Pharmaceutical compositions of amoxar and methods of making and using the same

Abstract

The present application relates to a pharmaceutical composition of nizatidine and a preparation method and use thereof. The pharmaceutical composition comprises an active ingredient and a carrier material; wherein the active ingredient is nizatidine 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 derivative, and the second carrier material is hydroxypropyl methyl cellulose and its derivative. The pharmaceutical composition has a low total impurity level and excellent physical and chemical stability.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to an enzalutamide pharmaceutical composition, its preparation method, and its uses. Background Technology

[0002] Enzalutamide's chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfonyliminoimidazoline-1-yl}-2-fluoro-N-methylbenzamide, and its molecular formula is C2. 21 H 16 F4N4O2S has the following structural formula:

[0003]

[0004] Enzalutamide is an androgen receptor inhibitor that competitively inhibits the binding of sex hormones to their receptors and also inhibits nuclear transport of androgen receptors and their interaction with DNA, thereby inhibiting the proliferation of prostate cancer cells and inducing their death.

[0005] Enzalutamide is a BCS class II drug characterized by low solubility and high permeability. Furthermore, enzalutamide is an ionic compound with very low solubility in water, unaffected by solvent pH. The preparation of such compounds into pharmaceutical compositions or formulations presents several challenges regarding water solubility; however, the issues of low bioavailability and poor absorption can be addressed by preparing solubilizing formulations (e.g., solid dispersions).

[0006] CN105358535A discloses an enzalutamide formulation and its preparation method. The solid dispersion particles are prepared by spray drying, with an average particle diameter of less than 50 μm, and the enzalutamide formulation exhibits improved solubility and absorption properties.

[0007] CN105030685A discloses an oral formulation of enzalutamide solid dispersion, which contains an effective amount of enzalutamide and a water-soluble polymer carrier for dispersing enzalutamide. The enzalutamide solid dispersion is prepared by spray drying, resulting in improved solubility and enhanced bioavailability, quality stability, and safety. Summary of the Invention

[0008] Therefore, the object of the present invention is to provide an enzalutamide pharmaceutical composition that overcomes the above-mentioned defects of the prior art, as well as its preparation method and use.

[0009] The present invention solves the above-mentioned technical problems through the following technical solutions:

[0010] In a first aspect, the present invention 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, wherein the first carrier material is an acrylic resin or a derivative thereof, and the second carrier material is hydroxypropyl methylcellulose or a derivative thereof.

[0011] In a second aspect, the present invention also provides a method for preparing the pharmaceutical composition described in the first aspect, comprising the following steps: providing an active ingredient, a first carrier material, a second carrier material, and optionally pharmaceutically acceptable excipients; mixing the active ingredient, the first carrier material, the second carrier material, and optionally pharmaceutically acceptable excipients, or directly introducing them into a hot melt extruder; and hot melt extruding the mixture to obtain the pharmaceutical composition.

[0012] Thirdly, the present invention also provides a pharmaceutical formulation comprising the pharmaceutical composition described in the first aspect.

[0013] In one embodiment, the pharmaceutical preparation is a solid dosage form. In a preferred embodiment, the pharmaceutical preparation is a tablet.

[0014] Fourthly, the present invention also provides the use of the pharmaceutical composition of the first aspect or the pharmaceutical preparation of the third aspect in the preparation of a medicament for the prevention or treatment of hyperproliferative diseases.

[0015] 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, preferably castration-resistant prostate cancer.

[0016] Fifthly, the present invention also provides a method for preventing or treating a proliferative disease, the method comprising the steps of administering to an individual in need a preventive or therapeutically effective amount of the pharmaceutical composition of the first aspect or the pharmaceutical preparation of the third aspect.

[0017] 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, preferably castration-resistant prostate cancer. Attached Figure Description

[0018] Figure 1 The PXRD comparative overlay spectrum of composition 1-1; wherein

[0019] ACC-6M is the test result of composition 1-1 under 40°C / 75%RH conditions for 6 months;

[0020] ACC-3M is the result of testing composition 1-1 at 40°C / 75%RH for 3 months;

[0021] LT-6M is the result of testing composition 1-1 at 25°C / 60%RH for 6 months;

[0022] LT-3M is the result of testing composition 1-1 for 3 months at 25°C / 60%RH. Detailed Implementation

[0023] The present invention will now be described in further detail. This description is for illustrative purposes only and is not intended to limit the invention. Those skilled in the art will readily understand other advantages and effects of the invention from the disclosure herein. The invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and alterations without departing from the spirit of the invention; these equivalent forms also fall within the scope defined by the appended claims.

[0024] General definitions and terms

[0025] Unless otherwise stated, all publications, patent applications, patents and other references mentioned herein are incorporated herein in their entirety by way of citation.

[0026] 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 invention pertains. In case of any conflict, the definitions provided herein shall prevail.

[0027] Unless otherwise stated, all percentages, parts, proportions, etc. are by weight.

[0028] When quantities, concentrations, or other values ​​or parameters are given as ranges, preferred ranges, or preferred upper and lower limits, or specific values, they should be understood as specifically disclosing all ranges formed by pairs of values ​​from any upper or preferred range and any lower or preferred range, regardless of whether the range is disclosed individually. Unless otherwise stated, when a numerical range is referred to herein, the range means including its endpoints and all integers and fractions within that range. The scope of this invention is not limited to the specific numerical values ​​referenced 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, and 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 subrange consisting of any two of these values, such as 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.

[0029] When used with a numerical variable, the terms “about” or “approximately” usually mean that the value of the variable and all values ​​of the variable are within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or a wider range (e.g., within ±15%, ±20%, ±25%, or ±30%).

