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Otic Drug Delivery Systems: Formulation Principles and Recent Developments

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Otic drug delivery systems: formulation principles

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Xu Liu, Mingshuang Li, Hugh Smyth & Feng Zhang

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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 2018
https://doi.org/10.1080/03639045.2018.1464022

REVIEW ARTICLE

Otic drug delivery systems: formulation principles and recent developments

Xu Liua, Mingshuang Lib, Hugh Smytha and Feng Zhanga
a
College of Pharmacy, The University of Texas at Austin, Austin, TX, USA; bDepartment of Communication Sciences and Disorders, The University
of Texas at Austin, Austin, TX, USA

ABSTRACT ARTICLE HISTORY

Disorders of the ear severely impact the quality of life of millions of people, but the treatment of these dis- Received 11 February 2018
orders is an ongoing, but often overlooked challenge particularly in terms of formulation design and prod- Revised 3 April 2018
uct development. The prevalence of ear disorders has spurred significant efforts to develop new Accepted 4 April 2018
therapeutic agents, but perhaps less innovation has been applied to new drug delivery systems to improve
KEYWORDS
the efficacy of ear disease treatments. This review provides a brief overview of physiology, major diseases, Otic drug delivery;
and current therapies used via the otic route of administration. The primary focuses are on the various intratympanic drug delivery;
administration routes and their formulation principles. The article also presents recent advances in otic intracochlear drug delivery;
drug deliveries as well as potential limitations. Otic drug delivery technology will likely evolve in the next ear disease
decade and more efficient or specific treatments for ear disease will arise from the development of less
invasive drug delivery methods, safe and highly controlled drug delivery systems, and biotechnology tar-
geting therapies.

Introduction Local drug delivery systems may have significant advantages

Millions of people worldwide suffer from various ear disorders and
associated conditions such as otitis media, hearing loss, tinnitus,
and Meniere’s disease. For example, the chronic otitis media or
otitis externa affects 3–5% of the US population, with an esti-
mated annual cost of more than $2.98 billion [1–3]. Potentially,
life-threatening infections can spread to surrounding tissues if
these diseases are not optimally treated, especially for immuno-
compromised patients. According to a WHO survey, 250 million
people worldwide have moderate to severe hearing loss. The
prevalence of hearing loss in the USA increases as the population
ages and causes serious social and economic burden [4,5].
Tinnitus, Meniere’s disease, and autoimmune inner ear disease are
also common disorders that significantly reduce an individual’s
quality of life [6–8].
The prevalence of ear disorders has spurred significant effort to
develop new therapeutic agents and some effort has also been
directed toward development of otic drug delivery systems to
improve the efficacy of treatments for diseases of the ear. The
demand for therapeutic treatments for ear disease is significant,
with a market of approximately $10 billion [4]. Fortunately, if
many of these diseases are properly diagnosed and treated in
their early stages, half of all hearing impairment including deaf-
ness may be successfully treated [9,10].
The ear is a very delicate and anatomically protected organ,
and this poses many challenges for otic drug delivery, especially
for the treatment of inner ear diseases. Traditional drug adminis-
tration routes (e.g. oral routes, injection, and topical routes) have
been mostly ineffective for treating inner ear diseases, due to
three major physical barriers for drug delivery to the ear: the tym-
panic membrane, the round and oval windows (OW), and the
blood–perilymph barrier (BPB) [11,12].
over systemic drug delivery systems depending on the disease
and therapeutic. Local drug delivery, in most cases, maximizes
drug concentration in the inner ear while minimizing systemic
exposure. Because of this ‘pharmacokinetic advantage,’ local drug
delivery systems are becoming the most common clinical therapy
method for the treatment of inner ear diseases [12]. Currently, the
three main pathways for local drug delivery to the inner ear are
the transtympanic, intratympanic, and intracochlear routes.
Developments in gene and stem cell therapy have also shown
that these therapies may be able to promote the regeneration of
the neural and hearing sensory cells in the inner ear, which pro-
vide another strategy for the treatment of hearing loss and other
ear diseases [13,14].
Otic drug delivery has gained increasing interest and has
advanced rapidly over the past few decades. Several review
articles on otic drug delivery have been published in the past
10 years, and they have covered the various aspects of otic drug
delivery (Table 1). However, most of these reviews focus on only
one particular drug delivery strategy or a specific disease type.
Only a very limited number of review papers have directly
addressed drug delivery to the ear. Moreover, there is a lack of
critical reviews that have summarized formulation design princi-
ples of the various local drug administration methods that guide
the development of otic drug products. Thus, this review high-
lights the basic formulation principles of the various local ear drug
administrations. In this article, we first provide a brief overview of
the anatomy and physiology of the ear as it relates to drug deliv-
ery. The major ear diseases and drug products are then discussed.
The advantages and disadvantages of otic administration routes
are reviewed and compared. This review also discusses promising
drug delivery systems for future clinical applications as well as the
current challenges that remain to be solved.

