Pharmaceutics final exam - TDD

Answer 1

“Between 1979 and 2002, a new patch was approved on average every 2.2 years.”

Between 2003–2007 the rate tripled to a new transdermal delivery system every 7.5 months.

“It is estimated that more than one billion transdermal patches are currently manufactured each year.”

Question 2

North America Drug Device Combination Market, By Product, 2014 - 2024 (USD Billion)

Answer 2

“Transdermal patches held the dominant share of over 35.0% in the product segment in 2015.

The substantial share can be attributed to the consistent technological advancements that present this drug delivery mode with benefits over conventional treatment methods.”

Question 3

Layers of the skin

Stratum Corneum:

Answer 3

Stratum Corneum
Epidermis
Dermis
Subcutaneous

Stratum Corneum:
“The horny outer layer of epidermis consisting of several layers of flat keratinized, non-nucleated dead or peeling cells.”

Question 4

Stratum corneum

Answer 4

10 µm thickness

15-25 layers of flattened corneocytes

Tightly packed cells protect the body from harmful material and from water loss

Drugs penetrate this layer by passive diffusion

Composition:
40% protein
40% water
What’s remaining? triglycerides, cholesterol and phospholipids

Question 5

Lipid component

Answer 5

An important determinant in the absorption process

Why? The majority of lipid is stored in the extracellular phase in the membrane surrounding cells.
—-Non-polar drugs tend to cross the cell barrier through the lipid-rich regions (transcellular route), whereas the polar drug favor transport between the cells (intercellular route)

The rate of drug movement depends on:
Concentration in the vehicle
Aqueous solubility
Oil-water partition coefficient between stratum corneum and vehicle

• Ideally, the drug should have some aqueous and lipophilic character

Question 6

Transdermal Drug Delivery Systems

Answer 6

Facilitate passage of therapeutic quantities of drug substances through the skin, and into the general circulation for their systemic effect.

Question 7

Chemical enhancement

Answer 7

Chemical enhancers improve percutaneous absorption
Acetone
Azone
Poly-ethylene glycol
DMSO

General considerations:
Efficacy in enhancing skin permeation
Low toxicity
Biocompatibility

Question 8

TDDS

Answer 8

The TDDS of choice should be developed to meet the needs of drug agents to be delivered by percutaneous absorption

Indicators of percutaneous drug absorption:
Measurable blood levels of the drug
Detectable excretion of the drug
Clinical response of the patient

Question 9

TDDS

Answer 9

The FDA approved the first TDDS in 1979.
- Scopolamine was used to prevent nausea and vomiting associated with travel mainly by sea.

Characteristics of the dosage form:
Circular patch (0.2 mm thick)
1.5 mg of drug (a belladonna alkaloid)
Delivers 1.5 mg of drug at a constant rate

Question 10

Scopolamine

Answer 10

Properties

Viscous liquid
Molecular weight: 303
Melting point: 59 ºC
Forms a crystal monohydrate
Soluble in: hot water, in alcohol,
ether, chloroform and acetone

Adhesive layer applied to skin saturates skin binding sites

In the case of scopolamine, the membrane system (not the skin), controls the rate of absorption. Why? Rate that drug is released is less than the skin’s ability to absorb

Question 11

Factors affecting percutaneous absorption

Answer 11

Physical and chemical properties of the skin

Molecular weight

Solubility and Pka

Partitioning coefficient

Nature of the carrier vehicle

Condition of the skin:
Age
Temperature
Site of administration
Race (Pigmentation -Dark and white skin)
Disease (i.e., Psoriasis)

Question 12

Other factors to consider

Answer 12

Drug concentration

Surface area to get better penetration

Physicochemical attraction to the skin

MW (molecular weights) between 100 and 800 are favored

Skin hydration favors the absorption

Thin horny layers are preferred

Long contact with skin = better absorption

Question 13

Design feature of transdermal drug delivery systems

Answer 13

Monolithic

Membrane-controlled transdermal systems

Chemical methods

Physical methods

Question 14

Monolithic Systems

Answer 14

This system incorporates a drug matrix layer between backing and frontal layers

Polymeric material controls rate of drug release so is often used in Monolithic systems.

Two types:
(1) With
(2) and without, excess drug inside the matrix

With excess drug: Drug reserve is used to assure continued drug saturation

Without excess drug: Used to maintain saturation at the stratum corneum layer, only.

Question 15

Monolithic systems

Answer 15

To prepare a monolithic system:
The drug and polymer are both dissolved or blended, cast as a matrix, and dried.

Most of these systems are designed to contain an excess of drug, and thus have drug-releasing capacity beyond the time frame recommended for replacement

Question 16

Membrane-controlled transdermal systems

Answer 16

Designed to contain a drug reservoir or “pouch”, usually in liquid or gel form, a rate-controlling membrane, and backing, adhesive, and protecting layers.

What is the advantage of this system over the Monolithic systems?
-As long as the drug in the reservoir system remains saturated, the drug release remains constant

Question 17

Membrane-controlled transdermal systems

Answer 17

To prepare this system the delivery unit is added to the drug reservoir, and sealed by a process called lamination.

