Transdermal Drug Delivery

Systems

Contents

I. Factors affecting percutaneous absorption

II. Percutaneous absorption enhancer

III. Design features of transdermal drug delivery

system

IV. Percutaneous absorption model

V. Advantages and disadvantages of TDDSs

VI. Examples of transdermal drug deliver systems

VII. General clinical considerations in the use of

TDDSs

Transdermal drug delivery systems (TDDSs) facilitate the passage of therapeutic quantities of drug substances through the skin and into the general circulation for their systemic effect.

For transdermal drug delivery, it

is considered ideal if the drug

penetrates through the skin to

the underlying blood supply

without drug buildup in the

dermal layers.

(3M Transdermal Drug Delivery http://www.3M.com/DDS)

Benefits of TDDSs

Eliminates potential pain associated with

injections

No first pass metabolism in liver

Eliminates gastrointestinal side effect

Improves patient compliance due to simpler,

pain free delivery

Potential for home administration

Disdvantages of TDDSs

Only relatively potent drugs are suitable

candidates for TDDS because of the natural

limits of drug entry imposed by the skin’s

impermeability.

Some patients develop contact dermatitis at

the site of application from one or more of

the system components, necessitating

discontinuation.

I. Factors affecting percutaneous

absorption

1. Drug concentration is an important factor.

2. The larger the area of application, the more

drug is absorbed.

3. The aqueous solubility of a drug determines the concentration presented to the absorption site, and the partition coefficient influences the rate of transport across the absorption site.

Drugs generally penetrate the skin better in their un-ionized form. Nonpolar drugs tend to across the cell barrier through the lipid-rich regions, whereas the polar drugs favor transport between cells.

4. Drugs with molecular weights of 100 to 800

and adequate lipid and aqueous solubility

can permeate skin. The ideal molecular

weight of a drug for transdermal drug

delivery is believed to be 400 or less.

5. Hydration of the skin generally favors

percutaneous absorption. The TDDS acts as

an occlusive moisture barrier through which

sweat cannot pass, increasing skin hydration.

6. Percutaneous absorption appears to be

greater when the TDDS is applied to a site

with a thin horny layer than with a thick one.

7. Generally, the longer the medicated

application is permitted to remain in contact

with the skin, the greater is the total drug

absorption.

II. Percutaneous absorption enhancers

There is great interest among

pharmaceutical scientists to develop

chemical permeation enhancers and

physical methods that can increase

percutaneous absorption of therapeutic

agents.

1. Chemical enhancers

A chemical skin penetration enhancer

increases skin permeability by reversibly

damaging or altering the physicochemical

nature of the stratum corneum to reduce

its diffusional resistance.

Increased hydration of the stratum corneum

A change in the structure of the lipids and lipoproteins

in the intercellular channels

solvent action

or

denaturation

More than 275 chemical compounds have been

cited in the literature as skin penetration enhancers;

they include

acetone, azone,

dimethyl acetamide, dimethyl formamide）,

dimethyl sulfoxide (DMSO

ethanol,

oleic acid,

polyethylene glycol, propylene glycol,

sodium lauryl sulfate ）.

The selection of a permeation enhancer

should be based on

its efficacy in enhancing skin permeation

its dermal toxicity

its physicochemical and biologic

compatibility with the system’s other

components.

2. Iontophoresis and sonophoresis

Iontophoresis is delivery of a charged chemical compound across the skin membrane using an electrical field.

Iontophoresis-enhanced transdermal delivery has shown some promise as a means of peptide and protein administration.

A number of drugs have been the subject of

iontophoretic studies, they include

lidocaine

dexamethasone

amino acids,

peptides

insulin

Verapamil

Propranolol

Sonophoresis, is a process that

exponentially increases the absorption of

topical compounds (transdermal delivery)

with high-frequency ultrasound.

Sonophoresis occurs because ultrasound

waves stimulate micro-vibrations within the

skin epidermis and increase the overall

kinetic energy of molecules making up

topical agents.

