Transdermal Drug Delivery Systems Overview

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Questions and Answers

What is the primary indication for the fentanyl iontophoretic transdermal system?

Chronic pain management

Management of anxiety disorders

Long-term treatment of cancer pain

Short term management of acute post-operative pain (correct)

Which feature is NOT associated with the IONSYS device?

Patient-controlled delivery system

Must be used in outpatient settings (correct)

Provides delivery for 24 hours or 80 doses

Requires titration of IV fentanyl before use

What benefit does sonophoresis provide in drug delivery?

Increases the viscosity of drug formulations

Delivers drugs via iontophoresis mechanism

Incorporates air to improve ultrasound wave dispersion

Disrupts lipids in the stratum corneum to enhance skin penetrability (correct)

Which of the following drugs is commonly delivered using iontophoresis?

Dexamethasone Signup and view all the answers

What formulation factor is important for effective sonophoresis?

Smooth and non-gritty vehicle Signup and view all the answers

What is the primary role of the impermeable backing membrane in transdermal drug delivery systems (TDDS)?

To block moisture from the skin and external environment Signup and view all the answers

What is a key characteristic of the adhesive layer in TDDS?

It must be non-irritating and pressure-sensitive Signup and view all the answers

What does the term 'matrix system' refer to in the context of TDDS?

A method of drug storage and release Signup and view all the answers

Which of the following statements about matrix systems is true?

They can contain an excess of drug or without an excess of drug Signup and view all the answers

What occurs if the adhesive layer in a TDDS fails?

Decreased absorption and potential overdoses Signup and view all the answers

How does a matrix without an excess of drug behave in TDDS?

It achieves saturation only when the drug level exceeds solubility limits Signup and view all the answers

What is the purpose of the release liner in TDDS?

To facilitate the release of the drug before application Signup and view all the answers

What thickness range is typical for an impermeable backing membrane used in TDDS?

2-3 mm Signup and view all the answers

What was the original name of the ZP Patch Technology developed by Alza Corp?

Macroflux Signup and view all the answers

Which of the following is NOT a clinical application associated with ZP Patch Technology?

ZP-Isulin for diabetes Signup and view all the answers

How does the needle-free injection technology deliver drug molecules into the skin?

By creating high-velocity jets of gas Signup and view all the answers

What is a limitation of the needle-free injection technology?

Inability to deliver drugs over extended periods Signup and view all the answers

For what purpose is Lidocaine Powder for injection primarily used?

Topical local analgesia before venipuncture Signup and view all the answers

In which age group is Lidocaine Powder indicated for use prior to venipuncture?

Children aged 3–18 Signup and view all the answers

What is the primary indication for SUMAVEL® DosePro®?

Acute treatment of migraine and cluster headache Signup and view all the answers

Which device is indicated for the administration of sumatriptan for migraine?

SUMAVEL® DosePro® Signup and view all the answers

What substance is used to create the high-velocity jets in needle-free injection devices?

Helium Signup and view all the answers

What is Zingo commonly known for in the context of pain management?

A jet injector for local analgesia Signup and view all the answers

What should be done if skin irritation occurs after using a transdermal system?

Consult with a physician. Signup and view all the answers

Which animal model is NOT typically used in in vivo studies for transdermal absorption?

Human cadaver Signup and view all the answers

What is the primary purpose of in vitro studies using diffusion cells?

To quantify drug release rates from transdermal preparations. Signup and view all the answers

What percentage of total drug content is absorbed from the lidocaine patch?

3% Signup and view all the answers

What is a limitation of in vitro studies mentioned in the content?

Variability in permeation can affect results. Signup and view all the answers

Which method is used to obtain excised human skin for in vitro studies?

Surgeries conducted for cosmetic reasons. Signup and view all the answers

Which skin equivalent was developed using neonatal human-derived epidermal keratinocytes?

EpidermFT Signup and view all the answers

What is the main disadvantage of animal skins compared to human skin in in vitro studies?

Animal skins are more permeable than human skin. Signup and view all the answers

What is the key function of in vivo studies for transdermal systems?

To relate blood levels after transdermal administration to therapeutic effects. Signup and view all the answers

Which of the following statements about discarded transdermal systems is true?

They contain residual drug and must be discarded safely. Signup and view all the answers

What is the primary indication for Transdermal Scopolamine?

Prevention of motion sickness Signup and view all the answers

Which transdermal delivery system is utilized for both Transdermal Testosterone and Transdermal Scopolamine?

Reservoir system Signup and view all the answers

How often is the Transdermal Contraceptive patch applied?

One patch per week for three weeks Signup and view all the answers

Which transdermal drug is specifically indicated for the treatment of ADHD?