CONTACT Feng Zhang feng.zhang@austin.utexas.edu College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, A1920, Austin, TX
78712, USA
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 X. LIU ET AL.
Table 1. Key review papers of the past decade on otic drug delivery.
Review topics
Topical ear treatment
Nanoparticles drug delivery to inner ear
Patent review about the treatment of inner ear diseases
Summary about inner ear drug delivery strategies, clinical applications and the
current hurdles
Intracochlear drug delivery
Intratympanic drug delivery
Gene and stem cell therapy for the inner ear disease
Biodegradable materials for local drug delivery to the inner ear
Figure 1. Anatomy of the human ear. Image was adapted from reference [22]. RWM: round window membrane; OW: oval window; IHCs: inner hair cells; OHCs: outer
hair cells.
Anatomy and physiology of the ear
The human ear consists of three major parts: the outer ear, the
middle ear, and the inner ear (Figure 1). The outer ear extends
from the auricle, or pinna, along the ear canal and ends at the
tympanic membrane (eardrum). A healthy ear canal is slightly
acidic, with a pH value between 5.0 and 5.7, which can inhibit
bacterial growth [41,42]. At the end of the ear canal lies the tym-
panic membrane, which separates the middle ear from the outer
ear. The middle ear includes the ossicular chain, which consists of
the malleus, incus, stapes, and a mucosal lining that keeps the
middle ear environment moist. The Eustachian tube provides a
conduit between the middle ear and the upper airway to allow for
equalization of middle ear pressure [43].
The inner ear includes the cochlea, the organs of balance, the
vestibule (utricle and saccule), and the semicircular canals. The
cochlea is separated into three fluid-filled compartments. The mid-
dle compartment, called the scala media, is filled with endolymph;
while the lower and upper compartments, the scala tympani and
scala vestibule, are both filled with perilymph. The basilar mem-
brane supports the organ of Corti, which consists of highly organ-
ized mechanosensory cells: the inner and outer hair cells (OHC)
and their supporting cells (SC).
In the auditory process, sound waves are generally collected by
the pinna into the auditory canal, which causes vibration of the
tympanic membrane. The major function of the tympanic
References
Harmes et al. [15], Kaushik et al. [16]
Li et al. [17], Valente et al. [12], Pyykko et al. [18,19], Pritz et al. [20], Gang
et al. [21]
Nguyen et al. [22]
El Kechai et al. [23], Staecker et al. [24], Liu et al. [11] Teresa et al. [25], Hoskison
et al. [26], Shibata et al. [27], McCall et al. [28], Salt et al. [29], Swan et al. [30]
Alles et al. [31]
Peppi et al. [32]. Ayoob et al. [33], Borenstein et al. [34], Borkholder et al. [35]
Pai et al. [36], Seggas et al. [37], Meyer and Thomas [7], Herraiz et al. [38]
Hideto et al. [13], Kohrman et al. [39]
Nakagawa et al. [40]
membrane is the transmission of sound waves to the ossicular
chain. These vibrations cause the movement of the ossicular chain,
and the piston-like motion of the stapes transfers the pressure
wave to the inner ear fluids via the OW. The vibrations of the
inner ear hair cells convert the acoustic information to a bioelec-
tric signal. This signal is then transmitted to the brainstem via the
cochlear nerve and ultimately to the cerebral cortex, where the
information is translated into auditory sensations.
The first major barrier to drug delivery to the ear is the tym-
panic membrane, which is elliptical and slightly conical in shape
and separates the middle ear from the outer ear. The tympanic
membrane is around 0.1 mm thick and consists of three layers: an
outer epidermal layer, an inner mucosal layer, and a middle
fibrous layer with collagen [44]. The tympanic membrane is
impenetrable to all but relatively small and moderately lipophilic
molecules due to its keratin and lipid-rich stratum corneum [45].
The tympanic membrane is the first barrier to drug delivery to the
middle and inner ear, so it must be breached if drugs are deliv-
ered through intratympanic injection or intracochlear injection.
Because of its structural similarity to skin, transtympanic delivery
can transport a drug across an intact tympanic membrane from
the ear canal into the middle or inner ear [46].
The second major barrier to drug delivery to the ear consists of
the round window membrane (RWM) and the oval window (OW)
[47]. These are semipermeable membranes, located at the base of
the cochlea, that separate the cochlea from the middle ear. They

