College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode 673008
Acute otitis media (AOM) is one of the most prevalent paediatric diseases worldwide and a primary cause of antibiotic prescriptions in children. Even while systemic antibiotics are widely used, poor medication penetration into the middle ear, increasing antimicrobial resistance, persisting bacterial subpopulations, and biofilm development frequently hinder therapeutic effects. Moreover, effective medicine transport to the site of infection is severely limited by the distinct morphological and physiological barriers of the ear, such as the tympanic membrane, Eustachian tube clearance, and the blood-labyrinth barrier. These difficulties underscore the need for tailored and localized therapeutic strategies that can minimize systemic exposure and side effects while achieving sustained and therapeutically appropriate medication concentrations within the middle ear. Recent advances in drug delivery science have introduced innovative strategies designed to overcome these barriers. Trans-tympanic and ototopical delivery systems, including hydrogels, in situ gelling systems, nanoengineered vesicular carriers (such as proniosomes, glycerosomes, transfersomes, spanlastics, and liposomal systems), and sustained-release scaffolds, have demonstrated enhanced tympanic membrane permeation, prolonged drug retention, improved antibiofilm activity, and reduced dosing frequency in preclinical studies. These next-generation localized platforms aim to optimize pharmacokinetics at the infection site, improve patient compliance, and mitigate the development of antibiotic resistance. The pathophysiological basis of AOM, the biological and anatomical hurdles to traditional therapy, and the new localized drug delivery technologies intended to get around these challenges are all covered in detail discussed in this review.
Acute otorrhea or tympanic membrane protrusion combined with middle ear inflammation and systemic sickness symptoms is known as otitis media (OM). It falls into either the acute otitis media (AOM) or chronic otitis media(COM) categories[1].AOM is the inflammation of the middle ear, which leads to fluid buildup behind the ear drum. It usually develops as a subsequent consequence of upper respiratory tract infections caused by bacteria or viruses, as the microorganism move from the Eustachian tube(ET) to the middle ear cavity[2].OM contributes significantly to the illness burden in developing nations and is one of the main causes of irreversible hearing loss in children[3]. Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are the three dominant bacterial otopathogens[4]. Even though bacteria are most frequently isolated from middle ear infections the viral infection also raises the risk of middle ear bacterial infection, an initial viral upper respiratory infection (URI) results in changes to the ET and nasopharyngeal inflammation. Damage to this surface can be especially dangerous because the ET usually protects the middle ear. Bacterial colonization rates may rise as a result of viral URI-induced alterations in the nasopharynx. In particular, the respiratory syncytial virus (RSV), coronavirus, and influenza A virus can increase bacterial adhesion to the nasopharynx[5]. According to available data, AOM may be a polymicrobial illness in which respiratory viruses and bacteria coexist and contribute to the disease's development rather than a strictly bacterial illness[6,7]. A viral URI usually precedes or coexists with AOM. Additionally, it has been demonstrated that around one-third of infants with viral URI experienced AOM within four weeks of the onset. The available data indicates that certain virus-bacterial interactions could be linked to a distinct risk of developing AOM through several pathways[5].AOM associated with earache, fever, irritability, hearing loss, and a number of nonspecific symptoms, including rhinitis, cough, restless nights, poor appetite, vomiting, diarrhoea, abdominal pain, and anorexia[8]. Acute mastoiditis is the most common severe complication of AOM and it is due to the extension of the infection to the mastoid process of the temporal bone [9]Treatment options may include antibiotics, pain relievers, and in some cases, surgical intervention to address persistent or recurrent infections[10]. An oral course of a broad-spectrum antibiotic is typically used in the traditional management of AOM[11].But it remains a major leading cause for antibiotic prescriptions in children[12]. Accounting for up to 40% of all prescriptions in some situations. The Italian Medicines Agency has noted an increase in the use of antibiotics; thus, it is crucial to implement campaigns and guidelines for their prudent use. Furthermore, compared to other European countries, Italy uses more broad-spectrum antibiotics, which have a bigger influence on the emergence of antibiotic resistance[13]. Although the targeted targets are two relatively small parts of the body, these systemic medications are dispersed throughout the body. The drug levels that can be reached in the middle ear are restricted by systemic distribution, which result in adverse consequences[14].Ototopical drug delivery presents a highly promising alternative to oral antibiotics for the administration of therapeutics to the middle ear. The localized delivery of antibiotics across the tympanic membrane (TM) directly to the middle ear could potentially enhance the local bioavailability of drug while minimizing antibiotic exposure of normal flora elsewhere in the body, which together reduce the selective pressures responsible for antibiotic resistance[15].In the treatment of OM, traditional otic drops in suspension or solution form were frequently utilized. However, there is a serious drawback to these ear dosage forms that the eustachian tube rapidly removes the drops that are delivered to the middle ear, requiring frequent administration and resulting in poor patient compliance[16]. It has been anticipated that novel antimicrobial treatment strategies using innovative drug delivery systems (DDS) will be developed in order to provide medications sufficient to kill germs without causing systemic side effects. For the antimicrobial therapy of AOM, trans-tympanic or sustained-release medication delivery may be the most promising option[17].
