A pharmaceutical composition comprising a benzonitrile derivative

Abstract

Disclosed is a pharmaceutical composition comprising a benzonitrile derivative, the pharmaceutical composition comprising the following components: (a) a compound of formula (I); and (b) polyvinylpyrrolidone; wherein 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 5-20. The pharmaceutical composition of the present application can be stably stored for a long time and has significantly better dissolution effect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically to a pharmaceutical composition comprising a benzonitrile derivative. Background Technology

[0002] The storage conditions of pharmaceutical products reflect their stability. Drugs or crystalline forms with lower melting points generally have relatively poor stability and require storage at lower temperatures, while those with higher melting points or crystalline forms have better stability and can generally be stored at room temperature. The optimal processing temperature for formulations should also be determined based on the thermal stability of the drug. The thermal degradation of drugs is usually closely related to their melting point, and degradation reactions occur rapidly above 20°C. Fatty liver and cancer both require long-term medication. The requirement for low-temperature storage will add considerable inconvenience to patients taking medication long-term and may lead to missed doses or improper storage, which may affect treatment efficacy and potentially delay or relapse of the disease. Furthermore, low-temperature refrigeration requires dedicated cold chain transportation vehicles and long-term refrigerators, which adds extra costs to the commercial development of the product. Therefore, to better meet clinical and commercial needs, it is necessary to find a stable pharmaceutical formulation and preparation method that can be stored at room temperature. Such a formulation will not only significantly increase the in vivo and in vitro solubility of the active ingredient, but more importantly, it will allow for storage at room temperature. The molecular formula of the compound shown in formula (I) is: C 24 H 24 N4O3, its structural formula is shown below:

[0003]

[0004] The equilibrium solubility of crystal form III and crystal form VI of the compound shown in formula (I) in different media without the addition of surfactant is shown in Table 1. This indicates that the equilibrium solubility of the active pharmaceutical ingredient of this compound is pH-dependent, and reasonable solubilization methods are required to increase its dissolution in vivo and in vitro.

[0005] Table 1 shows the equilibrium solubility of the compounds represented by formula (I) in media with different pH values.

[0006]

[0007]

[0008] Furthermore, the compound shown in formula (I) is slightly unstable at a high temperature of 60°C, and after 15 days of accelerated reaction, the total impurities increase by 0.31%. The excipient polyethylene glycol 6000 is unstable for GL01 at high temperatures. Specifically, after 15 days of accelerated reaction at 60°C, the total impurities may increase by 2.9%, with a significant increase in related substances. This is because polyethylene glycol 6000 has a low melting point (DSC results show that the melting point of polyethylene glycol 6000 is 58.6°C). After 15 days of accelerated reaction at 60°C, polyethylene glycol 6000 is semi-solid. It may undergo a condensation reaction with the compound shown in formula (I) at high temperatures, condensing with the hydroxyl groups and secondary amines therein to form unknown impurities.

[0009] Therefore, there is still a need to develop a formulation that will allow pharmaceutical compositions containing compounds of formula (I) to be stored stably for extended periods at temperatures of 25°C to 60°C and at high relative humidity, and will have significantly better dissolution performance. Summary of the Invention

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

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

[0012] and

[0013] (b) Polyvinylpyrrolidone;

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

[0015] Further, the composition further comprises component (c), wherein component (c) is a polymeric excipient and / or a non-polymeric excipient. Further, the polymeric excipient is selected from one or more of polyethylene glycol, polyethylene oxide, and polyvinyl alcohol. Further, the polymeric excipient is polyethylene glycol. Further, the non-polymeric material includes pharmaceutically acceptable pharmaceutical excipients and / or non-volatile weakly acidic, neutral, or weakly acidic inorganic substances. Further, the pharmaceutically acceptable pharmaceutical excipient is a pharmaceutically acceptable excipient with a melting point below 80°C. Further, the pharmaceutically acceptable excipient with a melting point below 80°C includes lipid materials, antioxidants, and / or surfactants. Further, the lipid material is selected from one or more of the following: triethyl citrate, medium-chain triglycerides, acetylated triethyl citrate, glyceryl monolinoleate, propylene glycol didecanoate, glyceryl monooleate, diethylene glycol monoethyl ether, myristic acid, hydrogenated castor oil, cetyl alcohol, octadecyl alcohol, cetearyl alcohol, stearic acid, palmitic acid, palmistearyl alcohol, polyglyceryl oleate, glyceryl monooleate, glyceryl monostearate, glyceryl distearate, glyceryl dispalmitate stearate, and glyceryl behenate. 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: polyethylene glycol 15-hydroxystearate (… HS15), Poloxamer 188, Poloxamer 407, Sodium Lauryl Sulfate, Polyethylene Glyceryl Oleate (Labrafac™ Lipoophile WL1349), Propylene Glycol Monocaprylate, Propylene Glycol Monolaurate, Polyethylene Glyceryl Laurate (HS15), Poloxamer 188, Poloxamer 407, Sodium Lauryl Sulfate, Polyethylene Glyceryl Oleate ... 44 / 14), polyethylene glycol stearate ( 50 / 13), Caprylic / Capric acid PEG-Glyceryl ester Sorbitol fatty acid ester (Span), Sorbitol fatty acid ester polyoxyethylene ether (Tween), Vitamin E polyethylene glycol succinate.

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

[0017] Further, the polyvinylpyrrolidone is polyvinylpyrrolidone 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 of component (b) to component (a) is 8 to 18. Further, the weight ratio of component (b) to component (a) is about 10 or about 15. Further, the weight ratio of component (b) to component (c) is 15 to 32. Further, the weight ratio of component (b) to component (c) is about 20 or about 30. Further, the weight ratio of component (a), component (b), and component (c) is about 1:(6 to 16):about 0.5. Further, the weight ratio of component (a), component (b), and component (c) is approximately 1:(8-12):approximately 0.5. Further, the weight ratio of component (a), component (b), and component (c) is approximately 1:approximately 10:approximately 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 crospovidone, such as crospovidone 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 stearate fumarate. Further, the dosage form of the pharmaceutical composition is an oral formulation. Further, the oral formulation is a tablet, granule, or capsule.

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

[0020] According to another aspect of the present invention, a method for preparing the above-mentioned pharmaceutical composition is provided, the method comprising the following steps: (1) mixing components (a), (b) and (c) after sieving 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 includes the following steps: (5) mixing and drying the granules with one or more sieved pharmaceutically acceptable excipients to form tablets or capsules. Further, the pharmaceutically acceptable excipients are selected from one or more of the following: fillers, disintegrants, and lubricants. Further, component (b) is polyvinylpyrrolidone. Further, 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 crospovidone, such as crospovidone XL-10. Further, the lubricant is sodium stearate fumarate.

[0022] Further, in step (2), the mixture is extruded using a hot melt extrusion apparatus to form an extrudate, wherein the screw diameter of the hot melt extrusion apparatus 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 extrusion apparatus is 5 mm to 40 mm, for example, about 8 mm, about 18 mm, about 27 mm, or about 30 mm. Further, the extrusion speed is 50 rpm to 150 rpm, for example, about 100 rpm.

[0023] Further, 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 heating zone temperature 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 extrusion device 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 higher than 6.0 Nm; [8] The sieve in step (4) is a 20 to 50 mesh sieve, for example, a 35 mesh 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 of drying in step (5) is not higher than 5%.

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

[0025] The beneficial effects of this invention are:

[0026] This invention employs a process of preparing a solid dispersion via hot melt extrusion, followed by pulverization, mixing with added excipients, and tableting. Research has found that using a certain proportion of polyvinylpyrrolidone as a solid dispersion carrier material in the formulation helps to rapidly improve the dissolution and stability of the compound of formula (I). Specifically, the pharmaceutical composition of this invention containing the compound of formula (I) can be stored stably for a long time and has significantly better dissolution performance. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without exceeding the scope of protection claimed by the present invention.

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

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

[0030] Figure 3 The diagram shows the dissolution results of the formulations of this invention in batches YF6021008, YF6021010, and YF6021007.

[0031] Figure 4 This is a schematic diagram of the XRPD results of the hot melt extruded product of the present invention after 0 days.

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

[0033] Figure 6This is a schematic diagram showing the dissolution results of 10 mg tablets and capsules of the present invention under a pH 6.8 dissolution method. Detailed Implementation

[0034] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

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

[0036] This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances.

[0037] The singular forms “a,” “an,” and “the” used in the specification and appended claims include plural indicators unless the context clearly specifies otherwise.

[0038] In this invention, the term "comprising" and "including" are synonymous. The terms "comprising," "including," "having," "containing," or any other variations thereof as used herein are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0039] As described in the background section, the compound represented by formula (I) (hereinafter referred to as "GL01") exhibits pH-dependent equilibrium solubility and suffers from poor stability and increased impurities under relatively high temperature conditions. To address these issues, 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] Components (a) and (b) are mixed and subjected to hot melt extrusion; wherein the weight ratio of component (b) to component (a) is 5 to 20.

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

[0045] In this invention, when a weight ratio, weight parts, temperature, speed, diameter, time, pressure, frequency, proportion, equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range "5 to 20" is disclosed, the described range should be interpreted as including 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 stated, the range is intended to include its endpoints and all values ​​to two decimal places within the range, and the effects of the invention can be achieved within the aforementioned range.

[0046] In a preferred embodiment, the composition further comprises component (c), wherein component (c) is a polymeric excipient and / or a non-polymeric excipient. In a preferred embodiment, the polymeric excipient is selected from one or more of polyethylene glycol, polyethylene oxide, and polyvinyl alcohol. In a preferred embodiment, the polymeric excipient is polyethylene glycol. In a preferred embodiment, the non-polymeric material comprises pharmaceutically acceptable excipients and / or non-volatile weakly acidic, neutral, or weakly acidic inorganic substances. In a preferred embodiment, the pharmaceutically acceptable excipient is a pharmaceutically acceptable excipient with a melting point below 80°C. In a preferred embodiment, the pharmaceutically acceptable excipient with a melting point below 80°C comprises lipid materials, antioxidants, and / or surfactants. In a preferred embodiment, the lipid material is selected from one or more of the following: triethyl citrate, medium-chain triglycerides, acetylated triethyl citrate, glyceryl monolinoleate, propylene glycol didecanoate, glyceryl monooleate, diethylene glycol monoethyl ether, myristol, hydrogenated castor oil, cetyl alcohol, octadecyl alcohol, cetearyl alcohol, stearic acid, palmitic acid, palmitosterol, polyglyceryl oleate, glyceryl monooleate, glyceryl monostearate, glyceryl distearate, glyceryl dispalmitate stearate, and glyceryl behenate. 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: polyethylene glycol 15-hydroxystearate (… HS15), Poloxamer 188, Poloxamer 407, Sodium Lauryl Sulfate, Polyethylene Glyceryl Oleate (Labrafac™ Lipoophile WL1349), Propylene Glycol Monocaprylate, Propylene Glycol Monolaurate, Polyethylene Glyceryl Laurate (HS15), Poloxamer 188, Poloxamer 407, Sodium Lauryl Sulfate, Polyethylene Glyceryl Oleate ... 44 / 14), polyethylene glycol stearate ( 50 / 13), Caprylic / Capric acid PEG-Glyceryl ester Sorbitol fatty acid ester (Span), Sorbitol fatty acid ester polyoxyethylene ether (Tween), Vitamin E polyethylene glycol succinate.

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

[0048] In a preferred embodiment, polyvinylpyrrolidone is polyvinylpyrrolidone VA64. In a preferred embodiment, 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 of component (b) to component (a) is 8 to 18. In a preferred embodiment, the weight ratio of component (b) to component (a) is about 10 or about 15. In a preferred embodiment, the weight ratio of component (b) to component (c) is 15 to 32. In a preferred embodiment, the weight ratio of component (b) to component (c) is about 20 or about 30. Further, the weight ratio of component (a), component (b), and component (c) is about 1:(6 to 16):about 0.5. Further, the weight ratio of component (a), component (b), and component (c) is approximately 1:(8-12):approximately 0.5. Further, the weight ratio of component (a), component (b), and component (c) is approximately 1:approximately 10:approximately 0.5.

[0049] In this document, a range can be expressed as "about" a particular value, and / or "about" another particular value. When expressing such a range, another implementation includes from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximation, it will be understood, by using the antecedent "about," that the particular value forms another implementation. It will be further understood that each endpoint of a range is significant relative to and independently of another endpoint. It should also be understood that many values ​​are disclosed herein, and each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It should also be understood that when "less than or equal to" the value, "greater than or equal to" the value, the possible range between these values ​​is also disclosed, as properly 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 this 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; and "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: fillers, disintegrants, and lubricants, based on the total weight of the pharmaceutical composition.

[0052] In this invention, the term "pharmaceutically acceptable" means a substance, such as a carrier or diluent, that does not destroy the biological activity or properties of a compound and is relatively non-toxic, such that, when administered to an individual, it will not cause unwanted biological effects or interact with any of its constituent components in a harmful manner.

[0053] In this invention, the term "pharmaceuticalally acceptable excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient (i.e., capable of eliciting the desired therapeutic effect without causing any undesirable local or systemic effects), which is 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 crospovidone, such as crospovidone 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 stearate fumarate.

[0055] The excipients mentioned above are preferably drug-inert, or may have synergistic or enhancing effects to enhance the therapeutic activity of the drug composition. The excipients mentioned above are merely examples, and the excipients actually used in this invention are not limited to the above excipients. They can be adjusted according to the actual situation to achieve the effects of this invention.

[0056] In a preferred embodiment, the pharmaceutical composition is in the form of an oral formulation. In another preferred embodiment, the oral formulation 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 drug, an anticancer drug, and / or an antiacne drug.

[0058] According to another aspect of the present invention, a method for preparing the above-mentioned pharmaceutical composition is provided, the method comprising the following steps: (1) mixing components (a), (b) and (c) after sieving 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 includes the step of: (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 excipient is selected from one or more of the following: fillers, disintegrants, and lubricants. In a preferred embodiment, component (b) is polyvinylpyrrolidone. In a preferred embodiment, 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 crospovidone, such as crospovidone XL-10. In a preferred embodiment, the lubricant is sodium stearate fumarate.

[0060] In a preferred embodiment, in step (2), the mixture is extruded using a hot melt extrusion apparatus to form an extrudate, wherein the screw diameter of the hot melt extrusion apparatus 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 apparatus is 5 mm to 40 mm, for example, about 8 mm, about 18 mm, about 27 mm, or about 30 mm. In a preferred embodiment, the extrusion speed is 50 rpm to 150 rpm, for example, 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 heating zone temperature 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 extrusion device 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 higher than 6.0 Nm; [8] The sieve in step (4) is a 20 to 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 of drying in step (5) is not higher than 5%.

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

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

[0064] In this invention, the term "prevention" includes both "treatment" and "prevention" unless specifically stated otherwise. The terms "therapeutic" and "therapeutic" should be understood accordingly. In this invention, the term "treatment" includes alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications caused by a disease or symptom; or preventing or treating signs caused by a disease or symptom. As used herein, a pharmaceutical composition or pharmaceutical preparation, upon administration, may improve a disease, symptom, or condition, particularly by improving its severity, delaying onset, slowing disease progression, or reducing the duration of the condition. Whether the administration is fixed or intermittent, continuous or intermittent, it may be attributable to or related to the administration.

[0065] According to another aspect of the present invention, a pharmaceutical composition is provided for the prevention and / or treatment of a condition in a subject characterized by dysregulation of the fatty acid synthase pathway. According to another aspect of the present invention, a pharmaceutical composition is provided for the prevention and / or treatment of cancer or tumor in a subject. According to another aspect of the present invention, a pharmaceutical composition is provided for the prevention and / or treatment of acne in a subject. According to another aspect of the present invention, a method for the prevention and / or treatment of a condition in a subject characterized by dysregulation of the fatty acid synthase pathway is provided, comprising administering an effective amount of the pharmaceutical composition to the subject. According to another aspect of the present invention, a method for the prevention and / or treatment of cancer or tumor in a subject is provided, comprising administering an effective amount of the pharmaceutical composition to the subject. According to another aspect of the present invention, a method for the prevention and / or treatment of acne in a subject is provided, comprising administering an effective amount of the pharmaceutical composition to the subject.

[0066] In this invention, the term "subject" refers to a mammal. A mammal can be a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects representing viral infection models, cancer models, tumor models, or acne models. Preferably, the subject is a human. The "effective amount" of the pharmaceutical composition or formulation used in this invention can achieve the desired therapeutic and / or preventative effects. The effective amount for this purpose will depend on, for example, the pharmaceutical composition, the route of administration, the stage and severity of the disease being treated, the individual's weight and overall health status, and the judgment of the prescribing physician. Dosage can be administered once a week, every two days, or daily, or even several times a day. Dosage units can be administered over a short period (e.g., weeks to months) or a longer period (months to years).

[0067] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0068] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0069] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0070] Example

[0071] 1. Screening of solubilizing excipients

[0072] This invention uses the improvement of GL01's dissolution rate in various dissolution media as an evaluation index to screen the types of solubilizing excipients.

[0073] Considering that the solubility of GL01 active pharmaceutical ingredient is pH dependent, the solubilizing effect of several common solubilizing excipients on GL01 was investigated. They were prepared according to Table 2 and added to 250 ml of pH 6.8 phosphate buffer solution. The mixture was shaken in a constant temperature shaker at 37°C and samples were taken at 2 hours and 24 hours. The percentage of GL01 dissolved is shown in Table 2.

[0074] Table 2. Study on the solubilizing effect of several common solubilizing excipients on GL01.

[0075]

[0076]

[0077] As shown in Table 2, compared to other excipients, polyvinylpyrrolidone VA64 (trade name: VA64 significantly improves the solubility of GL01 in pH 6.8 phosphate buffer. Polyvinylpyrrolidone VA64 (trade name: VA64) was selected. VA64) and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (trade name: VA64) To conduct subsequent experiments.

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

[0079] Method 1: Normally, drugs are transported through the human gastrointestinal tract first through the stomach (pH approximately 1.0-4.5), then to the small intestine (pH approximately 4.5-6.8) for absorption. To more accurately reflect the dissolution of GL01 in vivo, this invention employs more stringent dissolution conditions. Specifically, referring to Method 1 of the Dissolution and Release Determination Method for Enteric-coated Formulations in Part IV, 0931 of the 2020 edition of the Chinese Pharmacopoeia, the following procedure was followed: 750 ml of pH 1.0 hydrochloride buffer was stirred at 75 rpm for 1 hour, then 250 ml of sodium phosphate solution was added to adjust the pH to 6.8 before conducting the dissolution test (hereinafter referred to as the pH 1.0 followed by pH 6.8 dissolution method).

[0080] Method 2: As shown in Table 1, the equilibrium solubility of GL01 is relatively low at pH 6.8. This pH condition corresponds to the small intestine, the site of absorption in vivo, and is therefore representative. The specific procedure followed the paddle method, Part II, General Chapter 0931, Dissolution and Release Determination, of the Chinese Pharmacopoeia 2020. The medium was pH 6.8 phosphate buffer, hence this condition was chosen for the dissolution test (hereinafter referred to as the pH 6.8 dissolution method).

[0081] To improve the ability to distinguish dissolution conditions, a relatively stringent rotation speed of 50 rpm was selected for all rotations.

[0082] The preparation of 10mg GL01 formulations with different solubilizing excipients and different processes were investigated. The formulations and processes are shown in Tables 3 and 4.

[0083] Table 3. 10mg GL01 formulations prepared using different solubilizing excipients and different processes 1-3

[0084]

[0085]

[0086] Table 4. 10mg GL01 formulations prepared using different solubilizing excipients and processes 4-6

[0087]

[0088] Dissolution studies were conducted on the formulation prepared according to the above prescription, and the results are as follows: Figure 1 and Figure 2 As shown in Tables 3 and 4 above, the leaching results indicate that the mixture of GL01, polyvinylpyrrolidone VA64, and polyethylene glycol 6000 exhibits significant leaching advantages after hot melt extrusion granulation. Therefore, further optimization studies on the hot melt extrusion process and its formulation are warranted.

[0089] In addition, although the typical crystal forms III and VI of GL01 API have relatively high equilibrium solubility in hydrochloric acid solutions at pH 1.0 and pH 2.0 after 48 hours (as shown in Table 1), the dissolution data of GL01 API directly into capsules show that the dissolution rate of GL01 is relatively low. In the dissolution test at 2-3 hours, it failed to dissolve completely.

[0090] 3. Determination of the formulation and process of solid dispersions

[0091] The compatibility results of the raw materials and excipients revealed that polyvinylpyrrolidone (VA64) and GL01 were stable under various conditions. This invention attempts to add a small amount of polyethylene glycol 6000 to the VA64 carrier to lower the glass transition temperature (Tg) of the solid dispersion, thereby reducing the hot melt extrusion temperature, as excessively high hot melt extrusion temperatures may lead to degradation of the active pharmaceutical ingredient. Comparing the effect of polyethylene glycol 6000 addition on the hot melt extrusion effect, the results showed that with increasing polyethylene glycol 6000 dosage, the extrudate gradually changed from clear and transparent to cloudy and opaque, eventually becoming an opaque waxy substance. The transparency of the extruded material was used as the criterion for determining whether a solid dispersion had been successfully formed.

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

[0093] Table 5. Exploration of Formulation Ratios and Process Parameters for Hot Melt Extrusion of GL01

[0094]

[0095]

[0096] The feasibility study of the process revealed the following:

[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 will be opaque and the torque will be too large, and the equipment will not be able to operate normally. (2) When API and polyvinylpyrrolidone VA64 are prepared in a weight ratio of 1:5, 1:10, and 1:15, and 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 polyethylene glycol 6000 is added in excess, the extrudate will be opaque. In YF6021009, the ratio of polyvinylpyrrolidone VA64 to polyethylene glycol 6000 is 10:1, and the extrudate is found to be not completely transparent. The final study found that the ratio of polyvinylpyrrolidone VA64 to polyethylene glycol 6000 is more suitable in the range of 20:1 to 30:1. (3) The feasible screw speed is 20~150rpm.

[0098] Evaluation of quality control indicators:

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

[0100] API and polyvinylpyrrolidone VA64 were mixed at weight ratios of 1:5, 1:10, and 1:15, and then an appropriate amount of polyethylene glycol 6000 (batch numbers YF6021008, YF6021010, and YF6021007) was added. The successfully prepared GL01 solid dispersion was cooled and pulverized. Powder with a particle size of less than 35 mesh (500 μm) was weighed and mixed with the excipients according to the formulation in Table 6. Tablets were then prepared, and the results were used for dissolution curve comparison. Figure 3 As shown.

[0101] Table 6. Prescriptions for batches YF6021007, YF6021008, and YF6021010 of GL01 tablets.

[0102]

[0103]

[0104] Dissolution results showed that Formulation 10 (batch number YF6021010), with an API:VA64:PEG 6000 ratio of 1:10:0.5, had good dissolution ability. Formulation 7 (batch number YF6021007) may have had its dissolution affected due to excessively high amounts of VA64, which exhibited excessive viscosity during disintegration. Formulation 8 (batch number YF6021008) may have had its dissolution affected due to insufficient amounts of VA64, which was not enough to completely dissolve GL01.

[0105] (2) Study on the crystal transformation risk of amorphous active pharmaceutical ingredients in hot melt extruded solid dispersions:

[0106] GL01 formulation consists of an amorphous solid dispersion powder obtained through hot melt extrusion, cooling, and grinding, along with added silanized microcrystalline cellulose SMCC90, mannitol M100, crospovidone XL-10, and sodium stearate fumarate. In tablets, GL01 exists only in the solid dispersion powder. Therefore, studying the amorphous solid dispersion powder can effectively eliminate interference from added excipients and improve the sensitivity of detection.

[0107] Accelerated solid dispersion powder under humid and hot conditions, along with the supply of water molecules and external energy, increases the loosening of the copovidone polymer chains, thereby increasing the activity of the drug or excipient in the carrier system.

[0108] API and polyvinylpyrrolidone VA64 were mixed at weight ratios of 1:5, 1:10, and 1:15, and then an appropriate amount of polyethylene glycol 6000 (batch numbers YF6021008, YF6021010, and YF6021007) was added. The successfully prepared GL01 solid dispersion was cooled and then pulverized. The stability of the GL01 morphology in the solid dispersion was investigated under multiple accelerated 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 extruded products are all in an amorphous state.

[0110] In summary, using hot melt temperature, extruder torque, screw speed, and extrudate transparency as process evaluation indicators, and the solubilizing effect of solid dispersion on GL01 during the dissolution process, the degradation of related substances, and the risk of amorphous crystallization of GL01 as quality control evaluation indicators, the optimal formulation was determined to be GL01:polyvinylpyrrolidone VA64:polyethylene glycol 6000 in a weight ratio of 1:10:0.5, which can obtain hot melt extrudates with controllable quality and stable process.

[0111] 4. Confirmation of tablet formulation process

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

[0113] Table 7. Composition of Unit Dosage Formula for 10mg GL01 Tablets

[0114]

[0115] Dissolution profiles of tablets (10mg tablets: batch YF6021015-10) prepared using the optimized formulation process were studied in various dissolution media. The results in different media are shown in Tables 8-11. These results indicate that the 10mg tablets dissolved more than 85% within 15 minutes in all four dissolution media under low rotation speed (50 rpm) without any surfactants, demonstrating good in vitro rapid dissolution performance.

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

[0117]

[0118]

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

[0120]

[0121] Table 1. Summary of dissolution results of 10GL01 tablets (10mg) 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 experimental study of the formulation and manufacturing process of the tablets in beagle dogs.

[0127] This study aimed to compare the effects of different dosage forms of GL01 administered orally to beagle dogs on pharmacokinetics, and the results are shown in Table 12. The experiment involved three beagle dogs, administered 0.5 mg / kg intravenously, 10 mg / tablet / dog orally, and 10 mg / capsule / dog orally, in a single-dose cycle of 7 days.

[0128] Table 12 Results of a comparative study of oral PO and IV administration of 10mg tablets and 10mg capsules in beagle dogs

[0129]

[0130]

[0131] The 10mg tablets (batch number YF6021015-10) are listed in Table 7 for the unit dose formulation of 10mg GL01 tablets; the GL01 capsules (batch number YF60JN001) formulation information is listed in Table 4 for 10mg GL01 preparations made with different solubilizing excipients and different processes.

[0132] The results above show that: (1) the average bioavailability of 10mg tablets is 60.3% and the average exposure is 6815hr*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 1431hr*ng / mL, indicating that the absorption of the capsule formulation is significantly lower than that of the tablets. The bioavailability of 10mg capsules is only about 1 / 5 of that of 10mg tablets, which is significantly different (p<0.01). (3) GL01 is metabolized slowly in beagle dogs and has a longer half-life.

[0133] 6. Screening of dissolution conditions with differentiating strength for 10mg GL01 formulations.

[0134] In vivo studies in beagle dogs revealed that the bioavailability of 10mg capsules was only about 1 / 5 that of 10mg tablets. Dissolution behavior of GL01 tablets and capsules was investigated using two methods: pH 6.8 phosphate buffer and more stringent dissolution conditions (pH 1.0 followed by pH 6.8). The results are as follows... Figure 5 and Figure 6 As shown, the dissolution curves of 10mg GL01 tablets and capsules under pH 6.8 phosphate buffer conditions more accurately reflect the difference in bioavailability between the two in beagle dogs. Furthermore, at 30–45 min, the dissolution rate of 10mg GL01 tablets and capsules under pH 6.8 phosphate buffer conditions matched their bioavailability, and the dissolution rate of 10mg capsules was approximately 1 / 5 that of 10mg tablets.

[0135] In summary, the determined dissolution conditions are: pH 6.8 phosphate buffer, 50 rpm; the evaluation criterion is greater than 75% after 45 minutes.

[0136] 7. Determination of tablet preparation process

[0137] ① Raw material pretreatment: Before batching, GL01 and polyethylene glycol 6000 are passed through a 40-mesh sieve, while polyvinylpyrrolidone VA64, siliconized microcrystalline cellulose SMCC90, mannitol M100, crospovidone XL-10 and sodium stearate are passed through a 30-mesh sieve to remove caking during storage.

[0138] ② Premix: Mix GL01, polyvinylpyrrolidone VA64 and polyethylene glycol 6000 by hand in a resealable bag for 10 minutes;

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

[0140] Table 13 Extrusion parameters of hot melt extruder

[0141]

[0142] ④ Final Mixing: Based on the weight of the pulverized particles, weigh out the following according to the formula: siliconized microcrystalline cellulose SMCC90 (added), mannitol M100 (added), crospovidone XL-10 (added), and sodium stearate fumarate (added). Mix using a laboratory mixer at 20 rpm for 15 minutes. The final mixed particles should have a drying loss of ≤5.0%, and the GL01 content should be 90.0%–110.0% of the labeled content.

[0143] ⑤ Tableting: Tableting with a Xinma S60 tablet press. For GL01 tablets, the weight difference per tablet should be controlled within ±7.5%, and the average tablet weight difference within ±5.0%.

[0144] 10mg specification: hardness range 4-10kp, disintegration time requirement is complete disintegration within 15 minutes;

[0145] ⑥ Packaging: Both sizes of tablets are packaged in bottles of 30 tablets each, using high-density polyethylene bottles. Store in a sealed container at room temperature (below 30℃).

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

[0147] ① Raw material pretreatment

[0148] Before mixing, the raw and auxiliary materials are sieved through a 60-mesh sieve to remove any lumps that may have formed during storage.

[0149] ②Premixed

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

[0151] ③ Hot melt extrusion granulation

[0152] Hot melt extrusion: Using a pilot-scale equipment with a 27mm screw diameter, set the extrusion parameters according to Table 14. Take a uniformly premixed raw and auxiliary material and manually add it to the hot melt extruder. 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 II

[0154]

[0155]

[0156] ④ Crushing

[0157] Take the material after hot melt extrusion and cooling, and granulate it using a granulator. After secondary granulation, the particles are passed through a 40-mesh sieve.

[0158] ⑤ Final Mixing

[0159] Based on the weight of the pulverized material, weigh out the following according to the prescription: siliconized microcrystalline cellulose SMCC90 (added), mannitol M100 (added), crospovidone XL-10 (added), and sodium stearate fumarate (added). Mix using a laboratory mixer at 20 rpm for 15 minutes. The final granules should have a drying loss of ≤5.0% and a content of 90.0%–110.0% of the labeled content.

[0160] ⑥ Tableting

[0161] The weight difference of a single tablet should be controlled within ±7.5%, and the average weight difference should be controlled within ±5.0%.

[0162] The embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, any changes or modifications made by those skilled in the art based on the ideas of the present invention, its specific implementation methods, and its application scope, are all within the scope of protection of the present invention. Therefore, the content of this specification should not be construed as a limitation of 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) （I）； (b) Polyvinylpyrrolidone; and (c) Polyethylene glycol; Components (a), (b), and (c) are mixed and subjected to heated melt extrusion; The weight ratio of component (b) to component (a) is 5 to 20. The weight ratio of component (b) to component (c) is 20 to 30.

2. The pharmaceutical composition according to claim 1, characterized in that, The composition further comprises polymeric excipients and / or non-polymeric excipients.

3. The pharmaceutical composition according to claim 2, characterized in that, The polymer additives are selected from one or more of polyethylene oxide and polyvinyl alcohol.

4. The pharmaceutical composition according to claim 2, characterized in that, The non-polymer materials include pharmaceutically acceptable pharmaceutical excipients and / or non-volatile weakly acidic, neutral, or weakly acidic inorganic substances.

5. The pharmaceutical composition according to claim 4, characterized in that, The pharmaceutically acceptable pharmaceutical excipients are those with a melting point below 80°C.

6. The pharmaceutical composition according to claim 5, characterized in that, Pharmaceutically acceptable excipients with melting points below 80°C include lipid materials, antioxidants, and / or surfactants.

7. The pharmaceutical composition according to claim 6, characterized in that, The lipid material is selected from one or more of the following: triethyl citrate, medium-chain triglycerides, acetylated triethyl citrate, glyceryl monolinoleate, propylene glycol didecanoate, glyceryl monooleate, diethylene glycol monoethyl ether, myristol, hydrogenated castor oil, cetyl alcohol, octadecyl alcohol, cetyl octadecyl alcohol, stearic acid, palmitic acid, palmistearyl alcohol, polyglyceryl oleate, glyceryl monooleate, glyceryl monostearate, glyceryl distearate, glyceryl dispalmitate stearate, and glyceryl behenate.

8. The pharmaceutical composition according to claim 6, characterized in that, The antioxidant is 2,6-di-tert-butyl-p-cresol and / or vitamin E.

9. The pharmaceutical composition according to claim 6, characterized in that, The surfactant is selected from one or more of the following: 15-hydroxystearic acid polyethylene glycol ester (Kolliphor). ® HS15), Poloxamer 188, Poloxamer 407, Sodium Lauryl Sulfate, Polyethylene Glyceryl Oleate (Labrafac™ Lipoophile WL1349), Propylene Glycol Monocaprylate, Propylene Glycol Monolaurate, Polyethylene Glyceryl Laurate (Gelucire) ® 44 / 14), glyceryl stearate (Gelucire) ® 50 / 13), Caprylic / Capric Polyethylene Glyceryl Acetate (Labrasol) ® ), Sorbitol fatty acid ester (Span), Sorbitol fatty acid ester polyoxyethylene ether (Tween), Vitamin E polyethylene glycol succinate.

10. The pharmaceutical composition according to claim 1, characterized in that, The components (a), (b), and (c) are mixed and subjected to heat-melt extrusion at a temperature range of 110°C to 160°C.

11. The pharmaceutical composition according to claim 10, characterized in that, The components (a), (b), and (c) are mixed and subjected to heat-melt extrusion at a temperature range of 110°C to 150°C.

12. The pharmaceutical composition according to claim 11, characterized in that, The components (a), (b), and (c) are mixed and subjected to heat-melt extrusion at a temperature range of 120°C to 140°C.

13. The pharmaceutical composition according to claim 1, characterized in that, The polyvinylpyrrolidone is polyvinylpyrrolidone VA64.

14. The pharmaceutical composition according to claim 1, characterized in that, The polyethylene glycol is selected from one or more of the following: polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000.

15. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of component (b) to component (a) is 8 to 18.

16. The pharmaceutical composition according to claim 15, characterized in that, The weight ratio of component (b) to component (a) is about 10 or about 15.

17. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio between component (b) and component (c) is 20 or 30.

18. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of component (a), component (b) to component (c) is approximately 1: approximately 10: approximately 0.

5.

19. The pharmaceutical composition according to claim 1, characterized in that, 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: fillers, disintegrants, and lubricants.

20. The pharmaceutical composition according to claim 19, characterized in that, The pharmaceutical composition further comprises 40% to 80% by weight of filler, based on the total weight of the pharmaceutical composition.

21. The pharmaceutical composition according to claim 19, characterized in that, The filler is mannitol and / or silicified microcrystalline cellulose.

22. The pharmaceutical composition according to claim 21, characterized in that, The filler is mannitol M100 and / or silicified microcrystalline cellulose SMCC90.

23. The pharmaceutical composition according to claim 19, characterized in that, The pharmaceutical composition further comprises 5% to 15% by weight of a disintegrant, based on the total weight of the pharmaceutical composition.

24. The pharmaceutical composition according to claim 19, characterized in that, The disintegrant is crospovidone.

25. The pharmaceutical composition according to claim 24, characterized in that, The disintegrant is crospovidone XL-10.

26. The pharmaceutical composition according to claim 19, characterized in that, The pharmaceutical composition further comprises 0.5% to 8% by weight of a lubricant based on the total weight of the pharmaceutical composition.

27. The pharmaceutical composition according to claim 19, characterized in that, The lubricant is sodium stearate fumarate.

28. The pharmaceutical composition according to any one of claims 1 to 18, characterized in that, The dosage form of the pharmaceutical composition is an oral preparation.

29. The pharmaceutical composition according to claim 28, characterized in that, The oral preparation is a tablet, granule, or capsule.

30. The pharmaceutical composition according to any one of claims 1 to 18, characterized in that, The pharmaceutical composition further comprises one or more drugs and / or extracts.

31. The pharmaceutical composition according to claim 30, characterized in that, The drugs mentioned are antiviral drugs, anticancer drugs, and / or antiacne drugs.

32. A method for preparing the pharmaceutical composition according to any one of claims 1 to 27, characterized in that, The method includes the following steps: (1) Mix the sieved components (a), (b), and (c) to obtain a mixture; (2) The mixture is extruded at a hot melt extrusion temperature of 110℃~160℃ to form an extrudate; (3) Cooling the extrudate; and (4) The cooled extrudate is crushed and sieved to obtain particles of the pharmaceutical composition.

33. The method according to claim 32, characterized in that, The method further includes the following steps: (5) The granules are mixed with one or more sieved pharmaceutically acceptable excipients and dried to form tablets or capsules.

34. The method according to claim 32, characterized in that, Component (b) is polyvinylpyrrolidone.

35. The method according to claim 32, characterized in that, The component (c) is polyethylene glycol.

36. The method according to claim 33, characterized in that, The pharmaceutically acceptable excipients are selected from one or more of the following: fillers, disintegrants, and lubricants.

37. The method according to claim 36, characterized in that, The filler is mannitol and / or silicified microcrystalline cellulose.

38. The method according to claim 37, characterized in that, The filler is mannitol M100 and / or silicified microcrystalline cellulose SMCC90.

39. The method according to claim 36, characterized in that, The disintegrant is crospovidone.

40. The method according to claim 39, characterized in that, The disintegrant is crospovidone XL-10.

41. The method according to claim 36, characterized in that, The lubricant is sodium stearate fumarate.

42. The method according to claim 32, characterized in that, In step (2), the mixture is extruded using a hot melt extrusion apparatus to form an extrudate, wherein the screw diameter of the hot melt extrusion apparatus is between 5 mm and 50 mm, and the extrusion speed is between 10 rpm and 300 rpm.

43. The method according to claim 42, characterized in that, The screw diameter of the twin-screw hot melt extrusion unit is 5mm~40mm.

44. The method according to claim 43, characterized in that, The screw diameter of the twin-screw hot melt extrusion device is approximately 8 mm, approximately 18 mm, approximately 27 mm, or approximately 30 mm.

45. The method according to claim 42, characterized in that, The extrusion speed is 50 rpm to 150 rpm.

46. ​​The method according to claim 45, characterized in that, The extrusion speed is approximately 100 rpm.

47. The method according to claim 33, characterized in that, 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 either manual or mechanical; [3] The mixing time in step (1) is 5 min to 15 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℃~160℃; [6] The die temperature of the extrusion device in step (2) is 115℃~135℃; [7] The torque of the extrusion device in step (2) is no higher than 6.0 Nm; [8] The sieve in step (4) is a 20-50 mesh sieve; [9] The mixing time in step (5) is 10 min to 20 min; [10] The mixing speed in step (5) is 15 rpm to 25 rpm; [11] The weight loss of drying in step (5) is no higher than 5%.

48. The method according to claim 47, characterized in that, The mixing time in step (1) is approximately 10 minutes.

49. The method according to claim 47, characterized in that, The temperature of the heating zone of the extrusion device in step (2) is about 120°C to 140°C.

50. The method according to claim 47, characterized in that, The die temperature of the extrusion device in step (2) is about 125°C.

51. The method according to claim 47, characterized in that, The sieve in step (4) is a 35-mesh sieve or a 40-mesh sieve.

52. The method according to claim 47, characterized in that, The mixing time in step (5) is approximately 15 minutes.

53. The method according to claim 47, characterized in that, The mixing speed in step (5) is approximately 20 rpm.

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