A darolutamide pharmaceutical composition and a preparation method and use thereof

Abstract

The present invention relates to a pharmaceutical composition comprising the active ingredient darolutamide or a pharmaceutically acceptable salt thereof, a carrier material and a formulation improver. The present invention also relates to a solid preparation comprising the pharmaceutical composition of the present invention. The present invention also relates to a method for preparing the pharmaceutical composition and the solid preparation of the present invention.

Description

[0001] This application claims priority to Chinese Application No. 202111422274.6, filed on November 26, 2021, entitled “A darlotamide pharmaceutical composition and its preparation method and use thereof,” the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to a dalotamide pharmaceutical composition, its preparation method, and its uses. Background Technology

[0003] Darolutamide's chemical name is N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide, and its chemical structure is shown below.

[0004]

[0005] Darolactone is an oral nonsteroidal androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Developed by Bayer, darolactone was approved for marketing by the U.S. Food and Drug Administration (FDA) in 2019. Furthermore, a Phase III clinical trial of darolactone demonstrated that, compared to placebo combined with androgen deprivation therapy (ADT), darolactone in combination with ADT significantly prolonged median metastasis-free survival (MFS) (18.4 months vs. 40.4 months) and reduced the risk of disease metastasis or death by 59%, while also exhibiting a favorable safety profile.

[0006] Darolantadine is a poorly soluble, highly permeable drug (BCS Class II), practically insoluble (14-23 μg / mL) in aqueous media with pH 1-6.8. Single-dose pharmacokinetic studies showed that darolantadine's median T0... max The absorption time is 3-6 hours, indicating slow absorption. Darlotamide's terminal half-life is 10-15 hours. Under both fasting and fed conditions, the C600mg dose... max and AUC (0-t) Above 300mg. And regarding AUC... (0-t) The coefficient of variation (CV%) was higher at a dose of 300 mg (69.6%) than at a dose of 600 mg (41.4%).

[0007] Furthermore, the bioavailability of 300 mg dalolactam administered in a fasting state is approximately 30%. However, in a fed state, the bioavailability of a single dose of 300 mg or 600 mg dalolactam increases by 2.5 times and 2.8 times, respectively. Similarly, the AUC of 300 mg or 600 mg dalolactam administered in a fed state... (0-t) It increases by 2.5 times. This shows that dalotamide has a significant food effect.

[0008] WO2019032840A1 discloses a pharmaceutical composition comprising abiraterone acetate and dallotamide, wherein the pharmaceutical composition further comprises polyvinylpyrrolidone or vinylpyrrolidone / vinyl acetate copolymer as a first pharmaceutical excipient and sodium lauryl sulfate as a second pharmaceutical excipient. The inventors claim that this pharmaceutical composition has increased in vitro permeability under both fasting and eating conditions, thereby enabling a reduction in drug dosage and avoiding the limitations of fasting administration. However, the inventors have not demonstrated the aforementioned technical effects through examples. Summary of the Invention

[0009] In one aspect, the present invention relates to a pharmaceutical composition comprising the active ingredient dallotamide or a pharmaceutically acceptable salt thereof, a carrier material, and a formulation modifier, wherein the formulation modifier is selected from one or more of the following: sodium lauryl sulfate, polyethylene glycol succinate, poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, etc. Ethylene castor oil; the carrier material is selected from one or more of the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, eutectic, copovidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl acetate, cyclodextrin, sodium carboxymethyl ethyl cellulose, polyethylene oxide, cellulose acetate phthalate, and cellulose acetate trimellitate.

[0010] In one embodiment, the active ingredient dallotamine or a pharmaceutically acceptable salt thereof is present in a weight ratio of about 1:0.5 to 1:8 to the carrier material.

[0011] In one embodiment, the weight ratio of the active ingredient dallotamide or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.05 to 1:0.8.

[0012] In another aspect, the present invention relates to a solid dosage form comprising the pharmaceutical composition of the present invention.

[0013] In another aspect, the present invention relates to a method for preparing the pharmaceutical composition of the present invention, comprising the following steps: (1) weighing each component; (2) mixing the components of step (1) and performing hot melt extrusion to obtain the pharmaceutical composition.

