formulation TD Flashcards

1
Q

skin anatomy

A
  • Stratum corneum
    • Top 10um layer of skin
  • epidermis
    • Cells flatter, more keratinised moving up through layers
  • Dermis
    • Blood vessels, macrophages, mast cells
    • Sebaceous glands, hair glands
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2
Q

stratum corneum (main barrier)

A
  • Top 10um layer of skin
  • 10-20 layers of flattened, stratified, fully keratinised dead cells
  • Primary barrier to drug crossing the skin
    • Brick and mortar structure
      ○ Ordered, rigid bilayer structure
      ○ Access primarily via: intracellular lipidic domains
    • Lipids, cholesterol, fatty acids, ceramides
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3
Q

skin delivery 2 ways

A

topical
transdermal

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4
Q

topical

A
  • Shallow skin penetration
  • Local delivery
  • Cosmetics, antiseptics (local wound that affects only surface layer), anti-inflammatories
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5
Q

transdermal

A
  • Deep skin penetration (across stratum –> epidermis –> adipose tissue –> dermis –> blood vessels)
  • Systemic delivery
    - Nicotine, pain relief, hormonal regulation
    - Protects pdt + retain on surface of skin
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6
Q

adv of TD

A
  • Controlled release
    ○ Reservoir: (amt of drug + conc loaded into reservoir)
    ○ Duration of conTDtact: (size of patch, duration)
    ○ Decr dosing freq
  • No GI degradation/ irritation
    ○ More local skin irritation
  • Bypass hepatic 1st pass effect
  • Easy termination of input
    ○ Peel off and admin of drug stops, not high plasma conc left
  • Non-invasive
    ○ Painless, no skin breeched
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7
Q

disadv of TD

A
  • Variability b. people and location of admin on body
    ○ Thickness of skin differs
  • SC
    ○ Slows absorption, barrier
    ○ Rate limiting step
  • Skin irritation
    ○ Adhesive layer – removal
    ○ Drug int on skin surface
  • Easily removed by pt
  • Metabolic enzymes (specific chemical functional grps?)
  • BBB (via systemic delivery)
  • Systemic SE
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8
Q

8 factors that affect delivery

A
  • Skin condition: age, disease, injury, site
  • Skin thickness (diffusion layer)
  • Hydration of skin (stratum corneum)
  • Stimulation of skin
    • Phonophoresis/ ultrasound – vibration
    • Iontophoresis – heat
  • Physicochemical properties of drug
    • Lipophilicity, diffusion coefficient – LogP, size
  • Permeation enhancers (eg ethanol)
    • Reversible reduction in barrier resistance of SC w/o damaging viable cells
  • Conc gradient
    • Patch reservoir –> skin
    • 50% of Drug left in patch as there must be FLUX
  • Area of contact b. formulation & skin (SIZE)
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9
Q

hydration by

A
  • Natural: hydration, humidity
  • Manufactured:
    ○ Chemically (moisturise)
    ○ Physically (occlusive layer to trap water at site)
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10
Q

hydration affects

A

Water absorbed by lipid channels in between
Lipid channel widens, facilitate flow/ permeation of drug
- Size of corneocytes remain the same
- The gaps between WIDENS, better permeation

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11
Q

brain access via TD

A

Skin (barrier) –> blood –> (barrier) brain

* Drug sol flows through circ system 
	○ Reticuloendothelial system (RES) 
	○ Unless active targeting, drug is distributed everywhere =unwanted SE  
* Drug bypass BBB to access the brain 
	○ Blocks ~98% of small mole drug candidates 
	○ Paracellular (tight junctions) << transcellular transport
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12
Q

transcellular transport via

A

1) Active efflux transporters (REMOVE from organs into lumen)
○ P-gP, BCRP (breast cancer resistance protein), MRP (multi-drug resistance protein)

2) Endocytosis mediated transporters (INTO by Specific molecules/ functional grp binding)
○ Carrier-mediated transporters (LAT1, GLUT1, MCT1, OCTN2)
○ Receptor-mediated transporters (IR, TfR)

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13
Q

TD drug candidate lipinski

A
  • logP 1-3
    if too hydrophobic: repelled, still needs to be transported systemically
  • unionised
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14
Q

TD formulations

A
  • Topical: gel, creams (w-based/ oil-based), ointment
  • TD: patches
    ○ Sol/ susp in reservoirs
    ○ Polymer matrix
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15
Q

TD excipients

A
  • Preservatives - reduce microbial growth
  • Solvent, co-solv - dissolve drug
  • Viscosity modifier - flow of formulation in reservoir
  • Permeation enhancer - in contact w/ SC
    ○ Bioadhesive (stick to mucus layer)
    ○ SR agent (complex matrix)
  • Adhesives - stick to skin
    ○ May have properties: viscosity enhancers, matrix polymer
  • Polymer matrices (SR)
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16
Q

polymer matrices and Drug release depends on:

A
  • Diffusion coefficient of drug
  • SA
  • Conc of polymer > dilute (more crosslink)
  • Porosity/ tortuosity of polymer matrix
    * Intramolecular interactions (crosslink, H bonds)

drug encapsulated between matrix, diffuse out slowly

17
Q

permeation enhancers
- interaction with intercellular protein
- improve partition of the drug into stratum corneum

