CN112043679A

CN112043679A - Soft capsule preparation containing quinazoline compound and preparation method thereof

Info

Publication number: CN112043679A
Application number: CN202010889290.5A
Authority: CN
Inventors: 刘兵; 陈能安; 张诗龙; 马进; 董晓莉
Original assignee: Beijing Beike Huaxia Biological Medicine Technology Co ltd; Guangzhou Liushun Biotechnology Co ltd
Current assignee: Beijing Beike Huaxia Biological Medicine Technology Co ltd; Guangzhou Liushun Biotechnology Co ltd
Priority date: 2020-08-28
Filing date: 2020-08-28
Publication date: 2020-12-08
Anticipated expiration: 2040-08-28
Also published as: CN112043679B

Abstract

The invention relates to a soft capsule preparation of quinazoline compounds and a preparation method thereof, wherein the compounds have the function of a multi-target kinase inhibitor and belong to the technical field of biological medicine technology and pharmaceutical preparations. The invention provides a pharmaceutical preparation with improved bioavailability and stability, and a preparation method thereof. The preparation content composition consists of a fat-soluble carrier material, a solubilizer and an antioxidant, the capsule skin consists of animal bone glue, water, glycerol, an opacifier and other auxiliary materials known in the pharmaceutical field, and the preparation method is simple in preparation process, good in repeatability, high in safety and easy for industrial mass production.

Description

Soft capsule preparation containing quinazoline compound and preparation method thereof

Technical Field

The invention relates to a soft capsule preparation containing quinazoline compounds and a preparation method thereof, belonging to the technical field of biological medicine and pharmaceutical preparations.

Background

The applicant continuously applies for invention patent 2 times at home, wherein in the patent with the application number of 201910220652.9, the application discloses a multi-target kinase inhibitor, a pharmaceutical composition and a preparation method and application of the multi-target kinase inhibitor, wherein the chemical name of the disclosed multi-target kinase inhibitor compound (quinazoline compound) is 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea, and the structural formula of the disclosed multi-target kinase inhibitor compound is shown as the formula (I). The compound has a plurality of crystal forms, and the applicant continuously develops the crystal form of the compound and a preparation method thereof, and applies for a crystal form patent of the compound and a preparation method thereof with the application number of 201911402492.6. Through further research by the applicant, the compound is an insoluble drug, is almost insoluble in water, and has a pKa of about 3.3 and a Log P/D of about 3.08. The compound has high solubility in alcohols and lipids, and can be slightly dissolved in ethanol, methanol and various lipid adjuvants. Therefore, the applicant has continued to develop a soft capsule formulation of the present compound and a method for preparing the same.

Disclosure of Invention

In the previous researches, the applicant finds that the crystal form of the compound is A type, the stability is good, but the problem of poor solubility is not solved, and the bioavailability and the curative effect of the medicine in vivo are further influenced. Further research shows that the compound is easy to degrade under acidic conditions, the degradation is reduced along with the increase of the pH value of the solution, and the solubility of the compound is reduced along with the increase of the pH value of the solution. Therefore, under the condition of the above-mentioned many important factors, the research and development of new dosage forms of the compound are carried out, and the important significance is provided for solving the above-mentioned technical problems.

In the previous literature research, the applicant found that the cell membrane is a "fluid mosaic" structure, which is a complex composed of two-dimensional arrangement of lipid bilayer and protein molecule, and the distribution of lipid-embedded membrane silkworm egg white is obviously asymmetric. Due to the special existence of the membrane, most molecules and ions are difficult to pass through the cell membrane, only fat-soluble substances and gases and some medicines are easy to pass through directly, and some cations such as Na⁺、 K⁺、Ca⁺These are strongly polar hydrated ions and are therefore difficult to pass through hydrophobic regions of cell membrane lipids. The fat-soluble auxiliary materials can promote the medicine to permeate the digestive tract membrane to enter the blood circulation, thereby improving the bioavailability of the medicine; the solubilizer can increase the solubility of the insoluble drug in the solvent under the action of the solubilizer, thereby improving the bioavailability of the drug.

The invention aims to overcome the defects of the prior art and provide a quinazoline compound dosage form which can improve the bioavailability and has good stability and a preparation method thereof, in particular to a soft capsule preparation. The preparation is prepared by mixing quinazoline compounds with fat-soluble carrier materials, solubilizer, antioxidant and other pharmaceutically-known adjuvants, and making into soft capsule with animal bone glue (gelatin), glycerol, water and other pharmaceutically-known adjuvants.

The invention provides a soft capsule preparation containing quinazoline compounds, which comprises contents and a capsule shell, wherein the active ingredients in the contents are quinazoline compounds with a chemical structural formula shown as a formula (I),

the invention provides a soft capsule preparation containing quinazoline compounds shown as a structural formula (I), which is prepared by mixing and dissolving 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea serving as an active ingredient with a fat-soluble carrier material, a solubilizer, an antioxidant, other auxiliary materials and the like known in the pharmaceutical field into a suspension through a certain process, preparing a content into a soft capsule shell by further using animal bone glue, glycerol, water, other auxiliary materials and the like known in the pharmaceutical field, wrapping the content by using the soft capsule shell through a certain process, and pressing the content into a pill, namely the soft capsule disclosed by the invention.

As a preferable embodiment of the soft capsule preparation, the weight percentage of the quinazoline compound in the content is 1-50%.

As a preferred embodiment of the soft capsule preparation of the present invention, the content further comprises a fat-soluble carrier material, a solubilizer, an antioxidant and other pharmaceutical excipients well known in the pharmaceutical field, and the total weight percentage of the fat-soluble carrier material, the solubilizer and the antioxidant in the content is 50% to 99%.

As a preferable embodiment of the soft capsule preparation, the fat-soluble carrier material accounts for 40-97.97% of the content by weight.

As a preferred embodiment of the soft capsule preparation, the solubilizer accounts for 1.0 to 10 percent of the content by weight.

As a preferable embodiment of the soft capsule preparation, the antioxidant accounts for 0.01-0.05% of the content by weight.

