WO2016122218A2 - 신경정신계 장애의 치료를 위한 조성물 및 방법 - Google Patents

신경정신계 장애의 치료를 위한 조성물 및 방법 Download PDF

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WO2016122218A2
WO2016122218A2 PCT/KR2016/000903 KR2016000903W WO2016122218A2 WO 2016122218 A2 WO2016122218 A2 WO 2016122218A2 KR 2016000903 W KR2016000903 W KR 2016000903W WO 2016122218 A2 WO2016122218 A2 WO 2016122218A2
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disorders
component
disorder
composition
neuropsychiatric
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French (fr)
Korean (ko)
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WO2016122218A3 (ko
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이동현
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Generys Korea Corp
Generys Biopharmaceuticals Corp
Duke University
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Generys Korea Corp
Generys Biopharmaceuticals Corp
Duke University
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Priority to KR1020197017975A priority Critical patent/KR20190077590A/ko
Priority to ES16743696T priority patent/ES2985064T3/es
Priority to KR1020217023520A priority patent/KR20210095734A/ko
Priority to KR1020227017187A priority patent/KR20220071297A/ko
Priority to EP24169410.8A priority patent/EP4385575A3/en
Priority to KR1020207007722A priority patent/KR20200032759A/ko
Priority to CN201680007760.2A priority patent/CN107206093A/zh
Priority to KR1020187003387A priority patent/KR101994596B1/ko
Priority to EP16743696.3A priority patent/EP3251699B1/en
Priority to DK16743696.3T priority patent/DK3251699T3/da
Priority to JP2017540782A priority patent/JP6655090B2/ja
Priority to KR1020167021256A priority patent/KR20160103548A/ko
Application filed by Generys Korea Corp, Generys Biopharmaceuticals Corp, Duke University filed Critical Generys Korea Corp
Publication of WO2016122218A2 publication Critical patent/WO2016122218A2/ko
Publication of WO2016122218A3 publication Critical patent/WO2016122218A3/ko
Priority to US15/662,289 priority patent/US20170326127A1/en
Anticipated expiration legal-status Critical
Priority to US16/808,458 priority patent/US20200197383A1/en
Priority to US18/121,626 priority patent/US12311056B2/en
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Definitions

  • the present invention relates to R01 DA012768 entitled “Cocaine Withdrawal: Window of Treatment Opportunity”; R01 DA14323 entitled “Drug Development for Metamphetamine Abuse”; NS42124 entitled “Presynaptic Mechanisms and Treatment of Parkinson's Disease”; And US federal government funding under the NIH authorization of RC2 DA028905 entitled, “Novel Ondansetron Formulation for Combination Treatment of Psychostimulant Abuse". Thus, the federal government may have certain rights in the invention.
  • the present invention provides for the temporary control of intrinsic dysfunctional neural processes, psychostimulant use disorders (PUDs) and other substance-related and addictive disorders, post-traumatic stress disorders.
  • PEDs psychostimulant use disorders
  • PTSD post-traumatic stress disorder
  • LID trauma- and stressor-related disorders
  • LID levodopa-induced dyskinesia
  • the present invention is directed to compositions and methods of combination therapy that can reduce the symptoms and / or signs of neuropsychiatric disorders.
  • Misuse of cocaine (COC), methamphetamine (METH) and associated drugs is not only a primary psychiatric disorder, but also includes, for example, schizophrenia, Significant comorbid / risk factors in various other neuropsychiatric and diseases such as bipolar disorder, hepatitis C, and HIV continue to bear legal, socioeconomic and medical costs worldwide (see Whiteford et.
  • Drugs tested in previous clinical trials include other psychostimulants used alone (eg d-amphetamine, methylphenidate), selective dopamine (DA) or serotonin uptake inhibitors (eg fluoxetine), complete or partial DA Agonists ("full or partial DA agonist” (e.g. aripiprazole), DA antagonists (e.g. risperidone), GABA ( ⁇ -aminobutyric acid) agonists (e.g. gabapentin), central excipient modafinil .
  • psychostimulants used alone (eg d-amphetamine, methylphenidate), selective dopamine (DA) or serotonin uptake inhibitors (eg fluoxetine), complete or partial DA Agonists ("full or partial DA agonist” (e.g. aripiprazole), DA antagonists (e.g. risperidone), GABA ( ⁇ -aminobutyric acid) agonists (e.g
  • Additional drugs eg, bupropion, n-acetylcysteine, antiepileptic tiagabine and topiramate, etc.
  • other treatment modalities eg, anti-cocaine and anti-METH vaccines or transcranial magnetic stimulation
  • DA agonists and 5HT2, 5-HT3 or NK-1 receptor antagonists may result in sensitization and self-administration animals of PUD.
  • the behavioral and neurobiological alterations observed in the model can be reversed.
  • DA replacement therapy restores DA neurotransmission in the brain, causing symptoms and signs of PD and other related disorders. It is used to mitigate.
  • Dopamine (DA) precursor levodopa L-3,4-dihydroxyphenylalanine
  • LID levodopa-induced dyskinesia
  • levodopa sensitization plays an important role in LID development and maintenance. Due to the death of advanced DA neurons and / or “ectopic” DA synthesis and release at the 5-HT terminus, dysregulation of DA synthesis, release and clearance of extracellular DA may occur after levodopa administration. It is believed to cause excessive fluctuations in synaptic DA concentrations. These fluctuations in turn induce dysfunctional synaptic changes in the basal ganglia and other brain regions.
  • Another “anti-LID” strategy presented in conjunction with “persistent” levodopa treatment includes levodopa and “anti-LID drugs to prevent the development of LIDs or to block the expression of existing LIDs or to replace levobopa alternative drugs.
  • Parallel administration In addition, evaluation of many therapeutic or therapeutic candidates at various stages of development is currently underway. In recent years, despite the invasive nature and risk of short- and long-term complications, deep brain stimulation (DBS) has increased, whether such procedures directly alter the neurobiological changes that are key to LID, Or whether it indirectly affects levodopa dose reduction, secondary LID expression blockade, and / or mitigating PD progression, has not yet been systematically identified.
