Pharmaceutical composition containing heterocyclic compound

Abstract

The invention discloses a pharmaceutical composition containing a heterocyclic compound. The pharmaceutical composition comprises the following components: (a) a compound of formula (I); and (b) hydroxypropyl methylcellulose acetate succinate or copovidone; wherein the component (a) and the component (b) are mixed and subjected to hot melt extrusion, and the weight ratio of the component (b) to the component (a) is 0.4-0.8. The pharmaceutical composition disclosed by the invention can be stably stored for a long time under the conditions of room temperature and relatively high relative humidity, and has a remarkable and better dissolution effect. # imgabs0 #

Description

Technical Field

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

[0002] The storage conditions of drugs are a reflection of the stability of the drugs in the drugs. Drugs or crystal forms with lower melting points generally have relatively poor stability and need to be stored at lower temperatures, while drugs or crystal forms with higher melting points have better stability and can generally be stored at room temperature. The reasonable processing temperature of the preparation should also be reasonably formulated according to the thermal stability of the drug. The thermal degradation of drugs is usually closely related to their melting points, and the degradation reaction will occur rapidly after exceeding the melting point by 20°C. Both fatty liver and cancer require long-term medication. The requirement of low-temperature storage will add a lot of inconvenience to the patient's long-term medication and may lead to missed doses or improper storage, which may affect the treatment effect and may cause delays or recurrences of the disease. In addition, low-temperature refrigeration conditions also require special cold chain transportation tools and long-term refrigerators, which bring additional costs to the commercial development of the product. Therefore, in order to better meet clinical and commercial needs, it is necessary to find a stable drug preparation and preparation method that can be stored at room temperature. Such a preparation will not only greatly increase the in vivo and in vitro dissolution of the active ingredient, but more importantly, enable it to be stored at room temperature. The generic name of the compound represented by formula (I) is Denifanstat, which is a potent and safe selective oral small molecule inhibitor of fatty acid synthase and has the potential to be used in fatty liver and cancer research. Chemical name: 4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-1H-1,2,4-triazol-3-yl)benzoyl]piperidin-4-yl]benzonitrile, molecular formula: C 27 H 29 N5O, its structural formula is as follows:

[0003]

[0004] The compound represented by formula (I) has poor solubility in different media (pH=1-7) and will undergo phase change under conditions of high relative humidity.

[0005] Therefore, there is still a need to develop a formulation that will allow a pharmaceutical composition comprising a compound of formula (I) to be stably stored for a long period of time at room temperature and under conditions of high relative humidity, and have a significantly better dissolution effect. Summary of the invention

[0006] Based on this, the present invention provides a pharmaceutical composition comprising a heterocyclic compound, wherein the pharmaceutical composition comprises the following components:

[0007] (a) Compound of formula (I)

[0008]

[0009] (b) Hydroxypropyl methylcellulose acetate succinate or copovidone;

[0010] wherein component (a) and component (b) are mixed and subjected to hot melt extrusion;

[0011] The weight ratio of component (b) to component (a) is 0.4 to 0.8.

[0012] Further, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 145°C to 200°C. Further, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 155°C to 180°C. Further, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 155°C to 165°C. Further, the hypromellose acetate succinate is a HG grade of hypromellose acetate succinate. Further, the weight ratio between component (b) and component (a) is 0.5 to 0.7. Further, the weight ratio between component (b) and component (a) is about 0.66.

[0013] 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 excipients, wherein the pharmaceutically acceptable excipients are selected from one or more of the following: water-soluble fillers, water-insoluble fillers, disintegrants, glidants and lubricants. 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 cross-linked sodium carboxymethyl cellulose. 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 of a water-soluble filler, for example, about 33% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 20% to 25% by weight of a water-insoluble filler, for example, about 22% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.2% to 1% by weight of a disintegrant, for example, about 0.5% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight of a glidant, for example, about 1.5% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight of a lubricant, for example, about 1.5% by weight.

[0014] Further, the dosage form of the pharmaceutical composition is tablets, granules or capsules. Further, the pharmaceutical composition further comprises one or more drugs and / or extracts. Further, the drug is an anti-fatty liver drug, an anti-cancer drug and / or an anti-acne drug.

[0015] According to another aspect of the present invention, there is provided a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: (1) mixing the sieved component (a) with the 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 extrudate; (3) cooling the extrudate; and (4) pulverizing, granulating and sieving the cooled extrudate to obtain granules of the pharmaceutical composition.

[0016] Furthermore, the method further comprises the following steps: (5) mixing and drying the granules with one or more sieved pharmaceutically acceptable excipients to form tablets or capsules.

[0017] Furthermore, the mixing includes first mixing the glidant and part of the water-insoluble filler for a first time; 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.

[0018] Further, the component (b) is HG grade hydroxypropyl methylcellulose acetate succinate. Further, the water-soluble filler is mannitol, such as mannitol M100. Further, the water-insoluble filler is microcrystalline cellulose, such as microcrystalline cellulose PH102. Further, the disintegrant is cross-linked carboxymethyl cellulose sodium. Further, the glidant is colloidal silicon dioxide, such as colloidal silicon dioxide M5P. Further, the lubricant is magnesium stearate, such as magnesium stearate 2257.

[0019] Further, a mixture of components (a) and (b) is extruded using a twin-screw hot melt extruder, wherein the screw diameter of the twin-screw hot melt extruder is between 8 mm and 50 mm, and the extrusion speed is between 10 rpm and 300 rpm. Further, the screw diameter of the twin-screw hot melt extruder is 18 mm. Further, the extrusion speed is 75 rpm to 125 rpm, for example, about 100 rpm.

