CN106344495A

CN106344495A - Controlled release corticosteroid compositions and methods for the treatment of otic disorders

Info

Publication number: CN106344495A
Application number: CN201610730867.1A
Authority: CN
Inventors: 杰伊·利希特尔; 贝内迪克特·福尔拉特; 安德鲁·M·特拉梅尔; 塞尔希奥·G·杜龙; 法布里斯·皮乌; 路易斯·A·德拉玛丽; 叶强; 卡尔·勒贝尔; 迈克尔·克里斯托弗·斯凯夫; 杰弗里·P·哈里斯
Original assignee: University of California; Otonomy Inc
Current assignee: University of California; Otonomy Inc
Priority date: 2008-12-22
Filing date: 2009-12-10
Publication date: 2017-01-25
Also published as: AU2009330458B2; JP2015164943A; CN102112111A; CA2732686C; CA2732686A1; AU2009330458A1; WO2010074992A3; EP2299976A4; JP2018138585A; EP2299976A2; JP2017160232A; WO2010074992A2; JP6207093B2; JP2012513394A; JP6013736B2

Abstract

Disclosed herein are compositions and methods for the treatment of otic disorders with steroid, NSAID, and/or adenosine triphosphatase ("ATPase") modulator agents. In these methods, the steroidal, NSAID, and/or ATPase compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of these compositions and formulations onto or via perfusion into the targeted auris structure(s).

Description

For treating the control release ear sensory cell regulating composition of otic conditions

The application is to be on December 10th, 2009 applying date, Application No. 200980130562.5, invention entitled " is used for The divisional application of the application for a patent for invention of the control release ear sensory cell regulating composition for the treatment of otic conditions and method ".

Technical field

The present invention relates to for the control release ear sensory cell regulating composition treating otic conditions.

Cross reference

Present application for patent advocates following right: U.S. Provisional Application case the 61/th filed in 22 days December in 2008 No. 140,033, U.S. Provisional Application case filed in 13 days March in 2009 the 61/160,233rd, filed in 30 days March in 2009 U.S. Provisional Application case the 61/164,812nd, U.S. Provisional Application case filed in 30 days April in 2009 the 61/174,421st, UK Patent Application case filed in 24 days April in 2009 the 0907070.7th and U.S. Shen filed in 16 days July in 2009 Please case the 12/504th, 553, all patents are incorporated herein in entirety by reference.

Background technology

Vertebratess have a double-lug, are symmetrically located at the opposite side of head.Ear is used as the sensory receptor of detection sound Official and the organ maintaining balance and position.Ear is broken generally into three parts: external ear (outer ear), middle ear (auris Media/middle ear) and internal ear (auris interna/inner ear).

Content of the invention

Be described herein for by least one ear sensory cell regulator control release or be transferred to ear at least one The compositionss in structure or area, composite, manufacture method, Therapeutic Method, purposes, test kit and transfer device.In some embodiments In, ear sensory cell regulator is that ear sensory cell damages agent.In certain embodiments, ear sensory cell regulator is ear sensation Cell death agent.In certain embodiments, ear sensory cell regulator is that ear sensory cell protective agent (for example promotes ear sensation thin Born of the same parents are survived).In certain embodiments, ear sensory cell regulator is ear sensory cell growth/regenerative agent.It is disclosed herein and be used for controlling Treat or improve by internal ear gross loss is bad, hypoevolutism, malfunction, damage, fragility or the hearing disability caused by losing or decline Control release compositionss.In one embodiment, control release compositionss comprise therapeutically effective amount at least one auricularis unit and/ Or the regulator (also referred to as " ear sensory cell regulator ") of hair cell, ear are subjected to control release excipient and the acceptable matchmaker of ear Agent.

In certain embodiments, the target part of ear is middle ear.In other embodiments, the target part of ear is interior Ear.In other embodiments, the target part of ear is middle ear.In other embodiments again, the target part of ear is middle ear With internal ear.In certain embodiments, control release composite additionally comprises for ear sensory cell regulator is transferred to middle ear And/or the quick or immediate-release component of internal ear.All composites comprise middle ear and/or the acceptable excipient of internal ear.

The method that induction middle ear or interior in ear selectivity ear sensory cell damage and/or death are described herein, methods described Comprise to cast ear sensory cell regulator control release composite as herein described.Induction ear sensory cell growth is also described And/or reverse the infringement to ear sensory cell (such as hypoevolutism or malfunction ear sensory cell) and/or protection ear sensation In order to avoid injured method further, methods described comprises to cast cell (such as hypoevolutism or malfunction ear sensory cell) Ear sensory cell regulating composition as herein described.

Also disclosed herein is being used for the method treating otic conditions, methods described comprises to cast the control of ear sensory cell regulator Release composite.In certain embodiments, ear sensory cell regulator be poisonous substance (such as gentamycin (gentamicin)) and Inducing cell death.In certain embodiments, ear sensory cell regulator is otoprotective agent (such as amine phosphorus spit of fland (amifostine)), antioxidant etc..In certain embodiments, ear sensory cell regulator induces new ear sensory cell Growth, for example, express the adenoviruss of atoh1.In certain embodiments, ear sensory cell regulator is to reduce or suppression ear sensation The medicament of cell death, such as glutamate receptor modulators.

In certain embodiments, glutamate receptor modulators are glutamate receptor antagonists.In certain embodiments, paddy ammonia Acid acceptor antagonist is nmda receptor antagonist.In certain embodiments, the medicament adjusting nmda receptor is nmda receptor antagonist Agent.In certain embodiments, ear sensory cell regulator is that nutrient (for example promotes the medicine of healthy cell and/or tissue growth Agent).In certain embodiments, nutrient is somatomedin.In certain embodiments, somatomedin is brain-derived neurotrophy The factor (bdnf), ciliary neurotrophic factor (cntf), glial cell line derived neurotrophic sex factor (gdnf), neurotrophy Protein-3, neurotrophin -4, fibroblast growth factor (fgf), insulin like growth factor (igf) etc. and/or its Combination.In certain embodiments, ear sensory cell regulator is the medicament with protective effect, for example, reduce inflammation and/or sense The immune system cell of dye.In certain embodiments, immune system cell is macrophage, microglia (microglia) And/or microglia like cell.In certain embodiments, ear sensory cell regulator be na+ channel blocker and minimizing or Suppression ear sensory cell damages and/or dead.In certain embodiments, ear sensory cell regulator is otoprotective agent, for example, subtract Less, delay or the corticosteroid reversing the damage to ear sensory cell.In certain embodiments, ear sensory cell regulator is Cause the dead ototoxicity agent of ear sensory cell or poisonous substance.In certain embodiments, ear sensory cell regulator is that prb is adjusted Agent.In certain embodiments, ear sensory cell regulator is th receptor modulators.In certain embodiments, ear sensory cell is adjusted Section agent is the adenoviruss of expression brn3.In certain embodiments, ear sensory cell regulator is brn3 agonist.In some enforcements In example, ear sensory cell regulator is brn3 antagonist.In certain embodiments, ear sensory cell regulator is to promote ear sensation The stem cell of cell growth and/or regeneration and/or ear sensation noble cellss.

In certain embodiments, compositionss additionally comprise ear sensory cell regulator as releasing agent immediately (wherein immediately Release ear sensory cell regulator is and Controlled release formulation identical medicament), another ear sensory cell regulator, other therapeutic agent Or a combination thereof.

In certain embodiments, compositionss additionally comprise other therapeutic agents.In certain embodiments, described other therapeutic agent It is anesthetis, local action anesthetis, analgesic, antibiotic, Bendectin, antifungal, antimicrobial, preservative, disease-resistant Toxic agent, chemotherapeutics, diuretic, keratin-lytic agent, otoprotective agent (such as steroid), immunosuppressant, including (but not limited to) Such as calcineurin (calcineurin) inhibitor (ciclosporin (cyclosporine), tacrolimuss (tacrolimus), pimecrolimus (pimecrolimus)), macrolide (such as rapamycin (rapamycin)), cortex class The medicaments such as sterin, or a combination thereof.In certain embodiments, described other therapeutic agent is releasing agent immediately.In certain embodiments, Described other therapeutic agent is Controlled release formulation.

Transmission ear sensory cell regulator is disclosed herein to the control release composite of ear.In certain embodiments, throw Give compositionss so that compositionss are contacted with crest of fenestra cochleae, oeil de boeuf or tympanum.

Ear composite as herein described and Therapeutic Method have many and overcome composite described in the prior and treatment The circumscribed advantage not previously being realized of method.

Aseptic

Inner ear environment is the environment of isolation.Endolymph and perilymph are static fluid, and do not contact with blood circulation. Blood including blood-endolymph barrier and blood-perilymph barrier-lost-barrier (blb) by lost space (that is, vestibule and Cochlea space) in peculiar epithelial cell between tight connection composition.(such as ear sensation is thin for the presence restricted activity agent of blb Born of the same parents' regulator) to the transmission in the isolation microenvironment of internal ear.Tragus cell is dipped in endolymph or perilymph fluid, and potassium ion Cochlea recirculation critically important for hair cell function.When inner ear infections, leukocyte and/or immunoglobulin (for example should Answer microorganism infection) flow in endolymph and/or perilymph, and fluid of inner ear accurate ion composition by leukocyte and/or is exempted from The inflow of epidemic disease globulin is upset.In some cases, fluid of inner ear lead to hearing disability, disequilibrium from molecular change And/or auditory structures ossify.In some cases, or even trace pyrogen and/or microorganism all can cause internal ear isolation microenvironment In infection and relevant physiological change.

Owing to the sensitivity to infection for the internal ear, ear composite needs the sterilized water not yet recognized so far in prior art Flat (for example low biological load).Provided herein is there is low biological load through manufacture or by strict sterility requirements sterilizing and being suitable to throw Give the ear composite of middle ear and/or internal ear.In certain embodiments, ear compatible compositions as herein described are substantially free of heat Former and/or microorganism.

The compatibility with inner ear environment

Ionic equilibrium and perilymph are described herein and/or endolymph is compatible and the ear of any change that do not cause cochlear potentials Use composite.In a particular embodiment, the volume osmolality/osmolality of composite of the present invention is for example logical Cross using suitable salinity (such as sodium salt concentration) or endolymph is compatible and/or perilymph is compatible so that composite is become The tonicity agent of (that is, isotonic with endolymph and/or perilymph) is adjusting.In some cases, endolymph as herein described is compatible And/or the compatible composite of perilymph the interference minimum to inner ear environment and mammal (such as mankind) discomfort after casting (such as dizziness) degree is minimum.In addition, composite comprises biodegradable and/or dispersibles and/or in other words internal earrings Nontoxic polymer for border.In certain embodiments, composite as herein described does not contain preservative and auditory structures is done Disturb (the such as change of ph value or volume osmolality, stimulation) minimum.In certain embodiments, composite as herein described Comprise the antioxidant non-stimulated and/or nontoxic to ear's structure.

Administration frequency

The existing nursing standard of ear composite needs repeatedly to cast few drops through some skies (being for example up to two weeks) or notes for several times Penetrate (such as Injection in Tympanic Cavity), including the schedule accepting multiple injection daily.In certain embodiments, ear allotment as herein described Thing is control release composite and is cast with the administration frequency of minimizing compared with existing nursing standard.In some cases, work as ear When composite casts via Injection in Tympanic Cavity, the dosing frequency of minimizing relaxes and is just carrying out middle ear and/or disease of inner ear, disease or disease The discomfort being caused by multiple Injection in Tympanic Cavity of the individuality of shape treatment.In some cases, the Injection in Tympanic Cavity dispensing frequency of minimizing Rate makes the risk reduction of permanent damage eardrum (the such as perforation of ear drum).Composite as herein described to inner ear environment constant, hold Continue, extend, postpone or pulsating speed release bioactive agent, therefore avoid any transmutability that in otic conditions treatment, medicine exposes.

Therapeutic index

Ear composite as herein described cast in auditory meatus or ear vestibule in.Reach such as vestibule and cochlea organ will wear Cross middle ear, including round window membrane (round window membrane), oval window/stapes footplate, anular ligamentses and pass through otic capsule/ Temporal bone.Composite as herein described ear dispensing avoid activating agent the toxicity related to Systemic administration (such as liver toxicity, Cardiac toxicity, gastrointestinal side-effect, nephrotoxicity).In some cases, ear topical administration allows activating agent in no systemic active Target organ (such as internal ear) is reached in the case of agent accumulation.In some cases, ear topical administration provides higher activity Agent therapeutic index, in other words, will have the restricted systemic toxicity of administration.

Prevent from entering in pharyngotympanic tube

In some cases, the shortcoming of liquid formulation is intended to instill in pharyngotympanic tube and lead to composite quickly from interior Remove in ear.In certain embodiments, provided herein is comprising to be gelled under body temperature and keep (for example round with target audition surface Window) Long contact time polymer ear composite.In certain embodiments, composite additionally comprises permission composite and adheres to The mucomembranous adhesion agent of ear's mucomembranous surface.In some cases, ear composite as herein described avoids because activating agent is via pharynx drum Bank of tubes goes out or leaks and so that treatment benefit is decayed.

The description of some embodiments

Control release compositionss and the device for the treatment of otic conditions are described herein, it is thin that it comprises the ear sensation of therapeutically effective amount Born of the same parents' regulator, control release ear are subjected to excipient and ear is subjected to mediator.On the one hand, control release ear is subjected to excipient choosing From ear acceptable polymer, ear acceptable viscosity reinforcing agent, ear be subjected to gel, ear be subjected to coating, ear be subjected to foams, Ear is subjected to that microsphere or microgranule, ear are subjected to hydrogel, ear is acceptable is formed in situ spongy material, the acceptable light of ear Change radiation curable gel, ear is subjected to liposome, ear is subjected to Nano capsule or the acceptable thermal reversibility of nanosphere body, ear Gel or a combination thereof.In other embodiments, ear acceptable viscosity reinforcing agent is cellulose, cellulose ether, alginate, poly- second Alkene pyrrolidone, glue, cellulosic polymer or a combination thereof.In another embodiment, the amount of ear acceptable viscosity reinforcing agent Enough to provide the viscosity of about 1000 to about 1,000,000 centipoises.Another aspect, the amount of ear acceptable viscosity reinforcing agent be enough to The viscosity of about 50,000 to about 1,000,000 centipoises is provided.In certain embodiments, ear sensory cell regulator composite or group Compound is optimal to guarantee in maintenance for the osmolality or volume osmolality of target ear structure Stable.

In certain embodiments, the ph value of dispensing composition is dense with practical osmolality or volume infiltration mole Degree is to guarantee to remain stable in target ear structure.Perilymph be suitable for volume osmolality/osmolality be Maintain stable practicality in target ear structure/volume infiltration mole can be transmitted dense during casting pharmaceutical formulation as herein described Degree/osmolality.

For example, perilymphatic volume osmolality is between about 270-300mosm/l, and as herein described group The compound optionally formulated actual volume osmolality with offer about 150 to about 1000mosm/l.In some embodiments In, composite as herein described target effect site (such as internal ear and/or perilymph and/or endolymph) provide about 150 to Practicality within about 500mosm/l and/or volume osmolality can be transmitted.In certain embodiments, tune as herein described Join thing within target effect site (such as internal ear and/or perilymph and/or endolymph) provides about 200 to about 400mosm/l Actual volume osmolality.In certain embodiments, composite as herein described is in target effect site (such as internal ear And/or perilymph and/or endolymph) actual volume osmolality within about 250 to about 320mosm/l is provided.At certain In a little embodiments, composite as herein described provides in target effect site (such as internal ear and/or perilymph and/or endolymph) The appearance that perilymph within about 150 to about 500mosm/l, about 200 to about 400mosm/l or about 250 to about 320mosm/l is suitable for Long-pending osmolality.In certain embodiments, composite as herein described is in target effect site (such as internal ear and/or outer Lymph and/or endolymph) provide about 150 to about 500mosm/kg, about 200 to about 400mosm/kg or about 250 to about The osmolality that perilymph within 320mosm/kg is suitable for.Similarly, perilymphatic ph value is about 7.2-7.4, And the ph value formulated (for example by using buffer agent) of composite of the present invention is to provide about 5.5 to about 9.0, about 6.0 to about 8.0 Or the ph value that the perilymph of about 7.0 to about 7.6 is suitable for.In certain embodiments, the ph value of composite is in about 6.0 to about 7.6 models In enclosing.In some cases, endolymphatic ph value is about 7.2-7.9, and the ph value of composite of the present invention formulated (is for example passed through Using buffer agent) in the range of about 5.5 to about 9.0, in the range of about 6.5 to about 8.0 or in the range of about 7.0 to about 7.6.

Some aspects, ear acceptable control release excipient is biodegradable.Some aspects, the acceptable control of ear Release excipient processed is biological eliminable (for example degrading and/or by urine, feces or other exclusion approach exclusion).The opposing party Face, control release compositionss additionally comprise ear and are subjected to mucomembranous adhesion agent, the acceptable penetration enhancers of ear or the acceptable biology of ear Adhesive agent.

On the one hand, control release ear sensory cell regulating composition is transmitted using drug delivery device, and described medicine passes Delivery device is pin and syringe, pump, micro injecting device or a combination thereof.In certain embodiments, the ear sense of control release compositionss Feel that cell modulator has limited or non-systemic release, when systemic administration, there is toxicity, there is bad pk feature or its group Close.Some aspects, ear sensory cell regulator is small molecule agent.Other side, ear sensory cell regulator is antibody.

Also disclosed herein is the method for the treatment of otic conditions, methods described comprises to cast compositions disclosed herein and tune as follows Join thing: at least every 3,4,5,6,7,8,9,10,11,12,13,14 or 15 days once, at least once in a week, once every two weeks, often Once three weeks, every four weeks once, every five weeks once or once every six weeks；Or once a month, each two moon once, every three months one Secondary, every four months once, every five months once, every six months once, every seven months once, every eight months once, every nine months Once, every ten months once, every 11 months once or every 12 months once.In a particular embodiment, control as herein described The ear sensory cell that system release composite provides continuing dosage to internal ear between the subsequent dose of control release composite is adjusted Agent.That is, for only citing an actual example, if the ear sensory cell casting new dosage to round window membrane via Injection in Tympanic Cavity in every 10 days Regulator control release composite, then during this 10 days time, control release composite is provided with effect dosage to internal ear Ear sensory cell regulator (such as pass through round window membrane).

On the one hand, compositionss are cast so that compositionss and crest of fenestra cochleae (crista fenestrae cochleae), round window membrane Or tympanum contact.On the one hand, compositionss are to be cast by Injection in Tympanic Cavity.

In certain embodiments, provided herein is selective induction ear sensory cell damage method, methods described comprise throw Compositionss or device in the tympanum of ototoxicity agent that individuality in need comprises therapeutically effective amount, described compositionss or device is given to comprise Substantially low ototoxicity agent catabolite, described compositionss or device additionally comprise two or more and are selected from following spy Levy:

The ototoxicity agent to about 10 weight % for (i) about 0.1 weight % or its pharmaceutically acceptable prodrug or salt；

(ii) polyoxyethylene-polyoxy with formula e106 p70 e106 between about 14 weight % to about 21 weight % Propylene triblock copolymer；

(iii) appropriate amounts of sterilized water, buffered with provide between the ph value between about 5.5 and about 8.0；

(iv) many granules ototoxicity agent；

Gelation temperature between about 19 DEG C to about 42 DEG C of (v)；

(vi) microorganism agent of less than about 50 colony-forming units (cfu) of every gram of composite；

(vii) less than about 5 endotoxin units (eu) of per kilogram whose body weight；

(viii) the ototoxicity agent average dissolution time of about 30 hours；With

(ix) apparent viscosity of about 100,000cp to about 500,000cp.

In some embodiments of the method, ototoxicity agent discharge from compositionss or device continue at least 3 days when Between.In some embodiments of the method, ototoxicity agent discharges the time continuing at least 5 days from compositionss or device.? In some embodiments of methods described, ototoxicity agent is in substantially micronised particulate form.

The method that induction ear sensory cell growth is also provided herein, methods described comprises to cast individuality in need and comprises to treat Compositionss or device in the tympanum of the nutrient of effective dose, described compositionss or device comprise substantially low nutrient degraded and produce Thing, described compositionss or device additionally comprise two or more selected from following feature:

The nutrient to about 10 weight % for (i) about 0.1 weight % or its pharmaceutically acceptable prodrug or salt；

(iv) many granules nutrient；

Gelation temperature between about 19 DEG C to about 42 DEG C of (v)；

(viii) the nutrient average dissolution time of about 30 hours；With

(ix) apparent viscosity of about 100,000cp to about 500,000cp.

In some embodiments of the method, nutrient discharges the time continuing at least 3 days from compositionss or device. In some embodiments of the method, nutrient discharges the time continuing at least 5 days from compositionss or device.In described side In some embodiments of method, nutrient is in substantially micronised particulate form.

The method that mitigate ear intervention to the damage of ear sensory cell is also provided herein, methods described comprises to cast in need Individuality comprises compositionss or device in the tympanum of the otoprotective agent of therapeutically effective amount, and described compositionss or device comprise substantially low Otoprotective agent catabolite, described compositionss or device additionally comprise two or more and be selected from following feature:

The otoprotective agent to about 10 weight % for (i) about 0.1 weight % or its pharmaceutically acceptable prodrug or salt；

(iv) many granules otoprotective agent；

Gelation temperature between about 19 DEG C to about 42 DEG C of (v)；

(viii) the otoprotective agent average dissolution time of about 30 hours；With

(ix) apparent viscosity of about 100,000cp to about 500,000cp.

In some embodiments of the method, otoprotective agent casts before or during ear's intervention.In methods described Some embodiments in, otoprotective agent ear intervention after cast.In some embodiments of the method, otoprotective agent base It is in micronised particulate form in basis.

In some embodiments of said method, described compositionss or device comprise:

The ear sensory cell regulator to about 10 weight % for (i) about 0.1 weight % or it is pharmaceutically acceptable Prodrug or salt；

(iii) many granules ear sensory cell regulator；

(iv) gelation temperature between about 19 DEG C to about 42 DEG C；With

The apparent viscosity of (v) about 100,000cp to about 500,000cp.

In some embodiments of said method, described compositionss or device comprise:

(iii) many granules ear sensory cell regulator；

(iv) gelation temperature between about 19 DEG C to about 42 DEG C；With

(v) about 30 hours ear sensory cell regulator average dissolution time.

In some embodiments of said method, ear sensory cell regulator discharges from compositionss or device and continues at least The time of 3 days.In some embodiments of said method, ear sensory cell regulator discharge from compositionss or device continue to The time of few 5 days.In some embodiments of said method, ear sensory cell regulator discharges from compositionss or device and continues The time of at least 10 days.In some embodiments of said method, ear sensory cell regulator is in substantially micronized particles shape Formula.

In some embodiments of method described herein, compositionss cast through oeil de boeuf.In certain embodiments, described Ear and/or vestibular disorder are ototoxicity, chemotherapy induction hearing disability, sensorineural hearing loss, the funeral of noise-inducing audition Mistake, excitatory toxicity, Meniere/syndrome (meniere's disease/syndrome), endolymphatic hydrops, lost Inflammation, Ramsay-hunter syndrome (ramsay hunt's syndrome), vestibular neuronitis, tinnitus or microvascular compression are comprehensive Close disease.

Provided herein is the ototoxicity agent comprising to treat the therapeutically effective amount of ear disease or condition of illness (comprises substantially low ear Toxic agents catabolite) medical composition or device, described medical composition or device additionally comprise two or more Selected from following feature:

(iv) many granules ototoxicity agent；

Gelation temperature between about 19 DEG C to about 42 DEG C of (v)；

(viii) the ototoxicity agent average dissolution time of about 30 hours；With

(ix) apparent viscosity of about 100,000cp to about 500,000cp.

In certain embodiments, described medical composition or device comprise:

(iii) many granules ototoxicity agent；

(iv) gelation temperature between about 19 DEG C to about 42 DEG C；

The apparent viscosity of (v) about 100,000cp to about 500,000cp.

In certain embodiments, described medical composition or device comprise:

(iii) many granules ototoxicity agent；

(iv) gelation temperature between about 19 DEG C to about 42 DEG C；

The apparent viscosity of (v) about 100,000cp to about 500,000cp.

In certain embodiments, comprise the medical composition of ototoxicity agent or device is provided about between 200 and 400mosm/l Actual volume osmolality.In certain embodiments, comprise the medical composition of ototoxicity agent or device provides about 250 Actual volume osmolality and 320mosm/l between.

In certain embodiments, ototoxicity agent discharges the time continuing at least 3 days from compositionss or device.Real at some Apply in example, ototoxicity agent discharges the time continuing at least 5 days from compositionss or device.In certain embodiments, comprise ear poison The medical composition of property agent or device are the acceptable thermoreversible gels of ear.In certain embodiments, medical composition or dress Put and comprise to be in substantially the ototoxicity agent of micronised particulate form.

Provided herein is the nutrient comprising to treat the therapeutically effective amount of ear disease or condition of illness (comprises substantially low nutrition Agent catabolite) medical composition or device, described medical composition or device additionally comprise two or more and are selected from Following feature:

(iv) many granules nutrient；

Gelation temperature between about 19 DEG C to about 42 DEG C of (v)；

(viii) the nutrient average dissolution time of about 30 hours；With

(ix) apparent viscosity of about 100,000cp to about 500,000cp.

In certain embodiments, described medical composition or device comprise:

(iii) many granules nutrient；

(iv) gelation temperature between about 19 DEG C to about 42 DEG C；

(viii) the nutrient average dissolution time of about 30 hours；With

(ix) apparent viscosity of about 100,000cp to about 500,000cp.

In certain embodiments, comprise the medical composition of nutrient or device is provided about between 200 and 400mosm/l Actual volume osmolality.In certain embodiments, comprise the medical composition of nutrient or device provide about 250 with Actual volume osmolality between 320mosm/l.In certain embodiments, nutrient discharges from compositionss or device Continue the time of at least 3 days.In certain embodiments, nutrient discharges the time continuing at least 5 days from compositionss or device.

In certain embodiments, comprising the medical composition of nutrient or device is the acceptable thermoreversible gels of ear. In certain embodiments, medical composition or device comprise to be in substantially the nutrient of micronised particulate form.

In certain embodiments, any of above compositionss or device comprise:

(iii) many granules ear sensory cell regulator；

(iv) gelation temperature between about 19 DEG C to about 42 DEG C；With

(v) about 30 hours ear sensory cell regulator average dissolution time.

In certain embodiments, any of above medical composition or device comprise substantially low ear sensory cell regulator Catabolite.

In certain embodiments, above-mentioned medical composition or device provide the actual volume about between 150 and 500mosm/l Osmolality.In certain embodiments, above-mentioned medical composition or device provide the reality about between 200 and 400mosm/l Border volume osmolality.In certain embodiments, above-mentioned medical composition or device provide about 250 with 320mosm/l it Between actual volume osmolality.

In certain embodiments, ear sensory cell regulator discharges from above-mentioned medical composition or device and continues at least 3 It time.In certain embodiments, ear sensory cell regulator discharges from above-mentioned medical composition or device and continues at least 5 It time.In certain embodiments, ear sensory cell regulator discharges from above-mentioned medical composition or device and continues at least The time of 10 days.In certain embodiments, ear sensory cell regulator discharge from above-mentioned medical composition or device continue to The time of few 14 days.In certain embodiments, ear sensory cell regulator discharges from above-mentioned medical composition or device and continues The time of at least one moon.

In certain embodiments, above-mentioned medical composition or device comprise in neutral compound, free acid, free alkali, salt Or the ear sensory cell regulator of prodrug forms.In certain embodiments, above-mentioned medical composition or device comprise in neutralization The ear sensory cell regulator of compound, free acid, free alkali, salt or prodrug or a combination thereof form.In medicine group as herein described In some embodiments of compound or device, ear sensory cell regulator is cast with ester prodrugs form.

In certain embodiments, above-mentioned medical composition or device are the acceptable thermoreversible gels of ear.At medical group In some embodiments of compound or device, PULLRONIC F68 triblock copolymer is biological eliminable.

In certain embodiments, medical composition or device additionally comprise penetration enhancers.In certain embodiments, medicine Compositionss or device additionally comprise dyestuff.

In certain embodiments, medical composition or device additionally comprises ear sensory cell regulator or it pharmaceutically may be used Salt, prodrug or a combination thereof of accepting are as releasing agent immediately.

In some embodiments of medical composition or device, described ear sensory cell regulator comprises many granules.In doctor In some embodiments of drug composition or device, ear sensory cell regulator is in substantially micronised particulate form.At medical group In some embodiments of compound or device, ear sensory cell regulator is in micronization ear sensory cell regulator powder type.

In certain embodiments, above-mentioned medical composition or device comprise in terms of the weight of compositionss about 10% have logical The PULLRONIC F68 triblock copolymer of formula e106 p70 e106.In certain embodiments, above-mentioned medical composition Or device comprises in terms of the weight of compositionss about 15% PULLRONIC F68 three with formula e106 p70 e106 Block copolymer.In certain embodiments, above-mentioned medical composition or device comprise in terms of the weight of compositionss about 20% tool There is the PULLRONIC F68 triblock copolymer of formula e106 p70 e106.In certain embodiments, above-mentioned medicine group Compound or device comprise in terms of the weight of the compositionss about 25% polyoxyethylene-polyoxy third with formula e106 p70 e106 Alkene triblock copolymer.

In certain embodiments, above-mentioned medical composition or device comprise in terms of the weight of compositionss about 0.01% ear sense Feel cell modulator or its pharmaceutically acceptable prodrug or salt.In certain embodiments, above-mentioned medical composition or device Comprise in terms of the weight of compositionss about 0.05% ear sensory cell regulator or its pharmaceutically acceptable prodrug or salt.? In some embodiments, the ear sensory cell that above-mentioned medical composition or device comprise in terms of the weight of compositionss about 0.1% is adjusted Agent or its pharmaceutically acceptable prodrug or salt.In certain embodiments, above-mentioned medical composition or device comprise to combine The ear sensory cell regulator of the weight meter about 1% of thing or its pharmaceutically acceptable prodrug or salt.In certain embodiments, Above-mentioned medical composition or device comprise in terms of the weight of compositionss about 2.5% ear sensory cell regulator or its pharmaceutically Acceptable prodrug or salt.In certain embodiments, above-mentioned medical composition or device comprise in terms of the weight of compositionss about 5% Ear sensory cell regulator or its pharmaceutically acceptable prodrug or salt.In certain embodiments, above-mentioned medical composition Device comprise in terms of the weight of compositionss about 10% ear sensory cell regulator or its pharmaceutically acceptable prodrug or Salt.In certain embodiments, above-mentioned medical composition or device comprise in terms of the weight of compositionss about 20% ear sensory cell Regulator or its pharmaceutically acceptable prodrug or salt.In certain embodiments, above-mentioned medical composition or device comprise with The ear sensory cell regulator of the weight meter about 30% of compositionss or its pharmaceutically acceptable prodrug or salt.In some enforcements In example, above-mentioned medical composition or device comprise in terms of the weight of compositionss about 40% ear sensory cell regulator or its medicine Acceptable prodrug or salt on.In certain embodiments, above-mentioned medical composition or device comprise in terms of the weight of compositionss At most about 50% ear sensory cell regulator or its pharmaceutically acceptable prodrug or salt.

In certain embodiments, the ph value of above-mentioned medical composition or device is between about 5.5 to about 8.0.At some In embodiment, the ph value of above-mentioned medical composition or device is between about 6.0 to about 8.0.In certain embodiments, above-mentioned doctor The ph value of drug composition or device is between about 6.0 to about 7.6.In certain embodiments, above-mentioned medical composition or device Ph value between about 7.0 to about 7.6.

In certain embodiments, in above-mentioned medical composition or device, every gram of composite contains and is formed less than 100 bacterium colonies The microorganism agent of unit (cfu).In certain embodiments, in above-mentioned medical composition or device, every gram of composite contains less than 50 The microorganism agent of individual colony-forming units (cfu).In certain embodiments, every gram of composite in above-mentioned medical composition or device Containing the microorganism agent less than 10 colony-forming units (cfu).

In certain embodiments, above-mentioned medical composition or device contain per kilogram whose body weight and are less than 5 endotoxin lists Position (eu).In certain embodiments, above-mentioned medical composition or device contain per kilogram whose body weight and are less than 4 endotoxin units (eu).

In certain embodiments, above-mentioned medical composition or device provide the gelling temperature between about 19 DEG C to about 42 DEG C Degree.In certain embodiments, above-mentioned medical composition or device provide the gelation temperature between about 19 DEG C to about 37 DEG C.? In some embodiments, above-mentioned medical composition or device provide the gelation temperature between about 19 DEG C to about 30 DEG C.

In certain embodiments, medical composition or device are the acceptable thermoreversible gels of ear.In some embodiments In, PULLRONIC F68 triblock copolymer be biodegradable and/or biological eliminable (for example pass through biology Degradation process excludes copolymer from body, such as exclusion in urine, feces etc.).In certain embodiments, medicine as herein described Compositionss or device additionally comprise mucomembranous adhesion agent.In certain embodiments, medical composition as herein described or device be in addition Comprise penetration enhancers.In certain embodiments, medical composition as herein described or device additionally comprise thickening agent.At some In embodiment, medical composition as herein described or device additionally comprise dyestuff.

In certain embodiments, medical composition as herein described or device additionally comprise selected from following drug delivery dress Put: pin and syringe, pump, micro injecting device, wick, be formed in situ spongy material or a combination thereof.

In certain embodiments, medical composition as herein described or device are ear sensory cell regulator or its medicine and pharmacology Upper acceptable salt has medical group of limited release or non-systemic release, systemic toxicity, bad pk feature or a combination thereof Compound or device.In certain embodiments, medical composition as herein described or device comprise one or more ears sensation Cell modulator or its pharmaceutically acceptable salt, prodrug or a combination thereof are as releasing agent immediately.

In certain embodiments, medical composition as herein described or device be the ph value of medical composition or device be to be situated between The medical composition of ph value or device that between about 6.0 to about 7.6, perilymph is suitable for.

In some embodiments of medical composition as herein described or device, there is the poly- of formula e106 p70 e106 Oxygen ethylene-polyoxypropylene triblock copolymer is about 40:1 to about 5:1 with the ratio of thickening agent.In certain embodiments, thickening Agent is carboxymethyl cellulose, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

In certain embodiments, described ear and/or vestibular disorder are ototoxicity, chemotherapy induction hearing disability, sensation god Through property hearing disability, noise-inducing hearing disability, excitatory toxicity, Meniere/syndrome, endolymphatic hydrops, labyrinthitises, Ramsay-hunter syndrome, vestibular neuronitis, tinnitus or microvascular compression syndrome.

Brief description

Fig. 1 illustrates the comparison of non-sustained release and sustained release formulation.

Fig. 2 illustrates that concentration refines the impact of cmc solution viscosity to balun Northey (blanose).

Fig. 3 illustrates the impact to U.S.'s many shows (methocel) solution viscosity for the concentration.

Fig. 4 illustrates ear anatomy.

Fig. 5 shows the adjustable release characteristic prediction of four kinds of compositionss.

Specific embodiment

Provided herein is for treatment or improve by internal ear gross loss is bad, hypoevolutism, malfunction, damage, fragility or lose The control release compositionss of caused hearing disability or decline.In one embodiment, control release compositionss comprise treatment effectively At least one ear sensory cell (such as auricularis unit and/or hair cell) growth of amount and/or the regulator of regeneration, ear are subjected to Control release excipient and ear are subjected to mediator.In one embodiment, control release compositionss comprise therapeutically effective amount at least A kind of ear sensory cell damages regulator, ear is subjected to control release excipient and ear is subjected to mediator.In one embodiment, control Release composition processed comprises at least one of therapeutically effective amount and protects auricularis unit and/or hair cell in order to avoid damaged ear sensation is thin Born of the same parents or minimizing, the medicament of the reverse or delay damage to ear sensory cell, the acceptable control release excipient of ear and ear are subjected to Mediator.

In addition treatment ototoxicity, excitatory toxicity, sensorineural hearing loss, the funeral of noise-inducing audition are disclosed herein Mistake, Meniere/syndrome, endolymphatic hydrops, labyrinthitises, Ramsay-hunter syndrome, vestibular neuronitis, tinnitus and The control release ear sensory cell regulating composition of microvascular compression syndrome and composite.

Minority treatment product can be used for treating ototoxicity, excitatory toxicity, sensorineural hearing loss, noise-inducing are listened Power forfeiture, Meniere/syndrome, endolymphatic hydrops, labyrinthitises, Ramsay-hunter syndrome, vestibular neuronitis, ear Ring and microvascular compression syndrome；However, being transmitted using oral, the systemic routes through intravenously or intramuscularly interior approach at present These therapeutic agents.

Systemic medication casts and may result in drug level potential unequal, wherein in serum, cyclical level is higher and target in In ear organ structure, level is relatively low.It is then desired to a considerable amount of medicine is overcoming this unequal with to internal ear transmission enough Therapeutically effective amount.In addition, bioavailability is generally because medicine is reduced by liver metabolism.In addition, since it is desired that high serum amount To realize enough localized delivery to target site, so systemic medication casts may increase systemic toxicity and bad The probability of side effect.Systemic toxicity is likely to because therapeutic agent is decomposed by liver and processes, and formation can effectively eliminate to cast and control (metabolite of such as carbamazepine (carbamazepine) may result in liver to the toxic metabolites of any benefit that treatment agent is obtained Damage and lead to death in some patients) and occur.

In order to overcome, general transmits the toxicity of ear sensory cell regulator and the adjoint side effect that is not intended to (is generally understood as To cell, there is toxicity), it is disclosed herein for the method to middle ear and/or internal ear structures localized delivery ear sensory cell regulator And compositionss.Reach such as vestibule and cochlea organ will pass through middle ear or internal ear (include round window membrane, oval window/stapes footplate, Anular ligamentses) and pass through otic capsule/temporal bone.In other or alternate embodiment, ear control release composite can be via tympanum Interior injection is thrown on round window membrane or near round window membrane.In other embodiments, ear control release composite is after via ear In incision and surgical procedures entrance oeil de boeuf or crest of fenestra cochleae region or nearby throw on or near oeil de boeuf or crest of fenestra cochleae.In addition, ear Applied via syringe and pin with control release composite, wherein pin is inserted through tympanum and guides oeil de boeuf or crest of fenestra cochleae region.

In addition, the local treatment of internal ear can also be special including having bad pk using the therapeutic agent being previously not suitable for use Levy, bad picked-up, low general release and/or toxicity problem therapeutic agent.

Due to ear sensory cell regulator composite and compositionss can local targeting target and also exist biological in internal ear Blood barrier, so the ill effect caused by being treated using the previous toxicity characterizing or invalid ear sensory cell regulator Risk will reduce.Therefore, it is also contemplated by scope of embodiments herein in ototoxicity, excitatory toxicity, sensory nerve audition Forfeiture, noise-inducing hearing disability, Meniere/syndrome, endolymphatic hydrops, labyrinthitises, Ramsay-hunter syndrome, Using previously bad because of ear sensory cell regulator in the treatment of vestibular neuronitis, tinnitus and microvascular compression syndrome Effect or ineffectivity and the ear sensory cell regulator vetoed by professional person, including therapeutic agent.

Also include in embodiment disclosed herein being subjected to medicament and ear disclosed herein using other middle ear and/or internal ear Sensory cell regulator composite and combination of compositions.When deployed, these medicament auxiliary treatments are by autoimmune disorder, including Hearing disability caused by dizziness, tinnitus, hearing disability, disequilibrium, infection, inflammatory response or a combination thereof or balanced capacity are lost Or dysfunction.Therefore, it is also contemplated by using improvement or slow down dizziness, tinnitus, hearing disability, disequilibrium, infection, inflammatory response Or the medicament of the effect of a combination thereof is combined with ear sensory cell regulator as herein described.

In certain embodiments, to additionally comprise ear sensory cell regulator (wherein said as releasing agent immediately for compositionss Immediately release ear sensory cell regulator be and Controlled release formulation identical medicament), another ear sensory cell regulator, Qi Tazhi Treat agent or a combination thereof.In certain embodiments, compositionss additionally comprise other therapeutic agents.In certain embodiments, described other Therapeutic agent is anesthetis, local action anesthetis, analgesic, antibiotic, antiemetic, antifungal, antimicrobial, anti-corrosion Agent, antiviral agent, chemotherapeutics, diuretic, keratin-lytic agent, otoprotective agent, immunosuppressant, including (but not limited to) such as calcium Regulation of mental activities is solid through inhibitors of phosphatases (ciclosporin, tacrolimuss, pimecrolimus), macrolide (such as rapamycin), cortex class The medicaments such as alcohol, or a combination thereof.In certain embodiments, described other therapeutic agent is releasing agent immediately.In certain embodiments, institute Stating other therapeutic agents is Controlled release formulation.

Therefore, provided herein is control release ear sensory cell regulator composite and compositionss, it is used in local treatment Ear and/or internal ear structures, thus avoid the side effect caused by general casts ear sensory cell regulator.The ear of local application Sensory cell regulator composite and compositionss are compatible with middle ear and/or internal ear structures, and directly cast to wanted middle ear and/ Or internal ear structures (such as area cochleae or tympanum), or cast to the structure directly connecting with inner ear region, including but not limited to Round window membrane, crest of fenestra cochleae or oval fenestrated membrane.By specifically targeting middle ear or internal ear structures, can avoid caused by systemic treatment Adverse side effect.Additionally, treating ear's disease by providing control release ear sensory cell regulator composite or compositionss Disease, can provide constant and/or long-term ear sensory cell regulator source to the individuality suffering from otic conditions or patient, thus reducing Or eliminate treatment transmutability.

Injection in Tympanic Cavity therapeutic agent is by the technology in injection of therapeutic agent to middle ear and/or internal ear after tympanum.Although The success (Shu Keneixite (schuknecht), laryngoscope (laryngoscope) (1956) 66,859-870) already of this technology, But still suffer from some challenges.For example, reach round window membrane, the drug absorption site in internal ear is probably a kind of challenge.

However, Injection in Tympanic Cavity produces the undefined problem not being realized of some Current treatments schemes, such as change Perilymph and endolymphatic volume osmolality and ph value, and introduce the pathogen directly or indirectly damaging internal ear structures and Endotoxin.One of the reason technique may not yet recognize these problems is compositionss no in the tympanum of approved: internal ear Unique composite challenge is provided.Therefore, it is that the compositionss that body other parts are researched and developed are almost unrelated with compositionss in tympanum.

Independent of requirement (for example aseptic level, ph value, the volume being suitable to the ear composite casting the mankind in prior art Osmolality) guide.There is larger difference in the anatomy between the ear of different plant species animal.Auditory structures between species The result of difference is that the animal model of disease of inner ear is usual not as the instrument testing the therapeutic agent being developed for clinical approval Reliable.

Provided herein is meeting with regard to ph value, volume osmolality, ionic equilibrium, aseptic, endotoxin and/or pyrogen water The ear composite of flat strict standard.Ear compositionss as herein described are compatible with internal ear microenvironment (such as perilymph) and are suitable to Cast the mankind.In certain embodiments, the preclinical and/or clinical development phase of composite as herein described therapeutic agent in tympanum Between comprise dyestuff and compositionss that supplementary observation casts are to avoid the needs (for example removing perilymph) to aggressive program.

Provided herein is control release ear sensory cell regulator composite and compositionss, it is used for local treatment target ear and ties Structure, thus avoid the side effect caused by general casts ear sensory cell regulator composite and compositionss.Local application Ear sensory cell regulator composite and compositionss and device are compatible with target ear structure, and directly cast to wanted target ear Structure (such as area cochleae, tympanum or external ear), or cast to (including but not limited to round with the structure that inner ear region directly connects Fenestrated membrane, crest of fenestra cochleae or oval fenestrated membrane).By specifically targeting ear structure, the bad pair caused by systemic treatment can be avoided Effect.Additionally, clinical studies show makes medicine and the perilymph Long Term Contact of cochlea have benefit, such as when repeatedly giving to treat During agent, there is the clinical efficacy of improvement to sudden hearing disability.Therefore, by providing control release ear sensory cell regulator Composite or compositionss, to treat otic conditions, can provide constant and/or long-term to the individuality suffering from otic conditions or patient Ear sensory cell regulator source, thus reduce or eliminate treatment transmutability.Therefore, one embodiment as disclosed herein is to carry For enabling at least one ear sensory cell regulator with treatment effective dose release under variable or constant rate of speed, such as with Guarantee the compositionss of the continuous release of at least one medicament.In certain embodiments, ear sensory cell regulator disclosed herein with Release composite or composition forms cast immediately.In other embodiments, ear sensory cell regulator with continuous, variable or with The sustained release formulation of pulse mode release or its variant form cast.In other embodiments again, ear sensory cell is adjusted Agent composite is to be thrown with release immediately that is continuous, variable or discharging in a pulsing mode and sustained release formulation or its variant form Give.Release optionally depends on environment or physiological condition, and such as outer ion environment is (referring to for exampleRelease system, by force Raw company (johnson＆johnson)).

In addition, providing ear as herein described acceptable controlled-release is released to individual goal ear region in need (inclusion internal ear) Put ear sensory cell regulator composite or treatment, and in addition cast the ear sensory cell of individuality oral dose in need and adjust Agent.In certain embodiments, before casting ear acceptable control release ear sensory cell regulator composite, cast oral The ear sensory cell regulator of dosage, and subsequent oral dose is providing ear to be subjected to control release ear sensory cell regulator Gradually decrease in the time of composite.Or, during casting the acceptable control release ear sensory cell regulator composite of ear, Cast the ear sensory cell regulator of oral dose, and subsequent oral dose is providing ear to be subjected to control release ear sensation carefully Gradually decrease in the time of born of the same parents' regulator composite.Or, it is subjected to the regulation of control release ear sensory cell in the initial ear that casts After agent composite, cast the ear sensory cell regulator of oral dose, and subsequent oral dose is providing ear to be subjected to control Gradually decrease in the time of system release ear sensory cell regulator composite.

In addition, ear sensory cell regulator medical composition included by herein or composite or device also include supporting agent, Adjuvant (such as preservative, stabilizer, wetting agent or emulsifying agent), dissolution accelerator, the salt adjusting osmotic pressure and/or buffer agent. These supporting agents, adjuvant and other excipient should be compatible with the environment that target ear structure is located.Therefore, especially cover no ototoxicity or There is the ototoxic supporting agent of bottom line, adjuvant and excipient to allow to have under minimal side effect having to target area or region The otic conditions that effect treatment is covered herein.For preventing ototoxicity, ear sensory cell regulator medical composition disclosed herein or Composite or the distinct regions of device optional targeting target ear structure, including but not limited to tympanum, vestibule bony labyrinth and film fan Road, cochlea bony labyrinth and membranous labyrinth and the other anatomy being located in internal ear or physiological structures.

Some definition

As used herein term " ear is subjected to " includes not individual to being treated for composite, compositionss or composition The internal ear of body produces lasting adverse effect.As used herein " ear is pharmaceutically acceptable " refers to such as supporting agent or dilution It is for the biological activity of internal ear or property and relatively low to the toxicity of internal ear or low, that is, that the materials such as agent do not eliminate compound Material is cast individuality and is not produced improper biological agent or occurred mutually with contained any component in compositionss with harmful way Effect.

As used herein, by cast specific compound or medical composition and improve or mitigate specific ear disease, The symptom of disease or condition of illness refers to owing to casting compound or compositionss or tight caused by compound or compositionss by casting Any reduction of weight degree, outbreak postpone, progression or decreased duration, regardless of whether these effects be permanent or Temporary, lasting is still of short duration.

" antioxidant " is the pharmaceutically acceptable antioxidant of ear, and include such as butylated hydroxytoluene (bht), Sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol.In certain embodiments, when needing, antioxidant can strengthen Chemical stability.Antioxidant is additionally operable to offset the ototoxicity effect of some therapeutic agents, including thin with ear disclosed herein sensation The medicament that born of the same parents' regulator is applied in combination.

" internal ear " refers to internal ear, including cochlea and vestibular labyrinth and the oeil de boeuf connecting cochlea and middle ear.

