WO2024026463A1 - Composition for nasal delivery of an active compound - Google Patents

Abstract

The present inventive concept is directed to compositions that allow nasal delivery of an active compound. Particularly, the disclosed compositions include dimethyl sulfoxide (DMSO). one or more active compounds, water, and optionally a stabilizer and/or thickener. The disclosed compositions offer immediate systemic delivery, allowing the active compound to reach the central nervous system, effectively crossing the blood-brain barrier. The inventive concept also provides a method of administering pharmaceutically active ingredients to a subject in need thereof, for preventing or treating various conditions.

Description

COMPOSITION FOR NASAL DELIVERY OF AN ACTIVE COMPOUND

RELATED APPLICATION DATA

The present application claims the benefit of and priority to United States Provisional Application No. 63/392,956, filed on July 28, 2022, the content of which is hereby incorporated herein by reference as if set forth in its entirety.

TECHNICAL FIELD

The presently disclosed subject matter is generally directed to compositions for the nasal delivery of an active compound, and to methods of making and using the same.

BACKGROUND

Nasal drug delivery has been commonly used to treat local/respiratory ailments, such as congestion and allergies. Recently, however, there has been increased interest in the nose as an alternative to oral and parenteral delivery for many systemic drugs. The vascularized and immunogenic nasal mucosa present potential benefits for systemic absorption in terms of quick action, avoidance of any degradation and/or unwanted entero-hepatic metabolism of the drug (improved bio-availability), as well as improved immune response for vaccines. The nasal route may also provide an attractive needle- free alternative for currently injectable drugs that may improve patient compliance and allow extended use of self-medication for many chronic diseases/acute conditions.

However, one major limitation in nasal delivery is the Insufficient permeation of drugs across the nasal mucosa. Prior art attempts using surfactants (e.g., bile acids, Laureth 9, and taurodehydrofusidate) caused local cytotoxic effects on ciliated cells. Further, nasal delivery of poorly water soluble drugs that need to be given in a relatively high dose is often problematic. Particularly, the maximum volume to be given in each nostril is 100 to 125 pl and with a low solubility of the drug, it is normally not possible to achieve a simple solution formulation. Moreover, the compounds can also act as an irritant to mucosae. It is known that solutions of non-steroidal anti-inflammatory drugs at relatively high concentrations can be prepared by the use of certain salt forms (such as potassium) or by adjustment of pH. However, the osmolarity of such solutions can readily exceed isotonicity and, as a consequence, the solutions can be an irritant.

The presently disclosed subject matter relates to an aqueous-based pharmaceutical composition. More particularly, this invention relates to an aqueous composition comprising an active agent that is effective in treating a disease, disorder, or condition by virtue of its being present on the surfaces of the mucosa that line the nasal cavities. Thus, the presently disclosed subject matter relates generally to a new composition for delivery of one or more active compounds (e.g., drugs) to the nasal passages for systemic absorption. Depositing therapeutic drugs on the olfactoryepithelium has been shown to lead to rapid and direct uptake into the brain. This direct nose-to-brain delivery route bypasses the blood-brain-barrier, which keeps a majority of drugs or drug candidates from reaching the brain in any significant concentrations. Many studies have shown that depositing a drug on the olfactory epithelium, while minimizing drug absorption on the respiratory epithelium, is key to maximizing the fraction of drug that bypasses the blood-brain-barrier and reaches the brain. Accordingly, the disclosed compositions overcome the shortcomings of the prior art and allow for nasal delivery of an active compound.

SUMMARY

In some embodiments, the presently disclosed subject matter is directed to a nasally administrate composition including at least one active agent, wherein the composition includes about 25-75 weight percent water, about 0.001 -20 weight percent active agent, about 5-40 weight percent dimethyl sulfoxide (DMSO), based on the total weight of the composition.

In some embodiments, the composition further includes about 0.001 -10 weight percent of a thickener, based on the total weight of the composition.

In some embodiments, the thickener is selected from hydroxyethylcellulose, cationic water-soluble polymers, fatty alcohols, fatty acids, anionic polymers, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose, polyethylene glycol, pectin, agar, lignin, algin, vegetable gum, cellulose, cellulose derivatives, methyl cellulose, xanthan gum, tragacanth, adhesives, guar gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, poly(acrylates), cellulose derivative, hyaluronic acid, hyaluronic acid derivatives, chitin, collagen, starch, sulfated polysaccharides, carrageenan, sodium alginate, gelatin, pectin and combinations thereof.

In some embodiments, the composition further includes about 0.001 -10 weight percent of a stabilizer, based on the total weight of the composition.

In some embodiments, the stabilizer is selected from albumin, sialic acid, creatinine, glycine, niacinamide, sodium acetyitryptophanate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate, sodium saccharin, carbonate, bicarbonate, antioxidant, benzyl alcohol, paraben, chlorobutanol, benzalkonium salt, butyl hydroxytoluene, sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate, and the like.

