WO2022194198A1 - 一种拉考沙胺药物组合物、其制备方法及应用 - Google Patents

一种拉考沙胺药物组合物、其制备方法及应用 Download PDF

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WO2022194198A1
WO2022194198A1 PCT/CN2022/081161 CN2022081161W WO2022194198A1 WO 2022194198 A1 WO2022194198 A1 WO 2022194198A1 CN 2022081161 W CN2022081161 W CN 2022081161W WO 2022194198 A1 WO2022194198 A1 WO 2022194198A1
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lacosamide
pharmaceutical composition
sodium alginate
magnesium stearate
crospovidone
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PCT/CN2022/081161
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English (en)
French (fr)
Inventor
郭桢
陈祖佑
陈丽娜
王婷婷
应述欢
谢文凤
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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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Application filed by 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 filed Critical 上海博志研新药物技术有限公司
Priority to JP2023557091A priority Critical patent/JP2024510761A/ja
Priority to EP22770551.4A priority patent/EP4309648A1/en
Priority to US18/551,068 priority patent/US20240156736A1/en
Publication of WO2022194198A1 publication Critical patent/WO2022194198A1/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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to a lacosamide pharmaceutical composition, a preparation method and application thereof, and belongs to the field of pharmaceutical preparations.
  • Lacosamide is (2R)-2-acetamido-N-benzyl-3-methoxypropanamide, the molecular formula is C 13 H 18 N 2 O 3 , and the molecular weight is 250.29400.
  • Lacosamide is suitable for the treatment of patients with localized epilepsy aged four years and older, and can also be used as an adjuvant drug for the treatment of primary tonic-clonic epilepsy in patients aged four years and older.
  • Lacosamide is a BCS class I drug with good water solubility, easily soluble in methanol or acetone, and slightly soluble in acetonitrile or ethanol.
  • Lacosamide is a novel N-methyl-D-aspartate (NMDA) receptor glycine site antagonist, which belongs to a new class of functional amino acids. It is currently recognized that lacosamide can selectively enhance the slow inactivation of voltage-gated sodium channels (VGSCs), but does not affect the fast inactivation of sodium channels. At the same time, lacosamide may exert its anticonvulsant effect by cross-linking with Collapsin Response Mediator Protein 2 (CRMP-2), but the mechanism of action has not been fully clarified.
  • CRMP-2 Collapsin Response Mediator Protein 2
  • lacosamide raw material has extremely poor fluidity, low bulk density, poor mixing uniformity, excessive tablet filling depth, and difficulty in blanking.
  • the present invention provides a lacosamide pharmaceutical composition
  • the lacosamide pharmaceutical composition is a 24-hour slow-release drug.
  • the dissolution of the cosamide pharmaceutical composition simultaneously satisfies the following three characteristics:
  • C) dissolve no less than 65% (preferably no less than 70%, more preferably no less than 80%) of the active pharmaceutical ingredient within 24 hours;
  • the pharmaceutical active ingredient is selected from lacosamide, pharmaceutically acceptable complexes of lacosamide, pharmaceutically acceptable salts of lacosamide, pharmaceutically acceptable solvates of lacosamide and A pharmaceutically acceptable hydrate of lacosamide, preferably lacosamide or a pharmaceutically acceptable salt of lacosamide.
  • the medicinal active ingredient of the lacosamide pharmaceutical composition dissolves no more than 30% within 1 hour, dissolves 30%-55% within 6 hours, and dissolves no less than 24 hours within 24 hours. 80%.
  • the present invention also provides a lacosamide pharmaceutical composition, comprising the following components: a pharmaceutical active ingredient, a skeleton material and a swelling material;
  • the pharmaceutical active ingredient is selected from lacosamide, pharmaceutically acceptable complexes of lacosamide, pharmaceutically acceptable salts of lacosamide, pharmaceutically acceptable solvates of lacosamide and Lacosamide pharmaceutically acceptable hydrate;
  • Described skeleton material is selected from one or more in polyvinyl acetate povidone mixture, sodium alginate and hydroxypropyl methylcellulose;
  • the swelling material is selected from one or more of polyoxyethylene, carbomer and sodium alginate.
  • the lacosamide pharmaceutical composition is a lacosamide gastroretentive composition, preferably a lacosamide gastroretentive tablet.
  • the pharmaceutical active ingredient is preferably lacosamide.
  • the particle size of the active pharmaceutical ingredient is less than or equal to 30 mesh.
  • the weight percentage of the pharmaceutical active ingredient is preferably 1.0% to 50.0%, more preferably 5.0% to 40.0%, such as 20.00% or 18.18%, wherein the weight percentage refers to the amount of the pharmaceutical active ingredient. Weight as a percentage of the total weight of the lacosamide pharmaceutical composition.
  • the weight percentage of the swelling material is preferably 1.0% to 60.0%, such as 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%, wherein the weight percentage refers to the weight percentage of the swelling material in the total weight of the lacosamide pharmaceutical composition.
  • the weight percentage of the polyoxyethylene is preferably 5.0% to 60.0%, such as 5.0%, 10.0%, 15.0%, 20.0%, 25.0% , 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%, more preferably 10.0% to 40.0%, such as 16.73%, wherein the weight percentage refers to the weight of the polyoxyethylene accounts for the Laco Percentage of the total weight of the salamine pharmaceutical composition.
  • the weight percentage of the carbomer is preferably 1.0% to 15.0%, more preferably 1.5% to 10%, such as 3.00% or 6.00%, wherein, the weight percentage refers to the percentage of the weight of carbomer in the total weight of the lacosamide pharmaceutical composition.
  • the weight percentage of the sodium alginate is preferably 1.0% to 50.0%, such as 1.0%, 5.0%, 10.0%, 15.0%, 20.0% , 25.0%, 30.0%, 35.0%, 40.0%, 45.0% or 50.0%, more preferably 1.0% to 40.0%, such as 35.09%, 25.45% or 5.00%, wherein the weight percentage refers to the weight of sodium alginate As a percentage of the total weight of the lacosamide pharmaceutical composition.
  • the polyvinyl acetate-povidone mixture may be a mixture containing polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP),
  • PVAc polyvinyl acetate
  • PVP polyvinylpyrrolidone
  • a mixture of PVAc to PVP in a weight ratio of 80:19 preferably produced by BASF under the trade name KOLLIDON @ SR (abbreviated as "KSR"), contains an 80/19 (w/w) mixture of PVAc and PVP.
  • the weight percentage of the framework material is preferably 1.0% to 60.0%, such as 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0% %, 50.0%, 55.0% or 60.0%, wherein the weight percentage refers to the percentage of the weight of the matrix material in the total weight of the lacosamide pharmaceutical composition.
  • the weight percentage of the KSR is preferably 5.0% to 60.0%, more preferably 20.0% to 50.0%, such as 24.68% or 18.36%, wherein the The weight percent refers to the weight of KSR as a percentage of the total weight of the lacosamide pharmaceutical composition.
  • the weight percentage of the hydroxypropyl methylcellulose is preferably 1.0%-30.0%, more preferably 2.0%-20.0% , for example, 17.27%, 8.00%, 16.73% or 9.09%, wherein the weight percentage refers to the weight percentage of the hypromellose in the total weight of the lacosamide pharmaceutical composition.
  • the weight percentage of the sodium alginate is preferably 1.0% to 50.0%, more preferably 1.0% to 40.0%, such as 35.09%, 25.45% or 5.00%, wherein the weight percentage refers to the percentage of the weight of sodium alginate in the total weight of the lacosamide pharmaceutical composition.
  • the framework material eg, sodium alginate
  • a framework strength modifier e.g., sodium alginate
  • the skeleton strength modifier can be selected from water-soluble calcium salts, so as to form an insoluble calcium alginate gel skeleton with sodium alginate.
  • the water-soluble calcium salt may be selected from calcium hydrogen phosphate and/or calcium hydrogen phosphate dihydrate and the like.
  • the weight percentage of the skeleton regulator is preferably 0% to 30.0%, such as 0%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, more preferably 0% to 15.0%, such as 11.73% or 10.91%, wherein the weight percentage refers to the percentage of the weight of the matrix strength modifier in the total weight of the lacosamide pharmaceutical composition.
  • the lacosamide pharmaceutical composition of the present invention may further comprise one or more selected from disintegrants, diluents and lubricants.
  • the disintegrant may be selected from, for example, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, calcium carboxymethyl cellulose and low-substituted hydroxypropyl One or more of cellulose and the like.
  • the weight percentage of the disintegrant is preferably 0% to 30.0%, such as 0%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, more preferably 5% to 30.0%, such as 20.00%, 16.64%, 13.64% or 16.36%, wherein the weight percentage refers to the weight percentage of the disintegrant in the total weight of the lacosamide pharmaceutical composition.
  • the diluent is preferably selected from dextrose, lactose monohydrate, anhydrous lactose, sucrose, mannitol, xylitol, sorbitol One or more of sugar alcohol, microcrystalline cellulose, starch, pregelatinized starch, calcium hydrogen phosphate dihydrate, calcium hydrogen phosphate anhydrous, cyclodextrin and derivatives thereof.
  • the weight percentage of the diluent is preferably 0-40%, such as 0%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 30.5% or 40.0% %, such as 20.00% or 15.00%, wherein the weight percentage refers to the percentage of the weight of the diluent in the total weight of the lacosamide pharmaceutical composition.
  • the lubricant refers to a substance that is helpful for the processing steps of component mixing, granulation and tableting, which may be selected from talc, Stearic Acid, Metal Stearate, Stearate, Colloidal Silicon Dioxide, Glyceryl Behenate, Sodium Lauryl Sulfate, Hydrogenated Vegetable Oil, Mineral Oil, Poloxamer, Polyethylene Glycol and Sodium Chloride one or more of.
  • the metal stearate can be magnesium stearate; the stearate can be glyceryl stearate.
  • the weight percentage of the lubricant is preferably 0-3.0%, such as 0%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%, more preferably 0.5%-2.0% , for example, 1.10%, 1.20% or 1.65%, wherein the weight percentage refers to the percentage of the total weight of the lubricant in the total weight of the lacosamide pharmaceutical composition.
