otic, nasal and , nasal and opthalmic opthalmic dosage forms

OticOtic, Nasal and , Nasal and OpthalmicOpthalmic

Dosage FormsDosage Forms

Pharmaceutics IIPharmaceutics II

Dosage FormsDosage Forms

Dr. Bassel Hussein

Otic preparationsOtic preparationsOtic preparationsOtic preparations

�Otic preparations are sometimes referred to as

ear preparations.

� Solutions are the predominant dosage form

used for this route of administration, with rare

exceptions of suspensions and ointmentsexceptions of suspensions and ointments

� Ear preparations are usually placed in the ear

canal by drops in small amounts for:

� For removal of excessive cerumen (earwax); or

� For treatment of ear infections, inflammation, or

pain.

Anatomy of the EarAnatomy of the EarAnatomy of the EarAnatomy of the Ear

� The ear has a dual sensory function. In addition to its

role in hearing, it functions as the sense organ of

balance.

CerumenCerumen--removing solutionsremoving solutionsCerumenCerumen--removing solutionsremoving solutions

� Cerumen is a combination of the secretions of the sweat andsebaceous glands of the external auditory canal. The secretions, ifallowed to dry, form a sticky semisolid that holds shed epithelialcells, fallen hair, dust, and other foreign bodies that make their wayinto the ear canal.

� Excessive accumulation of cerumen in the ear may causeitching, pain, and impaired hearing. If not removed periodically,the cerumen may become impacted and its removal mademore difficult and painful.more difficult and painful.

� Traditionally, light mineral oil, vegetable oils, and hydrogenperoxide (peroxide releases oxygen, which disrupts the integrity ofthe impacted wax) have been commonly used to soften impactedcerumen for its removal.

� Recently, solutions of synthetic surfactants have been developedfor their ability to remove earwax. One of these agents,triethanolamine oleate in propylene glycol, which is used toemulsify the cerumen, thereby facilitating its removal.

� Cerumen removal usually involves placing the otic solution in theear canal with the patient's, inserting a cotton plug to retain themedication in the ear for 15 to 30 minutes, followed by gentleflushing of the ear canal with warm water using a rubber applicator.

Solutions for Ear InfectionsSolutions for Ear InfectionsSolutions for Ear InfectionsSolutions for Ear Infections

� The bacterial pathogens most commonly isolated from middle ear

effusions from patients with otitis media (inflammation of the middle

ear or tympanic membrane) are: Streptococcus pneumoniae,

Haemophilus influenzae, and Moraxella catarrhalis.

� The principle pathogens of otitis externa (inflammation of the

external auditory canal, commonly called swimmer’s ear) are P.

aeruginosa and S. aureus. Gram-negative species such asaeruginosa and S. aureus. Gram-negative species such as

Proteus, Klebsiella, and E. coli are also common.

� These ear infections are usually treated by topical application of

topical antibiotics including chloramphenicol, colistin sulfate,

neomycin, polymyxin B sulfate, and antifungal agents such as

nystatin.

� These agents are normally formulated as solutions or

suspensions containing glycerol or polyethylene glycol as the

vehicle. They are made viscous to maximize the contact time

between the medicinal agents and the infected tissue of the remote

ear.

Solutions for Ear InfectionsSolutions for Ear InfectionsSolutions for Ear InfectionsSolutions for Ear Infections

� These formulations consist of hygroscopic agents that

help in dehumidifying the tissues which lowers the

moisture content the bacteria need to survive, thus

preventing the infection from spreading.

� For better infection management these topical

preparations are to be given as an adjunct with thepreparations are to be given as an adjunct with the

systemic antibiotics administered orally.

� Besides the antibiotics used to treat otitis externa,

acetic acid in aluminum acetate solution and boric

acid in isopropyl alcohol are also employed. These

agents help to reacidify while the vehicles help to

dry the ear canal by eliminating water and hence

slowing the growth of P. aeruginosa.

AntiAnti--Inflammatory and Analgesic PreparationsInflammatory and Analgesic PreparationsAntiAnti--Inflammatory and Analgesic PreparationsInflammatory and Analgesic Preparations

� Solutions of dexamethasone sodium and

hydrocortisone are used to treat the

inflammation caused by the allergic or irritative

manifestations of the ear and the pruritus, which

follows the treatment of ear infections. These

corticosteroid may be given as ointments.corticosteroid may be given as ointments.

