Enzalutamide pharmaceutical composition, preparation method therefor, and use thereof

Abstract

The present invention relates to an enzalutamide pharmaceutical composition, a preparation method therefor, and use thereof. The pharmaceutical composition comprises an active ingredient and carrier materials. The active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof. The carrier materials include a first carrier material and a second carrier material. The first carrier material is acrylic resin and a derivative thereof. The second carrier material is hydroxypropyl methylcellulose and a derivative thereof. The total impurity level of the pharmaceutical composition is relatively low, and the pharmaceutical composition has excellent physical stability and chemical stability.

Description

Enzalutamide pharmaceutical composition, and preparation method and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, and in particular to an enzalutamide pharmaceutical composition, and preparation method and use thereof. BACKGROUND

[0002] Enzalutamide has a chemical name of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfonimidoyl-imidazolin-1-yl}-2-fluoro-N-methylbenzamide, a molecular formula of C 21 H 16 F4N4O2S, and a structural formula as follows:

[0003] Enzalutamide is a male hormone receptor inhibitor, which can competitively inhibit the binding of sex hormones to the receptor, and can inhibit the nuclear transport of the androgen receptor and the interaction of the receptor with DNA, thereby inhibiting the proliferation of prostate cancer cells and inducing cell death.

[0004] Enzalutamide is a BCS II drug, which has the characteristics of low solubility and high permeability. In addition, enzalutamide is an ionic compound, which has very low solubility in water and is not affected by the pH of the solvent. Such compounds will have various challenges in water solubility when prepared into a pharmaceutical composition or preparation, but the problem of low in vivo bioavailability and poor absorption of such compounds can be solved by preparing into a solubilized preparation (for example, preparing into a solid dispersion solubilized preparation).

[0005] CN105358535A discloses an enzalutamide preparation and a preparation method thereof. In the preparation, a solid dispersion particle is prepared by a spray drying method, the average particle diameter of the particle is less than 50 μm, and the enzalutamide preparation obtains improved solubility and absorption properties.

[0006] CN105030685A discloses an enzalutamide solid dispersion oral preparation, which contains an effective amount of enzalutamide and also contains a water-soluble polymer carrier for dispersing enzalutamide. In the preparation, the enzalutamide solid dispersion is prepared by a spray drying method, and the solubility is improved, and the bioavailability, quality stability and safety are improved. SUMMARY

[0007] Therefore, the purpose of the present application is to provide an enzalutamide pharmaceutical composition, and preparation method and use thereof which overcome the above-mentioned defects of the prior art.

[0008] The present application solves the above technical problems by the following technical solutions:

[0009] In a first aspect, the present application provides a pharmaceutical composition comprising an active ingredient and a carrier material; wherein the active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof; and the carrier material comprises a first carrier material and a second carrier material, the first carrier material is an acrylic resin and its derivatives, and the second carrier material is hydroxypropyl methylcellulose and its derivatives.

[0010] In a second aspect, the present application also provides a preparation method of the pharmaceutical composition of the first aspect, comprising the following steps: providing an active ingredient, a first carrier material, a second carrier material, and optionally a pharmaceutically acceptable adjuvant; mixing the active ingredient, the first carrier material, the second carrier material, and the optional pharmaceutically acceptable adjuvant or directly introducing them into a hot melt extruder; and performing hot melt extrusion on the mixture to obtain the pharmaceutical composition.

[0011] In a third aspect, the present application also provides a pharmaceutical preparation comprising the pharmaceutical composition of the first aspect.

[0012] In an embodiment, the pharmaceutical preparation is a solid preparation. In a preferred embodiment, the pharmaceutical preparation is a tablet.

[0013] In a fourth aspect, the present application also provides a use of the pharmaceutical composition of the first aspect or the pharmaceutical preparation of the third aspect in the preparation of a medicament for preventing or treating a hyperproliferative disease.

[0014] In an embodiment, the hyperproliferative disease is selected from one or more of the following group: benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer, preferably castration-resistant prostate cancer.

[0015] In a fifth aspect, the present application also provides a method for preventing or treating a hyperproliferative disease, comprising the step of administering to an individual in need thereof a prophylactically or therapeutically effective amount of the pharmaceutical composition of the first aspect or the pharmaceutical preparation of the third aspect.

[0016] In an embodiment, the hyperproliferative disease is selected from one or more of the following group: benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer, preferably castration-resistant prostate cancer. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 is a PXRD comparative overlay pattern of Composition 1-1; wherein

[0018] ACC-6M is the test result of Composition 1-1 under 40°C / 75% RH conditions for 6 months;

[0019] ACC-3M is the test result of Composition 1-1 under 40°C / 75% RH conditions for 3 months;

[0020] LT-6M is the test result of Composition 1-1 at 25°C / 60% RH for 6 months;

[0021] LT-3M is the test result of Composition 1-1 at 25°C / 60% RH for 3 months. DETAILED DESCRIPTION

[0022] The present application will be further described in the following detailed description of the application. Such description is for illustrative purposes only and is not intended to limit the application. Other advantages and efficiencies of the application will be readily apparent to those skilled in the art from the disclosure herein. The application can be carried out or implemented by other different embodiments and its

[0023] General Definitions and Terminology

[0024] All publications, patent applications, patents and other references mentioned herein, if any, are incorporated by reference in their entirety.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict between the definitions provided in this document and those provided in the patents, applications, published applications, and other publications identified above, the definition provided in this document controls.

[0026] All percentages, parts, ratios, etc. are by weight unless otherwise indicated.

[0027] When numerical ranges are given, unless expressly stated otherwise, the range is intended to include both the endpoints and all integers and fractions within that range. The scope of the present application is not limited to the specific values recited when defining the range. For example, "1 :0.1 to 1 :6" encompasses 1 :0.1, 1 :0.2, 1 :0.3, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.7, 1 :0.8, 1 :0.9, 1 :1, 1 :1.1, 1 :1.2, 1 :1.3, 1 :1.4, 1 :1.5, 1 :1.6, 1 :1.7, 1 :1.8, 1 :1.9, 1 :2, 1 :2.1, 1 :2.2, 1 :2.3, 1 :2.4, 1 :2.5, 1 :2.6, 1 :2.7, 1 :2.8, 1 :2.9, 1 :3, 1 :3.1, 1 :3.2, 1 :3.3, 1 :3.4, 1 :3.5, 1 :3.6, 1 :3.7, 1 :3.8, 1 :3.9, 1 :4, 1 :4.1, 1 :4.2, 1 :4.3, 1 :4.4, 1 :4.5, 1 :4.6, 1 :4.7, 1 :4.8, 1 :4.9, 1 :5, 1 :5.1, 1 :5.2, 1 :5.3, 1 :5.4, 1 :5.5, 1 :5.6, 1 :5.7, 1 :5.8, 1 :5.9, 1 :6, and any sub-range formed by any two values therein, e.g., 1 :0.2 to 1 :6, 1 :0.3 to 1 :5.5, 1 :0.4 to 1 :5, 1 :0.5 to 1 :4.5, 1 :0.6 to 1 :4, 1 :0.7 to 1 :3.5, 1 :0.8 to 1 :6, 1 :2 to 1 :6, 1 :2 to 1 :6, 1 :3 to 1 :5, etc.

