Compositions and methods for treating central nervous system disorders

Abstract

The present invention provides compositions and methods for treating cognitive, social or behavioral disabilities and neurodevelopmental disorders such as autism spectrum disorder (ASD) and 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 therapeutically effective amounts of anti-purinergic agents such as suramin to treat disorders in patients therewith.

Description

Technical Field

[0001] The present invention provides compositions and methods for treating cognitive, social or behavioral disabilities and neurodevelopmental disorders such as autism spectrum disorders (ASD) and 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 a therapeutically effective amount of antipurinergic agents (antipurinergic agents, such as suramin) and pharmaceutically acceptable salts, esters, solvates and prodrugs of these agents. The agent is delivered by intranasal (IN) administration. Background Art

[0002] Autism is associated with a combination of genetic and environmental factors, with a reported incidence of about 1 in 60 children in the United States. Autism is estimated to occur in about 25 million individuals worldwide. Autism is also known as autism spectrum disorder (ASD) because it includes a wide range of conditions characterized by challenges in social skills, repetitive behaviors, speech and nonverbal communication. In 2013, the American Psychiatric Association merged four different autism diagnoses into a single autism spectrum disorder diagnosis. These diagnoses include autism, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's syndrome. Signs of autism usually appear at the age of 2 or 3. Autism spectrum disorder is a condition related to brain development that affects how a person perceives and socializes with others, causing problems with social interaction and communication. This disorder can also include limited and repetitive behavior patterns.

[0003] Studies have shown that early intervention can lead 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 8Years-Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014 Surveillance Summaries / April 27, 2018 / 67(6); 1-23.

[0004] There is currently no cure for autism spectrum disorder, and there are no FDA-approved drugs to treat the core symptoms. Instead, various drugs (such as antipsychotics) are used to treat some of the accompanying non-core symptoms. Common symptoms include depression, epilepsy, anxiety, sleep disorders, and difficulty focusing. In addition, behavioral therapy and other pharmacological interventions are also used. However, the exact cause of autism is not fully understood, which makes new drug development challenging.

[0005] Fragile X syndrome (FXS) is a rare, inherited neurodevelopmental disorder that affects about 1 in every 4,000 males and females in the United States. It is associated with highly variable cognitive and behavioral manifestations and has many overlapping features with ASD. It is an X-linked disorder, meaning that a gene mutation occurs on the X chromosome. In FXS, there is a trinucleotide repeat expansion in the FMR1 gene. A trinucleotide expansion is a special type of gene mutation in which a sequence of three nucleotide base pairs is incorrectly repeated multiple times. In the case of FXS, the repeated trinucleotide sequence is cytosine-guanine-guanine (CGG). Typically, this DNA segment is repeated 5 to about 40 times. In people with FXS, the segment is repeated more than 200 times. This typically results in the absence of functional FMR1 mRNA transcripts, and the protein normally encoded by the transcript (fragile X mental retardation protein (FMRP)) is also absent.

[0006] Fragile X-associated tremor / ataxia (FXTAS) is a different disorder but is genetically related to FXS. It is an "adult-onset" rare inherited neurodegenerative disorder that usually affects males over the age of 50. Females make up only a small percentage of the FXTAS population, and their symptoms tend to be less severe. FXTAS affects the nervous system and progresses at different rates in different individuals.

[0007] People with FXS have a "full mutation" in the FMR1 gene (typically well over 200 CGG trinucleotide repeats), but people with FXTAS are considered premutation 'carriers' of the FMR1 gene because they have a CGG trinucleotide repeat number in the range of 55-200. The job of the FMR1 gene is to make a protein (FMRP) that is important for brain development. Researchers think that (for unknown reasons) having the premutation leads to an overproduction of FMR1 mRNA (which contains the expanded repeats). Researchers also suspect that high levels of the mRNA are responsible for causing the signs and symptoms of FXTAS, but more research is needed to confirm these hypotheses.

[0008] Individuals with FXTAS typically develop symptoms after the age of 55. As premutation carriers age, especially men, the likelihood of developing symptoms increases. For premutation males, this likelihood reaches 75% by the age of 75. The progression of symptoms (including memory loss, slow speech, tremors, and shuffling gait) is gradual, and interference with daily activities by tremors and falls occurs about ten years after the first onset of symptoms. Dependence on crutches or walkers occurs about 15 years after the first symptoms of the disorder are manifested. Some people with FXTAS show a gradual progression (i.e., symptoms remain stable for a period of time, but then suddenly worsen), with acute illness, major surgery, or other major life stressors causing symptoms to worsen more quickly.

[0009] The prevalence of FXTAS is unknown, but current estimates suggest that approximately 30%-40% of male FMR1 premutation carriers over age 50 in families with a known individual with Fragile X will eventually exhibit some features of FXTAS. There are no FDA-approved therapies for FXTAS, and currently used treatments target only the symptoms of the condition, not the pathophysiology itself.

[0010] Antipurinergic agents constitute a family of compounds that act on purinergic receptors. These receptors are the most abundant receptors in living organisms, and appear in the early stages of evolution, and are involved in regulating cell functions. Purinergic receptors are membrane receptors of a specific class that mediate various physiological functions, such as relaxation of certain types of smooth muscle, as a response to adenosine triphosphate (ATP) or adenosine release. Three different classes of purinergic receptors are known, referred to as P1, P2X and P2Y receptors. In addition, 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 purinergic receptors in activated cells and / or nearby cells, thereby regulating cell functions.

[0011] Chemical compounds that act on purinergic receptors are known. One of them is the compound suramin, which was first synthesized in the early 1900s. Suramin is a drug used to treat the parasitic disease trypanosomiasis, which is caused by protozoa of the species Trypanosoma brucei, more commonly known as African sleeping sickness. The drug is also used to treat river blindness. Since suramin is not orally bioavailable, it is administered by injection into a vein. However, at the doses required to treat African sleeping sickness, suramin can cause many side effects. These side effects include nausea, vomiting, diarrhea, abdominal pain, and a general feeling of malaise. Other side effects include skin sensations such as crawling or tingling, tenderness in the palms and soles of the feet, numbness in the extremities, watery eyes, and photophobia. In addition, nephrotoxicity is common, and peripheral neuropathy is also common when the drug is administered at high doses. Regarding pharmacokinetics, suramin is protein-bound in serum at approximately 99%-98% and has a half-life of 41-78 days, with an average of 50 days. Furthermore, suramin is not extensively metabolized and is eliminated by the kidneys. Therefore, in order to make suramin more effective as a treatment for conditions such as autism spectrum disorder, FXS or FXTAS, it would be desirable to minimize systemic levels of suramin by targeted delivery to brain tissue.

[0012] Recently, it has been reported that suramin has shown effects on several multi-system abnormalities in a mouse model of autism spectrum disorder. In addition, a small human study has been conducted on young 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 on March 13, 2013. doi: 10.1371 / journal. pone.0057380, PMCID: PMC3596371, PMID: 23516405. See also, PCT Patent Application Publication No. WO 2018 / 148580 A1, Vaughn et al., published on 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.

[0013] As can be seen from the foregoing, the treatment of autism spectrum disorder is still challenging. Although promising results have been obtained from early animal and human studies, it is recognized that a large amount of research is still needed to provide safe and effective anti-purinergic agents (such as suramin) for the treatment of autism. It is necessary to deliver the drug at an appropriate level to the brain tissue while also minimizing the level of blood and other tissues. However, it is difficult to deliver drugs across the blood-brain barrier ("BBB"), which is a natural protective mechanism for most mammals including humans. The blood-brain barrier is a highly selective semipermeable endothelial cell boundary that prevents solutes in the circulating blood from non-selectively crossing the extracellular fluid of the central nervous system where neurons reside. For compounds of higher molecular weight, this delivery across the blood-brain barrier is even more challenging. Suramin has a molecular weight of about 1300g / mol. An attempt to maximize the delivery across the blood-brain barrier is to use intranasal delivery to provide a higher level of drug at the nasal mucosa, with the aim of allowing the drug to enter the bloodstream in close proximity to the brain.

[0014] It is surprisingly found in the present invention that when certain penetration enhancers are used, the anti-purinergic agent suramin can potentially be safely and effectively administered intranasally to reach appropriate drug levels in brain tissue. Specifically, it has been surprisingly found that penetration enhancers such as methyl beta-cyclodextrin, caprylic acid capric acid polyethylene glycol-8 glyceride and 2-(2-ethoxyethoxy)ethanol are particularly useful for preparing intranasal suramin preparations with improved mucosal tissue permeability. These compositions also have the further unexpected benefit of targeting brain tissue while minimizing the systemic blood level of suramin drug actives. Therefore, these compositions will be useful for treating neurodevelopmental disorders, including but not limited to autism spectrum disorders, FXS, FXTAS, chronic fatigue syndrome (CFS) and post-traumatic stress syndrome (PTSD). Summary of the invention

[0015] Methods and compositions for treating cognitive, social or behavioral disabilities and neurodevelopmental disorders such as autism spectrum disorders, FSX, FXTAS, CFS and PTSD are described. More specifically, the present invention provides an intranasal administration (i.e., delivered via nasal route) composition comprising a therapeutically effective amount of an anti-purinergic agent (e.g., suramin) and a pharmaceutically acceptable salt, ester, solvate and prodrug thereof. Examples of useful compositions include intranasal administration compositions for treating autism spectrum disorders, comprising a therapeutically effective amount of suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof; a pharmaceutically acceptable carrier; and a permeation aid for delivering a therapeutically effective level of suramin actives to the brain. It is believed that these compositions minimize the systemic level of suramin while targeting brain tissue, thereby helping to minimize potential drug toxicity and adverse side effects.

[0016] The present invention is based on the surprising discovery that the transmucosal penetration of suramin as determined in in vitro assays is significantly higher when delivered in formulations containing various permeation enhancers such as methyl β-cyclodextrin, caprylocaproyl polyethylene glycol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol. When administered to mice, the compositions of the present invention were found to effectively deliver suramin to brain tissue and exhibit a brain tissue to plasma partition ratio. These compositions are designed to deliver suramin active across the blood-brain barrier to brain tissue while minimizing systemic levels to less than about 3 micromolar plasma levels and less than about 0.5 micromolar.

