CN117122601A - Pharmaceutical composition comprising crystalline forms of a compound and fumaric acid, and methods of preparation and use thereof - Google Patents

Pharmaceutical composition comprising crystalline forms of a compound and fumaric acid, and methods of preparation and use thereof Download PDF

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Publication number
CN117122601A
CN117122601A CN202310109648.1A CN202310109648A CN117122601A CN 117122601 A CN117122601 A CN 117122601A CN 202310109648 A CN202310109648 A CN 202310109648A CN 117122601 A CN117122601 A CN 117122601A
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China
Prior art keywords
compound
pharmaceutical composition
fumaric acid
formula
starch
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Inventor
何红燕
黄旺
吴小涛
王松笛
鲍标贵
李超
曲蕾
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Nanjing Gritpharma Co ltd
Beijing Grand Johamu Pharmaceutical Co Ltd
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Nanjing Gritpharma Co ltd
Beijing Grand Johamu Pharmaceutical Co Ltd
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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention provides a pharmaceutical composition comprising a crystalline form of a compound of formula (I) and fumaric acid, together with a physiologically acceptable/pharmaceutically acceptable excipient; wherein the crystalline form of the compound of formula (I) and fumaric acid uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three of 10.94, 19.06, 23.50, 24.66; wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of filler, disintegrant, lubricant, solubilizer, 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 diseases caused by coronaviruses in a subject, including children, adults or elderly. The pharmaceutical compositions described herein have high dissolution, dissolution rate and/or stability.

Description

Pharmaceutical composition comprising crystalline forms of a compound and fumaric acid, and methods of preparation and use thereof
Technical Field
The present invention relates to pharmaceutical compositions comprising a crystalline form of a compound with fumaric acid and one or more physiologically acceptable/pharmaceutically acceptable excipients, to a process for their preparation and to their 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, in particular novel coronaviruses, but there is still a need for a pharmaceutical composition for treating diseases caused by coronaviruses, in particular novel coronaviruses, to meet the urgent need of clinical treatment.
Disclosure of Invention
The present invention provides a solution to the above problems existing in the prior art.
In a first aspect of the present invention there is provided a pharmaceutical composition comprising a crystalline form of a compound of formula (I) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the compound of formula (I) has the structure:
wherein the crystalline form of the compound of formula (I) and fumaric acid uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three of 10.94, 19.06, 23.50, 24.66;
wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of filler, disintegrant, lubricant, binder, solubilizer, 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 compound of formula (I) with a crystalline form of fumaric acid and a physiologically acceptable/pharmaceutically acceptable excipient;
(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 invention, the use of a pharmaceutical composition of the invention in the manufacture of a medicament for treating a coronavirus-caused disease in a subject.
The inventive research shows that the pharmaceutical composition has high dissolution rate, dissolution rate and/or stability.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline form A of a compound of formula (I) with fumaric acid. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).
FIG. 2 is a Differential Scanning Calorimeter (DSC) profile and thermogravimetric analysis (TGA) profile of a compound of formula (I) with crystalline form A of fumaric acid.
FIG. 3 is an X-ray powder diffraction pattern of crystalline form B of the compound of formula (I) with fumaric acid. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).
Fig. 4 is a Differential Scanning Calorimeter (DSC) profile of crystalline form B of the compound of formula (I) and fumaric acid.
FIG. 5 is a thermogravimetric analysis (TGA) spectrum of crystalline form B of the compound of formula (I) with fumaric acid.
Figure 6 is an X-ray powder diffraction pattern showing the effect of stability of the compound of formula (I) with crystalline form a of fumaric acid at various stages in the preparation of the formulation. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).
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., crystalline forms of the compound of formula (I) and fumaric acid) being administered.
The physiologically acceptable/pharmaceutically acceptable excipients to be mixed with the crystalline form of fumaric acid of the compounds of formula (I) according to the application to form the pharmaceutical composition according to the application may depend on the intended method of administration of the pharmaceutical composition.
The pharmaceutical composition of the present application is preferably a solid formulation.
The pharmaceutical compositions of the present application may be formulated for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.
The pharmaceutical composition of the present application may be administered orally. Oral administration involves swallowing whereby the active ingredient (e.g. crystalline form of the compound of formula (I) of the application and fumaric acid) is absorbed from the intestine and delivered via the portal circulation to the liver (hepatic first pass metabolism) and finally into the Gastrointestinal (GI) tract.
