Review For Nasal Drug Delivery of Poorly Soluble Drugs

pharmaceutics
Review
Strategies to Improve Drug Strength in Nasal Preparations for
Brain Delivery of Low Aqueous Solubility Drugs
Patrícia C. Pires 1,2, *, Márcio Rodrigues 2,3,4 , Gilberto Alves 2,3 and Adriana O. Santos 2,3, *
1 Faculty of Pharmacy (FFUC-UC), University of Coimbra, Azinhaga de Santa Comba,

3000-548 Coimbra, Portugal
2 Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Avenida Infante D. Henrique,
6200-506 Covilhã, Portugal; [email protected] (M.R.); [email protected] (G.A.)
3 Faculty of Health Sciences (FCS-UBI), University of Beira Interior, Avenida Infante D. Henrique,
6200-506 Covilhã, Portugal
4 Center for Potential and Innovation of Natural Resources, Research Unit for Inland
Development (CPIRN-UDI-IPG), Polytechnic Institute of Guarda, 6300-559 Guarda, Portugal
* Correspondence: [email protected] or [email protected] (P.C.P.); [email protected] (A.O.S.)
Abstract: Intranasal administration is a promising route for brain drug delivery. However, it can be
difficult to formulate drugs that have low water solubility into high strength intranasal solutions.
Hence, the purpose of this work was to review the strategies that have been used to increase drug
strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers
(change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a
carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs).

The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to
Citation: Pires, P.C.; Rodrigues, M.;
local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many)
Alves, G.; Santos, A.O. Strategies to
different carrier nanosystems, on the other hand, could be safer for intranasal administration at
Improve Drug Strength in Nasal
reasonably high concentrations, depending on selected excipients and their dose. While added
Preparations for Brain Delivery of
Low Aqueous Solubility Drugs.
attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could
Pharmaceutics 2022, 14, 588. be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs,
https://doi.org/10.3390/ whether co-administered with a converting enzyme or not, can be used at very high concentrations,
pharmaceutics14030588 and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels.
Nevertheless, the choice of which strategy to use will always depend on the characteristics of the
Academic Editors: Ana
drug and must be a case-by-case approach.
Fernandez-Carballido, Cristina
Martín-Sabroso and Juan
Aparicio-Blanco
Keywords: brain delivery; intranasal; nanosystem; nose-to-brain; prodrug; solubilizer
Received: 20 February 2022

Accepted: 5 March 2022
Published: 8 March 2022 1. Introduction
Publisher’s Note: MDPI stays neutral Intranasal administration is most commonly used for the treatment of local affections,
with regard to jurisdictional claims in such as nasal congestion, rhinitis or sinusitis, symptoms that are generally related to
published maps and institutional affil- allergies or upper respiratory tract infections [1]. Nevertheless, having a large surface area-
iations. to-volume ratio and high vascularization, the nasal cavity is also favorable for systemic
drug absorption and has proven useful for therapeutic systemic effects, having several
potential advantages when compared to other routes [2,3]. One of these advantages is its
non-invasiveness and ease of administration, hence not requiring trained professionals
Copyright: © 2022 by the authors.
or in-hospital setting. This feature, together with potentially fast absorption and onset
Licensee MDPI, Basel, Switzerland.
This article is an open access article
of action, makes intranasal delivery favorable for the management of certain emergency
distributed under the terms and
situations such as acute seizure episodes or opioid overdose [4,5].
conditions of the Creative Commons
Moreover, the intranasal route has proven to be better accepted by adults and ado-
Attribution (CC BY) license (https:// lescents than the rectal route, and it can also be an alternative for patients for whom the
creativecommons.org/licenses/by/ oral and buccal routes are not suitable, such as in conditions associated with vomiting,
4.0/).
Pharmaceutics 2022, 14, 588. https://doi.org/10.3390/pharmaceutics14030588 https://www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2022, 14, 2 of 19
Pharmaceutics 2022, 14, 588 2 of 18
increased salivation, or inability to swallow. It can also offer an escape from the gastroin-
increased
testinal tract’s salivation, or inability and
acidic environment to swallow.
enzymes, It can
andalso
the offer an escape
first-pass hepatic from the gastroin-
metabolism,
testinal
being tract’s acidic
an alternative environment
for drugs with lowand oralenzymes, and the
bioavailability. first-pass
Hence, there hepatic metabolism,
are already many
being anmedicinal
intranasal alternative for drugs
products onwith
the low oralfor
market bioavailability. Hence,namely
systemic delivery, there are foralready many
the treat-
intranasal medicinal products on the market for systemic
ment of menopausal symptoms, endometriosis or migraine headache, among several delivery, namely for the treat-
ment of menopausal
other conditions [1,3]. symptoms, endometriosis or migraine headache, among several other
conditions
The intranasal[1,3]. route is particularly promising for brain drug delivery, since it makes
Thefor
it possible intranasal
drugs toroute
bypassis particularly
the blood–brainpromising
barrier, forwhich
brain has
druglittle
delivery,
to no since it makes it
permeability
possible
to most for drugs
of them, to bypass
and where theof
plenty blood–brain
molecules can barrier, which
undergo has littleactive
extensive to no efflux.
permeability
More- to
most of them, and where plenty of molecules can undergo extensive
over, even in the case of drugs that do cross the blood–brain barrier, it may allow for at active efflux. Moreover,
even
least partinofthethecase
drugof to
drugs that do cross
be transported the blood–brain
directly from the nasal barrier, it may
cavity to theallow
brain,for at least
poten-
part of the drug to be transported directly from the nasal cavity
tially increasing drug bioavailability in the biophase, therefore reducing therapeutic drugto the brain, potentially
increasing
doses drug bioavailability
and minimizing in the biophase,
systemic adverse effects [2].therefore reducing therapeutic drug doses
and minimizing systemic adverse
Direct nose-to-brain drug transport occurs effects [2]. through neuronal transport or passive dif-
Direct from
fusion, either nose-to-brain drug transport
the respiratory or olfactory occurs through
regions (Figureneuronal transport
1) [3,6,7]. From the orolfac-
passive
tory region (smaller surface area), the drugs will reach the brain directly via the olfactorythe
diffusion, either from the respiratory or olfactory regions (Figure 1) [3,6,7]. From
olfactory
nerve pathway. region
From (smaller surface area),
the respiratory regionthe drugs
(larger will area),
surface reach drugs
the brain directly
can either via the
diffuse
directly to the brain via the trigeminal nerve pathway, enter the systemic circulation,either
olfactory nerve pathway. From the respiratory region (larger surface area), drugs can or
diffuse directly to the brain via the trigeminal nerve pathway, enter the systemic circulation,
undergo mucociliary clearance (swallowing). After reaching the systemic circulation, the
or undergo mucociliary clearance (swallowing). After reaching the systemic circulation, the
drugs might still reach the brain indirectly, by crossing the blood–brain barrier (molecules
drugs might still reach the brain indirectly, by crossing the blood–brain barrier (molecules
with a lipophilic nature).
with a lipophilic nature).
Figure 1. Drug
Figure distribution
1. Drug pathways
distribution associated
pathways with
associated intranasal
with administration.
intranasal administration.
Despite
Despite its its numerous
numerous advantages,
advantages, intranasal
intranasal delivery
delivery also
also hashas
its its limitations,
limitations, thethe
most
most important
important being:
being: thethe
factfact
thatthat only
only a low
a low volume
volume cancan
be be administered
administered (maximum
(maximum
150–200
150–200 μLµLin in humans),
humans), therefore
therefore requiring
requiring potent
potent drugs
drugs or or high
high drug
drug strengths;
strengths; a short
a short
residence time in the nasal cavity due to mucociliary clearance, which
residence time in the nasal cavity due to mucociliary clearance, which can limit the time can limit the time
available for drug absorption to occur; enzymatic degradation
available for drug absorption to occur; enzymatic degradation and efflux transporters, and efflux transporters,
which
which could
could likewise
likewise reduce
reduce drug
drug absorption[2,3].
absorption [2,3].Furthermore,
Furthermore,ititisisalso
alsovery
veryimportant
important to
carefully consider formulation aspects, since none of the formulation’s
to carefully consider formulation aspects, since none of the formulation’s components components should
be irritant
should to thetonasal
be irritant mucosa,
the nasal its pH
mucosa, itsshould be similar
pH should to the
be similar tonasal mucosa’s
the nasal mucosa’s(5.0 to
(5.06.5),
and it should be isotonic to slightly hypertonic, all in order to avoid
to 6.5), and it should be isotonic to slightly hypertonic, all in order to avoid causing sen-causing sensations
of discomfort
sations or toxicity
of discomfort in the nasal
or toxicity in theepithelium and/or and/or
nasal epithelium enhanced mucociliary
enhanced clearance.
mucociliary
Moreover, preparation’s viscosity and/or bioadhesiveness should
clearance. Moreover, preparation’s viscosity and/or bioadhesiveness should be carefully be carefully considered,
since a high
considered, viscosity/adhesiveness
since can increase
a high viscosity/adhesiveness cancontact
increasetime with the
contact timenasal
withmucosa,
the nasalbut if
the viscosity is too high the drug diffusion from the formulation might
mucosa, but if the viscosity is too high the drug diffusion from the formulation might be be reduced, which
can lead
reduced, to decreased
which can lead absorption
to decreased [1,2,8].
absorption [1,2,8].
Independently of the administration route, it is difficult to formulate drugs that
have low water solubility at high strength without having to use substantial amounts of
cosolvents or surfactants, which are potentially toxic excipients. This is an even bigger
problem in intranasal delivery, since the drug has to be administered in a small volume, as
mentioned before, and thus even higher drug strengths are required [2,3].
Hence, the purpose of this work was to review the strategies that have been used to
increase drug solubility/strength in formulations intended to be administered intranasally,
to treat central nervous system disorders.
2. Overview of Intranasal Formulation Strategies for Drugs with Low