  • DBS deep brain stimulation
  • NCS-R National Comorbidity Survey Replication
  • Korean National Health Insurance statistics show that the total number of PTSD patients (outpatient and inpatient) was 6,981 in 2014, 6,741 in 2013 and 6,950 in 2012.
  • the number of male patients is 1.5 times higher than the number of female patients.
  • Age-based analysis in the range of 10 to 60 years of age shows relatively uniform patient numbers across all ages.
  • Treatment options currently known to have "significant” or “somewhat” benefits in the "Post-Traumatic Stress Disorder Pocket Guide” 2013 (Pocket Guide) include psychotherapy (eg, “cognitive”, “exposure”). ) “Treatment) and drug treatment.
  • antidepressants particularly selective serotonin or serotonin / norepinephrine reuptake inhibitors, has shown efficacy in randomized controlled trials; Only sertraline and paroxetine were approved by the US Food and Drug Administration (FDA) for the treatment of PTSD.
  • Benzodiazepines, atypical antipsychotics, and anticonvulsants have also been reviewed, but these drugs have not shown consistent efficacy and are not listed in the recommended drug list in the aforementioned guidelines.
  • the combination of exposure therapy and paroxetine has been reported to have no additional therapeutic effect compared to exposure therapy.
  • INDs investigational new drugs
  • a variety of neuropsychiatric disorders including PUD, LID and PTSD, are enhanced forms of the maladaptive dysfunctional neural circuits ("dysfunctional neural plasticity" or “dysfunctional memory”).
  • disorders-specific neural plasticity varies at several levels, including but not limited to neural mechanisms and processors, brain regions, brain region connectivity, brain networks, and network interactions within or without the brain, which are specific disorders.
  • are believed to underlie the signs and symptoms of see Headley and Pare, 2013 (Headley, DB, Pare, D (2013). In sync: gamma oscillations and emotional memory.Front Behav Neurosci 7: 170)).
  • Treatment-mediated normalization of such neuroplastic changes may lead to successful treatment results.
  • 1 shows a maintenance mechanism of a dysfunctional neural circuit.
  • the stable and strengthened "PUD neural circuit” is a psychostimulant itself (eg, "drug tasting"), drugs It can be reactivated by exposure to various stimuli such as environmental signals associated with use (eg, drug paraphernalia) or “stress” or the like (Childress et al., 1999 (Childress, AR, Mozley, PD, Mcelgin, W, Fitzgerald, J, Reivich, M, O'brien, CP (1999) .Limbic activation during cue-induced cocaine craving. The American journal of psychiatry 156: 11-18); Sinha, 2006 (Sinha, 2006) R, Garcia, M, Paliwal, P, Kreek, MJ, Rounsaville, BJ (2006) .Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.Archives of general psychiatry 63: 324-331)
  • LID is another reinforcement form of "dysfunctional neuroplastic change", in which pharmacokinetic (PK) and / or pharmacodynamic (PK) pharmacokinetic (PK) pharmacokinetic and / or pharmacodynamic effects This is maintained by subsequent reinforcement while decreasing in magnitude.
  • dysfunctional "PTSD neural circuits" in PTSD patients can be conceptualized to be maintained through repeated reactivation and reinforcement cycles. For example, function when the patient is exposed to a previously caused traumatic stressful event (e.g. noise reminding a bomb blast that killed a friend, riding in a car after a major car accident, etc.) The abnormal neural circuit can be reactivated. This reactivation causes reappearance of PTSD signs and symptoms and can be calmed if the reactivated PTSD circuit is reintensified to a stable but easily reactivated state. By reinforcement, PTSD symptoms and signs are attenuated to a state that can be reappeared by subsequent encounters of stimuli.
  • traumatic stressful event e.g. noise reminding a bomb blast that killed a friend, riding in a car after a major car accident, etc.
  • the abnormal neural circuit can be reactivated. This reactivation causes reappearance of PTSD signs and symptoms and can be calmed if the reactivated PTSD
  • the present invention provides for the temporary control of intrinsic dysfunctional neural processes, the stimulation of mental stimulant use (PUD) and other substance related addictive disorders, post-traumatic stress disorder (PTSD) and other traumatic and stress related disorders and levodopa-induced motor disorder It is an object of the present invention to provide compositions and methods of combination therapy that can reduce the symptoms and / or signs of neuropsychiatric disorders, including but not limited to LID) and other forms of motor disorders.
  • PID mental stimulant use
  • PTSD post-traumatic stress disorder
  • LID levodopa-induced motor disorder
  • the agent used in the combination method therapeutically reactivates a stable dysfunctional neural circuit into its "reactivated and unstable" state, thereby giving it a temporary unstable state.
  • the antagonist given at an appropriate time after administration of the agent, blocks reinforcement and subsequent circuit restabilization, and thus sequentially reactivates the maladapted memory and blocks its reinforcement to cause symptoms of neuropsychiatric disorders.
  • compositions and methods of combination therapy that can reduce the symptoms and / or signs of neuropsychiatric disorders, including but not limited to motor disorders (LID) and other forms of motor disorders.
  • PID psychostimulant use disorder
  • PTSD post-traumatic stress disorder
  • compositions and methods of combination therapy that can reduce the symptoms and / or signs of neuropsychiatric disorders, including but not limited to motor disorders (LID) and other forms of motor disorders.
  • compositions and methods of combination therapy that can reduce the symptoms and / or signs of neuropsychiatric disorders, including but not limited to disorders (LID) and other forms of motor disorders, and (1) tobacco use disorders, Other substance-related disorders including but not limited to alcohol use disorders and cannabis use disorders; (2) behavioral addiction disorders, including but not limited to habitual gambling and Internet addiction; (3) other trauma and stressor-related disorders, including but not limited to reactive attachment disorders, acute stress disorders and adaptation disorders; (4) anxiety disorders including but not limited to generalized anxiety disorder, panic disorder, agoraphobia, substance / drug-induced anxiety disorder; (5) OCD disorders, including but not limited to obsessive-compulsive disorder, body dysmorphic disorders, storage disorders, trichotillomania, and excoriation disorders; And (6) other neuropsychiatric disorders, including but not limited to disorders (LID) and other forms of motor disorders, and (1) tobacco use disorders, Other substance-related disorders including but not limited to alcohol use disorders and cannabis use disorders; (2) behavioral addiction disorders, including but not limited to habitual gambling and Internet addiction;
  • 1 is a diagram illustrating a mechanism for maintaining a dysfunctional neural circuit.