[0014] In another aspect, the present invention relates to a method for preparing the solid dosage form of the present invention, comprising the following steps: (1) preparing a pharmaceutical composition according to the above method; (2) pulverizing the pharmaceutical composition of step (1) to obtain pharmaceutical composition particles; (3) mixing the pharmaceutical composition particles of step (2) with a lubricant and other formulation modifiers to obtain a total mixed particle; and (4) pressing the total mixed particle of step (3) to obtain a solid dosage form.

[0015] In another aspect, the present invention relates to the use of the pharmaceutical compositions and solid dosage forms of the present invention in the preparation of medicaments for the treatment or prevention of prostate cancer. Detailed Implementation

[0016] 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 changes without departing from the spirit of the invention.

[0017] General definitions and terms

[0018] Unless otherwise stated, all publications, patent applications, patents and other references mentioned herein are incorporated herein in their entirety by way of citation.

[0019] 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.

[0020] Unless otherwise stated, all percentages, parts, proportions, etc. are by weight.

[0021] When a quantity, concentration, or other value or parameter is given as a range, preferred range, or preferred upper and lower limits, or a specific value, it 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 value referenced when defining the range. For example, "1-20" encompasses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and any subrange consisting of any two values ​​therein, such as 2-6, 3-5, 2-10, 3-15, 4-20, 5-19, etc.

[0022] 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.

[0023] The term "stoichiometric ratio" refers to the proportion of various substances by weight. For example, in this invention, the active ingredient is proportioned with fillers, binders, and lubricants in a specified weight ratio.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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 components. The expression “substantially constitutes” limits the scope to the specified elements, steps, or components, plus optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression “including” encompasses both the expressions “substantially constitutes” and “consisting of.”

[0030] The term "pharmaceutical acceptable" means that, within the bounds of normal medical judgment, contact with a patient's tissues will not cause undue toxicity, irritation, allergic reactions, etc., and that the benefits and risks are reasonable and that the product is effective for its intended use.

[0031] 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, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers. Non-limiting examples of carriers 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.

[0032] The terms “pharmaceutical active ingredient,” “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disease or condition.

[0033] 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.

[0034] The term "tablet" refers to a solid pharmaceutical dosage form that contains an active ingredient and optionally includes suitable excipients, such as diluents, binders, etc., and is prepared by compression or molding techniques. Examples of tablets include compressed tablets, multi-particle tablets, multi-compressed tablets, coated tablets, matrix tablets, osmotic pump tablets, and caplets.

[0035] The term "bulk density" refers to the mass of a given amount of particulate product divided by the total volume occupied by that amount.

[0036] The term "angle of repose" refers to the maximum angle formed between the free slope of powder accumulation and the horizontal plane. The smaller the angle of repose, the lower the friction and the better the flowability.

[0037] The term "dissolution" refers to the rate and extent to which a drug dissolves from a solid dosage form in a specified solvent.

[0038] Pharmaceutical Composition

[0039] In one aspect, the present invention relates to a pharmaceutical composition comprising the active ingredient dallotamine or a pharmaceutically acceptable salt thereof, a carrier material, and a formulation modifier.

[0040] Active ingredients

[0041] In one embodiment, the active ingredient is dallotamide or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the active ingredient is dallotamide.

[0042] carrier material

[0043] Carrier materials are materials that are usually in the form of particles and are used to carry active ingredients, which are basically distributed in the carrier material.

[0044] In one embodiment, the carrier material is selected from one or more of the following: hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g.) ), Eutrich (e.g.) The carrier material is selected from one or more of the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl acetate, cyclodextrin, sodium carboxymethyl ethyl cellulose, polyethylene oxide, cellulose acetate phthalate, and cellulose trimellitate. In a preferred embodiment, the carrier material is selected from one or more of the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polycaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and eutectic. A suitable carrier material helps improve the solubility of the pharmaceutical composition.

[0045] As an example, carrier materials that can be used include, but are not limited to, commercially available products from Shin-Etsu. (HPMCAS), BASF's commercially available products VA64 and Ashland's commercially available product, PVP K30.

