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pr3153 > ic18 pharm tech (transdermal) > Flashcards

ic18 pharm tech (transdermal) Flashcards

1
Q

what are the parts of the skin (skin anatomy and physiology)

A
  1. stratum corneum: top 10µm of skin, 10-20 layers of flattened, stratified fully keratinised dead cells
  2. epidermis: divided into various morphologically and compositionally different layers, cells become flatter and more keratinised moving up through layers
  3. dermis: blood vessels, macrophages, mast cells, sebaceous glands
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2
Q

what is the function and structure of the stratum corneum (outline the path of a drug crossing the stratum corneum)

A

stratum corneum serves as the primary barrier for the drug in crossing the skin

has a brick and mortar structure that is ordered and rigid bilayer (has proteins that help hold this structure), access primarily via the intracellular lipidic domains (bc cannot penetrate through hydrophilic corneocytes) such as lipids, cholesterol, fatty acid and ceramides to navigate through the lamellar membrane which has a balance of hydrophobic and hydrophilic regions

also has some access via appendages aka sweat ducts, hair follicles but these have low surface area

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3
Q

compare between topical and transdermal delivery (target delivery site and eg.)

A

topical: shallow skin penetration for local delivery; eg. comestics, antiseptic, anti-inflamm

transdermal: deep skin penetration for systemic delivery; eg. hormonal regulation, nicotine, pain relief

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4
Q

what are the advantages of transdermal delivery

A
  1. controlled release (reservoirs, duration of contact, size of patch) -> decr dosing freq
  2. bypasses hepatic first pass effect
  3. no GI irritation/ degradation
  4. easy termination of input
  5. non invasive
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5
Q

what are the disadvantages of transdermal delivery

A
  1. variability between people and location of administration on body (different thickness of skin)
  2. stratum corneum has slow absorption (bc barrier properties and cells in stratum corneum is fully keratinised and keratin is a protein that is hydrophobic) *rate limiting step
  3. can be removed by patient
  4. metabolic enzymes present in skin
  5. BBB via systemic delivery (along the way also got reticuloendothelial system)
  6. systemic s/e
  7. skin irritation (interactions and removal)
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6
Q

is keratin hydrophilic or hydrophobic

A

hydrophobic

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7
Q

what are the factors that affect transdermal delivery

A
  1. skin conditions: age, disease, injury, site
  2. skin thickness
  3. hydration of skin: natural vs manufactured (eg. using moisturiser which can enhance (i))
    (i) corneocyte stays the same but lipid channels can absorb water which causes it to plump thus making the channels wider to facilitate more flow of drug through the channel
  4. stimulation of skin (phonophoresis/ ultrasound, iontophoresis, heat)
  5. physicochemical properties of drug (lipophilicity - partition coeff, diffusion coeff)
  6. permeation enhancer: reversible reduction in barrier resistance of stratum corneum without damaging viable cells
  7. conc gradient
  8. area of contact between formulation and skin
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8
Q

how might drugs administered transdermally access the brain

A
  1. paracellular and transcellular transport
  2. CMT, RMT
  3. active efflux transporters (P-gp, BCRP, MRP)
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9
Q

what is the idea drug properties as stated by lipinski’s rule of 5 and what are the relevant modifications to suit transdermal delivery

A
  1. MW <500Da
  2. LogP <5
  3. H bond donors 5 or less
  4. H bond acceptors 10 or less
  5. unionised

MODIFIED FOR TD DELIVERY
LogP 1-3 bc skin is quite hydrophobic thus if drug too hydrophilic then it would repel thus limit to the extent of hydrophilicity

*negative LogP means hydrophilic

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10
Q

what are the types of delivery systems for topical and transdermal delivery

A
  1. topical: gel, cream (water/oil based), ointments
  2. transdermal: patch (solutions/ suspensions in reservoir), patch (polymer matrix)
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11
Q

what are the current products on the market that utilises transdermal delivery and what are its uses

A

transdermal patches in the market:

  1. rotigotine (neupro) for treatment of parkinson’s or restless leg syndrome
  2. fentanyl (duragesic) for pain relief
  3. estrogen (estraderm) for hormone replacement therapy
  4. nicotine (nicotinell) for nicotine replacement therapy
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12
Q

what are the excipients of solutions for patches and what are the functions of each excipient

A
  1. preservatives (to decr microbial growth)
  2. solvents/ co-solvents (to dissolve drugs that are not fully water or oil soluble)
  3. permeation enhancers (to affect structure of cells in the brick and mortar structure of the stratum corneum to allow drug to penetrate through more easily)
  4. adhesives (stick to skin)
  5. viscosity modifiers (to affect rheology aka flow rate, stability and drug release from polymer matrix)
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13
Q

list eg. of permeation enhancers

A

cyclodextrin, glyceryl monooleate, ethanol, propylene glycol

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14
Q

list eg. of solvents

A

ethanol, propylene glycol

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15
Q

list eg. of adhesives

A

calcium alginate, carbomer, poly(methyl vinyl ether/ maleic anhydride)

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16
Q

list eg. of viscosity modifiers

A

hyaluronate sodium, calcium alginate, carbomer, poly(methyl vinyl ether/ maleic anhydride), carboxymethylcellulose, hydroxypropylmethylcellulose