[0020] Furthermore, steps (1) to (5) of the method include any one or more of the following items [1] to

[28] : [1] the weight loss measurement result of drying in step (1) is not higher than 2%; [2] the drying temperature in step (1) is 55°C to 65°C, for example, about 60°C; [3] the crushing speed in step (1) is 5000rpm to 6000rpm, for example, about 5500rpm; [4] the sieve in step (1) is a 30-mesh sieve or a 40-mesh sieve; [5] the mixing time in step (1) is 10min to 20min , 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

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

[13] the melt pressure of the extruder in step (2) is not higher than 150 bar;

[14] the load pressure of the extruder in step (2) is not higher than 80%, 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 extruder in step (2) The processing rate of the machine is 0.1kg / h to 10kg / h;

[17] the mesh size of the crushing in step (4) is about 2mm;

[18] the frequency of the crushing in step (4) is 35Hz to 45Hz, for example, about 40Hz;

[19] the speed of the crushing in step (4) is 5000rpm to 6000rpm, for example, about 5500rpm;

[20] the rotation speed of the granulation in step (4) is 5000rpm to 6000rpm, for example, about 5500rpm;

[21] the mesh size of the granulation in step (4) is about 0.8mm;

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

[23] the particle size of the particles in step (4) is not higher than 250μm, for example, 100μm to 250μm;

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

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

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

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

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

[0021] The present invention provides a pharmaceutical composition comprising a heterocyclic compound, wherein the pharmaceutical composition comprises the following components:

[0022] (a) Compound of formula (I)

[0023]

[0024] (b) dispersed polymers;

[0025] wherein component (a) and component (b) are mixed at a temperature ranging from 140° C. to 250° C.;

[0026] The weight ratio of component (b) to component (a) is 0.4 to 0.8.

[0027] Furthermore, the dispersing polymer is hypromellose acetate succinate or copovidone.

[0028] Furthermore, component (a) and component (b) are mixed by hot melt extrusion.

[0029] Further, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 145° C. to 200° C. Further, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 155° C. to 180° C. Further, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 155° C. to 165° C.

[0030] Furthermore, the hypromellose acetate succinate is HG grade hypromellose acetate succinate.

[0031] Furthermore, the weight ratio between component (b) and component (a) is 0.5 to 0.7.

[0032] Further, the weight ratio between component (b) and component (a) is about 0.66.

[0033] 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 excipients, wherein the pharmaceutically acceptable excipients are selected from one or more of the following: water-soluble fillers, water-insoluble fillers, disintegrants, glidants and lubricants. 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 cross-linked sodium carboxymethyl cellulose. 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 of a water-soluble filler, for example, about 33% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 20% to 25% by weight of a water-insoluble filler, for example, about 22% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.2% to 1% by weight of a disintegrant, for example, about 0.5% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight of a glidant, for example, about 1.5% by weight. Further, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 1% to 3% by weight of a lubricant, for example, about 1.5% by weight.

[0034] Furthermore, the pharmaceutical composition is in the form of tablets, granules or capsules. Furthermore, the pharmaceutical composition further comprises one or more drugs and / or extracts.

[0035] According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and treating fatty liver. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and treating cancer. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and treating acne.

[0036] Beneficial effects of the present invention:

[0037] The present invention uses the free base monohydrate crystalline form of the compound of formula (I) to produce the pharmaceutical composition of the present invention. In order to increase the dissolution rate of the compound of formula (I) and promote the consistency of oral absorption, the auxiliary material hydroxypropyl methylcellulose acetate succinate-HG (HPMCAS-HG, a dispersed polymer) is used to prepare a hot melt extrusion dispersion intermediate (HMEDI) through a hot melt extrusion process, and the process converts the compound of formula (I) from the free base monohydrate crystalline form to a stable amorphous form. The pharmaceutical composition of the present invention is stably stored for a long time under room temperature and high relative humidity conditions, and has a significantly better dissolution effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without exceeding the scope of protection required by the present invention.

[0039] Figure 1 Schematic diagram of the equilibrium solubility test results of the monohydrate crystalline compound of formula (I), the amorphous compound of formula (I), and the hot melt extrudate dispersion intermediate of the present invention in buffer media under different pH conditions. DETAILED DESCRIPTION

[0040] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0041] Unless otherwise indicated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by those of ordinary skill in the field of the invention or the field in which the terms are used. Although any methods, conditions, substances or materials similar to or equivalent to those disclosed herein may be used in the practice of the present invention, preferred methods, conditions, substances or materials are described herein.

[0042] The present invention is intended to encompass all alternatives, variations and equivalents that may be included in the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0043] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0044] In the present invention, the term "comprising" is synonymous with "including". As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0045] As described in the background technology section, the compound represented by formula (I) has poor solubility in different media (pH = 1 to 7) and undergoes phase change under conditions of high relative humidity. In order to solve the above problems, the present invention provides a pharmaceutical composition comprising a heterocyclic compound, the pharmaceutical composition comprising the following components:

[0046] (a) Compound of formula (I)

[0047]

[0048] (b) Hydroxypropyl methylcellulose acetate succinate or copovidone;

[0049] wherein component (a) and component (b) are mixed and subjected to hot melt extrusion;

[0050] The weight ratio of component (b) to component (a) is 0.4 to 0.8.

[0051] The tablets of the present invention were developed and studied for three batches of raw materials of the compound of formula (I), all of which were monohydrate crystal forms (the synthesis method can refer to the synthesis method of ASC40 in WO2012122391A1). After hot melt extrusion, in the solid dispersion (HMEDI) prepared from a physical mixture of the compound of formula (I) containing the monohydrate crystal form (60% by mass) and HPMCAS-HG (40% by mass), all characteristic crystal diffraction peaks disappeared, indicating an amorphous state.

[0052] Since the performance of the formulation depends on maintaining the amorphous state of the raw material, in the stability study, the present invention monitors the phase change of HMEDI from amorphous to crystalline by XRPD and measuring the glass transition temperature by DSC. During the stability study, the present invention further monitors the dissolution change of the tablets of the present invention, which may indicate that the reduction in formulation performance is caused by the transformation of the amorphous state to the crystalline state. The present invention finds that since the compound of formula (I) undergoes a phase change under conditions of high relative humidity, that is, it is transformed from an amorphous amorphous state to a poorly soluble crystalline form, in order to keep the compound of formula (I) in an amorphous amorphous form when exposed to a humid or aqueous environment (such as the gastrointestinal tract), and in order to better prevent water from inducing the crystal transformation of the compound of formula (I), a study was conducted to examine HMEDI under accelerated conditions of temperature and humidity. The results of the XRPD analysis showed that under 25°C / 95%RH conditions, the HMEDI crushed powder in an open container did not undergo crystal transformation during the 30-day study period. At 25±2℃ / 60±5%RH and 40±2℃ / 75±5%RH, no signs of crystal formation and stability loss were observed for HMEDI packaged to prevent moisture absorption. This indicates that formulations made from HMEDI can resist phase change in the presence of exogenous water and may have better stability over a longer shelf life.

[0053] In the present invention, when weight parts, temperature, speed, diameter, time, pressure, frequency, ratio, equivalent, concentration, or other values ​​or parameters are expressed as a range, a preferred range, or a range limited by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range of "0.4 to 0.8" is disclosed, the described range should be interpreted as including the range of "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", "0.5 to 0.55", etc. When a numerical range is described herein, unless otherwise specified, the range is intended to include its end values ​​and all values ​​to two decimal places within the range, and the effects of the present invention can be achieved within the above range.