[0046] Formulation improver

[0047] In one embodiment, the formulation modifier is selected from one or more of the following: sodium lauryl sulfate, polyethylene glycol eurovis succinate, poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil. In a preferred embodiment, the formulation modifier is selected from one or more of the following: sodium lauryl sulfate, polyethylene glycol eurovis succinate, and triethyl citrate.

[0048] As an example, formulation modifiers that can be used include, but are not limited to, PMC Isochem's commercially available product VETPGS1000 and BASF's commercially available product... SLS and Merck KGaA's commercially available TEC products.

[0049] In this field, sodium dodecyl sulfate, polyethylene glycol succinate (VE), poloxamer, polyoxyethylene hydrogenated castor oil, stearyl alcohol, dibutyl sebate, triethyl citrate, butyl citrate, glycerin, polyethylene glycol, lecithin, sodium dioctyl sulfosuccinate, sodium taurocholate, polysorbate, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil are commonly used as surfactants or plasticizers in solid dosage forms. For example, they can make the coating film of coated tablets softer, thus making the coated tablets less prone to cracking and easier to store and transport. The inventors unexpectedly discovered that the formulation modifier used in this invention can achieve unexpected technical effects, such as further improving the solubility of the pharmaceutical composition, thereby improving the bioavailability of the drug, improving the stability of the drug, making the pharmaceutical composition easier to prepare, and thus saving energy consumption in production.

[0050] In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifier is polyethylene glycol, the carrier material is not polyvinylpyrrolidone and / or polyvinyl acetate-polyethylene glycol graft copolymer and / or hydroxypropyl cellulose.

[0051] In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifier is sodium dodecyl sulfate, the carrier material is not polyvinylpyrrolidone and / or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and / or hydroxypropyl cellulose.

[0052] In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifier is poloxamer, the carrier material is not polyvinylpyrrolidone and / or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and / or hydroxypropyl cellulose.

[0053] In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifier is two or three of polyethylene glycol, sodium dodecyl sulfate, and poloxamer, the carrier material is not polyvinylpyrrolidone and / or polyvinyl acetate-polyethylene glycol graft copolymer and / or hydroxypropyl cellulose.

[0054] In one embodiment, in the pharmaceutical composition of the present invention, when the formulation modifier is polyethylene glycol, sodium dodecyl sulfate, or poloxamer, the carrier material is not polyvinylpyrrolidone and / or polyvinyl caprolactam-vinyl acetate-polyethylene glycol graft copolymer and / or hydroxypropyl cellulose.

[0055] In other words, when the formulation modifier used is polyethylene glycol, sodium dodecyl sulfate, poloxamer or a combination thereof, the carrier material is not polyvinylpyrrolidone, not polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, not hydroxypropyl cellulose, or a combination of two or three of the above.

[0056] In a preferred embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is selected from one or more of the following: sodium dodecyl sulfate, polyethylene glycol succinate, dibutyl sebacate, triethyl citrate, butyl citrate, glycerin, and polyethylene glycol; the carrier material is selected from one or more of the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, eutectic, copovidone, methylcellulose, ethylcellulose, and sodium carboxymethyl cellulose; wherein when the formulation modifier is sodium dodecyl sulfate or polyethylene glycol, the carrier material is not polyvinylpyrrolidone and / or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0057] In a more preferred embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is selected from one or more of the following: sodium lauryl sulfate, polyethylene glycol succinate, and triethyl citrate; the carrier material is selected from one or more of the following: hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and eutectic; wherein when the formulation modifier is sodium lauryl sulfate, the carrier material is not polyvinylpyrrolidone and / or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0058] In one specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is polyethylene glycol succinate (VE), and the carrier material is hydroxypropyl methylcellulose acetate succinate. In one specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is polyvinylpyrrolidone (PVP), and the carrier material is hydroxypropyl methylcellulose acetate succinate. In one specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is polyethylene glycol succinate (VE), and the carrier material is hydroxypropyl methylcellulose acetate succinate and polyvinylpyrrolidone. In one specific embodiment, in the pharmaceutical composition of the present invention, the formulation modifier is triethyl citrate, and the carrier material is eutectic.