In some embodiments, the active agent is an analgesic, antimigraine antipyretic agent, anti-cancer agent, or combinations thereof.

In some embodiments, the active agent is selected from the group consisting of tramadol, ketoprofen, rizatriptan and pharmaceutically acceptable salts thereof.

In some embodiments, the active agent is an opioid.

In some embodiments, the active substance is an anti-Parkinson drug.

In some embodiments, the active substance is a sedative and/or hypnotic drug.

In some embodiments, the active substance is a peptide or a polypeptide.

In some embodiments, the presently disclosed subject matter is directed to methods of administering an active substance to a subject in need thereof. The method includes intranasal administration of the disclosed composition to the subject.

In some embodiments, the active substance is selected from the group consisting of an analgesic, antimigraine and/or antipyretic agent; an opioid; an anti-Parkinson drug; and a sedative and/or hypnotic drug.

In some embodiments, the presently disclosed subject matter is directed to a method of treating a disease, disorder, or condition in a subject in need thereof. Specifically, the method includes administering intranasally to the subject the disclosed composition, wherein the composition is suitable for application to the nasal mucosa and wherein the active agent treats the disease, disorder, or condition. In some embodiments, the presently disclosed subject matter is directed to nasally administrate compositions including a benzimidazole compound, water, and DMSO, based on the total weight of the composition.

In some embodiments, the benzimidazole compound is one of albendazole, fenbendazole, oxfenbendazole, thiabendazole, mebendazole, omeprazole, lansoprasole, or pantoprazole. In some embodiments, the benzimidazole compound is fenbendazole.

In some embodiments, the presently disclosed subject matter is directed to methods of treating brain cancer and/or symptoms associated with brain cancer including nasally administering an effective amount of a composition including fenbendazole to a subject in need thereof.

In some embodiments, the presently disclosed subject matter is directed to methods of treating a central nervous system disorder including nasally administering an effective amount of a composition including fenbendazole to a subject in need thereof.

In some embodiments, the presently disclosed subject matter is directed to methods of treating an infection including nasally administering an effective amount of a composition including fenbendazole to a subject in need thereof. In some embodiments, the infection is caused by Borrelia burgdorferi.

In some embodiments, the presently disclosed subject matter is directed to the use of a benzimidazole compound such as albendazole, fenbendazole, oxfenbendazole, thiabendazole, mebendazole, omeprazole, lansoprasole, or pantoprazole, and in some embodiments, fenbendazole, to prevent or treat disorders described herein by nasal administration of the benzimidazole compound to a subject in need thereof.

In some embodiments, the presently disclosed subject matter is directed to kits including a composition including fenbendazole and instructions for the use thereof.

DETAILED DESCRIPTION

The presently disclosed subject matter is introduced with sufficient details to provide an understanding of one or more particular embodiments of broader inventive subject matters. The descriptions expound upon and exemplify features of those embodiments without limiting the inventive subject matters to the explicitly described embodiments and features. Considerations in view of these descriptions will likely give rise to additional and similar embodiments and features without departing from the scope of the presently disclosed subject matter.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter pertains. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described.

Following long-standing patent law convention, the terms "a", "an", and "the" refer to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a device" can include a plurality of such devices, and so forth. It will be further understood that the terms "comprises," "comprising," "includes," and/or "including” when used herein specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

Unless otherwise indicated, all numbers expressing quantities of components, conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the instant specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

As used herein, the term "about", when referring to a value or to an amount of mass, weight, time, volume, concentration, and/or percentage can encompass variations of, in some embodiments 47-20%, in some embodiments 4-7-10%, in some embodiments 47-5%, in some embodiments -7-1 %, in some embodiments -7-0.5%, and in some embodiments ■7-0.1 %, from the specified amount, as such variations are appropriate in the disclosed packages and methods.

As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. Relative terms such as "below" or "above" or "upper" or "lower" or "horizontal" or "vertical" may be used herein to describe a relationship of one element, layer, or region to another element, layer, or region as illustrated in the drawing figures. It will be understood that these terms and those discussed above are intended to encompass different orientations of the device in addition to the orientation depicted in the drawing figures.

The embodiments set forth below represent the necessary information to enable those skilled in the art to practice the embodiments and illustrate the best mode of practicing the embodiments. Upon reading the following description, those skilled in the art will understand the concepts of the disclosure and will recognize applications of these concepts not particularly addressed herein. It should be understood that these concepts and applications fall within the scope of the disclosure and the accompanying claims.

The presently disclosed subject matter is directed to compositions that enable nasal delivery of an active compound. The term “composition” refers to a product that includes a specific component in any given amount or proportion, as well as any product that results directly or indirectly from a combination of specific components In a specific amount. Advantageously, nasal delivery can provide drug absorption into the systemic circulation, and it has been suggested that this route of administration can offer a pathway to transport drugs the brain. There exists a need for an effective carrier to enable enhanced nasal delivery of pharmaceutically active agents. Particularly, the disclosed compositions comprise, consist essentially of, or consist of dimethyl sulfoxide (DMSO), one or more active compounds, water, and optionally a stabilizer and/or thickener. The disclosed composition offers immediate system delivery, allowing the active compound to reach the central nervous system, effectively crossing the blood-brain barrier. The invention also provides a method of administering pharmaceutically active ingredients to a subject in need thereof, for treating various conditions as described below.

