Pharmaceutics IV (Dosage Forms and Formulations B)

Unit III

Ophthalmic, Otic and Nasal Preparations

Pabitra Subedi
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 Ophthalmic preparations
• They are specialized pharmaceutical preparations dosage forms designed to be
instilled onto the external surface of the eye (topical), administered inside
(intraocular) or adjacent (periocular) to the eye to treat eye diseases.
• Should be safe, sterile and effective in treating ocular diseases.

Quality requirements
• Quality requirements for ophthalmic preparations are crucial.
• They should be safe, effective, free from contaminants, and reliable.
• These preparations must meet strict and standard criteria as they are used directly in eye which
is very sensitive.
• Low quality preparations can cause potential adverse reactions.
• These requirements cover a wide range of physical, chemical, and microbiological standards,
which are essential in preventing complications and ensuring optimal therapeutic outcomes.
 Quality requirements
Sterility: Essential to prevent infections.
Tonicity: Must be isotonic with tear fluid to prevent irritation.

pH: Must be close to the natural pH of the eye (about 7.4).

Viscosity: Should have optimal viscosity for longer ocular retention.

Bioavailability: Must deliver the intended drug dose to the target tissue

Clarity, and Safety

 Sterility
Sterility absence of viable microbial contamination.
Requirement: Ophthalmic preparations must be sterile because the eye is highly
susceptible to infections. Contaminated ophthalmic formulations may result in eye
infections that could ultimately cause blindness.
How to make sterile?
Aseptic Manufacturing: All manufacturing processes must be conducted in a sterile
environment to minimize the risk of contamination.
1. Autoclaving:
• Heat sterilization
• Formulation in final containers by autoclaving at 121°C (250°F) for 15 minutes.
• Only for formulation that can tolerate high temperatures.
• Disadvantage = cannot be used for thermally instable formulations.
2. Membrane Filtration:
• Sterilization by filtration is commonly used for ophthalmic solutions that cannot
withstand heat.
• Membrane filters having a nominal pore size not greater than 0.45 μm.
• Disadvantage = Not suitable for suspensions.
• Advantage = the retention of all particulate matter (microbial, dust, fiber),
3. Preservation use of preservative agents in the formulation.
Requirement
Preservatives in ophthalmic dosage forms are crucial for maintaining the stability
and safety of the product during its shelf life and for preventing microbial
contamination after opening.

• Prevention of Microbial Contamination

• Ensuring Product Safety and Efficacy
• Prolonging Shelf Life

• Preservatives are typically used in multi-dose containers.

• Preservatives must be stable and have chemical and physical compatibility with
other formulation and packaging components.
• However, preservatives can be toxic to the ocular surface, particularly in the
setting of chronic, prolonged exposure, as in patients with glaucoma.
Preservative Concentration Notes

0.004% to 0.01% Most common preservative but

Benzalkonium Chloride (BAK) may cause irritation with
prolonged use.
EDTA 0.05% to 0.1% Often used in combination with
(Ethylenediaminetetraacetic other preservatives for
acid) antimicrobial action.
Chlorhexidine 0.01% to 0.05% Used in some formulations but
can cause stinging or burning.
Chlorobutanol 0.5% to 1% Less irritating than BAK but can
still cause mild discomfort.
Cannot be autoclaved
because it decomposes to
hydrochloric acid even
in moderate heat.
 Isotonicity
• Isotonicity refers to the condition where two solutions have the same osmotic pressure.

• If two solutions at different concentrations are separated by a semi-permeable

membrane, it allows only the solvent (water)molecules to pass through, from lower
(solute) concentrated solution to higher (solute)concentrated solution.
• This process is known as osmosis and the minimum pressure applied to stop the
osmosis phenomenon is called, osmotic pressure.

PRESSURE

• It is dependent on the concentration of solutes (such as salts or other dissolved

substances) in the solution.
• Osmolarity refers to the concentration of solutes in a solution, expressed in terms
of osmoles of solute per kilogram of solvent (mosm/kg).
• The tear film has an osmolarity of 280–320 mosm/kg, which is considered
isotonic.
• A solution is said to be isotonic when its effective osmole concentration is the
same as that of another solution.
• Hypertonic solutions can cause irritation, while hypotonic solutions can result in
ocular discomfort.
REQUIREMENT
• Ophthalmic preparations should be isotonic with the tear fluid to avoid imbalance
between fluids and eye tissues that can cause damage and irritation.