[0059] Other components

[0060] In one embodiment, the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable excipients.

[0061] In one embodiment, the pharmaceutical composition of the present invention may further comprise one or more of the following: buffers, acidifiers, stabilizers, and preservatives.

[0062] buffer

[0063] Buffers are pharmaceutical excipients that stabilize the pH of drug formulations.

[0064] In one embodiment, the buffer is selected from one or more of the following: citric acid buffer, malate buffer, maleate buffer, tartrate buffer.

[0065] Acidifier

[0066] Acidifiers are acids that are mainly used as excipients in drug preparation. They are used to adjust the pH of the drug and only provide acidity when in use, and usually do not introduce special biological activities.

[0067] In one embodiment, the acidifying agent is selected from one or more of the following: tartaric acid, carbonic acid, acetic acid, oxalic acid, and nitrous acid.

[0068] stabilizer

[0069] Stabilizers are specific chemical substances that interact with the active ingredients and / or general pharmaceutical excipients in a pharmaceutical composition to improve its stability.

[0070] In one embodiment, the stabilizer is selected from one or more of the following: methionine, lysine, and histidine.

[0071] preservative

[0072] Preservatives are compounds added to a pharmaceutical composition to prevent or delay microbial activity (growth and metabolism).

[0073] In one embodiment, the preservative is selected from one or more of the following: benzyl alcohol, benzyl benzoate, methylparaben, propylparaben, vitamin E, and vitamin A palmitate.

[0074] In one embodiment, the weight ratio of the active ingredient dallotamine or a pharmaceutically acceptable salt thereof to the carrier material is about 1:0.5 to 1:8. In a preferred embodiment, the weight ratio of the active ingredient dallotamine or a pharmaceutically acceptable salt thereof to the carrier material is about 1:1 to 1:4. In a more preferred embodiment, the weight ratio of the active ingredient dallotamine or a pharmaceutically acceptable salt thereof to the carrier material is about 1:2 to 1:4. For example, about 1:0.5, about 1:0.8, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, and ranges consisting of any two of these ratios. A suitable weight ratio of the active ingredient to the carrier material is beneficial for obtaining suitable solubility and dissolution rate. An excessively high weight ratio of the active ingredient to the carrier material does not effectively improve the solubility of the active ingredient; an excessively low weight ratio of the active ingredient to the carrier material will not more effectively improve the solubility of the active ingredient and will result in an excessively high viscosity of the solid dosage form, making its preparation difficult.

[0075] In one embodiment, the weight ratio of the active ingredient dallotamide or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.05 to 1:0.8. In a preferred embodiment, the weight ratio of the active ingredient dallotamide or a pharmaceutically acceptable salt thereof to the formulation modifier is about 1:0.1 to 1:0.5. For example, about 1:0.05, 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, and any range consisting of any two of these ratios. A suitable weight ratio of the active ingredient to the formulation modifier is beneficial for obtaining suitable solubility, concentration, and stability, resulting in a drug that is easy to store and absorb by the body. An excessively high weight ratio of the active ingredient to the formulation modifier does not effectively improve the solubility of the active ingredient; conversely, an excessively low weight ratio of the active ingredient to the formulation modifier does not effectively improve the solubility of the active ingredient and may even prevent preparation.

[0076] Bulk density

[0077] Bulk density, also known as packing density, refers to the mass of the pharmaceutical composition particles of this invention divided by their volume. A suitable bulk density is beneficial for the preparation of the pharmaceutical composition and its formulation, and consequently, for obtaining products with suitable solubility and dissolution rate.