[0054] In a preferred embodiment, the pharmaceutical composition comprises 20% to 30% by weight of component (a), such as about 24% by weight, based on the total weight of the pharmaceutical composition. In a preferred embodiment, the pharmaceutical composition comprises 10% to 20% by weight of component (a), such as about 16% by weight, based on the total weight of the pharmaceutical composition.

[0055] In a preferred embodiment, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 145°C to 200°C. In a preferred embodiment, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 155°C to 180°C. In a preferred embodiment, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature range of 155°C to 165°C.

[0056] In order to enable the compound of formula (I) of the present invention to better maintain an amorphous state, in a preferred embodiment, the hypromellose acetate succinate is HG grade hypromellose acetate succinate.

[0057] 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 about 0.66.

[0058] The scope in this article can be expressed as from "about" a specific value, and / or to "about" another specific value. When expressing such a scope, another embodiment includes from a specific value and / or to another specific value. Similarly, when a value is expressed as an approximation, by using the antecedent "about", it will be understood that the specific value forms another embodiment. It will be further understood that the endpoints of each range are important relative to the other endpoint and independently of the other endpoint. It should also be understood that many values ​​are disclosed herein, and in addition to the value itself, each value is also disclosed herein as "about" that specific value. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It should also be understood that when disclosing "less than or equal to" the value, "greater than or equal to the value", the possible range between these values ​​is also disclosed, as appropriately understood by those skilled in the art. For example, if the value "10" is disclosed, then "less than or equal to 10" and "greater than or equal to 10" are also disclosed.

[0059] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 24" includes ±5% of 24, or from 22.8 to 25.2; "about 16" includes ±5% of 16, or from 15.2 to 16.8; "about 0.66" includes ±5% of 0.66, or from 0.627 to 0.693.

[0060] In a preferred embodiment, the pharmaceutical composition further comprises 50% to 70% by weight, for example 55% to 65% by weight, of one or more pharmaceutically acceptable excipients, based on the total weight of the pharmaceutical composition, wherein the pharmaceutically acceptable excipients are selected from one or more of the following: water-soluble fillers, water-insoluble fillers, disintegrants, glidants and lubricants.

[0061] In the present invention, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to an individual.

[0062] In the present invention, the term "pharmaceutically acceptable excipient" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with subjects and active ingredients (i.e., capable of inducing the desired therapeutic effect without causing any undesirable local or systemic effects), which are well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995).

[0063] In order to better assist wetting and capillary action as a water-soluble filler and to better improve the tableting properties of the final mixture of the present invention, compared with other water-soluble fillers, in a preferred embodiment, the water-soluble filler is mannitol, such as mannitol M100.

[0064] In order to better assist solid crushing as a water-insoluble filler and better adjust the granulation density of the present invention, compared with other water-insoluble fillers, in a preferred embodiment, the water-insoluble filler is microcrystalline cellulose, such as microcrystalline cellulose PH102.

[0065] In order to better assist the solid disintegration and crushing of the tablet of the present invention, compared with other disintegrants, in a preferred embodiment, the disintegrant is cross-linked carboxymethyl cellulose sodium.

[0066] In order to better promote the flow of the powder of the present invention, compared with other glidants, in a preferred embodiment, the glidant is colloidal silicon dioxide, such as colloidal silicon dioxide M5P.

[0067] In order to better prevent agglomeration and adhesion in the production equipment of the pharmaceutical composition of the present invention, compared with other lubricants, in a preferred embodiment, the lubricant is magnesium stearate, such as magnesium stearate 2257.

[0068] The above-mentioned excipients are preferably pharmaceutically inert, or may have a synergistic or additive effect to enhance the therapeutic activity of the pharmaceutical composition, and the above-mentioned excipients are only listed. The excipients actually used in the present invention are not limited to the above-mentioned excipients and can be adjusted according to actual conditions to achieve the effects of the present invention.

[0069] In order to enhance the compressibility of the granules of the present invention, in a preferred embodiment, 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. When the weight ratio is less than 30%, the disintegration time of the tablet will be significantly prolonged, and when the weight ratio is higher than 35%, the granules will be mixed unevenly.

[0070] In order to enhance the compressibility of the particles of the present invention, in a preferred embodiment, the pharmaceutical composition further comprises 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. When the weight ratio is less than 20%, the particles will have poor compressibility and low hardness, and when the weight ratio is higher than 25%, the particles will be unevenly mixed.

[0071] In order to make the particles of the present invention show a roughly linear correlation between the increase in tableting pressure, the increase in tablet hardness and the increase in disintegration time, in a preferred embodiment, the pharmaceutical composition further comprises 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. When the weight proportion is less than 0.2%, the disintegration time of the tablet will be significantly prolonged, and when the weight proportion is higher than 1%, the tablet will disintegrate too quickly and disintegrate in the oral cavity during administration.

[0072] In a preferred embodiment, the pharmaceutical composition further comprises 1% to 3% by weight of a glidant, for example, about 1.5% by weight, based on the total weight of the pharmaceutical composition. When the weight ratio is less than 1%, the granules will have poor fluidity, and when the weight ratio is higher than 3%, the granules will have too low density and poor compressibility.

[0073] In order to reduce the discharge force of the tablet of the present invention, in a preferred embodiment, the pharmaceutical composition further comprises 1% to 3% by weight of a lubricant, for example, about 1.5% by weight, based on the total weight of the pharmaceutical composition. When the weight ratio is less than 1%, the punch will stick during the tableting process, and when the weight ratio is higher than 3%, the dissolution of the tablet will be reduced.

[0074] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 33" includes ±5% of 33, or from 31.35 to 34.65; "about 22" includes ±5% of 22, or from 20.9 to 23.1; "about 0.5" includes ±5% of 0.5, or from 0.475 to 0.525; "about 1.5" includes ±5% of 1.5, or from 1.425 to 1.575.

[0075] In a preferred embodiment, the pharmaceutical composition is in the form of tablets, granules or capsules. In a preferred embodiment, the pharmaceutical composition further comprises one or more drugs and / or extracts.

[0076] In a preferred embodiment, the drug is an anti-fatty liver drug and / or an anti-cancer drug.

[0077] According to another aspect of the present invention, there is provided a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: (1) mixing the sieved component (a) with the 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 extrudate; (3) cooling the extrudate; and (4) pulverizing, granulating and sieving the cooled extrudate to obtain granules of the pharmaceutical composition.

