Compositions and methods for treating central nervous system disorders

Abstract

The present invention provides compositions and methods for treating cognitive, social, or behavioral disorders, and neurodevelopmental disorders such as autism spectrum disorder (ASD), as well as other central nervous system disorders, such as fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), chronic fatigue syndrome (CFS), and post-traumatic stress syndrome (PTSD). The present invention provides compositions and methods for intranasal delivery (IN) of a therapeutically effective amount of an antipurinergic agent, such as suramin, to treat the disorder in a patient.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention provides compositions and methods for treating cognitive, social, or behavioral disorders, and neurodevelopmental disorders such as autism spectrum disorder (ASD), as well as other central nervous system disorders, such as fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), chronic fatigue syndrome (CFS), and post-traumatic stress syndrome (PTSD). The present invention provides compositions for delivering therapeutically effective amounts of antipurinergic agents, such as suramin, and pharmaceutically acceptable salts, esters, solvates, and prodrugs of these agents. The agents are delivered by intranasal (IN) administration. [Background technology]

[0002] Background of the Invention Autism is associated with a combination of genetic and environmental factors, and its incidence in the United States is reported to be approximately 1 in 60 children. Globally, approximately 25 million people are estimated to have autism. Autism is also known as autism spectrum disorder (ASD), due to the broad range of symptoms characterized by challenges with social skills, repetitive behaviors, speech, and nonverbal communication. In 2013, the American Psychiatric Association merged four distinct autism diagnoses into a single diagnosis: autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. Signs of autism typically appear by the age of 2 or 3. Autism spectrum disorder is a condition related to brain development that affects how a person perceives and interacts with others, leading to problems with social interaction and communication. The disorder may also include restrictive and repetitive behavioral patterns.

[0003] Research has shown that early intervention leads to positive outcomes. See Chaste P, Leboyer M (2012). "Autism risk factors: genes, environment, and gene-environment interactions." Dialogues in Clinical Neuroscience. 14(3):281-92. PMC 3513682. PMID 23226953; and Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report, Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014 Surveillance Summaries / April 27, 2018 / 67(6);1-23.

[0004] Currently, there is no cure for autism spectrum disorder, and no U.S. FDA-approved medications to treat the core symptoms. Instead, various medications, such as antipsychotics, are used to treat some of the associated non-core symptoms. Common symptoms include depression, seizures, anxiety, sleep disorders, and difficulty concentrating. Behavioral therapy and other pharmacological interventions are also used. However, the exact causes of autism are not fully understood, making the development of new medications difficult.

[0005] Fragile X syndrome (FXS) is a rare genetic neurodevelopmental disorder affecting approximately 1 in 4,000 men and women in the United States. It is associated with highly variable cognitive and behavioral symptoms and has many overlapping features with ASD. It is an X-linked disorder, meaning that a genetic mutation occurs on the X chromosome. In FXS, there is a trinucleotide repeat expansion in the FMR1 gene. A trinucleotide expansion is a specific type of genetic mutation in which a sequence of three nucleotide base pairs is inappropriately repeated multiple times. In FXS, the repeated trinucleotide sequence is cytosine-guanine-guanine (CGG). Typically, this DNA segment is repeated 5 to approximately 40 times. In individuals with FXS, this segment is repeated more than 200 times. This generally results in the absence of functional FMR1 mRNA transcripts and the protein normally encoded by these transcripts (Fragile X Mental Retardation Protein (FMRP)).

[0006] Fragile X-associated tremor / ataxia (FXTAS) is a distinct disorder from, but genetically related to, FXS. It is a rare, "adult-onset," inherited neurodegenerative disorder that typically affects men over the age of 50. Women make up a small proportion of the FXTAS population and tend to have milder symptoms. FXTAS affects the nervous system and progresses at different rates in different individuals.

[0007] While patients with FXS have a "full mutation" in the FMR1 gene (usually well over 200 CGG trinucleotide repeats), patients with FXTAS are considered "carriers" of a premutation in the FMR1 gene, with CGG trinucleotide repeats ranging from 55 to 200. The FMR1 gene's job is to make a protein (FMRP) that is important for brain development. Researchers believe (for unknown reasons) that the premutation causes overproduction of FMR1 mRNA (containing the expanded repeat). Researchers also suspect that high levels of mRNA may be responsible for the signs and symptoms of FXTAS, but more research is needed to confirm these hypotheses.

[0008] Patients with FXTAS typically experience symptoms after age 55. Premutation carriers, especially men, are more likely to experience symptoms as they age; this likelihood reaches 75% by age 75 for premutation men. Symptoms, including memory loss, slowed speech, tremor, and a shuffling gait, progress gradually, with interference with daily activities due to tremor and falls occurring approximately 10 years after the onset of the first symptoms. Dependence on a cane or walker occurs approximately 15 years after the first symptom of disability. Some individuals with FXTAS exhibit a gradual progression (i.e., symptoms plateau for a period of time, followed by a sudden worsening) in which symptoms worsen more rapidly with acute illness, major surgery, or other major daily stressors.

[0009] The prevalence of FXTAS is unknown, but current estimates suggest that in families where someone already has fragile X, approximately 30%–40% of male FMR1 premutation carriers over the age of 50 will eventually demonstrate some features of FXTAS. There is no FDA-approved treatment for FXTAS, and currently used treatments address only the symptomatic nature of the condition, rather than targeting the pathophysiology itself.

[0010] Antipurinergic drugs constitute a family of compounds that act on purinergic receptors. These receptors are the most abundant receptors in living organisms, emerged early in evolution, and are involved in regulating cellular function. Purinergic receptors are a specific class of membrane receptors that mediate various physiological functions, such as relaxation of certain types of smooth muscle, in response to the release of adenosine triphosphate (ATP) or adenosine. There are three distinct classes of purinergic receptors known as P1, P2X, and P2Y receptors. Purinergic signaling is a form of extracellular signaling. This signaling is mediated by purine nucleotides and nucleosides, such as adenosine and ATP. This signaling involves the activation of purinergic receptors within and / or nearby cells, thereby regulating cellular function.

[0011] Compounds that affect purinergic receptors are known. One of these is suramin, a compound first synthesized in the early 1900s. Suramin is a drug used to treat trypanosomiasis, a parasitic disease caused by the protozoan Trypanosoma brucei, more commonly known as African sleeping sickness. This drug is also used to treat river blindness. Because suramin is not orally bioavailable, it is administered by intravenous injection. However, at the doses required to treat African sleeping sickness, suramin causes numerous side effects. These include nausea, vomiting, diarrhea, abdominal pain, and general discomfort. Other side effects include skin sensations such as formication or tingling, tenderness in the palms and soles, numbness in the extremities, watery eyes, and photophobia. Furthermore, nephrotoxicity is common, as is peripheral neuropathy when the drug is administered at high doses. Regarding pharmacokinetics, suramin is approximately 99–98% protein-bound in serum, with a half-life ranging from 41–78 days, with an average of 50 days. Suramin is not extensively metabolized and is eliminated by the kidney. Therefore, to more effectively treat conditions such as autism spectrum disorder, FXS, or FXTAS, it would be desirable to minimize systemic concentrations of suramin using targeted delivery to brain tissue. Recently, suramin has been reported to affect several multisystem abnormalities in mouse models of autism spectrum disorder. A small human trial was also conducted in boys diagnosed with autism spectrum disorder. See "Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model," Robert K. Naviaux, PLoS One. 2013;8(3):e57380, published online March 13, 2013. doi:10.1371 / journal.pone.0057380, PMCID: PMC3596371, PMID: 23516405. See also PCT Patent Application Publication No. WO2018 / 148580A1 to Vaughn et al., published August 16, 2018. See also Naviaux, RK et al., “Low-dose suramin in autism spectrum disorder: a small, phase I / II, randomized clinical trial,” Annals of Clinical and Translational Neurology, 2017 May 26:4(7):491-505. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2018 / 148580A1 [Non-patent literature]

[0013] [Non-Patent Document 1] Chaste P, Leboyer M (2012). “Autism risk factors: genes, environment, and gene-environment interactions”. Dialogues in Clinical Neuroscience.14(3):281-92.PMC 3513682.PMID 23226953 [Non-patent document 2] Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report,Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years-Autism and Developmental Disabilities Monitoring Network,11 Sites,United States,2014 Surveillance Summaries / April 27,2018 / 67(6);1-23 [Non-patent document 3] Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC)Mouse Model Robert K. Naviaux, PLoS One.2013;8(3):e57380, published online March 13, 2013. doi:10.1371 / journal.pone.0057380, PMCID:PMC3596371,PMID:23516405 [Non-patent document 4] Naviaux, RK et al., ``Low-dose suramin in autism spectrum disorder: a small, phase I / II, randomized clinical trial'', Annals of Clinical and Translational Neurology, May 26, 2017: 4(7): 491-505 Summary of the Invention [Means for solving the problem]

[0014] From the foregoing, it is clear that the treatment of autism spectrum disorders remains challenging. Despite promising results from early animal and human studies, it is recognized that much research remains necessary to provide safe and effective delivery of antipurinergic drugs such as suramin for the treatment of autism. What is needed is to deliver appropriate concentrations of the drug to brain tissue while minimizing concentrations in the blood and other tissues. However, delivering drugs across the blood-brain barrier (BBB), a natural protective mechanism in most mammals, including humans, is challenging. The BBB is a highly selective, semipermeable barrier of endothelial cells that prevents solutes in circulating blood from nonselectively crossing into the extracellular fluid of the central nervous system, where neurons reside. Such delivery across the BBB is even more challenging for compounds with high molecular weights. The molecular weight of suramin is approximately 1300 g / mol. One route that attempts to maximize delivery across the BBB is to use intranasal delivery to provide higher drug concentrations at the nasal mucosa, with the goal of placing the drug in the bloodstream in close proximity to the brain. Surprisingly, the present invention has found that the use of certain penetration enhancers may enable the safe and effective intranasal administration of suramin, an antipurinergic drug, to achieve appropriate drug concentrations in brain tissue. Specifically, it has been surprisingly found that penetration enhancers such as methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol are particularly useful for preparing intranasal suramin formulations with improved mucosal tissue penetration. These compositions also have the unexpected advantage of targeting brain tissue while minimizing the systemic blood concentration of suramin active drug. Therefore, these compositions may be useful for treating neurodevelopmental conditions, including but not limited to autism spectrum disorder, FXS, FXTAS, chronic fatigue syndrome (CFS), and post-traumatic stress syndrome (PTSD).

[0015] Summary of the Invention Methods and compositions for the treatment of cognitive, social, or behavioral disorders and neurodevelopmental disorders, such as autism spectrum disorder, FSX, FXTAS, CFS, and PTSD, are described. More specifically, the present invention provides compositions for intranasal administration, i.e., delivery via the nasal route, comprising a therapeutically effective amount of an antipurinergic agent, such as suramin, and its pharmaceutically acceptable salts, esters, solvates, and prodrugs. Examples of useful compositions include compositions for intranasal administration comprising a therapeutically effective amount of suramin or its pharmaceutically acceptable salts, esters, solvates, or prodrugs, a pharmaceutically acceptable carrier, and a penetration aid for delivering a therapeutically effective concentration of the suramin active agent to the brain to treat autism spectrum disorder. These compositions are believed to target brain tissue while minimizing systemic concentrations of suramin, thereby helping to minimize potential drug toxicity and unwanted side effects.

[0016] The present invention is based on the surprising discovery that transmucosal permeation of suramin, as measured in in vitro assays, was significantly higher when delivered from formulations containing various permeation enhancers, such as methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol. The compositions of the present invention were found to be effective in delivering suramin to brain tissue when administered to mice, and a brain tissue / plasma partition ratio was demonstrated. These compositions are designed to deliver suramin active agent across the blood-brain barrier to brain tissue while minimizing systemic concentrations to less than about 3 micromolar in plasma and less than about 0.5 micromolar.

[0017] The methods of the present invention can be accomplished by methods involving the intranasal administration of a single dose of an antipurinergic agent, or multiple doses can be administered according to various treatment regimens.

[0018] Also provided herein is a device for patient or self-administration of an antipurinergic agent, comprising a nasal spray inhaler containing an aerosol spray composition of the antipurinergic agent. The composition may comprise an antipurinergic agent and a pharmaceutically acceptable dispersant or solvent system, and the device is designed (or metered) to dispense a metered amount of the aerosol formulation by forming a spray containing a dose of the antipurinergic agent. In other embodiments, the inhaler may contain the antipurinergic agent as a fine powder, in combination with a particulate dispersant and diluent, or for incorporation within particles of the dispersant or coating a particulate dispersant.

