A staggering number of people (over 15%) of the population suffer from hearing loss. the prevalence increases with age, with half the population over the age of 60 experiencing hearing loss. Despite being the third most common chronic condition after arthritis, hearing loss is largely managed (e.g., hearing aids) rather than treated.
The inner ear is an organ capable of rapidly generating an active immune response, although, like the brain, it has a blood labyrinthine barrier and few resident macrophages. Alhtough once considered an immunologically privileged organ, it has connections to the lymphatic system through cervical lymph nodes. Hearing loss in some invidiuals is thought to be mediated by local autoimmune resposnes, and treatment with immunosupressive drugs can restore some cochlear function. A number of otic drugs are in clinical trial stages. For example, SPI-1005 developed by Sound Pharmaceuticals and designed to protect sensory hair cells form noise induced hearing lss is currently in Phase II trials with the US Navy and Marine Corps. Merz Pharmaceuticals is also currently recuriting for Phase III trials with neramexane, which has shown promise in the treatment of tinnitus. Auris Medical also have Phase IIb trials with AM-101 for the treatment of acute inner ear tinnitus and AM-111 to treat acute sensorineural hearing loss. Both Adherex and Sound Pharmaceuticals also have drugs in clinical trials that protect against the adverse side effects of the chemotherapeutic cisplatin.
Common Agents Used in the Treatment of Hearing Disorders:
–Antiboiotics For example azalid antibiotics have been used for topical administration to the ear for the treatment and/or prevention of otic infections (US 2006/0046970). Clinical studies for treating Meniere’s disease using aminoglycoside antiotics such as gentamicin sulfate have been performed with some sucess (WO 97/38698). The local devliery of vancomycin has been shown to have clincial applicaiton for treating chronic otitis media caused by methicillin reistant Staphylococcus aureus (MRSA) (Lee, J. Controlled Release 96 (2004)).
–Glucocorticoids have been tranditionally used to reverse hearing loss in a variety of cochlear disorders. These include autoimmmune and other systemic immune diseases. However, their side effects prevent long term therapy. Most glucocorticoids have three physiological functions: anti-inflammation, immune suppression and increased sodium transport/reabsorption.
–Anti-Cytokine Therapy: Inhibitors of TNF? such as TNF soluble receptor type I has been shown to prevetn experimental otitis media with effusion (OME). The anti-TNF? antibody, Etanercept, has also been shown to reduce inflammatory response which leads to cochlear disease.
–Mineralocorticoid fludrocortisone has also been proposed for reversal of autoimmune hearing loss (US 2006/0013858).
Local Delivery
In recent years there has been increasing interest in the treatment of inner-ear disorders by local rather than systemic application of drugs. Substances are applied intratypanically, which means they are inected into the middle-ear cavity. This procedure is based on the premise that the drug will contact the round window membane (RWM) of the ochlea, enter the scala tympani (ST) and spread throught the ear. The target tissues might include the sensory hair cells, the afferent never fibers and supporintg cells of the cochlea (hearing) or vestibular (balance) portions of the inner ear. Several drugs that are applied directly to the inenr ear are in widespead clinical use for the treatment of inner-ear disorders.
However, the pharmacoknetics of drugs in the inner ear is not well defined and the field is plagued by technical problems in obtaining pure samples of the inenr ear fluids for analysis. Although in theory the local application of drugs to the inner ear has great potentail, in practice there are numerous technical difficulties to overcome. Important issues include (i) which parts of the ear do drugs reach, in what concentration and with what time coure? (ii) how do different delviery methods of application protocols influence the drug levels at each time point at the different locations in the ear? (iii) how variable are the drug levels achieved with different delivery protocols and what are the major sources of variation? (Salt, DDT, 10(19), 2005).
When substances are applied intratympanically, the assumption is that they will enter the scala tympani through the RWM and then be distibuted throughout the cochlear fluids. However, it is very difficult to predict the amounts odf drugs that will actually reach the cochlear fluid space (Nakagawa, Current Drug Therapy, 3(2), 2008).
–Implantable mini-pumps have been used for local drug delivery to the cochlea in animal experiments. The use of a local viral gene transfer a(adenoviral vectors)s a sustained treamtnet of the inner ear can also provide suffiicent proteiction form noise, drug toxicity and re-perfusion injury. There has also been great interest in the use of biomaterials for local drug delviery. Biodegradable polymers containing therapeutic molecules are placed on the RWM, with the therapeutic molecules released into the cochlear fluids form the polymers in a controlled manner via the RWM.
–Viral and Non-Viral Gene transfer: is being used for the sustained treatment of inner ear disorders. A gene known as Math1 and a key regulator of hair cell development which induces regeneration of hair cells and substantially improves hearing thresholds in the deaf inner ear after delivery to nonsensory cells through adenoviral vectors has been shown (Izumikawa, “Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 2005; 11: 271-276).
–Penetration enhancers: have been used to deliver medicaments across the tympanic membrane which is a formidable barrier against inroduciton of drugs into the middle ear (this is why antibiotics are typically taken orally). WO 2007/037874 describes enhances such as propylene glycol.