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Apoptosis inhibitor formulations for prevention of hearing loss

a technology of apoptosis inhibitors and formulations, applied in the direction of sense disorder, organic active ingredients, drug compositions, etc., can solve the problems of irreversible hearing loss, incidence and severity of ototoxicity, restricted social life, etc., to prevent pathological and/or physiological conditions, prevent ototoxicity, and maintain the release of apoptosis inhibitors

Inactive Publication Date: 2020-07-09
SPIRAL THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent relates to a controlled release formulation that delivers an apoptosis inhibitory agent to prevent hearing loss associated with exposure to ototoxic agents such as chemotherlahics, loud noise, aging, autoimmune inner ear disease or a combination thereof. The formulation 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. The apoptosis inhibitor is added to the formulation to form a homogeneous solution without causing gelation. The formulation has a viscosity suitable for injection through a needle. The patent also describes the use of the apoptosis inhibitor for the prophylaxis and prevention of ototoxicity associated with platinum-based chemother애.

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.

Method used

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  • Apoptosis inhibitor formulations for prevention of hearing loss
  • Apoptosis inhibitor formulations for prevention of hearing loss
  • Apoptosis inhibitor formulations for prevention of hearing loss

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Hydrogel for Loading 2-(4-(2,4-dichlorophenethyl)-3,6-dioxo-1-(2-(thiophen-2-yl)ethyl)piperazin-2-yl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide (LPT99)

[0165]In vitro experiments with LPT99 demonstrated its specificity for Apaf-1, resulting in inhibition of apoptotic protease activating factor-1 (Apaf-1). In a cellular model of CisPt-induced apoptosis, LPT99-treated cells showed a decreased release of Cytc from mitochondria, reduced caspase-3 activation, and an improved cell viability, evidence of the cytoprotective effect of LPT99 (Cervantes, et al., IEB Symposium, Montpellier, Abstract P77, “Inhibition of APAF-1 with LPT99 prevents cisplatin-induced apoptosis in HEI-OCl auditory cells”, Sep. 18, 2016; Maurillo-Cuesta, et al., IEB Symposium, Montpellier, Abstract P78, Inhibition of Apaf-1 with LPT99 prevents cisplatin-induced hearing loss, Sep. 18, 2016).

[0166]These studies showed that the compound LPT99 could be effective in preventing hearing loss due to exposure to cisp...

example 2

of the Final Product

[0182]The viscosity measurement of the hydrogel was performed to determine the behavior of the viscoelastic agent once gelled within the ear. The measurement was carried out following the European Pharmacopoeia Method, section 2.2.10 (measured at 37° C., body temperature).

[0183]P407 is a thermoreversible compound, existing in a liquid or gel state depending on its temperature. Accordingly, it can form a semi-solid gel at body temperature of 37° C., being liquid at room temperature. During the development process, this allowed formation of an easy to handle solution with the LPT99 molecule, which gels at 37° C., once the solution is administered to a patient.

[0184]Viscosity measurements were performed at 37° C. to simulate the real conditions of application of the gel, once it has gelled. The solution was first placed in a climatic chamber at 37° C. to gel (20 mL of solution for about 1 h), and once gelled, the viscosity was measured by maintaining this temperatur...

example 3

Studies Showing Efficacy of Formulation

[0211]Materials and Methods

[0212]The specificity of LPT99 was tested in vitro on Apaf-1, caspase 3, and caspase 9 (proteins from the apoptotic cascade), and a broad panel of potential pharmacological targets.

[0213]To identify off-target activities of LPT99, its selectivity against a panel of receptors (44 G-protein-coupled receptors [GPCR] and 4 non-GPCR), 4 ion channels, and 3 transporters were analyzed. The cell line, HEI-OCl (house ear institute organ of Corti 1), which expresses several characteristic markers of the organ of Corti sensory cells (Kalinec, et al., Audiol. Neurootol. 2003, 8(4), 177-89), was used to evaluate the efficacy of LPT99 in preventing apoptosis due to CisPt prevention. Cells were pre-incubated with LPT99, followed by CisPt prevention for 24 hours. Under these conditions, the 50% inhibitory concentration (IC50) for caspase 3 was 5.2±1.6 μM. Both LPT99 stereoisomers were equally effective and equivalent to the racemic m...

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PUM

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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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/34A61K9/00A61K31/496A61K9/08A61P27/16
CPCA61P27/16A61K31/496A61K9/0019A61K9/0046A61K47/34A61K9/08A61K9/0024A61K47/10
Inventor HERRERO, CARMENAYOOB, ANDREWHANES, JUSTINPERIS, HUGO
Owner SPIRAL THERAPEUTICS INC
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