As set forth above, the disclosed compositions include one or more active compounds. The term “active compound” refers to any molecule, preparation, mixture, and the like that upon administration or application produces a beneficial, desired, or expected effect. Suitable active compounds can therefore include one or more analgesic agents. The term “analgesic” refers to any agent that relieves or eliminates pain in a subject. Suitable analgesic agents can include (but are not limited to) ibuprofen, flurbiprofen, diclofenac, indomethacin, piroxicam, ketoprofen, etodclac, diflusinal, meloxicam, aceclofenac, fenoprofen, naproxen, tiaprofenic acid and tolmetin.

Suitable active agents not only include analgesic agents (such as NSAIDs) and drugs for the treatment of Parkinson's disease (e g., L-dopa and its derivatives, trihexyphenidyl, etc.), but also drugs where rapid onset of action may be required, such as drugs for the treatment of nausea and vertigo, convulsions, panic attacks, cardiac problems, impotence, erectile dysfunction, migraine, sedation, and withdrawal symptoms. Suitable drugs may also include benzodiazapines, midazolam, diazepam, and diamorphine.

Thus, the active agent can include antimalarial agents, such as artemisinin derivatives, dihydroartemisinin, artemotil, chloroquine, primaquine, doxycillin, quinine, aminoquinolines, cinchona alkaloids, antifolates, quinidine, melfoquine, halofantrine, lumefantrine, amodiaquine, pyronaridine, tafenoquine, artesunates, artemether, artemotil, biguanides, proguanil, chloproguanil, diaminopyrimidines, pyremethamine, trimethoprim, dapsone, sulfonamides, atovaquone, sulfadoxine-pyrimethamine, N-acetyl cysteine, piperaquine, DHA-piperaquine, lumefantrine, dermaseptins, bisphosphonates, quercitin etc. The drugs could be used alone or in combinations.

The active agent can also include one or more antibiotics, such as penicillin, cephalosporin, macrolide, tetracycline, aminoglycoside, anti-tuberculosis agent, doxycycline, ciprofloxacine, moxifloxacine, gatifloxacine, carbapenems, azithromycine, clarithromycine, erythromycine, ketolides, penems, tobramyicin, filgrastim, pentamidine, microcidin, clerocidin; amikacine, and the like.

The active agent can include anti-inflammatory drugs, such as steroidal agents, cannabinoids, leukotriene-antagonists, tacrolimus, sirolimus, everolimus, and the like.

The active agent can include antipyretics (e.g., paracetamol, ibuprofen, diclofenac, aspirin, etc.).

The active agent can include peptide and steroid hormones, such as insulin, insulin derivatives, insulin detemir, insulin monomeric, oxytocin, LHRH, LHRH analogues, adreno-corticotropic hormone, somatropin, leuprolide, calcitonin, parathyroid hormone, estrogens, testosterone, adrenal corticosteroids, megestrol, progesterone, sex hormones, growth hormones, growth factors, etc.

The active agent can include peptide and protein related drugs (e.g., amino acids, peptides, polypeptides, proteins), autonomic nervous system drugs, antidepressants (e.g., buspirone, venlafaxine, benzodiazepins, selective serotonin reuptake inhibitors (SSRIs), sertraline, citalopram, tricyclic antidepressants, paroxetine, trazodone, lithium, bupropion, sertraline, fluoxetine, etc.), agents for treating alcoholism and alcohol withdrawal, lipid-lowering agents (e.g., inhibitors of 3 hydroxy-3-methyigiutaryl-coenzyme A (HMG-CoA) reductase, simvastatin, atrovastatin, etc.), drugs for CNS or spinal cord (benzodiazepines, lorazepam, hydromorphone, midazolam, Acetaminophen, 4'- hydroxyacetanilide, barbiturates, anesthetics, etc.), anti-epilepsic agents (e.g., valproic acid and its derivatives, carbamazepin, etc.), angiotensin antagonists (e.g., valsartan, etc.), anti-psychotic agents and anti-schizophrenic agents (e.g., quetiapine, risperidone), antl-Alzheimer drugs (e g., cholinesterase inhibitors, galantamine, rlvastigmlne, donepezil, tacrine, memantine, N-methyl D~aspartate (NMDA) antagonists), antidementia drugs, anti-seizure drugs, prostaglandins for bladder dysfunction (e.g., oxybutynin, propantheline bromide, trospium, solifenacin succinate etc.), agents for the treatment of menopausal syndrome (e.g., estrogens, non-estrogen compounds, etc.), cytokines (e.g., TNF, interferons, IFN-alpha, IFN-beta, interleukins etc.), CNS stimulants, drugs to treat CNS infections, muscle relaxants, narcotics and antagonists (e.g., opiates, oxycodone etc.), painkillers (opiates, endorphins, tramadol HCI, codeine, NSAIDs, gabapentine, fentanil and pharmaceutically acceptable salts thereof etc.), hypnotics (Zolpidem, benzodiazepins, barbiturates, ramelteon, etc.), anti-migraine drugs (e.g., imipramine, propranolol, sumatriptan, etc.), diagnostic agents (e.g., phenolsulfonphthalein, dye T-1824, vital dyes, potassium ferrocyanide, secretin, pentagastrin, cerulein, etc.), ADHD related medication (e.g., methylphenidate, dexmethylphenidate, dextroamphetamine, d- and l-amphetamin racemic mixture, pemoline, etc.), diuretic agents, anti-osteoporotic agents (e.g., bisphosphonates, aledronate, pamidronate, tirphostins, etc.), drugs for treatment of asthma, drugs for post trauma, crisis, anxiety treatment, anti-spasmotic agents (e.g., papaverine, etc.), agents for treatment of multiple sclerosis and other neurodegenerative disorders (e.g., mitoxantrone, glatiramer acetate, interferon beta-la, interferon beta-1b, etc.).