[0028] The terms "about," "approximately," when used with a numerical value, generally mean that the value of the variable and all values of the variable are within experimental error (e.g., within 95% confidence interval for a mean value) or within ±10% of the stated value, or within a wider range (e.g., within ±15%, within ±20%, within ±25%, or within ±30%).

[0029] In the present context, the term "molar ratio" refers to the respective monomers in a polymer (e.g., the first carrier material) being present in a certain molar ratio in the respective polymer (e.g., the first carrier material).

[0030] The terms "comprising," "including," "having," "containing," or "involving," and any variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Those skilled in the art will understand that the terms "comprising" and "including," when used in the following claims, are intended to be construed in the manner set forth in the above paragraph. The term "consisting essentially of limits the scope of a claim to the specified materials or steps and to materials and steps that do not materially affect the basic and novel characteristic(s) of the claimed subject matter. "Consisting essentially of" thus contemplates some minor variations in the claimed subject matter. It is understood that the term "comprising" encompasses the terms "consisting of" and "consisting essentially of."

[0031] The term "selected from the group consisting of" means one or more elements from the group listed thereafter, independently selected, and can include combinations of two or more elements.

[0032] The terms "combination thereof and "mixture thereof, unless otherwise indicated, refer to a multi-component mixture of the recited elements, e.g., two, three, four, and up to the maximum possible multi-component mixture.

[0033] The terms "one or more" or "at least one" as used herein, means one, two, three, four, five, six, seven, eight, nine, or more.

[0034] As used herein, "first," "second," or like designations, when used to refer to elements, components, steps, etc., are used only for convenience in description and are not intended to limit the order or content of such elements, components, steps, etc. Thus, for example, a first material and a second material can be the same or different, and a first step can precede, follow, or be part of a second step.

[0035] In addition, where the number of components or elements of the application is not specified, there is no limit to the number of components or elements that can be present (or exist). Thus, "a" or "one" should be interpreted to "one or at least one" and the singular word form of "a", "an" and "the" include plural references unless the numeric amount clearly indicates a singular form.

[0036] The term "metered ratio" is the proportioning of the various substances by weight. For example, in the present application, the active ingredient (enzalutamide or a pharmaceutically acceptable salt thereof), the carrier material, and the optional pharmaceutically acceptable pharmaceutical adjuvants are proportioned by weight.

[0037] The terms "optional" or "optionally," as used herein, mean that the subsequent recited event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0038] The term "pharmaceutically acceptable" refers to those substances which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0039] The term "pharmaceutically acceptable excipient" refers to those carriers that do not interfere with the biological activity of the active compounds and are nontoxic to the organism in which they are administered. "Pharmaceutically acceptable excipient" includes, but is not limited to, glidants, sweetening agents, fillers, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersing agents, effervescent agents, stabilizers, or emulsifiers. Non-limiting examples of the carrier materials include calcium carbonate, calcium phosphate, various sugars and types of starch, gelatin, vegetable oils, polyethylene glycols, and the like. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0040] The term "active ingredient" refers to a chemical entity that is effective in treating or preventing a disease or condition of interest. In one embodiment, the active ingredient is amantadine or a pharmaceutically acceptable salt thereof.

[0041] The term "pharmaceutical composition" refers to a substance comprising one or more active ingredients in combination with a carrier material and, optionally, one or more pharmaceutically acceptable pharmaceutical excipients. It can be referred to simply as a composition in the present disclosure. For example, pharmaceutical composition 1-1 can be referred to simply as composition 1-1.

[0042] The term "pharmaceutical preparation" and the like refer to a pharmaceutical composition that is to be administered to a patient in need of treatment, which can generally be in the form of a powder, granule, pellet, capsule, tablet, solution, suspension, or patch, etc.

[0043] The term "dispersed at a molecular level" refers to the dispersion of a drug in a carrier material to form a single phase pharmaceutical composition. In the present disclosure, this term can refer to the dispersion of amantadine or a pharmaceutically acceptable salt thereof in a carrier material to form a single phase pharmaceutical composition (also referred to as a solid solution, dispersion, or solid dispersion), the resulting pharmaceutical composition of amantadine or a pharmaceutically acceptable salt thereof having a Tg value different from the Tg values of the carrier material and amantadine raw material.

[0044] The terms "dissolved in", "dispersed at a molecular level", "dispersion", "solid solution", "solid dispersion" are used herein as convenient to describe the pharmaceutical composition of the present disclosure at various stages of preparation and at various temperatures.

[0045] The term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" in relation to a drug, drug unit or active ingredient means a sufficient amount of the drug or agent to be acceptable in terms of side effects, but to achieve the intended effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate effective amount in each case can be determined by a person skilled in the art according to routine experiments.

[0046] The term "stable" can mean stable to heat, light, temperature and / or humidity. For example, the percentage of the maximum related substance or the total amount of related substances of the enzalutamide contained in the pharmaceutical composition or the preparation thereof is below a certain amount after the pharmaceutical composition or the preparation thereof is stored under predetermined conditions. In an embodiment, the percentage of the maximum related substance of enzalutamide after storage at 25°C / 60% RH for 1 month, storage at 25°C / 60% RH for 3 months, storage at 25°C / 60% RH for 6 months, storage at 40°C / 75% RH for 1 month, storage at 40°C / 75% RH for 3 months or storage at 40°C / 75% RH for 6 months can be 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less or 0.2% or less.

[0047] Pharmaceutical composition

[0048] The present application provides a pharmaceutical composition comprising an active ingredient and a carrier material; wherein the active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof; and the carrier material comprises a first carrier material and a second carrier material, the first carrier material is an acrylic resin and its derivatives, and the second carrier material is hydroxypropyl methyl cellulose and its derivatives.

[0049] Active ingredient

[0050] In an embodiment, the active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof.

[0051] As the pharmaceutically acceptable salt of the active ingredient used, it can include, but is not limited to, a salt formed with an inorganic acid, a salt formed with an organic acid, etc. Non-limiting examples of the salt formed with an inorganic acid include, but are not limited to, a salt formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Non-limiting examples of the salt formed with an organic acid include, but are not limited to, a salt formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0052] In a preferred embodiment, the active ingredient is enzalutamide.

[0053] The active ingredient, amoxil, used in the embodiments of the present application can be commercially available. An exemplary commercially available amoxil can be, for example, amoxil available from Pfizer Inc.

