Apoptosis inhibitor formulations for prevention of hearing loss

Abstract

A formulation for sustained release of an apoptosis inhibitor in the inner ear to protect from hearing loss, especially due to exposure to chemotherapy with drugs such as cisplatin. The formulation can be injected through a small gauge needle into the inner ear, where it gels to form a sustained release depot for controlled delivery of drug over a few days. In the preferred embodiment, the formulation includes a thermoresponsive sol-gel polymer such as POLOXAMER 407 and an apoptosis inhibitory agent, preferably an inhibitor of apoptotic protease activating factor-1 (APAF-1), in an effective amount to prevent hearing loss, for example, due to the administration of platinum-based chemotherapeutic agents. As demonstrated by the examples, the hydrogel provides sustained release of an apoptosis inhibitory agent, LPT99, an anti-apoptosis agent that inhibits apoptotic protease activating factor-1 (APAF-1), as well as safety and efficacy in in vitro and in vivo models.

Description

FIELD OF THE INVENTION[0001]The invention is in the field of formulations for prevention of hearing loss, particularly formulations containing an apoptosis inhibitor in a formulation providing controlled delivery over a period of days for preventing hearing loss associated with exposure to ototoxic agents such as chemotherapeutics, exposure to loud noise, aging, or autoimmune inner ear disease.BACKGROUND OF THE INVENTION[0002]Hearing loss is one of the most common disorders of the inner ear. According to the Hearing Loss Association of America (HLAA), approximately 48 million individuals, or 20% of the United States (US) population, are affected by hearing loss (hearingloss.org / content / basic-facts-about-hearing-loss). The impact of hearing loss on quality of life can be quite profound. An individual's emotional and mental state may be affected by the disrupted communication patterns caused by hearing loss, which can result in a restricted social life.[0003]Sensorineural hearing loss...

AI Technical Summary

Benefits of technology

[0014]A controlled release formulation delivers an apoptosis inhibitory agent, preferably an APAF-1 inhibitor, in an effective amount to prevent hearing loss associated with exposure to ototoxic agents such as chemotherapeutics, exposure to loud noise, aging, autoimmune inner ear disease or a combination thereof. The formulation is particularly effective in preventing otoxicity arising from the administration of platinum-based chemotherapeutic agents.

[0015]The formulation for otic delivery is in the form of a solution or suspension that effects a transition from a liquid state at room temperature to a hydrogel at body temperature. Preferred formulations are a solution, not suspension, of a synthetic polymer such as a POLOXAMER®, which are triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) available in different molecular weights and PPO / PEO ratios. The formulation is administered as a liquid which solidifies into the hydrogel at body temperature, so that the hydrogel provides sustained release of the apoptosis inhibitory agent for a period of between at least three to fifteen days in the ear.

[0017]Prior to introducing the apoptosis inhibitory agent, the phase-transition hydrogel forming polymer such as POLOXAMER® 407 preferably is formulated as a liquid product including an amount of POLOXAMER® 407 that at body temperature forms a hydrogel providing sustained release of the apoptosis inhibitory agent. The apoptosis inhibitor, preferably LPT99, is added to the formulation to form a homogeneous solution without causing gelation. LPT99 unexpectedly dissolves to a high concentration that increases the diffusive driving force through the round window membrane, and is extremely stable (remaining in solution, without forming precipitate) at room temperature. The formulation has a viscosity suitable for injection through a 23-G needle, typically through the tympanic membrane into the tympanic cavity. The formulation may further include sodium chloride, water, antioxidants, antimicrobials, detergents, solubilizing agents, crystallization inhibitors, viscosity modifiers, chelators, and buffers including, but not limited to, hydrogen phosphate di-sodium dodecahydrate and dihydrogen sodium phosphate dihydrate.

[0018]Preferred apoptosis inhibitors such as LPT99 and / or its pharmaceutically acceptable salts are useful for the prophylaxis and / or prevention of a pathological and / or physiological condition associated with an increase of apoptosis by means of its Apaf-1 inhibiting activity such as ototoxicity associated with platinum-based chemotherapeutic agents. Longer term release formulations or a depo or pump can be used to reduce age associated hearing loss.

Problems solved by technology

An individual's emotional and mental state may be affected by the disrupted communication patterns caused by hearing loss, which can result in a restricted social life.

However, the incidence and severity of ototoxicity is directly related to the cumulative CisPt dose.

Since these cells do not regenerative in humans, uncontrolled hair cell death results in irreversible hearing loss.

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