[0019] The present invention provides a method for treating a cognitive, social, or behavioral disorder comprising intranasally delivering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

[0020] In another aspect, the invention provides a method wherein the patient is a human.

[0021] In another aspect, the invention provides a method, wherein the cognitive, social, or behavioral disorder or neurodevelopmental disorder is selected from autism spectrum disorder, FSX, FXTAS, CFS, and PTSD.

[0022] In another aspect, the invention provides a method wherein the cognitive, social, or behavioral disorder or neurodevelopmental disorder is an autism spectrum disorder.

[0023] In another aspect, the invention provides a method wherein the cognitive, social, or behavioral disorder or neurodevelopmental disorder is FSX.

[0024] In another aspect, the invention provides a method wherein the cognitive, social, or behavioral disorder or neurodevelopmental disorder is FXTAS.

[0025] In another aspect, the invention provides a method wherein the cognitive, social, or behavioral disorder or neurodevelopmental disorder is CFS.

[0026] In another aspect, the invention provides a method wherein the cognitive, social, or behavioral disorder or neurodevelopmental disorder is PTSD.

[0027] In another aspect, the present invention provides a method, wherein said antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.

[0028] In another aspect, the present invention provides a method wherein the pharmaceutically acceptable salt is selected from alkali metal salts, alkaline earth metal salts, and ammonium salts.

[0029] In another aspect, the invention provides a method wherein the salt is a sodium salt.

[0030] In another embodiment, the invention provides a method wherein the salt is a hexasodium salt.

[0031] In another aspect, the present invention provides a method wherein the composition is an aqueous composition.

[0032] In another aspect, the invention provides a method wherein the composition further comprises a permeation enhancer.

[0033] In another aspect, the present invention provides a method, wherein the permeation enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof.

[0034] In another aspect, the invention provides a method wherein the permeation enhancer is methyl β-cyclodextrin.

[0035] In another embodiment, the invention provides a method wherein the permeation enhancer is caprylocaproyl macrogol-8 glyceride.

[0036] In another embodiment, the invention provides a method wherein the permeation enhancer is 2-(2-ethoxyethoxy)ethanol.

[0037] In another embodiment, the invention provides a method wherein the composition is administered at least once daily.

[0038] In another embodiment, the invention provides a method wherein the composition is delivered, i.e., dosed, at least twice daily.

[0039] In another embodiment, the invention provides a method wherein the composition is delivered, i.e., dosed, at least twice a week.

[0040] In another embodiment, the invention provides a method wherein the composition is delivered, i.e., dosed, at least once a week.

[0041] In another embodiment, the invention provides a method wherein the composition is delivered, i.e., dosed, at least once every two weeks.

[0042] In another embodiment, the invention provides a method wherein the composition is delivered, i.e., dosed, at least once a month, or at least once every four weeks.

[0043] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least once every about 41 to about 78 days.

[0044] In another embodiment, the invention provides a method wherein the composition is delivered, i.e., administered, at least once every 50 days.

[0045] In another embodiment, the invention provides a method wherein the composition is delivered, ie, dosed, at least once per interval based on the average half-life of suramin.

[0046] In another aspect, the present invention provides methods and compositions wherein the amount of suramin is based on the suramin active ingredient (ie, chemical entity) using a molecular weight (ie, molar mass) of 1297.26 grams / mole.

[0047] In another embodiment, the invention provides a method in which the plasma concentration of suramin in a patient is maintained at less than about 3 micromolar (μM) based on the suramin active agent.

[0048] In another embodiment, the invention provides a method in which the plasma concentration of suramin is maintained at less than about 2.75 micromolar based on the suramin active agent.

[0049] In another embodiment, the invention provides a method in which the plasma concentration of suramin is maintained at less than about 2.5 micromolar based on the suramin active agent.

[0050] In another embodiment, the invention provides a method in which the plasma concentration of suramin is maintained at less than about 2 micromolar based on the suramin active agent.

[0051] In another embodiment, the invention provides a method in which the plasma concentration of suramin is maintained at less than about 1 micromolar based on the suramin active agent.

[0052] In another embodiment, the invention provides a method in which the plasma concentration of suramin is maintained at less than about 0.5 micromolar based on the suramin active agent.

[0053] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is from about 1 ng / ml to about 1000 ng / ml.

[0054] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is at least about 1 ng / ml.

[0055] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is at least about 10 ng / ml.

[0056] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is at least about 50 ng / ml.

[0057] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is at least about 100 ng / ml.

[0058] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is at least about 250 ng / ml.

[0059] In another embodiment, the invention provides a method wherein the concentration of suramin in brain tissue is at least about 500 ng / ml. In another embodiment, the invention provides a method wherein the brain tissue / plasma partition ratio is at least about 0.05.

[0060] In another embodiment, the invention provides a method wherein the brain tissue / plasma partition ratio is at least about 0.1.

[0061] In another embodiment, the invention provides a method wherein the brain tissue / plasma partition ratio is at least about 0.25.

[0062] In another embodiment, the invention provides a method wherein the brain tissue / plasma partition ratio is at least about 0.50.

[0063] In another embodiment, the invention provides a method wherein the composition comprises from about 0.01 mg to about 200 mg of suramin per unit dose, based on the suramin active agent.

[0064] In another embodiment, the invention provides a method wherein the composition comprises from about 0.01 mg to about 100 mg of suramin per unit dose, based on the suramin active agent.

[0065] In another embodiment, the invention provides a method wherein the composition comprises from about 0.01 mg to about 50 mg of suramin per unit dose, based on the suramin active agent.

[0066] In another embodiment, the invention provides a method wherein the composition comprises from about 0.01 mg to about 25 mg of suramin per unit dose, based on the suramin active agent.

[0067] In another embodiment, the invention provides a method wherein the composition comprises from about 0.01 mg to about 10 mg of suramin per unit dose, based on the suramin active agent.

[0068] In another embodiment, the invention provides a method, wherein the composition comprises about 0.1 mg / kg to about 20 mg / kg of suramin per week based on the suramin active agent and patient weight.

[0069] In another embodiment, the invention provides a method wherein the composition comprises about 0.025 mg / kg to about 10 mg / kg of suramin per unit dose based on the suramin active agent and patient weight.

[0070] In another embodiment, the invention provides a method wherein the composition comprises about 0.05 mg / kg to about 6 mg / kg of suramin per unit dose based on the suramin active agent and patient weight.

[0071] In another embodiment, the invention provides a method, wherein the composition comprises about 0.0476 mg / kg to about 5.720 mg / kg of suramin per unit dose, based on the suramin active agent and patient weight (mass).

[0072] In another embodiment, the invention provides a method wherein the composition comprises less than about 1 mg / kg of suramin per unit dose, based on the suramin active agent and patient weight.

[0073] In another embodiment, the invention provides a method wherein the composition comprises less than about 0.5 mg / kg of suramin per unit dose, based on the suramin active agent and patient weight.

[0074] In another embodiment, the invention provides a method wherein the composition comprises less than about 0.25 mg / kg of suramin per unit dose, based on the suramin active agent and patient weight.

[0075] In another embodiment, the invention provides a method wherein the composition comprises less than about 0.1 mg / kg of suramin per unit dose, based on the suramin active agent and patient weight.

[0076] In another embodiment, the present invention provides a composition comprising a suramin active agent and a patient body surface area (BSA)-based dose of about 400 mg / m per unit dose. 2 The present invention provides a method comprising administering less than 100 mg of suramin to a subject.

[0077] In another embodiment, the present invention provides a composition comprising a suramin active agent and a suramin-containing composition comprising a suramin-containing composition and a suramin-containing composition, the ... 2 The present invention provides a method comprising administering less than 100 mg of suramin to a subject.

[0078] In another embodiment, the present invention provides a composition comprising a suramin active agent and a suramin-containing composition comprising a suramin-containing composition and a suramin-containing composition, the ... 2 The present invention provides a method comprising administering less than 100 mg of suramin to a subject.

[0079] In another embodiment, the present invention provides a composition comprising a suramin active agent and a suramin-containing ... 2 The present invention provides a method comprising administering less than 100 mg of suramin to a subject.

[0080] In another embodiment, the present invention provides a composition comprising a suramin active agent and a suramin-containing ... 2 The present invention provides a method comprising administering less than 100 mg of suramin to a subject.

[0081] In another embodiment, the present invention provides a composition comprising a suramin active agent and a suramin-containing ... 2 ~about 300mg / m 2 The present invention provides a method comprising administering suramin to a subject.

[0082] In another embodiment, the present invention provides a method for administering to a patient a suramin active agent having an AUC of about 80 μg *Provide a method that is less than day / L.

[0083] In another embodiment, the present invention provides a method for administering to a patient a suramin active agent having an AUC of about 75 μg * Provide a method that is less than day / L.

[0084] In another embodiment, the present invention provides a method for administering to a patient a suramin active agent having an AUC of about 50 μg * Provide a method that is less than day / L.

[0085] In another embodiment, the present invention provides a method for administering to a patient a suramin active agent having an AUC of about 25 μg * Provide a method that is less than day / L.

[0086] In another embodiment, the present invention provides a method for administering to a patient a suramin active agent having an AUC of about 10 μg * Provide a method that is less than day / L.

[0087] In another aspect, the present invention provides a method for administering to a patient a suramin active agent C max is less than about 75 micromolar per dose of the drug composition.

[0088] In another aspect, the present invention provides a method for administering to a patient a suramin active agent C max is less than about 7.5 micromolar per dose of the drug composition.

[0089] In another aspect, the present invention provides a method for determining the C plasma concentration of suramin that is active in a patient. max is less than about 0.1 micromolar. max Although not present, the amount may generally be about 0.01 micromolar or greater per dose of the drug composition.

[0090] In another aspect, the present invention provides a method wherein the composition is in the form of a nasal spray, i.e., a spray for intranasal administration.

[0091] In another embodiment, the invention provides a method wherein each unit dose comprises from about 0.01 ml to about 0.5 ml of liquid.

[0092] In another embodiment, the invention provides a method wherein each unit dose comprises about 0.1 ml of liquid.

[0093] In another aspect, the present invention provides a method for administering a composition to a subject, comprising administering to a subject a suramin active substance in a concentration of about 1 microgram / cm per hour through cultured human airway tissue. 2 ~About 200 micrograms / cm per hour 2 The present invention provides a method for indicating or being able to provide a permeation rate of suramin of 1000 ppm or more.

[0094] In another aspect, the invention provides a method wherein the composition further comprises an agent selected for osmolality regulation.

[0095] In another aspect, the invention provides a method wherein the composition further comprises an agent selected for osmolality regulation, said agent being selected from salts, such as, for example, sodium chloride.

[0096] In another aspect, the present invention provides a method wherein the composition further comprises a thickener.

[0097] In another aspect, the invention provides a method, wherein said autism spectrum disorder is selected from the group consisting of autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome.

[0098] In another aspect, the invention provides a method, wherein said autism spectrum disorder comprises one or more symptoms selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0099] In another aspect, the invention provides a method wherein treating said autism spectrum disorder, FXS, FXTAS, CFS or PTSD comprises ameliorating one or more symptoms compared to said patient's symptoms before said administration, and said one or more symptoms are selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0100] In another aspect, the invention provides a method, wherein treating said autism spectrum disorder, FXS, FXTAS, CFS or PTSD comprises improving said patient's assessment score compared to said patient's score before said administration.

[0101] In another aspect, the invention provides a method wherein said patient's assessment score improves by 10% or more compared to said patient's score prior to said administering.

[0102] In another aspect, the invention provides a method, wherein the assessment score is selected from ABC, ADOS, ATEC, CARS CGI, and SRS.

[0103] In another aspect, the invention provides a method in which a patient's ADOS score improves by 1.6 or more compared to said pre-administration score, or corresponding performance on a similar test improves.

[0104] In another embodiment, the invention provides a method wherein said improvement in ADOS score or similar test has a p-value of 0.05 or less.

[0105] In another embodiment, the invention provides a method wherein the effect size of improvement in said ADOS score or similar test is about 1 or greater.

[0106] In another embodiment, the invention provides a method, wherein the effect size of improvement in said ADOS score or similar test is about 2.9 or greater.

[0107] In another aspect, the present invention provides a method for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD, comprising administering to a human being in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein the plasma concentration of the antipurinergic agent is maintained at less than about 3 micromolar, or less than about 1 micromolar, or less than about 0.5 micromolar.