[0054] In one embodiment, the active ingredient is present in an amount of about 10% to about 35% by weight, preferably about 16% to about 33% by weight, based on the weight of the pharmaceutical composition. For example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33% by weight.

[0055] Suitable active ingredient content is advantageous for the active ingredient to achieve its therapeutic effect, while also being advantageous for the active ingredient to have a suitable ratio with other ingredients, thereby being advantageous for the dissolution and solubility of the active ingredient.

[0056] Carrier material

[0057] In one embodiment, the carrier material comprises a first carrier material and a second carrier material.

[0058] In the present application, the pharmaceutically active ingredient can be dispersed in the carrier material, thereby being encapsulated by the carrier material, whereby the solubility, dissolution, impurity level, and stability of the pharmaceutical composition can be improved.

[0059] In a specific embodiment, the carrier material is composed of a first carrier material and a second carrier material.

[0060] In one embodiment, the carrier material is present in an amount of about 60% to about 85% by weight, preferably about 65% to about 82% by weight, based on the weight of the pharmaceutical composition. For example, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85% by weight.

[0061] First carrier material

[0062] In one embodiment, the first carrier material comprises a copolymer of the first monomer and / or the third monomer with the second monomer. In another embodiment, the first carrier material comprises a copolymer of the first monomer with the second monomer and optionally the third monomer. In one particular embodiment, the first carrier material comprises a copolymer of the first monomer with the second monomer and the third monomer. In another particular embodiment, the first carrier material comprises a copolymer of the first monomer with the second monomer. In another particular embodiment, the first carrier material comprises a copolymer of the third monomer with the second monomer.

[0063] In one preferred embodiment, the first monomer of the first carrier material is selected from one or more of the group consisting of butyl methacrylate and methacrylic acid. In one preferred embodiment, the second monomer of the first carrier material is selected from one or more of the group consisting of methyl methacrylate and ethyl acrylate. In one preferred embodiment, the third monomer of the first carrier material comprises dimethylaminoethyl methacrylate.

[0064] In one embodiment, the first carrier material is selected from one or more of the group consisting of a copolymer of butyl methacrylate and / or dimethylaminoethyl methacrylate with methyl methacrylate, a copolymer of methacrylic acid with ethyl acrylate, and a copolymer of methacrylic acid with methyl methacrylate.

[0065] In one particular embodiment, the first carrier material comprises a copolymer of the first monomer with the second monomer, the first carrier material being selected from one or more of the group consisting of a copolymer of methacrylic acid with ethyl acrylate and a copolymer of methacrylic acid with methyl methacrylate. In one preferred embodiment, the first carrier material is a copolymer of methacrylic acid with ethyl acrylate.

[0066] In one particular embodiment, the first carrier material comprises a copolymer of the first monomer with the second monomer and the third monomer, the first carrier material being a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate with methyl methacrylate.

[0067] In one embodiment, the molar ratio of the first monomer to the second monomer is from about 1 :3 to about 2: 1, preferably from about 1 :2 to about 1 : 1. For example about 1 :3, about 1 :2, about 1 : 1, about 2: 1.

[0068] In one embodiment, the molar ratio of the first monomer to the third monomer is from about 1 :3 to about 2: 1, preferably from about 1 :2 to about 1 : 1. For example about 1 :3, about 1 :2, about 1 : 1, about 2: 1.

[0069] In one particular embodiment, the first carrier material can be a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate, wherein the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate is 1 :2: 1. In another particular embodiment, the first carrier material can be a copolymer of methacrylic acid and ethyl acrylate, wherein the molar ratio of methacrylic acid and ethyl acrylate is 1 : 1. In yet another particular embodiment, the first carrier material can be a copolymer of methacrylic acid and methyl methacrylate, wherein the molar ratio of methacrylic acid and methyl methacrylate is 1 : 1. In still another particular embodiment, the first carrier material can be a copolymer of methacrylic acid and methyl methacrylate, wherein the molar ratio of methacrylic acid and methyl methacrylate is 1 :2.

[0070] In one particular embodiment, the first carrier material can be selected from one or more of the group consisting of a copolymer of butyl methacrylate and dimethylaminoethyl methacrylate and methyl methacrylate (1 :2: 1) (e.g. under the trade name Eudragit® E 100 or Eudragit® E PO), a copolymer of methacrylic acid and ethyl acrylate (1 : 1) (e.g. under the trade name Eudragit® L 100-55 or Eudragit® L 30D-55), a copolymer of methacrylic acid and methyl methacrylate (1 : 1) (e.g. under the trade name Eudragit® L 100) and a copolymer of methacrylic acid and methyl methacrylate (1 :2) (e.g. under the trade name Eudragit® S 100).

[0071] In one preferred embodiment, the first carrier material is a copolymer of methacrylic acid and ethyl acrylate (1 : 1) (e.g. under the trade name Eudragit® L 100-55).

[0072] The first carrier material used in the practice of the present application can be commercially available.

[0073] Suitable first carrier material types are advantageous in improving the solubility of the active ingredient, resulting in improved drug dissolution of the pharmaceutical composition of the present application. In addition, suitable first carrier material types are advantageous in improving the stability of the pharmaceutical composition. Furthermore, suitable first carrier material types are advantageous in improving the purity of the pharmaceutical composition, resulting in a lower level of impurities in the pharmaceutical composition. In addition, suitable first carrier material types can result in a suitable friability of the pharmaceutical composition of the present application, which is advantageous in facilitating the processing of the formulation product.

[0074] Second carrier material

[0075] ​In one embodiment, the second carrier material is selected from one or more of the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, preferably hydroxypropyl methylcellulose.

[0076] In one embodiment, the second carrier material comprises hydroxypropyl methylcellulose having a viscosity of 500 mPa-s or less, preferably comprises hydroxypropyl methylcellulose having a viscosity of 100 mPa-s or less, more preferably comprises hydroxypropyl methylcellulose having a viscosity of 50 mPa-s or less, further more preferably comprises hydroxypropyl methylcellulose having a viscosity of 15 mPa-s or less, still further more preferably comprises hydroxypropyl methylcellulose having a viscosity of 10 mPa-s or less, particularly preferably comprises hydroxypropyl methylcellulose having a viscosity of 5 mPa-s or less.

[0077] In one embodiment, the second carrier material is selected from one or more of the group consisting of HPMC E3, HPMC E5, HPMC E6, HPMC E15 and HPMC K3. Herein, HPMC E3, HPMC E5, HPMC E6, HPMC E15 and HPMC K3 denote specific types of hydroxypropyl methylcellulose. In a preferred embodiment, the second carrier material is HPMC E5 and / or HPMC E3. In a more preferred embodiment, the second carrier material is HPMC E5 or HPMC E3. In a further preferred embodiment, the second carrier material is HPMC E5.

[0078] In one particular embodiment, the second carrier material is selected from one or more of the group consisting of HPMC E3 (such as the trade name Methocel E3 Premium LV, having a viscosity of 3 mPa-s), HPMC E5 (such as the trade name Methocel E5 Premium LV, having a viscosity of 5 mPa-s), HPMC E6 (such as the trade name Methocel E6 Premium LV, having a viscosity of 6 mPa-s), HPMC E15 (such as the trade name Methocel E15 Premium LV, having a viscosity of 15 mPa-s) and HPMC K3 (such as the trade name Methocel K3 Premium LV, having a viscosity of 3 mPa-s). Preferably, the second carrier material is HPMC E5 (such as the trade name Methocel E5 Premium LV) and / or HPMC E3 (such as the trade name Methocel E3 Premium LV). More preferably, the second carrier material is HPMC E5 (such as the trade name Methocel E5 Premium LV) or HPMC E3 (such as the trade name Methocel E3 Premium LV). Further more preferably, the second carrier material is HPMC E5 (such as the trade name Methocel E5 Premium LV).

[0079] Suitable second carrier material types are advantageous in improving the solubility of the active ingredient, resulting in improved drug dissolution of the pharmaceutical composition of the present application. In addition, suitable second carrier material types are advantageous in improving the stability of the pharmaceutical composition. Furthermore, suitable second carrier material types are also advantageous in improving the purity of the pharmaceutical composition, resulting in a reduction in the level of impurities in the pharmaceutical composition. In addition, suitable second carrier material types can result in a suitable friability of the pharmaceutical composition of the present application, which is easily pulverized during processing, thereby facilitating the processing of the formulation product.

[0080] In one embodiment, the active ingredient forms a solid dispersion with the carrier material.

[0081] Ratio of the first carrier material, the second carrier material and the active ingredient

[0082] In one embodiment, the weight ratio of the first carrier material to the second carrier material is from about 1 :0.1 to about 1 :2, preferably from about 1 :0.15 to about 1 :1. For example, about 1 :0.1, about 1 :0.15, about 1 :0.2, about 1 :0.25, about 1 :0.3, about 1 :0.35, about 1 :0.4, about 1 :0.45, about 1 :0.5, about 1 :0.55, about 1 :0.6, about 1 :0.65, about 1 :0.67, about 1 :0.7, about 1 :0.75, about 1 :0.8, about 1 :0.85, about 1 :0.9, about 1 :0.95, about 1 :1, about 1 :1.05, about 1 :1.1, about 1 :1.15, about 1 :1.2, about 1 :1.25, about 1 :1.3, about 1 :1.35, about 1 :1.4, about 1 :1.45, about 1 :1.5, about 1 :1.55, about 1 :1.6, about 1 :1.65, about 1 :1.7, about 1 :1.75, about 1 :1.8, about 1 :1.85, about 1 :1.9, about 1 :1.95, about 1 :2.

[0083] Suitable weight ratios of the first carrier material to the second carrier material are advantageous for improving the solubility of the active ingredient, and for providing the pharmaceutical composition of the present application with improved drug dissolution. In addition, suitable weight ratios of the first carrier material to the second carrier material are advantageous for improving the stability of the pharmaceutical composition. Furthermore, suitable weight ratios of the first carrier material to the second carrier material are also advantageous for improving the purity of the pharmaceutical composition, and for reducing the impurity level in the pharmaceutical composition. In addition, suitable weight ratios of the first carrier material to the second carrier material can provide the pharmaceutical composition of the present application with suitable friability, and the composition is easily pulverized during processing, thereby more advantageously facilitating the processing of the formulation product.

[0084] In one embodiment, the weight ratio of the active ingredient to the first carrier material is from about 1 :0.1 to about 1 :6, preferably from about 1 : 1 to about 1 :4, more preferably from about 1 : 1 to about 1 :3. For example, about 1 :0.1, about 1 :0.2, about 1 :0.3, about 1 :0.4, about 1 :0.5, about 1 :0.6, about 1 :0.7, about 1 :0.8, about 1 :0.9, about 1 : 1, about 1 : 1.1, about 1 : 1.2, about 1 : 1.3, about 1 : 1.4, about 1 : 1.5, about 1 : 1.6, about 1 : 1.7, about 1 : 1.8, about 1 : 1.9, about 1 :2, about 1 :2.1, about 1 :2.2, about 1 :2.3, about 1 :2.4, about 1 :2.5, about 1 :2.6, about 1 :2.7, about 1 :2.8, about 1 :2.9, about 1 :3, about 1 :3.1, about 1 :3.2, about 1 :3.3, about 1 :3.4, about 1 :3.5, about 1 :3.6, about 1 :3.7, about 1 :3.8, about 1 :3.9, about 1 :4, about 1 :4.1, about 1 :4.2, about 1 :4.3, about 1 :4.4, about 1 :4.5, about 1 :4.6, about 1 :4.7, about 1 :4.8, about 1 :4.9, about 1 :5, about 1 :5.1, about 1 :5.2, about 1 :5.3, about 1 :5.4, about 1 :5.5, about 1 :5.6, about 1 :5.7, about 1 :5.8, about 1 :5.9, about 1 :6.

[0085] The suitable weight ratio of the active ingredient to the first carrier material is advantageous for forming a stable amorphous solid dispersion, improving the solubility of the active ingredient, and providing the pharmaceutical composition of the present application with improved drug dissolution. In addition, the suitable weight ratio of the active ingredient to the first carrier material is advantageous for improving the stability of the pharmaceutical composition. Furthermore, the suitable weight ratio of the active ingredient to the first carrier material is also advantageous for improving the purity of the pharmaceutical composition, and reducing the impurity level in the pharmaceutical composition. In addition, the suitable weight ratio of the active ingredient to the first carrier material can provide the pharmaceutical composition of the present application with suitable friability, and the composition is easy to be pulverized during the processing, thereby being more advantageous for the processing of the formulation product.

[0086] In one embodiment, the weight ratio of the active ingredient to the second carrier material is from about 1 :0.1 to about 1 :3, preferably from about 1 :0.3 to about 1 :2. For example, about 1 :0.1, about 1 :0.2, about 1 :0.3, about 1 :0.4, about 1 :0.5, about 1 :0.6, about 1 :0.7, about 1 :0.8, about 1 :0.9, about 1 : 1, about 1 : 1.1, about 1 : 1.2, about 1 : 1.3, about 1 : 1.4, about 1 : 1.5, about 1 : 1.6, about 1 : 1.7, about 1 : 1.8, about 1 : 1.9, about 1 :2, about 1 :2.1, about 1 :2.2, about 1 :2.3, about 1 :2.4, about 1 :2.5, about 1 :2.6, about 1 :2.7, about 1 :2.8, about 1 :2.9, about 1 :3.

[0087] Suitable weight ratios of the active ingredient to the second carrier material facilitate the formation of stable amorphous solid dispersions, improve the solubility of the active ingredient, and result in pharmaceutical compositions of the present application having improved drug dissolution. In addition, suitable weight ratios of the active ingredient to the second carrier material facilitate improved stability of the pharmaceutical composition. Furthermore, suitable weight ratios of the active ingredient to the second carrier material also facilitate improved purity of the pharmaceutical composition, resulting in lower impurity levels in the pharmaceutical composition. In addition, suitable weight ratios of the active ingredient to the second carrier material can result in pharmaceutical compositions of the present application having suitable friability, which facilitates the ease of powdering of the composition during processing, thereby facilitating the processing of the formulation product.

[0088] In one embodiment, the active ingredient is dissolved in or dispersed at the molecular level in the carrier material. In a preferred embodiment, the active ingredient is dispersed at the molecular level in the carrier material.

[0089] Pharmaceutically acceptable excipients

[0090] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a preferred embodiment, the pharmaceutically acceptable excipient is selected from one or more of the group consisting of a plasticizer, a filler, a disintegrant, a lubricant, and a glidant.

[0091] Plasticizers

[0092] Plasticizer refers to any organic molecule that increases the flexibility and toughness of the final product by internally modifying or solvating the polymer molecules.

[0093] In one embodiment, the plasticizer is selected from one or more of the group consisting of polyethylene glycol, glycerol, triethyl citrate, vitamin E polyethylene glycol succinate, and poloxamer. In a preferred embodiment, the plasticizer is triethyl citrate.

[0094] The plasticizer used in the present application can be commercially available. For example, triethyl citrate can be purchased from Merck KgaA (Germany).

[0095] Filling agent

[0096] In the present application, the active ingredient and the carrier material can be further dispersed in a filling agent as a pharmaceutically acceptable excipient to further improve the solubility and dissolution of the pharmaceutical composition.

[0097] In one embodiment, the filling agent is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose starch, pregelatinized starch, polyvinylpyrrolidone, acacia powder, and gelatin. In a preferred embodiment, the filling agent is hydroxypropyl methylcellulose acetate succinate.

[0098] In another embodiment, the filling agent is filled outside of the active ingredient and the carrier material. In a preferred embodiment, the filling agent is filled outside of the solid dispersion formed by the active ingredient and the carrier material.

[0099] The filling agent used in the present application can be commercially available.

[0100] Disintegrant

[0101] In one embodiment, the disintegrant is selected from one or more of the group consisting of microcrystalline cellulose, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxymethyl starch, alginic acid, sodium alginate, guar gum, corn starch, and magnesium aluminum silicate. In a preferred embodiment, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0102] The disintegrant used in the present application can be commercially available.

[0103] Lubricant

[0104] In one embodiment, the lubricant is selected from one or more of the group consisting of magnesium stearate, stearic acid, stearate, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid ester, colloidal silicon dioxide, talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid, and hydrogenated vegetable oil. In a preferred embodiment, the lubricant is magnesium stearate.

[0105] The lubricant used in the present application can be commercially available.

[0106] Glidant

[0107] In one embodiment, the glidant is selected from one or more of the group consisting of: microfine silica and talc. In a preferred embodiment, the glidant is microfine silica.

[0108] The glidant used in the present application can be commercially available. For example, the microfine silica can be microfine silica of type Silica 200 Pharma, which is available from Evonik Operations GmbH. 200 Pharma, which is available from Evonik Operations GmbH.

[0109] Ratio of active ingredient to pharmaceutically acceptable excipient

[0110] In one embodiment, the weight ratio of the active ingredient to the plasticizer is from about 1 :0.05 to about 1 :0.3, preferably from about 1 :0.12 to about 1 :0.18. For example, about 1 :0.05, about 1 :0.06, about 1 :0.07, about 1 :0.08, about 1 :0.09, about 1 :0.1, about 1 :0.11, about 1 :0.12, about 1 :0.13, about 1 :0.14, about 1 :0.15, about 1 :0.16, about 1 :0.17, about 1 :0.18, about 1 :0.19, about 1 :0.2, about 1 :0.21, about 1 :0.22, about 1 :0.23, about 1 :0.24, about 1 :0.25, about 1 :0.26, about 1 :0.27, about 1 :0.28, about 1 :0.29, about 1 :0.3.

[0111] A suitable weight ratio of active ingredient to plasticizer helps to improve the purity of the pharmaceutical composition, reduce the impurity level in the pharmaceutical composition, and improve the flowability of the pharmaceutical composition, thereby facilitating the manufacture of the pharmaceutical composition product more favorably.

[0112] In one embodiment, the weight ratio of the active ingredient to the glidant is from about 1 :0.01 to about 1 :0.2, preferably from about 1 :0.06 to about 1 :0.13. For example, about 1 :0.01, about 1 :0.02, about 1 :0.03, about 1 :0.04, about 1 :0.05, about 1 :0.06, about 1 :0.07, about 1 :0.08, about 1 :0.09, about 1 :0.1, about 1 :0.11, about 1 :0.12, about 1 :0.13, about 1 :0.14, about 1 :0.15, about 1 :0.16, about 1 :0.17, about 1 :0.18, about 1 :0.19, about 1 :0.2.

[0113] A suitable weight ratio of active ingredient to glidant helps to improve the flowability of the pharmaceutical composition, thereby facilitating the manufacture of the pharmaceutical composition product more favorably. It should be understood that, within the scope of the present application, the above-mentioned technical features of the present application can be combined with each other, as well as with the technical features specifically described hereinafter (e.g. in the examples), to form new or preferred technical solutions.

[0114] Pharmaceutical preparation

[0115] In another aspect, the present application provides a pharmaceutical preparation comprising the pharmaceutical composition of the present application. In one embodiment, the pharmaceutical composition is a solid preparation, preferably a tablet.

[0116] The pharmaceutical composition of the present application can be further combined with pharmaceutically acceptable pharmaceutical excipients as needed to produce various preparations, which can be in the form of a powder, granules, pellets, capsules or tablets. In a preferred embodiment, the pharmaceutical preparation is a tablet.

[0117] It should be emphasized that the listed pharmaceutically acceptable pharmaceutical excipients are merely illustrative and representative, but not exhaustive. Therefore, the present application is not limited to the above-listed pharmaceutically acceptable excipients.

[0118] Method for preparing a pharmaceutical composition

[0119] The present application also provides a method for preparing the pharmaceutical composition of the present application, which comprises the steps of: providing an active ingredient, a first carrier material, a second carrier material, and optionally a pharmaceutically acceptable excipient; mixing the active ingredient, the first carrier material, the second carrier material, and the optional pharmaceutically acceptable excipient or directly introducing them into a hot melt extruder; and subjecting the mixture to hot melt extrusion to obtain the pharmaceutical composition.