In some embodiments, the active agent can be a drug or combination of drugs used to treat cancer. Thus, the active agent can include cytotoxic and cytostatic agents, which kill the cancer cells or reduce and/or stop their growth or proliferation. The modes of action of these anticancer drugs can vary and include antimetabolites (e.g., cytarabine, methotrexate, mercaptopurine or clofarabine), DNA cross-linking agents (e.g., cisplatin and its derivatives), DNA intercalating substances (e.g., doxorubicin), topoisomerase poisons (e.g., etoposide), kinase inhibitors (e.g., cetuximab), steroids (e.g.. dexamethasone) and/or mitotic inhibitors (e.g., vincristine). Any suitable agent that can be used to treat cancer can be used, such as (but not limited to) traditional chemotherapy drugs and repurposed cancer drugs such as mebendazole, fenbendazole, itraconazole, doxycycline, antifungals, anthelmintics, antibiotics, and antivirals.

The active agent is present in the composition in a pharmaceutically effective concentration. Such concentration will vary depending on the particular medicament or mixture of active agents used, the condition to be treated, and the nature of the individual being treated. For guideline purposes, it is recommended that the active agent comprise about 0.001 to about 20 weight percent of the composition, such as at least about (or no more than about) 0.001 , 0.01 , 0.1 , 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 weight percent, based on the total weight of the composition. However, it should be appreciated that the active agent can be present in the disclosed composition in an amount greater or less than the range given above. Moreover, a recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. As will be understood by one skilled in the art, ranges disclosed herein encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As set forth above, the disclosed composition further include dimethyl sulfoxide (DMSO), an organosulfur compound with the formula (CHs'^SO. DMSO is a polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in water.

In particular embodiments, the disclosed composition can include about 1-40 weight percent DMSO. Thus, the composition can include at least about (or no more than about) 1 , 5, 10, 15, 20, 25, 30, 35, or 40 weight percent DMSO, based on the total weight of the composition. However, it should be appreciated that the DMSO can be present in the disclosed composition in an amount greater or less than the range given above.

Optionally, the composition can include a stabilizer. The term “stabilizer” refers to a compound that is used to stabilize a therapeutic agent against a physical, chemical, or biochemical process that is expected to reduce the therapeutic activity of the substance. Suitable stabilizers that can be included in the disclosed composition can include (but are not limited to) one or more of albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophanate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate, sodium saccharin, carbonates, bicarbonates, antioxidants, benzyl alcohol, parabens, chlorobutanol, benzalkonium salts, butyl hydroxytoluene, sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate, and the like.

The disclosed composition can include about 0.001 -10 weight percent stabilizer (e.g., at least/no more than about 0.001 , 0.005, 0.01 , 0.05, 0.1 , 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 weight percent stabilizer, based on the total weight of the composition). It should further be appreciated that the composition can be stabilizer-free in some embodiments.

The disclosed composition can optionally include one or more thickeners. As used herein, the term “thickener” refers to any agent that makes a composition more dense or viscous in consistency. Suitable thickeners can include, for example, non-ionic water- soluble polymers such as hydroxyethylcellulose, cationic water-soluble polymers such as Polyquat 37, fatty alcohols, fatty acids, anionic polymers, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose, and polyethylene glycols, pectin, agar, lignin, algin, vegetable gums, cellulose, cellulose derivatives, methyl cellulose, xanthan gum, tragacanth, adhesives, guar gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, mucoadhesive polymer-systems like poly(acrylates), cellulose derivatives, hyaluronic acid, hyaluronic acid derivatives, chitin, collagen, starch, polyethylene glycol), sulfated polysaccharides, carrageenan, sodium alginate, gelatin, pectin and combinations thereof.