As a preferred embodiment of the soft capsule formulation of the present invention, the fat-soluble carrier material is one or more of glyceryl monocaprylate, glyceryl caprylate-caprate, propylene glycol monocaprylate, medium chain triglyceride, medium chain diglyceride, medium chain monoglyceride, glycerin, dehydrogenated soybean oil, vegetable oil, aromatic oil; the solubilizer is one or more of polyoxyethylene hardened castor oil, polyoxyethylene castor oil, fatty alcohol-polyoxyethylene ether, fatty alcohol-polyoxypropylene ether, polyoxyethylene sorbitan fatty acid ester, polyglycerol fatty acid ester, polysorbate 80, polyethylene glycol, propylene glycol, absolute ethyl alcohol and isopropanol; the antioxidant is one or more of fat-soluble vitamin E, butyl hydroxy anisol, dibutyl hydroxy toluene, tert-butyl hydroquinone, ascorbyl palmitate, etc.

As a preferred embodiment of the soft capsule formulation of the present invention, the fat-soluble microorganism E is one or more of d-alpha-tocopherol, d-alpha-tocopherol ester, dl-alpha-tocopherol ester, d-alpha-tocopherol ester hydrogen succinate, dl-alpha-tocopherol ester hydrogen succinate, beta-tocopherol, gamma-tocopherol.

In a preferred embodiment of the soft capsule preparation of the present invention, the capsule shell is made of at least one of purified water, glycerin, animal bone glue, gum arabic, an opacifier, a pigment, a plasticizer, and other excipients well known in the pharmaceutical field.

In a preferred embodiment of the soft capsule preparation of the present invention, the capsule shell comprises a plurality of excipients known in the pharmaceutical field selected from animal bone glue, purified water, glycerin, gum arabic, opacifier, pigment, plasticizer, and other excipients known in the pharmaceutical field; the optimal proportion of the animal bone glue, the glycerol and the purified water is 1:0.5: 0.7-1, and the total weight accounts for 99.70-99.85% of the capsule shell; the opacifier accounts for 0.1 to 0.15 percent of the weight of the capsule shell; the pigment accounts for 0-0.2% of the weight of the capsule shell; the plasticizer accounts for 0-0.1% of the weight of the capsule shell; the other pharmaceutically known auxiliary materials account for 0-0.1% of the capsule shell by weight.

In order to realize the first purpose of the invention, the invention adopts the following technical scheme: mixing 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea as an active ingredient with a fat-soluble carrier material, a solubilizer, an antioxidant and other auxiliary materials known in the pharmaceutical field, stirring uniformly to form a suspension, preparing a capsule shell by using animal bone glue (gelatin), glycerol, water and other auxiliary materials known in the pharmaceutical field, and pressing the contents into a soft capsule.

The fat-soluble carrier material in the soft capsule content in the above method is preferably selected from one or more of glyceryl monocaprylate, caprylic capric acid monoglyceride and diglyceride, propylene glycol monocaprylate, medium chain triglyceride, medium chain diglyceride, medium chain monoglyceride, glycerol, dehydrogenated soybean oil, vegetable oil, and aromatic oil; more preferably one or more of caprylic capric acid mono-di-glyceride, glyceryl monocaprylate and propylene glycol monocaprylate.

The solubilizer in the soft capsule content is preferably selected from one or more of polyoxyethylene hardened castor oil, polyoxyethylene castor oil, fatty alcohol polyoxyethylene ether, fatty alcohol polyoxyethylene-polyoxypropylene ether, polyoxyethylene sorbitan fatty acid ester, polyglycerol fatty acid ester, polysorbate 80, polyethylene glycol, propylene glycol and absolute ethyl alcohol, and has good compatibility and solubilization effect, no toxicity, high safety and small irritation.

The antioxidant in the soft capsule content is preferably an adjuvant with good compatibility, good antioxidant effect and high safety, and is selected from one or more of fat-soluble vitamin E, Butyl Hydroxy Anisole (BHA), dibutyl hydroxy toluene (BHT), tert-butyl hydroquinone (TBHQ), ascorbyl palmitate, etc. Wherein the fat-soluble microorganism E is selected from one or more of d-alpha-tocopherol, d-alpha-tocopherol ester, dl-alpha-tocopherol ester, hydrogen succinate d-alpha-tocopherol ester, hydrogen succinate dl-alpha-tocopherol ester, beta-tocopherol, -tocopherol and gamma-tocopherol.

The capsule shell of the soft capsule is preferably a capsule shell material with good stability and high safety, and the capsule shell material is selected from a plurality of purified water, glycerol, animal bone glue (gelatin), Arabic gum, opacifier, pigment, plasticizer and other auxiliary materials known in the pharmaceutical field; preferably purified water, glycerol, animal bone glue, titanium dioxide, citric acid.

The opacifier in the soft capsule shell is preferably an auxiliary material which has good shading effect, high safety and good intermiscibility, and is selected from one or more of titanium dioxide, magnesium oxide, iron oxide and the like; the pigment is preferably selected from one or more of natural pigment and artificial pigment, and has high solubility, good compatibility, and high safety; the plasticizer should preferably be an auxiliary material with good intermiscibility effect and high safety, and is selected from one or more of polyethylene glycol, sodium dodecyl sulfate, glyceryl triacetate and triethyl citrate; other excipients known in the pharmaceutical field should preferably have good solubility, good compatibility and high safety, and are selected from one or more of citric acid, sorbitol, starch and hydroxypropyl methylcellulose.

