WO2021238978A1 - 含硝羟喹啉前药的药物组合物及其制备方法和应用 - Google Patents

含硝羟喹啉前药的药物组合物及其制备方法和应用 Download PDF

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WO2021238978A1
WO2021238978A1 PCT/CN2021/096037 CN2021096037W WO2021238978A1 WO 2021238978 A1 WO2021238978 A1 WO 2021238978A1 CN 2021096037 W CN2021096037 W CN 2021096037W WO 2021238978 A1 WO2021238978 A1 WO 2021238978A1
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parts
weight
preparation
tablet
lubricant
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PCT/CN2021/096037
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English (en)
French (fr)
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陈杰
申帅
吴友斌
刘江华
郭玉申
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江苏亚虹医药科技股份有限公司
上海亚虹医药科技有限公司
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Priority to US17/999,470 priority Critical patent/US20230190732A1/en
Publication of WO2021238978A1 publication Critical patent/WO2021238978A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • 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
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • 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
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    • A61K9/2022—Organic macromolecular compounds
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    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a pharmaceutical composition containing a nitroquinoline prodrug, and a preparation method and application thereof.
  • Nitroxoline the full English name is Nitroxoline, and the chemical name is 5-nitro-8-hydroxyquinoline. It was developed as an oral antibiotic in the 1960s. It is mainly used for urinary system infections and has a relatively safe history of use. It was later replaced by the discovery and use of new antibiotics. In recent years, new studies have found that nitroquinoline can simultaneously inhibit the methionine aminopeptidase MetAP2 and the silent information regulator 2 related enzyme SIRT1 in vascular endothelial cells, exerting a synergistic inhibitory effect on tumor angiogenesis, and also It has an inhibitory effect on the proliferation of tumor cells. Therefore, nitroquinoline has been re-developed to treat tumors including bladder cancer.
  • Prodrugs are compounds obtained by chemical modification of active drugs, which are transformed into the original drugs by the action of enzymes in the body to exert their medicinal effects. Prodrugs are widely used in drug research and development. Prodrugs are a modification method of drugs that can overcome their various undesirable characteristics and properties. They can mainly bring the following advantages: increase drug solubility, improve drug absorption and distribution, and increase drug stability To reduce toxicity or adverse reactions, prolong the action time of the drug, and eliminate the unsuitable nature of the drug.
  • the inventors developed (S)-(5-nitroquinoline-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate for the above-mentioned nitroquinoline prodrugs through painstaking research. It is a new preparation with good stability and dissolution properties, and has good pharmacokinetic characteristics, can be advantageously used in the preparation of drugs, and has good clinical application prospects.
  • one of the objectives of the present invention is to provide a pharmaceutical composition containing nitroquinoline prodrug, which contains the following parts by weight: 100 parts of active pharmaceutical ingredients, 22.5-320 parts of fillers, 0- 40 parts of disintegrant, 0-95 parts of binder, and 2-30 parts of lubricant; per 100 parts by weight of active pharmaceutical ingredient, the total of the filler, the disintegrant and the binder
  • the dosage is 54-345 parts by weight;
  • the active pharmaceutical ingredient is (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate.
  • the active pharmaceutical ingredient can be prepared by the preparation method of Example 20 of the patent application with publication number WO/2020/063824.
  • the filler may be starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, calcium phosphate anhydrous, calcium phosphate anhydrous, and microcrystalline cellulose.
  • pregelatinized starch lactose, sucrose, mannitol and microcrystalline cellulose, more preferably a mixture of pregelatinized starch, mannitol and microcrystalline cellulose.
  • the weight ratio of the three is preferably 0.5-2:1:0.5-2, more preferably 0.8-1.3:1:0.8-1.3, and further More preferably 1.06-1.07:1:1.09-1.25.
  • the amount of the filler is preferably 50-320 parts by weight, more preferably 60-300 parts by weight, such as 100 or 200 parts by weight, and still more preferably 90-320 parts by weight per 100 parts by weight of the active pharmaceutical ingredient. 200 parts by weight, most preferably 90.8-93 parts by weight.
  • the disintegrant may be low-substituted hydroxypropyl methyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and crospovidone One or more of croscarmellose sodium and crospovidone are preferred, and crospovidone is more preferred.
  • the amount of the disintegrant is preferably 15-35 parts by weight, for example 31.5 parts by weight, more preferably 15-17 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
  • the binder may be one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and starch, preferably hydroxypropyl methyl cellulose, poly One or more of Vividone and starch.
  • the amount of the binder is preferably 10-50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
  • the total weight of the filler, the disintegrant and the binder is preferably 100-320 parts by weight, for example, 195 or 290 parts by weight , More preferably 100-120 parts by weight, for example 108 parts.
  • the lubricant may be one of stearic acid, magnesium stearate, calcium stearate, high molecular weight polyethylene glycol, sodium stearyl fumarate and sodium lauryl sulfonate.
  • stearic acid magnesium stearate, calcium stearate, high molecular weight polyethylene glycol, sodium stearyl fumarate and sodium lauryl sulfonate.
  • sodium stearyl fumarate and sodium lauryl sulfonate more preferably sodium stearyl fumarate.
  • the amount of the lubricant is preferably 2-10 parts by weight, such as 3.2 or 5 parts by weight, more preferably 2-8 parts by weight, and even more preferably 2- 2.1 parts by weight.
  • the pharmaceutical composition may further include a coating agent.
  • the type of the coating agent may be the type of the coating agent conventionally used in the art, for example, the coating agent under the trade name of Opadry.
  • the dosage of the coating agent can be a conventional dosage in the art, for example, the ratio of the mass of the coating agent to the mass of the pharmaceutical composition before coating is 1.5% to 6%, preferably 2% to 4%.
  • the pharmaceutical composition may further include one or more of a coloring agent, a pH adjusting agent, a surfactant, a stabilizer, and a fragrance.
  • the pharmaceutical composition may be a conventional dosage form in the art, such as a solid preparation, such as a granule, a powder, a capsule or a tablet, preferably a tablet, and more preferably an immediate-release tablet.
  • a solid preparation such as a granule, a powder, a capsule or a tablet, preferably a tablet, and more preferably an immediate-release tablet.