Make a note that either the drug delivery system, or the skin, may serve to control drug release.

Question 18

Chemical methods used to enhance drug delivery and penetration

Answer 18

These are chemicals that increase skin permeability by reversibly damaging or by altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance. How?
- Increased hydration of the stratum corneum, or
- Change properties of lipids and proteins

Examples include: DMSO (dimethylsulfoxide), ethanol, polyethylene glycol etc…

Question 19

Physical methods used to enhance drug delivery and penetration

Answer 19

Ionotophoresis

Sonophoresis

Question 20

Ionotophoresis

Answer 20

An applied electric field is used to deliver chemicals across the skin membrane by following mechanisms,
- Ionic-electric field interaction
- Increased permeability
- Electroosmosis produces bulk motion of solvent

Ex: Dexamethasone and verapamil

Question 21

Sonophoresis

Answer 21

High-frequency ultrasound used to deliver chemicals across the skin membrane
- Chemical enhancers may not be necessary

Ex: hydrocortisone, and salicyclic acid used in gels, creams and in lotions

Question 22

Ionotophoresis: a model

Answer 22

Charged drug molecules are transported into and through tissues with use of a small direct current

Current is passed through a drug-containing “active” electrode in contact with skin

Can be used to treat areas of inflammation such as tendonitis

Can be used as an alternative to more invasive procedures

Question 23

Sonophoresis

Answer 23

Advantage that compounds need not be ionized

More effective than topical applications alone

Cavitation (occurring in keratinocytes) gave rise to better penetration of vitamin A within cells, stimulating mRNA and this produced faster growth of keratinocytes and collagen production.

Question 24

Some examples of TDDS

Answer 24

Tranderm-Nitro
(Novartis)

Used to provide controlled release of nitroglycerin.

Used to treat angina.

Where applied?
Chest and upper arm of shoulder areas

Question 25

Some examples of TDDS

Answer 25

scopolamine

Used to provide controlled release of scopolamine over a 3 day period

Used to treat nausea related to travel, particularly by sea

Where applied?
Behind the ear.
One patch removed and another can be applied when desirable

Question 26

Transderm-Nitro
(Novartis)

Answer 26

Backing:
- Aluminized plastic

Drug reservoir content:
- Nitroglycerin adsorbed on lactose, colloidal silicon dioxide, and silicone medical fluid

Question 27

Transderm-Scop
(Novartis)

Answer 27

Backing:
- Aluminized polyester film

Drug reservoir contents:
- Scopolamine, mineral oil, and polyisobutylene

Question 28

Transdermal Nicotine

Answer 28

Dose: 7 to 22 mg of nicotine per/day

Treatment: 6-8 wks
- Should be replaced daily
- Should be discarded immediately after use
- Patients are provided with sustained levels of nicotine in blood

Where applied?
- Arm or upper front tors

Question 29

Transdermal Estradiol

Answer 29

Dose: 0.05 or 0.1 mg estradiol per/day

Treatment: 3 weeks of treatment followed by one without and so forth
- Patients are provided with 17-β estradiol for conditions associated with menopause, primary ovarian failure, etc…

Oral delivery is a problem, Why?
Estradiol –> Estrone

Where applied?
lower stomach area,
below your waistline

Question 30

Fentanyl Patch

Answer 30

Dose: Fentanyl 25 µg/hr
Treatment: 72 hrs

Where applied: Apply the patch to a dry, flat skin area on your upper arm, chest, or back.

This medicine is a tan, square,
transdermal system imprinted
with “FENTANYL 25 mcg/hr”.

Caution: “Do not use the patch form of fentanyl to relieve pain that is mild or that will go away in a few days. This medication is not for occasional (“as needed”) use.”

Question 31

Advantages of TDDS

Answer 31

Can avoid difficulties with gastrointestinal drug absorption

Can be used as a substitute for oral administration of medication

Can avoid first-pass elimination

The systems are non-invasive

Can provide extended therapy with a single application

Question 32

Advantages (continued) of TDDs

Answer 32

Drugs having a short half-life can be extended through the reservoir

Drug therapy may be terminated by removing the application from the skin surface

Ease of rapid identification of the medication in emergency situations

Question 33

Disadvantages

Answer 33

Only potent drugs are considered suitable candidates because only low plasma levels of drug can be maintained

Some patients may develop severe response to treatment at the site of application (i.e., dermatitis). In such cases treatments are usually terminated.

Question 34

General considerations in the use of TDDS

Answer 34

Extent of percutaneous absorption may vary according to site of application

TDDSs should be applied to clean dry skin areas

Use of skin lotions should be avoided

TDDS should not be physically altered in any way

Be careful not to damage TDDS when removing from package

Apply to areas not likely to be rubbed off by clothing

Question 35

General considerations in the use of TDDS

Answer 35

Must be worn for the full period of time as discussed in packing insert

Use clean hands when applying and removing TDDS

Always seek medical advice to sensitivity or any intolerance to the TDDS

Remove the patch when finished and discard as recommended.

Keep away from children