Topical dosage forms and transdermal drug delivery Flashcards
How many transdermal patches are currently manufactured each year?
It is estimated that more than one billion are currently manufactured each year
What are the layers of the skin?
Stratum corneum
Epidermis
Dermis
Subcutaneous
What is the stratum corneum? What are its features?
- 10 um in 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
What is the composition of the stratum corneum?
- 40% protein
- 40% water
- triglycerides, cholesterol, and phospholipids
Why wouldn’t you want to put a patch on bruised or damaged areas of the skin?
because the devices in the patch have membranes that control the rate the substance penetrates the skin, if the skin is damaged the drug may go very rapidly through these areas
Why is the lipid component of the skin an important determinant in the absorption process of a patch?
- the majority of lipid is stored in the extracellular phase in the membrane surrounding cells
- and a drug’s major route of penetration is through the intercellular channels
What is a drug’s major route of penetration?
through the intercellular channels
What does the reate of drug movement depend on?
- concentration in the vehicle
- aqueous solubility
- oil- water partition coefficient between stratum corneum
What would be an issue with a purely lipophilic drug in a patch?
The dosage form may have high affinity but when you apply the patch to the skin the drug doesn’t leave the patch
Why does a drug need some hydrophilic (aqueous) and some lipophilic character?
so it can penetrate layers of the skin
what do transdermal drug delivery systems do?
they facilitate the passage of therapeutic quantities of drug substances through the skin, and into the general circulation for their systemic effect
Why are chemical enhancers important in patches?
- chemical enhancers improve percutaneous absorption
What are some chemical enhancers?
- acetone
- azone
- poly-ethylene glycol
- DMSO (used for many different things - freeze cells and go back and use them later, in TDDS we are trying to get it to improve absorption by the skin)
How does 60% DMSO alter proteins and lipids in the skin?
- Low DMSO - not effective - didn’t alter fluid properties of membrane (lipids), did alter keratin
•High DMSO - membrane fluidity and keratin altered - improves percutaneous absorpt
What are some things necessary for a TDDS?
- needs efficacy in enhancing skin permeation (can’t manage condition if drug isn’t getting through skin)
- must have low toxicity ( don’t want toxic because they usually have a low toxic effect - benefit of patches)
- must be biocompatible
What are some indicators that the TDDS is working (i.e. percutaneous absorption is occurring)?
- measurable blood levels of the drug
- detectable excretion of the drug
- clinical response of the patient
When was the first TDDS approved by the FDA? What was it?
- 1979
- scopalamine was used to prevent nausea and vomiting associated with travel mainly by sea
What were characteristics of the first TDDS dosage form?
- circular patch (0.2mm thick)
- 1.5 mg of drug ( a belladonna alkaloid - bad taste) - only 1.5 mg of drug - if drug isn’t potent won’t be effective in patch
- delivers 1/4 mg of drug at a constant rate
What are the melting point and molecular weight of scopalamine?
303
59 degrees celsius
What enhancers could be used for scopalamine? (what is it soluble in?
hot water, alcohol, ether, chloroform and acetone
Where doest the drug go through before it enters your stratum corneum (skin)?
the patch membrane - has to go through two membranes
What controls the rate of absorption of scopalamine? Why?
The membrane (not the skin) controls the rate of absorption because the rate that the drug is released is less than the skin’s ability to absorb
If the rate in which drug substance penetrate the skin is slower than the rate at which the drug travels through the patch reservoir and semipermeable membrane, the
skin controls the absorption rate
*** The slower step is the rate limiting factor
If the rate in which the drug substance travels through the patch reservoir and semipermeable membrane is slower than the rate the drug substance penetrate the layers of the skin,
then the semipermeable membrane is the rate limiting step, not the skin
What are the factors that affect percutaneous absorption?
- physical and chemical properties of the skin
- molecular weight ( use a chemical enhancer if you need to use high weight)
- solubility and pka
- partitioning coefficient (hydrophilic or lipophilic)
- nature of the carrier vehicle ( how it communicates with skin layers)
- condition of the skin
how is the condition of the skin affected?
- age
- temperature (if very hot or cold outside the patch may be more effected than your skin)
- site of administration (percutaneous absorption much slower on heel of foot)
- race (pigmentation - dark and white skin) - stratum corneum more layers in darker skin - melanocytes no real absorption effect
- disease (i.e. psoriasis)
What molecular weights are favored for patches?
between 100 and 800
What does a monolithic TDDS system incorporate?
a drug matrix layer between backing and frontal layers
- polymeric material controls rate of drug release, so it is often used in monolithic systems
What are the two types of monolithic systems
- with excess drug inside the matrix: drug reserve is used to assure continued drug saturation
- without excess drug: used to maintain saturation at the stratum corneum layer, only (want to have stratum corneum saturated)
How is a monolithic system prepared?
