JP2012513394A - Controlled release of an ear sensory cell modulator composition for the treatment of otic disorders and methods thereof - Google Patents

Abstract

Disclosed herein are compositions and methods for the treatment of ear diseases or conditions using ear sensory cell modulator compositions and formulations comprising the ear sensory cell modulator compositions and formulations The formulations are administered topically to an individual with an otic disease or condition, the administration of these compositions and formulations directly onto or through the perfusion into the targeted ear structure. Application.
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Description

(Cross-reference)
This patent application includes US Provisional Patent Application No. 61 / 140,033 filed on December 22, 2008, US Provisional Patent Application No. 61 / 160,233 filed on March 13, 2009, 2009. US Provisional Patent Application No. 61 / 164,812 filed on March 30, US Provisional Patent Application No. 61 / 174,421 filed on April 30, 2009, filed April 24, 2009 Claims the benefit of published British patent application No. 0907070.7 and US patent application Ser. No. 12 / 504,533, filed Jul. 16, 2009. All of which are incorporated herein by reference in their entirety.

  Vertebrates have a pair of ears located in contrast on opposite sides of the head. The ear serves not only as a sensory organ for detecting sound, but also as an organ for maintaining balance and body position. The ear is generally divided into three parts: the outer ear, the middle ear (auris media or middle ear), and the inner ear (auris interna or inner ear).

  Described herein are compositions, formulations, manufacturing methods, treatment methods, uses, kits for controlled release or delivery of at least one ear sensory cell modulator to at least one structure or region of the ear. And a delivery device. In some embodiments, the ear sensory cell modulator is an ear sensory cell damaging agent. In some embodiments, the ear sensory cell modulator is an ear sensory cell death agent. In some embodiments, the ear sensory cell modulator is an ear sensory cell protective agent (eg, promotes survival of ear sensory cells). In some embodiments, the ear sensory cell modulator is an ear sensory cell growth / regeneration agent. Described herein are deafness or hearing caused by hair in the inner ear being destroyed, poorly developed, dysfunctional, damaged, fragile or missing A controlled release composition for treating or ameliorating the decline. In certain embodiments, the controlled release composition comprises at least one modulator of otic neurons and / or hair cells (also known as “ear sensory cell modulators”), controlled release of an otic acceptable excipient. And an effective amount for treatment of an ear-acceptable vehicle.

  In some embodiments, the target portion of the ear is the middle ear or auris media. In other embodiments, the target portion of the ear is the inner ear or auris interna. In other embodiments, the target portion of the ear is the middle ear or auris media. In still other embodiments, the target portion of the ear is both the auris media and the auris interna. In some embodiments, the controlled release formulation further comprises a rapid or immediate release component for delivering an ear sensory cell modulator to the middle and / or inner ear. All formulations contain excipients that are acceptable to the middle ear and / or inner ear.

  Described herein is a method for inducing damage and / or death of selective ear sensory cells in the middle ear or inner ear, the method comprising the ear sensory cell modulation described herein. Administration of a controlled release formulation. Described herein are ear sensory cell growth and / or reversal of damage to ear sensory cells (eg, dysfunctional, dysfunctional ear sensory cells) and / or ear sensory cells (eg, A method of inducing protection against further damage to dysfunctional, dysfunctional ear sensory cells), comprising the administration of an ear sensory cell modulator composition described herein.

  Also disclosed herein is a method for the treatment of otic disorders comprising the administration of an otic sensory cell modulator controlled release formulation. In some embodiments, the otic sensory cell modulator is a toxic agent (eg, gentamicin) and induces cell death. In some embodiments, the ear sensory cell modulator is an otoprotectant such as, for example, amifostine, an antioxidant. In some embodiments, the otic sensory cell modulating agent induces the growth of a new otic sensory cell, eg, an adenovirus that expresses Atoh1. In some embodiments, the ear sensory cell modulation is an agent that reduces or inhibits ear sensory cell death, eg, glutamate receptor modulators.

  In some embodiments, the glutamate receptor modulator is a glutamate receptor antagonist. In some embodiments, the glutamate receptor antagonist is an NMDA receptor antagonist. In some embodiments, the agent that modulates an NMDA receptor is an NMDA receptor antagonist. In some embodiments, the ear sensory cell modulating agent is a nutrient (eg, an agent that promotes healthy cell and / or tissue growth). In some embodiments, the nutrient is a growth factor. In some embodiments, the growth factor is brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophin. -4, fibroblast growth factor (FGF), insulin-like growth factor (IGF) or the like and / or combinations thereof. In some embodiments, the ear sensory cell modulating agent is an agent having immune system cells that reduce protective effects, such as inflammation and / or infection. In some embodiments, the immune system cells are macrophages, microglia, and / or microglia-like cells. In some embodiments, the ear sensory cell modulator is a Na + channel blocker and reduces or inhibits ear sensory cell damage and / or offspring. In some embodiments, the ear spacing cell modulating agent is an ear protectant, such as a corticosteroid that reduces, delays or reverses damage to ear sensory cells. In some embodiments, the otic sensory cell modulating agent is an ototoxic agent or toxic agent that causes otic sensory cell death. In some embodiments, the ear sensory cell modulator is a modulator of pRB. In some embodiments, the otic sensory cell modulator is a TH receptor modulator. In some embodiments, the ear sensory cell modulator is an adenovirus that expresses BRN3. In some embodiments, the ear sensory cell modulator is an agonist of BRN3. In some embodiments, the ear sensory cell modulator is an antagonist of BRN3. In some embodiments, the ear sensory cell modulator is a stem cell and / or a differentiated ear sensory cell that promotes growth and / or regeneration of ear sensory cells.

  In some embodiments, the composition further comprises an ear sensory cell modulator as an immediate release agent, wherein the immediate release ear sensory cell modulator is the same agent as the controlled release agent, a different ear sensory cell modulator, Additional therapeutic agents or combinations thereof.

  In some embodiments, the composition comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anesthetic, local action anesthetic, analgesic, antibiotic, antiemetic, antifungal, antimicrobial, antiseptic, antiviral, chemotherapeutic, diuretic Agents, keratolytic agents, ear protection agents (eg, steroids), immunosuppressants including, but not limited to, calcineurin inhibitors (cyclosporine, tacrolimus, pimecrolimus), macrolides such as rapamycin, corticosteroids or these It is a combination. In some embodiments, the additional therapeutic agent is an immediate release agent. In some embodiments, the additional therapeutic agent is a controlled release agent.

  Disclosed herein is a controlled release formulation for delivering an ear sensory cell modulator to the ear. In some embodiments, the composition is administered such that the composition contacts the cochlear window ridge, round window membrane, and tympanic cavity.

  The otic formulations and treatment methods described herein have a number of advantages that overcome the previously unrecognized limitations of the formulations and treatment methods described in the prior art.

The sterile inner ear environment is an isolated environment. Endolymph and perilymph are static fluids and are not in continuous contact with the circulatory system. The blood-maze-barrier (BLB) contains blood-endolymph-barrier and blood-perilymph-barrier, between dedicated epicerium cells in the maze space (i.e., the space between the vestibule and the cochlea). It consists of a tight bond. The presence of BLB limits the delivery of the active agent to the isolated microenvironment of the inner ear (eg otic sensory cell modulator). Ear hair cells are immersed in endolymph or perilymph fluid, and cochlear recirculation of potassium ions is important for hair cell function. When the inner ear is infected, there is an influx of leukocytes and / or immunoglobulin (e.g., in response to microbial infection) into the endolymph and / or perilymph, and the fine ionic composition of the inner ear fluid is leukocytes and / or It is upset by the influx of immunoglobulins. In certain instances, changes in the ionic composition of the inner ear fluid can result in hearing loss, loss of balance, and / or ossification of the auditory structure. In certain instances, even trace amounts of pyrogens and / or microorganisms can cause infection and cause physical changes associated within the isolated microenvironment of the inner ear.

  Due to the susceptibility of the inner ear to infection, otic preparations require aseptic levels (low contaminating microbial counts) not previously recognized in the prior art. Provided herein are formulations that are produced with a low contaminating microbial count or sterilized by stringent sterility requirements and are suitable for administration to the middle ear and / or inner ear. In some embodiments, the otic mixable compositions described herein are substantially free of pyrogens and / or microorganisms.

Compatibility with the inner ear environment Described herein are otic preparations with ionic balance that can be mixed into the perilymph and / or endolymph and do not cause any change in cochlear potential. In certain embodiments, the osmolarity / osmolality of the formulation is determined by, for example, using an appropriate salt concentration (e.g., sodium salt concentration), or endolymphatic and / or perilymph compatible with the formulation. Regulated by the use of an isotonic agent that provides (ie, isotonic with endolymph and / or perilymph). In some instances, the endolymphatic and / or perilymphcompatible formulations described herein provide minimal disruption to the inner ear environment and can be administered to an administering mammal (e.g., a human). Provides minimal discomfort (eg, rotational dizziness). Furthermore, the formulation comprises a biodegradable and / or non-biodegradable polymer and / or a polymer that is otherwise non-toxic to the inner ear environment. In some embodiments, the formulations described herein are free of preservatives and result in minimal discomfort (eg, changes in pH or molality, inflammation) within the auditory structure. In some embodiments, the formulations described herein comprise an antioxidant that is non-irritating and / or non-toxic to otic structures.

Frequency of dosing Current standards of care for otic preparations include multiple doses or injections (e.g., intratympanic injections) over several days (e.g., up to 2 weeks), including a schedule for frequent injections per day. Request. In some embodiments, the otic formulations described herein are sustained release formulations that are administered less frequently compared to current standards of care. In certain instances, when the otic formulation is administered via intratympanic injection, the reduced dosing cycle is more than one for individuals undergoing treatment for middle ear and / or inner ear disease, upset, or disease. Relieves discomfort caused by multiple injections into the tympanic chamber. In certain instances, a reduced dosing cycle of injection into the tympanic chamber reduces the risk of a permanent wound (eg, perforation) to the tympanic membrane. The formulations described herein provide a constant, sustained, extended, delayed, or pulsatile rate of release of the active agent into the inner ear environment, and thus during the treatment of otic disorders Avoid changing drug exposure.

Therapeutic Index The otic formulations described herein are administered to the ear canal or into the vestibule of the ear. For example, access to the vestibular and cochlear appliances occurs through the round window membrane, the oval window / scapular plate, the middle ear containing the annular ligament, and through the ear capsule / temporal bone. Administration of the formulations described herein to the ear avoids the toxicity (eg, liver toxicity, heart toxicity, gastrointestinal side effects, liver toxicity) associated with systemic administration of the active agent. In some examples, localized administration in the ear allows the active agent to reach the target organ (eg, the inner ear) without systemic administration of the active agent. In some instances, topical administration to the ear provides a high therapeutic index for the active agent, in other words, that has a dose-limiting systemic toxicity.

Prevention of drainage into the ear canal In some instances, a drawback of liquid formulations is their property of instilling into the ear canal, resulting in rapid clearance of the formulation from the inner ear. In certain embodiments, provided herein are gel-like at body temperature and remain in contact with the targeted auditory surface (e.g., round window) for an extended period of time. An otic preparation comprising a polymer. In some embodiments, the formulation further comprises a mucoadhesive that allows it to be applied to the mucosal surface of the ear. In some instances, the formulations described herein avoid attenuating the therapeutic effect due to drainage or leakage of the active agent through the ear canal.

DESCRIPTION OF SPECIFIC EMBODIMENTS Described herein are a therapeutically effective amount of an ear sensory cell modulator, a controlled release ear acceptable excipient, and an ear acceptable vehicle. A controlled release composition and device for treating an otic disorder. In one embodiment, the controlled release, ear-acceptable excipient is an ear-acceptable polymer, ear-acceptable viscosity promoter, ear-acceptable gel, ear-acceptable paint, ear Ear-acceptable foam, ear-acceptable microparticles or microparticles, ear-acceptable hydrogel, ear-acceptable in situ spongy material, ear-acceptable chemiradiation-curable gel, ear-acceptable Liposomes, ear-acceptable nanocapsules or nanospheres, ear-acceptable thermoreversible gels, ear-acceptable thermoreversible gels, or combinations thereof. In a further embodiment, the ear-acceptable viscosity enhancing agent is cellulose, cellulose, ether, alginate, polyvinyl pyrrolidone, gum, cellulose acid polymer, or combinations thereof. In yet another embodiment, the ear-acceptable viscosity enhancing agent is present in an amount sufficient to provide a viscosity of about 1000 to about 1,000,000 centipoise. In yet another aspect, the ear-acceptable viscosity enhancing agent is present in an amount sufficient to provide a viscosity of from about 50,000 to about 1,000,000 centipoise. In some embodiments, the otic sensory cell modulator formulation or composition is an osmolality or osmolarity of the targeted otic structure that is optimal to reliably maintain homeostasis.

  In some embodiments, the composition is formulated to be at pH, actual osmolality, and / or osmolarity to ensure that the target ear structure homeostasis is maintained. Osmolality / osmolality suitable for perilymph is the actual osmolality / delivery capability that maintains the homeostasis of the targeted ear structure during administration of the pharmaceutical formulations described herein Osmolarity / weight osmolality.

  For example, the osmolarity of perilymph is about 270-300 mOsm / L, and the compositions described herein are optionally formulated to have an actual osmolarity of about 150 to about 1000 mOsm / L. Is done. In certain embodiments, the formulations described herein have an actual osmolarity of about 150 to about 500 mOsm / L and / or at the target site of action (e.g., inner ear and / or perilymph and / or endolymph). Alternatively, a deliverable osmolarity is provided. In certain embodiments, the formulations described herein provide an actual osmolarity of about 200 to about 400 mOsm / L at the target site of action (eg, inner ear and / or perilymph and / or endolymph). . In certain embodiments, the formulations described herein provide an actual osmolarity of about 250 to about 320 mOsm / L at the target site of action (eg, inner ear and / or perilymph and / or endolymph). . In certain embodiments, the formulations described herein are about 150 to about 500 mOsm / L, about 200 to about 400 mOsm / L at the target site of action (e.g., inner ear and / or perilymph and / or endolymph). Or an osmolarity suitable for perilymph within the range of about 250 to about 320 mOsm / L. In certain embodiments, the formulations described herein are about 150 to about 500 mOsm / kg, about 200 to about 400 mOsm / kg at the target site of action (e.g., inner ear and / or perilymph and / or endolymph). Or an osmolality suitable for perilymph within the range of about 250 to about 320 mOsm / kg. Similarly, the pH of the perilymph is about 7.2 to 7.4, and the pH of the formulation is a suitable pH for the perilymph (e.g., using a buffer) from about 5.5 to about 9.0, about 6.0 to about It is formulated to be 8.0, or about 7.0 to about 7.6. In certain embodiments, the pH of the formulation is in the range of about 6.0 to about 7.6. In certain cases, the pH of the endolymph is about 7.2 to 7.9, and the pH of the formulation is within the range of about 5.5 to about 9.0 (e.g., using a buffer), about 6.5 to about 8.0. Formulated to be in the range, or in the range of about 7.0 to about 7.6.

  In some embodiments, the controlled release ear acceptable excipient is biodegradable. In some embodiments, the controlled release ear acceptable excipient is excreted from the body (eg, degraded and / or excreted by urine, feces, or other excretory routes). In another embodiment, the controlled release composition further comprises an ear acceptable mucoadhesive, an ear acceptable penetration enhancer, or an ear acceptable bioadhesive.

In one embodiment, the controlled release ear sensory cell modulator composition is delivered using a drug delivery device, which is a needle and syringe, pump, microinjection device, or a combination thereof. In some embodiments, the controlled release composition of the ear sensory cell modulator has limited systemic release or is not systemically released and is toxic when administered systemically, pK The properties are insufficient, or a combination of these properties. In some embodiments, the ear sensory cell modulator is a small molecule agent.
In other embodiments, the ear sensory cell modulating agent is an antibody.

  Also disclosed herein is a method of treating an otic disorder, which comprises 3, 4, 5, 6, 7, 8 together with the compositions and formulations disclosed herein. , 9, 10, 11, 12, 13, 14, or 15 days at least once, at least once a week, once every two weeks, once every three weeks, once every four weeks, 5 Once every week, or once every six weeks or once a month, once every two months, once every three months, once every four months, every five months Once, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months or It includes a step of administering once every 12 months. In certain embodiments, the controlled release formulations described herein provide a sustained dosage of the otic sensory cell modulator to the inner ear until the next dose of the controlled release formulation. That is, to name just one example, when a controlled release formulation of a new dosage of an otic sensory cell modulator is administered to the round window membrane every 10 days by intratympanic injection, the controlled release formulation is 10 Over the day, an effective dose of an otic sensory cell modulator is provided to the inner ear (eg, via the round window membrane).

  In some embodiments, the composition is administered such that the composition is in contact with the cochlear ridge, round window membrane, and tympanic cavity. In certain embodiments, the composition is administered by intratympanic injection.

  In some embodiments, provided herein is a method for selectively inducing damage to otic sensory cells, the method comprising a tympanic chamber comprising a therapeutically effective amount of an ototoxic agent. For an individual in need of a composition or device, a composition or device comprising a substantially low degradation product ototoxic agent, a composition or device further comprising two or more properties selected from: Administering, wherein the properties include: (i) an ototoxic agent, or about 0.1% to about 10% by weight of a pharmaceutically acceptable prodrug or salt; (ii) a polyoxyethylene--of general formula E106P70E106 From about 14% to about 21% by weight of the polyoxypropylene triblock copolymer, (iii) a suitable amount of sterile water buffered to a pH of about 5.5 to about 8.0, and (iv) of an ototoxic agent Multiple particles, (v) a gelling temperature between about 19 ° C and about 42 ° C, (vi) microbial agents per gram of formulation Less than 50 colony forming units (cfu), (vii) less than about 5 endotoxin units (kg) per kg of subject, (viii) an average degradation time of about 30 hours of ototoxic agents, and (ix) about 100,000 It is selected from apparent viscosities from cP to about 500,000 cP.

  In some embodiments of the method, the ototoxic agent is released from the composition or device over at least 3 days. In some embodiments of the method, the ototoxic agent is released from the composition or device over at least 5 days. In some embodiments, the ototoxic agent is essentially in the form of micronized particles.

  Also provided herein is a method of inducing the growth of ear sensory cells, the method comprising a tympanic composition or device comprising a therapeutically effective amount of a nutrient, Administering to an individual in need thereof a composition or device comprising a low degradation product nutrient, a composition or device further comprising two or more properties selected from: (I) from about 0.1% to about 10% by weight of a nutrient or pharmaceutically acceptable prodrug or salt; (ii) about 14% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106 % To about 21% by weight, (iii) an appropriate amount of sterile water, buffered to a pH of about 5.5 to about 8.0, (iv) multiple particles of nutrient, (v) about 19 ° C. to about Gelation temperature between 42 ° C., (vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation (cfu), (vii) test Weight 1kg per less than about 5 endotoxin units (EU), is selected from the apparent viscosity average degradation time of about 30 hours and (ix) approximately 100,000 cP to about 500,000 cP in (viii) nutrients.

  In some embodiments of the method, the nutrient is released from the composition or device over at least 3 days. In some embodiments of the method, the nutrient is released from the composition or device over at least 5 days. In some embodiments, the nutrient is essentially in the form of micronized particles.

Also provided herein is a method of mitigating ear sensory cell damage from an ear intervention procedure, the method comprising an intratympanic composition or device comprising a therapeutically effective amount of an ear protectant Administering to an individual in need thereof a composition or device comprising a substantially low degradation product ear protectant, a composition or device further comprising two or more properties selected from: The properties include: (i) about 0.1% to about 10% by weight of an ear protection agent, or pharmaceutically acceptable prodrug or salt; (ii) a polyoxyethylene-polyoxypropylene triblock of the general formula E106P70E106 From about 14% to about 21% by weight of the copolymer, (iii) an appropriate amount of sterile water buffered to a pH of about 5.5 to about 8.0, (iv) multiparticulates of an ear protectant, (v ) Gelation temperature between about 19 ° C and about 42 ° C, (vi) less than about 50 colonies of microbial agent per gram of formulation Adult unit (cfu), (vii) less than about 5 endotoxin units (EU) per kg of subject, (viii) an average degradation time of about 30 hours of ear protectant, and (ix) about 100,000 cP to about 500,000 It is selected from apparent viscosities to cP.

In some embodiments of the method, the otoprotectant is administered before or during the otic intervention procedure. In some embodiments of the method, the ear protectant is administered after the ear intervention procedure.
In some embodiments of the method, the ear protectant is essentially in particulate form.

  In some embodiments of the above-described methods, compositions or devices, the composition or device comprises (i) about 0.1% to about 0.1% by weight of an otic sensory cell modulator, or pharmaceutically acceptable prodrug or salt. 10% by weight, (ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) multiple particles of otic sensory cell modulators, (iv) about 19 ° C. With a gel temperature between ˜42 ° C. and (v) an apparent viscosity from about 100,000 cP to about 500,000 cP.

  In some embodiments of the above-described methods, compositions or devices, the composition or device comprises (i) about 0.1% to about 0.1% by weight of an otic sensory cell modulator, or pharmaceutically acceptable prodrug or salt. 10% by weight, (ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) multiple particles of otic sensory cell modulators, (iv) about 19 ° C. With a gel temperature between ˜42 ° C. and (v) an average degradation time of about 30 hours of the otic sensory cell modulator.

  In some embodiments of the methods described above, the ear sensory cell modulator is released from the composition or device over at least 3 days. In some embodiments of the methods described above, the ear sensory cell modulator is released from the composition or device over at least 5 days. In some embodiments of the methods described above, the otic sensory cell modulator is released from the composition or device over at least 10 days. In some embodiments of the methods described above, the otic sensory cell modulator is essentially in the form of finely divided particles.

  In some embodiments of the methods described herein, the composition described above is administered through a round window. In some embodiments, the ear and / or vestibular disorder is ototoxicity, chemotherapy-induced hearing loss, sensorineural hearing loss, noise-induced hearing loss, excitotoxicity, Meniere's disease / syndrome, endolymphatic hydrops, labyrinthitis Ramsey Hunt syndrome, vestibular neuronitis, tinnitus or microvascular compression syndrome.

  Provided herein is a pharmaceutical composition or device comprising a therapeutically effective amount of an ototoxic agent to treat an otic disease or illness, a substantially low degradation product of the ototoxic agent. The pharmaceutical composition or device further comprises two or more properties selected from: (i) about 0.1 weight of an ototoxic agent, or pharmaceutically acceptable prodrug or salt. % To about 10% by weight, (ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) buffered to a pH of about 5.5 to about 8.0 Appropriate amount of sterile water, (iv) multiple particles of ototoxic agent, (v) gelling temperature between about 19 ° C. and about 42 ° C., (vi) about 50 of microbial agent per gram of formulation Less than 5 colony forming units (cfu), (vii) less than about 5 endotoxin units (kg) per kg of subject, (viii) about 30 hours of ototoxic agents Degradation time, and (ix) is selected from among about 100,000 cP in apparent viscosity to about 500,000 cP.

  In some embodiments, a pharmaceutical composition or device described herein comprises (i) about 0.1% to about 10% by weight of an ototoxic agent, or pharmaceutically acceptable prodrug or salt, ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106, (iii) ototoxic agent multiparticulates, (iv) between about 19 ° C. and about 42 ° C. With a gel temperature and (v) an apparent viscosity from about 100,000 cP to about 500,000 cP.

In some embodiments, a pharmaceutical composition or device described herein comprises (i) about 0.1% to about 10% by weight of an ototoxic agent, or pharmaceutically acceptable prodrug or salt, ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) ototoxic agent multiparticulates, (iv) between about 19 ° C. and about 42 ° C. Gelation temperature,
And (v) an apparent viscosity from about 100,000 cP to about 500,000 cP.

  In some embodiments, a pharmaceutical composition or device comprising an ototoxic agent provides an actual osmolarity between about 200 and 400 mOsm / L. In some embodiments, a pharmaceutical composition or device comprising an ototoxic agent provides an actual osmolarity between about 250 and 320 mOsm / L.

In some embodiments, the ototoxic agent is released from the composition or device over at least 3 days. In some embodiments, the ototoxic agent is released from the composition or device over at least 5 days. In some embodiments, a pharmaceutical composition or device comprising an ototoxic agent is an ear acceptable thermoreversible gel. In some embodiments, the pharmaceutical composition or device essentially comprises an ototoxic agent in the form of micronized particles.

  Provided herein is a pharmaceutical composition or device comprising a therapeutically effective amount of a nutrient to treat an ear disease or disease, a substantially low degradation product of the nutrient, The pharmaceutical composition or device further comprises two or more properties selected from: (i) from about 0.1% to about 0.1% by weight of the nutrient, or pharmaceutically acceptable prodrug or salt. 10% by weight, (ii) about 14% to about 21% by weight of polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) buffered to a pH between about 5.5 and about 8.0 Appropriate amount of sterile water, (iv) multiple particles of nutrients, (v) gelling temperature of about 19 ° C to about 42 ° C, (vi) less than about 50 colonies of microbial agent per gram of formulation Forming units (cfu), (vii) Endotoxin units (EU) per kg body weight of subject less than about 5, (viii) Average nutrient content of about 30 hours of nutrients The solution time is selected from (ix) the apparent viscosity from about 100,000 cP to about 500,000 cP.

  In some embodiments, a pharmaceutical composition or device described herein comprises (i) about 0.1% to about 10%, (ii) a nutrient, or a pharmaceutically acceptable prodrug or salt, (ii) About 14% to about 21% by weight of polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) multiparticulates of nutrients, (iv) a gel between about 19 ° C. and about 42 ° C. (Viii) an average decomposition time of about 30 hours of nutrient, and (ix) an apparent viscosity from about 100,000 cP to about 500,000 cP.

  In some embodiments, a pharmaceutical composition or device comprising a nutrient provides an actual osmolarity between about 200 and 400 mOsm / L. In some embodiments, a pharmaceutical composition or device comprising a nutrient provides an actual osmolarity between about 250 and 320 mOsm / L. In some embodiments, the nutrient is released from the composition or device over at least 3 days. In some embodiments, the nutrient is released from the composition or device over at least 5 days.

  In some embodiments, the pharmaceutical composition or device comprising the nutrient is an ear acceptable thermoreversible gel. In some embodiments, the pharmaceutical composition or device comprises a nutrient, essentially in the form of micronized particles.

  In some embodiments, a pharmaceutical composition or device described herein comprises (i) about 0.1% to about 10% by weight of an otic sensory cell modulator, or pharmaceutically acceptable prodrug or salt. (Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106, (iii) multiparticulates of otic sensory cell modulators, (iv) about 19 ° C. to about With a gelation temperature between 42 ° C. and (v) an average degradation time of about 30 hours of the otic sensory cell modulator.

  In some embodiments, any pharmaceutical composition or device described above comprises a substantially low degradation product of an otic sensory cell modulator.

  In some embodiments, the pharmaceutical composition or device described above provides an actual osmolarity of about 150 to about 500 mOsm / L. In some embodiments, the pharmaceutical composition or device described above provides an actual osmolarity of about 200-400 mOsm / L. In some embodiments, the pharmaceutical composition or device described above provides an actual osmolarity of about 250-320 mOsm / L.

  In some embodiments, the ear sensory cell modulating agent is released from the pharmaceutical composition or device described above for at least 3 days. In some embodiments, the ear sensory cell modulating agent is released from the pharmaceutical composition or device described above for at least 5 days. In some embodiments, the ear sensory cell modulating agent is released from the pharmaceutical composition or device described above for at least 10 days. In some embodiments, the ear sensory cell modulator is released from the pharmaceutical composition or device described above for at least 14 days. In some embodiments, the ear sensory cell modulating agent is released from the pharmaceutical composition or device described above for at least 1 month.

  In some embodiments, the pharmaceutical composition or device described above comprises an otic sensory cell modulator as a neutral compound, free acid, free base, salt or prodrug. In some embodiments, the pharmaceutical composition or device described above comprises an otic sensory cell modulator as a neutral compound, free acid, free base, salt or prodrug, or a combination thereof. In some embodiments of the pharmaceutical compositions or devices described herein, the otic sensory cell modulator is administered in the form of an ester prodrug.

  In some embodiments, the pharmaceutical composition or device described above is an ear acceptable thermoreversible gel. In some embodiments of the pharmaceutical composition or device, the polyoxyethylene-polyoxypropylene triblock copolymer is excreted from the body.

In some embodiments, the pharmaceutical composition or device further comprises a penetration enhancer.
In some embodiments, the pharmaceutical composition or device described herein further comprises a dye.

  In some embodiments, the pharmaceutical composition or device includes an ear sensory cell modulator, or a pharmaceutically acceptable salt, prodrug, or combination thereof as an immediate release agent.

  In some embodiments of the pharmaceutical composition or device, the otic sensory cell modulator comprises a multiparticulate material. In some embodiments of the pharmaceutical composition or device, the ear sensory cell modulator is essentially in the form of finely divided particles. In some embodiments of the pharmaceutical composition or device, the ear sensory cell modulator is in the form of a micronized ear sensory cell modulator powder.

  In some embodiments, the pharmaceutical composition or device described above comprises about 10% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106 by weight of the composition. In some embodiments, a pharmaceutical composition or device described above comprises about 15% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106 by weight of the composition. In some embodiments, a pharmaceutical composition or device described above comprises about 20% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106 by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 25% of a polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106 by weight of the composition.

  In some embodiments, the pharmaceutical composition or device described above comprises about 0.01% otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 0.05% otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 0.1% otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 1% otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 2.5% otic sensory cell modulators, or pharmaceutically acceptable prodrugs or salts thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 5% otic sensory cell modulators, or pharmaceutically acceptable prodrugs or salts thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 10% otic sensory cell modulators, or pharmaceutically acceptable prodrugs or salts thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 20% otic sensory cell modulators, or pharmaceutically acceptable prodrugs or salts thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 30% otic sensory cell modulators, or pharmaceutically acceptable prodrugs or salts thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises about 40% otic sensory cell modulators, or pharmaceutically acceptable prodrugs or salts thereof, by weight of the composition. In some embodiments, the pharmaceutical composition or device described above comprises up to about 50% of an ear sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, by weight of the composition.

  In some embodiments, the pharmaceutical composition or device described above has a pH of about 5.5 to about 8.0. In some embodiments, the pharmaceutical composition or device described above has a pH of about 6.0 to about 8.0. In some embodiments, the pharmaceutical composition or device described above has a pH of about 6.0 to about 7.6. In some embodiments, the pharmaceutical composition or device described above has a pH of about 7.0 to about 7.6.

  In some embodiments, a pharmaceutical composition or device as described above contains less than 100 microbial agent colony forming units (cfu) per gram of formulation. In certain embodiments, a pharmaceutical composition or device as described above contains less than 50 colony forming units (cfu) of microbial agent per gram of formulation. In certain embodiments, a pharmaceutical composition or device as described above contains less than 10 microbial agent colony forming units (cfu) per gram of formulation.

  In some embodiments, the pharmaceutical composition or device described above comprises less than 5 endotoxin units (EU) per kg body weight of the subject. In some embodiments, the pharmaceutical composition or device described above comprises less than 4 endotoxin units (EU) per kg body weight of the subject.

  In some embodiments, the pharmaceutical composition or device described above provides a gelling temperature of about 19 ° C to about 42 ° C. In some embodiments, the pharmaceutical composition or device described above provides a gelling temperature of about 19 ° C to about 37 ° C. In certain embodiments, the pharmaceutical composition or device described above provides a gelling temperature of about 19 ° C to about 30 ° C.

  In some embodiments, the pharmaceutical composition or device is an ear acceptable thermoreversible gel. In some embodiments, the polyoxyethylene-polyoxypropylene triblock copolymer is biodegradable and / or excreted from the body (e.g., the copolymer is a biodegradation process such as urine, feces, etc. It is excreted from the body by excretion in the body). In some embodiments, the pharmaceutical composition or device described herein further comprises a mucoadhesive agent. In some embodiments, the pharmaceutical composition or device described herein further comprises a penetration enhancer. In some embodiments, the pharmaceutical composition or device described herein further comprises a thickening agent. In some embodiments, the pharmaceutical composition or device described herein further comprises a dye.

  In some embodiments, a pharmaceutical composition or device described herein comprises a drug delivery device selected from needles and syringes, pumps, microinjection devices, wicks, in situ spongy substances, or combinations thereof. In addition.

  In some embodiments, a pharmaceutical composition or device described herein has an otic sensory cell modulator, or a pharmaceutically acceptable salt thereof, with limited systemic release or systemically. Is a pharmaceutical composition or device characterized in that it does not release, has systemic toxicity, has poor pK properties, or has a combination of these properties. In some embodiments, a pharmaceutical composition or device described herein provides one or more ear sensory cell modulators, or pharmaceutically acceptable salts, prodrugs, or combinations thereof Contains as release agent.

  In some embodiments, a pharmaceutical composition or device described herein is characterized in that the pH of the pharmaceutical composition or device is a pH suitable for perilymph between about 6.0 and about 7.6. A pharmaceutical composition or device.

  In some embodiments of the pharmaceutical compositions or devices described herein, the ratio of polyoxyethylene-polyoxypropylene triblock copolymer of general formula E106P70E106 to thickener is from about 40: 1 to about 5: 1. In some embodiments, the thickening agent is carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose.

  In some embodiments, the ear and / or vestibular disorder is ototoxicity, chemotherapy-induced hearing loss, sensorineural hearing loss, noise-induced hearing loss, excitotoxicity, Meniere's disease / syndrome, endolymphatic hydrops, labyrinthitis Ramsey Hunt syndrome, vestibular neuronitis, tinnitus or microvascular compression syndrome.

The comparison of a non-release preparation and a release preparation is demonstrated. The influence of the concentration on the viscosity of aqueous solution of Blanose refined CMC is shown. The influence of the concentration on the viscosity of the aqueous solution of Methocel is shown. Shows ear tissue. Figure 4 shows the adjustable release characteristics expected from the four compositions.

  Described herein are deafness or hearing caused by hair in the inner ear being destroyed, poorly developed, dysfunctional, damaged, fragile or missing A controlled release composition for treating or ameliorating the decline. In one embodiment, the controlled release composition is acceptable to an ear sensory cell, eg, at least one modulator of growth and / or regeneration of an ear neuron and / or hair cell, controlled release ear. The vehicle comprises a therapeutically effective amount of an ear-acceptable vehicle. In one embodiment, the controlled release composition comprises a therapeutically effective amount of at least one modulator of an ear sensory cell disorder, a controlled release ear acceptable excipient, an ear acceptable vehicle. . In one embodiment, the controlled release composition comprises at least one agent that protects otic neurons and / or hair cells from damage or reduction or protects against reversal or delay of damage to otic sensory cells, controlled release A therapeutically effective amount of an ear-acceptable excipient, an ear-acceptable vehicle.

  Further disclosed herein is that ear and / or vestibular disorders are ototoxicity, excitotoxicity, sensorineural hearing loss, noise-induced hearing loss, Meniere's disease / syndrome, endolymphatic hydrops, labyrinth, Ramsey Hunt Compositions and formulations of controlled release ear sensory cell modulators for treating syndromes, vestibular neuronitis, tinnitus or microvascular compression syndromes.

  Slight therapeutic products include ototoxicity, excitotoxicity, sensorineural hearing loss, noise-induced hearing loss, Meniere's disease / syndrome, endolymphatic hydrops, labyrinth, Ramsey Hunt syndrome, vestibular neuronitis, tinnitus or microvascular compression It can be used to treat syndromes. However, systemic routes via oral, intravenous or intramuscular routes are currently used to deliver these therapeutic agents.

  Systemic administration of drugs results in higher circulating concentrations in the serum, but lower concentrations in organ structures in the target inner ear, which can lead to problems with potentially insufficient drug concentrations. As a result, a fairly large amount of drug is required to overcome this inequality in order to deliver a sufficiently therapeutically effective amount to the inner ear. Furthermore, bioavailability is often reduced by drug metabolism by the liver. In addition, systemic administration of drugs may increase the potential for systemic toxicity and adverse side effects as a result of the high serum concentration required to deliver sufficient local delivery to the target site. Systemic toxicity can also result from liver destruction and treatment of the therapeutic agent, forming toxic metabolites that effectively negate any benefit provided by the administered therapeutic agent (eg, metabolism of carbamazepine). Can cause liver damage and death in some patients).

  In order to overcome the toxic and attendant undesirable side effects of systemic delivery of otic sensory cell modulators (which are understood to be toxic to cells), described herein are Methods and compositions for local delivery to the middle and / or inner ear structure of sensory cell modulators. For example, access to the vestibular and cochlear organs occurs through the round window membrane, the oval window / scapular bone plate, the middle or inner ear containing the annular ligament, and through the ear capsule / temporal bone . In further or alternative embodiments, the otic controlled release formulation can be administered around or around the round window membrane via intratympanic injection. In other embodiments, the controlled release formulation for the ear is administered through or around a round window or cochlear window ridge, through an incision in the posterior pinna, and the round window or cochlear window ridge. In or around these areas by surgical treatment. Alternatively, the ear controlled release formulation is applied by a syringe and needle, and the needle is inserted into the tympanic membrane and directed to the area of the round window or cochlear window ridge.

  In addition, topical treatment of the inner ear uses previous undesired therapeutic agents, including agents with poor pK characteristics, poor absorption, low systemic release, and / or toxicity issues Also make it possible.

  Due to the local targeting of ear sensory cell modulator formulations and compositions, and due to the presence of the body's blood barrier in the inner ear, it has previously been characterized as being toxic or ineffective. The risk of side effects resulting from treatment with the drug will be reduced. Therefore, also considered within the scope of the embodiments herein are ototoxicity, excitotoxicity, sensorineural hearing loss, noise-induced hearing loss, Meniere's disease / syndrome, endolymphatic edema, labyrinth, Ramsey Hunt The use of ear sensory cell modulators in the treatment of syndrome, vestibular neuronitis, tinnitus and microvascular compression syndrome, which has been previously used by practitioners due to side effects or ineffectiveness of ear sensory cell modulators Includes rejected therapeutic agents.

  Also included in the embodiments disclosed herein are additional middle and / or inner ear acceptable in combination with the ear sensory cell modulator formulations and compositions disclosed herein. The use of drugs. When using such drugs, such drugs may be deafness, lack of hearing, lack of balance, or hearing loss due to autoimmune disorders including dizziness, tinnitus, hearing loss, balance disorder, infection, inflammatory response, or combinations thereof. Or help treat balance dysfunction. Accordingly, agents that ameliorate or reduce the effects of rotational dizziness, tinnitus, hearing loss, imbalance, infection, inflammatory response or combinations thereof are also used in combination with the otic sensory cell modulators described herein. Is considered.

  In some embodiments, the composition further comprises an ear sensory cell modulator as an immediate release agent, wherein the immediate release ear sensory cell modulator is the same agent as the controlled release agent, a different ear sensory cell modulator, Additional therapeutic agents or combinations thereof. In some embodiments, the composition comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anesthetic, local action anesthetic, analgesic, antibiotic, antiemetic, antifungal, antimicrobial, antiseptic, antiviral, chemotherapeutic, diuretic Agents, keratolytic agents, ear protectants, immunosuppressants including but not limited to drugs such as calcineurin inhibitors (cyclosporine, tacrolimus, pimecrolimus), macrolides such as rapamycin, corticosteroids or combinations thereof. In some embodiments, the additional therapeutic agent is an immediate release agent. In some embodiments, the additional therapeutic agent is a controlled release agent.

  Accordingly, provided herein are controlled release ear sensory cell modulator formulations and compositions for locally treating the structure of the middle ear and / or inner ear, thereby modulating ear sensory cell modulation. Avoid side effects resulting from systemic administration of the drug. Topically applied ear sensory cell modulator formulations and compositions are compatible with the structure of the middle ear and / or inner ear, and may be of the desired middle and / or inner ear structure, such as the cochlear area, or the tympanic chamber It is administered directly to any of the cavities or to a structure that is directly connected to the inner ear region, including but not limited to, round window membrane, cochlear ridge or round window membrane. By specifically targeting the structure of the middle ear or inner ear, side effects of the inner ear structure, the result of systemic treatment, are avoided. Furthermore, by providing a controlled release otic sensory cell modulator formulation or composition, treating an otic disorder can provide a constant and / or wide range of sources of otic sensory cell modulators for otic disorders. Provided to individuals or patients suffering from, treatment variations are reduced or eliminated.

  Intratympanic injection of a therapeutic agent is a technique in which the therapeutic agent is injected behind the eardrum to reach the middle ear and / or the inner ear. Despite the early success with this technology (Schuknecht, Laryngroscope (1956) 66, 859-870), several challenges remain. For example, access to the round window membrane, the site of drug absorption into the inner ear, is problematic.

  However, intratympanic injections are not recognized with currently available treatment regimens, some unrecognized problems, perilymph, changes in osmolarity and pH of endolymph, direct or indirect to the inner ear structure Creates problems such as pathologically damaging pathogens, introduction of endotoxins, etc. One reason the art is not aware of these problems is that there is no recognized composition in the tympanic chamber. The inner ear presents unique formulation problems. Thus, compositions developed for other parts of the body are almost entirely unsuitable for compositions in the tympanic chamber.

  There is no prior art guidance that considers the requirements (eg, sterility level, pH, osmolarity) for otic formulations that are suitable for human administration. There are a wide range of anatomical differences between animal ears across multiple species. As a result of differences in internal space in auditory structures, animal models with inner ear disease are often unreliable as tools for testing therapies developed for clinical approval.

  Provided herein are otic preparations that meet stringent criteria of pH, osmolarity, ionic balance, sterility, composition, endotoxin, and / or pyrogenicity. The otic compositions described herein are compatible with the inner ear microenvironment (eg, perilymph) and are suitable for administration to humans. In some embodiments, the formulations described herein can be dyed, obviate the need for invasive procedures (e.g., removal of perilymph) during preclinical and / or clinical development of intratympanic procedures. Helps visualize the dosing composition to prevent.

  Provided herein are controlled release ear sensory cell modulator formulations and compositions for the local treatment of target otic structures, thereby providing an ear sensory cell modulator formulation and composition. Avoid side effects resulting from systemic administration. Topically applied ear sensory cell modulator formulations and compositions and devices that are compatible with the target ear structure, such as the desired target ear structure, eg, cochlear area, tympanic or outer ear It is administered directly to either or to a structure that is directly connected to the inner ear region, including but not limited to a round window membrane, a cochlear ridge or a round window membrane. By specifically targeting the ear structure, harmful side effects resulting from systemic treatment are avoided. In addition, clinical studies have shown that the benefits of prolonged drug exposure to the perilymph of the cochlea, such as increasing the clinical effectiveness of sudden hearing loss when given therapeutic drugs multiple times. Accordingly, by providing a controlled release otic sensory cell modulator formulation or composition, treating an otic disorder can result in a constant and / or wide range of sources of otic sensory cell modulators being otic disorders. Provided to individuals or patients suffering from, treatment variations are reduced or eliminated. Accordingly, one embodiment disclosed herein provides a therapeutically effective dose of at least one otic sensory cell modulator at various or constant rates so as to continuously release at least one agent. It is to provide a composition that can be released. In some embodiments, the otic sensory cell modulator disclosed herein is administered as an immediate release formulation or composition. In other embodiments, the otic sensory cell modulating agent is released continuously, variably or in a pulsed manner, or in variations thereof, and administered as a sustained release formulation. In still other embodiments, the ear sensory cell modulator formulation is released continuously, variably or in a pulsed fashion, or variations thereof, and administered as an immediate release formulation and a sustained release formulation. This release is optionally dependent on environmental or physiological conditions, such as the external ionic environment (see, eg, the Oros® release system, Johnson & Johnson).

