Uy, Alyssa V. 2BPh
Chapter 11: TRANSDERMAL DRUG DELIVERY SYSTEMS
can increase drug absorption
Percutaneous Absorption
Multiple-application dosing rather than single bolus applications
The absorption of substances from outside the skin to positions beneath the skin, including entrance into the blood stream
Materials used to enhance absorption: surfactants, azone,
Penetration of the Skin by Drugs
PERCUTANEOUS ABSORPTION ENHANCERS
Drugs may penetrate intact skin after topical application
dimethylsulfoxide (DMSO), dimethylacetamide,
(a) through the walls of the hair follicles,(b) through the sweat
dimethylformamide, alcohol, acetone, propylene glycol, and
glands or the sebaceous glands, (c) or between the cells of the
polyethylene glycol.
horny layer.
Are designed to support the passage of drug substances from the
Mechanism Of Action For Percutaneous Absorption Enhancers
1.
systemic circulation.
Mechanism Of Action
surface of the skin, through its various layers, and into the
Reduction of the resistance of the stratum corneum by altering its physicochemical properties
The main route for the penetration of drug is generally through the epidermal layers, rather than through the hair follicles or the gland ducts, because the surface area of the latter is rather
2.
Alteration of the hydration of the stratum corneum
3.
Effecting a change in the structure of the lipids and lipoproteins in the cellular channels, through solvent action
minute compared to the area of the skin.
or denaturation
The percutaneous absorption of a drug generally results from
4.
direct penetration of the drug through the stratum corneum.
Permeation of the laminate barriers in stratum corneum can occur by diffusion via: 1.
Transcellular penetration (across the cells)
2.
Intercellular penetration (between the cells)
3.
Transappendageal penetration (via hair follicles, sweat and
Carrier mechanism in the transport of ionizable drugs
Percutaneous Absorption Models 2 Categories
1.
In vivo - skin penetration; performed in humans
or animal models Purposes:
a.
sebum glands, and pilosebaceous apparatus)
To verify and quantify the cutaneous bioavailability of a topical applied drug.
b.
To verify and quantify the systemic bioavailability of a transdermally delivered drug.
c.
To establish bioequivalence of different topical formulations of the same drug substanc
d.
To determine incidence and degrees of systemic toxicologic risk following the topical application of a specific drug/drug product
2.
DEPICTION OF FOUR LAYERED THERAPEUTIC
In Vitro - penetration studies human skin are limited
because of difficulties of procurement, storage, expense, and variability in permeation. Excised animal skins may
Factors Affecting Percutaneous Absorption
1.
Nature of the drug itself
2.
Nature of the vehicle
3.
The nature of the skin
4.
Presence of moisture
RESEARCH FINDINGS ABOUT PERCUTANEOUS ABSORPTION
Drug concentration is an important factor
Most drug is absorbed through percutaneous absorption when the drug substance is applied to a larger surface area.
The drug should have a greater physicochemical attraction to the skin than to the vehicle in which it is presented in order for the drug to leave the vehicle in favor the skin.
Drug absorption appears to be enhanced from vehicles that easily
also variable in quality and permeation. Alternative dermal absorption studies is Living Skin Equivalent (LSE) Iontophoresis and Sonophoresis Iontophoresis involves the delivery of charged chemical compounds
across the skin membrane using an applied electrical field. Examples: lidocaine, amino acids/peptides/insulin, verapamil, and
propanolol Sonophoresis, or high-frequency ultrasound, is also being studied as a
means to enhance transdermal drug delivery Examples: hydrocortisone, lidocaine, and salicylic acid in such
formulations as gels, creams and lotions
cover the skin surface, mix readily with the sebum, and bring the drug into contact with the tissue cells for absorption.
Vehicles that increase the hydration of the skin generally favor the percutaneous absorption of drugs.
The amount of rubbing in or inunction of the topical application
2 Basic Types of Transdermal Dosing System
1.
Those that control the rate of drug delivery to the skin.
2.
Those that allow the skin to control the rate of drug absorption
will have a bearing on the amount of drug absorbed, the longer the period of inunction, the greater the absorption.
Percutaneous absorption appears to be greater when the drug is
Objectives of Rate-Controlling TDDS
1.
Deliver the drug substances at a controlled rate, to the
applied to skin with a thin horny layer than with one that is thick.
intact skin of patients, for absorption into the systemic
The longer the period of time the medicated application is
circulation.
permitted to remain in contact with the skin, the greater will be the absorption.