  • FIG. 3 is a graph showing that the combination of DA agonist pergolide and 5-HT2A / 2C antagonist ketanserine significantly reduces levodopa-induced abnormal involuntary locomotion (LIAIM) in rats that are animal models of LID.
  • LIAIM levodopa-induced abnormal involuntary locomotion
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders Version 5
  • ICD-10 International Statistical Classification of Diseases and Related Health Problems version 10
  • target indications described within the present invention may belong to a primary diagnosis (person) or secondary diagnosis (person) or side effects or co-morbidity.
  • various neuropsychiatric disorders including but not limited to PUD, LID, and PTSD, can be conceptualized into stable, enhanced forms of dysfunctional maladaptable synaptic plasticity, which are repeated reactivation / reinforcement cycles. It can be maintained through.
  • pharmacological options are currently available for several neuropsychiatric disorders, most of these treatments are primarily "temporary" to ameliorate the signs and symptoms of target primary and / or co-morbid disorders. There is still a high unmet need for more effective pharmacological treatments capable of normalizing the underlying dysfunctional neural circuits (“disease modification”).
  • FIG. 2 shows a conceptual model of a combination therapy according to the present invention.
  • the first component (component 1) is used as a means to reactivate dysfunction neural circuits in a single embodiment from a stable state to a reactivated state and is transient This creates an unstable state of dysfunctional neural circuits.
  • the second component (component 2), provided in any embodiment or in a single composition, formulation or dosage form with the first component, is reintensified and subsequently stabilized in a stable state. To block.
  • compositions or formulations that are optimized in combination therapy and at the same time with patient comfort gradually reduce the symptoms and signs of the target disorder to an asymptomatic (subclinical) level and allow normal neurological function to be restored (eg, successful treatment). Repeatedly reactivates the dysfunctional memory and prevents reinforcement.
  • the compositions, methods and examples described in the present invention allow for the effective clinical application of such combination treatments in a single dosage form.
  • Combination therapy embodiments comprising two active components and described herein can be used for the treatment of neuropsychiatric disorders.
  • Disorders that can be treated with a combination therapy embodiment include PUD, LID, and PTSD.
  • Other disorders include (1) other substance related disorders including, but not limited to, tobacco use disorders, alcohol use disorders, and cannabis use disorders; (2) behavioral addiction disorders, including but not limited to habitual gambling and Internet addiction; (3) other trauma and stressor-related disorders, including but not limited to reactive attachment disorders, acute stress disorders and adaptation disorders; (4) anxiety disorders including but not limited to generalized anxiety disorder, panic disorder, agoraphobia, substance / drug-induced anxiety disorder; (5) OCD disorders, including but not limited to obsessive-compulsive disorder, body dysmorphic disorders, storage disorders, trichotillomania, and excoriation disorders; And (6) eating disorders including but not limited to anorexia nervosa, bulimia and binge eating disorders.
  • BDNF brain-derived neurotrophic factor
  • ⁇ -amino dopamine receptor subtype
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate
  • NMDA N -methyl-D-aspartate
  • mGluR5 metabotropic glutamate 5
  • Combination therapy can be implemented in any embodiment, dosage form, method or route that is compatible with clinical applications that are understood and practiced in the art.
  • Component 1 provides a means to change the maladaptive neural circuit from a stable state to a reactivated state, thereby temporarily imparting instability of the maladaptive neural circuit.
  • Component 2 included in any embodiment or unitary composition, formulation or dosage form in combination with component 1 blocks reintensification and subsequent stabilization into a stable state.
  • any such embodiment or single composition, formulation or dosage form optimizes the combination treatment and allows the components to be delivered in the body in a form and method that is highly comfortable for the patient, thus indicative of a target disorder and It makes it possible to reduce symptoms to asymptomatic levels.
  • the compositions, formulations, methods and exemplary embodiments described herein allow for the effective use of combination therapy as a single dosage form.
  • Component 1 may be selected from small molecules, other types of molecules, and modifications thereof (eg, agents, prodrugs, etc.).
  • Other types of molecules include small interfering ribohexane (siRNA), microRNAs, antisense oligonucleotides, aptamers, peptides, proteins (eg antibodies), naturally-occurring organic or inorganic molecules, chemical elements (Eg, lithium) and any synthetic compounds that are larger or smaller than the small molecule, include, but are not limited to, dysfunctional neural circuits, preferably through any safe, acceptable and effective route of administration. Can be nested into a single combination therapeutic dosage form to achieve dysfunctional neural circuit reactivation that transitions from a stable state to a reactivated and unstable state.
  • component 1 is a pharmacologically-effective indirect, with or without agonistic efficacy of norepinephrine (NE) and / or serotonin (5-HT). Or a direct DA agent or a pharmaceutically acceptable salt thereof. If a direct DA agent is selected, this agent may or may not show affinity for the D1-type or D2-type DA receptor.
  • NE norepinephrine
  • 5-HT serotonin
  • component 1 is a pharmacologically-effective indirect, with or without agonistic efficacy of norepinephrine (NE) and / or serotonin (5-HT).
  • NE norepinephrine
  • 5-HT serotonin
  • a direct DA agent or a pharmaceutically acceptable salt thereof If a direct DA agent is selected, this agent may or may not show affinity for the D1-type or D2-type DA receptor.
  • D1 and D1-type are used interchangeably herein and are used to mean either or both of the
  • stereoisomer of selected component 1 may also be any of the materials described in 1 above and variations thereof, as (1) as assessed by any analytical method known to those skilled in the art, and as a pharmacophore Such known physiochemical properties, including but not limited to) -based “docking”, virtual computational screening, and other in vitro / in silico assays; And / or (2) functional DA agents based on pharmacological profiles in vitro and / or in vivo.