Aqueous Solubility
Drugs could be intranasally administered simply in the form of dry powders, but the
slow dissolution of poorly water-soluble drugs will be a clear limiting factor. The dissolu-
tion limitation is the same with liquid suspensions, which are perhaps the most common
nasal liquid preparations for drugs with low aqueous solubility, generally intended for a
local effect. Nasal sprays of lipophilic corticosteroids (such as budesonide or fluticasone
propionate) are examples of such formulations. Nevertheless, the administration of these
preparations leads to most of the volume being swallowed, which means that the majority
of the drug is not going to have the intended local therapeutic effect. These drugs usually
have a lag time of up to several days to start having a therapeutic effect. In fact, even when
aiming for a local effect, better results can be obtained by solubilizing the drug. Examples
include the solubilization of budesonide in nasal formulations by using Captisol® , a pro-
prietary cyclodextrin derivative (sulfobutylether-β-cyclodextrin), or Budesolv, developed
using Marinosolv® , a proprietary solubilizing technology platform based on plant derived
saponins which form a micellar solution [9,10].
The development of solid dispersions can be expected to reduce the slow dissolution
limitation found in dry powders and suspensions of low water solubility drugs, and
examples of these are found in the scientific literature. The budesonide solid dispersion
Soluplus® , prepared through freeze-drying of a polymer-drug solution, showed faster
release compared to both water-based suspension and dry powder commercial products,
and higher permeation across a nasal cell model [11]. Cyclodextrin derivatives can also
be used in combination to prepare soluble inclusion complexes [12]. However, this review
will not focus on these approaches, but rather on liquid preparations (Table 1).
Alternatively to suspensions and solid dispersions, an emulsion (either liquid or
semisolid) could be used, but drug retention in the vehicle/base could originate similar
limitations in drug release. Alternatively, the limitations of slow dissolution/release of
the drug from suspensions or emulsions could be (at least partially) solved by reducing
particle or droplet size to a colloidal/nanometric range, thus increasing the specific surface
area, making drug dissolution or diffusion faster. Optionally, other nanometric drug
carriers can also be considered, with added functionalities, such as protecting drugs from
enzymatic and chemical degradation, increasing transport through biological membranes,
and overall promoting brain bioavailability [2,27,28]. Moreover, these nanosystems can
have components with permeation enhancing capability, that either act by increasing the
nasal membrane’s fluidity by creating temporary hydrophilic pores (due to extracting
proteins from it), decreasing the viscosity of the mucous layer, or transiently altering tight
junctions [3,29].
Nevertheless, there is no doubt that the simplest and most direct way to deliver the
drug readily available for absorption is to formulate it in an aqueous solution. Classical
ways to increase drugs’ water solubility are well known and include strategies related
to the modification of the chemical entity itself or strategies dependent on formulation
excipients. Modification of the drug molecule itself includes salt formation (which can
be useful when the chemical entity has an ionizable moiety) and hydrophilic prodrug
development (molecule with an additional moiety that has to be metabolized in order to
exhibit pharmacological activity), both of which can result in not only higher aqueous
solubility but also increased chemical stability [30]. As for strategies concerning formulation
excipients, these include pH control (useful with weak acidic or basic drugs), the use of
organic solvents (either the change of the solvent to an oil or, preferentially, the use of
water-miscible organic solvents in mixture with water), the use of hydrophilic surfactants
(above the critical micellar concentration), and the preparation of soluble complexes. In
addition, a combination of these strategies can also be employed.
Table 1. Formulation strategies for increasing drug strength of low water solubility drugs in liquid
nasal preparations.
Approximate Water Achieved Drug Drug Product or

Global Strategy Formulation Strategy Drug
Solubility (mg/mL) Strength 1 (mg/mL) Bibliographic Reference
Change in pH K-604 0.05 10.8 [13]

