MICRONEEDLE-BASED DRUG DELIVERY

SYSTEMS

Le Ngoc Duy
Lab of Applied Nanomedicine-
Yeungnam University
 Contents
 Introduction:
- Routes of Drug Administration
- Microneedle system
• Mechanism of microneedle
• Classification of Microneedles - Microneedle Production

 Applications of microneedle

• Vaccine delivery • Cancer therapy • Insullin delivery • Cell therapy

• Non-dermal applications of microneedle drug delivery systems

 Summary and future perspectives

 Introduction
 Routes of Drug Administration

Fig 1. The overall distribution of administration route of FDA-approval

pharmaceutical products.

Pharmaceutics, 2018, doi:10.3390/pharmaceutics10040263

 Introduction

Microneedles
 Microneedles (MNs) are micron-scaled needles measuring
100 to 1000 μm that were initially explored for delivery of
therapeutic agents across the skin

 The concept of miniature needles for drug delivery came

about in the 1960s, and it was patented by Alza Corporation
in 1971

 MNs represent solid or hollow tubes with a length of 50–

900 μm, less than 300 μm in diameter, of various shapes,
sizes, and densities per unit area of supporting or
adhesive membrane surface.

Fig2. Skin structure with a microneedle patch

Micromachines, 2020, Doi: 10.3390/mi11110961

 Introduction

 How MNs deliver drugs through the skin?

 MNs create a physical path of micron dimensions through

the upper layers of the epidermis, without reaching the
nerve endings (nociceptors) in the dermis.

 The drug is directly placed in the epidermis or upper dermis

layer which then goes into the systemic circulation and
shows a therapeutic response on reaching the site of action:

(1) Microneedle device with drug solution

(2) Device inserted into the skin
(3) Temporary mechanical disruption of the skin
Fig2. Skin structure with a microneedle patch
(4) Releasing the drug in the epidermis
(5) Transport of drug to the site of action
Micromachines, 2020, Doi: 10.3390/mi11110961
Patent Landscape 2020

https://www.knowmade.com/downloads/microneedles-for-drug-delivery-patent-landscape/
 Why microneedles over other methods?

 The delivery of right quantity of specified drug at the correct place at the right time is of utmost importance

The parenteral route:

 The fastest, direct and most reliable mode for drug delivery

 Lower bioavailability at targeted site, accumulation of drug in

undesired surrounding organs, rapid clearance from the blood,

Buccal or oral route

• Buccal or oral route administration is bound to undergo

degradation by the mucosal enzyme of the gut environment

Journal of Controlled Release, 2021, Doi:10.1016/j.jconrel.2021.08.054

 Why microneedles over other methods?

 The delivery of right quantity of specified drug at the correct place at the right time is of utmost importance

Transdermal drug delivery

Minimally invasive and easy to use, has very slow onset times
and low bioavailability

Microneedle DDS

 The idea of MNs was then proposed and brought in use as novel
drug vehicles for the first time in around 1970s

 MNs: simple, easy to administer, non-invasive with faster

healing action → as alternatives to hypodermic needles for
controlled, localized, safe and painless delivery in the dermal
and subcutaneous layers of not only vaccine but also drug and
gene
Journal of Controlled Release, 2021, Doi:10.1016/j.jconrel.2021.08.054
 Why microneedles over other methods?

Hypodermic needles Microneedles

Pain Painful Painless; faster healing at site of

application compared to
hypodermic needles
Patient compliance Poor Highly compliant
Administration Requires trained personnel for Could be self-administered
administration
 Microneedle systems

 Classification of Microneedles

Journal of Controlled Release, 2021, Doi:10.1016/j.jconrel.2021.08.054

 Microneedle Production
Materials

 The criteria for selecting material for microneedle

 Gentle manufacturing without damaging

sensitive and unstable molecules.

 Controlled or immediate drug release.

 Sufficient mechanical strength for skin

penetration.
 Microneedle Production

Microelectromechanical Systems (MEMS)

Laser Cutting

Droplet-Born Air Blowing Method (DAB)

 Microneedle Production

Micromolding Method
Atomized Spraying Method

3D printing
 Applications of microneedle

 All of the applications, except the cosmetic applications (e.g., Dermaroller®), are in the experimental phase

Cell therapy

Microsystems & nanoengineering, 2021, Doi: 10.1038/s41378-021-00298-3

 Applications of microneedle

MN patch

Hollow MN
Microneedle radiofrequency

Microneedle therapy system

Fig. Number of clinical studies included by diseases or microneedles types (2020).

