Intratympanic Gels for Inner Ear Disorders: A Scoping Review of Clinical Trials.

OBJECTIVE: Intratympanic injections are a safe, well tolerated procedure routinely performed by ENT's specialists. Intratympanic injections of gels have the potential to deliver therapeutics into the cochlea through the round window membrane prolonging the release of drugs in the inner ear compartment. Aim of the present review is to summarize clinical trials testing pharmacological treatments for inner ear pathologies through intratympanic gel formulations. DATA SOURCES: Online databases (Google scholar and PubMed) and registers (Clinicaltrials.gov and Euclinicaltrial) were used to identify clinical trials performed between 1990 and 2022. REVIEW METHODS: PRISMA criteria have been followed. Clinical trials testing gel formulations administered through local intratympanic injections and targeting inner ear disorders were included. All the reports were identified by the authors working in pairs sequentially selecting only studies respecting the inclusion criteria. RESULTS: A total of 45 clinical studies have been noticed; the gels for intratympanic injection are in the form of poloxamers or hyaluronic acid combinations; the trials found target different kind of inner ear disorders: acquired-stable SNHL, tinnitus, acute sudden SNHL, Meniere disease, cisplatin induced ototoxicity and hearing preservation in patients undergoing cochlear implant surgery. CONCLUSION: Few studies listed do not provide the specific kind of gel formulation used but only report the intratympanic delivery vehicle as "gel" or "thermogel". Multiple clinical studies have been targeting several forms of inner ear disorders by injecting different compounds through poloxamer and hyaluronic acid formulations. Larger and more advanced clinical stages are necessary to confirm the efficacy of these chemical compounds.

A state-of-the-art analysis of pharmacological delivery and artificial intelligence techniques for inner ear disease treatment.

Over the last several decades, both the academic and therapeutic fields have seen significant progress in the delivery of drugs to the inner ear due to recent delivery methods established for the systemic administration of drugs in inner ear treatment. Novel technologies such as nanoparticles and hydrogels are being investigated, in addition to the traditional treatment methods. Intracochlear devices, which utilize current developments in microsystems technology, are on the horizon of inner ear drug delivery methods and are designed to provide medicine directly into the inner ear. These devices are used for stem cell treatment, RNA interference, and the delivery of neurotrophic factors and steroids during cochlear implantation. An in-depth analysis of artificial neural networks (ANNs) in pharmaceutical research may be found in ANNs for Drug Delivery, Design, and Disposition. This prediction tool has a great deal of promise to assist researchers in more successfully designing, developing, and delivering successful medications because of its capacity to learn and self-correct in a very complicated environment. ANN achieved a high level of accuracy exceeding 0.90, along with a sensitivity of 95% and a specificity of 100%, in accurately distinguishing illness. Additionally, the ANN model provided nearly perfect measures of 0.99%. Nanoparticles exhibit potential as a viable therapeutic approach for bacterial infections that are challenging to manage, such as otitis media. The utilization of ANNs has the potential to enhance the effectiveness of nanoparticle therapy, particularly in the realm of automated identification of otitis media. Polymeric nanoparticles have demonstrated effectiveness in the treatment of prevalent bacterial infections in pediatric patients, suggesting significant potential for forthcoming therapeutic interventions. Finally, this study is based on a research of how inner ear diseases have been treated in the last ten years (2012-2022) using machine learning.

Relapsing autoimmune inner ear disease with significant response to methotrexate and azathioprine combination therapy: A case report and mini literature review.

RATIONALE: Autoimmune inner ear disease typically presents with bilateral hearing loss that progresses over weeks or months though its mechanisms are unknown. Corticosteroids are the first-line treatment, but their responses are variable and relapses are frequent. Thus, many experts have sought to replace corticosteroids with immunosuppressive agents. PATIENT CONCERNS: A 35-year-old woman experienced a progressive hearing impairment, initially on the left side and later becoming bilateral. Her response to corticosteroid monotherapy was temporary, and there have been two relapse episodes over several months. DIAGNOSES: Autoimmune inner ear disease was considered due to evidence of autoimmunity combined with a clinical course of bilateral and recurrent sensorineural hearing loss and a partial response to corticosteroid therapy. INTERVENTIONS: The patient received a 3-day mini-pulse of methylprednisolone at 250 mg/d, followed by 12 mg/d maintenance, and concurrently began an azathioprine regimen gradually increasing to 100 mg/day as a corticosteroid-sparing agent. OUTCOMES: Three weeks after immunosuppressive therapy, hearing and pure-tone audiometry improved, and after 7 weeks, methylprednisolone was tapered to 8 mg/d. The dosage was further reduced by adding methotrexate at 7.5 mg/week, resulting in a reduction to 4 mg/d as maintenance therapy after 4 weeks. LESSONS: For patients who are unresponsive to corticosteroids or experience difficulty tolerating them, a combination therapy of methotrexate and azathioprine is recommended as a viable alternative as this regimen is well-tolerated and yields positive outcomes.