  In addition, the ear-accepted controlled release ear sensory cell modulator formulations and treatments described herein are provided to the target ear region (including the inner ear) of an individual in need of treatment and need treatment The individual is further administered an oral dose of an otic sensory cell modulator. In some embodiments, the oral dose of the ear sensory cell modulator is administered prior to administration of the ear acceptable controlled release ear sensory cell modulator formulation, and then the ear acceptable controlled release ear sensory. During the time that the cell modulator formulation is provided, the oral dose is gradually reduced. Alternatively, an oral dose of an ear sensory cell modulator is administered during administration of an ear-accepted controlled release ear sensory cell modulator formulation, and then an ear acceptable controlled release ear sensory cell modulator. During the time that the drug formulation is provided, the oral dose is gradually reduced. Alternatively, the oral dose of the ear sensory cell modulator is administered after the start of the controlled release ear sensory cell modulator agent preparation acceptable to the ear, and then the controlled release ear sensory cell modulator acceptable to the ear. During the time that the drug formulation is provided, the oral dose is gradually reduced.

  In addition, the otic sensory cell modulator pharmaceutical composition or formulation or device included herein regulates carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, osmotic pressure. Salt and / or buffering agent. Such carriers, adjuvants, and other excipients will be compatible with the environment in the targeted ear structure (s). Thus, ototoxicity is eliminated or ototoxicity to enable effective treatment of the otic diseases envisaged herein and to minimize side effects in the targeted region or area. Particularly contemplated are minimal carriers, adjuvants and excipients. In order to prevent ototoxicity, the otic sensory cell modulator pharmaceutical composition or formulation or device disclosed herein optionally targets a discrete region of the targeted otic structure. This distinct region includes, but is not limited to, the tympanic chamber, vestibular and vestibular labyrinth, cochlear and cochlear labyrinth, and other anatomical or physiological structures located within the inner ear.

Particular Definitions Including. “Pharmaceutically acceptable to the ear” as used herein does not invalidate the biological activity or properties of the compound in relation to the inner ear, or the inner ear. ) Refers to a substance such as a carrier or diluent that relatively reduces or reduces toxicity. That is, the substance is administered to an individual so that it does not produce undesirable biological effects or adversely interact with any component of the composition in which the substance is contained.

  As used herein, ameliorating or reducing the symptoms of a particular otic disease, disorder or condition by administering a particular compound or pharmaceutical composition can be permanent or temporary. Anyway, due to administration of the above compound or composition, or in connection with administration of the above compound or composition, reducing severity, delaying onset, delaying progression, or duration Indicates shortening.

  “Antioxidants” are pharmaceutically audible antioxidants and include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium bisulfite, tocopherol. In certain embodiments, the antioxidant enhances chemical stability when necessary. Antioxidants are also used to neutralize the ototoxic effects of certain therapeutic agents, including agents used in combination with the otic sensory cell modulators disclosed herein.

  "Auris interna" refers to the inner ear, which includes the cochlea and vestibular labyrinths and the round window connecting the cochlea with the middle ear.

  “Inner ear bioavailability” refers to the percentage of an administered dose of a compound disclosed herein that becomes available in the inner ear of the animal or human being tested.

  “Auris media” refers to the middle ear that includes the tympanic chamber, ear ossicles, and the oval window that connects the middle ear to the inner ear.

  "Equilibrium disorder" refers to a disease, illness, or illness that causes a condition that causes dizziness or a sense of movement. This definition includes, but is not limited to, dizziness, rotational dizziness, imbalance, and fainting dizziness. Diseases are classified into, but not limited to, balanced diseases including Ramsey Hunt syndrome Meniere syndrome, mal de debarquement, benign paroxysmal positional vertigo, and labyrinthitis.

  “Plasma concentration” refers to the concentration of a compound provided herein in the plasma component of the blood of a subject.

A “carrier substance” is an excipient that is compatible with the release characteristics of an ear sensory cell modulator formulation, an inner ear, and a pharmaceutical formulation acceptable to the ear. Such carrier materials include, for example, binders, suspensions, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
“Pharmaceutically compatible carrier material” includes acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol ester, casein salt Including but not limited to sodium, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, calcium triphosphate, dipotassium phosphate, cellulose and cellulose conjugate, sodium sucrose stearoyl lactic acid, carrageenan, monoglyceride, diglyceride, pregelatinized starch, etc. Not.

  The term “diluent” refers to a chemical compound used to dilute an ear sensory cell modulator prior to delivery, which refers to a chemical compound used to adapt to the inner ear.

  A “dispersant” and / or “viscosity modifier” is a substance that controls the diffusivity and homogeneity of an otic sensory cell modulator through a liquid medium. Examples of diffusion facilitators / dispersants include, but are not limited to, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP, commercially known as Plasdone®), And carbohydrate-based dispersants, such as hydroxypropylcellulose (e.g., HPC, HPC-SL and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M and HPMC). K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, acetate stearate (HPMCAS), amorphous cellulose, magnesium magnesium silicate, triethanol , Polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4- (1,1,3,3-tetramethylbutyl) -phenol, ethylene oxide and formaldehyde (also known as tyloxapol), poloxamer (E.g. Pluronics F68 (R), F88 (R), F108 (R), which are block copolymers of ethylene oxide and propylene oxide), poloxamine (e.g. Tetronic 908 (R), Poloxamine 908 (R) ), A tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinyl Pyrrolidone K30, Polyvini Pyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (eg, polyethylene glycol has a molecular weight from about 300 to about 6000, from about 3350 to about 4000, from about 7000 to about 5400), sodium carboxymethylcellulose, Methylcellulose, polysorbate 80, sodium alginate, gums (eg, tragacanth gum and gum arabic), guar gum, xanthan including xanthan gum, sugar, cellulose compounds, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate 80, sodium alginate, sorbitan monolaurate Polyethoxylates, povidone, carbomers, polyvinyl alcohol (PVA), alginate, chitosan and combinations thereof. Plasticizers such as cellulose or triethyl cellulose are also used as dispersants. Dispersants useful for liposomal dispersions and self-emulsifying dispersions disclosed herein are dimyristoyl phosphatidylcholine, egg-derived natural phosphatidylcholine, egg-derived natural phosphatidylglycerol, cholesterol, isopropyl myristate. is there.

`` Drug absorption '' or `` absorption '' refers to a barrier (round window membrane as shown below) from the local site where the otic sensory cell modulator is administered, e.g., just from the round window membrane of the inner ear. Street, refers to the process of moving to the auris interna or inner ear structure.
The term “simultaneous administration” and the like, as used herein, is meant to encompass administration of an otic sensory cell modulator to one patient, the same or different routes of administration, or the same Alternatively, it is intended to include a treatment regimen in which the ear sensory cell modulator is administered at different times.

  The term “effective amount” or “therapeutically effective amount” as used herein is sufficient to anticipate to some extent alleviation of one or more diseases or conditions in a subject to be treated. It refers to the amount of the otic sensory cell modulator to be administered. For example, administration of the ear sensory cell modulator disclosed herein reduces and / or reduces the signs, symptoms or causes of tinnitus or balance disorder. For example, an “effective amount” used in therapy is the amount of an ear sensory cell modulator that is required to provide a reduction or amelioration of disease symptoms without undue side effects. Including the formulations disclosed herein. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a neuronal and / or hair cell modulator of the otic compositions disclosed herein to achieve the desired pharmacological effect or improved treatment without undue side effects. Is an effective amount. An “effective amount” or “therapeutically effective amount” is, in some embodiments, the metabolism of a compound administered, the age, weight, general condition of the subject, the disease being treated, the disease being treated. It can be understood that the severity of the disease and the judgment of the attending physician vary depending on the subject. It is also understood that in view of pharmacokinetics and pharmacology, an “effective amount” in a sustained release dosage form may differ from an “effective amount” in an immediate release dosage form.

  The term “enhancing” or “enhancing” refers to any adverse symptom resulting from either increasing or prolonging the effectiveness or duration of the desired effect of an otic sensory cell modulator, or administration of a therapeutic agent. It means to reduce. Thus, with respect to enhancing the effects of the ear sensory cell modulators disclosed herein, the term “enhancing” refers to the effects of other therapeutic agents used in combination with the ear sensory cell modulators disclosed herein. Refers to the ability to increase or lengthen either the effectiveness or duration of the. An “effective amount to enhance”, as used herein, is an ear sensation sufficient to enhance the effect of another therapeutic agent or ear sensory cell modulator of the target ear structure in the desired system. Refers to the amount of a cell modulating agent or other therapeutic agent. When used in patients, the effective amount for this application will vary depending on the severity and course of the disease, disorder or condition, previous treatment, patient health and response to the drug, and the judgment of the treating physician.

  The term “inhibiting” refers to preventing, delaying, or reversing the progression of a symptom, eg, a symptom of a patient in need of treatment.

  The terms “kit” and “product” are used synonymously.

  “Pharmacology” refers to factors that determine the biological response observed with respect to the concentration of a drug at a desired site within the middle ear and / or inner ear.

  “Pharmacokinetics” refers to factors that determine the acquisition and maintenance of an appropriate drug concentration at a desired site within the middle ear and / or inner ear.

  The term “modulator of otic nerve cells and / or hair cells” and “modulator of otic sensory cells” are synonymous.

  They include agents that promote the growth and / or regeneration of otic nerve cells and / or hair cells, and agents that destroy otic nerve cells and / or hair cells. In some embodiments, the otic sensory cell modulator has a therapeutic effect (e.g., reduced hearing loss) by promoting the growth and / or regeneration of otic sensory cells (e.g., neurons and / or hair cells) of the ear. provide. In some embodiments, the otic sensory cell modulator (e.g., a toxic agent) is a therapeutic effect (e.g., alleviation of rotational dizziness) due to destruction or damage of otic sensory cells (e.g., otic neurons and / or hair cells). I will provide a. In some embodiments, the otic sensory cell modulating agent treats and / or reverses damage to otic sensory cells (e.g., dysfunction of otic neurons and / or hair cells), or otic sensory. Reducing or delaying further damage (eg, cell death) to cells (eg, due to otoprotective effects or trophic effects) provides a therapeutic effect (eg, reduction of tinnitus due to acoustic trauma).

  The term “nutrient” means an agent that promotes the survival, growth and / or regeneration of ear sensory cells (eg, neurons and / or ear hair cells). In some embodiments, the nutrients reduce or inhibit oxidative damage and / or osteonecrosis and / or deterioration of the ear sensory cells. In some embodiments, the nutrient maintains normal ear sensory cells (eg, after surgical implantation of a medical device). In some embodiments, the nutritional agent upregulates the activity of an antioxidant enzyme (eg, during administration of an ototoxic agent). In some embodiments, the nutrient is an immunosuppressive agent (eg, an immunosuppressive agent used during ear surgery). In some embodiments, the nutrient is a growth factor (eg, a growth factor used after the transplantation method to promote otic cell growth).

The term “glutamate receptor antagonist” means a compound that interferes with or inhibits the activity of a glutamate receptor. In some embodiments, the receptor is an AMPA receptor or an NMDA receptor. In some embodiments, the glutamate receptor antagonist binds to a glutamate receptor. However, the unity does not produce a physiological response.
Glutamate receptor antagonists include partial agonists, inverse agonists, neutral or competitive antagonists, non-competitive antagonists, allosteric antagonists, and / or orthosteric antagonists.

The term “glutamate receptor agonist” means a compound that binds to and activates a glutamate receptor. The term further includes compounds that facilitate binding of the native ligand. In some embodiments, the receptor is an mGlu receptor.
Glutamate receptor agonists include partial antagonists, allosteric agonists, and / or orthosteric agonists.

  In prophylactic applications, compositions comprising the otic sensory cell modulators described herein are intended for patients susceptible to or at risk of being affected by a particular disease, disorder, or disease. Be administered. For example, such diseases include, but are not limited to, ototoxicity, excitotoxicity, sensorineural hearing loss, noise-induced hearing loss, Meniere's disease / syndrome, endolymphatic hydrops, labyrinth, Ramsey Hunt syndrome, vestibular neurons Includes inflammation, tinnitus or microvascular compression syndrome. Such an amount is defined as "a prophylactically effective amount or dose." In such use, the exact amount will also depend on the health status, weight, etc. of the patient.

  As used herein, a “pharmaceutical device” is any composition described herein that provides a container for sustained release of an active agent described herein when administered to the ear. Including things.

  As used herein, the term “substantially low degradation product” means that an agent with an activity of less than 5% by weight is a degradation product of the active agent. In a further embodiment, the term means that less than 3% by weight of the active agent is a degradation product of the active agent. In yet a further embodiment, the term means that less than 2% by weight of the active agent is a degradation product of the active agent. In a further embodiment, the term means that less than 1% by weight of the active agent is a degradation product of the active agent. In some embodiments, any individual impurities (e.g., degradation products such as metal impurities, active agents and / or excipients) present in the formulations described herein are 5% of the active agent. Less than wt%, less than 2 wt%, less than 1 wt%. Furthermore, the formulation must not precipitate or change color after production and storage.

  As used herein, “essentially in the form of a finely divided powder” is, by way of example, more than 70% by weight of the active agent in the form of a finely divided particulate of the active agent. Including being. In a further embodiment, the term means that more than 80% by weight of the active agent is in the form of a finely divided particulate of the active agent. In yet a further embodiment, greater than 90% by weight of the active agent is meant to be in the form of a finely divided particulate of the active agent.

  The term “ear interventional procedure” refers to external damage or trauma to one or more ear structures and refers to transplantation, ear surgery, injection, cannulation, and the like. Implants include inner ear or middle ear medical devices, examples of which include cochlear implants, hearing imparting devices, hearing improvement devices, short electrodes, microprosthetic or piston-like prosthetics, needles, stem cell transplants, drug delivery devices, Includes any cell-based therapy. Ear surgery includes middle ear surgery, inner ear surgery, tympanotomy (tympanic perforation), tympanic floor incision (labyrinthotomy), labyrinthotomy, mastoidectomy, stapes resection, Includes stapedotomy, endolymphatic saculotomy, etc. Injection includes injection in the middle ear, injection in the cochlea, injection across the round window membrane, and the like. Cannulation includes intramiddle, cochlear, endolymph, perilymph, vestibular cannulation, and the like.

  “Prodrug” refers to an otic sensory cell modulator that is converted in vivo to the parent drug. In certain embodiments, prodrugs are metabolized enzymatically by one or more steps or processes into a biologically, pharmaceutically or therapeutically active form of the compound. Pharmaceutically active compounds are modified so that the active compound is regenerated upon in vivo administration to produce a prodrug. In one embodiment, prodrugs are designed to alter the metabolic stability or migration properties of a drug, eliminate side effects or toxicity, or alter other properties or properties of the drug. The compounds provided herein are derivatized into suitable prodrugs in some embodiments.

  “Solubilizer” refers to a compound that is acceptable to the ear. Said compound aids or increases the solubility of the otic sensory cell modulator disclosed herein, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doxate, vitamin E TPGS , Dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salt, polyethylene glycol 200 to 600, glycofurol, Transquitol, propylene glycol, dimethyl isosorbide and the like.

  “Stabilizer” refers to a compound that is compatible with the inner ear environment, such as any antioxidant, buffer, acid, preservative, etc., that is compatible with the inner ear environment. Stabilizers include, but are not limited to: (1) improve the compatibility of excipients with containers or delivery systems (including syringes or glass bottles), (2) improve the stability of the components of the composition Or (3) any agent that improves the stability of the formulation.

  As used herein, “steady state” refers to when the amount of drug administered to the inner ear is equal to the amount of drug excluded during a single dosing interval, or within the targeted structure. This is the case when the drug exposure concentration reaches a certain level.

  As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

“Surfactants” include, for example, sodium lauryl sulfate, sodium doxate, Tween® 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomer, Refers to an aurally acceptable compound such as bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF).
Some other surfactants are, for example, polyoxyethylene (60), polyoxyethylene fatty acid glycerides of hydrogenated castor oil and vegetable oils, and polyoxyethylene alkyl ethers of, for example, octoxynol 10, octoxynol 40 And alkyl phenyl ether. In some embodiments, a surfactant is included to increase physical stability or for other purposes.

  The terms “treating”, “treating” or “treatment” as used herein are used to alleviate, attenuate or ameliorate a disease or condition, eg tinnitus symptoms, prevent further symptoms, Improve or prevent the underlying metabolic cause of symptoms, inhibit a disease or condition, for example, stop progression of a disease or condition, alleviate a disease or condition, reverse a disease or condition Alleviating a condition caused by a disease or illness, or stopping symptoms of a disease or illness either prophylactically and / or therapeutically.

  Other objects, features, and advantages of the methods and compositions described herein will become apparent from the detailed description that follows. However, the detailed description of the invention and the specific examples, while indicating specific embodiments, are given for illustration only.

Ear Anatomy As shown in Figure 4, the outer ear is the outer part of this organ, also known as pinna, auricle, ear canal (ear canal), and tympanic menbrane, ear drum It consists of the part facing the outside. The pinna, the fleshy part of the outer ear that is visible on the side of the head, collects sound waves and directs them to the ear canal. Thus, the function of the outer ear is, in part, to collect sound waves and direct them to the eardrum and middle ear.

  The middle ear is a cavity filled with air, called the tympanic chamber, behind the eardrum. The tympanic membrane (also known as the ear drum) is a thin membrane that separates the outer ear from the middle ear. The middle ear is located in the temporal bone, and includes three ear bones (the ossicles) of the tibia bone, quinuta bone, and stapes in this space. The ossicles are joined together by small ligaments, forming a bridge across the tympanic space. The gill bone is bonded to the eardrum at one end, bonded to the quinuta bone at the other end, and then bonded to the stapes. The stapes are connected to the oval window, and one of the two oval windows is located in the tympanic chamber. A fibrous tissue layer known as the annular ligament connects the stapes to the oval window. The sound wave from the outer ear first vibrates the eardrum. This vibration is transmitted to the cochlea through the ossicles and the oval window, and this movement is transmitted to the fluid in the inner ear. Thus, the ossicles are arranged to mechanically couple between the tympanic membrane and the fluid-filled inner ear oval window, and sound is transmitted to the inner ear and transformed for further processing. . If the ossicle, tympanic membrane, or oval window becomes stiff, stiff, or unable to move, it can cause hearing loss, such as otosclerosis or stiffness of the stapes.

  The tympanic chamber also connects to the throat through the ear canal. The ear canal provides the ability to equalize the pressure between the outside air and the middle ear cavity. The round window is an element of the inner ear, but is also connected to the tympanic chamber and opens toward the cochlea of the inner ear. The round window is covered by a round window membrane, which consists of three layers, the outer or mucus layer, the intermediate or fibrous layer, and the inner membrane, which is in direct communication with the cochlear fluid. Therefore, the round window is directly connected to the inner ear through the inner membrane.

  The movements in the oval and round windows are interconnected, i.e., as the stapes bone moves inward to the fluid of the inner ear by conveying this movement from the eardrum to the round window. The round window (or round window membrane) is pushed out correspondingly and away from the cochlear fluid. This movement of the round window moves the fluid in the cochlea, then moves the hair cells inside the cochlea and transmits an auditory signal. Hardening and stiffness in the round window membrane cause hearing loss because the cochlea fluid cannot move. Recent research has focused on implanting medical transducers in a round window that bypasses the normal conduction path through the oval window and provides amplified input to the cochlear chamber.

  Auditory signal conversion occurs in the inner ear. The fluid-filled inner ear (auris interna or inner ear) consists of two main elements: the cochlear and the vestibular apparatus. The inner ear is located, in part, in the bone labyrinth (osseous labyrinth or bony labyrinth), a series of intricate pathways in the temporal bone of the skull. The vestibular organ is an organ of balance sense and consists of three semicircular tubes and a vestibule. These three semicircular tubes are the movement of the head along three orthogonal planes of space by fluid movement and then signal processing by the sensory organs of the semicircular tube called the bulge They are arranged relative to each other so that they can be detected. The enormous ridge is provided with hair cells and supporting cells, and is covered with a semicircular gelatinous mass called cupra. Hair cell hair is embedded in cupra. The semicircular tube detects dynamic equilibrium, rotational or angular motion equilibrium.

  When the head is rapidly rotated, the semicircular tube moves with the head, but the endolymph in the membrane-like semicircular tube tends to remain stationary. Endolymph is pushed against cupra and tilted to one side. As the cupra tilts, the cupra bends some hairs of the hair cells of the vast crest, which triggers sensory impulses. Since each semicircular tube is located in a different plane, the enormous ridge corresponding to each semicircular tube responds differently to the same movement of the head. This creates a collection of impulses that travels to the central nervous system in the vestibular branch of the inner ear nerve. The central nervous system interprets this information and initiates an appropriate response to maintain balance. Of importance in the central nervous system is the cerebellum, which mediates the sense of balance and balance.

  The vestibule is the central part of the inner ear and is equipped with mechanoreceptors with hair cells that confirm the position of the head relative to static equilibrium or gravity. Static equilibrium plays a role when the head is not moving or moving in a straight line. The membranous labyrinth in the vestibule is divided into two sac-like structures, an oval sac and a spherical sac. Each structure also includes a small structure called a cyst, which is responsible for maintaining static equilibrium. The cyst is composed of sensory hair cells, and the sensory hair cells are embedded in a gelatinous mass (similar to cupra) covering the cyst. Calcium carbonate grains called otoliths are embedded in the gelatinous layer surface.

  When the head is in an upright position, the hair is straight along the plaque. As the head tilts, the gelatinous masses and otoliths tilt correspondingly and some hairs of the plaque hair cells bend. This bending action initiates a signal impulse to the central nervous system that travels through the vestibular branch of the inner ear nerve and relays the motor impulse in turn to the appropriate muscles to maintain balance.

  The cochlea is the part of the inner ear that is related to hearing. A cochlea has a tapered tubular structure and is wound into a shape resembling a snail. The inner side of the cochlea is divided into three regions, further defined by the location of the oval and basement membranes. The position above the oval membrane is the vestibular floor, extends from the oval window to the top of the cochlea, and contains perilymph, which is an aqueous solution with a low potassium concentration and a high sodium concentration. The basement membrane defines the area of the tympanic floor and extends from the top of the cochlea to the round window, which also contains perilymph. The basement membrane contains thousands of hard fibers, which gradually become longer from the round window toward the top of the cochlea. Basement membrane fibers vibrate when activated by sound. There is a cochlea tube between the vestibular floor and the trumpet floor, which ends as a closed sac at the top of the cochlea. The cochlear duct contains endolymph fluid, which is similar to cerebrospinal fluid and is rich in potassium.

  The Corti organ, which is the auditory organ, is on the basement membrane and extends upward toward the cochlear duct. The Corti organ contains hair cells, which have trichomes extending from the free surface and are in contact with a gelatinous surface called the cap membrane. Hair cells do not have axons but are surrounded by sensory nerve fibers that form the cochlear branches of the inner ear nerve (brain nerve VIII).

As mentioned above, the oval window, also known as an elliptical window, communicates with the stapes and relays sound waves that vibrate from the tympanic membrane. The vibration transmitted to the oval window increases the internal pressure of the cochlea filled with fluid via the perilymph and the vestibular / tympanic floor, and then the round window membrane responds and swells.
By cooperating that the inside of the oval window is pressurized / the inflating of the oval window to the outside, the fluid in the cochlea can be moved without changing the internal pressure of the cochlea. However, when vibrations are transmitted through the perilymph into the vestibular floor, a corresponding amplitude is created in the oval membrane. These corresponding amplitudes are transmitted through the endolymph of the cochlear duct and into the basement membrane. As the basement membrane oscillates or moves up and down, the Corti organ moves with it. The hair cell receptor of the organ of Corti then moves against the cap and mechanical deformation occurs in the cap. This mechanical deformation initiates nerve impulses that travel through the inner ear nerve to the central nervous system, where the received sound waves are mechanically converted into signals that are later processed by the central nervous system.

  Ear disorders result in symptoms including but not limited to hearing loss, nystagmus, dizziness, tinnitus, inflammation, infection and congestion. The ear disorders treated with the compositions disclosed herein are numerous and include ototoxicity, excitotoxicity, sensorineural hearing loss, noise-induced hearing loss, Meniere's disease / syndrome, endolymphatic hydrops, labyrinthitis , Ramsey Hunt syndrome, vestibular neuronitis, tinnitus and microvascular compression syndrome.

Excitotoxicity Excitotoxicity refers to the death or damage of nerves and / or hair cells by glutamate and / or similar substances.

  Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. Presynaptic cells release glutamate upon stimulation. Glutamate travels across the synapse, binds to receptors located in postsynaptic cells, and activates these neurons. Glutamate receptors include NMDA, AMPA and kainate receptors. The glutamate transporter is tasked with removing extracellular glutamate from the synapse. Certain events (eg, ischemia or stroke) can damage the glutamate transporter. This gives rise to excess glutamate that accumulates in the synapse. Excess glutamate within the synapse results in excessive activation of glutamate receptors.

  AMPA receptors are activated by the binding of both glutamate and AMPA. Activation of specific isoforms of AMPA receptors results in the opening of ion channels located in the neuronal plasma membrane. When the channel opens, Na + and Ca2 + ions flow into the neuron and K + ions flow out of the neuron.

  The NMDA receptor is activated by the binding of both glutamate and NMDA. Activation of the NMDA receptor results in the opening of ion channels located in the neuronal plasma membrane. However, these channels are blocked by Mg2 + ions. Activation of the AMPA receptor results in the excretion of Mg2 + ions from the ion channel to the synapse. When the ion channel opens and the ion channel ejects Mg2 + ions, Na + and Ca2 + ions flow into the neuron and K + ions flow out of the neuron.

  Excitotoxicity occurs when NMDA and AMPA receptors are overactivated by an excessive amount of ligand, such as an abnormal amount of glutamate. Excessive activation of these receptors results in excessive opening of ion channels under their control. This allows abnormally high levels of Ca2 + and Na + to enter the neuron. The flow of these levels of Ca2 + and Na + into nerve cells excites nerve cells more frequently, resulting in rapidly developing free radicals and inflammatory compounds in the cells. Free radicals eventually use up stored energy in cells and damage mitochondria. Furthermore, excess levels of Ca2 + and Na + ions activate excess levels of enzymes (including but not limited to phospholipases, endonucleases, proteases). Excessive activity of these enzymes results in damage to the cytoskeleton, plasma membrane, mitochondria, and sensory nerve DNA.

Tinnitus As used herein, “tinnitus” refers to a disorder characterized by the perception of sound in the absence of any external stimulus. In certain instances, tinnitus is described as a reverberant sound, mostly in one or both ears, either continuously or sporadically. Most often used as a diagnostic symptom of other diseases. There are two types of tinnitus: objective tinnitus and subjective tinnitus. The former is a sound created in the body that anyone can hear.
The latter can only be heard by affected individuals. The study estimates that more than 50 million Americans experience some type of tinnitus. Of these 50 million, about 12 million people experience severe tinnitus.

  There are several treatments for tinnitus. Lidocaine administered by infusion reduces or eliminates the noise associated with tinnitus in 60% to 80% of patients. Reuptake of selective neurotransmitter inhibitors, such as nortriptyline, sertraline, paroxetine, etc. also has a confirmed effect on tinnitus. Benzodiazepines are also prescribed to treat tinnitus. In some embodiments, the otic sensory cell modulating agent reduces or inhibits otic sensory cell damage and / or cell death associated with tinnitus.

  Sensorineural hearing loss is a type of hearing loss that results from an inner ear nerve (also known as the VIII cranial nerve) of the inner ear, or from a sensory cell (congenital, acquired) abnormality. The main abnormality of the inner ear is that of the ear hair cells.

Sensorineural hearing loss Sensorineural hearing loss is a type of hearing loss that results from an inner ear nerve (also known as the VIII cranial nerve) of the inner ear, or from a sensory cell (congenital, acquired) abnormality. The main abnormality of the inner ear is that of the ear hair cells.

  Cochlear dysplasia, chromosomal abnormalities, and congenital cholesteatoma are examples of congenital abnormalities that can result in sensorineural hearing loss. By way of example only, inflammatory diseases (e.g. purulent otitis media, tympanitis, mumps, measles, viral syphilis, autoimmune disorders), Meniere's disease, ototoxic drugs (e.g. aminoglycosides, loop diuretics) , Antimetabolites, salicyl salts, cisplatin), physical trauma, senile deafness, acoustic trauma (due to prolonged exposure to sound above 90 dB) can result in acquired sensorineural hearing loss It is.

  If the abnormality resulting in sensorineural hearing loss is an abnormality in the auditory tract, the sensorineural hearing loss is called central deafness. If the abnormality that results in sensorineural hearing loss is an abnormality in the auditory tract, sensory softness is called cutaneous hearing loss. In some embodiments, the ear sensory cell modulating agent is a nutrient (eg, BDNF, GDNF) that promotes the growth of ear sensory cells or reduces or reverses sound sensory hearing loss.

Noise-induced hearing loss Noise-induced hearing loss (NIHL) is caused by prolonged exposure to too loud voices or sounds. Exposure to sound above 85 decibels for a long time, repeatedly, or suddenly causes hearing loss. Hearing loss can also be caused by prolonged exposure to loud noise, such as loud music, heavy machinery or machinery, airplanes, gunshots or other human noise. NIHL causes damage to hair cells and / or auditory nerves. Hair cells are small sensory cells that convert acoustic energy into electrical signals. Sudden sounds result in permanent immediate hearing loss. This type of hearing loss is accompanied by tinnitus, such as ringing, groaning, or groaning in the ear or head that subsides over time. Hearing loss and tinnitus are experienced in one or both ears. Tinnitus continues continuously or occasionally throughout life. In addition, the process occurs more gently than sudden noise, but continued exposure to loud sounds damages the structure of hair cells, resulting in permanent hearing loss and tinnitus.

  In some embodiments, the ear protectant can reverse, reduce or improve NIHL. Examples of ear protection agents for treating or preventing NIHL include, but are not limited to, the ear protection agents described herein.

  Toxic hearing loss refers to hearing loss caused by a toxin. The hearing loss may be due to ear hair cells, trauma to the cochlea and / or cranial nerve VII. Multidrugs are known to be ototoxic. In many cases, ototoxicity is dose dependent. It may or may not improve with drug withdrawal.

  Known ototoxic drugs include, but are not limited to, aminoglycoside antibiotic class antibiotics (e.g., gentamicin or amikacin), some members of macrolide class antibiotics (e.g., erythromycin), glycoprotein class antibiotics Several members (e.g. vancomycin), salicylic acid, nicotine, several chemotherapeutic agents (e.g. actinomycin, bleomycin, cisplatin, carboplatin and vincristine), and some members of loop diuretic family drugs (e.g. furosemide) 6-hydroxydopamine (6-OH DPAT), 6,7-dinitroquinoxaline-2,3-dione, etc. (DNQX).

  Cisplatin and aminoglycoside antibiotic class antibiotics induce the production of reactive oxygen species (ROS). ROS directly damages cells by damaging DNA, polypeptides, and / or lipids. Antioxidants prevent damage from ROS by preventing them from forming or removing free radicals before they can damage cells. Both cisplatin and the aminoglycoside antibiotic class of antibiotics are thought to damage the ear by binding melanin in the vascular striatum of the inner ear.

  Salicylic acid is classified as ototoxic because it inhibits the function of the polypeptide prestin. Prestin regulates outer ear hair cell motility by controlling the exchange of chloride and carbonate across the plasma membrane of the outer ear hair cells. It is only found in the outer ear hair cells and not in the inner ear hair cells. Accordingly, disclosed herein is the use of a controlled release otic composition comprising an ear protectant (e.g., an antioxidant), which includes, but is not limited to, cisplatin treatment, aminoglycoside Prevent, ameliorate or alleviate the ototoxic effects of chemotherapy, including administration of antibiotics or salicylic acid or other ototoxic agents.

Endolymphedema Intralymphoma refers to an increase in water pressure within the inner lymphatic system of the inner ear. The endolymph and perilymph are separated by a thin film containing a plurality of nerves. Pressure changes stress the membranes and nerves that contain them. If the pressure is high enough, breakage may occur in these membranes. This results in a temporary loss of liquid mixing and function leading to cathodic suppression. Changes in the rate of vestibular nerve firing often lead to rotational dizziness. In addition, the Corti organ is affected. Distortion between the basement membrane and inner and outer hair cells triggers hearing loss and / or tinnitus.

  Causes include metabolic disorders, hormonal imbalances, autoimmune diseases, and viral, bacterial or fungal infections. Symptoms include hearing loss, dizziness, tinnitus, and a feeling of ear blockage. Nystagmus also appears. Treatments include benzodiazepines, diuretics (reducing water pressure), corticosteroids, and / or antibacterial, antiviral, or antibacterial agents.

Inner Otitis Otitis is an inflammation of the ear maze, which includes the vestibular system of the inner ear. Causes include bacterial infections, viral infections and fungal infections. It is also caused by head trauma or allergies. Symptoms of labyrinth include balance maintenance, dizziness, rotational dizziness, tinnitus and hearing loss. Recovery may take 1-6 weeks. However, chronic symptoms may exist for many years.

  There are several treatments for mazeitis. Prochlorperazine is often prescribed as an antiemetic. Serotonin reuptake inhibitors have been shown to stimulate new neurodevelopment in the inner ear. In addition, if the cause is a bacterial infection, treatment with antibiotics is prescribed. Also, if the disease is caused by a viral infection, treatment with corticoids and antiviral agents is recommended.

Meniere's Disease Meniere's disease is an idiopathic illness characterized by a sudden attack of dizziness, nausea, and vomiting that lasts 3-24 hours and gradually subsides. Over time, the above mentioned diseases are accompanied by progressive hearing loss, tinnitus, and ear tightness. The cause of Meniere's disease appears to be related to an imbalance of inner ear fluid homeostasis, including increased inner ear fluid production or decreased reabsorption.

  Studies of the vasopressin (VP) -mediated aquaporin 2 (AQP2) system in the inner ear suggest a role for VP in inducing endolymph products, thereby increasing pressure within the vestibular and cochlear structures . The level of VP was found to be upregulated in cases of endolymphatic edema (Meniere's disease). In addition, long-term administration of VP to guinea pigs was found to induce endolymphatic edema. Treatment with VP antagonists, including infusion of OPC-31260 (a competitive antagonist of V2-R) into the tympanic floor, resulted in a marked reduction in Meniere's symptoms. Other VP antagonists include WAY-140288, CL-385004, tolvaptan, conivaptan, SR 121463A and VPA 985. (Sanghi et al., Eur. Heart J. (2005), 26: 538-543, Palm et al. Nephrol. Dial Transplant, (1999), 14: 2559-2562).

  Other studies suggest a role for the estrogen-related receptor β / NR3B2Nr3b2 (ERR / Nr3b2) in regulating endolymph products and therefore pressurizes within the vestibular / cochlear organ. Mice knockout studies indicate a role for the polypeptide product of the Nr3b2 gene in controlling the product of endolymph fluid. Nr3b2 expression is localized to endolymphocrine linear marginal cells and vestibular dark cells of the cochlear vestibular organ, respectively. Furthermore, a conditional knockout of the Nr3b2 gene results in hearing loss and a decrease in endolymph fluid volume. Treatment with antagonists to ERR / Nr3b2 helps reduce the amount of endolymph and thus alters the pressure within the inner ear structure.

  Other treatments are aimed at treating symptoms that occur immediately and preventing recurrence. Avoidance of a low sodium diet, caffeine, alcohol and tobacco was recommended. Drug therapies that temporarily remove rotational dizziness attacks include antihistamines (including meclizine and other antihistamines) and central nervous system agents including barbituric acid and / or benzodiazepines including lorazepam or diazepam. Other examples of drugs useful for relieving symptoms include muscarinic antagonists, including scopolamine. Nausea and vomiting are mitigated by suppositories containing schizophrenia drugs, including the phenothiazine prochlorverazine.

  Surgical procedures used to relieve symptoms include disruption of vestibular and / or cochlear function to relieve dizziness symptoms. These procedures are aimed at either reducing the fluid pressure of the inner ear and / or destroying the balance function of the inner ear. Endolymphatic shunting that reduces fluid pressure may be placed in the inner ear to alleviate symptoms of vestibular dysfunction. Other treatments include gentamicin application that injects the tympanic membrane to destroy the sensory function of the hair cells, thereby completely eliminating the balance function of the inner ear. Cuts of the vestibular nerve may be used to control dizziness while maintaining hearing. In some embodiments, the ear sensory cell modulator promotes hair cell growth and allows the subject to restore inner ear balance function.

Meniere's Syndrome Meniere's syndrome, which exhibits symptoms similar to Meniere's disease, is thought to be a secondary distress of another disease process (eg, thyroid disease or inner ear inflammation due to syphilis infection). Thus, Meniere's syndrome interferes with the normal production or reabsorption of the endolymph, including endocrine abnormalities, electrolyte imbalance, autoimmune dysfunction, dysfunction, medicine, infection (e.g., parasitic infection) or dyslipidemia It is a secondary effect on various processes. Treatment of patients with Meniere's syndrome is similar to Meniere's disease.

Ramsey Hunt syndrome (shingles infection)
Ramsey Hunt syndrome is caused by an infection of the acoustic nerve shingles. In addition to severe ear pain, hearing loss and rotational dizziness, the infection causes blisters supplied by nerves in the outer ear, ear canal and facial or neck skin. If the facial nerve is compressed by swelling, the facial muscles may be paralyzed. Hearing loss may be temporary or may not heal, with rotational dizziness usually lasting from days to weeks.

  Treatment of Ramsey Hunt syndrome involves the administration of antiviral agents including acyclovir. Other antiviral agents include famciclovir and valacyclovir. A combination of antiviral and corticosteroid treatments may be used to improve herpes zoster infection. Analgesics or narcotics may be administered to relieve pain, and diazepam or other central nervous system agents may be administered to suppress rotational dizziness. Capsaitin, lidocaine patch and nerve block are optionally used. Surgery may be performed on the facial nerve that has been pressed to relieve facial paralysis.

Microvascular compression syndrome Microvascular compression syndrome (MCS), also called “vascular compression” or “neurovascular compression”, is a disorder characterized by rotational dizziness and tinnitus. Microvascular compression syndrome is caused by stimulation of cranial nerve VII by blood vessels. Other symptoms found in subjects with MCS include, but are not limited to, severe motion intolerance and neuralgia such as “quick spin”. MCS is treated with carbamazepine, TRILEPTAL (registered trademark) and baclofen. It may also be treated surgically.

Vestibular neuritis Vestibular neuritis (or vestibular neuropathy) is an acute, sustained dysfunction of the peripheral vestibular system. It is theorized that vestibular neuronitis is caused by disruption of afferent nerve input from one or both vestibular organs. Sources of this destruction include vestibular nerve and / or labyrinth virus infection and acute local anemia.

The most important finding when diagnosing vestibular neuronitis is spontaneous, unidirectional, horizontal nystagmus. It is often accompanied by nausea, vomiting symptoms and rotational dizziness.
However, hearing loss or other auditory symptoms are generally not associated.

  There are several treatments for mazeitis. H1-receptor antagonists such as dimenhydrinate, diphenhydramine, meclizine and promethazine reduce vestibular stimulation and reduce maze function by anticholinergic action. Benzodiazepines such as diazepam and lorazepam are also used to inhibit vestibular reactions due to the effect of benzodiazepines on GABAA receptors. Anticholinergics such as scopolamine are also prescribed. These function by inhibiting conduction in the vestibular and cerebellar pathways. Finally, corticoids (ie prednisone) are prescribed to improve inflammation of the vestibular nerve and related organs.

  Provided herein are ear sensory cell modulator compositions or formulations that modulate the deterioration of ear sensory cells (eg, ear neurons and / or hair cells). In some embodiments, an otic sensory cell modulator composition or formulation described herein reduces, delays, or delays the deterioration of otic sensory cells (e.g., otic neurons and / or hair cells). Or reverse. Also described herein are hearing loss or caused by hair in the inner ear being destroyed, dysplastic, dysfunctional, damaged, fragile or missing A controlled release composition for treating or ameliorating hearing loss. Further provided herein are ear sensory cell modulator compositions or formulations that promote the growth and / or regeneration of ear sensory cells (eg, neurons and / or ear hair cells). In some embodiments, the ear sensory cell modulator composition or formulation destroys ear sensory cells (eg, ear neurons and / or hair cells). In some embodiments, the ear sensory cell modulating agent is an ear protectant that reduces, reverses, or delays damage to ear sensory cells (eg, ear neurons and / or hair cells).

  Ear and vestibular disorders have causes and symptoms that are responsive to the pharmaceutical agents disclosed herein, or other pharmaceutical agents. Although not disclosed herein, otic sensory cell modulators that ameliorate or eradicate otic diseases are clearly included and intended to be within the scope of the presented embodiments. Yes.

  In addition, during systemic or topical application, toxic metabolites that are produced after treatment with a drug that has been previously shown to be toxic, harmful or ineffective in other organ systems, for example Due to drug toxicity in certain organs, tissues or systems, due to high concentrations required to obtain efficacy, due to inability to be released via systemic routes, or poor pK properties Are also useful in some embodiments herein. Therefore, pharmaceutical agents that have limited systemic release or are not released systemically, are toxic when administered systemically, have poor pK properties, or have a combination of these properties. It is envisioned to be within the scope of the embodiments disclosed in the specification.

  The otic sensory cell modulator formulations disclosed herein optionally target directly otic structures that require treatment. For example, one contemplated embodiment applies the otic sensory cell modulator formulation disclosed herein directly to the round window membrane or cochlear window of the inner ear, and the elements of the auris interna or inner ear To reach and treat directly. In other embodiments, the ear sensory cell modulating agent formulations disclosed herein are applied directly to the oval window. In yet other embodiments, direct access is obtained by direct microinjection into the inner ear (eg, microperfusion into the cochlea). Such embodiments also optionally include a drug delivery device that includes a needle and syringe, a pump, a microinjection device, a sponge-like material formed in situ that is acceptable to the ear, or these The combination is used to deliver an otic sensory cell modulator formulation.

  Some pharmaceutical agents are ototoxic, alone or in combination. For example, some chemotherapeutic agents include actinomycin, bleomycin, cisplatin, carboplatin and vincristine, and antibiotics include erythromycin, gentamicin, streptomycin, dihydrostreptomycin, tobramycin, netilmycin, amikacin, neomycin, kanamycin, echomycin (etiomycin ), Vancomycin, metronidizole, capreomycin, which are slightly highly toxic and differentially affect the vestibular and cochlear structures. However, in some instances, combinations with ototoxic drugs, such as cisplatin, gentamicin in combination with an otoprotectant, alleviate the ototoxic effects of the drug. In addition, localized application of potential ototoxic drugs mitigates the effects of toxicity, but otherwise uses lower doses with sustained efficacy or target doses for shorter periods. Through use, occurs by systemic administration.

  In some embodiments, the otic sensory cell modulator agent formulations disclosed herein further reduce ototoxicity of agents such as chemotherapeutic agents and / or antibiotics described herein. Or contain an ear protectant that attenuates, inhibits or improves the effects of other environmental factors, including excessive noise and the like. Examples of ear protectants include, but are not limited to, the ear protectants, thiols and / or mercapto groups and / or pharmaceutically acceptable salts described herein, or derivatives thereof (e.g., Prodrug).

  Otoprotectants allow the administration of ototoxic agents and / or antibiotics at doses higher than the maximum addictive dose. Otherwise, ototoxic agents and / or antibiotics are administered at lower doses due to ototoxicity. An ear protectant can optionally improve, reduce or eliminate the effects of environmental factors when administered alone, including but not limited to noise-induced hearing loss and tinnitus It contributes to hearing loss and its associated effects.

The amount of ear protectant on a molar: molar basis in any formulation described herein relative to an ototoxic chemotherapeutic agent (eg cisplatin) and / or an ototoxic antibiotic (eg gentamicin) is about It ranges from 5: 1 to about 200: 1 and ranges from about 5: 1 to about 100: 1, or from about 5: 1 to about 20: 1.
The amount of otoprotective agent on a molar basis in any formulation described herein relative to an ototoxic chemotherapeutic agent (e.g. cisplatin) and / or an ototoxic antibiotic (e.g. gentamicin) is about 50: 1. , About 20: 1, or about 10: 1. Any of the ear sensory cell modulator formulations described herein can be from about 10 mg / ml to about 50 mg / ml, from about 20 mg / ml to about 30 mg / ml, or from about 10 mg / ml to 25 mg / ml of the ear protectant. Contains up to ml.

