CN108057036B - Solid pharmaceutical composition of EGFR inhibitor - Google Patents
Solid pharmaceutical composition of EGFR inhibitor Download PDFInfo
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- CN108057036B CN108057036B CN201610976881.XA CN201610976881A CN108057036B CN 108057036 B CN108057036 B CN 108057036B CN 201610976881 A CN201610976881 A CN 201610976881A CN 108057036 B CN108057036 B CN 108057036B
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
- A61K9/2054—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
Abstract
The application belongs to the technical field of pharmacy, relates to a solid pharmaceutical composition of an EGFR inhibitor, and particularly relates to a solid pharmaceutical composition prepared from a compound of a formula (I) or pharmaceutically acceptable salt thereof as a raw material and a preparation method thereof. The solid pharmaceutical composition comprises, on the one hand, a diluent, a disintegrant and a lubricant; another aspect is a solid dispersion of a carrier material selected from the group consisting of cellulose-based compounds. The solid pharmaceutical composition obviously improves the water solubility and stability of the compound, has faster release rate and is beneficial to improving bioavailability.
Description
Technical Field
The invention relates to a solid pharmaceutical composition of an EGFR inhibitor, in particular to a solid pharmaceutical composition prepared by taking a compound of a formula (I) or pharmaceutically acceptable salt thereof as a raw material and a preparation method thereof, belonging to the technical field of pharmacy.
Background
The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays an important role in regulating the growth, repair and survival of tumor cells, neovascularization, invasion and metastasis, while being expressed in a substantial portion of human tumors. Epidermal Growth Factor Receptor (EGFR) is widely present in a variety of malignant tumor cells of epidermal origin: non-small cell lung cancer, breast cancer colorectal cancer, gastric cancer, prostate cancer, ovarian cancer, head and neck tumor.
Oral administration is the most common mode of administration of drugs. Following oral administration, the drug may be absorbed at many different sites along the gastrointestinal tract (including via the stomach, duodenum, jejunum, ileum, and colon). The different chemical environment of the gastrointestinal tract affects the solvent release of the medicament to affect the absorption of the active substance in the medicament. Wherein, the pH of the stomach environment is 1-3.5, the pH of the small intestine environment is 4-8, and the dissolution property and the permeation property which are obviously dependent on pH exist. The compounds described herein have a solubility under acidic conditions that is higher than that of basic conditions, but the pharmaceutically acceptable salts thereof have a solubility under basic conditions that is similar or slightly higher than that of the compounds under acidic conditions. Therefore, there is a need to develop pharmaceutical formulations to meet the requirements of clinical use for effectiveness and safety, both for solubility and bioavailability of the agents and for controlled release of the agents.
WO2016070816A1 discloses an EGFR inhibitor, which has low water solubility and is unfavorable for the dissolution and absorption processes of drugs in gastrointestinal tract after oral administration, so that the bioavailability is low and the treatment effect of the compound is affected. The application provides a solid pharmaceutical composition of the EGFR inhibitor, which has good stability, faster dissolution speed and higher bioavailability and is suitable for clinical use.
Disclosure of Invention
The application provides a solid pharmaceutical composition of a compound shown in a formula I or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula I is shown as follows:
wherein A is selected from
/>
R is selected from H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl,
Methanesulfonyl, ethanesulfonyl, isopropylsulfonyl or cyclopropanesulfonyl.
In some embodiments, the compound of formula I is selected from:
the pharmaceutically acceptable salts described herein are selected from the group consisting of hydrochloride, hydrobromide, phosphate, sulfate, nitrate, mesylate, trifluoroacetate, isethionate, maleate, fumarate, malate, citrate, succinate, lactate or acetate, preferably hydrochloride or mesylate. In the pharmaceutically acceptable salts of the compounds of formula I described herein, the molar ratio of the compounds of formula I to the acid ions forming the pharmaceutically acceptable salts may be selected from 2:1, 1:1, 1:2 or 1:3, depending on whether the particular compounds of formula I and acid ions form stable salts.