  • indirect DA agonist is selected as component 1 (eg, DA precursor, DA release or DA reuptake blocker)
  • pharmacologically effective NE and / or 5-HT antagonists eg, d-amphetamine, Methylphenidate, a selective dopamine norepinephrine reuptake inhibitor
  • indirect DA agonists eg, selective DA reuptake blockers
  • D1-type and D2-type DA receptor agonists are preferred over D1-selective or D2-selective receptor agonists.
  • agents that act as pharmacologically effective NE and / or 5-HT agents are also preferred over those that do not involve NE and / or 5-HT efficacy.
  • Agents and pharmaceuticals thereof that exhibit an immediate and pulsating release profile in in vitro and / or in vivo tests eg, in vitro dissolution tests, evaluation of in vivo pharmacokinetic parameters
  • the agent and its pharmaceutically acceptable salts and modified forms may have a terminal elimination half life (t1 / 2) of up to 20 hours in the human body. Suitable elimination half-life (t 1/2) is 10 hours or less, and even more eliminating half-life (t 1/2) is 5 hours or less.
  • Component 2 may be selected from small molecules, other types of molecules, and variants thereof (eg, agents, prodrugs, etc.).
  • Other forms of molecules include small interfering ribohexane, microRNAs, antisense oligonucleotides, aptamers, peptides, proteins (eg antibodies), naturally-occurring organic or inorganic molecules, chemical elements (eg lithium), and Any synthetic compounds that are larger or smaller than the small molecule are included, but are not limited to this, and are preferably delivered from any safe, acceptable and effective route of administration to ensure that the dysfunctional neural circuit is stable from reactivation and instability. Can be nested into a single combination therapeutic dosage form to block dysfunction neural circuit reinforcement.
  • component 2 comprises 5-HT2, 5-HT3 and NK-1 receptor subtypes, single-nucleotide polymorphs and other transcription, translation and translation of individual receptors expressed in human- Selective or non-selective receptor antagonist or inverse-agonist of 5-HT2 receptor, including post-modification, selective or non-selective receptor antagonist or inverse agonist of 5-HT3 receptor, selective or non-selective of NK-1 receptor Selective antagonist or inverse agonist.
  • ketanserin and its chemical isoforms eg, sorry serine
  • Mirtazapine and its chemical isomers eg, cetipyline
  • Ondansetron, granistron, dorasetron, paronosetron, and trophysetron may be included, but are not limited thereto.
  • any stereoisomer alone or a combination of each optimized ratio can be used.
  • Component 2 may also be any of the materials described in 3 above and variations thereof, as (1) as assessed by any analytical method known to those skilled in the art, and pharmacologically-based Such known physiochemical properties, including but not limited to “linkages”, virtual computational search, and other in vitro / insilico assays; And / or (2) functional antagonists in 5-HT2, 5-HT3 and / or NK-1 agonists based on in vitro and / or in vivo pharmacological profiles.
  • 5-HT2 antagonist or inverse agonist is selected as component 2
  • the 5-HT2 subtype prefers 5-HT2A subtype alone, 5-HT2C subtype alone or both 5-HT2A subtype and 5-HT2C subtype. Preferred over other preferred 5-HT2 antagonists or inverse agonists.
  • the antagonist or agonist is expected to be a physiological chemical expected as an antagonist, inverse or full or partial agonist at the alpha7 ( ⁇ 7) nicotinic receptor. , And may or may not exhibit pharmacological properties and / or profiles in vitro and in vivo.
  • Selective 5-HT3 antagonists are preferred over those expected as 5-HT3 antagonists themselves or as pharmacologically effective alpha7 nicotinic antagonists, inverse agonists or full or partial agonists.
  • NK-1 antagonist or inverse agonist When a pharmacologically effective NK-1 antagonist or inverse agonist is selected as component 2, the antagonist or inverse agonist is selective or selective for the NK-1 receptor subtype relative to the NK-2 and / or NK-3 receptor subtypes. It may not be. However, non-selective NK-1 antagonists are preferred over selective NK-1 antagonists.
  • Antagonists and agents thereof that exhibit delayed and pulsating release profiles in in vitro and / or in vivo tests known to those skilled in the art eg, in vitro dissolution tests, determination of in vivo pharmacokinetic parameters.
  • Scholarly acceptable salts and any modified forms are preferred over any other combination / permutation that exhibits an immediate, delayed, pulsating, prolonged / sustained release profile.
  • One preferred in vitro antagonist release profile is at least 10% dissolution at least 3 hours to at least 80% dissolution at 7 hours or less under gastric or enteric in vitro dissolution test conditions.
  • Antagonists and their pharmaceutically acceptable salts and modified forms may have a elimination half-life (t1 / 2) of up to 20 hours in the human body. Suitable elimination half-life t1 / 2 is 16 hours or less, even more eliminating half-life t1 / 2 is 14 hours or less and even more preferred elimination half-life t1 / 2 is in the range of 3 to 13 hours.
  • the maximum drug concentration for in vivo administration is defined as "Cmax" and the time at which Cmax is reached is defined as "Tmax".
  • the difference between the Tmax of the pharmacologically active form of component 1 and the Tmax of the pharmacologically active form of component 2 plays an essential role in determining the efficacy of the combination treatment.
  • the Tmax separation between the pharmacologically active form of plasma or serum concentrations of component 1 and component 2 in humans can range from 1 to 12 hours. Suitable ranges are 1 to 8 hours, and more suitable separations are 2 to 8 hours. Even more preferably 2 to 7 hours.
  • the Tmax of component 1 and / or component 2 is (1) the use of pharmacologically inactive prodrugs, including but not limited to performing activation in the gastrointestinal tract, blood, liver or other organs; Or (2) formulation-based modifications of the pharmacologically effective parent form.
  • formulation-based modifications can be used, including, but not limited to, pH-based, osmotic-based, liposome-based modifications, to achieve goals in vivo pharmacokinetic profiles in humans.
  • compositions for combination treatment may be embodied in any dosage form, including but not limited to tablets, capsules, solutions, gels, suspensions, films, patches, and suppositories.