[0017] The methods of the present invention may be achieved by a method comprising intranasal administration of a single dose of an anti-purinergic agent. Alternatively, multiple doses may be administered according to various treatment regimens.

[0018] The present invention also provides a device for patient administration or self-administration of an anti-purinergic agent, comprising a nasal spray inhaler containing an anti-purinergic agent aerosol spray composition. This composition may include an anti-purinergic agent and a pharmaceutically acceptable dispersant or solvent system, wherein the device is designed (or alternatively metered) to disperse a certain amount of aerosol preparation by forming a spray containing a certain dose of anti-purinergic agent. In other embodiments, the inhaler may contain an anti-purinergic agent in a fine powder, and further combined with a microparticle dispersant and a diluent, or alternatively the combined anti-purinergic agent is incorporated into the dispersant particles or coated with the microparticle dispersant.

[0019] The present invention provides a method for treating cognitive, social or behavioral disability, comprising intranasally delivering a therapeutically effective amount of a pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of an anti-purinergic 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 disability 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 disability or neurodevelopmental disorder is an autism spectrum disorder.

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

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

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

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

[0027] In another aspect, the present invention provides a method wherein the anti-purinergic 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 an alkali metal salt, an alkaline earth metal salt, and an ammonium salt.

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

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

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

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

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

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

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

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

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

[0038] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least twice a day.

[0039] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least twice a week.

[0040] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least once a week.

[0041] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least once every two weeks.

[0042] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least once a month or at least once every 4 weeks.

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

[0044] In another aspect, the invention provides a method wherein the composition is delivered, ie, administered, at least about once every 50 days.

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

[0046] In another aspect, the 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 g / mole.

[0047] In another aspect, the invention provides methods wherein the plasma level of suramin in the patient is maintained at less than about 3 micromolar (μM) based on the suramin active.

[0048] In another aspect, the invention provides methods wherein the plasma level of suramin is maintained at less than about 2.75 micromolar based on suramin active.

[0049] In another aspect, the invention provides methods wherein the plasma level of suramin is maintained at less than about 2.5 micromolar based on suramin active.

[0050] In another aspect, the invention provides methods wherein the plasma level of suramin is maintained at less than about 2 micromolar based on suramin active.

[0051] In another aspect, the invention provides methods wherein the plasma level of suramin is maintained at less than about 1 micromolar based on suramin active.

[0052] In another aspect, the invention provides methods wherein the plasma level of suramin is maintained at less than about 0.5 micromolar based on suramin active.

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

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

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

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

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

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

[0059] In another aspect, the invention provides a method wherein the brain tissue level of suramin is at least about 500 ng / ml.

[0060] In another aspect, the invention provides a method wherein the brain tissue to plasma partition ratio is at least about 0.05.

[0061] In another aspect, the invention provides a method wherein the brain tissue to plasma partition ratio is at least about 0.1.

[0062] In another aspect, the invention provides a method wherein the brain tissue to plasma partition ratio is at least about 0.25.

[0063] In another aspect, the invention provides a method wherein the brain tissue to plasma partition ratio is at least about 0.50.

[0064] In another aspect, the invention provides methods wherein the composition comprises from about 0.01 mg to about 200 mg per unit dose of suramin, based on the suramin active.

[0065] In another aspect, the invention provides methods wherein the composition comprises from about 0.01 mg to about 100 mg per unit dose of suramin, based on the suramin active.

[0066] In another aspect, the invention provides methods wherein the composition comprises from about 0.01 mg to about 50 mg per unit dose of suramin, based on the suramin active.

[0067] In another aspect, the invention provides methods wherein the composition comprises from about 0.01 mg to about 25 mg per unit dose of suramin, based on the suramin active.

[0068] In another aspect, the invention provides methods wherein the composition comprises from about 0.01 mg to about 10 mg per unit dose of suramin, based on the suramin active.

[0069] In another aspect, the invention provides methods wherein the composition comprises from about 0.1 mg / kg / week to about 20 mg / kg / week of suramin based on the suramin active and the patient's body weight.

[0070] In another aspect, the invention provides methods wherein the composition comprises from about 0.025 mg / kg to about 10 mg / kg per unit dose of suramin based on the suramin active and the patient's body weight.

[0071] In another aspect, the invention provides methods wherein the composition comprises from about 0.05 mg / kg to about 6 mg / kg per unit dose of suramin based on the suramin active and the patient's body weight.

[0072] In another aspect, the invention provides methods wherein the composition comprises from about 0.0476 mg / kg to about 5.720 mg / kg per unit dose of suramin based on the suramin active and the patient's body weight (mass).

[0073] In another aspect, the invention provides methods wherein the composition comprises less than about 1 mg / kg / unit dose of suramin based on the suramin active and the patient's body weight.

[0074] In another aspect, the invention provides methods wherein the composition comprises less than about 0.5 mg / kg / unit dose of suramin based on the suramin active and the patient's body weight.

[0075] In another aspect, the invention provides methods wherein the composition comprises less than about 0.25 mg / kg / unit dose of suramin based on the suramin active and the patient's body weight.

[0076] In another aspect, the invention provides methods wherein the composition comprises less than about 0.1 mg / kg / unit dose of suramin based on the suramin active and the patient's body weight.

[0077] In another aspect, the invention provides methods wherein the composition comprises less than about 400 mg / m suramin based on the suramin active and the body surface area (BSA) of the patient. 2 / unit dose of suramin.

[0078] In another aspect, the invention provides methods wherein the composition comprises less than about 200 mg / m suramin based on the suramin active and the body surface area (BSA) of the patient. 2 / unit dose of suramin.

[0079] In another aspect, the invention provides methods wherein the composition comprises less than about 100 mg / m suramin based on the suramin active and the body surface area (BSA) of the patient. 2 / unit dose of suramin.

[0080] In another aspect, the invention provides methods wherein the composition comprises less than about 50 mg / m suramin based on the suramin active and the patient's body surface area (BSA). 2 / unit dose of suramin.

[0081] In another aspect, the invention provides methods wherein the composition comprises less than about 25 mg / m suramin based on the suramin active and the patient's body surface area (BSA). 2 / unit dose of suramin.

[0082] In another aspect, the invention provides a method wherein the composition comprises from about 10 mg / m suramin active and the body surface area (BSA) of the patient. 2 About 300 mg / m 2 / unit dose of suramin.

[0083] In another aspect, the invention provides methods wherein the patient has a plasma level of suramin active of less than about 80 μg*day / L under the AUC.

[0084] In another aspect, the invention provides methods wherein the patient has a plasma level of suramin active of less than about 75 μg*day / L under the AUC.

[0085] In another aspect, the invention provides methods wherein the patient has a plasma level of suramin active of less than about 50 μg*day / L under the AUC.

[0086] In another aspect, the invention provides methods wherein the patient has a plasma level of suramin active of less than about 25 μg*day / L under the AUC.

[0087] In another aspect, the invention provides methods wherein the patient has a plasma level of suramin active of less than about 10 μg*day / L under the AUC.

[0088] In another aspect, the present invention provides a method wherein the patient's plasma level of suramin active is C max is less than about 75 micromoles per dose of the pharmaceutical composition.

[0089] In another aspect, the present invention provides a method wherein the patient's plasma level of suramin active is C max is less than about 7.5 micromoles per dose of the pharmaceutical composition.

[0090] In another aspect, the present invention provides a method wherein the patient's plasma level of suramin active is C max is less than about 0.1 micromolar. Although there is no minimum C max , but the amount may generally be higher than about 0.01 micromoles per dose of the pharmaceutical composition.

[0091] In another aspect, the present invention provides a method wherein the composition is in the form of a nasal spray, ie, a spray for intranasal administration.

[0092] In another aspect, the invention provides a method wherein each unit dose comprises from about 0.01 ml to about 0.5 ml of liquid.

[0093] In another aspect, the invention provides a method wherein each unit dose comprises about 0.1 ml of liquid.

[0094] In another aspect, the invention provides methods wherein the composition exhibits, i.e., is capable of providing, based on the suramin active, about 1 microgram / cm 2 of cultured human respiratory tissue. 2 / hour to about 200 μg / cm 2 / h of suramin penetration.

[0095] In another aspect, the present invention provides methods wherein the composition further comprises an agent selected for osmolality control.

[0096] In another aspect, the invention provides methods wherein the composition further comprises an agent selected for osmolality control, wherein the agent is selected from a salt, such as, for example, sodium chloride.

[0097] In another aspect, the present invention provides a method wherein the composition further comprises a thickener.

[0098] In another aspect, the present invention provides a method 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.

[0099] In another aspect, the invention provides a method wherein the autism spectrum disorder comprises one or more symptoms selected from the group consisting of difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0100] In another aspect, the invention provides methods wherein the treatment of autism spectrum disorder, FXS, FXTAS, CFS or PTSD comprises improving one or more symptoms relative to the patient's symptoms prior to said administering, wherein the one or more symptoms are selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

[0101] In another aspect, the invention provides methods wherein said treating of autism spectrum disorder, FXS, FXTAS, CFS or PTSD comprises improving said patient's assessment score relative to said patient's score prior to said administering.

[0102] In another aspect, the present invention provides a method wherein said patient's assessment score is improved by 10% or more relative to said patient's score before said administering.

[0103] In another aspect, the present invention provides a method wherein the assessment score is selected from the group consisting of ABC, ADOS, ATEC, CARSCGI, and SRS.

[0104] In another aspect, the invention provides a method wherein the patient's ADOS score improves by 1.6 or more relative to the score before said administration, or a corresponding improvement in performance in a similar test.

[0105] In another aspect, the invention provides methods wherein the p-value for the improvement in the ADOS score or a similar test is 0.05 or less.