[0108] In another aspect, the present invention provides an intranasal delivery pharmaceutical composition for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD, comprising: (a) a therapeutically effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, and (b) Permeation enhancers.

[0109] In another aspect, the present invention provides a composition further comprising (c) water.

[0110] In another aspect, the present invention provides a composition wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.

[0111] In another aspect, the present invention provides a composition, wherein when the composition is administered to a human in need thereof, the plasma concentration of suramin is maintained at less than about 3 micromolar based on the suramin active agent.

[0112] In another aspect, the present invention provides a composition wherein, when the composition is administered to a human in need thereof, the plasma concentration of suramin is maintained at less than about 1 micromolar, or less than about 0.5 micromolar, based on the suramin active agent.

[0113] In another aspect, the present invention provides the use of suramin, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, in the manufacture of a medicament for intranasal delivery of a therapeutically effective amount of suramin to treat autism spectrum disorder, FXS, FXTAS, CFS or PTSD in a patient, e.g., a human, in need of such treatment.

[0114] In another embodiment, the invention provides uses wherein the plasma concentration of suramin is maintained at less than about 3 micromolar, or less than about 1 micromolar, or less than about 0.5 micromolar based on the suramin active agent.

[0115] In another aspect, the present invention provides a device for administration to a patient, including administration selected from self-administration and administration to a patient by an individual other than the patient, comprising a nasal spray inhaler for administering a composition comprising an antipurinergic, the device being designed (or alternatively metered) to dispense a measured amount of the antipurinergic to treat autism spectrum disorder, FXS, FXTAS, CFS or PTSD in a patient in need of treatment.

[0116] In another aspect, the invention provides a device comprising a composition in which the antipurinergic agent is selected from a solution, emulsion, or powder.

[0117] These and other aspects of the present invention will become apparent from the disclosure herein. In an embodiment of the present invention, for example, the following items are provided: (Item 1) A method for treating cognitive, social, or behavioral disorders and neurodevelopmental disorders, comprising intranasally delivering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof. (Item 2) Item 10. The method of item 1, wherein the patient is a human. (Item 3) 3. The method of claim 2, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is selected from autism spectrum disorder, FSX, FXTAS, CFS, and PTSD. (Item 4) 4. The method of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is an autism spectrum disorder. (Item 5) 4. The method of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is FSX. (Item 6) 4. The method of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is FXTAS. (Item 7) 4. The method of item 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is CFS. (Item 8) 4. The method of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is PTSD. (Item 9) 5. The method of item 4, wherein the autism spectrum disorder is selected from the group consisting of autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome. (Item 10) 5. The method of claim 4, wherein the autism spectrum disorder comprises one or more symptoms selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors. (Item 11) 2. The method of claim 1, wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof. (Item 12) Item 12. The method according to item 11, wherein the pharmaceutically acceptable salt is selected from alkali metal salts, alkaline earth metal salts, and ammonium salts. (Item 13) 13. The method of claim 12, wherein the salt is a sodium salt. (Item 14) 13. The method of claim 12, wherein the salt is a hexasodium salt. (Item 15) Item 10. The method of claim 1, wherein the composition is an aqueous composition. (Item 16) Item 10. The method of claim 1, wherein the composition is a powdered composition. (Item 17) 16. The method of claim 15, wherein the composition further comprises a permeation enhancer. (Item 18) 18. The method of claim 17, wherein the permeation enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof. (Item 19) 19. The method of claim 18, wherein the permeation enhancer is methyl β-cyclodextrin. (Item 20) 19. The method of claim 18, wherein the permeation enhancer is caprylocaproyl macrogol-8 glyceride. (Item 21) 19. The method of claim 18, wherein the permeation enhancer is 2-(2-ethoxyethoxy)ethanol. (Item 22) 10. The method of claim 1, wherein the composition is administered, i.e., dosed, at least once a day, or at least twice a day, or at least once a week, or at least twice a week, or at least every other week (i.e., once every two weeks), or at least once a month, or at least once every four weeks. (Item 23) Item 10. The method of item 1, wherein the composition is delivered, i.e., administered, at least once every about 41 to about 78 days. (Item 24) 10. The method of claim 1, wherein the composition is delivered, i.e., administered, at least once every 50 days. (Item 25) 10. The method of claim 1, wherein the composition is delivered, i.e., dosed, at least once per time interval based on the average half-life of suramin. (Item 26) 10. The method of claim 1, wherein the patient's plasma concentration of suramin is maintained at less than about 3 micromolar (μM), or less than about 2.75 micromolar, or less than about 2.5 micromolar, or less than about 2 micromolar, or less than about 1 micromolar, or less than about 0.5 micromolar, based on the suramin active substance. (Item 27) Item 2. The method according to Item 1, wherein the patient has a suramin concentration in brain tissue of about 1 ng / ml to about 1000 ng / ml. (Item 28) 2. The method of claim 1, wherein the patient has a brain tissue concentration of suramin of at least about 1 ng / ml, or at least about 10 ng / ml, or at least about 50 ng / ml, or at least about 100 ng / ml, or at least about 250 ng / ml, or at least about 500 ng / ml. (Item 29) 2. The method of claim 1, wherein the brain tissue / plasma partition ratio of suramin is at least about 0.05, or at least about 0.1, or at least about 0.25, or at least about 0.50. (Item 30) 2. The method according to item 1, wherein the composition contains about 0.01 mg to about 200 mg of suramin per unit dose, based on the suramin active substance. (Item 31) Item 1. The method according to item 1, wherein the composition comprises, based on the suramin active substance, about 0.01 mg to about 100 mg, or about 0.01 mg to about 50 mg of suramin per unit dose, or about 0.01 mg to about 25 mg of suramin per unit dose, or about 0.01 mg to about 10 mg of suramin per unit dose. (Item 32) 2. The method of claim 1, wherein the composition comprises a suramin active agent and about 0.1 mg / kg per week to about 20 mg / kg per week of suramin based on the patient's body weight. (Item 33) 2. The method of claim 1, wherein the composition comprises a suramin active agent and about 0.025 mg / kg to about 10 mg / kg of suramin per unit dose or about 0.05 mg / kg to about 6 mg / kg of suramin per unit dose, based on the patient's body weight (mass). (Item 34) 2. The method of claim 1, wherein the composition comprises a suramin active agent and about 0.0476 mg / kg to about 5.720 mg / kg of suramin per unit dose based on the patient's body weight (mass). (Item 35) 10. The method of claim 1, wherein the composition comprises a suramin active agent and less than about 1 mg / kg of suramin per unit dose, or less than about 0.5 mg / kg of suramin per unit dose, or less than about 0.25 mg / kg of suramin per unit dose, or less than about 0.1 mg / kg of suramin per unit dose, based on the patient's body weight (mass). (Item 36) The composition has a dosage of about 400 mg / m based on the suramin active agent and the patient's body surface area (BSA). 2 less than suramin, or approximately 200 mg / m per unit dose 2 less than suramin, or about 100 mg / m per unit dose 2 less than suramin, or about 50 mg / m per unit dose 2 less than suramin, or about 25 mg / m per unit dose 2 2. The method of claim 1, comprising less than 100 mg of suramin. (Item 37) The composition has a dosage of about 10 mg / m based on the suramin active agent and the patient's body surface area (BSA). 2 ~about 300mg / m 2 2. The method according to item 1, comprising administering to a subject a suramin comprising: (Item 38) The AUC of the plasma concentration of the active substance of suramin in the patient is about 80 μg * day / L or less or approximately 75 μg * day / L or less or approximately 50 μg * day / L or less or approximately 25 μg * day / L or less than 10 μg * The method according to item 1, wherein the saturation of the blood glucose level is less than 100 mg / L. (Item 39) C of plasma concentration of suramin active substance for said patient max is less than about 75 micromolar, or less than about 7.5 micromolar, or less than about 0.1 micromolar, and optionally at least about 0.01 micromolar, based on a single dose. (Item 40) 2. The method according to item 1, wherein the composition is in the form of a nasal spray, i.e., a spray for intranasal administration. (Item 41) 2. The method of claim 1, wherein the composition is in the form of a unit dose, the unit dose comprising from about 0.01 ml to about 0.5 ml of liquid. (Item 42) 42. The method of claim 41, wherein the unit dose comprises about 0.1 ml of liquid. (Item 43) The composition delivers suramin active substance-based suramin through cultured human airway tissue at a rate of about 1 microgram / cm per hour. 2 ~About 200 micrograms / cm per hour 2 2. The method according to item 1, wherein the method indicates, i.e., is capable of providing, a permeation rate of suramin of 1000 ppm or more. (Item 44) 10. The method of claim 1, wherein the composition further comprises an agent selected for osmolality regulation. (Item 45) 45. The method according to item 44, wherein the agent selected for osmolality control is selected from salts such as sodium chloride. (Item 46) Item 10. The method of claim 1, wherein the composition further comprises a thickener. (Item 47) 2. The method of claim 1, wherein treating the autism spectrum disorder, FXS, or FXTAS comprises improving one or more symptoms compared to the patient's symptoms before administering, and the one or more symptoms are selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors. (Item 48) 2. The method of claim 1, wherein treating the autism spectrum disorder, FXS, or FXTAS comprises improving the patient's assessment score compared to the patient's score before the administration. (Item 49) 49. The method of claim 48, wherein the patient's assessment score improves by 10% or more compared to the patient's score before the administration. (Item 50) Item 49. The method of item 48, wherein the assessment score is selected from ABC, ADOS, ATEC, CARS CGI, and SRS. (Item 51) 51. The method of claim 50, wherein the patient's ADOS score or similar test improves by 1.6 or more compared to the score before administration, or the corresponding performance on a similar test improves. (Item 52) 51. The method of item 50, wherein the improvement in ADOS score or similar test has a p-value of 0.05 or less. (Item 53) 51. The method of item 50, wherein the size effect of improvement in the ADOS score or similar test is about 1 or greater or about 2.9 or greater. (Item 54) 1. A pharmaceutical composition for intranasal delivery for treating autism spectrum disorder, FXS, or FXTAS, comprising: (a) a therapeutically effective amount of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, and (b) Permeation enhancer A pharmaceutical composition comprising: (Item 55) (c) The composition according to item 54, further comprising water. (Item 56) 55. The composition of claim 54, wherein the antipurinergic is suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof. (Item 57) 56. The composition of claim 55, wherein the antipurinergic is suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof. (Item 58) Item 58. The composition according to Item 57, wherein the concentration of the suramin is about 10 mg / ml to about 200 mg / ml, the concentration of the permeation enhancer is about 25% to about 50%, or about 40% by weight, and water is used in an appropriate amount. (Item 59) 59. The method of claim 58, wherein the permeation enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof. (Item 60) 60. The method of claim 59, wherein the permeation enhancer is methyl β-cyclodextrin, or caprylocaproyl macrogol-8 glyceride, or 2-(2-ethoxyethoxy)ethanol. (Item 61) 57. The composition of claim 56, wherein when the composition is administered to a human in need thereof, the plasma concentration of the suramin in the patient is maintained at less than about 3 micromolar, or less than about 1 micromolar, or less than about 0.5 micromolar, based on the suramin active substance. (Item 62) Use of an antipurinergic agent, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, in the manufacture of a medicament for intranasal delivery of a therapeutically effective amount of suramin for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD in a patient, e.g., a human, in need thereof. (Item 63) 63. The use of item 62, wherein the antipurinergic is suramin, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof. (Item 64) 64. The use of item 63, wherein the plasma concentration of suramin is maintained at less than about 3 micromolar, or less than about 1 micromolar, or less than about 0.5 micromolar based on the suramin active substance. (Item 65) 1. A device for administration to a patient, including administration selected from self-administration and administration to said patient by an individual other than the patient, comprising a nasal spray inhaler for administering a composition comprising an antipurinergic agent, said device being designed to dispense a measured amount of said antipurinergic agent to treat autism spectrum disorder, FXS, FXTAS, CFS or PTSD in a patient in need of treatment. (Item 66) 66. The device of claim 65, wherein the antipurinergic agent comprises a composition selected from a solution, an emulsion, or a powder. [Brief explanation of the drawings]

[0118] [Figure 1] FIG. 1 shows a plot of cumulative drug permeation (mg) versus time (hours) for aqueous suramin compositions containing three different permeation enhancers and a control composition containing no permeation enhancer.

[0119] [Figure 2] FIG. 2 shows a plot of cumulative drug permeation (mg) versus time (hours) for aqueous suramin compositions containing five different permeation enhancers and a control composition containing no permeation enhancer.

