Pharmaceutical composition containing benzonitrile derivative

Abstract

The invention discloses a pharmaceutical composition containing a benzonitrile derivative. The pharmaceutical composition comprises the following components: (a) a compound of formula (I); and (b) a polyvinylpyrrolidone; wherein component (a) and component (b) are mixed and subjected to hot melt extrusion; wherein the weight ratio of the component (b) to the component (a) is 5-20. The pharmaceutical composition disclosed by the invention can be stably stored for a long time and has a remarkable and better dissolution effect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a pharmaceutical composition comprising a benzonitrile derivative. Background Art

[0002] The storage conditions of drugs are a reflection of the stability of the drugs in the drugs. Drugs or crystal forms with lower melting points generally have relatively poor stability and need to be stored at lower temperatures, while drugs or crystal forms with higher melting points have better stability and can generally be stored at room temperature. The reasonable processing temperature of the preparation should also be reasonably formulated according to the thermal stability of the drug. The thermal degradation of drugs is usually closely related to their melting points, and the degradation reaction will occur rapidly after exceeding the melting point by 20°C. Both fatty liver and cancer require long-term medication. The requirement of low-temperature storage will add a lot of inconvenience to the patient's long-term medication and may lead to missed doses or improper storage, which may affect the treatment effect and may cause delays or recurrences of the disease. In addition, low-temperature refrigeration conditions also require special cold chain transportation tools and long-term refrigerators, which bring additional costs to the commercial development of the product. Therefore, in order to better meet clinical and commercial needs, it is necessary to find a stable drug preparation and preparation method that can be stored at room temperature. Such a preparation will not only greatly increase the in vivo and in vitro dissolution of the active ingredient, but more importantly, enable it to be stored at room temperature. The molecular formula of the compound represented by formula (I): C 24 H 24 N4O3, its structural formula is as follows:

[0003]

[0004] The equilibrium solubility of the crystalline form III and the crystalline form VI of the compound represented by formula (I) in different media without the addition of surfactant is shown in Table 1, indicating that the equilibrium solubility of the raw material of the compound is pH-dependent, and it is necessary to adopt a reasonable solubilization method to increase its dissolution in vivo and in vitro.

[0005] Table 1 Equilibrium solubility of the compound represented by formula (I) in media with different pH values

[0006]

[0007]

[0008] In addition, the compound shown in formula (I) is slightly unstable at a high temperature of 60°C. After 15 days of acceleration, the total impurities increased by 0.31%. The auxiliary material polyethylene glycol 6000 is unstable for GL01 under high temperature conditions. Specifically, after 15 days of acceleration at 60°C, the total impurities may increase by 2.9%, and the related substances have a larger increase. The reason is that the melting point of polyethylene glycol 6000 is relatively low (DSC test results show that the melting point of polyethylene glycol 6000 is 58.6°C). After 15 days of acceleration at 60°C, polyethylene glycol 6000 is semi-solid. Polyethylene glycol 6000 may undergo condensation reaction with the compound shown in formula (I) at high temperature, and condense with the hydroxyl and secondary amine therein to form unknown impurities.

[0009] Therefore, there is still a need to develop a formulation that will allow a pharmaceutical composition comprising a compound of formula (I) to be stably stored for a long period of time at 25°C to 60°C and under conditions of high relative humidity, and have significantly better dissolution effects. Summary of the invention

[0010] Based on this, the present invention provides a pharmaceutical composition comprising a benzonitrile derivative, wherein the pharmaceutical composition comprises the following components:

[0011] (a) Compound of formula (I)

[0012] and

[0013] (b) polyvinylpyrrolidone;

[0014] Component (a) and component (b) are mixed and subjected to hot melt extrusion; wherein the weight ratio between the component (b) and the component (a) is 5 to 20.

[0015] Further, the composition further comprises component (c), wherein the component (c) is a polymer excipient and / or a non-polymer excipient. Further, the polymer excipient is selected from one or more of polyethylene glycol, polyoxyethylene and polyvinyl alcohol. Further, the polymer excipient is polyethylene glycol. Further, the non-polymer material includes a pharmaceutically acceptable pharmaceutical excipient and / or a non-volatile weak acid, neutral or weakly acidic inorganic substance. Further, the pharmaceutically acceptable pharmaceutical excipient is a pharmaceutically acceptable excipient having a melting point below 80°C. Further, the pharmaceutically acceptable excipient having a melting point below 80°C includes a lipid material, an antioxidant and / or a surfactant. Further, the lipid material is selected from one or more of the following: triethyl citrate, medium chain triglycerides, acetylated triethyl citrate, monolinoleyl glyceryl, propylene glycol dicaprylate, monooleyl glyceryl, diethylene glycol monoethyl ether, myristyl alcohol, hydrogenated castor oil, hexadecanol, stearyl alcohol, cetostearyl alcohol, stearic acid, palmitic acid, palmitostearyl alcohol, polyglycerol oleate, monooleyl glyceryl, monostearate glyceryl, distearate glyceryl, dipalmitostearyl glyceryl and behenate glyceryl. Further, the antioxidant is 2,6-di-tert-butyl-p-cresol and / or vitamin E. Further, the surfactant is selected from one or more of the following: 15-hydroxystearic acid polyethylene glycol ester ( HS15), poloxamer 188, poloxamer 407, sodium lauryl sulfate, oleic acid macrogol glyceride (LabrafacTM lipophile WL1349), propylene glycol monocaprylate, propylene glycol monolaurate, lauric acid macrogol glyceride ( 44 / 14), stearic acid macrogol glyceride ( 50 / 13), Caprylic / caprylic acid macrogol glyceride Sorbitan fatty acid esters (Span), sorbitan fatty acid ester polyoxyethylene ether (Tween), vitamin E polyethylene glycol succinate.

[0016] Further, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 110° C. to 160° C. Further, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 110° C. to 150° C. Further, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 120° C. to 140° C.

[0017] Further, the polyvinyl pyrrolidone is polyvinyl pyrrolidone VA64. Further, the polyethylene glycol is selected from one or more of the following: polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000. Further, the weight ratio between the component (b) and the component (a) is 8 to 18. Further, the weight ratio between the component (b) and the component (a) is about 10 or about 15. Further, the weight ratio between the component (b) and the component (c) is 15 to 32. Further, the weight ratio between the component (b) and the component (c) is about 20 or about 30. Further, the weight ratio between the component (a), the component (b) and the component (c) is about 1: (6 to 16): about 0.5. Further, the weight ratio of the component (a), the component (b) and the component (c) is about 1: (8-12): about 0.5. Further, the weight ratio of the component (a), the component (b) and the component (c) is about 1: about 10: about 0.5.