In some embodiments, preferably, the pharmaceutically acceptable salt of the compound of formula I described herein is selected from the group consisting of the hydrochloride salt of the compound of formula 2, the mesylate salt of the compound of formula 2, the hydrochloride salt of the compound of formula 9, the mesylate salt of the compound of formula 9, the hydrochloride salt of the compound of formula 13, and the mesylate salt of the compound of formula 13; more preferably, the compound is selected from the group consisting of monohydrochloride of the compound of formula 2, dihydrochloride of the compound of formula 2, trisulfate of the compound of formula 2, dimesylate of the compound of formula 2, trimesylate of the compound of formula 2, monohydrochloride of the compound of formula 9, dihydrochloride of the compound of formula 9, trisulfate of the compound of formula 9, monomesylate of the compound of formula 9, dimesylate of the compound of formula 9, trimesosulfonate of the compound of formula 13, monohydrochloride of the compound of formula 13, dihydrochloride of the compound of formula 13, trimesosulfonate of the compound of formula 13, dimesylate of the compound of formula 13, and trimesosulfonate of the compound of formula 13.
In one embodiment of the present application, the auxiliary materials of the solid pharmaceutical composition of the compound shown in formula I or the pharmaceutically acceptable salt thereof include diluents, disintegrants and lubricants.
In some embodiments, the diluent is selected from the group consisting of starch, pregelatinized starch, sucrose, lactose, fructose, maltose, trehalose, pullulan, polydextrose, dextrin, maltodextrin, microcrystalline cellulose, cellulose acetate, ethylcellulose, mannitol, sorbitol, erythritol, isomalt, lactitol, maltitol, polyethylene glycol, xylitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium chloride, or a mixture of any two or more thereof; preferably microcrystalline cellulose or a mixture of microcrystalline cellulose with the other diluents mentioned above; more preferably from microcrystalline cellulose, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol, or a mixture of microcrystalline cellulose and xylitol. The diluent is selected from the range of 60 to 95wt%, preferably from 65 to 95wt%, 70 to 95wt%, 75 to 95wt%, 80 to 95wt%, 85 to 95wt% or 90 to 95wt% of the pharmaceutical composition. When the diluent is selected from a mixture of microcrystalline cellulose and other diluents, the microcrystalline cellulose is present in the diluent in a range selected from 10 to 90wt%, preferably from 20 to 85wt%, 25 to 80wt%, 25 to 75wt%, 30 to 75wt%, 40 to 75wt%, 45 to 75wt%, 50 to 75wt%, 55 to 75wt%, 60 to 75wt%.
In some embodiments, the disintegrant may be selected from dry starch, sodium starch glycolate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, methyl cellulose, croscarmellose sodium, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, alginic acid, calcium alginate, sodium alginate, chitosan, colloidal silicon dioxide, glycine, guar gum, magnesium aluminum silicate, or povidone; preferably self-drying starch, sodium starch glycolate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, methyl cellulose, croscarmellose sodium, sodium carboxymethyl cellulose or calcium carboxymethyl cellulose; more preferably sodium carboxymethyl starch or low substituted hydroxypropyl cellulose. The disintegrating agent accounts for 1-10wt% of the range of the pharmaceutical composition; preferably from 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt% or 9wt%.
In some embodiments, the lubricant is selected from stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate, glyceryl tribehenate, palmitoyl stearyl glyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, or talc; preferably stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl behenate, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl monostearate or sodium stearyl fumarate; more preferably magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate. The lubricant accounts for 0.5-5 wt% of the pharmaceutical composition; preferably from 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 1.8wt%, 2.0wt%, 2.2wt%, 2.5wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.5wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.5wt% or 4.8wt%.
In some aspects, the pharmaceutical compositions of the present application comprise: 10 to 20 weight percent of compound shown in formula I or pharmaceutically acceptable salt thereof, 70 to 90 weight percent of diluent, 4 to 6 weight percent of disintegrant and 1 to 3 weight percent of lubricant; the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula 2, a monohydrochloride of the compound of formula 2, a dihydrochloride of the compound of formula 2, a trishloride of the compound of formula 2, a monomethane sulfonate of the compound of formula 2, a dimesylate of the compound of formula 2, a trimesosulfate of the compound of formula 9, a monohydrochloride of the compound of formula 9, a dihydrochloride of the compound of formula 9, a trishloride of the compound of formula 9, a monomethane sulfonate of the compound of formula 9, a dimesylate of the compound of formula 9, a trimesosulfate of the compound of formula 13, a monohydrochloride of the compound of formula 13, a dihydrochloride of the compound of formula 13, a monomesylate of the compound of formula 13, a dimesylate of the compound of formula 13, or a trimesoate of the compound of formula 13; the diluent is selected from microcrystalline cellulose, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; the disintegrating agent is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose; the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate.