HYPERTONIC ISOTONIC HYPOTONIC

• Hypertonic (higher osmolarity) or hypotonic (lower osmolarity) solutions can lead

to osmotic stress.
• Hypertonic solutions may draw water out of the ocular tissues, causing dryness,
while hypotonic solutions may lead to swelling of tissues.
• Tonicity agents (e.g., sodium chloride (0.9%), boric acid (1.9%)) are added to
maintain isotonicity.
• Solutions that are isotonic with tears are preferred.
• Example of Isotonic solution is 0.9 % NaCl.
• Body fluids, including blood and tears, have an osmotic pressure corresponding
to that of a 0.9% solution of sodium chloride.
• In practice, the isotonicity limits of an ophthalmic solution in terms of sodium
chloride may range from 0.6% to 2.0% without marked discomfort to the eye.
 pH and buffering
Requirement
The pH of an ophthalmic preparation may be adjusted and buffered for one or more of
the following purposes :
(a) for greater comfort to the eye
If pH is highly acidic or basic can cause irritation and damage

(b) to enhance the solubility and stability of the drug

Solubility is dependent in pH. In inappropriate pH drugs may precipitate.

(c) to enhance the drug’s bioavailability (i.e., by favoring unionized molecular species),
Weak acidic and basic drugs have higher absorption when unionized and is pH
dependent.

(d) to maximize preservative efficacy

BAK is more effective at slightly acidic to neural pH (4-7), pH below this range can
decrease its efficacy.
• The pH of normal tears is considered to be about 7.4
• Ideally, an ophthalmic solution should have the same pH, as well as the same
isotonicity value, as lacrimal fluid.
• This is not usually possible since, at pH 7.4, many drugs are not appreciably soluble
in water .
• Example
Pilocarpine hydrochloride eye drops are formulated at pH 4.5-5.5.
Because it is unstable in alkaline pH. It has better solubility in acidic
environment. Like most alkaloidal salts, it precipitate as the free alkaloid at
pH7.4 .
• Many ophthalmic drugs, are weakly acidic (or basic) and have only weak buffer
capacity.
• At lower pH (more acidic environment), weak acids are more likely to be non-
ionized, which enhances their lipid solubility. This can be beneficial for drugs that
need to penetrate the cornea, which is made up of lipids.
Some common buffering agents include:
• Phosphate buffers (e.g., sodium phosphate): Often used in solutions with a
neutral to slightly alkaline pH (around 7.4).
• Borate buffers (e.g., sodium borate): Used in slightly alkaline formulations.
• Citrate buffers (e.g., sodium citrate): Can be used to achieve a pH range of 4.5
to 6.5, often for acidic formulations.
• Acidic buffers (e.g., hydrochloric acid): Used to lower the pH of formulations
when an acidic environment is needed for drug stability or solubility.

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 Viscosity
• is a property of liquids related to the resistance to flow.
Requirement
It is a crucial parameter because it affects the retention time in the eye, therapeutic
effectiveness, and comfort for the patient.
After instillation of eye drops, most of the formulation is lost.

• Spillage
Less contact time/ retention time of drug and tissues
• Blinking
• Nasolacrimal drainage
• Increasing viscosity will increase ocular retention i.e., longer contact time of
drugs with ocular tissues which will improve drug effectiveness.
• But, if viscosity is very high, application will be difficult, also cause visual
impairment and discomfort to patients.
• Ideal Range for Viscosity: 10 to 50 centipoise (cP)

How is viscosity enhanced?

Thickening agents like methylcellulose, hydroxypropyl methylcellulose and
polyvinyl alcohol are used in ophthalmic solutions.

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 Ocular Bioavailability
Ocular bioavailability is extent and rate at which the drug in an ophthalmic
preparation reaches the site of action in the eye.
Ocular bioavailability is very low (< 5%). Factors affecting are
Biological
• Anatomy and physiology of eye
• normal tear volume=7 µl volume that can be accommodated without spillage=30
µl estimated drop volume =50 µl blinking > residual volume of ~ 10 µl.
• Corneal layers of different lipophilic nature.

