Methods and compositions for treating hearing impairment

Abstract

Methods and compositions for treating neurological disorders such as hearing impairment are provided. The method may include a method for treating tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease in a subject requiring such treatment by intranasal administration of a therapeutically effective amount of NMDP or a salt thereof. The composition may include an intranasal delivery formulation of a therapeutically effective amount of NMDP or a salt thereof for the treatment of neurological disorders.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Application No. 63 / 478,883, filed on 6 January 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Hearing impairment is a growing health problem with diverse and complex etiologies. While some forms of hearing impairment are clearly of genetic origin, others are virtually entirely, or at least partially, environmental.

[0003] One such common hearing impairment is tinnitus, particularly debilitating tinnitus that can lead to fatigue, stress, sleep disturbances, concentration problems, memory impairment, depression, anxiety, irritability, and headaches. Tinnitus affects about 20% of the population and is more common in older adults or those who are routinely exposed to loud noises as an occupational hazard.

[0004] Another hearing impairment is Meniere's disease, an inner ear disorder that can result in tinnitus (e.g., tinnitus-like symptoms), hearing loss or dysphonia, dizziness, and a feeling of fullness or congestion in the ear. This is not necessarily caused by exposure to loud noises and may have a genetic origin. Vertigo attacks can occur suddenly or after a short period of tinnitus-like symptoms or auditory blockage. A single vertigo attack may occur over a longer period. In other cases, many attacks may occur in clusters over several days. Some people with Meniere's disease experience extreme dizziness that can cause them to lose their balance and fall. Meniere's disease is often a severe and debilitating condition for those affected.

[0005] Treatment options for hearing impairments, such as tinnitus or Meniere's disease, are very limited, and most available treatments are non-pharmaceutical based, which do not directly treat chronic tinnitus but rather focus on subjective patient management of the condition, such as white noise machines or counseling. In this field, there is still a need for pharmaceutical compositions to alleviate, improve, and / or counteract one or more symptoms of tinnitus or Meniere's disease. [Overview of the project]

[0006] Pharmaceutical compositions for treating hearing impairment are disclosed herein. This disclosure relates to novel pharmaceutical formulations for delivering an effective amount of nimodipine (NMDP) for treating hearing impairment by transmucosal delivery, for example, intranasal delivery.

[0007] Mucosal delivery is recognized to offer several advantages over conventional methods of administering pharmaceutical formulations, such as intravenous administration, parenteral injection, or oral pills. For example, patients do not need to schedule and remember to take pill doses, nor do they need to undergo painful needle sticks. Administration is not affected by stomach or digestive problems. Mucosal delivery allows drugs to avoid degradation in the gastrointestinal tract or liver. Furthermore, mucosal delivery provides rapid delivery of the active ingredient to the subject, offering rapid relief of hearing impairment that may need to be treated quickly under certain circumstances, such as when the subject is driving a vehicle or engaged in work that requires hearing. However, formulation for intranasal delivery of nonpolar molecules such as NMDP is extremely difficult due to their low water solubility and the small volume of the nasal cavity, which limits the amount of solution that can be used to deliver the API to the subject when administered intranasally. In the art, there remains a need for intranasal formulations of NMDP that are effective in treating hearing impairment and for providing rapid relief of the symptoms of hearing impairment.

[0008] One or more embodiments disclosed herein include a pharmaceutical composition containing a therapeutically effective amount of NMDP, a composition formulated for intranasal administration, comprising a therapeutically effective amount of NMDP, a surfactant, a solvent, and a water-soluble cellulosic polymer. One or more embodiments disclosed herein include a pharmaceutical composition containing a therapeutically effective amount of NMDP, a composition formulated for intranasal administration, the composition comprising a therapeutically effective amount of NMDP, and a liquid vehicle, the liquid vehicle further comprising a surfactant, a water-soluble cellulosic polymer, a solvent, and water. One or more embodiments disclosed herein include a pharmaceutical composition containing a therapeutically effective amount of NMDP, a composition formulated for intranasal administration, comprising a therapeutically effective amount of NMDP, a surfactant, a water-soluble cellulosic polymer, a solvent, and water. In some embodiments, the formulation further comprises ethanol. In some embodiments, the ethanol is up to 5% (w / w). In some embodiments, the surfactant is polysorbate or a combination of polysorbates. In some embodiments, the surfactant is polysorbate 20 (TWEEN-20). In some embodiments, the surfactant is polysorbate 80 (TWEEN-80). In some embodiments, the surfactant is present in an amount of 0.00001% to 2% (w / w). In some embodiments, the surfactant is present in an amount of 0.05% (w / w) to 2% (w / w). In some embodiments, the water-soluble cellulosic polymer may include hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC)HEC, carboxymethylcellulose (CMC) and its sodium salt (CMC Na), or combinations thereof. In some embodiments, the water-soluble cellulosic polymer is present in an amount of 0.00001% to 2% (w / w). In some embodiments, the water-soluble cellulosic polymer is present in an amount of 0.05% (w / w) to 2% (w / w). In some embodiments, the solvent is PEG, an alkoxy derivative of polyethylene glycol, methoxypolyethylene glycol (mPEG), mPEG350, polyethylene glycol (PEG400), or combinations thereof.In some embodiments, the solvent is 0.00001% to 94% (w / w). In some embodiments, the solvent is 66% (w / w) to 94% (w / w). In some embodiments, the water is 0.0% to 50% (w / w). In some embodiments, the water is 0.0% to 20% (w / w). In some embodiments, the water is 0.00001% (w / w) to 50% (w / w). In some embodiments, the water is 0.0001% (w / w) to 20% (w / w). In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the nonionic surfactant is polysorbate or a combination of polysorbates. In some embodiments, the surfactant is polysorbate 20 (Tween-20). In some embodiments, the surfactant is polysorbate 80 (Tween-80). In some embodiments, polysorbate 80 (Tween-80) is present in an amount of 0.00001% to 2% (w / w). In some embodiments, polysorbate 80 (Tween-80) is present in an amount of 0.05% to 2% (w / w). In yet other embodiments, Tween-80 is present in an amount of less than approximately 2.5%. In some embodiments, the water-soluble cellulosic polymer is HPMC, HEC, CMC, sodium carboxymethylcellulose, or a combination thereof. In some embodiments, the water-soluble cellulosic polymer comprises HPMC alone. In some embodiments, HPMC is present in an amount of 0.00001% to 2% (w / w). In some embodiments, HPMC is present in an amount of 0.05% (w / w) to 2% (w / w). In some embodiments, the solvent is PEG, an alkoxy derivative of polyethylene glycol, mPEG, mPEG350, PEG400, or a combination thereof. In some embodiments, PEG, polyethylene glycol alkoxy derivatives, mPEG, mPEG350, PEG400, or combinations thereof are present in amounts of 0.0% to 94% (w / w).In some embodiments, PEG, polyethylene glycol alkoxy derivatives, mPEG, mPEG350, PEG400, or combinations thereof are present in an amount of 66% (w / w) to 94% (w / w). In some embodiments, water is present in an amount of 0.00001% to 20% (w / w). In some embodiments, water is present in an amount of 0.00% (w / w) to 20% (w / w).

[0009] One or more embodiments disclosed herein include a method for preparing an NMDP liquid composition, the method comprising the steps of: dissolving Tween 80 (<2% w / w) separately in mPEG350 and PEG400; mixing NMDP with the solution from step 1) to saturation solubility or a desired effective concentration; preparing an aqueous solution of HPMC or HPMC in a buffer (<2% w / w) having a pH value in the range of about 6.4 to about 7.4; adding the aqueous HPMC solution or HPMC buffer from step 3) to the respective solutions from step 2) while stirring; and allowing the mixture to stand to observe the stability of the solution or suspension. In some embodiments, the solution from step 2) is NMDP in a PEG / Tween 80 solution or NMDP in an mPEG / Tween 80 solution. In some embodiments, the concentration of NMDP is at least 68 mg / mL. In some embodiments, the concentration of NMDP is between 0.1 mg / mL and 100 mg / mL. In some embodiments, the concentration of NMDP is 68 mg / mL. In some embodiments, the concentration of NMDP is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 mg / mL.

[0010] In some embodiments, the concentration of NMDP is 50 mg / mL. In some embodiments, the surfactant, water-soluble cellulosic polymer, solvent, water, and ethanol comprise the liquid vehicle. In some embodiments, the liquid vehicle is less than 1000, 900, 800, 700, 600, 500, or 400 uL. In some embodiments, the liquid vehicle is less than 300 uL. In some embodiments, the liquid vehicle is less than 150 uL. In some embodiments, the NMDP is dissolved and suspended in the liquid vehicle, or dissolved and suspended.

[0011] Embodiments disclosed herein provide a method comprising intranasal administration of a therapeutically effective amount of NMDP or a salt thereof for treating a neurological disorder, such as hearing impairment including tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, in a subject in need thereof.

[0012] In some embodiments, the therapeutically effective dose of NMDP is about 0.1 mg to about 5 mg per kg of subject. In some embodiments, the method further comprises administering the pharmaceutical composition in a volume of about 10 μl to about 300 μl per dose. In some embodiments, the method further comprises bringing at least a portion of the therapeutically effective dose of the pharmaceutical composition into contact with the mucous membrane of at least one nasal cavity. In some embodiments, the method further comprises spraying a first amount of the pharmaceutical composition into a first nasal cavity, spraying a second amount of the pharmaceutical composition into a second nasal cavity, and optionally, after a pre-selected time delay, spraying a third amount of the pharmaceutical composition into the first nasal cavity. In some embodiments, the method further comprises optionally, administering at least a fourth amount of the pharmaceutical composition into a second nostril after a pre-selected time delay. In some embodiments, the therapeutic method achieves a bioavailability of about 80% to 125% of the bioavailability achieved with the same pharmaceutical composition administered intravenously. In some embodiments, the method further includes administering the pharmaceutical composition at any point before or after the onset of symptoms of tinnitus or Meniere's disease. In some embodiments, the method further includes administering the pharmaceutical composition at least once, twice, three, four, five, six, seven, eight, nine, or ten times daily. In some embodiments, a therapeutically effective dose of NMDP is administered intranasally every two hours. In some embodiments, a therapeutically effective dose of NMDP is administered intranasally every four hours. In some embodiments, the method further includes administering the pharmaceutical composition once a week. In some embodiments, the method further includes administering the pharmaceutical composition by low-dose therapy. In some embodiments, the method further includes administering the pharmaceutical composition by titration for vestibular symptoms. In some embodiments, the method further includes administering the pharmaceutical composition for at least one, two, three, four, five, six, fourteen, twenty-one, twenty-eight, sixty, twelve, or fourteen hundred days. In some embodiments, the method further includes administering the pharmaceutical composition in unit dosage form. In some embodiments, the method further includes administering the pharmaceutical composition in a manner that does not alter the intracochlear potential.In some embodiments, the method further includes increasing the dose of the subject's pharmaceutical composition until symptoms of inner ear dysfunction are observed. In some embodiments, symptoms of inner ear dysfunction include spontaneous nystagmus, balance disorders, motor intolerance, or hearing loss / decreased hearing, as observed with Frenzel glasses. In some embodiments, the method further includes administering the pharmaceutical composition by a drug delivery device. In some embodiments, the effects of the pharmaceutical composition are measured by an evaluation selected from the group consisting of a) measurement of changes in auditory brainstem response (ABR) threshold after administration of the pharmaceutical composition, b) changes in auditory speech recognition as measured by a words-in-noise test, c) changes in auditory speech recognition as measured by a digits-in-noise test, d) changes in low-frequency hearing threshold, e) changes in the incidence of adverse events after administration of the pharmaceutical composition, f) changes in the severity of tinnitus or Meniere's disease, g) changes in the volume of tinnitus or Meniere's disease, h) changes in the severity of dizziness, i) changes in ear fullness, j) changes in dizziness, and k) changes in hair cell function observed when measured by changes in ABR threshold. In some embodiments, the ABR threshold is measured in the frequency range of 200 Hz to 30 kHz.

[0013] Embodiments disclosed herein provide a method for treating tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease in a subject who requires it, the method comprising: administering an L-type calcium channel blocker to the subject; evaluating whether the subject has responded to the L-type calcium channel blocker; and, if the subject has responded to the L-type calcium channel blocker, administering a therapeutically effective amount of NMDP or a salt thereof to the subject.

[0014] In some embodiments, the method further comprises administering a therapeutically effective amount of NMDP or a salt thereof into the nasal cavity of a patient for the treatment of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease. In some embodiments, the therapeutically effective amount of NMDP is administered in a composition comprising a therapeutically effective amount of NMDP; a carrier; a citrate buffer; and benzalkonium chloride. In some embodiments, the therapeutically effective amount of NMDP is administered in a composition comprising a therapeutically effective amount of NMDP; one or more natural or synthetic carriers or any combination thereof in an amount of about 30% to about 95% (w / w); and a non-aqueous solvent of about 10% to about 70% (w / w); and a surfactant. In some embodiments, the therapeutically effective amount of NMDP is administered in a composition comprising at least one of PEG, mPEG, or water. In some embodiments, the therapeutically effective amount of NMDP is administered in a composition comprising PEG, mPEG, and water. In some embodiments, a therapeutically effective dose of NMDP is administered in a composition containing about 20% to about 90% (w / w) mPEG, about 10% to about 50% (w / w) PEG, and about 5% to about 20% (w / w) water and NMDP. In some embodiments, a therapeutically effective dose of NMDP is administered in a composition containing about 70% (w / w) mPEG, about 20% (w / w) PEG, and about 10% (w / w) water.

[0015] Embodiments disclosed herein provide a method for achieving an area under the therapeutic efficacy curve (AUC) extrapolated to infinity (AUC0-infinity) from the administration time of NMDP in a subject requiring such treatment, comprising intranasally administering an intranasal pharmaceutical composition to a subject, wherein the intranasal pharmaceutical composition comprises about 0.1 mg to about 5 mg / kg of NMDP or a pharmaceutically acceptable salt thereof; a buffer; and a surfactant, and the subject exhibits an AUC0-infinity of NMDP of about 200 h*ng / mL to 400 h*ng / mL after administration of the intranasal pharmaceutical composition to the subject.

[0016] One embodiment disclosed herein provides a pharmaceutical composition comprising a therapeutically effective amount of NMDP, a composition formulated for intranasal administration, comprising a therapeutically effective amount of NMDP; a buffer; a penetration enhancer; and a surfactant.

[0017] In some embodiments, the composition further comprises one or more components selected from vitamin E, benzyl alcohol, and dodecyl maltoside. In some embodiments, the concentration of NMDP in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 4 The dosages are 2.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, or 400 mg / ml. In some embodiments, the volume of the pharmaceutical composition administered is 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0 ml. In some embodiments, the pharmaceutical composition is a sustained-release formulation. In some embodiments, the pharmaceutical composition is a sustained-release formulation. In some embodiments, the pharmaceutical composition is a controlled-release formulation. In some embodiments, the pharmaceutical composition is released continuously, variablely, in a pulsatile manner, or a combination thereof. In some embodiments, the pharmaceutical composition is a unit dosage form. In some embodiments, the unit dosage form is a dry powder, a semi-solid, a mucosal adhesive formulation, an intranasal vesicle unit, or a solution dosage form. In some embodiments, the composition is aqueous. In some embodiments, the composition is in the form of a gel or a film. In some embodiments, the composition contains micronized particles. In some embodiments, the unit dosage form has a unit weight of about 10 mg to about 10 g. In some embodiments, the unit dosage form has a unit weight of about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about 300 mg, about 10 mg to about 500 mg, about 10 mg to about 1 g, or about 10 mg to about 5 g.In some embodiments, the solution dosage form has a unit dose of less than about 900 μL, 800 μL, 700 μL, 600 μL, 500 μL, 400 μL, 300 μL, 200 μL or less than 100 μL. In some embodiments, the pharmaceutical composition comprising NMDP has a concentration of about 0.1% to about 20% w / w of the formulation. In some embodiments, the pharmaceutical composition extends the residence time of the composition in the ear structure. In some embodiments, the formulation extends the residence time of the composition in the ear structure for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 8 days, or at least 14 days, at least 21 days, or at least 1 month, or at least 6 weeks after a single administration. In some embodiments, the formulation increases the bioavailability of the composition in the ear structure. In some embodiments, the formulation increases the steady-state level of the composition in the ear structure. In some embodiments, the formulation increases the time to reach a Cmax at a therapeutic concentration that can reduce the symptoms of hearing impairment in a subject who needs it. In some embodiments, the formulation extends the time that the concentration of the composition remains above the minimum therapeutic concentration (i.e., Cmin) required to reduce the symptoms of hearing impairment in a subject who needs it. In some embodiments, the concentration of the composition in the ear structure remains at or above approximately Cmin for at least 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 3 weeks or 1 month. In some embodiments, the pharmaceutical composition further comprises a second pharmaceutically active agent.

[0018] Aspects disclosed herein provide a pharmaceutical composition comprising a therapeutically effective amount of NMDP, the composition is formulated for intranasal administration, and the composition The composition comprises a therapeutically effective amount of NMDP; a solvent; and water. In some embodiments, the solvent is PEG, an alkoxy derivative of polyethylene glycol, mPEG, mPEG350, PEG400, or a combination thereof. In some embodiments, the solvent constitutes 0.00001% to 94% (w / w) of the composition. In some embodiments, the solvent constitutes 66% to 94% (w / w) of the composition. In some embodiments, water constitutes 0.00001% to 20% (w / w) of the composition. In some embodiments, the composition further comprises a first solvent and a second solvent. In some embodiments, the first solvent comprises mPEG and the second solvent comprises PEG. In some embodiments, mPEG comprises mPEG350. In some embodiments, PEG comprises PEG400. In some embodiments, a therapeutically effective dose of NMDP includes at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 60 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 110 mg / mL, or greater than 110 mg / mL. In some embodiments, mPEG constitutes about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, or about 80% to about 90% (w / w) of the composition; PEG constitutes about 10% to about 50%, about 20% to about 50%, about 30% to about 50%, or about 40% to about 50% (w / w) of the composition; and water constitutes about 5% to about 20%, about 10% to about 20%, or about 15% to about 20% (w / w) of the composition. In some embodiments, the composition further comprises ethanol. In some embodiments, ethanol constitutes about 1% to about 10%, about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, about 5% to about 10%, about 6% to about 10%, about 7% to about 10%, about 8% to about 10%, or about 9% to about 10% of the composition.

[0019] These and other objects and features of the present disclosure will be more fully understood by reading the following detailed description of the present disclosure in conjunction with the accompanying examples and drawings.

[0020] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference.

[0021] The novel features of the present disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description which illustrates exemplary embodiments in which the principles of the present disclosure are utilized, and to the accompanying drawings.

Brief Description of the Drawings

[0022] [Figure 1A] It is a diagram showing the results of a no-go test, indicating the effectiveness of treating tinnitus with various doses of a drug of interest compared to subjects treated with physiological saline. [Figure 1B] It is a diagram showing the results of a go test, indicating the motivation, hearing ability, and learning and memory of the subjects, and serving as a control for the no-go test regarding the effect of the drug on the behavior of the subjects. [Figure 2A] It is a chart summarizing the results indicating the motivation, hearing ability, and learning and memory of the subjects, and serving as a control for the no-go test regarding the effect of the drug on the behavior of the subjects. [Figure 2B] It shows a graph summarizing the results indicating the motivation, hearing ability, and learning and memory of the subjects, and serving as a control for the no-go test regarding the effect of the drug on the behavior of the subjects. [Figure 2C] It shows a chart summarizing the results of the no-go test, indicating the effectiveness of treating tinnitus or tinnitus-like symptoms with various doses of a drug of interest compared to subjects treated with physiological saline. [Figure 2D] A graph summarizing the results of the no-go trial is shown, illustrating the effectiveness of various doses of the drug of interest in treating tinnitus or tinnitus-like symptoms compared to subjects treated with saline. [Figure 3] This document summarizes the go / no-go test tone-based avoidance detection methodology used in this specification. [Modes for carrying out the invention]

[0023] NMDP is a calcium channel blocker (CCB) belonging to the dihydropyridine class, and is a highly lipophilic drug that rapidly crosses the blood-brain barrier.

[0024] Formulating NMDP for intranasal delivery is difficult due to its high lipophilicity, including its low number of hydrogen bond donors and high number of hydrogen bond acceptors. The NMDP molecule does not have many hydroxyl groups. Instead, NMDP has many carbonyl groups that do not provide electron-donating pairs, which reduces its water solubility by forming hydrogen bonds.

[0025] Furthermore, to facilitate intranasal administration of NMDP, an effective amount of NMDP should be dissolved or finely dispersed in a small liquid vehicle. If the volume is too large, it may be expelled forward through the nostrils or backward towards the pharynx, in which case the excess liquid is swallowed. As a result, with large doses, some of the NMDP may be lost from the absorption site, making it difficult, if not impossible, to reproducibly administer the correct dose of the therapeutic agent. Therefore, for intranasal administration, it is desirable to have a high concentration of dissolved NMDP or a dispersed NMDP content in a small liquid vehicle.

[0026] Furthermore, to support drug absorption through the nasal mucosa, two natural protective functions—mucosal ciliary clearance (MCC) and the barrier properties of the tissue—muscle must be avoided. The effective dose should ideally avoid the natural properties of the mucous layer as a protective layer, i.e., increase drug absorption, and the natural properties of the MCC as an effective cleansing mechanism. In other words, it is desirable to increase the residence time of the applied dose in the mucosal layer.

[0027] In response to an unmet need in the art for pharmaceutical compositions for treating hearing impairment, disclosed herein are pharmaceutical compositions for treating hearing impairment, such as tinnitus or Meniere's disease. This disclosure relates to a novel pharmaceutical formulation for delivering an effective amount of NMDP for treating hearing impairment by transmucosal delivery, such as intranasal delivery.

[0028] Mucosal delivery is recognized as offering several advantages over conventional methods of administering pharmaceutical formulations, such as intravenous, injection, or oral administration. For example, patients do not need to schedule and remember to take a pill dose, nor do they need to undergo painful needle sticks. Administration is unaffected by stomach or digestive problems. Mucosal delivery allows drugs to avoid degradation in the gastrointestinal tract or liver. Therefore, mucosal delivery is of particular interest for molecules with short half-lives and limited systemic bioavailability, such as NMDP. Furthermore, mucosal delivery provides rapid delivery of active agents to subjects, offering rapid relief of hearing impairments, such as tinnitus or Meniere's disease.

[0029] Mucosal administration, such as intranasal, buccal, sublingual, rectal, and pulmonary administration, is attracting particular attention because it avoids many of the drawbacks of injecting therapeutic agents while still providing potent and rapid systemic effects. To be an attractive alternative to injection, mucosal administration, such as intranasal administration, should not cause significant pain, discomfort, irritation, or irreversible damage to the mucosal surface. However, in cases of acute indications threatening health, relatively high local irritation to the mucosa may be acceptable.

[0030] For mucosal administration, such as intranasal, buccal, or rectal administration, the therapeutic agent should be applied to the mucosa in a vehicle that allows it to penetrate the mucosa or be absorbed through the mucosa. To penetrate the mucus, the vehicle must be biocompatible with mucus and therefore must have some degree of hydrophilicity. However, the vehicle should also preferably have lipophilic properties to dissolve a clinically appropriate amount of the therapeutic agent of interest.

[0031] The extensive network of capillaries beneath the mucosal surface, particularly in the nasal mucosa, is well-suited for providing rapid and effective systemic absorption of drugs, vaccines, and biological agents. Furthermore, the nasal epithelial membrane substantially contains a monolayer of epithelial cells (pseudostratified epithelium) and is therefore more suitable for drug administration than other mucosal surfaces with squamous epithelial layers, such as the mouth and vagina.

[0032] Intranasal delivery offers several advantages over other routes of administration, namely non-invasiveness, rapid achievement of therapeutically appropriate concentrations in the bloodstream, no first-pass metabolism, and ease of administration. Feasible transnasal delivery technologies have the potential to enable drug developers to create innovative medicines by using already approved products through new routes of administration. Intravenous administration of NMDP has several disadvantages compared to transmucosal administration, such as increased side effects. However, formulation for intranasal delivery of nonpolar molecules such as NMDP is extremely difficult due to their low water solubility and the small volume of the nasal cavity, which limits the amount of solution that can be used to deliver the API to the subject when administered intranasally. In this art, there remains a need for intranasal formulations of NMDP effective in treating hearing impairments, such as tinnitus or Meniere's disease, and for providing rapid relief of hearing impairment symptoms.

[0033] These researchers have developed a composition that alleviates symptoms of tinnitus or Meniere's disease after administration of one or more doses of the pharmaceutical composition by delivering an effective dose of NMDP equivalent via mucosal delivery.

[0034] definition Unless otherwise defined, all technical terms, notations, and other technical and scientific or specialized terms used herein are intended to have the same meaning as those generally understood by those skilled in the art in the field to which the claimed subject matter pertains. In some embodiments, terms having a generally understood meaning are defined herein for clarity and / or quick reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from those generally understood in the art.

[0035] Throughout this application, various embodiments can be presented in scope form. It should be understood that scope form descriptions are merely for convenience and brevity and should not be interpreted as inflexible limitations on the scope of this disclosure. Therefore, scope descriptions should be considered to specifically disclose all possible sub-ranges and the individual numbers within those ranges. For example, a scope description such as 1-6 should be considered to specifically disclose sub-ranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within those ranges, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0036] Where used herein and in the claims, the singular forms "a," "an," and "the" include multiple references unless otherwise explicitly indicated by the context. For example, the term "sample" includes multiple samples, including mixtures thereof.

[0037] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present or not (e.g., detection). These terms may include quantitative determination, qualitative determination, or both quantitative and qualitative determination. Evaluation may be relative or absolute. “Detecting the presence of ~” may, depending on the context, include determining the quantity of something that is present or not, in addition to determining whether it is present or not.

[0038] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” may be a biological entity containing expressed genetic material. A biological entity may be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject may be a tissue, cell, or offspring of a biological entity obtained in vivo or cultured in vitro. A subject may be a mammal. A mammal may be a human. A subject may be diagnosed or suspected of being at high risk of disease. In some embodiments, it is not necessary for a subject to be diagnosed or suspected of being at high risk of disease.

[0039] The term "in vivo" is used to describe events that occur inside a subject's body.

[0040] The term "ex vivo" is used to describe events that occur outside the body of a subject. Ex vivo assays are not performed on the subject; rather, they are performed on samples isolated from the subject. An example of an ex vivo assay performed on a sample is an "in vitro" assay.

[0041] The term "in vitro" is used to describe events that occur when experimental reagents are contained in a container to be held so that the material can be separated from the biological source from which it is obtained. In vitro assays can encompass cell-based assays in which live or dead cells are used. In vitro assays can also encompass cell-free assays in which intact cells are not used.

[0042] As used herein, the term “approximately” refers to a number within ±10% of that number. The term “approximately” range refers to a range that extends from 10% minus its lowest value to 10% plus its highest value.

[0043] As used herein, the terms “treatment” or “treating” are used in reference to pharmaceutical or other intervention regimens for obtaining beneficial or desired outcomes in a recipient. Beneficial or desired outcomes include, but are not limited to, therapeutic benefits and / or preventive benefits. A therapeutic benefit may refer to the eradication or improvement of the symptom or underlying condition being treated. Furthermore, a therapeutic benefit may be achieved by the eradication or improvement of one or more physiological symptoms associated with an underlying condition, such that improvement is observed in the subject, even though the subject may still have the underlying condition. A preventive effect includes delaying, preventing, or eliminating the onset of a disease or condition; delaying or eliminating the onset of symptoms of a disease or condition; delaying, stopping, or reversing the progression of a disease or condition; or any combination thereof. For a preventive benefit, a subject at risk of developing a particular disease, or a subject reporting one or more physiological symptoms of a disease, may receive treatment even if a diagnosis of the disease could not be made.

[0044] The term "NMDP" is intended to relate to NMDP or a pharmaceutically acceptable salt thereof. The term "equivalent to about... NMDP" is intended to relate to a specified volume, concentration, or amount of free NMDP base provided by a certain volume, concentration, or amount of a salt of NMDP. Thus, the specified amount relates to the amount of free NMDP base and not the amount of NMDP salt, despite the use of the salt in the composition. In one embodiment, the compositions, methods, and uses of the present disclosure involve the use of NMDP citrate.

[0045] The term “formulated” is intended to relate to the selection of excipients, carriers, vehicles, preservatives, stabilizers, etc., in the preparation of a pharmaceutical product using the composition. The term “formulated” is further intended to relate to the selection of a device for delivering the composition, or the selection of a storage device for administering or storing the composition.

[0046] The term “dosage unit” refers to a composition administered in a single dose by a single delivery action. In embodiments where the composition is formulated for transmucosal administration by nasal delivery, the dose unit is the volume of the composition to be administered or the amount of drug administered by a single delivery action. The delivery action is the action of delivering the dose unit. In this embodiment, the delivery action is the administration of the dose unit into the nasal cavity by a delivery system, e.g., a nasal spray or other means known to those skilled in the art. Suitable devices are commercially available, for example, from Pfeiffer and Valois. The terms “dosage” and “therapeutic dose” refer to the total amount of drug or volume of composition applied by the administration of dose units during therapy. The therapy refers to the administration of the composition during a single episode of hearing impairment including tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, the episode continuing until the tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease are relieved.

[0047] The term "onset time" is intended to mean the moment when a patient begins to experience tinnitus or Meniere's disease, or a reduction in the symptoms of tinnitus or Meniere's disease, as a result of a sufficient plasma concentration of NMDP. The plasma concentration sufficient to achieve all of this varies among patients, patient class and type, as well as the nature of tinnitus or Meniere's disease, or the symptoms of tinnitus or Meniere's disease experienced. "Effect" in "onset time" refers to tinnitus or Meniere's disease, or a reduction in the symptoms of tinnitus or Meniere's disease.