[0120] [Figure 3]Figure 3 shows plots of the total concentration of suramin (ng / ml) in mouse plasma and brain tissue when mice were given weekly intraperitoneal (IP) injections of 20 mg / kg for four consecutive weeks starting at 9 weeks of age (i.e., at 9, 10, 11, and 12 weeks of age).

[0121] [Figure 4] Figure 4 shows a plot comparing the total concentration of suramin (ng / ml) in mouse plasma and brain tissue when administered intranasally (IN) daily for 28 days. The IN suramin-containing composition of the invention was administered at a concentration of 100 mg / mL x 6 mL per spray, once daily, one spray per nostril (with approximately 2 minutes between applications to ensure absorption), for 28 days (56 sprays total over 28 days) starting at 9 weeks of age (i.e., daily administration during weeks 9, 10, 11, and 12 of age).

[0122] [Figure 5] Figure 5 shows a plot comparing the total concentration of suramin (ng / ml) in mouse plasma and brain tissue when administered intranasally (IN) every other day for 28 days. The composition of the invention containing IN suramin was administered at a concentration of 100 mg / mL x 6 mL per spray, as one spray per nostril every other day (with approximately 2 minutes between each application to ensure absorption), for 28 days (a total of 28 sprays over 28 days) starting at 9 weeks of age (i.e., daily administration during weeks 9, 10, 11, and 12 of age).

[0123] [Figure 6] Figure 6 shows a plot comparing the total concentration (ng / ml) of suramin in mouse plasma and brain tissue when administered intranasally (IN) once weekly for four weeks. The composition of the invention containing IN suramin was administered at a concentration of 100 mg / mL x 6 mL per spray, once weekly as one spray per nostril (with approximately two minutes between applications to ensure absorption), for four weeks (28 days) (a total of eight sprays over the 28 days) starting at nine weeks of age (i.e., daily administration at 9, 10, 11, and 12 weeks of age).

[0124] [Figure 7] Figure 7 shows a plot comparing the total percentage of suramin in the plasma of mice given intraperitoneal (IP) injections once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every two days for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0125] [Figure 8] Figure 8 shows a plot comparing the total percentage of suramin in brain tissue of mice given intraperitoneal (IP) injections once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every two days for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0126] [Figure 9] Figure 9 shows a plot comparing the total percentage of suramin in the plasma and brain tissue of mice given intraperitoneal (IP) injections once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every two days for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0127] [Figure 10] FIG. 10 shows a plot comparing the brain tissue and plasma distribution ratios of suramin in mice administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days). DETAILED DESCRIPTION OF THE INVENTION

[0128] definition As used herein, the following terms and abbreviations have the meanings indicated unless expressly stated to the contrary.

[0129] The term "ABC" as used herein refers to a rating scale for assessing autism known as the "Aberrant Behavior Checklist."

[0130] As used herein, the term "ADOS," also known as the "Autism Diagnostic Observation Schedule," is an instrument for diagnosing and assessing autism. The protocol consists of a series of structured and semi-structured tasks that involve social interaction between the examiner and the person being assessed.

[0131] As used herein, the term "ATEC," also known as the "Autism Treatment Evaluation Scale," is a 77-item diagnostic assessment tool developed at the Autism Research Institute. The ATEC was originally designed to evaluate the effectiveness of autism treatments, but is also used as a screening tool.

[0132] The term "AUC" as used herein, also known as "area under the curve," is a standard term in pharmacology, particularly pharmacokinetics. This term refers to the definite integral of the curve that describes the change in plasma drug concentration as a function of time. In practice, drug concentrations are measured at specific, discrete time points, and the trapezoidal rule is used to estimate the AUC. The AUC provides a measure of bioavailability and refers to the fraction of drug absorbed systemically. Knowing this, drug clearance can also be determined. The AUC reflects the actual body exposure to a drug after administration of a dose of the drug, usually expressed in mg. * h / L or μg * It is expressed in h / L (where "h" stands for time). Alternatively, AUC is expressed in mg * day / L or μg * It can be expressed as days / L.

[0133] As used herein, the term "based on suramin active substance" is meant to provide a basis for determining or calculating the amount of suramin based on the molecular weight (i.e., molar mass) of suramin of 1297.26 grams / mole. This is an important consideration for determining the amount of suramin when it is delivered as a salt or other form with a different total molecular weight, such as the hexasodium salt, which has a molecular weight (i.e., molar mass) of 1429.15 grams / mole.

[0134] As used herein, the term "CARS" is a behavioral rating scale, also known as the "Childhood Autism Rating Scale," intended to aid in the diagnosis and assessment of autism.

[0135] As used herein, the term "CFS" is also known as "chronic fatigue syndrome."

[0136] As used herein, the term "CGI" is also known as the "Clinical Global Impression" rating scale, and is a measure of symptom severity, treatment response, and treatment effectiveness in treatment studies of patients with psychological disorders.

[0137] As used herein, "C max The term "maximum (or peak) serum concentration" is a standard term in pharmacology, particularly pharmacokinetics, to define the maximum (or peak) serum concentration that a drug achieves in a particular compartment or test area of ​​the body after the drug is administered and before a second dose is administered.

[0138] As used herein, the term "FXS" means Fragile X Syndrome.

[0139] As used herein, the term "FXTAS" means Fragile X-associated tremor / ataxia syndrome.

[0140] As used herein, the term "IN" means intranasal.

[0141] The term "pharmaceutically acceptable" is used herein with respect to the compositions, i.e., formulations, of the present invention, and with respect to pharmaceutically acceptable salts, esters, solvates, and prodrugs of suramin. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of suramin and a pharmaceutically acceptable carrier. These carriers can include a wide variety of excipients. Pharmaceutically acceptable carriers are conventionally known carriers with an acceptable safety profile. The compositions are made using conventional formulation techniques. See, for example, Remington's Pharmaceutical Sciences, 17 th See, "Pharmaceutically Acceptable Salts," 17th edition, edited by Alfonso R. Gennaro, Mack Publishing Company, Easton, PA, 17th edition, 1985. With regard to pharmaceutically acceptable salts, these are described below.

[0142] As used herein, the term "PTSD" is also known as "post-traumatic stress syndrome."

[0143] As used herein, the term "SRS," also known as the "Social Responsiveness Scale," is a measure of autism spectrum disorder.

[0144] The term "subject" means a human patient or animal in need of treatment or intervention for an autism spectrum disorder.

[0145] The term "therapeutically effective" refers to the amount of suramin required to provide a meaningful or demonstrable benefit, as understood by a physician, to a subject, such as a human patient, in need of treatment. Conditions targeted for treatment include, for example, autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome. For example, meaningful or demonstrable benefit can be assessed or quantified using various clinical parameters. Demonstration of benefit can include, but is not limited to, that provided by models, including in vitro models, in vivo models, and animal models. An example of such an in vitro model is the permeation of active drugs tested using cultured human airway tissue (EpiAirway AIR-100) to simulate permeation through the nasal mucosa.

[0146] The term "intranasal" ("IN"), as used herein with respect to pharmaceutical compositions and active substances therein, refers to compositions administered through the nose for delivery across the mucous membranes within the nasal cavity. This membrane is a thin, well-vascularized membrane. Furthermore, this membrane is in close proximity to the brain, providing a means for maximizing drug transport across the blood-brain barrier (BBB). The BBB is a highly selective, semipermeable barrier that separates circulating blood from the brain from the extracellular fluid of the central nervous system. Delivering therapeutic agents to specific regions of the brain presents challenges in the treatment of many brain disorders. It should be noted that transmucosal administration differs from topical and transdermal administration. The U.S. Food and Drug Administration provides standards for a wide range of drug administration routes, or "administration routes." For example, the FDA provides the following definitions for intrasinus, intracerebral, intranasal, intranasal, topical, transdermal, and transmucosal drug administration routes: The administration routes useful in the present invention include intrasinus, intranasal, and intranasal, recognizing that transmucosal delivery via the nasal mucosa is also contemplated. These administration routes are distinct from inhalation, which is intended to deliver drugs to the lungs and bronchi. See, for example, U.S. Patent No. 8,785,500 to Charney et al., issued July 22, 2014, which discloses exemplary methods and compositions for intranasally administering active drugs. [Table 4] * National Cancer Institute See https: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / DataStandardsManualmonographs / ucm071667.htm.

[0147] As used herein, the terms "treat", "treating" or "treatment" include either prophylactic and / or therapeutic alleviation, reduction or amelioration of a symptom, such as autism and other central nervous system disorders, or preventing or reducing the risk of acquiring or exhibiting symptoms of a symptom, ameliorating or preventing the underlying cause of a symptom, suppressing a symptom, preventing the onset of a symptom, alleviating a symptom, inducing regression of a symptom, or arresting the symptoms of a symptom.

[0148] The methods of treatment using suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof or the pharmaceutical compositions of the invention in various embodiments also include the use of suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof in the manufacture of a medicament for the desired treatment, such as, for example, an autism spectrum disorder.

[0149] Slammin' The present invention utilizes a therapeutically effective amount of the antipurinergic suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, a permeation enhancer, and a pharmaceutically acceptable carrier to provide intranasal administration for the treatment of autism spectrum disorders.

[0150] Suramin is a sulfonic acid drug compound with CAS Registry Number 145-63-1 and ChemSpider ID 5168. One of its chemical names is 1,3,5-naphthalenetrisulfonic acid, 8,8'-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]]bis-. This compound is used to treat African sleeping sickness and river blindness and is known under the trade names Antrypol, 309F, 309 Fourneau, Bayer 205, Germanin, Moranyl, Naganin, and Naganine. However, this drug has not been approved by the U.S. FDA. It is administered intravenously. Suramin has been reported to have been studied in mouse models of autism and in Phase I / II human trials. See Naviaux, JC et al., "Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy," Translational Psychiatry. 4(6):e400 (2014). See also Naviaux, RK et al., "Low-dose suramin in autism spectrum disorder: a small, phase I / II, randomized clinical trial," Annals of Clinical and Translational Neurology, 2017 May 26:4(7):491-505.

[0151] The half-life of suramin is reported to range from approximately 41 to 78 days, with an average of 50 days. See Phillips, Margaret A.; Stanley, Jr., Samuel L. (2011) "Chapter 50: Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections." In Brunton, Laurence L.; Chabner, Bruce A.; Knollmann, Bjorn Christian (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.), McGraw Hill, pp. 1437-1438.

[0152] The chemical formula of suramin is C 51 H 40 NO 23 S6. Therefore, the molecular weight (i.e., molar mass) of suramin is 1297.26 grams / mole. Suramin is typically delivered as a sodium sulfonate salt, such as the hexasodium salt, which has a molecular weight (i.e., molar mass) of 1429.15 grams / mole. Note that these molecular weight values ​​will vary slightly depending on which atomic weight values ​​are used in the calculation. The chemical structure of suramin is shown directly below. [ka]

[0153] Pharmaceutically acceptable salts, esters, solvates, and prodrugs of suramin are useful in the methods and compositions of the present invention. As used herein, "pharmaceutically acceptable salts, esters, solvates, and prodrugs" refers to derivatives of suramin. Examples of pharmaceutically acceptable salts include, but are not limited to, alkali metal salts, alkaline earth metal salts, and ammonium salts. Examples of alkali metal salts include lithium, sodium, and potassium salts. Examples of alkaline earth metal salts include calcium and magnesium salts. Ammonium salts, such as NH4 + In addition to the ammonium salts themselves, various mono-, di-, tri-, and tetra-alkyl ammonium salts can be prepared. One or more alkyl groups of such ammonium salts can also be further substituted with groups such as hydroxyl groups to provide ammonium salts of alkanolamines. Ammonium salts derived from diamines such as 1,2-diaminoethane are contemplated herein. The hexasodium salt of suramin is useful herein.

[0154] Pharmaceutically acceptable salts, esters, solvates, and prodrugs of suramin can be prepared from the parent compound by conventional chemical methods. Generally, salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base in water or an organic solvent, or a mixture of both. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, and acetonitrile are generally preferred. Esters of suramin can be prepared by reacting the parent compound with an alcohol and removing the water formed from the reaction. Alternatively, other methods can be used. Anywhere from one to all six of the sulfonic acid groups of suramin can be esterified to form monoesters to hexaesters. Examples of these esters include mesylate (methanesulfonate), CH3SO3-; triflate (trifluoromethanesulfonate), CF3SO3-; ethanesulfonate (esylate), C2H5SO3-; tosylate (p-toluenesulfonate), CH3C6H4SO3-; benzenesulfonic acid (besylate), C6H5SO3-; closilate (closylate, chlorobenzenesulfonate), ClC6H4SO3-; camphorsulfonate (camsilate, camsylate), (C 10 H 15 O)SO3-; pipsylate (p-iodobenzenesulfonate derivative); and nosylate (p-nitrobenzenesulfonate derivative).