The pharmaceutical composition of the present application is preferably prepared in the form of an oral formulation. The shape of the oral preparation is not particularly limited, and may be any 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 dispersions or suspensions 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 a unit dosage 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 "novel coronavirus" of the present application refers to SARS-CoV-2, and includes all variants of SARS-CoV-2, such as NCBI or GISAID (global shared influenza data initiative organization) recorded variants, especially important variants having strong transmissibility, pathogenicity or immune evasion, such as WHO-specified Alpha, beta, gamma, delta, eta, iota, kappa or Lambda variants, and important variants specified later.
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 granules may be round, oval or angular and consist of a radiooriented crystalline aggregate of two anhydrous D-glucose polymers (amylose 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 application consists of the crystalline form of the compound of formula (I) with fumaric acid, one or more of the other active ingredients mentioned in the present application, and physiologically acceptable/pharmaceutically acceptable excipients.
In a specific embodiment, the pharmaceutical composition of the application consists of a crystalline form of the compound of formula (I) with fumaric acid and physiologically acceptable/pharmaceutically acceptable excipients.
In a specific embodiment, the crystalline form of the compound of formula (I) and fumaric acid is present in the pharmaceutical composition in a weight percentage of 15% to 60%, preferably 25% to 45%.
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% to 80%, preferably 30% to 65%.
In a specific embodiment, the weight percentage of disintegrant in the pharmaceutical composition is 1% to 10%, preferably 1% to 5%.
In a specific embodiment, the weight percentage of lubricant in the pharmaceutical composition is 0.5% -5%, preferably 0.5-3%.
In a specific embodiment, the weight percentage of the binder in the pharmaceutical composition is 0% to 10%, preferably 1-3%.
In a specific embodiment, the solubilizer is present in the pharmaceutical composition in an amount of 0% to 5%, preferably 0.5% to 3% by weight.
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% by weight.
In a specific embodiment, the weight ratio of the crystalline form of the compound of formula (I) 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.
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.
In a specific embodiment, the binder comprises one or more of hypromellose, hyprolose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, 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.
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.
In a specific embodiment, the crystalline form of the compound of formula (I) and fumaric acid uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further comprise any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, preferably further comprise any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, more preferably still further comprise any one or more of 14.73, 20.87, 21.49, 21.97, 25.39.
In a specific embodiment, the crystalline form of the compound of formula (I) and fumaric acid uses Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° are at 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8; preferably, it uses Cu-ka radiation, and the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° is shown in fig. 1.
In a specific embodiment, the differential scanning calorimetry pattern of the crystalline form of the compound of formula (I) with fumaric acid has an endothermic peak in the range 274 ℃ ± 2 ℃; preferably, the differential scanning calorimetric profile is as shown in fig. 2.
In a specific embodiment, the thermogravimetric profile of the crystalline form of the compound of formula (I) with fumaric acid is substantially free of weight loss or less than 0.5% weight loss in the range of 150 ℃ and undergoes decomposition at 240 ℃ ± 2 ℃; more preferably, the thermogravimetric analysis is as shown in figure 2.
In a specific embodiment, the ratio of the compound of formula (I) to fumaric acid is 1:1 in crystalline form of the compound of formula (I) to fumaric acid.
In the present application, the crystalline form of the compound of formula (I) and fumaric acid in the present application is sometimes also referred to as crystalline form a of the compound of formula (I) and fumaric acid, which is distinguished from other crystalline forms of the compound of formula (I) and fumaric acid, as referred to herein as crystalline form B of the compound of formula (I) and fumaric acid.
The characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° using Cu-ka radiation for the crystalline form B of the compound of formula (I) and fumaric acid include any three of 14.74, 22.80, 28.80 and 29.42 or 14.74, 22.80, 28.80 and 29.42. Specifically, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° using Cu-ka radiation for the crystalline form B of the compound of formula (I) and fumaric acid further include any one or more of 7.37, 10.68, 12.13, 19.26, 19.68, 25.03, 31.80, 37.30 and 37.85. Preferably, the crystalline form B of the compound of formula (I) and fumaric acid is irradiated with Cu-ka, and the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° is shown in fig. 3.
A differential scanning calorimetry pattern of the crystalline form B of the compound of formula (I) and fumaric acid starts phase transition at 132 ℃ and has a melting endotherm at about 266.4 ℃; more preferably, the thermogravimetric analysis is as shown in fig. 4.
