Journal of Drug Delivery Science and Technology 63 (2021) 102549

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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Review article

Donepezil—an updated review of challenges in dosage form design

Lalinthip Sutthapitaksakul a, b, Crispin R. Dass c, d, Pornsak Sriamornsak a, b, e, *
a
Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand
b
Pharmaceutical Biopolymer Group (PBiG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand
c
School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, 6845, Australia
d
Curtin Health Innovation Research Institute, Bentley, 6102, Australia
e
Academy of Science, The Royal Society of Thailand, Bangkok, 10300, Thailand

A R T I C L E I N F O A B S T R A C T

Keywords: Donepezil hydrochloride (DPH) was first launched in 1997 as a choline esterase inhibitor (ChEI). The USFDA has
Donepezil approved it for treatment of Alzheimer’s disease since it effectively enhances cholinergic activity by slowing the
Dosage form design clearance of acetylcholine in the brain. Although it is the most prescribed drug among ChEIs, a bitter taste with
Orodispersible
numbness to DPH is a substantial oral administration obstacle, and is a frequently reported adverse event.
Transdermal
Intranasal
Several studies have been conducted to overcome this problem by adding sweeteners and flavors, application of
Parenteral physical barriers, preparation of ion exchange resins, and inclusion complexes. Based on the pharmacological
Nose-to-brain delivery activity, the gastrointestinal effect is a frequently reported adverse event. Therefore, novel dosage forms intended
Taste masking to deliver through oral, topical/transdermal, parenteral, and intranasal routes have been designed and devel­
oped. In this review, findings from recent studies on DPH are summarized, and the challenges and obstacles of
DPH dosage form development are highlighted and discussed.

1. Introduction originated from the abnormal cleavage of amyloid precursor protein

1.1. Background of Alzheimer’s disease
Alzheimer’s disease (AD) is the most common type of dementia,
accounting for approximately 80% of all dementia cases [1]. By 2050,
the number of people with dementia is predicted to reach 152 million.
Additionally, dementia treatment cost, which is currently estimated to
be one trillion US dollars, is predicted to rise to two trillion US dollars by
2030 [2]. Since dementia increases with age, it can be found in 10% of
people over 65 and about 50% of people over 85 years. However, it can
be observed in younger people at the age of 20, possibly due to genetic
disorder [3]. Owing to the continuous increase in life-expectancy, the
incidence of dementia is anticipated to continuously increase, especially
among low-income and middle-income communities. Early-stage de­
mentia patients are predominantly found in low-level education and
healthcare populations.
Presently, the etiology of AD remains unclear. There are two main
pathological hallmarks of AD, which include neurofibrillary tangles
(NFTs) and amyloid beta (Aβ) plaques. NFTs are generated intra-
neuronally through the abnormal phosphorylation of tau proteins,
which are involved in microtubule assembly, while Aβ plaques
(APP) in the non-amyloidogenic pathway [4,5]. It is believed that the
deposition of NFTs and Aβ plaques, glutamate excitotoxicity, and
inflammation are the main causes of neuronal cell death [6].
To date, there are no effective medicines available to terminate or
reverse the destruction of neurons. The available medicines mainly
alleviate the cognitive dysfunction typical of AD patients. The United
States Food and Drug Administration (USFDA) currently approved four
medicines to treat AD. Based on their mechanism of action, they can be
divided into choline esterase inhibitor (ChEI) and N-methyl-D-aspartate
(NMDA) receptor antagonist.
Promising medicines are in the class of ChEIs, including donepezil,
galantamine, and rivastigmine that prevent the breakdown of acetyl­
choline (ACh). These medicines were hypothesized to be responsible for
the regulation of cognitive function. Another therapeutic agent, mem­
antine, an NMDA receptor antagonist, is responsible for receptor
blocking, resulting in neuron protection from excessive glutamate
excretion. Combining two classes of medicines, including donepezil and
memantine, has also been approved [7]. However, this article will
mainly focus on the development and evaluation of donepezil drug de­
livery systems.

* Corresponding author. Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand.
E-mail address: sriamornsak_p@su.ac.th (P. Sriamornsak).

