CN117159555A - Pharmaceutical composition, preparation method and application thereof - Google Patents
Pharmaceutical composition, preparation method and application thereof Download PDFInfo
- Publication number
- CN117159555A CN117159555A CN202210859918.6A CN202210859918A CN117159555A CN 117159555 A CN117159555 A CN 117159555A CN 202210859918 A CN202210859918 A CN 202210859918A CN 117159555 A CN117159555 A CN 117159555A
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- Prior art keywords
- methyl
- pharmaceutical composition
- triazol
- indazol
- dione
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 34
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- -1 (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione Chemical compound 0.000 claims abstract description 43
- QMPBBNUOBOFBFS-UHFFFAOYSA-N 6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CN1N=C(C=C(C(/N=C(\NC(N2CC3=NN(C)C=N3)=O)/N(CC(C=C(C(F)=C3)F)=C3F)C2=O)=C2)Cl)C2=C1 QMPBBNUOBOFBFS-UHFFFAOYSA-N 0.000 claims abstract description 41
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2022—Organic macromolecular compounds
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- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Landscapes
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- Chemical & Material Sciences (AREA)
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- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid and (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of a filler, a disintegrant, a lubricant, a solubilizer, a glidant. The invention also relates to a method for preparing said pharmaceutical composition and/or to the use thereof for preparing a medicament for treating or preventing diseases caused by coronaviruses in a subject, including children, adults or elderly. The pharmaceutical composition of the present invention has high stability and is capable of controlling the generation or increase in the amount of specific impurities.
Description
Technical Field
The present invention relates to a pharmaceutical composition, a method for its preparation and its use in the preparation of a medicament for the treatment of a coronavirus-induced disease in a subject.
Background
The prior art discloses compounds having therapeutic potential against diseases caused by coronaviruses, especially novel coronaviruses, such as the oral drug (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione developed by Japanese company. However, there is still a need for a safe and effective pharmaceutical composition, in particular of controlled quality, for the treatment of diseases caused by coronaviruses, in particular novel coronaviruses, which meets the urgent need for clinical treatment, as a pharmaceutical composition, the stability of which must be maintained. Some impurities come from the process used for manufacture, while others are due to the progressive degradation of the active ingredient. Stability must therefore be maintained and the amount of impurities minimized, regardless of the source of the impurities or the mechanism of degradation. Thus, there is a need to develop a safe, effective and quality-controllable composition comprising the active ingredient (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with acceptable stability characteristics for its final potency and impurity level.
Disclosure of Invention
The present invention provides a solution to the above problems existing in the prior art.
In a first aspect of the invention, there is provided a pharmaceutical composition comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) and crystalline forms of fumaric acid and (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione), and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of a lubricant, a filler, a solubilizing agent, a glidant.
In a second aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition of the present invention comprising the steps of:
(i) Mixing a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione with a crystalline form of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione;
(ii) Granulating the mixture obtained in the step (i), and sieving;
(iii) Optionally mixing the granules obtained in step (ii) with one or more other physiologically acceptable/pharmaceutically acceptable excipients besides the physiologically acceptable/pharmaceutically acceptable excipients described in step (i).
In a third aspect of the present invention, there is provided a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) for use in the quality control of crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1- [ (2, 4-triazol-3-yl) methyl ] -1, 5-triazin-2, 4-dione characterized in that the crystalline form of the pharmaceutical composition is characterized in that it, the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) was used as a control.
In a fourth aspect of the invention there is provided the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment or prophylaxis of a disease caused by a coronavirus in a subject.
The present invention has been found through inventive studies that the pharmaceutical composition of the present invention has high stability and is capable of controlling the generation or increase in the amount of specific impurities.
Description of the drawings:
FIG. 1 is the compound (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]-1- [ (2, 4, 5-trifluorophenyl) methyl ]]-1,3, 5-triazine-2, 4-dione) 1 H-NMR spectrum.
FIG. 2 is a HPLC related mass spectrum of example 1 for 0 day of the influence factor test. Wherein, the ordinate is absorbance [ mAU ], and the abscissa is time [ min ].
FIG. 3 is a HPLC related substance spectrum of example 1 under influence of factors (high temperature (60 ℃ C.) for 30 days. Wherein, the ordinate is absorbance [ mAU ], and the abscissa is time [ min ].
FIG. 4 is a HPLC related mass spectrum for example 6 accelerated stability test for 0 days. Wherein, the ordinate is absorbance [ mAU ], and the abscissa is time [ min ].
FIG. 5 is a HPLC related mass spectrum of example 6 for accelerated stability test for 1 month. Wherein, the ordinate is absorbance [ mAU ], and the abscissa is time [ min ].
FIG. 6 is a HPLC related mass spectrum of example 1 for accelerated stability test for 0 days. Wherein, the ordinate is absorbance [ mAU ], and the abscissa is time [ min ].
FIG. 7 is a HPLC related mass spectrum of example 1 for accelerated stability test for 1 month. Wherein, the ordinate is absorbance [ mAU ], and the abscissa is time [ min ].