Transdermal Methylphenidate Signup and view all the answers

What is the duration of the Transdermal Clonidine patch?

7 days Signup and view all the answers

Which transdermal drug is delivered using a matrix system and is indicated for pain management?

Transdermal Fentanyl Signup and view all the answers

What is the correct dosing schedule for Transdermal Estradiol in patients with an intact uterus?

3 weeks on, 1 week off Signup and view all the answers

Which of the following is a product available for Transdermal Nitroglycerin?

Minitran Signup and view all the answers

Which transdermal system is utilized for the delivery of both Buprenorphine and Estradiol?

Matrix system Signup and view all the answers

What characteristic defines the release duration of the Transdermal Fentanyl system?

72 hours Signup and view all the answers

Which of the following factors does NOT significantly affect drug absorption through the skin?

Ambient temperature Signup and view all the answers

What is the primary mechanism by which the Synera™ patch becomes activated?

Chemical reaction Signup and view all the answers

Which type of transdermal system may require removal before undergoing an MRI scan?

Metallic component patches Signup and view all the answers

What advantage do transdermal ointments, creams, and gels have over patches?

More localized drug delivery Signup and view all the answers

Which biological factor is least likely to increase the rate of percutaneous absorption?

Increased age of the patient Signup and view all the answers

What is a key disadvantage of transdermal drug delivery systems (TDDSs)?

Limited drug types suitable for delivery Signup and view all the answers

Which mathematical equation is relevant to the transport process affecting drug absorption through the skin?

Fick's First Law of Diffusion Signup and view all the answers

What are needle-free injections primarily designed for?

Minimizes pain and fear of needles Signup and view all the answers

How can molecular size affect drug absorption?

Smaller molecules typically penetrate better Signup and view all the answers

What is a primary function of skin hydration in relation to drug absorption?

Increases the permeability of the skin Signup and view all the answers

Study Notes

Impermeable Backing Membrane

Prevents drug from exiting the system
Protects the system from outside influences, such as moisture
Prevents moisture from the skin entering the system
Helps hydrate the skin, which increases penetration
Typically 2-3 mm thick
Can be made from transparent or pigmented polymer film

TDDS Layers

Drug reservoir or matrix system:
- Stores the drug and releases it at the skin site
Release membrane (sometimes called rate-controlling membrane)
- May or may not be present
Release liner
- Removed before application
- Enables drug release
Adhesive layer
- Maintains skin contact after application
- Must be pressure-sensitive
  - Able to adhere to skin with minimal pressure
  - Remains in place for the intended wear period
- Should be non-irritating, easy to remove, and compatible with other system components

Failure of Adhesive Layer

Many failures reported to the FDA
Patch detaches from the patient
Leads to decreased absorption, reduced clinical effects, and accidental overdosing in children
Cost implications include patch replacement if adhesive stability is poor

Types of TDDS: Matrix

AKA monolithic
Drug dispersed in matrix that lies between backing and adhesive layers, or within the adhesive itself
Matrix controls rate of drug release
Drug and matrix dissolved or blended, cast as the matrix, and dried
Gelled matrix produced in sheets or cylinders and cut to size

Types of TDDS: Matrix: Classification

Classified by the amount of drug present with regard to its equilibrium solubility and steady state concentration gradient at the stratum corneum
Without an excess of drug
- Drug maintains saturation at the stratum corneum only as long as the drug level in the device exceeds the solubility limit of the stratum corneum
- As matrix concentration drops below skin concentration, the transport of drug from the device to the skin gradually declines
With an excess of drug

Drugs Available in TDDS

Not an all-inclusive list

Transdermal Scopolamine (FYI)

First TDDS on the market
Indication: Prevention of motion sickness
Products available: Transderm Scōp
72-hour duration
Type of system: Reservoir

Transdermal Nitroglycerin (FYI)

Indication: Management of angina
Products available: Minitran (4 strengths), Nitro-Dur (6 strengths), and various generics
Daily dosing
Type of system: Matrix

Transdermal Estradiol (FYI)

Indication: Hormone replacement therapy
Continuous basis in patients without an intact uterus
Cyclic basis (3 weeks on, 1 week off) in patients with an intact uterus
Several products available
- Some combination products with norethindrone
- All matrix systems except Estraderm
- Dosed once or twice weekly

Transdermal Contraceptives (FYI)

Indication: Contraception
Products available: Ortho Evra, Xulane (estradiol / norelgestromin)
Dosing: 1 patch per week for 3 weeks, 1 week patch-free
Type of system: Matrix

Transdermal Testosterone (FYI)

Indication: Hormone replacement therapy
Products available: Androderm (2 strengths)
Once nightly dosing
Type of system: Reservoir

