WO2020244615A1 - 一种拉考沙胺药物组合物及其药物制剂 - Google Patents

一种拉考沙胺药物组合物及其药物制剂 Download PDF

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WO2020244615A1
WO2020244615A1 PCT/CN2020/094556 CN2020094556W WO2020244615A1 WO 2020244615 A1 WO2020244615 A1 WO 2020244615A1 CN 2020094556 W CN2020094556 W CN 2020094556W WO 2020244615 A1 WO2020244615 A1 WO 2020244615A1
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lacosamide
release
sustained
pharmaceutical composition
acceptable salt
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PCT/CN2020/094556
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English (en)
French (fr)
Inventor
吕少琼
李守峰
马红岩
郑�勋
王众勤
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上海奥科达生物医药科技有限公司
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Priority to CN202080053128.8A priority Critical patent/CN114173763A/zh
Priority to CA3148705A priority patent/CA3148705A1/en
Priority to EP20819422.5A priority patent/EP3981390A4/en
Publication of WO2020244615A1 publication Critical patent/WO2020244615A1/zh
Priority to US17/177,485 priority patent/US11337943B2/en
Priority to US17/664,513 priority patent/US11883374B2/en
Priority to US18/478,797 priority patent/US12042474B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the invention relates to a pharmaceutical composition of lacosamide and a pharmaceutical preparation thereof, in particular to a pharmaceutical composition of lacosamide as an active ingredient and a lacosamide sustained-release preparation containing the pharmaceutical composition.
  • sustained-release preparations are widely recognized and applied, and sustained-release preparations have many obvious clinical advantages, such as reducing the frequency of administration and maintaining a stable blood concentration for a longer period of time.
  • the oral sustained-release multiparticulate system has the technical feature of "dose distribution", which makes the distribution and absorption of the drug in the gastrointestinal tract more uniform.
  • Lacosamide also known as lacosamide, is an anticonvulsant, which has been approved for marketing in many countries for the treatment of partial seizures.
  • Lacosamide is well tolerated in the treatment of epilepsy.
  • the daily dose can reach 200-400 mg/day.
  • the most common side effects are dizziness, diplopia, headache and nausea.
  • the high daily dose of immediate-release preparations may lead to a high incidence of adverse reactions.
  • the incidence of side effects of lacosamide is directly related to the maximum steady-state plasma concentration of lacosamide (C max, ss ), and the efficacy of lacosamide in the treatment of epilepsy is mainly related to the area under the steady-state plasma concentration-time curve ( AUC ss ) related.
  • the marketed dosage forms of lacosamide include immediate-release tablets, oral solutions and intravenous solutions. Immediate release tablets (IR, ) It is administered twice a day, with specifications of 50mg, 100mg, 150mg and 200mg. So far, there is no sustained-release preparation of lacosamide that is taken orally once a day on the market. Therefore, there is a clinical need to develop a sustained-release formulation of lacosamide that is taken orally once a day to reduce adverse reactions and improve patient compliance.
  • IR immediate release tablets
  • the present invention provides a pharmaceutical composition of lacosamide, which comprises sustained-release multiparticulates, wherein each of the sustained-release multiparticulates comprises:
  • the drug-loaded core comprises an inert pellet core and an outer layer surrounding the inert pellet core, and the lacosamide or a pharmaceutically acceptable salt thereof is placed in the outer layer.
  • the lacosamide or a pharmaceutically acceptable salt thereof is uniformly dispersed in the drug-loaded core.
  • the lacosamide or a pharmaceutically acceptable salt thereof is released (w/w) according to one or more of the following in vitro dissolution rates: (a) 0.1-8% within 1 hour, (b ) 2-25% within 2 hours, (c) 18-70% within 4 hours and/or (d) 70-100% within 10 hours, 12 hours, 14 hours, 16 hours or 20 hours, of which
  • the dissolution rate was determined using the US Pharmacopoeia dissolution method II (paddle method), the rotating speed was 75 rpm, the temperature was 37 ⁇ 0.5°C, and the dissolution medium was 900ml 0.1N HCl.
  • the lacosamide or a pharmaceutically acceptable salt thereof is released (w/w) according to one or more of the following in vitro dissolution rates: (a) less than 8% in 1 hour, (b) Less than 12% within 2 hours, (c) less than 45% within 4 hours and/or (d) greater than 50% within 12 hours, wherein the dissolution rate is determined using USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measured in 900ml pH 1.0HCl/NaCl buffer for 2 hours, and then transferred the sample to 900ml pH 6.8 phosphate/NaCl buffer under the same dissolution method, speed and temperature for 4 hours, and then Under the same dissolution method, rotation speed and temperature, transfer the sample to 900ml pH 7.5 phosphate/NaCl buffer and continue the measurement for at least 6 hours.
  • USP Dissolution Method I basic method
  • the lacosamide or a pharmaceutically acceptable salt thereof accounts for about 40% to about 80% by weight of the particles.
  • the sustained-release agent accounts for about 5% to about 30% by weight of the particles.
  • the weight ratio of the lacosamide or a pharmaceutically acceptable salt thereof to the sustained release agent is about 15:1 to about 1:1.
  • the lacosamide pharmaceutical composition comprises the lacosamide or a pharmaceutically acceptable salt thereof in an amount of about 20 mg to about 600 mg.
  • the non-pH-dependent sustained-release agent is selected from ethyl cellulose, methyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl acetate, polyacrylate, polymethyl cellulose Acrylate, quaternary amino methacrylate copolymer type A (copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.2)), quaternary amino Methacrylate copolymer type B (copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylaminoethyl methacrylate (1:2:0.1)), copolymer of ethyl acrylate and methyl methacrylate And any mixtures of them.
  • quaternary amino methacrylate copolymer type A copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl
  • the lacosamide pharmaceutical composition further comprises an immediate-release part, wherein the lacosamide or a pharmaceutically acceptable salt thereof in the immediate-release part accounts for the lacosamide in the pharmaceutical composition. 1% to 40% (w/w) of the total amount of salamine or its pharmaceutically acceptable salt.
  • the present invention provides a sustained release formulation of lacosamide, which comprises the lacosamide pharmaceutical composition of the present invention, which is a capsule, sachet, sprinkle, caplet, lozenge, bag, tablet Or any other dosage form suitable for oral administration.
  • the present invention provides a sustained-release formulation of lacosamide, which comprises an immediate-release part and a sustained-release part, wherein lacosamide or a pharmaceutically acceptable salt thereof in the immediate-release part accounts for the formulation 1% to 40% (w/w) of the total amount of lacosamide or its pharmaceutically acceptable salt.
  • the present invention provides a method of treating neurological or psychiatric diseases or disorders, which comprises administering to a subject in need thereof a therapeutically effective amount of the lacosamide pharmaceutical composition of the present invention Or lacosamide sustained-release preparations.
  • the present invention provides the use of the lacosamide pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of neurological or psychiatric diseases or disorders.
  • the present invention provides the lacosamide pharmaceutical composition or lacosamide sustained-release preparation of the present invention, which is used for the treatment of neurological or psychiatric diseases or disorders.
  • the disease or condition is selected from epilepsy, migraine, essential tremor, restless limb syndrome, cluster headache, neuralgia, neuropathic pain, Tourette syndrome, infantile spasm, anxiety, double Phase disorder, psychosis, mania, schizophrenia, depression, dementia, autism, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, impulse control disorder, borderline personality disorder, addiction, Chronic neurodegenerative diseases, acute neurodegeneration and amyotrophic lateral sclerosis.
  • the disease or condition is partial-onset epilepsy.
  • the pharmaceutical composition or formulation is administered orally once a day.
  • the peak-trough fluctuation (PTF) of the pharmaceutical composition or formulation is less than about 70%.
  • the pharmaceutical composition or formulation administered orally once a day is the same as an immediate release formulation of the same daily dose of lacosamide administered orally twice a day In comparison, its PTF is reduced by at least 15%.
  • the pharmaceutical composition or formulation administered orally once a day is the same as an immediate release formulation of the same daily dose of lacosamide administered orally twice a day
  • the AUC ss and C max,ss are 80% to 125% of the immediate-release preparation.
  • Figure 1 depicts a particle in which the active ingredient is dispersed in a drug-loaded core.
  • Figure 2 depicts a particle with an active ingredient dispersed in an outer layer surrounding an inert pellet core.
  • Figure 3 shows the dissolution and release characteristics of the sustained-release multiparticulates of Example 4.
  • Figure 4 shows the dissolution and release characteristics of the sustained-release multiparticulates of Example 5.
  • Figure 5 shows the dissolution and release characteristics of the sustained-release multiparticulates of Example 6.
  • Figure 6 shows the dissolution and release characteristics of the sustained release multiparticulates of Example 7.
  • Figure 7 shows the dissolution and release characteristics of the sustained-release multiparticulates of Example 8.
  • Figure 8 shows the dissolution and release characteristics of the lacosamide sustained-release capsule of Example 10.
  • sustained-release formulations of lacosamide or a pharmaceutically acceptable salt thereof Without reducing its effectiveness, the preparation can adjust the dissolution of active ingredients, reduce PTF and adverse reactions.
  • lacosamide lacosamide
  • lacosamide active pharmaceutical ingredient
  • active ingredient active ingredient
  • lacosamide in the pharmaceutical compositions or formulations described herein can be used in various pharmaceutically acceptable forms, including but not limited to salts, hydrates, polymorphs, co-crystals, anhydrates, and amorphous forms. And its solvates.
  • sustained release refers to the slow release of the active pharmaceutical ingredient over an extended period of time greater than about 2 hours, preferably greater than about 4 hours, more preferably greater than about 8 hours, more preferably greater than about 12 hours, more preferably greater than about 16 hours to greater than about 24 hours.
  • immediate release means that the active pharmaceutical ingredient releases greater than or equal to about 80% in less than or equal to about 1 hour. Generally, the active pharmaceutical ingredient in the immediate-release preparation can release greater than or equal to about 80% in less than or equal to about 30 minutes.
  • sustained-release part or “immediate-release part” refers to particles that allow the active pharmaceutical ingredient to be released slowly or quickly, or when the particle has a two-layer or multi-layer sustained-release-rapid-release structure, it means that the active pharmaceutical ingredient is slowly released.
  • the release of a pharmaceutical composition or preparation means that the pharmaceutical composition or preparation is placed in an aqueous environment, and the active pharmaceutical ingredient contained therein leaves the pharmaceutical composition or preparation to dissolve in the aqueous environment.
  • the release amount of the active pharmaceutical ingredient in the pharmaceutical composition or preparation is obtained by the dissolution test in the aqueous medium described herein. The result of dissolution test is expressed as the percentage (w/w) released within the release time.
  • subject refers to a mammal, which may be an animal or a human.
  • multiparticulate or “multiparticulate system” as used herein refers to a system or combination containing many particles. These particles can exist in any form, including “pellets” and “beads”. ",” “granules”, “pills”, “mini tablets” or any structural unit, its nature and size are not subject to any restriction.
  • inert refers to the action or influence of a substance, which may or may not affect the bioavailability of the active pharmaceutical ingredient, but it has no pharmaceutical activity by itself .
  • the term "about” and similar descriptions when used with a numerical variable, usually means that the value of the variable and all the values of the variable are within the experimental error range (for example, within the 95% confidence interval of the mean ) Or within ⁇ 10% of the indicated value, whichever is greater.
  • peak-to-valley fluctuation or "PTF" used herein is calculated as 100%*(C max.ss -C min.ss )/(AUC ,tau,ss /tau), where C max.ss is the pull
  • C max.ss is the pull
  • C min.ss is the minimum steady-state plasma concentration of lacosamide
  • AUC .tau.ss is the plasma concentration-time within a dosing interval tau under steady-state conditions
  • tau is a dosing interval in hours. For example, if the pharmaceutical composition or sustained-release preparation of the present invention is administered once a day, the dosing interval is equal to 24 hours.
  • pH-independent means that the properties of a substance do not depend on the pH value or are not affected by the pH value of the medium or solution.
  • the present invention provides a pharmaceutical composition of lacosamide which is taken orally once a day and a preparation thereof.
  • the pharmaceutical composition or preparation controls the release of lacosamide or a pharmaceutically acceptable salt thereof at a certain rate, thereby reducing PTF, Reduce side effects and ensure the effectiveness of drugs.
  • the present invention provides a pharmaceutical composition of lacosamide, which comprises sustained-release multiparticulates, wherein each of the sustained-release multiparticulates comprises:
  • the drug-loaded core does not contain a sustained-release agent.
  • the sustained-release layer also does not contain active ingredients.
  • the pharmaceutical composition of the present invention is not a matrix to form a pharmaceutical composition, and the active ingredient and the sustained-release agent are placed in separate layers, and are not mixed together.
  • the sustained-release layer of the particles shown in Figs. 1 and 2 does not contain active ingredients.
  • lacosamide or a pharmaceutically acceptable salt thereof is uniformly dispersed in the drug-loaded core (as shown in Figure 1).
  • the drug-loaded core includes an inert pellet core (a center that does not contain an active ingredient) and an outer layer surrounding the inert pellet core, and lacosamide or a pharmaceutically acceptable salt thereof is placed In the outer layer (as shown in Figure 2).
  • each of the sustained-release multiparticulates further comprises an isolation layer between the drug-loaded core and the sustained-release layer.
  • each of the sustained-release multiparticulates further comprises a protective layer covering the sustained-release layer.
  • the sustained-release layer can also be wrapped with an immediate-release layer containing active ingredients, so that a certain amount of active ingredients can be quickly released after taking.
  • the added immediate-release layer can be wrapped directly outside the slow-release layer, or can be wrapped outside the protective layer outside the slow-release layer, and optionally another protective layer can be wrapped outside the immediate-release layer.
  • the drug-loaded core of the present invention can be prepared by various existing technologies known in the art, such as by extrusion spheronization, fluidized bed and tablet press.
  • the drug-loaded core contains at least one or more fillers, including but not limited to povidone (PVP), cross-linked povidone (PVPP), lactose, mannitol, sugar Class, microcrystalline cellulose, dibasic calcium phosphate, corn starch, starch, silicon dioxide, hydroxypropyl cellulose, etc.
  • the active ingredient is wrapped around the inert pellet core, and optionally, an isolation layer can be wrapped around the active ingredient.
  • the inert pellet core can be commercially available (such as sugar pellets, microcrystalline cellulose pellets, starch pellets, silicon dioxide pellets, etc.) or can be prepared by conventional methods (such as extrusion spheronization, fluidized bed method, etc.) ).
  • the particle size of the inert pellet core ranges from 100 ⁇ m to 1200 ⁇ m, preferably 150 ⁇ m to 1000 ⁇ m, more preferably 200 ⁇ m to 700 ⁇ m, more preferably 300 to 600 ⁇ m, and more preferably 300 to 500 ⁇ m.
  • the drug-loaded core contains at least one or more binders, and the active pharmaceutical ingredient (lacosamide or a pharmaceutically acceptable salt thereof) is mixed with at least one binder , And then wrapped on the inert pellet core.
  • Binders include but are not limited to povidone (PVP), hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, starch Pulp, gelatin, gum arabic and their mixtures, etc.
  • PVP povidone
  • HPC hydroxypropyl cellulose
  • MC methyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • sodium carboxymethyl cellulose starch Pulp, gelatin, gum arabic and their mixtures, etc.
  • the prepared lacosamide sustained-release multiparticulates have an average particle size of about 300 ⁇ m to about 1400 ⁇ m, preferably about 500 ⁇ m to about 1400 ⁇ m, more preferably about 600 ⁇ m to about 1400 ⁇ m, most preferably about 600 ⁇ m to about 1200 ⁇ m .
  • the active ingredient (lacosamide or a pharmaceutically acceptable salt thereof) used in this application has a particle size range (D90) of about 0.1 ⁇ m to about 1000 ⁇ m, preferably about 2 ⁇ m to about 200 ⁇ m, and more preferably about 2 ⁇ m to about 100 ⁇ m, most preferably about 2 ⁇ m to about 60 ⁇ m.
  • lacosamide or a pharmaceutically acceptable salt thereof is released (w/w) according to one or more of the following in vitro dissolution rates: (a) 0.1-8% within 1 hour, (b) 2 2-25% within hours, (c) 18-70% within 4 hours and/or (d) 70-100% within 10 hours, 12 hours, 14 hours, 16 hours or 20 hours, of which the dissolution The degree is determined by the US Pharmacopoeia dissolution method II (paddle method), the speed is 75rpm, the temperature is 37 ⁇ 0.5°C, and the dissolution medium is 900ml 0.1N HCl.
  • lacosamide or a pharmaceutically acceptable salt thereof is released (w/w) according to one or more of the following in vitro dissolution rates: (a) less than 8% in 1 hour, (b) 2 hours Less than 12% within, (c) less than 45% within 4 hours and/or (d) greater than 50% within 12 hours, wherein the dissolution rate is determined by USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5 °C, measured in 900ml pH 1.0HCl/NaCl buffer for 2 hours, and then transferred the sample to 900ml pH 6.8 phosphate/NaCl buffer for 4 hours under the same dissolution method, rotation speed and temperature, and then measured in the same Under the dissolution method, speed and temperature, transfer the sample to 900ml pH 7.5 phosphate/NaCl buffer and continue the measurement for at least 6 hours.
  • lacosamide or a pharmaceutically acceptable salt thereof is released at the following in vitro dissolution rates: (a) less
  • lacosamide or a pharmaceutically acceptable salt thereof is released (w/w) according to one or more of the following in vitro dissolution rates: (a) less than about 20% in 1 hour, (b) 4 About 20%-80% within hours, or (c) greater than about 80% within 12 hours, where the dissolution rate is determined by USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, pH 6.8 at 900ml The measurement was continued for 12 hours in phosphate buffer.
  • lacosamide or a pharmaceutically acceptable salt thereof is released at the following in vitro dissolution rates: (a) less than about 20% within 1 hour, (b) about 20%-80% within 4 hours, and (c) 12 More than about 80% in an hour.
  • the sustained-release agent (material) in the sustained-release layer can control the dissolution of the active ingredient, and the dissolution of the particles depends on the weight gain of the coating.
  • the sustained-release agent can be prepared by a known synthetic route or is directly commercially available.
  • non-pH-dependent sustained-release agents include, but are not limited to, ethyl cellulose, methyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl acetate, polyacrylate, polymethyl cellulose, etc.
  • quaternary amino methacrylate copolymer type A (copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.2)
  • quaternary amino Methacrylate copolymer type B copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylaminoethyl methacrylate (1:2:0.1)
  • copolymer of ethyl acrylate and methyl methacrylate And any mixtures of them.
  • the pH-independent sustained-release agent is selected from Eudragit RS100 (copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1)) , Eudragit RL100 (copolymer of ethyl acrylate, methyl methacrylate and chlorotrimethylaminoethyl methacrylate (1:2:0.2)) and combinations thereof.
  • the pH-independent sustained-release agent is Eudragit RS100 (copolymer of ethyl acrylate, methyl methacrylate, and trimethylaminoethyl methacrylate chloride (1:2:0.1)) and The combination of Eudragit RL100 (ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.2) copolymer), wherein the Eudragit RS100 (ethyl acrylate, Copolymer of methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1)) and the Eudragit RL100 (ethyl acrylate, methyl methacrylate and trimethyl methacrylate chloride)
  • the ratio of amino ethyl (1:2:0.2) copolymer) is greater than or equal to 3: 1, greater than or equal to 4: 1, greater than or equal to 5: 1, greater than or equal to 6:
  • the Eudragit RS100 ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1: 2:0.1) copolymer
  • the Eudragit RL100 ethyl acrylate, methyl methacrylate and chlorinated trimethylaminoethyl methacrylate (1:2:0.2) copolymer
  • the Eudragit RS100 ethyl acrylate, methyl methacrylate and chlorinated trimethylaminoethyl methacrylate (1:2:0.2) copolymer
  • the Eudragit RL100 ethyl acrylate, methyl methacrylate and chlorinated trimethylaminoethyl methacrylate (1:2:0.2) copolymer
  • the pH-independent sustained-release agent is Eudragit RS100 (copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1)).
  • the non-pH-dependent sustained-release agent is selected from ethyl cellulose, and its viscosity specifications include, but are not limited to, ethyl cellulose 7 cP, ethyl cellulose 10 cP, ethyl cellulose 20 cP and ethyl cellulose 100 cP, preferably, the viscosity specification of ethyl cellulose is 7 cP.
  • the sustained-release agent accounts for about 2% to about 50%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30% of the particle weight (w/w), About 7% to about 30%, about 8% to about 30%, about 8% to about 25%, about 10% to about 25%, about 10% to about 20%, or about 20% to about 30%. In some embodiments, the sustained-release agent accounts for about 8% to about 30% by weight of the particles. In a specific embodiment, the sustained-release agent is Eudragit RS100, and the sustained-release agent accounts for about 8% to about 30% by weight of the particles.
  • the sustained-release agent accounts for about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 5% to about 9% of the weight of the particles (w/w), About 5% to about 8%, about 5% to about 7%, or about 5% to about 6%. In some embodiments, the sustained-release agent accounts for about 5% to about 15% by weight of the particles. In a specific embodiment, the sustained-release agent is ethyl cellulose, and the sustained-release agent accounts for about 5% to about 15% by weight of the particles.
  • the weight ratio of lacosamide or a pharmaceutically acceptable salt thereof to the sustained-release agent is about 15:1 to about 1:1, about 15:1 to about 2:1, about 10:1 To about 2:1, about 8:1 to about 2:1, about 8:1 to about 3:1, about 10:1 to about 4:1, about 6:1 to about 3:1, about 5:1 To about 2:1.
  • the weight ratio of lacosamide or a pharmaceutically acceptable salt thereof to the sustained-release agent is about 8:1 to about 3:1.
  • the sustained-release agent is Eudragit RS100, and the weight ratio of lacosamide or a pharmaceutically acceptable salt thereof to the sustained-release agent is about 8:1 to about 3:1.
  • the weight ratio of lacosamide or a pharmaceutically acceptable salt thereof to the sustained release agent is about 12:1 to about 2:1, about 12:1 to about 5:1, about 12:1 To about 6:1, about 12:1 to about 7:1, about 12:1 to about 8:1, about 12:1 to about 9:1, or about 12:1 to about 10:1.
  • the weight ratio of lacosamide or a pharmaceutically acceptable salt thereof to the sustained-release agent is about 12:1 to about 5:1.
  • the sustained-release agent is ethyl cellulose, and the weight ratio of lacosamide or a pharmaceutically acceptable salt thereof to the sustained-release agent is about 12:1 to about 5:1.
  • the lacosamide pharmaceutical composition is administered orally once a day.
  • the lacosamide pharmaceutical composition comprises lacosamide or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 1000 mg, about 20 mg to about 600 mg, about 40 mg to about 200 mg, about 50 mg to About 300mg, about 50mg to about 600mg.
  • the lacosamide pharmaceutical composition comprises lacosamide in an amount of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 400 mg.
  • the sustained release time for the pharmaceutical composition or preparation to release the active ingredient in the aqueous medium is from about 2 hours to about 24 hours, from about 4 hours to about 24 hours, About 8 hours to about 24 hours, about 4 hours to about 12 hours, about 12 hours to about 24 hours, about 8 hours to about 12 hours, or about 12 hours to about 18 hours.
  • the sustained-release layer may also include one or more plasticizers, including but not limited to diethyl phthalate, triethyl citrate, dibutyl sebacate, poly Ethylene glycol, triacetin, tributyl citrate, glycerin and propylene glycol.
  • plasticizers including but not limited to diethyl phthalate, triethyl citrate, dibutyl sebacate, poly Ethylene glycol, triacetin, tributyl citrate, glycerin and propylene glycol.
  • the sustained-release layer may also include one or more porogens, including but not limited to polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone .
  • the porogen is hydroxypropyl methylcellulose.
  • the weight ratio of the porogen to the sustained-release agent is about 20%-80%; in some embodiments, the weight ratio of the porogen to the sustained-release agent is about 25%-75%; in some In an embodiment, the weight ratio of the porogen to the sustained-release agent is about 30%-70%; in some embodiments, the weight ratio of the porogen to the sustained-release agent is about 40%-70%; in a preferred embodiment In the scheme, the weight ratio of the porogen to the sustained-release agent is about 50%-65%; in a preferred embodiment, the weight ratio of the porogen to the sustained-release agent is about 50%-60%.
  • the sustained-release agent is ethyl cellulose, the porogen is hydroxypropyl methylcellulose, and the weight ratio of the porogen to the sustained-release agent is about 50%-60%.
  • the sustained-release layer may also include water-soluble small molecule agents, such as sugar or reducing sugar, lactose, sucrose, mannitol, sorbitol, and the like.
  • the barrier or protective layer materials that can be selectively coated may be commercially available, including but not limited to Opadry Talc, magnesium stearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, etc.
  • the average weight percentage of lacosamide or a pharmaceutically acceptable salt thereof is at least 20%, at least 25%, at least 30%, at least 35 %, at least 38%, at least 45%, at least 50%, up to 80%, up to 75%, or up to 70%. In some embodiments, in each of the multiparticulates, the average weight percentage of lacosamide or a pharmaceutically acceptable salt thereof is about 50% to about 60%. In some embodiments, lacosamide or a pharmaceutically acceptable salt thereof accounts for about 30% to about 90%, about 40% to about 80%, about 50% to about 70% or About 50% to about 60%.
  • the inert pellet core is a microcrystalline cellulose pellet with a particle size of 300-500 ⁇ m. After lacosamide is mixed with the adhesive PVPK30, it is wrapped on the inert pellet core. Eudragit As a sustained-release agent, its weight is 10%-25% of the weight percentage of the particles. In some embodiments, a layer containing The isolation layer makes the surface of the drug-loaded core smoother. In some embodiments, the sustained release layer of the particles can also be wrapped with a layer containing A protective layer to reduce friction between particles or to mask any bad taste or smell.
  • the inert pellet core is a microcrystalline cellulose pellet with a particle size of 300-500 ⁇ m.
  • Lacosamide is mixed with the adhesive povidone (PVP K30), and then wrapped on the inert pellet core.
  • the sustained-release layer uses ethyl cellulose as a sustained-release agent, and its weight is 5% to 15% of the particle weight percentage.
  • the sustained-release layer uses hydroxypropyl methylcellulose as a porogen, and the weight ratio of the porogen to the sustained-release agent is about 50%-60%.
  • the drug-loaded core is wrapped with a layer containing Opadry
  • the isolation layer makes the surface of the drug-loaded core smoother.
  • the sustained-release layer of the particles can also be wrapped with a layer containing Opadry A protective layer to reduce friction between particles or to mask any bad taste or smell.
  • the pharmaceutical composition of the present invention may also include a combination of a sustained-release part and an immediate-release part.
  • all lacosamide or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is formulated for sustained release, and the pharmaceutical composition does not contain an immediate release part.
  • the introduction of an immediate-release part in the pharmaceutical composition, together with a sustained-release part, the pharmaceutical composition can still release lacosamide or a pharmaceutically acceptable salt thereof over an extended period of time ,
  • the immediate release part provides an initial burst of drug release to make it reach the therapeutic blood concentration level faster.
  • the lacosamide or its pharmaceutically acceptable salt contained in the immediate-release part accounts for about 1% to about 50% of the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition. , About 5% to about 45%, about 5% to about 40%, about 10% to about 40%, about 15% to about 40%, about 15% to about 30%, about 15% to about 20%, about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 1% to about 10%, about 10% to about 30%, about 10% to about 20%, about 10% To about 15% or about 5% to about 10% (w/w).
  • the lacosamide pharmaceutical composition further comprises an immediate release part, wherein the lacosamide or its pharmaceutically acceptable salt in the immediate release part accounts for the lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition.
  • 1% to 40% (w/w) of the total amount of pharmaceutically acceptable salts preferably, lacosamide or its pharmaceutically acceptable salt in the immediate-release part accounts for lacosamide in the pharmaceutical composition Or 1% to 35% (w/w) of the total amount of the pharmaceutically acceptable salt thereof; preferably, lacosamide or its pharmaceutically acceptable salt in the immediate-release part accounts for the lacosamide in the pharmaceutical composition 10% to 30% (w/w) of the total amount of salamine or its pharmaceutically acceptable salt.
  • the lacosamide or its pharmaceutically acceptable salt contained in the immediate-release portion of the pharmaceutical composition accounts for about 1% of the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition. % To about 35% (w/w), preferably about 5% to about 30% (w/w).
  • lacosamide or its pharmaceutically acceptable salt contained in the sustained-release part of the pharmaceutical composition accounts for about 65% to about 65% of the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition. 99% (w/w), preferably about 70% to about 95% (w/w).
  • the lacosamide or its pharmaceutically acceptable salt contained in the sustained-release portion accounts for about 65% to about 65% of the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition.
  • the lacosamide or its pharmaceutically acceptable salt contained in the immediate-release part accounts for the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition minus the content of the lacosamide in the sustained-release part The remaining percentage.
  • the lacosamide or its pharmaceutically acceptable salt contained in the sustained-release part accounts for about 99%, about 95%, or about 95% of the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition.
  • the lacosamide or its pharmaceutically acceptable salt contained in the immediate-release part accounts for the drug About 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30% or about 35% of the total amount of lacosamide or its pharmaceutically acceptable salt in the composition ( w/w).
  • Lacosamide or its pharmaceutically acceptable salt contained in the immediate-release part accounts for the total amount of lacosamide or its pharmaceutically acceptable salt in the pharmaceutical composition minus the sustained-release part (fast-release part) The remaining percentage of lacosamide in the release part).
  • slow-release drugs can reduce PTF.
  • the sustained-release multiparticulates of lacosamide and the immediate-release part are combined in a certain ratio with It can further reduce PTF compared to not including the immediate release part.
  • the sustained release portion and the immediate release portion are physically connected or independent of each other.
  • the sustained-release part and the immediate-release part may be physically connected together to form a double-layer structure or a multilayer structure.
  • the sustained-release layer can also be coated with an immediate-release layer containing active ingredients, so that a certain amount of active ingredients can be released quickly after taking.
  • the added immediate-release layer can be wrapped directly outside the slow-release layer, or can be wrapped outside the protective layer outside the slow-release layer, and optionally another protective layer can be wrapped outside the immediate-release layer.
  • the sustained-release portion and the immediate-release portion are independent of each other and do not need to be physically connected to each other.
  • the immediate-release part may be in the form of a single unit or in the form of multiple particles, and the preparation method thereof may be the same as that of the sustained-release multi-particle except that the sustained-release layer is not covered.
  • the immediate-release part is composed of multiparticulates, for example, the immediate-release part is composed of drug-loaded particles without a sustained-release layer.
  • the prepared lacosamide immediate-release multiparticulate has an average particle size of about 300 ⁇ m to about 1200 ⁇ m, preferably about 500 ⁇ m to about 1200 ⁇ m, more preferably about 600 ⁇ m to about 1200 ⁇ m, most preferably about 600 ⁇ m to about 1000 ⁇ m .
  • lacosamide or a pharmaceutically acceptable salt thereof in a pharmaceutical composition comprising a combination of a sustained-release part and an immediate-release part is released according to one or more of the following in vitro dissolution rates (w/w): (a) about 10%-30% within 1 hour, (b) about 30%-90% within 4 hours, or (c) greater than about 90% within 12 hours, wherein the dissolution rate is determined using USP Dissolution Method I (basket Method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, continuous measurement for 12 hours in 900ml pH 6.8 phosphate buffer.
  • in vitro dissolution rates w/w
  • lacosamide or a pharmaceutically acceptable salt thereof is released at the following in vitro dissolution rates: (a) about 10%-28% within 1 hour, (b) about 28%-90% within 4 hours, and (c ) More than about 90% within 12 hours.
  • the present invention provides a sustained release formulation of lacosamide, which comprises the lacosamide pharmaceutical composition of the present invention, which is a capsule, sachet, sprinkle, caplet, lozenge, bag, tablet or Any other dosage form suitable for oral administration.
  • the formulation is a capsule, sachet or dusting agent.
  • the formulation is administered orally once a day.
  • the amount of lacosamide or a pharmaceutically acceptable salt thereof contained in the unit formulation of the formulation is about 20 mg to about 600 mg.
  • the preparation is a capsule
  • the pharmaceutical composition of the present invention can be enclosed in a suitable shell, such as a capsule of any suitable size, such as No. 000, No. 00, No. 0el, No. 0, No. 1, No. 2, No. 3, No. 4, or No. 5 capsules.
  • the amount of lacosamide or its pharmaceutically acceptable salt contained in a single capsule is about 1 mg to about 1000 mg, about 20 mg to about 600 mg, about 40 mg to about 200 mg, about 50 mg to about 300 mg, about 50 mg to about 600 mg. More preferably, the amount of lacosamide contained in a single capsule is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 400 mg.
  • the present invention provides a sustained-release formulation of lacosamide, which comprises an immediate-release part and a sustained-release part, wherein the lacosamide in the immediate-release part or a pharmaceutically acceptable salt thereof accounts for the lacosamide in the formulation.
  • the immediate-release part or the sustained-release part is composed of multiple particles, and the immediate-release part is composed of drug-loaded particles without a sustained-release layer.
  • the dissolution profile is evaluated in 900 ml 0.1N HCl at 75 rpm speed and 37 ⁇ 0.5° C.
  • the lacosamide described in the present invention has the in vitro dissolution characteristics of one or more of the following active ingredients (lacosamide or a pharmaceutically acceptable salt thereof):
  • the released active ingredients account for the total amount (w/w): about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 12%, about 0.1% to about About 10%, about 0.1% to about 8%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2 %, about 0.5% to about 20%, about 0.5% to about 15%, about 0.5% to about 12%, about 0.5% to about 10%, about 0.5% to about 8%, about 0.5% to about 6%, About 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 1% to about 20%, about 1% to about 15%, about 1% to about 12%, about 1 % To about 10%, about 1% to about 8%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, or about 1% to about 3%;
  • the released active ingredients account for the total amount (w/w): about 2% to about 40%, about 2% to about 30%, about 2% to about 25%, about 2% to About 20%, about 2% to about 15%, 2% to about 10%, about 2% to about 8%, about 5% to about 40%, about 5% to about 30%, about 5% to about 25% , About 5% to about 20%, about 5% to about 15%, 5% to about 10%, about 8% to about 40%, about 8% to about 30%, about 8% to about 25%, about 8 % To about 20%, about 8% to about 15% or about 8% to about 12%;
  • the released active ingredients account for the total amount (w/w): about 15% to about 90%, about 18% to about 90%, about 20% to about 80%, about 18% to About 80%, about 18% to about 70%, 18% to about 60%, about 18% to about 50%, about 18% to about 40%, about 18% to about 30%, about 25% to about 90% , About 25% to about 80%, about 25% to about 70%, about 25% to about 60%, about 25% to about 50%, about 25% to about 40%, about 25% to about 35% or about 25% to about 30%; and/or
  • the released active ingredients account for the total amount (w/w): about 50% to about 100%, about 70% to About 100%, about 60% to about 100%, about 50% to about 95%, about 70% to about 95%, or about 80% to about 100%.
  • the pharmaceutical composition or formulation has one, two, three, or four of the above dissolution characteristics.
  • the pharmaceutical composition or formulation provides the dissolution rate of the active ingredient having the above (a).
  • the pharmaceutical composition or formulation provides the dissolution rate of the active ingredient having the above (a) and (b).
  • the pharmaceutical composition or formulation provides an active ingredient dissolution rate having the above-mentioned (a), (b), and (c).
  • the pharmaceutical composition or formulation provides an active ingredient dissolution rate having the above-mentioned (a), (b), (c), and (d).
  • the pharmaceutical composition or preparation has an in vitro dissolution rate for the release of the following active ingredients: about 0.1% to about 8% released within 1 hour, about 2% to about 25% released within 2 hours, and released within 4 hours About 18% to about 70% and/or about 70% to about 100% released within 10 hours.
  • the dissolution rate was determined using the US Pharmacopoeia dissolution method II (paddle method), the rotating speed was 75 rpm, the temperature was 37 ⁇ 0.5°C, and the dissolution medium was 900ml 0.1N HCl.
  • the pharmaceutical composition or preparation has an in vitro dissolution rate for the release of the following active ingredients: about 0.1% to about 8% released within 1 hour, about 2% to about 14% released within 2 hours, and released within 4 hours About 20% to about 70% and/or about 70% to about 100% released within 10 hours.
  • the dissolution rate was determined using the US Pharmacopoeia dissolution method II (paddle method), the rotating speed was 75 rpm, the temperature was 37 ⁇ 0.5°C, and the dissolution medium was 900ml 0.1N HCl.
  • the lacosamide pharmaceutical composition or the sustained-release formulation of lacosamide according to the present invention has one or more of the following active ingredients (lacosamide or a pharmaceutically acceptable salt thereof) In vitro dissolution characteristics:
  • the active ingredient released within 1 hour is less than 10%, less than 8%, less than 6%, less than 5% or less than 4%;
  • the active ingredient released within 2 hours is less than 20%, less than 15%, less than 12%, less than 10%, less than 8%, less than 6% or less than 4%;
  • the active ingredient released within 4 hours is less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15% or less than 10%; and/or
  • the active ingredient released within 12 hours is greater than 40%, greater than 50%, greater than 60%, greater than 70% or greater than 80%.
  • the dissolution rate was determined using US Pharmacopoeia dissolution method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measuring in 900ml pH 1.0HCl/NaCl buffer for 2 hours, and then under the same dissolution method, rotating speed and temperature, The sample was transferred to 900ml pH 6.8 phosphate/NaCl buffer solution and the measurement continued for 4 hours, and then under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 7.5 phosphate/NaCl buffer solution and the measurement continued for at least 6 hours (always To 12 hours or 18 hours or 24 hours).
  • the pharmaceutical composition or formulation provides the dissolution rate of the active ingredient having the above (a) and (b).
  • the pharmaceutical composition or formulation provides an active ingredient dissolution rate having the above-mentioned (a), (b), and (c). In some embodiments, the pharmaceutical composition or formulation provides an active ingredient dissolution rate having the above-mentioned (a), (b), and (d). In some embodiments, the pharmaceutical composition or formulation provides an active ingredient dissolution rate having the above-mentioned (a), (b), (c), and (d).
  • the lacosamide pharmaceutical composition or lacosamide sustained-release preparation of the present invention has one or more of the following active ingredients (lacosamide or its pharmaceutically acceptable salt ) In vitro dissolution characteristics: (a) less than 8% of active ingredients released within 1 hour, (b) less than 12% of active ingredients released within 2 hours, (c) less than 45% of active ingredients released within 4 hours and/or (d) The active ingredient released within 12 hours is greater than 50%.
  • the dissolution rate is determined using USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, and measuring in 900ml pH 1.0HCl/NaCl buffer After 2 hours, under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 6.8 phosphate/NaCl buffer for 4 hours, and then under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 7.5 Continue the measurement in phosphate/NaCl buffer for 6 hours, 12 hours or 18 hours.
  • the sustained-release agent is a pH-independent sustained-release agent.
  • the pharmaceutical composition or preparation of the present invention has lacosamide or a pharmaceutically acceptable salt thereof according to the above-mentioned (a), (a) + (b), (a) + (d) ), (a)+(b)+(c), (a)+(b)+(d) or (a)+(b)+(c)+(d) release.
  • the lacosamide pharmaceutical composition or lacosamide sustained-release preparation of the present invention has one or more of the following active ingredients (lacosamide or its pharmaceutically acceptable salt ) In vitro dissolution characteristics: (a) less than 6% of active ingredients released within 1 hour, (b) less than 10% of active ingredients released within 2 hours, (c) less than 30% of active ingredients released within 4 hours and/or (d) The active ingredient released within 12 hours is greater than 50%.
  • the dissolution rate is determined using USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, and measuring in 900ml pH 1.0HCl/NaCl buffer After 2 hours, under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 6.8 phosphate/NaCl buffer for 4 hours, and then under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 7.5 Continue the measurement in phosphate/NaCl buffer for 6 hours, 12 hours or 18 hours.
  • the sustained-release agent is a pH-independent sustained-release agent.
  • the pharmaceutical composition or preparation of the present invention has lacosamide or a pharmaceutically acceptable salt thereof according to the above-mentioned (a), (a) + (b), (a) + (d) ), (a)+(b)+(c), (a)+(b)+(d) or (a)+(b)+(c)+(d) release.
  • the lacosamide pharmaceutical composition or lacosamide sustained-release preparation of the present invention has one or more of the following active ingredients (lacosamide or its pharmaceutically acceptable salt ) In vitro dissolution characteristics: (a) less than 4% of active ingredients released within 1 hour, (b) less than 8% of active ingredients released within 2 hours, (c) less than 20% of active ingredients released within 4 hours and/or (d) The active ingredient released within 12 hours is greater than 50%.
  • the dissolution rate is determined using USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, and measuring in 900ml pH 1.0HCl/NaCl buffer After 2 hours, under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 6.8 phosphate/NaCl buffer for 4 hours, and then under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 7.5 Continue the measurement in phosphate/NaCl buffer for 6 hours, 12 hours or 18 hours.
  • the sustained-release agent is a pH-independent sustained-release agent.
  • the pharmaceutical composition or preparation of the present invention has lacosamide or a pharmaceutically acceptable salt thereof according to the above-mentioned (a), (a) + (b), (a) + (d) ), (a)+(b)+(c), (a)+(b)+(d) or (a)+(b)+(c)+(d) release.
  • the lacosamide pharmaceutical composition or the sustained-release formulation of lacosamide according to the present invention has one or more of the following active ingredients (lacosamide or a pharmaceutically acceptable salt thereof )
  • active ingredients lacosamide or a pharmaceutically acceptable salt thereof
  • In vitro dissolution characteristics (a) less than 4% of active ingredients released within 1 hour, (b) less than 8% of active ingredients released within 2 hours, (c) less than 40% of active ingredients released within 4 hours and/or (d)
  • the active ingredient released within 12 hours is greater than 50%, and the dissolution rate is determined using USP Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, in 900ml pH 1.0HCl/34mM NaCl buffer After measuring for 2 hours, under the same dissolution method, rotation speed and temperature, the sample was transferred to 900ml pH 6.8 phosphate/100mM NaCl buffer for 4 hours, and then under the same dissolution method, rotation speed and temperature, the sample was transferred to Continue the measurement for 6 hours
  • the sustained-release agent is a pH-independent sustained-release agent.
  • the pharmaceutical composition or preparation of the present invention has lacosamide or a pharmaceutically acceptable salt thereof according to the above-mentioned (a), (a) + (b), (a) + (d) ), (a)+(b)+(c), (a)+(b)+(d) or (a)+(b)+(c)+(d) release.
  • lacosamide or its pharmaceutically acceptable salt is released at the following in vitro dissolution rates: (a) less than 4% within 1 hour, (b) less than 8% within 2 hours, (c) less than 40 within 4 hours % And (d) greater than 50% within 12 hours.
  • the present invention also provides a device including an immediate release part and a sustained release part.
  • the two parts can be mixed together or separated from each other.
  • the ratio between the two parts can be the same as the ratio in the above-mentioned pharmaceutical composition or formulation.
  • lacosamide or its pharmaceutically acceptable salt in the sustained-release portion accounts for about 65% to about 70% of the total amount of lacosamide or its pharmaceutically acceptable salt in the device. %, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, about 70% to about 80%, About 80% to about 90% or about 90% to about 95% (w/w).
  • the lacosamide or its pharmaceutically acceptable salt in the immediate release part accounts for the remaining percentage of the total amount of lacosamide or its pharmaceutically acceptable salt in the device.
  • the device contains the sustained-release particles and immediate-release particles prepared as described above. Both types of particles can be enclosed in the same capsule or container.
  • the present invention provides a method for treating neurological or psychiatric diseases or disorders, which comprises administering to a subject in need thereof a therapeutically effective amount of the lacosamide pharmaceutical composition of the present invention or Lacosamide sustained-release preparation.
  • the present invention provides the use of the lacosamide pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of neurological or psychiatric diseases or disorders.
  • the present invention provides the lacosamide pharmaceutical composition or the lacosamide sustained-release preparation of the present invention, which is used for the treatment of neurological or psychiatric diseases or disorders.
  • the disease or condition includes, but is not limited to, epilepsy, migraine, essential tremor, restless limb syndrome, cluster headache, neuralgia, neuropathic pain, Tourette syndrome, infantile spasm, anxiety , Bipolar disorder, psychosis, mania, schizophrenia, depression, dementia, autism, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, impulse control disorder, borderline personality disorder, adult Addiction, chronic neurodegenerative diseases, acute neurodegeneration and amyotrophic lateral sclerosis.
  • the disease or condition is partial-onset epilepsy.
  • the pharmaceutical composition or formulation is administered orally once a day.
  • the lacosamide pharmaceutical composition or the lacosamide sustained-release preparation of the present invention can adjust the in vivo release of active ingredients and reduce peak-to-valley fluctuation (PTF).
  • PTF peak-to-valley fluctuation
  • the PTF of the pharmaceutical composition or formulation is less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 35%, or less than about 30%. In a preferred embodiment, the PTF of the pharmaceutical composition or formulation is less than about 60%.
  • the pharmaceutical composition or formulation administered orally once a day is the same as an immediate release formulation of the same daily dose of lacosamide administered orally twice a day
  • its PTF is reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.
  • its PTF is reduced by at least 15%.
  • the pharmaceutical composition or formulation administered orally once a day is the same as an immediate release formulation of the same daily dose of lacosamide administered orally twice a day In comparison, the AUC ss and C max,ss are 75% to 125% of the immediate-release preparation. In some embodiments, the pharmaceutical composition or formulation administered orally once a day is the same as an immediate release formulation of the same daily dose of lacosamide administered orally twice a day In comparison, the AUC ss and C max,ss are 80% to 125% of the immediate-release preparation.
  • Mini tablet cores are prepared by direct compression on a single-punch tablet machine with a 3mm round punch. Ethyl cellulose (EC) and hydroxypropyl methyl cellulose are dissolved in ethanol/water to prepare a slow-release coating solution, and then this package The coating liquid coats the mini tablet cores.
  • the in vitro dissolution test uses the US Pharmacopoeia dissolution method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, and measuring in 500ml 0.1N hydrochloric acid dissolution medium for 24 hours. The dissolution samples were analyzed by high performance liquid chromatography (HPLC). The dissolution data of the prescription in Example 1 is shown in Table 2.
  • Example 2 for preparing multi-particles by the extrusion spheronization method.
  • Example 3 for preparing multi-particles by the extrusion spheronization method.
  • Table 5 The formulation of the fluidized bed coating of Example 4 for preparing sustained-release multiparticulates.
  • the dissolution in vitro was determined using US Pharmacopoeia dissolution method II (paddle method), rotating speed 75rpm, temperature 37 ⁇ 0.5°C, dissolution medium 900ml 0.1N hydrochloric acid.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 7 The formulation of the fluidized bed coating of Example 5 for preparing sustained-release multiparticulates.
  • the suspension of lacosamide and povidone is used as the drug coating liquid, and the drug coating liquid is evenly wrapped on the inert microcrystalline cellulose pellets using a fluidized bed to obtain drug-loaded pellets; Then, a sustained-release coating liquid composed of cellulose acetate and polyethylene glycol is wrapped on the surface of the drug-loaded pellets to obtain the desired different coating weight gain levels. Adjust the air inlet rate and material temperature to prevent spray drying of the coating liquid or excessive wetness of the pellets.
  • the particle size of the prepared pellets is about 600 ⁇ m to about 1200 ⁇ m.
  • the dissolution in vitro was determined using the US Pharmacopoeia dissolution method II (paddle method), the rotating speed was 75 rpm, the temperature was 37 ⁇ 0.5°C, and the dissolution medium was 900 ml of 0.1N hydrochloric acid.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the dissolution measurement in Example 5 also adopted the US Pharmacopoeia dissolution method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measuring in 900ml pH 1.0HCl/NaCl buffer for 2 hours, and then using the same dissolution method At the speed and temperature, the sample is transferred to 900ml pH 6.8 phosphate/NaCl buffer for 4 hours, and then under the same dissolution method, speed and temperature, the sample is transferred to 900ml pH 7.5 phosphate/NaCl buffer to continue Measure for 18 hours.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC), and the dissolution data are shown in Table 9 and Figure 4B.
  • Table 10 The formulation of the fluidized bed coating of Example 6 for preparing sustained-release multiparticulates.
  • the dissolution was measured using US Pharmacopoeia Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measuring in 900ml pH 1.0 buffer for 2 hours, and then transferring the sample to 900ml under the same dissolution method, rotating speed and temperature The measurement was continued for 4 hours in the pH 6.8 buffer solution, and then the sample was transferred to 900ml pH 7.5 buffer solution for a period of time under the same dissolution method, rotation speed and temperature.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 12 The formulation of the fluidized bed coating of Example 7 for preparing sustained-release multiparticulates.
  • the coating process is as described in Example 6.
  • the dissolution was measured using US Pharmacopoeia Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measuring in 900ml pH 1.0 buffer for 2 hours, and then transferring the sample to 900ml under the same dissolution method, rotating speed and temperature The measurement was continued for 4 hours in the pH 6.8 buffer solution, and then the sample was transferred to 900ml pH 7.5 buffer solution for a period of time under the same dissolution method, rotation speed and temperature.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 14 The formulation of the fluidized bed coating of Example 8 for preparing sustained-release multiparticulates.
  • the dissolution in vitro was determined using the US Pharmacopoeia dissolution method II (paddle method), the rotating speed was 75 rpm, the temperature was 37 ⁇ 0.5°C, and the dissolution medium was 900 ml of 0.1N hydrochloric acid.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 16 The formulation of the sustained-release multiparticulates of the lacosamide sustained-release capsule prepared by fluidized bed coating in Example 9.
  • the coating process is as described in Example 8.
  • the obtained sustained-release multiparticulates are filled into No. 0 capsules by a capsule filling machine.
  • the in vitro dissolution of the capsule was determined using the US Pharmacopoeia Dissolution Method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measuring in 900ml pH 1.0HCl/34mM NaCl buffer for 2 hours, and then using the same dissolution method, rotating speed and At temperature, the sample is transferred to 900ml pH 6.8 phosphate/100mM NaCl buffer for 4 hours, and then under the same dissolution method, speed and temperature, the sample is transferred to 900ml pH 7.5 phosphate/100mM NaCl buffer to continue the measurement 18 hours.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 18 shows the formulation of the sustained-release multiparticulates of lacosamide sustained-release capsules prepared by fluidized bed coating.
  • Table 18 The formulation of the sustained-release multiparticulates of the lacosamide sustained-release capsule prepared by the fluidized bed coating in Example 10.
  • Example 8 The coating process is as described in Example 8.
  • the obtained sustained-release multi-particulates are filled into capsules of suitable types by a capsule filling machine, such as No. 0, No. 1 and No. 4 capsules.
  • the in vitro dissolution test adopts US Pharmacopoeia dissolution method I (basket method), rotating speed 100rpm, temperature 37 ⁇ 0.5°C, measuring in 900ml pH 1.0HCl/NaCl buffer for 2 hours, and then under the same dissolution method, rotating speed and temperature , The sample was transferred to 900ml pH 6.8 phosphate/NaCl buffer solution for 4 hours, and then under the same dissolution method, speed and temperature, the sample was transferred to 900ml pH 7.5 phosphate/NaCl buffer solution for 18 hours. The dissolution samples were analyzed by high performance liquid chromatography (HPLC). The dissolution data of the three prescription lacosamide sustained-release capsules in Example 10 are shown in Table 19 and Figure 8.
  • Coating with Eudragit RS100 its in vitro dissolution and release characteristics are similar to the release characteristics of pH-dependent polymer coatings, such as delayed release for 1 hour, 3 hours or 5 hours in a medium of pH 1.0 or pH 1.0 to pH 6.8 .
  • this release characteristic can reduce or avoid the risk of sudden drug release in the body of sustained-release dosage forms.
  • Table 20 The formulation of the fluidized bed coating of Example 11 for preparing sustained-release multiparticulates.
  • the in vitro dissolution test uses the US Pharmacopoeia dissolution method I (basket method), the speed is 100rpm, the temperature is 37 ⁇ 0.5°C, and the dissolution medium is pH 6.8 phosphate buffer.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 22 The formulation of the fluidized bed coating of Example 12 for preparing sustained-release multiparticulates.
  • the in vitro dissolution test uses the US Pharmacopoeia dissolution method I (basket method), the speed is 100rpm, the temperature is 37 ⁇ 0.5°C, and the dissolution medium is pH 6.8 phosphate buffer.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 24 The formulation of the fluidized bed coating of Example 13 for preparing sustained-release multiparticulates.
  • the in vitro dissolution test uses the US Pharmacopoeia dissolution method I (basket method), the speed is 100rpm, the temperature is 37 ⁇ 0.5°C, and the dissolution medium is pH 6.8 phosphate buffer.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • fluidized bed coating preparation containing a combination of a sustained-release part and an immediate-release part (an immediate-release layer or an immediate-release multiparticulate) is shown in Table 26.
  • Table 26 The formulation of the lacosamide sustained-release preparation prepared by the fluidized bed coating of Example 14.
  • the prepared immediate-release pellets have a particle size of about 600 ⁇ m to about 1000 ⁇ m;
  • the sustained-release coating liquid composed of methylcellulose and triethyl citrate is wrapped on the surface of the immediate-release pellets, and then the Opadry isolation layer is wrapped to obtain sustained-release pellets.
  • the prepared sustained-release pellets The diameter is about 600 ⁇ m to about 1200 ⁇ m.
  • the two parts of the above-mentioned sustained-release pellets and immediate-release pellets are mixed uniformly according to a given ratio and filled into capsules.
  • the in vitro dissolution test uses the US Pharmacopoeia dissolution method I (basket method), the speed is 100rpm, the temperature is 37 ⁇ 0.5°C, and the dissolution medium is pH 6.8 phosphate buffer.
  • the dissolution samples were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • ER sustained-release
  • F1, F2, and F3 described in Example 10 Three sustained-release (ER) formulations for in vitro release profiles (F1, F2, and F3 described in Example 10) were designed, and their in vivo absorption profiles were predicted.
  • This embodiment also includes the combination of the above three prescriptions and the immediate release (IR) parts in different proportions. based on For the single-dose pharmacokinetic parameters of IR tablets, the steady-state AUC ss , C ss,max and C ss,min of these prescriptions were simulated and predicted by the pharmacokinetic software Gastroplus. The simulation results are shown in Table 28.
  • sustained-release (ER) formulations for in vitro release profiles (E11-1 and E11-4 described in Example 11) were also designed, and their in vivo absorption profiles were predicted.
  • This embodiment also includes the combination of the above two prescriptions and the immediate release (IR) parts in different proportions. based on For the single-dose pharmacokinetic parameters of IR tablets, the steady-state AUC ss , C ss,max and C ss,min of these prescriptions were simulated and predicted by the pharmacokinetic software Gastroplus. The simulation results are shown in Table 29. Lacosamide sustained-release multiparticulates introduced a certain proportion of the immediate-release part to further reduce PTF.