� To assist in relieving the pain that frequently

accompanies ear infection and inflammation, a

number of anti-infective otic preparations also

contain analgesic agents, such as antipyrine,

and local anesthetics, such as lidocaine,

dibucaine, and benzocaine.

Nasal Dosage FormsNasal Dosage FormsNasal Dosage FormsNasal Dosage Forms

Anatomy of the NoseAnatomy of the NoseAnatomy of the NoseAnatomy of the Nose

Internal

ostium

Middle

concha

Superior concha

(olfactory region)

ostium

Inferior

concha

� The nose is responsible for the temperature and

particulate regulation of inspired air and its passage into

the respiratory tract.

� The nasal cavity is covered by a typical respiratory

epithelium that contains four basic types of cells:

Nonciliated columnar cells (with microvilli on the mucosalNonciliated columnar cells (with microvilli on the mucosal

surface), goblet cells, basal cells, ciliated columnar cells.

� The respiratory epithelium is covered by a two-component

mucus layer: a bottom layer consisting of a low viscosity

sol surrounding the cilia and microvilli, and on the surface,

a more viscous and bioadhesive gel layer.

� The cilia beat continuously in the sol layer with a

frequency of 1000 strokes per minute, thereby moving the

surface gel layer toward the pharynx.

Representation of the respiratory mucosa consisting of four major cell types

Nasal preparationsNasal preparationsNasal preparationsNasal preparations

� Drugs are administered nasally for both local and

systemic action.

� Local administration is limited to the treatment of

congestion, rhinitis, sinusitis, (Cromolyn,

Beclomethasone, Ephedrine, Oxymetazoline,

Phenylephrine)Phenylephrine)

� Frequent or prolonged use may lead to chronic edema of

the nasal mucosa, that is, rhinitis medicamentosa,

aggravating the symptom that they are intended to relieve.

� Thus, they are best used for short periods (no longer than

3 to 5 days), and the patient should be advised not to

exceed the recommended dosage and frequency of use.

Nasal preparationsNasal preparationsNasal preparationsNasal preparations

� In recent years, scientists have shown tremendous interest

in exploring nasal administration for systemic drug

delivery.

� Nasal products for systemic therapy in the market, include

medications for the treatment of:

� Migraine (Sumatriptan, Dihydroergotamine, Butorphanol� Migraine (Sumatriptan, Dihydroergotamine, Butorphanol

tartrate)

� Prevention of angina pectoris (Nitroglycerin)

� Smoking cessation (Nicotine)

� Promote milk ejection in breastfeeding mothers (Oxytocin)

� Delivery of proteins (insulin) and vaccine through this route

is also under investigation.

Advantages Of Systemic Nasal DeliveryAdvantages Of Systemic Nasal DeliveryAdvantages Of Systemic Nasal DeliveryAdvantages Of Systemic Nasal Delivery

� Nasal delivery is a promising alternative for the

administration of drugs that are poorly

absorbed via the oral route.

� Fast absorption and rapid onset of action.

� Avoidance of hepatic and intestinal first pass� Avoidance of hepatic and intestinal first pass

effects is another reported benefit of nasal

systemic drug delivery.

� Ease of administration, convenience, and self-

medication resulting in improved patient

compliance.

Factors Affecting Systemic Nasal Drug DeliveryFactors Affecting Systemic Nasal Drug DeliveryFactors Affecting Systemic Nasal Drug DeliveryFactors Affecting Systemic Nasal Drug Delivery

1- Formulation pH

The pH of the formulation as well as the membrane surfacepH can affect the nasal absorption of drugs. Absorptionincreases in the pH that increases the ratio of un-ionizedform to the ionized form.

2- Lipophilicity of the Drug2- Lipophilicity of the Drug

The extent of nasal absorption increases with an increasein lipophilicity of drugs.

3- Effect of Molecular Size

Absorption from the nasal cavity decreases as themolecular size increases. Consequently the rate ofabsorption from the nasal cavity is very restrictive beyondmolecular weight 300.

Aqueous Nasal PreparationsAqueous Nasal PreparationsAqueous Nasal PreparationsAqueous Nasal Preparations

� The vehicle for an aqueous nasal preparation should:

1. have a pH in the range of 5.5 to 7.5.

2. have a mild buffer capacity.

3. be isotonic to nasal fluids (approximately equivalent to

0.9% sodium chloride).

4. not modify the normal mucous viscosity.4. not modify the normal mucous viscosity.

5. be compatible with normal ciliary motion and ionic

constituents of nasal secretions.