are considered either as barriers or as pathways in terms of drug
delivery to the cochlea.
The round window consists of three layers: (1) the outer epithe-
lium, which faces the middle ear; (2) the inner epithelium, which
bounds the inner ear; (3) and a middle connective tissue layer.
The outer and inner epithelial layers are separated by the connect-
ive tissue, which consists of fibroblasts, blood vessels, collagen,
and elastic fibers [48,49]. The round window has an average thick-
ness of 70 mm in humans, with a surface area around 2.2 mm2 [24].
Various animal models are used to evaluate otic drug delivery.
However, there are many differences between humans and other
species in the anatomy and physiology of the RWM [50]. The main
interspecies difference of the RWM is the overall thickness [51].
Substantial differences in RWM thickness exist between humans
70 mm, and rodents, with thicknesses of 10–14 lm for the chin-
chilla, and 12 lm for rats and 10–30 lm for guinea pigs. As the
physical barrier, the RWM isolates the cochlear perilymph from the
middle ear cavity. The diffusion of a drug across this membrane is
not only influenced by the thickness of the RWM, but also by its
physical conditions such as inflammation or morphological integ-
rity [52]. In another aspect, the elastic and semipermeable proper-
ties allow the round window to transport drugs into the cochlea
and to be used as the major pathway for drug delivery to the
inner ear from the middle ear [53]. Some studies have shown that
the factors that influence the permeability of the round window
include molecular size, concentration, solubility, and the electrical
charge of the molecule being transported and the thickness and
the condition of the RWM [51,52,54,55].
The OW is located near the scala vestibuli and contains the
footplate of the stapes and the annular ligament (Figure 1). This
structure has been suggested as a secondary route for drugs to
enter the perilymph of the vestibule [56]. However, it is difficult to
measure the amount of drug entering the inner ear through this
route [29]. Kang et al. used fluorescence technology to study and
quantify the intracochlear drug delivery through the OW. They
find that the fluorescently labeled bisphosphonate compound can
be delivered to the apical cochlear turn via the OW in the human
cochlea, and interstellar communication likely plays an important
role in determining patterns of drug delivery in the inner ear [57].
The third major barrier to drug delivery to the ear is the BPB.
The BPB is a physical and biochemical barrier between systemic
circulation and the cochlea. It is formed by a continuous capillary
endothelium that links blood vessels in the cochlea. The endothe-
lial cells are connected by tight junctions with no fenestrations
[48]. Like the blood–brain barrier, the BPB is permeable only to
small, lipid-soluble molecules. Molecules that are charged, water-
soluble, or have a high molecular weight may have low passive
diffusion across the barrier [58]. The BPB protects the ear from the
damage caused by exogenous and endogenous toxins in systemic
circulation, but it also presents challenges for efficient drug deliv-
ery from systemic circulation to the cochlea for treatment [59].
Major ear diseases and therapies
Many diseases can affect any of the three main compartments of
the human ear. The major diseases are summarized in Table 2.
Otitis externa is the most common disorder of the outer ear [60].
It affects the ear canal, with or without infection. This inflamma-
tion is usually generalized throughout the ear canal and can affect
the outer ear. It can be subdivided into acute (less than 6 weeks),
recurrent acute, and chronic (more than 3 months) [16]. Acute otitis
externa is a common clinical problem encountered in general
practice. It results from either a bacterial infection (90% of cases)
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 3
Table 2. The major diseases related to the parts of the human ear.
Outer ear Middle ear Inner ear
Diseases Acute external otitis Otitis media Hearing loss (sensorineural
(swimmer’s ear) hearing loss, noise inducing
hearing loss, sudden sensori-
neural hearing loss), auto-
immune inner ear disease,
Meniere’s disease, Tinnitus
or fungal infection (10% of cases). In certain cases, it may also be
associated with a variety of noninfectious dermatologic processes
[61,62]. Symptoms include ear discomfort, itchiness, discharge, and
impaired hearing.
Based on the latest clinical guidelines on the diagnosis and
management of acute otitis externa published by The American
Academy of Otolaryngology-Head and Neck Surgery Foundation,
the primary treatment of otitis externa includes management of
pain, administration of topical medications to control edema and
infection, removal of debris from the external auditory canal, and
avoidance of contributing factors [63]. Most acute otitis externa
can be successfully treated with over-the-counter analgesics and
topical eardrops. Commonly used eardrops include acetic acid
drops, which lower the pH of the ear canal; antibacterial or anti-
fungal preparations, which control bacterial or fungal growth. In
severe cases, treatment may require oral or intravenous antibiotic
therapy and narcotic analgesics [63].
Otitis media is the most common disorder of the middle ear
[64]. It is characterized by inflammation of the middle ear without
reference to etiology or pathogenesis. It is very common in chil-
dren. Otitis media can be subdivided into acute otitis media, otitis
media with effusion, chronic suppurative otitis media, and adhesive
otitis media [46]. Guidance for the medical and surgical manage-
ment of the different types of otitis media is well established
[2,65,66]. According to this guidance, the management of otitis
media should include an assessment of pain. Analgesics should be
used to treat pain regardless of whether antibiotic therapy is pre-
scribed. Antibiotic therapy and appropriate choices of antibiotic
agents should be carefully considered before the assessment of
the patient’s condition. Compared to systemic administration, local
delivery of antibiotics directly to the middle ear as a treatment for
otitis media could be an efficient strategy, and a safer one, in view
of the risk of systemic toxicity and emerging antibiotic resist-
ance [67,68].
Inner ear diseases mainly include hearing loss, Meniere’s disease,
tinnitus, and autoimmune inner ear disease. These are common
disorders that significantly influence an individual’s quality of life.
Hearing loss is one of the most common ear disorders in humans,
and it becomes increasingly prevalent with age [69,70]. Hearing
loss is the third most common chronic condition in the older
population (after arthritis and high blood pressure) [71]. The types
of hearing loss include sensorineural hearing loss, conductive hear-
ing loss, retrocochlear hearing loss, and mixed hearing loss. The dif-
ferent types of hearing loss result from different etiologies [25,72].
Meniere’s disease is a disorder of the inner ear with unknown
etiology. It is characterized by endolymphatic hydrops that occur
due to the dysfunction of types I and II spiral ligament fibrocytes.
The symptoms of Meniere’s disease include episodes of spontan-
eous, recurrent vertigo accompanied by fluctuating hearing loss
and intermittent tinnitus. The treatment of Meniere’s disease
includes the systemic and local administration of corticosteroids
and aminoglycoside (i.e. gentamicin, gadolinium, and kanamycin)
[31,73,74]. Tinnitus is defined as the experience of auditory percep-
tion in the absence of an external stimulus. It occurs in
4 X. LIU ET AL.

Table 3. Therapeutic agents and routes of administration for major ear diseases.
Type Molecule Diseases Route of administration References
Antibiotics Amoxicillin Acute otitis externa otitis media Systemic/local [26,79]
Ciprofloxacin
Neomycin
Antifungal Clotrimazole Otitis externa Systemic/local [60,80]
Tolnaftate
Antiviral Acyclovir Hearing loss due to viral infection Local [81,82]
Cidofovir Meniere’s disease
Ganciclovir
Anesthetic agents Benzocaine Pain from otitis Local [79,83]
Lidocaine Tinnitus
Steroids Dexamethasone Otitis Local [37,78,84]
Methylprednisolone Hearing loss
Prednisone Meniere’s disease
Tinnitus
Autoimmune inner ear disease
Aminoglycoside Gentamicin Meniere’s disease Local [6,85,86]
Streptomycin
Kanamycin
Antioxidants D-methionine Hearing loss Local [87–88]
Thiourea
n-Acetyl cysteine
Apoptosis inhibitors AM 111 Hearing loss Local [89,90]
(JNK inhibitor)
NMDA inhibitors Gacyclidine Tinnitus Local [91,92]
Ifenprodil
Esketamine
Gene Atonal homolog 1 (Atoh1) Hearing loss Local [13,39]
Stem cells