[0078] In a preferred embodiment, the method further comprises the following steps:

[0079] (5) The granules are mixed with one or more sieved pharmaceutically acceptable excipients and dried to form tablets or capsules.

[0080] In a preferred embodiment, the mixing includes first mixing the glidant and part of the water-insoluble filler for a first time; 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.

[0081] In a preferred embodiment, the component (b) is HG grade hydroxypropyl methylcellulose acetate succinate. In a preferred embodiment, the water-soluble filler is mannitol, such as mannitol M100. In a preferred embodiment, the water-insoluble filler is microcrystalline cellulose, such as microcrystalline cellulose PH102. In a preferred embodiment, the disintegrant is cross-linked sodium carboxymethyl cellulose. In a preferred embodiment, the glidant is colloidal silicon dioxide, such as colloidal silicon dioxide M5P. In a preferred embodiment, the lubricant is magnesium stearate, such as magnesium stearate 2257.

[0082] In a preferred embodiment, a mixture of components (a) and (b) is extruded using a twin screw hot melt extruder, wherein the screw diameter of the twin screw hot melt extruder is between 8 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 extruder is 18 mm. In a preferred embodiment, the extrusion speed is 75 rpm to 125 rpm, for example, about 100 rpm.

[0083] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 100" includes ±5% of 100, or from 95 to 105.

[0084] In a preferred embodiment, steps (1) to (5) of the method include any one or more of the following items [1] to

[28] : [1] the weight loss measurement result of drying in step (1) is not higher than 2%; [2] the drying temperature in step (1) is 55°C to 65°C, for example, about 60°C; [3] the pulverization speed in step (1) is 5000rpm to 6000rpm, for example, about 5500rpm; [4] the sieve in step (1) is a 30-mesh sieve or a 40-mesh sieve; [5] the mixing time in step (1) is 10min [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

[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 melt pressure of the extruder in step (2) is not higher than 150 bar;

[14] the load pressure of the extruder in step (2) is not higher than 80%, 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 rate of the extruder is 0.1 kg / h to 10 kg / h;

[17] the mesh size of the pulverization in step (4) is about 2 mm;

[18] the frequency of the pulverization in step (4) is 35 Hz to 45 Hz, for example, about 40 Hz;

[19] the speed of the pulverization in step (4) is 5000 rpm to 6000 rpm, for example, about 5500 rpm;

[20] the rotation speed of the granulation in step (4) is 5000 rpm to 6000 rpm, for example, about 5500 rpm;

[21] the mesh size of the granulation in step (4) is about 0.8mm;

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

[23] the particle size of the particles in step (4) is not higher than 250μm, for example, 100μm to 250μm;

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

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

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

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

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

[0085] Among them, regarding "

[23] the particle size of the particles in step (4) is not more than 250 μm, for example, 100 μm to 250 μm", the present invention investigates the effect of particle size on the dissolution profile of the hot melt extrudate dispersed intermediate (HMEDI). The hot melt extrudate dispersed intermediate (HMEDI) was milled and sieved to separate three particle size distributions (PSD): samples of <100 μm, 100-250 μm and >250 μm. The dissolution profiles of HMEDI particles with particle sizes <100 μm and 100-250 μm were similar to those of the SDD; larger particles with particle sizes >250 μm could not be dissolved smoothly and tended to agglomerate, form gels and produce lower concentrations of free compounds of formula (I) under SGF and SIF conditions. Based on these results, a PSD of 100 to 250 μm with suitable dissolution characteristics was selected for further development, and tablet blend excipients with similar PSDs were used to support suitable mixing uniformity. Hot melt extrusion dispersion intermediate (HMEDI) of the desired PSD was produced by crushing and sieving and directly using a hammer mill (with appropriate hammer speed and screen size). These batches of hot melt extrusion dispersion intermediate (HMEDI) were used for tableting feasibility studies.

[0086] In the present invention, "about" refers to a value within the range of ±5% of a specific value. For example, "about 60" includes ±5% of 60, or from 57 to 63; "about 5500" includes ±5% of 5500, or from 5225 to 5775; "about 15" includes ±5% of 15, or from 14.25 to 15.75; "about 20" includes ±5% of 20, or from 18 to 22; "about 90" includes ±5% of 90, or from 85.5 to 94.5; "about 130" includes ±5% of 1 ±5% of 30, or from 123.5 to 136.5; “about 160” includes ±5% of 160, or from 152 to 168; “about 2” includes ±5% of 2, or from 1.9 to 2.1; “about 40” includes ±5% of 40, or from 38 to 42; “about 0.8” includes ±5% of 0.8, or from 0.76 to 0.84; “about 4” includes ±5% of 4, or from 3.8 to 4.2.

[0087] According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and treating fatty liver. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and treating cancer. According to another aspect of the present invention, there is provided a use of the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and treating acne.

[0088] In the present invention, the term "prevention" includes "treatment" and "prevention", unless there is a specific description to the contrary. The terms "treatment" and "treatment" should be understood accordingly. In the present invention, the term "treatment" includes alleviating, inhibiting or improving the symptoms or conditions of the disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of diseases or symptoms, such as controlling the development of diseases or conditions; alleviating diseases or symptoms; reducing diseases or symptoms; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a pharmaceutical composition or a pharmaceutical preparation, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed administration or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the circumstances of administration.

[0089] According to another aspect of the present invention, there is provided a pharmaceutical composition as described above, for use in preventing and / or treating fatty liver in a subject. According to another aspect of the present invention, there is provided a pharmaceutical composition as described above, for use in preventing and / or treating cancer in a subject. According to another aspect of the present invention, there is provided a method for preventing and / or treating fatty liver in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described above. According to another aspect of the present invention, there is provided a method for preventing and / or treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described above. According to another aspect of the present invention, there is provided a method for preventing and / or treating acne in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described above.

[0090] In the present invention, the term "subject" is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse or cattle, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects representing fatty liver models or cancer models. Preferably, the subject is a human. The "effective amount" of the pharmaceutical composition or preparation used in the present invention can obtain the desired treatment and / or preventive effect. The effective amount for this purpose will depend on, for example, the pharmaceutical composition, the mode of administration, the stage and severity of the disease to be treated, the individual's body weight and overall health, and the judgment of the prescribing physician. The administration of the dosage can be once a week, or two days or once a day, or even several times a day. The dosage unit can be administered in a short period of time (e.g., weeks to months) or longer time periods (months to years).

