TW200800198A - Pharmaceutical dosage forms and compositions - Google Patents

Abstract

The invention relates to, for example, novel formulations and methods for the delivery of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally related compounds and/or metabolites; as well as to use of these formulations and methods for treating disease.

Description

200800198 IX. Description of the invention: [Individuals in the field of technology] The relevant application is based on the priority of the US application No. 5 60/715,417 filed on September 9, 2005. The full text of the announcement is hereby incorporated by reference. FIELD OF THE INVENTION The present invention relates to, for example, novel formulations, and the delivery of each cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[[,4]dioxin- a method for the preparation of a compound, a pharmaceutically acceptable salt thereof, a structural phase 10 compound, and/or a metabolite; The use of the formulation and the method of treating the disease. BACKGROUND OF THE INVENTION The data of the daring has been established. 5-HT〗 A is related to the cognitive process. 15 See, for example, Schechter LE et al. (lec〇z〇tan) (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulatory release of glutamate and acetylcholine in the hippocampus and possesses cognitive enhancement properties, / corpse £7 314 ·· 1274-1289,2005. 5-111^ receptor antagonist (4-cyano-N-[(2R)-[4-(2,3-dihydrobenzo[1,4] Di- morphine-5-20-based) piperidine-1·yl]propyl]-N-pyridin-2-yl-benzoguanamine hydrochloride (Lendon), its multiple in vitro and in vivo It is characterized in pharmacological tests as a drug for the treatment of cognitive impairment. In-vitro bonding and intrinsic Sexual measurements have clarified that the scutellaria is a potent and selective 5-11 butyl receptor antagonist. It can be understood by using in vivo microdialysis, which is labeled with 肉3 mg/kg 皮5 200800198 Injection) can antagonize the extracellular 5-HT reduction in hippocampus induced by 8 ΟΗ-DPAT stimulation dose (0.3 mg/kg subcutaneous injection), and it has no effect at 10 times higher dose alone. Tan can significantly enhance the stimulating release of potassium citrate and acetaminophen in the dentate gyrus of the hippocampus. Slowly _ 5 doses of scutellaria will not be in the behavioral mode indications of body function' Inducer tolerance or de-allergic. In the drug identification study w, 'Liancai Tantan (0.01-1 mg / kg intramuscular injection) is not a substitute for 8-OH-DPAT, and can produce a dose-related 5- HT!a co-effector distinguishes thorn _ _#. In the age-treated rhesus monkey (aged rhesus monkey) 10, the deduction of meat can be at the optimal dose (1 mg / kg orally) Significant improvement in task performance efficiency. In the apes, it was induced by the glutamate antagonist MK-801. Insufficient learning (as assessed by perce^uaiiy c〇mpiex and visual spatial resolution) and by specific choline hormonal lesions in the hippocampus (assessed by visual spatial resolution) can be attributed to 2 15 g / kg intramuscular injection) to completely change. The heterosynaptic nature affected by the carcass can be used in Alzheimer's disease, the biochemistry of potential cognitive loss In the case of the disease, a novel mechanism of action is infused into the compound. Because 4_cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]di 2〇口f speaks-5-yl)-pai π well small base] · propyl Buxin 咬 _2 苯 酿 ( 列 列 列 列 列 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 , , , , , , , , , , , , , , , , , , It is important to provide formulations of these active ingredients to provide optimal bioavailability and efficacy. The present invention is directed to these and other important needs. 6 SUMMARY OF THE INVENTION The present invention provides, inter alia, a formulation comprising 4-cyano-1^-{(2 phan-2-[4-(2,3-diaza-benzoquinone [1,4] ]二1:1号11井-5_基)-旅11井-1_基]-5 propyl)-Ν-ϋ ϋ定ϋ-2-yl-phenylenamine (also referred to as the column ), its medically acceptable salts, structurally related compounds, metabolic products, and combinations thereof. " Compounds provided by the present invention include: 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl) - σ σ-1-yl]-propyl}-N-indole quinone-2-yl-phenyl-amine or its salt form of 10% acceptable (for example, 4-{(2R)-2 -[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piped-1-yl]-propyl-N-pyridin-2-yl-benzoguanamine Hydrochloride) and its structurally related compounds and metabolites, including but not limited to: {(2R)_2-[4_(2,3-diaza-benzo[1,4]di-n-5-yl) - 旅讲-1-yl]-propyl}-N-ntb唆-2-yl-amine or its pharmaceutically acceptable salt, 4-alkyl 15 -N_{(2S)_2-[4-( 2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piped-1-yl]-propyl}-N-pyridin-2-yl-benzoguanamine or its medicine An acceptable salt; 4 - gas group - N- (2 - . well · 1 -yl-propyl)-N-pyrene ratio. -2-2-yl-benzoic acid amine or a pharmaceutically acceptable salt thereof; Ν-(5-a-pyridin-2-yl)-4-cyano-indole-[2-(4-hydroxy-piped- 1-yl)-propyl]-benzoguanamine or a pharmaceutically acceptable salt thereof; 20 N-(5-chloropyridin-2-yl)·4·cyano-Ν-{2-[4·( 2,3_Dihydro-benzo[1,4] 2 亏 σ well-5-yl)-Bristo-1 -yl]-propyl}-phenylenamine or its happine acceptable salt; 4-cyano-indole-{(2ΙΙ)·2-[4-(8-hydroxy-2,3-dihydro-benzo[1,4]dioxin-5-yl)-Lv 11 well-1 -yl]-propyl}-Ν-σ ratio 11 -12-phenyl-phenylamine or its therapeutic 7 200800198 acceptable salt; 4-cyano-N-{(2R)_2-[4- (3-hydroxy-2,3-dihydro-benzo[1,4]dioxin-5-yl)·pipelined_ι_yl]-propyl}_N-acridine·2_yl-phenylhydrazine An amine or a pharmaceutically acceptable salt thereof; 5 4 _ cyano_n_{(2R)-2-[4-(2-hydroxy-2,3-dihydro- benzo[1,4] dioxin-5 · ))-piperidin-1-yl]-propyl}-indole-acridin-2-yl-benzoguanamine or a pharmaceutically acceptable salt thereof; 4-murine-N-(2R-2-Brigade ϋ well-1 -yl-propyl) 唆-2_yl-phenyl octaamine, its pharmaceutically acceptable salt; 10 4_ cyano_N-{(2R)-2_[4_(8_{l-[8_(( 4-{(lS)-2-[(4-cyanobenzyl)-pyridine-2- Amino]-1-methylethyl}piperidinyl)·2,3_dihydro-1,4·benzoindole-5-yl]·2_methylpropyl}_2, 3_dihydro-1,4-benzoindole-5-yl) piperidin-1-yl]propyl}-indole-acridin-2-ylbenzamide or a pharmaceutically acceptable salt thereof; 15 4-cyano-N-{(2R)-2-[4-(8-{l-[8-(4-{(lS)_2-[(4-cyanobenzyl)) Amino]aminomethylethyl}piped-1-yl)-2,3-dihydro-1,4-benzobisindole-5-yl]butyl}-2,3-dihydro -1,4-benzoindole _5_yl) 啩-1-yl] propyl-N-pyridin-2-ylbenzamide or a pharmaceutically acceptable salt thereof; 4-cyano-N -{(2R)-2-[4-(8-{l-[8-(4-{(lS)-2-[(4-cyanoglutamic acid 20-yl)) (° ratio pyridine_2-yl) Amino H-methylethyl}piperidin-1-yl)-2,3-dihydro-1Λ_ Benzo-II-5-yl]hexyl}-2,3-dihydro-1,4-benzoic π号. Well_5_base) 0 yin-1-yl]propyl}-indole-pyridin-2-ylbenzamide or a pharmaceutically acceptable salt thereof; 4-cyano-N-{(2R )-2-[4-(8_{[8-(4_{(1S)-2_[(4_Cyano)) (° ratio -2-yl)amino]-1_methylethyl }旅啡小基)_2,3-Dihydro_1 4· 8 200800198 Benzopyrene-5-yl]fluorenyl}-2,3-dihydro-1,4-benzodioxime Pent-5-yl)piperidin-1-yl]propyl}-N-atb σ-but-2-ylphenylamine or a pharmaceutically acceptable salt thereof; 4-cyano-N-{(2R) -2-[4-(8-{l_[8-(4-{(lS)-2-[(4-cyanobenzyl)](ϋβσ-2-yl)amino]-1 - Methyl ethyl} brigade σ well-1 -yl)-2,3 -diaza-1,4_ 5 benzoquinone 2 5 -5 -yl]ethyl}-2,3 -di-r-1,4- Benzene bismuth-5·base) brigade. Well-1 -yl]propyl}-Ν-° ratio sigma-2-ylphenylamine or its pharmaceutically acceptable salt; and 4-cyano-N-[2(R)-(4- Cyano-benzoguanamine)-propyl]-Nu-pyridin-2-yl-benzoguanamine or a pharmaceutically acceptable salt thereof. In a specific embodiment, the compound is in the form of particles. In one aspect, the particles have an average diameter of no more than about 20 microns. In another aspect, the particles have an average diameter of from about 0.75 to about 10 microns. In another aspect, the particles have an average diameter of from about 2 to about 8 microns. The composition of the present invention comprises 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-15 alum; [1,4} bis. deficiency. well-5-yl) brigade ϋ _ 1 -yl]-propyl} -N-σ is more than 唆-2-yl-benzoguanamine or a pharmaceutically acceptable salt form thereof (for example, 4-{(2R)-[4-(2, 3-Dihydrobenzo[1,4]dioxin-5-yl)-piperid-1-yl]-propyl}·Ν-acridin-2-yl-benzoguanamine hydrochloride), A structurally related compound or metabolite as described herein. In certain embodiments, the compositions of the present invention comprise 20 4-cyano-N-{(2R)-2-[4-(2,3·dihydro-benzo[1,4]dioxin -5-yl)-piperidin-l-yl]-propyl}-N-° ratio. Din-2-yl-phenylamine or a pharmaceutically acceptable salt form thereof, and one or more structurally related compounds and/or metabolic drugs. In certain embodiments, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-peripipeline Plant-1-yl]-propyl}-N-acridin-2-yl-phenylhydrazine 200800198 Amine or a pharmaceutically acceptable salt form thereof, and structurally related compounds and/or metabolites thereof, as granules Forms are present in the composition. In one aspect, the particles have an average diameter of no more than about 20 microns. In another aspect, the particles have an average diameter of from about 0.75 to about 10 microns. In another 5 aspect, the ruthenium particles have an average diameter of from about 2 to about 8 microns. In certain embodiments, the structure-related compound and/or metabolite is comprised of 4-cyano-N-{(2R)-2_[4-(2,3-dihydro-benzo[1] , 4] dimorphine·5-yl)_piped-1-yl l-propyl}-indole-pyridin-2-yl-benzoguanamine or a pharmaceutically acceptable salt form thereof (for example, 4-{ (2 幻_2_[4_(2,3_Dihydro-benzo[[]] octazone 10 piper 4-yl]-propyl}- Ν-pyridin-2-yl-benzoguanamine hydrochloride The composition of the salt) is provided in each of the amounts less than about 1% by weight. In certain embodiments, the compositions of the present invention further comprise a pharmaceutically acceptable carrier. Implementation of the financial, the group secrets and dosage forms of the invention (including 4_ cyano good {(2R)-2-[4-(2,3-dihydro-benzo-tl, 4] twenty-six base)_ brigade 15 tons ·1·yl]propyl}_N "(tetra) _2 phenyl hydrazide or a pharmaceutically acceptable salt form thereof) has no - or a plurality of 4 - cyano groups - (211 b 2 cases 2, 3 - dichloro - Benzo[M]20 well I base)+well-1-yl]-propyl}. For example, a dimer of benzyl-benzoguanamine. If used in this context, "substantially free, some dimerization Each of the materials will be less than about G·5 wt% Present in the composition 20, each amount being less than about 0.3% by weight, preferably less than about 〇2% by weight, and each amount being less than about 〇1% by weight or even more Preferably (based on the total weight of the composition); and each amount in the dosage form is less than about 5% by weight, and the amount of the parent species is less than about 3% by weight, preferably less More preferably about 2% by weight and each amount is less than about 1% by weight or even more preferably based on the weight of the active ingredient in the dosage form of 200800198 5 . Accordingly, the present invention provides a formulation which Contains 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-slightly -1 -yl]- Propyl}-N-0 is in the form of a 4-butyl-benzoic acid amine or a pharmaceutically acceptable salt thereof which is substantially free of 4-cyano-N-{(2R)-2-[4- (2,3-diindole-benzo[1,4]dioxin-5-yl)-piperidin-1-yl]-propyl}-N-acridin-2-yl-benzoguanamine) / or other 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]2. σσ well-5-yl)- slightly -1 a dimer of a compound related to the structure of -N-att12-di-2-yl-phenylenamine. Typical 4-cyano -N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piped-1-yl]-propyl}_N- The dimer of acridin-2-yl·10 benzoguanamine is shown in Formulas 7 and 8. The dosage form of the present invention comprises 4-cyano-N_{(2R)-2-[4-(2,3_ Dihydro-benzoquinone [1,4]di-sigma-deficient-5-yl)-slightly σ丼-1 ·yl]-propyl}-Ν-σ ratio 唆_2_yl-benzoic acid amine or its medicinal Acceptable salt forms (eg, 4-{(211)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piped-1-yl) • propyl}-Ν-acridin-2-ylphenylhydrazine 15 • Amine hydrochloride), as described in the structure-related compounds or metabolites described herein. In certain embodiments, the dosage form of the invention will comprise 4-cyano-N_{(2R)-2-[4_(2,3-dihydro-benzo[1,4]dioxin-5- And / or a pharmaceutically acceptable salt form thereof, and one or more structurally related compounds and/or metabolites. In some 20th embodiment, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl )--Travel--1 -yl]-propyl}-N-atb-decyl-2-yl-phenyl-amine or its pharmaceutically acceptable salt form and its structurally related compounds and/or metabolites, as granules Formal dosage forms exist. In one aspect, the particles have an average diameter of no more than about 20 microns. In another aspect, the particle has a mean diameter of from 0.75 to about 10 microns. In another aspect, the particles have an average diameter of from about 2 to about 8 microns. In certain embodiments, the structure-related compound and/or metabolite is 4-cyano-N-{(2R)-2-[4-(2,3-di-rho-benzoquinone[1] , 4] 2 17 ϋ -5 - 5 - )) - 旅讲 1-基]· propyl}-Ν-11 than bit-2-yl-phenyl-amine or its pharmaceutically acceptable salt form (eg ' 4 -{(2R)-2-[4-(2,3 - di- oxo-benzoquinone [1,4] dioxin σ well-5-yl)-Brigade. Well-1 ki]-propyl} The dosage form of -indole-acridin-2-yl-phenylguanamine hydrochloride is provided in an amount less than about 0.1% by weight, based on the total weight of the dosage form. The name "active ingredient" refers to 4-cyano-N-{(2R)-2-[4-(2,3-dihydrobenzene 10 and [1,4]dioxin-5-yl)-piped 1-yl]-propyl}-N-acridin-2-ylbenzoylamine or a pharmaceutically acceptable salt form thereof (for example, 4-{(2R)-2-[4-(2,3) -Dihydro-benzo[1,4]dioxin-5-yl)-piped-1-yl]-propyl}-N-acridin-2-yl-benzoguanamine hydrochloride), structure Related compounds or metabolic products (as shown herein) and pharmaceutically acceptable salts thereof. 15 • In certain embodiments, in addition to the active ingredient (eg, 4-cyano-N-{(2R)_2-[4_(2,3·dihydro-benzo[1,4]di- morphine) 5_基)-piperidin-1-yl]·propyl}-Ν-11 to 11-but-2-ylphenylamine or its pharmaceutically acceptable salt form), the pharmaceutical composition and/or The dosage form comprises at least one rate controlling polymer and at least one organic acid. In certain embodiments, the organic acid is citric acid, citric acid monohydrate, ascorbic acid, aspartic acid, glutamic acid, fumaric acid, malic acid or tartaric acid. In certain embodiments, the organic acid is a citric acid or a polyfunctional organic acid. In some embodiments, the at least one release rate controlling polymer is methylcellulose. In some embodiments, the polymer is hydroxypropyl methylcellulose, hydroxypropyl 12 200800198 cellulose, hydroxyethyl cellulose or hydroxypropyl decyl cellulose phthalate. In certain embodiments, the hydroxypropyl methylcellulose is hypromellose 2208 or 2910 (eg, MethocelTM K4M, Mido ShowTM K15M, Mido ShowTM 100100M, Beauty Multi-show tmE10M, Mido Show TME4M, 5 Mido ShowTM K100LV, Mido ShowTM E50LV, Mido ShowTM E5, Mido, Show TME6 or Mido Show £151^/. In some implementations In the example, the organic % acid is citric acid and the rate controlling polymer is hypromellose 2208 (for example, MetcoTM K4M premium CR and/or Metso K100M _ premium CR). In certain embodiments, the pharmaceutical composition and/or dosage form further comprises at least one filler. In certain embodiments, the filler is microcrystalline cellulose, lactose, calcium carbonate, calcium phosphate, maltose paste Fine, dextrose, fructose, maltose, mannitol, starch or sucrose. In some embodiments, the microcrystalline cellulose is deuterated microcrystalline cellulose and the chyle is 15 lactose monohydrate. In some embodiments, the pharmaceutical composition and/or dosage form further comprises at least one lubrication In certain embodiments, the lubricant is magnesium stearate, talc, stearic acid or colloidal cerium oxide. Further, in certain embodiments, in addition to the active ingredient, the present invention The pharmaceutical composition and/or dosage form comprises at least one rate controlling polymer, at least one having 2 oxime acids, at least one filler, and at least one lubricant. In certain embodiments, the pharmaceutical compositions of the invention and/or The dosage form comprises from about 2 to about 45 or 46 parts of the release rate controlling polymer and from about 1 to about 5 parts of the organic acid per serving of the active ingredient. In certain embodiments, the pharmaceutical composition and/or dosage form Containing from about 0.4 to about 10 mg of effective ingredient 13 200800198. In certain embodiments, the pharmaceutical compositions and/or dosage forms of the invention comprise from about 50 to about 150 mg of rate controlling polymer, from about 5 to about 50. The milligrams of organic acid, from about 85 to about 179 milligrams of the filler, and from about 1 milligram of lubricant. In certain embodiments, it contains from about 2 to about 50 milligrams of organic acid. 5 In certain embodiments In addition to the active ingredients (for example, 4 -cyano, -N-{(2R)-[4_(2,3-dihydro-benzo[1,4]dioxan-5-yl)piped-1-yl; Ια propyl Ν Ν ^ The pharmaceutical composition and/or dosage form of the present invention comprises at least one filler and at least one lubricant, in addition to the pyridin-2-ylbenzoylamine or a pharmaceutically acceptable salt thereof. In certain embodiments Wherein the filler is microcrystalline 10 cellulose, lactose, calcium carbonate, calcium phosphate, maltodextrin, dextrose, fructose, maltose, mannitol, starch, sucrose or a mixture thereof. In certain embodiments, The filler is microcrystalline cellulose, chylofolia or a mixture thereof. In certain embodiments, the pharmaceutical composition and/or dosage form further comprises at least one lubricant. In certain embodiments, the lubricant is stearic acid magnesium citrate, talc, stearic acid or colloidal cerium oxide. In certain embodiments, the lubricant is magnesium stearate. ® In certain embodiments, the pharmaceutical composition and/or dosage form comprises from about 15 to about 300 parts of filler and from about 丨 to about 3 parts of lubricant per serving of active ingredient. In certain embodiments, the pharmaceutical composition and/or agent 20 comprises from about 0] to about 5 mg of 4-cyano-N-{(2R)-2-[4-(2,3-di) Hydrogen-benzo[1,4]二$耕-5-yl)_派σ井1-1-基]propyl}·Ν_σ ratio bite 2-yl-benzoguanamine or its pharmaceutically acceptable salt form . In certain embodiments, the pharmaceutical composition and/or dosage form comprises from about 80 to about 150 mg of one or more fillers and at least about 0.75 mg of one or more lubricants. 14 200800198 In certain embodiments, the dosage form of the invention is in the form of a tablet. In one aspect, the tablet is coated with a film. In certain embodiments, the compositions or dosage forms of the invention are in the form of a dry mixture. 5 The present invention provides a method of providing the compositions and dosage forms of the present invention. In some embodiments, the composition is compacted for a period of time under conditions effective to form its tablet. In some embodiments, the tablet is further coated with a film. The present invention also provides a method comprising mixing the active ingredient, at least one rate control polymer, and at least one organic acid, thereby forming a mixture. In certain embodiments, the method further comprises compacting the mixture for a period of time under conditions effective to form a tablet thereof. In some embodiments, the blowing agent is further coated with a film. The present invention also provides a method comprising mixing the active ingredient, at least one filler, and at least one lubricant, thereby forming a mixture. In certain embodiments, the method further comprises compacting the mixture for a period of time under conditions effective to form its tablet ♦. In some embodiments, the tablet is further coated with a film. In certain embodiments, the dosage form of the invention is alkali free. In some embodiments, the invention provides a method and process for administering a dosage form, compound or composition of the invention to a mammal (e.g., a human). In certain embodiments, the dosage form, compound or composition is administered orally. In one aspect, they are administered orally once every 12 or 24 hours. In another aspect, they are administered orally once every 48 hours. In some particularly preferred embodiments of a certain 20080000198, the dosage form, compound or composition is administered to treat Alzheimer's disease. In certain aspects, the present invention provides a method of administering an oral dosage form comprising a scutellaria to a pharmaceutically acceptable carrier to a patient. In some specific embodiments, the method comprises administering to the patient an oral dosage form comprising a lysine and a pharmaceutically acceptable carrier, and wherein a maximum plasma concentration is achieved in the patient ( Cmax) and a 24-hour plasma concentration (C24) in the patient, wherein the average ratio of Cmax/C24 in the patient population ranges from about 5:1 • to about 1.1:1. In certain embodiments, the average ratio 10 of Cmax/C24 is from about 3:1 to about 1.1:1, from about 2.8:1 to about 1.1:1 or from about 2.3:1 to about 1.1. In some views, the cmax and c24 values are measured after a single dose of the oral sputum dosage form is administered to the patient. In certain embodiments, the oral dosage form comprises about 5 mg of squash. In some views, the average tmax in the patient population is about 3.5 hours or more, or about 5 hours or more. In some of these views, the average Cmax in the patient population is about 100 ng/ml or less. In certain embodiments, these dosage forms are administered to reduce the negative side effects associated with administering the drug to the patient. In some embodiments, the methods comprise the step of identifying the patient's risk of adverse side effects by administering a scutellaria, followed by administering the oral dosage form to the patient. 20 In some views, this negative side effect is headache, dizziness, abnormal sensation, visual disturbance, tinnitus, or a combination thereof. In certain embodiments, the method of administering a pharmaceutically acceptable carrier comprises administering an oral dosage form comprising a lenght and a pharmaceutically acceptable carrier to a patient. And can reach a maximum of 16 in the patient 2008 20088 5