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Pre corneal loss of applied drugs immediately by
Tear fluid dilution
•Drugs is immediately diluted by tear after instillation in the eye.
Blinking
•Reflex blinking can cause loss of applied drugs.
Spillage
• During application, the instilled dose can spill.
Nasolacrimal drainage
• Reduces retention time and unwanted systemic absorption.
Biological factors affecting ocular bioavailability
Formulation factors
• Viscosity = low viscosity leads to low retention in eye leading to low absorption
• Drug concentration = if concentration is low, lower absorption
• pH = pH of formulation should be optimal not only for comfort but also better solubility
and stability of active drug
• Optimum lipophilicity/hydrophilicity = is important factor for corneal permeability of drugs as the
corneal layers have varying lipophilicity. For proper corneal permeability of
drug, it should have optimal lipophilicity/hydrophilicity. Corneal epithelial layer and endothelial
layers are lipophilic, so lipophilic drugs have better permeation however, middle layer stroma is
hydrophilic, so hydrophilic drugs have better permeation.

How to improve?
• Selection of appropriate dosage form
• Consideration in formulation factors as proper viscosity, pH, tonicity, lipophilicity.

Other considerations
• Clarity
• Free of particulate matter
Types of ophthalmic preparations

Solutions and suspensions

Ointment

Inserts

Contact lens
 Ophthalmic Solutions
• Ophthalmic solutions are sterile liquid preparations designed for instillation into
the eye.
• They typically contain one or more active pharmaceutical ingredients dissolved
in a suitable vehicle (such as water or saline).
Advantages:
• Easy to use, non-invasive.
• Quick onset of action since the drug is in solution and absorbed rapidly.
• Patient compliance
Limitations:
• Short residence time on the eye (due to drainage and tear flow).
• Requires frequent administration to maintain therapeutic levels.
 Ophthalmic suspensions
• Ophthalmic suspensions are liquid formulations in which the active drug is
suspended (not dissolved, for poorly water-soluble APIs) in a vehicle.
Advantages:
• Provides prolonged drug release compared to solutions, as the drug is gradually
released from the suspension.
Limitations:
• Needs shaking before each use.
• Can cause irritation if particles are too large or if the formulation is not stable.
 Ointments
• Ophthalmic ointments are semisolid, viscous preparations intended for application
to the eye.
• Commonly used for dry eye conditions, post-surgical healing, or conditions
requiring a prolonged drug effect (e.g., corticosteroids for inflammation).
Advantages:
• Prolonged drug action due to slow release and longer retention time on the eye.
• Useful for conditions requiring a sustained therapeutic effect.
Limitations:
• Can cause blurred vision due to the viscous nature of the ointment.
• Less convenient for daytime use because of visual impairment.
Types of Packaging of eye drops
• Small Glass Bottles with Separate Droppers:
• Older form of packaging.
• May include a separate glass or plastic dropper.
• Less commonly used today due to contamination risks.
• Soft Plastic Containers with Built-in Droppers:
• Most widely used packaging for ophthalmic solutions and suspensions.
• The built-in dropper simplifies administration and reduces contamination risk.

Packaging for ointment is in tubes

 Ocular inserts
• Specialized drug delivery systems designed for the sustained release of
medication to the eye over extended period, unlike conventional dosage forms
as eye drops.
• Defined as sterile, thin, mono or multilayered , drug-impregnated, solid or semi-
solid consistency devices placed into the cul-de-sac or conjuctival sac, whose size
and shapes are especially designed for ophthalmic application.
• Particularly for conditions such as dry eye, glaucoma, or infections.
• Examples, pilocarpine inserts, Lacrisert®.
 Classification
Ophthalmic inserts

Insoluble Soluble Bio erodible

Osmotic

Diffusion

Contact lens
 Insoluble ocular inserts
• Made from materials that do not dissolve in the eye.
• They remain intact while releasing the drug in a controlled manner over time.
• Diffusion and osmotic inserts release drugs through diffusion and osmosis.
Soluble inserts
• These types of inserts are entirely soluble so that they do not need to be removed
from their site of application.
• Made from collagen
Bio erodible
• Made from materials that degrade or erode within the eye.
• As they degrade, the drug is released gradually, and the material is eliminated from the
body without the need for removal.
• Consists bio erodible polymer which erodes and releases drug. Example = Lacrisert
• Sterile rod-shaped device, without any preservatives
Advantages of Ocular Inserts
• Sustained Drug Release: Ocular inserts offer a controlled release of the drug over a
longer period, reducing the need for frequent administration of eye drops.