1. Anatomy of ear: barriers to middle ear
The auditory system, a sensitive and well-structured organ, is in responsible for hearing and balance. It is divided into three anatomically separate areas: the outer ear, middle ear, and inner ear. The pinna and external auditory canal make up the outer ear, which extends to the TM, a tin barrier rich in lipids and keratin that is essential to sound transmission. The middle ear and pharynx are connected by the ET, which aids in balancing air pressure throughout the TM. For sensory processes linked to hearing and balance, the inner ear comprises the vestibular system and cochlea[18].
Figure :1 Structure of ear (created by BioRender.com)
With the middle ear, TM forms a barrier. The TM is made up of three layers: a stratified squamous keratinized epithelium on the outside, a collagen-rich fibro-elastic connective tissue in the middle, and a simple cuboidal mucosal epithelium on the inside. Human TM thickness varies from person to person and is generally between 80 and 100 μ m with a surface area of about 64.3 mm2. Because of its keratin- and lipid-rich stratum corneum (SC), it is impervious to all substances except a few tiny and somewhat lipophilic compounds. Partial hearing loss and middle ear infections can result from TM perforation[14].
Figure :2 Different layers of TM
2. Current treatment strategies
OM is most commonly treated with antibiotics. Oral amoxicillin is the first-line treatment for patients without a history of OM. A β-lactamase inhibitor, like clavulanate, is used in conjunction with amoxicillin for children who have purulent discharge, recurrent OM, or recent usage of β-lactam antibiotics. Cefdinir, cefpodoxime, cefuroxime, or ceftriaxone are substitutes for penicillin in moderate, delayed hypersensitivity situations. Azithromycin, clarithromycin, erythromycin/sulfisoxazole, or clindamycin are among the medications available to individuals with severe IgE-mediated hypersensitivity. Topical antibiotics are used if the tympanic membrane is perforated[19]. For AOM, amoxicillin is thought to be most affordable treatment option[20]. Oral antibiotics typically do not diffuse well into the middle ear, and the infections frequently develop biofilms, which further diminishes the effectiveness of antibiotic treatment[21,22].
3. Reasons for treatment failures in AOM
3.1 Antibiotic resistance
The presence of β-lactamase-producing bacteria is one of the primary resistance mechanisms in otitis media (OM). The PCV13 vaccine reduced total S. pneumoniae carriage by 18.2%, according to a large cross-sectional study of almost 13,000 children with acute OM (2001–2016). β-lactamase-producing S. pneumoniae bacteria were uncommon among carriers (0.8% of carriers, 0.4% overall). On the other hand, starting in 2012, the number of H. influenzae strains that produce β-lactamases rose dramatically, and they currently make up roughly 23.6% of isolates from OM patients[23]. Beyond antibiotic therapy, new treatment modalities must be developed due to the rise of antibiotic resistance[19].
3.2 Persistent bacterial population
Hypothesis suggests that there is a certain bacterial subpopulation that can persistently survive antimicrobial therapies[24]. The ability of a subpopulation to endure exposure to a bactericidal dose of antibiotics is known as persistence, as opposed to resistance, which is the capacity of bacteria to multiply when antibiotics are present. Antimicrobial persistent strains influence bacterial clearance failures and impact the effectiveness of antimicrobial therapy[17].