[0030] In this document, the term "molar ratio" refers to the presence of monomers in a polymer (such as the first carrier material) in a specific molar ratio within the corresponding polymer (such as the first carrier material).

[0031] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing terms such as “comprising” encompass the meaning of “consisting of.” The expression “consisting of” excludes any unspecified elements, steps, or ingredients. The expression “substantially constitutes” limits the scope to the specified elements, steps, or ingredients, plus optional elements, steps, or ingredients that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression “comprising” encompasses both the expressions “substantially constitutes” and “consisting of.”

[0032] The term “selected from…” means one or more elements from the groups listed below, selected independently, and may include combinations of two or more elements.

[0033] Unless otherwise stated, the terms "combination thereof" and "mixture thereof" refer to a multi-component mixture of the elements, such as two, three, four, and up to the maximum possible multi-component mixture.

[0034] As used herein, the terms “one or more” or “at least one” refer to one, two, three, four, five, six, seven, eight, nine or more.

[0035] The terms "first," "second," or similar expressions used in this document are used solely for descriptive convenience when referring to ingredients, components, steps, etc., and are not intended to restrict their order or content. Therefore, for example, the first and second materials may have the same or different compositions, and the first step may be performed before, simultaneously with, or after the second step.

[0036] Furthermore, if the number of components or parts of the present invention is not previously specified, it indicates that there is no limitation on the number of times a component or part may appear (or be present). Therefore, it should be interpreted as including one or at least one, and the singular form of a component or part also includes the plural, unless the value clearly indicates a singular number.

[0037] The term "stoichiometric ratio" refers to the proportion of various substances by weight. For example, in this invention, the active ingredient (enzalutamide or a pharmaceutically acceptable salt thereof), the carrier material, and optionally present pharmaceutically acceptable excipients are proportioned by weight in a specific ratio.

[0038] As used herein, the terms “optional” or “optionally” mean that the event or situation subsequently described may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0039] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0040] The term "pharmaceuticalally acceptable excipient" refers to carrier substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceuticalally acceptable excipients" include, but are not limited to, flow aids, sweeteners, fillers, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers. Non-limiting examples of carrier substances include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0041] The term "active ingredient" refers to a chemical entity that can effectively treat or prevent a target disease or condition. In one embodiment, the active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof.

[0042] The term "pharmaceutical composition" refers to a substance consisting of one or more active ingredients, a carrier material, and optionally one or more pharmaceutically acceptable excipients. In this invention, it may be simply referred to as a composition. For example, pharmaceutical composition 1-1 may be simply referred to as composition 1-1.

[0043] The term "pharmaceutical preparation" refers to a pharmaceutical composition administered to a patient in need of treatment, which can typically take the following forms: powder, granules, pills, capsules, tablets, solutions, suspensions, or patches.

[0044] The term "dispersion at the molecular level" refers to the dispersion of a drug within a carrier material to form a single-phase drug composition. In this invention, this term may refer to the dispersion of enzalutamide or a pharmaceutically acceptable salt thereof within a carrier material to form a single-phase drug composition (also referred to as a solid solution, dispersion, or solid dispersion), wherein the Tg value of the resulting enzalutamide or pharmaceutically acceptable salt thereof differs from the Tg values ​​of the carrier material and the enzalutamide active pharmaceutical ingredient.

[0045] The terms “dissolved in,” “dispersed at the molecular level,” “dispersion,” “solid solution,” and “solid dispersion” are used herein as is convenient to describe the pharmaceutical compositions of the present invention at various stages of preparation and at various temperatures.

[0046] For the purposes of a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of drug or pharmaceutical agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0047] The term "stable" can refer to stability against heat, light, temperature, and / or humidity. For example, after storing a pharmaceutical composition or formulation thereof under predetermined conditions, the percentage of the maximum related substance or the total amount of related substances contained in the pharmaceutical composition or formulation is below a specific amount. In one embodiment, the percentage of the maximum related substance of enzalutamide after storage at 25°C / 60%RH for 1 month, 3 months, 6 months, 1 month, 3 months, or 6 months, or after storage at 40°C / 75%RH for 1 month, 3 months, or 6 months, can be less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, or less than 0.2%.

[0048] Pharmaceutical Composition

[0049] The present invention provides a pharmaceutical composition comprising 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, wherein the first carrier material is an acrylic resin and its derivatives, and the second carrier material is hydroxypropyl methylcellulose and its derivatives.

[0050] Active ingredients

[0051] In one embodiment, the active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof.

[0052] Pharmaceutically acceptable salts of the active ingredient used may include, but are not limited to, salts formed with inorganic acids and salts formed with organic acids. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts 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, and p-toluenesulfonic acid.

[0053] In a preferred embodiment, the active ingredient is enzalutamide.

[0054] The active ingredient enzalutamide used in the embodiments of the present invention can be commercially available. An exemplary commercially available enzalutamide could be enzalutamide purchased from Allit Pharmaceuticals Inc.

[0055] In one embodiment, the content of the active ingredient, based on the weight of the pharmaceutical composition, is from about 10% by weight to about 35% by weight, preferably from about 16% by weight to about 33% by weight. Examples include about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, and about 33% by weight.

[0056] An appropriate content of active ingredients is beneficial for the active ingredients to achieve their therapeutic effects, and it also helps the active ingredients to have a suitable ratio with other ingredients, thereby facilitating the dissolution and solubility of the active ingredients.

[0057] carrier material

[0058] In one embodiment, the carrier material includes a first carrier material and a second carrier material.

[0059] In this invention, the active pharmaceutical ingredient can be dispersed in a carrier material and thus be encapsulated by the carrier material, thereby improving the solubility, dissolution rate, impurity level and stability of the pharmaceutical composition.