https://doi.org/10.1016/j.jddst.2021.102549
Received 1 March 2021; Received in revised form 23 April 2021; Accepted 23 April 2021
Available online 29 April 2021
1773-2247/© 2021 Elsevier B.V. All rights reserved.
L. Sutthapitaksakul et al.
1.2. Background of donepezil
1.2.1. Drug development
In 1983, donepezil was first invented in Tsukuba Research Labora­
tories, Eisai Co., Ltd., Japan, to overcome the limitations of the first
generation ChEIs, such as physostigmine and tacrine (see Fig. 1).
Although these drugs moderately enhance patients’ cognitive function,
poor pharmacokinetic profiles of physostigmine, and hepatotoxicity of
tacrine are still significant limitations of the drug. The development is
based on cholinergic hypothesis; it was believed that cholinergic
innervation deficiency in the basal forebrain is greatly related to the
unusual memory loss and cognitive function in AD patients [8,9]. As the
resulting compound had a long half-life with moderate acetylcholine
esterase (AChE) activity inhibition, several indanone derivatives were
synthesized. Among these, E2020 (or donepezil hydrochloride; DPH)
was discovered, and launched in 1997, in Atlanta, USA. DPH is second
generation ChEIs with highly selective inhibition of AChE over butyr­
ylcholinesterase, thus preventing the breakdown of ACh in synapses of
the central and peripheral nervous system. It enhances the cognitive
function of patients with mild to moderate AD symptoms without hep­
atotoxicity [10].
1.2.2. Dosing strategies
For mild to moderate AD, DPH is suggested to start at an oral dosage
of 5 mg daily and slowly titrate to 10 mg daily after four to six weeks of
treatment. A 23-mg extended-release tablet can be given to patients with
moderate to severe AD, who have been taking 10-mg DPH for at least
three months [11].
1.2.3. Clinical efficacy
DPH has been initially approved for mild to moderate AD in 1997
and severe AD in 2006. Its benefits have also been shown in other
conditions, including mild cognitive impairment, vascular dementia,
cognitive impairment in multiple sclerosis, Parkinson’s disease, and
dementia with Lewy bodies. Compared to placebo, these studies’ clinical
results showed a significant improvement of behavior, cognitive func­
tion, and daily activities [12–15]. Although recent clinical trials also
studied the role of DPH in patients with Down’s syndrome [16,17],
posterior cortical atrophy [18], depression, and cognitive impairment
[19], there were no significant efficacy in these patients.
Previous studies indicated that DPH is a symptomatic treatment.
However, several recent publications have documented the disease-
modifying potential of such a drug. The neuroprotective effect has
been demonstrated in different AD models, including oxygen-glucose
deprivation [20], Aβ-induced cell death [21–23] and
glutamate-induced cell death [24]. Therefore, this effect might help to
delay disease progression from cognitive impairment to AD [6].
1.2.4. Physicochemical properties
DPH is freely soluble in water (55 g/L at 25 ◦ C), chloroform, and
glacial acetic acid. It has a tertiary amine group with 8.9 pKa [25]. By
thermal analysis, the melting point is reported to be 224 ◦ C [26,27]. It is
a white to off-white solid with an intensely bitter taste. The bitterness
threshold recognized by six volunteers was reported to be 15–20 μg/mL
[28]. However, Zainuddin et al. [29] demonstrated a different result of
Fig. 1. Chemical structures of (a) physostigmine, (b) tacrine, and (c) DPH.
2
Journal of Drug Delivery Science and Technology 63 (2021) 102549
150 μg/mL [29]. Its molecular weight is 425.96 g/mol with a log P of
4.27 [25]. Although USFDA has approved hydrochloride salt, donepezil
free base (DPB) has been used as an active drug among several research
groups. It is less water-soluble (33 g/L). The melting point analyzed by
differential calorimetry is 85.6 ◦ C [30]. Thus, DPB might be suitable to
develop a lipid-based dosage form. However, its efficacy and toxicity
should be clearly elucidated.
1.2.5. Adverse events
According to its pharmacological activity, the most frequent adverse
events reported in at least 2% of mild to moderate AD patients at a
higher frequency than that of placebo in a controlled clinical trial of
Aricept® are nausea (11%), diarrhea (10%), insomnia (9%), muscle
cramps (6%), fatigue (5%), vomiting (5%), and anorexia (4%). These
events frequently appeared in patients who took a higher dosage.
However, patients recovered from these events within one to three
weeks after continuous usage and can be reduced using six weeks of
titration dosage. Other adverse events found are insomnia, fatigue,
muscle cramps, and anorexia. Also, DPH may have an effect on the vagus
nerve because of the cholinergic enhancement effect, causing the
blockage of sinoatrial and atrioventricular nodes. The incidence of
Torsades de pointes has also been reported. Similarly, the increase in
cholinergic activity results in gastric acid secretion. Thus, GI hemor­
rhage (1%) has been reported. The concurrent use of non-steroidal anti-
inflammatory drugs (NSAIDs) should be carefully monitored [11,
31–34].
To overcome the limitations of DPH including bitter taste and
adverse effect, and patient-related factors, including lack of under­
standing of their disease and medications, several novel dosage forms
and development technologies have been developed. In this article, it
has been categorized based on DPH-related problems.
2. Challenges in dosage form design and development
2.1. Bitter taste of DPH
As the taste sensation is caused by the interaction of soluble sub­
stances with the taste receptors, the bitter taste with numbness of DPH
might be a major problem affecting patient compliance. The conven­
tional tablets do not require taste-masking because the dosage form
would not disintegrate or dissolve until passing through the oral cavity.
The effective taste-masking technique may be a prerequisite for some
dosage forms such as oral solutions, suspensions, lozenges, chewable
tablets, orally disintegrating tablets (ODTs), and orally disintegrating
films (ODFs), where the actives possibly contact the taste receptors [35].
In the innovator product, Aricept® ODT, carrageenan is incorporated
into the ODTs to suppress the bitterness of DPH in the oral cavity. As
drug molecules intermediated within the sulfate groups of ɩ-carra­
geenan, the bitterness was masked [11,36]. Besides this product, Table 1
shows several attempts to develop taste-masking dosage forms to over­
come such a problem.
2.1.1. Addition of sweetening and flavoring agent
One of the low-cost and straightforward taste-masking techniques is
sensory masking by adding sweeteners and flavors. In a study by Liew
L. Sutthapitaksakul et al. Journal of Drug Delivery Science and Technology 63 (2021) 102549

Table 1
The oral dosage forms developed to mask the bitter taste of DPH.
Dosage Taste-masking Dose Optimized In vitro taste evaluation In vivo taste evaluation Reference
form strategy (mg) formulation
Taste evaluation Taste-masking Taste Bitterness Taste-masking
method criteria evaluation threshold evaluation
condition (μg/mL) procedure

ODTs Preparation of 5 Microspheres The sample was DPH One tablet 15.0–20.0 Bitterness intensity [28]
microspheres of containing DPH- shaken. concentration placed on the scale
DPH-Eudragit® EPO Eudragit® EPO at M: SSF (pH 6.2) after shaking < tongue
by spray drying the ratio of 1:2 V: 10 mL bitterness No.: 6
method Time: 60 s threshold t: after tablet
T: n.s. was
disintegrated
and held in the
mouth for 60s
ODFs Addition of 10 HPMC film based n.s. n.s. One film strip n.s. Palatability scale [37]
sweeteners containing 7% of placed on the (Taste, aftertaste,
aspartame, sucralose tongue. mouth feel, ease of
sucralose, or No.: 16 handling, and
saccharin sodium) t: n.s. acceptance)
ODTs Preparation of drug- 10 DPH-Amberlite® The sample was The Euclidian One tablet n.s. Bitterness intensity [41]
ion exchange resin IRP-64 at the ratio diluted with PW to distances of the placed on the scale
complex of DPH- of 1:2 10% w/v DPH and complexes to tongue
Amberlite® IRP-64 evaluated by native DPH No.: 12
by spray drying electronic tongue should be large. t: immediately
method after tablet was
disintegrated
ODTs Addition of 10 ODTs containing n.s. n.s. One tablet n.s. Palatability scale [42]
sweeteners 50% of Starlac and placed on the (Taste, aftertaste,
(ammonium 10% of tongue. mouth feel, ease of
glycyrrhizinate) ammonium No.: 16 handling, and
glycyrrhizinate t: n.s. acceptance)
ODFs Preparation of DPH/ 5 ODFs containing The sample was The Euclidian n.s n.s. n.s. [43]
hydroxypropyl- 4.7% of DPH/ dissolved to the distances of the
β-cyclodextrin 41.4% of HP-β-CD, concentration of complexes to
complex (DPH/HP- 41.9% of HPMC, 0.05 mg/mL DPH native DPH
β-CD) by liquid- and 16.7% of and evaluated by should be large
liquid extraction glycerol electronic tongue
method
ODFs Preparation of DPH 5 ODFs containing n.s. n.s. Test method n.s. Palatability score [44]
loaded HPMC, HPC, HPMC: HPC at the was not (initial taste,
PVP-K90, or ratio of 5: 1 and specified. mouthfeel,
pullulan films by glycerin of 1.6% No.: 6 disintegration
solvent casting w/w t: n.s. time, flavor,
method aftertaste, and
overall
acceptability)
The score was
calculated to
bitterness index.