  In addition, some pharmaceutical excipients, diluents, or carriers are potentially ototoxic. For example, the common preservative benzalkonium chloride is ototoxic and is therefore potentially harmful when introduced into vestibular and cochlear structures. Avoiding or combining appropriate excipients, diluents or carriers in formulating controlled release otic sensory cell modulator formulations, reducing or eliminating potential ototoxic compounds from the formulation, or It is recommended to reduce the amount of excipients, diluents or carriers. Optionally, controlled release otic sensory cell modulator formulations may be antioxidants to reduce the potential ototoxic effects that may result from the use of certain therapeutic agents such as excipients, diluents or carriers. Ototoxic protection agents such as alpha lipoic acid, calcium, fosfomycin or iron chelators.

Amifostine Considered for use with the formulations disclosed herein is an agent that modulates the deterioration of otic neurons and / or hair cells, and hair growth in the inner ear is disrupted by stunting It is an agent for treating or ameliorating hearing loss or hearing loss caused by certain, dysfunctional, damaged, fragile or missing. Thus, some embodiments incorporate the use of agents that rescue neurons and otic hair cells from cisplatin-induced ototoxicity.

  Amifostine (also known as WR-2721, or ETHYOL®) is an ear protectant. In certain instances, amifostine prevents or ameliorates damage caused by cisplatin to neurons and ear hair cells. In certain instances, a dose of 40 mg / kg or higher is necessary to prevent or ameliorate the ototoxic effects of cisplatin.

Salicylic acid Considered for use with the formulations disclosed herein is an agent that modulates the deterioration of otic neurons and / or hair cells, and hair growth in the inner ear is disrupted by stunting It is an agent for treating or ameliorating hearing loss or hearing loss caused by being dysfunctional, damaged, fragile or missing. Thus, some embodiments incorporate the use of salicylic acid. In certain instances, salicylic acid is an antioxidant, and when administered prior to treatment with an aminoglycoside, salicylic acid protects otic hair cells and spiral ganglion neurons from aminoglycoside ototoxicity.

Modulation of Atoh / Math1 Considered for use with the formulations disclosed herein are agents that promote the growth and / or neogenesis of neurons and / or ear hair cells. Atoh1 is a transcription factor that binds to the E-box. In particular examples, Atoh1 is expressed during vestibular and auditory system hair cell progression. In certain instances, Atoh1 knocked out mice did not develop ear hair cells. In certain instances, an adenovirus expressing Atoh1 stimulates growth and / or regeneration of otic hair cells in guinea pigs treated with ototoxic antibiotics. Thus, some embodiments incorporate regulation of the Atoh1 gene.

  In some embodiments, the subject is administered a vector that has been engineered to carry the human Atoh1 gene (“Atoh1 vector”). See US Publication No. 2004/02475750 for a disclosure of techniques for creating Atoh1 vectors. This document is incorporated herein by reference for disclosure. In some embodiments, the Atoh1 vector is a retrovirus. In some embodiments, the Atoh1 vector is not a retrovirus (eg, the Atoh1 vector is an adenovirus, a lentivirus, or METAFECTEN, SUPERFECT®, EFFECTENE® Or a polymer delivery system such as MIRUS TRANSIT).

  In some embodiments, the Atoh1 vector is incorporated into a controlled release ear acceptable microparticle or microparticle, hydrogel, liposome, or thermoreversible gel. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are injected into the inner ear. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are cochlear, Corti organs, vestibular labyrinths, or Injected into their combination.

In certain instances, after administration of the Atoh1 vector, the Atoh1 vector infects cells (eg, cochlear, Corti organ, and / or vestibular maze cells) at the administration location. In certain instances, the Atoh1 sequence is incorporated into the subject's genome (eg, when the Atoh1 vector is a retrovirus). In certain instances, treatment needs to be re-administered periodically (eg, when the Atoh1 vector is not a retrovirus). In some embodiments, the treatment is re-administered annually.
In some embodiments, the treatment is administered every six months. In some embodiments, if the subject's hearing loss is moderate (i.e., the subject cannot consistently hear frequencies below 41 dB to 55 dB) (i.e., the subject is Treatment cannot be heard consistently below 90 dB) and treatment is re-administered.

  In some embodiments, the subject is administered an Atoh1 polypeptide. In some embodiments, the Atoh1 polypeptide is incorporated into a controlled release ear acceptable microparticle or microparticle, hydrogel, liposome, or thermoreversible gel. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ forming spongy materials, nanocapsules or nanospheres, or thermoreversible gels. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are injected into the inner ear. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are cochlear, Corti organs, vestibular labyrinths, or Injected into their combination. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ forming spongy materials, nanocapsules or nanospheres, or thermoreversible gels are circular. It is installed in contact with the window membrane.

  In some embodiments, the subject is administered a pharmaceutically acceptable agent that modulates the expression of the activity of the Atoh1 gene or Atoh1 polypeptide. In some embodiments, expression of the activity of the Atoh1 gene or Atoh1 polypeptide is upregulated. In some embodiments, expression of the activity of the Atoh1 gene or Atoh1 polypeptide is downregulated.

  In particular examples, compounds that antagonize Atoh1 are identified (eg, by use of a high throughput screen). In some embodiments, the construct is designed such that the reporter gene is placed downstream of the E-box sequence. In some embodiments, the reporter gene is luciferase, CAT, GFP, β-lactamase or β-galactosidase. In certain instances, Atoh1 polypeptide binds to an E-box sequence and initiates transcription and expression of a reporter gene. In certain instances, an agonist of Atoh1 assists or facilitates binding of Atoh1 to the E-box sequence, thereby increasing reporter gene transcription and expression relative to a pre-defined baseline expression level. In certain instances, antagonists of Atoh1 prevent Atoh1 from binding to the E-box, thereby reducing transcription and expression of the reporter gene relative to a predefined baseline expression level.

BRN-3 Modulators Considered for use with the formulations disclosed herein are agents that promote the growth and / or regeneration of neurons and / or ear hair cells. BRN-3 is a group of transcription factors including but not limited to BRN-3a, BRN-3b and BRN-3c. In certain instances, they are expressed in post-mitotic hair cells. In certain instances, mouse hair cells with BRN-3c did not grow immobile hair and / or experienced cell death. In certain instances, the BRN3 gene regulates the differentiation of inner ear support cells into inner ear sensory cells. Thus, some embodiments incorporate regulation of the BRN3 gene and / or polypeptide.

  In some embodiments, the subject is administered a vector that has been engineered to carry the human BRN-3 gene (“BRN vector”). In some embodiments, the BRN3 vector is a retrovirus. In some embodiments, the BRN3 vector is not a retrovirus (e.g., the BRN3 vector is an adenovirus, is a lentivirus, or METAFECTEN, SUPERFECT, EFFECTENE: Or a polymer delivery system such as MIRUS TRANSIT).

In some embodiments, the subject is administered a BRN3 vector, or a volume sufficient to induce acoustic trauma, before, during or after exposure to an ototoxic agent (eg, aminoglycoside or cisplatin).

  In some embodiments, the BRN3 vector is incorporated into a controlled release ear acceptable microparticle or microparticle, hydrogel, liposome, or thermoreversible gel. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are injected into the inner ear. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are cochlear, Corti organs, vestibular labyrinths, or Injected into their combination.

In certain instances, after administration of the BRN3 vector, the BRN3 vector infects cells (eg, cells of the cochlea, Corti organ, and / or vestibular maze) at the administration location. In certain instances, the BRN3 sequence is incorporated into the subject's genome (eg, when the BRN3 vector is a retrovirus).
In certain instances, treatment needs to be re-administered periodically (eg, when the BRN3 vector is not a retrovirus).

  In some embodiments, the subject is administered a BRN3 polypeptide. In some embodiments, the BRN3 polypeptide is incorporated into a controlled release ear acceptable microparticle or microparticle, hydrogel, liposome, or thermoreversible gel. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ forming spongy materials, nanocapsules or nanospheres, or thermoreversible gels. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are injected into the inner ear. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are cochlear, Corti organs, vestibular labyrinths, or Injected into their combination. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ forming spongy materials, nanocapsules or nanospheres, or thermoreversible gels are circular. It is installed in contact with the window membrane.

  In some embodiments, the subject is administered a pharmaceutically acceptable agent that modulates the expression of BRN3 gene or BRN3 polypeptide activity. In some embodiments, the expression of BRN3 gene or BRN3 polypeptide activity is upregulated. In some embodiments, the expression of BRN3 gene or BRN3 polypeptide activity is downregulated.

  In some embodiments, compounds that antagonize BRN3 are identified (eg, by use of a high throughput screen). In some embodiments, the construct is designed such that the reporter gene is placed downstream of the BRN3 binding site. In some embodiments, the BRN3 binding site has an ATGAATTAAT (SBNR3) sequence. In some embodiments, the reporter gene is luciferase, CAT, GFP, β-lactamase or β-galactosidase. In certain instances, the BRN3 polypeptide binds to the SBNR3-sequence and initiates transcription and expression of the reporter gene. In certain instances, an agonist of BRN3 assists or facilitates binding of BRN3 to the SBNR3-sequence, thereby increasing reporter gene transcription and expression relative to a pre-defined baseline expression level. In certain instances, an antagonist of BRN3 prevents binding of BRN3 to SBNR3-, thereby reducing reporter gene transcription and expression relative to a predefined baseline expression level.

Carbamates Considered for use with the formulations disclosed herein are agents that modulate the deterioration of otic neurons and / or hair cells, and are stunted, in which hair in the inner ear is destroyed. It is an agent for treating or ameliorating hearing loss or hearing loss caused by certain, dysfunctional, damaged, fragile or missing. In certain instances, the carbamate compounds protect neurons and ear hair cells from glutamate-induced excitotoxicity. Thus, some embodiments incorporate the use of carbamate compounds. In some embodiments, the carbamate compound is 2-phenyl-1,2-ethanediol monocarbamate and dicarbamic acid, derivatives thereof, and / or combinations thereof.

Gamma-secretase inhibitors Considered for use with the formulations disclosed herein are agents that modulate the deterioration of otic neurons and / or hair cells, and the hair in the inner ear is destroyed, An agent for treating or ameliorating hearing loss or hearing loss caused by poor development, dysfunction, damage, fragility or deficiency. Thus, some embodiments incorporate the use of agents that inhibit Notch1 signaling. Notch1 is a transmembrane polypeptide involved in cell development. In some embodiments, the agent that inhibits Notch1 signaling is a gamma-secretase inhibitor. In certain instances, inhibition of Notch1 by gamma secretase inhibitors occurs as a result of otic hair cell generation / growth after treatment with ototoxic agents. In some embodiments, the gamma-secretase inhibitor is LY450139 (hydroxyl valeryl monobenzocaprolactam), L685458 (1S-benzyl-4R [1- [1-S-carbamyl-2-phenethylcarbamoyl) -1S-3-methyl Butylcarbamoyl] -2R-hydroxy-5-phenylpentyl} carbamic acid tert-butyl ester), LY411575 (N2-[(2S) -2- (3,5-difluorophenyl) -2-hydroxyethanoyl] -N1 [ (7S) -5-Methyl-6-oxo-6,7-dihydro-5H-dibenzo [bid] azepine-7yl] -L-alaninamide, MK-0752 (Merck), tarenflurvir, and / or BMS- 299897 (2-[(1R) -1-[[(4-chlorophenyl) sulfonyl] (2,5-difluorophenyl) amino] ethyl] -5-fluorobenzenepropanoic acid).

Glutamate Receptor Modulators Provided herein are methods for treating otic disorders characterized by dysregulation (eg, overactivity or overstimulation) of glutamate receptors. In some embodiments, the methods disclosed herein comprise administering to an individual in need a composition comprising a glutamate receptor antagonist. Although not disclosed herein, glutamate receptor antagonists useful for ameliorating or eradicating otic diseases are clearly included and intended to be within the scope of the embodiments shown. ing.

  Considered for use with the formulations disclosed herein are agents that modulate the deterioration of otic neurons and / or hair cells and are stunted, in which hair in the inner ear is destroyed An agent for treating or ameliorating hearing loss or hearing loss caused by being dysfunctional, damaged, fragile or deficient. Thus, some embodiments incorporate the use of agents that modulate glutamate receptors. In some embodiments, the glutamate receptor is an AMPA receptor and / or is a Group II or Group III mGlu receptor. In some embodiments, the glutamate receptor is an NMDA receptor. In some embodiments, the glutamate receptor modulator is a glutamate receptor antagonist. In some embodiments, the glutamate receptor antagonist is a non-competitive antagonist. In some embodiments, the glutamate receptor antagonist is a small molecule.

  In some embodiments, the agent that modulates an AMPA receptor is an AMPA receptor antagonist. In some embodiments, the agent that antagonizes the AMPA receptor is CNQX (6-cyano-7-nitroquinoxalinedione-2,3-dione, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl- Benzo [f] quinoxaline-2,3-dione, DNQX (6,7-dinitroquinoxaline-2,3-dione, kynurenic acid, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo- [f ] Quinoxaline, or a combination thereof.

In some embodiments, the glutamate receptor antagonist is an NMDA receptor antagonist. In some embodiments, the agent that modulates an NMDA receptor is an NMDA receptor antagonist. In some embodiments, the glutamate receptor antagonist is 1-aminoadamantane, dextromethorphan, dextrorphan, ibogaine, ifenprodil, (S) -ketamine, (R) -ketamine, memantine, dizocilpine (MK-801) , Gacyclidine, AM-101, traxoprodil, D-2-amino-5-phosphonopentanoic acid (D-AP5), 3-((±) 2-carboxypiperazin-4-yl) -propyl-1-phosphonic acid ( CPP), conantoquin, 7-chloroquinurenate (7-CK), lycostine, nitrous oxide, phencyclidine, riluzole, tiletamine, aptiganel, remacimide, DCKA (5, 7-dichloroquinurenic acid), Kynurenic acid, 1-aminocyclopropanecarboxylic acid (ACPC), AP7 (2-amino-7-phosphonoheptanoic acid), APV (R-2-amino-5-phosphonopentanoate, CPPene (3-[( R) -2-Carboxypiperazi -4-yl] -prop-2-enyl-1-phosphonic acid, (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy-4-phenylpiperidino ) -1-propanol), (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) -1-propanol), (3R, 4S) -3- (4- (4-fluorophenyl) -4-hydroxypiperidin-1-yl-)-chroman-4,7-diol), (1R ^* ; 2R ^* )-1- (4-hydroxy- 3-methylphenyl) -2- (4- (4-fluoro-phenyl) -4-hydroxypiperidin-1-yl) -propano-1-ol-mesylic acid, or combinations thereof. In some embodiments, the NMDA receptor antagonist is an arylcycloalkylamine. In some embodiments, the NMDA receptor antagonist is (S) -ketamine or a salt thereof. In some embodiments, the NMDA receptor antagonist is quinazoline. In some embodiments, the NMDA receptor antagonist is 7-CK or a salt thereof. In some embodiments, the NMDA receptor antagonist is AM-101 or a salt thereof.

  In some embodiments, the glutamate receptor antagonist is a peptide. In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide comprises (a) a transporter peptide and (b) a peptide that inhibits the interaction between the NMDA receptor and an NMDA receptor binding protein. Prepare. As used herein, “transporter peptide” means a peptide that facilitates peptide penetration into cells and tissues. In some embodiments, the transporter peptide is biodegradable.

  In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide comprises (a) a TAT peptide and (b) a peptide that inhibits the interaction of the NMDA receptor with an NMDA receptor binding protein. . In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide inhibits the interaction between (a) (D) -TAT peptide and (b) NMDA receptor and NMDA receptor binding protein The peptide is provided. In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide comprises (a) a transporter peptide and (b) an NR2B9c peptide. In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide comprises (a) a transporter peptide and (b) (D) -NR2B9c peptide. In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide comprises (a) (D) -TAT peptide and (b) (D) -NR2B9c peptide. In some embodiments, the glutamate receptor antagonist is a lytic peptide and the fusion peptide comprises (a) a transporter peptide and (b) (L) -NR2B9c peptide.

  In certain instances, overactivation of AMPA and NMDA glutamate receptors by binding excessive amounts of glutamate results in excessive opening of ion channels under control. In certain instances, this results in abnormally high levels of Ca2 + and Na + entering the neuron. In particular examples, Ca2 + and Na + entry into neurons activates a variety of enzymes including, but not limited to, phospholipases, endonucleases and proteases. In certain instances, the excessive activity of these enzymes results in damage to the cytoskeleton, plasma membrane, mitochondria, neuronal DNA. Furthermore, in certain instances, transcription of proapoptotic and anti-apoptotic genes is controlled by Ca2 + levels.

  In some embodiments, the mGlu receptor is a Group III mGlu receptor. In some embodiments, the Group III mGlu receptor is mGlu7. In some embodiments, the agent that modulates a Group III mGlu receptor is a Group III mGlu receptor agonist. In some embodiments, the Group III mGlu receptor agonist is ACPT-I ((1S, 3R, 4S) -1-aminocyclopentane-1,3,4-tricarboxylic acid, L-AP4 (L-(+ ) -2-amino-4-phosphonobutanoic acid), (S) -3, 4-DCPG ((S) -3,4-dicarboxyphenylglycine, (RS) -3, 4 DCPG ((RS) -3, 4-dicarboxyphenylglycine, (RS) -4-phosphonophenylglycine (RS) (PPG), AMN082 (N'-bis (diphenylmethyl) -1,2-ethanediamine (dihydroglolide), DCG-IV ((2S, 2′R, 3′R) -2- (2 ′, 3′-dicarboxycyclopropyl) glycine, or a combination thereof. In some embodiments, the mGlu receptor is mGlu7. In some embodiments, the agonist of mGlu7 is AMN082.In some embodiments, the mGlu receptor modulator is 3,5-dimethylpyrrole-2,4-dicarboxylic acid 2-propyl ester 4- ( 1,2,2-trimethyl group (Lopyl) (ester, (3,5-dimethyl PPP)), 3,3'-difluorobenzaldazine (DFB), 3,3'-dimethoxybenzaldazine (DMeOB), 3,3'-difluorobenzaldazine (DCB) and mol. Other allosteric modulators of mGluR5 disclosed in Pharmacology 2003, 64 and 731-740, (E) -6-methyl-2- (phenyldiazenyl) pyridin-3-ol (SIB 1757), (E) -2-Methyl-6-styrylpyridine (SIB 1893), 2-methyl-6- (phenylethynyl) pyridine (MPEP), (2-methyl-4-((6-methylpyridin-2-yl) Ethinyl) thiazole (MTEP)), 7- (hydroxyimino) cyclopropa [b] chromene-1α carboxylic acid ethyl ester (CPCCOEt), N-cyclohexyl-3-methylbenzo [d] thiazolo [3,2-a] imidazole-2 -Carboxamide (YM-298198), Tricyclo [3.3.3.1] nonanyl quinoxaline-2-carboxamide (NPS 2390), 6-methoxy-N- (4-methoxyphenyl) quinazoline- 4-amine (LY456239), the mGluR1 antagonist disclosed in WO2004 / 058754 and WO2005 / 009987, 2- (4- (2,3-dihydro-1H-inden-2-ylamino) -5,6,7,8- Tetrahydroquinazolin-2-ylthio) ethanol, 3- (5- (pyridin-2-yl) -2H-tetrazol-2-yl) benzonitrile, 2- (2-methoxy-4- (4- (pyridin-2-) Yl) oxazol-2-yl) phenyl) acetonitrile, 2- (4- (benzo [d] oxazol-2-yl) -2-methoxyphenyl) acetonitrile, 6- (3-methoxy-4- (pyridin-2- Yl) phenyl) imidazo [2,1-b] thiazole, (S)-(4-fluorophenyl) (3- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) piperidine 1-yl) methanone (ADX47273) and / or combinations thereof.

  The mGlu receptor does not directly control ion channels, unlike AMPA and NMDA receptors. However, in certain instances, these receptors indirectly control the opening of ion channels by activation of the biochemical cascade. mGlu receptors are divided into three groups. Group II and Group III members reduce or inhibit the postsynaptic potential by preventing or reducing the composition of cAMP. In certain instances, this results in a decrease in the release of neurotransmitters, particularly glutamate. GRM7 is a gene encoding the group III receptor, mGlu7 receptor. The agonism of mGlu7 leads to a decrease in glutamate synaptic concentration. This improves the excitotoxicity of glutamate.

  In some embodiments, the glutamate receptor is a Group II mGlu receptor. In some embodiments, the agent that modulates a Group II mGlu receptor is a Group II mGlu receptor agonist. In some embodiments, the Group II mGlu receptor agonist is LY389795 ((−)-2-thia-4-aminobicyclo-hexane-4,6-dicarboxylic acid, LY379268 ((−)-2-oxa- 4-aminobicyclo-hexane-4,6-dicarboxylic acid, LY354740 (+)-2-aminobicyclo-hexane-2,6 dicarboxylic acid, DCG-IV ((2S, 2'R, 3'R) -2- (2 ', 3'-dicarboxycyclopropyl) glycine, 2R, 4R-APDC (2R, 4R-4-aminopyrrolidine-2,4-dicarboxylic acid (S) (-3C4HPG ((S) -3-carboxy- 4-hydroxyphenylglycine), (S) -4C3HPG ((S) -4-carboxy-3-hydroxyphenylglycine, L-CCG-I ((2S, 1'S, 2'S) -2- (carboxycyclopropyl) glycine, And / or a combination thereof.

  In some embodiments, the glutamate receptor modulator is a nootropic agent. Considered for use in the formulations disclosed herein are nootropic agents that modulate neuronal signaling by activating glutamate receptors. In some instances, the nootropic agent treats or improves hearing loss (eg, NIHL) or tinnitus. Thus, some embodiments incorporate the use of nootropic agents, which include, but are not limited to, piracetam, oxacetam, aniracetam, pramiracetam, phenylpyracetam (for treatment of NIHL or tinnitus). Carfedon), etiracetam, levetiracetam, nefiracetam, nicoracetam, lordiracetam, nebracetam, fasolacetam, collacetam, dimiracetam, brivaracetam, serracetam, and / or rolipram.

Nutrients Considered for use of the formulations disclosed herein are agents that reduce or delay the deterioration of otic neurons and / or hair cells. In some embodiments, considerations for use of the formulations described herein include nutrition, such as agents that promote otic tissue and / or neuron and / or hair cell growth. It is an agent. Also contemplated for use of the compositions described herein is to treat or reduce hearing loss or hearing loss caused by hair destruction, poor growth, dysfunction, damage, fragility or loss in the inner ear. It is a drug for improvement. Thus, some embodiments incorporate the use of nutrients that promote the survival of neurons and ear hair cells and / or the growth of neurons and ear hair cells. In some embodiments, the nutrient that promotes survival of otic hair cells is a growth factor. In some embodiments, the growth factor is neurotrophic. In certain instances, neurotrophic is a growth factor that inhibits cell death, prevents cell damage, repairs damaged neurons and ear hair cells, and / or Induces differentiation into progenitor cells. In some embodiments, neurotrophic is brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophic Fin-4 and / or combinations thereof. In some embodiments, the growth factor is fibroblast growth factor (FGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), platelet derived growth factor (PGF) and / or agonists thereof. In some embodiments, the growth factor is an agonist of fibroblast growth factor (FGF) receptor, insulin-like growth factor (IGF) receptor, epidermal growth factor (EGF) receptor and / or platelet derived growth factor. It is. In some embodiments, the growth factor is a hepatocyte growth factor.

  In some embodiments, the nutrient and / or neurotrophic agent is BDNF. In some embodiments, the nutrient and / or neurotrophic agent is GDNF. In certain instances, BDNF and GDNF may be present in existing neurons (e.g., spiral ganglion neurons) and ear hair by repairing damaged cells, inhibiting ROS production, and / or inhibiting cell death. It is a neurotrophic agent that promotes cell survival. In certain instances, BDNF and GDNF also promote differentiation of neural / ear hair cell precursors. Further, in certain instances, BDNF and GDNF protect cranial nerve VII from deteriorating. In some embodiments, BDNF is administered with fibroblast growth factor.

  In some embodiments, the neurotrophic agent is neurotrophic factor-3. In certain instances, neurotrophic factor-3 promotes the survival of pre-existing neurons and otic hair cells, and promotes neuronal differentiation and otic hair cell differentiation. Further, in certain instances, neurotrophic factor-3 protects nerve VI from getting worse.

  In some embodiments, the neurotrophic agent is CNTF. In certain instances, CNTF promotes neurotransmitter synthesis and neuritis growth. In some embodiments, CNTF is administered with BDNF.

  In some embodiments, the nutrient and / or neurotrophic agent is GDNF. In certain instances, GDNF expression is increased upon treatment with an ototoxic agent. Furthermore, in certain instances, cells treated with exogenous GDNF have a higher survival rate after trauma than untreated cells.

  In some embodiments, the nutrient and / or growth factor is epidermal growth factor (EGF). In some embodiments, the EGF is heregulin (HRG). In certain instances, HRG stimulates the proliferation of sensory epithelium with vesicles. In certain instances, HRG-coupled receptors are found in the vestibular and auditory sensory epithelia.

  In some embodiments, the nutrient and / or growth factor is insulin-like growth factor (IGF). In some embodiments, the IGF is IGF-1. In some embodiments, IGF-1 is mecasermin. In certain instances, IGF-1 reduces damage induced by exposure to aminoglycosides. In certain instances, IGF-1 stimulates cochlear ganglion cell differentiation and / or maturation.

  In some embodiments, the FGF receptor agonist is FGF-2. In some embodiments, the FGF receptor agonist is IGF-1. Both FGF and IGF receptors are found in cells that contain the vesicular epithelium.

  In some embodiments, the growth factor is hepatocyte growth factor (HGF). In some instances, HGF protects cochlear hair cells from noise-induced damage and reduces ABR threshold fluctuations caused by exposure to noise.

  Also contemplated for use with the otic formulations described herein are growth factors, which include erythropoietin (EPO) and granulocyte colony stimulating factor (EPO). G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), growth differentiation factor-9 (GDF9), insulin-like growth factor (IGF), myostatin (GDF-8), platelet-derived growth factor (PDGF), thrombosis It includes poietin (TPO), transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) or combinations thereof. Also contemplated for use with the ear compositions described herein are trophic factors, which include the antioxidants and / or vitamins described herein. Including.

Anti-cell adhesion molecule-1 antibodies Contemplated for use with the otic formulations described herein are antibodies to anti-cell adhesion molecules (ICAM). In some instances, ICAM inhibits a cascade of reactive oxygen species associated with noise exposure. In some instances, modulation of the cascade of reactive oxygen species associated with noise exposure improves or reduces deterioration of otic neurons and / or hair cells. Accordingly, some embodiments incorporate the use of an agent that is an antibody to an ICAM (eg, anti-ICAM-1 Ab, anti-ICAM-2 Ab, etc.).

Ear Protective Agents Considered for use with the formulations disclosed herein are agents that modulate the deterioration of otic neurons and / or hair cells, and hair growth in the inner ear is destroyed It is an agent for treating or ameliorating hearing loss or hearing loss caused by being defective, dysfunctional, damaged, fragile or deficient. Thus, some embodiments incorporate the use of ear protection agents. In some embodiments, the otoprotective agent is a glutamate receptor antagonist, as described herein. In some embodiments, the ear protectant is a corticosteroid, as described herein. In some embodiments, the ear protectant is an agent that modulates glutathione peroxidase (GPx). The enzyme GPx reduces reactive oxygen species (ROS) in the cochlea and maintains neuronal and / or hair cell health in the inner ear. GPx modulators include, but are not limited to, glutathione peroxidase, which includes 2-phenyl-1,2-benzoisoselenazol-3 (2H) -one (Ebselen, SPI-1005), 6A -6B diselenic acid-6A, 6B'-selenium crosslinked β-cyclodextrin (6-diSeCD), and 2,2'-diseleno-bis-β-cyclodextrin (2-diSeCD).

In some embodiments, the use of an ear protectant reduces or ameliorates hearing loss or hearing loss due to hair destruction, stunting, dysfunction, damage, fragility or loss in the inner ear.
Ear protectants include, but are not limited to, D-methionine, L-methionine, ethionine, hydroxylmethionine, methioninol, amifostine, mesna (2-sulfanylethanesulfonate sodium), a mixture of D and L methionine, N- Acetylmethionine (NAM), normethionine, homomethionine, S-adenosyl-L-methionine, diethyldithiocarbamate, ebselen (2-phenyl-1,2-benzisoselenazol-3 (2H) -one), sodium thiosulfate AM-111 (Laboratoires Auris SAS), N-acetyl-DL-methionine, S-adenosylmethionine, cysteine, homocysteine, cysteamine, N-acetylcysteine (NAC), glutathione, glutathione・ Ethyl ester, glutathione diethyl ester, glutathione triethyl ester, cis Amine, cystathione, N, N'-diacetyl-L-cystine (DiNAC), (2 (R, S) -D-ribo- (1 ', 2', 3 ', 4'-tetrahydroxybutyl) -thiazolidine- 4 (R) -carboxylic acid (RibCys), 2-alkylthiazolidine 2 (R, S) -D-ribo- (1 ′, 2 ′, 3 ′, 4′-tetrahydroxybutyl) thiazolidine (RibCyst) and 2- Oxo-L-thiazolidine-4-carboxylic acid (OTCA), salicylic acid, leucovorin, leucovorin calcium, dexrazoxane, piracetam, oxiracetam, aniracetam, pramiracetam, phenylpyracetam (Carphedon), epiracetam, levetiracetam, nefiracetam, nicoracetam, olbracetam, Including fasolacetam, collacetam, dimiracetam, brivaracetam, seletracetam, rolipram and / or combinations thereof.

  In some embodiments, the ear protectant comprises a xanthine oxidase inhibitor. Examples of xanthine oxidase inhibitors include, but are not limited to, allopurinol, 1-methylalpurinol, 2-methylalpurinol, 5-methylalpurinol, 7-methylalpurinol, 1,5-dimethylalpurinol, 2,5 -Dimethylalpurinol, 1,7-dimethylalpurinol, 2,7-dimethylalpurinol, 5,7-dimethylalpurinol, 2,5,7-trimethylalpurinol, 1-ethoxycarbonylalpurinol, and 1-ethoxy Contains carbonyl-5-methylalpurinol.

  In some embodiments, the ear protectant is used in combination with a toxic substance.

Hair Cell Regeneration Modulators Considered for use with the formulations disclosed herein are agents that modulate the regeneration of otic neurons and / or hair cells, and the destruction and development of hair in the inner ear An agent for treating or ameliorating hearing loss or hearing loss caused by a defect, dysfunction, injury, fragility or defect. In some embodiments, the otic sensory cell modulator allows the cell to grow and / or regenerate otic hair cells and / or support cells. Thus, some embodiments incorporate the use of cyclin dependent kinase (CDK) modulators. In some embodiments, the CDK modulator is a p27Kip1 modulator. p27Kip1 mediates sensory hair cell regeneration into the organ of Corti. In some examples, sensory hair cells (eg, short hair cells) in the inner ear are regenerated by stimulating proliferation of feeder cells (eg, Hansen's disease cells, Ditels cells and / or columnar cells). In some examples, the modulator of the cyclin dependent kinase p27Kip1 is an antisense molecule (eg, siRNA molecule) or a peptide molecule (eg, an endogenous ligand for p27Kip1) that modulates the activity of p27Kip1.

  In some embodiments, the formulations described herein are nucleic acids and / or transcription factors (e.g., POU4F1, POU4F2, POU4F3, which can stimulate the formation of inner ear sensory hair cells or inner ear support cells Brn3a, Brn3b and / or Brn3c). Non-limiting examples of such nucleic acid molecules and / or transcription factors include, but are not limited to, molecules described in U.S. Patent Publication Nos. 20070041957, 20030203482, and the disclosure described in the literature includes: Which is incorporated herein by reference.

Immune cells Considered for use with the formulations disclosed herein are agents that reduce, reverse or delay the deterioration of otic neurons and / or hair cells, and the destruction of hair in the inner ear, A drug for treating or ameliorating hearing loss or hearing loss caused by poor growth, dysfunction, injury, fragility or deficiency. Thus, some embodiments incorporate the use of otic hair cells and cells involved in neuronal recovery. In some embodiments, the cells involved in the recovery of otic hair cells and neurons are macrophages, microglia, and / or microglia-like cells. In certain instances, macrophage and microglia concentrations are increased in ears damaged by treatment with ototoxic agents. In certain instances, microglia-like cells remove waste from ototoxic neomycin antibiotics.

Ototoxic agents and toxic substances Considered for use with the formulations disclosed herein are agents that destroy neurons and / or otic hair cells. Thus, some embodiments incorporate the use of agents that induce fatal damage and / or death in otic neurons and / or hair cells. In some embodiments, death of an ear sensory cell (eg, hair cell) treats a condition (eg, rotational dizziness) associated with any otic disease or condition described herein. In some embodiments, the toxic agent induces chemical lesions in the ear that relieve symptoms such as, by way of example, rotational dizziness. In some embodiments, the agent that causes lethal damage and / or induces death in otic neurons and / or hair cells is an aminoglycoside antibiotic (eg, gentamicin, also amikacin), a macrolide antibiotic (E.g. erythromycin), glycopeptide antibiotics (e.g. vancomycin), loop diuretics (e.g. furosemide), nicotine, 6-hydroxydopamine (6-OH DPAT), 6,7-dinitroquinoxaline-2,3-dione ( DNQX). In some embodiments, the compositions described herein comprise a toxic substance that is used to treat rotational dizziness by selectively destroying hair cells in the ear. In some such embodiments, otic compositions containing toxic substances are advantageous in the following respects. Since such compositions are administered non-systemically to the ear and do not cause the side effects associated with systemic administration of toxic substances, such compositions provide a therapeutic effect for the treatment of rotational dizziness.

  In some embodiments, the compositions described herein are useful for preclinical animal studies (eg, animal guinea pig model studies). In some examples, the compositions described herein containing toxic substances are used to induce chemical lesions in animal ears. In some examples, such animals are used for testing the therapeutic effects of the compositions described herein in animal models.

Modulation of Retinoblastoma Proteins Considered for use with the formulations disclosed herein are agents that modulate the deterioration of otic neurons and / or hair cells, and the destruction of hair in the inner ear A drug for treating or ameliorating hearing loss or hearing loss caused by poor development, dysfunction, injury, fragility or deficiency. Further contemplated herein are agents that destroy neurons and / or ear hair cells. Thus, some embodiments incorporate the use of agents that modulate retinoblastoma protein (pRB). pRB is a member of the pocket protein family. pRB is encoded by the RB1 gene. In certain instances, pRB inhibits the transition from G1 to S phase by binding to and inactivating the E2f family of transcription factors. In certain instances, pRB also regulates differentiation and hair cell survival. In certain instances, pRB knockout mice show increased proliferation of hair cells.

  In some embodiments, the agent that modulates one or more of pRB is an agonist of pRB. In some embodiments, the agent that modulates one or more of pRB is an antagonist of pRB. In certain instances, compounds that stimulate or antagonize pRB are identified (eg, by use of a high throughput screen). In some embodiments, the construct is designed such that the reporter gene is placed downstream of the E2F binding sequence. In some embodiments, the binding sequence is TTTCGCGC. In some embodiments, the reporter gene is luciferase, CAT, GFP, β-lactamase or β-galactosidase. In certain instances, E2f binds to a binding sequence that causes transcription and expression of a reporter gene. In certain instances, an agonist of pRB results in increased binding of pRB to E2f. In certain instances, increased binding of pRB and E2f results in decreased transcription and expression of the reporter gene. In certain instances, antagonists of pRB result in decreased binding of pRB to E2f. In certain instances, decreased binding of pRB and E2f results in an increase in reporter gene transcription and expression.

  In some embodiments, the agent that modulates pRB is an siRNA molecule. In certain instances, siRNA molecules inhibit transcription of the RB1 gene by RNA interference (RNAi). In some embodiments, double stranded RNA (dsRNA) molecules with sequences complementary to the RB1 mRNA sequence are generated (eg, by PCR). In some embodiments, 20-25 bp siRNA molecules with sequences complementary to RB1 mRNA are generated. In some embodiments, a 20-25 bp siRNA molecule has a 2-5 bp overhang on the 3 'end and 5' phosphate end and on the 3 'hydroxyl end of each strand. In some embodiments, the 20-25 bp siRNA molecule has a blunt end. For techniques for generating RNA, see Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) and Molecular Cloning: A Laboratory Manual, third edition (Sambrook and Russel, 2001), herein. `` Sambrook ''); Current Protocols in Nucleic Acid Chemistry John Wiley & See Sons, Inc., New York, 2000). These are hereby incorporated by reference for such disclosure.

  In some embodiments, dsRNA or siRNA molecules are incorporated into controlled release ear acceptable microparticles or microparticles, hydrogels, liposomes or thermoreversible gels. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are injected into the inner ear. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are cochlear, Corti organs, vestibular labyrinths, or Injected into their combination.

  In certain instances, after administration of a dsRNA or siRNA molecule, cells at the administration location (eg, cells of the cochlea, Corti organ, and / or vestibular labyrinth) are transformed with the dsRNA or siRNA molecule. In the specific example following transformation, the dsRNA molecule is cleaved into a number of fragments of about 20-25 bp to give siRNA molecules. In certain instances, the fragment has an approximately 2 bp overhang on the 3 ′ end of each strand.

  In some examples, siRNA molecules are split into two strands (guide strand and non-guide strand) by an RNA-induced silencing complex (RISC). In certain instances, the guide strand is incorporated into the catalytic component (ie, Argonaute) of RISC. The guide strand binds to a complementary RB1 mRNA sequence. In some examples, RISC cleaves RB1 mRNA. In some examples, RB1 gene expression is down-regulated.

  In some embodiments, sequences complementary to RB1 mRNA are incorporated into the vector. In some embodiments, the sequence is placed between two promoters. In some embodiments, the promoter is positioned in the opposite direction. In some embodiments, the vector communicates with the cell. In some examples, the cells are transformed with the vector. In some examples following transformation, the sense and non-sense strands of the sequence are generated. In certain instances, the sense and non-sense strands are hybridized to form a dsRNA molecule that is cleaved into siRNA molecules. In certain instances, the strands are hybridized to form siRNA molecules. In some embodiments, the vector is a plasmid (eg, pSUPER; pSUPER.neo; pSUPER.neo + gfp).

  In some embodiments, the vector is incorporated into a controlled release ear acceptable microparticle or microparticle, hydrogel, liposome, or thermoreversible gel. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are injected into the inner ear. In some embodiments, ear-acceptable microparticles, hydrogels, liposomes or microparticles, or thermoreversible gels. In some embodiments, the ear-acceptable microparticles, hydrogels, liposomes, paints, foams, in situ spongy materials, nanocapsules or nanospheres, or thermoreversible gels are cochlear, Corti organs, vestibular labyrinths, or Injected into their combination.

Thyroid hormone receptor modulation Considered for use with the formulations disclosed herein are agents that reduce or delay the deterioration of otic neurons and / or hair cells, and / or otic An agent to promote neuron and / or hair cells and to treat or ameliorate hearing loss or hearing loss caused by hair destruction, poor growth, dysfunction, damage, fragility or loss. Thus, some embodiments incorporate the use of agents that modulate thyroid hormone (TH) receptors. TH receptors are a family of nuclear hormone receptors. The family includes, but is not limited to, TRα1 and TRβ. In certain instances, TRβ knockout mice exhibit reduced responsiveness to auditory stimuli and reduced K + current in hair cells.

Sodium channel blockers Considered for use with the formulations disclosed herein are agents that modulate the deterioration of neurons and hair cells, and hair destruction, poor growth, dysfunction in the inner ear, A drug for treating or ameliorating hearing loss or hearing loss caused by damage, fragility or loss. In certain instances, excitotoxicity causes excessive opening of Na + channels. In certain instances, this results in excess Ca2 and Na + ions entering the neuron. In certain instances, neurons more often excite due to excessive influx of Na + ions into the neurons. In certain instances, this increased excitement results in a rapid accumulation of free radicals and compounds that cause inflammation. In certain instances, free radicals use up stored energy in cells and damage mitochondria. Further, in certain instances, excess levels of Na + ions activate excess levels of enzymes, which include but are not limited to phospholipases, endonucleases, proteases. In certain instances, the excessive activity of these enzymes results in damage to the cytoskeleton, plasma membrane, mitochondria, neuronal DNA. Thus, some embodiments incorporate the use of agents that antagonize Na + channel opening and reduce or reverse ear hair cell death and / or ear hair cell damage.

  In some embodiments, the agent that modulates one or more TH receptors is an agonist of one or more TH receptors. In some embodiments, the agonist of one or more TH receptors is T3 (3,5,3′-triiodo-L-thyronine, KB-141 (3,5-dichloro-4- (4-hydroxy-3 -Isopropylphenoxy) phenylacetic acid, GC-1 (3,5-dimethyl-4- (4'-hydroxy-3'-isopropylbenzyl) -phenoxy (acetic acid), GC-24 (3,5-dimethyl-4- ( 4'-hydroxy-3'-benzyl) benzylphenoxyacetic acid, sobetilome (QRX-431), 4-OH-PCB106 (4-OH-2 ', 3,3', 4 ', 5'-pentachlorobiphenyl, MB07811 ((2R, 4S) -4- (3-Chlorophenyl) -2-[(3,5-dimethyl-4- (4-hydroxy-3-isopropylbenzyl) phenoxy) methyl] -2-oxide- [1,3 , 2] -dioxaphosphonan), MB07344 (3,5-dimethyl-4- (4-hydroxy-3-isopropylbenzyl) phenoxy) methylphosphonic acid and combinations thereof In particular examples, KB-141, GC-1, Sobetilome, and GC-24 are selected for TRβ It is.

TRPV modulation Considered for use with the formulations disclosed herein are agents that modulate the deterioration of neurons and hair cells, and hair destruction, poor growth, dysfunction, damage in the inner ear, A drug for treating or ameliorating hearing loss or hearing loss caused by fragility or loss. Thus, some embodiments incorporate the use of agents that modulate TRPV receptors. TRPV (transient receptor potential vanilloid channels) receptors are a family of non-selective ion channels that are permeable to calcium, among other ions. There are 6 members of the family. That is, TPPV1-6. In certain instances, TPPV1 is upregulated after treatment with kanamycin. Furthermore, in certain instances, antagonism of TRPV4 receptor weakens mice against acoustic trauma. Further, in certain instances, capsaicin, an TRPV 1 agonist, prevents spontaneous hyperactivity after ischemia.

  In some embodiments, the agent that modulates one or more of the TRPV receptors is an agonist of one or more TRPV receptors. In some embodiments, the one or more agonists of the TRPV receptor is capsaicin, resiniferatoxin, or a combination thereof. In some embodiments, administration of an ear sensory cell that modulates a composition comprising a TRPV agonist reduces or reverses the deterioration of neurons and hair cells.