[0060] In one specific implementation, the carrier material is composed of a first carrier material and a second carrier material.

[0061] In one embodiment, the carrier material content is from about 60% to about 85% by weight, preferably from about 65% to about 82% by weight, based on the weight of the pharmaceutical composition. Examples include about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight, about 64% by weight, about 65% by weight, about 66% by weight, about 67% by weight, about 68% by weight, about 69% by weight, about 70% by weight, about 71% by weight, about 72% by weight, about 73% by weight, about 74% by weight, about 75% by weight, about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81% by weight, about 82% by weight, about 83% by weight, about 84% by weight, and about 85% by weight.

[0062] First carrier material

[0063] In one embodiment, the first carrier material comprises a copolymer formed from a first monomer and / or a third monomer and a second monomer. In another embodiment, the first carrier material comprises a copolymer formed from a first monomer, a second monomer, and optionally a third monomer. In a specific embodiment, the first carrier material comprises a copolymer formed from a first monomer, a second monomer, and a third monomer. In another specific embodiment, the first carrier material comprises a copolymer formed from a first monomer and a second monomer. In yet another specific embodiment, the first carrier material comprises a copolymer formed from a third monomer and a second monomer.

[0064] In a 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 a 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 a preferred embodiment, the third monomer of the first carrier material comprises dimethylaminoethyl methacrylate.

[0065] In one embodiment, the first carrier material is selected from one or more of the following: copolymers of butyl methacrylate and / or dimethylaminoethyl methacrylate with methyl methacrylate, copolymers of methacrylic acid with ethyl acrylate, and copolymers of methacrylic acid with methyl methacrylate.

[0066] In one specific embodiment, the first carrier material comprises a copolymer formed from a first monomer and a second monomer, wherein the first carrier material is selected from one or more of the group consisting of copolymers of methacrylic acid and ethyl acrylate and copolymers of methacrylic acid and methyl methacrylate. In a preferred embodiment, the first carrier material is a copolymer of methacrylic acid and ethyl acrylate.

[0067] In one specific implementation, the first carrier material comprises a copolymer formed by a first monomer, a second monomer, and a third monomer, wherein the first carrier material is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate.

[0068] 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, or about 2:1.

[0069] In one embodiment, 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. For example, about 1:3, about 1:2, about 1:1, about 2:1.

[0070] In one specific embodiment, the first carrier material may 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 specific embodiment, the first carrier material may be a copolymer of methacrylic acid and ethyl acrylate, wherein the molar ratio of methacrylic acid to ethyl acrylate is 1:1. In yet another specific embodiment, the first carrier material may be a copolymer of methacrylic acid and methyl methacrylate, wherein the molar ratio of methacrylic acid to methyl methacrylate is 1:1. In still another specific embodiment, the first carrier material may be a copolymer of methacrylic acid and methyl methacrylate, wherein the molar ratio of methacrylic acid to methyl methacrylate is 1:2.

[0071] In one specific embodiment, the first carrier material may be one or more selected from the group consisting of: a copolymer of butyl methacrylate and dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) (e.g., trade name Eutech E 100 or Eutech E PO), a copolymer of methacrylic acid and ethyl acrylate (1:1) (e.g., trade name Eutech L 100-55 or Eutech L 30D-55), a copolymer of methacrylic acid and methyl methacrylate (1:1) (e.g., trade name Eutech L 100), and a copolymer of methacrylic acid and methyl methacrylate (1:2) (e.g., trade name Eutech S100).

[0072] In a preferred embodiment, the first carrier material is a copolymer of methacrylic acid and ethyl acrylate (1:1) (as trade name suggests). L100-55).

[0073] The first carrier material used in the implementation of this invention can be commercially available.

[0074] A suitable type of first carrier material is beneficial for improving the solubility of the active ingredient, resulting in improved drug dissolution of the pharmaceutical composition of the present invention. Furthermore, a suitable type of first carrier material is beneficial for improving the stability of the pharmaceutical composition. In addition, a suitable type of first carrier material also helps to improve the purity of the pharmaceutical composition and reduce the level of impurities in the pharmaceutical composition. Moreover, a suitable type of first carrier material can give the pharmaceutical composition of the present invention a suitable friability, making the composition easy to pulverize during processing, thereby facilitating the processing of the formulation product.

[0075] Second carrier material

[0076] 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.

[0077] In one embodiment, the second carrier material comprises hydroxypropyl methylcellulose with a viscosity of less than 500 mPa·s, preferably hydroxypropyl methylcellulose with a viscosity of less than 100 mPa·s, more preferably hydroxypropyl methylcellulose with a viscosity of less than 50 mPa·s, even more preferably hydroxypropyl methylcellulose with a viscosity of less than 15 mPa·s, even more preferably hydroxypropyl methylcellulose with a viscosity of less than 10 mPa·s, and particularly preferably hydroxypropyl methylcellulose with a viscosity of less than 5 mPa·s.

[0078] 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. Wherein, HPMC E3, HPMC E5, HPMC E6, HPMC E15, and HPMC K3 represent 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.

[0079] In one specific embodiment, the second carrier material is selected from one or more of the following group: HPMC E3 (e.g., trade name Methocel E3 Premium LV, viscosity 3 mPa·s), HPMC E5 (e.g., trade name Methocel E5 Premium LV, viscosity 5 mPa·s), HPMC E6 (e.g., trade name Methocel E6 Premium LV, viscosity 6 mPa·s), HPMC E15 (e.g., trade name Methocel E15 Premium LV, viscosity 15 mPa·s), and HPMC K3 (e.g., trade name Methocel K3 Premium LV, viscosity 3 mPa·s). Preferably, the second carrier material is HPMC E5 (e.g., trade name Methocel E5 Premium LV) and / or HPMC E3 (e.g., trade name Methocel E3 Premium LV). More preferably, the second carrier material is HPMC E5 (e.g., trade name Methocel E5 Premium LV) or HPMC E3 (e.g., trade name Methocel E3 Premium LV). More preferably, the second carrier material is HPMC E5 (e.g., trade name Methocel E5 Premium LV).