[0106] In another aspect, the invention provides methods wherein the size effect of the improvement in the ADOS score or a similar test is about 1 or greater.

[0107] In another aspect, the invention provides methods wherein the effect size for improvement in the ADOS score or a similar test is about 2.9 or greater.

[0108] In another aspect, the present invention provides a method for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD, comprising administering to a person in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of an anti-purinergic agent or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein the plasma level of the anti-purinergic agent is maintained at less than about 3 micromolar, or less than about 1 micromolar, or less than about 0.5 micromolar.

[0109] In another aspect, the present invention provides a pharmaceutical composition for intranasal delivery for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD, comprising:

[0110] (a) a therapeutically effective amount of an anti-purinergic agent or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, and

[0111] (b) Penetration enhancers.

[0112] In another aspect, the present invention provides a composition further comprising (c) water.

[0113] In another aspect, the present invention provides a composition wherein the anti-purinergic agent is suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.

[0114] In another aspect, the invention provides compositions such that when the composition is administered to a human in need thereof, the plasma level of suramin is maintained at less than about 3 micromolar based on suramin active.

[0115] In another aspect, the invention provides compositions such that when the composition is administered to a human in need thereof, the plasma level of suramin is maintained at less than about 1 micromolar or less than about 0.5 micromolar based on suramin active.

[0116] 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 for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD in a patient in need thereof, such as a human.

[0117] In another aspect, the invention provides uses such that the plasma level 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.

[0118] In another aspect, the invention provides a device for patient administration, wherein patient administration includes administration selected from self-administration and administration to a patient by an individual other than the patient, the device comprising a nasal spray inhaler for administering a composition comprising an anti-purinergic agent, wherein the device is designed (or alternatively metered) to dispense an amount of the anti-purinergic agent for treating autism spectrum disorder, FXS, FXTAS, CFS or PTSD in a patient in need thereof.

[0119] In another aspect, the invention provides a device wherein the anti-purinergic agent comprises a composition selected from a solution, an emulsion, or a powder.

[0120] These and other aspects of the invention will be apparent from the disclosure herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] Figure 1 Shown is a graph of cumulative drug permeation (in mg) versus time (in hours) for aqueous suramin compositions containing three different permeation enhancers and a control composition containing no permeation enhancer.

[0122] Figure 2 Shown is a graph of cumulative drug permeation (in mg) versus time (in hours) for aqueous suramin compositions containing five different permeation enhancers and a control composition containing no permeation enhancer.

[0123] Figure 3 Shown is a graph of total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered by weekly intraperitoneal (IP) injections of 20 mg / kg to mice starting at 9 weeks of age and continuing for four weeks (i.e., given at 9, 10, 11, and 12 weeks of age).

[0124] Figure 4A graph comparing total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered intranasally (IN) daily for 28 days is shown. A composition of the invention comprising IN suramin (at a concentration of 100 mg / mL x 6 mL / spray) was administered starting at 9 weeks of age (i.e., given daily during 9, 10, 11, and 12 weeks of age) once daily with one spray / nostril (with approximately 2 minutes between each application to ensure absorption) for 28 days (a total of 56 sprays over a 28 day period).

[0125] Figure 5 A graph comparing total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered intranasally (IN) every other day for 28 days is shown. A composition of the invention comprising IN suramin (at a concentration of 100 mg / mL x 6 mL / spray) was administered starting at 9 weeks of age (i.e., daily during 9, 10, 11, and 12 weeks of age) once every other day as one spray / nostril (with approximately 2 minutes between each application to ensure absorption) for 28 days (a total of 28 sprays over a 28-day period).

[0126] Figure 6 Shown is a graph comparing total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered intranasally (IN) once weekly for 4 weeks.

[0127] Beginning at 9 weeks of age (i.e., given daily during 9, 10, 11, and 12 weeks of age) once a week with one spray / nostril (approximately 2 minutes between each application to ensure absorption) for 4 weeks (28 days) (a total of 8 sprays over a 28-day period).

[0128] Figure 7 Shown is a graph comparing the total percentage of suramin in mouse plasma when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0129] Figure 8 Shown is a graph comparing the total percentage of suramin in mouse brain tissue when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0130] Fig. 9Shown is a graph comparing the total percentage of suramin in mouse plasma and brain tissue when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0131] Fig.10 Shown is a graph comparing the brain tissue to plasma partitioning ratio of suramin in mice when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days). DETAILED DESCRIPTION

[0132] definition

[0133] As used herein, the following terms and abbreviations have the indicated meanings unless expressly stated to the contrary.

[0134] As used herein, the term "ABC", also known as the "Aberrant Behavior Checklist", is a rating scale used to assess autism.

[0135] As used herein, the term "ADOS", also known as the "Autism Diagnostic Observation Schedule", is a tool used to diagnose and assess 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.

[0136] 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. ATEC was originally designed to evaluate the effectiveness of autism treatments, but is also used as a screening tool.

[0137] As used herein, the term "AUC", also known as "area under the curve", is a standard term in pharmacology, particularly pharmacokinetics. The term refers to the definite integral of a curve that describes the change in drug concentration in plasma over time. In practice, drug concentrations are measured at certain discrete time points, and the trapezoidal rule is used to estimate AUC. AUC gives a measure of bioavailability and refers to the fraction of drug absorbed systemically. Knowing this, a technician can also determine the clearance rate of a drug. AUC reflects the actual body exposure to a drug after administering a dose of the drug, usually expressed in mg*h / L or μg*h / L (where "h" represents hours). Alternatively, AUC can be expressed in mg*day / L or μg*day / L.

[0138] As used herein, the term "based on suramin actives" is intended to provide a basis for determining or calculating the amount of suramin based on a suramin molecular weight (i.e., molar mass) of 1297.26 g / mole. This is an important consideration in determining the amount of suramin when suramin is delivered as a salt or other form (having a different overall molecular weight, such as, for example, the hexasodium salt having a molecular weight (i.e., molar mass) of 1429.15 g / mole).

[0139] As used herein, the term "CARS", also known as "The Childhood Autism Rating Scale", is a behavioral rating scale designed to aid in the diagnosis and assessment of autism.

[0140] As used herein, the term "CFS" is also known as "chronic fatigue syndrome."

[0141] As used herein, the term "CGI", also known as the "Clinical Global Impression" rating scale, is a measure of symptom severity, treatment response, and treatment efficacy in treatment studies for patients with psychological disorders.

[0142] As used herein, the term “C max " is a standard term in pharmacology, particularly pharmacokinetics, used to define the maximum (or peak) serum concentration of a drug achieved in a specific compartment or test area of ​​the body after administration of the drug and before a second dose is administered.

[0143] As used herein, the term "FXS" means Fragile X syndrome.

[0144] As used herein, the term "FXTAS" means fragile X-associated tremor / ataxia syndrome.

[0145] As used herein, the term "IN" means intranasal.

[0146] The term "pharmaceutically acceptable" is used herein with respect to the compositions (i.e. formulations) of the invention and also with respect to pharmaceutically acceptable salts, esters, solvates and prodrugs of suramin. The pharmaceutical compositions of the invention comprise a therapeutically effective amount of suramin and a pharmaceutically acceptable carrier. These carriers may contain a wide range of excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having an acceptable safety profile. The compositions are manufactured using conventional formulation techniques. See, for example, Remington's Pharmaceutical Sciences, 17 th edition, edited by Alfonso R. Gennaro, Mack Publishing Company, Easton, PA, 17th edition, 1985. Regarding pharmaceutically acceptable salts, they are described below.

[0147] As used herein, the term "PTSD" is also referred to as "post-traumatic stress syndrome."

[0148] As used herein, the term "SRS", also referred to herein as the "Social Responsiveness Scale", is a measure of autism spectrum disorder.

[0149] The term "subject" means a human patient or animal in need of treatment or intervention for an autism spectrum disorder.

[0150] The term "therapeutically effective" means to provide a subject (such as a human patient in need of treatment) with a significant or demonstrable benefit (as understood by a medical practitioner) required amount of suramin. The conditions intended to be treated include, for example, autism, childhood disintegrative disorder, non-specific pervasive developmental disorder (PDD-NOS) and Asperger's syndrome. For example, various clinical parameters can be used to assess or quantify significant or demonstrable benefits. Proof of benefit can also include those provided by a model, including but not limited to in vitro models, in vivo models and animal models. The example of such an in vitro model is the permeation of a drug active substance studied by simulating permeation across the nasal mucosa using cultured human respiratory tissue (EpiAirway AIR-100).

[0151] As used herein, the term "intranasal" ("IN") for pharmaceutical compositions and actives therein means a composition delivered across the mucosal membrane in the nasal cavity by nasal administration. This membrane is a thin mucosal membrane with good vascularization. In addition, this mucosa is in close proximity to the brain and provides a means of maximizing drug delivery across the blood-brain barrier. The blood-brain barrier is a highly selective semipermeable boundary that separates circulating blood from the extracellular fluid in the brain and central nervous system. The delivery of therapeutic agents to specific areas of the brain presents a challenge for the treatment of many brain disorders. It should be noted that transmucosal administration is different from topical administration and transdermal administration. The U.S. Food and Drug Administration (USFood&Drug Administration) provides a wide range of drug administration routes (i.e., "administration routes") standards. FDA provides the following definitions, such as for endosinusial, intracerebral, intranasal, nasal, topical, transdermal, and transmucosal drug administration routes. Routes of administration useful for the present invention include intranasal, intranasal, and transnasal, recognizing that transmucosal delivery through the nasal mucosa is also intended to be included. These routes of administration are distinguished from inhalation, which is intended to deliver the drug to the lungs and bronchi. See, for example, U.S. Pat. No. 8,785,500 to Charney et al., issued July 22, 2014, which discloses examples of methods and compositions for intranasal administration of pharmaceutical actives.

[0152]

[0153] *National Cancer Institute

[0154] See, https: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / DataStandardsManualmonographs / ucm071667.htm.

[0155] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating a disorder, such as autism and other central nervous system disorders, or preventing or reducing the risk of contracting a disorder or exhibiting symptoms of a disorder, ameliorating or preventing the underlying cause of symptoms, inhibiting a disorder, arresting the development of a disorder, relieving a disorder, causing regression of a disorder, or stopping symptoms of a disorder (prophylactically and / or therapeutically).

[0156] In various embodiments, the methods of treatment using suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof or a pharmaceutical composition of the invention also include the use of suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof in the manufacture of a medicament for a desired treatment, such as for autism spectrum disorder.

[0157] Suramin

[0158] The present invention provides intranasal administration for treating autism spectrum disorders utilizing a therapeutically effective amount of the anti-purinergic agent suramin, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof; a penetration enhancer; and also a pharmaceutically acceptable carrier.

[0159] Suramin is a sulfonic acid drug compound corresponding to CAS Registry Number 145-63-1 and ChemSpider ID 5168. One of the chemical names of suramin is: 1,3,5-naphthalenetrisulfonic acid, 8,8'-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]]bis-. The compound is a drug used to treat African sleeping sickness and river blindness and is known by the trade names Antrypol, 309F, 309Fourneau, Bayer 205, Germanin, Moranyl, Naganin, and Naganine. However, the drug is not approved by the US FDA. The drug is administered by intravenous injection. Suramin has reportedly been studied in a mouse model of autism and in Phase I / II human trials. See Naviaux, J Cetal., "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, May 26, 2017: 4(7): 491-505.

[0160] Suramin is reported to have a half-life of between about 41 and 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.

[0161] The chemical formula of suramin is C 51 H 40 N6O 23 S6. Thus, suramin has a molecular weight (i.e., molar mass) of 1297.26 g / mol. Suramin is typically provided as a sodium sulfonate salt, such as the hexasodium salt, which has a molecular weight (i.e., molar mass) of 1429.15 g / mol. Note that these molecular weight values ​​will vary slightly, depending on the atomic weight values ​​used for the calculations. The chemical structure of suramin is shown immediately below.

[0162]

[0163] Pharmaceutically acceptable salts, esters, solvates and prodrugs of suramin can be used in the methods and compositions of the present invention. As used herein, "pharmaceutically acceptable salts, esters, solvates and prodrugs" refer to suramin derivatives. 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 salts, sodium salts and potassium salts. Examples of alkaline earth metal salts include calcium salts and magnesium salts. Ammonium salts NH4 can be prepared + itself, as well as various monoalkyl, dialkyl, trialkyl and tetraalkyl ammonium salts. In addition, one or more alkyl groups of such ammonium salts may be further substituted with groups such as hydroxyl to provide ammonium salts of alkanolamines. Ammonium salts derived from diamines such as 1,2-diaminoethane are contemplated herein. Suramin hexasodium salt may be used herein.

[0164] Pharmaceutically acceptable salts, esters, solvates and prodrugs of suramin can be prepared from the parent compound by conventional chemical methods. Typically, salts can be prepared by reacting the compound in free acid form with a stoichiometric amount of an appropriate base in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Esters of suramin can be prepared by reacting the parent compound with an alcohol and removing the water formed by the reaction. Alternatively, other methods can be used. Any of one to all six sulfonate groups of suramin can be esterified to form a monoester to six esters. Examples of these esters include mesylate, methanesulfonate, CH3SO3-; triflate, trifluoromethanesulfonate, CF3SO3-; ethanesulfonate, esilate, esylate, C2H5SO3-; toluenesulfonate (toluenesulfonate), CH3C6H4SO3-; benzenesulfonic acid (benzenesulfonate), C6H5SO3-; closilate, closylate, chlorobenzenesulfonate, ClC6H4SO3-; camphorsulfonate (camsilate, camsylate, (C 10 H 15 O) SO3-; pipsylate (a derivative of p-iodobenzenesulfonate); and nosylate (a derivative of p-nitrobenzenesulfonate).

[0165] Suramin solvate means that one or more solvent molecules are associated with one or more suramin molecules, including fractional solvates, such as, for example, 0.5 and 2.5 solvates. The solvent can be selected from a wide range of solvents, including water, ethanol, isopropanol, etc. The prodrug of suramin can be prepared using conventional chemical methods, depending on the selected prodrug. A prodrug is a drug or compound that is metabolized (i.e., converted in vivo) to a pharmacologically active drug after administration. When the drug itself is poorly absorbed from the gastrointestinal tract, a prodrug can be designed to improve bioavailability. Prodrugs are intended to include covalently bonded carriers that release the active parent drug of the present invention in vivo when such prodrugs are administered. In some classifications, esters are considered prodrugs, such as suramin esters described herein. Other types of prodrugs can include sulfonamide derivatives and anhydrides.

[0166] Additionally, the various esters and prodrugs may include further derivatization to produce polyethylene glycol (PEG) and polypropylene glycol (PPG) derivatives and mixed derivatives, one example of which is a PEGylated derivative.

[0167] dose

[0168] For the treatment of African sleeping sickness, suramin is typically administered according to a treatment regimen of five intravenous injections of 20 mg / kg of the drug every 3-7 days over a total period of 4 weeks. Note that this suramin dose for the treatment of African sleeping sickness is relatively high, and the treatment regimen requires relatively frequent dosing, both of which can potentially cause drug toxicity and adverse reactions. Compared to the acute and potentially life-threatening African sleeping sickness, the potential for such toxicity and adverse reactions will be less tolerated for the treatment of conditions such as autism spectrum disorders, FXS or FXTAS (particularly children's).

[0169] For use of the invention in 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 (such as a nasal spray dose), based on the suramin active, wherein each administered spray dose will contain about 0.1 ml of liquid.

[0170] Compositions can also be determined on a weight basis. In one embodiment, the compositions useful herein contain from 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. In another embodiment, the compositions herein contain from 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.

[0171] For these aforementioned compositions comprising a specified amount or weight percent of suramin or the amount or weight percent of suramin is determined or calculated based on the actual amount of the suramin moiety (which has a molar mass of 1297.26 g / mol) and does not include the additional weight provided by any counterion or ester, solvate or prodrug moiety when a suramin salt, ester, solvate or prodrug is used. In other words, the composition is based on the amount or weight percent of the suramin chemical moiety.

[0172] In addition, because the present invention relates to intranasal delivery compositions and because it is highly desirable to limit systemic exposure, a unit dose can be formulated to limit systemic plasma levels of suramin. Typically, it is desirable to maintain suramin plasma levels at a concentration below about 3 micromolar. In further embodiments, it is desirable to maintain suramin plasma levels at a concentration below about 2 micromolar. In further embodiments, it is desirable to maintain suramin plasma levels at a concentration below about 1 micromolar. In further embodiments, it is desirable to maintain suramin plasma levels at a concentration below about 0.1 micromolar. In further embodiments, it is desirable to maintain suramin plasma levels at a concentration below about 0.05 micromolar. In further embodiments, it is desirable to maintain suramin plasma levels at a concentration below about 0.01 micromolar. Although a minimum systemic suramin plasma level may not be required as long as appropriate brain blood and tissue levels are maintained, it may generally be desirable that suramin plasma levels be greater than about 1 nanomolar.

[0173] Furthermore, because 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 undesirable side effects and maintain an appropriate safety window. Such systemic level limitation can be achieved by controlling PK / PD parameters. In some embodiments, a unit dose should exhibit at least one of the following plasma pharmacokinetic parameters for delivery of the unit dose: C max Less than about 75 micromolar (i.e., μM), or less than about 7.5 micromolar, or less than about 0.1 micromolar, or AUC less than about 80 μg*day / L, or less than about 75 μg*day / L, or less than about 50 μg*day / L, or less than about 25 μg*day / L, or less than about 10 μg*day / L. C max It may be greater than at least about 0.01 micromolar. max The values ​​can be converted from micromoles to ng / ml (based on suramin active, using a molecular weight of 1297.26 g / mole), meaning that 1 micromole is equivalent to 1297.26 ng / ml. If the skilled person wants to have an amount based on the hexasodium salt, a value of 1429.15 g / mole can be used for the conversion calculation.

[0174] Treatment methods and dosing regimens

[0175] 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 disorders, FXS or FXTAS and other neurological disorders.

[0176] The method comprises nasally administering to a human patient in need thereof a therapeutically effective amount of suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.

[0177] Various dosing regimens can be formulated and used based on the skills and knowledge of the physician or other practitioner. In some embodiments, the composition of the unit dose can be administered at least once a day, as described herein. In other embodiments, the composition of the unit dose can be administered at least twice a day, or at least once a week, or at least twice a week. Based on the pharmacokinetic and pharmacodynamic parameters of suramin, the dosage and regimen can be appropriately changed. Suramin is protein-bound in serum at approximately 99%-98% and has a half-life of 41-78 days, with an average of 50 days.

[0178] Therapy 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 therapy.

[0179] Evaluation of treatment

[0180] The present invention provides methods wherein 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, disruptive behavior and repetitive behavior. Various rating scales can be used to evaluate patients with autism spectrum disorder, FXS, FXTAS, CFS or PTSD to determine the severity level of their disorder and any improvements or changes after administration of treatment.

[0181] For example, the method provided by the present invention, wherein the treatment of autism spectrum disorder, FXS, FXTAS, CFS or PTSD comprises improving multiple or multiple symptoms of the patient relative to the symptoms before the therapy. The degree of improvement can be determined by comparing the evaluation score of the patient's symptoms relative to the score of the patient's symptoms before the administration. It is desirable to provide an improvement of 10% or more relative to the score of the patient before the administration of the treatment.

[0182] Examples of assessment scales for evaluating autism spectrum disorders include those selected from the group consisting of ABC, ADOS, ATEC, CARS CGI, and SRS.

