Treatment of essential tremor with (R)-2-(4-isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridine-2-yl)ethyl)acetamide

Abstract

To provide methods and materials for treating mammals having, or at risk of developing, one or more movement disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease).SOLUTION: There is provided an oral dosage form including a Cav3 antagonist or a pharmaceutically acceptable salt thereof, where the oral dosage form includes a control release component including the Cav3 antagonist, where the oral dosage form optionally includes an immediate release component including the Cav3 antagonist, where the oral dosage form, when administered a human being of almost 35 years old or older, can be effective to provide: a maximum blood plasma density (Cmax) of the Cav3 antagonist in a steady state in which the blood plasma density is twice or lower of a mean blood plasma density over 24 hours; and a blood plasma density of the Cav3 antagonist in a steady state of from about 400 nM to about 1000 nM for at least 18 hours.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Cross-reference of related applications This application is U.S. Patent Application No. 62 / 740,755, filed on October 3, 2018. Claiming the interests of, U.S. Patent Application No. 62 / 780,0 filed on December 14, 2018 We assert the benefit of No. 49. The disclosure of the prior application is deemed to be part of the disclosure of this application (and (as incorporated by reference into the disclosure of this application).

[0002] This invention relates to one or more motor disorders (e.g., essential tremor, epilepsy, and / or parkine). Methods for treating mammals that have or are at risk of developing (Sonson's disease) and This specification relates to materials. In particular, this specification relates to one or more T-type calcium channel antagonists A composition comprising (for example, one or more Cav3 antagonists such as CX-8998), and and one or more motor disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease) A composition relating to mammals that have or are at risk of developing the disease is administered to the lactating mammal. Regarding the treatment of animals. [Background technology]

[0003] Essential tremor is one of the most common movement disorders in adults. In a 2010 meta-analysis, Louis et al. (1998 Movement Dis) Orders 13(1):5-10) showed a pooled prevalence (all ages) of 0.9%. It was estimated that there was statistically significant heterogeneity between studies (I² = 99%, p < 0.001). 6 The prevalence in adults aged 5 years and older was estimated at 4.6% (Louis and Ferre Ira, 2010 Mov Disord. 25(5): 534-541). ET is lifespan. It does not shorten the time spent on daily living activities (ADL, e.g., writing and eating) at home and at work. This affects the patient's ability to perform certain tasks and negatively impacts their quality of life, social interaction, and mental state. (Lorenz et al., 2006 Mov Disord. 21(8)) :1114-1118;Louis et al.,2015 Parkinsonis m Relat Disord.21(7):729-735;George et a l., 1994 Psychosomatics. 35(6):520-523; and Z esiewicz et al.,2011 Neurology.77(19):17 52-1755). There is a growing recognition that ET is not a single-symptom disorder (Berm ejo-Pareja,2011 Nature Reviews Neurology .7(5):273-282). The effects on cognitive function are heterogeneous, affecting attention, executive function, Impairments include those in verbal fluency, visuospatial function, memory, and working memory (Bermej o-Pareja et al.,2012 “V.Cognitive Featur es of Essential Tremor:A Review of the C linical Aspects and Possible Mechanistic Underpinnings”, Tremor and Other Hyperki Page 2:0 in Netic Movements (Louis, ed.) 2012 2-74-541-1). In patients with ET, sleep was lower compared to their same-age controls. Disability and fatigue are also more frequently observed (Chandran et al., 2012 Act) a Neurol Scand. 125:332-7). Essential tremor usually progresses over time. It can worsen and become severe in some people. This can be a serious condition that affects many daily living activities. It is a major obstacle and can cause social embarrassment, phobias, depression, and anxiety.

[0004] T-type calcium channels are a family of electroactivating calcium channels (Cavs). - Members of - and each member further develops through meetings with various affiliated subunits. They are distinguished by unique pore-forming α subunits that have distinct physiological properties that can be linked. (Zamponi et al.,2015 Pharmacol Rev.67:82 1-70). The intrinsic and differential properties of T-type calcium channels are observed in membranes at relatively low potentials. This is the ability to be activated in the event of small depolarization, which in turn allows for further depolarization of the membrane, and additional Activation of ion channel subtypes and the initiation of action potentials in excitable cells This allows for a surge in the influx of calcium. Another important characteristic of this class of channels is their Relatively rapid inactivation (the "T" in "T-type" indicates transient) and from this inactive state This is a relatively slow functional recovery. Both of these properties are related to the Cav3 channel receiving sensory input. It allows for a transient response to small changes, and then a rapid reset, which in turn allows for this. Therefore, they play a crucial role in setting the resting membrane potential, and thus the overall activity of the cell. It plays an important role in stimulative and oscillating activity (Iftinca et al., 200 9 Trends Pharmacol Sci.30:32-40).

[0005] Cav3 is a T-type calcium channel, and its isoforms (Cav3.1, Ca v3.2 and Cav3.3), and their genes CACNA1G, CACNA1 H and CACNA1I were discovered and cloned in the early 1990s, and have low threshold potentials. Their function as open calcium channels has been elucidated (Perez-Reyes ,1998 Bioenerg Biomembr.30:313-8;Cribbs et al.,1998 Circ Res.83:103-9;Lee et al. ,1999 J Neurosci.19(6):1912-21). Cav3 iso The forms include the thalamocortical tract, of which Cav3.1 is the most commonly observed isoform. It is expressed throughout the central nervous system (CNS) and peripheral nervous system (Ertel e t al.,2000 Neuron.25:533-5). Cerebellar nucleus, substantia nigra, and external segment of the globus pallidus The globus pallidus internal segment and subthalamic nucleus (STN) exhibit oscillations in healthy hosts, but in pathological conditions, the nerves... Excessive rhythmicity has been observed in animals with a specific genetic makeup and in humans. Cav3 In subthreshold oscillations, as well as tremors, neuropathic pain, epilepsy, and Parkinson's disease... It has been found to be an excessive rhythmic mediator in the observed pathophysiological conditions. (Llinas, 2003 An R Acad Nac Med (Madr ).120:267-90;Handforth et al.,2005 Epile psia.46:1860-70;Llinas et al.,2007 Proc. Natl Acad Sci.104:17819-24;Park et al.,2 013 Front Neural Circuits.7:172).

[0006] The inferior olive (IO) appears to function as a source of tremors, and animal models suggest that the IO is... This suggests that it functions as an endogenous pacemaker (Long et al., 200 (2 J Neurosci. 22:10898-905). Essential tremor (ET) is caused by the cerebellum. This may be due to excessive periodic synchronous firing of IO neuronal populations, which affects the function of (E lbe et al.,1996 Mov Disord.11:70-78). Cav 3 is highly expressed in the IO and cerebellum. Cav3.1 is expressed in the IO. These are the main Cav3 isoforms. Within the cerebellar system, Cav3 is used in the Purkinje cell body. It is also found in cerebellar nuclei, astrocytes, basket cells, dendrites, and Golgi cells (Mol ineux et al.,2006 Proc Natl Acad Sci US A.103:5555-60). In these areas, Cav3 is the source of the tremor and It functions as a sustained rhythmic pacemaker (Park et al., 2010 P roc Natl Acad Sci US A.107:10731-6). [Overview of the project]

[0007] This specification applies to movement disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease). Methods and materials for treating mammals that have or are at risk of developing ) Provides, for example, one or more T-type calcium channel antagonists (e.g., CX- A composition containing one or more Cav3 antagonists (such as 8998) requires In mammals (for example, mammals with motor impairments or at risk of developing them), It may be administered to treat the mammal. CX-8998 has a highly selective electroactivity. It is a type Cav antagonist. As shown herein, CX-8998 The composition containing the oral dosage form is suitable for mammals (e.g., mammals with motor disorders). When administered orally, it is effective for approximately 12 hours (for example, with twice-daily doses) or approximately 24 hours. During intervals (for example, with once-daily administration), plasma levels of CX-8998 within a therapeutically beneficial range. The delayed emission and / or The first component is designed for sustained release, and the CX-8998 is designed for immediate release. It can be formulated to contain a calculated second component.

[0008] Currently, propranolol is the only drug approved in the United States for the treatment of essential tremor. It is a drug. Essential tremor, 2011, Academy of Neurology A new positive recommendation has been issued based on revised evidence-based guidelines regarding the treatment of (200 (Compared to the 5-year guidelines) The complete absence of the current approach to drug discovery is a significant issue. This proves that the results are poor (Zesiewicz et al., 2011 Ne Urology. 77(19):1752-1755). Therefore, one or more types of T in therapeutic doses. Type calcium channel antagonists (e.g., one or more Ca such as CX-8998) The ability to deliver v3 antagonists is unparalleled for treating individuals with essential tremor. , and provide opportunities that have not yet been realized. Furthermore, one or more T-type calcium channels Antagonists (e.g., one or more Cav3 antagonists such as CX-8998) By delivering the drug invasively and maintaining the therapeutic dose for an extended period, the necessary therapeutic effect is achieved. It can reduce the frequency of medication administration while maximizing daytime efficacy, C max Related to It can suppress adverse events and reduce nocturnal sleep disturbances (and potentially hormonal effects). It is possible.

[0009] In general, one aspect of this specification relates to a Cav3 antagonist or a pharmaceutically acceptable agent thereof. It is characterized by an oral dosage form containing a salt, wherein the dosage form contains the Cav3 antagonist. The formulation contains a controlled-release component, and the immediate-release component containing the Cav3 antagonist is controlled. It contains, and when administered to a person aged approximately 35 years or older, a) within 24 hours Cav3 antagonist C at steady state of less than twice the mean plasma concentration over time max and b) Cav3 ANTA in a steady state of approximately 400 nM to approximately 1000 nM for at least 18 hours It may be effective in providing gonist plasma concentration. The oral dosage form is when administered to humans. , steady state C with a Cav3 antagonist at 1-2 times the mean plasma concentration over 24 hours max It may be effective in maintaining [something]. The oral dosage form can be administered to humans once daily. Ca A v3 antagonist can have the following structure:

[0010] [ka]

[0011] Cav3 antagonists include hydrochloride. Oral dosage forms include capsules and pills. It may be a drug, tablet, or suspension. The controlled-release component may be particles, tablets, small tablets, solutions, or suspensions. May contain turbidity, capsules, or mixtures thereof. Particles may be granules, pellets, beads, It may be fine particles, nanoparticles, or mixtures thereof. The oral dosage form is a capsule. It may contain. The capsule is a gelatin capsule or hydroxypropyl methylcellulose capsule. It may be a capsule. A small number of multiple particles containing the Cav3 antagonist in the controlled release component. At least one particle may contain a coating containing a pH-sensitive enteric polymer. In this example, at least a portion of the pH-sensitive enteric polymer coating dissolves at approximately pH 6. It is possible. The pH-sensitive enteric polymer coating can dissolve at approximately pH 6. The enteric-coated polymer consists of approximately 6.25% methacrylate copolymer L by weight, and approximately 6.2 5% methacrylate copolymer S, about 1.25% triethyl citrate, and about 6.25 May contain % talc. In some cases, pH-sensitive enteric polymer coatings may contain small amounts of talc. However, some of it can dissolve at a pH of approximately 7. pH-sensitive enteric polymer coatings are pH It can dissolve at approximately 7. pH-sensitive enteric-coated polymers have an EUD of approximately 17.4% by weight. RAGIT® FS 30 D and approximately 2.6% PlasACRYL® ) May contain T20. The controlled release component is approximately 5.0% by weight of Cav3 antagonist. Sodium, approximately 57.7% lactose monohydrate, approximately 25.0% crospovidone, approximately 8.0% Anhydrous citric acid, approximately 2.0% sodium lauryl sulfate (SLS), approximately 2.0% hydro Xypropylcellulose (HPC), approximately 0.3% butylated hydroxyanisole (BH A) and may contain about 0.1% butylated hydroxytoluene (BHT). The oral dosage form is It may also contain an immediate-release component, where the immediate-release component is a Cav3 antagonist and multiple other components. Contains particles. One or more particles in the immediate-release component contain approximately 5.0% C by weight. AV3 antagonist, approximately 57.7% lactose monohydrate, approximately 25.0% crospovidone Dong, approximately 8.0% anhydrous citric acid, approximately 2.0% SLS, approximately 2.0% HPC, approximately 0.3 May contain % BHA and approximately 0.1% BHT. One of the particles in the immediate-release component may contain The above shows the Cav3 antagonist present in the immediate-release component when the oral dosage form is administered to humans. At least 80% of the strike may be released within 45 minutes of administration. The oral dosage form contains the immediate-release component. It contains approximately 30% Cav3 antagonist, and approximately 70% Cav3 antagonist in the controlled release component. May contain gonists. When administered to humans, the oral dosage form contains Cav3 agents within 30 minutes. C of the Tagonist max It may be effective to reach at least 25% of that. Cav3Anta Gonists can reduce the activity of T-type calcium channels.

[0012] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. It is characterized by an oral dosage form containing the Cav3 antagonist, wherein the dosage form contains the Cav3 antagonist. The dosage form contains an immediate-release component, and the Cav3 antagonist is optionally included in the immediate-release component. It contains, and when administered to a person under approximately 35 years of age, a) within 24 hours Cav3 antagonist C at steady state of 2.5 times or less the mean plasma concentration max ;reaching b) Cav3 in a steady state of approximately 400 nM to approximately 1000 nM for at least 15 hours It may be effective in providing tagonist plasma concentrations. The oral dosage form is used when administered to humans. Then, a steady state of Cav3 antagonist at 1 to 2.5 times the average plasma concentration over 24 hours is reached. C max It may be effective in maintaining [condition]. The oral dosage form can be administered to humans once daily. A Cav3 antagonist may have the following structure:

[0013] [ka]

[0014] Cav3 antagonists include hydrochloride. Oral dosage forms include capsules and pills. It may be a drug, tablet, or suspension. The controlled-release component may be particles, tablets, small tablets, solutions, or suspensions. May contain turbidity, capsules, or mixtures thereof. Particles may be granules, pellets, beads, It may be fine particles, nanoparticles, or mixtures thereof. The oral dosage form is a capsule. It may contain. The capsule is a gelatin capsule or hydroxypropyl methylcellulose capsule. It may be a capsule. A small number of multiple particles containing the Cav3 antagonist in the controlled release component. At least one particle may contain a coating containing a pH-sensitive enteric polymer. In this example, at least a portion of the pH-sensitive enteric polymer coating dissolves at approximately pH 6. It is possible. The pH-sensitive enteric polymer coating can dissolve at approximately pH 6. The enteric-coated polymer consists of approximately 6.25% methacrylate copolymer L by weight, and approximately 6.2 5 methacrylate copolymer S, approximately 1.25% triethyl citrate, and approximately 6.25% It may contain talc. In some cases, pH-sensitive enteric polymer coatings are less Some of them can dissolve at a pH of approximately 7. pH-sensitive enteric polymer coatings dissolve at a pH of approximately It can be dissolved in 7. pH-sensitive enteric-coated polymers contain approximately 17.4% EUDR by weight. AGIT® FS 30 D and approximately 2.6% PlasACRYL® May contain T20. The controlled release component is approximately 5.0% by weight of Cav3 antagonists. It contains approximately 57.7% lactose monohydrate, approximately 25.0% crospovidone, and approximately 8.0% Anhydrous citric acid, approximately 2.0% SLS, approximately 2.0% HPC, approximately 0.3% BHA, and approximately It may contain 0.1% BHT. The oral dosage form may also contain an immediate-release component, where the immediate-release component The component contains multiple particles, including a Cav3 antagonist. For more than one, the weight should be approximately 5.0% Cav3 antagonist and approximately 57.7% lactate. - Monohydrate, approximately 25.0% crospovidone, approximately 8.0% anhydrous citric acid, approximately 2.0% It may contain SLS, approximately 2.0% HPC, approximately 0.3% BHA, and approximately 0.1% BHT. One or more particles in the immediate-release component may be released immediately when the oral dosage form is administered to a human. At least 80% of the Cav3 antagonist present in the time-release component should be released within 45 minutes of administration. It can be released. The oral dosage form contains approximately 30% Cav3 antagonist in the immediate-release component, and The released component may contain approximately 70% Cav3 antagonist. The oral dosage form is administered to humans. If this happens, within 30 minutes, Cav3 Antagonist C max Reaching at least 25% It may be effective for this purpose. Cav3 antagonists activate T-type calcium channels. It can be reduced.

[0015] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. The present invention is characterized by an oral dosage form containing, where the dosage form contains a) the Cav3 antagonist a) an immediate-release component comprising one or more granules, and b) one comprising the Cav3 antagonist The oral dosage form may include a capsule containing a controlled-release component containing the above-mentioned granules, and the oral dosage form may be administered to humans. If this occurs, the mean plasma concentration of the Cav3 antagonist will be approximately 400 nM to 1000 nM. It may be effective in maintaining this for at least 12 hours. The oral dosage form is when administered to humans. To reduce the average plasma concentration of Cav3 antagonists between approximately 400 nM and 1000 nM It may also be effective in maintaining the effect for 18 hours. The oral dosage form, when administered to humans, lasts for approximately 40 hours. The mean plasma concentration of Cav3 antagonists ranging from 0 nM to approximately 1000 nM was measured over approximately 12 hours to approximately 24 hours. It may be effective for maintaining time. A Cav3 antagonist may have the following structure:

[0016] [ka]

[0017] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0018] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. The oral dosage form is characterized by containing a) one or more Cav3 antagonists. b) an immediate-release component containing the above granules, and b) one or more granules containing the Cav3 antagonist. The oral dosage form may include a tablet containing a controlled-release component, and when administered to humans... The mean plasma concentration of a Cav3 antagonist of approximately 400 nM to approximately 1000 nM is at least It may be effective for maintaining the effect for 12 hours. The oral dosage form, when administered to humans, is approximately 400 Maintaining mean plasma concentrations of Cav3 antagonists ranging from nM to approximately 1000 nM for at least 18 hours. It may be effective in maintaining the effect. The oral dosage form, when administered to humans, is approximately 400 nM to approximately 1 Maintain an average plasma concentration of 000nM Cav3 antagonist for approximately 12 to 24 hours. This may be effective. A Cav3 antagonist may have the following structure:

[0019] [ka]

[0020] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0021] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. The present invention is characterized by an oral dosage form containing, where the dosage form contains a) the Cav3 antagonist a) a control comprising an immediate-release component and one or more tablets containing the Cav3 antagonist. The oral dosage form contains a capsule containing a released ingredient, and when administered to humans, it delivers approximately 400 doses. Maintaining mean plasma concentrations of Cav3 antagonists ranging from nM to approximately 1000 nM for at least 12 hours. It may be effective in maintaining the effect. The immediate-release component may contain multiple granules. The immediate-release component is May contain multiple beads and / or pellets. One or more tablets may contain one or more small tablets. It may contain. The oral dosage form, when administered to humans, contains approximately 400 nM to approximately 1000 nM of C. This may be effective in maintaining the mean plasma concentration of the av3 antagonist for at least 18 hours. The oral dosage form, when administered to humans, contains approximately 400 nM to 1000 nM of Cav3 anamide. This may be effective in maintaining the average plasma concentration of the tagonist for approximately 12 to 24 hours. A v3 antagonist can have the following structure:

[0022] [ka]

[0023] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0024] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. The present invention is characterized by an oral dosage form containing, where the dosage form contains a) the Cav3 antagonist b) an immediate-release component which may be a liquid, and the Cav3 a A controlled-release component containing an antagonist, in the form of granules, beads, pellets, and / or small particles. Capsules containing the controlled-release component, which may include one or more solid components that may be tablets. When administered to humans, this oral dosage form contains approximately 400 nM to 1000 nM of the Ca. This may be effective in maintaining the mean plasma concentration of the v3 antagonist for at least 12 hours. The oral dosage form, when administered to humans, contains approximately 400 nM to 1000 nM of Cav3 antagonist. It may be effective in maintaining the mean plasma concentration of the gonist for at least 18 hours. The oral dosage form is When administered to humans, it contains approximately 400 nM to 1000 nM of Cav3 antagonists. It may be effective in maintaining mean plasma concentrations for approximately 12 to 24 hours. Cav3 Antagonism A st can have the following structure:

[0025] [ka]

[0026] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0027] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. It is characterized by an oral dosage form that includes, where the dosage form includes a capsule containing an inner capsule. Furthermore, the inner capsule is contained within the oral administration capsule, and as a result, the inner capsule A space exists between the outer surface and the inner surface of the oral administration capsule, and the outer surface of the inner capsule and The space between the inner surface of the oral administration capsule and the Cav3 antagonist is A fast-release component which may be a liquid, may contain the fast-release component, and the internal capacity The capsule contains a controlled-release component including the Cav3 antagonist, and the oral dosage form is When administered to humans, the Cav3 antagonist is administered at a concentration of approximately 400 nM to 1000 nM. It may be effective in maintaining the mean plasma concentration for at least 12 hours. The oral dosage form is effective in humans. When administered, the mean plasma concentration of the Cav3 antagonist is approximately 400 nM to 1000 nM. It may be effective in maintaining the concentration for at least 18 hours. The oral dosage form is administered to humans. In some cases, the mean plasma concentration of a Cav3 antagonist of approximately 400 nM to approximately 1000 nM is approximately 1 It may be effective to maintain it for 2 hours to about 24 hours. The Cav3 antagonist is as follows: Possible to have construction:

[0028] [ka]

[0029] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0030] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. The oral dosage form is characterized by containing the Cav3 antagonist, and the dosage form is characterized by a) an immediate release a) The immediate-release component, which is a liquid, and b) the Cav3 antagonist A suspension comprising a controlled-release component, wherein the controlled-release component may be in the form of granules, beads, pellets, etc. It comprises one or more solid components which may be small tablets, and / or small tablets. The dosage is suspended in the liquid, and when administered to humans, this oral dosage form contains approximately 400 ml. The mean plasma concentration of the Cav3 antagonist, ranging from nM to approximately 1000 nM, was maintained for at least 12 hours. It is effective for maintaining the concentration. The oral dosage form, when administered to humans, is approximately 400 nM to approximately 1 To maintain a mean plasma concentration of 000nM Cav3 antagonist for at least 18 hours It may be effective. The oral dosage form, when administered to humans, is approximately 400 nM to 1000 nM. It is effective in maintaining the mean plasma concentration of the Cav3 antagonist for approximately 12 to 24 hours. It's possible. A Cav3 antagonist could have the following structure:

[0031] [ka]

[0032] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0033] In another embodiment, this specification refers to a Cav3 antagonist or a pharmaceutically acceptable salt thereof. The oral dosage form is characterized by containing a) a liquid phase, and b) the Cav3 antagonist A fast-release component is included, and the fast-release component is in the form of granules, beads, pellets, and / or is one or more solid components which may be small tablets, suspended in a liquid, one or more The immediate-release component, including the solid component shown above, and c) the Cav3 antagonist, A controlled release component, wherein the controlled release component is in the form of granules, beads, pellets, and / or One or more solid components, which may be small tablets, suspended in a liquid, The oral dosage form comprises a suspension containing the controlled-release component, which includes a solid component, and is administered to humans. When administered, the mean blood of the Cav3 antagonist at a concentration of approximately 400 nM to 1000 nM is used. It may be effective in maintaining serum concentration for at least 12 hours. The oral dosage form is administered to humans. In this case, the mean plasma concentration of a Cav3 antagonist of approximately 400 nM to approximately 1000 nM is reduced. It may be effective in maintaining the effect for at least 18 hours. The oral dosage form, when administered to humans, The mean plasma concentration of a Cav3 antagonist at approximately 400 nM to 1000 nM was maintained for approximately 12 hours. It may be effective to maintain it for about 24 hours. The Cav3 antagonist has the following structure obtain:

[0034] [ka]

[0035] Cav3 antagonists include hydrochloride. This may reduce the activity of T-type calcium channels.

[0036] In another embodiment, this specification features a method for treating patients with motor impairments. The Act applies to patients who require the administration of the oral dosage forms provided herein (e.g., during exercise). This may include, or may essentially include, administering to patients with disabilities. The individual may be a human adult aged 35 or older. The patient may be a human adult under approximately 35 years of age. The motor impairment may be essential tremor, idiopathic generalized epilepsy with absence seizures, or Parkinson's disease. It may be a tremor related to the illness. The oral dosage form can be administered to the patient between 6 a.m. and noon. (For example, it may be administered once a day.) The oral dosage form is administered to the patient within 4 hours of waking up. It can be administered (for example, once daily). The controlled-release component is a Cav3 antagonist. The controlled release component may contain multiple particles, wherein the Cav3 antagonist in the controlled release component At least one of the plurality of particles contained herein is coated with a pH-sensitive enteric polymer. The coating includes a pH-sensitive enteric polymer coating, and at least a portion of the coating is intestinal p It dissolves in H. Patients may fast for at least 4 hours before the oral dosage form is administered. Cav3 antagonists are effective in reducing or eliminating tremors associated with movement disorders. It's possible. The patient would be compared to a human being who is only given the immediate-release component of a Cav3 antagonist. This may lead to a reduction in adverse events. Adverse events include dizziness, headache, euphoria, attention deficit, and paresthesia. Symptoms include: hallucinations, insomnia, dry mouth, taste disturbances, hypoesthesia, somnolence, lethargy, sleep disorders, nausea, vomiting, redness. Sysia, decreased level of consciousness, syncope, memory impairment, anxiety, restlessness, fatigue, irritability, constipation, tinnitus Loss of appetite, emotional disturbances, sexual dysfunction, double eyelids, nystagmus, drowsiness, measles-like rash, granulocytopenia, This can be agranulocytosis, erythrocytic hypoplasia, erythrocytic amorphism, or any combination thereof. .

[0037] Unless otherwise defined, the technical and scientific terms used herein are defined as those used in this specification. It has the same meaning as generally understood by those skilled in the art in the relevant technical field. Regarding "ba" and "nado (such as)" and their grammatical equivalents, please specify them in particular. Unless otherwise specified, it will be understood that the phrase "not limited to" follows. For example, The singular forms "a," "an," and "the" are plural unless explicitly indicated by the context. Includes references to: For example, the term “about” means “approximately” (e.g., approximately ±10 of the indicated value). This means %). Methods and materials similar to or equivalent to those described herein are part of the present invention. The following methods and materials may be used to carry out this, but preferred methods and materials are described below. Therefore, the specific features of the present invention described in relation to separate embodiments may be combined and used individually. It will be understood that it may be provided in one embodiment. Conversely, for the sake of brevity, a single embodiment may be provided. The various features of the present invention described in the application forms may be used separately or in any suitable subcombination. All publications, patent applications, patents, and other documents described herein may be provided. References are incorporated in their entirety by reference. In any case of inconsistency, including definitions, the present invention shall be referred to. The specification takes precedence. Furthermore, the materials, methods, and examples are illustrative and not intended to limit the scope. do not have.