[0091] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out according to conventional conditions or conditions recommended by the manufacturer.

[0092] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0093] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in this patent specification can be used in combination with any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0094] Example

[0095] 1. Investigation of hot melt extrusion solid dispersion process

[0096] The hot melt extrusion process is to mix a mixture of 60% of the compound of formula (I) and 40% of HPMCAS-HG in a screw-driven extruder cavity and heat and melt to produce a transparent and uniform amorphous extrudate. DSC and TGA analysis of the compound of formula (I) showed that its melting point was about 145°C, and weight loss occurred above 250°C, and the weight loss indicated that decomposition occurred. The DSC melting transition temperature of HPMCAS-HG was about 120°C, and the TGA weight loss indicated that decomposition occurred above 200°C. Based on this thermal characterization, 160°C was selected as the hot melt extrusion (HME) processing temperature, and the upper limit temperature was selected as 180°C to avoid decomposition of the compound of formula (I).

[0097] To improve the uniformity of the extrudate, the compound of formula (I) and HPMCAS-HG need to be premixed before hot melt extrusion. Since the particle size distribution D (v, 0.9) of HPMCAS-HG is usually less than about 1000 μm, its particle size distribution is reduced to D (v, 0.9) less than 250-300 μm through a pulverization step. The particle size distribution of HPMCAS-HG is controlled to be closer to the particle size distribution D (v, 0.9) of the compound of formula (I) (about less than 100-200 μm) to support the uniformity of the mixing process.

[0098] The premixed material is fed directly into the extrusion cavity at the main feed port of the 18mm twin-screw extruder. The extruder screw group is designed with a strong mixing zone to maintain moderate shear force to avoid material degradation. The extruder is driven by the screw and the feed rate, the cavity temperature is 160°C, the processing rate is about 1-2kg / h, and the process response values ​​of the extruder product temperature, extrusion load pressure% and melt pressure are monitored during the process. A load pressure exceeding 80% may shut down the extruder, while a higher melt pressure will cause the product temperature to rise and may cause product degradation. The process parameters and target ranges of the hot melt extrusion of the 18mm twin-screw extruder are shown in Table 1.

[0099] Table 1 18mm twin-screw extruder hot melt extrusion process parameters and target ranges

[0100] Hot melt extrusion parameters scope Screw speed 75-125rpm Cavity temperature 155-165℃ Product temperature 155-165℃ Extruder load pressure % 25-65％

[0101] After the process parameters are optimized, representative samples are collected at the beginning, middle and end of the extrusion (0, 30, 60, 180, 360 and 390 minutes) during the extrusion process of about 6.5 hours to monitor the product quality. There is no significant change in the relevant substances in the product, and the crystal form detection is amorphous. In addition, the present invention controls and pre-treats HPMCAS-HG: about 10g HPMCAS-HG is taken for drying loss determination, and the test result should be ≤2%, otherwise it is dried at 60±5℃ until the drying loss test result is ≤2%. It is crushed using a FHM-67 granulator and then passed through a 40-mesh sieve. The parameters are shown in Table 2.

[0102] Table 2 HPMCAS-HG crushing parameters

[0103]

[0104]

[0105] In addition, the present invention uses API in monohydrate crystal form, amorphous API, and hot melt extrudate dispersion intermediate to conduct equilibrium solubility experiments in buffer media under different pH conditions. The data are shown in Tables 3 and Figure 1 shown.

[0106] Table 3 Summary of equilibrium solubility (μg / ml) of monohydrate crystalline API, amorphous API, and hot melt extrudate dispersed intermediates

[0107]

[0108]

[0109] From Table 3 and Figure 1 It can be seen that (1) the hot melt extrusion dispersion intermediate can significantly improve the solubility of API in different media; (2) the solubility of the amorphous and monohydrate forms without hot melt extrusion process is basically the same, with no obvious improvement, indicating that the original amorphous form has no intrinsic ability to improve solubility. It is speculated that the amorphous API without hot melt extrusion will quickly precipitate into a more stable monohydrate form in the aqueous medium; (3) the hot melt extrusion dispersion intermediate can inhibit the rapid precipitation of API into a more stable monohydrate form.

[0110] The hot-melt extrusion dispersed intermediate of the present invention can be crushed to a selected particle size distribution. In addition to this advantage, the preparation obtained by the melt extrusion process also has the following advantages: ① The hot-melt extrusion process can well combine the drug and the polymer through the action of thermal energy and mechanical energy to prepare an amorphous state, and can maintain the stability of the drug for a long time, improve the solubility of the drug, and is more conducive to improving the bioavailability of poorly soluble drugs in the body; ② The hot-melt extrusion technology does not require a solvent when applied, and the solvent cost and environmental pressure are reduced accordingly; ③ At the same time, compared with spray drying, the instruments and equipment used for hot-melt extrusion occupy a small site space, especially at the scale-up production level.

[0111] 2. Secondary crushing process investigation

[0112] The present invention investigates the effect of particle size on the dissolution profile of a hot melt extrudate dispersed intermediate (HMEDI). The hot melt extrudate dispersed intermediate (HMEDI) was milled and sieved to separate three particle size distributions (PSD): samples of <100 μm, 100-250 μm and >250 μm. HMEDI particles with particle sizes <100 μm and 100-250 μm dissolved completely; larger particles with a particle size >250 μm could not dissolve smoothly and tended to agglomerate, forming gels and producing lower concentrations of free compounds of formula (I) under SGF and SIF conditions. Based on these results, a PSD with suitable dissolution characteristics was selected for further development, and tablet blend excipients with similar PSDs were used to support suitable mixing uniformity.

[0113] Reference value: D 90 Less than 300μm (more stringent requirements, D 90 The target is less than 50 mesh), D 50 Less than 120μm (more stringent requirements, D 50 The target is less than 120 mesh or D40 Less than 140 mesh).

[0114] Hot melt extrusion dispersion intermediate (HMEDI) of the desired PSD was produced by crushing and sieving and directly using a hammer mill (with appropriate hammer speed and screen size). These batches of hot melt extrusion dispersion intermediate (HMEDI) were used for tableting feasibility studies.

[0115] The secondary crushing process enables the material to have better fluidity and crushability during the secondary granulation, and has better dissolution and release behavior.

[0116] The material after 40 mesh sieve was tested for particle size distribution, and the particle size distribution is shown in Table 4.