6. be compatible with the active ingredient.

7. be stable.

8. be preserved. The antimicrobial preservatives are the

same as those used in ophthalmic solutions.

Nasal Dosage FormsNasal Dosage FormsNasal Dosage FormsNasal Dosage Forms

� Several types of dosage forms are used to deliver drugformulations in the nasal cavity based on the desiredabsorption profile. The following is a list of the variousdosage forms used to deliver drug formulations in thenasal cavity:

� Nasal drops: The simplest, commonest, and mostconvenient form

� Solution sprays: These systems can precisely deliver� Solution sprays: These systems can precisely delivervolumes as low as 25 µl

� Powders: developed for drugs that exhibit poor solutionstability, that act locally in the nasal cavity.

� Gels, emulsions and ointments: these prolongresidence of the formulation in the nasal cavity andenhance drug absorption.

� Novel delivery systems (e.g. microspheres,liposomes): they Increased mucosal retention andincrease absorption

Ophthalmic Dosage FormsOphthalmic Dosage FormsOphthalmic Dosage FormsOphthalmic Dosage Forms

Categories of Ophthalmic DrugsCategories of Ophthalmic DrugsCategories of Ophthalmic DrugsCategories of Ophthalmic Drugs

� Anesthetics: such as tetracaine, cocaine, and proparacaine.

� Antibiotic and antimicrobial agents: such as gentamicin,sulfacetamide, tetracycline, ciprofloxacin, ofloxacin,chloramphenicol, polymyxin B-bacitracin, and tobramycin.

� Anti-inflammatory agents: include steroidal agents such asprednisolone and dexamethasone, and nonsteroidal agents includediclofenac.

� Antifungal agents: Among the agents used topically against� Antifungal agents: Among the agents used topically againstfungal endophthalmitis and fungal keratitis are amphotericin B,natamycin, and flucytosine.

� Antiviral agents: trifluridine, idoxuridine, and vidarabine.

� Astringents: Used in the treatment of conjunctivitis. Zinc sulfate.

� Beta-adrenergic blocking agents: such as betaxolol and timololare used in the treatment of intraocular pressure and chronic open-angle glaucoma.

� Glaucoma agents: such as pilocarpine.

Categories of Ophthalmic DrugsCategories of Ophthalmic DrugsCategories of Ophthalmic DrugsCategories of Ophthalmic Drugs

� Mydriatics and cycloplegics: Mydriatics allowexamination of the fundus by dilating the pupil, e.g.atropine, scopolamine, homatropine.

� Protectants and artificial tears: Solutions employed asartificial tears or as contact lens fluids to lubricate the eyecontain agents such as carboxymethyl cellulose,methylcellulose, hydroxypropylmethyl cellulose, andmethylcellulose, hydroxypropylmethyl cellulose, andpolyvinyl alcohol.

� Vasoconstrictors and antihistamines: They causetransient constriction of the conjunctival blood vessels andremove redness due to minor eye irritation. Among thevasoconstrictors used topically are naphazoline,oxymetazoline, and tetrahydrozoline. Antihistamines, suchas pheniramine maleate, are included in some products toprovide relief of itching.

Anatomy of the eyeAnatomy of the eyeAnatomy of the eyeAnatomy of the eye

Topical Administration of Ophthalmic DrugsTopical Administration of Ophthalmic DrugsTopical Administration of Ophthalmic DrugsTopical Administration of Ophthalmic Drugs

� The topical route of administration is used to treat diseases thataffect the anterior segment of the eye such as keratitis,conjunctivitis, and glaucoma. However, topical delivery may notprovide the desired therapeutic concentration of the drug in theposterior segment of the eye to treat diseases there.

� Drug delivery vehicles used for topical administration includesolutions, colloids, emulsions, suspensions, ointments, solidhydrophilic inserts, therapeutic contact lenses, rate-controlledrelease systems, and new delivery systems such as liposomes andrelease systems, and new delivery systems such as liposomes andparticulates.

� The advantages of topical administration are:

� Convenient mode of administration

� Noninvasive

� Easy enough for self-administration

� Fewer systemic drug effects

� The disadvantages of topical administration are:

� Low ocular bioavailability

� Ineffectiveness in the treatment of posterior segment diseases

Factors Affecting the Bioavailability of Factors Affecting the Bioavailability of

Topically Administered DrugsTopically Administered Drugs



� Drug binding to tear proteins: The protein content oftears in humans is about 0.7% of the total body protein.Therefore the drug binding to the tear proteins may resultin a reduction in free drug concentrations available forpharmacological action at the target site.