  In some embodiments, the Na + channel blocker is vinpocetine ((3a, 16a) -ebrunamenin-14-carboxylic acid (ethyl ester), cipatrigine (2- (4-methylpiperazin-1-yl) -5- (2 , 3,5-trichlorophenyl) -pyrimidin-4-amine, amiloride (3,5-diamino-N- (aminoiminomethyl) -6-chloropyrazinecarboxamide hydrochloride, carbamazepine (5H-dibenzo [b, f] Azepine-5-carboxamide, TTX (octahydro-12- (hydroxymethyl) -2-imino-5,9: 7,10a-dimethane o-10aH- [1,3] dioxosino [6,5-d] pyrimidine-4 , 7,10,11,12-pentyl), RS100642 (1- (2,6-dimethyl-phenoxy) -2-ethylaminopropane hydrochloride, mexiletine (1- (2,6-dimethylphenoxy) -2- Aminopropane hydrochloride), QX-314 (N- (2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide, phenytoin (5,5-diphenyl)) Nilimidazolidine-2,4-dione), lamotrigine (6- (2,3-dichlorophenyl) -1,2,4-triazine-3,5-diamine, 4030W92 (2,4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethylpyrimidine, BW1003C87 (5- (2,3,5-trichlorophenyl) pyrimidine-2,4- (1.1 ethanesulfonate), QX-222 (2-[(2,6-dimethyl Phenyl) amino] -N, N, N-trimethyl-2-oxoeta (niminium chloride), ambroxol (trans-4-[[(2-amino-3,5-dibromophenyl) methyl] amino] cyclo ( Hexanol hydrochloride), R56865 (N- [1- (4- (4-fluorophenoxy) butyl] -4-piperazinyl-N-methyl-2-benzo-thiazolamine), ruberzole, ajumarin ((17R, 21) -azimarin -17,21-diol, procainamide (4-amno-N- (2-diethylaminoethyl) benzamide hydrochloride, flecainide, riluzole, or combinations thereof It is

Corticosteroids Considered for use with the compositions and formulations disclosed herein are agents that reduce, reverse or delay the deterioration of otic neurons and / or hair cells, and in the inner ear A drug for treating or ameliorating hearing loss or hearing loss caused by hair destruction, poor growth, dysfunction, damage, fragility or loss. Thus, some embodiments incorporate the use of agents that protect otic hair cells from ototoxins. In some embodiments, the agent that protects ear hair cells from toxins is a steroid. In some embodiments, the steroid that protects ear hair cells from toxins is a corticosteroid. In some embodiments, the corticosteroid is triamcinolone actinoid and / or dexamethasone. In certain instances, triamcinolone actinoids and dexamethasone protect ear hair cells from damage caused by the naturally occurring toxin, 4-hydroxy-2,3-nonenal (HNE), which is resistant to oxidative stress. Produced in the inner ear accordingly. Other corticoids include, but are not limited to, 21-acetoxypregnenolone, alclomethasone, algestone, amsinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, crocortron, clopredonol, corticosterone, cortisone, Cortivazole, deflazacote, desonide, desoxymetasone, dexamethasone, diflorazone, diflucortron, difluprednate, enoxolone, fluazacort, fluclonide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortron, Fluorometholone, fluperolone acetate, flupredonate acetate, fluprednisolone, fludroxycortide, pro Fluticasone onate, formocotal, harsinonide, halobetasol propionate, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, madipredon, medorizone, meprednisone, methylprednisolone, mometasone furancarboxylate, parameterzone, pre Donicalart, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednidene, limexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, or triamcinolone hexacetonate or Prodrugs or ester prodrugs thereof are included.

Stem cells and differentiated ear sensory cells Considered for use of the formulations disclosed herein are cell grafts that supplement or replace otic neurons and / or hair cells. In some embodiments, the agent is a stem cell. In some embodiments, the agent is a partially or fully differentiated ear sensory cell. In some embodiments, the differentiated ear sensory cells are derived from a human donor. In some embodiments, the differentiated ear sensory cell is derived from a stem cell. Its differentiation was induced under artificial (eg laboratory) conditions.

  Stem cells are cells that possess the ability to differentiate into a number of cell types. Totipotent stem cells can differentiate into embryonic cells or extraembryonic cells. Pluripotent cells can differentiate into cells derived from either endoderm, mesoderm or ectoderm. Pluripotent cells can differentiate into closely related cells (eg, hematopoietic stem cells). Unipotent cells can differentiate into only one type of cell, while other stem cells have the characteristics of self-renewal. In some embodiments, the stem cell is totipotent, pluripotent, multipotent, or pluripotent. Furthermore, stem cells may undergo mitosis without undergoing their own differentiation (ie, self-renewal).

  Embryonic stem (ES) cells are stem cells derived from the ectoderm tissue of the blastocyst or early stage fetal inner cell mass. ES cells are pluripotent. In some embodiments, the stem cell is an ES cell. Adult stem cells (also known as somatic cells or germline cells) are cells isolated from mature organisms, which have the characteristics of self-renewal and the ability to differentiate into a number of cell types. Adult stem cells are pluripotent (eg, stem cells found in umbilical cord blood), pluripotency, or pluripotency. In some embodiments, the stem cell is an adult stem cell.

  In some embodiments, stem cells and / or differentiated ear sensory cells are administered in combination with a differentiation stimulating agent. In some embodiments, the differentiation stimulating agent is a growth factor. In some embodiments, the growth factor is a neurotrophin (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 ( NT-4), or new neurotrophin-1 (NNT1)). In some embodiments, the growth factor is FGF, EGF, IGF, PGF, or a combination thereof.

  In some embodiments, stem cells and / or differentiated ear sensory cells are administered to a subject in need thereof as a controlled release agent. In some embodiments, the stem cells and / or differentiated ear sensory cells and Administered in combination. In some embodiments, the controlled release ear sensory cell modulator is a vector comprising an Atoh1 or BRN3 gene, an siRNA sequence targeting RB1, a growth factor, or a combination thereof.

  In some embodiments, stem cells and / or differentiated ear sensory cells are administered in the cochlea or vestibular maze. In some embodiments, stem cells and / or differentiated otic sensory cells are administered by intratympanic injection and / or posterior pinna incision. In some embodiments, the stem cells and / or differentiated ear sensory cells are contacted with a Corti organ, inner ear nerve, and / or enlarged twill.

Immediate Release Agent In some embodiments, the composition further comprises an otic neuron and / or hair cell modulator as an immediate release agent, wherein the otic neuron and / or hair cell immediate release modulator is controlled. The same agent as the released agent, a modulator different from the otic neurons and / or hair cells, an additional therapeutic agent, or a combination thereof. In some embodiments, the immediate release agent is a stem cell, differentiated ear sensory cell, immune system cell, vector with Atoh1 gene replication, vector with BRN3 gene replication, siRNA sequence, miRNA sequence, or combinations thereof is there

Direct injection In some embodiments, one of the drugs is injected directly into the inner ear, which includes injection through a round window membrane, while the second drug is in the form of a controlled release formulation. As such, the second agent is administered on or in contact with the round window membrane. In one embodiment, the directly administered agent is a stem cell, differentiated ear sensory cell, immune system cell, vector with replication of Atoh1 gene, vector with replication of BRN3 gene, siRNA sequence, miRNA sequence or these It is a combination.

Active Agent Concentrations In some embodiments, a composition described herein has a concentration of between about 0.01% and about 90%, between about 0.01% and about 50%, Between 0.1% and about 40%, between about 0.1% and 30%, between about 0.1% and 20%, between about 0.1% and about 10%, or about 0.1% Active pharmaceutical ingredient, active ingredient, or a pharmaceutically acceptable prodrug or salt thereof between about 5% by weight. In some embodiments, the compositions described herein can be between about 1% and about 50%, between about 5% and about 50%, between about 10% and about 10% by weight of the composition. Having a concentration of active pharmaceutical agent, active ingredient, or pharmaceutically acceptable prodrug or salt thereof between 40% or between about 10% and about 30% by weight. In some embodiments, a formulation described herein comprises an otic sensory cell modulator, about 70% by weight of the formulation. In some embodiments, the formulations described herein comprise an otic sensory cell modulator, about 60% by weight of the formulation. In some embodiments, the formulations described herein comprise an otic sensory cell modulator, about 50% by weight of the formulation. In some embodiments, the formulations described herein comprise an otic sensory cell modulator, about 40% by weight of the formulation. In some embodiments, a formulation described herein comprises an otic sensory cell modulator, about 30% by weight of the formulation. In some embodiments, a formulation described herein comprises an otic sensory cell modulator, about 20% by weight of the formulation. In some embodiments, the formulations described herein comprise an otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, about 15% by weight of the formulation. In some embodiments, a formulation described herein comprises an otic sensory cell modulator, about 10% by weight of the formulation. In some embodiments, the formulations described herein comprise about 5% by weight of the otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, the formulation. In some embodiments, the formulations described herein comprise about 2.5% by weight of the ear sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, the formulation. In some embodiments, the formulations described herein comprise about 1% by weight of the otic sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, the formulation. In some embodiments, the formulations described herein comprise about 0.5% by weight of the ear sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, the formulation. In some embodiments, the formulations described herein comprise about 0.1% by weight of the ear sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, the formulation. In some embodiments, the formulations described herein comprise about 0.01% by weight of the ear sensory cell modulator, or a pharmaceutically acceptable prodrug or salt thereof, formulation. In some embodiments, the formulations described herein are between about 0.1 mg / mL and about 70 mg / mL, between about 0.5 mg / mL and about 70 mg / mL, about 0.5 mg / mL. Between about 50 mg / mL, between about 0.5 mg / mL and about 20 mg / mL, between about 1 mg / mL and about 70 mg / mL, between about 1 mg and about 50 mg / mL, between about 1 mg / mL and about 20 mg / mL having a concentration of active agent between about 1 mg / mL and about 10 mg / mL, or between about 1 mg / mL and about 5 mg / mL, or a pharmaceutically acceptable prodrug or salt, It has a volume of active agent or pharmaceutically acceptable prodrug or salt.

Combination Therapy In some embodiments, any composition or device described herein includes one or more active agents and / or, but is not limited to, antiemetic agents, antibacterial agents, oxidation agents A second therapeutic agent is included, including an inhibitor, an antiseptic agent, or the like.

Antiemetics Antiemetics are optionally used in combination with the formulations disclosed herein. Antiemetics include promethazine, prochlorperazine, trimethbenzamide and triethylperazine. Other antiemetics include 5HT3 antagonists such as dolasetron, granisetron, ondansetron, tropisetron and palonosetron, and neuroleptics such as droperidol. In addition, antiemetics include antihistamines such as meclizine, phenothiazines such as perphenazine and thiethylperazine, domperidone, properidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide and combinations thereof. , Cannabinoids including dronabinol, nabilone, satibex and combinations thereof, anticholinergic drugs including scopolamine, and steroids including dexamethasone, trimethobenzamine, emetrol, propofol, muscimol and combinations thereof including.

Antibacterial Substances Antibacterial substances are also considered useful with the formulations disclosed herein. Antimicrobial substances include agents that act to inhibit or eradicate microorganisms including bacteria, fungi or parasites. Certain antimicrobial substances can be used to combat certain microorganisms. Thus, a skilled practitioner will know which antimicrobial agents are associated with or dependent on the identified microorganism or manifestation. Antibacterial substances include antibiotics, antiviral agents, antifungal agents and anthelmintic agents.

  Antibiotics are amikacin, gentamicin, kanamycin, neomycin, netilmycin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem, silastatin, meropenem, cefadroxyl, cephazoline, cephaloxin, cephaloxin, cephaloxin Cefamandole, cefoxitin, cefprodil, cefuroxime, cefixime, cefdinir, cefditorene, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, ceftizoxime, ceftriaxone, cefepime, ceftobiprolomycin, teicoplanin rolomycin Mycin, erythromai , Roxithromycin, troleandomycin, tethromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azulocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, medulocillin, methicillin, nafcillin, oxacillin, penicillin, penicillin, piracillin , Bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin (trovfloxacin), mafenide, prontodil, sulfacetamide, sulfamethizole , Sulfanimilimde, sulfsalazine, sulfisoxa Sulfsioxazole, trimethoprim, demeclocycline, doxycycline, minocycline, oxtetracycline, tetracycline, arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole , Mupirocin, nitrofurantoin, platencimycin, pyrazinamide, quinuspristin / dalfopristin, rifampin, tinidazole and combinations thereof.

  Antiviral agents include acyclovir, famciclovir and valacyclovir. Other antiviral agents are abacavir, acyclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, atripura, brivdin, cidofovir, combivir, edoxine, efavirenz, emtricitabine, enfuva Tide, entecavir, fomivirsen, fosamprenavir, foscalnet, phosphonet, ganciclovir, gardasil, ivacitabine, immunoville, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type, lamivudine, lopinavir, lobiride, MK-0518, maraviroc, moroxidine, nelfinavir, nevirapi Nexavir I, nucleoside analog, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitor, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil , Tipranavir, trifluridine, tridivir, tromantadine, tsurbada, valganciclovir, bicrivirok, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine and combinations thereof.

  Antifungal agents include amorolfine (amrolfine), butenafine (utenafine), naphthifine, terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, posaconazole, rubconazole, voriconazole, clotrimazole, econazole, miconazole, oxiconazole, sulfonazole , Nikkomycin Z, Caspofungin, Micafungin, Anidurafungin, Amphotericin B, Liposomal nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprozin, tolnaftate, undecylenate, and combinations thereof, It is not limited to these. Anthelmintic drugs include amitraz, amoscanate, avermectin, carbadox, diethylcarbamizine, dimethridazole, diminazen, ivermectin, macrophyllariside, malathion, mitaban, oxamniquine, permethrin, praziquantel, and pyrantel pamoate ( prantel pamoate), selamectin, sodium stibogluconate, thiabendazole and combinations thereof.

Antioxidants Acidifying agents are optionally used in combination with the compositions described herein. Acidifying agents are also considered beneficial when used with the formulations disclosed herein, which are agents that modulate the deterioration of otic neurons and / or hair cells. Thus, some embodiments incorporate the use of antioxidants. In some embodiments, the antioxidant is vitamin C, N-acetylcysteine, vitamin E, ebselen (2-phenyl-1,2-benzisoselenazol-3 (2H) -one (PZ 51 or DR3305 Also called L-methionine, idebenone (2- (10-hydroxydecyl) -5,6-dimethoxy-3-methyl-cyclohexa-2,5-diene-1,4-dione). In form, the antioxidant is a nutrient and promotes normal cell growth.

Antiseptic agents Antiemetics are optionally used in combination with the compositions disclosed herein. Antiseptic agents are also contemplated as useful with the formulations disclosed herein. Antiseptic agents include acetic acid, boric acid, gentian violet, hydrogen peroxide, carbamide peroxide, chlorhexidine, saline, mercurochrome, povidone iodine, polyhyroxine iodine, cresylate and aluminum acetate, and combinations thereof. Including, but not limited to.

  Other agents are optionally used in any composition or device described herein. In some embodiments, a monoamine oxidase inhibitor (eg, rasagiline, R (+)-N-propargyl-1-aminoindan) is used in any composition or device described herein. In some embodiments, an adenosine antagonist (e.g., R-N6-phenylisopropyladenosine, 1-2-oxothiazolidine-4-carboxylic acid (procysteine)) is any composition or device described herein. Used in. Any combination of active agent and / or second therapeutic agent is compatible with the compositions described herein.

Ear surgery and transplantationIn some embodiments, the pharmaceutical formulations, compositions and devices described herein can be combined with (e.g., transplantation, short term use, long term use) in combination with a transplant (e.g., cochlear implant). (Or removed) used. As used herein, an implant is an inner ear or middle ear medical device such as a cochlear implant, a hearing-improving device, a hearing improvement device, a short electrode, a microprosthesis or a piston-like prosthesis, a needle, a stem cell transplant , Drug delivery devices, any cell-based therapeutic agent or the like. In some instances, the transplant is used in conjunction with a patient experiencing hearing loss. In some instances, hearing loss is present at birth. In some instances, hearing loss is associated with diseases such as AIED, bacterial meningitis, etc., resulting in osteonecrosis and / or nerve damage with rapid obstruction of the cochlear structure and significant hearing loss.

  In some examples, the transplanted tissue is an immune cell or stem cell transplant in the ear. In some instances, the implant is a small electronic device with an outer portion placed behind the ear, and under the skin that provides a sense of sound to a person who is almost deaf or severely deaf Having a second part surgically placed. By way of example only, such cochlear medical devices bypass the damaged part of the ear and directly stimulate the auditory nerve. In some examples, a cochlear implant is used in unilateral hearing loss. In some examples, a cochlear implant is used for hearing loss in both ears.

  In some embodiments, the otic sensory cell modulator composition described herein in combination with an otic interventional procedure (e.g., intramural injection, stapes osteotomy, medical device implantation or cell-based transplantation) or Administration of the device results in otic structures such as stimulation, cell damage, cell death, concomitant damage to osteonecrosis, and / or osteonecrosis and / or external ear interventional procedures (e.g., in external devices and / or in the ear). Delay or prevent neuronal deterioration caused by In some embodiments, administration of an ear sensory cell modulator composition or device described herein in combination with a transplant allows for a more effective recovery of hearing loss compared to a transplant alone.

  In some embodiments, administration of the ear sensory cell modulator composition or device described herein was caused by an underlying disease (eg, bacterial meningitis, autoimmune ear disease (AIED)). It is possible to reduce damage to the structure of the cochlea and achieve cochlear device implantation. In some embodiments, administration of the compositions or devices described herein in connection with otic surgery, medical device implantation and / or cell transplantation results in otic surgery, medical device. Reduce or prevent cell damage and / or cell death (eg, ear sensory hair cell death and / or damage) associated with implantation and / or cell transplantation.

  In some embodiments, in connection with cochlear or stem cell transplantation, an ear sensory cell modulator composition or device described herein (eg, a composition or device comprising a growth factor) has trophic effects (eg, Promotes healthy growth of cells and / or implantation or transplantation). In some embodiments, trophic effects are desirable during ear surgery or during the injection procedure in the middle ear. In some embodiments, the trophic effect is desirably after attachment of a medical device or after cell transplantation. In some of such embodiments, the ear sensory cell modulator composition or device described herein is directly injected into the cochlea, by tympanic floor incision, or onto the round window membrane. Administered by adhesion.

  In some embodiments, administration of an anti-inflammatory composition or an immunosuppressant composition (e.g., a composition comprising an immunosuppressive agent such as a corticosteroid) may result in otic surgery, medical device implantation or cells. Reduce inflammation and / or infection associated with transplantation. In some examples, perfusion of a surgical area with an ear sensory cell modulator formulation described herein can result in post-surgical and / or post-transplant complications (e.g., inflammation, hair cell damage, Reduce or eliminate neurodegeneration, osteogenesis, etc.) In some examples, perfusion of the surgical area with the formulations described herein shortens recovery time after surgery or after transplantation. In some embodiments, the medical device is covered with the composition described herein prior to implantation in the ear.

  In one embodiment, the formulations described herein and methods of administration thereof are applicable to methods of direct perfusion of the inner ear portion. Accordingly, the formulations described herein are useful in combination with otic intervention. In some embodiments, the ear intervention procedure is an implantation method (eg, implantation of a device in a cochlea). In some embodiments, the otic intervention procedures described herein include, by way of non-limiting example, cochleostomy, labyrinthotomy, mastectomy, stapedectomy, Including surgery including stapedectomy and endolymphatic sacculotomy. In some embodiments, the inner ear portion is perfused with a formulation described herein prior to, during, after, or a combination of ear intervention procedures.

  In some embodiments, when perfusion is performed in combination with an ear intervention procedure, the ear sensory cell composition is an immediate release composition. In some of such embodiments, the immediate release formulation described herein is a non-hypertrophic composition and is a sustained release component (e.g., gelled like a polyoxyethylene-polyoxypropylene copolymer). Ingredient) is substantially not included. In some of such embodiments, the composition comprises less than 5% sustained release component (eg, a gelling component such as a polyoxyethylene-polyoxypropylene triblock copolymer) by weight of the formulation. In some of such embodiments, the composition comprises less than 2% sustained release component (eg, a gelling component such as a polyoxyethylene-polyoxypropylene triblock copolymer) by weight of the formulation. In some of such embodiments, the composition comprises less than 1% sustained release component (eg, a gelling component such as a polyoxyethylene-polyoxypropylene triblock copolymer) by weight of the formulation. In some of such embodiments, the compositions described herein used for perfusion of the surgical area are essentially free of gelling components, and the compositions are immediate release It is a composition.

In other embodiments, the compositions described herein are administered after an otic intervention procedure (eg, after implantation of a medical device or cell-based therapeutic agent).
In some of the embodiments, the composition described herein administered after the ear intervention treatment is an intermediate release composition or a sustained release composition and gelled as described herein. Includes ingredients.

Listed below (Table 1) provides examples of active agents contemplated for use with the formulations and devices disclosed herein.
One or more active agents are used in any of the formulations or devices described herein.

  Active agents used with the formulations disclosed herein (including pharmaceutically acceptable salts of these active agents)

  Provided herein are otic compositions that ameliorate or reduce otic disorders as described herein. Further provided herein is a method comprising administering the otic composition. In some embodiments, the composition or device is sterilized. Embodiments disclosed herein include means and processes for sterilizing a pharmaceutical composition or device disclosed herein for use in humans. The goal is to obtain safe pharmaceuticals that are relatively free of microorganisms that cause infection. The US Food and Drug Administration provides the regulatory publication `` Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing '', available at http://www.fda.gov/cder/guidance/5882fnl.htm Publications are hereby incorporated by reference in their entirety.

  As used herein, sterilization refers to the process of destroying or removing microorganisms present in a product or package. Any suitable method available is used to sterilize the object and composition. Methods that can be used to inactivate microorganisms include, but are not limited to, applying intense heat, applying lethal chemicals, or gamma radiation. In certain embodiments, the process of preparing the otic therapeutic formulation comprises exposing the formulation to a sterilization method selected from heat sterilization, chemical sterilization, radiation sterilization, or filter sterilization. The method used depends largely on the nature of the device or composition to be sterilized. A detailed description of many methods of sterilization is given in chapter 40 of "Remington: The Science and Practice of Pharmacy published by Lippincott, Williams & Wilkins" and is incorporated by reference with respect to this subject. .

Heat sterilization Many methods are available for sterilization by applying intense heat. One method is by using an autoclave with saturated steam. In this method, saturated steam at a temperature of at least 121 ° C. can be brought into contact with the object and sterilized. When the object is sterilized, heat is transferred directly to the microorganism or indirectly by heating the mass of the aqueous solution to be sterilized. This method is widely implemented because it gives the sterilization process flexibility, safety and economy.

  Dry heat sterilization is a method in which microorganisms are killed at a high temperature to remove pyrogens. This process is used to heat HEPA-filtered microbial-free air to a temperature of at least 130-180 ° C for the sterilization process and to a temperature of at least 230-250 ° C for the pyrogen removal process. Use a suitable device. Water for reconstitution of concentrated or powdered formulations is also sterilized in an autoclave. In certain embodiments, the formulations described herein comprise a micronized ear sensory cell modulator (e.g., a ketamine micropowder) that is sterilized by dry heat, wherein the dry heat is, e.g., at an internal powder temperature. Heating is performed at 130 to 140 ° C. for about 7 to 11 hours, or at an internal temperature of 150 to 180 ° C. for 1 to 2 hours.

Chemical sterilization methods Chemical sterilization methods are an alternative to products that cannot withstand intense heat sterilization. In this method, various bactericidal gases and vapors such as ethylene oxide, chlorine dioxide, formaldehyde or ozone are used as anti-apoptotic agents. For example, the bactericidal activity of ethylene oxide is due to the ability of ethylene oxide to act as a reactive alkylating agent. Therefore, the sterilization process requires that ethylene oxide vapor be in direct contact with the product to be sterilized.

Radiation Sterilization One advantage of radiation sterilization is that many types of products can be sterilized without thermal degradation or other damage. Commonly used radiation is gamma rays or beta rays from 60Co sources. Gamma ray permeability can be used to sterilize many types of products, including solutions, compositions, and heterogeneous mixtures. This bactericidal effect by irradiation is due to the interaction between γ rays and biopolymers. This interaction produces charged species and free radicals. Subsequent chemical reactions such as rearrangement and cross-linking processes lose the normal function of the biopolymer. In addition, the formulations described herein may be sterilized using beta rays in some cases.

Filtration Filtration sterilization is a method used to remove microorganisms from solution rather than destroy them. Filter the heat sensitive solution using a membrane filter. Such filters are thin, strong, homogeneous polymers of mixed cellulose derivative esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF) or polytetrafluoroethylene (PTFE) with a pore size of 0.1-0.22 μm. Have Solutions having various properties are optionally filtered using different filter membranes. For example, PVF membranes and PTFE membranes are well suited for filtering organic solvents, while aqueous solutions are filtered through PVF membranes or MCE membranes. Filter devices are available for use on many scales, from a point-of-use disposable filter attached to a syringe to a commercial scale filter used in a manufacturing plant. The membrane filter is sterilized by autoclaving or chemical sterilization. The membrane filtration system was verified according to the following standardized protocol (literature `` Microbiological Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3, Washington, DC: Health Industry Manufacturers Association, 1981 ''), Brevundimonas diminuta (ATCC 19146). For unusually small microorganisms such as), a membrane filter challenge test with a known amount (about 107 cm 2) is included.

  The pharmaceutical composition is optionally sterilized by passage through a membrane filter. Formulations with nanoparticles (US Pat. No. 6,139,870) or multilamellar layered vesicles (Richard et al. Intrernational Jounal of Pharmaceutics (2006), 312 (1-2: 144-50) break down the organized structure Without being sterilized through 0.22 μm filtration.

  In certain embodiments, the methods disclosed herein include sterilizing the formulation (or components thereof) by using filter sterilization. In another embodiment, the otic acceptable otic therapeutic agent formulation comprises particles such that the particle formulation is suitable for filter sterilization. In further embodiments, the particle formulation comprises particles having a size of less than 300 nm, a size of less than 200 nm, or a size of less than 100 nm. In another embodiment, the ear-acceptable formulation comprises a particle formulation, and the sterility of the particles is ensured by sterile filtering the solution of precursor components. In another embodiment, the ear acceptable formulation comprises a particle formulation, and the sterility of the particle formulation is ensured by pasteurization filtration. In further embodiments, pasteurization filtration is performed at a temperature between 0-30 ° C, between 0-20 ° C, between 0-10 ° C, between 10-20 ° C, or between 20-30 ° C. .

  In another embodiment, the process of preparing an ear acceptable particle formulation includes: That is, an aqueous solution containing the particle preparation is filtered at a low temperature through a sterile filter, the sterile solution is lyophilized, and the particle preparation is reconstituted with sterile water before administration. is there. In certain embodiments, the formulations described herein are manufactured as a suspension containing the micronized active pharmaceutical ingredient in a single vial formulation. One vial formulation is prepared by aseptically mixing a sterile poloxamer solution with a micronized sterile active ingredient (eg, ketamine) and transferring the formulation to a sterile pharmaceutical container. In certain embodiments, one vial containing the formulation described herein as a suspension is resuspended prior to dispensing and / or administration.

  In certain embodiments, the filtration procedure and / or filling procedure is performed at a temperature about 5 ° C. lower than the gel temperature (Tgel) of the formulation described herein, with a theoretical value of 100 cP, and a peristaltic pump Used and can be filtered in a reasonable time.

  In another embodiment, the otic acceptable therapeutic agent formulation comprises a nanoparticulate formulation suitable for filter sterilization. In further embodiments, the nanoparticle formulation comprises nanoparticles having a size of less than 300 nm, a size of less than 200 nm, or a size of less than 100 nm. In another embodiment, the ear-acceptable formulation comprises a microsphere formulation, and sterility is ensured by sterile filtering the organic solution and aqueous solution of the microsphere precursor. In another embodiment, the ear acceptable formulation comprises a thermoreversible gel formulation, and the sterility of the gel formulation is ensured by pasteurization filtration. In further embodiments, the pasteurization filtration is performed at a temperature between 0-30 ° C, or between 0-20 ° C, or between 0-10 ° C, or between 10-20 ° C, or between 20-30 ° C. Done in In another embodiment, the process of preparing an ear-acceptable thermoreversible gel formulation includes: That is, a step of filtering an aqueous solution containing a thermoreversible gel element at a low temperature through a sterilizing filter, a step of lyophilizing the sterilized solution, and restructuring the thermoreversible gel preparation before administration. It is a process to do.

  In certain embodiments, the active ingredients are dissolved in a suitable vehicle (eg, buffer) and sterilized separately (eg, by heat treatment, filtration, gamma radiation). In some instances, the active ingredients are sterilized separately in the dry state. In some examples, the active ingredients are sterilized as a suspension or as a colloidal suspension. The remaining excipients (e.g., fluid gel components present in the otic formulation) are sterilized in a separate step by a suitable method (e.g., filtering and / or irradiating a cold mixture of excipients) and then separated separately. The two solutions to be sterilized are mixed aseptically to provide the final ear formulation. In some cases, final aseptic mixing is performed immediately prior to administration of the formulations described herein.

  In some cases, polymer components (e.g., thermosetting, gelling, or mucoadhesive polymer components) by conventional sterilization methods (e.g., heat treatment (e.g. in an autoclave), gamma radiation, filtration) ) And / or the active agent in the formulation is irreversibly degraded. In some cases, sterilization of an otic formulation with a membrane (eg, 0.2 μM membrane) is not possible when the formulation contains a thixotropic polymer that gels during the filtration process.

  Accordingly, the present specification includes such that polymer components (e.g., thermosetting and / or gelling and / or mucoadhesive polymer components) and / or active agents are prevented from degrading during the sterilization process. A method of sterilizing an otic formulation is provided. In certain embodiments, an active agent (e.g., any otic therapeutic agent described herein) by using a buffer component in a specific pH range and using a specific ratio of gelling agent in the formulation. Reduces or eliminates the degradation of In certain embodiments, the formulations described herein can be sterilized by filtration by selecting an appropriate gelling agent and / or thermosetting polymer. In certain embodiments, a suitable thermosetting polymer and a suitable copolymer (e.g., a gelling agent) are used in combination with a specific pH range so that the therapeutic agent or polymer excipient does not substantially degrade. The described formulations can be sterilized at elevated temperatures. The advantage of the sterilization methods provided herein is that, in certain cases, the formulation is terminally sterilized by autoclaving, without substantial loss of active agent and / or excipients and / or polymer components during the sterilization process. In particular, it should be made substantially free of microorganisms and / or pyrogens.

Microorganisms Provided herein are otic acceptable compositions or devices that ameliorate or reduce the otic diseases described herein. Further provided herein is a method comprising administering the otic composition. In some embodiments, the composition or device is substantially free of microorganisms. Acceptable biocontamination levels or sterilization levels are based on applicable standards that define therapeutically acceptable otic compositions, including, but not limited to, US Pharmacopoeia Chapter 1111 (see below). For example, an acceptable level of sterilization (eg, biofouling) is about 10 colony forming units (cfu) per gram of formulation, about 50 cfu per gram of formulation, about 100 cfu per gram of formulation, about 500 cfu per gram of formulation, or per gram of formulation About 1000 cfu is mentioned. In certain embodiments, an acceptable biofouling level or sterilization level of a formulation includes less than 10 cfu / mL, less than 50 cfu / mL, less than 500 cfu / mL, or less than 1000 cfu / mL of a microbial agent. In addition, acceptable biofouling levels or sterilization levels include the exclusion of certain undesirable microbial agents. By way of example, certain undesirable microbial agents include, but are not limited to, Escherichia coli (E. coli), Salmonella sp. (Species), Pseudomonas aeruginosa (P. aeruginosa) and / or other specific microbial agents. .

  The degree of sterility of an ear treatment product acceptable to the ear is confirmed in the Sterilization Assurance Program according to Chapters 61, 62 and 71 of the US Pharmacopeia. A key element of the quality control, quality assurance and verification process through sterilization assurance is the sterilization test method. Sterilization tests are performed by two methods, by way of example only. The first method is direct inoculation, where the composition sample to be tested is added to the growth medium and incubated for a period of up to 21 days. Turbidity in the growth medium indicates contamination. The disadvantages of this method are that the sensitivity decreases when the amount of sampling from the mass of material is small, and that the detection of microorganisms is based on visual observation. An alternative is a sterilization test by membrane filtration. In this method, a volume of product is passed through a small membrane filter paper. The filter paper is then placed in the medium to promote microbial growth. This method has the advantage of increased sensitivity because it samples the entire product mass. Optionally, a commercially available Millipore Steritest sterilization test system is used to determine by sterility testing by membrane filtration. For filtration testing of creams or ointments, Steritest filter system No. TLHVSL210 is used. For filtration testing of emulsions or viscous products, Steritest filter system No. TLAREM210 or TDAREM210 is used. A Steritest filter system No. TTHASY210 is used for filtration testing of prefilled syringes. Steritest filter system No. TTHVA210 is used for filtration testing of substances dispersed as an aerosol or foam. For filtration testing of soluble powders in ampoules or vials, Steritest filter system No. TTHADA210 or TTHADV210 is used.

  Tests for E. coli and Salmonella use lactose cultures, incubate at 30-35 ° C. for 24-72 hours, in MacConkey agar and / or EMB agar for 18-24 hours, and / or Including using Rappaport medium. Tests for detecting P. aeruginosa include the use of NAC agar. US Pharmacopeia Chapter 62 further lists test procedures for certain undesirable microorganisms.

  In certain embodiments, any of the controlled release formulations described herein has less than about 60 microbial agent colony forming units (CFU) and less than about 50 colony forming units per gram of formulation, The colony forming unit is less than about 40, or the colony forming unit is less than about 30. In certain embodiments, the otic preparations described herein are formulated to have osmolarity equal to the endolymph and / or perilymph.

  Provided herein are otic compositions that ameliorate or reduce otic disorders as described herein. Further provided herein is a method comprising administering the otic composition. In some embodiments, the composition or device is substantially free of endotoxin. A further aspect of the sterilization process is to remove by-products (hereinafter “products”) that result from killing microorganisms. The removal of pyrogen from the sample by the pyrogen removal process. The pyrogen is endotoxin or exotoxin that elicits an immune response. An example of an endotoxin is a lipopolysaccharide (LPS) molecule found in the cell wall of Gram-negative bacteria. Sterilization procedures such as autoclaving or treatment with ethylene oxide kill bacteria, but LPS residues elicit inflammatory immune responses such as septic shock. Because of the wide variety of endotoxin molecular sizes, the presence of endotoxins is expressed in “endotoxin units” (EU). One EU is equivalent to 100 picograms of E. coli LPS. Humans may produce a response of only 5 EU / kg body weight. Biocontamination (eg, microbial limits) and / or sterilization (eg, endotoxin levels) are expressed in any unit as recognized in the art. In certain embodiments, the otic compositions described herein have a low endotoxin level compared to a conventional acceptable endotoxin level (e.g., 5 EU / kg for a subject's weight) (e.g., The subject's weight is less than 4 EU / kg). In certain embodiments, the otic acceptable otic therapeutic agent formulation has an EU of less than about 5 EU / kg of the subject's body weight. In other embodiments, the ear acceptable otic therapeutic agent formulation has an EU of less than about 4 EU / kg of the subject's body weight. In a further embodiment, the ear acceptable otic therapeutic agent formulation has an EU of less than about 3 EU / kg of the subject's body weight. In a further embodiment, the ear acceptable otic therapeutic agent formulation has an EU of less than about 2 EU / kg of the subject's body weight.

  In certain embodiments, the otic therapeutic agent or device acceptable to the ear has an EU of the formulation of less than about 5 EU / kg. In other embodiments, the otic acceptable otic therapeutic agent formulation has an EU of the formulation of less than about 4 EU / kg. In a further embodiment, the otic acceptable otic therapeutic agent formulation has an EU of less than about 3 EU / kg. In certain embodiments, an otic therapeutic agent formulation acceptable to the ear has a “product” EU of less than about 5 EU / kg. In other embodiments, the otic therapeutic agent formulation acceptable to the ear has a “product” EU of less than about 1 EU / kg. In a further embodiment, the otic acceptable otic therapeutic agent formulation has a “product” EU of less than about 0.2 EU / kg. In certain embodiments, the otic therapeutic agent formulation acceptable to the ear has a unit or “product” EU of less than about 5 EU / g. In other embodiments, the otic acceptable otic therapeutic agent formulation has a unit or “product” EU of less than about 4 EU / g. In a further embodiment, the otic acceptable otic therapeutic agent formulation has a unit or “product” EU of less than about 3 EU / g. In certain embodiments, the otic therapeutic agent formulation acceptable to the ear has a unit or “product” EU of less than about 5 EU / mg. In other embodiments, the otic acceptable otic therapeutic agent formulation has a unit or “product” EU of less than about 4 EU / mg. In a further embodiment, the otic acceptable otic therapeutic agent formulation has a unit or “product” EU of less than about 3 EU / mg. In certain embodiments, the otic compositions described herein contain from about 1 to about 5 EU / mL of the formulation. In certain embodiments, the otic compositions described herein contain about 2 to about 5 EU / mL of a formulation, about 3 to about 5 EU / mL of a formulation, or about 4 to about 5 EU / mL of a formulation. To do.

  In certain embodiments, an otic composition or device described herein has a low endotoxin concentration compared to a conventional acceptable endotoxin concentration (e.g., 0.5 EU / mL for a formulation) (e.g., For formulations, less than 0.5 EU / mL). In certain embodiments, the otic acceptable therapeutic agent formulation or device is less than about 0.5 EU / mL for the formulation. In other embodiments, the otic acceptable therapeutic agent formulation is less than about 0.4 EU / mL for the formulation. In a further embodiment, the otic acceptable therapeutic agent formulation is less than about 0.2 EU / mL for the formulation.

  The detection of pyrogens is done in several ways, by way of example only. Tests suitable for sterilization levels include those described in the US Pharmacopoeia (USP) Chapter 71 Sterility Tests (23rd edition, 1995). Rabbit pyrogen test and Limulus amebocyte lysate test are both specified in US Pharmacopeia Chapters 85 and 151 (USP23 / NF18, Biological Tests, The United States PHarmacopeial Convention, Rockville, MD, 1995) . An alternative pyrogen assay has been developed based on the monocyte activation-cytokine assay. Uniform cell lines suitable for quality control applications have been developed and show the ability to detect fever in samples that have passed the rabbit pyrogen test and the Limulus amebocyte lysate test (see Taktak et al., J. PHarm.PHarmacol (1990), 43: 578-82 "). In a further embodiment, pyrogenic removal is performed on an otic therapeutic agent formulation acceptable to the ear. In a further embodiment, the process of manufacturing an otic acceptable otic therapeutic agent formulation comprises testing the formulation for pyrogenicity. In certain embodiments, the compositions described herein are substantially free of pyrogens.

pH and actual osmolarity As used herein, “actual osmolarity” refers to active agent, gelling agent and / or thickener (eg, polyoxyethylene-polyoxypropylene copolymer). Means the osmolarity of the formulation as measured by what includes all excipients except carboxymethylcellulose, etc.). The actual osmolarity of the formulations described herein can be determined by any suitable method, eg, freezing point depression as described in Viegas et. Al., Int. J. Pharm., 1998, 160, 157-162. Measured by the method. In some cases, the actual osmolarity of the compositions described herein is determined by vapor pressure osmometry (e.g., vapor pressure drop method), which determines the osmolarity of the composition at higher temperatures. Measured. In some examples, the osmolality of a formulation comprising a gelling agent (e.g., a thermoreversible polymer) can be determined by a vapor pressure drop method at a higher temperature where the gelling agent is in the form of a gel. it can. The actual osmolarity of the otic formulations described herein is about 100 mOsm / kg to about 1000 mOsm / kg, about 200 mOsm / kg to about 800 mOsm / kg, about 250 mOsm / kg to about 500 mOsm / kg, or about 250 mOsm. / kg to about 320 mOsm / kg, or about 250 mOsm / kg to about 350 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg. In certain embodiments, the formulations described herein have an actual osmolarity of about 100 mOsm / L to about 1000 mOsm / L, about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L. About 250 mOsm / L to about 350 mOsm / L, about 250 mOsm / L to about 320 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.

  In certain embodiments, the osmolarity at the target site of action (e.g., perilymph) is the osmolarity delivered (i.e., passes or penetrates the round window membrane) of any formulation described herein. It is almost the same as the osmolarity of the substance. In certain embodiments, the formulations described herein have from about 150 mOsm / L to about 500 mOsm / L, from about 250 mOsm / L to about 500 mOsm / L, from about 250 mOsm / L to about 350 mOsm / L, from about 280 mOsm / L to about It has a deliverable osmolarity of 370 mOsm / L, or about 250 mOsm / L to about 320 mOsm / L.

  The main cation present in the endolymph is potassium. In addition, the endolymph has a high concentration of positively charged amino acids. The main cation present in the perilymph is sodium. In certain instances, the ionic composition of endolymph and perilymph controls hair cell electrochemical impulses. In certain instances, any change in ionic balance of the endolymph or perilymph results in hearing loss due to changes in the conduction of electrochemical impulses along the ear hair cells. In some embodiments, the compositions disclosed herein do not disrupt perilymph ionic balance. In some embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as the perilymph. In some embodiments, the compositions disclosed herein do not disrupt ionic balance of the endolymph. In some embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as the endolymph. In certain embodiments, the otic formulations described herein are formulated to provide an ionic balance that is compatible with the inner ear fluid (eg, endolymph and / or perilymph).

  The endolymph and perilymph have a pH close to the physiological pH of blood. The endolymph has a pH range of about 7.2 to 7.9 and the perilymph has a pH range of about 7.2 to 7.4. The in situ pH of the proximal endolymph is about 7.4 and the pH of the endolymph near the periphery is about 7.9.

  In some embodiments, the pH of the compositions described herein is adjusted to a pH in the range of about 5.5 to 9.0 that is compatible with the endolymph (eg, by using a buffer). In certain embodiments, the pH of the compositions described herein is adjusted to a pH in the range of about 5.5 to 9.0 that is compatible with perilymph. In some embodiments, the pH of the compositions described herein is adjusted to a pH in the range of about 5.5 to about 8.0, about 6 to about 8.0, or about 6.6 to about 8.0 that is compatible with the perilymph. In some embodiments, the pH of the compositions described herein is adjusted to a pH in the range of about 7.0 to 7.6 that is compatible with perilymph.

  In certain embodiments, useful formulations also include one or more pH adjusters or buffers. Suitable pH adjusting or buffering agents include, but are not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. Can be mentioned.

  In one embodiment, when one or more buffering agents are utilized in the formulations of the present disclosure, the one or more buffering agents are combined with, for example, a pharmaceutically acceptable vehicle, and the final formulation contains, for example, about It is present in an amount ranging from 0.1% to about 20%, from about 0.5% to about 10%. In certain embodiments of the present disclosure, the amount of buffer included in the gel formulation is such that the pH of the gel formulation does not interfere with the body's natural buffer system.

  In one embodiment, the diluent is also used to stabilize the compound because a more stable environment can be obtained. Salts dissolved in a buffer (which can also be pH controlled or maintained) are utilized in the art as diluents, including but not limited to phosphate buffered saline solutions.

  In some embodiments, the pH of the gel formulations described herein can be sterilized (eg, filtered or aseptically mixed or heat treated) and / or pharmaceuticals (eg, otic sensory cell modulators), It has a pH at which the gel preparation can be autoclaved (for example, final sterilization) without degrading the polymer constituting the gel. In order to reduce hydrolysis and / or degradation of the otic agent and / or gel polymer during sterilization, the pH of the buffer should be adjusted to 7-8 during the sterilization process (e.g., autoclaving at elevated temperatures). Designed to keep in the range.

  In certain embodiments, any of the gel formulations described herein are subject to terminal sterilization (e.g., heat treatment) of the gel formulation without degrading the pharmaceutical (e.g., otic sensory cell modulator) or the polymer that makes up the gel. And / or by autoclaving). For example, to reduce hydrolysis and / or degradation of the otic agent and / or gel polymer during autoclaving, the pH of the buffer should be such that the pH of the formulation at elevated temperatures is maintained in the range of 7-8. Designed to. Any suitable buffer is used depending on the otic agent used in the formulation. In some cases, TRISpKa decreases at about -0.03 / ° C with increasing temperature and PBS pKa increases at about 0.003 / ° C with increasing temperature, so autoclaving at 250 ° F (121 ° C) is , Significantly lower the pH in TRIS buffer (i.e., more acidic), while in PBS buffer, shift the pH relatively slightly upward, and therefore in TRIS than in PBS. The hydrolysis and / or degradation of the otic drug is greatly increased. Proper combination of buffers and polymer additives (eg, CMC) as described herein reduces otic drug degradation.

  In some embodiments, the pH is from about 5.0 to about 9.0, from about 5.5 to about 8.5, from about 6.0 to about 7.6, from about 7 to about 7.8, from about 7.0 to about 7.6, from about 7.2 to about 7.6, or from about 7.2 to about Formulations that are 7.4 are suitable for sterilization (eg, filtration or aseptic mixing or heat treatment) and / or autoclaving (eg, final sterilization) of the otic formulations described herein. In certain embodiments, a formulation having a pH of about 6.0, about 6.5, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6 is any composition described herein. Suitable for sterilization of goods (eg filtration or aseptic mixing or heat treatment and / or autoclaving (eg final sterilization)).

