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Pharmaceutical formulation and quality assurance > Transdermal drug delivery > Flashcards

Transdermal drug delivery Flashcards

1
Q

What are the advantages and disadvantages of transdermal drug delivery

A

Advantages:
-Avoids hepatic first pass metabolism – !Skin Metabolism!
-Avoids pain associated with injections
- Continuous “Sustained Release” drug delivery with infrequent dosing
- Permits self-administration – Vaccines
- Non-invasive (no needles or injections) – Needle injuries /contamination
- Improves patient compliance
- Reduces side effects
- Allows removal of drug source
Patient preferred

Disadvantages

  • Potent drugs only (few mg/24 hours)
  • Lag Time (not good for acute conditions)
  • Development of tolerance
  • Poor diffusion of large molecules
  • Allergic and Irritant reactions
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2
Q

What are the routes of transdermal drug absorption

A

Transcellular:
>Water soluble
> 25m diffusion path lenght
>Delivered through lipid structure of SC and corneocytes

Intercellular:
>Lipid-soluble drugs
>0.70% of relative surface are 350 m diffusion path length
>Drug diffuses through endogenous lipid within SC

Trans follicular:
>Via the pores
>0.10% of relative surface are 200 m diffusion path length

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3
Q

What are the formulation principles

A

Select a suitable drug

Release the drug
>Vehicle should not retain drug
>Appropriate release
>If lipophilic drug in lipophilic base then drug will stay in formulation, aqueous base more suitable

Use thermodynamics
> concentration gradient in favour of the drug -Near saturated solution
>

Alcohol can help
>Partitions into skin and provides transient reservoir for the drug
>Good solvent but evaporates from skin

Occlusion
>cover skin by blocking trans epidermal water loss

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4
Q

Fundamentals of skin permeation

A

passive diffusion process that can be described by the Fick’s law of diffusion (conc gradient)

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5
Q

What is fick’s first law

A

J = { DP / h} Cv = kp Cv

J = flux
D = apparent diffusivity in stratum corneum
P = SC / formulation partition coefficient
h = thickness of the barrier
Cv = Concentration in vehicle (donor solution)
kp = Drug’s permeability coefficient across the skin
(is formulation dependant)

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6
Q

What is lag time

A

The time period that is required to reach therapeutic level

LT=h2/ 6D

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7
Q

What is a steady state flux

A

It determines whether therapeutic levels can be reached

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8
Q

Examples of transdermal drugs

A

Buprenorphine
Fentanyl
Nicotine
Ethinyl

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9
Q

What are the general formulation options for transdermal formulation

A

general
>Semi-solid formulation: Increase residence time
> Patch: extend drug delivery through skin
> Liquid formation: Rapid short term input to permeate the skin

Skin type
>Normal to oily: gels
>Normal to dry: lotions
>dry skin: creams
>Skin site
   -Hairy: lotions, gels, and sprays
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10
Q

What are the clinical rationales that dictate topical choice and what are those choices ?

A

Wet, vesicular or weeping lesions: Aqueous base formulations

- Hydrophilic drugs: include water and a co-solvent but avoid alcohols 
- Hydrophobic drug: Mineral oil or aqueous co-solvent  but avoid alcohol

Dry, thickened scaly lesions: fatty formulations such as ointments or pastes
-Oil and waxes which include surfactants and glycol depending on formulation and drug solubility

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11
Q

For delivery to the skin what are the formulation options

A

Aqueous or oil based: isopropyl myristate, propylene glycol

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12
Q

For delivery through the skin what are the formulation options

A

Aqueous or oil based formulation: alcohols, glycols, oleic acid (can be a combination)

Combination of solvents
Alcohol may enhance delivery

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13
Q

How can transdermal drug delivery be enhanced

A

increase flux
>Skin barrier properties: increase diffusivity
>Nature of permeant to increase partition
> increase conc. of the drug in the vehicle/ formulation
>Select thin skin to put the patch on

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14
Q

When is maximum flu achieved

A

At saturation

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15
Q

what does it mean to be super saturation

A

Supersaturated solution is where drug is present in excess of solubility

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16
Q

How can a formulation be manipulated to enhance it’s uptake

A

-Partitioning can be encouraged into the SC by using a vehicle in which drug is only moderately soluble

  • Active should have appropriate physicochemical properties
    >Enhances partitioning in lipophilic SC
    >Ester-linked fatty acids can help and link can be cleaved in skin by esterases liberating the active