(acidification) Midazolam 0.01 5 Midazolam injection USP
Use of Complexation Allopregnanolone 0.001 16 [14]

solubilizers (cyclodextrins) Curcumin 0.006 ~3 [15]
Cosolvents and Midazolam 0.01 50 Nayzilam®

surfactants Diazepam 0.05 50–100 ValtocoTM
Nanosuspensions Curcumin 0.006 3.42 [16]
Curcumin 0.006 ~1.5 [15]
Polymeric nanosystems
Baicalein 0.2 0.8 2 [17]
Curcumin 0.006 500 [18]
Solid lipid nanoparticles Geraniol- ur-
Nanosuspensions and nanostructured lipid sodeoxycholic 0.0002 ~4.5 [19]
and incorporation carriers acid conjugate
into carrier
nanosystems Rimonabant 0.002 ~2 [20]
Liposomes and related Flibanserin 0.2 10 [21]
vesicular nanosystems Resveratrol 0.07 NR [22]
Nanometric emulsions 3 Curcumin 0.006 5 [23]
Polymer-coated
Curcumin 0.006 1.9 [24]
nanometric emulsions 4
Phenytoin 34.8 (equivalent to
(used as 0.07 50 mg/mL [25]
Drug molecule Salts and hydrophilic fosphenytoin) fosphenytoin)
modification prodrugs
Up to the equivalent
Diazepam
0.05 of ~13.5 mg/mL of [26]
(avizafone)
diazepam
1 In the case lyophilized systems, it was considered, sometimes estimated, the strength of the liquid suspension
used in vivo; 2 concentration after resuspension of the nanoparticles for nebulization (inhalation during 20 min);
3 microemulsions and nanoemulsions; 4 the one cited here was named by the authors as “amylolipid nanovesicles”;
NR—not reported for the final formulation.
The issue of the formulation having a short residence time in the nasal cavity, and
therefore decreasing the time available for drug absorption to occur (and consequently
bioavailability), can also be tackled by adding certain components to either nanocarriers
or solutions. The inclusion of a mucoadhesive polymer, such as pectin, chitosan, sodium
alginate, or certain cellulose derivatives, will help these formulations interact with the
nasal mucosa, and thereby retaining the preparation in the nasal cavity for a longer period
of time. The use of polymers that increase a formulation’s viscosity (viscosifiers), such
as cellulose derivatives, or gelling polymers, such as poloxamers, can also be an efficient
strategy in increasing the retention time in the nasal mucosa [2,3,31,32].
In order to help define formulation parameters, including in the case of nanofor-
mulations, bio/chemoinformatics (in silico) tools can be used, with some recent studies
having done a good job predicting nose-to-brain transport of antibiotics for the treatment
of meningitis, or even for combating COVID-19 [1,2]. Nevertheless, this review will focus
on the experimental approach.
Examples, benefits and limitations of all the mentioned experimental strategies (water-
solubilization and colloidal liquid dispersions) in the context of nasal preparations, in
particular aiming for nose-to-brain drug delivery, are discussed in the subsequent sections,
and summarized in Table 2. Frequently, different strategies can be found combined.
Table 2. Advantages and limitations of formulation strategies for increasing drug strength of low
water solubility drugs in liquid nasal preparations.
Global Strategy Formulation Strategy Advantages Limitations

Change in pH Irritation of the nose and
Increased drug solubility
(acidification) upper respiratory tract
Use of Safety is dependent on the

solubilizers Complexation Increased drug solubility, type of cyclodextrin, their
(cyclodextrins) protection, and permeation concentration, and the
administration route
Increased drug solubility and Irritation of the nose and
Cosolvents and surfactants
permeation upper respiratory tract
Increased drug strength, simplicity
Physical instability and drug
Nanosuspensions of preparation, controlled drug
precipitation
release, and reduced toxicity
Increased drug strength, controlled Physical instability, low
Polymeric nanosystems drug release, targeted drug delivery, drug loading, and excipients
and prolonged therapeutic effect not biocompatible
Nanosuspensions and Increased drug strength, high safety
incorporation into carrier Solid lipid nanoparticles and Physical instability and low
(biocompatible), and
nanosystems nanostructured lipid carriers drug loading
controlled release profile
Increased drug strength, high safety
Liposomes and related Physical instability and low
(biocompatible), and enhanced
vesicular nanosystems drug loading
permeation
Increased drug solubilization, easy
Physical instability and low
Nanometric emulsions preparation (some), and enhanced
drug solubilization
permeability
Might not be enough to
Salts and hydrophilic increase drug strength (has
Drug molecule modification Increased drug solubility and safety
prodrugs to be joined by other
strategies)
3. Use of Excipients for Enhanced Aqueous Solubility

3.1. Adjustment of the pH
The nasal mucosa’s pH is slightly acidic (≈5–6.5), hence a neutral to slightly acidic
pH is well tolerated. It would be ideal for this pH range to be sufficient to solubilize any
drug molecule, but, if that were the case, the drug would probably not even be considered
poorly water soluble. Some drugs require more extreme pH values for solubilization, and a
pH below 4 seems to be less well tolerated, as described in the following examples.
K-604 is a selective acyl-coenzyme A:cholesterol acyltransferase-1 inhibitor that blocks
cholesterol esterification, which in the brain has been linked to the clearance of amyloid beta
peptides and suppression of 24(S)-hydroxycholesterol induced neuronal cell death. Hence,
it can have potentially beneficial effects in several neurodegenerative disorders, such as
Alzheimer’s disease, also having recently been reported as a promising strategy to treat
glioblastoma [13,33]. Nevertheless, alongside having poor blood−brain barrier permeabil-
ity, its poor water solubility at neutral pH (0.05 mg/mL) makes it hard to formulate at high
strength. Yet, since K-6040 s solubility increases at a lower pH, Shibuya et al. [13] prepared
several solutions containing hydroxycarboxylic acids, either hyaluronic acid, gluconic acid
or citric acid, for intranasal administration. These solutions, with pH values ranging from
3.0 to 3.8, were able to solubilize an increased amount of K-604, 10.8 mg/mL, which is
216 times higher than its solubility in purified water. In vivo intranasal administration of
these solutions to mice showed enhanced drug delivery efficiency, since the obtained brain
and blood area under the drug concentration vs. time curve (AUC) values were approx-
imately between 100 and 211 times higher than those obtained with oral administration.
The citric acid solution, having reached the highest brain maximum drug concentration
(Cmax ), was selected for repeated intranasal administration, to assess therapeutic efficacy
(reduction of brain cholesteryl ester levels). However, even though the administration was
performed on seven consecutive days, the brain lipid profiles showed that after the first
day the brain cholesteryl ester levels had already been reduced up to 94%. Nevertheless,
after the 7-day time period, histological evaluations of respiratory and olfactory epithelium
of the mice in which the administration was performed showed slight disruption, which
could have led to enhanced drug permeability. Hence, although this approach seemed to
show high therapeutic promise, its safety profile does not seem ideal, as expected from an
acidic formulation.
The development of intranasal benzodiazepine medicines for sedation and seizure
control has received a substantial amount of attention. In general, clinical trials show that
intranasal benzodiazepines are at least as effective in stopping seizures and preventing their
recurrence as the same drugs administered through the intravenous, intramuscular, rectal,
or buccal routes [34–37]. One of the biggest focuses has been on intranasal midazolam,
which has a predicted intrinsic water solubility of only 0.00987 mg/mL [38]. Hence,
in intravenous administration simple acidified saline solutions (pH 3–4) are used, since
midazolam converts to its water-soluble form at this pH [39]. However, lacrimation, throat,
and nose burning, and general discomfort are associated with the intranasal administration
of these same preparations, which shows that albeit effective, there was still room for
improvement regarding formulation safety [4,40].
3.2. Cyclodextrins
Cyclodextrins are cyclic oligosaccharides with a central hydrophobic cavity that can
form inclusion complexes with hydrophobic drugs. The outer hydrophilic surface, which
will be in contact with the external aqueous environment, renders the complex water-
soluble, increasing apparent drug solubility [15].
Allopregnanolone (or brexanolone) is a neuroactive steroid (gamma-aminobutyric
acid A receptor positive modulator) approved by the FDA for the treatment of postpartum
depression in adult females, under the brand name ZulressoTM . Allopregnanolone’s
predicted water solubility is very low (only 0.00136 mg/mL), but with sulfobutylether-β-
cyclodextrin, the solubilizing agent in Zulresso, it was possible to obtain a concentrated
solution (5 mg/mL) for intravenous perfusion [41]. An adaptation of this formulation for
intranasal administration, an aqueous solution containing 0.9% NaCl and a large amount
of sulfobutylether-β-cyclodextrin (40%), reached a drug concentration of 16 mg/mL, and
has been shown to provide rapid seizure protection [14].
Curcumin is an extensively studied natural polyphenolic compound, with many
known properties, such as antioxidant and anti-inflammatory effects. These properties
could be useful for the treatment of many illnesses, such as Alzheimer’s disease [42]. Nev-
ertheless, its poor aqueous solubility (0.00575 mg/mL), high instability under physiological
conditions, rapid metabolism, and fast elimination lead to low oral bioavailability and poor
tissue distribution. Moreover, it also has very limited permeation through the blood–brain
barrier, which further restricts its delivery to the brain [15,43]. To tackle some of these issues,
Zhang et al. [15] studied the solubilization of curcumin by hydroxypropyl-β-cyclodextrin
(HP-β-CD, 300 mM), which increased from ~1.5 × 10−4 mM to ~3 mM (~2000-fold). They
also prepared inclusion complexes of curcumin:HP-β-CD, which were lyophilized and
resuspended in water at a greater drug strength. These inclusion complexes and which
performed better than chitosan-coated poly(lactic-co-glycolic acid) nanoparticles (described
in Section 4.2) in protecting the drug from degradation at physiological pH and promoting
bioavailability through the intranasal route, having reached much higher brain drug lev-
els than plasma’s, suggesting the existence of a considerable amount of direct transport
through the neuronal pathways. However, the administration volume was too large, and
the obtained bioavailability was not compared to other routes, which makes it difficult
to fully assess the potential of the developed formulation. Moreover, the inclusion com-
plexes did not perform much better than a simpler similar solution, made from curcumin
solubilized in DMSO first and then diluted with 0.3 M HP-β-CD.
As for safety, in general natural and modified cyclodextrins are considered safe,
since they are listed as inactive ingredients and accepted as excipients in pharmaceutical
products by the FDA. Nevertheless, their safety is dependent on the type of cyclodextrin,
their concentration and the administration route. For intranasal administration, preclinical
toxicity studies have shown that, in general, a concentration below 10% in the formulation
causes low to no local irritation [44].
3.3. Cosolvents and Surfactants

