WO2022083636A1 - 盐酸决奈达隆药物组合物、其制备方法及应用 - Google Patents

盐酸决奈达隆药物组合物、其制备方法及应用 Download PDF

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WO2022083636A1
WO2022083636A1 PCT/CN2021/124961 CN2021124961W WO2022083636A1 WO 2022083636 A1 WO2022083636 A1 WO 2022083636A1 CN 2021124961 W CN2021124961 W CN 2021124961W WO 2022083636 A1 WO2022083636 A1 WO 2022083636A1
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cyclodextrin
dronedarone hydrochloride
hydrochloride
inclusion
dronedarone
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PCT/CN2021/124961
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English (en)
French (fr)
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郭桢
覃伟
关瑷
陈丽
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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Publication of WO2022083636A1 publication Critical patent/WO2022083636A1/zh

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • 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
    • A61K9/205—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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to a pharmaceutical composition of dronedarone hydrochloride, its preparation method and application, in particular to the inclusion compound of dronedarone hydrochloride, its preparation method and application.
  • Dronedarone hydrochloride N-(2-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)benzofuran-5-yl)methanesulfonic acid
  • Amide hydrochloride molecular formula: C 31 H 44 N 2 O 5 S HCl, molecular weight: 593.2
  • the chemical structural formula of nedarone is as follows:
  • Dronedarone hydrochloride is an antiarrhythmic drug that is practically insoluble in water and readily soluble in dichloromethane and methanol.
  • the pH value of the human body from the stomach to the intestinal tract is gradually increased, so that although it is dissolved in the stomach after taking it, as the stomach empties into the intestinal tract, the dissolved dronedarone hydrochloride is precipitated, reducing its bioavailability. Spend.
  • the absolute bioavailability of dronedarone in the absence of food is low, approximately 4%, due to systemic first-pass metabolism; the absolute bioavailability of dronedarone when administered with a high-fat meal degree will increase to about 15%.
  • MULTAQ trade name for dronedarone
  • MULTAQ increases the risk of death, stroke, and heart failure; recommended dose for adults is 1 tablet (400 mg), 2 times a day. Take one tablet each with breakfast and dinner.
  • the present invention provides a dronedarone hydrochloride inclusion compound, which includes dronedarone hydrochloride and cyclodextrin, and the cyclodextrin does not include unsubstituted ⁇ -cyclodextrin.
  • the cyclodextrin may be selected from one of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin one or more.
  • the cyclodextrin is preferably hydroxypropyl- ⁇ -cyclodextrin and/or sulfobutyl- ⁇ -cyclodextrin.
  • the molar ratio of the cyclodextrin to the dronedarone hydrochloride is preferably 0.1-100, more preferably 0.2-10, still more preferably 0.3-5, such as 1, 1.7 or 2 , which means that the molar ratio is (0.1-100):1, more preferably (0.2-10):1, still more preferably (0.3-5):1, such as 1:1, 1.7:1 or 2:1.
  • the dronedarone hydrochloride inclusion complex preferably consists of dronedarone hydrochloride and cyclodextrin, and the cyclodextrin does not include unsubstituted ⁇ -cyclodextrin .
  • the cyclodextrin is preferably one of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin or variety.
  • the present invention also provides a method for preparing the dronedarone hydrochloride inclusion complex, which comprises the following steps: including dronedarone hydrochloride and cyclodextrin to obtain the dronedarone hydrochloride inclusion complex thing.
  • the inclusion of dronedarone hydrochloride and cyclodextrin is carried out in a solvent; preferably, the inclusion of dronedarone hydrochloride and an aqueous solution of cyclodextrin is carried out.
  • Described dronedarone hydrochloride inclusion complex can be carried out using known inclusion conditions in the art, preferably one or more of the following inclusion conditions in the present invention:
  • described solvent is preferably water or the mixed solvent of water and organic solvent
  • the organic solvent is preferably an alcohol solvent and/or a halogenated hydrocarbon solvent.
  • the alcohol solvent is preferably methanol and/or ethanol;
  • the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent;
  • the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the "mixed solvent of water and organic solvent” is preferably a mixed solvent of water and "one or more of methanol, ethanol and dichloromethane".
  • the mass concentration of the cyclodextrin aqueous solution is preferably 1% to 50%, more preferably 5% to 20%, such as 9%, 18%, 20% or 30%, wherein the mass concentration refers to the percentage of the mass of cyclodextrin to the total mass of the aqueous solution of cyclodextrin.
  • the mass-volume ratio of the dronedarone hydrochloride to the solvent is preferably 0.001mL/mg ⁇ 10mL/mg, more preferably 0.005mL/mg ⁇ 6 mg/mL, such as 0.03 mL/mg.
  • the volume-to-mass ratio refers to the ratio of the volume of the organic solvent to the mass of dronedarone hydrochloride.
  • the temperature of the inclusion is preferably 20°C to 80°C, more preferably 40°C to 70°C, for example, 60°C to 70°C.
  • the inclusion time is preferably 0.5 hours to 20 hours, more preferably 1 hour to 10 hours or 3 hours to 10 hours, for example, 2 hours to 5 hours hours or 5 to 7 hours.
  • the mixing is preferably stirring and mixing.
  • the preparation method of the dronedarone hydrochloride inclusion compound preferably adopts the following post-processing steps: dissolving dronedarone hydrochloride in an aqueous solution of cyclodextrin, carrying out inclusion, and after the inclusion is completed, cooling and filtering to obtain the obtained solution.
  • the described solution of dronedarone hydrochloride inclusion complex preferably adopts the following post-processing steps: dissolving dronedarone hydrochloride in an aqueous solution of cyclodextrin, carrying out inclusion, and after the inclusion is completed, cooling and filtering to obtain the obtained solution.
  • the solution of the dronedarone hydrochloride inclusion complex is removed from the solvent and dried to obtain the dronedarone hydrochloride inclusion complex.
  • the cooling temperature is preferably 10°C to 30°C, more preferably 20°C to 25°C.
  • the filtration is preferably performed by using a filter element.
  • the pore size of the filter element is preferably 0.22 microns to 0.8 microns, more preferably 0.45 microns to 0.8 microns.
  • the drying is preferably one or more of freeze drying, drying under reduced pressure, normal pressure drying and spray drying, more preferably freeze drying and/or Spray dry.
  • the freeze-drying can be vacuum freeze-drying.
  • the preparation method of dronedarone hydrochloride clathrate described in the present invention further preferably comprises the following concrete steps:
  • step b) adding dronedarone hydrochloride or a solution formed by dronedarone hydrochloride and a solvent to the cyclodextrin aqueous solution configured in step a) to obtain a dronedarone hydrochloride-cyclodextrin solution;
  • step c) including the dronedarone hydrochloride-cyclodextrin solution obtained in step b) to obtain the inclusion solution of dronedarone hydrochloride-cyclodextrin;
  • step c) Cooling, filtering, removing the solvent and drying the inclusion solution of dronedarone hydrochloride-cyclodextrin prepared in step c) to obtain the inclusion complex of dronedarone hydrochloride.
  • the temperature of the inclusion is preferably 20°C to 80°C, more preferably 40°C to 70°C, for example, 60°C.
  • the time of the inclusion is preferably 0.5 hours to 20 hours, more preferably 3 hours.
  • the cooling temperature is preferably 10°C to 30°C, more preferably 20°C to 25°C.
  • the filtration is preferably performed using a filter membrane.
  • the pore size of the filter membrane is preferably 0.22 microns to 0.8 microns, more preferably 0.45 microns to 0.8 microns.
  • the drying method is preferably one or more of freeze drying, reduced pressure drying, normal pressure drying and spray drying, more preferably freeze drying and/or spray drying.
  • the present invention also provides the application of the dronedarone hydrochloride inclusion complex in preparing a dronedarone hydrochloride drug, such as a pharmaceutical preparation.
  • a dronedarone hydrochloride drug such as a pharmaceutical preparation.
  • the medicament or pharmaceutical formulation is useful for the prevention and/or treatment of cardiac diseases or disorders, such as cardiac arrhythmias.