In some aspects, the pharmaceutical compositions of the present application comprise: 10 to 20 weight percent of compound shown in formula I or pharmaceutically acceptable salt thereof, 70 to 90 weight percent of diluent, 4 to 6 weight percent of disintegrant and 1 to 3 weight percent of lubricant; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is preferably selected from the compound shown in the formula 2, the trimesoyl salt of the compound shown in the formula 2, the compound shown in the formula 9, the monohydrochloride of the compound shown in the formula 9, the compound shown in the formula 13 or the dimesylate of the compound shown in the formula 13; the diluent is selected from microcrystalline cellulose, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; the disintegrating agent is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose; the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate.
In some embodiments, the pharmaceutical composition may further comprise a solubilizing agent selected from the group consisting of: hypromellose, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyhydroxypentadistearate, sodium lauryl sulfate, magnesium lauryl sulfate, sorbitan ester, glyceryl caprylate, glyceryl trioleate, polyoxylglyceride, povidone, pyrrolidone, poloxamer, phospholipid or vitamin E polyethylene glycol succinate, preferably from sodium lauryl sulfate or magnesium lauryl sulfate. The solubilizer accounts for 0.5-5wt% of the pharmaceutical composition; preferably from 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 1.8wt%, 2.0wt%, 2.2wt%, 2.5wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.5wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.5wt% or 4.8wt%.
In some aspects, the pharmaceutical compositions of the present application comprise: 10 to 20 weight percent of compound shown in formula I or pharmaceutically acceptable salt thereof, 70 to 90 weight percent of diluent, 4 to 6 weight percent of disintegrating agent, 1 to 3 weight percent of lubricant and 1 to 3 weight percent of solubilizer; the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula 2, a monohydrochloride of the compound of formula 2, a dihydrochloride of the compound of formula 2, a trishloride of the compound of formula 2, a monomethane sulfonate of the compound of formula 2, a dimesylate of the compound of formula 2, a trimesosulfate of the compound of formula 9, a monohydrochloride of the compound of formula 9, a dihydrochloride of the compound of formula 9, a trishloride of the compound of formula 9, a monomethane sulfonate of the compound of formula 9, a dimesylate of the compound of formula 9, a trimesosulfate of the compound of formula 13, a monohydrochloride of the compound of formula 13, a dihydrochloride of the compound of formula 13, a monomesylate of the compound of formula 13, a dimesylate of the compound of formula 13, or a trimesoate of the compound of formula 13; the diluent is selected from microcrystalline cellulose, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; the disintegrating agent is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose; the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate; the solubilizer is selected from sodium lauryl sulfate or magnesium lauryl sulfate.
In some aspects, the pharmaceutical compositions of the present application comprise: 10 to 20 weight percent of compound shown in formula I or pharmaceutically acceptable salt thereof, 70 to 90 weight percent of diluent, 4 to 6 weight percent of disintegrating agent, 1 to 3 weight percent of lubricant and 1 to 3 weight percent of solubilizer; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is preferably selected from the compound shown in the formula 2, the trimesoyl salt of the compound shown in the formula 2, the compound shown in the formula 9, the monohydrochloride of the compound shown in the formula 9, the compound shown in the formula 13 or the dimesylate of the compound shown in the formula 13; the diluent is selected from microcrystalline cellulose, a mixture of microcrystalline cellulose and lactose, a mixture of microcrystalline cellulose and starch, a mixture of microcrystalline cellulose and mannitol or a mixture of microcrystalline cellulose and xylitol; the disintegrating agent is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose; the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate; the solubilizer is selected from sodium lauryl sulfate or magnesium lauryl sulfate.
The solid pharmaceutical compositions of the present application may be formulated in a variety of forms intended to be suitable for oral administration to humans, including, for example, tablets, pills, capsules, powders or granules, and the like. In some aspects, the present application provides a tablet comprising a tablet core comprising a pharmaceutical composition as described above. The tablets may or may not have a coating.
The coating layer may be selected from film coatings. The film forming material of the film coating is selected according to the functions realized by the preparation, such as gastric dissolution function, enteric dissolution function, slow controlled release function, special stability function and the like. The film-forming material may be selected from common film-coating materials such as hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, film-forming acrylic polymers, methacrylic acid-methyl methacrylate copolymers, film-forming vinyl polymers, polyvinyl alcohol or polyvinyl acetate phthalate, and the like; can be selected from slow release coating materials such as methacrylate copolymers, ethyl cellulose or cellulose acetate, etc.; can be selected from enteric coating materials such as cellulose acetate phthalate, polyvinyl alcohol peptide acid ester, methacrylate copolymer, cellulose acetate trimellitate, hydroxypropyl cellulose titanate or hydroxypropyl cellulose succinate, etc. The amount of film-forming material used is selected according to the functions that can be achieved by the film coating. Alternatively, the film forming material will be selected from 30% to 90%, such as 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the film coating. Alternatively, the film-forming material is typically selected from 0.5% to 5%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% or 5.0% by weight of the pharmaceutical composition according to the invention.
Optionally, the film coating comprises additional components, such as plasticizers, colorants, dispersion aids, or opacifiers. Plasticizers may be used to improve the film flexibility and durability and adhesion characteristics of the film coating. Suitable plasticizers include, for example, glycerol, acetylated monoglycerides, citric acid esters (e.g., triethyl citrate), propylene glycol, polyethylene glycol (e.g., polyethylene glycol), triacetin (triacetin), triglycerides (e.g., castor oil), or phthalic acid esters (e.g., diethyl phthalate). Typically, the plasticizer, when used, is present in an amount of from 1% to 20%, e.g., 5% to 15% by weight, based on the weight of the film coating. Suitable opacifiers and colorants are well known and include, for example, titanium dioxide, ferric oxide (e.g., ferric oxide). Suitable dispersion aids include, for example, talc.
In some embodiments, suitable film coatings may be from commercially available concentrates which may be diluted with water prior to application to the composition, and which may include cellulose ethers and plasticizers, such as opappray from the company colacon TM Coating material series products.
In another embodiment of the present application, the solid pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is a solid dispersion, and the carrier material of the solid dispersion composition is selected from cellulose compounds.
In some embodiments, the cellulosic compound as a carrier material is enteric and is selected from Cellulose Acetate (CAP), hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), or carboxymethyl cellulose (CMEC); preferably selected from hypromellose phthalate (HPMCP) or hypromellose acetate succinate (HPMCAS). The carrier material is present in the solid dispersion in an amount of 40 to 90% by weight; suitably, optionally present at 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight; preferably, present in an amount of 60 to 80% by weight; more preferably, it is present in an amount of 70% by weight.
In some embodiments, the solid dispersion described herein may further comprise a stabilizer comprising vitamin E, dibutyl hydroxy toluene, butyl hydroxy anisole, soybean phospholipid, ascorbic acid, citric acid, or cysteine hydrochloride, preferably from butyl hydroxy anisole. Suitably, the stabilizer is present in the solid dispersion in an amount of from 0.05 to 0.5% by weight; suitably, optionally present at 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45% or 0.50% by weight; preferably, present in an amount of 0.10% to 0.30% by weight; more preferably, it is present in an amount of 0.20% by weight.
In some embodiments, the solid dispersion comprises 30 to 40wt% of a compound of formula I or a pharmaceutically acceptable salt thereof, 60 to 80wt% of a carrier material, and 0.10 to 0.30wt% of a stabilizer; the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula 2, a monohydrochloride of the compound of formula 2, a dihydrochloride of the compound of formula 2, a trishloride of the compound of formula 2, a monomethane sulfonate of the compound of formula 2, a dimesylate of the compound of formula 2, a trimesosulfate of the compound of formula 9, a monohydrochloride of the compound of formula 9, a dihydrochloride of the compound of formula 9, a trishloride of the compound of formula 9, a monomethane sulfonate of the compound of formula 9, a dimesylate of the compound of formula 9, a trimesosulfate of the compound of formula 13, a monohydrochloride of the compound of formula 13, a dihydrochloride of the compound of formula 13, a monomesylate of the compound of formula 13, a dimesylate of the compound of formula 13, or a trimesoate of the compound of formula 13; the carrier material is selected from hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS); the stabilizer is selected from butyl hydroxy anisole.
In some embodiments, the solid dispersion comprises 30 to 40wt% of a compound of formula I or a pharmaceutically acceptable salt thereof, 60 to 80wt% of a carrier material, and 0.10 to 0.30wt% of a stabilizer; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is preferably selected from the compound shown in the formula 2, the trimesoyl salt of the compound shown in the formula 2, the compound shown in the formula 9, the monohydrochloride of the compound shown in the formula 9, the compound shown in the formula 13 or the dimesylate of the compound shown in the formula 13; the carrier material is selected from hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS); the stabilizer is selected from butyl hydroxy anisole.
The solid dispersion of the present application can be prepared into a general pharmaceutical preparation, such as, but not limited to, a powder, a tablet, a pill, a capsule, or the like, by a known method using auxiliary materials such as diluents, disintegrants, binders, lubricants, colorants, suspending agents, sweeteners, surfactants, and the like as needed.
Examples of diluents include starch, pregelatinized starch, sucrose, lactose, fructose, maltose, trehalose, pullulan, polydextrose, dextrin, maltodextrin, microcrystalline cellulose, cellulose acetate, ethylcellulose, mannitol, sorbitol, erythritol, isomalt, lactitol, maltitol, polyethylene glycol, xylitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium chloride, or a mixture of any two or more.
Examples of disintegrants include dry starch, sodium starch glycolate, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, methyl cellulose, croscarmellose sodium, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, alginic acid, calcium alginate, sodium alginate, chitosan, colloidal silicon dioxide, glycine, guar gum, magnesium aluminum silicate, or povidone.
Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, pregelatinized starch, syrup, or starch syrup.
Examples of lubricants include stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate, glyceryl tribasic behenate, palmitoyl stearyl glyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, or talc.
Examples of the colorant include yellow iron oxide, brown iron oxide, red iron oxide, titanium oxide, food coloring blue, food coloring red or food coloring yellow.
Examples of suspending agents include polysorbates, polyethylene glycols, gum arabic, glycerol or gels.
Examples of sweeteners include aspartyl phenylalanine methyl ester, saccharin, sodium saccharin, starch syrup, or fructose.
Examples of surfactants include sodium lauryl sulfate, polysorbates, or polyoxyethylene hydrogenated castor oil.
Capsules the capsules may be prepared by mixing a solid dispersion of the compound of formula I or a pharmaceutically acceptable salt thereof as described above with any of the above excipients according to known methods, and filling the mixture into hard capsules made of gelatin, hydroxypropyl methylcellulose, polyvinyl alcohol, etc., or into soft capsules based on gelatin.
The solid pharmaceutical composition of the compound shown in the formula I or the pharmaceutically acceptable salt thereof obviously improves the water solubility and the stability of the compound and is beneficial to improving the bioavailability. The release rate is faster when prepared as a solid dispersion; especially when the carrier material is selected from hypromellose phthalate or hypromellose acetate succinate, the water solubility is better than other carrier materials. The stability of the solid dispersion can be significantly improved by further adding butyl hydroxy anisole.
Detailed Description
The following specific examples are presented to provide those skilled in the art with a more thorough understanding and practice of the invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Example 1
Pulverizing the trimesoyl salt of the compound of formula 2 by air flow, and sieving; pulverizing microcrystalline cellulose by air flow, and sieving; the screened trimesoyl salt of the compound of formula 2, microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate are added into a mixer hopper, mixed for 30 minutes, and dry tableted by a tablet press to form tablets. The material dosage is 1000 tablets, each tablet is equivalent to containing 20mg of the compound of formula 2, and the prescription composition is as follows:
table 1 composition of the formulation of the trimesoate tablet A of the compound of formula 2
Examples 2 to 9
Referring to the preparation method of example 1, tablets of examples 2 to 9 were prepared as follows:
example 2
Table 2 prescription composition of the trimesoate tablet B of the Compound of formula 2
Example 3
Table 3 prescription composition of the trimesoate tablet C of the Compound of formula 2
Example 4
Table 4 prescription composition of the trimesoate tablet D of the Compound of formula 2
Example 5
Table 5 formula composition of monohydrochloride tablet E of the Compound of formula 9
Example 6
Table 6 formula composition of monohydrochloride tablet E of compound of formula 9
Example 7
Table 7 prescription composition of the Dimesylate tablet F of the Compound of formula 13
Example 8
Table 8 prescription composition of the Dimesylate tablet G of the Compound of formula 13
Example 9
Table 9 prescription composition of the Dimesylate tablet H of the Compound of formula 13
Example 10
The trisulphonate salt of the compound of formula 2 and carboxymethyl cellulose are dissolved in a ratio of 3:7 by weight in a dichloromethane/ethanol mixed solution. The mixture solution was then spray dried by a spray dryer. The resulting dried product was further dried at 60℃for 10 hours using a vacuum dryer to obtain a solid dispersion I of the trimesylate of the compound of formula 2 in the form of a powder.
Referring to the preparation method of example 10, tablets according to examples 11 to 17 below:
examples 11 to 17
Referring to the preparation method of example 10, solid dispersions of the following examples 11 to 17 were prepared:
table 10 composition of solid dispersions of examples 11 to 17
Example 18
The dimesylate salt of the compound of formula 13, hypromellose acetate succinate and butyl hydroxy anisol are dissolved in a ratio of 30:69.8:0.2 by weight in a methylene chloride/ethanol mixed solution. The mixture solution was then spray dried by a spray dryer. The resultant dried product was further dried at 60℃for 10 hours using a vacuum dryer to obtain a solid dispersion Q of the dimesylate of the compound of formula 13 in the form of a powder.
Experimental example 1 stability test
According to the guidelines of the stability test of bulk drugs and pharmaceutical preparations, the stability of the solid pharmaceutical composition under the condition of acceleration test (60+/-2 ℃ and RH75% +/-5%) is examined. The results are shown below:
TABLE 11 stability test results
Experimental example 2 amorphous stability experiment of solid Dispersion
The solid dispersions obtained in examples 10 to 18 were placed in an atmosphere of 25.+ -. 2 ℃ and 60%.+ -. 5% RH, and sampled at the beginning, 2 weeks and 4 weeks, respectively, and the samples were subjected to powder XRD detection. It was found that initially, the samples of examples 10 to 18 were amorphous. The powder XRD pattern of the sample of example 10 at 2 weeks showed small peaks; the remaining sample powder XRD patterns showed no peaks. At 4 weeks, the powder XRD pattern of the sample of example 10 showed more pronounced characteristic peaks, and the number and intensity of peaks was greater than the powder XRD pattern of the sample of example 10 at 2 weeks; the remaining sample powder XRD patterns showed no peaks. Description of the phenomena the solid dispersion obtained in example 10 exhibited crystallization during standing.
Experimental example 3 dissolution test
900mL of purified water after degassing treatment is taken and added into each operation container, the temperature of the solvent is kept at 37+/-0.5 ℃ by heating, and the rotation speed is adjusted to be stable.
The solid pharmaceutical composition obtained in the above example was taken and put into a spin basket, lowered into a container, immediately started to time, and when 15min, 30min, 45min, 60min, 4h, 8h and 12h were carried out, a proper amount of solution was sucked at the prescribed sampling points, and filtered through a microporous filter membrane of 0.45 μm, and the sampling to filtration should be completed within 60 seconds. The filtrate was taken and the elution amount was measured by ultraviolet-visible spectrophotometry, and the results were as follows:
TABLE 12 dissolution test results
Claims (15)
1. A solid pharmaceutical composition of a compound of formula 2 or a pharmaceutically acceptable salt thereof:
the auxiliary materials of the solid pharmaceutical composition comprise a diluent, a disintegrating agent and a lubricant;
the diluent is selected from microcrystalline cellulose or a mixture of microcrystalline cellulose and lactose, the diluent accounts for 70-95 wt% of the pharmaceutical composition, and when the diluent is selected from a mixture of microcrystalline cellulose and other diluents, the microcrystalline cellulose accounts for 55-75 wt% of the diluent;
the disintegrating agent is selected from sodium carboxymethyl starch, and the disintegrating agent accounts for 2-8wt% of the range of the pharmaceutical composition;
the lubricant is selected from magnesium stearate, and the lubricant accounts for 0.5-4wt% of the pharmaceutical composition.
