A randomized, double-blind, double-dummy, placebo-controlled, 3-way crossover proof of concept study of intradermally administered desmopressin in healthy volunteers using a nanoporous microneedle array.

Peptides are selective and efficacious signaling molecules that bind to
specific cell surface receptors (Fosgerau & Hoffmann, 2015). However, the
therapeutic application of peptides has been restricted by their
physicochemical properties, such as a higher molecular weight and
hydrophilicity, which result in low bioavailability, poor transfer across
biological membranes, and a short plasma half-life. Peptide therapeutics are
currently most commonly administered via parenteral routes, i.e., injections or
intravenous infusions (Antosova, Mackova, Kral & Macek, 2009). These modes of
administration are both painful and costly and may lead to poor patient
compliance. Thus, there is a need for alternative administration routes for
therapeutic peptides.

MyLife Technologies (MLT) has developed a round nanoporous microneedle array
(npMNA), comprising of 170 microneedles per cm2. The diameter of the array is
15 mm and the length of the microneedles is 475 µm. The npMNA is made of a
ceramic (bio-inert) material and has a porosity of approximately 30%. The npMNA
consists of approximately 300 microneedles on a backplate, both equally
nanoporous, which allow for loading a liquid drug formulation of approximately
55 µL. An applicator is used to apply the npMNAs by pressing the tiny
microneedles through the stratum corneum into the viable epidermis and dermis.
After application the npMNA will remain in place by using dermal tape and a
strap for 8 hours, allowing for drug diffusion from the npMNAs into the skin.
In vivo and ex vivo experiments have shown that both antibodies and vaccines
can be successfully delivered to skin via the npMNAs (Boks, Unger, Engels,
Ambrosini, Kooyk & Luttge, 2015; de Groot et al., 2017; Verhoeven et al., 2012).

Desmopressin is a synthetic analog of the naturally occurring antidiuretic
hormone vasopressin. As such, it is used in the treatment of polyuric
conditions such as central diabetes insipidus and nocturnal enuresis.
Desmopressin is, in selected cases, also used for prophylaxis and treatment of
bleeding for patients with prolonged bleeding time, patients with mild
hemophilia A, and patients with Von Willebrand disease
(Farmacotherapeutischkompas). Desmopressin is available in different
formulations (intravenous (IV), intramuscular, oral, nasal) which are all
generally well tolerated (Vande Walle, Stockner, Raes & Norgaard, 2007).
However, the non-parenteral formulations have a low and variable
bioavailability (Fjellestad-Paulsen, Hoglund, Lundin & Paulsen, 1993).

1) To evaluate the safety and tolerability of MLT*s npMNAs
2) To evaluate the pharmacokinetics of intradermal desmopressin administration
via MLT*s npMNAs

This study is a phase 1, randomized, double-dummy, placebo-controlled,
single-blind, proof-of-concept design to evaluate the safety, tolerability and
pharmacokinetics of intradermal application of desmopressin via MLT*s npMNA in
healthy volunteers. A 3-way crossover design will be applied.

The treatments are IV 4 *g (arm 1) plus placebo via a npMNA (arm 2), 8 *g via a
npMNA (arm 1) plus IV placebo (arm 2) and 16 *g via a npMNA (arm 1) plus IV
placebo (arm 2). The washout period between the treatment periods will be 7 -
14 days.

Desmopressin (dilution of the nasal spray formulation) will be administered
intradermally

Since at this stage of the development only a single dose administration will
be investigated and the doses of the active compound, i.e. desmopressin
acetate, are identical compared to the current standard of care, the risks for
unexpected side effects are considered to be low. Also, for the formulation
excipients no precautions are required since these are safe and generally
applied in commercial products.
The microneedle array itself does not pose a significant safety risk for the
clinical trial, a complete *Failure Mode & Effect Analyses* for the complete
system was finalized on june-2017 and is on request available.
Allergic reactions as well as pain sensation or irritations are not expected
from the npMNAs due to the relatively low insertion depth of the npMNAs into
the skin (325*m), absence of free raw materials or degradation products
inherent to the material used in the npMNA production process (due to the
sintering), as well as the passive drug administration (diffusion based).
However, pain sensation, irritations or allergic reactions due to the
physicochemical properties of the type of drug administered by means of the
npMNAs cannot be ruled out.
Infections as a result of bacteria residing inside the microneedle arrays are
ruled out due to the high temperatures used during production of the arrays and
the relatively small pore sizes of the material that will prevent bacteria from
entering back into the npMNAs once sintered.
The risk of infection as a result of introduction of pathogens from the surface
area of the microneedle array into the skin are eliminated due to sterilisation
of the npMNAs prior to use and disinfection of the skin prior to application of
the npMNA. The drug formulation and the dilutions contain benzalkonium chloride
and are made fresh, and due to the low bioburden there is limited risk for
microbial contamination.
The npMNA from full solid Aluminum ceramic material is not expected to pose a
health risk as:
- It has a high biocompatibility (proven use in many implant solutions e.g.,
dental implants or joint implants without adverse effects),
- It is not biodegradable and is chemically a very stable and inert material.
- The microneedles have a limited penetration depth (limited invasiveness) into
the skin
- Has a relatively limited surface exposure to the body and has a relatively
short contact period with the body (max. 8 hours).
- The probability of unsintered nanoparticles introduced in the body is very
small. Even when introduced accidentally into the body, the absolute amount
(sub microgram level)
It is assumed to be unlikely that needles would break in the skin. However, in
case a needle breaks in the skin, the needle is too large (~100 *m range) for
uptake by the Langerhans cells and therefore it is unlikely that they will be
transported through the body and cause severe irritation. It is expected that
the needle can be detected visually and can be taken from the skin with
tweezers.