Disease-Modifying Antirheumatic Drugs in the Treatment of Autoimmune Inner Ear Disease: A Systematic Review and Meta-Analysis of Auditory and Vestibular Outcomes.

OBJECTIVE: To answer the following question: In patients with primary autoimmune inner ear disease (AIED), (population) what impact do disease-modifying antirheumatic agents (DMARDs) (intervention) when compared with no treatment or corticosteroids (comparison) have on auditory and vestibular outcomes (outcome)? STUDY DESIGN: Systematic review and meta-analysis. DATA SOURCES: According to PRISMA guidelines, PubMed, Scopus, CINAHL, and Cochrane Library databases were searched from inception to March 10, 2022. STUDY SELECTION: Studies of patients receiving DMARDs for the treatment of AIED were selected for review. Case reports, phase I/II trials, studies of patients with secondary AIED, and studies of AIED patients receiving solely corticosteroids were excluded. DATA EXTRACTION: Primary outcomes were pure-tone audiometry and speech discrimination scores at baseline and after DMARD treatment. Secondary outcomes were rates of subjective audiovestibular complaints and rates of adverse reactions. No objective vestibular outcomes underwent meta-analysis. DATA SYNTHESIS: Mean differences were calculated using RevMan 5.4. Heterogeneity was assessed with the Q test and I2 statistic. Pooled prevalence rates of audiovestibular symptoms were expressed as a percentage with 95% confidence intervals. RESULTS: Ten studies with a total of 187 patients were included. Treatments included methotrexate, etanercept, azathioprine, anakinra, cyclophosphamide, rituximab, and infliximab. Mean treatment duration was 10.8 ± 22.2 months and mean follow-up was 13.7 ± 8.1 months. The pure-tone audiometry and speech discrimination scores mean differences between baseline and post-DMARD were -2.1 [-4.1, -0.1] dB and 13.9 [8.5, 19.4] %, respectively. Seven studies reported 38 adverse events, four of which were classified as serious. CONCLUSION: DMARDs showed statistically significant improvement in auditory outcomes, as well as subjective symptoms, with relatively low rates of adverse events. They warrant further exploration to better compare with corticosteroids.

Repurposable Drugs That Interact with Steroid Responsive Gene Targets for Inner Ear Disease.

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere's disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials.

Use of biologics for treatment of autoimmune inner ear disease.

OBJECTIVE: Biologic medications are novel therapeutics in the treatment of Autoimmune Inner Ear Disease (AIED), an etiology of Sensorineural Hearing Loss (SNHL). The goal of this study is to review the currently available literature on the efficacy of biologic medications on autoimmune-mediated hearing loss and associated symptomology among patients with AIED. METHODS: A systematic review of Pubmed, Scopus, Cochrane, and Web of Science databases was conducted to identify studies investigating the impact of biologic medications on hearing outcomes. Bias assessment was independently conducted by three authors and studies were stratified based on risk of bias. RESULTS: Of 174 unique abstracts screened, 12 articles met inclusion criteria for formal review. One randomized control trial, seven prospective cohort studies, and four retrospective cohort studies were included. Seven biologic medications, Etanercept, Infliximab, Adalimumab, Golimumab, Rituximab, Anakinra, and Canakinumab, were identified targeting three unique molecular targets, TNF-α, CD20, and IL-1. CONCLUSION: The effects of biologic medications in treating SNHL was highly variable without clear efficacy of a drug or drug category, likely due to rarity of disease, multifactorial etiologies of AIED, and cohort heterogeneity. However, several medications alleviate symptoms associated with AIED, such as vertigo and tinnitus. While biologic medications may be promising therapeutics in AIED patients, the evidence is currently inconclusive. Large-scale randomized control trials and prospective cohort reviews are required to establish the efficacy of biologic medications in treating hearing loss.

Local drug delivery using poly(lactic-co-glycolic acid) nanoparticles in thermosensitive gels for inner ear disease treatment.