  • the lacosamide pharmaceutical composition preferably comprises the following components: a pharmaceutical active ingredient, a matrix material, a matrix strength modifier (optional), a swelling material, a disintegrant and a lubricant, or consists of the above components;
  • the pharmaceutical active ingredient is selected from lacosamide, pharmaceutically acceptable complexes of lacosamide, pharmaceutically acceptable salts of lacosamide, pharmaceutically acceptable solvates of lacosamide and lacosamide Salamine pharmaceutically acceptable hydrate;
  • Described skeleton material is selected from one or more in polyvinyl acetate povidone mixture (such as KSR), sodium alginate and hydroxypropyl methylcellulose;
  • the swelling material is polyoxyethylene and/or carbomer and/or sodium alginate.
  • the lacosamide pharmaceutical composition further preferably comprises the following components one, two, three, four, five or six, or the following components respectively Component composition:
  • Component 1 Lacosamide, Sodium Alginate, Crospovidone, Anhydrous Calcium Hydrogen Phosphate, Magnesium Stearate, Carbomer, Hypromellose;
  • Component two lacosamide, polyvinyl acetate-povidone mixture, crospovidone, magnesium stearate, sorbitol, carbomer, hypromellose;
  • Component three lacosamide, sodium alginate, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate;
  • Component four lacosamide, sodium alginate, crospovidone, polyoxyethylene, colloidal silicon dioxide, magnesium stearate, anhydrous calcium hydrogen phosphate;
  • Component 5 Lacosamide, Sodium Alginate, Crospovidone, Colloidal Silicon Dioxide, Magnesium Stearate, Hypromellose, Polyvinyl Acetate Povidone Mixture, Dicalcium Phosphate Dihydrate ;
  • Component six lacosamide, polyvinyl acetate-povidone mixture, crospovidone, magnesium stearate, sorbitol, sodium alginate, carbomer, hypromellose.
  • the lacosamide pharmaceutical composition is further preferably any one of the following prescriptions:
  • Prescription 1 18.18% lacosamide, 35.09% sodium alginate, 13.64% crospovidone (Kollidon CL, BASF), 11.73% anhydrous calcium hydrogen phosphate, 1.10% magnesium stearate, 3.00% carbomer (971 PNF, Lubrizol), 17.27% Hypromellose (K 4M, Ashland);
  • Prescription 2 20.00% lacosamide, 24.80% polyvinyl acetate povidone mixture, 20.00% crospovidone (Kollidon CL, BASF), 1.20% magnesium stearate, 20.00% sorbitol, 6.00% calorie Bohm (971 PNF, Lubrizol), 8.00% Hypromellose (K 4M, Ashland);
  • Formula 3 18.18% lacosamide, 35.09% sodium alginate, 16.64% crospovidone (Kollidon CL, BASF), 16.73% hypromellose (K 15M, Ashland), 0.55% colloidal Silicon dioxide, 1.10% magnesium stearate, 11.73% anhydrous calcium hydrogen phosphate;
  • Formulation five 18.18% lacosamide, 25.45% sodium alginate, 16.36% crospovidone (Kollidon CL, BASF), 0.55% colloidal silicon dioxide, 1.10% magnesium stearate, 9.09% hypromelline Cellulose (K 15M, Ashland), 18.36% polyvinyl acetate povidone mixture, 10.91% calcium hydrogen phosphate dihydrate;
  • Formulation VI 20.00% lacosamide, 24.80% polyvinyl acetate povidone mixture, 20.00% crospovidone (Kollidon CL, BASF), 1.20% magnesium stearate, 15.00% sorbitol, 5.00% seaweed sodium, 6.00% carbomer (971 PNF, Lubrizol), 8.00% hypromellose (K 4M, Ashland).
  • the lacosamide pharmaceutical composition described above is a 24-hour slow-release drug.
  • the lacosamide pharmaceutical composition described above is a 24-hour slow-release drug.
  • the dissolution of the cosamide pharmaceutical composition simultaneously satisfies the following three characteristics:
  • the above-mentioned lacosamide pharmaceutical composition dissolves no more than 30% within 1 hour, dissolves 30% to 55% within 6 hours, and dissolves no less than 80% within 24 hours.
  • the present invention also provides a preparation method of the lacosamide pharmaceutical composition, which includes a dry granulation process.
  • the dry granulation process includes the following steps:
  • Step 1 sieving the active ingredients of the medicine (also known as "lacosamide bulk drug") to remove clusters to obtain the sieved lacosamide bulk drug;
  • Step 2 mixing the sieved lacosamide crude drug obtained in step 1 with part of the skeleton material and the optional skeleton-containing strength regulator and disintegrant to obtain a premix;
  • Step 3 dry and granulate the premix obtained in step 2 through a granulator, then add an internal lubricant (such as magnesium stearate) to mix and perform dry granulation to obtain granules;
  • an internal lubricant such as magnesium stearate
  • Step 4 mixing the remaining skeleton material, swelling material, filler and the particles obtained in step 3, then adding an external lubricant (such as magnesium stearate) and continuing to mix for a period of time, tableting to obtain the lacosa Amine pharmaceutical compositions, such as lacosamide gastroretentive tablets;
  • an external lubricant such as magnesium stearate
  • the dry granulation process comprises the following steps:
  • Step 1 sieving the lacosamide bulk drug to remove the clusters to obtain the sieved lacosamide bulk drug
  • Step 2 mixing the sieved lacosamide crude drug obtained in step 1 with a skeleton material, a swelling material, a disintegrating agent, and a lubricant (such as colloidal silicon dioxide) to obtain a premix;
  • Step 3 dry and granulate the premix obtained in step 2 through a granulator, then add an internal lubricant (such as magnesium stearate) to mix and perform dry granulation to obtain granules;
  • an internal lubricant such as magnesium stearate
  • Step 4 mix the skeleton strength modifier with the granules obtained in step 3, then add an external lubricant (such as magnesium stearate) and continue to mix for a period of time and then press into tablets to obtain the lacosamide pharmaceutical composition, such as lacosamide gastric retention tablets;
  • an external lubricant such as magnesium stearate
  • the dry granulation process comprises the following steps:
  • Step 1 sieving the lacosamide bulk drug to remove the clusters to obtain the sieved lacosamide bulk drug
  • Step 2 mixing the sieved lacosamide crude drug obtained in step 1 with swelling material, disintegrating agent and lubricant (such as colloidal silicon dioxide) to obtain a premix;
  • swelling material such as colloidal silicon dioxide
  • Step 3 dry and granulate the premix obtained in step 2 through a granulator, then add an internal lubricant (such as magnesium stearate) to mix and perform dry granulation to obtain granules;
  • an internal lubricant such as magnesium stearate
  • Step 4 Mix the skeleton strength modifier, the skeleton material and the granules obtained in step 3, then add an external lubricant (such as magnesium stearate) and continue to mix for a period of time and then press into tablets to obtain the lacosamide drug compositions, such as lacosamide gastroretentive tablets;
  • an external lubricant such as magnesium stearate
  • the dry granulation process comprises the following steps:
  • Step 1 sieving the lacosamide bulk drug to remove the clusters to obtain the sieved lacosamide bulk drug
  • Step 2 mixing the sieved lacosamide crude drug obtained in step 1 with swelling material, disintegrating agent and lubricant (such as colloidal silicon dioxide) to obtain a premix;
  • swelling material such as colloidal silicon dioxide
  • Step 3 dry and granulate the premix obtained in step 2 by a granulator, continue to mix for a period of time, then add an internal lubricant (such as magnesium stearate) and mix and perform dry granulation to obtain granules;
  • an internal lubricant such as magnesium stearate
  • Step 4 Mix the skeleton strength modifier, the skeleton material and the granules obtained in step 3, then add an external lubricant (such as magnesium stearate) and continue to mix for a period of time and then press into tablets to obtain the lacosamide drug Compositions such as lacosamide gastroretentive tablets.
  • an external lubricant such as magnesium stearate
  • the present invention also provides the application of the lacosamide pharmaceutical composition in preparing medicines, preferably medicines for treating and/or preventing acute and chronic pain.
  • said "acute and chronic pain” is in particular non-neuropathic inflammatory pain, including chronic inflammatory pain, such as rheumatoid arthritis pain and/or secondary osteoarthritis pain.
  • the "chronic pain” refers to pain that lasts for a period of time, such as more than 3-6 months, but the following characteristic signs exist before and after this period of time, and signs of autonomic dysfunction may appear, For example, lethargy, sleep disturbance, decreased appetite, loss of taste, weight loss, decreased libido, and/or constipation.
  • the present invention also provides a method for treating and/or preventing acute and chronic pain, the method comprising oral administration of the above-mentioned lacosamide pharmaceutical composition or lacosamide gastroretentive tablet to a patient once a day.
  • the present invention also provides lacosamide gastroretentive tablets, which comprise the lacosamide pharmaceutical composition.
  • the specifications of the lacosamide gastroretentive tablet can be selected from 100 mg to 400 mg, for example, 100 mg, 200 mg or 400 mg.
  • the lacosamide pharmaceutical composition or the lacosamide gastroretentive tablet when the lacosamide pharmaceutical composition or the lacosamide gastroretentive tablet is ingested as a whole and enters the stomach of a patient, it can rapidly swell or swell in gastric juice, and has a good Rigid and elastic, with significant gastric retention effect.
  • pharmaceutically acceptable refers to a substance that, within the scope of normal medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergic reaction, etc. , has a reasonable ratio of pros and cons, and can be effectively used for its intended purpose.
  • said "solvate” refers to a molecular complex comprising a drug (eg lacosamide) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg ethanol) thing.
  • a drug eg lacosamide
  • solvent molecules eg ethanol
  • said "hydrate” means a solvate containing the drug and stoichiometric or non-stoichiometric water.
  • said crospovidone also known as Crospovidone or Crospovidonum
  • PVPP crospovidone
  • Crospovidone is a water-insoluble synthetic cross-linked N-vinyl-2-pyrrolidone homopolymer. Due to the water insolubility of the material itself, the exact molecular weight has not been determined.
  • Crospovidone can be produced by BASF under the trade name of KOLLIDON, or by ISP under the trade name of POLYPLASDONE TM by Ashland.
  • the polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, and the molecular weight (Mw) is generally about 1 ⁇ 10 5 to about 1 ⁇ 10 6 .
  • the polyethylene oxide (PEO) is also referred to as polyoxirane and polyoxyethylene.
