Pharmaceutics final exam - TDD Flashcards
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“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.”
North America Drug Device Combination Market, By Product, 2014 - 2024 (USD Billion)
“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.”
Layers of the skin
Stratum Corneum:
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.”
Stratum corneum
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
Lipid component
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
Transdermal Drug Delivery Systems
Facilitate passage of therapeutic quantities of drug substances through the skin, and into the general circulation for their systemic effect.
Chemical enhancement
Chemical enhancers improve percutaneous absorption
Acetone
Azone
Poly-ethylene glycol
DMSO
General considerations:
Efficacy in enhancing skin permeation
Low toxicity
Biocompatibility
TDDS
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
TDDS
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
Scopolamine
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
Factors affecting percutaneous absorption
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)
Other factors to consider
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
Design feature of transdermal drug delivery systems
Monolithic
Membrane-controlled transdermal systems
Chemical methods
Physical methods
Monolithic Systems
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.
Monolithic systems
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
Membrane-controlled transdermal systems
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
Membrane-controlled transdermal systems
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.
Chemical methods used to enhance drug delivery and penetration
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…
Physical methods used to enhance drug delivery and penetration
Ionotophoresis
Sonophoresis
Ionotophoresis
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
Sonophoresis
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
Ionotophoresis: a model
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
Sonophoresis
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.
Some examples of TDDS
Tranderm-Nitro
(Novartis)
Used to provide controlled release of nitroglycerin.
Used to treat angina.
Where applied?
Chest and upper arm of shoulder areas
Some examples of TDDS
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
Transderm-Nitro
(Novartis)
Backing:
- Aluminized plastic
Drug reservoir content:
- Nitroglycerin adsorbed on lactose, colloidal silicon dioxide, and silicone medical fluid
Transderm-Scop
(Novartis)
Backing:
- Aluminized polyester film
Drug reservoir contents:
- Scopolamine, mineral oil, and polyisobutylene
Transdermal Nicotine
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
Transdermal Estradiol
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
Fentanyl Patch
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.”
Advantages of TDDS
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
Advantages (continued) of TDDs
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
Disadvantages
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.
General considerations in the use of TDDS
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
General considerations in the use of TDDS
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