Pharmaceutics 2020, Doi:10.3390/pharmaceutics12111113

 Applications of microneedle
 Vaccine

 The skin is a multifunctional organ that constitutes the first line of host defense against external stressors

 A tightly regulated immune network within

the skin microenvironment:

 High density of professional antigen-

presenting cells (APCs) and immune-
accessory cells

 Develop effective skin-targeted vaccines

based on localized immune engineering

Figure: The skin as an immune-responsive organ

Advanced Drug Delivery Reviews, 2021, Doi:10.1016/j.addr.2021.01.022

 Applications of microneedle
 Vaccine

 Macromolecule antigens and adjuvants applied to the skin

topically or via traditional transdermal patches are
typically unable to penetrate the stratum corneum.

 Injections with conventional hypodermic needles: delivery

into the skin microenvironment is inconsistent, painful
and less suitable for global vaccination programs (the need
for medical expertise for proper administration, supply chain challenges,
and non-compliance due to trypanophobia and inconvenience)

Microneedles are a rapidly emerging technology platform for convenient, painless, and
controlled vaccine delivery to the skin
Advanced Drug Delivery Reviews, 2021, Doi:10.1016/j.addr.2021.01.022
 Applications of microneedle
 Microneedle Patch to Protect and Deliver DNA Nanovaccines Against COVID-19

Intramuscular
Without adjuvant
Intramuscular
Microneedle
Without adjuvant
Microneedle

In vivo cellular immune responses Production level of anti-S

protein IgG in serum

 Compared with intramuscular injection, SMN patch can deliver nanovaccines into intradermal for inducing potent and
durable adaptive immunity
 The storage at room temperature has no effects on the immunogenicity of SMN-DLP-RS

ACS Nano, 2021, Doi: 10.1021/acsnano.1c03252

 Applications of microneedle
 Anticancer therapeutic

 Microneedles for cancer therapy  Microneedles for the cancer immunotherapy

 Chemotherapy  Antigen vaccine

 Photothermal therapy (PTT) and  Gene vaccine

photodynamic therapy (PDT)

 Gene therapy (siRNA)  Antibody

 Cytokines

Biomaterials, 2021, Doi: 10.1016/j.biomaterials.2020.120410

 Applications of microneedle

 Microneedles for cancer therapy

• Microneedle for breast cancer therapy

which can be targeted by positioning the MNs on the surface
• Microneedles for skin cancer therapy

• Microneedles for prostate cancer therapy

• Microneedles for cervical cancer therapy

• Microneedles for oral cancer therapy

Journal of Controlled Release, 2021, Doi:10.1016/j.jconrel.2021.08.054

 Applications of microneedle
 Anticancer treatment

 Microneedle-Mediated Delivery of Lipid-Coated Cisplatin Nanoparticles

 Cisplatin is the first-line chemotherapeutic agent, but its systemic

toxicity and side effects severely limit its clinical use

 Cisplatin was encapsulated by tumor-targeting pH-responsive lipid

nanoparticles (LCC-NP)

 microneedle arrays loaded with cisplatin nanoparticles significantly

increased cytotoxicity and apoptosis in cancer cells with an
apoptotic index of 58.6%

 serum platinum, pulmonary toxicity, hepatotoxicity, and

nephrotoxicity were not detected in vivo

ACS Appl. Mater. Interfaces, 2018, Doi:10.1021/acsami.8b12926

 Applications of microneedle

 Microneedle System for Treating Superficial Tumors by Combination of Chemotherapy and Photothermal Therapy
 a light-activatable microneedle (MN) system that can repeatedly and simultaneously provide photothermal therapy
and chemotherapy to superficial tumors and exert synergistic anticancer effects

ACS Nano, 2016, https://doi.org/10.1021/acsnano.5b05043

 Applications of microneedle
 Microneedles for the cancer immunotherapy
 Antigen vaccine

Schematic representation of the B16F10 vaccine

tumor mode and efficacy of MNs vaccine

 MNs were prepared using silicone molds (hyaluronic acid–based MNs)- encapsulate the whole tumor lysate
(with melanin) and adjuvants

SCIENCE IMMUNOLOGY, 2017, DOI: 10.1126/sciimmunol.aan5692

 Applications of microneedle
 Microneedles for the cancer immunotherapy
 Gene vaccine: microneedle arrays decorated with ultra-pH responsive copolymers for cancer immunotherapy