- the drug and polumer are both dissolved or blended together, cast as a matrix and dried
Most monolithic systems are designed to contain an excess or not contain an excess of drug?
MOST are designed to contain an excess of the drug, and thus have drug - releasing capacity beyond the time frame recommended for replacement
What are membrane- controlled transdermal systems designed to contain?
They 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
What is the advantage of membrane- controlled transdermal systems over monolithic systems?
As long as the drug in the reservoir system remains saturated, the drug release remains constant
How is a membran- controlled transdermal system prepared?
the delivery unit is added to the drug reservoir, and sealed by a process called lamination
**either the drug delivery system, OR the skin may serve to control drug release
What are chemical methods used to enhance drug delivery and penetration?
They 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 do chemical methods reduce the diffusional resistance of the stratum corneum?
- increased hydration of the stratum corneum or
- change properties of lipids and proteins
What are examples of chemicals used to enhance drug delivery and penetration?
DMSO, ethanol, polyethylene glycol
**always select enhancers with knowledge of their toxicity
What are the two physical methods used to enhance drug delivery and penetration?
ionotophoresis and sonophoresis
What is ionotophoresis?
- an applied electric field is used to deliver chemicals across the skin membrane **drug needs to be inionic form
What are the mechanisms for ionotophoresis for a drug to deliver chemicals across the skin membrane?
- ionic electric field interaction
- increased permeability
- electroosmosis produces bulk motion of solvent
What are example of ionotophoresis
dexamethasone and verapamil
What is sonophoresis?
high frequency ultrasound used to deliver chemicals across the skin membrnae - chemical enhancers may not be necessary
What are examples of sonophoresis?
hydrocortisone and salicylic acid used in gels, creams and lotions
What is the small direct current used to transport charged drug molecules into and through tissues passed through
It passes through a drug - containing active electrode in contact with skin
What can ionotophoresis be used to treat?
areas of inflammation such as tendonitis
- can be used as an alternative to procedures that are more invasive
Is ionotophoresis or a monolithic system more efficient?
ionotophoresis
What are advantages of sonophoresis?
- compounds don’t need to be ionized
- more effective than topical applications alone
- cavitation (ocurring in keratinocytes) gave rise to better penetration of vitamin A within cells, stimulating mRNA and this produced faster growth of keratinocytes and collagen production
What is transderm-nitro (novartis)? What is is used to provide? What does it treat? Where is it applied
Transderm-nitro is nitroglycerin
It is used to provide controlled release of nitroglycerin
It is used to treat angina
Is is applied to the chest and upper arm of shoulder areas
What is scopalamine used for? What does it treat? Where is it applied
used to provide controlled release or scopolamine over 3 day period
- it treats nausea related to travel by sea
- it is applied behind the ear, once patch removed and another can be applied when desireable
What is the backing of transderm nitro made of?
What is the backing of transderm scop made of?
transderm nitro is aluminized plastic
Transderm scop is aluminized polyester film
What is the drug reservoir content of transderm nitro (novartis)?
nitroglycerin adsorbed on lactose, colloidal silicon dioxide, and silicone medical fluid
What are the drug reservoir contents of transderm scop?
scopalamine, mineral oil, and polyisoobutylene (Mw 303, viscous liquid)
What is the dose, treatment, and application of transdermal nicotine?
Dose: 7 to 22 mg of nicotine/day
Treatment: 6-8 wks, replace daily, disscard after use
Where applied: arm or upper front torso
What is the dose, and treatment of transdermal estradiol?
Dose: 0.05 or 0.1 mg estradiol per day
Treatment: 3 weeks of treatment followed by one w/o and so forth
- patients are provided with 17 beta estradiol for conditions associated with menopoause, primary ovarian failure, etc.
Why is oral delivery of estradiol a problem?
because it is converted to estrone which is inactive
What are 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
- drugs with a short half life can be extended through the reservoir
- drug therapy may be terminated by removing application from skin surface
- ease of rapid identification of the medication in emergency situations
What are disadvantages of TDDS?
- 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 or a different area is used
What are some general considerations in the use of TDDS?
- extent of percutaneous absorption may vary according to site of application
- TDDSs should be applied to very clean, dry skin areas
- use of skin lotions should be avoided ( will alter absorption)
- TDDs should not be physically altered in any way
- be careful not to damage TDDS when removing from package
What should be discussed with patients about TDDS?
- apply to areas not likelyt to be rubbed off by clothing
- 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
What happens if the condition to treat is located in the skin? For melanoma: can you get enough drug through the skin from the patch to treat?
may surgically remove the tumor and then apply the patch with chemotherapeutic function and deal with residual disease