  • the pharmaceutical composition is a tablet, and the tablet contains the following parts by weight: 100 parts of active pharmaceutical ingredients, 22.5-320 parts of fillers, 0-40 parts Disintegrant, 0-95 parts of binder and 2-30 parts of lubricant; relative to 100 parts by weight of active pharmaceutical ingredients, the total amount of filler, disintegrant and binder is 54-345 parts by weight; the active pharmaceutical ingredient is (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropylpyrrolidine-2-carboxylate;
  • the filler is one or more of pregelatinized starch, lactose, sucrose, mannitol and microcrystalline cellulose; the disintegrant is croscarmellose sodium and crospovidone One or two; the binder is one or more of hydroxypropyl methylcellulose, povidone and starch; the lubricant is sodium stearyl fumarate and lauryl sulfonate One or two of sodium.
  • the tablet is preferably a coated tablet, and the ratio of the mass of the coating agent in the coated tablet to the mass of the uncoated plain tablet is 1.5%-6%, preferably 2%-4% (for example 3%).
  • the pharmaceutical composition is a tablet, and the tablet contains the following parts by weight: 100 parts of active pharmaceutical ingredients, 22.5-320 parts of fillers, 15-17 parts of Disintegrant and 2-10 parts of lubricant; relative to 100 parts by weight of active pharmaceutical ingredients, the total amount of the filler and the disintegrant is 100-120 parts by weight (for example, 108 parts); the activity
  • the pharmaceutical ingredient is (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate;
  • the filler is a mixture of pregelatinized starch, mannitol and microcrystalline cellulose, and the weight ratio of the three is 0.5-2:1:0.5-2; the disintegrant is crosslinked Povidone; the lubricant is sodium stearyl fumarate.
  • the amount of the filler is preferably 60-300 parts by weight, more preferably 90-200 parts by weight, and most preferably 90.8-93 parts by weight.
  • the weight ratio of pregelatinized starch, mannitol and microcrystalline cellulose in the filler is preferably 0.8-1.3:1:0.8-1.3, more preferably 1.06-1.07:1:1.09-1.25.
  • the amount of the lubricant is preferably 2-8 parts by weight, more preferably 2-2.1 parts by weight.
  • the amount of the filler is 90.8-93 parts by weight; the weight ratio of pregelatinized starch, mannitol and microcrystalline cellulose in the filler is 1.06-1.07:1: 1.09-1.25; the amount of the lubricant is 2-2.1 parts by weight.
  • the tablet may not contain a binder.
  • the tablet is preferably a coated tablet, and the ratio of the mass of the coating agent in the coated tablet to the mass of the uncoated plain tablet is 1.5%-6%, preferably 2 %-4% (e.g. 3%).
  • Another object of the present invention is to provide a preparation method of the aforementioned granules, powders, capsules or tablets, all of which are conventional preparation methods in the art.
  • the preparation method includes the following steps:
  • the final preparation When the final preparation is granules, it can also be granulated by wet granulation conventional in the art.
  • the preparation method includes the following steps:
  • the preparation method includes the following steps:
  • the preparation method includes the following steps: directly mixing the components to obtain it.
  • the preparation method includes the following steps: on the basis of the aforementioned preparation method of granules, further, the obtained granules are filled into the capsule to obtain the preparation.
  • the preparation method includes the following steps: on the basis of the aforementioned preparation method of granules, further, the obtained granules are compressed to obtain a tablet.
  • Another object of the present invention is to provide a use of the aforementioned pharmaceutical composition or the aforementioned tablet in the preparation of a medicament for the treatment of infectious diseases or cancer.
  • the infectious disease may be, for example, a urinary tract infection.
  • the cancer may be bladder cancer, for example.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that the pharmaceutical composition of the present invention has good stability and excellent dissolution properties, and its pharmacokinetic properties are excellent, and can be advantageously used in clinical development and application.
  • Figure 1 shows the dissolution profiles of the immediate-release tablets prepared in Examples 1 to 8 and the tablets of Comparative Example 1.
  • Figure 2 shows the pharmacokinetic curves of the quick-release tablets prepared in Examples 1, 3, and 7.
  • the nitroquinoline prodrug is (S)-(5-nitroquinoline-8-yloxy)methyl 1-isopropylpyrrolidine-2-carboxylate, according to the patent application publication number WO/2020/ Prepared by the method disclosed in Example 20 in 063824.
  • Coating powder (trade name: Opadry): Shanghai Colorcon
  • Dissolution apparatus Tianjin Tianda Tianfa, RC8MD
  • Dissolution apparatus automatic sampler Tianda Tianfa, RCQ-8C
  • Dog food Beijing Keao Xieli Feed Co., Ltd.
  • the weight gain of the coating refers to the percentage of the weight of the coating to the weight of the plain tablet.
  • step (3) Mix the other components except lubricant in step (2), add 20-30mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • binder (10wt% hydroxypropyl methyl cellulose solution): Weigh about 90 mL of purified water, slowly add hydroxypropyl methyl cellulose, stir while adding, and let it stand until it is completely dissolved ,spare;
  • step (3) Mix the other components except lubricant in step (3), add the adhesive prepared in step (2) to wet granulation to prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to Moisture 1.5-3.5wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • step (3) Mix the other components except lubricant in step (2), add 25-30mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • Example 3-1 and Example 3-2 were prepared, which were defined as Example 3-1 and Example 3-2, respectively.
  • step (3) Mix the other components except lubricant in step (2), add 55-65mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • Example 4-1 the immediate-release tablets with coating weight gains of 2% and 4% were prepared, which were defined as Example 4-1 and Example 4-2, respectively.
  • Example 6-1 and Example 6-2 were prepared, which were defined as Example 6-1 and Example 6-2, respectively.
  • step (3) Mix the other components except lubricant in step (2), add 25-35mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • Example 7-1 and Example 7-2 were prepared, which were defined as Example 7-1 and Example 7-2, respectively.
  • step (3) Mix the other components except lubricant in step (2), add 25-35mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • Example 8-1 and Example 8-2 were prepared, which were defined as Example 8-1 and Example 8-2, respectively.
  • step (3) Mix the other components except lubricant in step (2), add 55-65mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • step (3) Mix the other components except lubricant in step (2), add 65-75mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • step (3) Mix the other components except lubricant in step (2), add 28-38mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulate, and dry at 60°C to moisture 1.5-3.5 wt%, use an 18-mesh sieve to dry the granules, then add lubricant and mix for 10 minutes;
  • step (3) Mix the components in step (2), add 65-75mL purified water for wet granulation, prepare soft material, pass through 18 mesh sieve, wet granulation, dry at 60°C to 1.5-3.5wt% moisture, use 18 Dry the granules through a mesh sieve and mix for 10 minutes;
  • TDP-6 was used to compress tablets and plain tablets, and sticky tablets appeared during the compression process, which was caused by the lack of lubricant in the prescription.
  • Nitrex has strong mobility and permeability, and because it is yellow or yellow-like, it is easy to dye other materials in contact with yellow.
  • Nitrex prodrug ((S)-(5-nitro) Quinolin-8-yloxy)methyl 1-isopropanoylpyrrolidine-2-carboxylate) is also yellow or yellow-like in color.
  • Example API accounted for% Coating weight gain Whether the color penetrates Example 3 47.64 3% no Example 3-1 47.64 2% no Example 3-2 47.64 4% no Example 4 25.00 3% no Example 4-1 25.00 2% no Example 4-2 25.00 4% no Example 6 33.33 3% no Example 6-1 33.33 2% no Example 6-2 33.33 4% no Example 7 47.62 3% no Example 7-1 47.62 2% no Example 7-2 47.62 4% no Example 8 47.62 3% no Example 8-1 47.62 2% no Example 8-2 47.62 4% no
  • Nitrexine is yellow or yellow-like, and has strong mobility and permeability.
  • the dyeability of the nitroquinoline prodrug-containing preparation of the present invention is greatly reduced, the cleaning difficulty and the production cost are also reduced, and it is industrialized production.
  • the impurity content of the quick-release tablets prepared in Examples 1, 3, and 8 were tested to determine the stability. The steps are as follows:
  • test solution II Take another batch of nitroquinoline prodrug and follow the above method to obtain test solution II.
  • test solution I is used to study the impurity content at room temperature and different storage time (0h, 6h, 12h, 18h, 24h), and the impurity content at 2-8°C and storage for 24 hours;
  • Test solution II is used to study the impurity content under two different stability conditions (the intermediate condition 30°C/65%RH and the accelerated condition 40°C/75%RH shown in Table 2).
  • Test Solution I Take 2mL of Test Solution I, Test Solution II or Test Solution III to a 100mL volumetric flask, add acetonitrile to dilute to the mark; then pipette 1mL of the above solution to a 10mL volumetric flask, make the volume of acetonitrile to the mark, shake well , That's it.
  • test solution I Place the test solution I at room temperature, take samples at 0h, 6h, 12h, 18h, 24h, and prepare a 0.2% self-control solution, inject the samples separately, and calculate the test solution I at each time point The single impurity content and total impurity content.
  • test solution I Place the test solution I in the refrigerator (2-8°C), take samples within 24 hours, prepare a 0.2% self-control solution, and inject the samples separately, and calculate the single impurities in the test solution I at this time point Content and total impurities.
  • test solution II Sample the test solution II at 0 day, one month under intermediate conditions (30°C/65%RH) and one month under accelerated conditions (40°C/75%RH), prepare 0.2% self-control solution, and inject the samples separately. Through self-control, calculate the single impurity content and total impurity content in the test solution II at this time point.
  • test solution III Sample the test solution III at 0 days and 6 months of acceleration, prepare a 0.2% self-control solution, and inject the samples separately. Through the self-control, calculate the single impurity content and total amount in the test solution III at each time point. Impurity content.
  • the instant release tablets of Examples 1, 3, and 8 of the present invention have good stability, and the types of components in other examples are basically similar to those of the above three examples, and the preparation process is similar, so it is inferred that other examples The stability is good.
  • the quick-release tablet of the present invention has good stability and controllable quality.
  • the dissolution rate of the instant-release tablet of the present invention is shown in Table 3 below, and the dissolution curve is shown in Figure 1.
  • Comparative Example 2 because of quality problems during the preparation process, Comparative Example 2 was peeling off from the coating and its appearance was unqualified, and Comparative Example 3 was unqualified in its friability during tableting. Comparative Example 4 It was because the sticky side was not up to standard during tablet pressing, so the dissolution test was not performed.
  • the rapid-release tablets prepared in Examples 1, 3, and 7 were used for animal PK experiments.
  • the experimental method is a single administration in Beagle dogs, among which: Example 1 is fasting administration while adding 20 mL of water; Example 3 is low-fat eating; Example 7 has two conditions, one is low-fat eating, the other It is high-fat eating.
  • Sample collection On the day of the experiment, 0.5 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, and 12h before and after administration, respectively. The collected whole blood sample is placed in an EDTA-K2 anticoagulation tube.
  • Sample processing Centrifuge for 10 minutes to separate the plasma, and collect the upper plasma sample into the sample tube.
  • Sample configuration Take 20 ⁇ L of plasma at each time point above and add 200 ⁇ L of acetonitrile ACN (Honeywell, USA), which contains 5ng/mL verapamil (China Institute for Food and Drug Control) and 50ng/mL glibenclamide (China Food and Drug Control Research Institute) protein precipitation.
  • the mixture was vortexed for 10 minutes and then centrifuged at 3700 rpm for 8 minutes. Then take 70 ⁇ L of the supernatant, add 70 ⁇ L of water to it, and vortex for 10 minutes.
  • An aliquot of 20 ⁇ L of the mixture was injected into the LC-MS/MS (Qtrap 5500, American AB SCIEX company) system for detection.
  • Example 1 Group The animals were fasted overnight before the administration. On the day of the administration, the animals resumed feeding 4 hours after the administration; during the experiment, the animals were allowed to drink freely.
  • the nitroquinoline prodrug will be converted into nitroquinoline when it enters the body. After intravenous injection of the nitroquinoline prodrug in Beagle dogs, it will be converted into the same dose AUC 0-inf as 11258ng ⁇ h ⁇ mL -1 . Compared with the value of the upper intravenous injection, the value of the above embodiment is the absolute bioavailability on the beagle.
  • Example 7 It can be found from the PK curve of Figure 2 that under the low-fat conditions of Example 1, Example 3 and Example 7, the Tmax is relatively small, so it can be seen that the drugs can quickly enter the beagle dog's body.
  • the high-fat Tmax of Example 7 is relatively long (3h).
  • the main analysis is that the addition of water in Example 1 will promote the absorption of the drug, which may be related to the dissolution of the drug.
  • high fat in Example 7 will affect the drug absorption time and C max (the highest blood drug concentration). Combining the aforementioned in vitro dissolution data and beagle PK data as a whole, the immediate-release tablet of the present invention can have a good effect of rapid onset.