[0018] Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 50% to 90% by weight of one or more of the following excipients: filler, disintegrant and lubricant. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 40% to 80% by weight of filler. Further, the filler is mannitol and / or silicified microcrystalline cellulose, such as mannitol M100 and / or silicified microcrystalline cellulose SMCC90. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 5% to 15% by weight of disintegrant. Further, the disintegrant is cross-linked polyvinylpyrrolidone, such as cross-linked polyvinylpyrrolidone XL-10. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.5% to 8% by weight of lubricant. Further, the lubricant is sodium stearyl fumarate. Further, the dosage form of the pharmaceutical composition is an oral preparation. Further, the oral preparation is a tablet, granule or capsule.

[0019] Furthermore, the pharmaceutical composition further comprises one or more drugs and / or extracts. Furthermore, the drug is an antiviral infection drug, an anticancer drug and / or an anti-acne drug.

[0020] According to another aspect of the present invention, there is provided a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: (1) mixing the sieved components (a), (b) and (c) to obtain a mixture; (2) extruding the mixture by hot melt extrusion at a hot melt extrusion temperature of 110°C to 160°C to form an extrudate; (3) cooling the extrudate; and (4) pulverizing and sieving the cooled extrudate to obtain particles of the pharmaceutical composition.

[0021] Further, the method further comprises the following steps: (5) mixing and drying the granules with one or more sieved pharmaceutically acceptable excipients, and processing them into tablets or capsules. Further, the pharmaceutically acceptable excipients are selected from one or more of the following: fillers, disintegrants and lubricants. Further, the component (b) is polyvinyl pyrrolidone. Further, the component (c) is polyethylene glycol. Further, the filler is mannitol and / or silicified microcrystalline cellulose, such as mannitol M100 and / or silicified microcrystalline cellulose SMCC90. Further, the disintegrant is cross-linked polyvinylpyrrolidone, such as cross-linked polyvinylpyrrolidone XL-10. Further, the lubricant is sodium stearyl fumarate.

[0022] Further, in step (2), the mixture is extruded using a hot melt extruder to form an extrudate, wherein the screw diameter of the hot melt extruder is between 5 mm and 50 mm, and the extrusion speed is between 10 rpm and 300 rpm. Further, the screw diameter of the twin-screw hot melt extruder is 5 mm to 40 mm, such as about 8 mm, about 18 mm, about 27 mm, about 30 mm. Further, the extrusion speed is 50 rpm to 150 rpm, such as about 100 rpm.

[0023] Furthermore, steps (1) to (5) of the method include any one or more of the following items [1] to

[11] : [1] the sieve in step (1) is a 30-mesh sieve or a 40-mesh sieve; [2] the mixing in step (1) is manual mixing or mechanical mixing; [3] the mixing time in step (1) is 5 min to 15 min, for example, about 10 min; [4] the temperature of zone 1 of the extruder in step (2) is room temperature; [5] the temperature of the heating zone of the extruder in step (2) is 110° C. to 160° C., for example, about 120° C. to 140° C.; [6] The die temperature of the extruder in step (2) is 115°C to 135°C, for example, about 125°C; [7] the torque of the extruder in step (2) is not higher than 6.0 Nm; [8] the sieve in step (4) is a 20-50 mesh sieve, for example, a 35 mesh sieve or a 40 mesh sieve; [9] the mixing time in step (5) is 10 min to 20 min, for example, about 15 min;

[10] the mixing speed in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm;

[11] the weight loss measurement result of drying in step (5) is not higher than 5%.

[0024] According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and treating a disease characterized by a disorder of the fatty acid synthase pathway. Further, the disease characterized by a disorder of the fatty acid synthase pathway is a viral infection. Further, the viral infection is a hepatitis C infection or a respiratory viral infection. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and treating cancer or tumors. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and treating acne.

[0025] Beneficial effects of the present invention:

[0026] The present invention adopts a preparation process of preparing a solid dispersion by hot melt extrusion, and mixing with an external auxiliary material after crushing and tableting. Studies have found that using a certain proportion of polyvinyl pyrrolidone as a solid dispersion carrier material in the prescription helps to quickly improve the dissolution and stability of the compound of formula (I). Specifically, the pharmaceutical composition of the present invention containing the compound of formula (I) can be stably stored for a long time and has a significantly better dissolution effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without exceeding the scope of protection required by the present invention.

[0028] Figure 1 It is a schematic diagram of the dissolution results of the preparation of the present invention and the control preparation under the dissolution method of first pH 1.0 and then pH 6.8.

[0029] Figure 2 It is a schematic diagram of the dissolution results of the preparation of the present invention and the control preparation under the pH 6.8 dissolution method.

[0030] Figure 3 It is a schematic diagram of the dissolution results of the preparations of the present invention from batches YF6021008, YF6021010, and YF6021007.

[0031] Figure 4 This is a schematic diagram of the XRPD results of the hot melt extrudate of the present invention at day 0.

[0032] Figure 5 The figure is a schematic diagram of the dissolution results of 10 mg tablets and capsules of the present invention under the dissolution method of first pH 1.0 and then pH 6.8.

[0033] Figure 6It is a schematic diagram of the dissolution results of 10 mg tablets and capsules of the present invention under the pH 6.8 dissolution method. DETAILED DESCRIPTION

[0034] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0035] Unless otherwise indicated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by those of ordinary skill in the field of the invention or the field in which the terms are used. Although any methods, conditions, substances or materials similar to or equivalent to those disclosed herein may be used in the practice of the present invention, preferred methods, conditions, substances or materials are described herein.

[0036] The present invention is intended to encompass all alternatives, variations and equivalents that may be included in the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0037] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0038] In the present invention, the term "comprising" is synonymous with "including". As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0039] As described in the background technology section, the compound represented by formula (I) (hereinafter referred to as "GL01") has a pH-dependent equilibrium solubility, poor stability under relatively high temperature conditions, and an increase in impurities. In order to solve the above problems, the present invention provides a pharmaceutical composition comprising a benzonitrile derivative, the pharmaceutical composition comprising the following components:

[0040] (a) Compound of formula (I)

[0041] and

[0042] (b) polyvinylpyrrolidone;

[0043] Component (a) and component (b) are mixed and subjected to hot melt extrusion; wherein the weight ratio between the component (b) and the component (a) is 5 to 20.