approximately 10–15% of the population and severely impairs the
quality of life in 1–2% of cases [33]. The pathology of tinnitus is
still unclear, but there are indications of potential involvement of
both peripheral and central neural components [75]. Results from
some studies indicate a beneficial effect on tinnitus after the use
of intratympanic dexamethasone injections in the treatment of
sudden hearing loss [76]. Autoimmune ear diseases result in hear-
ing loss when the immune regulation system is compromised
[8,77]. High-dose corticosteroids and the cytotoxic agent cyclo-
phosphamide are both safe and effective treatments of auto-
immune ear diseases [78].
Various treatments have been proposed for treating diseases of
the ear, whether they are infectious, inflammatory, metabolic, or
autoimmune conditions. Drugs can be delivered systemically, or
they can be directed locally to specific ear positions. Diseases of
the outer ear and some middle ear diseases are commonly treated
with topical antibiotics, antifungal agents, steroids, or anesthetic
agents. Inner ear diseases can be treated with steroids, aminogly-
coside, antioxidants, apoptosis inhibitors, or N-methyl-D-aspartate
(NMDA) inhibitors. Table 3 summarizes the main medicines used
for the treatment of ear diseases. In addition, an increasing num-
ber of new drugs now in development, either in the preclinical or
clinical research stage, are showing promising results for the treat-
ment of inner ear diseases [22,24,33,93].
Administration routes for otic drug delivery
Various administration routes have been developed for ear drug
delivery. The selection of the administration route depends on the
disease and the physicochemical properties of the drug substan-
ces. Generally, the administration routes for ear drug delivery can
be divided into systemic delivery routes and local drug delivery
routes. Table 4 summarizes the routes for ear drug administration.
Ear implants are beyond the scope of this article and readers are
directed to other recent review articles for detailed discussion of
ear implants [33,58,94,95].
Systemic drug delivery
Systemic drug delivery has multiple limitations, such as the BPB
and undesired side effects, but systemic drug delivery through
oral and intramuscular routes is still considered the most conveni-
ent method of drug administration to the various parts of ear. It is
currently accepted as the first-line approach in the treatment of
inner ear disorders [11]. Systemic drug delivery can be divided
into oral drug delivery and intravenous drug delivery.
Oral drug delivery is commonly used to treat middle ear and
inner ear disorders due to its convenience and easier compliance
by patients [15,16]. The bioavailability of oral delivery is limited
compared to local drug delivery, but it has wide appeal for many
patients. Oral antibiotics are commonly prescribed for treating
acute external otitis and otitis media [96]. However, the disadvan-
tages of oral antibiotics include the possibility of multidrug resist-
ance and imbalance of intestinal flora. Oral steroids, antioxidants,
and neuroprotective agents are commonly used to treat sudden
sensorineural hearing loss to improve hearing [26,97].
The other common systemic method is intravenous drug deliv-
ery (i.e. intravenous injection), which has been used for severe
middle ear infections such as acute mastoiditis and necrotizing oti-
tis externa. Intravenous steroids have also been used to treat hear-
ing loss and Meniere’s disease [98,99]. The side effects of
intravenous steroids are similar to those of oral steroids. Some
research has shown that steroid nanoparticles can reduce poten-
tial systemic side effects by improving oral bioavailabil-
ity [100,101].
Local drug delivery
During the past decade, interest in local drug delivery for the ther-
apy of ear diseases, especially for the inner ear, has increased sig-
nificantly. Compared to systemic administration, local application
has many advantages, especially for drugs that have a narrow
therapeutic window, significant first-pass metabolism, or serious
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 5

Table 4. Summary of the drug delivery routes to the ear.

Route Dosage form Disease Advantages Disadvantages
Systemic Oral Tablet Otitis media Self-administered Blood–cochlear barrier
Capsule Hearing loss Short-course Multidrug resistance
Meniere disease No interventions required Low local vascularization
Intravenous Solution Hearing loss High-dose Side effects
Nanomedicine Meniere disease
Local Topical Solution Acute Otitis externa Self-administered Limited applications
Suspension Otitis media Noninvasive Drops are unsuitable
Cream Short-course
Gel No interventions required
Nanomedicine
Transtympanic Hydrogels Otitis media Noninvasive Lower bioavailability
Nanomedicine Hearing loss
Meniere disease
Tinnitus
Intratympanic Suspension Hearing loss Easy access Invasive
Hydrogels Meniere disease Minimal risk of hearing loss Lower bioavailability
Nanomedicine Tinnitus Less surgical trauma Variability in dosage control
Autoimmune inner ear disease Local anesthesia Unknown pharmacokinetic profiles of drug
Intracochlear Solutions Hearing loss Dose control Highly invasive
Meniere disease Increased bioavailability Fluid leakage
Tinnitus Minor residual loss Difficult to access
Autoimmune inner ear disease General anesthesia