Note: M: test medium, V: volume of test medium, T: temperature, No.: number of volunteers, t: time point of evaluation, PW: purified water, n.s.: not specified.

et al. [37], taste-masked hydroxypropyl methylcellulose (HPMC)
based-ODFs were developed by adding aspartame (180- to 200-fold
sweeter than sucrose), sucralose (300- to 1000-fold sweeter than su­
crose), or saccharin sodium (300- to 600-folds sweeter than sucrose)
[37,38]. Since sucralose possesses the highest sweet intensity, the ODF
with 4.67% received the highest acceptance score from volunteers.
However, only a few amounts (less than 1%) are typically recom­
mended, since these sweeteners (aspartame, sucralose, and saccharin
sodium) have an unpleasant aftertaste. In addition to the synthetic
substance, ammonium glycyrrhizinate (AG), was used by the same
research group as sweeteners and herbal flavors for ODTs. The result
showed that the bitterness of 10-mg DPH was masked by around 6% of
AG, whose sweetness potency was 30- to 50-fold greater than that of
sucrose [39]. The human palatability test of these two studies also
demonstrated that the bitterness of DPH was successfully suppressed.
However, the use of a high concentration of sweeteners might be a
limitation of this approach due to the strong bitterness intensity and
hydrophilic nature of the DPH. Although special equipment or tech­
nology is not required for such techniques, a large number of sweeteners
might result in a rise in cost and processing difficulties. The
compatibility of sweeteners and flavors with other ingredients in the
formulation, stability, toxicity, adverse drug reaction and safety should
also be considered [40].
2.1.2. Application of physical barrier
An alternative taste-masking approach is applying a physical barrier,
which is a highly effective option in comparison to the addition of
sweeteners and flavors. The barrier blocks the taste signal transmission
by minimizing the contact of bitter substances and receptors; thus, the
bitterness could be masked. Taste-masking by incorporating DPH within
polymers, such as HPMC, hydroxypropyl cellulose (HPC), polyvinyl
pyrrolidone-K90 (PVP-K90), or pullulan film was investigated by Han
et al. [44]. The solvent casting technique was used to prepare ODFs in
their study. Although the film’s palatability test showed good accept­
ability, it should be noted that the taste-masking effect might be con­
nected to the synergistic effect of the film-forming agent and sucralose.
Based on the fact that the pH of saliva is reported to be 5.5–7.2 [45], a
polymer with pH-dependent solubility has been studied. Since these
polymers are soluble under gastric pH with insoluble or swellable
properties under oral pH, the bitterness of active drugs could be masked

3
L. Sutthapitaksakul et al.
without changing the drug release profile. According to the study of Yan
et al. [28], Eudragit® E, a methacrylate copolymer with pH-dependent
solubility, and spray-drying of dried microspheres with a different
ratio of DPH:polymer have been investigated. The in vitro drug release in
simulated saliva fluid (SSF) showed that drug release from microspheres
containing 1:2 ratio of DPH:polymer was 1.55% or 7.75 μg/mL within
60 s. Compared with the bitterness threshold of DPH of 15–20 μg/mL,
this ratio was considered to be a taste-masking formulation. However, it
should be noted that 1% of aspartame was also incorporated in ODTs.
Therefore, the taste-masking effect might be connected to the synergistic
taste-masking effect of Eudragit® E and aspartame.
2.1.3. Preparation of drug-ion exchange resin complex
Ion exchange resin is a high molecular weight polymer comprising of
anionic and cationic functional groups. The insoluble drug-resin com­
plex or resinate is formed through weak ionic bonding of each oppositely
charge substance. For taste masking purposes, the drug-resin complex
should not dissociate in the oral cavity. However, at gastric pH, resinate
would exchange their drug molecules with counter ions in the GI fluid.
Thus, taste-masking is achieved, and the actives can be absorbed
through the GI tract properly. DPH-ion exchange resin complex was
prepared for bitterness taste-masking by ODTs. Amberlite® IRP-64,
which is anion exchange resin, was used. Firstly, DPH-Amberlite®
IRP-64 resinate was prepared by spray-drying. The in vitro taste-masking
efficiency was tested using an electronic taste sensing system or elec­
tronic tongue, comparing the taste of the pure drug, ion exchange resin,
physical mixture, and optimal resinate. The result showed that the
Euclidian distance of the physical mixture is close to the pure drug.
Alternatively, resinate showed further distance to the pure drug
compared with the physical mixture, indicating bitter taste reduction of
resinate. The panelist testing of optimal resinate also showed a good
average bitterness index of 1.58, meaning that the bitterness was be­
tween the threshold of bitter to slightly bitter [41].
2.1.4. Preparation of inclusion complex
Another taste-masking technique is to prepare an inclusion complex.
Among several complexation substances, cyclodextrin is the most
extensively used. The inclusion complex masks the bitter taste of the
drug by decreasing drug solubility or decreasing drug molecules’ contact
on taste buds on the tongue. Therefore, the taste signal transmission is
reduced or terminated. Such an approach was used to prepare DPH/
cyclodextrin complexation of ODFs. Hydroxypropyl-β-cyclodextrin (HP-
β-CD) was applied to mask the bitterness of DPH by liquid-liquid solvent
extraction. After that, ODFs were prepared following the solvent casting
method with different film-forming polymers, including HPMC, pre­
gelatinized starch, polyethylene oxide, and low-substituted HPC. After
ODF evaluation, the optimized formulation contained 4.7% of DPH,
41.4% of HP-β-CD, 41.9% of HPMC, and 16.7% of glycerol. The in vitro
taste-masking using electronic tongue showed that the Euclidian dis­
tance of the optimized ODFs is larger than others, indicating taste-
masking has been accomplished [43].
Apart from the bitter taste problem, age-related or disease-related
swallowing difficulties may also affect the ability to swallow conven­
tional solid dosage forms since DPH has been used in AD elderly pa­
tients. The situation gets worse when several oral drugs have to be
swallow in a day [46]. The studies conducted among this group revealed
that approximately 84%–93% of patients suffered from a swallowing
problem [47]. Due to this particular consideration, it is necessary for
oral formulators to develop “easy-to-swallow” dosage forms, for
example, ODTs, ODFs (Table 1). For example, DPH-loaded orally dis­
integrating web with low molecular weight polyvinyl alcohol by elec­
trospinning method was also prepared by Nagy et al. [48]. Since these
dosage forms rapidly dissolve or disintegrate within seconds after
placement on the tongue, a solution or suspension is formed, allowing
easy swallowing without water intake.
Also, the important factor in determining the reliability of the human
4
Journal of Drug Delivery Science and Technology 63 (2021) 102549
taste evaluation for dosage form development is the design of a test
method. However, there is no compendial method designed explicitly
for taste-masking dosage forms; only bitterness evaluation is suggested
in the British Pharmacopeia. Since the human taste perception varies
depending on age, gender, and eating habits, the bitterness threshold
determination and panelist training are essential steps to ensure the
reliability and comparability of results. The bitterness threshold or
bitterness value is the lowest concentration of the test substance that can
be perceived as bitter. The panelists training can be conducted by pre­
senting pre-defined bitterness score solutions to the volunteers. Thus,
the reliability of sample rating scores of the volunteers is enhanced. The
determination method is reported in details by Suzuki et al. [49] and
Albertini et al. [50]. To avoid the limitation of human panelist testing,
especially in the preclinical step when the toxicity of new chemical drug
is not well elucidated, the taste sensing systems (electronic tongues) may
offer a promising approach for taste assessment [51].
2.2. Adverse events of DPH
The frequently reported adverse events of DPH are dose-dependent
and include nausea, diarrhea, insomnia, muscle cramps, fatigue, vom­
iting, and anorexia. Among these adverse events, GI adverse event
(GIAE) including nausea, diarrhea, and vomiting has been extensively
investigated among research groups. As the cholinergic enhancement
activity of DPH stimulates the stomach and intestinal motility, gastric
acid secretion, peptic ulcers, or GI bleeding, or both have also been re­
ported in clinical trials and some case reports [52,53]. Thus, these events
should be carefully monitored, especially in high-risk patients [10,11,
54]. To alleviate such problems, several novel dosage forms have been
developed (Table 2). These studies were classified based on the
administration route of the dosage form intended to be administered
through the oral, topical/transdermal, parenteral, and intranasal routes.
3. Novel dosage forms and development technologies
3.1. Dosage form intended to be administered orally
Clays, layer structured aluminum silicates with good acid absorption
capacity, were used to reduce gastric acid by proton absorption and
control drug release profile. The smectite clays, including laponite XLG,
saponite, and montmorillonite, were studied to intercalate DPH inside
their structure. Due to negative surface charge after hydration, these
clays possess cation exchange capacity (CEC), which can be arranged in
descending order as montmorillonite, saponite, and laponite. Eudragit®
E, a cationic polymer, was coated on the hybrid by spray drying to
replace the cation of DPH molecules through ion exchange reaction.
Drug release of spray-dried hybrid within 180 min showed a fast release
of all hybrids [55]. However, the reduction of GIAE was not evaluated in
this study. Since the smectite clays used were modified to a new hybrid,
new clays’ acid absorption capacity should be characterized to confirm
the main objectives of their study.
Since DPH dose increase resulted in an increased GIAE, the incidence
of this adverse event increased to approximately 2-fold while using a
maximum dose. As it is associated with the fluctuation of DPH plasma
concentration levels, the gradual dose titration within four to six weeks
is recommended to allow patients to adjust to the drug’s pharmacody­
namic effect. Also, it is hypothesized that GIAE is associated with a rapid
cholinergic system stimulation caused by rapid drug absorption. Co-
administration with food can improve the problem by a time delay to
maximum drug concentration [71,72]. To mitigate the GIAE issue,
DPB-loaded lyotropic liquid crystalline (LLC) mesophases were prepared
to assure consistent drug bioavailability. LLC mesophases were prepared
by mixing glyceryl monooleate, DPB-oleic acid solution, and water at
room temperature. The texture, swelling behavior, and mucoadhesive
properties of the formulation were evaluated. Results showed a
controlled drug release pattern for over 24 h. The authors mentioned
L. Sutthapitaksakul et al. Journal of Drug Delivery Science and Technology 63 (2021) 102549