[0078] In one embodiment, the bulk density of the pharmaceutical composition is about 0.40-0.50 g / mL. In a preferred embodiment, the bulk density of the pharmaceutical composition is about 0.42-0.49 g / mL. In a more preferred embodiment, the bulk density of the pharmaceutical composition is about 0.436-0.473 g / mL. For example, about 0.40g / mL, 0.41g / mL, 0.42g / mL, 0.423g / mL, 0.425g / mL, 0.427g / mL, 0.429g / mL, 0.43g / mL, 0.433g / mL, 0.436g / mL, 0.439g / mL, 0.44g / mL , 0.442g / mL, 0.445g / mL, , 0.448g / mL, 0.45g / mL, 0.451g / mL, 0.46g / mL, 0.466g / mL, 0.469g / mL, 0.47g / mL, 0.473g / mL, 0.48g / mL, 0.49g / mL.

[0079] Angle of repose

[0080] The angle of repose refers to the maximum angle formed by the free slope formed by the accumulation of pharmaceutical composition particles of the present invention and the horizontal plane. A smaller angle of repose indicates less friction between the pharmaceutical composition particles, meaning better flowability. A suitable angle of repose for the pharmaceutical composition particles is beneficial for the preparation of formulations, and consequently, for obtaining formulations with suitable solubility and dissolution rates.

[0081] In one embodiment, the angle of repose of the pharmaceutical composition is about 20-32°. In a preferred embodiment, the angle of repose of the pharmaceutical composition is about 21-30°. In a more preferred embodiment, the angle of repose of the pharmaceutical composition is about 22-28°. For example, it is about 20°, about 21°, about 22°, about 23°, about 24°, about 25°, about 26°, about 27°, about 28°, about 29°, about 30°, about 31°, or about 32°.

[0082] solid dosage forms

[0083] In another aspect, the present invention relates to a solid dosage form comprising the pharmaceutical composition of the present invention.

[0084] Preparation method of the present invention

[0085] Preparation of pharmaceutical compositions

[0086] In another aspect, the present invention relates to a method for preparing the pharmaceutical composition of the present invention, comprising the following steps:

[0087] (1) Weigh each component;

[0088] (2) Mix the components from step (1) and perform hot melt extrusion to obtain a pharmaceutical composition.

[0089] The active ingredients, carrier materials, and formulation modifiers are as defined above.

[0090] Step (1)

[0091] The components of the pharmaceutical composition are weighed according to a specific stoichiometric ratio (e.g., weight ratio). For example, the components of the pharmaceutical composition may be weighed according to the weight ratios shown in the following examples.

[0092] Step (2)

[0093] The hot melt extrusion of step (2) is performed using methods and instruments commonly used in the art. For example, the components of step (1) can be hot melt extruded using a Leistritz ZSE 12HP-PH-40D.

[0094] In one embodiment, the temperature of hot melt extrusion in step (2) is about 160±20°C.

[0095] Preparation of solid dosage forms

[0096] In another aspect, the present invention also relates to a method for preparing solid dosage forms, comprising the following steps:

[0097] (1) Prepare the pharmaceutical composition according to the above method;

[0098] (2) Pulverize the pharmaceutical composition of step (1) to obtain pharmaceutical composition particles;

[0099] (3) The pharmaceutical composition particles from step (2) are mixed with lubricant and other formulation modifiers to obtain total mixed particles;

[0100] (4) Press the total mixed particles from step (3) to obtain a solid dosage form.

[0101] Step (2)

[0102] The crushing in step (2) is carried out by methods commonly used in the art. For example, blade crushing and roller crushing can be used.

[0103] Step (3)

[0104] The mixing in step (3) can be performed using methods commonly used in the art. For example, V-type mixing and hopper mixing can be used.

[0105] Step (4)

[0106] The compression in step (4) can be performed using methods commonly used in the art. For example, hydraulic compression, mechanical compression, and pneumatic compression can be used. Equipment that can be used includes, for example, the ZP14 tablet press from Sinopharm Longli.

[0107] In one embodiment, the preparation of the solid dosage form of the present invention further comprises the following steps:

[0108] Step (5) Coating the solid dosage form from step (4) to obtain tablets.

[0109] The coating in step (5) can be performed using methods commonly used in the art. For example, an Ohara coating machine can be used.

[0110] It should be understood that the composition preparation methods listed above are merely illustrative and representative. Therefore, the composition preparation methods of the present invention are not limited to those listed above. Those skilled in the art can make various changes, adjustments, or equivalent substitutions to the preparation methods using conventional techniques, all of which do not exceed the scope of protection of the present invention.