[0080] A suitable type of second carrier material is beneficial for improving the solubility of the active ingredient, resulting in improved drug dissolution of the pharmaceutical composition of the present invention. Furthermore, a suitable type of second carrier material is beneficial for improving the stability of the pharmaceutical composition. In addition, a suitable type of second carrier material also helps to improve the purity of the pharmaceutical composition and reduce the level of impurities in the pharmaceutical composition. Moreover, a suitable type of second carrier material can give the pharmaceutical composition of the present invention a suitable friability, making the composition easy to pulverize during processing, thereby facilitating the processing of the formulation product.

[0081] In one embodiment, the active ingredient forms a solid dispersion with the carrier material.

[0082] The proportions of the first carrier material, the second carrier material, and the active ingredient

[0083] 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. Examples include 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, and about 1:1. Approximately 1:1.05, Approximately 1:1.1, Approximately 1:1.15, Approximately 1:1.2, Approximately 1:1.25, Approximately 1:1.3, Approximately 1:1.35, Approximately 1:1.4, Approximately 1:1.45, Approximately 1:1.5, Approximately 1:1.55, Approximately 1:1.6, Approximately 1:1.65, Approximately 1:1.7, Approximately 1:1.75, Approximately 1:1.8, Approximately 1:1.85, Approximately 1:1.9, Approximately 1:1.95, Approximately 1:2.

[0084] A suitable weight ratio of the first carrier material to the second carrier material is beneficial for improving the solubility of the active ingredient, resulting in improved drug dissolution of the pharmaceutical composition of the present invention. Furthermore, a suitable weight ratio of the first carrier material to the second carrier material is beneficial for improving the stability of the pharmaceutical composition. In addition, a suitable weight ratio of the first carrier material to the second carrier material also helps to improve the purity of the pharmaceutical composition and reduce the level of impurities in the pharmaceutical composition. Moreover, a suitable weight ratio of the first carrier material to the second carrier material can give the pharmaceutical composition of the present invention a suitable friability, making the composition easy to pulverize during processing, thereby further facilitating the processing of the formulation product.

[0085] 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, and more preferably from about 1:1 to about 1:3. For example, approximately 1:0.1, approximately 1:0.2, approximately 1:0.3, approximately 1:0.4, approximately 1:0.5, approximately 1:0.6, approximately 1:0.7, approximately 1:0.8, approximately 1:0.9, approximately 1:1, approximately 1:1.1, approximately 1:1.2, approximately 1:1.3, approximately 1:1.4, approximately 1:1.5, approximately 1:1.6, approximately 1:1.7, approximately 1:1.8, approximately 1:1.9, approximately 1:2, approximately 1:2.1, approximately 1:2.2, approximately 1:2.3, approximately 1:2.4, approximately 1:2.5, approximately 1:2.6, approximately 1:2.7, approximately 1:2.8, approximately 1:2.9, approximately 1:3 Approximately 1:3.1, Approximately 1:3.2, Approximately 1:3.3, Approximately 1:3.4, Approximately 1:3.5, Approximately 1:3.6, Approximately 1:3.7, Approximately 1:3.8, Approximately 1:3.9, Approximately 1:4, Approximately 1:4.1, Approximately 1:4.2, Approximately 1:4.3, Approximately 1:4.4, Approximately 1:4.5, Approximately 1:4.6, Approximately 1:4.7, Approximately 1:4.8, Approximately 1:4.9, Approximately 1:5, Approximately 1:5.1, Approximately 1:5.2, Approximately 1:5.3, Approximately 1:5.4, Approximately 1:5.5, Approximately 1:5.6, Approximately 1:5.7, Approximately 1:5.8, Approximately 1:5.9, Approximately 1:6.

[0086] A suitable weight ratio of active ingredient to first carrier material facilitates the formation of a stable amorphous solid dispersion, improves the solubility of the active ingredient, and enhances the drug dissolution rate of the pharmaceutical composition of the present invention. Furthermore, a suitable weight ratio of active ingredient to first carrier material improves the stability of the pharmaceutical composition. In addition, a suitable weight ratio of active ingredient to first carrier material also helps improve the purity of the pharmaceutical composition and reduce the level of impurities in the pharmaceutical composition. Moreover, a suitable weight ratio of active ingredient to first carrier material allows the pharmaceutical composition of the present invention to have suitable friability, making the composition easy to pulverize during processing, thereby further facilitating the processing of pharmaceutical products.

[0087] 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. Examples include 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, and about 1:3.

[0088] A suitable weight ratio of active ingredient to second carrier material facilitates the formation of a stable amorphous solid dispersion, improves the solubility of the active ingredient, and enhances the drug dissolution rate of the pharmaceutical composition of the present invention. Furthermore, a suitable weight ratio of active ingredient to second carrier material improves the stability of the pharmaceutical composition. In addition, a suitable weight ratio of active ingredient to second carrier material also helps improve the purity of the pharmaceutical composition and reduce the level of impurities in the pharmaceutical composition. Moreover, a suitable weight ratio of active ingredient to second carrier material can give the pharmaceutical composition of the present invention a suitable friability, making the composition easy to pulverize during processing, thereby further facilitating the processing of pharmaceutical products.

[0089] 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.

[0090] Pharmaceutically acceptable excipients

[0091] In one embodiment, the pharmaceutical composition further includes a pharmaceutically acceptable excipient. In a preferred embodiment, the pharmaceutically acceptable excipient is selected from one or more of the group consisting of plasticizers, fillers, disintegrants, lubricants, and flow aids.