The desired concentration of the thickening agent will depend on the agent selected and the viscosity desired. In some embodiments, the thickener is present in an amount that maintains the particles of active agent suspended in the composition during non-use and during spray of the composition into the nasal cavity, and also when the composition is deposited on the mucosal surfaces of the nasal cavities. As the composition is subjected to shear forces (e.g., by being agitated before spraying), the viscosity of the composition decreases, and it flows readily through the spray device. Upon application, the composition exits the spray device in the form of a fine plume that infiltrates and deposits on the mucosal surfaces of the nose (e.g., the anterior regions of the nose, the frontal sinus, the maxillary sinuses, and/or the turbinates that overlie the conchas of the nasal cavities. Thus, the composition can comprise a freely flowable liquid, and in sprayed form, a fine mist that finds its way to and deposits on the desired mucosa. In deposited and relatively unstressed form, the composition increases in viscosity and assumes its gel-like form which includes particles of the medicament suspended therein and which resists being cleared from the nasal passages by the inherent mucociliary forces that are present in the nasal cavities.

The disclosed composition can include 0.001-10 weight percent thickener (e.g., at least/no more than about 0.001 , 0.005, 0.01 , 0.05, 0.1 , 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 weight percent thickener, based on the total weight of the composition). It should further be appreciated that the composition can be thickener-free in some embodiments.

The disclosed composition further includes water, in an amount of about 50 weight percent. Thus, the composition can include at least about (or no more than about) 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 weight percent water, based on the total weight of the composition.

In some cases, the total amount of water needed for the composition is divided such that a portion (e.g., up to 20-30% of the total water amount) is added in conjunction with the active agent. Some physiologically active substances require basification or acidification of the medium to facilitate their dissolution. These physiologically active substances are first separately dissolved in an alkaline aqueous solution (or acidic aqueous solution, as required) followed by respective pH adjustment, and the clear aqueous solution with the physiologically active substance is mixed with the magnesium salt solution and the remaining amount of water and the resultant aqueous phase is combined with the phospholipids solution to form the composition.

It may also be appropriate to include buffering agents in the composition. For example, a buffer may be needed to maintain a pH that is compatible with nasal fluid and/or to ensure stability. It will be clear to the person skilled in the art that additional formulation components can be added to the composition. These could include agents that promote the transmucosal absorption of active agents such as surfactants. Preservative agents such as methyl parabenzoates, benzylalcohol, and chlorobutanol can also be added.

The composition can be prepared in any suitable way. For example, an aqueous suspension of the active agent can be formed and combined with an aqueous suspension that includes water, DMSO, and optional thickener and/or stabilizer. Thus, the preparation of the composition can be carried out by mixing under various methods, homogenization or stirring, typically at room temperature or at an elevated temperature.

The compositions of the invention can be prepared as liquid, viscous liquid, or gel. The active agent can be incorporated into different dosage forms acceptable for the nasal route of administration, e.g., into various nasal creams, nasal ointments, nasal suspensions, and nasal gels in addition to nasal liquids.

As used herein, “nasally administering” or "nasal administration” includes administering the disclosed compositions into the mucous membranes of the nasal passage or nasal cavity of a subject. For example, the compositions of the invention can be delivered to the nasal cavity as drops. Alternatively, liquid can be delivered to the nasal cavity as non-aerosol spray (packaged in a bottle with an atomizer attachment, such as a pump-sprayer) or as an aerosol spray packed in a container under pressure to emit pressurized suspension, as described in detail in Remington’s Pharmaceutical Sciences (16th edition, Chapters 83 and 92). Suitable delivery devices can therefore broadly include nasal sprays, metered-dose sprays, squeeze bottles, liquid droppers, disposable one-dose droppers, nebulizers, cartridge systems with unit-dose ampoules, single-dose pumps, bi-dose pumps, and multiple-dose pumps. Regarding spray devices, it should be noted that both single (unit) dose or multiple dose systems may be used. Typically, the volume of liquid that is dispensed in a single spray actuation is in the range of about 250 microliters/each nostril/single administration and the concentration of the active ingredient in the formulation may be readily adjusted such that one or more spray into the nostrils will comply with the dosage regimen.

After the disclosed composition has been administered to a subject, systemic delivery of the active compound through the circulation or for CNS delivery for treating CNS-originating diseases or conditions is accomplished. A wide range of active substances can be administered via the nasal route with the aid of DMSO and optionally the thickener and/or stabilizer to treat a neurological disorder, muscular disturbances, ticks, brain disorder, CNS disorder, insomnia, pain, anxiety, migraine, glioma, epilepsy, astroglioma, cancer, IBD, Chron's disease, loss of appetite, fear, distress, panic, tremor, multiple sclerosis, autism, Alzheimer, menopause, Parkinson, post-traumatic events, alcoholic and nonalcoholic fatty liver, hysteria, seizure and types of encephalopathy, including hepatic-encephalopathy.