  • Polyoxyethylene is a homopolymer of ethylene oxide, typically having a molecular weight (Mw) of from about 1 ⁇ 10 5 to about 1 ⁇ 10 7 or from about 1 ⁇ 10 6 to about 1 ⁇ 10 7 .
  • Mw molecular weight
  • Polyethylene oxide is available in various grades according to molecular weight and can be produced for Union Carbide under the trade name ).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the lacosamide pharmaceutical composition provided by the invention has good sustained-release performance, and the size of the tablet can be rapidly expanded during the in vitro dissolution process. During the process, the size of the sheet can be rapidly expanded, and after the expansion, it has good rigidity and elasticity, and has a significant gastric retention effect.
  • the lacosamide 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 retention time in the stomach of more than 12 hours, and a cumulative release rate of more than 80% in 24 hours. When the pharmaceutical composition remains in the stomach, the lacosamide can be released continuously.
  • the lacosamide gastroretentive tablets provided by the present invention are dissolved in a pH 1.0 hydrochloric acid solution and/or a pH 4.5 acetate buffer solution with a volume of 900 ml.
  • the degree can reach more than 80%.
  • the preparation process of the invention significantly improves the problems of poor fluidity of the raw material medicine and too low bulk density, which are difficult to fill in the tableting process and unstable in tablet weight.
  • the process is stable and the process parameters are adjustable and controllable, which is beneficial to the product.
  • the production is enlarged, and the marketization prospect is good.
  • Fig. 1 is the dissolution curve diagram of the sample of embodiment 2, 5, 6 and 7 in 0.1N hydrochloric acid;
  • Fig. 2 is the dissolution curve diagram of the sample of embodiment 1-7 in the acetate buffer of pH 4.5;
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 70 grams.
  • step 2 Take the sieved lacosamide crude drug obtained in step 1, place sodium alginate, lacosamide, crospovidone, anhydrous calcium hydrogen phosphate in a mixing tank and mix for about 20 minutes to obtain premix.
  • step 3 the premix obtained in step 2 is granulated by a granulator, the screen mesh aperture is 2.0mm, and the granulation speed is 200rpm; then add magnesium stearate inside, continue to mix and carry out dry granulation after about 5 minutes, get granules.
  • the pressure of the dry granulation press wheel is about 0-20kg/cm 2 , the speed of the press wheel is 8HZ, the feeding speed is 3HZ, the granulation speed is 12HZ, and the diameter of the secondary granulation screen is 0.8mm.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 160 grams.
  • step 2 Get the lacosamide crude drug after the sieving obtained in step 1, place the polyvinyl acetate povidone mixture, lacosamide and crospovidone in a mixing tank and mix for about 20 minutes to obtain a mixture.
  • step 3 The premix obtained in step 2 is granulated by a granulator, the screen mesh aperture is 2.0 mm, and the granulation speed is 200 rpm. Then add magnesium stearate inside, continue mixing for about 5 minutes, and then dry granulation to obtain granules.
  • the pressure of the dry granulation press wheel is about 0-20kg/cm 2 , the speed of the press wheel is 8HZ, the feeding speed is 2HZ, the granulation speed is 12HZ, and the diameter of the selected secondary granulation screen is 0.8mm.
  • step 4 Converting the amount of additional materials, adding hypromellose, sorbitol and carbomer to the particles obtained in step 3 and continuing to mix for about 15 minutes. Convert the dosage of the extra magnesium stearate, add the extra magnesium stearate and continue to mix for about 5 minutes; compress the final mixed material into a tablet (22.0mm*10.9mm almond-shaped shallow arc die).
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 70 grams.
  • step 2 2) Sodium alginate, lacosamide crude drug obtained in step 1, crospovidone, hypromellose, colloidal silicon dioxide are placed in a mixing tank and mixed for about 20 minutes to obtain a premix.
  • step 3 The premix obtained in step 2 is granulated by a granulator, the screen mesh aperture is 2.0 mm, and the granulation speed is 200 rpm. Then add magnesium stearate inside, continue mixing for about 5 minutes, and then dry granulation to obtain granules.
  • the dry granulation press wheel pressure is about 0-20kg/cm 2 , the press wheel rotation speed is 8HZ, the feeding speed is 3HZ, the granulation speed is 12HZ, and the diameter of the secondary granulation screen is 0.8mm.
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 70 grams.
  • step 2 2) Sodium alginate, the sieved lacosamide crude drug obtained in step 1, crospovidone, polyoxyethylene, and colloidal silicon dioxide are placed in a mixing tank and mixed for about 20 minutes to obtain a premix. thing.
  • step 3 The premix obtained in step 2 is granulated by a granulator, the mesh aperture is 2.0 mm, and the granulation speed is 200 rpm. Then add magnesium stearate inside, continue mixing for about 5 minutes, and then dry granulation to obtain granules.
  • the dry granulation press wheel pressure is about 0-20kg/cm 2 , the press wheel rotation speed is 8HZ, the feeding speed is 2HZ, the granulation speed is 12HZ, and the diameter of the secondary granulation screen is 0.8mm.
  • step 4 convert the additional material consumption, add the additional anhydrous calcium hydrogen phosphate in the granule obtained in step 3 and continue to mix for about 15 minutes; after adding the additional magnesium stearate, continue to mix for about 5 minutes, and the final mixed material is compressed into tablets ( 22.0mm*10.9mm almond-shaped shallow arc die).
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 330 grams.
  • Crospovidone (Kollidon CL, BASF) 180 16.36 Colloidal silica 6 0.55 Magnesium stearate (added) 6 0.55 Hypromellose (K 15M, Ashland) (extra) 100 9.09 Polyvinyl acetate povidone blend (KSR, plus) 202 18.36 Calcium hydrogen phosphate dihydrate (extra) 120 10.91 Magnesium stearate (extra) 6 0.55 total 1100 /
  • step 3 The premix obtained in step 2 is granulated by a granulator, the mesh aperture is 2.0 mm, and the granulation speed is 200 rpm. Then add magnesium stearate inside, continue mixing for about 5 minutes, and then dry granulation to obtain granules.
  • the dry granulation press wheel pressure is about 0-20kg/cm 2 , the press wheel rotation speed is 8HZ, the feeding speed is 2HZ, the granulation speed is 12HZ, and the diameter of the secondary granulation screen is 0.8mm.
  • step 4 convert the additional material consumption, add additional hypromellose, polyvinyl acetate-povidone mixture, calcium hydrogen phosphate dihydrate and continue to mix for about 15 minutes in the particle obtained in step 3; after adding additional magnesium stearate Mixing was continued for about 5 minutes and the final blend was compressed into tablets (22.0mm*10.9mm almond shaped shallow arc die).
  • Matrix tablets containing the following ingredients were produced as follows in batches of approximately 300 grams.
  • step 3 The premix obtained in step 2 is granulated by a granulator, the screen mesh aperture is 2.0 mm, and the granulation speed is 200 rpm. Add magnesium stearate inside, continue mixing for about 5 minutes, and then dry granulation to obtain granules.
  • the dry granulation press wheel pressure is about 0-20kg/cm 2 , the press wheel rotation speed is 8HZ, the feeding speed is 3HZ, the granulation speed is 12HZ, and the diameter of the secondary granulation screen is 0.8mm.
  • step 4 convert the additional material consumption, add sorbitol, carbomer, hypromellose, sodium alginate in the particle obtained in step 3 and continue to mix for about 15 minutes; after adding the magnesium stearate, continue to mix for about 5 minutes. minutes, the final blend was compressed into tablets (22.0mm*10.9mm almond-shaped shallow arc die).
  • composition of the recipe is the same as that of Example 5, and the batch is scaled up to 11,000 grams for production.
  • step 3 The premix obtained in step 2 is granulated by a granulator, the screen aperture is 2.0 mm, and the granulating speed is 200 rpm; after granulating, continue to mix for 5min, add magnesium stearate, and continue to mix for about 5 minutes Then dry granulation is carried out to obtain granules.
  • the dry granulation pressure wheel pressure is about 2-5bar, the side pressure pressure is 2-5bar, the pressure wheel rotation speed is 5-15rpm, the feeding speed is 5-15rpm, the granulation speed is 176rpm, and the selected secondary granulation screen has a diameter of 5-15rpm. 1.0mm.
  • step 4 Converting the amount of additional materials, adding hydroxypropyl cellulose, polyvinyl acetate-povidone mixture, and calcium hydrogen phosphate dihydrate to the particles obtained in step 3 and continuing to mix for about 15 minutes. Convert the dosage of the extra magnesium stearate, add the extra magnesium stearate and continue to mix for about 5 minutes, and press the final mixed material into a tablet (22.0mm*10.9mm almond-shaped shallow arc die).
  • the present invention uses the self-made lacosamide pharmaceutical composition obtained in Example 7 and the lacosamide tablet of Reference Example 1 to carry out a comparative study on the pharmacokinetic evaluation test of oral administration in beagle dogs.
  • the sampling time points of group 1 in the first cycle are 0.5hr, 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, 8hr, 12hr, 16hr, 24hr, 36hr and 48hr after administration, a total of 13 time points;
  • the sampling time points of the two groups were 0.25hr, 0.5hr, 1hr, 1.5hr, 2hr, 2.5hr, 3hr, 4hr, 6hr, 8hr, 12hr, 24hr and 48hr after administration, a total of 13 time points;
  • the sampling time points of group 1 in the second cycle are 0.25hr, 0.5hr, 1hr, 1.5hr, 2hr, 2.5hr, 3hr, 5hr, 8hr (the second administration after 8hr blood collection), 8.25hr, 8.5hr after administration , 9hr, 9.5hr, 10hr, 10.5hr, 11hr, 13hr, 16hr, 24hr and 48hr, a total of 20 time points; the sampling time points of the second group in the second cycle are 0.5hr, 1hr, 2hr, 3hr, 4hr after administration , 5hr, 6hr, 8hr, 12hr, 16hr, 24hr, 36hr and 48hr, a total of 13 time points.
  • Plasma samples were first frozen in dry ice, and then stored in a -60°C freezer for long periods of time until sample analysis.