2. The solid pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride or mesylate salts.
3. The solid pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of mesylate salts.
4. The solid pharmaceutical composition of claim 1, wherein the diluent is selected from the range of 75 to 95wt% of the pharmaceutical composition, and when the diluent is selected from the group consisting of microcrystalline cellulose and mixtures of other diluents, the microcrystalline cellulose is selected from the range of 60 to 75wt% of the diluent.
5. The solid pharmaceutical composition of claim 4, wherein the diluent is in the range of 80 to 95wt% of the pharmaceutical composition, and when the diluent is selected from the group consisting of microcrystalline cellulose and mixtures of other diluents, the microcrystalline cellulose is in the range of 60 to 75wt% of the diluent
6. The solid pharmaceutical composition of claim 1, wherein the disintegrant is in a range selected from 3 to 8wt% of the pharmaceutical composition.
7. The solid pharmaceutical composition of claim 6, wherein the disintegrant is in a range selected from 4 to 6wt% of the pharmaceutical composition.
8. The solid pharmaceutical composition of claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate; the lubricant is selected from the range of 1.0 to 3.0wt% of the pharmaceutical composition.
9. The solid pharmaceutical composition according to claim 1, wherein the adjuvant further comprises a solubilizing agent selected from sodium lauryl sulfate; the solubilizer accounts for 0.5-4wt% of the pharmaceutical composition.
10. The solid pharmaceutical composition according to claim 9, wherein the solubilizing agent comprises a range of from 1.0 to 2.0wt% of the pharmaceutical composition.
11. The solid pharmaceutical composition of claim 1, wherein the solid pharmaceutical composition has a coating layer selected from the group consisting of film coatings.
12. The solid pharmaceutical composition according to claim 1, characterized in that it is a solid dispersion, the carrier material used being selected from hydroxypropyl methylcellulose acetate succinate or carboxymethyl cellulose, said carrier material being present in the solid dispersion in an amount of 60-80% by weight.
13. The solid pharmaceutical composition of claim 12, wherein the carrier material is present in the solid dispersion in an amount of 70% by weight.
14. The solid pharmaceutical composition of claim 12, further comprising a stabilizer selected from the group consisting of butyl hydroxy anisole; the stabilizer is present in the solid dispersion in an amount of 0.10% to 0.30% by weight.
15. The solid pharmaceutical composition of claim 12, wherein the stabilizer is present in the solid dispersion in an amount of 0.20% by weight.
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| CN201610976881.XA CN108057036B (en) | 2016-11-07 | 2016-11-07 | Solid pharmaceutical composition of EGFR inhibitor |
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| CN201610976881.XA CN108057036B (en) | 2016-11-07 | 2016-11-07 | Solid pharmaceutical composition of EGFR inhibitor |
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| CN108057036B true CN108057036B (en) | 2023-06-13 |
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| CN110790749B (en) * | 2018-08-03 | 2023-07-14 | 北京普祺医药科技股份有限公司 | Nitrogen-containing heterocyclic compound, pharmaceutical composition and application thereof |
| CN110016017A (en) * | 2019-05-16 | 2019-07-16 | 益方生物科技（上海）有限公司 | Salt, polymorph and its pharmaceutical composition, the preparation method and application of a kind of pyrimidine compound |
| WO2021243596A1 (en) * | 2020-06-03 | 2021-12-09 | InventisBio Co., Ltd. | Aminopyrimidine compounds, preparation methods and uses thereof |
| TW202222795A (en) * | 2020-11-19 | 2022-06-16 | 大陸商上海翰森生物醫藥科技有限公司 | The salt, crystal form and preparation method of an indole-containing derivative |
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