Transdermal Flashcards
Explain the Skin structure:
Dead Layer: Surface scale, outside hair, and nail
Living Layer: Viable epidermis (100-150
µm), dermis, subcutaneous + structures found within (blood vessels, sweat glands)
the different layers represent different stages of keratocytes in their development
What is the outermost layer?
Stratum corneum (dead layer or horny layer - 10-15 µm)
-scale-like dead keratinocytes or corneocytes (made of the protein keratin) tightly packed and thereby building a barrier; in between corneocytes there are lipids -> only drugs with a certain property or log P can cross the barrier
-relative acidic (acid mantle), around pH 5 maintained by sebaceous fluids
What is beneath the Stratum corneum?
The viable Epidermis: Stratum lucidum, granulosm, spinosum, basale (100-150 µm) -> they are constantly replenishing
-no nerves or blood vessels -> no sensation or bleeding
-envelope: controls the amount of moisture lost
-keratinocytes (cells that make keratin), melanocytes (making the pigment), and other specialized cells
Which layer is only found in palms and souls?
What is the layer of transition?
-Palms and Souls: Stratum lucidum
-Between dead and living layer: Stratum granulosm (Layer of transition)
What is the prickly layer?
Where are melanocytes and pigmented cells located?
-Live prickly layer: Stratum spinosum -> contains keratinocytes
-Stratum basale: contains melanocytes
Content of the dermis and Subcutaneous Layer:
-Dermis: connective tissue, nerves, collagen and
elastin fibers, blood, lymphatic vessels, and appendages (hair follicles, sweat glands, sebaceous glands)
-Subcutaneous Layer: consists of lipocytes, arranged as fat lobules, most of the body fat (80%) in this layer -> insulation from cold, endocrine function
Definition of Transerdemal DDS:
-Topically administered, long-acting medicated DDS designed to achieve systemic therapeutic effects
Applications of TDDS:
▪ Birth Control
▪ Cessation of Smoking
▪ Coronary Heart Disease and Angina
▪ High Blood Pressure
▪ Hormone Replacement
▪ Menopausal Symptoms
▪ Pain
▪ Motion sickness
▪ Schizophrenia
What are the advantages of TDDSß
-Bypass first-pass metabolism, no drug degradation/ irritation in the GI
-Sustained drug delivery, and can be stopped anytime
-patient compliance, clinician not required
-Non-invasive, can be given to unconscious patients, alternative route
Name an example of TDDS:
Diclofenac Gel for joint pain -> can cause GI irritation, and GI ulcers long-time
-no risk of bleeding GI-ulcers, renal impairment, and hypertension
-but systemic absorption is possible
What are the limitations of DDS?
-Major barrier for hydrophilic and large MW drug -> log P: 1-3, MW <500 Da, and MP < 250°C for passive permeation + no charged/ionic drugs for passive diffusion
-no high-dose drugs
-irritating to the skin and potential allergic reactions (skin rashes)
-Limited time of affixation, + Variable adhesion to different skin types
-Variable percutaneous absorption efficiency (skin type, placement tissues)
-Bacterial and enzymatic drug metabolism under the patch
-Complex technology/high cost
Characteristics of the ideal TDDS?
-MW < 500 Da (large molecules like protein drugs with long AA chains)
-log P 1-3 (under 1 is too hydrophilic, greater than 3 too lipophilic (f.e. steroid drugs, Estradiol) and gets stuck in stratum corneum)
-potent: <50mg/day -> too high dose is not possible
-Short half-life (<10hr) -> with Transdermal the drug doesn’t have to be taken as often
-Non-irritating and non-allergenic
Important Characteristis of Transdermal DDS
Delivery of a constant rate of drugs per hour
f.e. Fentanyl Patch: constantly12mcg/hr
-Onset is slow: f.e. Daytrana, therapeutic effect after 2h, needs to be removed after 9h, there still will be drug in the skin that is going to be delivered after removing the patch
Transdermal Patches:
-designed for sustained drug delivery
Matrix/Monolithic
Matrix/Monolithic:
-Top: Backing layer
-Adhesive matrix: drug either dissolved or dispersed in an organic-based pressure-sensitive adhesives
-Release liner: protection from air or water
->Skin-controlled Drug release bc there is no membrane controlling the rate of release: Single-layered (1 layer of drug), Bi-layered (2 layers of drug)
CAN IT BE CUT??