[0183] The term “ABC” also known as the “Aberrant Behavior Checklist” is a rating scale used to assess 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 that involve social interactions between the examiner and the person being assessed. The term “ATEC” also known as the “Autism Treatment Evaluation Scale” is a 77-item diagnostic assessment tool developed at the Autism Research Institute. ATEC was originally designed to evaluate the effectiveness of autism treatments, but is also used as a screening tool. The term “CARS” also known as the “Autism Rating Scale in Childhood” is a behavioral rating scale designed to help diagnose and assess autism. The term “CGI” also known as the “Clinical Global Impression” rating scale is a measure of symptom severity, treatment response, and treatment efficacy in treatment studies for patients with psychological disorders. The term “SRS” also known as the “Social Responsiveness Scale” used in this article is a measure of autism spectrum disorders.

[0184] For example, method provided by the invention, wherein the patient's ADOS score improves by 1.6 or more relative to the score before applying the treatment, or the corresponding performance improvement in similar tests. In addition, method provided by the invention, wherein the p-value of the improvement of ADOS score or similar tests is 0.05 or less. On the other hand, method provided by the invention, wherein the size effect of the improvement of ADOS score or similar tests is about 1 or greater or at most about 2.9 or greater.

[0185] Intranasal formulations and penetration enhancers

[0186] The target indications of the compositions of the present invention relate to autism, FXS and FXTAS and other central nervous system diseases. Therefore, efforts are made to provide formulations that can easily reach brain regions by crossing the blood-brain barrier. A feasible route of administration is via nasal delivery by a nasal drug delivery system (i.e., intranasal (IN) formulation spray).

[0187] Useful compositions for intranasal delivery can be in the form of nasal sprays. These compositions can have actives in the form of aqueous compositions. In other embodiments, the active agent can be a fine powder, and further combined with a microparticle dispersant and a diluent, or alternatively combined to form or coat a microparticle dispersant. These compositions will generally be approximately about 0.01 ml to about 0.5 ml, with a target volume of about 0.1 ml / spray. One to two sprays can be applied to provide a unit dose.

[0188] The pharmaceutical composition herein may include a penetration enhancer. Surprisingly, the following penetration enhancers were found to increase the transmucosal tissue penetration of suramin: methyl beta-cyclodextrin, caprylocaproyl macrogol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol. The methyl beta-cyclodextrin material is also known as CAS registration number 128446-36-6 and trade name Methy betadex. The caprylocaproyl macrogol-8 glyceride material is also known as caprylocaproyl polyoxyl-8 glyceride and PEG-8 caprylic / capric glyceride, CAS registration number 85536-07-8 and trade name The material 2-(2-ethoxyethoxy)ethanol is also known as diethylene glycol ethyl ether, CAS registration number 111-90-0 and trade name Carbitol TM and P.

[0189] The penetration enhancer is typically used at about 40% by weight of the composition. Other useful ranges are 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.

[0190] The water in the composition is usually succinct (QS). The abbreviation QS stands for succinct, and means adding as much of an ingredient (in this case water) as possible, but no more, to achieve the desired result.

[0191] Other ingredients may include various salts for osmolality control and thickening agents.

[0192] In some embodiments, the composition may include the following functional ingredients:

[0193] 1. Active ingredient: Suramin, concentration 10 to 200 mg / mL

[0194] 2. Solvent / carrier, such as water

[0195] 3. Tissue permeation enhancer

[0196] 4. One or more preservatives

[0197] 5. Thickeners used to change the viscosity of the spray solution, and

[0198] 6. Buffer (pH adjuster) or osmolarity agent.

[0199] These formulations can be prepared using standard formulation and compounding techniques familiar to those of ordinary skill in the pharmaceutical and formulation arts.

[0200] In one embodiment, the compositions or formulations of the present invention comprise suramin or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof and a pharmaceutically acceptable carrier. These formulations can be manufactured using standard formulation and mixing techniques familiar to those of ordinary skill in the pharmaceutical and formulation arts.

[0201] In one aspect, the pharmaceutical composition is selected from a solution, a suspension or a dispersion for use as a spray or an aerosol. In other aspects, the preparation can be delivered as drops by a nasal dropper or applied directly to the nasal cavity. Other pharmaceutical compositions are selected from the group consisting of a gel, an ointment, a lotion, an emulsion, a cream, a foam, a mousse, a liquid, a paste, a jelly or a tape, which is applied to the nasal cavity.

[0202] Compositions useful herein wherein the pharmaceutically acceptable carrier is selected from water or a mixture of water and other water miscible components. In the case of an emulsion, the components need not be miscible with water.

[0203] In other embodiments, the composition may include a buffer to maintain the pH of the pharmaceutical formulation, a pharmaceutically acceptable thickener, a humectant, and a surfactant. Suitable buffers for use in the present invention include, for example, hydrochloride, acetate, citrate, carbonate, and phosphate buffers.

[0204] Pharmaceutically acceptable thickeners can be used to maintain the viscosity of the present composition at a desired level. Thickeners that can be used according to the present invention include, for example, xanthan gum, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, sodium carboxymethylcellulose (Na CMC) and mixtures thereof. The concentration of the thickener will depend on the selected medicament and the required viscosity.

[0205] The composition of the present invention also comprises a tolerance enhancer to reduce or prevent mucosal dryness (moisturizer) and prevent irritation thereof. Suitable tolerance enhancers that can be used in the present invention include, for example, moisturizers, sorbitol, propylene glycol, mineral oil, vegetable oil and glycerol; soothing agents, membrane conditioners, sweeteners and mixtures thereof. The concentration of one or more tolerance enhancers in the composition of the present invention will also vary with the selected agent.

[0206] In order to enhance the absorption of the drug by the nasal mucosa, an acceptable surfactant can be added to the intranasal preparation for treatment. Suitable surfactants that can be used according to the present invention include polyoxyethylene derivatives (such as, for example, Tween 80), polyoxyethylene 40 stearates, polyoxyethylene 50 stearates, fusidates, bile salts and Octoxynol of the fatty acid partial esters of sorbitan. Suitable surfactants include nonionic surfactants, anionic surfactants and cationic surfactants. These surfactants can be present in the intranasal preparation with a concentration in the range of from about 0.001% to about 20% by weight.

[0207] 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 may be used according to the present invention include, for example, bioadhesives and / or swelling / thickening agents.

[0208] Any other suitable absorption enhancer as known in the art may also be used in the present invention.

[0209] Preservatives may also be added to the compositions of the present invention. Suitable preservatives that may be used with the compositions of the present invention include, for example, benzyl alcohol, parabens, thimerosal, chlorobutanol, and benzalkonium, with benzalkonium chloride being preferred. Typically, the preservative will be present in the compositions of the present invention in a concentration of up to about 2% by weight. However, the exact concentration of the preservative will vary depending on the intended use and can be readily determined by one skilled in the art.

[0210] Absorption enhancers include (i) surfactants; (ii) bile salts (including sodium taurocholate); (iii) phospholipid additives, mixed micelles, or liposomes; (iv) alcohols (including polyols as discussed above, for example propylene glycol or polyethylene glycol, such as PEG3000, etc.); (v) enamines; (vi) nitric oxide donor compounds; (vii) long chain amphiphilic molecules; (viii) small hydrophobic uptake enhancers; (ix) sodium or salicylic acid derivatives; (x) acetoacetic glycerides; (xi) cyclodextrin or cyclodextrin derivatives; (xii) medium or short chain (e.g., C1 to C12) fatty acids; (xiii) chelating agents; (xiv) amino acids or salts thereof; and (xv) N-acetylamino acids or salts thereof.

[0211] 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 polyols.

[0212] An isotonizing agent can improve the tolerability of the formulation in the nasal cavity. A common isotonizing 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.

[0213] The thickener can improve the overall viscosity of the composition, preferably to a value close to the viscosity of the nasal mucosa. Suitable thickeners include methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate, hydroxypropylmethylcellulose, and chitosan.

[0214] Humectants or anti-irritants improve the tolerability of the composition upon repeated application. Suitable compounds include, for example, glycerol, tocopherol, mineral oil and chitosan.

[0215] Various additional ingredients may be used in the compositions of the present invention. The compositions may include one or more other ingredients selected from preservatives, antioxidants, emulsifiers, surfactants or wetting agents, emollients, film formers or viscosity modifiers. Based on the knowledge of those of ordinary skill in the pharmaceutical and formulation fields, these components may be employed and used at levels suitable for the formulation. The amount used may range from less than 1% by weight to as high as 90% or even in excess of 99% by weight.

[0216] On the one hand, a preservative may be included. On the other hand, an antioxidant may be included. On the other hand, an emulsifier may be included. On the other hand, an emollient may be included. On the other hand, a viscosity modifier may be included. On the other hand, a surfactant or wetting agent may be included. On the other hand, a film former may be included. On the other hand, 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, an aerosol. Based on the knowledge of those of ordinary skill in the art of medicine and formulation, these components may be adopted and used at a level suitable for the formulation.

[0217] It has surprisingly been found that penetration enhancers such as methyl beta-cyclodextrin, caprylocaproyl polyethylene glycol-8 glyceride, and 2-(2-ethoxyethoxy)ethanol are particularly useful for preparing intranasal suramin formulations with improved mucosal tissue penetration.

[0218] In another aspect, at least one preservative can be selected from the group consisting of parabens (including butyl paraben, ethyl paraben, methyl paraben and propyl paraben), sodium acetone bisulfite, alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butyl hydroxyanisole, butylene glycol, calcium acetate, calcium chloride, calcium lactate, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol. , edetic acid, glycerol, hexidine, imidurea, isopropyl alcohol, monothioglycerol, pentetic acid, phenol, phenoxyethanol, phenylethanol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium nitrate, potassium sorbate, propionic acid, propyl gallate, propylene glycol, sodium propyl paraben, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, sulfur dioxide, thimerosal, zinc oxide N-acetylcysteine ​​or a combination thereof. Based on the knowledge of ordinary technicians in the field of medicine and formulation, these components can be adopted and used at a level suitable for the formulation. The amount can be in the range of less than 1% by weight to up to 30% by weight.

[0219] On the other hand, at least one antioxidant can be selected from the group consisting of: sodium acetone bisulfite, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, lauryl gallate, isoascorbic 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. Based on the knowledge of ordinary technicians in the field of medicine and formulation, these components can be adopted and used at a level suitable for the formulation. The amount can be in the range of less than 1% by weight to up to 30% by weight.