Table 2
The dosage forms developed to overcome GIAE due to DPH.
Dosage form Administration Dose Strategy to overcome Optimized formulation In vitro evaluation In vivo evaluation Reference
route GIAE of DPH method method

Microparticles Oral n.s. Preparation of DPH- All DPH-clay hybrids Dissolution testing with n.s. [55]
clay (laponite XLG, coated by Eudragit® paddle apparatus under
saponite, and E100 with different drug the paddle speed of 50
montmorillonite) release profile were rpm
hybrid coated with successfully prepared M: SGF (pH 1.2)
Eudragit® E100 by V: 1000 mL
spray drying method Time: 180 min
T: 36.5 ◦ C
Transdermal Transdermal n.s. Preparation of DPB or DPB formulation Skin permeation study Pharmacokinetic study [56]
patches application DPH in PG with or containing 10 mg of DP using Keshary-Chien using Spraque-Dawley
without 1–5% fatty acid with 1% oleic acid diffusion cells rats
which were occluded Test skin: hairless Test sample:
on the skin with mouse skin and human transdermal
parafilm cadaver skin application of DPB or
M: PBS (pH 7.4) DPH in PG (10 mg/mL)
V: 6 mL with or without 1%
T: 37 ◦ C fatty acid
Analyzed sample:
blood
Transdermal Transdermal 4% Preparation of DPH- All DPH-loaded WEDD® n.s. Pharmacokinetic study [25]
patches application loaded WEDD® patches patches with various using hairless skin rats
which propelled the current density gave Test sample: DPH-
actives across the rat different loaded WEDD®
skin by iontophoretic pharmacokinetic profiles patches and control
method without DPH
Analyzed sample:
blood
Transdermal films Transdermal 1% Preparation of DP- The films containing DP- Skin permeation study n.s. [57]
application loaded sodium alginate loaded sodium alginate using Franz diffusion
matrix film with DL- matrix film with 3% DL- cells
limonene as a limonene Test skin: pig skin
penetration enhancer M: PBS (pH 6.5)
using water casting V: 12 mL
method T: 37 ± 1 ◦ C
Nanosuspension Intranasal 5 mg Preparation of DPB- The nanosuspension with DPB of 5 mg and the 1. Estimation of DPB [58]
loaded chitosan the mean size of 150 to nanosuspension content using Sprague-
nanosuspension by 100 nm with PDI of containing 5 mg Dawley rats
ionic-crosslinking 0.341, and EE of equivalent dose of DPB Test sample: intranasal
method 92–96%. were tested in dialysis administration of
bag under the stirring nanosuspension and
speed of 100 rpm. DPB suspension
M: n.s. through nostrils of
V: n.s. rats.
Time: n.s. Analyzed sample:
T: 37 ◦ C brain tissue
2. In vivo safety study
using Sprague-Dawley
rats
Test sample: intranasal
administration of
nanosuspension and
normal saline through
nostrils of rats
Analyzed sample:
blood and vital organs
Microspheres Subcutaneous n.s. Preparation of The microspheres Two milligrams of Pharmacokinetic study [59]
injection sustained release DPB- containing 20 mg of microspheres were using two groups of
loaded PLGA PLGA, 3% of PVA and shaken by horizontal rats (n = 4 per group).
microspheres by oil-in- water phase with 2% of shaker under the speed Test sample: IV
water emulsion solvent PVA for emulsion of 60 rpm. Then, the injection of DPH
evaporation method dilution of 16 mL supernatant was aqueous solution and
Size: mean diameter of analyzed at subcutaneous injection
29.4 ± 17.1 μm and a predetermined time. of DPB-loaded
span value of 0.85 M: PBS (pH 7.4) microspheres
DL: 15.92 ± 0.31% V: 6 mL suspension
EE: 78.79 ± 2.56% Time: up to 10 days Analyzed sample:
T: 37 ± 0.5 ◦ C blood
Lyotropic liquid Oral 16.67 g/g of Preparation of DPB- The formulation The in vitro drug release n.s. [30]
crystalline formulation loaded LLC mesophase containing DPB of 16.67 studies using USP II
(LLC) by direct mixing g/g, glyceryl monooleate apparatus with the
mesophase/ technique of 50 or 60%, oleic acid mixture of 0.1 N
matrix of 25%, and water of 25 hydrochloric acid and
or 15% polysorbate 80
(continued on next page)

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L. Sutthapitaksakul et al. Journal of Drug Delivery Science and Technology 63 (2021) 102549

Table 2 (continued )
Dosage form Administration Dose Strategy to overcome Optimized formulation In vitro evaluation In vivo evaluation Reference
route GIAE of DPH method method

Tip-loaded Transdermal n.s. Preparation of DPH- Tip-loaded microneedle The amount of DPH Pharmacokinetic study [60]
dissolving application loaded tips of containing DPH-hydroxy delivered into the skin using rats
microneedles dissolving propyl methyl cellulose- analysis using high Test sample: DPH-
microneedles by a ethanol and water performance liquid loaded tips of
micromolding method mixture at the ratio of 80: chromatography microneedle and oral
20 DPH solution
Analyzed sample:
blood
Microneedle films Transdermal n.s. Preparation of DPH- DPH-loaded microneedle In vitro drug delivery In vivo drug delivery [61]
application loaded microneedle films containing study employing Franz study using Sprague-
films by solvent casting Gantrez® AN139 of 15%, diffusion cell Dawley rats
technique and tripropylene glycol Test skin: porcine skin Test sample: DPH-
methyl ether of 7.5% M: PBS (pH 7.4) loaded film with a drug
T: 37 ± 1 ◦ C loading of either 2.5
mg/kg or 5.0 mg/kg
Analyzed sample:
blood
Solid lipid Intranasal DPB to lipid Preparation of DPB- DPB to lipid ratio of 1: 5, In vitro release and In vivo [62]
nanoparticles ratio of 1: 4 loaded solid lipid surfactant concentration release kinetic studies pharmacokinetic study
to 1: 6 nanoparticles by of 2.25% w/v, and in dialysis bag using male albino
solvent emulsification stirring time of 2.75 h M: PBS (pH 7.4) Wistar rats
diffusion technique V: 100 mL Test sample: optimized
Time: up to 24 h DPB solid lipid
T: 37 ± 0.5 ◦ C nanoparticles and DPB
solution
Analyzed sample:
blood, brain, and other
organs
Liposome Intranasal n.s Preparation of DPB- DPB-loaded liposome In vitro drug release in In vivo [63]
loaded liposome by thin containing 1,2-distearyl- dialysis sac pharmacokinetic study
layer hydration method sn-glycero-3-phodpho­ M: simulated nasal using male Wistar rats
choline, cholesterol, and fluid (pH 6.2–6.8) Test sample: DPB-
polyethylene glycol at V: 100 mL loaded intranasal
the ratio of 1: 2: 0.5 Time: up to 360 min liposomes (1 mg/kg)
T: 37 ◦ C Analyzed sample:
blood
Microspheres Subcutaneous n.s. Preparation of The microspheres Four milligrams of Drug release study [64]
injection sustained release DPB- containing 1: 5 of DPB: microspheres were using 42 Kunming
loaded PLGA PLGA (11.83% PLGA), shaken under the speed mice
microspheres by oil-in- 1.005% of PVA, and of 100 rpm. Then, the Test sample:
water emulsion solvent water-organic phase supernatant was subcutaneous injection
evaporation method volume ratio of 13.24 analyzed at of DPB-loaded
Size: mean diameter of predetermined time. microspheres
71.75 ± 0.35 μm and a M: PBS (pH 7.4) suspension
size distribution of 0.825 V: 8 mL Analyzed sample:
± 0.007 Time: up to 42 days residual microspheres
DL: 14.48 ± 0.41% T: 37 ◦ C after peeling skin off
Nanostructured Transdermal 0.25 or Preparation of DPB- The NLCs containing In vitro skin permeation n.s. [65]
lipid carrier- application 0.50% of loaded NLCs by hot DPB, stearic acid of study employing Franz
based gels formulation microemulsion 1.25%, oleic acid of diffusion cell
technique 0.75%, lecithin of 1.00%, Test skin: porcine ear
and sodium skin
taurodeoxycholate of M: PBS (pH 5.0)
0.25% T: 37 ◦ C
Nanoemulsions Intranasal 6.25 mg/mL Preparation of DPB- DPB-loaded In vitro release study Histological analysis [66]
loaded nanoemulsions nanoemulsions with using Franz diffusion using pigs
and DPB-loaded Pluronic® F-1227 cell Test sample: intranasal
nanoemulsions with Test tissue: dialysis isopropyl alcohol,
Pluronic F-1227 membrane DPB-loaded
M: methanol: nanoemulsions and
Transcutol-P DPB-loaded
T: 37 ± 0.5 ◦ C nanoemulsions with
Ex vivo permeation Pluronic® F-1227
study Analyzed sample:
Test tissue: porcine nasal mucosa
nasal mucosa
M: Transcutol-P: water
Ionic liquid (ILs) Transdermal n.s. Preparation of ILs form Donepezil- Skin PAMPA and BBB n.s. [67]
form of DPH application of DPH with different docosahexaenoic acid PAMPA
types of counterion by and donepezil-α linolenic Test skin: artificial skin
metathesis reaction acid M: standard Britton-
formulation Robinson buffer (pH
7.4)
T: 32 ◦ C
Molecular docking
(continued on next page)

6
L. Sutthapitaksakul et al. Journal of Drug Delivery Science and Technology 63 (2021) 102549

Table 2 (continued )
Dosage form Administration Dose Strategy to overcome Optimized formulation In vitro evaluation In vivo evaluation Reference
route GIAE of DPH method method

study
In vitro skin permeation
study
Microemulsions Intranasal n.s. Preparation of DPH- DPH-butter oil and DPH- Ex vivo nasal diffusion In vivo [68]
butter oil and DPH- omega-3 fatty acid-rich study pharmacokinetic study
omega-3 fatty acid-rich fish oil microemulsions Test tissue: goat nasal using Sprague-Dawley
fish oil microemulsions tissue rats
by physical mixing M: PBS (pH 6.4) Test sample: DPH
method In vitro cell solution, DPH-
permeability study microemulsion, DPH-
Test cell: mouse butter oil and DPH-
cerebral microvascular omega-3 fatty acid-
endothelial cell line rich fish oil
(bEnd3) microemulsion
Analyzed sample:
blood, and brain
Solid lipid Intranasal n.s. Preparation of DPB- DPB-loaded solid lipid In vitro release study n.s. [69]
nanoparticles loaded solid lipid nanoparticles labeled using the dialysis
nanoparticles labeled with rhodamine B and membrane method
with rhodamine B and targeted with M: PBS (pH 7.4)
targeted with apolipoprotein E containing 0.1% Tween
apolipoprotein E 80
V: 50 mL
Time: up to 24 h
T: 37 ◦ C
Cellular uptake study
Test cell: rat brain
endothelial cell line,
human cerebral
microvascular
endothelial cell line,
and human
neuroblastoma cell line
BBB co-culture model
and permeability study
Test cell: primary rat
brain endothelial cells,
pericytes, and
astrocytes
Nanofibers and Oral n.s. Preparation of chitosan Nanofibers containing Dissolution testing with In vivo bioavailability [70]
thin film blended with chitosan/hyperbranched basket apparatus study using male
hyperbranched chitosan blend M: PBS (pH 6.8) Wistar rats
polyester and V: 600 mL Test sample: orally
hyperbranched Time: 60 min administration of thin
chitosan T: 37 ± 0.5 ◦ C film and nanofiber
sheet
Analyzed sample:
blood