  In some embodiments, the formulation has a pH as described herein, for example, as a non-limiting example, a thickening such as a cellulosic thickener described herein. Contains agents (eg, agents that increase viscosity). In some cases, adding a secondary polymer (eg, a thickener) and adjusting the pH of the formulation as described above may substantially degrade any otic drug and / or polymer component in the otic formulation. Rather, the formulations described herein can be sterilized. In some embodiments, the ratio of thermoreversible poloxamer to thickener in a formulation having a pH described herein is about 40: 1, about 35: 1, about 30: 1, about 25. : 1, about 20: 1, about 15: 1, about 10: 1, or about 5: 1. For example, in certain embodiments, the sustained release and / or sustained release formulations described herein comprise a combination of poloxamer 407 (Pluronic F127) and carboxymethylcellulose (CMC) at about 40: 1, about 35 : 1, about 30: 1, about 25: 1, about 20: 1, about 15: 1, about 10: 1, or about 5: 1.

  In some embodiments, the amount of thermoreversible polymer in any formulation described herein is about 10%, about 15%, about 20%, about 25%, about 30% of the total weight of the formulation. %, About 35%, or about 40%. In some embodiments, the amount of thermoreversible polymer in any formulation described herein is about 10%, about 11%, about 12%, about 13%, about 14% of the total weight of the formulation. %, About 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 7.5% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 10% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 11% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 12% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 13% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 14% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 15% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 16% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 17% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 18% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 19% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 20% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 21% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 23% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer (eg, pluronic F127) in any formulation described herein is about 25% of the total weight of the formulation.

  In some embodiments, the amount of thickening agent (e.g., gelling agent) in any formulation described herein is about 1%, about 5%, about 10% of the total weight of the formulation, Or about 15%. In some embodiments, the amount of thickening agent (e.g., gelling agent) in any formulation described herein is about 0.5%, about 1%, about 1.5% of the total weight of the formulation, About 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5%.

  In some embodiments, a pharmaceutical formulation described herein has at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 month, at least about 2 months, It is stable with respect to pH for any period of at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, the formulations described herein are stable with respect to pH for at least about 1 week. Also described herein are formulations that are stable with respect to pH for at least about one month.

Isotonic agents In general, endolymph has a higher osmolality (osmotic pressure) than perilymph. For example, the endolymph has an osmolality of about 304 mOsm / kg H ₂ O, while the perilymph has an osmolality of about 294 mOsm / kg H ₂ O. In certain embodiments, an isotonic agent is added to the formulations described herein wherein the actual osmolality (osmotic pressure) of the otic formulation is from about 100 mOsm / kg to about 1000 mOsm / kg, about 200 mOsm / kg. To about 800 mOsm / kg, about 250 mOsm / kg to about 500 mOsm / kg, about 250 mOsm / kg to about 350 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg. In some embodiments, the formulations described herein have about 100 mOsm / L to about 1000 mOsm / L, about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L. It has a practical osmolarity of L to about 350 mOsm / L, about 280 mOsm / L to about 320 mOsm / L, or about 250 mOsm / L to about 320 mOsm / L.

In some embodiments, the deliverable osmolarity of any formulation described herein is isotonic (osmotic pressure) with the targeted ear structure (eg, endolymph, perilymph, etc.). Are designed to be equal). In certain embodiments, the otic compositions described herein have a post-delivery of about 250 to about 320 mOsm / L (; more preferably about 270 to about 320 mOsm / L) at the target site of action. Formulated to give osmolarity in lymph-compatible volume. In certain embodiments, the otic compositions described herein are about 250 to about 320 mOsm / kg H ₂ O at the target site of action; (more preferably) about 270 to about 320 mOsm / kg H 2. Formulated to give perilymph osmolality after delivery of ₂ O. In certain embodiments, deliverable osmolarity / formulation osmolality (ie, osmolarity of the formulation / gelling agent or thickener (eg, thermoreversible gel polymer) is not present) ) Can be made endolymphatic and / or perilymphatically compatible (eg, internal lymphatics) by using appropriate salt concentrations (eg, potassium or sodium salt concentrations) or when delivered to a target site. It is controlled by using an isotonic agent that makes the osmotic pressure equal to the lymph and / or perilymph). The osmolarity of formulations containing thermoreversible gel polymers is not reliable because various amounts of water associate with the monomer units of the polymer. The actual osmolarity of the formulation (ie, the osmolarity of the formulation in the absence of a gelling agent or thickener (eg, thermoreversible gel polymer)) is a reliable value and is appropriate for the appropriate method (eg, freezing point Measured by the descent method, vapor pressure drop method). In some cases, the formulations described herein may be administered to a mammal with minimal disruption to the inner ear environment when administered, for example, at a target site (e.g., perilymph). Deliverable osmolarity is provided to minimize pleasure (eg, dizziness and / or nausea).

  In some embodiments, any formulation described herein is isotonic (equal tonicity) in the perilymph and / or endolymph. Isotonic formulations are provided by adding an isotonic agent. Suitable tonicity agents include, but are not limited to, any pharmaceutically acceptable sugar, salts thereof, or any combination or mixture, such as, but not limited to, dextrose, glycerin, mannitol, sorbitol, chloride There are sodium and other electrolytes.

  Useful otic compositions contain one or more salts in the amount required to make the osmolality of the composition acceptable. Such salts include sodium cation, potassium cation or ammonium cation and chloride anion, citrate anion, ascorbate anion, borate anion, phosphate anion, bicarbonate anion, sulfate anion, Suitable salts include those having a thiosulfate anion or a bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

  In some embodiments, the formulations described herein have a pH and / or actual osmolarity as described herein, wherein the concentration of the active pharmaceutical ingredient is from about 1 μm to about 10 μm, about 1 mM to about 100 mM, about 0.1 mM to about 100 mM, about 0.1 nM to about 100 nM. In some embodiments, the formulations described herein have a pH and / or actual osmolality as described herein, wherein the concentration of the active pharmaceutical ingredient is the active ingredient of the formulation. About 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 7.5%, about 0.01% to 6%, about 0.01 to 5%, about 0.1% to about 10%, about 0.1% % To about 6%. In some embodiments, the formulations described herein have a pH and / or actual osmolality as described herein, wherein the concentration of the active pharmaceutical ingredient is the active ingredient of the formulation. About 0.1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to about 5 mg / mL. In some embodiments, a formulation described herein has a pH and / or actual osmolarity as described herein, wherein the concentration of the active pharmaceutical ingredient is the activity of the formulation. Ingredient volume of about 1 μg / mL to about 500 μg / mL, about 1 μg / mL to about 250 μg / mL, about 1 μg / mL to about 100 μg / mL, about 1 μg / mL to about 50 μg / mL, or about 1 μg / mL to About 20 μg / mL.

Particle size Size reduction is utilized to increase surface area and / or adjust the dispersibility of the formulation. Size reduction can also be used to maintain a constant mean particle size distribution (PSD) (eg, micron-sized particles, nanometer-sized particles, etc.) for any of the formulations described herein. Used. In some embodiments, any of the formulations described herein are multiparticulate, ie, multiple particle sizes (eg, micronized particles, nano-sized particles, non-constant particles, colloids Ie, the formulation is a multiparticulate formulation. In some embodiments, any formulation described herein includes one or more multiparticulate (eg, micronized) therapeutic agents. Micronization is a process that reduces the average diameter of particles of solid material. Micronized particles are those that are approximately micron in diameter to approximately nanometer in diameter. In some embodiments, the average diameter of the particles in the micronized solid is from about 0.5 μm to about 500 μm. In some embodiments, the average diameter of the particles in the micronized solid is from about 1 μm to about 200 μm. In some embodiments, the average diameter of the particles in the micronized solid is from about 2 μm to about 100 μm. In some embodiments, the average diameter of the particles in the micronized solid is from about 3 μm to about 50 μm. In some embodiments, the micronized particulate solid has a particle size of less than about 5 μm, less than about 20 μm, and / or less than about 100 μm. In some embodiments, a formulation comprising an ear sensory cell modulator that is not multiparticulate (eg, non-micronized) when particulate material (eg, micronized particles) of the ear sensory cell modulator is used. In comparison with the present invention, it is possible to provide a sustained and / or sustained release of the otic sensory cell modulator from any of the formulations described herein. In some examples, a formulation containing a multiparticulate (eg, micronized) ear sensory cell modulator is expelled from a 1 mL syringe fitted with a 27G needle without clogging or clogging. The

  In some examples, any particle in any formulation described herein is coated particles (eg, coated micronized particles, nanoparticles) and / or microspheres and / or liposome particles. It is. Examples of techniques for reducing the particle size include, for example, rough pulverization, milling (for example, air friction milling (jet mill milling), ball mill milling), coacervation, complex coacervation, high-pressure homogenization method, spray drying and / or An example is crystallization with a supercritical fluid. In some examples, the particles are sized by mechanical impact (eg, by hammer mill, ball mill and / or pin mill). In some examples, the particles are sized by fluid energy (eg, by a spiral jet mill, a loop jet mill, and / or a fluid bed jet mill). In some embodiments, the formulations described herein include crystalline particles and / or isotropic particles. In some embodiments, the formulations described herein include amorphous particles and / or anisotropic particles. In some embodiments, the formulations described herein include therapeutic agent particles wherein the therapeutic agent is a free base, or a salt, or a prodrug of a therapeutic agent, or any combination thereof.

  In some embodiments, the formulations described herein include one or more otic sensory cell modulators comprising nanoparticulate materials. In some embodiments, the formulations described herein comprise otic sensory cell modulator beads (eg, dextromethorphan beads), which are optionally coated with a controlled release excipient. ing. In some embodiments, the formulations described herein comprise granulated and / or size-reduced ear sensory cell modulators coated with controlled release excipients and granulated. The coated ear sensory cell modulating agent particles are optionally micronized and / or formulated into any of the compositions described herein.

  In some examples, to prepare a pulsed release otic drug formulation using the procedures described herein, an otic sensory cell modulator in a neutral molecule, free acid or free base state; and A combination with an ear sensory cell modulator salt is used. In some formulations, a micronized ear sensory cell modulator (and / or salt or prodrug thereof) is used to prepare a pulsed release otic pharmaceutical formulation using the procedures described herein. And a combination of coated particles (eg, nanoparticles, liposomes, microspheres). Alternatively, an ear sensory cell modulator (eg, micronized ear sensory cell modulator, free base, free acid or salt or prodrug thereof; multiparticulate ear sensory cell modulator, free base, free acid or Salt or a prodrug thereof) such as cyclodextrin, surfactant {eg poloxamer (407,398,188), Tween (80,60,20,81), PEG-hydrogenated castor oil, N-methyl-2-pyrrolidone A pulsed release profile is achieved by dissolving up to 20% of the dose delivered with the aid of a co-solvent and preparing the pulsed release formulation using any of the procedures described herein.

  In certain embodiments, any of the ear compatible formulations described herein comprise one or more micronized pharmaceuticals (eg, otic sensory cell modulators). In some embodiments, the micronized pharmaceutical comprises micronized particles, coated (e.g., with a sustained release coating) micronized particles, or a combination thereof. In some embodiments, a micronized medicament comprising micronized particles, coated micronized particles, or a combination thereof comprises an otic sensory cell modulator, a neutral molecule, a free acid, a free It is included as a base, salt, prodrug, or a combination thereof. In certain embodiments, the pharmaceutical compositions described herein include an otic sensory cell modulator as a finely divided powder. In certain embodiments, the pharmaceutical compositions described herein comprise an ear sensory cell modulator in the form of a particulate-ear sensory cell modulator powder.

  The multiparticulate and / or micronized otic sensory cell modulators described herein can use any type of matrix, including a solid matrix, a liquid matrix, or a gel matrix, to form the otic structure (eg, the inner ear). Delivered to. In some embodiments, the multiparticulate and / or micronized ear sensory cell modulator described herein uses any type of matrix, including a solid matrix, a liquid matrix or a gel matrix, Delivered to the ear structure (eg, inner ear) by injection.

Adjustable Release Characteristics Release of the active agent from the compositions or devices described herein can be optionally tuned to the desired release characteristics. In some embodiments, the compositions described herein are solutions that are substantially free of gelling components. In such instances, the composition provides an essentially immediate release of the active agent. In some of such embodiments, the composition is useful for perfusion of the ear structure, eg, during surgery.

  In some embodiments, the compositions described herein are solutions that are substantially free of gelling components and that include a micronized otic agent (eg, a corticosteroid). In some of such embodiments, the composition provides release of the active agent from about 2 days to about 4 days. In some embodiments, the compositions described herein include a gelling agent (eg, poloxamer 407) to provide active agent release over a period of about 1 day to about 3 days. In some embodiments, the compositions described herein include a gelling agent (eg, poloxamer 407) to provide release of the active agent over a period of about 1 day to about 5 days. In some embodiments, the compositions described herein include a gelling agent (eg, poloxamer 407) to provide release of the active agent over a period of about 2 days to about 7 days.

  In some embodiments, the compositions described herein include a gelling agent (eg, poloxamer 407) in combination with a micronized otic agent to provide sustained sustained release over a longer period of time. give. In some embodiments, a composition described herein comprises about 14-17% gelling agent (eg, poloxamer 407) and micronized otic agent for about 1 week to about 3 weeks. Giving sustained sustained release over a period of. In some embodiments, the compositions described herein comprise about 18-21% gelling agent (eg, poloxamer 407) and micronized otic agent for about 3 weeks to about 6 weeks. Provides sustained sustained release over a period of time.

  Thus, the amount of gelling agent in the composition and the particle size of the otic agent can be adjusted toward the desired release profile of the active agent from the composition.

As described herein, a composition comprising a micronized otic agent provides a sustained release over a longer period of time compared to a composition comprising a non-micronized otic agent.
In some instances, micronized otic agents provide a stable supply (eg, +/- 20%) of active agent by slow degradation and also serve as a reservoir for active agent; A good storage effect increases the residence time of the otic drug in the ear.
In certain embodiments, the selection of the appropriate particle size of the active agent (eg, micronized active agent) in combination with the amount of gelling agent in the composition is a period of time, day, week or month. Provides a tunable extended release profile that allows release of the active agent over a wide range.

  In some embodiments, the viscosity of the formulations described herein is designed to provide an appropriate release rate from the otic compatibility gel. In some embodiments, the concentration of a thickening agent (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer) allows for an adjustable mean dissolution time (MDT). MDT is inversely proportional to the release rate of the active agent from the compositions or devices described herein. Experimentally, the released otic agent optionally fits the Korsmeyer-Peppas equation below.

Where Q is the amount of otic drug released during time t, Q _α is the total amount of otic drug released, k is the nth order release constant, n is a dimensionless number related to the dissolution mechanism, and b is the initial value. The axis intercept characterizing the burst release mechanism, where n = 1 characterizes the erosion control mechanism. Mean dissolution time (MDT) is the sum of various time intervals during which drug molecules stay in the matrix prior to release divided by the total number of molecules and is optionally calculated by the following formula:

  For example, the linear relationship between the mean dissolution time (MDT) of a composition or device and the concentration of gelling agent (eg, poloxamer) is not due to diffusion, but due to erosion of the polymer gel (eg, poloxamer) It shows that it is released. In another example, the non-linear relationship is indicative of otic drug release by a combination of diffusion and / or polymer gel degradation. In another example, the faster gel drain time process (faster release of active agent) of the composition or device indicates a lower mean dissolution time (MDT). The concentration of gelling agent and / or active agent in the composition is tested to determine the appropriate parameters for MDT. In some embodiments, the injection volume is also tested to determine appropriate parameters for preclinical and clinical studies. The gel strength and concentration of the active agent affects the release kinetics of the otic agent from the composition. At low poloxamer concentrations, the elimination rate is accelerated (MDT is lower). Increasing the concentration of the otic drug in the composition or device extends the residence time and / or MDT of the otic drug in the ear.

  In some embodiments, the MDT for a poloxamer from a composition or device described herein is at least 6 hours. In some embodiments, the MDT for a poloxamer from a composition or device described herein is at least 10 hours.

  In some embodiments, the MDT for an active agent from a composition or device described herein is from about 30 hours to about 48 hours. In some embodiments, the MDT for an active agent from a composition or device described herein is from about 30 hours to about 96 hours. In some embodiments, the MDT for an active agent from a composition or device described herein is from about 30 hours to about 1 week. In some embodiments, the MDT for an active agent from a composition or device described herein is from about 1 week to about 6 weeks.

  In certain embodiments, the controlled release otic formulations described herein increase otic drug exposure and reduce the area under the curve (AUC) in otic fluids (eg, endolymph and / or perilymph). About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to a formulation that is not a controlled release ear formulation. In certain embodiments, the controlled release otic formulations described herein increase the exposure of the otic agent to increase the Cmax in the otic fluid (eg, endolymph and / or perilymph) and control release otic. About 40%, about 30%, about 20% or about 10% reduction compared to a non-conventional formulation In certain embodiments, the controlled release otic formulations described herein change (eg, decrease) the ratio of Cmax to Cmin as compared to a formulation that is not a controlled release otic formulation. In certain embodiments, the controlled release otic formulations described herein increase the exposure of the otic agent and control the length of time that the concentration of the otic agent is greater than or equal to Cmin. Increase by about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to a non-formulation. In certain instances, the controlled release otic formulations described herein delay time to Cmax. In certain instances, controlled stable release of the drug extends the time that the drug concentration remains above Cmin. In some embodiments, the otic compositions described herein extend the residence time of the drug in the inner ear and provide stable drug exposure properties. In some instances, increasing the concentration of the active agent within the composition saturates the clearance process and allows a faster and more stable constant state to be reached.

  In certain instances, once drug drug exposure (eg, concentration in the endolymph or perilymph) reaches a steady state, the drug concentration in the endolymph or perilymph is increased for an extended period (eg, 1 day). 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, 3 weeks, 6 weeks, 2 months). In some embodiments, the steady state concentration of active agent released from the controlled release formulation described herein is about 20 times the steady state concentration of active agent released from a non-controlled release formulation. About 50 times. FIG. 5 shows the tunable release of active agent from the four compositions expected.

Pharmaceutical formulations include herein a pharmaceutical composition or device comprising at least one otic sensory cell modulator and a pharmaceutically acceptable diluent, excipient or carrier. In some embodiments, the pharmaceutical composition comprises other therapeutic or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts for adjusting osmotic pressure, And / or contains a buffer. In other embodiments, the pharmaceutical composition also includes other therapeutic substrates.

  In some embodiments, the compositions or devices described herein include a dye that helps to enhance the visualization of the gel when applied. In some embodiments, dyes compatible with the otic acceptable compositions or devices described herein include Evans blue (e.g., 0.5% of the total weight of the otic formulation), methylene blue (e.g., 1% of the total weight of the otic preparation), isosulfan blue (eg 1% of the total weight of the otic preparation), trypan blue (eg 0.15% of the total weight of the otic preparation), and / or indocyanine Green (for example, 25 mg / vial). Other common dyes, e.g. FD & C Red 40, FD & C Red 3, FD & C Yellow 5, FD & C Yellow 6, FD & C Blue 1, FD & C Blue 2, FD & C Green 3, fluorescent dyes (e.g. fluorescein isothiocyanate, rhodamine, Alexa Fluors, DyLight Fluors) and / or dyes that can be visualized in combination with non-invasive imaging techniques such as MRI, CAT scans, PET scans, gadolinium-based MRI dyes, iodine-based dyes, barium-based dyes, etc. It is envisaged for use with any otic formulation described in the document. Other dyes that are compatible with any formulation or composition described herein are listed in the Sigma-Aldrich dye catalog (for such disclosure, incorporated herein by reference). ing).

  In some embodiments, mechanical or contrast devices are used to monitor or observe hearing impairment, balance disorder, or other otic diseases. For example, magnetic resonance imaging (MRI) devices are specifically envisioned to be within the scope of the embodiments, with MRI devices (eg, 3 Tesla MRI devices) evaluated for Meniere's disease progression, and then described herein. It can be treated with the disclosed pharmaceutical formulations. Also, gadolinium-based dyes, iodine-based dyes, barium-based dyes, etc. may be used with any ear-compatible composition or device described herein and / or any mechanical device or device described herein. It is envisioned for use with an imaging device. In certain embodiments, the medicament in the severity of the disease (eg, the size of endolymphatic edema), the penetration of the formulation into the inner ear, and / or the otic disease (eg, Meniere's disease) described herein. To evaluate the therapeutic effect of the formulation / device, gadolinium hydrate is used in combination with MRI and / or any of the pharmaceutical compositions or devices described herein.

  Any pharmaceutical composition or device described herein is administered by placing the pharmaceutical composition or device in contact with the cochlear ridge, round window, tympanic chamber, tympanic membrane, middle ear or outer ear. The

In one specific embodiment of the ear-accepted controlled release ear sensory cell modulator pharmaceutical formulation described herein, the ear sensory cell modulator is a “gel-acceptable gel formulation” herein. ”,“ Gel preparation acceptable for the inner ear ”,“ gel preparation acceptable for the middle ear ”,“ gel preparation acceptable for the outer ear ”,“ gel preparation for ear ”, or a variant name thereof. Provided in state. All compositional elements of the gel formulation must be compatible with the targeted ear structure. Further, the gel formulation provides controlled release of the ear sensory cell modulator to a desired site within the targeted ear structure; in some embodiments, the gel formulation is desired for the ear sensory cell modulator. A short-term or immediate release element for delivery to the target site. In other embodiments, the gel formulation has a sustained release element for delivering an otic sensory cell modulator.
In some embodiments, the gel formulation includes a multiparticulate (eg, micronized) ear sensory cell modulator. In some embodiments, the otic gel formulation is biodegradable. In other embodiments, the otic gel formulation includes a mucoadhesive excipient that allows attachment of the round window membrane to the outer mucus layer. In another embodiment, the otic gel formulation includes an excipient that promotes penetration; in a further embodiment, the otic gel formulation is between about 500-1,000,000 centipoise; between about 750-1,000,000 centipoise. Between about 1000 and 1,000,000 centipoise; between about 1000 and 400,000 centipoise; between about 2000 and 100,000 centipoise; between about 3000 and 50,000 centipoise; between about 4000 and 25,000 centipoise; between about 5000 and 200,000 centipoise; or Contains sufficient viscosity enhancer to provide a viscosity between about 6000 and 15,000 centipoise. In some embodiments, the otic gel formulation contains a viscosity enhancing agent sufficient to provide a viscosity of about 50000 to 1,000,000 centipoise.

  In some embodiments, the compositions or devices described herein are body temperature, low viscosity compositions or devices. In some embodiments, the low viscosity composition or device comprises from about 1% to about 10% viscosity enhancing agent (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). . In some embodiments, the low viscosity composition or device comprises from about 2% to about 10% viscosity enhancing agent (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). . In some embodiments, the low viscosity composition or device comprises from about 5% to about 10% viscosity enhancing agent (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). . In some embodiments, a viscosity enhancing agent (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer) is substantially free. In some embodiments, a low viscosity ear sensory cell modulator composition or device described herein provides an apparent viscosity of from about 100 cP to about 10,000 cP. In some embodiments, the low viscosity ear sensory cell modulator compositions or devices described herein provide an apparent viscosity of from about 500 cP to about 10,000 cP. In some embodiments, the low viscosity ear sensory cell modulator compositions or devices described herein provide an apparent viscosity of from about 1000 cP to about 10,000 cP. In some of such embodiments, the low viscosity otic sensory cell modulator composition or device includes, for example, but not limited to, middle ear surgery, inner ear surgery, tympanotomy, cochleoplasty, labyrinth, milk Administered in combination with external ear interventions including cutaneous open surgery, stapedectomy, stipedotomy, endolymphatic sacculotomy or the like The In some of such embodiments, the low viscosity ear sensory cell modulator composition or device is administered during an ear interventional procedure. In other such embodiments, the low viscosity ear sensory cell modulator composition or device is administered prior to the ear intervention procedure.

  In some embodiments, the composition or device described herein is a body temperature high viscosity composition or device. In some embodiments, the high viscosity composition or device comprises from about 10% to about 25% viscosity enhancing agent (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). . In some embodiments, the high viscosity composition or device comprises from about 14% to about 22% viscosity enhancer (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). . In some embodiments, the high viscosity composition or device comprises from about 15% to about 21% viscosity enhancer (eg, a gelling component such as a polyoxyethylene-polyoxypropylene copolymer). . In some embodiments, a high viscosity otic sensory cell modulator composition or device described herein provides an apparent viscosity of from about 100,000 cP to about 1,000,000 cP. In some embodiments, a high viscosity ear sensory cell modulator composition or device described herein provides an apparent viscosity of from about 150,000 cP to about 500,000 cP. In some embodiments, the high viscosity ear sensory cell modulator composition or device described herein provides an apparent viscosity of from about 250,000 cP to about 500,000 cP. In certain embodiments, the high viscosity composition or device is liquid at room temperature and is a gel between room temperature and body temperature (including individuals with severe fever, eg, fever up to about 42 ° C.) . In some embodiments, the high viscosity composition or device of an otic sensory cell modulator is administered as a monotherapy for the treatment of an otic disease or condition described herein. In some embodiments, the high viscosity composition or device of an otic sensory cell modulator is, for example, but not limited to, middle ear surgery, inner ear surgery, tympanic incision, cochleoplasty, labyrinth incision, mastectomy. Administered in combination with external ear intervention procedures, including stapedectomy, stapedotomy, endolymphatic sacculotomy, or the like. In some of such embodiments, the high viscosity ear sensory cell modulator composition or device is administered after the ear intervention procedure. In other such embodiments, the high viscosity ear sensory cell modulator composition or device is administered prior to the ear intervention procedure.

  In other embodiments, the inner ear pharmaceutical formulation described herein further comprises an otic acceptable hydrogel; in another embodiment, the otic pharmaceutical formulation comprises an otic acceptable microsphere or In yet another embodiment, the otic pharmaceutical formulation comprises an ear-acceptable liposome. In some embodiments, the otic pharmaceutical formulation comprises an ear acceptable foam; in another embodiment, the otic pharmaceutical formulation comprises an ear acceptable paint; in yet another embodiment. The otic pharmaceutical preparation comprises an in situ spongy material acceptable to the ear. In some embodiments, the otic pharmaceutical formulation comprises an ear-acceptable solvent release gel. In some embodiments, the otic pharmaceutical formulation comprises an actinic radiation curable gel. A further embodiment includes a thermoreversible gel in the otic drug and the formulation is fluid when the gel is prepared at or below room temperature, but the inner ear includes the tympanic cavity, round window membrane or cochlear ridge And / or when applying the gel in or near the target site of the middle ear, the otic pharmaceutical formulation is stiffen or cured to a gel-like substance.

  In further or alternative embodiments, the otic gel formulation may be administered to or near the round window membrane via intratympanic injection. In other embodiments, the otic gel formulation is introduced into the round window or cochlear window through an insertion through the incision in the posterior pinna and a surgical procedure on or near the round window or cochlear ridge area. It is administered at or near the ridges. Alternatively, the otic gel formulation is applied by a syringe and needle, which is inserted into the eardrum and introduced into the region of the round window or cochlear window ridge. An otic gel formulation is then deposited at or near the round window or cochlear ridge for local treatment of otic autoimmune diseases. In other embodiments, the otic gel formulation is applied via a microcatheter implanted in the patient, and in a further embodiment, the formulation is administered to or near the round window membrane by a pump device. In yet another embodiment, the otic gel formulation is administered to or near the round window membrane via a microinjection device. In yet other embodiments, the otic gel formulation is applied within the tympanic membrane. In some embodiments, the otic gel formulation is applied onto the tympanic membrane. In yet other embodiments, the otic gel formulation is applied to the surface or interior of the ear canal.

  In a more specific embodiment, any pharmaceutical composition or device described herein is a multiparticulate ear sensation in a liquid matrix (eg, a liquid composition for intratympanic injection, or an ear drop). Contains cell regulators. In certain embodiments, any pharmaceutical composition described herein comprises a multiparticulate ear sensory cell modulator in a solid matrix.

Controlled Release Formulations In general, controlled release drug formulations provide controlled release of the drug with respect to the site of release and release time in the body. As described herein, controlled release includes immediate release, timed release, sustained release, sustained release, variable release, pulsed release, bimodal release. Many advantages are gained by controlled release. First, the controlled release of pharmaceuticals reduces the number of doses, thereby minimizing repeated treatments. Second, controlled release treatment makes drug utilization more effective and reduces compounds remaining as a residue. Third, controlled release provides the potential for local drug delivery by placing the delivery device or formulation at the disease site. Furthermore, with controlled release, the use of a single dosage unit gives the opportunity to administer and release two or more different drugs, each with a unique release profile, or the same drug at different rates or different durations. An opportunity to release in time is given.

  Accordingly, one aspect of the embodiments disclosed herein provides an ear-accepted controlled release otic sensory cell modulator or device for treating autoimmune and / or inflammatory diseases. It is to be. Embodiments of controlled release of the compositions and / or formulations and / or devices disclosed herein include, but are not limited to, excipients, agents that are acceptable for use in the inner ear or other ear structures Or it is given by various drugs including substances. Merely by way of example, such excipients, agents or materials may be an ear-acceptable polymer, an ear-acceptable thickener, an ear-acceptable gel, an ear-acceptable paint, an ear-acceptable. Foam, ear-acceptable xerogel, ear-acceptable microparticles or microspheres, ear-acceptable hydrogel, ear-acceptable spongy material, ear-acceptable chemoradiotherapy gel, ear Include an acceptable solvent release gel, an ear acceptable liposome, an ear acceptable nanocapsule or nanosphere, an ear acceptable thermoreversible gel, or a combination thereof.

Ear-acceptable gels Gels, sometimes called jelly, are defined in various ways. For example, the US Pharmacopeia defines a gel as a semi-solid tissue consisting of either a suspension of small inorganic particles or a large organic molecule with a liquid in it. The gel includes a single phase structure or a two-phase structure. Single-phase gels consist of organic polymers that are uniformly distributed throughout the liquid in a manner that there is no apparent boundary between the dispersed polymer and the liquid. Some single phase gels are prepared from synthetic polymers (eg, carbomers) or natural rubber (eg, tragacanth). In some embodiments, single phase gels are typically water tissue, but may also be made using alcohol and oil. A biphasic gel consists of a network of small discrete particles.

  Gels can also be classified as hydrophobic or hydrophilic. In certain embodiments, the hydrophobic gel substrate comprises liquid paraffin using polyethylene, or fatty oil gelled with colloidal silica, or aluminum or zinc soap. In contrast, hydrophobic gel substrates are typically water, glycerol, or gelled with a suitable gelling agent (eg, tragacanth, starch, cellulose derivatives, carboxyvinyl polymers, and aluminum magnesium silicate). Consists of propylene glycol. In certain embodiments, the rheology of the compositions or devices disclosed herein is pseudoplastic, plastic, thixotropic, or dilatant.

  In one embodiment, the otic acceptable viscosity-enhanced formulations described herein are not liquid at room temperature. In certain embodiments, the increased viscosity formulation is characterized by a phase transition between room temperature and body temperature (including severe fever, including fever individuals up to about 42 ° C.). . In some embodiments, the phase transition is 1 ° C. below body temperature, 2 ° C. below body temperature, 3 ° C. below body temperature, 4 ° C. below body temperature, and 6 ° C. below body temperature. Occurs at temperatures 8 ° C below body temperature or 10 ° C below body temperature. In some embodiments, the phase transition occurs at a temperature about 15 ° C. below body temperature, about 20 ° C. below body temperature, or about 25 ° C. below body temperature. In certain embodiments, the gelation temperature (Tgel) of the formulations described herein is about 20 ° C, about 25 ° C, or about 30 ° C. In certain embodiments, the gelation temperature (Tgel) of the formulations described herein is about 35 ° C, or about 40 ° C. In one embodiment, administration of any formulation described herein at about body temperature reduces or eliminates the dizziness associated with intratympanic administration of an otic formulation. Included in the definition of body temperature is the body temperature of an unhealthy individual, including healthy individuals or individuals with fever (up to 42 ° C.). In some embodiments, a pharmaceutical composition or device described herein is liquid at about room temperature and is administered at or near room temperature to reduce or ameliorate side effects such as, for example, dizziness .

  A polymer composed of polyoxypropylene and polyoxyethylene forms a thermoreversible gel when incorporated into an aqueous solution. These polymers have the ability to change from a liquid state to a gel state at temperatures close to body temperature, thus making it possible to apply useful formulations to the targeted ear structure. The phase transition from the liquid state to the gel state varies depending on the polymer concentration and the components in the solution.

  Poloxamer 407 (PF-127) is a nonionic surfactant composed of a polyoxyethylene-polyoxypropylene copolymer. Other poloxamers include 188 (F-68 grade), 237 (F-87 grade), and 338 (F-108 grade). The poloxamer aqueous solution is stable in the presence of acid, alkali and metal ions. PF-127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106P70E106 and an average molecular weight of 13,000. The polymer can be further purified by suitable methods that increase the gelability of the polymer. The polymer contains about 70% ethylene oxide that provides hydrophilicity. This polymer is one of a series of poloxamer ABA block copolymers, whose members have a common chemical formula shown in Chemical Formula 1 below.

PF-127 is of particular interest because when heated to body temperature, this concentrated solution of copolymer (> 20% w / w) converts from a clear solution of low viscosity to a solid gel. This phenomenon therefore suggests that the gel preparation forms a semi-solid structure and a sustained release depot when placed in contact with the body. Furthermore, PF-127 has good solubility and low toxicity and is therefore considered a good vehicle for drug delivery systems.

  In an alternative embodiment, the thermal gel is a PEG-PLGA-PEG triblock copolymer (Jeong etal, Nature (1997), 388: 860-2; Jeong etal, J. Control. Release (2000), 63: 155- 63; Jeong etal, Adv. Drug Delivery Rev. (2002), 54: 37-51)). The polymer exhibits sol-gel behavior over concentrations from about 5% w / w to about 40% w / w. Depending on this desired property, the lactide / glycolide molar ratio in the PLGA copolymer ranges from about 1: 1 to about 20: 1. The resulting copolymer is soluble in water and is a free flowing liquid at room temperature, but forms a hydrogel at body temperature. A commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 from Boehringer Ingelheim. This material is composed of a PGLA copolymer of 50:50 poly (DL-lactide-co-glycolide), 10% w / w of PEG and has a molecular weight of about 6000.

  ReGel® is a low molecular weight type biodegradable block copolymer having reversible thermal gelation properties as described in U.S. Patent Nos. 6,004,573, 6,117,949, 6,201,072, and 6,287,588. Is a trademark of MacroMed Incorporated. It also includes biodegradable polymeric pharmaceutical carriers disclosed in pending US patent application series Nos. 09 / 906,041, 09 / 559,799 and 10 / 919,603. The biodegradable drug carrier comprises an ABA type or BAB type triblock copolymer or mixtures thereof, the A block comprises a relatively hydrophobic, biodegradable polyester or poly (orthoester), and a B block Is relatively hydrophilic and contains polyethylene glycol (PEG), the copolymer has a hydrophobic content of 50.1-83 wt%, a hydrophilic content of 17-49.9 wt%, and finally The molecular weight of the block copolymer is 2000 to 8000 daltons. This drug carrier is water soluble at temperatures below normal mammalian body temperature and, when subjected to reversible thermal gelation, exists as a gel at a temperature equal to the physiological body temperature of the mammal. Biodegradable hydrophobic A polymer blocks include polyesters or poly (orthoesters), where polyesters are D, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid , L-lactic acid, glycolide, glycolic acid, ε-caprolactone, ε-hydroxyhexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acid, malic acid, and copolymers thereof And an average molecular weight of about 600 to 3000 daltons. The hydrophilic B block segment is preferably polyethylene glycol (PEG) having an average molecular weight of about 500-2200 daltons.

  Additional biodegradable thermoplastic polyesters include AtriGel® (obtained from Atrix Laboratories, Inc.) and / or, for example, US Pat. Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; No. 5,990,194; in which suitable biodegradable thermoplastic polyesters are disclosed as thermoplastic polymers. Examples of suitable biodegradable thermoplastic polyesters include polylactide, polyglycolide, polycaprolactone, copolymers thereof, terpolymers thereof, and any combination thereof. In some such embodiments, suitable biodegradable thermoplastic polyesters are polylactides, polyglycolides, copolymers thereof, terpolymers, or combinations thereof. In one embodiment, the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide) with carboxy end groups; from about 30% to about 40% by weight of the composition Present; and has an average molecular weight of about 23,000 to about 45,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide) without carboxy end groups; from about 40% to about 50% by weight of the composition. Present to weight percent; and has an average molecular weight of from about 15,000 to about 24,000. In further or alternative embodiments, the end group of poly (DL-lactide-co-glycolide) depends on the polymerization method and is either hydroxyl, carboxyl or ester. Polymers having hydroxyl and carboxyl groups at the ends are obtained by polycondensation of lactic acid or glycolic acid. When a cyclic lactide monomer or glycolide monomer is subjected to ring-opening polymerization with water, lactic acid or glycolic acid, a polymer having the same end group is obtained. However, ring opening polymerization of a cyclic monomer with a monosubstituted alcohol (eg, methanol, ethanol, or 1-dodecanol) provides a polymer having one hydroxyl end group and one ester end group. When the cyclic monomer is subjected to ring-opening polymerization with a diol such as 1,6-hexanediol or polyethylene glycol diol, a polymer having only hydroxyl groups at the end groups is obtained.

Because the thermoreversible gel polymer system dissolves more completely at low temperatures, the dissolution method involves adding the desired amount of polymer to the amount of water used at low temperatures. In general, after wetting the polymer by shaking, the mixture is covered with a lid and placed in a cold chamber or a constant temperature container at about 0-10 ° C. to dissolve the polymer. The mixture is stirred or shaken to dissolve the thermoreversible gel polymer more quickly.
Subsequently, ear sensory cell modulators and various additives such as buffers, salts and preservatives are added and dissolved. In some examples, when insoluble in water, the ear sensory cell modulator and / or other pharmaceutically active agent is suspended. The pH is adjusted by adding an appropriate buffer. By incorporating a round window membrane mucoadhesive carbomer, such as Carbopol® 934P, into the composition in any way, the mucoadhesive properties of the round window membrane are imparted to the thermoreversible gel (Majithiya et.al, AAPS Pharm Sci Tech (2006), 7 (3), p.E1; EP0551626, both of which are hereby incorporated by reference for such disclosure).

  In one embodiment, there is an ear acceptable pharmaceutical gel formulation that does not require the use of added thickeners. Such gel formulations incorporate at least one pharmaceutically acceptable buffer. One embodiment is a gel formulation comprising an ear sensory cell modulator and a pharmaceutically acceptable buffer. In another embodiment, the pharmaceutically acceptable excipient or carrier is a gelling agent.

  In other embodiments, the pharmaceutical formulation of useful ear-acceptable otic sensory cell modulators also includes one or more pH adjusters or buffers to provide the appropriate pH to the endolymph or perilymph. Yes. Suitable pH adjusting agents or buffers include, but are not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. Can be mentioned. Such pH adjusting agents and buffers may cause the pH of the composition to be between about 5 and about 9, in some embodiments between about 6.5 and about 7.5, and in yet other embodiments. It is included in an amount necessary to maintain a pH of about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5. In one embodiment, when one or more buffers are utilized in a formulation of the present disclosure, one or more buffers may be combined with, for example, a pharmaceutically acceptable vehicle and included in the final formulation. For example, in an amount ranging from about 0.1% to about 20%, from about 0.5% to about 10%. In certain embodiments of the present disclosure, the amount of buffer included in the gel formulation is such that the pH of the gel formulation does not interfere with the natural buffer system of the inner ear or middle ear, or the native or perilymph natural buffer. The amount does not interfere with the pH; this amount depends on where in the cochlea the ear sensory cell modulator formulation is targeted. In some embodiments, a buffer solution at a concentration from about 10 μm to about 200 mM is present in the gel formulation. In certain embodiments, a concentration of buffer from about 5 mM to about 200 mM is present. In certain embodiments, a buffer solution at a concentration from about 20 mM to about 100 mM is present. In one embodiment, the buffer is a buffer such as acetate or citrate that is slightly acidic pH. In one embodiment, the buffer is a sodium acetate buffer having a pH of about 4.5 to about 6.5. In one embodiment, the buffer is a sodium citrate buffer having a pH of about 5.0 to about 8.0, or about 5.5 to about 7.0.

  In an alternative embodiment, the buffer used is tris (hydroxymethyl) aminomethane, bicarbonate, carbonate or phosphate at a slightly basic pH. In one embodiment, the buffer is a sodium bicarbonate buffer having a pH of about 6.5 to about 8.5, or about 7.0 to about 8.0. In another embodiment, the buffer is a dibasic sodium phosphate buffer having a pH of about 6.0 to about 9.0.

Also described herein is a controlled release formulation or device comprising an otic sensory cell modulator and a thickener. Suitable thickeners include, by way of example only, gelling agents and suspensions. In one embodiment, the increased viscosity formulation does not include a buffer.
In other embodiments, the increased viscosity formulation comprises a pharmaceutically acceptable buffer.
If necessary, sodium chloride or other isotonic agents are used in any manner to adjust isotonicity.

  By way of example only, ear-acceptable viscosity agents include hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate. Other viscosity enhancers that are compatible with the targeted ear structure include, but are not limited to, acacia (gum arabic) and agar, magnesium aluminum silicate, sodium alginate, sodium stearate, hibermata, bentonite, carbomer, carrageenan , Carbopol, xanthan, cellulose, microcrystalline cellulose (MCC), seratonia, chitin, carboxymethylated chitosan, tsunomata, dextrose, fur cerelan, gelatin, gacha gum, guar gum, hectorite, lactose, sucrose, bacugadextrin , Mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, araya gum, xanthan gum, gum tragacanth, ethyl cellulose, ethyl hydroxy Cylcellulose, ethylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, poly (hydroxy-ethyl methacrylate, oxypolygelatin, pectin, polygelin, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly (methoxyethyl methacrylate, poly (methoxyethoxyethyl methacrylate), hydroxypropylcellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethylcellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone) ), Splenda®, (dextrose, bacugadextrin and sucralose), or combinations thereof. In embodiments, the excipient that increases viscosity is a combination of MCC and CMC, hi another embodiment, the thickener is a combination of carboxymethylated chitosan or chitin and alginate. And the combination of an alginate and an otic sensory cell modulator disclosed herein acts as a controlled release formulation to inhibit diffusion of the otic sensory cell modulator from the formulation, and in any manner, A combination of carboxymethylated chitosan and alginate is used to help increase the permeability of the otic sensory cell modulator through the round window membrane.

  Some embodiments include a formulation with increased viscosity comprising from about 0.1 mM to about 100 mM otic sensory cell modulator, a pharmaceutically acceptable viscosity agent, and water for injection. The concentration of the viscous agent is sufficient to provide a final viscosity of from about 100 to about 100,000 cP to the increased viscosity formulation. In certain embodiments, the viscosity of the gel is about 100 to about 50,000 cP, about 100 cP to about 1,000 cP, about 500 cP to about 1500 cP, about 1000 cP to about 3000 cP, about 2000 cP to about 8,000 cP, about 4,000 cP to about 50,000. cP, in the range of about 10,000 cP to about 500,000 cP, about 15,000 cP to about 1,000,000 cP. In other embodiments, if a higher viscosity medium is desired, the biocompatible gel is at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 70% by weight. , Including at least about 75% by weight, or at least about 80% by weight of the ear sensory cell modulator. For highly concentrated samples, the biocompatible viscosity-enhanced formulation is at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, At least about 75 wt%, at least about 85 wt%, at least about 90 wt%, or at least about 95 wt%, or more.

