasion is assisted by producing a
cornea-destroying enzyme and 2-3
organisms can achieve infection

Considerations in preparing

ophthalmic products

I. STERILITY
- eye preparation must be sterile
- preservative is added to maintain sterility
between use
- eye preparation used for traumatized eye
(operation, diagnosis)
-- no preservative
-- use as single dose
**** Eye preparation must be tested for
sterility (Sterility test)****

Considerations in preparing
ophthalmic products

Method of Sterilization

Moist-heat sterilization
Dry heat sterilization
Sterilization by filtration
Gas sterilization
Ionizing radiation

Considerations in preparing

ophthalmic products

Steps of Preparing Eye Products (Eye drops / Eyewash

solution)

1. Mixing (solution)

2. Filtration (remove particle)

3. Filling

4. Sterilization

Heat-stable drug

Moist-heat sterilization

12 3 4

Heat-labile drug

filtration sterilization

12 4 3

Considerations in preparing
ophthalmic products

Method of Sterilization for Eyedrops (B.P.C.)
1. Method A Heating in an autoclave
115-118 C 10 lb/in2 30 min
2. Method B Filtration
3. Method C Maintaining at 98 -100  C
30 min
Ex chloramphenicol, cocaine HCl, Neomycin

sulfate, physostigmine sulfate

Considerations in preparing

ophthalmic products

Extemporaneous eye preparation
-Sterilization by bacterial filtration
Method
Freshly prepared solution, transfer to
strerile eye bottle through bact filter

*** Must be prepared under LAF (aseptic
technique) equipment must be sterile
prior to use **********

Membrane filter for eye preparation



Considerations in preparing
ophthalmic products

II. Preservatives
-maintain sterility of product
throughout treatment
-not used in product for traumatized
eye/ (single use product is suggested)

Considerations in preparing
ophthalmic products

II. Preservatives
Concerns about using preservatives
1. Formulation Stability
pH, additive, drug, container material
2. No ideal pres.
3. Max level
4. combined use
5. single dose, non-preserve solution?

Considerations in preparing

ophthalmic products

II. Preservatives

1. Esters of p-hydroxy benzoic acid

MP (0.02%) + PP (0.01%)

2. Organic mercurial compounds

Phenylmercuric nitrate (PMN 0.002 %w/v)

Phenylmercuric acetate (PMA 0.002 %w/v)

Nitromersal 1 : 2500

Thimerosal 1:5000-1:20000

3. Cationic surfactants

Benzalkonium chloride 0.01 % w/v

4. Alcohol-derivative

Chlorobutanol 0.5 %

Phenylethyl alcohol 0.5 %

5. Antibiotics

Polymyxin B sulfate

Considerations in preparing

ophthalmic products

II. Preservatives

Disadvantage
1. Esters of p-hydroxy benzoic acid

-mold growth
-water solubility
2. Organic mercurial compounds
-incompatible with halide
-strong adsorption with rubbers
-mercurialentis (everyday use eyedrops are not
suggested)
-Precipitation at low pH for nitromersal and

thimerosal

Considerations in preparing

ophthalmic products

Disadvantage

3. Cationic surfactants

-incompatible with anionic medicament : Fluorescein,
sulfonamides, nitrates, salicylates

-incompatible with high conc of non-ionic compound (MC,
HPMC conc > 5 %)

-ineffective at pH< 5
-adsorb and inactivate by suspension of hydrocortisone
-ppt if use with rubber lubricated with

stearate/microcrystalline polyethylene

4. Chlorobutanol

- hydrolyzed in solution at high temperature
(autoclave/steamer)

- “HCl” incompatible with AgNO3 /Na sulfonamide

Considerations in preparing
ophthalmic products

Preservative Mixture

BZCl 0.01 % + 1000 USP Units/ml polymyxin B

or

BZCl 0.01 % + 0.01-0.1 % disodium EDTA

Considerations in preparing
ophthalmic products

III. Vehicles
Concerns about vehicles
1. To make volume for eye solution
2. Isotonic with body fluid
3. Buffer controls pH
4. Stock vehicle is preserved solution