  • the dosage form may be a pharmaceutical composition, which comprises Component 1 and Component 2 as the active ingredient, and may further include pharmaceutically acceptable additives such as excipients, carriers, etc. for formulation.
  • the additives are pharmaceutically acceptable, and may be used as long as they can aid in formulating and help ingestion.
  • a predetermined amount of the active ingredient is included as a powder or in granules, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions.
  • Each formulation may be formulated by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with a carrier consisting of one or more essential ingredients.
  • the composition is prepared by uniformly and finely mixing the active ingredient with the liquid carrier or the finely divided solid carrier or both, and if necessary, shaping the product into the desired appearance.
  • tablets may be formulated by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form such as powders or granules, optionally mixed with excipients, non-limiting examples of binders, lubricants, inert diluents and / or surfactants or dispersants, in a suitable machine.
  • Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.
  • the present invention further includes formulations comprising anhydrous pharmaceutical compositions and active ingredients as water may facilitate the degradation of some compounds.
  • water may be added in the pharmaceutical arts as a means of stimulating long term storage to measure features such as the lifetime or stability of the preparation over time.
  • Anhydrous pharmaceutical compositions and formulations of the present invention may be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and formulations of the invention comprising lactose may produce anhydrides when substantial contact with moisture and / or humidity is expected during manufacture, packaging and / or storage.
  • Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties.
  • anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in a suitable prescribed kit. Examples of suitable packaging include, by way of non-limiting example, hermetically sealed foils, plastics, etc., unit dose containers, foam packs and strip packs.
  • the active ingredient can be formulated in a pharmaceutical mixture with the pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a variety of forms depending on the form of preparation suitable for administration.
  • any conventional pharmaceutical medium may be an oral liquid preparation (e.g. suspensions, solutions and elixirs) or aerosols, for example water, glycols, oils, alcohols, flavors, Carriers such as preservatives, colorants, etc. may be used;
  • Or carriers such as, for example, starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants can be used in the case of oral solid preparations in some embodiments that do not utilize lactose use.
  • suitable carriers include powders, capsules and tablets with solid oral preparations. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
  • Suitable binders for use in pharmaceutical compositions and formulations include, but are not limited to, corn starch, potato starch, or other starch, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered trad. Gercans, guar gum, cellulose and derivatives thereof (e.g. ethylcellulose, cellulose acetate, carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, gelatinized starch, hydroxypropylmethylcellulose, undetermined Nitrocellulose and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered trad.
  • Gercans guar gum
  • cellulose and derivatives thereof e.g. ethylcellulose, cellulose acetate, carboxymethylcellulose, sodium carboxymethylcellulose
  • polyvinylpyrrolidone methylcellulose
  • fillers suitable for use in the pharmaceutical compositions and formulations disclosed herein include, but are not limited to, talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powdered cellulose, dexrate, kaolin, mannitol, Silicic acid, sorbitol, starch, gelatinized starch and mixtures thereof.
  • Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can produce tablets that can disintegrate in bottles. Too little may be insufficient to cause disintegration and the rate and extent of release of the active ingredient (s) from the formulation may be altered. Thus, a sufficient amount of disintegrant may be used to form the formulations of the compounds disclosed herein so that the release of the active ingredient (s) is unfavorably altered. The amount of disintegrant used may vary depending on the type of formulation and the mode of administration and can be readily identified by those skilled in the art. About 0.5 to about 15 weight percent disintegrant, or about 1 to about 5 weight percent disintegrant, may be used in the pharmaceutical composition.
  • Disintegrants that can be used to form the pharmaceutical compositions and formulations of the present invention include, by way of non-limiting examples, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polyacrylic potassium, sodium Starch glycolate, potato or tapioca starch, other starch, gelatinized starch, other starch, clay, other algin, other cellulose, gum or mixtures thereof.
  • Lubricants that can be used to form the pharmaceutical compositions and formulations of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, white mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium la Uryl sulfate, talc, hardened vegetable oils (eg, peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof.
  • hardened vegetable oils eg, peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil and soybean oil
  • zinc stearate ethyl oleate, ethyl laurate, agar, or mixtures thereof.
  • Further lubricants include, for example, cycloid silica gel, solidified aerosols of synthetic silica, or mixtures thereof.
  • the lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.
  • aqueous suspensions and / or elixirs are suitable for oral administration
  • the essential active ingredients thereof are diluents such as various sweeteners or flavoring agents, colorants or dyes and, if desired, water, ethanol, propylene glycol, glycerin and various combinations thereof. Together with emulsifiers and / or suspending agents.
  • Tablets can be uncoated or coated by known techniques to delay degradation and absorption in the gastrointestinal tract, providing long lasting action.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be used.
  • Formulations for oral use may also be present in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, the active ingredient being water or oil Medium, for example, peanut oil, liquid paraffin or olive oil. Tablets may disintegrate tablets for rapid release of the therapeutic agent.
  • Surfactants that can be used to form the pharmaceutical compositions and formulations of the present invention include, by way of non-limiting example, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of one or more hydrophilic surfactants and one or more lipophilic surfactants can be used.
  • Suitable hydrophilic surfactants can typically have an HLB value of at least 10, while suitable lipophilic surfactants can usually have an HLB value of about 10 or less.
  • An empirical variable used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic and have higher solubility from oils, while surfactants with higher HLB values are more hydrophilic and have higher solubility in aqueous solutions.
  • Hydrophilic surfactants are usually contemplated for compounds with HLB values greater than about 10, and anionic, cationic, or zwitterionic compounds in which the HLB scale is generally not applicable.
  • lipophilic (ie hydrophobic) surfactants are compounds having an HLB value of about 10 or less.
  • HLB values of the surfactants are only general guidelines that are generally used for preparing industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; Fusidate; Fatty acid derivatives, oligopeptides and polypeptides of amino acids; Glyceride derivatives, oligopeptides and polypeptides of amino acids; Lecithin and cured lecithin; Lysorecithin and cured lysocithin; Phospholipids and derivatives thereof; Lysophospholipids and derivatives thereof; Carnitine fatty acid ester salts; Alkyl sulfates; Fatty acid salts; Sodium docusate; Acylactylates; Monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; Succinylated monoglycerides and diglycerides; Citric acid esters of monoglycerides and diglycerides; And mixtures thereof.