" internal ear bioavailability " refers to the compound disclosed herein of cast dosage in the animals or humans studied Internal ear in available percentage ratio.

" middle ear " refer to middle ear, including tympanum, auditory ossicles and the oval window connecting middle ear and internal ear.

" disequilibrium " is to instigate individuality to feel aggrieved surely or have disease, disease or the condition of illness of sensation of movement.This definition Including dizziness, dizziness, disequilibrium and nearly faintness (pre-syncope).The disease being classified as disequilibrium includes but is not limited to Ramsay-hunter syndrome, Meniere, log in difficult disease (mal de debarquement), benign paroxysmal positional Dizziness and labyrinthitises.

" plasma concentration " refers to concentration in the plasma component of individual blood for the compound provided herein.

" carrier material " is the release profiles with ear sensory cell regulator, internal ear and the acceptable pharmaceutical formulation of ear The compatible excipient of matter.These carrier material include such as binding agent, suspending agent, disintegrating agent, filler, surfactant, increasing Solvent, stabilizer, lubricant, wetting agent, diluent etc.." the pharmaceutically compatible carrier material of ear " include but is not limited to Ah Draw primary glue (acacia), gelatin, silica colloidal, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, gather Vinylpyrrolidone (pvp), cholesterol, cholesteryl ester, sodium caseinate, soybean lecithin, taurocholic acid, phosphatidylcholine, Sodium chloride, tricalcium phosphate, dikalium phosphate, cellulose and cellulose combination, sugared sodium stearoyl lactate, carrageenan (carrageenan), monoglyceride, diglyceride, pregelatinized starch etc..

Term " diluent " refers to for dilution ear sensory cell regulator and the chemical combination compatible with internal ear before transmission Thing.

" dispersant " and/or " viscosity modifier " is to control diffusion in liquid medium for the ear sensory cell regulator and all The material of one property.The example of diffusion promoting agent/dispersant includes but is not limited to hydrophilic polymer, electrolyte, tween60 or 80, peg, Polyvinylpyrrolidone (pvp；It is referred to as on the market), and it is based on carbon hydrate The dispersant of thing, such as hydroxypropyl cellulose (such as hpc, hpc-sl and hpc-l), hydroxypropyl methyl cellulose (such as hpmc K100, hpmc k4m, hpmc k15m and hpmc k100m), sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, Hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate stearate (hpmcas), noncrystalline cellulose, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol (pva), vinyl pyrrolidone/vinyl acetate Polymer (the also referred to as Tai Luosha of copolymer (s630), 4- (1,1,3,3- tetramethyl butyl)-phenol and oxirane and formaldehyde Pool (tyloxapol)), poloxamer (poloxamer) (such as PluronicWithIt is epoxy second Alkane and the block copolymer of expoxy propane)；(for example spy seeks Ni Ke with pool Lip river sand amine (poloxamine)Also referred to as pool Lip river Husky amineIt is by the tetrafunctional block copolymerization obtained by adding expoxy propane and oxirane successively to ethylenediamine Thing (BASF AG (basf corporation), New Jersey Pa Xipani (parsippany, n.j.)), polyvinyl pyrrole Alkanone k12, PVP k17, Polyvinylpyrrolidone k25 or Polyvinylpyrrolidone k30, polyvinylpyrrolidine (molecular weight of such as Polyethylene Glycol is about 300 to about 6000 or about for ketone/vinyl acetate copolymer (s-630), Polyethylene Glycol 3350 to about 4000 or about 7000 to about 5400), sodium carboxymethyl cellulose, methylcellulose, Polyoxyethylene Sorbitan Monooleate, alginic acid Sodium, glue (such as tragacanth and arabic gum, guar gum, xanthan class (xanthans), including xanthan gum), sugar, cellulose family are (all As sodium carboxymethyl cellulose, methylcellulose, sodium carboxymethyl cellulose), Polyoxyethylene Sorbitan Monooleate, sodium alginate, polyethoxylated Sorbitan monolaurate, polyethoxylated sorbitan monolaurate, polyvidone (povidone), card ripple Nurse (carbomer), polyvinyl alcohol (pva), alginate, shitosan (chitosan) and a combination thereof.Also using such as cellulose Or the plasticizer such as triethyl group cellulose is as dispersant.It is applied to the liposomal dispersion of ear sensory cell regulator disclosed herein Dispersant in liquid and self emulsifying dispersion liquid is dimyristoyl phosphatidyl choline, the native phosphatidylcholine from ovum, is derived from The natural phospholipid acyl glycerol of ovum, cholesterol and isopropyl myristate.

" drug absorption " or " absorption " refers to that ear sensory cell regulator is (only for example, interior from the part of dispensing The round window membrane of ear) and pass through barrier (round window membrane, as mentioned below) to enter the moving process of internal ear or internal ear structures.As this paper institute The term " casting altogether " etc. using intends to cover to cast single patient ear sensory cell regulator, and be intended to by identical or Different dosing ways or the therapeutic scheme casting ear sensory cell regulator in the identical or different time.

As used herein term " effective dose " or " therapeutically effective amount " refer to that the cast ear sensory cell of expection is adjusted Section agent be enough to mitigate the amount of one or more symptoms of treated disease or condition of illness to a certain extent.For example, Cast ear sensory cell regulator medicament disclosed herein result be reduce and/or mitigate the symptom of tinnitus or disequilibrium, Symptom or the cause of disease.For example, " effective dose " using for treatment is that ear sensory cell regulator (includes tune disclosed herein Join thing) slow down or improve disease symptomses and no excessive amount needed for adverse side effect.Term " therapeutically effective amount " includes for example pre- Anti- effective dose." effective dose " of the neuron of ear compositionss disclosed herein and/or hair cell regulator is effectively to reach to be wanted Pharmacological effect or treatment improve and the amount of no excessive adverse side effect.It will be appreciated that in certain embodiments, " effective dose " or The metabolism of " therapeutically effective amount " compound because being cast, individual age, body weight, general status, treated condition of illness, treated The change of the judgement of the order of severity of condition of illness and prescribing physician and with individual change.It should also be clear that based on pharmacokinetics and The consideration of pharmacodynamicss, " effective dose " that extend in release administration form can with " effective dose " in release administration form immediately no With.

Term " enhancing " refers to increase or extend the effect of desired effect or the persistent period of ear sensory cell regulator, or Weaken any unfavorable symptom occurring with casting therapeutic agent.Therefore, just strengthen ear sensory cell regulator disclosed herein For effect, term " enhancing " is to refer to increase or extend its that be applied in combination with ear sensory cell regulator disclosed herein The effect of the effect of its therapeutic agent or persistent period.As used herein " enhancing effective dose " refers to ear sensory cell regulator Or other therapeutic agent enough to strengthen another therapeutic agent or ear sensory cell regulator in the target ear structure in wanted system Effect amount.When in for patient, to this purposes effectively amount will depend upon disease, disease or condition of illness the order of severity and The course of disease, previous therapies, the health status of patient and the reaction to medicine and the judgement for the treatment of doctor.

Term " suppression " includes stoping, slows down or reverse the development of such as condition of illness of the patient that must treat or entering of condition of illness Exhibition.

Term " test kit " and " product " synonymously use.

" pharmacodynamicss " refer to determine that middle ear and/or interior in ear want position biological with respect to observed by drug level The factor of reaction.

" pharmacokinetics " refer to determine to want position to reach in middle ear and/or interior in ear and maintain suitable drug level Factor.

" auricularis unit and/or hair cell regulator " is synonym with " ear sensory cell regulator ".It includes promoting ear The medicament of neuron and/or capillary intracellular growth and/or regeneration and the medicament destroying auricularis unit and/or hair cell.Real at some Apply in example, ear sensory cell regulator passes through to promote ear sensory cell (such as auricularis unit and/or hair cell) growth and/or again Raw offer treatment benefit (for example mitigating hearing disability).In certain embodiments, ear sensory cell regulator (such as poisonous substance) leads to Cross destruction or ear sensory cell (such as auricularis unit and/or hair cell) offer treatment benefit (for example mitigating dizziness) is provided.? In some embodiments, ear sensory cell regulator passes through treatment and/or reverses (the such as auricularis unit of the damage to ear sensory cell And/or hair cell dysfunction) or reduce or postpone (for example logical to the damage further (such as cell death) of ear sensory cell Cross applying ear protective effect or Nutrition) treatment benefit (for example mitigating the tinnitus caused by acoustic trauma) is provided.

Term " nutrient " meaning is to promote survival, the growth of ear sensory cell (such as auricularis unit and/or hair cell) And/or the medicament of regeneration.In certain embodiments, nutrient reduces or suppresses oxidative damage and/or the bone of ear sensory cell Regeneration and/or degeneration.In certain embodiments, nutrient maintains healthy ear sensory cell (for example to implant medical science in surgical operation After device).In certain embodiments, nutrient raises the activity (for example during casting ototoxicity agent) of antioxidase.? In some embodiments, nutrient is immunosuppressant (immunosuppressant using during such as ear's surgical operation).At some In embodiment, nutrient be somatomedin (after such as implant procedure using somatomedin promote ear cell grow).

Term " glutamate receptor antagonists " meaning is interference or the compound of suppression glutamate receptor activity.Real at some Apply in example, receptor is ampa receptor or nmda receptor.In certain embodiments, glutamate receptor antagonists combine glutamate receptor Body, but described combination does not produce physiological reaction.Glutamate receptor antagonists include partial agonist, inverse agonist, neutrality or Competitive antagonist, noncompetitive antaganist, allosteric antagonist and/or normotopia antagonist.

Term " glutamate receptor agonists " meaning is with reference to glutamate receptor and to activate the compound of described receptor.Described Term comprises additionally in the compound promoting native ligand to combine.In certain embodiments, described receptor is mglu receptor.Glutamic acid Receptor stimulating agent includes partial antagonist, allosteric agonist and/or normotopia agonist.

In prophylactic use, the compositionss comprising ear sensory cell regulator as herein described are cast and is susceptible to suffer from specific disease Disease, disease or condition of illness or be in the patient in specified disease, disease or condition of illness risk.For example, described condition of illness is included (but not Be limited to) ototoxicity, excitatory toxicity, sensorineural hearing loss, noise-inducing hearing disability, Meniere/syndrome, Endolymphatic hydrops, labyrinthitises, Ramsay-hunter syndrome, vestibular neuronitis, tinnitus and microvascular compression syndrome.This Amount is defined as " prevention effective dose or dosage ".In this purposes, exact amount additionally depends on the health status of patient, body weight etc..

As used herein, " medical devices " provide the prolongation for activating agent as herein described after including casting ear The compositionss any as herein described of the reservoir of release.

The activating agent that term " the substantially low catabolite " meaning is less than 5 weight % is the catabolite of activating agent. In other embodiments, the activating agent that this term meaning is less than 3 weight % is the catabolite of activating agent.Again other real Apply in example, the activating agent that this term meaning is less than 2 weight % is the catabolite of activating agent.In other embodiments, this The activating agent that the one term meaning is less than 1 weight % is the catabolite of activating agent.In certain embodiments, tune as herein described Joining any individual impurities (such as metal impurities, activating agent and/or excipient catabolite etc.) present in thing is activating agent Less than 5 weight %, less than 2 weight % or less than 1 weight %.In certain embodiments, composite does not contain precipitation during storing, Or after manufacture and storage no color change.

As used herein, " being in substantially micronized powder " only for example includes the activity more than 70 weight % Agent is in the micronised particulate form of activating agent.In other embodiments, this term meaning is greater than the activating agent of 80 weight % Micronised particulate form in activating agent.In other embodiments again, this term meaning is greater than the activating agent of 90 weight % Micronised particulate form in activating agent.

Term " ear's intervention " meaning is the external damage to one or more ear structures or wound and inclusion implantation Thing, ear's surgical operation, injection, cannulation etc..Implant includes internal ear or middle ear medical apparatus, and the example includes cochlea Implant, hearing protection devices, hearing improved device, noncontinuous electrode, micro- prosthese or piston sample prosthese；Pin；Stem cell graft；Medicine Thing transfer device；Any therapeutic agent based on cell；Deng.Ear's surgical operation include middle Otologic Surgical Proce- dures, interior Otologic Surgical Proce- dures, Myringotomy, cochlea otomy, labyrinthotomy, mastoidectomy, stapedectomy, Stapedotomy, endolymph sacculus Otomy etc..Injection includes Injection in Tympanic Cavity, intracochlear injection, passes through round window membrane injection etc..Cannulation includes in tympanum, In cochlea, endolymph, perilymph or vestibule cannulation etc..

" prodrug " refers in vivo change into the ear sensory cell regulator of parent drug.In certain embodiments, front Medicine becomes the biological activity of compound, medicinal activity or therapeutic activity shape through one or more steps or process enzymatic metabolism Formula.For manufacturing prodrug, pharmaceutical active compounds are modified so that reactive compound will regenerate after in vivo casting.? In one embodiment, prodrug is designed to change metabolic stability or the transmission feature of medicine, shields side effect or toxicity or changes Become further feature or the property of medicine.In certain embodiments, compound provided herein is derivatized to suitable prodrug.

" solubilizing agent " refers to that the deliquescent ear contributing to or strengthening ear sensory cell regulator disclosed herein is subjected to Compound, such as triacetin, triethyl citrate, ethyl oleate, ethyl caprilate, sodium lauryl sulfate, many storehouses ester Sodium (sodium docusate), vitamin e tpgs, dimethyl acetylamide, n- methyl pyrrolidone, n- hydroxyethyl hydroxyethyl Ketone, Polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cyclodextrin, ethanol, n-butyl alcohol, isopropanol, cholesterol, gallbladder Juice salt, polyethylene glycol 200-600, Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), TC (transcutol), propylene glycol and isosorbide dimethyl ether (dimethyl isosorbide) etc..

" stabilizer " refers to the compound compatible with inner ear environment, such as any antioxidant, buffer agent, acid, preservative Deng.Stabilizer including but not limited to can produce the reagent of any following effect: (1) improves excipient and container or transmission system The compatibility of (including syringe or vial), (2) improve the stability of composition component, or (3) improve composite stability.

As used herein " stable state " refers to be spaced internal diabetes when the amount of the medicine casting internal ear is equal to an administration time During the amount of the medicine removing, produce steady or constant level medicine in object construction and expose.

As used herein term " individual " is used for referring to animal, preferably mammal, including the mankind or non-human.Term Patient is used interchangeably with individuality.

" surfactant " refers to the acceptable compound of ear, such as sodium lauryl sulfate, docusate sodium, polysorbate60 or 80th, triacetin, vitamin e tpgs, dehydrated sorbitol mono-fatty acid ester, polyoxyethylene sorbitan list Oleic acid The copolymer of ester, polysorbate, poloxamer, bile saltss, glyceryl monostearate, oxirane and expoxy propane, for example(BASF AG (basf)) etc..Some other surfactants include polyoxyethylene fatty glyceride ester and plant Thing oil, such as polyoxyethylene (60) castor oil hydrogenated；With polyoxyethylene alkyl ether and alkyl phenyl ether, such as Octoxinol 10 (octoxynol 10), Octoxinol 40 (octoxynol 40).In certain embodiments, include surfactant with enhancing thing Reason stability or for other purposes.

As used herein term " treatment " inclusion is preventative and/or therapeutic relaxes, alleviates or improve disease or disease Shape (such as tinnitus) symptom, the other symptom of prevention, the potential metabolic disease improving or preventing symptom is because suppressing disease or condition of illness (example As stoped disease or disease symptom development), palliate a disease or condition of illness, so that disease or condition of illness is disappeared, mitigation is caused by disease or condition of illness Condition of illness, or terminate disease or the symptom of condition of illness.

By the following detailed description, other targets of method described herein and compositionss, feature and advantage will become aobvious and It is clear to.It should be appreciated, however, that describe in detail only illustratively providing when indicating specific embodiment with instantiation.

The anatomy of ear

As shown in figure 4, external ear be organ exterior section and by auricle (pinna/auricle), auditory meatus (external auditory meatus) and Tympanum to outer portion (also referred to as eardrum) constitute.Auricle is the pulp of external ear it is seen that in the side of head, it is used for collecting Sound wave and by sonic guide auditory meatus.Therefore, the funtion part of external ear is to collect sound wave and by sonic guide tympanum and middle ear.

Middle ear are the cavitys of air filling, and referred to as tympanum, at tympanum rear.Tympanum is also referred to as eardrum, be separate external ear with The thin film of middle ear.Middle ear are located in temporal bone, and include three pieces of oticas (auditory ossicles): malleus, incus and stapes in this space. Auditory ossicles links together via tiny ligament, is developed across the bridge in tympanum space.One end of malleus is attached to tympanum, before it End is connected to incus, and incus is connected to stapes.Stapes is attached to oval window, and oval window is in intratympanic two windows One.The fibrous tissue layer of referred to as anular ligamentses connects stapes and oval window.Tympanum is caused to shake first from the sound wave of external ear Dynamic.Vibration is propagated via auditory ossicles and oval window and is reached cochlea, motion is transferred to the fluid in internal ear.Therefore, auditory ossicles Arrangement provides the mechanical linkage between tympanum and the oval window of fluid filled internal ear, wherein sound transitions and be transformed into internal ear for Process further.The hardness of auditory ossicles, tympanum or oval window, rigidity or activeness are lost and are led to hearing disability, such as otosclerosis Disease or stapes rigidity.

Tympanum is also connected to throat via pharyngotympanic tube.Pharyngotympanic tube can balance the pressure between extraneous air and middle ear cavity Power.Oeil de boeuf be internal ear an assembly but also can be close in tympanum, it leads to the cochlea of internal ear.Oeil de boeuf is covered by round window membrane, Round window membrane is made up of three layers: outer layer or mucous layer, intermediate layer or fibrous layer and inner membrance, and inner membrance is directly connected with cochlear fluid. Therefore, oeil de boeuf is directly connected with internal ear via inner membrance.

Motion in oval window and oeil de boeuf be interconnection, i.e. when stapes by tympanum motion travel to oval window with respect to When fluid of inner ear moves inward, oeil de boeuf (round window membrane) is correspondingly released and away from cochlear fluid.This motion of oeil de boeuf makes ear Fluid motion in snail, this leads to cochlea inner hair cellss to move again, thus force signal is listened in conversion.Round window membrane hardening or rigid because not Cochlear fluid motion can be made to lead to hearing disability.Nearest research has concentrated on implantation mechanical transducer on oeil de boeuf, described Transducer bypasses normal conduction path the input to the offer amplification of cochlea chamber via oval window.

Audible signal conversion occurs in internal ear.The internal ear of fluid filled is made up of two primary clusterings: cochlea and vestibule Organ.Inner ear part is located in bony labyrinth, and bony labyrinth is the passage of series of complex in cranium temporal bone.Vestibular apparatuies are organ of equilibration And be made up of three semicircular duct and vestibule.Three semicircular duct arranged opposite each other makes can be by the motion of fluid come detection head Portion's the moving of three orthogonal planes along along space, and subsequently by the sensory organ (referred to as crista ampullariss) of semicircular duct, signal is carried out Reason.Crista ampullariss contain hair cell and sertoli cell, and are referred to as the dome-shaped gelatinous mass covering of cupula ampullaris.The hair of hair cell It is embedded in cupula ampullaris.Semicircular duct detects dynamic equilibrium, i.e. the balance of rotation or angular movement.

Although when head quick rotation, semicircular duct moves with head, and the endolymph fluid being located in semicircular ducts inclines To in remaining stationary as.Endolymph fluid pushes against cupula ampullaris, and cupula ampullaris is to lopsidedness.When cupula ampullaris tilts, it makes crista ampullariss Hair cell on some hairs bending, and then trigger sensation pulse.Because each semicircular duct is located in Different Plane, each semicircular canal The corresponding crista ampullariss of the pipe differently same movement in response to head.This measure produces chimeric pulse, and this pulse is in vestibule snail god Central nervous system is traveled on the vestibular buanchess of warp.Central nervous system explains this information and causes suitable reaction to maintain Balance.It is important that cerebellum in central nervous system, cerebellum mediation equilibrium sense and balance.

Vestibule is the middle body of internal ear, and containing having the hair finding out static equilibrium or head with respect to the position of gravity The mechanoreceptor of cell.Play a role when static equilibrium is in head still or along rectilinear movement.Membranous labyrinth in vestibule is divided into Two capsule spline structures, i.e. utriculuss and sacculus.Each structure contains the little structure of referred to as capsule speckle again, and this little structure is responsible for remaining quiet State balances.Capsule speckle is made up of the Sensory hair cell being embedded in the gelatinous mass (similar to cupula ampullaris) covering capsule speckle.Referred to as ear The Calcium Carbonate grain of stone is embedded in gel layer surface.

When portion is located at vertical position right overhead, hair is erect along capsule speckle.When head inclination, gelatinous mass and otolith accordingly incline Tiltedly, make some mao of bending on capsule Mylabris cell.This flecition initiates signal pulse, signal pulse to central nervous system Vestibular buanchess via vestibulocochlear nerves are advanced, and then relay motion impulse to maintain balance to suitable muscle.

Cochlea is related to audition part in internal ear.Cochlea is the conical pipe spline structure being curled into similar Limax shape. It is divided into three areas, these three areas are defined by the position of vestibular membrane and basement membrane further inside cochlea.Part above vestibular membrane It is vestibular canal, vestibular canal extends to cochlea summit from oval window, and contains perilymph fluid, a kind of potassium content is low and sodium content is high Waterborne liquid.Basement membrane defines tympanic canal area, and tympanic canal area extends to oeil de boeuf and contains perilymph from cochlea summit.Basement membrane contains There are thousands of rigid fibers, the length of these fibers is gradually increased to cochlea summit from oeil de boeuf.Substrate membrane fiber is by sound Vibration when sound stimulates.It is cochlear duct in the middle of vestibular canal and scala tympani, cochlear duct is with the closing capsule of cochlea apex as end.Cochlea Pipe contains endolymph fluid, and similar to marrowbrain fluid and potassium content is high for endolymph fluid.

Ke for the sensory organ that (corti) organ is for audition, on basement membrane and extend upwardly in cochlear duct. Ke contains hair cell for organ, and hair cell has and extends from its Free Surface and contact the hair of the referred to as gelatinous surface of tectorial membrane Sample outthrust.Although hair cell does not have aixs cylinder, it is formed the sensation of the ramus cochleae of vestibule front yard cochlear nerve (cranial nerve viii) Nerve fiber is surrounded.

As discussed, oval window (also referred to as fenestra ovalis) is connected with stapes to relay the sound wave from vibrophone.Transfer to The vibration of oval window makes the pressure within fluid filled cochlea increase via perilymph and vestibular canal/tympanic canal, and this pressure increases Plus cause oeil de boeuf film reaction to extend again.The oval window coordinated inwardly extrudes/and oeil de boeuf outward expansion makes i-coch fluid fortune Move and do not change pressure in cochlea.However, when travelling across the perilymph in vestibular canal when vibration, it produces phase in vestibular membrane Should vibrate.These corresponding vibrations travel across the endolymph of cochlear duct, and transfer to basement membrane.When basement membrane vibration or on During lower motion, Ke moves along basement membrane for organ.Ke replaces the hair cell receptor in organ subsequently to move relative to tectorial membrane, leads to There is mechanically deform in tectorial membrane.This mechanically deform causes Nerve impulse, during Nerve impulse advances to via vestibulocochlear nerve Pivot nervous system, the sound wave being received mechanically is propagated as signal, and these signals are then processed by central nervous system.

Disease

Otic conditions produce various symptoms, including but not limited to hearing disability, nystagmuies, dizziness, tinnitus, inflammation, Infection and hyperemia.Otic conditions with compositions disclosed herein treatment are numerous and include ototoxicity, excitatory toxicity, sensation god Through property hearing disability, noise-inducing hearing disability, Meniere/syndrome, endolymphatic hydrops, labyrinthitises, Ramsay-Hunter Syndrome, vestibular neuronitis, tinnitus and microvascular compression syndrome.

Excitatory toxicity

Excitatory toxicity refers to that glutamic acid and/or similar substance make neuron and/or tragus cell death or damage.

Glutamic acid is the abundantest zest neurotransmitters in central nervous system.Presynaptic neuron after stimulation can Discharge glutamic acid.Glutamic acid flows through synapse, is incorporated into the receptor on postsynaptic neuron, and activates these neurons. Glutamate receptor includes nmda, ampa and kainic acid receptor.The work of glutamate transporter is from prominent by extracellular glutamate Remove in touching.Some events (such as ischemia or apoplexy) can damage these transporters.This can lead to synapse Glutamic Acid mistake Many accumulations.In synapse, excessive glutamic acid can cause glutamate receptor overactivity.

Ampa receptor is activated by the combination of glutamic acid and ampa.The work of some same work(iso series of ampa receptor Change can cause the ion channel in neuron plasma membrane to open.When passage is opened, na+ and ca2+ ion stream enters in neuron And k+ ion flows out from neuron.

Nmda receptor is activated by the combination of glutamic acid and nmda.The activation of nmda receptor can cause positioned at nerve Ion channel in first plasma membrane is opened.However, these passages are blocked by mg2+ ion.The activation of ampa receptor can cause mg2+ from Son is discharged to synapse from ion channel.When ion channel is opened and during mg2+ ion evacuated ion passage, na+ and ca2+ ion stream Enter in neuron and k+ ion flows out from neuron.

When nmda receptor and ampa receptor are by combining excess ligand, the glutamic acid of such as abnormal amount and during overactivity, Produce excitatory toxicity.These receptor overactivities can cause ion channel to open too much at the control.This makes exception Ca2+ and na+ of high-load enters in neuron.Ca2+ and na+ of these contents flows in neuron and neuron can be caused higher The electric discharge of frequency ground, thus cause free radical and inflammatory compound accumulate in rapidly intracellular.Free radical finally damages mitochondrion, Consume the energy stores of cell.Additionally, the enzyme of the excessive content of ca2+ and na+ ion activation of excessive content, including (but do not limit In) phospholipase, Cobra venom endonuclease and protease.The overactivity of these enzymes cause the cytoskeleton to sensory neuron, plasma membrane, Mitochondrion and the destruction of dna.In certain embodiments, ear sensory cell regulator is to reduce or suppression excessive neuronal electric discharge And/or the glutamate receptor antagonists of Neuronal cell death.In certain embodiments, it is disclosed herein and be characterised by for treatment The medical composition of the abnormal ear disease of nmda function of receptors.

Tinnitus

As used herein, " tinnitus " refers to be characterised by there is not the disease feeling sound under any environmental stimuli. In some cases, tinnitus is continuous or sporadically occurs in one or two ear, and is usually described as the tinkle of bells most.It is the most frequently used Make the diagnostic symptom of Other diseases.There is two kinds of tinnitus: objective tinnituses and subjective tinnitus.The former is anyone The audible sound producing in vivo.The latter is only that diseased individuals can be heard.Research is estimated, the American more than 50,000,000 Experience some form of tinnitus.At this in 50,000,000, the serious tinnitus of about 1,002 million peoples' experience.

There is several treatment for tinnitus.Can be reduced or eliminated about by intravenous administration lignocaine (lidocaine) The noise related to tinnitus in 60%-80% patient.Such as nortriptyline (nortriptyline), Sertraline (sertraline) display that for ear with the selectivity neurotransmitters reuptake inhibitor such as paroxetine (paroxetine) Effect of ring.Benzodiazepine is also used for treating tinnitus.In certain embodiments, ear sensory cell regulator reduce or suppression with The related ear sensory cell of tinnitus damages and/or dead.

Sensorineural hearing loss

Sensorineural hearing loss is a class by vestibulocochlear nerves (also referred to as cranial nerve viii) or internal ear sensory cell Hearing disability caused by existing defects (congenital and posteriority).Most of internal ear defect is tragus cell defect.

Cochlea hypoplasia, chromosome deficiency and congenital cholesteatoma are can cause sensorineural hearing loss congenital The example of property defect.By non-limiting examples, inflammatory diseases (for example suppurative labyrinthitis, meningitiss, parotitiss, measles, Viral syphilis and autoimmune disorder), Meniere, be exposed to ototoxic drug (such as aminoglycoside, loop diuretic (loop diuretics), antimetabolite, salicylate (salicylate) and cisplatin (cisplatin)), physical trauma, old Year property is deaf and acoustic trauma (being exposed to the sound more than 90db for a long time) can cause posteriority sensory nerve audition Lose.

If causing the defect that the defect of sensorineural hearing loss is Auditory Pathway, then sensory nerve audition is lost Lose and be referred to as maincenter hearing disability.If causing the defect that the defect of sensorineural hearing loss is Auditory Pathway, then sensation Neural hearing loss is referred to as cortical deafness.In certain embodiments, ear sensory cell regulator is to promote the life of ear sensory cell Nutrient (such as bdnf, gdnf) that is long and reducing or reverse sensorineural hearing loss.

Noise-inducing hearing disability

Noise-inducing hearing disability (nihl) be be exposed to one section of long period of too noisy or noisy sound go it After cause.Long-time or repeat or pulsed exposures can lead to hearing disability in the sound of 85 decibels or more than 85 decibels.Audition is lost Lose be also possible to because be exposed to noise and excitement for a long time noise under and occur, such as loud music, jumbo or machine, aircraft, big gun The fire or other noise based on the mankind.Nihl causes the damage to hair cell and/or auditory nerve.Hair cell is so that acoustic energy is converted Become to be sent to the little sensory cell of the signal of telecommunication of brain.Pulse sound can cause hearing disability immediately, and this is probably permanent Property.This kind of hearing disability may be with tinnitus, and that is, the tinkle of bells, buzz or roar in ear or head, and this may be at any time Between and disappear.Hearing disability and tinnitus are likely to occur in one or two ears, and tinnitus may in whole life cycle not Disconnected or or continue.Be continuously exposed to noise and excitement noise also can damage hair cell structure, thus cause permanent hearing disability and Tinnitus, but this process is incremental compared with impulsive noise.

In certain embodiments, otoprotective agent reversible, minimizing or improve nihl.Treatment or the otoprotective agent of prevention nihl Example include but is not limited to otoprotective agent as herein described.

Ototoxicity

Ototoxicity refers to the hearing disability being caused by toxin.This hearing disability can be by tragus cell, cochlea and/or cranial nerve The damage of vii causes.Known multi-medicament has ototoxicity.Ototoxicity is frequently depend upon dosage.After cutting out medicine, ear Toxicity may be lasting or reversible.

Known ototoxic drug includes but is not limited to aminoglycoside antibioticss (such as gentamycin and amikacin (amikacin)), some members (such as erythromycin) of macrolide antibiotics, some member's (examples of glycopeptide antibioticss As vancomycin (vancomycin)), salicylic acid, nicotine, some chemotherapeutants (such as D actinomycin D (actinomycin), Bleomycin (bleomycin), cisplatin (cisplatin), carboplatin (carboplatin) and vincristine (vincristine)) Some members (such as furosemide (furosemide)), 6- hydroxy dopamine (6- with loop of Henle diuretic family medicine Oh dp at), 6,7- dinitro quinoxaline -2,3- diketone (dnqx) etc..

Cisplatin and the product of aminoglycoside antibioticss induction active oxygen (reactive oxygen species, " ros ") Raw.Ros directly can make cell damage by damaging dna, polypeptide and/or lipid.Antioxidant pass through prevent ros formed or Remove free radical before ros damaging cells to prevent the damage of ros.Cisplatin and aminoglycoside antibioticss are considered as passing through In conjunction with the usually ear damage of the black in vessels of internal ear stricture of vagina.

Salicylic acid is categorized as the function that ototoxic drug is because its suppression polypeptide pressure element (prestin).Pressure element is logical Cross and control chloride ion and carbonate to pass through the plasma membrane of external ear hair cell to exchange, to mediate the motion of external ear hair cell.Only in external ear Find pressure element in hair cell, do not find in inner ear hair cells.Therefore, it is disclosed herein and comprise otoprotective agent (such as antioxidation Agent) control release ear compositionss purposes, it is used for preventing, improve or mitigate including but not limited to plus cisplatin in treatment, ammonia Base glucosides or salicylic acid dispensing or other ototoxicity medicament are in interior chemotherapeutic ototoxicity effect.

Endolymphatic hydrops

Endolymphatic hydrops refers to that in the endolymphatic system of internal ear, hydraulic pressure increases.Endolymph and perilymph are by containing multiple nerves Thin film separation.Pressure oscillation can oppress the nerve that film has with it.If pressure is enough big, then may cause brokenly in film Ring.This can cause fluid to mix, and lead to depolarization to block and of short duration sexual function is lost.The change of vestibular nerve discharge rate is usually Cause dizziness.In addition, organ of Corti also may be affected.The deformation of basement membrane and inner hair cellss and outer hair cell can lead to Hearing disability and/or tinnitus.

The cause of disease includes dysbolismus, non-equilibrium of hormones, autoimmune disease and virus, antibacterial or fungal infection.Symptom bag Include hearing disability, dizziness, tinnitus and bulge of the ear.It is likely to that nystagmuies occur.Treatment includes general and casts benzodiazepine (benzodiazepine), diuretic (minimizing Fluid pressure), corticosteroid and/or antibacterial agent, antiviral agent or anti-true Microbial inoculum.

Labyrinthitises

Labyrinthitises are the labyrinthus oticuss inflammation containing inner ear labyrinth system.The cause of disease includes antibacterial, virus and fungal infection.Its May be caused by head injury or anaphylaxis.The symptom of labyrinthitises includes being difficult to maintain balance, dizziness, dizziness, tinnitus and audition Lose.Recover to need for one to six week；However, chronic sympton there may be for many years.

There is several treatment to labyrinthitises.Prochlorperazine (prochlorperazine) is often referred to shown as antiemetic.Blood Plain clearly reuptake inhibitor shows there is stimulation to new nerve growth in internal ear.In addition, if the cause of disease is bacterium infection, that Instruction antibiotic therapy, and if condition of illness is caused by virus infection, then suggestion corticosteroid and antiviral agent are controlled Treat.

Meniere

Meniere is a kind of idiopathic condition of illness, it is characterized by dizziness, nausea and vomiting break out, sustainable 3 to 24 hours, and can gradually disappear.In gradual hearing disability, tinnitus and ear, feeling of stress is with this disease, after the course of disease.Mei Ni The cause of disease of Er Shi disease may be uneven related to fluid of inner ear stable state, and generation increase or re-absorption including fluid of inner ear subtract Few.

Aquaporin 2 (aqp2) systematic research that vassopressin in internal ear (vp) mediates is shown, vp drenches in induction Bar produces, thus the pressure aspect increasing in vestibule and cochlear structures works.Find vp content in endolymphatic hydrops (Mei Nier Family name's disease) raise in case, and find that casting vp for a long time in guinea pig can induce endolymphatic hydrops.Use vp antagonist for treating, including Infusion opc-31260 (a kind of competitive antagonist of v2-r)) in tympanic canal, Meniere's disease symptoms can be made to significantly decrease. Other vp antagonisies include way-140288, cl-385004, tolvaptan (tolvaptan), conivaptan (conivaptan), sr 121463a and vpa 985.(Sang Ji (sanghi) et al., heart of Europe magazine (eur.heart j.) (2005)26:538-543；Pa Mu (palm) et al., nephrology, dialysis, transplantation (nephrol dial transplant) (1999)14:2559-2562).

Other studies have shown that, estrogen-related receptor β/nr3b2 (err/nr3b2) is adjusting endolymph generation, therefore adjusts Pressure aspect in section vestibule/cochlea organ works.Gene knockout research display in mice, the polypeptide of nr3b2 gene produces Thing works in terms of adjusting endolymph fluid generation.The expression of nr3b2 is respectively positioned in cochlea and the secretion of vestibular apparatuies In the Strial marginal cell of lymph and vestibule dark cell.In addition, the conditional gene rejecting of nr3b2 gene can cause deaf and interior Lymph Fluid Volume reduces.Can help to reduce endolymph volume with the antagonist for treating of err/nr3b2, therefore change internal ear structures Pressure.

Other treatments can be for the symptom processing at once and prevention of recurrence.Advocate low sodium diet, it is to avoid caffeine, ethanol and Tobacco product.Can temporarily mitigate onset of vertigo medicine include antihistaminic (including Mycospor profit piperazine and other antihistaminics) and Central nervous system agents, including barbiturate (barbiturate) and/or benzodiazepine, including lorazepam Or stable (diazepam) (lorazepam).The other examples that can be used for the medicine of mitigation symptoms include muscarinic type antagonist, Including hyoscyamine (scopolamine).Can be subtracted including phenothiazines medicine prochlorperazine by the suppository containing psychosis Light nausea and vomiting.

Surgical procedure in order to mitigation symptoms includes the function of destroying vestibule and/or cochlea to mitigate vertigo symptoms. These programs are intended to reduce the Fluid pressure in internal ear and/or the equilibrium function destroying internal ear.Can carry out mitigating stream in internal ear The endolymphatic shunt program of body pressure, to mitigate the symptom of vestibular dysfunction.Other treatments include applying gentamycin, its The function of Sensory hair cell can be destroyed when being injected in eardrum, thus eradicating the equilibrium function of internal ear.Vestibule can also be cut off Nerve, this controllable dizziness while retaining audition.In certain embodiments, ear sensory cell regulator promotes hair cell life Length and so that individual recovery internal ear equilibrium function.

Menieres disease

Menieres disease shows the symptom similar with Meniere it is believed that it is the first caused by such as syphiliss The secondary disease of another lysis such as shape gland disease or internal ear inflammation.Therefore, Menieres disease is interference endolymph Normal generation or the secondary effect of resorbent various processes, including cryptorrhea, electrolyte imbalance, autoimmune function Obstacle, Drug therapy, infection (such as parasitic infection) or hyperlipidemia.The treatment of Menieres disease patient similar to Meniere.

Ramsay-hunter syndrome (herpes zoster infection)

Ramsay-hunter syndrome is caused by acous herpes zoster infection.This infection may cause serious Otalgia, hearing disability, in dizziness, and external ear, occur on the face in auditory meatus and by these innervations or skin of neck Blister.If bulge extrudes nervus facialiss, then facial muscle is likely to become paralysis.Hearing disability can be temporary or permanent , and vertigo symptoms typically last for a couple of days to several weeks.

The treatment of Ramsay-hunter syndrome is include casting including the antiviral agent including acyclovir (acyclovir). Other antiviral agent include famciclovir (famciclovir) and valacyclovir (valacyclovir).Can also adopt disease-resistant Toxic agent combines to improve herpes zoster infection with corticosteroid therapies.Analgesics or anesthetics can also be cast to mitigate pain Bitterly, and cast stable or other central nervous system agents to suppress dizziness.Optionally employ capsaicin (capsaicin), profit Many caines paster and nerve block.Surgical operation can also be carried out to mitigate facial paralysis to the nervus facialiss of extruding.

Microvascular compression syndrome

Microvascular compression syndrome (mcs) is also called " perstriction " or " neural blood vessel compressing ", is that one kind is characterized as dizzy The dizzy disease with tinnitus.It is by blood vessel to caused by the stimulation of cranial nerve vii.The other diseases finding in the individuality with mcs Shape include but is not limited to serious motion unbearably with the neuralgia as " rotating (quick spin) rapidly ".Mcs card Horse Xiping (carbamazepine),With baclofen (baclofen) treatment.It also can surgically come Treatment.

Vestibular neuronitis

Vestibular neuronitis or vestibular nerve disease are a kind of acute and lasting surrounding's labyrinthine system dysfunctions.Before deduction Front yard neuronitiss are suffered brokenly caused by ring by the afferent neuron input from one or two vestibular apparatus.The reason this broken ring Including vestibular nerve and/or lost virus infection and acute ischemic.

When diagnosing vestibular neuronitis, the most great being the discovery that is spontaneous, unidirectional, horizontal nystagmuss.Its usually companion There are Nausea and vomiting and dizziness.However, it is typically without hearing disability or other audition symptom.

There is several treatment to vestibular neuronitis.Such as dimenhydrinate (dimenhydrinate), diphenhydramine (diphenhydramine), the Mycospor profit h1- receptor antagonist such as piperazine and promethazine can reduce vestibule thorn by anticholinergic effect Swash and suppress labyrinthine function.For example stabilize and also may be used to because acting on gabaa receptor press down with benzodiazepines such as lorazepams Vestibular response processed.Also indicate that anticholinergic, such as hyoscyamine.These anticholinergic pass through to suppress in vestibulocerebellum path Conductivity works.Finally, indicate corticosteroid (i.e. prednisone) to improve the inflammation of vestibular nerve and related organ.

Medical agent

Provided herein is adjusting the ear sensory cell regulator that ear sensory cell (such as auricularis unit and/or hair cell) is degenerated Compositionss or composite.In certain embodiments, ear sensory cell regulating composition as herein described or composite mitigate or Postpone or reverse the degeneration of ear sensory cell (such as auricularis unit and/or hair cell).Also disclosed herein is being used for treating or improving By internal ear gross loss is bad, obstacle, malfunction, the control release of damage, the hearing disability caused by fragility or loss or decline combine Thing.In addition, provided herein is promoting the ear sensation of (the such as auricularis unit and/or hair cell) growth of ear sensory cell and/or regeneration Cell enhancer compositions or composite.In certain embodiments, ear sensory cell regulating composition or composite destroy ear Sensory cell (such as auricularis unit and/or hair cell).In certain embodiments, ear sensory cell regulator be otoprotective agent and Mitigate, reverse or postpone the damage to ear sensory cell (such as auricularis unit and/or hair cell).

Ear and vestibular disorder have the cause of disease and the symptom of response medical agent disclosed herein or other medical agent.Herein not Ear sensory cell regulator that is open but can improving or eradicate otic conditions is clearly included in the scope of embodiments of institute's presentation And it is intended to belong to described scope

Additionally, previously shown for example because formed after liver processing toxic metabolite, medicine certain organs, tissue or Toxicity in system, reach high-load required for effect, can not be via systemic routes release or bad pk feature complete Body is applied or toxic, harmful or invalid medical agent is applied to some of this paper during being locally applied to other tracts Embodiment.Therefore, there is limited release or the medical agent of non-systemic release, systemic toxicity, bad pk feature or a combination thereof It is covered by the range of embodiment disclosed herein.

Ear sensory cell regulator composite disclosed herein is optionally directly targeted ear structure in need for the treatment of；For example expected An embodiment be that ear sensory cell regulator composite disclosed herein is directly applied to round window membrane or the fenestra cochleae of internal ear On ridge, thus directly reaching and treatment internal ear or internal ear assembly.In other embodiments, ear sensory cell disclosed herein is adjusted Section agent composite is directly applied to oval window.In other embodiments again, by for example utilizing cochlea microperfusion technique directly micro- note Penetrate and directly reach in internal ear.These embodiments also optionally comprise drug delivery device, and wherein said drug delivery device passes through It is formed in situ spongy material using pin and syringe, pump, micro injecting device, ear are acceptable or its any combinations transmits ear Sensory cell regulator composite.

Some medical agents alone or in combination when there is ototoxicity.For example, following some medicament appropriateness are poisonous to great Toxicity: chemotherapeutics, including D actinomycin D, bleomycin, cisplatin, carboplatin and vincristine；And antibiotic, including erythromycin, celebrating Big mycin, streptomycin, dihydrostreptomycin, tobramycin (tobramycin), netilmicin (netilmicin), A meter Ka Star, neomycin, kanamycin (kanamycin), she replace mycin (etiomycin), vancomycin, metronidazole, capreomycin (capreomycin) vestibule and cochlear structures are affected, and to some extent.However, in some cases, ototoxic drug (example As cisplatin, gentamycin) act on the ototoxicity combining reduction medicine of otoprotective agent.Additionally, the potential ototoxicity of local application Medicine also by using small amount but maintain effect or using aim parameter but continue the shorter time and mitigate systemic administration meeting The toxic action occurring.

In certain embodiments, ear sensory cell regulator composite disclosed herein additionally comprises otoprotective agent, described Otoprotective agent can reduce, suppress or improve the ototoxicity of the medicaments such as all chemotherapeutics as described herein and/or antibiotic, or fall Low, suppression or improve the impact including other environmental factorss such as excessive noise.The example of otoprotective agent includes but is not limited to this Otoprotective agent described in literary composition, mercaptan and/or thiol derivative and/or its pharmaceutically acceptable salt or derivant are (before for example Medicine).

Otoprotective agent allows ototoxicity agent and/or antibiotic to cast with the dosage higher than maximum toxicity dose；Otherwise, attribution In ototoxicity, ototoxicity agent and/or antibiotic should be cast with relatively low dosage.Otoprotective agent is also fair when optionally individually casting Permitted to improve, reduce or eliminate to cause hearing disability and with impact (including but not limited to noise-inducing hearing disability and tinnitus) Environmental factorss impact.

The protectant amount of any composite middle ear as herein described is with respect to ototoxicity chemotherapeutics (such as cisplatin) and/or ear Toxic antibiotics (such as gentamycin) by mole: in about 5:1 to about 200:1, about 5:1 to about 100:1 or about 5:1 in terms of mole To about 20:1.The protectant amount of any composite middle ear as herein described is with respect to ototoxicity chemotherapeutics (such as cisplatin) And/or ototoxicity antibiotic (such as gentamycin) is about 50:1, about 20:1 or about 10:1 in mol.As herein described any Ear sensory cell regulator composite comprises about 10mg/ml to about 50mg/ml, about 20mg/ml to about 30mg/ml or about 10mg/ Ml to 25mg/ml otoprotective agent.

Additionally, some pharmaceutical excipient, diluent or supporting agent have potential ototoxicity.For example, benzalkonium chloride, A kind of Determination of common preservatives, has ototoxicity, if be therefore introduced in vestibule or cochlear structures, then may be harmful to.In allotment control It is proposed that avoiding or combining suitable excipient, diluent or supporting agent with from tune during system release ear sensory cell regulator composite Join the amount reducing or eliminating possible ototoxicity component in thing or reducing described excipient, diluent or supporting agent.Control release ear Sensory cell regulator composite optionally includes otoprotective agent, such as antioxidant, alpha lipoic acid, calcium, fosfomycin or ferrum chelating Agent, can be acted on by the possible ototoxicity being produced using particular therapeutic agent or excipient, diluent or supporting agent with offsetting.

Amifostine (amifostine)

Cover be available for composite disclosed herein using adjust auricularis unit and/or medicament that hair cell is degenerated and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.Cause This, some embodiments merge to use rescues neuron and ear's hair cell against the ototoxic medicament of cisplatin induced.

Amifostine (also referred to as wr-2721 or) it is a kind of otoprotective agent.In some cases, its prevention or Improve the damage to neuron and ear's hair cell being caused by cisplatin.In certain situations it is desirable to 40mg/kg or 40mg/kg Above dosage acts on come the ototoxicity to stop or to improve cisplatin.

Salicylic acid

Cover be available for composite disclosed herein using adjust auricularis unit and/or medicament that hair cell is degenerated and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.Cause This, the merging of some embodiments uses salicylic acid.In some cases, salicylic acid is a kind of antioxidant, and when with amino sugar When casting before glycoside treatment, it protects ear's hair cell and Spiral ganglion neuron from aminoglycoside ototoxicity.

Atoh/math1 is adjusted

Cover and be available for composite disclosed herein using promoting neuron and/or ear's capillary intracellular growth and/or regeneration Medicament.Atoh1 is the transcription factor with reference to e-box.In some cases, it is in the hair cell period of development of vestibule and auditory system Between express.In some cases, reject the mice aplasia ear hair cell of atoh1.In some cases, express atoh1's Adenoviruss stimulate the growth of ear's hair cell of Cavia porcelluss and/or regeneration through ototoxicity antibiotic treatment.Therefore, some embodiments Merge and adjust atoh1 gene.

In certain embodiments, (" atoh1 carries to cast the individual engineered carrier to deliver mankind's atoh1 gene Body ").With regard to formed atoh1 carrier technology disclosure referring to U.S. Publication case the 2004/02475750th, its announcement Content is incorporated herein by reference.In certain embodiments, atoh1 carrier is retrovirus retrovirus.In some embodiments In, atoh1 carrier is not that (for example it is adenoviruss to retrovirus retrovirus；Slow viruss；Or polymer transmission system, such as metafectene、Or mirus transit).