3.3 Biofilm formation
The creation of bacterial biofilm is an issue that prevents effective medication delivery to treat AOM[25–27]. The development of biofilms by otopathogens results in antibiotic resistance and immune system evasion[28]. Antibiotic resistance is increasingly linked to the pathophysiology of upper aerodigestive diseases. Bacteria adhere to a surface and can live with lower metabolic and reproductive rates when the biofilm aggregates. Antibiotics have a hard time breaking through the barrier that biofilms create, and the difficulty of cultivating biofilms frequently makes identification difficult[19].
4. Localised delivery of drug to ear
The ear is a biologically and anatomically protected organ. Therefore, it appears to be challenging to administer drugs to the diseased location, a number of attempts have been made using conventional delivery routes (oral and injection), all of which have demonstrated little efficacy and significant therapeutic disadvantages[29]. Because of the oval and circular windows, the TM, the blood-labyrinthine barrier (BLB), and the poor blood flow to the ear, the ear disease cannot be effectively treated. Thus, the best method for effectively treating ear disorders is local drug delivery[30,31]. Targeted drug delivery to the diseased area may be possible with localized ear therapy, resulting in higher therapeutic dosages and fewer systemic side effects. Additionally, by improving the drug's local bioavailability, it offers a very promising substitute for oral administration for patients whose systemic treatment has not worked or whom they cannot tolerate[15,32].
Conventional ear drops, in the form of suspension or solution, have been widely utilized historically. Antibiotics or combination of antibiotics and steroids are the most commonly given ear drops[33–36]. Ear drops containing topical antibiotics are less likely to result in resistance than systemic ones because the topical antibiotic concentrations at the infection site were higher than the minimum inhibitory concentration (MIC). Additionally, it was discovered that they had few adverse effects, including allergies and local discomfort. However, there is a significant disadvantage to such otic drops. Instilled liquid is quickly removed from the middle ear by the ET. Consequently, frequent application will be necessary, resulting in low patient compliance[37].
Additionally, otic foams, creams, and ointments have been used and have been shown to be more effective than solutions and suspensions at enhancing medication retention in the ear[38,39]. However, a major drawback of topical distribution is the potential for ototoxicity, especially at very high drug concentrations[40].
The goal of intratympanic medication delivery to the middle ear is to efficiently reach the middle and inner ears[41,42]. Another name for the intratympanic procedure is trans-tympanic[43,44]. The medication is injected or perfused into the middle ear to accomplish this. Because this method may readily enter the middle ear cavity, it is utilized to treat conditions like OM by directly inserting the medication using a gauge needle[45]. Another method for achieving trans-tympanic distribution is non-invasive ototopical administration using a drug carrier system[30,46]. However, this non-invasive administration through intact TM is challenging because to the stratum corneum layer's poor permeability, which acts as a trans-tympanic diffusion barrier[15].To penetrate the intact TM ototopically in this scenario, innovative drug delivery devices are required[37].
5. Innovative medication delivery techniques for effective localized middle ear delivery
In order to achieve a therapeutic drug concentration in the middle and inner ear, it is crucial to control the retention time and provide a continuous release profile. This will minimize the frequency of administration and optimize therapy. Newly created drug delivery systems were so tried, showing promising therapeutic potential[37].
5.1 Hydrogel and in-situ gel
Hydrogels are three-dimensional, hydrophilic, biocompatible, and biodegradable networks of polymeric matrix that can be manufactured or natural. Their viscosity can prevent rapid drug loss, particularly through the ET. Furthermore, prolonged drug release at the site of action may result from the increased drug deposition in the ear using hydrogels[37].
Ear delivery of drugs has also made use of organogels and in-situ gels. Gelation can prolong medication release, enhance drug absorption, and reduce outflow of the administered dosage[47,48].