10 15

20 plasma concentrations (cmax) and a 24-hour plasma concentration (C24) in the patient, wherein the average ratio of Cmax/C24 in the patient population ranges from about ·4··^ to about U··1. In some specific implementations, the average ratio of c_/C24 is from about 2.3:1 to about L1 ••卜约2··] to about]”····About! $ ·· ! to about! Work·· 1 or about L5··! to about L!··!. In some viewpoints, Cmax and CM values are measured in a steady state in a fasting group. In some specific implementations, each patient is given approximately 10 mg of sedum. In some views, the average Cmax in the patient population was 35 〇Ng/ml. In certain frequency embodiments, administration of these dosage forms reduces the negative field effects associated with administering the drug to the patient. In certain embodiments, the methods comprise the step of identifying the patient for the risk of a negative side effect by administering a scutellaria, followed by administering the oral dosage form to the patient. In some views, the negative side effects are headache, dizziness, paresthesia, visual disorder, tinnitus, or a combination thereof. The invention also provides a method comprising administering to a patient an oral dosage form comprising a scutellaria and a pharmaceutically acceptable carrier, which achieves an average maximum plasma concentration (c_) in the patient population and The patient population reached: an average 24-hour plasma concentration (c24), wherein the ratio of the average c_/average Q was from about 5: β_·5: 丨. In some views, the ratio of the average g-average a# is from about 2·8: 1 to about hl: 卜 about 2: i to about U: 1 or about 15: ★ to, spoon L1 · 1 in some views The Cmax and c24 values were measured after giving the single-dose oral dosage form to the patient. In other views, the Cmax and C24 values are measured in a steady state in the fasting group. In some embodiments 4 oral dosage forms comprise about 5 mg of serrata. In some embodiments, (7) these dosage forms may reduce the negative side effects associated with administering the drug to the patient 17 200800198. In certain embodiments, the methods comprise the step of identifying the patient for a risk of a negative side effect by administering a scutellaria, followed by administering the oral dosage form to the patient. In some views, the negative side effects are headache, dizziness, paresthesia, visual disorder, tinnitus or a combination thereof. The present invention also provides a method comprising splitting an oral agent comprising a cinnabar and a pharmaceutically acceptable carrier into a patient, and achieving an average maximum plasma concentration (cmax) in the luxuriant group and An average 12 hour plasma concentration (Cl2) was achieved in the patient population, wherein the ratio of the average Cmax/average c24 was from about 3:1 to about 0.5:1. In some embodiments, the ratio of the average shape/average C12 is from about 2:1 to about L·1:1 or from about 1.5:1 to about 1.1:1. In certain embodiments, administration of these dosage forms reduces the negative side effects associated with administering the medicinal to the patient. In certain embodiments, the methods comprise the step of diagnosing the patient's risk of adverse side effects 15 by administering a scutellaria, followed by administering the oral dosage form to the patient. In some views, the negative side effects are headache, dizziness, paresthesia, visual acuity, tinnitus, or a combination thereof. In certain embodiments, the present invention provides a method of administering a scutellaria to a patient comprising administering to the oral dosage form comprising a lysine and a pharmaceutically acceptable carrier Patient, which was at 37. (:, in the USP plastic 11 dissolution apparatus, measured at 50 rPm in 9 mM USP pH 6.8 phosphate buffer and used a settling agent for each dosage form, the plastic has one Intra-tube dissolution profile, which in the device will release no more than 40% of the squash in about 2 hours of measurement; and in the set of 2008 200800198, will be released under about 12 hours of measurement </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; ^ 5 The oral dosage form of the carrier is administered to the patient, and (1) an average cmax is achieved in the patient population, which is less than the administration of the equivalent agent *f from the immediate release formulation to the The average cmax obtained for the patient population (4); (9) the average tmax achieved in the patient population, which is greater than the tmax obtained from the immediate release formulation in which the equivalent dose is administered to the patient population; Iii) up to 10% of the concentration of carcass versus time, the curve has in the patient population The area under the curve (AUC), which is substantially the same as the Auc obtained by administering an equal dose of acesulfame to the patient population from the immediate release dosage form. In certain embodiments, the oral dosage form can Obtain an average Cmax of about 1 〇〇NEK/ml or less and/or an average tmax of about 4 hours to about 8 hours and/or an average AUC of 15 about (8) to about 2500 ngh/ml. These measurements are measured after administration of a single dose of an oral dosage form (eg, a single dose of 5 mg of φ acesulfame). In certain embodiments, the oral dosage form can achieve less than 400 ng/ The average Cmax of milliliters (e.g., an average Cmax of about 350 ng/ml), and/or an average tmax of about 4 hours to about 8 hours and/or an average AUC of about 5500 to about 6300 ngh/ml. In some views, these measurements are measured in a steady state in a fasting group. In some views, 10 mg of scutellaria is administered daily to a patient. In some embodiments, These dosage forms can reduce the negative side effects associated with the administration of the drug to the patient. In certain embodiments, these methods 19 200800198 include the step of administering the π dosage form to the patient by administering the statin to the patient. The negative side effects are headache, dizziness, sensation-loss, tinnitus or a combination thereof. Seeing the loss of Wei, 5 simple description of the figure 1 is after the administration of a single dose of 5 mg of the squash, three == The average column of the formulation and an immediate release formulation: a plot of 曰/辰度 versus time.

Figure 2 shows the average number of Alzheimer's patients who received immediate oral doses of multiple oral doses ($1 per day) and sustained release (1 mg per dose). A plot of plasma concentration versus time data. ~ Figure 3 is a single or multiple oral dose (4) to find a milligram of scutellaria sustained release formulation (as described in the case of the case of the disease in the case of Lezheimer's disease, the blood concentration of the meat and blood on the time The data is shown in Figure 15. The first day shows 24 hours of data. (4) The day shows ❹ to 72 hours.

