WO2018095403A1 - 一种吡啶酮类衍生物药物组合物及其制备方法 - Google Patents

一种吡啶酮类衍生物药物组合物及其制备方法 Download PDF

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WO2018095403A1
WO2018095403A1 PCT/CN2017/112829 CN2017112829W WO2018095403A1 WO 2018095403 A1 WO2018095403 A1 WO 2018095403A1 CN 2017112829 W CN2017112829 W CN 2017112829W WO 2018095403 A1 WO2018095403 A1 WO 2018095403A1
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pharmaceutical composition
weight
mannitol
microcrystalline cellulose
composition according
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English (en)
French (fr)
Inventor
丁欢
张代美
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to US16/462,317 priority Critical patent/US10709699B2/en
Priority to JP2019523766A priority patent/JP2019535696A/ja
Priority to CA3041561A priority patent/CA3041561A1/en
Priority to CN201780016842.8A priority patent/CN108778281B/zh
Priority to EP17873406.7A priority patent/EP3545957A4/en
Publication of WO2018095403A1 publication Critical patent/WO2018095403A1/zh
Anticipated expiration legal-status Critical
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a method comprising 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy
  • melanoma is the most aggressive type of skin cancer and is the leading cause of death from skin diseases.
  • the National Cancer Institute estimates that in 2013, 76,690 Americans will be diagnosed with melanoma, and 9,480 people will die of the disease.
  • About half of melanoma patients carry a mutated BRAF protein kinase gene that promotes melanoma growth and spread, with V600 accounting for the majority.
  • cytotoxic dacarbazine chemotherapy was the main treatment for malignant melanoma.
  • dacarbazine is a DNA alkylation preparation that not only has a large side effect, but also has a response rate of only about 10%, and the 1-year survival rate is only about 36%.
  • Mekinist is the first MEK inhibitor to be used as a single-agent oral tablet for the treatment of unresectable melanoma or metastatic melanoma in adults with BRAF V600E or V600K mutations.
  • BRAF V600E mutations account for approximately metastatic melanoma.
  • V600K mutations accounted for approximately 10% of all BRAF V600 mutations in metastatic melanoma.
  • patients who received Mekinist treatment had a tumor survival delay of 3.3 months compared with those who received chemotherapy.
  • CN103998041A discloses an oral solid preparation of the MEK inhibitor trimetinib which is substantially free of water and which solves the stability of the solid preparation, the dissolution rate and the solvent removal of the trimetinib solvate when administered in vivo. Adverse pharmacodynamic problems caused by chemotherapy.
  • CN104902876A discloses a powder formulation comprising trimetinib and a solubilizing agent selected from the group consisting of cyclodextrin-based pharmaceutical excipients to solve the dissolution of the powder formulation and the solvation of trimetinib. The problem of desolvation when the substance is administered in vivo.
  • WO2015058589 discloses and claims 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl- 1,6-Dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, which is useful as an inhibitor of MEK activity, particularly in the treatment of cancer.
  • WO2016155473 discloses 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl-1,6 Form I crystal of dihydropyridine-3-carboxamide p-toluenesulfonate (Compound A) and a process for the preparation thereof.
  • the form of the pharmaceutically active compound having low solubility presents various challenges in the preparation of high quality solid pharmaceutical compositions or solid preparations (e.g., tablets, granules, micropowders), while Compound A and its salts have low solubility, all of which are described above. There is no mention of how to solve such problems to provide a composition with satisfactory dissolution.
  • the present invention provides an oral solid pharmaceutical composition
  • an oral solid pharmaceutical composition comprising the active ingredient 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl) Oxo)-6-carbonyl-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, and hypromellose.
  • the pharmaceutical composition has improved properties such as rapid dissolution, good stability, and acceptable dissolution and disintegration properties. These improved properties help to ensure safe and effective administration, and the preparation process is simple and more suitable for process production.
  • the active ingredient may be included in an amount of 0.01 to 10%, preferably 0.1 to 5%, and may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.7 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.0% by weight of the pharmaceutical composition.
  • the active ingredient of the present invention 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl -1,6-dihydropyridine-3-carboxamide in oral solid drug group
  • the weight of the compound is 0.125 mg, 0.5 mg, 1 mg, 2 mg; or a pharmaceutically acceptable salt of the active ingredient of the present invention, such as a tosylate salt, which has a weight of 0.168 mg, 0.674 mg, 1.340 mg, 2.694 in the pharmaceutical composition.
  • the mg is based on 100 mg (100 mg/part) of the oral solid pharmaceutical composition per serving.
  • the amount of the hypromellose of the present invention is 0.5 to 10%, preferably 1 to 5% by weight of the pharmaceutical composition, and may be 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8. 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0%, more preferably 1.5 to 3%, by weight of the pharmaceutical composition.
  • the hypromellose of the present invention has a weight of 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg in the oral solid pharmaceutical composition. 3.0 mg, based on 100 mg (100 mg/part) of the oral solid pharmaceutical composition per serving.
  • the active ingredient in the pharmaceutical composition of the present invention needs to be micronized prior to preparation to achieve the desired particle size.
  • 90% of the particles of the active ingredient have a particle size of less than or equal to 50 ⁇ m (which may be expressed as D90 or d (0.9)), and may be 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, preferably less than or equal to 10 ⁇ m.
  • the pharmaceutical composition of the present invention may further contain at least one pharmaceutical excipient of a filler, a disintegrant, a glidant, a lubricant, and a coating agent.
  • the "by weight of the pharmaceutical composition" of the present invention is a range of the amount of use of the active ingredient or other kind of medicinal excipients in the weight of the core without the coating agent. For details, see Example 1.
  • the filler provides volume, the tablet is made to the actual size of the processable treatment, and may also aid in processing to improve the physical properties of the pharmaceutical composition such as flowability, compressibility and hardness of the solid formulation. Since the amount of the filler used in the pharmaceutical composition is large and it is in direct contact with the active ingredient (or active compound), the interaction of the filler with the active ingredient is of particular interest to those skilled in the art.
  • the fillers of the present invention are known or determinable by those skilled in the art and may preferably be, but are not limited to, at least one of mannitol, lactose, microcrystalline cellulose, pregelatinized starch, and calcium hydrogen phosphate.
  • the filler of the present invention is used in an amount of 30 to 95% by weight of the pharmaceutical composition, preferably 50 to 94%, and may be 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 76, 80, 82, 86, 88, 89, 90, 91, 92, 93, 94% by weight of the pharmaceutical composition.
  • the filler of the present invention has an weight of 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg in an oral solid pharmaceutical composition.
  • the solid pharmaceutical composition is calculated as 100 mg (100 mg/part) per serving.
  • the filler is preferably at least one of mannitol and microcrystalline cellulose; further, the pharmaceutical composition of the present invention uses mannitol and microcrystalline cellulose as a filler, wherein the nectar
  • the weight ratio of the alcohol to the microcrystalline cellulose is from 1.5:1 to 10:1.
  • the weight ratio of mannitol to microcrystalline cellulose is from 1.8:1 to 4:1. It can be 1.9:1, 2:1, 2.:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1.
  • Disintegrants are used to promote disruption or disintegration of the pharmaceutical composition after administration.
  • the disintegrants of the present invention are known or determinable by those skilled in the art and may be selected from, but not limited to, starch, cellulose, gums, crosslinked polymers, and foaming agents such as corn starch, potato starch, pre- Gelatinized starch, modified corn starch, croscarmellose sodium, crospovidone, sodium starch glycolate, magnesium aluminum silicate HV, methyl cellulose, microcrystalline cellulose, cellulose, colloidal Silica, natural sponge, cation exchange resin, preferably self-cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, crospovidone or low-substituted hydroxypropyl cellulose, croscarmellose sodium, At least one of sodium carboxymethyl starch, crospovidone or low-substituted hydroxypropyl cellulose.
  • the disintegrant of the present invention is used in an amount of 2 to 15% by weight of the pharmaceutical composition, and may be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15% by weight of the pharmaceutical composition.
  • Lubricants are commonly used to facilitate processing, prevent formulation materials from adhering to production equipment, less friction between particles, improve the flow rate of the formulation, and aid in the removal of the formulation from the production equipment.
  • the lubricants of the present invention are known or determinable by those skilled in the art and may be selected from, but not limited to, talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate), Polyethylene glycol, ethylene oxide polymer, liquid paraffin, sodium phosphate, leucine, sodium stearyl fumarate, preferably from magnesium stearate, stearic acid, palmitic acid, calcium stearate At least one of talc, carnauba wax, sodium stearyl fumarate; further, the lubrication of the present invention
  • the amount of the agent is 0.1 to 5% by weight based on the total weight of the pharmaceutical composition, and may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,
  • a pharmaceutical composition comprising:
  • the filler is preferably at least one of mannitol and microcrystalline cellulose;
  • the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone or low substitution.
  • the lubricant is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, sodium stearyl fumaratekind.
  • the filler is a mixture of mannitol and microcrystalline fibers, and the weight ratio of the two pharmaceutical excipients is from 1.5:1 to 10:1, preferably from 1.8:1 to 4:1.
  • the pharmaceutical composition of the present invention may further comprise a coating agent, and the coating agent (non-localized release coating) may be, but not limited to, hypromellose, methyl cellulose, and B.
  • the coating agent non-localized release coating
  • the coating agent may be, but not limited to, hypromellose, methyl cellulose, and B.
  • the invention also provides a process for the preparation of a pharmaceutical composition according to the invention, which comprises: 1) 1-((6-bromoquinolin-4-yl)thio)cyclobutylcarboxylic acid or its pharmaceutically acceptable
  • the salt is mixed with the disintegrant and optionally at least one of the pharmaceutically acceptable excipients selected from the group consisting of fillers, binders, lubricants, and glidants, 2) the mixture obtained from 1) is granulated and then tableted or filled.
  • the coating agent is Opadry, hypromellose, ethyl cellulose or polyvinyl alcohol, preferably Europe Badai.
  • the granulation method used in the present invention may be wet granulation or dry granulation.
  • wet granulation scheme When the wet granulation scheme is selected, fluidized bed granulation or high shear wet granulation may be employed.
  • the high speed shear granulation process steps are as follows:
  • step 3 Add a lubricant to the granules in step 2 and mix.
  • step 3 The mixture in step 3 is compressed into tablets.
  • the fluidized bed granulation process steps are as follows:
  • step 2 The powder mixture in step 1 is fluidized, and the solution containing hypromellose is sprayed onto the powder mixing surface, dried, and granulated.
  • step 3 Add a lubricant to the granules in step 2 and mix.
  • step 3 The mixture in step 3 is compressed into tablets.
  • the granulation method employs high speed shear granulation and fluidized bed granulation.
  • the present invention also provides an oral solid pharmaceutical composition
  • an oral solid pharmaceutical composition comprising the active ingredient 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl) Oxo)-6-carbonyl-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, mannitol and microcrystalline cellulose, wherein the weight ratio of mannitol to microcrystalline cellulose is 1.5:1 ⁇ 10:1, the pharmaceutical composition can be improved very well; further, the weight ratio of mannitol to microcrystalline cellulose is 1.8:1 to 4:1, which can be 1.9:1, 2:1, 2.2:1.
  • the amount of the alcohol and the amount of the microcrystalline cellulose are 30 to 95% by weight, preferably 50 to 94% by weight of the pharmaceutical composition, and may be 50, 52, 54, 56, 58, 60, 62, 64, 66, 68. 70, 72, 76, 80, 82, 86, 88, 89, 90, 91, 92, 93, 94% by weight of the pharmaceutical composition.
  • the filler of the present invention has an weight of 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg in an oral solid pharmaceutical composition.
  • the solid pharmaceutical composition is calculated as 100 mg (100 mg/part) per serving.
  • the oral solid pharmaceutical composition (solid preparation) of the present invention may be a tablet, a granule, Powder (including fine granules), or capsules.
  • the solid preparation can be obtained by a widely known preparation method, and the maximum water content of the final dried granule after granulation is controlled to be 3% or less, and then filled into capsules or directly packaged into granules.
  • the dosage form is a tablet
  • the humidity of the tableting environment is controlled during the tableting process to ensure that the water content of the final tablet is less than 3% (3% or less), and the final composition is ensured by vacuum drying the final composition.
  • the amount of water is less than 3%.
  • the pharmaceutical composition of the present invention employs a tablet
  • it can be prepared by compressing the granules obtained as described above.
  • the pressure of compression can be determined within an appropriate range, and the pressure is preferably from 1 to 10 kN.
  • the shape of the tablet is not particularly limited, and is preferably a lenticular shape, a disc shape, a circular shape, an elliptical shape (such as a caplet sheet), a teardrop shape or a polygonal shape (such as a triangle or a diamond shape).
  • the prepared tablets may be coated by spraying a suspension/solution of the coating agent through a pancoater. After the coating is completed, the moisture content of the final tablet is controlled to within 3% by a drying process.
  • the drying temperature can be selected from 40 to 80 ° C, preferably from 50 to 60 ° C.
  • the drying method can be carried out by ordinary oven drying or vacuum drying.
  • the granules obtained as described above may be used as they are or may be granulated into a desired granule by a suitable technique.
  • the granules thus prepared may be coated with a suspension of the spray coating agent with a coating agent.
  • the dissolution rate of the pharmaceutical composition according to the present invention is determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four-part general rule 0931, and the pH 6.8 phosphate buffer is used as the dissolution medium, preferably 1000 ml of pH 6. 8 phosphate buffer, and the dissolution test of the composition of the invention at a paddle speed of 50 rpm at 37 ⁇ 0.5 ° C, the dissolution rate of greater than or equal to 90% in 45 minutes, may be greater than or equal to 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, 100%, preferably greater than or equal to 94%.
  • the dissolution rate in 30 minutes is greater than or equal to 80%, and may be greater than or equal to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, preferably greater than or equal to 85%.
  • 6-Dihydropyridine-3-carboxamide can be obtained by the method described in WO2015058589 and WO2016155473.
  • the pharmaceutical excipients used in the present invention are all commercially available It is commercially available, such as lactose, microcrystalline cellulose, and the like.
  • Figure 1 Shows the dissolution profile of the tablet of Example 1 in pH 6.8 phosphate buffer.
  • Figure 2 shows the dissolution profile of the tablet of Example 2 in pH 6.8 phosphate buffer.
  • Figure 3 shows the dissolution profile of the tablet of Example 4 in pH 6.8 phosphate buffer.
  • Compound A 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl-1,6-di Hydropyridine-3-carbamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose, croscarmellose sodium according to the ratio in Table 1, using a high-speed shear granulator Wet granulation, 5% aqueous solution prepared with povidone K30 or 3% or 4% aqueous solution made of hypromellose as wettifier, wet granules and drying of wet materials, then Dry granules (water content less than 3%) are dry granulated, and a prescribed amount of magnesium stearate is added and mixed well. The resulting total mixed granules were compressed into tablets.
  • the dissolution rate of the tablets of Examples 1 to 4 was measured according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four general rules 0931. 1000 ml of pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Experimental Example 1, the dissolution of Compound A was slow and incomplete; in Experimental Examples 2 and 3, the dissolution of Compound A was rapid but incomplete. In Example 4, Compound A was eluted rapidly and completely dissolved. The dissolution data are shown in Table 2 below, and the dissolution profile is shown in Figure 1.
  • Compound A 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl-1,6-di Hydropyridine-3-carbamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose, croscarmellose sodium according to the ratio in Table 3, using a high-speed shear granulator Wet granulation, 4% aqueous solution made of hypromellose is used as wetting agent, wet granules and drying treatment of wet materials, then dry granules (less than 3% moisture) are dry granulated and added to the prescription. Amount of magnesium stearate, mixed evenly. The resulting total mixed granules were compressed into tablets.
  • the dissolution rate of the tablets in Experimental Examples 4 to 7 was measured according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition four general rules 0931. 1000 ml of pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Experimental Examples 4 to 7, the dissolution was complete.
  • the dissolution data is shown in Table 4 below, and the dissolution profile is shown in Figure 2.
  • Compound A 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl-1,6-di Hydropyridine-3-carboxamide p-toluenesulfonate (hereinafter referred to as Compound A) was passed through an 80 mesh sieve and micronized by a Mcone jet mill (squeezing pressure 4 bar, injection pressure 6 bar), and then directly using a Malvern laser. The particle size was measured by a particle size analyzer (Mastersizer 2000), and the results are shown in Table 5 below.
  • Raw material processing method Raw material particle size d (0.5) Raw material particle size d (0.9) 80 mesh sieve 4.940 14.148 Airflow micronization 2.587 5.494
  • the dissolution rate of the tablets of Example 4 was determined according to the second method (paddle method) for the determination of dissolution in accordance with the Chinese Pharmacopoeia 2015 Edition, General Rules, Form 0931. 1000 ml of pH 6.8 phosphate buffer was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm.
  • the results show that the particle size of the raw material pulverized by the jet mill is less than the particle size of the raw material treated by the 80 mesh sieve, and is less than 10 ⁇ m; the sample prepared by the 80 mesh treated raw material is incompletely eluted; the micronized treatment by the jet mill
  • the dissolution rate of the sample prepared from the raw material was significantly faster than that of the sample prepared from the 80 mesh treated material, and the dissolution was complete.
  • the dissolution data is shown in Table 6 below, and the dissolution profile is shown in Figure 3.
  • Compound A 2-((2-Fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxo)-6-carbonyl-1,6-di Hydropyridine-3-carbamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose, croscarmellose sodium according to the ratio in Table 1, using a high-speed shear granulator Wet granulation, 3% aqueous solution made of hypromellose is used as wetting agent, wet granules are dried and dried, then dry granules (less than 3% moisture) are dry granulated and added. Prescribe the amount of magnesium stearate and mix well. The resulting total mixed granules were compressed into tablets.

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Abstract

本发明提供了一种吡啶酮类衍生物药物组合物及其制备方法。具体而言，本发明提供了一种含有吡啶酮类衍生物或其可药用盐的药物组合物及其制备方法，所述的药物组合物包含活性成分2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐，和羟丙甲纤维素，该药物组合物具有良好的溶出度。

Description

一种吡啶酮类衍生物药物组合物及其制备方法 技术领域
本发明属于药物制剂领域，具体涉及一种含有2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐的药物组合物及其制备方法。
背景技术
黑色素瘤是最具有侵略性类型的皮肤癌，是来自皮肤疾病的主要死亡病因。美国国家癌症研究所估计，2013年，76690美国人将被诊断患有黑色素瘤，而9480人将死于此病。约半数的黑色素瘤患者带有突变的BRAF蛋白激酶基因，该异常突变能促使黑色素瘤生长和扩散，而V600占其中的多数。遗憾的是在2011年之前，采用细胞毒素达卡巴嗪化疗是治疗恶性黑色素瘤的主要疗法。达卡巴嗪是一种DNA烷基化制剂，不仅副作用大，而且应答率只有10％左右，1年生存率大约只有36％。2011年Yervoy和Zelboraf两个突破性新药的上市改变了黑色素瘤的治疗现状。2013年5月29日，美国食品药品监督管理局(FDA)批准葛兰素史克(GSK)新药Mekinist(trametinib)用于晚期或不可切除黑色素瘤的治疗。Mekinist为首个MEK抑制剂，作为一种单药口服片剂，适用于携带BRAF V600E或V600K突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者的治疗，BRAF V600E突变约占转移性黑色素瘤所有BRAF V600突变的85％，V600K突变约占转移性黑色素瘤所有BRAF V600突变的10％。Mekinist在322例患者试验中，接受Mekinist治疗比接受化疗的患者肿瘤生存期延迟3.3个月。
CN103998041A公开了MEK抑制剂曲美替尼的口服固体制剂，该固体制剂所用赋形剂基本不含有水，以及解决固体制剂稳定性、溶出度以及曲美替尼溶剂化物在体内给药时去溶剂化而导致的不良药效学问题。
CN104902876A公开含有曲美替尼和增溶剂的粉末制剂，所述增溶剂选自环糊精类药用辅料，以解决粉末制剂溶出度和曲美替尼溶剂化 物在体内给药时去溶剂化的问题。
WO2015058589公开并要求保护了2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐，其作为MEK活性的抑制剂是有用的，特别是在癌症的治疗中。WO2016155473公开了2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(化合物A)的I型结晶及其制备方法。
Figure PCTCN2017112829-appb-000001
具有低溶解度的药用活性化合物形式在制备高质量的固体药物组合物或固体制剂(如片剂、颗粒、微粉)时会存在多种挑战，而化合物A及其盐溶解度较低，前述文献均未提及如何解决这样的问题，以提供溶出度令人满意的组合物。
发明内容
本发明提供一种口服固体药物组合物，含有活性成分2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐，和羟丙甲纤维素。该药物组合物具有溶出迅速、稳定性良好和可接受的溶出度和崩解度性质等改良性质，这些改良性质有助于确保安全有效的用药，且其制备工艺简单，更适合工艺化生产。
在本发明的实施方案中，所述活性成分的含量可以为0.01～10％，优选为0.1～5％，可为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.7、3.9、4.1、4.3、4.5、4.7、4.9、5.0％，以药物组合物重量计。
进一步地，本发明活性成分2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺在口服固体药物组 合物中重量为0.125mg、0.5mg、1mg、2mg；或本发明活性成分的可药用盐，譬如甲苯磺酸盐，其在药物组合物中重量为0.168mg、0.674mg、1.348mg、2.694mg，以口服固体药物组合物每份100mg(100mg/份)计。
进一步地，本发明所述羟丙甲纤维素的用量占药物组合物重量的0.5～10％，优选1～5％，可为1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0％，更优选为1.5～3％，以药物组合物重量计。
进一步地，本发明所述羟丙甲纤维素在口服固体药物组合物中重量为2.0mg、2.1mg、2.2mg、2.3mg、2.4mg、2.5mg、2.6mg、2.7mg、2.8mg、2.9mg、3.0mg，以口服固体药物组合物每份100mg(100mg/份)计。
为了保证药物组合物具有好的溶出性质，本发明所述的药物组合物中活性成分在成药前需要经过微粉化，以达到期待颗粒粒径。在实施例中，所述活性成分中90％颗粒的粒径小于或等于50μm(可表述为D90或d(0.9))，可以为50、45、40、35、30、25、20、15、10、9、8、7、6、5、4、3、2、1，优选小于或等于10μm。
本发明所述的药物组合物还可以含有填充剂、崩解剂、助流剂、润滑剂、包衣剂中的至少一种药用辅料。
本发明所述的“以药物组合物重量计”为不包含包衣剂的片芯重量计算活性成分或其他种类药用辅料的使用量数值范围，具体可参见实施例1。
填充剂提供体积，将片剂制成可加工处理的实际大小，也可能有助于加工处理，改善药物组合物的物理性质如流动性，可压缩性和固体制剂的硬度。由于在药物组合物中所用填充剂的用量较大，其与活性成分(或活性化合物)直接接触，因此，填充剂与活性成分的相互作用是本领域技术人员特别关注的。本发明所述填充剂为本领域技术人员所知或可确定的，可优选自但不限于甘露醇、乳糖、微晶纤维素、预胶化淀粉、磷酸氢钙中的至少一种。本发明所述填充剂的用量占药物组合物重量的30～95％，优选为50～94％，可为50、52、54、56、58、 60、62、64、66、68、70、72、76、80、82、86、88、89、90、91、92、93、94％，以药物组合物重量计。
进一步地，本发明所述填充剂在口服固体药物组合物中重量为80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg，以口服固体药物组合物每份100mg(100mg/份)计。
在本发明实施例中，所述填充剂优选自甘露醇、微晶纤维素中的至少一种；进一步地，本发明所述的药物组合物选用甘露醇和微晶纤维素作为填充剂，其中甘露醇与微晶纤维素的重量比为1.5:1～10:1，为了进一步改善制备片剂过程中的涩冲现象，甘露醇与微晶纤维素的重量比为1.8:1～4:1，可以为1.9:1、2:1、2.2:1、2.4:1、2.6:1、2.8:1、3:1、3.2:1、3.4:1、3.6:1、3.8:1、4:1。
崩解剂被用来促进给药后药物组合物的破碎或崩解。本发明所述崩解剂为本领域技术人员所知或可确定的，可选自但不限于淀粉、纤维素、胶、交联聚合物，和发泡剂，如玉米淀粉、土豆淀粉、预胶凝淀粉、改性玉米淀粉、交联羧甲基纤维素钠、交联聚维酮、淀粉乙醇酸钠、硅酸镁铝HV、甲基纤维素、微晶纤维素、纤维素、胶体二氧化硅、天然海绵、阳离子交换树脂，优选自交联羧甲基纤维素钠，羧甲基淀粉钠，交联聚维酮或低取代羟丙基纤维素，交联羧甲基纤维素钠，羧甲基淀粉钠，交联聚维酮或低取代羟丙基纤维素中的至少一种。进一步地，本发明所述崩解剂的用量占药物组合物重量的2～15％，可为2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15％，以药物组合物重量计。
润滑剂通常用来促进加工，防止制剂材料粘附到生产设备，较少颗粒间的摩擦，改善制剂的流动速率，和有助于制剂从生产设备中排出。本发明所述润滑剂为本领域技术人员所知或可确定的，可选自但不限于滑石粉、硬脂酸盐(如，硬脂酸镁、硬脂酸钙、硬脂酸锌)，聚乙二醇，环氧乙烷聚合物，液状石蜡、月桂剂磷酸钠、亮氨酸、硬脂酰富马酸钠，优选自硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡、硬脂富马酸钠中至少一种；进一步地，本发明所述润滑 剂的用量为药物组合物总重量的0.1～5％，可为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、1.2、1.4、1.6、1.8、2、2.2、2.4、2.6、2.8、3.0、3.2、3.4、3.6、3.8、4、4.2、4.4、4.6、4.8、5％，优选为0.5～3％，以药物组合物重量计。
在本发明实施方案中，提供了一种药物组合物，含有：
a)0.1～5％重量的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐，
b)2～15％重量的崩解剂，
c)50～94％重量的填充剂，
d)1.5～3％重量的羟丙甲纤维素，
e)任选0.5～3％重量的润滑剂，
其中，所述填充剂优选自甘露醇、微晶纤维素中至少一种；所述崩解剂选自交联羧甲基纤维素钠，羧甲基淀粉钠，交联聚维酮或低取代羟丙基纤维素中的至少一种；所述润滑剂选自硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡、硬脂富马酸钠中至少一种。
进一步地，所述填充剂由甘露醇和微晶纤维混合而成，两种药物辅料的重量比为1.5:1～10:1，优选为1.8:1～4:1。
在具体实施例中，本发明所述的药物组合物还可含有包衣剂，所述包衣剂(非定位释放包衣)可以为但不限于羟丙甲纤维素、甲基纤维素、乙基纤维素、甲基纤维素或羟丙基纤维素、聚乙烯醇、聚维酮、聚乙酸乙烯酯树脂或聚乙烯醇缩醛二乙氨基乙酸酯、甲基丙烯酸氨基烷基酯共聚物RS和丙烯酸乙酯-甲基丙烯酸甲酯共聚物分散体，糖类包括糖醇蔗糖、甘露醇糊，或商品名为欧巴代，优选为欧巴代。
本发明还提供了制备本发明所述的药物组合物的方法，该方法包括：1)将1-((6-溴喹啉-4-基)硫基)环丁基甲酸或其可药用盐与崩解剂和任选自填充剂、粘合剂、润滑剂、助流剂中至少一种药用辅料相混合，2)将从1)获得的混合物制粒后压片或灌装胶囊、直接压片或直接灌装胶囊；进一步地，造粒步骤后还包括包衣步骤，所述包衣剂为欧巴代、羟丙甲纤维素、乙基纤维素或聚乙烯醇，优选欧巴代。
本发明采用的制粒方式可为湿法制粒或干法制粒，当选用湿法制粒方案时，可以采用流化床制粒或高剪切湿法制粒。
在本发明具体实施例中，采用高速剪切制粒工艺步骤如下：
1)将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐和填充剂、崩解剂中相混合，
2)将含有羟丙甲纤维素的溶液加入步骤1中制成软材后进行湿整粒后，干燥，整粒，
3)向步骤2中的颗粒状物加入润滑剂并混合。
4)将步骤3中的混合物压制成片剂。
在本发明具体实施例中，采用流化床制粒工艺步骤如下：
1)将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐和填充剂、崩解剂中相混合，
2)将步骤1中粉末混合物进行流化，再将含有羟丙甲纤维素的溶液喷雾至粉末混合表面后，干燥，整粒，
3)向步骤2中的颗粒状物加入润滑剂并混合。
4)将步骤3中的混合物压制成片剂。
在本发明优选实施例中，所述的制粒方式采用高速剪切制粒、流化床制粒。
本发明还提供一种口服固体药物组合物，含有活性成分2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐、甘露醇和微晶纤维素，其中甘露醇与微晶纤维素的重量比为1.5:1～10:1，可以很好的改善药物组合物；进一步地，甘露醇与微晶纤维素的重量比为1.8:1～4:1，可为1.9:1、2:1、2.2:1、2.4:1、2.6:1、2.8:1、3:1、3.2:1、3.4:1、3.6:1、3.8:1、4:1；另外，本发明所述的口服固体药物组合物中甘露醇的用量和微晶纤维素的用量合计占药物组合物重量的30～95％，优选为50～94％，可为50、52、54、56、58、60、62、64、66、68、70、72、76、80、82、86、88、89、90、91、92、93、94％，以药物组合物重量计。
进一步地，本发明所述填充剂在口服固体药物组合物中重量为80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg，以口服固体药物组合物每份100mg(100mg/份)计。
本发明所述的口服固体药物组合物(固体制剂)可为片剂、粒剂、 粉剂(包括精细的粒剂)，或者胶囊剂。固体制剂可通过广泛已知的制备方法得到，制粒后最终干燥颗粒的最大含水控制3％以下，然后灌装胶囊或直接包装为颗粒剂。当剂型为片剂，在压片过程中控制压片环境湿度保证最终素片的含水量小于3％(3％以下)，并通过对最终的组合物采用真空干燥法处理保证最终组合物的含水量小于3％。
当本发明所述的药用组合物采用片剂时，可通过压缩如上所述获得的颗粒制备。可将压缩的压力在适当范围内确定，压力优选1～10kN。而且，片剂形状无特殊限制，优选扁豆形、圆盘形、圆形、椭圆形(如囊片)、泪滴形或多角形(如三角形或菱形)。可通过盘式包衣机(pancoater)喷洒包衣剂的混悬液/溶液的方式将制备的片剂进行包衣。在包衣完成后，再通过干燥过程将最终片剂的水分含量控制在3％以内。干燥温度可选择40～80℃，优选50～60℃。干燥方法可采用普通烘箱干燥或者真空干燥。
当本发明药用组合物采用粒剂时，如上所述获得的颗粒可直接使用或者可通过适当技术造粒成期望的粒状。另外，可将由此制备的颗粒通过喷洒包衣剂的混悬液/溶液用包衣剂包衣。
本发明所述2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺的可药用盐为对甲苯磺酸盐。
本发明所述的药物组合物的溶出度根据中国药典2015版四部通则0931法溶出度测定第二法(桨法)进行测定，以pH6.8磷酸盐缓冲液作为溶出介质，优选1000ml的pH6.8磷酸盐缓冲液，并在37±0.5℃下以50rpm的桨速对本发明组合物进行溶出试验，45分钟溶出度大于或等于90％，可以大于或等于90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％，优选大于或等于94％。
进一步地，30分钟溶出度大于或等于80％，可以大于或等于80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％，优选大于或等于85％。
本发明所述的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺可按照WO2015058589和WO2016155473中所述方法获得。本发明所用药用辅料均可通过商业 途径购得，譬如乳糖、微晶纤维素等。
附图说明
图1：显示实施例1的片剂在pH6.8磷酸盐缓冲液中的溶出曲线。
图2：显示实施例2的片剂在pH6.8磷酸盐缓冲液中的溶出曲线。
图3：显示实施例4的片剂在pH6.8磷酸盐缓冲液中的溶出曲线。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1
将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(以下简称化合物A)、甘露醇、微晶纤维素、交联羧甲基纤维素钠按表1中的比例，采用高速剪切制粒机进行湿法制粒，以聚维酮K30配制成的5％的水溶液或者羟丙甲纤维素配制成的3％或4％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表1
Figure PCTCN2017112829-appb-000002
根据中国药典2015版四部通则0931法溶出度测定第二法(桨法)，对实施例1～4中的片剂进行溶出度测定。使用1000ml的pH6.8磷酸盐缓冲液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实验例1中，化合物A溶出缓慢且不完全；实验例2和3中，化合物A溶出迅速但不完全。实施例4中，化合物A溶出迅速且完全溶出。溶出数据如下表2所示，溶出曲线见图1。
表2
Figure PCTCN2017112829-appb-000003
实施例2
将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(以下简称化合物A)、甘露醇、微晶纤维素、交联羧甲基纤维素钠按表3中的比例，采用高速剪切制粒机进行湿法制粒，羟丙甲纤维素配制成的4％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表3
Figure PCTCN2017112829-appb-000004
Figure PCTCN2017112829-appb-000005
根据中国药典2015版四部通则0931法溶出度测定第二法(桨法)，对实验例4～7中的片剂进行溶出度测定。使用1000ml的pH6.8磷酸盐缓冲液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实验例4～7中，溶出完全。溶出数据如下表4所示，溶出曲线见图2。
表4
Figure PCTCN2017112829-appb-000006
实施例3
将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(以下简称化合物A)分别过80目筛处理和使用Mcone气流粉碎机微粉化处理(粉碎压力4bar，进样压力6bar)后，直接用马尔文激光粒径测定仪(Mastersizer 2000)测定粒径，结果见下表5。
