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(12) Patent Application Publication (10) Pub. No.: US 2010/0311655 A1 Leonard Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0311655 A1 Leonard Et Al US 20100311655A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0311655 A1 Leonard et al. (43) Pub. Date: Dec. 9, 2010 (54) INTRANASAL CARBETOCIN Related U.S. Application Data FORMULATIONS AND METHODS FOR THE TREATMENT OF AUTISM (60) Provisional application No. 60/942,607, filed on Jun. 7, 2007. (75) Inventors: Alexis Kays Leonard, Maple Valley, WA (US); Joshua O. Publication Classification Sestak, Lawrence, KS (US); Henry R. Costantino, Woodinville, WA (51) Int. Cl. (US); Anthony P. Sileno, A638/II (2006.01) Brookhaven Hamlet, NY (US); A6IP 25/22 (2006.01) Lalit Raj Peddakota, San Diego, A6IP 25/24 (2006.01) CA (US); Kayvon Emile Sharghi, A6IP 25/18 (2006.01) Seattle, WA (US); Garland M. (52) U.S. Cl. ....................................................... 514/11.6 Bellamy, Bothell, WA (US); Jason Philip Gesty, Seattle, WA (US) (57) ABSTRACT Correspondence Address: Methods and compositions containing oxytocin oran oxyto Eckman Basu LLP cin analog. Such as carbetocin, are provided for the prevention 2225 E. Bayshore Road, Suite 200 and treatment of autism spectrum disorders, related disorders Palo Alto, CA 94.303-3220 (US) and symptoms of Such disorders. The methods and composi tions of this disclosure are effective in the treatment of social (73) Assignee: MDRNA, INC. Bothell, WA (US) withdrawal, eye contact avoidance, repetitive behaviors, (21) Appl. No.: 12/599,267 anxiety, attention deficit, hyperactivity, depression, loss of speech, Verbal communication difficulties, aversion to touch, (22) PCT Filed: Sep. 28, 2007 visual difficulties, comprehension difficulties, and Sound and light sensitivity. Additional compositions and methods are (86). PCT No.: PCT/US07f79994 provided which employ oxytocin or an oxytocin analog in combination with a secondary or adjunctive therapeutic agent S371 (c)(1), to yield more effective treatment tools against autism spec (2), (4) Date: Jul. 7, 2010 trum disorders and related disorders. Patent Application Publication Dec. 9, 2010 Sheet 1 of 4 US 2010/0311655 A1 5 He-O- 1 4 - H0 3 s C e-0- SS He -0- 2 KH 1 y = 0.1348x + 1.2887 R= 0.7608 O O 5 10 15 2O 25 30 35 Perm (ug) Patent Application Publication US 2010/0311655 A1 25 - 2 %2 2 %3 % it tar Cit tar Cit phOS phos arg arg 3.0 3.5 7.0 8.0 10.0 Patent Application Publication Dec. 9, 2010 Sheet 3 of 4 US 2010/0311655 A1 -- Duratocin 50 ug IM fe - IN Carbetocin 500 ug 800 I v A'A'A IN Carbetocin 300 ug o-c-e-IN Carbetocin 150 ug O 40 80 120 160 200 240 280 320 360 Patent Application Publication Dec. 9, 2010 Sheet 4 of 4 US 2010/0311655 A1 5000 $ - IM i -o- 10 Me-B-CD at 10 Me-B-CD, opt 4000 * 10 Me-B-CD + EtOH, opt - 10 Me. B-CD+ CMC + PG 3000 -A-20 Me-B-CD + EtOH, opt -- 20 Me-B-CD-EtOH + HPMC, opt -- 20 Me-B-CD + EtOH + CMC, opt 2000 1OOO O 60 120 180 240 Time (min) US 2010/031 1655 A1 Dec. 9, 2010 INTRANASAL CARBETOCN to reject people, act strangely, and lose language and Social FORMULATIONS AND METHODS FOR THE skills they had previously acquired. In other cases, there is a TREATMENT OF AUTISM plateau in development that becomes increasingly noticeable. 0005. The underlying causes of autism spectrum and TECHNICAL FIELD related disorders are unclear. Postmortem and MRI studies have implicated anomalies in many major brain structures 0001. The present disclosure relates to methods and com including the cerebellum, cerebral cortex, limbic system, cor positions for the treatment of neurological and psychiatric pus callosum, basal ganglia, and brain stem. Other research is disorders. In specific embodiments, this disclosure relates to examining the role of neurotransmitters such as serotonin, the treatment of neurological and psychiatric disorders using dopamine, and epinephrine. carbetocin and related oxytocin analogs. 0006 Currently, autism spectrum disorders are treated using applied behavior analysis or other behavior modifica BACKGROUND tion techniques; dietary modification such as a gluten or 0002 Autism spectrum disorders are a group of diseases casein free diet, or large doses of vitamin B6 in combination characterized by varying degrees of impairment in commu with magnesium. Medications prescribed for autism address nication skills, social interactions, and restricted, repetitive specific symptoms such as anxiety and depression and and stereotyped patterns of behavior. The difference in the include agents such as fluoxetine, fluvoxamine, Sertraline and diseases depends on the time of onset, the rate of symptom clomipramine Antipsychotic medications such as chlorprom development, the severity of symptoms, and the exact nature azine, thioridazine, and haloperidol have been used to treat of the symptoms. These disorders range from mild to severe behavioral problems. Anticonvulsants such as arbamazepine, impairment and include Such diseases as autism, Asperger's lamotrigine, topiramate, and valproic acid have been given to syndrome, PDD-NOS, Rett's disorder, childhood disintegra prevent seizures. tive disorder, semantic communication disorder, non-verbal 0007 Results of a study (Hollander et al., American Col learning disabilities, high functioning autism, hyperlexia and lege of Neuropsychopharmacology Annual Meeting, Decem Some aspects of attention deficit hyperactivity disorder. ber 2006) were reported to show that autistic adults who were While the exact number of children with autism spectrum given an intravenous doses of oxytocin had a statistically disorders is unclear, rates in localized areas of the United significant reduction in repetitive behaviors that are associ States vary from 3.4 children per one thousand to 6.7 children ated with autism. per one thousand. Further, recent studies estimate that 15,000 0008 Unfortunately, current treatments for autism spec children aged three through five years, and 78,000 children trum and related disorders are mainly symptomatic and have and young adults aged six through twenty-one years in the proven unsuccessful in allowing Such children and adults to United States have autism. Rates in Europe and Asia are become symptom, or disorder, free. There is therefore an similar, with as many as six per one thousand children having unmet need in the art for alternative treatments for autism at least one autism spectrum disorder. Additionally, there are spectrum disorders and related pathologies. number of related disorders including anxiety disorders, obsessive-compulsive disorders, Social deficit disorders, SUMMARY OF THIS DISCLOSURE repetitive disorders and cognitive deficit disorders which 0009. It is an object of the present disclosure to provide exhibit symptoms similar to those displayed in autism spec methods and compositions for the treatment of neurological trum disorders, greatly increasing the size of the affected and psychiatric disorders. population. 0010. It is an additional object of the present disclosure to 0003 Characteristics of autism spectrum disorders provide methods and compositions for the treatment of include Social withdrawal and averted gaze including an autism spectrum disorders and disorders that include related inability to make eye contact, repetitive behaviors and obses symptoms Such as developmental disorders, anxiety disor sions, stereotyped movements, anxiety, attention deficit, ders, repetitive disorders, and cognitive deficit disorders. hyperactivity, depression, a reclusive personality, and the 0011. It is another object of the present disclosure to pro inability to understand feelings. Patients afflicted with autism vide novel formulations of oxytocin and related analogs spectrum disorders may have an aversion to physical affec including carbetocin for the treatment of autism spectrum tion or contact, ignore communication from others, or if disorders and related disorders. Socially engaged, demonstrate a marked inability to commu 0012. It is a further object of the present disclosure to nicate or relate to others. Communication difficulties may provide compositions and methods for treating and prevent manifest as a monotone Voice, an inability to control the ing symptoms of autism spectrum disorders and related dis volume of their voice, echolalia or an inability to talk at all. orders including, but not limited to, Social withdrawal, eye Individuals with autism spectrum disorders may also Suffer contact avoidance, repetitive behaviors, anxiety, attention from visual difficulties, comprehension difficulties, sound deficit, hyperactivity, depression, loss of speech, Verbal com and light sensitivity and mental retardation. munication difficulties, aversion to touch, visual difficulties, 0004 Children with autism spectrum disorders do not fol comprehension difficulties, and Sound and light sensitivity. low the typical patterns of child development. In some chil 0013 This disclosure achieves these objects and satisfies dren, hints of future problems may be apparent from birth. In additional objects and advantages by providing novel and most cases, the problems in communication and Social skills Surprisingly effective methods and compositions for treating become more noticeable as the childlags further behind other and/or preventing autism spectrum disorders, related disor children the same age. Some children initially develop nor ders and symptoms of Such disorders using oxytocin and mally and then begin to develop differences in the way they Oxytocin analogs. react to people and other unusual behaviors. Some parents 0014. Useful oxytocin and oxytocin analogs within the report the change as being Sudden, and that their children
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