Transdermal Clonidine (FYI)

Indication: Hypertension
Products available: Catapres-TTS (3 strengths)
7-day duration
Type of system: Reservoir

Transdermal Fentanyl (FYI)

Indication: Pain management
Products available: Duragesic (5 strengths)
72-hour duration
Type of system: Matrix

Transdermal Buprenorphine (FYI)

Approved June 2010 in US, available in Europe since 2001
Indication: Management of moderate to severe chronic pain
Products available: Butrans (5 strengths)
7-day duration
Type of system: Matrix

Transdermal Methylphenidate (FYI)

Indication: Treatment of ADHD
Products available: Daytrana (4 strengths)
9-hour wear period: Why? ZP Patch Technology

ZP Patch Technology

Originally known as Macroflux by Alza Corp
Platform technology in various stages of clinical trials
- ZP-PTH for osteoporosis
- ZP-Glucagon for severe hypoglycemia
- ZP-Triptan for migraine
- GLP-1 for diabetes

Needle-free Injections: Velocity-based Techniques

Uses high velocities to force particles across the stratum corneum
Device pushes drug molecules into the skin by creating a high-velocity jet (>100 m/s) of compressed gas (usually helium) that accelerates through the nozzle of the device carrying drug particles with it
Inability to deliver drugs over longer periods; however, well-suited for vaccination

Lidocaine Powder for Injection

Powder Intradermal Injection System: Used on intact skin to provide topical local analgesia
Indications
- Prior to venipuncture or peripheral intravenous cannulation in children 3–18 years of age
- Prior to venipuncture in adults

SUMAVEL® DosePro®

Sumatriptan Injection: For adults, acute treatment of migraine with or without aura, and the acute treatment of cluster headache
Lidocaine for local analgesia
Why? Wear system for the full period of time stated in the package directions.
Consult physician if skin irritation results
After removal, fold systems in half with the adhesive layer together
- Systems contain residual drug: only 3% of total drug content is absorbed from the lidocaine patch (Lidoderm)

Percutaneous Absorption Models

Focus on this topic in class

In Vivo Studies

Most relevant when conducted in humans
Animal models may be used
- Weanling pig
- Rhesus monkey
- Hairless rat
- Mouse

In Vivo Studies: Uses

Determine bioavailability
Establish bioequivalence of different formulations of the same drug
Determine toxicological risk
Relate blood levels after transdermal administration to systemic therapeutic effects

In Vitro Studies

Diffusion cell:
- Human skin
- Animal skin
- Epidermal cells
- Dermal cells
Employed in vitro to quantify the release rates of drugs from transdermal preparations

In Vitro Studies: Diffusion Cell

Skin is clamped into the cell
Investigators measure the compound passing from the stratum corneum side through to a fluid bath
Determines if the drug can pass through

In Vitro Studies: Limitations

Limited due to: - Difficulty in obtaining material - Storage - Expense - Variability in permeation - Animal skins are more permeable than human skin

In Vitro Studies: Excised Human Skin

Sources:
- Autopsies
- Amputations
- Cosmetic surgery
- Human cadaver

In Vitro Studies: Alternative Test Materials

Shed black rat snake skin
- Nonliving
- Pure stratum corneum
- Hairless
- Similar to human skin, but slightly less permeable

In Vitro Studies: Commercially Available Human Skin Equivalents

SkinEthic RHE
Episkin
Epiderm
EpidermFT
StrataTest
Epidermal Skin Test 1000 (EST1000)
Advanced Skin Test 2000 (AST2000)

Physical Absorption Enhancers: Iontophoresis

IONSYS
- Fentanyl iontophoretic transdermal system
- Indication: Short-term management of acute post-operative pain
- Schedule II drug
- Patient-controlled system
- Provides on-demand delivery for 24 hours, or 80 doses
- Should only be used with hospitalized patients
- Titrate drug to acceptable level (minimum effective dose) on IV fentanyl before initiating treatment
Device consists of:
- Plastic top housing: Contains a 3 volt lithium battery and electronic components
- Bottom housing: Contains hydrogel containing drug, excipients, and skin adhesive

Physical Absorption Enhancers: Iontophoresis: Other Uses

Iontophoresis of pilocarpine:
- Induce sweating in diagnosis of cystic fibrosis
  - Practiced since the 1930’s
  - Still the most useful test
  - Increased Cl- in sweat is diagnostic for CF
Topical delivery of fluoride to teeth
Dexamethasone:
- Anti-inflammatory agent
- Delivered directly into joints

Physical Absorption Enhancers: Iontophoresis: Uses

Commonly used with drugs for veterinary use
- NSAIDs
- Corticosteroids
- Anti-inflammatory agents
- Antibiotics
- Local anesthetics
Being investigated for protein delivery