[0038] Details of one or more embodiments of the present invention are described in the accompanying drawings and the detailed description below. Other features, purposes, and advantages of the present invention are described in detail in the description and drawings, and in the claims. This will become clear. [Brief explanation of the drawing]

[0039] [Figure 1]This graph shows the change from baseline to day 28 in the Tremor Research Group (TRG) Essential Tremor Rating Scale (TETRAS)-Performance Subscale (PS), as assessed by the clinical trial investigator. [Figure 2] This graph shows the changes in TETRAS-Activities of Daily Living (ADL) from baseline to day 15 and day 28. [Figure 3] This graph shows the change in the TETRAS total score from baseline to day 15 and day 28. [Figure 4] This graph shows the changes in the TETRAS-PS spiral drawing task from baseline to day 28. [Figure 5] This graph shows the change in functional tremor frequency from baseline to day 15 and day 28, as measured by digital spirography. [Figure 6] This graph shows the difference between the clinically oriented global impression (CGI-I) and placebo levels at day 28. [Figure 7] Includes graphs showing the difference between placebo and patient overall impression of change (PGIC) at days 15 and 28. [Figure 8] This graph shows the difference between the group and the placebo group on the Goal Achievement Scale (GAS). [Figure 9] This graph shows the percentage increase compared to placebo at days 15 and 28 for subjects who were satisfied with the anti-tremor medication (QUEST sub-item). [Figure 10] This graph shows the CX-8998 plasma concentrations that yield clinical efficacy on days 15 and 28. [Figure 11A] This includes a graph showing exposure to CX-8998 metabolites after twice-daily (BID) administration of CX-8998. CX-8998 metabolite M01 is shown. [Figure 11B] This includes a graph showing exposure to CX-8998 metabolites after twice-daily (BID) administration of CX-8998. The graph shows CX-8998 metabolite M02. [Figure 11C] This includes a graph showing exposure to CX-8998 metabolites after twice-daily (BID) administration of CX-8998. CX-8998 metabolite M03 is shown. [Figure 11D] This includes a graph showing exposure to CX-8998 metabolites after twice-daily (BID) administration of CX-8998. The graph shows CX-8998 metabolite M04. [Figure 12] This graph shows the relationship between CX-8998 plasma concentration and response. Baseline and placebo responses are represented by shaded areas. [Figure 13] Includes a graph showing the tolerance of adverse events associated with dose escalation. [Figure 14] Includes a graph summarizing electrocardiogram outliers in the safety analysis population. [Figure 15] Includes a graph showing no difference between CX-8998 and placebo in the safety analysis population. [Figure 16] This is a dataset and forest plot of subgroup analyses of TETRAS performance subscale total scores in the largest analysis population assessed by physicians. [Figure 17] This shows the dataset and forest plot for subgroup analysis of the TETRAS Activities of Daily Living subscale in the largest analysis population. [Figure 18] The chromatogram of CX-8998 includes partial separation and suboptimal peak widths for metabolites M01, M02, M03, and M04. [Figure 19] The chromatogram of CX-8998 contains undesirable secondary interactions that result in poor peak shapes. [Figure 20] This sample contains a chromatogram of CX-8998 showing separation close to baseline separation of CX-8998 and its metabolites M01, M02, M03, and M04. [Figure 21] The chromatogram shows that acetylation with acetic anhydride under basic conditions appeared to be selective for M04 and exhibited a high reaction yield. [Figure 22-1]This graph shows the time course of the reaction at 50°C for M04-Ac formed in the reaction of individual analytes to the reaction of the mixed analytes. [Figure 22-2] This graph shows the time course of the reaction at 50°C for M04-Ac formed in the reaction of individual analytes to the reaction of the mixed analytes. [Figure 23] This graph shows the percentage of remaining M04 after increasing the amount of acetic anhydride or pyridine in a derivatization reaction of human plasma extract at 50°C for 30 minutes. [Figure 24] This graph shows the time course of the reaction at 50°C for samples containing individual analytes, based on peak area. [Figure 25] These are representative chromatograms of CX-8998, M01, M02, M03, and M04 in human plasma samples. [Figure 26] This graph shows the emission of CX-8998 from immediate release (IR) beads. [Figure 27] Includes graphs showing the immediate-release profile of CX-8998 at once-daily doses and the steady-state state at daily doses. [Figure 28] Includes graphs showing the release profiles of CX-8998 with a single dose in elderly men and with seven daily doses in young men. [Figure 29] This graph shows the effect of age on the release of CX-8998. [Figure 30] This graph shows the effect of age on pharmacokinetics (PK). [Figure 31-1] Includes a graph of plasma concentrations of CX-8998 in elderly patients after a single morning dose. [Figure 31-2] Includes a graph of plasma concentrations of CX-8998 in elderly patients after a single morning dose. [Figure 32] Includes graphs showing the correlation of the results. [Figure 33] Includes graphs of plasma concentrations of CX-8998 in young patients after a single morning dose. [Figure 34] Includes graphs showing the correlation of the results. [Figure 35-1] Includes graphs of plasma concentrations of CX-8998 in young patients after multiple administrations. [Figure 35-2] Includes graphs of plasma concentrations of CX-8998 in young patients after multiple administrations. [Figure 36] The graph includes a release profile for young adult males, showing a burst of approximately 6 mg followed by a nearly constant burst of approximately 12 mg over 12 hours. [Figure 37] Includes a graph showing the release profile in an elderly adult male, with a burst of approximately 7 mg followed by a burst of approximately 12 mg over 12 hours at a slightly decreasing rate. [Figure 38] Includes a graph showing the zero-order release from the infiltration pump tablet. [Figure 39] Includes a graph showing primary release from a matrix tablet containing coated beads within a capsule. [Figure 40] Includes graphs showing burst and primary release from infiltration pump tablets with IR emission coating. [Figure 41] The graph includes a graph showing burst release and primary release from a mixture of IR beads and sustained-release beads in a matrix tablet having an IR coating. [Figure 42] The graph includes two bursts delayed by 3 hours from a mixture of IR beads and pH6 enteric-coated beads in IR tablets having enteric coating and IR coating. [Figure 43] The graph includes two 6-hour delayed bursts from a mixture of IR beads and pH7 enteric-coated beads in IR tablets having enteric coating and IR coating. [Figure 44] Includes graphs showing the targeted exposure range of CX-8998 in responders based on TETRAS and overall impression. [Figure 45] Includes a graph showing the upper limit of the dose. [Figure 46] This graph shows the target exposure levels and PK profiles of total and unbound CX-8998, as well as TAM, in plasma after administration of 10 mg BID of CX-8998. [Figure 47A] An exemplary T-CALM design is shown. This includes a schematic diagram of the exemplary T-CALM design. [Figure 47B] An exemplary T-CALM design is shown. A flowchart of the exemplary T-CALM design is included. [Figure 48] A-D include graphs showing the change from baseline in TETRAS-PS as assessed by the clinical trial investigator. [Figure 49] Sections A through D include graphs showing the change from baseline in TETRAS-ADL and TETRAS total. [Figure 50] Sections A and B include graphs showing the overall clinical impression of improvement on day 28. [Figure 51] Includes a graph showing the differences in TETRAS performance subscores. The upper panel shows the score differences for each item, where a negative score indicates a lower score by an independent video evaluator (CR) compared to the investigator (PR). The upper panel shows the score differences across all visits. [Figure 52] Includes graphs showing the endogenous solubility of CX-8998 free base (FB) and CX-8998 HCl formulations. [Figure 53] Includes a graph showing the emission from IR beads. [Figure 54] A and B include graphs showing the dissolution rates of IR beads having the first formulation (Figure 54A) and the second formulation (Figure 54B). [Figure 55] Figures A and B include graphs showing the dissolution rates of the CX-8998 formulation under acidic conditions (Figure 55A) and neutral pH conditions (Figure 55B). [Figure 56] Includes graphs showing the CX-8998 emission profiles of IR beads, MR1 beads, and MR2 beads. [Figure 57A] Includes a graph showing the CX-8998 emission profile of the IR beads after storage. [Figure 57B] Includes a graph showing the CX-8998 emission profile of MR1 beads after storage. [Figure 57C]Includes a graph showing the CX-8998 emission profile of MR2 beads after storage. [Figure 58] Includes graphs showing simulated dissolution rates of IR and MR1 beads in various ratios in elderly individuals. [Figure 59] Includes graphs showing simulated dissolution rates of IR and MR2 beads in various ratios in elderly individuals. [Figure 60] Includes graphs showing simulated dissolution rates of IR and MR1 beads in various ratios in non-elderly individuals. [Figure 61] Includes graphs showing simulated dissolution rates of IR and MR2 beads in various ratios in non-elderly individuals. [Figure 62A] Includes graphs showing simulated dissolution rates for various 25 mg formulations with 40% IR, 25% MR1 (pH 6), and 35% MR2 (pH 7). [Figure 62B] Includes graphs showing simulated dissolution rates for various 15 mg formulations with 40% IR, 25% MR1 (pH 6), and 35% MR2 (pH 7). [Figure 62C] Includes graphs showing simulated dissolution rates for various 8 mg dosage forms of formulations having 40% IR, 25% MR1 (pH 6), and 35% MR2 (pH 7). [Figure 63A] A includes a graph showing an exemplary distribution of Cmax values ​​for CX-8998 after single-dose administration (1 × 8 mg) of CX-8998. [Figure 63B] B includes a graph showing an exemplary distribution of AUC0-72h values ​​for CX-8998 after single-dose administration (1 × 8 mg) of CX-8998. [Figure 64A] This includes a graph showing the time to onset of adverse events after single-dose administration (1 x 8 mg) of CX-8998. [Figure 64B] This includes a graph showing the time to resolution of adverse events after single-dose administration (1 x 8 mg) of CX-8998. [Figure 64C]This includes a graph showing the duration of adverse events after single-dose administration (1 x 8 mg) of CX-8998. [Figure 64D] This includes a graph showing the concentrations at which adverse events occurred after single-dose administration (1 x 8 mg) of CX-8998. [Figure 65] This graph includes a graph showing the PK profile of IR CX-8998 single-dose administration (1 × 8 mg) compared to concentrations of CNS and psychiatric adverse events. The shaded area represents the 5th to 95th percentile. [Figure 66] This graph includes a graph showing the PK profile of MR1 CX-8998 at a single dose (1 × 8 mg) compared to concentrations of CNS and psychiatric adverse events. The shaded area represents the 5th to 95th percentile. [Figure 67] This graph includes a graph showing the PK profile of MR2 CX-8998 single-dose administration (1 × 8 mg) compared to concentrations of CNS and psychiatric adverse events. The shaded area represents the 5th to 95th percentile. [Figure 68] Includes graphs showing adverse events for each treatment period. [Figure 69] Includes a graph showing an exemplary dissolution profile of IR CX-8998 beads from lot L364-01036. [Figure 70] Includes a graph showing an exemplary dissolution profile of CR(pH6) CX-8998 beads from lot L364-01037. [Figure 71] Includes a graph showing an exemplary dissolution profile of CR(pH7) CX-8998 beads from lot L364-01038. [Figure 72A] This includes graphs showing the plasma concentrations of CX-8998, metabolite M01, and metabolite M02 after single-dose administration of IR CX-8998. [Figure 72B] This includes graphs showing the plasma concentrations of CX-8998, metabolite M01, and metabolite M02 after single-dose administration of MR1 CX-8998. [Figure 72C] This includes graphs showing the plasma concentrations of CX-8998, metabolite M01, and metabolite M02 after single-dose administration of MR2 CX-8998. [Figure 73] A includes a graph showing the mean plasma concentrations of CX-8998 over time (hourly) in patients in a fasted state versus a fed state. B shows the plasma concentrations of CX-8998 over time (hourly) for individual patients in a fasted state versus a fed state. The graph includes diamonds representing samples in a fasted state and triangles representing samples in a fed state. [Figure 74] Includes graphs illustrating exemplary once-daily dosing of MR2 CX-8998 and twice-daily dosing of IR CX-8998.

[0040] The same reference symbol in different drawings refers to the same element. [Modes for carrying out the invention]

[0041] This specification applies to movement disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease). To treat mammals (e.g., human patients) that have or are at risk of developing ) The present invention provides methods and materials for the following: In some examples, the present invention provides one or more T-type calcium Channel antagonist (e.g., one or more Cav3 antagonists such as CX-8998) Compositions containing (and) and movement disorders (e.g., essential tremor, epilepsy, and / or paroxysmal serotonin) The present invention provides for the use of such compositions in the manufacture of drugs for treating Kinson's disease.

[0042] In some cases, one or more T-type calcium channel antagonists (e.g., CX A composition containing one or more Cav3 antagonists such as -8998 is one or more components A controlled-release composition comprising the following components, where each component is administered to a human patient. The release rate of one or more T-type calcium channel antagonists from the composition To modify the degree (for example, to achieve a specific target pharmacokinetic outcome) It can be formulated into a dosage form. For example, a composition containing CX-8998 is an oral dosage form, and the dosage form is When administered orally to mammals (e.g., human patients with motor impairments), it takes approximately 12 hours. Alternatively, provide the mammal with therapeutically effective plasma levels of CX-8998 for approximately 24 hours. Designed for delayed and / or sustained emission of the CX-8998 so that it can do so. The first component, and optionally the second component designed for immediate release of CX-8998. This may be the oral dosage form having the following properties.

[0043] In some cases, one or more T-type calcium channel antagonists (e.g., CX A composition containing one or more Cav3 antagonists (such as -8998) is administered to human patients. Even if it is designed to deliver a specific target pharmacokinetic outcome, For example, T-type calcium channel antagonists have plasma concentrations in human patients If the levels are too high, it can cause undesirable symptoms (e.g., adverse effects or side effects). Therefore, and T-type calcium channel antagonists, when plasma concentrations are too low, It may have little to no effect (for example, little to no therapeutic effect). Therefore, the dosage form, after being administered to a human patient, exceeds the minimum effective concentration and is at the maximum concentration. Beyond this point, certain undesirable symptoms become more common, so the maximum concentration should be kept to a minimum. It can provide plasma concentrations exceeding those of T-type calcium channel antagonists, and over long periods of time. It is desirable to be able to do so. For example, one or more T-type calcium channels When administered as a single oral dose, compositions containing antagonists are effective in human patients. while maintaining an average plasma concentration above 400 nM, a maximum plasma concentration of 1200 nM or less can be achieved and such plasma concentration can be maintained for at least 12 hours, at least 15 hours, or at least 18 hours.

[0044] In some examples, this specification uses compositions comprising one or more T-type calcium channel antagonists ( for example, one or more Cav3 antagonists such as CX-8998). For example, a composition comprising one or more T-type calcium channel antagonists (for example, an oral dosage form designed for delayed release and / or sustained release of CX-8998 such that when administered orally to a patient with a movement disorder, it can provide a therapeutically effective plasma level of CX-8998 to the patient for about 12 hours, and optionally a second component designed for immediate release of CX-8998, such oral dosage form) can be administered to a patient having or at risk of developing a movement disorder to treat the patient. The methods and materials provided herein can be used to provide the action of CX-8998 that persists over a long period (for example, about 24 hours) to patients who require it. For example, if an oral dosage form of a composition containing CX-8998 contains a first component designed for delayed release and / or sustained release of CX-8998 as well as a second component designed for immediate release of CX-8998, the immediate release component can be effective to quickly achieve a therapeutically effective plasma level of CX-8998 in the patient and the delayed release component and / or sustained release component can be effective to maintain a therapeutically effective plasma level of CX-8998 in the patient.

[0045] ​​​​​​ composition This specification describes one or more T-type calcium channel antagonists (e.g., CX-8) A composition containing one or more Cav3 antagonists such as 998 (e.g., pharmaceutically acceptable) The composition provided is a T-type calcium channel antagonist. This can inhibit (e.g., reduce or eliminate) the activity of T-type calcium channels. In some examples, this specification provides compositions comprising CX-8998. CX-8998 (Also known as MK-8998) can inhibit Cav3 (for example, nanomo A highly selective electroactivating calcium (which can inhibit Cav3 at nM titers) It is a um channel (Cav) antagonist and is highly selective for Cav3. For example, it has >100 times higher selectivity compared to other ion channel targets. CX-899 8. Dose-dependent reduction of tremor, reduction and / or elimination of seizures, and / or reduction of pain. It may be used for and / or removal. When used herein, the term "CX-899" "8" may also refer to the CX-8998 structural analogue, however, the CX-8998 structural analogue is The pharmaceutical functions of CX-8998 described herein (e.g., dose-dependent reduction of tremor) (Maintains reduction and / or elimination of seizures, and / or reduction and / or elimination of pain) The chemical name of CX-8998 is not limited to (R)-2-(4-I Sopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyrid N-2-yl(ethyl)acetamide and 2-(4-isopropylphenyl)-N-{( 1R)-1-(5-(2,2,2-trifluoroethoxy)pyridine-2-yl)ethyl Acetamide hydrochloride is one example. The chemical structure of CX-8998 is shown below.

[0046] [ka]

[0047] CX-8998 can be any appropriate form of CX-8998. In some examples, C X-8998 can be in base form (e.g., the free base form of a compound). In some examples... CX-8998 may be in the form of a salt (e.g., a salt form of a compound). CX-899 If 8 is a salt, then CX-8998 salt can be any suitable salt. CX-8998 salt For example, any suitable acid (e.g., hydrochloric acid, citric acid, hydrobromic acid, maleic acid, phosphoric acid) Examples include salts formed by sulfuric acid, fumaric acid, and tartaric acid. For example, CX-8 998 could be CX-8998 hydrochloride (e.g., CX-8998-HCl). In that example, CX-8998 can be deuterized. In some examples, CX-8998 is , could be a polymorphic form of CX-8998. In some cases, CX-8998 is CX- It may be a structural isomer of 8998 (for example, a tautomer of CX-8998).

[0048] In some examples, the compositions provided herein (e.g., CX-8998) One or more components of a composition containing one or more T-type calcium channel antagonists ( For example, a pharmaceutically acceptable composition can cross the blood-brain barrier. For example, a composition can cross the blood-brain barrier. If X-8998 is present, then CX-8998 may cross the blood-brain barrier. For example, CX If a composition containing -8998 also contains one or more additional components, then the CX-8998 is It can be released from the composition and can cross the blood-brain barrier. For example, when a composition containing CX-8998 also contains one or more additional components, the CX-8998 can be released from the composition and can cross the blood-brain barrier, while the one or more additional components cannot cross the blood-brain barrier.

[0049] In some examples, one or more components of the compositions provided herein (e.g., compositions containing one or more T-type calcium channel antagonists such as CX-8998) (e.g., pharmaceutically acceptable compositions) do not cross the blood-brain barrier. For example, when a composition containing CX-89 98 also contains one or more additional components, the CX-8998 can be released from the composition and can cross the blood-brain barrier, while the one or more additional components cannot cross the blood-brain barrier.

[0050] Compositions containing one or more T-type calcium channel antagonists (e.g., one or more Cav3 antagonists such as CX-8998) (e.g., pharmaceutically acceptable compositions ) may contain, in addition to or instead of the T-type calcium channel antagonist, metabolites of the T-type calcium channel antagonist. In some embodiments, the T-type calcium channel antagonist present in the compositions described herein can be metabolized to one or more metabolites of the T-type calcium channel antagonist (e.g., metabolized by a mammal after administration of the composition to the mammal). In some examples, metabolites of T-type calcium channel antagonists such as metabolites of CX-8998 can be T-type calcium channel antagonists (e.g., Cav3 antagonists). For example ​​For example, if the composition contains CX-8998, the composition contains one or more CX-8998 metabolites. It may contain products and / or CX-8998 may be metabolized into one or more CX-8998 metabolites. It is possible. CX-8998 metabolites can be any suitable metabolite. In some examples... The metabolites may be bound to proteins (e.g., plasma proteins). In this example, the metabolite may be free (for example, not bound to any protein). i) In some cases, metabolites can cross the blood-brain barrier (e.g., cerebrospinal fluid (CS)). F) and / or may be present in the CNS). Examples of CX-8998 metabolites include, limited to While not directly related, metabolites 01 (M01), M02, M03, and M04 can be cited. In some examples, the compositions described herein may include M01 and M02, and / or These can be metabolized into these products. The chemical structures of exemplary CX-8998 metabolites are shown below.

[0051] [ka]

[0052] In some examples, compositions containing one or more T-type calcium channel antagonists ( For example, a T-type calcium channel antagonist in a pharmaceutically acceptable composition (e.g. For example, one or more Cav3 antagonists such as the CX-8998 are all three Cav It may be selective for the three isoforms (for example, it may selectively bind to them). In this context, "selective" means that a Cav3 antagonist competes with a Cav3 channel. And other voltage-activated calcium channels (for example, cardiac L-type channels (Cav1), etc.) compared to the high-voltage-activated channels), and / or compared to other types of ion channels (e.g., chloride ion channels, potassium channels, and sodium channels) may be more potent. Selectivity can be determined using any suitable method. For example, selectivity can be determined by comparing the IC of a Cav3 antagonist when inhibiting a first type of ion channel (e.g., Cav3 channel) with the IC when inhibiting a second type of ion channel (e.g., 50 sodium channel). The IC in inhibiting the first type of channel can be compared with the IC 50 in inhibiting the second type of channel. When the IC in inhibiting the first type of channel is lower than the IC 50 in inhibiting the second type of channel, the Cav3 antagonist can be considered selective for the first type of channel. An IC 50 ratio of 0.1 or less means a selectivity of 10-fold or more. An IC ratio of 0.01 or less means a selectivity of 100-fold or more. An IC 50 ratio of 0.001 or less means a selectivity of 1000-fold or more. In some examples, the T-type calcium channel antagonists in the compositions described herein may have a selectivity for Cav3 of 10-fold or more, 100-fold or more, or 1000-fold or more compared to other types of ion 50 channels. For example, when the T-type calcium channel antagonist in the composition described herein is CX-8998, the composition may have a selectivity of more than 100-fold compared to other ion channels. In some examples, the T-type calcium channel antagonists in the compositions described herein may be selective for one or more Cav3 isoforms (e.g., 50 For example, the T-type calcium channel antagonists in the compositions described herein may have a selectivity for Cav3 of 10-fold or more, 100-fold or more, or 1000-fold or more compared to other types of ion channels. For example, when the T-type calcium channel antagonist in the composition described herein is CX-8998, the composition may have a selectivity of more than 100-fold compared to other ion channels. In some examples, the T-type calcium channel antagonists in the compositions described herein may be selective for one or more Cav3 isoforms (e.g., When the T-type calcium channel antagonist in the composition described herein is CX-8998, the composition may have a selectivity of more than 100-fold compared to other ion channels. In some examples, the T-type calcium channel antagonists in the compositions described herein may be selective for one or more Cav3 isoforms (e.g., one or more Cav3 isoforms (e.g., Cav3.1, Cav3.2, and / or Cav3.3) can be selectively targeted. For example, the compositions described herein include all three Cav3 isoforms (e.g., It can selectively target Cav3.1, Cav3.2, and Cav3.3.

[0053] In some cases, one or more compositions described herein (e.g., CX-8998) may be used. Composition containing a T-type calcium channel antagonist) Nel antagonists may have state-dependent modes of selectivity for Cav3. For example, the T-type calcium channel antagonist in the composition described herein is desorbed Under hyperpolarized conditions, the selectivity for Cav3 is approximately 29 to 45 times higher compared to polar conditions. For example, the T-type calcium channel antagonist in the composition described herein If it is CX-8998, then CX-8998 is Cav3 (for example, Cav3.3) It may have selectivity for this, and under depolarization conditions, it has an IC of approximately 3.6 nM. 50 It may have, under hyperpolarization conditions An IC with approximately 161 nM 50 It may have T-type calcium in the compositions described herein. If the Um channel antagonist is CX-8998, then CX-8998 is, Under polarization conditions, IC exhibits an antagonistic effect with Cav3.3 at approximately 84 nM. 50 It may have, under hyperpolarization conditions IC with an antagonistic effect with Cav3.3 of approximately 2.4 μM 50 It may have. For example, this specification If the T-type calcium channel antagonist in the composition described is CX-8998 The CX-8998 may have selectivity for Cav3.1, and under depolarization conditions, approximately 69 nM IC 50It may have an IC of approximately 2.4 μm under hyperpolarization conditions. 50 It may have.

[0054] In some examples, compositions containing one or more T-type calcium channel antagonists ( For example, a T-type calcium channel antagonist in a pharmaceutically acceptable composition (e.g. For example, one or more Cav3 antagonists such as the CX-8998 are powerful Cav3 antagonists. It may be an antagonist. For example, T-type calcium channels in the compositions described herein If the agonist is CX-8998, then CX-8998 is the other ion channel It may be more powerful in its competition with Cav3 compared to it. For example, CX-8998 is n It may have an M titer (for example, an nM level of CX-8998 is sufficient to counteract Cav3). (This is the case.) In some examples, the T-type calcium channel in the compositions described herein is A tagagonist is one or more Cav3 isoforms (e.g., Cav3.1, Cav3.1). 2, and / or Cav3.3) may be strongly inhibited. Several examples are described herein. The T-type calcium channel antagonist in the composition is all three Cav3 isopropyl alcohol It can strongly inhibit foam (e.g., Cav3.1, Cav3.2, and Cav3.3). .

[0055] One or more T-type calcium channel antagonists (e.g., CX-8998) A composition containing one or more Cav3 antagonists (for example, a pharmaceutically acceptable composition) ) may contain one or more Cav3 antagonists as the sole active ingredient(s).

[0056] One or more T-type calcium channel antagonists (e.g., CX-8998) A composition containing one or more Cav3 antagonists (for example, a pharmaceutically acceptable composition) ) contains one or more T-type calcium channel antagonists and one or more additional active ingredients It may also include, for example, one or more T-type calcium channel antagonists. The patient has one or more motor disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease). May contain one or more additional drugs used to treat a disease. Examples of drugs used to treat the disorder include, but are not limited to, beta-blockers. Drugs (e.g., propranolol), antiseizure drugs (e.g., primidone, gabapentin, topi) Lamat, zonisamide, ethosuximide, pregabalin, valproic acid, phenytoin, and (Mibefurazil), tranquilizers (e.g., alprazolam and clonazepam), one or more types Administration of dopamine agonists (e.g., carbidopa / levodopa, pramipexole, ro Pinirole, rotigotine, and apomorphine), monoamine oxidase B (MAO B) ) inhibitors (e.g., seresylin, rasagiline, and safinamide), catechol-O-methol tyltransferase (COMT) inhibitors (e.g., entacapone and tolcapone), and antico Phosphates (e.g., benztropine and trihexyphenidyl) are examples.

[0057] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX-89) A composition containing one or more T-type calcium channel antagonists, such as 98, It may contain one or more additional components (e.g., one or more inactive components). For example, therapeutically An effective amount of CX-8998 may be formulated into a composition containing one or more additional components. Mammals that have or are at risk of developing the above-mentioned motor disorders (e.g., essential tremor, It may be administered to treat the mammal(s) with epilepsy and / or Parkinson's disease. The following are described herein (for example, one or more T-type calcium channel antagonists): Used to formulate compositions (e.g., pharmaceutically acceptable compositions) containing Any additional components (e.g., pharmaceutically acceptable carriers) may be of high purity. It may be substantially free of potentially harmful impurities (for example, at least Nationa l Formulary (NF) grade and / or United States P (Harmacopeia (USP) grade). For example, when intended for administration to humans. The compositions described herein are subject to the US Food and Drug Administration. Regulations applicable by the National Commission and / or similar regulatory bodies in other countries It may be manufactured or formulated under the standards of good pharmaceutical manufacturing as defined herein. For example, in this specification. The compositions described may be sterile and / or nearly isotonic and / or US All (for example) by the Food and Drug Administration It may be in full compliance with the current Good Manufacturing Practices for Pharmaceuticals.

[0058] The compositions described herein (for example, one or more T-type calcium compounds such as CX-8998) Compositions containing channel antagonists are formulated into pharmaceutically acceptable compositions. For example, a therapeutically effective amount of CX-8998 can be formulated into a pharmaceutically acceptable composition. Acquired, one or more motor disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease) In order to treat mammals that have or are at risk of developing ) It may be administered. As used herein, the term “pharmaceutically acceptable” means “sound medically acceptable.” Within the bounds of judgment, if excessive toxicity, irritation, allergic reaction, or other problems or complications occur... Suitable for use in contact with human and animal tissues without the need for additional protection, with reasonable benefits / risks. This refers to a compound, material, composition, and / or dosage form that corresponds to the ratio. For example, a therapeutically effective amount of C X-8998 contains one or more pharmaceutically acceptable carriers (e.g., additives, diluents, and / or It can be formulated with (or excipients). In some cases, the pharmaceutically acceptable carrier is this It may be the active ingredient of the composition described in the specification. A pharmaceutically acceptable carrier is described herein. If the active ingredient of the composition, the pharmaceutically acceptable carrier is the active ingredient of the composition. It may have one or more functions. For example, pharmaceutically acceptable carriers include fillers, diluents, Fillers, binders, disintegrants, wicking agents, matrix-forming polymers, coating agents pH-sensitive polymers, pore-forming agents, glidants, lubricants, osmotic agents, wetting agents, antioxidants , antibacterial agents, solubility enhancers, penetration enhancers, crystallization inhibitors, and / or combinations as specified herein It may be a solvent in the product. In some cases, pharmaceutically acceptable carriers are described herein. It may be an inert component of the composition. Pharmacochemically acceptable carriers are solid, semi-solid, or liquid. It can be a biomaterial. A pharmaceutically acceptable carrier is one or more T-type calcium channels. Any pharmaceutically acceptable compound that acts as a solvent, carrier, or medium for an antagonist. It may be. A pharmaceutically acceptable substance that can be used in the pharmaceutically acceptable compositions described herein. Examples of carriers that can be used include, but are not limited to, lactose monohydrate and crospovid. Ingredients: citric acid, sodium lauryl sulfate, ion exchanger, alumina, aluminum stearate Nium, lecithin, serum proteins, e.g., human serum albumin, buffering substances, e.g., Phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid Riceride mixture, water, salt or electrolyte, for example, protamine sulfate, disodium monohydrogen phosphate Um, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate Nesium, polyvinylpyrrolidone, cellulose, cellulosic substances, carboxymethyl cellulose Sodium coagulose, polyacrylate, wax, polyethylene-polyoxypropylene blotch Polyethylene glycol (PEG; PEG-containing molecules, e.g., vitamin E) PEG succinate and PEG-200), Tween, e.g., Tween-80, Cyclodextrin, dimethyl sulfoxide (DMSO), wool fat, lactose, dextrin Sucrose, sorbitol, mannitol, starch, acacia gum, phosphate Calcium, alginic acid, tragacanth, gelatin, calcium silicate, microcrystalline cellulose Examples include polyvinylpyrrolidone, syrup, and methylcellulose. The compositions described include, for example, fillers (e.g., lactose, sucrose, mannitol, Processed or unprocessed starch, cellulose derivatives, e.g., microcrystalline cellulose, hydroxy cypropylcellulose, croscarmellose sodium, and inorganic salts, for example (Calcium phosphate), disintegrant (e.g., croscarmellose, sodium starch glycolate) Thorium and crospovidone), binder (e.g., cellulose derivatives (e.g., hydro Parental compounds such as hydroxypropyl methylcellulose, carbopol, povidone, and modified starch. Aqueous polymers), surfactants (e.g., acyl sulfate, polysorbate, etc., polysol β-80, fatty acids and their derivatives, poloxamers, tergitol, and Other amphiphilic molecules), lubricants (e.g., talc, magnesium stearate, and mineral oil) , wetting agents, emulsifiers and suspending agents, preservatives (e.g., methyl benzoate and hydroxybenzoic acid It may also include propyl(propyl), sweeteners, and / or flavoring agents. Some examples are described herein. A pharmaceutically acceptable set containing one or more T-type calcium channel antagonists. The ingredients are lactose monohydrate, crospovidone, citric acid, and sodium lauryl sulfate. This may include. For example, if the composition described herein includes CX-8998, the composition This consists of approximately 5% CX-8998, approximately 60% lactose monohydrate, and approximately 25% by weight. It may contain crospovidone, approximately 8% citric acid, and approximately 2% sodium lauryl sulfate. The use of certain additional components (e.g., pharmaceutically acceptable carriers) allows for the creation of one or more T-type Pharmaceutical salts from calcium channel antagonists (e.g., CX-8998-HCl) It is understood that the formation of pharmaceutically acceptable salts of CX-8998, such as salts, may occur. Let's do it.

[0059] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It can be formulated into unit dosage forms. The term "unit dosage form" refers to a formulation for human subjects and other mammals. This refers to physically separated units suitable as unit doses, where each unit is a suitable pharmaceutical excipient. It contains a predetermined amount of active ingredients calculated to produce the desired therapeutic effect in conjunction with [another ingredient]. In some cases, the unit dose may be administered once daily (e.g., once-daily dose). In this example, the unit dose may be administered more frequently than once a day (e.g., BID or three times a day). TID). For example, the unit dose is approximately 0.5 mg to 1,000 mg (1 g) per day. It may contain one or more T-type calcium channel antagonists (for example, per day Approximately 0.5mg to 900mg, approximately 0.5mg to 800mg, approximately 0.5mg to 700mg mg, about 0.5mg to about 600mg, about 0.5mg to about 500mg, about 0.5mg to about 4 00mg, about 0.5mg~about 300mg, about 0.5mg~about 200mg, about 0.5mg~ Approx. 100mg, Approx. 0.5mg~Approx. 50mg, Approx. 0.5mg~Approx. 30mg, Approx. 0.5mg~ Approximately 20 mg, approximately 5 mg to approximately 1,000 mg, approximately 10 mg to approximately 1,000 mg, approximately 25 mg ~1,000mg, 100mg~1,000mg, 200mg~1,000mg g, about 300mg to about 1,000mg, about 400mg to about 1,000mg, about 500mg ~approximately 1,000mg, approximately 600mg~approximately 1,000mg, approximately 750mg~approximately 1,000mg g, about 5mg to about 750mg, about 10mg to about 500mg, about 15mg to about 400mg, Approx. 20mg to approx. 300mg, approx. 25mg to approx. 250mg, approx. 30mg to approx. 200mg, approx. 3mg to about 30mg, about 5mg to about 25mg, about 8mg to about 16mg, about 40mg to about 1 50 mg, or approximately 50 mg to approximately 100 mg of CX-8998). In some cases, each The amount contains approximately 8 mg of CX-8998. In some cases, each dose is approximately 10 mg. Contains CX-8998. In some cases, each dose contains approximately 16 mg of CX-8998. Contains. In some cases, each dose contains approximately 20 mg of CX-8998. In this example, each dose contains approximately 24 mg of CX-8998.