[0092] plasticizer

[0093] Plasticizers are any organic molecules that increase the flexibility and toughness of the final product by internally modifying or solvating polymer molecules.

[0094] In one embodiment, the plasticizer is selected from one or more of the group consisting of polyethylene glycol, glycerin, triethyl citrate, vitamin E polyethylene glycol succinate, and poloxamer. In a preferred embodiment, the plasticizer is triethyl citrate.

[0095] The plasticizer used in this invention can be commercially available. For example, triethyl citrate can be purchased from Merck KgaA (Germany).

[0096] filler

[0097] In this invention, the active ingredient and carrier material can be further dispersed in a filler that is a pharmaceutically acceptable excipient to further improve the solubility and dissolution of the pharmaceutical composition.

[0098] In one embodiment, the filler 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, gum arabic powder, and gelatin. In a preferred embodiment, the filler is hydroxypropyl methylcellulose acetate succinate.

[0099] In another embodiment, the filler is disposed outside the active ingredient and the carrier material. In a preferred embodiment, the filler is disposed outside the solid dispersion formed by the active ingredient and the carrier material.

[0100] The filler used in this invention can be commercially available.

[0101] Disintegrant

[0102] In one embodiment, the disintegrant is selected from one or more of the group consisting of: microcrystalline cellulose, carboxymethyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxymethyl starch, alginate, sodium alginate, guar gum, corn starch, and magnesium aluminum silicate. In a preferred embodiment, the disintegrant is crospovidone sodium carboxymethyl cellulose.

[0103] The disintegrant used in this invention can be commercially available.

[0104] lubricant

[0105] In one embodiment, the lubricant is selected from one or more of the group consisting of: magnesium stearate, stearic acid, stearates, sodium stearate fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid esters, micronized silica gel, talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitoyl stearate, stearic acid, and hydrogenated vegetable oils. In a preferred embodiment, the lubricant is magnesium stearate.

[0106] The lubricant used in this invention can be commercially available.

[0107] Flow aid

[0108] In one embodiment, the flow aid is selected from one or more of the group consisting of micronized silica gel and talc. In a preferred embodiment, the flow aid is micronized silica gel.

[0109] The flow aid used in this invention can be commercially available. For example, micronized silica gel can be of the following type: 200Pharma's micronized silica gel was purchased from Evonik Operations GmbH.

[0110] The ratio of active ingredient to pharmaceutically acceptable excipients

[0111] 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, approximately 1:0.05, approximately 1:0.06, approximately 1:0.07, approximately 1:0.08, approximately 1:0.09, approximately 1:0.1, approximately 1:0.11, approximately 1:0.12, approximately 1:0.13, approximately 1:0.14, approximately 1:0.15, approximately 1:0.16, approximately 1:0.17, approximately 1:0.18, approximately 1:0.19, approximately 1:0.2, approximately 1:0.21, approximately 1:0.22, approximately 1:0.23, approximately 1:0.24, approximately 1:0.25, approximately 1:0.26, approximately 1:0.27, approximately 1:0.28, approximately 1:0.29, approximately 1:0.3.

[0112] An appropriate weight ratio of active ingredient to plasticizer helps improve the purity of the pharmaceutical composition, reduce the level of impurities in the pharmaceutical composition, and improve the flowability of the pharmaceutical composition, thereby making it more conducive to the preparation of the pharmaceutical composition product.

[0113] In one embodiment, the weight ratio of the active ingredient to the gliding agent 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, and about 1:0.2.

[0114] A suitable weight ratio of active ingredient to flow aid helps improve the flowability of the pharmaceutical composition, thereby making the preparation of the pharmaceutical composition product more favorable. It should be understood that, within the scope of this invention, the above-described technical features of this invention, as well as those specifically described below (such as in the examples), can be combined with each other to constitute new or preferred technical solutions.

[0115] pharmaceutical preparations

[0116] In another aspect, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of the present invention. In one embodiment, the pharmaceutical composition is a solid dosage form, preferably a tablet.

[0117] The pharmaceutical compositions of the present invention can be further combined with pharmaceutically acceptable excipients as needed to formulate various preparations, which may be in the form of powders, granules, pills, capsules, or tablets. In a preferred embodiment, the pharmaceutical preparation is a tablet.

[0118] It should be emphasized that the pharmaceutically acceptable excipients listed herein are merely illustrative and representative, and not exhaustive. Therefore, this invention is not limited to the pharmaceutically acceptable excipients listed above.

[0119] Preparation method of pharmaceutical composition

[0120] The present invention also provides a method for preparing the pharmaceutical composition of the present invention, comprising the following steps: providing an active ingredient, a first carrier material, a second carrier material, and optionally pharmaceutically acceptable excipients; mixing the active ingredient, the first carrier material, the second carrier material, and optionally pharmaceutically acceptable excipients or directly introducing them into a hot melt extruder; and hot melt extruding the mixture to obtain the pharmaceutical composition.

[0121] In one specific implementation, the preparation method may include the following steps:

[0122] S1: Preheat the hot melt extruder to 110℃-200℃;

[0123] S2: Add the mixture of the pre-mixed components in the metered ratio to the hot melt extruder, or add the components in the metered ratio directly to the hot melt extruder;

[0124] S3: Extrude and cool the resulting extrudate to obtain the pharmaceutical composition of the present invention.

[0125] In one embodiment, the components in the hot melt extrusion process include enzalutamide or a pharmaceutically acceptable salt thereof, a carrier material, and optionally a pharmaceutically acceptable pharmaceutical excipient.

[0126] In one embodiment, the hot melt extrusion method further includes cooling the extrudate from step S3, pulverizing and sieving it, and optionally mixing it with a pharmaceutically acceptable pharmaceutical excipient.

[0127] There are no particular limitations on the cooling method used in the preparation method of the present invention, which may include air cooling, water cooling, mechanical cooling, etc.

[0128] There are no particular limitations on the type of extruder suitable for use in this invention, including but not limited to single-screw or twin-screw hot melt extruders. In one embodiment, the extruder used to prepare the pharmaceutical composition of this invention is a twin-screw extruder. In this case, there are no particular limitations on the type of screw rotation, including but not limited to co-rotating twin-screw, counter-rotating twin-screw, and twin-cone screw rotation modes.

[0129] In one embodiment, the extruder used to prepare the pharmaceutical composition of the present invention is preferably a co-rotating twin-screw extruder.

[0130] In one embodiment, the temperature set for the hot melt extruder is from about 110°C to about 200°C, preferably from about 150°C to about 200°C, and more preferably from 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, and about 200°C.

[0131] In one embodiment, the screw 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, and about 400 rpm.

[0132] In one embodiment, the feeder 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, and about 80 rpm.

[0133] In one embodiment, the ratio of screw length to diameter (L / D) can be selected from about 20 to about 40, preferably from 25 to 35, and more preferably from 25 to 30. For example, the ratio of screw length to 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, or about 40.

[0134] Therapeutic uses and applications of pharmaceutical compositions or pharmaceutical preparations

[0135] The present invention also provides the use of the pharmaceutical compositions or pharmaceutical preparations of the present invention in the preparation of medicaments for the prevention or treatment of hyperproliferative diseases.

[0136] 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.

[0137] The present invention also provides a method for preventing or treating proliferative diseases, the method comprising the steps of administering to an individual in need a preventive or therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation of the present invention.

[0138] 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.

[0139] The present invention also provides a pharmaceutical composition or pharmaceutical preparation for the prevention or treatment of hyperproliferative diseases.

[0140] 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.

[0141] Beneficial effects

[0142] The pharmaceutical compositions of the present invention have low total impurity levels and excellent physical and chemical stability.

[0143] For example, the use of suitable first and second carrier materials in this invention helps to improve the purity of the pharmaceutical composition, resulting in a lower total impurity level. It also improves the physical and chemical stability of the pharmaceutical composition, which is beneficial for industrial production, transportation, and storage. Furthermore, suitable first and second carrier materials can also give the pharmaceutical composition a suitable degree of friability, making it easier to pulverize during processing, thus further facilitating the processing of pharmaceutical products.

[0144] Furthermore, the pharmaceutical composition of the present invention, comprising a first carrier material and a second carrier material in a suitable weight ratio, contributes to improved purity and a lower total impurity level, while also providing improved physical and chemical stability, which is beneficial for industrial production, transportation, and storage. In addition, a suitable weight ratio of the first carrier material to the second carrier material also allows the pharmaceutical composition of the present invention to have suitable friability, making it easier to pulverize during processing, thus further facilitating the processing of pharmaceutical products.

[0145] Example

[0146] The present invention will now be described in further detail with reference to specific embodiments.

[0147] It should be noted that the following embodiments are merely examples to clearly illustrate the technical solutions of the present invention, and are not intended to limit the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here, and obvious variations or modifications derived therefrom are still within the protection scope of this invention. Unless otherwise specified, the instruments, equipment, and reagents used herein are commercially available.

[0148] Reagents and impurities:

[0149] The main reagents used in the following examples and comparative examples are as follows:

[0150] The manufacturer of enzalutamide (the active ingredient) is Allit Pharmaceutical Co., Ltd.

[0151] The model of Utch is L100-55, manufactured by Evonik Operations GmbH;

[0152] The model number of the micronized silica gel is 200Pharma, manufactured by Evonik Operations GmbH;

[0153] The manufacturer of triethyl citrate (TEC) is Merck KgaA (Germany);

[0154] Hydroxypropyl methylcellulose (abbreviated as HPMC) is model number Methocel E5 Premium LV, manufactured by Nutrition & Biosciences USA1, LLC.

[0155] Hydroxypropyl methylcellulose acetate succinate (abbreviated as HPMCAS) is available in the following models: Aqoat AS-LG, Aqoat AS-LF, Aqoat AS-MG, Aqoat AS-MF, Aqoat AS-HG, or Aqoat AS-HF. The manufacturer is Shin-Etsu Chemical Industry Co., Ltd.

[0156] In this paper, 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-thioimidazolidinyl]-2-fluorobenzoic acid; and impurity RRT0.6 refers to an impurity with a relative retention time (RRT) of 0.6. In this field, industry standards do not require a clear attribution of the structure of all detected impurities; therefore, some unknown impurities are expressed using their relative retention times.

[0157] Test method:

[0158] 1. Powder X-ray Diffraction (PXRD)

[0159] Take an appropriate amount of the analyte (active drug, drug-loaded composition, or blank composition) and record the powder X-ray diffraction pattern under the conditions of Cu target, voltage 45kV, and current 45mA (BRUKER D8 ADVANCE X-ray diffractometer).

[0160] 2. Determination of impurities

[0161] Preparation of the test solution: Randomly select 5 sample tablets and place them in a 500mL volumetric flask. Add 50mL of water, shake to disperse, add approximately 300mL of acetonitrile, and sonicate for 20 minutes to dissolve enzalutamide. Cool to room temperature, dilute to the mark with acetonitrile, and shake well. Take a portion of the solution, centrifuge at 12000 rpm for 5 minutes, accurately measure 3.5mL of the supernatant, place it in a 20mL volumetric flask, dilute to the mark with diluent, and shake well.