Considerations in preparing

ophthalmic products

Isotonic

– Body fluid (blood/tear) osmotic pressure
~ 0.9 % w/v NaCl

– Any solution having O.P.~ 0.9 % w/v
NaCl……………….. Isotonic solution

– Eye drop must be made isotonic to
reduce irritation

– Hypertonic solution
– Hypotonic solution *****
– Isotonic agent : NaCl, dextrose, others

Considerations in preparing
ophthalmic products

Isotonic

– NaCl is not used for AgNO3 eye drop

(Ag+ + Cl- AgCl)

Dextrose/NaNO3
– Eyedrop in some case is hypertonic

– Isotonic limits for eye solution “ 0.6-2 %”

– Tonicity of eyewash solution is much
more important than eyedrop

Freezing point depression (Tf 1%)

• Tear/body fluid reduce freezing point =0.52
ºC = 0.9 % sodium chloride

Ex 1% Boric acid eyewash solution 100 ml

Tear fluid = 0.52 ºC
Tf 1% Boric acid = 0.29 ºC
NaCl required = 0.23 ºC = …….. gm
0.52 ºC NaCl 0.9%
0.23 ºC NaCl 0.4% =0.4 gm

Sodium Chloride Equivalent (E)

E of drug = amount (gm) sodium chloride
equivalent in osmotic pressure to drug 1gm

Calculation

1. Change the drug to NaCl Amount (gm)

Ephredine HCl (1.2 g x 0.3) +
Chlorobutanol (0.3 g x 0.24) = 0.432 gm

2. Calculate amount of 0.9% NaCl in 60 ml

preparation (100 ml = 0.9 gm or
=0.54 gm)

3. Sodium chloride to make isotonic solution =

0.54 – 0.432 = 0.11 gm

Sodium Chloride Equivalent (E)

E of drug = amount (gm) sodium chloride
equivalent in osmotic pressure to drug 1gm

Calculation

1. Change the drug to NaCl Amount (gm)

Ephredine HCl (1.2 g x 0.3) +
Chlorobutanol (0.3 g x 0.24) = 0.432 gm

2. Calculate amount of 0.9% NaCl in 60 ml

preparation (100 ml = 0.9 gm or
=0.54 gm)

3. Sodium chloride to make isotonic solution =

0.54 – 0.432 = 0.11 gm

White-Vincent Method

• Calculate water (V) to make solute isotonic first and
adjust to volume with buffered isotonic vehicle

Rx

Phenacaine HCl 0.06 gm (E=0.16)

Boric acid 0.30 gm (E =0.50)

Sterile distilled water ad 100 ml

M.ft. isotonic solution
NaCl equivalent = (0.06 x 0.16) + (0.30 x 0.50)

= 0.0096 + 0.15 = 0.1596 g
0.9 g NaCl water to 100 ml
0.1596 g NaCl water to 100/0.9=111.1 x 0.1596 = 17.7 ml

V = [(W1 x E1)+ (W2 x E2)] x 111.1
= ( W1 x E1 x 111.1) + ( W2 xE2 x 111.1)

Considerations in preparing
ophthalmic products

Buffer

Objective of using buffer in eye preparation
1. Reduce discomfort
2. Increase stability
3. Control optimum activity of drug

Considerations in preparing

ophthalmic products

Tear pH 7.4

– Buffering power
–
– Rapidly Neutralize unbuffered solution
(pH 3.5-10.5)
–
Very acid drug (adrenaline acid tartrate,
– pilocarpine HCl) have to formulate using
buffered vehicle to control pH ~ pH tear

Highly buffered solution (phosphate
buffer pH 5) cause sore eye because it
will not be neutralized by tear

Considerations in preparing
ophthalmic products

Tear

Eye preparation should have low buffer
capacity and adjust to tear pH (~7.4) to
- easily adjust to pH by tear
- easily change the drug to free base (active

form)
Problem ??