[0155] A solvate of suramin refers to one or more solvent molecules associated with one or more suramin molecules, including fractional solvates such as 0.5 solvates and 2.5 solvates. Solvents can be selected from a wide range of solvents, including water, ethanol, isopropanol, and the like. Prodrugs of suramin can be prepared using conventional chemical methods, depending on the prodrug selected. Prodrugs are drugs or compounds that are metabolized (i.e., converted in the body) after administration to become pharmacologically active drugs. Prodrugs can be designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. Prodrugs are intended to include covalently bonded carriers that release the active parent drug of the present invention in vivo upon administration of such prodrugs. In some classifications, esters are considered prodrugs, such as the esters of suramin described herein. Other types of prodrugs may include sulfonamide derivatives and anhydrides.

[0156] Additionally, various esters and prodrugs can include further derivatization to create polyethylene glycol (PEG) and polypropylene glycol (PPG) derivatives and mixed derivatives, examples of which are PEGylated derivatives.

[0157] Dosage To treat sleeping sickness, suramin is typically administered intravenously at 20 mg / kg every 3–7 days for five doses over a four-week period. The relatively high doses of suramin required for the treatment of sleeping sickness, along with the relatively frequent dosing required by the treatment regimen, can potentially lead to drug toxicity and adverse reactions. These potential toxicities and adverse reactions are less well tolerated for conditions such as autism spectrum disorder, FXS, or FXTAS, particularly in children, compared to the acute and potentially life-threatening nature of sleeping sickness.

[0158] In the present invention for treating autism spectrum disorders, the dosage of suramin in the administered composition will range from about 0.01 mg to about 200 mg per dose, or from about 0.01 mg to about 100 mg per dose, based on the suramin active agent, such as a nasal spray dose, with each administered spray dose containing about 0.1 ml of liquid.

[0159] Compositions can also be determined by weight. In one embodiment, the compositions useful herein contain about 0.01% to about 60% by weight of suramin or a pharmaceutical salt, ester, solvate, or prodrug thereof, based on the weight of the suramin active agent. In another embodiment, the compositions herein contain about 0.1% to about 25% by weight of suramin or a pharmaceutical salt, ester, solvate, or prodrug thereof, based on the weight of the suramin active agent.

[0160] For these aforementioned compositions containing a specified amount or weight percentage of suramin, the amount or weight percentage of suramin is determined or calculated based on the actual amount of the suramin moiety, which has a molar mass of 1297.26 grams / mole, and does not include additional weight contributed by counterions, or ester, solvate, or prodrug moieties when a suramin salt, ester, solvate, or prodrug is used. In other words, the composition is based on the amount or weight percentage of the suramin chemical moiety.

[0161] Furthermore, since the present invention relates to intranasal delivery compositions, limiting systemic exposure is highly desirable, and therefore, the unit dosage may be formulated to limit systemic plasma concentrations of suramin. Generally, it may be desirable to maintain suramin plasma concentrations below about 3 micromolar. In further embodiments, it may be desirable to maintain suramin plasma concentrations below about 2 micromolar. In further embodiments, it may be desirable to maintain suramin plasma concentrations below about 1 micromolar. In further embodiments, it may be desirable to maintain suramin plasma concentrations below about 0.1 micromolar. In further embodiments, it may be desirable to maintain suramin plasma concentrations below about 0.05 micromolar. In further embodiments, it may be desirable to maintain suramin plasma concentrations below about 0.01 micromolar. Although a minimum systemic plasma concentration of suramin may not be necessary as long as adequate brain blood and tissue concentrations are maintained, generally, a plasma concentration of suramin greater than about 1 nanomolar may be desirable.

[0162] Furthermore, as the present invention relates to intranasal compositions and methods of treatment, it is highly desirable to limit systemic exposure of suramin to minimize the potential for drug toxicity and unwanted side effects and maintain an appropriate safety window. This limitation of systemic concentration can be achieved by controlling the PK / PD profile. In some embodiments, a unit dose should demonstrate at least one of the following plasma pharmacokinetic parameters for delivery of that unit dose: C max is less than about 75 micromolar (i.e., μM), or less than about 7.5 micromolar, or less than about 0.1 micromolar, or an AUC of about 80 μg * day / L or approximately 75 μg * day / L or less, or approximately 50 μg * Days / L or less, or approximately 25 μg * day / L or approximately 10 μg * Less than day / L. C max may be at least about 0.01 micromolar or greater.max Values ​​can be converted from micromolar to ng / ml (based on suramin active substance using a molecular weight of 1297.26 grams / mole), meaning that 1 micromolar is equivalent to 1297.26 ng / ml. If the amount based on the hexasodium salt is required, the value of 1429.15 grams / mole can be used in the conversion calculation.

[0163] Methods of Treatment and Dosage Regimen The present invention utilizes a therapeutically effective amount of suramin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier to treat autism spectrum disorder, FXS, or FXTAS, and other neurological conditions.

[0164] The method comprises intranasally administering a therapeutically effective amount of suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, to a human patient in need thereof.

[0165] Various dosing regimens can be prescribed and used based on the skill and knowledge of the physician or other practitioner. In some embodiments, a unit dose of the composition described herein can be applied at least once daily. In other embodiments, a unit dose of the composition can be applied at least twice daily, or at least once weekly, or at least twice weekly. The dosage and dosing regimen can be appropriately varied based on the pharmacokinetic and pharmacodynamic parameters of suramin. Suramin is approximately 99-98% protein-bound in serum and has a half-life of 41-78 days, with an average of 50 days.

[0166] Treatment may be continued, at the discretion of the physician or practitioner, until the desired therapeutic effect is achieved. In some cases, it may be desirable to continue long-term or maintenance treatment.

[0167] Treatment evaluation The present invention provides a method in which the autism spectrum disorder, FXS, FXTAS, CFS, or PTSD comprises one or more symptoms selected from the group consisting of difficulty communicating, difficulty interacting with others, and disruptive and repetitive behaviors. Patients with autism spectrum disorder, FXS, FXTAS, CFS, or PTSD can be evaluated using various rating scales to determine the level of severity of their disorder and any improvement or change with the administration of treatment.

[0168] For example, the present invention provides a method for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD, comprising improving more and more of the patient's symptoms compared to the symptoms before treatment.Improvement can be determined by comparing the patient's symptom assessment score with the patient's symptom score before said administration.It is desirable to achieve a 10% or more improvement compared to the patient's score before administering treatment.

[0169] Examples of rating scales for assessing autism spectrum disorders include those selected from the ABC, ADOS, ATEC, CARS CGI, and SRS.

[0170] The term "ABC" is known as the "Aberrant Behavior Checklist," a rating scale for assessing autism. The term "ADOS" is also known as the "Autism Diagnostic Observation Schedule." The protocol consists of a series of structured and semi-structured tasks involving social interactions between the examiner and the subject. The term "ATEC," also known as the "Autism Treatment Evaluation Scale," is a 77-item diagnostic assessment tool developed by the Autism Research Institute. The ATEC was originally designed to evaluate the effectiveness of autism treatments, but it is also used as a screening tool. The term "CARS," also known as the "Childhood Autism Rating Scale," is a behavioral rating scale intended to aid in the diagnosis and evaluation of autism. The term "CGI," also known as the "Clinical Global Impression" rating scale, is a measure of symptom severity, treatment response, and treatment effectiveness in treatment studies of patients with psychological disorders. The term "SRS," also known as the "Interpersonal Responsiveness Scale," is used herein to measure autism spectrum disorders.

[0171] For example, the present invention provides methods in which a patient's ADOS score improves by 1.6 or more compared to the score before treatment administration, or the corresponding performance on a similar test improves. Further, the present invention provides methods in which the p-value of the improvement in ADOS score or similar test is 0.05 or less. In another embodiment, the present invention provides methods in which the size effect of the improvement in ADOS score or similar test is about 1 or more, or about 2.9 or more.

[0172] Formulations for Intranasal Administration and Permeation Enhancers The target indication of the composition of the present invention is related to autism, FXS, FXTAS and other central nervous system diseases.Therefore, efforts are being made to provide a formulation that can easily reach brain region by passing through the blood-brain barrier.The feasible administration route is through nasal drug delivery system, that is, through the nasal cavity by intranasal (IN) formulation spray.

[0173] Compositions useful for intranasal delivery can be in the form of a nasal spray. These compositions can have the active agent in the form of an aqueous composition. In other embodiments, the active agent can be a fine powder, further combined with, or alternatively combined with, a particulate dispersant and a diluent to form or coat a particulate dispersion. These compositions are generally on the order of about 0.01 ml to about 0.5 ml, with a target volume of about 0.1 ml per spray. One to two sprays can be applied to provide a unit dose.

[0174] The pharmaceutical compositions herein may contain a permeation enhancer. Surprisingly, the following permeation enhancers have been found to increase transmucosal tissue penetration of suramin: methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol. The material methyl β-cyclodextrin (methyl-β-cyclodextrin) is also known by the CAS Registry Number 128446-36-6 and the trade name Methyl Betadex. The material caprylocaproyl macrogol-8 glyceride is also known by the CAS Registry Number 85536-07-8 and the trade name Labrasol® as caprylocaproyl polyoxyl-8 glyceride and PEG-8 caprylic / capric glyceride. The material 2-(2-ethoxyethoxy)ethanol is also known as diethylene glycol ethyl ether by the CAS Registry Number 111-90-0 and the trade names Carbitol™ and Transcutol® P.

[0175] Permeation enhancers are generally used at about 40% by weight of the composition, with other useful ranges being from about 0.1% to about 90% by weight of the composition, or from about 1% to about 80% by weight of the composition, or from about 10% to about 75% by weight of the composition, or from about 25% to about 50% by weight of the composition.

[0176] The water in a composition is usually QS. The abbreviation QS stands for Quantum satis, meaning that you add just enough of an ingredient (in this case, water) to achieve the desired result, but no more.

[0177] Other ingredients may include various salts for osmolality control and viscosity increasing agents.

[0178] In some embodiments, the composition can include the following functional ingredients: 1. Active ingredient: Suramin, concentration 10-200mg / mL 2. Solvent / carrier, e.g., water 3. Tissue penetration enhancers 4. One or more preservatives 5. Thickeners to modify the viscosity of the spray solution, and 6. Buffering agents (pH adjusters) or osmotic agents.

[0179] These formulations may be prepared using standard formulation and compounding techniques well known to those skilled in the pharmaceutical and formulation arts.

[0180] In one embodiment, a composition or formulation of the invention comprises suramin or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. These formulations can be made using standard formulation and mixing techniques well known to those skilled in the pharmaceutical and formulation arts.

[0181] In one embodiment, the pharmaceutical composition is selected from a solution, suspension, or dispersion for administration as a spray or aerosol. In another embodiment, the formulation can be delivered as droplets using a dropper or applied directly to the nasal cavity. Other pharmaceutical compositions are selected from the group consisting of gels, ointments, lotions, emulsions, creams, foams, mousses, liquids, pastes, jellies, or tapes to be applied to the nasal cavity.

[0182] Useful herein are compositions in which the pharmaceutically acceptable carrier is selected from water or a mixture of water and other water-miscible ingredients. In the case of emulsions, the ingredients do not need to be miscible with water.

[0183] In other embodiments, the compositions can include a buffer to maintain the pH of the drug formulation, a pharmaceutically acceptable thickener, a humectant, and a surfactant. Buffers suitable for use in the present invention include, for example, hydrochloride, acetate, citrate, carbonate, and phosphate buffers.

[0184] The viscosity of the composition of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent.Thickening agents that can be used according to the present invention include, for example, xanthan gum, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, sodium carboxymethylcellulose (Na CMC) and mixtures thereof.The concentration of the thickening agent depends on the selected agent and the desired viscosity.

[0185] The compositions of the present invention also contain a tolerance enhancer to reduce or prevent the drying of the mucous membrane (humectant) and prevent its irritation. Suitable tolerance enhancers that can be used in the present invention include, for example, humectants, sorbitol, propylene glycol, mineral oil, vegetable oil, and glycerol, soothing agents, membrane modifiers, sweeteners, and mixtures thereof. The concentration of one or more tolerance enhancers in the composition will also vary with the agent selected.