2.
The system should possess the proper physicochemical characteristics to permit the ready release of the drug
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substance and facilitate its partition from the delivery 3.
2.
system into the stratum corneum.
irritated, cut, or abraded. This is to assure the intended amount
The system should occlude the skin to ensure the one-way
and rate of transdermal drug delivery and absorption.
flux of the drug substance. 4.
3.
The transdermal system should have a therapeutic 4.
7.
The patch should be worn for the period of time stated in the
system
product’s instructions. Following period, the patch should be
The system’s adhesive, vehicle, and active agent should be
removed and a fresh patch applied as directed.
nonirritating and nonsensitizing to the skin of the patient. 6.
The patch should be removed from its protective package, being careful not to tear or cut.
advantage over other dosage forms and drug delivery 5.
The transdermal patch should not be applied to skin that is oily,
5.
Patches generally may be left on when showering, bathing, or
The patch should adhere well to the patient’s skin and its
swimming. Should a patch premature dislodge, an attempt may
physical size and appearance and placement on the body
be made to reapply it, or it may be replaced with a fresh patch--
should not be a deterrent to use.
the latter being worn for a full time period before it is replaced.
The system should not permit the proliferation of the skin
6.
bacteria beneath the occlusion.
The patient should be instructed to cleanse the hands thoroughly before and after applying the patch. patch. Care should be taken not to rub the eyes or touch the mouth during handling the patch.
7.
If irritation results, patient should seek re-evaluation.
Advantages of TDDS
1.
2. 3.
Other Transdermal Therapeutic Systems
Avoids gastrointestinal drug absorption difficulties caused by
1.
Testoderm , is available Testosteron transdermal system - Testoderm,
gastrointestinal pH, enzymatic activity, drug interactions with
for hormone replacement in men who have an absence or
food, drinks, or other orally administered drugs.
deficiency of testosterone.
Substitutes for oral administration of medication when that
Dose: 10 mg for delivery of 4 mg/day; 15 mg for
routes is unsuitable, as in instances of vomiting and/or diarrhea.
delivery of 6mg/day. The patches are applied to
Avoids first-pass effect, that is, the initial pass of a drug substance
scrotal skin where optimal absorption occurs. The
through the systemic and portal circulation following
patches are worn 22 to 24 hours daily for 6 to 8 weeks.
gastrointestinal absorption (thereby possibly avoiding the drug’s
4. 5.
2.
deactivation by digestive and liver enzymes).
consisting of karaya, a substance known for its non -
Avoids the risks and inconveniences of parenteral therapy and the
irritating and self-adhesive properties. It is use for the
variable absorption and metabolism associated with oral therapy.
treatment of viral wart infections
Provides the capacity for multiday therapy with a single application, thereby improving patient compliance over use of
other dosage forms requiring more frequent dose administration. 6.
7.
Trans-Ver-Sal - contains 15% salicylic acid in a vehicle
Technology Of Transdermal Delivery Systems (2 Types)
1. Monolithic systems - incorporate a drug matrix layer between
Extends the activity of drugs having short half-life through the
backing and frontal layers. The drug matrix layer is composed
reservoir of drug present in the therapeutic delivery system and
of a polymeric material in which the drug is dispersed. The
its controlled release characteristics.
polymer matrix controls the rate at which drug is released for
Provides capacity to terminate drug effect rapidly (if clinically
percutaneous absorption.
desired) by removal of drug application from the surface of the
Ex.: Nitro-Dur and Nitrodisc
skin. 8.
2. Membrane controlled transdermal system - are design to contain
Provides ease of rapid identification of the medication in
a drug reservoir, usually in liquid or gel form, a rate controlling
emergencies (e.g. non responsive, unconscious or comatose
membrane, and backing, adhesive, and protecting layers
patient) Disadvantages of TDD Systems
1.
The transdermal route administration is unsuitable for drugs that irritate or sensitize the skin.
2.
Ex.: Transderm-Nitro and Transderm-Scop
Examples Of TDD Systems
1. Clonidine - Catapress –TTS
Four-layered patch:
Only relative potent drugs are suitable candidates for transdermal
a.
backing layer of pigmented polyester film
delivery due to the natural limits of drug entry imposed by the
b.
drug reservoir of clonidine, mineral oil,
skin’s impermeability. impermeability.