In certain embodiments, atoh1 carrier is incorporated to the acceptable microsphere of control release ear or microgranule, hydrogel, fat In plastid or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foam Body, be formed in situ spongy material, Nano capsule or nanosphere body or thermoreversible gels injection internal ear in.In some embodiments In, the acceptable microsphere of ear or microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, ear is subjected to Microsphere, hydrogel, liposome, varnish, foams, be formed in situ spongy material, Nano capsule or nanosphere body or heat In reversible gel injection cochlea, organ of Corti, vestibular labyrinth or a combination thereof.

In some cases, after casting atoh1 carrier, the infection of atoh1 carrier casts cell (the such as ear at position Snail, organ of Corti and/or vestibular labyrinth cell).In some cases, atoh1 sequence be incorporated to individuality genome in (for example when When atoh1 carrier is retrovirus retrovirus).In some cases, therapy will need periodically to cast (for example when atoh1 carrier again When being not retrovirus retrovirus).In certain embodiments, therapy casts every year again.In certain embodiments, therapy is thrown every half a year again Give.In certain embodiments, therapy is individual moderate (i.e. individuality can not hear the frequency less than 41db to 55db from start to finish) Cast again during to depth (i.e. individuality can not hear the frequency less than 90db from start to finish) hearing disability.

In certain embodiments, cast individual atoh1 polypeptide.In certain embodiments, atoh1 polypeptide is incorporated to control release In the acceptable microsphere of ear or microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, ear is subjected to Microsphere, hydrogel, liposome, varnish, foams, be formed in situ spongy material, Nano capsule or nanosphere body or heat Reversible gel.In certain embodiments, the acceptable microsphere of ear or microgranule, hydrogel, liposome or thermoreversible gels. In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foams, be formed in situ spongy material, In Nano capsule or nanosphere body or thermoreversible gels injection internal ear.In certain embodiments, the acceptable microsphere of ear or Microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, lipid Body, varnish, foams, be formed in situ spongy material, Nano capsule or nanosphere body or thermoreversible gels injection cochlea, Ke In Ti Shi device, vestibular labyrinth or a combination thereof.In certain embodiments, the acceptable microsphere of ear or microgranule, hydrogel, liposome Or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foams, scene Form spongy material, Nano capsule or nanosphere body or thermoreversible gels are placed contacts with round window membrane.

In certain embodiments, cast the activity of the individual expression adjusting atoh1 gene or atoh1 polypeptide pharmaceutically Acceptable medicament.In certain embodiments, the activity rise of the expression of atoh1 gene or atoh1 polypeptide.In some embodiments In, the activity down-regulation of the expression of atoh1 gene or atoh1 polypeptide.

In some cases, differentiate exciting or antagonism atoh1 compound (for example by using high flux screening).One In a little embodiments, construct is designed to the downstream making reporter gene be placed on e-box sequence.In certain embodiments, report Gene is luciferase, cat, gfp, beta-lactamase or beta galactosidase.In some cases, atoh1 polypeptide combines e- Box sequence and the transcript and expression of initiation reporter gene.In some cases, atoh1 agonist helps or promotes atoh1 to combine In e-box sequence, thus strengthen the transcript and expression of reporter gene with respect to predetermined baseline expression level.In some cases, Atoh1 Antagonist block atoh1 is incorporated into e-box, thus reduce the transcription of reporter gene with respect to predetermined baseline expression level And expression.

Brn-3 regulator

Cover and be available for composite disclosed herein using promoting neuron and/or ear's capillary intracellular growth and/or regeneration Medicament.Brn-3 is one group of transcription factor, including but not limited to brn-3a, brn-3b and brn-3c.In some cases, its It is expressed in postmitotic hair cell.In some cases, reject the hair cell aplasia stereocilium of the mice of brn-3c And/or generation cell death.In some cases, brn3 gene regulation inner ear supporting cell is divided into internal ear sensory cell.Cause This, some embodiments merge the regulation of brn3 gene and/or polypeptide.

In certain embodiments, (" brn3 carries to cast the individual engineered carrier to carry mankind's brn-3 gene Body ").In certain embodiments, brn3 carrier is retrovirus retrovirus.In certain embodiments, brn3 carrier is not reverse transcription disease (for example it is adenoviruss to poison；Slow viruss；Or polymer transmission system, such as metafectene,Or mirus transit).

In certain embodiments, be enough to induce listen being exposed to ototoxicity agent (such as aminoglycoside or cisplatin) or loudness Individual brn3 carrier is cast before, during or after feeling the sound damaging.

In certain embodiments, brn3 carrier is incorporated to the acceptable microsphere of control release ear or microgranule, hydrogel, lipid In body or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foams, It is formed in situ in spongy material, Nano capsule or nanosphere body or thermoreversible gels injection internal ear.In certain embodiments, The acceptable microsphere of ear or microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, ear is acceptable Microsphere, hydrogel, liposome, varnish, foams, it is formed in situ spongy material, Nano capsule or nanosphere body or heat can In inverse property gel injection cochlea, organ of Corti, vestibular labyrinth or a combination thereof.

In some cases, after casting brn3 carrier, the infection of brn3 carrier casts cell (the such as ear at position Snail, organ of Corti and/or vestibular labyrinth cell).In some cases, brn3 sequence be incorporated to individuality genome in (for example when When brn3 carrier is retrovirus retrovirus).In some cases, therapy by needing periodically to cast again (for example when brn3 carrier not When being retrovirus retrovirus).

In certain embodiments, cast individual brn3 polypeptide.In certain embodiments, brn3 polypeptide is incorporated to control release ear In acceptable microsphere or microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, ear is acceptable Microsphere, hydrogel, liposome, varnish, foams, it is formed in situ spongy material, Nano capsule or nanosphere body or heat can Inverse property gel.In certain embodiments, the acceptable microsphere of ear or microgranule, hydrogel, liposome or thermoreversible gels.? In some embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foams, it is formed in situ spongy material, receives In rice glue capsule or nanosphere body or thermoreversible gels injection internal ear.In certain embodiments, ear acceptable microsphere or micro- Grain, hydrogel, liposome or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, Varnish, foams, it is formed in situ spongy material, Nano capsule or nanosphere body or thermoreversible gels injection cochlea, Ke replace In family name's device, vestibular labyrinth or a combination thereof.In certain embodiments, the acceptable microsphere of ear or microgranule, hydrogel, liposome or Thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foams, live shape Become spongy material, Nano capsule or nanosphere body or thermoreversible gels are placed contacts with round window membrane.

In certain embodiments, cast pharmaceutically may be used of activity of the individual expression adjusting brn3 gene or brn3 polypeptide The medicament accepting.In certain embodiments, the activity rise of the expression of brn3 gene or brn3 polypeptide.In certain embodiments, The expression of brn3 gene or the activity down-regulation of brn3 polypeptide.

In certain embodiments, differentiate exciting or antagonism brn3 compound (for example by using high flux screening).? In some embodiments, construct is designed to the downstream making reporter gene be placed on brn3 binding site.In certain embodiments, Brn3 binding site has sequence atgaattaat (sbnr3).In certain embodiments, reporter gene be luciferase, cat, Gfp, beta-lactamase or beta galactosidase.In some cases, brn3 polypeptide combines sbnr3 sequence and causes reporter gene Transcript and expression.In some cases, brn3 agonist helps or promotes brn3 to be incorporated into sbnr3 sequence, thus with respect to Predetermined baseline expression level strengthens the transcript and expression of reporter gene.In some cases, brn3 Antagonist block brn3 combines In sbnr3, thus reduce the transcript and expression of reporter gene with respect to predetermined baseline expression level.

Carbamate

Cover be available for composite disclosed herein using adjust auricularis unit and/or medicament that hair cell is degenerated and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.At certain In the case of a little, carbamate compounds protect the excitatory toxicity that neuron and ear's hair cell induce from glutamic acid.Cause This, the merging of some embodiments uses carbamate compounds.In certain embodiments, carbamate compounds are 2- benzene Base -1,2- ethylene glycol single-amido acid ester and diurethane, its derivant and/or a combination thereof.

Inhibitors of gamma-secretase

Cover be available for composite disclosed herein using adjust auricularis unit and/or medicament that hair cell is degenerated and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.Cause This, some embodiments merge the medicament using suppression notch1 signal transduction.Notch1 is to participate in cytocerastic transmembrane polypeptide. In certain embodiments, the medicament of suppression notch1 signal transduction is inhibitors of gamma-secretase.In some cases, with ear poison Property agent treatment after inhibitors of gamma-secretase suppression notch1 ear hair cell can be caused to produce/growth.In some embodiments In, inhibitors of gamma-secretase is ly450139 (hydroxypentanoyl base list benzo caprolactam), l685458 (1s- benzyl -4r [1- [1-s- carbamyl -2- phenethyl-carbamoyl) -1s-3- methyl butyl carbamyl] -2r- hydroxyl -5- phenylpentyl } T-butyl carbamate)；Ly411575 (n2- [(2s) -2- (3,5- difluorophenyl) -2- hydroxyacetyl]-n1 [(7s) -5- first Base -6- oxo -6,7- dihydro -5h- dibenzo [bid] nitrogen -7 base]-l- aminopropanamide), mk-0752 (Merck (merck)), Tower husband Bill (tarenflurbil) and/or bms-299897 (2- [(1r)-l- [[(4- chlorphenyl) sulfonyl] (2,5- difluoro Phenyl) amino] ethyl] -5- fluorobenzene propanoic acid).

Glutamate receptor modulators

Provided herein is treatment is characterised by the ear of glutamate receptor regulation and control abnormal (such as overactivity or overstimulation) The method of disease.In certain embodiments, method disclosed herein comprises to cast that to comprise glutamate receptor short of money to individuality in need The compositionss of anti-agent.Herein be not disclosed but be applied to improve or eradicate otic conditions glutamate receptor antagonists clearly include In the scope of embodiments of institute's presentation and be intended to belong to described scope.

Cover be available for composite disclosed herein using adjust auricularis unit and/or medicament that hair cell is degenerated and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.Cause This, some embodiments merge using the medicament adjusting glutamate receptor.In certain embodiments, glutamate receptor is ampa receptor And/or i-th i group or the i-th ii group mglu receptor.In certain embodiments, glutamate receptor is nmda receptor.In some embodiments In, glutamate receptor modulators are glutamate receptor antagonists.In certain embodiments, glutamate receptor antagonists are non-competing Property antagonist.In certain embodiments, glutamate receptor antagonists are small molecules.

In certain embodiments, the medicament adjusting ampa receptor is ampa receptor antagonist.In certain embodiments, antagonism The medicament of ampa receptor is cnqx (6- cyano group -7- nitroquinoxaline -2,3- diketone)；Nbqx (2,3- dihydroxy -6- nitro -7- Sulfamoyl-benzo [f] quinoxaline -2,3- diketone)；Dnqx (6,7- dinitro quinoxaline -2,3- diketone)；Kynurenic acid； 2,3- dihydroxy -6- nitro -7- sulfamoyl benzo-[f] quinoline or a combination thereof.

In certain embodiments, glutamate receptor antagonists are nmda receptor antagonists.In certain embodiments, adjust The medicament of nmda receptor is nmda receptor antagonist.In certain embodiments, glutamate receptor antagonists be 1- aminoadamantan, Dextromethorphan (dextromethorphan), dextrorphan (dextrorphan), ibogaine (ibogaine), ifenprodil (ifenprodil), (s)-ketamine (ketamine), (r)-ketamine, memantine (memantine), dizocilpine (dizocilpine) (mk-801), gacyclidine (gacyclidine), am-101, Qu Suoluo ground (traxoprodil), d-2- Amino -5- phosphonate group valeric acid (d-ap5), 3- ((±) 2- carboxypiperazin -4- base)-propyl group -1- phosphoric acid (cpp), Conantokin (conantokin), 7- chlorine kynuramine acid (7-chlorokynurenate, 7-ck), licostinel (licostinel), an oxygen Change nitrogen, phencyclidine (phencyclidine), riluzole (riluzole), tiletamine (tiletamine), N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine (aptiganel), auspicious Mead (remacimide), dcka (5,7- dichloro kynurenic acid), kynurenic acid, 1- amino ring Third formic acid (acpc), ap7 (2- amino -7- phosphonate group enanthic acid), apv (r-2- amino -5- phosphonate group valerate), cppene (3- [(r) -2- carbonyl piperazine -4- base] -propyl- 2- thiazolinyl -1- phosphonic acids)；(+)-(1s, 2s) -1- (4- hydroxy-pheny) -2- (4- hydroxyl Base -4- phenyl (n- piperidyl)) -1- propanol；(1s, 2s) -1- (4- hydroxy 3-methoxybenzene base) -2- (4- hydroxy-4-phenyl (n- piperidyl)) -1- propanol；(3r, 4s) -3- (4- (4- fluorophenyl) -4- hydroxy piperidine -1- base -)-chromane -4,7- glycol； (1r*, 2r*) -1- (4- hydroxy-3-methyl phenyl) -2- (4- (4- fluoro-phenyl) -4- hydroxy piperidine -1- base) -propyl- 1- alcohol-first Sulphonic acid ester or a combination thereof.In certain embodiments, nmda receptor antagonist is cycloalkyl aryl amine.In certain embodiments, Nmda receptor antagonist is (s)-ketamine or its salt.In a kind of a little embodiment of quinazoline, nmda receptor antagonist is quinoline azoles Quinoline.In certain embodiments, nmda receptor antagonist is 7-ck or its salt.In certain embodiments, nmda receptor antagonist is Am-101 or its salt.

In certain embodiments, glutamate receptor antagonists are peptides.In certain embodiments, glutamate receptor antagonists are Fusogenic peptide, comprises (a) transport protein peptide and (b) suppresses nmda receptor and the interaction of nmda receptor interacting protein matter Peptide.As used herein, " transport protein peptide " meaning is the peptide promoting peptide to penetrate in cell and tissue.In some embodiments In, transport protein peptide is tat.

In certain embodiments, glutamate receptor antagonists are fusogenic peptides, comprise (a) tat peptide and (b) suppresses nmda receptor Peptide with the interaction of nmda receptor interacting protein matter.In certain embodiments, glutamate receptor antagonists are to merge Peptide, comprises (a) (d)-tat peptide and (b) suppresses the peptide of nmda receptor and the interaction of nmda receptor interacting protein matter.? In some embodiments, glutamate receptor antagonists are fusogenic peptides, comprise (a) transport protein peptide and (b) nr2b9c peptide.Real at some Apply in example, glutamate receptor antagonists are fusogenic peptides, comprise (a) transport protein peptide and (b) (d)-nr2b9c peptide.In some enforcements In example, glutamate receptor antagonists are fusogenic peptides, comprise (a) (d)-tat peptide and (b) (d)-nr2b9c peptide.In some embodiments In, glutamate receptor antagonists are fusogenic peptides, comprise (a) transport protein peptide and (b) (l)-nr2b9c peptide.

In some cases, ampa and nmda glutamate receptor is because with reference to excessive glutamate, overactivity can control at it Excessively open down ion channel.In some cases, ca2+ and na+ that this produces unusual high levels enters neuron.Some In the case of, ca2+ and na+ flows in neuron and can activate multiple enzymes, including but not limited to phospholipase, Cobra venom endonuclease and egg White enzyme.In some cases, these enzyme overactivities produce to cytoskeleton, plasma membrane, mitochondrion and neuron dna and damage.Separately Outward, in some cases, the transcription of multiple rush apoptogenes and anti-apoptotic genes expression is controlled by ca2+ level.

Mglu receptor, different from ampa and nmda receptor, does not directly control ion channel.However, in some cases, its By activating opening of biochemical cascade indirect control ion channel.Mglu receptor is divided into three groups.In some cases, the i-th i The member of group and iii group passes through prevention or the formation of reduction camp reduces or suppression postsynaptic potential.In some cases, this draws Play neurotransmitter, the release of especially glutamic acid reduces.Grm7 is coding mglu7 receptor, the gene of an i-th ii group receptor. In some cases, the agonism of mglu7 causes the synaptic concentration of glutamic acid to reduce.This improves glutamate excitotoxicity.

In certain embodiments, glutamate receptor is the i-th i group mglu receptor.In certain embodiments, adjust the i-th i group The medicament of mglu receptor is the i-th i group mglu receptor stimulating agent.In certain embodiments, the i-th i group mglu receptor stimulating agent is Ly389795 ((-) -2- thia -4- amino bicyclic-hexane -4,6- dicarboxylic acid esters)；Ly379268 ((-) -2- oxa- -4- amino Bicyclo--hexane -4,6- dicarboxylic acid esters)；Ly354740 ((+) -2- amino bicyclic-hexane -2,6- dicarboxylic acid esters)；dcg-iv ((2s, 2'r, 3'r) -2- (2', 3'- dicarboxyl cyclopropyl) glycine)；2r, 4r-apdc (2r, 4r-4- amino-pyrrolidine -2, 4- dicarboxylic acid esters), (s) -3c4hpg ((s) -3- carboxyl -4- hydroxyphenyl)；(s) -4c3hpg ((s) -4- carboxyl -3- Hydroxyphenyl)；L-ccg-i ((2s, 1's, 2's) -2- (carboxycyclopropyl) glycine) and/or a combination thereof.

In certain embodiments, mglu receptor is the i-th ii group mglu receptor.In certain embodiments, the i-th ii group mglu is subject to Body is mglu7.In certain embodiments, the medicament adjusting the i-th ii group mglu receptor is the i-th ii group mglu receptor stimulating agent.? In some embodiments, the i-th ii group mglu receptor stimulating agent is acpt-i ((1s, 3r, 4s) -1- Aminocyclopentane -1,3,4- front threes Acid)；L-ap4 (l- (+) -2- amino -4- phosphonate group butanoic acid)；(s) -3,4-dcpg ((s) -3,4- dicarboxyphenyi glycine)； (rs) -3,4-dcpg ((rs) -3,4- dicarboxyphenyi glycine)；(rs) -4- phosphonate group phenylglycine ((rs) ppg)； Amn082 (, double (the diphenyl methyl) -1,2- ethylendiamine dihydrochloride of n'-)；Dcg-iv ((2s, 2'r, 3'r) -2- (2', 3'- bis- Carboxycyclopropyl) glycine) and/or a combination thereof.In certain embodiments, mglu receptor is mglu7.In certain embodiments, Mglu7 agonist is amn082.In certain embodiments, mglu receptor modulators are 3,5- dimethyl pyrrole -2,4- dioctyl phthalate 2- propyl ester 4- (1,2,2- trimethyl-propyl) ester (3,5- dimethyl ppp)；3,3'- difluoro benzalazine (dfb), 3,3'- dimethoxy Base benzalazine (dmeob), 3,3'- dichloro benzalazine (dcb) and molecular pharmacology (mol.pharmacol.) 2003,64,731- The other mglur5 allosteric modulators disclosing in 740；(e) -6- methyl -2- (phenyl-diazenyl) pyridine -3- alcohol (sib 1757)；(e) -2- methyl -6- stibazole (sib1893)；2- methyl -6- (phenylene-ethynylene) pyridine (mpep), 2- first Base -4- ((6- picoline -2- base) acetenyl) thiazole (mtep)；7- (oxyimino) ring third [b] chromene -1- dioctyl phthalate second Ester (cpccoet), n- cyclohexyl -3- methyl benzo [d] thiazole simultaneously [3,2-a] imidazoles -2- Methanamide (ym-298198), three rings [3.3.3.1] nonyl quinoxaline -2- Methanamide (nps2390)；6- methoxyl group-n- (4- methoxyphenyl) quinazoline -4- amine (ly 456239)；The mglur1 antagonist disclosing in wo2004/058754 and wo2005/009987；2- (4- (2,3- dihydro -1h- Indenes -2 base amino) -5,6,7,8- tetrahydro quinazoline -2- base sulfenyl) ethanol；3- (5- (pyridine -2- base) -2h- tetrazolium -2- base) benzene Formonitrile HCN, 2- (2- methoxyl group -4- (4- (pyridine -2- base) azoles -2- base) phenyl) acetonitrile；2- (4- (benzo [d] azoles -2- base) - 2- methoxyphenyl) acetonitrile；6- (3- methoxyl group -4- (pyridine -2- base) phenyl) imidazo [2,1-b] thiazole；(s)-(4- fluorobenzene Base) (3- (3- (4- fluorophenyl)-l, 2,4- diazole -5- base) piperidin-1-yl) ketone (adx47273) and/or a combination thereof.

In certain embodiments, glutamate receptor modulators are Fructus Alpiniae Oxyphyllae agent.Cover and be available for composite use disclosed herein By activating the Fructus Alpiniae Oxyphyllae agent that glutamate receptor adjusts the signal transduction of neuron.In some cases, Fructus Alpiniae Oxyphyllae agent treatment or improvement Hearing disability (such as nihl) or tinnitus.Therefore, some embodiments merge the Fructus Alpiniae Oxyphyllae agent using treatment nihl or tinnitus, including (but not limited to) piracetam (piracetam), oxiracetam (oxiracetam), aniracetam (aniracetam), pula Western smooth (pramiracetam), phenyl piracetam (phenylpiracetam) (carphedon (carphedon)), etiracetam (etiracetam), levetiracetam (levetiracetam), nefiracetam (nefiracetam), nicoracetam (nicoracetam), Rolziracetam (rolziracetam), nebracetam (nebracetam), fasoracetam (fasoracetam), MKC-231 (coluracetam), dimiracetam (dimiracetam), Bloomsbury cut down western smooth (brivaracetam), Sai Laixitan (seletracetam) and/or rolipram (rolipram).

Nutrient

Cover and be available for composite disclosed herein using the medicament mitigating or postponing auricularis unit and/or hair cell degeneration. In certain embodiments, cover and be available for compositionss as herein described medicament as nutrient is used, for example promote ear tissue and/ Or the medicament of neuron and/or capillary intracellular growth.It is also contemplated by being available for compositionss as herein described using treatment or improvement by internal ear Gross loss is bad, obstacle, malfunction, damage, fragility or loss caused by hearing disability or decline medicament.Therefore, some enforcements Example merges using the nutrient promoting neuron and tragus cell survival and/or neuron and tragus cell growth.Real at some Apply in example, the nutrient promoting tragus cell survival is somatomedin.In certain embodiments, somatomedin is neurotrophy Element.In some cases, neurenergen is prevention cell death, prevention primary cellular defect, the neuron recovering infringement and tragus Cell and/or the somatomedin of induction CFU-GM differentiation.In certain embodiments, neurenergen is brain-derived neurotrophy Sex factor (bdnf), CNTF (cntf), glial cellline-derived neurotrophic factor (gdnf), neurotrophy Protein-3 (nt-3), neurotrophin -4 (nt-4) or a combination thereof.In certain embodiments, somatomedin is fibroblast Somatomedin (fgf), insulin like growth factor (igf), epidermal growth factor (egf), platelet-derived growth factor (pgf) And/or its agonist.In certain embodiments, somatomedin is the life of fibroblast growth factor (fgf) Receptors, insdri sample The long factor (igf) receptor, epidermal growth factor (egf) receptor, the agonist of platelet-derived growth factor.In some embodiments In, somatomedin is hepatocyte growth factor.

In certain embodiments, nutrient and/or neurenergen are bdnf.In certain embodiments, nutrient and/or Neurenergen is gdnf.In some cases, bdnf and gdnf be by repair damage cell, suppression ros generation and/ Or suppress cell death to promote the neurotrophy of existing neuron (such as Spiral ganglion neuron) and tragus cell survival Element.In some cases, it also promotes ancestral's neurocyte and ancestral's tragus cell differentiation.In addition, in some cases, it protects brain Neural vii is in order to avoid degenerate.In certain embodiments, bdnf casts with reference to fibroblast growth factor.

In certain embodiments, neurenergen is NT-3.In some cases, NT-3 Promote existing neuron and tragus cell survival, and promote ancestral's neurocyte and ancestral's tragus cell differentiation.In addition, in some situations Under, its protection vii nerve is in order to avoid degenerate.

In certain embodiments, neurenergen is cntf.In some cases, cntf promote neurotransmitters synthesis and Neuritiss are developed.In certain embodiments, cntf casts with reference to bdnf.

In certain embodiments, nutrient and/or neurenergen are gdnf.In some cases, gdnf expression is passed through Process to increase with ototoxicity agent.In addition, in some cases, the cell being processed with exogenous gdnf is in post-traumatic survival rate Higher than untreated cell.

In certain embodiments, nutrient and/or somatomedin are epidermal growth factor (egf).In certain embodiments, Egf is heregulin (hrg).In some cases, hrg stimulates the hypertrophy of utriculuss sensory epithelium.In some cases, hrg knot Close receptor to find in vestibule and audition sensory epithelium.

In certain embodiments, nutrient and/or somatomedin are insulin like growth factor (igf).In some enforcements In example, igf is igf-1.In certain embodiments, igf-1 is mecasermin (mecasermin).In some cases, igf-1 Weaken the damage because being exposed to aminoglycoside induction.In some cases, igf-1 stimulates the differentiation of nervus cochleae ganglion cell And/or it is ripe.

In certain embodiments, fgf receptor stimulating agent is fgf-2.In certain embodiments, igf receptor stimulating agent is igf-1.Fgf is found in the cell constituting oval capsular epithelium with igf receptor.

In certain embodiments, somatomedin is hepatocyte growth factor (hgf).In some cases, hgf protection cochlea Hair cell damages and reduces, from noise-induced, the abr threshold shifting that noise exposure causes.

It is also contemplated by being available for ear composite described herein using following somatomedin, including erythropoietin (epo), granulocyte colony-stimulating factor (g-csf), granulocyte-macrophage colony stimutaing factor (gm-csf), Growth and Differentiation The factor -9 (gdf9), insulin like growth factor (igf), myostatin (myostatin) (gdf-8), platelet source Property somatomedin (pdgf), thrombopoietin (tpo), transforming growth factor α (tgf- α), transforming growth factor β (tgf- β), VEGF (vegf) or a combination thereof.It is also contemplated by being available for ear compositionss described herein using described herein Trophic factors, including antioxidant and/or vitamin.

Protective effect of anti intercellular adhesion moleculer 1 antibody

Cover the antibody being available for that composite disclosed herein uses adhesion molecule (icam) between anti-cell.In certain situation Under, icam blocks the cascade of the active oxygen related to noise exposure.In some cases, adjust the work related to noise exposure Property oxygen class cascade can improve or slow down auricularis unit and/or hair cell degeneration.Therefore, some embodiments merging is used conduct The medicament of icam antibody (for example anti-icam-1ab, anti-icam-2ab etc.).

Otoprotective agent

Cover be available for composite disclosed herein using adjust auricularis unit and/or medicament that hair cell is degenerated and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.Cause This, the merging of some embodiments uses otoprotective agent.In certain embodiments, otoprotective agent is that glutamate receptor as herein described is short of money Anti-agent.In certain embodiments, otoprotective agent is corticosteroid as herein described.In certain embodiments, otoprotective agent is Adjust the medicament of glutathione peroxidase (gpx).Auricularis in active oxygen (ros) in enzyme gpx minimizing cochlea and maintenance Unit and/or the health of hair cell.Gpx regulator includes but is not limited to glutathione peroxidase mimic, such as 2- phenyl- 1,2- benzisoxa selenazoles -3 (2h) -one (ebselen (ebselen), spi-1005), 6a, 6b- bis- selenic acid -6a', 6b'- selenium bridging Beta-schardinger dextrin-(6-disecd) and 2,2'- bis- seleno-bis--beta-schardinger dextrin-(2-disecd).

In certain embodiments, can be slowed down using otoprotective agent or improve by internal ear gross loss is bad, obstacle, malfunction, damage Wound, the hearing disability that fragile or loss is caused or auditory dysesthesia.Otoprotective agent includes but is not limited to d- methionine, l- first sulfur Propylhomoserin, ethionine, hydroxyl methionine, methanthiol, amifostine, mesna (2- sulfenyl ethane sulfonic acid sodium), d- first sulfur The mixture of propylhomoserin and l- methionine, n- acetyl methionine (nam), fall methionine, homomethionine, s- adenosine- L- methionine, diethyldithiocarbamate, ebselen (ebselen) (2- phenyl -1,2- benzisoxa selenazoles -3 (2h) - Ketone), sodium thiosulfate, am-111 (a kind of jnk inhibitor of cell-permeable, (laboratory ear sas (laboratoires Auris sas)), n- acetyl group-dl- methionine, s- S-adenosylmethionine, cysteine, homocysteine, cysteamine, n- Acetylcysteine (nac), Glutathione, effect of glutathione ethyl ester, Glutathione diethylester, Glutathione triethyl, half Guang Amine, cystathionie, n, n'- diacetyl-l- cystine (dinac), 2 (r, s)-d- core-(1', 2', 3', 4'- tetrahydroxy butyl)- Thiazolidine -4 (r)-formic acid (ribcys), 2- alkylthiazolidine 2 (r, s)-d- core-(1', 2', 3', 4'- tetrahydroxy butyl) thiazole Alkane (ribcyst) and 2- oxygen-l- Thiazolidine -4- formic acid (otca), salicylic acid, formyl tetrahydrofolic acid (leucovorin), formyl Calcium leucovorin (leucovorin calcium), dexrazoxane (dexrazoxane), piracetam, oxiracetam, Hui Laxi Smooth, pramiracetam, phenyl piracetam (carphedon), etiracetam, levetiracetam, nefiracetam, nicoracetam, Lora west Smooth, nebracetam, fasoracetam, MKC-231, dimiracetam, Bloomsbury cut down western smooth, Sai Laixitan, rolipram and/or its group Close.

In certain embodiments, otoprotective agent includes xanthine oxidase inhibitor.Xanthine oxidase inhibitor non- Limitative examples include allopurinol (allopurinol)；1- methylallopurinol；2- methylallopurinol；5- methyl is not fast Purine alcohol；7- methylallopurinol；1,5- dimethylallopurinol；2,5- dimethylallopurinol；1,7- dimethylallopurinol； 2,7- dimethylallopurinol；5,7- dimethylallopurinol；2,5,7- trimethyl allopurinol；The other purine of 1- carbethoxyl group Alcohol；With 1- carbethoxyl group -5- methylallopurinol.

In certain embodiments, otoprotective agent and poisonous substance are applied in combination.

Hair cell regeneration modulator

Cover be available for composite disclosed herein using the medicament adjusting auricularis unit and/or hair cell regeneration and treatment or Improve by internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, fragility or the hearing disability caused by losing or decline.One In a little embodiments, ear sensory cell regulator makes tragus cell and/or sertoli cell hypertrophy and/or regeneration.Therefore, some enforcements Example merges usage cycles element dependant kinase (cdk) regulator.In certain embodiments, cdk regulator is that p27kip1 is adjusted Agent.P27kip1 mediates the Sensory hair cell regeneration of organ of Corti.In some cases, (for example undercoat is thin for internal ear Sensory hair cell Born of the same parents) by stimulate sertoli cell (such as Hensen's cell (hansen's cell), deiters cells (deiter's cell) and/or Skin strangles cell (pillar's cell) etc.) hypertrophy and regenerate.In some cases, cyclin-dependent kinase p27kip1 is adjusted Agent be adjust p27kip1 activity antisense molecule (such as sirna molecule) or peptide molecule (endogenouss of such as p27kip1 are joined Body).

In certain embodiments, composite described herein comprises to stimulate internal ear Sensory hair cell or internal ear to support carefully The nucleic acid of the formation of born of the same parents and/or transcription factor (such as pou4f1, pou4f2, pou4f3, brn3a, brn3b and/or brn3c Deng).The non-limiting examples of described nucleic acid molecules and/or transcription factor include but is not limited to U. S. application publication the Molecule described in No. 20070041957 and No. 20030203482, the disclosure in described publication is by reference It is incorporated herein.

Immune system cell

Cover that to be available for composite disclosed herein first and/or hair cell degeneration using slowing down, reversing or postponing auricularis Medicament and treatment or improve by internal ear gross loss is bad, obstacle, malfunction, damage, fragility or the hearing disability caused by losing or under The medicament of fall.Therefore, some embodiments merge using the cell participating in ear's hair cell and neuron reparation.In some embodiments In, participating in ear's hair cell and the cell of neuron reparation is that macrophage, microglia and/or microglia sample are thin Born of the same parents.In some cases, the concentration of macrophage and microglia is in the ear sustaining damage because of ototoxicity agent treatment Can increase.In some cases, microglia like cell removes the waste caused by ototoxicity antibiotic neomycin.

Ototoxicity agent and poisonous substance

Cover and be available for composite disclosed herein using the medicament destroying neuron and/or ear's hair cell.Therefore, some Embodiment merges the medicament using lethal damage and/or induction auricularis unit and/or ear's Hair Cell Death.In some enforcements In example, the death of ear sensory cell (such as hair cell) can treat the disease related to any ear disease as herein described or condition of illness Shape (such as dizziness).In certain embodiments, poisonous substance induces the chemical pathological changes mitigating the symptoms such as dizziness in ear.? In some embodiments, the medicament of lethal damage and/or induction auricularis unit and/or ear's Hair Cell Death is aminoglycoside Antibiotic (such as gentamycin and amikacin), macrolide antibiotics (such as erythromycin), glycopeptide antibiotic (such as ten thousand Ancient mycin), loop diuretic (such as furosemide), nicotine, 6- hydroxy dopamine (6-ohdpat), 6,7- dinitro quinoline Quinoline -2,3- diketone (dnqx) etc..In certain embodiments, compositionss as herein described comprise mean for selective destruction ear In hair cell treat dizziness poisonous substance.In some described embodiments, the ear compositionss comprising poisonous substance are favourable；Described Compositionss provide the treatment benefit for the treatment of dizziness, because its non-systemic casts to ear and do not produce casts poison with general The related side effect of thing.

In certain embodiments, compositionss as herein described are applied to preclinical animal research (such as animal guinea pig model Research).In some cases, the compositionss as herein described comprising poisonous substance are used for induced chemical sexually transmitted disease (STD) change in animal ear. In some cases, the therapeutic efficiency in animal model using described animal testing compositionss as herein described.

Retinoblastoma Protein is adjusted

Cover and be available for composite disclosed herein using regulation auricularis unit and/or hair cell degeneration, promotion auricularis unit And/or the medicament of capillary intracellular growth and treatment or improve by internal ear gross loss is bad, obstacle, malfunction, damage, fragility or lose institute The hearing disability causing or the medicament of decline.In addition cover the medicament destroying neuron and/or ear's hair cell herein.Therefore, one A little embodiments merge using the medicament adjusting Retinoblastoma Protein (prb).Prb is the one-tenth of pocket protein familieses Member.It is by rb1 gene code.In some cases, it passes through with reference to transcription factor e2f family and is allowed to inactivation suppression from the g1 phase It is converted to the s phase.In some cases, it also regulates and controls the differentiation of hair cell and survival.In some cases, prb rejects mice and shows Show that the hypertrophy of hair cell increases.

In certain embodiments, the medicament adjusting one or more prb is the agonist of prb.In some embodiments In, the medicament adjusting one or more prb is the antagonist of prb.In some cases, discriminating is exciting or antagonism prb Compound (for example by using high flux screening).In certain embodiments, construct is designed to make reporter gene be placed on The downstream of e2f binding sequence.In certain embodiments, binding sequence is tttcgcgc.In certain embodiments, reporter gene is Luciferase, cat, gfp, beta-lactamase or beta galactosidase.In some cases, e2f combines and causes reporter gene to turn Record and the binding sequence of expression.In some cases, the agonist of prb causes the combination of prb and e2f to increase.In some situations Under, the increase of the combination of prb and e2f causes the transcript and expression of reporter gene to reduce.In some cases, the antagonist of prb The combination causing prb and e2f reduces.In some cases, the reduction of the combination of prb and e2f cause reporter gene transcription and Expression increases.

In certain embodiments, the medicament adjusting prb is sirna molecule.In some cases, sirna molecule passes through rna Interference (rnai) suppression rb1 genetic transcription.In certain embodiments, produce and there are the double of the sequence complementary with rb1mrna sequence Chain rna (dsrna) molecule (for example passes through pcr).In certain embodiments, produce the 20- with the sequence complementary with rb1mrna 25bp sirna molecule.In certain embodiments, 20-25bp sirna molecule the 3' end of each chain have 2-5bp cantilever and 5' phosphate terminal and 3' hydroxyl terminal.In certain embodiments, 20-25bp sirna molecule has blunt end.With regard to producing rna sequence The technology of row, referring to molecular cloning: laboratory manual (molecular cloning:a laboratory manual), second edition (mountain nurse Brooker (sambrook) et al., 1989) and molecular cloning: laboratory manual (molecular cloning:a Laboratory manual), the 3rd edition (mountain nurse Brooker (sambrook) and Russell (russel), 2001), herein Collectively referenced as " mountain nurse Brooker (sambrook) "；Current protocols (current protocols in molecular biology Molecular biology) (f.m. Ah's Sobel (f.m.ausubel) et al. compiles, and 1987, the supplementary issue including to calendar year 2001)； Current protocols (current protocols in nucleic acid chemistry) John Wiley father and son in nucleic acid chemistry Company (john wiley＆sons, inc.), New York (new york), 2000, its disclosure is hereby incorporated herein by In.

In certain embodiments, dsrna or sirna molecule is incorporated to the acceptable microsphere of control release ear or microgranule, water In gel, liposome or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, painting Agent, foams, be formed in situ spongy material, Nano capsule or nanosphere body or thermoreversible gels injection internal ear in.One In a little embodiments, the acceptable microsphere of ear or microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, The acceptable microsphere of ear, hydrogel, liposome, varnish, foams, it is formed in situ spongy material, Nano capsule or nanometer In spheroid or thermoreversible gels injection cochlea, organ of Corti, vestibular labyrinth or a combination thereof.

In some cases, after casting dsrna or sirna molecule, (such as cochlea, Ke replaces to cast the cell at position Family name's device and/or vestibular labyrinth cell) through the transition of dsrna or sirna molecule.In some cases, after transition, dsrna molecule splits Solution becomes multiple fragments of about 20-25bp, thus obtaining sirna molecule.In some cases, fragment has about at each chain 3' end The cantilever of 2bp.

In some cases, the silencing complex (risc) that sirna molecule is induced by rna be divided into two chains (guiding chain and Anti-guiding chain).In some cases, guiding chain is incorporated in the catalyst component (that is, argonaute) of risc.In some cases, Guiding chain combines complementary rb1mrna sequence.In some cases, risc cracking rb1mrna.In some cases, rb1 gene Down-regulated expression.

In certain embodiments, the sequence complementary with rb1mrna is incorporated in carrier.In certain embodiments, described sequence Between two promoteres.In certain embodiments, promoter is oriented with opposite direction.In certain embodiments, carrier with thin Born of the same parents contact.In some cases, cell carrier makes the transition.In some cases, after transition, produce the sense strand of sequence and anti- Adopted chain.In some cases, sense strand and antisense strand hybridization form dsrna molecule, and it can be cleaved into sirna molecule.Some In the case of, chain hybridization forms sirna molecule.In certain embodiments, carrier is plasmid (such as psuper；psuper.neo； psuper.neo+gfp).

In certain embodiments, carrier be incorporated to the acceptable microsphere of control release ear or microgranule, hydrogel, liposome or In thermoreversible gels.In certain embodiments, the acceptable microsphere of ear, hydrogel, liposome, varnish, foams, scene Formed in spongy material, Nano capsule or nanosphere body or thermoreversible gels injection internal ear.In certain embodiments, ear can The microsphere accepting or microgranule, hydrogel, liposome or thermoreversible gels.In certain embodiments, the acceptable microsphere of ear Body, hydrogel, liposome, varnish, foams, it is formed in situ spongy material, Nano capsule or nanosphere body or thermal reversibility In gel injection cochlea, organ of Corti, vestibular labyrinth or a combination thereof.

Thyroid Hormone Receptors are adjusted

Cover and be available for composite disclosed herein using slowing down or reverses auricularis unit and/or hair cell to degenerate and/or rush Enter auricularis unit and/or the medicament of capillary intracellular growth and treatment or improve by internal ear gross loss is bad, obstacle, malfunction, damage, crisp Medicament that is weak or losing caused hearing disability or decline.Therefore, some embodiments merge using regulation thyroxin (th) The medicament of receptor.Th receptor is nuclear hormone receptor families.This family includes but is not limited to tr α 1 and tr β.In some situations Under, tr β rejects mice and shows to the k+ electric current reduction in the reaction reduction and hair cell of auditory stimuluses.

In certain embodiments, the medicament adjusting one or more th receptors is one or more th receptors Agonist.In certain embodiments, the agonist of one or more th receptors is that (3,5,3'- tri- iodo- l- thyroid are former for t3 Propylhomoserin)；Kb-141 (the chloro- 4- of 3,5- bis- (4- hydroxyl -3- cumene epoxide) phenylacetic acid)；Gc-1 (3,5- dimethyl -4- (4'- hydroxyl -3'- isopropylbenzyl)-phenoxyacetic acid)；Gc-24 (3,5- dimethyl -4- (4'- hydroxyl -3'- benzyl) Benzyl phenoxyacetic acid)；Rope cloth tretamine (sobetirome) (qrx-431)；4-oh-pcb106(4-oh-2',3,3',4', 5'- pentachlorodiphenyl)；Mb07811 ((2r, 4s) -4- (3- chlorphenyl) -2- [(3,5- dimethyl -4- (4- hydroxyl -3- cumene Methyl) phenoxy group) methyl] -2- oxonium ion base-[1,3,2]-two phosphine oxide alkane)；Mb07344 (3,5- dimethyl -4- (4- hydroxyl - 3- isopropylbenzyl) phenoxy group) methylphosphonic acid) and a combination thereof.In some cases, kb-141, gc-1, rope cloth tretamine and Gc-24 has selectivity to tr β.

Trpv is adjusted

Cover and be available for composite disclosed herein using the medicament adjusting neuron and hair cell degeneration and treatment or improvement By internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, the hearing disability caused by fragility or loss or decline.Therefore, one A little embodiments merge using the medicament adjusting trpv receptor.Transient receptor potential channel capsaicin (transient receptor Potential channel vanilloid, trpv) receptor is calcium transparent non-selective ion channel family.Have six Individual family member: trpv1-6.In some cases, with, after kanamycin treatment, trpv1 raises.In addition, in some cases, The antagonism of trpv4 receptor makes mice be vulnerable to acoustic trauma.In addition, in some cases, capsaicin (capsaicin) a kind of, trpv1 agonist, the motion after prevention ischemia event is hyperfunction.

In certain embodiments, the medicament adjusting one or more trpv receptors is that one or more trpv are subject to The agonist of body.In certain embodiments, the agonist of one or more trpv receptors is capsaicin, superpower Capsaicin Or a combination thereof (resiniferatoxin).In certain embodiments, cast the ear sensory cell regulation group comprising trpv agonist Compound can slow down or reverses neuronal and hair cell degeneration.

Sodium channel blockers

Cover and be available for composite disclosed herein using the medicament adjusting neuron and hair cell degeneration and treatment or improvement By internal ear gross loss is bad, obstacle, malfunction, the medicament of damage, the hearing disability caused by fragility or loss or decline.In some feelings Under condition, excitatory toxicity causes na+ passage excessively to open.In some cases, this causes excessive na+ ion to enter neuron In.In some cases, flowing in excessive na+ ion causes neuron more frequently to discharge in neuron.In some cases, This electric discharge increase makes free radical and inflammatory compound accelerated accumulation.In some cases, radical damage mitochondrion, consumption The energy storage of most cell.In addition, in some cases, the enzyme of the na+ ion activation excessive levels of excessive levels, including (but Be not limited to) phospholipase, Cobra venom endonuclease and protease.In some cases, these enzyme overactivities to cytoskeleton, plasma membrane, Mitochondrion and neuron dna produce and damage.Therefore, some embodiments merge opening and reduce or inverse using antagonism na+ passage Transfer ear Hair Cell Death and/or the medicament of tragus cell injury.

In certain embodiments, na+ channel blocker is vinpocetine (vinpocetine) ((3a, 16a)-Ai Namei Rather -14- Ethyl formate ((3a, 16a)-eburnamenine-14-carboxylic acid ethyl ester))；Western handkerchief is bent Closely (sipatrigine) (2- (4- methylpiperazine-1-yl) -5- (2,3,5- trichlorophenyl)-pyrimidine -4- amine)；Amiloride (amiloride) (3,5- diaminourea-n- (aminoiminomethyl) -6- chloropyrazine carboxamide hydrochloride)；Carbamazepine (carbamazepine) (5h- dibenzo [b, f] nitrogen -5- Methanamide)；Ttx (octahydro -12- (hydroxymethyl) -2- imino group - 5,9:7,10a- dimethano -10ah- [1,3] two pungent simultaneously [6,5-d] pyrimidine -4,7,10,11,12- amylalcohol (octahydro- 12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10ah-[l,3]dioxocino[6,5-d]py rimidine-4,7,10,11,12-pentol))；Rs100642 (1- (2,6- Dimehtyl-phenoxy) -2- ethylamino propane Hydrochlorate)；Mexiletine (mexiletine) ((1- (2,6- dimethyl phenoxy) -2-aminopropane hydrochlorate))；Qx-314 (bromine Change n- (2,6- dimethylphenylamino carbamoylmethyl) triethyl ammonium)；Phenytoin (phenytoin) (5,5- diphenyl-imidazole Alkane -2,4- diketone)；Lamotrigine (lamotrigine) (6- (2,3- Dichlorobenzene base) -1,2,4- triazine -3,5- diamidogen)； 4030w92 (2,4- diaminourea -5- (2,3- Dichlorobenzene base) -6- l)；Bw1003c87 (5- (2,3,5- trichloro-benzenes Base) pyrimidine -2,4-1.1- ethane sulfonate)；Qx-222 (chlorination 2- [(2,6- 3,5-dimethylphenyl) amino]-n, n, n- trimethyl- 2- oxo second ammonium)；Ambroxol (ambroxol) (trans -4- [[(2- amino -3,5- dibromo phenyl) methyl] amino] hexamethylene alkoxide Hydrochlorate)；R56865 (n- [1- (4- (4- fluorophenoxy) butyl] -4- piperidyl-n- methyl -2- benzo-thiazole amine)；Lu pei Shandong Azoles (lubeluzole)；Ajmaline (ajmaline) ((17r, 21 α)-；Ah 's orchid -17,21- glycol ((17r, 21alpha) - ajmalan-17,21-diol))；Procainamide (procainamide) (4- amino-n- (2- diethylamino ethyl) benzene first Amide hydrochloride)；Flecainide (flecainide)；Auspicious azoles happy (riluzoleor) or a combination thereof.

Corticosteroid

Cover and be available for compositions disclosed herein and composite auricularis are first and/or capillary using slowing down, reversing or postponing Medicament that born of the same parents degenerate and treatment or improve by internal ear gross loss is bad, obstacle, malfunction, damage, fragility or the audition caused by losing The medicament lost or decline.Therefore, some embodiments merge the medicament using protection ear hair cell against ear toxin.One In a little embodiments, protection ear hair cell is steroid against the medicament of ear toxin.In certain embodiments, protection ear hair Cell is corticosteroid against the steroid of ear toxin.In certain embodiments, corticosteroid is Triamcinolone Acetonide (triamicinolone actenoide) and/or dexamethasone (dexamethasone).In some cases, Triamcinolone Acetonide Protect ear's hair cell with dexamethasone against toxin 4- hydroxyl -2 naturally occurring produced by internal ear response oxygen stress, The damage that 3- nonenyl aldehyde (hne) causes.Other corticosteroid include but is not limited to 21- prebediolone acetate (21- Acetoxypregnenolone), alclometasone (alclometasone), algestone (algestone), amcinonide (amcinonide), beclometasone, betamethasone, budesonide (budesonide), chloroprednisone (chloroprednisone), clobetasol, clobetasone (clobetasone), clocortolone (clocortolone), chlorine sprinkle Buddhist nun's alcohol (cloprednol), corticosterone (corticosterone), cortisone (cortisone), cortivazol (cortivazol), deflazacort (deflazacort), desonide (desonide), desoximetasone (desoximetasone), Dexamethasone, diflorasone (diflorasone), diflucortolone (diflucortolone), difluprednate (difluprednate), enoxolone (enoxolone), Fluazacort (fluazacort), flucloronide (flucloronide), flumetasone (flumethasone), flunisolide (flunisolide), fluocinolone acetonide (fluocinolone Acetonide), Fluocinonide (fluocinonide), fluocortin butyl (fluocortin butyl), fluocortolone (fluocortolone), fluorometholone (fluorometholone), fluperolone acetate (fluperolone acetate), acetic acid Fluprednidene (fluprednidene acetate), fluprednisolone (fluprednisolone), flurandrenolide (flurandrenolide), fluticasone propionate (fluticasone propionate), formocortal (formocortal), Halcinonide (halcinonide), clobetasol propionate (halobetasol propionate), halometasone (halometasone), halopredone acetate (halopredone acetate), hydrocortamate (hydrocortamate), hydrogen Change cortisone (hydrocortisone), loteprednol (loteprednol etabonate), mazipredone (mazipredone), medrysone (medrysone), meprednisone (meprednisone), methylprednisolone (methylprednisolone), momestasone furoate (mometasone furoate), paramethasone (paramethasone), Prednicarbate (prednicarbate), prednisolone (prednisolone), 25- diethylamino-prednisolone acetate (prednisolone25-diethylamino-acetate), Inflamase (prednisolone sodium Phosphate), prednisone (prednisone), valeric acid prednisolone (prednival), prednylidene (prednylidene), Rimexolone (rimexolone), tixocortol (tixocortol), triamcinolone, Triamcinolone Acetonide, triamcinolone benetonide (triamcinolone benetonide) or triamcinolone hexacetonide or its phosphate prodrug or ester prodrugs.