  • examples of preferred ionic surfactants include lecithin, risolecithin, phospholipids, lysophospholipids and derivatives thereof; Carnitine fatty acid ester salts; Alkyl sulfates; Fatty acid salts; Sodium docusate; Acylactylates; Monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; Succinylated monoglycerides and diglycerides; Citric acid esters of monoglycerides and diglycerides; And mixtures thereof.
  • Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidyl acid, lysophosphatidylserine, PEG-phosphatidyl Ethanolamine, PVP-phosphatidylethanolamine, lactyl esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, mono / Citric acid esters of diglycerides, collyl sarcosine, caproate, caprylate, caprate, la
  • Hydrophilic nonionic surfactants include, but are not limited to, alkylglucosides; Alkyl maltosides; Alkylthioglucoside; Lauryl macrogol glycerides; Polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ether; Polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; Polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoester and polyethylene glycol fatty acid diester; Polyethylene glycol glycerol fatty acid ester; Polyglycerol fatty acid ester; Polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid ester; Hydrophilic transesterification products of one or more members of the group consisting of polyols and glycerides, vegetable oils, cured vegetable oils, fatty acids and sterols; Polyoxyethylene sterols, derivatives and analogs thereof; Polyoxy
  • hydrophilic-nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate Eight, PEG-15 Oleate, PEG-20 Oleate, PEG-20 Dioleate, PEG-32 Oleate, PEG-200 Oleate, PEG-400 Oleate, PEG-15 Stearate, PEG-32 Distea Latex, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryltrioleate, PEG-32 dioleate, PEG-20 glyceryllaurate, PEG-30 glycerilla Urate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG
  • Suitable lipophilic surfactants include fatty alcohols; Glycerol fatty acid esters; Acetylated glycerol fatty acid esters; Lower alcohol fatty acid esters; Propylene glycol fatty acid esters; Sorbitan fatty acid esters; Polyethylene glycol sorbitan fatty acid ester; Sterols and sterol derivatives; Polyoxyethylated sterols and sterol derivatives; Polyethylene glycol alkyl ether; Sugar esters; Saccharide ethers; Lactic acid derivatives of monoglycerides and diglycerides; Hydrophobic transesterification products of one or more members of the group consisting of polyols and glycerides, vegetable oils, hardened vegetable oils, fatty acids and sterols; Oil soluble vitamin / vitamin derivatives; And mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of one or more members of the group consisting of polyols and vegetable oils, hardened vegetable oils and triglycerides.
  • the composition may include solubilizers that excel in solubility of the active ingredient and the like and minimize precipitation. This may be particularly important for compositions for parenteral use, such as compositions for injection. Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other ingredients such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizing agents include, but are not limited to, alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol Dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropylmethylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; Ethers of polyethyleneglycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; Amides and other nitrogen containing compounds such as 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkyl
  • solubilizers can also be used.
  • Non-limiting examples include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxy Propylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethyleneglycol 200-100, glycofurol, transcutol, propyleneglycol and dimethylisosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that may be included is not particularly limited.
  • An amount of solubilizer may be limited to a biologically acceptable amount that can be easily measured by those skilled in the art.
  • the solubilizer may be in a weight ratio of 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt%, based on the combined weight of drug and other excipients. If necessary, very small amounts of solubilizers such as 5%, 2%, 1% or less may also be used.
  • the solubilizer may be present in an amount from about 1% to about 100%, more generally from about 5% to about 25% by weight.
  • the composition may further comprise one or more pharmaceutically acceptable additives and excipients.
  • the additives and excipients include, but are not limited to, tackifiers, antifoams, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, Binders, fillers, plasticizers, lubricants and mixtures thereof.
  • acids or bases may be incorporated into the compositions to facilitate processing, to improve stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, aluminum silicate magnesium, synthetic aluminum silicate, synthetic hydrocalcite, hydroxide Aluminum magnesium, disopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, trisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS) and the like.
  • acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carboxylic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, Hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid And bases which are salts such as uric acid.
  • acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric
  • Salts of polyprotic acid such as sodium phosphate, dihydrogen hydrogen phosphate and sodium dihydrogen phosphate can also be used.
  • the cation can be any conventional and pharmaceutically acceptable cation such as ammonium, alkali metal, alkaline earth metal and the like. As non-limiting examples, it may include sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and the like.
  • suitable organic acids are acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carboxylic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, iso Ascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid,
  • the present invention provides an injectable pharmaceutical composition comprising an agent which reduces or eliminates side effects of component 1 and component 2, in particular component 1, as active ingredients.
  • the present invention provides an injectable pharmaceutical composition comprising a combination of agents that reduce or eliminate the side effects of component 1 and pharmaceutical excipients suitable for injection.
  • the components and amounts of the formulations in the compositions are as described herein.
  • Forms that can be introduced for administration of the new compositions of the invention by injection are aqueous or oily suspensions, or emulsions, sesame oil, corn oil, cottonseed oil, or peanut oil and elixir, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical media. It includes.
  • Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.
  • Sterile injectable solutions are prepared by filtered sterilization after introducing the active ingredients in the required amount in a suitable solvent with various other ingredients as enumerated above, as required.
  • dispersions are prepared by introducing various sterilized active ingredients into a sterile medium comprising a basic dispersion medium and the required other ingredients from those enumerated above.
  • preferred methods of preparation are vacuum drying and freeze drying techniques which form any further desired ingredients from the powder of the active ingredient and its presterilized solution.
  • compositions of the present invention may be in solid, semisolid, or liquid form suitable for topical or topical administration, such as gels, water soluble jelly, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, It may be formulated as a preparation in an emulsion, saline solution, dimethyl sulfoxide (DMSO) solution.
  • DMSO dimethyl sulfoxide
  • dense carriers can provide prolonged exposure to the active ingredient.
  • solution preparations can further provide immediate exposure of the active ingredient to the selected portion.
  • the pharmaceutical compositions may also include suitable solid or gel carriers or excipients, which are compounds that can increase the permeation rate of therapeutic molecules across the stratum corneum permeable barrier of the skin or facilitate their delivery.
  • suitable solid or gel carriers or excipients include wetting agents (eg urea), glycols (eg propylene glycol), alcohols (eg ethanol), fatty acids (eg oleic acid), surfactants (eg isopropyl myristot and Sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxide, terpene (e.g. menthol), amine, amide, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, Gelatins and polymers such as polyethylene glycol.
  • wetting agents eg urea
  • glycols eg propylene glycol
  • alcohols eg ethanol
  • transdermal delivery means eg patches or minipumps.
  • transdermal means can be used to provide continuous or discontinuous infusion of the active ingredient in a controlled amount.
  • the present invention provides transdermal means for introducing agents and / or antagonists.
  • transdermal means for the delivery of pharmaceutical preparations are well known in the art. See, for example, US Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such means can be constructed by continuous delivery, pulsatile delivery, or immediate delivery of the pharmaceutical formulation.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof and pharmaceutically acceptable powders.
  • Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above.
  • the composition is administered by oral or nasal respiratory route for local or systemic effects.
  • the composition in a pharmaceutically acceptable solvent can be misted using an inert gas.
  • the mist solution may be directly aspirated from the mist apparatus or the mist apparatus may be attached to a facemask tent, or an intermittent positive pressure respirator.
  • the solution, suspension, or powder composition may be administered from a means for delivering the formulation by suitable means, preferably orally or intranasally.
  • compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, intrarectal, intramedullary, intraocular, nasal, epidural, or spinal cord administration.
  • pharmaceutically acceptable excipients suitable for sublingual, buccal, intrarectal, intramedullary, intraocular, nasal, epidural, or spinal cord administration.
  • the preparation of such pharmaceutical compositions is well known in the art.
  • Combination therapeutic dosage forms include any route including, but not limited to, oral, intravenous, intranasal, inhalation (eg, dose-measuring lungs), sublingual, transdermal, subcutaneous, intracranial routes and It may be administered via the method.
  • Neuropsychiatric disorders that can be treated with combination therapy include PUD, LID and PTSD.
  • indications include (1) other substance related disorders including, but not limited to, tobacco use disorders, alcohol use disorders, and cannabis use disorders; (2) behavioral addiction disorders, including but not limited to habitual gambling and Internet addiction; (3) other trauma and stress related disorders, including but not limited to reactive attachment disorders, acute stress disorders, and adaptive disorders; (4) anxiety disorders including but not limited to panic anxiety disorder, panic disorder, agoraphobia, substance / drug-induced anxiety disorder; (5) obsessive-compulsive disorders, including but not limited to obsessive-compulsive disorders, somatoform disorders, storage disorders, hair growth walls and skin peeling disorders; And (6) eating disorders including but not limited to anorexia nervosa, bulimia and binge eating disorders.
  • Combination dosage forms can be used in combination with other therapies and dosage forms to achieve additional or synergistic effects over the effects of a given combination dosage form alone.
  • therapies or dosage forms that can be used in combination with combination therapy include behavioral and anti-epileptics such as cognitive behavioral therapy, extinction therapy and exposure therapy. ), Antipsychotics, antidepressants and ketamine, including but not limited to medication.
  • Combination therapy is synergistic, to the extent that many of the symptoms and signs of this disorder are often observed in patients with comorbid disorders, secondary symptoms / symptoms, and / or other primary neuropsychiatric diagnoses as side effects of treatment of such disorders. It can be used as an adjuvant, additive, improved and / or prophylactic treatment.
  • component 1 is any uncensored or any other immediate-release formulation of methylphenidate and component 2 is any delayed, pulsating-release formulation of ondansetron. Any combination / permutation of methylphenidate and ondansetron dosage may be used.
  • the preferred dosage for methylphenidate in the dosage form is 0.1-80 mg equivalent of unmodified methylphenidate hydrochloride, and the preferred dosage range for ondansetron formulation is 0.1-32 mg equivalent of unmodified ondansetron hydrochloride. .
  • a more preferred dosage range for methylphenidate in the dosage form is an equivalent of 1-80 mg of unmodified methylphenidate hydrochloride, and a more preferred dosage range for an ondansetron formulation is 1-16 mg of unmodified ondansetron hydrochloride Is equivalent to A more preferred dosage range for methylphenidate in the dosage form is an equivalent of 5-60 mg of unmodified methylphenidate hydrochloride, and a more preferred dosage range for an ondansetron formulation is 4-16 mg of unmodified ondansetron hydrochloride Is equivalent to Any fixed-dose permutation of methylphenidate and ondansetron within the preferred equivalent dosage range can be implemented within a single dosage form.
  • any stereoisomer alone or a combination of each optimized ratio thereof may be used in the combination therapy embodiments.
  • Esmirtazapine, the S (+) stereoisomer of the antidepressant mirtazapine (e.g., Remeron®) as component 2 in dosage forms for the treatment of LID has been shown to have One example of the preferred use is.
  • Mirtazapine is a tetracyclic, tetracyclic, piperazino-azepine compound (1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a]).
  • Commercially available mirtazapine formulations eg, Remeron®
  • the drug has a high affinity for the 5-HT2A and 5-HT2C receptors as well as for the 5-HT3, adrenergic ⁇ 2 and histamine H1 receptors.
  • the drug has minimal affinity for the 5-HT1A receptor, the drug also has 5-HT1A through blocking of ⁇ 2 adrenergic self- and heterologous receptors and an indirect increase in subsequent serotonin release.
  • This drug is a 5-HT2 and 5-HT3 receptor antagonist, 5-HT1A-mediated serotonin functional delivery is preferentially enhanced (functional 5-HT1A agonist).
  • esmirtazapine Compared to the R (-) enantiomer, esmirtazapine exhibits (1) higher affinity for 5-HT2A and 5-HT2C (and ⁇ 2 adrenergic functional) receptors; (2) can be absorbed faster (but not more excessively) through the "enantioselective" transport process in the intestinal wall; (3) can accumulate more in the brain. This finding suggests that a relatively lower oral dose of Component 2 may be effective in the combination treatment of LID. In addition, esmirtazapine has a shorter terminal elimination half-life (t1 / 2), about 50%, compared to the R (-) enantiomer.
  • esmirtazapine is associated with a lower incidence of deleterious side effects such as excessive daytime sleepiness compared to racemate miratzapine (eg Remeron®) or the R (-) enantiomer.
  • Esmirtazapine is mainly metabolized to CYP2D6, which shows a clinically significant genetic polymorphism. Thus, his clearance is twice as low at lower metabolites as compared to excessive metabolites. Thus, while any dosage of esmirzapine is implemented in a single combination therapeutic dosage form, determination of the CYP2D6 phenotype in the individual patient prior to commencement of the combination therapy results in pharmacogenetic preference for the individual patient. It may be acceptable to select a tazapine dosage (“personalized drug”).
  • Example 1 [MPh-IR + Ond-PR2]: Clinical Phase 2A Stability / Efficacy Concept Verification
  • Ond-PR2 is a bead formulation made from ondansetron as an active pharmaceutical ingredient (API).
  • MPh-IR is an immediate-release general formulation of methylphenidate.
  • [MPh-IR + Ond-PR2] is a single encapsulated dosage form consisting of MPh-IR and Ond-PR2 as components 1 and 2, respectively.
  • Phase 1 Subsequent to in vitro dissolution testing and PK and safety assessment (Phase 1) among normal healthy volunteers, we performed a concept-proven, randomized, double-blind, placebo-controlled clinical phase 2A stability / efficacy trial. Was performed. Residing through the residency program, we searched a total of 48 patients who met the DSM-4 criteria for primary stimulus abuse, and 30 eligible subjects were selected from either [MPh-IR + Ond-PR2] or placebo-treated groups. Randomized into groups.
  • BOLD blood oxygen dependence
  • PK parameters of the two components were measured by quantifying serum methylphenidate and ondansetron concentrations;
  • 24-hour blood PK samples were collected after a single oral administration of [MPh-IR + Ond-PR2] capsules to determine if these parameters changed after once daily administration for 14 days.
  • Descriptive statistics for blood methylphenidate (MPh-IR) and ondansetron (Ond-PR2) concentrations at each time point were summarized as mean, standard deviation, and coefficient of variation. Prediction and statistical analysis of PK parameters were performed using SAS 9.3 and BABE Solution.
  • Table 1 shows the PK parameters of methylphenidate and ondansetron after a single oral administration of the [MPh-IR + Ond-PR2] combination capsule on the first and last days of treatment (Days 1 and 14, respectively). No significant changes were observed in Cmax, Cmin, Tmax, t1 / 2, AUC (0-24), AUC (0-infinite) and Kel parameters for either methylphenidate or ondansetron between Days 1 and 14. Did.
  • Tmax segregation between the two components of [MPh-IR + Ond-PR2] (methylphenidate and ondansetron) in individual test subjects ranged from 2 to 7 hours with no change during 14 days of treatment (day 1, respectively) And 4.5 ⁇ 1.2 vs 4.4 ⁇ 1.4 at day 14: mean ⁇ SD).
  • T means the possibility of obtaining the predicted value of the mean group deviation (eg, -1.63 for cocaine signal reactivity) when the actual difference is zero.
  • the mean group deviation e.g. -1.63 for cocaine signal reactivity
  • 95% CI 95% Confidence Inverval
  • To -0.14) means 95% confidence. Confidence intervals that do not contain zero declare a significant deviation with 95% confidence between treatments.
  • the mean deviation number eg, -1.63 for the cocaine craving score
  • is the simple mean deviation between the combination and placebo treated patients in our one trial (ie n 24).
  • the LIAIM level of the test animals was evaluated by measuring the LIAIM score three times twice a week during levodopa administration using the standard LIAIM grading scale. After LIAIM construction, animals with LIAIM scores of greater than 25 with a severe LIAIM score and combined limbs and body axis observed were selected, and these animals were subjected to (1) pergolide (0.1) for two weeks.
  • the present invention can be used in the pharmaceutical industry and related industries, such as the preparation of compositions for the combined treatment of neuropsychiatric disorders.

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PCT/KR2016/000903 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법 Ceased WO2016122218A2 (ko)

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ES16743696T ES2985064T3 (es) 2015-01-28 2016-01-28 Composición que comprende metilfenidato y ondansetrón para su uso en trastornos relacionados con la toxicomanía
KR1020217023520A KR20210095734A (ko) 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법
KR1020227017187A KR20220071297A (ko) 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법
EP24169410.8A EP4385575A3 (en) 2015-01-28 2016-01-28 Composition comprising methylphenidate and ondansetron for use in substance-related disorders
KR1020207007722A KR20200032759A (ko) 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법
CN201680007760.2A CN107206093A (zh) 2015-01-28 2016-01-28 用于治疗神经精神类障碍的组合物及方法
KR1020187003387A KR101994596B1 (ko) 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법
DK16743696.3T DK3251699T3 (da) 2015-01-28 2016-01-28 Sammensætning omfattende methylphenidat og ondansetron til anvendelse i stofrelaterede forstyrrelser
EP16743696.3A EP3251699B1 (en) 2015-01-28 2016-01-28 Composition comprising methylphenidate and ondansetron for use in substance-related disorders
KR1020197017975A KR20190077590A (ko) 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법
KR1020167021256A KR20160103548A (ko) 2015-01-28 2016-01-28 신경정신계 장애의 치료를 위한 조성물 및 방법
JP2017540782A JP6655090B2 (ja) 2015-01-28 2016-01-28 神経精神系障害の治療のための組成物および方法
US15/662,289 US20170326127A1 (en) 2015-01-28 2017-07-28 Composition and method for treatment of neuropsychiatric disorders
US16/808,458 US20200197383A1 (en) 2015-01-28 2020-03-04 Composition and method for treatment of neurophychiatric disorders
US18/121,626 US12311056B2 (en) 2015-01-28 2023-03-15 Composition and method for treatment of neuropsychiatric disorders

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