In-situ gel advantages[49]
Table 1. Applications of hydrogels and in-situ gels in middle ear delivery
|
Gel base |
Drug loaded |
Route of administration |
Status of evaluation |
Major findings |
References |
|
Hyaluronic acid |
Ciprofloxacin and dexamethasone |
Trans-tympanic injection |
In-vitro dissolution study In-vivo study (animal studies) |
Dexamethasone and ciprofloxacin were released from the hydrogel for three weeks as a result of each drug's dissolution rate being nearly 50% lower than that of individual drug release. The safety of hydrogel's active and inactive components was demonstrated by ototoxicity tests conducted on guinea pigs, which served as a foundation for hydrogel formulations with sustained release. |
[50] |
|
Poloxamer®407–Polybutyl-phosphoester (P407-PBP) + Chemical permeation enhancers (sodium dodecyl sulfate, limonene) and bupivacaine |
Ciprofloxacin Hydrochloride |
Trans-tympanic delivery |
In-vitro study Ex-vivo study In-vivo study (chinchillas’ model) |
In chinchillas treated with P407-PBP containing drug + chemical permeation enhancers, the drug concentration in the middle ear fluid peaked at 369 g/ml, which is 92–738 times the minimum inhibitory concentration of Streptococcus pneumonia. A single hydrogel dose containing 8 mg of ciprofloxacin produced a peak drug concentration that was about 1000 times greater than oral antibiotic therapy at a daily dose of 6 mg. |
[51] |
|
Poloxamer-407, carbopol-940, and HPMC |
Norfloxacin |
Non-invasive trans-tympanic delivery |
Stability studies Cumulative Drug Release Ex-vivo Permeation Study |
F10 was chosen for a 60-day stability study since it had the most desirable features among the formulations. The F10 formulation achieved 95.6% of drug release at 360 minutes, according to ex-vivo release measurements. |
[52] |
|
Hyaluronic acid (HA) + Carboxymethyl cellulose (CMC) |
Ciprofloxacin/ Hydrocortisone |
Ototopical agent |
In-vivo animal study |
In case of OM with abraded mucosa, a combination of steroids and antibiotics integrated into HA-CMC hydrogels can effectively reduce fibrosis and adhesion in the middle ear. |
[53] |
5.2 Nanoengineered vesicular carriers
Regarding nanocarriers, they are colloidal systems at the nanoscale that can be delivered via different approaches, with ear delivery being one of the area of particular attention[54–58].
Several works have explored to improve TM permeability and enhance drug bioavailability in the ear through formulation of innovative drug delivery systems, such as proniosomes[59], glycerosomes[16], spanlastics[60], transferosomes [46] as well as glycerylated systems[61].
Table 2. Applications of nanotechnology in middle ear drug delivery
|
Nanocarrier - type |
Formulation base |
Drug loaded |
Route of drug administration |
Status of evaluation |
Major findings |
Ref |
|
Proniosomes |
Lecithin, span 65, cholesterol and Brij L4 |
Ofloxacin |
Non-invasive trans-tympanic delivery |
Ex-vivo trans tympanic permeation. Microbiological assays. In-vivo characterisation. |
Greater permeation profile after 24h and higher antibacterial and antibiofilm activities. Higher safety in ototopical administration |
[59] |
|
Nano fiber scaffold |
Ethyl cellulose and polyhydroxybutyrate polymer |
Ciprofloxacin and amoxicillin |
|
In-vitro drug release study (thermal shaker) Antimicrobial test Cell culture assay using MTT Animal testing Histological analysis |
Various inhibition zones ranging between 10 mm and 21 mm against S. aureus, P. aeruginosa, and E. coli. prolonged release of antibiotics from drug-loaded nanofibers. The controlled release of both antibiotics within nanofibers aided in the prevention of infection in the tympanic membrane of animals. |
[62] |
|
Glycerosomes |
Phosphatidylcholine (PC), glycerol cholesterol (CHO, stabilized cholesterol 95 %, nitrogen flushed) |
Triamcinolone acetonide |
Non-invasive ototopical application |
Ex-vivo TM permeation and deposition studies |
Greater flux and deposition Tolerability and efficacy in alleviating OM |
[16] |
|
Polyethylene glycol decorated nanoliposomes |