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Abstract

含硝羟喹啉前药的药物组合物及其制备方法和应用。该药物组合物包含如下重量份数的各组分：100份活性药物成分、22.5-320份填充剂、0-40份崩解剂、0-95份粘合剂和2-30份润滑剂；相对于每100重量份的活性药物成分，所述填充剂、所述崩解剂和所述粘合剂的总用量为54-345重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。该药物组合物具有良好的稳定性、溶出性质和药代动力学特征。

Description

含硝羟喹啉前药的药物组合物及其制备方法和应用 技术领域
本发明涉及含硝羟喹啉前药的药物组合物及其制备方法和应用。
背景技术
硝羟喹啉，英文全称为Nitroxoline，化学名为5-硝基-8-羟基喹啉，在六十年代曾被开发为口服抗生素药物，主要用于泌尿系统感染，具有较安全的使用历史，后来由于新型抗生素的发现和使用而被取代。最近几年新的研究发现，硝羟喹啉可同时抑制血管内皮细胞中的甲硫氨酸氨基肽酶MetAP2和沉默信息调节因子2相关酶类SIRT1，发挥肿瘤血管新生的协同抑制效应，同时还对肿瘤细胞的增殖有抑制作用。因此，硝羟喹啉又重新被开发用于治疗包括膀胱癌在内的肿瘤。
前药是活性药物经过化学修饰后得到的化合物，其在体内通过酶的作用转化为原来的药物而发挥药效。前药在药物研发中有广泛的应用，前药是药物的一种修饰方法，能够克服其种种不良特点和性质，主要可以带来如下优势:增加药物溶解度、改善药物吸收与分布、增加药物稳定性、降低毒性或不良反应、延长药物作用时间和消除药物不适宜性质等。
为了延长硝羟喹啉的半衰期，公开号为WO/2020/063824的专利申请中做了大量的研究工作，其中公开一种硝羟喹啉的前药，(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯，该前药在进入体内后被代谢成硝羟喹啉而发挥作用，且该前药能够使得硝羟喹啉在体内的半衰期延长，以达到减小给药频率的目的。
然而，现有技术中尚没有针对上述硝羟喹啉前药的制剂。
发明内容
本发明人经过潜心研究开发了针对上述硝羟喹啉前药，(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯的新的制剂，且该制剂具有良好的稳定性和溶出性质，并且具有良好的药代动力学特征，可有利地用于药物的制备，具有良好的临床应用前景。
因此，本发明的目的之一是提供一种含硝羟喹啉前药的药物组合物，其包含如下重量份数的各组分：100份活性药物成分、22.5-320份填充剂、0-40份崩解剂、0-95份粘合剂和2-30份润滑剂；相对于每100重量份的活性药物成分，所述填充剂、所述崩解剂和所述粘合剂的总用量为54-345重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。
上述药物组合物中，所述活性药物成分(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯的结构式如下：
Figure PCTCN2021096037-appb-000001
该活性药物成分可通过公开号为WO/2020/063824的专利申请实施例20的制备方法制得。
上述药物组合物中，所述填充剂可为淀粉、预胶化淀粉、部分预胶化淀粉、乳糖、蔗糖、甘露醇、山梨醇、有水磷酸钙、无水磷酸钙和微晶纤维素中的一种或多种，优选预胶化淀粉、乳糖、蔗糖、甘露醇和微晶纤维素中的一种或多种，更优选预胶化淀粉、甘露醇和微晶纤维素的混合物。当所述填充剂为预胶化淀粉、甘露醇和微晶纤维素的混合物时，三者的重量比优选0.5-2:1:0.5-2，更优选0.8-1.3:1:0.8-1.3，进一步更优选1.06-1.07:1:1.09-1.25。
上述药物组合物中，相对于每100重量份的活性药物成分，所述填充剂的用量优选50-320重量份，更优选60-300重量份，例如100或200重量份，进一步更优选90-200重量份，最优选90.8-93重量份。
上述药物组合物中，所述崩解剂可为低取代羟丙基甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠、交联羧甲基纤维素钠和交联聚维酮中的一种或多种，优选交联羧甲基纤维素钠和交联聚维酮中的一种或两种，更优选交联聚维酮。
上述药物组合物中，相对于每100重量份的活性药物成分，所述 崩解剂的用量优选15-35重量份，例如31.5重量份，更优选15-17重量份。
上述药物组合物中，所述粘合剂可为羟丙基纤维素、羟丙基甲基纤维素、聚维酮和淀粉中的一种或多种，优选羟丙基甲基纤维素、聚维酮和淀粉中的一种或多种。
上述药物组合物中，相对于每100重量份的活性药物成分，所述粘合剂的用量优选10-50重量份。
上述药物组合物中，相对于每100重量份的活性药物成分，所述填充剂、所述崩解剂和所述粘合剂的总重量份优选100-320重量份，例如195或290重量份，更优选100-120重量份，例如108份。
上述药物组合物中，所述润滑剂可为硬脂酸、硬脂酸镁、硬脂酸钙、高分子量聚乙二醇、硬脂富马酸钠和十二烷基磺酸钠中的一种或多种，优选硬脂富马酸钠和十二烷基磺酸钠中的一种或两种，更优选硬脂富马酸钠。
上述药物组合物中，相对于每100重量份的活性药物成分，所述润滑剂的用量优选2-10重量份，例如3.2或5重量份，更优选2-8重量份，进一步更优选2-2.1重量份。
上述药物组合物中，所述药物组合物还可包含包衣剂。所述包衣剂的种类可为本领域常规使用的包衣剂的种类，例如商品名为欧巴代的包衣剂。所述包衣剂的用量可为本领域常规用量，例如所述包衣剂的质量与未包衣前的药物组合物的质量的比值为1.5％-6％，优选2％-4％。
上述药物组合物中，所述药物组合物还可包含着色剂、pH调节剂、表面活性剂、稳定剂和香料中的一种或多种。
上述药物组合物中，所述药物组合物可为本领域常规的剂型，如固体制剂，例如颗粒剂、粉末剂、胶囊剂或片剂，优选片剂，进一步优选速释片剂。
在本发明的一个优选实施方案中，所述药物组合物为片剂，所述片剂包含如下重量份数的各组分：100份活性药物成分、22.5-320份填充剂、0-40份崩解剂、0-95份粘合剂和2-30份润滑剂；相对于每100重量份的活性药物成分，所述填充剂、所述崩解剂和所述粘合剂的总 用量为54-345重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯；
所述填充剂为预胶化淀粉、乳糖、蔗糖、甘露醇和微晶纤维素中的一种或多种；所述崩解剂为交联羧甲基纤维素钠和交联聚维酮中的一种或两种；所述粘合剂为羟丙基甲基纤维素、聚维酮和淀粉中的一种或多种；所述润滑剂为硬脂富马酸钠和十二烷基磺酸钠中的一种或两种。其中，所述片剂优选包衣片，且所述包衣片中包衣剂的质量与未包衣前的素片的质量的比值为1.5％-6％，优选2％-4％(例如3％)。
