DDS: Transdermal Flashcards by bal singh

What are the functions of the skin?

Largest organ of body (by weight) @ 2 m²

Functions:

Protection from environment (physical, chemical, microbiological)
Maintain temp., electrolyte & fluid balance
Component of immune, nervous & endocrine systems
Synthesis, processing and metabolism of proteins, lipids, glycans, signaling molecules

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Why are chemicals applied to the skin?

Cleanse skin
Improve or restore barrier
Enhance beauty and slow ageing – cosmetic/cosmeceutical
Treat disease associated with skin and underlying tissues
Systemic absorption (TDD)
Accident

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What are drugs used in the following;

A) superficial

B) appendaegeal

C) epidermal/dermal

D) systemic

E) deeper tissue

Sunscreens, cosmetics, insect repellents, barrier products

Anti-acne, anti-infectives

Antihistamines, anaesthetics, antimitotics, scopolamine

Nitroglycerin, nicotine, hormone replacement therpay

Analgesics and antiinflammatories

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What are the advantages of TDD (transdermal drug delivery)

Convenience and accessibility of skin
Avoid G.I. tract – stability, irritation, variability
Avoid 1st pass metabolism
Constant & continuous drug input
Prolonged application time
Rapid termination of drug input - safety

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What are the disadvantages/limitations of TDD?

Not suitable for immediate/rapid effect
Depends on skin permeability
Depends on physicochemical properties of drugs
Limited PK clearance range
Potential for metabolism in skin
Potential for development of tolerance
Skin irritancy/allergic reactions

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What makes up the below antaomy of the skin

A) Epidermis

B) Dermis (1-2 mm)

C) Hypodermis and subcutaneous tissue (1-2mm)

Stratum corneum or horny layer (10-20μm)
Viable epidermis (50-100 μm)

Connective tissue, nerve, lymphatic & vascular vessels; appendages

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What is the process of how a drug enters the skin and is/isn’t systematically absorbed?

The drug initially penetrates through the stratum corneum and then passes through the deeper epidermis and dermis without drug accumulation in the dermal layer.

When drug reaches the dermal layer, it becomes available for systemic absorption via the dermal microcirculation

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What is the main barrier to penetration?

Stratum corneum

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What some non-invasive in vivo assessment methods for skin penetration?

Skin blanching assay: vasoconstrictors
TiVi image analysis (Wheels Bridge): vasodilators
Dermainspect: multiphoton microscopy: fluorescence lifetime imaging (MPM-FLIM)
Real-time imaging of penetration of fluorescent molecule within the epidermis

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What does ‘flux mean’? (Fick’s law of diffusion)

In delivery systems involving transdermal patches, the drug is stored in a reservoir (reservoir type) or drug dissolved in a liquid or gel-based reservoir (matrix type).

The starting point for the evaluation of the kinetics of drug release from a transdermal patch is an estimation of the drug compound’s maximum flux across the skin (flux (J))

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When does maximum flux occur?

(skin penetration: passive diffusion)

Maximum flux occurs when c_app = solubility limit of drug in applied formulation

ca_pp= conc of permeant in applied vehcile

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What are some factors influencing skin penetration?

Age – pre-term infants
Condition – injury or disease
anatomical site
blood flow
skin metabolism
Species – animal v human

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What happens to the skin in atopic dermatitis?

Increased transepidermal water loss (TEWL)

stratum corneum lipids are modified

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Rank in order of rabit,rat,pig,monkey human the relative in vivo absorption of different chemicals

Most to least:

rabbit>rat>pig>monkey>human

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What are two types of enzymes involved in skin metabolism? Give examples for each one.

Endogenous enzymes

Hormones, steroids, inflammatory mediators

Exogenous enzymes

drugs, pesticides, environmental & industrial chemicals

Metabolising potential estimated about 2% of the liver

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What are examples of skin metabolism?

Polycyclic aromatic hydrocarbons (in soot) – relatively harmless but activated in skin to DNA binding chemicals – scrotal CANCER in chimney sweeps
Activation of inactive pro-drugs eg. Steroid esters

What are the effects of vehicle in TDD?

Hydration by occlusion
Release & absorption according to type of formulation
Vehicle components biologically inert?
Vehicle components affect skin permeability?
Enhancement of flux or sustained release

What can the vehicle influence in TDD? Include positive and negatives.

Solubility of penetrant (thermodynamic activity/concentration) in vehicle
Partitioning – from vehicle to skin

Positive

Enhancement in:

Increase solubility in skin
Modify the barrier – increase diffusion coefficient

Negative

Damage the stratum corneum or skin integrity

> disrupt lipid structure

> dentaure proteins

What are some drug properties that can affect skin permeation?

Molecular weight/volume
Melting point
Partition coefficient – vehicle/stratum corneum & stratum corneum/stratum granulosum
Solubility in oil and water
Hydrogen bonding groups

How does TDD delivery rate relate to molecular weight and melting point?

Lower molecular weight (between 100 and 200 DA) and lower melting point =increased delivery rate

What log P value is good from NSAID and Salicylate POV for skin permeation

NSAID: LogP between 2 and 5

Salicylate: LogP between 1 and 4

What are the factors that affect selection of drug candidates for TDD?