side effects. The advantages of local drug delivery are (1) the abil-
ity to bypass the BPB, (2) higher local drug concentration, and (3)
reduced side effects. Four types of local delivery systems are cur-
rently in use: topical, transtympanic, intratympanic, and coch-
lear delivery.
Topical drug delivery
Topical drug delivery has long played an important role in treating
ear disorders. This route involves direct administration of a drug
into the ear canal. Commonly used topical medications include
topical antibiotic, and antifungal drugs in the form of drops [102],
gels [103], or foams [104]. Otic topical drug administration pro-
vides a variety of advantages [105]. The most significant advan-
tage is the ability to achieve a local drug concentration much
higher than what could be achieved via systemic administration.
This is often required for therapeutic purposes; for example, the
elimination of biofilm bacteria requires 10–1000 times higher con-
centrations of antibiotics than planktonic bacteria. Other advan-
tages of topical drug delivery include rapid delivery, good patient
compliance, and the ability to combine different drugs into a sin-
gle formulation [106]. The major limitation of topical drug delivery
is the potential ototoxicity for some drugs, especially if the drug
concentration is very high [106].
Transtympanic drug administration
The tympanic membrane is the first barrier to the delivery of
drugs to the middle ear and inner ear. Successful transtympanic
delivery relies on drug diffusion through the intact tympanic
membrane from the ear canal into the middle and inner ear
(Figure 2) [46]. This process can be facilitated by permeation
enhancers [103,107]. Localized and sustained antibiotic delivery
directly to the middle ear by transtympanic administration to treat
otitis media has been achieved using chemical permeation
enhancers contained within a hydrogel. Using magnetic fields to
delivery magnetic drug nanoparticles has been demonstrated to
be a viable method to facilitate drug permeation through the tym-
panic membrane [108]. Recent studies have shown that peptides
can be actively transported through the intact tympanic
membrane of rats that have otitis media. This offers a new drug
delivery platform for the noninvasive delivery of gene therapy vec-
tor to the middle ear [109,110]. What we need to pay an attention
is that currently most of these methods are still in the preclinical
stage and have not advanced to clinical evaluation. One potential
disadvantage of transtympanic delivery is the limited amount of
drug that can be transported across the tympanic membrane.
Intratympanic drug administration
The middle ear has been used as a reservoir for drugs that can
then diffuse through the round window into the inner ear.
Intratympanic drug delivery involves injecting the drug in the mid-
dle ear cavity, and the drug substances then diffuse from the mid-
dle ear cavity into the cochlea (Figure 3). Drug diffusion across the
RWM is driven by the concentration gradient between the middle
ear and the perilymph-filled scala tympani on the opposite side of
the RWM. The drug diffusion rate depends on various factors, such
as the molecular weight, configuration, concentration gradient, lip-
ophilicity, and electrical charge of the drug, as well as the thick-
ness of the RWM [7]. The volume of intratympanic injection in
published studies ranges from 0.3 to 0.5 ml [7]. The RWM as a por-
tal to inner ear therapy has been studied extensively in animals;
however, very few study focused on the influence of inter-species
differences on intratympanic delivery. The thickness of the human
RWM, the presence of false membranes, the presence of tissue
plugs, and bony obliteration might influence the passage of sub-
stances through human RWM [25]. The influence of inter-species
differences on intratympanic drug delivery should be carefully
considered when designing human clinical trials. Table 4 summa-
rizes the advantages and disadvantages of this administra-
tion route.
Small pharmaceutical devices such as the osmotic pump,
microcatheter, and microWick have also been used for intratym-
panic drug delivery [25,33]. A number of clinical studies have been
published on the intratympanic injection of steroids for the treat-
ment of hearing loss and Meniere’s disease [37,84,111]. The limita-
tions of intratympanic drug delivery include the anatomic barriers
to drug absorption from the middle ear to the inner ear, the loss
of drug in the middle ear through the Eustachian tube, and the
6 X. LIU ET AL.
Figure 2. Different strategies for promoting transtympanic drug delivery. Image was adapted from reference [103].
Figure 3. Different ear components with intratympanic and intracochlear routes for local drug delivery to the inner ear. Image was adapted from reference [22].
unknown pharmacokinetic profiles of medications administered by
this route [29,112]. Controlled delivery systems, such as biodegrad-
able hydrogel and nanoparticles, were developed to overcome
these limitations of intratympanic drug delivery [23,113,114].
Intracochlear drug administration
Compared with intratympanic drug delivery, intracochlear drug
delivery bypasses the middle ear and allows drugs to reach the
intended sites directly. Intracochlear delivery can achieve better
drug bioavailability than other delivery methods [34]. Intracochlear
administration methods include direct injections, cochlear
implants, osmotic mini-pumps, and reciprocating perfusion [11].
The simplest method for drug delivery to the inner ear is the dir-
ect injection of drugs into the cochlea using a syringe. Small vol-
ume (approximately 5 mL) of drug solutions can be injected
directly into the cochlea through the RWM using 30–36 G fine-
gauge microneedle [115,116]. This method provides accurate
delivery for acute drug application to the base of the cochlea. In
addition, the use of microneedle for drug delivery across RWM
could create temporary microperforation in the RWM to greatly
enhance diffusion and duration of therapeutic agents.
Furthermore, the measurement of sealing the injection site could
reduce the fluid leaks that result from cochlear perforation,
improved the drug retention in perilymph [116]. The application
of microneedle minimizes damage to the RWM and prevents the
unintended disruption of endocochlear pressure fluctuation [117].
Furthermore, microneedles are being designed to detect precisely
the moment of penetration without tearing the RWM [118]. The
amount of the injected substance retained in cochlear perilymph
following an intracochlear injection could be measured using
fluorescein technology [57,116,119].
Cochlear implants and osmotic pumps offer some of the best
methods for controlled, automatic, complex dosing of numerous
compounds into the cochlea [28]. Although intracochlear adminis-
tration is more effective than intratympanic administration,
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 7

intracochlear drug delivery still has some limitations: It is invasive, Table 5. The common excipients used for topical otic drug delivery systems.
and it has potential toxicity due to the complex pharmacokinetics Function category Excipients Dosage forms
of the inner ear with locally delivered drugs [32,120]. pH modifier Acetic acid Solution, suspension,
Calcium carbonate liquid, drops
Citric acid
Strategies for developing otic formulations Hydrochloric acid
Benzethonium chloride
Topical drug delivery Benzyl alcohol
Hydrochloric acid
Typically, the dosage forms of topical otic drug administration Lactic acid
include ear drops, foams, gels, creams, and ointments. Drugs can Monopotassium phosphate
Sodium acetate
be dissolved or dispersed in water, glycerol, diluted alcohol, or
Sodium borate
propylene glycol. The selection of solvent vehicles depends on the Sodium citrate
solubility of the drug, because the concentration must be high Sodium phosphate, dibasic,
enough to account for the low-dose volume. monobasic
Sodium hydroxide
The viscosity of a topical formulation is also important, because Sulfuric acid
of the effect that viscosity has on the ability to effectively deliver Tromethamine
a drug to the site of infection. Excipients to increase the formula- Antimicrobial Aluminum acetate
tion viscosity can be added to retain formulations within the ear. preservative Benzalkonium chloride
Otic foam is commonly used to improve drug retention time in Benzethonium chloride
Benzyl alcohol
the ear canal. Studies have shown that the ciprofloxacin foam for- Boric acid
mulation is more efficacious than the solution for acute otitis Chlorobutanol
externa [104,121]. Isopropyl alcohol
Another important factor in formulating a topical agent is pH. Phenethyl alcohol
Methylparaben
Traditionally, topical otic preparations are acidic solutions or sus- Potassium metabisulfite
pensions with a pH of 3–4. Bacterial growth is inhibited at this pH Propylparaben
level [102]. Based on FDA inactive ingredient database and Thiomersal
approved topical otic products on market, the common used exci- Suspending agent Aluminum sulfate
pients are summarized in Table 5. Cetyl alcohol
Hydroxyethyl cellulose
Methylparaben
Polyvinyl alcohol
Intratympanic drug delivery
Stabilizing agent/thickening Creatinine
The cochlea is extremely sensitive to the fluid volume and ionic agent Hydrogenated soybean lecithin
Povidone K30
composition change, so intratympanic drug administration must Povidone K90
maintain the homeostasis of the inner fluids. The solution used for Poloxamer 407
intratympanic drug delivery must be within physiological pH range Emollient Cupric sulfate
(7.1–7.4). In addition, the formulation must be sterile, isotonic, and Glycerol
preservative free, as preservatives may affect round window per- Polyoxyl 40 Stearate
meability and lead to toxicity in the cochlear cells [55]. Solubilizing agent/wetting Polysorbate 20
agent Polysorbate 80
Formulations for intratympanic drug delivery can be solutions, sus-
Tyloxapol
pensions, hydrogels, or nanoparticles [12,38].
Tonicity agent Sodium chloride
The major advantage of hydrogels and nanoparticles is their Sodium sulfite
ability to deliver drugs for extended periods of time, thereby Ointment base Mineral oil Oil, ointment
greatly increasing the period of performance over solution formu- Peanut oil
lations. In addition, the hydrogel-based delivery system can enable Petrolatum
precise targeting of tissues and organs through the use of trigger-
ing mechanisms. These triggers such as pH, temperature, pressure,
or electrical potential will cause the hydrogel to swell and release OtiprioV is the first and only commercial intratympanic injection
R