Stem cell and the ear sensory cell of differentiation

Cover and be available for composite disclosed herein using the pre-existing auricularis unit of supplement and/or replacement and/or capillary The cellular transplant of born of the same parents.In certain embodiments, medicament is stem cell.In certain embodiments, medicament is partially or completely to divide The ear sensory cell changed.In certain embodiments, the ear sensory cell of differentiation comes from non-human donor.In certain embodiments, divide The ear sensory cell changed comes from stem cell, and the differentiation of stem cell induces under the conditions of artificial (such as laboratory).

Stem cell is ability to be divided into the cell of various kinds of cell type.Myeloid-lymphoid stem cell can break up embryoblast or embryo Outer cell.Pluripotent cell can be divided into the cell with any entoderm, mesoderm or ectodermal origin.Pluripotent cell can divide It is melted into closely related cell (such as hematopoietic stem cell).Although unipotent cell can be divided into only one kind of cell, such as Equally there is the feature of self renewal with other stem cell.In certain embodiments, stem cell be all-round, pluripotency, multipotency or Single energy.In addition, stem cell can carry out mitosiss and not carry out itself differentiation (that is, self renewal).

Embryo does the stem cell that (es) cell is derived from the ectodermal histological of inner cell mass of blastaea or early stage plumule.Es is thin Born of the same parents are pluripotencies.In certain embodiments, stem cell is es cell.(also referred to as somatic cell or system genitale are thin for ripe stem cell Born of the same parents) it is from the detached cell of organism developed, wherein said cell has the feature of self renewal and is divided into various kinds of cell The ability of type.Ripe stem cell is pluripotency (stem cell finding for example in cord blood), multipotency or single energy.? In some embodiments, stem cell is ripe stem cell.

In certain embodiments, the ear sensory cell of stem cell and/or differentiation is combined with differential stimulus agent and casts.At some In embodiment, differential stimulus agent is somatomedin.In certain embodiments, somatomedin is neurotrophin, for example nerve Somatomedin (ngf), brain-derived neurotrophy sex factor (bdnf), NT-3 (nt-3), neurotrophin -4 Or new neuronal nutrient protein -1 (nnt1) (nt-4).In certain embodiments, somatomedin be fgf, egf, igf, pgf or its Combination.

In certain embodiments, the ear sensory cell of stem cell and/or differentiation casts individuality in need as control release Agent.In certain embodiments, the ear sensory cell of stem cell and/or differentiation combines throwing with control release ear sensory cell regulator Give individual conduct releasing agent (for example in cell suspending liquid) immediately in need.In certain embodiments, control release ear sensation Cell modulator is the carrier of the sirna sequence, somatomedin or a combination thereof that comprise atoh1 or brn3 gene, targeting rb1.

In certain embodiments, the ear sensory cell of stem cell and/or differentiation casts cochlea or vestibular labyrinth.Real at some Apply in example, the ear sensory cell of stem cell and/or differentiation casts via Injection in Tympanic Cavity and/or postauricular incision.In some enforcements In example, the ear sensory cell of stem cell and/or differentiation is contacted with organ of Corti, vestibulocochlear nerves and/or crista ampullariss.

Releasing agent immediately

In certain embodiments, compositionss additionally comprise auricularis unit and/or hair cell regulator as releasing agent immediately (release regulator immediately of wherein auricularis unit and/or hair cell is and Controlled release formulation identical medicament), another auricularis Unit and/or hair cell regulator, other therapeutic agent or a combination thereof.In certain embodiments, releasing agent is stem cell, differentiation immediately Ear sensory cell, immune system cell, with atoh1 gene copy carrier, with brn3 gene copy carrier, Sirna sequence, mirna sequence or a combination thereof.

Direct injection

In certain embodiments, a kind of medicament is directly injected in internal ear, including through round window membrane, and second medicament cast in Contact in middle ear, on middle ear or with round window membrane so that described second medicament is in control release formulation.In some embodiments In, the medicament directly casting is stem cell, the ear sensory cell of differentiation, immune system cell, the load with atoh1 gene copy Body, the carrier with brn3 gene copy, sirna sequence, mirna sequence or a combination thereof.

Surfactant concentration

In certain embodiments, the concentration of the active pharmaceutical ingredient of compositionss as herein described is in terms of the weight of compositionss About 0.01% to about 90%, about 0.01% to about 50%, about 0.1% to about 70%, about 0.1% to about 50%, about 0.1% to about 40%th, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10% or about 0.1% to about 5% activity one-tenth Divide or its pharmaceutically acceptable prodrug or salt.In certain embodiments, the active medicaments agent of compositionss as herein described Concentration is in terms of the weight of compositionss about 1% to about 50%, about 5% to about 50%, about 10% to about 40% or about 10% to about 30% active component or its pharmaceutically acceptable prodrug or salt.In certain embodiments, composite bag as herein described Ear sensory cell regulator containing in terms of the weight of composite about 70 weight %.In certain embodiments, allotment as herein described Thing comprises the ear sensory cell regulator of in terms of the weight of composite about 60 weight %.In certain embodiments, as herein described Composite comprises the ear sensory cell regulator of in terms of the weight of composite about 50 weight %.In certain embodiments, this paper institute The composite stated comprises the ear sensory cell regulator of in terms of the weight of composite about 40 weight %.In certain embodiments, originally Composite described in literary composition comprises the ear sensory cell regulator of in terms of the weight of composite about 30 weight %.In some embodiments In, composite as herein described comprises the ear sensory cell regulator of in terms of the weight of composite about 20 weight %.Real at some Apply in example, composite as herein described comprises ear sensory cell regulator or its doctor of in terms of the weight of composite about 15 weight % Pharmaceutically acceptable prodrug or salt.In certain embodiments, composite as herein described comprises in terms of the weight of composite about The ear sensory cell regulator of 10 weight %.In certain embodiments, composite as herein described comprises the weight with composite The ear sensory cell regulator of meter about 5 weight % or its pharmaceutically acceptable prodrug or salt.In certain embodiments, herein Ear sensory cell regulator that described composite comprises in terms of the weight of composite about 2.5 weight % or its pharmaceutically can connect The prodrug being subject to or salt.In certain embodiments, composite as herein described comprises the ear of in terms of the weight of composite about 1 weight % Sensory cell regulator or its pharmaceutically acceptable prodrug or salt.In certain embodiments, composite bag as herein described Ear sensory cell regulator containing in terms of the weight of composite about 0.5 weight % or its pharmaceutically acceptable prodrug or salt. In certain embodiments, the ear sensory cell that composite as herein described comprises in terms of the weight of composite about 0.1 weight % is adjusted Section agent or its pharmaceutically acceptable prodrug or salt.In certain embodiments, composite as herein described comprises with composite The ear sensory cell regulator of weight meter about 0.01 weight % or its pharmaceutically acceptable prodrug or salt.In some enforcements In example, the concentration of the active pharmaceutical ingredient of composite as herein described or its pharmaceutically acceptable prodrug or salt is to allocate The stereometer of thing about 0.1 is to about 70mg/ml, about 0.5mg/ml to about 70mg/ml, about 0.5mg/ml to about 50mg/ml, about 0.5mg/ml to about 20mg/ml, about 1mg are to about 70mg/ml, about 1mg to about 50mg/ml, about 1mg/ml to about 20mg/ml, about The activating agent of 1mg/ml to about 10mg/ml or about 1mg/ml to about 5mg/ml or its pharmaceutically acceptable prodrug or salt.

Combination treatment

In certain embodiments, any combinations thing as herein described or device comprise one or more activating agents and/ Or second therapeutic agent, described second therapeutic agent including but not limited to Bendectin, antimicrobial, antioxidant, preservative etc..

Antiemetic

Antiemetic is optionally applied in combination with composite disclosed herein.Antiemetic includes promethazine (promethazine), prochlorperazine, trimethobenzamide (trimethobenzamide) and thiethylperazine (triethylperazine).Other antiemetic include 5ht3 antagonist, such as dolasetron (dolasetron), granisetron (granisetron), ondansetron (ondansetron), tropisetron (tropisetron) and palonosetron (palonosetron)；And psychosis, such as droperidol (droperidol).Other antiemetic include hydryllin, Such as Mycospor profit piperazine (meclizine)；Azophenlyene class, such as perphenazine (perphenazine) and thiethylperazine (thiethyl perazine)；Dopamine antagonist (dopamine antagonist), including Domperidone (domperidone), fluorine piperazine profit Many (properidol), haloperidol (haloperidol), chlorpromazine, promethazine, prochlorperazine, metoclopramide And a combination thereof (metoclopramide)；Cannabine, including dronabinol (dronabinol), nabilone (nabilone), plug For Vicks VapoRub (sativex) and a combination thereof；Anticholinergic, including scopolamine (scopolamine)；And steroid, including Dexamethasone (dexamethasone)；Trimethobenzamide, more tell peaceful (emetrol), propofol (propofol), 5-aminomethyl-3-hydroxyisoxazole And a combination thereof (muscimol).

Antimicrobial

It is also contemplated by antimicrobial to be used together with composite disclosed herein.Antimicrobial include acting on suppression or The medicament of microbiological eradication (including antibacterial, funguses or parasite).Specific antimicrobial can be used for resisting specified microorganisms. Therefore, experienced practitioner will be appreciated by, and antimicrobial is related or suitable by the symptom of the microorganism depending on identifying or display With.Antimicrobial includes antibiotic, antiviral agent, antifungal and antiparasitic.

Antibiotic may include amikacin, gentamycin, kanamycin, neomycin, netilmicin, streptomycin, appropriate Bradley Mycin, paromomycin (paromomycin), geldanamycin (geldanmycin), herbimycin (herbimycin), chlorine carbon Cephalo (loracarbef), ertapenem (ertapenem), donipenem (doripenem), imipenum (imipenem), Cilastatin (cilastatin), meropenem (meropenem), cephalo azanol benzyl (cefadroxil), cefazolin (cefazolin), cefalotin (cefalotin), cephalo amine benzyl (cefalexin), cefaclor (cefaclor), cephalo Meng Many (cefamandole), cefalotin (cefoxitin), cefprozil (defprozil), cefuroxime (cefuroxime), Cefixime (cefixime), Cefdinir (cefdinir), cefditoren (cefditoren), cefoperazone (cefoperazone), cefotaxime (cefotaxime), cefpodoxime (cefpodoxime), ceftazidime (ceftazidime), ceftibuten (ceftibuten), ceftizoxime (ceftizoxime), ceftriaxone (ceftriaxone), cefepime (cefepime), cephalo are than general (ceftobiprole), teicoplanin (teicoplanin), vancomycin, Azithromycin (azithromycin), clarithromycin (clarithromycin), red mould Plain (dirithromycin), erythromycin, Roxithromycin (roxithromycin), triacetyloleandomycin (troleandomycin), Ketek (telithromycin), spectinomycin (spectinomycin), azteronam (aztreonam), amoxicillin (amoxicillin), Ampicillin (ampicillin), azlocillin (azlocillin), block this XiLin (carbenicillin), cloxacillin (cloxacillin), dicloxacillin (dicloxacillin), flucloxacillin (flucloxacillin), mezlocillin (mezlocillin), methicillin (meticillin), nafthicillin (nafcillin), oxazacillin (oxacillin), penicillin (penicillin), piperacillin (piperacillin), replace Cassie orchid (ticarcillan), bacitracin (bacitracin), colistin (colistin), polymyxin b (polymyxin B), Ciprofloxacin (ciprofloxacin), enoxacin (enoxacin), Gatifloxacin (gatifloxacin), levofloxacin Star (levofloxacin), lomefloxacin (lomefloxacin), Moxifloxacin (moxifloxacin), norfloxacin (norfloxacin), Ofloxacin (ofloxacin), trovafloxacin (trovfloxacin), mafenide (mafenide), Prontosil (prontosil), sulfacetamide (sulfacetamide), sulfamethizole (sulfamethizole), sulfanilamide (sulfanimilimde), sulfasalazine (sulfsalazine), ganda (sulfsioxazole), trimethoprim (trimethoprim), demeclocycline (demeclocycline), doxycycline (doxycycline), minocycline, oxytetracycline (oxtetracycline), tetracycline (tetracycline), arsphenamine (arsphenamine), chloromycetin (chloramphenicol), clindamycin (clindamycin), lincomycin (lincomycin), ethambutol (ethambutol), fosfomycin (fosfomycin), fusidinic acid (fusidic acid), furazolidone (furazolidone), isoniazid (isoniazid), Linezolid (linezolid), metronidazole (metronidazole), not Luo Xing (mupirocin), nitrification nitrofurantoin (nitrofurantoin), flat board mycin (platensimycin), pyrazine acyl Amine (pyrazinamide), Quinupristin (quinuspristin)/dalfopristin (dalfopristin), rifampicin (rifampin), tinidazole (tinidazole) and a combination thereof.

Antiviral agent may include acyclovir (acyclovir), famciclovir (famciclovir) and general La Xiluowei (valacyclovir).Other antiviral agent include Abacavir (abacavir), acyclovir (aciclovir), A Defu Wei (adfovir), amantadine (amantadine), amprenavir (amprenavir), Abiduoer (arbidol), A Zhana Wei (atazanavir), Ah Ti pula (artipla), brivudine (brivudine), cidofovir (cidofovir), Ka Beiwei (combivir), edoxudine (edoxudine), efavirenz (efavirenz), emtricitabine (emtricitabine), grace Good fortune Wei ground (enfuvirtide), Yin Tifu (entecavir), Fu Weisen (fomvirsen), Fosamprenavir (fosamprenavir), good fortune card Nat (foscarnet), good fortune not Nat (fosfonet), ganciclovir (ganciclovir), Jia Dexi (gardasil), ibacitabine (ibacitabine), Yi Nuowei (imunovir), idoxuridine (idoxuridine), miaow Quinoline is not special (imiquimod), indinavir (indinavir), inosine (inosine), integrase inhibitor, interferon (include Iii type interferon, ii type interferon, i type interferon), Lamivudine (lamivudine), Lopinavir (lopinavir), Lip river Wei amine (loviride), mk-0518, La Weinuo (maraviroc), Moroxydine (moroxydine), viracept see nelfinaivr (nelfinavir), Nevirapine (nevirapine), Neck sand Wei (nexavir), nucleoside analog, Ao Sita are big (oseltamivir), penciclovir (penciclovir), Peramivir (peramivir), Pulekang Buddhist nun (pleconaril), Podophyllotoxin (podophyllotoxin), protease inhibitor, reverse transcriptase inhibitors, virazole (ribavirin), Buddha's warrior attendant Ethamine (rimantadine), ritonavir (ritonavir), Saquinavir (saquinavir), videx (stavudine), paracetamol Wei (tenofovir), paracetamol Wei (tenofovir disoproxil), tipranavir (tipranavir), trifluridine (trifluridine), three association Wei (trizivir), tromantadine (tromantadine), Troyes reaches (truvada), valganciclovir (valganciclovir), Wei Kelinuo (vicriviroc), vidarabine (vidarabine), big draw miaow fixed (viramidine), zalcitabine (zalcitabine), zanamivir (zanamivir), Zidovudine (zidovudine) and a combination thereof.

Antifungal may include amorolfine (amrolfine), butenafine (utenafine), naftifine (naftifine), terbinafine (terbinafine), flucytosine (flucytosine), fluconazol (fluconazole), Itraconazole (itraconazole), Ketoconazole (ketoconazole), posaconazole (posaconazole), ravuconazole (ravuconazole), voriconazole (voriconazole), clotrimazole (clotrimazole), econazole (econazole), Miconazole (miconazole), oxiconazole (oxiconazole), sulconazole (sulconazole), terconazole (triaconazole) (terconazole), tioconazole (tioconazole), nikkomycin z (nikkomycin z), Caspofungin (caspofungin), MFG (micafungin), anidulafungin (anidulafungin), amphotericin b (amphotericin b), liposome Ni Siting (liposomal nystastin), pimaricin (pimaricin), sallow are mould Plain (griseofulvin), ciclopirox olamine (ciclopirox olamine), haloprogin (haloprogin), tolnaftate (tolnaftate), undecylenate (undecylenate) and a combination thereof.Antiparasitic may include Amitraz (amitraz), amoscanate (amoscanate), avilamycin (avermectin), carbadox (carbadox), diethylcarbamazine (diethylcarbamizine), dimetridazole (dimetridazole), diminazene (diminazene), double hydrogen remove entomogenous fungi Plain (ivermectin), filaricide (macrofilaricide), Malathion (malathion), meter Ta Ban (mitaban), Oxamniquine (oxamniquine), Permethrin (permethrin), praziquantel (praziquantel), Pyrantel Pamoate (prantel pamoate), plug draw rhzomorph (selamectin), sodium stibogluconate (sodium stibogluconate), corruption (thiabendazole) and a combination thereof absolutely.

Antioxidant

Antioxidant is optionally used with combination of compositions as herein described.It is also contemplated by antioxidant and tune disclosed herein Join thing to be used together as the medicament adjusting auricularis unit and/or hair cell degeneration.Therefore, some embodiments merging uses antioxygen Agent.In certain embodiments, antioxidant is vitamin c, n- acetylcysteine, vitamin e, ebselen (ebselen) (2- phenyl -1,2- benzisoxa selenazoles -3 (2h) -one) (being also called pz 51 or dr3305), l- methionine, Chinese mugwort Ground benzoquinone (idebenone) (2- (10- hydroxydecyl) -5,6- dimethoxy -3- methyl-cyclohexyl -2,5- diene -1,4- two Ketone).In certain embodiments, antioxidant is nutrient and promotes healthy cells.

Preservative

Preservative is optionally used with combination of compositions as herein described.It is also contemplated by preservative and composite disclosed herein It is used together.Preservative includes but is not limited to acetic acid, boric acid, Gentian Violet, hydrogen peroxide, urea peroxide, chlorhexidine (chlorhexidine), saline, merbromin (mercurochrome), povidone iodine (povidone iodine), poly- hydroxyl iodine (polyhyroxine iodine), cresylate and aluminum acetate and its mixture.

Other medicaments are optionally in any combinations thing as herein described or device.In certain embodiments, monoamine oxygen Change enzyme inhibitor (such as Lei Sha Jilin (rasagiline), r (+)-n- propargyl -1- aminoidan) it is used for as herein described In what compositions or device.In certain embodiments, adenosine antagonist (such as r-n6- propyloxy phenyl base adenosine, 1-2- oxo thiophene Oxazolidine -4- formic acid (Procysteine (procysteine)) is used in any combinations thing as herein described or device.Activating agent And/or any combinations of second therapeutic agent are all compatible with compositionss as herein described.

Otologic Surgical Proce- dures and implant

In certain embodiments, pharmaceutical formulation as herein described, compositionss or device with (for example implantation, short-period used, Life-time service or removal) implant (such as cochlear implant) is applied in combination.As used herein, implant include internal ear or in Ear medical apparatus, the example includes cochlear implant, hearing protection devices, hearing improved device, noncontinuous electrode, micro- prosthese or piston Sample prosthese；Pin；Stem cell graft；Drug delivery device；Any therapeutic agent based on cell；Deng.In some cases, implant Thing combines and occurs the patient of hearing disability to use.In some cases, there is hearing disability during birth.In some cases, Hearing disability is with the condition of illness causing osteanagenesis and/or nerve injury and cochlear structures quick disappearance and profound hearing loss (such as Aied, bacterial meningitises etc.) related.

In some cases, implant is the immunocyte in ear or stem cell graft.In some cases, implant It is little electronic installation, it is had and is placed on ear exterior section below and is placed in skin by operation and helps offer To depth is deaf or Part II of seriously hard of hearing person's sound perception.For example, described cochlea medical apparatus implant bypasses Ear undamaged portion and directly stimulation auditory nerve.In some cases, cochlear implant is used in unilateral deafness.In some feelings Under condition, cochlear implant is used in bilateral ear deafness.

In certain embodiments, cast ear sensory cell regulating composition as herein described or device to intervene with ear (such as Injection in Tympanic Cavity, stapedectomy, medical apparatus implant or the graft based on cell) combination can postpone or prevent The collateral damage to ear structure that (installing external device (ED) and/or cell for example in ear) causes, example are intervened by outside ear As stimulation, cell injury, cell death, osteanagenesis and/or neuron are degenerated further.In certain embodiments, cast herein Described ear sensory cell regulating composition or device make hearing disability more with implant combination compared with being separately implantable thing Effectively recover.

In certain embodiments, cast ear sensory cell regulating composition as herein described or device can reduce by allowing Be successfully implanted into that the potential condition of illness (such as bacterial meningitises, autoimmune ear disease (aied)) of cochlea device causes to cochlea The infringement of structure.In certain embodiments, cast compositionss as herein described or device combines ear's surgical operation, medical apparatus Implantation and/or cell transplantation can reduce or prevent and ear surgical operation, medical apparatus implantation and/or related thin of cell transplantation Cellular damage and/or death (such as ear Sensory hair cell is dead and/or damages).

In certain embodiments, cast ear sensory cell regulating composition as herein described or device (for example comprises to give birth to The compositionss of the long factor or device) (such as promotion cell is good for have Nutrition with reference to cochlear implant or stem cell graft Kang Shengchang and/or make implant or transplanting object area in organization healing).In certain embodiments, Nutrition is outside ear Wanted during section's intra-operative or Injection in Tympanic Cavity program.In certain embodiments, Nutrition be install medical apparatus it Wanted afterwards or after cell transplantation.In some described embodiments, ear sensory cell regulating composition as herein described or Device is injected via direct cochlea, to be cast on oeil de boeuf via cochlea otomy or via being deposited on.

In certain embodiments, cast antiinflammatory as herein described or immunosuppressant composite (for example comprises such as cortex class The compositionss of the immunosuppressant such as sterin) can reduce to ear's surgical operation or implantation medical apparatus or cellular transplant related Inflammation and/or infection.In some cases, irrigate ear sensory cell regulator composite as herein described to confined surgical areas Surgical site infections and/or implantation infectious-related complication (such as inflammation, damage of hair cell, deterioration of neurons, osteanagenesis can be reduced or eliminated Deng).In some cases, extensive after surgical site infections being shortened or implant to confined surgical areas perfusion composite as herein described The multiple time.In certain embodiments, with compositionss as herein described coating before medical apparatus are in implantation ear.

On the one hand, composite as herein described and its dispensing pattern are applied to the direct method irrigating internal ear compartment.Therefore, Composite as herein described be applied to ear intervention combine.In certain embodiments, ear's intervention is that implant procedure (for example exists Implantable hearing device in cochlea).In certain embodiments, ear's intervention is surgical operation, and including but not limited to cochlea cuts Art, labyrinthotomy, mastoidectomy, stapedectomy, Stapedotomy, endolymph sacculotomy, myringotomy etc.. In certain embodiments, ear intervention before, ear intervention during or ear intervention after or a combination thereof, to internal ear compartment fill Note composite as herein described.

In certain embodiments, when perfusion with ear intervene combine carry out when, ear sensory cell compositionss are to discharge immediately Compositionss.In some described embodiments, the composite of release immediately as herein described is the compositionss and substantially not of non-thickening Containing prolongation release component (such as bonding component, such as Pluronic F68).In some described embodiments, Compositionss contain (the such as bonding component, such as polyoxyethylene-polyoxy of the prolongation release component less than 5% in terms of composite weight Propylene triblock copolymer).In some described embodiments, compositionss contain the prolongation less than 2% in terms of composite weight to be released Put component (such as bonding component, such as PULLRONIC F68 triblock copolymer).In some described embodiments, group Compound contains (the such as bonding component, such as polyoxyethylene-polyoxy third of the prolongation release component less than 1% in terms of composite weight Alkene triblock copolymer).In some described embodiments, for irrigating the compositionss essence as herein described of confined surgical areas Upper do not contain bonding component, and be release composition immediately.

In other embodiments, compositionss as herein described (are for example implanted medical apparatus or are based on after ear's intervention After the therapeutic agent of cell) cast.In some described embodiments, the compositionss as herein described that cast after ear's intervention It is to discharge immediately or extended-release composition, and contain bonding component as herein described.

(table 1) presented below covers the example of the activating agent using for composite disclosed herein and device.One kind or one Plant above activating agent to be used in any composite as herein described or device.

The activating agent (including the pharmaceutically acceptable salt of these activating agents) using for composite disclosed herein

(table 1)

General sterilizing methods

Provided herein is improving or mitigate the ear compositionss of otic conditions as herein described.In addition provide herein and comprise to cast The method of described ear compositionss.In certain embodiments, compositionss or device are sterilized.Embodiment disclosed herein includes The method that medical composition disclosed herein or device for the mankind is sterilized and technique.Aim at offer relatively not Containing the safe medical product leading to the microorganism infected.FDA (u.s.food and drug Administration) in publication " industrial directory: using Bactericidal medicine product (guidance produced by aseptic process For industry:sterile drug products produced by aseptic processing) " middle offer management Guide, can be fromhttp://www.fda.gov/cder/guidance/5882fnl.htmObtain, it is in entirety by reference It is incorporated herein.

As used herein, the sterilizing meaning is the work for the microorganism in the presence of destroying or remove product or packing Skill.Using any suitable method that can be used for object and compositionss sterilizing.Can be used for making microorganism deactivated method include (but It is not limited to) apply very hot, lethal chemical product or gamma-radiation.In certain embodiments, it is a kind of to prepare ear treatments composite Technique, it comprises the sterilizing methods making composite stand selected from heat sterilization, chemosterilization, radiation sterilization or filtration sterilization.Made Method is substantially dependent on the property of device subject to sterilization or compositionss.The detailed description of many sterilizing methods is provided in profit Lei Mingdun: the pharmaceutical science that Ping Kete (lippincott), WILLIAMS-DARLING Ton (williams) and Louis Wilkins (wilkins) are published With put into practice in (remington:the science and practice of pharmacy) the 40th chapter, and with regard to this master Topic, is incorporated herein by reference.

Heat sterilization

Many methods can be used for by apply very hot sterilizing.A kind of method is by using saturated vapor autoclaving Device.In this process, the saturated vapor that temperature is at least 121 DEG C is made to contact object subject to sterilization.In object feelings subject to sterilization Under condition, heat is transferred directly to microorganism, or by heating aqueous solution entirety indirect transfer subject to sterilization to microorganism.This method It is widely implemented, because it has motility, safety and economy in sterilization process.

Dry heat sterilization is a kind of method for killing microorganism and carry out pyrogen removal at high temperature.This technique is being suitable to The no microbial air filtering through hepa is heated to at least 130-180 DEG C of the temperature of sterilization process and is used for pyrogen removal Carry out at least device of 230-250 DEG C of temperature of technique.Restore concentration or the water of powder composite also uses autoclave Sterilizing.In certain embodiments, composite as herein described comprises to heat (for example in 130-140 DEG C of inside powder by dry type Heat about 7-11 hour at last temperature, or heat 1-2 hour under 150-180 DEG C of internal temperature) the micronization ear sense that sterilizes Feel cell modulator (such as chloramines micropowder).

Chemosterilization

Chemosterilization method is the alternative method for being unable to undergo extremely heat-killed product.In this process, using many Plant the gas with bactericidal property and steam (such as oxirane, chlorine dioxide, formaldehyde or ozone) as anti-apoptotic agent.Epoxy The bactericidal activity of ethane is generated from for example because it can act as reactive alkylating agent.Therefore, sterilization process needs oxirane Steam and product directly contact subject to sterilization.

Radiation sterilization

One advantage of radiation sterilization is can be to perhaps eurypalynous product in the case of no thermal degradation or other infringement Product are sterilized.Frequently with radiation be β radiation or be derived from⁶⁰The gamma-radiation in co source.Gamma-emitting penetrating power allows it to be used for The sterilizing of many product types, including solution, compositionss and heterogeneous mixture.The bactericidal action irradiated is generated from gamma-radiation Interaction with biomacromolecule.This interaction produces charged material and free radical.Such as reset and crosslinked mistake The subsequent chemical reaction such as journey lead to these biomacromolecules to lose normal function.Composite as herein described also optionally employs β and shines Penetrate sterilizing.

Filter

Filtration sterilization is a kind of for removing but the method for not destroying microorganism from solution.It is right that film filter is used for filtering Heat sensitive solution.Described filter is mixed cellulose ester (mce), Kynoar (pvf；Also referred to as pvdf) or polytetrafluoro The thin and firm uniform polymeric of ethylene (ptfe), and aperture is in the range of 0.1 to 0.22 micron.There are various features Solution is optionally using different filtration membrane filtrations.For example, pvf and ptfe film is very suitable for filtering organic solvent, and water Solution is via pvf or mce membrane filtration.Filter for installation can use under many scales, uses from the single-point being connected to syringe Disposable filter is to the commercial size filter for maker.Film filter is gone out using autoclave or chemosterilization Bacterium.The checking of membrane filtration system is according to the standard scheme (microbial assessment of the filter for being sterilized to liquid (microbiological evaluation of filters for sterilizing liquids), the 3rd phase of volume 4, China Contain a special zone (washington, d.c): health industries AEM (health industry manufacturers ), association 1981) carry out and be related to known quantity (about 10⁷Individual/cm²) such as defect shortwave Zymomonas mobiliss (brevundimonas diminuta) (atcc 19146) abnormal little microorganism excites film filter.

Medical composition to sterilize optionally by through film filter.Comprise nanoparticle (U.S. Patent No. 6,139, No. 870) or multilamellar liposome (Richard (richard) et al., Inpharm magazine (international journal of Pharmaceutics) (2006), 312 (1-2): 144-50) composite can be gone out by filtering via 0.22 micron filter Bacterium and do not destroy its organizational structure.

In certain embodiments, method disclosed herein comprises by means of filtration sterilization, composite (or its component) to be entered Row sterilizing.In another embodiment, ear acceptable ear treatments agent composite comprises particle, and wherein said particle composite is fitted In filtration sterilization.In another embodiment, described particle composite comprises to be smaller in size than 300nm, is smaller in size than 200nm, size Particle less than 100nm.In another embodiment, the acceptable composite of ear comprises particle composite, and wherein particle is aseptic Property can be guaranteed by aseptic filtration forerunner's component solution.In another embodiment, the acceptable composite of ear comprises particle tune Join thing, the aseptic of wherein particle composite filters to guarantee by cryogenic sterile.In another embodiment, cryogenic sterile filters Between 0 DEG C and 30 DEG C, between 0 DEG C and 20 DEG C, between 0 DEG C and 10 DEG C, between 10 DEG C and 20 DEG C or between 20 DEG C and 30 DEG C At a temperature of carry out.

In another embodiment, it is a kind of technique preparing ear acceptable particle composite, it comprises: warp at low temperature Aqueous solution containing particle composite is filtered by sterilising filter；Lyophilizing sterile solution；Restored with sterilized water with before casting Particle composite.In certain embodiments, composite as herein described is manufactured into and cures containing micronised active in form of suspension The single bottle composite of medicine composition.Single bottle composite pass through aseptic mixing aseptic Poloxamer solution with sterile micronised Active component (such as ketamine) and transfer to prepare in aseptic medicinal container by composite.In certain embodiments, dividing Before joining and/or casting, by the single bottle settling flux containing the composite as herein described in form of suspension.

In a particular embodiment, filter and/or to-fill procedure is in the gelation temperature (t less than composite as herein described_Gelling) At about 5 DEG C and it is less than under theoretical value 100cp in viscosity and carries out, to allow to filter using peristaltic pump within the reasonable time.

In another embodiment, ear acceptable ear treatments agent composite comprises nanoparticle composite, wherein said Nanoparticle composite is suitable to filtration sterilization.In another embodiment, described nanoparticle composite comprises to be smaller in size than 300nm, it is smaller in size than 200nm or the nanoparticle being smaller in size than 100nm.In another embodiment, the acceptable composite of ear Comprise microsphere composite, the wherein aseptic of microsphere is guaranteed by aseptic filtration forerunner's organic solution and aqueous solution.? In another embodiment, the acceptable composite of ear comprises thermoreversible gels composite, and the wherein aseptic of gel composite is led to Cross low temperature aseptic filtration to guarantee.In another embodiment, cryogenic sterile filter between 0 DEG C and 30 DEG C or 0 DEG C with 20 DEG C it Between or 0 DEG C and 10 DEG C between or 10 DEG C and 20 DEG C between or 20 DEG C with 30 DEG C at a temperature of between carry out.In another embodiment In, it is a kind of technique preparing ear acceptable thermoreversible gels composite, it comprises: at low temperature via sterilising filter Filter the aqueous solution containing thermoreversible gels component；Lyophilizing sterile solution；Restore thermal reversion with before casting with sterilized water Property gel composite.

In certain embodiments, active component is dissolved in suitable mediator (such as buffer) and separately sterilizes (example As by heat treatment, filtration, gamma-radiation).In some cases, active component separately sterilizes in the dry state.In some feelings Under condition, active component is sterilized with suspension or colloidal suspensions form.(for example filtered using the method being suitable in a further step And/or irradiate the excipient mixture of cooling) to remaining excipient (fluid gel group in the presence of such as ear composite Point) sterilized；Then by aseptic for two kinds of solution of separate sterilizing mixing to provide final ear composite.In certain situation Under, finally aseptic be blended in will cast composite as herein described before carry out.

In some cases, (such as heat treatment (for example in autoclave), γ shine the sterilizing methods being usually used Penetrate, filter) lead to the polymers compositionss (such as thermosetting, gelling or Mucoadhesive polymers component) in composite and/or work Property agent is irreversibly degraded.In some cases, if composite is included in the thixotropic polymer can be gelled in filter process, that Can not possibly ear is sterilized with composite by membrane filtration (such as 0.2 micron membranes).

Therefore, provided herein is the sterilizing methods of ear composite, it prevents polymers compositionss (such as thermosetting and/or glue Solidifying and/or Mucoadhesive polymers component) and/or activating agent degrade in sterilization process.In certain embodiments, by using The specific ph value scope of the buffer composition and gellant special ratios in composite come to reduce or elimination activity agent (for example this Literary composition described in any ear treatments agent) degraded.In certain embodiments, suitable gellant and/or thermosetting polymer are selected Allow by filtration, composite as herein described to be sterilized.In certain embodiments, using suitable thermosetting polymer With the permission of combining of the specific ph value scope of composite, high temperature is carried out to described composite with suitable copolymer (such as gellant) Sterilizing and therapeutic agent or polymeric excipient are not substantially degraded.The advantage of sterilization provided herein is, some In the case of, process via autoclaving and composite carried out with final sterilization and activating agent and/or excipient and/or polymers compositionss No any loss during sterilization steps, and composite becomes to be substantially free of microorganism and/or pyrogen.

Microorganism

Provided herein is improving or mitigate the acceptable compositionss of ear or the device of otic conditions as herein described.Herein in addition The method comprising to cast described ear compositionss is provided.In certain embodiments, compositionss or device are substantially free of microorganism. Acceptable biological load or sterility are the applied codes treating upper acceptable compositionss based on definition, including (but not It is limited to) American Pharmacopeia (united states pharmacopeia)<1111>chapter and subsequent content.For example, it is subjected to Aseptic (such as biological load) degree include about 10 colony-forming units (cfu) of every gram of composite, every gram of composite is about 50cfu, every gram of composite about 100cfu, every gram of composite about 500cfu or every gram of composite about 1000cfu.In some embodiments In, the acceptable biological load level of composite or aseptic include less than 10cfu/ml, less than 50cfu/ml, be less than 500cfu/ml or be less than 1000cfu/ml microorganism agent.In addition, acceptable biological load level or aseptic include exclusion and refer to Fixed harmful microorganism agent.For example it is intended that harmful microorganism agent include but is not limited to escherichia coli (escherichia coli/e.coli), Salmonella (salmonella sp.), bacillus pyocyaneus (pseudomonas ) and/or other specified microorganisms agent aeruginosa/p.aeruginosa.

The aseptic of ear acceptable ear treatments agent composite is according to American Pharmacopeia<61>,<62>and<71>Zhang Youwu Bacterium property ensures program validation.The key components of the control of aseptic guaranteed quality, quality guarantee and proof procedure are aseptics The method of test.Only for example, carry out aseptic test using two methods.First is direct inoculation, wherein will be to be tested The sample of compositionss be added in growth medium and cultivate the time up to 21 days.The turbidity instruction of growth medium is dirty Dye.The shortcoming of this method includes the sampling small scale of integral material, and this can reduce sensitivity, and based on range estimation detection microorganism Growth.A kind of alternative method is the test of membrane filtration aseptic.In this approach, the product making certain volume passes through little membrane filtration Paper.Then, filter paper is put in the medium to promote growth of microorganism.The advantage of this method is that sensitivity is higher, because Whole product is sampled.Optionally employing can be from the aseptic test of Mi Libo (millipore) steritest buied on the market System to be measured by the test of membrane filtration aseptic.For the filtration test of emulsifiable paste or ointment, using No. tlhvsl210 Steritest filtration system.For the filtration test of emulsion or viscous product, using tlarem210 or No. tdarem210 Steritest filtration system.For the filtration test of pre-filled syringe, filter system using tthasy210 steritest System.For the filtration test of the material being distributed into aerosol or foams, using tthva210 steritest filtration system. For the filtration test of the soluble powder in ampoule or bottle, using tthada210 or tthadv210 steritest Filtration system.

The test of escherichia coli and Salmonella includes the lactose broth using cultivation 24-72 hour at 30-35 DEG C, 18-24 hour is cultivated in MacConkey (macconkey) and/or emb agar, and/or using Rappaport (rappaport) culture Base.The test of detection bacillus pyocyaneus is included using nac agar.In addition American Pharmacopeia<62>chapter is enumerated and is harmful to micro- life for specifying The test program of thing.

In certain embodiments, any control release composite as herein described all has less than about in every gram of composite 60 colony-forming units (cfu), less than about 50 colony-forming units, less than about 40 colony-forming units or less than about The microorganism agent of 30 colony-forming units.In certain embodiments, ear as herein described with composite formulated with interior pouring Bar and/or perilymph are isotonic.

Endotoxin

Provided herein is improving or mitigate the ear compositionss of otic conditions as herein described.In addition provide herein and comprise to cast The method of described ear compositionss.In certain embodiments, compositionss or device are substantially free of endotoxin.Sterilization process another On the one hand be kill microorganism (hereinafter referred to as "Product") when remove by-product.Pyrogen removal technique removes depyrogenation from sample. Pyrogen is endotoxin or the extracellular toxin of induction immunoreation.An endotoxic example is can in gram-negative bacterial cell wall Lipopolysaccharide (lps) molecule seen.When autoclaving processes or kills antibacterial with sterilizing programs such as ethylene oxide treatment, The induction of lps residue inspires scorching immunoreation, such as septic shock.Because endotoxic molecular dimension can be widely varied, institute Represented with " endotoxin unit " (eu) with endotoxic presence.1eu is equivalent to 100 pik escherichia coli lps.The mankind can be to as little as Every kg body weight 5eu produces reaction.Biological load (such as microbial limit) and/or aseptic (such as level of endotoxin) are with institute In genus field, any unit of accreditation represents.In certain embodiments, with generally acceptable endotoxin content (such as per kilogram Whose body weight 5eu) compare, ear compositionss as herein described contain relatively low endotoxin content (for example per kilogram whose body weight < 4eu).In certain embodiments, ear acceptable ear treatments agent composite has per kilogram whose body weight and is less than about 5eu.? In other embodiments, ear acceptable ear treatments agent composite has per kilogram whose body weight and is less than about 4eu.Implement other In example, ear acceptable ear treatments agent composite has per kilogram whose body weight and is less than about 3eu.In other embodiments, ear Acceptable ear treatments agent composite has per kilogram whose body weight and is less than about 2eu.

In certain embodiments, ear acceptable ear treatments agent composite or device have every kilogram of composite and are less than about 5eu.In other embodiments, ear acceptable ear treatments agent composite has every kilogram of composite and is less than about 4eu.In other In embodiment, ear acceptable ear treatments agent composite has every kilogram of composite and is less than about 3eu.In certain embodiments, Ear acceptable ear treatments agent composite has every kilogram of product and is less than about 5eu.In other embodiments, the acceptable ear of ear Portion's therapeutic agent composite has every kilogram of product and is less than about 1eu.In other embodiments, ear acceptable ear treatments agent allotment Thing has every kilogram of product and is less than about 0.2eu.In certain embodiments, ear acceptable ear treatments agent composite has every gram Unit or product are less than about 5eu.In other embodiments, ear acceptable ear treatments agent composite has every gram of unit or product Product are less than about 4eu.In other embodiments, ear acceptable ear treatments agent composite has every gram of unit or product is less than about 3eu.In certain embodiments, ear acceptable ear treatments agent composite has every milligram of unit or product is less than about 5eu.? In other embodiments, ear acceptable ear treatments agent composite has every milligram of unit or product is less than about 4eu.Other real Apply in example, ear acceptable ear treatments agent composite has every milligram of unit or product is less than about 3eu.In some embodiments In, ear as herein described is with containing about 1 to about 5eu in every milliliter of composite of composite.In certain embodiments, as herein described Ear, with containing about 2 to about 5eu in every milliliter of composite of composite, contains about 3 to about 5eu in every milliliter of composite, or every milliliter About 4 to about 5eu are contained in composite.

In certain embodiments, compared with generally acceptable endotoxin content (such as every milliliter composite 0.5eu), this Ear compositionss described in literary composition or device contain relatively low endotoxin content (such as every milliliter composite < 0.5eu).In some enforcements In example, ear acceptable ear treatments agent composite or device have every milliliter of composite and are less than about 0.5eu.In other embodiments In, ear acceptable ear treatments agent composite has every milliliter of composite and is less than about 0.4eu.In other embodiments, ear can The ear treatments agent composite accepting has every milliliter of composite and is less than about 0.2eu.

Only for example, if carrying out pyrogen test using drying method.Suitable aseptic test includes American Pharmacopeia (united states pharmacopoeia, usp)<71>aseptic tests (sterility tests) (the 23rd edition, 1995) Described in test.American Pharmacopeia<85>and<151>chapter (usp23/nf 18, biological test (biological tests), American Pharmacopeia specification (the united states pharmacopeial convention), Rockville, MD (rockville, md), 1995) rabbit pyrogen test is described in detail in and tests (limulus with LAL amebocyte lysate test).Develop substituting pyrogen analysis based on monocyte activation-cytokine analysis.? Develop the homogeneous cell line being suitable to quality control application and be proved to detect that passing through the test of rabbit pyrogen deforms with king crab Pyrogenicity (Plutarch Plutarch (taktak) et al., pharmacy and pharmacology's magazine in the sample of cell solute test (j.pharm.pharmacol.)(1990),43:578-82).In another embodiment, ear acceptable ear treatments agent is adjusted Join thing to carry out reducing phlegm and internal heat origin operation.In another embodiment, the manufacturing process of ear acceptable ear treatments agent composite comprises to survey Try the pyrogenicity of composite.In certain embodiments, composite as herein described is substantially free of pyrogen.

Ph value and actual volume osmolality

As used herein " actual volume osmolality " meaning be by include activating agent and except gellant and/ Or the tune of all excipient measurements beyond thickening agent (such as Pluronic F68, carboxymethyl cellulose etc.) Join the volume osmolality of thing.The actual volume osmolality of composite as herein described is by any suitable method Measurement, such as dimension loud, high-pitched sound this (viegas) et al., Inpharm magazine (int.j.pharm.), described in 1998,160,157-162 Cryoscopic method.In some cases, the actual volume osmolality of compositionss as herein described by allow measure combination Vapour pressure osmometry (the such as vapor pressure lowering method) measurement of thing volume osmolality at relatively high temperatures.? Under certain situation, vapor pressure lowering method allows mensure to comprise the composite of gellant (such as thermal-reversible polymers) in gellant Volume osmolality under higher temperature in gel form.The practical weight infiltration of ear composite as herein described rubs Your concentration be about 100mosm/kg to about 1000mosm/kg, about 200mosm/kg to about 800mosm/kg, about 250mosm/kg extremely About 500mosm/kg or about 250mosm/kg are to about 320mosm/kg or about 250mosm/kg to about 350mosm/kg or about 280mosm/kg to about 320mosm/kg.In certain embodiments, the actual volume infiltration mole of composite as herein described is dense Degree is about 100mosm/l to about 1000mosm/l, about 200mosm/l to about 800mosm/l, about 250mosm/l to about 500mosm/l, about 250mosm/l are to about 350mosm/l, about 250mosm/l to about 320mosm/l or about 280mosm/l to about 320mosm/l.

In certain embodiments, the volume osmolality at target effect site (such as perilymph) place with described herein The transmission of any composite volume osmolality (that is, through or infiltration round window membrane material volume infiltration mole Concentration) roughly the same.In certain embodiments, the transmitted volume osmolality of composite as herein described is about 150mosm/l to about 500mosm/l, about 250mosm/l are to about 500mosm/l, about 250mosm/l to about 350mosm/l, about 280mosm/l to about 370mosm/l or about 250mosm/l to about 320mosm/l.

Dominant cation in the presence of endolymph is potassium.In addition, endolymph has the positively charged amino acid of high concentration.Outward Dominant cation in the presence of lymph is sodium.In some cases, endolymph and perilymphatic ion composition adjust hair cell Electrochemistry pulse.In some cases, any change of endolymph or perilymphatic ionic equilibrium all can be because of electrochemistry pulse Change along ear's hair cell conduction and lead to hearing disability.In certain embodiments, compositions disclosed herein is not destroyed Perilymphatic ionic equilibrium.In certain embodiments, compositions disclosed herein have identical with perilymph or substantially the same Ionic equilibrium.In certain embodiments, compositions disclosed herein does not destroy endolymphatic ionic equilibrium.In some embodiments In, compositions disclosed herein has the ionic equilibrium identical or substantially the same with endolymph.In certain embodiments, herein Described ear with composite formulated with provide with the compatible ionic equilibrium of fluid of inner ear (such as endolymph and/or perilymph).

Endolymph and perilymphatic ph value are close to physiology's ph value of blood.Endolymphatic ph value scope is about 7.2-7.9； Perilymphatic ph value scope is about 7.2-7.4.Near-end endolymphatic original position ph value is about 7.4, and far-end endolymphatic ph value is About 7.9.

In certain embodiments, the ph value of composite as herein described is adjusted (for example by using buffer) to arrive about The compatible ph value scope of 5.5 to 9.0 endolymph.In a particular embodiment, the ph value of composite as herein described is adjusted to The ph value scope that the perilymph of about 5.5 to about 9.0 is suitable for.In certain embodiments, the ph value of composite as herein described is adjusted Save about 5.5 to about 8.0, about 6 to about 8.0 or about 6.6 to about 8.0 perilymph be suitable for scope.In certain embodiments, The ph value scope that the perilymph that the ph value of composite as herein described is adjusted to about 7.0-7.6 is suitable for.