-Control over pH can ensure that neutral compounds are maintained that permeate better
>Ion-pairing agents can also assist

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17
Q

What is an adhesive patch

A
  • It is one layer of drug contained in an adhesive polymer
  • Has a reservoir of high loading capacity
  • Degree of control is small and the ultimate control barrier is the stratum corneum
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18
Q

What are layered patches and how do they work

A
  • They have a different polymer composition/different polymer to provide drug containing matrix
  • Made of one or more sub-layers
  • can increase drug content in the system or control drug release for longer delivery

-Main drawback is the area of contact between patch and skin is larger than the active area

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19
Q

What is a reservoir patch and how does it work

A
  • it is pioneered from Alza
  • A reservoir of the drug in a lipid state and a polymer membrane separating the reservoir form the adhesive tape
  • the membrane acts a rate-controlled element
  • Patch should be a reasonable size
20
Q

What are the component in a patch

A
  • Release liner
  • Adhesive
  • Backing layer
  • Matrix/reservoir
  • Rate-limiting membrane
21
Q

-Release liner properties

A
  • Temporarily covers adhesive layer and is removed
  • Made from polymers: Ethylene vinyl acetate, aluminium foil
  • Must easily peel away but bond firmly to prevent accidental removal
  • Prevent loss of volatile component
22
Q

Adhesive components properties

A
  • Crucial to TDDS
  • Pressure sensitive adhesive used: Acrylates, polyisobutylene, polyoxane

They must:

  • Stick to the skin for the patches lifetime
  • Non-irritating and non-allergenic
  • Compatible with drug and to other excipients
  • Presence of drug can affect properties and is only seen in vivo
23
Q

Backing layers properties

A

There are many materials depending on design, size and length of use

Relatively short use small patches- occlusive backing layer
> Hydrates skin, improve drug absorption (polyethylene or polyester films)

Larger longer use patch may allow vapour transmission - polyvinylchloride films

Backing layer should allow multidirectional stretch, pliable to move with the skin

24
Q

Matrix/reservoir properties

A
  • prepped by dissolving drug and polymer in common solvent before adding plasticizer
  • Viscosity modified by conc of polymer or by cross-linking chains in matrix.
  • Reservoir have viscous liquid: silicone or co-solvents system occasionally with ethanol
25
Q

Rate limiting membrane properties

A
  • Transdermal patches were originally designed to control rate of delivery of active ingredient
  • Membrane must be compatible with the drug, non-toxic, stable and pliable
  • separate reservoirs from underlying adhesive or multiple drug-in adhesive- layers
26
Q

Examples of rate controlled transdermal delivery

A

Clonidine
>Potent anti-hypertensive , well absorbed in GI tract, long half-life, modest clearance
>Induces immunological skin reaction
>Transdermal patch to reduce side effects and patient compliance
>Reservoir type

Oestradiol
>High hepatic first-pass effect results to an unfavourable ratio of estrone to the drug itself
>Sustained plasma concentrations with transdermal application
>First patch a reservoir worn for 3 up to 4 days

27
Q

What determine the rate control of transdermal ddrugs

A

determined by the area of contact between patch and skin

28
Q

Factors of rate control in transdermal delivery

A

> Transdermal delivery can be achieved by adjusting the size of the system
delivery is not so sensitive to the loading of the patch especially when the input rate is controlled by the skin
design of a patch does not guarantee that it will control the delivery rate

29
Q

Advantages of transdermal opioid therapy

A

> Peaks and troughs avoided which would lead to side effects
reduced need for dosage administration
Fentanyl and buprenorphine unsuitable for the treatment of acute pain

30
Q

Fentanyl TDDS

A
  • Soluble in both fat and water with low MW and high potency
  • Designed at 4 constant rates
  • steady-state serum concentration is reached after 24 h and maintained as long as the patch is renewed.
  • Durogesic® reservoir patch is mostly phased out and replaced with Durogesic® Dtrans®—a matrix design
31
Q

Skin modifications done to enhance penetration

A

Penetration enhancers disrupt the highly organised lipid layer by:

> Interacting with cellular proteins
Increasing partitioning into the membrane

Penetration enhancers should be

  • Pharmacologically inert
  • Modify skin barrier in a reversible manner
  • Non-toxic
  • Non- irritating
  • Compatible with drugs and excipients
  • Acceptable to patients (good skin feel, odourless, colourless etc
32
Q