[0048] The term "duration of action" refers to the duration over which a patient consistently experiences tinnitus or Meniere's disease, or a reduction in the symptoms of tinnitus or Meniere's disease.

[0049] "Long-term" refers to a period exceeding approximately four months, preferably exceeding approximately six months.

[0050] The phrase "an amount effective in suppressing one or more symptoms of tinnitus or Meniere's disease" refers to the dose of the therapeutic compound that reduces one or more symptoms of tinnitus or Meniere's disease in a subject after delivery of the pharmaceutical composition.

[0051] The terms used herein are for illustrative purposes only to describe specific embodiments and are not intended to limit the disclosure. The terms “comprising” and “comprises” as used in the claims should not be construed as limiting to the components and processes listed thereafter. They do not exclude other components or processes. They should be construed as specifying the presence of the described features, integers, processes and / or components as mentioned, but not as excluding the presence and / or addition of one or more other features, integers, processes or components, or groups thereof. Accordingly, the scope of the expression “composition comprising A and B” is not limited to a composition comprising only components A and B. Similarly, the scope of the expression “method comprising processes X and Z” is not limited to a method comprising only those processes.

[0052] Where used herein, the term “approximately” refers to a number within ±10% of that number. The term “approximately” range refers to a range that spans 10% minus its lowest value and 10% plus its highest value. For example, the term “approximately” can be immediately understood as being within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. As an example, the numerical range “approximately 1 to approximately 5” shall be interpreted to include not only the explicitly listed values ​​of approximately 1 to approximately 5, but also the individual values ​​and subranges within the indicated range. This includes, at a minimum, the degree of experimental error, technical error, and instrumental error expected for a given experiment, technique, or instrument used to measure the value.

[0053] Where used herein, the term "and / or" includes any combination of one or more of the related enumerated items. Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Terms defined, for example, in commonly used dictionaries, should be construed to have the meaning consistent with their meaning in the context of this specification and the related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Well-known features or configurations may not be described in detail for the sake of brevity and / or clarity.

[0054] When an element is described as "on top of," "attached to," "connected to," "joined to," or "in contact with" another element, it will be understood that it may be directly on top of, attached to, connected to, joined to, or in contact with the other element, or that there may be an intervening element. In contrast, when an element is described, for example, as "directly on top of," "directly attached to," "directly connected to," "directly joined to," or "in direct contact with" another element, there is no intervening element. It will also be understood by those skilled in the art that a reference to a structure or form positioned "adjacent" to another form may have a portion that overlaps with or is beneath the adjacent form.

[0055] The terms “activator,” “pharmaceutical activator,” “activity,” “API,” “pharmaceutical active ingredient,” “active substance,” “active molecule,” “active compound,” or “drug” are used interchangeably with NMDP or its salts.

[0056] Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by those skilled in the art in which this disclosure pertains. Terms defined, for example, in commonly used dictionaries, should be construed to have meanings consistent with those in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Well-known features or configurations may not be described in detail for the sake of brevity and / or clarity.

[0057] The disintegrants contained in the disclosed compositions are inert carriers, as described in detail below. It should be noted that “disintegrant,” “carrier,” “diluent,” and “de-agglomerant” are used interchangeably herein and refer to inert components added to pharmaceutical compositions, including the second type of particles described above.

[0058] When the "mucosal delivery enhancer" is added to a formulation containing water, salt and / or a general buffer and NMDP (control formulation), it increases the maximum concentration (C) of blood, serum, or cerebrospinal fluid. max Mucosal delivery enhancers are defined as chemicals and other excipients that result in formulations that significantly increase the transport of NMDP across mucosa, as measured by the area under the curve (AUC) in a concentration-versus-time plot. Mucosa includes the mucosal surfaces of the nose, mouth, intestines, cheeks, bronchopulmonary system, vagina, and rectum, and all mucus-secreting membranes that line the inside of all body cavities or passages that communicate with the outside. Mucosal delivery enhancers are sometimes also called carriers, excipients, additives, enhancers, or boosters (e.g., thickeners).

[0059] "Endotoxin-free formulations" means formulations containing NMDP and one or more mucosal delivery enhancers that are substantially free of endotoxins and / or associated pyrogens. Endotoxins include toxins that are trapped inside microorganisms and released only when the microorganisms decompose or die. Pyrogens include thermostable substances (glycoproteins) that induce heat generation from the outer membranes of bacteria and other microorganisms. These substances can cause fever, hypotension, and shock when administered to humans. The manufacture of endotoxin-free formulations may require specialized equipment and experts and can be significantly more expensive than the manufacture of endotoxin-containing formulations.

[0060] "Non-injection administration" means any method of delivery that does not involve direct injection into an artery or vein, such as by a needle, syringe, or other invasive method of pushing or injecting (typically a fluid) into something, particularly to introduce it into a part of the body. Non-injection administration includes non-injection methods of subcutaneous injection, intramuscular injection, intraperitoneal injection, and mucosal delivery.

[0061] In some embodiments, “Subject” is a subject whose symptoms and symptoms, physical examination results and / or psychological examination results are determined and recorded in relation to the individual’s condition (i.e., state of disease or disability). As used herein, disease or disability is hearing impairment. As used herein, disease or disability is tinnitus or Meniere’s disease. As used herein, “Subject” is intended to be, but not necessarily limited to, a human subject. A subject may be male or female and may be of any race or ethnicity, for example, but not limited to, Caucasian, African American, African, Asian, Hispanic, Native American, etc. As used herein, a subject is an animal, in particular a mammal that can be treated according to the methods of this disclosure or screened for veterinary and pharmaceutical or pharmaceutical drug development purposes, for example, dogs, cats, cattle, goats, horses, sheep or both, pigs, rodents (e.g., rats and mice), rabbits, primates (including non-human primates), etc. In some embodiments of this disclosure, a subject may include a patient or human requiring therapeutic treatment for a treatable disorder.

[0062] NMDP composition The pharmaceutical compositions of this disclosure contain NMDP or a salt thereof in a suitable solvent at a concentration equivalent to about 0.4 to 75 mg / mL of NMDP. In some embodiments, the concentration equivalent of NMDP may be greater than 75 mg / mL. In some embodiments, the concentration equivalent of NMDP may be 25 mg / mL. In some embodiments, the concentration equivalent of NMDP may be 50 mg / mL. In some embodiments, the concentration equivalent of NMDP may be 75 mg / mL. In some embodiments, the concentration equivalent of NMDP may be 100 mg / mL. The compositions are typically formulated appropriately for transmucosal administration to deliver NMDP via the nasal mucosa.

[0063] The therapeutically effective dose of NMDP or its salt may be at least 1 μg of NMDP or its salt per kg of subject. The therapeutically effective dose of NMDP or its salt may also be less than 100 mg of NMDP or its salt per kg of subject. The therapeutically effective dose of NMDP or its salt is in the range of 1 μg to 1000 mg of NMDP or its salt per kg of subject. In some embodiments, the therapeutically effective dose of NMDP or its salt is in the range of 16 mg to 24 mg of NMDP or its salt per kg of subject. In some embodiments, the therapeutically effective dose of NMDP or its salt is in the range of 30 mg to 100 mg of NMDP or its salt per kg of subject. In some embodiments, the therapeutically effective dose of NMDP or its salt is in the range of 30 mg to 100 mg of NMDP or its salt per kg of subject.

[0064] A therapeutically effective dose of NMDP or a salt thereof can be administered before the onset of hearing impairment, such as tinnitus or Meniere's disease. A therapeutically effective dose of NMDP or a salt thereof can be administered at least about one hour before the onset of hearing impairment, for example, at least about one hour, two hours, three hours, four hours, five hours, six hours, twelve hours, 24 hours, 36 hours, forty-eight hours, three days, four days, five days, six days, seven days, two weeks, three weeks, or one month before the onset of hearing impairment. A therapeutically effective dose of NMDP or a salt thereof can be administered less than one month before the onset of hearing loss, for example, less than one hour, two hours, three hours, four hours, five hours, six hours, twelve hours, twenty-four hours, thirty-six hours, forty-eight hours, three days, four days, five days, six days, seven days, two weeks, three weeks, or one month before the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered at least 12 hours before the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered less than 10 days before the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered 12 hours to 10 days before the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered 12 hours to 48 hours before the onset of hearing impairment.

[0065] A therapeutically effective dose of NMDP or a salt thereof can be administered after or at the same time as the onset of hearing impairment, such as tinnitus or Meniere's disease. A therapeutically effective dose of NMDP or a salt thereof can be administered at least about 1 minute after the onset of hearing impairment, for example, at least about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 12 minutes, 24 minutes, 36 minutes, 48 ​​minutes, 54 minutes, or 60 minutes after the onset of hearing impairment. A therapeutically effective dose of NMDP or a salt thereof can be administered at least about 1 hour after the onset of hearing impairment, for example, at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 1 month after the onset of hearing impairment. A therapeutically effective dose of NMDP or a salt thereof may be administered less than approximately one month after the onset of hearing loss, for example, less than approximately one hour, two hours, three hours, four hours, five hours, six hours, twelve hours, twenty-four hours, thirty-six hours, forty-eight hours, three days, four days, five days, six days, seven days, two weeks, three weeks, or one month after the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered at least 12 hours after the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered less than ten days after the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered 12 to ten hours after the onset of hearing impairment. In some embodiments, a therapeutically effective dose of NMDP or a salt thereof is administered 12 to 48 hours after the onset of hearing impairment.

[0066] Effective dose range The therapeutically effective dose of NMDP may depend on the subject's body weight. In some embodiments, the therapeutically effective dose of NMDP is at least about 1 mg of NMDP per kg of subject, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 200 mg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is less than about 1000 μg of NMDP per kg of subject, for example, less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 μg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 1 μg to 1000 μg of NMDP per kg of subject, for example, approximately 1 to 700, 1 to 500, 1 to 300, 1 to 100, 1 to 50, 1 to 10, 10 to 700, 10 to 500, 10 to 300, 10 to 100, 10 to 80, 10 to 60, 10 to 40, 10 to 20, 50 to 700, 50 to 500, 50 to 300, 50 to 100, 100 to 700, 100 to 500, 100 to 300, 300 to 700, 300 to 500, or 500 to 700 μg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 1 μg to 10 μg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 10 μg to 100 μg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 100 μg to 500 μg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 1 μg to 1000 mg of NMDP per kg of subject, for example, approximately 1 to 700, 1 to 500, 1 to 300, 1 to 100, 1 to 50, 1 to 10, 10 to 700, 10 to 500, 10 to 300, 10 to 100, 10 to 80, 10 to 60, 10 to 40, 10 to 20, 50 to 700, 50 to 500, 50 to 300, 50 to 100, 100 to 700, 100 to 500, 100 to 300, 300 to 700, 300 to 500, or 500 to 700 mg of NMDP per kg of subject.In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 16 mg to 24 mg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 30 mg to 100 mg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 50 mg to 140 mg of NMDP per kg of subject. In some embodiments, the therapeutically effective dose of NMDP is in the range of approximately 115 mg to 125 mg of NMDP per kg of subject. The therapeutically effective dose of NMDP may also be the daily dose of NMDP administered to a subject.

[0067] In a pharmaceutical composition containing a therapeutically effective amount of NMDP and one or more APIs, the amount of API in the pharmaceutical composition may depend on the subject's body weight. In some embodiments, the amount of API in the pharmaceutical composition is at least about 1 mg of API per kg of subject, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200 mg of API per kg of subject. In some embodiments, the amount of API in the pharmaceutical composition is less than about 1 mg of API per kg of subject, for example, less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200 mg of API per kg of subject. In some embodiments, the amount of API in the pharmaceutical composition is in the range of about 1 to 200 mg of API per kg of subject. In some embodiments, the therapeutically effective dose of the API is in the range of about 30 mg to 100 mg of API per kg of subject. In some embodiments, the therapeutically effective dose of the API is in the range of about 50 mg to 140 mg of API per kg of subject. The therapeutically effective dose of the API may also be the daily dose of the API to the subject. For example, the daily dose of a sodium channel blocker, antioxidant, NMDA antagonist, SSRI, or combination SSRI / NMDA antagonist may be about 1 to 500 mg / day, preferably 4 to 250 mg / day.

[0068] The concentration of NMDP in a pharmaceutical composition may be at least about 0.1% by weight, for example, at least about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. The concentration of NMDP in a pharmaceutical composition may be less than about 99% by weight, for example, less than about 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, or less than 99%. The concentration of NMDP in a pharmaceutical composition may range from approximately 0.1% to 99% by weight, for example, 0.1-0.5%, 0.1-1%, 0.5-1%, 1-2%, 1-5%, 1-10%, 2-5%, 2-10%, 5-10%, 10-15%, 15-20%, 20-30%, 30-50%, 50-70%, 70-90%, 90-95%, or 95-99%. In some embodiments, the concentration of NMDP in the pharmaceutical composition is in the range of 1-10%. In some embodiments, the concentration of NMDP in the pharmaceutical composition is in the range of 10-50%. In some embodiments, the concentration of NMDP in the pharmaceutical composition is in the range of 70-90%.

[0069] The concentration of the API in the pharmaceutical composition may be at least about 0.1% by weight, for example, at least about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. The concentration of the API in the pharmaceutical composition may be less than about 99% by weight, for example, less than about 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, or less than 99%. The concentration of the API in the pharmaceutical composition may range from approximately 0.1 to 99% by weight, for example, 0.1 to 0.5%, 0.1 to 1%, 0.5 to 1%, 1 to 2%, 1 to 5%, 1 to 10%, 2 to 5%, 2 to 10%, 5 to 10%, 10 to 15%, 15 to 20%, 20 to 30%, 30 to 50%, 50 to 70%, 70 to 90%, 90 to 95%, or 95 to 99%. In some embodiments, the concentration of the API in the pharmaceutical composition is in the range of 1 to 10%. In some embodiments, the concentration of the API in the pharmaceutical composition is in the range of 10 to 50%. In some embodiments, the concentration of the API in the pharmaceutical composition is in the range of 70 to 90%.

[0070] The therapeutically effective dose of NMDP may be in the form of a dry powder, semi-solid, mucosal adhesive preparation, intranasal vesicle units, or solution dosage form. The dry powder, semi-solid, mucosal adhesive preparation, intranasal vesicle units, or solution dosage form may have a unit weight of at least about 1 mg, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, or 900 mg. The dry powder, semi-solid, mucosal adhesive preparation, intranasal vesicle units, or solution dosage form may have a unit weight of at least about 1 g, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 g. Dry powder, semi-solid, mucosal adhesive preparation, intranasal vesicle units, or solution dosage forms may have a unit weight of less than approximately 1000 mg, for example, at least approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, or 900 mg. Dry powder, semi-solid, mucosal adhesive preparation, intranasal vesicle units, or solution dosage forms may have a unit weight of less than approximately 100 g, for example, less than approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 g. The dry powder, semi-solid, mucosal adhesive preparation, intranasal vesicle units, or solution dosage forms may have unit weights ranging from approximately 1 mg to 10 g, for example, approximately 1 mg to 10 mg, 10 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 400 mg, 400 mg to 600 mg, 600 mg to 800 mg, 800 mg to 1 g, 1 g to 2 g, 2 g to 5 g, or 5 g to 10 g. The therapeutically effective dose of NMDP may be in solution dosage form. The solution dosage form may have a unit volume of at least about 1 mL, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, or 900 mL.The solution dosage form may have a unit volume of less than approximately 1000 mL, for example, less than approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800 or 900 mL. The solution dosage form may have a unit volume range of approximately 1 to 500 mL, for example, 1 to 500, 1 to 300, 1 to 100, 1 to 80, 1 to 60, 1 to 40, 1 to 20, 1 to 10, 1 to 5, 10 to 500, 10 to 300, 10 to 100, 10 to 80, 10 to 60, 10 to 40, 10 to 20, 20 to 500, 20 to 300, 20 to 100, 2 It can have a range of 0-80, 20-60, 20-40, 40-500, 40-300, 40-100, 40-80, 40-60, 60-500, 60-300, 60-100, 60-80, 80-500, 80-300, 80-100, 100-500, 100-300, or 300-500 mL.

[0071] Combination therapy A therapeutically effective amount of NMDP or a salt thereof may be the sole active ingredient (API). Alternatively, a therapeutically effective amount of NMDP or a salt thereof may be used in combination with one or more additional APIs. Pharmaceuticals, compositions, kits, and methods for preventing or treating hearing impairment by administering NMDP or a salt thereof, for example, a therapeutically effective amount of NMDP or a salt thereof, and one or more active ingredients (APIs), for example, a therapeutically effective amount of APIs, are disclosed herein.

[0072] One or more APIs may include one or more sodium channel blockers, antioxidants, spin trappers, N-methyl-D-aspartate (NMDA) antagonists, selective serotonin reuptake inhibitor (SSRI) antagonists, dopamine release agents (DRAs), acetylcholine release inducers, norepinephrine reuptake inhibitors (NERIs), monoamine oxidase-A inhibitors (MAIs), serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), selective norepinephrine reuptake inhibitors (NSRIs), serotonin reuptake inhibitors (5HT SRIs), zonisamides, gabapentin, cannabinoids, or any combination thereof.

[0073] Also disclosed herein are pharmaceuticals, compositions, kits and methods for treating or preventing hearing impairment in subjects in need by administering a therapeutically effective dose of NMDP or a salt thereof and one or more pharmacokinetic ingredients (APIs). One or more APIs may be administered in a therapeutically effective dose. One or more APIs may include one or more sodium channel blockers, antioxidants, spin trappers, N-methyl-D-aspartate (NMDA) antagonists, selective serotonin reuptake inhibitor (SSRI) antagonists, dopamine-releasing agents (DRAs), acetylcholine-releasing inducers, norepinephrine reuptake inhibitors (NERIs), monoamine oxidase-A inhibitors (MAIs), serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), selective norepinephrine reuptake inhibitors (NSRIs), serotonin reuptake inhibitors (5HT SRIs), zonisamide, gabapentin, cannabinoids, or any combination thereof.

[0074] One or more APIs may contain one or more antioxidants or spin traps. For example, one or more antioxidants or spin traps may include allopurinol, glutathione, L-carnitine, methionine, or any combination thereof. One or more APIs may contain one or more NMDA antagonists. For example, one or more NMDA antagonists may include riluzole, caloverine, memantine, magnesium, or any combination thereof. One or more APIs may contain one or more SSRI antagonists. For example, one or more SSRI antagonists may include fluoxetine, sertraline, S-citalopram, alaproclate, or any combination thereof. One or more APIs may contain one or more DRAs. For example, one or more DRAs may include amantadine. One or more APIs may contain one or more acetylcholine-releasing inducers or NERIs. For example, one or more acetylcholine-releasing inducers or NERIs may include bifemerane. One or more APIs may contain one or more MAIs or SRIs. For example, one or more MAIs or SRIs may contain pyrrindol. One or more APIs may contain one or more SNRIs. For example, one or more SNRIs may contain milnacipran, bicifazine, or both. One or more APIs may contain one or more CCBs. For example, one or more CCBs may contain NMDP, verapamil, or both. One or more APIs may contain one or more NSRIs. For example, one or more NSRIs may contain atomoxetine. One or more APIs may contain one or more 5TH SRIs. For example, one or more 5TH SRIs may contain inderoxazine. One or more APIs may contain zonisamide.

[0075] One or more APIs may contain one or more drugs, such as gabapentin. Other usable drugs are anticonvulsants. Other drugs that may be used are drugs that stimulate gamma-aminobutyric acid (GABA) receptors. One or more APIs may contain cannabinoids. For example, cannabinoids may be marijuana or any extract or synthetic composition of marijuana that can stimulate cannabinoid receptors, CB1 receptors, CB2 receptors, or G-coupled receptors. These drugs may be used in combination with nimodipine or a salt thereof.

[0076] kit Disclosed herein is a kit for treating or preventing hearing impairment in subjects in need, comprising NMDP or a salt thereof, and written instructions for treating or preventing hearing impairment using NMDP or a salt thereof. NMDP or a salt thereof may be a therapeutically effective amount of NMDP or a salt thereof. A therapeutically effective amount of NMDP or a salt thereof may be in tablet, capsule, caplet, spray, powder, gel cap, powder, or solution dosage form. For example, a therapeutically effective amount of NMDP or a salt thereof may be in powder dosage form. The kit may further include a sterile solution. The kit may further include a sterile solution to be mixed with a therapeutically effective amount of NMDP or a salt in powder dosage form before administration. The kit may further include one or more active pharmaceutical ingredients (APIs). One or more APIs may include one or more antioxidants, spin trappers, N-methyl-D-aspartate (NMDA) antagonists, selective serotonin reuptake inhibitor (SSRI) antagonists, dopamine release agents (DRAs), acetylcholine release inducers, norepinephrine reuptake inhibitors (NERIs), monoamine oxidase-A inhibitors (MAIs), serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), selective norepinephrine reuptake inhibitors (NSRIs), serotonin reuptake inhibitors (5HT SRIs), zonisamides, gabapentin, cannabinoids, or any combination thereof.

[0077] molecular mechanism This specification discloses methods for modulating calcium signaling pathways in subjects requiring such modification, including administering a therapeutically effective dose of NMDP or a salt thereof. Calcium signaling pathways can be modulated by inhibiting calcium influx via voltage-activated calcium channels, α2-adrenergic receptor-agonist calcium channels, or both. Calcium signaling pathways can be modulated, for example, by inhibiting cytosolic calcium pool release in corpus cavernosum smooth muscle cells. Calcium signaling pathways can be modulated, for example, by inhibiting the production of tumor necrosis factor-α induced by calcium influx. Calcium signaling pathways can be modulated by blocking voltage-gated calcium channels. Calcium signaling pathways can be modulated by affecting the function of calcium-ATPases, calcium release channels, or both. Calcium signaling pathways can be modulated by intracellular calcium release, blocking calcium influx, or both. Calcium signaling pathways can be modulated by blocking endosomal calcium channels, such as two-pore channels. Calcium signaling pathways can be modulated by blocking T-type and / or L-type calcium currents. Calcium signaling pathways can be modulated by inhibiting the activity of BKCa channels. Calcium signaling pathways can be regulated by inhibiting calcium release activating channels.

[0078] This specification discloses methods for modulating oxidative pathways in subjects requiring such modification, including administering a therapeutically effective dose of NMDP or a salt thereof. Oxidative pathways can be modulated by reducing oxidative stress, downregulating miRNA-155, reducing TNF-α in the NF-κB signaling pathway, or a combination thereof. Oxidative pathways can be modulated by capturing free radicals. Oxidative pathways can be modulated by reducing peroxide levels. Oxidative pathways can be modulated by modulating the redox state of cells. Oxidative pathways can be modulated by inhibiting reactive oxygen species formation, suppressing Mac-1 upregulation, promoting neutrophil adhesion to fibrinogen, or any combination thereof. Oxidative pathways can be modulated by preventing hydrogen peroxide-induced oxidative neuronal damage.

[0079] This specification discloses methods for modulating anti-inflammatory pathways in subjects requiring such modification, including administering a therapeutically effective dose of NMDP or a salt thereof. Anti-inflammatory pathways can be modulated by reducing tubulation in the angiogenic process. For example, reducing tubulation in the angiogenic process can inhibit the post-receptor pathway of IL-1α and / or platelet-derived growth factor-BB in chronic inflammation. Anti-inflammatory pathways can be modulated by suppressing leukocyte infiltration into air pouches induced by IL-1 and / or TNF. Anti-inflammatory pathways can be modulated by inhibiting prostaglandin E synthesis. Anti-inflammatory pathways can be modulated by inhibiting IL-1, TNF-αIL-6, IL-8, IgG, neutrophil phagocytosis, or any combination thereof. For example, IL-1, TNF-αIL-6, and / or IL-8 may originate from monocytes. IgG may originate from B cells. The anti-inflammatory pathway can be regulated by suppressing the lipopolysaccharide-induced increase in the secretion of TNF-α, IL-1β, and / or high mobility group box 1 by peritoneal macrophages.

[0080] Patient Selection In one embodiment, a method is presented for selecting a subject in need of treatment for hearing impairment or symptoms of hearing impairment, comprising: administering an L-type calcium channel blocker to the subject; selecting the subject for treatment of hearing impairment or symptoms of hearing impairment if the subject responds to the L-type calcium channel blocker; and administering a therapeutically effective amount of NMDP or a salt thereof to the subject if the subject responds to the L-type calcium channel blocker. In some embodiments, the L-type calcium channel blocker includes carbamazepine. In some embodiments, the patient exhibits hearing loss. In some embodiments, the patient exhibits one or more symptoms relating to a) hearing loss, b) changes in auditory speech recognition as measured by a words-in-noise test, c) changes in auditory speech recognition as measured by a digits-in-noise test, d) changes in low-frequency hearing threshold, e) changes in the severity of tinnitus or Meniere's disease, g) changes in the volume of tinnitus or Meniere's disease, h) changes in the severity of dizziness, i) changes in ear fullness, j) changes in dizziness, and k) changes in hair cell function as observed when measured by changes in ABR threshold.

[0081] In one embodiment, a method is presented for selecting a subject in need of treatment for tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, comprising: administering an L-type calcium channel blocker to the subject; selecting the subject for treatment for tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease if the subject responds to the L-type calcium channel blocker; and administering a therapeutically effective amount of NMDP or a salt thereof to the subject if the subject responds to the L-type calcium channel blocker. In some embodiments, the L-type calcium channel blocker includes carbamazepine.

[0082] Conditions to be treated The hearing impairment in subjects requiring this treatment may be NIHL, ARHL, drug-induced or trauma-induced hearing loss, or tinnitus or Meniere's disease. The hearing impairment in subjects may also include combinations of two or all four of the listed conditions. For example, tinnitus or Meniere's disease and drug-induced hearing loss may be caused by ototoxic drugs. Ototoxic drugs may include chemotherapeutic agents, antineoplastic agents, antibiotics, loop diuretics, quinine or quinine-like compounds, or salicylates or salicylate-like compounds. In some embodiments, the ototoxic drug is not streptomycin. In some embodiments, the antibiotic is not streptomycin. In some embodiments, the hearing impairment is not caused by streptomycin.

[0083] This specification discloses pharmaceuticals, compositions, kits, and methods for preventing and / or treating hearing impairments, including, but not limited to, noise-induced hearing loss (NIHL), age-related hearing loss (ARHL or presbycusis), drug-induced or trauma-induced hearing loss, central auditory processing disorder (CAPD), tinnitus, or Meniere's disease.

[0084] NIHL - Noise-induced hearing loss NIHL is one of the most significant health problems caused by occupational and recreational environments. However, there are currently no FDA-approved drugs for mitigating NIHL, and the development of effective treatments is hindered by the diverse cellular and molecular pathways involved in NIHL. NIHL can cause damage ranging from the depletion of ear hair cells to their loss. Therefore, NIHL can result from overstimulation of hair cells and supporting structures. Structural damage to hair cells (primarily outer hair cells) can lead to hearing loss, which may be characterized by attenuation and distortion of incoming auditory stimuli.

[0085] NIHL can be caused by a single exposure to excessive noise. For example, exposure to sounds above 80 dB, 90 dB, 100 dB, 110 dB, 120 dB, 130 dB, 140 dB, or 150 dB in a short period of time may cause NIHL. Alternatively, NIHL can also be caused by repeated exposure to noise over a period of time. For example, exposure to sounds above 60 dB, 65 dB, 70 dB, 75 dB, 80 dB, 85 dB, 90 dB, 95 dB, or 100 dB for more than 8 hours per day may cause NIHL. Symptoms of NIHL may include tinnitus or Meniere's disease, ear pain, hyperacusis, dizziness, vertigo, and / or vestibular damage to the inner ear.

[0086] Pharmaceuticals, compositions, kits and methods for treating or preventing hearing loss (e.g., NIHL) in subjects in need thereof are disclosed herein, the methods comprising administering a therapeutically effective amount of NMDP or a salt thereof. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reduce or eliminate NIHL. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to stop or prevent NIHL. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reverse NIHL or at least partially restore hearing. Subjects may be at risk of developing hearing loss (e.g., NIHL), or subjects may already have hearing loss (e.g., NIHL).

[0087] ARHL or age-related hearing loss Age-related hearing loss (ARHL), or presbycusis, is a major health problem for which there is currently no cure or preventative medication. Age-related hearing loss progresses gradually over time, and its initial stages are virtually imperceptible to the affected individual. The cause of ARHL is generally thought to be the degeneration of the auditory nervous system, particularly the auditory nerve of the ear. This is the most common form of hearing loss in people over 55 years of age.

[0088] Early noise exposure can cause ARHL or age-related hearing loss. Subjects may have or be at risk of developing hearing loss (e.g., ARHL or age-related hearing loss). For example, subjects may have or be at risk of developing hearing loss (e.g., ARHL or age-related hearing loss) at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 years of age. In some embodiments, subjects may be 50 years of age.

[0089] Pharmaceuticals, compositions, kits and methods for treating or preventing hearing loss (e.g., ARHL or age-related hearing loss) in subjects in need thereof are disclosed herein, the methods comprising administering a therapeutically effective amount of NMDP or a salt thereof. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reduce or eliminate ARHL or age-related hearing loss. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to stop or prevent ARHL or age-related hearing loss. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reverse ARHL or age-related hearing loss, or at least partially restore hearing. Subjects may be at risk of developing hearing loss (e.g., ARHL or age-related hearing loss). Alternatively, subjects may already have hearing loss (e.g., ARHL or age-related hearing loss).