 Upon skin implantation, the ultra-sharp-pH-responsive

OSM-(PEG-PAEU) transformed to anionic copolymers, and
could trigger the DNA vaccine and poly(I:C) release, owing
to electrostatic repulsion

OSM-(PEG-PAEU)
Biomaterials, 2018, Doi:10.1016/j.biomaterials.2018.09.008
  Cell therapies for the treatment of skin disorders:

 Genetically modified epidermal stem cells can be

transplanted to regenerate the skin in patients
with epidermolysis bullosa

 Melanocytes can be transplanted to treat vitiligo

 Dendritic cell (DC)-based immunotherapy: a safe

treatment for melanoma

Fig. : Schematic illustration of the transdermal delivery of cells using cryoMNs.

Nature biomedical engineering, 2021, Doi: 10.1038 / s41551-021-00720-1

 Vaccination by cryoMNs carrying antigen-loaded DCs

 The microneedles are fabricated by stepwise cryogenic micromoulding of

cryogenic medium with pre-suspended cells, and can be easily inserted
into porcine skin and dissolve after deployment of the cells

 The delivery of ovalbumin-pulsed dendritic cells via the cryomicroneedles

elicited higher antigen-specific immune responses and led to slower
tumor growth than intravenous and subcutaneous injections of the cells
Nature biomedical engineering, 2021, Doi: 10.1038 / s41551-021-00720-1
Non-Dermal applications of microneedle drug delivery systems

Drug Delivery and Translational Research, 2021, Doi:10.1007/s13346-021-00922-9

 Non-Dermal applications of microneedle drug delivery systems
 Capsule-based microneedle devices

 Luminal Unfolding Microneedle Injector (LUMI) design.

LUMI devices were ingested in waterproof enteric capsules

 Orally dosed device which physically inserts drug loaded

microneedles into the small intestine and bypasses the
need for diffusion into the tissue wall

Nature Medicin, 2019, Doi: 10.1038 / s41591-019-0598-9 Platform technology to orally deliver therapeutic doses of macromolecule drugs
 Non-Dermal applications of microneedle drug delivery systems

Nature Medicin, 2019, Doi: 10.1038 / s41591-019-0598-9 Platform technology to orally deliver therapeutic doses of macromolecule drugs
 Non-Dermal applications of microneedle drug delivery systems

Limitations

 Low dosing sizes : A single patch 1 cm2 held up to 0.6 mg in the tips
alone

 Require gastrointestinal fluid, filled with degradative enzymes, to

interact with the drug formulation for a short period of time before
tissue wall injection

 LUMI device relied on gastric emptying to move from the stomach to

the small intestine. But Gastric emptying times can vary significantly
in the population.

 Hypoglycemic onset for insulin delivered via the small intestine

occurred more quickly than subcutaneous dosing, but this did not
factor into account the time necessary for the device to reach the
duodenum
Nature Medicin, 2019, Doi: 10.1038 / s41591-019-0598-9
 Non-Dermal applications of microneedle drug delivery systems
 Oral delivery of monoclonal antibodies, peptides and small molecule drugs

Mw of drugs delivered using L-SOMA

LD up to 4 mg of bioavailable drug

Unaffected by gastric emptying time

L-SOMA: oral pill for liquid drug injections into the gastric submucosa
Nat Biotechnol, 2021, Doi: 10.1038/s41587-021-01024-0
 Non-Dermal applications of microneedle drug delivery systems

Blood plasma glucose levels after dosing an L-SOMA capsule Blood plasma glucose levels after subcutaneously
loading human insulin inject recombinant human insulin

Unaffected by gastric emptying time

Nat Biotechnol, 2021, Doi: 10.1038/s41587-021-01024-0
 Summary and future perspectives

Advantages of microneedle Before making the next research

 MNs: simple, easy to administer, non-  The manufacturing process and the financial cost involved
in scaling
invasive with faster healing action → as
alternatives to hypodermic needles for
 The potential risk of allergic response
controlled, localized, safe and painless
delivery in the dermal, subcutaneous
 Consider the biocompatibility of the MNs
layers and mucosa of not only vaccine but
also drug and gene
 Focus should be shifted to metastatic cancers instead of
superficial cancer

 How to activate the immune cells beneath the skin (e.g.,

DCs, at a maximum extent)
Thank you for your attention!