As previously mentioned, intranasal benzodiazepines have shown to be at least as
effective in stopping seizures and preventing their recurrence as intravenous, intramus-
cular, rectal, or buccal administrations of the same drugs [34–37]. Several clinical trials
with intranasal administration of benzodiazepines have been undertaken, either using
parenteral solutions employing cosolvents, or alternative formulations, including using a
liquid surfactant as solvent (Polyoxyl 35 castor oil or Cremophor® EL, nowadays brand
name Kolliphor® EL) (reviewed by Pires et al. [4]). Midazolam and diazepam innovative
formulations have since reached the market. Nayzilam® , a midazolam nasal spray, devel-
oped by Proximagen, Ltd. (London, UK), received FDA approval in 2019 for the acute
treatment of seizure clusters. However, the drug’s solubilization (at 50 mg/mL) was only
achieved by using ethanol, polyethylene glycol-6 methyl ether, polyethylene glycol 400, and
propylene glycol [45]. ValtocoTM , a diazepam formulation with drug strengths between 50
and 100 mg/mL developed by Neurelis, also reached the market in 2020 for the same indi-
cation. Valtoco’s vehicle is composed of vitamin E, ethanol, benzyl alcohol, and n-dodecyl
beta-d-maltoside (Intravail® —proprietary surfactant used as permeation enhancer) [46–48].
Hence, drug solubilization was in both cases performed by adding high amounts of organic
cosolvents and/or surfactants to the preparations. Nevertheless, organic solvents have
been associated with reports of lacrimation, alteration in taste sensation, rhinorrhea, and
burning and general discomfort in the nose and upper respiratory tract to different extents,
depending on the exact excipients and their dose [4,40,49–53]. Despite favorable results
regarding the approved midazolam and diazepam intranasal formulations, there seems
to be scope for improvement regarding formulation tolerability. In fact, side effects could
be expected to have a stronger negative impact in treatment compliance in more frequent,
non-emergency, treatment regimens.
4. Nanometric Dispersions
4.1. Nanosuspensions
Nanosuspensions are dispersions of fine colloidal solid drug particles (<1000 nm,
also named drug nanocrystals) in an aqueous vehicle, stabilized by surfactants. They are
especially useful if a given molecule has poor solubility in both aqueous and non-aqueous
solvents. Nanosuspensions are relatively simple to prepare and have been stated to have
several advantages over other nanoformulations, such as controlled drug release, targeted
drug delivery, improved bioavailability, reduced dosing frequency, reduced toxicity, and
better stability [54,55].
Clozapine is an atypical antipsychotic drug frequently used to treat schizophrenia
symptoms and acts by blocking dopamine D2 and serotonin 5-HT2 receptors, having few
extrapyramidal side effects [56]. Nevertheless, its water solubility is only 0.186 mg/mL [57],
which makes strategies to increase its strength in formulation highly relevant. Additionally,
its poor dissolution rate, high gastrointestinal degradation and high hepatic first-pass
metabolism in oral forms makes it difficult for the drug to reach the brain, and its severe ad-
verse drug reactions (such as agranulocytosis, hepatotoxicity, and cardiotoxicity) lead many
patients to discontinue the treatment [56]. Therefore, Patel et al. [56] suggested that explor-
ing a non-invasive route other than oral administration, such as intranasal administration,
could be beneficial. Moreover, to tackle clozapine’s solubility problem, a nanosuspension
was developed using a combination of (+)-alpha-tocopherol polyethylene glycol 1000 succi-
nate, a surfactant, stabilizer, and permeation enhancer, and polyvinylpyrrolidone K-30, a
suspending agent. The obtained formulation drug strength was moderate (0.5 mg/mL),
but still more than 42 times higher than its water solubility. The in vivo pharmacokinetic
study compared the intranasal administration of the developed nanosuspension and the
oral administration of a conventional suspension to rats. Results showed that clozapine
brain AUC was significantly higher for the intranasal group (when compared to the oral
route), and that the nasal route resulted in a very high brain-to-plasma concentration ratio
at 1 h. Aside from having high efficacy in reaching the brain through intranasal adminis-
tration, the developed nanosuspension also appeared to be safe, since in histopathology
studies the nasal mucosa treated with the nanosuspension did not show any signs of
epithelial damage.
Curcumin was also developed as a suspension of nanocrystals, which promoted
uptake by olfactory ensheathing cells, a particular type of glial cells that accompany the
unmyelinated olfactory axon of receptor neurons (compared to the free curcumin). Final
formulation drug strength was 3.42 mg/mL, which is approximately 570 times higher
than curcumin’s predicted water solubility. However, the formulation was not evaluated
in vivo [16].
4.2. Polymeric Carrier Nanosystems

