CN108057036B - Solid pharmaceutical composition of EGFR inhibitor - Google Patents

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

A solid pharmaceutical composition of EGFR inhibitor

Technical Field

The present invention relates to a solid pharmaceutical composition of an EGFR inhibitor, in particular to a solid pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof as a raw material and a preparation method thereof, belonging to the technical field of pharmacy.

Background Art

The epidermal growth factor receptor (EGFR) signal transduction pathway plays an important role in regulating the growth, damage repair and survival, angiogenesis, invasion and metastasis of tumor cells, and is expressed in a considerable number of human tumors. The epidermal growth factor receptor (EGFR) is widely present in a variety of epidermal malignant tumor cells: non-small cell lung cancer, breast cancer, colorectal cancer, gastric cancer, prostate cancer, ovarian cancer, head and neck tumors.

Oral administration is the most common way of drug administration. After oral administration, the drug can be absorbed at many different sites along the gastrointestinal tract (including via the stomach, duodenum, jejunum, ileum and colon). The different chemical environments of the gastrointestinal tract can affect the solvent release of the drug to affect the absorption of the active substance in the drug. Among them, the environmental pH of the stomach is 1 to 3.5, and the environmental pH of the small intestine is 4 to 8, and there are significant pH-dependent solubility and permeability properties. The solubility of the compound described in this application under acidic conditions is higher than that under alkaline conditions, but the solubility of its pharmaceutically acceptable salt under alkaline conditions is similar to or slightly higher than that under acidic conditions. Therefore, it is necessary to develop pharmaceutical preparations to meet the requirements of effectiveness and safety for clinical use, which not only meet the requirements of the drug for solubility and bioavailability, but also control the release of the drug.

WO2016070816A1 discloses a class of EGFR inhibitors, which have low water solubility, are not conducive to the dissolution and absorption process of the drug in the gastrointestinal tract after oral administration, resulting in low bioavailability, affecting the therapeutic effect of the compounds. The present application provides a solid pharmaceutical composition of the EGFR inhibitor, which has good stability, faster dissolution rate and higher bioavailability, and is suitable for clinical use.

Summary of the invention

The present application provides a solid pharmaceutical composition of a compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula I is as follows:

Among them, A is selected from

甲磺酰基、乙磺酰基、异丙磺酰基或环丙磺酰基。R is selected from H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl,

methylsulfonyl, ethylsulfonyl, isopropylsulfonyl or cyclopropylsulfonyl.

In some embodiments, the compound represented by formula I is selected from:

The pharmaceutically acceptable salt described in the present application is selected from hydrochloride, hydrobromide, phosphate, sulfate, nitrate, methanesulfonate, trifluoroacetate, isethionate, maleate, fumarate, malate, citrate, succinate, lactate or acetate, preferably hydrochloride or methanesulfonate. In the pharmaceutically acceptable salt of the compound of formula I described in the present application, the molar ratio of the compound of formula I to the acid radical ion forming the pharmaceutical salt can be selected from 2:1, 1:1, 1:2 or 1:3, and the specific ratio is based on whether the compound of formula I can form a stable salt with the acid radical ion.

In some embodiments, preferably, the pharmaceutically acceptable salt of the compound of formula I described in the present application is selected from the hydrochloride of the compound of formula 2, the methanesulfonate of the compound of formula 2, the hydrochloride of the compound of formula 9, the methanesulfonate of the compound of formula 9, the hydrochloride of the compound of formula 13 or the methanesulfonate of the compound of formula 13; more preferably, it is selected from the monohydrochloride of the compound of formula 2, the dihydrochloride of the compound of formula 2, the trihydrochloride of the compound of formula 2, the monomethanesulfonate of the compound of formula 2, the dimethanesulfonate of the compound of formula 2, the trimethanesulfonate of the compound of formula 2, the monohydrochloride of the compound of formula 9, the dihydrochloride of the compound of formula 9, the trihydrochloride of the compound of formula 9, the monomethanesulfonate of the compound of formula 9, the dimethanesulfonate of the compound of formula 9, the trimethanesulfonate of the compound of formula 9, the monohydrochloride of the compound of formula 13, the dihydrochloride of the compound of formula 13, the trihydrochloride of the compound of formula 13, the monomethanesulfonate of the compound of formula 13, the dimethanesulfonate of the compound of formula 13 or the trimethanesulfonate of the compound of formula 13.