[0090] Traumatic brain injury and subarachnoid hemorrhage The majority of all patients with traumatic brain injury (TBI) develop tinnitus, and more than 20% of patients who experience subarachnoid hemorrhage (SAH) develop hearing impairment. Therefore, in some embodiments, the compositions and methods disclosed herein may be administered to treat TBI and / or SAH-induced hearing impairment. In some embodiments, the NMDP formulations disclosed herein may be administered to treat TBI and / or SAH-induced hearing impairment, such as tinnitus.

[0091] Drug-induced hearing loss Ototoxic drugs, such as chemotherapeutic agents, antineoplastic agents, antibiotics, loop diuretics, quinine or quinine-like compounds, and salicylates or salicylate-like compounds, can cause drug-induced hearing loss. For example, aminoglycosides are antibiotics used to treat Gram-negative bacterial infections and some aerobic Gram-positive bacterial infections. However, despite their usefulness, they have serious side effects, including ototoxicity associated with the destruction of sensory hair cells in the organ of Corti of the cochlea of ​​the inner ear. Furthermore, surgery near or on the auditory nerve can cause hearing loss, which can subsequently lead to tinnitus or tinnitus-like symptoms.

[0092] Pharmaceuticals, compositions, kits and methods for treating or preventing hearing loss (e.g., traumatic or drug-induced hearing loss) in subjects in need thereof are disclosed herein, the methods comprising administering a therapeutically effective amount of NMDP or a salt thereof. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reduce or eliminate this type of hearing loss. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to stop or prevent this type of hearing loss. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient not only to prevent drug-induced hearing loss but also to restore at least partial hearing. Subjects may be at risk of developing hearing loss (e.g., drug-induced hearing loss). Or, subjects may already have hearing loss (e.g., drug-induced hearing loss). In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient not only to prevent drug-induced hearing loss but also to act synergistically with cancer drugs to kill cancer cells.

[0093] A therapeutically effective dose of NMDP or a salt thereof can prevent the development of traumatic or drug-induced hearing loss. For example, a method for preventing drug-induced hearing loss is disclosed herein, comprising administering a therapeutically effective dose of NMDP or a salt thereof to a subject in need, prior to administering one or more ototoxic drugs to the subject for the treatment of a condition other than hearing loss. Administration of a therapeutically effective dose of NMDP or a salt thereof may be initiated up to approximately 12 months (e.g., 1 to 60 days) before administration of one or more ototoxic drugs. Administration of a therapeutically effective dose of NMDP or a salt thereof may also be initiated on the same day as administration of one or more ototoxic drugs. In some embodiments, administration of a therapeutically effective dose of NMDP or a salt thereof may be initiated up to approximately 12 months before administration of one or more ototoxic drugs, for example, at 1 hour, 6 hours, 12 hours, 24 hours, 2 days, 4 days, 6 days, 8 days, 10 days, 20 days, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or 12 months prior. In some embodiments, administration of a therapeutically effective dose of NMDP or a salt thereof may be initiated 1 to 12 months prior to administration of one or more ototoxic drugs, for example, 1 to 2 days, 2 to 10 days, 10 days to 1 month, 1 to 3 months, 3 to 6 months, or 6 to 12 months prior.

[0094] A therapeutically effective amount of NMDP or a salt thereof can treat or prevent drug-induced hearing loss, for example, improve drug-induced hearing loss, alleviate or eliminate tinnitus or Meniere's disease, partially or completely restore hearing, or prevent further hearing loss caused by the ototoxic effects of one or more ototoxic drugs. The methods disclosed herein provide the administration of a pharmaceutical composition in response to a significant decrease in auditory function caused by or occurring during the administration of one or more ototoxic drugs.

[0095] Administration of a therapeutically effective dose of NMDP or a salt thereof may be continued for the duration of one or more ototoxic drugs. Administration of a therapeutically effective dose of NMDP or a salt thereof may be stopped on the same day as discontinuation of one or more ototoxic drugs. Administration of a therapeutically effective dose of NMDP or a salt thereof may be continued for at least about one day after discontinuation of one or more ototoxic drugs, for example, at least about 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 20 days, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or 12 months. In some embodiments, administration of a therapeutically effective dose of NMDP or a salt thereof may be continued for at least about 1 day to 12 months after discontinuation of one or more ototoxic drugs, for example, 1 to 2 days, 2 to 10 days, 10 days to 1 month, 1 month to 3 months, 3 months to 6 months, or 6 months to 12 months.

[0096] Some examples of ototoxic drugs include certain antibacterial and antineoplastic drugs. For example, some ototoxic drugs are chemotherapeutic agents, e.g., antineoplastic agents and antibiotics. Other possible candidates include loop diuretics, quinine or quinine-like compounds, and salicylates or salicylate-like compounds. Accordingly, pharmaceuticals, compositions, kits, and methods for treating or preventing hearing loss caused by ototoxic drugs are disclosed herein, wherein the ototoxic drug may be an antineoplastic agent (e.g., ototoxic aminoglycoside antibiotics), e.g., cisplatin, antibiotics, e.g., aminoglycosides, loop diuretics, quinine, quinine-like compounds, salicylates or salicylate-like compounds.

[0097] Examples of ototoxic aminoglycoside antibiotics include, but are not limited to, neomycin, paromomycin, ribostamycin, lividomycin, kanamycin, amikacin, tobramycin, biomycin, gentamicin, shisomecin, netylmycin, streptomycin, dibekacin, holtimycin, and dihydrostreptomycin, or combinations thereof. Specific antibiotics include neomycin B, kanamycin A, kanamycin B, gentamicin C1, gentamicin C1a, and gentamicin C2. Accordingly, pharmaceuticals, compositions, kits, and methods for treating or preventing drug-induced hearing loss are disclosed herein, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to a subject who has been, is being, or is scheduled to be treated with one or more aminoglycosides. In some embodiments, the ototoxic aminoglycoside antibiotic is not streptomycin. In some embodiments, the hearing impairment is not caused by the ototoxic aminoglycoside antibiotic. In some embodiments, the hearing impairment is not caused by streptomycin.

[0098] Hearing impairment induced by aminoglycosides can be prevented or mitigated by the pharmaceuticals, compositions, kits, and methods disclosed herein. While aminoglycosides are particularly useful due to their rapid bactericidal action against infections of aminoglycoside-sensitive organisms, their use has historically been limited to more severe and complex infections due to ototoxic and nephrotoxic side effects. For this reason, aminoglycosides have been considered to have a lower treatment / risk ratio compared to other antibiotics used systemically. Accordingly, improved treatment methods for aminoglycoside-sensitive infections, comprising administering an antimicrobially effective amount of aminoglycosides and the pharmaceutical compositions disclosed herein to a subject, are also disclosed herein. It should be recognized that recommended doses of aminoglycosides have been established. The methods disclosed herein are effective when aminoglycosides are administered in the range of approximately 100–500%, particularly approximately 100–250%, and more specifically approximately 100–150%, of currently recommended doses (generally available on the product labels and accompanying information of commercially available aminoglycoside drug products). The improved method provides a preventive measure against aminoglycoside-induced hearing loss and / or tinnitus or Meniere's disease, thereby expanding the therapeutic index of aminoglycoside drugs.

[0099] The disclosed pharmaceutical compositions can be administered concurrently with one or more ototoxic drugs of the same dosage form. For example, an improved method for treating an infection in a subject is provided by administering an aminoglycoside antibiotic and a therapeutically effective amount of the disclosed pharmaceutical composition. Alternatively, the aminoglycoside antibiotic and the disclosed pharmaceutical composition can be administered to a subject in separate dosage forms.

[0100] One or more ototoxic drugs may also be chemotherapeutic agents for the treatment of cancer in a subject. For example, an improved method for treating cancer in a subject is provided by administering a chemotherapeutic agent (e.g., an antineoplastic chemotherapeutic agent) and a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0101] Examples of ototoxic antineoplastic chemotherapeutic agents include cisplatin or cisplatin-like compounds, taxol or taxol-like compounds, and other chemotherapeutic agents thought to cause ototoxic hearing impairment, such as vincristine, antineoplastic drugs used to treat hematological malignancies and sarcomas. Accordingly, the methods disclosed herein can be used to treat ototoxicity (e.g., drug-induced hearing loss) in subjects who are scheduled to be treated, are being treated, or have been treated with antineoplastic agents, such as cisplatin or cisplatin-like compounds, taxol or taxol-like compounds, and other chemotherapeutic agents thought to cause ototoxic hearing impairment, such as vincristine, antineoplastic drugs used to treat hematological malignancies and sarcomas.

[0102] Central Auditory Processing Disorder (CAPD) Central auditory processing disorder (CAPD) is associated with difficulties in perceptually processing auditory information in the central nervous system (CNS). Testing for CAPD may include auditory discrimination tests; auditory temporal processing and patterning tests; dichotic speech tests; mono-ear low-redundancy speech tests; binaural interaction tests; electroacoustic measurements; and electrophysiological measurements.

[0103] Pharmaceuticals, compositions, kits and methods for treating or preventing hearing loss (e.g., CAPD) in subjects in need thereof are disclosed herein, the methods comprising administering a therapeutically effective amount of NMDP or a salt thereof. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reduce or eliminate CAPD. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to stop or prevent CAPD. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reverse CAPD or at least partially restore hearing. Subjects may be at risk of developing hearing loss (e.g., CAPD), or subjects may already have hearing loss (e.g., CAPD).

[0104] Tinnitus Tinnitus is the perception of sound in the ear even without external auditory stimuli. The most frequent symptom of tinnitus is ringing in the ears, but it can also manifest as sounds such as crickets, hums, pulses, ocean waves, buzzers, or even music. Tinnitus can be temporary, intermittent, or even permanent, and its severity can range from a quiet background ringing to an overwhelming auditory sensation that drowns out external sound sources.

[0105] Tinnitus can be caused by one or more factors, such as the administration or exposure to ototoxic substances (e.g., aspirin overdose), exposure to short bursts of extreme noise (e.g., gunshots or explosions), or prolonged exposure to high-decibel noise (e.g., aircraft engine noise, high-decibel music concerts, or the use of high-decibel headphones), or central auditory processing disorders as discussed herein.

[0106] Pharmaceuticals, compositions, kits and methods for treating or preventing hearing impairment (e.g., tinnitus) in subjects in need thereof are disclosed herein, the methods comprising administering a therapeutically effective amount of NMDP or a salt thereof. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reduce or eliminate hearing impairment (e.g., tinnitus). In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reduce or eliminate hearing impairment (e.g., tinnitus) or treat its symptoms. In some embodiments, the therapeutically effective amount of NMDP or a salt thereof is sufficient to reverse hearing impairment (e.g., tinnitus) or at least partially restore hearing. Subjects may be at risk of developing hearing impairment (e.g., tinnitus). Or, subjects may already have hearing impairment (e.g., tinnitus).

[0107] Meniere's disease Meniere's disease is an inner ear disorder that can cause tinnitus (ringing in the ears), hearing loss or decreased hearing, dizziness, and a feeling of fullness or congestion in the ear. Attacks of dizziness can occur suddenly or after a brief period of tinnitus or hearing blockage. A single attack of dizziness may occur over a longer period. In other cases, many attacks may occur in clusters over several days. Some people with Meniere's disease experience extreme dizziness, sometimes to the point of losing balance and falling. Meniere's disease is often a severe and debilitating condition for those affected.

[0108] Meniere's disease can develop at any age, but it is more common in adults aged 40-60. The National Institute of Hearing and Communication Disorders (NIDCD) estimates that approximately 615,000 individuals in the United States are currently diagnosed with Meniere's disease, with an estimated 45,500 new cases diagnosed each year. Meniere's disease usually affects only one ear. While not bound by any specific theory, the symptoms of Meniere's disease may be caused by the accumulation of fluid in the inner ear compartments. There is no known cure for Meniere's disease. There remains a significant need for improved pharmaceutical compositions and methods of use for the treatment of Meniere's disease.

[0109] Salts, stereoisomers, polymorphs, and derivatives As described above with reference to specific compounds, stereoisomers, polymorphs, metabolites, derivatives, and / or salts of active compounds can also be utilized. Examples of therapeutically acceptable salts include, but are not limited to, inorganic or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Therapeutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, tornesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. Therapeutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in a non-aqueous medium such as water or an organic solvent, or a mixture thereof, e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa, 1985, p. 1418).

[0110] Stereoisomers are compounds composed of the same atoms with the same bond order but different three-dimensional configurations of atoms that are not interchangeable. The three-dimensional structure is called the stereoconfiguration. Two types of stereoisomers are enantiomers and diastereomers. Enantiomers are two stereoisomers that are mirror images of each other and cannot be superimposed. This property of enantiomers is known as chirality. The terms "racemate," "racemic mixture," or "racemic modification" refer to a mixture of equal amounts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are bonded. The selection of appropriate chiral columns, eluents, and conditions necessary to achieve separation of enantiomer pairs is well known to those skilled in the art using standard techniques (see, for example, Jacques, J. et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981). Diastereomers are two stereoisomers that are not mirror images but also cannot be superimposed. Diastereoisomers have different physical properties, and these differences can be used to easily separate them from one another. The metabolites of the above compounds arise from biochemical processes in which living cells interact with the active parent drug or other formulations or compounds in vivo. Metabolites include products or intermediates from any metabolic pathway.

[0111] API NMDP is a calcium channel blocker (CCB) belonging to the dihydropyridine class, and is a highly lipophilic drug that rapidly crosses the blood-brain barrier. Its chemical structure and related properties are shown below. NMDP can be used to treat tinnitus associated with hearing loss, Meniere's disease, dizziness and tinnitus associated with traumatic brain injury and subarachnoid hemorrhage, and to prevent hearing loss during surgery for vestibular schwannoma.

[0112] NMDP belongs to Class II of the Biopharmaceutical Classification System (BCS). It has low water solubility but good permeability due to its high lipophilicity (log p=3.41). NMDP is a weakly basic compound with a predicted pka value of 5.41. NMDP is readily soluble in ethanol. NMDP is available in several FDA-approved dosage forms, including soft gelatin capsules, tablets, and liquid and oral solutions for intravenous administration (Sweetman and Martindale, 2002). Some of the physical properties of NMDP (NMD) are shown in the table below. [Table 1]

[0113] In humans, NMDP can be rapidly absorbed after oral administration, and peak concentrations can be achieved within one hour. Extracentral nervous system bioavailability is 100% after intravenous administration, and 3-30% after oral administration due to extensive first-pass metabolism. Due to high affinity binding of plasma proteins to NMDP, only about 5% of NMDP reaches the brain.

[0114] API concentration The compositions of this disclosure typically have concentrations corresponding to about 0.4–75 mg / mL of NMDP, 0.5–40 mg / mL of NMDP, 0.6–35 mg / mL of NMDP, 0.7–25 mg / mL of NMDP, 0.75–15 mg / mL of NMDP, or 1–10 mg / mL of NMDP. Suitable compositions have concentrations corresponding to at least about 0.4 mg / mL of NMDP, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL or 5 mg / mL of NMDP, e.g., 7 mg / mL, e.g., 10 mg / mL, e.g., about 15 mg / mL, about 20, about 25, about 35, about 45, about 60, about 80, about 100, about 150, about 125, about 150, about 180, about 225, about 275, and about 400 mg / mL of NMDP.

[0115] As described, the composition is delivered as a dose unit, the dose being approximately 10 to 500 μL, for example 10 to 200 μL, preferably approximately 50 to 150 μL, of one or more dose units. In embodiments where delivery is via the nasal mucosa, the delivery unit corresponds to a volume provided by ejection or spraying, depending on the device used to deliver the composition and the dose unit.

[0116] If the intranasal application exceeds approximately 200 μl, there is a risk of the formulation being lost to the larynx or lost through the nostrils. Therefore, in some embodiments, the formulation for intranasal administration cannot exceed 200 μl per application. Accordingly, the volumes according to this disclosure include volumes selected from 10 μl, 25 μl, 50 μl, 75 μl, 100 μl, 150 μl, 200 μl, 250 μl, 300 μl, 350 μl, and 400 μl, and the volume can preferably be delivered to both nostrils.

[0117] In one embodiment, the composition is formulated for nasal delivery of a dosage unit containing at least about 70 μg of NMDP, for example 80, 90, or 100 μg, for example 125, 150, 200, 250, or 300 μg, for example 350, 400, 450, 500 μg, for example 550, 600, 650, 700, 750, 800, 850, 900, or 950 μg, for example 1000, 1050, 1100, 1250, or 1300 μg, for example 1350, 1400, 1450, 1500 μg, for example 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or 1950 μg equivalent, for example a dosage unit equivalent to 2000 μg of NMDP.

[0118] Alternatively, to define it, the composition is formulated for transmucosal delivery of dose units equivalent to approximately 70-2500 mg of NMDP, for example, 70-1800 mg, 70-1500 mg, 70-1200 mg, 70-1000 mg, 70-500 mg, and 75-300 mg of NMDP.

[0119] This disclosure further relates to a method for administering NMDP or a pharmaceutically acceptable salt thereof into the circulatory system of an individual requiring relief of symptoms of acute tinnitus or Meniere's disease or tinnitus or Meniere's disease. The therapeutic dose is such that it is sufficient to treat acute tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease within a limited time of action. To obtain a plasma concentration sufficient to treat acute tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, the therapeutic dose is typically in the range of at least about 1 to about 5 mg / kg or about 50 mg to about 250 mg. To administer NMDP into the circulatory system within an acceptable period without delivery by injection, NMDP is administered to the patient's mucosa in a pharmaceutical vehicle for transmucosal delivery of NMDP.

[0120] The dose sufficient to alleviate tinnitus or Meniere's disease or the symptoms of tinnitus or Meniere's disease may vary between patients and within individual patients. For the treatment of relatively moderate acute tinnitus or Meniere's disease or the symptoms of tinnitus or Meniere's disease, the therapeutic dose may include at least 70 μg of NMDP, preferably at least 100 μg of NMDP, at least 150 μg of NMDP, for example, 200 μg of NMDP. For the treatment of more severe acute tinnitus or Meniere's disease or the symptoms of tinnitus or Meniere's disease, the therapeutic dose may include at least 250 μg of NMDP, preferably at least 300 μg of NMDP, at least 400 μg of NMDP, for example, 500 μg of NMDP, 1000 μg of NMDP, 1500 μg of NMDP, or 2000 μg of NMDP. If a patient is suffering from severe acute tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, or if the patient has acquired tolerance to NMDP, higher doses may be required and administered in accordance with this disclosure. Such higher doses include therapeutic doses containing 25 mg of NMDP, at least 30 mg of NMDP, e.g., at least 40 mg of NMDP, at least 50 mg of NMDP, at least 100 mg, at least 150 mg, at least 200 mg, at least 400 mg, at least 600 mg, and at least 1000 mg. Even higher doses may be desirable, such as a therapeutic dose of 1300 mg of NMDP, preferably at least 1400 mg of NMDP, at least 1500 mg of NMDP, e.g., 1700 mg of NMDP. In some embodiments, treatment may involve patients who may require a therapeutic dose containing 1800–2500 mg of NMDP.

[0121] As stated, the compositions of this disclosure for transmucosal delivery are more concentrated than compositions known to those skilled in the art. In one embodiment, the compositions are formulated so that a therapeutic dose contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 30, 35, 40, 45, 50, 100, or 300 dose units.

[0122] An important aspect of this disclosure is that tinnitus or Meniere's disease, or relief of symptoms of tinnitus or Meniere's disease, can be obtained immediately after administration of NMDP. Therefore, acute tinnitus or Meniere's disease, or relief of symptoms of tinnitus or Meniere's disease, should be obtained immediately after the administration of the first delivery of a dose unit or therapeutic dose, such that the administration of the composition has an onset time of less than 10 minutes, e.g., less than 9 minutes, or less than 8 minutes. In some embodiments, the onset time of the composition may be more than 10 minutes, e.g., 15 minutes, 20 minutes, 25 minutes, 30 minutes, or more than 30 minutes.

[0123] In some embodiments, in addition to a very short onset of action, the reduction of tinnitus or Meniere's disease or the symptoms of tinnitus or Meniere's disease is maintained for at least 30 minutes. In some embodiments, administration of the composition maintains the duration of action over a period of at least 30 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 240 minutes, at least 360 minutes, at least 480 minutes, at least 600 minutes, at least 720 minutes, at least 840 minutes, at least 960 minutes, or at least 1080 minutes, 20 hours, 22 hours, 24 hours, 36 hours, 48 ​​hours, or 60 hours.

[0124] The compositions have a pseudo-"sustained-release" effect compared to intravenous administration, which has a very rapid onset of action but a very short duration of action. The intranasal compositions described herein, upon administration, typically have bioavailability of 75% or more of that of intravenous administration, for example, 80% or more, or 90% or more. Bioavailability can be determined by its AUC, as is known to those skilled in the art.

[0125] The method of disclosure includes administering NMDP in dose units of approximately 70 to 2500 mg, and the C obtained by said administration. max,nasal / C max,iv The ratio decreases within the therapeutic dose range of approximately 70–2500 mg, with increasing dose units delivered with an equivalent amount of NMDP.

[0126] API formulations To facilitate intranasal administration of NMD, an effective amount of NMDP should be dissolved or finely dispersed in a small amount of liquid vehicle, for example, less than about 1,000 μL (microliters), preferably less than 300 μL, and for example less than 150 μL. If the amount is large, it will be expelled forward through the nostrils or backward towards the pharynx, in which case the excess liquid will be swallowed. As a result, if a large amount is administered, some of the NMDP may be lost from the absorption site, and it may be difficult, if not impossible, to reproducibly administer the correct dose of the therapeutic agent. Therefore, for intranasal administration, it is desirable to have a high dissolved NMDP concentration or dispersed NMDP content in a small amount of liquid vehicle. Furthermore, in order to support drug absorption through the nasal mucosa, two natural protective functions, namely mucosal ciliary clearance (MCC) and the barrier properties of the tissue, must be avoided. It is desirable that the effective dose can avoid the natural properties of the mucous layer as a protective layer, i.e., increasing drug absorption, and the natural properties of the MCC as an effective cleansing mechanism. In other words, it is desirable to increase the residence time of the applied dose to the mucous membrane. Suitable surfactants for the present invention are nonionic surfactants. Suitable nonionic surfactants for the present invention are polysorbates, in particular polysorbate 20 (Tween 20) and polysorbate 80 (Tween 80). Tween-80 (polyoxyethylene sorbitan monooleate) is an oleate, and Tween-20 (polyoxyethylene sorbitan monolaurate) is a laurate. Both are listed in the FDA list of inactive ingredients for nasal spray applications. Both Tween 20 and Tween 80 are miscible with water. The chemical structure of Tween 80 is shown below. [ka]

[0127] Suitable water-soluble cellulosic polymers for use in the present invention include, but are not limited to, hydroxypropyl methylcellulose (HPMC; also known as hypromellose), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), sodium CMC, sodium CMC and MCC, natural gums such as xanthan gum, guar gum, acacia gum, tragacanth gum and / or sodium carboxymethylcellulose. These polymers are also listed in the FDA list of inactive ingredients for nasal spray applications. HPMC is a preferred polymer used in the present invention. HPMC is a nonionic water-soluble cellulose derivative that has a hydrogen bonding potential and stabilizing ability to prevent crystallization of amorphous materials. Approximately 1% HPMC in phosphate buffer (pH 6.8) can also increase drug solubility. In some embodiments, the HPMC used in the formulation exhibits viscosity values ​​of approximately 2–4,000 mPa.s, approximately 4–60 mPa.s, and / or approximately 4–6 mPa.s in a 2% (w / v) aqueous solution at 20°C. In some cases, the HPMC is E6, E50, or E4M. In some embodiments, preferred HPMCs used in formulations are approximately 50 to approximately 100 kDa, approximately 50 to approximately 150 kDa, approximately 50 to approximately 200 kDa, approximately 50 to approximately 250 kDa, approximately 50 to approximately 300 kDa, approximately 50 to approximately 350 kDa, approximately 50 to approximately 400 kDa, approximately 50 to approximately 500 kDa, approximately 50 to approximately 600 kDa, approximately 50 to approximately 700 kDa, approximately 50 to approximately 800 kDa, approximately 50 to approximately 900 kDa, approximately 50 to approximately 1100 kDa, and approximately 50 to approximately 1500 kDa. Da may include molecular weights of approximately 50-100 kDa, 100-150 kDa, 100-200 kDa, 100-250 kDa, 100-300 kDa, 100-350 kDa, 100-400 kDa, 100-500 kDa, 100-600 kDa, 100-700 kDa, 100-800 kDa, 100-900 kDa, 100-1100 kDa, or 100-1500 kDa.In some embodiments, polyethylene glycol (PEG) or its methoxy derivatives, such as methoxy-polyethylene glycol (mPEG), or a combination of mPEG / PEG, can be good solvents for poorly water-soluble NMDP. In some embodiments, low molecular weight PEG, mPEG, and / or mixtures of PEG and mPEG can be used. In some embodiments, low viscosity formulations can be prepared using PEG, mPEG, and / or mixtures of PEG and mPEG.

[0128] The structure of polyethylene glycol (PEG) is shown in I below:

[0129] I:HO-(CH2CH2O)-H, where n is a number in the range of 1 to 25.

[0130] The structure of alkoxy-polyethylene glycol is represented by the following II:

[0131] II:RO-(CH2CH2O)-H, where R is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl, and n, the average number of oxyethylene repeating units, is a number in the range of approximately 1 to approximately 25.

[0132] Measurement of the effects of pharmaceutical compositions The composition is intended to treat, alleviate, or reduce the symptoms of acute or breakthrough tinnitus or Meniere's disease, or tinnitus or Meniere's disease, based on an assessment including: a) measurement of changes in auditory brainstem response (ABR) threshold; b) changes in auditory speech recognition as measured by a words-in-noise test; c) changes in auditory speech recognition as measured by a digits-in-noise test; d) changes in low-frequency hearing threshold; e) changes in the incidence of adverse events after administration of the pharmaceutical composition; f) changes in the severity of tinnitus or Meniere's disease; g) changes in the volume of tinnitus or Meniere's disease; h) changes in the severity of dizziness; i) changes in ear fullness; j) changes in dizziness; and k) changes in hair cell function observed when measured by changes in ABR threshold.

[0133] In further embodiments, the compositions, dosage units, uses, and methods of the present disclosure are characterized by their therapeutic effect on acute tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease, as measured as described herein. One method of recording tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease according to the present disclosure includes measuring the onset of tinnitus or Meniere's disease or the reduction of symptoms of tinnitus or Meniere's disease. Time is measured immediately before administration of the treatment, for example by starting a stopwatch. Time is recorded, for example by stopping the stopwatch, when the subject certainly feels a meaningful reduction of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease. When administered, the compositions of the present disclosure have a reduction score of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease in the range of 2 to 7, for example 2, 3, 4, 5, 6, and 7, preferably for example 3, 4, 5, and 6, as measured by PID after delivery of 1 dosage unit, in response to the delivery of 2 or fewer dosage units.

[0134] A treatment is considered successful if at least 50% of subjects experience an onset of action within 15 minutes of administration. Similarly, the duration of the effect can be measured as the difference between the onset of the effect and the earlier of the time the subject declared the effect had ceased or the time the subject took emergency medication. A treatment is considered successful if at least 50% of subjects experience a duration of at least 30 minutes of relief from tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease.

[0135] Another measure is the 11-point numerical rating scale for tinnitus, Meniere's disease, or the severity of tinnitus symptoms (TI) (0 = no tinnitus or tinnitus symptoms, 10 = unbearable tinnitus or tinnitus symptoms). TI i is, at time T i TI refers to the intensity of tinnitus or tinnitus symptoms in the patient. i This is at the following point in time (T i ), is measured at one or more of the following times: before treatment (baseline), at the point of significant reduction in tinnitus or tinnitus symptoms, every 15 minutes during the first 2 hours after administration of the treatment, and every 30 minutes during the next 2 hours. A 40% reduction in the mean TI within 15 minutes after treatment can be considered a success. Of course, other time points and intervals may be chosen.

[0136] TI0 is the baseline tinnitus or tinnitus symptom intensity (assessed using a scale as disclosed above) at time T0 (before administration of treatment). The difference in tinnitus or tinnitus symptom intensity (TID) is the difference at time TI0 (after administration of treatment). i TI0 is the tinnitus or tinnitus symptom intensity compared to the patient's own tinnitus. A mean TID of 2 obtained within 15 minutes after administration is considered a success.

[0137] Further measurements include the area under the TID curve, or the sum of the differences in the intensity of tinnitus or tinnitus symptoms (STID), where TI is measured at the time disclosed above. A 4-hour STID mean of 3 is considered a success.

[0138] One method relates to a measure of the intensity of tinnitus or Meniere's disease or tinnitus symptoms disclosed herein, and reduction of tinnitus or tinnitus symptoms is based on the tinnitus or tinnitus symptom score measured near the administration time TI0 and the tinnitus or tinnitus symptom score measured at the time TI i after administration. It is measured as a tinnitus or tinnitus symptom intensity difference (TID) of at least 30%, for example at least 40%. The time after administration can be selected from one or more of 3 minutes, 5 minutes, 7 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes after administration. These times are used when the purpose of the measurement is to evaluate the immediate effect of administration. When measurement of the duration of treatment is desired, reduction of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease is based on the scores measured immediately before administration TI0 and at the time TI i after administration, and is measured as a tinnitus or Meniere's disease or tinnitus or Meniere's disease symptom intensity difference (TID), and the time after administration is selected from 45 minutes, 60 minutes, 75 minutes, 90 minutes, and 120 minutes after administration. One alternative is to measure the effect from a given time after administration to a later time, in which case the desired time range is selected individually.

[0139] The reduction score for tinnitus or Meniere's disease or tinnitus or Meniere's disease symptoms can be measured according to the methods disclosed herein or on a scale of 1 - 100%, where 100% is tinnitus or tinnitus symptoms described as intolerable by the patient and 0% means no tinnitus or tinnitus symptoms. The score is preferably at least 30% from the start until the maximum reduction effect is obtained.