� Conjunctival drug absorption: The conjunctiva is ahighly vascularized mucous membrane lining the inside ofthe eyelids and the anterior sclera. Drugs are betterthe eyelids and the anterior sclera. Drugs are betterabsorbed across conjunctiva than cornea because of itsgreater surface area and high permeability. However, suchnonproductive conjunctival absorption is a majorprecorneal loss factor and may lead to side effects, since itserves as a major route of entry into systemic circulation.

� Systemic drug absorption: A fraction of the topicallyapplied dose that reaches the nasal mucosa through thenasalacrimal duct drainage may be absorbed systemically,leading to potential systemic side effects.





�Melanin binding: The presence of melaninpigment in the iris and ciliary body can affectthe ocular bioavailabilty of the topically applieddrug. Drugs such as ephedrine and timolol canbind to the melanin with a high binding capacity,and only a small fraction of the bound drug isand only a small fraction of the bound drug isslowly released.

� Drug metabolism: Various enzymes in the eyecan metabolize the active drug, resulting indecreased ocular bioavailabilty. The cornealepithelium and the iris ciliary body are the mostmetabolically active.

Formulation of Ophthalmic SolutionsFormulation of Ophthalmic SolutionsFormulation of Ophthalmic SolutionsFormulation of Ophthalmic Solutions

1- Viscosity Enhancers� Viscosity Enhancers help in prolonging the retention

time of the drug in the precorneal area. They alsodecrease the lacrimal drainage of the drug. Water-solublepolymers are used as viscosity enhancers such ascellulose derivatives and polyvinyl alcohol.

� Viscosity for ophthalmic solutions is considered optimal inthe range 15-25 cp (viscosity of water is 1 cp at 20oC).the range 15-25 cp (viscosity of water is 1 cp at 20oC).

� Administration of a highly viscous solution results in reflextearing and blinking to restore the original viscosity.Therefore an optimum concentration of viscosityenhancers should be used.

� Certain polymers such as poly (acrylic acid) andhyaluronic acid, have the ability to interact with themucus layer that covers the corneal surface. Thisadhesive capacity further improves the retention of thepolymer solution in the preocular area.


2- Tonicity Agents

� Topically instilled solutions must be isotonic with tears.

Instillation of a hypotonic or hypertonic solution may cause

discomfort or irritation. This might result in reflex tears

and reflex blinks, subsequently leading to drug loss.

� Tears and other body fluids including blood have an� Tears and other body fluids including blood 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.

� Tonicity agents such as sodium chloride, buffering salts,

dextrose, and mannitol can be employed.

Tonicity adjustmentTonicity adjustmentTonicity adjustmentTonicity adjustment

� Osmotic pressure together with vapor pressure,

boiling point, and freezing point, form the so-

called colligative properties of solutions. These

properties depend on the number of particles

(moles) in solution, and a change in any one of(moles) in solution, and a change in any one of

them will be accompanied by corresponding

changes in the others.

� A comparison of freezing points between the

solutions is most used to perform calculations

necessary to prepare isosmotic solutions.

Tonicity adjustmentTonicity adjustmentTonicity adjustmentTonicity adjustment

W% = 0.52- a

b

� Where w is the concentration in grams per 100 mL

of the adjusting substance in the final solution

� The freezing point of both blood serum and tears is

–0.52°

� a: is the freezing point depression of the unadjusted

hypoosmotic solution

� b: is the freezing point depression produced by 1%

w/v of the adjusting substance

Example: calculations using freezing point depressionExample: calculations using freezing point depressionExample: calculations using freezing point depressionExample: calculations using freezing point depression

Rx

Sodium chloride: 0.18 g

Glucose: x g

Sterile water: enough to make 100 ml

� A 1% w/v solution of sodium chloride depresses the freezing point of water by 0.576°.point of water by 0.576°.

� The depression of the freezing point of the unadjusted solution of sodium chloride will therefore be 0.18 × 0.576 = 0.1037° (a).

� A 1% w/v solution of anhydrous glucose depresses the freezing point of water by 0.10° (b).

� Substituting these values for a and b in the formula:

W = (0.52 – 0.1037) / 0.10 = 4.2% w/v of anhydrous glucose should be added to make the solution iso-osmotic.