[0060] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) This is any appropriate amount of one or more T-type calcium channel antagonists (e.g., C May contain X-8998). One or more T-type calcium compounds in the compositions described herein. The amount (e.g., percentage or concentration) of the channel antagonist is determined by the dosage, chemical properties (e.g., It can vary depending on numerous factors, including hydrophobicity and the route of administration. For example, if the composition is If CX-8998 is included, the composition contains approximately 0.5% to approximately 60% of CX-8998 by weight. This may include 8998 (for example, approximately 1% to 60%, approximately 3% to 60%, approximately 5% to 60%). Approximately 8% to 60%, approximately 10% to 60%, approximately 12% to 60%, approximately 15% to 60%, Approximately 20% to 60%, approximately 25% to 60%, approximately 30% to 60%, approximately 40% to 60%, Approximately 50% to 60%, approximately 0.5% to 50%, approximately 0.5% to 40%, approximately 0.5% to 3% 0%, approximately 0.5% to approximately 20%, approximately 0.5% to approximately 15%, approximately 0.5% to approximately 10%, approximately 0.5 %~approximately 7%, approximately 0.5%~approximately 5%, approximately 0.5%~approximately 2%, approximately 1%~approximately 50%, approximately 5%~approximately 30%, approximately 10% to 20%, approximately 1% to 5%, approximately 5% to 10%, approximately 10% to 15% Approximately 15% to 20%, approximately 20% to 30%, approximately 30% to 40%, or approximately 40% to 50% CX-8998). In some examples, the composition is about 5% CX-8998 by weight. It may include 998.

[0061] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It can be formulated for administration in any suitable form. The compositions described herein are solid Body form (e.g., tablets or capsules), liquid form (e.g., solutions or suspensions), and It is in a semi-solid form (e.g., gel, lotion, cream, ointment, soft gel, or gummy) It is possible. Examples of forms in which the compositions described herein may be formulated are limited to the following: However, solvents, suspensions, tablets, pellets, beads, pills, powders (for example, freeze-dried powders) Powder, granules, licking agent, sachet, cachet, elixir, emulsion, syrup, Arosols (e.g., solid aerosols or liquid aerosols), lotions, creams, and Examples include ointments. In some cases, the dosage forms of the compositions described herein are one or more additional Additional ingredients (e.g., cosmetic ingredients and / or fragrance ingredients) may also be included. In this case, the solid composition may contain one or more particles (for example, one or more granules, one or more Pellet, one or more beads, one or more microparticles, and / or one or more nanoparticles, Or mixtures of granules, pellets, beads, fine particles, and nanoparticles, and their derivatives. (Combination). If the composition contains one or more particles, the particles may be of any suitable size. For example, particles can have a maximum dimension (e.g., diameter) of approximately 0.2 mm to approximately 2.0 mm. For example, approximately 0.2mm to approximately 1.8mm, approximately 0.2mm to approximately 1.5mm, approximately 0.2mm to approximately 1.2mm, approximately 0.2mm to approximately 1.0mm, approximately 0.2mm to approximately 0.8mm, approximately 0.2mm ~approximately 0.6mm, approximately 0.5mm~approximately 2.0mm, approximately 0.7mm~approximately 2.0mm, approximately 1.0 mm to approximately 2.0 mm, approximately 1.2 mm to approximately 2.0 mm, approximately 1.5 mm to approximately 2.0 mm, approximately 1 0.8mm to approximately 2.0mm, approximately 0.3mm to approximately 1.8mm, approximately 0.5mm to approximately 1.5mm, (Approximately 0.5 mm to approximately 1.0 mm, or approximately 1.0 mm to approximately 1.5 mm). In some cases, The particles may have a maximum dimension of approximately 0.5 mm to approximately 1 mm. The composition contains one or more particles. In this case, the particle can be any suitable shape. For example, the particle could be circular (for example, a sphere). The form may be one or more non-functional coatings (e.g., one or more). For example, the dosage form may be one or more non-functional coatings. It does not contain a T-type calcium channel antagonist, and one of the compositions described herein One or more coatings that do not alter the release of the above T-type calcium channel antagonists This may include (for example) one or more forms of the compositions described herein. For example, the oral dosage form is a capsule (for example, a soft gelatin capsule, a hard gelatin capsule, or It may be contained within a hydroxypropyl methylcellulose hard capsule. For example, this specification The compositions described in this document are hard gelatin capsules or hydroxypropyl methylcellulose capsules. It may be contained within a capsule. The capsule may be of any shape (e.g., elliptical). When the compositions described herein are contained within capsules, the capsules may be of any appropriate size. (For example, No. 4, No. 3, No. 2, No. 1, No. 0, No. 00, No. 000, No. 0EL, or No. 00E) It may be a type L capsule. In some cases, one or more T-type calcium channels are present. A pharmaceutically acceptable composition containing a tagonist may be a sterile composition. For example, A pharmaceutically acceptable composition containing one or more T-type calcium channel antagonists. In terms of substances, antioxidants (e.g., butylated hydroxyanisole (BHA) and / or Butylated hydroxytoluene (BHT), stabilizers, buffers, bacteriostatic agents, and the composition Aqueous and non-aqueous sterile injections that may contain a solute to be isotonic with the intended recipient's blood. Examples include aqueous and non-aqueous sterile suspensions that may contain liquids, as well as suspending agents and thickeners. In some cases, one or more T-type calcium channel antagonists described herein A pharmaceutically acceptable composition containing Streptococcus is a pellet containing multiple Cav3 antagonists. Capsules containing beads containing a t and / or Cav3 antagonist may include For example, if a composition described herein contains CX-8998, the composition may contain multiple Pellets and / or beads containing CX-8998 It may contain capsules.

[0062] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It can be formulated for administration at any appropriate time. In some cases, CX- A pharmaceutically acceptable composition containing 8998 may be an immediate-release composition. When used, the term "immediate release" means all (e.g., 100%) or substantially all ( For example, at least 70%, at least 75%, at least 80%, at least 85%, At least 90%, at least 95%, at least 97%, at least 98%, or less At least 99% of the active ingredients (for example, one or more T-type calcium such as CX-8998) (Channel antagonist) Approximately 30 minutes (for example, approximately 35 minutes, approximately 4 minutes) after administration of the composition. Composition formulated to be released within 0 minutes, approximately 45 minutes, approximately 50 minutes, or approximately 60 minutes. This refers to the immediate release composition containing CX-8998, which is released within approximately 45 minutes. It can be formulated to release 5% CX-8998. In some cases, immediate-release composition In some cases, no intentional attempt is made to alter the release rate of the active ingredient. A pharmaceutically acceptable composition containing CX-8998 is a controlled-release composition (for example, Release-controlled compositions), for example, delayed-release compositions, sustained-release compositions, or sustained-release compositions. It is possible. As used herein, the term “controlled release” refers to the plasma concentration profile of the active ingredient. This can optimize the dosage and / or make it more convenient for the patient (e.g., dosage frequency). The active ingredient (for example, one or more T-type calcium such as CX-8998) in a manner that enables reduction This refers to compositions formulated to release a (sodium channel antagonist). In some examples, the controlled-release composition may contain a single component. A substance may contain multiple components (e.g., two, three or more), each of which is active in a specific manner. They are formulated to release active ingredients. For example, controlled-release compositions are formulated for immediate release. One or more components to be formulated, as well as formulated for delayed release and / or sustained release. It may contain one or more components. As used herein, the term “delayed release” refers to the active ingredient (For example, one or more T-type calcium channel antagonists such as CX-8998) This refers to a composition formulated to delay the release of a substance. For example, the composition is in an oral dosage form. In this case, the delayed-release composition delays the release of the active ingredient until the composition has passed through the stomach. It can be formulated (for example, the drug may be destroyed or inactivated by gastric juice, (or to prevent the drug from irritating the gastric mucosa at certain points.) In some cases, a delayed-release composition is used. The substance is such that the dosage form or one or more components of the dosage form delay its release until it moves further down the intestinal tract. It can be formulated. For example, a composition containing CX-8998 can be used to obtain a delayed-release composition. It can be coated with a delayed emission coating. In some examples, the delayed emission coating It can be formed from one or more slowly eroding polymers. In some examples, delayed The release coating can be formed from one or more pH-independent polymers. In some examples... The delayed-release coating may be formed from one or more pH-sensitive polymers. For example, pH-sensitive enteric polymers are insoluble at low pH but soluble at higher pH. As a result, enteric-coated polymers are less effective at low stomach pH levels (for example, at pH levels of approximately 1 to 3). An impermeable layer may form, but the more neutral pH of the intestinal tract (e.g., pH of about 5 to about 8), e.g. For example, once exposed to a pH greater than approximately 6, as in the small intestine, or a pH greater than approximately 7, as in the large intestine... When exposed, it can swell and then be eroded. For example, pH-sensitive carbomers are low It is almost insoluble at pH (for example, at a pH of approximately 1 to 5), but not at neutral or alkaline pH values. It expands (for example, at a pH above approximately 6) and forms a thick gel. In some cases, CX- A pharmaceutically acceptable composition containing 8998 may be a sustained-release composition. For example, one or more granules, one or more pellets, one or more beads, one or more microparticles , and / or a solid composition containing one or more particles such as one or more nanoparticles) If a coating is included, the coating may be of any appropriate thickness. For example, The coating can have a thickness of approximately 50 μm to approximately 100 μm (for example, approximately 50 μm to approximately 90 μm). μm, approx. 50 μm to approx. 80 μm, approx. 50 μm to approx. 70 μm, approx. 50 μm to approx. 60 μm, approx. 60μm ~ approx. 100μm, approx. 70μm ~ approx. 100μm, approx. 80μm ~ approx. 100μm, approx. 9 0μm~approx. 100μm, approx. 60μm~approx. 90μm, approx. 70μm~approx. 80μm, approx. 60μm (~approximately 70 μm, approximately 70 μm to approximately 80 μm, or approximately 80 μm to approximately 90 μm). For example, Coating is the weight of the coated particles (for example, the weight of uncoated particles). It may have a thickness that is effective in increasing the thickness by approximately 20% compared to the child. The term "sustained release" (SR) refers to a drug that maintains a substantially constant concentration (e.g., minimum effective concentration) for an extended period. The active ingredient (e.g., one or more T23 This refers to a composition formulated to release a type calcium channel antagonist. In some cases, sustained-release compositions maintain a substantially constant drug concentration (e.g., minimum effective concentration). It can maintain this for a certain period of time. For example, a sustained-release composition may expand upon contact with water and activate It may contain one or more hydrophilic polymers that can prevent the release of the drug. For example, a sustained-release composition. This includes one or more soluble polymers such as ethylcellulose and soluble pore-forming agents. It may include a sustained-release composition. For example, the sustained-release composition may be formulated as beads or pellets. In such cases, the sustained-release composition contains one or more polymers (for example, pH-insensitive polymers and The formulation may contain (and / or pH-sensitive polymers). In some examples, CX-8998 A pharmaceutically acceptable composition containing this may be a controlled-release composition.

[0063] In some cases, controlled release compositions are referred to as "burst releases." Therefore, at least some of the active ingredients (for example, one or more T-type calcium such as CX-8998) It rapidly releases a channel antagonist. In some examples, from a controlled release composition Burst releases from the components of the or controlled-release composition are separate from the immediate-release components of the composition. It can be used. In some cases, from or components of a controlled-release composition. These burst releases can be used as a substitute for immediately released components in a composition.

[0064] In some cases, one or more T-type calcium channel antagonists described herein pharmaceutically acceptable compositions containing nistr are delayed-release compositions and / or sustained-release compositions. At least one component (e.g., a first component) containing, and optionally, an immediate-release composition It may contain a component (for example, a second component) containing CX. For example, the composition described herein may contain CX If -8998 is included, in some embodiments, the composition is at least CX-89 98 first components formulated for delayed release and / or sustained release, and optionally It may contain a second component formulated for the immediate release of CX-8998. A pharmaceutically acceptable product containing one or more T-type calcium channel antagonists is listed. The composition is formulated for the delayed and / or sustained release of CX-8998. The first component, and optionally, the second component formulated for the immediate release of CX-8998. If the composition contains the component, it may contain any appropriate proportion of that component. A pharmaceutically acceptable product containing one or more T-type calcium channel antagonists as described in the book. The composition being formulated for the delayed release and / or sustained release of CX-8998 If the formulation contains one component and a second component formulated for the immediate release of CX-8998, The composition may be used in any appropriate amount (for example, about 10%, about 15%, about 20%, about 25%, about 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately The first component in the proportions of 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% , and any appropriate amount (for example, about 10%, about 15%, about 20%, about 25%, about 30%) Approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, It may contain the second component in an amount of approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95%. For example, the composition is formulated for the delayed release and / or sustained release of CX-8998. Approximately 40% of the first component is used, and it is formulated for the immediate release of CX-8998. It may contain 60% of the second component. For example, the composition may contain delayed release and / or Alternatively, the first component, which makes up about 25% of the formulation, is formulated for sustained release, as well as the slow release of CX-8998. Approximately 35% of the second component is formulated for delayed release and / or sustained release (e.g., the same The first component is different (for example, in its composition and / or its release profile), (A second component formulated for delayed-release and / or sustained-release of CX-8998), Furthermore, it may contain approximately 40% of a third component formulated for the immediate release of CX-8998. The composition contains one or more active ingredients (e.g., CX-8998) at two or more different times. When designed to release a T-type calcium channel antagonist, the first The release of (e.g., delayed release and / or sustained release) and subsequent release (e.g., immediate release) ) may overlap. If the composition contains two or more active ingredients at different times (e.g., CX-8998 Designed to release one or more T-type calcium channel antagonists. In such cases, the first release (e.g., delayed release and / or sustained release) and subsequent releases ( For example, immediate emission can be continuous (for example, non-overlapping).

[0065] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) The emission rate can be determined using any suitable method. For example, high-performance liquid chromatography Dissolution tests by Raffy (HPLC) and / or spectrophotometric methods (e.g., one-step or two-step tests) (Stepwise dissolution test) shows that one or more T-type calcium channel antagonists (e.g., CX -8998) is a composition containing one or more T-type calcium channel antagonists. It can be used to determine the rate at which it is released. In some examples, the release rate of the composition is , it may be determined as described in other literature (for example, United States P See Chapter 117 of Harmacopeia (USP).

[0066] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) The T-type calcium channel antagonist within may have any suitable dissolution rate. In a few examples, the T-type calcium channel antagonists in the compositions described herein are , a nearly pure T-type calcium channel antagonist (for example, one that is not present in the composition) T-type calcium channel antagonists) have almost the same dissolution rate (e.g., about 90%~ It may have a dissolution rate that is approximately 110% identical. For example, the T-type in the compositions described herein. If the calcium channel antagonist is CX-8998, then the CX in the composition -8998 may have almost the same dissolution rate as nearly pure CX-8998 (for example, dissolution (Assuming the solvent's surface area, stirring speed, pH, and / or ionic strength are kept constant.)

[0067] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It is designed for any appropriate type of administration (e.g., oral, topical, parenteral, inhalation). It is possible. In some cases, the composition is designed for oral administration (e.g., as an oral dosage form). It is possible. For example, if the composition contains CX-8998, the composition may contain CX-8998 oral preparations. It can be designed as a physical form.

[0068] When administered orally, one or more T-type calcium channel antagonists Pharmaceuticals containing (for example, one or more Cav3 antagonists such as CX-8998) The composition may be in the form of, for example, pills, tablets, capsules, solutions, or suspensions. In that example, one or more T-type calcium channel antagonists described herein A pharmaceutically acceptable composition containing is a pellet containing multiple Cav3 antagonists. and / or may include capsules containing beads containing a Cav3 antagonist. In that example, the capsule contains a component comprising a delayed-release and / or sustained-release composition (for example, the The first component comprises, and optionally, a component containing an immediate-release composition (e.g., a second component). For example, if the composition contains CX-8998, the composition is partially released immediately. Multiple CXs are formulated for delayed release and / or sustained release. Contains pellets containing -8998 and / or beads containing CX-8998. Capsules may be included. In some examples, one or more T-type calciums as described herein. Pharmacologically acceptable compositions containing channel antagonists include Cav3 antagonists. The composition may include a capsule containing multiple granules containing CX-8998. In such cases, the composition is formulated in part for immediate release and in part for delayed release and / or This is a capsule containing multiple granules containing CX-8998, formulated for sustained release. May include cells. In some examples, one or more T-type calcium cells as described herein. A pharmaceutically acceptable composition containing a channel antagonist is one containing two or more (e.g., two, The tablets may include three, four or more layers. In some examples, the tablets have delayed release and / Alternatively, a component comprising a sustained-release composition (e.g., the first layer), and optionally, an immediate-release composition It may contain components containing substances (e.g., a second layer). For example, the composition may contain CX-8998. In this case, the composition contains a layer of CX-8998 formulated for immediate release, as well as a delayed release layer. Tablets containing a layer of CX-8998 formulated for release and / or sustained release. It may be seen. In some cases, one or more T-type calcium channels described herein A pharmaceutically acceptable composition containing an antagonist is a core and one or more (e.g., one) The tablets may include two, three or more coatings. For example, a tablet may have a core and a coating. If a fining is included, the tablet core is formulated for delayed release and / or sustained release. The tablet core may contain CX-8998, and the tablet core is formulated for immediate release. It can be coated with a coating containing 998. For example, the tablet can be coated with a core and a coating. If a fining is included, the tablet core containing CX-8998 will be CX-899 from the core. The tablet core may be coated with a coating that delays and / or prolongs the release of 8. They can be further coated with CX-8998, which is formulated for immediate release. In the example, if the tablet includes a core and a coating, the tablet is an infiltration pump tablet. (For example, a tablet has an osmotic pressure-driven delivery system.) For example, an osmotic pump tablet has a core and The tablet core may include CX-8998 and an osmotic agent, The tablet core has a semipermeable membrane with one or more holes (e.g., at least one precise perforation). It may be coated with a coating that, as a result, allows water to diffuse across the semipermeable film, CX-8998 as a liquid and / or suspension is passed through the hole(s) from the tablet core. It can generate osmotic pressure that can push out. In some cases, osmotic pump tablets are CX-8998( For example, one or more coatings containing CX-8998 (formulated for immediate release) It can be coated with a coating. In some examples, the capsule contains an ingredient that is an immediate-release composition. (For example, one or more particles, such as tablets, beads, pellets, granules, and / or powders) , or mixtures thereof), as well as formulated for delayed release and / or sustained release. It may contain ingredients (e.g., tablets or coatings) that include CX-8998. For example, If the composition contains CX-8998, the composition is subject to delayed release and / or sustained release. A first tablet containing CX-8998 formulated for immediate release, and optionally, a tablet for immediate release. The composition may include a second tablet containing CX-8998 formulated for this purpose. For example, the composition may include C If X-8998 is included, the composition is formulated for immediate release. Multiple beads, pellets, granules, and / or powders containing, as well as delayed release and / Or it may contain tablets containing CX-8998 formulated for sustained release. In this example, the composition contains one or more components for immediate release and delayed release and / or holding Contains one or more components for subsequent release.

[0069] When administered locally, one or more T-type calcium channel antagonists Pharmaceuticals containing (for example, one or more Cav3 antagonists such as CX-8998) The composition is administered transdermally, into the epidermis, into the eyes, and / or into mucous membranes (e.g., into the nasal cavity, transvaginally). It can be administered (by mouth, rectum, etc.). When administered by local administration, one or more Cav3 agents may be used. Pharmaceutical compositions containing antagonists include, for example, transdermal patches, ointments, lotions, and creams. Forms include: liquids, gels, drops, suppositories, sprays, liquids, and powders (e.g., lyophilized powders). It is possible.

[0070] When administered parenterally, one or more T-type calcium channel antagonists A drug containing a drug (for example, one or more Cav3 antagonists such as CX-8998) The drug composition is administered intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, intracranially (for example, subarachnoid space). It may be administered by injection or infusion (or intraventricular injection). When administered parenterally A pharmaceutical composition containing one or more T-type calcium channel antagonists is, for example, Liquids, gels, drops, suppositories, sprays, powders (e.g., freeze-dried powders), emulsions It can take the form of a cereal, suspension, microparticles, in situ gel, or drug-containing implant. When administered parenterally, one or more T-type calcium channel antagonists A pharmaceutical composition containing stront may be administered in the form of one or more bolus doses, or Continuous perfusion (e.g., by an injection pump, or by an implantable device that provides sustained release) It may be administered by [method / organization].

[0071] When administered by inhalation (e.g., by inhalation), one or more T-type calcium chains Nell antagonist (for example, one or more Cav3 antagonists such as CX-8998) A pharmaceutical composition containing ) can be administered intrapulmonaryly (for example, into the nasal cavity, upper respiratory tract, or lower respiratory tract). (May be administered). For example, containing one or more T-type calcium channel antagonists. The administration of the pharmaceutical composition is in liquid (e.g., aerosol) and / or solid (e.g., powder) form. This may include inhalation or gas injection. When administered by inhalation, one or more T A pharmaceutical composition containing a type calcium channel antagonist is, for example, a liquid (e.g., It may be in the form of a solvent or suspension, gel, or powder (e.g., lyophilized powder). When administered by administration, it contains one or more T-type calcium channel antagonists. The pharmaceutical composition may be used, for example, in a nasal spray pump, a nebulizer, a metered-dose inhaler, or in a dry It can be administered by inhaling powder.

[0072] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It can be administered locally or systemically. In some cases, one or more T-type calcium cells are used. Compositions containing channel antagonists can be administered orally to mammals systemically (for example) It can be administered to humans. For example, if the composition contains CX-8998, the composition may be administered to humans. Capsules (for example, some formulated for immediate release and some for delayed release and / or long-lasting release) Multiple CX-8998-containing pellets and / or CX-8 are formulated for sustained release. It can be formulated as an oral dosage form, such as a capsule containing 998-containing beads.

[0073] Any suitable method may be used to construct the composition described herein (e.g., a pharmaceutically acceptable composition) (For example, one or more T-type calcium channel antagonists such as CX-8998) It can be used to formulate compositions containing ( ). The solid compositions described herein Examples of methods that may be used for formulation include, but are not limited to, dry mixing. Wet granulation, spray drying, hot melt extrusion, roller compaction, compression, extrusion molding, Spherical shaping, fluidized bed drying, tray drying, fluidized bed coating, pan coating, and encapsulation Examples include compounding. Used to formulate the liquid and semi-solid compositions described herein. Examples of methods for obtaining this include, but are not limited to, high-shear mixing, homogenization, and microfluidics. These include chemical processing, media grinding, filtration, freeze-drying, and pressure sterilization. The compositions described herein are If pellets and / or beads are included, such pellets and / or beads are the active ingredient (For example, one or more T-type calcium channel antagonists such as CX-8998) And optionally, additional components such as selected excipients (e.g., lactose monohydrate, crosin). Povidone (e.g., polyplasdone XL-10), citric acid, sodium lauryl sulfate Hydroxypropyl cellulose (HPC), such as (SLS) and HPC-SL, microcrystalline cellulose Lullose, croscarmellose sodium, magnesium stearate, hydroxypropyl Extrusion and spheroidization of wet mass containing pyrmethylcellulose, povidone, and talc. It can be produced by, for example, CX-8998, lactose monohydrate, crospovidone, Extrusion and spheroidization of wet lumps of citric acid and sodium lauryl sulfate are performed relative to the weight. Approximately 5% CX-8998, approximately 60% lactose monohydrate, and approximately 25% crospovidone. pellets and / or beads containing approximately 8% citric acid and approximately 2% SLS (for example) For example, C X-8998, lactose monohydrate, crospovidone, citric acid, and sodium lauryl sulfate Extrusion and spheroidization of the wet mass of Lime is approximately 5% by weight of CX-8998, approximately 6 0% lactose monohydrate, approximately 25% crospovidone, approximately 8% citric acid, and approximately 2% SLS-containing pellets and / or beads (e.g., immediate release pellets and / or It can be used to produce pellets and / or beads. In some examples, pellets and / or beads can be produced. The process involves mixing the dry ingredients and slowly adding water while stirring with a planetary mixer. The process involves extruding the resulting wet mass, spheroidizing the extruded material, and then obtaining This can be prepared by drying pellets and / or beads in a fluidized bed dryer. These processes will be understood by those skilled in the art. The compositions described herein are granules If it contains, the granules contain an active ingredient (for example, one or more T-type calcium such as CX-8998). (Umbrane channel antagonist) and optionally additional components such as selected excipients (e.g.) For example, lactose monohydrate, crospovidone (e.g., polyplasdone XL-10), Econic acid, SLS, HPC-SL and other HPCs, microcrystalline cellulose, croscarmellose Wet granulation method for wet masses containing sodium, magnesium stearate, and TPGS It can be produced by, for example, CX-8998, lactose monohydrate, microcrystalline cellulose. S, croscarmellose sodium, HPC, magnesium stearate, and TPGS The wet granulation method of the wet mass yields approximately 2% CX-8998 and approximately 20% lacto by weight. Chromosomal hydrate, approximately 63% microcrystalline cellulose, approximately 3% croscarmellose sodium, Contains approximately 3% HPC, approximately 0.5% magnesium stearate, and approximately 10% TPGS. It can be used to generate granules (e.g., immediate-release granules). In some examples, The granules are dried in a V-blender or in the bowl of a planetary mixer or high-shear granulator. Mix the dry powder, add water or a binder solution, and mix in a planetary mixer or high-shear mixer. Granulation in a ser, crushing or sieving, in a fluidized bed dryer or box dryer Drying, optionally grinding the dried granules, and then processing them as a lubricant and / or Alternatively, it can be prepared by mixing with a glidant. These processes are known to those skilled in the art. It will be understood.

[0074] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) Delayed-release pellets and / or beads and / or sustained-release pellets and / or beads If it contains , the delayed-release pellets and / or beads and / or sustained-release pellets and / or beads are pellets and / or beads with a sustained release coating and / or This can be produced by coating with a delayed emission coating. For example, Letts and / or beads (e.g., immediate release pellets and / or beads) are used in Wur Using a fluidized bed coater equipped with a ster insert, sustained release coating and / or Alternatively, it can be coated with a delayed-release coating. For example, granular sugar (non-pareile) or inert edible spheres such as granular microcrystalline cellulose (Schgrets) (for example, type 1) The above contains T-type calcium channel antagonists (for example, coating Edible spheres (which have been processed using a Wurster insert) are used with a fluidized bed coater. They may be coated with sustained-release coatings and / or delayed-release coatings. In some cases, film coating methods are used, for example, fluidized bed spray coating. The process is used to coat (for example, spheres, pellets, and / or beads) Other processes for coating spheres, pellets, and / or beads may be applied. The term is understood by those skilled in the art. In some examples, sustained-release beads / pellets and / or Delayed-release pellets / beads are created by coating immediately-release pellets / beads. They can be produced as follows: for example, delayed-release pellets / beads and / or sustained-release beads / pellets. The kit contains immediately released pellets / beads, a sustained-release coating, and / or a delayed-release coating. It can be produced by coating with a coating. In some examples, delayed emission pellets To / beads and / or sustained-release beads / pellets are any immediate-release pellets / beads They can be generated independently of each other. For example, delayed-release pellets / beads and / or sustained-release beads. Pellets are pellets / beads (for example, uncoated pellets / beads). By formulating the product (for example, CX-8998) to provide sustained release of the active ingredient, It can be generated.

[0075] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It can be sterilized using any suitable method. In some examples, the composition described herein The materials can be sterilized by conventional sterilization techniques. In some examples, the compositions described herein are... It can be filtered and sterilized.

[0076] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) It can have any suitable pH. For example, one or more T-type calcium channels The pH of a pharmaceutically acceptable composition containing a gonist may range from approximately 3 to approximately 11. In that example, the pharmaceutically acceptable drug contained one or more T-type calcium channel antagonists. The pH of the accepted composition may range from 5 to approximately 9. In some examples, one or more T-type calcium compounds are used. The pH of pharmaceutically acceptable compositions containing um channel antagonists is approximately 7 to approximately 8. The use of certain additional components (e.g., pharmaceutically acceptable carriers) may be specified in this specification. The pH of the composition described in this document may be altered (for example, it may be used to alter it). This will be understood.

[0077] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition containing may include one or more detectable labels. In some examples, detectable Such labels may be suitable for use in vivo in mammals (e.g., humans). Examples of identification include, but are not limited to, radioactive isotopes (for example, 14 C), non-radiating Sex isotopes (e.g., deuterium and 13 Examples include C), spin labeling, fluorescent tags, and enzymes. For example, if the composition contains CX-8998, then CX-8998 is, 14 C-labeled CX- It could be 8998. For example, a detectable label is an image of the composition after administration to a mammal. It can be detected to enable imaging. Imaging is performed by a physician or another specialist in this field. The house determines the space and / or time in which the administered composition is present within the mammal. It can be made possible.

[0078] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains one or more T-type calcium channel antagonists and methyl cells. Rose, polyethylene glycol (PEG) 400, PEG-200, Tween-80 , and / or may contain cyclodextrin. For example, a composition containing CX-8998 In this case, the composition may contain CX-8998 and about 0.5 to about 1% methylcellulose. For example, if a composition contains CX-8998, the composition contains CX-8998 and about It may contain 90% PEG 400. For example, if the composition contains CX-8998, The composition may contain CX-8998 and about 80% PEG-200. For example, the composition may be If CX-8998 is included, the composition contains CX-8998 and about 10% Tween- It may include 80. For example, if the composition contains CX-8998, then the composition may contain CX-8 It may contain 998% and approximately 30% cyclodextrin.

[0079] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains one or more T-type calcium channel antagonists and methyl cells. The composition may contain rose and / or polysorbate-80. For example, if the composition is CX-899 If 8 is included, the composition is CX-8998, about 0.5% methylcellulose, and about It may contain 10% polysorbate-80. For example, if the composition contains CX-8998. The composition contains CX-8998, about 0.5% methylcellulose, and about 0.1% methylcellulose. May contain resorbate-80.