[0186] To enhance the absorption of drugs through the nasal mucosa, therapeutically acceptable surfactants can be added to the intranasal formulation. Suitable surfactants that can be used in accordance with the present invention include, for example, polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydride, such as Tween® 80, polyoxyl 40 stearate, polyoxyethylene 50 stearate, fusidates, bile salts, and octoxynol. Suitable surfactants include nonionic, anionic, and cationic surfactants. These surfactants can be present in the intranasal formulation at a concentration ranging from about 0.001% to about 20% by weight.

[0187] In the present invention, other optional ingredients may also be incorporated into the nasal delivery system, provided that they do not interfere with the action of the drug or significantly reduce the absorption of the drug across the nasal mucosa. Such ingredients may include, for example, pharmaceutically acceptable excipients and preservatives. Excipients that can be used in accordance with the present invention include, for example, bioadhesives and / or swelling / thickening agents.

[0188] Other suitable absorption enhancers known in the art may also be used in the present invention.

[0189] Preservatives can also be added to the composition.Suitable preservatives that can be used with the composition include, for example, benzyl alcohol, paraben, thimerosal, chlorobutanol and benzalkonium chloride, and benzalkonium chloride is preferred.Generally, the preservative will be present in the composition at a concentration of up to about 2% by weight.However, the exact concentration of the preservative will vary according to the purpose of use, and can be easily confirmed by those skilled in the art.

[0190] Absorption enhancers include (i) surfactants; (ii) bile salts (including sodium taurocholate); (iii) phospholipid additives, mixed micelles, or liposomes; (iv) alcohols (including polyols as described above, e.g., propylene glycol or polyethylene glycols such as PEG3000); (v) enamines; (vi) nitric oxide donor compounds; (vii) long-chain amphiphilic molecules; (viii) small molecule hydrophobic uptake enhancers; (ix) sodium or salicylic acid derivatives; (x) glycerol esters of acetoacetic acid; (xi) cyclodextrins or cyclodextrin derivatives; (xii) medium- or short-chain (e.g., C1-C12) fatty acids; and (xiii) chelating agents; (xiv) amino acids or salts thereof; and (xv) N-acetylamino acids or salts thereof.

[0191] Solubility enhancers can increase the concentration of the drug or its pharmaceutically acceptable salt in the formulation. Useful solubility enhancers include, for example, alcohols and polyalcohols.

[0192] Tonicity agents can improve the tolerance of intranasal formulations. A common tonicity agent is NaCl. Preferably, when the formulation is an isotonic intranasal dosage formulation, it contains about 0.9% NaCl (v / v) in the aqueous portion of the liquid carrier.

[0193] The thickener can improve the overall viscosity of the composition, preferably to a value close to that of the nasal mucosa. Suitable thickeners include methylcellulose, carboxymethylcellulose, polyvinypyrrolidone, sodium alginate, hydroxypropylmethylcellulose, and chitosan.

[0194] Humectants or anti-irritants improve the tolerability of the composition over repeated use. Suitable compounds include, for example, glycerol, tocopherol, mineral oil, and chitosan.

[0195] Various additional ingredients can be used in the compositions of the present invention. The compositions can include one or more additional ingredients selected from preservatives, antioxidants, emulsifiers, surfactants or humectants, emollients, film-forming agents, or viscosity adjusters. These ingredients can be used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. These amounts can range from less than 1 weight percent to up to 90 weight percent, or even more than 99 weight percent.

[0196] In one embodiment, a preservative can be included. In another embodiment, an antioxidant can be included. In another embodiment, an emulsifier can be included. In another embodiment, an emollient can be included. In another embodiment, a viscosity modifier can be included. In another embodiment, a surfactant or humectant can be included. In another embodiment, a film-forming agent can be included. In another embodiment, the pharmaceutical composition is in a form selected from the group consisting of a gel, an ointment, a lotion, an emulsion, a cream, a liquid, a spray, a suspension, a jelly, a foam, a mousse, a paste, a tape, a dispersion, and an aerosol. These ingredients can be employed and used in concentrations appropriate for the formulation based on the knowledge of one skilled in the art of pharmaceuticals and formulations.

[0197] Surprisingly, it has been found that permeation enhancers such as methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol are particularly useful in preparing intranasal suramin formulations with improved permeation through mucosal tissues.

[0198] In another embodiment, the at least one preservative is selected from the group consisting of parabens (including butylparaben, ethylparaben, methylparaben, and propylparaben), acetone sodium bisulfite, alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, calcium acetate, calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, edetic acid, glycerin, hexetidine, imidurea, isopropyl alcohol, monothiophene, methylparaben ... The following ingredients may be selected from the group consisting of glycerol, pentetic acid, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium nitrate, potassium sorbate, propionic acid, propyl gallate, propylene glycol, sodium propylparaben, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, sulfur dioxide, thimerosal, zinc oxide, and N-acetylcysteine, or combinations thereof.These ingredients can be used in the formulation at appropriate concentrations based on the knowledge of those skilled in the art of pharmaceuticals and formulations.These amounts can range from less than 1% to 30% by weight.

[0199] In another embodiment, the at least one antioxidant can be selected from the group consisting of acetone sodium bisulfite, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, dodecyl gallate, erythorbic acid, fumaric acid, malic acid, mannitol, sorbitol, monothioglycerol, octyl gallate, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin E polyethylene glycol succinate, and N-acetylcysteine, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation arts. The amounts can range from less than 1 weight percent to 30 weight percent.

[0200] In another embodiment, the at least one emulsifier is selected from the group consisting of acacia, agar, ammonium alginate, calcium alginate, carbomer, sodium carboxymethylcellulose, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, glyceryl monooleate, glyceryl monostearate, hectorite, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, lanolin, lanolin alcohol, lauric acid, lecithin, linoleic acid, magnesium oxide, medium chain triglycerides, methylcellulose, mineral oil, monoethanolamine, myristic acid, octyldodecanol, oleic acid, oleyl alcohol, palm oil, palmitic acid, pectin, phospholipids, poloxamer, polycarbophil, polyoxyethylene alkyl ether, polyoxyethylene methyl ether, methylcellulose, methylcellulose, mineral oil, monoethanolamine, myristic acid, octyldodecanol, oleic acid, oleyl alcohol, palm oil, palmitic acid, pectin, phospholipids, poloxamer, polycarbophil, polyoxyethylene alkyl ether, polyoxyethylene methyl ... The additives may be selected from the group consisting of ethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polyoxyl 15 hydroxystearate, polyoxyglycerides, potassium alginate, propylene glycol alginate, propylene glycol dilaurate, propylene glycol monolaurate, saponite, sodium borate, sodium citrate dehydrate, sodium lactate, sodium lauryl sulfate, sodium stearate, sorbitan esters, starch, stearic acid, sucrose stearate, tragacanth, triethanolamine, tromethamine, vitamin E polyethylene glycol succinate, wax, and xanthan gum, or combinations thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. The amounts can range from less than 1 weight percent to 30 weight percent.

[0201] In another embodiment, the at least one emollient can be selected from the group consisting of almond oil, aluminum monostearate, butyl stearate, canola oil, castor oil, cetostearyl alcohol, cetyl alcohol, cetyl palmitate, cholesterol, coconut oil, cyclomethicone, decyl oleate, diethyl sebacate, dimethicone, ethylene glycol stearate, glycerin, glyceryl monooleate, glyceryl monostearate, isopropyl isostearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, lecithin, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, palm kernel oil, palm oil, petrolatum, polyoxyethylene sorbitan fatty acid esters, propylene glycol dilaurate, propylene glycol monolaurate, safflower oil, squalene, sunflower oil, tricaprylin, triolein, wax, xylitol, zinc acetate, or combinations thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation arts, and these amounts can range from less than 1 weight percent to as much as 60 weight percent.

[0202] In another embodiment, the at least one viscosity modifier is selected from the group consisting of acacia, agar, alginic acid, aluminum monostearate, ammonium alginate, attapulgite, bentonite, calcium alginate, calcium lactate, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, cellulose, ceratonia, ceresin, cetostearyl alcohol, cetyl palmitate, chitosan, colloidal silicon dioxide, corn syrup solids, cyclomethicone, ethylcellulose, gelatin, glyceryl behenate, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose. The ingredient may be selected from the group consisting of cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, myristyl alcohol, octyldodecanol, palm oil, pectin, polycarbophil, polydextrose, polyethylene oxide, polyoxyethylene alkyl ether, polyvinyl alcohol, potassium alginate, propylene glycol alginate, pullulan, saponite, sodium alginate, starch, sucrose, sugar, sulfobutyl ether beta-cyclodextrin, tragacanth, trehalose, and xanthan gum, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. The amount can range from less than 1 weight percent to 60 weight percent.

[0203] In another embodiment, the at least one film-forming agent can be selected from the group consisting of ammonium alginate, chitosan, colophony, copovidone, ethylene glycol and vinyl alcohol graft copolymer, gelatin, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, polymethacrylate, poly(methyl vinyl ether / maleic anhydride), polyvinyl acetate dispersion, polyvinyl acetate phthalate, polyvinyl alcohol, povidone, pullulan, pyroxylin, and shellac, or a combination thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the pharmaceutical and formulation fields. These amounts can range from less than 1 weight percent to up to 90 weight percent, or even more than 99 weight percent.

[0204] In another embodiment, the at least one surfactant or wetting agent can be selected from the group consisting of docusate sodium, phospholipids, sodium lauryl sulfate, benzalkonium chloride, cetrimide, cetylpyridinium chloride, alpha-tocopherol, glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxyl 15 hydroxystearate, polyoxyglycerides, propylene glycol dilaurate, propylene glycol monolaurate, sorbitan ester, sucrose stearate, tricaprylin, and vitamin E polyethylene glycol succinate, or combinations thereof. These ingredients can be employed and used in the formulation at appropriate concentrations based on the knowledge of those skilled in the art of pharmaceuticals and formulations. The amount can range from less than 1 weight percent to 30 weight percent.

[0205] In another embodiment, a buffering agent can be included. In another embodiment, an emollient can be included. In another embodiment, an emulsifier can be included. In another embodiment, an emulsion stabilizer can be included. In another embodiment, a gelling agent can be included. In another embodiment, a humectant can be included. In another embodiment, an ointment base or oily vehicle can be included. In another embodiment, a suspending agent can be included. In another embodiment, an acidulant can be included. In another embodiment, an alkalizing agent can be included. In another embodiment, a bioadhesive material can be included. In another embodiment, a coloring agent can be included. In another embodiment, a microencapsulating agent can be included. In another embodiment, a hardening agent can be included. These ingredients can be employed and used in the formulation at concentrations appropriate to the formulation based on the knowledge of those skilled in the pharmaceutical and formulation arts. These amounts can range from less than 1 weight percent up to 90 weight percent, or even more than 99 weight percent.

[0206] When the active ingredient is delivered as a powder, the powdered material is often combined with a powdered dispersant. In other embodiments, the active substance can be combined with a dispersant to form particles containing both the active substance and the dispersant. In still other embodiments, the active substance can be coated onto the surface of the dispersant. Examples of dispersants include a wide range of ingredients, including sugars such as lactose, glucose, and sucrose.

[0207] Those skilled in the pharmaceutical and formulation arts can determine appropriate concentrations of the essential and optional components of the compositions of the present invention.

[0208] Methods for preparing suramin compositions are also contemplated as part of this invention and will be apparent to those skilled in the pharmaceutical and formulation arts using standard formulation and compounding techniques.

[0209] Also provided herein is a device for patient or self-administration of an antipurinergic agent, comprising a nasal spray inhaler containing an aerosol spray formulation of an antipurinergic agent and a pharmaceutically acceptable dispersant or solvent system, the device being designed (or metered) to dispense a metered amount of the aerosol formulation by forming a spray containing a dose of the antipurinergic agent. In other embodiments, the inhaler may contain the antipurinergic agent as a fine powder, which may be further combined, or alternatively combined, with a particulate dispersant and diluent to form or coat a particulate dispersant. [Example]

[0210] The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given for illustrative purposes only and are not to be construed as limitations of the invention, since many variations thereof are possible without departing from the spirit and scope of the invention.

[0211] Example 1 Compositions for intranasal delivery The following compositions are prepared using standard equipment and procedures. [Table A] * Based on suramin hexasodium salt with a molecular weight of 1429.15 g / mole

[0212] Dissolve suramin sodium salt in water with gentle mixing. Add cyclodextrin with mixing until dissolved. Allow the resulting solution to stand for 2 hours before use.

[0213] The composition can be packaged in a spray bottle for intranasal administration.