3.
polyisobutylene, and colloidal silicon dioxide
Technical difficulties are associated with the adhesion of the
c.
systems to different skin types and under various environment
the rate of drug delivery
conditions, and the development of rate-controlling drug delivery features which are economically feasible and therapeutically
a microporous polypropylene membrane controlling
d.
advantageous for more than a few drug substances.
an adhesive formulation of agents
Uses: antihypertensive clonidine at a constant rate for 7 days, once a week dosing in the upper arm or torso.
2. Estradiol - Estraderm General Considerations in the use of TDD Sy stems
1.
The site selected for application should be clean clean, dry, and hairless (but not shaved) Example: nitroglycerin - chest; estradiol - buttocks or abdoment; scopolamine - behind the ear; nicotine –upper trunk or upper outer arm.
Four layered patch: a.
transparent polyester film
b.
drug reservoir of estradiol and alcohol gelled with hydroxypropyl cellulose
c. d.
an ethylenevinyl acetate copolymer membrane an adhesive formulation of light mineral and polyisobutylene
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Uses: design to release 17 B-estradiol continuously. Applied twice weekly over a cycle of 3 weeks. The patch is generally
applied to the abdomen, altering sites with each application. 3. Nicotine – Nicotrol
Multi-layered rectangular patch: a.
outer backing of laminated polyester film
b.
rate-controlling adhesive, nonwoven material, and nicotine, disposable liner removed prior to use - Aid in smoking cessation programs
4. Nitroglycerin - Deponit
Nitroglycerin in a matrix of lactose, plasticizer, polyisobutylene, and aluminized plastic
Use: to provide controlled release of nitroglycerin continuously for a 24 hour period. Patches are applied to
COMPONENTS
inner part of upper arm, shoulders, or chest.
5. Nitroglycerin Nitroglycerin - Nitro - Dur
Nitroglycerin in a gel like matrix composed of glycerin,
Drug - Drug solution in direct contact with release liner
Adhesive - Serves to adhere the components of the patch
Membrane - Controls the release of the drug from the reservoir
Backing - Protects the patch from the outer environment
together along with adhering the patch to the skin
water, lactose, polyvinyl alcohol, povidone and sodium citrate sealed in a polyester foil polyethylene laminate
and multi-layer patches
Use: same as # 4
6. Scopolamine - Transderm – Scop
Liner - Protects the patch during storage. The liner is removed
prior to use.
Four layered patch: a.
backing layer of aluminized polyester film
b.
drug reservoir of scopolamine, mineral oil & polyisobutylene
c.
a microporous polypropylene membrane for rate delivery of scopolamine
d.
adhesive of polyisobutylene, mineral oil, and scopolamine
Use: for continuous release of scopolamine over a 3-day period as required for the prevention of nausea and vomiting associated with motion sickness. The patch is
placed behind the ear . When repeated administration is desired, the first patch is removed and the second patch placed behind the other ear
VIVELLE-DOT
This contains estradiol in a multipolymeric adhesive that helps in the development and maintenance of the female reproductive system and secondary sexual characteristics. NEUPRO
This is a skin patch designed to treat symptoms of early Parkinson's disease. DENTI PATCH
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This is a band-aid-like patch inserted on your gum to numb it before an injection NITRO-DUR
This contains nitroglycerin which is a type of vasodilator. This is used to prevent chest pain caused by angina. It will not help to stop an episode of chest pain. DAYTRANA
This is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children six to 12 years of age. ORTHO EVRA
It is a contraceptive used by women to prevent pregnancy
NICOTINE PATCH
It is used as a temporary aid for smoking-cessation programs. It helps to control the symptoms of nicotine withdrawal (irritability, headache, fatigue, insomnia) and thus helps you to concentrate on overcoming the psychological and behavioral aspects of your smoking habit. MYLAN ESTRADIOL PATCH
This patch is designed to release Estradiol continuously upon application to intact skin for the treatment of moderate to severe vasomotor and vulvovaginal symptoms associated with menopause, and for prevention of postmenopausal osteoporosis. NICORETTE PATCH
This contains a low dose of nicotine that is intended to help quit smoking by reducing the unpleasant nicotine withdrawal effects. ESTRADERM PATCH
This patch contains estradiol that is a form of estrogen in female sex hormone the regulates many processes in the body. NICOTROL PATCH
This helps avoid the discomfort of nicotine withdrawal symptoms when you quit smoking by giving you a controlled, sustained dose of nicotine
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