L-α-phosphatidyl-choline (PC) from egg yolk, cholesterol and polyethylene glycol 400 (PEG 400) and ethanol (95%) |
Levofloxacin |
Non-invasive trans-tympanic delivery |
Ex-vivo permeation study In-vivo study (drug deposition in TM and histopathological study) |
Improved drug permeation across the TM relative to nanoliposomes lacking PEG 400 and drug solution. Enhanced drug deposition inside the TM. High tolerability in ototopical administration |
[63] |
|
Nano-spanlastics |
Span 60 (sorbitan monostearate), tween 40 (polyoxyethylene 20 sorbitan monopalmitate), Brij 35 (polyoxyl 23 lauryl ether), cremophor RH 40 (polyoxyl 40 hydrogenated castor oil), L-a-phosphatidylcholine from egg yolk, sodium cholate |
Ciprofloxacin |
Non-invasive trans-tympanic delivery |
Ex-vivo TM permeation and drug deposition studies |
Increased drug permeation across the TM of albino rabbits when compared to ciprocin drops. |
[60] |
|
Terpene?augmented novasomes |
Fenchone, span 65, cholesterol, |
Levofloxacin |
Non-invasive targeted therapy |
Ex-vivo evaluation Microbiological assays In vivo analysis
|
Enhanced permeation through the tympanic membrane compared to conventional levofloxacin solution. Exhibit superior antibacterial and antibiofilm activity. |
[18] |
|
Brijosomes |
Cholesterol, polyoxyethylene (20) cetyl ether (Brij® 58), polyoxyethylene (2) oleyl ether (Brij® 92), |
Ciprofloxacin |
Non -invasive trans-tympanic delivery |
Ex-vivo trans-tympanic permeation study Microbiological tests In vivo study |
Enhanced penetration and flux compared to ciprofloxacin solution. Microbiological assessments confirmed superior antibacterial and antibiofilm activities Histopathological examination confirmed the formulation’s safety for ototopical delivery |
[64] |
|
Transfersomes |
l-α-Phosphatidylcholine (PC) from egg yolk, cholesterol (CH), Span 20 (sorbitan monolaurate), Span 60 (sorbitan monostearate), Span 65 (sorbitan tristearate), Pluronic L-121, Pluronic P-123, Pluronic F-127, Pluronic F-68, sodium cholate, sodium deoxycholate, Cremophor EL, and Cremophor RH 40 |
Ciprofloxacin |
Non-invasive trans-tympanic ototopical delivery |
Ex-vivo permeation studies (through ear skin and TM of rabbits), and in-vivo evaluation. |
Showed enhanced ex-vivo drug flux through ear skin and TM and greater extent of in-vivo drug deposition in the TM of albino rabbits when compared with the commercial product |
[46] |
CONCLUSION
One of the most prevalent diseases in children and a primary cause of antibiotic use is acute otitis media (AOM). However, because they do not reach enough concentrations in the middle ear, conventional oral antibiotics frequently do not yield the best outcomes. Treatment efficacy is further diminished by issues such biofilm formation, persistent bacteria, and antibiotic resistance. Drug distribution to the infection site is additionally restricted by the ear's natural barriers, including the tympanic membrane and Eustachian tube clearance. A promising alternative is the administration of drugs locally to the middle ear. Hydrogels, in-situ gels, and nano-based carriers are examples of novel systems that can enhance drug penetration through the tympanic membrane, prolong the duration of drug retention, and offer sustained release. These innovative techniques may help combat antibiotic resistance, limit systemic side effects, and lower dosage frequency. Before these technologies become standard therapies, further clinical research is required, despite the fact that many of them have demonstrated promising results in laboratory and animal tests. Overall, novel localized drug delivery techniques have great promise for enhancing the treatment of acute otitis media and overcoming the drawbacks of traditional therapy.
REFERENCES
Fathima Safa E K, Archana O, Rifana C K, Dr. Manoj K, Targeted Middle Ear Drug Delivery in Acute Otitis Media: Navigating Tympanic Membrane Barriers through Advanced Localized Therapies, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 3, 2798-2811. https://doi.org/10.5281/zenodo.19191142
/10.5281/zenodo.19191142