在本发明的进一步优选实施方案中，所述药物组合物为片剂，所述片剂包含如下重量份数的各组分：100份活性药物成分、22.5-320份填充剂、15-17份崩解剂和2-10份润滑剂；相对于每100重量份的活性药物成分，所述填充剂和所述崩解剂的总用量为100-120重量份(例如108份)；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯；
所述填充剂为预胶化淀粉、甘露醇和微晶纤维素的混合物，且三者的重量比为三者的重量比为0.5-2:1:0.5-2；所述崩解剂为交联聚维酮；所述润滑剂为硬脂富马酸钠。
在上述进一步优选实施方案中，所述填充剂的用量优选60-300重量份，更优选90-200重量份，最优选90.8-93重量份。
在上述进一步优选实施方案中，所述填充剂中预胶化淀粉、甘露醇和微晶纤维素的重量比优选0.8-1.3:1:0.8-1.3，更优选1.06-1.07:1:1.09-1.25。
在上述进一步优选实施方案中，所述润滑剂的用量优选2-8重量份，更优选2-2.1重量份。
在上述进一步优选实施方案中，优选地，所述填充剂的用量为90.8-93重量份；所述填充剂中预胶化淀粉、甘露醇和微晶纤维素的重量比为1.06-1.07:1:1.09-1.25；所述润滑剂的用量为2-2.1重量份。
在上述进一步优选实施方案中，所述片剂可不含粘合剂。
在上述进一步优选实施方案中，所述片剂优选包衣片，且所述包衣片中包衣剂的质量与未包衣前的素片的质量的比值为1.5％-6％，优选2％-4％(例如3％)。
本发明的另一目的是提供一种前述的颗粒剂、粉末剂、胶囊剂或片剂的制备方法，所述制备方法均可为本领域常规的制备方法。
当最终制得的制剂为颗粒剂时，可采用本领域常规的干法制粒，此时，所述制备方法包括如下步骤：
S1：将除润滑剂之外的其余组分进行混合，得混合物I；
S2：将所述混合物I与润滑剂混合，即得。
当最终制得的制剂为颗粒剂时，也可采用本领域常规的湿法制粒，
当所述制剂含有粘合剂时，所述制备方法包括如下步骤：
S1：将除润滑剂和粘合剂之外的其余组分与含有粘合剂的溶液混合，湿整粒，干燥，干整粒，得干颗粒；
S2：将所述干颗粒与润滑剂混合，即得；或者，
当所述制剂不含有粘合剂时，所述制备方法包括如下步骤：
S1：将除润滑剂之外的其余组分与水混合，湿整粒，干燥，干整粒，得干颗粒；
S2：将所述干颗粒与润滑剂混合，即得。
当最终制得的制剂为粉末剂时，所述制备方法包括如下步骤:直接将各组分混合，即得。
当最终制得的制剂为胶囊剂时，所述制备方法包括如下步骤:在前述的颗粒剂的制备方法的基础上，进一步地，将所得颗粒填充至胶囊，即得。
当最终制得的制剂为片剂时，所述制备方法包括如下步骤：在前述的颗粒剂的制备方法的基础上，进一步地，将所得颗粒压片，即得。
本发明的另一目的是提供一种前述的药物组合物或前述的片剂在制备治疗感染性疾病或癌症的药物中的用途。所述感染性疾病例如可为尿路感染。所述癌症例如可为膀胱癌。
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。
本发明的积极进步效果在于：本发明的药物组合物，具有良好的稳定性和优异的溶出性质，并且其药代动力学性质优异，可有利地用于临床开发和应用。
附图说明
图1为实施例1至8制得的速释片及对比例1的片剂的溶出曲线。
图2为实施例1、3、7制得的速释片的药代动力学曲线。
具体实施方式
以下将结合实施例更详细地阐述本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。本领域技术人员可在本发明的范围内做出各种其他改变和改进。
实验试剂：
硝羟喹啉前药为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯，根据专利申请公开号WO/2020/063824中实施例20公开的方法制得。
淀粉：辽宁东源或法国罗盖特
预胶化淀粉：上海卡乐康
微晶纤维素：JRS PHARMA(瑞登梅尔)
羟丙基甲基纤维素：美国Dow(陶氏化学)或日本信越
乳糖：德国美剂乐
硬脂富马酸钠：JRS PHARMA(瑞登梅尔)
十二烷基磺酸钠：德国巴斯夫
交联聚维酮：JRS PHARMA(瑞登梅尔)或美国ISP或德国巴斯夫
甘露醇：法国罗盖特
纯化水：泰州圣洁达
交联羧甲基纤维素钠：美国杜邦
聚维酮：德国巴斯夫
包衣粉(商品名：欧巴代)：上海卡乐康
实验仪器：
电子天平：上海舜宇恒平，FA1004
溶出仪：天津天大天发，RC8MD
溶出仪自动取样器：天大天发，RCQ-8C
压片机：上海天凡，TDP-6
压片机：上海天祥，ZPS008
干法制粒机：南京宏钢盛，GK-25
包衣机：泰州金泰，BY-300
包衣机：浙江小伦，BGB-5F
紫外分光光度计：日本岛津，UV-2700
液相色谱仪：日本岛津，LC-20AT
犬粮：北京科奥协力饲料有限公司
下文中，包衣增重指的是包衣的重量占素片的重量的百分比。
各实施例及对比例的组成和用量如下所示:
Figure PCTCN2021096037-appb-000002
实施例1
制成500片，每片约160mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入20-30mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
实施例2
制成500片，每片约450mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、粘合剂、崩解剂和润滑剂；
(2)制备粘合剂(10wt％的羟丙基甲基纤维素溶液):称量约90mL纯化水，缓慢将羟丙基甲基纤维素加入，边加边搅拌，静置，待完全溶解，备用；
(3)将API和其他各组分过60目筛，备用；
(4)将步骤(3)中除润滑剂之外的其他组分混合，加入步骤(2)制得的粘合剂湿法制粒制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(5)使用ZPS008压片，压制素片；
(6)使用BGB-5F包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
实施例3
制成120片，每片约800mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入25-30mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
另外，按照如上相同的成分、用量和制备方法，制得包衣剂增重 分别为2％和4％的速释片，分别定义为实施例3-1和实施例3-2。
实施例4
制成500片，每片约400mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、粘合剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入55-65mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