In certain embodiments, applicable composite also includes one or more ph value regulators or buffer agent.Suitable The ph value regulator closing or buffer agent including but not limited to acetate, bicarbonate, ammonium chloride, citrate, phosphate, its Pharmaceutically acceptable salt and a combination thereof or mixture.

In one embodiment, when in composite of the present invention using one or more buffer agents, described buffer agent (for example with pharmaceutically acceptable mediator) combines and is present in final composite that (amount is for example about 0.1% to about 20%th, in the range of about 0.5% to about 10%).In certain embodiments of the present invention, the buffer agent that gel composite includes Amount is so that the ph value of gel composite does not disturb the amount of body natural buffered system.

In one embodiment, also carry out stable compound using diluent, because it can provide more stable environment.Institute The salt (may also provide ph value control or maintain) that is dissolved in buffer solution is used as diluent in genus field, including (but not It is limited to) phosphate buffered salt solution.

In certain embodiments, the ph value of any gel composite as herein described allows in medical agent (such as ear sensation Cell modulator) or constitute gel polymer non-degradable in the case of gel composite is sterilized (for example pass through filter Or aseptic mixing or heat treatment and/or autoclaving process (such as final sterilization)).For reduce sterilizing during ear medicament and/ Or the hydrolysis of gelatin polymer and/or degraded, the ph value of buffer is designed to that (for example high temperature is high in sterilizing by composite ph value Pressure sterilization treatment) during maintain in the range of 7-8.

In a particular embodiment, the ph value of any gel composite as herein described allows in medical agent (such as ear sensation Cell modulator) or constitute gel polymer non-degradable in the case of final sterilization carried out to gel composite (for example pass through Heat treatment and/or autoclaving are processed).For example, for reducing ear medicament and/or gel polymerisation during autoclaving is processed The hydrolysis of thing and/or degraded, the ph value of design buffer maintains composite ph value in the range of 7-8 at high temperature.Depending on allotment Depending on ear medicament used in thing, any suitable buffer can be used.In some cases, because the pk of tris_aWith about- 0.03/ DEG C increases with temperature and reduces, and the pk of pbs_aIncreased with increased temperature with about 0.003/ DEG C, so 250 Carry out autoclaving under (121/ DEG C) to process so that the ph value of tris buffer significantly offsets downward (that is, acidity is bigger), and pbs Hydrolysis in tris of ph little the offsetting up of value relative extent of buffer, therefore ear medicament and/or the increasing of degraded manyly Plus ratio is much more in pbs.The degraded of ear medicament is by using buffer as described herein with polymeric additive (for example Cmc) appropriately combined and reduce.

In certain embodiments, be suitable to ear composite as herein described sterilizing (for example pass through to filter or aseptic mixing or Heat treatment and/or autoclaving process (such as final sterilization)) composite ph value between about 5.0 and about 9.0, about 5.5 And between about 8.5, between about 6.0 and about 7.6, between about 7 and about 7.8, between about 7.0 and about 7.6, about 7.2 with Between 7.6 or between about 7.2 and about 7.4.In a particular embodiment, it is suitable to sterilizing (the example of any composite as herein described As by filtering or aseptic mixing or heat treatment and/or autoclaving process (such as final sterilization)) composite ph value be about 6.0th, 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.

In certain embodiments, composite has ph value as described herein, and (for example viscosity strengthens to include thickening agent Agent), as non-limiting examples, all thickening agents based on cellulose as described herein.In some cases, second polymer (such as thickening agent) add and composite as described herein the permission of ph value composite as herein described sterilized and Ear medicament in ear composite and/or the no any substantial degradation of polymers compositionss.In certain embodiments, have as this In the composite of ph value described in literary composition the ratio of thermal reversibility poloxamer and thickening agent be 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, sustained release as herein described And/or extend release composite and comprise combining of Poloxamer 407 (Pluronic f127) and carboxymethyl cellulose (cmc), two The ratio of person 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.

In certain embodiments, in any composite as herein described, the amount of thermal-reversible polymers is the gross weight of composite About 10%, about 15%, about 20%, about 25%, about 30%, about 35% or about the 40% of amount.In certain embodiments, described herein Any composite in thermal-reversible polymers amount be composite gross weight about 10%, about 11%, about 12%, about 13%th, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24% or about 25%.In certain embodiments, thermal-reversible polymers (such as pluronic in any composite as herein described F127 (pluronic f127)) amount be composite gross weight about 7.5%.In certain embodiments, as herein described In what composite, the amount of thermal-reversible polymers (such as pluronic f127) is about the 10% of the gross weight of composite.At some In embodiment, in any composite as herein described, the amount of thermal-reversible polymers (such as pluronic f127) is composite About the 11% of gross weight.In certain embodiments, thermal-reversible polymers (such as Pu Langni in any composite as herein described Gram f127) amount be composite gross weight about 12%.In certain embodiments, in any composite as herein described, heat can The amount of inverse property polymer (such as pluronic f127) is about the 13% of the gross weight of composite.In certain embodiments, herein In described any composite, the amount of thermal-reversible polymers (such as pluronic f127) is the pact of the gross weight of composite 14%.In certain embodiments, thermal-reversible polymers (such as pluronic f127) in any composite as herein described Measure about 15% of the gross weight for composite.In certain embodiments, thermal reversibility polymerization in any composite as herein described The amount of thing (such as pluronic f127) is about the 16% of the gross weight of composite.In certain embodiments, as herein described In what composite, the amount of thermal-reversible polymers (such as pluronic f127) is about the 17% of the gross weight of composite.At some In embodiment, in any composite as herein described, the amount of thermal-reversible polymers (such as pluronic f127) is composite About the 18% of gross weight.In certain embodiments, thermal-reversible polymers (such as Pu Langni in any composite as herein described Gram f127) amount be composite gross weight about 19%.In certain embodiments, in any composite as herein described, heat can The amount of inverse property polymer (such as pluronic f127) is about the 20% of the gross weight of composite.In certain embodiments, herein In described any composite, the amount of thermal-reversible polymers (such as pluronic f127) is the pact of the gross weight of composite 21%.In certain embodiments, thermal-reversible polymers (such as pluronic f127) in any composite as herein described Measure about 23% of the gross weight for composite.In certain embodiments, thermal reversibility polymerization in any composite as herein described The amount of thing (such as pluronic f127) is about the 25% of the gross weight of composite.

In certain embodiments, in any composite as herein described, the amount of thickening agent (such as gellant) is composite About the 1% of gross weight, about 5%, about 10% or about 15%.In certain embodiments, thickening in any composite as herein described The amount of agent (such as gellant) be composite gross weight about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%th, about 3.5%, about 4%, about 4.5% or about 5%.

In certain embodiments, pharmaceutical formulation as herein described is stable in how lower period in office for ph value : at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least 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 1 The moon, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months or at least about 6 months.In other embodiments In, composite as herein described for ph value in the period of at least about 1 week in be stable.It is also described for ph value It is stable composite in the period of at least about 1 month.

Tonicity agents

In general, endolymphatic osmolality is higher than perilymph.For example, endolymphatic weight infiltration Molar concentration is about 304mosm/kg h₂O, and perilymphatic osmolality is about 294mosm/kg h₂o.Some In embodiment, add a certain amount of tonicity agents in composite as herein described to provide the practical weight infiltration of ear composite Molar concentration is about 100mosm/kg to about 1000mosm/kg, about 200mosm/kg to about 800mosm/kg, about 250mosm/kg To about 500mosm/kg or about 250mosm/kg to about 350mosm/kg or about 280mosm/kg to about 320mosm/kg.One In a little embodiments, the actual volume osmolality of composite as herein described is about 100mosm/l to about 1000mosm/l, About 200mosm/l to about 800mosm/l, about 250mosm/l are to about 500mosm/l, about 250mosm/l to about 350mosm/l, about 280mosm/l to about 320mosm/l or about 250mosm/l to about 320mosm/l.

In certain embodiments, the transmitted volume osmolality of any composite as herein described is through design and mesh Mark ear's structure (such as endolymph, perilymph etc.) is isotonic.In a particular embodiment, ear as herein described is formulated with compositionss With target effect site provide about 250 to about 320mosm/l and preferably from about 270 transmission to about 320mosm/l perilymph Suitable volume osmolality.In a particular embodiment, ear as herein described with compositionss formulated with interacting goals Position provides about 250 to about 320mosm/kg h₂The osmolality that the perilymph of the transmission of o is suitable for；Or about 270 to About 320mosm/kg h₂The osmolality of o.In a particular embodiment, after being delivered to target site, for example logical Cross using suitable salinity (concentration of such as potassium salt or sodium salt) or make composite become compatible with endolymph and/or with The transferable volume infiltration that the tonicity agents of perilymph compatible (that is, isotonic with endolymph and/or perilymph) adjust composite rubs (that is, there is downward in non-gelling agent or thickening agent (such as thermoreversible gels polymer) by concentration/osmolality in you Join the volume osmolality/osmolality of thing).Owing to forming of the different water yields and the monomeric unit of polymer Close, the volume osmolality of the composite comprising thermoreversible gels polymer is insecure measuring.The reality of composite Border volume osmolality (that is, composite in the presence of non-gelling agent or thickening agent (such as thermoreversible gels polymer) Volume osmolality) be reliably to measure, and by any suitable method (such as cryoscopic method, steam descent method) Measurement.In some cases, composite as herein described provides producing least interference to inner ear environment and causing after casting Transferable volume osmolality (the such as target of the discomfort (such as dizziness and/or nausea) of mammal minimum degree Position (such as perilymph)).

In certain embodiments, any composite as herein described is isotonic with perilymph and/or endolymph.Isotonic composite There is provided by adding tonicity agents.Suitable tonicity agents include but is not limited to any pharmaceutically acceptable sugar, salt or its What combination or mixture, such as, but not limited to dextrose, glycerol, Mannitol, Sorbitol, sodium chloride and other electrolyte.

The osmolality that applicable ear compositionss include one or more and make compositionss is being subjected to In the range of required amount salt.Described salt include with sodium, potassium or ammonium cation and chloride ion, citrate, Vitamin C acid group, Borate, phosphate radical, bicarbonate radical, the salt of sulfate radical, thiosulfate anion or bisulfite anion；Suitable salt includes chlorine Change sodium, potassium chloride, sodium thiosulfate, sodium sulfite and ammonium sulfate.

In certain embodiments, composite as herein described has ph value as described herein and/or actual volume infiltration Molar concentration, and the concentration of active pharmaceutical ingredient is between about 1 μm and about 10 μm, between about 1mm and about 100mm, about Between 0.1mm and about 100mm, between about 0.1mm and about 100nm.In certain embodiments, composite as herein described has Ph value and/or actual volume osmolality as described herein, and the concentration of active pharmaceutical ingredient is with the weight of composite Be calculated as between about 0.01%- about 20%, between about 0.01%- about 10%, between about 0.01%- about 7.5%, about 0.01%-6% Between, the active component between about 0.01-5%, between about 0.1- about 10% or between about 0.1- about 6%.In some embodiments In, composite as herein described has ph value as described herein and/or actual volume osmolality, and active medicaments become The concentration divided is with the stereometer of composite between about 0.1mg and about 70mg, between about 1mg and about 70mg/ml, in about 1mg And about 50mg/ml between, between about 1mg/ml and about 20mg/ml, between about 1mg/ml and about 10mg/ml, in about 1mg/ Activating agent between ml and about 5mg/ml or between about 0.5mg/ml and about 5mg/ml.In certain embodiments, described herein Composite there is ph value as described herein and/or actual volume osmolality, and the concentration of active pharmaceutical ingredient with The volume of composite is calculated as between about 1 μ g/ml and about 500 μ g/ml, between about 1 μ g/ml and about 250 μ g/ml, in about 1 μ g Activity and about 100 μ g/ml between, between about 1 μ g/ml and about 50 μ g/ml or between about 1 μ g/ml and about 20 μ g/ml Agent.

Particle diameter

Reduce the dissolution properties to increase surface area and/or adjust composite using size.It is additionally operable to maintain this paper institute The consistent average particle size distribution (psd) (such as micro-size particless, nanometer particle etc.) of any composite stated.In some enforcements Example in, any composite as herein described comprises many granules, that is, comprise multiple particle diameters (for example micronized particles, nanometer particle, The uncertain particle of size (non-sized particle), colloidal particle；I.e. composite is many granules composite.In some enforcements In example, any composite as herein described comprises one or more many granule (such as micronization) therapeutic agents.Micronization is The technique reducing the average diameter of solid material particle.The diameter of micronized particles is about micron-scale to about nano-scale. In certain embodiments, the average diameter of the particle in micronizing solid is about 0.5 μm to about 500 μm.In certain embodiments, The average diameter of the particle in micronizing solid is about 1 μm to about 200 μm.In certain embodiments, the grain in micronizing solid The average diameter of son is about 2 μm to about 100 μm.In certain embodiments, the average diameter of the particle in micronizing solid is about 3 μm to about 50 μm.In certain embodiments, micronizing solid granule comprises less than about 5 microns, is less than about 20 microns and/or is less than About 100 microns of particle diameter.In certain embodiments, with comprise non-multi granule (for example non-micronization) ear sensory cell regulator Composite is compared, and allows ear sensory cell regulator from herein using ear sensory cell regulator granule (such as micronized particles) Extend release and/or sustained release in described any composite.In some cases, containing many granules (such as micronization) ear The composite of sensory cell regulator sprays from the 1ml syringe being furnished with 27g pin and does not have any blocking or block.

In some cases, the particle that any particle in any composite as herein described is coated (is for example coated with The micronized particles crossed, nanoparticle) and/or microsphere and/or liposome particles.Particle diameter reduce technology include for example milling, Grind (for example gas mill grind (jet grinding), ball milling), cohesion, complex coacervation, high pressure homogenizing, spray drying and/or Crystalization in supercritical fluid.In some cases, grain is controlled by mechanical shock (such as hammer mill, ball mill and/or needle mill) The size of son.In some cases, by fluid energy (such as spiral spray grinder, circulation jet mill and/or fluidisation Bed jet mill) control particle size.In certain embodiments, composite as herein described comprise crystalline particle and/or Isotropism particle.In certain embodiments, composite as herein described comprises amorphous particle and/or anisotropic particles.? In some embodiments, composite as herein described comprises therapeutic agent particle, wherein therapeutic agent be the free alkali of therapeutic agent or salt, Or prodrug or its any combinations.

In certain embodiments, composite as herein described comprises one or more ear sensory cell regulators, its Middle ear sensory cell regulator comprises nano-particle.In certain embodiments, composite as herein described comprises to be optionally coated with The ear sensory cell regulator beadlet (such as dextromethorphan (dextromethorphan) beadlet) of control release excipient.One In a little embodiments, composite as herein described comprises to granulate and/or size reduces and scribbles the ear sense of control release excipient Feel cell modulator；Then optionally by described granular coated ear sensory cell regulator granule micronization and/or tune It is assigned in any combinations thing as herein described.

In some cases, by using program as herein described using in neutral molecule, free acid or free alkali form Ear sensory cell regulator and ear sensory cell regulator salt combine the ear medicament formulation to prepare pulse release.? In some composites, by using any program as herein described use micronization ear sensory cell regulator (and/or its salt or Prodrug) to prepare pulse release ear medicament and adjust with combining of coated particle (such as nanoparticle, liposome, microsphere) Join thing.Or, by by means of cyclodextrin, surfactant (such as Poloxamer 407,338,188), tween (80,60,20, 81), the ear of up to 20% transmission dosage is felt by peg- castor oil hydrogenated, auxiliary solvent (as n- N-methyl-2-2-pyrrolidone N) etc. Cell modulator (such as micronization ear sensory cell regulator, free alkali, free acid or its salt or prodrug；Many granules ear is felt Cell modulator, free alkali, free acid or its salt or prodrug) dissolve and prepare pulse release using any program as herein described Composite is reaching pulsed release profile.

In a particular embodiment, any ear compatibility composite as herein described comprises one or more micronizations doctor Medicament (such as ear sensory cell regulator).In some described embodiments, micronization medical agent comprises micronized particles, coating Micronized particles or a combination thereof that (for example scribble and extend release coating) crosses.In some described embodiments, comprise micronization grain The micronization medical agent of sub, coated micronized particles or a combination thereof comprises in neutral molecule, free acid, free alkali, its salt, The ear sensory cell regulator of prodrug or any combinations form.In certain embodiments, medical composition as herein described comprises Ear sensory cell regulator in micronized powder.In certain embodiments, medical composition as herein described comprise be in The ear sensory cell regulator of ear sensory cell regulator micronized form.

Many granules as herein described and/or micronization ear sensory cell regulator (are included by means of any kind of substrate Solid, liquid or gel-type vehicle) it is delivered to ear structure (such as internal ear).In certain embodiments, many granules as herein described and/ Or micronization ear sensory cell regulator by means of any kind of substrate (including solid, liquid or gel-type vehicle) via tympanum Interior injection is delivered to ear structure (such as internal ear).

Adjustability release characteristic

Release from any composite as herein described, compositionss or device for the activating agent optionally can be tuned into releasing of wanting Put feature.In certain embodiments, compositionss as herein described are to be substantially free of the solution of bonding component.In described situation Under, compositionss provide substantially discharging immediately of activating agent.In some described embodiments, compositionss are applied to perfusion ear knot Structure, such as in surgery intra-operative.

In certain embodiments, compositionss as herein described are to be substantially free of bonding component and comprise micronization ear medication The solution of agent (such as corticosteroid).In some described embodiments, the activating agent of compositionss was released in about 4 days at about 2 days Put.

In certain embodiments, compositionss as herein described comprise gellant (such as Poloxamer 407) and activating agent exists Release in the time of about 1 day to about 3 days.In certain embodiments, compositionss as herein described comprise gellant (such as pool Lip river sand Nurse 407) and activating agent discharge within the time of about 1 day to about 5 days.In certain embodiments, compositionss as herein described comprise Gellant (such as Poloxamer 407) and activating agent discharged within the time of about 2 days to about 7 days.

In certain embodiments, compositionss as herein described comprise gellant (such as Poloxamer 407) and micronization ear With pharmaceutical agent combinations and provide the long period in long lasting for release.In certain embodiments, compositionss bag as herein described Gellant (such as Poloxamer 407) containing about 14-17% and micronization ear medicament；And within the time of about 1 week to about 3 weeks Long lasting for release.In certain embodiments, the gellant that compositionss as herein described comprise about 18-21% (for example moors Lip river Husky nurse 407) and micronization ear medicament；And long lasting for release within the time of about 3 weeks to about 6 weeks.

Therefore, in compositionss, the particle diameter of the amount of gellant and ear medicament can be transferred to and obtain the ear medicament wanted from combination Release profiles in thing.

As described herein, the compositionss comprising micronization ear medicament and the compositionss phase comprising non-micronization ear medicament Than the prolongation release providing in one section of longer time.In some cases, micronization ear medicament provides surely via slow degraded Fixed activating agent supply (for example, +/- 20%), and the bank as activating agent；Described bank effect increases ear medicament in ear Holdup time in piece.In a particular embodiment, activating agent (such as micronized active agents) and the compositionss of suitable particle diameter are selected The amount combination of middle gellant provides and allows the adjustable prolongation that activating agent discharged within the hours, days, weeks or months time to release Put feature.

In certain embodiments, the viscosity of any composite as herein described be designed to provide be suitable for from the ear compatibility The speed of release in gel.In certain embodiments, thickening agent (such as bonding component, such as PULLRONIC F68 copolymerization Thing) concentration provide adjustable average dissolution time (mdt).Mdt and activating agent are from compositionss as herein described or device Rate of release is inversely proportional to.Experimentally, optionally the ear medicament of release is fitted to Cowes Mel-Pei Pasi equation (korsmeyer-peppas equation)

\frac{q}{q_{α}} = {kt}^{n} + b

Wherein q is the amount of the ear medicament discharging during time t, q_αIt is total burst size of ear medicament, k is the release of n time Constant, n is the dimensionless number related to dissolution mechanism and b is y-intercept, characterizes the releasing mechanism of initially outburst, wherein n=1 table Levy erosion control mechanism.Average dissolution time (mdt) is to stay drug molecule in substrate before different periods release and remove With molecule sum, and optionally it is calculated as below:

m d t = \frac{{nk}^{- 1 / n}}{n + 1}

For example, the concentration of the average dissolution time (mdt) of compositionss or device and gellant (such as poloxamer) Between linear relationship instruction ear medicament because polymer gel (such as poloxamer) corrosion rather than via dispersal events.Another In one example, non-linear relation indicates the combination release via diffusion and/or polymer gel degraded for the ear medicament.In another reality In example, gel exclusion time-histories faster (activating agent release is faster) instruction average dissolution time (mdt) of compositionss or device is shorter. The suitable parameter to determine mdt for the concentration of bonding component and/or activating agent in test compositionss.In certain embodiments, also survey Examination volume injected is to determine preclinical and clinical research suitable parameter.The gel strength of activating agent and concentration impact ear medicament Release dynamics from compositionss.Under low poloxamer concentration, supersession rate accelerates (mdt is shorter).Compositionss or device The increase of middle ear drug concentration extends holdup time in ear for the ear medicament and/or mdt.

In certain embodiments, mdt from compositionss as herein described or device for the poloxamer is at least 6 hours.? In some embodiments, mdt from compositionss as herein described or device for the poloxamer is at least 10 hours.

In certain embodiments, mdt from compositionss as herein described or device for the activating agent is about 30 hours to about 48 Hour.In certain embodiments, mdt from compositionss as herein described or device for the activating agent be about 30 hours little to about 96 When.In certain embodiments, mdt from compositionss as herein described or device for the activating agent is about 30 hours to about 1 week.One In a little embodiments, activating agent is about 1 week to about 6 weeks from the mdt of compositionss as herein described or device.

In certain embodiments, any control release ear composite as herein described be not that control release ear is allocated The composite of thing is compared the exposure increasing ear medicament and is made below the curve of ear's fluid (such as endolymph and/or perilymph) Long-pending (auc) increases about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%.In certain embodiments, Any control release ear composite as herein described can increase ear compared with the composite not being control release ear composite With open-assembly time of medicament and make the c of ear's fluid (such as endolymph and/or perilymph)_maxReduce about 40%, about 30%, about 20% or about 10%.In certain embodiments, any control release ear composite as herein described be not control release ear Compare change (for example reducing) c with the composite of composite_maxWith c_minRatio.In certain embodiments, as herein described What control release ear composite can increase the exposure of ear medicament compared with the composite not being control release ear composite And make ear drug concentration be higher than c_minTime span increase about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%.In some cases, control release composite as herein described postpones to reach c_maxTime.In some feelings Under condition, the control of medicine stably discharges and can extend drug level and will be kept above c_minTime.In certain embodiments, herein Described ear compositionss can extend the holdup time in internal ear for the medicine and offer is stablized medicine and exposed curve.In certain situation Under, the concentration increase of activating agent in compositionss runs through reset procedure and allows to reach more rapid and more stable stable state.

In some cases, once the medicine of medicine exposes (concentration in such as endolymph or perilymph) reaches stable state, In endolymph or perilymph, the concentration of medicine is maintained at about therapeutic dose or therapeutic dose and continues one section of long period (for example 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 1 week, 3 weeks, 6 weeks, 2 months).In certain embodiments, from controlled-release is released as herein described The Css putting the activating agent of release in composite is to be never the activating agent discharging in the composite of control release composite About 20 to about 50 times of Css.Fig. 5 shows the adjustable release of prediction from four kinds of compositionss for the activating agent.

Pharmaceutical formulation

Provided herein is medical composition or device, it includes at least one ear sensory cell regulator and pharmaceutically acceptable Diluent, excipient or supporting agent.In certain embodiments, medical composition includes other medical science or medical agent, supporting agent, assistant Agent, such as preservative, stabilizer, wetting agent or emulsifying agent, dissolution accelerator, salt and/or buffer agent for adjusting osmotic pressure. In other embodiments, medical composition also contains other therapeutic substances.

In certain embodiments, compositionss as herein described or device include dyestuff to help when applying strengthen to gel Observation.In certain embodiments, acceptable compositionss or the compatible dyestuff of device include ivens with ear as herein described Blue (evans blue) (such as ear with the 0.5% of composite gross weight), methylene blue (methylene blue) (for example use by ear The 1% of composite gross weight), isosulfan blue (isosulfan blue) (such as ear with the 1% of composite gross weight), trypan blue (trypan blue) (such as ear with the 0.15% of composite gross weight) and/or indocyanine green (indocyanine green) (for example every bottle 25mg).Other common dyes, such as fd＆c are red 40, fd＆c is red 3, fd＆c Huang 5, fd＆c Huang 6, fd＆c indigo plant 1, Fd＆c indigo plant 2, fd＆c are green 3, (such as Fluorescein isothiocyanate (fluorescein isothiocyanate) is if pellet for fluorescent dye Bright (rhodamine), alexa fluors, dylight fluors) and/or can be in conjunction with such as mri, cat scanning, pet scanning Dyestuff Deng non-invasive imaging technique observation.It is also contemplated by being used together gadolinio mri with any ear composite as herein described Dyestuff, iodo dyestuff, bario dyestuff etc..List under the dyestuff entry of Sigma-Aldrich (sigma-aldrich) catalogue The other dyestuffs compatible with any composite as herein described or compositionss (with regard to described disclosure, wrap by reference Include herein).

In certain embodiments, monitor or check audition, balance or other otic conditions using machinery or imaging device. For example, especially cover nuclear magnetic resonance (mri) device in the range of described embodiment, wherein mri device (such as 3 special this Draw (tesla) mri device) Meniere's disease progression and the successive treatment of pharmaceutical formulation disclosed herein can be assessed.Also contain Lid is made together with any ear compatible compositions as herein described or device and/or any machinery as herein described or imaging device With gadolinio dyestuff, iodo dyestuff, bario dyestuff etc..In certain embodiments, using gadolinium hydrate and mri and/or described herein Any medical composition or device combine inside to assess disease severity (scale of such as endolymphatic hydrops), compositionss Infiltration in ear and/or pharmaceutical formulation/device control curative effect in ear disease as herein described (such as Meniere) Power.

Any medical composition as herein described or device are by making compositionss or device and crest of fenestra cochleae, oeil de boeuf, tympanum, drum Film, middle ear or external ear contact and to cast.

One in ear as herein described acceptable control release ear sensory cell regulator pharmaceutical formulation specifically real Apply in example, ear sensory cell regulator provides in gel-type vehicle, gel-type vehicle is referred to herein as " the acceptable gel of ear Composite ", " internal ear acceptable gel composite ", " middle ear acceptable gel composite ", " external ear acceptable gel tune Join thing ", " ear gel composite " or its version.The all components of gel composite must be compatible with target ear structure. In addition, gel composite control release ear sensory cell regulator is to the wanted position of target ear structure；In certain embodiments, Gel composite also has release immediately or quick release for ear sensory cell regulator is delivered to wanted target site Component.In other embodiments, gel composite has the sustained-released component for transmitting ear sensory cell regulator.One In a little embodiments, gel composite comprises many granules (such as micronization) ear sensory cell regulator.In certain embodiments, ear It is biodegradable with gel composite.In other embodiments, ear gel composite include mucosal adhesive excipient with Allow to adhere to the exterior mucosa layer of round window membrane.In other embodiments again, ear gel composite includes penetration enhancers and assigns Shape agent；In other embodiments, ear gel composite contains the viscosity intensifier enough to provide following viscosity: about 500 and 1, Between 000,000 centipoise；Between about 750 and 1,000,000 centipoises；Between about 1000 and 1,000,000 centipoises；About 1000 with Between 400,000 centipoises；Between about 2000 and 100,000 centipoises；Between about 3000 and 50,000 centipoises；About 4000 and 25,000 Between centipoise；Between about 5000 and 20,000 centipoises；Or about 6000 and 15,000 between centipoise.In certain embodiments, ear is used Gel composite contains the viscosity intensifier enough to provide the viscosity between about 50,0000 and 1,000,000 centipoises.

In certain embodiments, compositionss as herein described or device are low viscosity compositions or device under body temperature.? In some embodiments, low viscosity compositions or device contain about 1% to about 10% viscosity intensifier (for example such as polyoxyethylene- The bonding components such as poiyoxypropylene copolymer).In certain embodiments, low viscosity compositions or device contain about 2% to about 10% Viscosity intensifier (bonding component such as such as Pluronic F68).In certain embodiments, low viscosity group Compound or device contain about 5% to about 10% viscosity intensifier (the gelling group such as such as Pluronic F68 Point).In certain embodiments, low viscosity compositions or device are substantially free of viscosity intensifier (such as such as polyoxyethylene-poly- The bonding components such as oxypropylene copolymer).In certain embodiments, low viscosity ear sensory cell regulating composition as herein described Or the apparent viscosity of device is about 100cp to about 10,000cp.In certain embodiments, low viscosity ear sensation as herein described is thin The apparent viscosity of born of the same parents' regulating composition or device is about 500cp to about 10,000cp.In certain embodiments, as herein described The apparent viscosity of low viscosity ear sensory cell regulating composition or device is about 1000cp to about 10,000cp.Described in some In embodiment, low viscosity ear sensory cell regulating composition or device are intervened to combine with outside ear and are cast, described outside ear Portion intervenes such as surgical operation, and including but not limited to middle Otologic Surgical Proce- dures, interior Otologic Surgical Proce- dures, myringotomy, cochlea are cut Open art, labyrinthotomy, mastoidectomy, stapedectomy, Stapedotomy, endolymph sacculotomy etc..Some institute State in embodiment, low viscosity ear sensory cell regulating composition or device cast during ear's intervention.In other described realities Apply in example, low viscosity ear sensory cell regulating composition or device cast before ear's intervention.

In certain embodiments, compositionss as herein described or device are high viscosity composition or device under body temperature.? In some embodiments, high viscosity composition or device contain about 10% to about 25% viscosity intensifier (for example such as polyoxyethylene- The bonding components such as poiyoxypropylene copolymer).In certain embodiments, high viscosity composition or device contain about 14% to about 22% Viscosity intensifier (bonding component such as such as Pluronic F68).In certain embodiments, high viscosity group Compound or device contain the (gelling such as such as Pluronic F68 of about 15% to about 21% viscosity intensifier Component).In certain embodiments, the apparent viscosity of high viscosity ear sensory cell regulating composition as herein described or device is About 100,000cp to about 1,000,000cp.In certain embodiments, high viscosity ear sensory cell regulator group as herein described The apparent viscosity of compound or device is about 150,000cp to about 500,000cp.In certain embodiments, as herein described high viscous The apparent viscosity of degree ear sensory cell regulating composition or device is about 250,000cp to about 500,000cp.Described in some In embodiment, high viscosity composition or device be at room temperature liquid and about room temperature and body temperature (include the individuality of serious fever, For example be up to about 42 DEG C) between be gelled.In certain embodiments, ear sensory cell regulator high viscosity composition or device are with list One therapy casts for treating ear disease as herein described or condition of illness.In certain embodiments, high viscosity ear sensory cell Regulating composition or device are intervened to combine with outside ear and are cast, described outside ear intervention such as surgical operation, including (but Be not limited to) in Otologic Surgical Proce- dures, interior Otologic Surgical Proce- dures, myringotomy, cochlea otomy, labyrinthotomy, mastoidectomy, Stapedectomy, Stapedotomy, endolymph sacculotomy etc..In some described embodiments, high viscosity ear sensory cell Regulating composition or device cast after ear's intervention.In other described embodiments, high viscosity ear sensory cell is adjusted Agent compositionss or device cast before ear's intervention.

In other embodiments, in addition internal ear pharmaceutical formulation as herein described provides ear acceptable hydrogel；Again In other embodiments, ear pharmaceutical formulation provides the acceptable microsphere of ear or microgranule；In other embodiments again, ear medicine is adjusted Joining thing provides the acceptable liposome of ear.In certain embodiments, ear pharmaceutical formulation provides the acceptable foams of ear；Again In other embodiments, ear pharmaceutical formulation provides the acceptable varnish of ear；In other embodiments again, ear pharmaceutical formulation provides Ear is acceptable to be formed in situ spongy material.In certain embodiments, ear pharmaceutical formulation provides the acceptable solvent of ear to release Put gel.In certain embodiments, ear pharmaceutical formulation provides actinic radiation curable gel.Other embodiments are adjusted in ear medicine Join thing and include thermoreversible gels, so that at room temperature or after preparing gel less than room temperature, composite is fluid, but gel is applied After among internal ear and/or middle ear target site (including tympanum, round window membrane or crest of fenestra cochleae) or nearby, ear pharmaceutical formulation becomes Hard or harden into gel-like substance.

In other or alternate embodiment, ear gel composite can be thrown on round window membrane via Injection in Tympanic Cavity or circle Near fenestrated membrane.In other embodiments, ear gel composite cuts after via ear and surgical procedures enter oeil de boeuf or snail In window ridge region or nearby throw on or near oeil de boeuf or crest of fenestra cochleae.In addition, ear gel composite is via syringe and pin Apply, wherein pin is inserted through tympanum and guides oeil de boeuf or crest of fenestra cochleae region.Ear gel composite is then deposited over oeil de boeuf or fenestra cochleae For local treatment autoimmune otic conditions on or near ridge.In other embodiments, ear gel composite is via implantation The microtubular of patient is applied, and in other embodiments again, composite is thrown on or near round window membrane via pump installation.Again its In its embodiment, ear gel composite is applied on or near round window membrane via micro injecting device.In other embodiments again, Ear gel composite is applied in tympanum.In certain embodiments, ear gel composite is applied on tympanum.Again other In embodiment, ear gel composite is applied in auditory meatus or in auditory meatus.

In other specific embodiments, any medical composition as herein described or device comprise many granules ear sensory cell Regulator is in fluid matrix (being for example used for fluid composition or the ear drop of Injection in Tympanic Cavity).In certain embodiments, Any medical composition as herein described comprises many granules ear sensory cell regulator in solid matrix.

Control release composite

In general, when discharging position and release in vivo of control release type modification of drug thing Drug controlled release Between.As discussed herein, control release refers to discharge immediately, sustained release, sustained release, extends release, variable release, pulsation Release and bimodulus release.Controlled-release is released is placed with many advantages.First, the control release of medical agent allows relatively low administration frequency therefore Repetitive therapy is minimized.Second, the treatment of control release type produces more effective drug utilization and less compound is with remnants Thing form remains.3rd, control release provides and carries out topical remedy by transfer device or composite are placed in disease location The possibility of transmission.In addition, control release provides to cast and discharge two or more by means of single dose unit respectively having The possibility of unique different pharmaceutical of release profiles, or the possibility of same medicine is discharged with different rates or various durations.

Therefore, the one side of embodiment disclosed herein is that offer is used for treating autoimmune disorder and/or inflammation Ear acceptable control release ear sensory cell regulating composition or device.Compositions disclosed herein and/or composite And/or the control release aspect of device is given by various medicaments, including but not limited to excipient, can be in internal ear or other Using the medicament being accepted or material in ear's structure.Only for example, described excipient, medicament or material include ear be subjected to Polymer, the acceptable viscosity intensifier of ear, the acceptable gel of ear, the acceptable varnish of ear, the acceptable foams of ear, The acceptable xerogel of ear, the acceptable microsphere of ear or the acceptable hydrogel of microgranule, ear, ear is acceptable is formed in situ sea Continuous shape material, ear acceptable actinic radiation curable gel, ear acceptable solvent release gel, the acceptable lipid of ear The acceptable Nano capsule of body, ear or the acceptable thermoreversible gels of nanosphere body, ear or a combination thereof.

The acceptable gel of ear

Gel, sometimes referred to as gel (jellies), are defined in many ways.For example, American Pharmacopeia is fixed Adopted gel is the semi-solid systems that the suspension being made up of little inorganic particulate or the big organic molecule being interspersed with liquid form.Gel Including single-phase or binary system.Single-phase gels are by organic macromolecule there is not obvious border between scattered macromole and liquid Mode be evenly distributed in whole liquid composition.Some single-phase gels are by synthetic macromolecule (such as Carbomer) or by natural Prepared by glue (such as tragacanth).In certain embodiments although single-phase gels are usually aqueouss, but will also use alcohol and oil system Standby.Two-phase gel is made up of the network of little individual particle.

Gel also can be categorized into hydrophobic or hydrophilic.In certain embodiments, the substrate of hydrophobic gel is by liquid Body paraffin and polyethylene or fatty oil and colloidal silica silica gel or aluminum or zinc soap composition.By contrast, hydrophobic gel Substrate generally by water, glycerol or propylene glycol be suitable for gellant (such as tragacanth, starch, cellulose derivative, carboxylic ethylene Based polyalcohol and aluminium-magnesium silicate) gelling composition.In certain embodiments, the rheology of compositions disclosed herein or device is false Plasticity, plasticity, thixotropy or dilatancy.

In one embodiment, the acceptable composite of the enhanced ear of viscosity as herein described is not liquid at room temperature. In certain embodiments, the enhanced composite of viscosity is characterised by (including the individuality of severe fever, for example in room temperature with body temperature Be up to about 42 DEG C) between undergo phase transition.In certain embodiments, phase transformation is less than 1 DEG C of body temperature, less than 2 DEG C of body temperature, less than body temperature 3 DEG C, occur less than 4 DEG C of body temperature, less than 6 DEG C of body temperature, less than 8 DEG C of body temperature or less than at 10 DEG C of body temperature.In certain embodiments, phase Become and occurring less than about 15 DEG C of body temperature, less than about 20 DEG C of body temperature or less than at about 25 DEG C of body temperature.In a particular embodiment, this paper institute The gelation temperature (t gel) of the composite stated is about 20 DEG C, about 25 DEG C or about 30 DEG C.In certain embodiments, as herein described The gelation temperature (t gel) of composite is about 35 DEG C or about 40 DEG C.In one embodiment, substantially cast this paper institute under body temperature Any composite stated can reduce or suppress the dizziness related to casting ear composite in tympanum.The definition of body temperature includes health Unhealthy individual body temperature that is individual or including fever individual (being up to about 42 DEG C).In certain embodiments, doctor as herein described Drug composition or device are substantially liquid at room temperature and cast at room temperature at room temperature or substantially, to reduce or to improve such as The side effect such as dizziness.

The polymer being made up of polyoxypropylene and polyoxyethylene forms thermoreversible gels when being incorporated in aqueous solution.These Polymer can become gel-like state from liquid at a temperature of body temperature, thus obtaining being applied to the suitable of target ear structure Use composite.The phase transformation of liquid to gel state depends on the polymer concentration in solution and composition.

Poloxamer 407 (poloxamer 407) (pf-127) is be made up of Pluronic F68 non- Ion-type surfactant.Other poloxamers include 188 (f-68 levels), 237 (f-87 levels), 338 (f-108 levels).Pool Lip river is husky Nurse aqueous solution is stable in the presence of acid, alkali metal and metal ion.Pf-127 be there is formula e106 p70 e106 can The PULLRONIC F68 triblock copolymer buied, average molar mass is 13,000.Described polymer can be furthermore with The appropriate methodology purification of the gelling property of polymer can be strengthened.It contains about 70% oxirane, is its hydrophilic reason.Its It is a series of one of poloxamer aba block copolymers, poloxamer aba block copolymer member has as follows Chemical formula.

Pf-127 is paid special attention to, because the concentrated solution (> 20%w/w of copolymer) when being heated to body temperature from low viscosity Clear solution is transformed into solid gel.Therefore, this phenomenon shows when contacting with body, and gel preparation can form semi-solid knot Structure and sustained releasing type store up storehouse (depot).Additionally, pf-127 has good solvability, low toxicity, it is accordingly regarded as medicine and passes The good medium of delivery system.

In an alternative em bodiment, heat-sensitive gel (thermogel) be peg-plga-peg triblock copolymer (just (jeong) et al., natural (nature) (1997), 388:860-2；Just (jeong) et al., control release magazine (j.control.release)(2000),63:155-63；Just (jeong) et al., advanced drugs transmission comment (adv.drug delivery rev.)(2002),54:37-51).Polymer represents sol-gel in about 5%w/w to about 40%w/w concentration Characteristic.Depending on wanted property, in plga copolymer, the mol ratio of lactide/glycolides is in about 1:1 to about 20:1 scope Interior.In gained copolymer water soluble, and form free flowing liquid at room temperature, but form hydrogel under body temperature.Commercially available Peg-plga-peg triblock copolymer is the resomer being manufactured by Boehringer Ingelheim (boehringer ingelheim) rgp t50106.This material is made up of the pgla copolymer of 50:50 poly- (dl- lactide-co-glycolide), and contains 10%w/w Peg, and molecular weight is about 6000.

Be Micro Co., Ltd. (macromed incorporated) a class low-molecular-weight biodegradable embedding The trade name of section copolymer, its have as U.S. Patent No. 6,004,573, the 6th, No. 117949, the 6th, 201, No. 072 and Reverse thermogelling matter described in No. 6,287,588.Its U.S. Patent Application No. 09/906,041 in also including applying for Number, the biodegradable polymer pharmaceutical carriers disclosed in No. 09/559,799 and No. 10/919,603.Biodegradable Pharmaceutical carriers comprise aba type or bab type triblock copolymer or its mixture, wherein a block has relative hydrophobicity and bag Containing biodegradable polyester or poly- (ortho esters), and b block has relative hydropathy and comprises Polyethylene Glycol (peg), described The hydrophobicity content of copolymer between 50.1 weight % to 83 weight % and hydrophilic content in 17 weight % to 49.9 weights Between amount %, and total block copolymer molecular weight is between 2000 dalton and 8000 dalton.Pharmaceutical carriers are less than normal Represent water solublity at a temperature of mammal body temperature and the reversible hot glue of experience coagulates, therefore equal to physiology's mammal body temperature At a temperature of with gel form exist.Biodegradable hydrophobicity a polymer blocks comprise polyester or poly- (ortho esters), wherein Polyester is by the monomer synthesis selected from the group consisting of: d, l- lactide, d- lactide, l- lactide, d, l- lactic acid, d- Lactic acid, l- lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic, 6-caprolactone, ε-hydroxycaproic acid, gamma-butyrolacton, gamma-hydroxybutyric acid, δ-valerolactone, δ-hydroxypentanoic acid, hydroxybutyric acid, malic acid and its copolymer, and mean molecule quantity about 600 dalton and 3000 dalton it Between.Hydrophilic b block sections is preferably Polyethylene Glycol (peg), mean molecule quantity about 500 dalton and 2200 dalton it Between.

Other biodegradable thermoplastic polyesters include(by Atri gram this laboratory (atrix Laboratories, inc.) provide) and/or for example U.S. Patent No. 5,324,519, No. 4,938,763, the 5,702nd, Thermoplastic polyester disclosed in No. 716, No. 5,744,153 and No. 5,990,194；The biodegradable heat being wherein suitable for Plasticity polyester is open with thermoplastic polymer.The example of suitable biodegradable thermoplastic's polyester includes polylactic acid, poly- second is handed over Ester, polycaprolactone, its copolymer, its terpolymer and its any combinations.In some described embodiments, suitable biology Biodegradable thermoplastic polyester is polylactic acid, PGA, its copolymer, its terpolymer or a combination thereof.In an embodiment In, biodegradable thermoplastic polyester is 50/50 poly- (the dl- lactide-co-glycolide) with carboxy terminal groups；Account for The about 30wt.% of compositionss to about 40wt.%；And mean molecule quantity is about 23,000 to about 45,000.Or, in another enforcement In example, biodegradable thermoplastic polyester is 75/25 poly- (dl- lactide-co-glycolide) of no carboxy terminal groups；Account for The about 40wt.% of compositionss to about 50wt.%；And mean molecule quantity is about 15,000 to about 24,000.Real in other or replacement Apply in example, depending on polymerization, the end group of poly- (dl- lactide-co-glycolide) is hydroxyl, carboxyl or ester.Lactic acid or The polycondensation of glycolic provides the polymer containing terminal hydroxyl and carboxyl.Cyclic lactide or glycolide monomer and water, lactic acid or The ring-opening polymerisation of glycolic provides the polymer containing same end group.However, with monofunctional alcohol (such as methanol, ethanol or 1- Dodecanol) open loop that carries out cyclic monomer provides the polymer containing a hydroxyl and an ester end group.Cyclic monomer with The ring-opening polymerisation of glycol (such as 1,6-HD or Polyethylene Glycol) provides the polymer of only hydroxyl end group.

Because the polymer system of thermoreversible gels is more completely dissolved at low temperature, dissolving method is included in low temperature Add the desired amount of polymer in the lower water to amount to be used.In general, after by vibrating wetting polymer, cover Mixture and be placed in cold house or in about 0-10 DEG C of thermostatic container so that polymer dissolving.Stirring or oscillation mixture are so that warm Reversible gel polymer dissolves more quickly.Then ear sensory cell regulator and such as buffer agent, salt and preservative are added Etc. various additives and dissolve.In some cases, if ear sensory cell regulator and/or other pharmaceutical active do not dissolve in Water, then suspended.Adjust ph value by adding suitable buffer agent.Glue optionally by being incorporated to round window membrane in composite Film adhesive agent Carbomer is (such asThermoreversible gels 934p) are made to have round window membrane mucoadhesive characteristics (Ma Jiti Sub- (majithiya) et al., American Pharmaceutical scientist association's medical sci-tech (aaps pharmscitech) (2006), 7 (3), the E1 page；Ep0551626, with regard to described disclosure, both are incorporated herein by reference).

One embodiment is the ear acceptable medicine gel composite not needed using the viscosity intensifier adding.These Gel composite is associated with least one pharmaceutically acceptable buffer agent.On the one hand be comprise ear sensory cell regulator and The gel composite of pharmaceutically acceptable buffer agent.In another embodiment, pharmaceutically acceptable excipient or load Agent is gellant.

In other embodiments, applicable ear acceptable ear sensory cell regulator pharmaceutical formulation also include one kind or More than one ph value regulators or buffer agent are suitable for endolymph or perilymphatic ph value to provide.Suitable ph value regulator or Buffer agent includes but is not limited to acetate, bicarbonate, ammonium chloride, citrate, phosphate, it is pharmaceutically acceptable Salt and a combination thereof or mixture.The amount of these included ph value regulators and buffer agent is the ph value maintaining compositionss in about ph Required amount between 5 and about ph 9, in one embodiment, ph value between about 6.5 to about 7.5, and in another embodiment, Ph value is about 6.5,6.6,6.7,6.8,6.9,7.0,7.1,7.2,7.3,7.4,7.5.In one embodiment, when the present invention adjusts When joining in thing using one or more buffer agents, described buffer agent for example combine with pharmaceutically acceptable mediator and in Amount in final composite is for example in the range of about 0.1% to about 20%, about 0.5% to about 10%.The present invention certain In a little embodiments, in gel composite, the amount of included buffer agent is so that the ph value of gel composite does not disturb middle ear or interior The natural buffered system of ear or do not disturb endolymph or the amount of perilymphatic natural ph value: adjust depending on ear sensory cell regulator Join thing with the where in cochlea as target.In certain embodiments, there are about 10 μm in gel composite to about 200mm concentration Buffer agent.In certain embodiments, there is the buffer agent to about 200mm concentration for the about 5mm.In certain embodiments, exist about 20mm to about 100mm concentration buffer agent.One embodiment is that acetate or citrate in subacidity ph value etc. are slow Electuary.In one embodiment, buffer agent is the sodium acetate buffer that ph value is about 4.5 to about 6.5.In one embodiment, Buffer agent be ph value be about 5.0 to about 8.0 or about 5.5 to about 7.0 sodium citrate buffer agent.

In an alternative embodiment, buffer agent used is three (hydroxymethyl) aminomethane in alkalescence ph value, carbon Sour hydrogen salt, carbonate or phosphate.In one embodiment, buffer agent be ph value be about 6.5 to about 8.5 or about 7.0 to about 8.0 sodium bicarbonate buffer agent.In another embodiment, buffer agent is the disodium hydrogen phosphate buffering that ph value is about 6.0 to about 9.0 Agent.

The control release composite that comprise ear sensory cell regulator and viscosity intensifier or device are also described.Only lift For example, suitable viscosity intensifier includes gellant and suspending agent.In one embodiment, the enhanced composite of viscosity does not wrap Include buffer agent.In other embodiments, the enhanced composite of viscosity includes pharmaceutically acceptable buffer agent.If necessary, appoint Choosing adjusts tension force using sodium chloride or other tonicity agents.

