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Dosage Forms II > Exam 3 Topical and Transdermal Drug Delivery > Flashcards

Exam 3 Topical and Transdermal Drug Delivery Flashcards

1
Q

What does cutaneous and transdermal delivery do?

A

uses the skin as a route to introduce drug into the body

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2
Q

The skin is a what?

A

barrier! it prevents something from coming into the body

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3
Q

What are the layers of the skin?

A

stratum corneum (outermost layer and is the most tenacious skin barrier) → living epidermis → dermis → subcutaneous fatty tissue → subcutaneous vasculature

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4
Q

What are some important things to know about stratum corneum?

A
  1. main barrier to permeation
  2. brick and mortar model → bricks are the dead cells and mortar is the lipid
  3. the dead cells are not permeable because they are so dense
  4. permeation occurs by partitioning through the lipid material (mortar) between the dead cells (bricks) → more likely to go through the lipid layer especially for lipophilic drugs
  5. functions as a lipid barrier
  6. state of hydration is directly related to the ease of permeation → absorbs better if skin is hydrated rather than dry
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5
Q

What is another name for the stratum corneum?

A

the dead skin layer

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6
Q

What is the living epidermis?

A
  1. also called viable epidermis
  2. living cells without capillaries (no blood vessels) → cells get nutrition by diffusion from dermis layer
  3. source of skin color and tanning since it contains pigment of skin
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7
Q

What is the dermis?

A
  1. contains capillaries
  2. drug needs to reach these capillaries to achieve systemic action
  3. contains pain, thermal, and tactile sensors → can feel the pain of a papercut
  4. injury must reach dermis to produce scarring
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8
Q

What happens if you have a papercut and it only goes through the living epidermis?

A

no bleeding or scarring

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9
Q

What happens if you have a papercut and it goes through the dermis?

A

bleeding and scarring occurs

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10
Q

What is important to note about hair follicles and sweat glands?

A

secondary route of drug absorption that bypasses the stratum corneum

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11
Q

What are the six functions of the skin?

A
  1. containment
  2. microbial barrier
  3. chemical barrier
  4. radiation barrier
  5. electrical barrier
  6. thermal barrier and body temperature regulation
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12
Q

What is the main function of the skin?

A

containment! covers everything and contains the body

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13
Q

What is the containment function of the skin?

A

confine underlying tissues and restrain their movement

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14
Q

What is the microbial barrier function of the skin?

A
  1. pH of skin is 5 which inhibits growth of bacteria → antimicrobial activity!
  2. sebum contains bacteriostatic and fungistatic fatty acids (propanoic, butanoic, hexanoic, and heptanoic acids)
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15
Q

What is the chemical barrier function of the skin?

A

permeability resistance of stratum corneum is several orders of magnitude greater than other barrier membranes of the body → is a challenge to bring in drug to the body since we have to breach to bring it into the body

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16
Q

What is the radiation barrier function of the skin?

A

exposure to UV stimulates synthesis of melanin (is a reservoir of UV) which absorbs UV rays

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17
Q

What is the electrical barrier function of the skin?

A
  1. offers high impedance to the flow of an electrical current
  2. need to treat the skin with salt solutions and overcome the impedance to measure body potentials (EEG or EKG) → use granular salt suspensions, creates pastes containing electrolytes
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18
Q

What is the thermal barrier and body temperature regulation function of the skin?

A

maintains 98.6 degrees Fahrenheit (37 degrees Celsius) by dilating or constricting blood vessels or sweating (depending on weather)

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19
Q

What are the two types of drug delivery types?

A
  1. topical

2. transdermal

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20
Q

What is topical drug delivery?

A
  1. local effects on barrier function → surface effects and stratum corneum effects
  2. drug action on the skin’s glands
  3. effects in deep tissues

aka drug stays there

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21
Q

What is transdermal drug delivery?

A

systemic drug delivery → drug penetrates through the skin to the dermis and gets into blood vessels to provide systemic effect

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22
Q

What are the two types of local effects on barrier function via topical drug delivery?

A
  1. surface effects

2. stratum corneum effects

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23
Q

What are examples of surface effects (affects localized surface of skin) of topical drug delivery?

A
  1. zinc oxide paste for diaper rash
  2. sunblocks and sunscreens → epidermis layer
  3. lip balms for chapped lips → stratum corneum
  4. calamine lotion for poison ivy and poison oak
  5. antibiotics for a localized infection
  6. deodorants
  7. medicated soaps
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24
Q

What are examples of stratum corneum effects of topical drug delivery?