Polymeric carrier nanosystems are, as the name implies, nanosystems made of poly-
mers. These polymers can be tailored to adjust surface charge, cargo-loading and cargo-
release capability, and surface decoration with specific chemical moieties can prevent the
nanosystem’s recognition by the immune system’s cells or reach and attach to a certain
therapeutic target. A variety of subtypes can be described, based on either the structure of
the nanosystem or the polymer.
Although the classification can differ between authors, polymeric nanoparticles can be
considered a subtype of polymeric nanosystems described as matrix-like compact colloidal
systems made of water-insoluble polymers, in which drugs are dissolved, entrapped,
encapsulated, or attached to. Regardless of having a highly variable size range within the
nanometric scale, their surface hydrophobicity and controlled drug release capacity make
them promising candidates, having been reported to prolong the extent of therapeutic
effect [1,28].
Curcumin has also been encapsulated in chitosan-coated poly(lactic-co-glycolic acid)
nanoparticles for intranasal administration by Zhang et al. [15]. Poly(lactic-co-glycolic
acid) is a biocompatible and biodegradable copolymer that has been widely used to deliver
hydrophobic drugs within nanoparticles. Chitosan was chosen to coat the surface of the
nanoparticles since it can transiently open the tight junctions between nasal mucosa epithe-
lial cells to enhance paracellular drug transport to the brain. The developed formulation
was administered intranasally to mice, however, it had an inferior performance when
compared to the cyclodextrin inclusion complexes described in Section 3.2.
Polymeric micelles, being another subtype of polymeric nanosystems, are made of
polymers as well, but their composition differs from polymeric nanoparticles in the way that
they are made of amphiphilic block copolymers that spontaneously self-assemble, forming
a hydrophobic core and a hydrophilic corona. Because of these structural characteristics, the
polymeric micelles’ core can solubilize and incorporate lipophilic drugs, and the hydrophilic
corona will be a stabilizing interface between the hydrophobic core and the external aqueous
environment, making it a nanosystem with high kinetic stability [58–60].
Baicalein is a plant derived flavonoid compound with antioxidant and anti-inflammatory

properties that have been associated with neuroprotective effects. Hence, it could be po-
tentially beneficial in the treatment of disorders such as Alzheimer’s disease, in which it
has been known to inhibit Tau protein assembly and aggregate formation (which is related
to intra-neuronal functional loss), or Parkinson’s disease, in which it has been reported to
reduce several pro-inflammatory cytokines’ production and overall suppress neuroinflam-
matory pathways [61,62]. Nevertheless, although it is a molecule with high permeability
through the biological barriers, baicalein has poor water solubility (0.153 mg/mL) [63].
Moreover, after oral administration this drug is extensively metabolized in the intes-
tine and liver. In order to try to formulate baicalein at a high strength, and protect
it from metabolism, Zhang et al. [17] developed poly(ethylene glycol)-block-poly(D,L-
lactide) micelles, a biodegradable and nontoxic amphiphilic di-block polymer. In these
micelles, baicalein was encapsulated into the poly(D,L-lactide) core (hydrophobic), and the
poly(ethylene glycol) coating (hydrophilic) allowed the formation of micellar structures
in aqueous media. Intranasal administration of an aerosol of these micelles to mice led
to brain Cmax and AUC values that were 1.44 and 1.50 times higher than those obtained
with the oral administration of a baicalein coarse powder suspension. Therefore, these
results seem to show that the intranasal administration of the developed baicalein micelles
could facilitate brain drug delivery, when compared with oral dosing. Furthermore, toxicity
studies showed that the micelles had much less cytotoxicity in neuronal cells than a drug
solution, and a 5-day continuous daily intranasal administration study showed that the
nasal mucosa maintained its integrity, with no evidence of tissue necrosis or inflammation.
This suggests that the developed formulation could be safe for chronic administration.
4.3. Solid Lipid Nanoparticles and Nanostructured Lipid Carriers

Lipid-based matrix-type nanoparticles have long been regarded as having a high safety
profile due to their biocompatible and biodegradable lipid composition. These matrices
have also been claimed to improve the stability of labile molecules, consequently improving
their bioavailability, while guaranteeing a controlled release profile [20,64,65]. Additionally,
solid lipid nanoparticles, made of solid lipids dispersed in water or an aqueous surfactant
solution, have been reported to allow increased nasal retention (due to occlusive effect and
mucous membrane adhesion) [64,65].
The natural compound geraniol (GER) is known to promote the survival of dopamin-
ergic neurons by enhancing the production of antioxidant enzymes, reducing apoptotic
marker expression, and increasing the production of neurotrophic factors. On the other
hand, the secondary bile acid ursodeoxycholic acid (UDCA) has shown to have a protective
effect against mitochondria-dependent programmed cell death in parkinsonian patients.
In order to combine the neuroprotective, anti-inflammatory and antioxidant properties
of these two molecules to treat Parkinson’s disease, Junior et al. [19] synthesized a pro-
drug containing both. Thus, they produced GER-UDCA, a highly hydrophobic conjugate,
which led to an extremely low water solubility molecule (0.00023 mg/mL). Hence, the
authors decided to formulate this conjugate into solid lipid nanoparticles containing the
lipid glyceryl dibehenate (Compritol® ATO 888), and the hydrophobic surfactant sorbitan
trioleate (Span® 85). The in vivo intranasal administration of these solid lipid nanoparticles
to rats showed a selective uptake of GER-UDCA to the cerebrospinal fluid, suggesting
the existence of a direct nose-to-brain pathway. Furthermore, the solid lipid nanoparti-
cles seemed to prolong and enhance brain drug levels, when compared to the oral route.
Moreover, the histopathological evaluation of rat nasal mucosa showed no signs of damage
after the nanosystem’s administration, whereas GER alone (glycerol and water dispersion)
caused high levels of irritation. Therefore, intranasal administration of the developed
GER-UDCA solid lipid nanoparticles demonstrated the ability to induce nose-to-brain
conjugate permeation, without damaging the nasal mucosa.
Nanostructured lipid carriers are lipid nanoparticles made of a mixture of solid and
liquid lipids, which create an imperfect and disordered crystal matrix within which hy-
drophobic drugs can be better accommodated than in solid matrices. They have been stated
to allow rapid uptake, high drug loading, and very good long-term stability [20,66].
There are many diseases that have been described to benefit from the pharmacological
manipulation of the endocannabinoid signaling, including several that affect the central
nervous system (movement and anxiety disorders, cognitive dysfunction, neuropathic
pain, etc.). However, cannabinoid drugs are known to have low solubility in aqueous
media. Esposito et al. [20] used rimonabant (water solubility 0.002 mg/mL) [67] as a model
cannabinoid antagonist to try to address this issue and formulated it within nanostructured
lipid carriers for intranasal administration. These carriers contained a lipid mixture of
tristearin and triglyceride (Miglyol 812 N), and the surfactant polysorbate 80, which has
been described to increase brain targeting and inhibit the P-glycoprotein (existing in both
the nasal cavity and the blood–brain barrier). The achieved drug strength, 2.147 mg/mL,
was more than 1000 times higher than rimonabant’s water solubility. The intranasal
administration of these nanostructured lipid carriers to rats led to high brain/blood ratios,
and these ratios were also higher than the obtained from the intranasal administration of a
rimonabant solution (made of polyethylene glycol, polysorbate 80, and saline solution at
90%). Since polysorbate 80 was present in both the nanocarrier and the solution, it appeared
that the nanosystem itself did in fact have an additional role in promoting brain targeting.
Another promising nanostructured lipid carrier system was the one developed by Madane
et al. [18], containing curcumin, for the treatment of brain cancer. The composition included
Precirol® ATO5 (solid matrix), Capmul® MCM (liquid lipid), Tween® 80 (surfactant), and soya
lecithin (stabilizer). The obtained particle size (146.8 nm) and PDI (0.18) values were good,
and the nanostructured lipid carrier had increased cytotoxicity in astrocytoma-glioblastoma
when compared to a drug suspension. In histopathologic studies, no change in sheep nasal
mucosa was observed 6 h after applying curcumin-loaded nanostructured lipid carrier system.
Moreover, in vivo pharmacokinetic studies showed that the intranasal administration of the
developed nanosystem was possible at a high dose (50 mg), resuspended in 0.1 mL, and led to
higher brain drug levels (Cmax of 86,201 ± 8182 ng/g at 120 min) when compared to the drug
suspension (Cmax of 54,321 ± 2098.8 ng/g at 180 min).
4.4. Liposomes and Liposome-Related Vesicular Nanosystems