Only for example, the acceptable viscosity agent of ear includes hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyethylene pyrrole Pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, hyaluronate sodium.Other compatible with target ear structure is glued Degree reinforcing agent includes but is not limited to arabic gum, agar, Magnesiumaluminumsilicate, sodium alginate, sodium stearate, Fucus Vesiculosus (bladderwrack), swollen soil, Carbomer, carrageenan, carbopol (carbopol), xanthan gum, cellulose, Microcrystalline Cellulose (mcc), algaroba (ceratonia), chitin, carboxy methylation poly- Fructus Vitis viniferae amine sugar, chondrus ocellatus Holmes (chondrus), dextrose, red Algin (furcellaran), gelatin, gum ghatti (ghatti gum), guar gum, hectorite (hectorite), Lactose, sugarcane Sugar, maltodextrin, Mannitol, Sorbitol, Mel, corn starch, wheaten starch, rice starch, potato starch, gelatin, Hog gum (sterculia gum), xanthan gum, tragacanth, ethyl cellulose, ethylhydroxyethylcellulose, ethyl-methyl fiber Element, methylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, poly- (hydroxyethyl methacrylate second Ester), oxypolygelatin (oxypolygelatin), pectin, polygeline (polygeline), polyvidone, propylene carbonate, first Base vinyl ether/maleic anhydride copolymer (pvm/ma), poly- (methoxyethyl methacrylate), poly- (methyl methacrylate Epoxide ethoxyethyl group ester), hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hpmc), sodium carboxymethyl cellulose (cmc), two Silicon oxide, Polyvinylpyrrolidone (pvp: polyvidone),(dextrose, maltodextrin and Sucralose) or its group Close.In a particular embodiment, viscosity strengthens excipient is mcc and the combining of cmc.In another embodiment, viscosity intensifier is Carboxymethyl chitosan or chitin are combined with alginate.Chitin and alginate and ear sensory cell disclosed herein The combination of regulator is worked with control release formulation, limits ear sensory cell regulator and spreads from composite.This Outward, optionally employ combining to help to increase that ear sensory cell regulator passes through round window membrane of Carboxymethyl chitosan and alginate Permeability.

Some embodiments are the enhanced composites of viscosity, comprise about 0.1mm and about 100mm ear sensory cell regulator, Pharmaceutically acceptable viscosity agent and water for injection, concentration in water for the viscosity agent be enough to provide final viscosity be about 100 to The enhanced composite of viscosity of about 100,000cp.In certain embodiments, the viscosity of gel about 100 to about 50,000cp, about 100cp to about 1,000cp, about 500cp are to about 1500cp, about 1000cp to about 3000cp, about 2000cp to about 8,000cp, about 4,000cp to about 50,000cp, about 10,000cp are to about 500,000cp, about 15,000cp to the scope of about 1,000,000cp Interior.In other embodiments, when needing even more tacky medium, biocompatible gel comprises by weight at least about 35%th, at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75% or even at least about 80% is left Right ear sensory cell regulator.In the sample of high enrichment, biocompatible viscosity strengthens composite and comprises by weight At least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85%, At least about 90% or at least about 95% or more than 95% ear sensory cell regulator.

In certain embodiments, the viscosity of the gel composite of this paper presentation is measured by the mode of any description.Citing comes Say, in certain embodiments, calculate gel as herein described using lvdv-ii+cp cone and plate viscometer and axis of cone formula cpe-40 The viscosity of composite.In other embodiments, fly (brookfield) (shaft type and cup type) viscometer using rich power to calculate herein The viscosity of described gel composite.In certain embodiments, the range of viscosities being mentioned above is to measure at room temperature.In other In embodiment, the range of viscosities being mentioned above is measurement under body temperature (mean body temperature of such as healthy human).

In one embodiment, the acceptable composite of the enhanced ear of pharmaceutically acceptable viscosity comprises at least one Ear sensory cell regulator and at least one gellant.Suitable gellant for preparing gel composite includes but is not limited to Cellulose, cellulose derivative, cellulose ether (such as carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylol Cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, Sargassum Hydrochlorate (such as alginic acid), silicate, starch, tragacanth, carboxy vinyl polymer, carrageenan, paraffin, vaseline and it is any Combination or mixture.In some other embodiments, using hydroxypropyl methyl cellulose, (how elegant U.S.A is) conduct Gellant.In certain embodiments, also by the use of viscosity intensifier as herein described as the glue of the gel composite of this paper presentation Solidifying agent.

In certain embodiments, ear treatments agent disclosed herein is distributed with ear acceptable varnish form.As this paper institute Use, varnish (also referred to as film former) is to comprise solvent, monomer or polymer, activating agent and one or more optional doctors The solution of pharmaceutically acceptable excipient.After being applied to tissue, solvent evaporates, and stays and comprises monomer or polymer and activating agent Shallow layer.Coating protection activity agent and it is maintained site of administration with stationary state.This measure can reduce the work of possible loss Property agent amount and accordingly increase pass to individuality amount.As non-limiting examples, varnish includes collodion (for example elastic Pyroxylin Glue, usp) and comprise the solution of saccharide silicone copolymers and cross-linking agent.Collodion is containing Pyroxylin (nitrocellulose) Ether/ethanol solution.After administration, ether/ethanol solution evaporation, leave Pyroxylin thin film.Comprising saccharide silicone copolymers In solution, saccharide silicone copolymers form coating after solvent evaporates and causes the crosslinking of saccharide silicone copolymers.With regard to applying Other disclosure of agent, referring to Lei Mingdun: pharmaceutical science and put into practice (remington:the science and practice Of pharmacy), it is incorporated herein with regard to the content of this theme.Cover varnish used herein be elasticity with It is caused to pass through ear to propagate without interference with pressure wave.In addition, varnish can be with liquid (that is, solution, suspension or emulsion), semisolid (that is, gel, foams, pastel or jelly) or aerosol form are applied.

In certain embodiments, ear treatments agent disclosed herein is distributed with control release foam forms.It is applied to this Compositionss disclosed in literary composition the example of foamed supporting agent can include but is not limited to alginic acid and its derivant, carboxymethyl cellulose (include such as glucosan, glucan derivative, pectin, starch, modified starch with its derivant, collagen protein, polysaccharide, such as There is extra carboxyl and/or amide groups and/or the starch with hydrophilic side-chains), cellulose and its derivant, agar and its spread out Biological (such as through agar that polyacrylamide is amine stabilized), polyethylene glycol oxide, methacrylic acid glycol ester, gelatin, glue are (such as yellow Virgin rubber (xanthum gum), guar gum (guar gum), karaya (karaya gum), gellan gum (gellan gum), Arabic gum (arabic gum), tragacanth and locust bean gum) or a combination thereof.It is also desirable to the salt of aforementioned supporting agent, for example Sodium alginate.Composite optionally additionally comprises foaming agent, and it promotes foams to be formed, including surfactant or external propulsion Agent (external propellant).The example of suitable foaming agent includes cetrimonium bromide (cetrimide), lecithin, fertilizer Soap, silicone etc..Such asBe also suitable etc. the surfactant that can certainly buy on the market.

In certain embodiments, depending on specific ear sensory cell regulator, other medical agents used or excipient/add Plus agent, other gel composites are also suitable, thus are considered as within the scope of the invention.For example, it is contemplated that it is other commercially available The gel of compound, combination or crosslinking, substrate, hydrogel and polymer and gelatin derived from gel based on glycerol, glycerol Spread out with its derivant, alginate and the gel based on alginate and even various natural and synthesis hydrogel and hydrogel Raw compound is all be applied to ear sensory cell regulator composite as herein described.In certain embodiments, ear can connect The gel being subject to includes but is not limited to alginate hydrogelGel (rehabilitation treasured (convatec), the general woods in New Jersey Si Dun (princeton, n.j.))；Hydrogel (rehabilitation treasured (convatec)),(Johnson ＆ Johnson's medical science (johnson＆johnson medical), Texas Arlington (arlington, tex.))；(v) vinegar Meng Southern hydrogel (acemannan hydrogel) (Ka Lingdun Laboratories, Inc (carrington laboratories, inc.), Texas Irving (irving, tex.))；GlycerogelHydrogel (Switzerland-product company of the U.S. (swiss- American products, inc.), Dallas, Texas (dallas, tex.)) and aseptic(Johson ＆ Johnson (johnson&johnson)).In other embodiments, biodegradable biocompatibility gel is also represented by being present in herein Compound in the acceptable composite of ear of disclosure and description.

It is developed for mammal dispensing and the composite for the formulated compositionss for mankind's dispensing at some In, the acceptable gel of ear accounts for the substantially whole of composition weight.In other embodiments, the acceptable gel of ear accounts for combination Thing be up to about 98 weight % or about 99 weight %.When need substantially nonfluid or during the substantially composite of viscosity it is desirable to So.In another embodiment, when the ear needing viscosity smaller or mobility is bigger acceptable medicine gel composite, adjust The biocompatibility gel section joining thing accounts at least about 50 weight % of compound, at least about 60 weight %, at least about 70 weights Amount % or even at least about 80 weight % or 90 weight %.Cover all intermediate integer in the range of these all in the model of this case In enclosing, and in some alternative embodiments, bigger (thus viscosity is less) the acceptable gel combination of ear of allotment mobility, The gel of such as mixture or matrix components account for no more than about 50 weight %, no more than about 40 weight %, no more than about 30 weights The compositionss of amount %, or even account for no more than about 15 weight % or the compositionss of about 20 weight %.

The acceptable suspending agent of ear

In one embodiment, pharmaceutically acceptable viscosity strengthens composite and includes at least one ear sensory cell tune Section agent, wherein said composite additionally comprises at least one suspending agent, and wherein said suspending agent helps give composite controlled-release is released Put feature.In certain embodiments, suspending agent is additionally operable to increase ear acceptable ear sensory cell regulation composite and compositionss Viscosity.

Only for example, suspending agent includes following compound, such as Polyvinylpyrrolidone, such as Polyvinylpyrrolidone K12, PVP k17, Polyvinylpyrrolidone k25 or Polyvinylpyrrolidone k30；Vinyl pyrrolidone/second Vinyl acetate copolymer (s630)；Sodium carboxymethyl cellulose；Methylcellulose；Hydroxypropyl methyl cellulose (hypromellose Element)；Stearic acid acetic acid hydroxymethyl cellulose；Polyoxyethylene Sorbitan Monooleate；Hydroxyethyl cellulose；Sodium alginate；Glue, such as tragacanth With Radix Acaciae senegalis, guar gum；Xanthan gum class, including xanthan gum；Sugar；Cellulosic plastics, such as sodium carboxymethyl cellulose, methyl Cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, Polyoxyethylene Sorbitan Monooleate, sodium alginate, poly- Ethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, polyvidone etc..Real at some Apply in example, applicable waterborne suspension also contains one or more polymer as suspending agent.Applicable polymer includes Water-soluble polymer, such as cellulosic polymer, such as hydroxypropyl methyl cellulose；And insoluble polymer, such as crosslinked Carbonyl bearing polymer.

In one embodiment, the present invention is provided in comprise the ear sensory cell of therapeutically effective amount in hydroxyethylcellulose gel The acceptable gel combination of ear of regulator.Obtain hydroxyethyl cellulose (hec) in dry powdered form, it is in water or aqueous buffered Restore in solution that (typically about 200cps to about 30,000cps, corresponding to about 0.2 to about 10% to obtain the viscosity wanted hec).In one embodiment, the concentration of hec is between about 1% and about 15%, between about 1% and about 2%, or about 1.5% with about Between 2%.

In other embodiments, in addition the acceptable composite of ear strengthening composite including gel composite and viscosity wraps Include excipient, other medical science or medical agent, supporting agent, adjuvant, such as preservative, stabilizer, wetting agent or emulsifying agent, dissolving promote Agent, salt, solubilizing agent, defoamer, antioxidant, dispersant, wetting agent, surfactant or a combination thereof.

Ear acceptable actinic radiation curable gel

In other embodiments, gel is actinic radiation curable gel, thus cast in target ear structure or nearby after, Form the gelling properties wanted using actinic radiation (or light, including ultraviolet light, visible or infrared light).Only for example, make There is provided actinic radiation with optical fiber to form the gelling properties wanted.In certain embodiments, optical fiber and gel cast device and are formed Individual unit.In other embodiments, optical fiber and gel cast device and are provided separately.

The acceptable solvent of ear discharges gel

In certain embodiments, gel is solvent release gel, so that the gelling properties wanted are casting target ear structure In or nearby after formed, it is when the solvent diffuse in the gel composite of injection goes out gel, is formed to have and wants gel The gel of property.For example, comprise sucrose acetate isobutyrate, pharmaceutically acceptable solvent, one or more The composite of additive and ear sensory cell regulator casts on or near round window membrane: the composite that solvent diffuse goes out injection carries For having the bank wanting gelling properties.For example, using water-soluble solvent, when solvent quickly diffuses out the composite of injection When provide high viscosity bank.On the other hand, provide the less bank of viscosity using hydrophobic solvent (such as benzyl benzoate).Ear The example that acceptable solvent discharges gel composite is that Durect Corp. (durect corporation) sells saber^tmTransmission system.

Ear is acceptable to be formed in situ spongy material

It is also contemplated by the range of embodiment using the spongy material being formed in situ in internal ear or middle ear.In some enforcements In example, spongy material is formed by hyaluronic acid or derivatives thereof.Spongy material is soaked with the ear sensory cell regulator wanted And be placed into middle in ear with control release ear sensory cell regulator in middle in ear, or contact placement with round window membrane with control release Ear sensory cell regulator is to interior in ear.In certain embodiments, spongy material is biodegradable.

Round window membrane mucomembranous adhesion agent

It is also contemplated by scope of embodiments in ear sensory cell regulator composite disclosed herein and compositionss and device Add round window membrane mucomembranous adhesion agent.It is biomembranous that term ' mucosal adhesive ' is incorporated into adventitia of three layers of round window membrane etc. for finger The material of mucin layer.It is as round window membrane Mucoadhesive polymers, polymer has some general physiochemical characteristics, such as Anionic hydrophilic is dominant and many hydrogen bonds form group, are suitable to the surface nature of moistening mucus/mucosal tissue surfaces or be enough to The motility of infiltration mucus network.

The round window membrane mucomembranous adhesion agent that acceptable composite is used together with ear includes but is not limited at least one can Dissolubility polyvinyl pyrrolidone polymers (pvp)；Water inflatable but water-fast threadiness crosslinked carboxy functional-type polymer； Crosslinking poly- (acrylic acid) is (for example947p)；Carbomer homopolymer；Carbomer copolymer；Hy-drophilic polysaccharide glue, wheat Bud magma essence, cross-linked alginate glue gel, water-dispersible poly- carboxylated vinyl polymer, at least two be selected from dioxy Change the grain fraction of group or its mixture of titanium, silicon dioxide and clay composition.Round window membrane mucomembranous adhesion agent is optionally and ear can The viscosity accepting increases excipient composition and uses, or is used alone to increase the mutual of composite and mucous layer target ear assembly Effect.In non-limiting examples, mucomembranous adhesion agent is maltodextrin.In certain embodiments, mucomembranous adhesion agent is Alginate glue.When deployed, the round window membrane mucomembranous adhesion agent feature giving compositionss is in the ear sense enough to transmit effective dose Feel that cell modulator compositionss reach the amount of coating mucosa and hereafter transmit compositionss to the mucous layer of such as round window membrane or crest of fenestra cochleae Level to involved area (only for example, including vestibulum auris internae and/or cochlear structures).When deployed, determine and carry herein For compositionss mucoadhesive characteristics, and using this information (and provided herein other teaching), determine suitable amount. A kind of method determining enough mucosal adhesives includes monitoring the change that compositionss are interacted with mucous layer, including (but do not limit In) measurement compositionss retain in the case of the absence and presence of mucosal adhesive excipient or the holdup time change.

Mucomembranous adhesion agent have been described in for example U.S. Patent No. 6,638,521, No. 6,562,363, the 6,509,028th Number, the 6th, 348, No. 502, the 6th, 319, No. 513, the 6th, 306, No. 789, in the 5th, 814, No. 330 and the 4th, 900, No. 552, Its respective disclosure is incorporated herein by reference.

In another non-limiting examples, mucomembranous adhesion agent be for example, at least two be selected from titanium dioxide, silicon dioxide and In addition the grain fraction of clay, wherein compositionss did not used any liquid diluting before casting, and in the presence of silicon dioxide, level For compositionss about 3 weight % to about 15 weight %.Smoke-like silicon dioxide, precipitated silica is included in the presence of silicon dioxide Silicon, reunion silicon dioxide, gel silicas and its mixture.Kaolin mineral, serpentine minerals, illiteracy is included in the presence of clay De- stone, illite or its mixture.For example, clay include lithium diatomaceous earth (laponite), bentonite, Strese Hofmann's hectorite., saponite, Montmorillonite or its mixture.

In non-limiting examples, round window membrane mucomembranous adhesion agent is maltodextrin.Maltodextrin is by water Solution optionally derives from Semen Maydiss, the carbohydrate produced by starch of Rhizoma Solani tuber osi, Semen Tritici aestivi or other plant product.Maltodextrin Optionally it is used alone or is applied in combination with other round window membrane mucomembranous adhesion agents so that compositions disclosed herein has mucosa and glues Attached feature.In one embodiment, to increase combination disclosed herein using maltodextrin with combining of carbopol polymer The round window membrane mucoadhesive characteristics of thing or device.

In another embodiment, round window membrane mucomembranous adhesion agent is alkyl-glucosides and/or sugared Arrcostab.As used herein " alkyl-glucosides " meaning be compound comprise any hydrophilic being connected to hydrophobic alkyl sugar (such as sucrose, maltose or Glucose).In certain embodiments, round window membrane mucomembranous adhesion agent is alkyl-glucosides, and wherein alkyl-glucosides comprises sugar via acyl Amine key, amine key, amino-formate bond, ehter bond, thioether bond, ester bond, thioester bond, glycosidic bond, thiosugar glycosidic bond and/or uride are bonded In hydrophobic alkyl (for example comprising the alkyl of about 6 to about 25 carbon atoms).In certain embodiments, round window membrane mucomembranous adhesion agent Be hexyl-, heptyl-, octyl group-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, myristyl-, 15 Alkyl-, cetyl-, heptadecyl-and octadecyl α-or β-d- maltoside；Hexyl-, heptyl-, octyl group-, nonyl-, Decyl-, undecyl-, dodecyl-, tridecyl-, myristyl-, pentadecyl-, cetyl-, heptadecyl-and Octadecyl α-or β-d- glucoside；Hexyl-, heptyl-, octyl group-, nonyl-, decyl-, undecyl-, dodecyl-, 13 Alkyl-, myristyl-, pentadecyl-, cetyl-, heptadecyl-and octadecyl α-or β-d- sucrose glycosides；Hexyl-, Heptyl-, octyl group-, dodecyl-, tridecyl-and the thio maltoside of myristyl-β-d-；Lauryl.beta.-maltoside； Heptyl-or the thio-α-of octyl group -1- or β-d- pyranglucoside；Alkyl thiosucrose glycosides；Alkyl maltotriosides；Sucrose β- The long-chain fat race carbonic acid amide of amino alkyl ether；Isomaltulose (palatinose) or Isomalt amine (isomaltamine) It is connected to the derivant of alkyl chain via amido link and Isomalt amine is connected to the derivant of alkyl chain via urea；Sucrose β-ammonia The long-chain fat race carbonic acid uride of base-alkyl ether and the long-chain fat race carbonic acid amide of sucrose beta-amino-alkyl ether.Real at some Apply in example, round window membrane mucomembranous adhesion agent is alkyl-glucosides, wherein alkyl polyglucoside is maltose, sucrose, glucose or a combination thereof warp Be connected to by glycosidic bond have 9-16 carbon atom alkyl chain (for example nonyl-, decyl-, dodecyl-and myristyl sugarcane Glucosides；Nonyl-, decyl-, dodecyl-and myristyl glucoside；With nonyl-, decyl-, dodecyl-and myristyl Maltoside).In certain embodiments, round window membrane mucomembranous adhesion agent is alkyl-glucosides, and wherein alkyl polyglucoside is dodecyl wheat Bud glucosides, tridecyl maltoside and TDM.

In certain embodiments, round window membrane mucomembranous adhesion agent is alkyl polyglucoside, and wherein alkyl polyglucoside is containing at least one Portugal The disaccharide of grape sugar.In certain embodiments, the acceptable penetration enhancers of ear are to comprise alpha-d-galactopy glucoside-β-pyrans Portugal Glucosides, dodecyl -4-o- alpha-d-galactopy glucoside-β-glycopyranoside and/or n-tetradecane base -4-o- alpha-d-galactopy The surfactant of glucoside-β-glycopyranoside.In certain embodiments, round window membrane mucomembranous adhesion agent is alkyl-glucosides, Wherein critical micelle concentration (cmc) in pure water or aqueous solution for the alkyl-glucosides is less than about 1mm.In certain embodiments, oeil de boeuf Film mucomembranous adhesion agent is alkyl-glucosides, and wherein the oxygen atom in alkyl-glucosides replaces through sulphur atom.In certain embodiments, circle Fenestrated membrane mucomembranous adhesion agent is alkyl-glucosides, and wherein alkyl polyglucoside is β-anomer.In certain embodiments, round window membrane mucosa glues Attached dose is alkyl-glucosides, wherein alkyl polyglucoside comprise 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%th, 99.1%, 99.5% or 99.9% β-anomer.

Ear acceptable control release particle

Ear sensory cell regulator disclosed herein and/or other medical agent are optionally incorporated in enhancing or promote ear sensation The control release particle of the localized delivery of cell modulator, lipid complex, liposome, nanoparticle, microgranule, microsphere, group In aggressiveness, Nano capsule or other medicament.In certain embodiments, using the list that there is at least one ear sensory cell regulator Individual viscosity strengthens composite, and in other embodiments, comprises two kinds using there is at least one ear sensory cell regulator Or two or more different viscosity strengthens the pharmaceutical formulation of the mixture of composite.In certain embodiments, also adopt colloidal sol, Gel and/or biocompatible substrate be combined to provide wanting of control release ear sensory cell regulating composition or composite Feature.In certain embodiments, control release ear sensory cell regulator composite or compositionss are tried through one or more Agent crosslinking is to be altered or modified the property of compositionss.

The example of the microsphere related to pharmaceutical formulation disclosed herein includes: Lu Qi l.a. (luzzi, l.a.), medicine Learn Journal of Psychology (j.pharm.psy.) 59:1367 (1970)；U.S. Patent No. 4,530,840；Louis d.h. (lewis, d.h.), " control release (controlled release from lactide/glycolides polymer for the bioactivator Of bioactive agents from lactides/glycolide polymers) ", as the biology of drug delivery system Degradable polymer (biodegradable polymers as drug delivery systems), look into pungent m. (chasin, M.) compile with bright lattice r. (langer, r.), Marcel moral Kerr Corp (marcel decker) (1990)；U.S. Patent No. 4, No. 675,189；Bake (beck) et al., " poly- (lactic acid) and poly- (lactic-co-glycolic acid) contraception transmission system (poly (lactic acid)and poly(lactic acid-co-glycolic acid)contraceptive delivery ) ", systems long-acting steroids contraceptive method (long acting steroid contraception), meter Xie Er d.r. (mishell, d.r.) compiles, Lai Wen publishing house (raven press) (1983)；U.S. Patent No. 4,758,435；United States Patent (USP) No. 3,773,919；U.S. Patent No. 4,474,572.The example being deployed into the protein therapeutic agent of microsphere includes: the U.S. Patent the 6,458,387th；U.S. Patent No. 6,268,053；U.S. Patent No. 6,090,925；U.S. Patent No. 5, No. 981,719；With U.S. Patent No. 5,578,709, and its disclosure is incorporated herein by reference.

Although microsphere generally has spherical, erose microgranule is also possible to.The variable dimension of microsphere, Diameter is from submicron to 1000 microns.Being suitable to the microsphere that acceptable composite is used together with ear disclosed herein is sub-micro Rice is to the microsphere of 250 micron diameters, thus allowing to offer medicine by being injected with standard model pin.The acceptable microsphere of ear by Manufacture size range by any method preparation using the microsphere being accepted in Injectable composition.Optionally with for throwing The standard model pin of fluid composition is given to inject.

Suitable example for the matrix material in the ear acceptable control release particle of this paper includes poly- (second Alkyd), poly- d, l- lactic acid, poly- l- lactic acid, the copolymer of foregoing, poly- (aliphatic carboxylic acid), copolymerized oxalate, in poly- caproic acid Ester, polydioxanone (polydioxonene), poly- (orthocarbonic ester), poly- (acetal), poly- (lactic acid-caprol acton), poly- former Acid esters, poly- (glycolic-caprolactone), polydioxanone, condensing model, poly- phosphorus piperazine (polyphosphazine) and natural poly- Compound, including albumin, casein and some waxes (glyceryl monostearate and glycerol distearate) etc..Various can from The PLG material (plga) buied on the market is optionally in method disclosed herein.Citing comes Say, poly- (d, l- lactic-co-glycolic acid) can be from Boehringer Ingelheim company (boehringer-ingelheim) with resomer Rg 503h buys.The molar percentage of this product consists of 50% lactide and 50% Acetic acid, hydroxy-, bimol. cyclic ester.Wide scope molecule can be obtained Amount and these copolymers of lactic acid and glycolic ratio.One embodiment is included using polymer poly (d, l- lactide-co-second Lactide).In this analog copolymer, lactide and the molar ratio of Acetic acid, hydroxy-, bimol. cyclic ester include about 95:5 to the scope of about 50:50.

The molecular weight of matrix material has certain importance.Molecular weight is sufficiently high satisfactory being formed Polymer coating, that is, polymer should be good film former.Gratifying molecular weight is generally in 5,000 to 500,000 roads In the range of you pause.From the viewpoint of molecular weight can affect polymer biodegradation speed, the molecular weight of polymer is also critically important. For the diffusion mechanism of drug release, polymer should be still complete in all medicines before microgranule release, then degrades.When During polymeric excipient biological corrosion, medicine also discharges from microgranule.By suitable selective polymer material, can prepare a kind of micro- Spheroid composite is so that thus obtained microsphere body represents dispersal events and biodegradation releasing properties.This be applied to obtain multiphase release mould Formula.

Known multiple method compound being encapsulated in microsphere.In these methods, agitator, stirring are generally used Machine or other kinetics hybrid technology by the dispersion of ear sensory cell regulator or are emulsifiable in the solvent containing wall-forming materials.Then Remove solvent from microsphere, obtain thereafter microsphere product.

In one embodiment, control release ear sensory cell regulator composite passes through in ethylene-vinyl acetate copolymer In substrate and pleasant sensory cell regulator and/or other medical agent are preparing.(referring to U.S. Patent No. 6,083,534, its Disclosure is incorporated herein).In another embodiment, ear sensory cell regulator is incorporated to poly- (lactic acid-ethanol) or poly- l- In lactic acid microspheres body.Id. in another embodiment, ear sensory cell regulator is encapsulated in alginic acid ester microsphere.(referring to U.S. State's patent the 6th, 036,978, its disclosure is incorporated herein).It is encapsulated ear sensory cell and adjust immunomodulator compounds or compositionss The polymer based on biocompatibility methacrylate optionally in composite disclosed herein and method.Multiple bases Polymer system in methacrylate can be from buying, such as with the eudragit polymer of evonik sale on the market.First One of base acrylate polymer is suitable for the property that aspect is composite and changes because being incorporated to various co-polymers.Citing comes Say, the property of poly- (acrylic acid -co- methyl methacrylate) microgranule mucosal adhesive strengthens, because the carboxyl in poly- (acrylic acid) Form hydrogen bond (Parker (park) et al., pharmaceutical research (pharm.res.), (1987) 4 (6): 457-464) with mucin.Become Change the property that the ratio between acrylic acid and methyl methacrylate monomer can be used for telocopolymerization thing.Based on methacrylic acid The microgranule of ester is additionally operable in protein therapeutic composite (Na Ha (naha) et al., microencapsulation magazine (journal of ), microencapsulation 2008 2 months 4 days (disclosing online)).In one embodiment, viscosity described herein strengthens ear Acceptable composite comprises ear sensory cell regulator microsphere, wherein said microsphere by methacrylate polymers or Copolymer is formed.In another embodiment, viscosity enhancing composite described herein comprises ear sensory cell regulator microsphere, Wherein microsphere has mucosa-adherent.Also clearly cover other controlled release durg delivery systems in embodiment disclosed herein, including It is incorporated to or deposited polymer material or substrate on solid containing ear sensory cell regulator or hollow ball.Available ear sense Feel that the type of the not notable controlled release durg delivery system lost of cell modulator activity uses teaching disclosed herein, example and principle Determine.

One example of the conventional micro capsule method of pharmaceutical preparation is shown in U.S. Patent No. 3,737,337, and it discloses interior Appearance is incorporated herein by reference.Using conventional mixer, including (when prepared by dispersion liquid) vibrator and high-speed stirred Device etc., the ear sensory cell regulator material being encapsulated waiting or embedding is dissolved or dispersed in the organic solution of polymer (a phase). Reuse conventional mixer, such as super mixer, vibromixer or even spray nozzle, dispersion in aqueous phase (b) contains In solution state or suspended state core material phase (a), in the case, the granularity of microsphere will be not only by phase (a) Concentration and to be determined by emulsion or sized micro-spheres.Using the conventional method of microencapsulation ear sensory cell regulator, when logical Cross stirring, agitation, vibration or other kinetics hybrid technology, generally after one relatively long time, activating agent will be contained With the solvent emulsion of polymer or when being scattered in immiscible solution, form microsphere.

The building method of microsphere is also described in U.S. Patent No. 4,389,330 and U.S. Patent No. 4,530,840 In, its disclosure is incorporated herein by reference.The ear wanted sensory cell regulator is dissolved or dispersed in suitably Solvent in.The matrix material being added in the medium containing medicament can give product with respect to the amount of active component and think The active agent load wanted.Optionally, all the components of ear sensory cell regulator microsphere product can be blended together in solvent In medium.The suitable solvent of energy pharmaceutical dissolution and matrix material includes organic solvent, such as acetone, halogenated hydrocarbons (such as Chloroform, dichloromethane etc.), aromatic hydrocarbon compound, halogenated aromatic hydrocarbon compound, cyclic ether, alcohol, ethyl acetate etc..

Mixture in solvent for each composition of emulsifying in continuous phase machining medium；Described continuous phase medium makes continuous Form the microdroplet dispersion containing instruction composition in phase medium.Certainly, continuous phase machining medium and the necessary unmixing of organic solvent, And inclusion water, but optionally using the non-aqueous medias such as dimethylbenzene and toluene and artificial oil and natural oil.Optionally, Xiang Lian Surfactant is added to prevent the size of solvent microdroplet in particle coagulation and control emulsion in continuous phase machining medium.Preferably table Face activating agent disperse medium combination is the mixture of 1 to 10 weight % poly- (vinyl alcohol) Yu Shuizhong.Dispersion liquid passes through mechanical agitation The material of mixing is formed.Emulsion carrys out shape optionally by the addition droplet activating agent wall-forming materials solution in continuous phase machining medium Become.Although the temperature during emulsion is formed is not particular importance, the size of its impact microsphere and quality and medicine are even Dissolubility in continuous phase.Wish that there is in continuous phase medicament as few as possible.Additionally, regarding the solvent adopting and continuous phase processing Jie Depending on matter, temperature can not be too low, and otherwise solvent and machining medium will solidify, or from the point of view of practical purpose, machining medium will become Too sticky, or temperature can not be too high, otherwise machining medium will evaporate or liquid machining medium can not maintain.Additionally, medium temperature Can not too high so that negatively affecting the stability of the particular agent being incorporated in microsphere.Therefore, dispersive process is in any maintenance Carry out at a temperature of steady operation conditions, preferable temperature is about 15 DEG C to 60 DEG C, depending on selected medicine and excipient.

The dispersion liquid being formed is stable emulsion, and in the first step of solvent removal process, optionally from this point Organic solvent immiscible liquids is partly removed in dispersion liquid.Made a return journey using technology such as heating, applying decompression or a combination of both Except solvent.Although for the temperature of evaporation solvent is unimportant from microdroplet, should not be so high as to the set microgranule system so that it is degraded Ear sensory cell regulator employed in standby, also should not high obtain so that evaporation rate of solvent is too soon thus produce in wall-forming materials Raw defect.In general, remove 5% to 75% solvent in the first solvent removal step.

After first stage, separated in solvent Immiscible fluid medium from fluid media (medium) using any easily separation method Disperse particleses.So that it takes up a position, for example, being decanted fluid from microsphere or filtering microsphere suspension.In addition, it is necessary to when, make Various combinations with isolation technics.

After separating microsphere from continuous phase machining medium, the residual solvent in microsphere is removed by extraction.At this In step, microsphere is suspended in same continuous phase machining medium (with or without surfactant) or another used in step 1 In liquid.Spe medium removes solvent but insoluble microsphere from microsphere.During extraction, optionally remove and be dissolved with solvent Spe medium and with fresh spe medium displacement.This measure is preferably constantly carried out.The spe medium of established methodology supplements speed The variable of determination when methods described is carried out, therefore need not predefine the exact boundary of described speed.Most of solvents from After removing in microsphere, by being exposed in the air or passing through other conventional drying technique (such as vacuum drying, desiccant dryness Deng) dry microspheres body.This method is highly effective to being encapsulated ear sensory cell regulator, because obtaining up to 80 weight %, excellent The core load of choosing up to 60 weight %.

Or, prepare the Microspheres body containing ear sensory cell regulator by using static mixer.Static Or motionless blender is made up of the pipeline or pipe receiving multiple static mixing agent.Static mixer is in the pipeline of relatively short length Uniformly mix with providing in the relatively short time.With static mixer, enable flow across blender rather than blender certain A part of (such as blade) is moved through fluid.

Optionally form emulsion using static mixer.When forming emulsion using static mixer, a number of factors determines Emulsion particle diameter, interfacial tension between the density including various solution to be mixed or phase and viscosity, the volume ratio of each phase, phase, Static mixer parameter (pipe diameter；The length of hybrid element；The number of hybrid element) and by the linear speed of static mixer Degree.Temperature is variable, because its impact density, viscosity and interfacial tension.Control variable is that linear velocity, shear rate and unit are long The pressure drop of degree static mixer

It is to form the microsphere containing ear sensory cell regulator, combination organic faciess and water using static mixer method Phase.Organic faciess and aqueous phase to a great extent or substantially unmixing, wherein aqueous phase constitutes the continuous phase of emulsion.Organic faciess include Ear sensory cell regulator and wall-forming polymer or matrix material.By ear sensory cell regulator has been dissolved in Being prepared in machine solvent or other solvent being suitable for or by the dispersion liquid containing ear sensory cell regulator for the formation or emulsion is had Machine phase.Pumping organic faciess and aqueous phase, so that biphase simultaneously flow through static mixer, are consequently formed and comprise to adjust containing ear sensory cell Section agent is encapsulated in the emulsion of the microsphere in matrix material.Pumping organic faciess and aqueous phase flow through static mixer and enter greatly To extract or to remove organic solvent in amount coolant (quench liquid).From microsphere, optionally remove organic solvent, with When in coolant wash or stirring microsphere.After microsphere washs in the coolant, sieving separating, and be dried.

In one embodiment, prepare microsphere using static mixer.Although this method is not limited to discussed above molten Liquid abstraction technique, but be used together with other Encapsulation techniques.For example, this method optionally with separated Encapsulation techniques one Rise and use.For realizing this measure, prepare the organic faciess of the ear sensory cell regulator comprising to be suspended or dispersed in polymer solution. Non-solvent second does not mutually contain the solvent that can dissolve polymer and activating agent.Preferably non-solvent second is mutually silicone oil.By static mixed Organic faciess and non-solvent are mutually pumped in the non-solvent coolant such as heptane clutch.The semi-solid particle of cooling is with fully hardened And washing.Microencapsulation includes spray drying, the combination of solvent evaporation, evaporation and extraction and melt extrudes.

In another embodiment, microencapsulation is directed to use with the static mixer using single solvent.This method is retouched in detail It is set forth in U. S. application case the 08/338th, 805, its described disclosure is incorporated herein by reference.Another replacement Method is directed to use with the static mixer using cosolvent.In this process, preparation comprises biodegradable polymeric adhesive Agent and the biodegradable microspheres of ear sensory cell regulator, it comprises the no halogenated hydrocarbons of at least two substantially innoxious solvents Admixture is with pharmaceutical dissolution and polymer.The solvent blends of the medicament containing dissolving and polymer are scattered in aqueous solution with shape Become drop.Then gained emulsion is added in the aqueous extraction medium preferably comprising at least one of described admixture solvent, by This controls the extraction yield of each solvent, thus forming the biodegradable microspheres containing medicine and pharmacology activating agent.This method excellent Point is to need less spe medium, because a kind of dissolubility in water for solvent is substantially unrelated with another solvent, and especially In the solvent using especially difficult extraction, solvent selectivity increases.

It is also contemplated by nanoparticle to be used together with ear sensory cell regulator disclosed herein.Nanoparticle is a size of about The material structure of 100nm or below 100nm.Nanoparticle is to form suspension in one of pharmaceutical formulation purposes, because Particle surface be enough to overcome density variation with the interaction of solvent.When can carry out aseptic filtration when nanoparticle is sufficiently small, To nanoparticle suspension sterilizing (for example, with reference to U.S. Patent No. 6,139,870, its described disclosure side to quote Formula is incorporated herein).Nanoparticle comprises at least one solution being emulsifiable in surfactant, phospholipid or fatty acid or aqueouss are divided Hydrophobicity in dispersion liquid, water-insoluble and water non-dispersible property polymer or copolymer.Optionally by ear sensory cell regulator It is concomitantly introduced in nanoparticle with polymer or copolymer.

It is also contemplated by herein penetrating round window membrane in control release structure simultaneously and reach internal ear and/or the lipid of middle ear target is received Rice glue capsule.Lipin nanometer capsule is optionally by emulsifying capric acid and Trivent OCG (labrafac wl 1349；Mean molecule Measure as 512), soybean lecithin (s75-3；69% phosphatidylcholine and other phospholipid), surfactant (for example Solutol hs15) mixture of free Polyethylene Glycol 660 (Polyethylene Glycol 660 hydroxy stearic acid ester with), nacl and water formed. Mixture is stirred at room temperature, obtains oil-in-water emulsion.After under magnetic stirring with the gradual heating of the speed of 4 DEG C/min, Close to 70 DEG C, the transparent of one section of short time interval should occur, the phase (Water-In-Oil drop) of reversion occurs when 85 DEG C.Then 85 DEG C and 60 DEG C between three coolings and heat cycles are applied with the speed of 4 DEG C/min, and in rapid dilution at a temperature of 0 DEG C In cold water, prepared Nano capsule suspension.For being encapsulated ear sensory cell regulator, described reagent optionally will use cold water Add before dilution.

It is made to insert also by cultivating ear sensory cell regulator together with the aqueous micellar solution of ear activating agent 90 minutes Enter in lipin nanometer capsule.Then so that suspension is vortexed, then cool down 1 minute in ice bath.

The acceptable surfactant of suitable ear is such as cholic acid or taurocholate.Taurocholic acid, by cholic acid and cattle The conjugate that sulfonic acid is formed, is the completely metabolizable sulfonate surfactants of one kind.Taurocholic acid analog, Tauroursodeoxycholic Acid Sour (tudca), be a kind of naturally occurring cholic acid and be taurine and ursodesoxycholic acid (udca) conjugate.Optionally use Other naturally occurring anion surfactants (such as sulphuric acid galactose brain glycosides), neutral surface active agent's (such as lactoside Base ceramide (lactosylceramide)) or zwitterionic surfactant (such as sphingomyelins, phosphatidylcholine, Petiolus Trachycarpi Acylcarnitine) prepare nanoparticle.

The acceptable phospholipid of ear is selected from for example natural, synthesis or semi-synthetic phospholipid；Lecithin (phosphatidylcholine) is such as pure Lecithin or soybean phospholipid (lecithin e100, lecithin e80 and phospholipon series, such as phospholipon90), PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, dipalmitoyl phosphatidyl choline, two palmityl phosphorus Phosphatidylcholine glyceride, dimyristoyl phosphatidyl choline, Distearoyl Phosphatidylcholine and phosphatidic acid, or more specifically using it Mixture.

For the acceptable composite of ear use fatty acid be selected from for example lauric acid, myristic acid, Palmic acid, stearic acid, Isostearic acid, arachidic acid, behenic acid, Oleic acid, nutmeg olefin(e) acid, palmitoleic acid, linoleic acid, α-linoleic acid, arachidonic acid, two Ten carbon 5 alkene acids, sinapic acid, docosahexenoic acid etc..

The acceptable surfactant of suitable ear is selected from known organic and inorganic pharmaceutical excipients.Described excipient bag Include various polymer, low-molecular-weight oligomer, natural product and surfactant.Preferred surface modifying agent include non-electrical release and Ionic surfactant.Two or more surface modifier is applied in combination.

The representative example of the acceptable surfactant of ear includes hexadecyl pyrrole ingot, gelatin, casein, lecithin Fat (phospholipid), glucosan, glycerol, arabic gum, cholesterol, tragacanth, stearic acid, calcium stearate, glyceryl monostearate, ten Eight hexadecanol, cetomacrogol emulsifying wax (cetomacrogol emulsifying wax), Isosorbide Dinitrate, polyoxyethylene alkane Base ether, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, bromination dodecyl trimethyl ammonium, Myrj 45, silica sol, phosphate ester, sodium lauryl sulphate, carboxymethylcellulose calcium, hydroxy propyl cellulose Plain (hpc, hpc-sl and hpc-l), hydroxymethyl cellulose (hpmc), sodium carboxymethyl cellulose, methylcellulose, hydroxy ethyl fiber Element, hydroxypropyl cellulose, Hydroxypropyl Methylcellulose Phathalate, amorphous cellulose, aluminium-magnesium silicate, triethanolamine, poly- second Enol (pva), Polyvinylpyrrolidone (pvp), 4- (1,1,3,3- tetramethyl butyl)-phenol and oxirane and formaldehyde poly- Compound (also referred to as tyloxapol (tyloxapol), scholar shellfish bright (superione) and triton (triton)), poloxamer, pool Lip river Husky amine (poloxamnine), a kind of charged phospholipids, such as two myristoyl phosphatidyl glycerol, sulfo-succinic acid dioctyl Ester (doss))；1508th, the dialkyl of sodium sulfo-succinate, duponol p, tritons x-200, Crodestas f-110, poly- to isononyl phenoxy group ((+)-2,3-Epoxy-1-propanol), crodestas sl-40 (standing grain major company (croda, inc.))；And sa90hco, it is c₁₈h₃₇ch₂(con(ch₃)-ch₂(choh)₄(ch₂oh)₂(Eastman Kodak Co (eastman kodak co.))；Capryl-n- methyl glucose amide；Positive decyl β-d- pyranglucoside；Positive decyl β-d- Pyrans maltoside；Dodecyl β-d- pyranglucoside；Dodecyl β-d- maltoside；Heptanoyl group-n- methyl Glucamide；N-heptyl-β-d- pyranglucoside；N-heptyl β-d- thioglycoside；N-hexyl β-d- Glucopyranose. Glycosides；Pelargonyl group-n- methyl glucose amide；N-nonyl β-d- pyranglucoside；Caprylyl-n- methyl glucose amide；N-octyl- β-d- pyranglucoside；Octyl group β-d- thioglucopyranoside etc..These surfactants most of are known medicine Excipient and be described in detail in pharmaceutical excipient handbook (handbook of pharmaceutical excipients), by U.S. State's medicine association (american pharmaceutical association) and Britain medicine and pharmacology meeting (pharmaceutical Society of great britain) combined publication (Pharmaceutical Press (pharmaceutical press), 1986), it is taken off Show that content is especially incorporated herein by reference.

Hydrophobicity, water-insoluble and the non-dispersible polymer of water or copolymer are selected from bio-compatible and biodegradable Polymer, such as lactic acid or glycolic acid polymer and its copolymer or polylactic acid/polyoxyethylene (or polyoxypropylene) copolymer (preferred molecular weight is between 1000 and 200,000), poly butyric polymer, containing at least fatty acid of 12 carbon atoms Polylactone or condensing model.

Nanoparticle can be certainly added with by reunion or solvent evaporation technique and comprise effective ingredient and hydrophobicity, water-insoluble The phospholipid of unmixing organic faciess of property polymer non-dispersible with water or copolymer and the aqueous liquid dispersion of oleate or solution obtain ?.Mixture described in pre-emulsification, then homogenizing effect evaporation of organic solvent, obtain the aqueouss of very small dimensions nanoparticle Suspension.

Optionally adopt ear sensory cell regulator nanoparticle in embodiment category for the various method manufactures.These methods Including gasification, such as free jet expansion, laser vaporization, spark eroding, discharge-induced explosion and chemical vapor deposition；Physical, Including mechanical wear (such as " high speed bead mill (pearlmilling) " technology, Cananga odorata Nanosys Inc. (elan Nanosystems)), supercritical co2 and solvent displacement after interface deposition.In one embodiment, using solvent displacement.By The size of the nanoparticle that the method manufactures easily with the concentration of polymer in organic solvent, mixing rate and used in the process of table Face activating agent change.Continuous flow mixer provides necessary turbulent flow to guarantee small particle.Have described that a type of optional use In prepare nanoparticle continuous flowing mixing arrangement (Hansen (hansen) et al., physical chemistry magazine (j phys chem), 92,2189-96,1988).In other embodiments, can using ultrasonic unit, flow through homogenizer or supercritical co2 device Prepare nanoparticle.

If be directly synthesized to obtain suitable nanoparticle homogeneity, then manufacture using size exclusion chromatography (SEC) Particle containing highly homogeneous medicine, that is, do not contain involved other components in its manufacture.Using size exclusion chromatography (sec) technology Ear sensory cell regulator or other pharmaceutical compound and free ear sensation that (such as gel filtration chromatography) separating particles combine Cell modulator or other pharmaceutical compound, or the suitable particle size range selecting the regulator nanoparticle of sensory cell containing ear.Respectively Plant sec medium (such as superdex 200, superose 6, sephacryl 1000) all can certainly buy on the market, and be used for The fractional distillation based on size of described mixture.Additionally, optionally using centrifugation, membrane filtration and using other molecule screening plants, Crosslinked gel/material and thin film carry out purified nanotubes particle.

The acceptable cyclodextrin of ear and other stablize composite

In one embodiment, the acceptable composite of ear additionally comprises cyclodextrin.Cyclodextrin is containing 6,7 or 8 The oligosacharides cyclic of glucopyranose units, is referred to as alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin.Cyclodextrin has enhancing water The hydrophilic exterior of solubility, and form the hydrophobic interior of cavity.In aqueous environments, the hydrophobic parts of other molecules are led to The hydrophobic cavity often entering cyclodextrin forms inclusion compound (inclusion compound).In addition, cyclodextrin can also Other types of non-bond is occurred to interact with the molecule within not in hydrophobic cavity.Each glucopyranose units of cyclodextrin There are three free hydroxyl, or alpha-cyclodextrin has 18 hydroxyls, beta-schardinger dextrin-has 21 hydroxyls, and gamma-cyclodextrin has 24 hydroxyls.One or more these hydroxyls can be reacted with any reagent in some reagent and be spread out with forming multiple cyclodextrin Biology, including hydroxypropyl ether, sulfonate and sulfoalkyl ether.Beta-schardinger dextrin-and HP-β-CD (hp β cd) are shown below Structure.

In certain embodiments, improve the dissolubility of medicine in medical composition as herein described using cyclodextrin.? In the case of many enhancing dissolvings, it is related to inclusion compound；But the other phase interactions between cyclodextrin and soluble compound With also improving dissolubility.HP-β-CD (hp β cd) can be buied no pyrogen product form.It is to be easily soluble in water In non-hygroscopic white powder.Hp β cd is heat-staple and non-degradable under neutral Ph.Therefore, cyclodextrin improves treatment Dissolubility in compositionss or composite for the agent.Therefore, in certain embodiments, include cyclodextrin to increase the acceptable ear of ear Dissolubility in composite as herein described for the sensory cell regulator.In other embodiments, cyclodextrin is in addition in this paper institute It is used as control release excipient in the composite stated.

Only for example, available cyclodextrin derivative includes alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, ethoxy β-ring Dextrin, Hydroxyropyl y-cyclodextrin, sulphated p-cyclodextrin, sulphation alpha-cyclodextrin, sulfobutyl ether beta-schardinger dextrin-.

In compositions disclosed herein and method, the concentration of cyclodextrin used is with physiochemical properties, pharmacokinetics Matter, side effect or adverse events, composite Consideration or other to therapeutically active agent or its salt or the related factor of prodrug, Or in compositionss the property of other excipient and change.Therefore, in some cases, according to compositions disclosed herein and method The concentration of cyclodextrin using or amount will optionally change.When deployed, increase ear sensory cell regulator dissolubility and/ Or serve as the amount of the cyclodextrin needed for control release excipient in any composite as herein described using as herein described former Reason, example and teaching are being selected.

Be applied to the acceptable composite of ear disclosed herein other stabilizers include for example fatty acid, fatty alcohol, alcohol, Long-chain fatty acid ester, long chain ether, the hydrophilic derivatives of fatty acid, Polyvinylpyrrolidone, polyvinylether, polyvinyl alcohol, hydrocarbon, Hydrophobic polymer, moisture absorption polymer and a combination thereof.In certain embodiments, also using the amide analogue of stabilizer. In other embodiments, selected stabilizer changes the hydrophobicity (such as Oleic acid, wax) of composite, or various groups in improvement composite The mixing (such as ethanol) dividing, controls the moisture (such as pvp or Polyvinylpyrrolidone) in formula, controls phase mobility (fusing point is higher than material, long-chain fatty acid, alcohol, ester, ether, amide etc. or its mixture of room temperature；Wax), and/or improve join Side and the compatibility (such as Oleic acid or wax) of encapsulation materials.In another embodiment, some conducts in these stabilizers are used Solvent/co-solvent (such as ethanol).In other embodiments, the amount of stabilizer be enough to suppress ear sensory cell regulator Degraded.The example of described stabilizer includes but is not limited to: (a) about 0.5% arrives about 2%w/v glycerol, and (b) about 0.1% arrives about 1%w/v methionine, (c) about 0.1% arrive about 2%w/v MTG, (d) about 1mm to about 10mm edta, (e) about 0.01% arrives about 2%w/v ascorbic acid, and (f) 0.003% arrives about 0.02%w/v polysorbate80, and (g) 0.001% arrives about 0.05%w/v polysorbate20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) many sulphuric acid penta gathers Sugar and other heparinoid, (m) bivalent cation, such as magnesium and zinc；Or (n) a combination thereof.

Other ear acceptable ear sensory cell regulator composites being suitable for include one or more resistant to aggregation and add Plus agent to strengthen the stability of ear sensory cell regulator composite by reducing protein aggregation speed.Selected resistant to aggregation adds Plus agent depends on the property of the such as condition that the ear sensory cell regulator such as ear sensory cell regulator antibody is exposed.Citing comes Say, stand to stir and some composites of thermal stress need the resistant to aggregation different from the composite standing lyophilizing and restore to add Agent.Only for example, applicable resistant to aggregation additive include the simple aminoacid such as urea, chlorination guanidine, glycine or arginine, Alkyl saccharide and the tables such as the polymer such as sugar, polyhydric alcohol, polysorbate, Polyethylene Glycol and glucosan, alkyl polyglucoside Face activating agent.

When needing, other composites being suitable for optionally include the acceptable antioxidant of one or more ears to strengthen Chemical stability.Only for example, suitable antioxidant includes ascorbic acid, methionine, sodium thiosulfate and inclined sulfurous Sour hydrogen sodium.In one embodiment, antioxidant is selected from metal-chelator, containing mercaptan compound and other general stabilizer.

Other compositionss being suitable for include the acceptable surfactant of one or more ears to strengthen physically stable Property or for other purposes.Suitable nonionic surfactant include but is not limited to polyoxyethylene fatty glyceride ester and Vegetable oil, such as polyoxyethylene (60) castor oil hydrogenated；With polyoxyethylene alkyl ether and alkyl phenyl ether, such as Octoxinol 10th, Octoxinol 40.

In certain embodiments, the acceptable pharmaceutical formulation of ear as herein described for degradation in office how It is stable in lower period: at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least 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 Week, at least about 3 months, at least about 4 months, at least about 5 months or at least about 6 months.In other embodiments, as herein described Composite for degradation in the period of at least about 1 week in be stable.It is also described for degradation It is stable composite in the period of at least about 1 month.

In other embodiments, by another surfactant (cosurfactant) and/or buffer agent with a kind of or a kind of Pharmaceutically acceptable mediator described previously herein combines so that product is maintained by surfactant and/or buffer agent above Under the ph value of optimal stability.Suitable cosurfactant includes but is not limited to: a) natural and synthesis lipophilic agent, Such as phospholipid, cholesterol and cholesterol fatty acid ester and its derivant；B) nonionic surfactant, including such as polyoxy second Alkene aliphatic alcohol ester, fatty acid esters of sorbitan (span (span)), polyoxyethylene sorbitan fatty acid ester (such as polyoxy Ethylene (20) Arlacel-80 (Tween 80), polyoxyethylene (20) Arlacel-60 (polysorbate60), Polyoxyethylene (20) Arlacel-20 (polysorbas20) and other tween, Isosorbide Dinitrate, glyceride, for example Myrj is hard with glyceryl triacetate (glycerol triacetate/triacetin), Polyethylene Glycol, hexadecanol, hexadecanol Lipidol, stearyl alcohol, polysorbate80, poloxamer, pool Lip river sand amine, castor oil derivatives are (for examplerh40、cremphor a25、cremphor a20、) and other cremophor, sulfo group el Succinate, alkyl sulfate (sls)；Peg glycerin fatty acid ester, such as peg-8 glyceryl caprylate/decanoin (labrasol), peg-4 glyceryl caprylate/decanoin (labrafac hydro wl 1219), peg-32 glyceryl Laurel The sub- oil of acid esters (gelucire 444/14), peg-6 glycerin mono-fatty acid ester (labrafil m 1944 cs), peg-6 glyceryl Acid esters (labrafil m 2125 cs)；Propylene glycol mono and di fatty acid ester, such as glycol laurate, the third two Alcohol caprylate/decanoin；700th, ascorbyl -6- cetylate, stearylamine, sodium lauryl sulfate, polyoxyethylene three Monoricinoleate and its any combinations or mixture；C) anionic surfactant includes but is not limited to carboxymethyl fibre The plain calcium of dimension, sodium carboxymethyl cellulose, dioctylis sulfosuccinas natricuses, sodium alginate, alkyl polyoxyethylene sulfates, lauryl sulfur Sour sodium, triethanolamine stearate, potassium laurate, bile saltss and its any combinations or mixture；With d) cationic is lived Property agent, such as cetrimonium bromide and chlorination dodecyl dimethyl benzyl-ammonium.

In another embodiment, when being lived using one or more common surfaces in the acceptable composite of the ear of the present invention During property agent, described cosurfactant is for example combined and the amount in final composite with pharmaceutically acceptable mediator For example in the range of about 0.1% to about 20%, about 0.5% to about 10%.

In one embodiment, the hlb value of surfactant is 0 to 20.In other embodiments, the hlb of surfactant It is worth for 0 to 3,4 to 6,7 to 9,8 to 18,13 to 15,10 to 18.

In one embodiment, also stablize ear sensory cell regulator or other pharmaceutical compound using diluent, because There is provided more stable environment for it.The salt (may also provide ph value control or maintain) that is dissolved in buffer solution is used as dilution Agent, including but not limited to phosphate buffered saline solution.In other embodiments, gel composite and endolymph or outer Lymph is isotonic: depending on the cochlea part of the target as ear sensory cell regulator composite.Isotonic composite passes through to add Tonicity agents provide.Suitable tonicity agents include but is not limited to any pharmaceutically acceptable sugar, salt or any a combination thereof or Mixture, such as, but not limited to dextrose and sodium chloride.In other embodiments, the amount of tonicity agent is about 100mosm/kg Arrive about 500mosm/kg.In certain embodiments, the amount of tonicity agent is about 200mosm/kg to about 400mosm/kg, about 280mosm/kg to about 320mosm/kg.As described herein, the amount of tonicity agents will depend upon the object construction of pharmaceutical formulation.

Applicable tension force compositionss also include making the osmolality of compositionss can connect in perilymph or endolymph One or more salt of required amount in the range of being subject to.Described salt is included with sodium, potassium or ammonium cation and chloride ion, lemon Lemon acid group, Vitamin C acid group, borate, phosphate radical, bicarbonate radical, sulfate radical, thiosulfate anion or bisulfite anion Salt；Suitable salt includes sodium chloride, potassium chloride, sodium thiosulfate, sodium sulfite and ammonium sulfate.

In certain embodiments, the acceptable gel composite of ear disclosed herein alternatively or additionally contain preservative with Prevent growth of microorganism.The acceptable preservative of suitable ear for the enhanced composite of viscosity as herein described is included (but not Be limited to) benzoic acid, boric acid, p-hydroxybenzoate, alcohol, quaternary ammonium compound, stable chlorine dioxide, mercurial (such as nitric acid benzene Hydrargyrum and thimerosal), the mixture of above-mentioned substance etc..

In another embodiment, only for example, in the acceptable composite of the ear of this paper presentation, preservative is anti-micro- Biological agent.In one embodiment, composite includes preservative, only for example, methyl parahydroxybenzoate, bisulfite Sodium, sodium thiosulfate, ascorbic acid, methaform, thimerosal, p-Hydroxybenzoate, benzyl alcohol, phenylethanol etc..Another In embodiment, the concentration of methyl parahydroxybenzoate is about 0.05% to about 1.0%, about 0.1% to about 0.2%.In another reality Apply in example, gel is prepared by mixing water, methyl parahydroxybenzoate, hydroxyethyl cellulose and sodium citrate.In another reality Apply in example, gel is prepared by mixing water, methyl parahydroxybenzoate, hydroxyethyl cellulose and sodium acetate.In another enforcement In example, mixture to be sterilized by processing in 120 DEG C of autoclavings for about 20 minutes, and thin with ear sensation disclosed herein in right amount Before the mixing of born of the same parents' regulator, test ph value, methyl parahydroxybenzoate concentration and viscosity.

In drug delivery mediator, the suitable acceptable waterborne-type preservation of ear used includes sodium sulfite, thio sulfur Sour sodium, ascorbic acid, methaform, thimerosal, p-Hydroxybenzoate, benzyl alcohol, Yoshinox BHT (bht), phenyl second Alcohol etc..The amount of these reagent is typically about 0.001 weight % to about 5 weight %, and amount is preferably from about 0.01 weight Amount % to about 2 weight %.In certain embodiments, ear compatibility composite as herein described does not contain preservative.

Round window membrane penetration enhancers

In another embodiment, composite additionally comprises one or more round window membrane penetration enhancers.Through oeil de boeuf There are round window membrane penetration enhancers to strengthen in penetrating through of film.Round window membrane penetration enhancers are advantageous for the material casting altogether It is transmitted through the chemical entities of round window membrane.Round window membrane penetration enhancers are grouped according to chemical constitution.Such as sodium lauryl sulfate, the moon Sodium metasilicate, polyoxyethylene -20- cetyl ether, lauryl alcohol -9, dodecyl sodium sulfate, dioctylis sulfosuccinas natricuses, polyoxy Ethylene -9- lauryl ether (ple),80th, nonylphenoxy polyethylene (np-poe), polysorbate plasma type with non- Ionic surfactant can be used as round window membrane penetration enhancers.Bile saltss (such as sodium glycocholate, NaTDC, cattle sulphur gallbladder Double hydrogen Fusidate Sodiums of the double hydrogen Fusidate Sodium (sodium taurodihydrofusidate) of sour sodium, cattle sulphur, sugar etc.), fatty acid and Derivant (such as Oleic acid, caprylic acid, monoglyceride and diglyceride, lauric acid, acyl group choline, caprylic acid, fatty acyl carnitine, the last of the ten Heavenly stems Sour sodium etc.), chelating agen (edta, citric acid, salicylate etc.), sulfoxide (such as dimethyl sulfoxide (dmso), dodecyl first Base sulfoxide etc.) and alcohol (ethanol, isopropanol, glycerol, propylene glycol etc.) also be used as round window membrane penetration enhancers.

In certain embodiments, the acceptable penetration enhancers of ear are the surfactant comprising alkyl polyglucoside, wherein alkane Base glucosides is myristyl-β-d- maltoside.In certain embodiments, the acceptable penetration enhancers of ear are to comprise alkyl sugar The surfactant of glycosides, wherein alkyl polyglucoside are dodecyl-maltosides.In some cases, penetration enhancers are transparent Matter acid enzyme (hyaluronidase).In some cases, hyaluronidase is the mankind or cattle hyaluronidase.In certain situation Under, hyaluronidase is that (in such as human sperm, (the neat nurse of hello is public for visible hyaluronidase, ph20 for mankind's hyaluronidase Department (halozyme)),(Baxter International Ltd (baxter international, inc.)).? Under certain situation, hyaluronidase be cattle hyaluronidase (such as bovine testicular hyaluronidase,(An Fasi Reach drugmaker (amphastar pharmaceuticals)),(Puri nurse drugmaker (primapharm, inc)).In some cases, hyaluronidase is sheep hyaluronidase,(ista drugmaker (ista pharmaceuticals)).In some cases, hyaluronidase as herein described is restructuring hyaluronidase.In some feelings Under condition, hyaluronidase as herein described is humanization restructuring hyaluronidase.In some cases, hyalomitome as herein described Sour enzyme is Pegylation hyaluronidase (such as pegph20 (hello Qi Mu company (halozyme))).In addition, covering the U.S. (its disclosure is hereby incorporated herein by for patent the 7,151,191st, No. 6,221,367 and No. 5,714,167 In) the peptide sample penetration enhancers that describe are as another embodiment.These penetration enhancers are aminoacid and peptide derivant and can Realize drug absorption and do not affect the integrity of film or intercellular tight junction by the diffusion of passive across cell.

The permeable liposome of round window membrane

Also ear sensory cell regulator composite or compositionss can be encapsulated using liposome or lipid particle.Relax dispersion Phospholipid in aqueous medium forms multilamellar liposome, and each lipid layer is separated by the region of wherein retention aqueous medium.To these Multilamellar liposome carries out ultrasonic Treatment or turbulences form unilamellar vesicles, frequently referred to liposome, a size of about 10- 1000nm.These liposomees have the advantages that many as ear sensory cell regulator or other medical agent supporting agent.It is biological Inert, biodegradable, nontoxic and no antigen.The liposome being formed has various sizes and has different compositions And surface characteristic.In addition, its position that can retain plurality of reagents and disintegrate in liposome discharges described reagent.

The suitable phospholipid being herein used for the acceptable liposome of ear is such as phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE and phospholipid Acyl serine, sphingomyelins, cuorin, plasmalogen, phosphatidic acid and cerebroside, especially for adjusting with the ear sensory cell of this paper Agent is dissolved in the phospholipid in nontoxic pharmaceutically acceptable organic solvent together.Preferably phospholipid is such as phosphatidylcholine, phosphorus Acyl ethanolamine, Phosphatidylserine, phosphatidylinositols, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, phosphatidyl glycerol etc. and its mixture, especially For lecithin, such as soybean lecithin.In composite of the present invention the amount of phospholipid used about 10% to about 30%, preferably from about In the range of 15% to about 25%, and it is especially about 20%.

Preferably adopt the feature of lipotropy additive selective modification liposome.Only for example, the example of these additives Including stearylamine, phosphatidic acid, tocopherol, cholesterol, cholesteryl hemisuccinate and lanoline extract.Lipotropy used adds Plus the amount of agent is in the range of 0.5% to 8%, preferably 1.5% to 4%, and it is especially about 2%.In general, lipotropy adds The ratio of the amount of agent and the amount of phospholipid is in the range of about 1:8 to about 1:12, and is especially about 1:10.Described phospholipid, lipotropy add Plus agent with ear sensory cell regulator and other pharmaceutical compounds with dissolve the nontoxic pharmaceutically acceptable of described composition Organic solvent system is used in combination.Described solvent system does not merely have to be completely dissolved ear sensory cell regulator, and it is necessary Composite is allowed to have stable single bilayered liposome.Solvent system comprises the isosorbide two of the amount of about 8% to about 30% (Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), that is, oxolane is poly- for methyl ether (dimethylisosorbide) and tetraethylene glycol (TEG) Glycol ether (tetrahydrofurfuryl alcohol polyethylene glycol ether)).In described solvent system In system, the ratio of the amount of isosorbide dimethyl ether and the amount of tetraethylene glycol (TEG) is in about 2:1 to about 1:3, especially about 1:1 to about 1:2.5's In the range of, and preferably from about 1:2.Therefore, in final composition the amount of tetraethylene glycol (TEG) from 5% to 20%, especially 5% to 5%, And preferably from about 10%.Therefore, in final composition the amount of isosorbide dimethyl ether in 3% to 10%, especially 3% to 7% model In enclosing, and preferably from about 5%.

The term " organic component " that following article uses refers to comprise the mixed of described phospholipid, lipotropy additive and organic solvent Compound.Ear sensory cell regulator is dissolvable in water in organic component, or alternate manner is to maintain the fully active of medicament.Final tune The amount joining thing middle ear sensory cell regulator can be in the range of 0.1% to 5.0%.In addition, can add such as in organic component Other composition such as antioxidant.Example includes tocopherol, butylatedhydroxyanisole, Yoshinox BHT, ascorbic acid palm fibre Glycerin monostearate, ascorbic acid oleate etc..

Or, prepare liposomal formulation: (a) as follows with regard to the heat-resisting other medicine of ear sensory cell regulator or appropriateness In a reservoir phospholipid and organic solvent system are heated to about 60-80 DEG C, dissolve described active component, then add any other Blender, and stirring mixture is until being completely dissolved；B aqueous solution is heated to 90-95 DEG C and wherein in second container by () Dissolving preservative, cools down mixture, then adds remaining auxiliary blender and remaining water, and stirring mixture is until completely molten Solution；Aqueous components are thus obtained；C () organic faciess are transferred directly in aqueous components, use high-efficiency mixing device (for example high simultaneously Shear mixer) homogenize described combination, and (d), when homogenizing further, adds viscosity intensifier in gained mixture. Aqueous components are optionally placed at equipped with the fitted vessel of homogenizer, and by be injected with unit by stages between manufacture turbulent flow To realize homogenizing.Can be using any hybrid component or the homogenizer that mixture is applied with high shear force.In general, can adopt 20,000rpm, especially about 3,000rpm can be accelerated to from about 1,500rpm and accelerate to the blender of about 6,000rpm.It is suitable for using Viscosity intensifier in method and step (d) is such as xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or its mixing Thing.The amount of viscosity intensifier is depending on the property and concentration of other compositions and typically in the range of about 0.5 to 2.0% or as about 1.5%.For preventing the material degradation using during liposomal formulation preparation, the noble gases such as nitrogen or argon are preferably used to rush Wash all solution and execute all steps under an inert atmosphere.Great majority knot is usually contained by liposome prepared by said method Together in the active component in double-layer of lipoid, and it is not required to liposome to be separated and un-encapsulated material.

In other embodiments, the acceptable composite of ear (include gel composite and the enhanced composite of viscosity) is in addition Including excipient, other medical science or medical agent, supporting agent, adjuvant, such as preservative, stabilizer, wetting agent or emulsifying agent, dissolving promote Enter agent, salt, solubilizing agent, defoamer, antioxidant, dispersant, wetting agent, surfactant or a combination thereof.

Suitable supporting agent for the acceptable composite of ear as herein described includes but is not limited to and target ear structure The compatible any pharmaceutically acceptable solvent of physiological environment.In other embodiments, substrate is pharmaceutically acceptable The combining of surfactant and solvent.

In certain embodiments, other excipient include stearoyl fumaric acid sodium, diethanolamine cetyl base sulphuric acid Ester, isostearate, GREMAPHOR GS32, nonoxinol 10 (nonoxyl 10), Octoxinol 9, sodium lauryl sulfate, Isosorbide Dinitrate is (Arlacel-20, Arlacel-80, Arlacel-40, de- Water sorbitol monostearate, Arlacel-83, sorbitan trioleate, anhydro sorbitol three stearic acid Ester, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan monostearate, Sorbitan dioleate, anhydro sorbitol sesquialter isostearate, sorbitan sesquistearate, anhydro sorbitol Three isostearates), its pharmaceutically acceptable salt of lecithin and a combination thereof or mixture.

In other embodiments, supporting agent is polysorbate.Polysorbate is the nonionic table of Isosorbide Dinitrate Face activating agent.The polysorbate being applied to the present invention includes but is not limited to polysorbate20, polysorbate40, poly- mountain Pears alcohol ester 60, polysorbate80 (Tween 80) and its any combinations or mixture.In other embodiments, using polysorbate Ester 80 is as pharmaceutically acceptable supporting agent.

In one embodiment, for preparing the acceptable viscosity of water dissolvable ear based on glycerol of medicine transmission mediator Strengthen composite to comprise to adjust containing at least about 0.1% water dissolvable glycerol compounds or more at least one ear sensory cell Agent.In certain embodiments, the percentage ratio of ear sensory cell regulator total pharmaceutical formulation weight or volume about 1% with Change between about 95%, between about 5% and about 80%, between about 10% and about 60% or between bigger percentage ratio.In some enforcements In example, in the ear sensory cell regulator composite that each treatment is suitable for the amount of compound be prepared to make compound any both Determine to obtain the dosage being suitable in unit dose.Cover such as dissolubility, bioavailability, biological half-life, dispensing way herein The factors such as footpath, product storage period and other pharmacological considerations.

If necessary, ear acceptable medicine gel also contains cosolvent, preservative, cosolvent, ion in addition to buffer agent Intensity and osmolality regulator and other excipient.The acceptable water soluble buffers of suitable ear are alkali metal Or alkaline earth metal carbonate, phosphate, bicarbonate, citrate, borate, acetate, succinate etc., such as phosphoric acid Sodium, sodium citrate, sodium borate, sodium acetate, sodium bicarbonate, sodium carbonate and trometamol (tris).The amount foot of these reagent So that the ph value of system to be maintained 7.4 ± 0.2 and preferably 7.4.Thus, buffer agent in terms of the weight of total composition up to 5%.

Strengthen the dissolubility of ear sensory cell regulator using cosolvent, however, some ear sensory cell regulators or Other pharmaceutical compounds are soluble.It is suspended in polymer mediator generally by means of suitable suspension or viscosity intensifier.

Additionally, some pharmaceutical excipient, diluent or supporting agent are likely to be of ototoxicity.For example, benzalkonium chloride, A kind of Determination of common preservatives, has ototoxicity, if be therefore introduced in vestibule or cochlear structures, then may be harmful to.In allotment control It is proposed that avoiding or combining suitable excipient, diluent or supporting agent with from tune during system release ear sensory cell regulator composite Join the amount reducing or eliminating possible ototoxicity component in thing or reducing described excipient, diluent or supporting agent.Control release ear Sensory cell regulator composite optionally includes otoprotective agent, such as antioxidant, alpha lipoic acid, calcium, fosfomycin or ferrum chelating Agent, can be acted on because of the possible ototoxicity being caused using particular therapeutic agent or excipient, diluent or supporting agent with offsetting.

The following is and treat upper acceptable ear composite:

Or, composite disclosed herein is also contemplated by otoprotective agent in addition at least one activating agent and/or excipient, bag Include the medicaments such as (but not limited to) antioxidant, alpha lipoic acid, calcium, fosfomycin or iron chelating agent, can be because using specific with counteracting The possible ototoxicity effect that therapeutic agent or excipient, diluent or supporting agent cause.

Therapeutic mode

Medication and time-histories

The medicine being delivered to internal ear is by orally, intravenously or intramuscularly interior approach general casts.However, being directed to internal ear The pathological Systemic administration of locality increases the probability of systemic toxicity and adverse side effect, and produces the non-rich of medicine The distribution of effect, in this distribution, the medicine of visible high-load in serum and correspondingly visible lower content in internal ear.

Injection in Tympanic Cavity therapeutic agent is by the technology in injection of therapeutic agent to the middle ear and/or internal ear at tympanum rear.One In individual embodiment, composite as herein described directly casts on round window membrane via through injection of tympanum.In another embodiment, originally Ear acceptable ear sensory cell regulator composite described in literary composition casts oeil de boeuf via leading to the non-of internal ear through tympanum approach On film.In other embodiments, composite as herein described casts on round window membrane via the surgical leading to round window membrane, bag The crest of fenestra cochleae containing modification.

In one embodiment, transmission system is the crest of fenestra cochleae that can pierce through tympanum and directly reach round window membrane or internal ear Syringe and needle device.In certain embodiments, the pin on syringe is wider than No. 18 pins.In another embodiment, pin number is 18 Number to No. 31.In another embodiment, pin number is No. 25 to No. 30.Depending on ear sensory cell regulating composition or composite Denseness or viscosity, the pin number of syringe or hypodermic needle can respective change.In another embodiment, the internal diameter of pin can pass through Reduce pin (commonly referred to thin-walled or ultra-thin-wall pin) wall thickness come to increase with reduce pin blocking probability, to maintain suitable simultaneously Needle-like number.

In another embodiment, pin is for the instant hypodermic needle transmitting gel composite.Hypodermic needle can be It is intended for single use pin or disposable pin.In certain embodiments, syringe can be used for transmitting and pharmaceutically can connect as disclosed herein Be subject to based on gel sensory cell containing ear regulating composition, wherein syringe has press-fit type (press-fit) Or screw type (twist-on) (luer-lock) joint (luer).In one embodiment, syringe is hypodermic syringe.? In another embodiment, syringe is made up of plastics or glass.In another embodiment, hypodermic syringe is the injection of being intended for single use property Device.In another embodiment, glass syringe can be sterilized.In another embodiment, sterilizing is entered using autoclave OK.In another embodiment, syringe comprises cylindrical syringe body, and wherein gel composite is stored in it before use In.In other embodiments, syringe comprises cylindrical syringe body, wherein medicine and pharmacology based on gel as disclosed herein Upper acceptable ear sensory cell regulating composition is stored in wherein before use, its allow advantageously with suitable medicine and pharmacology Upper acceptable buffer mixing.In other embodiments, syringe can contain other excipient, stabilizer, suspending agent, dilution Agent or a combination thereof are to stablize or otherwise stably to store ear sensory cell regulator contained therein or other medicineization Compound.

In certain embodiments, syringe comprises cylindrical syringe body, wherein main body by compartment, and each compartment can At least one component of storage ear acceptable ear sensory cell regulator gel composite.In another embodiment, have every The syringe of room main body allows to mix each component before being expelled in middle ear or internal ear.In other embodiments, transmission system System comprises multiple syringes, and each syringe of multiple syringes contains at least one component of gel composite so that each component exists It is pre-mixed before injection or mix after injection.In another embodiment, syringe disclosed herein comprises at least one Accumulator, wherein at least one accumulator comprises ear sensory cell regulator or pharmaceutically acceptable buffer or viscosity increases Strong agent (such as gellant) or a combination thereof.Optionally Injection in Tympanic Cavity is carried out using the commercially available injection device in simplest form, such as There is injection tube, the instant plastic injector of the needle assembly containing pin, the plunger containing plunger rod and fixing flange.

In certain embodiments, transfer device is the device being designed for casting therapeutic agent middle ear and/or internal ear.Only lift For example, Jia Le Pharmaceuticals Ltd (gyrus medical gmbh) provides observation REN (round window niche) Micro- otoscope (micro-otoscope) with transmission medicine to REN；Arenberg (arenberg) in U.S. Patent No. 5, Fluid is transmitted to the medical treatment device of internal ear structures described in 421, No. 818, the 5th, 474, No. 529 and the 5th, 476, No. 446, With regard to described disclosure, each patent is incorporated herein by reference.U.S. Patent Application No. 08/874,208 (is closed In described disclosure, it is incorporated herein by reference) implantable fluid transfer conduit is described to transmit therapeutic agent to internal ear Surgical method.Patent Application Publication 2007/0167918 (with regard to described disclosure, is herein incorporated by reference this In literary composition) in addition combined ear aspirator and pill dispenser for fluid sampling in tympanum and pharmacy application described.

Adjust the acceptable compositionss of ear of immunomodulator compounds containing ear sensory cell as herein described or composite can cast For preventative and/or therapeutic treatment.In therapeutic application, to the trouble having been inflicted with autoimmune disease, condition of illness or disease Person cast enough to cure or at least partly stop the symptom of disease, disease or condition of illness amount the combination of ear sensory cell regulator Thing.To this purposes effectively amount will depend upon the order of severity of disease, disease or condition of illness and the course of disease, previous therapies, patient strong Health state and the judgement of the reaction to medicine and treating physician.

Dosing frequency

In certain embodiments, compositions disclosed herein casts individuality in need once.In certain embodiments, herein Disclosed compositionss cast individuality in need once more than.In certain embodiments, cast compositions disclosed herein for the first time, Then cast compositions disclosed herein for the second time.In certain embodiments, cast compositions disclosed herein for the first time, then Cast compositions disclosed herein with third time second.In certain embodiments, cast compositions disclosed herein for the first time, Then second, third time and cast compositions disclosed herein the 4th time.In certain embodiments, cast public herein for the first time The compositionss opened, then second, for the third time, cast compositions disclosed herein the 4th time and the 5th time.In some embodiments In, cast compositions disclosed herein for the first time, then for drug holiday.

The number of times casting individuality compositionss in need depends on the judgement of medical professional, disease, the serious journey of disease Degree and the individual reaction to composite.In certain embodiments, compositions disclosed herein casts and suffers from slight acute pathologies Individuality in need is once.In certain embodiments, compositions disclosed herein casts and suffers from having of moderate or severe acute condition of illness Need individuality once more than.In the case that the condition of illness of patient is not improved, based on the judgement of doctor, can Long-term administration ear sense Feel cell modulator dispensing, cast for a long time, including the whole life persistent period of patient, to improve or otherwise to control System or the restriction disease of patient or the symptom of condition of illness.

In the case that the condition of illness of patient does not improve, based on the judgement of doctor, can Long-term administration ear sensory cell regulator Compound is offerd medicine, and casts for a long time, including the whole life persistent period of patient, to improve or otherwise to control or limit The disease of patient processed or the symptom of condition of illness.

In the case that patient's states are improved, based on the judgement of doctor, can continuously give ear sensory cell regulator chemical combination Thing is offerd medicine；Or, the drug dose being cast can temporarily reduce or temporary suspension a period of time (i.e. " drug holiday ").Medicine The length of vacation from 2 days to 1 year, only for example, including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 My god, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days and 365 days.During drug holiday, it can be 10%-100% that dosage reduces, only for example, including 10%, 15%th, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%th, 95% and 100%.

Once ear's condition of illness of patient is improved, cast maintenance ear sensory cell if necessary and adjust agent dose.Connect , optionally the dosage offerd medicine or frequency are reduced according to symptom or both extremely keep the level of disease, disease or condition of illness improvement.At certain In a little embodiments, after any recurrence in symptom, patient needs long-term intermittent treatment.

The amount corresponding to this amount of ear sensory cell regulator will change depending on following factor: such as specific compound, The disease condition particular situation related with its order of severity, case, including the concrete ear sensory cell regulator for example being cast, Dosing way, the auto-immune pathologies treated, the target area treated and individual treated or host.However, it is general For, the dosage for the human treatment that grows up would generally be in the range of each dispensing 0.02-50mg, and preferably offer medicine 1- every time 15mg.Desired dosage is provided with single dose or simultaneously (or in the short term) or the fractionated dose being cast with appropriate intervals.

In certain embodiments, initially dispensing is specific ear sensory cell regulator, and subsequently offeing medicine is different allotments Thing or ear sensory cell regulator.

The pharmacokinetics of control release composite

In one embodiment, in addition composite disclosed herein provides ear sensory cell regulator vertical from compositionss Discharge, or in 1 minute or in 5 minutes or in 10 minutes or in 15 minutes or in 30 minutes or 60 Discharge in minute or in 90 minutes.In other embodiments, at least one ear sensory cell regulator of therapeutically effective amount from In compositionss immediately or in 1 minute or in 5 minutes or in 10 minutes or in 15 minutes or in 30 minutes, Or discharge in 60 minutes or in 90 minutes.In certain embodiments, compositionss comprise to provide at least one ear sensory cell The pharmaceutically acceptable gel composite of the ear discharging immediately of regulator.The other embodiments of composite may also include enhancing The reagent of the composite viscosity including herein.

In other or another embodiment, composite provides the prolongation release of at least one ear sensory cell regulator to adjust Join thing.In certain embodiments, the persistent period that at least one ear sensory cell regulator spreads from composite is more than 5 points Clock or 15 minutes or 30 minutes or 1 hour or 4 hours or 6 hours or 12 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 5 months or 6 months or 9 months or 1 year.In other embodiments, The persistent period that at least one ear sensory cell regulator of therapeutically effective amount discharges from composite was more than 5 minutes or 15 points Clock or 30 minutes or 1 hour or 4 hours or 6 hours or 12 hours or 18 hours or 1 day or 2 days or 3 days or 4 My god 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, composite provides the release immediately of ear sensory cell regulator to discharge composite with extending. In other embodiments again, composite contain 0.25:1 ratio or 0.5:1 ratio or 1:1 ratio or 1:2 ratio or 1:3, Or the release immediately of 1:4 ratio or 1:5 ratio or 1:7 ratio or 1:10 ratio or 1:15 ratio or 1:20 ratio with prolong Long release composite.In another embodiment, composite provides release immediately and second ear of the first ear sensory cell regulator The prolongation release of sensory cell regulator or other therapeutic agent.In other embodiments again, composite provides at least one ear sense Feel the release immediately of cell modulator and at least one therapeutic agent and extend release composite.In certain embodiments, composite There is provided respectively 0.25:1 ratio 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 the first ear sensory cell regulator of 1:7 ratio or 1:10 ratio or 1:15 ratio or 1:20 ratio and second therapeutic agent Release immediately with extend release composite.

In one embodiment, at least one ear sensory cell that composite provides therapeutically effective amount in disease location is adjusted Section agent, exposes substantially free of general.In another embodiment, composite provides at least the one of therapeutically effective amount in disease location Plant ear sensory cell regulator, substantially can't detect general and expose.In other embodiments, composite carries in disease location For at least one ear sensory cell regulator of therapeutically effective amount, seldom detect or undetectable to general exposure.

The combination of release immediately, sustained release and/or prolongation release ear sensory cell regulating composition or composite can With other medical agents and excipient disclosed herein, diluent, stabilizer, tonicity agents and other group subassembly.Thus, depend on In ear sensory cell regulator used, desired denseness or viscosity or selected transfer mode, embodiment disclosed herein Alternative aspect is correspondingly combined with release immediately, sustained release and/or prolongation release embodiment.

In certain embodiments, by composite being injected in the round window membrane of test animal (including such as Cavia porcelluss or chinchilla) On or near measuring the pharmacokinetics of ear sensory cell regulator composite as herein described.In in the period of determining (for example, Within 1 week period, the pharmacokinetics of the 6th hour, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days and 7 days test composites Learn), to test euthanizing animals and test 5ml perilymph fluid sample.Take out internal ear and test the regulation of ear sensory cell The presence of agent.When needing, the content of the other organ middle ear sensory cell regulator of measurement.In addition, by taking out from test animal Blood sample is taken to measure the general content of ear sensory cell regulator.For determining whether composite hinders audition, optionally right The audition of test animal is tested.

Or, internal ear (taking out from test animal) is provided and measures the migration of ear sensory cell regulator.As again One replacement, provides the vitro model of round window membrane, and measures the migration of ear sensory cell regulator.

Test kit/product

This case also provides the test kit of the symptom of prevention, the disease treating or improving mammal or disease.Described reagent Box typically will comprise one or more ear sensory cell regulator control release compositionss disclosed herein or device and institute State the operation instructions of test kit.This case is also contemplated by one or more ear sensory cell regulator control release compositionss Purposes, it is used for treating, alleviate, mitigate or improve for manufacture and suffers from, suspects with inner ear disorders or be in development inner ear disease The medicament of the symptom of disease, dysfunction or disease of mammal (the such as mankind) among disease risk.

In certain embodiments, test kit include divided to accommodate the containers such as one or more bottles, pipe Carrier, packaging or container, the container such as bottle, pipe respectively includes an independent unit used in method described herein Part.Suitable container includes such as bottle, bottle, syringe and test tube.In other embodiments, container by such as glass or is moulded The multiple materials such as material are formed.

Product provided herein contains packaging material.Packaging material for pack medical product are also provided herein.Referring to Such as U.S. Patent No. 5,323,907, No. 5,052,558 and No. 5,033,252.The example of medical packaging material includes (but not limited to) blister package, bottle, pipe, inhaler, pump, bag, bottle, container, syringe, bottle and any be suitable to be recruited Join thing and predetermined dispensing pattern and the packaging material for the treatment of.Expected multiple ear sensory cell regulator composites provided herein and Compositionss are as can be by casting any disease be benefited to internal ear, disease by ear sensory cell regulator control release Disease or multiple treatments of condition of illness.

In certain embodiments, it is desirable to test kit from the viewpoint of business and user use composite as herein described Including one or more extra vessel, respectively having one or more various materials (is in optionally such as conc forms Reagent, and/or device).The non-limiting examples of described material include but is not limited to buffer agent, diluent, filter, pin, Syringe；List carrier, packaging, container, bottle and/or the pipe label of inclusions and/or operation instructions and carry operation instruction The package insert of book.Optionally include a group profile book.In another embodiment, label can be located on container or subsidiary container. In another embodiment, when alphabetical, the digital or other character forming label is pasted, moulds or be etched in container itself, mark Label can be located on container；When label is present in storage or the inside carrier also accommodating container, it can attach container, for example, pack Inset form.In other embodiments, label can be used for indicating that inclusions will be used for specific treatment use.In another embodiment In, label also indicates that the directions for use of inclusions, the directions for use such as in method described herein.

In certain embodiments, medical composition is present in and contains compound provided herein containing one or more In the packaging of unit dosage forms or dispenser device.In another embodiment, packaging for example contains metal or plastic foil, such as steeps Cover packaging.In another embodiment, packaging or dispenser device can be enclosed dispensing description.In another embodiment, packaging or Allotter also attaches the bulletin of the form that the subsidiary government authorities in medical manufacture, use or sale of container specify, institute State bulletin reflection mechanism and ratify described medicament forms for the mankind or veterinary's dispensing.In another embodiment, described bulletin is for example Label or the product inset of approval that to be FDA ratified with regard to prescription drug.In another embodiment In, also prepare the compositionss allocated in compatibility pharmaceutical carrier containing compound provided herein, be placed on suitable container In, and the label for the treatment of instruction condition of illness in addition.

Example

Example 1- prepares thermoreversible gels amn082 composite

Composition	Amount (the milligram number of every gram of composite)
		amn082	3.0
Methyl parahydroxybenzoate	0.3
		Hydroxypropyl methyl cellulose	3.0
Poloxamer 407	54
		Tris hcl buffer (0.1m)	239.7

Amn082 provides in solid form.It is 10mm that its rehydration in water becomes final molar concentration.

By first Poloxamer 407 (BASF AG (basf corp.)) being suspended in tris hcl buffer (0.1m) prepare the gel composite containing 1.0%amn082 of 10g batch of material in.At 4 DEG C stirring mixing Poloxamer 407 and Tris is overnight dissolved completely in tris with guaranteeing Poloxamer 407.Add hydroxypropyl methyl cellulose, P-hydroxybenzoic acid first Ester and extra tris hcl buffer (0.1m).Stir described compositionss until observing dissolving.Add amn082 solution and Blend compositions are until obtaining homogeneous gel.Mixture is maintained at a below room temperature until using.

Example 2- prepares mucosal adhesive thermoreversible gels amn082 composite

Composition	Amount (the milligram number of every gram of composite)
		amn082	3.0
Methyl parahydroxybenzoate	0.3
		Hydroxypropyl methyl cellulose	3.0
Carbopol 934p	0.6
		Poloxamer 407	54
Tris hcl buffer (0.1m)	239.1

By first Poloxamer 407 (BASF AG (basf corp.)) and carbopol 934p being suspended in tris The mucoadhesive gel composite containing 1.0%amn082 of 10g batch of material is prepared in hcl buffer (0.1m).Stir mixed at 4 DEG C Close Poloxamer 407, carbopol 934p and tris is overnight dissolved completely in tris to guarantee Poloxamer 407 and carbopol 934p In.Add hydroxypropyl methyl cellulose, methyl parahydroxybenzoate and extra tris hcl buffer (0.1m).Stirring is described Compositionss are until observing dissolving.Add amn082 solution and blend compositions are until obtaining homogeneous gel.Mixture is maintained Less than room temperature until use.

The cnqx composite based on hydrogel for the example 3- preparation

First pass through and be gently mixed cnqx to prepare paste composite with water until cnqx dissolves.Then, by up to Blended wax oil at a temperature of 60 DEG C, trihydroxy stearate and cetyldimethicon copolyol are preparing oil matrix. Cooling oil matrix is to room temperature, and adds cnqx solution.The biphase single-phase aqueous gels homogeneous until formation of mixing.

Example 4- prepares gel carbamazepine composite

Composition	Amount (the milligram number of every gram of composite)
		Carbamazepine	6.4
Shitosan	3.2
		Sodium glycerophosphate	12.8
Water	134.4

Titration 5ml acetic acid solution is about 4.0 until ph value.Add shitosan so that ph value is about 5.5.Then by Karma west Put down and be dissolved in chitosan solution.By filtering, this solution is sterilized.In addition preparation 5ml phosphoglycerol sodium water solution and Sterilizing.Mixing both solution, and form desired gel at 37 DEG C in 2 hours.

Example 5- prepares mucosal adhesive thermoreversible gels d- methionine composite

D- methionine is dissolved in phosphate buffer.By first by Poloxamer 407 (BASF AG (basf corp.)) and carbopol 934p be suspended in the mucosa containing d- methionine preparing 10g batch of material in phosphate buffer Adhesive gel composite.At 4 DEG C, stirring mixing Poloxamer 407, carbopol 934p and phosphate buffer are overnight to guarantee Poloxamer 407 and carbopol 934p are dissolved completely in buffer.Add hydroxypropyl methyl cellulose, benzene first in mixture Alcohol and extra phosphate buffer.Stir described compositionss until observing dissolving.Add d- methionine solution and mixing Compositionss are until obtaining homogeneous gel.Mixture is maintained at a below room temperature until using.

Example 6- prepares liposome amn082 composite

Composition	Amount (milligrams per gram)
		amn082	3.0
Soybean lecithin	200.0
		Cholesterol	20.0
Tetraethylene glycol (TEG)	100.0
		Isosorbide dimethyl ether	50.0
Methyl parahydroxybenzoate	2.0
		Propyl p-hydroxybenzoate	0.2
bht	0.1
		Sodium chloride	1.0
hpmc	15.0
		Sodium hydroxide	0.6
Citric acid	1.0
		Pure water, usp	603.6

Heating soy lecithin, tetraethylene glycol (TEG) and isosorbide dimethyl ether to about 70-75 DEG C.By cholesterol and Butylated hydroxy Toluene is dissolved in the mixture of described heating.Stirring is until being completely dissolved.About 1/3rd water is added by another container Heat arrives 80-95 DEG C, and under agitation preservative methyl parahydroxybenzoate and propyl p-hydroxybenzoate is dissolved in heating In water.Cooling solution to about 25 DEG C, then adds amn082, disodiumedetate, sodium chloride, sodium hydroxide and Fructus Citri Limoniae Acid.Add remaining water and stir until being completely dissolved.By means of vacuum, organic mixture is transferred in aqueous mixture, with When so that combination is homogenized until obtaining homogeneous product with high-shear mixer.Add hydroxyl by means of vacuum in biphase mixture Propyl methocel, is homogenized with blender simultaneously.Form single bilayered liposome.

The thermoreversible gels containing (s)-ketamine for the example 7- preparation

Composition	Amount (the milligram number of every gram of composite)
		(s)-ketamine	21.0
Methyl parahydroxybenzoate	2.1
		Hydroxypropyl methyl cellulose	21.0
Poloxamer 407	378
		Tris hcl buffer (0.1m)	1677.9

By first Poloxamer 407 (BASF AG (basf corp.)) being suspended in tris hcl buffer (0.1m) prepare the gel composite containing 1.0% (s)-ketamine of 10g batch of material in.Stirring mixing Poloxamer 407 at 4 DEG C Overnight it is dissolved completely in tris with guaranteeing Poloxamer 407 with tris.Add hydroxypropyl methyl cellulose, P-hydroxybenzoic acid Methyl ester and extra tris hcl buffer (0.1m).Stir described compositionss until observing dissolving.Add (s)-ketamine Solution and blend compositions are until obtaining homogeneous gel.Mixture is maintained at a below room temperature until using.

Example 8- preparation comprises thermoreversible gels (the s)-Ketamine Compositions of micronization (s)-chloramines ketone powder

Composition	Amount (the milligram number of every gram of composite)
		(s)-ketamine	20.0
bht	0.002
		Poloxamer 407	160.0
Pbs buffer (0.1m)	9.0

Contain 2.0% micronization (s)-ketamine, 13.8mg bis- hydration phosphorus with the deionized water dissolving of 8.2g aseptic filtration (you are scientific and technological for winged generation for acid disodium usp (winged generation that is scientific and technological (fisher scientific.))+3.1mg monohydrate sodium dihydrogen phosphate usp (fisher scientific.))+74mg sodium chloride usp (winged generation you scientific and technological (fisher scientific.)) 10g batch of material Gel composite, and adjust ph value to 7.4 with 1m naoh.Cooling buffer solution, and under mixing, to the pbs solution of cooling In be spilled into 1.6g Poloxamer 407 (BASF AG (basf corp.), containing about 100ppm bht), mixed solution is until institute Poloxamer is had all to dissolve.Using 0.22 μm of aseptic syringe filter (Millipore Corp. (millipore of 33mm pvdf Corp.)) aseptic filtration poloxamer transfer in 2ml sterile glass bottle (Hui Dun (wheaton)) in an aseptic environment, Seal with aseptic butyl rubber stoppers (golden boolean (kimble)) closed vial and with 13mm aluminum envelope (golden boolean (kimble)).Will 20mg micronization (s)-ketamine is placed in other cleaning pyrogen removal bottle, with aseptic butyl rubber stoppers (golden boolean (kimble)) closed vial and with 13mm aluminum envelope (golden boolean (kimble)) sealing, at 140 DEG C, dry heat sterilization is carried out to bottle (winged generation that science and technology (fisher scientific) isotemp baking oven) 7 hours.In dispensing to carry out experiment as herein described Before, using No. 21 pins (hundred Emily Dickinson being connected to 1ml asepsis injector (hundred Emily Dickinson (becton dickinson)) (becton dickinson)) in the bottle containing 20mg sterile micronised (s)-ketamine, the transmission cold poloxamer of 1ml is molten Liquid, being sufficiently mixed suspension by vibration guarantees the homogeneity of suspension.Then extract suspension with No. 21 syringes, and will Pin changes No. 27 pins into and is offerd medicine.

Example 9- preparation comprises the thermoreversible gels micronization am-101 compositionss of penetration enhancers

Composition	Amount (the milligram number of every gram of composite)
		am-101	20.0
Methyl parahydroxybenzoate	1.0
		Lauryl.beta.-maltoside (a3)	1.0
hpmc	10.0
		Poloxamer 407	180.0
Tris hcl buffer (0.1m)	789.0

Delayed by 1.80g Poloxamer 407 (BASF AG (basf corp.)) is suspended in 5.00g tris hcl Rush the gel composite containing 2.0% micronization am-101 preparing 10g batch of material in liquid (0.1m), and stirring mixing is each at 4 DEG C Component is overnight to guarantee to be completely dissolved.Add (s)-ketamine (200.0mg), hydroxypropyl methyl cellulose (100.0mg), to hydroxyl Yl benzoic acid methyl ester (10mg) and Lauryl.beta.-maltoside (10mg) and extra tris hcl buffer (0.1m) (2.89g) stir, and further and be completely dissolved until observing.Mixture is maintained at a below room temperature until using.