In one technical solution of the present application, the excipients of the solid pharmaceutical composition of the compound represented by Formula I or a pharmaceutically acceptable salt thereof include a diluent, a disintegrant and a lubricant.

In some embodiments, the diluent is selected from starch, pregelatinized starch, sucrose, lactose, fructose, maltose, trehalose, pullulan, polydextrose, dextrin, maltodextrin, microcrystalline cellulose, cellulose acetate, ethyl cellulose, 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 and the above-mentioned other diluents; more preferably, 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 accounts for 60-95wt% of the pharmaceutical composition, preferably 65-95wt%, 70-95wt%, 75-95wt%, 80-95wt%, 85-95wt% or 90-95wt%. When the diluent is selected from a mixture of microcrystalline cellulose and other diluents, the microcrystalline cellulose accounts for 10-90wt% of the diluent, preferably 20-85wt%, 25-80wt%, 25-75wt%, 30-75wt%, 40-75wt%, 45-75wt%, 50-75wt%, 55-75wt%, 60-75wt%.

In some embodiments, the disintegrant can be selected from dry starch, sodium starch glycolate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, methylcellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, alginic acid, calcium alginate, sodium alginate, chitosan, colloidal silicon dioxide, glycine, guar gum, magnesium aluminum silicate or polyvinylpyrrolidone; preferably from dry starch, sodium starch glycolate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, methylcellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose or calcium carboxymethyl cellulose; more preferably from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose. The disintegrant accounts for 1 to 10 wt% of the pharmaceutical composition; preferably from 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt% or 9 wt%.

In some embodiments, the lubricant is selected from stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, palmitoyl stearyl glyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium 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 0.5-5wt% of the pharmaceutical composition; preferably 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 embodiments, the pharmaceutical composition of the present application includes: 10-20wt% of the compound represented by formula I or a pharmaceutically acceptable salt thereof, 70-90wt% of a diluent, 4wt-6wt% of a disintegrant, and 1wt-3wt% of a lubricant; the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula 2, a monohydrochloride of a compound of formula 2, a dihydrochloride of a compound of formula 2, a trihydrochloride of a compound of formula 2, a monomethanesulfonate of a compound of formula 2, a dimethanesulfonate of a compound of formula 2, a trimethanesulfonate of a compound of formula 2, a compound of formula 9, a monohydrochloride of a compound of formula 9, a dihydrochloride of a compound of formula 9, a trihydrochloride of a compound of formula 9, a monomethanesulfonate of a compound of formula 9, and a compound of formula 9. The dimethanesulfonate of the compound of formula 9, the trimethanesulfonate of the compound of formula 13, the monohydrochloride of the compound of formula 13, the dihydrochloride of the compound of formula 13, the trihydrochloride of the compound of formula 13, the monomethanesulfonate of the compound of formula 13, the dimethanesulfonate of the compound of formula 13 or the trimethanesulfonate 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 disintegrant 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 of the present application includes: 10-20wt% of the compound shown in formula I or a pharmaceutically acceptable salt thereof, 70-90wt% of a diluent, 4wt-6wt% of a disintegrant, and 1wt-3wt% of a lubricant; the compound shown in formula I or a pharmaceutically acceptable salt thereof is preferably selected from the group consisting of a compound of formula 2, a trimesylate of a compound of formula 2, a compound of formula 9, a monohydrochloride of a compound of formula 9, a compound of formula 13, or a dimesylate of a 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 disintegrant 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 include a solubilizer selected from the group consisting of: hydroxypropyl methylcellulose, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyhydroxypentadecanostearate, sodium lauryl sulfate, magnesium lauryl sulfate, sorbitan esters, caprylic acid glyceryl, triolein, polyoxyglycerol esters, povidone, pyrrolidone, poloxamer, phospholipids or vitamin E polyethylene glycol succinate, preferably sodium lauryl sulfate or magnesium lauryl sulfate. The solubilizer accounts for 0.5-5wt% of the pharmaceutical composition; preferably 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 embodiments, the pharmaceutical composition of the present application includes: 10-20wt% of the compound represented by formula I or a pharmaceutically acceptable salt thereof, 70-90wt% of a diluent, 4wt-6wt% of a disintegrant, 1wt-3wt% of a lubricant, and 1wt-3wt% of a solubilizer; the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula 2, a monohydrochloride of a compound of formula 2, a dihydrochloride of a compound of formula 2, a trihydrochloride of a compound of formula 2, a monomethanesulfonate of a compound of formula 2, a dimethanesulfonate of a compound of formula 2, a trimethanesulfonate of a compound of formula 2, a compound of formula 9, a monohydrochloride of a compound of formula 9, a dihydrochloride of a compound of formula 9, a trihydrochloride of a compound of formula 9, a monomethanesulfonate of a compound of formula 9, a dimethanesulfonate of a compound of formula 9 Salt, trimesylate of the compound of formula 9, compound of formula 13, monohydrochloride of the compound of formula 13, dihydrochloride of the compound of formula 13, trihydrochloride of the compound of formula 13, monomethanesulfonate of the compound of formula 13, dimesylate of the compound of formula 13 or trimesylate 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 disintegrant 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 embodiments, the pharmaceutical composition of the present application includes: 10-20wt% of the compound shown in formula I or a pharmaceutically acceptable salt thereof, 70-90wt% of a diluent, 4wt-6wt% of a disintegrant, 1wt-3wt% of a lubricant, and 1wt-3wt% of a solubilizer; the compound shown in formula I or a pharmaceutically acceptable salt thereof is preferably selected from the group consisting of a compound of formula 2, a trimesylate of a compound of formula 2, a compound of formula 9, a monohydrochloride of a compound of formula 9, a compound of formula 13, or a dimesylate of a 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 disintegrant 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 composition of the present application can be formed into a variety of preparations suitable for oral administration to humans, such as tablets, pills, capsules, powders or granules, etc. In some embodiments, the present application provides a tablet, the tablet comprising a core, the core comprising the pharmaceutical composition as described above. The tablet may have a coating layer or may not have a coating layer.