What are chemical permeation enhancement

A

Compounds that promote skin permeability by altering the skin structure

33
Q

mode of actions of chemical permeation enhancement

A
  1. Increasing the fluidity of the SC lipid bilayer
  2. Interaction with intercellular proteins
  3. Disruption or extraction of intercellular lipids
    4 .Increasing the drug thermodynamic activity
  4. Increasing the SC hydration
34
Q

List the some examples of chemical permeation enhancement

A

Solvents alkyl-esters, dimethyl sulfoxide, pyrrolidine

Surfactants- sodium lauryl sulfate, SDS

Fatty acids-oleic acid, undecanoic acid, linoleic acid

Alcohols-octanol, nonanol

Terpenes-menthol, limonene, thymol

Lactam-laurocapram (Azone)

35
Q

Chemical permeation enhancement

A

Water: safest and most widely used
Transdermal flux in most through hydrated skin compared to dry tissue
Occlusion is an effective means to increase permeability

Ethanol and other low MW alcohols:
Ethanol can disrupt the intercellular lipid packing and increase diffusivity but can also diffuse into membrane act as solvent within SC into which drugs can easily partition

Dimethyl sulfoxide (DMSO): can interact with lipid bilayer head groups and disrupt close packing

Fatty acids e.g. oleic acid: insert along the SC lipid chains to disrupt packing

Azone: posesses and bulky polar head group and lipid chain
Can insert with in the lipid lamellae and disrupt at both head groups and chains

Terpenes (fragrance agent) and surfactant

36
Q

What is a jet injector

A
37
Q

What is microporation

A

It is a way to overcome the skin barrier and is based on the formation of the micropores into the stratum corneum

Microchannels forms by external means: Microneedles, ultrasound, Electroporation, radiofrequency and lasers

38
Q

What are the mechanical approaches to transdermal drug delivery

A

Tape striping: Remove stratum corneum using single adhesive tape

Microneedles: Multiple microscopy projections on one side of the patch
>Length: 25-200 um
>Based width: 50-250 um
>Tip diameter: 1-25 um

39
Q

What are microneedles

A

They are needles that are painless, and are strong dermal permeabilization

They are long enough to perforate top layer of the epidermis but too short to activate nerve endings

Skin recovers barriers within 3-4 hours

40
Q

Examples of microneedle medications

A

Naltrexone which are administered to avoid first pass metabolism

41
Q

What are other available microporation techniques available

A

> Sonoporation (low frequency ultrasound cavitation):
Thermal ablation: (Heating sources such as laser, radiofrequency)
Iontophoresis (application of electrical currents)
Electroporation (high voltage pulse)

  • human growth hormones (radiofrequency),
  • gene transfer (laser), insulins (sonoporation, electroporation, laser),
  • vaccine (sonoporation, electroporation).
42
Q

Describe the process of iontophoresis

A

Skin patches that use 0.1-1mA /cm Squared of electrical currents for mins - hours

Increases speed / rate of delivery
>Lidocaine, fentanyl, migraine drugs

Rate = applied constant current

amount of drug delivered is determined by the maximal current applied before the pain level is reached.

NOT USED FOR LARGE MOLECULES

43
Q

Examples of iontophoresis

A

Glucowatch: Reverse iontophersis

ALZA E-TRANS: fentanyl

44
Q

Describe Electroporation

A

Pores are formedthrough the application of short and high voltages, 50-500 volts

proper designed systems can minimise sensation for the voltage pulse and facilitate drug delivery,especially of hydrophilic and charged molecules into the skin

Small and higher MW can be delivered

45
Q

what is a disadvantage/draw back of electroporation

A

Main drawbacks are the lack of quantitative delivery,cell death with damage of proteinsand, thus, the bioactivity

46
Q

Describe sonophoresis

A

Ultrasound is an oscillation sound pressure waveand can be used to transport drugs across the skin.
>include thermal effects, as well as cavitation effects

20 kilohertz to 60 megahertz

Delivery of drugs independently of charge and size

High-intensity ultrasounds can cause second-degree burns,limiting the delivery of many macromolecules

47
Q

What is the thermal approach to transdermal drug delivery

A

stratum corneum is selectively depletedat the site of heating without deeper tissue damage

> Short exposure prevents damage

Pharmaceutical formulation and quality assurance (14 decks)

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