  • LC-MS/MS liquid chromatography tandem mass spectrometry
  • Female Beagle dogs were orally administered with 1 tablet of BCM-332 (200mg/tablet, single dose) and 2 tablets of the control formulation (100mg/tablet, single dose), T max , AUC last , AUC INF and T 1 There was no significant difference in /2 (P>0.05), there was a statistically significant difference in Cmax (P ⁇ 0.05), and there was a significant statistical difference in MRT INF (P ⁇ 0.01).
  • Example 2 The dissolution curves of Example 2, Examples 5 to 7 in 0.1N hydrochloric acid are shown in Figure 1; the dissolution curves of Examples 1 to 7 in pH4.5 acetate buffer are shown in Figure 2;
  • Table 1 and Table 2 The results of the pharmacokinetic evaluation test for oral administration in beagle dogs described in Example 8 are shown in Table 1 and Table 2; the blood drug concentration-time curve diagram of the oral administration pharmacokinetic evaluation test for Beagle dogs described in Example 8 is shown in the figure 3 and FIG. 4; Table 3 and Table 4 describe the results of the T-test test for pharmacokinetic parameters of the oral administration pharmacokinetic evaluation test for beagle dogs described in Example 8.
  • the lacosamide pharmaceutical composition of the present invention exhibits a good sustained-release effect both in vitro and in vivo, can rapidly expand during the in vitro dissolution process, and has good rigidity and elasticity after expansion.
  • This product provides stable and good gastric retention effect.
  • all the beagle dogs taking Example 7 had no abnormality in the whole process, indicating that the composition of the present invention is safer.

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Abstract

一种拉考沙胺药物组合物、其制备方法及应用。该拉考沙胺药物组合物具备1小时内溶出不超过40％，6小时内溶出20％～70％，24小时内溶出不低于65％的效果。其在体外溶出过程中片形尺寸可迅速膨大，膨大后具备良好的刚性和弹性，具有显著的胃内滞留效果。

Description

一种拉考沙胺药物组合物、其制备方法及应用
本申请要求享有2021年3月17日向中国国家知识产权局提交的申请号为202110286177.2，名称为“一种拉考沙胺药物组合物、其制备方法及应用”的中国发明专利在先申请的优先权权益。上述在先申请的全文通过引用的方式并入本文。
技术领域
本发明涉及一种拉考沙胺药物组合物、其制备方法及应用，属于药物制剂领域。
背景技术
拉考沙胺(Lacosamide)化学名为(2R)-2-acetamido-N-benzyl-3-methoxypropanamide，分子式为C 13H 18N 2O 3，分子量为250.29400。拉考沙胺适用于四岁及以上局限性癫痫患者的治疗，也可作为辅助药物，用于治疗四岁及以上患者的原发性强直-阵挛性癫痫。拉考沙胺为BCS I类药物，水溶性较好，易溶于甲醇或丙酮，微溶于乙腈或乙醇。
拉考沙胺是一种新型N-甲基-D-天冬氨酸(NMDA)受体甘氨酸位点拮抗剂，属于新一类的功能性氨基酸。目前公认拉考沙胺可选择性增强电压门控钠通道(Voltage-Gated Sodium Channels，VGSCs)的慢失活，但不影响钠通道快失活。同时，拉考沙胺可能通过与脑衰反应调节蛋白2(Collapsin Response Mediator Protein 2，CRMP-2)交联这一作用途径发挥抗惊厥作用，但该作用机制尚未完全明确。
拉考沙胺整体抗惊厥作用及耐受性良好，但其不良反应在一定程度上限制了给药剂量。在对重症或产生明显耐药性的癫痫患者进行治疗时，大幅增大拉考沙胺的给药剂量可能导致较为严重的不良反应。此外，对于癫痫或神经痛患者而言，每日频繁多次给药对患者的生活造成了不便，且易造成血药浓度不稳定，诱发不良反应。而且，拉考沙胺原料药流动性极差，堆密度小，粉末直接压片存在混合均匀度不佳、压片填充深度过大、下料困难等问题。
因此，亟需开发一种服药频率低、能够提高癫痫患者的顺应性、毒副作用低、 治疗效果好、血药浓度稳定性良好的拉考沙胺药物制剂。
发明内容
为改善上述问题，本发明提供了一种拉考沙胺药物组合物，所述的拉考沙胺药物组合物为24小时缓慢释放药物。优选地，在USP方法(溶出设备第2法，900ml，0.1N盐酸，50rpm和/或溶出设备第2法，900ml，pH4.5的醋酸盐缓冲液，50rpm)条件下，所述的拉考沙胺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％(优选不超过35％，进一步优选不超过30％)的药物活性成分；
B)在6小时内溶出20％～70％(包括20％和70％两个点值，优选25％～60％，进一步优选30％～55％)的药物活性成分；
C)在24小时内溶出不低于65％(优选不低于70％，进一步优选不低于80％)的药物活性成分；
其中，所述的药物活性成分选自拉考沙胺、拉考沙胺药学上可接受的配合物、拉考沙胺药学上可接受的盐、拉考沙胺药学上可接受的溶剂化物和拉考沙胺药学上可接受的水合物，优选拉考沙胺或拉考沙胺药学上可接受的盐。
根据本发明的实施方案，所述的拉考沙胺药物组合物的药物活性成分在1小时内溶出不超过30％，在6小时内溶出30％～55％，在24小时内溶出不低于80％。
本发明还提供了一种拉考沙胺药物组合物，包含以下组分：药物活性成分、骨架材料和溶胀材料；
其中，所述的药物活性成分选自拉考沙胺、拉考沙胺药学上可接受的配合物、拉考沙胺药学上可接受的盐、拉考沙胺药学上可接受的溶剂化物和拉考沙胺药学上可接受的水合物；
所述的骨架材料选自聚醋酸乙烯酯聚维酮混合物、海藻酸钠和羟丙甲基纤维素中的一种或多种；
所述的溶胀材料选自聚氧乙烯、卡波姆和海藻酸钠中的一种或多种。
根据本发明的实施方案，所述的拉考沙胺药物组合物为拉考沙胺胃滞留组合物，优选拉考沙胺胃滞留片。
根据本发明的实施方案，所述的拉考沙胺药物组合物中，所述的药物活性成分优选拉考沙胺。
根据本发明的实施方案，所述的药物活性成分的粒径小于或等于30目。
根据本发明的实施方案，所述的药物活性成分的重量百分比优选1.0％～50.0％，进一步优选5.0％～40.0％，例如20.00％或18.18％，其中所述的重量百分比是指药物活性成分的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，所述的拉考沙胺药物组合物中，所述的溶胀材料的重量百分比优选1.0％～60.0％，例如1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％、50.0％、55.0％或60.0％，其中所述的重量百分比是指溶胀材料的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，当所述的溶胀材料为聚氧乙烯时，所述的聚氧乙烯的重量百分比优选5.0％～60.0％，例如5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％、50.0％、55.0％或60.0％，进一步优选10.0％～40.0％，例如16.73％，其中所述的重量百分比是指聚氧乙烯的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，当所述的溶胀材料为卡波姆时，所述的卡波姆的重量百分比优选1.0％～15.0％，进一步优选1.5％～10％，例如3.00％或6.00％，其中所述的重量百分比是指卡波姆的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，当所述的溶胀材料为海藻酸钠时，所述的海藻酸钠的重量百分比优选1.0％～50.0％，例如1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％或50.0％，进一步优选1.0％～40.0％，例如35.09％、25.45％或5.00％，其中所述的重量百分比是指海藻酸钠的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，所述的拉考沙胺药物组合物中，所述的聚醋酸乙烯酯聚维酮混合物可以为含有聚乙酸乙烯酯(PVAc)和聚乙烯吡咯烷酮(PVP)的混合物，例如PVAc与PVP的重量比为80:19的混合物，优选BASF生产，商品名为KOLLIDON @SR(简称“KSR”)，其中含有PVAc和PVP的80/19(w/w)混合物。
根据本发明的实施方案，所述的骨架材料重量百分比优选1.0％～60.0％，例如1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％、50.0％、55.0％或60.0％，其中所述的重量百分比是指骨架材料的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，当所述的骨架材料为KSR时，所述的KSR的重量 百分比优选5.0％～60.0％，进一步优选20.0％～50.0％，例如24.68％或18.36％，其中所述的重量百分比是指KSR的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，当所述的骨架材料为羟丙基甲基纤维素时，所述的羟丙基甲基纤维素的重量百分比优选1.0％～30.0％，进一步优选2.0％～20.0％，例如17.27％、8.00％、16.73％或9.09％，其中所述的重量百分比是指羟丙甲基纤维素的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，当所述的骨架材料为海藻酸钠时，所述的海藻酸钠的重量百分比优选1.0％～50.0％，进一步优选1.0％～40.0％，例如35.09％、25.45％或5.00％，其中所述的重量百分比是指海藻酸钠的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，所述的骨架材料(例如海藻酸钠)可进一步与骨架强度调节剂共同使用。