  • the dronedarone hydrochloride pharmaceutical preparation includes a dronedarone hydrochloride inclusion complex and pharmaceutically acceptable auxiliary materials.
  • pharmaceutically acceptable adjuvants include but are not limited to carriers or excipients, such as selected from fillers, disintegrants, binders, lubricants, coating agents, excipients, flavoring agents and Penetration enhancer.
  • the fillers include but are not limited to lactose, microcrystalline cellulose, corn starch, calcium hydrogen phosphate, mannitol, glucose, sucrose, pregelatinized starch, mannitol starch mixture, starch lactose mixture , silicified microcrystalline cellulose and dextran; preferably one or more of lactose, microcrystalline cellulose and pregelatinized starch.
  • the disintegrants include but are not limited to dry starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium and effervescent Disintegrant; preferably one or more of low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium.
  • the binder includes but is not limited to povidone (also known as polyvinylpyrrolidone, PVP, the polyvinylpyrrolidone can be PVP K30 or PVP VA64), methyl cellulose, hydroxyl One or more of propyl methylcellulose, hydroxypropyl cellulose and sodium alginate; preferably one or more of PVP K30, PVP VA64 and hydroxypropyl methylcellulose.
  • povidone also known as polyvinylpyrrolidone, PVP
  • PVP polyvinylpyrrolidone
  • the polyvinylpyrrolidone can be PVP K30 or PVP VA64
  • methyl cellulose hydroxyl
  • propyl methylcellulose hydroxypropyl cellulose
  • sodium alginate preferably one or more of PVP K30, PVP VA64 and hydroxypropyl methylcellulose.
  • the lubricants include, but are not limited to, stearic acid-based lubricants, polyethylene glycol-based lubricants, magnesium lauryl sulfate, talc, silicon dioxide, hydrogenated castor oil and behenic acid Glycerides; preferably one or more of silicon dioxide, hydrogenated castor oil and glyceryl behenate.
  • stearic acid lubricants such as one or more of magnesium stearate, calcium stearate, stearic acid and sodium stearyl fumarate; described polyethylene glycol lubricants such as poly Ethylene Glycol 4000 and/or Polyethylene Glycol 6000.
  • the coating agent is selected from ordinary gastric-soluble coating powder and enteric-coated coating powder.
  • Gastric soluble coating powder includes Opadry HPMC type matrix and/or PVA moisture-proof type; enteric coating powder includes acrylic resin polymer (such as acrylic resin No. I, II or III), phthalic acid Cellulose acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl alcohol phthalate (PVAP) and cellulose acetate trimellitate (CAT), etc.; preferably Opadry HPMC type, One or more of PVA moisture-proof type, acrylic resin and hydroxypropyl methylcellulose phthalate.
  • CAP phthalic acid Cellulose acetate
  • HPPMCP hydroxypropyl methylcellulose phthalate
  • PVAP polyvinyl alcohol phthalate
  • CAT cellulose acetate trimellitate
  • the excipients include, but are not limited to, pullulan.
  • the bulking agent includes, but is not limited to, dextran.
  • the flavoring agents include, but are not limited to, one or more of steviol glycosides, aspartame and citric acid.
  • the penetration enhancer includes, but is not limited to, Tween.
  • the Tween can be Tween 80.
  • the pharmaceutical preparations of dronedarone hydrochloride include but are not limited to tablets (such as sublingual tablets, sustained-release tablets, osmotic pump tablets, orally disintegrating tablets), granules, capsules, and pellets , oral liquid, injection and lyophilized powder for injection, etc., preferably tablet or capsule.
  • the strength of the tablet ie the content of active ingredient therein
  • the strength of the tablet may be 1-100 mg, eg 10-30 mg, such as 18 mg, 20 mg or 25 mg.
  • the weight percent content of the nonedarone hydrochloride may be 5-20%, such as 10-14%, such as 10%, 11%, 12% , 13% or 14%.
  • the weight percentage of the cyclodextrin may be 40-90%, such as 50-85%, such as 50%, 51%, 52%, 53% %, 54%, 55%, 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, or 85%.
  • the present invention also provides the preparation process of the dronedarone hydrochloride pharmaceutical preparation, including direct mixing and tableting process, wet granulation process, dry granulation process and the like.
  • the solution of the clathrate complex of dronedarone hydrochloride or the composition comprising the solution and pharmaceutically acceptable excipients can also be prepared into a freeze-dried sublingual tablet through a vacuum freeze-drying technique.
  • the present invention also provides a pharmaceutical formulation (preferably a sublingual tablet) selected from any of the following formulations:
  • Prescription 1 10.53% nonedarone hydrochloride, 52.21% hydroxypropyl-beta cyclodextrin, 1.75% pullulan, 35.09% dextran, 0.26% steviol glycosides and 0.02% aspartame;
  • Formulation 2 10.53% nonedarone hydrochloride, 52.21% hydroxypropyl-beta cyclodextrin, 1.75% pullulan, 35.09% dextran, 0.11% Tween 80, 0.26% steviol glycosides and 0.02% aspartame ;
  • Formulation 3 13.07% nonedarone hydrochloride, 80.96% sulfobutyl-beta cyclodextrin, 2.18% pullulan, 2.18% steviol glycosides, 1.45% citric acid, 0.11 Tween 80 and 0.04% aspar Tan;
  • Formulation 4 13.07% Denedarone Hydrochloride, 80.96% Sulfobutyl-Beta Cyclodextrin, 2.18% Pullulan, 2.18% Steviol Glycosides, 1.45% Citric Acid, 0.11 Tween 80, and 0.04% Aspar Tan.
  • the present invention also provides the application of the dronedarone hydrochloride pharmaceutical preparation in the preparation of a drug for treating arrhythmia.
  • the present invention also provides methods of preventing and/or treating cardiac diseases, such as cardiac arrhythmias, comprising administering to a patient an effective amount, such as a therapeutically effective amount, of said dronedarone hydrochloride clathrate, dronedarone hydrochloride clathrate solution or the pharmaceutical preparation.
  • a patient is a human.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature ranging from 10°C to 35°C, such as 10°C, 15°C, 20°C, 25°C, 30°C, and 35°C.
  • the dronedarone hydrochloride inclusion complex, its solution and the pharmaceutical preparation of the present invention have good stability, greatly improve the solubility in water, the solubility of dronedarone hydrochloride can be increased by about 90 times at the highest, and the bioavailability is high. Suitable for industrial production.
  • the preparation operation of the dronedarone hydrochloride inclusion compound of the invention is simple, and the prepared dronedarone hydrochloride inclusion compound is easy to prepare a preparation.
  • the in vitro solubility of the dronedarone hydrochloride preparation of the invention is greatly improved, the precipitation in the high pH environment of the human body is avoided, the bioavailability of the product is improved, and the preparation is suitable for industrial production.
  • the sublingual tablet prepared by the invention improves the dissolution rate in pH 6.8 phosphate buffer, can avoid the first-pass effect of the liver and the destruction and degradation of the gastrointestinal tract, is conducive to maintaining the drug effect and improves the drug
  • the bioavailability of the drug is suitable for patients with dysphagia, and at the same time, the dosage can be reduced, and the toxic and side effects of the drug on the gastrointestinal tract and liver can be alleviated.