17
Q

list eg. of a bioadhesive

A

glycerol monooleate

18
Q

list eg. of a polymer matrix

A

hyaluronate sodium, calcium alginate, carboxymethylcellulose, hydroxypropylmethylcellulose

19
Q

what are the excipient func of glycerol monooleate

A

permeation enhancer, bioadhesive, sustained release agent

func as a sustained release agent bc can form intricate structures that help to slow down movement of drug

20
Q

what are the excipient func of hyaluronate sodium

A

viscosity modifer, humectant, matrix polymer

humectant = hydrates skin

21
Q

what are the factors in which release of drug from a polymer matrix is dependent on

A

release of drug from polymer matrix is dependent on:

  1. diffusion coefficient of drug
  2. surface area
  3. concentration (higher concentration of polymer can incr crosslinking and tangling to slow down drug release vs if diluted in water then will become too dispersed)
  4. porosity/ tortuosity of polymer matrix (determined by intramolecular interactions like crosslinking and Hbonding or incorporating charged groups)
22
Q

what are transdermal formulations packaged in (elaborate on the func of the packagings)

A

patches are sealed in individual pouches, either
i) plastic or polymer lining (to maintain hydration)
or ii) aluminium lining (if light sensitive)

packaging is sealed to
i) maintain integrity of adhesive
ii) maintain integrity of product
iii) maintain hydration

23
Q

what are the different types of patch design (illustrate schematic diagrams of each design type) also what is the property of excipients that allows for such different design types

A
  1. membrane: drug dispersed in a separate depot, rate controlling membrane limits the amount of drug release over time (backing layer, drug reservoir, rate controlling membrane, adhesive)
  2. matrix: drug dispersed into a matrix but separate to the adhesive layer (backing layer, drug in matrix, adhesive)
  3. drug-in-adhesive matrix: drug combined with adhesive and released from this matrix (backing layer, drug in adhesive matrix)

bc excipients can have multiple excipient func (have both adhesive and matrix polymer func eg. calcium alginate)

24
Q

what is the function of the various components in a transdermal patch

A
  1. backing layer: to protect drug and contents (typically made of an impermeable material that would protect the drug and contents from drying out, exposed to light (by using Al lined) and air etc)
  2. membrane: polymer matrix, composition/chemistry, thickness and porosity/tortuosity determines release
  3. adhesive: silicone, rubber and adhesives and permeation enhancers
  4. liner: protect adhesive (removed upon sticking patch)
25
Q

what are the special considerations for transdermal patches

A
  1. release rate of drug from patch
    i) potential for leaching and extraction of drug into backing or other layers (or interact with other layers; components can flow back and forth)
    ii) temperature (incr in temperature may cause incr release of drug which can be dangerous)
    iii) crystallinity of drug over time (drugs may crystallise depending on temp and would affect release rate)
  2. strength of adhesion (between layers, influence of sweat, skin etc)
  3. disposal
    i) in order to maintain conc gradient such that drug diffusion is maximised, these patches usually have high conc of drug -> risk of someone else having a dose of the drug if not properly disposed
26
Q

considering rotigotine (neupro), elaborate on moa, product characteristics, application directions, API (MW, LogP, Hbond donor and acceptor, ionisability), design type, excipients and their func, PK (duration of patch, half life upon patch removal)

A

moa: dopamine receptor agonist (not fully understood) to treat parkinson’s or restless leg syndrome

product characteristics: larger dose = larger patch size

application:
i) select a body site that has not been used yet (bc prev site might be irritated/ may be tender which would incr permeability of the skin which would incr drug penetration and affect the consistency of drug administration)
ii) remove the protective layer to expose adhesive layer
iii) immediately stick to skin (dont let it expose to environment and dust)
iv) hair removed for that selected site to ensure maximal adhesion
v) to maintain adhesion, warm up area slightly to further activate adhesion (place palm over patch applied to skin)

API MW: 315

API LogP: 4.7

API Hbond donor: 1

API Hbond acceptor: 3

ionisability: ionisable bc tertiary amine and phenol (but both pKa high 10.03 and 10.97)

*in unionised state, likely poor water solubility bc LogP high and low number of Hbond donor and acceptors

design type: drug-in adhesive matrix

excipients:
i) ascorbyl palmitate (antioxidant)
ii) povidone (polymer and potential adhesive)
iii) silicone adhesive
iv) sodium metabisulfite (antioxidant)
v) DL-alpha-tocopherol

*antioxidants protect drug and contents from oxidation

PK: 45% released in 24hr (aka duration of patch), terminal half life of 5-7hr upon patch removal

27
Q

considering fentanyl (duragesic), elaborate on moa, API (MW, LogP, Hbond donor and acceptor, ionisability), design type, excipients, PK (duration to ss, half life upon patch removal)

A

moa: opioid agonist for pain relief

API MW: 336.5

API LogP: 4.05

API Hbond donor: 0

API Hbond acceptor: 2/3

ionisability: yes bc tertiary amine

design type: membrane

excipients:
i) alcohol (minute amounts) (permeation enhancer)
ii) ethylene-vinyl acetate copolymer (polymer matrix)
iii) hydroxyethyl cellulose (viscosity modifier, matrix polymer)
iv) polyester (matrix polymer)
v) silicone (adhesive)

PK: 3d to ss plasma conc, 7hr half life after patch removal

pr3153 (18 decks)

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