[0117] Table 4 Particle size distribution of HPMCAS-HG after crushing and passing through 40 mesh sieve

[0118]

[0119] From the particle size distribution, it can be seen that under the pulverization conditions, D(v,0.9)≈270μm, which meets the requirement that the HPMCAS-HG particle size distribution D(v,0.9) is less than 250-300μm. The pulverization process can effectively control the particle size distribution range of HPMCAS-HG.

[0120] HMEDI pulverization: Bulk density and particle size distribution of pulverized powder intermediates

[0121] The particle size of HMEDI plays an important role in the downstream process of the final solid dosage form. Therefore, a study of the pulverization process was conducted to explore the effects of pulverization speed and screen size on the particle size distribution of the pulverized extrudate. 60% of the hot melt extrudate of the compound of formula (I) was fed from the extruder to a cooling roller to isolate the extrudate as a free-flowing sheet. Under various pulverization conditions, about 150 g of the HME flake sample of the compound of formula (I) was fed into a hammer mill equipped with a forward hammer head for pulverization to significantly reduce the particle size. The pulverization speed and screen size were changed until the particle size distribution D (v, 0.9) continued to decrease to about less than 300 μm, and D (v, 0.5) was about less than 120 μm (as shown in Table 5, test numbers 1-3).

[0122] Table 5 In-process particle size test results of the hot melt extrudate of 60% of the compound of formula (I) crushed

[0123]

[0124]

[0125] The data show that the particle size decreases as the pulverization speed increases. Although there is no significant difference in particle size as the screen size changes, it is observed that larger particles are retained in the 27 mesh sieve, so the 27 mesh sieve is rejected. According to the results of the pulverization study, the pulverization parameters finally selected are shown in Table 6. 4kg of flaky compound of formula (I) extrudates were used to amplify the HME pulverization process to prepare HMEDI. By XRPD and DSC analysis, the HMEDI batch was amorphous. The particle size distribution is unimodal, and D (v, 0.9) is approximately less than 222 μm (as shown in Table 5, test number 4). It was found that the bulk density and tap density were 0.55g / mL and 0.71g / mL, respectively. The bulk density and particle size distribution were controlled within a range suitable for uniform mixing with tableting excipients.

[0126] Table 6 Final comminution parameters of hot melt extrudate (HMEDI) containing 60% of the compound of formula (I)

[0127] project Setting reference values Crushing speed 5500rpm Screen size 20 mesh Mill configuration Hammer forward

[0128] Among them, 20 mesh is the screen that comes with the secondary granulator.

[0129] In the intermediate test batch production of various specifications of the present invention (i.e., a small-scale test of the product before large-scale mass production), the material after hot melt extrusion cooling is taken and first-stage crushing is performed by a crusher equipped with a 2.0 mm aperture screen, and the crushing frequency is 40±5 Hz; after the crushing, a granulator equipped with a 0.8 mm aperture screen is used for secondary granulation, and the crushing speed is 5500±500 rpm, and the particles after the secondary granulation are passed through a 40-mesh sieve to remove large particles. The parameters of the secondary granulation are shown in Table 7.

[0130] Table 7 Secondary granulation parameters of intermediate test batch

[0131] project Setting reference values Rotation speed 5500±500rpm Screen size 0.8mm Mill configuration Hammer forward Alarm temperature 50℃

[0132] During the production of intermediate test batches (batch numbers R4020001 to R4020009), about 50 g of material after secondary granulation was taken from each batch for particle size distribution testing. The sieves selected were 40 mesh, 50 mesh, 60 mesh, 70 mesh, and 140 mesh. The results showed that the particle size distribution D(v, 0.9) after secondary granulation of the intermediate test batches was less than 270 μm, and D(v, 0.5) was about less than 120 μm, which met the requirements of the controlled particle size distribution D(v, 0.9) being less than 300 μm and D(v, 0.5) being less than 120 μm.

[0133] The bulk density and tap density of the intermediate test batch were controlled within the range suitable for uniform mixing with tableting excipients, which were 0.56-0.65 and 0.70-0.73 respectively.

[0134] 3. Selection of excipients in drug compositions - optimization of direct tableting of final mixed granules

[0135] Increasing the amount of friable material in the formulation improves the compression curve, tablet appearance, and surface strength, thereby improving friability performance. Early formulations were tableted using a single punch tablet press, and 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 tableting pressure and tablet hardness, disintegration was too fast (<1min). The disintegration time is inversely proportional to the proportion of cross-linked sodium carboxymethyl cellulose used in the formulation. When 0.5% w / w cross-linked sodium carboxymethyl cellulose was used, the final mixed granules showed a roughly linear correlation between increased tableting pressure, increased tablet hardness, and increased disintegration time. In order to optimize the formulation prescription, increasing the amount of magnesium stearate 2257 lubricant from 0.5% to 1.5% can reduce the expulsion force to less than 300N. The final optimized prescription is shown in Table 8.

[0136] Table 8 Content of each ingredient in the optimized prescription

[0137]

[0138] The small batch of tablets obtained by tableting on a single punch tablet press based on the optimized formulation formula had suitable tablet hardness and disintegration results. 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.

[0139] Table 9 Average compression force, hardness and disintegration time of 25 mg and 100 mg tablets

[0140]

[0141] The formulation composition during process scale-up is shown in Table 10.

[0142] Table 10 Formulation composition during process scale-up

[0143]

[0144] Note: * as anhydrous free base equivalent. The actual amount of the compound of formula (I) will be adjusted according to the content of each batch of raw materials.

[0145] 4. Impurity profile of hot melt extrudate dispersed intermediate (HMEDI) and stability under long-term storage conditions at 25°C

[0146] This study found that since the hot melt extrusion process involves melting and mixing the API (i.e., compound of formula (I)) with the HPMCAS-HG polymer at elevated temperatures to form an amorphous extrudate, the hot melt extrudate dispersed intermediate (HMEDI) was evaluated using a validated current method for formulation-related substances to investigate any purity differences in the API in the HMEDI compared to the initial purity of the API used in each batch. No new degradation products were found in all batches of hot melt extrudate dispersed intermediate (HMEDI), and the purity and impurities remained essentially unchanged compared to the corresponding API batches used, indicating that no significant degradation occurred during the hot melt extrusion process and no chemical reaction occurred with the polymer excipients.

[0147] The stability test results of the tablets of the present invention of the three specifications in Table 10 stored at 40°C for 6 months and at 25°C for 18 months showed that the purity and content of the HMEDI batch remained basically unchanged, with no significant degradation trend; the water content did not change significantly; the XRPD results showed amorphous state, indicating that the crystal form did not change during storage; and the DSC remained unchanged. The above results show that the preparation is stable.

[0148] 5. Tablet preparation process

[0149] Pretreatment of raw materials

[0150] Before tablet production, the crystal form and particle size distribution of the compound of formula (I) are determined. The crystal form of the reference compound of formula (I) is the free base monohydrate crystal form, and the reference particle size distribution should meet D 50 ≤105.77μm and D 90 ≤229.88μm.

[0151] Take Hydroxypropyl Methylcellulose Acetate Succinate AS-HG for drying loss test, the test result should be ≤2%, otherwise dry at 60±5℃ until the moisture test result is ≤2%. Use FHM-67 granulator equipped with 0.8mm aperture screen to crush, the crushing speed is 5500±500rpm. Pass the crushed material through 40 mesh sieve.

[0152] Colloidal silicon dioxide M5P, microcrystalline cellulose PH102, mannitol M100, and cross-linked sodium carboxymethyl cellulose were sieved through a 30-mesh sieve, magnesium stearate 2257 was sieved through a 40-mesh sieve, and the compound of formula (I) was sieved through a 30-mesh sieve to remove possible lumps of the materials during storage.

[0153] ② Premix

[0154] The compound of formula (I) and hydroxypropyl methylcellulose acetate succinate AS-HG were weighed and added into the 5L hopper of the HLS50 laboratory mixer. The mixing time was set to 15 min and the mixing speed was set to 20 rpm for mixing.

[0155] Hot melt extrusion granulation

[0156] Hot melt extrusion: Set the extrusion parameters according to Table 11. Take the premixed raw materials and add them manually to the hot melt extruder. Adjust the feeding speed and the extrusion screw speed to match the feeding speed with the discharge speed.

[0157] Table 11 Extrusion parameters of hot melt extrusion granulation

[0158]

[0159] Crushing: Take the material after hot melt extrusion and cooling, and use a crusher equipped with a 2.0mm aperture screen to perform primary crushing, and the crushing frequency is 40±5Hz; after the crushing, use a granulator equipped with a 0.8mm aperture screen to perform secondary granulation, and the crushing speed is 5500±500rpm, and the particles after secondary granulation are passed through a 40-mesh sieve.

[0160] Total Mix

[0161] Total Mix 1

[0162] According to the weight after crushing and the prescription conversion, colloidal silicon dioxide M5P and part of microcrystalline cellulose PH102 are first mixed manually and added to a 10L hopper. Then the granules after hot-melt granulation, mannitol M100, cross-linked sodium carboxymethyl cellulose and the remaining microcrystalline cellulose PH102 are added to the above hopper. The mixing time is set to 15 minutes and the mixing speed is 20 rpm for mixing.

[0163] Total Mix 2

[0164] Add magnesium stearate 2257 after passing through a 40-mesh sieve into the mixing hopper, set the mixing time to 4 minutes, and mix at a mixing speed of 20 rpm.

[0165] After the final mixing, the drying loss of the granules should be ≤5.0%, and the content of the compound of formula (I) should be 90.0% to 110.0% of the labeled content.

[0166] Tablet pressing

[0167] The tablets of the present invention are tableted using a high-speed tablet press, and the weight difference of each tablet is controlled within ±7.5%, the average weight difference is within ±5.0%, the hardness range is 9.0-12.0 kp, the friability is ≤0.5%, and the disintegration time limit is required to be completely disintegrated within 15 minutes.

[0168] bottled

[0169] Use a tablet counting plate with 30 tablets, fill them together into a high-density polyethylene bottle for oral solid medicine, tighten the safety cap, and seal it with aluminum foil using a sealing machine.

[0170] Check the sealed sample bottles and ensure that the sealing meets the requirements.

[0171] Hot melt extrusion dispersion intermediates (HMEDIs) are designed to maintain the API in an amorphous form in an aqueous environment, but also to rapidly release the API in the intestine for systemic absorption. Four tablet strengths [25 mg, 50 mg, 75 mg, and 100 mg] were studied. Four batches of the total blend with appropriate properties were pressed using different punch die sets. The formulations are shown in Table 12, and the formulation dosage was scaled up in equal proportions.

[0172] Table 12 Composition of the components in the total blend of the tablets of the present invention in the strengths of 25 mg, 50 mg, 75 mg and 100 mg

[0173]

[0174] 6. Tablet testing

[0175] 6.1 Dissolution

[0176] 6.1.1 Dissolution conditions

[0177] Test objects: intermediate test batches (batch numbers R4020001, R4020002, R4020007), the preparation process of which refers to “5. Tablet preparation process flow”.

[0178] Dissolution medium: as shown in Table 13.

[0179] Method: Chinese Pharmacopoeia Volume IV General Chapter 0931 Second Method Paddle Method.

[0180] Speed: 75 revolutions per minute.

[0181] Sampling point: Take samples at set time points and take the filtrate as the test solution without adding an equal amount of isothermal dissolution medium.

[0182] Table 13 Dissolution curve study conditions

[0183]

[0184] Among them, 0.01 mol / L hydrochloric acid solution containing 0.5% SLS (method 1) was used as the standard dissolution medium.

[0185] 6.1.2 Determination method

[0186] Sigma Ascentis Express C 18 2.7um, 4.6×100mm chromatographic column or equivalent chromatographic column, with water-acetonitrile = 50:50 (containing 0.1% formic acid (chromatographic grade)) as mobile phase, flow rate: 0.75ml / min; column temperature: 40℃; detection wavelength: 240nm. Accurately weigh about 15mg of the reference compound of formula (I) and place it in a 100mL volumetric flask, add 20ml of acetonitrile and ultrasonically dissolve it, add dissolution medium to dilute to the scale, as the reference solution. Accurately measure 3μl of the reference solution and the test solution, respectively, inject them into the liquid chromatograph, record the chromatogram, calculate the cumulative dissolution percentage at each time point by peak area according to the external standard method, and draw a dissolution curve.

[0187] 6.1.3 Results

[0188] The dissolution results of the intermediate test samples of 25 mg (batch number R4020001), 50 mg (batch number R4020002) and 75 mg tablets (batch number R4020007) in four dissolution media are shown in Tables 14, 15, 16 and 17.