->System-controlled Drug Release contains a rate-controlling membrane:
Multi-layered -> Backing layer -> Drug layer -> Rate- Controlling membrane -> skin contact membrane -> Release liner
CANT BE CUT!!
Why should the System-controlling Patch never be cut?
The patch is losing its ability to release the drug at a constant rate
Transdermal Patches
Reservoir
Reservoir: Contain drug in the form of solution, gel, or suspension, Multi-layer design (drug between Backing layer and rate-controlling membrane) + System-controlled Drug Release
-disadvantage: dose dumping and abuse potential
(same disadvantage for Matrix/Monolithic patches??)
How to apply patches:
-Place carefully on a clean, dry, hairless area
-Follow the instructions of the doctor or package
-Rotate location
-Don’t overlap patches
-Take care of loose patches
-Shower is possible, but not for a long period of time
-Store and discard patches carefully (keep away from pets and children)
-Avoid heating pads: it can release the drug of other patches faster
-Don’t cut a reservoir patch. A matrix patch may still be cut
What are strategies to increase the permeation through the skin?
Adding to the formulation of the drug
-Passive: Vesicular/carrier-mediated, Chemical enhancers f.e. propylene glycol, Eutectic systems (lower the MP), Prodrug (so it can cross the skin, and on-site it turns to the drug)
-Active: Physically techniques to reduce the barrier of the skin
Thermal: Laser and radiofrequency
Electrical: Iontophoresis and electroporation
Mechanical: Microneedles
Others: Ultrasound, Jet injectors
Explain Chemical enhancers:
(PASSIVE)
-Mechanism:
* Delipidize stratum corneum (dissolve the lipids and thereby enhances permeation)
* Increase drug solubility in formulation and skin
* Improve partitioning of drug into the skin
* Keratolytic effect on the skin
* Increase skin hydration
Explain Microneedles:
(ACTIVE)
-Overcome epidermal “barrier” by piercing the skin to provide a channel for drug transport
-Designed to be painless (pierce only stratum corneum barrier and not viable, nerve containing
tissue)
-Types of Microneedles: Solid (Stainless-steel), Coated, Dissolving, Hollow
Types of Microneedles
HOLLOW
-Hollow allows transdermal delivery of liquid formulations (up to 2 mL capacity)
Types of Microneedles
Dissolving Microneedles
-Dissolving Microneedles: dissolve within minutes after insertion into the skin to release encapsulated
drug or vaccine (Example: flu vaccine, the skin has immune cells)
-Made of maltose, hyaluronic acid, cellulose polymer
Types of Microneedles
Coated Microneedles
-thin screen of micro projections
-creates superficial pathways through the skin’s outer layer
-to deliver therapeutic small molecules,
peptides, biopharmaceuticals, and vaccines
-needle-free alternative for fast bolus drug delivery
Iontophoresis
Active increased delivery
-Applying a direct electric current (not more than 0.5 mA/cm2 that introduces and ionized ur unionized drug to the intact skin
-drug reservoir, which is placed at the anode, and a return reservoir, placed at the cathode (with saline solution)
-When the current is switched on, the positively charged drug molecules are forced away from the anode -> through the skin in exchange for Cl ions??
For negatively charged drugs vice versa
For positive charged drugs, positive current is used; for negative drugs, negative current is used??
Ablative Laser
Active increased delivery
-device creates micropores of the desired size and depth almost painlessly (by evaporating water in the skin)
-drug permeates lateral and downwards into the tissue through channel-like pores
Example: P.L.E.A.S.E.® (Precise Lasers Epidermal System)
-Often used for larger molecules (> 500 Da) or hydrophilic molecules