[0044] The present invention uses a hot melt extrusion process to uniformly dissolve the GL01 API in the carrier material to form a transparent solid dispersion extrudate. Regardless of the crystal form (crystal form III and crystal form VI), the GL01 API is distributed in the solid dispersion in a molecular state and has a good dissolution behavior, thereby significantly reducing the impact of changes in the solubility of the API caused by changes in the crystal form of the GL01 API.

[0045] In the present invention, when weight ratios, weight parts, temperature, speed, diameter, time, pressure, frequency, proportion, equivalent, concentration, or other values ​​or parameters are expressed as ranges, preferred ranges, or ranges defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether the range is disclosed separately. For example, when the range "5 to 20" is disclosed, the described range should be interpreted as including the ranges "5 to 20", "5 to 18", "5 to 16", "5 to 15", "5 to 12", "5 to 10", "5 to 20", "8 to 20", "10 to 20", "12 to 20", "15 to 20", "18 to 20", "8 to 18", "8 to 15", "8 to 12", "8 to 10", "10 to 15", etc. When a numerical range is described herein, unless otherwise specified, the range is intended to include its end values ​​and all values ​​to two decimal places within the range, and the effects of the present invention can be achieved within the above range.

[0046] In a preferred embodiment, the composition further comprises component (c), wherein the component (c) is a polymer excipient and / or a non-polymer excipient. In a preferred embodiment, the polymer excipient is selected from one or more of polyethylene glycol, polyoxyethylene and polyvinyl alcohol. In a preferred embodiment, the polymer excipient is polyethylene glycol. In a preferred embodiment, the non-polymer material includes pharmaceutically acceptable pharmaceutical excipients and / or non-volatile weak acids, neutral or weakly acidic inorganic substances. In a preferred embodiment, the pharmaceutically acceptable pharmaceutical excipient is a pharmaceutically acceptable excipient having a melting point below 80°C. In a preferred embodiment, the pharmaceutically acceptable excipient having a melting point below 80°C includes a lipid material, an antioxidant and / or a surfactant. In a preferred embodiment, the lipid material is selected from one or more of the following: triethyl citrate, medium chain triglycerides, acetylated triethyl citrate, monolinoleyl glyceryl, propylene glycol dicaprylate, monooleyl glyceryl, diethylene glycol monoethyl ether, myristyl alcohol, hydrogenated castor oil, hexadecanol, stearyl alcohol, cetostearyl alcohol, stearic acid, palmitic acid, palmitostearyl alcohol, polyglycerol oleate, monooleyl glyceryl, monostearate glyceryl, distearate glyceryl, dipalmitostearyl glyceryl and behenate glyceryl. In a preferred embodiment, the antioxidant is 2,6-di-tert-butyl-p-cresol and / or vitamin E. Further, the surfactant is selected from one or more of the following: 15-hydroxystearic acid polyethylene glycol ester ( HS15), poloxamer 188, poloxamer 407, sodium lauryl sulfate, oleic acid macrogol glyceride (LabrafacTM lipophile WL1349), propylene glycol monocaprylate, propylene glycol monolaurate, lauric acid macrogol glyceride ( 44 / 14), stearic acid macrogol glyceride ( 50 / 13), Caprylic / caprylic acid macrogol glyceride Sorbitan fatty acid esters (Span), sorbitan fatty acid ester polyoxyethylene ether (Tween), vitamin E polyethylene glycol succinate.

[0047] In a preferred embodiment, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 110°C to 160°C. In a preferred embodiment, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 110°C to 150°C. In a preferred embodiment, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 120°C to 140°C.

[0048] In a preferred embodiment, the polyvinyl pyrrolidone is polyvinyl pyrrolidone VA64. In a preferred embodiment, the polyethylene glycol is selected from one or more of the following: polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000. In a preferred embodiment, the weight ratio between the component (b) and the component (a) is 8 to 18. In a preferred embodiment, the weight ratio between the component (b) and the component (a) is about 10 or about 15. In a preferred embodiment, the weight ratio between the component (b) and the component (c) is 15 to 32. In a preferred embodiment, the weight ratio between the component (b) and the component (c) is about 20 or about 30. Further, the weight ratio between the component (a), the component (b) and the component (c) is about 1: (6 to 16): about 0.5. Further, the weight ratio of the component (a), the component (b) and the component (c) is about 1: (8-12): about 0.5. Further, the weight ratio of the component (a), the component (b) and the component (c) is about 1: about 10: about 0.5.

[0049] The scope in this article can be expressed as from "about" a specific value, and / or to "about" another specific value. When expressing such a scope, another embodiment includes from a specific value and / or to another specific value. Similarly, when a value is expressed as an approximation, by using the antecedent "about", it will be understood that the specific value forms another embodiment. It will be further understood that the endpoints of each range are important relative to the other endpoint and independently of the other endpoint. It should also be understood that many values ​​are disclosed herein, and in addition to the value itself, each value is also disclosed herein as "about" that specific value. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It should also be understood that when disclosing "less than or equal to" the value, "greater than or equal to the value", the possible range between these values ​​is also disclosed, as appropriately understood by those skilled in the art. For example, if the value "10" is disclosed, then "less than or equal to 10" and "greater than or equal to 10" are also disclosed.

[0050] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 10" includes ±5% of 10, or from 9.5 to 10.5; "about 15" includes ±5% of 15, or from 14.25 to 15.75; "about 20" includes ±5% of 20, or from 19 to 21; "about 30" includes ±5% of 30, or from 28.5 to 31.5; "about 1" includes ±5% of 1, or from 0.95 to 1.05; "about 0.5" includes ±5% of 0.5, or from 0.475 to 0.525.

[0051] In a preferred embodiment, the pharmaceutical composition further comprises 50% to 90% by weight of one or more of the following excipients: a filler, a disintegrant, and a lubricant, based on the total weight of the pharmaceutical composition.

[0052] In the present invention, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to an individual.

[0053] In the present invention, the term "pharmaceutically acceptable excipient" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with subjects and active ingredients (i.e., capable of inducing the desired therapeutic effect without causing any undesirable local or systemic effects), which are well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995).