[0189] Table 14 Summary of dissolution results of the tablets of the present invention in 0.01 mol / L hydrochloric acid solution containing 0.5% SLS

[0190]

[0191]

[0192] Table 15 Summary of dissolution results of the tablets of the present invention in pH 3.0 citric acid buffer containing 0.5% SLS

[0193]

[0194] Table 16 Summary of dissolution results of the tablets of the present invention in pH 4.5 acetate buffer containing 0.5% SLS

[0195]

[0196]

[0197] Table 17 Summary of dissolution results of the tablets of the present invention in pH 6.8 phosphate buffer containing 0.5% SLS

[0198]

[0199] 6.1.4 Conclusion

[0200] All three tablet specifications were tested under standard non-sedimentation dissolution conditions. The release patterns of tablets of various specifications were similar, with a release rate of more than 80% at 30 minutes and complete release at about 45-60 minutes.

[0201] The dissolution behaviors in the four different media were basically the same, and the dissolution curves obtained had small differences between batches. The RSD of the dissolution values ​​at all corresponding time points of the four dissolution curves of the three batches of tablets was <10%, with similar dissolution trends and endpoints.

[0202] And hot melt extrudate dispersion intermediates (HMEDIs) are designed to maintain the API in an amorphous form in an aqueous environment, but also to rapidly release the API in the intestine for systemic absorption.

[0203] 6.2 Pharmacokinetic parameters

[0204] The preparation process of tablets with batch number R4020002 and early research and development batch number G-18-014A was carried out according to “5. Tablet preparation process flow”, and their pharmacokinetic parameters are shown in Table 18.

[0205] Table 18 Plasma drug concentration data and pharmacokinetic parameters of tablets with batch number R4020002 and batch number G-18-014A after a single oral administration to beagle dogs (mean results of three beagle dogs).

[0206]

[0207] The tablets of the present invention have similar in vitro release behaviors, indicating that the dissolution conditions in the quality standards can better reflect the in vitro and in vivo correlation.

[0208] The embodiments of the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core idea. At the same time, changes or deformations made by those skilled in the art based on the ideas of the present invention, the specific implementation methods and application scope of the present invention, all belong to the scope of protection of the present invention. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A pharmaceutical composition comprising a heterocyclic compound, characterized in that: The pharmaceutical composition comprises the following components: (a) Compound of formula (I) (b) Hydroxypropyl methylcellulose acetate succinate or copovidone; wherein component (a) and component (b) are mixed and subjected to hot melt extrusion; The weight ratio of component (b) to component (a) is 0.4 to 0.

8.

2. The pharmaceutical composition according to claim 1, characterized in that Components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature ranging from 145°C to 200°C; Preferably, components (a) and (b) are mixed and subjected to hot melt extrusion at a temperature in the range of 155°C to 180°C; Preferably, components (a) and (b) are mixed and subjected to hot melt extrusion 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 between component (b) and component (a) is 0.5 to 0.7; More preferably, the weight ratio between component (b) and component (a) is about 0.

66.

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

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The dosage form of the pharmaceutical composition is tablets, granules or capsules; Preferably, the pharmaceutical composition further comprises one or more drugs and / or extracts; More preferably, the drug is an anti-fatty liver drug, an anti-cancer drug and / or an anti-acne drug.

5. A method for preparing the pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: (1) mixing the sieved component (a) with the 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 extrudate; (3) cooling the extrudate; and (4) The cooled extrudate is crushed, sized and sieved to obtain granules of the pharmaceutical composition.

6. The method according to claim 5, characterized in that The method further comprises the following steps: (5) mixing and drying the granules with one or more sieved pharmaceutically acceptable excipients to form tablets or capsules; Preferably, the mixing includes first mixing the glidant and part of the water-insoluble filler for a first time; then adding the granules, the water-soluble filler, the disintegrant and the remaining water-insoluble filler for a second time; and finally adding the lubricant for mixing; More preferably, the component (b) is HG grade hydroxypropyl methylcellulose acetate succinate; More preferably, the water-soluble filler is mannitol, such as mannitol M100; More preferably, the water-insoluble filler is microcrystalline cellulose, such as microcrystalline cellulose PH102; More preferably, the disintegrant is cross-linked carboxymethyl cellulose sodium; More preferably, the glidant is colloidal silicon dioxide, such as colloidal silicon dioxide M5P; More preferably, the lubricant is magnesium stearate, such as magnesium stearate 2257; Preferably, the mixture of components (a) and (b) is extruded using a twin-screw hot melt extruder, wherein the screw diameter of the twin-screw hot melt extruder is between 8 mm and 50 mm, and the extrusion speed is between 10 rpm and 300 rpm; Preferably, the screw diameter of the twin-screw hot melt extruder is 18 mm; Also preferably, the extrusion speed is 75 rpm to 125 rpm, such as about 100 rpm.

7. The method according to claim 5 or 6, characterized in that: Steps (1) to (5) of the method include any one or more of the following items [1] to [28]: [1] The weight loss during drying in step (1) is not more than 2%; [2] The drying temperature in step (1) is 55°C to 65°C, for example, about 60°C; [3] The speed of the pulverization in step (1) is 5000 rpm to 6000 rpm, for example, about 5500 rpm; [4] The sieve in step (1) is a 30-mesh sieve or a 40-mesh sieve; [5] The mixing time in step (1) is 10 min to 20 min, for example, about 15 min; [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 extruder zones 4 to 10 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 melt pressure of the extruder in step (2) is not more than 150 bar; [14] The load pressure of the extruder in step (2) is not higher than 80%, 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 rate of the extruder in step (2) is 0.1 kg / h to 10 kg / h; [17] The sieve aperture of the crushing in step (4) is about 2 mm; [18] The frequency of the pulverization in step (4) is 35 Hz to 45 Hz, for example, about 40 Hz; [19] The speed of the pulverization in step (4) is 5000 rpm to 6000 rpm, for example, about 5500 rpm; [20] The rotation speed of the pelletizing in step (4) is 5000 rpm to 6000 rpm, for example, about 5500 rpm; [21] The sieve aperture of the granulation in step (4) is about 0.8 mm; [22] The sieve in step (4) is a 40 mesh sieve; [23] The particle size of the particles in step (4) is not greater than 250 μm, for example, 100 μm to 250 μm; [24] The time of the first mixing in step (5) is 10 min to 20 min, for example, about 15 min; [25] The rotation speed of the first mixing in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm; [26] The time of the second mixing in step (5) is 2 min to 6 min, for example, about 4 min; [27] The rotation speed of the second mixing in step (5) is 15 rpm to 25 rpm, for example, about 20 rpm; [28] The weight loss measurement result of drying in step (5) is not more than 5%.

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

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

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

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