Liposomes are biocompatible and biodegradable vesicles made of phospholipid and
cholesterol bilayers. One or more aqueous compartments can exist depending on how many
bilayers they have [1,27]. Several variations of these particles have been developed, with one
of them being transfersomes. Transfersomes have membrane incorporated edge activators
in their lipidic bilayers, which gives them high flexibility and deformability [68]. These
edge activators are usually single-chain surfactants, which makes it easier for these vesicles
to change their shape and squeeze between cells, enhancing their mucosal permeation.
They have also been reported to enhance nasal mucosa permeation by opening new pores
through the paracellular tight junctions [21,22].
Flibanserin is a non-hormonal drug used for the treatment of hypoactive sexual
appetite disorder in women, acting by decreasing serotonin and increasing dopamine
and norepinephrine levels [21]. Its oral administration leads to reduced bioavailability,
which can be associated with hepatic first-pass metabolism, but also with its low water
solubility (0.178 mg/mL) [69]. Ahmed et al. [21] decided to formulate flibanserin into
transfersomes, containing the phospholipid phosphatidylcholine, and the hydrophobic
surfactants Span® 65 and 80 (since Spans—sorbitane esters—are common and efficient
edge activators). The authors loaded a hydroxypropyl methylcellulose (HPMC) matrix
with the transfersomes, making a flibanserin transfersome loaded HPMC based hydrogel.
By using HPMC, a mucoadhesive and viscosifying polymer, the purpose was also to
extend the residence time of the formulation in the nasal cavity and have a sustained
drug release. The achieved drug strength was 10 mg/mL, which is a more than 56-fold
increase when compared to the drug’s water solubility. The in vivo pharmacokinetic
study compared the intranasal administration of the transfersome hydrogel with the
administration of a simple hydrogel, through the same route, to rats. The transfersome
hydrogel led to brain Cmax and AUC values that were twice as high (when compared
to the simple hydrogel), suggesting an enhanced brain delivery due to the nanosystem.
In the authors’ opinion, this could be attributed to the synergistic effect of the flexibility
and deformability of the transfersomes, and the permeation enhancing capabilities of the
surfactants. Furthermore, histopathological evaluation of the nasal tissues showed no signs
of damage or inflammation, which could be interpreted as the developed formulation
being safe.
Resveratrol is an antioxidant and anti-inflammatory plant derived polyphenol, with a
wide range of associated possible therapeutic effects. It has been pointed out as potentially
efficient in the treatment and prevention of many neurodegenerative disorders, such as
Alzheimer’s disease, in which it has been shown to reduce inflammatory cytokine release,
improve mitochondrial energetic function and enhance Aβ-peptide clearance [70]. Yet, its
application remains limited by several issues, such as a short biological half-life, which is
a consequence of extensive intestinal and hepatic metabolism, leading to it having a very
low oral bioavailability [22]. Moreover, it has poor aqueous solubility (0.0688 mg/mL) [71],
which makes it difficult to formulate at high strength. To tackle this issue, Salem et al. [22]
formulated resveratrol into transfersomes, containing Cremophor® RH 40, ethanol and
soya lecithin, and put them into a hydrogel, having Poloxamer 407 and Carbopol® 934 in its
composition. Although having other functions within the formulation (cosolvent, and mu-
coadhesive and gelling polymer, respectively), ethanol and Carbopol were also included to
serve as permeation enhancers. The in vivo pharmacokinetic study compared the intranasal
administration of the developed transfersomes hydrogel with the oral administration of a
resveratrol oral suspension to rats. Although brain drug levels were not determined, the
results showed that the resveratrol concentration in plasma after intranasal administration
of the transfersome hydrogel was significantly higher at all time points, when compared to
the oral suspension, with plasma Cmax increasing by 2-fold and AUC by more than 20-fold.
Moreover, the transfersome hydrogel led to sustained plasma levels, with the drug being
quantifiable up to 24 h after the intranasal administration was performed. Additionally,
the histopathological examination of the rats’ nasal mucosa showed no signs of severe
tissue degeneration.
4.5. Nanometric Emulsions