根据本发明的实施方案，所述的骨架强度调节剂可以选自水溶性钙盐，从而与海藻酸钠生成不溶性的海藻酸钙凝胶骨架。
根据本发明的实施方案，所述的水溶性钙盐可以选自磷酸氢钙和/或磷酸氢钙二水合物等。
根据本发明的实施方案，所述的骨架调节剂的重量百分比优选0％～30.0％，例如0％、1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％，进一步优选0％～15.0％，例如11.73％或10.91％，其中所述的重量百分比是指骨架强度调节剂的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，本发明所述的拉考沙胺药物组合物可进一步包含选自崩解剂、稀释剂和润滑剂中的一种或多种。
根据本发明的实施方案，所述的崩解剂可以选自例如交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠、羧甲基纤维素钙和低取代羟丙基纤维素等中的一种或多种。
根据本发明的实施方案，所述的崩解剂的重量百分比优选0％～30.0％，例如0％、1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％，进一步优选5％～30.0％，例如20.00％、16.64％、13.64％或16.36％，其中所述的重量百分比是指崩解剂的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，所述的拉考沙胺药物组合物中，所述的稀释剂优选选自右旋糖、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、无水磷酸氢钙和环糊精及其衍生物中的一种或多种。
根据本发明的实施方案，所述的稀释剂的重量百分比优选0～40％，例如0％、1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、30.5％或40.0％，例如20.00％或15.00％，其中所述的重量百分比是指稀释剂的重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，所述的拉考沙胺药物组合物中，所述的润滑剂是指有助于组分混合、制粒和压片等加工步骤的物质，其可以选自滑石、硬脂酸、硬脂酸金属盐、硬脂酸酯、胶态二氧化硅、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或多种。
根据本发明的实施方案，所述的硬脂酸金属盐可以为硬脂酸镁；硬脂酸酯可以为硬脂酸甘油酯。
根据本发明的实施方案，所述的润滑剂的重量百分比优选0～3.0％，例如0％、0.5％、1.0％、1.5％、2.0％、2.5％或3.0％，进一步优选0.5％～2.0％，例如1.10％、1.20％或1.65％，其中所述的重量百分比是指润滑剂的总重量占拉考沙胺药物组合物总重量的百分比。
根据本发明的实施方案，所述的拉考沙胺药物组合物优选包含以下组分：药物活性成分、骨架材料、骨架强度调节剂(任选存在)、溶胀材料、崩解剂和润滑剂，或由上述组分组成；
其中，所述的药物活性成分选自拉考沙胺、拉考沙胺药学上可接受的配合物、拉考沙胺药学上可接受盐、拉考沙胺药学上可接受溶剂化物和拉考沙胺药学上可接受水合物；
所述的骨架材料选自聚醋酸乙烯酯聚维酮混合物(如KSR)、海藻酸钠和羟丙基甲基纤维素中的一种或多种；
所述的溶胀材料为聚氧乙烯和/或卡波姆和/或海藻酸钠。
根据本发明的实施方案，所述的拉考沙胺药物组合物进一步优选包含以下组分一、组分二、组分三、组分四、组分五或组分六，或分别由下述组分组成：
组分一：拉考沙胺、海藻酸钠、交联聚维酮、无水磷酸氢钙、硬脂酸镁、卡波姆、羟丙甲纤维素；
组分二：拉考沙胺、聚醋酸乙烯酯聚维酮混合物、交联聚维酮、硬脂酸镁、山梨醇、卡波姆、羟丙甲纤维素；
组分三：拉考沙胺、海藻酸钠、交联聚维酮、羟丙甲纤维素、胶态二氧化硅、硬脂酸镁、无水磷酸氢钙；
组分四：拉考沙胺、海藻酸钠、交联聚维酮、聚氧乙烯、胶态二氧化硅、硬脂酸镁、无水磷酸氢钙；
组分五：拉考沙胺、海藻酸钠、交联聚维酮、胶态二氧化硅、硬脂酸镁、羟丙甲纤维素、聚醋酸乙烯酯聚维酮混合物、二水磷酸氢钙；
组分六：拉考沙胺、聚醋酸乙烯酯聚维酮混合物、交联聚维酮、硬脂酸镁、山梨醇、海藻酸钠、卡波姆、羟丙甲纤维素。
根据本发明示例性的实施方案，所述的拉考沙胺药物组合物还进一步优选以下任一处方：
处方一：18.18％拉考沙胺、35.09％海藻酸钠、13.64％交联聚维酮(Kollidon CL，BASF)、11.73％无水磷酸氢钙、1.10％硬脂酸镁、3.00％卡波姆(971 PNF，Lubrizol)、17.27％羟丙甲纤维素(K 4M，亚什兰)；
处方二：20.00％拉考沙胺、24.80％聚醋酸乙烯酯聚维酮混合物、20.00％交联聚维酮(Kollidon CL，BASF)、1.20％硬脂酸镁、20.00％山梨醇、6.00％卡波姆(971 PNF，Lubrizol)、8.00％羟丙甲纤维素(K 4M，亚什兰)；
处方三：18.18％拉考沙胺、35.09％海藻酸钠、16.64％交联聚维酮(Kollidon CL，BASF)、16.73％羟丙甲纤维素(K 15M，亚什兰)、0.55％胶态二氧化硅、1.10％硬脂酸镁、11.73％无水磷酸氢钙；
处方四：18.18％拉考沙胺、35.09％海藻酸钠、16.64％交联聚维酮(Kollidon CL，BASF)、16.73％聚氧乙烯(WSR COAGULANT,陶氏杜邦)、0.55％胶态二氧化硅、1.10％硬脂酸镁、11.73％无水磷酸氢钙；
处方五：18.18％拉考沙胺、25.45％海藻酸钠、16.36％交联聚维酮(Kollidon CL，BASF)、0.55％胶态二氧化硅、1.10％硬脂酸镁、9.09％羟丙甲纤维素(K 15M，亚什兰)、18.36％聚醋酸乙烯酯聚维酮混合物、10.91％二水磷酸氢钙；
处方六：20.00％拉考沙胺、24.80％聚醋酸乙烯酯聚维酮混合物、20.00％交联聚维酮(Kollidon CL，BASF)、1.20％硬脂酸镁、15.00％山梨醇、5.00％海藻酸钠、6.00％卡波姆(971 PNF，Lubrizol)、8.00％羟丙甲纤维素(K 4M，亚什兰)。
优选地，上文所述的拉考沙胺药物组合物为24小时缓慢释放药物。优选地，在USP方法(溶出设备第2法，900ml，0.1N盐酸，50rpm和/或溶出设备第2 法，900ml，pH4.5的醋酸盐缓冲液，50rpm)条件下，所述的拉考沙胺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％(优选不超过35％，进一步优选不超过30％)的所述药物活性成分，例如拉考沙胺或其药学上可接受的盐；
B)在6小时内溶出20％～70％(优选25％～60％，进一步优选30％～55％)的所述药物活性成分，例如拉考沙胺或其药学上可接受的盐，包括20％和70％两个点值；
C)在24小时内溶出不低于65％(优选不低于70％，进一步优选不低于80％)的所述药物活性成分，例如拉考沙胺或其药学上可接受的盐。
例如，上文所述的拉考沙胺药物组合物在1小时内溶出不超过30％，在6小时内溶出30％～55％，在24小时内溶出不低于80％。
本发明还提供了所述的拉考沙胺药物组合物的制备方法，所述制备方法包括干法制粒工艺。
根据本发明示例性的实施方案，所述的干法制粒工艺包括以下步骤：
步骤1：将所述药物活性成分(又称“拉考沙胺原料药”)过筛去团，得到过筛后的拉考沙胺原料药；
步骤2：将步骤1得到的过筛后的拉考沙胺原料药与部分骨架材料以及任选存在的含骨架强度调节剂、崩解剂混合，得到预混物；
步骤3：将步骤2得到的预混物经整粒机干整粒，然后加入内加润滑剂(如硬脂酸镁)混合后进行干法制粒，得到颗粒；
步骤4：将剩余骨架材料、溶胀材料、填充剂与步骤3制得的颗粒进行混合，然后加入外加润滑剂(如硬脂酸镁)继续混合一段时间后压片，得到所述的拉考沙胺药物组合物，如拉考沙胺胃滞留片；
或者，根据本发明示例性的实施方案，所述的干法制粒工艺包括以下步骤：
步骤1：将拉考沙胺原料药过筛去团，得到过筛后的拉考沙胺原料药；
步骤2：将步骤1得到的过筛后的拉考沙胺原料药与骨架材料、溶胀材料、崩解剂、润滑剂(如胶态二氧化硅)混合，得到预混物；
步骤3：将步骤2得到的预混物经整粒机干整粒，然后加入内加润滑剂(如硬脂酸镁)混合后进行干法制粒，得到颗粒；
步骤4：将骨架强度调节剂与步骤3制得的颗粒进行混合，然后加入外加润滑剂(如硬脂酸镁)继续混合一段时间后压片，得到所述的拉考沙胺药物组合物，如拉考沙胺胃滞留片；
或者，根据本发明示例性的实施方案，所述的干法制粒工艺包括以下步骤：
步骤1：将拉考沙胺原料药过筛去团，得到过筛后的拉考沙胺原料药；
步骤2：将步骤1得到的过筛后的拉考沙胺原料药与溶胀材料、崩解剂、润滑剂(如胶态二氧化硅)混合，得到预混物；
步骤3：将步骤2得到的预混物经整粒机干整粒，然后加入内加润滑剂(如硬脂酸镁)混合后进行干法制粒，得到颗粒；
步骤4：将骨架强度调节剂、骨架材料与步骤3制得的颗粒进行混合，然后加入外加润滑剂(如硬脂酸镁)继续混合一段时间后压片，得到所述的拉考沙胺药物组合物，如拉考沙胺胃滞留片；
或者，根据本发明示例性的实施方案，所述的干法制粒工艺包括以下步骤：
步骤1：将拉考沙胺原料药过筛去团，得到过筛后的拉考沙胺原料药；
步骤2：将步骤1得到的过筛后的拉考沙胺原料药与溶胀材料、崩解剂、润滑剂(如胶态二氧化硅)混合，得到预混物；
步骤3：将步骤2得到的预混物经整粒机干整粒，继续混合一段时间，然后加入内加润滑剂(如硬脂酸镁)混合后进行干法制粒，得到颗粒；
步骤4：将骨架强度调节剂、骨架材料与步骤3制得的颗粒进行混合，然后加入外加润滑剂(如硬脂酸镁)继续混合一段时间后压片，得到所述的拉考沙胺药物组合物，如拉考沙胺胃滞留片。
本发明还提供了所述的拉考沙胺药物组合物在制备药物，优选用于治疗和/或预防急性和慢性疼痛的药物中的应用。
根据本发明的实施方案，所述的“急性和慢性疼痛”特别是非神经性炎性疼痛，包括慢性炎性疼痛，例如类风湿性关节炎疼痛和/或继发性骨关节炎疼痛。
根据本发明的实施方案，所述的“慢性疼痛”是指疼痛延续一段时间，例如3-6个月以上，但是下述特征性体征在这段时间前后存在，可出现植物神经功能紊乱体征，例如倦怠、睡眠紊乱、食欲降低、味觉丧失、体重减轻、性欲降低和 /或便秘。
本发明还提供一种治疗和/或预防急性和慢性疼痛的方法，所述方法包括使患者每日口服一次上述拉考沙胺药物组合物或者拉考沙胺胃滞留片。
本发明还是提供了拉考沙胺胃滞留片，其包含所述的拉考沙胺药物组合物。优选地，所述的拉考沙胺胃滞留片的规格可以选自100mg至400mg，例如为100mg、200mg或400mg。
根据本发明的实施方案，当所述的拉考沙胺药物组合物或者拉考沙胺胃滞留片被整体摄取，进入患者胃内时，可在胃液中迅速膨胀或溶胀，膨大后具备良好的刚性和弹性，具有显著的胃内滞留效果。
本发明的上下文中，所述的“药学上可接受的”是指如下物质，其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。
本发明的上下文中，所述的“溶剂化物”是指含药物(例如拉考沙胺)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)的分子配合物。当溶剂与药物紧密结合时，所形成配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，配合物通常具非化学计量性。
本发明的上下文中，所述的“水合物”表示含药物和化学计量或非化学计量的水的溶剂化物。
本发明的上下文中，所述的交联聚维酮(PVPP)也被称为Crospovidone或Crospovidonum，其为水不溶性的合成交联N-乙烯基-2-吡咯烷酮均聚物。由于材料本身的水不溶性，确切的分子量尚未确定。交联聚维酮可以为BASF生产的，其商品名为KOLLIDON，也可以为ISP生产的，供应商为亚什兰，其商品名为POLYPLASDONE TM。
根据本发明的实施方案，所述的聚醋酸乙烯酯(PVAc)为乙酸乙烯酯的均聚物，分子量(Mw)通常为约1×10 5至约1×10 6。
根据本发明的实施方案，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(Mw)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Union Carbide生产，其商品名为
Figure PCTCN2022081161-appb-000001
)。
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。
本发明所用试剂和原料均市售可得。
有益效果
本发明提供的拉考沙胺药物组合物具有良好的缓释性能，体外溶出过程中片形尺寸可迅速膨大，本发明所制备的拉考沙胺药物组合物具有良好的缓释性能，体外溶出过程中片形尺寸可迅速膨大，膨大后具备良好的刚性和弹性，具有显著的胃内滞留效果。本发明提供的拉考沙胺药物组合物，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达到12小时以上，24小时累积释放度可达80％以上。该药物组合物滞留在胃内时，可持续释放拉考沙胺。
本发明提供的拉考沙胺胃滞留片在体积为900ml的pH1.0盐酸溶液和/或pH4.5的醋酸盐缓冲液中，采用USP第二法转速50rpm进行溶出实验，24小时累积释放度可达80％以上。
本发明的制备工艺显著改善了原料药流动性不佳，堆密度过低所导致的压片过程中填充困难、片重不稳等问题，工艺稳定，工艺参数可调可控，有利于本品的生产放大，市场化前景好。
附图说明
图1为实施例2、5、6和7的样品于0.1N盐酸中的溶出曲线图；
图2为实施例1-7的样品于pH4.5的醋酸盐缓冲液中的溶出曲线图；
图3为实施例8中雄性比格犬口服给予实施例7和参照例1制剂后，拉考沙胺的平均药时曲线图(N＝3)；
图4为实施例8中雌性比格犬口服给予实施例7和参照例1制剂后，拉考沙胺的平均药时曲线图(N＝3)。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。此外，将本发明中实施例与参照例进行对比，进一步证明本发明在缓释和胃内滞留效果上的明显优势。
参照例1
一次性进口市售对照药拉考沙胺片(100mg，美国，UCB Pharma SA)备用。
实施例1
含有以下成分的基质片剂按如下方法生产，批量约70克。
成分 重量(mg) 占比(％)
拉考沙胺 200 18.18
海藻酸钠 386 35.09
交联聚维酮(Kollidon CL，BASF) 150 13.64
无水磷酸氢钙 129 11.73
硬脂酸镁(内加) 6 0.55
卡波姆(971 PNF，Lubrizol)(外加) 33 3.00
羟丙甲纤维素(K 4M，亚什兰)(外加) 190 17.27
硬脂酸镁(外加) 6 0.55
合计 1100 /
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药。
2)取步骤1得到的过筛后的拉考沙胺原料药，将海藻酸钠、拉考沙胺、交联聚维酮、无水磷酸氢钙置于混合罐中混合约20分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm；然后加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为0-20kg/cm 2，压轮转速为8HZ，进料速度为3HZ，整粒转速为12HZ，所选用二级整粒筛网孔径为0.8mm。
4)折算外加物料用量，加入外加羟丙甲纤维素、卡波姆后继续混合约15分钟；加入外加硬脂酸镁后继续混合5min。将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)。
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，pH4.5醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
时间(分钟) 累积释放度(％)
0 0
30 4.5
60 7.9
120 13.6
240 23.1
360 31.5
540 43.3
720 53.5
960 67.9
1200 83.7
1440 92.5
溶出后片形尺寸及刚性和弹性测试结果如下：
Figure PCTCN2022081161-appb-000002
实施例2
含有以下成分的基质片剂按如下方法生产，批量约160克。
成分 重量(mg) 占比(％)
拉考沙胺 200 20.00
聚醋酸乙烯酯聚维酮混合物(KSR) 248 24.80
交联聚维酮(Kollidon CL,BASF) 200 20.00
硬脂酸镁(内加) 6 0.60
山梨醇(外加) 200 20.00
卡波姆(971 PNF，Lubrizol)(外加) 60 6.00
羟丙甲纤维素(外加) 80 8.00
硬脂酸镁(外加) 6 0.60
合计 1000 /
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药。
2)取步骤1得到的过筛后的拉考沙胺原料药，将聚醋酸乙烯酯聚维酮混合物、拉考沙胺、交联聚维酮置于混合罐中混合约20分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm。然后加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为0-20kg/cm 2，压轮转速为8HZ，进料速度为2HZ，整粒转速为12HZ，所选用二级整粒筛网孔径为0.8mm。
4)折算外加物料用量，在步骤3得到的颗粒中加入羟丙甲纤维素、山梨醇和卡波姆后继续混合约15分钟。折算外加硬脂酸镁用量，加入外加硬质酸镁后继续混合约5分钟；将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)。
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，0.1N盐酸和pH4.5 醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
Figure PCTCN2022081161-appb-000003
溶出后片形尺寸及刚性和弹性测试结果如下：
Figure PCTCN2022081161-appb-000004
实施例3
含有以下成分的基质片剂按如下方法生产，批量约70克。
成分 重量(mg) 占比(％)
拉考沙胺 200 18.18
海藻酸钠 386 35.09
交联聚维酮(Kollidon CL，BASF) 183 16.64
羟丙甲纤维素(K 15M，亚什兰) 184 16.73
胶态二氧化硅 6 0.55
硬脂酸镁(内加) 6 0.55
无水磷酸氢钙(外加) 129 11.73
硬脂酸镁(外加) 6 0.55
合计 1100 /
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药；
2)将海藻酸钠、步骤1得到的拉考沙胺原料药、交联聚维酮、羟丙甲纤 维素、胶态二氧化硅置于混合罐中混合约20分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm。然后加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为0-20kg/cm 2，压轮转速度8HZ，进料速度为3HZ，整粒转速为12HZ，所选用二级整粒筛网孔径为0.8mm。
4)折算外加物料用量，向步骤3得到的颗粒中加入外加无水磷酸氢钙后继续混合约15分钟。折算外加硬脂酸镁用量，加入外加硬脂酸镁后继续混合约5分钟，将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，pH4.5醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
时间(分钟) 累积释放度(％)
0 0
30 4.6
60 7.8
120 13.1
240 22.6
360 31.6
540 45.0
720 59.0
960 75.8
1200 86.5
1440 92.5
溶出后片形尺寸及刚性和弹性测试结果如下：
Figure PCTCN2022081161-appb-000005
实施例4
含有以下成分的基质片剂按如下方法生产，批量约70克。
成分 重量(mg) 占比(％)
拉考沙胺 200 18.18
海藻酸钠 386 35.09
交联聚维酮(Kollidon CL,BASF) 183 16.64
聚氧乙烯(WSR COAGULANT，陶氏杜邦) 184 16.73
胶态二氧化硅 6 0.55
硬脂酸镁(内加) 6 0.55
无水磷酸氢钙(外加) 129 11.73
硬脂酸镁(外加) 6 0.55
合计 1100 /
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药。
2)将海藻酸钠、步骤1得到的过筛后的拉考沙胺原料药、交联聚维酮、聚氧乙烯、胶态二氧化硅置于混合罐中混合约20分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm。然后加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为0-20kg/cm 2，压轮转速度8HZ，进料速度为2HZ，整粒转速为12HZ，所选用二级整粒筛网孔径为0.8mm。
4)折算外加物料用量，向步骤3得到的颗粒中加入外加无水磷酸氢钙后继续混合约15分钟；加入外加硬脂酸镁后继续混合约5分钟，将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)。
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，pH4.5醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
时间(分钟) 累积释放度(％)
0 0
30 4.5
60 7.5
120 12.7
240 21.4
360 29.6
540 41.3
720 52.6
960 66.0
1200 77.5
1440 87.2
溶出后片形尺寸及刚性和弹性测试结果如下：
Figure PCTCN2022081161-appb-000006
实施例5
含有以下成分的基质片剂按如下方法生产，批量约330克。
成分 重量(mg) 占比(％)
拉考沙胺 200 18.18
海藻酸钠 280 25.45
交联聚维酮(Kollidon CL，BASF) 180 16.36
胶态二氧化硅 6 0.55
硬脂酸镁(内加) 6 0.55
羟丙甲纤维素(K 15M，亚什兰)(外加) 100 9.09
