Intratympanic administration

Barriers to pharmacologic treatment of the inner ear

The inner ear (labyrinth) is a protected part of the body. It is hidden in the temporal bone, behind the middle ear and the ear drum. In addition, it is very tiny: the cochlea measures about the size of the fingernail on the
little finger. Therefore, therapeutically targeting the inner ear is not easy.

The blood labyrinth barrier is a major physiological divider separating the inner ear from systemic circulation. Systemic drug dose levels capable of having a therapeutic effect on the inner ear are often high enough to cause adverse side effects. Or put the other way round: at tolerable systemic dose levels, therapeutic concentrations may be difficult to achieve inside the inner ear.

 

Intratympanic administration as a solution

An alternative approach is to deliver drugs locally through intratympanic (i.t.) administration to maximize efficacy and minimize systemic side effects. With this approach, the drug is administered via a needle through the anesthetized ear drum into the middle ear cavity. The drug then diffuses across the semi-permeable round window membrane (RWM) into the inner ear. Thanks to the local, targeted administration, small concentrations are sufficient to achieve desired therapeutic concentrations in the inner ear or more particularly in the cochlea.

The i.t. administration procedure by which our therapeutics are delivered to the RWM is a minimally invasive procedure that is relatively simple to perform by an experienced otolaryngologist (ear, nose and throat doctor, or ENT) specialist. For the administration, patients lie on a stretcher or on a reclined exam chair, treated ear up; the procedure is performed under local anesthesia of the eardrum by using a microscope. Following the procedure, patients rest for 20 to 30 minutes to ensure maximum physical contact of the drug with the RWM. The tympanic membrane heals rapidly, usually within a few days, and the procedure may be performed several times. Potential side effects may include a temporary change in hearing or tinnitus perception, sensation of ear fullness or some ear discomfort. Such effects typically resolve with the closure of the eardrum which usually happens a few days following the administration.

I.t. administration has been performed since the '40s of the last century. As of today, there is no approved drug for i.t. administration; some ENTs are administering corticosteroids in case of ASNHL or gentamicin in case of Menière's Disease with this administration approach.

 

The importance of using gel formulations

One of the key shortcomings of current i.t. approaches is the use of injectable solutions that may easily drain off via the Eustachian tube, e.g. upon swallowing, thus preventing or reducing effective diffusion into the cochlea. With our proprietary gel formulations for i.t. administration, we overcome this "draining off", facilitate contact with the RWM and achieve effective diffusion into the cochlea. Both Keyzilen™ and AM-111 are formulated in a viscous gel of sodium hyaluronate that is biocompatible, biodegradable, and isotonic (that is, having the same salt concentration and therefore not causing any pressure build up on either side of the RWM).