The coating layer can be selected from film coating. The film-forming material of the film coating is selected according to the function achieved by the preparation, such as achieving gastric solubility, enteric solubility, slow-release function, special stability function, etc. The film-forming material can be selected from ordinary film coating materials, such as hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, film-forming acrylic polymer, methacrylic acid-methyl methacrylate copolymer, film-forming vinyl polymer, polyvinyl alcohol or polyvinyl acetate phthalate, etc.; can be selected from sustained-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 function that the film coating can achieve. Optionally, the film-forming material will be selected from 30% to 90% by weight of the film coating, such as 30%, 40%, 50%, 60%, 70%, 80% or 90%. Optionally, the film-forming material is typically selected from 0.5% to 5% by weight of the pharmaceutical composition according to the present invention, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% or 5.0%.

Optionally, the film coating comprises other components, such as plasticizer, colorant, dispersant or opacifier. Plasticizer can be used to improve the film flexibility and durability and adhesion characteristics of the film coating. Suitable plasticizers include, for example, glycerol, acetylated monoglyceride, citric acid ester (such as triethyl citrate), propylene glycol, polyethylene glycol (such as polyethylene glycol), triacetin (triacetin), triglyceride (such as castor oil) or phthalate (such as diethyl phthalate). Usually, plasticizer is based on the weight of film coating when used to exist in an amount of 1% to 20% such as 5% to 15% by weight. Suitable opacifier and colorant are well-known and include, for example, titanium dioxide, ferric oxide (such as iron oxide). Suitable dispersant includes, for example, talc.

In some embodiments, suitable film coatings may be obtained from commercially available concentrates that may be diluted with water before application to the composition and may include a cellulose ether and a plasticizer, such as Colorcon's Opaspray ^™ coating material line.

In another technical solution of the present application, the solid pharmaceutical composition of the compound represented by 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 cellulose compound used as the carrier material is enteric and is selected from cellulose ester (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) or carboxymethyl ethylcellulose (CMEC); preferably hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS). The carrier material is present in the solid dispersion in an amount of 40 to 90% by weight; suitably, it can be optionally present in an amount of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight; preferably, it is 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 in the present application may further include a stabilizer, the stabilizer including vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, soybean lecithin, ascorbic acid, citric acid or cysteine hydrochloride, preferably butylated hydroxyanisole. Suitably, the stabilizer is present in the solid dispersion in an amount of 0.05-0.5% by weight; suitably, it can be optionally present in an amount of 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45% or 0.50% by weight; preferably, it is present in an amount of 0.10%-0.30% by weight; more preferably, it is present in an amount of 0.20% by weight.