Detailed Description
In the present application, relative humidity is represented by RH, and represents the percentage of saturated water vapor (saturated water vapor pressure) in the case where the amount of water vapor (water vapor pressure) contained in a gas (typically, in air) is the same as that of air.
The term "physiologically acceptable/pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the active ingredient (e.g., (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and crystalline form of fumaric acid that are administered in accordance with the present application.
The physiologically acceptable/pharmaceutically acceptable excipients that are admixed with the crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) of the present application with fumaric acid to form the pharmaceutical compositions of the present application may depend on the intended method of administration of the pharmaceutical composition.
The pharmaceutical composition of the present invention is preferably a solid formulation.
The pharmaceutical compositions of the present invention may be formulated for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.
The pharmaceutical composition of the present invention may be administered orally.
The pharmaceutical composition of the present invention is preferably prepared in the form of an oral formulation. The shape of the oral preparation is not particularly limited, and may be any one of a circle, a capsule, a ring (doughnut), a rectangle, and the like.
For solid preparations, for example, tablets, capsules, powders, granules, lozenges, and the like may be mentioned.
The solid formulation may be coated with a coating agent and may have indicia and letters for identification and further score lines for separation. The coating is carried out with the addition of conventional coating media and film forming agents (commonly referred to collectively as coating materials) familiar to those skilled in the art. The coating may be performed using, for example, a sugar coated substrate, a water-soluble film coated substrate, an enteric film coated substrate, a slow release film coated substrate, or the like. For sugar coated substrates, a combination of sucrose and one or more selected from the group consisting of: talc, precipitated calcium carbonate, gelatin, acacia, pullulan, carnauba wax, and the like. For the water-soluble film-coated substrate, for example, a cellulose polymer such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, or the like can be used; synthetic polymers such as polyvinyl acetal diethylaminoethyl ester, aminoalkyl methacrylate copolymer E [ Eudragit E (trade name) ], polyvinyl pyrrolidone, and the like; polysaccharides such as pullulan and the like. For the enteric film-coated substrate, for example, a cellulose polymer such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, or the like can be used; acrylic polymers such as methacrylic copolymer L [ Eudragit L (trade name) ], methacrylic copolymer LD [ Eudragit L-30D55 (trade name) ], methacrylic copolymer S [ Eudragit S (trade name) ] and the like; naturally occurring substances, such as shellac and the like; etc. For the sustained-release film-coated substrate, for example, a cellulose polymer such as ethyl cellulose, cellulose acetate, etc. can be used; acrylic polymers such as aminoalkyl methacrylate copolymer RS [ Eudragit RS (trade name) ], ethyl acrylate-methyl methacrylate copolymer suspension [ Eudragit NE (trade name) ] and the like. Two or more of the above coating bases may be mixed in a suitable ratio. Furthermore, coating additives may be used in coating. For the coating additive, for example, a photo masking agent and/or a coloring agent such as titanium oxide, talc, iron oxide, etc. may be used; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbate, and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, and the like.
Solid formulations may be formulated for immediate release (i.e., immediate release) and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.
When the solid preparation is a tablet, any pharmaceutically acceptable excipient commonly used for preparing solid preparations can be used. Tablets may be prepared by compression or molding, optionally with one or more physiologically acceptable/pharmaceutically acceptable excipients. Compressed tablets may also be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or capsule, optionally mixed with a binder, lubricant, filler, solubilizer or disintegrant. Shaped tablets may be prepared by shaping a mixture of the moistened powdered compound and an inert liquid dispersion medium in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The formulation of the tablets is described in "Pharmaceutical Dosage Forms: tablets, vol.1 ", by H.Lieberman and L.Lachman, marcel Dekker, N.Y., 1980.
When the solid formulation is a capsule, any conventional encapsulation is suitable, for example using the carriers mentioned above in a hard gelatin capsule. When the composition is in the form of a soft gelatin capsule, any physiologically acceptable/pharmaceutically acceptable excipient commonly used to prepare dispersing or suspending agents may be considered and incorporated into a soft gelatin capsule.
The pharmaceutical formulation may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy, whereby unit doses may be administered to a subject. Preferably, the pharmaceutical composition is in unit dosage form, e.g., a solid formulation in unit dosage form (e.g., a tablet, powder, dry suspension, granule, or capsule).
The term "subject" refers to an animal, including but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In particular, the subject is 0 years old or older, 1 year old or older, 2 years old or older, 4 years old or older, 5 years old or older, 10 years old or older, 12 years old or older, 13 years old or older, 15 years old or older, 16 years old or older, 18 years old or older, 20 years old or older, 25 years old or older, 30 years old or older, 35 years old or older, 40 years old or older, 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, 80 years old or older, 85 years old or older, 90 years old or older, 95 years old or older, 100 years old or older, or 105 years old or older.
The term "novel coronavirus" refers to 2019 novel coronavirus (2019-nCoV) or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) published by the international committee for classification of viruses at month 2 of 2020, which has the same meaning as 2019-nCoV, and also includes all variants thereof, such as all variants of the 2019 novel coronavirus, e.g., NCBI or GISAID (global shared influenza data initiative organization) listing, particularly including important variants of greater importance, such as transmissibility, pathogenicity, or immune evasion, e.g., WHO-designated Alpha, beta, gamma, delta, eta, iota, kappa, or Lambda variants, and later designated important variants.
The term "starch" generally means a starch having the empirical formula (C 6 H 10 O 5 ) n (wherein n is 300-1000) and has a molecular weight of 50,000-160,000 and consists of amylose and amylopectin, both starches being polysaccharides based on alpha-glucose units. Starch is derived from plant material and is usually present in the form of very small particles (5-25 microns in diameter) consisting of a layered layer of starch molecules formed around a core. The starch particles may be round, oval or angular and are made of two anhydrous D-glucose polymers (amylose Powder and amylopectin). Amylose is a linear polymer of hundreds of glucose units linked by alpha-1-4 glycosidic linkages. Amylopectin is a branched polymer with alpha-1-6 glycosidic linkages at the branching site and thousands of glucose units with alpha-1-4 linkages in the linear region. Individual branches may have 20-30 glucose residues. Specifically, the starch is selected from starches having an amylose content in the range of 10 to 40% by weight. Typical examples are corn starch, potato starch, rice starch, tapioca starch and wheat starch.
The term "pregelatinized starch" is intended to define a starch that is broken down in whole or in part by chemical and/or mechanical processing in the presence of water and subsequently dried. Some types of pregelatinized starch can be modified to provide them with improved compressibility and flowability characteristics. Typical pregelatinized starches contain 5% free amylose, 15% free amylopectin and 80% unmodified starch. The pregelatinized starch can be corn starch processed by the chemical and/or mechanical methods described above. Other types of starches besides corn starch may be pregelatinized, such as rice or potato starch.
In a specific embodiment, the pharmaceutical composition of the invention consists of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) and crystalline forms of fumaric acid, (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione, and physiologically acceptable/pharmaceutically acceptable excipients.
In a specific embodiment, the pharmaceutical composition of the invention consists of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) and crystalline forms of fumaric acid, (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione, (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-2, 4-triazol-3-yl) methyl ] -1- [ (1, 2, 4-triazol-5-yl) methyl ] -3- [ (1, 4-triazol-3-yl) methyl ] -1, 4-triazin-2, 4-dione and pharmaceutically acceptable excipients.
In a specific embodiment, (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione according to the invention is in crystalline form, preferably in anhydrous crystalline form.
In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) of the present invention is an anhydrous crystalline form with fumaric acid.
In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid is present in the pharmaceutical composition in a weight percentage of 15% -60%, preferably 25% -45%, e.g. 15%,16%,17%,18%, 19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%, 36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%, 53%,54%,55%,56%,57%,58%,59% or 60%.
In a specific embodiment, the weight percentage of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) of the present invention in the pharmaceutical composition is 1% or less, preferably 0.5% or less, further preferably 0.2% or less, more preferably 0.01% or less; for example, 0.9%,0.8%,0.7%,0.6%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%, 0.06%,0.05%,0.04%,0.03%,0.02% or less than 0.01%.
In a specific embodiment, the (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione of the present invention is present in the pharmaceutical composition in a weight percentage of less than 1%, preferably less than 0.5%, more preferably less than 0.2%, more preferably less than 0.01%, for example less than 0.9%,0.8%,0.7%,0.6%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%, 0.06%,0.05%,0.04%,0.03%,0.02% or less than 0.01%.
In a specific embodiment, the pharmaceutical composition of the invention is a (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione in the pharmaceutical composition in a weight percentage of 0.2% or less, preferably 0.1% or less, more preferably 0.05% or less, further preferably 0.01% or less, e.g. 0.9%,0.8%,0.7%,0.6%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%, 0.04%,0.03% or less, in a high temperature 60 ℃, high humidity RH92.5% and light conditions or in a light condition of 40 ℃ ±2 ℃, more preferably 0.05% or less, e.9%, 0.7%,0.6%,0.5%, 0.3%,0.2%, 0.09%,0.08%, 0.06%, 0.0.05%, 0.05%, 0.0.05%, 0.0.0.05% or less.
In a specific embodiment, the pharmaceutical composition of the invention is a (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione in the pharmaceutical composition in a weight percentage of 0.2% or less, preferably 0.1% or less, more preferably 0.01% or less, such as 0.9%,0.8%,0.7%,0.6%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%,0.05%,0.04%,0.03% or less, 0.02% or less, after being left for 5 days or 10 days or 30 days at a high temperature of 60 ℃, high humidity RH92.5% and light conditions, or at 40 ℃ of RH75% ± 2%, RH.
In a specific embodiment, the pharmaceutical composition of the invention has a single impurity content of no more than 0.1% or a total impurity of no more than 0.5% under accelerated stability for 1 month test (e.g. at 40 ℃ ± 2 ℃ under RH75% ± 5%).
