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Biopharmaceutical Technology > DDS: Transdermal > Flashcards

DDS: Transdermal Flashcards

1
Q

What are the functions of the skin?

A
  • 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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2
Q

Why are chemicals applied to the skin?

A
  • 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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3
Q

What are drugs used in the following;

A) superficial

B) appendaegeal

C) epidermal/dermal

D) systemic

E) deeper tissue

A

A)

Sunscreens, cosmetics, insect repellents, barrier products

B)

Anti-acne, anti-infectives

C)

Antihistamines, anaesthetics, antimitotics, scopolamine

D)

Nitroglycerin, nicotine, hormone replacement therpay

E)

Analgesics and antiinflammatories

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4
Q

What are the advantages of TDD (transdermal drug delivery)

A
  • 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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5
Q

What are the disadvantages/limitations of TDD?

A
  • 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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6
Q

What makes up the below antaomy of the skin

A) Epidermis

B) Dermis (1-2 mm)

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

A

A)

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

B)

  • Connective tissue, nerve, lymphatic & vascular vessels; appendages

C)

  • N/A
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7
Q

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

A

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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8
Q

What is the main barrier to penetration?

A

Stratum corneum

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9
Q

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

A
  • 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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10
Q

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

A

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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11
Q

When does maximum flux occur?

(skin penetration: passive diffusion)

A

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

capp = conc of permeant in applied vehcile

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12
Q

What are some factors influencing skin penetration?

A
  • Age – pre-term infants
  • Condition – injury or disease
  • anatomical site
  • blood flow
  • skin metabolism
  • Species – animal v human
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13
Q

What happens to the skin in atopic dermatitis?

A

Increased transepidermal water loss (TEWL)

  • stratum corneum lipids are modified
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14
Q

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

A

Most to least:

rabbit>rat>pig>monkey>human

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15
Q

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

A

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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16
Q

What are examples of skin metabolism?

A
  • 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
17
Q

What are the effects of vehicle in TDD?

A
  • 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
18
Q

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

A
  • 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

19
Q

What are some drug properties that can affect skin permeation?

A
  • Molecular weight/volume
  • Melting point
  • Partition coefficient – vehicle/stratum corneum & stratum corneum/stratum granulosum
  • Solubility in oil and water
  • Hydrogen bonding groups
20
Q

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

A

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

21
Q

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

A

NSAID: LogP between 2 and 5

Salicylate: LogP between 1 and 4

22
Q

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

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

> Partition coefficient

> Molecular weight

> Solubility in water and oils

> Melting point

  • Tolerance, allergy, irritancy – any predictable problems?
23
Q

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

A

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

24
Q

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

A
  • 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)
25
Q

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

A

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)

26
Q

For a TDD reservoir system;

A) What does it consist of?

B) How does it allow for constant release?

original TDD system design

A

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

27
Q

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

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
28
Q

Provide examples of the following options for skin penetration enhancement

A) Formulation

B) Physical

C) Chemical

E) Penetration retarders

A

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

29
Q

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

A

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​
30
Q

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

A

Increased flux

31
Q

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

A

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
32
Q

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

A
  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
33
Q

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

A
  • Sonoprep™ (Sontra) –> Lidocaine to reduce needle pain
  • Prelude™ Skin Prep System
  • Symphony™ CGM System
34
Q

What is magnetophoresis? What is an example?

A

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

35
Q

How are micoroneedles/microarrays use for TDD?

A

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

36
Q

What are the types of microneedles/microarrays?

A
  1. Solid microneedles
  2. Coated microneedles
  3. Dissolvable microneedles
  4. Hollow microneedles
37
Q

What are some other delivery systems?

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

Biopharmaceutical Technology (16 decks)

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