  In some embodiments, the viscosity of the gel formulations disclosed herein is measured by any described means. For example, in some embodiments, LVDV-II + CP Cone PlateViscometer and Cone Spindle CPE-40 are used to calculate the viscosity of the gel formulations described herein. In other embodiments, a Brookfield (spindle and cup) viscometer is used to calculate the viscosity of the gel formulations described herein. In some embodiments, the viscosity ranges referred to herein are measured at room temperature. In other embodiments, the viscosity ranges referred to herein are measured at body temperature (eg, average body temperature of a healthy human).

  In one embodiment, the pharmaceutically acceptable viscosity-enhanced ear-acceptable formulation comprises at least one ear sensory cell modulator and at least one gelling agent. Suitable gelling agents for use in preparing a gel formulation include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, Methylcellulose), guar gum, xanthan gum, locust bean gum, alginate (eg, alginic acid), silicate, starch, tragacanth, carboxyvinyl polymer, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropyl methylcellulose (Methocel®) is used as the gelling agent. Also, in certain embodiments, the thickeners described herein are utilized as gelling agents for the gel formulations disclosed herein.

In some embodiments, the otic treatment agents described herein are formulated as an ear acceptable paint. As used herein, a paint (also known as a film-forming element) is a solvent, monomer or polymer, active agent, and optionally one or more pharmaceutically acceptable excipients. , And so on. After application to the tissue, the solvent evaporates, leaving behind a thin coating of monomer or polymer and active agent. The coating protects the active agent and keeps it immobilized at the site of application. This reduces the amount of active agent lost and correspondingly increases the amount delivered to the subject. As a non-limiting example, the paint includes a collodion (eg, elastic collodion, USP), and a solution containing a saccharide siloxane copolymer and a crosslinker.
Collodion is an ethyl ether / ethanol solution containing piroxylin (nitrocellulose). After application, the ethyl ether / ethanol solution evaporates leaving a thin film of piroxylin. In a solution containing a saccharide siloxane copolymer, the saccharide siloxane copolymer forms a coating after initiating crosslinking of the saccharide siloxane copolymer by evaporation of the solvent.
For further disclosure regarding paints, see Remigton ("The Science and Practice of Pharmacy" incorporated herein by reference). The paint envisioned for use in the specification of the present disclosure is flexible so as not to interfere with the propagation of the compression wave through the ear. Further, the paint can be applied as a liquid (ie, solution, suspension or emulsion), semi-solid (ie, gel, foam, paste or jelly), or aerosol.

  In some embodiments, the otic therapeutic agent described herein is formulated as a controlled release foam. Examples of suitable foam carriers used in the compositions described herein include, but are not limited to, alginate and its derivatives, carboxymethylcellulose and its derivatives, collagen, polysaccharides, such as dextran, dextran Stabilized with modified starch, cellulose and their derivatives, agar and polyacrylamide, such as starches having derivatives, pectin, starch, additional carboxyl and / or carboxamide groups and / or having hydrophilic side chains Derivatives thereof such as agar, polyethylene oxide, glycol methacrylate, gelatin, gums (such as xanthan, guar, karaya, gellan, arabic, tragacanth, and locust bean gum), or combinations thereof. Also suitable are salts of the aforementioned carriers (eg sodium alginate). The formulation optionally further comprises a foaming agent that promotes foam formation, which includes a surfactant or an external enhancer. Examples of suitable foaming agents include cetrimide, lecithin, soap, silicone and the like. Commercially available surfactants such as Tween® are also suitable.

  In some embodiments, other gel formulations may be useful depending on the particular otic sensory cell modulator, other pharmaceutical agent or excipient / additive used, and are thus considered within the scope of this disclosure. . For example, other commercially available glycerin-based gels, glycerin-derived compounds, conjugated or cross-linked gels, matrices, hydrogels, and polymers include gelatin and its derivatives, alginate, alginate-based gels, and various Like natural and synthetic hydrogels and compounds derived from hydrogels, all are expected to be useful in the otic sensory cell modulator formulations described herein. In some embodiments, the ear-acceptable gel includes, but is not limited to, alginate hydrogel SAF®-gel (ConvaTec, Princeton, NJ), Duoderm® Hydroactive Gel (ConvaTec), Nu-gel® (Johnson & Johnson Medical, Arlington, Tex.); Carrasyn® (V) Acemannan Hydrogel (Carrington laboratories, Inc., Irving, Tex.); Glycerin gel The agents Elta® Hydrogel (Swiss-American Products, Inc., Dallas, Tex.), And KY® Sterile (Johnson & Johnson). In a further embodiment, the biodegradable biocompatible gel also corresponds to the compound present in the ear acceptable formulation disclosed and described herein.

  In some formulations developed for administration to mammals, and for compositions formulated for administration to humans, an ear-acceptable gel substantially reduces the total weight of the composition. is occupying. In other embodiments, the ear acceptable gel accounts for about 98%, or even about 99% of the weight of the composition. This is desirable when a substantially liquid free or substantially viscous formulation is required. In a further embodiment, if a slightly lower viscosity or slightly more fluid ear acceptable pharmaceutical gel formulation is desired, the biocompatible gel portion of the formulation is at least about 50% by weight of the compound, at least It comprises about 60%, at least about 70%, or at least about 80%, or 90% by weight. All intermediate numbers within these ranges are assumed to be within the scope of this disclosure, and in some alternative embodiments, more fluid (and hence less viscous) ears. An acceptable gel composition is formulated, for example, the gel or matrix elements of the mixture account for no more than about 50%, no more than about 40%, no more than about 30% by weight of the composition, Or about 15% by weight or less than about 20% by weight of the composition.

  In one embodiment, the at least one ear sensory cell modulator is included in a pharmaceutically acceptable high viscosity formulation, wherein the formulation further comprises at least one suspension, Helps to give controlled release properties to the formulation. In some embodiments, the suspension also serves to increase the viscosity of the ear-acceptable otic sensory cell modulating agent formulations and compositions.

  Suspensions include polyvinylpyrrolidone (eg, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630)), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose (hypromellose) , Hydroxymethylcellulose acetate stearate, polysorbate 80, hydroxyethylcellulose, sodium alginate), gums (eg tragacanth gum, gum arabic, guar gum, xanthan gum including xanthan gum), sugar, cellulose compounds (eg sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose) , Hydroxypropyl methylcellulose, hydro Shi ethylcellulose), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like. In some embodiments, useful aqueous suspensions contain one or more polymers as a suspension. Useful polymers include water soluble polymers (eg, cellulose polymers such as hydroxypropylmethylcellulose) and water insoluble polymers such as crosslinked carboxyl-containing polymers.

  In one embodiment, the present disclosure provides an ear-acceptable gel-like composition having a therapeutically effective amount of an ear sensory cell modulator in a hydroxyethyl cellulose gel. Hydroxyethyl cellulose (HEC) is reconstituted in water or an aqueous buffer to give the desired viscosity (generally about 200 cps to about 30,000 cps, corresponding to about 0.2 to about 10% HEC). Obtained as a dry powder. In one embodiment, the concentration of HEC is between about 1% to about 15%, about 1% to about 2%, or about 1.5% to about 2%.

  In other embodiments, otic acceptable formulations, including gel formulations and viscosity-enhanced formulations, further include excipients, other drugs or pharmaceutical agents, carriers, adjuvants, such as preservatives, Stabilizers, wetting or emulsifying agents, dissolution accelerators, salts, solubilizers, antifoaming agents, antioxidants, dispersing agents, wetting agents, surfactants and combinations thereof.

Ear-acceptable chemoradiotherapy gel In other embodiments, the gel is a chemoradiotherapy gel, administered to or near the targeted ear structure, actinic radiation (or ultraviolet, visible or infrared). After use, the desired gel properties are formed. By way of example only, fiber optics are used to deliver actinic radiation to form the desired gel properties.
In some embodiments, the fiber optics and gel administration device form an integral unit. In other embodiments, the fiber optics and gel administration device are provided separately.

Ear-acceptable solvent-releasing gel In some embodiments, the gel is a solvent-releasing gel that forms the desired gel properties after being administered to or near the targeted ear structure. That is, the solvent in the injected formulation diffuses outside the gel to form a gel with the desired gel properties. For example, a formulation comprising sucrose acetate isobutyrate, a pharmaceutically acceptable solvent, one or more additives and an otic sensory cell modulator are administered at or near the round window cell membrane; external to the injected formulation The diffusion of the solvent provides a depot with the desired gel properties. For example, if the solvent diffuses rapidly from the injected formulation, the use of a water soluble solvent provides a high viscosity depot.
On the other hand, the use of a hydrophobic solvent (eg, benzyl benzoate) provides a low viscosity depot. One example of an ear-acceptable solvent release gel formulation is the SABER ™ Delivery System marketed by DURECT Corporation.

In situ spongy material acceptable to the ear The use of spongy material formed in situ in the inner ear or middle ear is also contemplated to be within the scope of this embodiment. In some embodiments, the spongy material is formed from hyaluronic acid or a derivative thereof. The spongy material is impregnated with the desired otic sensory cell modulator and provides controlled release of the otic sensory cell modulator into the middle ear or to the inner ear to provide controlled release of the otic sensory cell modulator. It is placed in contact with the round window membrane. In some embodiments, the spongy material is biodegradable.

Round window membrane mucoadhesive agents Also, within the scope of the embodiments, round window membrane mucoadhesive agents may be added with the otic sensory cell modulator formulations and compositions and devices disclosed herein. It is assumed that there is. The term “mucoadhesion” is used for substances that bind to a mucin layer of a biological membrane, such as, for example, a membrane outside a three-layer round window membrane. In order to function as a mucoadhesive polymer for round window membranes, this polymer is suitable for, for example, the surface of a highly mucous / mucosal tissue with significant anionic hydrophilicity and wettability with many hydrogen bond-forming groups. It has some general physicochemical characteristics such as properties or flexibility sufficient to penetrate the mucus network.

Round window membrane mucoadhesives used with ear-acceptable formulations include, but are not limited to, at least one soluble polyvinylpyrrolidone (PVP); a water-swellable but water-insoluble fibrous cross-linked carboxy Functionalized polymers; cross-linked poly (acrylic acid) (eg, Carbopol® 947P); carbomer homopolymer; carbomer copolymer; hydrophilic polysaccharide gum, maltodextrin, cross-linked alginate gum gel, And water dispersible polycarboxylated vinyl polymer, at least two particulate material elements selected from the group consisting of titanium dioxide, silicon dioxide and clay, or combinations thereof.
To enhance the interaction between the composition and the mucosal layer of the target ear element, the round window membrane mucoadhesive is optionally combined with an excipient that increases the acceptable viscosity of the ear, or Used alone. In one non-limiting example, the mucoadhesive is maltodextrin. In some embodiments, the mucoadhesive is alginate rubber. In use, the mucoadhesive properties of the round window membrane imparted to the composition are determined by the effective amount of the otic sensory cell modulating agent, for example, the amount that coats the mucosa on the mucosal layer of the round window membrane or cochlear window crest. Deliverable and then the composition is at a sufficient level to reach the affected area, such as the vestibular structure of the inner ear and / or the cochlear structure (just an example). In use, the mucoadhesive properties of the compositions presented herein are determined, and this information (along with other teachings contained herein) is used to determine the appropriate amount. One method for determining sufficient mucoadhesive properties includes, but is not limited to, monitoring changes in the interaction of the composition with the mucosal layer, when there are mucoadhesive excipients. Measuring the change in the location or retention time of the composition with and without.

  Mucoadhesives are described, for example, in U.S. Pat. Which is incorporated herein by reference for all disclosures.

  In another non-limiting example, the mucoadhesive is a component of at least two particles selected from, for example, titanium dioxide, silicon dioxide, and clay, and the composition is further diluted with any liquid prior to administration. And the level (amount) of silicon dioxide, if present, is from about 3% to about 15% of the weight of the composition. Silicon dioxide, when present, includes atomized silicon dioxide, precipitated silicon dioxide, coacervated silicon dioxide, gel silicon dioxide and mixtures thereof. Clays, when present, include kaolin minerals, serpentine minerals, smectites, illites or mixtures thereof. For example, the clay includes laponite, bentonite, hectorite, saponite, montmorillonite or mixtures thereof.

In one non-limiting example, the round window membrane mucoadhesive agent is maltodextrin.
Maltodextrins are carbohydrates produced by hydrolysis of starch obtained by selecting from corn, potato, wheat or other plant products. Maltodextrins are used alone or in combination with other round window membrane mucoadhesives to impart mucoadhesive properties to the compositions described herein. In one embodiment, the combination of maltodextrin and carbopol polymer is used to enhance the mucoadhesive properties of the round window membrane of the compositions or devices described herein.

  In another embodiment, the round window membrane mucoadhesive agent is an alkyl-glycoside and / or a monosaccharide alkyl ester. As used herein, “alkyl-glycoside” means a compound having any hydrophilic monosaccharide (eg, sucrose, maltose or glucose) attached to a hydrophobic alkyl. In some embodiments, the round window membrane mucoadhesive agent comprises an alkyl-glycoside to a hydrophobic alkyl (e.g., an alkyl comprising about 6-25 carbon atoms), an amide bond, an amine bond, a carbamate bond, Alkyl-glycosides having sugars linked by ether bonds, thioether bonds, ester bonds, thioester bonds, glycoside bonds, thioglycoside bonds, and / or ureido bonds. In some embodiments, the round window membrane mucoadhesive agent is hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, Α-D-maltoside or β-D-maltoside of heptadecyl- and octadecyl; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl- , Heptadecyl-, and octadecyl α-D-glucoside or β-D-glucoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl -, Heptadecyl-, and octadecyl α-D-scroside or β-D-scroside; hexyl-, heptyl-, Β-D-thiomaltoside of octyl-, dodecyl-, tridecyl-, and tetradecyl; maltose glycoside of dodecyl group; α-D-glucopyranoside or β-D-glucopyranoside of heptyl- or octyl-1-thio; alkylthiosucrose; alkyl Maltotrioside; long-chain aliphatic carbonate of sucrose β-amino-alkyl ether; derivative of palatinose or isomaltamine bound to the alkyl chain by an amide bond, and derivative of isomaltamine bound to the alkyl chain by urea And a long chain aliphatic carbonate ureido of sucrose β-amino-alkyl ether and a long chain aliphatic carbonate amide of sucrose β-amino-alkyl ether. In some embodiments, the round window membrane mucoadhesive agent comprises an alkyl glycoside having a glycosidic linkage to an alkyl chain of 9 to 16 carbon atoms (e.g., nonyl-, decyl-, dodecyl-, and tetradecyl scrosides). Nonyl-, decyl-, dodecyl-, and tetradecyl glucoside; and nonyl-, decyl-, dodecyl-, and tetradecyl maltoside), alkyl-, which is maltose, sucrose, glucose, or a combination thereof It is a glycoside. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl glycoside is dodecyl maltoside and tetradecyl maltoside.

  In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl-glycoside is a disaccharide having at least one glucose. In some embodiments, the ear-acceptable penetration enhancer is α-D-glucopyranosyl-β-glucopyranoside, n-dodecyl-4-O-α-D-glucopyranosyl-β-glucopyranoside, and / or n- A surfactant having tetradecyl-4-O-α-D-glucopyranosyl-β-glucopyranoside. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl-glycoside has a critical micelle concentration (CMC) of less than about 1 mM in pure water or in aqueous solution. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside wherein an oxygen atom in the alkyl-glycoside is replaced with a sulfur atom. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl glycoside is a beta anomer. In some embodiments, the round window membrane mucoadhesive agent comprises an alkyl glycoside of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% of the beta anomer. , 99%, 99.1%, 99.5%, or 99.9% of alkyl-glycosides.

Ear-accepted controlled release particles The ear sensory cell modulators described herein are controlled release particles, lipid complexes, liposomes, nano-particles that facilitate or facilitate localized delivery of an ear sensory cell modulator. It is incorporated in any way into particles, microparticles, microspheres, coacervates, nanocapsules or other drugs. In some embodiments, a single high viscosity formulation with at least one ear sensory cell modulator is used, while in other embodiments, two or more with at least one ear sensory cell modulator are present. A pharmaceutical formulation with a mixture of separate high viscosity formulations is used. In some embodiments, combinations of sols, gels and / or biocompatible matrices are also used to provide controlled release otic sensory cell modulator compositions or formulations. In certain embodiments, a controlled release ear sensory cell modulator formulation or composition is cross-linked by one or more agents to alter or improve the properties of the composition.

  Examples of microspheres related to the pharmaceutical formulations described herein include: Luzzi, LA, J. Pharm. Psy. 59: 1367 (1970); US Pat. No. 4,530,840; Lewis, DH, “Controlled Release of Bioactive Agents from Lactides / Glycolide Polymers” in Biodegradable Polymers as Drug Delivery Systems, Chasin, M. and Langer, R., eds., Marcel Decker (1990); US Pat. No. 4,675,189; Beck et al, “ Poly (lactic acid) and Poly (lactic acid-co-glycolic acid) Contraceptive Delivery Systems, ”in Long Acting Steroid Contraception, Mishell, DR, ed., Raven Press (1983); US Pat. No. 4,758,435; US Pat. No. 3,773,919 No .; U.S. Pat. No. 4,474,572. (Disclosed) examples of protein therapeutics formulated as microspheres include: US Pat. No. 6,458,387; US Pat. No. 6,268,053; US Pat. No. 6,090,925; US Pat. No. 5,981,719: and US Pat. No. 5,578,709 Are hereby incorporated by reference for their disclosure.

Irregularly shaped microspheres are possible, but the microspheres usually have a spherical shape. Microspheres can vary in size in the range from submicron to 1000 microns in diameter. Microspheres suitable for use with the ear acceptable formulations described herein are submicron to 250 microns in diameter and can be administered by injection using a standard gauge needle. Ear-acceptable microspheres are prepared by any method that produces microspheres in an acceptable size range for use in injectable compositions. Infusion is accomplished in any manner using a standard gauge needle used for administration of the liquid composition.

Suitable examples of polymeric matrix materials for use in the ear-controlled controlled release particulate material of the present disclosure include poly (glycolic acid) and poly-d, l-lactic acid, poly-1-lactic acid, the aforementioned copolymers , Poly (aliphatic carboxylic acid), copolyoxalate, polycaprolactone, polydioxanone, poly (orthocarbonate), poly (acetal), poly (lactic caprolactone), polyorthoester, poly (caprolactone glycolate), polydioxonene , Polyanhydrides, polyphosphazenes, and natural polymers containing waxes such as albumin, casein, glycerin mono- and distearate, and the like. A variety of commercially available poly (lactide-co-glycolide) materials (PLGA) are used in selection of the methods described herein.
For example, poly (d, l-lactide-co-glycolic acid) is commercially available as RESOMER RG 503 from Boehringer-Ingelheim. The product is a composition of 50% lactide lactide and 50% glycolide. These copolymers are available in a wide range of ratios of molecular weight and lactic acid to glycolic acid. One embodiment includes the use of the polymer poly (d, l-lactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers includes the range of about 95: 5 to about 50:50.

  The molecular weight of the polymeric matrix material is important to some extent. The molecular weight should be high enough so that it forms a good polymer coating, i.e. the polymer is a good film-forming material. Usually a good molecular weight is in the range of 5,000 to 500,000 daltons. The molecular weight of the polymer is also important from the viewpoint that the molecular weight affects the biodegradation rate of the polymer. Due to the diffusion mechanism of drug release, the polymer should remain unchanged until all of the drug is released from the microsphere and degraded. The drug is also released from the microspheres as a polymeric excipient, bioerodes. By appropriate selection of the polymeric material, the microsphere formulation is formed such that the produced microspheres exhibit both diffusive and biodegradable properties. This helps to provide a multiphase release pattern.

  Various methods are known for encapsulating compounds in microspheres. In these methods, the otic sensory cell modulator is usually dispersed in a solvent containing a wall-forming material using a stirrer, agitator, or other kinetic mixing technique. Or it is emulsified. The solvent is then removed from the microsphere, after which the microsphere product is obtained.

In one embodiment, the controlled release otic sensory cell modulator formulation is made via incorporation of an otic sensory cell modulator and / or other pharmaceuticals into an ethylene vinyl acetate copolymer matrix. (See US Pat. No. 6,083,534, which is incorporated herein for that disclosure).
In another embodiment, the ear sensory cell modulating agent is incorporated into poly (lactic acid-glycolic acid) or poly-L-lactic acid microspheres (Id.). In yet another embodiment, the ear sensory cell modulator is encapsulated in alginate microspheres. (See US Pat. No. 6,036,978, incorporated herein for that disclosure). A biocompatible methacrylic acid-based polymer for encapsulating an otic sensory cell modulator compound or composition is optionally used in the formulations and methods disclosed herein. A wide range of methacrylic acid-based polymer systems are available on the market, such as the EUDRAGIT polymer available from Evonik. One useful aspect of methacrylic acid polymers is that the properties of the formulation are altered by incorporating various copolymers. For example, poly (acrylic acid-co-methyl methacrylic acid) fine particles have a carboxylic acid group in poly (acrylic acid) as mucin (Park et al, Pharm. Res. (1987) 4 (6): 457-464). The formation of hydrogen bonds exerts enhanced mucoadhesive properties. Variation in the ratio of acrylic acid to methyl methacrylic acid monomer helps to adjust the properties of the copolymer. Methacrylic acid-based microparticles have also been used in protein-based therapeutic formulations (Naha et al, Journal of Microencapsulation 04 February, 2008 (online publication)). In one embodiment, the otic acceptable high viscosity formulation described herein comprises an ear sensory cell modulator microsphere, wherein the microsphere is formed from a methacrylic acid polymer or copolymer. In a further embodiment, the high viscosity formulation described herein comprises otic sensory cell modulator microspheres, wherein the microspheres are mucoadhesive. Other controlled release systems, including incorporation or deposition of polymeric materials or matrices into solid or hollow spheres containing otic sensory cell modulators, are also explicitly incorporated within the embodiments disclosed herein. ing. The type of controlled release system that can be utilized without significant loss of activity of the ear sensory cell modulator is determined using the teachings, examples, and principles disclosed herein.

  An example of a conventional microencapsulation process for drug preparation is shown in US Pat. No. 3,737,337, which is incorporated herein by reference for its disclosure. The otic sensory cell modulator material to be encapsulated or implanted is dissolved or dissolved in an organic solution (phase A) of the polymer using a conventional mixer including a vibrator and a high speed stirrer (in preparation for dispersion). Distributed. The dispersion of the phase (A) containing the core material in solution or suspension is carried out in the aqueous phase (B), again using a conventional mixer such as a high speed mixer, vibratory mixer, or spray nozzle. In some cases, the microsphere particle size is determined not only by the concentration of phase (A), but also by the emulsion or microsphere size. Using conventional techniques for microencapsulation of otic sensory cell modulators, active agents and polymers are often mixed by stirring, rocking, shaking, or other kinetic mixing techniques for a relatively long time. When the containing solvent is emulsified or dispersed in an immiscible solution, microspheres are formed.

  Conventional methods for making microspheres are described in US Pat. No. 4,389,330 and US Pat. No. 4,530,840, which are hereby incorporated by reference for their disclosure. The desired otic sensory cell modulator is dissolved or dispersed in a suitable solvent. The polymer matrix material is added to the medium containing the drug in an amount relative to the active ingredient that gives the product loaded with the active drug as desired. Optionally, all components of the ear sensory cell modulator microsphere product can be mixed together in a solvent medium. Suitable solvents for drugs and polymer matrix materials include organic solvents such as acetone, halogenated hydrocarbons such as chloroform, homologues such as methylene chloride, aromatic hydrocarbon compounds, halogenated aromatic hydrocarbon compounds. , Organic solvents such as cyclic ether, alcohol and ethyl acetate.

The mixture of components in the solvent is emulsified in the continuous phase medium (the continuous phase medium is such that a dispersion of microdroplets containing the indicated components is formed in the continuous phase medium). Of course, the continuous phase medium and the organic solvent must be immiscible, and the (continuous phase medium) contains water (optionally non-aqueous media such as xylene, toluene, synthetic oils, natural oils, etc.) Used). Surfactants are added to the continuous phase medium in any way to prevent the microspheres from agglomerating and to control the size of the solvent microdroplets in the emulsion. A preferred surfactant-dispersion medium combination is 1-10% by weight poly (vinyl alcohol) in a water mixture. The dispersion is formed by mechanical agitation of the mixed material. Emulsions can also be formed in any manner by adding small droplets of a material solution that forms the active agent wall to the continuous phase medium. The temperature during the formation of the emulsion is not particularly critical, but affects the size and nature of the microspheres and the solubility of the drug in the continuous phase. It is desirable that the continuous phase be as free of drug as possible. Further, depending on the solvent used and the continuous phase medium, the temperature should not be too low, otherwise the solvent and medium will solidify or the medium will be too sticky for practical purposes. On the other hand, if it is too high, the medium will evaporate or the fluid medium will not be maintained. Furthermore, the temperature of the medium should not be so high that the stability of certain drugs incorporated into the microspheres is adversely affected.
Thus, the dispersing step is performed at any temperature that maintains stable processing conditions, with the preferred temperature being about 15 ° C. to 60 ° C., depending on the drug and excipient chosen.

  The formed dispersion is a stable emulsion, from which the immiscible fluid of the organic solvent is partially selected and removed in the first step of the solvent removal step. The solvent is removed by common techniques such as heating, application of reduced pressure, or a combination of both. The temperature utilized to evaporate the solvent from the microdroplets is not critical, but should not be too high to degrade the otic sensory cell modulator used in the preparation of a given microparticle, and the walls It must not be so high that the solvent evaporates at such a rapid rate as to cause defects in the material forming the film. Usually, 5 to 75% of the solvent is removed in the first solvent removal step.

  After the first step, the dispersed microparticles in the solvent-immiscible fluid medium are separated from the fluid medium by any suitable separation method. Thus, for example, the fluid is decanted from the microsphere or the microsphere suspension is filtered. If desired, still other various combinations of separation techniques can be used.

  Following separation of the microspheres from the continuous phase medium, the remainder of the solvent in the microspheres is removed by extraction. At this stage, the microspheres are suspended in the same continuous phase medium used in the first step, with or without a surfactant, or in another liquid. The extraction medium removes the solvent from the microspheres but does not dissolve the microspheres. In any manner, during extraction, the extraction medium containing the dissolved solvent is removed and replaced with fresh extraction medium. This is best done on a continuous surface. The extraction media replenishment rate for a given process is variable and is determined when the process is being performed, so the exact limit of the rate should not be determined in advance. After most of the solvent has been removed from the microspheres, the microspheres are dried by exposure to air or other conventional drying techniques such as vacuum drying or drying through a desiccant. This step is effective in encapsulating otic sensory cell modulators, because up to 80% by weight, preferably up to 60% by weight of core loadings can be obtained.

  Alternatively, controlled release microspheres containing otic sensory cell modulators are prepared by use of a static mixer. Static or static mixers are equipped with conduits or tubes that receive many static mixed drugs. Static mixers provide homogeneous mixing in a relatively short length of conduit and in a relatively short time. With static mixers, fluid moves through the mixer rather than some parts of the mixer, such as blades, moving through the fluid.

  Static mixers are used in any way to form an emulsion. When using a static mixer to form an emulsion, the density and viscosity of the various solutions and phases to be mixed, the volume ratio of the phases, the interfacial tension between the phases, the parameters of the static mixer (conduit diameter, mixing element length Several factors determine the particle size of the emulsion, including the number of mixing elements), and the linear velocity through the static mixer. Temperature is variable because it affects density, viscosity, and interfacial tension. Variables to control are linear velocity, shear rate, and pressure drop per unit length of the static mixer.

  The organic and aqueous phases are combined to form microspheres containing otic sensory cell modulators using a static mixer process. The organic and aqueous phases are almost or substantially immiscible and the aqueous phase forms the continuous phase of the emulsion. The phase includes not only the polymer or polymer matrix material that forms the wall, but also the otic sensory cell modulator. The organic phase is prepared by dissolving the ear sensory cell modulator in an organic solvent or other suitable solvent, or by forming a dispersion or emulsion containing the ear sensory cell modulator. The organic and aqueous phases have microspheres containing otic sensory cell modulators that are pumped so that the two phases flow simultaneously through a static mixer, thereby encapsulating in a polymer matrix material An emulsion is formed. The organic and aqueous phases are pumped through a static mixer into a large volume of quench liquid to extract or remove the organic solvent. The organic solvent is removed from the microspheres in any manner while being washed or stirred in the quench solution. After the microspheres are washed in the quench solution, they are separated by a sieve and dried.

  In one embodiment, the microspheres are prepared using a static mixer. The process is not limited to the solvent extraction technique described above, and other encapsulation techniques are also used. For example, as an option, the process is used with a phase separation encapsulation technique. To do so, an organic phase is prepared having an ear sensory cell modulator suspended or dispersed in a polymer solution. The non-solvent second phase contains no solvent for the polymer and active agent. A preferred non-solvent type second phase is silicone oil. The organic phase and the non-solvent phase are pumped through a static mixer into a non-solvent quench solution such as heptane. Semi-solid particles are quenched for complete solidification and washing. Microencapsulation processes include spray drying, solvent evaporation, a combination of evaporation and extraction, and melt extrusion.

  In another embodiment, the microencapsulation process includes the use of a static mixer with a single solvent. This process is described in detail in US patent application Ser. No. 08 / 338,805, which is incorporated herein by reference for its disclosure. An alternative process involves the use of a static mixer with a co-solvent. In this step, a biodegradable microsphere with a biodegradable polymer linkage and an active pharmaceutical agent is prepared, which does not contain a halogenated hydrocarbon to dissolve both the drug and the polymer, and has at least two Contains a substantially non-toxic solvent mixture. A mixture of dissolved drug and solvent containing polymer is dispersed in an aqueous solution to form droplets. The resulting emulsion is then preferably added to an aqueous extraction medium containing at least one solvent in the mixture, whereby the extraction rate of each solvent is controlled and further contains a pharmaceutically active agent. Biodegradable microspheres are formed. The solubility of one solvent in water is substantially independent of the other, and the increased selectivity of the solvent has the advantage that this process requires less extraction medium, especially for solvents that are difficult to extract. is there.

  Nanoparticles are also contemplated for use with the otic sensory cell modulators described herein. A nanoparticle is a material structure with a size of about 100 nm or less. One use of nanoparticles in pharmaceutical compositions is the formation of suspensions because the interaction with the solvent on the particle surface is strong enough to overcome the density difference. Nanoparticle suspensions are sterilized because the nanoparticles are small enough to undergo sterile filtration (see, e.g., U.S. Patent No. 6,139,870, which is incorporated herein by reference for its disclosure). Is). The nanoparticles comprise at least one hydrophobic, water-insoluble, and water-dispersible polymer or copolymer emulsified in a surfactant, phospholipid, or fatty acid solution or water-soluble dispersion. The ear sensory cell modulating agent is introduced into the nanoparticles together with the polymer or copolymer in any way.

  Lipid nanocapsules as controlled release structures are also considered in this disclosure to penetrate the round window membrane and reach the inner and / or middle ear targets. Lipid nanocapsules include capric and caprylic neutral fat (Labrafac WL1349; avg.mw 512), soy lecithin (LIPOID® S75-3; 69% fozfatidylcholine and other phospholipids), It is formed by emulsifying a surfactant (eg, SOLUTOL HS15), polyethylene glycol 660 hydroxystearate, and free polyethylene glycol 660, such as NaCl and water. In order to obtain an oil emulsion in water, the mixture is stirred at room temperature. After heating gradually at a rate of 4 ° C./min under magnetic stirring, a short-term clearing occurs near 70 ° C. and a reverse phase (small droplets of water in oil) is obtained at 85 ° C. Then, between 85 ° C and 60 ° C, cooling and heating are performed for 3 cycles at a rate of 4 ° C / min, and rapidly diluted in cold water at a temperature close to 0 ° C, a suspension of nanocapsules Is generated. To encapsulate the ear sensory cell modulating agent, the agent is added in any manner just prior to dilution with cold water.

  The ear sensory cell modulator is introduced into the lipid nanoparticles by incubating for 90 minutes with an aqueous micellar solution of a drug active in the ear. The suspension is then vortexed every 15 minutes and then quenched in an ice-water bath for 1 minute.

  Suitable ear-acceptable surfactants are, by way of example only, cholic acid or taurocholic acid salts. Taurocholic acid is a complex formed from cholic acid and taurine, and is a sufficiently metabolizable sulfonic acid surfactant. Taurocholic acid, an analog of taurocholic acid, is a naturally occurring bile acid that is a complex of taurine and ursodeoxycholic acid (UDCA). Optionally, other naturally formed anionic surfactants (e.g., galactocerebroside sulfate), neutral surfactants (e.g., lactosylceramide) or zwitterionic surfactants (e.g., Sphingomyelin, fozfatidylcholine, palmitoylcarnitine) are used to prepare nanoparticles.

  By way of example, the ear-acceptable phospholipids are selected from, for example, natural, synthetic, or semi-synthetic phospholipids; ), Etc., and phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, dipalmitoylphosphatidylcholine, dipalmitoylglycerophosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine and phosphatidic acid Or mixtures thereof are used in particular.

  Fatty acids for use with ear-acceptable formulations include, for example, lauric acid, mysristic acid, palmitic acid, stearic acid, isostearic acid, aragdic acid, behenic acid, oleic acid, myristoleic acid, palmitoleic acid , Linoleic acid, α-linoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, and the like.

  Suitable auris-acceptable surfactants are selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers include nonionic and ionic surfactants. Two or more surface modifiers may be used in combination.

Representative examples of surfactants acceptable to the ear include cetylpyridinium chloride, gelatin, casein, lecithin (phospholipid), dextran, glycerin, gum arabic, cholesterol, gum tragacanth, stearic acid, calcium stearate, glycerol monostearate. Rate, cetostearyl alcohol, cetomacrogol emulsified wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester; dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal dioxide Silicon, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropylcellulose (HPC, HPC-SL and HPC-L), hydroxypropyl Chill cellulose (HPMC), sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl-cellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinyl pyrrolidone 4- (1,1,3,3-tetramethylbutyl) -phenolic polymer (also known as tyloxapol, superione and triton), poloxamer, poloxamine, dimyristoyl phosphatidylglycerol combined with (PVP), ethylene oxide and formaldehyde Dioctylsulfosuccinic acid (DOSS); Tetronic® 1508, dialkyl ester of sodium sulfosuccinate, Duponol P, Tritons X-200, Crodetas F-110, p-isonononi Phenoxypoly - (glycidol), Crodestas SL-40 dialkyl esters of (Croda Inc.); and a _{C 18 H 37 CH 2 (CON} (CH 3) -CH 2 (CHOH) 4 (CH 2 OH) 2 SA9OHCO ( Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl β-D-maltose Glycosides; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; -Noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; Most of these surfactants are known as pharmaceutical excipients and were published jointly by The American Pharmaceutical Association and the Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986), “The Pharmaceutical Handbook of Pharmaceutical Excipeints”, which is specifically incorporated as a reference for its disclosure.

  Hydrophobic, water-insoluble, water-nondispersible polymers or copolymers are, for example, lactic acid polymers or glycolic acid polymers and copolymers thereof, polylactic acid / polyethylene (or polypropylene) oxide copolymers, preferably having a molecular weight of 1000 Selected from biocompatible, biodegradable polymers such as those of ~ 200,000, polyhydroxybutyric acid polymers, polylactones that are fatty acids containing at least 12 carbon atoms, or polyanhydrides.

  Nanoparticles can be obtained from aqueous dispersions or solutions of phospholipids and oleates by coacervation or solvent evaporation techniques, in which active active ingredients and hydrophobic, water-insoluble , And an immiscible organic phase comprising a non-dispersible polymer or copolymer in water. The mixture is pre-emulsified and then homogenized and evaporated with an organic solvent to obtain an aqueous suspension of ultra-small nanoparticles.

Various methods are optionally used to create otic sensory cell modulator nanoparticles within the scope of the embodiments. These include vaporization methods such as free jet expansion, laser evaporation, electrical discharge machining, electronic explosion, and chemical vapor deposition; mechanical polishing (e.g., pearlmilling technology, Elan Nanosystems) following dissolvable replacement There are physical methods such as solvent substitution after deposition at the interface with supercritical CO ₂ . In one embodiment, a solvent replacement method is used.
The size of the nanoparticles produced by this method is sensitive to the concentration of the polymer in the organic solvent; the mixing speed; and the surfactant used in the process. A continuous flow mixer provides the turbulence necessary to ensure a small particle size. One type of continuous flow mixing device optionally used to prepare nanoparticles has been described (Hansen et al J phys Chem 92, 2189-96, 1988). In other embodiments, an ultrasonic device, a flow through homogenizer, or a supercritical CO ₂ device is used to prepare the nanoparticles.

  If appropriate nanoparticle homogeneity is not obtained by direct synthesis, molecular sieve chromatography is used to create highly uniform drug-containing particles that are free of other components associated with their production. To separate the otic sensory cell modulators and other pharmaceutical compounds bound to the particles from the free otic sensory cell modulators and other pharmaceutical compounds, or to adjust the size of the nanoparticles containing the otic sensory cell modulators to an appropriate size. To select, molecular sieve chromatography (SEC) techniques such as gel filtration chromatography are used. For fractionation based on the size of such a mixture, various SEC media such as Superdex 200, Superose 6, Sephacryl 1000 are commercially available. In addition, the nanoparticles are purified in any manner by centrifugation, membrane filtration, and by use of other molecular sieving equipment, cross-linked gels / substances, and membranes.

Ear-acceptable cyclodextrins and other stabilized formulations In certain embodiments, the ear-acceptable formulations alternatively comprise cyclodextrins. Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units and are called α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, respectively. Cyclodextrins have a hydrophilic exterior that enhances water solubility and a hydrophobic interior that forms a cavity. In an aqueous environment, the hydrophobic portions of other molecules often enter the hydrophobic cavities of cyclodextrins and form inclusion compounds. In addition, cyclodextrins are also capable of another type of action, non-binding interactions with molecules that are not inside the hydrophobic cavity. Cyclodextrins have three free hydroxyl groups in each glucopyranosyl unit, or 18 hydroxyl groups on α-cyclodextrin, 21 hydroxyl groups on β-cyclodextrin, and 24 hydroxyl groups on γ-cyclodextrin. One or more of these hydroxyl groups react with any number of reagents to form a wide variety of cyclodextrin derivatives including hydroxypropyl ethers, sulfonates, and sulfoalkyl ethers. The structures of β-cyclodextrin and hydroxypropyl-β-cyclodextrin (HPβCD) are shown in the following chemical formula 2.

  In some embodiments, the use of cyclodextrins in the pharmaceutical compositions described herein improves drug solubility. Inclusion compounds often incorporate enhanced solubility; other interactions between cyclodextrins and insoluble compounds also improve solubility. Hydroxypropyl-β-cyclodextrin (HPβCD) is commercially available and is available as a pyrogen free product. It is a non-hygroscopic white powder that dissolves easily in water. HPβCD is thermally stable and does not degrade at neutral pH. Thus, cyclodextrins improve the solubility of therapeutic agents in a composition or formulation. Thus, in some embodiments, cyclodextrins are included in the formulations described herein to increase the solubility of the ear-acceptable otic sensory cell modulator. In other embodiments, the cyclodextrin further functions as a controlled release excipient in the formulations described herein.

  By way of example only, the cyclodextrin derivatives used include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, β-cyclodextrin sulfate, α-sulfate α -Cyclodextrin, sulfobutyl ether β-cyclodextrin.

  The concentration of cyclodextrin used in the compositions and methods disclosed herein depends on the properties of the therapeutically useful agent, or salt or prodrug thereof, or other excipients in the composition. It varies depending on the relevant physiochemical properties, pharmacokinetic properties, side effects or contingencies, formulation considerations, or other factors. Thus, within a particular environment, the concentration or amount of cyclodextrin used in accordance with the compositions and methods disclosed herein will vary as needed. In use, in any formulation described herein, the amount of cyclodextrin required to enhance the solubility and / or function as a controlled release excipient of the otic sensory cell modulator is: Selection is made using the principles, examples, and teachings described herein.

  Other stabilizers useful in the ear acceptable formulations disclosed herein include, for example, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone , Polyvinyl ether, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In some embodiments, amide analogs of stabilizers are also used. In further embodiments, the selected stabilizer alters the hydrophobicity of the formulation (e.g., oleic acid, wax) or improves the mixing of various ingredients in the formulation (e.g., ethanol) Control the moisture level in (e.g. PVP or polyvinylpyrrolidone) and (e.g. substances with a melting point higher than room temperature of long chain fatty acids, alcohols, esters, amides, etc., or mixtures thereof; of wax) Controls migration and / or improves the affinity of a formulation with an encapsulant (eg, oleic acid or wax). In another embodiment, some of these stabilizers are used as a solvent / co-solvent (eg, ethanol). In other embodiments, the stabilizer is present in an amount sufficient to inhibit degradation of the ear sensory cell modulator. Examples of these stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerin, (b) about 0.1% to about 1% w / v methionine, ( c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003 % To about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

  Further useful ear sensory cell modulator agent-acceptable formulations include one or more anti-aggregation additives to increase the stability of the ear sensory cell modulator formulation by reducing the rate of protein aggregation. The anti-aggregation additive selected will depend on the characteristics of the condition to which the ear sensory cell modulator, eg, the ear sensory cell modulator antibody is exposed. For example, certain formulations that are subjected to agitation and thermal stress require different anti-aggregating additives than formulations that undergo lyophilization and reconstitution. Useful anti-aggregating additives include, by way of example only, simple amino acids such as urea, guanidine chloride, glycine or arginine, sugars, polyhydric alcohols, polysorbates, polymers such as polyethylene glycol and dextran, alkyl glycosides Alkyl saccharides such as, and surfactants.

  Optionally, other beneficial formulations include one or more ear-acceptable antioxidants to enhance chemical stability where required. Suitable antioxidants include ascorbic acid, methionine, sodium thiosulfate, and sodium bisulfite by way of example only. In one embodiment, the antioxidant is selected from metal chelators, thiol-containing compounds, and other common stabilizers.

  Still other useful compositions include one or more ear-acceptable surfactants to increase physical stability or for other purposes. Suitable nonionic surfactants are, by way of example only, polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and, for example, polyoxyethylene alkyl ethers, There are alkyl phenyl ethers such as octoxynol 10 and octoxynol 40.

  In some embodiments, the pharmaceutically acceptable pharmaceutical formulation described herein has at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about About 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least Stable to compound degradation over a period of about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, the formulations described herein are stable against compound degradation over a period of at least about 1 week. Formulations that are stable to compound degradation over a period of at least about 1 month are also described herein.

  In other embodiments, additional surfactants (co-surfactants) and / or buffers maintain the product at an optimum pH for the surfactants and / or buffers to be stable. As such, it is combined with one or more pharmaceutically acceptable vehicles as previously described herein. Optimal co-surfactants include, but are not limited to: a) Natural and synthetic lipophilic drugs such as phospholipids, cholesterol, cholesterol fatty acid esters and derivatives thereof; b) Nonionic surfactants such as polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans) Polyoxyethylene sorbitan fatty acid esters (for example, polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20), and other Tweens, sorbitan esters, glycerin esters such as Myrj, glycerin triacetate (triacetin), polyethylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamer , Poloxamine, polyoxyethylene castor oil derivatives (eg Cremophor® RH40, Cremphor A25, Cremphor A20, Cremophor® EL) and other Cremophors, sulfosuccinic acid, alkyl sulfate (SLS); PEG-8 glyceryl Caprylate / Caprate (Labrasol), PEG-4 Glyceryl Caprylate / Caprate (Labrafac Hydro WL 1219), PEG-32 Glyceryl Laurate (Gelucire 444/14), PEG-6 Glyceryl Monooleate (Labrafil M 1944 CS), PEG glyceryl fatty acid esters, such as PEG-6 glyceryl linoleate (Labrafil M 2125 CS); propylene glycol mono, such as propylene glycol laurate (propylene glycol caprylate / caprate) -And di-fatty acid esters; Brij® 700, ascorbyl acid-6-palmitate, stearylamine, sodium lauryl sulfate, polyoxyethyl Triiricinoleate, and any combination or mixture thereof; c) Anionic surfactants include but are not limited to calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium sulfosuccinate, dioctyl, sodium alginate, alkyl There are polyoxyethylene sulfate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts, and any combination or mixture thereof; and d) cationic surfactants such as cetyl bromide Examples include trimethylammonium and lauryldimethylbenzylammonium chloride.