Thermogravimetric analysis of crystalline form B of the compound of formula (I) with fumaric acid begins to lose a small amount of adsorbed water or solvent when heated to 110 ℃, to 140 ℃, a weight loss of 0.737%; more preferably, the thermogravimetric analysis is as shown in fig. 5.
In a specific embodiment, the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (e.g. a 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 invention is in the form of a solid formulation in unit dosage form (such as a tablet, powder, dry suspension, granule or capsule), the pharmaceutical composition comprises 1mg to 500mg, preferably 10mg to 300mg, more preferably 50mg to 200mg of active ingredient (i.e. crystalline form of the compound of formula (I) and fumaric acid as described herein and optionally one or more other active ingredients) per unit dose; for example, the pharmaceutical composition comprises 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg or 200mg of active ingredient 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: the compound of formula (I) is mixed with the crystalline form of fumaric acid, the filler, the disintegrant, the optional binder, the optional solubilizer, and the glidant in sequence. Specifically, step (i) is achieved by: the compound of formula (I) is first mixed with the crystalline form of fumaric acid and the filler, and then the disintegrant, optional binder, optional solubilizer, glidant are added for mixing. Preferably, step (i) is achieved by: the compound of formula (I) is first mixed with the crystalline form of fumaric acid and the first filler, and then the second filler, the disintegrant, the optional binder, the optional solubilizer, the glidant are added and mixed. The first filler and the second filler may be the same or different, and preferably, the first filler is the cellulose filler according to the present application, and the second filler is the starch filler according to the present 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 depending on the 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 means of a dry granulator. 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 the particles from step (ii) with a lubricant. 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, 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 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 invention 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 invention 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 invention 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 the crystalline form of the compound of formula (I) according to the application with fumaric acid for the preparation of a pharmaceutical composition comprising the crystalline form of the compound of formula (I) with fumaric acid and a physiologically acceptable/pharmaceutically acceptable excipient. In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above.
In yet another aspect, the present application provides another method of preparing a pharmaceutical composition of the present application comprising the steps of: (i) Mixing a compound of formula (I) with a crystalline form of fumaric acid and a physiologically acceptable/pharmaceutically acceptable excipient; (ii) tabletting the mixture obtained in step (i). In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above.
The various embodiments described herein, or of different preferred classes of embodiments, may be combined arbitrarily unless otherwise indicated.
The present application 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 application are within the scope of the application. The compounds or reagents used in the following examples are commercially available or may be 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 Bicheng seaweed Co., ltd, microcrystalline cellulose was purchased from Sian Gao pharmaceutical Co., ltd, croscarmellose sodium was purchased from Jiangxi alpha Gao pharmaceutical Co., ltd, colloidal silicon dioxide was purchased from Shanghai Feng pharmaceutical Co., ltd, magnesium stearate was purchased from Hebei Pengyo Biotechnology Co., ltd, sodium stearyl fumarate was purchased from Wuhan Kano Biotechnology Co., and sodium dodecyl sulfate was purchased from Sian brocade Source Biotechnology Co., ltd, pregelatinized starch was purchased from Hebei invasive Source Biotechnology Co., crosslinked povidone was purchased from Sian Anhua pharmaceutical Co., ltd, copovidone was purchased from Hai Chen pharmaceutical technology Co., and hydroxypropyl cellulose was purchased from Mirabi chemical (Nanj) Co., lactose was purchased from Shanghai Tao Co., ltd.
Examples
I. Preparation and characterization of crystalline forms of the compound of formula (I) and fumaric acid
Example 1
(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 fumaric acid solid form (15.2 mg) was taken and 1.0mL of acetone was added to prepare a suspension, which was stirred in suspension at room temperature for 3-7 days, or at 20-50℃for 1 day, the suspension was isolated, and the solid was dried in vacuo to give white solid crystalline form A (14.7 mg).
Comparative example 1
A mixture of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione (1.17 g,2.2 mmol) and fumaric acid (274 mg,2.4 mmol) in EtOAc (5.9 mL) was stirred at room temperature for 45min. The suspension was filtered to give a white solid 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 fumaric acid co-crystals, referred to herein as crystalline form B (1.37 g) of the compound of formula (I) and fumaric acid.
The solid samples obtained in example 1 and comparative example 1 were characterized by an X-ray powder diffractometer PANalytical Empyrean (pamalytical, NL). The 2 theta scanning angle is from 3 degrees to 45 degrees, the scanning step length is 0.013 degrees, and the testing time is 5 minutes and 8 seconds. The voltage and current of the light pipe are 45kV and 40mA respectively when the sample is tested, and the sample disk is a zero background sample disk.
XRPD diffraction peak data for crystalline form a of compound of formula (I) and fumaric acid
The above characteristic diffraction peaks, the principal characteristic diffraction peaks being selected from any three of 10.94, 19.06, 23.50, 24.66, further comprising any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, further comprising any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, or further comprising any one or more of 14.73, 20.87, 21.49, 21.97, 25.39, or further comprising at 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8, in particular the XRPD pattern of the compound of formula (I) and crystalline form a of fumaric acid is as shown in figure 1.
XRPD diffraction peak data for crystalline form B of compound of formula (I) and fumaric acid
Diffraction angle 2 theta (°) d value Relative intensity (%)
7.37 12.00 28.8
10.68 8.28 14.5
12.13 7.29 10.2
14.74 6.01 33.9
19.26 4.61 28.9
19.68 4.51 24.7
22.80 3.90 54.9
25.03 3.55 25.4
28.80 3.10 100.0
29.42 3.03 39.8
31.80 2.81 19.8
37.30 2.41 9.5
37.85 2.38 9.7
Of the above diffraction peaks, the main characteristic peaks were selected from any three of 14.74, 22.80, 28.80 and 29.42 or at 14.74, 22.80, 28.80 and 29.42. In addition to the above main characteristic peaks, characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ±0.2° using cu—kα radiation were 7.37, 10.68, 12.13, 19.26, 19.68, 25.03, 31.80, 37.30 and 37.85. Specifically, the XRPD patterns of the crystalline form B of the compound of formula (I) and fumaric acid are shown in figure 3.
Conclusion: by comparing the characteristic peaks of XRPD, the characteristic peaks of the crystal form A and the crystal form B are obviously different, and can be determined as two different crystal forms.
The inventors have examined the accelerated stability of the two crystalline forms after determining the different crystalline forms of the compound of formula (I) and fumaric acid. Specifically, the compound of formula (I) prepared in example 1 was placed in a stability test box at 40 ℃ under 75% Relative Humidity (RH) with the crystalline form a of fumaric acid and the crystalline form B of the compound of formula (I) prepared in comparative example 1, and left for 2 months, sampled at 1 month and 2 months, respectively, and the appearance was observed and the purity was checked, and compared with the results for 0 day, as detailed in the following table.
Results: the compound of the formula (I) and the crystal form A of fumaric acid have good stability under the conditions of 40 ℃ and 75% Relative Humidity (RH), and maintain stable appearance and purity within 2 months, and the crystal form A is not dissociated or transformed; in contrast, crystalline form B is unstable and undergoes dissociation or seeding.
The present inventors continued to study a formulation comprising the compound of formula (I) and crystalline form a of fumaric acid and crystalline form B of the compound of formula (I) and examined the effect of the formulation on the basis of determining that there is a difference in stability between the two crystalline forms.
Formulation examples
Example 1
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with the crystalline form A of fumaric acid and mannitol;
(2) Adding microcrystalline cellulose, croscarmellose sodium, sodium dodecyl sulfate and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving 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 tabletting hardness is 85N, so as to obtain tablets with the tablet weight of 375 mg.
Example 2
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The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form A of fumaric acid and microcrystalline cellulose;
(2) Adding pregelatinized starch, crospovidone, sodium dodecyl sulfate and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving 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 controlling the average weight difference to +/-3% by adopting 9.5mm round punch, wherein the tabletting hardness is 70N, so as to obtain a tablet with the tablet weight of 375 mg.
Example 3
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form A of fumaric acid and microcrystalline cellulose;
(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose, sodium dodecyl sulfate, copovidone and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving 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 tabletting hardness is 70N-80N, so as to obtain tablets with the tablet weight of 375 mg.
Example 4
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form A of fumaric acid and microcrystalline cellulose;
(2) Adding pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium and colloidal silicon dioxide 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 34.9874g 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.
Example 5
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The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form A of fumaric acid and lactose;
(2) Adding microcrystalline cellulose and sodium dodecyl sulfate into the mixture obtained in the step (1) and uniformly mixing;
(3) Grinding the mixture obtained in the step (2) into fine powder;
(4) Sieving the fine powder obtained in the step (3) with a 120-mesh sieve, and filling into packaging materials (such as small bags) to obtain powder or dry suspension with a weight of 375mg per package.
Example 6
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form A of fumaric acid and lactose;
(2) Adding microcrystalline cellulose and sodium dodecyl sulfate into the mixture obtained in the step (1) and uniformly mixing;
(3) Grinding the mixture obtained in the step (2) into fine powder;
(4) Sieving the fine powder obtained in the step (3) with a 120-mesh sieve, and filling into packaging materials (such as small bags) to obtain powder or dry suspension with a weight of 375mg per package.
Example 7
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with the crystalline form A of fumaric acid and mannitol;
(2) Adding microcrystalline cellulose and sodium dodecyl sulfate into the mixture obtained in the step (1) and uniformly mixing;
(3) Grinding the mixture obtained in the step (2) into fine powder;
(4) Sieving the fine powder obtained in the step (3) with a 120-mesh sieve, and filling into packaging materials (such as small bags) to obtain powder or dry suspension with a weight of 375mg per package.
Comparative example 1
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form B of fumaric acid and mannitol;
(2) Adding microcrystalline cellulose, croscarmellose sodium, sodium dodecyl sulfate and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving 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 tabletting hardness is 85N, so as to obtain tablets with the tablet weight of 375 mg.
Comparative example 2
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form B of fumaric acid and microcrystalline cellulose;
(2) Adding pregelatinized starch, crospovidone, sodium dodecyl sulfate and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving 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 controlling the average weight difference to +/-3% by adopting 9.5mm round punch, wherein the tabletting hardness is 70N, so as to obtain a tablet with the tablet weight of 375 mg.
Comparative example 3
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form B of fumaric acid and microcrystalline cellulose;
(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose, sodium dodecyl sulfate, copovidone and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;
(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving 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 tabletting hardness is 70N-80N, so as to obtain tablets with the tablet weight of 375 mg.
Comparative example 4
The preparation method comprises the following steps:
(1) Uniformly mixing a compound of the formula (I) with a crystalline form B of fumaric acid and microcrystalline cellulose;
(2) Adding pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium and colloidal silicon dioxide 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 34.9874g 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.
Effect examples
1. In vitro dissolution experiments
The experimental method is as follows: the paddle method was used at a speed of 75 revolutions per minute, 900ml of dissolution medium. The dissolution profiles of the products obtained in examples 1-4 and comparative examples 1-4, respectively, were determined in a dissolution medium, i.e., purified water, pH1.2+0.2% Tween 80. And respectively taking a proper amount of dissolution liquid at 5min, 10min, 15min, 30min, 45min and 60min, filtering, taking the subsequent filtrate as a sample solution, and measuring the in-vitro dissolution rate.
The specific measurement results are shown in the following table:
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conclusion: in the dissolution medium of purified water pH1.2+0.2% Tween 80, the products of examples 1-4 adopting the crystalline form A have faster dissolution rate and higher in vitro dissolution rate, and can meet the dissolution requirement. The products of comparative examples 1-4 in the form of crystals B have lower dissolution rate and can not meet the dissolution requirement that the dissolution rate is more than or equal to 75% in 60min, and are not suitable for subsequent preparation development.
2. Stability test of crystalline form A of Compound of formula (I) and fumaric acid during preparation of formulations
This study focused on the stability of the crystalline form a of the compound of formula (I) and fumaric acid during preparation of the formulation in the formulation examples described above, as determined by sampling at various time points during preparation of the formulation. Specifically, taking example 2 of formulation example as an example, samples were sampled before the start of formulation preparation, after step (3) of formulation preparation and before step (4) and after step (5) of formulation preparation, and analyzed with an X-ray powder diffractometer PANalytical Empyrean (PANalytical, NL) (wherein the 2θ scan angle was from 3 ° to 45 °, the scan step was 0.013 °, the test time was 5 minutes 8 seconds; the light pipe voltage and current were 45kV and 40mA, respectively, when the samples were tested, the sample pan was a zero background sample pan).
Conclusion: the X-ray powder diffraction pattern (i.e., fig. 6) of the blank adjuvant before the preparation of the formulation, the crystalline form a of the compound of formula (I) and fumaric acid (abbreviated as crystalline form a), the particles comprising the compound of formula (I) and fumaric acid (abbreviated as formulation intermediate made of crystalline form a) obtained in step (3) and the resulting tablet comprising the compound of formula (I) and fumaric acid (abbreviated as formulation made of crystalline form a) shows that the compound of formula (I) and fumaric acid are stable and no transcrystalline during the preparation of the formulation. This demonstrates that the crystalline form a of the compound of formula (I) and fumaric acid are well compatible with the various excipient components in the formulation, which do not affect the stability of the crystalline form a of the compound of formula (I) and fumaric acid during the formulation.