the drug in a controlled fashion. Chitosan [30,113], hyaluronic acid
[23], poloamer 407 [111,122], and PLGA [68,123] are commonly
used to prepare hydrogel formulations. When developing hydro-
gels for intratympanic drug delivery, several important parameters
for treating otitis media. It is a single-dose otic ciprofloxacin sus-
pension with thermosensitive liquid-to-gel technology developed
by Otonomy, Inc. Poloxamer 407 is used in order to achieve a
hydrogel at body temperature. Another product OtividexV from
R

must be evaluated: (1) injectability through long and fine needles,
(2) residence time of the hydrogel in the middle ear, (3) drug
release and diffusion profiles, and (4) the ototoxicity of the hydro-
gel. Computer mathematical simulation shows that a major factor
controlling both the amount of drug entering the inner ear and
the distribution of drug loading along the length of the ear is the
duration the drug remains in the middle ear space [124]. Several
studies revealed that drug formulated in hydrogel shared signifi-
cantly more prolonged exposure than those formulated in aque-
ous solutions in the inner ear in both in vitro and in vivo
models [111,125].
Otonomy, using the same technology for Meniere’s disease treat-
ment, is in a phase-3 clinical trial.
Nanoparticle drug delivery systems have garnered much atten-
tion in the past decades for drug delivery to the inner ear. These
systems are of particular interest due to several advantages, such
as improving the solubility and bioavailability of poorly water-sol-
uble drugs delivered to the ear as well as providing for more effi-
cient and more accurate treatment [21]. Multiple nanoparticle
drug delivery systems have been studied, including liposome
[126], lipid nanocapsules [127], PLGA nanoparticles [128], polymer-
somes [114,129], and superparamagnetic nanoparticles. The critical
8 X. LIU ET AL.
Figure 4. Cell types present in the cochlea and the endogenous or transgenic
expression pattern of several genes required for hearing function. SV is the stria
vascularis cell, IHC is the inner ear hair cell, OHC is the outer hair cell, SP is the
spiral prominence cell, SC is the supporting cell, SG is the spiral ganglion cell,
and MC is the mesothelial cell. Image was adapted from reference [39].
properties of nanoparticles for intratympanic administration are
their permeability through the RWM, their distribution in the coch-
lea, their drug release profile, and their potential ototoxicity
[18,19]. Currently, no commercial nanoparticle product for intra-
tympanic administration exists; however, the application of nano-
particles to guide drugs to the inner ear after they are
administered to the middle ear shows great potential in ani-
mal models.
Intracochlear drug delivery
In intracochlear administration, the drug is introduced directly into
the cochlea via injection to overcome the barriers of the middle
ear (Figure 2) [35]. Similar to intratympanic drug delivery, the solu-
tion used for intracochlear drug delivery should be sterile, isotonic,
preservative free, and have a pH ranging from 7.1–7.4; since even
small changes in the inner ear fluids (e.g. composition, pH, osmo-
lality, and volume) could lead to deafness and ototoxicity.
A safe and robust technique for intracochlear delivery of drugs
is still under development. To date, most of the published studies
were conducted in animal models [116,130]. Very few clinical
study has evaluated intracochlear formulations to treat inner ear
disorders [94]. The first clinical trials focus on intracochlear drug
delivery is underway [131]. Based on pharmacokinetic data from in
vivo investigations in guinea pigs, dexamethasone concentration
in the perilymph of the scala tympani was estimated for different
application strategies in humans by means of a validated com-
puter model for calculation of substance concentrations in inner
ear fluids [131]. The simulation results indicated the continuous
intracochlear application of OzurdexV in addition to a cochlear
R
implant electrode carrier resulted in a stable drug concentration.
Although intracochlear drug delivery system is highly invasive
with lack of control over drug release profiles, intracochlear drug
delivery will likely become a promising approach to treat a host of
currently intractable diseases of the inner ear, given the develop-
ment of precision injection technology and our improved under-
standing of the mechanisms of inner ear diseases.
Table 6. List of drugs and excipients that may cause ototoxicity.
Drugs Solvents Other excipients
Topical and systemic antibiotics Polyethylene glycol Antiseptics
All aminoglycosides Propylene glycol Acetic acid
Platinum compounds Benzalkonium chloride Alcohol
Chloramphenicol Chlorhexidine
Polymyxin B Cresylate
Amphotericin B Gentian violet
Bacitracin Povidone iodine
Chloramphenicol
Macrolides
Nystatin
Nonsteroidal anti-inflammatory drugs
Salicylates
Indomethacin
Ibuprofen
Phenylbutazone
Paracetamol
Topical combinations
Polymyxin/neomycin/hydrocortisone
Ticarcilline/clavulanate
Biological formulations
Gene delivery and stem cell therapy are also promising
approaches to treat inner ear diseases [13,132]. Various biological
formulations are either in the preclinical or clinical stage, and no
product has yet been approved by the FDA.
Studies have shown that specific genes play a pivotal role in
governing hair cell differentiation and regeneration. Genetic
manipulation of these genes in humans would lead to protection,
replacement, and regeneration of the function cells relating to
hearing, including inner hair cells (IHC), OHC, and the spiral gan-
glion cells (SG) of the auditory nerve [39]. Successful gene therapy
must target a range of cell types using viral, nanoparticle, or lipo-
somes vectors. Multiple types of epithelial SC, stria vascularis cells
(SV), and spiral prominence cells play important roles in hearing
function (Figure 4). When determining the optimal vector, one
should consider potential side effects, cell specificity, duration of
gene expression, and access for delivery [13]. The major limitations
of gene therapy include immune response, lack of access to the
scala media, and the targeting efficiency of the gene [11].
Stem cell therapy provides a good option for treating hearing
loss [121]. Stem cell therapy uses embryonic stem cells, fetal dorsal
root ganglia, and otocyst cells in the inner ear to restore damaged
hair cells.
Potential ototoxicity
When delivered directly to the ear in large quantities, the drug
and its delivery carrier have the potential for ototoxicity regardless
of the administration route [20,133]. Toxicity in the middle and
inner ear is a major cause of sensorineural hearing loss, tinnitus,
and dizziness or vertigo [93,134]. It is essential to evaluate the oto-
toxic effect of otic formulations, not only on the inner ear but also
on the middle ear and tympanic membrane [135,136]. Table 6 pro-
vides the wide range of substances that can cause middle and
inner ear toxicity, including therapeutic drugs, antiseptics, and the
inert components of vehicles [137–139]. Aminoglycoside antibiot-
ics and platinum-based chemotherapeutic agents are the two
major classes of indispensable drugs that can cause serious oto-
toxicity [140,141]. The mechanisms underlying these side effects
are believed to involve the production of reactive oxygen species
in the cochlea, which can trigger hair cell-death pathways
[142,143]. The strategies for minimizing ototoxicity include local
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 9