[0120] In a specific embodiment, the method for preparing can comprise the steps of:

[0121] S1: preheating the hot melt extruder to 110°C to 200°C;

[0122] S2: adding a mixture of the components in a mixed ratio to the hot melt extruder, or directly adding the components in a mixed ratio to the hot melt extruder;

[0123] S3: extruding and cooling the resulting extrudate to obtain the pharmaceutical composition of the present application.

[0124] In one embodiment, the components in the hot melt extrusion method include a mixture of nizatidine or a pharmaceutically acceptable salt thereof, a carrier material, and an optional pharmaceutically acceptable pharmaceutical excipient.

[0125] In one embodiment, the hot melt extrusion method further comprises, after cooling the extrudate of step S3, crushing and sieving, and optionally mixing with a pharmaceutically acceptable pharmaceutical excipient.

[0126] The cooling method in the method for preparing the present application is not particularly limited and can include air cooling, water cooling, mechanical cooling, etc.

[0127] The type of extruder suitable for use in the present application is not particularly limited and includes, but is not limited to, a single screw or a twin screw type hot melt extruder. In one embodiment, the extruder used to prepare the pharmaceutical composition of the present application is a twin screw type extruder. In this case, the type of screw rotation is not particularly limited and includes, but is not limited to, a co-rotating twin screw, a counter-rotating twin screw and a double taper screw rotation mode.

[0128] In one embodiment, the extruder used to prepare the pharmaceutical composition of the present application is preferably a co-rotating twin screw type extruder.

[0129] In one embodiment, the temperature setting of the hot melt extruder is about 110°C to about 200°C, preferably about 150°C to about 200°C, more preferably about 170°C to about 190°C. For example, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C, about 150°C, about 155°C, about 160°C, about 165°C, about 170°C, about 175°C, about 180°C, about 185°C, about 190°C, about 195°C, about 200°C.

[0130] In one embodiment, the screw rotation speed is about 100 to about 400 rpm, preferably about 120 to about 200 rpm, more preferably about 140 to about 180 rpm. For example, about 100 rpm, about 150 rpm, about 200 rpm, about 250 rpm, about 300 rpm, about 350 rpm, about 400 rpm.

[0131] In one embodiment, the feeder rotation speed is about 10 to about 80 rpm, preferably about 10 to about 50 rpm, more preferably about 20 to about 40 rpm. For example, about 10 rpm, about 15 rpm, about 20 rpm, about 25 rpm, about 30 rpm, about 35 rpm, about 40 rpm, about 45 rpm, about 50 rpm, about 55 rpm, about 60 rpm, about 65 rpm, about 70 rpm, about 75 rpm, about 80 rpm.

[0132] In one embodiment, the ratio of screw length and diameter (L / D) can be selected from about 20 to about 40, preferably 25 to 35, more preferably 25 to 30. For example, the ratio of screw length and diameter (L / D) is about 20, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40.

[0133] Therapeutic methods and uses of pharmaceutical compositions or medicaments

[0134] The present application also provides use of the pharmaceutical composition of the present application or the pharmaceutical preparation of the present application in the preparation of a medicament for preventing or treating a hyperproliferative disease.

[0135] In one embodiment, the hyperproliferative disease is selected from one or more of the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer. In a preferred embodiment, the hyperproliferative disease is castration-resistant prostate cancer.

[0136] The present application also provides a method for preventing or treating a hyperproliferative disease, the method comprising the step of administering to an individual in need thereof a prophylactically or therapeutically effective amount of the pharmaceutical composition of the present application or the pharmaceutical preparation of the present application.

[0137] In one embodiment, the hyperproliferative disease is selected from one or more of the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer. In a preferred embodiment, the hyperproliferative disease is castration-resistant prostate cancer.

[0138] The present application also provides a pharmaceutical composition or a pharmaceutical preparation for preventing or treating a hyperproliferative disease.

[0139] In one embodiment, the hyperproliferative disease is selected from one or more of the group consisting of benign prostatic hyperplasia, prostate cancer, breast cancer, and ovarian cancer. In a preferred embodiment, the hyperproliferative disease is castration-resistant prostate cancer. Advantages

[0140] The pharmaceutical composition of the present application has a low level of total impurities and excellent physical stability and chemical stability.

[0141] For example, the present application employs suitable first carrier material and second carrier material to help the pharmaceutical composition of the present application to have improved purity, a low level of total impurities, and at the same time, to have improved physical stability and chemical stability, which is beneficial to industrial production, transportation, and storage. In addition, suitable first carrier material and second carrier material can also help the pharmaceutical composition of the present application to have suitable friability, which is easy to be pulverized during processing, thereby being more beneficial to the processing of the preparation product.

[0142] In addition, the pharmaceutical composition of the present application contains the first carrier material and the second carrier material in a suitable weight ratio, which helps to improve the purity of the pharmaceutical composition of the present application, reduce the total impurity level, and at the same time, improve the physical and chemical stability of the pharmaceutical composition of the present application, which is beneficial to industrial production, transportation and storage. In addition, the suitable weight ratio of the first carrier material and the second carrier material can also make the pharmaceutical composition of the present application have a suitable friability, so that the composition is easy to be crushed during processing, thereby being more beneficial to the processing of the preparation product.

[0143] Examples

[0144] The scheme of the present application will be further described in detail below in combination with specific examples.

[0145] It should be noted that the following examples are only examples for clearly illustrating the technical scheme of the present application, and are not a limitation of the present application. For those skilled in the art, other different forms of changes or variations can be made on the basis of the above description, and here it is not necessary and impossible to exhaust all the embodiments, and the changes or variations derived therefrom are still within the protection scope of the present application. Unless otherwise specified, the instruments and reagent materials used in this paper are commercially available.

[0146] Reagents and impurities:

[0147] In the following examples and comparative examples, the main reagents used are as follows:

[0148] The manufacturer of nizatidine (active ingredient) is Otsuka Pharmaceutical Co., Ltd.;

[0149] The model of Eudragit is Eudragit® L100-55, and the manufacturer is Evonik Operations GmbH; The model of micronized silica gel is Aerosil® 200 Pharma, and the manufacturer is Evonik Operations GmbH;

[0150] The model of micronized silica gel is Aerosil® 200 Pharma, and the manufacturer is Evonik Operations GmbH;

[0151] The manufacturer of triethyl citrate (abbreviation: TEC) is Merck KgaA (Germany);

[0152] The model of hydroxypropyl methylcellulose (abbreviation: HPMC) is Methocel E5 Premium LV, and the manufacturer is Nutrition & Biosciences USA 1, LLC;

[0153] ​Hydroxypropyl methylcellulose acetate succinate (abbreviated as HPMCAS) of the type Aqoat AS-LG, Aqoat AS-LF, Aqoat AS-MG, Aqoat AS-MF, Aqoat AS-HG or Aqoat AS-HF, produced by Shin-Etsu Chemical Co., Ltd.

[0154] Herein, impurity B is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-2,4-dioxo-1- imidazolidinyl}-2-fluorobenzamide; impurity ENZ-B is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]- 5,5-dimethyl-4-oxo-2-thioxoimidazolidinyl]-2-fluorobenzoic acid; and impurity RRT 0.6 refers to an impurity with a relative retention time (RRT) of 0.6. In the art, industry standards do not require explicit attribution of the structure of all detected impurities, so some unknown impurities are expressed by their relative retention times.

[0155] Test methods:

[0156] 1. Powder X-ray diffraction (PXRD)

[0157] A suitable amount of the test substance (raw material, drug-loaded composition or blank composition) was taken and the powder X-ray diffraction pattern was recorded under the conditions of a Cu target, voltage 45 kV, current 45 mA (D8 ADVANCE X-ray diffractometer manufactured by BRUKER).

[0158] 2. Determination of impurities

[0159] Preparation of the test sample solution: 5 tablets were randomly sampled, placed in a 500 mL volumetric flask, 50 mL of water was added, shaken to disperse, about 300 mL of acetonitrile was added, and enzalutamide was dissolved by ultrasonic treatment for 20 minutes. After cooling to room temperature, the solution was diluted to the mark with acetonitrile and shaken well. A portion of the solution was centrifuged at 12000 rpm for 5 minutes, and 3.5 mL of the supernatant was accurately measured and placed in a 20 mL volumetric flask. The solution was diluted to the mark with diluent and shaken well to obtain the test sample solution.

[0160] Example 1 Combination of enzalutamide with different carrier materials

[0161] 1. Preparation

[0162] The components and amounts of the enzalutamide compositions are shown in Table 1-1D.

[0163] Preparation method: the components and amounts shown in Table 1-1D were mixed uniformly in a mixer, and then added into the feeding hopper of a co-rotating twin-screw extruder (Omicron 12, India Steer Company), the sleeve temperature of the extruder was controlled between about 170°C to about 230°C, and extrusion was carried out. The obtained extrudates were cooled, crushed, and sieved to obtain compositions 1-1D to 1-5D.

[0164] Table 1-1D Components and amounts (mg / unit) of compositions of enzalutamide

[0165] 2. Evaluation of physical and chemical properties

[0166] 2.1 The test results of the appearance of the extrudates and the crystal form of the active pharmaceutical ingredient in the extrudates are shown in Table 1-2D.

[0167] Table 1-2D Appearance of extrudates and test results of powder X-ray diffraction (PXRD)

[0168] As can be seen from the above table, each of the above compositions can form a solid dispersion, and the active ingredient (enzalutamide) in the solid dispersion is in an amorphous state.

[0169] 2.2 The evaluation of the crushing operability of the extrudates is shown in Table 1-3D.

[0170] Table 1-3D Evaluation of the crushing operability of the extrudates

[0171] As can be seen from the above table, the extrudates corresponding to compositions 1-1D and 1-2D using hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl methylcellulose (HPMC) as the carrier material are difficult to crush, and it is difficult to obtain uniform fine powder of the solid dispersion.

[0172] 2.3 Impurity test

[0173] The impurity test results are shown in Table 1-4D.

[0174] Table 1-4D Impurities of the compositions

[0175] As can be seen from the above table, the total impurity levels of compositions 1-1D to 1-5D using hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl methylcellulose (HPMC) or Eudragit as the carrier material are relatively high (the total impurities include impurity B, impurity ENZ-B and impurity RRT 0.6), and the total impurity levels are 0.9% to 1.3%.

[0176] Example 1 Composition containing enzalutamide, Eudragit, HPMC and TEC

[0177] 1.1. Preparation

[0178] The components and amounts of the compositions of enzalutamide are shown in Table 1-1.

[0179] Preparation method: the components and amounts shown in Table 1-1 were mixed in a mixer, and then added into the hopper of a co-rotating twin-screw extruder (Omicron 12, India Steer), the sleeve temperature of the extruder was controlled between about 170°C to about 190°C, and then extruded. The obtained extrudate was cooled, crushed, and sieved to obtain the compositions 1-1 to 1-3.

[0180] Table 1-1 Components and amounts of the compositions of enzalutamide (mg / unit)

[0181] 1.2. Evaluation of physical and chemical properties

[0182] (1) The test results of the appearance of the extrudate and the crystal form of the active ingredient in the extrudate are shown in Table 1-2.

[0183] Table 1-2 Appearance of the extrudate and test results of powder X-ray diffraction (PXRD)

[0184] As can be seen from the above table, the above-mentioned compositions can all form solid dispersions, and the active ingredient (enzalutamide) in the solid dispersion is in an amorphous state.

[0185] (2) The evaluation of the crushing operability of the extrudate is shown in Table 1-3.

[0186] Table 1-3 Evaluation of the crushing operability of the extrudate

[0187] As can be seen from the above table, the extrudate of the above-mentioned compositions is easier to crush, thereby being more conducive to the processing of the preparation product.

[0188] (3) Impurity test

[0189] The impurity test results are shown in Table 1-4.

[0190] Table 1-4 Impurities of the compositions

[0191] As can be seen from the above table, the total impurity levels of the compositions 1-1 to 1-3 using Eudragit and HPMC as the carrier material are low (the total impurities include impurity B, impurity ENZ-B and impurity RRT 0.6), and the total impurity level is 0.3%. Therefore, the composition of the present application can ensure the stability of the active ingredient, and greatly reduce the impurities generated during production and storage.

[0192] Example 2 Compositions containing nizatidine, Eudragit and HPMC

[0193] 2.1. Preparation

[0194] The components and amounts of the nizatidine compositions are shown in Table 2-1.

[0195] Preparation method: The components and amounts shown in Table 2-1 were mixed in a mixer and then fed into the hopper of a co-rotating twin-screw extruder (Omicron 12, Steer, India) with the barrel temperature controlled between about 170°C and about 190°C. The resulting extrudate was cooled, comminuted and sieved to obtain compositions 2-1 to 2-4.

[0196] Table 2-1 Components and amounts (mg / unit) of nizatidine compositions

[0197] 2.2. Evaluation of physical and chemical properties

[0198] (1) The results of the appearance of the extrudate and the crystalline form of the active ingredient in the extrudate are shown in Table 2-2.

[0199] Table 2-2 Appearance of the extrudate and results of the powder X-ray diffraction (PXRD) test

[0200] As can be seen from the above table, each of the above compositions can form a solid dispersion, and the active ingredient (nizatidine) in the solid dispersion is in an amorphous state.

[0201] (2) The evaluation of the comminution workability of the extrudate is shown in Table 2-3.

[0202] Table 2-3 Evaluation of the comminution workability of the extrudate

[0203] As can be seen from the above table, the extrudate of each of the above compositions is more easily comminuted, thus facilitating the processing of the formulation product.

