TW200944205A - Compositions, kits and methods of a titration schedule for pardoprunox compounds - Google Patents

Abstract

The present invention is directed to compositions, kits, and methods for a titration schedule to facilitate the treatment of a central nervous system condition or disorder by administering a plurality of dosage units of a composition comprising a compound 7-(4-methyl)-1-piperazinyl-2(3H)-benzoxazolone (INN pardoprunox).

Description

200944205 VI. INSTRUCTIONS: FIELD OF THE INVENTION 5 Ο 10 [001] The present invention relates to a compound containing 7-(4-mercapto)-1 -piperidinyl-2(3H)-stupid with a multi-dose unit Compositions, kits and methods of administration of oxazolone (INNM salt padoprunox) or a combination thereof to promote treatment of central nervous system (CNS) conditions or disorders. t: Prior Art 3 Background of the Invention [002] The compound 7-(4-methyl)-1-° thiophene-2(3H)-benzone. Sit _ (INN Padonuo) as follows:

15 [003] WO 00/029397 describes and claims the above formula (ie 7-(4-mercapto)-1-° bottom β well base-2(3H)-benzo- ace "sit" The right of the hydrochloride. In addition, W005/107754 also describes and claims the right to deliver pardurno hydrochloride by iontophoresis. Both WO 00/029397 and W〇〇5/l〇r754 are incorporated herein by reference. [004] Parkinson's disease (PD) is a neurodegenerative condition that produces progressive damage to both motor and non-motor function. Current dopaminergic treatments target PD synthesis 200944205 but can also induce annoying symptom fluctuations and dyskinesias. These effects may be caused by pulsed stimulation of dopamine receptors (Nutt et al., Trends Neurosci 2000; 23 (10 Suppl): S109-S115; Olanow et al., Trends Neurosci 2000; 23 (10 Suppl): S117-S126 Therefore, the concept of dopamine system is receiving attention because it avoids under-stimulation and over-stimulation. Some dopamine agonists exert agonism in brain regions with low dopamine stress, while under high dopamine tension conditions Exerting a nodgic effect (McCreary et al., In: Ronken E, van Scharrenburg GJM, 10 editors. Parkinson's disease (Solvay pharmaceutical conferences). USA: IOS Press; 2002: 51-58; McDougall et al., Psychopharmacology 2005; :431-439; Koller and Herbster, Neurology 1987;37(4):723-727). Therefore, these formulations have the potential to provide full efficacy against PD during maintenance therapy while avoiding receptor "over-stabbing" And related adaptive changes, these are characteristic of full agonists. In addition, avoiding excessive receptor stimulation can also reduce the occurrence of typical dopaminergic adverse events (AEs) such as dyskinesia (McCreary et al. In: Ronken E, van Scharrenburg GJM, editors. Parkinson's disease (Solvay Pharmaceuticals conferences). USA: IOS Press; 20 2002: 51-58.). Although some dopamine agonists have also been studied for the treatment of PD (Lieberman et al. ,NeuiOlogy 1987; 37(5): 863-865.; Verhagen Metman et al., Mov Disord 1994; 9(5): 577-581; Ruggieri et al., Clin Neuropharmacol 1991; 14(5): 450-456 ), but remains to be studied for clinical value. 200944205 [005] Leg Hyperactivity Syndrome (RLS) is a sensorimotor disorder characterized by uncontrollable leg movements. This impulse is accompanied by pain and unpleasant feelings. It is often worse (Martin, Consult Pharm. 2007, 22(11), 907 24). The goal of /alpha therapy rls is to alleviate the main symptoms of the disorder and establish normal sleep. Dopamine agonists are artificially first-line treatment (Winkelman et al) Geriatrics 2007, 62(10), 13-6). However, the dose of dopamine agonist for RLS is much less than the dose used to treat pd. Dopamine agonists are most likely to be used to treat RLS at a daily dose that is significantly lower than the dose required to treat symptoms of motor PD. Gabapentin and Crow 10 tablets are longer than treatment for refractory cases. [006] Padonuno (7_(4-A) Base)-1_. Bottom cultivating base_2(3H)-benzoxazole' 嗣, also known as SLV308) is a partial dopamine D2 and D3 receptor agonist with full 5-HT!A agonist activity (Glennon Et al” Synapse 2006; 60: 599-608). Animal model studies have shown that Padonuno has significant and long-lasting anti-PD effects, and there is evidence of antidepressant and anti-anxiety effects (McCreary et al., In: Ronken E, van Scharrenburg GJM, φ editors. Parkinson's disease (Solvay Pharmaceuticals conferences). USA: IOS Press; 2002: 51-58; Johnston et al., Mov Disord 2005; 20(S 10): P16: Poster). Therefore, since Padolu 2 is well tolerated by healthy human subjects, it is prudent to verify that Padonuno has the utility of treating PD. [007] As described above, the compound is well tolerated during the clinical study of the drug of patoprinoline hydrochloride, but undesired adverse events (such as nausea, vomiting, and high erectility may occur during the start of treatment). Blood pressure), said not 5 200944205 Good event may lead to treatment interruption and / or patient non-compliance treatment plan under some circumstances. Therefore, there is a need to not only reduce these undesirable side effects at the beginning of the treatment, but also to ensure that the patient is compliant with the treatment plan. It has been surprisingly found that these 5 side effects can be prevented by initially administering 5 doses at very low dose levels below the maintenance level and by gradually increasing the dose of the patopol compound according to the particular administration schedule. At least - kind. [008] As used herein, the term "padorenol compound," refers to the active compound 7-(4-methyl)-1-° bottom '1 well base-2(3H)-benzo. Oxides and pharmaceutically acceptable salts, solvates and hydrates thereof, and solvates and hydrates thereof, in accordance with the invention. "At least one padorino compound, as used herein, means one or more of the above active compounds. A mixture of the above active compounds. The pharmaceutically acceptable salt of Pardonuol or its N-oxide can be obtained by using standard methods well known in the art (for example, by mixing the compound of the present invention with a suitable acid (e.g., mineral acid or organic acid). 15 SUMMARY OF THE INVENTION Summary of the Invention [009] The present invention relates to the use of a compound containing a Padozoine (such as the compound 7-(4-methyl)-1-branched base-2(3H)-stupid and evil A multi-dose unit of oxazolone to promote a composition, 20 sets, and methods of administration of a CNS condition or disorder. For example, the present invention relates to a composition scheme for promoting a drug dosage regimen for treating a central nervous system condition comprising a plurality of composition unit doses, each of said unit doses comprising at least one padorino compound wherein said unit dose The amount of the at least one padurno compound is increased throughout the dosage regimen. 200944205 [010] The present invention also discloses a kit for administering a dosage regimen for promoting M neuropathy in a treatment comprising a plurality of composition unit doses, the single 'S dose comprising at least one species of Pakino a compound wherein the unit dose is increased by 5 plus 0 over the entire dosage regimen by the amount of the at least one partonuol compound [011] The present invention also relates to a central nervous system for treating a subject in need thereof A method of administering a systemic condition comprising administering to a subject a composition regimen comprising a plurality of said unit doses, each of said unit Φ doses comprising at least one padonuone compound, wherein said unit The dose is increased by the amount of the at least one padurno compound in 10 entire dosing schedules. Finally, the present invention also discloses a method of reducing at least one side effect associated with the initiation of treatment with patoprino (such as nausea, vomiting, and orthostatic hypotension), comprising administering a composition regimen comprising a plurality of composition unit doses, each The unit doses comprise at least one of the padonuone compounds, wherein the 15 unit dose is increased by the amount of the at least one padonueno compound throughout the dosage regimen. © [〇12] The term "administration schedule" as used herein, refers to a pharmac active agent time-course dosage regimen based in part on a target dose and/or a maintenance dose. [013] Padourino compounds are used to treat cns disorders, such as Emotional barriers 20 disorders, leg hyperactivity syndrome, and Parkinson's disease. The dosage specifications in the present invention are expressed in terms of padourin base equivalents. As used herein, the term "paladolinol, refers to compound 7-(4-methyl H). - ° Chen " Wells-2 (3H) - stupid and oxazolone (INN Padano), as follows: 7 200944205

The term "specification" refers to the amount of active ingredient present in a pharmaceutical agent. A typical dosing regimen is equivalent to a dose of 0.1 mg to 12 mg, but it can also be administered at a higher dose (eg, to a dose equivalent to 42 mg of papadonol/indole); it may be based in part on the patient's 5 CNS condition and other conditions. The severity changes the dose. [014] For example, the dose (target dose and/or maintenance dose) of the padurno compound may be equivalent to 3.3 mg of parandipine/day, 0.6 mg of padoruno/day, 0.9 mg of pado. Lunau/Day, 1.2mg Padoluol/Day, 1.5mg Padourinoline/Day, 3.0mg Padoreline/Day, 4.5mg Padourinoline/曰, 10 6.0mg Pa Prolific test / day, 9.0mg Pado production test / day, 12.0mg Pado production test / day, 15.0mg Pado production test / day, 21.0mg Padoluo test / day, 24.0mg Pa Dorothy 絵7曰, 27.0mg Padoluol test / 曰, 30.0mg Pado 诺 test / day, 36.0mg Padoluo test / day or 42.0mg Padogeno test / 曰 dose. The sputum dose can be achieved by administering the same unit dose or different unit doses 15 times, twice or three times. In clinical studies, the efficacy, safety, and tolerability of padonuone suggests that it is an effective formulation for the treatment of patients with early and late Parkinson's disease and leg hyperactivity syndrome. Despite the efficacy, safety, and tolerability of pasaleno treatment, it can lead to adverse events during the initiation of treatment, leading to discontinuation of treatment and/or inconsistent therapeutic use. As used herein, the term "isolated unit of -4, abutarum dose" means a quantity of active ingredient such as a tablet or capsule. [016] The day or (four) day of administration of the dosage unit dosage form of the papadlonol in the dosage regimen, the application schedule may be selected, for example, from 3-84 consecutive days, such as 3-H, and may also be, for example, 3 ~49n u Segmentation time history, "Day. It is also possible to segment the time unit in a single time unit or even in a time unit of seven or two, three, four, five, and six time units. In this case In the following, the same unit dose of the Padorino compound can be used in the dosage meter. Days, 4th, and 5th^" time units of different durations, such as 1st, 2nd, 3rd It can be a combination of 3-20, "day and 7th time units. The number of time units and the dosing plan are, for example, 4, 5, 6, 7, 8, 1 (), 12 or 15 For example, the dosing schedule can be based on the target and/or maintenance dose; for example, depending on the patient's disease and condition and/or age and/or gender, low target and/or dose Elevate across many days (such as 56 days), or by the more Pato:: doses and shorter durations (such as 3 曰). Each unit dose increases the size or amount of the m compound with the next The dosage plan is to gradually increase the dose to the target dose and/or the maintenance dose. In addition, it is also possible to give an overall increase in the size and quantity of the agent ==:=1. For example, the first unit dose is compared before the first dose. The unit dose and the final unit dose, the amount of the compound is increased. The first low dose of the start of the dosing regimen has the equivalent of ο.1 or 0, the dose of the white test, the dose is Divided into 1, 2 or 3 unit doses. In the present invention, all mosquito doses or specifications are based on daily administration of 3 unit doses. The daily dose of the daily dose of the Paderino compound 200944205 is divided into 2 unit doses. The specified unit dose is multiplied by 1.5; when a daily dose of the padurno compound is administered in a single dosage unit, the specified unit dose is multiplied by 3. In some embodiments, the dosage regimen begins with - The first dose (denoted as number 0) is administered in a single dose. [017] In one embodiment, each of the composition unit doses is selected from the group consisting of from about 0.025 mg to about 0.075 mg, from about 0.075 to about 0.15. Mg, from about 0.15 mg to about 0.25 mg, from about 0.25 mg to about 0.35 mg, from about 0.35 mg to about 0. 45 mg, from about 0.45 mg to about 0.55 mg, from about 0.55 mg to about 0.65 mg, from about 0.65 mg to about 0.8 mg, from about 0.8 mg to about 1.2 mg, from about 1.2 mg to about 1.7 mg, from about 10 to 1.7 mg to about 2.2. Mg, from about 2.2 mg to about 2.7 mg, from about 2.7 mg to about 3.5 mg, from about 3.5 mg to about 4.5 mg, from about 4.5 mg to about 5.5 mg, from about 5.5 mg to about 6.5 mg, from about 6.5 mg to about 7.5 mg. A single gauge dose of from about 7.5 mg to about 8.5 mg, from about 8.5 mg to about 9.5 mg, from about -9.5 mg to about 11 mg, and from about 11.00 mg to about 13.0 mg of Padarino. When selecting each unit dose of a different specification, the specification may be the following specifications in the above listed group. In another embodiment, each of said composition unit doses is selected from the group consisting of from about 0.04 mg to about 0.06 mg, from about 0.08 mg to about 0.12 mg, from about 0.18 mg to about 0.22 mg, from about 0.28. Mg-about 0.32 mg, about 0.38 mg to about 0.42 mg, about 0.48 mg to about 0.52 mg, about 0.58 mg to about 0.62 mg, about 20 0.68 mg to about 0.72 mg, about 0.78 mg to about 0.82 mg, about 0.88 mg. - about 0.92 mg, about 0.98 mg to about 1.1 mg, about 1.3 to about 1.7 mg, about 1.8 mg to about 2.211, about 2.3111 § - about 2.711, about 2.811 - about 3.211, about 3.8 to about 4.2. Mg, from about 4.8 to about 5.2 mg, from about 5.8 to about 6.2 mg, from about 6.8 mg to about 7.2 mg, from about 7.8 mg to about 8.2 mg, from about 8.8 mg to about 9.2 mg, from about 9.8 mg to about 10.4 mg 10 200944205 and A single gauge dose of about ll'6 mg to about 12.4 mg of panotenoline. When selecting each unit dose of a different specification, the specifications may be the following specifications in the above listed group. [019] In another embodiment, the specification or amount 5 of each unit dose may be selected from the group consisting of about 5 mg, about 0.1 mg, about 0.2 mg, about 3 mg, about 0.4 mg, about 0.4 mg. 0.5 mg, about 6.6 mg, about 7.7 mg, about 1. 〇mg, about j 5 mg, about 2. 〇mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 5. 〇mg, about 60 mg An early specification dose of about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10 mg, and about i2. 020 [020] In the administration schedule, the unit dose may be about 1丨 to 3 times the amount or specification of the agent of the patopronol compound (may also be about 1.5-2.5 of the prodrug, for example). The magnitude of the increase is increased. For the first dose of the administration schedule, although there is no pre-agent, the previous dose can be estimated based on the remaining dose of the administration schedule. If desired, the dosing schedule can be provided in the form of a single unit dose to achieve the desired overall specification. [021] The specifications for the unit doses described in paragraphs [〇16]-[〇19] are based on a dose of 3 units per unit of administration. The specification should be multiplied by 1.5 when the unit dose is applied twice per sputum, and the specification should be multiplied by 3 when applied daily. The composition of the present invention may take the form of a kit comprising, for example, a plurality of unit doses in the form of tablets for administration of the final and/or maintenance dose. The present invention is also directed to a kit for promoting a treatment regimen for treating a central nervous system condition comprising a plurality of composition unit doses comprising at least one species of Pasanomycin, wherein said unit dose is given The amount of Padoban compound is increased during the medicinal process. The size or amount of each unit 11 200944205 dose can be selected from the different specifications listed above. In general, the dosing schedule for achieving the final maintenance dose selected to treat the symptoms of PD is very long in the dosing schedule for achieving a maintenance dose for the treatment of RLS. This is due to the fact that the daily maintenance dose of certain dopamine agonists required to treat RLS is significantly lower than the effective sputum maintenance dose of the phase dopamine agonist used to treat PD. When the padonuone compound is administered once daily, the dosing schedule for RLS will contain at least 3 unit doses, and at least 6 unit doses when administered daily for 2 times the papadonol compound, At least 9 unit doses are administered 3 times daily for the padurno compound. [023] In one embodiment, the kit comprises 6 unit doses corresponding to from about 0.08 mg to about 0.12 mg of pardonolino base, and 6 gauges corresponding to from about 0.18 mg to about 0.22 mg of Paddo. The unit dose of the ruinine, 9 gauges corresponds to a unit dose of about 0.28 mg to about 0.32 mg of padogeno, 9 gauges equivalent to a unit dose of about 0.38 mg to about 0.42 mg of panotenoline, 12 The 15 gauges correspond to a unit dose of about 0.48 mg to about 0.52 mg of Padarino, 9 gauges equivalent to a unit dose of about 0.68 mg to about 0.72 mg of Padarino, and 12 gauges equivalent to about 0.9 mg. - a unit dose of about 1.1 mg padarudino base, 21 gauges equivalent to about 1.4 mg to about 1.6 mg of the unit dose of the Padarino test and 21 specifications corresponding to about 1.9 mg - about 2.1 mg of Padre Unit 20 dose of the base. The kit optionally further comprises an additional unit dosage corresponding to a unit dose of from about 0.08 mg to about 0.12 mg of Padrino or a unit dose of three gauges corresponding to from about 0.04 mg to about 0.06 mg of Padoronol. [024] In a more specific embodiment, the kit comprises 6 units corresponding to a unit dose of about 0.1 mg Padolanol, and 6 units corresponding to about 200944205 0.2 mg of patopronol. The dosage, 9 specifications corresponds to a unit dose of about 3 mg of pardolinol, 9 units equivalent to about 4 mg of padolumine unit dose, 12 specifications equivalent to about 5 mg of parandipine The unit dose, 9 specifications correspond to a unit dose of about 7 mg padoreline base, 12 5 gauges equivalent to a unit dose of about LOmg pasqualino base, 21 specifications equivalent to about 1.5 mg padolu The unit dose of the base and 21 gauges correspond to a unit dose of the padurno compound of about 2.0 mg of panotenoline. The kit optionally further comprises an additional unit size equivalent to about 0.1 mg of partonalol base unit or 3 units equivalent to about 〇5 帕 5 mg of patricourone. [025] In yet another embodiment, the kit comprises 6 unit doses corresponding to a specification of from 0.08 mg to about 0.12 mg of pardonolino base, and six gauges corresponding to from about 0.18 mg to about 0.22 mg of Paddo. The unit dose of the ruinine, 9 gauges corresponds to a unit dose of from about 0.28 mg to about 0.32 mg of panotenoline, 21 gauges corresponding to a unit dose of from about 0. 48 mg to about 0.52 mg of palodoline and 21 15 The specifications are equivalent to about 98.98mg-about l.img of the unit dose of padurnoline, 21 specifications corresponding to a unit dose of about 1.4mg-about 1.6mg Paduoluo and 21 specifications equivalent to about A unit dose of a dorsolide compound of 1.9 mg to about 2.1 mg of panotenoline. The kit optionally further comprises an additional unit size corresponding to a unit dose of from about 0.08 mg to about 0.14 mg of pardolinol or three gauge phases of from 20 mg to about 0.06 mg of pardolino. The unit dose of the base. [026] In still more specific embodiments, the kit comprises 6 units corresponding to a unit dose of about 0.1 mg Papadonol, and 6 units corresponding to a specification of about 0.2 mg Padonuno. The dose, 9 specifications is equivalent to about 3. 3mg of the unit dose of pasqualino base, 21 specifications equivalent to about mg 5mg Padonuno 13 200944205 test unit dose, 21 specifications equivalent to m.Gmg Pado The unit dosage of sputum, 21 specifications corresponds to a unit dose of about 5 mg of padurnoline and 2 units of a pardurno compound equivalent to a unit dose of about 2.0 mg of panotenoline. The kit optionally further comprises an additional unit size equivalent to about 〇Jmg Pado 5 Renoline or a unit dosage of 3 specifications corresponding to about 0.05 mg of Pardonolidine. [027] In yet another embodiment, the kit comprises 6 unit doses corresponding to a specification of 0.08 mg to about 0.14 mg Padorino, and 6 gauges corresponding to about 0.18 mg to about 22.22 mg Pa The unit dose of doreline base, 9 specifications 10 corresponds to a unit dose of about 0.28 mg to about 0.32 mg of pardolinol and 21 gauges equivalent to about 0.48 mg-about 52.52 mg of parandipine. A unit dose of the padurno compound. The kit optionally further comprises an additional unit dosage corresponding to a unit dose of from about 0.08 mg to about 0.12 mg of pardolinol or a unit dosage of three gauges corresponding to from about 0.04 mg to about 0.06 mg of panotenoline. [028] In still more specific embodiments, the kit comprises 6 gauges

The cell is equivalent to a unit dose of about 0.1 mg Papadolol, 6 units corresponding to a unit dose of about 0.2 mg of panotenoline, and 9 units corresponding to a unit dose of about 3 mg of Q Padarino base. And a 21-unit equivalent of a unit dose of a padurno compound of about 〇5 mg Pado. The kit optionally further contains a specification other than 20, which corresponds to a unit dose of about 1 mg of partonuline or 3 gauges equivalent to a unit dose of about 0.05 mg of panotenoline. [029] In yet another embodiment, the kit comprises 18 unit doses corresponding to about 0.08 mg to about 1.2 mg of Pado, and 18 gauges corresponding to about 0.15 mg to about 〇25 mg. The unit dose of padolurine base, 18 gauge 14 200944205 is equivalent to a unit dose of about 0.25mg-about 35.35mg Padoluol, _ specification equivalent to about 〇.35mg-about 45.45m_多董The unit dose of the test, optionally including a unit dose equivalent to about 45.45mg' about 55mg Padonuno, 18 specifications equivalent to about Q55mg 'track 8 called Padono 5 test unit Dosage, job size is equivalent to about Q8mg about 丨, Pado production unit dose and 18 specifications equivalent to about 12mg_about 18 mailpay production unit dose. The kit optionally further comprises an additional unit size corresponding to a unit dose of from about 0.08 mg to about G.12 mg of padurano or three units corresponding to a unit dose of from about 0.04 rng to about 0.06 mg of panotenoline. . 10 [030] In a more specific embodiment, the kit comprises 18 unit doses equivalent to about G.lmg Pakano, and 18 gauges equivalent to about 0.2 mg of panotenoline. The unit dose, 18 specifications is equivalent to about mg3mg. The unit dose of the Padoyan test is equivalent to a unit dose of about 〇4 called Padoluno. It also optionally contains 18 specifications equivalent to about 5 kPa. The unit dose of the multi-M 15 no base, 18 specifications corresponds to a unit dose of about 7. 7 mg of panotenuline, 18 units equivalent to about i 〇mg Padonuo unit dose and 18 specifications equivalent A unit dose of a padoruno compound of about umg patoprinoline. The kit optionally also contains an additional unit size equivalent to about 〇1 mg of patopronol or a unit dose of three gauges equivalent to about 5 mg of Padreol. [031] In yet another embodiment, the kit comprises 12 unit doses corresponding to about 0.08 mg to about 2 mg of partonuline base, and 12 gauges corresponding to about 0-15 mg to about 0.25 mg. The unit dose of doxorubicin, 12 specifications corresponds to a unit dose of about 0.25 mg to about 35 mg of pardolinol, and 12 of 15 200944205 specifications correspond to about 0.35 mg to about 45.45 mg of parandipine. The unit dose, optionally containing 12 gauges equivalent to about 45'45mg^〇.55mg Padodon test. The unit dose, 12 specifications equivalent to about 〇55mg_about mg8mgPadulino® The unit dose, 12 gauges corresponds to a unit dose of about mg 瓜 瓜 丨 mg 2 mg # 多 鲁 诺 5 base and 12 units corresponding to a unit dose of about 1.2 mg to about 1.8 mg of patopronol. The kit optionally further comprises an additional specification corresponding to about 0.08 mg to about 〇. A unit dose of 12 mg of panotenoline or three gauges corresponds to about 0.04 mg to about 〇. 6 mg of patopronol. Unit dose. [〇32] In still more specific embodiments, the kit comprises 12 unit doses of β 10 gram equivalent to about l.1 mg of Pakano, and (2) solid size equivalent to about 0.2 mg of Paddo The unit dose, 12 specifications equivalent to __ Padoluno unit dose, 12 specifications equivalent to about 0.4mg Padonuo unit dose, and optionally contain 12 specifications equivalent to about 5 mail The unit dose of Padoluo test, 12 specifications is equivalent to about 〇7 called Pado's test of single-dose 12 specifications equivalent to *々1〇mg Padonuo unit dose and (2) solid specifications A unit dose of Pado disk that was called Pado's limb test at about 15 points. Optionally, the kit further comprises an additional unit size equivalent to about 0.1 mg of Padotun's test unit or 3 units equivalent to about 0_05 mg of Padogan. 2〇[〇33] In another embodiment, the kit comprises at least 3 compositions comprising increasing amounts of a padodano compound, and in yet another embodiment the kit comprises at least 7 An increasing amount of the composition of the padurno compound. [034] The unit dosage in the kits listed in the above paragraph [〇21]_[〇33] 16 The amount of the 200944205 quantity is based on the unit dose administered three times a day. When the unit dose is administered twice a day, the unit dose specification in the kit should be multiplied by 1.5, and when the unit dose is administered once a day, the unit in the kit The dose specification should be multiplied by 3. [035] The kit may take the form of a package, such as a blister pack or dispenser, comprising a plurality of tablets organized in a sequence that can perform the desired dosage schedule, and optionally including a maintenance dose, There are also indicia for displaying continuous gauges and/or consecutive days, for example, placed adjacent to the tablet. [036] In yet another embodiment, the kit may take the form of a package comprising a plurality of capsules, particulate aerosols, suppositories, and/or dispersing agents to form the unitary doses. The unit dosage can be prepared by mixing the padurno compound separately or together with an inert <pharmaceutically acceptable excipient, carrier and/or pharmaceutically acceptable ingredient. [037] may be by the active ingredient (such as the patoprino compound) and solid powder ingredients (such as lactose, sucrose, sorbitol, mannitol, house powder, amylopectin, cellulose derivatives, gelatin) or other suitable Ingredients, and with binders, disintegrants and lubricants (such as povidone, crospovidone, stearic acid, calcium decanoate, sodium stearyl fumarate and polyethylene glycol wax) Mixing to prepare the compositions of the present invention. The mixture can then be processed into granules, compressed into tablets and/or in any known pharmaceutical form such as suppositories and/or dispersing agents. [038] Soft gelatin capsules may also be formulated as a composition comprising a mixture of a carrier comprising an active ingredient of the invention, a vegetable oil, a fat or other suitable soft gelatin capsule. Hard gelatin capsules may contain granules of the active ingredient. The hard gelatin capsules may also contain the active ingredient and solid powder ingredients (e.g., lactose, cane, sugar, sorbitol, mannitol, malt potato starch, corn starch, amylopectin cellulose derivative or gelatin). .

Furthermore, the compositions of the present invention may comprise at least one pharmaceutical excipient. Non-limiting examples of suitable excipients include suspending agents (eg, tree gum, xanthan gum, cellulose, and sugar), moisturizing agents (eg, sorbitol), solubilizing agents (eg, ethanol, water, PEG, and poly). Ethylene glycol), surfactants (such as sodium lauryl sulfate, spar, Tween and cetylpyridinium), preservatives, antioxidants (such as parabens and vitamins E and C), elimination Blocking agents, coating agents, chelating agents (such as EDTA), stabilizers, antimicrobial agents, antifungal or anti-microbial agents (eg, parabens, tri-tert-butanol, phenol, sorbic acid), Isotonic agents (eg sugar, sodium vaporized), thickeners (eg methylcellulose), flavorings (eg chocolate, thalmantin, aspartame, root beer or watermelon or other flavors stable at pH 7-9) ), defoamer (eg, samarium oil, dimethyl tartaric acid), degumming agent, glidant, lubricant, adjuvant, colorant, diluent, 15 wetting agent, preservative, carrier, binder (eg hydroxypropyl decyl cellulose, polyethylene, pyrrolidone, other cellulosics and starch) , diluents (such as lactose and other sugars, starches, dicalcium phosphate and cellulosics), disintegrants (such as palace powder © polymer and cellulosic), glidants (such as colloidal oxime) and water-insoluble or water-soluble Lubricant. 20 [040] The active ingredient may be pre-mixed separately with other inactive ingredients prior to mixing the ingredients. The active ingredients may be mixed with each other before being mixed with the inactive ingredients. [041] Unless otherwise stated in the examples or elsewhere, all of the numbers 18 200944205 used in the present specification and the "monthly patents", which indicate the amount of active ingredient, reaction conditions, etc., are modified by ''about'. Numerical parameters appearing below and in the scope of the claims are approximations, and may vary depending on the needs of the present disclosure. Finally, it is not intended to limit the application of the equivalent principles within the scope of the present application. All numerical parameters are based on valid figures. The number and the conventional four 5 rounding method are processed. [〇42] Although the numerical range and the wide range of parameter settings are approximate processing, the numerical values appearing in the specific embodiment are also shown with the utmost precision. Contains the inherent error caused by the standard deviation introduced in the corresponding measurement process. The invention will be described by the following examples, but it is not intended to limit the scope of the invention. FIG. Treatment interruption results in the dose escalation group (♦) treatment discontinuation results in the smaller dose escalation group () and treatment discontinuation in the placebo group Fruit (▲) 〇 15 [Embodiment] Example 1 : Materials and Methods [043] The synthesis of Paddonia hydrochloride can be carried out according to w〇〇0/29397 and Drugs of the Future 2001, 26, 128-32. (7-(4-Methyl-1-piperidyl)-2(3H)- oxazolone hydrochloride). Commercially available pharmaceutical grade microcrystalline cellulose, poly-dimensional, cross-polymerization Vetidone, colloidal phthalic anhydride, sodium stearyl fumarate, microcrystalline cellulose and Opadry®. Example 2: Preparation of tablets of different specifications [044] The specifications were prepared according to the following method. -lOmgPado 19 200944205 Reynolds/tablet tablets (see Table 丨 and Table 2 for all specifications required): [045] Dissolve the patopronol hydrochloride in water to make 75 8 % The water-soluble liquid is used as a granulating liquid. [046] The required amount of microcrystalline cellulose, povidone and crospovidone are mixed. [047] The granulating liquid and the remaining water are added to the mixture, The mixture was granulated. [048] After drying, the granules were filtered using 1 mm rasp to give a homogeneous mixture. [049] The desired amount of colloidal phthalic anhydride and sodium stearyl alcohol fumarate were added to the ® 10 powder mixture and versus Mixing. [050] The final powder mixture was compressed into tablets having a core weight of 240 mg. - Table 1 Ingredients 0.1 mg Tablets 0.2 mg Tablets 0.3 mg Tablets 0.4 mg Tablets 0.5 mg Tablets 0.7 mg Tablets Reference 1 Quantity (kg) Padourol Hydrochloride 0.01445 0.02891 0.04336 0.05781 0.07228 0.1012 Microcrystalline Cellulose (Avicel PH102®) 28.000 27.990 27.980 27.960 27.950 27.930 Ph. Eur. Kollidon 25® 1.350 1.350 1.350 1.350 1.350 1.350 Ph Eur. vaginal ketone 0.300 0.300 0.300 0.300 0.300 0.300 Ph. Eur. Colloidal phthalic anhydride (Aerosil 200 Pharma®) 0.0300 0.0300 0.0300 0.0300 0.0300 0.0300 Ph. Eur. Sodium stearyl fumarate 0.300 0.300 0.300 0.300 0.300 0.300 Ph. Eur. Pure water 11.500 11.500 11.500 11.500 11.500 11.500 Ph. Eur. If the Ph. Eur quality standard cannot be used, USP/NF quality sample 20 200944205 can be used. Table 2 Ingredients l.Omg tablets 1.5mg tablets 2.0mg tablets Agent 4.0mg Tablets 6.0mg Tablets 8.0mg Tablets 10mg Tablets Reference 1 Ph.Eur tray, EUr Ph· Eur. Ph· Eur. Ph. Eur· Eur. Amount (kg) Padoruoline microcrystalline fiber Prime (Avi Cel PH 102®) Povidone (Kollidon 25®) crospovidone colloidal anhydride (Aerosil 200 Pharma®) stearyl sterol sodium fumarate pure water 0.1445 27.880 I. 350 0.300 0.0300 0.300 II. 500 0.2169 27.800 I 350 0.300 0.0300 0.300 II. 500 0.2891 27.730 I. 350 0.300 0.0300 0.300 II. 500 0.5781 27.440 I. 350 0.300 0.0300 0.300 II. 500 0.8673 27.150 I. 350 0.300 0.0300 0.300 II. 500 1.156 26.860 I. 350 0.300 0.0300 0.300 II 500 1.445 26.580 I. 350 0.300 0.0300 0.300 II. 500 If the Ph. Eur quality standard cannot be used, the USP/NF quality standard can be used. [051] A suspension of the desired Opadry 16 coating material was prepared in pure water. The tablets were coated by spraying with an Opadry® suspension of about 3 to 5% of the tablet core weight. Pack the product and inspect it. [052] All tablet specifications were prepared according to the corresponding method by reducing or increasing the amount of pasanoproton hydrochloride (compensated to the same final weight with a certain amount of microcrystalline cellulose), it is known to obtain for each tablet Different coating compositions were used for different colors of the formulation (see Tables 1 and 2). Other specifications can be prepared by the same method, including specifications of 〇.〇511^'〇.15111§, 0.611^, 0.911^, 1.2111§, 2.1mg, 3.0mg, 4.5mg, 7.5mg and 12.0mg. . Example 3: Clinical Studies [053] Different dosing schedules were used in different clinical studies. [054] Study in the Proof of Pnnciple 'p〇P) experiment (s3〇8.2.o〇4) based on double-blind use of placebo as a control (including 138 randomized and treated subjects) The effect of palines on monotherapy in the efficacy, safety and tolerability of early PD. After the solid-elastic elastic administration period (average duration of 24 days), the subjects were continued for ^ 21 200944205 with a maintenance dose for three weeks (9, 12, 15, 18, 24, 30, 36 or 45 mg/曰) . Each time the drug was administered orally three times (tid) (morning, noon, and evening), but any missed dose was administered. 5 10 15 20 [055] Submitted to the 3rd within 20 days by administering a combination of a single dosage unit or a single dosage unit according to a predetermined schedule of delivery of 〇.3mg/曰-9mg/曰 within 10曰. 〇mg/day dose of Padalino. Apply throughout the day

The daily dose is administered in the form of 3 dosage units. To a dose of 3 〇mg/曰, the administration is based only on tolerance, meaning that if well tolerated by the patient, the dose should be increased daily (to step 10) or at intervals (steps 10-14) (see Table 3). ). If the patient is unable to tolerate the daily dose due to a bad event, the dose to the patient should be reduced to the previous level (the administration step is slowed down by one step). At this point, the patient should be kept at the lower dose for 2 full days (at least 6 doses) and then try again at a higher level. In the morning, you need to lose the agent #. For a given dosing step, only one subsequent second N-return is allowed to be repeated. It is allowed to take 3 doses of the drug (in different administration steps). If the patient still determines the (four) scale after continuous test, the riding position will be reduced to 91. The dose level will not be allowed to enter the dose maintenance period. #ι眚维捭^痛职少9_日_量位准, The patient maintains this dose level during the full dose maintenance period. (4) Patients who are sexually permitted and expect more severe work's administration period lasts for 2 sides. Take: 2, continue to increase the dose to achieve the personal optimal maintenance dose (9: decrease in the required dose. Continued treatment) 3 weeks. Then reduce; the patient: during the period of withdrawal. 垔,. 2-4 weeks, and 1 week with 22 200944205 Table 3. Experiment S308.2.004 for the use of the Paloronol group昼 Dosing step Total sputum dose time 1 0.3mg 1曰2 〇.6mg 1曰3 〇.9mg 1曰4 1.2mg 1曰5 1.5mg 1曰6 2.1mg 1曰7 3.0mg 1曰8 4.5mg 1 a 9 6.0mg 1曰10 9,0mg 2曰11 12.0mg 2曰12 15.0mg 2曰13 18.0mg 2曰14 24.0mg 2曰15 30.0mg 3-4 days 16 36.0mg 3-4 days 17 45.0mg 3- 4th ❹

[056] Approximately 40% of subjects were treated with a dose of > 3 mg/day of padurano, of which approximately 16% reached the highest dose level of 45 mg/day, indicating that if good tolerance is maintained Receptive, a small group of subjects need to be administered a high dose of 5 to achieve sufficient efficacy. The efficacy results of the subjects treated with the doses of 9-15 mg/day, 18-30 mg/曰, and > 30-45 mg/day were further evaluated and plotted with dose/effect data, showing no significant efficacy. difference. However, the higher dose range and functional resolution of the experimental design using tolerance-based elastic doses were hindered. 10 [057] The results of Experiment S308.2.004 show that tolerance can be improved by reducing the rate of administration', which was applied in the following experiment S308.3.005. In this experiment (mainly safety trials), 62 subjects with PD (characterized by symptom fluctuations) were randomly assigned to one of three different treatment groups, namely 2 Pado 23 200944205 Reno treatment group ( The total daily dose was 3-4.3-42 mg, three times daily (1)): group 1 [25 subjects] and group 2 [26 subjects (4) placebo group [u-speaker-]. The experiment included a 7-week period of increasing dose of Padorino (for adjuvant treatment). The effects of two different dosing schedules on safety and financial affordability were studied and the dose and time and/or protocol adjustments required to treat L dopa were studied (see Figure 4). The difference between the two papalonol groups is the dosing step taken to achieve the main experimental dose level at the same time, called (weekly, larger dose increase) versus group 2 (every 3-4 days, smaller) The dose was increased to the same "last week, the main dose of pasanoquinol." In the more gradual administration group, more than 92% of the subjects (24 〇1 26 in 26) reached 18 mg / 曰 or The higher dose' and 65% (17 of 26) reached the final dose level of 42 mg/day. The higher dose group showed a higher rate of treatment interruption (see Figure 1, larger dose increase group). Treatment discontinuation results (♦) vs. treatment discontinuation in the smaller dose-increasing group (_) and treatment discontinuation in the placebo group (▲). 15 [〇58] In the smaller dose-increasing group to 18 mg/day dose During the course of the procedure (1 subject experienced an interruption of treatment at 6 mg/day), the treatment interruption rate due to treatment-related adverse events was 4%. In the 13 3〇mg/day of the exposure, '15% The tester (4 party testers) had no specific dose or administration step due to treatment-related adverse events, resulting in a treatment interruption rate greater than 2%. Untolerable. Limits the need for adjustment of LD〇pA in each treatment group. 24 200944205 Table 4. Dosing schedule for the S308.3.005 experiment. Papogenol total dose (mg) Zhou Yi group 1 group 2 Consolation Agent 1 0.3 0.3 Placebo 2 0.6 0.6 Placebo 3 0.9 0.9 Placebo 4 1.2 1.2 Placebo 5-6 1.5 1.5 Placebo 1 7-8 2.1 2.1 Placebo 9-10 3 3 Placebo 11-12 4.5 4.5 Placebo 2 13-15 6 6 Placebo 16-18 12 9 Placebo 3 19-21 12 12 Placebo dose level 1 22-24 18 15 Placebo 4 25-28 18 18 Placebo dose level 2 29-31 24 21 placebo 5 32-35 24 24 placebo dose level 3 36-38 30 27 placebo 6 39-42 30 30 placebo dose level 4 43-45 42 36 placebo 7 46-49 42 42 placebo dose Level 5

[059] Based on the results of the administration tolerance of experiments S308.2.004 and S308.3.005, the following conclusions were drawn in the design of the drug administration plan for the development of key clinical studies of Padono: 5 • Some patients can tolerate doses below 12 mg/day • 12-24 mg/曰 is acceptable financial support • 30-36 mg/day is judged according to individual patient needs • >45 mg/day can only be provided A negligible proportion of patients who can receive this dose 10 [060] For the vast majority of patients, the minimum effective dose is 12 mg / 曰. However, according to individual patients, as shown by the results of experiments S308.2.004 and S308.3.005, it is concluded that a significantly higher dose of Padolu 25 200944205 (to 42 mg/曰) is required to achieve efficacy. This results in the following dosing schedules to be used for the complete critical development program. Table 5. Dosing schedules used in the key program. Perindua sinensis dose (mg) 1 0.3 2 0.6 3 0.9 4 1.2 5-6 1.5 1 7-8 2.1 9-10 3 11-12 4.5 2 13 -14 6 15 6 16-18 9 3 19-21 12 Dose level 1 22-24 15 4 25-28 18 Dose level 2 29-31 21 5 32-35 24 Dose level 3 36-38 27 6 39 -42 30 Dosage level 4 43-45 36 7 46-49 42 Dosage level 5

[061] For the first critical trial of patients with early PD (experiment S308.3.001) 5 , two fixed-dose groups were compared (6 mg/day [n=115, group 1] and 12 mg/曰[n=118, Efficacy and safety of group 2]) and the elastic dose group (12-42 mg/曰 [n=116, group 3]) and the placebo group (n=119) in the efficacy and safety of patoprino (see Table 6 for administration) Counting). The dosing schedule used in Group 3 corresponds to the dosing schedule shown in Table 5. 10 [062] The initial measurement of UPDRS in all treatment groups was statistically significantly higher than in the placebo group, and the resistance was better in the 6 mg/day fixed-dose group than in the higher-dose group. 26 200944205 Table 6. Administration plan used in experiment S308.3.001 Total dose of pasqualorol (ms) Weekly group 1 group 2 group 3 placebo 1 0.3 0.3 0.3 placebo 2 0.6 0.6 0.6 placebo 3 0.9 0.9 0.9 placebo 4 1.2 1.2 1.2 placebo 5-6 1.5 1.5 1.5 placebo 1 7-8 2.1 2.1 2.1 placebo 9-10 3 3 3 comfort _agent 11-12 4.5 4.5 4.5 placebo 2 13-15 6 6 6 placebo 16-18 6 9 9 placebo 3 19-21 6 12 12 placebo dose level 1 22-24 6 12 15 placebo--- J 4 25-28 6 12 18 placebo dose level 2 29 -31 6 12 21 Placebo 5 32-35 6 12 24 Placebo dose 36-38 6 12 27 Placebo---L-1 6 39-42 6 12 30 Placebo dose level 4 43-45 6 12 36 Placebo — 1 | 7 46-49 6 12 42 Placebo dose level 5

063 [063] From this experiment, the minimum effective dose for patients with early ρρ was lower than the previously expected 12 mg/曰 in patients with early PD, and it was poorly tolerated for doses greater than 6 mg/day. [064] Based on these data, the drug delivery schedule was further modified to improve tolerance. Two doses of 6 mg/曰 dose were administered to patients with early PD at different rates as the highest dose for early pD patients. Compared with the protocol used in the experiment S308.3.001 (2 weeks), the drug delivery plan was slowed down more than 2.5 weeks (5 weeks to 6 mg/曰, and each dose was increased for 4 days). The slowest drug administration plan Slowed for more than 5 weeks (7 weeks to 6 mg / day, each dose increase is maintained for 6 days). Table 7 shows the dosing schedule. The dosage shown is a daily dose '3 doses, the third day exception' to the first single dose, preferably at night. 27 200944205 Table 7. Adding one dose per 4曰 and 6曰 to the final dose of 1.5, 3 and 6mg Padox (Pdx)/day for 2 dosing weeks a Final Pdx 1.5 mg/ d Administration 1 (mg/d) Final Pdx 3 mg/d Administration 1 (mg/d) Final Pdx 6 mg/d Administration 1 (mg/d) Final Pdx 1.5 mg/d Administration 2 (mg/d) ) Final Pdx 3mg/d administration 2 (mg/d) Final Pdx 6mg/d administration 2 (mg/d) 0 0.1 0.1 0.1 0.1 0.1 0.1 1 0.3 0.3 0.3 0.3 0.3 0.3 2 0.3 0.3 0.3 0.3 0.3 0.3 1 3 0.3 0.3 0.3 0.3 0.3 0.3 4 0.3 0.3 0.3 0.3 0.3 0.3 5 0.3 0.3 0.3 0.6 0.6 0.6 6 0.3 0.3 0.3 0.6 0.6 0.6 7 0.6 0.6 0.6 0.6 0.6 0.6 8 0.6 0.6 0.6 0.6 0.6 0.6 2 9 0.6 0.6 0.6 0.9 0.9 0.9 10 0.6 0.6 0.6 0.9 0.9 0.9 11 0.6 0.6 0.6 0.9 0.9 0.9 12 0.6 0.6 0.6 0.9 0.9 0.9 0.9 0.9 0.9 0.9 1.2 1.2 1.2 0.9 0.9 0.9 0.9 1.2 1.2 1.2 0.9 0.9 0.9 0.9 1.2 1.2 1.2 3 16 0.9 0.9 0.9 1.2 1.2 1.2 17 0.9 0.9 0.9 1.5 1.5 1.5 18 0.9 0.9 0.9 1.5 1.5 1.5 19 1.2 1.2 1.2 1.5 1.5 1.5 20 1.2 1.2 1.2 1.5 1.5 1.5 21 1.2 1.2 1.2 1.5 2.1 2.1 22 1.2 1.2 1.2 1.5 2.1 2.1 4 23 1.2 1.2 1.2 1.5 2.1 2.1 24 1.2 1.2 1.2 1.5 2.1 2.1 25 1.5 1.5 1.5 1.5 3.0 3.0 26 1.5 1.5 1.5 1.5 3.0 3.0 27 1.5 1.5 1.5 1.5 3.0 3.0 28 1.5 1.5 1.5 1.5 3.0 3.0 29 1.5 1.5 1.5 1.5 3.0 4.5 5 30 1.5 1.5 1.5 1.5 3.0 4.5 31 1.5 2.1 2.1 1.5 3.0 4.5 32 1.5 2.1 2.1 1.5 3.0 4.5 33 1.5 2.1 2.1 1.5 3.0 6.0 34 1.5 2.1 2.1 1.5 3.0 6.0 35 1.5 2.1 2.1 1.5 3.0 6.0 36 1.5 2.1 2.1 1.5 3.0 6.0 6 37 1.5 3.0 3.0 1.5 3.0 6.0 38 1.5 3.0 3.0 1.5 3.0 6.0 39 1.5 3.0 3.0 1.5 3.0 6.0 40 1.5 3.0 3.0 1.5 3.0 6.0 41 1.5 3.0 3.0 1.5 3.0 6.0 42 1.5 3.0 3.0 1.5 3.0 6.0 43 1.5 3.0 4.5 1.5 3.0 6.0 7 44 1.5 3.0 4.5 1.5 3.0 6.0 45 1.5 3.0 4.5 1.5 3.0 6.0 46 1.5 3.0 4.5 1.5 3.0 6.0 47 1.5 3.0 4.5 1.5 3.0 6.0 48 1.5 3.0 4.5 1.5 3.0 6.0 49 1.5 3.0 6.0 1.5 3.0 6.0 28 200944205 m 10 m [065 Based on identifiable disease progression and the aforementioned efficacy and tolerability results, the expected dose increase to 18 mg padurano/曰 is well tolerated by the late pd population because 92% of the subjects in the experiment S308.3.005 can This dose level is reached in the absence of financial or safety issues. Based on the efficacy results of Experiment S308.3.001, a dose of 6 mg/day or lower is also effective, but this may differ from the previously developed dopamine agonist in the advanced disease population. The effective dose range in the late PD population is expected to be private 12 days. For the patient population, the fastest 2 = g/day shown in Table 9 may be used. Add 2 weeks to reach the dose (see ^(9)

PDX

29 200944205 [066] If necessary, add one more dose to 18 mg/day (see Table 9). In this case, the dose at 49th will be 15mg. In another alternative embodiment, a single dose of 0.1 mg is substituted for 3 doses of 0.05 mg in a dose of 1 Torr. 5 Table 9. Additional dose schedule for late PD with a dose increase of 4 mg per day to a final dose of 18 mg Padox (Pdx)/day. Peripheral PDX administration 2 50 15 51 15 8 52 15 53 18 54 18 55 18 56 18

[067] The dosing schedule can be further optimized by simplifying the dosing step/increasing the dose to 3 mg/曰 over the first week. From the standpoint of tolerance, the steps of removing 1.2 mg/day and 2.1 mg/day in the above protocol are feasible, and finally simplifying the steps from 0.9 mg/day to facilitate the administration in clinical practice. Agent

Amount (see the dosing schedule of Table 10). Table 10. Simplified dosing 昼 weekly dose (mg) 1 0.15 early and late PD 2 0.3 3 0.6 4 1.5 5 3 I: simple description of the figure 3 Figure 1: treatment interruption results of the larger dose increase group ( ♦) Contrast smaller 30 200944205

Treatment discontinuation results in the dose escalation group () and treatment discontinuation results in the placebo group (▲). [Main component symbol description] (none) 31

Claims (1)

200944205 VII. Patent application scope: 1. A dosage form of a patoprinoline compound for obtaining a maintenance dose for treating a central nervous system condition after a period of time in which the dose of the compound of the patopronol compound is prepared. The composition used in the sputum comprises, in 5 ways, a composition unit dose of a plurality of said pasalino compounds, and each of said unit doses comprises at least one padodone compound, wherein said dosage regimen The period of time is divided into at least three time periods, and the dose of the at least one partonuol compound is increased in specifications throughout the dosage schedule for each time period. ® 10 2. The use of claim 1 in the scope of claim 1, wherein the number of time periods is at least 5. 3. For the use of the first item of the patent application, wherein the time period is selected from one day, two days, three days, four days, five days or seven days. 4. The use of claim 1 in the scope of claim 1, wherein the period of time is at least 2 inches. 15. The use of claim 1, wherein the unit dose is administered once daily, twice daily, or three times daily. Q 6. The use of claim 1, wherein the unit dose is selected from the group consisting of from about 0.025 mg to about 0.075 mg, from about 0.075 mg to about 0.125 mg, from about 0.15 mg to about 0.25 mg, and about 0.25 mg- About 0.35 mg, about 0.35 mg-20, about 0.45 mg, about 0.45 mg to about 0.55 mg, about 0.55 mg to about 0.65 mg, about 0.65 mg to about 0.8 mg, about 0.8 mg to about 1.2 mg, about 1.2 mg to about 1.7 mg, from about 1.7 mg to about 2.2 mg, from about 2.2 mg to about 2.7 mg, from about 2.7 mg to about 3.5 mg, from about 3.5 mg to about 4.5 mg, from about 4.5 mg to about 5.5 mg, from about 5.5 mg to about 6.5 mg. From about 6.5 mg to about 7.5 mg, from about 7.5 mg to about 8.5 mg, from about 8.5 mg to 32 200944205, about 9.5 mg, from about 9.5 mg to about 11 mg, and from about 11 mg to about 13.0 mg of Pado*. A single gauge dose of the Padoluol compound. 7. The use according to claim 1, wherein the unit dose is selected from the group consisting of from about 0.04 mg to about 0.06 mg, from about 0.08 mg to about 0.12 mg, from about 5 0.18 mg to about 0.22 mg, about 0.28 mg. - about 0.32 mg, from about 0.38 mg to about 0.42 mg, from about 0.48 mg to about 0.52 mg, from about 0.58 mg to about 0.62 mg, from about 0.68 mg to about 0.72 mg, from about 0.78 mg to about 0.82 mg, from about 0.88 mg to about 0.92 mg, from about 0.98 mg to about 1.1 mg, from about 1.3 to about 1.7 mg, from about 1.8111 L-@ about 2.2 mg, from about 2.3 mg to about 2.7 mg, from about 2.8 mg to about 3.2 mg, from about 3.8 to about 10. Mg, from about 4.8 to about 5.2 mg, from about 5.8 to about 6.2 mg, from about 6.8 mg to about 7.2 mg, from about 7.8 mg to about 8.2 mg, from about 8.8 mg to about 9.2 mg, from about 9.8 mg to about 10.4 mg and about A single gauge dose of 11.6 mg to about 12.4 mg of Padarino's Pardoluol compound. 8. The use of claim 1, wherein the unit dosage size 15 or amount can be selected from the group consisting of about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5. Mg, about 0.6 mg, about 0.7 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 A single gauge dose of mg, about 9.0 mg, about 10 mg, and about 12.0 mg of patopronol. 20 9. The use of claim 1 wherein, after the first dose of the first dose of at least one papadino compound is administered in the first period of time, the dosage specification of the patoprino compound for the next period of time is the previous period The dose is about 1.1-3 times. 10. The use of claim 1, wherein the Padonuno compound 33 200944205 is padurno hydrochloride. 11. A kit comprising at least three different compositions comprising increasing amounts of a padonuone compound'. — 12. The kit of claim 11 containing at least seven compositions containing an increasing amount of a Padarino compound. 13. The kit of claim 11 wherein said unit dose is selected from the group consisting of about 25 mg to about 0.075 mg, from about 0.075 mg to about 0.15 mg, from about 0.15 mg to about 0.25 mg, and about 0.25. Mg-about 0.35 mg, about 0.35 mg to about 0.45 mg, about 0.45 mg to about 0.55 mg, about 0.55 mg to about 0.65 mg, from about 0.65 mg to about 0.8 mg, from about 0.8 mg to about 1.2 mg, about 1.2. Mg to about 1.7 mg, from about 1.7 mg to about 2.2 mg, from about 2.2 mg to about 2.7 mg, from about 2.7 mg to about 3.5 mg, from about 3.5 mg to about 4.5 mg, from about 4.5 mg to about 5.5 mg, from about 5.5 mg. - about 6.5 mg, about 6.5 mg to about 7.5 mg, about 7.5 mg to about 8.5 mg, about 8.5 mg to about 9.5 mg, about 9.5 mg to about 11 mg, and about 11 mg to about 13.0 mg of Pado 15 Single-measurement dose of Padoluol compound. 14. The kit of claim 11 wherein said unit dose is selected from the group consisting of Q corresponding to from about 0.04 mg to about 0.06 mg, from about 0.08 mg to about 0.12 mg, from about 0.18 mg to about 0.22 mg, and about 0.28 mg. - about 0.32 mg, from about 0.38 mg to about 0.42 mg, from about 0.48 mg to about 0.52 mg, from about 0.58 mg to about 0.62 mg, from about 20 0.68 mg to about 0.72 mg, from about 0.78 mg to about 0.82 mg, from about 0.88 mg - About 0.92 mg, about 0.98 mg to about 1.1 mg, about 1.3 to about 1.7 mg', about 1.8 mg to about 2.2 mg, about 2.3 mg to about 2.7 mg, about 2.8 mg to about 3.2 mg, about 3.8 to about 4.2 mg. , from about 4.8 to about 5.2 mg, from about 5.8 to about 6.2 mg, from about 6.8 mg to about 7.2 mg, from about 7.8 mg to about 8.2 mg, from about 8.8 mg to about 9.2 mg, from about 9.8 mg to about 34, and from about 10.4 mg. A single gauge dose of 11.6 mg to about 12.4 mg of papadronol base. The kit of claim 11 wherein the unit dosage size or amount is selected from the group consisting of about 0.05 mg, about 0.1 mg, about 0.2 mg, about 5 0.3 mg, about 0.4 mg, About 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about A single gauge dose of 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10 mg, and about 12.0 mg of Padarino's Partonuol® compound. 10. The kit of claim 11, wherein the unit dose is in a size or amount selected from the group consisting of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, A single gauge dose of a Padorudino compound of about 0.7 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, and about 3.Omg of panotenoline. 15 17. The kit of claim 11, wherein the unit dose specification or amount is selected from the group consisting of about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.5 mg, and about 1.0 mg. A single gauge dose of Padoluol compound tested by Padoluno. 18. The kit of claim 11 wherein the dosage form of the pardurno compound of any specification other than the minimum specification is about 1.1 to 3 times the dosage of the previous specification. 19. The kit of claim 11, wherein the dosage form of the pardurno compound of any specification other than the minimum specification is about 1.5 to 2.5 times the dosage of the previous specification. 35 200944205 20. The kit of claim 11, wherein the padurano compound is padurno hydrochloride. 21. If the kit of claim 11 is applied, it is in the form of a blister pack or dispenser. 5 22. A composition for promoting treatment of at least one central nervous system condition comprising a plurality of unit doses according to a dosing schedule, wherein each of said unit doses comprises at least one padonueno compound, and Wherein the unit dose increases the amount of the at least one padonueno compound during dosing to achieve a maintenance dose. 36 200944205 IV. Designated representative map: (1) The representative representative of the case is: (1). (2) A brief description of the symbol of the representative figure: (none) 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: