WO2022007758A1 - 一种布瓦西坦药物组合物、其制备方法及应用 - Google Patents

一种布瓦西坦药物组合物、其制备方法及应用 Download PDF

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WO2022007758A1
WO2022007758A1 PCT/CN2021/104586 CN2021104586W WO2022007758A1 WO 2022007758 A1 WO2022007758 A1 WO 2022007758A1 CN 2021104586 W CN2021104586 W CN 2021104586W WO 2022007758 A1 WO2022007758 A1 WO 2022007758A1
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brivaracetam
weight
percentage
pharmaceutical composition
ksr
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PCT/CN2021/104586
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English (en)
French (fr)
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郭桢
陈丽娜
温益峰
王婷婷
应述欢
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上海博志研新药物技术有限公司
上海博志研新药物研究有限公司
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Priority to JP2021568880A priority Critical patent/JP7423013B2/ja
Priority to EP21787288.6A priority patent/EP3964201A4/en
Priority to US17/604,567 priority patent/US20220304934A1/en
Publication of WO2022007758A1 publication Critical patent/WO2022007758A1/zh

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
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    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
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    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention belongs to the field of pharmaceutical compositions, and relates to a brivaracetam pharmaceutical composition, a preparation method and application thereof.
  • Brivaracetam is an antiepileptic drug used clinically as a monotherapy for patients with partial-onset epilepsy aged 4 years and older.
  • brivaracetam also known as brivaracetam
  • the molecular formula is C 11 H 20 N 2 O 2
  • its structural formula is:
  • Brivaracetam is a white or off-white crystalline powder, a BCS class I drug, easily soluble in water (0.7g/mL), pH 1.2 hydrochloric acid solution (0.85g/mL), pH 4.5 buffer solution (0.85g/mL) and pH 7.4 buffer (0.84g/mL), the terminal half-life is short (9h), therefore, the effective blood concentration of the drug in vivo is maintained for a short time.
  • the existing commercially available preparations are brivaracetam tablets, brivaracetam oral liquid and brivaracetam injection. The specifications of oral solution and brivaracetam injection are both 10mg/mL.
  • the administration method of commercially available brivaracetam tablets is: the recommended starting dose is 50 mg twice a day, and the dose may be adjusted to 25 mg twice a day or 100 mg twice a day according to individual patient tolerance and treatment response. That is, the commercially available tablet cannot effectively control the dose in vivo in clinical use due to its rapid release. In addition, this method of administration needs to adjust the dose according to the progress of the patient's condition after taking the medicine, which is not conducive to the patient taking the medicine by himself.
  • brivaracetam tablets prepared in the prior art are immediate-release tablets, and UCB's patent (authorization announcement number: CN102046153B) discloses a new pharmaceutical composition containing Brivaracetam, which can control the drug
  • the release rate of the drug provides at least 16h of therapeutic effect when administered.
  • the release rate of the pharmaceutical composition prepared by this method is relatively fast, and no product of this process is seen on the market.
  • the present invention provides a brivaracetam pharmaceutical composition, which is a 24-hour slow-release drug, and its dissolution meets the following three characteristics simultaneously:
  • the active pharmaceutical ingredient can be selected from brivaracetam, pharmaceutically acceptable complexes of brivaracetam, pharmaceutically acceptable salts of brivaracetam, pharmaceutically acceptable solvates of brivaracetam and one, two or more of the pharmaceutically acceptable hydrates of brivaracetam.
  • the dissolution of the brivaracetam pharmaceutical composition simultaneously satisfies the following three characteristics:
  • the brivaracetam pharmaceutical composition is a 24-hour slow-release drug, and its dissolution meets the following three characteristics at the same time:
  • B) dissolve 30%-70% of the active pharmaceutical ingredient within 6 hours; preferably, dissolve 30%-70% of the brivaracetam or a pharmaceutically acceptable salt thereof within 6 hours;
  • the dissolution of the brivaracetam pharmaceutical composition simultaneously satisfies the following three characteristics:
  • B) dissolve 30%-65% of the active pharmaceutical ingredient within 6 hours; preferably, dissolve 30%-65% of the brivaracetam or its pharmaceutically acceptable salt within 6 hours;
  • the dissolution of the brivaracetam pharmaceutical composition satisfies the following three characteristics simultaneously:
  • B) dissolve 30%-65% of the active pharmaceutical ingredient within 6 hours; preferably, dissolve 30%-65% of the brivaracetam or its pharmaceutically acceptable salt within 6 hours;
  • the “dissolution” refers to the cumulative dissolution rate of the active pharmaceutical ingredient (such as brivaracetam or a pharmaceutically acceptable salt thereof); further, the cumulative dissolution rate is measured in pH 4.5 acetate buffer.
  • the dissolution rate of the brivaracetam or a pharmaceutically acceptable salt thereof increases gradually over time.
  • the present invention provides a brivaracetam pharmaceutical composition, which comprises a pharmaceutical active ingredient, a matrix-forming agent and a swelling agent;
  • the pharmaceutical active ingredient is selected from one, two or more of the following substances: brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable complex of brivaracetam
  • the salts, the pharmaceutically acceptable solvates of brivaracetam and the pharmaceutically acceptable hydrates of brivaracetam are selected from one, two or more of the following substances: brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable complex of brivaracetam
  • the matrix-forming agent refers to a substance that can provide structural integrity and help to control or prolong the drug release rate; for example, selected from one, two or more of the following substances: polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), carbomer, polysaccharide, polyacrylic resin, polyvinyl acetate povidone mixture ( hereinafter referred to as KSR) and polyvinyl alcohol;
  • PVAc polyvinyl acetate
  • PVP polyvinylpyrrolidone
  • carbomer polysaccharide
  • polyacrylic resin polyacrylic resin
  • KSR polyvinyl acetate povidone mixture
  • polyvinyl alcohol polyvinyl alcohol
  • the swelling agent refers to a substance that can absorb water from gastric juice to cause the size of the solid preparation to expand, and can affect the drug release rate by generating channels or by forming a hydrophilic colloid;
  • the alginate can be the salt formed by alginic acid and metal ions (such as sodium ion, potassium ion), such as sodium alginate and/or potassium alginate;
  • metal ions such as sodium ion, potassium ion
  • described calcium salt can be the salt formed by inorganic acid and calcium ion, or the salt formed by organic acid and calcium ion; for example, a kind of calcium chloride, calcium hydrogen phosphate and calcium hydrogen phosphate dihydrate, two or three.
  • the pharmaceutical active ingredient is preferably brivaracetam.
  • the weight percentage of the pharmaceutical active ingredient is 2.00% to 50.00%, more preferably 3.00% to 20.00%, such as 9.10%, 11.10%, 9.09%, 4.55% or 18.18%; the weight percentage is Refers to the percentage of the weight of the active pharmaceutical ingredients in the total weight of the brivaracetam pharmaceutical composition.
  • the weight percentage of the matrix-forming agent is 5.00% to 60.00%, more preferably 30.00% to 50.00%, such as 49.10%, 50.00%, 38.00%, 36.09%, 36.36%, 38.91% % or 36.54%; the weight percentage refers to the percentage of the weight of the matrix-forming agent in the total weight of the brivaracetam pharmaceutical composition.
  • the KSR can be produced by BASF under the trade name of KOLLIDON @ SR, containing an 80/19 (w/w) mixture of PVAc and PVP.
  • the polysaccharide is selected from the group consisting of one, two or more of the following polysaccharides: xanthan gum, inulin, guar gum, chitosan, carob gum, carrageenan and cellulose derivative.
  • the cellulose derivative is selected from the group consisting of one, two or more of the following: ionic cellulose polymers and non-ionic cellulose polymers.
  • the ionic cellulose polymer is selected from the group consisting of carboxymethyl cellulose (CMC), carboxymethyl cellulose sodium salt, carboxymethyl cellulose calcium salt, carboxyethyl cellulose (CEC), carboxymethyl cellulose (CEC), carboxymethyl cellulose Methyl ethyl cellulose (CMEC), hydroxyethyl methyl cellulose acetate phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxypropyl cellulose acetate phthalate ( HPCAP), one, two or more of hydroxypropyl cellulose acetate succinate (HPCAS) and hydroxypropyl methylcellulose acetate phthalate (HPMCAP).
  • CMC carboxymethyl cellulose
  • CEC carboxymethyl cellulose sodium salt
  • carboxymethyl cellulose calcium salt carboxyethyl cellulose
  • CEC carboxymethyl cellulose
  • CEC carboxymethyl cellulose Methyl ethyl cellulose
  • CMEC carboxymethyl cellulose Methyl
  • the nonionic cellulose polymer is selected from the group consisting of methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), One, two or one of hypromellose (HPMC), hydroxypropyl methylcellulose acetate, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose more variety.
  • MC methyl cellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HPC hydroxypropyl cellulose
  • HPMC hypromellose
  • the swelling agent may or may not be soluble in water.
  • the swelling agent can be selected from cross-linked polyvinyl pyrrolidone (PVPP), polyethylene oxide (PEO), cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, One, two or more of carboxymethylcellulose calcium, carboxymethylcellulose, and polacrilin potassium.
  • the weight percentage of the swelling agent is 5.00% to 60.00%, more preferably 20.00% to 50.00%, such as 40.80%, 37.90%, 31.00%, 35.46%, 36.36%, 38.17% or 34.55%;
  • the weight percentage refers to the percentage of the weight of the swelling agent in the total weight of the brivaracetam pharmaceutical composition.
  • the brivaracetam pharmaceutical composition may further include lubricants and/or diluents.
  • the lubricant refers to a substance that helps in processing steps such as component mixing and tableting, and can be selected from the group consisting of talc, stearic acid, metal stearate, stearate, One or two of glyceryl citrate, sodium lauryl sulfate, hydrogenated vegetable oil, mineral oil, poloxamer (copolymer of ethylene oxide and propylene oxide), polyethylene glycol, and sodium chloride species or more.
  • the metal stearate is selected from one, two or three selected from calcium stearate, magnesium stearate and zinc stearate, preferably magnesium stearate.
  • the stearate is selected from one, two or more of polyoxyethylene stearate, glyceryl monostearate, and glyceryl palm stearate.
  • the diluent refers to a substance that can improve the fluidity of the pharmaceutical composition, enhance the compressive strength or hardness, reduce the friability, etc., during the mixing and tableting of the components.
  • the diluent is selected from the group consisting of dextrose, lactose monohydrate, lactose anhydrous, sucrose, mannitol, xylitol, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dihydrate One, two or more of calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, cyclodextrin and cyclodextrin derivatives.
  • the cyclodextrin is selected from one, two or more of ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin;
  • the cyclodextrin derivative is selected from Self-included cyclodextrin glucose derivatives, cyclodextrin hydroxypropyl derivatives, cyclodextrin methyl derivatives, cyclodextrin ethyl derivatives, cyclodextrin acetyl derivatives, cyclodextrin sulfobutyl derivatives One, two or more of ionic cyclodextrin derivatives, etc.
  • the weight percentage of the lubricant may be 0-3.00%, more preferably 0.50%-2.00%, such as 1.00%, and the weight percentage means that the weight of the lubricant accounts for the proportion of the lubricant The percentage of the total weight of the pharmaceutical composition of racetam.
  • the weight percentage of the diluent may be 0-30.00%, more preferably 0-20.00%, such as 18.90%, 18.36%, 17.18%, 17.36% or 9.73%
  • the weight of the Percentage refers to the weight of the diluent as a percentage of the total weight of the brivaracetam pharmaceutical composition.
  • the brivaracetam pharmaceutical composition has the dissolution profile as indicated above.
  • the brivaracetam pharmaceutical composition provided by the invention has stable properties and is suitable for oral administration once a day. When administered in a solid dosage form, the pharmaceutical composition has a longer gastric residence time than an immediate release formulation. When the pharmaceutical composition remains in the stomach, the brivaracetam can be released continuously.
  • the brivaracetam pharmaceutical composition is composed of a pharmaceutical active ingredient, a matrix-forming agent and a swelling agent;
  • Described active pharmaceutical ingredient is selected from brivaracetam, the pharmaceutically acceptable complex of brivaracetam, the pharmaceutically acceptable salt of brivaracetam, the pharmaceutically acceptable solvate of brivaracetam and one, two or more of the pharmaceutically acceptable hydrates of brivaracetam;
  • the matrix forming agent is selected from one, two or more of polyvinyl acetate (PVAc), polyvinyl pyrrolidone (PVP), KSR, carbomer and polysaccharide;
  • the swelling agent is selected from one, two or more of cross-linked polyvinylpyrrolidone (PVPP), polyethylene oxide (PEO), alginate and calcium salt.
  • PVPP polyvinylpyrrolidone
  • PEO polyethylene oxide
  • alginate alginate and calcium salt.
  • the brivaracetam pharmaceutical composition may be composed of the following components: brivaracetam, KSR, cross-linked polyvinylpyrrolidone (PVPP), polyethylene oxide (PEO), carbomer and magnesium stearate.
  • the brivaracetam pharmaceutical composition may be composed of the following components: brivaracetam, KSR, cross-linked polyvinylpyrrolidone (PVPP), polyethylene oxide (PEO), carbomer mol, lactose and magnesium stearate.
  • PVPP cross-linked polyvinylpyrrolidone
  • PEO polyethylene oxide
  • carbomer mol lactose and magnesium stearate.
  • the brivaracetam pharmaceutical composition may be composed of the following components: brivaracetam, KSR, cross-linked polyvinylpyrrolidone (PVPP), polyethylene oxide (PEO), carboxymethyl Sodium starch base, hypromellose, pregelatinized starch, carbomer, microcrystalline cellulose and magnesium stearate.
  • the brivaracetam pharmaceutical composition may be composed of the following components: brivaracetam, KSR, cross-linked polyvinylpyrrolidone (PVPP), sodium alginate, calcium chloride, carboxylate Sodium methyl starch, hypromellose, pregelatinized starch, microcrystalline cellulose and magnesium stearate.
  • VPP cross-linked polyvinylpyrrolidone
  • the brivaracetam pharmaceutical composition is composed of the following components: brivaracetam, KSR, cross-linked polyvinylpyrrolidone (PVPP), sodium carboxymethyl starch, hydroxypropylmethyl Cellulose, pregelatinized starch, carbomer, microcrystalline cellulose and magnesium stearate.
  • VPP cross-linked polyvinylpyrrolidone
  • the brivaracetam pharmaceutical composition is composed of the following components: brivaracetam, KSR, cross-linked polyvinylpyrrolidone (PVPP), polyethylene oxide (PEO), carboxymethyl Sodium starch, hypromellose, pregelatinized starch, carbomer and magnesium stearate.
  • the brivaracetam pharmaceutical composition is selected from any of the following formulations:
  • Formulation 1 9.1% brivaracetam, 40.0% KSR (ie KOLLIDON@SR), 20.0% cross-linked polyvinylpyrrolidone (PVPP), 20.8% polyethylene oxide (PEO), 9.1% carbomer and 1.0% stearin Magnesium acid; the percentage refers to the percentage by weight, and the percentage by weight refers to the percentage of the weight of a single component accounting for the total weight of the brivaracetam pharmaceutical composition;
  • Formulation 2 11.1% brivaracetam, 40.0% KSR (ie KOLLIDON@SR), 20.0% cross-linked polyvinylpyrrolidone (PVPP), 17.9% polyethylene oxide (PEO), 10.0% carbomer and 1.0% stearin Magnesium acid; the percentage refers to the percentage by weight, and the percentage by weight refers to the percentage of the weight of a single component accounting for the total weight of the brivaracetam pharmaceutical composition;
  • Formula 3 11.1% brivaracetam, 30.0% KSR (ie KOLLIDON@SR), 15.0% cross-linked polyvinylpyrrolidone (PVPP), 16.0% polyethylene oxide (PEO), 8.0% carbomer, 18.9% lactose and 1.0% magnesium stearate; the percentage refers to the percentage by weight, and the percentage by weight refers to the percentage of the weight of a single component in the total weight of the brivaracetam pharmaceutical composition;
  • Formula 4 11.1% brivaracetam, 30.0% KSR (ie KOLLIDON@SR), 15.0% cross-linked polyvinylpyrrolidone (PVPP), 16.0% polyethylene oxide (PEO), 8.0% carbomer, 8.9% lactose, 10.0% hydroxypropyl- ⁇ -cyclodextrin and 1.0% magnesium stearate; the percentages refer to weight percentages, and the weight percentages refer to the weight of individual components in the brivaracetam pharmaceutical composition percentage of total weight;
  • Formulation five 9.09% brivaracetam, 29.09% KSR (ie KOLLIDON@SR), 15.46% cross-linked polyvinylpyrrolidone (PVPP), 14.55% polyethylene oxide (PEO), 5.45% sodium carboxymethyl starch, 5.00% Hypromellose, 10.00% pregelatinized starch, 2.0% carbomer, 8.36% microcrystalline cellulose, and 1.0% magnesium stearate; the percentages are by weight, and the percentages by weight are individual The weight of the component accounts for the percentage of the total weight of the brivaracetam pharmaceutical composition;
  • Formula 6 9.09% brivaracetam, 29.09% KSR (ie KOLLIDON@SR), 15.46% cross-linked polyvinylpyrrolidone (PVPP), 10.00% sodium alginate, 4.55% calcium chloride, 6.36% sodium carboxymethyl starch , 7.27% hypromellose, 7.27% pregelatinized starch, 9.91% microcrystalline cellulose and 1.0% magnesium stearate; the percentages refer to weight percentages, and the weight percentages refer to individual components The percentage of weight in the total weight of the brivaracetam pharmaceutical composition;
  • Formula 7 4.55% brivaracetam, 30.0% KSR (ie KOLLIDON@SR), 16.36% cross-linked polyvinylpyrrolidone (PVPP), 15.46% polyethylene oxide (PEO), 6.36% sodium carboxymethyl starch, 5.91% Hypromellose, 11.09% pregelatinized starch, 3.0% carbomer, 6.27% microcrystalline cellulose, and 1.0% magnesium stearate; the percentages are by weight, and the percentages by weight are individual The weight of the component accounts for the percentage of the total weight of the brivaracetam pharmaceutical composition;
  • Formula 8 18.18% brivaracetam, 29.09% KSR (ie KOLLIDON@SR), 14.55% cross-linked polyvinylpyrrolidone (PVPP), 14.55% polyethylene oxide (PEO), 5.45% sodium carboxymethyl starch, 5.45% Hypromellose, 9.73% pregelatinized starch, 2.0% carbomer, and 1.0% magnesium stearate; the percentages refer to weight percentages, and the weight percentages refer to the weight of individual components in the Percentage of the total weight of the brivaracetam pharmaceutical composition.
  • the present invention also provides a brivaracetam sustained-release tablet, comprising the above pharmaceutical composition.
  • the brivaracetam sustained-release tablet is composed of a tablet core and a coating, and the tablet core comprises the above-mentioned pharmaceutical composition.
  • the tablet core is composed of the following components by weight: 2.00%-50.00% brivaracetam, 5.00%-60.00% matrix forming agent, 5.00%-60.00% swelling agent, 0-3.00% Lubricant and 0% to 30.00% of diluent, the said percentage refers to the percentage of the weight of the single component in the total weight of the brivaracetam sustained-release tablet.
  • the tablet core is composed of the following components by weight: 5.00%-50.00% brivaracetam, 5.00%-60.00% matrix forming agent, 5.00%-60.00% swelling agent, 0-3.00% Lubricant and 0%-30.00% diluent, the weight percentage refers to the percentage of the weight of a single component in the total weight of the brivaracetam sustained-release tablet.
  • the tablet core is composed of the following components by weight: 3.00%-20.00% brivaracetam, 30.00%-50.00% matrix forming agent, 20.00%-50.00% swelling agent, 0.50-2.00% Lubricant and 0% to 20.00% of diluent, the percentages refer to the percentage of the weight of individual components in the total weight of the brivaracetam sustained-release tablet.
  • the core of the brivaracetam sustained-release tablet is composed of the following components by weight: 6.00%-15.00% brivaracetam, 30.00%-50.00% matrix-forming agent, 30.00%-50.00% % swelling agent, 0.50-2.00% lubricant and 0-20.00% diluent, the weight percentage refers to the weight percentage of a single component in the total weight of the brivaracetam sustained-release tablet.
  • the core of the brivaracetam sustained-release tablet can be selected from any formula:
  • Formulation 1 9.1% brivaracetam, 40.0% KSR (ie KOLLIDON@SR), 20.0% cross-linked polyvinylpyrrolidone (PVPP), 20.8% polyethylene oxide (PEO), 9.1% carbomer and 1.0% stearin Magnesium acid; the percentage refers to the percentage by weight, and the percentage by weight refers to the percentage of the weight of a single component accounting for the total weight of the tablet core of the brivaracetam sustained-release tablet;
  • Formulation II 11.1% brivaracetam, 40.0% KSR (ie KOLLIDON@SR), 20.0% cross-linked polyvinylpyrrolidone (PVPP), 17.9% polyethylene oxide (PEO), 10.0% carbomer and 1.0% stearin Magnesium acid; the percentage refers to the percentage by weight, and the percentage by weight refers to the percentage of the weight of a single component accounting for the total weight of the tablet core of the brivaracetam sustained-release tablet;
  • Formulation three 11.1% brivaracetam, 30.0% KSR (ie KOLLIDON@SR), 15.0% cross-linked polyvinylpyrrolidone (PVPP), 16.0% polyethylene oxide (PEO), 8.0% carbomer, 18.9% lactose and 1.0% magnesium stearate; the percentage refers to the percentage by weight, and the percentage by weight refers to the percentage of the weight of a single component accounting for the total weight of the core of the brivaracetam sustained-release tablet;
  • Formulation four 11.1% brivaracetam, 30.0% KSR (ie KOLLIDON@SR), 15.0% cross-linked polyvinylpyrrolidone (PVPP), 16.0% polyethylene oxide (PEO), 8.0% carbomer, 8.9% lactose, 10.0% hydroxypropyl- ⁇ -cyclodextrin and 1.0% magnesium stearate; the percentages refer to weight percentages, and the weight percentages refer to the weight of individual components in the brivaracetam sustained-release tablet percentage of the total core weight;
  • Formulation 5 9.09% brivaracetam, 29.09% KSR (ie KOLLIDON@SR), 15.46% cross-linked polyvinylpyrrolidone (PVPP), 14.55% polyethylene oxide (PEO), 5.45% sodium carboxymethyl starch, 5.00% Hypromellose, 10.00% pregelatinized starch, 2.00% carbomer, 8.36% microcrystalline cellulose, and 1.00% magnesium stearate; the percentages are by weight, and the percentages by weight are individual The weight of the component accounts for the percentage of the total weight of the core of the brivaracetam sustained-release tablet;
  • Formulation VI 9.09% brivaracetam, 29.09% KSR (ie KOLLIDON@SR), 15.46% cross-linked polyvinylpyrrolidone (PVPP), 10.00% sodium alginate, 4.55% calcium chloride, 6.36% sodium carboxymethyl starch , 7.27% hypromellose, 7.27% pregelatinized starch, 9.91% microcrystalline cellulose and 1.00% magnesium stearate; the percentages refer to weight percentages, and the weight percentages refer to individual components The percentage of weight in the total weight of the tablet core of the brivaracetam sustained-release tablet;
  • Formula 7 4.55% brivaracetam, 30.0% KSR (ie KOLLIDON@SR), 16.36% cross-linked polyvinylpyrrolidone (PVPP), 15.46% polyethylene oxide (PEO), 6.36% sodium carboxymethyl starch, 5.91% Hypromellose, 11.09% pregelatinized starch, 3.00% carbomer, 6.27% microcrystalline cellulose, and 1.00% magnesium stearate; the percentages are by weight, and the percentages by weight are individual The weight of the component accounts for the percentage of the total weight of the core of the brivaracetam sustained-release tablet;
  • Formula 8 18.18% brivaracetam, 29.09% KSR (ie KOLLIDON@SR), 14.55% cross-linked polyvinylpyrrolidone (PVPP), 14.55% polyethylene oxide (PEO), 5.45% sodium carboxymethyl starch, 5.45% Hypromellose, 9.73% pregelatinized starch, 2.00% carbomer and 1.00% magnesium stearate; the percentages are by weight, and the weight percentages are the percentages of the individual components in the Percentage of the total core weight of brivaracetam extended-release tablets.
  • the present invention also provides the preparation method of the brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet, and the preparation method can be direct compression, dry granulation, wet granulation or melt granulation .
  • the preparation method of described brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet is selected from any one of the following methods:
  • Method 1 directly mixing and tableting the various components of the pharmaceutical composition (such as active pharmaceutical ingredients, matrix-forming agents and swelling agents) to obtain tablets, namely the brivaracetam sustained-release tablet;
  • Method 2 Part of the components (including active pharmaceutical ingredients, matrix-forming agents and swelling agents, diluents, lubricants) are granulated by a fluidized bed or dry method to granulate the API and each component, and then It is mixed with the remaining components (including matrix forming agents, swelling agents, diluents and lubricants, etc.), and compressed to obtain tablets, namely the brivaracetam sustained-release tablet.
  • the tablet may be further coated to obtain a coated tablet, that is, the brivaracetam sustained-release tablet.
  • the present invention also provides the application of the brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet in preparing medicine. Further, the medicament is used for the treatment and/or prevention of the following diseases: epilepsy, Parkinson's, dyskinesia, migraine, tremor, essential tremor, bipolar disorder, chronic disease, neuropathic pain or bronchial, asthma or Allergies and other diseases.
  • the present invention also provides a method for treating a condition of a patient responsive to brivaracetam, the method comprising: orally administering the above-mentioned brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet to the patient once a day.
  • the brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet When the brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet is ingested as a whole and enters the stomach of a patient, it can float rapidly in gastric juice and slowly expand or swell. The formulation expands to a size that prevents it from exiting the stomach via the pylorus.
  • the diameter of the pylorus of an adult is about 12 mm, so the size of the expanded preparation is higher than 13 mm, for example, 13 mm to 20 mm.
  • the brivaracetam sustained-release tablet can have any shape, such as round, oval, irregular, polygonal and the like.
  • the "pharmaceutically acceptable” refers to the salts, complexes, solvates, and hydrates of drugs (such as brivaracetam), which are suitable for contact with the patient's tissue within the scope of normal medical judgment. Without inappropriate toxicity, irritation, allergic reaction, etc., it has a reasonable ratio of advantages and disadvantages, and can be effectively used for its intended purpose.
  • solvate refers to a molecular complex comprising a drug (eg, brivaracetam) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg, ethanol).
  • a drug eg, brivaracetam
  • solvent molecules eg, ethanol
  • the "hydrate” refers to a solvate containing a drug (eg, brivaracetam) and stoichiometric or non-stoichiometric water.
  • the polyvinylpyrrolidone is also called povidone or povidonum, which is a homopolymer of 1-vinyl-pyrrolidin-2-one, and the molecular weight Mw is usually about 1 ⁇ 10 3 to About 1 ⁇ 10 7 , about 2.5 ⁇ 10 3 to about 3 ⁇ 10 6 , or about 1 ⁇ 10 4 to about 1 ⁇ 10 5 .
  • Polyvinylpyrrolidone can be produced by BASF, its trade name is KOLLIDON, or it can be produced by ISP, its trade name is
  • the polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, and the molecular weight M w is usually about 1 ⁇ 10 5 to about 1 ⁇ 10 6 .
  • KSR can be produced by BSAF, and its trade name is Nominal 80/19 (w/w) mixture of PVAc and PVP.
  • polyethylene oxide is also referred to as polyethylene oxide (polyoxirane) and polyoxyethylene (polyoxyethylene).
  • Polyoxyethylene is a homopolymer of ethylene oxide, and its molecular weight is Mw is typically from about 1 ⁇ 10 5 to about 1 ⁇ 10 7 or from about 1 ⁇ 10 6 to about 1 ⁇ 10 7 .
  • Polyethylene oxide is available in various grades depending on molecular weight and is available from UnionCarbide under the tradename
  • the invention significantly improves the defects of the prior art, such as too fast release rate of the brivaracetam preparation, many times of administration, difficult control of the drug dosage, large toxic and side effects, limited therapeutic effect and the like.
  • the brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet provided by the present invention has sustained-release effect, and compared with the existing gel matrix sustained-release preparation, the release curve is smoother, the drug release rate is effectively reduced, and the control
  • the effective dose of the drug in the body can achieve the effects of more stable blood drug concentration, reduced toxic and side effects, fewer daily administration times, and improved medication compliance.
  • the brivaracetam pharmaceutical composition or brivaracetam sustained-release tablet provided by the present invention also has excellent stability.
  • Fig. 1 is the dissolution curve diagram of tablet A, B, C, D, E, F, G, H prepared by the present invention and the sustained-release tablet prepared by patent CN102046153B;
  • Figure 2 is the drug-time curve diagram of the test article and the original research reference group in the PK study in Beagle dogs.
  • Brivaracetam purchased from Ruyuan Dongguang Pharmaceutical Co., Ltd., purity: 98% to 102%.
  • Polyethylene oxide manufactured by DUPONT under the trade name of POLYOX TM .
  • KSR produced by BSAF, its trade name is Nominal 80/19 (w/w) mixture of PVAc and PVP.
  • Oval-shaped tablets A, B, C, D, E, F, G and H with the following core compositions were prepared by direct compression.
  • Example 1 Compared with the dissolution results (Table 3) of ordinary tablets (common tablets are commercially available brivaracetam tablets, the trade name is BRIVIACT, the manufacturer is UCB, Inc., and the prescription is shown in Table A)), Example 1 was prepared The tablet sample has a significant sustained release effect.
  • the brivaracetam pharmaceutical composition/tablet of the present invention achieves dissolution of more than 83% in about 24 hours, and the sustained-release effect is obviously better than that of ordinary tablets and brivaracetam disclosed in patent CN102046153B. slow-release tablets.
  • This experiment selected 3 Beagle dogs, 2 males and 1 female.
  • the administration dose (calculated as active ingredient) of the test product group (tablet E in Example 1) and the original research control group (that is, ordinary tablets) were both 100 mg/piece/day, and the test product group was given a single dose , the original research control group was administered 1 tablet every 8 hours, a total of 2 times.
  • 3 Beagle dogs were given the test article orally first, which was the test article group.
  • the test article group was given before the drug (one day before the administration), and 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h after the end of the administration.
  • the samples were placed under high temperature and high humidity conditions (60°C/saturated potassium nitrate solution, humidity 75% RH) for 30 days, and samples were taken on the 10th and 30th days to detect related substances and dissolution curves, and investigate the stability.
  • the results are as follows:

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Abstract

提供了一种布瓦西坦药物组合物、其制备方法及应用。所述药物组合物包括药物活性成分、基质形成剂和溶胀剂。所述布瓦西坦药物组合物具有缓释作用，与普通凝胶骨架缓释制剂相比释放曲线更平缓，达到了降低药物释放速率、控制药物在体内的有效剂量、血药浓度更加平稳、降低毒副作用、降低每日给药次数的目的。

Description

一种布瓦西坦药物组合物、其制备方法及应用
本申请要求申请人于2020年7月9日向中国国家知识产权局提交的专利申请号为202010655757.X，发明名称为“一种布瓦西坦药物组合物、其制备方法及应用”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物组合物领域，涉及一种布瓦西坦药物组合物、其制备方法及应用。
背景技术
布瓦西坦为一种抗癫痫药物，临床上作为4岁及以上部分发作型的癫痫患者的单药治疗。
布瓦西坦(brivaracetam，也称布立西坦)的化学名称为(2S)-2-[(4R)-2-氧代-4-丙基四氢-1H-吡咯-1-基]丁酰胺((2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide)，分子式为C 11H 20N 2O 2，其结构式为：
Figure PCTCN2021104586-appb-000001
布瓦西坦为白色或类白色结晶粉末，为BCS I类药物，易溶于水(0.7g/mL)、pH 1.2盐酸溶液(0.85g/mL)、pH 4.5缓冲液(0.85g/mL)和pH 7.4缓冲液(0.84g/mL)，终末半衰期较短(9h)，因此，该药物在体内有效血药浓度维持时间较短。现有市售制剂为布瓦西坦片、布瓦西坦口服液和布瓦西坦注射液，布瓦西坦片规格较多，分为10mg、25mg、50mg、75mg和100mg，布瓦西坦口服液和布瓦西坦注射液规格均为10mg/mL。
市售布瓦西坦片的给药方法为：推荐起始剂量50mg，每天2次，根据个体患者耐受性和治疗反应，剂量可能调整为25mg每天2次或者100mg每天2次。即该市售片由于释放较快，在临床使用中无法有效控制体内剂量。此外，该给药方法需根据服药后患者的病情进展调整剂量，不利于患者自行服药。
现有技术制备的布瓦西坦片大多数为速释片，UCB公司的专利(授权公告号：CN102046153B)公开了一种包含布立西坦(Brivaracetam)的新的药物组合物，能够控制药物的释放速率，给药时提供至少16h的治疗效果。但该方法制备的药物组合物释放速率偏快，且未见该工艺的产品上市。
因此，亟需开发一种缓释片，以达到降低药物释放速率、控制药物在体内的有效剂量、降低每日给药次数的目的。每日给药一次可提高患者顺从性，且可通过减少药物在血液中的最高含量，延长药物在体内的时间，控制药物在体内的有效剂量，降低药物毒副作用，达到有效的治疗效果。
发明内容
为改善上述技术问题，本发明提供了一种布瓦西坦药物组合物，其为24小时缓慢释放药物，其溶出同时满足以下三个特征：
A)在1小时内溶出不超过40％的药物活性成分；
B)在6小时内溶出20％～70％的药物活性成分；
C)在24小时内溶出不低于65％的药物活性成分；
所述药物活性成分可以选自布瓦西坦、布瓦西坦的药学上可接受的配合物、布瓦西坦的药学上可接受的盐、布瓦西坦的药学上可接受的溶剂化物和布瓦西坦的药学上可接受的水合物中的一种、两种或更多种。
优选地，所述布瓦西坦药物组合物的溶出同时满足以下三个特征：
A)在1小时内溶出不超过40％的所述布瓦西坦或其药学上可接受的盐；
B)在6小时内溶出20％～70％的所述布瓦西坦或其药学上可接受的盐；
C)在24小时内溶出不低于65％的所述布瓦西坦或其药学上可接受的盐。
优选地，所述布瓦西坦药物组合物，其为24小时缓慢释放药物，其溶出同时满足以下三个特征：
A)在1小时内溶出不超过35％的所述药物活性成分；优选地，在1小时内溶出不超过35％的所述布瓦西坦或其药学上可接受的盐；
B)在6小时内溶出30％～70％的所述药物活性成分；优选地，在6小时内溶出30％～70％的所述布瓦西坦或其药学上可接受的盐；
C)在24小时内溶出不低于75％的所述药物活性成分；优选地，在24小时内溶出不低于75％的所述布瓦西坦或其药学上可接受的盐。
还优选地，所述的布瓦西坦药物组合物的溶出同时满足以下三个特征：
A)在1小时内溶出不超过30％的所述药物活性成分；优选地，在1小时内溶出不超过30％的所述布瓦西坦或其药学上可接受的盐；
B)在6小时内溶出30％～65％的所述药物活性成分；优选地，在6小时内溶出30％～65％的所述布瓦西坦或其药学上可接受的盐；
C)在24小时内溶出不低于75％的所述药物活性成分；优选地，在24小时内溶出不低于75％的所述布瓦西坦或其药学上可接受的盐。
更优选地，所述的布瓦西坦药物组合物的溶出同时满足以下三个特征：
A)在1小时内溶出不超过30％的所述药物活性成分；优选地，在1小时内溶出不超过30％的所述布瓦西坦或其药学上可接受的盐；
B)在6小时内溶出30％～65％的所述药物活性成分；优选地，在6小时内溶出30％～65％的所述布瓦西坦或其药学上可接受的盐；
C)在24小时内溶出不低于80％的所述药物活性成分；优选地，在24小时内溶出不低于80％的所述布瓦西坦或其药学上可接受的盐。
其中，所述“溶出”指药物活性成分(如布瓦西坦或其药学上可接受的盐)的累积溶出度；进一步地，所述累积溶出度在pH 4.5醋酸缓冲液中测得。本领域技术人员能够理解，随着时间增加，所述布瓦西坦或其药学上可接受的盐的溶出度逐渐增加。
本发明提供了一种布瓦西坦药物组合物，其包括药物活性成分、基质形成剂和溶胀剂；
所述的药物活性成分选自下述物质中的一种、两种或更多种：布瓦西坦、布瓦西坦的药学上可接受的配合物、布瓦西坦的药学上可接受的盐、布瓦西坦的药学上可接受的溶剂化物和布瓦西坦的药学上可接受的水合物；
所述的基质形成剂是指可提供结构完整性并有助于控制或延长药物释放速率的物质；例如，选自包括下述物质中的一种、两种或更多种：聚醋酸乙烯酯(PVAc)、聚乙烯吡咯烷酮(PVP)、卡波姆、多糖、聚丙烯酸树脂、聚醋酸乙烯酯聚维酮混合物(
Figure PCTCN2021104586-appb-000002
以下简称KSR)和聚乙烯醇；
所述的溶胀剂是指可从胃液吸水导致固体制剂的尺寸膨胀，而且可以通过产生通道或通过形成亲水胶体而影响药物释放速率的物质；例如选自包括下述物质中的一种、两种或更多种：交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲基纤维素钙、羧甲纤维素、海藻酸盐、钙盐和波拉克林钾。
进一步地，所述的海藻酸盐可以为海藻酸与金属离子(例如钠离子、钾离子)形成的盐，例如海藻酸钠和/或海藻酸钾；
进一步地，所述的钙盐可以为无机酸与钙离子形成的盐，或有机酸与钙离子形成的盐；例如选自氯化钙、磷酸氢钙和二水磷酸氢钙中的一种、两种或三种。
根据本发明的实施方案，所述的药物活性成分优选为布瓦西坦。例如，所述的药物活性成分的重量百分比为2.00％～50.00％，进一步优选为3.00％～20.00％，例如为9.10％、11.10％、9.09％、4.55％或18.18％；所述的重量百分比是指药物活性成分的重量占布瓦西坦药物组合物总重量的百分比。
根据本发明的实施方案，所述的基质形成剂的重量百分比为5.00％～60.00％，进一步优选为30.00％～50.00％，例如为49.10％、50.00％、38.00％、36.09％、36.36％、38.91％或36.54％；所述的重量百分比是指基质形成剂的重量占布瓦西坦药物组合物总重量的百分比。其中，所述的KSR可以为BASF产，商品名为KOLLIDON @SR，含有PVAc和PVP的80/19(w/w)混合物。
例如，所述的多醣选自包括下述多糖中的一种、两种或更多种：黄原胶、菊粉、瓜耳树胶、壳聚糖、角豆胶、角叉菜胶和纤维素衍生物。
例如，所述的纤维素衍生物选自包括下述物质中的一种、两种或更多种：离子性纤维素聚合物和非离子性纤维素聚合物。
优选地，所述的离子性纤维素聚合物选自包括羧甲基纤维素(CMC)、羧甲基纤维素钠盐、羧甲基纤维素钙盐、羧乙基纤维素(CEC)、羧甲基乙基纤维素(CMEC)、醋酸羟乙基甲基纤维素邻苯二甲酸酯、醋酸羟乙基甲基纤维素琥珀酸酯、羟丙基纤维素醋酸邻苯二甲酸酯(HPCAP)、乙酸羟丙基纤维素琥珀酸酯(HPCAS)和乙酸羟丙基甲基纤维素邻苯二甲酸酯(HPMCAP)中的一种、两种 或更多种。
优选地，所述的非离子性纤维素聚合物选自包括甲基纤维素(MC)、乙基纤维素(EC)、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙甲纤维素(HPMC)、羟丙基甲基纤维素醋酸酯、羟乙基甲基纤维素、羟乙基纤维素醋酸酯和羟乙基乙基纤维素中的一种、两种或更多种。
根据本发明的实施方案，所述的溶胀剂可溶于水或不溶于水。优选地，所述的溶胀剂可以选自交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲基纤维素钙、羧甲纤维素和波拉克林钾中的一种、两种或更多种。
进一步地，所述的溶胀剂的重量百分比为5.00％～60.00％，进一步优选为20.00％～50.00％，例如为40.80％、37.90％、31.00％、35.46％、36.36％、38.17％或34.55％；所述的重量百分比是指溶胀剂的重量占布瓦西坦药物组合物总重量的百分比。
根据本发明的实施方案，所述的布瓦西坦药物组合物还可以包括润滑剂和/或稀释剂。
根据本发明的实施方案，所述的润滑剂是指有助于组分混合和压片等加工步骤的物质，可以选自滑石、硬脂酸、硬脂酸金属盐、硬脂酸酯、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、矿物油、泊洛沙姆(poloxamer)(环氧乙烷和环氧丙烷的共聚物)、聚乙二醇和氯化钠中的一种、两种或更多种。进一步地，所述的硬脂酸金属盐选自包括硬脂酸钙、硬脂酸镁和硬脂酸锌中的一种、两种或三种，优选硬脂酸镁。进一步地，所述的硬脂酸酯选自包括聚氧乙烯硬脂酸酯、单硬脂酸甘油酯和棕榈硬脂酸甘油酯等的一种、两种或更多种。
根据本发明的实施方案，所述的稀释剂是指在组分混合和压片期间，可改善药物组合物的流动性、增强压缩强度或硬度、减弱易碎性等的物质。例如，所述的稀释剂选自包括右旋糖、乳糖一水合物、无水乳糖、蔗糖、甘露醇、木糖醇、山梨糖醇、微晶纤维素、淀粉、预胶化淀粉、二水磷酸氢钙、无水磷酸氢钙、环糊精及环糊精衍生物中的一种、两种或更多种。进一步地，所述的环糊精选自包括α-环糊精、β-环糊精和γ-环糊精中的一种、两种或更多种；所述的环糊精衍生物选自包括环糊精葡萄糖衍生物、环糊精羟丙基衍生物、环糊精甲基衍生物、环糊精乙基衍生物、环糊精乙酰基衍生物、环糊精磺丁基衍生物和离子性环糊精衍生物等中的一种、两种或更多种。
根据本发明的实施方案，所述的润滑剂的重量百分比可以为0～3.00％，进一步优选为0.50％～2.00％，例如为1.00％，所述的重量百分比是指润滑剂的重量占布瓦西坦药物组合物总重量的百分比。
根据本发明的实施方案，所述的稀释剂的重量百分比可以为0～30.00％，进一步优选为0～20.00％，例如18.90％、18.36％、17.18％、17.36％或9.73％，所述的重量百分比是指稀释剂的重量占布瓦西坦药物组合物总重量的百分比。
优选地，所述布瓦西坦药物组合物具有如前文所示的溶出特征。
本发明提供的布瓦西坦药物组合物，性质稳定，适用于每日口服一次。当以固体剂型施予时，该药物组合物在胃内滞留时间长于速释制剂。该药物组合物滞留在胃内时，可持续释放布瓦西坦。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物由药物活性成分、基质形成剂和溶胀剂 组成；
所述的药物活性成分选自布瓦西坦、布瓦西坦的药学上可接受的配合物、布瓦西坦的药学上可接受的盐、布瓦西坦的药学上可接受的溶剂化物和布瓦西坦药的药学上可接受的水合物中的一种、两种或更多种；
所述的基质形成剂选自聚醋酸乙烯酯(PVAc)、聚乙烯基吡咯烷酮(PVP)、KSR、卡波姆和多糖中的一种、两种或更多种；
所述的溶胀剂选自交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、海藻酸盐和钙盐中的一种、两种或更多种。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物可以由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、卡波姆和硬脂酸镁。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物可以由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、卡波姆、乳糖和硬脂酸镁。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物可以由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、卡波姆、微晶纤维素和硬脂酸镁。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物可以由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮(PVPP)、海藻酸钠、氯化钙、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、微晶纤维素和硬脂酸镁。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮(PVPP)、羧甲基淀粉钠、羟丙甲基纤维素、预胶化淀粉、卡波姆、微晶纤维素和硬脂酸镁。
根据本发明优选的实施方案，所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮(PVPP)、聚氧化乙烯(PEO)、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、卡波姆和硬脂酸镁。
根据本发明示例性的实施方案，以百分比计，所述的布瓦西坦药物组合物选自以下任一配方：
配方一：9.1％布瓦西坦、40.0％KSR(即KOLLIDON@SR)、20.0％交联聚乙烯吡咯烷酮(PVPP)、20.8％聚氧化乙烯(PEO)、9.1％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方二：11.1％布瓦西坦、40.0％KSR(即KOLLIDON@SR)、20.0％交联聚乙烯吡咯烷酮(PVPP)、17.9％聚氧化乙烯(PEO)、10.0％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方三：11.1％布瓦西坦、30.0％KSR(即KOLLIDON@SR)、15.0％交联聚乙烯吡咯烷酮(PVPP)、16.0％聚氧化乙烯(PEO)、8.0％卡波姆、18.9％乳糖和1.0％硬脂酸镁；所述的百分比是指重量百分比， 所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方四：11.1％布瓦西坦、30.0％KSR(即KOLLIDON@SR)、15.0％交联聚乙烯吡咯烷酮(PVPP)、16.0％聚氧化乙烯(PEO)、8.0％卡波姆、8.9％乳糖、10.0％羟丙基-β-环糊精和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方五：9.09％布瓦西坦、29.09％KSR(即KOLLIDON@SR)、15.46％交联聚乙烯吡咯烷酮(PVPP)、14.55％聚氧化乙烯(PEO)、5.45％羧甲基淀粉钠、5.00％羟丙甲纤维素、10.00％预胶化淀粉、2.0％卡波姆、8.36％微晶纤维素和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方六：9.09％布瓦西坦、29.09％KSR(即KOLLIDON@SR)、15.46％交联聚乙烯吡咯烷酮(PVPP)、10.00％海藻酸钠、4.55％氯化钙、6.36％羧甲基淀粉钠、7.27％羟丙甲纤维素、7.27％预胶化淀粉、9.91％微晶纤维素和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方七：4.55％布瓦西坦、30.0％KSR(即KOLLIDON@SR)、16.36％交联聚乙烯吡咯烷酮(PVPP)、15.46％聚氧化乙烯(PEO)、6.36％羧甲基淀粉钠、5.91％羟丙甲纤维素、11.09％预胶化淀粉、3.0％卡波姆、6.27％微晶纤维素和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
配方八：18.18％布瓦西坦、29.09％KSR(即KOLLIDON@SR)、14.55％交联聚乙烯吡咯烷酮(PVPP)、14.55％聚氧化乙烯(PEO)、5.45％羧甲基淀粉钠、5.45％羟丙甲纤维素、9.73％预胶化淀粉、2.0％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比。
本发明还提供了一种布瓦西坦缓释片，包含上述药物组合物。
优选地，所述布瓦西坦缓释片由片芯和包衣组成，所述片芯包含上述药物组合物。
优选地，所述的片芯由以下重量百分含量的组分组成：2.00％～50.00％布瓦西坦、5.00％～60.00％基质形成剂、5.00％～60.00％溶胀剂、0～3.00％润滑剂和0％～30.00％稀释剂，所述的百分比是指单个组分的重量占布瓦西坦缓释片总重量的百分比。
优选地，所述的片芯由以下重量百分含量的组分组成：5.00％～50.00％布瓦西坦、5.00％～60.00％基质形成剂、5.00％～60.00％溶胀剂、0～3.00％润滑剂和0％～30.00％稀释剂，所述的重量百分含量是指单个组分的重量占所述布瓦西坦缓释片总重量的百分比。
优选地，所述的片芯由以下重量百分含量的组分组成：3.00％～20.00％布瓦西坦、30.00％～50.00％基质形成剂、20.00％～50.00％溶胀剂、0.50～2.00％润滑剂和0％～20.00％稀释剂，所述的百分比是指单个组分的重量占所述布瓦西坦缓释片总重量的百分比。
优选地，所述的布瓦西坦缓释片的片芯由以下重量百分含量的组分组成：6.00％～15.00％布瓦西 坦、30.00％～50.00％基质形成剂、30.00％～50.00％溶胀剂、0.50～2.00％润滑剂和0～20.00％稀释剂，所述的重量百分含量是指单个组分的重量占所述布瓦西坦缓释片总重量的百分比。
根据本发明示例性的实施方案，以百分比计，所述的布瓦西坦缓释片的片芯可以选自任一处方：
处方一：9.1％布瓦西坦、40.0％KSR(即KOLLIDON@SR)、20.0％交联聚乙烯吡咯烷酮(PVPP)、20.8％聚氧化乙烯(PEO)、9.1％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方二：11.1％布瓦西坦、40.0％KSR(即KOLLIDON@SR)、20.0％交联聚乙烯吡咯烷酮(PVPP)、17.9％聚氧化乙烯(PEO)、10.0％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方三：11.1％布瓦西坦、30.0％KSR(即KOLLIDON@SR)、15.0％交联聚乙烯吡咯烷酮(PVPP)、16.0％聚氧化乙烯(PEO)、8.0％卡波姆、18.9％乳糖和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方四：11.1％布瓦西坦、30.0％KSR(即KOLLIDON@SR)、15.0％交联聚乙烯吡咯烷酮(PVPP)、16.0％聚氧化乙烯(PEO)、8.0％卡波姆、8.9％乳糖、10.0％羟丙基-β-环糊精和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方五：9.09％布瓦西坦、29.09％KSR(即KOLLIDON@SR)、15.46％交联聚乙烯吡咯烷酮(PVPP)、14.55％聚氧化乙烯(PEO)、5.45％羧甲基淀粉钠、5.00％羟丙甲纤维素、10.00％预胶化淀粉、2.00％卡波姆、8.36％微晶纤维素和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方六：9.09％布瓦西坦、29.09％KSR(即KOLLIDON@SR)、15.46％交联聚乙烯吡咯烷酮(PVPP)、10.00％海藻酸钠、4.55％氯化钙、6.36％羧甲基淀粉钠、7.27％羟丙甲纤维素、7.27％预胶化淀粉、9.91％微晶纤维素和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方七：4.55％布瓦西坦、30.0％KSR(即KOLLIDON@SR)、16.36％交联聚乙烯吡咯烷酮(PVPP)、15.46％聚氧化乙烯(PEO)、6.36％羧甲基淀粉钠、5.91％羟丙甲纤维素、11.09％预胶化淀粉、3.00％卡波姆、6.27％微晶纤维素和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
处方八：18.18％布瓦西坦、29.09％KSR(即KOLLIDON@SR)、14.55％交联聚乙烯吡咯烷酮(PVPP)、14.55％聚氧化乙烯(PEO)、5.45％羧甲基淀粉钠、5.45％羟丙甲纤维素、9.73％预胶化淀粉、2.00％卡波姆和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比。
本发明也提供了所述的布瓦西坦药物组合物或布瓦西坦缓释片的制备方法，所述制备方法可以为 直接压片法、干法制粒、湿法制粒或者熔融制粒法。
例如，所述的布瓦西坦药物组合物或布瓦西坦缓释片的制备方法选自以下任意一种方法：
方法一：将所述的药物组合物的各组分(例如药物活性成分、基质形成剂和溶胀剂)直接混合、压片，得到片剂，即所述布瓦西坦缓释片；
方法二：将部分各组分(包括药物活性成分、基质形成剂和溶胀剂、稀释剂、润滑剂)通过流化床或者干法造粒，使原料药(API)与各组分成粒，然后与剩余组分(包括基质形成剂、溶胀剂、稀释剂和润滑剂等)混合，压片，得到片剂，即所述布瓦西坦缓释片。
根据本发明的实施方案，所述的片剂可以进一步进行包衣处理，得到包衣片剂，即所述布瓦西坦缓释片。
本发明还提供了所述的布瓦西坦药物组合物或者布瓦西坦缓释片在制备药物中的应用。进一步地，所述药物用于治疗和/或预防下述疾病：癫痫症、帕金森、运动障碍、偏头痛、颤动、特发性震颤、双向情感障碍、慢性病、神经性疼痛或支气管、哮喘或过敏性等疾病。
本发明还提供一种治疗对布瓦西坦具有反应性的患者的病症的方法，所述方法包括，使患者每日口服一次上述布瓦西坦药物组合物或者布瓦西坦缓释片。
当所述的布瓦西坦药物组合物或者布瓦西坦缓释片被整体摄取，进入患者胃内时，可在胃液中迅速漂浮并慢慢膨胀或溶胀。制剂膨胀至一定尺寸，可防止其经由幽门离开胃。成人的幽门直径为约12mm，故膨胀后的制剂尺寸高于13mm，例如为13mm～20mm。所述的布瓦西坦缓释片可具有任何性状，例如圆形、椭圆形、不规则形状、多边形等。
本发明中，所述的“药学上可接受的”是指药物(例如布瓦西坦)的盐、配合物、溶剂化物、水合物，在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。
所述的“溶剂化物”是指含药物(例如布瓦西坦)和化学计量或非化学计量的一种或多种药学上可接受溶剂分子(例如乙醇)的分子络合物。当溶剂与药物紧密结合时，所形成络合物具有明确的化学计量，而不依赖于湿度。然而，当该溶剂具弱结合性(如在通道溶剂化物和吸湿性化合物中)时，溶剂含量依赖于湿度和干燥条件；在该情况下，络合物通常具非化学计量性。
所述的“水合物”表示含药物(例如布瓦西坦)和化学计量或非化学计量的水的溶剂化物。
本发明中，所述的聚乙烯吡咯烷酮(PVP)也被称为povidone或povidonum，其为1-乙烯基-吡咯烷-2-酮的均聚物，分子量M w通常为约1×10 3至约1×10 7、约2.5×10 3至约3×10 6或约1×10 4至约1×10 5。聚乙烯基吡咯烷酮可以为BASF产的，其商品名为KOLLIDON，也可以为ISP产的，其商品名为
Figure PCTCN2021104586-appb-000003
本发明中，所述的聚醋酸乙烯酯(PVAc)为乙酸乙烯酯的均聚物，分子量M w通常为约1×10 5至约1×10 6。
KSR可以为BSAF产，其商品名为
Figure PCTCN2021104586-appb-000004
标称为PVAc和PVP的80/19(w/w)混合物。
本发明中，所述的聚氧化乙烯((PEO)，也被称为聚环氧乙烷(polyoxirane)和聚氧乙烯(polyoxyethylene)。聚氧化乙烯为环氧乙烷的均聚物，其分子量M w通常为约1×10 5至约1×10 7或约1×10 6至约1×10 7。聚氧化乙烯根据分子量具有各种等级，可以为UnionCarbide产，其商品名为
Figure PCTCN2021104586-appb-000005
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明的有益效果
本发明显著改善了现有技术中布瓦西坦制剂释放速率过快、给药次数多、药物剂量不容易控制、毒副作用大、治疗效果有限等缺陷。本发明提供的布瓦西坦药物组合物或者布瓦西坦缓释片，具有缓释作用，与现有的凝胶骨架缓释制剂相比释放曲线更平缓，有效降低了药物释放速率，控制药物在体内的有效剂量，从而实现了血药浓度更加平稳、毒副作用降低、每日给药次数降低，以及改善用药依从性的效果。并且，本发明提供的布瓦西坦药物组合物或者布瓦西坦缓释片还具有优异的稳定性。
附图说明
图1为本发明制得的片剂A、B、C、D、E、F、G、H与专利CN102046153B制备的缓释片的溶出曲线图；
图2为Beagle犬体内的PK研究时供试品和原研对照品组的药时曲线图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1中原辅料的来源：
布瓦西坦：采购于乳源东阳光药业有限公司，纯度：98％～102％。
交联聚乙烯吡咯烷酮：重庆斯泰克瑞登梅尔材料技术有限公司，其商品名为
Figure PCTCN2021104586-appb-000006
聚氧化乙烯：DUPONT产，其商品名为POLYOX TM。
KSR：BSAF产，其商品名为
Figure PCTCN2021104586-appb-000007
标称为PVAc和PVP的80/19(w/w)混合物。
实施例1
采用直接压片法制备具有如下片芯组成(表1-1和表1-2)的椭圆形片剂A、B、C、D、E、F、G和H。
表1-1片剂的片芯组成
Figure PCTCN2021104586-appb-000008
Figure PCTCN2021104586-appb-000009
表1-2片剂的片芯组成
Figure PCTCN2021104586-appb-000010
(一)溶出度测试
溶出结果(表2)表明，片剂A-H的体外溶出(pH 4.5醋酸缓冲液，根据中国药典(2020版)0931第二法，50rpm，37±0.5℃，900mL)符合要求。与专利CN102046153B中释放最缓慢的实施例(表2)对比，本发明实施例1制备的片剂样品溶出较慢(溶出曲线图见图1)。与普通片剂(普通片剂为市售的布瓦西坦片，商品名BRIVIACT，厂家为UCB,Inc.，处方如表A所示))的溶出结果(表3)对比，实施例1制备的片剂样品具有显著的缓释效果。
表A普通片剂的处方
Figure PCTCN2021104586-appb-000011
表2不同片剂的溶出结果
Figure PCTCN2021104586-appb-000012
备注：*为CN102046153B中公开的实施例中布瓦西坦缓释片溶出最慢的结果。
表3普通片剂溶出结果(pH 4.5醋酸缓冲液)
片剂 时间(min) 5 10 15 20 30
普通片剂 累积溶出度(％) 74.8 100.3 101.8 101.9 101.9
备注：累积溶出度数值超过100％为检测误差所致。
由上述溶出度数据可以看出，本发明的布瓦西坦药物组合物/片剂在24小时左右达到溶出83％以 上，缓释效果明显优于普通片剂和专利CN102046153B中公开的布瓦西坦缓释片剂。
(二)Beagle犬体内的PK研究
本试验选用Beagle犬3只，雄性2只，雌性1只。供试品组(实施例1中的片剂E)及原研对照组(即普通片剂)的给药剂量(以活性成分计)均为100mg/只/天，供试品组单次给药，原研对照组每8h给药1片，共给药2次。3只Beagle犬先口服供试品，为供试品组，供试品组于药前(给药前一天)，给药结束后0.5h、1h、2h、3h、4h、6h、8h、12h、16h、24h、30h、36h、48h的时间点采集血样；7天后(供试品已完全洗脱)该3只Beagle犬口服原研对照，为原研对照组，原研对照组于药前(给药前一天)，第一次给药结束后0.25h、0.5h、0.75h、1h、1.25h、1.5h、2h、3h、5h、8h(采集后第二次给药)、8.25h、8.5h、8.75h、9h、9.25h、9.5h、10h、11h、13h、16h、24h的时间点采集血样。
结果如表4所示。
表4
Figure PCTCN2021104586-appb-000013
结果表明，供试品组半衰期延长，达峰时间延长，最大血药浓度低于原研对照组(即市售品)，AUC值与原研对照组接近(药-时曲线见图2)。
(三)稳定性测试
将样品置于高温高湿条件(60℃/饱和硝酸钾溶液，湿度75％RH)下放置30天，于第10、30天取样，检测有关物质和溶出曲线，考察稳定性，结果如下：
表5
Figure PCTCN2021104586-appb-000014
表6
Figure PCTCN2021104586-appb-000015
结果表明，本发明制得的布瓦西坦缓释片稳定性良好。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种布瓦西坦药物组合物，其特征在于：其为24小时缓慢释放药物，其溶出同时满足以下三个特征：
    A)在1小时内溶出不超过40％的药物活性成分；
    B)在6小时内溶出20％～70％的药物活性成分；
    C)在24小时内溶出不低于65％的药物活性成分；
    所述药物活性成分选自布瓦西坦、布瓦西坦的药学上可接受的配合物、布瓦西坦的药学上可接受的盐、布瓦西坦的药学上可接受的溶剂化物和布瓦西坦的药学上可接受的水合物中的一种、两种或更多种；
    优选地，所述布瓦西坦药物组合物的溶出同时满足以下三个特征：
    A)在1小时内溶出不超过40％的所述布瓦西坦或其药学上可接受的盐；
    B)在6小时内溶出20％～70％的所述布瓦西坦或其药学上可接受的盐；
    C)在24小时内溶出不低于65％的所述布瓦西坦或其药学上可接受的盐。
  2. 如权利要求1所述的布瓦西坦药物组合物，其特征在于：其为24小时缓慢释放药物，其溶出同时满足以下三个特征：
    A)在1小时内溶出不超过35％的所述药物活性成分；优选地，在1小时内溶出不超过35％的所述布瓦西坦或其药学上可接受的盐；
    B)在6小时内溶出30％～70％的所述药物活性成分；优选地，在6小时内溶出30％～70％的所述布瓦西坦或其药学上可接受的盐；
    C)在24小时内溶出不低于75％的所述药物活性成分；优选地，在24小时内溶出不低于75％的所述布瓦西坦或其药学上可接受的盐；
    优选地，所述的布瓦西坦药物组合物为24小时缓慢释放药物，其溶出同时满足以下三个特征：
    A)在1小时内溶出不超过30％的所述药物活性成分；优选地，在1小时内溶出不超过30％的所述布瓦西坦或其药学上可接受的盐；
    B)在6小时内溶出30％～65％的所述药物活性成分；优选地，在6小时内溶出30％～65％的所述布瓦西坦或其药学上可接受的盐；
    C)在24小时内溶出不低于75％的所述药物活性成分；优选地，在24小时内溶出不低于75％的所述布瓦西坦或其药学上可接受的盐；
    还优选地，所述的布瓦西坦药物组合物为24小时缓慢释放药物，其溶出同时满足以下三个特征：
    A)在1小时内溶出不超过30％的所述药物活性成分；优选地，在1小时内溶出不超过30％的所述布瓦西坦或其药学上可接受的盐；
    B)在6小时内溶出30％～65％的所述药物活性成分；优选地，在6小时内溶出30％～65％的所述布瓦西坦或其药学上可接受的盐；
    C)在24小时内溶出不低于80％的所述药物活性成分；优选地，在24小时内溶出不低于80％的所述布瓦西坦或其药学上可接受的盐。
  3. 一种布瓦西坦药物组合物，其特征在于，所述药物组合物包括：药物活性成分、基质形成剂和溶胀剂；
    所述的药物活性成分选自下述物质中的一种、两种或更多种：布瓦西坦、布瓦西坦的药学上可接受的配合物、布瓦西坦的药学上可接受盐、布瓦西坦的药学上可接受溶剂化物和布瓦西坦的药学上可接受水合物；
    所述的基质形成剂选自包括下述物质中的一种、两种或更多种：聚醋酸乙烯酯、聚乙烯基吡咯烷酮、KSR、卡波姆、多糖、聚丙烯酸树脂、聚醋酸乙烯酯聚维酮混合物和聚乙烯醇中的一种或多种；
    所述的溶胀剂选自包括下述物质中的一种、两种或更多种：交联聚乙烯吡咯烷酮、聚氧化乙烯、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲基纤维素钙、羧甲纤维素、海藻酸盐、钙盐和波拉克林钾中的一种或多种；
    优选地，所述的药物活性成分为布瓦西坦；
    和/或，
    所述的基质形成剂为聚醋酸乙烯酯、聚乙烯基吡咯烷酮、KSR、卡波姆和多醣中的一种、两种或更多种；
    和/或，
    所述的溶胀剂为交联聚乙烯吡咯烷酮、聚氧化乙烯和羧甲基淀粉钠中的一种、两种或更多种；
    还优选地，所述的药物活性成分的重量百分比为2.00％～50.00％；所述的重量百分比是指药物活性成分的重量占所述布瓦西坦药物组合物总重量的百分比；
    和/或，
    所述的基质形成剂的重量百分比为5.00％～60.00％，所述的重量百分比是指基质形成剂的重量占所述布瓦西坦药物组合物总重量的百分比；
    和/或，
    所述的溶胀剂的重量百分比为5.00％～60.00％，所述的重量百分比是指溶胀剂的重量占所述布瓦西坦药物组合物总重量的百分比；
    优选地，所述的药物活性成分的重量百分比为3.00％～20.00％，所述的重量百分比是指药物活性成分的重量占所述布瓦西坦药物组合物总重量的百分比；
    和/或，
    所述的基质形成剂的重量百分比为30.00％～50.00％，所述的重量百分比是指基质形成剂的重量占所述布瓦西坦药物组合物总重量的百分比；
    和/或，
    所述的溶胀剂的重量百分比为20.00％～50.00％，所述的重量百分比是指溶胀剂的重量占所述布 瓦西坦药物组合物总重量的百分比。
  4. 如权利要求3所述的布瓦西坦药物组合物，其特征在于：所述的多醣选自包括下述物质中的一种、两种或更多种：黄原胶、菊粉、瓜耳树胶、壳聚糖、角豆胶、角叉菜胶和纤维素衍生物；
    优选地，所述的纤维素衍生物选自包括下述物质中的一种、两种或更多种：离子性纤维素聚合物和非离子性纤维素聚合物；
    优选地，所述的离子性纤维素聚合物选自包括下述物质中的一种、两种或更多种：羧甲基纤维素、羧甲基纤维素钠盐、羧甲基纤维素钙盐、羧乙基纤维素、羧甲基乙基纤维素、醋酸羟乙基甲基纤维素邻苯二甲酸酯、醋酸羟乙基甲基纤维素琥珀酸酯、羟丙基纤维素醋酸邻苯二甲酸酯、乙酸羟丙基纤维素琥珀酸酯和乙酸羟丙基甲基纤维素邻苯二甲酸酯；
    和/或，
    所述的非离子性纤维素聚合物选自包括下述物质中的一种、两种或更多种：甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙甲纤维素、羟丙基甲基纤维素醋酸酯、羟乙基甲基纤维素、羟乙基纤维素醋酸酯和羟乙基乙基纤维素。
  5. 如权利要求3或4所述的布瓦西坦药物组合物，其特征在于：所述的布瓦西坦药物组合物进一步包括润滑剂和/或稀释剂；
    优选地，所述的润滑剂选自滑石、硬脂酸、硬脂酸金属盐、硬脂酸酯、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、矿物油、泊洛沙姆、聚乙二醇和氯化钠中的一种、两种或更多种；
    和/或，
    所述的稀释剂选自右旋糖、乳糖一水合物、无水乳糖、蔗糖、甘露醇、木糖醇、山梨糖醇、微晶纤维素、淀粉、预胶化淀粉、二水磷酸氢钙、无水磷酸氢钙、环糊精和环糊精衍生物中的一种、两种或更多种；
    优选地，所述的硬脂酸金属盐选自包括硬脂酸钙、硬脂酸镁和硬脂酸锌中的一种、两种或更多种；
    和/或，
    所述的硬脂酸酯选自包括聚氧乙烯硬脂酸酯、单硬脂酸甘油酯和棕榈硬脂酸甘油酯中的一种、两种或更多种；
    和/或，
    所述的环糊精选自包括α-环糊精、β-环糊精和γ-环糊精中的一种、两种或更多种；
    和/或，
    所述的环糊精衍生物选自包括环糊精葡萄糖衍生物、环糊精羟丙基衍生物、环糊精甲基衍生物、环糊精乙基衍生物、环糊精乙酰基衍生物、环糊精磺丁基衍生物和离子性环糊精衍生物中的一种、两种或更多种；
    优选地，所述的润滑剂的重量百分比为0～3.00％，所述的重量百分比是指润滑剂的重量占所述布瓦西坦药物组合物总重量的百分比；
    和/或，
    所述的稀释剂的重量百分比为0～30.00％，所述的重量百分比是指稀释剂的重量占所述布瓦西坦药物组合物总重量的百分比；
    优选地，所述的润滑剂的重量百分比为0.50％～2.00％，所述的重量百分比是指润滑剂的重量占所述布瓦西坦药物组合物总重量的百分比；
    和/或，
    所述的稀释剂的重量百分比为0～20.00％，所述的重量百分比是指稀释剂的重量占所述布瓦西坦药物组合物总重量的百分比。
  6. 如权利要求3-5任一项所述的布瓦西坦药物组合物，其特征在于：
    所述的布瓦西坦药物组合物由药物活性成分、基质形成剂和溶胀剂组成；
    所述的药物活性成分选自布瓦西坦、布瓦西坦的药学上可接受的配合物、布瓦西坦的药学上可接受的盐、布瓦西坦的药学上可接受的溶剂化物和布瓦西坦的药学上可接受的水合物中的一种、两种或更多种；
    所述的基质形成剂选自聚醋酸乙烯酯、聚乙烯基吡咯烷酮、KSR、卡波姆和多糖中的一种、两种或更多种；
    所述的溶胀剂选自交联聚乙烯吡咯烷酮、聚氧化乙烯、海藻酸盐和钙盐中的一种、两种或更多种；
    优选地，所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮、聚氧化乙烯、卡波姆和硬脂酸镁；
    或者，
    所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮、聚氧化乙烯、卡波姆、乳糖和硬脂酸镁；
    或者，
    所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮、聚氧化乙烯、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、卡波姆、微晶纤维素和硬脂酸镁；
    或者，
    所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮、海藻酸钠、氯化钙、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、微晶纤维素和硬脂酸镁；
    或者，
    所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、卡波姆、微晶纤维素和硬脂酸镁；
    或者，
    所述的布瓦西坦药物组合物由以下组分组成：布瓦西坦、KSR、交联聚乙烯吡咯烷酮、聚氧化乙烯、羧甲基淀粉钠、羟丙甲纤维素、预胶化淀粉、卡波姆和硬脂酸镁；
    优选地，所述的布瓦西坦药物组合物选自以下任一配方：
    配方一：9.1％布瓦西坦、40.0％KSR、20.0％交联聚乙烯吡咯烷酮、20.8％聚氧化乙烯、9.1％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占药物组合物总重量的百分比；
    配方二：11.1％布瓦西坦、40.0％KSR、20.0％交联聚乙烯吡咯烷酮、17.9％聚氧化乙烯、10.0％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    配方三：11.1％布瓦西坦、30.0％KSR、15.0％交联聚乙烯吡咯烷酮、16.0％聚氧化乙烯、8.0％卡波姆、18.9％乳糖和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    配方四：11.1％布瓦西坦、30.0％KSR、15.0％交联聚乙烯吡咯烷酮、16.0％聚氧化乙烯、8.0％卡波姆、8.9％乳糖、10.0％羟丙基-β-环糊精和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    配方五：9.09％布瓦西坦、29.09％KSR、15.46％交联聚乙烯吡咯烷酮、14.55％聚氧化乙烯、5.45％羧甲基淀粉钠、5.00％羟丙甲纤维素、10.00％预胶化淀粉、2.0％卡波姆、8.36％微晶纤维素和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    配方六：9.09％布瓦西坦、29.09％KSR、15.46％交联聚乙烯吡咯烷酮、10.0％海藻酸钠、4.55％氯化钙、6.36％羧甲基淀粉钠、7.27％羟丙甲纤维素、7.27％预胶化淀粉、9.91％微晶纤维素和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    配方七：4.55％布瓦西坦、30.0％KSR、16.36％交联聚乙烯吡咯烷酮、15.46％聚氧化乙烯、6.36％羧甲基淀粉钠、5.91％羟丙甲纤维素、11.09％预胶化淀粉、3.0％卡波姆、6.27％微晶纤维素和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    配方八：18.18％布瓦西坦、29.09％KSR、14.55％交联聚乙烯吡咯烷酮、14.55％聚氧化乙烯、5.45％羧甲基淀粉钠、5.45％羟丙甲纤维素、9.73％预胶化淀粉、2.0％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦药物组合物总重量的百分比；
    优选地，所述布瓦西坦药物组合物具有如权利要求1或2所示的溶出特征。
  7. 一种布瓦西坦缓释片，其特征在于，所述布瓦西坦缓释片由片芯和包衣组成，所述片芯包含权利要求1-6任一项所述的药物组合物；
    优选地，所述的片芯由以下重量百分含量的组分组成：2.00％～50.00％布瓦西坦、5.00％～60.00％ 基质形成剂、5.00％～60.00％溶胀剂、0～3.00％润滑剂和0～30.00％稀释剂，所述的重量百分含量是指单个组分的重量占所述布瓦西坦缓释片总重量的百分比；
    优选地，所述的布瓦西坦缓释片的片芯由以下重量百分含量的组分组成：3.00％～20.00％布瓦西坦、30.00％～50.00％基质形成剂、20.00％～50.00％溶胀剂、0.50％～2.00％润滑剂和0～20.00％稀释剂，所述的重量百分含量是指单个组分的重量占所述布瓦西坦缓释片总重量的百分比。
  8. 如权利要求7所述的布瓦西坦缓释片，其特征在于：
    所述的布瓦西坦缓释片的片芯为以下任一处方：
    处方一：9.1％布瓦西坦、40.0％KSR、20.0％交联聚乙烯吡咯烷酮、20.8％聚氧化乙烯、9.1％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方二：11.1％布瓦西坦、40.0％KSR、20.0％交联聚乙烯吡咯烷酮、17.9％聚氧化乙烯、10.0％卡波姆和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方三：11.1％布瓦西坦、30.0％KSR、15.0％交联聚乙烯吡咯烷酮、16.0％聚氧化乙烯、8.0％卡波姆、18.9％乳糖和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方四：11.1％布瓦西坦、30.0％KSR、15.0％交联聚乙烯吡咯烷酮、16.0％聚氧化乙烯、8.0％卡波姆、8.9％乳糖、10.0％羟丙基-β-环糊精和1.0％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方五：9.09％布瓦西坦、29.09％KSR、15.46％交联聚乙烯吡咯烷酮、14.55％聚氧化乙烯、5.45％羧甲基淀粉钠、5.00％羟丙甲纤维素、10.00％预胶化淀粉、2.0％卡波姆、8.36％微晶纤维素和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方六：9.09％布瓦西坦、29.09％KSR、15.46％交联聚乙烯吡咯烷酮、10.00％海藻酸钠、4.55％氯化钙、6.36％羧甲基淀粉钠、7.27％羟丙甲纤维素、7.27％预胶化淀粉、9.91％微晶纤维素和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方七：4.55％布瓦西坦、30.0％KSR、16.36％交联聚乙烯吡咯烷酮、15.46％聚氧化乙烯、6.36％羧甲基淀粉钠、5.91％羟丙甲纤维素、11.09％预胶化淀粉、3.00％卡波姆、6.27％微晶纤维素和1.00％硬脂酸镁；所述的百分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比；
    处方八：18.18％布瓦西坦、29.09％KSR、14.55％交联聚乙烯吡咯烷酮、14.55％聚氧化乙烯、5.45％羧甲基淀粉钠、5.45％羟丙甲纤维素、9.73％预胶化淀粉、2.00％卡波姆和1.00％硬脂酸镁；所述的百 分比是指重量百分比，所述的重量百分比是指单个组分的重量占所述布瓦西坦缓释片的片芯总重量的百分比。
  9. 权利要求1-6任一项所述的布瓦西坦药物组合物或权利要求7或8所述布瓦西坦缓释片的制备方法，其特征在于，所述制备方法为直接压片法、干法制粒、湿法制粒或者熔融制粒法。
  10. 权利要求1-6任一项所述的布瓦西坦药物组合物或权利要求7或8所述的布瓦西坦缓释片在制备药物中的应用；
    优选地，所述药物用于治疗和/或预防下述疾病：癫痫症、帕金森、运动障碍、偏头痛、颤动、特发性震颤、双向情感障碍、慢性病、神经性疼痛或支气管、哮喘或过敏性等疾病。
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CN113908153B (zh) 2024-03-26
CN113908153A (zh) 2022-01-11
JP7423013B2 (ja) 2024-01-29
US20220304934A1 (en) 2022-09-29

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