In a specific embodiment, the physiologically acceptable/pharmaceutically acceptable excipient is selected from one or more of fillers, disintegrants, lubricants, binders, solubilizers, glidants. In particular, the physiologically acceptable/pharmaceutically acceptable excipients consist of fillers, disintegrants, lubricants, optional binders, optional solubilizers, and glidants.
In a specific embodiment, the filler is present in the pharmaceutical composition in a weight percentage of 10% -80%, preferably 30% -65%, for example 11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%, 22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%, 36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%, 50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,61%,62%,63%, 64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%, 78%,79% or 80%. Alternatively, the filler may be present in the pharmaceutical composition (e.g., per unit dose of the pharmaceutical composition) in an amount of 50-300mg, preferably 100-280mg, and more preferably 110-250mg, for example, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, or 300mg.
In a specific embodiment, the weight percentage of disintegrant in the pharmaceutical composition is 1% to 10%, preferably 1% to 5%, for example 2%,3% or 4%. Alternatively, the disintegrant may also be 1mg to 15mg, more preferably 5mg to 8mg, for example 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg, in a pharmaceutical composition (e.g., a pharmaceutical composition per unit dose).
In a specific embodiment, the weight percentage of lubricant in the pharmaceutical composition is 0.5% -5%, preferably 0.5-3%, for example 0.6%,0.7%,0.8%,0.9%,1%,2% or 3%. Alternatively, the lubricant may be 1mg to 15mg, and more preferably 5mg to 8mg, for example, 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, or 14mg.
In a specific embodiment, the weight percentage of binder in the pharmaceutical composition is 0% -10%, preferably 1-3%, for example 1.1%,1.2%,1.3%,1.4%,1.5%,1.6%,1.7%,1.8%,1.9%,2%,2.1%, 2.2%,2.3%,2.4%,2.5%,2.6%,2.7%,2.8%,2.9% or 3%. Alternatively, the binder may also be present in the pharmaceutical composition (e.g. per unit dose of the pharmaceutical composition) in an amount of 1mg-15mg, further preferably 5mg-8mg, e.g. 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg.
In a specific embodiment, the weight percentage of the solubilizing agent in the pharmaceutical composition is 0% -5%, preferably 0.5-3%, for example 0.6%,0.7%,0.8%,0.9%,1%,1.5%,2%,2.5% or 3%. Alternatively, the solubilizer may be present in the pharmaceutical composition (e.g., pharmaceutical composition per unit dose) in an amount of 1mg to 15mg, more preferably 5mg to 8mg, for example, 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg.
In a specific embodiment, the glidant is present in the pharmaceutical composition in an amount of 0.5% to 5%, preferably 0.5% to 3%, for example 0.6%,0.7%,0.8%,0.9%,1%,1.5%,2%,2.5% or 3% by weight. Alternatively, the glidant may be present in the pharmaceutical composition (e.g. per unit dose of the pharmaceutical composition) in an amount of 1mg to 15mg, more preferably 5mg to 8mg, for example 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg.
In a specific embodiment, the weight ratio of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione to fumaric acid to the filler is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.
In a specific embodiment, the weight ratio of disintegrant to lubricant is in the range of 1:4 to 4:1, preferably in the range of 1:2 to 2:1.
In a specific embodiment, the weight ratio of glidant to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.
In a specific embodiment, the weight ratio of solubilizer, if present, to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.
In a specific embodiment, the weight ratio of binder, if present, to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.
In a specific embodiment, the filler comprises one or more of lactose, anhydrous calcium bicarbonate, sugar alcohols, celluloses, and starches. For example, the sugar alcohol filler includes one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol. For example, the cellulosic filler includes one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose. For example, the starch-based filler includes one or more of corn starch, potato starch, sweet potato starch, and pregelatinized starch, preferably pregelatinized starch.
Specifically, the filler is selected from one or more of lactose, anhydrous calcium bicarbonate, sugar alcohols, celluloses and starches. For example, the sugar alcohol filler is selected from one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol, preferably mannitol. For example, the cellulose filler is selected from one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose, preferably microcrystalline cellulose and/or silicified microcrystalline cellulose. For example, the starch-based filler is selected from one or more of corn starch, potato starch, sweet potato starch and pregelatinized starch, preferably pregelatinized starch.
For example, the filler is microcrystalline cellulose, pregelatinized starch, mannitol, or a mixture of two or more thereof (e.g., a mixture of microcrystalline cellulose and pregelatinized starch, or a mixture of microcrystalline cellulose and mannitol).
In a specific embodiment, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch, and potato starch. Specifically, the disintegrating agent is selected from one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch and potato starch, preferably crospovidone, croscarmellose sodium and/or hydroxypropyl cellulose.
In a specific embodiment, the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate. Specifically, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate, preferably magnesium stearate and/or sodium stearyl fumarate. For example, the lubricant is magnesium stearate, or magnesium stearate and sodium stearyl fumarate.
In a specific embodiment, the binder comprises one or more of hypromellose, hyprolose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, copovidone, and polyvinylpyrrolidone. Specifically, the binder is selected from one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone and polyvinylpyrrolidone, preferably hypromellose, hyprolose and/or copovidone. Specifically, the binder may be present or absent.
In a specific embodiment, the solubilizing agent comprises one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil, and poloxamer. Specifically, the solubilizer is selected from one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer, preferably sodium dodecyl sulfate.
In a specific embodiment, the glidant comprises colloidal silicon dioxide and/or talc. In particular, the glidant is selected from colloidal silicon dioxide and/or talc, for example colloidal silicon dioxide.
In a specific embodiment, the physiologically acceptable/pharmaceutically acceptable excipient is selected from one or more of pregelatinized starch, microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide. In particular, the physiologically acceptable/pharmaceutically acceptable excipients consist of pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide. Wherein the weight percentage or content of the specific physiologically acceptable/pharmaceutically acceptable excipients (such as pregelatinized starch, microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate and/or colloidal silicon dioxide) is as defined above.
In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid uses Cu-K alpha radiation and the characteristic diffraction peak of the X-ray powder diffraction pattern expressed in terms of 2 theta values.+ -. 0.2 ℃ further comprises any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, preferably still further comprises any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, more preferably still further comprises any one or more of 14.73, 20.87, 21.49, 21.97, 25.39.
In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid uses Cu-K alpha radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2 theta values.+ -. 0.2 ℃ are at 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8.
In a specific embodiment, the differential scanning calorimetry pattern of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid has an endothermic peak in the range of 274 ℃ + -2 ℃.
In a specific embodiment, the thermogravimetric profile of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione with fumaric acid is substantially free of weight loss or less than 0.5% weight loss over a range of 150 ℃ and undergoes decomposition at 240 ℃ ± 2 ℃.
In a specific embodiment, (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione is present in a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione to fumaric acid in a 1:1 ratio.
In a specific embodiment, the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (e.g., tablet, powder, dry suspension, granule or capsule).
In a specific embodiment, the pharmaceutical composition is in unit dosage form, e.g., a solid formulation in unit dosage form (e.g., a tablet, powder, dry suspension, granule, or capsule).
When the oral solid preparation of the present invention is preferably a tablet, the tablet may have a film coating for easy swallowing of the tablet. The film coating may comprise a film coating agent (e.g., hydroxypropyl methylcellulose, polyethylene glycol (macrogol), talc) and a colorant (e.g., titanium dioxide, iron oxide pigment yellow).
In a specific embodiment, when the pharmaceutical composition of the present invention is in the form of a solid preparation in unit dosage form (such as a tablet, powder, dry suspension, granule or capsule), 1mg to 500mg, preferably 10mg to 300mg, more preferably 50mg to 200mg of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid are contained per unit dose of the pharmaceutical composition; for example, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 151mg, 152mg, 152.1mg, 152.2mg, 152.3mg, 152.4mg, 152.5mg, 152.6mg, 152.7mg, 152.8mg, 152.9mg, 153mg, 154mg, 155mg, 160mg, 165mg, 170mg, 180mg, 185mg, 190mg, 195mg or 200mg of active ingredient is contained in the pharmaceutical composition per unit dose.
When the pharmaceutical composition is an oral preparation (such as tablets, powder, dry suspension, granules and capsules), the administration of the pharmaceutical composition is convenient for a subject, or the administration compliance of the subject (especially children, the elderly or dysphagia patients) is improved, and the risk possibly brought by excessive administration of the injection medicine is avoided.
In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the application, step (i) is carried out by: a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione and crystalline forms of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione is mixed (homogeneously) sequentially with a filler, a disintegrant, optionally a binder, optionally a solubilizer, and a glidant. Specifically, step (i) is achieved by: first a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione is mixed (homogeneously) with the crystalline form of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione, and then a disintegrant, optionally a binder, optionally a solubilizer, a glidant are added (homogeneously) mixed. Preferably, step (i) is achieved by: first a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione is mixed (homogeneously) with the crystalline form of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione and then a second filler, a disintegrant, optionally a binder, optionally a solubiliser, a glidant are added (homogeneously). The first filler and the second filler may be the same or different, and preferably, the first filler is a cellulose filler as described in the application, and the second filler is a starch filler as described in the application. Preferably, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device such as a hopper mixer.
In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the invention, step (ii) is carried out by: subjecting the mixture obtained in step (i) to wet granulation or dry granulation and sieving. In particular, wet granulation or dry granulation is a process that one skilled in the art can perform according to formulation requirements. Preferably, wet granulation is carried out by mixing the mixture obtained in step (i) with water and granulating by a wet granulator; alternatively, dry granulation is performed by granulating the mixture obtained in step (i) by a dry granulator or by granulating the mixture obtained in step (i) by pressing it into large pieces, crushing, sieving. Preferably, the sieving is accomplished through a 20-80 mesh screen (e.g., a 40-60 mesh screen).
In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the invention, step (iii) is carried out by: mixing (homogenizing) the particles obtained in step (ii) with a lubricant. In particular, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device such as a hopper mixer.
In a specific embodiment, the method of preparing a pharmaceutical composition of the present invention further comprises the steps of: (iv) tabletting the mixture obtained in step (iii). In particular, tabletting is performed by a tablet press (e.g., a single punch tablet press).
In a specific embodiment, the subject is a human, preferably a child, adult or elderly human, for example a child aged 0-18 years (e.g. 0-12 years), an adult aged 19-59 years or elderly human aged 60 years or older. In particular, when the pharmaceutical composition of the application is a granule or a dry suspension, the subject is preferably a child (e.g., a child aged 0-12); when the pharmaceutical composition of the present application is in the form of a tablet or capsule, the subject is preferably an adult or an elderly person; when the pharmaceutical composition of the present application is an oral liquid formulation, the subject is preferably a child (e.g., a child aged 0-12 years), an elderly person, or a dysphagia person.
In a further aspect, the present application also provides the use of a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) according to the present application with crystalline forms of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition comprises (or consists of: (6E) -crystalline forms of 6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) with fumaric acid, (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione), and physiologically acceptable/pharmaceutically acceptable excipients. In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above.
In yet another aspect, the present invention provides another method of preparing a pharmaceutical composition of the present invention comprising the steps of: (i) Mixing (homogeneity) a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with a crystalline form of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione; (ii) tabletting the mixture obtained in step (i). In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above.
In yet another aspect, the invention also provides a composition or solid comprising (or consisting of) the following components: (6E) Crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid and (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione. Specifically, the weight percentage of (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) in the composition or the solid is 1% or less, preferably 0.5% or less, further preferably 0.2% or less; and/or the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid is 98% or more, preferably 99% or more, further preferably 99.5% or more, more preferably 99.8% or more by weight in the pharmaceutical composition.
The various embodiments described herein, or of different preferred classes of embodiments, may be combined arbitrarily unless otherwise indicated.
The inventors have found that pharmaceutical compositions (e.g. formulations) comprising crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid are unstable during storage or under high temperature, high humidity and/or light irradiation (e.g. wherein the total impurity content is significantly increased), and that the present invention achieves a high or unexpected effect of the pharmaceutical composition during storage or under high temperature, high humidity and/or light irradiation by controlling the specific impurity (e.g. (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione)) content in the pharmaceutical composition to a certain extent (e.g. to 0.2% or below.
The present invention is illustrated below by way of examples, but it should not be construed that the scope of the inventive subject matter is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention. The compounds or reagents used in the following examples are commercially available or are prepared by conventional methods known to those skilled in the art; the laboratory apparatus used is commercially available.
Specifically, in the preparation examples, mannitol was purchased from Qingdao double-ingredient seaweed Co., ltd, microcrystalline cellulose was purchased from Sian Tian Zheng pharmaceutical Co., ltd, croscarmellose sodium was purchased from Jiangxi alpha Gao pharmaceutical Co., ltd, colloidal silicon dioxide was purchased from Shanghai Feng Hong pharmaceutical Co., ltd, magnesium stearate was purchased from Hebei Pengyi Biotechnology Co., ltd, sodium stearyl fumarate was purchased from Wuhan Kano Biotechnology Co., ltd, sodium lauryl sulfate was purchased from Sian brocade Source Biotechnology Co., ltd, and pregelatinized starch was purchased from Hebei Innova Biotechnology Co., ltd.
Examples
I. Preparation example
45 g of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluoro-phenyl) methyl ] -1,3, 5-triazine-2, 4-dione are added into 450ml of 10V acetone, evenly mixed, 9.8 g of fumaric acid is added after the mixture is fully stirred evenly, the reaction solution starts to be heated to 55 ℃ for reflux reaction for 4-5 hours, the mixture is naturally cooled to 25 ℃ at room temperature after the reaction is completed, the mixture is fully stirred for 4-5 hours at room temperature, after suction filtration is carried out, a filter cake is washed by a proper amount of Ethyl Acetate (EA), white solid powder is obtained, 52 g of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 5-trifluoro-phenyl) methyl ] -3, 5-dione is obtained after vacuum drying, and the mixture is crystallized into the solid (about 95%) of (2, 95%).
Formulation examples
Example 1
| Component (A) | Weight percent | Dosage g |
| API | 40.64％ | 38.12 |
| Microcrystalline cellulose | 40％ | 37.5 |
| Pregelatinized starch | 13.86％ | 12.99 |
| Croscarmellose sodium | 2％ | 1.875 |
| Colloidal silica | 2％ | 1.875 |
| Magnesium stearate | 1.5％ | 1.476 |
The preparation method comprises the following steps:
(1) Uniformly mixing an API (i.e., a solid comprising crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione obtained in the preparation example with fumaric acid) with colloidal silica;
(2) Adding microcrystalline cellulose, pregelatinized starch and croscarmellose sodium into the mixture prepared in the step (1), and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing the pieces, and sieving the pieces with a 20-mesh sieve;
(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate;
(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tablet hardness is 70N-80N, so as to obtain the tablet with the tablet weight of 375 mg.
Examples 2-6 were prepared using different batches of API for the following formulations:
example 2
| Component (A) | Weight percent | Dosage g |
| API | 40.64％ | 38.12 |
| Microcrystalline cellulose | 40％ | 37.5 |
| Pregelatinized starch | 13.36％ | 12.525 |
| Croscarmellose sodium | 2％ | 1.875 |
| Colloidal silica | 3％ | 2.813 |
| Magnesium stearate | 1％ | 0.938 |
The preparation method comprises the following steps:
(1) Uniformly mixing the API and microcrystalline cellulose;
(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose and colloidal silicon dioxide into the mixture prepared in the step (1), and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing the pieces, and sieving the pieces with a 20-mesh sieve;
(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate;
(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tablet hardness is 70N-80N, so as to obtain the tablet with the tablet weight of 375 mg.
Example 3
| Component (A) | Weight percent | Dosage g |
| API | 40.64％ | 38.12 |
| Microcrystalline cellulose | 40％ | 37.5 |
| Pregelatinized starch | 12.36％ | 11.564 |
| Croscarmellose sodium | 2％ | 1.875 |
| Colloidal silica | 3％ | 2.813 |
| Magnesium stearate | 1％ | 0.938 |
| Stearyl sodium fumarate | 1％ | 0.938 |
The preparation method comprises the following steps:
(1) Uniformly mixing the API and microcrystalline cellulose;
(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose and colloidal silicon dioxide into the mixture prepared in the step (1), and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing the pieces, and sieving the pieces with a 20-mesh sieve;
(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate and sodium stearyl fumarate;
(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tablet hardness is 70N-80N, so as to obtain the tablet with the tablet weight of 375 mg.
Example 4
| Component (A) | Weight percent | Dosage g |
| API | 40.64％ | 38.12 |
| Microcrystalline cellulose | 39％ | 36.56 |
| Pregelatinized starch | 12.36％ | 11.564 |
| Croscarmellose sodium | 2％ | 1.875 |
| Colloidal silica | 3％ | 2.813 |
| Magnesium stearate | 1％ | 0.938 |
| Stearyl sodium fumarate | 1％ | 0.938 |
| Sodium dodecyl sulfate | 1％ | 0.938 |
The preparation method comprises the following steps:
(1) Uniformly mixing the API and microcrystalline cellulose;
(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose, colloidal silicon dioxide and sodium dodecyl sulfate into the mixture prepared in the step (1), and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing the pieces, and sieving the pieces with a 20-mesh sieve;
(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate and sodium stearyl fumarate;
(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tablet hardness is 70N-80N, so as to obtain the tablet with the tablet weight of 375 mg.
Example 5
The preparation method comprises the following steps:
(1) Uniformly mixing the API with microcrystalline cellulose and mannitol;
(2) Adding crosslinked sodium carboxymethyl cellulose, colloidal silicon dioxide and sodium dodecyl sulfate into the mixture prepared in the step (1), and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing the pieces, and sieving the pieces with a 20-mesh sieve;
(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate and sodium stearyl fumarate;
(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tablet hardness is 70N-80N, so as to obtain the tablet with the tablet weight of 375 mg.
Example 6
| Component (A) | Weight percent | Dosage g |
| API | 40.64％ | 38.12 |
| Microcrystalline cellulose | 40％ | 37.5 |
| Pregelatinized starch | 13.86％ | 12.97 |
| Croscarmellose sodium | 2％ | 1.875 |
| Colloidal silica | 2％ | 1.875 |
| Magnesium stearate | 1.5％ | 1.406 |
The preparation method comprises the following steps:
(1) Uniformly mixing the API and the microcrystalline cellulose;
(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose and colloidal silica into the mixture obtained in the step (1) and uniformly mixing;
(3) Performing wet granulation on the mixture obtained in the step (2) by using 43.731g of purified water, sieving with a 20-mesh sieve, and drying at 60 ℃ for 2 hours; (4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate;
(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tabletting hardness is 70N-80N, so as to obtain tablets with the tablet weight of 375 mg.
The substances relevant to the above examples 1 to 6 were measured according to high performance liquid chromatography (four-part rule 0512 of Chinese pharmacopoeia 2020 edition) (namely, HPLC method was measured on the Informance of Agilent Technologies 1260) under the conditions of chromatographic column: C18 column, sample injection volume: 10. Mu.l, fluidity: water+acetonitrile; 50:50; flow rate: 1.0ml/min; column temperature: 30 ℃ C., detection wavelength: 254 nm), wherein the single impurity and total impurity contents of the examples 1 to 6 were respectively:
The mono-hetero in the above table refers to the compound (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione.
Effect examples
Test stability test, for the products of examples 1-3 and 5-6, respectively packaging with oral high density polyethylene bottle (60 ml), packaging with 1 bag of solid medicinal paper bag silica gel desiccant (2.0 g), and testing influence factors to examine the light (total illuminance is not less than 1.2X10) 6 Lux.hr, and near ultraviolet energy not lower than 200w.hr/m 2 ) The effect on the percentage of each component in the product is achieved by 5 days, 10 days, high temperature (60 ℃) and high humidity (92.5% RH,25 ℃) for 5 days, 10 days and 30 days.