Limited permeation due to lipid barrier

of the skin

Enhanced permeation by disruption of lipid

barrier cavitation

It is thought that high-frequency ultrasound

can influence the integrity of the stratum

corneum and thus affect its penetrability.

Among the agents examined are

hydrocortisone,

lidocaine,

salicylic acid

in such formulations as gels, creams, and

lotions.

III. Design features of transdermal drug

delivery systems

TDDSs are designed to support the passage

of drug substances from the surface of the

skin through its various layers and into the

systemic circulation.

Transdermal drug delivery systems may be constructed of a

number of layers, including

1) an occlusive backing membrane to protect the system from environmental

entry and from loss of drug from the system or moisture from the skin. It

should be occlusive to retain moisture and hydrate the site of application,

enabling increased drug penetration (ensure one-way drug flux into stratum

corneoum). E.g., films of polypropylene, polyethylene, polyolefin are used as

backing liners.

2) the drug reservoir or matrix sysetm to strore and release the drug at the skin-

site;

3) a release liner, which is removed before application and enables drug release

4) an adhesive layer to maintain contact with the skin after application. It

should be pressure-sensitive, providing ability to adhere to the skin with

minimal pressure and remain in place for the intended period of wear.

It should be non-irritating, easy to peel off after use, permit drug flux into the

skin, and compatible with other system components.

In some TDDs, the adhesive layer may contain the drug (e.g., polybutyl acrylate)

Technically, TDDSs may

be categorized into two

types,

1) Monolithic

Monolithic systems

incorporate a drug

matrix layer between

backing and frontal

layers.

Technically, TDDSs may

be categorized into two

types,

1) Monolithic

The drug-matrix layer is composed of a

polymeric material in which the drug is

dispersed.

The polymer matrix controls the rate at which

the drug is released for percutaneous

absorption.

In the preparation of monolithic systems, the

drug and the polymer are dissolved or

blended together, cast as the matrix, and

dried.

2) Membrane-controlled systems.

Transderm-Nitro, Transderm-Scop

Form-fill-seal from lamination process

Membrane-controlled transdermal systems

are designed to contain a drug reservoir, or

pouch, usually in liquid or gel form, a rate-

controlling membrane, and backing,

adhesive, and protecting layers.

Membrane-controlled systems have the advantage over monolithic systems in that as long as the drug solution in the reservoir remains saturated, the release rate of drug through the controlling membrane remains constant.

In both monolithic and reservoir systems, drug release rate is controlled by either skin or the device (artificial membrane).

TDDs are packaged in individual sealed packets to preserve and protect them until use.

IV. Percutaneous absorption models

1. In vivo studies

In vivo skin penetration studies may be

undertaken for one or more of the

following purposes:

1) To verify and quantify the cutaneous

bioavailability of a topically applied drug.

2) To verify and quantify the systemic

bioavailability of a transdermal drug.

3) To establish bioequivalence of different

topical formulations of the same drug

substance.

4) To determine the incidence and degree of

systemic toxicologic risk following topical

application of a specific drug or drug

product.

5) To relate resultant blood levels of drug in

human to systemic therapeutic effects.

The most relevant studies are performed in

humans, however, animal models may be

used insofar as they may be effective as

predictors of human response.

Biologic samples used in drug penetration

and drug absorption studies include skin

sections, venous blood from the application

site, blood from the systemic circulation,

and excreta (urine, feces, and expired air).

2. In vitro studies

Skin permeation may be tested in vitro using various skin tissues (human or animal whole skin, dermis or epidermis) in a diffusion cell.

In vitro penetration studies using human skin are limited because of difficulties of procurement, storage, expense, and variation in permeation.

Animal skins are much more permeable than human skin. One alternative that has been shown to be effective is shed snake skin.

The material may be used in cell culture

studies or in standard diffusion cells.

Diffusion cell systems are employed in vitro

to quantify the release rates of drugs from

topical preparations.