[0140] Further measurements, as described above, are immediately before administration PI0 and at the time PI iThe sum of tinnitus or tinnitus symptom intensity differences (STID) is based on a score measured, and the time after administration is selected from any time as desired, including the time disclosed herein. In one embodiment, the sum of tinnitus or tinnitus symptom intensity differences is measured from at least two values ​​measured over a period of at least 30 minutes, preferably at least 45 minutes, preferably at least 60 minutes, for example 90 minutes. Furthermore, the sum of tinnitus or tinnitus symptom intensity differences can be measured from at least five values, for example at least seven values, preferably at least ten values, for example 11, 12, or 13 values.

[0141] In other embodiments, therapeutic doses of NMDP or a salt thereof may also be administered to mucous membranes selected from one or more of the buccal mucosa, airway mucosa, e.g., tracheal mucosa and / or pulmonary mucosa. In further embodiments of the present disclosure, therapeutic doses may be administered to two or more sites in the same treatment, or the patient may choose the route of administration on an individual basis. Where nasal administration implies nasal irritation, acute nocturnal tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease may be treated by buccal administration.

[0142] Area under the curve When used herein, "peak concentration of NMDP in plasma (C) max )", "Area under the concentration-time curve (AUC) of NMDP in plasma", "Time to maximum plasma concentration of NMDP (t max ")" is a pharmacokinetic parameter known to those skilled in the art. Laursen et al., Eur.J.Endocrinology 135:309-315, 1996. The "concentration-time curve" measures the concentration of NMDP in the subject's serum against the time after the dose of NMDP is administered to the subject either intranasally or via the mucosal route. max " is the maximum concentration of NMDP in the auricular structure or serum of a subject after a single dose of NMDP administered to the subject. max " is the time from the administration of a single dose of NMDP to the subject until the concentration of NMDP in the subject's serum or auricular structure reaches its maximum.

[0143] When used herein, the "area under the concentration-time curve (AUC) of NMDP in plasma or auricular structures" is calculated by adding the remaining area according to the linear trapezoidal formula. A 23% decrease or 30% increase between two doses is detected with 90% probability (Type II error β = 10%). The "rate of delivery" or "rate of absorption" is defined as the rate at which the maximum concentration (C) is reached. max Time until ) reaches (t max It is estimated by the comparison of C. max and t max Both are analyzed using nonparametric methods. Pharmacokinetic comparisons of intramuscular, subcutaneous, intravenous, and intranasal NMDP administration are performed by analysis of variance (ANOVA). Significance is assessed using the Bonferroni-Holmes sequential procedure for pairwise comparisons. Dose-response relationships between the three nasal doses are estimated by regression analysis. P<0.05 is considered significant. Results are presented as mean + / - SEM.

[0144] In one embodiment, intranasal doses of NMDP achieve transient serum levels of approximately 5 pg / mL to 280 pg / mL, 10 pg / mL to 100 pg / mL, 20 pg / mL to 50 pg / mL, or 25 pg / mL to 250 pg / mL. With intranasal formulations, the transient NMDP serum blood levels achieved may be lower or higher than those typically obtained by other routes of administration. In some embodiments, the beneficial effects achieved by intranasal administration are similar to those obtained from steady-state serum NMDP levels of approximately 5 ng / dL to 180 ng / dL.

[0145] A comparison of the area under the total concentration-time curve (AUC) or mean concentration of NMDP in subjects treated with intranasal NMDP and patients treated with NMDP via another route, such as oral administration, provides a basis for determining the bioequivalence of different administration routes. When the AUC or mean concentration is similar, the biological effects achieved are often similar despite different administration routes or different concentration-time profiles. Therefore, in one embodiment, the present disclosure intends to achieve a mean serum NMDP concentration of about 5 pg / mL to about 250 pg / mL over 24 hours by intranasal administration of the disclosed composition.

[0146] In one embodiment, an intranasal dose of NMDP achieves transient concentration levels in the auricle structure of approximately 5 pg / mL to 280 pg / mL, 10 pg / mL to 100 pg / mL, 20 pg / mL to 50 pg / mL, or 25 pg / mL to 250 pg / mL. With intranasal formulations, the transient serum ear levels of NMDP achieved may be lower or higher than those typically obtained by other routes of administration.

[0147] The peak plasma concentration achieved by intravenous administration of NMDP is associated with side effects such as respiratory depression. In embodiments, the peak plasma concentration of the pharmaceutical composition is sufficient to provide the desired effect (furthermore, to be achieved rapidly and sustained for a sufficiently long period). Accordingly, the present disclosure further relates to a composition in which the administration of two or fewer dose units has a peak plasma concentration of 5% to 75% of the peak plasma concentration obtained by intravenous administration of the dose unit within a therapeutic dose range of about 20 to 2500 mg, preferably a peak plasma concentration of 30% to 75% of the peak plasma concentration obtained by intravenous administration of the dose unit within a therapeutic dose range of about 20 to 2500 mg.

[0148] In some embodiments, repeated administration of dose units does not increase peak plasma levels. With intravenous administration, repeated administration continues to raise plasma concentrations to undesirably high levels. In some embodiments, repeated transmucosal administration of dose units of NMDP or a salt thereof does not continue to raise plasma concentrations. In some embodiments, within a therapeutic dose range of about 50 to 2500 mg, when comparing equivalent amounts of NMDP delivered by both modes of administration (nasal vs. intravenous), the C dose decreases with increasing dose units. max,nasal / C max,iv It is something that brings about a ratio.

[0149] formulation Compounds or therapeutically acceptable salts thereof can be formulated as pharmaceutical compositions. Such compositions are dosage unit formulations optionally containing therapeutically acceptable conventional non-toxic carriers, adjuvants, and vehicles, and can be administered nasally by inhalation spray. In some embodiments, the pharmaceutical compositions can be administered in oral dose forms such as tablets.

[0150] Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980).

[0151] The active compound (or a therapeutically acceptable salt thereof) may be administered either on its own or in the form of a pharmaceutical composition in which the active compound is mixed or admixtured with one or more therapeutically acceptable carriers, excipients, or diluents. The pharmaceutical composition may be formulated in a conventional manner using one or more therapeutically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the active compound into therapeutically usable preparations. The appropriate formulation depends on the chosen route of administration.

[0152] Furthermore, the formulation may include conventional carriers, such as plasticizers, pigments, colorants, flow enhancers, stabilizers, pore-forming agents, and surfactants.

[0153] Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dried starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium dioxide, magnesium aluminum silicate, and powdered sugar. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, cellulose, e.g., hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, as well as synthetic polymers, e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. Disintegrants may include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropylcellulose, pregelatinized starch, clay, cellulose, arginine, gum, or crosslinked polymers, such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp). Stabilizers are used, for example, to inhibit or delay drug degradation reactions, including oxidation reactions.

[0154] Surfactants can be anionic, cationic, amphoteric, or nonionic. Suitable anionic surfactants include, but are not limited to, those containing carboxylate ions, sulfonate ions, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium salts of long-chain alkyl sulfonates and alkylaryl sulfonates, e.g., sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinate, e.g., sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinate, e.g., bis-(2-ethylthioxyl)sodium sulfosuccinate; and alkyl sulfonates, e.g., sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, e.g., benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene, and coconutamines. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4 oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0155] If desired, tablets, beads, granules, or particles used for administering the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances, such as humectants or emulsifiers, dyes, pH buffers, or preservatives.

[0156] Pharmaceutical compounds can be complexed with other drugs as part of a therapeutic formulation. Pharmaceutical compositions can take the form of, for example, liquid formulations for nasal administration prepared in water or other aqueous vehicles, and may contain various suspending agents, such as methylcellulose, alginate, tragacanth, pectin, kergin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol. Liquid formulations may also include solutions, emulsions, syrups, and elixirs containing humectants, sweeteners, and colorants and flavorings along with the active compound. A variety of liquid and powder formulations for patient inhalation can be prepared by conventional methods.

[0157] Furthermore, combinations of immediate-release compositions and delayed-release / sustained-release compositions can be formulated together.

[0158] In some embodiments, NMDP is formulated into dosage forms as a sole active pharmaceutical ingredient (API). Such NMDP dosage forms can be used alone or in combination with one or more additional doses containing one or more active pharmaceutical ingredients for the prevention or treatment of hearing loss. In such cases, the daily dose of NMDP may be provided, conveniently, in a single dosage form as described herein, or divided among two, three, four or more doses.

[0159] As described above, compositions containing NMDP or a salt thereof are administered mucosally by contacting the mucosal tissue of the vagina, nose, rectum, or mouth with a composition in a suitable dosage form. In one embodiment, the composition is administered via the nasal mucosa, i.e., into the nasal cavity. The nasal mucosa provides a useful anatomical site for systemic delivery. Nasal tissue is richly vascularized and provides an attractive site for rapid and efficient absorption. The adult nasal cavity has a volume of about 20 mL and provides about 180 cm³ for drug absorption, partly due to the microvilli present along the pseudostratified epithelial cells of the nasal mucosa. 2 It has a large surface area.

[0160] Nasal preparations comprising the above-described compositions can take various forms for administration as nasal drops, nasal sprays, gels, ointments, creams, powders, or suspensions, using dispensers or other devices as needed. Various dispensers and delivery vehicles, including single-dose ampoules, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, etc., are known in the art.

[0161] More generally, preparations can take the form of solid, semi-solid, or liquid. In the case of solid form, the components can be mixed together by blending, rotational mixing, freeze-drying, solvent evaporation, co-grinding, spray-drying, and other techniques known in the art. Such solid preparations provide a dry powder composition for intranasal administration, preferably having particles in the range of about 5 to about 500 microns, more preferably 50 to 250 microns.

[0162] Semi-solid preparations suitable for intranasal administration can take the form of aqueous or oily gels or ointments. For example, the above-mentioned components can be mixed with microspheres of starch, gelatin, collagen, dextran, polylactide, polyglycolide, or other similar materials that can form hydrophilic gels. When the microspheres are loaded with the drug and administered, they can form a gel that adheres to the nasal mucosa.

[0163] Nasal spray formulations In one embodiment, the nasal preparation is in liquid form and may include aqueous solutions, aqueous suspensions, oil solutions, oil suspensions, or emulsions, depending on the physicochemical properties of the composition components. The liquid preparation is administered as a nasal spray or nasal drop using a device known in the art, including a nebulizer capable of delivering a selected volume of the formulation as a droplet aerosol. For example, commercially available spray pumps with delivery volumes of 50 or 100 μL are available, for example, from Valois (Congers, NY) along with adult and pediatric sized spray tips. In one embodiment, a composition comprising at least NMDP is administered intranasally by aerosol spray in a daily dose of about 30 to about 200 μL.

[0164] Liquid preparations can be prepared by known procedures. For example, aqueous preparations for nasal administration can be prepared by dissolving, suspending, or emulsifying NMDP or a salt thereof in water, a buffer, or other aqueous medium, or in an oily base such as pharmaceutically acceptable oils such as olive oil, lanolin, silicone oil, glycerin, or fatty acids.

[0165] The compositions according to this disclosure can be applied to the nasal cavity as liquids, sprays, aerosols, nebulizers, or semi-solid preparations. Semi-solid preparations may be present in a gel, w / o or o / w cream, or hydrophilic / lipophilic ointment base. The compositions may contain molecularly dispersed (soluble, solubilized, etc.) activators or fine particles / crystals of activators. The compositions may be administered from a cartridge system with nasal sprays, metering / dose sprays, squeeze bottles, liquid droppers, disposable single-dose droppers, nebulizers, unit-dose ampoules, single-dose pumps, double-dose pumps, multi-dose pumps, or any other device. For example, the compositions according to this disclosure may be delivered from / stored in spray or aerosol devices / containers, as described in detail in Remington's Pharmaceutical Sciences (16th edition, Chapters 83 and 92).

[0166] With regard to spray devices, it should be noted that both single-dose (unit) and multi-dose systems can be used. Typically, spray devices comprise a bottle and a pump, and such devices are commercially available from various suppliers. Typically, the volume of liquid dispensed in a single-spray operation ranges from 5 to 250 microliters per nostril per single dose, and the concentration of the active ingredient in the formulation can be easily adjusted so that one or more sprays into the nostrils fulfill the administration regimen. This disclosure also provides dose cartridges for use in spray devices or nasal delivery devices loaded with the above compositions.

[0167] As used herein, intranasal administration, or intranasal administration, involves administering the composition into the nostrils of a mammal's nose, into the mucous membrane of the nasal passage or nasal cavity. Such formulations may be administered, for example, as nasal sprays, nasal inhalers, nasal drops, aerosols, propellants, pressurized dispersions, aqueous aerosols, nebulizers, nasal suspensions, dropper administration, nasal gels, nasal powders, nasal ointments and nasal creams using any new or old type of device. Administration of the compositions of this disclosure may also be done using nasal tampons or nasal sponges containing the composition.

[0168] In some embodiments, a therapeutically effective amount of NMDP is administered in a composition comprising a carrier, citrate buffer, and benzalkonium chloride. In some embodiments, the composition may further comprise a non-aqueous solvent. In some embodiments, the composition may further comprise a surfactant. In some embodiments, the amount of carrier may be present in amounts of about 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 90% by weight, or 95% by weight. In some embodiments, the amount of non-aqueous solvent may range from about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 40% by weight, about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, or about 95% by weight. In some embodiments, the amount of surfactant in the composition may be in the range of about 0.00001%, about 0.0001%, about 0.001%, about 0.01%, about 0.1%, about 1%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 60%.

[0169] In some embodiments, a therapeutically effective amount of NMDP is administered in an intranasal composition that does not contain a nonionic surfactant.

[0170] In some embodiments, the intranasal composition free of nonionic surfactants comprises PEG, mPEG, water, and NMDP. In some embodiments, the intranasal composition free of nonionic surfactants comprises a composition comprising about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, or about 80% to about 90% (w / w) of mPEG or mPEG350, about 10% to about 50%, about 20% to about 50%, about 30% to about 50%, or about 40% to about 50% (w / w) of PEG or PEG400, and about 5% to about 20%, about 10% to about 20%, or about 15% to about 20% (w / w) of water and NMDP. In some embodiments, the concentration of NMDP in the non-ionic surfactant-free intranasal composition is at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 60 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 110 mg / mL, or greater than 110 mg / mL. In some embodiments, a therapeutically effective amount of NMDP is administered in an intranasal composition containing about 70% (w / w) mPEG350, about 20% (w / w) PEG400, and about 10% (w / w) water. In some embodiments, the concentration of NMDP in the intranasal composition is at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 60 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 110 mg / mL, or greater than 110 mg / mL.

[0171] In some embodiments, the intranasal composition free of nonionic surfactants comprises PEG, mPEG, water, ethanol, and NMDP. In some embodiments, the intranasal composition free of nonionic surfactants comprises about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, or about 80% to about 90% (w / w) of mPEG or mPEG350, about 10% to about 50%, about 20% to about 50%, about 30% to about 50%, or about 40% to about 50% The composition comprises % (w / w) PEG or PEG400, and about 5% to about 20%, about 10% to about 20%, or about 15% to about 20% (w / w) water, about 1% to about 10%, about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, about 5% to about 10%, about 6% to about 10%, about 7% to about 10%, about 8% to about 10%, or about 9% to about 10% ethanol, and NMDP. In some embodiments, the concentration of NMDP in the intranasal composition is at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 60 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 110 mg / mL, or greater than 110 mg / mL.

[0172] In some embodiments, a therapeutically effective amount of NMDP is administered in a composition comprising one or more forms of alkoxy-polyethylene glycol.

[0173] RO-(CH2CH2O)nH, where R is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In some embodiments, the average number of oxyethylene repeating units is in the range of about 1 to about 25, and the alkoxy-polyethylene glycol is of formula I:

[0174] It is represented by RO-(CH2CH2O)nH(I), where R is (C1-C6)alkyl and n is the average number of oxyethylene repeating units, ranging from approximately 1 to approximately 25. The term "(C1-C6)alkyl" refers to alkyl groups having 1 to 6 carbon atoms. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclopentyl, cyclobutylmethylene, cyclobutylethylene, cyclohexyl, cyclopropylpropylene, cyclobutylethylene, and cyclopentylmethylene.

[0175] In some embodiments, ethylene glycol can be used in the form of a single compound or as a mixture of two or more methoxy-n-ethylene glycols.

[0176] In some examples, alkoxy-polyethylene glycols are polyethylene glycol 200 (PEG200), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), and polyethylene glycol 1000 (PEG1000). The term "PEG200" is understood to mean polyethylene glycol with an average molecular weight of approximately 200 daltons. The term "PEG400" is understood to mean polyethylene glycol with an average molecular weight of approximately 400 daltons. The term "PEG600" is understood to mean polyethylene glycol with an average molecular weight of approximately 600 daltons. The term "PEG1000" is understood to mean polyethylene glycol with an average molecular weight of approximately 1000 daltons.

[0177] In certain embodiments, the alkoxy-polyethylene glycol is methoxy-polyethylene glycol 350 (mPEG350), methoxy-polyethylene glycol 550 (mPEG550), or methoxy-polyethylene glycol 750 (mPEG750). The term "mPEG350" is understood to mean methoxy-polyethylene glycol having an average molecular weight of about 350, and in certain embodiments, the average "n" shown in Formula I is 7.2. The term "mPEG550" is understood to mean methoxy-polyethylene glycol having an average molecular weight of about 550, and in certain embodiments, the average "n" shown in Formula I is 11.8. The term "mPEG750" is understood to mean methoxy-polyethylene glycol having an average molecular weight of about 750, and in certain embodiments, the average "n" shown in Formula I is 16.3.

[0178] Specific preferred alkoxy-polyethylene glycols include Carbowax® mPEG350, Carbowax® mPEG550, or Carbowax® mPEG750, all commercially available from Dow Chemical Company. Both mPEG350 and mPEG550 are colorless liquids with a boiling point of about 155°C, miscible with water, alcohols such as methanol, ethanol, n-propanol, glycerol, and various oils in any proportion. Alkoxy-polyethylene glycols are known by other names; for example, methoxy-polyethylene glycol is also known as monomethyl polyethylene glycol and poly(ethylene glycol) methyl ether.

[0179] In some embodiments, the composition can be optimized with respect to, for example, bioadhesion, mucosal adhesion, viscosity, and sprayability. For example, mPEG350 can still solubilize therapeutic agents at concentrations equivalent to PEG200, but the resulting composition has a lower viscosity. In some embodiments, lower viscosity has a positive effect on sprayability compared to PEG200 with a lower molecular weight, which is important when the formulation is sprayed.

[0180] In some embodiments, the composition comprises components selected from polyethylene glycol, propylene glycol, methoxypropylene glycol, ethanol, and water. In some embodiments, NMDP is solubilized in one or more forms of alkoxy-polyethylene glycol to reduce viscosity. In some embodiments, lower viscosity formulations are prepared for nasal spray formulations. Pharmaceutical compositions obtained at a temperature of 20°C have viscosities in the range of about 1.5 cP to about 60 cP, or about 2 cP to about 50 cP, or about 3 cP to about 40 cP, or about 4 cP to about 30 cP, or about 5 cP to about 25 cP. In certain embodiments, alkoxy-polyethylene glycol can constitute about 0.1% (w / w) to about 80% (w / w) or about 0.5% (w / w) to about 70% (w / w) of the composition. In certain other embodiments, alkoxy-polyethylene glycol may constitute about 5% (w / w) to about 80% (w / w), or about 30% (w / w) to about 75% (w / w), or about 40% (w / w) to about 70% (w / w) of the composition. For certain hydrophilic drugs, alkoxy-polyethylene glycol may constitute about 0.1% (w / w) to about 80% (w / w), or about 0.5% (w / w) to about 70% (w / w), or about 1% (w / w) to about 60% of the composition. For certain lipophilic drugs, alkoxy-polyethylene glycol may constitute about 1% (w / w) to about 80% (w / w), or about 2% (w / w) to about 65% (w / w), or about 5% (w / w) to about 50% of the composition. Furthermore, the therapeutic agent can constitute approximately 0.001% (w / v) to approximately 20% (w / v) of the composition, or approximately 0.1% (w / v) to approximately 10% (w / v) of the composition.

[0181] The pH of the pharmaceutical composition may be in the range of approximately 4.5 to approximately 8.5, or approximately 4.5 to approximately 7.5, or approximately 4.5 to approximately 6.5, or approximately 5.5 to approximately 8.5, or approximately 6.5 to approximately 8.5, or approximately 5.5 to approximately 7.5.

[0182] By using one or more of the alkoxy-polyethylene glycols described herein, the resulting pharmaceutical compositions can be optimized, for example, with respect to bioadhesion, viscosity, and sprayability. For instance, mPEG350 can still solubilize therapeutic agents at concentrations equivalent to PEG200, but the resulting compositions have lower viscosity. As a result, this substitution surprisingly has a positive effect on sprayability compared to PEG200 with a lower molecular weight, which is important when the formulation is sprayed.

[0183] It will be understood that excipients necessary for formulation, stability, and / or bioavailability may be included in the preparation. Exemplary excipients include sugars (glucose, sorbitol, mannitol, sucrose), uptake enhancers (chitosan), thickeners and stability enhancers (celluloses, polyvinylpyrrolidone, starch, etc.), buffers, preservatives, and / or acids and bases for pH adjustment.

[0184] In one embodiment, an absorption-enhancing component is included. Exemplary absorption-enhancing components include surfactant acids, such as cholic acid, glycocholic acid, taurocholic acid and other cholic acid derivatives, chitosan, and cyclodextrin. In some embodiments, cyclodextrin is included in the preparation.

[0185] Examples of exemplary surfactants include nonoxynol, octoxynol, tween, span, sodium lauryl sulfate, and sorbitan monopalmitate. Examples of exemplary absorption enhancers include bile salts and their derivatives, fusidic acid and its derivatives, oleic acid, lecithin, lysolecithin, dodecanoyl phosphatidylcholine (DDPC), sucrose monododecanoate, n-dodecyl-β-D-maltopyranoside, pectin, chitosan, α-, β-, and γ-cyclodextrins and their derivatives, pegylated caprylic / capric acid glycerides and their derivatives, such as Softigen and Labrasol. Examples of exemplary superabsorbent polymers include polyethylene glycol, propylene glycol, or mixtures thereof having an average molecular weight in the range of 200 to 7500, or single ethylene glycols, such as tetraethylene glycol and pentaethylene glycol. Examples of exemplary alcohols include ethanol and isopropyl alcohol. Examples of lipids include vegetable oils, soybean oil, peanut oil, coconut oil, corn oil, olive oil, sunflower oil, monoglycerides, diglycerides, mono / diglycerides, and mono / di / triglycerides. Examples of osmotic pressure regulators include glycerol, dextrose, maltose, sucrose, mannitol, xylitol, and various salts (e.g., sodium chloride). Examples of pH regulators include buffers and acids (e.g., nitric acid, phosphoric acid, acetic acid). Examples of preservatives include methyl parahydroxybenzoate, phenylethyl alcohol, or benzoic acid. Examples of propellants include air exchange such as butane or nitrogen. Examples of excipients for adjusting the HLB of the formulation include Tween 20, 25, 40, 45, 65, 85, Span 20-80, Brij 30-98, and acacia. Exemplary enzyme inhibitors include, for example, aprotinin and other peptidase inhibitors, diisopropyl fluorophosphate (DFP), and carbopol. Exemplary stabilizers include, for example, cyclodextrins.

[0186] It may be useful to include additional compounds that enhance the solubility of the therapeutic agent. Examples of such solubilizers include, for example, alcohols and polyols, e.g., ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transktol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, PEGylated mono / di-caprylic / capric glycerides, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins (e.g., α-, β-, or γ-cyclodextrins) and cyclodextrin derivatives; polyethylene glycol ethers or tetrahydrofurfuryl alcohol PEG ethers having an average molecular weight of about 200 to about 6000 (Glycoflore, marketed by BASF under the trade name Tetraglycol); surfactants, e.g., sodium lauryl sulfate, oleic acid, linoleic acid, monooleic acid, lecithin, lysolecithin, deoxycholate, taurodiol Oxycholate, glycochenodeoxycholate, polyoxyethylene X-lauryl ether where X is 9-20, tauro-24,25-dihydrofusidate sodium, polyoxyethylene ether, polyoxyethylene sorbitan ester, pt-octylphenoxypolyoxyethylene, N-lauryl-β-D-maltopyranoside, 1-dodecyl azacycloheptan-2-azon; amides, e.g., 2-pyrrolidone, 2-piperidone, caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone , N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, caprolactone and its isomers, valerolactone and its isomers, β-butyrolactone and its isomers;Other solubilizers known in the art include, for example, dimethylacetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methylpyrrolidone (Pharmasolve (ISP)), monooctanoin, and diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol).

[0187] Preferred additional solubilizers include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-1000, PEG300, PEG400, Transcutol, and dimethyl isosorbide, sorbitol, glycerol, triacetin, glycoflor, and propylene glycol. Typically, if present, the solubilizer is present in amounts of about 0.1% (w / v) to about 50% (w / v), about 1% (w / v) to about 40% (w / v), or about 2% (w / v) to about 25% (w / v). Furthermore, the liquid pharmaceutical composition may contain water in amounts of, for example, about 2% (w / v) to about 99% (w / v), about 10% (w / v) to about 95% (w / v), or about 20% (w / v) to about 90% (w / v) of the liquid composition.

[0188] As discussed, the composition may contain preservatives. In addition, or instead, the composition may be sterilized. Sterilization can be achieved by filter sterilization, autoclaving, ionizing radiation, such as exposure to gamma rays, UV irradiation, and chemical sterilization. In one embodiment, the sterile composition is at least about 10 3 It has a sterility assurance level. The resulting liquid composition is preferably stable at room temperature, and after storage at 20°C for 30 days, or more preferably for 6 months, the degradation of the therapeutic agent is less than 5% by weight, 4% by weight, 3% by weight, 2% by weight, or 1% by weight.

[0189] Furthermore, the formulation may also contain sweeteners or flavorings. Examples of sweeteners or flavorings include, for example, acacia syrup, acesulfame potassium, anethole, anise oil, aromatic elixir, aspartame, benzaldehyde, benzaldehyde elixir, cyclodextrin, caraway, caraway oil, cardamom oil, cardamom seeds, cardamom spirit, cardamom tincture, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, and citrate syrup. Ingredients: Clove oil, cocoa, cocoa syrup, coriander oil, dextrose, eriodictiol, eriodictiol fluid extract, eriodictiol syrup, fragrance, ethyl acetate, ethyl vanillin, fennel oil, ginger, ginger fluid extract, ginger oleoresin, glucose, sugar, maltodextrin, glycerin, licorice, licorice elixir, licorice extract, pure licorice extract, licorice fluid extract, licorice syrup, honey, isoalcohol erythritol Examples include xylitol, lavender oil, lemon oil, lemon tincture, maltodextrin, maltose, mannitol, methyl salicylate, menthol, nutmeg oil, bitter orange oil, orange blossom oil, orange blossom water, bitter orange oil, sweet orange peel tincture, orange spirit, orange syrup, peppermint, peppermint oil, peppermint spirit, peppermint water, phenylethyl alcohol, raspberry juice, raspberry syrup, rosemary oil, rose oil, rose water, saccharin, calcium saccharin, sodium saccharin, sarsaparilla syrup, sarsaparilla compounds, sorbitol solution, spearmint, spearmint oil, sucrose, sucralose syrup, thyme oil, tolu balsam, tolu balsam syrup, wintergreen oil, vanilla, vanilla tincture, vanillin, cherry syrup, xylitol, or combinations thereof.

[0190] Furthermore, the formulation may optionally contain a taste masking agent. Examples of masking agents include, for example, cyclodextrins, cyclodextrin emulsions, cyclodextrin particles, cyclodextrin complexes, or combinations thereof.

[0191] dry powder composition In certain embodiments, the NMDP composition prepared according to the method described herein can be designed to a desired NMDP level. For example, in one embodiment, when the microspheres are separated and decomposed by at least 77.8% of decoagulating particles (e.g., lactose monohydrate), the level of NMDP hydrochloride or its hydrate in the form of microspheres is about 22.2% w / w. In some embodiments, the final composition may then be introduced into a disposable administration device, such as those described below, to provide a dose of about 50 to about 2500 mg of NMDP hydrochloride in a single intranasal administration.

[0192] The pharmaceutical compositions described herein may comprise disposable dosing units for intranasal administration that provide a predetermined measured dose of NMDP or a salt thereof. An example of a disposable unit is the Unit Dose Powder Device (UDS) manufactured by Aptar Pharma. This type of device for powder spraying can be used for systemic delivery of small, precisely measured doses of NMDP formulations by patients or caregivers who are not healthcare professionals or have not received medical training.

[0193] This disclosure further relates to single-dose dose unit forms (also called dose unit devices, dose devices, or drug devices) of the pharmaceutical compositions of this disclosure (containing an opioid receptor antagonist, specifically NMDP or a pharmaceutically acceptable salt thereof, e.g., NMDP hydrochloride, as the active ingredient) for intranasal administration to subjects, specifically disposable dose unit forms, wherein a dose unit is loaded with a predetermined dose of the composition and provides a subject with a measured dose of the pharmaceutically active ingredient contained in the composition. In some embodiments, the dose unit form is storage stable. In addition to the dose unit devices described above, the NMDP compositions of this disclosure can be administered using syringe-driven devices and pump-driven spray atomizers. Double-dose and multi-dose devices are also intended within the scope of this disclosure. In some embodiments, the NMDP contained in the dose devices of this disclosure is retained in an amorphous form.

[0194] A composition and its dosage unit according to this embodiment of the present disclosure, containing NMDP or a pharmaceutically acceptable salt thereof as an active opioid receptor antagonist, is also referred to herein as an NMDP composition and an NMDP dosage unit, respectively.