另外，按照如上相同的成分、用量和制备方法，制得包衣剂增重分别为2％和4％的速释片，分别定义为实施例4-1和实施例4-2。
实施例5
制成500片，每片约450mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将API和填充剂混合10分钟，干法制粒，筛网18目筛，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
实施例6
制成500片，每片约300mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、粘合剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将API与填充剂、粘合剂混合10分钟，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
另外，按照如上相同的成分、用量和制备方法，制得包衣剂增重分别为2％和4％的速释片，分别定义为实施例6-1和实施例6-2。
实施例7
制成500片，每片约210mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入25-35mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
另外，按照如上相同的成分、用量和制备方法，制得包衣剂增重分别为2％和4％的速释片，分别定义为实施例7-1和实施例7-2。
实施例8
制成500片，每片约210mg。
速释片制备方法：
(1)按照上表分别称取各处方量的API、填充剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入25-35mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％， 用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，即得该实施例的速释片。
另外，按照如上相同的成分、用量和制备方法，制得包衣剂增重分别为2％和4％的速释片，分别定义为实施例8-1和实施例8-2。
对比例1
制成500片，每片约408mg。
片剂制备方法：
(1)按照上表分别称取各处方量的API、填充剂、粘合剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入55-65mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，制得片剂。
对比例2
制成500片，每片约465mg。
片剂制备方法：
(1)按照上表分别称取各处方量的API、填充剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入65-75mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片；
(5)使用BY-300包薄膜衣，包衣增重3％，包衣液浓度15wt％，包衣过程中，发现片面起皮鼓包，判断是崩解剂过多，吸水膨胀导致片面不合格。
对比例3
制成500片，每片约225mg。
片剂制备方法：
(1)按照上表分别称取各处方量的API、填充剂、崩解剂和润滑剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中除润滑剂之外的其他组分混合，加入28-38mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，然后加入润滑剂，混合10分钟；
(4)使用TDP-6压片，压制素片，脆碎度不合格，减重＞1％；不再进行下一步包衣。
对比例4
制成500片，每片约460mg。
片剂制备方法：
(1)按照上表分别称取各处方量的API、填充剂和崩解剂；
(2)将API和其他各组分过60目筛，备用；
(3)将步骤(2)中的各组分混合，加入65-75mL纯化水湿法制粒，制备软材，过18目筛湿整粒，60℃干燥至水分1.5-3.5wt％，用18目筛干整粒，混合10分钟；
(4)使用TDP-6压片，压制素片，压片过程中出现黏片，是处方中缺少润滑剂导致。
测试例1穿透性试验
硝羟喹啉具有很强的迁移性和渗透性，且因其为黄色或类黄色，很容易将其他接触的材料染成黄色，硝羟喹啉前药((S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯)颜色也为黄色或类黄色。
将实施例3、4、6、7和8中制得的不同增重的速释片分别置于白色塑料瓶中，再将白色塑料瓶放置在60℃烘箱中考察10天。观察硝羟喹啉前药是否会穿透包衣膜将白色塑料瓶染黄。其穿透性结果如下表1所示。
表1本发明速释片在不同包衣增重下的颜色穿透性试验结果
实施例 API占比％ 包衣增重 颜色是否穿透
实施例3 47.64 3％ 否
实施例3-1 47.64 2％ 否
实施例3-2 47.64 4％ 否
实施例4 25.00 3％ 否
实施例4-1 25.00 2％ 否
实施例4-2 25.00 4％ 否
实施例6 33.33 3％ 否
实施例6-1 33.33 2％ 否
实施例6-2 33.33 4％ 否
实施例7 47.62 3％ 否
实施例7-1 47.62 2％ 否
实施例7-2 47.62 4％ 否
实施例8 47.62 3％ 否
实施例8-1 47.62 2％ 否
实施例8-2 47.62 4％ 否
由表1可以看出，包衣增重2％至4％，高温60℃，10天均未有颜色穿透，可见包衣增重2％-4％可以满足需要。
硝羟喹啉为黄色或类黄色，具有较强的迁移性和渗透性，而本发明的含有硝羟喹啉前药的制剂的染色性大大降低，清洁难度及生产成本也降低，为工业化生产提供便利；同时不需要使用复杂高成本的包衣工艺，如糖衣、较厚的薄膜衣或其他阻隔性包衣，只需要进行常规的薄膜包衣，工艺简单工业化生产成本低，从而减少患者和国家医疗成本。
测试例2稳定性试验
分别测试实施例1、3、8中制得的速释片的杂质含量，以测定稳定性，其步骤如下：
1、供试液I和供试液II的制备方法
取一个批次的硝羟喹啉前药约25mg，至50mL容量瓶中，加约30mL乙腈超声10分钟，冷却至室温，用乙腈稀释定容至刻度，混匀，取上述溶液适量，过滤，得供试液I。
取另一个批次的硝羟喹啉前药，按照上述方法，得供试液II。
其中，供试液I，用于研究常温及不同存放时间(0h、6h、12h、18h、24h)下的杂质含量，以及，2-8℃及存放24小时下的杂质含量；
供试液II，用于研究两个不同稳定性条件(如表2所示的中间条件30℃/65％RH和加速条件40℃/75％RH)下的杂质含量。
2、供试液III的制备方法