In order to accomplish the first object of the present invention, the second object of the present invention provides a method for preparing a quinazoline compound-containing soft capsule formulation, comprising the steps of:

(1) preparation of capsule skin

(1a) Sieving gelatin by 20 meshes for pretreatment, removing large lumps, and weighing the pretreated gelatin; weighing opacifier, pigment, plasticizer or other auxiliary materials known in the pharmaceutical field, and dispersing and dissolving with a proper amount of purified water to obtain a mixture solution 1 for later use;

(1b) weighing purified water, heating to 30-40 ℃, adding the gelatin in the step (1a), soaking for 1-2 hours while stirring, heating to 60-70 ℃, adding glycerol for multiple times, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for more than 30min to obtain a mixed glue solution;

(1c) vacuumizing and degassing the mixed glue solution in the step (1b) until no bubbles exist, stirring at a low speed so as to avoid generating bubbles, adding the mixture solution 1 in the step (1a) into the degassed mixed glue solution, continuously stirring and fully mixing until the color is uniform to obtain the final glue solution, then performing vacuum degassing to remove gas in the glue solution, keeping the temperature of the glue solution at 60-65 ℃, and stirring at a low rotating speed so as to prevent the opacifier from precipitating;

(2) preparation of Contents

(2a) Weighing quinazoline compounds as raw materials, carrying out low-temperature airflow superfine grinding, and controlling the particle size D of the raw materials₉₀Less than 10 μm to obtain micronized powder material;

(2b) weighing 1/2 fat-soluble carrier material and superfine pulverized raw material, putting into a mixing barrel, and stirring at high speed for 10-30 min by using a high-speed homogenizer to obtain a mixture solution 2; weighing the residual 1/2 fat-soluble carrier material, solubilizer and fat-soluble vitamin E, putting into a mixing barrel, and stirring at high speed for 10-30 min by using a high-speed homogenizer to obtain a mixture solution 3; pouring the mixture solution 2 into the mixture solution 3 and continuously stirring for 30-60 min to obtain a content solution;

(3) pressed pill

Controlling the temperature of the pill pressing chamber below 25 ℃ and the relative humidity less than 45%, setting the temperature of a capsule box of the soft capsule machine at 45-55 ℃, the air supply temperature of a soft capsule roller at 10-15 ℃, the temperature of a liquid medicine spray head at 37-47 ℃, and controlling the thickness of a capsule skin of the soft capsule at 0.5-1.0 mm, and pressing the soft capsule;

(4) drying

Putting the soft capsules prepared by the pelleting press into a drying device in a roller for drying by blowing, wherein the rotating speed of the roller is 5-30 rpm, and drying for 10-20 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%;

(5) washing pill

Sterilizing the capsule by using 70-75% of alcohol (edible alcohol), soaking the capsule in 95% of alcohol (edible alcohol) for 20-30 min, taking out and draining;

(6) secondary drying

And (3) flatly spreading the washed soft capsules in a room, naturally evaporating and drying water and alcohol in capsule shells at the room temperature of 25-30 ℃ and the relative humidity of below 50% for 10-30 hours until the surfaces of the capsule shells are dried, thus obtaining the soft capsule preparation containing the quinazoline compounds.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention provides a new formulation of quinazoline compounds, namely soft capsules, which is prepared by firstly carrying out superfine grinding pretreatment on raw material medicines to obtain medicines with the grain diameter smaller than 10 mu m, so that the medicines can obtain better dissolving effect in vivo, and the dissolution and the in vivo absorption of the medicines are improved; the addition of new dosage forms provides more choices for patients and improves patient compliance.

(2) In the content of the soft capsule, fat-soluble carrier material, solubilizer and raw materials are used for high-speed homogenizing, stirring and mixing, and further, part of the medicine is dissolved in the fat-soluble carrier material in advance, so that the medicine can be better absorbed in vivo.

(3) The invention uses fat-soluble carrier material, effectively reduces the degradation effect of gastric acid on the medicine when the medicine enters the stomach, improves the safety of the medicine, and further improves the bioavailability of the medicine in the body.

(4) The preparation process of the preparation has the advantages of small dosage of organic solvent in the used auxiliary materials, simple preparation process and environmental protection.

Drawings

Fig. 1 is a graph showing the degradation of three dosage forms of quinazoline compounds in a medium with a pH of 1.0.

Fig. 2 is a graph showing the degradation of three dosage forms of the quinazoline compound in a medium with a pH of 1.2.

Fig. 3 is a graph showing the dissolution rate of the quinazoline compound in a medium with a pH value of 1.2.

FIG. 4 is a graph showing the individual dose profiles of quinazoline compounds in plasma after single oral gavage of Beagle dogs in three dosage forms of quinazoline compounds.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.

Example 1

This example is a soft capsule containing 3mg of quinazoline compound 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea (formula i) per capsule and process for preparation.

TABLE 11000 Soft Capsule prescription containing quinazoline Compound

Note: the mark indicates the amount of loss, and the total amount is 2.5 times of the single-dose capsule shell.

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 249.63 g; 0.94 g of titanium dioxide is weighed and dispersed with a proper amount of purified water to obtain a mixture solution 1 for later use.

b, weighing 249.63 g of purified water, heating to 30-40 ℃, adding 249.63 g of gelatin in the step a, soaking while stirring for 2 hours, heating to 60-70 ℃, adding 124.81 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 40 min.

c, vacuumizing and degassing the mixed glue solution obtained in the step b until no bubbles exist, stirring at a low speed to avoid bubbles, adding the mixture solution 1 obtained in the step a into the degassed mixed glue solution, continuously stirring and fully mixing until the color is uniform to obtain the final glue solution, then vacuumizing and removing gas in the glue solution, keeping the temperature of the glue solution between 60 and 65 ℃, and stirring at a low rotating speed to prevent the opacifier from precipitating.

(2) Preparation of Contents

a, weighing 51 g of quinazoline compound raw material, carrying out low-temperature airflow superfine grinding, and controlling the particle size D of the raw material₉₀Less than 10 μm to obtain micronized ultra-fine powder raw material for later use.

Weighing 1/2 caprylic capric acid mono-diglyceride (146.96 g) and 30 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 5000rpm for 20min by using a high-speed homogenizer to obtain a mixture solution 2; weighing 3.0 g of polysorbate 80, 0.09 g of fat-soluble vitamin E and the residual 1/2 g of caprylic capric acid mono-diglyceride (146.96 g), putting into a dosing barrel, and stirring and mixing at the rotating speed of 500-1000 rpm by using a homogenizer for 30min to obtain a mixture solution 3; and pouring the mixture solution 2 into the mixture solution 3, and continuously stirring for 30-60 min by using a high-speed homogenizer at the rotating speed of 5000-10000 rpm to obtain the content solution.

(3) Pressed pill

Controlling the temperature of the pill pressing chamber below 25 deg.C and relative humidity below 45%, setting the capsule temperature of a soft capsule machine (RGY2X15F type soft capsule machine-Shanghai Tianxiang Jiantai pharmaceutical machinery Co., Ltd.) at 50 deg.C, the air supply temperature of a soft capsule roller at 10-15 deg.C, the temperature of a liquid medicine spray head at 37-47 deg.C, and controlling the thickness of the capsule shell at 0.5-1.0 mm, and pressing into soft capsule.

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 5rpm, and the soft capsule is dried for 20 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

The capsule is first sterilized with 70-75% alcohol, soaked in 95% alcohol for 30min and drained.

(6) Secondary drying

The secondary drying is also called pill shaping. Spreading the washed capsule in a drying chamber (at room temperature of 25-30 deg.C and relative humidity below 50%), naturally evaporating water and alcohol in capsule shell, and drying for 30 hr until the surface of the capsule shell is dried. Thus obtaining the soft capsule of the invention.

Example 2

This example is a soft capsule containing 25mg of quinazoline compound 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea (formula i) per capsule and process for preparation.

Table 21000 soft capsule prescription containing quinazoline compound

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 249.63 g; weighing 0.94 g of titanium dioxide, and dispersing with a proper amount of purified water to obtain a mixture solution 1 for later use;

b, weighing 249.63 g of purified water, heating to 30-40 ℃, adding 249.63 g of gelatin in the step a, soaking while stirring for 1.5 hours, heating to 60-70 ℃, adding 124.81 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 30 min.

(2) Preparation of Contents

a, weighing 42.5 g of quinazoline compound raw material, carrying out low-temperature airflow superfine grinding, and controlling the particle size D of the raw material₉₀Less than 10 μm to obtain micronized ultra-fine powder raw material for later use.

Weighing 1/2 caprylic capric acid mono-diglyceride (111.2 g) and 25 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 8000rpm for 30min by using a high-speed homogenizer to obtain a mixture solution 2; weighing 2.5 g of polysorbate 80, 0.08 g of fat-soluble vitamin E, 0.03 g of butylated hydroxyanisole and the residual 1/2 g of caprylic capric acid mono-diglyceride (namely 111.2 g), putting into a dosing barrel, and stirring and mixing at the rotating speed of 700rpm by using a homogenizer for 30min to obtain a mixture solution 3; pouring the mixture solution 2 into the mixture solution 3, and continuously stirring for 60min at 8000rpm by using a high-speed homogenizer to obtain a content solution.

(3) Pressed pill

Controlling the temperature of the pill pressing chamber below 25 deg.C and relative humidity below 45%, setting the capsule temperature of a soft capsule machine (RGY2X15F type soft capsule machine-Shanghai Tianxiang Jiantai pharmaceutical machinery Co., Ltd.) at 45 deg.C, the air supply temperature of a soft capsule roller at 10-15 deg.C, the temperature of a liquid medicine spray head at 40 deg.C, and controlling the thickness of the capsule shell at 0.5-1.0 mm, and pressing into soft capsule.

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 30rpm, and the soft capsule is dried for 20 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

The capsule is first sterilized with 70-75% alcohol, soaked in 95% alcohol for 20min, taken out and drained.

(6) Secondary drying

Example 3

This example is a soft capsule containing 50mg of quinazoline compound 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea (formula i) per capsule and process for preparation.

Table 31000 Soft Capsule formulations containing quinazolines

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 283.66 g; weighing 0.94 g of titanium dioxide, and dispersing with a proper amount of purified water to obtain a mixture solution 1 for later use;

b, weighing 198.57 g of purified water, heating to 30-40 ℃, adding 283.66 g of gelatin in the step a, soaking while stirring for 2 hours, heating to 60-70 ℃, adding 141.83 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 45 min.

(2) Preparation of Contents

a, weighing 85 g of quinazoline compound raw material, carrying out low-temperature airflow superfine grinding, and controlling the particle size D of the raw material₉₀Less than 10 μm to obtain micronized ultra-fine powder raw material for later use.

Weighing 1/2 caprylic capric acid mono-diglyceride (89.34 g) and 50 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 9000rpm for 30min by using a high-speed homogenizer to obtain a mixture solution 2; weighing 21.25 g of polysorbate 80, 0.08 g of fat-soluble vitamin E and the residual 1/2 g of caprylic capric acid mono-diglyceride (89.34 g), putting into a dosing barrel, and stirring and mixing at 700rpm by using a homogenizer for 30min to obtain a mixture solution 3; the mixture solution 2 was poured into the mixture solution 3 and stirred continuously for 60min at 9000rpm using a high-speed homogenizer to obtain a content solution.

(3) Pressed pill

Controlling the temperature of the pill pressing chamber below 25 deg.C and relative humidity below 45%, setting the capsule temperature of a soft capsule machine (RGY2X15F type soft capsule machine-Shanghai Tianxiang Jiantai pharmaceutical machinery Co., Ltd.) at 45 deg.C, the air supply temperature of a soft capsule roller at about 15 deg.C, the temperature of a liquid medicine spray head at 40 deg.C, controlling the thickness of the capsule shell at 0.5-1.0 mm, and pressing into soft capsule.

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 30rpm, and the soft capsule is dried for 10 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

The capsule is first sterilized with 70-75% alcohol, soaked in 95% alcohol for 25min, taken out and drained.

(6) Secondary drying

The secondary drying is also called pill shaping. Spreading the washed capsule in a drying chamber (at room temperature of 25-30 deg.C and relative humidity below 50%), and naturally evaporating water and alcohol in capsule shell for 25 hr until the surface of the capsule shell is dried. Thus obtaining the soft capsule of the invention.

Example 4

This example is a soft capsule containing 75mg of quinazoline compound 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea (formula i) per capsule and process for preparation.

TABLE 41000 Soft Capsule formulations containing quinazolines

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 299.55 g; weighing 1.13 g of titanium dioxide, and dispersing with a proper amount of purified water to obtain a mixture solution 1 for later use;

b, weighing 299.55 g of purified water, heating to 30-40 ℃, adding 299.55 g of gelatin in the step a, soaking while stirring for 2 hours, heating to 60-70 ℃, adding 149.78 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 50 min.