[0162]

[0163] Comparative Example 1: Composition of enzalutamide with different carrier materials

[0164] 1. Preparation

[0165] The components and dosages of the enzalutamide composition are shown in Table 1-1D.

[0166] Preparation method: According to the components and dosages shown in Table 1-1D, mix the components evenly in a mixer and then add them to the feed hopper of a co-rotating twin-screw extruder (Omicron 12, Steer, India). Control the extruder barrel temperature between approximately 170°C and approximately 230°C for extrusion. Cool, pulverize, and sieve the resulting extrudate to obtain compositions 1-1D to 1-5D.

[0167] Table 1-1: Components and Dosage of Enzalutamide Composition (mg / unit)

[0168]

[0169] 2. Evaluation of physicochemical properties

[0170] 2.1 The results of the test on the appearance of the extrudate and the crystal form of the active pharmaceutical ingredient in the extrudate are detailed in Table 1-2D.

[0171] Table 1-2 Appearance and Powder X-ray Diffraction (PXRD) Test Results of D Extrusions

[0172] Test Project Composition 1-1D Composition 1-2D Composition 1-3D Composition 1-4D Composition 1-5D Extrusion appearance transparent transparent transparent transparent transparent Active pharmaceutical ingredient crystal form amorphous amorphous amorphous amorphous amorphous

[0173] As can be seen from the table above, all of the above compositions can form solid dispersions, and the active ingredient (enzalutamide) in the solid dispersions is in an amorphous state.

[0174] 2.2 The feasibility assessment of extruded material crushing is detailed in Table 1-3D.

[0175] Table 1-3 Evaluation of the feasibility of pulverizing D extrudates

[0176] Test Project Composition 1-1D Composition 1-2D Crushing operability difficulty difficulty

[0177] As can be seen from the table above, the extrudates corresponding to compositions 1-1D and 1-2D with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or hydroxypropyl methylcellulose (HPMC) as carrier materials are difficult to pulverize and it is difficult to obtain uniform solid dispersion fine powder.

[0178] 2.3 Impurity Testing

[0179] The results of the impurity test are detailed in Table 1-4D.

[0180] Table 1-4 Impurities in the Composition

[0181] Impurity Name Composition 1-1D Composition 1-2D Composition 1-3D Composition 1-4D Composition 1-5D General Miscellaneous 1.0％ 1.0％ 0.9％ 1.0％ 1.3％

[0182] As can be seen from the table above, the total impurity levels of compositions 1-1D to 1-5D using hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), or Utec as carrier materials are relatively high (total impurities include impurity B, impurity ENZ-B, and impurity RRT0.6), ranging from 0.9% to 1.3%.

[0183] Example 1: A composition containing enzalutamide, eutectic, HPMC, and TEC

[0184] 1.1. Preparation

[0185] The components and dosages of the enzalutamide composition are shown in Table 1-1.

[0186] Preparation method: According to the components and dosages shown in Table 1-1, mix the components evenly in a mixer and then add them to the feed hopper of a co-rotating twin-screw extruder (Omicron 12, Steer, India). Control the extruder barrel temperature between approximately 170°C and approximately 190°C for extrusion. Cool, pulverize, and sieve the resulting extrudate to obtain compositions 1-1 to 1-3.

[0187] Table 1-1 Components and dosage of enzalutamide composition (mg / unit)

[0188]

[0189] 1.2. Evaluation of Physicochemical Properties

[0190] (1) The results of the test on the appearance of the extrudate and the crystal form of the active pharmaceutical ingredient in the extrudate are detailed in Table 1-2.

[0191] Table 1-2 Appearance and Powder X-ray Diffraction (PXRD) Results of Extrudates

[0192] Test Project Composition 1-1 Composition 1-2 Compositions 1-3 Extrusion appearance transparent transparent transparent Active pharmaceutical ingredient crystal form amorphous amorphous amorphous

[0193] As can be seen from the table above, all of the above compositions can form solid dispersions, and the active ingredient (enzalutamide) in the solid dispersions is in an amorphous state.

[0194] (2) For the assessment of the operability of extruded material crushing, see Table 1-3.

[0195] Table 1-3 Assessment of the feasibility of extruding material pulverization

[0196] Test Project Composition 1-1 Composition 1-2 Compositions 1-3 Crushing operability easy easy easy

[0197] As can be seen from the table above, the extrudates of the above compositions are easier to pulverize, which is more conducive to the processing of pharmaceutical products.

[0198] (3) Impurity testing

[0199] The results of the impurity test are detailed in Table 1-4.

[0200] Table 1-4 Impurities in the Composition

[0201] Impurity Name Composition 1-1 Composition 1-2 Compositions 1-3 General Miscellaneous 0.3％ 0.3％ 0.3％

[0202] As can be seen from the table above, compositions 1-1 to 1-3 using Eutrich and HPMC as carrier materials have low total impurity levels (total impurities include impurity B, impurity ENZ-B, and impurity RRT0.6), with a total impurity level of 0.3%. Therefore, the compositions of the present invention can ensure the stability of the active ingredients and greatly reduce impurities generated during production and storage.

[0203] Example 2: Composition containing enzalutamide, eutectic, and HPMC

[0204] 2.1. Preparation

[0205] The components and dosages of the enzalutamide composition are shown in Table 2-1.

[0206] Preparation method: According to the components and dosages shown in Table 2-1, mix the components evenly in a mixer and then add them to the feed hopper of a co-rotating twin-screw extruder (Omicron 12, Steer, India). Control the extruder barrel temperature between approximately 170°C and approximately 190°C for extrusion. Cool, pulverize, and sieve the resulting extrudate to obtain compositions 2-1 to 2-4.

[0207] Table 2-1 Components and dosage of enzalutamide composition (mg / unit)

[0208]

[0209] 2.2. Evaluation of Physicochemical Properties

[0210] (1) The results of the test on the appearance of the extrudate and the crystal form of the active pharmaceutical ingredient in the extrudate are detailed in Table 2-2.

[0211] Table 2-2 Appearance and Powder X-ray Diffraction (PXRD) Results of Extruded Materials

[0212] Test Project Composition 2-1 Composition 2-2 Composition 2-3 Composition 2-4 Extrusion appearance transparent transparent transparent transparent Active pharmaceutical ingredient crystal form amorphous amorphous amorphous amorphous

[0213] As can be seen from the table above, all of the above compositions can form solid dispersions, and the active ingredient (enzalutamide) in the solid dispersions is in an amorphous state.

[0214] (2) For details of the feasibility assessment of extrusion crushing, please refer to Table 2-3.

[0215] Table 2-3 Assessment of the feasibility of extruding material pulverization

[0216] Test Project Composition 2-1 Composition 2-2 Composition 2-3 Composition 2-4 Crushing operability easy easy easy easy

[0217] As can be seen from the table above, the extrudates of the above compositions are easier to pulverize, which is more conducive to the processing of pharmaceutical products.

[0218] (3) Impurity testing

[0219] The results of the impurity test are detailed in Table 2-4.

[0220] Table 2-4 Impurities in Enzalutamide Compositions

[0221] Impurity Name Composition 2-1 Composition 2-2 Composition 2-3 Composition 2-4 General Miscellaneous 0.3％ 0.3％ 0.3％ 0.4％

[0222] As can be seen from the table above, compositions 2-1 to 2-4 using Eutrich and HPMC as carrier materials have low total impurity levels (total impurities include impurity B, impurity ENZ-B, and impurity RRT0.6), ranging from 0.3% to 0.4%. Therefore, the compositions of the present invention can ensure the stability of the active ingredients and greatly reduce impurities generated during production and storage.

[0223] Example 3: Stability study of compositions containing enzalutamide, eutectic, HPMC, and TEC

[0224] Good physical and chemical stability of solid dispersions is an important indicator in formulation development. The results of the physical and chemical stability of the active ingredient in composition 1-1 within the carrier material are shown in Table 3-1, and the PXRD pattern of composition 1-1 is shown below. Figure 1 As shown.

[0225] Table 3-1 Stability results of composition 1-1

[0226]

[0227] As can be seen from the table above, the content of active ingredients, total impurity levels, and moisture content in the compositions of the present invention remained essentially unchanged after 6 months at 25℃ / 60%RH and 6 months at 40℃ / 75%RH. This demonstrates that the compositions of the present invention possess excellent physical and chemical stability, which is beneficial for industrial production, transportation, and storage.

[0228] In summary, based on the relevant descriptions in the comparative examples and embodiments, it can be seen that by using specific carrier materials, the compositions of the present invention can achieve low impurity levels, ensure rapid dissolution, and possess excellent physical and chemical stability.

[0229] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. The true scope and spirit of the present invention are shown in the appended claims, and the description and embodiments are merely exemplary.

Claims

1. A pharmaceutical composition, characterized in that, It is made of active ingredients, carrier materials and pharmaceutically acceptable excipients; The active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof; The carrier material is a first carrier material and a second carrier material. The first carrier material is Utec L100-55. The second carrier material is HPMC E5; The weight ratio of the active ingredient to the first carrier material is 1:1 to 1:3; The weight ratio of the active ingredient to the second carrier material is 1:0.3 to 1:2; The weight ratio of the first carrier material to the second carrier material is 1:0.15 to 1:1; The pharmaceutically acceptable excipients are plasticizers and flow aids; The plasticizer is triethyl citrate; The flow aid is micronized silica gel; The weight ratio of the active ingredient to the plasticizer is from 1:0.12 to 1:0.18; The weight ratio of the active ingredient to the glidant is 1:0.06 to 1:0.

07.

2. A pharmaceutical composition, characterized in that, It is made of active ingredients, carrier materials and pharmaceutically acceptable excipients; The active ingredient is enzalutamide or a pharmaceutically acceptable salt thereof; The carrier material is a first carrier material and a second carrier material. The first carrier material is Utec L100-55. The second carrier material is HPMC E5; The weight ratio of the active ingredient to the first carrier material is 1:1 to 1:3; The weight ratio of the active ingredient to the second carrier material is 1:0.3 to 1:2; The weight ratio of the first carrier material to the second carrier material is 1:0.15 to 1:1; The pharmaceutically acceptable excipient is a flow aid; The flow aid is micronized silica gel; The weight ratio of the active ingredient to the gliding agent is 1:0.07 to 1:0.

13.

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

4. A method for preparing a pharmaceutical composition according to any one of claims 1-3, comprising the following steps: Provide active ingredients, a first carrier material, a second carrier material, and pharmaceutically acceptable excipients; The active ingredient, the first carrier material, the second carrier material, and pharmaceutically acceptable excipients are mixed or introduced directly into a hot melt extruder; The above mixture is subjected to hot melt extrusion to obtain the pharmaceutical composition.

5. A pharmaceutical formulation prepared from the pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutical preparation is a solid dosage form.

6. The pharmaceutical formulation as described in claim 5, characterized in that, The pharmaceutical preparation is a tablet.

7. Use of a pharmaceutical composition as described in any one of claims 1-3 or a pharmaceutical preparation as described in claim 5 in the preparation of a medicament for the prevention or treatment of hyperproliferative diseases; The aforementioned hyperproliferative disease is prostate cancer.

8. The use as described in claim 7, characterized in that, The aforementioned hyperproliferative disease is castration-resistant prostate cancer.

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