分别随机取相应实施例的0天和6个月(加速条件为40℃/75％RH)的速释片5片置200mL容量瓶中，加甲醇超声溶解(约45分钟)，待冷却至室温后，用甲醇定容至刻度，摇匀，过滤，精密移取1mL续滤液至20mL容量瓶中，用乙腈稀释至刻度，摇匀，得供试液III。
3、0.2％自身对照溶液的制备方法
取供试液I、供试液II或供试液III 2mL至100mL容量瓶中，加乙腈稀释定容至刻度；再移取上述溶液1mL至10mL容量瓶中，乙腈定容至刻度，摇匀，即得。
4、杂质含量测定
将供试液I，置于室温下，分别在0h、6h、12h、18h、24h取样，并配制0.2％自身对照溶液，分别进样，通过自身对照，计算每个时间点供试液I中的单杂含量及总杂含量。
将供试液I，置于冰箱(2-8℃)条件下，在24h取样，并配制0.2％自身对照溶液，分别进样，通过自身对照，计算该时间点供试液I中的单杂含量及总杂含量。
将供试液II，分别在0天、中间条件(30℃/65％RH)一个月和加速条件(40℃/75％RH)一个月时取样，配制0.2％自身对照溶液，分别进样，通过自身对照，计算该时间点供试液II中的单杂含量及总杂含量。
将供试液III，分别在加速0天和6个月时取样，并配制0.2％自身对照溶液，分别进样，通过自身对照，计算每个时间点供试液III中的单杂含量及总杂含量。
其中，色谱条件如下：
Figure PCTCN2021096037-appb-000003
Figure PCTCN2021096037-appb-000004
杂质含量测定结果如下表2所示。
表2硝羟喹啉前药溶液和本发明速释片的杂质含量
Figure PCTCN2021096037-appb-000005
注：-表示未检出
由表2可以看出，本发明实施例1、3和8的速释片稳定性良好，其他实施例组分的种类和上述3个实施例基本近似，同时制备工艺相 近，所以推断其他实施例稳定良好，综上所述本发明的速释片，稳定性良好，质量可控。
测试例3溶出度试验
分别测试实施例1-8的速释片和对比例1中制备的片剂的溶出度。用紫外分光光度计测定吸光度，按照外标法，分别计算溶出度，方法如下：
在37℃、900mL、0.1N HCl介质中，采用篮法75rpm，6片，分别在5、10、15、20、30、45、60分钟时取样10mL，补液10mL，样品稀释40倍，在243nm波长下紫外可见分光光度计检测。称取5mg API至100mL容量瓶中，加入上述0.1N HCl介质超声溶解稀释并定容至刻度，稀释5倍作为对照品，在243nm波长下紫外可见分光光度计检测。
本发明速释片的溶出度如下表3所示，其溶出曲线如图1所示。
表3实施例1至8的速释片和对比例1的片剂的溶出度
Figure PCTCN2021096037-appb-000006
对比例2、3和4，因为在制备过程中出现质量问题，对比例2是包衣时起包掉皮、外观性状不合格，对比例3是压片时脆碎度不合格，对比例4是压片时黏冲片面不合格，故没有进行溶出检测。
由上表3和图1可知，实施例1至8的速释片的溶出曲线根据处方组成辅料的变化，溶出曲线略有差异，但是均符合体外快速释放的要求(15分钟溶出不低于标示量的80％)。而对比例1的处方中填充剂、崩解剂及粘合剂三者的总用量过大，导致产品的溶出和实施例1至8相比慢很多，不符合预期快速释放的目标(15分钟溶出不低于标示量的 80％)。
测试例4药代动力学实验
用实施例1、3和7中制备的速释片进行动物PK实验。实验方法为比格犬体内单次给药，其中：实施例1是空腹给药同时加喂20mL水；实施例3是低脂进食；实施例7两个条件，一个是低脂进食，另一个是高脂进食。
具体实验方法：
动物信息：比格犬，n＝3，北京玛斯生物技术有限公司；
动物饮食状态：给药前动物禁食过夜，实验过程中自由饮水，其他按照分组方案；
样品收集：实验当天，分别于给药前和给药后0.083、0.25、0.5、0.75、1、1.5、2、2.5、4、6、8、10、12h时间点，经由颈静脉采血0.5mL，采集的全血样品置于EDTA-K2抗凝管中。
样品处理：离心10分钟分离血浆，收集上层血浆样品至样品管中。
样品配置：取上述各个时间点的血浆20μL，分别加入200μL的乙腈ACN(美国Honeywell)，其中包含5ng/mL维拉帕米(中国食品药品检定研究院)和50ng/mL格列本脲(中国食品药品检定研究院)的蛋白质沉淀。将混合物涡旋10分钟，然后在3700rpm条件下离心8分钟。然后取70μL的上清液，再向其中加入70μL的水，然后涡旋10分钟。将等份的20μL混合物注入LC-MS/MS(Qtrap 5500，美国AB SCIEX公司)系统进行检测。
实施例1组：给药前动物禁食过夜，给药当天，动物给药4h后恢复给食；实验过程中，动物可自由饮水。
实施例3组：给药前动物禁食过夜，实验过程中，动物可自由饮水，每只动物于给药当天灌胃给予约150mL的流食(犬粮:犬饮用水＝30g:120mL匀制而成)，动物给药6h后正常给食。
实施例7低脂进食组:给药前动物禁食过夜，实验过程中，动物可自由饮水，每只动物于给药当天灌胃给予约150mL的流食(犬粮:犬饮用水＝30g:120mL匀制而成)，动物给药6h后正常给食。
实施例7高脂进食组:给药前动物禁食过夜，实验过程中，动物可 自由饮水，每只动物于给药当天灌胃给予约150mL的流食(犬粮:橄榄油:犬饮用水＝30g:28mL:120mL匀制而成)，动物给药6h后正常给食。
所得药代动力学参数，如下表4所示，药代动力学曲线见图2。
表4本发明速释片的药代动力学参数
Figure PCTCN2021096037-appb-000007
注：硝羟喹啉前药进入体内会转换成硝羟喹啉，比格犬的静脉注射硝羟喹啉前药后，折算成相同剂量AUC 0-inf为11258ng·h·mL -1，用上述实施例的值比上静脉注射的值即为比格犬上的绝对生物利用度。
从图2的PK曲线可以发现，实施例1空腹、实施例3和实施例7低脂条件下，T max较小，故可知药物均能快速进入比格犬体内。实施例7高脂的T max相对较长(3h)，分析主要原因是实施例1加水会促进药物吸收，可能和药物的溶解相关。另外，实施例7中高脂会影响药物吸收时间和C max(最高血药浓度)。结合前述体外溶出数据和比格犬PK数据整体看，本发明的速释片能够起到快速起效的良好效果。
本发明的速释片，患者口服后能够迅速吸收(T max＝0.67-3小时)，生物利用度较高，有些甚至高达90％以上。
以上详细描述了本发明的优选实施方案，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单的变型，包括各个技术特征以任何其他的合适方式进行组合，这些简单变型和组合同样视为本发明所公开的内容，均属于本发明的保护范围。

Claims (10)

  1. 一种含硝羟喹啉前药的药物组合物，其特征在于，其包含如下重量份数的各组分:100份活性药物成分、22.5-320份填充剂、0-40份崩解剂、0-95份粘合剂和2-30份润滑剂；相对于每100重量份的活性药物成分，所述填充剂、所述崩解剂和所述粘合剂的总用量为54-345重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。