Time information. J Figure 4 is a graph comparing the mean concentration of melanostats versus time in patients with Alzheimer's disease who received multiple oral doses of 1 mg and SR (10 mg QD). [Embodiment] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides, inter alia, a formulation comprising 4 cyano-- (10) state-like benzo[cafe]5-based]-end-group]-prop a compound and/or a metabolite of the structural phase 200800198. As used herein, the term "formulation" refers to a compound, composition, and dosage form such as, for example, immediate release and sustained release dosage forms. The invention also provides a process for making the formulation and administering the same to a mammal. Preferred formulations for use in the present invention are those which act as serotonin activating agents and which have a 5 ΗΤ 1 Α knot activity. In particular, the preferred compound acts as a 5-HT1A antagonist. See, for example, us_b_6, 784, 294, _ US, 8.6, 626, 626, US-B_6, 469, GG7, US-B-6, 586, 436, 10 US-A-5, 710, 149, US-A-6, 127, 357, and WO 97/03982, These publications are hereby incorporated by reference in their entirety for all purposes in their entireties. The compounds of the present invention and compositions comprising more than one of the compounds of the present invention can be prepared by those skilled in the art of organic synthesis using well-known methods, using readily available reagents and starting materials, see, for example, Ep_B_〇 512755, 15 WO 97/03982, US-B-6, 127, 357, US-B-6, 469, 007, US-B-6, 713, 626, US-B-6, 784, 294, and US-A-20030208075A, and the disclosures of which are incorporated herein by reference. Used herein for all purposes. The method comprises the use of the amine sulfonate 4,5-dihydro-5S-methyl-3-(2-pyridyl)-3Η[1 ·2·3]$嗟 _2_2,2_ dioxide Alkylation of i_(2,3 dihydro 20-1,4-benzoindole) Hydrochloric acid to obtain an aminosulfonic acid intermediate which can be hydrolyzed to {(2卟2妙(2, 3-Dihydro-benzo[I,4]dioxin_5·yl)-piped-1-yl]-propyl}α-pyridyl-2-yl-amine followed by 4-cyanobenzylhydrazine Treatment of the {(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-bred small propyl group by a chlorine group 2-yl-amine, and 4-cyano group is obtained. 200800198 -N-{(2R)-2-[4-(2,3-dihydro] benzo[1,4]dioxin-5-yl) -piperidin-l_yl]-propyl}-N-pyridin-2-yl-phenylguanamine base. Treatment of 4-cyano-N-{(2R)-2-[4_( with chlorous acid) 2,3-Dihydrobenzo[14]diphenylene)-piperidin-1-yl]·propyl b Ntidine_2-yl-benzoinamine to obtain the hydrochloride salt. ' 5 In some embodiments of the present invention, the processing and purification of a further comprises 4-cyano-N_{(2R)_2_[4-(2,3-dihydro-benzo[14]dioxin _5 • base) · slightly -1-yl]-propyl} seven-pyridyl-2-yl-benzoguanamine and its pharmaceutically acceptable salts For example, in one embodiment, one comprising p4_cyanoquinone is called (211)-2-[4-(2,3-dihydro-benzo[1,4]disaki+5- Alkaloids/glutamines (formulated by the method disclosed herein) in an organic solvent, in the case of Shi Xi Gel treatment and filtration to remove the structurally related compounds (eg, the dimers represented by Formulas 7 and 8). The remaining product can then be concentrated and recrystallized to provide, for example, 4-cyano-N- {(2R)-2-[4-(2,3_Dihydro-benzo[ι,4]dioxin-5-yl)_° bottom tillage small base]_ 15 propyl}·Ν-acridine- 2_yl-benzoguanamine hydrochloride. Preferred formulations of the invention may be used to modulate (e.g., antagonize or effect) 5-ΗΤ1Α receptor activity and usefully treat diseases, such as CNS disorders, including (but Not limited to) schizophrenia (and other mental illnesses such as paranoia and mano-depressive conditions), Parkinson's disease and other motor disorders, anxiety (eg, generalized anxiety disorder) , panic attacks and obsessions and obsessive-compulsive disorder) (eg, due to serotonin reuptake inhibitors and synergistic effects of serotonin norepinephrine reuptake inhibitors), Alzheimer's disease, Tourette's syndrome, migraine, autism, attention Insufficient symptoms and hyperactivity disorders. Preferred formulations may be useful for treating sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, abnormal appetite disorders (such as, for example, obesity, anorexia, and appetite) with 22 200800198 Wang), sexual dysfunction and treatment of alcohol, drugs and nicotine withdrawal. 5 Preferred formulations of the invention may also be usefully used to treat cognitive disorders including, but not limited to, cognitive disorders associated with mild dysfunction (Μα), Alzheimer's and other dementias (including Lewy bodies, Business management and post-stroke treatment. According to the present invention, cognitive disorders associated with surgical procedures, traumatic brain injury or stroke can also be treated. Furthermore, preferred formulations are useful for treating diseases in which the cognitive disorder is a common disease, such as, for example, Parkinson's disease, autism, and attention deficit disorders. Despite its high solubility in water (about 51 mg/ml at 25 〇), it provides 4-cyano-N-{(2R)-2-[4-(2,3-diox) in micronized form. -Benzo[1,4]diterpenoid·5·yl), cultivating, 1_yl]-propyldihydro-π-pyridyl-2-yl-aniline and 15 salts thereof are preferred. For its part, the present invention provides a formulation comprising a micronized and non-micronized form of a gas-N-{(2R)-2-[4-(2,3-dihydro-benzene) And [1,4] two g cultivative-5-yl)-breasted carbaryl]-propyl-N-pyridin-2-yl-benzoguanamine, its pharmaceutically acceptable salt, structurally related compound or metabolism product. For the purposes of the present invention, the micronized form of the compound is in the form of particles having an average diameter of no more than about 20 microns. It will be appreciated that the compounds of the present invention may be in the form of particles having an average diameter greater than about 20 microns, such as particles having an average diameter of from about 20 microns to about 3 Å or about 500 microns. Preferably, the particles have an average diameter of about 1 Å and an average diameter of from about 〇75 to about 10 μm, more preferably from about 2 to about 8 μm 23 200800198. Methods of miniaturization or particle size reduction are well known and are therefore not described in detail herein. As will be understood, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)- Piperidin-1-yl]-propyl}-Ntidine-2-yl 5-phenylguanamine;

In the present invention, the compound of Formula 1 can be prepared in the form of a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic salts. Suitable non-organic salts include, for example, inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrogen acid , hydrochloric acid, ethyl acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, mucic acid, nitrate 15 acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, - Benzene sulfonic acid and its analogs. Hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid are particularly preferred, and the hydrochloride is the best. In certain embodiments, the 4-cyano-N-{(2R)-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperidin Plough_1_yl]- 24 200800198 Formulation of propyl}-N-pyridin-2-yl-benzoguanamine or a pharmaceutically acceptable salt thereof will also comprise one or more structurally related compounds (which can be used well known Method to detect and quantify). Examples of the compound related to this structure include, but are not limited to, those of the compound represented by Formula 2-9 and pharmaceutically acceptable salts thereof, including, for example: {(2R)-2-[4-(2 ,3-dihydro-benzo[1,4]dioxin-5-yl)-piped-1.-yl]-propyl}-N-pyridin-2-yl-amine or its pharmaceutically acceptable Salt; 4-cyano-N-{(2S)-2-[4-(2,3-dihydro-benzo[1,4]disazo-5-yl) lining-1-yl] -propyl}-N-indol-2-yl-phenylenamine or a salt thereof at a pH of 10; 4-cyano-N-(2-pipeth-1-yl-propyl)-N Pyridin-2-ylbenzoylamine or a pharmaceutically acceptable salt thereof; 4-cyano-N-[(2R)-2-piped-1-yl-propyl]-N-pyridine-2- Benzo-benzoguanamine or a pharmaceutically acceptable salt thereof; 15 ν·(5·chloro-acridin-2-yl)-4-cyano-oxime [2·(4-hydroxy-piped-1- ))-propyl-benzamide or a pharmaceutically acceptable salt thereof; • Ν-(5-chloro-pyridin-2-yl)-4-cyano-N-[(2R)-2-( 4-hydroxy-piperidin-1-yl)-propyl]-benzoguanamine or a pharmaceutically acceptable salt thereof; N-(5-gas-.bybiti-2-yl)-4-oxy-N - {2-[4-(2,3-dimur-benzoquinone [1,4] 20 2 11 σ σ well-5-yl)- slightly 0丼-1-yl]-propyl}-benzene An amine or a pharmaceutically acceptable salt thereof; Ν-(5-gas-° ratio -2-定-2-yl)-4-murine_N-{(2R)-2-[4-(2,3- Dinitro-1,4-benzoquinone sigma-5-yl)-nivine ketone-1-yl]-propyl}benzamide or a pharmaceutically acceptable salt thereof; 25 200800198 4-cyano -N- {(2R)-2-[4-(8_ {1-[8·(4- {(1 S)-2_[(4-cyanobenzylidenyl-2-yl)amino]-) I-methylethyl}linphine-1·yl)-2,3-diaza-1,4_ pheno-bi-supplement-5-yl]-2-methylpropyl}·2,3_dihydrogen -1,4_benzobismorphin-5-yl)piped-1-yl]propyl}-N-acridin-2-ylbenzamide or a pharmaceutically acceptable salt thereof; 4-cyano --N-{(2R)-2-[4-(8-{1_[8·(4-{(1 S)-2-[(4-cyanobenzylidene))) -yl)amino]-1-methylethyl} brigade σ well-1 -yl)-2,3 -dichloro-1,4_benzoindole-5-yl]butyl}-253- Hydrogen 1,4·benzoindole-5-yl), glutamic-1-yl]propyl, TvM, pyridyl-2-ylbenzamide or a pharmaceutically acceptable salt thereof; 10 4-cyano -N-{(2R)-2-[4-(8-{l-[8-(4-{(lS)-2_[(4-cyanobenzyl) hydrazin-2-yl)amine ]]-1-methylethyl}parhen-1-yl)·2,3·dihydro·1,4-benzobis σ, etc. 5-yl]hexyl}-2,3-dihydro- 1,4-Benzene σ 啡 _ _ _ _ ) α α _ _ _ _ _ _ _ _ _ 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 2R)-2-[4_(8-{[8-(4-{(lS)-2-[(4-cyanoaryl 15 base)) (° ratio -2-yl)amino]-1 -methylethyl}pyrrolidyl)_2,3_digas_ι 4·benzodiazepine 17 well-5-yl]methyl}-2,3·dihydro-1,4-benzoic啡 ) ) 旅 -1 -1 -1 -1 -1 -1 -1 } } } } } } } } } } } } 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- [4-(8-{l-[8-(4-{(lS)_2-[(4·Cyanobenzyl))(°~β-2-yl)amino]-1-methyl-ethyl基}旅啡小基)_2,3_二气_ι 4 20 benzodiazepine-yl]ethyl}_2,3-dihydro-1,4-benzobis, morphyl) 1-yl]propyl}-N-indol-2-ylbenzamide or a pharmaceutically acceptable salt thereof; and 4-cyano-N-[2(R)-(4-cyano-benzoquinone) Amine) - propyl] violent bite _2 melamine or a pharmaceutically acceptable salt thereof. 26 200800198

Equation 4

Equation 5 27 200800198

10 wherein Ri is -CH3, -CH(CH3)2, -CH2CH2CH3, CH2CH2CH2CH3 or -CH2CH2CH2CH2CH3. 28 200800198 Including - the present invention provides - a formulation, such as: 2, 3, 4, 5, 6, 7, 8, or 9: or it is acceptable to be _. In this hair _ a money ^ object compound will contain 4 shy ^ These will be 匕 ^ mouse base - N_ { (2R) 2_ [4_ (2, 3 · dihydro 3 singular-5-yl) - mouth mouth and! #,开Π,4]二 m]·propylbu ν·(tetra)_2_yl·benzene Acceptable (four), and-or a variety of formulas 2, 3, 4, 5, 6, 7

a compound or a pharmaceutically acceptable salt thereof. In certain embodiments 8 or 9, the formulation of the present invention may comprise 4-cyano_n_{(2r)_2 - W 10 15 20 benzo[1,4]di-·5·yl) _料_1·基]_«}·Ν_ Heart amine or its pharmaceutically acceptable salt, {(2κ)_2_[4·(2,3_: hydrogen·stupid = one phenolic winter base)-brochlet small Base]_propyl} such as bite 2_yl-amine or its pharmaceutically acceptable salt, and 4-cyano-indole_{(23)-2-[4_(2,3-dihydro-benzoyl) , 4] Di- morphin-5-yl)-piperidin-:-yl]-propyl hydrazine _σ-pyridinyl-2-ylbenzoylamine or a pharmaceutically acceptable salt thereof. Accordingly, the present invention provides a method comprising 4-cyano-indolyl-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-parphine Small propyl}-N-pyridine-2-yl-benzoguanamine hydrochloride, {(2R)_2-[4_(2,3-dihydro- benzo[1,4]- σ gram _5 ))-Phenyl small group]-propyl}-Nn ratio α _2 _ yl amine and cyanocyano-N-{(2S)_2-[4-(2,3-dihydro- benzo[ 1,4] Diterpenoid _5_yl)-piperidin-1-yl]-propyl}-N-indole-2-yl-benzoguanamine hydrochloride formulation. When the structure-related compound described above is present in 4-cyano-N_{(2R)-2-[4-(2,3-dihydro·accumin [1,4] diterpene-5,yl) When the composition of the small group of -propyl}-N-pyridin-2-yl-benzoguanamine or a pharmaceutically acceptable salt thereof is preferred, the former is more preferred and the latter is less than about 10%. The amount present in the composition is preferred and is present in an amount less than about 5% and more preferably less than about 29 200800198 1% or 0.1% or even better (e.g., in an amount from about 0 08% to about 〇) 27%)). 4-cyano-indole_{2-[4-(2,3·dihydro-benzo[i,4]dioxa-5-yl)-bran-1-yl]-propyl}-N-bite The -2-yl-benzoguanamine includes a pair of palmitic centers, and the R_isomer can be used in greater amounts. Formulations (e.g., 5 compounds, compositions or dosage forms) of the invention may include both ruler and 8 isomers, and are not limited to a single mirror image or a mixture of particular mirror images. The present invention also provides a formulation comprising 4_cyano*{2 called 2,3_dihydro-benzo[10)^hearted small base]-propyl b. ling 2_yl·benzoquinone (four) Metabolites. The 10 metabolites of Yunchen include (but are limited to) 4-cyano-N_{(2R) o-(8_trans-base-2,3 digas-benzo[1,^十井_5_基) temple well Small base]-propyl) such as butyl-2-phenylamine or its commercially acceptable salt, 4-cyano-N-{(2R)_2-[4-(3-hydroxy-2) , 3-dihydrogen: stupid [M] twenty wells _5 base) _ brigade spray base] _ propyl b N_ acridine yl benzoguanamine or its pharmaceutically acceptable salt, 4-cyano --N_K2R)_2_[4_(2_ 15 hydroxy 2,3-dihydro-benzo[1,4]disakisin-5-yl)-piped]_yl]-propyl Ν·Ν2 base • The present amine or its pharmaceutically acceptable salt, and the cyano N (2R, 2-parphin small-propyl) ratio. Din-2-yl-codantamine or a pharmaceutically acceptable salt thereof. As understood, these metabolic products are represented by Formulas 10-13. It will be appreciated that these metabolites can be used as pharmaceutically active compounds under their own conditions and in pharmaceutical dosage forms, either alone or in combination with other pharmaceutically active compounds. 30 200800198

HO

31 200800198

The present invention provides an immediate release and a sustained release dosage form comprising one or more active ingredients, for example, 4-cyano-N-{(2R)-2-[4-(2,3-dioxin-benzene) And [1,4] two sigma sigma-5-yl)-Jiakou well-1 -yl]-propyl}-N-11 than biti-2-yl-benzoamine, its pharmaceutically acceptable Salts, structurally related compounds and their metabolites with 5-ΗΤ1Α binding activity. The "release rate" of a drug refers to the amount of drug that is released from the dosage form per unit time, for example, milligrams of drug (mg/hr) released per hour. The rate of drug release can be calculated, for example, in an in vitro dosage form dissolution test condition well known in the art. As used herein, the rate of drug release obtained at a particular time "after administration" refers to the rate of drug release in the tube obtained at a particular time after completion of the appropriate dissolution test. Methods for performing the dissolution 15 test or release rate test are well known in the art. The time at which a specified percentage of the drug in the dosage form has been released may be as a "Τχ" value, where "X" is the percentage of drug that has been released. In assessing the release of a drug from an oral dosage form, the reference metric typically used is the time when the drug within the dosage form has been released 70% or 90%. For this dosage form, this metric means 20 is "T7G" or "Τ90". 32 200800198 10 15 20 For the purposes of the present invention, the name "immediate release formulation," means a formulation of the active compound from which the drug can be supplied to the "fast and instant"; for example, - including activity a compound which does not interfere with the rapid dissolution of the active compound from the formulation. The immediate release of the precursor lacks the release of the controlled mixture or otherwise hinders release of the active compound from the formulation. The species, or the amount of such polymers or species involved, is sufficiently small to not hinder the release of the active compound from the ligand (relative to other agents lacking the same formulation of the polymer or species). The actual form of __ is mixed with microcrystalline cellulose (such as 'Avieel®® (trademark from fmc Corporation)) (for example, 4·cyano- N-side·2 elevation, 3_dihydro-benzene eggs, 4]two.§耕_5_基)·End-bubupropyl}·Ν发·2·yl·benzamide, its pharmaceutically acceptable Salt, structurally related compounds or metabolites, which can be less than (four) hours Producing greater than 75% of the solubility of the active ingredient in a 0.1 N HCl solution. For use herein; g-supported release, "sustained release formulation", "sustained release dose formulation" and the like are defined as - Formulations comprising substances which prevent the release of the active compound from the formulation (relative to "immediate release" as described above, formulations, for example, lack of release rate controlling polymers or other release inhibitors relative to other aspects The same formulation). Therefore, the name ''sustained release, can be applied to any number of extended release forms' and it is considered to be substantially delayed with delayed release, time-limited release, extended release, time-limited stylized release, limited time Release, release upon limited application, sustained release, slow action, long-acting effect, delayed action, interval release, 33 200800198 "Put, prolonged immortal, extended limbs are synonymous with similar nouns. ...named k-speed release" "Medium-speed release" and "rapid release," intended to mean continuous release formulations of, for example, Ά文, which can be relatively slow relative to each other. Medium or fast rate to release the active compound. : Known cockroaches, the performance release formulation can cause the active compound rate to be released from the dosage form, allowing it to effectively increase the reach of the most therapeutic/initial The time that the day guard will spend (such as compared to the immediate release formulation). The illusion (not limited to) can increase by 5〇% or more, 1(10)% or more, ι5〇%, or even 200% or More time (e.g., as compared to immediate release formulations, for example, compared to other formulations that lack release rate controlling polymers or other hindered release materials). Scales can also be V-induced active compounds. Released from the dosage form at a rate such that it is effective to reduce the maximum therapeutic concentration of the compound (as compared to immediate release formulations) such as, without limitation, it can be reduced by at least 1%, at least 2%, at least 15 25/°, at least 30%, at least 40% or at least 50% (compared to immediate release formulations). The sustained release formulation may also result in the active compound being liberated at a rate k of the dosage form such that it is effective to increase the amount of time (relative to the immediate release formulation) to maintain the pharmaceutically effective concentration of the active compound, for example (not limited thereto) which may increase the amount of time by at least 25%, at least 50%, at least 75%, at least 20 1〇0%, or at least 125% (relative to the immediate release formulation to maintain the pharmaceutically effective concentration of the active compound) The amount of time). Satisfying any of the foregoing criteria is sufficient to formulate a formulation into the "sustained release form, formulation. The present invention provides a method comprising administering a disclosed dosage form to a patient to continually release the active ingredient. The rate at which the active compound is released from the dosage form 34 200800198 is zero. In another aspect, the rate at which the active ingredient is released from the dosage form is ascending. Release is preferred during the month. The rate-controlled polymer is - inhalable and/or absorbing liquids - thus preventing the release of the hydrogel from the drug in the stomach compared to Remington's Medical Sciences (Remingt〇n, s ρ}ι_ααΐ as used in this article 'name' Release rate controlling polymer, which is intended to mean any polymer substance f suitable for pharmaceutical use, which may prevent the drug substance from being released in this dosage form. The release rate controlling polymer inhibits the drug