Table 7. Summary of the latest local otic drug delivery product pipeline developments.
Company Product/description Research stage Administration route Indication
OtiprioV (ciprofloxacin otic suspenstion)
R
Otonomy Approved by FDA (2015) Intratympanic injection Otitis media
OtividexV (dexamethasone)
R
Phase III Meniere disease
OTO-311 (gacyclidine) Phase I Tinnitus
Auris/Xigen AM-111 (brimapitide) Phase III Intratympanic injection Hearing loss
KeyzilenV (esketamine)
R
Auris Phase III Intratympanic injection Tinnitus
Edison pharmaceuticals EPI-743 (antioxidant) Phase II Oral Hearing loss
Sound pharmaceuticals SPI-1005 (ebselen) Phase II Oral Hearing loss
Meniere disease
SPI-3005 (ebselen and allopurinol) Phase I Oral Chemotherapy or aminoglycoside-induced
ototoxicity
Autifony AUT00063 Phase I Systemic injection Hearing loss
GenVec/Novartis CGF166 (Atoh1 gene) Phase I intralabyrinthine injection Hearing loss
Sensorion SENS-401 (R-azasetron besylate/ Phase I Oral Hearing loss
A 5-HT3 receptor antagonist)
Nordmark Ancord (fibrinogenase) Phase II Systemic injection Hearing loss
PedmarkV (sodium thiosulfate)
R
Fennec Phase III Intratympanic injection Cisplatin-induced hearing loss
GSK Vestipitant (NK1 receptor antagonist) Phase II Oral Tinnitus
Synphora Latanoprost (PGF2 alpha agonist) Phase II Intratympanic injection Meniere disease
Strekin STR-001 (peroxisome proliferator-activated Phase II Intratympanic injection Hearing loss
receptor-gamma) agonist