[0080] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains approximately 2 milligrams of one or more of the components as a mixture of components that are wet-granulated together. The above may contain a T-type calcium channel antagonist and magnesium stearate. For example, if the composition contains CX-8998, the composition is finely granulated together with the CX-8998. Crystalline cellulose, lactose, croscarmellose sodium, vitamin E PEG Approximately 2 milligrams of C as a mixture of xicinate and hydroxypropyl cellulose. X-8998 (for example, the free base equivalent of CX-8998), and magnesium stearate. It may contain zinc.

[0081] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains approximately 10 mg of one or more T-type calcium channels in the immediate-release component. Luantagonist and delayed-release component containing approximately 10 mg of one or more T-type calcium compounds It may contain a nel antagonist. For example, if the composition contains CX-8998, the composition The product contains approximately 10 mg of CX-8998 (for example, free salts of CX-8998) in its immediate-release component. (Base equivalent), and 10 mg of CX-8998 in the delayed-release component (for example, CX-8998 It may contain free base equivalents. In some cases, the immediately released components are produced by extrusion and spheroidization. It may contain immediately released beads, and the delayed-release component is formed by extrusion and spheroidization. And, dissolution p in a pH of approximately 5.5 to approximately 7 (for example, pH 6, pH 6.5, or pH 7) It may contain beads coated with one or more pH-sensitive enteric polymers containing H. .

[0082] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains approximately 7 milligrams of one or more T-type calcium compounds in the immediate-release component. The channel antagonist and delayed-release component contain approximately 13 milligrams of one or more T-type calcium compounds. It may contain a um channel antagonist. For example, if the composition contains CX-8998. The composition contains approximately 7 milligrams of CX-8998 (for example, CX-8) in the immediate-release component. (Free base equivalent of 998), and approximately 13 milligrams of CX-8998 in the delayed-release component (e.g., For example, it may contain the free base equivalent of CX-8998. In some cases, the immediate-release component is It may contain immediate-release beads formed by extrusion and spheroidization, and the delayed-release component is extruded Formed by shape and spheroidization, with a pH of approximately 5.5 to 7 (for example, pH 6, pH 6.5, Alternatively, coated with one or more pH-sensitive enteric polymers having a solubility pH of pH 7. It may include beads.

[0083] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition containing CX-8998 is formulated for delayed release and / or sustained release. A first component having granules containing CX-8998, and CX-8998 that releases immediately A solid agent containing a second component having granules containing CX-8998, which is formulated for use in the field. It may be a release-controlled composition in the form of (e.g., pills, capsules, and tablets). For example, a release-controlled composition. The capsule contains CX-8998, and the delayed release and / or sustained release of CX-8998. It may contain a first component having granules formulated for dispensing, and optionally containing CX-8998. It may also contain a second component having granules formulated for immediate release of CX-8998. For example, controlled-release tablets contain CX-8998, and the delayed release and / or may comprise a first component having granules formulated for sustained release, optionally CX A second granule containing -8998 and formulated for immediate release of CX-8998 It may also contain the following components. In some examples, it contains CX-8998 and the delayed release of CX-8998. A first component having granules formulated for release and / or sustained release, and optionally It contains CX-8998 and has granules formulated for the immediate release of CX-8998. The second component is compressed into a tablet (for example, a single-layer tablet and a tablet having two or more layers). obtain.

[0084] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains two or more (e.g., two, three, four or more) solid dosage forms (e.g., A controlled-release composition comprising pills, capsules, and tablets, wherein at least one The solid dosage form contains CX-8998, which is formulated for immediate release of CX-8998. At least one solid dosage form is available for the delayed release and / or sustained release of CX-8998. It contains CX-8998 which is formulated. For example, a controlled-release composition contains two or more solid agents. Including the form, where at least one solid dosage form is formulated for immediate release of CX-8998. A solid dosage form containing CX-8998, which is modified, is a delay of CX-8998. Contains CX-8998 formulated for release and / or sustained release, and two or more of the above. The solid dosage form may constitute a single dose.

[0085] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition containing CX-8998 is formulated for delayed release and / or sustained release. One or more tablets (for example, one, two, three, four or more) containing CX-8998 The agent, and / or CX-8998, is formulated for delayed release and / or sustained release. One or more (e.g., one, two, three, four or more) miniature tablets containing CX-8998 A first component having an agent, and optionally formulated for the immediate release of CX-8998. A controlled-release composition having a capsule containing a second component containing CX-8998. For example, a controlled-release capsule contains CX-8998 and has a delayed release of CX-8998. One or more tablets and / or one or more tablets formulated for release and / or sustained release. The first component may have a tablet form and optionally contain CX-8998. It may also contain a second component formulated for immediate release. In some cases, CX-899 One containing 8, formulated for delayed release and / or sustained release of CX-8998. A first component comprising the above tablets and / or one or more small tablets, and optionally, CX One or more tablets containing -8998 and formulated for immediate release of CX-8998 A second component, which may have one or more small tablets, may be present within the capsule. In this example, it contains CX-8998 and the delayed and / or sustained release of CX-8998 A first component having one or more tablets and / or one or more small tablets formulated for , and optionally, a formulation containing CX-8998 for immediate release of CX-8998. A second component having the processed powder may be present within the capsule. In some examples, CX-8 Contains 998 and formulated for delayed-release and / or sustained-release of CX-8998. A first component comprising one or more tablets and / or one or more small tablets, and optionally, It contains CX-8998 and has granules formulated for the immediate release of CX-8998. The second component may be present within the capsule. In some examples, it contains CX-8998 and C One or more tablets formulated for delayed release and / or sustained release of X-8998 and / or a first ingredient having one or more small tablets, and optionally containing CX-8998 It has beads and / or pellets formulated for immediate release of CX-8998. The second component may be present within the capsule.

[0086] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition containing CX-8998 is formulated for delayed release and / or sustained release. A first solid component containing CX-8998 (e.g., granules, beads, pellets, and Tablets), and optionally, CX-8998 formulated for immediate release. A capsule containing a second liquid component (e.g., a solution or suspension) containing 8. It may be a controlled-release composition. For example, a controlled-release capsule contains CX-8998 and C A first having granules formulated for delayed release and / or sustained release of X-8998 It may contain solid components, contains CX-8998, and is formulated for the immediate release of CX-8998. It may contain a second liquid component. In some examples, it contains CX-8998 and CX-8 A first component having granules formulated for delayed release and / or sustained release of 998, Optionally, a formulation containing CX-8998 and formulated for the immediate release of CX-8998. The second liquid component may be present within the capsule. In some examples, it may contain CX-8998. It has beads formulated for the delayed release and / or sustained release of CX-8998 and / or a first component having pellets, and optionally containing CX-8998, CX- A second liquid component, formulated for the immediate release of 8998, may be present within the capsule. In some cases, the product contains CX-8998, and the delayed release and / or sustained release of CX-8998 is present. One or more (e.g., one, two, three, four or more) tablets formulated for release The first component and optionally contains CX-8998, and for the immediate release of CX-8998 The second liquid component, formulated for this purpose, contains capsules and / or CX-8998, C One or more formulations for delayed-release and / or sustained-release of X-8998 (e.g.) They may be present in small tablets (one, two, three, four or more).

[0087] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains a first (e.g., outer) capsule and a second (e.g., inner) capsule. A cell (for example, a space exists between the outer surface of the second capsule and the inner surface of the first capsule) The second capsule is sized to fit inside the first capsule. CX-8998 has (L) and is formulated for delayed release and / or sustained release. A first component containing -8998, and optionally CX-8 formulated for immediate release. It may be a controlled-release composition containing a second component containing 998. For example, a controlled-release composition containing 998. A capsule, which includes an internal capsule that is housed within the controlled release capsule, The capsule contains CX-8998 and provides delayed and / or sustained release of CX-8998. It may contain a first ingredient formulated for this purpose, and optionally contain CX-8998 and CX-89 98 granules formulated for immediate release, contained within the inner capsule, and / or The second component is contained in the space between the inner capsule and the outer capsule. It is possible. In some cases, the outer capsule contains CX-8998, and the CX-8998 is slow to react. Solid components formulated for extended release and / or sustained release (e.g., granules, beads, etc.) An internal capsule containing a first component, which is a tablet (such as a small tablet or small tablet), and optional A liquid component containing CX-8998, formulated for the immediate release of CX-8998. It may contain a second component which is (for example, a solution or suspension), where CX-8998 The liquid component contained and formulated for immediate release of CX-8998 is present if It exists in the space between the outer surface of the inner capsule and the inner surface of the outer capsule. In that example, the outer capsule contained CX-8998, and for the immediate release of CX-8998 It may contain an inner capsule having a first component formulated for this purpose, and the inner capsule is C The first component contains X-8998 and is formulated for the immediate release of CX-8998. It may include a coating that can delay the release of the substance.

[0088] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The composition contains a liquid phase (e.g., a solution) and a plurality of solid components suspended in the liquid phase. Release is a suspension containing (for example, tablets such as granules, beads, pellets, and small tablets) It may be a controlled composition. For example, a controlled release suspension containing a liquid phase and a plurality of solid components is CX - May contain one or more T-type calcium channel antagonists, such as -8998, in the liquid phase. Alternatively, one or more T-type calcium channel antagonists are suspended in the liquid phase. It may contain body components, or one or more T-type calcium channel antagonists in liquid. It can be contained both in the phase and in the solid components suspended in the liquid phase. In some examples, CX- It contains 8998 and multiple solid components formulated for the immediate release of CX-8998, and Contains CX-8998 and manufactured for the delayed and / or sustained release of CX-8998. The compounded second solid components can be suspended in the liquid phase of the controlled-release suspension. In this example, the controlled release suspension contains CX-8998 and is for the immediate release of CX-8998. It may contain a formulated liquid phase, containing CX-8998, and the delayed release of CX-8998 and / or may contain multiple solid components formulated for sustained release and suspended in the liquid phase. ru.

[0089] Treatment method This specification applies to mammals that have or are at risk of developing one or more motor disorders. For example, methods for treating humans are also provided. For example, a person having one or more motor impairments. Or, mammals at risk of developing the disease may be treated in accordance with this specification. The composition described (for example, one or more T-type calcium channels such as CX-8998) A composition containing a tagonist may be administered. The term “to treat” or “treatment” is ( 1) To prevent motor disorders, for example, to prevent motor disorders that may easily develop, and the symptoms of such motor disorders Or to prevent such motor impairment in individuals who have not yet experienced or shown overall symptoms. (2) To suppress motor impairment, for example, the experience of symptoms or overall symptoms of motor impairment or To suppress the motor impairment in the individual (i.e., the symptoms and / or overall) (3) To suppress the further onset of symptoms; and (4) To improve motor impairments, for example, motor impairments To improve the motor disorder in individuals experiencing or exhibiting symptoms or overall symptoms of harm. (That is, reversing the symptoms and / or overall symptoms), for example, severe motor impairment To reduce the degree, or to reduce or alleviate one or more symptoms of a motor impairment, This refers to one or more of these conditions. For example, a feeding condition that involves motor impairment or is at risk of developing it. When an animal is administered a composition containing CX-8998, the combination containing CX-8998 The product may be effective in reducing or eliminating one or more symptoms of the movement disorder. Examples of symptoms of the disorder, though not limited to these, include tremors (e.g., rhythmic tremor), and Stable gait (e.g., ataxia), dystonic movements, freezing of movement (bradykinesia), tics, spasms Other motor disorders, seizures, pain, sensory disturbances, psychiatric symptoms, cognitive impairment, hearing impairment, and mood swings. These include: If the symptom is a tremor, the tremor is any appropriate type of tremor (for example, This may include familial tremor, action tremor, postural tremor, motor tremor, and / or resting tremor. In some cases, mammals with motor impairments or at risk of developing them are given the opportunity to have the mammals that have motor impairments. A composition containing CX-8998 is administered to reduce or eliminate tremors in mammals. To obtain. If the symptom is a tremor, the tremor may occur in any suitable part of a mammal (e.g., hand, It can affect the head, voice, arms, fingers, legs, jaw, and other parts of the mammalian body. In this example, mammals that have or are at risk of developing motor impairments are considered to be mammals A composition containing CX-8998 to reduce or eliminate tremors in the hand(s). It may be administered. For example, one or more T-type calcium channel antagonists may be administered according to this specification. As described in the book, mammals that need it (for example, those with motor impairments, (In mammals at risk of developing the disease) one or more of the motor disorders in those mammals. The severity levels are, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 percent It may be administered to reduce by more than one cent. Any appropriate method may be used depending on the severity of the motor impairment and / or it can be used to assess the symptoms of motor impairment. In some cases, the severity of motor impairment The severity and / or symptoms of motor impairment may include assessments of one or more general functional scales. In some cases, the severity of the motor impairment and / or the symptoms of the motor impairment are one or more specific This may include assessment of functional scales. It assesses the severity and / or symptoms of motor impairment. Examples of methods that may be used for this purpose include, but are not limited to, the measurement of activities of daily living. (For example, measured using TETRAS), the overall clinical impression of improvement (for example, CGI) -Measured using I), the patient's overall impression of the change (e.g., using PGIC) (measured by), tremor-specific goal achievement (e.g., measured using GAS), Quality of life (for example, measured using the QUEST tremor treatment satisfaction sub-item), and and the Archimedean spiral (for example, using a pen and paper as in the TETRAS-PS subitem) Measured using and / or using a tablet and stylus as in iMotor Examples include (which are measured digitally using a device). In some cases, the severity of the motor impairment and / or methods for measuring symptoms of motor impairment are described in the Examples section. It could be such. For example, when measuring activities of daily living using TETRAS, The higher the core score, the worse the tremor, so a decrease in score indicates an improvement in tremor. For example, it may be used to assess the severity and / or symptoms of a motor impairment. The method may be described in other literature (e.g., Elble et al, 2 013 Movement Disorders,28 1793;Jankovik J and Tolosa E.Parkinson's Disease and Movement Disorders.1988 Baltimore-Milnic h:Fahn et al. in Urban & Schwarzenberg “C clinical rating scale for Tremor”, p.225- 34; and Haubenberger et al., 2016 Movement Di soorders,31,No.9;Fahn et al.(eds.) Recent Developments in Parkinson's Disease,Vol. 2.1987 Florham Park, NJ. Macmillan Health Fahn et al., “Member Information in Care Information s of the UPDRS Development Committee”, p pp. 153-163 and 293-304; American Academy of New Guidelines for the management of essential tremor by urology, e.g., aan.com / Guid Enter via the website elines / home / GuidelineDetail / 492 Available; and according to the American Academy of Neurology Parkinson's disease treatment guidelines, for example, movementdisorders.o rg / MDS-Files1 / Resources / PDFs / Treatmentsf orMotorSymptomsofPD-2018.pdf is available on the website. (See "Things").

[0090] In some cases, one or more T-type calcium channel antagonists (e.g., CX A composition containing one or more Cav3 antagonists such as -8998 (for example, pharmaceutically (Permitted compositions) are mammals (e.g., those having one or more motor disorders or developing a disease). It can be administered to mammals that are at risk of developing a condition, while the mammal is fasting. For example, Mammals are administered a composition containing one or more T-type calcium channel antagonists. Before that, at least 4 hours (for example, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours) You may fast for approximately 9 hours, 10 hours, 11 hours, or 12 hours (and (They may have been instructed to fast.)

[0091] In some cases, one or more T-type calcium channel antagonists (e.g., CX A composition containing one or more Cav3 antagonists such as -8998 (for example, pharmaceutically (Permitted compositions) are mammals (e.g., those having one or more motor disorders or developing a disease). In mammals that are at risk of developing this condition, the drug is administered when the mammal is in a state of (for example, not fasting). It is possible.

[0092] Do you have a movement disorder (e.g., essential tremor, epilepsy, and / or Parkinson's disease)? or any suitable mammal at risk of developing the disease, as described herein. It may be placed as described herein (for example, one or more T models such as CX-8998). Treatment (by administering a composition containing a type 1 calcium channel antagonist) Examples of mammals that could be affected include, but are not limited to, humans and non-human primates (for example) Examples include monkeys, dogs, cats, horses, cows, pigs, sheep, mice, and rats. In some cases, individuals who have or are at risk of developing a motor impairment may have the motor impairment To reduce or eliminate one or more symptoms of harm, one or more T-type chemicals such as CX-8998 Treatment may be performed with a composition containing a lucium channel antagonist.

[0093] Mammals having one or more motor disorders as described herein (e.g., CX- A composition containing one or more T-type calcium channel antagonists such as 8998 When treated (by administration), the mammal may be of any appropriate age. In a few examples, the people suitable for the treatment are adults (e.g., young adults, middle-aged adults, and elderly adults). For example, human adults are those 18 years of age or older (for example, 20 years of age or older, 30 years of age or older, 40 years of age or older). The above applies to those aged 50 or older, 60 or older, 65 or older, 70 or older, or 75 or older. In some cases, adults are approximately 18 to 100 years old (for example, approximately 18 to 90 years old, approximately 18 to approximately 80 years old, approximately 18 to approximately 75 years old, approximately 18 to approximately 70 years old, approximately 18 to approximately 65 years old, approximately 18 to approximately 60 years old, approximately 18 to approximately 55 years old, approximately 18 to approximately 50 years old, approximately 18 to approximately 45 years old, approximately 18 to approximately 40 years old, approximately 20 to approximately 100 years old, approximately 30 to approximately 100 years old, approximately 40 to approximately 100 years old Ages: approximately 50-100, approximately 60-100, approximately 65-100, approximately 70- Approximately 100 years old, approximately 75 to approximately 100 years old, approximately 80 to approximately 100 years old, approximately 20 to approximately 55 years old, approximately 2 0 to approximately 40 years old, approximately 22 to approximately 39 years old, approximately 40 to approximately 80 years old, approximately 40 to approximately 66 years old, approximately 4 Ages 0-60, 50-80, 55-75, 57-75, and This can be around 57 to 70 years old. In some cases, the person suitable for treatment is a young person (for example) For example, a human being is a person under 18 years old. For example, a human adolescent is a person between approximately 1 and 18 years old (for example, approximately 1 Ages 1 to approximately 17, approximately 1 to approximately 16, approximately 1 to approximately 15, approximately 1 to approximately 14, approximately 1 to approximately 1 3 years old, approximately 1 to 12 years old, approximately 1 to 11 years old, approximately 1 to 10 years old, approximately 1 to 8 years old, approximately 1 Ages 1-5, 1-3, 5-18, 10-18, 12-18 8 years old, approximately 15-18 years old, approximately 16-18 years old, approximately 2-16 years old, approximately 5-15 years old This could be approximately 8 to 12 years old, approximately 2 to 8 years old, or approximately 5 to 15 years old. For example, The young man could be around 16 years old.

[0094] Mammals having one or more motor disorders as described herein (e.g., CX- A composition containing one or more T-type calcium channel antagonists such as 8998 When administered, the mammal may be female or male.

[0095] Mammals having one or more motor disorders as described herein (e.g., CX- A composition containing one or more T-type calcium channel antagonists such as 8998 When treating (by administration), one or more T-type calcium cells such as CX-8998 may be used. Compositions containing channel antagonists can be administered at any appropriate time. In this example, one or more T-type calcium channel antagonists such as CX-8998 are used. The contained composition can be administered to mammals in the morning. For example, one such composition such as CX-8998. The composition containing the above T-type calcium channel antagonist is effective from around 6:00 AM to noon. Around that time (for example, around 6am to around 11am, around 6am to around 10am, around 6am to Around 9 AM, around 6 AM to 8 AM, around 6 AM to 7 AM, around 7 AM to noon, Around 8:00 AM to 12:00 PM, around 9:00 AM to 12:00 PM, around 10:00 AM to 12:00 PM, around 11:00 AM to 12:00 PM Around 7 AM to 11 AM, around 8 AM to 10 AM, around 7 AM to 9 AM, It may be administered to mammals between approximately 8:00 AM and 10:00 AM, or between approximately 9:00 AM and 11:00 AM. For example, one or more T-type calcium channel antagonists such as CX-8998 Compositions containing this ingredient should be consumed within approximately 4 hours (for example, approximately 4 hours after waking up, approximately 3 hours after waking up). Approximately 2 hours after waking up, approximately 1 hour after waking up, approximately 30 minutes after waking up, or immediately after waking up. It can be administered to mammals.

[0096] Mammals having one or more motor disorders as described herein (e.g., CX- A composition containing one or more T-type calcium channel antagonists such as 8998 When administered, the mammal will have any appropriate motor impairment(s). It may have. In some cases, the movement disorder may include tremor. For example, in this specification The methods and materials provided are for the treatment of mammals that have or are at risk of developing tremors. It can be used to place one or more T-type calcium channels such as CX-8998. Examples of motor disorders that can be treated by administering compositions containing antagonists include This is not limited to, but includes essential tremor, Parkinson's disease (for example, Parkinson's disease) Tremors related to (e.g., spinocerebellar ataxia and Friedreich's ataxia), Epilepsy (e.g., idiopathic generalized epilepsy with absence seizures and childhood epilepsy), dystonia (For example, generalized dystonia, focal dystonia, pantothenate kinase-associated neurodegeneration) (PKAN, and Harelforden-Spats disease), unilateral ballism, cerebellar dysfunction, atet dyskinesia, spasticity, bradykinesia, tardive dyskinesia, Huntington's disease, myoclonus, tardive dyskinesia Rett syndrome, chorea, tics, progressive supranuclear palsy, multiple system atrophy, corticobasal nerve Nodular degeneration, plasticity, restless legs / arm syndrome, orthostatic tremor, stiff person Examples include syndromes, hyperkinetic disorders, Rett syndrome, and Wilson's disease. In some cases... Mammals that have essential tremor or are at risk of developing it, such as CX-8998. Administer a composition containing one or more T-type calcium channel antagonists. It can be treated by [method]. In some cases, squirrels have or are developing Parkinson's disease. Mammals with a certain type of protein have one or more T-type calcium channels such as CX-8998. This can be treated by administering a composition containing a gonist.

[0097] In some cases, one or more T-type calcium channel antagonists (e.g., CX A composition containing one or more Cav3 antagonists such as -8998 (for example, pharmaceutically (Permitted compositions) may cause other pathological conditions and / or disorders, for example, but are not limited to However, they have neuropathic pain, psychiatric disorders, autism spectrum disorder, and obsessive-compulsive disorder. Alternatively, it may be administered to mammals at risk of developing the disease.

[0098] Mammals having one or more motor disorders as described herein (e.g., CX- A composition containing one or more T-type calcium channel antagonists such as 8998 When administered, the mammal may be treated as any appropriate as described herein. A certain amount of composition (e.g., a pharmaceutically acceptable composition) (e.g., 1 such as CX-8998) A composition containing one or more T-type calcium channel antagonists may be administered. In some cases, mammals have one or more motor impairments or are at risk of developing them. It contains one or more T-type calcium channel antagonists, such as CX-8998. A therapeutically effective dose of the composition may be administered. The term "therapeutically effective dose" is defined by researchers, veterinarians, and medical professionals. A tissue, system, animal, individual, or human life desired by the mentor or other clinician. An active compound that induces a physical or therapeutic reaction (for example, one such compound like CX-8998) This refers to the amount of the above T-type calcium channel antagonist. The effective dose of more than one type of T-type calcium channel antagonist depends on the severity of the motor impairment and / Or one or more symptoms / complications related to motor impairment, route of administration, age of mammal and general Possibility of co-use with other therapeutic procedures, such as the patient's health condition, the use of excipients, and the use of other medications. Furthermore, it may vary depending on the judgment of the physician performing the procedure. For example, the composition (e.g., veterinary medicine and (A composition for use in research animals such as dogs or rats) per day Approximately 1 mg / kg body weight to approximately 1000 mg / kg body weight (for example, approximately 5 mg / kg body weight per day) g ~ approx. 1000 mg / kg body weight, approx. 10 mg / kg body weight ~ approx. 1000 mg / kg body weight, approx. 20mg / kg body weight ~ approx. 1000mg / kg body weight, approx. 25mg / kg body weight ~ approx. 1000m g / kg body weight, approx. 30 mg / kg body weight ~ approx. 1000 mg / kg body weight, approx. 50 mg / kg body weight g ~ approx. 1000 mg / kg body weight, approx. 75 mg / kg body weight ~ approx. 1000 mg / kg body weight, approx. 100mg / kg body weight ~ approx. 1000mg / kg body weight, approx. 250mg / kg body weight ~ approx. 100 0 mg / kg body weight, approximately 500 mg / kg body weight to approximately 1000 mg / kg body weight, approximately 750 mg / body weight kg ~ approx. 1000mg / body weight kg, approx. 1mg / body weight kg ~ approx. 750mg / body weight kg , approx. 1mg / kg to approx. 500mg / kg, approx. 1mg / kg to approx. 300mg / kg Body weight in kg, approximately 1 mg / kg to approximately 250 mg / kg, approximately 1 mg / kg to approximately 20 0 mg / kg body weight, approximately 1 mg / kg body weight to approximately 150 mg / kg body weight, approximately 1 mg / kg body weight ~Approx. 125mg / kg, approx. 1mg / kg ~ approx. 100mg / kg, approx. 1mg / Weight kg ~ approx. 75 mg / kg, approx. 1 mg / kg ~ approx. 50 mg / kg, approx. 1 m g / body weight kg ~ approx. 30 mg / body weight kg, approx. 5 mg / body weight kg ~ approx. 500 mg / body weight kg, Approx. 10mg / kg body weight ~ approx. 300mg / kg body weight, approx. 15mg / kg body weight ~ approx. 200mg / body weight kg, approx. 20mg / body weight kg ~ approx. 100mg / body weight kg, approx. 25mg / body weight kg ~ Approx. 75mg / kg body weight, approx. 10mg / kg body weight ~ approx. 30mg / kg body weight, approx. 20mg / kg Body weight in kg ~ approximately 50 mg / kg, approximately 30 mg / kg ~ approximately 60 mg / kg, or A single dose of one or more T-type carboxylates (approximately 50 mg / kg body weight to approximately 75 mg / kg body weight) may be used. The composition may include a lucium channel antagonist. For example, the composition may include CX-8998. In this case, the dose of CX-8998 may be approximately 10 mg / kg body weight per day. For example, If the composition contains CX-8998, the dose of CX-8998 is approximately 30 mg / day It can be body weight in kg. For example, if the composition contains CX-8998, the use of CX-8998 The amount may be approximately 60 mg / kg of body weight per day. For example, in a composition (for example, used in humans) The composition for use is approximately 10 μg / kg body weight to approximately 1000 μg / kg body weight per day. (For example, approximately 10 μg / kg body weight to approximately 900 μg / kg body weight per day, approximately 10 μg / body weight) Weight kg ~ approx. 800 μg / kg body weight, approx. 10 μg / kg body weight ~ approx. 700 μg / kg body weight, approx. 10μg / kg body weight ~ approx. 600μg / kg body weight, approx. 10μg / kg body weight ~ approx. 500μg / Weight kg, approx. 10 μg / kg body weight ~ approx. 400 μg / kg body weight, approx. 10 μg / kg body weight ~ approx. 300μg / kg body weight, approximately 10μg / kg body weight to approximately 200μg / kg body weight, approximately 10μg / Weight kg ~ approx. 100 μg / kg body weight, approx. 10 μg / kg body weight ~ approx. 50 μg / kg body weight, approx. 50μg / kg body weight ~ approx. 1000μg / kg body weight, approx. 100μg / kg body weight ~ approx. 1000 μg / kg body weight, approx. 200 μg / kg body weight ~ approx. 1000 μg / kg body weight, approx. 300 μg / kg Body weight kg ~ approx. 1000μg / body weight, approx. 400μg / body weight kg ~ approx. 1000μg / body weight kg, approx. 500 μg / kg body weight ~ approx. 1000 μg / kg body weight, approx. 600 μg / kg body weight ~ Approximately 1000μg / kg body weight, approximately 700μg / kg body weight~Approx. 1000μg / kg body weight, approximately 8 00μg / kg body weight ~ approx. 1000μg / kg body weight, approx. 900μg / kg body weight ~ approx. 1000 μg / kg body weight, approximately 50 μg / kg body weight to approximately 900 μg / kg body weight, approximately 100 μg / kg body weight kg ~ approx. 800 μg / kg body weight, approx. 200 μg / kg body weight ~ approx. 700 μg / kg body weight, approx. 300μg / kg body weight ~ approx. 600μg / kg body weight, approx. 400μg / kg body weight ~ approx. 500μ g / kg body weight, approx. 100 μg / kg body weight ~ approx. 200 μg / kg body weight, approx. 200 μg / kg body weight kg ~ approx. 300 μg / kg body weight, approx. 300 μg / kg body weight ~ approx. 400 μg / kg body weight, approx. 400μg / kg body weight ~ approx. 500μg / kg body weight, approx. 500μg / kg body weight ~ approx. 600μ g / kg body weight, approx. 600 μg / kg body weight ~ approx. 700 μg / kg body weight, approx. 700 μg / kg body weight kg ~ approximately 800 μg / kg body weight, or approximately 800 μg / kg body weight ~ approximately 900 μg / kg body weight g) may contain one or more T-type calcium channel antagonists in a single dose. For example, if the composition contains CX-8998, the dose of CX-8998 per day is It may be approximately 100 μg / kg body weight. For example, if the composition contains CX-8998, CX The dose of -8998 may be approximately 300 μg / kg body weight per day. For example, the composition If CX-8998 is included, the dose of CX-8998 is approximately 600 μg / kg of body weight per day. It may be g. In some cases, the dosage depends on the type and progression of the disease or disorder, and specific The patient's overall health status, the relative biological efficacy of the selected compound, the formulation of excipients, And it may depend on variables such as the route of administration. In some cases, the dose is increased over time. To obtain. For example, the dosage is adjusted over a certain period until the final dose (e.g., one week, two weeks, The dosage may be gradually increased over three or four weeks. In some cases, the dosage may be decreased over time. For example, after one or more symptoms have been reduced or eliminated, the dose may be reduced to a maintenance dose. The dosage may be, for example, once, twice, three times, or four times a day. In some cases, the dosage may be administered once a day. In some cases, the dosage may be administered twice a day. It is possible.

[0099] In some cases, the compositions described herein (e.g., pharmaceutically acceptable compositions) (For example, one or more T-type calcium channel antagonists such as CX-8998) The effective amount of one or more T-type calcium channel antagonists in the composition containing is This can be estimated from dose-response curves derived from in vitro or in vivo model experimental systems. Effective The amount (e.g., the therapeutically effective dose) may remain constant or may slide. The dose may be adjusted to be variable depending on the response of the mammal to the treatment. Various factors can influence the actual effective amount used for a particular purpose. For example, the influence of diet. (For example, whether the mammal to which the composition is administered is in a state of eating or fasting) (e.g., whether it is), frequency of administration, duration of treatment, use of multiple treatment drugs, route of administration, and motor impairment (e.g.) For example, the severity of essential tremor, epilepsy, and / or Parkinson's disease is the actual amount administered. An increase or decrease in the effective amount may be required.

[0100] The frequency of administration is such that it does not cause significant toxicity to mammals and does not cause motor disorders (e.g., essential tremor, etc.). It may reduce the severity of epilepsy and / or Parkinson's disease at any frequency. The administration frequency is approximately once a week to three times a day, approximately twice a month to six times a day, or approximately twice a week to one day a day. It may be approximately once. The frequency of administration may remain constant or may be variable during the treatment period. Possible. Compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., Contains one or more T-type calcium channel antagonists such as CX-8998. The treatment process with the composition may include a rest period. For example, one or more T in a therapeutically effective amount. A pharmaceutically acceptable composition containing a type 1 calcium channel antagonist is used for 2 weeks. It may be administered daily for a two-week period during which the rest period continues, and such a dosing plan may be repeated multiple times. It is possible that various factors, as with the effective dose, influence the actual frequency of administration used for a particular purpose. This can have an impact. For example, the effective dose, duration of treatment, use of multiple treatment drugs, route of administration, and exercise. The severity of the disorder (e.g., essential tremor, epilepsy, and / or Parkinson's disease) is determined by the administration. An increase or decrease in frequency may be requested.

[0101] The compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g., CX- (A composition containing one or more T-type calcium channel antagonists, such as 8998) The effective duration for administering it is to avoid causing significant toxicity to mammals and to prevent motor impairment (for example). Any period of time to reduce the severity of essential tremor, epilepsy, and / or Parkinson's disease. This is possible. For example, the effective period can vary from a few days to a few weeks, months, or even years. Obtain. In some cases, motor disorders (e.g., essential tremor, epilepsy, and / or parkine) may occur. The effective treatment period for N'Son's disease can range from approximately one month to approximately ten years. In a few examples, motor disorders (e.g., essential tremor, epilepsy, and / or Parkinson's disease) may be present. The effective duration of the treatment may be uncertain (e.g., the lifespan of the treated mammal). For example, a composition containing one or more T-type calcium channel antagonists is used in infant feeding. Animals (for example, mammals that have or are at risk of developing one or more motor disorders) Approximately 1 week to 9 weeks (for example, approximately 1 week to 8 weeks, approximately 1 week to 7 weeks, approximately 1 week to 9 weeks) Approximately 6 weeks, approximately 1 to 5 weeks, approximately 1 to 4 weeks, approximately 1 to 3 weeks, approximately 1 week to Approximately 2 weeks, approximately 2 weeks to approximately 9 weeks, approximately 3 weeks to approximately 9 weeks, approximately 4 weeks to approximately 9 weeks, approximately 5 weeks to Approximately 9 weeks, approximately 6-9 weeks, approximately 7-9 weeks, approximately 8-9 weeks, approximately 2 weeks Approximately 8 weeks, approximately 3 to 7 weeks, approximately 4 to 6 weeks, approximately 2 to 4 weeks, approximately 3 weeks Between approximately 5 weeks, 4 to 6 weeks, 5 to 7 weeks, or 6 to 8 weeks. It may be administered. In some cases, compositions containing CX-8998 may be used on mammals (e.g., 1 Mammals with or at risk of developing one or more motor impairments) for about two weeks (for example) It can be administered for approximately 15 days. In some cases, compositions containing CX-8998 are used in adulterated children. Mammals (e.g., mammals that have or are at risk of developing one or more motor disorders) It may be administered for about 4 weeks (for example, about 28 days). For example, one or more types of T calcium Compositions containing a channel antagonist are used in mammals (for example, those with one or more motor impairments). It can be administered to mammals (that have or are at risk of developing the disease) for approximately 8 weeks or more. For example, a composition containing one or more T-type calcium channel antagonists is used in mammals. For example, in mammals that have one or more motor disorders or are at risk of developing them, approximately 1 It may be administered for more than two weeks. For example, one or more T-type calcium channel antagonists Compositions containing st are for mammals (for example, those having one or more motor disorders or developing It can be administered to mammals (at risk of developing) for about two months or more. For example, one or more T-type causative agents. Compositions containing a calcium channel antagonist are used in mammals (e.g., one or more motors). It may be administered to mammals with or at risk of developing the disorder for approximately 4 months or longer. For example, a composition containing one or more T-type calcium channel antagonists is used in infant feeding. Animals (for example, mammals that have or are at risk of developing one or more motor disorders) It can be administered for approximately 6 months or more. For example, one or more T-type calcium channels Compositions containing gonists are used in mammals (for example, those having one or more motor impairments or developmental disorders). It can be administered to mammals at risk of developing the disease for approximately 12 months or more. For example, one or more species. Compositions containing T-type calcium channel antagonists are found in mammals (e.g., one or more). In mammals with or at risk of developing motor impairments, exposure for approximately 24 months or more. It may be possible. Multiple factors may influence the actual effective duration used for a particular treatment. For example, the effective period depends on the frequency of administration, the effective dose, the use of multiple treatment drugs, the route of administration, and This may vary depending on the severity of the condition being treated.

[0102] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. When a substance is administered a composition containing CX-8998, the composition contains CX-8998. Minimum effective concentration (MEC) (for example, the concentration required to produce the therapeutic effect described herein) It is considered effective in achieving the minimum concentration of CX-8998 in mammalian plasma. For example, the MEC of the CX-8998 is approximately 100nM to approximately 1800nM (for example, approximately 2 00nM~Approx. 1800nM, Approx. 300nM~Approx. 1800nM, Approx. 400nM~Approx. 1800 nM, about 500nM to about 1800nM, about 700nM to about 1800nM, about 1000nM ~about 1800nM, about 1200nM to about 1800nM, about 1500nM to about 1800nM , about 100nM to about 1500nM, about 100nM to about 1200nM, about 100nM to about 1 000nM, about 100nM to about 800nM, about 100nM to about 700nM, about 100nM ~about 600nM, about 100nM to about 500nM, about 100nM to about 400nM, about 100 nM ~ approx. 300 nM, approx. 200 nM ~ approx. 1500 nM, approx. 300 nM ~ approx. 1200 nM, Approx. 500nM ~ Approx. 1000nM, Approx. 600nM ~ Approx. 800nM, Approx. 200nM ~ Approx. 400 It can be nM, approximately 400nM to 600nM, or approximately 300nM to 500nM. In some examples, compositions containing CX-8998 have approximately 200 nM of CX-8998 in their ME Mammals that achieve C (e.g., those with or developing one or more motor disorders) It can be administered to mammals at risk. In some examples, compositions containing CX-8998. This is to achieve a MEC of approximately 209 nM in mammals (for example, one or more It can be administered to mammals that have or are at risk of developing the above motor disorders. In that example, the composition containing CX-8998 had approximately 215 nM of MEC of CX-8998. Mammals that can achieve this (for example, squirrels that have or develop one or more motor disorders) It can be administered to mammals (that have a cephalopod).

[0103] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. The subject is administered a composition containing one or more Cav3 antagonists, such as CX-8998. In such cases, the composition may be (for example, in mammalian blood and / or plasma samples, etc.) MEC of Cav3 antagonists (multiple possible) in blood samples obtained from mammals It may be effective to maintain it for any appropriate time. For example, the MEC of the CX-8998 is In mammals, at least about 12 hours (for example, about 12 hours, about 13 hours, about 14 hours) Approximately 15 hours, approximately 16 hours, approximately 17 hours, approximately 18 hours, approximately 19 hours, approximately 20 hours, approximately 21 hours (The duration is approximately 22 hours, 23 hours, 24 hours, 25 hours, or 26 hours.) For example, the MEC for the CX-8998 takes about 10 to 15 hours (for example, about 10 hours). Between approximately 14 hours, approximately 10 hours to approximately 13 hours, approximately 10 hours to approximately 12 hours, approximately 10 hours to approximately 1 1 hour, approximately 11 to 15 hours, approximately 12 to 15 hours, approximately 13 to 15 hours, Approximately 14 hours to 15 hours, approximately 11 hours to 14 hours, approximately 12 hours to 13 hours, approximately 11 hours It can be maintained for a period of approximately 12 hours, or approximately 13 to 14 hours. In some cases, CX Compositions containing -8998 maintain the MEC of CX-8998 for approximately 12 hours. To objects (for example, mammals that have or are at risk of developing one or more motor disorders) It may be administered. For example, the MEC of CX-8998 is approximately 22 to 26 hours (for example, Approximately 22 hours to 25 hours, approximately 22 hours to 24 hours, approximately 22 hours to 23 hours, approximately 23 hours Between approximately 26 hours, approximately 24 hours to approximately 26 hours, approximately 25 hours to approximately 26 hours, approximately 23 hours to approximately 2 It can be maintained for 5 hours, or approximately 23 to 24 hours. In some cases, the CX-899 The composition containing 8 maintains the MEC of CX-8998 for approximately 24 hours in mammals (for example) If administered to mammals that have or are at risk of developing one or more motor disorders obtain.

[0104] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. When an object is administered a composition containing CX-8998, the composition contains CX-8998 The maximum safe concentration (e.g., well-tolerated in mammalian plasma (e.g., dizziness, headache)) Euphoria, attention deficit, paresthesia, hallucinations, insomnia, dry mouth, taste disturbances, hypoesthesia, somnolence, lethargy, Sleep disturbances, nausea, vomiting, akathisia, decreased level of consciousness, syncope, memory impairment, anxiety, restlessness Fatigue, irritability, constipation, tinnitus, loss of appetite, emotional disturbances, sexual dysfunction, double vision, nystagmus, drowsiness, Side effects include measles-like rash, granulocytopenia, agranulocytosis, erythrocytosis, and erythrocytosis. and / or to minimize adverse events, reduce them, or This may be effective in achieving the maximum concentration of CX-8998 (without dripping). For example, CX The maximum safe concentration of -8998 is approximately 1000 nM to 1800 nM (for example, approximately 1100 nM). M ~ approx. 1800nM, approx. 1200nM ~ approx. 1800nM, approx. 1300nM ~ approx. 1800n M, about 1400nM to about 1800nM, about 1500nM to about 1800nM, about 1600n M ~ approx. 1800nM, approx. 1700nM ~ approx. 1800nM, approx. 1000nM ~ approx. 1700n M, about 1000nM to about 1600nM, about 1000nM to about 1500nM, about 1000n M ~ approx. 1400nM, approx. 1000nM ~ approx. 1300nM, approx. 1000nM ~ approx. 1200n M, about 1000nM to about 1100nM, about 1100nM to about 1700nM, about 1200n M ~ approx. 1600nM, approx. 1300nM ~ approx. 1500nM, approx. 1100nM ~ approx. 1300n M, about 1200nM to about 1400nM, about 1300nM to about 1500nM, about 1400n It can be M ~ approximately 1600 nM, or approximately 1500 nM ~ approximately 1700 nM.

[0105] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. The substance was administered a composition containing one or more Cav3 antagonists, such as CX-8998. In this case, the composition has a C content below the acceptable threshold for Cav3 antagonists (multiple antagonists are possible). max This may be effective in maintaining (for example, the maximum concentration achieved in mammalian plasma). For example, the C of CX-8998 max This is less than approximately 1800 nM (for example, approximately 1700 nM) , about 1600nM, about 1500nM, about 1400nM, about 1300nM, about 1200nM , about 1100nM, about 1000nM, about 990nM, about 980nM, about 970nM, about 9 60nM, about 950nM, about 940nM, about 930nM, about 920nM, about 910nM, It could be around 900nM. For example, the C of CX-8998 max It is approximately 900 nM ~approximately 1800 nM (for example, approximately 1000 nM to approximately 1800 nM, approximately 1200 nM to approximately 18 00nM, about 1400nM to about 1800nM, about 1500nM to about 1800nM, about 16 00nM~Approx. 1800nM, Approx. 900nM~Approx. 1700nM, Approx. 900nM~Approx. 1500 nM, about 900nM to about 1400nM, about 900nM to about 1300nM, about 900nM to Approximately 1200 nM, approximately 900 nM to approximately 1100 nM, approximately 1000 nM to approximately 1500 nM, It can be approximately 1200nM to approximately 1400nM. In some examples, the CX-8998 The composition contains approximately 900 nM of CX-8998 C max Mammals (example) to achieve For example, administered to mammals that have one or more motor disorders or are at risk of developing them. It is possible. In some examples, compositions containing CX-8998 contain about 1000 nM of CX-8998. 98 C max Mammals that achieve this (for example, those with one or more motor impairments or It can be administered to mammals that are at risk of developing the disease.

[0106] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. The substance was administered a composition containing one or more Cav3 antagonists, such as CX-8998. In that case, the composition will have a concentration of approximately 3,000 nM*hour to approximately 10,000 nM*hour. This is effective in maintaining the area under the curve (AUC) of the Cav3 antagonist(s). For example, the AUC of the CX-8998 is approximately 3,000 nm * hour to approximately 9,000 nM*hour, approximately 3,000nM*hour~approximately 8,000nM*hour, approximately 3,0 00nM*hour ~ approx. 7,000nM*hour, approx. 3,000nM*hour ~ approx. 6 ,000nM*hour, about 3,000nM*hour~about 5,000nM*hour, Approx. 3,000nM*hour~Approx. 4,000nM*hour, Approx. 4,000nM*hou r~approx. 10,000nM*hour, approx. 5,000nM*hour~approx. 10,000nM *hour, approx. 6,000nM*hour ~ approx. 10,000nM*hour, approx. 7,00 0nM*hour ~ approx. 10,000nM*hour, approx. 8,000nM*hour ~ approx. 1 0,000nM*hour, about 9,000nM*hour~about 10,000nM*hou r, about 4,000nM*hour~about 9,000nM*hour, about 5,000nM*h our~about 8,000nM*hour, about 6,000nM*hour~about 7,000nM *hour, approx. 4,000nM*hour ~ approx. 6,000nM*hour, approx. 5,000 nM*hour ~ approx. 7,000nM*hour, approx. 6,000nM*hour ~ approx. 8,0 00 nM*hour, or approximately 7,000 nM*hour to approximately 9,000 nM*hour It is possible. AUC is calculated over any appropriate time (for example, if one or more movement impairments are present). Any adverse reaction after administration of a composition containing CX-8998 to mammals at risk of developing the disease AUC can be measured at any appropriate time interval (e.g., one or more movements). Compositions containing CX-8998 for mammals that have a disorder or are at risk of developing one. AUC can be measured for any appropriate duration after administration. For example, AUC can be measured for about 12 hours. AUC 0-24 or AUC 24 ) ~ approx. 36 hours (AUC 0-36 or AUC 36 ;example For example, approximately 12 to 32 hours, approximately 12 to 28 hours, approximately 12 to 24 hours, approximately 12 hours to approximately 20 hours, approximately 12 hours to approximately 18 hours, approximately 18 hours to approximately 36 hours, approximately 22 hours ~36 hours, 24 hours~36 hours, 15 hours~32 hours, 18 hours~24 hours Duration: Approximately 12 hours to 15 hours, approximately 15 hours to 18 hours, approximately 18 hours to 22 hours, approximately Between 22 hours and approximately 26 hours, approximately 26 hours and approximately 30 hours, or approximately 30 hours and approximately 32 hours. It can be measured. In some cases, AUC is approximately 24 hours (e.g., AUC 0-24 or AUC 24 ) can be measured during this period.

[0107] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. The substance was administered a composition containing one or more Cav3 antagonists, such as CX-8998. In such cases, the composition contains MEC (for example, approximately) of CX-8998 in the mammal. CX-8998 (400nm) and CX-8998 C max (For example, about 1000 nM) Maintain the plasma concentration (e.g., mean plasma concentration) of the Cav3 antagonist(s) between [the specified agent] and [the specified agent]. It may be effective for this purpose. For example, a composition containing CX-8998 is administered to a mammal. In this case, the composition contains approximately 400 nM of CX-8998 to approximately 10 in the mammal. It is effective in maintaining the mean plasma concentration of CX-8998, which is 00nM. It is possible. For example, when a composition containing CX-8998 is administered to a mammal, the composition As shown in Figure 74, the substance maintains the mean plasma concentration of CX-8998 in the mammal. It may be effective for the delayed release of CX-8998 and / or a first component formulated for sustained release, and optionally, immediate release of CX-8998 If it contains a second component formulated for release, the delayed release and / or The first component, formulated for sustained release, is the MEC of CX-8998 (for example, Approximately 400nm CX-8998) and CX-8998 C max (For example, about 1000 nM) It is effective in maintaining the plasma concentration (e.g., mean plasma concentration) of CX-8998 between ) and ). As a result, the composition contains MEC of CX-8998 and C of CX-8998. max and This may be effective in maintaining the concentration of CX-8998 during the period of immediate release of CX-8998. The second ingredient formulated for this purpose, if present, is at least MEC( CX-8998). For example, plasma concentration (e.g., mean plasma) of at least approximately 400 nM of CX-8998 It may be effective in rapidly achieving the desired concentration (e.g., in less than approximately 60 minutes). For example, CX -8998 A first component formulated for delayed release and / or sustained release, and optional CX-8998 contains a second component formulated for immediate release of CX-8998. When a composition containing CX-899 is administered to a mammal, the composition will not reach CX-899 in less than approximately 60 minutes. It may be effective in achieving an average plasma concentration of 8, and in the mammal in question, approximately 400 nM CX-8998 ~ Mean plasma concentration of CX-8998, which is approximately 1000 nM. This may be effective in maintaining [the condition]. This can be achieved by the compositions described herein, including CX-8998. The mean plasma concentration of CX-8998 obtained is measured over any appropriate period (e.g., one or more exercise sessions). Compositions containing CX-8998 for mammals that have a disorder or are at risk of developing one. It can be maintained for any appropriate duration after administration. For example, from about 400 nM to about 100 The mean plasma concentration of CX-8998, which is 0 nM, is maintained for at least approximately 12 hours (for example, approximately 12 hours, approximately 13 hours, approximately 14 hours, approximately 15 hours, approximately 16 hours, approximately 17 hours, approximately 18 hours Approximately 19 hours, approximately 20 hours, approximately 21 hours, approximately 22 hours, approximately 23 hours, approximately 24 hours, approximately 25 hours It can be an hour, or about 26 hours. In some cases, the CX-8998 is about 400 nm. The average plasma concentration of CX-8998, which is approximately 1000 nM, is approximately 12 hours to approximately 36 hours (for example) For example, approximately 12 to 32 hours, approximately 12 to 28 hours, approximately 12 to 24 hours, approximately 1 2 hours to approximately 20 hours, approximately 12 hours to approximately 18 hours, approximately 18 hours to approximately 36 hours, approximately 22 hours to Approximately 36 hours, approximately 24 hours to approximately 36 hours, approximately 15 hours to approximately 32 hours, approximately 18 hours to approximately 24 hours Between approximately 12 hours to 15 hours, 15 hours to 18 hours, 18 hours to 22 hours, and 2 hours. (Maintained for 2 hours to approximately 26 hours, approximately 26 hours to approximately 30 hours, or approximately 30 hours to approximately 32 hours) It is possible. For example, between a CX-8998 with approximately 400nM and a CX-8998 with approximately 1000nM The mean plasma concentration can be maintained for approximately 18 hours. For example, approximately 400 nM of CX-8998~ An average plasma concentration of approximately 1000 nM of CX-8998 can be maintained for about 24 hours. If a composition containing CX-8998 is administered to a mammal, the composition will be used to protect the mammal. In mammals, the CX-8998 ranges from approximately 400 nM to approximately 1000 nM. It may be effective in maintaining the mean plasma concentration of CX-8998 for about 24 hours (for example, about 2 (It may have an AUC of approximately 400 nM*hour and approximately 1000 nM*hour over 4 hours.)

[0108] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. The substance was administered a composition containing one or more Cav3 antagonists, such as CX-8998. In such cases, the composition should be administered 24 hours after administration (for example,

number

number

[0109] In some cases, infant feeding has one or more motor disorders, or is at risk of developing them. The substance was administered a composition containing one or more Cav3 antagonists, such as CX-8998. In such cases, the composition contains one or more Cav3 antagonists, such as CX-8998. Immediate-release compositions (for example, immediate-release compositions containing one or more Cav3 antagonists in the same dose) C achieved by the composition max Less than C max This may be effective in achieving it. For example, when a composition containing CX-8998 is administered to a mammal, the composition contains CX C achieved by an immediate release composition containing -8998max Approximately 30% to 70% (example) For example, approximately 30% to 60%, approximately 30% to 50%, approximately 30% to 40%, and approximately 40% to 7%. Low CX (0%, approximately 50%-70%, approximately 60%-70%, or approximately 40%-60%) -8998 C max It may be effective in maintaining it.

[0110] In some cases, the person has one or more motor impairments as described herein, or Mammals at risk of developing the disease (for example, one or more T-type calcium such as CX-8998) A method of treatment (by administering a composition containing a um channel antagonist) is , confirming that the mammal has one or more motor disorders or is at risk of developing them. This may also include any appropriate method to confirm that a mammal has a motor disorder. It can be used to confirm that mammals have or are at risk of developing motor disorders. The methods are not limited to these, but include investigating the medical history of mammals, and Investigating family history, physical examination (e.g., tendon reflexes, muscle strength and tone, feeling specific sensations) (Neurological examination including checking the ability to move, posture and coordinated movements, and / or gait) Clinical tests (e.g., blood and / or urine of mammals for thyroid disease, metabolic disorders, drug side effects) Use, alcohol level, and / or level of chemicals that may cause tremors Clinical tests (including examinations), imaging (e.g., functional imaging), and motion tests. (For example, drinking from a glass, keeping both arms extended, writing, and / or Motion tests that evaluate the tremor itself, including spiral depiction, and / or dopamine transporters One possible approach is to perform a scan. In some cases, mammals have motor impairments. Confirming whether or not one is at risk of developing the disease may include genetic testing. For example, A test to determine the presence or absence of one or more gene variants associated with movement disorders, If mammals have or are at risk of developing a movement disorder (e.g., essential tremor) It can be used to confirm, for example, the genetics associated with movement disorders (e.g., essential tremor). Child variants may be those described in other literature (e.g., Odgerel et al,2018 bioRxiv doi:http: / / dx.doi.org (See / 10.1101 / 248443).

[0111] In some cases, one or more motor disorders (e.g., essential tremor, epilepsy, and / or) Mammals that have or are at risk of developing Parkinson's disease are described herein. (For example, one or more T-type calcium channel antagonists such as CX-8998) When the treatment is performed by administering a composition containing a gonist, the treatment may involve one or more This may also include additional treatments. Treatments may include the administration of one or more medications, one or more functional foods. Administration of drugs, physical therapy, occupational therapy, surgical procedures, ultrasound thalamic ablation, neurostimulation techniques, digital therapy Any appropriate treatment, such as medicine and alternative medicine (e.g., one or more motor disorders and / or This may be a treatment method used to address one or more symptoms related to movement disorders. Having or developing one or more symptoms associated with essential tremor and / or essential tremor Examples of treatments that may be used to treat mammals at risk include, but are limited, However, administration of one or more beta-blockers (e.g., propranolol), or one or more anti- Reaction medications (e.g., primidone, gabapentin, topiramate, pregabalin, zonisamide) Administration of , and ethosuximide, one or more tranquilizers (e.g., alprazolam and cholangiocarcinoma). Administration of lonazepam, injection of onabotulinum toxin A (Botox), physiotherapy, occupational therapy. Therapy, surgery (e.g., deep brain stimulation), ultrasound thalamic ablation (e.g., guided / focused ultrasound) (e.g., ultrasonic thalamus ablation), nerve stimulation (e.g., transcranial magnetic stimulation), and digital therapy (e.g., Examples include devices such as wearable tremor suppression devices and tools such as tremor spoons. In some cases, patients have essential tremor and / or one or more symptoms associated with essential tremor. Or, treatments that may be used to treat mammals at risk of developing the disease are other References (for example, books by the American Academy of Neurology) Guidelines for the management of stative tremor, for example, aan.com / Guidelines / home (See / GuidelineDetail / 492 for details) It may be one or more of the following: Parkinson's disease and / or Parkinson's disease-related conditions. It can be used to treat mammals that have or are at risk of developing the symptoms of this condition. Examples of treatment methods include, but are not limited to, one or more dopamine agonists (e.g., For example, carbidopa / levodopa, pramipexole, ropinirole, rotigotine, and apo Administration of morphine, one or more monoamine oxidase B (MAO B) inhibitors (e.g., Administration of celeziline, rasagiline, and safinamide, and one or more catechol-O-methicillin. Administration of tyltransferase (COMT) inhibitors (e.g., entacapone and tolcapone), 1 Administration of one or more anticholinergic agents (e.g., benztropine and trihexyphenidyl), Treatment options include amantadine administration, physical therapy, occupational therapy, and surgery (e.g., deep brain stimulation). In some cases, one or more Parkinson's disease and / or Parkinson's disease-related conditions may be present. It may be used to treat mammals that have or are at risk of developing the above symptoms. The treatment method is described in other literature (for example, American Academy of Neurology). Guidelines for the treatment of Parkinson's disease by logy, e.g., movementdisor ders.org / MDS-Files1 / Resources / PDFs / Treat The website for mentsforMotorSymptomsofPD-2018.pdf This may be described in (see available products). One or more motor impairments Mammals that are harmed or at risk of developing the disease may have one or more T-type calcium sacs. Channel antagonist (e.g., one or more Cav3 antagonists such as CX-8998) If a patient is administered a composition containing (t) and one or more additional treatments are given, then one or more The above additional treatments may be administered simultaneously or separately. For example, one or more types of calcium T A composition containing a mu-channel antagonist (e.g., CX-8998) is administered first. Then, one or more additional treatments may be administered, or vice versa.

[0112] This specification refers to compositions described herein (e.g., pharmaceutically acceptable compositions) (e.g.) For example, it contains one or more T-type calcium channel antagonists such as CX-8998. Method for identifying the presence, absence, or amount of the total active moiety (TAM) in a composition. The law is also provided. As used herein, the term "TAM" means the active ingredient present in the composition. This refers to the entirety of the part. For example, if the composition contains CX-8998, then TAM is CX-899 8, M01, M02, M03, and / or M04 may include one or more of these. If the composition contains CX-8998, this method uses C-8998 and metabolite M01 This may include identifying the presence, absence, or quantity of M02, M03, and M04. In that example, mass spectrometry (MS) was used for CX-8998, M01, M02, M03, and / Alternatively, it can be used for the quantification of M04 (e.g., simultaneous quantification). Any suitable MS The method can be used. In some cases, liquid chromatography tandem MS (LC / MS) is used. Biochemical analysis by MS ( / MS) was performed on C-8998 and its metabolites M01, M02, and M03. , and can be used for simultaneous quantification of M04. For example, LC / MS / MS can be used for CX- It can be used to quantify the TAM associated with 8998. In some examples, the composition is TAM in (e.g., CX-8998, M01, M02, M03, and / or M04) The presence, absence, or identification of the quantity of ) is important for system performance qualification, quantification range, and calibration. Acceptance criteria for assay linearity, assay accuracy and precision, and / or assay recovery. This can be useful in determining CX-8998. For example, if the composition contains CX-8998, then CX-8 Identification of the presence, absence, or quantity of 998, M01, M02, M03, and / or M04 is System performance qualification, quantification range, calibration linearity, assay accuracy, and This can be useful in determining acceptance criteria for accuracy and / or assay recovery rates.

[0113] This specification also provides kits containing one or more of the materials described herein. For example The materials provided in the kit described herein are for one or more motor impairments (e.g., this Having or being at risk of developing (straight tremor, epilepsy, and / or Parkinson's disease) Used to treat a mammal (e.g., human) as described herein. Obtain. In some cases, one or more T-type calcium channel antagonists (e.g., A composition containing one or more Cav3 antagonists such as CX-8998 (e.g., pharmaceutical) A composition that is generally acceptable may be combined with packaging materials and sold as a kit. For example, the kit is provided in a unit dose or multi-dose container, as described herein. The composition may contain more than one T-type calcium channel antagonist. The container is as follows: It can be an appropriate size (for example, a 60cc container). The container can be made of any suitable material. For example, it could be high-density polyethylene (HDPE) such as white HDPE. The container is tightly packed. This may include things that close (e.g., things that keep children safe). Anything that closes is acceptable. A suitable material could be polypropylene (for example, 33mm white polypropylene). In some cases, the desiccant is not included in the bottle. In some cases, cotton is not included in the bottle. In some examples, the kit includes a component that is a sustained-release composition (e.g., a first component), and Optionally, tablets or capsules having an immediate-release component (e.g., a second component) Pharmaceuticals described herein in the form of (e.g., tablets or capsules for oral administration) The composition may include a generally acceptable CX-8998. In some examples, such a kit The packaging materials contained in it are usually, for example, one or more motor disorders (e.g., essential tremor, palsy) Mammals that have or are at risk of developing cancer and / or Parkinson's disease. How the composition is used to treat (for example, a human) as described herein It has instructions or a label indicating whether it can be used. For example, the kit has a composition At least about 4 hours before taking the substance (for example, about 4 hours, about 5 hours, about 6 hours, about 7 hours) I won't eat for about 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. It may include instructions or labels for use directed to sea urchin mammals. For example, the kit may include a composition This may include instructions or labels for use that instruct mammals to take the substance with food. For example, the kit should be used within approximately 4 hours of waking up (for instance, 4 hours after waking up, 3 hours after waking up). Later, 2 hours after waking up, 1 hour after waking up, 30 minutes after waking up, or immediately after waking up. This may include instructions or labels for use that instruct mammals to take the composition. In this example, the packaging materials included in such a kit typically show how the composition can be stored. (For example, it should be stored at approximately 15°C to 30°C or approximately 20°C to 25°C.) It comes with instructions or a label for use.

[0114] The present invention is further described in the following embodiments, which are described in the claims. This does not limit the scope of the present invention. [Examples]

[0115] Essential Tremor Rating Scale (TETRAS) In 2008, the Tremor Research Group first identified the essential vibration of TRG. The Battle Rating Scale (TETRAS) was published (Elble et al., 2008 Mov Disord.23(Suppl 1):S1-6). TETRAS This involves a 9-item performance subscale (PS) and 12-item activities of daily living (ADL). ) Consists of subscales. TETRAS is an ET that requires no instruments other than a pen and paper. Developed as a rapid clinical assessment tool. Application of the performance subscale takes less than 10 minutes. That's all there is to it. To reduce the evaluator's empirical bias, objective measurement methods are used in the scale. It is possible.

[0116] To evaluate the inter-rater reliability of TETRAS, Elble et al. (2012 Mov Disord.27(12):1567-1569) reported 44 patients with ET and Fifty TETRAS tests were video recorded, including evaluations from six control subjects. The severity of ET was The severity ranged from mild to severe. Ten specialists conducted assessments with intervals of 1-2 months between assessments. The patient in the video was evaluated twice. Of the 10 evaluators, 6 were involved in the development of TETRAS. And the four of them never used this scale.

[0117] Inter-rater reliability of a scale is measured by intraclass correlation in a two-way variable model using a perfect match definition. Inter-rater and intra-rater ICC were used for calculations of head and upper limb tremors. The range is 0.86 to 0.96, and for the total score, ICC is 0.94 and 0.9 The result was 6. ICC's robustness was lower in terms of voice, face, torso, and legs (Elb le et al.2012 Mov Disord.27(12):1567-156 9).

[0118] The TETRAS performance subscale is widely used in clinical practice, and high levels are among the indicators of high performance. It has acceptable validity and high inter-rater reliability. TETRAS ADL and Performance The core is highly correlated, and TETRAS assessment of upper limb function is correlated with upper limb tremor transducers. It shows a strong correlation with measurements (acceleration measurement) (Mostile et al., 2010 M (ov Disord.25(12):1938-1943). TETRAS is a study of the time course of It has also been shown to be sensitive to changes in tremor (Voller et al., 2014). Mov Disord.29(4):555-558).

[0119] A higher score indicates a worse tremor, while a decrease in the score indicates an improvement in the tremor.

[0120] Example 1: From baseline in TETRAS-PS as evaluated by the clinical trial investigator Significant changes up to day 28 TETRAS Performance Subscale Performance subscales quantify tremors in the head, face, voice, limbs, and torso. Each item is evaluated on a scale of 0 to 4, with upper limb tremor scoring using increments of 0.5 points. This is recognized. A specific amplitude range (measured in centimeters) defines the evaluation of tremor. The evaluator first estimates the maximum amplitude of the tremor, and then assigns a corresponding rating. The sum of individual evaluation scores ranges from 0 to 64, and the overall performance score is calculated. The following is a complete list of TETRAS performance subscales.

[0121] [Table 1-1]

[0122] [Table 1-2]

[0123] [Table 1-3]

[0124] [Table 1-4]

[0125] The principal investigator (or co-principal investigator) will use the TETRAS performance subscale. The TETRAS performance subscale, provided by the clinical trial investigator, is used to score the performance. The scores were used for statistical analysis of effectiveness.

[0126] The efficacy analysis of the TETRAS performance subscale was performed by considering the treatment, the combination of anti-tremor drugs, and the treatment. The type of setup and the baseline value of the TETRAS performance subscale are fixed effects. The analysis was performed using an analysis of covariance (ANCOVA) model. TETRAS performance The mean change from baseline in the scale was different in the CX-8998 group compared to the placebo group. As shown (Figure 1 and Table 1). All tests are least squares (LS) mean using the ANCOVA model. The analysis was performed using a two-tailed test with a significance level of α=0.05. The data deviated from a normal distribution. To indicate a discrepancy, a paired rank test was performed.

[0127] [Table 2]

[0128] Example 2: Significant changes in TETRAS-ADL from baseline to day 15 and day 28 change TETRAS Activities of Daily Living subscale The ADL subscale includes eating and drinking, dressing and self-care hygiene, carrying objects, and Items assessed on scales described in other literature, including fine motor skills. This includes a large number of our cases (for example, Parkinson's Disease and Mov ment Disorders(Jankovic et al., eds.),Ba Intimore: Fahn in Williams & Wilkins, 1993 et al., “Clinical rating scale for tremor ”, pages 225-234;Louis,2000 Arch Neurol. 57(10):1522-1524; and Bain et al., 1993 J Ne Urol Neurosurg Psychiatry 56(8):868-873 (See reference). Each item is rated on a scale from 0 to 4, where 0 indicates normal activity and 4 indicates severe activity. This indicates a degree of abnormality. The sum of the individual scores is in the range of 0 to 48, and provides an overall score. The complete list of TETRAS ADL subscales is as follows:

[0129] [Table 3-1]

[0130] [Table 3-2]

[0131] [Table 3-3]

[0132] The analysis of TETRAS-ADL is the same type as described for TETRAS-PS. The test was performed using the ANCOVA model with a two-tailed test at a significance level of α = 0.05. (Figure 2 and Table 2).

[0133] [Table 4]

[0134] Example 3: Significance of TETRAS total score from baseline to day 15 and day 28 Change TETRAS Total Score The TETRAS total score is calculated based on the total score of the TETRAS performance subscales. Defined as the sum of the TETRAS ADL subscale scores. TETRAS Total The score aggregates both patient-reported outcomes and objective measurements of tremor amplitude into a single score. The analysis of TETRAS-ADL will be performed using the same method as described for TETRAS-PS. The analysis was performed using a type ANCOVA model with a two-tailed test at a significance level of α = 0.05. (Figure 3 and Table 3).

[0135] [Table 5]

[0136] Example 4: TETRAS-PS spiral plotting operation from baseline to day 28 (Item 6) Significant change in ) According to the Archimedean spiral item (item 6) of the TETRAS-PS subscale, tremor severity The TETRAS scoring system for severity incorporates a standardized clinical assessment of the functional tremor impact. The clinical trial physician is using a ballpoint pen on a page of standard paper (letter paper) without ruled lines. I will demonstrate how to draw Archimedes' spiral, which fills approximately 1 / 4 of the space. (Spiral lines) The distance should be approximately 1.3 cm (0.5 inches). Next, the clinical trial physician will examine the subject Ask them to copy the spiral. Examine and score each hand separately. Pen The limbs should be held so that no part of them touches the table, and the paper should be arranged in a way that suits the patient's drawing style. The device is fixed in place on the table. The tremor in the spiral motion is scored, rather than the movement of the limbs. .

[0137] 0 = Normal; 1 = Mild: Almost invisible tremor; 2 = Mild: Noticeable tremor; 3 = Moderate :Part of the image is unrecognizable; 4 = Severe: The image is unrecognizable

[0138] Sum the scores for both hands on item 6 of the TETRAS-PS subscale, and get 15 The mean change from baseline was calculated at day 1 and day 28 (Figure 4 and Table 4). Significance was calculated using the Mann-Whitney nonparametric t-test (two-sided).

[0139] [Table 6]

[0140] Example 5: Digital spirography from baseline to day 15 and day 28 ( Functional vibration measured by digital spirography (imotor) Significant changes in battle frequency iMotor, developed by Apptomics, Inc., is for patients with motor impairments. This is an application specifically designed to objectively quantify a person's motor function (e.g., For example, see Mitsi et al., 2017 Front.Neurol.8:273. (See reference). This application allows patients to complete a series of diagnostic tests that measure motor function. To demand that something be done.

[0141] In iMotor's entry on the Archimedean spiral, the target audience is tablet-based applications. You will be prompted to draw a spiral using a digital stylus on the screen. The target is the central gray dot that starts from the spiral's starting point, without lifting the stylus from the screen. You will be instructed to trace a line. This test will not be timed. The subject will complete the task twice. You will be asked to complete the task once with your right hand and once with your left hand.

[0142] Functional tremor frequency (Hz) is based on the number and timing of the stylus crossing the center line. Calculated by iMotor's algorithm. 15th and 28th day from baseline. The average change in eye level was calculated for each dominant hand. Statistical significance was determined using Mann Whitney's method. The results were calculated using a nonparametric t-test (two-tailed) (Figure 5 and Table 5).

[0143] [Table 7]

[0144] Example 6: Significant difference in clinically rigorous impression (CGI-I) compared to placebo at day 28. Clinical General Impression Scale The Clinical Global Impression Scale (CGI) is used in clinical trials sponsored by the NIMH to assess the effectiveness of test drugs. Provides a concise, independent assessment from a clinician's perspective of the patient's overall function before and after initiation. Developed for use in (Guy (ed.), ECDEU Assessment) Manual for Psychopharmacology.Rockville, MD:US Department of Health,Education,and Welfare Public Health Service Alcohol,D rug abuse,and Mental Health Administrati (on; 1976). CGI is a method of depicting patient history, psychosocial circumstances, symptoms, behavior, and the symptoms. A summary assessment scale that considers all available information, including information on the impact on the patient's functional capacity. The degree is CGI assesses the severity of the disease at baseline, and the base It has two types of CGI improvement scores that evaluate the change from the original line.

[0145] CGI-Improvement (CGI-I) CGI-I represents a single 7-step improvement or change from baseline CGI-S. The assessment consists of evaluations, regardless of whether the change is entirely attributable to the drug treatment. The evaluators are as follows: The question was, "How much has the subject's problem changed compared to the state of the subject's problem at the start of treatment?" The score for selecting one response based on "Did you?" is as follows: 1 = Very Improved; 2 = Significantly improved; 3 = Slightly improved; 4 = No change; 5 = Slightly worse. It worsened; 6 = considerably worsened; 7 = very worsened.

[0146] Treatment success, as measured by CGI-I, was summarized using descriptive statistics. The difference between treatment groups was... Using the ANCOVA model, which uses treatment, anti-tremor drug use, and facility type as fixed effects. This was evaluated (Figure 6 and Table 6).

[0147] [Table 8]

[0148] Example 7: Patient's overall impression of changes (PGIC) at days 15 and 28 Significant difference compared to racebo The Global Rating of Change (GRC) scale quantifies the improvement or deterioration of a patient's condition over time. They are typically designed to determine the effectiveness of the intervention or to record the clinical course of the condition. The GRC scale assesses the patient's current health status at the start of treatment. The system is asked to recall the state and then calculate the difference between the two. (Simplicity of the GRC scale) This facilitates their implementation and makes them applicable to a wide range of patients (for example, Kamper et al.,2009 The Journal of Manual See & Manipulative Therapy 17(3):163-170. (Regarding the subject).

[0149] The Patient's Overall Impression of Change (PGIC) is a 7-point scale consisting of the following single question: It is: "Regarding your essential tremor, you are currently taking the investigational drug." How would you describe it compared to when you first started? Please select one of the following answers. : "Severely worsened, considerably worsened, slightly worsened, no change, slightly improved" "It has improved considerably, it has improved a lot."

[0150] The success of the treatment as measured by PGIC was summarized using descriptive statistics. The difference between the treatment groups was: Using the ANCOVA model with treatment, anti-tremor drug use, and facility type as fixed effects We evaluated it (Figure 7 and Table 7).

[0151] [Table 9]

[0152] Example 8: Significant difference compared to placebo in the Goal Achievement Scale (GAS) The Goal Achievement Scale (GAS) is a set of written goals between a physician and a patient. It is a tool that involves development and was used to monitor the patient's progress. GAS is 1 Developed in 1968 (e.g., Kiresuk & Sherman, 1968 Com) Refer to Community Mental Health Journal 4:443-453. (Regarding light), spasticity (for example, Ashford et al., 2006 Physiot) See her Res Int.11(1):24-34) and multiple sclerosis (K han et al.,2008 Arch Phys Med Rehabil.89 (4):652-9) has been used in patients with physical disabilities.

[0153] GAS is not a health condition that applies generally, but rather a test regarding the goals that individual patients desire. The discussion will focus on determining which health goals are most important to the patient through goal-oriented care. Encourage the patient to express themselves clearly. Then, the patient and the clinician will work together to achieve them. The progress can be monitored.

[0154] The target group will define three health goals at baseline. An example of a goal is drinking from a cup. The skills include buttoning a shirt and the ability to write. The goal is active or passive This is possible. All goals are specially tailored to the individual, and each target is at baseline. Each goal is rated on a 3-point scale regarding its level of importance (1 = fairly important; 2 = very important). 3. It is required to evaluate based on the extremely important criteria. The clinical trial physician is required to evaluate the achievement of each objective. The feasibility of the goal must be considered before it is set, and adjustments must be made as necessary. Once each goal is set, the clinical trial physician will not be able to achieve each of the set goals. The degree of difficulty in the case is measured on a different three-level scale (1 = likely; 2 = possible; 3 = You will be asked to evaluate based on suspicion.

[0155] Progress towards each goal is scored on a 5-point scale: -2 = worse than baseline (improvement) Undesirable result); -1 = No change from baseline; 0 = The default goal was achieved (expected) The result was; +1 = better than expected; +2 = the best possible result.

[0156] Each GAS is positioned on a range of -2 to 2, from worst to best result. The difference between treatment groups is defined as the treatment, use of anti-tremor drugs, and type of facility being fixed effects in the ANCOV study. The evaluation was performed using Model A (Figure 8 and Table 8).

[0157] Overall GAS score = 50 + (10 * sum of weights) / (0.7 * sum of weights**2) The square root of ) + [0.3 * (sum of weights)**2].

[0158] [Table 10]

[0159] Example 9: Percentage of subjects satisfied with the anti-tremor drug on days 15 and 28 compared to placebo Significant increase relative to (QUEST sub-item) QUEST has five subscales (physical activity, mental health, communication, hobbies). A 30-item questionnaire that contributes to the total score (leisure and work / finances), as well as sexual function. And three further items regarding satisfaction with tremor control and drug side effects during the final month of treatment. The initial report provides preliminary support regarding its reliability and effectiveness. Internal consistency Sex scores are very good or excellent across all four scales and the total score, and labor / finance Regarding the scale, it is moderately high (e.g., Troster et al., 2005 P See Arkinsonism Relat Disord. 11(6):367-373. (Referring to the light). These confidence coefficients also support the construct validity of QUEST.

[0160] At baseline, on day 15, and on day 28, 100% of participants who answered the following questions positively were included. The fractions were summarized as follows: "Have you been satisfied with the tremor control provided by anti-tremor medication over the past month?" ?(Y / N)」. Statistical significance compared to placebo was determined using Fisher's exact test. The calculations were performed (Figure 9 and Table 9).

[0161] [Table 11]

[0162] Example 10: Plasma concentration of CX-8998 that yielded clinical efficacy on days 15 and 28. degree The efficacy of CX-8998 in rat models of CNS diseases is 300-700 nM. The efficacy of CX-8998 at equivalent concentrations was demonstrated. Dose-response analysis of human drug EEG data. This refers to the dose at CX8998 plasma concentrations exceeding 200-300 nM (4 mg BID) and A reduction of over 25% in alpha wave power occurred in a concentration-dependent manner (and during binding to the CNS target). The markers were identified. The model showed that a single dose of 8 mg resulted in α approximately 12 hours after administration. This suggests a reduction of more than 25% in wave power. Adverse event data regarding dose-response The analysis showed that the incidence of CNS and psychiatric adverse events increases at concentrations above 800 nM. This suggested that, based on human PK profiles from healthy volunteers, dietary intake conditions The final steady state of CX-8998 at a 10 mg BID dose of 200-800 nM under these circumstances. The state concentration was targeted in T-CALM.

[0163] From all T-CALM subjects, at the second visit (trough concentration at 4 mg BID dose), Third dose (trough concentration with 8 mg BID), and fourth dose (trough concentration with 10 mg BID) A blood sample was taken before the administration of CX-8998. In addition, on the fourth visit, 4 hours before administration Samples were collected within a time frame of 4-6 hours after administration, aiming to be as close to the immediate post-administration period as possible. (That is, a total of two PK samples were collected during the fourth visit.)

[0164] Cavion has the latest FDA guidance (FDA, Guidance for I industry:Bioanalytical Method Validation, May 2018, fda.gov / downloads / drugs / guidance Rat, dog, and human plasma samples obtained according to the method described in s / ucm070107.pdf. For simultaneous quantification of CX-8998 and its metabolites (M01, M02, M03, and M04) Biochemical analysis methods using liquid chromatography-tandem mass spectrometry (LC / MS / MS) We developed and validated the assay performance, and the system performance qualifications were satisfactory. Quantification range, calibration linearity, assay accuracy and precision, and / or up The recovery rate met the acceptance criteria. These "5-in-1" biochemical analysis methods The CX-8998 and its four metabolites were identified in samples collected at T-CALM. Used for quantification (Figure 10 and Table 10).

[0165] [Table 12]

[0166] Example 11: Exposure to CX-8998 metabolites after BID administration of CX-8998 CX-8998 metabolites M01-M04 are active Cav3 antagonists. The "5-in-1" biochemical analysis method involves CX-89 in samples collected at T-CALM. 98 metabolites M01, M02, M03, and M04 were used to quantify them (Figure 11). (and Table 11).

[0167] [Table 13-1]

[0168] [Table 13-2]

[0169] These data are from two or more Cav3 antagonists (e.g., CX-8998 and The study demonstrates that a composition containing a combination of its active metabolites is relevant to the treatment of motor disorders. .

[0170] Example 12: Responder analysis using TETRAS and CGI-I Based on a specific scale cutoff value, the subject exhibits a certain threshold for response to treatment. Responder analysis was used to describe the proportions. Table 12 shows the three TETRAS scales. (Performance subscales, activities of daily living, and total score) at least 5 The percentage of subjects that achieved improvement from the baseline in points, and the percentage of subjects that used CGI-I Subjects that were evaluated as improved (slightly improved, considerably improved, and greatly improved) The proportions were summarized. Statistical analysis was performed using Fisher's exact test.

[0171] [Table 14]

[0172] An improvement of at least 5 points in the TETRAS endpoint or in overall clinical impression The percentage of subjects that achieved a response defined by any level of improvement. Fisher's positive Statistical analysis using confirmation tests. The table below shows detailed data for each endpoint.

[0173] [Table 15]

[0174] [Table 16]

[0175] [Table 17]

[0176] [Table 18]

[0177] [Table 19]

[0178] [Table 20]

[0179] [Table 21]

[0180] [Table 22]

[0181] Example 13: Relationship between CX-8998 plasma concentration and reaction Using the following Hill formula, C of CX-8998 min Exposure level and TETRAS-P Evaluation of the relationship between the change in S from baseline and the response (E) as measured: Reaction = E max *C min ^b / (C min ^b+EC 50 ^b) E max and EC 50 The values ​​were estimated to be approximately -4.1 and 250 nM; however However, the value of "b" was not statistically significant.

[0182] Summary of PK / PD findings: Assessment is based on CX-8998, analyte combination, or total activity. Partial (TAM; total exposure to all measured Cav3 antagonists, e.g., CX) The concentration value (C) of the total exposure to -8998 and all of its metabolites. min ) using and trough concentration samples at the time of each clinical trial visit (T=0 hours) or post-administration concentration samples (T=4 hours); The study was conducted under steady-state conditions using (only on day 28). The pharmacodynamic variables evaluated (reactions) were: ) includes TETRAS Performance Subscales, TETRAS Activities of Daily Living, and TET This includes the change from baseline in the total RAS score.

[0183] Analysis revealed that the concentration range was not low enough to fully define the PK / PD relationship. This indicates that the full pharmacological effect was achieved within the expected therapeutic range of 200-800 nM. This suggests that it has been achieved.

[0184] The changes in TETRAS PS are shown in Figure 12, which were obtained using other PD markers. This is representative of similar results (e.g., changes in TETRAS total score).

[0185] Example 14: Patient population The patient population enrolled in T-CALM had a mean baseline TETR of 28.4 points. AS-PS score, mean baseline TETRAS-ADL score of 26 points, and The average time since ET diagnosis was 23 years. In addition, the majority of patients (64%) had concomitant anti-vibration therapy. Those who had taken war drugs and not ET drugs were treated with first and second-line ET therapy. It was treatment-resistant or intolerant. Therefore, it was moderately to severely resistant to current treatments. In the ET population, efficacy was observed when added to standard treatment.

[0186] [Table 23]

[0187] Example 15: Adverse Event Profile This confirms that the safety and tolerability profile of the CX-8998 is of good quality. Under the most common (>2%) treatments related to the investigational drug, recognized by organ-specific major classifications and basic terms. This is a summary of the adverse events that occurred.

[0188] [Table 24]

[0189] Example 16: Tolerance to adverse events due to dose escalation T-CALM used the following dose escalation scheme: 4 mg BID (8 mg / day) Week 1 of ), Week 2 of 8mg BID (16mg / day), and Week 2 of 10mg BID (2 Weeks 3 and 4 of 0 mg / day. Also, the fact that the dose was increased at the beginning of weeks 2 and 3. Nevertheless, reports of adverse events decrease after the first week of medication. This is because patients receive CX-89 It shows rapid tolerance to CNS and psychiatric adverse events related to 98. Figure 13). Adverse events were coded using MedDRA V20.0. Investigational drug Only adverse events that occurred under treatment with an onset date within 30 days of drug discontinuation after the start of treatment are included. Reported. For subjects that have experienced the same coded event more than once, one instance was recorded. An elephant was shown. Adverse events were attributed to the week of the trial based on the date of onset, i.e., the visit to the hospital. Events that occurred after the first visit but before the second visit were classified as occurring in the first week of the clinical trial.

[0190] [Table 25-1]

[0191] [Table 25-2]

[0192] Example 17: No cardiovascular safety findings observed at effective doses. A holistic analysis of outliers in the electrocardiogram showed no CVS safety signals. The result was calculated as the average of the triple-repeated records at each time point. Baseline was the dose on day 1. Defined as the average of the previously obtained triple-iteration values. If this value is unavailable, the screen The average of the triple-repetition recordings obtained during the training was used. A summary of electrocardiogram outliers is shown in Figure 14. As shown in Figure 15, no difference was observed between CX-8998 and placebo.

[0193] Example 18: Subgroup Analysis Exploratory subgroup analyses of primary and secondary efficacy endpoints were conducted using baseline parameters. This includes the following subgroups formed by the data. 1. Gender: Male and Female 2. Age at the time of informed consent as described below: Up to 65 years old and >6 Target for 5-year-olds 3. Based on the baseline value of the TETRAS performance score evaluated by central assessment. Baseline severity is assessed as: greater than the median and less than the median. 4. TETRAS Performance Subscale items 4A (Postural Tremor), 4B (Flapping) >1 point between the right and left sides regarding either tremor or 4C (motion tremor) Baseline tremor asymmetry is defined as the difference in tensors: the presence or absence of asymmetry. present 5. The sum of postural tremors (left hand and right hand) divided by the sum of motor tremors (sum of left hand and right hand) Postural tremor (S) of TETRAS performance is defined by the ratio of the sum of the right and left hands. Baseline ratio of subscale item 4A) to motion tremor (subscale item 4C): Moderate Greater than the median ratio and less than the median ratio 6. Postural tremor as measured by Kinesia ONE, defined and classified in the same way as the ratios described above. Baseline ratio of motion tremor 7. Total resting tremor score measured by Kinesia ONE at baseline. A. The sum of the resting scores (left hand and) that are above (existing) or below (missing) the median. Baseline resting tremor, defined as the sum of resting tremors in the right hand: presence and absence of resting tremor and absence of resting tremor 8.1 Concomitant medication for essential tremor: Yes and No, taking beta-blockers The target subgroups will also be investigated. 9. Use of primidone within two weeks prior to or during the screening period. Primidone use at the start of the study, defined as subjects who discontinued the study: Primidone use and No primidone taken

[0194] The TETRAS-PS (Figure 16) and TETRAS-ADL (Figure 17) are representative of the results. The individual endpoints included are shown. Increased improvement with Cav3 antagonist treatment is demonstrated. The subset of patients to be acquired includes women, patients with more severe tremors, and anti-tremor patients. This includes individuals not taking any medications. Low levels of resting tremor and postural tremor versus movement tremor. Subjects with a lower ratio may also achieve a higher level of improvement.

[0195] Example 19: A single biochemical analysis assay to separate M02 and M04 in human plasma Analytical methods for measuring CX-8998 and its metabolites CX-8998 and M01, M02, M03, and M0 in human plasma K2EDTA Liquid chromatography-tandem mass spectrometry (LC / MS / M) for simultaneous quantification of four concentrations Method S was developed, qualified, and validated. The analyte CX-8998 was obtained from human plasma. A 5-in-1 assay for the simultaneous quantification of M01, M02, M03, and M04. To develop a system that can retain and separate all compounds within a reasonable execution time, an HP (High Power) system is needed. The LC method was necessary. Furthermore, due to the properties of the isobars of M02 and M04, these alternatives Baseline isolation was required for accurate quantification of the reaction product.

[0196] Since it has an MW of approximately 400 g / mol and a calculated logP value between 3 and 5, there are 5 All compounds were primary candidates for analysis by reverse-phase chromatography. Based on the structural differences, CX-8998, M01, M03 and either M02 or M04 The separation between them was not difficult. The challenge was M02 and its isogravitational isomer, M0 The goal was to develop conditions that would allow for baseline decomposition between 4 and Ag. ilent ZORBAX Extend-C18, Agilent Eclipse Using XDB C18 and Phenomenex Synergi MaxRP columns We tested various initial screenings (data not shown); however, all of them were M O2 and M04 could not be satisfactorily separated. Ultimately, Phenomenex Luna The C18 column exhibits the highest resolution between M02 and M04, and further enhances the HPLC method It was selected for optimization purposes.

[0197] We will first investigate chromatography using the Phenomenex Luna C18. This was the first experiment using a Luna C18 (30x2.0mm, 3μm) column. As a result, only partial separation between M02 and M04 was achieved, and the peaks of M01 and M03 were not separated. The width was below optimal (Figure 18).

[0198] The optimization to reduce peak width and increase peak resolution included the following adjustments: Sample solvent composition (lower organic component content for enhanced retention) Mobile phase modifier (reduces secondary interactions) Ion pairing (improving peak shape by altering retention behavior) Solvent strength of the organic mobile phase (decrease in strength to enhance retention, and change in selectivity)

[0199] However, none of these methods resulted in satisfactory separation between M02 and M04. Furthermore, the peak width remained below optimal.

[0200] Chromatography using Phenomenex Luna Phenyl-Hexyl - Chromatography that primarily relies on hydrophobic interactions (e.g., C18) is necessary for the required separation. It was concluded that it was not strong enough to achieve this. By introducing further types of interactions, selection It can enhance properties. Phenylhexyl columns have electron-rich aromatic phenylhexyl Based on the hexyl phase, unique electrostatic interactions, hydrogen bonding interactions, and dipole interactions are observed. Provided. Due to these unique chemical properties, sufficient for separating M02 and M04. We hypothesized that it could produce specificity. Compared to the C18-based system, Slightly better peak separation was observed between precipitates, however, this column type The peak (30×2mm, 3μm) shows undesirable secondary interactions and poor peak shape. This resulted in (Figure 19).

[0201] Chromatography with Phenomenex Kinetex PFP: Very Electric The phase to which the air-negative pentafluorophenyl (PFP) group is attached is an electron-deficient phenyl ring. In part, compared to conventional C18-based columns or phenylhexyl reversed-phase columns... Alternative selectivity (hydrophobic interaction, pi-pi interaction, dipole-dipole interaction, hydrogen) It provides high retention of halogen-related compounds (as well as bond interaction and shape selectivity). Near-baseline separation of all five analytes from plasma samples is possible due to the chemical properties of this substance. This was achieved using a lam type (100 × 2.1 mm, 2.6 μm, and Figure 20).

[0202] An extremely long run time was required to provide sufficient separation of all analytes. Therefore, this method is extremely time-consuming and inefficient for analyzing expected clinical trial plasma samples. It would be extremely difficult. The ideal execution time should be 15 minutes or less. We investigated matrix optimization to further reduce execution time: Increasing the column temperature allows for the use of higher flow rates without hindering column efficiency. Shorter column length

[0203] Unfortunately, these changes resulted in a decrease in resolution between M02 and M04. It was not possible to shorten the execution time of the method.

[0204] Development of sample derivatization: A reasonable method using chromatography while maintaining execution time. Derivatization of the analytes was investigated as an alternative method for separating M02 and M04. The structural difference between 2 and M04 is the position of one hydroxyl group (3°-OH in M02; M04) Since only the 1°-OH group is present, the sterically hindered 3°-OH group remains unreacted, It must be able to react selectively with 1°-OH groups. This will allow for larger reactions. A structural difference must be introduced to enable separation in chromatography. We investigated various OH group derivatization methods from the literature, and selective acylation of the primary alcohol moiety and Dansylation was selected and tested.

[0205] [Table 26]

[0206] Acetylation under acidic conditions was selective, but the M04 reaction product had a low reaction yield. It appeared to form a complex mixture. Minimal derivatization was observed via dansylation. The reaction with TFA resulted in a complex mixture of M04 reaction products (data not shown). Acetylation with acetic anhydride under oxidative conditions appears to be selective for M04, and high resistance The response yield is shown (Figure 21). The signal intensity of M04 is due to its reaction with the reagent, and other factors are involved. The signal intensity appeared to be 1 / 100th of that of the precipitate. The formation of the M04 product peak was Detected at 8.48 minutes (compared to the unreacted M04 peak at 7 minutes) at 439.4 m / z. Therefore, this is relative to the mass of M04 (M04-Ac) entities that are acetylated at one site. It responded. This is consistent with the daughter fragment observed in all other analytes, the daughter at 204 m / z. This was confirmed by observation of the fragments.

[0207] M04 Acetylation Reaction Kinetics: Determining Reaction Kinetics up to 2 Hours at 50°C Subsequently, experiments were conducted to observe the reaction and stability of the plasma over time. as equivolute amounts of acetic anhydride and pyridine, both individually and in mixtures containing other analytes. The reaction kinetics of M04 at 2.5 μg / mL were evaluated. The derivatization reaction was compared with other analytes. Formation of M04-Ac occurs approximately 30 to 60 minutes into the reaction at 50°C, regardless of its presence or absence. A plateau was reached. Approximately 6% of M04 remained unreacted after about 30 minutes of reaction. (Figure 22).

[0208] [Table 27]

[0209] To reduce the amount of unreacted M04, the volumes of pyridine and acetic anhydride were adjusted accordingly. This was increased to 2.5 times and 5 times (Figure 23).

[0210] The best yield was achieved when the volume ratio of plasma:pyridine:acetic anhydride was 1:2.5:5. (The percentage of unreacted M04 was approximately 2.2%). This condition was selected to verify the effectiveness of the method. Increasing the reaction temperature as a means of improving reaction yield is due to potential concerns about analyte instability. This was not investigated. 2.5 μg / mL CX in the presence of equal volumes of acetic anhydride and pyridine. The stability of -8998, M01, M02, and M03 at 50°C was also evaluated. Overall, CX-8998, M01, M02, and M03 are stable for up to 130 minutes in a reaction at 50°C. It appeared that way (Figure 24).

[0211] After chromatography optimization, 1-2000 ng / mL of human plasma K2EDTA For quantification of the concentrations of CX-8998, M01, M02, M03, and M04, the following 5- An in-1 LC / MS / MS assay was performed.