A
  1. emolliency: softening horny tissue (aka the outermost layer of the skin aka stratum corneum)
  2. keratolysis: chemical digestion and removal of horny tissue
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25
Q

What are examples of drug action on the skin’s glands for topical drug delivery?

A
  1. antiperspirants → aluminum chloride (irritate and close the orifice of eccrine glands to impede sweat flow)
  2. acne → soap, alcoholic solutions, antibiotics, retinoids (reset the process of epidermal proliferation and differentiation → prevents the formation of lesions)
  3. hair removers (depilatories)
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26
Q

What are some examples of the effects in deep tissues (or even subcutaneous area) of topical drug delivery?

A
  1. topical corticosteroids
  2. non-steroidal anti-inflammatory drugs
  3. local anesthetics: benzocaine
  4. lighten excessively pigmented skin: hydroquinone (to lighten darkened skin)
  5. skin cancer: 5-fluorouracil (for chemo to avoid systemic side effects)
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27
Q

What are the five different topical drug delivery platforms?

A
  1. ointments
  2. pastes
  3. creams
  4. gels
  5. rigid foams
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28
Q

For ointments, what are the different types of bases?

A
  1. hydrocarbon bases
  2. silicone bases
  3. absorption bases
  4. water soluble bases
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29
Q

What is the ranking of the bases of ointments in terms of hydrophobic to hydrophilic?

A

hydrocarbon bases → silicone bases → absorption bases → water soluble bases

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30
Q

What are examples of hydrocarbon bases used in ointments?

A
  1. petrolatum

2. polyethylene dissolved in mineral oil (Plastibase)

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31
Q

What do silicone bases in ointments contain?

A

contains polydimethylsiloxane oil

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32
Q

What are absorption bases used in ointments?

A

ointments containing W/O emulsifiers (W/O emulsion containing aqueous solution of a drug)

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33
Q

What are examples of water soluble bases used in ointments?

A

polyethylene glycol ointment → a popular polymer and hydrophilic because of the oxygens (OH groups)

34
Q

What are pastes as a topical drug delivery platform?

A

ointments into which a high concentration of insoluble particulate solids (starch, calcium carbonate, talc) are added

35
Q

What are creams as a topical drug delivery platform?

A

O/W or W/O emulsion

36
Q

What are gels as a topical drug delivery platform?

A
  1. usually hydrogels such as hand sanitizer
  2. liquid phase trapped in matrix of a natural or synthetic polymer (tragacanth, pectin, carrageenan, methylcellulose, carboxymethylcellulose, carbopol)
  3. example: topical scalp gels (not too greasy)
37
Q

What are rigid foams as a topical drug delivery platform?

A
  1. like an emulsion but liquid phase is gas
  2. air or other gas emulsified in a liquid phase (like whipped cream)
  3. liquid phase may contain a drug
  4. aerosol shaving creams, medicated quick breaking antiseptic foams
38
Q

What are some things to know about transdermal drug delivery?

A
  1. some drugs can penetrate the skin and enter systemic circulation by going to subcutaneous area where there is access to blood vessels/systemic circulation
  2. of particular interest for drugs that have a systemic short half life, undergo extensive first pass metabolism, thus, requiring frequent dosing
39
Q

When should a transdermal patch be considered?

A

if the drug has a short half life and undergoes first pass metabolism

40
Q

What kinds of drugs are delivered trasndermally?

A
  1. small drugs → no more than 400 daltons

2. lipid soluble drugs → have to got through lipid bilayer

40
Q

What kinds of drugs are delivered trasndermally?

A
  1. small drugs → no more than 400 daltons

2. lipid soluble drugs → have to got through lipid bilayer

41
Q

What are the typical layers found in a transdermal patch?

A
  1. backing membrane → most outermost layer
  2. drug reservoir
  3. rate controlling microporous membrane → controls drug permeation
  4. skin contact adhesive → attach patch to skin
42
Q

What are some other things to know about transdermal drug delivery?

A
  1. generally impenetrable → principle resistance is stratum corneum
  2. permeability correlates with drug’s MW and Ko/w
  3. useful for drugs with high skin permeability and low dose requirement
43
Q

What is the equation that correlates permeability with drug’s MW and Ko/w?

A

log P = -2.7 + 0.71logKo/w - 0.0061M

where P is permeability coefficient (how well drug permeates), M is MW (under 1000 daltons since the heavier, more difficult to deliver by skin), and Ko/w which is the oil/water partition coefficient (high K value, more hydrophobic since it wants to partition more in oil)

44
Q

What types of drugs are not good candidates for transdermal delivery?