  • Fig. 1 shows the X-RPD spectrum of the dronedarone hydrochloride-cyclodextrin inclusion complex prepared in Example 5;
  • Figure 2 shows the average plasma drug concentration-time curve of Beagle dogs after a single oral dose of tablet A-test article (specification: 100 mg/tablet) and reference substance MULTAQ (specification: 400 mg/tablet); wherein, Represents the drug-time curve of blood drug concentration in vivo after a single oral administration of 100 mg tablet A-test article to Beagle dogs, Represents the drug-time curve of blood drug concentration in Beagle dogs after a single oral dose of 400 mg of MULTAQ;
  • Figure 3 shows the mean plasma drug concentration-time logarithmic graph after a single oral dose of tablet A-test article and reference substance MULTAQ in Beagle dogs; in Figure 3 Represents the mean plasma drug concentration-time logarithmic plot of single oral tablet A-test article in Beagle dogs, Represents the mean plasma drug concentration-time logarithmic plot of Beagle dogs after a single oral dose of the tablet reference substance MULTAQ;
  • Figure 4 shows the dissolution profile of dronedarone hydrochloride tablets in pH4.5 dissolution medium; Represents the dissolution profile of tablet A-test article-1 (20mg), Represents the dissolution profile of tablet A-test article-2 (20mg), Represents the dissolution profile of tablet A-test article-3 (20mg), represents the dissolution profile of RLD;
  • Figure 5 shows the dissolution curve of dronedarone hydrochloride tablets in pH 6.8 dissolution medium, wherein represents the dissolution profile of RLD, Represents the dissolution profile of A-test article-1 (20mg), Represents the dissolution profile of A-test article-2 (20mg), Represents the dissolution profile of A-test article-3 (20mg);
  • Fig. 6 shows the dissolution profiles of reference preparation and dronedarone hydrochloride sublingual tablets prepared in Examples 10-13, Represents the dissolution profile of the reference preparation; Represents the dissolution profile of the penedarone sublingual tablet prepared in Example 10; Represents the dissolution profile of the penedarone sublingual tablet prepared in Example 11; Represents the dissolution profile of the penedarone sublingual tablet prepared in Example 12; The dissolution profile of the penedarone sublingual tablet prepared in Example 13 is shown.
  • Dronedarone hydrochloride is added to the 20% sulfobutyl- ⁇ -cyclodextrin aqueous solution (the mass percentage refers to the mass of sulfobutyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin).
  • ⁇ -cyclodextrin aqueous solution mass percentage in a magnetic stirrer, 60 ° C (water bath) inclusion for 7 hours, let cool to room temperature (20 ° C ⁇ 25 ° C), filter, rotary evaporation, freeze-drying, to obtain tetrahydrochloride.
  • Dronedarone hydrochloride-cyclodextrin inclusion complex X-powder diffraction (X-RPD) showed that dronedarone hydrochloride had no characteristic peak after inclusion by sulfobutyl- ⁇ -cyclodextrin, forming amorphous, Thus, the solubility of dronedarone hydrochloride is greatly improved, and the X-RPD spectrum of the dronedarone hydrochloride-cyclodextrin inclusion complex prepared in Example 5 is shown in Figure 1 .
  • the dronedarone hydrochloride inclusion compound prepared in Example 5 was compressed into tablets, and the obtained tablet A-testing substance (specification: 100 mg/tablet) and reference preparation MULTAQ-reference substance (specification: 400 mg/tablet, competition Luo Fei), for oral administration to Beagle dogs before meals, 1 tablet at a time, single administration. After administration, venous blood was drawn from the limbs, and two-cycle cross-pharmacokinetic experiments were carried out to investigate the in vivo bioavailability.
  • Direct tableting process Weigh each raw and auxiliary material according to the prescription, mix colloidal silicon dioxide and dronedarone hydrochloride inclusion complex and sieve, and sequentially add pregelatinized starch, lactose, and crospovidone and mix for 20 minutes. Add hydrogenated castor oil and mix for 5 minutes. Die and compress, and coat to obtain Tablet A-Test Sample-1.
  • Dry granulation process Weigh each raw and auxiliary material according to the prescription amount, mix colloidal silicon dioxide and dronedarone hydrochloride inclusion complex and sieve, and sequentially add pregelatinized starch, lactose, and 1/2 of the prescription amount of crospovidin The ketones were mixed for 20 minutes, then 1/2 the recipe amount of hydrogenated castor oil was added and mixed for 5 minutes, the mixture was granulated by a dry granulator, and 1/2 recipe amount of crospovidone and 1/2 recipe amount of hydrogenated castor oil were added to the granules. , mix for 10 minutes, use Die and compress, and coat to obtain Tablet A-Test Sample-2.
  • Wet granulation process Weigh each raw and auxiliary material according to the recipe quantity, mix colloidal silicon dioxide and dronedarone hydrochloride inclusion complex and sieve, and sequentially add pregelatinized starch, lactose, and 1/2 recipe amount of crospovidin ketone, mix for 10 minutes in a wet granulator, add purified water or 30%-50% ethanol solution for granulation, dry the wet granules in an oven or fluidized bed, add 1/2 prescription amount of crospovidone and Hydrogenated castor oil, mixed for 10 minutes, with Die and compress, and coat to obtain Tablet A-Test Sample-3.
  • Example 9 Dissolution test of samples of Examples 6-8
  • the samples (specification: 20 mg) and the reference preparation (specification: 400 mg) of Examples 6, 7 and 8 were dissolved in 900 ml of pH4.5 acetate buffer solution and pH6.8 phosphate buffer solution, and the slurry method was used for dissolution testing, and pH4.5 dissolution medium
  • the dissolution curve data of Dronedarone Hydrochloride Tablets in pH 6.8 dissolution medium is shown in Table 4; the dissolution curve data of Dronedarone Hydrochloride Tablets in pH 4.5 dissolution medium is shown in Figure 4 4;
  • the dissolution curve of dronedarone hydrochloride tablets in pH 6.8 dissolution medium is shown in Figure 5.
  • Example 10 Sublingual tablet formulation 1
  • Raw material name effect Single tablet (mg) percentage% neveredarone hydrochloride API 20.00 10.53 Hydroxypropyl-beta cyclodextrin Solubilizers 99.19 52.21 Pullulan excipient 3.33 1.75 Dextran filler 66.67 35.09 steviol glycosides flavoring agent 0.50 0.26 aspartame flavoring agent 0.03 0.02 Tablet weight mg / 190 100.00
  • the API and cyclodextrin are included to make them completely included (the solution is clear and transparent), cooled to room temperature and filtered, and then other auxiliary materials such as excipients, fillers, flavoring agents, penetration enhancers and other auxiliary materials are added in sequence for stirring.
  • auxiliary materials such as excipients, fillers, flavoring agents, penetration enhancers and other auxiliary materials are added in sequence for stirring.
  • make it completely dissolved (the solution is clear and transparent), quantitatively drop it into a blister mold, place it in a freeze-drying machine, and adjust suitable freeze-drying parameters to freeze-dry it to obtain a sublingual tablet (the same below).
  • Example 11 Sublingual tablet formulation 2
  • Raw material name effect Single tablet (mg) percentage% neveredarone hydrochloride API 20.00 10.53 Hydroxypropyl-beta cyclodextrin Solubilizers 99.19 52.21 Pullulan excipient 3.33 1.75 Dextran filler 66.67 35.09 Tween 80 Penetration enhancer 0.20 0.11 steviol glycosides flavoring agent 0.50 0.26
  • Example 12 Sublingual tablet formulation 3
  • Raw material name effect Single tablet (mg) percentage% neveredarone hydrochloride API 18.00 13.07 Sulfobutyl-beta cyclodextrin sodium Solubilizers 111.48 80.96 Pullulan excipient 3.00 2.18 steviol glycosides filler 3.00 2.18 aspartame flavoring agent 0.06 0.04 Citric acid flavoring agent 2.00 1.45 Tween 80 Penetration enhancer 0.15 0.11 Tablet weight mg / 138 100
  • Example 13 Sublingual tablet formulation 4
  • Raw material name effect Single tablet (mg) percentage% neveredarone hydrochloride API 25.00 13.07 Sulfobutyl-beta cyclodextrin sodium Solubilizers 154.82 80.96 Pullulan excipient 4.17 2.18 steviol glycosides flavoring agent 4.17 2.18 aspartame flavoring agent 0.08 0.04
  • Citric acid flavoring agent 2.78 1.45 Tween 80 Penetration enhancer 0.21 0.11 Tablet weight mg / 191 100.00
  • Example 14 Dissolution testing of samples of Examples 10-13
  • Example 10-13 In pH 6.8 phosphate buffer, the dissolution profiles of Examples 10-13 are shown in Figure 6; in pH 6.8 phosphate buffer, the dissolution data of Examples 10-13 are shown in Table 5.
  • the reference preparation is Genedarone Hydrochloride Tablets (400 mg) produced by Sanofi.
  • Dronedarone hydrochloride is slowly added to the 20% sulfobutyl- ⁇ -cyclodextrin aqueous solution (the mass percentage refers to the mass of sulfobutyl- ⁇ -cyclodextrin and the sulfobutyl group).
  • the mass percentage refers to the mass of sulfobutyl- ⁇ -cyclodextrin and the sulfobutyl group.
  • - ⁇ -cyclodextrin aqueous solution mass percentage in a magnetic stirrer, 60 °C (water bath) inclusion for 6 hours, let cool to room temperature (20 °C ⁇ 25 °C), filter, spray-dry to obtain droneda hydrochloride 375 g of sulfonated butyl- ⁇ -cyclodextrin inclusion compound, the yield is about 83%.
  • Example 16 Solubility testing of samples of Examples 10-13 and 15
  • Example 10-13 and 15 were respectively put into 15 mL of 37 °C water, the sublingual tablet immediately disperses, and a little particle sinks, which can be completely dissolved within 5min, which meets the requirements of the sublingual tablet.
  • the reference preparation cannot be dissolved in water for 24 hours.

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Abstract

一种盐酸决奈达隆包合物、制备方法及应用。盐酸决奈达隆包合物包括盐酸决奈达隆和环糊精，所述的环糊精不包括未带取代基的β-环糊精，盐酸决奈达隆包合物溶液稳定性好，在水中的溶解度大大提高，比盐酸决奈达隆的溶解度提高了90倍左右，生物利用度高，适合于工业化生产。

Description

盐酸决奈达隆药物组合物、其制备方法及应用
本申请要求享有下列在先申请的优先权权益：2020年10月20日向中国国家知识产权局提交的申请号为202011121736.6，名称为“盐酸决奈达隆包合物、制备方法及应用”的中国发明专利申请，和2021年8月4日向中国国家知识产权局提交的申请号为202110889937.9，名称为“盐酸决奈达隆药物组合物、其制备方法及应用”的中国发明专利申请。上述在先申请的全文通过引用的方式并入本文。
技术领域
本发明涉及一种盐酸决奈达隆药物组合物、其制备方法及应用，尤其是盐酸决奈达隆包合物、制备方法及应用。
背景技术
盐酸决奈达隆(Dronedarone hydrochloride)化学名为N-(2-丁基-3-(4-(3-二丁基氨基丙氧基)苯甲酰基)苯并呋喃-5-基)甲磺酰胺盐酸盐，分子式：C 31H 44N 2O 5S HCl，分子量：593.2；绝奈达隆的化学结构式如下：
Figure PCTCN2021124961-appb-000001
盐酸决奈达隆是一款抗心律失常药物，在水中几乎不溶，易溶于二氯甲 烷和甲醇。盐酸决奈达隆在水性溶液中的溶解度呈现pH依赖性，当pH值为3-5时有最大的溶解度，约为1-2mg/ml；当pH值为6-7时溶解度显著降低；当pH＝7时其溶解度约为10μg/ml。人体从胃到肠道的pH值是逐渐升高的，导致其服用后虽然在胃中溶解，但随着胃排空进入肠道后，溶解的盐酸决奈达隆析出，降低了其生物利用度。
由于系统性的首过代谢，无食物时决奈达隆的绝对生物利用度很低，约为4％；当决奈达隆与高脂肪餐一起给药时，决奈达隆的绝对生物利用度会增加至约15％。在一项安慰剂对照研究中，严重心衰患者近期需要住院治疗，或因症状恶化需要转诊到专门的心力衰竭诊所(ANDROMEDA研究)，服用MULTAQ(决奈达隆上市药物商品名)的患者死亡率增加了两倍以上；在失代偿性心力衰竭或永久性心房颤动的患者中，MULTAQ使死亡、卒中和心力衰竭的风险增加；成年人的推荐剂量为每次1片(400mg)，每日2次。早餐和晚餐时各服一片。
因此，提高盐酸决奈达隆的溶解度，改变其给药途径避免肝脏的首过代谢从而提高其生物利用度，减少该药物的给药剂量可以提高用药安全性，是目前急需解决的技术难题。
发明内容
本发明提供了一种盐酸决奈达隆包合物，其包括盐酸决奈达隆和环糊精，所述的环糊精不包括未带取代基的β-环糊精。
根据本发明的实施方案，所述的环糊精可以选自α-环糊精、γ-环糊精、羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或多种。
根据本发明的实施方案，所述的环糊精优选羟丙基-β-环糊精和/或磺丁基-β-环糊精。
根据本发明的实施方案，所述的环糊精与所述的盐酸决奈达隆与的摩尔 比值优选0.1～100，进一步优选0.2～10，再进一步优选0.3～5，例如1、1.7或2，其表示摩尔比值为(0.1～100):1，进一步优选(0.2～10):1，再进一步优选(0.3～5):1，例如1:1、1.7:1或2:1。
根据本发明的实施方案，所述的盐酸决奈达隆包合物，优选由盐酸决奈达隆和环糊精组成，所述的环糊精不包括未带取代基的β-环糊精。
根据本发明的实施方案，所述的环糊精优选α-环糊精、γ-环糊精、羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或多种。
本发明还提供了所述的盐酸决奈达隆包合物的制备方法，其包括以下步骤：将盐酸决奈达隆与环糊精进行包合，得到所述的盐酸决奈达隆包合物。优选地，将盐酸决奈达隆与环糊精在溶剂中进行包合；优选地，将盐酸决奈达隆与环糊精水溶液进行包合。
所述的盐酸决奈达隆包合物可以采用本领域中的已知包合条件进行，本发明中优选以下包合条件中的一种或多种：
在所述的盐酸决奈达隆包合物的制备方法中，当存在时，所述的溶剂优选水或水与有机溶剂的混合溶剂；
所述的有机溶剂优选醇类溶剂和/或卤代烃类溶剂。其中，所述的醇类溶剂优选甲醇和/或乙醇；所述的卤代烃类溶剂优选氯代烃类溶剂；所述的氯代烃类溶剂优选二氯甲烷。所述的“水与有机溶剂的混合溶剂”优选水与“甲醇、乙醇和二氯甲烷中的一种或多种”的混合溶剂。
在所述的盐酸决奈达隆包合物的制备方法中，所述环糊精水溶液的质量浓度优选1％～50％，进一步优选5％～20％，例如9％、18％、20％或30％，其中所述的质量浓度是指环糊精的质量与环糊精水溶液总质量的百分比。
在所述的盐酸决奈达隆包合物的制备方法中，所述盐酸决奈达隆与所述的溶剂的质量体积比优选0.001mL/mg～10mL/mg，进一步优选0.005mL/mg～6mg/mL，例如0.03mL/mg。所述的体积质量比是指有机溶剂的 体积与盐酸决奈达隆质量的比值。
在所述的盐酸决奈达隆包合物的制备方法中，所述的包合的温度优选20℃～80℃，进一步优选40℃～70℃，例如60℃～70℃。
在所述的盐酸决奈达隆包合物的制备方法中，所述的包合的时间优选0.5小时～20小时，进一步优选1小时～10小时或3小时～10小时，例如2小时～5小时或5～7小时。
在所述的盐酸决奈达隆包合物的制备方法中，所述的混合优选搅拌混合。
所述的盐酸决奈达隆包合物的制备方法优选采用以下后处理步骤：将盐酸决奈达隆溶于环糊精水溶液中，进行包合，包合结束后，冷却、过滤，得到所述的盐酸决奈达隆包合物的溶液；
或者，将盐酸决奈达隆溶于环糊精水溶液中，进行包合，包合结束后，冷却、过滤、除去溶剂、干燥得到所述的盐酸决奈达隆包合物；
或者，将所述的盐酸决奈达隆包合物的溶液除去溶剂、干燥得到所述的盐酸决奈达隆包合物。
在所述的盐酸决奈达隆包合物的制备方法后处理步骤中，所述的冷却的温度优选10℃～30℃，进一步优选20℃～25℃。
在所述的盐酸决奈达隆包合物的制备方法后处理步骤中，所述的过滤优选采用滤芯进行。所述的滤芯的孔径优选0.22微米～0.8微米，进一步优选0.45微米～0.8微米。
在所述的盐酸决奈达隆包合物的制备方法中，所述的干燥优选冷冻干燥、减压干燥、常压干燥和喷雾干燥中的一种或多种，进一步优选冷冻干燥和/或喷雾干燥。其中，所述的冷冻干燥可以为真空冷冻干燥。
本发明中所述的盐酸决奈达隆包合物的制备方法，进一步优选包括以下具体步骤：
a)配置环糊精水溶液；
b)将盐酸决奈达隆或盐酸决奈达隆与溶剂形成的溶液加入到步骤a)配置的环糊精水溶液中，得到盐酸决奈达隆-环糊精溶液；
c)将步骤b)得到的盐酸决奈达隆-环糊精溶液进行包合，得到盐酸决奈达隆-环糊精的包合溶液；
d)将步骤c)制得的盐酸决奈达隆-环糊精的包合溶液，冷却、过滤、除去溶剂、干燥，得到盐酸决奈达隆包合物即可。
步骤c)中，所述的包合的温度优选20℃～80℃，进一步优选40℃～70℃，例如60℃。
步骤c)中，所述的包合的时间优选0.5小时～20小时，进一步优选3小
时～10小时，例如7小时。
步骤d)中，所述的冷却的温度优选10℃～30℃，进一步优选20℃～25℃。
步骤d)中，所述的过滤优选采用滤膜进行。所述的滤膜的孔径优选0.22微米～0.8微米，进一步优选0.45微米～0.8微米。
步骤d)中，所述的干燥方式优选冷冻干燥、减压干燥、常压干燥和喷雾干燥中的一种或多种，进一步优选冷冻干燥和/或喷雾干燥。
本发明还提供了所述的盐酸决奈达隆包合物在制备盐酸决奈达隆药物，例如药物制剂中的应用。优选地，所述药物或药物制剂可用于预防和/或治疗心脏疾病或病症，例如心律失常。
所述的盐酸决奈达隆药物制剂包括盐酸决奈达隆包合物和药学上可接受的辅料。所述的“药学上可接受的辅料”包括但不限于载体或赋形剂，例如选自填充剂、崩解剂、粘合剂、润滑剂、包衣剂、赋形剂、矫味剂和促渗剂。
根据本发明的实施方案，所述的填充剂包括但不限于乳糖、微晶纤维素、玉米淀粉、磷酸氢钙、甘露醇、葡萄糖、蔗糖、预胶化淀粉、甘露醇淀粉混合物、淀粉乳糖混合物、硅化微晶纤维素和右旋糖酐；优选乳糖、微晶纤维素和预胶化淀粉中的一种或多种。
根据本发明的实施方案，所述的崩解剂包括但不限于干淀粉、羧甲淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠和泡腾崩解剂；优选低取代羟丙基纤维素、交联聚维酮和交联羧甲基纤维素钠中的一种或多种。
根据本发明的实施方案，所述的粘合剂包括但不限于聚维酮(又名聚乙烯吡咯烷酮，PVP，所述的聚乙烯吡咯烷酮可以为PVP K30或PVP VA64)、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素和海藻酸钠中的一种或多种；优选PVP K30、PVP VA64和羟丙基甲基纤维素中的一种或多种。
根据本发明的实施方案，所述的润滑剂包括但不限于硬脂酸类润滑剂、聚乙二醇类润滑剂、月桂醇硫酸镁、滑石粉、二氧化硅、氢化蓖麻油和山嵛酸甘油酯；优选二氧化硅、氢化蓖麻油和山嵛酸甘油酯中的一种或多种。所述的硬脂酸类润滑剂例如硬脂酸镁、硬脂酸钙、硬脂酸和硬脂富马酸钠中的一种或多种；所述的聚乙二醇类润滑剂例如聚乙二醇4000和/或聚乙二醇6000。
根据本发明的实施方案，所述的包衣剂选自普通胃溶型包衣粉和肠溶型包衣粉。胃溶型包衣粉包括欧巴代HPMC型基质和/或PVA防潮型；肠溶型包衣粉包括丙烯酸树脂类聚合物(例如丙烯酸树脂Ⅰ号、Ⅱ号或Ⅲ号)、邻苯二甲酸醋酸纤维素(CAP)、羟丙基甲基纤维素酞酸酯(HPMCP)、聚乙烯醇酞酸酯(PVAP)和醋酸纤维素苯三酸酯(CAT)等；优选欧巴代HPMC型、PVA防潮型、丙烯酸树脂和羟丙基甲基纤维素酞酸酯中的一种或多种。
根据本发明的实施方案，所述的赋形剂包括但不限于普鲁兰多糖。
根据本发明的实施方案，所述的填充剂包括但不限于右旋糖酐。
根据本发明的实施方案，所述的矫味剂包括但不限于甜菊糖苷、阿司帕坦和枸橼酸中的一种或多种。
根据本发明的实施方案，所述的促渗剂包括但不限于吐温。所述的吐温 可以为吐温80。
根据本发明的实施方案，所述的盐酸决奈达隆药物制剂包括但不限于片剂(如舌下片剂、缓释片、渗透泵片、口崩片)、颗粒剂、胶囊、微丸、口服液、注射液和冻干粉针等，优选片剂或胶囊剂。
根据本发明的实施方案，所述片剂的规格(即其中活性成分的含量)可以为1～100mg，例如10～30mg，如18mg、20mg或25mg。
根据本发明的实施方案，以所述药物制剂的总重量计，所述盐酸绝奈达隆的重量百分比含量可以为5～20％，例如10～14％，如10％、11％、12％、13％或14％。
根据本发明的实施方案，以所述药物制剂的总重量计，所述环糊精的重量百分比含量可以为40～90％，例如50～85％，例如50％、51％、52％、53％、54％、55％、60％、65％、70％、75％、80％、81％、82％、83％、84％或85％。
本发明还提供了所述的盐酸决奈达隆药物制剂的制备工艺，包括直接混合压片工艺、湿法制粒工艺和干法制粒工艺等。
根据本发明的实施方案，也可以经过真空冷冻干燥技术将所述的盐酸绝奈达隆包合物的溶液或包含该溶液和药学上可接受的辅料的组合物制备成冻干舌下片。
本发明还提供选自以下任一处方的药物制剂(优选舌下片剂)：
处方1：10.53％盐酸绝奈达隆、52.21％羟丙基-β环糊精、1.75％普鲁兰多糖、35.09％右旋糖酐、0.26％甜菊糖苷和0.02％阿司帕坦；
处方2：10.53％盐酸绝奈达隆、52.21％羟丙基-β环糊精、1.75％普鲁兰多糖、35.09％右旋糖酐、0.11％吐温80、0.26％甜菊糖苷和0.02％阿司帕坦；
处方3：13.07％盐酸绝奈达隆、80.96％磺丁基-β环糊精、2.18％普鲁兰多糖、2.18％甜菊糖苷、1.45％枸橼酸、0.11吐温80和0.04％阿司帕坦；
处方4：13.07％盐酸绝奈达隆、80.96％磺丁基-β环糊精、2.18％普鲁兰多糖、2.18％甜菊糖苷、1.45％枸橼酸、0.11吐温80和0.04％阿司帕坦。
本发明还提供了所述的盐酸决奈达隆药物制剂在制备治疗心律失常的药物中的应用。
本发明还提供了预防和/或治疗心脏疾病，例如心律失常的方法，包括向患者施用有效量，例如治疗有效剂量的所述盐酸决奈达隆包合物、盐酸决奈达隆包合物的溶液或所述药物制剂。在一个实施方案中，所述患者是人。
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。
根据本发明的实施方案，所述的室温是指环境温度为10℃～35℃，例如10℃、15℃、20℃、25℃、30℃、35℃。
有益效果
本发明的盐酸决奈达隆包合物及其溶液和药物制剂的稳定性好、在水中的溶解度大大提高，相对于盐酸决奈达隆的溶解度最高可提高90倍左右，生物利用度高，适合于工业化生产。本发明的盐酸决奈达隆包合物制备操作简单，制得的盐酸决奈达隆包合物易于制备制剂。本发明的盐酸决奈达隆制剂体外溶解度大大提高，避免在人体高pH值环境中沉淀析出，提高产品的生物利用度，适合于工业化生产。本发明所制备的舌下片剂，提高了在pH6.8磷酸盐缓冲液中的溶出度，可以避开肝脏的首过效应以及胃肠道的破坏和降解，有利于保持药效，提高药物的生物利用度，适合于吞咽困难患者，同时还可以降低给药剂量，减轻药物对胃肠道和肝脏的毒副作用。
附图说明
图1表示实施例5制得的盐酸决奈达隆-环糊精包合物X-RPD图谱；
图2表示Beagle犬单次口服片剂A-供试品(规格：100mg/片)和对照品MULTAQ(规格：400mg/片)后的平均血浆药物浓度-时间曲线图；其中，
Figure PCTCN2021124961-appb-000002
表示Beagle犬单次口服给予100mg剂量片剂A-供试品后体内血药浓度药时曲线，
Figure PCTCN2021124961-appb-000003
表示Beagle犬单次口服给予400mg剂量MULTAQ后体内血药浓度药时曲线；
图3表示Beagle犬单次口服片剂A-供试品和对照品MULTAQ后的平均血浆药物浓度-时间对数图；图3中
Figure PCTCN2021124961-appb-000004
表示Beagle犬单次口服片剂A-供试品的平均血浆药物浓度-时间对数图，
Figure PCTCN2021124961-appb-000005
表示Beagle犬单次口服片剂对照品MULTAQ后的平均血浆药物浓度-时间对数图；
图4表示pH4.5溶出介质中盐酸决奈达隆片溶出曲线图；其中
Figure PCTCN2021124961-appb-000006
表示片剂A-供试品-1(20mg)的溶出曲线图，
Figure PCTCN2021124961-appb-000007
表示片剂A-供试品-2(20mg)的溶出曲线图，
Figure PCTCN2021124961-appb-000008
表示片剂A-供试品-3(20mg)的溶出曲线图，
Figure PCTCN2021124961-appb-000009
表示RLD的溶出曲线图；
图5表示pH6.8溶出介质中盐酸决奈达隆片溶出曲线图，其中
Figure PCTCN2021124961-appb-000010
表示RLD的溶出曲线图，
Figure PCTCN2021124961-appb-000011
表示A-供试品-1(20mg)的溶出曲线图，
Figure PCTCN2021124961-appb-000012
表示A-供试品-2(20mg)的溶出曲线图，
Figure PCTCN2021124961-appb-000013
表示A-供试品-3(20mg)的溶出曲线图；
图6表示参比制剂和实施例10-13制得的盐酸决奈达隆舌下片的溶出曲线图，
Figure PCTCN2021124961-appb-000014
表示参比制剂的溶出曲线图；
Figure PCTCN2021124961-appb-000015
表示实施例10制得的绝奈达隆舌下片的溶出曲线图；
Figure PCTCN2021124961-appb-000016
表示实施例11制得的绝奈达隆舌下片的溶出曲线图；
Figure PCTCN2021124961-appb-000017
表示实施例12制得的绝奈达隆舌下片的溶出曲线图；
Figure PCTCN2021124961-appb-000018
表示实施例13制得的绝奈达隆舌下片的溶出曲线图。
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。
实施例1
盐酸决奈达隆：羟丙基-β-环糊精＝1:1(物质的摩尔比)
分别称取盐酸决奈达隆0.050g，羟丙基-β-环糊精0.127g，按照以下方法制备包合物。
将盐酸决奈达隆用1.5ml甲醇溶解后，滴加至质量百分比为9％的羟丙基-β-环糊精水溶液中(所述的质量百分比，是指羟丙基-β-环糊精的质量与羟丙基-β-环糊精水溶液质量的百分比)，在磁力搅拌机中，60℃(水浴)包合7小时，放冷至室温(20℃～25℃)，过滤，旋蒸，冷冻干燥，即得盐酸决奈达隆羟丙基-β-环糊精包合物，收率95％。
实施例2
盐酸决奈达隆：羟丙基-β-环糊精＝1:2(物质的摩尔比)
分别称取盐酸决奈达隆0.200g，羟丙基-β-环糊精1.013g，按照以下方法制备包合物。
将盐酸决奈达隆用6ml甲醇溶解后，滴加至质量百分比为9％的羟丙基-β-环糊精水溶液中(所述的质量百分比，是指羟丙基-β-环糊精的质量与羟丙基-β-环糊精水溶液质量的百分比)，在磁力搅拌机中，60℃(水浴)包合7小时，放冷至室温(20℃～25℃)，过滤，旋蒸，冷冻干燥，即得盐酸决奈达隆羟丙基-β-环糊精包合物1.109g，收率91％。
实施例3
盐酸决奈达隆：磺丁基-β-环糊精＝1:0.14(物质的摩尔比)
分别称取盐酸决奈达隆0.051g，磺丁基-β-环糊精0.101g按照以下方法制备包合物。
将盐酸决奈达隆用1.5ml甲醇溶解后，滴加至质量百分比为9％的磺丁基-β-环糊精水溶液中(所述的质量百分比，是指磺丁基-β-环糊精的质量与磺丁基-β-环糊精水溶液质量的百分比)，在磁力搅拌机中，60℃(水浴)包合7小时，放冷至室温(20℃～25℃)，过滤，旋蒸，冷冻干燥，即得盐酸决奈达隆磺丁基-β-环糊精包合物，收率95％。
实施例4
盐酸决奈达隆：磺丁基-β-环糊精＝1:1.08(物质的摩尔比)
分别称取盐酸决奈达隆0.205g，磺丁基-β-环糊精0.809g，按照以下方法制备包合物。
将盐酸决奈达隆用6ml甲醇溶解后，滴加至质量百分比为9％的磺丁基-β-环糊精水溶液中(所述的质量百分比，是指磺丁基-β-环糊精的质量与磺丁基-β-环糊精水溶液质量的百分比)，在磁力搅拌机中，60℃(水浴)包合7小时，放冷至室温(20℃～25℃)，过滤，旋蒸，冷冻干燥，即得盐酸决奈达隆磺丁基-β-环糊精包合物0.918g，收率为：91％。
实施例5
盐酸决奈达隆：磺丁基-β-环糊精＝1:1.70(物质的摩尔比)
分别称取盐酸决奈达隆62.5978g，磺丁基-β-环糊精387.480g，按照以下方法制备包合物。
将盐酸决奈达隆加入至质量百分比为20％的磺丁基-β-环糊精水溶液 中(所述的质量百分比，是指磺丁基-β-环糊精的质量与磺丁基-β-环糊精水溶液质量的百分比)，在磁力搅拌机中，60℃(水浴)包合7小时，放冷至室温(20℃～25℃)，过滤，旋蒸，冷冻干燥，即得盐酸决奈达隆磺丁基-β-环糊精包合物488.41g，收率为：90.0％。实施例1-5制得的盐酸决奈达隆包合物在水中的溶解度(37℃，振荡24小时)见表1。
表1盐酸决奈达隆包合物在水中的溶解度表
Figure PCTCN2021124961-appb-000019
由表1可见，本发明的盐酸决奈达隆-环糊精包合物在水中的溶解度得到了显著的提高，提高倍数达到7～92倍。