3. Stability experiments of formulations comprising crystalline form A of the Compound of formula (I) with fumaric acid
Packaging the products of examples 1-4 with oral high density polyethylene bottle (60 ml), adding 1 bag of solid medicinal paper bag silica gel desiccant (2.0 g), and testing the influence factor under illumination (total illuminance not less than 1.2X10) 6 Lux.hr, and near ultraviolet energy not lower than 200w.hr/m 2 ) The effect on the content of each component in the product is achieved by placing the product for 5 days and 10 days under the conditions of high temperature (60 ℃) and high humidity (92.5% RH,25 ℃).
Conclusion: under illumination (total illuminance not less than 1.2X10) 6 Lux.hr, and near ultraviolet energy not lower than 200w.hr/m 2 ) The products of examples 1-4 were relatively stable under the conditions of the high temperature (60 ℃) and high humidity (92.5% RH,25 ℃) influence factor test, wherein the content of each component (including the crystalline form A of the compound of formula (I) and fumaric acid) was substantially unchanged. This indicates that the crystalline form a of fumaric acid and the compound of formula (I) in the products of examples 1-4 are not transcrystalline, and that the compatibility between the crystalline form a of fumaric acid and the various excipients, including the compound of formula (I), is better, and the products of examples 1-4 are more stable under light, high temperature and high humidity conditions.
The foregoing embodiments have been provided for the purpose of illustrating the general principles of the present invention, and are not meant to limit the scope of the invention, but to limit the scope of the invention.

Claims (10)

1. A pharmaceutical composition comprising a crystalline form of a compound of formula (I) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the compound of formula (I) has the structure:
wherein the crystalline form of the compound of formula (I) and fumaric acid uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59 and 23.8; wherein the physiologically acceptable/pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, binders, glidants;
wherein,
the weight ratio of the crystalline form of the compound of formula (I) to fumaric acid to the filler is in the range of 1:3 to 3:1;
the weight ratio of disintegrant to lubricant is in the range of 1:4 to 4:1; and/or the number of the groups of groups,
the weight ratio of binder to lubricant is in the range of 1:3 to 3:1;
wherein the filler comprises one or more of lactose, anhydrous calcium bicarbonate, sugar alcohols, celluloses and starches; the disintegrating agent comprises one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, carboxymethyl starch sodium, corn starch and potato starch; the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate and sodium stearyl fumarate; the adhesive comprises one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone and polyvinylpyrrolidone; and/or the glidant comprises colloidal silicon dioxide and/or talc.
2. The pharmaceutical composition of claim 1, wherein the sugar alcohol filler comprises one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol; the cellulose filler comprises microcrystalline cellulose; the starch filler comprises one or more of corn starch, potato starch, sweet potato starch and pregelatinized starch.
3. The pharmaceutical composition of claim 1, wherein the sugar alcohol filler comprises one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol; the cellulose filler comprises powdered cellulose; the starch filler comprises one or more of corn starch, potato starch, sweet potato starch and pregelatinized starch.
4. The pharmaceutical composition of claim 1, wherein the sugar alcohol filler comprises one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol; the cellulose filler comprises silicified microcrystalline cellulose; the starch filler comprises one or more of corn starch, potato starch, sweet potato starch and pregelatinized starch.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the crystalline form of the compound of formula (I) and fumaric acid is irradiated with Cu-ka, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2Θ values ± 0.2 ° further comprise any one or more of 7.81, 10.14, 11.50, 11.93, 12.31.
6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral solid formulation, the pharmaceutical composition being in unit dosage form.
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 compound of formula (I) with a crystalline form of fumaric acid and a physiologically acceptable/pharmaceutically acceptable excipient;
(ii) Granulating the mixture obtained in the step (i), and sieving;
(iii) 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. Use of a pharmaceutical composition according to any one of claims 1-6 for the manufacture of a medicament for treating a novel coronavirus-caused disease in a subject.
9. The use of claim 8, wherein the subject is a human.
10. The use of claim 9, wherein the subject is a child, adult, or elderly person.
CN202310109648.1A 2022-05-27 2022-06-13 Pharmaceutical composition comprising crystalline forms of a compound and fumaric acid, and methods of preparation and use thereof Pending CN117122601A (en)

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