1. At pH 7.4 drug will not dissolve and will precipitate
2. At pH which drug is stable (3-5), drug is not active

Considerations in preparing
ophthalmic products

Ex Atropine Eyedrop (Atropine sulfate……pH 6.8
max soluble pH and give optimum activity)

- sterile by autoclaving is not allowed
- short life
To increase stability
1. Prepare at lower pH using buffer (low )
2. Prepare eye solution at pH 6.8 and lyophilize it

Vehicle of adjusted pH for
Eye Preparation USP

Boric Acid Vehicle

 Isotonic but pH <5
 Boric acid 1.9 g dissolve in water to 100 ml
 Unbuffer (easily neutralized by tear)
 Heat Sterilization is OK

Special Boric Acid Vehicle

 Boric acid vehicle + 0.1 % sodium sulfite
 For readily oxidized drug : adrenaline,

physostigmine

Vehicle of adjusted pH for
Eye Preparation USP

Isotonic Phosphate Vehicle

 Buffer Solution pH range from 5.9 to 8.0
 Isotonic Buffered Vehicle for extemporaneous eye

preparation by White Vincent Method

 Salts of hyoscin, homatropine and pilocarpine

have low stability in this vehicle

 Incompatible with zinc salt

Solution I Solution II pH NaCl required
(ml) (ml) for Isotonic
(g/100ml)
NaH2PO4 Na2HPO4
(8g/L) (9.47g/L) 5.9 0.52
90 6.2 0.51
80 10 6.5 0.50
70 20 6.6 0.49
60 30 6.8 0.48
50 40 7.0 0.46
40 50 7.2 0.45
30 60 7.4 0.44
20 70 7.7 0.43
10 80 8.0 0.42
0 90
0

Vehicle of adjusted pH for
Eye Preparation USP

Stock Vehicle
**Add preservatives ***

Stock Vehicle 1 Stock Vehicle 2
NaCl 0.9 gm Boric acid 1.9 gm
BZCl 1:10000 BZCl 1:10000
Sterile D.W. to Sterile D.W. to
100 ml 100 ml
AgNO3 : drug
Zinc : drug
Zinc Nitrate BZCl
salicylate

PMN

Vehicles for Eye Preparation

(Dispensing of Medication)

Vehicles for eye preparation
1. Gr 1 (gr1, gr 1A)
Gr1 boric acid vehicle (pH 5)
****To reduce irritation of drug (highly acid
drug)****
* local anesthetics (---caine)
Increase stability
* Zinc

--------------------------------------------------------------------------------
Gr1A boric acid vehicle (pH 5) + antioxidant

* Phenyleprine,
Physostigmine -- highly acid drug and readily
oxidised
Epinephrine
(nitrate, salicylate, tartrate)

Vehicles for Eye Preparation

(Dispensing of Medication)

Vehicles for eye preparation
1. Gr 2
Gr2 Isotonic phosphate vehicle pH 6.5
(pres : BZCl + EDTA disodium)
****To maintain activity of drug****
drug is stable (soluble) at pH 2-3 but
inactive
alkaloidal drug
• Atropine
• Ephedrine
• Eucatropine
• Pilocarpine
(sulfate or HCl)

IV Viscosity

Use of Viscosity Inducing agent
1. Prolong action
2. Protective
3. Lubricant for dry eye patient
suitable viscosity : 25-50 cps
thickener : MC, PVA, HPC
USP recommended thickener in eyedrop
: 0.5 % MC 4000

IV Viscosity

Use of Cellulose derivative
1. non-ionic
2. sterilised by autoclaving
3. not suitable to be sterilised by
membrane filtration
4. heat labile drug
-thickener and drug separately
sterilised and aseptically mixed

V Stability

To Increase Stability

1. pH adjustment

-Reduce discomfort

-Maintain chemical stability

-Improved clinical response

2. Antioxidant added

2.1 Reducing agent

-Na metabisulfite, Na thiosulfate used for

: adrenaline, phenylephrine, physostigmine,
sulfacetamide

Na metabisulfite will

-react with rubber closure (rubber closure
must be pretreated)

-accelerate non-oxidative degradation of
sulfacetamide

V Stability

To Increase Stability

2. Antioxidant added
2.2 Sequestering agent

“ EDTA “ used instead of Na metabisulfite
in Sulfacetamide E.D. BPC
“ 8-OH quinolone sulfate“ used in
Adrenaline E.D., neutral BPC
3. Volume supplied
NMT 10 ml