In some embodiments, the solid dispersion described in the present application includes 30-40 wt% of the compound represented by formula I or a pharmaceutically acceptable salt thereof, 60-80 wt% of a carrier material, and 0.10-0.30 wt% of a stabilizer; the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula 2, a monohydrochloride of a compound of formula 2, a dihydrochloride of a compound of formula 2, a trihydrochloride of a compound of formula 2, a monomethanesulfonate of a compound of formula 2, a dimethanesulfonate of a compound of formula 2, a trimethanesulfonate of a compound of formula 2, a compound of formula 9, a monohydrochloride of a compound of formula 9, a dihydrochloride of a compound of formula 9, The trihydrochloride of the compound of formula 9, the monomethanesulfonate of the compound of formula 9, the dimethanesulfonate of the compound of formula 9, the trimethanesulfonate of the compound of formula 9, the compound of formula 13, the monohydrochloride of the compound of formula 13, the dihydrochloride of the compound of formula 13, the trihydrochloride of the compound of formula 13, the monomethanesulfonate of the compound of formula 13, the dimethanesulfonate of the compound of formula 13 or the trimethanesulfonate 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 butylated hydroxyanisole.

In some embodiments, the solid dispersion described in the present application includes 30-40 wt% of the compound represented by formula I or a pharmaceutically acceptable salt thereof, 60-80 wt% of a carrier material, and 0.10-0.30 wt% of a stabilizer; the compound represented by formula I or a pharmaceutically acceptable salt thereof is preferably selected from the group consisting of a compound of formula 2, a trimesylate of a compound of formula 2, a compound of formula 9, a monohydrochloride of a compound of formula 9, a compound of formula 13, or a dimesylate of a compound of formula 13; the carrier material is selected from hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS); and the stabilizer is selected from butylated hydroxyanisole.

The solid dispersion of the present application can be made into a general pharmaceutical preparation by known methods using auxiliary materials such as diluents, disintegrants, binders, lubricants, colorants, suspending agents, sweeteners and surfactants as needed. The form of the pharmaceutical preparation is, for example, but not limited to, powder, tablets, pills or capsules.

Examples of diluents include starch, pregelatinized starch, sucrose, lactose, fructose, maltose, trehalose, pullulan, polydextrose, dextrin, maltodextrin, microcrystalline cellulose, cellulose acetate, ethyl cellulose, 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.

Examples of disintegrants include dry starch, sodium starch glycolate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, methylcellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, alginic acid, calcium alginate, sodium alginate, chitosan, colloidal silicon dioxide, glycine, guar gum, magnesium aluminum silicate or povidone.

Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 dibehenate, glyceryl tribehenate, palmitoylstearoyl glyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate or talc.

Examples of the coloring agent 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 glycol, gum arabic, glycerin or gelatin.

Examples of sweeteners include aspartame, saccharin, saccharin sodium, starch syrup or fructose.

Examples of surfactants include sodium lauryl sulfate, polysorbate or polyoxyethylene hydrogenated castor oil.

Capsules can be prepared according to known methods by mixing a solid dispersion of the compound of formula I or a pharmaceutically acceptable salt thereof with any of the above-mentioned excipients, and loading the mixture into a hard capsule made of gelatin, hydroxypropyl methylcellulose, polyvinyl alcohol, etc., or into a gelatin-based soft capsule.

The solid pharmaceutical composition of the compound of formula I or its pharmaceutically acceptable salt in the present application significantly improves the water solubility and stability of the compound, and helps to improve the bioavailability. When prepared as a solid dispersion, the release rate is faster; especially when the carrier material is selected from hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate, the water solubility is better than other carrier materials. The stability of the solid dispersion can be significantly improved by further adding butylated hydroxyanisole.

DETAILED DESCRIPTION

The purpose of the following specific embodiments is to enable those skilled in the art to more clearly understand and implement the present invention. They should not be considered as limiting the scope of the present invention, but are merely exemplary and typical representations of the present invention.