[0195] The NMDP compositions of this disclosure are intended, in particular, for the treatment of tinnitus or Meniere's disease. The treatment of tinnitus or Meniere's disease as referred herein should be interpreted as meaning the alleviation or reversal of the effects of tinnitus or Meniere's disease, and associated symptoms, such as hearing loss and ear pressure, among other things. The NMDP compositions and their dosage units according to this disclosure have been shown to be significantly effective.

[0196] In some embodiments, the NMDP intranasal powder formulation according to the present disclosure is administered for intranasal administration, and a high proportion of NMDP particles, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 86%, reaches the turbinate region. In some embodiments, the NMDP intranasal powder formulation according to the present disclosure is administered for intranasal administration, and a high proportion of NMDP particles, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 86%, reaches the auricle region. In some embodiments, about 15%, about 20%, about 25%, about 30%, or about 35% are in the intermediate portion of the olfactory region. In some embodiments, less than 10% of NMDP particles remain in the nose, and less than 1% reach the lungs, providing an effective amount of NMDP and an improved therapeutic effect to the subject being treated.

[0197] This specification provides a kit for the treatment / reversal of tinnitus or Meniere's disease. The kit comprises at least one dose unit of an NMDP powder composition as disclosed herein and instructions for use. The dose unit may be a single dose, a two-dose unit, or a multi-dose unit.

[0198] In one embodiment, a pharmaceutical composition in the form of a dry powder for intranasal (nasal-to-brain) N2B administration to a patient requiring it comprises solid particles of NMDP and solid particles of a diluent, wherein the pharmaceutical composition is substantially free of excipients other than the solid diluent, and the pharmaceutical composition comprises at least 90% of NMDP particles having an average particle size of 10 to 30 microns, less than 10% of particles of the at least one activator having an average particle size of about 5 to 50 microns, and particles of the diluent having an average particle size of 50 to 200 microns.

[0199] In some embodiments, the composition may consist of a solid diluent, such as lactose monohydrate or a lactose functional analog. In another embodiment, a pharmaceutical composition in the form of a dry powder for intranasal administration by transmucosal systemic delivery via the upper nasal mucosa (turbinates and lymphoid tissue located in the posterior part of the nasal cavity) comprises NMDP or a salt thereof having an average particle size in the range of 10 to 30 microns. In some embodiments, at least 90% of the particles have an average particle size of 5 to 30 microns, and the diluent has an average particle size in the range of 50 to 200 microns. As described above, the diluent is also used to prevent aggregation of the dry powder particles containing NMDP or a salt thereof.

[0200] The compositions of the embodiments can be delivered by any one of the nasal devices known in the art, such as a pressurizing device, a dry powder sprayer, or a bidirectional nasal device. Multi-dose devices and single-dose devices can be used.

[0201] The NMDP content of the embodiment's composition can be adjusted to provide the total dose of drug necessary to achieve a therapeutic effect as a single dose in one nostril. Drug administration can be repeated in another nostril to double the amount of active material. The storage stability of the embodiment's composition can be determined under accelerated and ambient conditions.

[0202] In some embodiments, the compositions herein may contain NMDP and a diluent, such as lactose or a lactose functional analog, and may be substantially free of other excipients, such as surfactants, lipid agents, solvents, or propellants. The solid diluent in the embodiments may be selected from lactose monohydrate or lactose monohydrate functional analogs, such as lactose, cellulose and derivatives, starch and derivatives, dextrose, sorbitol, mannitol, maltitol, xylitol, or mixtures thereof. The solid diluent may be lactose monohydrate.

[0203] Lactose may exist in the form of α-lactose monohydrate, anhydrous β-lactose, or amorphous lactose. The pharmaceutical composition of the embodiment may further comprise one or more pharmaceutically acceptable diluents, excipients, or both. The pharmaceutical composition of the embodiment may be prepared in the form of a powder, a simple powder mixture, powder microspheres, coated powder microspheres, liposome dispersion, or a combination thereof.

[0204] In some embodiments of this disclosure, a therapeutically effective dose of NMDP or a salt thereof corresponds to about 10 mg of NMDP administered intranasally as a single dose, or, optionally, about 50 mg or 2500 mg of NMDP administered in multiple doses. In some embodiments, the therapeutically effective dose corresponds to about 3, 4, 5, 6, 7 or 8 to about 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 80, 90, 100, 120, 150, 200 or 2500 mg of NMDP, respectively. In some embodiments, NMDP or a salt thereof is the only pharmaceutically active compound in the pharmaceutical composition. In some embodiments, a therapeutic method using the NMDP powder composition and formulation according to this disclosure is used to measure the plasma concentration-time curve of NMDP in the patient over about 0.13 to about 0.75 hours. max For example, 0.25 hours of T max It can be provided as follows. Methods of treatment with the NMDP powder composition and formulation according to this disclosure can provide an average maximum plasma concentration of NMDP of approximately 20 pg / mL to approximately 25, 30, 40, 45, 50, 70, 90, 100, 120, 150, 180, 200, 250, 500, 1000 ng / mL, or 20 ng / mL, 50, 100, 150, or 250 ng / mL within 15 minutes of administration. The methods of treatment with the NMDP powder compositions and formulations according to this disclosure can provide an average maximum concentration of NMDP of approximately 20 pg / mL to approximately 25, 30, 40, 45, 50, 70, 90, 100, 120, 150, 180, 200, 250, 500, 1000 ng / mL, or 20 ng / mL, 50, 100, 150, or 250 ng / mL within 15 minutes of administration to the auricular structure.

[0205] The devices used for intranasal delivery of the compositions of the embodiments can be designed to provide appropriate plume shapes and spray patterns for the initial and storage compositions. In some embodiments, these compositions may have a narrow particle size distribution with a median diameter of 5 to 50 microns.

[0206] Liposome composition A method for administering NMDP or a salt thereof to a patient in need is provided herein, the method comprising intranasal administration of a composition comprising a therapeutically effective amount of NMDP or a salt thereof, a phospholipid, one or more C2-C4 alcohols and water, wherein the concentrations of the phospholipid and one or more alcohols in the composition are in the range of 0.2 to 70% by weight and 10 to 70% by weight, respectively. In some embodiments, the water content of the composition is 10%, 20%, 30%, 40%, 50%, or 60% by weight, and the phospholipid forms vesicles in the composition. In some embodiments, the concentration of NMDP or a salt thereof is in the range of 0.5 to 25% by weight.

[0207] Aqueous compositions comprising NMDP or a salt thereof in combination with one or more short-chain alcohols containing phospholipids at a concentration of 0.2 to 50% by weight are provided herein. In some embodiments, the weight concentration of water is at least 30% by weight. In some embodiments, the weight concentration of the alcohols is in the range of 10 to 50% by weight, which can be adapted for use as an intranasal drug delivery vehicle. In some embodiments, the concentration of NMDP or a salt thereof in the composition is in the range of 0.5 to 25% by weight.

[0208] Accordingly, in one embodiment, the use of a vesicular composition comprising NMDP or a salt thereof, phospholipids, one or more C2-C4 alcohols and water for intranasal administration to treat one or more symptoms of tinnitus or Meniere's disease in patients requiring it is described herein. In some embodiments, the concentrations of the phospholipids and one or more alcohols in the composition are in the range of 0.2 to 50% by weight and 10 to 50% by weight, respectively, and the water content of the composition is 10 to 50% by weight. In some embodiments, the concentration of NMDP or a salt thereof is in the range of 0.5 to 25% by weight.

[0209] Phospholipids suitable for use in the preparation of compositions according to this disclosure include phosphatidylcholine (PC), hydrogenated phosphatidylcholine, phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylglycerol (PPG), and phosphatidylinositol (PL). The chemical structures of phospholipids that can be used in accordance with this disclosure are described in U.S. Patent No. 4,614,730, which is incorporated herein by reference. Preferably, the phospholipids are present in the compositions of this disclosure for intranasal delivery of NMDP for the treatment of tinnitus or Meniere's disease at a concentration of 0.5 to 15% by weight.

[0210] As used herein, the term C2-C4 alcohol refers to alkanols containing two, three, or four carbon atoms. Alcohols used in accordance with this disclosure specifically include ethanol, 1-propanol, isopropyl alcohol, and tert-butyl alcohol. In some embodiments, the concentration of ethanol in the composition is in the range of 1% to 20%, 30%, 40%, 50%, 60%, or 70% by weight. According to one embodiment of this disclosure, the composition further comprises one or more water-miscible polyols, particularly glycols (1,2-diols, e.g., ethylene glycol and propylene glycol), in concentrations of 1% to 30%, 40%, or 50% by weight.

[0211] The composition can be prepared by mixing various components, namely water, phospholipids, one or more C2-C4 alcohols (and optionally one or more polyols), and NMDP or a salt thereof, under conditions that allow for vesicle formation. In some embodiments, the composition can be conveniently prepared by dissolving the phospholipids in alcohol (or an alcohol / glycol mixture), then adding NMDP or a salt thereof in either aqueous or solid form, followed by the addition of water. Alternatively, a dispersion of phospholipids and NMDP or a salt thereof in water can be prepared, and the alcohol can be added thereto, preferably with heating and stirring, and optionally together with a polyol (e.g., a mixture of ethanol and propylene glycol).

[0212] Alternatively, lyophilized lipid vesicles containing the active ingredient can be prepared first, and then dispersed in a mixture of water, C2-C4 alcohols, and optionally polyols.

[0213] In some embodiments, the size of the vesicles may range from 50 nm to several microns, more specifically up to 5 μm. In some embodiments, the compositions according to this disclosure may include additional excipients known in the art, such as surfactants, preservatives, thickeners, cosolvents, adhesives, antioxidants, buffers, viscosity and absorption enhancers, and agents that can adjust the pH and molar osmotic pressure of the formulation. Additional excipients that can be used with the compositions and methods herein are described elsewhere herein.

[0214] In another embodiment, a method is provided for administering a pharmaceutical active ingredient to a patient in need thereof, the method comprising intranasal administration of a vesicular composition comprising a therapeutically effective amount of the ingredient, a phospholipid, one or more C2-C4 alcohols and water, wherein the concentrations of the phospholipid and one or more alcohols in the composition are in the range of 0.2 to 10% by weight and 12 to 30% by weight, respectively, and the water content of the composition is 20% by weight or more, preferably 30% by weight or more.

[0215] Sustained-release formulation In some embodiments, the Disclosure describes methods and dosage forms for sustained NMDP delivery for the treatment of symptoms associated with tinnitus or Meniere's disease in mammalian subjects. In some embodiments, mucosal delivery of NMDP formulated with one or more mucosal delivery enhancers is envisioned to substantially normalize the dose-release of NMDP and / or be sustained over an effective delivery period of about 0.1 to about 2.0 hours, about 0.4 to about 1.5 hours, about 0.7 to about 1.5 hours, or about 0.8 to about 1.0 hours after mucosal administration. The sustained release of NMDP achieved can be facilitated by repeated administration of exogenous NMDP utilizing the methods and compositions of the Disclosure.

[0216] In some embodiments, the mucosal delivery enhancers of the present disclosure can enhance the therapeutic activity of mucosally administered NMDP by resulting in an effective increase in delivery, e.g., an increase in maximum plasma concentration (Cmax) or Cmax in the auricular structure. Another factor influencing the therapeutic activity of NMDP in the auricular structure for the treatment of tinnitus or Meniere's disease is residence time (RT). In some embodiments, sustained-release enhancers, in combination with intranasal delivery enhancers, increase the Cmax of NMDP in the auricular structure and increase the residence time (RT). Increases in residence time at the mucosal delivery site (e.g., nasal mucosa), the treatment site (e.g., auricular structure) and / or in systemic circulation are intended herein. In some embodiments, the polymer delivery vehicles and other agents and methods of the present disclosure that result in sustained-release enhanced formulations may include polyethylene glycol (PEG).

[0217] Semi-solid formulations and viscous gel formulations In some of the methods contemplated herein, the intranasal NMDP nasal pharmaceutical composition is applied to the outer lateral wall of the nasal cavity (opposite the nasal septum) of each nostril, preferably locally located on the cartilage of the lateral outer wall of each nostril, from approximately the center of the outer wall (opposite the nasal septum) to approximately the apex just below that portion. Once the deposition of the nasal pharmaceutical composition is complete within each nostril, the external nose is gently and carefully squeezed and / or rubbed into the subject, thereby preparing the deposited nasal pharmaceutical composition for sustained release of NMDP by maintaining contact with the mucous membrane within the nasal cavity. A typical dose of NMDP nasal pharmaceutical composition deposited by nasal application is about 50 to about 150 microliters per non-cavitation, preferably about 100 microliters per nasal cavity.

[0218] In carrying out the method of the present disclosure, approximately 50 microliters to approximately 150 microliters of the pharmaceutical composition of the present disclosure may be administered daily into each nostril of a subject, for example, for 1, 2, 3, or 4 weeks, 3, 4, 5, 6, 7, or 8 weeks, or intermittently, for example, for 2, 3, 4, 5, or 6 consecutive months or longer, or once, twice, or three times per week, or as needed for hearing impairment.

[0219] The methods disclosed herein include a dosage concentration of an intranasal NMDP composition, the number of daily doses, the duration of treatment, a parenteral method, and, in some embodiments, a number of applications per day, week, month, or year, and a pre-filled multi-dose applicator system for delivering effective dose levels of NMDP or mixtures thereof in an intranasal composition to deliver an effective amount of NMDP or mixtures thereof.

[0220] In some embodiments, the viscosity of the nasal pharmaceutical compositions of the present disclosure is at least about 500 cps (e.g., cP) and is in the range of about 500 cps to about 100,000 cps before administration of the thixotropic properties associated with a portion of the novel nasal pharmaceutical composition. In some embodiments, the viscosity is about 1,000 cps to about 75,000 cps, about 2,500 cps to about 50,000 cps, and about 2,500 cps to about 50,000 cps and may be in the range of about 5,000 cps to about 25,000 cps before administration or pumping with respect to the thixotropic properties associated with a portion of the novel nasal pharmaceutical composition. In some embodiments, the compositions have a viscosity of about 10 to about 100 cps, about 10 to about 90 cps, about 10 to about 80 cps, about 10 to about 70 cps, about 10 to about 60 cps, or about 10 to about 50 cps.

[0221] In some embodiments, the applicator system of the present disclosure is, for example, an airless fluid, an immersion tube fluid distribution system or pump, or any other system suitable for performing the method of the present disclosure. The applicator system or pump includes, for example, a chamber pre-filled with multiple doses of the intranasal NMDP gel of the present invention, which is closed by an actuator nozzle. The actuator nozzle may include an outlet channel and a tip, and the actuator nozzle is configured to (a) provide coherent delivery of a uniform volume of the intranasal NMDP gel of the present disclosure to be applied to the nasal cavity around the patient's nasal cavity, and (b) conform to the inner surface of the user's nostril for deposition at each indicated location within the patient's nostril as intended by the novel method and teaching of the present disclosure. Preferably, the pump design is configured, when inserted into the nasal cavity, to ensure that the nasal tip is positioned within the nasal cavity so that the gel is distributed within the appropriate location within the nasal cavity when the gel is distributed.

[0222] The oily gel, emulsion, or cream can be applied to the inside of the nasal opening by approximately one inch (non-air) using a dispenser tip that is appropriately designed to reach and attach to a container. To prevent injury, the tip is preferably rounded. The nose is then massaged to diffuse the composition into a thin film inside the non-hollow interior, aiding in the absorption of the active ingredients into the mucous membrane tissue.

[0223] Examples of pre-filled multi-dose applicator systems include, for example, (a) Ursatec, Verpackung-GmbH, Schillerstr. Wendel, COMOD system (available from Germany), (b) airless system, digital airless applicator system available from RD 149 27380 Charleval, France or 250 North Route 303 Congers, Albion, or NY 10950, (c) nasal applicator from Neopac, The Tube, Hoffmann Neopac AG, Burgdorfstrasse 22, Postfach, 3672 Oberdiessbach, Switzerland, or (d) cannabinoid pharmaceutical compositions.

[0224] Preferably, the intranasal NMDP pharmaceutical composition is filled into a non-storage, airless, multi-dose device that can accurately deliver the volume of the NMDP pharmaceutical composition at a higher viscosity.

[0225] According to certain embodiments, the composition comprises (1) an NMDP therapeutic active substance; (2) an oily vehicle; and (3) a wetting agent, or a mixture of wetting agents, and / or a pharmaceutically acceptable surfactant or a mixture of surfactants.

[0226] According to certain embodiments, the oily vehicle is recognized as one or more pharmaceutically acceptable and generally safe lipids.

[0227] According to certain embodiments, the oily vehicle is selected from the group consisting of pharmaceutically acceptable vegetable oils, monoglycerides, diglycerides, sucrose acetate isobutyrate (SAIB), synthetic triglycerides, and combinations thereof. According to certain embodiments, pharmaceutically acceptable vegetable oils include sweet almond oil (prunus dulcis), virgin almond oil (prunus amid glarus), aloe vera oil (aroebabadensis), apricot kernel oil (fruit pandanus Armenia car), argan oil (California RY labor), avocado oil (PERE Seah Americana), apricot oil (fruity Taunus Armenia car), amla oil (preamble Rica operational during the day lease), borage oil (swabbing Opie during the day lease), black seed oil (age Gela sativa), carrot oil (Dow Syracuse Caro L), coconut oil (nose Syracuse nusi Pera), corn oil, cucumber oil (Cucumis sativa), tea ulmu gras oil (hydroxy-no-kapuseu Wig Tia Taunus), and emu oil (draw My funny nobae-Hall). Grandi kids), moon yikkot oil (Oe Bruno Terra Bien Nice), linseed oil (rineom Wuxi City Tatiana stopped), grape seed oil (Vitus Beanie Blow), hazelnut oil (ahbekeu Kana), Yo bar refined oil (deep diamond cyano difference norbornene-cis), moringa grown in 5 days (Moringa), e Lula oil ('s Klee Rocca Ria non LEA), wheat germ oil, tree tikum No Les, macadamia oil (Macadamia Terni polyamic), cantaloupe oil (Kubu Miss melon), Maersk oil (Abel MossCheese (Moss primary tooth), mustard oil (Azadi lakh other indica), olive oil (Oleic Ah Europa), peach kernel oil (Fruity Taunus Pere Chicago), peanut oil (Arachis hypo geah), pomegranate oil (Fu Nika Gras natum), programme soral leah oil (Programmed soral leah Cora Come polyamic), Supreme rose oil (Oe Bruno Terra Bien Needle), papaya seed oil (K Rica papaya), rosehip oil (Rosa Ruby-based labor), safflower oil, (refined) sesame seed oil (Cesar stopped Indy Com), raw wood oil (Hippo wave Lam Noi death), both oil (Soya Heath the blood), sunflower oil (Heli no tooth should Taunus), sweet almond oil (Fruit pandanus Ami moon Russ Barr moon Syracuse), sweet cherry kernel oil (Fruity The oil is selected from the group consisting of Taunus Oh Away, walnut oil (Jugeul Lance Reg A), and watermelon oil (Citrus vulgaris).

[0228] According to certain embodiments, the oily vehicle comprises castor oil and / or sesame oil and / or SAIB.

[0229] According to certain embodiments, the wetting agent or mixture of wetting agents, and / or the mixture or surfactant of pharmaceutically acceptable surfactants is polysorbate, polyoxyethylene hydrogenated vegetable oil, polyoxyethylene vegetable oil; polyoxyethylene sorbitan fatty acid ester; polyoxyethylene-polyoxypropylene block copolymer; polyglycerol fatty acid ester; polyoxyethylene glyceride; polyoxyethylene sterol, or its derivatives or analogues; polyol and reaction mixture of at least one member of the group consisting of fatty acids, glycerides, vegetable oil, hydrogenated vegetable oil, fractionated oil and sterol; tocopheryl polyethylene glycol succinate; sugar ester; sugar ether; sucrose glyceride; alkyl glucoside; alkyl maltoside; and Lukylthioglycoside; lauryl macrogol glyceride; polyoxyethylene alkyl ether; polyoxyethylene alkylphenol; polyethylene glycol fatty acid ester; polyethylene glycol glycerol fatty acid ester; polyoxyethylene sorbitan fatty acid ester; polyoxyethylene-polyoxypropylene block copolymer, e.g., Poloxamer-108, 188, 217, 238, 288, 338, 407, 124, 182, 183, 212, 331 or 335, or combinations thereof; ionic hydrophilic surfactant, e.g., sodium dodecyl sulfate or sodium doxate; bile acids; cholic acid; deoxycholic acid; chenodeoxycholic acid; selected from the group consisting of salts thereof, salts thereof, and mixtures thereof.

[0230] According to certain embodiments, the composition comprises rheological modifiers, such as colloidal silica, silicate, alumina, high molecular weight polymers or solid / wax materials, beeswax, alumina, silicate, and high melting point waxes and / or cetostearyl alcohol.

[0231] According to certain embodiments, the composition further comprises minerals, osmotic complements, thickeners and / or hydrophilic polymers. According to certain embodiments, the hydrophilic polymer is selected from the group consisting of HPMC, HPC, sodium CMC, sodium CMC and MCC, natural gums such as xanthan gum, guar gum, acacia gum, and tragacanth gum, corn starch, potato starch; and starch, for example, starch. According to a particular embodiment, the surfactant is glycol distearate, sorbitan trioleate, propylene glycol isostearate, glycol stearate, sorbitan sesquioleate, lecithin, sorbitan oleate, sorbitan monostearate NF, sorbitan stearate, sorbitan isostearate, stearate-2, olet-2, glyceryl laurate, ceNMDPh-2, PEG-30 dipolyhydroxystearate, glyceryl stearate SE, PEG-8 sorbitan laurate, sorbitan laurate, sorbitan laurate, sorbitan monolaurate, sorbitan monolaurate, sorbitan monolaurate, for example, Labrafil M1944CS, Laureth-4, PEG-7 Glyceryl Cocoate, PEG-20 Almond Glyceride, Polyoxyethylene Glyceride, PEG-25 Hydrogenated Castor Oil, Stearamide MEA, Glyceryl Stearate (and) PEG-100 Stearate, Polysorbate 85, PEG-7 Oleate, Cetearyl Glucoside, Stearamide MEA, PEG-10, Oleth-10 / Polyoxyl 10 Oleyl Ether NF, Ceteth-10, PEG-8 Laurate, Cocamide MEA, Polysorbate 60 The following are selected from the group consisting of NF, polysorbate 60, polysorbate 80, isostearate-20, PEG-60 almond glyceride, PEG-20 methyl glucose sesquistearate, ceteareth-20, oleate-20, Steareth-20, Steareth-21, Steareth-21, Ceteth-20, and Steareth-100.

[0232] Excipients and other components in the formulation In various aspects of this disclosure, improved nasal mucosal delivery formulations and methods are provided, which enable the delivery of NMDP and / or other therapeutic agents across the mucosal barrier (e.g., mucosal surface) between the administration and one or more selected target sites. Certain formulations can be specifically adapted to selected target cells, tissues or organs, or even specific disease conditions. In other aspects of this disclosure, improved transnasal delivery formulations and methods provide efficient and selective endocytosis or transcytosis of NMDP, specifically routed along defined intracellular or intercellular pathways. As understood herein, NMDP may be efficiently loaded at an effective concentration in a carrier or other delivery vehicle and then administered and maintained in a stabilized form, for example, upon administration to the nasal mucosa and / or while passing through one or more intracellular compartments and / or membranes to the target site of drug action (e.g., bloodstream or defined tissue, organ or extracellular compartment). NMDP may be delivered in a delivery vehicle or otherwise modified (e.g., into the form of a prodrug), and the release or activation of NMDP may be triggered by physiological stimuli (e.g., pH changes, lysosomal enzymes, etc.). In certain embodiments, NMDP may be pharmacologically inactive until it reaches its target site for activity. NMDP and other formulation components are non-toxic (or have reduced toxicity to tolerable levels) and non-immunogenic. In this regard, carriers and other formulation components are generally selected for their ability to be rapidly degraded and / or eliminated under physiological conditions. At the same time, the formulation is chemically and physically stable in dosage forms for effective storage.

[0233] In the mucosal delivery formulations and methods of this disclosure, NMDP is often administered in combination with or in conjunction with a carrier or vehicle suitable for mucosal delivery. As used herein, the term "carrier" includes pharmaceutically acceptable solid or liquid fillers, diluents, or encapsulating materials. As used herein, the carrier may be a mucosal delivery enhancer.

[0234] Water-containing liquid carriers may contain pharmaceutically acceptable additives, such as acidifiers, alkalizers, antimicrobial preservatives, antioxidants, buffers, chelating agents, complexing agents, solubilizers, humectants, solvents, suspending agents and / or thickeners (e.g., thickeners), isotonic agents, wetting agents, or other biocompatible materials. As disclosed herein, humectants include, but are not limited to, propylene glycol, glycerin, glyceryl triacetate, polyols, polymer polyols, lactic acid, and urea. Within this disclosure, pharmaceutical formulations may contain one wetting agent, or any combination or mixture of two or more wetting agents.

[0235] The solubilizers included in the compositions herein may include cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methyl-β-cyclodextrin. Such solubilizers can be used alone or in any mixture or combination of two or more solubilizers in pharmaceutical formulations. Some examples of materials that can function as pharmaceutically acceptable carriers are sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol Recalls, polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate, ethyl laurate; agar; buffers, e.g., magnesium hydroxide, aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salines, acetates, glycine, histidine, arginine, glutamate, lysine, methionine, lactate, formate, and glycolates; Ringer's solution; ethyl alcohol and phosphate buffer, as well as other non-toxic, suitable substances used in pharmaceutical formulations.

[0236] In some embodiments, pharmaceutical formulations for transmucosal, e.g., intranasal delivery of NMDP or a salt thereof as described herein may comprise any one buffer or any combination or mixture of two or more buffers. The buffers have a pK in the range of about 5 to about 9, or about 6 to about 8. a The composition may also contain wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants, as desired by the prescriber. Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), ethylene glycoltetraacetic acid (EGTA), sorbitol, tartaric acid, and phosphoric acid. According to this disclosure, any one or any mixture or combination of chelating agents may be included in the pharmaceutical formulation. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the specific mode of administration.

[0237] The mucosal delivery compositions and methods of this disclosure utilize various mucosal delivery enhancers that enhance the delivery of NMDP into or beyond the mucosal surface. In this regard, delivery of NMDP beyond the mucosal epithelium may occur "transcellularly" or "paracellularly." The extent to which these pathways contribute to the overall flux and bioavailability of NMDP depends on the mucosal environment, the physicochemical properties of the activator, and the properties of the mucosal epithelium. In some embodiments, the methods and compositions of this disclosure provide significantly enhanced transport of NMDP or a salt into and beyond the mucosal epithelium via paracellular pathways. In some embodiments, the methods and compositions of this disclosure provide significantly enhanced transport of NMDP or a salt into and beyond the mucosal epithelium via transcellular pathways, either or otherwise, in a single method or composition.

[0238] As used herein, mucosal delivery enhancers include agents that enhance or otherwise modulate the release or solubility (e.g., from the drug delivery vehicle), diffusion rate, permeability and timing, uptake, residence time, stability, effective half-life, peak or sustained concentration levels, clearance, and other desired mucosal delivery properties (e.g., measured at the delivery site or at a selected active target site such as blood flow or the central nervous system) of NMDP or other bioactive compounds. Thus, enhancement of mucosal delivery may occur by one or more diverse mechanisms, such as increased diffusion, transport, persistence, or stability of NMDP; increased membrane fluidity; modulation of the availability or action of calcium and other ions that regulate intracellular or paracellular permeability; solubilization of mucosal components (e.g., lipids); changes in non-protein and protein sulfhydryl levels in mucosal tissue; increased water flux across the mucosal surface; modulation of epithelial junctional physiological function; decreased viscosity of mucus covering the mucosal epithelium; decreased mucosal ciliary clearance rate; and other mechanisms.

[0239] As used herein, “mucosal effective dose of NMDP” refers to the effective mucosal delivery of NMDP to a target site (i.e., auricular structure) for drug activity in a subject requiring it, which may include various delivery or transport routes. For example, NMDP or a salt thereof may travel through intercellular spaces (e.g., voids) in the mucosa to reach the adjacent blood vessel wall in the Eustachian tube, while by another route the drug may be passively or actively taken up (i.e., internalized) into mucosal cells to act within the cell, or be expelled (e.g., released), or carried out of the cell to reach a secondary target site such as the tympanic membrane. The methods and compositions of this disclosure can facilitate the transport of NMDP or a salt thereof along one or more such alternative (transcellular or paracellular) pathways, or act directly on mucosal tissue or proximal vascular tissue to facilitate the absorption or osmosis of NMDP or a salt thereof. Facilitation of absorption or osmosis in this context is not limited to these mechanisms.

[0240] Suitable surfactants that can be used in accordance with this disclosure include ionic, nonionic, or amphoteric surfactants. More specifically, hydrophilic surfactants (e.g., Tweens, Tween 80, Myrj, Brjs, Labrasol, etc.) or lipophilic surfactants (e.g., Span 20, Span 60, Myrj, Arlacel 83, etc.) can be suitably used, preferably in concentrations ranging from 0 to 25% by weight.

[0241] Suitable preservatives that can be used with the formulation of the present invention include, for example, benzyl alcohol, parabens, chlorobutanol, benzalkonium salts, and combinations thereof. Some examples of antioxidants include tocopherol, butylhydroxytoluene, sodium metabisulfite, potassium metabisulfite, and ascorbyl palmitate. These preservatives and antioxidants can be present in the formulation at concentrations of about 0.001% to about 5% w / w.