Example: Calculate the amount of sodium chloride to Example: Calculate the amount of sodium chloride to

be added to make the following solution isotonicbe added to make the following solution isotonic

Example: Calculate the amount of sodium chloride to Example: Calculate the amount of sodium chloride to

be added to make the following solution isotonicbe added to make the following solution isotonic

Rx

Ephedrine sulfate: 1 g

Sodium chloride: x g

Sterile water: enough to make 100 ml

(Sodium chloride equivalent E is 0.23)

Calculate the weight in grams of sodium chloride that isCalculate the weight in grams of sodium chloride that isequivalent to the weight in grams of ephedrine sulfate:

quantity of the drug × sodium equivalent.

1.0 g × 0.23 = 0.23 g

A total of 0.9% of sodium chloride is required for isotonicity ifno other salts are present, the amount of sodium chloride tobe added is:

0.90 – 0.23 = 0.67 g


3- Buffering Agents

� The physiological pH of tears is 7.4. The tear fluid has asmall buffer capacity; hence the pH of tears alters rapidlywith addition of greater amounts of acid or alkali.

� Ophthalmic formulations have to be suitably buffered forthe following reasons:

� To maintain physiological pH upon topical administration:� To maintain physiological pH upon topical administration:The exposure of the eye to acidic or alkaline fluids maycause damage to the epithelial cells, resulting in ocularirritation and discomfort.

� To enhance drug penetration through changes in the degreeof drug ionization: The penetration of drug across the corneacan be improved by selecting the pH that favors the un-ionized form of the drug.

� To improve the stability of the product.


4- Preservatives� Ophthalmic formulations must be sterile. Sterility is defined as

the absence of living organisms from a given setting.

� It is preferable to sterilize ophthalmics in their final containers byautoclaving at 121°C for 15 minutes. In case of thermal instability ofthe formulation, bacterial filters (0.22 micron) may be used.

� Most ophthalmic formulations are packed in multipledosecontainers. As a result, medication may easily become� Most ophthalmic formulations are packed in multipledose

containers. As a result, medication may easily becomecontaminated during use. A suitable antimicrobial preservative ormixture of preservatives has to be added in ophthalmicpreparations.

� Desirable properties of effective antimicrobial preservative are:

� Broad spectrum of activity

� Compatibility with other ingredients

� Nontoxic and nonirritant properties

� Chemical stability

� Rapid action

Benzalkonium chloride 0.004 - 0.01%

Chlorobutanol 0.5%

Phenylmercuric acetate or nitrate 0.004%

Thimerosal 0.005 to 0.01%

Methyl paraben 0.18%

Propyl paraben 0.02%

� In concentrations tolerated by the eye, these preservative areineffective against some strains of Pseudomonas aeruginosa,which can invade an abraded cornea and cause ulceration andeven blindness.

� However, preservative mixtures of benzalkonium chloride (0.01%)and either polymyxin B sulfate (1000 USP Units/mL) or disodiumethylenediaminetetraacetate (0.01 to 0.1%) are effective againstmost strains of Pseudomonas. The latter agent, which iscommonly employed as a chelating agent for metals, rendersstrains of P. aeruginosa more sensitive to benzalkonium chloride.

Ophthalmic Dosage Forms Other Than Ophthalmic Dosage Forms Other Than

solutionssolutions


solutionssolutions

1- Suspensions

� Ophthalmic suspensions provide slow dissolution and prolongedrelease of drug. For optimum therapeutic effect, the rate ofdissolution of particles and the rate of absorption through thecornea must be faster than the rate of loss of drug from the eye.The size of the suspended drug particle is important for patientcomfort and therapeutic effectiveness. The particle size isgenerally less than 10 µm in diameter. Steroids are frequentlygenerally less than 10 µm in diameter. Steroids are frequentlyadministered in the form of suspensions.

2. Ophthalmic Ointments

� Drugs administered as ointments have better bioavailability thandrops primarily owing to reduced dilution of drug with the tears,prolonged corneal contact time, and reduced drainage.

� The main disadvantage of ointments is that they cause blurringof vision and an increased incidence of contact dermatitis.


solutionssolutions


solutionssolutions

3- Ocular Inserts (ocusert )

� An ocusert is an insoluble ophthalmic insert that releases

drug at a constant and reproducible rate for a prolonged

period of time.

� It consists of a central core or drug reservoir sandwiched

between two semipermeable membranes.between two semipermeable membranes.

� It is placed in the cul-de-sac.

� Ocuserts are commercially available for pilocarpine.

otic, nasal and , nasal and opthalmic opthalmic dosage forms

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