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Flashcards in 3.) Microneedles Deck (22)
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What are the advantages of microneedle drug delivery (compared to conventional hypodermic needles used IM/SC)?

- Painless
- Ease of use by patients
- Safe needle disposal (no need for sharps)
- Eliminate spread of pathogens due to re-use of needles (decreasing HIV/Hep related incidents)
- Good for drugs unsuitable for PO delivery due to poor PK


How do microneedles achieve painless delivery of drugs?

- MNs penentrate the stratum corneum (top layer of the epidermis) and into the viable epidermis
- Thus avoiding contact with nerve fibres and blood vessels residing in the Dermis (dermal layer)
>>> Avoid nerves = avoid pain


What are the PK benefits associated with MNs?

- Higher bioavailability (avoid first-pass)
- Faster absorption
>>> Higher peak serum levels achieved compared with hypodermic needles, whilst also achieved earlier than S/C


What are the main types of MNs?

- Solid MNs (silicon or polymer)
- Hollow MNs


Describe the fabrication method of silicon solid MNs.

Via photolithography:
- Silicon wafer base material is coated with silicon dioxide and silicon nitride (oxide + nitride deposition)
- Photoresist layer is spun on top of nitride layer
- UV exposure w/photomask - which blocks UV light exposure to specific areas of the photoresist layer
- Excess (areas exposed to UV) are washed away with developer
- Oxide and nitride layers are removed with Reactive Ion Etching (RIE - bombard of high energy ions remove layers exposed to UV)
- Photoresist layer is then removed with another chemical/developer
- Potassium hydroxide (KOH) used for etching, removing silicon away from silicon substrate
>>> Resultant solid MN array


Why were the first MNs manufactured years after the first patent was filed?

- 1976 patent OG
- Lack of manufacturing tools
- First paper demonstrating successful MNs in 1998
>>> Photolithography (technique used in semi-conductors in microelectronics, circuit boards etc.) was the breakthrough to allow microfabrication


How does the fabrication process for polymer solid MNs differ from silicon solid MNs?

- Photolithography initial steps almost identical (though only one oxide layer instead of two)
- Once etching has been completed to leave silicon mould, an additional MICRO MOULDING process is carried out:
1) Omnicoat: spun on to separate polymer from silicon after moulding
2) UV curable polymer melt/moltenmonomer is spun on (poured into mould)
3) Cure with UV: solidifying monomer/polymer, similarly using photomask to choose areas to cure
4) Excess monomer/polymer removed (areas not exposed to UV), separate polymer MN mould from silicon


What are the two different methods of fabricating hollow MNs?

- Reactive Ion Etching (RIE)
- Sacrificial micromoulding + selective electrodeposition


How is RIE used to fabricate hollow MNs?

- Silicon wafer raw starting material
- RIE targeted down middle to create tunnel - forming tube-like structure
- Less intense RIE used to then etch away excess on sides of tunnel, forming thin walled, hollow MN


Describe how sacrificial micromoulding + selective electrodeposition are used to fabricate hollow MNs?

1) Fabrication of master structure with a laser ablated cavity (makes tiny slot)
2) Use master structure to form micromould (w/protruding pillar that will form lumen exit hole)
3) Make replica using micromould (pour raw material into micromould)
4) Sputtering of gold seed layer onto the replica
5) Electrodeposition of metal everywhere except cavity, followed by dissolving of sacrificial base material to release metal hollow MN


What are the 4 major delivery modes using MNs?

1) Solid MNs
2) Drug coated MNs
3) Drug encapsulated MNs
4) Hollow MNs for drug delivery through lumen/bore


Describe how drug delivery is achieved with Solid MNs.

Effectively a pre-treatment of skin, followed by patch:
- MN is applied to skin, and removed to form micron-scale pores in skin surface (increase diffusion of drug)
- Patch/other drug formulation then applied to the skin for slow diffusion of drug through pores and into the body


What materials are used to make Solid MNs? (skin pre-treatment)

- Silicon
- Metal
- Polymer
- Ceramic


Describe how drug delivery is achieved with Drug coated MNs.

Still a solid MN, but one that is coated with a thin layer on its surface as a carrier to load drugs (e.g. poison coated dart vibes)
- MN is applied/inserted as before, but then is kept applied for specific duration of time
- Drug dissolution in water of skin


What are the 5 considerations for the processes of coating drugs onto MNs?

Dipping/spraying are the most common methods, with the following considerations:
1) Controlled wetting and spreading of drug solution on MNs (homologous layer)
2) Drug should be water-soluble for skin dissolution
3) Adhesion between dried drug coating and MN should be enough during insertion into skin
4) Coating excipients and solvents should be safe
5) Coating process is compatible with drug (to no degrade/damage the drug e.g. high temp, UV exposure)


Describe how drug delivery is achieved with Drug encapsulated MNs. Differences to Drug coated MNs?

Drugs are inside MN, not on just on the surface as with drug coated MNs:
- Allowing greater amount of drug to be delivered
- MN dissolves to yield drug


What materials are used to make Drug encapsulated MNs, and what does it depend on?

Desired PK profile (immediate release, MR):

Rapid dissolving:
- Water-soluble sugars and polymers (dextran, polyvinylpyrrolidone)
- Photopolymerisable liquid monomers (methacrylic acid)

Slow dissolving:
- Biodegradable polymers (PLGA - day/week profile)


What considerations are there with regards to the design of Drug encapsulated MNs?

Two main considerations:
- Thermo-sensitive compounds such as proteins should be encapsulated at moderate conditions (too hot = degradation/denaturing)
- Speed of dissolution of MNs dictates time/duration MN needs to be inserted into skin
>>> E.g. can remove rapid-dissolving MN patch more quickly than slow dissolving MN patch


Describe how drug delivery is achieved with Hollow MNs.

Hollow MNs can facilitate drug delivery in two ways: via infusion of liquid drug formulation (3-component process), or via diffusion into skin via needle bore/lumen.


What are the advantages associated with Hollow MNs for drug delivery?

- Enables greater control over the amount and timing of drug delivery (external pump controlling infusion rate of drug)
- Separation of MNs from drug during manufacturing (potentially cheaper, only applicable to 3-component model)


What are the disadvantages associated with Hollow MNs for drug delivery?

- System is more complex: requires three components, drug reservoir, pump and the associated intricate microfluidic networks
- Potentially more expensive (not outweighing cost saving of separation of MN vehicle to drug reservoir?)


What considerations are there in the design and manufacture of Hollow MNs?

- Hollow MNs must have enough mechanical strength to withstand insertion (must not bend/collapse - applicable to all MNs)
- Leak-free infusion into skin and coupling to a drug reservoir: can not leave gap between MN and skin or would yield drug wastage