聚醋酸乙烯酯聚维酮混合物(KSR，外加) 202 18.36
二水磷酸氢钙(外加) 120 10.91
硬脂酸镁(外加) 6 0.55
合计 1100 /
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药。
2)将海藻酸钠、步骤1得到的过筛后的拉考沙胺原料药、交联聚维酮、胶态二氧化硅置于混合罐中混合约20分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm。然后加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为0-20kg/cm 2，压轮转速度8HZ，进料速度为2HZ，整粒转速为12HZ，所选用二级整粒筛网孔径为0.8mm。
4)折算外加物料用量，向步骤3得到的颗粒中加入外加羟丙甲纤维素、聚醋酸乙烯酯聚维酮混合物、二水磷酸氢钙后继续混合约15分钟；加入外加硬脂酸镁后继续混合约5分钟，将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)。
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，0.1N盐酸和pH4.5醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
Figure PCTCN2022081161-appb-000007
溶出后片形尺寸及刚性和弹性测试结果如下：
Figure PCTCN2022081161-appb-000008
实施例6
含有以下成分的基质片剂按如下方法生产，批量约300克。
成分 重量(mg) 占比(％)
拉考沙胺 200 20.00
聚醋酸乙烯酯聚维酮混合物(KSR) 248 24.80
交联聚维酮(Kollidon CL，BASF) 200 20.00
硬脂酸镁(内加) 6 0.60
山梨醇(外加) 150 15.00
海藻酸钠(外加) 50 5.00
卡波姆(971 PNF，Lubrizol)(外加) 60 6.00
羟丙甲纤维素(K 4M，亚什兰)(外加) 80 8.00
硬脂酸镁(外加) 6 0.60
合计 1000 /
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药。
2)将聚醋酸乙烯酯聚维酮混合物、步骤1得到的过筛后的拉考沙胺原料药、交联聚维酮置于混合罐中混合约20分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm。加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为0-20kg/cm 2，压轮转速度8HZ，进料速度为3HZ，整粒转速为12HZ，所选用二级整粒筛网孔径为0.8mm。
4)折算外加物料用量，向步骤3得到的颗粒中加入外加山梨醇、卡波姆、羟丙甲纤维素、海藻酸钠后继续混合约15分钟；加入外加硬脂酸镁后继续混合约5分钟，将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)。
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，0.1N盐酸和pH4.5醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
Figure PCTCN2022081161-appb-000009
溶出后片形尺寸及刚性和弹性测试结果如下：
Figure PCTCN2022081161-appb-000010
实施例7
处方组成与实施例5相同，放大批量至11000克进行生产。
工艺步骤：
1)将拉考沙胺原料药经30目筛网过筛去团，得到过筛后的拉考沙胺原料药；
2)将海藻酸钠、步骤1得到的过筛后的拉考沙胺原料药、交联聚维酮、胶态二氧化硅置于混合罐中混合约15分钟，得到预混物。
3)将步骤2得到的预混物经整粒机整粒，筛网孔径为2.0mm，整粒速度为200rpm；整粒后继续混合5min，加入内加硬脂酸镁，继续混合约5分钟后进行干法制粒，得到颗粒。干法制粒压轮压力约为2-5bar，侧压压力2-5bar，压轮转速度5-15rpm，进料速度为5-15rpm，整粒转速为176rpm，所选用二级整粒筛网孔径为1.0mm。
4)折算外加物料用量，向步骤3得到的颗粒中加入外加羟丙基纤维素、聚醋酸乙烯酯聚维酮混合物、二水磷酸氢钙后继续混合约15分钟。折算外加硬 脂酸镁用量，加入外加硬脂酸镁后继续混合约5分钟，将终混物料压制成片剂(22.0mm*10.9mm杏仁形浅弧型冲模)。
拉考沙胺体外释放采用USP(溶出设备第2法，900ml，0.1N盐酸和pH4.5醋酸盐缓冲液，50rpm)进行测量，体外释放结果如下：
Figure PCTCN2022081161-appb-000011
实施例8
本发明使用实施例7所得自制拉考沙胺药物组合物和参照例1的拉考沙胺片进行了比格犬口服给药药代动力学评价试验的比较研究。
试验共采用6只比格犬，雌雄各半，分成2组，每组3只/性别，第一周期第1组和第2组分别口服给予受试制剂1片(200mg/片，单次给药)和对照制剂2片(100mg/片，单次给药)，间隔至少一周冲洗期后，第二周期第1组和第2组分别口服给予对照制剂2片(100mg/片，一次一片，给药间隔8hr)和受试制剂1片(200mg/片，单次给药)。
第一周期第1组采样时间点为给药后0.5hr、1hr、2hr、3hr、4hr、5hr、6hr、8hr、12hr、16hr、24hr、36hr和48hr，一共13个时间点；第一周期第2组采样时间点为给药后0.25hr、0.5hr、1hr、1.5hr、2hr、2.5hr、3hr、4hr、6hr、8hr、12hr、24hr和48hr，一共13个时间点；
第二周期第1组采样时间点为给药后0.25hr、0.5hr、1hr、1.5hr、2hr、2.5hr、3hr、5hr、8hr(8hr采血后第二次给药)、8.25hr、8.5hr、9hr、9.5hr、10hr、10.5hr、11hr、13hr、16hr、24hr和48hr，一共20个时间点；第二周期第2组采样时间点为给药后0.5hr、1hr、2hr、3hr、4hr、5hr、6hr、8hr、12hr、16hr、24hr、36hr和48hr，一共13个时间点。
根据设定的时间点，前肢头静脉或其它合适静脉采集约500uL全血至含K2- EDTA的抗凝离心管中，离心前放于湿冰上保存。采样后2hr内离心样品(以3000g离心力在2-8℃下离心5min)获得血浆。血浆样品先置于干冰中冻存，然后放于-60℃冰箱长期保存直至样品分析。
血浆样品采集完成后，采用已验证的液相色谱串联质谱(LC-MS/MS)分析方法定量测定比格犬血浆中拉考沙胺的浓度。通过WinNonlin8.2软件，按非房室模型计算药动学参数。
用Microsoft Excel 2007对药动学参数T max、C max、AUC last、AUC INF、T 1/2和MRT INF进行配对双尾T-test(two tailed T-test)检验。检验结果显示：
雄性Beagle犬口服给予BCM-332受试1片(200mg/片，单次给药)及对照制剂2片(100mg/片，一次一片，给药间隔8hr)后，T max、AUC last、AUC INF和T 1/2没有显著性差异(P>0.05)，C max和MRT INF有统计学差异(P<0.05)；
雌性Beagle犬口服给予BCM-332受试1片(200mg/片，单次给药)及对照制剂2片(100mg/片，单次给药)后，T max、AUC last、AUC INF和T 1/2没有显著性差异(P>0.05)，C max有统计学差异(P<0.05)，MRT INF有显著统计学差异(P<0.01)。
实施例2、实施例5～实施例7于0.1N盐酸中的溶出曲线图见图1；实施例1～实施例7于pH4.5醋酸盐缓冲液中的溶出曲线图见图2；实施例8所述比格犬口服给药药代动力学评价试验结果见表1和表2；实施例8所述比格犬口服给药药代动力学评价试验血药浓度-时间曲线图见图3和图4；实施例8所述比格犬口服给药药代动力学评价试验药动学参数T-test检验结果如表3和表4所述。
表1雄性比格犬口服给予实施例7和参照例1制剂后拉考沙胺的平均药动学参数
(Mean±SD,N＝3)
Figure PCTCN2022081161-appb-000012
表2雌性比格犬口服给予实施例7和参照例1制剂后拉考沙胺的平均药动学参数
(Mean±SD,N＝3)
Figure PCTCN2022081161-appb-000013
表3雄性比格犬口服给予实施例7和参照例1制剂后药动学参数T-test检验结果
Figure PCTCN2022081161-appb-000014
*p<0.05,**p<0.01(two tailed T-test)
表4雌性比格犬口服给予实施例7和参照例1制剂后药动学参数T-test检验结果
Figure PCTCN2022081161-appb-000015
*p<0.05,**p<0.01(two tailed T-test)
测试期间，对比格犬状态的观察结果如下：
Figure PCTCN2022081161-appb-000016
由实施例1-8的测试结果可见，本发明的拉考沙胺药物组合物在体外和体内均表现出良好的缓释效果，体外溶出过程中能够迅速膨胀，膨胀后刚性和弹性良好，为本品提供了稳定良好的胃内滞留效果。并且，服用实施例7的所有比格犬全程无异常，说明本发明的组合物安全性更好。

Claims (10)

  1. 一种拉考沙胺药物组合物，其中所述的药物组合物为24小时缓慢释放药物；
    优选地，在USP方法(溶出设备第2法，900ml，0.1N盐酸，50rpm和/或溶出设备第2法，900ml，pH4.5的醋酸盐缓冲液，50rpm)条件下，所述的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％(优选不超过35％，进一步优选不超过30％)的药物活性成分；
    B)在6小时内溶出20％～70％(包括20％和70％两个点值，优选25％～60％，进一步优选30％～55％)的所述药物活性成分；
    C)在24小时内溶出不低于65％(优选不低于70％，进一步优选不低于80％)的所述药物活性成分；
    优选地，所述的拉考沙胺药物组合物的药物活性成分在1小时内溶出不超过30％，在6小时内溶出30％～55％，在24小时内溶出不低于80％；
    其中，所述的药物活性成分选自拉考沙胺、拉考沙胺药学上可接受的配合物、拉考沙胺药学上可接受的盐、拉考沙胺药学上可接受的溶剂化物和拉考沙胺药学上可接受的水合物，优选拉考沙胺或拉考沙胺药学上可接受的盐。
  2. 一种拉考沙胺药物组合物，包含以下组分：药物活性成分、骨架材料和溶胀材料；
    其中，所述的药物活性成分选自拉考沙胺、拉考沙胺药学上可接受的配合物、拉考沙胺药学上可接受的盐、拉考沙胺药学上可接受的溶剂化物和拉考沙胺药学上可接受的水合物；
    所述的骨架材料选自聚醋酸乙烯酯聚维酮混合物、海藻酸钠和羟丙甲基纤维素中的一种或多种；
    所述的溶胀材料为聚氧乙烯和/或卡波姆和/或海藻酸钠；
    优选地，所述的拉考沙胺药物组合物为拉考沙胺胃滞留组合物，优选拉考沙胺胃滞留片。
  3. 如权利要求2所述的药物组合物，其中：
    所述的药物活性成分的重量百分比优选1.0％～50.0％，进一步优选5.0％～40.0％；
    所述的溶胀材料的重量百分比优选1.0％～60.0％；