In some embodiments, methods of treating brain cancer and/or symptoms associated with brain cancer are provided. The methods include nasally administering an effective amount of a composition including a benzimidazole to a subject in need thereof. In particular embodiments, the benzimidazole isalbendazole, fenbendazole, oxfenbendazole, thiabendazole, mebendazole, omeprazole, lansoprasole, or pantoprazole, and in some embodiments, fenbendazole. In some embodiments, the subject’s brain cancer is relapsed. In some embodiments, the subject’s brain cancer is refractory. The symptoms associated with brain cancer include, but are not limited to, at least one of loss of motor function, balance and/or coordination; tremors; confusion; dementia; overall cognitive decline; and incontinence.

In further embodiments, methods of treating a central nervous system (CNS) disorder are provided, the methods including nasally administering an effective amount of a composition including a benzimidazole, such as fenbendazole, to a subject in need thereof. CNS disorders include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, prion disease, Amyotrophic lateral sclerosis, motor neuron disease, Huntington’s disease, spinal muscular atrophy, and spinocerebellar ataxia.

In still other embodiments, methods of treating an infection including nasally administering an effective amount of a composition including a benzimidazole, such as fenbendazole, to a subject in need thereof is also provided. In some embodiments, the infection is caused by a microorganism having its conventional meaning in the art and includes bacteria, protozoa, yeasts, molds, and viruses. In some embodiments, the microorganism is a bacterium, for example, a Proteobacterium (including subgroups, alpha, beta, delta and gamma), such as, for example, an Alphaproteobacteria (e.g.. Bartonella spp., Brucella spp., Ehrlichia spp., Rasbo bacteria, Afipia, Anaplasma, and the like), including nanobacteria. In other embodiments, the microorganism may be a Corynebacterium, a bacterium belonging to the group Apicomplexa, for example, Babesia/Theileria, Firmicutes, Fusobacteria, Planctomycetales, Spirochete, for example, Borreiia, Burkholderia pickettii, Streptococcus thermophillis, or division Archaea bacteria. In some embodiments, the microorganism belongs to the group Mollicutes, for example, Mycoplasma spp., and the like. In some embodiments, the microorganism may be, for example, Bartonella spp., Borreiia spp., Anaplasma spp., Ehrlichia spp., Babesia/Theileria spp., Rickettsia spp., or Mycoplasma spp. In some embodiments, the microorganism may be Bartonella spp., for example, B. henselae, B. quintans, B. alsatica, B. elizabethae, B. koehlerae, B. vinsonii subsp. berkhoffii genotype I, B. vinsonii subsp. berkhoffii genotype II, B. vinsonii subsp. berkhoffii genotype III, B. vinsonii subsp. berkhoffii genotype IV, B. vinsonii subsp. vinsonii, and/or B. clarridgeiae. In some embodiments, the microorganism may be Borreiia spp., for example, B. burgdorferi, B. bissettii, B. garinii, B. mayonii, B. hermsii, B. parked, B. turicatae, B. miyamotoi, and/or B. afzelii. In some embodiments, the infection is a Borreiia burgdorferi infection.

The term “subject” as used herein can refer to avian, vertebrate and mammalian species. According to some embodiments of the present disclosure, the mammal is a non-human mammal. In some embodiments, the mammal is a human subject. Human subjects of all genders are suitable subjects according to the present invention. Further, the subjects relevant to this disclosure may identify as male or female and may be any age such as less than 12 months to over 100 including newborns, infants, juveniles, adolescents, teenagers, adults and geriatrics. Subjects relevant to this disclosure further include any species and may be of any race or ethnicity, including, but not limited to, Caucasian, African-American, African, Asian, Hispanic, Indian, etc., and combined backgrounds.

Particularly relevant subjects to this inventive concept are subjects who suffer from the diseases or disorders described herein. Other subjects include those who have failed medical therapy for the diseases or disorders described herein. Still others include those having risk factors for the diseases or disorders described herein.

In other embodiments, the term “subject” includes veterinary use, such as with any of a variety of animals including (but not limited to) cats, dogs, horses, pigs, goats, ponies, hamsters, rats, mice, gerbils, guinea pigs, chinchillas, rabbits, deer, buffalo, bison, birds, lizards, cattle, sheep, llamas, camels, and the like.

Advantageously, the nasai administration of the active agent using disclosed the composition can provide for direct access to sites of action, such as the cerebrospinal fluid and the nervous ganglia associated with conditions such as migraine. Consequently, the required dose of the active agent administered nasally may be less than that required when given by an oral route.

It should be understood that the amount of active agent applied to each of the nasal passages will vary depending on the particular medicament used, the nature of the condition being treated, and the nature of the individual being treated. For guideline purposes, the unit dosage applied to one of the nasal cavities can comprise about 200 to about 450 mcg of the active agent.