Stability results of example 1 formulation:
wherein the structure of mono-hetero (i.e., (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione)) and the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) and its fumaric acid crystalline form is close and difficult to separate, and the formulation product is admixed with impurities as described above, the inventors have found that the content of the above-mentioned mono-hetero in the final formulation is strictly controlled, that when the content limit is below 0.2%, the stability of the formulation is better, and the total hetero content is substantially controlled to be below the limit of 0.5% enabling the quality control of the formulation to be controlled as required by the formulation. However, when the content of the single impurity in the preparation prescription is more than 0.3%, other single impurities (such as degradation products) are easily generated in the preparation, the total impurity content is rapidly increased, and the preparation prescription is unstable under the conditions of high temperature and high humidity while the impurity content of the preparation prescription exceeds the limit. The content of the single impurity has little influence on the stability of the preparation under the illumination condition.
The inventors further selected that example 1 and example 6 were subjected to conventional acceleration tests in a stability test chamber at 40 ℃ ± 2 ℃ and RH75% ± 5%, and left for 1 month, with the following specific results:
through an accelerated stability test, the stability of the preparation can be ensured by controlling mono-impurity (namely, (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) below the limit of 0.2 percent, but when the content of the mono-impurity in the preparation prescription is above 0.3 percent, the acceleration of the preparation is easily induced to generate other mono-impurities, so that the total impurity content is obviously increased, and the stability and quality controllability of the preparation are greatly influenced.
The foregoing embodiments have been provided for the purpose of illustrating the general principles, technical solutions and advantages of the present invention in further detail, and it should be understood that the foregoing embodiments are merely illustrative of the present invention and are not intended to limit the scope of the present invention, but any modification, equivalent replacement, improvement, etc. that comes within the spirit and scope of the present invention should be construed as included in the scope of the present invention.
Claims (10)
1. A pharmaceutical composition comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) and crystalline forms of fumaric acid and (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione), and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of a filler, a disintegrant, a lubricant, a binder, a solubilizer, a glidant.
2. The pharmaceutical composition according to claim 1, wherein the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid is present in the pharmaceutical composition in a weight percentage of 10% to 60%, preferably 20% to 45%.
3. The pharmaceutical composition according to claim 1, wherein the weight percentage of (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) in the pharmaceutical composition is 1% or less, preferably 0.5% or less, further preferably 0.2% or less.
4. A pharmaceutical composition according to any one of claims 1-3, wherein the filler is present in the pharmaceutical composition in a weight percentage of 10% -80%, preferably 30% -65%;
wherein the weight percentage of the disintegrating agent in the pharmaceutical composition is 1% -10%, preferably 1% -5%;
wherein the weight percentage of the lubricant in the pharmaceutical composition is 0.5-5%, preferably 0.5-3%;
wherein the weight percentage of the binder in the pharmaceutical composition is 0% -10%, preferably 1-3%;
Wherein the weight percentage of the solubilizer in the pharmaceutical composition is 0% -5%, preferably 0.5-3%;
and/or
Wherein, the weight percentage of the glidant in the medicine composition is 0.5% -5%, preferably 0.5% -3%.
5. The pharmaceutical composition according to any one of claims 1-4, wherein the filler comprises one or more of lactose, anhydrous calcium bicarbonate, sugar alcohols, celluloses and starches; for example, the sugar alcohol filler includes one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol; for example, the cellulosic filler includes one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose; for example, the starch-based fillers include one or more of corn starch, potato starch, sweet potato starch, and pregelatinized starch;
wherein the disintegrating agent comprises one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, carboxymethyl starch sodium, corn starch and potato starch;
wherein the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate;
Wherein the adhesive comprises one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone and polyvinylpyrrolidone;
wherein the solubilizer comprises one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer;
and/or
Wherein the glidant comprises colloidal silicon dioxide and/or talcum powder.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (e.g. a tablet, powder, dry suspension, granule or capsule);
and/or the number of the groups of groups,
wherein the pharmaceutical composition is in unit dosage form, e.g., a solid formulation in unit dosage form (e.g., a tablet, powder, dry suspension, granule, or capsule).
7. A process for the preparation of a pharmaceutical composition according to any one of claims 1-6, comprising the steps of:
(i) Mixing a solid comprising (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione with a crystalline form of fumaric acid and/or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione;
(ii) Granulating the mixture obtained in the step (i), and sieving;
(iii) Optionally mixing the granules obtained in step (ii) with one or more other physiologically acceptable/pharmaceutically acceptable excipients besides the physiologically acceptable/pharmaceutically acceptable excipients described in step (i).
8. The use of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) for controlling the quality of crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1, 3-triazin-dione, the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) or (6E) -6- [ (6-chloro-1-methyl-1H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) was used as a control.
9. Use of the pharmaceutical composition of any one of claims 1-6 for the manufacture of a medicament for treating or preventing a coronavirus-caused disease in a subject; preferably, wherein the subject is a human, such as a child, adult, or elderly person.
10. Use according to claim 9, wherein the coronavirus is a novel coronavirus.
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