[0204] (3) Impurity test

[0205] The results of the impurity test are shown in Table 2-4.

[0206] Table 2-4 Impurities of nizatidine compositions

[0207] As can be seen from the above table, the total impurities level of compositions 2-1 to 2-4 using Eudragit and HPMC as carrier materials is low (total impurities including impurity B, impurity ENZ-B and impurity RRT 0.6), and the total impurities level is 0.3% to 0.4%. Therefore, the composition of the present application can ensure the stability of the active ingredient, and greatly reduce the impurities generated during production and storage.

[0208] Stability study of compositions containing enzalutamide, Eudragit, HPMC and TEC

[0209] Good physical and chemical stability of solid dispersions is an important index in formulation development. The physical stability and chemical stability results of the distribution state of the active ingredient in the carrier material in composition 1-1 are shown in Table 3-1, and the PXRD pattern of composition 1-1 is shown in Figure 1.

[0210] Table 3-1 Stability results of composition 1-1

[0211] As can be seen from the above table, under the conditions of 25℃ / 60% RH for 6 months and 40℃ / 75% RH for 6 months, the content of the active ingredient, the total impurities level and the moisture content in the composition of the present application are basically unchanged. Therefore, the composition of the present application has excellent physical stability and chemical stability, which is beneficial to industrial production, transportation and storage.

[0212] In summary, according to the relevant description of the comparative examples and examples, by using a specific carrier material, the composition of the present application can achieve a low impurity level, ensure rapid dissolution, and has excellent physical stability and chemical stability.

[0213] The above embodiments of the present application are described in detail, but the content described is only the preferred embodiments of the present application, and cannot be considered as limiting the scope of the present application. The true scope and spirit of the present application are shown by the appended claims, and the description and examples are only exemplary.

Claims

1. A pharmaceutical composition, characterized in that It includes an active ingredient and a carrier material; Wherein, the active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof; The carrier material comprises a first carrier material and a second carrier material, The first carrier material is acrylic resin and its derivatives, The second carrier material is hydroxypropyl methylcellulose and its derivatives.

2. The pharmaceutical composition according to claim 1, wherein The weight ratio of the first support material to the second support material is from about 1:0.1 to about 1:2, preferably from about 1:0.15 to about 1:1; and / or, The weight ratio of the active ingredient to the first carrier material is from about 1:0.1 to about 1:6, preferably from about 1:1 to about 1:4, more preferably from about 1:1 to about 1:3; and / or, The weight ratio of the active ingredient to the second carrier material is from about 1:0.1 to about 1:3, preferably from about 1:0.3 to about 1:

2.

3. The pharmaceutical composition according to claim 1 or 2, wherein The active ingredient is dissolved or dispersed at the molecular level in the carrier material.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The first carrier material includes a copolymer formed by a first monomer and / or a third monomer and a second monomer; Preferably, The first monomer is selected from one or more of the following groups: butyl methacrylate and methacrylic acid; The second monomer is selected from one or more of the following groups: methyl methacrylate and ethyl acrylate; The third monomer includes dimethylaminoethyl methacrylate; More preferably, the first carrier material is selected from one or more of the following groups: copolymers of butyl methacrylate and / or dimethylaminoethyl methacrylate and methyl methacrylate, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and methyl methacrylate; and / or, The molar ratio of the first monomer to the second monomer is from about 1:3 to about 2:1, preferably from about 1:2 to about 1:1; The molar ratio of the first monomer to the third monomer is about 1:3 to about 2:1, preferably about 1:2 to about 1:

1.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The second carrier material includes hydroxypropyl methylcellulose having a viscosity of less than 500 mPa·s, preferably includes hydroxypropyl methylcellulose having a viscosity of less than 100 mPa·s, more preferably includes hydroxypropyl methylcellulose having a viscosity of less than 50 mPa·s, further more preferably includes hydroxypropyl methylcellulose having a viscosity of less than 15 mPa·s, even further more preferably includes hydroxypropyl methylcellulose having a viscosity of less than 10 mPa·s, and particularly preferably includes hydroxypropyl methylcellulose having a viscosity of less than 5 mPa·s.

6. The pharmaceutical composition according to claim 5, wherein The second carrier material is selected from one or more of the following groups: HPMC E3, HPMC E5, HPMC E6, HPMC E15 and HPMC K3; Preferably, the second carrier material is HPMC E5 and / or HPMC E3; More preferably, the second carrier material is HPMC E5 or HPMC E3; Even more preferably, the second carrier material is HPMC E5.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein The pharmaceutical composition further comprises a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from one or more of the following groups: a plasticizer, a filler, a disintegrant, a lubricant and a glidant; Preferably, The plasticizer is selected from one or more of the following groups: polyethylene glycol, glycerol, triethyl citrate, vitamin E polyethylene glycol succinate and poloxamer, preferably triethyl citrate; and / or, The filler is selected from one or more of the following groups: hydroxypropyl methylcellulose acetate succinate, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose starch, pregelatinized starch, polyvinyl pyrrolidone, gum arabic powder and gelatin, preferably hydroxypropyl methylcellulose acetate succinate; and / or, The disintegrant is selected from one or more of the following groups: microcrystalline cellulose, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxymethyl starch, alginic acid, sodium alginate, guar gum, corn starch and magnesium aluminum silicate, preferably cross-linked sodium carboxymethyl cellulose; and / or, The lubricant is selected from one or more of the following groups: magnesium stearate, stearic acid, stearate salts, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid esters, micronized silica gel, talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid and hydrogenated vegetable oil, preferably magnesium stearate; and / or, The glidant is selected from one or more of the following groups: micro-powder silica gel and talc, preferably micro-powder silica gel.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein The weight ratio of the active ingredient to the plasticizer is from about 1:0.05 to about 1:0.3, preferably from about 1:0.12 to about 1:0.18; and / or, The weight ratio of the active ingredient to the glidant is about 1:0.01 to about 1:0.2, preferably about 1:0.06 to about 1:0.

13.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of: Providing an active ingredient, a first carrier material, a second carrier material, and optionally a pharmaceutically acceptable excipient; The active ingredient, the first carrier material, the second carrier material and the optional pharmaceutically acceptable excipients are mixed or introduced directly into a hot melt extruder; The mixture is subjected to hot melt extrusion to obtain the pharmaceutical composition.

10. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 8; Preferably, the pharmaceutical preparation is a solid preparation; More preferably, the pharmaceutical preparation is a tablet.

11. Use of the pharmaceutical composition according to any one of claims 1 to 8 or the pharmaceutical preparation according to claim 10 in the preparation of a medicament for preventing or treating a hyperproliferative disease; Preferably, the hyperproliferative disease is selected from one or more of the following groups: benign prostatic hyperplasia, prostate cancer, breast cancer and ovarian cancer; more preferably, the hyperproliferative disease is castration-resistant prostate cancer.

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