Nanometric emulsions are colloidal liquid-in-liquid dispersions that have the advan-
tage of being quite easy to prepare, since certain formulas emulsify spontaneously just by
adding the aqueous phase component to the mixture of oil and surfactants in the right
proportions [1]. These nanosystems can be separated into two main types: nanoemulsions
and microemulsions. Although it is not easy to distinguish between them, with opinions
and definitions varying within the scientific literature, microemulsions are thermodynami-
cally stable systems, and nanoemulsions are not, having, however, a relatively high kinetic
stability [72–74]. Moreover, in general, microemulsions are considered to have a smaller
droplet size range (10–100 nm) than nanoemulsions (20–200 nm). When compared to
liquid macroemulsions, nanometric emulsions have a higher surface area and free energy,
and increased physical stability, hence potentially having a longer shelf life [75]. Their
lipophilic nature, good permeability, and solubilizing effect make them promising systems
for the incorporation of liposoluble drugs [76]. Indeed, there are innumerous examples
of intranasal delivery of nanometric emulsions containing different drugs, either plain
or containing a mucoadhesive and/or viscosifying agent to increase the formulations’
retention in the nasal mucosa [28]. Another strategy to increase this retention would be
to promote in situ gelling by adding, for example, a thermosensitive polymer to the nano
or microemulsion’s external phase, which when in contact with the higher temperature of
the nasal mucosa will increase the formulations viscosity, creating nanoemulgels. These
nanoemulgels combine the properties of both nanoemulsions and gels: increased stability
and drug solubility (nanoemulsions), and increased viscosity with potentially enhanced
retention times (gels) [77]. It is also possible to encapsulate or coat the nanodroplets with a
polymer shell, such as in the production of “amylolipid nanovesicles” described ahead in
Section 4.6 [24].
Another curcumin formulation, in this case a microemulsion, was developed by Shinde
et al. [23], for the treatment of brain cancer. Obtained drug strength was 5 mg/mL, which
is 869 times higher than curcumin’s predicted water solubility. The developed formulations
had Capmul® MCM, with or without docosahexaenoic acid-rich oil, in their composition,
as well as Tween® 80, ethanol and water. Histopathological studies in rats confirmed safety
of the microemulsions (blank and containing curcumin) on the nasal mucosa and brain
even after the intranasal administration for 14 days. However, the developed formulations
were cytotoxic in a concentration dependent manner to human glioblastoma cells and
inclusively formulations containing not only curcumin, but also docosahexaenoic acid-
rich oil, showed higher cytotoxicity, probably due to a synergistic anticancer activity. In
in vivo pharmacokinetic studies, the developed microemulsions led to a higher brain drug
concentration when compared to a curcumin solution, with the microemulsion containing
Capmul® MCM + docosahexaenoic acid-rich oil performing better than the one having
Capmul® MCM only, which suggests that this oil has drug transport enhancing abilities,
either by enabling nose-to-brain drug transport, and/or by enhancing drug permeation.
Additionally, the intranasal administration of these same formulations led to higher brain
drug levels than the intravenous route.
Safety considerations for nanometric emulsions are similar to what was previously
discussed for the solubilization by use of surfactants and cosolvents (Section 3.3), since both
of these classes of excipients are typically used in nano and microemulsions in addition to
oils. Therefore, the choice of excipients should be performed considering the solubilizing
power for a specific drug, physical aspects of emulsion formation, and safety issues, also
considering of course the desired concentration/dose of administration. While the safety of
most of these excipients is well established for cutaneous, oral, or intravenous/parenteral
administration, their safety for the intranasal route is not as well-known. More studies
should be studied with excised tissues are useful to obtain information on permeation,
metabolism, efflux, and toxicity.
4.6. Polymer-Coated Nanometric Emulsions

An interesting novel system encapsulating curcumin, which added novel functionality
to nanometric emulsions, were the curcumin “amylolipid nanovesicles” developed by
Sintov et al. [24]. This nanovesicles with curcumin were prepared by using a microemulsion
as the precursor nanosystem, consisting of polyoxyl 40 hydrogenated castor oil, cocoa butter
(theobroma oil), tetraglycol, and glyceryl oleate. After addition of starch, a crosslinking
reaction was promoted between starch and divanillin in the aqueous phase of the water-in-
oil microemulsion or in the aqueous channels formed in the bicontinuous microemulsion.
These systems were named “amylolipid nanovesicles” and had mean size between 130 and
150 nm and polydispersity index between 0.11–0.20. The optimized formulation (with 2%
crosslinked starch) of curcumin-loaded amylolipid nanovesicles at a dose of 160 µg/kg was
tested by intranasal route in a pharmacokinetic study in rats. Brain and plasma levels were
141.5 ng/g and 11.9 ng/mL, respectively, 1 h after administration. These concentrations
were significantly higher than those achieved by the intravenous route at the same dose, for
which curcumin was not detected in the brain, and the plasma level was approximately one
half of the level achieved after intranasal administration. This work clearly illustrates that
the success of nose-to-brain drug delivery is supported not only by the increase in drug
solubility, but also on promotion of efficient direct transport to the brain. In this regard,
a lot of work can still be performed in order to fully understand how to better explore
this route.
5. Drug Molecule Modification