Xis version, an example of a release rate-controlling polymer found by Gennaro, Mack Publishing C〇., East〇n, pA, 199〇 . Certain preferred release rate controlling polymers suitable for use in the present invention include, but are not limited to, hydroxypropylcelluloses, methylcelluloses, polymethacrylates, methacrylic acid-mercaptoacrylic acid Ester copolymer, vinegar fiber 15 element, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethyl cellulose, polyvinyl acetate phthalate, hydroxypropyl Methylcellulose phthalate, polyethylene oxide, hydroxypropyl methylcellulose (such as, for example, hypromellose 2208 and 2910) and combinations of two or more thereof. Suitable release rate control polymers are commercially available from companies such as Mido 20 ShowTM K4M, Mido ShowTM 1515, Mido Show tmK100M, Mido ShowTM E4M, Mido ShowTM 100100LV, Mido Show TME50LV, Beauty Multi-show TME5, Mido ShowTM E6, Mido ShowTM E15LV; and SureleaseTM available from Colorcon; and EudragitTM, RS TM RL (available from Rohm GmbH &amp; Co.). At 35 200800198, or a combination thereof, the formulation of the present invention will comprise a propyl f-based fiber formed from a high density matrix of propylmethylcellulose, a low density matrix.

The sustained release formulation of the present invention comprises at least one release rate controlled polymer. The release rate controlling polymer is preferably present in the formulation in an amount ranging from about 10% to about 75% by weight, more preferably from about 2% to about 6% by weight. In a specific embodiment of the tree, the rate-controlling polymer is present in an amount of from about 5 〇 to about 15 〇 in a 250 mg dosage form. In certain embodiments, the release rate controlling polymer is cellulose, such as, for example, propylmethylcellulose formed from matrix 10, cellulose-based ethylcellulose, such as 'Medical ShowTM K4M Premium CR or Mido® K1 Depletion Premium In addition to comprising at least one release rate controlling polymer, the sustained release dosage form of the present invention typically comprises at least one agent (e.g., an organic acid) that improves the release rate 15 in the intestine. For the purposes of this document, the name "organic acid" I includes any acid that can be safely ingested by a caregiver. Although not intended to be limited by any particular reason, it is believed that the acid can improve the X CT of the drug product in the intestine. Examples of organic acids suitable for use in the towels of the present invention include (but are not limited to tartaric acid, malic acid, anti- Alkenedioic acid, aspartic acid, glutamic acid, gan &quot; 夂 fefee hexanoic acid, succinic acid, ascorbic acid, oleic acid or lactic acid. Preferred organic acids are citric acid or polyfunctional organic The organic acid is preferably present in the range from about 1% to about 3 G%, more preferably from about 2% to about 10% by weight. In a particular embodiment of the invention, the organic The acid may be from about 5 to about 5 mg in a 25 mg of Form J 'from about 5 to about 25 mg more than 36 200800198. In some embodiments, the amount of the organic acid is from about 2 to About 5 〇 mg. The sustained release formulation is substantially free of alkali. The formulation, agent or composition used in the present invention and on the babe is referred to as the formulation, dosage form or composition. Less than about 1% alkali, less than about 5% of the base is better than 5 and less than about 1% or 1% of the base. As used herein, the name "alkali Refers to a chemical compound that functions as a proton acceptor. In addition to the active compound and release rate controlling polymer, the formulations of the present invention may comprise any of a wide variety of suitable materials that impart beneficial properties to the formulation. Solubility modifiers, such as surfactants, such as, for example, sodium lauryl sulfate, acidic compounds, antioxidants, pH modifiers, chelating agents, fillers, disintegrants, binders, lubricants, stabilizers Agent (including water-soluble excipients such as sugars; and water-dispersible excipients such as, for example, microcrystalline cellulose, colloidal silica, evening microcrystalline cellulose, and temple powder In certain embodiments, the formulation is provided at a level of about 6 or 15 (e.g., to about 6). The water-soluble excipient or water-dispersible excipient is Examples of limitations include lactose, mannitol, Yan sugar, and the like. The water-soluble formulation can be present in a range (% by weight) depending on the particular therapeutic target desired. In the invention, except In other aspects, the percentages and parts are expressed in parts by weight or percentage by weight. In general, the water-soluble excipients can range, for example, from about 〇% to about 5% or to about 99. %, about 2% to about 25%. Examples of the water-dispersible excipients include microcrystalline cellulose, colloidal polyoxo-oxide, and microcrystalline cellulose (Prussow ( Pr fine lv) TM), _ class, cross-linked Weimethionin and 37 200800198. Analogous examples of the stabilizer are non-limiting examples including antioxidants such as BHA, BHT, ascorbic acid, tocopherols and Analogs. Non-limiting examples of suitable metal chelators include EDTA, citric acid, and the like. Non-limiting examples of such pH modifying agents include citric acid, cis- _ and the like. Non-limiting examples of such binders include powders, PVP (polyvinylpyrrolidone), HPMC (hydroxypropylmethylcellulose) HPC (hydroxypropylcellulose), and the like. Non-limiting examples of such flow adjuvants include magnesium stearate and the like. Examples of the non-limiting limit of the solubility modifier include surfactants such as sodium lauryl sulfate or polysorbate (e.g., Tween 80) and the like. In a specific embodiment of the vehicle, the sustained release formulation of the present invention comprises the active ingredient, at least one release rate controlling polymer, an organic acid, at least one filler, and at least one lubricant. 15 Examples of such lubricants include, but are not limited to, stearic acid, magnesium stearate, glyceryl behenate, talc, mineral oil (in PE (3), colloidal cerium oxide, and the like. 'It is to be understood that any lubricant well known in the art can be used in the formulations described herein. The lubricant can range, for example, from about 0.2% to about 5% by weight. In one embodiment of the invention In one embodiment, the amount of the lubricant in the 250 mg dosage form is about 1 mg. Examples of the filler include, but are not limited to, deuterated microcrystalline cellulose, cellulose, cellulose acetate, cellulose. Diacetate, cellulose triacetate, lactose monohydrate, anhydrous lactose, calcium carbonate, calcium phosphate (eg, binary anhydrate), maltodextrin, dextrose, fructose, maltose, 38 200800198 ganol, Starch, starch (e.g., pregelatinized), sucrose, and lactose. However, it is to be understood that any of the fillers well known in the art can be used in the formulations described herein. Can be, for example, from about 25% to about 75%' Or to about 99% by weight. In a specific embodiment of the invention (Example 5(6) 'Typical sustained release formulation), the filling dose present in the 250 mg dosage form is from about 85 to about 179 mg. The sustained release dosage form can comprise any convenient percentage and parts (relative to other ingredients) of the active compound. Typically, the formulation contains an active ingredient (in percentage) from about 〇3°/. to about 25%, preferably from about 10% to about 15%. In certain embodiments, the formulation comprises from about 1% to about 25%, preferably from about 1% to about 25%, by weight of active ingredient. 2% to about 15% 〇 In a preferred embodiment, the sustained release formulation will comprise from about 2 to about 46 parts of the drug relative to the control polymer and from about 〇4 to about iq parts, To improve the release rate of each active ingredient in the intestine. It comprises about 1 〇 to about 46 parts of the release rate controlling polymer and about 1 to about 5 parts of the agent is better, Φ to improve the active ingredient of each part in the intestine. Release rate in. For example, in one embodiment, a rapid sustained release Type of formulation in each serving of active ingredients (eg '4- disorder-N-{(2R)-2-[4-(2-3-two gas 2〇-benzo[Μ] twenty well-5- Base) - piperidinyl group - propyl group. Contains about 10 parts of release rate controlling polymer and about 5 parts of organics under bite _2_yl phenylene amine or a pharmaceutically acceptable salt thereof In another embodiment, a medium speed sustained release formulation is applied to each active ingredient (eg, 4-cyano-N-{(2R)-2-[4_(2 3- 2 gas- Benzene 39 200800198 [1 '4] - η-deficient _5 kibrin quinone propyl propyl group, such as butyl benzoylamine or a pharmaceutically acceptable salt thereof, contains about 25 parts of release rate controlled polymerization And about 5 parts of organic acid. - In another embodiment, a slow sustained release formulation is present at 5 parts per serving (eg, 4_cyano·Ν·{(2^2_[4_(2,3_:ιbenzo) [1,4] twenty wells _5_base) (iv) small bases]•propyl}_Ν•対_2•yl.phenylenamine or a pharmaceutically acceptable salt thereof) containing about 3 parts of release rate Controlling the polymer and about 1 part of the organic acid. In another embodiment, the sustained release formulation is in an amount of 1 〇 of the active ingredient of icos-5-yl)-slightly oligo]-propyl }, such as benzoic acid or a pharmaceutically acceptable salt thereof, comprises about 18 parts of a release rate controlling polymer and about 1 part of an organic acid. In another specific embodiment, the sustained release formulation is at 15 active ingredients per part (eg, 4-cyano_N_{(2R)_2_[4_(2,3-dichloro-benzo(10)) _5·基················································· . In some specific closures, the continuous formulation comprises about 5 milligrams of active ingredient, about 50 to 150 milligrams of release rate controlling polymer, about 5 to about 50 milligrams of organic acid, and secret 179 milligrams. The filler and the lubricant of the old grams. In some embodiments, the release form contains about 2 mg of active ingredient, about 50 to 150 mg of release rate controlling polymer, about 40 200800198 2 to about 50 mg of organic acid, about 85 to about 179. A gram filler and about 1 mg of lubricant. In certain embodiments, a typical sustained release formulation comprises about 5 mg of active ingredient and about 5 mg of a release 5 rate controlling polymer in a 25 mg tablet. This typical formulation may further comprise, for example, about 169 mg of a filler, about 25 mg of an organic acid (or other agent that improves the rate of release in the intestine), and about 1 mg of a lubricant. In certain embodiments, a typical sustained release formulation comprises about 5 mg of active ingredient and about 125 mg of released 速率 rate controlling polymer in a 250 mg lozenge. This typical formulation may further comprise, for example, about 94 grams of a filler, about 25 milligrams of an organic acid (or other agent that improves the rate of release in the intestine), and about 1 milligram of lubricant. In certain embodiments, a typical sustained release formulation comprises about 5 mg of active ingredient and about 15 mg of release 15 rate controlling polymer in a 250 mg lotion. This typical formulation may further comprise, for example, about 89 gram of filler, about 5 mg of organic acid (or other agent that improves the rate of release in the intestine), and about 1 mg of lubricant. In certain embodiments, a typical sustained release formulation comprises about 5 milligrams of active ingredient and about 92 milligrams of release 2 rate rate controlling polymer in a 250 milligram spin. This typical formulation may further comprise, for example, about 150 mg of a filler, about 5 mg of an organic acid (or other agent that improves the rate of release in the intestine), and about 1 mg of a lubricant. In certain embodiments, a typical sustained release formulation comprises about 2 grams of active ingredient in a 250 mg tablet and a release of about 92 mg. This typical formulation may include, for example, a loading of about 1% gram of hair, about 23 gram of organic acid (or other agent that improves the rate of release in the intestine), and about 1 milligram of lubricant. The sustained release formulation of the present invention may be in any form suitable for administration to the Wei animal and is not limited to the examples shown therein. ,

10 In a particular embodiment, the formulation of the invention is in the form of a coated pellet or sphere. A non-limiting example of such a formulation is a sphere comprising - an active compound core in an inert matrix, and coated with - a release rate controlling polymer as disclosed herein. Examples of suitable release rate control polymers are those described in this article with polymers that are not related to Shuaiyi, such as polymethacrylic acid Lai, Yuchaite TMivs, YuchaiteTM RS/RL, vinegar Cellulose, ethylcellulose, hydroxypropylmethylcellulose, (tetra)-based cellulose, (tetra)ethylcellulose, and the like. 15 纟 In certain embodiments, the formulations of the invention are in the form of pellets. Examples of such formulations include those comprising pellets, wherein the pellet comprises an active compound layer on the surface of an inert core (e.g., sugar spheres), and a surface comprising - or more release rate controlling polymers coating. In other specific embodiments, the formulation is in the form of a capsule (e.g., a hard or soft gelatin capsule 20 and/or powder). In certain embodiments, the formulations of the invention are in the form of tablets. The weight percentage of active compound in this plastic 5-week formulation is from about 0.3% to about 25%' and about G·3/. Up to about 15% is preferred. In certain embodiments, the weight percent of active compound in a typical formulation of this type is from about 1% to about 25%, and from about 2% to about 15%, and preferably from about 2% to about 15%. A non-limiting example of such a tablet is a co-compressed bond, for example, "tablet-in-tablet" and a matrix lozenge. The co-compacted tablet may comprise a core and an external compression coating. 5 either or both of the core and external compression coatings may comprise the active compound fool and/or one or more release rate controlling polymers. In certain embodiments, the dosage form is a co-compacted tablet wherein both the core and the external compression coating comprise the active compound and at least one release rate control ♦ polymer (one of Preferred is hydroxypropyl methylcellulose). Preferred matrix formation

10 Polymers include hydroxypropyl methylcellulose selected from the following: Mido ShowTM K4M's Mondo ShowTM K15M, Metso ShowTM 100100M, Mido ShowTM Ε1〇Μ, Mondo TME10M, Mido Show tmE4M, Mido Show K4M, Mido ShowTM K100LV, Mido Show tmE50LV, Mondo TME5, Mondo TmE6, Mondo TME15LV or a combination of two or more. 15 In certain embodiments, the tablet is a matrix lozenge. The base-forming composition may include waxes, gums, polyethylene oxides, carbapols, propylmethylcelluloses, hydroxypropylcelluloses, dream ethylcelluloses. Classes, polymethacrylates or other polymers as described in the present gastric rate control. In certain embodiments, the matrix linkage can be prepared by mixing the active compound with a matrix forming polymer in the mixture. In some embodiments, the tablet is a matrix-tablet comprising a wax-based stomach. This suspect can be prepared as follows. For example, you can give it a gift (such as a Brazilian palm, a octadecyl hexadecanol mixture or a fatty acid or a group thereof), 43 200800198 and always: sputum and filler (such as micro Crystalline cellulose and = agents, fillers, lubricants and the like), and cold storage. The prepared preparation can be selectively coated with two = release rate controlled release polymer, which can be used as a suitable financial adaptation. This is not a limited case of Brazilian palm, a mixture of ten or ten flavors, fatty acids or

Mixtures of more or more. The matrix lozenge may also comprise - or a plurality of release rate controlling polymers as described herein. 10 shirts are specifically implemented, the matrix tablet is - contains polyethylene oxide

Alkyl-based bond' wherein the substrate can be, for example, without limitation, a polyepylene tree, such as Sentry polyoxTM (10) Union Carbide Corporation or Its equivalent. Suitable Polios include PolysTM WSRN-10, N-6K, WSR-1105N 15 or WSR 303. The molecular weight range of the Polios view can be, for example, 1 〇〇, 〇〇〇 to 7,000,000, or 9 〇〇, 〇〇〇 to 5,000,000. The polyethylene oxide can be present in the total amount (by weight), for example, from about 5% or from about 10% to about 40% or about 75% of the formulation, from about 5% to about 4 Torr. % or from about 10% to about 20% is preferred. The matrix blowing agent may also include one or more 2〇 release rate controlling polymers as described herein. In certain embodiments, the matrix tablet is a tablet comprising one or more release rate controlling polymers (as the matrix forming polymer) as described herein. In certain embodiments, the tablet comprises one or more hydroxypropyl methylcelluloses as described in the matrix as described herein as a substrate. In certain preferred embodiments, high viscosity hydroxypropyl methylcellulose (such as Metuoxiu Μ4Μ) may be used in excellent amounts, for example, from about 15% to about 70% by weight, And about 8% to about 5% are preferred. Other south viscosity polymers can also be used, such as, for example, Mido Hide κ κι $jyj, Beauty 5

10 15

20 Multi ShowTM Κ100Μ or Mido ShowTM E4M and its analogues. In certain embodiments, low viscosity hydroxypropyl methylcellulose, E50LV, Metso® Ε5, Metodox® 6 or Metsubishi® ν or combinations thereof and the like can be used. In certain embodiments, both high viscosity and low viscosity hydroxypropyl methylcellulose can be used in the matrix. In certain embodiments, when the low density thiomethylcellulose is present in the range of from about 15% to about 7 G% (more than 25% to about 5%), the high density of the propyl group The base cellulose is present in an amount (by weight) of from about 2% to about (10). The core composition or component may be included in any layer of the dosage form of the present invention, and a release rate controlling polymer (which is included in the layer containing the active compound: or a social shot (including inclusion of an active person) may be used. a layer, such as an enteric coating, to achieve sustained release of the active compound: a coating onto a pellet, bead or ellipsoid comprising the active compound, and a hybrid injection comprising the enteric coating itself in. Some of the matrix mirror-compounds of the present invention are present in an amount (by weight) of from about 0.02 to about J. Up to about 4%. Pregnancy = inventing the thin or smear of the drug, and the release rate of the polymer or the cation涂45 200800198 Special &amp; layer known as a coating or cover, or any combination thereof. In certain preferred embodiments, the tablet of the formulation of the present invention is coated with a film. The present invention provides a method for preparing a 4-cyano group {(R) 2_[4-(2,3' dihydro-abido[ι,4]diamyl _5-yl)-speaking small group]_ A method and/or process for the sustained release formulation of 5 propylbuprofen, a pharmaceutically acceptable salt thereof, a structurally related compound, and/or a metabolite. In a specific embodiment, a composition comprising the active ingredient and at least one rate controlling polymer and at least one organic acid is compacted for a period of time under conditions effective to form a bonding agent. In some embodiments, the tablet is further coated with, for example, a film. In another specific embodiment, the active ingredient is mixed with at least one release rate controlling polymer and at least one organic acid, thereby forming a mixture which can be further compacted for a period of time under conditions of forming a tablet. . In some embodiments, the tablet is coated, for example, with a film. I5 In a preferred embodiment, the mixture is a dry mixture. In some specific cases, the Hunan roller is compacted to prepare the formulation. For example, a tablet can be prepared by granulation followed by milling. In some embodiments, the active ingredient, a filler (eg, microcrystalline fibers and a polymer (eg, hydroxypropyl methylcellulose) are granulated and then ground. Then, the: 2 Fines and other excipients such as, for example, citric acid and magnesium stearate. 9 In accordance with the present invention, there are also a number of techniques that are already available to obtain sustained release oral formulations, including those described above. , and micro and giant capsules, fibers, polymerization (high density and low density) and non-polymeric matrix II 46 200800198

10 15

'Sponge plastics, lipid granules, micelles, gels, physically disperse the drug in poly=, porous, microporous or non-porous matrix, adsorb onto the ion exchange tree, and chemically or biodegradable The matrix and its analogues are mixed or 2 to ^ above. The active compound can be formulated using a formula that allows the drug to achieve a single-maximum concentration, or the drug can be formulated to be capable of being shipped by a second or picopulse pulse. B ^ ‘ a liquid (4) includes syrups, suspensions, emulsions, and medicinal solutions. The liquid carrier may include an organic or water-based test, and may be modified by a pharmaceutical additive such as a solubilizing agent, an emulsifier, a slow-reducing agent, a flavoring agent, a suspending agent, a supplement, a coloring, and a (10) agent. , stabilizer or osmoregulators, S... combination. The aqueous carrier can also include, for example, a polymeric substance or an oil. Seven people also provide immediate release dosage forms. The immediate release dosage form of the present invention I (9) active ingredient, for example, 4·cyanide 2, 3-zirconium_open [1,4]-. The final 5_ base) then] _ base] _ propyl ν Μ 2 _ _ 2 - 醯 醯 醯 醯 醯 醯 医 医 医 医 医 医 醯 醯 醯 醯 醯 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受 可接受In some specific embodiments. The active ingredient of Hai can be micronized. The immediate release formulation is substantially non-testable. In a preferred embodiment, the immediate release formulation comprises the active ingredient, at least one filler, and at least a slip agent. The novelty of the present invention may additionally include any of a wide variety of materials which impart beneficial properties to the formulation. Such materials include, for example, solubility modifiers (such as surfactants such as, for example, 'lauric acid lysine, acidic compounds), fillers, lubricants, 47 200800198 antioxidants, pH modifiers, chelating agents, disintegrants, combinations Agent, diazepam excipient (which includes water-soluble excipients such as sugars; and water-dispersible excipients such as microcrystalline cellulose, colloidal polyoxynitride, deuterated microcrystalline fibers And starch). Typical ranges for such lubricants range from about 〇 2% to about 5 5% by weight. In one embodiment of the invention, the amount of the lubricant in the 15 mg form is from about 0.5 to about 1 mg. The range of the filler can be, for example, from about 70% to about 99% by weight. In a particular embodiment of the invention, the filler is present in an amount of from about 8 Torr to about 149 mg in a 150 mg dosage form. The immediate release dosage form of the present invention may comprise any convenient percentage and part 10 (relative to other ingredients) of the active compound. The formulation typically comprises from about 0.05% to about 10% by weight of the active ingredient. - For example, in one embodiment, the immediate release formulation is in each active ingredient (eg, 4-cyano-characteristic {(2,3-dihydro-benzo[1') 4] 1% cultivating -5-base) · slightly π well small base p propyl group pyridine bite _2 _ benzoylamine or μ its pharmaceutically acceptable salt) containing about 297 parts of filler and Approximately 15 parts of the lubricant. In another embodiment, the immediate release formulation is in each of the active ingredients (eg, 4-cyano-character { (called 2-[4-(2,3-dihydro) -Benzo[M]: 圬-5-yl)-piperidinyl] propylpyridin-2-ylbenzoylamine or a pharmaceutically acceptable salt thereof, comprising about 29 parts of a filler and About 0.15 parts of lubricant. In another specific embodiment, the immediate release formulation is in each of the ingredients (for example, 4-cyano county {(2R)-2-[4_(2,3_two) Hydrogen-benzo[1,4]di(tetra)-5-yl)propyl}_N" than 7-2|Benzene amine or its medicinal salt 48 200800198 pharmaceutically acceptable salt) contains about bay filler and about 0.75 Part of the lubricant. In a specific embodiment, the immediate release formulation is in each of the ingredients (for example, 4_cyano·N_{called 2 Yang, 3•2 _Benzene _ ♦ can be. Well base) 耕 七 七 ] _ _ _ 比 比 比 比 比 比 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含 包含3 parts of lubricant 0 The immediate release formulation contemplated by the present invention may be in any form suitable for administration to a mammal, and is not limited to the examples presented herein. 10 The present invention provides a species comprising 4·cyanide Base _Ν·{called 2_[4_(2,3_dihydro-benzo[1,4]-a-based)+well small base]_propyl buppyrazine-phenyl-amine, its medicinal Immediate release of the accepted salt and/or its metabolites - preparation method and/or process of the formulation. In a specific embodiment, under the condition that the tablet can be effectively formed, the compaction comprises the active ingredient and at least 15 A composition of a filler and at least one lubricant for a period of time. In some embodiments, the tablet is further coated with, for example, a film. In certain embodiments, the active ingredient is at least one of the fillers And mixing with the skid/slip agent, thus forming a mixture. Further compacting the mixture under conditions in which the tablet can be formed In some specific examples, the bond is further coated with, for example, a film. In some embodiments, the formulation is prepared by roller compaction. The immediate release dosage form can be continued. The release dosage form is, for example, in the form of a coated pellet, sphere, capsule, powder or suspect. Thus, in accordance with the present invention, sustained release and immediate release dosage forms have been provided, 49 200800198 which includes both oral and parenteral sustained release dosage formulations. Therefore, the present invention includes a number of techniques for the presence of a secretis immediate release-oral (four) formulation. The active compounds according to the invention can be delivered via mucosal, vaginal, rectal, ocular, transdermal, intrauterine routes and the like. 5 Therefore, the present invention provides, inter alia, a 4-cyano-N-{(2R)-2-[4&lt;2 3 -dihydro-benzo[1,4]dioxin-5-yl)-piperidin- a dosage form of kibpropyl}·Ν•pyridyl alum amide, a pharmaceutically acceptable salt thereof, a structure-related compound, and/or a metabolite, an immediate delivery of cyanocyano-Ν·{(2ίΙ)-2_[4· (2,3·Dihydro-benzo[1,4]di, __5_yl)4-mentyl-based]_10-propyl bromide ratio, fixed _2_yl-benzoguanamine, which is pharmaceutically acceptable Salt, structure-related compounds and/or methods of metabolites, and continuous transmission ^ Essence County {(2 Office 2_[4_(2,3·Dihydro.benzo[[]] twenty wells) Method for "Chen Geng Xiaoji l·propyl}-Ν_pyridone_2_yl-benzoguanamine, a pharmaceutically acceptable salt thereof, a structure-related compound and/or a metabolite over a prolonged period of 15 cycles In certain embodiments, the dosage form can be administered every 24 hours, once every 12 hours, or every 6 hours. "The dosage forms described herein can be promoted via a number of routes including oral administration. Immediate or sustained release of the active compound in a mammal In a preferred embodiment, the dosage form comprises the compound decyl cyano N {(2R) 2 仏 (2,3-dihydrobenzo[1,4] ico[_5_yl]) | kibpropyl}-purine-pyridine-2-yl-benzoylamine (the preferred hydrochloride salt of which is generally referred to as 歹=口肉坦). In a preferred embodiment of the invention, a歹 歹 扣 扣 扣 与 与 与 与 与 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 Pharmacokinetic curves (as compared to immediate release dosage forms). When administered to a patient population, an oral dosage form containing a scutellaria can achieve an average maximum (eg, crest) in the patient population. 5 degrees (Cmax), and the average minimum sedum plasma concentration = (cmin) obtained in the patient population. The preferred sustained release dosage form of the invention will reduce its variation in plasma levels in the patient population. The preferred sustained release dosage form of the present invention will reduce its variation in maximum and trough plasma levels in the patient population. As used herein, the peak or maximum concentration (cmax) of an active ingredient (such as scutellaria) in plasma, the area of an active ingredient (such as scutellaria) in plasma versus concentration versus time (AUC) And the time (tmax) at which the active ingredient (such as the scutellaria) reaches the maximum plasma concentration in the plasma is a pharmacokinetic parameter well known to those skilled in the art. Kinetics (Applied Bi〇pharmaceutics and corpse / ^ brain (10) ^ 叫, Chapter 7; Scarle and Yu (Yu), 4th edition, 1999). These pharmacokinetic parameters were measured in a steady state in the fasting group unless otherwise noted. The concentration versus time curve measures the concentration of active ingredient 20 in the serum of a patient versus time after oral administration of a dosage form. "Cmax, is the maximum concentration of the active ingredient in the serum of the patient after administration of the dosage form to the subject. "tmax" is the active ingredient in the serum of the patient after administration of the dosage form to the patient The time at which the maximum concentration is reached. The plasma drug concentration at any point after administration of the drug is (e.g., c9* or C24〃4). "c-bottom" refers to the bottom of the dose interval 51 200800198. Plasma drug concentration. "Plasma drug concentration," or "plasma concentration" is expressed as mass per unit volume, typically in nanograms per milliliter. Those skilled in the art will recognize that the plasma drug concentration obtained in each patient will vary due to variability in the parameters affecting absorption, distribution, metabolism, and excretion of the drug between patients. For this reason, the average values obtained from the patient group ("patient group") are used herein unless otherwise indicated. As used herein, the area under the curve of 10 degree concentration versus time in plasma is calculated according to the linear up/l〇gd〇wn trapezoidal rule. (AUC). Estimate the "transfer rate," or "absorption rate" by comparing the time (tmax) to the maximum concentration (Cmax). Use the mother-free method to analyze both Cmax and tmax. Use the variance analysis (anova) Comparison of pharmacokinetics between immediate and performance-release formulations. P &lt; 0.05 is considered significant. Results are provided as mean + / _ SEM. Equivalent drug 15 kinetic parameters are usually referred to for this test. The 90% confidence interval for the ratio of the central value of the pharmacokinetic parameter of the reference formulation is comprised between about 0.8 and about 1.25. In one aspect of the invention, the sustained release formulation will be achieved in a patient a cmax and a C24 in the patient, wherein the average ratio of 20 Cmax/C24 in the patient population ranges from about 5:1 to about 1.1··i. In certain preferred embodiments, 'in the patient population The average ratio of Cmax/C24 is from about 3 ·· i to about 1.1 : 约 2.8 : 1 to about L1 ·· i, about 2·5 to about u ·· i, about 2 3 ·· 1 to about 1·1 : 1 or even about 2 : 1 to about 1.1 : 1 or about 1 5 : i to about ii : i. Therefore, in some embodiments , in the patient population (: 11 ^ / (: 24 average 52 200800198 rate, spoon 5. In other specific embodiments, the average ratio of cmax / c24 in the patient population is about 3, about 2.8, about 2.5 or even about 2.3, about 2 or about 1.5. In a particular embodiment, the c_ and C24 values are measured after administration of a single dose of the drug to the patient. In some embodiments, 5 mg 5 of a single-dose drug. In other specific embodiments, these cmax and c24 values are measured in a steady state in a fasted group.

In one aspect of the invention, the sustained release formulation will achieve a Cmax in the patient and a c24 in the patient, wherein the average ratio of Cmax/C24 in the patient population ranges from about 24:1 to about i: 1. About to about 1": 10b about 2: 1 to about u: 卜 about h9 to about U: 卜 about 1.5: 1 to about 1.1: 1 or about 1.25 · 1 to about U: Bu, therefore, in certain In a specific embodiment, the average ratio of C jobs/C24 in the patient population is about 23. In other embodiments, the average ratio of cmax/c24 in the patient population is about 2, about 19, about i 5 or even about 1.25. In one view, these cmaxK24 values are measured in the fasting group under steady state 15 (e.g., after 28 times (four) of the drug is administered to the patient). In certain embodiments, the drug is administered in a daily dose of 1 mg. In other embodiments, these Cmax and c24 values are measured after a single dose of the drug is administered to the patient. In some embodiments, the change between Cmax and Ci2 or c24 20 in the patient population can be characterized by a percentage change. For example, in some cases, the average ratio of c/C24 or cmax/c12 in a group of patients who have been administered sedum will not exceed about 25%, in the patient group (10) Also _ _ = no more than about 100%, about 50%, (10)% or even about 25%. In certain specific 53 200800198 embodiments, cmax and C12 or c24 are measured in a steady state. In other embodiments, 'cmax and Cmin are measured after a single dose of the drug is administered to the patient. In certain aspects of the invention, the sustained release formulation will achieve an average cmax in the group of 5 patients. And an average c24 is reached in the patient population, wherein the ratio of the average Cmax/average c24 is from about 5:1 to about 1.1:1. In certain preferred embodiments, the ratio of average Cmax/average c24 is from about 2.8:1 to about 1·1··1, from about 2:4 to about 1.1:1, from about 2.3 to about 1.1:1, about 2 : 1 to about 1.1 : 1, about 1.5 : 1 to about i_i : 1 or even about 1 25 : i to about ij : 1. Thus, in some embodiments, the ratio of average Cmax/average C24 is about 5, about 2.8, about 2.4, about 2.3, about 2, about 1.5, or even about 1.25. In one aspect, these Cmax and C24 values were measured after a single dose of the drug was administered to the patient. In certain embodiments, 5 mg of a single dose of the drug is administered. In one aspect, these cmax and C24 values are measured in a fasted group under steady state (eg, 15 after 28 doses of the drug are administered to the patient). In one aspect of the invention, the sustained release formulation will achieve an average Cmax in the patient population and an average c12 in the patient population, wherein the average Cmax/average Cu ratio is from about 3:1 to about 1 ·1 : 1. In some preferred embodiments, the average Cmax/average c12 ratio is from about 2.3:1 to about 1.1, 1, about 2:1 to about ΐ·ι:ι, about 9 to about ij: i, about 15:1 to about 1.1:1 or about 1.25:1 to about u: !. Thus, in some embodiments, the ratio of average Cmax/average C&gt;2 is about 2.3. In other embodiments, the ratio of average Cmax/average Cu is about 2, about, about 175, or even 54 200800198, scoop 1·5 about 1.4, about 1.3, about (2), about i2, or about u. In some of the present embodiments, I and ^ are measured in a steady state. C progenitors and Cl2 were measured after other specific implementations of the drug administration to the patient. In certain embodiments, the drug is administered in a dose of 5 mg. A two-car 乂L's performance-release formulation can maintain a treatment period of more than 24 hours, which provides a daily-time dose of better sustained release formulation. It can reduce the incidence or severity of side effects with the treatment of phase 13 of the treatment. This negative side effect includes headache, dizziness, paresthesia, visual disturbances, tinnitus or a combination thereof. 1) The incidence of side effects is reduced. When measured in a group for comparison of the immediate release type of scutellaria, the incidence of side effects in the patient group is reduced, not all of the side effects. disappear. In the sustained release of the improved pharmacokinetic profile, the formulation has a dissolution profile that will release 15 out of the meat of no more than about 4 〇〇/0 at a measurement of about 2 hours. Tan, and about 50 to 85 〇 / 〇 will be released at the measurement of about 12 hours. It can be measured at 37 °C using a device 11 (paddle) at 50 rpm in 900 ml of USP pH 6.8 phosphate buffer (when passed to usp). Or the solubility of oral (iv). The use of a settling agent can be used for each type of bond or type. The filtered sample of the dissolution medium was collected at the time specified. The sample can be analyzed by chromatography on a reverse phase high performance liquid chromatography column and measured together with well known concentrations of the standard to measure the amount of active ingredient dissolved. The concentration of the active ingredient in each sample was measured by comparing the peak reaction of the chromatogram of the sample with the peak reaction accompanying the obtained standard chromatogram. Certain sustained release formulations may preferably reduce the peak plasma level of the scutellaria, but not to the extent of the Cmin (eg, the bottom) of the scutellaria or the absorption range of the scutellaria in the patient. Substantial impact. The sustained release formulation may achieve certain pharmacokinetic parameters when compared to the Lie 5 release dosage form. An example of such an immediate release formulation is a combination of microcrystalline cellulose (such as Avisco® (a commercial company of FMC), lactose monohydrate and magnesium stearate, which In the HC1 solution of o.1N, greater than 75% of the solubility of the active ingredient 10 can be produced in less than 25 hours. Certain sustained release formulations of the present invention preferably achieve an average cmax in the patient population. , which is lower than the average cmax achieved in the patient population in which the immediate release dosage form is administered. The average peak plasma level is reduced by at least about 10/◦ preferably by at least about 20%. In some embodiments, The average 15 peak plasma level is reduced by at least about 30% or more. In some embodiments, the mean peak plasma level is reduced by more than 50%. A single dose of 5 mg of the oral dose formulation achieves about 1 in the patient population. The average Cmax of 〇Nike/ml or lower is preferred. In another aspect of the invention, a multi-dose dose of 1 gram of dexamethasone can achieve about 350 ng/ml in the patient population. Average Cmax. In some specific embodiments In the steady state, the Cmax is measured. In other embodiments, the Cmax is measured after a single dose of the drug is administered to the patient. Certain sustained release formulations of the invention may preferably be achieved in a patient population. The average tmax, which is greater than the average tmax achieved in the patient population for administration of the immediate release dosage form, 56 200800198. The tmax is preferably two, three or even four times better. In some embodiments of the invention, The average tmax achieved in a patient population for administration of a sustained release dosage form of scutellaria is from about 4 to about 8 hours. The sustained release formulation of the present invention preferably achieves an average C-valley in the patient population, Substantially equal to that achieved in a patient population that is administered an immediate release dosage form. Maintenance can be achieved with those obtained from immediate release dosage forms

The degree of bottoming of the degree of comparison can maintain the therapeutic efficacy of the active ingredient. The preferred sustained release formulation of the present invention should achieve an interval of at least 8% of the average C-valley over 24 hours when compared to the immediate release agent 10 over the 12 hour interval. In certain embodiments, the average c(d) is at least about 90% or at least about 95% when compared to an immediate release dosage form. 15 20 In order to maintain the efficacy of the treatment, it is also preferred that the total amount of the scutellaria (AUC) absorbed by the sputum release dosage form is substantially equal to the immediate release formulation during the 24-hour dose interval. The amount of meat (four) that is absorbed. Thus, in a preferred embodiment, the sustained release dosage form achieves a 4 averaging whip in the * population, which is substantially equal to the average of the patient caps achieved in the immediate release dosage form. For example, when # is compared with the immediate release in 2, the touch and q should reach an average AUC of at least _%. In a 4b: tune:: when compared to an immediate release dosage form over a 24-hour interval:; the second eagle is at least about 90% or at least 95%. The Auc is about 125% of the AUC of the average release formulation. No more than this immediately. The present invention provides a method of including a Jiang Yi surname green 匕栝 to turn the % release coffee. In certain embodiments, &amp;, the patient's, and the sustained release dosage form are used to treat Alzheimer's disease in 57 200800198 patients. In some embodiments, the method of administering a sustained release of sputum also includes the step of identifying the patient's risk of adverse side effects by administering a scutellaria. In an exemplary embodiment of the invention, in order to discriminate against a treatable target patient in accordance with the methods of the present invention, an approved screening method can be used to measure the symptoms of Alzheimer's condition in the patient. In some views, routine medical procedures can be employed to determine whether the patient has suffered or is susceptible to - or multiple side effects associated with the administration of an immediate release agent. Patients who have suffered one or more of these side effects or are prone to - or a variety of these side effects can be classified as patients on the risk of side effects by administering the drug. In other aspects, an electrocardiographic measurement can be made to determine if the patient has any cardiac abnormalities (e.g., slow heartbeat), which can indicate that he or she can be better treated by a reduced formulation. These and other routine methods allow the clinician to identify patients in need of treatment with the methods and formulations of the present invention. 15 Preferred sustained release formulations of the present invention achieve certain average pharmacokinetic parameters in a patient population. The patient population can be selected based on the standard procedures used to conduct the randomized study. The patient population contains at least 12 selected individuals who do not have background knowledge of the metabolism of this type of drug in their body. 20 EXAMPLES Example 1: Identification of 4·cyano_N-{(2R)_2-[4-(2,3-dihydro-stupidin 14]two 3 cultivating bases) The metabolites of bit_2_yl-benzamine were extracted using a solvent (containing 10% methanol in ethyl acetate), followed by 58 200800198 semi-preparative HPLC to separate four fingers into M8, Mil, M12. And the metabolic products of M13. Semi-preparative HPLC was performed on a mixture of cesium acetonitrile/water containing 1 mM ammonium acetate on a 1⁄18 column (1:18 column (7.8) &lt; 300 mm, 10 μm). (ρΗ=4.5) was used as the mobile phase. 5 The structure of the metabolic product was determined based on NMR and mass spectrometry data. For NMR, all samples were dissolved in CD3CN. For the sample Mil, about 10% was added. D2〇 is used to increase the solubility. Proton and COSY data are obtained on all samples. For samples containing Mil and M12, HSQC and HMBC data can also be obtained to determine the structure. 10 Transmitted in dihydrobenzo-[1, 4] Hydroxylation of the diterpene-piperidine moiety to form the Meta, M12 and M13 metabolites. NMR studies were performed to determine the hydroxylation sites in these metabolites and to confirm the structure of M8.

Mil: Mil's 1D proton spectrum shows two aromatic protons in the 2,3-dihydro-benzo[M] diterpene fraction, and instead of 3 15 as in the parent compound, this indicates a benzene ring. Hydroxylation occurs on it. The two proton signals are bimodal, and this suggestion has been lightened at the C6 or cs position. In order to distinguish the two regio isomers, the ID NOE experiment was performed because it is expected to have a fairly strong n〇e correlation between the benzene proton and the travel proton. C6 is not related to this. This NOE correlation can be more accurately observed in this 1DN〇E experiment. Therefore, the structure of M11 is shown below, wherein the undone is on the C8 of the 2,3-dihydro-benzo[1,4]di-alpha moiety. 59 200800198

M12: The ID proton spectrum of M12 is more complex than expected for this metabolite. However, careful analysis of the spectrum suggests that the sample include isomers. Comparing the proton spectra of the M12 metabolite with its parent compound indicates that the aromatic 5 moiety and the piper moiety in M12 are quite intact. However, the protons of the 1,4-dioxole ring are quite different. Three secondary methyl signals were observed at 5.5, 5.15 and 5.1 ppm. For the sample, these methine protons can be integrated into one equivalent of protons. The HSQC data show that these methines have a carbon shift between 80 and 88 ppm, which is suggested to be hydroxylated on one of the diterpenoids. The COSY spectrum showed that the low magnetic 10 field methine protons were correlated with the methylene protons of the diterpene ring, which confirmed hydroxylation on the diterpene ring. The fact that more than two sets of signals were observed showed the presence of a palmitic isomer in the sample. It is not clear that the pair of palmitic isomers are produced by the enzyme or by racemization in the sample purification step. Based on the NMR results, the structure of the M12 is as follows:

60 15 200800198

M13: Compare the proton spectrum of M13 and M12. ^^ is very similar to M13. All aromatic protons observed in the parent compound can be observed in M13, which suggests that the aromatic moiety is intact in the metabolite. It has been shown that in M13, hydroxylation can also occur on the dip. Similar to M12, the M13 includes isomers as indicated by the four methine protons observed at 5.5, 5.19, 5.10, and 4.86 ppm. It should be noted that the signal strength of these four sub-bases will change over time, suggesting that the ratio of these isomers has changed. A similar change was observed in M12. In combination with the analysis results of M12, it can be shown that the observed NMR spectra of M12 and M13 are not representative of their original components. The NMR analysis indicated that M12 and M13 can be produced by crystallization on the second smear (which is consistent with the 2 and 3 positions). M12 and M13 can be rearranged and both can be racemized.

M8: Proton and COSY spectra of M8 were obtained for this sample. This data is consistent with the proposed M8 structure based on MS/MS analysis by DSM. The ton of the pyridine moiety, the piperene moiety and the cyano-propyl benzoguanamine moiety are all intact. The only omitted group compared to the parent compound is the 2,3-dihydro-benzo[1,4] bisazide moiety. 61 200800198

Example 2: with 4_qi---{(2 magic_2_[4-(2,3-dihydrobenzo[14]di- succinyl-5-yl)-piperidin-1-yl]-propyl b The structure of the structure-related compound of N_pyridine-2-ylbenzoylamine is different from the structure-related compound represented by formula 2-9. By preparative chromatography, from 4-cyano-n ](2R)_2_[4-(2,3-Dihydro-Benzene [1,4] Diterpenoid] Pipelined··[propyl}_Ν_α-pyridyl-2-yl-benzoguanamine For the preparation, the structure-related compound is isolated in an amount of about 丨mg and purity, and the spoon is 90/〇. The structure is established by using nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry, and measuring the number of protons that can be exchanged. Further processing as follows: 4-cyano-N](2R)_2_[4_(2,3-dihydro=open[1,4] twenty well_5_yl)_娘讲小基]_propyl &amp; Preparation of a pyridinium-diphenyl-aniline salt. The starting material is converted to a base by an aqueous solution of sodium hydroxide and ethyl acetate. The ethyl acetate/liquid mixture produced by azeotropic drying Dilute with heptane to obtain a 3:1 mixture of ethyl acetate/heptane and treated with silica gel. Repeatedly filtered and concentrated. The mixture is used to remove the helium. The base is treated with 1 liter of hydrogen chloride in ethyl acetate in ethyl acetate solution. The product is dissolved in the thermally degraded ethanol. The addition of $ and concentration of the mixture The product is crystallized by cooling and knife-pulled by filtration. The final cake is dried. This method can reduce the winter cyano N {(2R)_2-[4-(2,3-dihydro-benzo) [1,4] Second, the degree of dimer impurity of ___ _ _ _ _ _ _ _ _ _ _ _ phenyl benzoylamine. 62 200800198 Example 3: typical sustained release type of the present invention Component component function per button amount (mg) Fast medium-speed slow active core: 4-cyano-N-{(2R)-2"[4-(2,3-dihydro-benzo[1, 4·]2. Deficient 17 well-5-yl)-slightly-l-yl]-propyl)-N-pyridin-2-yl-benzoguanamine hydrochloride 3 Activity 5.0 5.0 5.0 Deuterated microcrystalline cellulose ( Prosov® HD90) Filler 169.0 94.0 88.75 HPMC (Medical ShowTMK4M Premium CR) Polymer 50.0 125.0 37.5 HPMC (Medical ShowTM K100M Premium CR) Polymer - - 112.75 Stearic Acid MgNF Lubricant 1.0 1.0 1.0 Anhydrous citric acid to improve in the intestine Rate 25.0 25.0 5.0 Core Child Weight (mg) 250 250 250 Film Coating: Opadry White (YS-1-18202A) White Film 7.5 7.5 7.5 Oubadai Transparent (YS-1-19025A) Transparent Film 1.25 1.25 1.25 Total lozenge weight (mg) 258.75 258.75 258.75 a: The amount of active ingredient may need to be adjusted depending on its release effectiveness.

63 200800198 Example 4: A typical sustained release formulation of the invention.

Component component function per button amount (mg) 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]2°? Base) - Brigade. Well-1-yl]-propyl}-14-pyridin-2-yl-benzoguanamine hydrochloride&quot; Active 5.0 2.0 microcrystalline cellulose (Aviso®?^! 112) Filling agent 46.5 52.5 Fast-flowing lactose filling Agent 100.00 100.00 HPMC (Medical ShowTM^!^! Quality CR) Polymer 55.00 55.00 HPMC (Medo Show _0001^ Quality CRLH) Polymer 37.50 37.50 Stearic Acid MgNF Lubricant 1.0 1.0 Water-free citric acid to improve Release rate in the intestine 5.00 2.00 Core weight (mg) 250 250 Oubadai white (YS4-18202A) White film 7.5 7.5 Oubaday transparent (YS4-19025A) Transparent film 1.25 1.25 Total tablet weight (mg) 258.75 258.75 a : The amount of the active ingredient may need to be adjusted depending on its release efficacy. 64 200800198 Example 5: A typical immediate release formulation of the invention. 〇·5 mg of spinner component requirement (kg) Weight/% by weight Input (mg/rotation) Micronized active ingredient a, b 0.5 0.33 0.50 Lactose monohydrate, NFb 79.17 118.75 Microcrystalline cellulose, NF 20.00 30.00 Magnesium stearate, NF • 50 0.75 Total 100.0 150.00 1 has a composition of 4-cyano-N- {(2R)-2-[4-(2,3-dihydro-benzo[1, 4] Dioxin-5-based)-Brigade 11 well-1-yl]-propyl}-Ν-π ratio bit-2-yl·this toramine hydrochloride.

a: the sexual moiety (free state base) is theoretically 93% of 4-cyano _^-{(211)-2-[4-(2,3-dihydro-benzo[I,4] diterpene -5-yl)-Plantic-1-yl]-propyldiazine-σ-pyridin-2-yl-benzoylamine hydrochloride drug substance. The actual amount added is based on the effectiveness of the hydrochloric acid drug substance. The input amount listed in the above table is based on the weight of the active ingredient. b: If the efficacy of the hydrochloric acid drug substance is not at loo%, it is necessary to adjust the input amount of the drug substance to match the adjustment of the input amount of the lactose monohydrate. c : including excess. The theoretical amount is 0.075 kg. 1·〇mg of tablet ingredients requirements (mg) Weight/% by weight Input (mg/rotation) Micronized active ingredient a'b 1.0 0.67 1.0 Lactose monohydrate, NFb 78.83 118.25 Microcrystalline cellulose, NF 20.00 30.00 Magnesium stearate, NF 0.50 0.75 Total 100.0 150.00 The active ingredient is 4-cyano-N- {(2R)-2-[4-(2,3-dihydro-benzo[1,4] $ σ井_5_基)-Nangyan-1-yl]-propyl}-oxime-pyridin-2-yl-benzoguanamine hydrochloride.

a : the active moiety (free state base) is theoretically 93% of 4-cyano-N-{(2R)H4-C2,3-dibenzo[1,4]diodenum_5·yl)ϋ · 1 -yl]-propyl} 吼唆 吼唆 · 2 · benzyl-benzoguanamine hydrochloride substance. The actual amount added is based on the effectiveness of the hydrochloric acid drug substance. The input amount listed in the upper $矣 is based on the weight of the active ingredient. b: If the potency of the hydrochloric acid drug substance is not 100%, it is necessary to adjust the input of the drug substance to match the adjustment of the input amount of the lactose monohydrate. ' c : Includes excess. The theoretical amount is 0.075 kg. 65 200800198 2·5 mg of tablet ingredient requirements (mg) Weight/% by weight 丄 input (milk/green added ιί \ micronized active ingredient a, b 2.5 — 1.67 2.50 lactose monohydrate, NFb 77.83 116.75 Microcrystalline cellulose, nf 20.00 30.00 magnesium stearate, NF • 50 0.75 total 100.0 150.00 brown small base • propyl) - Ν 比 than bit -2- benzoic acid amine salt,: a L,, - base Piper a: $ Tongue part (free state base) is theoretically 93% of 4-cyano_N_{(2R 知土$[1,4] 哼 哼 ^-基^-Pentin-1-yl] _propyl}_;^-bite-2-yl-benzoguanamine-acidic acid 1 歆===ΙίΐΙΙΙ__. The above table is shown in Table C: including excess. The theoretical amount is 〇·〇75 kg. 5.0 mg of key ingredient requirement (mg) Weight/% by weight Mountain input (grams/tablets) Micronized active ingredient a, b 5.0 3.33 5.0 Lactose monohydrate, NFb 76.17 114.25 Microcrystalline cellulose, nf 20.00 30.00 Magnesium stearate, NF • 50 0.75 Total 100.0 150.00 The active ingredient is 4-cyano-N- {(2R)-2-[4-(2,3-dihydro-stupid[M] -5-yl)-bred-l-yl]-propyl-N-pyridine 2-yl-benzoguanamine hydrochloride.

a ·· The active moiety (free state base) is theoretically 93% of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4] Now speaking -5-base)-Brigade-1-yl]-propyl yN-13 is a drug substance that is more specific than -2-yl-benzoguanamine hydrochloride. The actual amount added is based on the effectiveness of the hydrochloric acid drug substance. The amount of input listed in the upper &amp; table is based on the weight of the active ingredient. b: If the potency of the hydrochloric acid drug substance is not 100%, it is necessary to adjust the input amount of the drug substance to match the adjustment of the input amount of the lactose monohydrate. 〃 c : Including excess. The theoretical amount is 0.075 kg. 66 200800198 Example 6: Typical manufacturing instructions for a typical immediate release spinner 1. Feed lactose monohydrate and microcrystalline cellulose into a suitable container. 2.·4-Cyano-N-{(2R)-[4_(2,3-dihydro-benzo[1,4]di-p-menthyl) 讲 -1--1-yl]-propyl-N-pyridine The -2-yl-benzoguanamine hydrochloride is fed to a suitable 5 size tumbling machine mixing tank. A small portion of the fed lactose monohydrate is added and mixed into a tumble mixer. 3. The premix from step 2, followed by the microcrystalline cellulose, is passed through a 5 micron screen into a suitable size tumbling tank. Mixed people. 4. Transfer the premix from step 3 to a suitably sized tumble mix 10 tank. The remaining lactose monohydrate was passed through a 500 micron screen into the mixing tank. mixing. 5_ Weigh the mixture and calculate the amount of magnesium stearate required for the ingredient. The magnesium stearate is fed into a suitable container and mixed with a portion of the mixture from step 4. 15 6. The premix was passed through a 5 micron screen and into the remaining mixture in the mixing tank. The final mixture is mixed. 7. Press the mixture from step 6 using a suitable compacting machine fitted with a suitable tool to produce a bond having the desired weight and hardness. 8. Dust removal, check weight and visual inspection of the finished tablets. 20 Example 7: Single dose study between three sustained release formulations and one immediate release formulation of the scutellaria serrata. This study is a three-transformed release formulation and an immediate release type. Single dose, randomized, 4-cycle, crossover, and bioequivalence studies between healthy formulations on healthy subjects. Fasting overnight. 67 200800198 After at least 10,000 hours, the dose is administered orally. The formulation used in this study was 53⁄4 g immediate release (IR), 5 mg modified rapid release formulation (MR (fast)), 5 mg modified towel release formulation (10) R (Medium speed)) and 53⁄4 grams of modified slow release formulation (MR (slow speed)). These 5 formulations &amp; are provided in Example 3. 0.5, 1, 1, 5, 2, 3, 4, 6, 8, 1 , 3, 4, 6, 8, 1 , 12, 16, 24, 30, 36, and 48 within 2 hours of the test object, administration, and after administration of the test object At the hour, blood samples for the analysis of the broth were obtained. For the four-cycle crossover study, the variance analysis was used to compare the plasma concentration data and ρκ parameters of the scutellaria platans between the four formulations. An additional estimate of the geometric mean (log-to-conversion) of the maximum observed concentration (Cmax) of the squash meat is relative to the bioavailability, the area under the concentration-time curve (AUC), and the time from the AUC to the last measurable concentration ( AUCT) and its 90% confidence limit determine the amount of difference between these four formulations. The immediate release of the tablet was used as a reference treatment. Using a two-pass test, the logarithmic scale is used to construct a 90% confidence limit for parameter evaluation. When the 90% confidence limit falls within the interval (0·80, 1.25), the four treatments (formulations) are judged to have bioequivalence. A total of 20 subjects were involved in the pharmacokinetic data for this analysis. Figure 1 provides the average concentration versus time for the four formulations. As shown in Figure 1, the average Cmax of the IR formulation was 278.5 ng/ml. 2〇 The average value of the modified release formulation is less than 100 Ng/ml. The Cmax values for the MR (fast) and MR (medium speed) formulations were 99.7 and 95.1 ng/ml, respectively. The MR (slow speed) formulation had a Cmax value of 58.4 ng/ml. The Tmax of this IR formulation occurred at 0.88 hours. The Tmax values for MR (fast), MR (medium speed), and MR (slow speed) occur at 5.63, 8.83, and 7.90 hours, respectively. 200800198 The AUC values for this IR, MR (fast) and MR (medium speed) formulations ranged from 2058.8 to 2246.8 ngh/ml. The MR (slow) formulation has an AUC value of 1565.0 ngh/ml. For MR (fast) and MR (medium speed), the average AUC ratio of MR to IR formulations is greater than 1%. The average ratio of MR (slow speed) to the AUC of IR 5 was 79.3%. The average ratio of Cmax squash concentration at 24 hours (Cmax/C2 ratio) ranges from 23 (for IR formulations) to values 2·8, 2.3, and 3.5 (different to MR (fast) ), MR (medium speed), MR (slow speed) for the formulation). Example 8: Multiple dose study between three sustained release formulations of scutellaria and an immediate release 10 release formulation This study was a randomized, double-blind, placebo-controlled study to assess the following Safety, financial acceptability, pharmacokinetics, and pharmacodynamics studies: 1) Oral administration of multiple doses of 0.5, 1, 1, 2.5, and 5 mg of scutellaria using an immediate release (IR) formulation (eg, Two doses per dose (ql2h)) 15 to patients with mild to appropriate Alzheimer's disease (AD; age range = 53 to 80 years); and 2) use of sustained release (SR) formulations, 10 mg of multiple doses are administered orally (eg, once per dose (QD)) to patients with mild to appropriate Alzheimer's disease. Part 1: IR Formulation 20 In the 0.5, 1, and 2.5 mg dose groups (Groups 1-3), six subjects received scutellaria and 2 received placebo; however, at 5 mg Of the dose groups (group 4), there were 2 subjects receiving scutellaria and 4 receiving placebo. On days 1 and 28, within 2 hours of administration of the test object and after administration of the test object, 5, 1, 1.5, 2, 4, 8, 24 (only day 1) 69 200800198 At 28 hours (only on the 28th day), a sample of money for the analysis of the broth was obtained. Part 2: SR Formulations In this study, 12 subjects received a sputum meat emulsion (1 mg mg. 5 QD SR formulation) and 4 received a placebo. On the first day, in the first two doses (within 2 hours of test object giving), after 5, i, i5, and 24 hours of dose; and on the 28th day, at the initial dose, 1, After the 2, 4, 8, 24, 48 and 72 hour doses, blood samples for the analysis of the broth were obtained. ® A total of 11 AD patients (age range = 52 to 90 years) participated in 10 pharmacokinetic data for this analysis. After single and multiple doses of the SR formulation, a plateau-like concentration versus time curve (up to a 24-hour period) can be seen for all Bayesian subjects, and peak/bottom fluctuations (ie, Cmax) at steady state /Cmin)=1.9. After 24 hours, it can be seen that the concentration of the squash is beginning to decrease. In Part 1, after administration of both single and multiple doses, it can be seen that the average tmax of the column 15 and the 1R formulation ranged from 1 to 1.5 hours. In comparison, after - single and multiple doses, the mean value of the scutellaria and SR formulations were different for each • 8 and 4 hours. After a single dose of the SR formulation, the dose-dependent pharmacokinetic parameters Cmax and AUCq24 at doses of 5 mg and 1 mg are as follows: · 5 mg of SR single dose: Cmax = 99 7 Ng / ml, 20 AUC〇_24=1845 Nike hours/ml; 1〇mg^^ single dose··

Cmax^lOj Nek/ml ' AUC〇_24= 3 7 3 8.3 Ngh/ml. Based on a pharmacokinetic model of single-dose plasma concentration data obtained with a 5 mg SR formulation, it is predicted that the QD drug prediction of the Sr formulation predicts similar exposure (AucG_24), lower at steady state. Of the 70 200800198

Cmax and similar cmin (compared to ql2h and IR formulations). Consistent with these predictions, in AD patients, after administration of 5 mg of ql2hIR formulation, the average decoction of sulphate was steadily rated (AUCo-24) at 5788 ng*hr/ml; After 10 mg of the QDSR formulation, it was 6111 Nike* 5 hours/ml. The average value of 5 mg of ql2h IR was consistent with a Cmax of 450 Ng/ml (predicted model = 425 Ng/ml), which was stable compared to the 1 〇-mg QD SR formulation. State Cmax is 353 Ng/ml (predicted model = 319 Ng/ml). For 5 mg of ql2h IR and 10

• For milligrams of QD SR formulation, the bottom 10° concentration at the end of the dose interval is 180 Ng/mL and 184 Ng/mL. For a 10 mg QD SR formulation, the average Cmax/cmin ratio at steady state was 1.91. For 5 mg of q 12h IR, the average Cmax/Cmin ratio at steady state is 2.4. 5 mg of ql2h IR for the mean tmaj 〇.8, and 1 〇 mg of the QD SR formulation for the average tmax Is 4.2. 15 Example 9: Side effects' The table below illustrates the reduction in the incidence of side effects after treatment with a sustained release formulation (eg, compared to the immediate release formulation of the scutellaria). 71 200800198 Treatment of emergency side effects (TEAEs) Immediate release type (IR) for sustained release formulations TEAE stalks of sardine 5 mg IR sirloin 5 mg SR-fast stalks of sardine 5 mg SR-medium speed headache 1 0 0 Dizziness 9 0 1 Paresthesia 1 0 0 Visual disorder 2 0 0 Tinnitus 1 0 0 Total 14 0 1 Although the above 5 volumes have been described in detail for the purpose of clarity, it should be clear to the skilled worker. It will be understood from the disclosure that certain changes and modifications may be made without departing from the scope of the appended claims. All of the publications and patent documents cited above are hereby incorporated by reference in their entirety for all purposes in the same extent as the same as the same. [Simple description of pottery] Figure 1 is a graph showing the average concentration of sulphate versus time for three release-release formulations and one immediate release formulation after administration of a single dose of 5 mg of scutellaria. . 15 Brother 2 picture shows Alzheimer's disease in immediate release (5 times a day) and continuous release (daily-time 1G mg) of multiple oral doses. The money concentration is a sinogram. The figure is a sample of Alzheimer's disease in a dose of 72 200800198 scutellaria sustained release formulation (as described in Part 2 of Example 8) in a single and multiple oral doses. A plot of concentration versus time data. The first day showed 0 to 24 hours of data. The 28th day shows data from 0 to 72 hours. 5 Figure 4 is a graph comparing the mean plasma concentration versus time data for patients with Alzheimer's disease who received multiple oral doses of IR (5 mg) and SR (10 mg QD). [Main component symbol description] (none) 73

Claims (1)