[0220] On the other hand, at least one emulsifier can be selected from the group consisting of gum arabic, agar, ammonium alginate, calcium alginate, carbomer, sodium carboxymethylcellulose, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, glyceryl monooleate, glyceryl monostearate, hectorite, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl methylcellulose, 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 castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyethylene glycol 15 hydroxystearate, polyoxyglycerol ester, potassium alginate, propylene glycol alginate, propylene glycol dilaurate, propylene glycol monolaurate, soapstone, sodium borate, sodium citrate dehydrate, sodium lactate, sodium lauryl sulfate, sodium stearate, sorbitan ester, starch, stearic acid, sucrose stearate, tragacanth, triethanolamine, tromethamine, vitamin E polyethylene glycol succinate, wax and xanthan gum or a combination thereof. Based on the knowledge of ordinary technicians in the field of medicine and formulation, these components can be adopted and used at a level suitable for the formulation. The amount can be in the range of less than 1% by weight to up to 30% by weight.

[0221] On the other hand, at least one emollient can be selected from the group consisting of: almond oil, aluminum monostearate, butyl stearate, rapeseed oil, castor oil, cetostearyl alcohol, cetyl alcohol, cetyl palmitate, cholesterol, coconut oil, cyclomethicone, decyl oleate, diethyl sebacate, polydimethylsiloxane, ethylene glycol stearate, glycerol, 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, vaseline, polyoxyethylene sorbitan fatty acid ester, propylene glycol dilaurate, propylene glycol monolaurate, safflower oil, squalene, sunflower oil, tricaprylin, triolein, wax, xylitol, zinc acetate or its combination. Based on the knowledge of those of ordinary skill in the field of medicine and formulation, these components can be adopted and used at a level suitable for formulation. Amounts may range from less than 1% by weight to as much as 60% by weight.

[0222] In another aspect, at least one viscosity modifier can be selected from the group consisting of gum arabic, agar, alginic acid, aluminum monostearate, ammonium alginate, attapulgite, bentonite, calcium alginate, calcium lactate, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, cellulose, carob bean gum, ozokerite, cetostearyl alcohol, cetyl palmitate, chitosan, colloidal silicon dioxide, corn syrup solids, cyclomethicone, ethylcellulose, gelatin, glyceryl behenate, guar gum, hectorite, hydrophobic gum The invention can be used in combination with any of the following compositions: silica, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, myristyl alcohol, octyldodecanol, palm oil, pectin, polycarbophil, polyglucose dextrose, 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. Based on the knowledge of those skilled in the art of medicine and formulation, these components can be adopted and used at a level suitable for the formulation. The dosage can be in the range of less than 1% to as high as 60% by weight.

[0223] On the other hand, at least one film former can be selected from the group consisting of ammonium alginate, chitosan, rosin, copolyvidone, 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, nitrocellulose and shellac or a combination thereof. Based on the knowledge of ordinary technicians in the field of medicine and formulation, these components can be adopted and used at a level suitable for the formulation. The amount can be in the range of less than 1% by weight to as high as 90% or even more than 99% by weight.

[0224] On the other hand, at least one surfactant or wetting agent can be selected from the group consisting of docusate sodium, phospholipids, sodium lauryl sulfate, benzalkonium chloride, cetrimonium bromide, cetylpyridinium chloride, alpha tocopherol, glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyethylene glycol 15 hydroxystearate, polyoxyglycerol esters, propylene glycol dilaurate, propylene glycol monolaurate, sorbitan esters, sucrose stearate, tricaprylin and vitamin E polyethylene glycol succinate or a combination thereof. Based on the knowledge of ordinary technicians in the field of medicine and formulation, these components can be adopted and used at a level suitable for the formulation. The amount can be in the range of less than 1% by weight to up to 30% by weight.

[0225] On the other hand, a buffer may be included. On the other hand, an emollient may be included. On the other hand, an emulsifier may be included. On the other hand, an emulsion stabilizer may be included. On the other hand, a gelling agent may be included. On the other hand, a humectant may be included. On the other hand, an ointment base or an oily vehicle may be included. On the other hand, a suspending agent may be included. On the other hand, an acidulant may be included. On the other hand, an alkalizing agent may be included. On the other hand, a bioadhesive material may be included. On the other hand, a colorant may be included. On the other hand, a microencapsulation agent may be included. On the other hand, a stiffening agent may be included. Based on the knowledge of ordinary technicians in the field of medicine and formulation, these components can be adopted and used at levels suitable for the formulation. The amount can range from less than 1% by weight to as high as 90% or even more than 99 by weight.

[0226] When the active ingredient is delivered in powder form, the powdered material is usually combined with a powdered dispersant. In other embodiments, the active can be combined with a dispersant to form particles containing both the active and the dispersant. In other embodiments, the active can be coated on the surface of the dispersant. Examples of dispersants include a variety of ingredients, including sugars such as lactose, glucose and sucrose.

[0227] One of ordinary skill in the pharmaceutical and formulation arts can determine appropriate levels of the essential and optional components of the compositions of the present invention.

[0228] Methods of preparing suramin compositions are also intended to be part of the invention and will be apparent to one of ordinary skill in the pharmaceutical and formulation arts using standard formulation and mixing techniques.

[0229] The present invention also provides a device for patient administration or self-administration of an anti-purinergic agent, comprising a nasal spray inhaler containing an aerosol spray formulation of an anti-purinergic agent and a pharmaceutically acceptable dispersant or solvent system, wherein the device is designed (or alternatively metered) to disperse a dose of the aerosol formulation by forming a spray containing a dose of the anti-purinergic agent. In other embodiments, the inhaler may contain an anti-purinergic agent in the form of a fine powder, and further combined with a microparticle dispersant and a diluent, or alternatively combined to form or coat the microparticle dispersant.

[0230] Example

[0231] The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples given are for illustrative purposes only and should not be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the present invention.

[0232] Example 1 : Compositions for intranasal delivery

[0233] The following compositions were prepared using standard mixing equipment and procedures.

[0234]

[0235] *Based on suramin hexasodium salt having a molecular weight of 1429.15 g / mol

[0236] Dissolve suramin sodium salt in water by gentle mixing. Add cyclodextrin with mixing until dissolved. Allow the resulting solution to sit for 2 hours before use.

[0237] The composition can be packaged in a spray bottle for intranasal administration.

[0238] Alternatively, the composition is prepared with an equal weight of caprylocaproyl macrogol-8 glyceride or and 2-(2-ethoxyethoxy)ethanol in place of methyl beta-cyclodextrin.

[0239] The composition can be used to treat autism spectrum disorders.

[0240] Example 2 : Compositions for intranasal delivery

[0241] The following compositions were prepared using standard mixing equipment and procedures.

[0242]

[0243] *Based on suramin hexasodium salt having a molecular weight of 1429.15 g / mol

[0244] Dissolve suramin sodium salt in water by gently mixing. Add sodium chloride and hydroxypropyl methylcellulose with mixing. Add cyclodextrin with mixing until dissolved. Allow the resulting solution to sit for 2 hours before use.

[0245] The composition can be packaged in a spray bottle for intranasal administration.

[0246] Alternatively, the composition is prepared with an equal weight of caprylocaproyl macrogol-8 glyceride or and 2-(2-ethoxyethoxy)ethanol in place of methyl beta-cyclodextrin.

[0247] The composition can be used to treat autism spectrum disorders.

[0248] Example 3 :Tissue penetration of suramin

[0249] Four formulations AD were prepared using the methods of Examples 1 and 2 and were found to be stable for at least 4 weeks over a three month period at 25°C and 60% relative humidity.

[0250] Formulation A - 100 mg / mL suramin hexasodium salt in water (no excipients)

[0251] Formulation B - 100 mg / mL Suramin hexasodium salt in water containing 40% Methy betadex

[0252] Formulation C - 100 mg / mL suramin hexasodium salt in water containing 40% HP (hydroxypropyl)-cyclodextrin

[0253] Formulation D - 160 mg / mL suramin hexasodium salt in water (no excipients)

[0254] These formulations also contained 0.1% hydroxypropylmethylcellulose (ie, HPMC E5, from Dow Chemicals) as a solution thickener; and 0.75% sodium chloride as an osmolarity agent.

[0255] These four formulations were evaluated in an in vitro permeation study using cultured human airway tissue (EpiAirway AIR-100, purchased from MatTek Corporation) following an established drug permeability protocol (EpiAirway™ Drug Permeation Protocol, MatTek Corporation, 2014). The EpiAirway represents the upper airway extending from the trachea to the main bronchi, so it is used to measure drug delivery from nasal formulations.

[0256] For receiver fluid preparation, the technician pre-warms EpiAirway assay medium to 37°C. Using aseptic technique, the technician pipettes 0.3 mL of medium into each well of a sterile 24-well plate. Label the wells. Use 0.2 mL of donor solution on the tissue.

[0257] Permeability experiment: after overnight balance, the cell culture insert is moved to 1h hole, and the donor solution is pipetted onto the tissue. The plate is returned to the incubator. After 30 minutes of permeation time, the tissue is moved to 2 hours hole. Similarly, after 2.0, 3.0, 4.0 and 6.0 hours of total time, the tissue is moved. There is no need to supplement the donor solution. Alternatively, the technician can remove the receiving solution fully at the appropriate time, and replace it with a fresh pre-warmed receiving solution. Use HPLC to analyze the solution and detect at 238nm.

[0258] Table 1 below provides the average cumulative amount of suramin (in mg) that has permeated over time.

[0259]

[0260] The results of the study are also shown graphically in Figure 1 In the figure, the cumulative amount of drug permeated (mg) is plotted against time (hours).

[0261] These data demonstrate that Formulation B containing Methybetadex provides significantly better permeation in the tissue permeation assay compared to Formulations A, C, and D. Furthermore, as seen from the comparison of Formulations A and D, having a higher drug concentration may be beneficial for increased permeation.

[0262] Example 4 :Tissue penetration of suramin

[0263] Six formulations AF were prepared using the methods of Examples 1 and 2 and were found to be stable for at least 4 weeks under ambient conditions.

[0264] Formulation A - 200 mg / mL suramin in water (no excipients)

[0265] Formulation B - 140 mg / mL suramin in water containing 40% polysorbate 80 (Tween 80)

[0266] Formulation C - 140 mg / mL Suramin in water with 40% Methy betadex

[0267] Formulation D - 140 mg / mL suramin in water containing 40% sulfobutyl ether beta-cyclodextrin (Captisol)

[0268] Formulation E - 140 mg / mL suramin in water containing 40% 2-(2-ethoxyethoxy)ethanol (Transcutol P)

[0269] Formulation F - 140 mg / mL Suramin (Labrasol) in water

[0270] The tissue permeability study was performed using the method of Example 3.

[0271] Table 2 below provides the average cumulative amount of suramin (in mg) that has permeated over time.

[0272]

[0273] The results of the study are also shown graphically in Figure 2In which the cumulative amount of drug permeated (mg) is plotted against time (hours). These data demonstrate that Formulation C containing methyl beta-cyclodextrin (Methy betadex), Formulation E containing 2-(2-ethoxyethoxy)ethanol (Transcutol P), and Formulation F containing caprylic capric acid macrogol-8 glyceride (Labrasol) provide significantly better permeation than Formulations A, B, and D in the tissue permeation test.

[0274] Furthermore, the results from Examples 3 and 4 were surprising.

[0275] Cyclodextrins are sugar molecules that are bound together into rings of various sizes. Specifically, the sugar unit is called a pyranose glucoside - a glucose molecule that exists in a pyranose (six-membered) ring configuration. 6, 8 or 10 pyranose glucosides are bound to each other to form α-, β- and γ-cyclodextrins, respectively. Cyclodextrin forms a toroid (truncated cone) configuration with multiple hydroxyl groups at each end. This allows it to encapsulate hydrophobic compounds without losing its solubility in water. In other applications, cyclodextrins can be used to bring hydrophobic drug molecules into biological systems as tissue permeation enhancers. It is reported that cyclodextrins form inclusion complexes with a variety of hydrophobic drugs, thereby increasing their distribution and solubility in tissue membranes. Methyl β-cyclodextrin (betadex) is a type of cyclodextrin. Methyl β-cyclodextrin is used in at least one commercially available intranasal product, estradiol (Aerodiol), to enhance the permeation of drug molecules estradiol (MW = 272.4) through tissues. Due to its small size (MW = 272.4), estradiol molecules can be easily encapsulated into cyclodextrin rings and thus achieve enhanced delivery to biological tissues.

[0276] However, we have discovered a way in which methyl beta-cyclodextrin can and is able to encapsulate suramin, a much larger molecule than would normally be considered compatible. It was surprising to find that methyl beta-cyclodextrin was effective with suramin. One of ordinary skill in the art would not have expected that such a large molecule could be encapsulated into a cyclodextrin ring.

[0277] Another useful penetration enhancer is Transcutol P (diethylene glycol monoethyl ether). This is 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. In addition, it is not commonly used to enhance large molecules, such as suramin.

[0278] Another useful penetration enhancer is Labrasol (caprylocaproyl macrogol-8 glycerides). This is 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.

[0279] Example 5 :Determination of suramin in plasma and brain tissue

[0280] The following examples describe mouse studies conducted to determine the delivery of suramin to plasma and brain tissue when administered intraperitoneally (IP) or intranasally (IN) according to different treatment regimens. For this study, male Fmr1-knockout B6.129P2-Fmr1tm1Cgr / J TG mice were purchased from Jackson Laboratories in Bar Harbor, Maine. These mice were approximately 8 weeks old. These mice exhibited dendritic spine abnormalities in multiple regions of the brain. The absence of FMRP in these mice triggers overactivation of RAC1, a protein of the Rho GTPase subfamily that plays a key role in dendritic morphology and synaptic function. These B6.129P2-Fmr1tm1Cgr / J TG mice provide an animal model of cognitive disability and neurodevelopmental disorders.

[0281] The mice were maintained in group cages (6 mice / cage based on treatment group) in a controlled environment (temperature: 21.5°C ± 4.5°C and relative humidity: 35%-55%) under a standard 12-hour light / 12-hour dark light cycle (light turned on at 06:00). The mice were housed in the research facility for approximately one week. For health monitoring purposes, the weight of all mice was recorded.

[0282] The mice were divided into the following 5 test groups, with 6 mice in each group.

[0283] Group 1: Animals were administered suramin 20 mg / kg by intraperitoneal (IP) injection once a week starting at 9 weeks of age and continuing for four weeks (ie, given at 9, 10, 11 and 12 weeks of age). Suramin was formulated in normal saline.

[0284] Group 2: Animals were administered saline 5 mL / g by intraperitoneal (IP) injection once a week starting at 9 weeks of age and continuing for four weeks (ie, given at 9, 10, 11 and 12 weeks of age). This was the control group.

[0285] Group 3: The following suramin formulation (at a concentration of 100 mg / mL x 6 mL / spray) was administered intranasally (IN) once daily as one spray / nostril application (with approximately 2 minutes between each application to ensure absorption) for 28 days (a total of 56 sprays over the 28-day period) beginning at 9 weeks of age (i.e., given daily during 9, 10, 11, and 12 weeks of age).

[0286] Group 4: The following suramin formulation (at a concentration of 100 mg / mL x 6 mL / spray) was administered intranasally (IN) as one spray / nostril every other day for 28 days (a total of 28 sprays over a 28-day period) beginning at 9 weeks of age (i.e., given every other day during 9, 10, 11, and 12 weeks of age).

[0287] Group 5: The following suramin formulation (at a concentration of 100 mg / mL x 6 mL / spray) was administered intranasally (IN) once a week for 4 weeks (28 days) with one spray / nostril application beginning at 9 weeks of age (i.e., given weekly during 9, 10, 11, and 12 weeks of age) (8 sprays total over the 28-day period).

[0288] The following is the intranasal (IN) formulation of suramin administered to Groups 3, 4, and 5 above.

[0289]

[0290]

[0291] *HPMC E5 is a water-soluble cellulose ether polymer [hydroxypropyl methylcellulose (HPMC)] available from DuPont.

[0292] The above formulation was made by dissolving suramin sodium salt in water by gentle mixing. The remaining ingredients except cyclodextrin were added with mixing. The cyclodextrin was then added with mixing until dissolved. The resulting solution was allowed to sit for 2 hours before use.

[0293] Blood samples were collected from all mice at the end of 12 weeks of age. Brain tissue was harvested from all mice after sacrifice at 13-14 weeks of age. Standard sample preparation and analysis techniques were used to obtain data.

[0294] The results of this study are shown in Table 3. The data are presented as mean plasma concentrations (in both ng / ml and μM) and mean brain tissue concentrations (in ng / g and mmol / g) for each animal group. The mean brain tissue to plasma partition ratio for each group is also presented. Note that such calculations are not applicable to the group administered a saline control (Group 2) because suramin was not detected in brain tissue and the small plasma levels were essentially noise from the analytical method.

[0295]

[0296] 1 BQL means below quantifiable limit.

[0297] 2 NA means not applicable.

[0298] 3The distribution ratios were calculated directly from the raw data rather than from the average values ​​presented in the table.

[0299] The research results also showed Figures 3 to 10 .

[0300] Figure 3 Shown is a graph of total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered by weekly intraperitoneal (IP) injections of 20 mg / kg to mice starting at 9 weeks of age and continuing for four weeks (i.e., given at 9, 10, 11, and 12 weeks of age).

[0301] Figure 4 A graph comparing total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered intranasally (IN) daily for 28 days is shown. A composition of the invention comprising IN suramin (at a concentration of 100 mg / mL x 6 mL / spray) was administered starting at 9 weeks of age (i.e., given daily during 9, 10, 11, and 12 weeks of age) once daily with one spray / nostril (with approximately 2 minutes between each application to ensure absorption) for 28 days (a total of 56 sprays over a 28 day period).

[0302] Figure 5 A graph comparing total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered intranasally (IN) every other day for 28 days is shown. A composition of the invention comprising IN suramin (at a concentration of 100 mg / mL x 6 mL / spray) was administered starting at 9 weeks of age (i.e., daily during 9, 10, 11, and 12 weeks of age) once every other day as one spray / nostril (with approximately 2 minutes between each application to ensure absorption) for 28 days (a total of 28 sprays over a 28-day period).

[0303] Figure 6 A graph comparing total suramin concentrations (in ng / ml) in plasma and brain tissue of mice when administered intranasally (IN) once weekly for 4 weeks is shown. A composition of the invention comprising IN suramin (at a concentration of 100 mg / mL x 6 mL / spray) was administered starting at 9 weeks of age (i.e., daily during 9, 10, 11, and 12 weeks of age) once weekly as one spray / nostril (with approximately 2 minutes between each application to ensure absorption) for 4 weeks (28 days) (a total of 8 sprays over a 28 day period).

[0304] Figure 7Shown is a graph comparing the total percentage of suramin in mouse plasma when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0305] Figure 8 Shown is a graph comparing the total percentage of suramin in mouse brain tissue when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0306] Fig. 9 Shown is a graph comparing the total percentage of suramin in mouse plasma and brain tissue when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0307] Fig.10 Shown is a graph comparing the brain tissue to plasma partitioning ratio of suramin in mice when administered intraperitoneally (IP) once a week for 4 weeks (28 days), intranasally (IN) once a day for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once a week for 4 weeks (28 days).

[0308] These results demonstrate that anti-purinergic agents such as suramin can be delivered intranasally to reach plasma and brain tissue levels, and changes in the brain tissue to plasma partition ratio can be observed. These results demonstrate that anti-purinergic agents such as suramin can be delivered to the brain of a mammal by intranasal (IN) administration.