Note: M: test medium, V: volume of test medium, T: temperature, DL: drug loading, EE: encapsulation efficiency, n.s.: not specified.

that these formulations could provide a controlled DPB release for oral
administration, which will be beneficial to improve GIAE [30].
3.2. Dosage form intended to administer through topical/transdermal
route
The topical/transdermal route offers good advantages over others
since it is a non-invasive administration route. Also, it also provides
several benefits, including first-pass metabolism circumvention, easy-to-
use, and more convenience for patients to self-administer.
It also provided constant plasma level of drug and minimized the
GIAE of DPH [73]. In addition, the transdermal route has got a lot of
attention from the pharmaceutical industry. Teikoku Pharma USA, Inc.
developed Aricept® transdermal patches for once-weekly administra­
tion under a licensing agreement with Eisai Co., Ltd., and then submitted
to US FDA in 2010. The application was, however, withdrawn from the
US FDA in 2012 [74]. Although this route might be an excellent choice
for DPH administration, it is known that only limited amounts of drugs
are administrable via this route. Following the rule of five, this corre­
lates with drug physicochemical properties to determine high
absorption and permeation. The molecular weight of DPH is 425.96
g/mol with log P of 4.27 [25]. The number of hydrogen bond acceptors
and donors are four and zero, respectively. Although none of the factors
break the rule, the molecular weight and log P of DPH are approximate
to these factors’ margin (molecular weight <500 g/mol and log P < 5).
Therefore, an effective delivery device is necessary to achieve a desired
therapeutic effect.
3.2.1. Transdermal patches/films
Recently, donepezil transdermal patches were developed by Icure
Pharmaceutical Inc. (South Korea) and tested in phase III clinical trial
with 399 participants. This study compared the efficacy and safety of 25-
cm2 and 50-cm2 transdermal patches to 5-mg and 10-mg Aricept®
tablets in mild to moderate AD patients [75].
DPB or DPH-loaded transdermal patches were prepared based on
clinical trial results of rivastigmine transdermal patches, which sug­
gested that the patches’ efficacy is similar to that of the capsules [76].
On the other hand, GIAE was found to be lower. To improve drug skin
permeability, the transdermal patches were developed using different
carbon length fatty acids as a skin penetration enhancer. The