Physical Absorption Enhancers: Sonophoresis

AKA Phonophoresis, ultrasound
Transport drug across skin using high frequency ultrasound
- Drug is mixed with a coupling agent
  - Gel (usually)
  - Ointment
  - Cream
- Ultrasonic energy is transferred from the phonophoresis device to the skin, through this coupling agent

Physical Absorption Enhancers: Sonophoresis: Thought

Thought to disrupt lipids in the stratum corneum
Increases skin penetrability

Physical Absorption Enhancers: Sonophoresis: Example

Hydrocortisone (1-10%)

Physical Absorption Enhancers: Sonophoresis: Formulation factors

Vehicle must be smooth and non-gritty
Should have relatively low viscosity
- Makes application easier
- Improves movement of the transducer head during the ultrasound process
Air should not be incorporated
- Air bubbles may disperse the ultrasound waves

Photodynamic Therapy

Focus on this topic in class

Percutaneous absorption

The process by which drugs penetrate the skin and enter the bloodstream.

Factors Affecting Percutaneous Absorption

Skin hydration: Increased hydration increases absorption by increasing skin permeability and decreasing the diffusion path.
Drug concentration: Higher concentration increases absorption due to a higher driving force for diffusion.
Lipid/aqueous solubility and partition coefficient: Drugs with higher lipid solubility are more readily absorbed through the skin. The partition coefficient (K) measures the drug's preference for the lipid phase compared to the aqueous phase.
Molecular size and shape: Smaller molecules with a lower molecular weight are more readily absorbed.
Surface area: Larger surface area increases absorption due to increased exposure to the drug.
Contact time: Longer contact time allows for greater drug penetration and absorption.

Transdermal Drug Delivery Systems (TDDS)

Types of TDDS:
- Matrix Patches: Drug is embedded in a polymer matrix, and release occurs by diffusion.
  - Layers:
    - Backing layer: Protects the system and provides mechanical strength.
    - Drug reservoir: Contains the medication.
    - Rate-controlling membrane: Controls the drug release rate.
    - Adhesive layer: Attaches the patch to the skin.
    - Liner: Protects the adhesive layer before application.
- Reservoir Patches: Contain a drug reservoir separated from the skin by a rate-controlling membrane.
  - Manufacturing Process: Matrix patches are prepared by mixing the drug with the polymer matrix, while reservoir patches involve separate drug loading, membrane layering, and adhesive application.
EvaMist: Underwent FDA safety review due to the potential for skin irritation and allergic reactions from the adhesive used.
Synera™: Activation occurs through the application of heat from a chemical reaction between the patch and the skin's moisture.

Advantages and Disadvantages of TDDSs

Advantages:
- Consistent and controlled drug delivery
- Non-invasive
- Extended drug release periods
- Improved patient compliance
Disadvantages:
- Limited drug types suitable for transdermal delivery
- Skin irritation or allergic reactions
- Limited drug loading capacity
- Potential for interactions with other topical medications
- Not suitable for everyone, such as those with sensitive skin

Clinical Considerations for TDDSs

Avoid placement at the belt line, as it may lead to premature patch detachment.
Remove TDDSs containing metal components before MRI scans.
Consult with a healthcare professional for appropriate use and potential complications.

Other Routes of Drug Administration

Iontophoresis (IP): Uses electrical current to enhance transdermal drug delivery.
- Advantages: Increases penetration of charged molecules
- Disadvantages: Potential for skin irritation, limited drug types
- Drugs currently given by IP: Local anesthetics, anti-inflammatories, and antibiotics
Ionsys: A transdermal drug delivery system containing fentanyl, used for chronic pain management.
Needle-free injections: Deliver drugs using high pressure to propel the drug into the skin.
Photodynamic Therapy: Uses a combination of light and a photosensitizing drug to target and destroy diseased cells.
- Advantages: Can be applied topically, minimally invasive, highly selective for disease cells.
- Disadvantages: Can cause temporary redness and swelling, requires repeated treatments.

In Vitro Percutaneous Absorption Studies

Alternative Materials: Artificial membranes designed to mimic the barrier properties of human skin.

Physical Absorption Enhancers

Chemical enhancers: Alter the skin barrier properties by interacting with the skin's lipids or proteins.
Physical enhancers: Enhance absorption by increasing skin permeability through mechanical means, such as ultrasound, microneedles, or heat.

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Description

Explore the critical components of transdermal drug delivery systems (TDDS), focusing on the impermeable backing membrane, drug reservoir layers, and adhesive properties. Understand how these systems are designed to enhance drug absorption while preventing moisture interference. This quiz will test your knowledge on the principles and challenges of TDDS.