A

large drugs and drugs with low potency (smaller area is used not the whole body)

45
Q

Most transdermal patches are what type?

A

membrane modulated

46
Q

What happens if the patch is cut?

A

drug comes out all at once since the drug reservoir is destroyed

47
Q

With the drug + adhesive layer, how is the dose released?

A

dose delivered is related to the size of the patch

48
Q

What are some typical active ingredients in transdermal patches?

A

clonidine, ethinyl oestradiol, norelgestromin, lidocaine, epinephrine, nicotine, nitroglycerin, 17beta-estradiol, oxybutin, scopolamine, testosterone

49
Q

What are the different types of transdermal patches?

A

membrane modulated (all 4 layers), adhesive dispersion (3 layers), and matrix dispersion (2 layers)

50
Q

What drugs are typically bad for transdermal delivery?

A

big and hydrophilic drugs (like proteins)

51
Q

Can growth hormone be delivered transdermally?

A

no → it is a protein so it has a hard time to be delivered transdermally

52
Q

How do the following drugs enter by skin? (nicotine, clonidine, nitroglycerin, estradiol, scopolamine, fentanyl)

A

nicotine: due to small MW
clonidine: due to small MW
nitroglycerin: due to small MW
estradiol: due to lipophilicity (larger Ko/w)
scopolamine: ???
fentanyl: due to lipophilicity (larger Ko/w)

53
Q

What are some things to know about transdermal nitroglycerin?

A
  1. MW is 227.09 daltons so enters the skin via small MW
  2. half life is 3 minutes
  3. slightly soluble in water, soluble in common organic solvents
  4. indication: prevention of angina pectoris (chest pain) due to coronary artery disease, not used for immediate relief of acute attacks
  5. patch contains 5 layers: backing, drug reservoir, semipermeable membrane, adhesive, and protective peel strip
54
Q

If you need fast drug action, is transdermal route the way to go?

A

NO → by mouth via lingual or sublingual is better

55
Q

What are some things to know about transdermal rivastigmine?

A
  1. Exelon patch by Novartis
  2. approved by FDA in 2007
  3. indicated for memory problems (dementia) associated with Alzheimer’s disease or Parkinson’s disease
  4. 4.6 mg/24h, 9.5 mg/24h, 13.3 mg/24h → have to replace patch everyday in which a total daily dose of less than 6 mg is 4.6 mg/24h and a total daily dose of 6-12 mg is 9.5 mg/24h
  5. patch has 4 layers → backing film, drug product (acrylic matrix) → serves as reservoir as the drug and polymer are mixed together and the polymer controls drug release, adhesive (silicone matrix), release liner
  6. MW of 250.34 daltons so it is relatively small
  7. sparingly soluble in water, very soluble in ethanol, acetonitrile, n-octanol, ethyl acetate
    8.
56
Q

Is the nitroglycerin patch or the rivastigmine patch better to be cut?

A

rivastigmine since the polymer controls the drug release compared to the nitroglycerin patch that has a drug reservoir and if it is cut, all drug will be released

57
Q

What are some things to know about transdermal contraceptives?

A
  1. Ortho Evra by Janssen was discontinued in 2014
  2. Xulane by Mylan
  3. 150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol
  4. matrix types transdermal system → 3 layers in which backing layer is the polymer layer for structural support, middle layer is the adhesive and matrix and active ingredients (rate controlling layer), and third layer is the release liner
  5. once a week for 3 weeks
  6. apply to outer arm, abdomen, buttock, or back but rotate site to get consistent drug delivery!
58
Q

What are some comparisons to using the patch instead of the pill for contraceptive purposes?

A
  1. patch has a higher risk of venous thromboembolism
  2. patch has higher steady state concentrations and lower peak concentration in addition to higher AUC and Css,ave compared to the pill
  3. pharmacokinetics (Cmax, AUC, Tmax) is different for the patch than the pill → more bioavailability with the patch so there is more side effects associated with the patch
59
Q

What are the different drug diffusion mechanisms through the skin?

A

protein rich cells (bricks) are separated by thin layer of intercellular lipids (mortar)

  1. across the cellular intercellular regions in series (across cells and in between cells)
  2. across the lipid intercellular spaces (in between cells)
  3. across thin lipid layers sandwiched between flattened protein cells (across cells)
60
Q

Most drugs choose what method to get through the skin?

A

in between the cells in the lipid layer

61
Q

What are the different factors affecting permeability?