• Improved Bioavailability: Since they can deliver drugs directly to the eye, the
bioavailability of the drug is better compared to conventional eye drops.

• Enhanced Patient Compliance: By reducing the frequency of drug administration,

ocular inserts improve patient adherence for chronic eye diseases.

• Reduced Systemic Side Effects: minimized the likelihood of systemic side effects

• Minimizes Drug loss : Unlike eye drops, which are often lost as soon as applied,
ocular inserts provide more targeted and sustained drug exposure.
Disadvantages of Ocular Inserts
1.Uncomfortable: Maybe uncomfortable and can have feeling of foreign object in the
eye.

2. Risk of Infection: Improper handling, placement, or removal of the insert can lead
to infections.

3.Expensive: Ocular inserts can be more costly compared to conventional treatments

like eye drops or oral medications.

4.Complex: Some types of ocular inserts need to be removed after their therapeutic
effect is over, requiring medical intervention or further procedures.
 Contact lens
Contact lenses are thin, curved lenses placed directly on the surface of the eye
(cornea) to correct refractive vision errors or to serve as a therapeutic or cosmetic
device.

The three basic types of contact lenses are classified by their chemical composition
and physical properties as
• Hard,
• Soft, and
• Rigid gas permeable (RGP)
Hard contact lenses
• Provide durability and clear, crisp vision.
• Termed hard because they are made of a rigid plastic resin, polymethylmethacrylate
(PMMA).
• Only cover part of the cornea.
• Practically impermeable to oxygen and moisture
• Rigid in nature so, some patients find them difficult to wear.
• To prevent direct contact with the cornea, solutions are used to wet the lens and
provide a cushioning layer between the cornea and the inner surface of the lens.
Soft contact lenses
• Soft contact lenses are made of a hydrophilic transparent plastic, hydroxyethyl
methacrylate (HEMA), or silicone with small amounts of cross-linking agents that provide
a hydrogel network.
• Soft lenses contain 30% - 80% water, which enables enhanced oxygen permeability.
• They cover entire cornea.
• Less durable than hard contact lens.
• Can absorb drug applied to the eye.

Rigid Gas Permeable (RGP) Lenses:

• These lenses are made from durable plastic hydrophobic materials that allow oxygen to
reach the cornea.
• Durable and easy to handle.
Characteristic Hard contact lens Soft contact lens Rigid Gas Permeable
(RGP)

Material Rigid plastic Flexible, hydrogels plastic materials that

Polymethylmethacrylate, (HEMA) or silicon allow oxygen transmission
PMMA (e.g., silicone,
fluorosilicone)
Oxygen permeability Low Moderate to high Higher than hard contact
lens

Comfort and adaptation Uncomfortable at first and Very comfortable, very Less comfortable than soft
longer adaptation short adaptation time lenses but more
comfortable than hard
lenses. Moderate
adaptation
Vision Very good Good (less than hard and Very good
RGP contact lens)

Durability Very durable Less durable Moderate

High maintenance

Risk of infection High, proper cleaning Lower risk Lower risk than hard
needed contact lens
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 Cleaning and maintenance of lens
• It is important that contact lenses receive appropriate care to retain their shape and
optical characteristics and for safe use.
(a)cleaning to loosen and remove lipid and protein deposits,
(b) rinsing to remove the cleaning solution and material loosened by cleaning, and
(c) disinfection to kill microorganisms.

• If the lenses are not maintained at properly, deposit buildup, discoloration, and microbial
contamination can occur leading to infection.
 Cleaning and maintaining hard contact lens