  In a further embodiment, when one or more co-surfactants are utilized in the otic acceptable formulation disclosed in the present invention, the surfactant is combined with, for example, a pharmaceutically acceptable vehicle. And present in the final formulation in an amount ranging from about 0.1% to about 20% and from about 0.5% to about 10%.

In one embodiment, the surfactant has an HLB value of 0-20. In further embodiments, the surfactant has an HLB value of 0-3, 4-6, 7-9, 8-18, 13-15, 10-18.

  In one embodiment, the diluent is also used to stabilize otic sensory cell modulators or other pharmaceutical compounds because the diluent provides an additional stable environment. Salts that are dissolved in a buffer (which can also provide control or maintenance of pH) are utilized as diluents, including but not limited to phosphate buffered saline. In other embodiments, the gel formulation is isotonic with the endolymph or perilymph, depending on the portion of the cochlea to which the otic sensory cell modulator formulation is targeted. Isotonic formulations are provided by adding an isotonic agent. Suitable tonicity agents include, but are not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, including but not limited to dextrose and sodium chloride. In a further embodiment, the tonicity agent is present in an amount from about 100 mOsm / kg to about 500 mOsm / kg. In some embodiments, the tonicity agent is present in an amount of about 200 mOsm / kg to about 400 mOsm / kg, about 280 mOsm / kg to about 320 mOsm / kg. The amount of tonicity agent depends on the target structure of the pharmaceutical formulation, as described herein.

  Useful isotonic compositions also contain one or more salts in an amount necessary to bring the osmotic pressure of the composition to an acceptable range for the perilymph or endolymph. Such salts have a cation of sodium, potassium or ammonium and anions of chlorine, citric acid, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfuric acid, thiosulfuric acid or sulfite; Examples of such salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

  In some embodiments, the ear acceptable gel formulations described herein include preservatives alternatively or additionally to inhibit microbial growth. Suitable ear-acceptable preservatives used in the viscosity enhancing formulations described herein include benzoic acid, boric acid, p-hydroxybenzoic acid, alcohol, quaternary compounds, stabilized chlorine dioxide, Examples include, but are not limited to, mercury-containing materials (eg, merfen and thimerosal), mixtures of the foregoing, and the like.

In a further embodiment, the preservative is, by way of example only, an antimicrobial agent in the otic acceptable formulation described herein. In one embodiment, the formulation includes, by way of example only, methyl paraben, sodium bisulfite, sodium thiosulfate, ascorbate, chlorobutanol, thimerosal, paraben, benzyl alcohol, phenylethanol and others. In another embodiment, the concentration of methyl paraben is from about 0.05% to about 1.0%, from about 0.1% to about 0.2%. In a further embodiment, the gel is prepared by mixing water, methyl paraben, hydroxyethyl cellulose and sodium citrate.
In a further embodiment, the gel is prepared by mixing water, methyl paraben, hydroxyethyl cellulose and sodium acetate. In a further embodiment, the mixture is sterilized by autoclaving at 120 ° C. for about 20 minutes, and the pH, methyl paraben concentration, and viscosity are mixed prior to mixing the appropriate amount of the ear sensory cell modulator disclosed herein. Are tested.

  Suitable ear-acceptable water-soluble preservatives used in drug delivery vehicles are sodium bisulfite, sodium thiosulfate, ascorbate, chlorobutanol, thimerosal, paraben, benzyl alcohol, butylated hydroxytoluene (BHT), Contains phenylethanol and others. These agents are usually present in an amount of about 0.001% to about 5% by weight, preferably in an amount of about 0.01% to about 2% by weight. In some embodiments, the otic acceptable formulations described herein do not include preservatives.

Round window membrane penetration enhancer In another embodiment, the formulation further comprises one or more round window membrane penetration enhancers. Penetration through the round window membrane is enhanced by the presence of a round window membrane penetration enhancer. A round window membrane penetration enhancer is a chemical that facilitates the transport of co-administered substances through the round window membrane. Round window membrane penetration enhancers are classified according to chemical structure. Ionic and nonionic surfactants such as sodium lauryl sulfate, sodium laurate, polyoxyethylene-20-cetyl ether, laureth-9, sodium dodecylsulfate, sodium dioctylsulfosuccinate, polyoxyethylene-9 -Lauryl ether (PLE), Tween (registered trademark) 80, nonylphenoxypolyethylene (NP-POE), polysorbate and the like function as a round window membrane penetration enhancer. Bile salts (e.g., sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium glycodihydrofusidate), fatty acids and derivatives (e.g., oleic acid, capric acid, mono-glycerides and diglycerides) -Glycerides, lauric acid, acylcholine, caprylic acid, acylcarnitine, sodium caprylate, etc.), chelating agents (e.g., EDTA, citric acid, salicylate chelate, etc.), sulfoxides (e.g., dimethyl sulfoxide (DMSO), decylmethyl sulfoxide, etc.) ), And alcohols (eg, ethanol, isopropanol, glycerol, propanediol, etc.) also function as round window membrane penetration enhancers.

In some embodiments, the ear-acceptable penetration enhancer is an alkyl-glycoside-containing surfactant, wherein the alkyl glycoside is tetradecyl-β-D-maltoside. In some embodiments, the ear-acceptable penetration enhancer is an alkyl-glycoside-containing surfactant, wherein the alkyl glycoside is tetradecyl-maltoside. In a particular example, the penetration enhancer is hyaluronidase. In particular examples, the hyaluronidase is human or bovine hyaluronidase. In some examples, the hyaluronidase is human hyaluronidase (eg, hyaluronidase found in human sperm, PH20 (Halozyme), Hyelenex® (Baxter International, Inc.)). In some examples, the hyaluronidase is bovine hyaluronidase (eg, bovine testicular hyaluronidase, Amphadase® (Amphastar Pharmaceuticals), Hydase® (PrimaPharm, Inc.)). In some examples, the hyaluronidase is a sheep hyaluronidase, Vitrase® (ISTA Pharmaceticals). In a particular example, the hyaluronidase described herein is a recombinant hyaluronidase. In some examples, the hyaluronidase described herein is a humanized recombinant hyaluronidase. In some examples, the hyaluronidase described herein is a PEGylated hyaluronidase (eg, PEGPH20 (Halozyme)). In addition, peptidomimetic penetration enhancers described in US Pat. Nos. 7,151,191, 6,221,367, and 5,714,167, which are incorporated in this disclosure as a reference for their disclosure, are envisioned as further embodiments. .
These penetration enhancers are amino acids and peptide derivatives (derviatives) that allow drug absorption by passive intercellular diffusion without affecting the integrity of tight junctions between membranes or cells.

Round window membrane penetrating liposomes Liposomes or lipid particles can also be used to encapsulate formulations or compositions of otic sensory cell modulators. Phospholipids gently dispersed in an aqueous medium form multilamellar vesicles with encapsulated aqueous media regions that separate the lipid layers. Sonication or vigorous agitation of these multilamellar vesicles results in the formation of unilamellar vesicles approximately 10-1000 nm in size, commonly known as liposomes. These liposomes have many advantages as carriers for otic sensory cell modulators or other pharmaceutical agents. They are biologically inert, biodegradable, non-toxic and non-antigenic. Liposomes are formed in various sizes with various compositions and surface properties. Furthermore, they can encapsulate a wide variety of drugs and release the drug at the site of liposome disruption.

  Suitable phospholipids used in the ear-acceptable liposomes herein are, for example, phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine, sphingomyelin, cardiolipin, plasmalogen, phosphatidic acid and cerebroside, especially non- It is toxic and can be dissolved in a pharmaceutically acceptable organic solvent together with the otic sensory cell modulating agent herein. Preferred phospholipids are, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lysophosphatidylcholine, phosphatidylglycerol and the like, and mixtures thereof, in particular lecithin, such as soy lecithin. The amount of phospholipid used in the formulations of the present invention is about 10% to about 30%, preferably about 15% to about 25%, especially about 20%.

  Lipophilic additives can be effectively utilized to selectively modify the properties of the liposomes. Examples of such additives include, by way of example, stearylamine, phosphatidic acid, tocopherol, cholesterol, cholesterol hemisuccinate and lanolin extract. The amount of lipophilic additive used is in the range 0.5-8%, preferably 1.5-4%, in particular about 2%. Usually, the ratio between the amount of lipophilic additive and the amount of phospholipid ranges from about 1: 8 to about 1:12, in particular about 1:10. Phospholipids, fat-soluble additives and otic sensory cell modulators and other pharmaceutical compounds are used with non-toxic, pharmaceutically acceptable organic solvent systems in which the above ingredients are dissolved. The solvent system must not only completely dissolve the otic sensory cell modulator but also allow a formulation with a stable single bilayer liposome. The solvent system contains dimethylisosorbide and tetraglycol (glycolfur, tetrahydrofurfuryl alcohol polyethylene glycol ether) in an amount of about 8 to about 30%. In the solvent system, the ratio of the amount of dimethyl isosorbide to the amount of tetraglycol ranges from about 2: 1 to about 1: 3, in particular from about 1: 1 to about 1: 2.5, preferably about 1: 2. . The amount of tetraglycol in the final composition is therefore in the range from 5 to 20%, in particular from 5 to 15%, preferably about 10%. The amount of dimethyl isosorbide in the final composition is therefore in the range of 3-10%, in particular in the range of 3-7%, preferably about 5%.

  As used herein below, the term “organic component” corresponds to a mixture comprising a phospholipid, a lipophilic additive and an organic solvent. Ear sensory cell modulators are dissolved in other means to maintain the overall activity of the organic composition or drug. The amount of the ear sensory cell modulator in the final formulation is in the range of 01.-5.0%. In addition, other ingredients such as antioxidants are added to the organic ingredients. Examples (of them) include tocopherol, butylhydroxyanisole, butylhydroxytoluene, ascorbyl palmitate, ascorbyl oleate and the like.

  Liposome formulations can be used for active thermoactive otic sensory cell regulators or other pharmaceuticals, in which (a) phospholipids and organic solvent systems are heated to about 60-80 ° C. , Then add any pharmaceutical agent and stir the mixture until a complete lysate is obtained; (b) heat the aqueous solution to 90-95 ° C. in a second container to preserve the preservative In it, allow the mixture to cool naturally, then add the remainder of the supplemental drug product and the rest of the water, and stir the mixture until a complete solution is obtained; prepare the aqueous component in this way (C) feed the organic phase directly into the aqueous component while homogenizing the mixture using a high performance mixing device (eg, high shear mixer), and (d) produced during further homogenization Prepared by adding a viscosity enhancer to the mixture. Optionally, the water soluble component is placed in a suitable container equipped with a homogenizer and homogenized by creating a large turbulent flow while injecting the organic component. Any mixing method for applying a high shear force to the mixture, or a homogenizer can be used. Usually, mixers capable of speeds of about 1,500 to 20,000 rpm, especially about 3,000 to about 6,000 rpm may be used. Suitable thickeners for use in step (d) are, for example, xanthan gum, hydroxypropylcellulose, hydroxypropylmethylcellulose or mixtures thereof. The amount of thickener depends on the nature and concentration of the other ingredients and is usually in the range of about 0.5-2.0%, or about 1.5%. To prevent degradation of the materials used during the preparation of the liposomal formulation, purify all solutions with an inert gas such as nitrogen or argon and perform all steps in an inert environment It is useful. Liposomes prepared by the methods described above usually contain most of the active ingredients bound in a lipid bilayer and it is not necessary to separate the liposomes from unencapsulated material.

  In other embodiments, the otic acceptable formulations, including gel formulations and viscosity-enhanced formulations, may further comprise excipients, other therapeutic or pharmaceutical agents, (carriers, preservatives, stabilizers, Further included are adjuvants (such as wetting or emulsifying agents), dissolution enhancers, salts, solubilizers, antifoams, antioxidants, dispersants, wetting agents, surfactants, and combinations thereof.

  Suitable carriers for use in the otic acceptable formulations described herein include, but are not limited to, any pharmaceutically acceptable solvent that is compatible with the physiological environment of the target otic structure. Yes. In other embodiments, the base is a combination of a pharmaceutically acceptable surfactant and solvent.

  In some embodiments, other excipients include sodium stearyl fumarate, diethanolamine cetyl sulfate, isostearate, polyethoxylated castor oil, nonoxyl 10, octoxynol 9, sodium lauryl sulfate, sorbitan ester (sorbitan monolaurate) Sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan dioleate Sorbitan sesquiisostearate, sorbitan sesquistearate, sorbitan triisostearate), lecithin, pharmaceutically acceptable salts thereof, There are combinations or mixtures.

  In other embodiments, the carrier is a polysorbate. Polysorbate is a nonionic surfactant of sorbita ester. Polysorbates useful in the present disclosure include, but are not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween), and any combination or mixture thereof. In a further embodiment, polysorbate 80 is utilized as a pharmaceutically acceptable carrier.

  In one embodiment, a water-soluble glycerin-based ear-enhanced viscosity-enhanced formulation is used in the formulation of a pharmaceutical delivery vehicle, the delivery vehicle being at least 0.1% or more water soluble. At least one ear sensory cell modulator containing a sex glycerin compound. In some embodiments, the proportion of the otic sensory cell modulator formulation is between about 1% and about 95%, between about 5% and about 80%, between about 10% and about 60% of the total pharmaceutical formulation. It varies with a weight or volume in or between. In some embodiments, the amount of compound in each of the therapeutically useful ear sensory cell modulators is formulated so that an appropriate dosage is obtained at any given dosage of the compound. In addition to solubility, bioavailability, biological half-life, route of administration, product shelf life, factors such as pharmacological considerations are contemplated herein.

  If desired, the ear-acceptable pharmaceutical gels can also be co-solvents, preservatives, cosolvents, ionic strength and osmolality adjusters, and other associated forms in addition to buffers. Agent is included. Suitable ear-acceptable water-soluble buffers are alkaline or alkaline earth metal carbonates, alkaline earth metal phosphates, alkaline earth metal bicarbonates, alkaline earth metal citrates, alkaline Earth metal borates, alkaline earth metal acetates, alkaline earth metal succinates, etc., for example, sodium phosphate, sodium citrate, sodium borate, sodium acetate, sodium bicarbonate, sodium carbonate and tromethamine (TRIS) Sodium. These agents are present in an amount sufficient to maintain the pH of the system at 7.4 ± 0.2, and preferably 7.4. Thus, the buffer is as much as 5% based on the weight of the total composition.

  Cosolvents are used to increase the solubility of ear sensory cell modulators, however, some ear sensory cell modulators or other pharmaceutical compounds are insoluble. These are often suspended in the polymer vehicle using a suitable suspending agent or viscosity enhancing agent.

In addition, some pharmaceutical excipients, diluents or carriers are potentially ototoxic.
For example, benzalkonium chloride, a common preservative, is ototoxic and is therefore potentially harmful when incorporated into vestibular or cochlear structures. Avoiding or combining appropriate excipients, diluents or carriers in formulating controlled release otic sensory cell modulator formulations, reducing or eliminating potential ototoxic compounds from the formulation, or It is recommended to reduce the amount of excipients, diluents or carriers. Optionally, controlled release otic sensory cell modulator formulations may be formulated with antioxidants, alpha, to counter the potential ototoxic effects that result from using certain therapeutic agents, excipients, diluents or carriers. Contains ototoxic protection agents such as lipoic acid, calcium, fosfomycin or iron chelators.

  Therapeutically acceptable ear formulation:

  The formulations disclosed herein are also not intended to be limiting in order to counter the use of certain therapeutic agents or excipients, and potential ototoxic consequences that may arise from the excipient or carrier. Not included, but includes an ear protection agent in addition to at least one active agent and / or excipient, including agents such as antioxidants, alpha lipoic acid, calcium, fosfomycin or iron chelators.

Methods of Treatment Dosing Methods and Schedules Drugs delivered to the inner ear have been administered by the oral, intravenous, and intramuscular routes.
However, systemic administration for local pathology in the inner ear increases the potential for systemic toxicity and side effects, creating a non-productive distribution of the drug. In this distribution, high levels of drug are found in the serum and correspondingly low levels of drug are found in the inner ear.

  Intratympanic injection of a therapeutic agent is a technique in which the therapeutic agent is injected behind the eardrum to reach the middle ear and / or the inner ear. In one embodiment, the formulations described herein are administered directly to the round window membrane via intratympanic injection. In other embodiments, the ear-acceptable ear sensation modulating agent described herein is administered to the round window membrane by a non-tympanic injection method into the inner ear. In a further embodiment, the formulations described herein are administered to the round window membrane via a surgical method to the round window membrane comprising a step comprising alteration of the cochlear window ridge.

  In one embodiment, the delivery system is a syringe and needle device that penetrates the tympanic membrane and can reach the round window membrane or the cochlear crest of the inner ear directly. In some embodiments, the syringe needle is a wider needle than an 18 gauge needle. In another embodiment, the needle gauge is from 18 gauge to 31 gauge. In further embodiments, the needle gauge is from 25 gauge to 30 gauge. Depending on the thickness or viscosity of the ear sensory cell modulator compound or preparation, the gauge level of the syringe or hypodermic needle can be changed as appropriate. In other embodiments, the inner diameter of the needle reduces the wall thickness of the needle (generally referred to as a thin-walled or specially thin-walled needle) to reduce the possibility of needle occlusion while maintaining an appropriate needle gauge. It can be increased by reducing.

  In other embodiments, the needle is a hypodermic needle used for immediate delivery of the gel formulation. The hypodermic needle is a single use needle or a disposable needle. In some embodiments, the syringe can be utilized for delivery of a compound that includes a pharmaceutically acceptable gel-based otic sensory cell modulator described herein, and the syringe is an interference fit ( Luer) or torsion (luer lock) accessories. In one embodiment, the syringe is a hypodermic syringe. In other embodiments, the syringe is made of plastic or glass. In yet other embodiments, the hypodermic syringe is a single use syringe. In a further embodiment, the glass syringe is sterilizable. In a further embodiment, sterilization occurs by autoclaving. In other embodiments, the syringe comprises a cylindrical syringe body and the gel formulation is stored prior to use. In other embodiments, the syringe comprises a cylindrically shaped syringe body and the pharmaceutically acceptable gel-based composition of the otic sensory cell modulator as disclosed herein is used prior to use. Once stored, the composition is conveniently mixed with a suitable pharmaceutically acceptable buffer. In other embodiments, the syringe contains other excipients, stabilizers, suspending agents, diluents or combinations thereof and stabilizes the ear sensory cell modulator or other pharmaceutical compound contained therein. Or otherwise store stably.

  In some embodiments, the syringe comprises a cylindrical syringe body, such that each partition is capable of storing at least one compound of an ear-acceptable cell sensory agent gel formulation acceptable to the ear. Are delimited. In a further embodiment, the compound can be mixed prior to injection into the middle or inner ear by means of a syringe having a partitioned body. In other embodiments, the delivery system comprises multiple syringes, each syringe of which contains at least one compound of a gel formulation, whereby each compound is premixed prior to injection. Or each compound is pre-mixed before being mixed after injection. In further embodiments, the syringes described herein comprise at least one container, wherein the at least one container is an otic sensory cell modulator, or a pharmaceutically acceptable buffer or gelling agent or these Viscosity enhancers such as combinations are provided. Commercially available injection devices optionally adopt the simplest shape as a syringe barrel, a syringe needle assembly with a syringe needle, a plunger with a plunger rod, and a ready-to-use plastic syringe with a holding flange, Perform intratympanic injections.

  In some embodiments, the delivery device is an instrument designed for administration of a therapeutic agent to the middle ear and / or the inner ear. By way of example only, GYRUS Medical GmbH provides a microotope for visualization of round window niches and drug delivery to round window niches. Ehrenberg described a treatment device for delivering fluid to the inner ear structure in the following patents: US Pat. Nos. 5,421,818, 5,474,529, and 5,476,446, each incorporated herein by reference for disclosure purposes. For disclosure purposes, US patent application Ser. No. 08 / 874,208, incorporated herein by reference, describes a surgical method for implanting a fluid transfer conduit for delivering a therapeutic agent to the inner ear. ing. For disclosure, US Patent Application Publication No. 2007/0167918, which is incorporated herein by reference, further describes a combination of an ear aspirator and a drug retrieval container for fluid sampling and drug application in the middle ear. .

  An ear-acceptable composition or formulation comprising an ear sensory cell modulator compound described herein is administered as a prophylactic treatment and / or treatment. In therapeutic applications, the otic sensory cell modulator composition cures or at least partially halts signs of a disease, symptom, or disorder for a patient already suffering from an autoimmune disease, symptom, or illness. Is administered in a sufficient amount. The effective amount for this use depends on the severity and course of the disease, condition or disorder, drug history, patient health and drug responsiveness and the judgment of the treating physician.

Frequency of administration In some embodiments, the compositions disclosed herein are administered once to an individual in need thereof. In some embodiments, the compositions disclosed herein are administered more than once to an individual in need thereof. In some embodiments, the first administration of the composition disclosed herein is followed by the second administration of the composition disclosed herein. In some embodiments, the first administration of the composition disclosed herein is followed by the second and third administration of the composition disclosed herein. In some embodiments, the first administration of the compositions disclosed herein is followed by the second, third and fourth administrations of the compositions disclosed herein. In some embodiments, the first administration of the composition disclosed herein is followed by the second, third, fourth and fifth administration of the composition disclosed herein. In some embodiments, there is a drug holiday following the first administration of the composition disclosed herein.

  The number of times that the composition is administered to an individual in need thereof depends on specialist judgment, the disorder, the severity of the disorder and the individual's response to the formulation. In some embodiments, the compositions disclosed herein are administered once to an individual in need with their mild acute illness. In some embodiments, the compositions described herein are administered more than once to an individual in need, having moderate or severe acute disease. If the patient's symptoms do not improve, the ear sensory cell regulatory cell modulator is routinely based on the judgment of the physician to recover, or otherwise control or limit the patient's disease or symptoms of symptoms. That is, it is administered for a long period of time, such as during the life of the patient.

  If the patient's symptoms do not improve, the ear sensory cell modulator compound is routinely used based on the judgment of the physician to recover, or otherwise control or limit the patient's disease or symptoms of symptoms. I.e., for a long period of time, such as throughout the life of the patient.

  If the patient's condition improves, the doctor's judgment may be given continuous administration of the otic sensory cell modulator compound, or alternatively, the administration of the drug may be reduced temporarily or for a certain period of time. May be temporarily suspended during the period (ie during the drug holiday). The drug holiday is between 2 days and 1 year, and by way of example only, 2, 3, 4, 5, 6, 7, 10, 12, 12, 15, 20, Day, 35 day, 50 day, 70 day, 100 day, 120 day, 150 day, 180 day, 200 day, 250 day, 280 day, 3000 day, 320 day, 350 day, and 365 day. The dose reduction during the drug holiday is 10% to 100%, and by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%.

  Once the patient's ear condition has improved, a maintenance ear sensory cell modulator dose is administered if necessary. Depending on the symptoms, the dose or frequency of administration or both are optionally reduced continuously until the improved disease, disorder or condition is maintained. In certain embodiments, patients require intermittent treatment over a long period of time for any recurrence of symptoms.

  The amount of the ear sensory cell modulating agent corresponding to such an amount is, for example, the specific ear sensory cell modulating agent administered, the route of administration, the autoimmune disease to be treated, the target site to be treated, and the subject to be treated. Depending on the particular environment surrounding the disease, including the specimen or host, etc., it depends on factors such as the particular compound, the disease state and its severity. However, doses generally used for adult treatment are generally in the range of 0.02-50 mg per dose, preferably 1-15 mg per dose. The desired dose is expressed as a single dose or divided doses, administered simultaneously (or at short intervals) or at appropriate intervals.

  In some embodiments, the first administration is a specific otic sensory cell modulator and the subsequent administration is a different formulation or otic sensory cell modulator.

Pharmacokinetics of Controlled Release Formulations In one embodiment, the formulations disclosed herein provide immediate release of an otic sensory cell modulator from a composition, or within 1 minute, or within 5 minutes, or within 10 minutes. Or release within 15 minutes or 30 minutes or 60 minutes or 90 minutes. In other embodiments, the amount of at least one ear sensory cell modulator useful for treatment is immediate or within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, Or released from the composition within 60 minutes or within 90 minutes. In certain embodiments, the composition comprises an pharmaceutically acceptable gel formulation that imparts immediate release of at least one ear sensory cell modulator. Additional formulation embodiments may also include agents that increase the viscosity of the formulations described herein.

  In other or further embodiments, the formulation provides an ear sensory cell modulator of at least one ear sensory cell sustained release formulation. In certain embodiments, the diffusion of at least one ear sensory cell modulator from the formulation is 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 Time, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, Or 25 days, or 30 days, or 45 days, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 9 months, or 1 year. In other embodiments, the therapeutically effective amount of at least one ear sensory cell modulator is 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 122 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days , Or 25 days, or 30 days, or 45 days, or 2 months, or 3 months, or 4 months, or 55 months, or 6 months, or 9 months, or 1 year.

  In other embodiments, the formulation provides a sustained release otic sensory cell modulator formulation. In still other embodiments, the formulation is 0.25: 1, or 0.5: 1 ratio, or 1: 1 ratio, or 1: 2 ratio, or 1: 3, or 1: 4 ratio, or 1 : 5 ratio, or 1: 7 ratio, or 1:10 ratio, or 1:15 ratio, or immediate release and sustained release formulation 1:20 ratio of immediate release and sustained release formulation . In a further embodiment, the formulation provides an immediate release of the first otic sensory cell modulating agent and a sustained release second otic sensory cell modulating agent or other therapeutic agent. In still other embodiments, the formulation provides at least one immediate release and sustained release formulation of at least one ear sensory cell modulator and at least one therapeutic agent. In certain embodiments, the formulation is a 0.25: 1 ratio, or a 0.5: 1 ratio, or a 1: 1 ratio, or a 1: 2 ratio, or a 1: 3 ratio, or a 1: 4 ratio, or A ratio of 1: 5, 1: 7, 1:10, 1:15, or 1:20 of the first otic sensory cell modulator and second therapeutic agent Provide immediate release and sustained release formulations, respectively.

  In certain embodiments, the formulation provides a therapeutically effective amount of at least one ear sensory cell modulator at a site of disease that is essentially not associated with systemic exposure. In additional embodiments, the formulation provides a therapeutically effective amount of at least one ear sensory cell modulator at a site of disease that is essentially without detectable systemic exposure. In other embodiments, the formulation provides a therapeutically effective amount of at least one ear sensory cell modulator at a site of disease with little or no detectable systemic exposure.

Combinations of immediate release, delayed release, and / or sustained release otic sensory cell modulator compositions or formulations are disclosed herein as excipients, diluents, stabilizers, isotonic agents, and herein. It may be combined with other pharmaceuticals as well as other compositions.
Thus, depending on the ear sensory cell modulator used, the desired thickness or viscosity, or the mode of delivery selected, alternative aspects of the embodiments disclosed herein are immediate release. , Delayed release and / or sustained release embodiments as appropriate.

In certain embodiments, the pharmacokinetics of the otic sensory cell modulators described herein are in the vicinity of the round window membrane or round window membrane of a test animal (including guinea pigs or chinchillas as an example only). Determined by injecting the formulation.
At a determined period (for testing the pharmacokinetics of the formulation over a week, e.g. 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days) Test animals are euthanized and a 5 mL sample of perilymph fluid is tested. The inner ear is removed and tested for the presence of otic sensory cell modulators. Ear sensory cell modulating agent levels are measured in other organs as needed. In addition, systemic levels of systemic ear sensory cell modulators are measured by drawing a blood sample from the test animal. The hearing of the test animal is optionally tested to determine if the formulation interferes with hearing.

  Alternatively, the inner ear is provided (removed from the test animal) and the migration of the ear sensory cell modulator is measured. In yet another embodiment, an in vitro model of a round window membrane is provided to measure the migration of otic sensory cell modulators.

Kits / Products This disclosure also provides kits for preventing, treating and ameliorating symptoms of mammalian diseases or disorders. Such kits generally comprise one or more ear sensory cell modulator controlled release compositions, or devices disclosed herein, and instructions for using the kit. The present disclosure also treats or alleviates a disease, dysfunction, or symptom of a disorder in a mammal, such as a human, who has, is suspected of having, or is at risk of developing an inner ear disorder It is contemplated to use one or more otic sensory cell modulator controlled release compositions during the manufacture of a drug to reduce, weaken or improve.

  In some embodiments, the kit comprises a transporter, package, or container that is sectioned to contain one or more containers, such as vials, tubes, etc., each of which is described herein. One of the distinct elements used in the method. Suitable containers include, for example, bottles, vials, syringes and test tubes. In other embodiments, the container is formed from a variety of materials such as, for example, glass or plastic.

  The articles of manufacture provided herein include packaging materials. A packaging material used to package a pharmaceutical product is also presented herein. See, for example, US Pat. No. 5,323,907, US Pat. No. 5,052,558, and US Pat. No. 5,033,252. Pharmaceutical packaging materials include blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for administration and treatment in the selected formulation and intended mode. For example, but not limited to. The various otic sensory cell modulator pharmaceutical compositions provided herein are as various treatments for any disease, disorder, or condition that would benefit from controlled release administration of otic sensory cell modulators to the inner ear. Is intended.

  In some embodiments, the kit includes one or more additional containers, each container having one or more different containers desirable from a commercial and user standpoint for the use of the formulations described herein. With materials (such as reagents and / or devices, optionally in concentrated form). Non-limiting examples of such materials include buffers, excipients, filters, needles, syringes, carriers, packaging, containers, vials and / or tubes that list contents and / or instructions for use and / or Includes but is not limited to package inserts with instructions for use. A set of instructions is optionally included. In some embodiments, the label is on or associated with the container. In further embodiments, when letters, numbers or other symbols forming the label are attached, molded into the container itself, or etched, the label is on the container, for example as a package insert, A label is associated with a container when it is in a receptacle or carrier that also holds the container. In other embodiments, the label can be used to indicate that the contents are to be used for a particular therapeutic application. In yet other embodiments, the label also indicates instructions for use of the contents, such as in the methods described herein.

  In certain embodiments, the pharmaceutical composition is present in a pack or dispenser device comprising one or more unit dose forms comprising a compound provided herein. Other embodiments include metal or plastic foils, such as blister packs. In a further embodiment, the pack or dispenser device is accompanied by instructions for administration. In a further embodiment, the pack or dispenser is also accompanied by a notice associated with the packaging container in a form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceuticals. The notice reflects the approval by the agency in the form of a drug for human or veterinary administration. In another embodiment, the notice is a label approved by the US Food and Drug Administration for prescription drugs, an approved product insert, for example. In yet another embodiment, a composition comprising a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in a suitable container, and labeled Labeled for treatment of the condition.

(Example)
Example 1-Preparation of thermoreversible gel AMN082 formulation

  AMN082 is supplied as a solid. AMN082 is rehydrated in water to a final molar concentration of 10 mM.

  A 10 g batch of gel formulation containing 1.0% of AMN082 is prepared by first suspending Poloxamer 407 (Basuf) in Tris HCl buffer (0.1 M). To ensure complete dissolution of poloxamer 407 in the tris, poloxamer 407 and Tris are mixed at 4 ° C. with stirring overnight. Hypromellose, methyl paraben and additional Tris HCl buffer (0.1 M) are added. The composition is agitated until degradation is observed. A solution of AMN082 is added and the composition is mixed until a homogeneous gel is produced. The mixture is maintained at or below room temperature until use.

Example 2-Preparation of mucoadhesive thermoreversible gel AMN082 formulation

  AMN082 is supplied as a solid. AMN082 is rehydrated in water to a final molar concentration of 10 mM.

  A mucoadhesive 10 g batch gel formulation containing 1.0% of AMN082 is prepared by first suspending Poloxamer 407 (Basuf) and Carbopol 934P in Tris HCl buffer (0.1 M). . In order to ensure complete dissolution of Carbopol 934P with Poloxamer 407, Poloxamer 407, Carbopol 934P and Tris are mixed under stirring overnight at 4 ° C. Hypromellose, methyl paraben and additional Tris HCL buffer (0.1 M) are added. The composition is agitated until degradation is observed. AMN082 solution is added and the composition is mixed until a homogeneous gel is produced. The mixture is kept below room temperature until use.

Example 3-Preparation of CNQX formulation based on hydrogel

The cream type formulation is initially prepared by gently mixing CNQX with water until CNQX is dissolved.
The oil base is then prepared by mixing paraffin oil, trihydrostearic acid and cetyl dimethicone copolyol at an elevated temperature to 60 ° C. The oil base is cooled to room temperature. CNQX solution is also added. The two phases are mixed until a homogeneous single phase hydrogel is formed.

Example 4-Preparation of gel carbamazepine formulation

  A 5 ml solution of acetic acid is titrated to a pH of about 4.0. Chitosan is added to achieve a pH of about 5.5. The carbamazepine is then dissolved in the chitosan solution. This solution is sterilized by filtration. A 5 ml aqueous solution of glycerophosphate disodium is also prepared and sterilized. The two solutions are mixed within 2 hours at 37 ° C. to form the desired gel.

Example 5-Preparation of thermoreversible gel D methionine formulation with mucoadhesive properties

  D-methionine is dissolved in phosphate buffer. A 10 g batch of mucoadhesive gel formulation containing D-methionine is prepared by first suspending Poloxamer 407 (Basuf) and Carbopol 934P in phosphate buffer. To ensure a complete solution of poloxamer 407 and Carbopol 934P in the buffer, poloxamer 407, Carbopol 934P and phosphate buffer are mixed overnight under stirring at 4 ° C. Hypromellose, benzyl alcohol and additional phosphate buffer are added to the mixture. The composition is agitated until dissolution is observed. D methionine solution is added and the composition is mixed until a homogeneous gel is produced. The mixture is kept below room temperature until use.

Example 6-Preparation of liposomal AMN082 formulation

  AMN082 is supplied as a solid. Rehydrated in water to a final molar concentration of 10 mM.

  Soy lecithin, tetraglycol and dimethyl isosorbide are heated at about 70-75 ° C. Dissolve cholesterol and butylhydroxytoluene in the heated mixture. Stir until complete dissolution is obtained. Heat about one third of the water to 80-95 ° C. in a separate container and dissolve the preservatives methylparaben and propylparaben in the heated water with stirring. The solution is cooled to about 25 ° C. and then AMN082, edetate disodium, sodium chloride, sodium hydroxide and citric acid are added. Add the rest of the water and stir to obtain a complete solution. The organic mixture is transferred to the hydrate mixture by vacuum while homogenizing the combination by high shear mixing until a homogeneous product is obtained. While homogenizing with a mixer, add hydroxypropyl methylcellulose to the biphasic mixture by vacuum. A single bilayer liposome is formed.

Example 7-Preparation of thermoreversible gel containing (S) ketamine 15

  A set of 10 g gel formulations containing 1.0% (S) -ketamine is obtained by first suspending Poloxamer 407 (Basff) in Tris HCl buffer (0.1 M). Prepared. To ensure complete dissolution of poloxamer 407 in the tris, poloxamer 407 and Tris are mixed overnight under stirring at 4 ° C. Hypromellose, methyl paraben and additional Tris HCl buffer (0.1 M) are added. The composition is agitated until dissolution is observed. A solution of (S) -ketamine is added and the composition is mixed until a homogeneous gel is produced. The mixture is kept below room temperature until use.

Example 8-Preparation of thermoreversible gel (s) -ketamine composition containing micronized (S) -ketamine powder

  10 g batch of 2% micronized (S) -ketamine, 13.8 mg sodium phosphate dibasic dihydrate USP (Fisher Scientific.), And 3.1 mg sodium phosphate monobasic monohydrate (Fisher Scientific.), And 74 mg sodium chloride USP (Fisher Scientific.) Were dissolved using 8.2 g sterile filtered distilled water and the pH was adjusted to 7.4 using 1 M NaOH. The buffer solution is cooled and 1.6 g poloxamer 407 (BASF, containing about 100 ppm BHT) is sprinkled into the chilled PBS solution with mixing, and the solution is mixed until all the poloxamer is dissolved. . The poloxamer is sterile filtered using a 33 mm PVDF 0.22 micrometer sterile syringe filter (Millipore) and delivered to a sterile environment in a 2 mL sterile glass vial (Wheaton), which is a sterile butyl rubber stopper (Kimble). Closed, sealed with 13 mm aluminum seal (kimbles) and crimped. 20 mg micronized (S) -ketamine is placed in a separate clean pyrogen-free vial, the vial is closed with a sterile butyl rubber stopper (kimble) and sealed with a 13 mm aluminum seal (kimble) And crimped and the vials are dry heat sterilized at 140 ° C. for 7 hours (Fisher Scientific Isotemp oven). Prior to the experimental administration described herein, 1 mL of cooled poloxamer solution was sterilized to 20 mg using a 21 G needle (Becton Dickinson) attached to a 1 mL sterile syringe (Becton Dickinson). Delivered into a vial containing micronized (S) -ketamine, shaken well mixed and suspended to ensure suspension homogeneity. The suspension was then collected using a 21G syringe and the needle was replaced with a 27G needle for administration.

Example 9-Preparation of thermoreversible gel of micronized AM-101 composition containing transdermal absorption enhancer

A 10 g batch of 2.0% micronized prednisone formulation was prepared by suspending 1.80 g poloxamer 407 (BASF) in 5.00 g Tris HCl buffer (0.1 M) To ensure proper dissolution, the ingredients are mixed at 4 ° C. overnight under stirring. (S) -ketamine (200.0 mg), hydroxypropyl methylcellulose (100.0 mg), methylparaben (10 mg), dodecyl maltoside (10 mg) and additional Tris HCl buffer (0.1 M) (2.89 g) were added to complete Stir further until proper dissolution is observed.
The mixture is kept below room temperature until use.

Example 10-Effect of pH on autoclaved 17% poloxamer 407NF / 2% otic drug degradation product in PBS buffer
Stock solution of 17% poloxamer 407/2% dexamethasone was 351.4 mg sodium chloride (Fisher Scientific.), 302.1 mg sodium phosphate dibasic anhydride (Fisher Scientific.), 122.1 mg sodium phosphate monobasic anhydrous (Fisher Scientific.) And the appropriate amount of otic drug were prepared by dissolving with 79.3 g of sterile filtered distilled water. The solution was cooled in an ice cold water bath and then 17.05 g of poloxamer 407NF (SPECTRUM CHEMICALS) was sprinkled into the cooled solution with mixing. The mixture was further mixed until the poloxamer was completely dissolved. The pH of this solution is measured.

Take an aliquot (approximately 30 mL) of the above solution 17% poloxamer 407/2% otic agent in PBS pH 5.3 and adjust the pH to 5.3 by adding 1M HCL.

Remove an aliquot (approximately 30 mL) of the above stock solution of 17% poloxamer 407/2% ear drug in PBS pH 8.0 and adjust the pH to 8.0 by adding 1 M HCl.

  PBS buffer (pH 7.3) is 805.5 mg sodium chloride (Fisher Scientific.), 606 mg sodium phosphate dibasic anhydride (Fisher Scientific.), 247 mg sodium phosphate monobasic anhydride (Fisher Scientific.) And then quantified (QS) to 200 g using sterile filtered distilled water.

  A 2% solution of the otic drug in PBS pH 7.3 is prepared by dissolving an appropriate amount of the otic drug in PBS buffer and quantified to 10 g using PBS buffer.

  1 mL samples are individually placed in 3 mL screw cap glass vials (with rubber lining) and closed tightly. Vials are placed in a Market Forge-sterilmatic autoclave (setting, slow liquid) and sterilized at 250 degrees Fahrenheit for 15 minutes. After autoclaving, the samples were left to cool to room temperature and then placed in the refrigerator. The sample was homogenized by mixing the vials while cooling.

  Appearance (eg, discoloration and / or precipitation) was observed and recorded. HPLC analysis uses a Luna C18 (2), 3 μm, using a 30-80 acetonitrile gradient (1-10 minutes) (water-absorbing acetonitrile mixture containing 0.05% TFA) for a total of 15 minutes. , 100 Angstrom, 250 × 4.6 mm column). Samples were diluted by taking 30 μL of sample and dissolved in 1.5 mL of 1: 1 acetonitrile water mixture. The purity of the otic drug in the autoclaved sample is recorded.

  A formulation comprising DNQX, D-methionine, micronized AM-101, micronized (S) -ketamine was prepared according to the above procedure and to determine the effect of pH on degradation during the autoclave sterilization process. Inspected using the above procedure.

Example 11-Effect of Autoclave Sterilization on Release Properties and Viscosity of 17% Poloxamer 407NF / 2% Ear Drug in PBS
Samples from (autoclaved and non-autoclaved) are evaluated for measured release characteristics and viscosity in order to evaluate the effect of the heat sterilization method on the gel properties.

  Lysis was carried out at 37 ° C. in snap wells (6.5 μm diameter polycarbonate membrane with 0.4 μm pore size). 0.2 mL gel was placed in a snap well and left to cure, then 0.5 mL was placed in a reservoir and shaken using a Labline orbit shaker at 70 rpm. Samples were taken every hour (0.1 mL was removed and replaced with warm buffer). The sample was analyzed for poloxamer concentration by UV at 624 nm using the cobalt thiocyanate method against an external calibration curve. Briefly, a 20 μL sample was mixed with 1980 μL of a 15 mM cobalt thiocyanate solution and the absorbance was measured at 625 nm using an Evolution 160 UV / Vis spectrophotometer (Thermo Scientific). .

  The released otic agent is applied to the Korsmeyer-Peppas equation.

  Q is the amount of otic drug released at time t, Qα is the total amount of otic drug released, k is the release constant at position n, and n is a dimensionless number related to the dissolution mechanism. And b is the axis intercept characterizing the initial burst release mechanism, where n = 1 characterizes the erosion control mechanism. The mean dissolution time (MDT) is the sum of the different periods in the matrix before the drug molecules are released divided by the total molecular weight and is calculated by the following formula:

The viscous material is measured at 0.08 rpm (shear speed 0.31 s ^-1 ) equipped with a water jacket temperature control unit (temperature gradient from 15 to 34 ° C at 1.6 ° C / min). This was performed using a Brokfield viscometer RVDV-II + P equipped with a CPE-51 spindle. TGEL is defined as the inflection point of the curve where the increase in viscosity occurs due to the Solgel transition.

  A formulation comprising DNQX, D-methionine, micronized AM-101, micronized (S) -ketamine is prepared by the procedure described above and examined using the procedure described above to determine Tgel.

Example 12-Degradation product of formulation containing 2% otic agent and 17% poloxamer 407NF after heat sterilization (autoclave) and secondary polymer solution A for viscosity
Solution A: A pH 7.0 solution containing sodium carboxymethylcellulose (CMC) in PBS buffer was 178.35 mg sodium chloride (Fisher Scientific), 300.5 mg sodium phosphate dibasic anhydride (Fisher Scientific), Prepared by dissolving 126.6 mg sodium phosphate monobasic anhydride (Fisher Scientific) with 78.4 sterile filtered distilled water. Then 1 g of Blanose 7M65 CMC (Hercules, 5450 cP @ 2% viscosity) was sprinkled into the buffer, heated to aid dissolution, and the solution was then cooled.

  A pH 7.0 solution containing 17% poloxamer 407NF, 1% CMC, and 2% otic drug in PBS buffer is cooled in 8.1 g of solution A in an ice-cold water bath, and then an appropriate amount of otic drug is added. And then mix. 1.74 g of poloxamer 407NF (Spectrum Chemicals) is sprinkled into the cold solution while being mixed. The mixture is further mixed until all poloxamers are completely dissolved.

  2 mL of the sample was placed in a 3 mL screw cap glass vial (with rubber lining) and closed tightly. Vials were placed in Market Forge-sterilmatic autoclave (setting, slow liquid) and sterilized at 250 degrees Fahrenheit for 25 minutes. After autoclaving, the sample was left to reach room temperature and then placed in the refrigerator. The sample was homogenized by mixing while the vial was cooled.