[0214] Alternatively, the composition is prepared by replacing methyl β-cyclodextrin with an equal weight of caprylocaproyl macrogol-8 glyceride or 2-(2-ethoxyethoxy)ethanol.

[0215] The compositions are useful for treating autism spectrum disorders.

[0216] Example 2: Composition for intranasal delivery The following compositions are prepared using standard equipment and procedures. [Table B] * Based on suramin hexasodium salt with a molecular weight of 1429.15 g / mole

[0217] Dissolve suramin sodium salt in water with gentle mixing. Add sodium chloride and hydroxypropyl methylcellulose with mixing. Add cyclodextrin with mixing until dissolved. Allow the resulting solution to stand for 2 hours before use.

[0218] The composition can be packaged in a spray bottle for intranasal administration.

[0219] Alternatively, the composition is prepared by replacing methyl β-cyclodextrin with an equal weight of caprylocaproyl macrogol-8 glyceride or 2-(2-ethoxyethoxy)ethanol.

[0220] The compositions are useful for treating autism spectrum disorders.

[0221] Example 3: Tissue penetration of suramin Four formulations AD were prepared using the methods of Examples 1 and 2 and were found to be stable for at least 4 weeks at 25°C and 3 months at 60% relative humidity. Formulation A - 100 mg / mL suramin hexasodium salt in water (no excipients) Formulation B - 100 mg / mL suramin hexasodium salt and 40% methyl beta-cyclodextrin (methylbetadex) in water Formulation C - 100 mg / mL suramin hexasodium salt in water with 40% HP (hydroxypropyl)-cyclodextrin Formulation D - 160 mg / mL suramin hexasodium salt in water (no excipients)

[0222] The formulation also contained 0.1% hydroxypropyl methylcellulose (i.e., HPMCE5 from Dow Chemicals) as a solution thickener and 0.75% sodium chloride as an osmotic agent.

[0223] These four formulations were evaluated in an in vitro permeation study using cultured human airway tissue (EpiAirway AIR-100, purchased from MatTek Corporation) according to an established drug permeation protocol (EpiAirway™ Drug Permeation Protocol, MatTek Corporation, 2014). EpiAirway represents the upper airway, extending from the trachea to the primary bronchi, and is therefore used to measure drug delivery from nasal formulations.

[0224] To prepare the receiver fluid, pre-warm the EpiAirway assay medium to 37°C. Using sterile technique, pipette 0.3 mL of medium into each well of a sterile 24-well plate. Label the wells. Use 0.2 mL of donor solution for the tissue.

[0225] Permeability experiments: After overnight equilibration, transfer the cell culture inserts to the 1-hour wells and pipette the donor solution into the tissue. Return the plate to the incubator. After 30 minutes of permeability, transfer the tissue to the 2-hour wells. Similarly, transfer tissue after 2.0, 3.0, 4.0, and 6.0 hours. There is no need to replenish the donor solution. Alternatively, remove the receiver solution completely and replace it with fresh, pre-warmed receiver solution at the appropriate time. This solution was analyzed using HPLC with detection at 238 nm.

[0226] Table 1 below shows the average cumulative amount of suramin (mg) permeated as a function of time. [Table 1]

[0227] The results of the study are also shown graphically in Figure 1, where the cumulative amount of drug permeated (mg) is plotted against time (hours).

[0228] These data show that formulation B, which contains methyl β-cyclodextrin (methylbetadex), provides significantly superior permeation compared to formulations A, C, and D in the tissue permeation assay. Also, as can be seen from the comparison of formulations A and D, having a higher drug concentration can be advantageous for improving permeation.

[0229] Example 4: Tissue penetration of suramin Six formulations A through F were prepared using the methods of Examples 1 and 2 and were found to be stable for at least 4 weeks at ambient conditions. Formulation A - 200 mg / mL suramin in water (no excipients) Formulation B—140 mg / mL suramin and 40% polysorbate 80 (Tween® 80) in water Formulation C - 140 mg / mL suramin in water with 40% methyl beta-cyclodextrin (methylbetadex) Formulation D - 140 mg / mL suramin in water with 40% sulfobutyl ether β-cyclodextrin (Captisol) Formulation E - 140 mg / mL suramin in water with 40% 2-(2-ethoxyethoxy)ethanol (Transcutol P) Formulation F - Suramin (Labrasol) 140 mg / mL in water

[0230] Tissue penetration studies were performed using the method of Example 3.

[0231] Table 2 below shows the average cumulative amount of suramin (mg) permeated as a function of time. [Table 2]

[0232] The results of the study are also presented graphically in Figure 2, where the cumulative amount of drug permeated (mg) is plotted against time (hours). These data show that Formulation C, containing methyl β-cyclodextrin (methylbetadex), Formulation E, containing 2-(2-ethoxyethoxy)ethanol (Transcutol P), and Formulation F, containing caprylocaproyl macrogol-8 glyceride (Labrasol), provide significantly superior permeation compared to Formulations A, B, and D in the tissue permeation assay.

[0233] Moreover, the results of Examples 3 and 4 are surprising.

[0234] Cyclodextrins are sugar molecules linked together by rings of various sizes. Specifically, the sugar units, called glucopyranosides, are glucose molecules present in a pyranose (six-membered) ring structure. Six, eight, or ten glucopyranosides are linked together to form α-, β-, and γ-cyclodextrins, respectively. Cyclodextrins form a toroidal (frustum of a cone) structure with multiple hydroxyl groups at both ends, allowing them to encapsulate hydrophobic compounds without losing their aqueous solubility. Among other uses, cyclodextrins can be used to transport hydrophobic drug molecules into biological systems as tissue penetration enhancers. Cyclodextrins have been reported to form inclusion complexes with various hydrophobic drugs, thereby enhancing their partitioning into tissue membranes and solubility. Methyl β-cyclodextrin (Betadex) is a type of cyclodextrin. Methylbetadex is used in at least one commercially available intranasal product, estradiol (Aerodiol), to facilitate the transtissue penetration of the drug molecule estradiol (MW = 272.4). Due to its small size (MW = 272.4), the estradiol molecule can be easily encapsulated within a cyclodextrin ring, thus achieving enhanced delivery to biological tissues.

[0235] However, the present inventors have discovered a way in which methyl beta-cyclodextrin can also encapsulate suramin, a much larger molecule than is generally considered compatible. It is surprising to find that methyl betadex works on suramin. Those skilled in the art would not have expected that such a large molecule could be encapsulated in a cyclodextrin ring.

[0236] Another useful permeation enhancer is Transcutol P (diethylene glycol monoethyl ether), an excipient that has been reported to enhance the skin permeability of some small molecule drug compounds in various topical / transdermal formulations. Nevertheless, it has not been used as an excipient in intranasal products and has not been used extensively to enhance macromolecules such as suramin.

[0237] Another useful permeation enhancer is Labrasol (caprylocaproyl macrogol-8 glyceride), an excipient that has been reported to enhance the skin permeability of some drug compounds in some topical / transdermal formulations. It has not been used as an excipient in intranasal products.

[0238] Example 5: Measurement of suramin in plasma and brain tissue The following example describes mouse studies conducted to measure suramin delivery to plasma and brain tissue when administered intraperitoneally (IP) or intranasally (IN) following different treatment regimens. For the study, male Fmr1-knockout B6.129P2-Fmr1tm1Cgr / J TG mice were purchased from The Jackson Laboratory in Bar Harbor, Maine. These mice were approximately 8 weeks old. These mice exhibit dendritic spine abnormalities in multiple brain regions. Absence of FMRP in these mice leads to overactivation of RAC1, a protein of the Rho GTPase subfamily that plays an important role in dendritic morphology and synaptic function. These B6.129P2-Fmr1tm1Cgr / J TG mice provide an animal model of cognitive and neurodevelopmental disorders.

[0239] Mice were maintained in group cages (six mice per cage based on treatment group) in a controlled environment (temperature: 21.5 ± 4.5 °C, relative humidity: 35-55%) under a standard 12-hour light / 12-hour dark lighting cycle (lights on at 06:00). Mice were housed in the research facility for approximately 1 week. The weight of all mice was recorded for health monitoring purposes.

[0240] Mice were divided into the following five test groups with six mice per group: Group 1: Animals received an intraperitoneal (IP) injection of 20 mg / kg suramin once a week for four consecutive weeks starting at 9 weeks of age (i.e., at 9, 10, 11, and 12 weeks of age). Suramin was formulated in normal saline. Group 2: Animals received an intraperitoneal (IP) injection of 5 mL / g saline once a week for four consecutive weeks starting at 9 weeks of age (i.e., at 9, 10, 11, and 12 weeks of age). This was the control group. Group 3: Intranasal (IN) administration of the following suramin formulations at a concentration of 100 mg / mL x 6 mL per spray, administered once daily as one spray per nostril (approximately 2 minutes between applications to ensure absorption) for 28 days (a total of 56 sprays over 28 days) starting at 9 weeks of age (i.e., administered once daily at 9, 10, 11, and 12 weeks of age): Group 4: Intranasal (IN) administration of the following suramin formulations at a concentration of 100 mg / mL x 6 mL per spray, administered as one spray per nostril, once every other day for 28 days (a total of 28 sprays over 28 days) starting at 9 weeks of age (i.e., once every other day during 9, 10, 11, and 12 weeks of age): Group 5: Intranasal (IN) administration of the suramin formulation described below at a concentration of 100 mg / mL x 6 mL per spray, administered as one spray per nostril, once weekly for 4 weeks (28 days) beginning at 9 weeks of age (i.e., administered once weekly during 9, 10, 11, and 12 weeks of age).

[0241] Below is the intranasal (IN) formulation of suramin administered to Groups 3, 4, and 5 above. [Table 5] * HPMC E5 is a water-soluble cellulose ether polymer (hydroxypropyl methylcellulose (HPMC)) available from DuPont.

[0242] The above formulation is made by dissolving suramin sodium salt in water with gentle mixing. The remaining ingredients, except for cyclodextrin, are added with mixing. The cyclodextrin is then added with mixing until dissolved. The resulting solution is allowed to stand for 2 hours before use.

[0243] Blood samples were collected from all mice at the end of 12 weeks of age. Brain tissue was collected from all mice sacrificed at 13–14 weeks of age. Data were acquired using standard sample preparation and analytical techniques.

[0244] The results of this study are shown in Table 3. Data are expressed as mean plasma concentrations (both ng / ml and μM) and mean brain tissue concentrations (both ng / g and mmol / g) for each animal group. Also shown are the mean brain tissue-to-plasma partition ratios for each group. Note that such calculations are not applicable to the saline control group (Group 2), as suramin was not detected in brain tissue and the small plasma concentrations are essentially noise from the analytical method. [Table 3] 1 BQL means below quantifiable limit. 2 NA means not applicable. 3 The partition ratios are calculated directly from the raw data rather than the averages shown in the tables.

[0245] The results of the tests are also shown in the plots in Figures 3 to 10.

[0246] Figure 3 shows plots of the total concentration of suramin (ng / ml) in mouse plasma and brain tissue when mice were given weekly intraperitoneal (IP) injections of 20 mg / kg for four consecutive weeks starting at 9 weeks of age (i.e., at 9, 10, 11, and 12 weeks of age).

[0247] Figure 4 shows a plot comparing the total concentration of suramin (ng / ml) in mouse plasma and brain tissue when administered intranasally (IN) daily for 28 days. The IN suramin-containing composition of the invention was administered at a concentration of 100 mg / mL x 6 mL per spray, once daily, one spray per nostril (with approximately 2 minutes between applications to ensure absorption), for 28 days (56 sprays total over 28 days) starting at 9 weeks of age (i.e., daily administration during weeks 9, 10, 11, and 12 of age).

[0248] Figure 5 shows a plot comparing the total concentration of suramin (ng / ml) in mouse plasma and brain tissue when administered intranasally (IN) every other day for 28 days. The composition of the invention containing IN suramin was administered at a concentration of 100 mg / mL x 6 mL per spray, as one spray per nostril every other day (with approximately 2 minutes between each application to ensure absorption), for 28 days (a total of 28 sprays over 28 days) starting at 9 weeks of age (i.e., daily administration during weeks 9, 10, 11, and 12 of age).

[0249] Figure 6 shows a plot comparing the total concentration (ng / ml) of suramin in mouse plasma and brain tissue when administered intranasally (IN) once weekly for four weeks. The composition of the invention containing IN suramin was administered at a concentration of 100 mg / mL x 6 mL per spray, once weekly as one spray per nostril (with approximately two minutes between applications to ensure absorption), for four weeks (28 days) (a total of eight sprays over the 28 days) starting at nine weeks of age (i.e., daily administration at 9, 10, 11, and 12 weeks of age).