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Abstract

一种拉考沙胺药物组合物及其药物制剂。所述药物组合物包含缓释多颗粒，其中所述缓释多颗粒的每个包含：（a）载药核芯，其包含拉考沙胺或其药学上可接受的盐；和（b）包裹所述载药核芯的缓释层。还提供一种口服一日一次的拉考沙胺缓释制剂。

Description

一种拉考沙胺药物组合物及其药物制剂 技术领域
本发明涉及一种拉考沙胺药物组合物及其药物制剂，具体涉及一种拉考沙胺作为活性成分的药物组合物以及包含所述药物组合物的拉考沙胺缓释制剂。
背景技术
在制药领域，缓释制剂被广泛认知和应用，缓释制剂具有很多明显的临床优势，如减少给药频率和在较长时间内维持稳定的血药浓度。口服缓释多颗粒系统具有“剂量分布”的技术特征，使药物在胃肠道中的分布、吸收更均匀。
拉考沙胺(Lacosamide)也称为拉科酰胺，是一种抗惊厥药，已在多个国家批准上市，用于治疗癫痫部分性发作。拉考沙胺治疗癫痫耐受性良好，日剂量可达200-400毫克/天，最常见的副作用是头晕、复视、头痛和恶心。速释制剂给予高的日剂量可能导致高的不良反应发生率。拉考沙胺的副作用发生率与拉考沙胺最大稳态血药浓度(C max,ss)直接相关，而拉考沙胺治疗癫痫的疗效主要与稳态血药浓度-时间曲线下面积(AUC ss)相关。拉考沙胺上市剂型有速释片、口服溶液和静脉注射溶液。速释片(IR，
Figure PCTCN2020094556-appb-000001
)每日给药两次，规格有50mg、100mg、150mg和200mg。至今为止还没有每日口服一次的拉考沙胺缓释制剂上市。因此，存在开发每日口服一次的拉考沙胺缓释制剂的临床需求，以减少不良反应，提高患者的依从性。
发明内容
在第一方面，本发明提供拉考沙胺药物组合物，其包含缓释多颗粒，其中所述缓释多颗粒的每个包含：
(a)载药核芯，其包含拉考沙胺或其药学上可接受的盐；和
(b)包裹所述载药核芯的缓释层，其包含非pH依赖型缓释剂。
在一些实施方案中，所述载药核芯包含惰性丸芯和包裹所述惰性丸芯的外层，所述拉考沙胺或其药学上可接受的盐置于所述外层中。
在一些实施方案中，所述拉考沙胺或其药学上可接受的盐均匀分散在所述载药核芯中。
在一些实施方案中，所述拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)：(a)1小时内0.1-8％，(b)2小时内2-25％，(c)4小时内18-70％和/或(d)10小时内、12小时内、14小时内、16小时内或20小时内70-100％，其中该溶出度测定采用美国药典溶出方法II(桨法)，转速75rpm，温度37±0.5℃，溶出介质为900ml 0.1N HCl。
在一些实施方案中，所述拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)：(a)1小时内小于8％，(b)2小时内小于12％，(c)4小时内小于45％和/或(d)12小时内大于50％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定至少6小时。
在一些实施方案中，所述拉考沙胺或其药学上可接受的盐占所述颗粒的重量百分含量为约40％至约80％。
在一些实施方案中，所述缓释剂占所述颗粒的重量百分含量为约5％至约30％。
在一些实施方案中，所述拉考沙胺或其药学上可接受的盐与所述缓释剂的重量比为约15:1至约1:1。
在一些实施方案中，所述拉考沙胺药物组合物包含所述拉考沙胺或其药学上可接受的盐的量为约20mg至约600mg。
在一些实施方案中，所述非pH依赖型缓释剂选自乙基纤维素、甲基纤维素、醋酸纤维素、邻苯二甲酸乙酸纤维素、聚乙酸乙烯酯、聚丙烯酸酯、聚甲基丙烯酸酯、季胺基甲基丙烯酸酯共聚物A型(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物)、季胺基甲基丙烯酸酯共聚物B型(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物以及它们的任何混合物等。
在一些实施方案中，所述拉考沙胺药物组合物还包含速释部分，其中所述速释部分中的拉考沙胺或其药学上可接受的盐占所述药物组合物中拉考沙胺或其药学上可接受的盐总量的1％至40％(w/w)。
在第二方面，本发明提供拉考沙胺缓释制剂，其包含本发明所述的拉考沙胺药物组合物，其是胶囊、小袋、撒剂、囊片、锭剂、袋、片剂或任何其它适合口服的剂型的形式。
在第三方面，本发明提供拉考沙胺缓释制剂，其包含速释部分和缓释部分，其中所述速释部分中的拉考沙胺或其药学上可接受的盐占所述制剂中拉考沙胺或其药学上可接受的盐总量的1％至40％(w/w)。
在第四方面，本发明提供一种治疗神经病学或精神病学疾病或病症的方法，其包括向有此需要的受试者给药治疗有效量的本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂。
在第五方面，本发明提供本发明所述的拉考沙胺药物组合物在制备用于治疗神经病学或精神病学疾病或病症的药物中的用途。
在第六方面，本发明提供本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂，其用于治疗神经病学或精神病学疾病或病症。
在一些实施方案中，所述疾病或病症选自癫痫、偏头痛、特发性震颤、不宁肢体综合征、丛集性头痛、神经痛、神经性疼痛、Tourette综合征、婴儿痉挛、焦虑、双相障碍、精神病、躁狂症、精神分裂症、抑郁症、痴呆症、孤独症、强迫症、创伤后应激障碍、注意力缺陷多动障碍、冲动控制障碍、边缘线人格障碍、成瘾、慢性神经退行性疾病、急性神经变性和肌萎缩侧索硬化。优选地，所述疾病或病症是部分发作性癫痫。
在一些实施方案中，所述药物组合物或制剂口服一日一次给药。
在一些实施方案中，所述药物组合物或制剂的峰谷波动(Peak-Trough Fluctuation，PTF)小于约70％。
在一些实施方案中，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
Figure PCTCN2020094556-appb-000002
相比，其PTF降低至少15％。
在一些实施方案中，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
Figure PCTCN2020094556-appb-000003
相比，其AUC ss与C max,ss为速释制剂的80％至125％。
附图说明
图1描述了一种活性成分分散在载药核芯中的颗粒。
图2描述了一种活性成分分散在包裹惰性丸芯的外层中的颗粒。
图3显示实施例4的缓释多颗粒的溶出释放特征。
图4显示实施例5的缓释多颗粒的溶出释放特征。
图5显示实施例6的缓释多颗粒的溶出释放特征。
图6显示实施例7的缓释多颗粒的溶出释放特征。
图7显示实施例8的缓释多颗粒的溶出释放特征。
图8显示实施例10的拉考沙胺缓释胶囊的溶出释放特征。
具体实施方式
本文中的各种实施方案披露了拉考沙胺或其药学上可接受的盐的缓释制剂。在不降低其有效性的前提下，该制剂可调节活性成分的溶出度，降低PTF和不良反应。
以下内容虽然可以参考或举例说明一种药物组合物或制剂的具体实施方案，但不仅限于所述药物组合物或制剂的列举范围。鉴于实用性和经济性方面的考虑，本领域技术人员可以进行各种修改，例如活性成分的含量和该制剂用于治疗疾病或病症的给药方案。
除非另有定义，本文使用的所有技术和科学术语具有与本发明所属领域技术人员通常理解的相同的含义。若存在矛盾，则以本申请提供的定义为准。
本文所使用的术语“一个”、“一种”指“一个或多个”、“一种或多种”或者“至少一个”、“至少一种”。也就是说，本发明中的“一个”、“一种”任何元素或组成并不排除存在多个元素或组成的可能性。
本文所使用的术语“拉考沙胺”、“拉科酰胺”、“活性药物成分”、“活性成分”是指化合物(R)-2-乙酰氨基-N-苄基-3-甲氧基丙酰胺，英文名称Lacosamide。本文所述的药物组合物或制剂中的拉考沙胺可使用其药学上可接受的各种形式，包括但不限于盐、水合物、多晶型物、共晶体、无水物、非晶形及其溶剂化物。
本文所使用的术语“缓释”是指活性药物成分在一段延长的时间内缓慢释放，所述延长的时间大于约2小时、优选大于约4小时、更优选大于约8小时、更优选大于约12小时、更优选大于约16小时至大于约24小时。
本文所使用的术语“速释”是指活性药物成分在小于或等于约1小时内释放大于或等于约80％。通常情况下，在速释制剂中的活性药物成分可在小于或等于约30分钟内释放大于或等于约80％。
本发明中，“缓释部分”或“速释部分”是指使活性药物成分缓释或速释的颗粒，或当颗粒为双层或多层的缓释-速释结构时指使活性药物成分缓释或速释的颗粒部分。
当描述药物组合物或制剂的“释放”时，是指药物组合物或制剂置于水性环境中，其所含活性药物成分离开药物组合物或制剂而溶解在水环境中的部分。除非另有说明，该药物组合物或制剂中活性药物成分的释放量是通过本文所述的水性介质中的溶出度测定所获得。溶出度测定结果以释放时间内所释放的百分含量(w/w)表示。
术语“受试者”是指哺乳动物，可以是动物或者人。
本文在说明书和权利要求书中所使用的术语“包含”不具有限制性含义。此类术语应理解为包括规定的步骤、要素或步骤组、要素组，但不排除任何其他的步骤、要素或步骤组、要素组。
除非另有说明，本文所使用的术语“多颗粒”或“多颗粒系统”是指一种包含了很多颗粒的系统或组合，这些颗粒可以以任何形式存在，包括“微丸”、“小球”、“颗粒”、“小丸”、“迷你片”或任何结构单元，其性质和尺寸不受任何限制。
本文所使用的术语“惰性”或“惰性的”是指一种物质的作用或影响，它可能影响活性药物成分的生物利用度或不影响活性药物成分的生物利用度，但是其本身没有药物活性。
本文所使用的术语“约”和类似的描述，当与数值变量一起使用时，通常指该变量的数值和该变量的所有数值在实验误差范围内(例如，在平均值的95％置信区间内)或在指示值的±10％范围内，以较大者为准。
本文所使用的术语“峰谷波动”或“PTF”的计算公式为100％*(C max.ss-C min.ss)/(AUC ,tau,ss/tau)，其中C max.ss为拉考沙胺的最大稳态血药浓度，C min.ss为拉考沙胺的最小稳态血药浓度，AUC .tau.ss为稳态条件下一个给药间隔tau内的血药浓度-时间曲线下面积，tau是以小时为单位的一个给药间隔，例如本发明的药物组合物或缓释制剂一日给药一次，则给药间隔等于24小时。
术语“非pH依赖”是指一种物质的性质不依赖pH值或不受介质或溶液中的pH值影响。
本文所述的“尤特奇RS100”是指丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，“尤特奇RL100”是指丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物。本文所述的尤特奇(Eudragit)产品的商品名、化学组成和注册名称在下表中列出：
Figure PCTCN2020094556-appb-000004
Figure PCTCN2020094556-appb-000005
本发明提供一种每日口服一次的拉考沙胺药物组合物及其制剂，该药物组合物或制剂控制拉考沙胺或其药学上可接受的盐以一定的速率释放，从而降低PTF，减少副作用，并且确保药物有效性。
药物组合物
一方面，本发明提供拉考沙胺药物组合物，其包含缓释多颗粒，其中所述缓释多颗粒的每个包含：
(a)载药核芯，其包含拉考沙胺或其药学上可接受的盐；和
(b)包裹所述载药核芯的缓释层，其包含非pH依赖型缓释剂。
在优选的实施方案中，该载药核芯中不包含缓释剂。
在优选的实施方案中，缓释层中也不包含活性成分。本发明的药物组合物不是基质形成药物组合物，活性成分和缓释剂分别置于相互独立的层里，并没有混合在一起。例如，图1和图2所示的颗粒的缓释层中均不含活性成分。
在一些实施方案中，拉考沙胺或其药学上可接受的盐均匀分散在载药核芯中(如图1所示)。
或者，在一些实施方案中，该载药核芯包含惰性丸芯(不含活性成分的中心)和包裹所述惰性丸芯的外层，拉考沙胺或其药学上可接受的盐置于该外层中(如图2所示)。
在优选的实施方案中，缓释多颗粒的每个还包含在载药核芯和缓释层之间的隔离层。
在优选的实施方案中，缓释多颗粒的每个还包含包裹缓释层的保护层。
在一些实施方案中，缓释层外还可再包裹一层含有活性成分的速释层，使其在服用后能快速释放一定量的活性成分。该增加的速释层可直接包裹在缓释层外，也可包裹在缓释层外的保护层外，还可以选择性的在该速释层外再包裹一层保护层。
本发明的载药核芯可通过本领域已知的各种现有技术制得，如通过挤出滚圆法、流化床和压片机制备。在一些实施方案中，该载药核芯中包含至少一种或多种填充剂，填充剂包括但不限于聚维酮(PVP)、交联聚维酮(PVPP)、乳糖、甘露醇、糖类、微晶纤维素、磷酸氢钙、玉米淀粉、淀粉、二氧化硅、羟丙基纤维素等。
在一些实施方案中，如图2所示，活性成分包裹在惰性丸芯外，可选地，还可在活性成分外再包裹一层隔离层。该惰性丸芯可以是商业上通用的(如糖丸、微晶纤维素丸、淀粉丸、二氧化硅丸等)或通过常规方法可制得的(如挤出滚圆法，流化床法等)。
在一些实施方案中，该惰性丸芯的粒径范围为100μm-1200μm，优选150μm-1000μm，更优选200μm-700μm，更优选300-600μm，更优选300-500μm。在一些实施方案中，该载药核芯中包含至少一种或多种粘合剂，活性药物成分(拉考沙胺或其药学上可接受的盐的形式)与至少一种粘合剂混合，然后包裹在该惰性丸芯上。粘合剂包括但不限于聚维酮(PVP)、羟丙基纤维素(HPC)、甲基纤维素(MC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠、淀粉浆、明胶、阿拉伯胶及它们混合物等。
在一些实施方案中，制得的拉考沙胺缓释多颗粒的平均粒径为约300μm至约1400μm，优选约500μm至约1400μm，更优选约600μm至约1400μm，最优选约600μm至约1200μm。
本申请中使用的活性成分(拉考沙胺或其药学上可接受的盐)原料的粒径范围(D90)为约0.1μm至约1000μm，优选约2μm至约200μm，更优选约2μm至约100μm，最优选约2μm至约60μm。
在一些实施方案中，拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)：(a)1小时内0.1-8％，(b)2小时内2-25％，(c)4小时内18-70％和/或(d)10小时内、12小时内、14小时内、16小时内或20小时内70-100％，其中该溶出度测定采用美国药典溶出方法II(桨法)，转速75rpm，温度37±0.5℃，溶出介质为900ml 0.1N HCl。
在一些实施方案中，拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)： (a)1小时内小于8％，(b)2小时内小于12％，(c)4小时内小于45％和/或(d)12小时内大于50％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定至少6小时。优选地，拉考沙胺或其药学上可接受的盐按以下体外溶出度释放：(a)1小时内小于6％，(b)2小时内小于10％和(c)4小时内小于30％。
在一些实施方案中，拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)：(a)1小时内小于约20％，(b)4小时内约20％-80％，或(c)12小时内大于约80％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 6.8磷酸盐缓冲液中持续测定12小时。优选地，拉考沙胺或其药学上可接受的盐按以下体外溶出度释放：(a)1小时内小于约20％，(b)4小时内约20％-80％和(c)12小时内大于约80％。