administration of antioxidants or steroids to protect the inner ear
[144–146]. Next generation aminoglycoside antibiotics and plat-
inum compounds with less ototoxicity are being devel-
oped [147,148].
Recent advances in otic drug delivery
Significant advances in otic drug delivery have been achieved in
the past decade. In the past few years, several patents have been
filed on new compounds and drug delivery systems for the treat-
ment of inner ear diseases [22]. An improved understanding of
the mechanisms of inner ear diseases has led to new drugs that
target the voltage-gated potassium ion channels, glutamate recep-
tors, and inhibitors of the notch developmental signaling pathway
in order to treat hearing loss, tinnitus, and peripheral vestibular
dysfunction [22,149].
The development of sustained drug delivery to the RWM is also
crucial for local delivery to the inner ear. El Kechai et al. [23] eval-
uated a hyaluronic acid liposomal gel for the sustained delivery of
a corticoid to the inner ear after local injection into the middle ear
in a guinea pig model. Prolonged residence time at the site of
injection, as well as in the round window, was achieved without
negative effect on the hearing thresholds of the animal. The pres-
ence of liposomes in the formulation resulted in sustained drug
release in the perilymph for 30 d.
Yu et al. developed an injectable PEG-Silk hydrogel to achieve
sustained release of glucocorticoid. The glucocorticoid concentra-
tion in the perilymph remained above 100 ng/mL for at least 10 d
for the PEG-Silk formulation, but less than 12 h for the control for-
mulation of free glucocorticoid [150].
The advancement of new polymer materials and nanoparticle
therapies also provide alternative strategies to improve drug per-
meation through the inner ear barriers and target particular cells
in the inner ear [17,40]. Yoon et al. developed Arg8-conjugated
nanoparticles as a controlled drug release system for inner ear
therapy. The study results show that the nanoparticle is a promis-
ing candidate for drug or gene delivery [114]. It has been reported
that the incorporation of nanoparticle systems into a hydrogel
increases the residence time of the nanocarrier in the middle ear,
thus enhancing drug concentration in the inner ear.
Lajud et al. [113] have developed a nanohydrogel in which the
liposome was incorporated into a chitosan hydrogel. They discov-
ered that the nanohydrogel releases the liposome in a controlled
and sustained manner, and their in vivo study demonstrated that
intact liposomes were delivered into the perilymphatic space and
reached cellular structures in the scala media.
An increasing number of new chemical entities are in the pre-
clinical or clinical stage. Table 7 summarizes the product pipeline
for local otic drug delivery. Many of these compounds have dem-
onstrated promising results for treating inner ear disorders in an
effective and targeted manner [27,36]. Significant advances in
characterizing the drug release study in the inner ear will promote
the development of inner ear drug delivery [151,152].
Current challenges in otic drug delivery
Although significant advances in otic drug delivery were achieved
in the last decade, many challenges have yet to be overcome. The
difficulties are mainly related to the biology of the ear and the
molecular mechanisms of the inner ear diseases [149]. The path-
ology of some of inner ear diseases is poorly understood, includ-
ing sensorineural hearing loss, Meniere’s disease, and tinnitus
[132,149,153]. Our limited knowledge of these inner ear diseases
makes it challenging to find an effective drug and delivery strat-
egy. With a better understanding of the anatomy of the inner ear
and the pathology of inner ear diseases, more effective otic drug
products will be available on the market [154,155].
In addition, the pharmacokinetics of drugs in the inner ear are
not well defined, and data are limited regarding drug distribution,
round window permeability, and local bioavailability in the inner
ear [120,156]. There are no standard testing methods for evaluat-
ing inner ear drug delivery. For example, Franz diffusion cells are
commonly used to evaluate transdermal and topical drug delivery
formulations. However, this method, as well as the use of other
existing in vitro diffusion cell systems, may not be suitable to
evaluate drug diffusion through the middle ear and the RWM. A
convenient and efficient in vitro diffusion cell method for evaluat-
ing intratympanic formulations for inner ear drug delivery is not
yet available [20].
Furthermore, because the fluid volume in the inner ear is
extremely small, it is difficult to provide adequate samples for ana-
lysis by conventional analytical methods. Highly sensitive techni-
ques, such as LC-MS, are more adapted for assays in perilymph
samples, but the technique is complex and expensive.
Measurement of drug concentration at different locations in the
10 X. LIU ET AL.
cochlea presents a technical challenge for studying the perilymph
pharmacokinetics [156].
Although local drug delivery to the inner ear has been widely
accepted in clinical practice, the choice of drugs and application
protocols in human is largely empirically derived [157]. Study of
the pharmacokinetics of drugs in inner ear will become increas-
ingly important for optimization of clinical practice and the devel-
opment of otic drugs [35]. There are significant obstacles to study
the pharmacokinetics of drugs in inner ear. The pharmacokinetic
properties derived from animal experiments might not represent
those in humans. Pharmacokinetic is also affected by the inner ear
diseases. The computer simulation software developed by Salt has
demonstrated significant promise in facilitating the understanding
of drug pharmacokinetic in the inner ear [120,158–161]. To date,
the cochlear fluids simulator software is one of the most compre-
hensive simulation programs of the ear. It can be used to calculate
the effective drug concentration achieved when drug is delivered
directly to the inner ear of guinea pig, mouse, and human. The
simulation mechanism is based on the mathematical calculation of
physical process, which involves solute dispersal through diffusion,
longitudinal fluid flow, and clearances to other compartments.
This approach has been validated in numerous experiments in
which ion-selective electrodes were used to quantify the spread of
marker substances in the cochlear fluids [162].
Researchers have employed both in vitro and in vivo methods
to investigate otic drug delivery systems, but the in vitro–in vivo
correlation study is overlooked, and few reports compare the in
vitro and in vivo methods [11]. Generally, in vitro–in vivo correl-
ation for otic drugs is poor due to (1) the difference in the anat-
omy and physiology of the inner ear between the human and
other species, (2) the difference in RWM permeability in vitro and
in vivo, and (3) the lack of cochlear clearance in vitro. Future
research and development of an effective in vitro evaluation
method for inner ear drug delivery is needed.
Last but not least, the toxicity and safety of new inner ear drug
delivery systems are generally not well established. The inner ear
is a complex and subtle organ. Adverse effects and complications
of inner ear drug delivery can lead to severe side effects such as
hearing loss. The potential ototoxicity of novel drug delivery sys-
tems should be carefully examined.
Conclusion
Otic drug delivery, especially for the inner ear, is undergoing rapid
development. A wide range of drug delivery systems have been
developed in the last decade. Otic drug delivery can be divided
into systemic and local drug delivery.
Despite potential side effects, systemic drug delivery is a min-
imally invasive approach and is very convenient for self-adminis-
tration. Therefore, systematic delivery continues to play an
important role in otic drug delivery.
Local drug delivery can be further categorized as topical, intra-
tympanic, and intracochlear. Local drug delivery has the unique
advantages of achieving high therapeutic concentration in the ear
and minimizing systemic side effects.
The most suitable drug delivery route should be optimized
based on the disease, the potential side effects, and the require-
ments of the individual patient. Development of otic formulations
should follow these basic formulation principles to ensure efficient
and specific treatment for each type of ear disease.
Although many challenges in otic drug development still
remain, continued progress toward understanding the biology of
the ear has resulted in the development of novel drug delivery
systems, including hydrogels, nanoparticles, and other minimally
invasive drug delivery methods. These delivery systems offer bet-
ter treatment options with reduced side effects and a better qual-
ity of life for individuals who suffer from diseases of the ear.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Hugh Smyth http://orcid.org/0000-0002-6582-5869
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