  After autoclaving, no precipitation or discoloration was observed. HPLC analysis uses a Luna C18 (2), 3 μm, using a 30-80 acetonitrile gradient (1-10 minutes) (water-absorbing acetonitrile mixture containing 0.05% TFA) for a total of 15 minutes. , 100 Angstrom, 250 × 4.6 mm column). Samples were diluted [take a 30 μL sample and dissolve in 1.5 mL of a 1: 1 acetonitrile water mixture]. The purity of the otic drug in the autoclaved sample is recorded.

  The viscous material is measured at 0.08 rpm (shear speed 0.31 s-1) equipped with a water jacket temperature control unit (with a temperature gradient from 15 to 34 ° C at 1.6 ° C / min). This was performed using a Brokfield viscometer RVDV-II + P equipped with a CPE-51 spindle. Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the solgel transition.

  Degradation was performed at 37 degrees Celsius on a non-autoclaved sample in Snapwell (6.5 mm diameter polycarbonate membrane with 0.4 μm pore size), with 0.2 mL of gel in the Snapwell And then left to cure, 0.5 mL is placed in the reservoir and shaken using a Labline shaker at 70 rmm. Samples were taken every hour (0.1 mL was removed and replaced with warm buffer). Samples were analyzed for dexamethasone concentration by UV at 245 nm against an external calibration standard curve.

  Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine were examined using the procedure described above and after heating 2% otic drug and 17% poloxamer Determining the degradation product of formulations containing 407NF and conferring the effect of the secondary polymer on the viscosity.

Example 13-Effect of buffer type on degradation products of formulations containing poloxamer 407NF after heat sterilization (autoclave).
TRIS buffer is made by dissolving 377.8 mg sodium chloride (Fisher Scintific) and 602.9 mg Tromethamine (Sigma Chemical Co.), then adjusted to pH 7.4 with 1M hydrogen chloride and sterile filtered. Quantified (QS) to 100 g with DI water.

Stock solution containing 25% poloxamer 407 solution in Tris buffer
While mixing 15 g of poloxamer 407NF (Spectrum Chemicals), the 45 g TRIS buffer was cooled in an ice bath and then sprinkled into the buffer. The mixture is further mixed until all the poloxamers are completely dissolved.

  A series of formulations was prepared with the stock solution. The appropriate amount of otic agent (or salt or prodrug thereof) and / or micronized / coated / liposome formulation (or salt or prodrug thereof) is used in all experiments.

Stock solution (pH 7.3) containing 25% poloxamer 407 solution in PBS buffer
The PBS buffer described above is used. 704 mg sodium chloride (Fisher Scientific), 601.2 mg sodium phosphate dibasic anhydride (Fisher Scientific), 242.7 mg sodium phosphate monobasic anhydride (Fisher Scientific), 140.4 g sterile filtered distilled water And dissolved. The solution was cooled in an ice cold water bath, after which 50 g of poloxamer 407NF (SPECTRUM CHEMICALS) was sprinkled into the cold solution while mixing. The mixture was further mixed until the poloxamer was completely dissolved.

A series of formulations was prepared with the stock solution.
An appropriate amount of otic agent (or salt or prodrug thereof) and / or micronized / coated / liposomal particulate material (or salt or prodrug thereof) is used for all experiments.

Tables 2 and 3 list samples prepared using the procedure described above. An appropriate amount of otic agent is added to give a final concentration of 2% to the otic agent in the sample.
Table 2. Preparation of samples containing Tris buffer i-20

Table 3 Preparation of samples containing PBS buffer (pH 7.3)

1 mL samples are individually placed in 3 mL screw cap glass vials (with rubber lining) and closed tightly. The vial was placed in a Market Forge-sterilmatic autoclave (setting, slow liquid) and sterilized at 250 degrees Fahrenheit for 25 minutes.
After autoclaving, the sample was left to cool to room temperature. The vials were placed in the refrigerator and mixed while cooling to homogenize the sample.

  HPLC analysis uses a Luna C18 (2), 3 μm, using a 30-80 acetonitrile gradient (1-10 minutes) (water-absorbing acetonitrile mixture containing 0.05% TFA) for a total of 15 minutes. , 100 Angstrom, 250 × 4.6 mm column). Samples were diluted with [30 μL sample taken, 1.5 mL of 1: 1 acetonitrile water mixture]. The purity of the otic drug in the autoclaved sample is recorded. The stability of the formulation between TRIS buffer and PBS buffer was compared.

The viscous material is measured at 0.08 rpm (shear speed 0.31 s ^-1 ) equipped with a water jacket temperature control unit (temperature gradient from 15 to 34 ° C at 1.6 ° C / min). This was performed using a Brokfield viscometer RVDV-II + P equipped with a CPE-51 spindle. Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the solgel transition. Only formulations that show no change after autoclaving are analyzed.

  Formulations containing DNQX, D-methionine, micronized AM-101, or micronized (S) -ketamine contain 2% otic drug and 17% poloxamer 407NF after heat sterilization (autoclaving) In order to determine the effect of the secondary polymer on the degradation product and viscosity of the containing formulation, it was examined using the procedure described above. The stability of the formulation containing the micronized otic drug is compared to the stability of the non-micronized otic drug.

Example 14-Pulsed release of otic drug
A combination of D-methionine and D-methionine hydrochloride (1: 1 ratio) was used to modulate the otic drug pulsed using the procedure described herein. Twenty percent of the delivered dose of D-methion was solubilized in the 17% poloxamer solution of Example 10 with the aid of beta cyclodextrin. The remaining 80% of the otic drug was then added to the mixture and the final formulation was prepared using any of the procedures described herein.

  DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine prepared according to the procedures and examples described above were described herein to determine pulsed release characteristics. Inspected using procedures.

EXAMPLE 15 Preparation of 17% Poloxamer 407/2% Ear Drug / 78 ppm Evans Blue in PBS A stock solution of Evans Blue (5.9 mg / mL) in PBS buffer was [5.9 mg Evans Blue (Sigma Chemical Co) was prepared by dissolving in 1 mL PBS buffer (eg from Example 10).

  A stock solution containing 25% poloxamer 407 solution in PBS buffer was used for this study. The appropriate amount of otic drug was added to prepare a formulation containing 2% otic drug (Table 4).

Table 4 Preparation of poloxamer 407 samples containing Evans Blue

  Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine were prepared according to the procedure described above and filtered through a 0.22 μm PVDF syringe filter (Millipore corporation). Autoclaved.

  The formulation is administered to the middle ear of a guinea pig according to the procedure described herein, and the formulation ability and the location of the gel in contact with the gel is confirmed after administration and 24 hours after administration. It was.

Example 16-Final sterilization of poloxamer 407 formulation with and without visualization dye
17% poloxamer 407/2% otic agent / phosphate buffer, pH 7.3
709 mg sodium hydrochloride (Fisher Scientific), 742 mg sodium phosphate dibasic anhydrous USP (Fisher Scientific), 251.1 mg sodium phosphate monobasic monohydrate USP (Fisher Scientific) and the appropriate amount of ear The drug is dissolved with 158.1 g of sterile filtered distilled water. The solution was cooled in an ice cold water bath, after which 34.13 g of poloxamer 407NF (Spectrum chemicals) was sprinkled into the cold solution while mixing. The mixture was further mixed until the poloxamer was completely dissolved.

17% poloxamer 407/2% otic drug in phosphate buffer / 59ppm Evans Blue Take 2 mL of 17% poloxamer 407/2% otic drug in phosphate buffer and 5.9 mg / mL in PBS buffer solution In an Evans blue (Sigma-Aldrich chemical Co) solution, 2 mL of PBS buffer solution was added.

25% poloxamer 407/2% otic agent in phosphate buffer
330.5 mg sodium hydrochloride (Fisher Scientific), 334.5 mg sodium phosphate dibasic anhydrous USP (Fisher Scientific), 125.9 mg sodium phosphate monobasic monohydrate USP (Fisher Scientific) and appropriate amounts Are dissolved in 70.5 g of sterile filtered distilled water.

  The solution was cooled in an ice cold water bath, after which 25.1 g of poloxamer 407NF (Spectrum chemicals) was sprinkled into the cold solution while being mixed. The mixture was further mixed until the poloxamer was completely dissolved.

Take 25 mL of 25% poloxamer 407/2% otic drug in phosphate buffer / 59 ppm Evans Blue 25% poloxamer 407/2% otic drug in phosphate buffer, 5.9 mg / mL in PBS buffer 2 mL of a solution of Evans Blue (Sigma-Aldrich chemical Co) was added.

  2 mL of the formulation was placed in a 2 mL Wheaton serum glass vial, sealed with 13 mm butyl str (kimble stoppers) and crimped with an aluminum seal. Vials were placed in MarketForge-sterilmatic autoclave (setting, slow liquid) and sterilized at 250 degrees Fahrenheit for 25 minutes. After autoclaving, the sample was left to cool to room temperature and then placed in the refrigerator. The vials were placed in the refrigerator and mixed while cooling to homogenize the sample. Sample dissolution or precipitation after autoclaving was recorded.

  HPLC analysis was performed using a Luna C18 (2) (3 μm, 100 Å, 250 × 4.6 mm column, using a 30-95 methanol 4 gradient (1-6 minutes) for a total of 22 minutes followed by a homogeneous solvent for 11 minutes. ) With an Agilent 1200 equipped with Samples were diluted with 30 μL of sample and dissolved in 0.97 mL of water. The main peaks are recorded in the table below. The purity before autoclaving is always below 99% using this method.

  The viscous material is measured at 0.08 rpm (shear speed 0.31 s-1) equipped with a water jacket temperature control unit (with a temperature gradient from 15 to 34 ° C at 1.6 ° C / min). This was performed using a Brokfield viscometer RVDV-II + P equipped with a CPE-51 spindle. Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the sol-gel transition.

  Formulations containing DNQX, D-methionine, micronized AM-101 or (S) -ketamine are prepared according to the procedures described herein and the above method is used to determine the stability of the formulation Inspected.

Example 17-In Vitro Comparison of Release Properties Gels described herein are performed at 37 degrees Celsius in Snapwell (6.5 mm diameter polycarbonate membrane with 0.4 μm pore size) 0.2 mL of the formulation is placed in a snap well and then left to harden, 0.5 mL buffer is placed in a reservoir and shaken using a Labrin Orbit shaker at 70 rpm. Samples were taken every hour (0.1 mL was removed and replaced with warm buffer). Samples are analyzed at otic drug concentrations by 245 nm UV light against an external calibration standard curve. Pluronic (trade name) concentration is analyzed at 624 nm using the cobalt thiocyanate method. The relative rank order of mean dissolution time (MDT) as a function of% P407 is determined. The linear relationship between formulation mean dissolution time (MDT) and P407 concentration indicates that the otic drug is released by erosion of the polymer gel (poloxamer) and not via diffusion. A non-linear relationship indicates release of the otic drug through a combination of diffusion and / or alteration of the polymer gel.

  Alternatively, the samples were analyzed using the method described in Lee Shin-Yu's paper: “Acta Pharmaceuticals Kashinika, 2008, 43 (2), 208-203” and as a function of% P407. The relative rank order of the mean dissolution time (MDT) of is determined.

  Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine prepared according to the procedures described herein are for determining the release characteristics of an otic drug Inspected using the above method.

Example 18-In Vitro Comparison of Gelation Temperature The effect of poloxamer 188 and otic agents on the gelation temperature and viscosity of poloxamer 407 is evaluated for the purpose of manipulating the gelation temperature.

A 25% poloxamer 407 stock solution in PBS buffer and the aforementioned PBS solution are used.
A poloxamer 188NF manufactured by BASF is used. The proper amount of otic drug is added to the solutions listed in Table 5 to provide a 2% formulation of the otic drug.

Table 5 Preparation of samples containing poloxamer 407 / poloxamer 188, i-23

  The average dissolution time, viscosity, and gelation temperature of the above-described formulations are measured using the procedures described herein.

  The equation is fit to the data obtained and can be used to estimate the average dissolution time (hours) based on the gelation temperature of the F127 / F68 mixture (between 17-20% F127 and 0-10% F68).

Tgel = -1.8 (% F127) +1.3 (% F68) +53

  The equation was fit to the data obtained and using the results obtained in Example 12, the average dissolution based on the gelation temperature of the F127 / F68 mixture (between 17-25% F127 and 0-10% F68) Can be used to estimate time (time).

MDT = -0.2 (Tgel) +8

Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine are prepared by adding appropriate amounts of the otic agents listed in Table 5.
The gelation temperature of the formulation is determined using the procedure described above.

Example 19-Determination of temperature range for sterile filtration The viscosity at low temperature is measured to help guide the temperature range in which sterile filtration must occur to reduce the possibility of clogging.

  Viscosity measurements were made using a Brookfield viscometer RVDV-II + P rotating the CPE-40 spindle at 1, 5 and 10 rpm (shear rate 7.5.37.5 and 75 s-1), with a jacket water temperature control unit (temperature gradient) Is carried out at a temperature of 1.6 ° C./min.

  Tgel of 17% Pluronic P407 is determined as a function to increase the concentration of otic drugs. The increase in Tgel for the 17% pluronic formulation is assessed by:

ΔTgel = 0.93 [% ear drug]

  Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine, prepared according to the procedures described herein, determine the temperature range for sterile filtration Inspected using the above procedure. For Tgel, the effect of increasing the amount of otic drug and the apparent viscosity of the formulation is recorded.

Example 20-Determination of manufacturing conditions Table 6 Viscosity / filtration conditions of potential formulations during manufacturing

  An 8 liter batch of 17% P407 placebo is manufactured to evaluate manufacturing / filtration conditions. The placebo is manufactured by filling 6.4 liters of distilled water in a 3 gallon SS pressure vessel and let it cool in the refrigerator overnight. The next morning, the tank was taken out (water temperature 5 ° C., RT 18 ° C.), 48 g of sodium chloride, 29.6 g of dibasic dihydrate sodium phosphate, 10 g of monobasic monohydrate sodium phosphate were added, and an overhead mixer (IKARW20 ( Product name) Dissolved by 1720 rpm After half an hour, when the buffer solution was dissolved (solution temperature 8 ° C., RT 18 ° C.), 1.36 kg of poloxamer 407NF (Spectrum Chemical Co.) was added to the buffer solution at intervals of 15 minutes. Water was slowly sprinkled (solution temperature 12 ° C., RT 18 ° C.), then the speed was increased to 2430 rpm, and after another hour mixing, the mixing speed was reduced to 1062 rpm (complete dissolution).

  Room temperature is maintained below 25 ° C. to keep the temperature of the solution below 19 degrees. The temperature of the solution is kept below 19 degrees up to 3 hours of production without requiring refrigeration / cooling of the container.

Three different Sartoscale (trade name) (Sartorius Stedim) filters with a surface area of 17.3 cm 2 were evaluated at a solution pressure of 20 psi and a temperature of 14 ° C.
1) Sartopore (registered trademark) 2, 0.2 μm 5445307 HS-FF (PES), flow rate 16 mL / min
2) Sartobran (registered trademark) P, 0.2 μm 5235307 HS-FF (cellulose ester), flow rate 12 mL / min
3) Sartopore (registered trademark) 2XLI, 0.2 μm 5445307 IS-FF (PES), flow rate 15 mL / min

  Sartopore® 2 filter 5441307H4-SS is used, and 0.45 μm, 0.2 μm Sartopore® 2 150 sterile capsule (trade name: Sartorius Stedim) with a surface area of 0.015 m 2 at 16 psi pressure) And filtered. The flow rate was measured at 16 psi and about 100 mL / min, but the flow rate was unchanged and the temperature was maintained in the range of 6.5-14 ° C. The solution pressure drop and temperature increase caused the flow rate to increase due to the solution viscosity increase. During the process, the alteration of the solution is monitored.

Table 7 Expected filtration times for 17% poloxamer 407 placebo in the melting temperature range of 6.5 to 14 ° C. using Sartopore 2 (0.2 μm filter with 16 psi pressure)

Viscosity, Tgel and UV / Vis absorption were checked before filtration evaluation. Pluronic UV / Vis spectra were obtained with Evolution160 (trade name) (Thermo Scientific). The peak in the range of 250 to 300 nm is due to the BHT stabilizer present in the raw material (poloxamer). Table 8 lists the physicochemical properties of the solution before and after filtration.
Table 8 Physicochemical properties of 17% poloxamer 407 placebo solution before and after filtration i-26

The above process applies to the manufacture of the 17% P407 formulation and includes temperature analysis of room conditions.
Preferably, a maximum temperature of 19 ° C. reduces the cost of cooling the vessel during manufacture.
In some cases, jacketed containers are used for further solution temperature control, facilitating solving manufacturing problems.

Example 21-In vitro release from autoclaved micronized sample to otic drug 17% poloxamer 407 / 1.5% otic drug in Tris buffer
250.8 mg sodium chloride (Fisher Scintific) and 302.4 mg Tromethamine (Sigma Chemical Co.) were dissolved in 39.3 g sterile filtered distilled water and adjusted to pH 7.4 with 1M HCl. The above solution 4.9 was used, and an appropriate amount of micronized otic drug was suspended and dispersed well. 2 mL of the formulation was transferred to a 2 mL glass vial (Wheatonserum glass vial), sealed with 13 mm butyl styrene (kimble stoppers) and crimped with a 13 mm aluminum seal. Vials were placed in Market Forge-sterilmaticautoclave (setting, slow liquid) and sterilized at 250 degrees Fahrenheit for 25 minutes. After autoclaving, the sample was left to cool to room temperature. The vials were placed in a refrigerator and mixed and cooled to homogenize the sample. Sample dissolution or precipitation after autoclaving was recorded.

  In a snap well (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm), the dissolution took place at 37 degrees Celsius, 0.2 mL of gel was placed in the snap well and allowed to cure, then 0.5 mL of PBS buffer is placed in the reservoir and vibrated at 70 rpm using a Labrin Orbit shaker. Samples are taken every hour [0.1 ml is removed and replaced with a warm buffer containing 2% PEG-40 hydrogenated castor oil (BASF) to facilitate solubility of the otic drug. ] Samples are analyzed at otic drug concentrations by 245 nm UV light against an external calibration standard curve. The release ratio is compared with other formulations described herein. The MDT time is calculated for each sample.

  Solubilization of the otic drug in the 17% poloxamer system was evaluated by measuring the concentration of the otic drug in the supernatant after centrifuging the sample at 15000 rpm for 10 minutes using an Eppendorf centrifuge 5424 (trade name). . The otic drug concentration in the supernatant was measured by UV at 245 nm against an external calibration standard curve.

  Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine prepared according to the procedures described herein provide a release rate of the otic drug from each formulation. Inspected using the above procedure to measure.

Example 22 Release Ratio or MDT and Viscosity of a Formulation Containing Sodium Carboxymethylcellulose
17% Poloxamer 407/2% Ear Drug / 1% CMC (Blanose 7M from Hercules)
PBS buffer solution of sodium carboxymethylcellulose (CMC) (pH 7.0) in 78.1 g of sterile filtered distilled water, 205.6 mg sodium chloride (Fisher Scientific), monobasic phosphate dihydrate sodium phosphate Prepared by dissolving 372.1 mg (Fisher Scientific), 106.2 mg monobasic monohydrate sodium phosphate (Fisher Scientific). To facilitate dissolution, 1 g of Blanose® 7MCMC (Hercules, Viscosity 533cP @ 2%) was sprinkled into the buffer solution, heated, then the solution was cooled, and Poloxamer 407NF (Spectrum Scientific) ) Was sprayed into the cooled solution and mixed at the same time. A formulation containing 17% poloxamer 407NF / 1% CMC / 2% otic drug in PBS buffer was made by adding / dissolving appropriate amount to 9.8g of the above solution, and all otic drug was completely dissolved Until mixed.

17 Poloxamer 407/2% Ear Drug / 0.5% CMC (Blanose 7M65)
Sodium carboxymethylcellulose (CMC) solution (pH 7.2) in PBS buffer was added 257 mg sodium chloride (Fisher Scientific), dibasic dihydrate sodium phosphate (Fisher Scientific) in 78.7 g of sterile filtered distilled water. 375 mg, monobasic monohydrate sodium phosphate (Fisher Scientific) 108 mg. To facilitate dissolution, 0.502 g of Blanose® 7M65CMC (Hercules, viscosity 5600 cP @ 2%) was sprinkled into the buffer solution, heated, then the solution was cooled and Poloxamer 407NF (Spectrum Scientific) 17.06 g was sprinkled into the cooled solution and mixed at the same time. 17% poloxamer 407NF / 1% CMC / 2% otic drug in PBS buffer was made by adding / dissolving appropriate amount to 9.8g of the above solution and mixing until all otic drug was completely dissolved .

17% Poloxamer 407/2% Ear Drug / 0.5% CMC (Blanose 7H9)
Sodium carboxymethylcellulose (CMC) solution (pH 7.3) in PBS buffer was dissolved in 78.6 g of sterile filtered distilled water, 256.5 mg sodium chloride (Fisher Scientific), dibasic dihydrate sodium phosphate (Fisher Scientific) 374 mg, monobasic monohydrate sodium phosphate (Fisher Scientific) 107 mg, and then 0.502 g Blanose® 7H9CMC (Hercules, Viscosity, for ease of dissolution) 5600 cP @ 1%) was sprinkled into the buffer solution, heated, then the solution was cooled, and 17.03 g of Poloxamer 407NF (Spectrum Scientific) was sprinkled into the cooled solution and mixed at the same time. A 17% poloxamer 407NF / 1% CMC / 2% otic drug solution in PBS buffer was made by adding / dissolving the appropriate amount of otic drug solution to 9.8g of the above solution to completely dissolve the otic drug. Until mixed.

  The viscosity measurement is rotated at 0.08 rpm (shear speed 0.6 s-1) equipped with a water jacket temperature control unit (gradient from 10 to 34 ° C. at 1.6 ° C./min.) This was performed using a Brokfield viscometer RVDV-II + P with a CPE-40 spindle. Tgel is defined as the inflection point of the curve where the increase in viscosity occurs due to the solgel transition.

  Lysis was carried out at 37 ° C. in snap wells (6.5 μm diameter polycarbonate membrane with 0.4 μm pore size). 0.2 mL of gel is placed in the snap well and allowed to harden, then 0.5 mL of PBS buffer is placed in the reservoir and shaken at 70 rpm using a Labrin Orbit shaker. Samples are taken every hour and 0.1 mL is removed and replaced with warm PBS buffer. Samples are analyzed for otic drug concentration by UV at 245 nm against an external calibration standard curve. The release rate is compared with the formulation disclosed in the above example. Also, MDT time is calculated for each of the above formulations.

  Formulations containing DNQX, D-methionine, micronized AM-101 or micronized (S) -ketamine prepared according to the above procedure are tested according to the above procedure and release of the formulation containing sodium carboxymethylcellulose Determine the relationship between rate and / or average dissolution time and viscosity. Any correlation between the average dissolution time (MDT) and the apparent viscosity (measured at a temperature 2 ° C. below the gelation temperature) is recorded.

Example 23-Effect of Poloxamer Concentration and Ear Drug Concentration on Release Kinetics A series of compositions including varying the concentration of gelling agent and micronized dexamethasone was prepared using the procedure described above. The average dissolution time (MDT) for each composition in Table 9 was determined using the procedure described above.

Table 9 Preparation of poloxamer / ear drug composition

  The effect of gel strength and otic drug concentration on the release kinetics of the otic drug from the composition or device was determined by measuring MDT for poloxamers and MDT for otic drugs. The half-life of the otic drug and the average residence time of the otic drug were also determined for each formulation by measuring the concentration of the otic drug in the perilymph.

  As described above, the apparent viscosity of each composition was measured. A thermoreversible polymer gel concentration of about 15.5% in the composition or device described above provided an apparent viscosity of about 270,000 cP. A thermoreversible polymer gel concentration of about 16% in the composition or device described above provided an apparent viscosity of about 360,000 cP. A thermoreversible polymer gel concentration of about 17% in the composition or device described above provided an apparent viscosity of about 480,000 cP.

  Compositions comprising micronized DNQX, D methionine, micronized AM-101 or micronized (S) -ketamine prepared according to the above procedure are tested using the above procedure, and each The release rate of the otic drug from the composition is determined.

Example 24-Application of Enhanced Viscous Ear Sensory Cell Modifier Formulation on Round Window Membrane A formulation comprising AM-101 prepared according to Example 8 was prepared and used in a 15 gauge luer lock style Fill a 5 ml siliconized glass syringe fitted with a needle. Lidocaine is applied topically to the tympanic membrane and small incisions are made to visualize the middle ear cavity. The needle tip was guided to a location on the round window membrane, and the ear sensory cell modulator preparation was applied directly on the round window membrane.

Example 25-In vivo study of injection into the middle ear of an otic sensory cell modulator formulation into guinea pigs
A cohort of 21 guinea pigs (Charles River, females weighing 200-300 g) has 50 microliters of different P407 otic drug formulations containing 0-50% otic drug as described herein in the middle ear. Injected into. The gel removal time course for each formulation is determined. The faster gel removal time course of the formulation indicates a lower mean dissolution time (MDT). Therefore, the injection volume and concentration of the ear sensory cell modulator in the formulation is tested to determine the optimal parameters for preclinical and clinical studies.

Example 26-In vivo sustained release kinetics
A cohort of 21 guinea pigs (Charles River, females weighing 200-300 g) is injected into the middle ear with 50 microliters of 17% Pluronic F127 formulation buffered at 280 mOsm / kg. The formulation contains 1.5-35% by weight of an otic drug regulator. Animals are dosed on day 1. The release profile for the formulation is determined based on the analysis of perilymph.

Example 27-Evaluation of (S) -ketamine in tinnitus mouse model
Twelve Harlan Sprague-Dawley mice weighing 20 to 24 g are used. Each mouse is trained to not drink water from the water dispenser during silence and to refrain from drinking in the presence of sound. Each mouse receives 350 mg of aspirin per kilogram of body weight (mg / kg).

  Control group mice (n = 10) are administered a physiological saline after aspirin administration. The experimental group (n = 10) aspirin administration is followed by (S) -ketamine (400 mg / kg body weight). Administration occurs via intra-ear injection.

  Following administration of (S) -ketamine, mice are monitored for drinking in the absence of ambient sounds.

Example 28-Method for evaluating N-acetylcysteine (NAC) and induction of ototoxic hearing loss in a mouse model of toxic hearing loss caused by cisplatin
Twelve Harlan Sprague-Dawley mice weighing 20 to 24 g are used.
A reference value for the auditory brainstem response at 4-20 mHz is measured. Mice are treated with cisplatin (6 mg / kg body weight). Cisplatin is delivered to the aorta by IV infusion.

Treatment Control group mice (n = 10) are administered physiologic saline after cisplatin administration. The experimental group (n = 10) is administered NAC (400 mg / kg body weight) after cisplatin administration.

Analyzing Results Electrophysiological Tests The auditory brainstem response threshold (ABR) auditory threshold for each animal's click stimulus to each ear is first measured and also measured one week after the experimental procedure. Animals are placed in a single layer acoustic booth (Industrial Acoustic Co, Bronx, NY, USA) on a heating pad. Subcutaneous electrodes (Astro-Med, Inc. Crass Instrument Division, West Waewick, RI, USA) were inserted into the apex (exploration electrode), mastoid process (reference), and hind limb (base). The click stimulus (0.1 ms) is computer processed and delivered to a Beyer DT 48,200 Ohm speaker attached to the otoscope for placement in the outer auditory canal. The recorded ABR is amplified and digitized by a battery-powered preamplifier and inserted into the Tucker Davis Technology ABR recording system. This recording system provides stimulation, recording, and averaging functions to a computer (Tucker Davis Technology, Gainesville, FL, USA). Subsequently, the decreasing amplitude stimulus is represented in the 5-dB step for the animal, and the recorded stimulus-locked activity is averaged (n = 512) and displayed. The threshold is defined as the stimulation level between records with no clearly detectable response and records with a clearly identifiable response.

Example 29-Clinical trial of (S) -ketamine as a treatment for tinnitus Active ingredient: (S) -Ketamine Dose: 10 nanograms were delivered to 10 μL of thermoreversible gel. The release of (S) -ketamine is controlled release and occurs for 30 (30) days.

Intra-ear injection

Treatment duration: 12 weeks

Methodology, one centromere, expected, randomized, double-blind, placebo-controlled, parallel group, adaptive

Inclusion criteria: Men and women between the ages of 18 and 64.
• Subjects who experience subjective tinnitus.
・ The duration of tinnitus is more than 3 months.
・ There is no treatment for tinnitus within 4 weeks.

Evaluation criteria and efficacy (primary)
1.Total score and efficacy of tinnitus questionnaire (secondary)
1.Hearing measurement (mode, frequency, tinnitus size, pure tone audiogram, speech geogram)
2. Quality of life questionnaire / safety
1. Treatment groups were compared for the incidence of early termination, adverse reactions during treatment, laboratory modulation and ECG modulation.

Study Design Subjects are divided into three treatment groups. The first group is safety samples. The second group is intent to treat (ITT) samples. The third group is effective for the efficacy (VfE) group.

  For each group, half of the subjects to be given (S) -ketamine and the other half is placebo.

Statistical methods The primary efficacy analysis is based on the total score of the tinnitus questionnaire in the ITT sample. As a covariant, statistical analysis is based on covariance analysis (ANCOVA) at baseline. The last observation also carried the value forward as a dependent variable. The factor is “treatment”. The homogeneity of the regression slope is tested. The analysis is repeated for VfE samples.

  As well as the quality of life, hearing measurements (mode, frequency, tinnitus size, pure tone audiogram, speech geogram) are also analyzed by the aforementioned model. The suitability of the model is not tested. P values are exploratory and are not adjusted due to diversity.

Example 30-AMN082 Evaluation Study Objectives for Cisplatin-Induced Ototoxic Hearing Loss The primary objective of this study was to determine the safety and efficacy of AMN082 (100 mg) compared to placebo in preventing cisplatin-induced ototoxic hearing loss Is to evaluate.

Method Study Design A multicenter, double-blind, randomized, placebo-controlled, parallel group study comparing phasebo and AMN082 (100 mg) during the treatment of this study phase 3, ie cisplatin-induced ototoxin It is. Approximately 140 subjects are enrolled in the study and are randomly selected (1: 1) for one of the two treatment groups based on the randomized order. Each group will receive either AMN082 100 mg or placebo.

  Samples that do not complete the study are not replaced. Patients receive weekly chemotherapy (70 mg / m2 dose for 7 weeks and daily irradiation cisplatin. The following chemotherapy, patients administered directly as gel formulation on subject round window membrane for 8 weeks You will receive a study drug (AMN082 500 mg or a matching placebo).

  Each patient will receive an assessment prior to treatment with cisplatin. Each patient will receive an assessment 2-4 weeks after the final dose of cisplatin. The pre-treatment audiogram is compared to the post-treatment audiogram to determine the degree of addictive hearing loss caused by cisplatin. Patients will then receive assessments at 4-week intervals following AMN082 treatment.

Main criteria for inclusion
Male or female outpatients aged 18-75 are receiving chemotherapy with cisplatin. Patients receive at least 3 rounds of chemotherapy. If the subject becomes pregnant during the study, the study is canceled immediately and no medication is administered.

Exclusion criteria Patients undergoing middle ear surgery. Patients with active external or middle ear disease. Patients who have a pure tone average of> 40dB HL.

Example 31-Clinical trial of AM-101 as a treatment for noise-induced hearing loss Active ingredient: AM-101
Dose: A composition containing 4% by weight of micronized AM-101 is delivered in a 10 μL dose of a thermoreversible gel. AM-101 release is controlled release and occurs for 3 weeks.

  Route of administration: injection in the middle ear

  Treatment duration: 12 weeks, 1 injection every 3 weeks

Methodology, one centromere, expected, randomized, double-blind, placebo-controlled, parallel group, adaptive

Inclusion criteria, male and female subjects between 18 and 64 years of age, acoustic trauma followed by hearing loss documented by audiograms and medical reports with at least 15 dB of inner ear hearing loss, at least 3 Acute tinnitus that lasted for a month.
・ No treatment for tinnitus within 4 weeks.

Evaluation criteria and efficacy (primary)
1.Total score and efficacy of tinnitus questionnaire (secondary)
1.Hearing measurement (method, frequency, tinnitus, pure tone audiogram, speech geogram loudness)
2. Quality of life questionnaire / safety
1. Treatment groups were compared for premature termination, adverse reactions during treatment, incidence of laboratory modulation and ECG modulation.

Study Design Subjects are divided into three treatment groups. The first group is safety samples. The second group is treatment intent (ITT) samples. The third group is effective for the efficacy (VfE) group.

  For each group, half of the subjects to be given AM-101 and the placebo to the remaining subjects.

Statistical methods The primary efficacy analysis is based on the total score of the tinnitus questionnaire on the ITT sample. As a covariant, statistical analysis is based on covariance analysis (ANCOVA) at baseline. The last observation also carried the value forward as a dependent variable. The factor is “treatment”. The homogeneity of the regression slope is tested. The decomposition is repeated for VfE samples.

  Auditory measurements (method, frequency, tinnitus size, pure tone audiogram, speech geogram) as well as quality of life are analyzed by the above-mentioned model. The suitability of the model is not tested. The P value is exploratory and is not adjusted for diversity.

Example 32-Clinical trial active ingredient of (s) -ketamine as treatment combined with transplantation of cochlear hearing device Active ingredient: Combined with dexamethasone administration (S) Ketamine use: used as pre- and post-operative wash solution Micronized (S) -ketamine and micronized dexamethasone. The release of (S) -ketamine and dexamethasone is immediate.

Study design
Twenty patients will be enrolled in the study. Ten patients will be in the control group. There will also be 10 patients in the treatment group.
Eligible criteria ・ Having severe sensorineural hearing loss in both ears ・ Having a functioning auditory nerve ・ Non-listening (average about 70+ decibels) Live for a certain short (at least) time If you have infants and young children who have a good family of conversation skills and language skills, or have a spontaneous family to practice conversation skills and language skills using treatment Do not get enough benefits from listening to your help ・ Do not have a medical reason to avoid surgery

  Each patient will be exposed to electrode insertion and drug treatment. The treatment group will be exposed to perfusion of the surgical area with the test composition before and after surgery. Patients will be monitored for 6 weeks. Speech audiograms will be assessed for trauma within the cochlea based on hearing tests as well as quality of life. The occurrence of secondary infection and / or inflammation will be monitored.

Example 33-Clinical trial speech audiogram of an ear sensory cell modulator combined with surgery The intention of this study is that a composition comprising a combination of AM-101 and dexamethasone administered in combination with tympanic perforation has an ear tube Determining whether it is safe and effective in preventing and / or treating middle ear infections in a patient.

Study Type: Intervention

Study design:
This would be a non-inferior open label study to compare sustained release of the composition in the middle ear with current care standards in combination with tympanic perforation. Current care standards require the use of ear loss 5 to 7 days after surgery. The study is designed to test whether administration of a sustained release composition during surgery eliminates the need for outpatient treatment. The test hypothesis is that administration of a single injection of sustained release composition at the time of surgery is not inferior to the administration of ear drop after surgery.

Inclusion standards:
6 months to 12 years of deafness in one or both ears have not undergone ear surgery other than tube placement in the last year, and there is no disease or symptom that negatively affects the treatment of the study No other systemic antibacterial therapy is required during the study No analgesic use (other than acetaminophen) is allowed

Exclusion criteria: Age

Research protocol:
Twenty patients will be divided into two groups.
The first group of patients will receive an infusion of a sustained release composition comprising micronized AM-101 and micronized dexamethasone prepared according to Example 22 during surgery. Each patient will undergo tympanic perforation for tube placement. During the surgical procedure, the surgeon will clean the ear and while the tympanic incision is made, the surgeon injects the test composition into the middle ear space. The tube is inserted after injection of the sustained release composition into the middle ear space. The test composition is prepared in the operating room by retention of a dry finely divided powder of AM-101 and dexamethasone with other excipients. Alternatively, the test composition is a suspension ready for injection.

  The patient's second group will be given an ear-tracking method containing unmicronized AM-101 and non-micronized dexamethasone as an immediate release component administered 5-7 days after surgery.

  Patients continue follow-up visits for one month, monitored weekly. Any difference in treatment outcome between the two groups is recorded.

Primary endpoint: Time secondary endpoints for withdrawal of otorrhea as recorded by the parent or guardian by the patient are clinical cure rate; microbiology results, treatment failure, disease recurrence.

  The treatment results for each group of patients are compared to determine: That is, administration of a sustained release composition comprising AM-101 and dexamethasone in combination with tympanic perforation results in AM-101 and dexamethasone after surgery for reducing ear leakage for reduction of infection and / or inflammation associated with tympanic perforation It is worse than the administration of the ear-drop method including.

While preferred embodiments of the invention have been shown and described herein, such embodiments are provided by way of example only. Various alternatives to the embodiments described herein are optionally employed in practicing the present invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. Yes.

Claims (28)

A method of selectively inducing damage to otic sensory cells comprising a tympanic composition or device comprising a therapeutically effective amount of an ototoxic agent, a substantially low degradation product ototoxic agent A composition or device comprising: administering to an individual in need a composition or device further comprising two or more properties selected from:
(I) from about 0.1% to about 10% by weight of an ototoxic agent, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) a suitable amount of sterile water buffered to a pH of about 5.5 to about 8.0;
(Iv) multiparticulates of ototoxic agents,
(V) a gelling temperature between about 19 ° C and about 42 ° C;
(Vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation;
(Vii) less than about 5 endotoxin units (EU) per kg of subject weight;
(Viii) an average degradation time of about 30 hours of the ototoxic agent, and
(Ix) A method characterized in that it is selected from apparent viscosities from about 100,000 cP to about 500,000 cP.   2. The method of claim 1, wherein the ototoxic agent is released from the composition or device over at least 3 days.   The method of claim 1, wherein the ototoxic agent is released from the composition or device over at least 5 days.   The method of claim 1 wherein the ototoxic agent is essentially in the form of micronized particles. A method for inducing growth of an ear sensory cell, comprising: a tympanic composition or device comprising a therapeutically effective amount of a nutrient; a composition comprising a nutrient with a substantially low degradation product; or Administering to an individual in need of a device, a composition or device further comprising two or more properties selected from:
(I) from about 0.1% to about 10% by weight of a nutrient, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) a suitable amount of sterile water buffered to a pH of about 5.5 to about 8.0;
(IV) Nutrient multiple particles,
(V) a gelling temperature between about 19 ° C and about 42 ° C;
(Vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation;
(Vii) less than about 5 endotoxin units (EU) per kg of subject weight;
(Viii) an average degradation time of about 30 hours of nutrients; and
(Ix) A method characterized in that it is selected from apparent viscosities from about 100,000 cP to about 500,000 cP.   6. The method of claim 5, wherein the nutrient is released from the composition or device over at least 3 days.   6. The method of claim 5, wherein the nutrient is released from the composition or device over at least 5 days.   6. A method according to claim 5, wherein the nutrient is essentially in the form of finely divided particles. A method of mitigating damage to ear sensory cells from an ear intervention procedure, comprising: a tympanic composition or device comprising a therapeutically effective amount of an ear protectant, a substantially low degradation product ear protectant A composition or device comprising: administering to an individual in need a composition or device further comprising two or more properties selected from:
(I) from about 0.1% to about 10% by weight of an ear protectant, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) a suitable amount of sterile water buffered to a pH of about 5.5 to about 8.0;
(Iv) multiple particles of an ear protectant,
(V) a gelling temperature between about 19 ° C and about 42 ° C;
(Vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation;
(Vii) less than about 5 endotoxin units (EU) per kg of subject weight;
(Viii) an average degradation time of about 30 hours of the ear protectant, and
(Ix) a method selected from apparent viscosities from about 100,000 cP to about 500,000 cP.   10. The method of claim 9, wherein the ear protectant is administered before the ear intervention procedure or during the ear intervention procedure.   The method of claim 9, wherein the ear protection agent is administered after the ear intervention procedure.   The method of claim 9, wherein the ear protectant is essentially in the form of finely divided particles. A pharmaceutical composition or device comprising a therapeutically effective amount of an ototoxic agent to treat an otic disease or disease, a substantially low degradation product of the ototoxic agent, wherein the pharmaceutical composition or device comprises: And further comprising two or more properties selected from:
(I) from about 0.1% to about 10% by weight of an ototoxic agent, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) a suitable amount of sterile water buffered to a pH of about 5.5 to about 8.0;
(Iv) multiparticulates of ototoxic agents,
(V) a gelling temperature between about 19 ° C and about 42 ° C;
(Vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation;
(Vii) less than about 5 endotoxin units (EU) per kg of subject weight;
(Viii) an average degradation time of about 30 hours of the ototoxic agent, and
(Ix) A pharmaceutical composition or device characterized in that it is selected from an apparent viscosity of about 100,000 cP to about 500,000 cP. The pharmaceutical composition or device is
(I) from about 0.1% to about 10% by weight of an ototoxic agent, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) ototoxic agent multiparticulates,
14. The pharmaceutical composition of claim 13, comprising (iv) a gelling temperature between about 19 [deg.] C. and about 42 [deg.] C., and (v) an apparent viscosity from about 100,000 cP to about 500,000 cP. Object or device.   14. The pharmaceutical composition or device of claim 13, wherein the pharmaceutical composition or device provides an actual osmolarity between about 200-400 mOsm / L.   14. The pharmaceutical composition or device of claim 13, wherein the pharmaceutical composition or device provides an actual osmolarity between about 250-320 mOsm / L.   14. The pharmaceutical composition or device of claim 13, wherein the ototoxic agent is released from the composition or device over at least 3 days.   14. The pharmaceutical composition or device of claim 13, wherein the ototoxic agent is released from the composition or device over at least 5 days.   14. A pharmaceutical composition or device according to claim 13 which is a thermoreversible gel acceptable to the ear.   134. The pharmaceutical composition or device of claim 133, wherein said ototoxic agent is essentially in particulate form. A pharmaceutical composition or device comprising a therapeutically effective amount of a nutrient to treat an ear disease or disease, a substantially low degradation product of the nutrient, the pharmaceutical composition or device comprising: Further comprising two or more properties selected from:
(I) from about 0.1% to about 10% by weight of a nutrient, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) a suitable amount of sterile water buffered to a pH between about 5.5 and about 8.0;
(Iv) multiple particles of nutrients,
(V) a gelling temperature of about 19 ° C to about 42 ° C;
(Vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation;
(Vii) less than about 5 endotoxin units (EU) per kg of subject weight;
(Viii) an average degradation time of about 30 hours of the nutrient, and
(Ix) A pharmaceutical composition or device selected from an apparent viscosity of about 100,000 cP to about 500,000 cP. The composition or device is
(I) from about 0.1% to about 10% by weight of a nutrient, or a pharmaceutically acceptable prodrug or salt;
(Ii) about 14% to about 21% by weight of a polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E106P70E106;
(Iii) multiple particles of nutrients,
(Iv) a gelling temperature between about 19 ° C and about 42 ° C;
(Viii) an average degradation time of about 30 hours of nutrients; and
22. The pharmaceutical composition or device of claim 21, wherein (ix) is selected from an apparent viscosity from about 100,000 cP to about 500,000 cP.   23. The pharmaceutical composition or device of claim 21, wherein the pharmaceutical composition or device provides an actual osmolarity between about 200-400 mOsm / L.   24. The pharmaceutical composition or device of claim 21, wherein the pharmaceutical composition or device provides an actual osmolarity between about 250-320 mOsm / L.   The pharmaceutical composition or device of claim 21, wherein the nutrient is released from the composition or device over at least 3 days.   The pharmaceutical composition or device of claim 21, wherein the nutrient is released from the composition or device over at least 5 days.   22. The pharmaceutical composition or device of claim 21, wherein the pharmaceutical composition or device is an ear acceptable thermoreversible gel.   The pharmaceutical composition or device of claim 21, wherein the nutrient is essentially in the form of microparticles.