A
  1. hydration → the more hydrated, the greater the drug permeability since the water associated with polar head groups of lipid bilayer loosens the lipid packing and make the bilayer more fluid
  2. solubility of drug in stratum corneum → lipophilic drugs penetrate better
  3. excipients → solvents and surfactants can affect the structure of the skin
  4. pH → affects drug ionization status
62
Q

What are the different methods to enhance penetration?

A
  1. chemical enhancer
  2. low voltage electrical enhancement (iontophoresis)
  3. ultrasound
  4. high voltage electrical enhancement (electroporation)
  5. microneedles and thermal poration
63
Q

What is iontophoresis?

A

uses low voltage electrical current to drive charged drugs through the skin → temporarily drives charged drug through the skin

64
Q

What is electroporation?

A
  1. uses high voltage (short) to create transient pores in the skin → physically opens up skin to create a pore (not permanent)
  2. early stage but very good
65
Q

What is ultrasound?

A

uses low frequency ultrasonic energy to disrupt the stratum corneum → disrupts skin structure to temporarily open up window for drug to go through

66
Q

What are (chemical) penetration enhancers?

A

disrupts the skin chemically so drug can penetrate better → if you keep a transdermal patch at the same site, more drug will go in than originally designed → why you should rotate sites!

examples include alcohol, DMSO, surfactants, acetone, ethyl acetate

67
Q

What are prodrugs?

A

make lipophilic/hydrophobic

68
Q

What are the four main enhancers?

A
  1. ionic surfactants
  2. ascorbate, dithiothreitol
  3. azone
  4. dimethyl sulfoxide (DMSO)
69
Q

What is the mechanism of ionic surfactants?

A

disorder the lipid layer of stratum corneum to swell and/or leach out some of the structural components, thus reducing the diffusional resistance

70
Q

What is the mechanism of ascorbate and dithiothreitol?

A

reducing agents that disrupt disulfide bonds of proteins in keratinized cells → affect the protein structure to loosen skin structure

71
Q

What is the mechanism of azone?

A

nonpolar, oily liquid that fluidizes intracellular lipid lamella region of the stratum corneum

72
Q

What is the mechanism of dimethyl sulfoxide (DMSO)?

A

dipolar solvent that enters the aqueous region of stratum corneum and interacts with the lipid polar heads to expand hydrophilic region between the polar heads

73
Q

What do both azone and DMSO do to the lipid bilayer?

A

they both loosen up the lipid bilayer but do so in different ways

74
Q

How does azone loosen up the lipid bilayer?

A

goes into the carbon chain of the hydrophobic tails and loosens up the bilayer

75
Q

How does DMSO loosen the lipid bilayer?

A

interchelates into the lipid bilayer and gets in between the polar head groups to open up the lipid bilayer’s packing

76
Q

What are microneedles?

A

tiny needles that are typically painless and creates a pore

77
Q

What are some things to know about microneedles?

A
  1. pretreatment to increase skin permeability before the subsequent application of a drug loaded patch → poke with patch in which it makes pores with needles then the drug is applied with the patch
  2. coated with the drug that is released from the needles while they are embedded in the skin → coat and poke in which the needles are coated with the drug and then is poked into the skin
  3. hollow microneedles have also been fabricated and used to flow drug solutions into the skin → drug is poured on top of the hollow microneedles
78
Q

What are the typical size of microneedles?

A

can range from 150 micrometers tall to 1000 micrometers tall → but still so much smaller than a regular sized needle

79
Q

What is an example of drug delivery via microneedles?

A

the drug is contained within the needle (fluorescent dye is used to visualize) and the needle is made from PVP polymer → as the polymer is dissolving, the drug is also dissolving into the skin

80
Q

What are some common errors in transdermal patch administration?

A
  1. preparation → removal of the patch from the packaging, removal of the protective foil, alternation of the patch
  2. removal
  3. application
  4. monitoring → influence of heat, patch displacement
  5. storage and disposal
81
Q

What are some things that patients don’t realize with transdermal patches?

A
  1. patch must be applied directly to the skin (should not tape a patch on top of the other)
  2. they must remove the protective liner
  3. they need to use one patch at a time
  4. where to place (know the recommended locations and to rotate the area of application to avoid skin irritation)
  5. when to change
  6. transparent patches (not good)
  7. TTS: transdermal therapeutic system vs Tuesday, Thursday, and Saturday
  8. pediatric patch issue: some patches should NOT be cut

Dosage Forms II (20 decks)

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