缓释层中的缓释剂(材料)可控制活性成分的溶出度，该颗粒的溶出度取决于包衣增重。该缓释剂可由已知的合成路径制得或是商业上直接可用的。在一些实施方案中，非pH依赖型缓释剂包括但不限于乙基纤维素、甲基纤维素、醋酸纤维素、邻苯二甲酸乙酸纤维素、聚乙酸乙烯酯、聚丙烯酸酯、聚甲基丙烯酸酯、季胺基甲基丙烯酸酯共聚物A型(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物)、季胺基甲基丙烯酸酯共聚物B型(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物以及它们的任何混合物等。在一些实施方案中，非pH依赖型缓释剂选自尤特奇RS100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)、尤特奇RL100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物)及其组合。在一些实施方案中，非pH依赖型缓释剂为尤特奇RS100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)和尤特奇RL100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物)的组合，其中所述尤特奇RS100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)与所述尤特奇RL100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物)的比例为大于或等于3:1、大于或等于4:1、大于或等于5:1、大于或等于6:1、大于或等于7:1、大于或等于8:1或大于或等于9:1；可选地，所述尤特奇RS100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)与所述尤特奇RL100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物)的比例为约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约9.5:1或约9.9:1。在一些实施方案中，非pH依赖型缓释剂为尤特奇RS100(丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物)。在优选的实施方案中，非pH依赖型缓释剂选自乙基纤维素，其黏度规格包括但不限于乙基纤维素7cP、乙基纤维素10cP、乙基纤维素20cP和乙基纤维素100cP，优选地，乙基纤维素的黏度规格为7cP。
在一些实施方案中，缓释剂占颗粒重量(w/w)的约2％至约50％、约5％至约50％、约5％至约40％、约5％至约30％、约7％至约30％、约8％至约30％、约8％至约25％、约10％至约25％、约10％至约20％或约20％至约30％。在一些实施方案中，缓释剂占颗粒的重量百分含量为约8％至约30％。在一个具体的实施方案中，缓释剂为尤特奇RS100，缓释剂占颗粒的重量百分含量为约8％至约30％。
在一些实施方案中，缓释剂占颗粒重量(w/w)的约5％至约20％、约5％至约15％、约5％至约10％、约5％至约9％、约5％至约8％、约5％至约7％或约5％至约6％。在一些实施方案中，缓释剂占颗粒的重量百分含量为约5％至约15％。在一个具体的实施方案中，缓释剂为乙基纤维素，缓释剂占颗粒的重量百分含量为约5％至约15％。
在一些实施方案中，拉考沙胺或其药学上可接受的盐与缓释剂的重量比为约15:1至约1:1、约15:1至约2:1、约10:1至约2:1、约8:1至约2:1、约8:1至约3:1、约10:1至约4:1、约6:1至约3:1、约5:1至约2:1。优选地，拉考沙胺或其药学上可接受的盐与缓释剂的重量比为约8:1至约3:1。在 一个具体的实施方案中，缓释剂为尤特奇RS100，拉考沙胺或其药学上可接受的盐与缓释剂的重量比为约8:1至约3:1。
在一些实施方案中，拉考沙胺或其药学上可接受的盐与缓释剂的重量比为约12:1至约2:1、约12:1至约5:1、约12:1至约6:1、约12:1至约7:1、约12:1至约8:1、约12:1至约9:1或约12:1至约10:1。优选地，拉考沙胺或其药学上可接受的盐与缓释剂的重量比为约12:1至约5:1。在一个具体的实施方案中，缓释剂为乙基纤维素，拉考沙胺或其药学上可接受的盐与缓释剂的重量比为约12:1至约5:1。
在一些实施方案中，拉考沙胺药物组合物口服一日一次给药。在一些实施方案中，拉考沙胺药物组合物包含拉考沙胺或其药学上可接受的盐的量为约1mg至约1000mg、约20mg至约600mg、约40mg至约200mg、约50mg至约300mg、约50mg至约600mg。
在优选的实施方案中，拉考沙胺药物组合物包含拉考沙胺的量为约50mg、约100mg、约150mg、约200mg、约300mg或约400mg。
在一些实施方案中，当拉考沙胺或其药学上可接受的盐与缓释剂(如Eudragit
Figure PCTCN2020094556-appb-000006
)的重量比为约8:1至约3:1时，该药物组合物或制剂在水性介质中释放活性成分的缓释时间为约2小时至约24小时、约4小时至约24小时、约8小时至约24小时、约4小时至约12小时、约12小时至约24小时、约8小时至约12小时或约12小时至约18小时。
在一些实施方案中，缓释层还可以包含一种或多种增塑剂，增塑剂包括但不限于邻苯二甲酸二乙酯、柠檬酸三乙酯、癸二酸二丁酯、聚乙二醇、甘油三乙酸酯、柠檬酸三丁酯、甘油和丙二醇。
在一些实施方案中，缓释层还可以包含一种或多种致孔剂，致孔剂包括但不限于聚乙二醇、羟丙基甲基纤维素、羟丙基纤维素和聚乙烯吡咯烷酮。在优选的实施方案中，致孔剂为羟丙基甲基纤维素。缓释层中不同致孔剂的选择会影响缓释剂的用量，较低的缓释剂的用量会导致较差的工艺稳健性。对于本申请的拉考沙胺药物组合物，申请人发现选用羟丙基甲基纤维素作为致孔剂，可控制适当的缓释剂用量，实现较好的工艺稳健性。
在一些实施方案中，致孔剂占缓释剂的重量比例为约20％-80％；在一些实施方案中，致孔剂占缓释剂的重量比例为约25％-75％；在一些实施方案中，致孔剂占缓释剂的重量比例为约30％-70％；在一些实施方案中，致孔剂占缓释剂的重量比例为约40％-70％；在优选的实施方案中，致孔剂占缓释剂的重量比例为约50％-65％；在优选的实施方案中，致孔剂占缓释剂的重量比例为约50％-60％。在一个具体的实施方案中，缓释剂为乙基纤维素，致孔剂为羟丙基甲基纤维素，致孔剂占缓释剂的重量比例为约50％-60％。
在一些实施方案中，缓释层还可包含水溶性小分子试剂，如糖或还原糖、乳糖、蔗糖、甘露醇、山梨醇等。
在一些实施方案中，可选择性包衣的隔离层或保护层材料可以是商业上通用的，包括但不限于欧巴代
Figure PCTCN2020094556-appb-000007
滑石粉、硬脂酸镁、羟丙基甲基纤维素、羟丙基纤维素等。
在一些实施方案中，在多颗粒的每个中，其拉考沙胺或其药学上可接受的盐所占的平均重量百分含量为至少20％、至少25％、至少30％、至少35％、至少38％、至少45％、至少50％、高达80％、高达75％或高达70％。在一些实施方案中，在多颗粒的每个中，拉考沙胺或其药学上可接受的盐所占的平均重量百分含量为约50％至约60％。在一些实施方案中，拉考沙胺或其药学上可接受的盐占颗粒的重量百分含量为约30％至约90％、约40％至约80％、约50％至约70％或约50％至约60％。
在一些实施方案中，惰性丸芯为微晶纤维素丸，其粒径为300-500μm。将拉考沙胺与粘合剂PVPK30混合后，包裹在该惰性丸芯上。缓释层以Eudragit
Figure PCTCN2020094556-appb-000008
作为缓释剂，其重量为颗粒重量百分含量的10％～25％。在一些实施方案中，在载药核芯上包裹一层含有
Figure PCTCN2020094556-appb-000009
的隔离层，使载药核芯表面更光滑。在一些实施方案中，该颗粒的缓释层外还可以包裹一层含有
Figure PCTCN2020094556-appb-000010
的保护层，以减少颗粒之间的摩擦或掩盖任何不好的味道或气味。
在一些实施方案中，惰性丸芯为微晶纤维素丸，其粒径为300-500μm。将拉考沙胺与粘合剂聚维酮(PVP K30)混合后，包裹在该惰性丸芯上。缓释层以乙基纤维素作为缓释剂，其重量为颗粒 重量百分含量的5％～15％。缓释层以羟丙基甲基纤维素作为致孔剂，致孔剂占缓释剂的重量比例为约50％-60％。在一些实施方案中，在载药核芯上包裹一层含有欧巴代
Figure PCTCN2020094556-appb-000011
的隔离层，使载药核芯表面更光滑。在一些实施方案中，该颗粒的缓释层外还可以包裹一层含有欧巴代
Figure PCTCN2020094556-appb-000012
的保护层，以减少颗粒之间的摩擦或掩盖任何不好的味道或气味。
虽然本发明主要描述的是包含缓释多颗粒的拉考沙胺药物组合物，但本发明所述的药物组合物还可包含缓释部分与速释部分的组合。具体地，在一些实施方案中，药物组合物中所有的拉考沙胺或其药学上可接受的盐均制成缓释，该药物组合物中并不含速释部分。在一些实施方案中，在该药物组合物中引入速释部分，与缓释部分组合一起，该药物组合物仍然能使拉考沙胺或其药学上可接受的盐在一段延长的时间内释放，该速释部分提供了一个初始的药物突释使其更快的达到治疗血药浓度水平。该速释部分中包含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的百分含量为约1％至约50％、约5％至约45％、约5％至约40％、约10％至约40％、约15％至约40％、约15％至约30％、约15％至约20％、约1％至约40％、约1％至约30％、约1％至约20％、约1％至约10％、约10％至约30％、约10％至约20％、约10％至约15％或约5％至约10％(w/w)。
在一些实施方案中，所述拉考沙胺药物组合物还包含速释部分，其中速释部分中的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的1％至40％(w/w)；优选地，其中速释部分中的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的1％至35％(w/w)；优选地，其中速释部分中的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的10％至30％(w/w)。
在一些实施方案中，药物组合物的速释部分中包含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的约1％至约35％(w/w)，优选约5％至约30％(w/w)。相应地，药物组合物中缓释部分所含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的约65％至约99％(w/w)，优选约70％至约95％(w/w)。在一些实施方案中，缓释部分中所含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的约65％至约70％、约70％至约75％、约75％至约80％、约80％至约85％、约85％至约90％、约90％至约95％、约70％至约80％、约80％至约90％或约90％至约95％(w/w)。速释部分中所含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量减去缓释部分中的拉考沙胺的剩余百分含量。优选地，缓释部分中所含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的约99％、约95％、约90％、约85％、约80％、约75％、约70％或约65％(w/w)，速释部分中所含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量的约1％、约5％、约10％、约15％、约20％、约25％、约30％或约35％(w/w)。速释部分(缓释部分)中所含的拉考沙胺或其药学上可接受的盐占药物组合物中拉考沙胺或其药学上可接受的盐总量减去缓释部分(速释部分)中的拉考沙胺的剩余百分含量。通常将药物制成缓释可降低PTF，对于本申请的拉考沙胺缓释多颗粒，申请人还令人惊讶地发现，拉考沙胺缓释多颗粒与速释部分按一定比例组合与不包含速释部分相比可进一步降低PTF。
在一些实施方案中，缓释部分与速释部分物理连接或相互独立。
在一些实施方案中，缓释部分与速释部分可以物理连接一起制成双层结构或多层结构。例如，在一些实施方案中，缓释层外还可再包裹一层含有活性成分的速释层，使其在服用后能快速释放一定量的活性成分。该增加的速释层可直接包裹在缓释层外，也可包裹在缓释层外的保护层外，还可以选择性的在该速释层外再包裹一层保护层。
在一些实施方案中，缓释部分与速释部分相互独立，不需要彼此物理连接。例如，在一些实施方案中，速释部分可以是单个单元形式或多颗粒形式，其制备方法除了不包裹缓释层，其余制备过程可以与缓释多颗粒相同。在优选的实施方案中，速释部分由多颗粒组成，例如，速释部分由没有包裹缓释层的载药颗粒组成。
在一些实施方案中，制得的拉考沙胺速释多颗粒的平均粒径为约300μm至约1200μm，优选约 500μm至约1200μm，更优选约600μm至约1200μm，最优选约600μm至约1000μm。
在一些实施方案中，包含缓释部分和速释部分的组合的药物组合物中拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)：(a)1小时内约10％-30％，(b)4小时内约30％-90％或(c)12小时内大于约90％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 6.8磷酸盐缓冲液中持续测定12小时。优选地，拉考沙胺或其药学上可接受的盐按以下体外溶出度释放：(a)1小时内约10％-28％，(b)4小时内约28％-90％和(c)12小时内大于约90％。
制剂
另一方面，本发明提供拉考沙胺缓释制剂，其包含本发明所述的拉考沙胺药物组合物，其是胶囊、小袋、撒剂、囊片、锭剂、袋、片剂或任何其它适合口服的剂型的形式。优选地，所述制剂是胶囊、小袋或撒剂。
在一些实施方案中，所述制剂口服一日一次给药。
在一些实施方案中，所述制剂的单位制剂中包含所述拉考沙胺或其药学上可接受的盐的量为约20mg至约600mg。
在优选的实施方案中，所述制剂为胶囊，本发明所述的药物组合物可以包封在合适的外壳中，如任何合适尺寸的胶囊，如000号、00号、0el号、0号、1号、2号、3号、4号或5号胶囊。单个胶囊中包含拉考沙胺或其药学上可接受的盐的量为约1mg至约1000mg、约20mg至约600mg、约40mg至约200mg、约50mg至约300mg、约50mg至约600mg。更优选地，单个胶囊中包含拉考沙胺的量为约50mg、约100mg、约150mg、约200mg、约300mg或约400mg。
另一方面，本发明提供拉考沙胺缓释制剂，其包含速释部分和缓释部分，其中速释部分中的拉考沙胺或其药学上可接受的盐占制剂中拉考沙胺或其药学上可接受的盐总量的1％至40％(w/w)；优选地，其中速释部分中的拉考沙胺或其药学上可接受的盐占制剂中拉考沙胺或其药学上可接受的盐总量的1％至35％(w/w)；优选地，其中速释部分中的拉考沙胺或其药学上可接受的盐占制剂中拉考沙胺或其药学上可接受的盐总量的5％至30％(w/w)；优选地，其中速释部分中的拉考沙胺或其药学上可接受的盐占制剂中拉考沙胺或其药学上可接受的盐总量的10％至30％(w/w)。在优选的实施方案中，速释部分或缓释部分由多颗粒组成，速释部分由没有包裹缓释层的载药颗粒组成。
在一些实施方案中，当采用美国药典溶出方法II(桨法)，在75rpm转速、37±0.5℃的温度下，在900ml 0.1N HCl中评估溶出曲线时，本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂具有以下一种或多种活性成分(拉考沙胺或其药学上可接受的盐)的体外溶出特性：
(a)在1小时内，释放的活性成分占总量的(w/w)：约0.1％至约20％，约0.1％至约15％，约0.1％至约12％，约0.1％至约10％，约0.1％至约8％，约0.1％至约6％，约0.1％至约5％，约0.1％至约4％，约0.1％至约3％，约0.1％至约2％，约0.5％至约20％，约0.5％至约15％，约0.5％至约12％，约0.5％至约10％，约0.5％至约8％，约0.5％至约6％，约0.5％至约5％，约0.5％至约4％，约0.5％至约3％，约1％至约20％，约1％至约15％，约1％至约12％，约1％至约10％，约1％至约8％，约1％至约6％，约1％至约5％，约1％至约4％或约1％至约3％；
(b)在2小时内，释放的活性成分占总量的(w/w)：约2％至约40％，约2％至约30％，约2％至约25％，约2％至约20％，约2％至约15％，2％至约10％，约2％至约8％，约5％至约40％，约5％至约30％，约5％至约25％，约5％至约20％，约5％至约15％，5％至约10％，约8％至约40％，约8％至约30％，约8％至约25％，约8％至约20％，约8％至约15％或约8％至约12％；
(c)在4小时内，释放的活性成分占总量的(w/w)：约15％至约90％，约18％至约90％，约20％至约80％，约18％至约80％，约18％至约70％，18％至约60％，约18％至约50％，约18％至约40％，约18％至约30％，约25％至约90％，约25％至约80％，约25％至约70％，约25％至约60％，约25％至约50％，约25％至约40％，约25％至约35％或约25％至约30％；和/或