[0054] In a preferred embodiment, the pharmaceutical composition further comprises 40% to 80% by weight of a filler, based on the total weight of the pharmaceutical composition. In a preferred embodiment, the filler is mannitol and / or silicified microcrystalline cellulose, such as mannitol M100 and / or silicified microcrystalline cellulose SMCC90. In a preferred embodiment, the pharmaceutical composition further comprises 5% to 15% by weight of a disintegrant, based on the total weight of the pharmaceutical composition. In a preferred embodiment, the disintegrant is cross-linked polyvinylpyrrolidone, such as cross-linked polyvinylpyrrolidone XL-10. In a preferred embodiment, the pharmaceutical composition further comprises 0.5% to 8% by weight of a lubricant, based on the total weight of the pharmaceutical composition. In a preferred embodiment, the lubricant is sodium stearyl fumarate.

[0055] The above-mentioned excipients are preferably pharmaceutically inert, or may have a synergistic or additive effect to enhance the therapeutic activity of the pharmaceutical composition, and the above-mentioned excipients are only listed. The excipients actually used in the present invention are not limited to the above-mentioned excipients and can be adjusted according to actual conditions to achieve the effects of the present invention.

[0056] In a preferred embodiment, the dosage form of the pharmaceutical composition is an oral preparation. In a preferred embodiment, the oral preparation is a tablet, granule or capsule.

[0057] In a preferred embodiment, the pharmaceutical composition further comprises one or more drugs and / or extracts. In a preferred embodiment, the drug is an antiviral infection drug, an anticancer drug and / or an anti-acne drug.

[0058] According to another aspect of the present invention, there is provided a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: (1) mixing the sieved components (a), (b) and (c) to obtain a mixture; (2) extruding the mixture by hot melt extrusion at a hot melt extrusion temperature of 110°C to 160°C to form an extrudate; (3) cooling the extrudate; and (4) pulverizing and sieving the cooled extrudate to obtain particles of the pharmaceutical composition.

[0059] In a preferred embodiment, the method further comprises the following steps: (5) mixing and drying the granules with one or more sieved pharmaceutically acceptable excipients to form tablets or capsules. In a preferred embodiment, the pharmaceutically acceptable excipients are selected from one or more of the following: fillers, disintegrants and lubricants. In a preferred embodiment, the component (b) is polyvinyl pyrrolidone. In a preferred embodiment, the component (c) is polyethylene glycol. In a preferred embodiment, the filler is mannitol and / or silicified microcrystalline cellulose, such as mannitol M100 and / or silicified microcrystalline cellulose SMCC90. In a preferred embodiment, the disintegrant is cross-linked polyvinylpyrrolidone, such as cross-linked polyvinylpyrrolidone XL-10. In a preferred embodiment, the lubricant is sodium stearyl fumarate.

[0060] In a preferred embodiment, in step (2), the mixture is extruded using a hot melt extrusion device to form an extrudate, wherein the screw diameter of the hot melt extrusion device is between 5 mm and 50 mm, and the extrusion speed is between 10 rpm and 300 rpm. In a preferred embodiment, the screw diameter of the twin-screw hot melt extrusion device is 5 mm to 40 mm, such as about 8 mm, about 18 mm, about 27 mm, about 30 mm. In a preferred embodiment, the extrusion speed is 50 rpm to 150 rpm, such as about 100 rpm.

[0061] In a preferred embodiment, steps (1) to (5) of the method include any one or more of the following items [1] to

[11] : [1] the sieve in step (1) is a 30-mesh sieve or a 40-mesh sieve; [2] the mixing in step (1) is manual mixing or mechanical mixing; [3] the mixing time in step (1) is 5 min to 15 min, for example, about 10 min; [4] the temperature of zone 1 of the extruder in step (2) is room temperature; [5] the temperature of the heating zone of the extruder in step (2) is 110° C. to 160° C., for example, about 120° C. to 140° C.; [6] The die temperature of the extruder in step (2) is 115°C to 135°C, for example, about 125°C; [7] The torque of the extruder in step (2) is not higher than 6.0 Nm; [8] The sieve in step (4) is a 20-50 mesh sieve, for example, a 35 mesh sieve or a 40 mesh sieve; [9] The mixing time in step (5) is 10 min to 20 min, for example, about 15 min;

[10] The mixing speed in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm;

[11] The weight loss measurement result of drying in step (5) is not higher than 5%.

[0062] In the present invention, "about" refers to a value within a range of ±5% of a particular value. For example, “about 8” includes ±5% of 8, or from 7.6 to 8.4; “about 18” includes ±5% of 18, or from 17.1 to 18.9; “about 27” includes ±5% of 27, or from 25.65 to 28.35; “about 30” includes ±5% of 30, or from 28.5 to 31.5; “about 100” includes ±5% of 100, or from 95 to 105; “about 10” includes ±5% of 10, or from 9.5 to 10.5; “about 140” includes ±5% of 140, or from 133 to 147; “about 125” includes ±5% of 125, or from 118.75 to 131.25; “about 15” includes ±5% of 15, or from 14.25 to 15.75; “about 20” includes ±5% of 20, or from 19 to 21.

[0063] According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and treating a disease characterized by a disorder of the fatty acid synthase pathway. In a preferred embodiment, the disease characterized by a disorder of the fatty acid synthase pathway is a viral infection. In a preferred embodiment, the viral infection is a hepatitis C infection or a respiratory viral infection. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and treating cancer or tumors. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and treating acne.

[0064] In the present invention, the term "prevention" includes "treatment" and "prevention", unless there is a specific description to the contrary. The terms "treatment" and "treatment" should be understood accordingly. In the present invention, the term "treatment" includes alleviating, inhibiting or improving the symptoms or conditions of the disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of diseases or symptoms, such as controlling the development of diseases or conditions; alleviating diseases or symptoms; reducing diseases or symptoms; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a pharmaceutical composition or a pharmaceutical preparation, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed administration or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.

[0065] According to another aspect of the present invention, there is provided a pharmaceutical composition as described above, for use in preventing and / or treating a condition characterized by a disorder of the fatty acid synthase pathway in a subject. According to another aspect of the present invention, there is provided a pharmaceutical composition as described above, for use in preventing and / or treating a cancer or tumor in a subject. According to another aspect of the present invention, there is provided a pharmaceutical composition as described above, for use in preventing and / or treating acne in a subject. According to another aspect of the present invention, there is provided a method for preventing and / or treating a condition characterized by a disorder of the fatty acid synthase pathway in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described above. According to another aspect of the present invention, there is provided a method for preventing and / or treating a cancer or tumor in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described above. According to another aspect of the present invention, there is provided a method for preventing and / or treating acne in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described above.

[0066] In the present invention, the term "subject" is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse or cattle, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects representing viral infection models or cancer models or tumor models or acne models. Preferably, the subject is a human. The "effective amount" of the pharmaceutical composition or preparation used in the present invention can obtain the desired treatment and / or prevention effect. The amount effective for this purpose will depend on, for example, the pharmaceutical composition, the mode of administration, the stage and severity of the disease to be treated, the individual's body weight and overall health, and the judgment of the prescribing physician. The dosage can be given once a week, or once every two days or every day, or even several times a day. The dosage unit can be given in a short period of time (e.g., weeks to months) or longer periods of time (months to years).

[0067] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out according to conventional conditions or conditions recommended by the manufacturer.

[0068] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0069] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in this patent specification can be used in combination with any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0070] Example

[0071] 1. Screening of solubilizing excipients

[0072] The present invention screens the types of solubilizing excipients by taking improving the solubility of GL01 in various dissolution media as an evaluation index.

[0073] Considering that the solubility of GL01 API is pH-dependent, the solubilization effects of several conventional solubilizing excipients on GL01 were investigated. They were formulated according to Table 2 and added to 250 ml of pH 6.8 phosphate buffer, respectively. The mixture was shaken in a constant temperature shaker at 37°C, and samples were taken at 2 hours and 24 hours, respectively. The dissolution percentage of GL01 is shown in Table 2.

[0074] Table 2 Study on the solubilization effect of multiple conventional solubilizing excipients on GL01

[0075]

[0076]

[0077] From the results in Table 2, we can see that compared with other excipients, polyvinyl pyrrolidone VA64 (trade name VA64) can significantly improve the solubility of GL01 in pH 6.8 phosphate buffer. VA64) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (trade name ) for subsequent experiments.

[0078] 2. Screening of different solubilizing excipients and different processes

[0079] Method 1: Usually, the drug is transported through the stomach with a lower pH value (pH of about 1.0-4.5) in the human gastrointestinal tract, and then transported to the small intestine with a higher pH value (pH of about 4.5-6.8) for absorption. In order to more truly reflect the dissolution of GL01 in vivo, the present invention selects more stringent dissolution conditions for research. The specific operation is to refer to the enteric-coated preparation method 1 of the fourth part 0931 dissolution and release determination method of the Chinese Pharmacopoeia 2020 edition. First, stir 750ml of pH1.0 hydrochloride buffer at 75 rpm for 1 hour, then add 250ml of sodium phosphate solution to adjust the medium to pH6.8, and perform a dissolution test (hereinafter referred to as the pH1.0 and then pH6.8 dissolution method).

[0080] Method 2: From the solubility data in Table 1, it can be seen that under pH 6.8, the equilibrium solubility of GL01 is relatively low, and this pH condition corresponds to the small intestine, the absorption site in the body, which is representative. The specific operation is based on the second method of the paddle method in the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia 0931 Dissolution and Release Determination Method. The medium is pH 6.8 phosphate buffer, so this condition was selected for the dissolution test (hereinafter referred to as the pH 6.8 dissolution method).

[0081] In order to improve the ability to distinguish the dissolution conditions, the rotation speed was selected to be a more stringent 50 rpm.

[0082] The 10 mg GL01 preparations prepared by different solubilizing excipients and different processes were investigated. The formulation processes are shown in Tables 3 and 4.

[0083] Table 3 10 mg GL01 preparations prepared by different solubilizing excipients and different processes 1 to 3

[0084]

[0085]

[0086] Table 4 10 mg GL01 preparations prepared by different solubilizing excipients and different processes 4 to 6

[0087]

[0088] The dissolution study of the preparation prepared by the above prescription was carried out, and the results were as follows Figure 1 and Figure 2 As shown in Table 3 and Table 4, the dissolution results of the mixture of GL01, polyvinyl pyrrolidone VA64 and polyethylene glycol 6000 have obvious dissolution advantages after hot melt extrusion granulation, so the hot melt extrusion process and its formulation were subsequently optimized.

[0089] In addition, although the equilibrium solubility of typical crystalline form III and crystalline form VI of GL01 API in pH 1.0 and pH 2.0 hydrochloric acid solutions for 48 hours is relatively high (as shown in Table 1), the dissolution data of GL01 API direct capsule filling shows that the dissolution rate of GL01 is relatively low, and it was not completely dissolved in the 2-3 hour dissolution test.

[0090] 3. Determination of solid dispersion formulation process

[0091] The compatibility results of raw materials and auxiliary materials reveal that polyvinyl pyrrolidone VA64 and GL01 are stable under all conditions. The present invention attempts to add a small amount of polyethylene glycol 6000 to the polyvinyl pyrrolidone VA64 carrier to reduce the glass transition temperature (Tg) of the solid dispersion, thereby reducing the temperature of hot melt extrusion, because too high a hot melt extrusion temperature may cause degradation of the raw material. Comparing the effect of the amount of polyethylene glycol 6000 added on the hot melt extrusion effect, it is found that with the increase in the amount of polyethylene glycol 6000, the extrudate gradually changes from clear and transparent to turbid and opaque, and finally becomes opaque and waxy. The transparency of the extruded material is used as the basis for judging whether the solid dispersion is made.

[0092] The prescription ratio and process parameters of the hot melt extrusion process of GL01 were explored. The hot melt temperature, extruder torque, screw speed, and transparency of the extrudate were used as process evaluation indicators. The solubilization effect of the solid dispersion on GL01 during the dissolution process, the degradation of related substances, and the risk of GL01 amorphous transformation were used as quality control evaluation indicators. The parameters were studied and the results are shown in Table 5.

[0093] Table 5 Exploration of hot melt extrusion process prescription ratio and process parameters of GL01

[0094]

[0095]

[0096] The feasibility of the process was investigated and found to be:

[0097] (1) The feasible temperature range of the hot melt extrusion heating zone is 130℃~160℃. If the temperature is as low as 120℃, the extrudate is opaque and the torque is large, and the equipment cannot operate normally; (2) API and polyvinyl pyrrolidone VA64 are prepared in a weight ratio of 1:5, 1:10, and 1:15. When an appropriate amount of polyethylene glycol 6000 is added, the material can be extruded. However, if polyethylene glycol 6000 is not added, a higher hot melt extrusion temperature is required, which may cause high-temperature thermal degradation of GL01; if excessive polyethylene glycol 6000 is added, the extrudate is opaque. In YF6021009, the ratio of polyvinyl pyrrolidone VA64: polyethylene glycol 6000 is 10:1, and it is found that the extrudate is not completely transparent. The final study found that the range of polyvinyl pyrrolidone VA64: polyethylene glycol 6000 is more suitable in the range of 20:1~30:1; (3) The feasible screw speed is 20~150rpm.

[0098] Quality control indicator evaluation:

[0099] (1) Dissolution of the extrudate after crushing and tableting:

[0100] API and polyvinylpyrrolidone VA64 were mixed at a weight ratio of 1:5, 1:10, and 1:15, and then an appropriate amount of polyethylene glycol 6000 was added. The batch numbers were YF6021008, YF6021010, and YF6021007. The successfully prepared GL01 solid dispersion was cooled and crushed, and powders smaller than 35 mesh (500 μm) were weighed and mixed with the additional excipients according to the prescription in Table 6 to prepare tablets for dissolution curve comparison. The results are shown in Figure 3 shown.

[0101] Table 6 Prescription of GL01 tablets in batches YF6021007, YF6021008 and YF6021010

[0102]

[0103]

[0104] The dissolution results showed that prescription 10 (batch number YF6021010) with a prescription ratio of API: polyvinyl pyrrolidone VA64: polyethylene glycol 6000 of 1:10:0.5 had better dissolution ability. Prescription 7 (batch number YF6021007) may be affected by the dissolution due to the excessive dosage of polyvinyl pyrrolidone VA64. During the disintegration process, a large amount of polyvinyl pyrrolidone VA64 showed excessive viscosity. Prescription 8 (batch number YF6021008) may be affected by the dissolution due to the low dosage of polyvinyl pyrrolidone VA64, which was not enough to completely dissolve GL01.

[0105] (2) Study on the crystal transformation risk of amorphous APIs produced by hot melt extrusion solid dispersions:

[0106] The GL01 preparation is composed of amorphous solid dispersion powder after hot melt extrusion, cooling and grinding, and added silicified microcrystalline cellulose SMCC90, mannitol M100, cross-linked polyvinylpyrrolidone XL-10 and sodium stearyl fumarate. In the tablet, GL01 is only present in the solid dispersion powder. Therefore, the study of amorphous solid dispersion powder can effectively eliminate the interference of added excipients and improve the sensitivity of detection.

[0107] When solid dispersion powder is accelerated under wet and hot conditions, the provision of water molecules and external energy will increase the loosening of the copolyvidone polymer chain, thereby increasing the activity of the drug or excipient in the carrier system.

[0108] API and polyvinylpyrrolidone VA64 were mixed in a weight ratio of 1:5, 1:10, and 1:15, and then an appropriate amount of polyethylene glycol 6000 was added. The batch numbers were YF6021008, YF6021010, and YF6021007. The successfully prepared GL01 solid dispersion was pulverized after cooling. It is intended to explore the stability of the morphology of GL01 in the solid dispersion through accelerated investigations under multiple conditions. The crystal form detection results of the solid dispersion under multiple accelerated conditions are shown below.

[0109] Among them, the XRPD results of the hot melt extrusion process on day 0 are as follows Figure 4 As shown, the hot melt extrudates are all in an amorphous state.

[0110] In summary, the hot melt temperature, extruder torque, screw speed and transparency of the extrudate were used as process evaluation indicators, and the solubilization effect of the solid dispersion on GL01 in the dissolution process, the degradation of related substances and the risk of GL01 amorphous transformation were used as quality control evaluation indicators. The optimal formula was determined to be GL01: polyvinyl pyrrolidone VA64: polyethylene glycol 6000 in a weight ratio of 1:10:0.5, which could obtain a hot melt extrudate with controllable quality and stable process.

[0111] 4. Confirmation of tablet formulation process

[0112] Based on the solid dispersion formulation process development, 10 mg GL01 tablets were developed and determined with dissolution curve, related substances and stability as indicators. The optimized formulation composition is shown in Table 7.

[0113] Table 7 Unit dose prescription composition of 10 mg GL01 tablets

[0114]

[0115] Tablets (10 mg tablets: batch YF6021015-10) prepared by the optimized formulation process were studied for dissolution curves in various dissolution media. The results in different media are shown in Tables 8 to 11. From the results, it can be seen that the 10 mg tablets can be dissolved more than 85% in 15 minutes in the four dissolution media at a low speed of 50 rpm without any surfactant, and all have good in vitro rapid dissolution effects.

[0116] Table 8 Summary of dissolution results of GL01 tablets (10 mg) in pH 6.8 phosphate solution (n=6)

[0117]

[0118]

[0119] Table 9 Summary of dissolution results of GL01 tablets (10 mg) in water (n=6)

[0120]

[0121] Table 10 Summary of dissolution results of GL01 tablets (10 mg) in pH 1.0 buffer solution (n=6)

[0122]

[0123]

[0124] Table 11 Summary of dissolution results of GL01 tablets (10 mg) in pH 4.0 buffer solution (n=6)

[0125]

[0126] 5. In vivo study of tablets for formulation confirmation in beagle dogs

[0127] This study aims to compare the effects of different dosage forms of GL01 on pharmacokinetics in beagle dogs given a single oral dose, and the results are shown in Table 12. The experimental design is to use 3 beagle dogs, intravenous injection of 0.5 mg / kg, oral administration of 10 mg / tablet / dog, oral administration of 10 mg / capsule / dog, and single administration in a cycle of 7 days.

[0128] Table 12 Comparative study results of 10 mg tablets, 10 mg capsules, PO and IV administration in beagle dogs

[0129]

[0130]

[0131] Among them, the 10mg tablet (batch number YF6021015-10) refers to the unit dose prescription composition of 10mg GL01 tablets in Table 7; the prescription information of GL01 capsules (batch number YF60JN001) refers to the 10mg GL01 preparations prepared by different solubilizing excipients and different processes in Table 4.

[0132] The above results show that: (1) The average bioavailability of 10 mg tablets is 60.3%, and the average exposure is 6815 hr*ng / mL, and the data have good parallelism. (2) In contrast, GL01 capsules have a lower average bioavailability of 13%, and an average exposure of 1431 hr*ng / mL, indicating that the absorption of the capsule formulation is significantly worse than that of the tablets. The bioavailability of 10 mg capsules is only about 1 / 5 of that of 10 mg tablets, and there is a significant difference (p<0.01); (3) GL01 is metabolized slowly in beagle dogs and has a longer half-life.

[0133] 6. Screening of dissolution conditions with differentiated strength for 10 mg GL01 preparation

[0134] In vivo experiments on beagle dogs found that the bioavailability of 10 mg capsules was only about 1 / 5 of that of 10 mg tablets. Two methods were selected: pH 6.8 phosphate buffer and more stringent dissolution conditions (pH 1.0 and then pH 6.8 dissolution method) to investigate the dissolution behavior of GL01 tablets and capsules. The results are as follows: Figure 5 and Figure 6 The dissolution curves of 10mg GL01 tablets and capsules in pH 6.8 phosphate buffer can more truly reflect the difference in bioavailability of the two in beagle dogs. At 30-45min, the dissolution rates of 10mg GL01 tablets and capsules in pH 6.8 phosphate buffer match the bioavailability, and the dissolution rate of 10mg capsules is about 1 / 5 of that of 10mg tablets.

[0135] In summary, the dissolution conditions determined were pH 6.8 phosphate buffer, 50 rpm; the evaluation standard was greater than 75% in 45 min.

[0136] 7. Determination of tablet preparation process

[0137] ① Pretreatment of raw materials and auxiliary materials: GL01 and polyethylene glycol 6000 were sieved through a 40-mesh sieve before compounding, and polyvinyl pyrrolidone VA64, silicified microcrystalline cellulose SMCC90, mannitol M100, cross-linked polyvinylpolypyrrolidone XL-10 and sodium stearyl fumarate were sieved through a 30-mesh sieve to remove lumps during storage;

[0138] ② Premixing: Manually mix GL01, polyvinyl pyrrolidone VA64 and polyethylene glycol 6000 in a ziplock bag for 10 minutes;

[0139] ③Hot melt extrusion granulation: In an experimental hot melt extruder with a screw diameter of 8 mm, set the extrusion parameters according to Table 13. After preheating to the set temperature, keep warm for 15 minutes. Take the premixed raw and auxiliary materials and add them manually. By adjusting the feeding speed and the extrusion screw speed, the feeding speed is matched with the discharge speed;

[0140] Table 13 Extrusion parameters of hot melt extruder 1

[0141]

[0142] ④ Final mixing: According to the weight after crushing, weigh silicified microcrystalline cellulose SMCC90 (additional), mannitol M100 (additional), cross-linked polyvinylpyrrolidone XL-10 (additional) and sodium stearyl fumarate (additional) according to the prescription conversion, and use a laboratory mixer to mix at a mixing speed of 20rpm and a mixing time of 15min. After the final mixing, the drying loss of the granules should be ≤5.0%, and the GL01 content should be 90.0% to 110.0% of the labeled content;

[0143] ⑤ Tablet pressing: tablet pressing by Xinma S60 tablet press. Control GL01 tablets, the difference of single tablet weight is controlled within ±7.5%, and the difference of average tablet weight is controlled within ±5.0%;

[0144] 10mg specification: hardness range 4~10kp, disintegration time limit requires complete disintegration within 15 minutes;

[0145] ⑥ Packaging: Both specifications of tablets are packaged in bottles with 30 tablets per bottle, packaged in high-density polyethylene bottles, and stored in a sealed state at room temperature (below 30°C).

[0146] 8. Determination of pilot scale-up process

[0147] ①Pretreatment of raw materials and auxiliary materials

[0148] Before mixing, the raw and auxiliary materials are sieved with a 60-mesh sieve to remove lumps during storage.

[0149] ② Premix

[0150] Weigh GL01, polyvinyl pyrrolidone VA64 and polyethylene glycol 6000 and add them into the hopper of HLS50 laboratory mixer. Set the mixing time to 15 minutes and the mixing speed to 20 rpm for mixing.

[0151] ③Hot melt extrusion granulation

[0152] Hot melt extrusion: Use a pilot scale-up device with a screw diameter of 27 mm to set the extrusion parameters according to Table 14. Take the premixed raw materials and add them to the hot melt extruder manually. Adjust the feeding speed and the extrusion screw speed to match the feeding speed with the discharge speed.

[0153] Table 14 Extrusion parameters of hot melt extruder 2

[0154]

[0155]

[0156] ④ Crushing

[0157] Take the material after hot melt extrusion and cooling, use a granulator to granulate it, and pass the granules after secondary granulation through a 40-mesh sieve.

[0158] ⑤ Final mixing

[0159] According to the weight after crushing, weigh silicified microcrystalline cellulose SMCC90 (additional), mannitol M100 (additional), cross-linked polyvinylpyrrolidone XL-10 (additional) and sodium stearyl fumarate (additional) according to the prescription, and mix them using a laboratory mixer at a mixing speed of 20 rpm and a mixing time of 15 minutes. After the final mixing, the drying loss of the particles should be ≤5.0%, and the content should be 90.0% to 110.0% of the labeled content.

[0160] ⑥ Tablet pressing

[0161] The weight difference of individual tablets was controlled within ±7.5%, and the average weight difference was controlled within ±5.0%.

[0162] The embodiments of the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core idea. At the same time, changes or deformations made by those skilled in the art based on the ideas of the present invention, the specific implementation methods and application scope of the present invention, all belong to the scope of protection of the present invention. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A pharmaceutical composition comprising a benzonitrile derivative, characterized in that: The pharmaceutical composition comprises the following components: (a) Compound of formula (I) and (b) polyvinylpyrrolidone; wherein component (a) and component (b) are mixed and subjected to hot melt extrusion; The weight ratio of the component (b) to the component (a) is 5-20.

2. The pharmaceutical composition according to claim 1, characterized in that The composition further comprises component (c), wherein the component (c) is a polymer excipient and / or a non-polymer excipient; Preferably, the polymer excipient is selected from one or more of polyethylene glycol, polyoxyethylene and polyvinyl alcohol; Preferably, the polymer excipient is polyethylene glycol; Preferably, the non-polymer material comprises a pharmaceutically acceptable pharmaceutical excipient and / or a non-volatile weak acid, a neutral or weakly acidic inorganic substance; Preferably, the pharmaceutically acceptable excipient is a pharmaceutically acceptable excipient having a melting point below 80°C; More preferably, the pharmaceutically acceptable excipient having a melting point below 80°C comprises a lipid material, an antioxidant and / or a surfactant; Preferably, the lipid material is selected from one or more of the following: triethyl citrate, medium chain triglycerides, acetylated triethyl citrate, monolinolein, propylene glycol dicaprylate, monoolein, diethylene glycol monoethyl ether, myristyl alcohol, hydrogenated castor oil, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, stearic acid, palmitic acid, palmitostearyl alcohol, polyglycerol oleate, monoolein, monostearin, distearin, disalmitostearin and behenin; Preferably, the antioxidant is 2,6-di-tert-butyl-p-cresol and / or vitamin E; Preferably, the surfactant is selected from one or more of the following: 15-hydroxystearate polyethylene glycol ester ( HS15), poloxamer 188, poloxamer 407, sodium lauryl sulfate, oleic acid macrogol glyceride (LabrafacTM lipophile WL1349), propylene glycol monocaprylate, propylene glycol monolaurate, lauric acid macrogol glyceride ( 44 / 14), stearic acid macrogol glyceride ( 50 / 13), Caprylic / caprylic acid macrogol glyceride Sorbitan fatty acid esters (Span), sorbitan fatty acid ester polyoxyethylene ether (Tween), vitamin E polyethylene glycol succinate.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature ranging from 110° C. to 160° C.; Preferably, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 110°C to 150°C; Preferably, the component (a) and the component (b) are mixed and subjected to hot melt extrusion at a temperature range of 120°C to 140°C; More preferably, the polyvinyl pyrrolidone is polyvinyl pyrrolidone VA64; More preferably, the polyethylene glycol is selected from one or more of the following: polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000; Preferably, the weight ratio between the component (b) and the component (a) is 8 to 18; Also preferably, the weight ratio between the component (b) and the component (a) is about 10 or about 15; Preferably, the weight ratio between the component (b) and the component (c) is 15 to 32; Also preferably, the weight ratio between the component (b) and the component (c) is about 20 or about 30; More preferably, the weight ratio between the component (a), the component (b) and the component (c) is about 1:(6-16):about 0.5; More preferably, the weight ratio between the component (a), the component (b) and the component (c) is about 1:(8-12):about 0.5; More preferably, the weight ratio between the component (a), the component (b) and the component (c) is about 1: about 10: about 0.

5.

4. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises 50% to 90% by weight of one or more of the following excipients: a filler, a disintegrant, and a lubricant, based on the total weight of the pharmaceutical composition; Preferably, the pharmaceutical composition further comprises 40% to 80% by weight of a filler based on the total weight of the pharmaceutical composition; Preferably, the filler is mannitol and / or silicified microcrystalline cellulose, such as mannitol M100 and / or silicified microcrystalline cellulose SMCC90; Preferably, the pharmaceutical composition further comprises 5% to 15% by weight of a disintegrant, based on the total weight of the pharmaceutical composition; Preferably, the disintegrant is crospovidone, such as crospovidone XL-10; Preferably, the pharmaceutical composition further comprises 0.5% to 8% by weight of a lubricant based on the total weight of the pharmaceutical composition; Preferably, the lubricant is sodium stearyl fumarate.

5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The dosage form of the pharmaceutical composition is an oral preparation; Preferably, the oral preparation is a tablet, granule or capsule; More preferably, the pharmaceutical composition further comprises one or more drugs and / or extracts; Also preferably, the drug is an antiviral infection drug, an anticancer drug and / or an anti-acne drug.

6. A method for preparing the pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: (1) mixing the sieved components (a), (b) and (c) to obtain a mixture; (2) extruding the mixture by hot melt extrusion at a hot melt extrusion temperature of 110° C. to 160° C. to form an extrudate; (3) cooling the extrudate; and (4) The cooled extrudate is crushed and sieved to obtain granules of the pharmaceutical composition.

7. The method according to claim 5, characterized in that The method further comprises the following steps: (5) mixing and drying the granules with one or more sieved pharmaceutically acceptable excipients to form tablets or capsules; Preferably, the component (b) is polyvinyl pyrrolidone; Preferably, the component (c) is polyethylene glycol; Preferably, the pharmaceutically acceptable excipient is selected from one or more of the following: a filler, a disintegrant and a lubricant; More preferably, the filler is mannitol and / or silicified microcrystalline cellulose, such as mannitol M100 and / or silicified microcrystalline cellulose SMCC90; More preferably, the disintegrant is crospovidone, such as crospovidone XL-10; More preferably, the lubricant is sodium stearyl fumarate; Preferably, in step (2), the mixture is extruded using a hot melt extrusion device to form an extrudate, wherein the screw diameter of the hot melt extrusion device is between 5 mm and 50 mm, and the extrusion speed is between 10 rpm and 300 rpm; Preferably, the screw diameter of the twin-screw hot melt extruder is 5 mm to 40 mm, for example, about 8 mm, about 18 mm, about 27 mm, about 30 mm; Also preferably, the extrusion speed is 50 rpm to 150 rpm, for example, about 100 rpm; Particularly preferably, steps (1) to (5) of the method include any one or more of the following items [1] to [11]: [1] The sieve in step (1) is a 30-mesh sieve or a 40-mesh sieve; [2] The mixing in step (1) is performed manually or mechanically; [3] The mixing time in step (1) is 5 min to 15 min, for example about 10 min; [4] The temperature of zone 1 of the extruder in step (2) is room temperature; [5] The temperature of the heating zone of the extrusion device in step (2) is 110°C to 160°C, for example, about 120°C to 140°C; [6] The die temperature of the extruder in step (2) is 115°C to 135°C, for example, about 125°C; [7] The torque of the extrusion device in step (2) is not more than 6.0 Nm; [8] The sieve in step (4) is a 20-50 mesh sieve, such as a 35 mesh sieve or a 40 mesh sieve; [9] The mixing time in step (5) is 10 min to 20 min, for example, about 15 min; [10] The mixing speed in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm; [11] The weight loss measurement result of drying in step (5) is not more than 5%.

8. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating a disease characterized by a disorder of the fatty acid synthase pathway; Preferably, the condition characterized by dysregulation of the fatty acid synthase pathway is a viral infection; More preferably, the viral infection is hepatitis C infection or a respiratory viral infection.

9. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating cancer or tumors.

10. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for preventing and treating acne.

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