In these systems, skin membranes or

synthetic membranes may be employed as

barriers to the flow of drug and vehicle to

simulate the biologic system.

V. Advantages and disadvantages of TDDSs

The advantages of TDDSs are:

1. They can avoid gastrointestinal drug

absorption difficulties caused by

gastrointestinal pH, enzymatic activity and

drug interactions with food, drink, or other

orally administered drugs.

2. They can substitute for oral administration

of medication when that route is unsuitable,

as in instances of vomiting and/or diarrhea.

3. They avoid the first-pass effect, that is, the

initial pass of a drug substance through the

systemic and portal circulation following

gastrointestinal absorption, theraby possibly

avoiding the drug’s deactivation by digestive

and liver enzymes.

4. The systems are noninvasive, avoiding the

inconvenience of parenteral therapy.

5. They provide extended therapy with a single

application, thereby improving patient

compliance over other dosage forms

requiring more frequent dose administration.

6. The activity of drugs having short half-lives

is extended through the reservoir of drug

present in the therapeutic delivery system

and its controlled release characteristics.

7. Drug therapy may be terminated rapidly by

removal of the application from the surface

of the skin.

8. Ease of rapid identification of the

medication in emergencies (e.g.,

nonresponsive, unconscious, or comatose

patient) due to the physical presence,

features and identifying-markings on the

TDDS.

The disadvantages of TDDSs are:

1. Only relatively potent drugs are suitable candidates for transdermal delivery due to the natural limits of drug entry imposed by the skin’s impermeability.

2. Some patients may develop contact dermatitis at the site of application due to one or more of the system components, necessitating discontinuation.

VI. Examples of transdermal drug

delivery systems

1. Transdermal scopolamine

It was the first TDDS to receive

FDA approval.

The Transderm-Scop system is a

circular flat patch 0.2 mm thick

and 2.5 cm2 in area.

VI. Examples of transdermal drug

delivery systems

The TDDS contains 1.5 mg of scopolamine and is designed

to deliver approximately 1 mg of scopolamine at an

approximately constant rate to the systemic circulation over

the 3 day life-time of the system.

The patch is worn in a hairless area behind the ear.

Because of the small size of the patch, the system is

unobtrusive, convenient, and well accepted by the patient.

Applied at least 4 hours before the activity that causes motion

sickness.

2. Transdermal Nitroglycerin

A number of nitroglycerin-containing

TDDSs have been developed, including

Deponit (Schwarz)

Minitran (3M Pharmaceuticals)

Nitro-Dur (Key)

Transderm-Nitro (Novartis)

Each of these products maintains

nitroglycerin drug delivery for 24 hours after

application.

Nitroglycerin is used widely in the prophylactic treatment of angina.

It has a relatively low dose, short plasma half-life, high peak plasma levels, and inherent side effects when taken sublingually, a popular route.

It is rapidly metabolized by the liver when taken orally, this first-pass effect is bypassed by the transdermal route.

The various nitroglycerin TDDSs control the

rate of drug delivery through a membrane

and/or controlled release from the matrix or

reservoir.

The rate of drug release depends on the

system. In the Transderm-Nitro system,

nitroglycerin 0.02 mg is delivered per hour

for every square centimeter of patch, whereas

in the Deponit system, each square

centimeter delivers approximately 0.013 mg

of nitroglycerin per hour.

Not all nitroglycerin systems have the same

construction. For example, the Transderm-

Nitro TDDS is a four-layer drug pouch

system, whereas the Deponit TDDS is a thin

two-layer matrix system resembling.

Patients should be given explicit

instructions regarding the use of

nitroglycerin transdermal systems.

Generally, these TDDSs are placed on the

chest, back, upper arms, or shoulders.

The patient should understand that physical

exercise and elevated ambient temperatures,

such as in a sauna, may increase the

absorption of nitroglycerin.

3. Transdermal clonidine

The first transdermal system for

hypertension, Catapres TTS (clonidine

transdermal therapeutic system, Boehringer

Ingelheim), was marketed in 1985.