7
L. Sutthapitaksakul et al.
formulation was prepared by dissolving various DPB and DPH dosages in
propylene glycol (PG) with or without fatty acid. The in vitro permeation
study was carried out on diffusion cells using hairless mouse skin,
showing that the permeation rate of DPB and DPH was most enhanced
by stearic acid (C18) and palmitic acid (C16), respectively. The in vitro
permeability result of DPB showed that the permeation rate decreased
with an increasing number of double bonds in unsaturated fatty acids.
Oleic acid with one double bond (C18:1) was the most appropriate
enhancer for DPB as the permeation rate increased by approximately
19-fold. In contrast to DPH, the results showed that the permeation rate
was increased up to 35-fold while unsaturated fatty acid with only one
double bond (palmitoleic acid, C16:1) was incorporated. The in vivo
pharmacokinetic study in rats showed that pharmacokinetic parameters
of the DPB with 1% oleic acid and DPH with fatty acids were higher than
those without fatty acids. The steady-state concentration of all formu­
lations was maintained for approximately 48 h. Therefore, the authors
suggested that this transdermal drug delivery system with skin en­
hancers might be an appropriate product for clinical use [56]. The skin
permeation enhancer was also employed to prepare DPH-loaded sodium
alginate matrix type film by the water casting method. The effect of
DL-limonene concentration as a skin penetration enhancer was investi­
gated. The in vitro skin permeation study was carried out with Franz
diffusion cells using pig skin. The results showed that the amount of
permeated DPH was enhanced by 2.82-fold while DL-limonene concen­
tration increased from 1% to 3% [57]. However, there was no significant
difference in enhancing effect than of DL-limonene (5%).
In another study, the skin permeability of DPH was improved by
transforming ionic liquid (ILs). ILs improve permeability property by
disrupting cell membrane integrity and fluidization, thus facilitating
drug delivery across or into skin [77,78]. ILs were prepared by reacting
DPH with anionic counter ions, including docusate sodium, oleate so­
dium, linoleate sodium, ibuprofen sodium, α-linolenic sodium, and do­
cosahexaenoic sodium. The skin parallel artificial membrane
permeability assays (skin PAMPA) results during the first 6 h showed
that permeation percentage of donepezil-docosahexaenoic acid and
donepezil-α linolenic acid ILs was higher than that of donepezil. How­
ever, these permeation percentage differences were lower in 12 h of
testing due to steady-state flux. The blood-brain barrier (BBB) parallel
artificial membrane permeability assay (BBB PAMPA) was also
employed to investigate the effect of IL formation on BBB permeation.
The results showed that IL formulation had the ability to cross the BBB.
After that, drug-in-adhesive transdermal patches of ILs were prepared.
The result showed that donepezil-docosahexaenoic acid and donepezil-α
linolenic acid has higher permeability capacity than native donepezil.
Therefore, the authors suggested that ILs may be an alternative trans­
dermal way for effective delivery of DPH [67].
To enhance skin permeability by circumventing the stratum cor­
neum, which is a permeation barrier, DPH was loaded in the tips of
dissolving microneedles prepared by micromolding to overcome its low
skin permeability and improve drug loading. DPH was added to
hydroxypropyl methyl cellulose solution at different concentrations. The
tip was prepared by blending DPH-hydroxypropyl methylcellulose-
ethanol and water, while the needle base was prepared by carboxy
methylcellulose-water. The insertion test was conducted using porcine
skin and three arrays of 100 microneedles with different amounts of
DPH. The pharmacokinetic results showed that a high drug loading
could be encapsulated in the tips. DPH delivered amount was over 95%
within 5 min of insertion while the tips were fully dissolved within 15
min. Also, the Cmax of tip-loaded microneedle was four times higher than
that of the oral administration. The authors suggested that their tip-
loaded microneedle may be a transdermal alternative to deliver DPH
with good patient acceptance [60]. Another example also produced DPB
and DPH-loaded hydrogel-forming microneedle films to enhance drug
delivery across the skin. Gantrez® S-97, polyethylene glycol, and
Na2CO3 were blended to fabricate microneedle arrays by the molding
method. DPB or DPH, Gantrez® AN 139 or S-97, copolymers of methyl
8
Journal of Drug Delivery Science and Technology 63 (2021) 102549
vinyl ether and maleic anhydride (PMVE/MAH), copolymers of methyl
vinyl ether and maleic acid (PMVE/MA), or PVP and plasticizers were
blended to prepare a film using a solvent casting method. The in vitro
drug release study was conducted using Franz diffusion cells and
demonstrated that the permeation of DPH was enhanced. Drug delivery
of these two formulations was further analyzed in vivo with
Sprague-Dawley rats. After blood sample analysis, the results showed
that DPH levels detected in a film containing 5.0 mg/kg dose were
higher than that of 2.5 mg/kg. It continuously increased over 24 h. The
authors suggested that these dosage forms may be used to deliver hy­
drophilic drugs since such hydrogel-forming microneedle could create
an aqueous environment facilitating drug release [61].
3.2.2. Iontophoretic delivery
Iontophoretic transdermal delivery uses a low electrical current to
drive a charged drug molecule into the skin. This electrical current
would interfere with skin structures, facilitating drug delivery based on
two main delivery mechanisms, including electromigration and elec­
troosmosis. Electromigration is the term defining the repulsion of the
anode to positive charge ions and cathode to negative charge ions. On
the other hand, electroosmosis is the movement of water caused by
convection [79,80]. According to the study of Salujaand et al. [25], DPH
delivery by iontophoretic method was investigated. The gel formulation
containing DPH was injected into absorbent pads and attached to
wearable electronic drug delivery (WEDD) patches, an iontophoretic
delivery platform built with active electrodes and connected to a power
supply. After that, the active drug was propelled across abdominal re­
gions of rat skin by voltage-direct current. Blood was collected over 72 h
and analyzed. The transdermal patches’ pharmacokinetic profile
showed that the plasma levels increased with increasing current density
[25]. However, the ability of the patches to overcome the cholinergic
side effect issues, which the authors raised in the introduction, were not
evaluated.
3.2.3. Gels
DPB-loaded nanostructured lipid carrier (NLC)-based gel was pre­
pared to enhance drug skin permeability and overcome the adverse ef­
fect of donepezil. Hot microemulsion technique was used to prepare NLC
by employing stearic acid as a solid lipid, oleic acid as a liquid lipid,
lecithin as a surfactant, and sodium taurodeoxycholate as a co-
surfactant. The authors also mentioned that lecithin was used as a
cutaneous absorption enhancer as it can interact with skin lipid. The size
of NLCs was around 200 nm. In vitro drug release test employing Franz
diffusion cell and cellulose acetate dialysis membrane (12–14 kDa cut
off) of DPB-loaded NLC gels showed an initial burst release, followed by
sustained release of 50% over 48 h.
In contrast to free drug gels, a complete drug release of around 100%
was obtained within 24 h. In vitro, skin permeation study using porcine
ear skin with Franz diffusion cell showed a lower permeated percentage
than drug release test. Cumulative DPB permeated over 40% was ob­
tained from 0.50% of the DPB-loaded NLCs while that of 0.25% of the
DPB-loaded NLCs was around 15% within 72 h of the test. The authors
concluded that the skin permeation enhancing effect might contribute to
the increased contact with the skin, occlusive effect, and sustained
release property of the formulation [65]. However, it should be noted
that the skin permeation result of free drug gels was not shown in the
study.
3.3. Dosage form intended for administration via injection
Some researchers prefer the injection method to deliver DPH
directly. Based on the study of Guo et al. [59] and Fang et al. [64],
injectable DPH-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) micro­
spheres have been prepared using the emulsion solvent evaporation
technique. PLGA, a biocompatible and biodegradable polymer approved
by the FDA to be used as a drug delivery system, was used as a sustained
L. Sutthapitaksakul et al.
drug release to overcome GIAE and compliance problems.
Guo et al. [59] prepared oil-in-water emulsions using dichloro­
methane as a solvent or oil phase. To enhance drug loading of the mi­
crospheres, DPH was modified to DPB, which has low water solubility
before encapsulation. After that, it was mixed with PLGA to produce the
oil phase. This phase was then emulsified into a water phase containing
different concentrations of polyvinyl alcohol. After that, the oil-in-water
emulsion was centrifuged and dried to obtain microspheres. The in vitro
drug release profile in PBS showed a sustained cumulative drug release
of 88.44% over 10 days. The pharmacokinetics study in rats showed that
the DPB concentration peaked in plasma within a day after a single dose
of subcutaneous administration, and drug levels were detected up to 15
days.
Moreover, the authors also reported a good in vitro-in vivo release
profile correlation of the microspheres. Therefore, they concluded that
the microspheres developed can be a sustained release dosage form for
AD [59]. Since the modification of the salt form of DPH might affect such
a drug’s safety and efficacy, it should be noted that these issues are
considered re-evaluated. In another study, sustained-release micro­
spheres were also prepared by a similar technique. DPB was also used as