[0309] Incorporated by Reference

[0310] The entire disclosure of each patent document, including correction certificates, patent application documents, scientific articles, government reports, websites, and other references mentioned herein, is incorporated herein by reference in its entirety for all purposes. In the event of a conflict in terminology, the present specification controls.

[0311] Equivalent form

[0312] Without departing from the spirit or essential characteristics of the present invention, the present invention may be implemented in other specific forms. The foregoing embodiments are considered to be illustrative in all respects, rather than limiting the invention described herein. In various embodiments of the method and composition of the present invention, in the case where the terms included are used with respect to the enumerated steps of the method or the components of the composition, it is also considered that the method and composition are substantially composed of the enumerated steps or components, or are composed of the enumerated steps or components. In addition, it should be understood that as long as the present invention remains operable, the order of the steps or the order in which certain actions are performed is insignificant. In addition, two or more steps or actions can be performed simultaneously.

[0313] In the specification, unless the context clearly stipulates otherwise, the singular form also includes the plural form. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by ordinary technicians in the field to which the present invention belongs. In the event of a conflict, the present specification will prevail.

[0314] Additionally, it should be recognized that in some cases a composition may be described as consisting of the components prior to mixing because upon mixing some of the components may further react or transform into additional materials.

[0315] Unless otherwise indicated, all percentages and ratios used herein are by weight. It is recognized that the mass of an object is often referred to as its weight in everyday use and for most common scientific purposes, but mass technically refers to the amount of matter of an object, while weight refers to the force on an object due to gravity. Furthermore, in common use, the "weight" (mass) of an object is what is determined when the object is "weighed" (mass) on a scale or balance.

Claims

1. Use of a pharmaceutical composition for the preparation of a medicament for treating cognitive, social or behavioral disability and neurodevelopmental disorders, the pharmaceutical composition comprising a therapeutically effective amount of an anti-purinergic agent and a penetration enhancer; wherein the anti-purinergic agent is suramin or a pharmaceutically acceptable salt thereof; The penetration enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylic capric macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof; The penetration enhancer has a concentration of from 25% to 50% or 40% by weight.

2. The use according to claim 1, wherein the medicament is for use in humans.

3. The use according to claim 2, wherein the cognitive, social, behavioral disability or neurodevelopmental disorder is selected from autism spectrum disorder, FSX, FXTAS, CFS and PTSD.

4. The use according to claim 3, wherein the cognitive, social, behavioral disability or neurodevelopmental disorder is an autism spectrum disorder.

5. The use according to claim 3, wherein the cognitive, social, behavioral disability or neurodevelopmental disorder is FSX.

6. The use according to claim 3, wherein the cognitive, social, behavioral disability or neurodevelopmental disorder is FXTAS.

7. The use according to claim 3, wherein the cognitive, social, behavioral disability or neurodevelopmental disorder is CFS.

8. The use according to claim 3, wherein the cognitive, social, behavioral disability or neurodevelopmental disorder is PTSD.

9. The use according to 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 and Asperger's syndrome.

10. The use according to claim 4, wherein the autism spectrum disorder comprises one or more symptoms selected from the group consisting of difficulty communicating, difficulty interacting with others, and repetitive behaviors.

11. The use according to claim 1, wherein the pharmaceutically acceptable salt is selected from alkali metal salts, alkaline earth metal salts and ammonium salts.

12. Use according to claim 11, wherein the salt is a sodium salt.

13. The use according to claim 11, wherein the salt is the hexasodium salt.

14. The use according to claim 1, wherein the composition is an aqueous composition.

15. The use according to claim 1, wherein the composition is a powdered composition.

16. The use according to claim 1, wherein the penetration enhancer is methyl β-cyclodextrin.

17. The use according to claim 1, wherein the penetration enhancer is caprylic capric macrogol-8 glyceride.

18. The use according to claim 1, wherein the penetration enhancer is 2-(2-ethoxyethoxy)ethanol.

19. The use according to claim 1, wherein the composition is applied, i.e., administered, at least once a day, at least twice a day, at least once a week, at least twice a week, at least once every two weeks, at least once a month, or at least once every four weeks.

20. The use according to claim 1, wherein the composition is delivered, i.e. administered, at least once every 41 to 78 days.

21. The use according to claim 1, wherein the composition is delivered, i.e. administered, at least once every 50 days.

22. The use according to claim 1, wherein the composition is delivered, i.e., administered, at least once per time interval based on the mean half-life of suramin.

23. The use of claim 1, wherein the plasma level of suramin in the patient is maintained at less than 3 μM, less than 2.75 μM, less than 2.5 μM, less than 2 μM, less than 1 μM, or less than 0.5 μM based on the suramin active.

24. The use according to claim 1, wherein the brain tissue level of suramin in the patient is from 1 ng / mL to 1000 ng / mL.

25. The use of claim 1, wherein the brain tissue level of suramin in the patient is at least 1 ng / mL, at least 10 ng / mL, at least 50 ng / mL, at least 100 ng / mL, at least 250 ng / mL, or at least 500 ng / mL.

26. The use of claim 1, wherein the brain tissue to plasma partition ratio of suramin is at least 0.05, at least 0.1, at least 0.25, or at least 0.

50.

27. The use according to claim 1, wherein the composition comprises from 0.01 mg to 200 mg per unit dose of suramin based on suramin active.

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

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

30. The use according to claim 1, wherein the composition comprises from 0.025 mg / kg to 10 mg / kg / unit dose of suramin or from 0.05 mg / kg to 6 mg / kg / unit dose of suramin based on the suramin active and the patient's body weight.

31. The use of claim 1, wherein the composition comprises from 0.0476 mg / kg to 5.720 mg / kg / unit dose of suramin based on the suramin active and the patient's body weight.

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

33. The use of claim 1, wherein the composition comprises less than 400 mg / m 2 based on the suramin active and the body surface area of ​​the patient. 2 / unit dose of suramin, less than 200 mg / m 2 / Unit dose of suramin, less than 100 mg / m 2 / unit dose of suramin, less than 50 mg / m 2 / unit dose of suramin, or less than 25 mg / m 2 / unit dose of suramin.

34. The use of claim 1, wherein the composition comprises from 10 mg / m 2 based on suramin active and body surface area of ​​the patient. 2 Up to 300 mg / m 2 / unit dose of suramin.

35. The use of claim 1, wherein the patient's plasma level of suramin active has an AUC of less than 80 μg*day / L, less than 75 μg*day / L, less than 50 μg*day / L, less than 25 μg*day / L, or less than 10 μg*day / L.

36. The method of claim 1, wherein based on a single dose, the patient's plasma level of suramin active is C max Less than 75 micromolar, less than 7.5 micromolar, or less than 0.1 micromolar, optionally at least 0.01 micromolar.

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

38. The use according to claim 1, wherein the composition is in the form of a unit dose comprising from 0.01 mL to 0.5 mL of liquid.

39. The use according to claim 38, wherein the unit dose comprises 0.1 mL of liquid.

40. The use of claim 1, wherein the composition exhibits, i.e., is capable of providing, based on suramin active, 1 microgram / cm 2 / hour to 200 μg / cm 2 / hour permeation rate of suramin through cultured human respiratory tissue.

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

42. The use according to claim 41, wherein the agent selected for osmolarity control is a salt.

43. The use according to claim 1, wherein the composition further comprises a thickener.

44. The use according to claim 1, wherein the treatment of autism spectrum disorder, FXS or FXTAS comprises improving one or more symptoms relative to the patient's symptoms before the administration, wherein the one or more symptoms are selected from difficulty communicating, difficulty interacting with others, and repetitive behaviors.

45. The use of claim 1, wherein the treatment of autism spectrum disorder, FXS or FXTAS comprises improving the patient's assessment score relative to the patient's score prior to the administration.

46. ​​The use according to claim 45, wherein the patient's assessment score is improved by 10% or more relative to the patient's score before the administration.

47. The use according to claim 45, wherein the assessment score is selected from ABC, ADOS, ATEC, CARS CGI and SRS.

48. The use according to claim 47, wherein the patient's ADOS score is improved by 1.6 or more relative to the score before the administration, or a corresponding performance improvement.

49. The use according to claim 47, wherein the p-value for the improvement in the ADOS score is 0.05 or less.

50. The use according to claim 47, wherein the effect size of the improvement in the ADOS score is 1 or greater or 2.9 or greater.

51. A pharmaceutical composition for intranasal delivery for treating autism spectrum disorder, FXS or FXTAS, consisting of the following components: (a) a therapeutically effective amount of an anti-purinergic agent, and (b) penetration enhancers; wherein the anti-purinergic agent is suramin or a pharmaceutically acceptable salt thereof; The penetration enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylic capric macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof; The penetration enhancer has a concentration of from 25% to 50% or 40% by weight.

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

53. The composition of claim 51, wherein the suramin has a concentration from 10 mg / mL to 200 mg / mL.

54. The method of claim 51, wherein the penetration enhancer is methyl beta-cyclodextrin, caprylocaproyl macrogol-8 glyceride, or 2-(2-ethoxyethoxy)ethanol.

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

56. A device for patient administration, wherein the patient administration comprises administration selected from the group consisting of: self-administration and administration to a patient by an individual other than the patient; the device comprising a nasal spray inhaler for administering a composition consisting of an anti-purinergic agent and a penetration enhancer, wherein the device is designed to dispense an amount of the anti-purinergic agent to treat autism spectrum disorder, FXS, FXTAS, CFS, or PTSD in a patient in need thereof; wherein the anti-purinergic agent is suramin or a pharmaceutically acceptable salt thereof; The penetration enhancer is selected from the group consisting of methyl β-cyclodextrin, caprylic capric macrogol-8 glyceride, 2-(2-ethoxyethoxy)ethanol, and combinations thereof; The penetration enhancer has a concentration of from 25% to 50% or 40% by weight.

57. The device of claim 56, wherein the anti-purinergic agent comprises a composition selected from a solution, an emulsion, or a powder.

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