    例如，当所述的溶胀材料为聚氧乙烯时，所述的聚氧乙烯的重量百分比优选5.0％～60.0％，进一步优选10.0％～40.0％；当所述的溶胀材料为卡波姆时，所述的卡波姆的重量百分比优选1.0％～15.0％，进一步优选1.5％～10％；当所述的溶胀材料为海藻酸钠时，所述的海藻酸钠的重量百分比优选1.0％～50.0％，进一步优选1.0％～40.0％；
    优选地，所述的聚醋酸乙烯酯聚维酮混合物可以为含有聚乙酸乙烯酯(PVAc)和聚乙烯吡咯烷酮(PVP)的混合物，例如PVAc与PVP的重量比为80:19的混合物，优选BASF生产的商品名为KOLLIDON @SR的聚醋酸乙烯酯聚维酮混合物；
    所述的骨架材料重量百分比优选1.0％～60.0％；当所述的骨架材料为KSR时，所述的KSR的重量百分比优选5.0％～60.0％，进一步优选20.0％～50.0％；当所述的骨架材料为羟丙基甲基纤维素时，所述的羟丙基甲基纤维素的重量百分比优选1.0％～30.0％，进一步优选2.0％～20.0％；当所述的骨架材料为海藻酸钠时，所述的海藻酸钠的重量百分比优选1.0％～50.0％，进一步优选1.0％～40.0％。
    优选地，所述的骨架材料(例如海藻酸钠)可进一步与骨架强度调节剂共同使用；
    所述的骨架强度调节剂可以选自水溶性钙盐，例如磷酸氢钙和/或磷酸氢钙二水合物等；
    所述的骨架调节剂的重量百分比优选0％～30.0％，进一步优选0％～15.0％。
  4. 如权利要求2或3所述的药物组合物，其中所述的拉考沙胺药物组合物还包含选自崩解剂、稀释剂和润滑剂中的一种或多种；
    所述的崩解剂可以选自例如交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠、羧甲基纤维素钙和低取代羟丙基纤维素等中的一种或多种；所述的崩解剂的重量百分比优选0％～30.0％，进一步优选5％～30.0％；
    所述的稀释剂优选选自右旋糖、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、无水磷酸氢钙和环糊精及其衍生物中的一种或多种；所述的稀释剂的重量百分比优选0～40％；
    所述的润滑剂可以选自滑石、硬脂酸、硬脂酸金属盐(如硬脂酸镁)、硬脂酸酯(如硬脂酸甘油酯)、胶态二氧化硅、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或多种；所述的润滑剂的重量百分比优选0～3.0％，进一步优选0.5％～2.0％。
  5. 如权利要求2-4任一项所述的药物组合物，其中所述的拉考沙胺药物组合物优选包含以下组分：药物活性成分、骨架材料、骨架强度调节剂(任选存在)、溶胀材料、崩解剂和润滑剂；
    其中，所述的药物活性成分选自拉考沙胺、拉考沙胺药学上可接受的配合物、拉考沙胺药学上可接受盐、拉考沙胺药学上可接受溶剂化物和拉考沙胺药学上可接受水合物；
    所述的骨架材料选自聚醋酸乙烯酯聚维酮混合物、海藻酸钠和羟丙基甲基纤维素中的一种或多种；
    所述的溶胀材料为聚氧乙烯和/或卡波姆和/或海藻酸钠。
  6. 如权利要求2-5任一项所述的药物组合物，其中所述药物组合物包含以下组分一、组分二、组分三、组分四、组分五或组分六，或分别由下述组分组成：
    组分一：拉考沙胺、海藻酸钠、交联聚维酮、无水磷酸氢钙、硬脂酸镁、卡波姆、羟丙甲纤维素；
    组分二：拉考沙胺、聚醋酸乙烯酯聚维酮混合物、交联聚维酮、硬脂酸镁、山梨醇、卡波姆、羟丙甲纤维素；
    组分三：拉考沙胺、海藻酸钠、交联聚维酮、羟丙甲纤维素、胶态二氧化硅、硬脂酸镁、无水磷酸氢钙；
    组分四：拉考沙胺、海藻酸钠、交联聚维酮、聚氧乙烯、胶态二氧化硅、硬脂酸镁、无水磷酸氢钙；
    组分五：拉考沙胺、海藻酸钠、交联聚维酮、胶态二氧化硅、硬脂酸镁、羟丙甲纤维素、聚醋酸乙烯酯聚维酮混合物、二水磷酸氢钙；
    组分六：拉考沙胺、聚醋酸乙烯酯聚维酮混合物、交联聚维酮、硬脂酸镁、 山梨醇、海藻酸钠、卡波姆、羟丙甲纤维素。
    优选地，所述药物组合物还进一步优选以下任一处方：
    处方一：18.18％拉考沙胺、35.09％海藻酸钠、13.64％交联聚维酮(Kollidon CL，BASF)、11.73％无水磷酸氢钙、1.10％硬脂酸镁、3.00％卡波姆(971 PNF，Lubrizol)、17.27％羟丙甲纤维素(K 4M，亚什兰)；
    处方二：20.00％拉考沙胺、24.80％聚醋酸乙烯酯聚维酮混合物、20.00％交联聚维酮(Kollidon CL，BASF)、1.20％硬脂酸镁、20.00％山梨醇、6.00％卡波姆(971 PNF，Lubrizol)、8.00％羟丙甲纤维素(K 4M，亚什兰)；
    处方三：18.18％拉考沙胺、35.09％海藻酸钠、16.64％交联聚维酮(Kollidon CL，BASF)、16.73％羟丙甲纤维素(K 15M，亚什兰)、0.55％胶态二氧化硅、1.10％硬脂酸镁、11.73％无水磷酸氢钙；
    处方四：18.18％拉考沙胺、35.09％海藻酸钠、16.64％交联聚维酮(Kollidon CL，BASF)、16.73％聚氧乙烯(WSR COAGULANT,陶氏杜邦)、0.55％胶态二氧化硅、1.10％硬脂酸镁、11.73％无水磷酸氢钙；
    处方五：18.18％拉考沙胺、25.45％海藻酸钠、16.36％交联聚维酮(Kollidon CL，BASF)、0.55％胶态二氧化硅、1.10％硬脂酸镁、9.09％羟丙甲纤维素(K 15M，亚什兰)、18.36％聚醋酸乙烯酯聚维酮混合物、10.91％二水磷酸氢钙；
    处方六：20.00％拉考沙胺、24.80％聚醋酸乙烯酯聚维酮混合物、20.00％交联聚维酮(Kollidon CL，BASF)、1.20％硬脂酸镁、15.00％山梨醇、5.00％海藻酸钠、6.00％卡波姆(971 PNF，Lubrizol)、8.00％羟丙甲纤维素(K 4M，亚什兰)。
  7. 如权利要求1-6任一项所述的药物组合物的制备方法，包括干法制粒工艺。
  8. 权利要求1-6任一项所述的药物组合物在制备药物，优选用于治疗和/或预防急性和慢性疼痛的药物中的用途；
    优选地，所述的“急性和慢性疼痛”为非神经性炎性疼痛，包括慢性炎性疼痛，例如类风湿性关节炎疼痛和/或继发性骨关节炎疼痛。
  9. 根据权利要求8所述的用途，其中所述的“慢性疼痛”是指疼痛延续一段时间，例如3-6个月以上，但是下述特征性体征在这段时间前后存在，可出现植物神经功能紊乱体征，例如倦怠、睡眠紊乱、食欲降低、味觉丧失、体重减轻、性欲降低和/或便秘。
  10. 一种拉考沙胺胃滞留片，其包含如权利要求1-6任一项所述的药物组合物；
    优选地，所述的拉考沙胺胃滞留片的规格选自100mg至400mg。
PCT/CN2022/081161 2021-03-17 2022-03-16 一种拉考沙胺药物组合物、其制备方法及应用 WO2022194198A1 (zh)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080031945A1 (en) * 2006-08-01 2008-02-07 Wolfram Eisenreich Gastro retentive delivery system
CN101330907A (zh) * 2005-11-02 2008-12-24 辉瑞产品公司 含普瑞巴林、基质形成剂和溶胀剂并适于每日口服一次的固体药物组合物
US20120219631A1 (en) * 2009-11-03 2012-08-30 Lupin Limited Modified release formulation of lacosamide
CN102670544A (zh) * 2012-06-05 2012-09-19 石家庄四药有限公司 一种拉科酰胺缓释片及其制备方法
CN103561727A (zh) * 2010-12-02 2014-02-05 优时比制药有限公司 每日给药1次的拉科酰胺制剂
EP2801351A1 (en) * 2013-05-08 2014-11-12 Sanovel Ilac Sanayi ve Ticaret A.S. Modified Release Formulations of Lacosamide
WO2018062955A1 (ko) * 2016-09-29 2018-04-05 에스케이케미칼(주) 라코사미드 서방성 제제
CN111818913A (zh) * 2018-02-14 2020-10-23 丸仁制药株式会社 含有拉科酰胺的药剂学缓释性组合物
CN111840239A (zh) * 2014-10-24 2020-10-30 江苏恒瑞医药股份有限公司 一种普瑞巴林缓释制剂

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101330907A (zh) * 2005-11-02 2008-12-24 辉瑞产品公司 含普瑞巴林、基质形成剂和溶胀剂并适于每日口服一次的固体药物组合物
US20080031945A1 (en) * 2006-08-01 2008-02-07 Wolfram Eisenreich Gastro retentive delivery system
US20120219631A1 (en) * 2009-11-03 2012-08-30 Lupin Limited Modified release formulation of lacosamide
CN103561727A (zh) * 2010-12-02 2014-02-05 优时比制药有限公司 每日给药1次的拉科酰胺制剂
CN102670544A (zh) * 2012-06-05 2012-09-19 石家庄四药有限公司 一种拉科酰胺缓释片及其制备方法
EP2801351A1 (en) * 2013-05-08 2014-11-12 Sanovel Ilac Sanayi ve Ticaret A.S. Modified Release Formulations of Lacosamide
CN111840239A (zh) * 2014-10-24 2020-10-30 江苏恒瑞医药股份有限公司 一种普瑞巴林缓释制剂
WO2018062955A1 (ko) * 2016-09-29 2018-04-05 에스케이케미칼(주) 라코사미드 서방성 제제
CN111818913A (zh) * 2018-02-14 2020-10-23 丸仁制药株式会社 含有拉科酰胺的药剂学缓释性组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AHN JAE SOON, KIM KANG MIN, NAM DAE SIK, KANG KYOUNG UN, CHOI PETER S., JEONG SEO YOUNG: "Preparation of Lacosamide Sustained-release Tablets and Their Pharmacokinetics in Beagles and Mini-pigs", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, KOREAN CHEMICAL SOCIETY, KR, vol. 35, no. 2, 20 February 2014 (2014-02-20), KR , pages 557 - 561, XP055967496, ISSN: 0253-2964, DOI: 10.5012/bkcs.2014.35.2.557 *

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