an active. However, the design of an experimental approach was used to
find the optimal formulation. Drug release kinetics of the microspheres
was also investigated. A pharmacokinetic study demonstrated that the
microspheres successfully sustained drug release of about 90% up to 42
days for in vitro testing, whereas only 21 days for in vivo testing in
Kunming mice. The result showed that erosion was the main mechanism
affecting the drug release, with the rate of erosion in vivo being faster
than that in vitro. The authors hypothesized that this effect contributed
to some physiological reactions that might enhance water absorption or
accelerate polymer degradation [64]. Although GIAE was mentioned as
a primary objective of these studies, an effort to overcome the problem
was not directly evaluated. Moreover, despite patient compliance being
mentioned as a main aim, the authors administered the dosage form
through subcutaneous injection, an invasive method. So, the compliance
of developed dosage might be questionable.
3.4. Dosage form intended to be administered through intranasal route
According to previous studies, it is preferred to deliver DPH orally
and transdermally, which are peripheral administration routes. Drug
molecules are supposed to be delivered to the brain through the blood
circulation. However, this route’s efficacy is limited because of the BBB,
which prevents hazardous substances from entering the central nervous
system. Briefly, a low brain permeability and consequent low drug
concentration in the brain are the main limitations of this route.
Compared to intranasal, drug molecules are mainly delivered through
the neuronal route, which is a direct nasal–brain route. The nasal cavity
anatomy can be divided into three cavities: the vestibular region, res­
piratory region, and olfactory region. Among these regions, the respi­
ratory region covers the largest area of the nasal cavity. After drug
molecules pass into the nasal cavity, it will get through the mucociliary
clearance of the vestibular region, followed by enzymatic degradation
and short retention time. These barriers might be an important challenge
for the formulator to develop drug delivery systems to overcome such
systems. After passing through the vestibular region, drug molecules
enter the posterior region to contact the respiratory and olfactory re­
gions. The respiratory region is highly supplied by blood vessels and
trigeminal sensory neurons, facilitating high-extent drug transport to the
pons and cerebrum. However, only a low drug extent is delivered to the
olfactory and frontal brain. In addition to the major pathway, fewer
amounts of drugs are delivered through the BBB. Compared with others,
the nose–brain delivery route offers several advantages, including pa­
tient convenience, BBB circumvention, first-pass metabolism avoidance,
and quicker attainment of therapeutic drug level [81–83]. The
nanotechnology-based drug delivery system may be a promising
approach to overcome the limitations of BBB.
9
Journal of Drug Delivery Science and Technology 63 (2021) 102549
DPB-loaded chitosan nanosuspension was prepared for intranasal
administration by Bhavna et al. [58], to mitigate GI side effects and
prolong drug action. The nanosuspension was prepared by the
ionic-crosslinking method of DPB and chitosan; tripolyphosphate was
used as a crosslinker. The in vitro drug release test showed an
improvement of cumulative drug release in comparison with conven­
tional suspension. Similarly, in vivo drug content determination of DPB
nanosuspension showed a higher drug concentration both in the plasma
and brain as compared to the intranasal solution. Moreover, the safety
test showed no toxicity in all rats, as there was no mortality, body
weight, and hematological changes. Therefore, the authors concluded
that the intranasal DPB-loaded nanosuspension might be used as a novel
alternative route to deliver DPB to the brain [58].
The DPB-loaded liposomal formulation was developed by Al Asmari
et al. [63], aiming to improve the bioavailability of intranasal formu­
lation. The liposomes were prepared by thin-film hydration method
using cholesterol, polyethylene glycol and 1,2-distearyl-sn-glycero-3-­
phosphocholine. In comparison to oral and intranasal administration
of DPB, the intranasal DPB-loaded liposomes resulted in a major
improvement in pharmacokinetic parameters. Under a microscope,
histopathological examination of formed liposomes revealed no major
changes in tissue after intranasal administration, suggesting the safety of
the formulation [63].
To improve the permeation across BBB, Khunt et al. [68] used a
permeation enhancer, i.e., butter oil and omega-3 fatty acid-rich fish oil,
to prepare DPH microemulsions for intranasal administration. The ex
vivo nasal diffusion study using Franz diffusion cells with goat nasal
tissue of DPH-butter oil and DPH-omega-3 fatty acid-rich fish oil
microemulsions showed an improved drug diffusion over DPH solution
and DPH microemulsion. The in vitro cell permeability study using cell
line of these two formulations showed a decrease of transepithelial
electrical resistance, indicating the permeation change. The drug extent
after intranasal administration of DPH-butter oil and DPH-omega-3 fatty
acid-rich fish oil microemulsion was higher than the control samples in
an in vivo pharmacokinetic study in rat brain, suggesting a promising use
of these oils as a nose-brain permeation enhancer [68].
Apart from microemulsions, DPB nanoemulsions and DPB-Pluronic®
F-127 nanoemulsions were developed by Espinoza et al. [66]. Pluronic®
F-127 nanoemulsions had significantly higher drug amount and pre­
diction parameters than DPB nanoemulsions, according to findings of an
ex vivo permeation study. It was suggested that using a nanoemulsion
with a permeation enhancer to deliver DPB through the BBB might be a
promising alternative.
There has been an increased interest in the production of solid lipid
nanoparticles for nose-to-brain drug delivery in recent years. Solvent
emulsification diffusion was used to make solid lipid nanoparticles of
glyceryl monostearate blended with polysorbate 80 and poloxamer 188.
The effect of processing parameters and optimization was studied by
Box-Behnken design. As compared to intravenous DPB solution and
intranasal DPB solution in pharmacokinetic and biodistribution studies
in rats, the optimized nanoparticles showed an increase in AUC of
approximately 2 folds [62]. Topal et al. [83] have also developed
DPB-loaded solid lipid nanoparticles by homogenization-sonication
method. The particles were labeled with rhodamine B and targeted
with apolipoprotein E, a ligand of the lipoprotein receptor in the BBB, to
ensure that DPB was delivered effectively. Apolipoprotein E increased
DPB cellular uptake in a cell line, according to the findings. Further­
more, in the co-culture BBB model, permeation was increased [69]. It
was discovered that combining solid lipid nanoparticles with a targeting
ligand may be a promising technique for overcoming the BBB’s
limitations.
Some studies prefer to use DPB as an active instead of DPH, espe­
cially for lipid-based drug delivery systems, such as LLC, patches,
microneedles, NLC, injectable microspheres, and intranasal nano­
suspension. Since DPB is a lipophilic form, their compatibility with lipid
excipients is more than that of DPH. However, it should be noted that the
L. Sutthapitaksakul et al.
therapeutic efficacy and toxicity of DPB should be clearly elucidated.
4. Conclusion and future prospects
Recently, there is no effective drug for AD; most available drugs are
symptomatic. Current research is focused on the clinical role of DPH as a
disease-modifying agent in both preclinical and clinical studies. Due to
AD’s extremely complicated and ambiguous pathogenesis, there are still
some controversies about a suitable model selection. Among several
studies, the bitter taste is a significant problem for conventional oral
dosage forms, which is an original administration route of DPH. Several
approaches have been employed for taste-masking, including the addi­
tion of sweeteners and flavors, application of physical barriers, prepa­
ration of ion exchange resins, and inclusion complexes. Future research
should emphasize a combinatorial approach, which may prove to be an
efficient taste-masking strategy. Due to the fluctuation of plasma DPH
concentration levels, GIAE was frequently reported as an adverse event.
To alleviate the adverse effects, studies should focus on the development
of controlled drug release formulations for maintaining a constant level
of drug concentration in the plasma. The dosage forms intended to be
administered through oral, topical/transdermal, injection, and intra­
nasal routes have been developed to overcome such adverse events and
control the drug release. Transdermal drug delivery systems might be an
excellent alternative choice. Recent studies show that intranasal drug
delivery systems’ potential as it directly delivered DPH to the brain. A
key consideration for successful delivery includes efficient delivery to
the BBB and therapeutic concentration achievement. Since a compre­
hensive knowledge of AD target factors is essential for designing drug
delivery systems for clinical use, most studies at this stage are preclin­
ical. The mechanism of drug transfer from the nose to the brain must be
clarified to facilitate drug delivery system development to target a
suitable region of the nasal cavity. Further functionalization with li­
gands targeting suitable regions on the BBB might improve DPH brain
entry.
Declaration of competing interest
None.
Acknowledgements
Financial funding from the Ministry of Higher Education, Science,
Research and Innovation (Thailand) through Reinventing University
System Program (fiscal year 2021) is gratefully acknowledged.
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