盐酸决奈达隆-环糊精包合物X-粉末衍射(X-RPD)显示，盐酸决奈达隆被磺丁基-β-环糊精包合后无特征峰，形成无定型物，从而大幅提高盐酸决奈达隆的溶解度，实施例5制得的盐酸决奈达隆-环糊精包合物X-RPD图谱见图1。
动物PK实验
将实施例5制得的盐酸决奈达隆包合物进行压片，所得片剂A-供试品(规格：100mg/片)与参比制剂MULTAQ-对照品(规格：400mg/片，赛洛菲生产)，进行Beagle犬餐前口服给药，一次1片，单次给药。给药后抽取 四肢静脉血，进行双周期交叉药代动力学实验，进行体内生物利用度考察。
结果显示Beagle犬单次口服给予100mg剂量片剂A-供试品后，C max为157±63.4ng/mL；Beagle犬单次口服给予400mg剂量MULTAQ后，C max为121±29.2ng/mL，低于100mg剂量片剂A-供试品的血药浓度峰值。即本发明规格为参比制剂规格的1/4，生物利用度却优于参比制剂。体内血药浓度药时曲线见图2。
制剂处方
表2盐酸决奈达隆片制剂处方
原辅料名称 mg/片 处方占比％
规格 20 N/A
盐酸决奈达隆包合物 163.4 32.7％
乳糖 191.6 38.3％
预胶化淀粉 60.0 12.0％
交联聚维酮 50.0 10.0％
胶体二氧化硅 20.0 4.0％
氢化蓖麻油 15.0 3.0％
欧巴代 15.0 3.0％
总重 515.0 100％
实施例6：片剂A-供试品-1
直接压片工艺：按照处方量称量各原辅料，将胶体二氧化硅与盐酸决奈达隆包合物混合过筛，依次加入预胶化淀粉、乳糖、交联聚维酮混合20分钟，再加入氢化蓖麻油混合5分钟，混合物用
Figure PCTCN2021124961-appb-000020
冲模压片，包衣得片剂A-供试品-1。
实施例7：片剂A-供试品-2
干法制粒工艺：按照处方量称量各原辅料，将胶体二氧化硅与盐酸决奈达隆包合物混合过筛，依次加入预胶化淀粉、乳糖、1/2处方量交联聚维酮混合20分钟，再加入1/2处方量氢化蓖麻油混合5分钟，混合物用干法制粒机制粒，颗粒中加入外加1/2处方量交联聚维酮和1/2处方量氢化蓖麻油，混合10分钟，用
Figure PCTCN2021124961-appb-000021
冲模压片，包衣得片剂A-供试品-2。
实施例8：片剂A-供试品-3
湿法制粒工艺：按照处方量称量各原辅料，将胶体二氧化硅与盐酸决奈达隆包合物混合过筛，依次加入预胶化淀粉、乳糖、1/2处方量交联聚维酮，置于湿法制粒机中混合10分钟，加入纯化水或30％-50％乙醇溶液制粒，湿颗粒烘箱或流化床干燥后，加入外加1/2处方量交联聚维酮和氢化蓖麻油，混合10分钟，用
Figure PCTCN2021124961-appb-000022
冲模压片，包衣得片剂A-供试品-3。
实施例9：实施例6-8样品溶出试验
实施例6、7、8的样品(规格：20mg)与参比制剂(规格：400mg)在pH4.5醋酸缓冲溶液和pH6.8磷酸缓冲溶液900ml，浆法进行溶出检测，pH4.5溶出介质中盐酸决奈达隆片溶出曲线数据见表3；pH6.8溶出介质中盐酸决奈达隆片溶出曲线数据见表4；pH4.5溶出介质中盐酸决奈达隆片溶出曲线图见图4；pH6.8溶出介质中盐酸决奈达隆片溶出曲线图见图5。
表3 pH4.5溶出介质中盐酸决奈达隆片溶出数据表
Figure PCTCN2021124961-appb-000023
Figure PCTCN2021124961-appb-000024
表4 pH6.8溶出介质中盐酸决奈达隆片溶出数据表
Figure PCTCN2021124961-appb-000025
动物PK实验及体外溶出实验都显示，改良型盐酸决奈达隆片剂A供试品的体内生物利用度和体外溶出都较原研制剂大幅提高。理论上实现了小剂量的盐酸决奈达隆达到与高剂量原研制剂同等的生物利用度，从而降低了原研药的不良反应，提高了患者的顺应性，也降低了生产成本。
实施例10：舌下片处方1
盐酸决奈达隆：羟丙基-β-环糊精＝1:2(物质的量之比)，HP-β-CD(羟丙 基-β环糊精)的水溶液浓度为18％，所述的浓度是指羟丙基-β环糊精的质量占羟丙基-β环糊精水溶液总质量的百分比。
原辅料名称 作用 单片(mg) 百分比％
盐酸绝奈达隆 API 20.00 10.53
羟丙基-β环糊精 增溶剂 99.19 52.21
普鲁兰多糖 赋形剂 3.33 1.75
右旋糖酐 填充剂 66.67 35.09
甜菊糖苷 矫味剂 0.50 0.26
阿司帕坦 矫味剂 0.03 0.02
片重mg / 190 100.00
首先将API与环糊精进行包合、使其完全包合后(溶液澄清透明)冷却至室温后过滤，然后依次加入赋形剂、填充剂、矫味剂、促渗剂等其他辅料进行搅拌使其完全溶解(溶液澄清透明)、定量滴加至泡罩模具中，置于冷冻干燥机中，调整合适的冻干参数将其进行冷冻干燥，即得舌下片(下同)。
实施例11：舌下片处方2
盐酸决奈达隆：羟丙基-β-环糊精＝1:2(物质的量之比)，HP-β-CD(羟丙基-β环糊精)的水溶液浓度为18％，所述的浓度是指羟丙基-β环糊精的质量占羟丙基-β环糊精水溶液总质量的百分比。
原辅料名称 作用 单片(mg) 百分比％
盐酸绝奈达隆 API 20.00 10.53
羟丙基-β环糊精 增溶剂 99.19 52.21
普鲁兰多糖 赋形剂 3.33 1.75
右旋糖酐 填充剂 66.67 35.09
吐温80 促渗剂 0.20 0.11
甜菊糖苷 矫味剂 0.50 0.26
阿司帕坦 矫味剂 0.03 0.02
片重mg / 190 100.00
实施例12：舌下片处方3
盐酸决奈达隆：磺丁基-β-环糊精＝1:1.7(物质的量之比)，SBE-β-CD(磺丁基-β-环糊精)的水溶液浓度为20％，所述的质量浓度是指磺丁基-β-环糊精的质量与环糊精水溶液总质量的百分比。
原辅料名称 作用 单片(mg) 百分比％
盐酸绝奈达隆 API 18.00 13.07
磺丁基-β环糊精钠 增溶剂 111.48 80.96
普鲁兰多糖 赋形剂 3.00 2.18
甜菊糖苷 填充剂 3.00 2.18
阿司帕坦 矫味剂 0.06 0.04
枸橼酸 矫味剂 2.00 1.45
吐温80 促渗剂 0.15 0.11
片重mg / 138 100
实施例13：舌下片处方4
盐酸决奈达隆：磺丁基-β-环糊精＝1:1.7(物质的量之比)，SBE-β-CD(磺丁基-β-环糊精)的水溶液浓度为30％，所述的质量浓度是指磺丁基-β-环糊精的质量与环糊精水溶液总质量的百分比。
原辅料名称 作用 单片(mg) 百分比％
盐酸绝奈达隆 API 25.00 13.07
磺丁基-β环糊精钠 增溶剂 154.82 80.96
普鲁兰多糖 赋形剂 4.17 2.18
甜菊糖苷 矫味剂 4.17 2.18
阿司帕坦 矫味剂 0.08 0.04
枸橼酸 矫味剂 2.78 1.45
吐温80 促渗剂 0.21 0.11
片重mg / 191 100.00
实施例14：实施例10-13样品溶出试验
在pH6.8磷酸盐缓冲液中，实施例10-13的溶出度曲线图见图6；在pH6.8磷酸盐缓冲液中，实施例10-13的溶出度数据见表5。参比制剂为赛诺菲生产的盐酸绝奈达隆片(400mg)。
表5参比制剂(厂家：赛诺菲Sanofi)与实施例10-13溶出结果对比(n＝3)
Figure PCTCN2021124961-appb-000026
由表5可见，在pH6.8磷酸盐缓冲液中，实施例10-13的溶出度均大于参比制剂，实施例12和13的溶出度尤其突出。
实施例15
盐酸决奈达隆：磺丁基-β-环糊精＝1:1.7(物质的摩尔比)
分别称取盐酸决奈达隆63g，磺丁基-β-环糊精390g，按照以下方法制备包合物。
将盐酸决奈达隆缓慢加至质量百分比为20％的磺丁基-β-环糊精水溶液中(所述的质量百分比，是指磺丁基-β-环糊精的质量与磺丁基-β-环糊精水溶液质量的百分比)，在磁力搅拌机中，60℃(水浴)包合6小时，放冷至室温(20℃～25℃)，过滤，喷雾干燥，即得盐酸决奈达隆磺丁基-β-环糊精包合物375g，收率约为：83％。
实施例16：实施例10-13和15样品溶解度试验
实施例10-13和15所得样品分别投入15mL 37℃水中，舌下片立即散开，少许颗粒下沉，5min内均可完全溶解，符合舌下片要求。而参比制剂在水中无法24h仍然无法溶解。
其中，实施例15制得的盐酸决奈达隆包合物在水中的溶解度(37℃，振荡24小时)见表6。
表6盐酸决奈达隆包合物在水中的溶解度表
Figure PCTCN2021124961-appb-000027
由表6可见，本发明的盐酸决奈达隆-环糊精包合物在水中的溶解度得到了显著的提高，提高倍数达到92倍。

Claims (10)

  1. 一种盐酸决奈达隆包合物，其特征在于：包括盐酸决奈达隆和环糊精，条件是所述的环糊精不包括未带取代基的β-环糊精。
    优选地，所述的环糊精选自α-环糊精、γ-环糊精、羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或多种。
  2. 如权利要求1所述的盐酸决奈达隆包合物，其特征在于：所述的环糊精与所述的盐酸决奈达隆与的摩尔比值为(0.1～100):1，例如(0.2～10):1，优选(0.3～5):1。
  3. 如权利要求1或2所述的盐酸决奈达隆包合物，其特征在于：所述的盐酸决奈达隆包合物由盐酸决奈达隆和环糊精组成，所述的环糊精不包括未带取代基的β-环糊精。
  4. 如权利要求1～3任一项所述的盐酸决奈达隆包合物的制备方法，其特征在于：将盐酸决奈达隆与环糊精进行包合，得到所述的盐酸决奈达隆包合物；
    优选地，将盐酸决奈达隆与环糊精在溶剂中进行包合；
    优选地，将盐酸决奈达隆与环糊精水溶液进行包合。
  5. 如权利要求4所述的盐酸决奈达隆包合物的制备方法，其特征在于：
    当存在时，所述的溶剂为水或水与有机溶剂的混合溶剂，优选地，所述盐酸决奈达隆与所述的溶剂的体积质量比值为0.001mL/mg～1mL/mg；
    和/或，
    所述环糊精水溶液的质量浓度为1％～50％，所述的质量浓度是指环糊精 的质量与环糊精水溶液总质量的百分比；
    和/或，
    所述的包合的温度为20℃～80℃；
    和/或，
    所述的包合的时间为0.5小时～20小时；
    和/或，
    所述的混合为搅拌混合；
    和/或，
    所述的制备方法包括：盐酸决奈达隆溶于环糊精水溶液中，进行包合，包合结束后，冷却、过滤，得到所述的盐酸决奈达隆包合物的溶液；
    优选地，所述制备方法包括以下具体步骤：
    a)配置环糊精水溶液；
    b)将盐酸决奈达隆或盐酸决奈达隆与有机溶剂形成的溶液加入到步骤a)配置的环糊精水溶液中，得到盐酸决奈达隆-环糊精溶液；
    c)将步骤b)得到的盐酸决奈达隆-环糊精溶液进行包合，得到盐酸决奈达隆-环糊精的包合溶液；
    d)将步骤c)制得的盐酸决奈达隆-环糊精的包合溶液，冷却、过滤、除去溶剂、干燥，得到盐酸决奈达隆包合物。
  6. 一种盐酸决奈达隆药物制剂，其特征在于：所述药物制剂包含权利要求1～3任一项所述的盐酸决奈达隆包合物和药学上可接受的辅料；
    优选地，所述药物制剂选自片剂(如舌下片剂、缓释片、渗透泵片、口崩片)、颗粒剂、胶囊、微丸、口服液、注射液和冻干粉针。
  7. 如权利要求6所述的药物制剂，其特征在于：所述的“药学上可接受 的辅料”包括但不限于选自下列辅料的至少一种：载体或赋形剂，例如选自填充剂、崩解剂、粘合剂、润滑剂、包衣剂、赋形剂、矫味剂和促渗剂；
    例如，所述的填充剂包括但不限于乳糖、微晶纤维素、玉米淀粉、磷酸氢钙、甘露醇、葡萄糖、蔗糖、预胶化淀粉、甘露醇淀粉混合物、淀粉乳糖混合物、硅化微晶纤维素和右旋糖酐；优选乳糖、微晶纤维素和预胶化淀粉中的一种或多种；
    例如，所述的崩解剂包括但不限于干淀粉、羧甲淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠和泡腾崩解剂；优选低取代羟丙基纤维素、交联聚维酮和交联羧甲基纤维素钠中的一种或多种；
    例如，所述的粘合剂包括但不限于聚维酮、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素和海藻酸钠中的一种或多种；优选PVP K30、PVP VA64和羟丙基甲基纤维素中的一种或多种；
    例如，所述的润滑剂包括但不限于硬脂酸类润滑剂、聚乙二醇类润滑剂、月桂醇硫酸镁、滑石粉、二氧化硅、氢化蓖麻油和山嵛酸甘油酯；优选二氧化硅、氢化蓖麻油和山嵛酸甘油酯中的一种或多种；所述的硬脂酸类润滑剂例如硬脂酸镁、硬脂酸钙、硬脂酸和硬脂富马酸钠中的一种或多种；所述的聚乙二醇类润滑剂例如聚乙二醇4000和/或聚乙二醇6000；
    例如，所述的包衣剂选自普通胃溶型包衣粉和肠溶型包衣粉。胃溶型包衣粉包括欧巴代HPMC型基质和/或PVA防潮型；肠溶型包衣粉包括丙烯酸树脂类聚合物、邻苯二甲酸醋酸纤维素、羟丙基甲基纤维素酞酸酯、聚乙烯醇酞酸酯和醋酸纤维素苯三酸酯等；优选欧巴代HPMC型、PVA防潮型、丙烯酸树脂和羟丙基甲基纤维素酞酸酯中的一种或多种。
  8. 如权利要求7所述的药物制剂，其特征在于：
    所述的赋形剂包括但不限于普鲁兰多糖；
    和/或，
    所述的填充剂包括但不限于右旋糖酐；
    和/或，
    所述的矫味剂包括但不限于甜菊糖苷、阿司帕坦和枸橼酸中的一种或多种；
    和/或，
    所述的促渗剂包括但不限于吐温。
  9. 如权利要求6-8任一项所述的药物制剂，其特征在于：所述药物制剂选自以下任一处方的舌下片剂：
    处方1：10.53％盐酸绝奈达隆、52.21％羟丙基-β环糊精、1.75％普鲁兰多糖、35.09％右旋糖酐、0.26％甜菊糖苷和0.02％阿司帕坦；
    处方2：10.53％盐酸绝奈达隆、52.21％羟丙基-β环糊精、1.75％普鲁兰多糖、35.09％右旋糖酐、0.11％吐温80、0.26％甜菊糖苷和0.02％阿司帕坦；
    处方3：13.07％盐酸绝奈达隆、80.96％磺丁基-β环糊精、2.18％普鲁兰多糖、2.18％甜菊糖苷、1.45％枸橼酸、0.11吐温80和0.04％阿司帕坦；
    处方4：13.07％盐酸绝奈达隆、80.96％磺丁基-β环糊精、2.18％普鲁兰多糖、2.18％甜菊糖苷、1.45％枸橼酸、0.11吐温80和0.04％阿司帕坦。
  10. 如权利要求1～3任一项所述的盐酸决奈达隆包合物或权利要求6～9任一项所述的药物制剂的用途；
    优选地，如权利要求1～3任一项所述的盐酸决奈达隆包合物用于制备药物，所述药物为药物制剂；
    优选地，所述药物或药物制剂用于预防和/或治疗心脏疾病或病症，例如心律失常。
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