Clonidine lends itself to transdermal delivery

because of its lipid solubility, high volume of

distribution, and therapeutic effectiveness in

low plasma concentrations.

The TDDS provides controlled release of

clonidine.

Catapres TTS is available in several sizes,

with the amount of drug released

proportional to the patch size.

To ensure constant release over the 7-day

use period, the drug content is greater than

the total amount of drug delivered.

Catapres TTS is available in several sizes,

with the amount of drug released

proportional to the patch size.

Clonidine flows in the direction of the lower

concentration at a constant rate limited by a

rate-controlling membrane.

Therapeutic plasma clonidine levels are

achieved in 2-3 days after initial application.

Application of a new system to a fresh skin

site is performed at weekly intervals.

The system is applied to the hairless area of

intact skin on the upper outer arm or chest.

4. Transdermal Nicotine

Nicotine TDDSs are used as adjuncts in smoking cessation

programs.

In a blinded study, users of nicotine TDDSs are more than

twice as likely to quit smoking than individuals wearing a

placebo patch.

The nicotine TDDSs provide sustained blood levels of

nicotine as “nicotine-replacement-therapy” to help the

patient establish and sustain remission from smoking.

Motivation to quit smoking is enhanced through the

reduction of withdrawal symptoms and by partially stisfying

the nicotine craving and desired sensory feelings provided

by smoking.

The commercially available patches contain from 7 to 22 mg

of nicotine for daily application during the course of

treatment ranging from about 6 to 12 weeks.

A nicotine TDDS usually is applied to the arm or upper

front torso, with patients advised not to smoke when

wearing the system.

Some of the nicotine replacement programs provide a

gradual reduction in nicotine dosage form during the

treatment program.

5. Transdermal Estradiol

The Estraderm TDDS delivers 17-estradiol

through a rate-limiting membrane

continuously upon application to intact skin.

Two systems provide delivery of 0.05 or 0.1

mg estradiol per day.

Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause, female hypogonadism, primary ovarian failure, and atrophic conditions caused by deficient endogenous estrogen production, such as atrophic vaginitis and kraurosis valvae.

Transdermal administration produces therapeutic serum

levels of estradiol (half-life is about 1 hr) with lower

circulating levels of estrone and estrone conjugates than

does oral therapy and requires a smaller total dose.

The systemic side effects from oral estrogens can be

reduced by using the transdermal dosage forms.

Therapy is usually administered on a cycling schedule (3

weeks of therapy followed by 1 week without).

patch is applied on a dry, clean skin on the trunk of the

body, either the abdomen or upper quadrant of buttocks. It

should be applied to the waistline because tight clothes

may damage or dislodge it.

Examples: Climara patch (matrix system containing

estradiol),

Climara Pro patch (matrix system containing estradiol and

levonorgestrel)

6. Transdermal contraceptive systems

Examples: Ortho Evra combination contraceptive patch

(matrix system containing norelgestromin and ethinly

estradiol), with a surface area of 20 cm2, it contains 6 mg

norelgestromin and 0.75 ethinyl estradiol.

Applied on upper arm, your stomach, your buttocks, or your upper

back

Remove the patch and apply a new one on the same day each week

for three weeks in a row. At the end of the third week, remove the

patch and do not apply a new one for 7 full days. Your period

should start during this time Do not allow more than 7 days to pass

before starting your next 3-week patch cycle

7. Transdermal testosterone

Testosterone transdermal systems, Testoderm (Alza) and

Androderm (SmithKline Beecham), are available with various

delivery rates as hormone replacement therapy in men who

have an absence or deficiency of testosterone.

The Testoderm is designed to be applied daily following

stretching a dry and clean scrotal skin by one hand and

pressing the adhesive of the patch by the other(50 times

permeable as other skin site), usually in the morning to mimic

endogenous testosterone release.

Optimum serum levels are reached within 2 to 4 hours after

application. The patch is worn 22 to 24 hours daily for 6 to 8

weeks.