[0212] Sample preparation procedure: For CX-8998, M01, and M02 with protein precipitation Refer to previously verified methods (Merck, West Point, SBP 261) The following procedures were adopted and used for qualification assessment: 1. Prepare serial dilutions of the reference and internal standard solutions in 1:1 diH2O:ACN. To 2.0.2 mL of human plasma K2EDTA, add 10 μg each of the reference standard and internal standard solution. Add L 3. Precipitate plasma proteins with 0.6 mL of ACN. 4. Centrifuge and obtain the supernatant. 5. Evaporate and dry the supernatant at 5.50°C. The sample is reconstituted in 0.1 mL of dichloromethane by ultrasonic treatment for 6.5 minutes. 7. Derivatization with 20 μL each of acetic anhydride and pyridine at 50°C for 30 minutes. Evaporate and dry at 8.50°C. 9. After 10 minutes of ultrasonic treatment, the sample was placed in 0.1% formic acid in a 1:1 diH2O:ACN mixture. Reconstruct *To use 100 μL of acetic anhydride and 50 μL of pyridine, the volume is suitable for the method. Optimization was performed after performance evaluation. This was done to achieve a higher reaction yield for M04-Ac, except for assay performance. These were minor changes with no expected impact on performance. Therefore, these volume ratios were requalified. It wasn't worth it. Chromatography parameters 0.1% (v / v) FA in MPA diH2O 0.1% (v / v) of FA in MPB ACN Column Phenomenex Kinetex PFP (50 x 2.1 mm, 1 (00 Å, 5 μm) Injection volume 10μL Execution time: 14 minutes Autosampler temperature: 2°C to 8°C Column temperature: 30°C Needle cleaning 0.1% (v / v) FA in CAN

[0213] [Table 28]

[0214] Mass spectrometry parameters: Analyte is measured using Micromass MassLynx (registered trademark). Micromass Quattro controlled by software version 4.0 (Registered Trademark) - Monitoring was performed using an LC tandem triple quadrupole mass spectrometer. The typical MS parameters (ESI positive, MRM mode) were as follows:

[0215] [Table 29]

[0216] Chromatography. 10 ng / mL CX-8998, M01, M in human plasma samples. Figure 25 shows the typical chromatographic performance after injection of 02, M03, and M04. .

[0217] In this study, CX-8998 in human plasma K2EDTA and its metabolites 5-in-1 LC / MS for simultaneous quantification of M01, M02, M03, and M04 We developed an MS assay. Due to the properties of the M02 and M04 isobars, we used a conventional C18-based assay. Complete separation could not be achieved through hydrophobic interactions using the reversed-phase system. Evaluate other alternative reversed-phase columns and utilize pentafluorophenyl (PFP) group-bound columns. Although near-perfect separation was achieved using this method, the execution time was extremely long. Therefore, it is specific to M04. We have successfully developed a specific acetylation derivatization method, which allows for a reasonable assay execution time of 5 This enabled satisfactory chromatographic separation of all analytes.

[0218] Subsequently, an LC / MS / MS assay was performed to simultaneously quantify all five analytes using human blood. All analytes in the plasma are qualified within a calibration range of 1 to 2000 ng / mL. The assay performance was satisfactory, and the system met performance requirements, quantification range, and other criteria. Calibration linearity, assay accuracy and precision, and / or assay recovery. It met the acceptance criteria. A slight carryover in chromatography was CX Observations were made for -8998. Some impurities were observed in the reference standard, but only very small amounts. The level is such that the impact on calibration is minimal. Interference with M02 detection Low residual levels of unreacted M04 were observed, resulting in all dryness. The sum of the crossovers results in only a minimum bias of approximately 7.1% in the M02 quantification. It is expected to have a limited effect. Regarding the quantification of M02 at various ratios of M04 in the sample. The accuracy limits of the assay were confirmed during the validation of the method's effectiveness.

[0219] Example 20: A broad safety margin between human therapeutic exposure and toxicological findings in non-clinical studies. Safety margins of CX-8998 and its metabolites M01 and M02 in rats and dogs NOAEL doses (300 mg / kg / day and 30 mg / kg / day, respectively) Exposure in a 90-day repeated-dose toxicity study revealed a total of (conjugated and unconjugated) CX- For 8998, M01, and M02, the steady state was estimated with 10 mg BID administration. Human plasma concentration (C ss ) and area under the curve (AUC 24 ) Calculated based on the value. In addition , the active ingredients (CX-8998, M01, and M02) or the so-called "total active portion" (T We also calculated the safety margin for the sum of exposures to AM.

[0220] AUC of CX-8998 in total for males and females 24 The safety margin is different for each rat. The ratios were calculated to be 19 times and 41 times for males and 24 times and 26 times for females. A total of CX-8998 C ss The safety margins were 39 times and 91 times, respectively, in rats. The safety margin in rats was calculated to be 68 times and 74 times in dogs. In males, it was about half that of females, but in dogs, the safety margin was similar across both sexes. there were.

[0221] Total AUC of CX-8998, M01, and M02 24 The safety margin for (female / male) is, In rats, the ratios were 41 / 19, 13 / 6.8, and 62 / 31, respectively, and in dogs, The calculations were 26 / 24, 5.6 / 6.5, and 25 / 26 times (Table 20). CX- The sum of 8998, M01, and M02 is C ss The safety margin (male / female) is in rats. These are 91 / 39, 21 / 13, and 104 / 56 times, respectively, and for dogs, they are 74 / 68. It was calculated to be 8 / 10 and 46 times.

[0222] TAM TotalAUC 24 The safety margins were 32 and 16 times in female and male rats, respectively. The results were calculated to be 17 times and 16 times for both male and female dogs. Total TAM C s s The safety margins were 62 and 31 times in female and male rats, respectively, and in female and male dogs. The calculations showed that the ratios were 39 times and 37 times, respectively.

[0223] [Table 30]

[0224] Example 21: Development of the CX-8998 formulation CX-8998 is available in 1mg, 2mg, 3mg, 4mg, 8mg, 12mg, and 18mg doses. The formulation was put into g capsules and used as a single dose in the morning. Capsules with different dosages were used. This provides a highly flexible dose escalation schedule, enabling an ideal dosage plan.

[0225] The performance of the CX-8998 immediate-release capsule was tested in human subjects, and in a 900 mL acidic medium in the stomach. The evaluation was performed in a simulated gastrointestinal tract used to mimic the actual digestive process.

[0226] The rapid release of CX-8998 from the immediate-release formulation in an acidic medium is shown in Figure 26. Generally, the plasma profile showed dose-proportionality in the dose range of 2–18 mg. The compartment PK model was followed. Slight changes in terminal phase disappearance rate and redistribution were observed. This was observed in elderly patients (Figure 29).

[0227] To generate a theoretical release profile, the area between the minimum effective concentration and the maximum tolerable concentration is We developed an in silico model that produces the desired plasma concentration value in a steady state. To predict the behavior of the CX-8998 in the chemical system and throughout the body, the model was created using an independent dataset. We verified this against T.

[0228] For single morning administration of 2 mg, 4 mg, 8 mg, 12 mg, and 18 mg in elderly men Further optimization was performed. The PK parameters for elderly men are shown below.

[0229] [Table 31]

[0230] Elderly patients after a single morning dose of 2 mg, 4 mg, 8 mg, 12 mg, or 18 mg capsules. The plasma concentrations of CX-8998 in patients are shown in Figure 31. Predicted results for elderly patients. The correlation between the observed results is shown in Figure 32.

[0231] Optimal results for healthy men from a single morning dose of 1 mg, 3 mg, 8 mg, and 12 mg. The chemical reaction was performed simultaneously. The PK parameters in young males are shown below.

[0232] [Table 32]

[0233] The highest exposure to CX-8998 associated with different doses in healthy volunteers was as follows: It is a street: [Table 33]

[0234] In young patients after a single morning dose of 1 mg, 3 mg, 8 mg, and 12 mg capsules The plasma concentrations of CX-8998 are shown in Figure 33. Predicted and observed results for young patients. The correlation is shown in Figure 34. Multiple morning doses of 1 mg, 3 mg, 8 mg, and 12 mg capsules. Figure 35 shows the plasma concentrations of CX-8998 in young patients after a single dose.

[0235] In young and elderly subjects, a single daily dose of 12 mg / day and multiple daily doses are used. A comparison of the release profile simulations is shown in Figure 28.

[0236] By optimizing the matrix or combining beads with different emission profiles, By doing so (for example, immediate release (IR) + sustained release (SR) or IR + delayed release (DR) )) To determine the target release profile, release profiles from different matrices The process was evaluated using an in silico model. The primary release from the permeation pump tablet is shown in Figure 38. The primary release from the matrix tablet containing coated beads within the capsule. This is shown in Figure 39. Burst release from infiltration pump tablets having an IR emission coating and The primary release is shown in Figure 40. IR beads and in a matrix tablet having an IR coating. Burst release and primary release from the mixture of enteric-coated beads are shown in Figure 41. A mixture of IR beads and pH 7 enteric-coated beads, which are IR tablets with IR coating. Figure 42 shows two bursts delayed by 3 hours from the enteric coating and IR coating. Six hours later, a mixture of IR beads and pH6 enteric-coated beads containing IR tablets with a coating was found. The two extended bursts are shown in Figure 10. Based on the model, the ideal in young adult males. The release profile is approximately 1 mg in a burst followed by approximately 6 mg at a nearly constant rate over 12 hours. It is a 2mg burst (Figure 36), and the ideal release profile in elderly men is approximately 7mg. A burst of g followed by a burst of approximately 12 mg over 12 hours at a slightly decreasing rate. Yes (Figure 37).

[0237] We have developed sustained-release (SR) beads with multiple types of sustained-release and enteric coatings. Some SR matrix beads use representative polymers (e.g.) to achieve sustained release. For example, it was developed using hydroxypropyl methylcellulose or carbopol. Some SR matrix beads achieve pH-independent release from tablets. Developed using a sustained-release osmosis pump. Some SR matrix beads have a pH of 6 Alternatively, to achieve release at pH 7, and to utilize the poor solubility of CX-8998 at high pH values. Therefore, by using a delayed-release (DR) coating on IR beads to provide sustained release Developed. Some SR matrix beads rely on the slow erosion of the coating. This achieves the law, and thereby sustains the release of drugs from the IR matrix. Developed using Eudragit RS / RL30D coating.

[0238] Example 22: CX-8998 twice daily (BID) 9 ETs with an insufficient response to an anti-tremor drug (e.g., propranolol) A randomized, double-blind, placebo-controlled, parallel-group trial involving 5 patients (NCT03) 101241) was performed. After consent and screening, the subjects were CX-8998 (10 Either the dose is gradually increased up to mg BID or placebo is administered orally for 28 days. Participants were randomized to assess clinical assessment scales, patient-reported outcomes, and tremor accelerometer measurements. Records and digital spirography were collected at baseline (first visit) and on day 15. Data was collected on the third visit and on day 28 (fourth visit).

[0239] Plasma concentrations of CX-8998 were measured at the target level by multiple different doses delivered twice daily. The predictable exposure in the steady state, where the target was achieved, is shown (Figure 10).

[0240] TETRAS (Essential Tremor Rating Scale) is evaluated by the clinical trial physician. Performance subscale (p=0.027), TETRAS ADL (p=0.04) 9) TETRAS total score (p=0.007), and overall clinical impression of improvement (p=0. 001) showed significant improvement (Figure 44). There were no major safety or tolerability concerns.

[0241] Upper dose limit based on tolerability profile: Up to 10 mg BID, lower incidence of CN This produces concentrations associated with S AEs. The S-shaped correlation indicates that the frequency of CNS AEs is approximately 700-80. This suggests that a significant increase may begin at a CX-8998 plasma concentration of 0 nM (Figure 45).

[0242] The trial achieved proof of concept in the ET, and the primary and secondary efficacy endpoints were met. The patient population and the escalation scheme are key central trial design parameters. It was determined that CX-8998 was safe and well-tolerated in ET patients. These results are expected to enable late-stage clinical development of CX-8998 in ET.

[0243] CX-8998 and CX-8998 metabolites, including the total active portion (TAM) of CX-8998. 98 formulations were developed. For example, TAM is plasma protein bound (f u) CX-8998, M01, and M0, adjusted with the effects associated with CX-8998. It could be the sum of the two concentrations (Cu, ss_TAM).

[0244] [Table 34]

[0245] Total and unbound CX-8 in plasma after administration of 10 mg BID The target exposure levels and PK profiles for 998 and TAM are shown in Figure 46.

[0246] Example 23: Target CX-8998 concentration Exemplary target concentrations for CX-8998 were established as shown in Appendix A.

[0247] Example 24: Study design for efficacy endpoint and digital biomarker selection and methodology The T-CALM trial used up to 10 mg BID to reduce the severity (amplitude) of ET. To evaluate the efficacy of the quantity of CX-8998. The optional / additional components of the T-CALM main trial are , Three different digital monitors for accurate quantification of changes in motor function in ET patients This is a T-CALM digital sub-trial evaluating the feasibility of the ring platform. A schematic T-CALM design is shown in Figure 47.

[0248] The T-CALM trial was a proof-of-concept, multicenter, double-blind, randomized, placebo-controlled trial. This is a row-group trial. The screening period is up to 4 weeks. Any trial procedure can be performed. Before proceeding, the patient reads and signs the informed consent form. CX-8998 is C Because it may be metabolized by YP3A, primidone (potent CYP3A4) The use of inductive factors is excluded. Therefore, patients taking primidone are subject to drug safety A 6-week screening period is given to allow for discontinuation. A single anti-tremor drug at a stable dose other than limidone is permitted during the trial. Patients who meet the criteria will be randomized to treatment group A or B. Group A will receive 10 mg BID. Group B is administered CX-8998 in gradually increasing doses. Group B is administered a balanced dose of placebo. Participants in the randomized trial were given a 4-week double-blind dose-escalation period, followed by the most... After administering the final dose, a one-week safety observation period will begin. (Baseline: Day 1) ) The patient will undergo safety and tremor evaluation before administration of the test procedure. During the first week, the patient Patients receive 4 mg of the investigational drug or an equivalent dose of placebo twice daily. Day 8 (week 2) In the eyes, the patient will receive a safety assessment at the clinic and 8 mg (or an equivalent dose of placebo) daily. The dose escalation to two doses will be evaluated. On day 15 (week 3), the patient will be evaluated for safety and efficacy. Sex evaluation, and final dose escalation to 10 mg (or a balanced dose of placebo) twice daily. I will report this to the clinic. The last visit for efficacy evaluation will be on day 28 (week 4). The final visit for safety evaluation was on day 35 (week 5). Blood samples were taken on the 8th. CX-899 was administered before the dose on days 15 and 28, and approximately 4 hours after the dose on day 28. Sample 8 is collected for plasma concentration measurement. If an unbearable adverse event (AE) occurs at any dose... If permitted, the dose may be given on the 8th or 15th day or before those scheduled visits. At that time, the dose may be reduced to the next lowest dose. Lowest planned dose (4 mg BID) If the dose is unbearable, it may be reduced to 2 mg BID. Increasing the dose after reduction is permitted. If patients do not tolerate dose reduction, they will be discontinued from treatment.

[0249] Patients who are screened and meet the eligibility criteria for the T-CALM main trial will receive additional treatment. Patients have the option to participate in the T-CALM digital secondary trial. Patients in the secondary trial will be subject to the same criteria as in the primary trial. Participants will be randomly enrolled in either CX-8998 or placebo in the same ratio as in the trial (1:1). After the formal consent is signed, the patient will use two digital tools, iMotor Alternatively, you can use either or both of Kinesia 360, or objectively assess motor function. The option to conduct additional tests using Kinesia One for measurement is provided. The administration plan and safety evaluation schedule for the secondary study are identical to those of the primary study. During their visit to the clinic, patients in the iMotor group of the secondary trial were evaluated in the presence of the trial staff. Complete. Patients in the Kinesia 360 group of the secondary trial wore the device and screen. Data is collected for two days after the run-up, and then the device is returned to the testing facility. The data collected in between serves as a baseline exercise assessment for Kinesia 360. The baseline assessment using iMotor is performed before medication administration at baseline (day 1). This will be conducted after the completion of safety and tremor evaluations in the T-CALM main trial. Weeks 1 and 2 At the end of the process, safety evaluations and evaluations by Kinesia 360 and iMotor will be completed. The data will be collected. The final effectiveness measurements for both devices will be collected at the end of the 4-week visit. The last safety evaluation visit was at the end of week 5.

[0250] The trial included moderate to severe ET patients who were not adequately treated with standard therapeutic approaches. The following group will be enrolled. The key eligibility criteria for the T-CALM main trial are as follows: 1. Signed informed consent has been obtained for all trial participants. 2. Men and women aged 18-75 are registered. 3. This includes patients with moderate to severe ET who were first diagnosed before the age of 65. 4. At least one of the three TETRAS-PS procedures in the upper limb Also, a tremor severity score of 2 5. A TETRAS-PS score of at least 15 at the time of screening. 6. The dosage of the maximum one permitted concomitant anti-tremor drug is stable; strong CYP inducer The use of primidone is excluded. 7. Surgical intervention has been ruled out.

[0251] A complete list of inclusion / exclusion criteria for the T-CALM main trial can be found at ClinicalTrial. It is available online at s.gov under registration number NCT03101241.

[0252] The eligibility criteria for the optional T-CALM digital supplementary trial are as follows: 1. The patient must meet all eligibility criteria of the T-CALM main trial protocol. No 2. Patients may be able to meet user requirements when assessed by facility staff. You must 3. Patients will not be able to participate in the optional T-CALM digital subtrial until they agree to do so. Digital devices / downloads are not available for loan.

[0253] The primary, secondary, and exploratory efficacy endpoints of the T-CALM trial are listed below. ru.

[0254] The primary endpoint is TETRAS performance from baseline to day 28. This is a subscale change. Secondary endpoints include T from baseline to day 28. This shows the changes in the ETRAS Activities of Daily Living (ETRAS) and Kinesia One scores. The exploratory endpoint exists. T from baseline to day 15 and day 28. Changes in ETRAS total score (independent video evaluators) and at Kinesia One Measure change. TETRAS Performance Subscale (Independent Video Evaluator) and The change in the Kinesia One score from baseline to day 15 will be evaluated. At the end of treatment, the success of the procedure was assessed by the patient's overall impression of change (PGIC) and the clinical overall impression of improvement. (CGI-I), Goal Achievement Scale (GAS), and the quality of life of patients with essential tremor It is measured using a questionnaire (QUEST).

[0255] The T-CALM digital subtrial has two exploratory endpoints. Kines The ia 360 measures changes in tremor amplitude from baseline to day 15 and day 28. The iMotor trial involved digital spirometry from baseline to days 15 and 28. The study assesses five simple motor functions, including those involving graphs.

[0256] Several performance scales and objective biomonitoring were used in the T-CALM main trial. These tools are used in trials to more accurately reveal patients' responses to ET treatment. This generates relevant and convergent effectiveness data that can be used for this purpose.

[0257] Essential Tremor Rating Scale (TETRAS; e.g., Elble et al.) (See l., 2012 Mov Disord.27:1567-1569) 9 performance subscales and 12 activities of daily living (ADL) subscales It consists of scales. These subscales are drawn using the pen and paper method. Provides rapid clinical assessment (<10 minutes). Performance subscales include head, face, voice, Tremor amplitude (severity) of the limbs and torso, as well as writing, drawing spirals, and pen markings above dots. Functional tests that include maintaining a certain level of tremor are rated on a 5-point scale, with 0 indicating no tremor and 4 indicating severe tremor. Measured using an evaluation scale. The sum of individual scores is a performance subsystem from 0 to 64. Generates a comprehensive score. The TETRAS performance subscale is used in clinical trials at clinical sites. The score is determined by both the attending physician and an independent video evaluator. The score was statistically analyzed as the change from baseline to day 28, and the primary efficacy It functions as an endpoint. Optimal evaluation method (investigator vs. independent video evaluator) The TETRAS performance subscale (as determined by the TETRAS performance subscale) is selected for late-stage clinical development. Performance subscale data will also be used for exploratory analyses of efficacy on day 15. The ADL subscale includes speaking, eating, drinking, dressing, self-care, writing, and handling objects. The assessment evaluates daily living activities such as carrying things. Patients rate each item from 0 (normal activity) to 4 ( Severe abnormalities are scored. The overall score ranges from 0 to 48, and secondary effectiveness evaluations are also included. The changes are analyzed from the baseline point to day 28. TETRAS total score (performance subset) from day 15 to day 28 Changes in the total of (L and ADL) are evaluated as exploratory endpoints.

[0258] The Kinesia One platform uses T as a digital marker for tremor severity. - Used in CALM. Kinesia One is used for tremor assessment in ET patients. Regarding the monitoring of the severity of motor symptoms in Parkinson's disease using only limited data F It is approved by DA. The score derived by the algorithm is for Parkinson's disease. These are primarily created using algorithms, and their effectiveness in ET is limited (e.g.) For example, Hoffman et al.,2011 Conf Proc IEEE En See Med Biol Soc. 2011:4378-81. Kines The ia One device is worn on the index finger of each ET patient, and TETRAS performance It is worn in the clinic after the subscale is completed. Resting tremor, postural tremor, movement tremor, and Four tasks were administered to assess lateral flapping tremor in patients with respect to the left and right sides. It will be executed. From baseline to day 28, the score will be measured in Kinesia One score. Changes are evaluated as secondary efficacy endpoints. (Kinesia One data) This concerns the change in acceleration measurement scores from baseline to day 15, and the changes from day 15 to day 15. For an exploratory analysis of the effectiveness of changes in amplitude measurements from baseline at day 28. It is also used for this purpose. Consistent finger sensor wear and consistent task execution are essential for effective Kine. This is an important factor in the SIA One score.

[0259] Due to the adverse effects of ET on daily activities and health, several quality of life assessments are based on Patient perception of disability and effectiveness of drug therapy from the start of treatment (day 28) to the end of treatment (day 28). These are conducted to evaluate more accurately. Each of these questionnaires and scales is used for ET patients. It requires a significant amount of input from the user, and the data deals with exploratory effectiveness endpoints. It is used for [purpose].

[0260] Questionnaire on the quality of life of patients with essential tremor (e.g., Troster et al.,2005 Parkinsonism Relat Disord.1 (See 1:367-373) This describes the daily routine of ET patients from baseline to day 28. It is used to assess the impact of ET on daily life. The questionnaire has five subscales (body 30 related to physical activity, mental health, communication, hobbies / leisure, and work / finances Includes item and total scores. Satisfaction with sexual function, tremor control, and side effects of drug therapy. There are also three additional items related to this. Whether symptomatic or therapeutic, the treatment program for ET If the lamb is beneficial, the patient may respond to the QUEST in a positive manner. The QUEST includes questions that are not expected to change within the 28-day timeframe. However, Some items, such as satisfaction with tremor control, can generate insightful data.

[0261] The Clinical Global Impression Scale (CGI) is a clinician's assessment of a patient's function before and after trial medication. Creating an impression (for example, Guy, Assessment Manual for Ps ychopharmacology.Rockville,MD:Department of Health,Education,and Welfare Public Health Service Alcohol,Drug Abuse,and Me See National Health Administration, 1976. The GI overall score takes into account the patient's medical history, mental health status, and symptoms and behaviors related to functional ability. CGI-Improvement (CGI-I) is a measure of overall improvement or CGI-Severity (CGI-S). Includes a single 7-point scale for change from the line. The evaluating clinician is asked to "consider the change from the start of treatment." The question is: "How much has your patient changed compared to the condition of your other patients?" Select one response based on the following criteria (from 1 = greatly improved to 7 = greatly worsened).

[0262] The patient's overall impression of change (PGIC) is related to the improvement or deterioration over time following ET treatment. To quantify the patient's impression of the subject (for example, Guy, Assessment Manual) l for Psychopharmacology.Rockville,MD:De part of Health,Education,and Welfare Public Health Service Alcohol,Drug Abuse e, and Mental Health Administration, 1976 (See reference). The patient uses the PGIC scale to assess their current health relative to the start of treatment. Evaluate the condition and calculate the difference. The 7-point scale is, "Regarding your ET, you "How would you describe yourself now compared to when you first started taking the investigational drug?" Ask a question. The patient will respond with one of seven options, ranging from very bad to very good. I'll respond with that.

[0263] Goal Achievement Scale (GAS) (e.g., Kiresuk et al., 1968) (See Community Ment Health J.4:443-453) This is to create a written set of goals desired by each individual patient to track the progress of treatment. This requires dialogue between the physician and the ET patient. At baseline, each patient has three individual Set health goals and assign each goal a rating of 1 (very important), 2 (very important), or 3 (extremely important). Assess the difficulty of each goal as follows: Clinicians rate the difficulty of each goal as follows: Probable = 1; Possible Evaluate as follows: =2; Suspicious=3. During the trial, if the course worsened from baseline = The result is scored on a 5-point scale from -2 to +2 (the best predicted result).

[0264] Two additional biomonitoring tools measure changes in the motor function of ET patients. The T-CALM digital subtrial is used to investigate the ability. The data is exploratory. It is used for efficacy endpoints.

[0265] Kinesia 360 (Great Lakes NeuroTechnology) (e.g., Cleveland, OH, USA) (For example, Pullam et al., 2 014 Parkinsonism Relat Disord.20:37-40 (Regarding the device) uses sensors on the wrist and ankle to collect objective and continuous exercise data. This is a home-use monitoring system. The Kinesia 360 kit is a Kinesia home-use monitoring system. a smartphone with the 360 ​​application installed, two wearables Includes sensors and charging device. The sensors are attached to each ET patient's wrist and ankle daily. It acquires linear acceleration and angular velocity in three dimensions. At the end of each day, the exercise data is smartly stored. The data is uploaded from the phone to the central server. The data includes the occurrence and severity of tremors. Furthermore, the patient's level of daily living activities is processed to provide a detailed description.

[0266] iMotor (Apptomics, Inc., Wellesley Hills, U. SA MA) (For example, Mitsi et al., 2017 Front. Neuro (See l.13:273) This objectively measures the motor function of patients with abnormal movements. It is a tablet-based application. The iMotor trial involved scheduled hospital visits. This will only be done in between. Each ET patient will perform five simple tasks on a tablet. (required: finger tapping, hand tapping, hand pronation and supination, light stimulation) (Reactions and spiral drawing with a digital stylus). Each task has a 30-second time limit. Yes, and it is performed twice (once for each hand).

[0267] Adverse events that occur under all treatment conditions are classified into major organ categories and basic drug regulatory terms. Codified in MedDRA version 20, and shown in frequency tables for each treatment group. Adverse events include maximum severity, drug-related adverse events, serious adverse events, and discontinuation of the study. It is characterized by the adverse events that led to it.

[0268] Other safety assessments include physical examination, neurological examination, vital signs, and clinical tests (hematological, Chemical and urine analysis, urinary drug screening, pregnancy tests, electrocardiogram (ECG), colon The Bier Suicide Severity Rating Scale (C-SSRS), the Epworth Sleepiness Scale (ESS), and M Iami University Parkinson's Disease Hallucination Questionnaire (UM-PDHQ) (e.g., Papapetro See poulos et al., 2008 BMC Neurol. 8:21. ) are some examples.

[0269] All statistical analyses are performed using version 9.4 or higher based on a predetermined statistical analysis plan. It is performed by the SAS system. Based on Phase 2 trials of comparable designs, approximately 92 The sample size of human patients was used in the T-CALM main trial to assess the safety and performance of CX-8998. It has sufficient power to provide proof-of-concept data on effectiveness.

[0270] There is no formal method for determining sample size. At least 30 patients should be tested for CX-8998. Alternatively, it has been proposed to randomize participants to a placebo.

[0271] Example 25: The book of CX-8998, a selective modulator of T-type calcium channels. Safety and efficacy in patients with essential tremor Essential tremor (ET) is a debilitating disorder that significantly impairs quality of life (QOL). Drug therapy is not optimal. T-CALM selectively modifies T-type calcium channels. The safety and efficacy of the regulator (CX-8998) in ET patients were evaluated.

[0272] This example shows CX being gradually increased up to 10 mg twice daily in ET patients aged 18-75 years. This document describes the randomized, double-blind, proof-of-concept phase 2 trial (T-CALM) that evaluated -8998. The patient has moderate to severe ET and can take up to one stable dose of anti-tremor medication (primi Concomitant use of (excluding Don) was permitted. Trial participants received either CX-8998 or Pla for 28 days. Patients were randomized (1:1) to receive sebum. The primary and secondary endpoints were baseline. TETRAS Performance Scale (PS) and TETRAS Daily from day 28 to day 28 The change was in the Activities of Daily Living (ADL) score. The exploratory endpoint was the overall impression of the change. This included CGI, Global Action Structure (GAS), and QOL scores. Safety and tolerability were assessed. It was monitored. T-CALM is registered on ClinicalTrials.gov. (NCT03101241)

[0273] T-CALM concerns the further development of CX-8998 in the under-treated ET. Designed to have appropriate power to enable decision-making. The eligibility criteria are: Carefully defined to ensure the selection of a clearly defined cohort of ET patients. Clinical assessment using effective performance scales, objective biometric tools, and quality of life questionnaires. Meaningful and convergent clinician-measured outcomes and patient-reported outcomes M was used as an important endpoint to evaluate drug efficacy in the T-CALM trial. The results are based on several clinically relevant and convergent efficacy endpoints, including CX. -8998 reduces tremor severity, and CX-8998 has a favorable safety and tolerability profile. It was proven that he possessed the file.

[0274] method Study design and participants T-CALM is a 28-day 10 mg B treatment for patients with moderate to severe ET. The efficacy, safety, and tolerability of CX-8998 after dose escalation to target ID will be evaluated. A multicenter (22 US facilities), double-blind, randomized, placebo-controlled study was conducted to achieve this. It was designed as a two-phase proof-of-concept trial.

[0275] Key eligibility criteria for the T-CALM trial include signing informed consent, 18 Men and women up to 75 years of age, first ET diagnosis before age 65, TETRAS-PS item 4 Three techniques (holding the upper limb forward and horizontally, and holding the upper limb to the side and horizontally while bending the elbow) (Stretching and bringing hands close together near the chin, and finger-nose or jaw-nose examination) At least two tremor severity scores in at least one upper limb, At the time of cleaning, a total TETRAS-PS score of at least 15, no anti-tremor medication, This was either the combination of a stable dose of one type of anti-tremor drug or the combination of a single type of anti-tremor drug. Primidone was It is excluded because it is a potent CYP inducer that can affect the metabolism of CX-8998. Patients who underwent surgical intervention for ET were also excluded. A complete list of selection / exclusion criteria is available. The ClinicalTrials.gov registration number NCT03101241 It is available online.

