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Targeting Therapeutics for the Middle and Inner Ear
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?
PharmTech» Could you describe the state-of-the-art for these kinds of therapeutics?
»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.
PharmTech» What advantages do poloxamers offer?
»LeBel: The value of poloxamers is that one can easily draw them into a syringe while they're in solution. [One] can use a traditional 25–27 gauge, with a 4-inch needle, which is long enough to advance through the ear canal and inject the solution into the tympanic cavity or middle ear. Within seconds of encountering the patient's higher body temperature, the solution transitions to a gel. As a gel, the formulation adheres to the epithelial lining of the middle-ear space, where it can remain in place long enough to deliver the drug for a prolonged period of time to the inner-ear fluids.
One other feature of poloxamers is that you can also adjust the concentrations of the polymers to optimally control a drug's release profile. You can develop short or longer-acting drugs by altering the relative concentrations of the polymers.
PharmTech» How long can poloxamers retain a drug in the ear cavity?
»LeBel: In animal studies, the observed duration was as short as three consecutive days and as long as six weeks. But we suspect drug can be retained for two or three months.
PharmTech» How will regulators respond to this formulation?
»LeBel: Several of these components, independently and in mixtures, are already on the US Food and Drug Administration's safe list. In addition, these components are in approved pharmaceutical preparations and are commercially available. We typically purchase poloxamer from BASF [Ludwigshafen, Germany]. We recently held our pre-investigational new drug (IND) filing meeting with FDA. We intend to file an IND later this year for the purpose of testing our first drug candidate in humans, and they seem to concur with our strategy, pending formal FDA review of our IND.
PharmTech» Can you tell me about the indication you'll be filing on and more specifically about the steroid?
»LeBel: We'll be testing the use of the steroid dexamethasone in this formulation to treat Meniere's disease.
PharmTech» How did you choose that active pharmaceutical ingredient (API)?
»LeBel: There have been numerous publications in the medical literature suggesting that steroids injected intratympanically provide clinical benefit in the treatment of Meniere's. Many papers report a reduced frequency in episodes of vertigo. But not everyone is in agreement about the results, and we believe that part of the problem is the issue of limited drug exposure. That is, there's some question about whether the adequate delivery of drugs to the middle ear with adequate exposure to the drug can produce a therapeutic benefit. We're hoping that Otonomy's new formulation will allow physicians to settle that question once and for all.
Our clinical trial, which we project will start early in 2010, will look at the dose/response profile of dexamethasone in Poloxamer 407 versus Poloxamer 407 alone in patients with Meniere's disease. Our goal would be to provide a formulation that allows for sustained steroid exposure for approximately one month.
PharmTech» How do you imagine the drug will be packaged once it reaches commercial release?
»LeBel: Ideally, we'd like to offer it in a prefilled syringe or single-use vial. We don't yet know whether it will be premixed or mixed on injection.
PharmTech» Can other APIs be delivered this way?
»LeBel: Yes. The platform is very flexible and theoretically can be used for local delivery of small-molecule antibiotics to treat infections as well as small-molecule glutamate receptor antagonists to help treat certain kinds of hearing loss. In addition, we think it can be used to deliver larger molecule neurotrophic factors such as brain-derived neurotrophic factor or glial-cell line derived neurotrophic factor, which may alo be useful in treating hearing loss. We also imagine that we can combine the basic poloxamers with additional ingredients (e.g., permeabilizing agents, bulking agents, stabilizers, or solubilizers) as needed to optimize drug delivery.
PharmTech» Could this formulation be used to treat diseases in other organs?
»LeBel: Poloxamers are used in other pharmaceutical preparations to deliver drugs to the eye, gums, and abdomen. However, we're dedicated to treatments for inner- and middle-ear disorders at this time.
*Mayoclinic.com defines Meniere's disease as follows: Meniere's disease is a disorder of the inner ear that causes abnormal sensory perceptions, including a sensation of a spinning motion (vertigo), hearing loss usually in one ear, fullness or pressure in the same ear, and ringing in the same ear (tinnitus). People in their 40s and 50s are more likely than people in other age groups to develop Meniere's disease. Estimates of the number of people with Meniere's disease vary significantly, but according to the National Institute on Deafness and Other Communication Disorders, about 615,000 people in the United States have the disease.