Intratympanic (IT) therapies have been explored to address several side effects that could be caused by systemic administration of steroids to treat inner ear diseases. For effective drug delivery to the inner ear, an IT delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and thermosensitive gels to maintain sustained release. Dexamethasone (DEX) was used as a model drug. The size and zeta potential of PLGA NPs and the gelation time of the thermosensitive gel were measured. In vitro drug release was studied using a Franz diffusion cell. Cytotoxicity of the formulations was investigated using SK-MEL-31 cells. Inflammatory responses were evaluated by histological observation of spiral ganglion cells and stria vascularis in the mouse cochlea 24 h after IT administration. In addition, the biodistribution of the formulations in mouse ears was observed by fluorescence imaging using coumarin-6. DEX-NPs showed a particle size of 150.0 ± 3.2 nm in diameter and a zeta potential of -18.7 ± 0.6. The DEX-NP-gel showed a gelation time of approximately 64 s at 37 °C and presented a similar release profile and cytotoxicity as that for DEX-NP. Furthermore, no significant inflammatory response was observed after IT administration. Fluorescence imaging results suggested that DEX-NP-gel sustained release compared to the other formulations. In conclusion, the PLGA NP-loaded thermosensitive gel may be a potential drug delivery system for the inner ear.

Evaluation of a transtympanic delivery system in Mus musculus for extended release steroids.

OBJECTIVE: The current investigation evaluated a novel extended release delivery system for treating inner ear diseases. The platform technology consists of a film forming agent (FFA) and microsphere component to localize and extend drug delivery within the ear. STUDY DESIGN: Studies evaluated dissolution kinetics of microspheres with multiple encapsulates, testing of a variety of FFAs, and ability to localize to the round window membrane in mice in vivo. SETTING: Studies were completed at Orbis Biosciences and The University of Kansas Medical Center. SUBJECTS: In conjunction with in vitro characterization, an infrared dye-containing microsphere formulation was evaluated for round window membrane (RWM) localization and general tolerability in C57/BL6 Mus musculus for 35 days. METHODS: In vitro characterization was performed using upright diffusion cells on cellulose acetate membranes, with drug content quantified by high performance liquid chromatography. Mus musculus dosing of infrared dye-containing microspheres was performed under anesthesia with a 27 GA needle and 2.0 µL injection volume RESULTS: In vitro dissolution demonstrates the ability of the FFA with microsphere platform to release steroids, proteins, peptides, and nucleic acids for at least one month, while necroscopy shows the ability of the FFA with dye-loaded microspheres to remain localized to Mus musculus RWM for the same period of time, with favorable tolerability. CONCLUSIONS: Combining FFA and microsphere for localized drug delivery may enable cost-effective, extended release local delivery to the inner ear of new and existing small molecules, proteins, peptides, and nucleic acids.

Inner ear drug delivery: Recent advances, challenges, and perspective.

Effective and safe treatment of auditory and vestibular diseases has become increasingly dependent on inner ear drug delivery systems. This review highlights recent advances in inner ear drug delivery research and technologies. The focus is on strategies to overcome delivery barriers and to improve drug residence and targeting, with special attention to in vivo animal and human studies. The research in gene and stem cell delivery to the inner ear is briefly reviewed. Newly developed research tools to address experimental challenges and safety issues are discussed. Local drug delivery to the inner ear with non-invasive or minimally invasive approaches still remains challenging. Nanocarrier-based systems with sustained and targeted delivery properties may be promising for future clinical applications. Precisely controlled intratympanic and intracochlear administration with minimized trauma to the delicate inner ear represents the future perspective in inner ear drug research and development. Trans-oval window delivery may be promising as it allows direct delivery of drugs to the vestibule for vestibular disorders while avoiding the undesired effects due to drug distribution to the cochlea.

Anatomical basis of drug delivery to the inner ear.

The isolated anatomical position and blood-labyrinth barrier hampers systemic drug delivery to the mammalian inner ear. Intratympanic placement of drugs and permeation via the round- and oval window are established methods for local pharmaceutical treatment. Mechanisms of drug uptake and pathways for distribution within the inner ear are hard to predict. The complex microanatomy with fluid-filled spaces separated by tight- and leaky barriers compose various compartments that connect via active and passive transport mechanisms. Here we provide a review on the inner ear architecture at light- and electron microscopy level, relevant for drug delivery. Focus is laid on the human inner ear architecture. Some new data add information on the human inner ear fluid spaces generated with high resolution microcomputed tomography at 15 µm resolution. Perilymphatic spaces are connected with the central modiolus by active transport mechanisms of mesothelial cells that provide access to spiral ganglion neurons. Reports on leaky barriers between scala tympani and the so-called cortilymph compartment likely open the best path for hair cell targeting. The complex barrier system of tight junction proteins such as occludins, claudins and tricellulin isolates the endolymphatic space for most drugs. Comparison of relevant differences of barriers, target cells and cell types involved in drug spread between main animal models and humans shall provide some translational aspects for inner ear drug applications.

Animal model studies yield translational solutions for cochlear drug delivery.

The field of hearing and deafness research is about to enter an era where new cochlear drug delivery methodologies will become more innovative and plentiful. The present report provides a representative review of previous studies where efficacious results have been obtained with animal models, primarily rodents, for protection against acute hearing loss such as acoustic trauma due to noise overexposure, antibiotic use and cancer chemotherapies. These approaches were initiated using systemic injections or oral administrations of otoprotectants. Now, exciting new options for local drug delivery, which opens up the possibilities for utilization of novel otoprotective drugs or compounds that might not be suitable for systemic use, or might interfere with the efficacious actions of chemotherapeutic agents or antibiotics, are being developed. These include interesting use of nanoparticles (with or without magnetic field supplementation), hydrogels, cochlear micropumps, and new transtympanic injectable compounds, sometimes in combination with cochlear implants.

Clinical trials for inner ear drugs: Design and execution challenges.

The development of therapies for the inner ear presents unique opportunities and challenges. On the one hand, the ear presents an opportunity for localized drug delivery to avoid systemic side effects. However, we do not understand the pathobiology of many common ear disorders clearly enough to develop rational therapeutic solutions. Further, identification of biomarkers beyond conventional audiometry and balance testing to track disease progress and recovery remain elusive. Because of the comparatively low incidence and prevalence of many inner ear disorders, as well as issues with respect to timing of drug delivery for certain diseases, multi-center, multi-investigator collaborative networks are required to promote effective clinical trial design.

Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications.

Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration.

Controlled drug release to the inner ear: Concepts, materials, mechanisms, and performance.

Progress in drug delivery to the ear has been achieved over the last few years. This review illustrates the main mechanisms of controlled drug release and the resulting geometry- and size-dependent release kinetics. The potency, physicochemical properties, and stability of the drug molecules are key parameters for designing the most suitable drug delivery system. The most important drug delivery systems for the inner ear include solid foams, hydrogels, and different nanoscale drug delivery systems (e.g., nanoparticles, liposomes, lipid nanocapsules, polymersomes). Their main characteristics (i.e., general structure and materials) are discussed, with special attention given to underlining the link between the physicochemical properties (e.g., surface areas, glass transition temperature, microviscosity, size, and shape) and release kinetics. An appropriate characterization of the drug, the excipients used, and the formulated drug delivery systems is necessary to achieve a deeper understanding of the release process and decrease variability originating from the drug delivery system. This task cannot be solved by otologists alone. The interdisciplinary cooperation between otology/neurotology, pharmaceutics, physics, and other disciplines will result in improved drug delivery systems for the inner ear.

The Balance of Tissue Inhibitor of Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Autoimmune Inner Ear Disease Patients.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein implicated in the control of inflammation in a number of autoimmune diseases. We hypothesized that the balance of TIMP-1 and matrix metalloproteinase-9 (MMP-9) may influence the control or perpetuation of inflammation in corticosteroid-responsive (RES) and corticosteroid-resistant (NR) autoimmune inner ear disease (AIED) patients. In the present study, we observed that plasma from AIED patients exhibited greater levels of TIMP-1 values compared with normal healthy controls. TIMP-1 abrogates lipopolysaccharide-mediated interleukin (IL)-1ß release from peripheral blood mononuclear cells in a dose-dependent manner. RES AIED patients have higher basal TIMP-1 levels and produce more TIMP-1 in response to IL-1ß. Conversely, consistent with our previous studies, we found that NR patients have higher basal MMP-9 levels and produce more MMP-9 levels in response to IL-1ß.

Recent advances in therapeutics and drug delivery for the treatment of inner ear diseases: a patent review (2011-2015).

INTRODUCTION: Inner ear disorders such as hearing loss, tinnitus, and Ménière's disease significantly impact the quality of life of affected individuals. Treatment of such disorders is an ongoing challenge. Current clinical approaches relieve symptoms but do not fully restore hearing, and the search for more effective therapeutic methods represents an area of urgent current interest. Areas covered: Thirty four patents and patent applications published from 2011 to 2015 were selected from the database of the U.S. Patent and Trademark Office (USPTO) and World Intellectual Property Organization (WIPO), covering new approaches for the treatment of inner ear disorders described in the patent literature: 1) identification of new therapeutic agents, 2) development of sustained release formulations, and 3) medical devices that facilitate delivery of such agents to the inner ear. Expert opinion: The search for effective treatments of inner ear disorders is ongoing. Increased understanding of the molecular mechanisms of hearing loss, Ménière's disease, and tinnitus is driving development of new therapeutic agents. However, delivery of these agents to the inner ear is a continuing challenge. At present, combination of a suitable drug with an appropriate mode of drug delivery is the key focus of innovative research to cure inner ear disorders.