200800198 X. Patent Application Range: 1. A method comprising administering an oral-administered dosage form to a patient, wherein the dosage form comprises a scutellaria and a pharmaceutically acceptable system, and the pharmaceutically acceptable system is A maximum plasma concentration (c_) is reached in 15 20 and a 24-hour plasma concentration (c24) is achieved in the patient patient, wherein the average ratio of 'A in the patient population ranges from about 5:1 to about ι·ι:1. 2. The method of claim 1, wherein the single-quantity sigma dosage form is administered to a patient and measured. 3. ^ The method of claim 2, wherein the oral dosage form comprises about $1 gram of squash. The method of claim 2, wherein the sputum in the patient population is from the priest, the η. The Cmax is about 1 〇〇N/ml or lower. 5. The method of claim 丨Wherein the average ratio of Cmax/C24i in the patient population ranges from about 3: i to about u··^. 6. The value of c_ and c24 is measured in the fifth application of the patent application after the administration of the morning dose of the oral coffee to the patient. 7.c. The method of claim 1, wherein the average ratio of max/C24 in the patient population is from about 2.8:1 to about u··J. 8. The method of claim 1, wherein the average ratio of max 24 in the patient population ranges from about 2.3:1 to about u··J. 9. If the patent application range is 1 in the patient population, the flat max is about 3.5 hours or more. 1〇·If the scope of the patent application is 1st, the method “where the flat gtmax in the patient population is about 5 hours or more. 74 200800198 11· A method comprising administering an oral dosage form to a patient, wherein The dosage form comprises a medicinal carrier and a pharmaceutically acceptable carrier, and which achieves a maximum plasma concentration (cmax) in the patient and a 24-hour blood concentration (c24) in the patient, the towel being in the patient The average ratio of the melons of the group of towels is from about 2.4:1 to about 1.1:1. 12. The method of claim 2, wherein in the fasting group, the Cmax and C24 are measured under steady state. The method of claim 2, wherein the method of providing the patient with a daily dose of about 〇 〇 〇 肉 肉 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 350 Ng/ml. In the method of claim n, wherein the average ratio of Cmax/c24 in the patient population is from about 2.3:1 to about u: i. Μ &amp; a method in which the average ratio of Cmax/C24 in the patient population is from 2: 1 to about 1.1: 1. 17. The method of claim </ RTI> wherein the average ratio of Cmax/C24 in the patient population ranges from about 1 #9:1 to about u:i. The method of claim U, wherein the average ratio of Cmax/c24 in the patient population ranges from about 15:1 to about u: 1. 20 1Q y•-type includes administering an oral dosage form to the patient. The method wherein the dosage form comprises a scutellaria and a pharmaceutically acceptable carrier, and which achieves an average maximum plasma concentration (Cmax) in the patient population and an average 24-hour plasma concentration in the patient population (C24) And wherein the ratio of the average Cmax/average c24 is from about 5:1 to about 0.5: 1. 75. The method of claim 19, wherein after administering a single dose of the oral dosage form to the patient, The method of claim 20, wherein the oral dosage form comprises about 5 mg of the squash stalk. • 5 22. The method of claim 19, wherein the average Cmax / average • C24 ratio from about 2.8 · 1 to about 1.1 : 1. 23 · Apply The method of claim 19, wherein the ratio of the average average Φ c24 is from about 2:1 to about 1.1: 1. %, as in the method of claim 19, wherein the Cmax/average C24 ratio is from about 1.5. : 1 to about 1.1 : ;!. &amp;-A method comprising administering a -π coffee to a patient, wherein the dosage form comprises a scutellaria and a pharmaceutically acceptable carrier, and which can be achieved in the patient population - an average maximum plasma concentration ( Cmax) and an average 12-hour plasma concentration 仏 in the patient population, wherein the ratio of the average C_/average Cl2 15 is from about 3:1 to about 0.5:1. • 26. The method of claim 18, wherein the average Cmax/average Ci2 ratio is from about 2:1 to about ι·ι:1. 27. The method of claim 18, wherein the ratio of the flat _/average c12 is from about 丨·5:1 to about Li:1. A method for reducing the negative side effects associated with administering a gentamicin to a patient, comprising administering an "oral dosage form" to a patient, wherein the dosage form comprises a scutellaria and a pharmaceutically acceptable (d), and can achieve a plasma concentration (cmax) in the patient and a 24-hour plasma concentration (c24) in the patient, wherein the average ratio of C_/C24 in the patient group is 76 200800198 from about 5:1 To about li: 1. 29. The method of claim 28, wherein the Cmax and c24 values are measured after a single dose of the oral dosage form is administered to the patient. 3 A method of reducing the negative side effects associated with administration of a scutellaria to a patient, comprising administering an oral dosage form to a patient, wherein the dosage form comprises a scutellaria and a pharmaceutically acceptable system And can achieve - maximum plasma concentration (Cmax) in the disease f and achieve a 24-hour plasma concentration (c24) in the sputum, wherein the average ratio of Cmax / C24 in the patient population is from about 2 · 4 : 1 To about 1.1 ·· i. 31. The method of claim 30, wherein in the fasting group, the cmax and c24 values are measured in a stable state. ^ 3 2 - a method for reducing the negative side effects associated with administration of a scutellaria to a patient, comprising: identifying a patient's risk of negative side effects by administering a scutellite; and The oral dosage form is administered to a patient, wherein the dosage form comprises a scutellaria and a pharmaceutically acceptable carrier, and a maximum plasma concentration (cmax) can be achieved in the patient and a 24-hour plasma concentration is achieved in the patient (C24) ), wherein the average ratio of C-/C24 in the patient population ranges from about 5:1 to about 1.1:1. The method of claim 32, wherein the 4CmjC24 value is measured after administration of the single-dose oral dosage form to the patient. The method of claim 32, wherein the negative side effect is headache, dizziness, paresthesia, visual abnormality, ear, or heart and human. 77 200800198 Μ. The method of claim 32, wherein The incidence of this negative side effect can be reduced. 36. A method for reducing the negative side effects associated with administration of a scutellaria to a patient, which includes identifying the patient by negatively administering the stalk The risk of side effects; and the administration of the oral dosage form to the patient, wherein the dosage form comprises a medicinal carrier and a pharmaceutically acceptable carrier, which achieves a maximum blood/increase (Cmax) in the patient and in the patient A 24-hour plasma concentration (Gy, wherein the average ratio of Cmax/C24 in the patient population is from about 2:4: i to about 1.1 ··1 〇37. The method of claim 36, wherein In the fasting group, the cmax and c24 values are measured under steady state. 38. If the method of claim 36 is applied, the negative side effects of the towel are headache, dizziness, paresthesia, visual disorder, tinnitus or Combination. 39· The method of claim 36, wherein the incidence of the negative side effect can be reduced. 4. A method for administering a scutellaria to a patient, the method comprising administering an oral θ 彳 to a patient, Wherein the dosage form comprises a cinnabar and a pharmaceutically acceptable carrier, wherein in a USP Type II dissolution apparatus, at 50 rpm in 900 ml of USP pH 6.8 phosphate buffer at 37 ° C When measured and used as a settling agent for each dosage form, the dosage form has an in-tube dissolution profile wherein: in the apparatus, no more than 4% of the 78 is released at the measurement of about 2 hours. And in the device, releasing about 5% to about 85% of the stalks at about 12 hours of measurement. 41. A method of administering a medicinal to a patient, the method comprising: Oral dosage form for administration to a patient, wherein the (4) comprises a medicinal carrier and a pharmaceutically acceptable carrier, and (1) an average of ^ can be achieved in the patient population, which is less than an immediate release formulation Obtained when an equal dose of scutellaria is administered to a patient population The average &lt;:^,; (ii) an average tmax can be achieved in the patient population that is greater than the tmax obtained when an equal dose of the acesulfame is administered to the patient population from the immediate release formulation; Iii) a score of concentration of carnitine versus time can be achieved, the curve having an area under the curve (AUC) in the patient population, which is substantially equivalent to the administration of equal doses of the drug to the immediate release dosage form. The AUC obtained in the patient group is the same. 42. The method of claim 41, wherein the oral dosage form achieves an average cmax of about 1 〇〇N/ml or less. 43. The method of claim 42, wherein the icmax is measured after administration of a single dose of the oral dosage form. 44. The method of claim 43, wherein the oral dosage form comprises about 5 mg of scutellaria. 45. The method of claim 41, wherein the oral dosage form achieves an average tmax of from about 4 hours to about 8 hours. 79 200800198 46. The method of applying the patent _41 can achieve an average fox of about 2 to about 2500 ngh/ml. 47. The method of claim 46, wherein the average AUC is measured after administration of a single dose of the oral dosage form. 10 15 48. The method of claim 47, wherein the oral dosage form comprises about 5 mg of scutellaria. 49. If the method of claim 41 of Wei Wei is applied, the mouth _ type can achieve an average of less than 400 Ng/ml. 5〇. If you apply for the special (4) 49 items, the cap oral coffee can reach an average of about 350 Ng / ml. 51. The method of claim 49, wherein in the fasting group, the Cmax 〇 A is measured in a steady state as in the method of claim 51, wherein the iq mg is labeled daily. Administration to the patient. 'Where the oral dosage form can be max ° ' wherein the oral dosage form can be achieved. 53. The method of claim 41 of the patent application achieves an average of about 4 hours to about 8 hours. 54. The method of claim 41 is about 5500. The average AUC to about 6300 ngh/ml. 55. A method for reducing the negative side effects associated with administering a gentamicin to a patient&apos; comprising administering an oral dosage form to a patient, wherein the dosage form comprises a scutellite and is pharmaceutically acceptable The carrier, and (1) thereof, can be achieved in the patient population - an average Cmax which is less than the average cmax obtained when a similar dose of the scutellaria is administered to the patient population from the immediate release formulation; 20 200800198 ( Ii) an average tmax can be achieved in the patient population that is greater than the tmax obtained from the immediate release formulation when an equal dose of the scutellaria is administered to the patient population; and (in) a list of scutellaria concentrations can be achieved A curve versus time that has an area under the curve (AUC) in the patient population that is substantially the same as the AUC obtained when the equivalent dose of the scutellaria is administered to the patient population from the immediate release dosage form. . 56. A method for reducing the side effects associated with administering a scutellaria to a patient, comprising: identifying a patient's risk of adverse side effects by administering a scutellaria; and administering an oral dosage form Administering to a patient, wherein the dosage form comprises a dextromethorphan and a pharmaceutically acceptable carrier, and (1) is achievable in the patient population - an average c_ which is less than the equivalent dose from the immediate release formulation The average value obtained when the medicinal medicinal administration is administered to the patient population is &lt;^^; the average tmax obtained by the release formulation of equal doses of the sessile meat; and (8) may be achieved in the patient population _ lithographic _, which is greater than When the immediate release of the drug is administered to the patient group, the curve of the concentration of the carcass to the time can be achieved. The AUC obtained at the time of the group is the same. Line, the area under the curve (AUC) of the curve, which is essentially [equal doses of dextromethorphan administered to patients including a method of treating a patient with Alzheimer's disease, 81 200800198 The sustained release formulation is administered to the patient. 5 10 15 20 58 - The use of a scutellaria can be used to prepare an agent comprising an oral dosage form in combination with a pharmaceutically acceptable carrier, and which achieves a maximum plasma concentration (cmax) in a patient And achieving a 24-hour plasma concentration in the patient (CM, wherein the average ratio in the patient population is from about 5:1 to about 1.1:1. 59. - the use of the species of scutellaria, which can be used to prepare a An agent in the form of an oral dosage form with a pharmaceutically acceptable carrier, and which achieves a maximum plasma concentration (cmax) in the patient and a 24-hour plasma concentration (C24) in the patient. The average ratio of patients in the group of towels is from about 2.4:1 to about ΐ·ΐ: 1. 6〇·----------------------------------------------------------------------------------------------- An oral dosage form of the agent, and which can be achieved in the patient population - mean maximum plasma concentration (c_) and an average 24 hour plasma concentration in the patient population), wherein the average cw average C24 ratio is from about 5 : 1 to about 〇.5 : i. 61. The use of a t-tank which can be used to prepare an agent in the form of an oral dosage form comprising a carrier which can be conjugated to a medicinal agent and can be doubled in the patient group 1 The concentration of money (^) and in the patient population - flat: the concentration of the boots (Ci2), wherein the ratio of the flat Cl2 is from about 3: 1 to about 〇·5: !. A use of a scutellaria sulphate which can be used to prepare an oral dosage form which is capable of reducing the administration of a medicinal preparation to a patient, wherein the dosage form comprises a squid and - The drug can be administrated with 82 02. 200800198, and a maximum plasma concentration (cmax) can be achieved in the patient and a 24-hour plasma concentration (Cm) can be achieved in the patient, where the Cmax in the patient population The average ratio of C24 is from about 5 ··1 to about u ··1. 63. The use of a squash, which can be used to prepare an agent in an oral dosage form that reduces the side effects associated with administering a scutellaria to a patient, wherein the oral dosage form comprises a squash And a pharmaceutically acceptable carrier, and a maximum mortar concentration (Cmax) can be achieved in the patient and a 24-hour plasma concentration (C24) is achieved in the patient, wherein the average ratio of Cmax/C24 in the patient population From about 2.4: 1 to about 1 1 : 1 〇 10 64 · - the use of a variety of stalks, which can be used to prepare an oral dosage form comprising a lysine and a pharmaceutically acceptable carrier An agent, although measured in a USP Type II dissolution apparatus at 5 rpm in 9 mM usp pH 6.8 phosphate buffer at 37, and using a settling agent for each dosage form, The dosage form has an in-tube dissolution profile, in which: 15 in the crucible device, no more than 40% of the decals will be released at the measurement of about 2 hours; and in the device, the measurement is performed in about 12 hours. About 50% to about 85% of the meat will be released. 〇 65. The use of a scutellaria can be used to prepare an agent in an oral dosage form which can be used in a patient and which comprises a medicinal carrier and a pharmaceutically acceptable carrier, and (1) An average Cmax is achieved in the patient population, which is less than the average Cmax obtained from the immediate release formulation when an equal dose of scutellaria is administered to the patient population 83 200800198; (ii) an average can be achieved in the patient population Tmax, which is greater than the tmax obtained when an equal dose of the acesulfame is administered to the patient population from the immediate release formulation; and (iii) a concentration versus time curve for the drug can be achieved, the curve being in the patient The population has an area under the curve (AUC) that is substantially the same as the AUC obtained when an equal dose of the acesulfame is administered to the patient population from the immediate release dosage form. 66. - a type of agent that can be used to prepare an oral dosage form that can be used in a patient to contain a medicinal carrier and a pharmaceutically acceptable carrier, and (1) can be used in a patient population An average Cmax is achieved which is less than the average cmax obtained when an equal dose of the acesulfame is administered to the patient population from the immediate release formulation; (9) an average tmax can be achieved in the patient population that is greater than immediate release a tmax obtained by administering a dose of the same amount of the chopped meat emulsion to the patient population; and (iv) a achievable-cluster concentration versus time curve, the curve having a curve in the patient group - in the curve τ Area (Auc), which is substantially the same as the AUC obtained when an equal dose of dextromethorphan is administered to a patient population from an immediate release dosage form. 67. - The use of a scutellaria sulphate - which can be used to prepare - an oral dosage form that reduces the negative side effects associated with administration of a scutellaria to a patient, including: 84 200800198 Meat to identify the risk of a patient with negative side effects; and to administer an oral dosage form comprising a tyrosin and a pharmaceutically acceptable carrier to the patient, and 5 (i) can achieve a patient population The average Cmax, which is less than the average Cmax obtained when an equal dose of acesulfame is administered to the patient population from an immediate release formulation; (ii) an average tmax can be achieved in the patient population that is greater than immediate release The formula determines the mean tmax obtained by administering an equal dose of scutellaria to the patient population; and (iii) achieving a concentration versus time curve of the scutellaria, the curve having one in the patient population The area under the curve (AUC), which is essentially the same as the AUC obtained when an equal dose of the acesulfame is administered to the patient population from the immediate release dosage form. The use of any one of claims 57 to 66, wherein the agent is used to treat Alzheimer's disease in a patient. 85