Cleaning Soaking Wetting

To remove debris To store in To decrease their

and deposits disinfecting hydrophobic
solution while characteristics.
not using
 Solutions used for care
1. Cleaning solutions
• Surfactant cleaner . Example, poloxamer-407
2. Soaking solutions
• Contain a sufficient concentration of disinfecting agent, usually 0.01%
benzalkonium chloride and 0.01% edetate sodium, to kill surface bacteria.
3. Wetting solutions
• Ingredients include a viscosity-increasing agent, such as hydroxyethyl cellulose; a
wetting agent, such as polyvinyl alcohol; preservatives, such as benzalkonium
chloride or edetate disodium; and buffering agents and salts to adjust the pH and
maintain tonicity.
4. Mixed-purpose solutions
• Combination of above solutions
 Routine Care of Soft Contact Lenses
A. Cleaning
• Removes lipid and protein deposits.
• Use surfactant cleaners (e.g., nonionic detergents) or enzymatic cleaners (e.g., papain,
pancreatin) to dissolve proteins.
• Cleaning method:
• Apply cleaning solution to the lens and gently rub with fingertips or palm for ~20
seconds.
• The ingredients in these cleaners usually include a nonionic detergent (Poloxamer 407),
wetting agent(Polyvinyl alcohol) , chelating agent (EDTA), buffers(phosphate buffer), and
preservatives (BAK) in vehicle (purified water).
B. Rinsing
• Use sterile, isotonic saline solutions to remove cleaning agents and debris.
C. Disinfection
• Prevents microbial growth:
Thermal Method:
• Heat previously clean lenses placed in specially designed heating unit in saline
solution for 10 minutes at minimum of 80°C
Chemical Method:
• Previously chlorhexidine used
• Use hydrogen peroxide systems.
• Neutralize hydrogen peroxide to avoid irritation.
D. Storage
• Store in isotonic saline or multi-purpose solutions.
• Use preservative-free solutions for sensitive eyes.
Pharmacologic Categories of Ophthalmic Drugs
1.Anesthetics: Tetracaine, proparacaine.
2. Antibiotics: Ciprofloxacin, tobramycin.
3. Antifungals: Amphotericin B, natamycin.
4. Anti-inflammatory agents:
1. Steroids: Dexamethasone, prednisolone.
2. NSAIDs: Diclofenac, ketorolac.
5. Glaucoma agents: Timolol, pilocarpine, latanoprost.
6. Artificial tears: Carboxymethylcellulose, polyvinyl alcohol.
 Nasal drug delivery
• Nasal mucosa has been considered as a potential administration route to achieve faster
and higher level of drug absorption.
• It is permeable to more compounds than the gastrointestinal tract due to lack of
pancreatic and gastric enzymatic activity, neutral pH of the nasal mucus and less
dilution by gastrointestinal contents.

NASAL PREPARATIONS
• Nasal preparations are pharmaceutical formulations designed for administration
through the nasal cavity, targeting local or systemic effects.
Common Forms:
• Solutions to be used as Drops, sprays.
• Jellies
 Advantages
• Non-invasive, safe and painless.
• Drug degradation that is observed in the gastrointestinal tract is absent.
• Hepatic first pass metabolism is avoided.
• Rapid drug absorption and quick onset of action can be achieved.
• The nasal bioavailability for smaller drug molecules is good.
• Drugs that are orally not absorbed can be delivered to the systemic circulation by
nasal drug delivery
• Drugs possessing poor oral absorption and poor stability in GIT fluids are given by nasal
route.
 Disadvantages and challenges
• Nasal epithelium limits permeability of hydrophilic and high molecular weight
drugs.
• Small volumes of administration (25–200 μL).
• Mucociliary clearance and low residence time
• Nasal surface area is smaller that limits drug absorption.
• Relatively inconvenient to patients when compared to oral delivery systems since
there is a possibility of nasal irritation.
• Some drugs and excipients can cause irritation to the nasal mucosa.
• Runny nose influences absorption
• Possible inaccuracy in dosage due to improper administration technique
 Anatomy and Functionality of Nasal Cavity
Structure:
• Divided into vestibule, respiratory, and olfactory regions.
• High vascularization in the respiratory region facilitates absorption.
• Vestibule = Forward section of nasal cavity lying within & above nasal cavity.
• Respiratory = external openings are called nostrils that open into nasopharynx,
leading to trachea and oesophagus.
• Olfactory = small area in the roof of the nasal cavity of about 10 cm2
• Facilitates the drug delivery to brain.
• Nasal cavity is covered with a mucous membrane.
• Mucus secretion is composed of 95% water, 2% mucin, 1% salts, 1% of other
proteins
 Mechanism of Drug Absorption
• Passage of drug through the mucus is the first step in the absorption
from the nasal cavity.
• Uncharged, small particles easily pass through mucus but charged and
large particles may find it difficult to cross.
• Two major mechanisms