[0250] Figure 7 shows a plot comparing the total percentage of suramin in the plasma of mice given intraperitoneal (IP) injections once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every two days for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0251] Figure 8 shows a plot comparing the total percentage of suramin in brain tissue of mice given intraperitoneal (IP) injections once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every two days for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0252] Figure 9 shows a plot comparing the total percentage of suramin in the plasma and brain tissue of mice given intraperitoneal (IP) injections once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every two days for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0253] FIG. 10 shows a plot comparing the brain tissue and plasma distribution ratios of suramin in mice administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) once every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0254] These results demonstrate that antipurinergic drugs such as suramin can be delivered intranasally to achieve plasma and brain tissue concentrations, and that variations in brain tissue-to-plasma partition ratios can be observed. These results demonstrate that antipurinergic drugs such as suramin can be delivered to the mammalian brain by intranasal (IN) administration.

[0255] Incorporation by Reference The complete disclosure of each patent document, including certificates of amendment, patent application documents, scientific articles, government reports, websites, and other references referred to herein, is incorporated herein in its entirety for all purposes. In the event of a conflict in terminology, the present specification will control.

[0256] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are to be considered in all respects illustrative rather than limiting of the invention described herein. In various embodiments of the methods and compositions of the present invention, when the term "comprising" is used in reference to recited method steps or composition components, it is also contemplated that the method and composition consist essentially of or consist of the recited steps or components. Furthermore, it should be understood that the order of steps or the order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0257] In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification will prevail.

[0258] Additionally, it should be recognized that, because certain components may further react or be converted into additional materials upon mixing, in certain instances the composition may be described as consisting of the components prior to mixing.

[0259] All percentages and ratios used herein are by weight unless otherwise specified. While the mass of an object is often referred to as its weight in everyday usage, and most frequently for scientific purposes, it is recognized that mass technically refers to the amount of matter in an object, while weight refers to the force an object experiences due to gravity. Also, in common usage, the "weight" (mass) of an object is determined when the object is "weighed" (massed) on a scale or balance.

Claims

1. 1. A pharmaceutical composition for treating cognitive, social, or behavioral disorders and neurodevelopmental disorders, comprising an antipurinergic agent and a permeation enhancer, wherein the composition is delivered intranasally to a patient in need thereof, wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, or solvate thereof, and the permeation enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof.

2. The pharmaceutical composition of claim 1 , wherein the patient is a human.

3. 3. The pharmaceutical composition of claim 2, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is selected from autism spectrum disorder, FXS, FXTAS, CFS, and PTSD.

4. 4. The pharmaceutical composition of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is an autism spectrum disorder.

5. 4. The pharmaceutical composition of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is FXS.

6. 4. The pharmaceutical composition of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is FXTAS.

7. 4. The pharmaceutical composition of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is CFS.

8. 4. The pharmaceutical composition of claim 3, wherein the cognitive, social, behavioral, or neurodevelopmental disorder is PTSD.

9. 5. The pharmaceutical composition of claim 4, wherein the autism spectrum disorder is selected from the group consisting of autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome.

10. 5. The pharmaceutical composition of claim 4, wherein the autism spectrum disorder comprises one or more symptoms selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

11. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from an alkali metal salt, an alkaline earth metal salt, and an ammonium salt.

12. 12. The pharmaceutical composition of claim 11, wherein the salt is a sodium salt.

13. 12. The pharmaceutical composition of claim 11, wherein the salt is a hexasodium salt.

14. The pharmaceutical composition of claim 1 , wherein the composition is an aqueous composition.

15. 10. The pharmaceutical composition of claim 1, wherein the composition is a powdered composition.

16. 2. The pharmaceutical composition of claim 1, wherein the permeation enhancer is methyl β-cyclodextrin.

17. 2. The pharmaceutical composition of claim 1, wherein the permeation enhancer is caprylocaproyl macrogol-8 glyceride.

18. 2. The pharmaceutical composition of claim 1, wherein the permeation enhancer is 2-(2-ethoxyethoxy)ethanol.

19. 10. The pharmaceutical composition of claim 1, wherein the composition is administered, i.e., dosed, at least once daily, or at least twice daily, or at least once weekly, or at least twice weekly, or at least every other week (i.e., once every two weeks), or at least once monthly, or at least once every four weeks.

20. 10. The pharmaceutical composition of claim 1, wherein the composition is delivered or dosed at least once every 41 to 78 days.

21. 10. The pharmaceutical composition of claim 1, wherein the composition is delivered or dosed at least once every 50 days.

22. 10. The pharmaceutical composition of claim 1, wherein the composition is delivered, i.e., dosed, at least once per time interval based on the average half-life of suramin.

23. 10. The pharmaceutical composition of claim 1, wherein the patient's plasma concentration of suramin is maintained at less than 3 micromolar (μM), or less than 2.75 micromolar, or less than 2.5 micromolar, or less than 2 micromolar, or less than 1 micromolar, or less than 0.5 micromolar, based on the suramin active substance.

24. 2. The pharmaceutical composition according to claim 1, wherein the patient has a brain tissue concentration of suramin of 1 ng / ml to 1000 ng / ml.

25. 2. The pharmaceutical composition of claim 1, wherein the patient has a brain tissue concentration of suramin of at least 1 ng / ml, or at least 10 ng / ml, or at least 50 ng / ml, or at least 100 ng / ml, or at least 250 ng / ml, or at least 500 ng / ml.

26. 2. The pharmaceutical composition of claim 1, wherein the brain tissue / plasma partition ratio of suramin is at least 0.05, or at least 0.1, or at least 0.25, or at least 0.

50.

27. 2. The pharmaceutical composition of claim 1, wherein the composition comprises 0.01 mg to 200 mg of suramin per unit dose, based on the suramin active substance.

28. 2. The pharmaceutical composition of claim 1, wherein the composition comprises, based on the suramin active substance, 0.01 mg to 100 mg, or 0.01 mg to 50 mg of suramin per unit dose, or 0.01 mg to 25 mg of suramin per unit dose, or 0.01 mg to 10 mg of suramin per unit dose.

29. 10. The pharmaceutical composition of claim 1, wherein the composition comprises suramin active agent and 0.1 mg / kg per week to 20 mg / kg per week of suramin based on the patient's body weight.

30. 10. The pharmaceutical composition of claim 1, wherein the composition comprises 0.025 mg / kg to 10 mg / kg of suramin per unit dose or 0.05 mg / kg to 6 mg / kg of suramin per unit dose, based on the suramin active substance and the patient's body weight (mass).

31. 10. The pharmaceutical composition of claim 1, wherein the composition comprises 0.0476 mg / kg to 5.720 mg / kg of suramin per unit dose based on the suramin active substance and the patient's body weight (mass).

32. 2. The pharmaceutical composition of claim 1, wherein the composition comprises less than 1 mg / kg of suramin per unit dose, or less than 0.5 mg / kg of suramin per unit dose, or less than 0.25 mg / kg of suramin per unit dose, or less than 0.1 mg / kg of suramin per unit dose, based on the suramin active substance and the patient's body weight (mass).

33. The composition comprises 400 mg / m2 per unit dose based on the suramin active substance and the patient's body surface area (BSA). ２ Suramin less than 200 mg / m per unit dose ２ Suramin less than 100 mg / m per unit dose ２ Suramin less than 50 mg / m per unit dose ２ Suramin less than 25 mg / m per unit dose ２ 10. The pharmaceutical composition of claim 1, comprising less than 100 mg of suramin.

34. The composition comprises 10 mg / m2 of suramin active agent per unit dose based on the patient's body surface area (BSA). ２ ~300 mg / m ２ 2. The pharmaceutical composition of claim 1, comprising suramin of

35. The AUC of the plasma concentration of the active substance of suramin for the patient is 80 μg ＊ days / L or less than 75 μg ＊ days / L or less than 50 μg ＊ days / L or less than 25 μg ＊ days / L or less than 10 μg ＊ The pharmaceutical composition of claim 1, wherein the total amount of the composition is less than 100 mg / L.

36. C of plasma concentration of suramin active substance for said patient ｍａｘ 2. The pharmaceutical composition of claim 1, wherein, based on a single dose, is less than 75 micromolar, or less than 7.5 micromolar, or less than 0.1 micromolar, and optionally is at least 0.01 micromolar.

37. 2. The pharmaceutical composition of claim 1, wherein the composition is in the form of a nasal spray, i.e., a spray for intranasal administration.

38. 10. The pharmaceutical composition of claim 1, wherein the composition is in unit dosage form, the unit dosage comprising from 0.01 ml to 0.5 ml of liquid.

39. 39. The pharmaceutical composition of claim 38, wherein the unit dose comprises 0.1 ml of liquid.

40. The composition induces a suramin-based aerobic response through cultured human airway tissue at a rate of 1 microgram / cm per hour based on suramin active substance. ２ ~200 micrograms / cm per hour ２ The pharmaceutical composition of claim 1, which exhibits or is capable of providing a permeation rate of suramin of

41. 10. The pharmaceutical composition of claim 1, wherein the composition further comprises an agent selected for osmolality control.

42. 42. The pharmaceutical composition of claim 41, wherein the agent selected for osmolality control is selected from salts.

43. The pharmaceutical composition of claim 1 , wherein the composition further comprises a viscosity enhancing agent.

44. 4. The pharmaceutical composition of claim 3, wherein treating the autism spectrum disorder, FXS, or FXTAS comprises improving one or more symptoms compared to the patient's symptoms before intranasally delivering the composition to the patient, and the one or more symptoms are selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

45. 4. The pharmaceutical composition of claim 3, wherein treating the autism spectrum disorder, FXS, or FXTAS comprises improving the patient's assessment score compared to the patient's score before intranasally delivering the composition to the patient.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the patient's assessment score is improved by 10% or more compared to the patient's score before intranasal delivery of the composition to the patient.

47. 46. ​​The pharmaceutical composition of claim 45, wherein the assessment score is selected from ABC, ADOS, ATEC, CARS CGI, and SRS.

48. 48. The pharmaceutical composition of claim 47, wherein the patient's ADOS score or similar test improves by 1.6 or more compared to the score before administration, or the corresponding performance on a similar test improves.

49. 48. The pharmaceutical composition of claim 47, wherein the improvement in the ADOS score or similar test has a p-value of 0.05 or less.

50. 48. The pharmaceutical composition of claim 47, wherein the size effect of improvement in the ADOS score or similar test is 1 or greater or 2.9 or greater.

51. 1. A pharmaceutical composition for intranasal delivery for treating autism spectrum disorder, FXS, or FXTAS, comprising: (a) a therapeutically effective amount of an antipurinergic agent which is suramin, or a pharmaceutically acceptable salt, ester, or solvate thereof; and (b) a permeation enhancer selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof. A pharmaceutical composition comprising:

52. 52. The composition of claim 51, further comprising: (c) water.

53. 53. The composition of claim 52, wherein the concentration of the suramin is 10 mg / ml to 200 mg / ml, the concentration of the permeation enhancer is 25% to 50%, or 40% by weight, and water is present in an appropriate amount.

54. 52. The composition of claim 51, wherein when the composition is administered to a patient in need thereof, the plasma concentration of the suramin in the patient is maintained at less than 3 micromolar, or less than 1 micromolar, or less than 0.5 micromolar, based on the suramin active substance.

55. 1. Use of an antipurinergic agent and a permeation enhancer in the manufacture of a medicament for intranasal delivery of a therapeutically effective amount of suramin to treat autism spectrum disorder, FXS, FXTAS, CFS, or PTSD in a patient in need thereof, wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, or solvate thereof, and the permeation enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof.

56. 56. The use of claim 55, wherein the plasma concentration of suramin is maintained at less than 3 micromolar, or less than 1 micromolar, or less than 0.5 micromolar based on the suramin active substance.

57. 1. A composition comprising an antipurinergic agent and a permeation enhancer for the intranasal delivery of suramin to treat autism spectrum disorder, FXS, FXTAS, CFS, or PTSD in a patient in need thereof, wherein the antipurinergic agent is suramin, or a pharmaceutically acceptable salt, ester, or solvate thereof, and the permeation enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylocaproyl macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof.

58. 58. The composition of claim 57, wherein the plasma concentration of suramin is maintained at less than 3 micromolar, or less than 1 micromolar, or less than 0.5 micromolar based on the suramin active substance.

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