The composition of the present invention may be adjusted, if necessary, to approximately the same osmotic pressure as that of the body fluids. This may be desirable where the composition is to be applied to delicate tissue membranes, such as those found in the nasal cavity. For example, compositions comprising NSAIDs can exceed isotonicity, becoming hypertonic. A composition which has been adjusted in this manner is said to be isotonic and will tend not to swell or contract the tissues with which it comes into contact and will result in minimal discomfort on application. The formation of isotonic solutions can be achieved by adding an ionic compound to the composition such as sodium chloride, or by adding glycerol. As used herein, the terms “effective amount” or “therapeutically effective amount,” refer to a quantity sufficient to achieve a desired therapeutic and/or prophylactic (prevention) effect, e.g., an amount which results in the full or partial amelioration of disorders or symptoms in a subject. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will depend on the type and severity of the disorder or symptom and on the characteristics of the individual, such as general health, age, sex, body weight, and tolerance to drugs. It will also depend on the degree, severity, and type of disorder or symptom. The compositions can also be administered in combination with one or more additional compounds or compositions. In some embodiments, multiple doses are administered. In some embodiments, multiple therapeutic compositions or compounds are administered. In the methods described herein, the compositions may be administered to a subject having one or more signs or symptoms of a disorder described herein.

Moreover, by the terms “treat,” “treating” or “treatment of,” it is intended that the severity of the disorder or the symptoms of the disorder are reduced, or the disorder is partially or entirely eliminated, as compared to that which would occur in the absence of treatment. Treatment does not require the achievement of a complete cure of the disorder.

By the terms “preventing" or “prevention,” it is intended that the inventive methods eliminate or reduce the incidence or onset of the disorder, as compared to that which would occur in the absence of the measure taken. Alternatively stated, the present methods slow, delay, control, or decrease the likelihood or probability of the disorder in the subject, as compared to that which would occur in the absence of the measure taken.

The compositions of the present disclosure can be provided in a kit for the prevention and/or treatment of the diseases and/or disorders described herein. As used herein, '‘kit” refers to an assembly of components packaged together with optional instructions regarding how to use the components of the kit. According to embodiments of the present invention, the kits may include all components necessary for the prevention and/or treatment of the diseases and/or disorders described herein including the compositions of the disclosure, or a subset of the elements in any combination. EXAMPLE

A composition including 2000mg of 99.9% fenbendazole API (Thermo-Fisher Scientific), pharmaceutical grade 99.9% DMSO (Heiltropfen Inc.), distilled water, sodium chloride, glycerin, and potassium sorbate was administered to two subjects experiencing chronic symptoms that had not been resolved with traditional treatments for their symptoms. One subject had been experiencing prolonged decreased neurocognitive function and chronic sinus and ear infections and the other subject was diagnosed with terminal metastatic melanoma and multiple tumors in the brain. Each subject used the composition three times per day applying to each nostril for a period of about 14 days. Approximately 1.2 to 2.4 ml of the composition was delivered to the nasal passages of the subjects.

Within three weeks of receiving treatment, the subject experiencing prolonged decreased neurocognitive function and chronic sinus and ear infections reported an increase in mental clarity and complete resolution of chronic sinus and ear infections. The subject diagnosed with terminal metastatic melanoma and multiple tumors in the brain reported complete resolve of the following symptoms: loss of motor function, balance and coordination; tremors; confusion; dementia; overall cognitive decline; and incontinence.

Exemplary embodiments of the methods and components of the presently disclosed subject matter have been described herein. As noted elsewhere, these embodiments have been described for illustrative purposes only, and are not limiting. Other embodiments are possible and are covered by the presently disclosed subject matter. Such embodiments will be apparent to persons skilled in the relevant art(s) based on the teachings contained herein. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments but should be defined only in accordance with the following claims and their equivalents.

Claims

CLAIMS What is chimed is:

1 . A nasally administrate composition comprising at least one active agent, wherein the composition comprises about 25-75 weight percent water, about 0.001-20 weight percent active agent, about 5-40 weight percent DMSO, based on the total weight of the composition.

2. The composition of claim 1 , further comprising about 0.001 -10 weight percent of a thickener, based on the total weight of the composition.

3. The composition of claim 2, wherein the thickener is selected from hydroxyethylcellulose, cationic water-soluble polymers, fatty alcohols, fatty acids, anionic polymers, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose, polyethylene glycol, pectin, agar, lignin, algin, vegetable gum, cellulose, cellulose derivatives, methyl cellulose, xanthan gum, tragacanth, adhesives, guar gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, poly(acrylates), cellulose derivative, hyaluronic acid, hyaluronic acid derivatives, chitin, collagen, starch, sulfated polysaccharides, carrageenan, sodium alginate, gelatin, pectin and combinations thereof.

4. The composition of claim 1 , further comprising about 0.001 -10 weight percent of a stabilizer, based on the total weight of the composition.