The pbs buffer containing 17% Poloxamer 407 nf/2% ear medicament that example 10:ph value is processed to autoclaving Catabolite impact

By deionized water dissolving 351.4mg sodium chloride (the winged generation that science and technology (fisher with 79.3g aseptic filtration Scientific)), 302.1mg anhydrous dibasic sodium phosphate (winged generation that is scientific and technological (fisher scientific)), the anhydrous phosphorus of 122.1mg Acid dihydride sodium (winged generation that is scientific and technological (fisher scientific)) and appropriate ear prepare 17% Poloxamer 407/2% with medicament The stock solution of ear medicament.Cool down solution in ice-cold water-bath, then under mixing, be spilled into 17.05g pool Lip river in cold soln Husky nurse 407nf (this hundred full chemistries company (spectrum chemicals)).Further blend mixture is complete until poloxamer CL.Measure the ph value of this solution.

Pbs, ph 5.3 containing 17% Poloxamer 407/2% ear medicament.Take the aliquot of above-mentioned solution (about 30ml), and by interpolation 1m hcl regulation ph value to 5.3.

Pbs, ph 8.0 containing 17% Poloxamer 407/2% ear medicament.Take the aliquot of above-mentioned stock solution (about 30ml), and by interpolation 1m naoh regulation ph value to 8.0.

By deionized water dissolving 805.5mg sodium chloride (the winged generation that science and technology (fisher with aseptic filtration Scientific)), 606mg anhydrous dibasic sodium phosphate (winged generation that is scientific and technological (fisher scientific)), 247mg anhydrous phosphoric acid two Hydrogen sodium (winged generation that is scientific and technological (fisher scientific)), then supplies 200g to prepare pbs buffer (ph 7.3).

Prepare ear medication by being dissolved in pbs buffer and supplying 10g with pbs buffer appropriate ear with medicament 2% solution in pbs (ph 7.3) for the agent.

1ml sample is individually placed in 3ml screw-cap glass bottle (having rubber lining), and deadend.By bottle It is placed in equine Buddhist lattice (market forge) sterilmatic autoclave (environment, slow liquid) and under 250 Sterilizing 15 minutes.After autoclaving, cooling sample, to room temperature, is subsequently placed in refrigerator.Take advantage of cold mixing bottle, make sample homogenizing Change.

Observe outward appearance (for example fade and/or precipitate) and record.Using equipped with (2) 3 μm of luna c18,250 × 4.6mm tubing string) Ah's Grant (agilent) 1200 use 30-80 acetonitrile gradient (1-10min) (containing 0.05%tfa's Water-acetonitrile mixture) carry out hplc analysis, total operating time is 15 minutes.By taking 30 μ l samples and with 1.5ml 1:1 acetonitrile Aqueous mixtures dissolving carrys out dilute sample.Record autoclaving processes the purity of sample middle ear medicament.

Using said procedure test according to said procedure preparation comprise dnqx, d- methionine, micronization am-101 or The composite of micronization (s)-ketamine is to determine the impact to degraded for the ph value during autoclaving process step.

Example 11: autoclaving process to the release profiles of the pbs containing 17% Poloxamer 407 nf/2% ear medicament and The impact of viscosity

The release profiles of aliquot (autoclaving is processed and non-autoclaving is processed) of evaluate sample and viscosity measurement To assess the impact to gelling properties for the heat sterilization.

Carry out in film nesting (snapwell) (aperture is the polycarbonate membrane of 0.4 μm of diameter 6.5mm) at 37 DEG C Dissolving.0.2ml gel is placed in film nesting and is allowed to harden, then 0.5ml is placed in accumulator and is won using excellent Lay (labline) orbit shaker vibrates under 70rpm.Per hour obtain sample (extract 0.1ml and with temperature buffer exchange).Phase For external calibration standard curve, uv is utilized to analyze the poloxamer concentration of sample under 624nm using Cobaltous rhodanide method.Letter Singly say, mix 20 μ l samples and 1980 μ l 15mm Cobaltous rhodanide solution, and use evolution 160uv/vis light splitting light Degree meter (the silent science and technology (thermo scientific) of match) measures absorbance under 625nm.

The ear medicament of release is fitted to Cowes Mel-Pei Pasi equation (korsmeyer-peppas equation)

\frac{q}{q_{α}} = {kt}^{n} + b

Wherein q is the amount of the ear medicament discharging during time t, q_αIt is total burst size of ear medicament, k is the release of n time Constant, n is the dimensionless number related to dissolution mechanism and b is y-intercept, characterizes the releasing mechanism of initially outburst, wherein n=1 table Levy erosion control mechanism.Average dissolution time (mdt) is to stay drug molecule in substrate before different periods release and remove With molecule sum, and it is calculated as below:

m d t = \frac{{nk}^{- 1 / n}}{n + 1}

Using having equipped with water leg temperature conditioning unit (temperature rises to 34 DEG C with 1.6 DEG C/min from 15 DEG C) (shear rate is 0.31s to 0.08rpm^-1) under rotation cpe-51 axle Brookfield viscometer (brookfield viscometer) Rvdv-ii+p measures viscosity.T gelling is defined as the point of inflexion on a curve that viscosity increases because of sol-gel transition.

Using said procedure test according to said procedure preparation comprise dnqx, d- methionine, micronization am-101 or The composite of micronization (s)-ketamine is gelled with determining t.

Example 12: add second polymer to the composite containing 2% ear medicament and 17% Poloxamer 407 nf in heat Catabolite after sterilizing (autoclaving process) and the impact of viscosity

Solution a: by (you are scientific and technological for winged generation with the deionized water dissolving 178.35mg sodium chloride of 78.4 aseptic filtrations (fisher scientific)), 300.5mg anhydrous dibasic sodium phosphate (winged generation you scientific and technological (fisher scientific)), 126.6mg AMSP (winged generation that is scientific and technological (fisher scientific)) is prepared in pbs buffer and comprises carboxylic first The solution (ph 7.0) of base sodium cellulosate (cmc), is then spilled into 1g blanose 7m65cmc (in Hull gram in buffer solution This (hercules), viscosity when 2% is 5450cp) and heat to help dissolve, then cool down solution.

By cooling down 8.1g solution a in ice-cold water-bath, then add appropriate ear medicament, then mix, to be prepared in The solution (ph 7.0) of 17% Poloxamer 407 nf/1%cmc/2% ear medicament is comprised in pbs buffer.Under mixing, to It is spilled into 1.74g Poloxamer 407 nf (this hundred full chemistries company (spectrum chemicals)) in cold soln.Mix further Mixture is completely dissolved until all poloxamers.

Above-mentioned for 2ml sample is placed in 3ml screw-cap glass bottle (having rubber lining), and deadend.Bottle is put Go out in equine Buddhist lattice (market forge) sterilmatic autoclave (environment, slow liquid) and under 250 Bacterium 25 minutes.After autoclaving is processed, cooling sample, to room temperature, is subsequently placed in refrigerator.Take advantage of bottle still cold when mixing, make sample Product homogenize.

After autoclaving it was observed that precipitating or fading.Using equipped with (2) 3 μm of luna c18, 250 × 4.6mm tubing string) Ah's Grant (agilent) 1200 use 30-80 acetonitrile gradient (1-10min) (containing 0.05%tfa Water-acetonitrile mixture) carry out hplc analysis, total operating time be 15 minutes.By taking 30 μ l samples and with 1.5ml 1:1 second The dissolving of nitrile aqueous mixtures carrys out dilute sample.Record autoclaving processes the purity of sample middle ear medicament.

Using having equipped with water leg temperature conditioning unit (temperature rises to 34 DEG C with 1.6 DEG C/min from 15 DEG C) (shear rate is 0.31s to 0.08rpm^-1) under rotation cpe-51 axle Brookfield viscometer rvdv-ii+p measurement viscosity.T is gelled It is defined as the knee of curve that viscosity increases because of sol-gel transition.

Carry out non-autoclaving at 37 DEG C in film nesting (aperture is the polycarbonate membrane of 0.4 μm of diameter 6.5mm) Process the dissolving of sample.0.2ml gel is placed in film nesting and is allowed to harden, then 0.5ml is placed in accumulator and makes Win orbit shaker with excellent Lay to vibrate under 70rpm.Per hour obtain sample (extract 0.1ml and with temperature buffer exchange).Phase For external calibration standard curve, analyze the ear drug concentration of sample under 245nm using uv.

Contain dnqx, d- methionine, micronization am-101 or micronization (s)-ketamine using said procedure test bag Composite is to determine that adding second polymer goes out in heat to the composite containing 2% ear medicament and 17% Poloxamer 407 nf The impact of catabolite and viscosity after bacterium (autoclaving process).

Example 13: buffer type to the composite containing Poloxamer 407 nf heat sterilization (autoclaving process) it The impact of catabolite afterwards

By deionized water dissolving 377.8mg sodium chloride (the winged generation that science and technology (fisher with aseptic filtration Scientific)) and 602.9mg trometamol (sigma chemical company (sigma chemical co.)), then supply 100g preparing tris buffer, adjusts ph value to 7.4 with 1m hcl.

The stock solution of the tris buffer containing 25% Poloxamer 407 solution:

Weigh 45g tris buffer, cool down in ice-cold bath, then under mixing, be spilled into 15g pool Lip river in buffer Husky nurse 407nf (this hundred full chemistries company (spectrum chemicals)).Blend mixture is until all pool Lip rivers sand further Nurse is completely dissolved.

Prepare a series of composites with above-mentioned stock solution.All experiments are using appropriate ear with medicament (or its salt or prodrug) And/or the ear in micronization/coating/liposome particles form is with medicament (or its salt or prodrug).

The stock solution (ph 7.3) of the pbs buffer containing 25% Poloxamer 407 solution:

Using above-mentioned pbs buffer.Deionized water dissolving 704mg sodium chloride (winged generation that section with 140.4g aseptic filtration Skill (fisher scientific)), 601.2mg anhydrous dibasic sodium phosphate (winged generation you scientific and technological (fisher scientific)), 242.7mg AMSP (winged generation that is scientific and technological (fisher scientific)).Cool down solution in ice-cold water-bath, so Afterwards under mixing, it is spilled into 50g Poloxamer 407 nf (this hundred full chemistry company (spectrum in cold soln chemicals)).Further blend mixture is completely dissolved until poloxamer.

The sample using said procedure preparation listed by table 2 and 3.Add appropriate ear medicament with the sample in each sample The ear medicament that ultimate density is 2% is provided.

The sample containing tris buffer for table 2. preparation

Sample	Ph value	25% stock solution (g)	Tris buffer (g)
				20%p407/2% ear medicament/tris	7.45	8.01	1.82
18%p407/2% ear medicament/tris	7.45	7.22	2.61
				16%p407/2% ear medicament/tris	7.45	6.47	3.42
18%p4072% ear medicament/tris	7.4	7.18	2.64
				4% ear medicament/tris	7.5	-	9.7
2% ear medicament/tris	7.43	-	5
				1% ear medicament/tris	7.35	-	5
2% ear medicament/tris (suspension)	7.4	-	4.9

The sample of buffer containing pbs (ph 7.3) prepared by table 3.

Sample	25% stock solution (g) in pbs	Pbs buffer (g)
			20%p407/2% ear medicament/pbs	8.03	1.82
18%p407/2% ear medicament/pbs	7.1	2.63
			16%p407/2% ear medicament/pbs	6.45	3.44
18%p407/2% ear medicament/pbs	-	2.63
			2% ear medicament/pbs	-	4.9

1ml sample is individually placed in 3ml screw-cap glass bottle (having rubber lining), and deadend.By bottle It is placed in equine Buddhist lattice (market forge) sterilmatic autoclave (environment, slow liquid) and under 250 Sterilizing 25 minutes.After autoclaving is processed, cooling sample is to room temperature.Bottle is placed in refrigerator, and takes advantage of cold mixing so that sample Product homogenize.

Using equipped with (2) 3 μm of luna c18,250 × 4.6mm tubing string) Ah's Grant (agilent) 1200 Carry out hplc analysis, total operating time using 30-80 acetonitrile gradient (1-10min) (water-acetonitrile mixture containing 0.05%tfa) For 15 minutes.By take 30 μ l samples and with 1.5ml 1:1 acetonitrile aqueous mixtures dissolving come dilute sample.At record autoclaving The purity of reason sample middle ear medicament.Relatively stability in tris with pbs buffer for the composite.

Using having equipped with water leg temperature conditioning unit (temperature rises to 34 DEG C with 1.6 DEG C/min from 15 DEG C) (shear rate is 0.31s to 0.08rpm^-1) under rotation cpe-51 axle Brookfield viscometer rvdv-ii+p measurement viscosity.T is gelled It is defined as the knee of curve that viscosity increases because of sol-gel transition.Only analysis autoclaving does not show change after processing Composite.

Contain dnqx, d- methionine, micronization am-101 or micronization (s)-ketamine using said procedure test bag Composite is to determine that adding second polymer goes out in heat to the composite containing 2% ear medicament and 17% Poloxamer 407 nf The impact of catabolite and viscosity after bacterium (autoclaving process).The relatively composite containing micronization ear medicament is micro- with non- The efflorescence ear stability of medicament formulation homologue.

Example 14: pulse release type ear composite

By using program as herein described, using the combination of d- methionine and d- methionine hydrochloride, (ratio is 1:1) prepare pulse release type ear medicament formulation.By means of beta-schardinger dextrin-, will be molten for the d- methionine of 20% transmission dosage Solution is in 17% Poloxamer solution of example 10.Then add remaining 80% ear medicament in mixture, and using this Any program described in literary composition prepares final composite.

Using program test as herein described dnqx, d- methionine, micro- comprised according to said procedure and example preparation The pulse release type composite of efflorescence am-101 or micronization (s)-ketamine is to measure pulsed release profile.

Example 15: the pbs containing 17% Poloxamer 407/2% ear medicament/78ppm azovan blue for the preparation

By dissolving 5.9mg azovan blue (sigma chemical company (sigma with 1ml pbs buffer (from example 10) Chemical co)) prepare stock solution in pbs buffer for the azovan blue (5.9mg/ml).

Using the stock solution of the pbs buffer soln containing 25% Poloxamer 407 in this research.To stock solution The appropriate ear medicament of middle interpolation is to prepare the composite (table 4) comprising 2% ear medicament.

The Poloxamer 407 sample containing azovan blue for table 4 preparation

Dnqx, d- methionine, micronization am-101 or micronization (s)-ketamine are comprised according to said procedure preparation Composite, and via 0.22 μm of pvdf syringe filter (Millipore Corp. (millipore corporation)) aseptic mistake Filter autoclaving process.

Give the above-mentioned allotment of middle ear of Cavia porcelluss by the ability that program as herein described and composite are gelled after contact Thing, and after administration with administration after 24 hours identification gel position.

Example 16: with and without the final sterilization of the Poloxamer 407 composite of developing dye

17% Poloxamer 407/2% ear medicament/phosphate buffer, ph7.3:With 158.1g aseptic filtration go from Sub- water dissolution 709mg sodium chloride (winged generation that is scientific and technological (fisher scientific)), 742mg dehydration disodium hydrogen phosphate usp (winged generation You scientific and technological (fisher scientific)), 251.1mg monohydrate sodium dihydrogen phosphate usp (your scientific and technological (fisher of winged generation )) and appropriate ear medicament scientific.Cool down solution in ice-cold water-bath, then under mixing, be spilled into in cold soln 34.13g Poloxamer 407 nf (this hundred full chemistries company (spectrum chemicals)).Further blend mixture until Poloxamer is completely dissolved.

Phosphate buffer containing 17% Poloxamer 407/2% ear medicament/59ppm azovan blue:Take 2ml 17% Poloxamer 407/2% ear medicament/phosphate buffer and interpolation 2ml 5.9mg/ml azovan blue (Sigma-Alder Ritchie chemical company (sigma-aldrich chemical co)) pbs buffer soln.

25% Poloxamer 407/2% ear medicament/phosphate buffer:Deionization with 70.5g aseptic filtration is water-soluble Solution 330.5mg sodium chloride (winged generation that is scientific and technological (fisher scientific)), 334.5mg remove water disodium hydrogen phosphate usp (winged generation that Scientific and technological (fisher scientific)), 125.9mg monohydrate sodium dihydrogen phosphate usp (your scientific and technological (fisher of winged generation )) and appropriate ear medicament scientific.

Cool down solution in ice-cold water-bath, then under mixing, be spilled into 25.1g Poloxamer 407 nf (this in cold soln Hundred full chemistry companies (spectrum chemicals)).Further blend mixture is completely dissolved until poloxamer.

Phosphate buffer containing 25% Poloxamer 407/2% ear medicament/59ppm azovan blue:2ml25% is taken to moor Luo Shamu 407/2% ear medicament/phosphate buffer and add 2ml 5.9mg/ml azovan blue (in Sigma-Alder Strange chemical company (sigma-aldrich chemical co)) pbs buffer soln.

2ml composite is placed in 2ml vial (Hui Dun (wheaton) serum vial), and uses 13mm butyl Styrene (golden boolean (kimble) stopper) seals, and seals sealing with 13mm aluminum.Bottle is placed in equine Buddhist lattice (market Forge) sterilize 25 minutes in sterilmatic autoclave (environment, slow liquid) and at 250 times.Autoclaving After process, cooling sample to room temperature, then freezing is placed.Bottle is placed in refrigerator, and takes advantage of cold mixing so that sample homogenizing Change.Record Sample Fade after autoclaving or precipitation.

Using equipped with (2) 3 μm of luna c18,250 × 4.6mm tubing string) Ah's Grant (agilent) 1200 Successively using 30-95 methanol: acetate buffer (ph 4) gradient (1-6min) and constant gradient (11 minutes) carry out hplc analysis, Total operating time is 22 minutes.By taking 30 μ l samples and with 0.97ml water dissolution come dilute sample.Main peak record is in the following table. Using the method, before autoclaving is processed, purity is consistently greater than 99%.

Comprise dnqx, d- methionine, micronization am- using said procedure test according to prepared by program as herein described 101 or the stability to determine composite for the composite of micronization (s)-ketamine.

Example 17: in vitro the comparing of release profiles

Dissolved in film nesting (aperture is the polycarbonate membrane of 0.4 μm of 6.5mm diameter) at 37 DEG C, will 0.2ml gel as herein described composite is positioned in film nesting and is allowed to harden, and then 0.5ml buffer is placed in accumulator In and using excellent Lay win orbit shaker vibrate under 70rpm.Obtain sample per hour (to extract 0.1ml and put with warm buffer Change).Ultraviolet using 245nm analyzes the ear drug concentration of sample with respect to external calibration standard curve.Make under 624nm Analyze Pluronic concentration with Cobaltous rhodanide method.Determine the relative degrees of the average dissolution time (mdt) with %p407 change Order.Linear relationship instruction ear medicament between composite average dissolution time (mdt) and p407 concentration is because of polymer gel (poloxamer) corrodes and discharges, rather than via dispersal events.Non-linear relation instruction ear medicament via diffusion and/or is polymerized The combination release of thing gel degradation.

Or, using Li Xinyu (li xin-yu) paper [Acta Pharmaceutica Sinica (acta pharmaceutica sinica) 2008,43 (2): 208-203] the method analysis sample describing, and determine the average dissolution time (mdt) becoming with %p407 Rank order.

Comprise dnqx, d- methionine, micronization am- using said procedure test according to prepared by program as herein described 101 or the release profiles to determine ear medicament for the composite of micronization (s)-ketamine.

Example 18: in vitro the comparing of gelation temperature

For the purpose manipulating gelation temperature, assessment Poloxamer 188 and ear medicament are to Poloxamer 407 composite Gelation temperature and the impact of viscosity.

Pbs buffer stock solution and above-mentioned pbs solution using 25% Poloxamer 407.Using from BASF (basf) Poloxamer 188 nf.Add appropriate ear medicament to provide ear medicament 2% in the solution described in table 5 Composite.

The sample containing Poloxamer 407/Poloxamer 188 for table 5 preparation

Measure average dissolution time, viscosity and the gelation temperature of above-mentioned composite using program as herein described.

The data being obtained is fitted to equation, and f127/f68 mixture (17-20% can be estimated using this equation F127 and 0-10%f68) gelation temperature.

t_Gelling=-1.8 (%f127)+1.3 (%f68)+53

The data being obtained is fitted to equation, and f127/f68 can be based on using the result obtaining in examples detailed above and mix The gelation temperature of thing (17-25%f127 and 0-10%f68) utilizes this equation estimation average dissolution time (hr).

Mdt=-0.2 (t_Gelling)+8

Comprise dnqx, d- methionine, micropowder by adding appropriate ear in the solution described in table 5 and being prepared with medicament Change the composite of am-101 or micronization (s)-ketamine.Determine composite gelation temperature using said procedure.

Example 19: measure the temperature range of aseptic filtration

Viscosity under measurement low temperature needs to carry out aseptic filtration to reduce the temperature range of blocking probability to help instruct.

Using having 1,5 equipped with water leg temperature conditioning unit (temperature rises to 25 DEG C with 1.6 DEG C/min from 10 DEG C) (shear rate is 7.5,37.5 and 75s with 10rpm^-1) under rotation cpe-40 axle Brookfield viscometer rvdv-ii+p measurement viscous Degree.

It is incremented by the t gelling measuring 17% Pluronic p407 with ear drug concentration.17% Pluronic is estimated by following formula The increase of the t gelling of composite:

δt_Gelling=0.93 [ear medicament %]

Comprise dnqx, d- methionine, micronization am- using said procedure test according to prepared by program as herein described 101 or the temperature range to determine aseptic filtration for the composite of micronization (s)-ketamine.Record adds the ear medication of incrementss Agent is to the t gelling of composite and the impact of apparent viscosity.

Example 20: determine manufacturing condition

Table 6. manufactures/filtercondition under possible composite viscosity

^a37.5s^-1The viscosity recording under shear rate

The 17%p407 placebo manufacturing 8 liters of batch of materials is to assess manufacture/filtercondition.By 6.4 liters of deionized waters are put Manufacture placebo in 3 gallons of ss pressure vessels, and cool overnight in refrigerator.Morning, taking-up tank (5 DEG C of water temperature, 18 DEG C of room temperature), and add 48g sodium chloride, 29.6g dehydration disodium hydrogen phosphate and 10g monohydrate sodium dihydrogen phosphate, and mixed with overhead type Clutch (ika rw20,1720rpm) dissolves.After half an hour, once buffer solution (8 DEG C of solution temperature, 18 DEG C of room temperature), 15 Minute is slowly spilled into 1.36kg Poloxamer 407 nf (this hundred full chemistry company (spectrum in interval in buffer solution Chemicals)) (12 DEG C of solution temperature, 18 DEG C of room temperature), then speed increases to 2430rpm.Remix 1 hour afterwards, will mix Speed is down to 1062rpm (being completely dissolved).

Room temperature is maintained at a below 25 DEG C to keep solution temperature to be less than 19 DEG C.Manufacture starts rear solution temperature and is maintained at a below 19 DEG C are up to 3 hours, need not freeze/cooling container.

In solution at 20psi and 14 DEG C, assessment surface area is 17.3cm²Three different Sai Duosike (sartoscale) (Sai Duolisisitaidi company (sartorius stedim)) filter

1) sartopore 2,0.2 μm of 5445307hs-ff (pes), flow velocity: 16ml/min

2) sartobran p, 0.2 μm of 5235307hs-ff (cellulose esters), flow velocity: 12ml/min

3) sartopore 2xl1,0.2 μm of 5445307is-ff (pes), flow velocity: 15ml/min

Using sartopore 2 filter 5441307h4-ss, the use of surface area is 0.015m²0.45,0.2 μm The aseptic capsule of sartopore 2 150 (Sai Duolisisitaidi company (sartorius stedim)) under solution temperature Filtered under 16psi pressure.Under 16psi, flow velocity is tested to be about 100ml/min, when temperature maintains 6.5-14 DEG C of scope When interior, flow velocity is unchanged.The decreasing pressure of solution and increasing temperature cause flow velocity to reduce because solution viscosity increases.In this mistake The colour fading of solution is monitored during journey.

Table 7. 17% Poloxamer 407 placebo is in 6.5-14 DEG C of solution temperature ranges using sartopore 2 The filtration time that 0.2 μm of filter is predicted to obtain under 16psi pressure

Filter	Size (m²)	The flow velocity (ml/min) of estimation	Filter 8 liters of time (estimated value)
				Sartopore 2,4	0.015	100ml/min	80min
Sartopore 2,7	0.05	330ml/min	24min
				Sartopore 2,8	0.1	670ml/min	12min

Before filtering evaluation, check that viscosity, t gelling and uv/vis absorb.Pluronic uv/vis spectrum by Evolution 160uv/vis (the silent science and technology (thermo scientific) of match) obtains.Peak attribution in the range of 250-300nm There is bht stabilizer (poloxamer) in raw material.Table 8 list above-mentioned solution before filtration with physical chemistry afterwards Matter.

Table 8. 17% Poloxamer 407 placebo solution before filtration with physicochemical properties afterwards

Sample	T is gelled (DEG C)	Viscosity at 19 DEG C^a(cp)	Absorbance under 274nm
				Before filtration	22	100	0.3181
After filtration	22	100	0.3081

^a37.5s^-1The viscosity recording under shear rate

Above-mentioned technique is applied to manufacture 17%p407 composite, and includes the temperature analysis of indoor conditionss.Preferably, maximum The cost of cooling container during 19 DEG C of temperature reduction manufacture.In some cases, control solution further using jacketed vessel Temperature is to reduce the problem of manufacture view.

Example 21: the in vitro release of the micronization sample middle ear medicament that autoclaving is processed

Tris buffer containing 17% Poloxamer 407/1.5% ear medicament: by 250.8mg sodium chloride (winged generation that section Skill (fisher scientific)) and 302.4mg trometamol (sigma chemical company (sigma chemical co.)) molten Solution, in the deionized water of 39.3g aseptic filtration, adjusts ph value to 7.4 with 1m hcl.Using the above-mentioned solution of 4.9g, and will be appropriate Micronization ear medicament fully suspends and disperses.2ml composite is transferred to 2ml vial (Hui Dun (wheaton) serum glass Glass bottle) in, and sealed with 13mm butylstyrene (golden boolean (kimble) stopper), and seal sealing with 13mm aluminum.By bottle It is placed in equine Buddhist lattice (market forge) sterilmatic autoclave (environment, slow liquid) and under 250 Sterilizing 25 minutes.After autoclaving is processed, cooling sample is to room temperature.Bottle is placed in refrigerator, and takes advantage of cold mixing so that sample Product homogenize.Record Sample Fade after autoclaving or precipitation.

Dissolved in film nesting (aperture is the polycarbonate membrane of 0.4 μm of 6.5mm diameter) at 37 DEG C, will 0.2ml gel is positioned in film nesting and is allowed to harden, and then 0.5ml pbs buffer is placed in accumulator and uses excellent Lay Rich orbit shaker vibrates under 70rpm.Obtain sample per hour and [extract 0.1ml and with castor oil hydrogenated containing 2%peg-40 The warm pbs buffer exchange of (BASF (basf)) is to strengthen ear medicament dissolubility].With respect to external calibration standard curve, Ear drug concentration by the ultraviolet analysis sample of 245nm.Compare rate of release with other composite disclosed herein.Calculate The mdt time of each sample.

By using Ai Bende (eppendorf) centrifuge 5424, under 15,000rpm, Centrifuge A sample is surveyed for 10 minutes afterwards The amount supernatant middle ear concentration of medicament assesses the dissolving of 17% poloxamer system middle ear medicament.With respect to external calibration Standard curve, by the ear drug concentration in the ultraviolet measurement supernatant of 245nm.

Comprise dnqx, d- methionine, micronization am- using said procedure test according to prepared by program as herein described 101 or micronization (s)-ketamine composite to determine rate of release from each composite for the ear medicament.

Example 22: the rate of release of the composite containing sodium carboxymethyl cellulose or mdt and viscosity

17% Poloxamer 407/2% ear medicament/1%cmc (Hull Chris (hercules) blanose 7m): logical Cross 205.6mg sodium chloride (winged generation that is scientific and technological (fisher scientific)), 372.1mg bis- hypophosphite monohydrate disodium (winged generation that Scientific and technological (fisher scientific)), 106.2mg monohydrate sodium dihydrogen phosphate (your scientific and technological (fisher of winged generation Scientific prepare the pbs buffer of sodium carboxymethyl cellulose (cmc) in the deionized water)) being dissolved in 78.1g aseptic filtration Solution (ph 7.0).It is spilled into 1g blanose 7m cmc (Hull Chris (hercules), viscosity when 2% in buffer solution For 533cp) and it is heated into the solution of flowing, then cool down solution, and it is husky to be spilled into 17.08g pool Lip river under mixing in cold soln Nurse 407nf (this hundred full chemistries company (spectrum chemicals)).Appropriate by adding/dissolving in the above-mentioned solution of 9.8g Ear with medicament and mixes and comprises 17% poloxamer until all ears are completely dissolved with medicament to be prepared in pbs buffer The composite of 407nf/1%cmc/2% ear medicament.

17% Poloxamer 407/2% ear medicament/0.5%cmc (blanose 7m65): by by 257mg sodium chloride (winged generation that is scientific and technological (fisher scientific)), 375mg bis- hypophosphite monohydrate disodium (winged generation that science and technology (fisher Scientific)), 108mg monohydrate sodium dihydrogen phosphate (winged generation that is scientific and technological (fisher scientific)) is dissolved in 78.7g The pbs buffer soln (ph 7.2) of sodium carboxymethyl cellulose (cmc) is prepared in the deionized water of aseptic filtration.To buffer solution In be spilled into 0.502g blanose 7m65cmc (Hull Chris (hercules), when 2%, viscosity is 5450cp) and and be heated into The solution of flowing, then cools down solution, and (this hundred is changed entirely to be spilled into 17.06g Poloxamer 407 nf under mixing in cold soln Company (spectrum chemicals)).By adding/dissolving appropriate ear medicament in the above-mentioned solution of 9.8g and mix straight It is completely dissolved the pbs buffer soln to prepare 17% Poloxamer 407 nf/1%cmc/2% ear medicament to ear with medicament.

17% Poloxamer 407/2% ear medicament/0.5%cmc (blanose 7h9): by by 256.5mg sodium chloride (winged generation that is scientific and technological (fisher scientific)), 374mg bis- hypophosphite monohydrate disodium (winged generation that science and technology (fisher Scientific)), 107mg monohydrate sodium dihydrogen phosphate (winged generation that is scientific and technological (fisher scientific)) is dissolved in 78.6g The pbs buffer soln (ph 7.3) of sodium carboxymethyl cellulose (cmc) is prepared, then to buffering in the deionized water of aseptic filtration It is spilled into 0.502g blanose 7h9 cmc (Hull Chris (hercules), when 1%, viscosity is 5600cp) in solution and add Heat becomes the solution of flowing, then cools down solution, and (this hundred to be spilled into 17.03g Poloxamer 407 nf under mixing in cold soln Full chemistry company (spectrum chemicals)).By adding/dissolving appropriate ear medicament in 9.8 above-mentioned solution and mix Close until ear be completely dissolved with medicament to prepare 17% Poloxamer 407 nf/1%cmc/2% ear medicament pbs buffer molten Liquid.

Using having equipped with water leg temperature conditioning unit (temperature rises to 34 DEG C with 1.6 DEG C/min from 10 DEG C) (shear rate is 0.6s to 0.08rpm^-1) under rotation cpe-40 axle Brookfield viscometer rvdv-ii+p measurement viscosity.T gelling is fixed Justice is the knee of curve that viscosity increases because of sol-gel transition.

Dissolved in film nesting (aperture is the polycarbonate membrane of 0.4 μm of diameter 6.5mm) at 37 DEG C.Will 0.2ml gel is placed in film nesting and is allowed to harden, and then 0.5ml pbs buffer is placed in accumulator and is won using excellent Lay Orbit shaker vibrates under 70rpm.Per hour obtain sample, extract 0.1ml and with temperature pbs buffer exchange.With respect to outer Portion's calibration standard curve, analyzes the ear drug concentration of sample under 245nm using uv.Rate of release is public with examples detailed above The composite opened is made comparisons, and calculates the mdt time of above-mentioned each composite.

Using said procedure test according to said procedure preparation comprise dnqx, d- methionine, micronization am-101 or The composite of micronization (s)-ketamine is to determine the rate of release of the composite containing sodium carboxymethyl cellulose and/or averagely molten Relation between solution time and viscosity.Record average dissolution time (mdt) (is surveyed when 2 DEG C with apparent viscosity below gelation temperature Amount) between any relation.

Example 23: the poloxamer concentration and ear drug concentration impact to release dynamics

Prepare a series of compositionss of gellant comprising variable concentrations and micronised dexamethasone using said procedure.Make Average dissolution time (mdt) with each compositionss in above-mentioned program determination table 9.

Table 9: prepare poloxamer/ear medicament composition

Sample	ph	mdt
			15.5%p407/1.5% dexamethasone/pbs	7.4	46 hours
16%p407/1.5% dexamethasone/pbs	7.4	40 hours
			17%p407/1.5% dexamethasone/pbs	7.4	39 hours
15.5%p407/4.5% dexamethasone/pbs	7.4	> 7 days
			16%p407/4.5% dexamethasone/pbs	7.4	> 7 days
17%p407/4.5% dexamethasone/pbs	7.4	> 7 days

The impact of gel strength and ear drug concentration release dynamics from compositionss or device to ear medicament is led to The mdt of the mdt and measurement ear medicament that cross measurement poloxamer determines.Dense in outer lymph also by measurement ear medicament Degree measures the half-life of ear medicament of each composite and the mean residence time of ear medicament.

The apparent viscosity of each compositionss measured as described above.In above-mentioned composition or device, about 15.5% thermal reversibility gathers Compound gel strength provides the apparent viscosity of about 270,000cp.About 16% thermal reversibility polymerization in above-mentioned composition or device Thing gel strength provides the apparent viscosity of about 360,000cp.About 17% thermal-reversible polymers in above-mentioned composition or device Gel strength provides the apparent viscosity of about 480,000cp.

Comprise micronization dnqx, d- methionine, micronization am- using said procedure test according to prepared by said procedure 101 or micronization (s)-ketamine compositionss to determine rate of release from each compositionss for the ear medicament.

Example 24: application viscosity strengthens ear sensory cell regulator composite on round window membrane

Preparation is according to the composite comprising am-101 of example 8 preparation, and loads in 5ml siliceous glass syringe, connects In the disposable pin of No. 15 Luer rotation locks.Lignocaine (lidocaine) is locally applied to tympanum, and produces little otch to allow Observation middle ear cavity.Needle point is imported the position above round window membrane, and ear sensory cell regulator composite is directly applied to On round window membrane.

Example 25: Injection in Tympanic Cavity ear sensory cell adjusts the in vivo test of composite in Cavia porcelluss

Group (Charles River (charles river), female, weight 200-300g) Injection in Tympanic Cavity 50 to 21 Cavia porcelluss μ l contains the difference p407- ear medicament formulation as herein described of 0 to 50% ear medicament.Measure the gel row of each composite Except time-histories.The gel exclusion time-histories of composite indicates that average dissolution time (mdt) is shorter sooner.Therefore, test injection volume and The concentration of composite middle ear sensory cell regulator is to determine preclinical and clinical research optimal parameter.

Example 26: in vivo extend release dynamics

Group (Charles River (charles river), female, weight 200-300g) Injection in Tympanic Cavity 50 to 21 Cavia porcelluss μ l buffers the 17% pool Lip river for 280mosm/kg and the ear sensory cell regulator containing in terms of composite weight 1.5% to 35% Buddhist nun gram f-127 composite.Animal was administered in 1st day.Based on the release profiles that perilymphatic analysis is determined with composite.

Example 27: in tinnitus mouse model, (s)-ketamine is estimated

Ha Lunsi para Ge-Dao Li (harlan sprague-dawley) mice using 12 weights 20 to 24g.Training Each mice drinks water during voiceless sound from water dispenser, but resists in the presence of having sound and do not drink water.Cast each mice often public Jin body weight 350mg aspirin (mg/kg).

After casting aspirin, cast matched group (n=10) saline.After casting aspirin, cast experimental group (n= 10) (s)-ketamine (per kilogram of body weight 400mg).Dispensing is carried out via Injection in Tympanic Cavity.

After casting (s)-ketamine, in the presence of monitoring no external sound, whether mice drinks water.

Example 28: in the ototoxicity mouse model of cisplatin induced, n- acetylcysteine (nac) is estimated

Method and material

Induction ototoxicity

Ha Lunsi para Ge-Dao Li (harlan sprague-dawley) mice using 12 weights 20 to 24g.Measurement The baseline auditory brainstem response (abr) of 4-20mhz.Process mice with cisplatin (per kilogram of body weight 6mg).Cisplatin is filled by intravenouss Defeated it is delivered to aorta.

Process

After casting cisplatin, cast matched group (n=10) saline.After casting cisplatin, cast experimental group (n=10) nac (often public Jin body weight 400mg).

Interpretation of result

Electro physiology is tested

Initially and measure the auditory brainstem response threshold to ticking Sound stimulat for the every animal per ear in 1 week after experimental arrangement The Hearing Threshold of value (abr).Animal is held in place single wall isolation booth (the industrial acoustics company in heating plate (industrial acoustics co), USA New York Bronx (bronx, ny, usa)) in.By subintegumental electrode (A Siqu Pharmaceuticals (astro-med, inc.) Ge Lasi instrument branch company (grass instrument division), U.S. sieve obtains The fertile Brunswick (west warwick, ri, usa) in island state west) it is inserted in calvarium (active electrode), mastoid process (reference) and back leg (ground connection) On.Ticking Sound stimulat (0.1 millisecond) is produced by computer, and is delivered to 200 Europe being equipped with the otoscope being placed in external auditory meatus Beyer dt 48 speaker of nurse.Recorded abr digitized are amplified by battery-operated preamplifier, and input is right Stimulation, record and average function provide Plutarch-Davis's technology (tucker-davis technologies) of computer controls Abr record system (Plutarch-Davis's technology (tucker davis technology), Fla. Gainesville (gainesville, fl, usa)) in.The stimulation that amplitude to animal offer with 5db as stride continuously falls progressively, and ask for being remembered Stimulating the meansigma methodss (n=512) of locking activity and showing under record.Threshold definitions are that no substantially detectable response substantially may be used with having Irritation level between the record of identification.

Example 29- (s)-ketamine is as the clinical trial of tinnitus treatment

Active component: (s)-ketamine

Dosage: transmit 10ng in 10 μ l thermoreversible gels.S the release of ()-ketamine is control release and at 30 days Interior generation.

Dosing way: Injection in Tympanic Cavity

The treatment persistent period: 12 weeks

Methodology

Single centre

Perspective

At random

Double blinding

Placebo

Parallel group

Adaptability

Inclusive criteria

Masculinity and femininity between 18 years old and 64 years old for the age is individual.

Individuality with subjective tinnitus.

The tinnitus persistent period was more than 3 months.

Do not treat tinnitus within 4 weeks

Evaluation criteria

Effect (main)

1. tinnitus questionnaire overall score

Effect (secondary)

1. tin force (pattern, frequency, Tinnitus volume, audiogram, speech audiogram)

2. quality of life questionnaire

Safety

1. the terminal of comparison therapy group shifts to an earlier date incidence rate, treatment occurs adverse events, laboratory abnormalities and ecg are abnormal.

Research design

Individuality is divided into three treatment groups.First group is Safety Sample.Second group is treatment of purpose (intent-to- Treat, itt) sample.3rd group is effect effectively (vfe) group.

For each group, half individuality gives (s)-ketamine, and remaining gives placebo.

Statistical method

The overall score based on tinnitus questionnaire in itt sample for the primary efficacy analysis.Statistical analysiss are based on covariance analysis (ancova), wherein using baseline as covariant and the last value observing gained is as dependent variable.The factor is " treatment ".Survey Try the homogeneity of regression slope.Described analysis is repeated to vfe sample.

Also listen force (pattern, frequency, Tinnitus volume, audiogram, speech audiogram) via foregoing model analysis And quality of life.The not appropriateness of test model.P value is exploration and is not adjusted according to multiplicity.

Example 30- is directed to cisplatin induced ototoxicity and assesses amn082

Goal in research

The main target of this research will be with respect to placebo, assess amn082 (100mg) in prevention cisplatin induced ear Safety in toxicity and effect.

Method

Research design

This will be to compare amn082 (100mg) and 3 phase multicenter double blind randoms of placebo in cisplatin induced ototoxicity to pacify Console agent comparison parallel group research.There are about 140 individualities and will participate in this research, and suitable based on being randomly assigned of formulating of sponsor Sequence, is randomly assigned (1:1) one of to 2 treatment groups.Each group will accept amn082 100mg or placebo.

Do not replaced the individuality of this research undone.Patient will accept weekly chemotherapy, and (dosage is 70mg/m²Cisplatin, Continue 7 weeks, and daily radiotherapy).After chemotherapy, patient will accept directly to cast the research on individual round window membrane with gel composite Medicine (placebo of amn082 500mg or coupling), continues 8 weeks.

Each patient will accept hearing evaluation before each plus cisplatin in treatment.In 2 to 4 week after the cisplatin of final dose, each patient will Accept hearing evaluation.By audiogram after audiogram before comparison therapy and treatment to determine the ototoxic degree of cisplatin induced.Hereafter, Patient will accept hearing evaluation with 4 weeks for interval, treat with amn082 simultaneously.

Main inclusive criteria

Accept age of cisplatin chemotherapy sex out-patient between 18 years old and 75 years old.Expected acceptance minimum 3 The patient of wheel chemotherapy.If individuality is become pregnant during studying, then she will immediately exit from and no longer cast research medicine.

Exclusion standard

Carry out the patient of middle Otologic Surgical Proce- dures.Patient with active external ear or middle ear diseases.Aforementioned pure tone average > The patient of 40db hl.

Example 31-am-101 treats the clinical trial of noise-inducing hearing disability

Active component: am-101

Dosage: transmission comprises the compositionss of 4 weight % micronization am-101 in the thermoreversible gels of 10 μ l dosage. The release of am-101 is control release and occurs within 3 weeks.

Dosing way: Injection in Tympanic Cavity

The treatment persistent period: 12 weeks, injection in every 3 weeks was once.

Methodology

Single centre

Perspective

At random

Double blinding

Placebo

Parallel group

Adaptability

Inclusive criteria

Acoustic trauma is followed by being at least 15db by audiogram and doctor's audit report proved internal ear hearing disability Hearing disability.

Continue the acute tinnitus of at least 3 months.

Do not carry out previous tinnitus treatment within 4 weeks

Evaluation criteria

Effect (main)

1. tinnitus questionnaire overall score

Effect (secondary)

1. tin force (pattern, frequency, Tinnitus volume, audiogram, speech audiogram)

2. quality of life questionnaire

Safety

Research design

Individuality is divided into three treatment groups.First group is Safety Sample.Second group is treatment of purpose (itt) sample.The Three groups is effect effectively (vfe) group.

For each group, half individuality gives am-101, and remaining gives placebo.

Statistical method

The clinical trial that example 32- (s)-ketamine to treat is combined with implantation hearing impairment of cochlea device

Active component: (s)-ketamine is combined with dexamethasone

Dosage: comprise the compositionss of micronization (s)-ketamine and micronised dexamethasone, as lavation before surgical operation Solution and surgical site infections irrigation solution.S the release of ()-ketamine and dexamethasone is to discharge immediately.

Research design

There are 20 patients will participate in this research.10 patients will be for matched group and 10 patients will be treatment group.

Criterion of acceptability

Two ears are suffering from severe to depth preception nerve hearing impairment

There is the auditory nerve working

Live at least one shorter time in the case of no audition (averagely about 70+ decibel hearing disability)

There is good speech, language and communicative skill, or child and teen-age in the case of, have and ground with treatment Study carefully speech and family's wish of linguistic skill

Can not be fully benefited from the sonifer (hearing aids) of other species

No avoid the medical science reason of surgical operation

Each patient will be carried out with cochlea otomy and electrode insertion.Will be with surveying before surgical operation and after surgical operation The confined surgical areas of examination compositionss perfusion therapy group.Patient will be monitored 6 weeks.Will based on listen force, speech audiogram and Damage in appraisal of life quality cochlea.Generation by monitoring secondary infection and/or inflammation.

The clinical trial that example 33- ear sensory cell regulator composite is combined with surgical operation

The purpose of this research is that mensure combines the group comprising am-101 and dexamethasone casting with myringotomy Whether the compositionss closed are safe and efficient in the middle ear infection of the patient that prevention and/or treatment have syrinx.

Research type:Intervention

Research design:This will be that the existing nursing standard of comparison discharges compositionss and myringotomy in tympanum with using prolongation The non-pessimum open label research of combination.Existing nursing standard needs in surgical site infections 5-7 days using ear drop.This grinds Study carefully to be designed to test and cast in surgical operation whether sustained-release composition can exempt the needs to outpatient therapy.Survey Examination hypothesis is that in surgical operation casting the injection of single extended-release composition is not inferior to cast ear with dripping in surgical site infections Agent.

Inclusive criteria

6 months to 12 years old, one or two ear auditory forfeitures

Patient may need not carry out the Otologic Surgical Proce- dures in addition to pipe is placed in one's last year

Patient may not suffer from any will negative effect and study the disease carrying out or condition of illness

Patient may not be needed any other general antimicrobial therapy during studying

Do not allow using analgesic (in addition to acetaminophen (acetaminophen))

Exclusion standard:Age

Research approach:20 patients are divided into two groups.First group of patient will accept according to example 22 in surgery intra-operative The injection of the extended-release composition comprising micronization am-101 and micronised dexamethasone of preparation.Each patient will carry out tympanum Otomy is to place pipe.In surgery intra-operative, surgeon by clean ear, and when myringotomy otch is opened, outward Section doctor will test in compositionss injection middle ear space.After extended-release composition is injected middle ear space, insertion tube.Survey Examination compositionss are prepared with other excipient by the micronised powder that is dried of suspension am-101 and dexamethasone in situations in the surgery room, Or test compositionss are the suspensions preparing that can be used at any time injecting.

Second group of patient will give to comprise non-micronization am-101 and non-micronised dexamethasone as immediate-release component Ear drop, 5-7 days will be cast in surgical site infections.

Monitoring patient, follows the tracks of follow-up weekly, continues 1 month.Any difference of therapeutic outcome between two groups of record.

Main result measures:Time by the termination discharge of ear of patient father and mother or guardian's record.

Secondary outcome measurement:Clinical cure rate；Microorganism result；Endodontic failure；Palindromia.

Relatively each group patient therapeutic outcome with determine reduce the blennorrhea related to myringotomy, infection and/or Whether aspect of inflammation is cast the extended-release composition comprising am-101 and dexamethasone and is combined with myringotomy and be not inferior to The ear drop comprising am-101 and dexamethasone is cast after surgical operation.

Although having been shown and described the preferred embodiments of the present invention herein, these embodiments only carry by way of example For.The various replacement schemes optionally adopting embodiment as herein described implement the present invention.Wish that following claims define this The category of invention, therefore covers the method and structure in described Claims scope and its equivalent.

Claims

1. a kind of aseptic medicinal composition, it is used for treating ear's disease by casting in tympanum on or near ear round window membrane Disease, described compositionss comprise 0.1 weight % to 10 weight % micronized gacyclidine powder and comprise 14 weight % to 21 weights The acceptable thermoreversible gels of ear of amount % Poloxamer 407, so that described gacyclidine was persistently worn through the time of at least 5 days Cross round window membrane to discharge to internal ear.

2. compositionss according to claim 1, wherein said otic conditions are tinnitus.

3. compositionss according to claim 1, wherein said gacyclidine continued to release to internal ear through the time of at least 7 days Put.

4. the compositionss according to any claim in Claim 1-3, wherein said compositionss provide about 250 to arrive about The actual volume osmolality of 320mosm/l.