Androderm is designed to be applied nightly to the skin of

back, abdomen, upper arms, or thighs (should not be applied

to the scrotum).

7. Transdermal methylphenidate

It is a matrix-based patch, available in different strengths:

10, 15, 20 and 30 mg.

Drug release delivered over 9 hrs and is dependent on patch

size and wear time.

Indicated for attention deficit hyperactivity disorder. It is

given to students 2 hrs prior to the time the effect is needed

that is, at school, school and removed later in the day after

school earlier than the 9 hrs limit.

It obviates the need for oral medication to be administered

during the day and trips to the school nurse’s office.

7. Other transdermal therapeutic systems

Cardiovascular agents,

Diltiazem

Isosorbide dinitrate

Propranolol

Nifedipine

Mepindolol

Verapamil

Physostigmine, xanomeline for Alzheimer’s disease therapy,

Naltrexone and methadone for substance addiction,

Buspirone for anxiety，

Bupropion for smoking cessation，

Papaverine for male impotence，

Oxybutynin (Oxytrol): reduces muscle spasms of the bladder

and urinary tract. Oxybutynin is used to treat symptoms of

overactive bladder, such as frequent or urgent urination,

incontinence (urine leakage), and increased night-time urination.

Levonorgestrel with estradiol (contraceptive)

VII. General clinical considerations in

the use of TDDSs

The patient should be advised of the following general

guidelines along with product-specific instructions in the use of TDDSs.

1. Percutaneous absorption may vary with the site of application.

The preferred application site is stated in the package insert of the product). the patient should be advised of the importance of using the recommended site and rotating locations within that site. Rotating locations are important to allow the skin beneath a patch to regain its normal permeability after being occluded and to prevent skin irritation.

Skin site must not be reused within 1 week.

VII. General clinical considerations in

the use of TDDSs

2. TDDSs should be applied to clean, dry skin that is

relatively free of hair and not oily, irritated, inflamed,

broken, or callused. • Moist skin can accelerates drug permeation.

• Oily skin can impair the adhesion of the patch.

• If hair is present, it should be carefully cut, dry-shaved. Wet-shaving and a depilatory agent is advised for use, due to the possibility or removing the outermost layers of stratrum corneum, thus affecting the rate and extent of drug permeation.

3. Use of skin lotion should be avoided at the application site,

because lotions affect skin hydration and can alter the

partition coefficient between the drug and the skin.

4. TDDSs should not be physically altered by cutting, as an

attempt to reduce the dose, since this destroys the integrity

of the system.

5. A TDDS should be removed from its protective package,

with care not to tear or cut into the unit. The adhesive layer

should be exposed with care without touching the adhesive

surface (sometimes it contains drug) with fingertips. The

patch should be firmly pressed against the skin site with

the heel of the hand for about 10 sec to ensure uniform

contact and adhesion.

6. A TDDS should be placed at a site that will not subject it to

being rubbed off by clothing or movement. The patch may

be left on when showering, bathing or swimming. Should a

patch prematurely dislodge, an attempt may be made to

reapply it or it may be replaced with a fresh one.

7. A TDDS should be worn for the full period stated in the

product’s instructions. Following that period, it should be

removed and replaced with a fresh system as directed.

8. The patient or caregiver should be instructed to cleanse the

hands thoroughly before and after applying a TDDS. Care

should be taken not to rub the eyes or touch the mouth

during handling of the patch.

9.If the patient exhibits sensitivity or intolerance to a TDDS

or if undue skin irritation results, the patient should seek

reevaluation.

10. Upon removal, a used TDDS should be folded in half

with the adhesive layer together so that it cannot be reused.

The used patch, which contains residual drug, should be

placed in the replacement patche's pouch and discarded in

a manner safe to kids and pets.

Refer to table 11.1 in pages 347 and 348

of the book.

Patches (not systems)

Example: Lidoderm (lidocaine) for postherpetic neuralgia.

• The patient can apply up to 3 patches a day, depending on the directions for use.