  2. 根据权利要求1所述的含硝羟喹啉前药的药物组合物，其特征在于，所述填充剂选自淀粉、预胶化淀粉、部分预胶化淀粉、乳糖、蔗糖、甘露醇、山梨醇、有水磷酸钙、无水磷酸钙和微晶纤维素中的一种或多种；优选预胶化淀粉、乳糖、蔗糖、甘露醇和微晶纤维素中的一种或多种；更优选预胶化淀粉、甘露醇和微晶纤维素的混合物，其中，三者的重量比优选0.5-2:1:0.5-2，更优选0.8-1.3:1:0.8-1.3，进一步更优选1.06-1.07:1:1.09-1.25；
    和/或，相对于每100重量份的活性药物成分，所述填充剂的用量为50-320重量份，优选60-300重量份，更优选90-200重量份，最优选90.8-93重量份；
    和/或，所述崩解剂选自低取代羟丙基甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠、交联羧甲基纤维素钠和交联聚维酮中的一种或多种，优选交联羧甲基纤维素钠和交联聚维酮中的一种或两种，更优选交联聚维酮；
    和/或，相对于每100重量份的活性药物成分，所述崩解剂的用量为15-35重量份，优选15-17重量份；
    和/或，所述粘合剂选自羟丙基纤维素、羟丙基甲基纤维素、聚维酮和淀粉中的一种或多种，优选羟丙基甲基纤维素、聚维酮和淀粉中的一种或多种；
    和/或，相对于每100重量份的活性药物成分，所述粘合剂的用量为10-50重量份；
    和/或，相对于每100重量份的活性药物成分，所述填充剂、所述 崩解剂和所述粘合剂的总重量份为100-320重量份，优选100-120重量份。
  3. 根据权利要求1或2所述的含硝羟喹啉前药的药物组合物，其特征在于，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、高分子量聚乙二醇、硬脂富马酸钠和十二烷基磺酸钠中的一种或多种，优选硬脂富马酸钠和十二烷基磺酸钠中的一种或两种，更优选硬脂富马酸钠；
    和/或，相对于每100重量份的活性药物成分，所述润滑剂的用量为2-10重量份，优选2-8重量份。
  4. 根据权利要求1至3中任一项所述的含硝羟喹啉前药的药物组合物，其特征在于，所述药物组合物还包含包衣剂；所述包衣剂的质量与未包衣前的药物组合物的质量的比值为1.5％-6％，优选2％-4％；
    和/或，所述药物组合物还包含着色剂、pH调节剂、表面活性剂、稳定剂和香料中的一种或多种。
  5. 根据权利要求1至4中任一项所述的含硝羟喹啉前药的药物组合物，其特征在于，所述药物组合物为固体制剂，优选颗粒剂、粉末剂、胶囊剂或片剂，更优选片剂，进一步优选速释片剂。
  6. 一种含硝羟喹啉前药的片剂，其特征在于，所述片剂包含如下重量份数的各组分:100份活性药物成分、22.5-320份填充剂、0-40份崩解剂、0-95份粘合剂和2-30份润滑剂；相对于每100重量份的活性药物成分，所述填充剂、所述崩解剂和所述粘合剂的总用量为54-345重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯；
    所述填充剂为预胶化淀粉、乳糖、蔗糖、甘露醇和微晶纤维素中的一种或多种；所述崩解剂为交联羧甲基纤维素钠和交联聚维酮中的一种或两种；所述粘合剂为羟丙基甲基纤维素、聚维酮和淀粉中的一种或多种；所述润滑剂为硬脂富马酸钠和十二烷基磺酸钠中的一种或两种；其中，所述片剂优选包衣片，且所述包衣片中包衣剂的质量与 未包衣前的素片的质量的比值为1.5％-6％，优选2％-4％。
  7. 一种含硝羟喹啉前药的片剂，其特征在于，所述片剂包含如下重量份数的各组分：100份活性药物成分、22.5-320份填充剂、15-17份崩解剂和2-10份润滑剂；相对于每100重量份的活性药物成分，所述填充剂和所述崩解剂的总用量为100-120重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯；
    所述填充剂为预胶化淀粉、甘露醇和微晶纤维素的混合物，且三者的重量比为0.5-2:1:0.5-2；所述崩解剂为交联聚维酮；所述润滑剂为硬脂富马酸钠；
    其中，所述填充剂的用量优选60-300重量份，更优选90-200重量份，最优选90.8-93重量份；
    其中，所述填充剂中预胶化淀粉、甘露醇和微晶纤维素的重量比优选0.8-1.3:1:0.8-1.3，更优选1.06-1.07:1:1.09-1.25；
    其中，所述润滑剂的用量优选2-8重量份，更优选2-2.1重量份；
    其中，优选地，所述填充剂的用量为90.8-93重量份；所述填充剂中预胶化淀粉、甘露醇和微晶纤维素的重量比为1.06-1.07:1:1.09-1.25；所述润滑剂的用量为2-2.1重量份。
  8. 根据权利要求7所述的含硝羟喹啉前药的片剂，其特征在于，所述片剂不含粘合剂；
    和/或，所述片剂为包衣片，且所述包衣片中包衣剂的质量与未包衣前的素片的质量的比值为1.5％-6％，优选2％-4％。
  9. 一种颗粒剂、粉末剂、胶囊剂或片剂的制备方法，其特征在于，所述制备方法中所用的原料为根据权利要求1至5中任一项所述的含硝羟喹啉前药的药物组合物；
    当最终制得的制剂为颗粒剂时，
    所述制备方法为干法制粒，所述制备方法包括如下步骤：
    S1：将除润滑剂之外的其余组分进行混合，得混合物I；
    S2：所述混合物I与润滑剂混合，即得；
    或者，
    所述制剂含有粘合剂，且所述制备方法为湿法制粒，所述制备方法包括如下步骤：
    S1：将除润滑剂和粘合剂之外的其余组分与含有粘合剂的溶液混合，湿整粒，干燥，干整粒，得干颗粒；
    S2：将所述干颗粒与润滑剂混合，即得；
    或者，
    所述制剂不含有粘合剂，且所述制备方法为湿法制粒，所述制备方法包括如下步骤：
    S1：将除润滑剂之外的其余组分与水混合，湿整粒，干燥，干整粒，得干颗粒；
    S2：将所述干颗粒与润滑剂混合，即得；
    当最终制得的制剂为粉末剂时，所述制备方法包括如下步骤：直接将各组分混合，即得；
    当最终制得的制剂为胶囊剂时，所述制备方法包括如下步骤：在所述颗粒剂的制备方法的基础上，进一步地，将所得颗粒填充至胶囊，即得；
    当最终制得的制剂为片剂时，所述制备方法包括如下步骤:在所述颗粒剂的制备方法的基础上，进一步地，将所得颗粒压片，即得。
  10. 一种根据权利要求1至5中任一项所述的含硝羟喹啉前药的药物组合物或根据权利要求6至8中任一项所述的含硝羟喹啉前药的片剂在制备治疗感染性疾病或癌症的药物中的用途；所述感染性疾病优选尿路感染；所述癌症优选膀胱癌。
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