5. The composition of claim 4, wherein the stabilizer is selected from albumin, sialic acid, creatinine, glycine, niacinamide, sodium acetyltryptophanate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate, sodium saccharin, carbonate, bicarbonate, antioxidant, benzyl alcohol, paraben, chlorobutanol, benzalkonium salt, butyl hydroxytoluene, sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate, and the like. The composition of ciaim 1 , wherein the active agent is an analgesic, antimigraine antipyretic agent, or combinations thereof. The composition of claim 1 , wherein the active agent is an opioid or a benzimidazole. The composition of claim 1 , wherein the active agent is an anti-cancer drug or combination of drugs. The composition of claim 1 , wherein the active substance is an anti-Parkinson drug. The composition of claim 1 , wherein the active substance is a sedative and/or hypnotic drug. The composition of claim 1 , wherein the sedative and/or hypnotic drug is brotizolam or a pharmaceutically acceptable salt thereof. The composition of claim 1 , wherein the active substance is a peptide or a polypeptide. A method of administering an active substance to a subject in need thereof, comprising intranasal administration of the composition of claim 1 . The method of claim 13, wherein the composition further comprises about 0.001 - 10 weight percent of a thickener, based on the total weight of the composition. The method of claim 13, wherein the composition further comprises about 0.1-10 weight percent of a stabilizer, based on the total weight of the composition. The method of claim 13, wherein the active substance is selected from the group consisting of an analgesic, antimigraine and/or antipyretic agent; an opioid; an antiParkinson drug; and a sedative and/or hypnotic drug. The method of claim 13, wherein the active substance is an anti-cancer drug. A method of treating a disease, disorder, or condition in a subject in need thereof, the method comprising administering intranasally to the subject the composition of ciaim 1 ; wherein the composition is suitable for application to the nasal mucosa; and wherein the active agent treats the disease, disorder, or condition. The method of claim 18, wherein the active agent is an analgesic, antimigraine and/or antipyretic agent; an opioid; an anti-Parkinson drug; a sedative, an anticancer drug, and/or hypnotic drug, or combinations thereof. The method of claim 18, wherein the subject is a human. A nasally administrable composition comprising a benzimidazole compound, water and dimethyl sulfoxide (DMSO), based on the total weight of the composition. The composition of claim 21 , wherein the composition comprises about 0.001-20 weight percent of a benzimidazole compound, about 25-75 weight percent water, and about 5-40 weight percent DMSO, based on the total weight of the composition. The composition of claim 21 or 22, wherein the benzimidazole compound is one of albendazole, fenbendazole, oxfenbendazole, thiabendazole, mebendazole omeprazole, lansoprasole, or pantoprazole. The composition of claim 23, wherein the benzimidazole compound is fenbendazole. The composition of claim 21 or 22, further comprising about 0.001 -10 weight percent of a thickener, based on the total weight of the composition. The composition of claim 25, wherein the thickener is selected from hydroxyethylcellulose, cationic water-soluble polymers, fatty alcohols, fatty acids, anionic polymers, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose, polyethylene glycol, pectin, agar, lignin, algin, vegetable gum, cellulose, cellulose derivatives, methyl cellulose, xanthan gum, tragacanth, adhesives, guar gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, poly(acrylates). cellulose derivative, hyaluronic acid, hyaluronic acid derivatives, chitin, collagen, starch, sulfated polysaccharides, carrageenan, sodium alginate, gelatin, pectin and combinations thereof. The composition of claim 21 or 22, further comprising about 0.001 -10 weight percent of a stabilizer, based on the total weight of the composition. The composition of claim 27, wherein the stabilizer is selected from albumin, sialic acid, creatinine, glycine, niacinamide, sodium acetyltryptophanate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate, sodium saccharin, carbonate, bicarbonate, antioxidant, benzyl alcohol, paraben, chlorobutanol, benzalkonium salt, butyl hydroxytoluene, sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate, and the like. A method of treating brain cancer and/or symptoms associated with brain cancer comprising nasally administering an effective amount of a composition comprising fenbendazole to a subject in need thereof. The method of claim 29, wherein the composition comprises:

(a) about 0.001-20 weight percent of fenbendazole:

(b) about 25-75 weight percent water, and

(c) about 5-40 weight percent DMSO, based on the total weight of the composition. The method of claim 29 or 30, wherein the brain cancer is relapsed. The method of claim 29 or 30, wherein the brain cancer is refractory. The method of claim 29, wherein the symptoms associated with brain cancer include at least one of loss of motor function, balance and/or coordination; tremors; confusion; dementia; overall cognitive decline; and incontinence. A method of treating a central nervous system disorder comprising nasally administering an effective amount of a composition comprising fenbendazole to a subject in need thereof. A method of treating an infection comprising nasally administering an effective amount of a composition comprising fenbendazole to a subject in need thereof. The method of claim 35, wherein the infection is a Borrelsa burgdorferi infection. The method of claim 34 or 35, wherein the composition comprises:

(a) about 0.001-20 weight percent of fenbendazole;

(b) about 25-75 weight percent water, and

(c) about 5-40 weight percent DMSO, based on the total weight of the composition. A kit comprising:

(a) a composition comprising:

(i) about 0.001 -20 weight percent of fenbendazole;

(ii) about 25-75 weight percent water, and

(iii) about 5-40 weight percent DMSO, based on the total weight of the composition; and

(b) instructions for the use thereof.