[0242] Regarding buffers, the nasal delivery system may include a buffer to maintain the formulation at a pH of approximately 7.0. The specific buffer may, of course, vary depending on the specific nasal delivery system used and the specific active molecule selected. Suitable buffers for use in this disclosure include, for example, acetic acid, citrate, prolamin, carbonate and phosphate buffers, and combinations thereof. The pharmaceutical formulations of this disclosure may include pH adjusters.

[0243] With respect to thickeners, the viscosity of the formulations of this disclosure can be maintained to a desired level using pharmaceutically acceptable thickeners. Examples of thickeners that can be added to the compositions of this disclosure include methylcellulose, xanthan gum, tragacanth, adhesives, guar gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, mucosal adhesive polymers such as poly(acrylate), cellulose derivatives, hyaluronic acid, hyaluronic acid derivatives, chitin, collagen, pectin, starch, poly(ethylene glycol), sulfated polysaccharides, carrageenan, sodium alginate, gelatin, pectin, and combinations thereof. The desired concentration of the thickener depends on the selected agent and the desired viscosity.

[0244] The composition may also contain gel-forming or bioadhesive compounds, such as carbopol, alginate, scleroglucan, cellulose derivatives, starch, albumin, pluronic gel, diethylaminoethyl (DEAE)-sefadex, polycarbophil, hyaluronic acid, hyaluronate, starch, gelatin, collagen, etc. The composition may also be incorporated into w / o cream, o / w cream, hydrophilic or lipophilic ointment, gel, or other semi-solid base. The composition may be delivered to the nasal cavity as droplets, mist, aerosol, or dots by the use of pipettes, special devices, evaporators, vaporizers, etc.

[0245] The formulations of this disclosure may also contain agents such as tolerance enhancers to reduce or prevent drying of the mucous membrane and prevent irritation thereof.

[0246] In some embodiments, NMDP or its salts can also be introduced into viscous bases by adding them to conventionally used components of the above-mentioned delivery systems, such as natural gums, cellulose and derivatives, acrylic polymers (e.g., Carbopol) and vinyl polymers (polyvinylpyrrolidone), scleroglucan, xylan, alginates, calcium alginate, hyaluronates, collagenates, starch gels, gelatinous systems, and chitosan carriers.

[0247] In some embodiments, the compositions disclosed herein may further comprise benzalkonium chloride (BKC) and / or ethylenediaminetetraacetic acid (EDTA). In some embodiments, the compositions may contain, for example, 0.01, 0.05, 0.1, 0.2, 0.3, or 0.5% w / v of BKC. In some embodiments, the compositions may contain 0.01, 0.05, 0.1, 0.2, 0.3, or 0.5% w / v of EDTA.

[0248] The mechanism of absorption enhancement may differ depending on the various mucosal delivery enhancers of this disclosure, but useful reagents in this context will be selected according to the physicochemical properties of specific NMDP or other activators or delivery enhancers, without substantially adversely affecting mucosal tissue. In this regard, delivery enhancers that increase the penetration or permeability of mucosal tissue often alter the protective permeability barrier of the mucosa to some extent. For such delivery enhancers to be valuable within this disclosure, it is generally desirable that any significant change in mucosal permeability be reversible within an appropriate timeframe for the desired duration of drug delivery. Furthermore, there should be no substantial cumulative toxicity, nor any permanent adverse changes induced in the barrier properties of the mucosa with long-term use.

[0249] In certain embodiments of this disclosure, absorption enhancers for co-administration or combination formulations with NMDP are selected from small hydrophilic molecules, including, but not limited to, dimethyl sulfoxide (DMSO), dimethylformamide, ethanol, propylene glycol, and 2-pyrrolidone. Alternatively, long-chain amphiphilic molecules, such as deacylmethyl sulfoxide, azone, sodium lauryl sulfate, oleic acid, and bile salts, can be used to enhance mucosal penetration of NMDP. In further embodiments, surfactants (e.g., polysorbates) are used as adjuncts, processing agents, or formulation additives to enhance intranasal delivery of NMDP. Agents such as DMSO, polyethylene glycol, and ethanol, when present in sufficiently high concentrations in the delivery environment (e.g., by pre-administration or incorporation into a therapeutic formulation), can enter the aqueous phase of the mucosa, altering its solubilizing properties and thereby enhancing the distribution of NMDP (e.g., therapeutic or pharmaceutical formulation) from the vehicle to the mucosa.

[0250] Further mucosal delivery enhancers useful in coordinated administration and processing methods and combination formulations include, but are not limited to, mixed micelles; enamines; nitric oxide donors (e.g., S-nitroso-N-acetyl-DL-penicillamine, NOR1, NOR4, which are preferably administered co-administered with NO scavengers, e.g., carboxy-PITO or doclofenac sodium); sodium salicylate; glycerol esters of acetoacetate (e.g., glyceryl-1,3-diacetoacetate or 1,2-isopropyllideneglycerin-3-acetoacetate); and other release-diffusion enhancers or intraepithelial or transepithelial penetration enhancers that are physiologically compatible with mucosal delivery.

[0251] Other absorption enhancers can be selected from a variety of carriers, bases, and excipients that enhance the mucosal delivery, stability, activity, or transepithelial penetration of NMDP. These include, in particular, cyclodextrins (e.g., cyclodextrin) and β-cyclodextrin derivatives (e.g., hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, and heptakis(2,6-di-O-methyl-β-cyclodextrin)). These compounds may be conjugated with one or more active ingredients and may further be formulated in an oily base to enhance the bioavailability of glucose-regulating peptides contained in the mucosal formulations of this disclosure. Further absorption enhancers suitable for mucosal delivery include medium-chain fatty acids, including monoglycerides and diglycerides (e.g., sodium caprate-coconut oil extract, Capmul), and triglycerides (e.g., amylodextrin, Estaram 299, Miglyol 810).

[0252] The mucosal therapeutic and prophylactic compositions of this disclosure may be supplemented with any suitable penetration enhancer to promote the absorption, diffusion, or penetration of NMDP across the mucosal barrier. The penetration enhancer may be any pharmaceutically acceptable agent. Accordingly, in more detailed embodiments of this disclosure, compositions are provided that incorporate one or more penetration enhancers selected from sodium salicylate and salicylic acid derivatives (such as acetyl salicylate, choline salicylate, and salicylamide); amino acids and their salts (including monoaminocarboxylic acids such as glycine, alanine, phenylalanine, proline, and hydroxyproline; hydroxyamino acids such as serine; acidic amino acids such as aspartic acid and glutamic acid; and basic amino acids such as lysine, their alkali metal salts, or alkaline earth metal salts); and N-acetylamino acids (such as N-acetylalanine, N-acetylphenylalanine, N-acetylserine, N-acetylglycine, N-acetyllysine, N-acetylglutamic acid, N-acetylproline, and N-acetylhydroxyproline) and their salts (alkali metal salts and alkaline earth metal salts). The methods and compositions disclosed herein also include substances commonly used as emulsifiers (e.g., sodium oleyl phosphate, sodium lauryl phosphate, sodium lauryl sulfate, sodium myristyl sulfate, polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, etc.), caproic acid, lactic acid, malic acid, and citric acid, and their alkali metal salts, pyrrolidone carboxylic acid, alkylpyrrolidone carboxylic acid esters, N-alkylpyrrolidone, proline acyl esters, etc., as penetration enhancers in the methods and compositions disclosed herein.

[0253] A variety of components and additives are intended for use in the methods and formulations of this disclosure. Examples of such solubilizers are cyclodextrins (CDs) and their derivatives. These CDs have been found to bind to hydrophobic patches of proteins in a manner that significantly inhibits aggregation. This inhibition is selective with respect to both the CDs and the proteins involved. Such selective inhibition of protein aggregation provides further advantages in the intranasal delivery methods and compositions of this disclosure. Further agents for use in this context include CD dimers, trimers, and tetramers with diverse geometric shapes that selectively block protein-protein interactions controlled by linkers, peptides, peptide derivatives, analogs, and peptide mimetic compounds. In one embodiment, the specific binding of hydrophobic side chains reported for CD polymers is extended to proteins through the use of peptides and peptide mimetic compounds that similarly block protein aggregation. A wide range of suitable methods and anti-aggregants are available for incorporation into the compositions and procedures intended herein.

[0254] Charge modifiers, pH control agents, and methods To improve the transport properties of biological activators (including NMDP) or other active polymers and small molecule drugs for enhancing delivery across hydrophobic mucosal barriers, the compositions herein may also be used with reagents for “charge modification” of selected biological activators or delivery enhancers described herein. In this regard, the relative permeability of a polymer is generally related to its partition coefficient. a Furthermore, the degree of ionization of molecules, which depends on the pH of the mucosal surface, also affects permeability. As described herein, the permeation and distribution of biological activators, including NMDP and its analogues, for mucosal delivery can be facilitated by charge modification or charge diffusion of the activator or permeabilizer, which can be achieved, for example, by modifying the charged functional group, by altering the pH of the delivery vehicle or solution to which the activator (or precursor thereof) is delivered, or by the coordinated administration of a charge- or pH-modifying reagent with the activator (or precursor).

[0255] Consistent with these general teachings, mucosal delivery of charged polymer species, including NMDP and other bioactive peptides and proteins, in the methods and compositions of the present disclosure is substantially improved when the activator is delivered to the mucosal surface in a substantially non-ionized or neutrally charged state.

[0256] Certain compositions of one or more mucosal formulations within this disclosure, comprising NMDP salts (NMDP) and other biologically active peptide and protein components, can be charge-modified to increase the positive charge density of the peptide or protein. These modifications also extend to the cationization of peptide and protein conjugates, carriers, and other delivery forms disclosed herein. Cationization provides a convenient means of altering the in vivo distribution and transport properties of proteins and macromolecules within this disclosure. Cationization is carried out in a manner that substantially preserves the biological activity of the activator and limits potentially harmful side effects, including tissue damage and toxicity.

[0257] In some embodiments, the composition may include a buffer. A "buffer" is generally used to maintain the pH of a solution at a nearly constant value. Examples of commonly used buffer salts include glutamates, acetates, citrates, glycine, histidine, arginine, lysine, methionine, lactates, formates, glycolates, tartrates, phosphates, and mixtures thereof.

[0258] Mucus-dissolving agents, mucus-removing agents, and methods In some embodiments, the compositions and methods herein for mucosal delivery, such as intranasal delivery of NMDP or a salt thereof, may optionally incorporate effective mucolytics or mucolytics, which have the function of breaking down, thinning, or removing mucus from the surface of the nasal mucosa to promote the absorption of the intranasally administered composition. In some embodiments, mucolytics or mucolytics are administered synergistically as adjunct compounds to enhance the intranasal delivery of the bioactive agent. Alternatively, an improved formulation is provided in which an effective amount of mucolytic or mucolytic is incorporated as a processing agent in the multiprocessing method of the present disclosure or as an additive in the combination formulation of the present disclosure to enhance the intranasal delivery of the biotherapeutic compound by reducing the barrier effect of nasal mucus.

[0259] A variety of mucolytics and mucolytics are available for incorporation into the methods and compositions of this disclosure. Based on their mechanisms of action, mucolytics and mucolytics can often be classified into the following groups: proteases that cleave the protein core of mucin glycoproteins (e.g., pronase, papain); sulfhydryl compounds that split mucoprotein disulfide bonds; and surfactants that cleave non-covalent bonds in mucus (e.g., Triton X-100, Tween 20). Further compounds in this context include, but are not limited to, bile salts and surfactants, such as sodium deoxycholate, sodium taurodeoxycholate, sodium glycocholate, and lysophosphatidylcholine.

[0260] The effectiveness of bile salts that lead to the structural breakdown of mucus is in the order of deoxycholate > taurocholate > glycocholate. Other effective agents that reduce mucus viscosity or adhesion and enhance intranasal delivery by the method of this disclosure include, for example, short-chain fatty acids and mucolytics that act by chelation, such as N-acyl collagen peptides, bile acids, and saponins (the latter being Ca, which plays an important role in maintaining the mucus layer structure). 2+ and / or Mg 2+(It works by chelating.)

[0261] Further mucolytic agents for use in the methods and compositions of this disclosure include N-acetyl-L-cysteine ​​(ACS), a potent mucolytic agent that has been reported to reduce both the viscosity and adhesion of bronchopulmonary mucus and moderately increase the transnasal bioavailability of human growth hormone in anesthetized rats (7.5 to 12.2%). These and other mucolytic or mucolytic agents are brought into contact with the nasal mucosa in conjunction with the administration of a biological activator, typically in a concentration range of about 0.2 to about 20 mM, to reduce the polar viscosity and / or elasticity of intranasal mucus.

[0262] Furthermore, other mucolytic or mucolytic agents can be selected from a range of glycosidase enzymes capable of cleaving glycosidic bonds within mucoglycoproteins. α-Amylase and β-Amylase are representative of this class of enzymes, although their mucolytic effects may be limited. In contrast, bacterial glycosidases allow these microorganisms to penetrate the mucus layer of their hosts.

[0263] For use in combination with the biological agents described herein, nonionic surfactants are generally also useful as mucolytics or mucolytics.

[0264] Ciliary stabilizing agent and method The self-cleaning ability of certain mucosal tissues (e.g., nasal mucosa) through mucociliary clearance is necessary as a protective function (for example, to remove dust, allergens, and bacteria), and therefore it is understood that this function should not be substantially impaired by mucosal-administered drugs. Mucociliary transport in the airways is a particularly important defense mechanism against infection. To achieve this function, the pulsation of the ciliary body in the passages of the nose and airways moves a layer of mucus along the mucosa to remove inhaled particles and microorganisms.

[0265] In some embodiments, ciliary quiescent agents can be incorporated into the methods and compositions of the present disclosure to increase the residence time of mucosal (e.g., intranasal) administered formulations containing NMDP and other biological agents disclosed herein. In particular, the delivery of such agents in the methods and compositions of the present disclosure is significantly enhanced in certain embodiments by coordinated administration or combination formulations of one or more ciliary quiescent agents that function to reversibly inhibit the ciliary body activity of mucosal cells, thereby providing a transient and reversible increase in the residence time of mucosal-administered pharmaceutical agents. For use in these embodiments of the present disclosure, the ciliary quiescent factors described herein are all candidates for good use as ciliary quiescent factors (depending on concentration, duration, and mode of delivery) in appropriate amounts, whether specific or indirect in their activity, that result in a transient (i.e., reversible) decrease or cessation of mucosal ciliary body clearance at the mucosal site of administration, thereby enhancing the delivery of NMDP and other biological agents disclosed herein without unacceptable adverse side effects.

[0266] In more detailed embodiments, specific ciliary quiescence factors may be used in combination formulations or coordinated administration protocols with NMDP and its salts, as well as one or more other biological activators disclosed herein. A variety of isolated bacterial ciliary quiescence factors characterized in the literature may be used in specific embodiments of this disclosure. For example, ciliary quiescence factors derived from the bacterium Pseudomonas aeruginosa include phenazine derivatives, pio compounds (2-alkyl-4-hydroxyquinoline), and rhamnolipid (also known as hemolycin). In some embodiments, phenazine derivatives can also inhibit ciliary motility. In some embodiments, the composition may include rhamnolipid that associates with the altered ciliary membrane.

[0267] Surfactants and Methods In more detailed aspects of the present disclosure, one or more membrane penetration enhancers can be used within the mucosal delivery methods or formulations of the NMDP and other biologically active agents disclosed herein to enhance mucosal delivery. Membrane penetration enhancers in this context include: (i) surfactants; (ii) bile salts; (iii) phospholipid additives, mixed micelles, liposomes or carriers; (iv) alcohols; (v) enamines; (vi) NO donor compounds; (vii) long-chain amphiphilic molecules; (viii) small hydrophobic penetration enhancers; (ix) sodium or salicylic acid derivatives; (x) glycerol esters of acetoacetic acid; (xi) cyclodextrins or β-cyclodextrin derivatives; (xii) medium-chain fatty acids; (xiii) chelating agents; (xiv) amino acids or their salts; (xv) N-acetyl amino acids or their salts; (xvi) enzymes that degrade selected membrane components; (xvii) inhibitors of fatty acid synthesis; (xviii) inhibitors of cholesterol synthesis; or (xix) can be selected from any combination of the membrane penetration enhancers described in (i)-(xviii).

[0268] Certain surfactants, also called surfactants, are readily incorporated into the mucosal delivery formulations and methods of this disclosure as mucosal absorption enhancers. These surfactants, which can be administered in conjunction with NMDP and other biological agents disclosed herein, or formulated in combination, can be selected from a broad set of known surfactants. Surfactants are generally classified into three classes: (1) nonionic polyoxyethylene ethers, e.g., vitamin E TPGS, and / or D-α-tocopheryl polyethylene glycol succinate; (2) bile salts, e.g., sodium glycocholate (SGC) and deoxycholate (DOC); and (3) fusidic acids and derivatives of fusidic acids, e.g., sodium taurodihydrofusidate (STDHF). The mechanisms of action of these various classes of surfactants typically involve the solubilization of biological agents. In the case of proteins and peptides, which often form aggregates, the surfactant properties of these absorption enhancers can enable interaction with proteins, thereby allowing smaller units, such as surfactant-coated monomers, to be more readily maintained in solution. These monomers are perhaps more transportable units than aggregates. Other examples of surfactants include L-α-phosphatidylcholine didecanoyl (DDPC), polysorbate 80, and polysorbate 20. Further surfactants include polyethylene glycol, cetyl alcohol, polyvinylpyrrolidone, polyvinyl alcohol, lanolin alcohol, and sorbitan monooleate. In some embodiments, the surfactants of this disclosure may be present in pharmaceutical formulations alone or in any mixture or combination. In some embodiments, bile salts and some fusidic acid derivatives have been reported to inhibit protein degradation by nasal homogenates.

[0269] Thickening agent Thickeners or suspending agents can affect the release rate and / or absorption of drugs from dosage formulations. Some examples of materials that can function as pharmaceutically acceptable thickeners are gelatin; methylcellulose (MC); hydroxypropylmethylcellulose (HPMC) and its derivatives; carboxymethylcellulose (CMC); cellulose; starch; heptadextrin; poloxamer; pluronics; CMC sodium; sorbitol; acacia; povidone; carbopol (as used herein, carbopol is a carbomer and carbopol is also known as carbomer homopolymer type B or Carbopol® 974P NF polymer); polycarbophil; chitosan; chitosan microspheres; alginate microspheres; chitosan glutamate; amberlite resin; hyaluronan; ethylcellulose; maltodextrin DE; drum-dried corn starch (DDWM); degradable starch microspheres (DSM); deoxyglycocholate (GDC); hydroxyethylcellulose (HEC); hydroxypropylcellulose (HPC); microcrystalline cellulose (MCC); polymethacrylic acid and polyethylene glycol; sulfobutyl ether B cyclodextrin; cross-linked eldexomer starch biospheres; sodium taurodihydrofusidate (STDHF); N-trimethylchitosan chloride (TMC); degraded starch microspheres; amberlite resin; chitosan nanoparticles; spray-dried crospovidone; spray-dried dextran microspheres; spray-dried microcrystalline cellulose; and cross-linked eldexomer starch microspheres.

[0270] As used herein, carbomer thickeners include acrylic acid homopolymer, acrylic acid resin, acrylic acid, polymer, acrylic polymer, acrylic resin, Acrysol A 1, Acrysol A 3, Acrysol A 5, Acrysol AC 5, Acrysol WS-24, Acrysol ase-75, Antiprex 461, Antiprex A, Arasorb 750, Arasorb S100F, Arolon, Aron, Aron A 10H, Atactic Poly(acrylic acid), CCRIS 3234, Carbomer 1342, Carbomer 910, Carbopol 1342, Carbopol 910, Carbopol 934, Carbopol 934P, Carbopol 940, Carbopol 941, Carbopol 960, Carbopol 961, Carbopol 971P, Carbopol 974P, Carbopol 980, Carbopol 981, Carboset 515, Carboset resin No.515, Carboxyvinyl polymer, Carboxypolymethylene, Carpolene, Colloid 119 / 50, Cyguard 266, Dispex C40, Dow Latex 354, G-Cure, Good-rite K 37, Good-rite K 702, Good-rite K 732, Good-rite K-700, Good-rite K 727, Good-rite WS 801, Haloflex 202, Haloflex 208, Joncryl 678, Junlon 110, Jurimer AC 10H, Jurimer AC 10P, NSC 106034, NSC 106035, NSC 106036, NSC 106037, NSC 112122, NSC 112123, NSC 114472, NSC 165257, Nalfloc 636, Neocryl A-1038, OLD 01, P 11H, P 11H, P-11H, PA 11M, PAA-25, Pemulen TR-1, Pemulen TR-2, Poly(acrylic acid), Polyacrylate, Polyacrylate elastomer, Polymer of acrylic acid crosslinked with pentaerythritol allyl ether, Polymer of acrylic acid crosslinked with pentaerythritol allyl ether, Carboxyvinyl polymerized acrylic acid, Polytex 973, Primal ASE 60, Propenic acid polymer, R968, Racryl, Revacryl A 191, Rohagit SD 15, Sokalan PAS, Solidokoll N, Synthemul 90-588, TB 1131, Teccol, Texcryl, Versicol E 7, Versicol E15, Versicol E9, Versicol K 11, Versicol This includes, but is not limited to, S 25, Viscalex HV 30, Viscon 103, WS 24, WS 801, XPA, and others. Other thickeners described in Ugwoke et al., Adv. Drug Deliv. Rev. 29:1656-57, 1998, are incorporated by reference. Any one thickener or any combination or mixture of thickeners may be included in the pharmaceutical formulations disclosed herein.

[0271] Nitric oxide donor agent and method In other relevant aspects of the Disclosure, a nitric oxide (NO) donor is selected as a membrane penetration enhancer to enhance the mucosal delivery of one or more NMDPs and other biological agents disclosed herein. Various NO donors are known in the Art and are useful at effective concentrations in the methods and formulations of the Disclosure. Exemplary NO donors include, but are not limited to, nitroglycerin, nitroprusside, NOC5 [3-(2-hydroxy-1-(methyl-ethyl)-2-nitrosohydrazino)-1-propanamine], NOC12 [N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethaneamine], SNAP [S-nitroso-N-acetyl-DL-penicillamine], NORI, and NOR4. In the methods and compositions of the Disclosure, an effective amount of a selected NO donor is formulated to be administered synergistically or in combination with one or more NMDPs and / or other biological agents disclosed herein, either intramucosal or via the mucosal epithelium.

[0272] Drugs for modulating epithelial junction structure and / or physiological function This disclosure provides pharmaceutical compositions comprising one or more NMDPs and / or other biological agents in combination with one or more mucosal delivery enhancers disclosed herein, which are formulated into such pharmaceutical preparations for mucosal delivery.

[0273] Permeabilizing agents typically reversibly enhance paraepithelial transport by modulating the epithelial junctional structure and / or physiological function of the mucosal epithelial surface of a subject. This effect is typically related to the inhibition of homotype or heterotype binding between epithelial membrane adhesion proteins of adjacent epithelial cells by the permeabilizing agent. Target proteins for this blockage of homotype or heterotype binding can be selected from various relevant junctional adhesion molecules (JAMs), occurdins, or claudins. Examples include antibodies, antibody fragments, or single-chain antibodies that bind to the extracellular domains of these proteins.

[0274] In further additional detailed embodiments, the Disclosure provides permeabilizing peptides for enhancing mucosal epithelial paracellular transport. The peptides typically act in the compositions and methods of the Disclosure by modulating epithelial junctional structure and / or physiological function in mammalian subjects. In specific embodiments, the peptides inhibit homotype and / or heterotype binding of epithelial membrane adhesion proteins selected from junctional adhesion molecules (JAMs), occurdins, or claudins.

[0275] One such agent that has been widely studied is a bacterial toxin derived from Vibrio cholerae, known as "zonula occludens toxin" (ZOT). In these embodiments of the present disclosure, ZOT is administered in conjunction with or in combination with the activators of the compositions and methods herein in an effective amount that significantly enhances the absorption of the activator by reversibly increasing nasal mucosal permeability, without substantial adverse side effects.

[0276] Vasodilators and methods In some embodiments, the compositions and methods of this specification may include the administration of vasodilators, more specifically vasodilators. These compounds function within this disclosure to modulate the structure and physiological function of the submucosal vascular system and to increase the transport rate of NMDP and other biologically active agents into and through the mucosal epithelium, and / or to specific target tissues or compartments (e.g., auricular structures).

[0277] Vasodilators for use within this disclosure typically induce submucosal vasodilation by either decreasing cytoplasmic calcium, increasing nitric oxide (NO), or inhibiting myosin light chain kinase. They are generally classified into nine classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin II receptor antagonists, α-adrenergic and imidazole receptor antagonists, β1-adrenergic agonists, phosphodiesterase inhibitors, eicosanoids, and NO donors.

[0278] In the particular methods and compositions of this disclosure, the selected vasodilator is administered in conjunction with one or more NMDPs (e.g., systemically or intranasally, simultaneously or in a time relationship that is effective in combination) or formulated in combination with an effective amount to enhance the mucosal absorption of the activator and deliver it to a target tissue or compartment (e.g., auricular structure) in the subject.

[0279] Selective transport enhancers and methods The compositions and delivery methods of this disclosure may optionally incorporate selective transport enhancers that facilitate the transport of one or more biological agents. These transport enhancers can be used in combination formulations or coordinated administration protocols with one or more NMDP formulations disclosed herein to coordinately enhance the delivery of one or more additional biological agents across the mucosal transport barrier, thereby enhancing mucosal delivery of the agents to target tissues or compartments (e.g., auricular structures) of the subject. Alternatively, the transport enhancers can be used in combination formulations or coordinated administration protocols, with or without enhancement of the delivery of additional biological agents, to directly enhance the mucosal delivery of one or more NMDPs.

[0280] Exemplary selective transport enhancers for use within this aspect of the Disclosure include, but are not limited to, glycosides, sugar-containing molecules, and binders, such as lectin binders known to specifically interact with epithelial transport barrier components. For example, certain “bioadhesive” ligands, including various plant and bacterial lectins, can bind to cell surface sugar moieties via receptor-mediated interactions and be used as carriers or conjugate transport mediators to enhance mucosal, e.g., nasal delivery of biological agents within the Disclosure. Certain bioadhesive ligands within the Disclosure mediate the transmission of biological signals to epithelial target cells, triggering the selective uptake of the adhesive ligand via specific cellular transport processes (endocytosis or transcytosis). Thus, these transport mediators can be used as “carrier systems” to stimulate or direct the selective uptake of one or more NMDPs and other biological agents into and / or through the mucosal epithelium. These and other selective transport enhancers significantly enhance mucosal delivery of macromolecular biopharmaceuticals (particularly peptides, proteins, oligonucleotides, and polynucleotide vectors) within the Disclosure. Lectins are plant proteins that bind to specific sugars found on the surface of glycoproteins and glycolipids in eukaryotic cells. Concentrated lectin solutions have a "mucotractive" effect, and various studies have demonstrated rapid receptor-mediated endocytosis (RME) across mucosal surfaces of lectins and lectin conjugates (e.g., concanavalin A conjugated with colloidal gold particles). Further research has reported that the lectin uptake mechanism may be utilized for in vivo targeting of intestinal drugs. Some of these studies have reported improved systemic uptake after oral administration to rats by covalently binding polystyrene nanoparticles (500 nm) to tomato lectin.

[0281] In addition to plant lectins, microbial adhesion and invasion factors provide a rich source of candidates for use as adhesives / selective transport carriers in the mucosal delivery methods and compositions of this disclosure. The bacterial adhesion process requires two components: bacterial "adhesins" (adhesion or colony-forming factors) and receptors on the host cell surface. Bacteria that cause mucosal infections must penetrate the mucus layer before they can attach themselves to the epithelial surface. This attachment is usually mediated by bacterial pili or pili structures, but other cell surface components may also be involved in this process. Adhesive bacteria colonize mucosal epithelium by proliferation and initiation of a series of biochemical reactions within target cells via signaling mechanisms (with or without the aid of toxins). In connection with these invasive mechanisms, a wide variety of bioadhesive proteins (e.g., invasin, internalin) are known to be initially produced by various bacteria and viruses. These enable the extracellular attachment of such microorganisms with impressive selectivity to host species and even to specific target tissues. The signals transmitted by such receptor-ligand interactions trigger the transport of intact living microorganisms into and ultimately through epithelial cells via endocytosis and transcellular transport processes. Such spontaneous phenomena can be utilized, according to the teachings herein, to enhance the delivery of biologically active compounds into or beyond the mucosal epithelium and / or to other designated target sites of drug action (e.g., by conjugating biological activators such as NMDP with adhesins).

[0282] Various bacterial and plant toxins that bind to the epithelial surface in a specific lectin-like manner are also useful in the methods and compositions of this disclosure. For example, diphtheria toxin (DT) rapidly enters host cells via RME. Similarly, the B subunit of Escherichia coli's thermolabile toxin binds to the brush margin of intestinal epithelial cells in a highly specific lectin-like manner. The uptake and transcytosis of this toxin into the basolateral aspect of intestinal cells has been reported in vivo and in vitro. In other studies, the transmembrane domain of Escherichia coli's diphtheria toxin was expressed as a maltose-binding fusion protein and chemically conjugated to high-Mw poly-L-lysine. The resulting complex has been successfully used to mediate the internalization of a reporter gene in vitro. In addition to these examples, Staphylococcus aureus produces a set of proteins (e.g., Staphylococcus enterotoxin A (SEA), SEB, and toxic shock syndrome toxin 1 (TSST-1)), which act as both superantigens and toxins. Studies on these proteins have reported dose-dependent, enhanced transcytosis of SEB and TSST-1 in Caco-2 cells.