(2) Preparation of Contents

Weighing 127.5 g of quinazoline compound raw material, carrying out low-temperature airflow superfine grinding, and controlling the particle size D of the raw material₉₀Less than 10 μm to obtain micronized ultra-fine powder raw material for later use.

Weighing 1/2 caprylic capric acid mono-diglyceride (76.15 g) and 75 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 9500rpm for 30min by using a high-speed homogenizer to obtain a mixture solution 2; weighing 22.5 g of polysorbate 80, 0.08 g of fat-soluble vitamin E and the residual 1/2 g of caprylic capric acid mono-diglyceride (76.15 g), putting into a dosing barrel, and stirring and mixing at 800rpm by using a homogenizer for 30min to obtain a mixture solution 3; the mixture solution 2 was poured into the mixture solution 3 and stirred continuously for 60min at 9500rpm using a high-speed homogenizer to obtain a content solution.

(3) Pressed pill

Controlling the temperature of the pill pressing chamber below 25 deg.C and relative humidity below 45%, setting capsule box temperature of soft capsule machine (RGY2X15F type soft capsule machine-Shanghai Tianxiang Jiantai pharmaceutical machinery Co., Ltd.) at 50 deg.C, soft capsule roller air supply temperature at about 15 deg.C, liquid medicine spray head temperature at 40 deg.C, controlling the thickness of capsule shell at 0.5-1.0 mm, and pressing into soft capsule.

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 5rpm, and the soft capsule is dried for 15 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

(6) Secondary drying

The secondary drying is also called pill shaping. Spreading the washed capsule in a drying chamber (at room temperature of 25-30 deg.C and relative humidity below 50%), naturally evaporating water and alcohol in capsule shell, and drying for 10 hr until the surface of the capsule shell is dried. Thus obtaining the soft capsule of the invention.

Example 5

This example is a soft capsule containing 100mg of quinazoline compound 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea (formula i) per capsule and process for preparation.

Table 51000 soft capsule prescription containing quinazoline compound

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

b, weighing 299.55 g of purified water, heating to 30-40 ℃, adding 299.55 g of gelatin in the step a, soaking while stirring for 1.8 hours, heating to 60-70 ℃, adding 149.78 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 50 min.

(2) Preparation of Contents

a, weighing 170 g of quinazoline compound raw material, carrying out low-temperature airflow superfine grinding, and controlling the particle size D of the raw material₉₀Less than 10 μm to obtain micronized ultra-fine powder raw material for later use.

Weighing 1/2 caprylic capric acid mono-diglyceride (39.97 g) and 100 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 10000rpm by using a high-speed homogenizer for 30min to obtain mixture suspension 2; weighing 16 g of polysorbate 80, 0.06 g of fat-soluble vitamin E, 4 g of polyoxyethylene hardened castor oil and the residual 1/2 g of caprylic capric acid mono-diglyceride (namely 39.97 g), putting into a dosing barrel, and stirring and mixing at the rotating speed of 1000rpm by using a homogenizer for 30min to obtain a mixture solution 3; pouring the mixture solution 2 into the mixture solution 3, and continuously stirring for 60min at 10000rpm by using a high-speed homogenizer to obtain a content suspension.

(3) Pressed pill

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 25rpm, and the soft capsule is dried for 20 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

(6) Secondary drying

Example 6

This example is a soft capsule containing 30mg of quinazoline compound 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea (formula i) per capsule and process for preparation.

Prescription of table 61000 soft capsule containing quinazoline compound

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

b, weighing 249.63 g of purified water, heating to 30-40 ℃, adding 249.63 g of gelatin in the step a, soaking while stirring for 1-2 hours, heating to 60-70 ℃, adding 124.81 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 45 min.

(2) Preparation of Contents

b, weighing 1/2 glyceryl monocaprylate (132.71 g) and 30 g of the superfine crushed raw material, putting the raw material into a mixing barrel, and stirring and mixing the raw material and the raw material by using a high-speed homogenizer at the rotating speed of 10000rpm for 30min to obtain a mixture suspension 2; weighing 4.5 g of polyoxyethylene sorbitan fatty acid ester, 0.09 g of fat-soluble vitamin E, polyoxyethylene hardened castor oil and the rest 1/2 glyceryl monocaprylate (namely 132.71 g), putting into a mixing barrel, and stirring and mixing at the rotating speed of 1000rpm by using a homogenizer for 30min to obtain a mixture solution 3; pouring the mixture solution 2 into the mixture solution 3, and continuously stirring for 60min at 10000rpm by using a high-speed homogenizer to obtain a content suspension.

(3) Pressed pill

(4) Drying

(5) Washing pill

(6) Secondary drying

Example 7

Table 71000 soft capsule prescription containing quinazoline compounds

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 199.80 g; weighing 0.94 g of titanium dioxide, and dispersing with a proper amount of purified water to obtain a mixture solution 1 for later use;

b, weighing 199.80 g of purified water, heating to 30-40 ℃, adding 199.80 g of gelatin in the step a, soaking while stirring for 1 hour, heating to 60-70 ℃, adding 99.90 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 30 min.

(2) Preparation of Contents

Weighing caprylic capric acid mono-diglyceride (124.71 g) and 30 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 8000rpm for 30min by using a high-speed homogenizer to obtain mixture suspension 2; weighing 4.5 g of polysorbate 80, 0.09 g of fat-soluble vitamin E, polyoxyethylene hardened castor oil and glyceryl monocaprylate (140.70 g), putting into a mixing barrel, and stirring and mixing at the rotation speed of 750rpm by using a homogenizer for 30min to obtain a mixture solution 3; the mixture solution 2 was poured into the mixture solution 3 and stirred continuously for 60min at 8000rpm using a high speed homogenizer to obtain a content suspension.

(3) Pressed pill

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 5rpm, and the soft capsule is dried for 10 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

(6) Secondary drying

Example 8

Table 81000 soft capsule prescription containing quinazoline compounds

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 260.03 g; weighing 0.94 g of titanium dioxide, and dispersing with a proper amount of purified water to obtain a mixture solution 1 for later use;

b, weighing 234.02 g of purified water, heating to 30-40 ℃, adding 260.03 g of gelatin in the step a, soaking while stirring for 1 hour, heating to 60-70 ℃, adding 130.01 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for more than 40 min.

(2) Preparation of Contents

a weighing quinazoline compound pro51 g of the raw materials are subjected to low-temperature airflow superfine grinding, and the particle size D of the raw materials is controlled₉₀Less than 10 μm to obtain micronized ultra-fine powder raw material for later use.

Weighing 1/2 caprylic capric acid mono-diglyceride (90.2 g) and 30 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 10000rpm by using a high-speed homogenizer for 30min to obtain mixture suspension 2; weighing 19.5 g of polysorbate 80, 0.05 g of fat-soluble vitamin E, 0.05 g of ascorbyl palmitate and the rest 1/2 of caprylic capric acid mono-diglyceride (namely 90.2 g), putting into a mixing barrel, and stirring and mixing at the rotating speed of 800rpm by using a homogenizer for 30min to obtain a mixture solution 3; pouring the mixture solution 2 into the mixture solution 3, and continuously stirring for 60min at 10000rpm by using a high-speed homogenizer to obtain a content suspension.

(3) Pressed pill

(4) Drying

(5) Washing pill

(6) Secondary drying

The secondary drying is also called pill shaping. Spreading the washed capsule in a drying chamber (at room temperature of 25-30 deg.C and relative humidity below 50%), naturally evaporating water and alcohol in capsule shell, and drying for 20 hr until the surface of the capsule shell is dried. Thus obtaining the soft capsule of the invention.

Example 9

Soft capsule prescription of 91000 quinazoline compounds

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

a, crushing and sieving gelatin by a 20-mesh pretreatment, removing large lumps, and weighing 259.77 g; weighing 0.94 g of titanium dioxide and 0.63 g of citric acid, and dispersing with a proper amount of purified water to obtain a mixture solution 1 for later use;

b, weighing 233.79 g of purified water, heating to 30-40 ℃, adding 259.77 g of gelatin in the step a, soaking while stirring for 2 hours, heating to 60-70 ℃, adding 129.88 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for 50 min.

(2) Preparation of Contents

Weighing 1/2 caprylic capric acid mono-diglyceride (103.97 g) and 25 g of superfine pulverized raw material, putting into a mixing barrel, and stirring and mixing at 10000rpm by using a high-speed homogenizer for 30min to obtain a mixture suspension 2; weighing 17 g of polysorbate 80, 0.08 g of fat-soluble vitamin E and the remaining 1/2 g of caprylic capric acid mono-diglyceride (103.97 g), putting into a mixing barrel, and stirring and mixing at 800rpm by using a homogenizer for 30min to obtain a mixture solution 3; pouring the mixture solution 2 into the mixture solution 3, and continuously stirring for 60min at 10000rpm by using a high-speed homogenizer to obtain a content suspension.

(3) Pressed pill

(4) Drying

(5) Washing pill

(6) Secondary drying

Example 10

Table 101000 soft capsule prescription containing quinazoline compound

The preparation process of the soft capsule comprises the following steps:

(1) preparation of capsule skin

b, weighing 233.79 g of purified water, heating to 30-40 ℃, adding 259.77 g of gelatin in the step a, soaking while stirring for 1 hour, heating to 60-70 ℃, adding 129.88 g of glycerol, continuously stirring, keeping the temperature at 60-70 ℃, and continuously stirring for more than 30 min.

(2) Preparation of Contents

Weighing caprylic capric acid mono-diglyceride (140.28 g) and superfine pulverized raw material 25 g, putting into a mixing barrel, and stirring and mixing at 9000rpm for 30min by using a high-speed homogenizer to obtain mixture suspension 2; weighing 10.5 g of polysorbate 80, 0.08 g of fat-soluble vitamin E and propylene glycol monocaprylate (namely 74.15 g), putting into a dosing barrel, and stirring and mixing at the rotating speed of 800rpm by using a homogenizer for 30min to obtain a mixture solution 3; the mixture solution 2 was poured into the mixture solution 3 and stirred for further 60min at 9000rpm using a high-speed homogenizer to obtain a content suspension.

(3) Pressed pill

Controlling the temperature of the pill pressing chamber below 25 deg.C and relative humidity below 45%, setting the capsule box temperature of the soft capsule machine at 50 deg.C, the air supply temperature of the soft capsule roller at about 15 deg.C, the temperature of the liquid medicine spray head at 40 deg.C, and controlling the thickness of the capsule shell of the soft capsule at 0.5-1.0 mm, and pressing into soft capsule.

(4) Drying

The soft capsule prepared by the pelleting machine is put into a drying device in a roller for drying by blowing, the rotating speed of the roller is 13rpm, and the soft capsule is dried for 15 hours under the conditions that the room temperature is 15-25 ℃ and the relative humidity is 20-45%.

(5) Washing pill

(6) Secondary drying

The secondary drying is also called pill shaping. Spreading the washed capsule in a drying chamber (at room temperature of 25-30 deg.C and relative humidity below 50%), naturally evaporating water and alcohol in capsule shell, and drying for 15 hr until the surface of the capsule shell is dried. Thus obtaining the soft capsule of the invention.

Effect example 1

The results of taking 1 tablet of the quinazoline compound of each of examples 3 and 8 (50mg) of the present invention and 50mg of the quinazoline compound tablet or hard capsule (specification: 50mg) disclosed in application No. 201910220652.9 (HCL: 9mL → 1000mL) were dissolved in a ph1.0 medium, comparing the stability after dissolution of the three formulations in the ph1.0 medium, sampling 50, 100, 150, 200, 300, 400, 500, and 600min after administration, precisely measuring 10 μ L each of the solutions in the three media, injecting the solutions into a high performance liquid chromatograph, measuring by the following chromatographic conditions and methods, recording a chromatogram, calculating the concentration of the drug remaining in the medium by the peak area according to an external standard method, and detecting the degradation of the drug in the ph1.0 medium by the high performance liquid chromatography are shown in fig. 1 and table 11. As is apparent from fig. 1 and table 11, the degradation rate of the soft capsules in the medium of ph1.0 is slow compared to that of the tablets and hard capsules.

Chromatographic conditions are as follows: shimadzu LC-2030C 3D high performance liquid chromatograph; a chromatographic column: shimadzustein C18, 250mm × 4.6mm × 5 μm, RD-LC-1001; column temperature: 30 ℃; sample cold plate temperature: 15 ℃; sample introduction amount: 10 uL; mobile phase A: water; mobile phase B: methanol; flow rate: 1.0 mL/min; detection wavelength: 190 and 800 nm. Isocratic analysis (methanol: water 55:45) analysis time 20 min.

TABLE 11 degradation of the three dosage forms in pH1.0 medium

Effect example 2

The drug preparations (50mg) of examples 3 and 8 of the present invention were each dissolved in ph1.2 medium (HCL: 7.65mL → 1000mL) together with 1 tablet or hard capsule (50mg in each specification) of the quinazoline compound disclosed in application No. 201910220652.9, stability of the three formulations after dissolution in ph1.2 medium was compared, and after the administration, 50, 100, 150, 200, 250, 300, 350, 400, 450, and 500min, 10 μ L of each solution in the three media was precisely measured and injected into a high performance liquid chromatograph, and measured under the following chromatographic conditions and methods, chromatograms were recorded, the concentration of the drug remaining in the medium was calculated by peak area according to the external standard method, and the degradation of the drug in ph1.2 medium was detected by high performance liquid phase detection, and the results are shown in fig. 2 and table 12. As is apparent from fig. 2 and table 12, the degradation rate of the soft capsules in the medium of ph1.2 is slow compared to that of the tablets and hard capsules.

TABLE 12 degradation of the three dosage forms in pH1.2 medium

Effect example 3

Dissolution of 3 pharmaceutical preparations (50mg) of examples 3, 5 and 8 of the present invention, respectively, was measured in a pH1.2 medium (HCL: 7.65mL → 1000mL) with a quinazoline compound tablet or a hard capsule (50mg in each specification) disclosed in application No. 201910220652.9, and the dissolution behavior of the three preparations in the pH1.2 medium was compared.

The dissolution test adopts the test method of determining the dissolution and the release which is required by 0931 item in the fourth part of the Chinese pharmacopoeia 2015 edition, the volume of dissolution medium is 900mL, the rotating speed is 50rpm, the operation is carried out according to the method, the timing is carried out after the administration, 5mL of dissolution liquid (needing to be added with a supplement liquid into a dissolution cup) is manually taken out after 5min, 10min, 15min, 30min, 45min and other time points, and 1mL of subsequent filtrate is taken as a test solution after 3mL of filtration. Precisely weighing 50mg of the compound reference substance, placing in a 100mL measuring flask, adding methanol to dissolve and dilute to scale, and shaking to obtain mother liquor. Precisely measuring 5mL of the mother solution, placing the mother solution in a 50mL measuring flask, adding methanol for dilution to scale, and shaking up to obtain a reference solution. Precisely measuring the two solutions by 10 μ L, injecting into a liquid chromatograph, measuring according to the following method, and recording chromatogram; the dissolution amount was calculated from the peak area according to the external standard method and plotted, and the dissolution profile is shown in fig. 3.

TABLE 13 dissolution (%) of the three dosage forms in pH1.2 medium

The results of this dissolution rate comparison experiment in pH1.2 medium are shown in Table 13. As is clear from Table 13, the dissolution behavior of the samples of examples 3, 5 and 8 of the present invention was substantially the same as that of the tablets and hard capsules. Further analysis of the results revealed that the instant dissolution rate of the sample of this example did not decrease in the medium at pH 1.2.

Effect example 4

The in vivo bioavailability comparison experiment was carried out on the pharmaceutical preparation of example 5 of the present invention and the quinazoline compound tablet or hard capsule disclosed in application No. 201910220652.9, and the experimental procedures and results were as follows:

beagle dog in vivo bioavailability test

6 Beagle dogs of 6-7 months age, male dogs with a weight of about 7-8 kg were randomly divided into 3 groups of 2 dogs. Fasting was performed for 12h before administration, and water was freely available. A two-cycle randomized crossover trial design was used, each trial was administered under Beagle awake conditions, giving 1 soft capsule (1 tablet or 1 hard capsule) of example 2 of the present invention, equivalent to 25mg (calculated as active ingredient) per dog, and a washout period of 14 days. Water is not forbidden in the whole test process, and food can be eaten 4h after administration. Venous blood was collected at 0.5mL before and at 0, 5 minutes (+ -30 seconds), 15 minutes (+ -1 minute), 30 minutes (+ -2 minutes), 1 hour (+ -2 minutes), 2 hours (+ -5 minutes), 4 hours (+ -5 minutes), 8 hours (+ -15 minutes), 24 hours (+ -30 minutes), and 48 hours (+ -1 hour) after dosing, respectively. Placing the whole blood sample in an ice box before centrifugation, centrifuging at 4 ℃ for about 1800g for 10 minutes after the sample collection of each time point is finished, separating plasma, subpackaging into 2 tubes, wherein one tube is 50 mu L, and the rest plasma is stored in the other tube and stored in a refrigerator at-80 ℃ for detection.

Control solution: accurately weighing appropriate amount of reference substance, adding methanol to dissolve and dilute, and making into 500 μ g/mL reference substance mother liquor. Precisely measuring 5mL of reference mother liquor, placing in a 50mL measuring flask, adding methanol to dilute to scale, and shaking to obtain reference solution.

The detection method comprises the following steps: precisely absorbing 0.5mL of supernatant of the plasma sample, placing the supernatant in an EP tube, adding 0.5mL of methanol solution, and uniformly mixing by vortex to obtain a test solution. The control solution and the sample solution were measured accurately at a volume of 10. mu.L each, and the measured solution was injected into a high performance liquid chromatograph and measured by the following method. Recording the chromatogram, calculating the drug time concentration by peak area according to an external standard method, respectively calculating the blood drug concentration, and drawing an average drug-time curve.