[0276] Randomization and masking Patients were randomized in a 1:1 ratio to receive either CX-8998 or placebo. The study was stratified by concomitant use of anti-tremor drugs and by the testing facility (participation or non-participation in the secondary trial). The conditioned code was prepared by an open-label statistician who was not involved in conducting the trial.

[0277] Sponsors, patients, investigators, and voluntary parties involved in conducting the trial or analyzing the data. Others were not informed of their treatment assignment until after the test was completed and the blinding was lifted. CX- 8998 was formulated into capsules containing the active drug mixed with a mixture of excipients. The placebo dose was formulated in the same capsule along with an equivalent mixture of excipients.

[0278] procedure A schematic diagram of the test is shown in Figure 47A. After informed consent, eligible subjects will undergo a one-week trial. During the 4-week double-blind administration period, while safety monitoring continued, the dose was gradually increased up to 10 mg BID. Participants were randomized to receive either a dose of CX-8998 or a balanced dose of placebo. The elephant received 4 mg BID of CX-8998 (or a balanced dose of placebo B) during the first week. The patient was administered (ID), followed by a safety evaluation at the clinic on day 8 and a treatment of 8 mg BID or swab. The appropriate dose was evaluated for increasing the dose to the placebo BID. Day 15 (Week 3) ) Patients should be informed of the safety and efficacy of 10 mg BID or swab at the clinic. The final dose escalation to the corresponding placebo BID was evaluated. Final efficacy evaluation The patient came in for evaluation on the 28th day (4th week). During the first and second weeks, as needed... Then, a reduction to the next lower dose was permitted, and only one reduction was allowed. Tolerability of the dose reduction was... Patients who failed to demonstrate the desired outcome were withdrawn from the study. Further dose increases were not permitted. Ta.

[0279] The safety procedures are coordinated in the Drug Regulatory Terminology (MedDRA) version 20. This included the collection of all treated TEAEs (adverse events that occurred under treatment). This includes the maximum severity, drug-related adverse events, serious adverse events, and the number of cases leading to patient discontinuation. Adverse events were classified. Other safety assessments included physical examination, neurological examination, vital signs, and clinical assessment. Tests (hematological, chemical, and urinalysis), urinalysis for drug testing during screening, pregnancy tests, Electrocardiogram (ECG), Columbia Suicide Severity Rating Scale (C-SSRS), Epworth Sleepiness Test Kale (ESS) and the University of Miami Parkinson's Disease Hallucination Questionnaire (UM-PDHQ) .

[0280] Outcome Table 22 outlines the methods for determining the efficacy and safety endpoints of T-CALM. The Tremor Rating Scale (TETRAS) is a 9-item performance subsystem. It consists of the PS (Performance Skills) scale and 12 subscales of Activities of Daily Living (ADL). The indicator was the change in TETRAS-PS score from baseline to day 28. ETRAS-PS is performed (in real time) by the clinical trial physician for each patient at the clinical site, and Each patient's videotape was reviewed and scored by five independent video evaluators. Both sets of scores were statistically analyzed. Due to the lack of precedent, this double approach was used. The purpose of the law is to provide the optimal evaluation method for late-stage clinical development (TETRAS- by the clinical trial physician). The choice was between PS (PlayStation) and TETRAS-PS (Tetras-PS) as evaluated by independent video evaluators. The endpoint is the TETRAS-ADL subscale from baseline to day 28. Score changes were measured by Kinesia ONE from baseline to day 28. Changes in acceleration measurement scores, as well as safety and tolerability: electrocardiogram (ECG) parameters Change from baseline, clinical laboratory assessment of clinical safety, Columbia Suicide Severity Scale (C-SSRS), Epworth Sleepiness Scale (ESS), University of Miami Parkinson's Disease Hallucination Memory questionnaire (UM-PDHQ), vital signs, dropout rate (%), and dropout rate due to adverse events (AEs). (%). The following exploratory endpoints were also included: the total TETRAS score. Changes from the baseline to day 15 and day 28; TETRAS-PS score, TETR AS-ADL subscale score, and 15% of baseline from Kinesia ONE. Changes up to day 1; Patient's overall impression of change (PGIC), Clinical overall impression (CGI) schedule The questionnaire includes a score, a General Assessment Scale (GAS), and a questionnaire on the quality of life for patients with essential tremor. The score and treatment success on days 15 and 28, as measured by (QUEST).

[0281] [Table 35-1]

[0282] [Table 35-2]

[0283] [Table 35-3]

[0284] statistical analysis All statistical analyses were performed using the SAS system (version 9.4 or later). Action The sample size of 43 patients per group was determined by TETRAS from baseline to day 28. - For the primary endpoint of PS score change, the standard deviation was set to 7.5 and α = 0.05. Assuming this, we can detect a difference of at least 5.5 points between CX-8998 and placebo. It had at least 90% detection power. This calculation was performed using two independent mean values ​​of will Based on the Coxon-Mann-Whitney test, a general but unconfirmed standard deviation. We assumed a normal distribution for each treatment group with differences. We confirmed that 86 patients would be included in the efficacy analysis. To make this truly possible, we planned to enroll approximately 92 patients. (ITT) The analysis population includes all randomized patients, and the breakdown of patients and demographics is as follows: It was used for the following purpose. The safety analysis population (SAS) was defined as receiving at least one dose of the investigational drug. All randomized patients who received the drug were included. The largest analysis population (FAS) was small. At least one dose of the investigational drug was administered, and baseline evaluation and at least one post-baseline evaluation were performed. This includes all patients who underwent line efficacy evaluation. FAS is for all efficacy evaluations. It was used.

[0285] The primary efficacy endpoints were FAS, as well as treatment, use of anti-tremor drugs, study site, and Analysis of covariance (ANCOVA) with baseline TETRAS-PS score as a fixed effect. The analysis was performed using a model. The statistical tests were conducted using the least squares (LS) mean and the ANCOVA model. The test was performed using a two-tailed test with a significance level of α = 0.05. TETRAS-PS on day 28. Multiple imputation was used to estimate missing values ​​for patients with incomplete scores. Exploratory efficacy endpoints were analyzed similarly. The p-values ​​in secondary and exploratory analyses were given by name. They were considered superior.

[0286] result The T-CALM trial period was 2017-2018, with the patient's first visit date being August 2017. On the 29th of the month, the patient's last visit date was July 16, 2018. See Figure 47 for patient breakdown. Shown in B. The ITT analysis population was either CX-8998 (N=48) or placebo (N=4 7) The trial included 95 patients randomized to receive the drug. The trial included 37 patients in the CX-8998 group. The study was completed in 77% of the patients and 42 patients (89%) in the placebo group. Adverse events The discontinuation of treatment occurred in 8 patients (17%) treated with CX-8998 and 3 patients treated with placebo. This occurred in 6% of cases. The primary efficacy analysis population (pre-determined mITT) was small. At least one dose of the investigational drug will be administered, and baseline evaluation and at least one post-treatment evaluation will be performed. 37 subjects in the CX-8998 group and 4 subjects in the placebo group who completed baseline efficacy evaluation. It included four subjects.

[0287] Baseline demographic characteristics are shown in Table 23. Male and female patients are classified as CX- Participants were assigned to either the 8998 group or the placebo group in a nearly equal manner. Age, race, and ethnicity were as follows: Similar results were observed between the X-8998 group and the placebo group. Baseline ET characteristics are shown in Table 24. The CX-8998 group and the placebo group showed the same results for most baseline ET characteristics. The balance was good. The only exception was the use of beta-blockers, which was 44% in the CX-8998 group. In comparison, the placebo group showed a rate of 62%.

[0288] [Table 36]

[0289] [Table 37-1]

[0290] [Table 37-2]

[0291] [Table 37-3]

[0292] During the trial, patients were permitted to use up to one anti-tremor drug in combination, excluding primidone. The drug was administered to 28 patients (58%) in the CX-8998 group and 33 patients in the placebo group. 70% were used. One group consisted of CX-8998 (10%) and placebo (17%). In order to treat co-existing conditions such as anxiety, insomnia, and hypertension, patients in this department may receive more than one (for example) treatment. He was also taking anti-tremor drugs such as benzodiazepines and beta-blockers. Selective beta-blockers were observed in both the CX-8998 group (29%) and the placebo group (36%). It was the most frequently used anti-tremor drug. The anti-tremor drug was used in 20 patients with CX-8998 and 1 In the four placebo patients, the treatment was not administered in combination, and of these patients (12%), 11 received standard treatment. Try the drug (propranolol, primidone, or both) and assess its effectiveness or tolerability. The clinical trial site reported that it was discontinued for reasons related to vibration. The remaining 23 patients underwent anti-vibration treatment. Either they had no history of using war drugs, or they were unable to obtain information about it. Compliance with investigational drug administration was 99.3% for CX-8998 and 97% for placebo. They were equivalent at 0.7%.

[0293] The primary endpoint was independent video evaluators from baseline to day 28. The change in the average LS (±SE) of TETRAS-PS, which is scored more precisely, is shown for the CX-8998. The values ​​were -1.8±0.81 for the group and -2.3±0.78 for the placebo group, and there was no significant difference. p=0.696) (Table 25). The same endpoint was scored by the clinical trial physician (themselves). When the sample was mixed, as shown in Figure 48A and Table 25, the average score was (-2.8) compared to the placebo group. Compared to ±0.77, CX-8998 (-4.8±0.80) showed a significant improvement. (p=0.017). Sensitivity analysis showed that the primary endpoint (independent video evaluators and therapists) was positive. The results (measured by the trial physician) were confirmed. Pre-determined subgroup analyses of the primary endpoints showed that more severe ETs A stronger response was observed in patients with the condition (Figure 48B and Table 26). Based on concomitant use of anti-tremor drugs. The pre-determined subgroup analysis was performed on patients who were not using anti-tremor drugs at baseline. The group showed significantly greater improvement compared to the placebo group. (Figures 48C and 48) D and Table 26).

[0294] [Table 38-1]

[0295] [Table 38-2]

[0296] [Table 39-1]

[0297] [Table 39-2]

[0298] [Table 39-3]

[0299] The TETRAS-ADL subscale score was used on day 15 (exploratory endpoint) and The difference in change from baseline between treatment groups, evaluated on day 28 (secondary endpoint), was At both time points, the CX-8998 group showed a significant decrease (improvement) compared to placebo. As shown in Figure 49A, the mean LS (±SE) was compared between CX-8998 and placebo. On day 15, the values ​​were -4.5±0.87 and -1.4±0.85, respectively (p=0.005). On day 28, the values ​​were -4.5±1.12 and -1.6±1.08 (p=0.049). Pre-determined subgroup analysis of secondary endpoints on day 28 showed that more severe ET A greater response was observed in CX-8998 patients with TETRA (Figure 49B). In contrast to S-PS, the TETRAS-ADL score is determined in advance based on the combination of anti-tremor drugs. The subgroup analysis performed was performed on the subgroup that was using anti-tremor drugs concurrently at baseline. It showed a significantly greater improvement compared to placebo (Figure 49C).

[0300] To estimate detectable clinical changes in TETRAS-ADL improvement, TETRAS- Post-hoc analysis of ADL scores is measured using CGI-I or PGIC as anchors. The study was performed on a subset of patients who achieved the minimum possible improvement in their scores. Analysis revealed that A decrease of 3-4 points from baseline in the TETRAS-ADL score is considered by clinicians. This is a detectable change, while on the other hand, it is a decrease of 2-4 points from the baseline score. However, it became clear that this represented a significant change for the patients (Table 27).

[0301] [Table 40]

[0302] TETRAS total score (TETRAS-PS score evaluated by the clinical trial investigator + Patient-assessed TETRAS-ADL subscale score (LS mean ±SE) The results for CX-8998 compared to placebo were -7.5±1.42 and on day 15, respectively. -3.7±1.38, p=0.040) and day 28 (-9.0±1.66 and -4.2 The TETRAS-PS score showed a significant improvement (±1.60, p=0.029) (Figure 49D). If A is evaluated by an independent video evaluator, the TETRAS total score is: CX-8 While improvement was observed in group 998, there was no statistically significant difference at day 15 or day 28.

[0303] Kines at day 15 (exploratory endpoint) and day 28 (secondary endpoint) The ia ONE score (triaxial acceleration measurement and gyroscope measurement) is, at any point in time No significant difference was observed between CX-8998 and placebo. (Table 28)

[0304] [Table 41-1]

[0305] [Table 41-2]

[0306] The average LS (±SE) of the CGI-I score is CX-8998 (1.0±0.13). On day 28 (exploratory endpoint), compared to placebo (0.4±0.13), (p =0.001) Significantly larger (improved) (Figure 50A and Table 29). On day 28, Compared to 7% in the racebo group (Figure 50B), 23% of patients treated with CX-8998 showed a significant improvement. It was rated as significantly improved. The PGIC average score was rated as 15 days (exploratory end). (Points) showed a significantly larger improvement (p=0.003), and on day 28 (exploratory endpoint) A significant improvement was observed in the input (p = 0.089). (Table 30) The average GAS score was CX-8998 patients (44.8±1.72) on day 28 (exploratory endpoint) ) was significantly larger (improved) compared to placebo (40.0±1.67) (p=0 0.034). GA includes a post-hoc analysis of the proportion of patients who achieved one or more goals. The detailed results for S are shown in Table 31.

[0307] [Table 42]

[0308] [Table 43]

[0309] [Table 44]

[0310] The QUEST questionnaire showed that CX-8998 patients had a higher percentage of patients with On day 5 (36% vs. 9%) and day 28 (18% vs. 9%), side effects were observed with these treatments. In the trials, a higher percentage of CX-8998 patients showed results on day 15 (38% vs. 11%). The study revealed that %) and on day 28 (38% vs. 14%), patients expressed satisfaction with symptom control. (Table 32) CX-8998 group in question area scores on day 15 or day 28. No significant difference was reported between the patient group and the placebo group (data not shown).

[0311] [Table 45]

[0312] At least one TEAE was present in 49% of patients in the CX-8998 group compared to placebo. They were present in 58%. As predicted, TEAEs in the CX-8998 group were primarily neurological. The findings were academic and psychiatric. TEAEs were mainly mild to moderate in both groups. TEAEs in the CX-8998 group were mainly reported during the first week of the trial, TEAEs in the placebo group were reported throughout the entire study period (Table 33). CX- The most commonly reported drug-related TEAEs in group 8998 were dizziness, headache, Euphoria, attention deficit, paresthesia, hallucinations (illusions, mainly visual hallucinations when eyes are closed), insomnia These included dizziness, nausea, drowsiness, and vomiting, which are most commonly seen with placebos. These were TEAEs related to (Table 33).

[0313] [Table 46]

[0314] Serious adverse events (SAEs) of alcohol withdrawal syndrome, major depressive disorder, and suicidal ideation are considered CX -Reported in one patient in group 8998. This patient was observed during screening. He had a history of long-term alcohol dependence and depression accompanied by suicidal attempts, which he did not disclose. These SAEs were considered unrelated to the investigational drug. SAEs were observed in the placebo group. It did not occur. Discontinuation of the study treatment due to TEAEs was 2 (4%) in the placebo group. This occurred in 8 patients (17%) in the CX-8998 group compared to the other group. (TEAEs) Dose reduction was performed in 6% of patients in the CX-8998 group and 2% of patients in the placebo group. These were generally performed during the first two weeks of treatment (Table 34).

[0315] [Table 47]

[0316] Observed differences in TETRAS performance subscores result from different scoring systems for each item. To shed light on whether or not this was a contributing factor, and the factors that underlie the evaluations where such items do not match. The extent to which it was possible was investigated through analysis (Figure 51). The upper panel of Figure 51 shows the difference in scores for each item. (Evaluation by independent video evaluators [PR] - Evaluation by clinical investigators [CR]) Here, a negative score is a result of an independent video evaluator comparing the clinical trial physician (PR) to the independent video evaluator. This shows a lower score due to CR. As shown in Figure 51, initially, all items were treated. It was scored relatively lower by independent video evaluators compared to the physicians conducting the trial. Secondly, More importantly, some items showed particularly large differences in scores. These items were: Leg tremors, tremors associated with standing, facial tremors, and tongue thrusting (Tp2: facial tremor; Tp3 :Voice tremor; Tp5Al:Extended left lower limb; Tp5Ar:Extended right lower limb; Tp9:When standing ). Consistent with these observations, the groups and investigators evaluated by independent video evaluators ANOVA, which compares the groups evaluated by the instructor for each individual item, showed 14 out of 19 items. The study showed a statistically significant difference (p-value < 0.05). This was observed in leg tremor, orthostatic tremor, and fine tremor. All relevant items reached significance. Interestingly, the discrepancies were due to the scores of specific items. The magnitude of the difference appears systematic in that it was consistently maintained between visits. Furthermore, items 5Al and 5Ar consistently showed significant differences in scores across all visits (Figure 5). 1. Lower panel).

[0317] Clinically significant differences in clinical laboratory parameters between the CX-8998 group and the placebo group. It was not detected. Clinical findings in vital signs, ECG, or neurological and physical examinations. No significant anomalies occurred.

[0318] Example 26: Formulation of CX-8998HCl salt and CX-8998 free base The CX-8998IR formulation releases as much CX-8998 as possible as rapidly as possible. Pressing to produce beads containing -8998HCl salt or CX-8998 free base Exemplary CX-8998IR formulations were prepared using extrusion molding / spheroidization.

[0319] In one experiment, the sample contained either CX-8998HCl salt or CX-8998 free base. The formulations used are shown in Table 35.

[0320] [Table 48] The release profile is shown in Figure 54A.

[0321] Formulations containing microcrystalline cellulose, which are typically used in IR formulations of other active ingredients, Approximately 80% of the CX-8998 were released, and it took an hour to achieve this level of release.

[0322] In one experiment, the formulations containing CX-8998 free base are shown in Table 36.

[0323] [Table 49] The release profile is shown in Figure 54B.

[0324] A formulation containing lactose monohydrate (for example, one that does not contain microcrystalline cellulose) It released over 80% of its CX-8998 within 20 minutes.

[0325] Example 27: CX-8998 bead formulation that does not contain microcrystalline cellulose Microcrystalline cellulose is typically used in drug beads formed by extrusion / spheroidization. It is an important component. It does not contain microcrystalline cellulose and provides rapid release of CX-8998. The formulation is provided in Table 37. The dissolution results of this formulation are shown in Figure 55.

[0326] [Table 50]

[0327] BHA and BHT are dissolved in ethanol in the first beaker, while citric acid and SL are added. S and HPC were dissolved in water in the second beaker. The two solutions were combined, and the remaining The ingredients were sprayed and mixed in a V-blender to form a paste. Then, the paste The material was extruded using an extrusion molding machine, and the extruded material was immediately transferred to a spheroidizing device. The resulting moist material The drug beads were dried in a fluidized bed dryer.

[0328] Example 28: CX-8998 Delayed-Release (DR) Bead Formulation The CX-8998 DR formulation is an optional treatment in which the release of CX-8998 after administration is significantly delayed. It may be a composition of the same name. The emission of CX-8998 from the composition of this example is 6.0-6. This can be controlled by applying a pH-sensitive coating that targets dissolution within a pH range of 5. The composition is shown in Table 38.

[0329] [Table 51]

[0330] The core beads were prepared as described in Example 27. The dried beads were then processed in Wurster The above was suspended in 95% isopropanol after being placed in a fluidized bed dryer equipped with an insert. The coating was applied by spray coating with the coating components. This continued until the mass was approximately 20% of the mass of the uncoated beads. (Residual solvent included) The beads were dried in a fluidized bed dryer until the quantity was very small.

[0331] Example 29: CX-8998 Delayed-Release Bead Formulation (Slower Release) Another delayed-release bead formulation targets slower release in the intestinal tract. The composition of this formulation... This is shown in Table 39.

[0332] [Table 52]

[0333] The core beads were prepared as described in Example 27. The dried beads were then processed in Wurster The above coating components were placed in a fluidized bed dryer equipped with an insert and suspended in purified water. The coating was applied by spray coating. In spray coating, the mass of the coating is the coating This continued until the mass of the undried beads was reduced to about 20%. The beads were then dried in a fluidized bed dryer. Set.

[0334] Example 30: 8 mg of CX-8998 controlled-release capsules for twice-daily administration. By combining the immediate-release beads of Example 27 with the delayed-release beads of Example 28 A controlled-release formulation was produced. Approximately 12 capsules were filled into size 0 hard gelatin capsules. 8 mg of immediate-release beads and approximately 104 mg of delayed-release beads were manually filled. Each filled capsule contained 8 mg equivalent of CX-8998 free base.

[0335] Example 31: 8 mg of CX-8998 controlled-release capsules for a single daily dose. By combining the immediate-release beads of Example 27 with the delayed-release beads of Example 29, A controlled-release formulation was produced. Approximately 85mg per capsule was encapsulated in a size 0 hard gelatin capsule. The immediate-release beads (mg) and the delayed-release beads (approximately 158 mg) were manually filled. Therefore, Each filled capsule contained 8 mg equivalent of CX-8998 free base.

[0336] Example 32: 20 mg of CX-8998 controlled-release capsules for twice-daily administration. By combining the immediate-release beads of Example 27 with the delayed-release beads of Example 28 A controlled-release formulation was produced. Approximately 3 capsules were filled into size 00 hard gelatin capsules. 20 mg of immediate-release beads and approximately 260 mg of delayed-release beads were manually filled. Therefore Each filled capsule contained 20 mg equivalent of CX-8998 free base.

[0337] Example 33: 20 mg of CX-8998 controlled-release capsules for twice-daily administration. By combining the immediate-release beads of Example 27 with the delayed-release beads of Example 29, A controlled-release formulation was produced. Approximately 21 capsules were filled into size 0 hard gelatin capsules. 2 mg of immediate-release beads and approximately 395 mg of delayed-release beads were manually filled. Each filled capsule contained 20 mg equivalent of CX-8998 free base.

[0338] Example 34: Dissolution of MR1 20 mg capsules The capsule described in Example 32 was dissolved in 3% T in 0.1N hydrochloric acid in a USP Type 2 dissolving apparatus. The solution was administered in a medium containing ergitol for 2 hours, followed by 3 hours in a pH 6.8 phosphate buffer solution. The test was conducted for 12 hours in a medium containing % tergitol. Average data are presented in Table 40. To provide.

[0339] [Table 53]

[0340] Example 35: Dissolution of MR2 20 mg capsules The capsule described in Example 33 was dissolved in 3% T in 0.1N hydrochloric acid in a USP Type 2 dissolution apparatus. The solution was administered in a medium containing ergitol for 2 hours, followed by 3 hours in a pH 6.8 phosphate buffer solution. The test was conducted for 12 hours in a medium containing % tergitol. Average data are shown in Table 41. To provide.

[0341] [Table 54]

[0342] Example 36: Pharmacokinetics of the CX-8998 formulation The bead formulations of Examples 27-29 were evaluated for their solubility. IR, MR1, and MR2 The dissolution rates are shown in Figure 56. These rates were obtained for IR, MR1, and MR2 at 40°C / 75%RH over 10 days. Figure 57 shows the dissolution rate after storage or after 10 days of storage at 5°C.

[0343] The dissolution rate of bead formulations was used for PK modeling. The in vitro release profile was input into a PK model developed based on IR data. As separate two-compartment models for the elderly and non-elderly ("younger"), PK modeling was performed on the bead ratio and total dose. Different ratios of IR and MR1, as well as Different ratios of IR and MR2-mediated PK can be predicted. The total dose is the target C max , C min , or C ave It can be optimized based on this.

[0344] The combination of IR and MR1 in elderly individuals over a 7-day time course and in a steady state. The dissolution rate of se is shown in Figure 58. 60%IR / 40%MR1 shows rapid uptake (low t ma x ) and C max A decrease was demonstrated.

[0345] IR and MR2 / CR7 in elderly patients over a 7-day time course and in a steady state. Figure 59 shows the dissolution rates of the combinations. 60%IR / 40%MR2 / CR7 is rapidly dissolving. (low) tmax ), C max We demonstrated a reduction and extension of the duration.

[0346] Combinations of IR and MR1 in non-elderly individuals over a 7-day period and in a steady state. The dissolution rate of the mixture is shown in Figure 60. 60%IR / 40%MR1 is C max It demonstrated a decline. However, it did not demonstrate an improvement in duration of action compared to IR.

[0347] IR and MR2 / CR7 in non-elderly individuals over a 7-day period and at a steady state. Figure 61 shows the dissolution rates of the combinations. 60%IR / 40%MR2 / CR7 is used by non-elderly individuals. The study demonstrated a favorable ratio among the subjects.

[0348] Example 37: Combination of CX-8998 prototype formulation The profiles between BID and QD (sustained-release) are similar, and the minimum value for therapeutic effect is... To achieve this, and to maintain the target concentration within the ideal range only during the time when BID and QD are occurring. Relative bioavailability testing is used to ensure that the maximum permissible concentration is avoided. It can be done.

[0349] The simulation was performed using 40% IR, 25% MR1 (pH 6), and 35% MR2 / CR. The treatment was administered using a formulation containing pH 7, in doses of 25 mg, 15 mg, and 8 mg. The simulated dissolution rates for various dosage forms are shown in Figure 62.

[0350] [Table 55]

[0351] [Table 56]

[0352] Example 38: Clinical pharmacokinetics of CX-8998 formulation Biomedical use to evaluate the pharmacokinetics of various CX-8998 formulations in human subjects. A performance test was conducted.

[0353] method This is based on two CR trials comparing the initial IR capsule formulation with a maximum of 15 participants. The safety, tolerability, and PK of the drug were evaluated in an open-label, single-dose, randomized, 3-way crossover study. This is a single-center trial. Participants must meet the eligibility criteria for the trial within 28 days prior to the administration of the first dose of the investigational drug. Screening will be conducted for this. Subjects who meet the eligibility criteria for the study will be screened before the administration of the first dose of the investigational drug. I was admitted to the clinical research unit in the afternoon of that day (period 1 / day 1). I continued to meet the trial eligibility criteria. The subjects were randomized to a treatment sequence and received a single 8 mg dose of CX-8998. Each treatment is administered in a randomized order, with a minimum washout period of 7 days between treatments. This is separated from the previous procedure: The first IR capsule under fasting conditions (four capsules, each containing 2 mg of CX-8998) Capsule) (Treatment A), CR test formulation #1 (IR beads and controlled release type 1 [MR1] beads) under fasting conditions A multi-particle capsule formulation containing 8 mg of CX-8998 (Treatment B), and CR test formulation #2 (IR beads and controlled-release type 2 [MR2] beads) under fasting conditions A multi-particle capsule formulation containing 8 mg of CX-8998 (Treatment C). CR test formulation #2 (IR beads and controlled-release type 2 [MR2] beads) under dietary intake conditions A multi-particle capsule formulation containing 8 mg of CX-8998 (Procedure D).

[0354] Procedures A, B, and C are separated by a washout period of at least 7 days. Procedure A, The subjects receiving B and C are those who have undergone the CR test formulation #2 (treatment D) under dietary intake conditions. Additional treatments may also be administered. Treatment D is administered after the first three treatments. The administration of treatments A, B, and C is separated by approximately four weeks to allow for the analysis of the sample. .

[0355] 1. Treatment The following is a list of abbreviations for test procedures and their order of use in TFL. [Table 57]

[0356] 2. Sample Size Design In two previous single-dose PK trials, the average performance after a single dose of 12 mg of CX-8998 was observed. The average inter-patient coefficient of variation (CV%) is the observed maximum plasma concentration (C max ) about 21 The percentage ranged from % to 35%, and the area under the curve (AUC) ranged from 22% to 26%. (Trials PN001 / Part 1 and PN002 / Part 2). Inter-patient variability was 18% (single Assuming that 35% is approximately ...

Claims

1. A pharmaceutical composition comprising a Cav3 antagonist, to be administered orally once daily to a person having a motor disorder, for use in the treatment of the person, The aforementioned Cav3 antagonist is CX-8998 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprises a controlled-release component containing the Cav3 antagonist and an immediate-release component containing the Cav3 antagonist. When the pharmaceutical composition is administered to a human once daily, the maximum plasma concentration (Cmax) of the Cav3 antagonist, calculated by dividing it by the mean plasma concentration of the Cav3 antagonist 24 hours after administration, is ( 【Chemistry 2】 The pharmaceutical composition is effective in maintaining the ratio between approximately 1.0 and approximately 5.

0.

2. The pharmaceutical composition according to claim 1, wherein the plasma concentration of the Cav3 antagonist is the plasma concentration at a steady state.

3. The pharmaceutical composition according to claim 1 or 2, wherein the Cav3 antagonist is a hydrochloride salt.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the controlled-release component comprises a plurality of particles containing the Cav3 antagonist or a pharmaceutically acceptable salt thereof, and comprises a coating containing a pH-sensitive enteric polymer.

5. The pharmaceutical composition according to claim 4, wherein the pH-sensitive enteric polymer has a dissolution pH of approximately 5.5 to 7.

6. The pharmaceutical composition according to claim 5, wherein the pH-sensitive enteric polymer has a dissolution pH of approximately 7.

7. The pharmaceutical composition according to any one of claims 4 to 6, wherein the particles in the controlled release component are beads.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition contains an immediate-release component comprising the Cav3 antagonist or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, comprising approximately 40% of the immediate-release component and approximately 60% of the controlled-release component.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the immediate-release component comprises a plurality of particles containing the Cav3 antagonist or a pharmaceutically acceptable salt thereof, and the particles in the immediate-release component are optionally beads.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein each of the immediate-release component and the controlled-release component further comprises lactose monohydrate.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the movement disorder is essential tremor or tremor associated with Parkinson's disease.

13. The pharmaceutical composition according to claim 12, wherein the aforementioned movement disorder is essential tremor.

14. The pharmaceutical composition according to claim 12, wherein the movement disorder is a tremor associated with Parkinson's disease.

15. The pharmaceutical composition according to claim 14, wherein the treatment is effective in reducing or eliminating tremors associated with Parkinson's disease.

16. The pharmaceutical composition according to claim 1, which is administered within four hours of the patient waking up.

17. The pharmaceutical composition according to claim 1, wherein the human is an adult.

18. The pharmaceutical composition according to claim 14, wherein the adult is 18 years of age or older.

19. The pharmaceutical composition according to claim 1, wherein the unit dose of the pharmaceutical composition contains about 0.5 mg to about 20 mg of the Cav3 antagonist or a pharmaceutically acceptable salt thereof.

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