[0283] Viral hemagglutinins constitute another type of transporter for facilitating mucosal delivery of biological agents in the methods and compositions of this disclosure. The first step in many viral infections is the binding of surface proteins (hemaglutinins) to mucosal cells. These binding proteins have been identified for most viruses, including rotavirus, varicella-zoster virus, semliki forest virus, adenovirus, potato leafol virus, and reovirus. These and other exemplary viral hemagglutinins can be used in combination formulations (e.g., mixtures or conjugate formulations) or coordinated administration protocols with one or more NMDPs disclosed herein to coordinately enhance mucosal delivery of one or more additional biological agents. Alternatively, viral hemagglutinins can be used in combination formulations or coordinated administration protocols, with or without enhancement of delivery of additional biological agents, to directly enhance mucosal delivery of one or more NMDPs.

[0284] A variety of endogenous selective transport mediators are also available for use within this disclosure. Mammalian cells have developed combinations of mechanisms to promote the internalization of specific substrates and target them to designated compartments. Collectively, these processes of membrane deformation are called “endocytosis” and include phagocytosis, phagocytosis, receptor-mediated endocytosis (clathrin-mediated RME), and potocytosis (non-clathrin-mediated RME). RME, as its name suggests, is a highly specific cell biological process by which various ligands bind to cell surface receptors, are subsequently internalized, and transported into the cell. In many cells, the endocytosis process is so active that the entire membrane surface is internalized and replaced in less than 30 minutes. Two classes of receptors have been proposed based on their orientation on the cell membrane: the amino terminus of type I receptors is located extracellularly on the membrane, while type II receptors have this same protein tail in the intracellular environment.

[0285] Further embodiments of this disclosure utilize transferrin as a carrier or stimulant of the RME of a mucosally delivered biological activator. Transferrin, an 80 kDa iron-transporting glycoprotein, is efficiently taken up by cells via the RME. Transferrin receptors are found on the surface of most proliferating cells and are increased in number on erythroblasts and many types of tumors. Transcytosis of transferrin (Tf) and transferrin conjugates has been reported to be enhanced in the presence of the fungal metabolite brefeldin A (BFA). Other studies have reported that BFA treatment rapidly increases apical endocytosis of both lysine and HRP in MDCK cells. Therefore, BFA and other agents that stimulate receptor-mediated transport can be used within the methods of this disclosure as agents formulated in combination (e.g., conjugates) and / or administered synergistically to enhance the receptor-mediated transport of a biological activator, such as NMDP.

[0286] Polymer delivery vehicle and method In certain embodiments of this disclosure, NMDP, other bioactive agents disclosed herein, and delivery enhancers described herein are incorporated, individually or in combination, into a mucosal (e.g., nasal) administered formulation comprising a biocompatible polymer acting as a carrier or base. Such polymer carriers include, among other polymer forms, polymer powders, matrices, or particulate delivery vehicles. The polymers may be of plant, animal, or synthetic origin. Often, the polymers are crosslinked. Furthermore, in these delivery systems, NMDP can be functionalized to covalently bond to the polymer, making it inseparable from the polymer. In other embodiments, the polymer is chemically modified with enzyme or other drug inhibitors that can degrade or inactivate the bioactive agent and / or delivery enhancer. In certain formulations, the polymer is a partially or completely water-insoluble but water-swellable polymer, such as a hydrogel. In some embodiments, the polymer is inherently water-interacting and / or hydrophilic.

[0287] To extend the biological activity of NMDP, and other biological agents disclosed herein, as well as any delivery enhancers, These agents can be incorporated into a polymer matrix, such as a polyorthoester, polyanhydride, or polyester. In some embodiments, this results in sustained activity and release of the activator, determined, for example, by the degradation of the polymer matrix. Absorption-enhancing polymers intended for use within this disclosure may include derivatives and chemically or physically modified versions of the aforementioned types of polymers, in addition to other natural or synthetic polymers, gums, resins, and other agents, as well as blends of these materials with each other or with other polymers. In some embodiments of the formulations of this disclosure, polymers such as nylon, acrylan, and other normally hydrophobic synthetic polymers can be sufficiently modified by reaction to become water-swellable and / or form stable gels in aqueous media. The absorption-enhancing polymers of this disclosure may include polymers from the group of homopolymers and copolymers based on various combinations of the following vinyl monomers: acrylic acid and methacrylic acid, acrylamide, methacrylamide, hydroxyethyl acrylate or methacrylate, vinylpyrrolidone, polyvinyl alcohol and its copolymers and terpolymers, polyvinyl acetate, its copolymers and terpolymers with the monomers listed above, and 2-acrylamido-2-methylpropanesulfonic acid (AMPS®). In some embodiments, copolymers of the monomers listed above may be used with copolymerizable functional monomers, such as acrylic or methacrylamide acrylate or methacrylate esters.Additional absorption-promoting polymers contemplated within the present disclosure include dextran, those classified as dextrins, and those from the class of materials classified as natural gums and resins, or from the class of natural polymers, such as processed collagen, chitin, chitosan, pullulan, zooglan, alginate and modified alginates such as "Kelcoloid" (polypropylene glycol-modified alginate), gellan gum such as "Kelocogel", xanthan gum such as "Keltrol", estastin, α-hydroxybutyrate and its copolymers, hyaluronic acid and its derivatives, polylactic acid and glycolic acid.

[0288] In some embodiments, the polymers contemplated within the present disclosure are olefinically unsaturated carboxylic acids containing at least one activated carbon-carbon olefin double bond and at least one carboxyl group, i.e., acids or functional groups that are readily convertible during polymerization to acids containing an olefin double bond that functions readily due to its presence at the α-β position relative to the carboxyl group or as part of the terminal methylene group in the monomer molecule. This class of olefinically unsaturated acids includes materials such as acrylic acid itself, α-cyanoacrylic acid, β-methylacrylic acid (crotonic acid), α-phenylacrylic acid, β-acryloxypropionic acid, cinnamic acid, p-chlorocinnamic acid, 1-carboxy-4-phenylbutadiene-1,3, itaconic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric acid, acrylic acids represented by tricarboxyethylene.

[0289] In some embodiments intended in the compositions and methods herein, the absorption enhancer may include methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, butyl acrylate, isobutyl acrylate, methyl methacrylate, methyl ethyl acrylate, ethyl methacrylate, octyl acrylate, heptyl acrylate, octyl methacrylate, isopropyl methacrylate, 2-ethylhexyl methacrylate, nonyl acrylate, hexyl acrylate, n-hexyl methacrylate, and the like. Higher alkyl acrylic esters are decyl acrylate, isodecyl methacrylate, lauryl acrylate, stearyl acrylate, behenyl acrylate, and mericyl acrylate, as well as their methacrylate versions. Mixtures of two or more long-chain acrylic esters can be successfully polymerized with one of the carboxyl monomers. Other comonomers include olefins, which include alpha-olefins, vinyl ethers, vinyl esters, and mixtures thereof.

[0290] Other vinylidene monomers, including acrylonitrile, can also be used as absorption enhancers in the methods and compositions of this disclosure to enhance the delivery and absorption of one or more NMDPs and other biological activators herein, for example, to enhance the delivery of activators to target tissues or compartments (e.g., auricular structures) in a subject. In some embodiments, the α,β-olefin unsaturated nitrile may be a monoolefin unsaturated nitrile having 3 to 10 carbon atoms, such as acrylonitrile, methacrylonitrile, etc. Acrylamides containing 3 to 35 carbon atoms, including monoolefin unsaturated amides, can also be used. Typical amides include acrylamide, methacrylamide, Nt-butylacrylamide, N-cyclohexylacrylamide, higher alkylamides containing 8 to 32 carbon atoms in the alkyl group on the nitrogen, and acrylamides containing N-alkylolamides of α,β-olefin unsaturated carboxylic acids, including those with 4 to 10 carbon atoms, such as N-methylolacrylamide, N-propanolacrylamide, N-methylolmethacrylamide, N-methylolmaleimide, N-methylolmaleamic acid ester, and N-methylol-p-vinylbenzamide.In other embodiments, the absorption-enhancing materials are, as is known to those skilled in the art, α-olefins containing 2 to 18 carbon atoms, more preferably 2 to 8 carbon atoms; dienes containing 4 to 10 carbon atoms; vinyl esters and allyl esters, e.g., vinyl acetate; vinyl aromatics, e.g., styrene, methylstyrene, and chlorostyrene; vinyl and allyl ethers and ketones, e.g., vinyl methyl ether and methyl vinyl ketone; chloroacrylates; cyanoalkyl acrylates, e.g., α-cyanomethyl acrylate, as well as α-, β-, and γ-cyanopropyl acrylates; alkoxyacrylates, e.g., methoxyethyl acrylate; haloacrylates as chloroethyl acrylate; vinyl halides and vinyl chloride, vinylidene chloride, etc.; divinyl, diacrylate, and other polyfunctional monomers, e.g., divinyl ether, diethylene glycol diacrylate, ethylene glycol dimethacrylate, methylene-bis-acrylamide, allyl pentaerythritol, etc.; and bis(β-haloalkyl) alkenyl phosphonates, e.g., bis(β-chloroethyl) vinyl phosphonate, etc. The copolymer, in which the carboxy-containing monomer is a trace component and the other vinylidene monomers present as major components, can be easily prepared according to the methods disclosed herein.

[0291] In some embodiments, the absorption enhancers intended in the methods and compositions herein may consist of synthetic copolymers from the group of acrylic and methacrylic acids, acrylamide, methacrylamide, hydroxyethyl acrylate (HEA) or methacrylate (HEMA), and vinylpyrrolidone, which interacts with water and is swellable. Other very useful hydrogel polymers are poly(vinylpyrrolidone) starch, carboxymethylcellulose, and swellable but insoluble versions of polyvinyl alcohol. In some embodiments, the polymer hydrogel materials intended in this disclosure include (poly)hydroxyalkyl (meth)acrylates; anionic and cationic hydrogels: poly(electrolyte) composites; poly(vinyl alcohol) with low acetate residue: swellable mixtures of crosslinked agar and crosslinked carboxymethylcellulose: swellable compositions containing methylcellulose mixed with low crosslinked agar; water-swellable copolymers produced by dispersion of fine copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene; water-swellable polymers of N-vinyl lactam; swellable sodium salts of carboxymethylcellulose; and the like.

[0292] In some embodiments, polymers intended herein for mucosal delivery of biological activators, including NMDP, include pectin; polysaccharides, e.g., agar, acacia, karaya, tragacanth, algin and guar and their crosslinked versions; acrylic acid polymers, copolymers and salt derivatives, polyacrylamides; water-swellable indene maleic anhydride polymers; starch graft copolymers; acrylate-type polymers and copolymers having water absorption of about 2 to 400 times their original weight; diesters of polyglucans; mixtures of crosslinked poly(vinyl alcohol) and poly(N-vinyl-2-pyrrolidone); polyoxybutylene-polyethylene block copolymer gels; carob gum; polyester gels; polyurea gels; polyether gels; polyamide gels; polyimide gels; polypeptide gels; polyamino acid gels; polycellulose gels; crosslinked indene-maleic anhydride acrylate polymers; and polysaccharides. In some embodiments, the hydrogel polymers intended herein are crosslinked to effectively contain the biological activator.

[0293] Crosslinked networks can be formed by free radical copolymerization of unsaturated monomers. Polymer hydrogels can also be formed by crosslinking pre-formed polymers by reacting functional groups found in polymers, such as alcohols, acids, and amines, with groups such as glyoxal, formaldehyde or glutaraldehyde, or bis-anhydride. Polymers can also be crosslinked with any polyene, e.g., decadiene or trivinylcyclohexane; acrylamide, e.g., N,N-methylene-bis(acrylamide); polyfunctional acrylate, e.g., trimethylolpropane triacrylate; or polyfunctional vinylidene monomers containing at least two terminal CH2< groups, e.g., divinylbenzene, divinylnaphthalene, allyl acrylate, etc. In certain embodiments, the crosslinked monomers used for preparing copolymers are polyalkenyl polyethers having two or more alkenyl ether groups per molecule, which may optionally have alkenyl groups, therein are olefin double bonds bonded to terminal methylene groups (e.g., produced by etherification of polyhydric alcohols containing at least two carbon atoms and at least two hydroxyl groups). Other crosslinked monomers include, for example, diallyl esters, dimethallyl ethers, allyl or methallyl acrylates and acrylamides, tetravinylsilanes, polyalkenylmethanes, diacrylates and dimethacrylates, divinyl compounds such as divinylbenzene, polyallyl phosphates, diallyloxy compounds and phosphite esters.

[0294] In other aspects of this disclosure, mucosal delivery of NMDP and other biological activators disclosed herein is enhanced by retaining the activator in a sustained-release or enzymatically or physiologically protective carrier or vehicle, such as a hydrogel that shields the activator from the action of degrading enzymes. In certain embodiments, the activator may be conjugated to a carrier or vehicle by chemical means, and additional agents such as enzyme inhibitors or cytokines may be mixed or conjugated thereto. Alternatively, the activator may be immobilized by sufficient physical capture within a carrier or vehicle, such as a polymer matrix.

[0295] Polymers, such as the hydrogels in this disclosure, can incorporate functionally linked agents, such as glycosides chemically incorporated into the polymer, to enhance the intranasal bioavailability of the active agent formulated with them. Examples of such glycosides include glucosides, fructosides, galactosides, arabinosides, mannosides and their alkyl-substituted derivatives, as well as natural glycosides, such as arbutin, phlorizin, amygdalin, digitonin, saponins, and indican. There are several ways in which typical glycosides can be linked to polymers. For example, the hydrogen atoms of the hydroxyl groups of glycosides or other similar carbohydrates can be substituted with alkyl groups from the hydrogel polymer to form ethers. Alternatively, the hydroxyl groups of glycosides can be reacted to esterify the carboxyl groups of the polymer hydrogel to form polymer esters in situ. Another approach is to use the condensation of acetobromo glucose and cholesta-5-en-3β-ol on a maleic acid copolymer. N-substituted polyacrylamides can be synthesized by the reaction of an activated polymer with an ω-aminoalkyl glycoside: (1) (carbohydrate-spacer)(n)-polyacrylamide, a "pseudopolysaccharide"; (2) (carbohydrate-spacer)(n)-phosphatidylethanolamine(m)-polyacrylamide, a neoglycolipid, a derivative of phosphatidylethanolamine; (3) (carbohydrate-spacer)(n)-biotin(m)-polyacrylamide. These biotinylated derivatives can bind to lectins on mucosal surfaces to promote the absorption of biological activators, such as polymer-encapsulated NMDP.

[0296] Bioadhesive delivery vehicle and method In some embodiments, the combination formulations and / or coordinated administration methods herein incorporate an effective amount of a non-toxic bioadhesive as an adjunct or carrier to enhance the mucosal delivery of one or more biological agents. In this context, the bioadhesive exhibits general or specific adhesion to one or more components or surfaces of the target mucosa. This enhancement of epithelial permeability often enables effective transmucosal delivery of large macromolecules to, for example, the basal portion of the nasal epithelium or adjacent extracellular compartments or plasma or CNS tissue or body fluids. In some embodiments, the bioadhesives disclosed herein are useful in the combination formulations and coordinated administration methods herein, which may incorporate an effective amount and form of the bioadhesive to extend the persistence of one or more NMDPs and other biological agents, or otherwise increase mucosal absorption. The bioadhesive can be administered coordinately as an adjunct or as an additive in the combination formulations herein. In certain embodiments, the bioadhesive acts as a “pharmaceutical adhesive,” while in other embodiments, the bioadhesive’s adjunct delivery or combination formulation helps enhance contact between the biological agent and the nasal mucosa by, in some embodiments, promoting specific receptor-ligand interactions with epithelial cell “receptors,” and in other embodiments, by increasing epithelial permeability and significantly increasing the drug concentration gradient measured at the target site (e.g., liver, plasma, or CNS tissue or fluids). Further additional bioadhesives within this disclosure act as enzyme (e.g., protease) inhibitors to enhance the stability of mucosally administered biotherapeutic agents delivered in conjunction with or in combination formulations with the bioadhesive.

[0297] The ability of various bioadhesive polymers in the methods and compositions of this disclosure to serve as mucosal, for example, nasal delivery platforms, can be readily assessed by determining their ability to retain and release NMDP, as well as their ability to interact with the mucosal surface after the activator has been incorporated into them. Furthermore, known methods can be applied to determine the biocompatibility of selected polymers with the tissue of the mucosal administration site. If the target mucosa is covered with mucus (i.e., no mucolytic or mucolytic treatment has been performed), it can function as a link to the underlying mucosal epithelium. Thus, the term “bioadhesive” as used herein also encompasses mucosal adhesive compounds useful for enhancing the mucosal delivery of biological activators in this disclosure. However, adhesive contact to mucosal tissue mediated by adhesion to the mucosal gel layer may be limited by incomplete or transient adhesion between the mucus layer and the underlying tissue, particularly on the nasal surface where rapid mucus clearance occurs. In this regard, mucin glycoproteins are continuously secreted and form viscoelastic gels immediately after their release from cells or glands. However, the luminal surface of the adhesive gel layer is continuously eroded by mechanical, enzymatic, and / or ciliary action. If such activity is more pronounced, or if a longer adhesion time is desired, the coordinated administration and combined formulation methods of this disclosure may further incorporate mucolytic and / or ciliary quiescence methods or agents as disclosed above herein.

[0298] Typically, mucosal adhesive polymers for use within this disclosure are natural or synthetic polymers that adhere to the surface of moist mucosal tissue by complex but nonspecific mechanisms. In addition to these mucosal adhesive polymers, this disclosure also describes methods and compositions for incorporating bioadhesives that adhere directly to the cell surface rather than to the mucus by specific interactions, including receptor-mediated interactions. An example of a bioadhesive that functions in this particular manner is a group of compounds known as lectins.

[0299] In certain aspects of this disclosure, bioadhesive materials for enhancing intranasal delivery of biological activators comprise a matrix of hydrophilic, e.g., water-soluble or swellable polymers or a mixture of polymers that can adhere to moist mucosal surfaces. These adhesives can be formulated as ointments, hydrogel (see above) films, and other application forms. Often, these adhesives are mixed with biological activators to achieve delayed release or local delivery of the activator. Some are formulated with additional components to facilitate the penetration of the activator through the nasal mucosa, for example, into the auricular channels of an individual.

[0300] A variety of polymers, both natural and synthetic, exhibit significant binding to mucus and / or mucosal epithelial surfaces under physiological conditions. The strength of this interaction can be readily measured by mechanical peeling or shearing tests. When applied to a moist mucosal surface, many dry materials adhere spontaneously, at least slightly. After such initial contact, some hydrophilic materials begin to attract water by adsorption, swelling, or capillary force, and if this water is absorbed from the underlying substrate or polymer-tissue interface, the adhesion may be sufficient to achieve the goal of enhancing mucosal absorption of biological agents. While such “adhesion by hydration” can be very strong, formulations adapted to use this mechanism must account for swelling that follows, as a conversion to some cellulose derivatives, which are generally non-adhesive when the dose is applied to hydrated mucus, e.g., in a pre-hydrated state. In some embodiments, bioadhesive drug delivery systems for mucosal administration are effective within this disclosure when such materials are applied in the form of dry polymer powders, microspheres, or film-type delivery forms.

[0301] Acrylic hydrogels are flexible and, when partially swollen, have no abrasive properties, thereby reducing abrasion that could cause damage to the tissue they are in contact with, making them well-suited for bioadhesion. In some embodiments, the methods and compositions of the present disclosure may also involve the use of a carrier, for example, a polymer delivery vehicle, such as a mucosal adhesive poly(acrylic acid) derivative polycarbophil, which partially functions to protect a biological activator from proteolysis and at the same time provides enhanced penetration of peptides or proteins into or through the nasal mucosa.

[0302] Other mucosal adhesive polymers in this disclosure, such as chitosan, are reported to enhance the permeability of certain mucosal epithelium, even when applied as aqueous solutions or gels. Another mucosal adhesive polymer reported to directly affect epithelial permeability is hyaluronic acid and its ester derivatives. Chitosan is an N-deacetylation product of chitin, a naturally occurring polymer widely used to prepare microspheres for oral and intranasal formulations. In one aspect of this disclosure, o-methylisourea is used to convert the amine of chitosan to its guanidinium moiety. The guanidinium compound is prepared, for example, by a reaction between an iso-normal solution of chitosan at a pH greater than 8.0 and o-methylisourea.

[0303] In some embodiments, the bioadhesive is a lectin. Lectins are non-immune (glyco)proteins that bind to polysaccharides or complex carbohydrates. Several plant lectins have been studied as possible drug absorption enhancers. One plant lectin, kidney bean (Phaseolus vulgaris) hemagglutinin (PHA), shows high oral bioavailability of over 10% after being fed to rats. Tomato (Lycopersicon esculeutum) lectin (TL) appears to be safe for various modes of administration.

[0304] Microemulsion delivery method In some embodiments, the NMDP intranasal delivery formulation may include a microemulsion system stabilized with a nonionic surfactant such as Cremophor RH 40 or Labrasol, and may contain various oils including isopropyl myristate, Labrafil M 1944CS, or Maisine 35-1. The formulation may contain 8% Labrafil M 1944CS, 30% Cremophor RH 40 / ethanol (3:1), and water, with an NMDP solubility of up to 6.4 mg / ml, a droplet size of 30.3+ / -5.3 nm, and no ciliary toxicity. After a single intranasal administration of such a preparation at a dose of 2 mg / kg, plasma concentrations can reach a peak (e.g., Cmax) at 1 hour, exhibiting an absolute bioavailability of approximately 32%.

[0305] Liposome and micelle delivery vehicles The coordinated administration methods and combination formulations of this disclosure may incorporate effective lipid or fatty acid-based carriers, processing agents, or delivery vehicles to provide improved formulations for mucosal delivery of NMDP and other biological activators. For example, various formulations and methods for mucosal delivery are provided, including mixing or encapsulating one or more of these activators, as well as peptides or proteins, in liposomes, mixed micelle carriers, or emulsions, or administering them coordinately together to enhance chemical and physical stability and extend the half-lives of NMDP and other activators in mucosal delivery.

[0306] In some embodiments, delivery systems for biological agents include small lipid vesicles known as liposomes. These can be made from natural, biodegradable, non-toxic, and non-immunogenic lipid molecules and can efficiently capture or bind drug molecules within or on their membranes.

[0307] In other embodiments, nimodipine and other activators described herein can be used in combination with polymers and liposomes to bring about favorable properties of both vehicles, such as encapsulation within natural polymer fibrin and controllable release through the use of covalent crosslinking, as well as the addition of antifibrinolytic agents to fibrin polymers. In other embodiments, liposomes may include surfactant mixed micelles containing cationic lipids, long-chain and medium-chain fatty acids, as well as fatty acids, long-chain fatty acids, fusogenic lipids, unsaturated fatty acids and monoglycerides, such as oleic acid, linoleic acid, monooleic acid, etc., medium-chain fatty acids (C6-C12) and monoglycerides, sodium salts of medium-chain fatty acids (C6-C12) and carriers for enhancing mucosal delivery of NMDP, and other biological activators disclosed herein. Fatty acids can be used in soluble forms of sodium salts or by the addition of non-toxic surfactants, such as polyoxyethylated hydrogenated castor oil, sodium taurocholate, etc. The fatty acids and mixed micelle preparations envisioned in this disclosure include, but are not limited to, sodium caprylate (C8), sodium caprate (C10), sodium laurate (C12), or sodium oleate (C18), which may be combined with bile salts, such as glycocholates and taurocholates.

[0308] PEGylation In alternative embodiments, the NMDP salt is conjugated to a polyalkylene oxide polymer, particularly polyethylene glycol (PEG), along with other biologically active peptides and proteins. U.S. Patent No. 4,179,337. The PEG polymers intended in this disclosure include SC-PEG, U-PEG-10000, NHS-PEG-3400-biotin, T-PEG-5000, T-PEG-12000, and TPC-PEG-5000, having molecular weights of 2000, 5000, 10000, 12000, and 20000.

[0309] The section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described. [Examples]

[0310] The following examples are included for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0311] Example 1 NMDP intranasal preparation In this example, NMDP was dissolved using sonication in a solution containing a carrier, citrate buffer, benzalkonium chloride, and water to obtain a solution containing approximately 50 mg / mL of NMDP. Then, 50 μL of the composition was administered into each nostril of a subject using an intranasal drug delivery device. Blood samples were then collected at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration was determined by high-performance liquid chromatography (HPLC). The pharmacokinetics of NMDP delivered by intranasal administration could then be compared to those of NMDP delivered by intravenous administration. The pharmacokinetics of intranasally administered NMDP were comparable to those of intravenously administered NMDP.

[0312] Example 2 NMDP intranasal preparation containing surfactant In this example, NMDP is dissolved using sonication in a solution containing approximately 30% to approximately 95% (w / w) of one or more natural or synthetic carriers, approximately 10% to approximately 70% (w / w) of a non-aqueous solvent, and a surfactant to obtain a solution containing approximately 50 mg / mL of NMDP. 50 μL of the composition is then administered into each nostril of a subject using an intranasal drug delivery device. Blood samples are then collected at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration is determined by high-performance liquid chromatography (HPLC). The pharmacokinetics of NMDP delivered by intranasal administration can then be compared to those of NMDP delivered by intravenous administration. The pharmacokinetics of intranasally administered NMDP are comparable to those of intravenously administered NMDP.

[0313] Example 3 NMDP intranasal preparation that does not contain surfactants In this example, NMDP is dissolved in a solution containing approximately 60% to 80% (w / w) mPEG350, approximately 10% to 30% (w / w) PEG400, and approximately 5% to 15% (w / w) water, and free of nonionic surfactants. A 50 μL composition containing approximately 100 mg / mL of NMDP is then administered into each nostril of a subject using an intranasal drug delivery device. Blood samples are then collected at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration is determined by high-performance liquid chromatography (HPLC). The pharmacokinetics of NMDP delivered by intranasal administration can then be compared to those of NMDP delivered by intravenous administration. The pharmacokinetics of intranasally administered NMDP are comparable to those of intravenously administered NMDP.

[0314] Example 4 A surfactant-free NMDP intranasal preparation containing ethanol. In this example, NMDP is dissolved in a solution containing approximately 60% to 80% (w / w) mPEG350, approximately 10% to 30% (w / w) PEG400, approximately 5% to 15% (w / w) water, and approximately 5% to 15% ethanol, and is free of nonionic surfactants. A 50 μL composition containing approximately 100 mg / mL of NMDP is then administered into each nostril of a subject using an intranasal drug delivery device. Blood samples are then collected at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration is determined by high-performance liquid chromatography (HPLC). The pharmacokinetics of NMDP delivered by intranasal administration can then be compared to those of NMDP delivered by intravenous administration. The pharmacokinetics of intranasally administered NMDP are comparable to those of intravenously administered NMDP.

[0315] Example 5 Manufacturing and intranasal formulation of NMDP Nasal compositions of NMDP can be prepared for administration as a pharmacopoeia to a patient for one of the indications described herein. Briefly, NMDP, buffer, benzalkonium chloride, and optionally other components (e.g., sodium chloride or other osmotic regulators, sorbitol or other sweeteners, flavorings, etc.) can be prepared to a volume somewhat less than the target final volume of the solution. The components can then be mixed until all components are dissolved. The pH can then be adjusted as needed by adding a suitable acid or base, e.g., HCl, NaOH, or a complementary acid or base to the buffer. Once the desired pH is achieved, water can be added until the solution reaches a quantifiable volume. The resulting solution can then be packaged in a container suitable for shipment and distribution. In some embodiments, the suitable container includes a nasal pump. In other embodiments, the suitable container may include vials, such as amber glass vials, glass ampoules, glass bottles sealed with inert rubber septa and crimped caps, or other suitable pharmaceutical vials.

[0316] Example 6 Treatment of tinnitus with NMDP Subjects suffering from tinnitus are treated with approximately 1–10 mg / kg of intranasal delivered NMDP. Subjects are treated with the intranasal delivery formulation of Example 15, F1, or F2. The time to Cmax is approximately 20 minutes. Subjects notice a reduction in tinnitus or other symptoms of tinnitus after administration of the intranasal formulation. Subjects are re-administered the formulation approximately every 2–4 hours as needed to treat symptoms of tinnitus. The amount of NMDP required for administration to subjects using the intranasal delivery formulation is less than that required for oral administration.

[0317] Example 7 Intranasal administration of NDMP Six volunteer subjects suffering from tinnitus were treated with intranasal delivery of NMDP at a dose of approximately 1–10 mg / kg. Subjects were treated every 2–4 hours with a 50 μL nasal spray preparation per nostril, prepared as described in Example 5. A 100 μL dose delivered approximately 20 mg of NMDP at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration was determined by high-performance liquid chromatography (HPLC). The time to Cmax was approximately 1 hour. The pharmacokinetics of intranasal NMDP delivery could then be compared to those of intravenous NMDP delivery. The pharmacokinetics of intranasal NMDP were comparable to those of intravenous NMDP.

[0318] Example 8 Intranasal vesicular composition In this example, approximately 2500 mg of NMDP was dissolved in a solution containing phospholipids, one or more C2-C4 alcohols, and water to obtain a solution containing approximately 200 mg / mL of NMDP. The composition contained vesicles, ranging in size from 50 nm to several microns, more specifically up to 5 μm, exhibiting good properties for enhancing nasal absorption. The vesicles were then visualized by transmission electron microscopy (TEM) and scanning electron microscopy. Subsequently, TEM analysis was performed using an electron microscope with an acceleration voltage of 100 kV.

[0319] Next, 50 μL of the composition is administered into each nostril of the subject using an intranasal drug delivery device. Blood samples are then collected at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration is determined by high-performance liquid chromatography (HPLC). The pharmacokinetics of NMDP delivered by intranasal administration can then be compared to those of NMDP delivered by intravenous administration. The pharmacokinetics of NMDP delivered by intranasal administration are comparable to those of NMDP delivered by intravenous administration.