(d)在10小时内、12小时内、14小时内、16小时内或20小时内，释放的活性成分占总量的(w/w)： 约50％至约100％，约70％至约100％，约60％至约100％，约50％至约95％，约70％至约95％或约80％至约100％。在一些实施方案中，该药物组合物或制剂具有上述中的一种、两种、三种或四种溶出特性。在一些实施方案中，该药物组合物或制剂提供具有上述(a)的活性成分溶出度。在一些实施方案中，该药物组合物或制剂提供具有上述(a)和(b)的活性成分溶出度。在一些实施方案中，该药物组合物或制剂提供具有上述(a)、(b)和(c)的活性成分溶出度。在一些实施方案中，该药物组合物或制剂提供具有上述(a)、(b)、(c)和(d)的活性成分溶出度。
在一些实施方案中，该药物组合物或制剂具有如下活性成分释放的体外溶出度：1小时内释放约0.1％至约8％，2小时内释放约2％至约25％，4小时内释放约18％至约70％和/或10小时内释放约70％至约100％。该溶出度测定采用美国药典溶出方法II(桨法)，转速75rpm，温度37±0.5℃，溶出介质为900ml 0.1N HCl。
在一些实施方案中，该药物组合物或制剂具有如下活性成分释放的体外溶出度：1小时内释放约0.1％至约8％，2小时内释放约2％至约14％，4小时内释放约20％至约70％和/或10小时内释放约70％至约100％。该溶出度测定采用美国药典溶出方法II(桨法)，转速75rpm，温度37±0.5℃，溶出介质为900ml 0.1N HCl。
在一些实施方案中，本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂具有以下一种或多种活性成分(拉考沙胺或其药学上可接受的盐)的体外溶出特性：
(a)在1小时内释放的活性成分小于10％，小于8％，小于6％，小于5％或小于4％；
(b)在2小时内释放的活性成分小于20％，小于15％，小于12％，小于10％，小于8％，小于6％或小于4％；
(c)在4小时内释放的活性成分小于50％，小于45％，小于40％，小于35％，小于30％，小于25％，小于20％，小于15％或小于10％；和/或
(d)在12小时内释放的活性成分大于40％，大于50％，大于60％，大于70％或大于80％。
该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定至少6小时(一直到12小时或18小时或24小时)。在一些实施方案中，该药物组合物或制剂提供具有上述(a)和(b)的活性成分溶出度。在一些实施方案中，该药物组合物或制剂提供具有上述(a)、(b)和(c)的活性成分溶出度。在一些实施方案中，该药物组合物或制剂提供具有上述(a)、(b)和(d)的活性成分溶出度。在一些实施方案中，该药物组合物或制剂提供具有上述(a)、(b)、(c)和(d)的活性成分溶出度。
在一些典型的实施方案中，本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂具有以下一种或多种活性成分(拉考沙胺或其药学上可接受的盐)的体外溶出特性：(a)1小时内释放的活性成分小于8％，(b)2小时内释放的活性成分小于12％，(c)4小时内释放的活性成分小于45％和/或(d)12小时内释放的活性成分大于50％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定6小时、12小时或18小时。在一些实施方案中，缓释剂为非pH依赖型缓释剂。在一些实施方案中，本发明所述的药物组合物或制剂，其拉考沙胺或其药学上可接受的盐按上述(a)，(a)+(b)，(a)+(d)，(a)+(b)+(c)，(a)+(b)+(d)或(a)+(b)+(c)+(d)释放。
在一些典型的实施方案中，本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂具有以下一种或多种活性成分(拉考沙胺或其药学上可接受的盐)的体外溶出特性：(a)1小时内释放的活性成分小于6％，(b)2小时内释放的活性成分小于10％，(c)4小时内释放的活性成分小于30％和/或(d)12小时内释放的活性成分大于50％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和 温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定6小时、12小时或18小时。在一些实施方案中，缓释剂为非pH依赖型缓释剂。在一些实施方案中，本发明所述的药物组合物或制剂，其拉考沙胺或其药学上可接受的盐按上述(a)，(a)+(b)，(a)+(d)，(a)+(b)+(c)，(a)+(b)+(d)或(a)+(b)+(c)+(d)释放。
在一些典型的实施方案中，本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂具有以下一种或多种活性成分(拉考沙胺或其药学上可接受的盐)的体外溶出特性：(a)1小时内释放的活性成分小于4％，(b)2小时内释放的活性成分小于8％，(c)4小时内释放的活性成分小于20％和/或(d)12小时内释放的活性成分大于50％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定6小时、12小时或18小时。在一些实施方案中，缓释剂为非pH依赖型缓释剂。在一些实施方案中，本发明所述的药物组合物或制剂，其拉考沙胺或其药学上可接受的盐按上述(a)，(a)+(b)，(a)+(d)，(a)+(b)+(c)，(a)+(b)+(d)或(a)+(b)+(c)+(d)释放。
在一些典型的实施方案中，本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂具有以下一种或多种活性成分(拉考沙胺或其药学上可接受的盐)的体外溶出特性：(a)1小时内释放的活性成分小于4％，(b)2小时内释放的活性成分小于8％，(c)4小时内释放的活性成分小于40％和/或(d)12小时内释放的活性成分大于50％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/34mM NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/100mM NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/100mM NaCl缓冲液中继续测定6小时、12小时或18小时。在一些实施方案中，缓释剂为非pH依赖型缓释剂。在一些实施方案中，本发明所述的药物组合物或制剂，其拉考沙胺或其药学上可接受的盐按上述(a)，(a)+(b)，(a)+(d)，(a)+(b)+(c)，(a)+(b)+(d)或(a)+(b)+(c)+(d)释放。优选地，拉考沙胺或其药学上可接受的盐按以下体外溶出度释放：(a)1小时内小于4％，(b)2小时内小于8％，(c)4小时内小于40％和(d)12小时内大于50％。
另一方面，本发明还提供包含速释部分和缓释部分的装置。该两部分可以混合在一起或彼此分开。两部分之间的比例可以与上述药物组合物或制剂中的比例相同。例如，在一些实施方案中，缓释部分中的拉考沙胺或其药学上可接受的盐占装置中拉考沙胺或其药学上可接受的盐总量的：约65％至约70％、约70％至约75％、约75％至约80％、约80％至约85％、约85％至约90％、约90％至约95％、约70％至约80％、约80％至约90％或约90％至约95％(w/w)。速释部分中的拉考沙胺或其药学上可接受的盐占装置中拉考沙胺或其药学上可接受的盐总量的剩余百分含量。在一些实施方案中，该装置中包含上述制成的缓释颗粒和速释颗粒。两种类型的颗粒可以封装在相同的胶囊或容器中。
治疗方法和用途
另一方面，本发明提供一种治疗神经病学或精神病学疾病或病症的方法，其包括向有此需要的受试者给药治疗有效量的本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂。
另一方面，本发明提供本发明所述的拉考沙胺药物组合物在制备用于治疗神经病学或精神病学疾病或病症的药物中的用途。
另一方面，本发明提供本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂，其用于治疗神经病学或精神病学疾病或病症。
在一些实施方案中，所述疾病或病症包括但不限于癫痫、偏头痛、特发性震颤、不宁肢体综合征、丛集性头痛、神经痛、神经性疼痛、Tourette综合征、婴儿痉挛、焦虑、双相障碍、精神病、 躁狂症、精神分裂症、抑郁症、痴呆症、孤独症、强迫症、创伤后应激障碍、注意力缺陷多动障碍、冲动控制障碍、边缘线人格障碍、成瘾、慢性神经退行性疾病、急性神经变性和肌萎缩侧索硬化。优选地，所述疾病或病症是部分发作性癫痫。
在一些实施方案中，所述药物组合物或制剂口服一日一次给药。
本发明所述的拉考沙胺药物组合物或拉考沙胺缓释制剂可以调节活性成分的体内释放，并降低峰谷波动(PTF)。在一些实施方案中，所述药物组合物或制剂的PTF小于约70％、小于约60％、小于约50％、小于约40％、小于约35％或小于约30％。在优选的实施方案中，所述药物组合物或制剂的PTF小于约60％。
在一些实施方案中，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
Figure PCTCN2020094556-appb-000013
相比，其PTF降低至少5％、至少10％、至少15％、至少20％或至少25％。优选地，其PTF降低至少15％。
在一些实施方案中，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
Figure PCTCN2020094556-appb-000014
相比，其AUC ss与C max,ss为速释制剂的75％至125％。在一些实施方案中，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
Figure PCTCN2020094556-appb-000015
相比，其AUC ss与C max,ss为速释制剂的80％至125％。
本发明通过以下实施例进一步说明，但并不将本发明的范围限制于这些实施例。
实施例1--缓释迷你片的制备
缓释迷你片的处方如表1所示。
表1.实施例1的缓释迷你片的处方。
Figure PCTCN2020094556-appb-000016
迷你片片芯选用3mm圆冲在单冲压片机上直接压片制备，将乙基纤维素(EC)和羟丙基甲基纤维素溶于乙醇/水中制备缓释包衣液，然后将此包衣液包衣在迷你片片芯上。体外溶出度测定选用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在500毫升0.1N盐酸溶出介质中测定24小时。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例1中的处方的溶出数据见表2。
表2.实施例1的缓释迷你片的溶出数据。
Figure PCTCN2020094556-appb-000017
实施例2--挤出滚圆法制备多颗粒
挤出滚圆法制备多颗粒的处方如表3所示。
表3.实施例2的挤出滚圆法制备多颗粒的处方。
Figure PCTCN2020094556-appb-000018
将拉考沙胺与微晶纤维素、交联聚维酮、聚维酮一起加入湿法制粒机中，混匀后，在搅拌状态下加入适量的水制得湿软材；将湿软材转移到挤出机中，在筛网孔径0.8mm和挤出速度25rpm的条件下挤出；将柱状湿挤出物放入滚圆机内，在滚圆速度800rpm的条件下滚圆1-3分钟；然后将所得微丸于50℃下干燥，至干燥失重(LOD)小于3％；将干燥后的微丸过筛，收集20～30目之间的微丸。
实施例3--挤出滚圆法制备多颗粒
挤出滚圆法制备多颗粒的处方如表4所示。
表4.实施例3的挤出滚圆法制备多颗粒的处方。
Figure PCTCN2020094556-appb-000019
将拉考沙胺与微晶纤维素、一水乳糖、交联聚维酮、聚维酮一起加入湿法制粒机中，混匀后，在搅拌状态下加入适量的水制得湿软材；将湿软材转移到挤出机中，在筛网孔径0.8mm和挤出速度25rpm的条件下挤出；将柱状湿挤出物放入滚圆机内，在滚圆速度800rpm的条件下滚圆1-3分钟；然后将所得微丸于50℃下干燥，至干燥失重(LOD)小于3％；将干燥后的微丸过筛，收集20～30目之间的微丸。
实施例4--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表5所示。
表5.实施例4的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000020
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以达到所需的载药水平；然后在载药微丸上包裹欧巴代隔离层，再将由乙基纤维素和聚乙二醇组成的缓释包衣液包裹在该载药微丸表面，以获得所需的不同包衣增重水平。调节进 风速率和物料温度以防止包衣液喷雾干燥或微丸过湿。制得的微丸的粒径为约600μm至约1200μm。
体外溶出度测定选用美国药典溶出方法II(桨法)，转速75rpm、温度37±0.5℃、溶出介质为900毫升0.1N盐酸。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例4中的4个处方的溶出数据如表6和图3所示。
表6.实施例4的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000021
实施例5--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表7所示。
表7.实施例5的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000022
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以获得载药微丸；然后将由醋酸纤维素和聚乙二醇组成的缓释包衣液包裹在该载药微丸表面，以获得所需的不同包衣增重水平。调节进风速率和物料温度以防止包衣液喷雾干燥或微丸过湿。制得的微丸的粒径为约600μm至约1200μm。
体外溶出度测定选用美国药典溶出方法II(桨法)，转速75rpm、温度37±0.5℃、溶出介质为900毫升0.1N盐酸。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例5中的两个处方的溶出数据如表8和图4A所示。
表8.实施例5的缓释多颗粒的溶出数据(方法II)。
Figure PCTCN2020094556-appb-000023
实施例5中的溶出度测定还采用了美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定18小时。溶出样品采用高效液相色谱(HPLC)方法分析，溶出数据如表9和图4B所示。
表9.实施例5的缓释多颗粒的溶出数据(方法I)。
Figure PCTCN2020094556-appb-000024
实施例6--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表10所示。
表10.实施例6的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000025
Figure PCTCN2020094556-appb-000026
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以达到所需的载药水平；然后在载药微丸上包裹欧巴代隔离层，再将由尤特奇RS100/尤特奇RL100(3:1)、柠檬酸三乙酯和滑石粉组成的缓释混悬液包裹在该载药微丸表面，以获得所需的包衣水平(例如10％、15％、20％、25％，w/w)。调节进风速率和物料温度以防止包衣液喷雾干燥或微丸过湿。制得的微丸的粒径为约600μm至约1200μm。
溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5缓冲液中继续测定一段时间。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例6中的四个处方的拉考沙胺缓释多颗粒溶出数据如表11和图5所示。
表11.实施例6的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000027
实施例7--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表12所示。
表12.实施例7的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000028
Figure PCTCN2020094556-appb-000029
该包衣工艺如实施例6所述。
溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5缓冲液中继续测定一段时间。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例7中的四个处方的拉考沙胺缓释多颗粒的溶出数据如表13和图6所示。
表13.实施例7的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000030
实施例8--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表14所示。
表14.实施例8的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000031
Figure PCTCN2020094556-appb-000032
除在缓释层外多包裹一层保护层外，其余包衣工艺如实施例6所述。
体外溶出度测定选用美国药典溶出方法II(桨法)，转速75rpm、温度37±0.5℃、溶出介质为900毫升0.1N盐酸。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例8中的两个处方的溶出数据如表15和图7所示。
表15.实施例8的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000033
实施例9--流化床包衣制备拉考沙胺缓释胶囊
流化床包衣制备拉考沙胺缓释胶囊的缓释多颗粒的处方如表16所示。
表16.实施例9流化床包衣制备拉考沙胺缓释胶囊的缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000034
Figure PCTCN2020094556-appb-000035
该包衣工艺如实施例8所述，获得的缓释多颗粒通过胶囊填装机将其填装到0号胶囊中。
该胶囊体外溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/34mM NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/100mM NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/100mM NaCl缓冲液中继续测定18小时。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例9中的三个处方的拉考沙胺缓释胶囊的溶出数据如表17所示。
表17.实施例9的拉考沙胺缓释胶囊的溶出数据。
Figure PCTCN2020094556-appb-000036
实施例10--流化床包衣制备拉考沙胺缓释胶囊
流化床包衣制备拉考沙胺缓释胶囊的缓释多颗粒的处方如表18所示。
表18.实施例10流化床包衣制备拉考沙胺缓释胶囊的缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000037
Figure PCTCN2020094556-appb-000038
该包衣工艺如实施例8所述，获得的缓释多颗粒通过胶囊填装机将其填装到适合型号的胶囊中，如0号、1号和4号胶囊。
该体外溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 1.0HCl/NaCl缓冲液中测定2小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 6.8磷酸盐/NaCl缓冲液中继续测定4小时，随后在相同的溶出方法、转速和温度下，样品转移至900ml pH 7.5磷酸盐/NaCl缓冲液中继续测定18小时。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例10中的三个处方的拉考沙胺缓释胶囊的溶出数据如表19和图8所示。采用尤特奇RS100包衣，其体外溶出释放特征类似于采用pH依赖型聚合物包衣的释放特征，如在pH 1.0或pH 1.0至pH 6.8的介质中迟释1小时、3小时或5小时。该释放特征与普通缓释剂型的释放特征相比，可减少或避免缓释剂型在体内有药物突释的风险。
表19.实施例10的拉考沙胺缓释胶囊的溶出数据。
Figure PCTCN2020094556-appb-000039
实施例11--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表20所示。
表20.实施例11的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000040
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以达到所需的载药水平；然后在载药微丸上包裹欧巴代隔离层，再将由乙基纤维素、羟丙基甲基纤维素和柠檬酸三乙酯组成的缓释包衣液包裹在该载药微丸表面，以获得所需的不同包衣增重水平。调节进风速率和物料温度以防止包衣液喷雾干燥或微丸过湿。制得的微丸的粒径为约600μm至约1200μm。
体外溶出度测定选用美国药典溶出方法I(篮法)，转速100rpm、温度37±0.5℃、溶出介质为pH 6.8磷酸盐缓冲液。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例11中的6个处方的溶出数据如表21所示。
表21.实施例11的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000041
实施例12--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表22所示。
表22.实施例12的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000042
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以达到所需的载药水平；然后在载药微丸上包裹欧巴代隔离层，再将由乙基纤维素、羟丙基甲基纤维素和柠檬酸三乙酯组成的缓释包衣液包裹在该载药微丸表面，以获得所需的不同包衣增重水平。调节进风速率和物料温度以防止包衣液喷雾干燥或微丸过湿。制得的微丸的粒径为约600μm至约1200μm。
体外溶出度测定选用美国药典溶出方法I(篮法)，转速100rpm、温度37±0.5℃、溶出介质为pH 6.8磷酸盐缓冲液。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例12中的6个处方的溶出数据如表23所示。
表23.实施例12的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000043
实施例13--流化床包衣制备缓释多颗粒
流化床包衣制备缓释多颗粒的处方如表24所示。
表24.实施例13的流化床包衣制备缓释多颗粒的处方。
Figure PCTCN2020094556-appb-000044
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以达到所需的载药水平；然后在载药微丸上包裹欧巴代隔离层，再将由乙基纤维素、羟丙基甲基纤维素和柠檬酸三乙酯组成的缓释包衣液包裹在该载药微丸表面，以获得所需的不同包衣增重水平。调节进风速率和物料温度以防止包衣液喷雾干燥或微丸过湿。制得的微丸的粒径为约600μm至约1200μm。
体外溶出度测定选用美国药典溶出方法I(篮法)，转速100rpm、温度37±0.5℃、溶出介质为pH 6.8磷酸盐缓冲液。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例13中的7个处方的溶出数据如表25所示。
表25.实施例13的缓释多颗粒的溶出数据。
Figure PCTCN2020094556-appb-000045
实施例14--流化床包衣制备拉考沙胺缓释制剂
流化床包衣制备包含缓释部分和速释部分(速释层或速释多颗粒)的组合的处方如表26所示。
表26.实施例14的流化床包衣制备拉考沙胺缓释制剂的处方。
Figure PCTCN2020094556-appb-000046
将拉考沙胺和聚维酮的混悬液作为上药包衣液，使用流化床将该上药包衣液均匀地包裹到惰性微晶纤维素丸上，以达到所需的载药水平，然后在载药微丸上包裹欧巴代隔离层，以获得速释微丸，制得的速释微丸的粒径为约600μm至约1000μm；再将由乙基纤维素、羟丙基甲基纤维素和柠檬酸三乙酯组成的缓释包衣液包裹在速释微丸表面，然后再包裹欧巴代隔离层，可获得缓释微丸，制得的缓释微丸的粒径为约600μm至约1200μm。
选取其中一批的缓释微丸，将拉考沙胺和聚维酮的混悬液作为上药包衣液包裹在该缓释微丸表面，以达到所需的载药水平，然后再包裹欧巴代保护层，将此含有速释和缓释两部分的微丸装填到胶囊壳中(E14-2)。
而处方E14-3是将上述缓释微丸和速释微丸两部分微丸按给定比例混合均匀，装填于胶囊中。
体外溶出度测定选用美国药典溶出方法I(篮法)，转速100rpm、温度37±0.5℃、溶出介质为pH 6.8磷酸盐缓冲液。溶出样品采用高效液相色谱(HPLC)方法分析，该实施例14中的3个处方的溶出数据如表27所示。
表27.实施例14的缓释制剂的溶出数据。
Figure PCTCN2020094556-appb-000047
实施例15--通过GastroPlus模拟稳态药动学参数
设计了三种体外释放曲线的缓释(ER)处方(实施例10中所述的F1、F2和F3)，并预测了其体内的吸收曲线。本实施例还包括上述三种处方与不同比例的速释(IR)部分组合。基于
Figure PCTCN2020094556-appb-000048
IR片剂的单剂量药代动力学参数，利用药代动力学软件Gastroplus对这些处方的稳态AUC ss、C ss,max和C ss,min进行了模拟预测。模拟结果如表28所示。
表28.稳态药动学参数模拟。
Figure PCTCN2020094556-appb-000049
另外，还设计了两种体外释放曲线的缓释(ER)处方(实施例11中所述的E11-1和E11-4)，并预测了其体内的吸收曲线。本实施例还包括上述两种处方与不同比例的速释(IR)部分组合。基于
Figure PCTCN2020094556-appb-000050
IR片剂的单剂量药代动力学参数，利用药代动力学软件Gastroplus对这些处方的稳态AUC ss、C ss,max和C ss,min进行了模拟预测。模拟结果如表29所示。拉考沙胺缓释多颗粒引入一定比例的速释部分可进一步降低PTF。
表29.稳态药动学参数模拟。
Figure PCTCN2020094556-appb-000051
Figure PCTCN2020094556-appb-000052

Claims (13)

  1. 拉考沙胺药物组合物，其包含缓释多颗粒，其中所述缓释多颗粒的每个包含：
    (a)载药核芯，其包含拉考沙胺或其药学上可接受的盐；和
    (b)包裹所述载药核芯的缓释层，其包含非pH依赖型缓释剂；并且
    优选地，其中所述载药核芯中不包含所述缓释剂。
  2. 权利要求1所述的拉考沙胺药物组合物，其中所述载药核芯包含惰性丸芯和包裹所述惰性丸芯的外层，所述拉考沙胺或其药学上可接受的盐置于所述外层中。
  3. 权利要求1所述的拉考沙胺药物组合物，其中所述拉考沙胺或其药学上可接受的盐均匀分散在所述载药核芯中。
  4. 权利要求1-3所述的拉考沙胺药物组合物，其中所述拉考沙胺或其药学上可接受的盐按以下一种或多种体外溶出度释放(w/w)：(a)1小时内小于约20％，(b)4小时内约20％-80％，或(c)12小时内大于约80％，其中该溶出度测定采用美国药典溶出方法I(篮法)，转速100rpm，温度37±0.5℃，在900ml pH 6.8磷酸盐缓冲液中持续测定12小时。
  5. 权利要求1-4所述的拉考沙胺药物组合物，其中所述拉考沙胺或其药学上可接受的盐占所述颗粒的重量百分含量为约40％至约80％。
  6. 权利要求1-5所述的拉考沙胺药物组合物，其中所述缓释剂占所述颗粒的重量百分含量为约5％至约30％。
  7. 权利要求1-6所述的拉考沙胺药物组合物，其中所述拉考沙胺或其药学上可接受的盐与所述缓释剂的重量比为约15:1至约1:1。
  8. 权利要求1-7所述的拉考沙胺药物组合物，其包含所述拉考沙胺或其药学上可接受的盐的量为约20mg至约600mg。
  9. 权利要求1-8所述的拉考沙胺药物组合物，其中所述非pH依赖型缓释剂选自乙基纤维素，甲基纤维素，醋酸纤维素，邻苯二甲酸乙酸纤维素，聚乙酸乙烯酯，聚丙烯酸酯，聚甲基丙烯酸酯，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，丙烯酸乙酯-甲基丙烯酸甲酯共聚物以及它们的任何混合物等；
    优选地，所述非pH依赖型缓释剂为丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，并且
    优选地，所述非pH依赖型缓释剂为乙基纤维素。
  10. 权利要求1-9所述的拉考沙胺药物组合物，其还包含速释部分，其中所述速释部分中的拉考沙胺或其药学上可接受的盐占所述药物组合物中拉考沙胺或其药学上可接受的盐总量的1％至35％(w/w)；
    优选地，其中所述速释部分中的拉考沙胺或其药学上可接受的盐占所述药物组合物中拉考沙胺或其药学上可接受的盐总量的5％至30％(w/w)；
    优选地，其中缓释部分与速释部分物理连接或相互独立；
    更优选地，其中所述速释部分为所述缓释层外包裹的含有拉考沙胺或其药学上可接受的盐的速释层，并且
    更优选地，其中所述速释部分由没有包裹所述缓释层的载药颗粒组成。
  11. 拉考沙胺缓释制剂，其包含权利要求1-10中任一项所述的拉考沙胺药物组合物，其是胶囊、小袋、撒剂、囊片、锭剂、袋、片剂或任何其它适合口服的剂型的形式；
    优选地，所述制剂口服一日一次给药；
    更优选地，所述制剂的单位制剂中包含所述拉考沙胺或其药学上可接受的盐的量为约20mg至约600mg；
    更优选地，所述制剂为胶囊，单个胶囊中包含所述拉考沙胺或其药学上可接受的盐的量为约20 mg至约600mg；并且
    最优选地，单个胶囊中包含所述拉考沙胺的量为约50mg、约100mg、约150mg、约200mg、约300mg或约400mg。
  12. 拉考沙胺缓释制剂，其包含速释部分和缓释部分，其中所述速释部分中的拉考沙胺或其药学上可接受的盐占所述制剂中拉考沙胺或其药学上可接受的盐总量的1％至35％(w/w)；
    优选地，其中所述速释部分中的拉考沙胺或其药学上可接受的盐占所述制剂中拉考沙胺或其药学上可接受的盐总量的5％至30％(w/w)；并且
    更优选地，其中所述速释部分或缓释部分由多颗粒组成。
  13. 一种治疗神经病学或精神病学疾病或病症的方法，其包括向有此需要的受试者给药治疗有效量的权利要求1-10中任一项所述的拉考沙胺药物组合物或权利要求11或12所述的拉考沙胺缓释制剂，其中所述疾病或病症选自癫痫、偏头痛、特发性震颤、不宁肢体综合征、丛集性头痛、神经痛、神经性疼痛、Tourette综合征、婴儿痉挛、焦虑、双相障碍、精神病、躁狂症、精神分裂症、抑郁症、痴呆症、孤独症、强迫症、创伤后应激障碍、注意力缺陷多动障碍、冲动控制障碍、边缘线人格障碍、成瘾、慢性神经退行性疾病、急性神经变性和肌萎缩侧索硬化；
    优选地，其中所述疾病或病症是部分发作性癫痫；
    优选地，所述药物组合物或制剂口服一日一次给药；
    更优选地，所述药物组合物或制剂的PTF小于约60％；
    更优选地，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
    Figure PCTCN2020094556-appb-100001
    相比，其PTF降低至少15％；并且
    更优选地，口服一日一次给药的所述药物组合物或制剂与口服一日两次给药的相同拉考沙胺日剂量的速释制剂
    Figure PCTCN2020094556-appb-100002
    相比，其AUC ss与C max,ss为速释制剂的80％至125％。
PCT/CN2020/094556 2019-06-06 2020-06-05 一种拉考沙胺药物组合物及其药物制剂 WO2020244615A1 (zh)

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US20220280456A1 (en) 2022-09-08
EP3981390A4 (en) 2023-01-25
CN112043681A (zh) 2020-12-08
CN114404393A (zh) 2022-04-29
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