Example 1

The trimesylate of the compound of formula 2 is pulverized by air flow and sieved; microcrystalline cellulose is pulverized by air flow and sieved; the sieved trimesylate of the compound of formula 2, microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate are added to the mixer hopper, mixed for 30 minutes, and dry-pressed by a tablet press to form tablets. The material feed amount is 1000 tablets, each tablet is equivalent to containing 20 mg of the compound of formula 2, and the prescription composition is as follows:

Table 1 Prescription composition of the trimesylate tablet A of the compound of formula 2

Embodiment 2 to Embodiment 9

Referring to the preparation method of Example 1, the tablets of Examples 2 to 9 were prepared as follows:

Example 2

Table 2 Prescription composition of the trimesylate tablet B of the compound of formula 2

Example 3

Table 3 Prescription composition of the trimesylate tablet C of the compound of formula 2

Example 4

Table 4 Prescription composition of the trimesylate tablet D of the compound of formula 2

Example 5

Table 5 Prescription composition of monohydrochloride tablet E of compound of formula 9

Example 6

Table 6 Prescription composition of monohydrochloride tablet E of compound of formula 9

Example 7

Table 7 Prescription composition of dimesylate tablets F of compound of formula 13

Example 8

Table 8 Prescription composition of dimesylate tablets G of compound of formula 13

Example 9

Table 9 Prescription composition of dimesylate tablets H of compound of formula 13

Example 10

The trimesylate salt of the compound of formula 2 and carboxymethyl ethyl cellulose are dissolved in a dichloromethane/ethanol mixed solution at a weight ratio of 3:7. The mixed solution is then spray dried by a spray dryer. The obtained dry product is further dried at 60° C. for 10 hours using a vacuum dryer to obtain a powdery solid dispersion I of the trimesylate salt of the compound of formula 2.

Referring to the preparation method of Example 10, tablets of Examples 11 to 17 are prepared as follows:

Example 11 to Example 17

Referring to the preparation method of Example 10, the solid dispersions of Examples 11 to 17 were prepared as follows:

Table 10 Composition of solid dispersions of Examples 11 to 17

Embodiment 18

The dimethanesulfonate of the compound of formula 13, hydroxypropyl methylcellulose acetate succinate and butyl hydroxyanisole were dissolved in a dichloromethane/ethanol mixed solution at a weight ratio of 30:69.8:0.2. The mixed solution was then spray dried by a spray dryer. The obtained dry product was further dried at 60° C. for 10 hours using a vacuum dryer to obtain a powdery solid dispersion Q of the dimethanesulfonate of the compound of formula 13.

Experimental Example 1: Stability Experiment

According to the "Guidelines for Stability Testing of APIs and Pharmaceutical Preparations", the stability of the solid pharmaceutical composition described in this application was investigated under accelerated test conditions (60°C ± 2°C, RH 75% ± 5%). The results are as follows:

Table 11 Stability test results

Experimental Example 2 Amorphous Stability Test of Solid Dispersion

The solid dispersions obtained in Examples 10 to 18 were placed in an environment of 25±2°C and RH60%±5%, and samples were taken at the initial stage, 2 weeks, and 4 weeks, respectively. The samples were tested by powder XRD. It was found that, initially, the samples of Examples 10 to 18 were amorphous. At 2 weeks, the powder XRD spectrum of the sample of Example 10 showed a small peak; the powder XRD spectrum of the other samples showed no peaks. At 4 weeks, the powder XRD spectrum of the sample of Example 10 showed a more obvious characteristic peak, and the number and intensity of the peaks were greater than the powder XRD spectrum of the sample of Example 10 at 2 weeks; the powder XRD spectrum of the other samples showed no peaks. The phenomenon shows that the solid dispersion obtained in Example 10 showed crystallization during the placement process.

Experimental Example 3 Dissolution Determination Experiment

Take 900 mL of degassed purified water and add it to each operating container. Heat the solvent to maintain the temperature at 37±0.5°C and adjust the rotation speed to make it stable.

The solid pharmaceutical composition obtained in the above example was added to the rotating basket, lowered into the container, and the timing was immediately started. At 15 min, 30 min, 45 min, 60 min, 4 h, 8 h, and 12 h, an appropriate amount of solution was taken at the specified sampling point, and filtered through a 0.45 μm microporous filter membrane. The sampling to filtration should be completed within 60 seconds. The filtrate was taken and the dissolution amount was determined by UV-visible spectrophotometry. The results are 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.