[0320] Example 9 Dry powder NMDP formulation Dissolve approximately 2500 mg of NMDP in a mixture of acetone (12 g) and ethanol (12 g) while stirring at 300 rpm. Place a magnetic bar of appropriate size in a container and add lactose monohydrate (2.3 g). Set the stirring speed to 150 rpm. Spray-dry the clear, homogeneous solution of the activator (sumatriptan succinate) at an inlet air temperature of 60°C and an outlet temperature of 55°C to obtain a dry powder of the activator, which is then further blended in situ with lactose monohydrate in the container. Stirring is maintained throughout the process. The actual weight of NMDP as an activator in the resulting sumatriptan / lactose composition is approximately 15% w / w. The composition is then mixed with an additional amount of lactose to reach the desired 10% activator (NMDP) concentration.

[0321] Example 10 Mucosal adhesion preparations A 20g batch of mucosal adhesive gel formulation containing 2.0% NMDP was prepared by suspending 20.0 mg of Carbopol 934P and 1.80 g of Poloxamer 188 (BASF Corp.) in 5.00 g of TRIS HC1 buffer (0.1 M), and mixing the components overnight at 4°C with agitation to ensure complete dissolution. Additional components, including hydroxypropyl methylcellulose (100.0 mg), methylparaben (10 mg), and additional TRIS HC1 buffer (0.1 M) (2.87 g), were added, and further mixing was performed until complete dissolution was observed. Tacrolimus (100 g) was added to the NMDP and mixed while maintaining activity. The mixture was kept below room temperature until use.

[0322] Example 11 Microemulsion formulation NMDP is dissolved at a concentration of approximately 50 mg / mL in a microemulsion system of oil containing Cremophor RH 40 and Labrasol, stabilized with a nonionic surfactant, as well as isopropyl myristate, Labrafil M 1944CS, and Maisine 35-1. The formulation contains 8% Labrafil M 1944CS, 30% Cremophor RH 40 / ethanol (3:1), and water, with a maximum solubility of NMDP up to 6.4 mg / mL, a droplet size of 30.3+ / -5.3 nm, and no ciliary toxicity.

[0323] Next, 50 μL of the composition was administered into each nostril of the subject using an intranasal drug delivery device. Blood samples were then collected at 0, 2, 5, 10, 15, 30, and 60 minutes, and the NMDP concentration was determined by high-performance liquid chromatography (HPLC). The pharmacokinetics of NMDP delivery by intranasal administration could then be compared with those of NMDP delivery by intravenous administration. After a single intranasal administration of this preparation at a dose of 2 mg / kg, plasma concentrations peaked at 1 hour, and the absolute bioavailability was approximately 32%.

[0324] Example 12 Treatment of tinnitus induced in mice In this embodiment, mice suffering from noise-induced tinnitus are treated with an intranasal delivery formulation of NMDP, such as the formulation of Example 1.

[0325] As shown in Figure 3, a sound-based avoidance detection (SBAD) method was used for tinnitus detection and for testing animal responses to different pharmacological doses of NMDP. Using a shuttle box divided into two compartments, mice were trained for 15 days to traverse from end to end on an audible cue in "Go" tests and to remain silent and still in "No-Go" tests. Animals had a 5-minute acclimatization period in the shuttle box, after which tests were initiated, with 100 random assignments per day, each lasting approximately 30–40 minutes. The audible cues were played randomly as white noise or narrowband noise at 5, 10, 16, 20, and 32 kHz, and randomly at intensities of 75, 80, or 85 dB. To enhance the training sessions, mice were also shocked if they did not traverse from one compartment to the other during Go tests, and if they moved between compartments silently during No-Go tests. Furthermore, hurdles were added to enhance the training. After 15 days of training, the mice were tested for 3 days to obtain baseline scores that were compared to noise exposure and 3 days of retraining.

[0326] After training was completed and the mice achieved a high success rate in testing, they were exposed to noise trauma for tinnitus. To ensure that the mice still had hearing, one ear was protected with an earplug, and the other ear was exposed to the noise. The mice were placed in a sound booth where they were exposed to broadband noise of 120 dB at 4–25 kHz for 2–4 hours. After noise exposure, the mice were housed for one month and then tested to see if they had developed tinnitus. During these testing periods, the mice were tested in a shuttle box for three days, where Go and No-Go tests were performed. In the No-Go test, the mice were not shocked because it was expected that mice with tinnitus would cross the compartment without an audible cue. To ensure that they retained hearing and could hear the audible cue, the mice continued to be shocked in the Go test. In the examination of the results of testing after noise exposure, tinnitus-positive mice had a higher average error rate in the No-Go test compared to trained mice. To ensure a significant difference in No-Go test scores, a chi-squared test was completed comparing the post-noise exposure test to the baseline test. However, if mice did not have tinnitus, the test was performed after waiting an additional month, and another month if necessary.

[0327] Mice initially received a dose of NMDP via intraperitoneal injection (ip). Go and No-Go scores were compared using the Social Science Statistics chi-square test. The chi-square test was used first to determine whether mice were tinnitus-positive by comparing the No-Go baseline score (before noise exposure or after saline injection) to the No-Go score (after noise exposure) (significant differences (p<0.05) in at least two of the tests indicated tinnitus-positive mice). Following this conclusion, mice were appropriately tested to determine whether their No-Go scores could be improved by different drug doses and combinations. In the Go scores, NMDP did not affect the mice's ability to hear the presented sounds. In the No-Go tests, NMDP did not affect the mice's scores, indicating that concentrations of 10, 30, and 50 mg / kg (iP) did not cause any behavioral changes and should be appropriate doses for the tests.

[0328] Tinnitus was assessed by comparing No-Go scores three months after noise exposure to baseline. Mice showed a significant decrease on all three days of the study, indicating that these mice had tinnitus. One or more mice served as control animals. When examining the Go scores of tinnitus animals tested with specific drugs, mice showed a significant increase in No-Go correct answer scores after NMDP treatment, indicating that NMDP is effective in treating tinnitus in these mice.

[0329] Figures 1A and 1B show the results of No-Go and Go tests in mice treated (ip) with 10, 30, and 50 mg / kg of NMDP. Figure 1A shows that mice showed only modest improvement at the 10 mg / kg dose, which was within at least one error range of the saline candidate, and significant improvement at the 30 mg / kg and 50 mg / kg doses, approaching nearly 100% correct answers, indicating that tinnitus in mice is indeed reduced by 30 mg / kg and 50 mg / kg doses of NMDP. Furthermore, Figure 1B shows that mice treated with saline and mice treated with 10 mg / kg and 30 mg / kg of NMDP had nearly the same 100% correct answer rate in the Go test, indicating that the mice actually completed the test as trained and that the data obtained from the experiment are reliable. Mice treated with 50 mg / kg showed lower accuracy in the Go test, likely indicating that they began experiencing some level of drug-induced side effects from a 50 mg / kg dose of NMDP.

[0330] Figures 2A and 2C are plots showing the baseline results of individual mice in the Go and No-Go tests in the specified tests, respectively, when treated with saline, when treated with NMDP at doses of 10 mg / kg, 30 mg / kg, and 50 mg / kg, and when treated with NMDP containing the intranasal formulation of Example 15 F1 at a dose of 0.9 mg / mouse (or 30 mg / kg, mean mouse body weight 30 g at this stage, approximately 5-6 months old). Figures 2B and 2D are bar graphs showing the accuracy rates of the mice's performance in the Go and No-Go tests. As can be observed in Figure 2B for the Go test, the mice treated with saline and the mice treated with 10 mg / kg and 30 mg / kg of NMDP had nearly the same 100% accuracy rate in the Go test, indicating that the mice actually completed the test as they were trained and that the data obtained from the experiment are reliable. Mice treated intranasally with 50 mg / kg and 0.9 mg / mouse showed lower accuracy rates in the Go test, likely indicating they had begun to experience some level of drug-induced side effects. As can be observed in Figure 2C for the No-Go test, mice showed only modest improvement at the 10 mg / kg dose, indicating this was within the margin of error of at least one saline candidate, while mice showed significant improvement approaching nearly 100% accuracy at the 30 mg / kg, 50 mg / kg, and 0.9 mg / mouse intranasal delivery doses, indicating that tinnitus in mice was indeed treated by 30 mg / kg, 50 mg / kg, and 0.9 mg / mouse.

[0331] Furthermore, the close correlation between the decrease in correct response rate in Figure 2C and mice treated intranasally with 50 mg / kg (ip) and 0.9 mg / mouse (likely indicating drug-induced side effects), as well as the close correlation between the significant improvement in correct response rate in Figure 2D and 30 mg / kg, 50 mg / kg, and 0.9 mg / mouse (indicating effective treatment of tinnitus), indicates that the intranasal delivery dose of 0.9 mg / mouse produced a similar effect on mice as the 30 mg / kg and 50 mg / kg doses administered by intraperitoneal injection. The 0.9 mg intranasal delivery dose of NMDP is equivalent to only about 30 mg / kg of NMDP and was as effective as the 30 mg / kg and 50 mg / kg doses administered by intraperitoneal injection, providing strong evidence for the usefulness of the intranasal delivery formulation and demonstrating that the NMDP dose can be significantly reduced when administered via the intranasal formulation.

[0332] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous variations, modifications, and substitutions will be conceivable to those skilled in the art without departing from the present disclosure. It should be understood that various alternative forms to the embodiments of the present invention described herein may be used in carrying out the invention. The following claims define the scope of the present disclosure, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. A method for treating hearing impairment or symptoms of hearing impairment in a subject requiring such treatment, comprising administering a therapeutically effective amount of NMDP or an L-type calcium channel blocker to the subject intranasally.

2. The method according to claim 1, wherein the hearing impairment is tinnitus or Meniere's disease.

3. A method for treating hearing impairment or symptoms of hearing impairment in a subject who requires it, a. Administer an L-type calcium channel blocker to the subject. b. To evaluate whether the subject responded to the L-type calcium channel blocker, and c. A method comprising administering a therapeutically effective amount of NMDP or a salt thereof to the subject if the subject has responded to the L-type calcium channel blocker.

4. The method according to claim 3, wherein the hearing impairment is tinnitus or Meniere's disease.

5. A method for selecting a subject who needs treatment for tinnitus or Meniere's disease or the symptoms of tinnitus or Meniere's disease, a. Administer an L-type calcium channel blocker to the subject. b. If the subject responds to the L-type calcium channel blocker, the subject is selected for the treatment of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease. c. A method comprising administering a therapeutically effective amount of NMDP or a salt thereof to the subject if the subject has responded to the L-type calcium channel blocker.

6. The method according to any one of claims 3 or 5, wherein the L-type calcium channel blocker comprises carbamazepine.

7. The method according to any one of claims 3 or 5, further comprising administering a therapeutically effective amount of NMDP or a salt thereof into the nasal cavity of the patient for the treatment of tinnitus or Meniere's disease or symptoms of tinnitus or Meniere's disease.

8. The aforementioned therapeutically effective amount of NMDP is a. The therapeutically effective amount of NMDP b. Carrier c. Citrate buffer d. Benzalkonium chloride, and e. Ethylenediaminetetraacetic acid The method according to claim 7, administered with a composition containing the following:

9. The aforementioned therapeutically effective amount of NMDP is a. The therapeutically effective amount of NMDP b. One or more natural or synthetic carriers or any combination thereof in an amount of approximately 10% to approximately 95% (w / w), and c. A non-aqueous solvent of approximately 10% to approximately 95% (w / w), and d. Surfactants The method according to claim 7, provided in a composition comprising:

10. The aforementioned therapeutically effective amount of NMDP is a. Polyethylene glycol b. Methoxy-polyethylene glycol, and c. water The method according to claim 7, provided in a composition comprising at least one of the following.

11. The method according to any one of claims 1 to 5, wherein the therapeutically effective amount of NMDP is about 0.1 mg to about 5 mg per kg of the subject.

12. The method according to any one of claims 1 to 11, further comprising administering the pharmaceutical composition in a volume of about 10 μl to about 300 μl per dose.

13. The method according to any one of claims 1 to 12, further comprising bringing at least a portion of the therapeutically effective amount of the pharmaceutical composition into contact with the mucous membrane of at least one nasal cavity.

14. The method according to any one of claims 1 to 13, further comprising spraying a first amount of the pharmaceutical composition into a first nostril, spraying a second amount of the pharmaceutical composition into a second nostril, and optionally, after a predetermined time delay, spraying a third amount of the pharmaceutical composition into the first nostril.

15. The method according to claim 14, further comprising, in some cases, administering at least a fourth amount of the pharmaceutical composition into the second nostril after a predetermined time interval.

16. The method according to any one of claims 1 to 15, wherein the treatment method achieves a bioavailability of about 80% to 125% of the bioavailability achieved with the same pharmaceutical composition administered intravenously.

17. The method according to any one of claims 1 to 16, further comprising administering the pharmaceutical composition at any point before or after the onset of symptoms of tinnitus or Meniere's disease.

18. The method according to any one of claims 1 to 17, further comprising administering the pharmaceutical composition at least once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.

19. The method according to any one of claims 1 to 5, wherein the therapeutically effective amount of NMDP is administered intranasally every two hours.

20. The method according to any one of claims 1 to 5, wherein the therapeutically effective amount of NMDP is administered intranasally every four hours.

21. The method according to any one of claims 1 to 5, further comprising administering the pharmaceutical composition once a week.

22. The method according to any one of claims 1 to 12, further comprising administering the pharmaceutical composition by low-dose therapy.

23. The method according to any one of claims 1 to 22, further comprising administering the pharmaceutical composition by titration for vestibular symptoms.

24. The method according to any one of claims 1 to 23, further comprising administering the pharmaceutical composition for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 14 days, 21 days, 28 days, 60 days, 120 days, or 400 days.

25. The method according to any one of claims 1 to 24, further comprising administering the pharmaceutical composition in a unit dosage form.

26. The method according to any one of claims 1 to 25, further comprising administering the pharmaceutical composition in order not to alter the intracochlear potential.

27. The method according to any one of claims 1 to 26, further comprising increasing the dose of the pharmaceutical composition to the subject until symptoms of inner ear damage are observed.

28. The method according to claim 27, wherein the symptoms of the inner ear disorder include spontaneous nystagmus, balance disorders, motor intolerance, or hearing loss / decreased hearing as observed with Frenzel glasses.

29. The method according to any one of claims 1 to 27, further comprising administering the pharmaceutical composition by a drug delivery device.

30. The method according to any one of claims 1 to 29, wherein the effect of the pharmaceutical composition is measured by an evaluation selected from the group consisting of a) measurement of changes in ABR and / or DPOAE amplitude and threshold after administration of the pharmaceutical composition, b) changes in auditory speech recognition measured by a words-in-noise test, c) changes in auditory speech recognition measured by a digits-in-noise test, d) changes in low-frequency hearing threshold, e) changes in the incidence of adverse events after administration of the pharmaceutical composition, f) changes in the severity of tinnitus or Meniere's disease, g) changes in the volume of tinnitus or Meniere's disease, h) changes in the severity of dizziness, i) changes in ear blockage, j) changes in the feeling of dizziness, and k) changes in hair cell function observed when measured by changes in ABR threshold.

31. The method according to claim 30, wherein the measurement of the ABR threshold is performed in a frequency range of 250 Hz to 20 kHz.

32. A method for achieving an area under the therapeutic efficacy curve (AUC) extrapolated to infinity (AUC0-infinity) from the administration time of NMDP in a subject requiring it, comprising intranasal administration of an intranasal pharmaceutical composition to the subject, wherein the intranasal pharmaceutical composition is (i) Approximately 0.2 mg to approximately 250 mg / kg of NMDP, or a pharmaceutically acceptable salt thereof. (ii) Buffer, and (iii) Contains surfactants, A method wherein, after administering the intranasal pharmaceutical composition to the subject, the subject exhibits AUC0-infinity of NMDP, which is approximately 270 h*ng / mL to 340 h*ng / mL.

33. A pharmaceutical composition comprising a therapeutically effective amount of NMDP, wherein the composition is formulated for intranasal administration, and the composition a. Therapeutic dose of NMDP b. buffer solution c. Penetration enhancer, and d. A pharmaceutical composition containing a surfactant.

34. The pharmaceutical composition according to claim 33, wherein the composition further comprises one or more components selected from vitamin E, vitamin E TPGS, ethanol, benzyl alcohol, and dodecyl maltoside.

35. The pharmaceutical composition according to any one of claims 33 or 34, wherein the concentration of NMDP in the administered pharmaceutical composition is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / ml.

36. The pharmaceutical composition according to any one of claims 33 to 35, wherein the volume of the pharmaceutical composition administered is 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0 ml.

37. A pharmaceutical composition according to any one of claims 33 to 35, which is a sustained-release formulation.

38. A pharmaceutical composition according to any one of claims 33 to 35, which is a sustained-release formulation.

39. A controlled-release formulation of the pharmaceutical composition according to any one of claims 33 to 35.

40. A pharmaceutical composition according to any one of claims 33 to 35, which is released continuously, variablely, in a pulsatile manner, or in a combination thereof.

41. A pharmaceutical composition according to any one of claims 33 to 35, which is a unit dosage form.

42. The pharmaceutical composition according to claim 41, wherein the unit dosage form is a dried powder, a semi-solid, a mucosal adhesive preparation, an intranasal vesicle unit, or a solution dosage form.

43. The pharmaceutical composition according to claim 42, wherein the composition is aqueous.

44. The pharmaceutical composition according to claim 43, wherein the composition is in the form of a gel or a film.

45. The pharmaceutical composition according to any one of claims 33 to 44, wherein the composition comprises finely milled particles.

46. The pharmaceutical composition according to claim 41, wherein the unit dosage form has a unit weight of about 10 mg to about 10 g.

47. The method according to claim 42, wherein the solution dosage form has a unit dose volume of less than about 600 μL.

48. The pharmaceutical composition according to any one of claims 33 to 47, comprising NMDP at a concentration of about 0.1% to about 20% w / w of the aforementioned formulation.

49. A pharmaceutical composition according to any one of claims 33 to 48, which extends the residence time of the composition in the ear structure.

50. The pharmaceutical composition according to claim 49, wherein the formulation extends the residence time of the composition in the ear structure for a period of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 8 days, or at least 14 days, at least 21 days, or at least 1 month, or at least 6 weeks after a single dose.

51. The pharmaceutical composition according to claim 33, wherein the formulation increases the bioavailability in the ear structure of the composition.

52. The pharmaceutical composition according to claim 51, wherein the formulation increases the steady-state level in the ear structure of the composition.

53. The pharmaceutical composition according to claim 52, wherein the formulation extends the time to reach a therapeutic concentration Cmax that can alleviate the symptoms of hearing impairment in the subject in need thereof.

54. The pharmaceutical composition according to claim 53, wherein the formulation extends the time for which the concentration of the composition remains above the minimum therapeutic concentration (i.e., Cmin) required to alleviate the symptoms of hearing impairment in the subject requiring it.

55. The pharmaceutical composition according to claim 54, wherein the concentration of the composition in the ear structure remains at approximately Cmin or higher for at least 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 3 weeks, or 1 month.

56. A pharmaceutical composition according to any one of claims 33 to 55, further comprising a second pharmacoactive agent.

57. A pharmaceutical composition comprising a therapeutically effective amount of NMDP, wherein the composition is formulated for intranasal administration, and the composition a. A therapeutically effective dose of NMDP, and b. Surfactants c. Solvent, and d. A pharmaceutical composition comprising a water-soluble cellulose polymer.

58. The pharmaceutical composition according to claim 57, further comprising water.

59. A pharmaceutical composition according to any one of claims 57 to 58, further comprising ethanol.

60. The pharmaceutical composition according to any one of claims 57 to 59, wherein the ethanol is at most 5% (w / w).

61. The pharmaceutical composition according to any one of claims 57 to 60, wherein the surfactant is polysorbate or a combination of polysorbates.

62. The pharmaceutical composition according to any one of claims 57 to 61, wherein the surfactant is polysorbate 20 (TWEEN-20).

63. The pharmaceutical composition according to any one of claims 57 to 61, wherein the surfactant is polysorbate 80 (TWEEN-80).

64. The pharmaceutical composition according to any one of claims 57 to 61, wherein the surfactant is present in an amount of 0.00001% or more and 2% or less (w / w).

65. The pharmaceutical composition according to any one of claims 57 to 64, wherein the surfactant is 0.05% (w / w) or more and 2% or less (w / w).

66. The pharmaceutical composition according to any one of claims 57 to 65, wherein the water-soluble cellulose polymer is HPMC, HEC, CMC, sodium carboxymethylcellulose, or a combination thereof.

67. The pharmaceutical composition according to any one of claims 57 to 66, wherein the water-soluble cellulose polymer is present in an amount of 0.00001% or more and 2% or less (w / w).

68. The pharmaceutical composition according to any one of claims 57 to 67, wherein the water-soluble cellulose polymer is present in an amount of 0.05% (w / w) or more and 2% or less (w / w).

69. The pharmaceutical composition according to any one of claims 57 to 68, wherein the solvent is PEG, an alkoxy derivative of polyethylene glycol, mPEG, mPEG350, PEG400, or a combination thereof.

70. The pharmaceutical composition according to any one of claims 57 to 69, wherein the solvent is 0.00001% or more and 94% (w / w) or less.

71. The pharmaceutical composition according to any one of claims 57 to 69, wherein the solvent is 66% (w / w) or more and 94% (w / w) or less.

72. The pharmaceutical composition according to any one of claims 57 to 71, wherein the amount of water is 0.00001% or more and 50% or less (w / w).

73. The pharmaceutical composition according to any one of claims 57 to 72, wherein the amount of water is 0.00001% or more and 30% or less (w / w).

74. The pharmaceutical composition according to any one of claims 57 to 73, wherein the water is 5% or more (w / w) and 50% or less (w / w).

75. The pharmaceutical composition according to any one of claims 57 to 74, wherein the water is 5% or more (w / w) and 30% or less (w / w).

76. A pharmaceutical composition comprising a therapeutically effective amount of NMDP, wherein the composition is formulated for intranasal administration, and the composition a. A therapeutically effective dose of NMDP, and b. Surfactants c. Water-soluble cellulose polymers d. Solvent, and e. A pharmaceutical composition containing water.

77. The pharmaceutical composition according to claim 76, further comprising three solvents.

78. The pharmaceutical composition according to any one of claims 76 to 77, wherein the three solvents include at least three of PEG, polyethylene glycol alkoxy derivatives, mPEG, mPEG350, PEG400, or a combination thereof.

79. The pharmaceutical composition according to any one of claims 76 to 78, wherein the surfactant is polysorbate or a combination of polysorbates.

80. The pharmaceutical composition according to any one of claims 76 to 79, wherein the surfactant is polysorbate 20 (Tween-20).

81. The pharmaceutical composition according to any one of claims 76 to 79, wherein the surfactant is polysorbate 80 (Tween-80).

82. The pharmaceutical composition according to claim 81, wherein the polysorbate 80 (Tween-80) is present in an amount of 0.00001% or more and 2% or less (w / w).

83. The pharmaceutical composition according to claims 81 to 82, wherein the polysorbate 80 (Tween-80) is present in an amount of 0.05% or more (w / w) and 2% or less (w / w).

84. The pharmaceutical composition according to any one of claims 73 to 83, wherein the water-soluble cellulose polymer is HPMC, HEC, CMC, sodium carboxymethylcellulose, or a combination thereof.

85. The pharmaceutical composition according to any one of claims 73 to 84, wherein the water-soluble cellulose polymer comprises only HPMC.

86. The pharmaceutical composition according to any one of claims 76 to 85, wherein the HPMC is 0.00001% or more and 2% or less (w / w).

87. The pharmaceutical composition according to any one of claims 76 to 86, wherein the HPMC is 0.05% or more (w / w) and 2% or less (w / w).

88. The pharmaceutical composition according to any one of claims 73 to 87, wherein the solvent is PEG, an alkoxy derivative of polyethylene glycol, mPEG, mPEG350, PEG400, or a combination thereof.

89. The pharmaceutical composition according to any one of claims 73 to 88, wherein the PEG, polyethylene glycol alkoxy derivative, mPEG, mPEG350, PEG400, or a combination thereof is present in an amount of 0.00001% or more and 94% or less (w / w).

90. The pharmaceutical composition according to any one of claims 73 to 89, wherein the PEG, polyethylene glycol alkoxy derivative, mPEG, mPEG350, PEG400, or a combination thereof is present in an amount of 66% (w / w) or more and 94% (w / w) or less.

91. The pharmaceutical composition according to any one of claims 73 to 90, wherein the amount of water is 0.00001% or more and 50% or less (w / w).

92. The pharmaceutical composition according to any one of claims 73 to 91, wherein the water is 5% or more (w / w) and 50% or less (w / w).

93. The pharmaceutical composition according to any one of claims 73 to 92, wherein the amount of water is 0.00001% or more and 30% or less (w / w).

94. The pharmaceutical composition according to any one of claims 73 to 93, wherein the water is 5% or more (w / w) and 30% or less (w / w).

95. A method for preparing an NMDP liquid composition, 1) A step of dissolving Tween 80 (<2% w / w) separately in mPEG350 and PEG400, 2) A step of mixing NMDP with the solution from step 1) to saturation solubility or to a desired effective concentration. 3) A step of preparing an aqueous solution of HPMC or HPMC in a buffer solution (<2% w / w) having a pH value in the range of approximately 6.4 to approximately 7.

4. 3) A method comprising the steps of adding the HPMC aqueous solution or HPMC buffer from step 3) to each of the solutions from step 2) while stirring, and allowing the mixture to stand to observe the stability of the solution or suspension.

96. The method according to claim 95, wherein the solution in step 2) is NMDP in PEG / Tween 80 solution or NMDP in mPEG / Tween 80 solution.

97. The pharmaceutical composition according to any one of claims 57 to 96, wherein the concentration of NMDP is 68 mg / mL or more.

98. The pharmaceutical composition according to any one of claims 57 to 97, wherein the concentration of NMDP is 0.1 mg / mL or more and 1 mg / mL or less.

99. The pharmaceutical composition according to any one of claims 57 to 98, wherein the concentration of NMDP is 68 mg / mL.

100. The pharmaceutical composition according to any one of claims 57 to 99, wherein the concentration of NMDP is 50 mg / mL.

101. The pharmaceutical composition according to any one of claims 57 to 100, wherein the surfactant, water-soluble cellulose polymer, solvent, water, and ethanol comprise a liquid vehicle.

102. The pharmaceutical composition according to any one of claims 57 to 101, wherein the liquid vehicle is less than 1,000 uL.

103. The pharmaceutical composition according to any one of claims 57 to 102, wherein the liquid vehicle is less than 300 uL.

104. The pharmaceutical composition according to any one of claims 57 to 103, wherein the liquid vehicle is less than 150 uL.

105. The pharmaceutical composition according to any one of claims 57 to 104, wherein the NMDP is dissolved in, suspended in, or dissolved in and suspended in the liquid vehicle.

106. A pharmaceutical composition comprising a therapeutically effective amount of NMDP, wherein the composition is formulated for intranasal administration, and the composition is a. A therapeutically effective dose of NMDP, and b. Including a liquid vehicle, the liquid vehicle is i. Surfactants, ii. Water-soluble cellulose polymers, iii. Solvents, and iv. A pharmaceutical composition further containing water.

107. a. The liquid vehicle is i. The surfactant, ii. The water-soluble cellulose polymer, iii. The solvent, and iv. The water A pharmaceutical composition according to claim 76 or 96, comprising:

108. A pharmaceutical composition comprising a therapeutically effective amount of NMDP, wherein the composition is formulated for intranasal administration, and the composition is a. Therapeutic effective dose of NMDP, b. Solvent, and c. A pharmaceutical composition containing water.

109. The pharmaceutical composition according to claim 108, wherein the solvent is PEG, an alkoxy derivative of polyethylene glycol, mPEG, mPEG350, PEG400, or a combination thereof.

110. The pharmaceutical composition according to any one of claims 108 to 109, wherein the solvent is 0.00001% or more and 94% (w / w) or less.

111. The pharmaceutical composition according to any one of claims 108 to 110, wherein the solvent is 66% (w / w) or more and 94% (w / w) or less.

112. The pharmaceutical composition according to any one of claims 108 to 111, wherein the amount of water is 0.00001% or more and 20% or less (w / w).

113. The pharmaceutical composition according to claim 108, wherein the composition further comprises a first solvent and a second solvent.

114. The pharmaceutical composition according to claim 113, wherein the first solvent contains mPEG and the second solvent contains PEG.

115. The pharmaceutical composition according to claim 114, wherein the mPEG comprises mPEG350.

116. The pharmaceutical composition according to claim 114, wherein the PEG comprises PEG400.

117. The pharmaceutical composition according to claim 108, wherein the therapeutically effective amount of NMDP comprises at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 60 mg / mL, at least 65 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 95 mg / mL, at least 100 mg / mL, at least 110 mg / mL, or more than 110 mg / mL.

118. The pharmaceutical composition according to claim 114, wherein the mPEG constitutes about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, or about 80% to about 90% (w / w) of the composition, the PEG constitutes about 10% to about 50%, about 20% to about 50%, about 30% to about 50%, or about 40% to about 50% (w / w) of the composition, and the water constitutes about 5% to about 20%, about 10% to about 20%, or about 15% to about 20% (w / w) of the composition.

119. The pharmaceutical composition according to claim 108, further comprising ethanol.

120. The pharmaceutical composition according to claim 119, wherein the ethanol constitutes about 1% to about 10%, about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, about 5% to about 10%, about 6% to about 10%, about 7% to about 10%, about 8% to about 10%, or about 9% to about 10% of the composition.

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