Daily dose and potency – limit few mg/day
Clearance kinetics: t½, V_d
Physicochemical properties

> Partition coefficient

> Molecular weight

> Solubility in water and oils

> Melting point

Tolerance, allergy, irritancy – any predictable problems?

What is the effect of half-life on the predicted plasma levels for a drug delivered transdermally?

Longer half life = increased plasma levels for a longer period of time

What are some indications for TDD patches? Include the drug names.

Hormone replacement (testosterone, estrogens, progestogens)
Angina (nitroglycerin)
Pain relief (fentanyl, buprenorphine)
Hypertension (clonidine)
Motion sickness (scopolamine) –
Smoking cessation (nicotine)
Treat overactive bladder (oxybutinin)
Depression (selegilene)
ADHD (methylphenidate)

What are the types of transdermal delivery devices (passive systems)? What do all the devices have in common?

**All devices are diffusion-controlled release** * Reservoir systems * Matrix or drug-in-adhesive matrix systems \> TDD next generation e.g. Patchless patch system (Acrux, Melbourne)

For a **TDD reservoir system**; A) What does it consist of? B) How does it allow for constant release? *original TDD system design*

A) * Impermeable backing * Reservoir of gel containing drug, solvent, enhancers, ant-irritants, gelling agent * Release membrane controlling rate of delivery * Adhesive B) Drug from reservoir slowly partitions into membrane and adhesive --\> constant release

For TDD matrix/adhesive system; A) What three layers is it composed of? B) Initially what happens? C) How does it compare to TDD matrix device?

A) * Impermeable backing * Core polymer matrix containing drug and penetration enhancer * Release liner B) * Initial rapid drug release, slows as drug in matrix depletes C) * Sleeker and thinner than reservoir type

Provide examples of the following options for **skin penetration enhancement** A) Formulation B) Physical C) Chemical E) Penetration retarders

A) Hydration/occlusion – Supersaturation – Ion-pair – Lipidation – Eutectic mixtures – Vesicles – Chaperons – Nanotechnology B) \*Iontophoresis – Jet propulsion – Ablation – \*Sonophoresis – \*Microneedles – \*Magnetophoresis – \*Elongated microparticles C) Organic solvents – Azone – \*Fatty acids, alcohols & glycols – \*Surfactants – \*Terpenes D) Barrier creams – Chemicals eg. N-0915

What are the main mechnanisms of actions of **chemical skin penetration enhancers?** Give examples of these drugs.

**Increase diffusion coefficient** * Disorder the stratum corneum lipids eg. _Azone, oleic acid, DMSO, terpenes, surfactants_ * Extraction of stratum corneum lipids eg. _ethanol, acetone, surfactants_ * Denature protein in corneocytes **Increase drug solubility in skin** * eg. _propylene glycol, ethanol, transcutol, N-methyl pyrrolidone_

What is the influence of propylene glycol (**drug solubility enhancer)** on the permeation of ibuprofen from saturated solutions through rat skin

**Increased flux**

What is **iontophoresis (electrical method)**? what does it involve? Why is it used? AE?

small electric current (0.5 mA/cm2) applied to drug reservoir on skin surface * Same charged electrode as solute to produce repulsion effect * **Drives solute away from electrode into skin**; also electroosmosis effect – water movement Why * Numerous research applications – small drugs, peptides and proteins AE * Local erythema at site is common – release of cytokine, prostaglandin & other mediators, vasodilatation

What is an example of drugs and devcies used in iontophoresis?

1. idoSite™ (Vyteris Inc.): lidocaine HCl and epinidrione --\> 10 min application to reduce needle pain 2. Ionsys™ (Alza è Incline Therapeutics Inc) --\> Fentanyl for patient controlled analgesia (withdrawn due to corrosion) 3. Zecuity™ (NuPathe Inc.): sumatriptan for migraine--\> 6.5 mg sumatriptan delivered over 4 h

What is an example of drug and device used in sonophoresis?

* Sonoprep™ (Sontra) --\> Lidocaine to reduce needle pain * Prelude™ Skin Prep System * Symphony™ CGM System

What is magnetophoresis? What is an example?

Application of magnetic energy * Murthy et al – 10mT stationary magnet field * Benson et al – time varied magnetic field with average 0.25mT (Dermaportation) * OBJ Pty Ltd, Perth \> Pulsed electromagnetic field (Dermaportation: e- Skin™) \> Magnetic micro-array (ETP) \> Field in motion magnetic micro-array (FIM) \> Pharmaceutical, cosmetic, personal care, infection control/hygiene

How are micoroneedles/microarrays use for TDD?

Create physical pathway through the upper epidermis * ≈600 μm length; ≈80 μm width at base * Array of ≈3x3 mm * Various microneedle designs * Depth of insertion less than cutaneous nerves \> Potential for large proteins & peptides including vaccines

What are the types of microneedles/microarrays?

1. Solid microneedles 2. Coated microneedles 3. Dissolvable microneedles 4. Hollow microneedles

What are some other delivery systems?

* Nano-needles (nano patch) --\> array of 1000s of vaccine coated microprojections * Elongate microparticles (EMP: Foroderm)