A

cyclodextrin
glyceryl monoleate
ethanol
propylene glycol

18
Q

solvent

A

ethanol
propylene glycol

19
Q

viscosity modifier

A

carboxymethyl cellulose, HPMC
hyaluronate sodium
calcium alginate
carbomer
poly(methyl vinyl ester/ maleic anhydride)

20
Q

matrix polymer

A

glyceryl monooleate (SR agent)
carboxymethyl cellulose, HPMC
hyaluronate sodium
calcium alginate
povidone (SR)

21
Q

adhesive

A

calcium alginate
carbomer
povidone
poly(methyl vinyl ester/ maleic anhydride)

glyceryl monooleate (bioadhesive)
silicone, rubber, adhesives

22
Q

humectant

A

hyaluronate sodium

hydrates skin, better permeation (brick, mortar)

23
Q

packaging and storage

A
  • Patches sealed in indiv pouches
    ○ Plastic/ polymer lining (maintain hydration in patch)
    ○ Al lining (protect from light degradation)
  • Sealed packaging
    ○ Maintain integrity of adhesive
    ○ Maintain integrity of pdt (oxidation, reduction, temp)
    ○ Maintain hydration
24
Q

designs of patches (3)

A

1) membrane patch (bulky, reservoir, matrix, adhesive separate)

2) matrix patch (drug in matrix, no reservoir)

3) drug-in-adhesive matrix patch (drug+polymer+adhesive)

  • calcium alginate
  • povidone
25
parts of a patch
* backing layer (ontop, impermeable) * membrane (polmer matrix) * adhesive * liner (protects adhesive, remove just before admin)
26
backing layer
○ Impermeable layer (plastic/ polymer lining, additional Al lining) ○ Protects drug and contents ○ Maintain patch: hydration, stability (light, Oxidation) ○ support and protection of drug-loaded adhesive from environ
27
membrane, polymer layer
○ Polymer matrix ○ Release rate depends on: * Composition/ chemistry, thickness and porosity/ tortuosity (channels in matrix)
28
adhesive
silicone, rubber, adhesives permeatiion enhancers (prime skin for better permeation)
29
special considerations of TD patch
* release rate of drug * toxicity/ ADR/ ineffectiveness * temp (no heated blankets, incr SE) * crystallinity of drug over time * strength of adhesion * b. clothes layers, influence of sweat, hair * disposal of patch * high conc left in patch --> needed to create a flux (release)
30
release rate of drug affected by
* potential for leaching, extraction of drug from backing * drug remains in reservoir, not fluxed/ released * substances from backing layer (may be toxic) leached * temp (not use heated blankets, incr SE) * crystallinity of drug over time (crystal/ amorphous -- melting point)
31
rotigotine/ neupro
* drug in adhesive * dopamine receptor agonist (PD) backing film, drug matrix, protective liner
32
admin of patch
* Apply on skin that was not used previously ○ Adhered skin is more tender, rate of drug penetration affected ○ rotate sites, not repeat in 14d ○ shave hairy site 3d before apply * Immediately apply to skin after peeling protective layer from adhesive ○ Exposed to microbials ○ Affect adhesiveness of patch * 30s Warm up area to activate adhesion ○ Better adhere to skin
33
rotigotine API
* MW: 315.48 g/mol * logP: 4.7 * Hydrogen bond donor (1) * Hydrogen bond acceptor (3) * Ionisable --yes 3*amine & OH ○ pKa is weak, affected by pH of body + formulation ○ Usually uncharged to have higher LogP, better partition into lipo layer of skin ○ may become ionised for systemic circulation
34
rotigotine composition
* Ascorbyl palmitate -- antioxidant * Sodium metabisulfite -- antioxidant * DL-alpha tocopherol vit E -- anti oxidant * Povidone -- polymer, SR, adhesive * Silicone adhesive
35
PK/PD of rotigotine
* ~45% released in 24hrs (0.2mg/cm2) ○ Cmax dependent on patch dose * repeated daily use to maintain steady state conc * After removing patch, ○ Plasma lvl decr with t1/2: 5-7hrs
36
fentanyl/ duragesic
* opioid agonist -- pain relief (repeat 72h application) * drug in membrane (bulky: reservoir, release mem, adhesive -- separated) * dose depeds on conc in patch + size of patch backing layer, drug reservoir,mem, silicone, protective liner * rotate sites, do not shave (clipped)
37
fentanyl API
* MW: 336.5g/mol * logP: 4.05 * Hydrogen bond donor (0) * Hydrogen bond acceptor (2) Ionisable, +ve charged
38
fentanyl composition
* Alcohol *-- permeation enhancer (found on adhesive) ○ Minute amounts, less irritation to skin * Ethylene-vinyl acetate copolymer -- matrix * Hydroxyethyl cellulose -- matrix * Polyester -- backing layer (no water passes through) * Silicone -- adhesive
39
PK/PD of fentanyl
* SS plasma conc after ~ 3days ○ Large variability (pt) * Plasma conc depend on patch dose * large conc variability even at maintenance * After removing patch ○ t1/2 ~ 7hrs