Pharmacokinetic parameters t1/2, Vz or Vz/F or VSS, AUC0-t, AUC0- ∞, Cl or Cl/F, MRT, Cmin, Cavg, AUC 0-tau, etc. were calculated using the Phoenix WinNonlin 6.4 non-atrioventricular model with multiple doses reaching steady state Cmin, Cavg, AUC 0-tau, etc. Two significant digits are reserved for t1/2, MRT and Tmax in the above parameters, and three significant digits are reserved for the rest parameters. The blood concentration, the drug-induced parameters and the like are described by mean values plus or minus standard deviation or median (range).

Tmax, Cmax and Cmin are measured values;

AUC 0-t: calculating by adopting a linear trapezoidal method, wherein t is the last time for quantifying the blood concentration;

AUC0- ∞ AUC0-t + Ct/λ z, Ct is the blood concentration at the last quantifiable time point, and λ z is the terminal elimination rate constant;

terminal elimination half-life t1/2 ═ 0.693/λ z;

the average residence time MRT is AUMC/AUC;

clearance (Cl, Cl/F) ═ D/AUC0- ∞ (D is the dose administered);

apparent volume of distribution (Vz, Vz/F) ═ D/(λ z · AUC0 ∞);

bioavailability F ═ 100% (AUC nasal drops × D vein)/(AUC venous × D nasal drops);

AUC0- τ is the area under the drug time curve one dosing interval (τ) after reaching steady state;

mean steady state plasma concentration Cavg ═ AUC0- τ/τ;

carrying out difference statistics on main pharmacokinetic parameters by adopting a T test (Excel 2010), carrying out a homogeneity test of variances by using an F-test, and when the variances are uniform (P is more than 0.05), analyzing by adopting an equal variance T test (T-test); when the variance is not uniform (P is less than or equal to 0.05), the variance t test (t-test) is adopted for analysis.

The pharmacokinetic parameters are shown in Table 14, the drug concentrations in plasma are shown in Table 15, the exposure comparisons are shown in Table 16, and the time course graph is shown in FIG. 4.

TABLE 14 pharmacokinetic parameters of Beagle dog three dosage forms for single oral gavage

TABLE 15 blood concentration (ng/mL) in individual animals of Beagle dogs in three dosage forms for single oral gavage

Time(h)	Oral gavage (tablet)	Oral gavage (hard capsule)	Gavage via mouth (example 5)
				0	BLQ	BLQ	BLQ
0.0833	BLQ	BLQ	BLQ
				0.25	3.43	4.98	8.56
0.5	72	78	132
				1	118	128	266
2	122	126	298
				4	140	153	232
8	120	128	176
				24	91.5	93.4	151
48	37.3	39.6	61.2

TABLE 16 Absolute bioavailability of Beagle Canine Single oral gavage LS

From tables 14-16, it can be seen that the main pharmacokinetic parameters, blood concentration and bioavailability of the soft capsules are significantly improved compared with the tablets and hard capsules, and particularly the exposure, peak concentration, elimination half-life and bioavailability are greatly improved.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A soft capsule preparation containing quinazoline compounds is characterized by comprising contents and a capsule shell, wherein the active ingredients in the contents are quinazoline compounds with a chemical structural formula shown in a formula (I),

2. the soft capsule preparation according to claim 1, wherein the weight percentage of the quinazoline compound in the content is 1% to 50%.

3. The soft capsule preparation of claim 1, wherein the content further comprises fat-soluble carrier material, solubilizer, antioxidant and other pharmaceutical excipients well known in the pharmaceutical field, and the total weight percentage of the fat-soluble carrier material, solubilizer and antioxidant in the content is 50-99%.

4. The soft capsule formulation of claim 3, wherein the fat-soluble carrier material comprises from 40% to 97.97% by weight of the contents.

5. The soft capsule formulation of claim 3, wherein the solubilizer is present in the content in an amount of 1.0% to 10% by weight.

6. The soft capsule formulation of claim 3, wherein the antioxidant comprises 0.01% to 0.05% by weight of the contents.

7. The soft capsule formulation of claim 3, wherein the fat-soluble carrier material is one or more of glyceryl monocaprylate, propylene glycol monocaprylate, medium chain triglycerides, medium chain diglycerides, medium chain monoglycerides, glycerol, dehydrogenated soybean oil, vegetable oils, aromatic oils; the solubilizer is one or more of polyoxyethylene hardened castor oil, polyoxyethylene castor oil, fatty alcohol-polyoxyethylene ether, fatty alcohol-polyoxypropylene ether, polyoxyethylene sorbitan fatty acid ester, polyglycerol fatty acid ester, polysorbate 80, polyethylene glycol, propylene glycol, absolute ethyl alcohol and isopropanol; the antioxidant is one or more of fat-soluble vitamin E, butyl hydroxy anisol, dibutyl hydroxy toluene, tert-butyl hydroquinone, ascorbyl palmitate, etc.

8. The soft capsule formulation of claim 7, wherein the lipid-soluble microorganism E is one or more of d-alpha-tocopherol, d-alpha-tocopherol ester, dl-alpha-tocopherol ester, d-alpha-tocopherol ester with hydrogen succinate, dl-alpha-tocopherol ester with hydrogen succinate, beta-tocopherol, gamma-tocopherol.

9. The soft capsule formulation of claim 1, wherein the capsule shell is composed of at least one of purified water, glycerin, animal bone glue, gum arabic, an opacifier, a pigment, a plasticizer, and other excipients well known in the pharmaceutical art.

10. The method for preparing a soft capsule formulation according to any one of claims 1 to 9, comprising the steps of:

(1) preparation of capsule skin

(2) preparation of Contents

(2a) Weighing quinazoline compounds as raw materials, and performing low-temperature airflow ultramicro powderCrushing and controlling the particle diameter D of the raw material₉₀Less than 10 μm to obtain micronized powder material;

(3) pressed pill

(4) drying

(5) washing pill

Sterilizing the capsule by using 70-75% of alcohol, soaking the capsule for 20-30 min by using 95% of alcohol, taking out and draining;

(6) secondary drying