Salt formation is a very common method of increasing water solubility and disso-
lution rates of acidic and basic drugs [78], such that most drugs are usually already ob-
tained/prepared as salts. However, this must be associated with pH control, since the salt
form of an acidic drug might originate a basic pH, which is not compatible with intranasal
administration, or require pH adjustment for maximum solubility. Nevertheless, many
times this will not be enough to achieve a formulation drug strength that is high enough
for intranasal delivery. For example, phenytoin sodium still has a reduced solubility in
acidic and neutral pH, and the parenteral solution at 50 mg/g is only possible to obtain by
combining pH > 10 and propylene glycol.
Prodrugs are pharmacologically inactive molecules that can be metabolized to origi-
nate their active counterpart, usually by enzymatic cleavage of one or more promoieties.
Prodrug development is a strategy used to overcome several problems that can be associ-
ated with active molecules, such as instability, poor absorption or distribution, toxicity, and
poor solubility [79].
Phenytoin is an antiepileptic drug that acts by blocking voltage-gated sodium channels,
thereby inhibiting the positive feedback loop that results in neuronal propagation of action
potentials. Nevertheless, it has low aqueous solubility (0.0711 mg/mL), which makes it
difficult to formulate at high strength [80]. On the contrary, its hydrophilic phosphate
ester prodrug, fosphenytoin, is highly soluble in water, especially in the form of disodium
salt. Although one could think that it would be likely for fosphenytoin’s anionic nature
to hinder its nasal absorption, Antunes Viegas et al. [81] demonstrated that the nasal
mucosa has phosphatase activity, promoting the in-situ bioconversion of fosphenytoin
to phenytoin. Moreover, in addition to the conversion to phenytoin and subsequent
permeation, a small part of fosphenytoin could permeate an ex vivo model of porcine nasal
mucosa in prodrug form.
Having these results in mind, Pires et al. [25] developed simple aqueous-based formu-
lations containing the prodrug fosphenytoin, the mucoadhesive and viscosifying polymer
HPMC, and albumin to increase nose-to-brain transport. The achieved drug strength for
an isotonic solution was around 34.8 mg/mL of phenytoin equivalents (50 mg/mL of
fosphenytoin), which is 489 times higher than phenytoin’s aqueous solubility. Moreover,
this was achieved while using very safe excipients only, and also safe levels of osmolality.
In vivo pharmacokinetic results showed that, despite no fosphenytoin being detected in
neither mouse blood nor brain (fast bioconversion), the intranasal administration of fos-
phenytoin led to high brain phenytoin levels. Although the intravenous administration
of a fosphenytoin solution was faster in making the drug reach the brain, which could be
due to the need of prodrug conversion occurring before drug diffusion through the nasal
mucosa, the obtained brain Cmax values were similar between intranasal and intravenous
administrations, which suggests similar efficacy (albeit delayed). Moreover, blood Cmax
was considerably higher for the intravenous administration, which suggests that the in-
tranasal route could be safer, because lower systemic drug levels could lead to a decrease in
systemic side effects. Additionally, the presence of albumin in the formulation prolonged
phenytoin’s brain drug levels, which led to a higher brain AUC than that obtained with
the intravenous route. Moreover, it is important to add that even after a small single dose
administration half of the lower limit of mice’s therapeutic level was already reached.
Diazepam is another anticonvulsant drug, acting by indirectly enhancing gamma-
aminobutyric acid inhibitory effects in neuronal excitability [82]. Having poor water
solubility (0.05 mg/mL), and as happens with other benzodiazepines, diazepam requires
cosolvents or other excipients to improve its strength in formulation, which can be highly
irritating to the nasal mucosa. To solve this problem, Rautiola et al. [26] decided to use di-
azepam’s water-soluble lysine prodrug, avizafone, and co-administer it with its converting
enzyme, aminopeptidase B. The in vivo pharmacokinetic results showed that intranasal
avizafone + enzyme resulted in rapid absorption of diazepam, with high brain and blood
levels. Nevertheless, there was no evidence of direct nose-to-brain transport, and hence
most of the drug probably reached the systemic circulation before passing the blood–brain
barrier and indirectly reaching the brain. Still, this prodrug/enzyme combination in an
aqueous vehicle was a successful strategy to formulate diazepam without the use of poten-
tially toxic excipients, being administered through a non-invasive route, and with efficacy
in making the drug reach the brain. Moreover, histological analysis of the nasal tissues
post-administration showed no inflammatory signs, with very few minimal to mild lesions,
and hence the strategy was considered safe.
6. Final Remarks
We reviewed the strategies that can be used to increase the drug strength of synthetic
or plant derived low molecular weight drugs, with an already established indication or
potential for treating several neurological and psychiatric diseases. The strategies can be
many, but not all are equally adequate for a specific route, namely intranasal administration.
We described different strategies, reported by different authors for the same drugs.
However, it is not easy to compare them. For example, curcumin has been subjected to
different encapsulation/solubilization strategies, in particular, as cited above, complexation
with cyclodextrins and incorporation into different nanosystems (nanosuspensions, solid
lipid nanoparticles, nanostructured lipid carriers, nanometric emulsions, and polymer-
coated nanometric emulsions) resulting, in general, in a (variable) increase in drug strength.
However, other determinants (administration dose/volume or direct nose-to-brain trans-
port) can influence brain levels significantly, which cannot be directly compared. For
midazolam, cosolvents and surfactants resulted in a commercially available formulation
(ValtocoTM ), but the strategy to change the pH to more acidic values was also evaluated,
showing tolerability issues. Regarding diazepam, cosolvents and surfactants were em-
ployed, and, also, resulted in a commercially available formulation (Nayzilam® ), but a salt
and a hydrophilic prodrug strategy were also evaluated. The prodrug resulted in higher
brain and blood concentrations in rats, thus proving to be a successful strategy to formulate
diazepam without the use of potentially toxic excipients.
In fact, the strategy of decreasing the formulation’s pH below 4 (required to ionize
certain drugs) appeared to disrupt the nasal epithelium and cause significant nasal dis-
comfort, which makes it not safe for intranasal delivery. Cyclodextrins (in particular, the
most water-soluble derivatives) seem to be safe—the question is whether a sufficiently
high drug strength can be obtained, which must be evaluated case-by-case. Cosolvents
and surfactants’ solubilization capacity vs. tolerability profile can vary substantially, de-
pending on the administered dose of the formulation and these excipients’ concentration
in the preparations themselves. Even some of these excipients that are safely used in
parenteral formulations appear to be toxic or poorly tolerated in intranasal delivery. On
the other hand, in general, nanoformulations seemed to be safer, showing little to no signs
of nasal epithelial damage or inflammation, and cytotoxicity in neuronal cells being low
or inexistent.
Nanosuspensions, polymeric nanoparticles, polymeric micelles, solid lipid nanoparti-
cles, nanostructured lipid carriers, transfersomes, and nanometric emulsions all succeeded
in increasing several drugs’ strength in formulation, reaching up to 1000-fold when com-
pared to their water solubility. Moreover, overall, these formulations led to high brain drug
levels, with some also reaching high brain-to-plasma ratio values, which could indicate
direct nose-to-brain drug transport. Additionally, when compared to other administration
routes, such as oral or intravenous, these intranasal formulations were more effective
at achieving and/or prolonging brain drug levels. Furthermore, the studies that had
pharmacodynamic evaluation concluded that the developed nanosystems were in fact
therapeutically effective.
On the other hand, hydrophilic prodrugs, whether co-administered with a converting
enzyme or not, resulted in a fast prodrug to parent drug conversion, and led to high brain
drug levels, although there was no sign of nose-to-brain transport. Nevertheless, it was
still a successful strategy in formulating low solubility drugs without the use of potentially
toxic excipients.
It is hard to say what might be the best strategy for the future. The intranasal adminis-
tration of either a nanosystem or a hydrophilic prodrug seems to be effective in increasing
formulation drug strength and making the drug reach the brain, while also being seemingly
safe for the nasal mucosa. However, considering the perspective of the pharmaceutical
industry, nanometric formulations might not be an alluring option, since they can be overall
more expensive to produce (when compared to more simple formulations), and there might
be a significant difficulty with their scale-up process. Hence, since the use of cosolvents
and surfactants has led to formulations that have already reached the market, this might be,
for now, the most promising strategy for intranasal delivery, given a careful consideration
on choosing the safest excipients, or considering safe limits. Nevertheless, the choice of
which strategy should be applied will always depend on the characteristics of the drug,
and therefore a case-by-case approach should be considered.
Author Contributions: Conceptualization, P.C.P. and A.O.S.; writing—original draft preparation,

P.C.P. and A.O.S.; writing—review and editing P.C.P., M.R., G.A. and A.O.S.; All authors have read
and agreed to the published version of the manuscript.
Funding: The authors acknowledge the base (UIDB/00709/2020) and programmatic (UIDP/00709/2020)
funding given to Health Sciences Research Centre (CICS-UBI) by national funds through the Portuguese
Foundation for Science and Technology/MCTES.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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Review For Nasal Drug Delivery of Poorly Soluble Drugs

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pharmaceutics

1 Faculty of Pharmacy (FFUC-UC), University of Coimbra, Azinhaga de Santa Comba,

Received: 20 February 2022

Pharmaceutics 2022, 14, 588. https://doi.org/10.3390/pharmaceutics14030588 https://www.mdpi.com/journal/pharmaceutics

2. Overview of Intranasal Formulation Strategies for Drugs with Low

Approximate Water Achieved Drug Drug Product or

Change in pH K-604 0.05 10.8 [13]

Use of Complexation Allopregnanolone 0.001 16 [14]

Cosolvents and Midazolam 0.01 50 Nayzilam®

NR—not reported for the final formulation.

Global Strategy Formulation Strategy Advantages Limitations

Use of Safety is dependent on the

3. Use of Excipients for Enhanced Aqueous Solubility

3.3. Cosolvents and Surfactants

4.2. Polymeric Carrier Nanosystems

Baicalein is a plant derived flavonoid compound with antioxidant and anti-inflammatory

4.3. Solid Lipid Nanoparticles and Nanostructured Lipid Carriers

4.4. Liposomes and Liposome-Related Vesicular Nanosystems

4.5. Nanometric Emulsions

4.6. Polymer-Coated Nanometric Emulsions

5. Drug Molecule Modification

Author Contributions: Conceptualization, P.C.P. and A.O.S.; writing—original draft preparation,

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