Paracellular Transcellular

Transport of drug through aqueous Transport of drug through lipoidal

route route
Slow and passive Active transport via carrier
mediated
 Factors Influencing Nasal Drug Absorption

Physiological Conditions of Physicochemical Properties of

Nose Drug and formulation

• Nasal Blood Flow • Molecular Weight

• Mucociliary Clearance • Lipophilicity of Drug
• Enzymatic Degradation • Stability and solubility of
• Nasal pH Drug
• Pathological Condition of • Particle size
Nose • Drug formulation
Nasal blood flow
• The blood vessels supplying to the nasal mucosa are crucial as drugs are
absorbed through nasal membrane enter systemic circulation.
• Increased blood flow = high absorption and decreased blood flow = low absorption.

Mucociliary clearance
• Mucociliary clearance is a natural defense mechanism of the nasal passage to remove
foreign particles, microorganisms, and excess mucus from the respiratory tract.
• This process typically clears the nasal cavity of drugs within minutes to hours, depending
on their formulation and properties.

Enzymatic degradation
• Although first pass metabolism is avoided, drugs may be metabolized in lumen of nasal
cavity due to the presence of broad range of metabolic enzymes as hydrolases, aldolase,
carboxylesterase.
Nasal pH
• The pH of nasal mucus typically ranges from 4.5 to 6.5, which can influence solubility and
stability of drugs.

Pathological condition of nose

• Congestion can reduce nasal blood flow so decrease drug absorption
• Blocked nasal passage decrease drug absorption

Molecular Size:
• Small molecules (less than 1000 Da) tend to be absorbed more easily through the nasal
mucosa.
• Special formulations (e.g., nanoparticles or absorption enhancers) needed for larger
molecules, such as peptides or proteins.
Lipophilicity/Hydrophilicity:
• Lipophilic drugs tend to pass through nasal mucosa more easily as nasal membrane is
lipophilic.
• Hydrophilic drugs may require formulations that enhance their permeability or use penetration
enhancers.

Solubility and stability

• The solubility of a drug in nasal mucus affects how quickly it can dissolve and be absorbed.
The stability may be affected by enzymes of nasal cavity.

Particle Size:
• Smaller particles are absorbed better than larger particles .

Drug Formulation:
• The formulation type (liquids, gels, powders, nanoparticles) and additives (e.g., penetration
enhancers, stabilizers, preservatives) can affect the stability, retention, and absorption of drugs in
the nasal cavity. For example, mucoadhesive formulations can prolong retention time.
 How to improve nasal absorption?
A. Structural Modification
B. Formulation Design
a) Viscosity Modifiers
b) Absorption Enhancers
c) Bio Adhesive Polymers
d) Liposomes

A. Structural modification
• Chemical modification of molecular structure of drug which can alter physicochemical
properties of drugs.
B. Formulation design
Viscosity enhancers
• Increases the nasal resident time of formulation.
• Example, methyl cellulose, hydroxy propyl methyl cellulose.
Absorption enhancers
• For better absorption of poorly absorbed drugs Example, surfactants (laureth-9), bile salts
(deoxy cholate), chelators (citric acid).
Bio adhesive polymers
• Polymers used to increase adhesion in nasal musoca.
• Increases contact time.
Liposomes
• They are composed of lipid layers that can have both hydrophilic and lipophilic drugs.
• Enhance permeability and contact time of drugs.
 Nasal solutions
• Inhalation solutions are drugs or drug solutions administered through the nasal
or oral respiratory route. They can be used for:
• Local Action: Targeting the bronchial tree for conditions like asthma or bronchitis.
• Systemic Effects: Delivering medication through absorption in the lungs.
 Nasal Decongestant Solutions
• Aqueous, isotonic to nasal fluids (approximately equivalent to 0.9% sodium chloride),
buffered to maintain drug stability at the normal pH range of the nasal fluids (pH 5.5 to
6.5) and stabilized and preserved as required.
• Packaged in dropper bottles or in plastic spray bottles, usually containing 15 to 30 mL of
medication.
• Provide relief from nasal congestion by constricting blood vessels in the nasal
mucosa.
Examples of Agents:
• Epinephrine, phenylephrine.
Caution:
• Prolonged use can lead to chronic edema of nasal mucosa.
• Suitable for short period as 3-5 days
Nasal drops
• Nasal drops are one of the most convenient and simple systems for nasal delivery.
• These are instilled into the nose by dropper.
• Main disadvantage is lack of dose precision.
• E.g.:- ephedrine nasal drops

Nasal sprays
• These are aqueous or alcoholic preparations.
• More accurate than drops.
• By using metered pumps, nasal spray can deliver an exact dose
• E.g.:- adrenaline & atropine spray.
Nasal powder
• This dosage form may be developed if solution & suspension dosage forms cannot be
developed e.g due to lack of drug stability .

Nasal Gels
• These are high viscosity thickened formulations.

The MAD ( Mucosal Atomization Device )

• Delivers a pre-determined volume of atomized medication that is absorbed systemically.
• It achieves medication levels comparable to injections.
• Greater control over-dosing.
 Otic preparations
• Otic preparations are pharmaceutical formulations designed for application in the
ear.
• Used to treat conditions like infections, inflammation, and pain.
• These include solutions, suspensions, and ointments.

Application
• Treat conditions such as ear infections (otitis media and externa).
• Remove earwax (cerumen).
• Relieve pain or itching.
• Address fungal or bacterial infections.
 Ear
• The external ear is made up of the pinna (auricle) and the external auditory canal.
• Cerumen, commonly known as ear wax is produced as a part of the
body’s normal defense mechanisms.
• It is produced by ceruminous glands and sebaceous glands in outer ear canal.
• Composed of fatty acids, proteins, cholesterol.
• Acts as barrier to foreign particles, has microbial action and also prevents ear
infections.
• It has self cleaning mechanism but in some cases, excess production can occur which can
block ear canal causing hearing difficulty, pain, irritation. So may require ear drops for
management.
 Drugs used in treating Otic Disorders
• Antibiotic - chloramphenicol, ciprofloxacin, colistin sulfate, gentamicin
sulfate, neomycin and polymyxin B sulfate
• Antifungal agents – polysorbate, gentian violet, nystatin
• Anti-inflammatory
• Antiseptics
• Cleansing solutions
• Wax softeners
Otic Solutions
• Clear, water-based formulations designed for easy application in the ear canal.

Applications:
• Antibiotics for bacterial infections (e.g., ciprofloxacin, ofloxacin).
• Anti-inflammatory agents for pain and swelling (e.g., corticosteroids like
hydrocortisone).
• Cerumenolytics to dissolve earwax (e.g., carbamide peroxide, hydrogen peroxide).

Formulation Requirements:
• pH adjustment: Typically acidic (pH ~3–4) to match the natural ear canal
environment and prevent bacterial growth.
• Viscosity agents: Increase retention in the ear (e.g., glycerin).
• Preservatives: Prevent contamination during use.
Otic Suspensions
• Heterogeneous mixtures where active drug particles are dispersed in a liquid
medium.

Applications:
• Used when the drug is insoluble in water.
• Common in combination products (e.g., antibiotic-steroid combinations like
ciprofloxacin-dexamethasone).
Key Features:
• Requires shaking before use for uniform dosing.
• Provides prolonged contact time for enhanced efficacy.

Otic Ointments
• Semi-solid formulations applied inside the ear for prolonged action. And are applied to
exterior of ear.
 Formulation and Evaluation of Tafluprost Ophthalmic Solution

Category Material
Active Pharmaceutical
Tafluprost
Ingredient (API)
Solubilizing Agent Hydroxypropyl beta cyclodextrin
Sodium dihydrogen phosphate
Buffering Agents
monohydrate, Disodium
phosphate
Osmolality Adjuster Sodium chloride
Preservative Benzalkonium chloride
Vehicle Water for Injection (WFI)
 Opthalmicsolutionpreparation
• Preformulation studies
• Physical characterization of Tafluprost (API) for appearance, physical state, color, and
odor.
• Preparationof Solution
• Fixed quantities ofAPI and preservative,BAK used.
• Concentration of otherexcipients varied.
• Method
• Vehicle 70% of totalvolume used.
• Sodium dihydrogen phosphate, disodium phosphate, sodium chloride, and
benzalkonium chloride were added sequentially under stirring until a clear solution was
formed.
• Finally add the batch quantity of API and stir until it get dissolve and make up volume.
 Ophthalmicsuspensionpreparation
1. Selection of Drug and Solubility Enhancer:
• Choose an active pharmaceutical ingredient (API) and appropriate solubility
enhancers or stabilizers like surfactants.

2. Preparation of Suspension Base:

•Use a sterile aqueous medium containing viscosity enhancers such as
hydroxypropyl methylcellulose (HPMC) to improve suspension stability.

3. Particle Size Reduction:

•Reduce the drug particle size to submicron levels using techniques like high-
pressure homogenization or wet milling to enhance bioavailability.
4. Sterilization:
•Sterilize using filtration (0.22 µm filter) or by heat sterilization, ensuring the
system remains stable.

5. Addition of Preservatives and Buffers:

•Add preservatives like benzalkonium chloride and buffers to maintain the pH at 6.5-7.4
for ocular compatibility.

6. Mixing and Filling:

• Mix all components under aseptic conditions and fill in sterile dropper bottles.

Ingredient Category
API (e.g., dexamethasone) Therapeutic agent
HPMC Viscosity enhancer, stabilizer
Benzalkonium chloride Preservative
Phosphate buffer pH adjustment
Sterile water Vehicle
 Ophthalmic ointment preparation
1. Selection of Base:
• Use a non-aqueous base like petrolatum or lanolin for sustained drug release.
2. Mixing of API:
• Incorporate the API into the molten base under sterile conditions.
3. Homogenization:
• Ensure even dispersion of the API to maintain uniformity.
4. Cooling and Sterilization:
•Cool the ointment under aseptic conditions, then sterilize using gamma radiation or filtration
through high-precision filters.
5. Packaging:
• Fill into sterile aluminum tubes or unit-dose containers in an aseptic environment.

Ingredient Category
API (e.g., chloramphenicol) Therapeutic agent
Petrolatum Ointment base
Lanolin Emollient
Antioxidants (e.g., BHT) Stability enhancer
Evaluation parameters of Ophthalmic preparations

1) Sterility test
2) Clarity test
3) Leakage test
4) Metal particles in opthalmic products.
5) Assay
6) pH
7) Viscosity
 Sterility test
1. Direct inoculation method
• The test samples are test using culture media.

2. Membrane filtration method

• Filtering of test samples using membrane filter.
• Wash the membrane filter.
• Transfer it to the media Eg : Soya digest media..
• Then check for microbial growth
 Clarity test
Visual inspection
• Bottles are viewed in light & dark background.

Instrumental Method
• A light ray is passed
• The light gets scattered into the Product
• The instrument images all the undissolved particles in the product .
 Leakage test
• Take 10 ophthalmic ointments
• Wipe it well at both the ends
• It should be sealed
• Keep it in hot air oven for 60 ± 3°C for 8 hours
• If there is no leakage the ophthalmic preparation passes the test.
• If leakage is observed from one, but not more than one, of the tubes, repeat the
test with 20 additional tubes of the Ointment.
• The requirement is met if no leakage is observed from the first 10 tubes tested, or
if leakage is observed from not more than one of 30 tubes tested.
 Metalparticles
• 10 tubes of ophthalmic ointment is taken in a separate petri dish free from
scratch.
• Then it is heated at 85 °C for 2 hours
• Then cool at room temperature to solidify
• Slightly invert the petridishes on the stage of a suitable microscope
• Observe the metallic compounds in it .
• Count the number of metal particles that are 50µm or larger in any dimension.
• The requirements are met if the total number of such particles in all 10tubes does not
exceed 50, and if not more than 1tube is found to contain more than 8 such particles
 Assay &pH
• The sample is titrated against the standard.
• pH :
• The pH of the ophthalmic preparation should be equal to that of lachrymal secretions.
• OPTIMUM PH :7.4 The pH is tested usind the pH paper or pH meter

Viscosity
• OPTIMAL VISCOSITY : 15 – 25 Centipoise
• They are added to increase the ocular contact time.
• And to reduce the surface tension
• Viscosity is measured by Brookfield’s viscometer & Rolling ball viscometer.
 Stability

Stability study can be done by 2 methods:

• Accelerated stability study
• Freeze thaw method