• The patch can be cut for a smaller size prior to the removal of the release liner.

• The patient should wash his hands before and after handling the lidoderm patch.

• After use, it should be disposed in a way that avoids accidental exposure to kids and pets.

Patches (not systems)

Questions

1. Explain shortly

- transdermal drug delivery systems

- iontophoresis

- sonophoresis

- percutaneous absorption enhancers

2. What factors could affect percutaneous drug

absorption?

3. How to increase percutaneous absorption of drug by

physical and chemical methods?

4. What types of drugs could be designed as TDDSs

and how?

5. How to design transdermal drug delivery systems?

6. How to study the percutaneous absorption of drug

using in vitro and in vivo models?

6. What are the characteristics of transdermal drug

delivery systems?

7. How many different types of transdermal

nitroglycerin are in the market? Explain their

characteristics respectively.

8. What are the clinical considerations in the use of

TDDSs?

Sterile preparations (I) Ophthalmic Preparations

Ophthalmic preparations:

Definition: They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular or intravitreal) to the eye or used in conjunction with an ophthalmic device.

The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments. But these preparations when in­stilled into the eye are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage.

The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts , intravitreal injections and implants.

Drugs used for ocular delivery:

Miotics e.g. pilocarpine Hcl

Mydriatics e.g. atropine

Cycloplegics e.g. atropine

Anti-inflammatories e.g. corticosteroids

Anti-infectives (antibiotics, antivirals and antibacterials)

Anti-glucoma drugs e.g. pilocarpine Hcl

Surgical adjuncts e.g. irrigating solutions

Diagnostic drugs e.g. sodiumfluorescein

Anesthetics e.g. tetracaine

Anatomy and Physiology of the Eye:

Anatomy and Physiology of the Eye

(Cont.): The sclera: The protective outer layer of the eye, referred to as the “white

of the eye” and it maintains the shape of the eye.

The cornea: The front portion of the sclera, is transparent and allows light to enter the eye. The cornea is a powerful refracting surface, providing much of the eye's focusing power.

The choroid is the second layer of the eye and lies between the sclera and the retina. It contains the blood vessels that provide nourishment to the outer layers of the retina.

The iris is the part of the eye that gives it color. It consists of muscular tissue that responds to surrounding light, making the pupil, or circular opening in the center of the iris, larger or smaller depending on the brightness of the light.

Anatomy and Physiology of the Eye

(Cont.):

The lens is a transparent, biconvex structure, encased in a thin transparent covering. The function of the lens is to refract and focus incoming light onto the retina.

The retina is the innermost layer in the eye. It converts images into electrical impulses that are sent along the optic nerve to the brain where the images are interpreted.

The macula is located in the back of the eye, in the center of the retina. This area produces the sharpest vision.

Anatomy and Physiology of the Eye

(Cont.): The inside of the eyeball is divided by the lens into two fluid-

filled sections.

The larger section at the back of the eye is filled with a colorless gelatinous mass called the vitreous humor.

The smaller section in the front contains a clear, water-like material called aqueous humor.

The conjunctiva is a mucous membrane that begins at the edge of the cornea and lines the inside surface of the eyelids and sclera, which serves to lubricate the eye.

Absorption of drugs in the eye:

Factors affecting drug availability:

1- Rapid solution drainage by gravity, induced lachrymation,

blinking reflex, and normal tear turnover:

- The normal volume of tears = 7 ul, the blinking eye can

accommodate a volume of up to 30 ul without spillage, the

drop volume = 50 ul

lacrimal nasal drainage:

Absorption of drugs in the eye:

2- Superficial absorption of drug into the conjunctiva and sclera and rapid removal by the peripheral blood flow:

3- Low corneal permeability (act as lipid barrier) In general:

- Transport of hydrophilic and macromolecular drugs occurs through scleral route

- Lipophilic agents of low molecular weight follow transcorneal transport by passive diffusion.

- N.B. the drug should have dual solubility (oil and water soluble) to traverse the corneal epithelium (lipid barrier) then the aqueous humour.

Absorption of drugs in the eye:

General safety considerations:

A. Sterility:

- Ideally, all ophthalmic products would be finally sterilized in the final packaging.

- Only a few ophthalmic drugs formulated in simple aqueous vehicles are stable to normal autoclaving temperatures and times (121°C for 20-30 min).

*Such heat-resistant drugs may be packaged in glass or other heat-deformation-resistant packaging and thus can be sterilized in this manner.

- Most ophthalmic products, however cannot be heat sterilized due to the active principle or polymers used to increase viscosity are not stable to heat.

A. Sterility (cont.):

* Most ophthalmic products are aseptically manufactured and

filled into previously sterilized containers in aseptic

environments, using aseptic filling-and-capping techniques.

A. Sterility (cont.):

B. Ocular toxicity and irritation:

- Albino rabbits are used to test the ocular toxicity and irritation

of ophthalmic formulations.

- The procedure is based on the examination of the conjunctiva,

the cornea or the iris.

C.Preservation and preservatives:

Preservatives are included in multiple-dose eye solutions for maintaining the product sterility during use.

Preservatives not included in unit-dose package.

The use of preservatives is prohibited in ophthalmic products that are used at the of eye surgery because, if sufficient concentration of the preservative is contacted with the corneal endothelium, the cells can become damaged causing clouding of the cornea and possible loss of vision.

So, these products should be packaged in sterile, unit-of-use containers.

The most common organism is Pseudomonas aeruginosa that grows in the cornea and causes loss of vision.

C.Preservation and preservatives:

C.Preservation and preservatives:

Examples of preservatives:

1- Cationic wetting agents:

• Benzalkonium chloride (0.01%)

• It is generally used in combination with 0.01-0.1% disodium

edetate (EDTA). The chelating, EDTA has the ability to

render the resistant strains of PS aeruginosa more sensitive to

benzalkonium chloride.

2- Organic mercurials:

• Phenylmercuric nitrate 0.002-0.004%

phenylmercuric acetate 0.005-0.02%.

C.Preservation and preservatives:

3-Esters of p-hydroxybenzoic acid:

• Mixture of 0.1% of both methyl and propyl hydroxybenzoate

(2 :1)

4- Alcohol Substitutes:

• Chlorobutanol(0.5%). Effective only at pH 5-6.

• Phenylethanol (0.5%)

Ideal ophthalmic prepration:

Following characteristics are required to optimize ocular drug delivery system:

Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritative and comfortable form.

Appropriate rheological properties.

CLASSIFICATION OF OCULAR DOSAGE

FORMS:

Topical eye drops:

-Solutions

- Suspensions

- Powders for

Reconstitution

- Gel-forming solution

-Ointments

- Gels

- Ocular inserts

A. Topical Eye drops:

1- Solutions:

- Ophthalmic solutions are sterile solutions, essentially free from

foreign particles, suitably compounded and packaged for

instillation into the eye.

1- Solutions:

1- Solutions:

Disadvantages of eye solutions:

1-The very short time the solution stays at the eye surface.

The retention of a solution in the eye is influenced by viscosity, pH and the

instilled volume.

2- its poor bioavailability (a major portion i.e. 75% is lost via nasolacrimal

drainage)

3- the instability of the dissolved drug

4- the necessity of using preservatives.

2- suspensions:

to prevent irritation or scratching of the

Cornea.

2- Suspensions:

3- Powders for Reconstitution:

4- Gel-Forming Solutions

Some polymers that act as gelling agents are added to the solution such as: 1. Carbopol 940

2. Hydroxypropylmethyl cellulose

3. Hydroxyethyl cellulose.

4- Gel-Forming Solutions

Inactive Ingredients in Topical Drops:

1- Tonicity-Adjusting Agents:

Isotonicity

Lacrimal fluid is isotonic with blood having an isotonicity value

Corresponding to that of 0.9% Nacl solution

2- pH Adjustment and Buffers:

pH adjustment is very important as pH affects:

1- to render the formulation more stable

2- The comfort, safety and activity of the product.