表5
原料处理方式 原料粒径d(0.5) 原料粒径d(0.9)
80目筛 4.940 14.148
气流微粉化 2.587 5.494
实施例4
将实施例3中处理好的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(以下简称化合物A)分别与甘露醇、微晶纤维素、交联羧甲基纤维素钠按表1中实验例4的比例，采用高速剪切制粒机进行湿法制粒，羟丙甲纤维 素配制成的4％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
根据中国药典2015版四部通则0931法溶出度测定第二法(桨法)，对实施例4中的片剂进行溶出度测定。使用1000ml的pH6.8磷酸盐缓冲液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，用气流粉碎机粉碎处理的原料粒径要小于过80目筛处理原料的粒径，且小于10μm；过80目处理的原料制备的样品溶出不完全；用气流粉碎机微粉化处理的原料制备的样品溶出速度明显较过80目处理的原料制备的样品快，且溶出完全。溶出数据如下表6所示，溶出曲线见图3。
表6
Figure PCTCN2017112829-appb-000007
实施例5
将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(以下简称化合物A)、甘露醇、微晶纤维素、交联羧甲基纤维素钠按表1中的比例，采用高速剪切制粒机进行湿法制粒，以羟丙甲纤维素配制成的3％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表7
Figure PCTCN2017112829-appb-000008
Figure PCTCN2017112829-appb-000009
实验例2中微晶纤维素用量较少，片剂制备过程中出现涩冲现象，实验例5中增加微晶纤维素用量，涩冲现象有所改善，实验例3中完全没有出现。

Claims (16)

  1. 一种口服固体药物组合物，含有活性成分2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐，和羟丙甲纤维素，优选所述活性成分的含量为0.01～10％，更优选为0.1～5％。
  2. 根据权利要求1所述的药物组合物，其特征在于所述羟丙甲纤维素的用量占药物组合物重量的0.5～10％，优选为1～5％，更优选为1.5～3％。
  3. 根据权利要求1或2所述的药物组合物，其特征在于所述药物组合物中还含有填充剂，所述填充剂选自甘露醇、乳糖、微晶纤维素、预胶化淀粉、磷酸氢钙中的至少一种，优选自甘露醇、微晶纤维素中的至少一种；更优选填充剂由甘露醇和微晶纤维素组成，最优选所述甘露醇与微晶纤维素的重量比为1.5:1～10:1，最优选为1.8:1～4:1。
  4. 根据权利要求3所述的药物组合物，其特征在于所述填充剂的用量占药物组合物重量的30～95％，优选为50～94％。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于所述药物组合物还含有崩解剂、助流剂、润滑剂、包衣剂中的至少一种药用辅料。
  6. 根据权利要求5所述的药物组合物，其特征在于所述崩解剂选自交联羧甲基纤维素钠，羧甲基淀粉钠，交联聚维酮或低取代羟丙基纤维素中的至少一种，优选所述崩解剂的用量占药物组合物重量的2～15％。
  7. 根据权利要求5所述的药物组合物，其特征在于所述润滑剂选自硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡、硬脂富马酸钠中至少一种，优选所述润滑剂的用量占药物组合物重量的 0.1～5％，更优选为0.5～3％。
  8. 根据权利要求1-7任一项所述的药物组合物，其特征在于所述活性成分的可药用盐为对甲苯磺酸盐。
  9. 一种口服固体药物组合物，含有如下成分：
    a)0.1～5％重量的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐，
    b)2～15％重量的崩解剂，所述崩解剂选自交联羧甲基纤维素钠，羧甲基淀粉钠，交联聚维酮或低取代羟丙基纤维素中的至少一种，
    c)50～94％重量的填充剂，所述填充剂选自甘露醇、微晶纤维素中至少一种，
    d)1.5～3％重量的羟丙甲纤维素，
    e)0.5～3％重量的润滑剂，所述润滑剂选自硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡、硬脂富马酸钠中至少一种。
  10. 根据权利要求9所述的药物组合物，其特征在于所述填充剂由甘露醇和微晶纤维素组成，优选所述甘露醇与微晶纤维素的重量比为1.5:1～10:1，更优选为1.8:1～4:1。
  11. 一种口服固体药物组合物，含有活性成分2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐、甘露醇和微晶纤维素，所述甘露醇与微晶纤维素的重量比为1.5:1～10:1，优选为1.8:1～4:1。
  12. 根据权利要求11所述的药物组合物，其特征在于所述活性成分的含量为0.01～10％，优选为0.1～5％；所述甘露醇的用量和所述微晶纤维素的用量合计占药物组合物重量的30～95％，优选为50～94％。
  13. 根据权利要求11或12所述的药物组合物，其特征在于所述药物组合物中还含有羟丙甲纤维素，优选所述羟丙甲纤维素的用量占药物组合物重量的0.5～10％，优选1～5％，更优选1.5～3％。
  14. 根据权利要求1-13任一项所述的药物组合物，其特征在于所述的药物组合物的溶出度根据中国药典2015版四部通则0931法溶出度测定第二法(桨法)进行测定，所述活性成分的溶出度在45分钟大于或等于90％，优选大于或等于94％。
  15. 根据权利要求14所述的药物组合物，其特征在于所述活性成分的溶出度在30分钟大于或等于80％，优选大于或等于85％。
  16. 制备权利要求1-15任一项所述的药物组合物的方法，包括：将2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧代)-6-羰基-1,6-二氢吡啶-3-甲酰胺或其可药用盐与崩解剂和任选自填充剂、粘合剂、润滑剂、助流剂中至少一种药用辅料相混合，2)将从1)获得的混合物制粒后压片或灌装胶囊、直接压片或直接灌装胶囊。
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