This article is part of PharmTech's supplement "Injectable Drug Delivery."
PharmTech» Otonomy has developed a formulation platform that enables local delivery of drugs into the ear to treat middle- and inner-ear conditions such as Meniere's disease*, certain forms of hearing loss, and infection. The diseases have traditionally been treated by surgical means. I understand the company had an unusual beginning. Can you tell me about that?
»LeBel: At this time, it remains a challenge to get therapeutics into the middle and inner ear. The only targeted delivery available requires a surgeon to insert a tube into the middle ear and infuse drugs through it for the treatment of otitis media. Some physicians today employ a technique in which they inject drugs via a syringe into the middle ear, referred to as intratympanic administration. These drugs are typically formulations approved for intravenous administration, yet no one has studied their suitability for direct access to the middle or inner ear. Beyond that, there's the additional problem of drainage. Fluid drains from the ear through the Eustachian tubes, and therefore drugs can't remain in the compartment long enough to provide much therapeutic benefit.
Oral delivery of therapeutics had also been tried. But the doses required to ensure therapeutic benefit to the ear are sometimes so high as to risk inducing some kind of systemic toxicity. The ideal would be to deliver a drug directly to the middle ear in such a way as to reduce elimination through the Eustachian tubes, and limit systemic exposure.
PharmTech» Is that what Otonomy has developed?
»LeBel: Essentially yes. Lichter and Harris reasoned that they could overcome these challenges if they could produce a formulation that kept drugs in the middle ear, and is also safe and tolerable. The goal was to focus on an injectable formulation for intratympanic delivery and optimal retention of the drug, allowing it to diffuse through the round window membrane of the cochlea and gain access to the inner-ear fluids.
Otonomy has developed a formulation that is essentially a mixture of copolymers (polyethylene glycol and polypropylene) combined with a steroid. Key to this mixture's suitability is its thermo-reversible properties. At room temperature, [the mixture] is a solution. After the mixture is injected into the middle ear, the temperature rises to body temperature, and the mixture transitions to a gel state. We can also manipulate the relative concentrations of the gel's components to alter the temperature at which the mixture transitions from solution to gel. We refer to our lead formulation as OTO–104, which is a steroid in Poloxamer 407 and might be useful in sinusitis surgery and laryngeal surgery to prevent scarring.