Eye irritation increase in tear fluid secretion

Rapid loss of medication.

3- to enhance aqueous solubility of the drug.

4- to enhance the drug bioavailability

5- to maximize preservative efficacy

2- pH Adjustment and Buffers:

pH & buffer

3- Stabilizers & Antioxidants:

4- Surfactants:

5- Viscosity-Imparting Agents:

(to retard the rate of

setting of particles)

Disadvantages: 1- produce blurring vision as when dry form

a dry film on the eye lids

2- make filtration more difficult

6- Vehicles:

Packaging:

Eye drops have been packaged almost entirely in plastic dropper bottles.

Advantages:

- convenience of use by the patient

- decreased contamination potential

- lower weight

- lower cost

Packaging: A special plastic ophthalmic package made of polypropylene is

introduced. The bottle is filled then sterilized by steam under

pressure at 121°C.

Packaging:

The glass bottle is made sterile by dry-heat or steam autoclave

sterilization.

Amber glass is used for light-resistance.

B. Semisolid Dosage Forms: Ophthalmic Ointments and Gels:

Formulation:

**It is suitable for moisture sensitive drugs and has

longer contact time than drops.

-Ointments are used as vehicles for antibiotics, sulfonamides,

antifungals and anti-inflammatories.

-Petrolatum vehicle used as an ocular lubricant to treat dry eye

syndromes.

B. Semisolid Dosage Forms: Ophthalmic Ointments and Gels:

*Gels have increased residence time and enhanced bioavailability than

eye drops.

N.B. Emulsion bases should not be used in the eye owing to ocular

irritation produced by the soaps and surfactants used to form the

Emulsion.

Chlorobutanol and methyl- and propylparaben are the

most commonly used preservatives in ophthalmic ointments.

B. Semisolid Dosage Forms: Ophthalmic Ointments and Gels:

B. Semisolid Dosage Forms: Ophthalmic Ointments and Gels:

Packaging:

C. Solid Dosage Forms Ocular Inserts

Ophthalmic inserts are defined as sterile solid or semisolid

preparations, with a thin, flexible and multilayered structure,

for insertion in the conjunctival sac.

Advantages:

Increasing contact time and improving bioavailability.

Providing a prolong drug release and thus a better efficacy.

Reduction of adverse effects.

Reduction of the number administrations and thus better

patient compliance.

C. Ocular Inserts I. Insoluble inserts:

Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate.

e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system

- Designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release pilocarpine continuously at a steady rate for 7 days for treatment of glucoma.

C. Ocular Inserts I. Insoluble inserts:

II.Soluble Ocular inserts:

- Soluble inserts consists of all monolytic polymeric devices that at the

end of their release, the device dissolve or erode.

Types a) Based on natural polymers e.g. collagen.

b) Based on synthetic or semi synthetic polymers e.g. Cellulose derivatives – Hydroxypropyl cellulose, methylcellulose or Polyvinyl alcohol, ethylene vinyl acetate copolymer.

- The system soften in 10-15 sec after introduction into the upper conjuctivall sac, gradually dissolves within 1 h, while releasing the drug.

- Advantage: being entirely soluble so that they do not need to be removed from their site of application.

D. Intraocular Dosage Forms

They are ophthalmic products that introduced into the interior

structures of the eye primarily during ocular surgery.

Requirements for formulation:

1- sterile and pyrogen-free

2- strict control of particulate matter

3- compatible with sensitive internal tissues

4- packaged as preservative-free single dosage

D. Intraocular Dosage Forms: 1- Irrigating Solutions

It is a balanced salt solution was developed for hydration and clarity of

the cornea during surgery.

D. Intraocular Dosage Forms 2- Intraocular Injections

D. Intraocular Dosage Forms 3- Viscoelastics

D. Intraocular Dosage Forms 4- Intravitral Implant

,,,Manufacturing Environment of ophthalmics: