Pharmaceutical composition containing heterocyclic compounds

Abstract

The present invention discloses a pharmaceutical composition containing a heterocyclic compound. The pharmaceutical composition of the present invention comprises the following components: (a) Formula (I) [Case 1] The compound is represented by TIFF2026530133000025.tif27165 and (b) hypromellose acetate succinate or copovidone, and components (a) and (b) are mixed and subjected to hot melt extrusion, with a weight ratio of component (b) to component (a) being 0.4 to 0.8. The pharmaceutical composition disclosed by the present invention can be stored stably for a long period of time under room temperature and relatively high humidity conditions and has a remarkably excellent dissolving effect.

Description

[Technical Field]

[0001] The present invention relates to the technical field of pharmaceutical formulations, and more particularly to pharmaceutical compositions containing heterocyclic compounds. [Background technology]

[0002] The storage conditions for a pharmaceutical formulation reflect the stability of the raw materials it contains. If a drug or crystalline form has a low melting point, it generally has relatively low stability and requires storage at low temperatures. Conversely, if a drug or crystalline form has a high melting point, it is highly stable and can usually be stored at room temperature. The appropriate processing temperature for a formulation also needs to be reasonably determined based on the thermal stability of the raw materials. The thermal decomposition of a drug is usually closely related to its melting point; above 20°C, the decomposition reaction proceeds rapidly. Both fatty liver disease and cancer require long-term medication. The requirement for low-temperature storage poses a significant inconvenience for patients taking medication over extended periods, potentially leading to missed doses or improper storage, affecting treatment effectiveness, and potentially causing delayed or recurrent symptoms. Furthermore, low-temperature freezing conditions necessitate dedicated cold chain transport facilities and the long-term use of refrigerators, incurring additional costs for product commercialization. Therefore, to better meet clinical and commercial needs, it is necessary to find stable drug formulations and their preparation methods that can be stored at room temperature. Such formulations not only significantly improve the in vivo and in vitro solubility of the active ingredient, but, more importantly, enable storage at room temperature. The compound represented by formula (I), generic name denifanstat, is a potent, safe, and selective oral small molecule inhibitor of fatty acid synthase and has potential use in fatty liver and cancer research. Its chemical name is 4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-1H-1,2,4-triazole-3-yl)benzoyl]piperidine-4-yl]benzonitrile, and its molecular formula is C 27 H 29 N5O, its structural formula is as follows: [ka] The compound represented by formula (I) has low solubility in various media (pH = 1 to 7) and undergoes a phase transition under high relative humidity conditions.

[0003] Therefore, there remains a need to develop a pharmaceutical composition containing the compound of formula (I) that can be stored stably for a long period of time under room temperature and relatively high humidity conditions, and that also has a remarkably superior dissolving effect. [Overview of the project]

[0004] Based on this, the present invention provides a pharmaceutical composition comprising a heterocyclic compound, the pharmaceutical composition comprising the following components: (a) Compound of formula (I), [ka] (b) Hypromellose acetate succinate or copovidone Mix components (a) and (b), and then apply the mixture using a hot melt extrusion method or a spray drying method. The weight ratio of component (b) to component (a) is 0.4 to 0.8.

[0005] Furthermore, component (a) and component (b) are mixed and subjected to melt extrusion or spray drying at a temperature in the range of 145°C to 200°C. Furthermore, component (a) and component (b) are mixed and subjected to melt extrusion or spray drying at a temperature in the range of 155°C to 180°C. Furthermore, component (a) and component (b) are mixed and subjected to melt extrusion or spray drying at a temperature in the range of 155°C to 165°C. Furthermore, the hypromellose acetate succinate is HG grade hypromellose acetate succinate. Furthermore, the weight ratio of component (b) to component (a) is 0.5 to 0.7. Furthermore, the weight ratio of component (b) to component (a) is approximately 0.66.

[0006] Furthermore, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 50% to 70% by weight, for example, 55% to 65% by weight, of one or more pharmaceutically acceptable adjuvants, where the pharmaceutically acceptable adjuvants are selected from one or more of the following: water-soluble fillers, water-insoluble fillers, disintegrants, lubricants, and diluents. Furthermore, the water-soluble filler is mannitol, for example, mannitol M100. Furthermore, the water-insoluble filler is microcrystalline cellulose, for example, microcrystalline cellulose PH102. Furthermore, the disintegrant is croscarmellose sodium. Furthermore, the diluent is colloidal silicon dioxide, for example, colloidal silicon dioxide M5P. Furthermore, the diluent is magnesium stearate, for example, magnesium stearate 2257. Furthermore, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 30% to 35% by weight, for example, about 33% by weight, of water-soluble fillers. Furthermore, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 20% to 25% by weight, for example, about 22% by weight of a water-insoluble filler. Furthermore, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.2% to 1% by weight, for example, about 0.5% by weight of a disintegrant. Furthermore, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight, for example, about 1.5% by weight of a lubricant. Furthermore, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight, for example, about 1.5% by weight of a lubricant.

[0007] Furthermore, the dosage form of the pharmaceutical composition is a tablet, granule, or capsule. The pharmaceutical composition further comprises one or more drugs and / or extracts. The drugs are anti-fatty liver drugs, anticancer drugs, and / or anti-acne drugs.

[0008] According to another aspect of the present invention, a method for preparing the aforementioned pharmaceutical composition is provided, the method comprising: (1) mixing a sieved component (a) with a dried, pulverized, and sieved component (b) to obtain a mixture; (2) extruding the mixture by hot melt extrusion at a hot melt extrusion temperature of 145°C to 200°C to form an extruded product, or dissolving the mixture in an organic solvent such as ethanol or dichloromethane and spray-drying it; (3) cooling the extruded product or spray-dried product; and (4) pulverizing, sizing and sieving the cooled extruded product or spray-dried product to obtain granules of the pharmaceutical composition.

[0009] Furthermore, the method further comprises the step of (5) mixing the granules with one or more sieved pharmaceutically acceptable adjuvants, drying them, and processing them into tablets or capsules.

[0010] Furthermore, the mixing process involves first mixing the lubricant with a portion of the water-insoluble filler, then adding the granules, water-soluble filler, disintegrant, and the remaining water-insoluble filler for a second mixing, and finally adding the lubricant and mixing.

[0011] Furthermore, component (b) is HG grade hypromellose acetate succinate. Furthermore, the water-soluble filler is mannitol, for example, mannitol M100. Furthermore, the water-insoluble filler is microcrystalline cellulose, for example, microcrystalline cellulose PH102. Furthermore, the disintegrant is croscarmellose sodium. Furthermore, the lubricant is colloidal silicon dioxide, for example, colloidal silicon dioxide M5P. Furthermore, the lubricant is magnesium stearate, for example, magnesium stearate 2257.

[0012] Furthermore, a twin-screw thermal extruder is used to extrude the mixture of component (a) and component (b). The screw diameter of this twin-screw thermal extruder ranges from 8 mm to 50 mm, and the extrusion speed ranges from 10 rpm to 300 rpm. In addition, the screw diameter of the twin-screw thermal extruder is 18 mm. The extrusion speed is 75 rpm to 125 rpm, for example, about 100 rpm.

[0013] Furthermore, steps (1) to (5) of the method include one or more of the following items [1] to

[28] : [1] the drying loss in step (1) is 2% or less; [2] the drying temperature in step (1) is 55°C to 65°C, e.g., about 60°C; [3] the grinding speed in step (1) is 5000 rpm to 6000 rpm, e.g., about 5500 rpm; [4] the sieve in step (1) is 30 mesh or 40 mesh; [5] the mixing time in step (1) is 10 to 20 minutes, e.g., about 15 minutes [6] The mixing speed in step (1) is 15 to 25 rpm, for example, about 20 rpm; [7] The temperature of zone 1 of the extruder in step (2) is 70°C to 110°C, for example, about 90°C; [8] The temperature of zone 2 of the extruder in step (2) is 110°C to 150°C, for example, about 130°C; [9] The temperature of zone 3 of the extruder in step (2) is 155°C to 165°C, for example, about 160°C;

[10] The temperatures of zones 4 to 10 of the extruder in step (2) are 155°C to 165°C, for example, about

[11] The temperature of zone 11 of the extruder in step (2) is 140°C to 180°C, for example, about 160°C;

[12] The die temperature of the extruder in step (2) is 150°C to 170°C, for example, about 160°C;

[13] The melting pressure of the extruder in step (2) is 150 bar or less;

[14] The load pressure of the extruder in step (2) is 80% or less, for example, 25% to 65%;

[15] The cooling belt speed of the extruder in step (2) is 1 m / min to 10 m / min;

[16] Step (2 The processing speed of the extruder in step (4) is 0.1 kg / h to 10 kg / h;

[17] The opening diameter of the sieve for grinding in step (4) is approximately 2 mm;

[18] The grinding frequency in step (4) is 35 Hz to 45 Hz, for example, approximately 40 Hz;

[19] The grinding speed in step (4) is 5000 rpm to 6000 rpm, for example, approximately 5500 rpm;

[20] The rotational speed for particle size adjustment in step (4) is 5000 rpm to 6000 rpm, for example, approximately 5500 rpm;

[21] The opening diameter of the sieve for particle size adjustment in step (4) is approximately 0.is 8 mm;

[22] the sieve in step (4) is 40 mesh;

[23] the particle size of the granules in step (4) is 250 µm or less, for example from 100 µm to 250 µm;

[24] the duration of the first mixing in step (5) is 10 minutes to 20 minutes, for example about 15 minutes;

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

[26] the duration of the second mixing in step (5) is 2 minutes to 6 minutes, for example about 4 minutes;

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

[28] the measurement result of loss on drying in step (5) is 5% or less.

[0014] The present invention provides a pharmaceutical composition comprising a heterocyclic compound, and the pharmaceutical composition comprises the following components: (a) a compound of formula (I),

Chemical Formula

[0015] Here, the weight ratio of component (b) to component (a) is 0.4 to 0.8.

[0016] Further, the dispersion polymer is hypromellose acetate succinate or copovidone.

[0017] Further, component (a) and component (b) are mixed by a hot melt extrusion apparatus.

[0018] Further, component (a) and component (b) are mixed and subjected to hot melt extrusion or spray drying at a temperature in the range of 145°C to 200°C. Further, component (a) and component (b) are mixed and subjected to hot melt extrusion or spray drying at a temperature in the range of 155°C to 180°C. Further, component (a) and component (b) are mixed and subjected to hot melt extrusion or spray drying at a temperature in the range of 155°C to 165°C.

[0019] Further, hypromellose acetate succinate is an HG-grade hypromellose acetate succinate.

[0020] Further, the weight ratio of component (b) to component (a) is 0.5 to 0.7.

[0021] Further, the weight ratio of component (b) to component (a) is about 0.66.

[0022] Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 50% to 70% by weight, for example 55% to 65% by weight, of one or more pharmaceutically acceptable adjuvants, wherein the pharmaceutically acceptable adjuvant is selected from one or more of the following: water-soluble fillers, water-insoluble fillers, disintegrants, lubricants and glidants. Further, the water-soluble filler is mannitol, for example mannitol M100. Further, the water-insoluble filler is microcrystalline cellulose, for example microcrystalline cellulose PH102. Further, the disintegrant is croscarmellose sodium. Further, the glidant is colloidal silicon dioxide, for example colloidal silicon dioxide M5P. Further, the lubricant is magnesium stearate, for example magnesium stearate 2257. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 30% to 35% by weight, for example about 33% by weight, of the water-soluble filler. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 20% to 25% by weight, for example about 22% by weight, of the water-insoluble filler. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.2% to 1% by weight, for example about 0.5% by weight, of the disintegrant. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight, for example about 1.5% by weight, of the glidant. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises about 1% to 3% by weight, for example about 1.5% by weight, of the lubricant.

[0023] Furthermore, the dosage form of the pharmaceutical composition is a tablet, granule, or capsule. Furthermore, the pharmaceutical composition further comprises one or more drugs and / or extracts. Furthermore, the compound of formula (I) is in an amorphous solid form. Furthermore, when thermally analyzed using differential scanning calorimetry (DSC), the amorphous solid form exhibits an endothermic peak at approximately 98°C. Furthermore, in thermal analysis by modulated differential scanning calorimetry (MDSC), the amorphous solid form has a glass transition temperature of approximately 113°C. Furthermore, the amorphous solid form substantially exhibits the X-ray powder diffraction (XRPD) pattern shown in Figure 2. Furthermore, the amorphous solid form is prepared as follows: a thermal melt extrusion dispersion intermediate is prepared by thermal melt extrusion or spray drying using a specific adjuvant, thereby transforming the compound of formula (I) from crystalline to a stable amorphous state.

[0024] According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided for use in the preparation of a drug for the prevention or treatment of fatty liver. According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided for use in the preparation of a drug for the prevention or treatment of cancer. According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided for use in the preparation of a drug for the prevention or treatment of acne.

[0025] The beneficial effects of this invention are as follows: In this invention, the pharmaceutical composition is prepared using the crystalline form of the free base monohydrate of compound (I). To improve the dissolution rate of compound (I) and promote the consistency of oral absorption, hypromellose succinate acetate-HG (HPMCAS-HG, a dispersion polymer) is used as an adjuvant, and a thermal melt extrusion dispersion intermediate (HMEDI) is prepared via thermal melt extrusion. This process converts compound (I) from the crystalline form of the free base monohydrate to a stable amorphous form. The pharmaceutical composition disclosed in this invention can be stored stably for a long period of time under room temperature and relatively high humidity conditions and has a remarkably excellent dissolution effect.

[0026] The pharmaceutical compositions disclosed in this invention can be stored stably for a long period of time under room temperature and relatively high humidity conditions, and have remarkably excellent dissolving effects.

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments are briefly introduced below. Clearly, the drawings described below represent only a few embodiments of the present invention. Those skilled in the art can create other drawings from these without departing the scope of protection intended by the present invention. [Brief explanation of the drawing]

[0028] [Figure 1] This schematic diagram shows the results of equilibrium solubility experiments in buffer media under different pH conditions for the monohydrate crystalline form, amorphous form, and the thermal melt extrusion dispersion intermediate of the compound of formula (I). [Figure 2] The X-ray powder diffraction (XRPD) pattern of the amorphous form of the compound of formula (I) is shown. [Modes for carrying out the invention]

[0029] The technical solutions in embodiments of the present invention will be described clearly and completely below with reference to the drawings of embodiments of the present invention. Clearly, the embodiments described are some, but not all, embodiments of the present invention. All other embodiments that can be obtained by those skilled in the art without inventive effort based on embodiments of the present invention are included within the scope of protection of the present invention.

[0030] Unless otherwise specified, all technical and scientific terms and abbreviations used herein have meanings that are generally understood by those skilled in the art in the field of the present invention or the field to which the terms apply. In carrying out the present invention, methods, conditions, substances, or materials similar to or equivalent to those disclosed herein may be used, but preferred methods, conditions, substances, or materials are described herein.

[0031] This invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will understand that there are many methods and substances similar to or equivalent to those described herein that can be applied to the practice of this invention. This invention is by no means limited to the methods and substances described herein.

[0032] As used herein and in the appended claims, the singular forms "a," "an," and "the" shall also have plural meanings unless the context clearly indicates otherwise.

[0033] In this invention, the term “comproses” is synonymous with “includes.” As used herein, “comprising,” “including,” “having,” “containing,” or any other variation thereof, means non-exclusive inclusion. For example, if a composition, step, method, product, or apparatus includes the listed elements, it is not necessarily limited to these elements and may include other elements not expressly described or elements inherent in the composition, step, method, product, or apparatus.

[0034] As described in the background art section, compounds of formula (I) have problems with low solubility in various media (pH = 1 to 7) and undergoing phase transitions under high relative humidity conditions. To solve the above problems, the present invention provides a pharmaceutical composition comprising a heterocyclic compound, the pharmaceutical composition comprising the following components: (a) Compound of formula (I), [ka] (b) Hypromellose acetate succinate or copovidone Mix components (a) and (b), and then subject to hot melt extrusion or spray drying. The weight ratio of component (b) to component (a) is 0.4 to 0.8.

[0035] In the development of the tablets of the present invention, three batches of the active pharmaceutical ingredient of compound (I) were studied, all in monohydrate crystalline form (for the synthesis method, see the synthesis of ASC40 described in WO2012122391A1). After thermal melt extrusion, in the solid dispersion (HMEDI) prepared from a physical mixture containing the monohydrate crystalline form of compound (I) (60% by mass) and HPMCAS-HG (40% by mass), all the diffraction peaks of the characteristic crystalline form disappeared, resulting in an amorphous state.

[0036] Since the performance of the formulation depends on maintaining the active pharmaceutical ingredient in an amorphous state, in the present invention, during stability testing, the phase transition of HMEDI from an amorphous state to a crystalline state was monitored by measuring the glass transition temperature using XRPD and DSC. In the stability testing, the present invention further monitored changes in the solubility of the tablets of the present invention. Changes in solubility may indicate a decrease in formulation performance due to the change from an amorphous state to a crystalline state. In the present invention, it was found that the compound of formula (I) undergoes a phase transition under high relative humidity conditions, i.e., changes from an amorphous state to a less soluble crystalline state. Therefore, in order to maintain the amorphous state of the compound of formula (I) even when exposed to a wet or aqueous environment (e.g., in the gastrointestinal tract), and to more effectively prevent moisture from causing changes in the compound of formula (I), research was conducted to investigate HMEDI under accelerated temperature and humidity conditions. XRPD analysis results showed that, under conditions of 25°C / 95%RH, the pulverized HMEDI powder in an open container did not undergo crystallization during a 30-day test period. Under conditions of 25±2°C / 60±5%RH and 40±2°C / 75±5%RH, no signs of crystal formation affecting stability were observed in HMEDI packaged to prevent moisture absorption. This suggests that formulations made from HMEDI can suppress phase transitions even in the presence of exogenous water and may exhibit excellent stability during long-term storage.

[0037] In the present invention, when parts by weight, temperature, velocity, diameter, time, pressure, frequency, percentage, equivalent, concentration, or other values ​​or parameters are expressed as a range, a preferred range, or a range defined by a preferred upper limit and a preferred lower limit, it should be understood that all ranges formed by combining any upper limit or preferred value and any lower limit or preferred value are clearly disclosed, regardless of whether such ranges are described individually or not. For example, if the range "0.4 to 0.8" is disclosed, the range should be interpreted to include ranges such as "0.4 to 0.8", "0.4 to 0.7", "0.4 to 0.6", "0.4 to 0.5", "0.5 to 0.8", "0.5 to 0.7", "0.5 to 0.6", "0.6 to 0.8", "0.6 to 0.7", "0.7 to 0.8", "0.4 to 0.75", "0.4 to 0.65", "0.4 to 0.55", "0.4 to 0.45", "0.5 to 0.75", "0.5 to 0.65", and "0.5 to 0.55". When a numerical range is described in this specification, unless otherwise specified, the range is intended to include all values ​​at both ends and all values ​​within the range up to two decimal places, and the effects of the present invention can be achieved within the above range.

[0038] In a preferred embodiment, based on the total weight of the pharmaceutical composition, the pharmaceutical composition contains component (a) in an amount of 20% to 30% by weight, for example, about 24%. In a preferred embodiment, based on the total weight of the pharmaceutical composition, the pharmaceutical composition contains component (a) in an amount of 10% to 20% by weight, for example, about 16%.

[0039] In a preferred embodiment, component (a) and component (b) are mixed and subjected to melt extrusion or spray drying at a temperature in the range of 145°C to 200°C. In a preferred embodiment, component (a) and component (b) are mixed and subjected to melt extrusion or spray drying at a temperature in the range of 155°C to 180°C. In a preferred embodiment, component (a) and component (b) are mixed and subjected to melt extrusion or spray drying at a temperature in the range of 155°C to 165°C.

[0040] To facilitate the maintenance of the compound of formula (I) of the present invention in an amorphous form, in preferred embodiments, the hypromellose acetate succinate is HG grade hypromellose acetate succinate.

[0041] In a preferred embodiment, the weight ratio of component (b) to component (a) is 0.5 to 0.7. In a preferred embodiment, the weight ratio of component (b) to component (a) is 0.66.

[0042] The scope of this specification may be expressed as "about" one particular value and / or "about" another particular value. When such a range is expressed, another embodiment includes one particular value and / or another particular value. Similarly, the preceding use of "about" means that when a value is expressed as an approximation, a particular value forms another embodiment. It should be understood that each endpoint of a range is important both in relation to the other endpoint and independently of the other endpoint. Many of the values ​​disclosed herein are disclosed not only as the value itself but also as an "about" value. For example, if the value "10" is disclosed, "about 10" is also disclosed. Also, when "less than or equal to" or "greater than or equal to" is disclosed, the possible ranges between these values ​​are also disclosed in a manner that a person skilled in the art will understand appropriately. For example, if the value "10" is disclosed, "less than or equal to 10" and "greater than or equal to 10" are similarly disclosed.

[0043] In this invention, "approximately" means a value within ±5% of a specific value. For example, "approximately 24" includes 24 ± 5%, i.e., from 22.8 to 25.2; "approximately 16" includes 16 ± 5%, i.e., from 15.2 to 16.8; and "approximately 0.66" includes 0.66 ± 5%, i.e., from 0.627 to 0.693.

[0044] In a preferred form, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 50% to 70% by weight, for example, 55% to 65% by weight, of one or more pharmaceutically acceptable adjuvants, where the pharmaceutically acceptable adjuvants are selected from one or more of water-soluble fillers, water-insoluble fillers, disintegrants, lubricants, and diluents.

[0045] In the present invention, the term "pharmaceutically acceptable" refers to a substance such as a carrier or diluent that does not impair the biological activity or properties of the compound and is relatively non-toxic; that is, administering the substance to an individual does not cause undesirable biological effects or harmful interactions with other components contained therein.

[0046] In this invention, the term “pharmaceutically acceptable excipient” means a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and active ingredients (i.e., produces a desired therapeutic effect without causing undesirable local or systemic effects) and is widely known in the art (see, for example, Remington's Pharmaceutical Sciences Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995).

[0047] In the present invention, mannitol, such as mannitol M100, is preferred as a water-soluble filler to aid in the wetting and capillary action of the final mixture and to improve the tablet-making properties compared to other water-soluble fillers.

[0048] In the present invention, in order to function better as a water-insoluble filler for assisting in the crushing of solids and for more appropriately adjusting the granulation density, in preferred embodiments, the water-insoluble filler is microcrystalline cellulose, for example, microcrystalline cellulose PH102, compared to other water-insoluble fillers.

[0049] In order to better promote the disintegration and fragmentation of the tablet solids of the present invention than other disintegrants, a preferred embodiment is croscarmellose sodium as the disintegrant.

[0050] In order to better promote the powder flowability of the present invention compared to other lubricants, in a preferred embodiment, the lubricant is colloidal silicon dioxide, for example, colloidal silicon dioxide M5P.

[0051] In order to better prevent solidification and adhesion phenomena in the manufacturing equipment for the pharmaceutical composition of the present invention, in a preferred embodiment, the lubricant is magnesium stearate, for example, magnesium stearate 2257, compared to other lubricants.

[0052] The aforementioned adjuvants are preferably pharmaceutically inactive or have synergistic or additional effects that enhance the therapeutic activity of the pharmaceutical composition. The above adjuvants are merely examples, and the adjuvants actually used in the present invention are not limited to these, and can be adjusted according to the actual situation, in which case the effects of the present invention can be achieved.

[0053] To improve the compressibility of the granules of the present invention, in preferred embodiments, the pharmaceutical composition further comprises 30% to 35% by weight of a water-soluble filler, for example, about 33% by weight, based on the total weight of the pharmaceutical composition. If the weight percentage is less than 30%, the disintegration time of the tablets is significantly prolonged, while if the weight percentage exceeds 35%, the mixing of the granules may become uneven.

[0054] To improve the compressibility of the granules of the present invention, in preferred embodiments, the pharmaceutical composition further contains 20% to 25% by weight of a water-insoluble filler, for example, about 22% by weight, based on the total weight of the pharmaceutical composition. If the weight percentage is less than 20%, the compressibility of the granules will be poor, and as a result, the hardness may be low. On the other hand, if the weight percentage exceeds 25%, the mixing of the granules may become uneven.

[0055] In order for the granules of the present invention to exhibit a nearly linear correlation between increased tablet forming pressure, increased tablet hardness, and increased disintegration time, in a preferred embodiment, the pharmaceutical composition further contains 0.2% to 1% by weight of a disintegrant, for example, about 0.5% by weight, based on the total weight of the pharmaceutical composition. If the weight percentage is less than 0.2%, the disintegration time of the tablet is significantly prolonged. On the other hand, if the weight percentage exceeds 1%, the tablet disintegrates too much and may disintegrate in the mouth when taken.

[0056] In preferred embodiments, the pharmaceutical composition further contains 1% to 3% by weight of a lubricant, for example, about 1.5% by weight, based on the total weight of the pharmaceutical composition. If the weight percentage is less than 1%, the granules may have poor flowability. On the other hand, if the weight percentage exceeds 3%, the granules may have too low a density, resulting in poor compressibility.

[0057] To reduce the ejection force of the tablets of the present invention, in preferred embodiments, the pharmaceutical composition further contains 1% to 3% by weight of lubricant, for example, about 1.5% by weight, based on the total weight of the pharmaceutical composition. If the weight percentage is less than 1%, adhesion to the punch may occur during the tableting process. On the other hand, if the weight percentage exceeds 3%, the dissolution of the tablets may decrease.

[0058] In this invention, "approximately" means a value within ±5% of a specific value. For example, "approximately 33" includes 33 ± 5%, i.e., from 31.35 to 34.65; "approximately 22" includes 22 ± 5%, i.e., from 20.9 to 23.1; "approximately 0.5" includes 0.5 ± 5%, i.e., from 0.475 to 0.525; and "approximately 1.5" includes 1.5 ± 5%, i.e., from 1.425 to 1.575.

[0059] In a preferred embodiment, the dosage form of the pharmaceutical composition is a tablet, granules, or capsule. In a preferred embodiment, the pharmaceutical composition further comprises one or more drugs and / or extracts.

[0060] In a preferred embodiment, the drug is an anti-fatty liver drug and / or an anticancer drug.

[0061] According to another aspect of the present invention, a method for preparing the aforementioned pharmaceutical composition is provided, the method comprising: (1) mixing a sieved component (a) with a dried, pulverized, and sieved component (b) to obtain a mixture; (2) extruding the mixture by hot melt extrusion at a hot melt extrusion temperature of 145°C to 200°C to form an extruded product, or dissolving the mixture in an organic solvent such as ethanol, dichloromethane, or acetonitrile and spray-drying it; (3) cooling the extruded product or spray-dried product; and (4) pulverizing, sizing, and sieving the cooled extruded product or spray-dried product to obtain granules of the pharmaceutical composition.

[0062] In a preferred embodiment, the method further includes the following steps:

[0063] (5) Mixing the granules with one or more sieved pharmaceutically acceptable adjuvants, drying, and processing into tablets or capsules.

[0064] In a preferred embodiment, the mixing process involves first mixing the lubricant with a portion of the water-insoluble filler, then adding the granules, water-soluble filler, disintegrant, and the remaining water-insoluble filler for a second mixing, and finally adding the lubricant and mixing.

[0065] In a preferred embodiment, component (b) is HG grade hypromellose acetate succinate. In a preferred embodiment, the water-soluble filler is mannitol, for example, mannitol M100. In a preferred embodiment, the water-insoluble filler is microcrystalline cellulose, for example, microcrystalline cellulose PH102. In a preferred embodiment, the disintegrant is croscarmellose sodium. In a preferred embodiment, the lubricant is colloidal silicon dioxide, for example, colloidal silicon dioxide M5P. In a preferred embodiment, the lubricant is magnesium stearate, for example, magnesium stearate 2257.

[0066] In a preferred embodiment, a twin-screw hot-melt extruder is used to extrude a mixture of component (a) and component (b). The screw diameter of this twin-screw hot-melt extruder ranges from 8 mm to 50 mm, and the extrusion speed ranges from 10 rpm to 300 rpm. In a preferred embodiment, the screw diameter of the twin-screw hot-melt extruder is 18 mm. In a preferred embodiment, the extrusion speed is 75 rpm to 125 rpm, for example, about 100 rpm.

[0067] In this invention, "approximately" means a value within ±5% of a specific value. For example, "approximately 100" includes 100 ± 5%, i.e., from 95 to 105.

[0068] In a preferred embodiment, steps (1) to (5) of the method include one or more of the following items [1] to

[28] : [1] the measurement result of the loss on drying in step (1) is 2% or less; [2] the drying temperature in step (1) is 55°C to 65°C, e.g., about 60°C; [3] the grinding speed in step (1) is 5000 rpm to 6000 rpm, e.g., about 5500 rpm; [4] the sieve in step (1) is 30 mesh or 40 mesh; [5] the mixing time in step (1) is 10 minutes to 20 minutes, e.g., about 15 minutes; [6] the mixing speed in step (1) is 15 rpm to 25 rpm, e.g., about 20 rpm; [7] the temperature of zone 1 of the extruder in step (2) is 70°C to 110°C, e.g., about 90°C; [8] the temperature of zone 2 of the extruder in step (2) is 110°C [9] The temperature of zone 3 of the extruder in step (2) is 155°C to 165°C, for example, about 160°C;

[10] The temperature of zones 4 to 10 of the extruder in step (2) is 155°C to 165°C, for example, about 160°C;

[11] The temperature of zone 11 of the extruder in step (2) is 140°C to 180°C, for example, about 160°C;

[12] step ( 2) The die temperature of the extruder in step (2) is 150°C to 170°C, for example, about 160°C;

[13] The melting pressure of the extruder in step (2) is 150 bar or less;

[14] The load pressure of the extruder in step (2) is 80% or less, for example, 25% to 65%;

[15] The cooling belt speed of the extruder in step (2) is 1 m / min to 10 m / min;

[16] The processing speed of the extruder in step (2) is 0.The grinding speed is between 1 kg / h and 10 kg / h;

[17] The opening diameter of the grinding sieve in step (4) is approximately 2 mm;

[18] The grinding frequency in step (4) is between 35 Hz and 45 Hz, for example, approximately 40 Hz;

[19] The grinding speed in step (4) is between 5000 rpm and 6000 rpm, for example, approximately 5500 rpm;

[20] The rotational speed for particle size adjustment in step (4) is between 5000 rpm and 6000 rpm, for example, approximately 5500 rpm;

[21] The opening diameter of the particle size adjustment sieve in step (4) is approximately 0.8 mm;

[22] The sieve in step (4) is 40 mesh.

[23] The particle size of the granules in step (4) is 250 μm or less, for example, between 100 μm and 250 μm;

[24] The time for the first mixing in step (5) is 10 to 20 minutes, for example, about 15 minutes;

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

[26] The time for the second mixing in step (5) is 2 to 6 minutes, for example, about 4 minutes;

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

[28] The measurement result of the loss on drying in step (5) is 5% or less.

[0069] Regarding the point that "

[23] The particle size of the granules in step (4) is 250 μm or less, for example, between 100 μm and 250 μm," the present invention investigated the effect of particle size on the dissolution curve of the molten extrusion dispersion intermediate (HMEDI). The molten extrusion dispersion intermediate (HMEDI) was pulverized and sieved to separate it into samples having three particle size distributions (PSD): <100 μm, 100-250 μm, and >250 μm. The dissolution curves of HMEDI granules with a particle size of less than 100 μm and HMEDI granules with a particle size of 100-250 μm were similar to the dissolution curve of SDD. On the other hand, larger granules with a particle size exceeding 250 μm did not dissolve smoothly, were prone to aggregation, formed gels, and resulted in a decrease in the concentration of the free compound of formula (I) under SGF and SIF conditions. Based on these results, PSDs with suitable solubility properties ranging from 100 to 250 μm were selected for further development, and tablet mixing aids with similar particle size distributions were used to ensure proper mixing uniformity. The desired PSDs were produced by grinding and sieving, and then directly using a hammer mill (with appropriate hammer speed and sieve size). Feasibility studies were conducted for tableting using these batches of HMEDI.

[0070] In this invention, an amorphous solid-form spray-dried dispersion (SDD) improved the solubility and dissolution rate of the compound of formula (I). The dissolution results of the pulverized powder of the fused-molten extrusion dispersion intermediate (HMEDI) were equivalent to those of the SDD.

[0071] In this invention, spray-dried dispersion (SDD) powders tend to achieve relatively high API solubility concentrations (typically >1000 μg / mL) in acidic (approximately pH 1.2) simulated gastric juice (SGF). When the medium is switched to a more alkaline (approximately pH 6.8) simulated fasting intestinal fluid (FaSSIF), the concentration decreases 5-6 times. HPMCAS-HG is known as an enteric coating agent and is insoluble in gastric juice, but dissolves immediately upon entering the small intestine. The high solubility concentration of the compound of formula (I) observed in spray-dried dispersion (SDD) may be related to the proportion of the compound molecule of formula (I) exposed on the surface of the polymer dispersion granules. APIs dissolved in the acidic gastric environment decrease in solubility concentration when they move from the stomach to the higher pH of the intestine. This is likely because the originally ionized API precipitates from the solution due to the change in pH and changes to an insoluble monohydrate crystalline form. Increasing the amount of HPMCAS-HG in the spray-dried dispersion (SDD) from 25% to 40% in the heat-melt extrusion dispersion intermediate (HMEDI) reduces the dissolution rate of the API in acidic aqueous media, and the amorphous form of the active pharmaceutical ingredient is retained until release in the intestines. Studies on the dissolution behavior during the gastrointestinal transfer of a typical batch of the heat-melt extrusion dispersion intermediate (HMEDI) of the compound of formula (I) can support the above theory.

[0072] In this invention, "approximately" means a value within ±5% of a specific value. For example, "approximately 60" includes 60±5%, i.e., 57 to 63; "approximately 5500" includes 5500±5%, i.e., 5225 to 5775; "approximately 15" includes 15±5%, i.e., 14.25 to 15.75; "approximately 20" includes 20±5%, i.e., 18 to 22; "approximately 90" includes 90±5%, i.e., 85.5 to 94.5; "approximately 130" includes 130±5%, i.e., 123.5 to 136.5; "approximately 160" includes 160±5%, i.e., 152 to 168; and "approximately 2" includes 2±5%, i.e., 1.9 to 2.1. "Approximately 40" includes 40±5%, i.e., 38 to 42. "Approximately 0.8" includes 0.8 ± 5%, i.e., from 0.76 to 0.84. "Approximately 4" includes 4 ± 5%, i.e., from 3.8 to 4.2.

[0073] In a preferred embodiment, the compound of formula (I) is in an amorphous solid form. In a preferred embodiment, the amorphous solid form exhibits an endothermic peak at approximately 98°C when thermally analyzed using differential scanning calorimetry (DSC). In a preferred embodiment, the amorphous solid form has a glass transition temperature of approximately 113°C in thermal analysis by modulated differential scanning calorimetry (MDSC). In a preferred embodiment, the amorphous solid form substantially exhibits the X-ray powder diffraction (XRPD) pattern shown in Figure 2. In a preferred embodiment, the amorphous solid form is prepared as follows: a thermal melt extrusion dispersion intermediate is prepared by thermal melt extrusion or spray drying using a specific adjuvant, thereby transforming the compound of formula (I) from crystalline to stable amorphous.

[0074] According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided for use in the preparation of a drug for the prevention or treatment of fatty liver. According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided for use in the preparation of a drug for the prevention or treatment of cancer. According to another aspect of the present invention, the aforementioned pharmaceutical composition is provided for use in the preparation of a drug for the prevention or treatment of acne.

[0075] In the present invention, the term “prevention” includes “treatment” and “preventive measures” unless otherwise specified. The terms “therapeutic” and “therapeutically” should be interpreted appropriately, respectively. In the present invention, the term “treatment” includes alleviating, suppressing, or improving the symptoms or condition of a disease, suppressing the development of complications, improving or preventing an underlying metabolic syndrome, suppressing the progression of a disease or condition, for example, controlling the progression of a disease or condition, alleviating a disease or condition, regressing a disease or condition, alleviating complications caused by a disease or condition, or preventing or treating signs caused by a disease or condition. As used herein, a pharmaceutical composition or pharmaceutical preparation can improve a disease, condition, or condition after administration, particularly by reducing its severity, delaying its onset, slowing its progression, or shortening its duration. This includes circumstances resulting from or related to administration, whether fixed or temporary, continuous or intermittent.

[0076] Another aspect of the present invention provides the use of the aforementioned pharmaceutical composition in the manufacture of a drug for preventing and / or treating fatty liver of a target. Another aspect of the present invention provides the use of the aforementioned pharmaceutical composition in the manufacture of a drug for preventing and / or treating cancer of a target. Another aspect of the present invention provides a method for preventing and / or treating fatty liver of a target, the method comprising administering a therapeutically effective amount of the aforementioned pharmaceutical composition to a target. Another aspect of the present invention provides a method for preventing and / or treating cancer of a target, the method comprising administering a therapeutically effective amount of the aforementioned pharmaceutical composition to a target. Another aspect of the present invention provides a method for preventing and / or treating acne of a target, the method comprising administering a therapeutically effective amount of the aforementioned pharmaceutical composition to a target.

[0077] In this invention, the term “subject” means a mammal. Mammals may be, but are not limited to, humans, non-human primates, mice, rats, dogs, cats, horses, or cattle. Non-human mammals may be advantageously used as subjects to represent models of fatty liver or cancer. Preferably, the subject is human. The “effective amount” of a pharmaceutical composition or formulation used in this invention is the amount that achieves the desired therapeutic and / or preventive effect. The effective amount for this purpose will vary, for example, depending on the pharmaceutical composition, mode of administration, stage and severity of the disease being treated, the patient’s weight and overall health, and the judgment of the prescribing physician. Dosages may be administered once a week, every other day, once a day, or several times a day. Dosage units may be administered over a short period (e.g., several weeks to several months) or a long period (several months to several years).

[0078] The present invention will be further illustrated by the following examples. It should be understood that these examples are for illustrative purposes only and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not indicated are typically performed under conventional conditions or conditions recommended by the manufacturer.

[0079] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Furthermore, similar or equivalent methods and materials may be applied in the methods of the present invention. Preferred methods and materials described herein are for illustrative purposes only.

[0080] In the present invention, the features described above or in the examples can be combined in any way. All features disclosed herein can be combined in any combination. Various features disclosed herein can be replaced by alternative features that serve the same, equivalent, or similar purposes. Thus, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. [Examples]

[0081] 1. Investigation of solid dispersion processes by thermal melt extrusion The fused thermal extrusion process involves mixing 60% compound (I) and 40% HPMCAS-HG in a screw-driven extruder barrel and thermally melting the mixture under controlled temperature to produce a clear, uniform amorphous extruded material. DSC and TGA analyses of compound (I) show a melting point of approximately 145°C, with weight loss occurring above 250°C, suggesting decomposition. The DSC melting transition temperature of HPMCAS-HG is approximately 120°C, while the TGA weight loss indicates decomposition above 200°C. Based on these thermal properties, 160°C was selected as the processing temperature for fused thermal extrusion (HME), and 180°C was selected as the upper temperature limit to avoid decomposition of compound (I).

[0082] To improve the uniformity of the extruded material, the compound of formula (I) and HPMCAS-HG were pre-mixed before thermal melt extrusion. The particle size distribution D(v,0.9) of HPMCAS-HG is normally less than approximately 1000 μm, but this was reduced by the grinding step so that D(v,0.9) was less than 250-300 μm. To ensure uniformity during the mixing process, the particle size distribution of HPMCAS-HG was adjusted to approximate that of the compound of formula (I) (D(v,0.9) less than approximately 100-200 μm).

[0083] The pre-mixed material was fed directly into the extruder barrel through the main feed port of the 18mm twin-screw extruder. The extruder's screw configuration was designed with a strong mixing section to maintain moderate shear force and prevent material degradation. The extruder was driven by the screw and feed rate, with a barrel temperature of 160°C and a processing rate of approximately 1-2 kg / h. During the process, process response parameters such as extruded product temperature, extruder load pressure %, and melting pressure were monitored. The extruder may stop if the load pressure exceeds 80%, while high melting pressure can cause an increase in product temperature and product degradation. The parameters of the thermal melt extrusion process and the target range for the 18mm twin-screw extruder are shown in Table 1.

[0084] [Table 1] After optimizing the process parameters, representative samples were collected at the start, middle, and end of the extrusion process (0, 30, 60, 180, 360, and 390 minutes) to monitor product quality during the approximately 6.5-hour extrusion process. No significant changes were observed in the relevant substances in the product, and all samples were confirmed to be in amorphous form. Furthermore, the present invention includes the management and pretreatment of HPMCAS-HG, and approximately 10 g of HPMCAS-HG was taken and the loss on drying was measured. The test result must be ≤2%. Otherwise, it was dried at 60±5°C until the loss on drying test result was ≤2%. Next, it was ground using an FHM-67 size adjuster and passed through a 40-mesh sieve with the parameters shown in Table 2.

[0085] [Table 2] Furthermore, in this invention, equilibrium solubility experiments were conducted for monohydrate crystalline API, amorphous API, and thermal melt extrusion dispersion intermediates in buffer solutions under different pH conditions. The data are shown in Table 3 and Figure 1.

[0086] Table 3. Summary of equilibrium solubility (μg / ml) of monohydrate crystalline API, amorphous API, and thermal fusion extruded dispersion intermediates. [Table 3] As can be seen from Table 3 and Figure 1, (1) the molten extrusion dispersion intermediate can significantly improve the solubility of the API in different media. (2) The amorphous form and monohydrate that have not undergone the molten extrusion process exhibit essentially the same solubility, with no clear improvement observed. This indicates that the original amorphous form alone does not possess the inherent ability to improve solubility, and it is presumed that the amorphous API that has not undergone molten extrusion rapidly precipitates as a more stable monohydrate crystalline form in aqueous media. (3) The molten extrusion dispersion intermediate can suppress the rapid precipitation of the API into a more stable monohydrate crystalline form.

[0087] The thermal extrusion dispersion intermediate of the present invention can be ground to a selected particle size distribution. In addition to this advantage, formulations obtained by the thermal extrusion process also have the following advantages: (1) The thermal extrusion process utilizes thermal and mechanical energy to effectively bond the drug and polymer, forming an amorphous state. This maintains the long-term stability of the drug, improves solubility, and further improves the bioavailability of poorly soluble drugs in vivo. (2) Since no solvent is required for the application of thermal extrusion technology, solvent costs are reduced and the environmental impact is minimized. (3) Compared to spray drying, the equipment used in thermal extrusion occupies less space, especially at the scale-up production level.

[0088] 2. Investigation of the secondary grinding process In this invention, the effect of particle size on the dissolution curve of a thermally melted extruded dispersion intermediate (HMEDI) was investigated. The HMEDI was pulverized and sieved to separate it into samples with three particle size distributions (PSD): <100 μm, 100-250 μm, and >250 μm. HMEDI granules with particle sizes of <100 μm and 100-250 μm dissolved completely, but the larger granules with a particle size of >250 μm did not dissolve smoothly, instead agglomerating and forming a gel, resulting in a decrease in the concentration of the free compound of formula (I) under SGF and SIF conditions. Based on these results, PSDs with appropriate dissolution properties were selected for further development, and excipients for tablet mixing with similar particle size distributions were used to ensure appropriate mixing uniformity.

[0089] Reference value: D 90 is less than 300 μm (as a stricter requirement, D 90 The target value is less than 50 mesh), D 50 is less than 120 μm (as a stricter requirement, D 50 The target value is less than 120 mesh, or D 40 (less than 140 mesh).

[0090] Hot-melt extruded dispersion intermediates (HMEDI) with the desired PSD were produced by grinding and sieving using a hammer mill directly (with appropriate hammer speed and sieve size). Feasibility studies were conducted for tablet formation using these batches of hot-melt extruded dispersion intermediates (HMEDI).

[0091] The secondary grinding process provides the material with better fluidity and grindability during secondary size adjustment, while also improving dissolution and release properties.

[0092] The material that passed through a 40-mesh sieve was subjected to a particle size distribution test, and the results are shown in Table 4.

[0093] [Table 4] The particle size distribution shows that D(v,0.9) is approximately 270 μm under these grinding conditions, satisfying the requirement that HPMCAS-HG's particle size distribution D(v,0.9) be less than 250-300 μm. This grinding process effectively controls the particle size distribution range of HPMCAS-HG.

[0094] HMEDI Grinding: Bulk density and particle size distribution of the ground powder intermediate. The particle size of HMEDI plays a crucial role in the downstream process of the final solid dosage form. Therefore, tests were conducted on the grinding process to investigate the effects of grinding rate and sieve size on the particle size distribution of the ground extruded material. A 60% hot-melt extruded material of the compound of formula (I) was fed from the extruder onto cooling rollers, and the extruded material was divided into free-flowing flakes. Under various grinding conditions, approximately 150 g of HME flake samples of the compound of formula (I) were fed into a hammer mill equipped with forward-facing hammers and ground to significantly reduce the particle size. The grinding rate and sieve size were varied until the particle size distribution consistently decreased to approximately D(v,0.9)<300 μm and D(v,0.5)<120 μm (shown in Table 5, test numbers 1-3).

[0095] [Table 5] The data showed that particle size decreased as the grinding speed increased. While no significant difference in particle size was observed with changes in sieve size, the 27-mesh sieve was rejected because it retained larger granules. Based on the grinding test results, the final selected grinding parameters are shown in Table 6. HMEDI was prepared by enhancing the HME grinding process using 4 kg of flake extrusions of the compound of formula (I). XRPD and DSC analysis showed that the HMEDI batch was amorphous. The particle size distribution was unimodal, with D(v,0.9) less than approximately 222 μm (shown in Table 5, test number 4). Bulk density and tap density were 0.55 g / mL and 0.71 g / mL, respectively. The bulk density and particle size distribution were controlled within a range suitable for uniform mixing with the tablet adjuvant.

[0096] [Table 6] The 20-mesh sieve is included in the secondary size adjustment machine.

[0097] In the production of pilot-scale batches in this invention (i.e., small-scale product testing before large-scale mass production), the material was removed after thermal extrusion and cooling, and primary grinding was performed at a milling frequency of 40±5Hz using a milling machine equipped with a sieve with a 2.0mm opening. After grinding, secondary particle separation was performed at a grinding speed of 5500±500rpm using a size adjustment machine equipped with a sieve with a 0.8mm diameter. The granules after secondary particle separation were passed through a 40-mesh sieve to remove large granules. The secondary particle separation setting parameters are shown in Table 7.

[0098] [Table 7] In the production of pilot-scale batches (batch numbers R4020001 to R4020009), approximately 50g of material after secondary separation was taken from each batch and a particle size distribution test was performed. Sieves of 40 mesh, 50 mesh, 60 mesh, 70 mesh, and 140 mesh were used. The results showed that in all pilot-scale batches, the particle size distribution after secondary separation was less than 270 μm for D(v,0.9) and approximately less than 120 μm for D(v,0.5), indicating that the control requirements of approximately less than 300 μm for D(v,0.9) and approximately less than 120 μm for D(v,0.5) were met.

[0099] The bulk density and tap density of the pilot-scale batches were controlled within a range suitable for uniform mixing with the tablet adjuvant, being 0.56–0.65 and 0.70–0.73, respectively.

[0100] 3. Selection of adjuvants in pharmaceutical compositions - Optimization of direct compression of final mixed granules Increasing the amount of brittle material in the formulation can improve the compression profile, tablet appearance, and surface strength, thereby potentially enhancing the brittleness performance. Initial formulations were compressed using a single-stroke tablet press. The results showed that increasing the ratio of mannitol M100 to microcrystalline cellulose PH102 improved the compressibility of the final mixed granules. However, even with increased compression pressure and tablet hardness, disintegration remained too rapid (less than 1 minute). Disintegration time was inversely proportional to the proportion of croscarmellose sodium used in the formulation. When croscarmellose sodium was contained at 0.5% w / w, the final mixed granules showed an approximately linear correlation between increased compression pressure, increased tablet hardness, and increased disintegration time. To optimize the formulation, the amount of magnesium stearate 2257 as a lubricant was increased from 0.5% to 1.5%, reducing the ejection force to less than 300 N. The final optimized formulation is shown in Table 8.

[0101] [Table 8] Small tablets compressed using an optimized formulation on a single-shot tablet press exhibited appropriate hardness and disintegration. The 25 mg tablets (batch number T7-127-92) and 100 mg tablets (batch number T7-127-93) had good tablet properties. The results are shown in Table 9.

[0102] [Table 9] Table 10 shows the formulations used during process scale-up.

[0103] [Table 10]

[0104] 4. Impurity profile and stability of thermal melt extrusion dispersion intermediate (HMEDI) under long-term storage conditions at 25°C. In this study, since the hot melt extrusion process involves melting and mixing the active pharmaceutical ingredient (i.e., the compound of formula (I)) with HPMCAS-HG polymer at high temperature to form an amorphous extrudate, it was found that the current validated method for evaluating related substances in pharmaceutical formulations was used to evaluate hot melt extrusion dispersion intermediates (HMEDI). This was performed to investigate whether there is a difference between the initial purity of the API used in each batch and the API purity in the HMEDI. No new decomposition products were detected in any batches of hot melt extrusion dispersion intermediates (HMEDI). The purity and impurity profiles remained essentially unchanged compared to the corresponding API batches used. This indicates that no significant degradation occurred during the hot melt extrusion process, and no chemical interaction with the polymeric auxiliary materials occurred.

[0105] For the three strengths of the inventive tablets in Table 10, the results of stability studies stored at 40°C for 6 months and at 25°C for 18 months showed that the purity of HMEDI and the content of the batches remained essentially unchanged, no significant degradation trend was observed, there was also no significant change in moisture content, XRPD results showed an amorphous state, suggesting no change in crystalline form during storage, and the DSC profile also remained unchanged. The above results indicate that the formulation is stable.

[0106] 5. Tablet Manufacturing Process Flow (1) Pretreatment of raw materials and auxiliary materials Prior to tablet manufacture, the crystal form and particle size distribution of the compound of formula (I) were determined. The reference crystalline form of the compound of formula (I) is free base monohydrate, and the reference particle size distribution is D 50 ≦105.77μm, D 90 ≦229.88μm shall be satisfied.

[0107] For drying loss measurement, hypromellose acetate succinate AS-HG was collected. The test result had to be ≤2%; otherwise, it was dried at 60±5°C and processed until the humidity test result was ≤2%. Grinding was performed using an FHM-67 size-adjustable machine equipped with a sieve with a 0.8 mm opening at a grinding speed of 5500±500 rpm. The ground material was passed through a 40-mesh sieve.

[0108] Colloidal silicon dioxide M5P, microcrystalline cellulose PH102, mannitol M100, and croscarmellose sodium were passed through a 30-mesh sieve, magnesium stearate 2257 was passed through a 40-mesh sieve, and the compound of formula (I) was passed through a 30-mesh sieve. In this way, the possibility of aggregate formation in the material during storage was eliminated.

[0109] (2) Premixing The compound of formula (I) and the hypromellose acetate succinate AS-HG were weighed and placed in the 5L hopper of an HLS50 experimental mixer. Mixing was carried out under the following conditions: mixing time 15 minutes, mixing speed 20 rpm.

[0110] (3) Thermal melt extrusion granulation Thermal melt extrusion: Extrusion parameters were set as shown in Table 11. Uniformly pre-mixed raw materials and auxiliary materials were taken and manually fed into the thermal melt extruder. By adjusting the feed rate and the extrusion screw speed, the feed rate could be matched to the discharge rate.

[0111] [Table 11] Grinding: After thermal melt extrusion and cooling, the material was removed and subjected to primary grinding at a grinding frequency of 40±5Hz using a grinder equipped with a 2.0mm diameter sieve. After grinding, secondary particle separation was performed at a grinding speed of 5500±500rpm using a size adjustment machine equipped with a 0.8mm diameter sieve. The granules after secondary separation were passed through a 40-mesh sieve.

[0112] (4)Final mixing Final mixing 1 Based on calculations using the weight and formulation after grinding, a portion of colloidal silicon dioxide M5P and crystalline cellulose PH102 were first manually mixed and then added to a 10L hopper. Subsequently, the granules after heat melt granulation were added to the hopper along with mannitol M100, croscarmellose sodium, and the remaining crystalline cellulose PH102. Mixing was carried out under the following conditions: mixing time 15 minutes, mixing speed 20 rpm.

[0113] Final mixing 2 Magnesium stearate 2257, which had passed through a 40-mesh sieve, was added to a mixing hopper. Mixing was carried out under the following conditions: mixing time 4 minutes, mixing speed 20 rpm. The drying loss of the granules after final mixing should be ≤5.0%, and the content of the compound of formula (I) should be between 90.0% and 110.0% of the indicated content.

[0114] (5) Tablet A high-speed tablet press was used for compression. The tablets of the present invention met the requirements of having individual tablet weight variation within ±7.5%, average tablet weight variation within ±5.0%, hardness range of 9.0-12.0 kp, disintegration ≤0.5%, and complete disintegration time within 15 minutes.

[0115] (6) Bottled Thirty tablets were counted using a counting plate and filled into high-density polyethylene bottles for oral solid medications. The bottles were sealed by screwing on a safety cap and then sealing them with aluminum foil using a sealing machine.

[0116] When the sealed sample bottles were inspected, it was required that their airtightness meet the specified standards.

[0117] The heat-melt extrusion dispersion intermediate (HMEDI) was designed to maintain the API in an amorphous state in an aqueous environment and to rapidly release the API in the intestinal tract for systemic absorption. Four tablet strengths (25 mg, 50 mg, 75 mg, and 100 mg) were tested. Four batches of the final mixture with appropriate properties were compression-molded using different punch and die sets. The formulations are shown in Table 12, with proportionally adjusted component amounts.

[0118] [Table 12] 6. Tablet Test 6.1. Melting 6.1.1.Dissolution conditions Test subjects: Pilot scale batches (batch numbers: R4020001, R4020002, R4020007). The preparation process followed "5. Tablet Manufacturing Process Flow". Dissolved substances: As shown in Table 13. Method: General Rules 0931 of the Fourth Section of the Chinese Pharmacopoeia, Method 2 (paddle method). Rotation speed: 75 revolutions per minute. Sampling points: Samples were taken individually at the specified time points. The subsequent filtrate was used as the test solution without replenishing with an equal volume of dissolving medium at the same temperature.

[0119] [Table 13] Among these, a 0.01 mol / L hydrochloric acid solution containing 0.5% SLS (Method 1) was used as the standard dissolution medium.

[0120] 6.1.2.Measurement method The column contains Sigma Ascentis Express C 18A 2.7 μm, 4.6 x 100 mm column or equivalent was used, and the mobile phase was water-acetonitrile = 50:50 (containing 0.1% formic acid (chromatographic grade)). The flow rate was 0.75 ml / min, the column temperature was 40°C, and the detection wavelength was 240 nm. Approximately 15 mg of the standard compound of formula (I) was accurately weighed and placed in a 100 mL volumetric flask. It was dissolved in 20 ml of acetonitrile by sonication, and then diluted to a fixed volume with the elution test solution to obtain the standard solution. Precisely measured fixed amounts (3 μl each) of the standard solution and the test sample solution were injected into a liquid chromatograph. The chromatogram was recorded, and the cumulative dissolution rate at each time point was calculated from the peak area using the external standard method. Subsequently, the dissolution profile was plotted.

[0121] 6.1.3.Results The dissolution results for pilot-scale batch samples of 25 mg (batch number R4020001), 50 mg (batch number R4020002), and 75 mg (batch number R4020007) tablets, obtained with four different dissolving media, are shown in Tables 14, 15, 16, and 17.

[0122] [Table 14] [Table 15] [Table 16] [Table 17] 6.1.4. Conclusion Dissolution tests for all three tablet strengths were conducted under standard non-dissolution conditions. The release profiles were similar regardless of strength, with over 80% released in 30 minutes and complete release achieved within approximately 45-60 minutes.

[0123] The dissolution behavior was essentially consistent across the four different media, and the resulting dissolution profiles showed minimal variation between batches. In the three tablet batches, the relative standard deviation (RSD) of dissolution values ​​at all corresponding time points across the four dissolution profiles was less than 10%, indicating similar dissolution trends and endpoints.

[0124] The heat-melt extrusion dispersion intermediate (HMEDI) is designed to maintain the API in an amorphous state in an aqueous environment and to rapidly release the API in the intestinal tract for systemic absorption.

[0125] 6.2 Pharmacokinetic Parameters Tablets of batch number R4020002 and the previous development batch number G-18-014A were manufactured as described in "5. Tablet Manufacturing Process Flow," and the corresponding pharmacokinetic parameters are shown in Table 18.

[0126] [Table 18] The tablets of the present invention exhibit similar in vitro release behavior, demonstrating that the dissolution conditions in the quality standards can appropriately reflect the in vitro-in vivo correlation.

[0127] Embodiments of the present invention have been described in detail above. This document uses specific examples to illustrate the principles and methods of carrying out the present invention. The above description of embodiments is provided solely to aid in understanding the methods and core concepts of the present invention. On the other hand, any improvements or modifications made by those skilled in the art based on the concepts of the present invention within a particular embodiment and its scope of application are also covered by the present invention. In summary, nothing in this specification should be construed as a limitation of the present invention.

Claims

1. A pharmaceutical composition containing a heterocyclic compound, wherein the pharmaceutical composition comprises the following components: (a) Compound of formula (I), 【Chemistry 1】 (b) Characterized by containing hypromellose acetate succinate or copovidone, Mix component (a) and component (b), and subject to hot melt extrusion or spray drying. The pharmaceutical composition wherein the weight ratio of component (b) to component (a) is 0.4 to 0.

8.

2. Mix component (a) and component (b), and subject to hot melt extrusion or spray drying at a temperature in the range of 145°C to 200°C. Preferably, component (a) and component (b) are mixed and subjected to hot melt extrusion or spray drying at a temperature in the range of 155°C to 180°C. Preferably, component (a) and component (b) are mixed and subjected to hot melt extrusion or spray drying at a temperature in the range of 155°C to 165°C. More preferably, the hypromellose acetate succinate is HG grade hypromellose acetate succinate. More preferably, the weight ratio of component (b) to component (a) is 0.5 to 0.

7. The pharmaceutical composition according to claim 1, more preferably, having a weight ratio of component (b) to component (a) of 0.

66.

3. Based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 50% to 70% by weight, for example, 55% to 65% by weight, of one or more pharmaceutically acceptable adjuvants, wherein the pharmaceutically acceptable adjuvants are selected from one or more of the following: water-soluble fillers, water-insoluble fillers, disintegrants, lubricants, and diluents. Preferably, the water-soluble filler is mannitol, for example, mannitol M100. Preferably, the water-insoluble filler is microcrystalline cellulose, for example, microcrystalline cellulose PH102. Preferably, the disintegrant is croscarmellose sodium. Preferably, the lubricant is colloidal silicon dioxide, for example, colloidal silicon dioxide M5P. Preferably, the lubricant is magnesium stearate, for example, magnesium stearate 2257. More preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 30% to 35% by weight, for example, about 33% by weight, of a water-soluble filler. More preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 20% to 25% by weight, for example, about 22% by weight of a water-insoluble filler. More preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.2% to 1% by weight, for example, about 0.5% by weight, of a disintegrant. More preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight, for example, about 1.5% by weight, of a lubricant. The pharmaceutical composition according to claim 1, more preferably, the pharmaceutical composition further comprises 1% to 3% by weight, for example about 1.5% by weight, of a lubricant based on the total weight of the pharmaceutical composition.

4. The dosage form of the aforementioned pharmaceutical composition is a tablet, granules, or capsule. Preferably, the pharmaceutical composition further comprises one or more drugs and / or extracts, The pharmaceutical composition according to any one of claims 1 to 3, more preferably, wherein the drug is an anti-fatty liver drug, an anticancer drug, and / or an anti-acne drug.

5. A method for preparing a pharmaceutical composition according to any one of claims 1 to 4, wherein the method involves the following steps: (1) To obtain a mixture by mixing the sieved component (a) with the dried, crushed, and sieved component (b); (2) Forming an extruded product by extruding the mixture by hot melt extrusion at a hot melt extrusion temperature of 145°C to 200°C, or dissolving the mixture in an organic solvent such as ethanol, dichloromethane, or acetonitrile and spray drying it; (3) Cooling the extruded or spray-dried material; (4) The method comprising crushing, separating and sieving the cooled extruded or spray-dried material to obtain granules of a pharmaceutical composition.

6. The above method further (5) The process includes mixing the granules with one or more sieved pharmaceutically acceptable adjuvants, drying them, and processing them into tablets or capsules. Preferably, the mixing includes performing an initial mixing with a portion of the lubricant and water-insoluble filler, then adding the granules, the water-soluble filler, the disintegrant, and the remaining water-insoluble filler for a second mixing, and finally adding the lubricant for mixing. More preferably, component (b) is HG grade hypromellose acetate succinate, More preferably, the water-soluble filler is mannitol, for example, mannitol M100. More preferably, the water-insoluble filler is microcrystalline cellulose, for example, microcrystalline cellulose PH102. More preferably, the disintegrant is croscarmellose sodium. More preferably, the lubricant is colloidal silicon dioxide, for example, colloidal silicon dioxide M5P. More preferably, the lubricant is magnesium stearate, for example, magnesium stearate 2257. Furthermore, preferably, a twin-screw type thermal melt extruder is used to extrude the mixture of component (a) and component (b), characterized in that the screw diameter of the twin-screw type thermal melt extruder is in the range of 8 mm to 50 mm, and the extrusion speed is in the range of 10 rpm to 300 rpm. Furthermore, preferably, the screw diameter of the twin-screw type thermal melting extruder is 18 mm. Furthermore, the method according to 5 is characterized in that the extrusion speed is preferably 75 rpm to 125 rpm, for example, about 100 rpm.

7. Steps (1) to (5) of the above method correspond to the following items [1] to [28]: [1] The measurement result of the loss on drying in step (1) must be 2% or less. [2] The drying temperature in step (1) is 55°C to 65°C, for example, about 60°C. [3] The grinding speed in step (1) is 5000 rpm to 6000 rpm, for example, about 5500 rpm. [4] The sieve in step (1) shall be a 30-mesh or 40-mesh sieve. [5] The mixing time in step (1) should be 10 to 20 minutes, for example, about 15 minutes. [6] The mixing speed in step (1) is 15 rpm to 25 rpm, for example, about 20 rpm. [7] The temperature of Zone 1 of the extruder in step (2) is 70°C to 110°C, for example, about 90°C. [8] The temperature of Zone 2 of the extruder in step (2) is 110°C to 150°C, for example, about 130°C. [9] The temperature of Zone 3 of the extruder in step (2) is 155°C to 165°C, for example, about 160°C. [10] The temperature of zones 4 to 10 of the extruder in step (2) is 155°C to 165°C, for example, about 160°C. [11] The temperature of zone 11 of the extruder in step (2) is 140°C to 180°C, for example, about 160°C. [12] The die temperature of the extruder in step (2) is 150°C to 170°C, for example, about 160°C. [13] The melting pressure of the extruder in step (2) shall be 150 bar or less. [14] The load pressure of the extruder in step (2) shall be 80% or less, for example, 25% to 65%. [15] The cooling belt speed of the extruder in step (2) shall be 1 m / min to 10 m / min. [16] The processing speed of the extruder in step (2) shall be 0.1 kg / h to 10 kg / h. [17] The opening diameter of the sieve used for crushing in step (4) is approximately 2 mm. [18] The grinding frequency in step (4) is 35 Hz to 45 Hz, for example, about 40 Hz. [19] The grinding speed in step (4) is 5000 rpm to 6000 rpm, for example, about 5500 rpm. [20] The rotational speed in step (4) is 5000 rpm to 6000 rpm, for example, about 5500 rpm. [21] The opening diameter of the sieve used for particle separation in step (4) is approximately 0.8 mm. [22] The sieve in step (4) shall be a 40-mesh sieve. [23] The particle size of the granules in step (4) is 250 μm or less, for example, 100 μm to 250 μm. [24] The mixing time in step (5) should be 10 to 20 minutes, for example, about 15 minutes. [25] The initial mixing rate in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm. [26] The time for the second mixing in step (5) should be 2 to 6 minutes, for example, about 4 minutes. [27] The rate of the second mixing in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm. The method according to claim 5 or 6, characterized by comprising one or more of the following: [28] showing that the measurement result of the loss on drying in step (5) is 5% or less.

8. The compound of formula (I) is in an amorphous solid form, Preferably, the amorphous solid form, when thermally analyzed using differential scanning calorimetry (DSC), shows an endothermic peak at approximately 98°C. Preferably, the amorphous solid form has a glass transition temperature of approximately 113°C as determined by thermal analysis using modulated differential scanning calorimetry (MDSC). Preferably, the amorphous solid form has an X-ray powder diffraction pattern (XRPD) as shown in Figure 2, according to any one of claims 1 to 4.

9. The amorphous solid form is prepared as follows: The pharmaceutical composition according to any one of claim 8, wherein a molten extruded intermediate is prepared using a specific adjuvant by a molten extrusion process or a spray drying process, thereby converting the compound of formula (I) from a crystalline form to a stable amorphous form.

10. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of an agent for the prevention or treatment of fatty liver.

11. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of an agent for the prevention or treatment of cancer.

12. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of an agent for the prevention or treatment of acne.

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