[0111] Pharmaceutical uses

[0112] The present invention also relates to a method for preventing and treating prostate cancer, the method comprising administering a therapeutically effective amount of the pharmaceutical composition or solid dosage form of the present invention to an individual in need.

[0113] The pharmaceutical compositions or solid dosage forms of the present invention can be used for the prevention and treatment of prostate cancer.

[0114] The present invention also relates to the use of the pharmaceutical compositions or solid dosage forms of the present invention in the preparation of medicaments for the prevention and treatment of prostate cancer.

[0115] Beneficial effects

[0116] Compared to existing dalotamide pharmaceutical compositions, the dalotamide pharmaceutical composition of the present invention further improves the solubility of the active ingredient, thereby obtaining a pharmaceutical composition with excellent solubility and effectively improving the bioavailability of the composition. Therefore, the dalotamide pharmaceutical composition of the present invention allows for low-dose administration and reduces the food effect.

[0117] In addition, the dalotamide pharmaceutical composition of the present invention has excellent stability and is suitable for storage at room temperature, reducing the requirements for storage and transportation.

[0118] Furthermore, the dalotamid pharmaceutical composition of the present invention has a suitable bulk density and angle of repose, which confirms its good flowability, making it easy to formulate into tablets and other forms, suitable for large-scale scale-up and industrial production.

[0119] Furthermore, by using suitable carrier materials and formulation modifiers, the dalotamide drug composition of the present invention has significantly improved solubility, solubility and stability compared to the prior art; and the obtained drug composition particles have improved bulk density and angle of repose, making them easier to press and other operations to prepare solid dosage forms, thereby effectively reducing production energy consumption.

[0120] Example

[0121] The present invention will now be described in further detail with reference to specific embodiments.

[0122] 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.

[0123] Material

[0124] Darlotamine: Purchased from Shanghai Pengpin Biotechnology Co., Ltd.;

[0125] PVP: Purchased from BASF VA64;

[0126] Purchased from Ashland, PVP K30;

[0127] HPMACAS: Purchased from Shin-Etsu.

[0128] HPMCP: Hydroxypropyl methylcellulose phthalate purchased from Shin-Etsu Corporation;

[0129] Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: purchased from BASF.

[0130] Udoch: Purchased from Evonik Degussa.

[0131] VE TPGS: Purchased from PMC Isochem, VE TPGS1000;

[0132] SLS: Purchased from BASF

[0133] TEC: Purchased from Merck KGaA.

[0134] Determination of solubility

[0135] Weigh approximately 200 mg of sample into a 50 ml shake flask, then add 50 ml of pH 6.8 medium. Mix the sample thoroughly and place it in a shaker. Set the shaker temperature to 37.2 °C and the shaking speed to 50 rpm. Take a sample after 4 hours and filter it through a 0.45 μm filter membrane to collect the filtrate. Analyze the filtrate using high-performance liquid chromatography (HPLC) at a wavelength of 286 nm.

[0136] Dissolution determination

[0137] In the following examples, the dissolution of the formulation was determined using the USP II method (paddle method) of the United States Pharmacopeia, with the specific parameters as follows.

[0138] Dissolution method USP II method (paddle method) Dissolution medium Phosphate buffer at pH 6.8 Medium volume 1000ml rotational speed 75rpm temperature 37℃±5℃

[0139] Dissolution sample analysis: The solution obtained in the dissolution test was filtered through a 0.45 μm filter membrane and the filtrate was collected. The solution was then analyzed by high performance liquid chromatography at a wavelength of 260 nm.

[0140] Content test method: Dissolve the sample to be tested in methanol to make the concentration of dalotamide 100 μg / ml, and determine it by high performance liquid chromatography at a wavelength of 286 nm.

[0141] The test method for related substances is as follows: The sample to be tested is dissolved in methanol to make the concentration of dalotamide 150 μg / ml, and the concentration is determined by high performance liquid chromatography at a wavelength of 286 nm.

[0142] Preparation Examples

[0143] Example 1: Preparation of the dalotamid pharmaceutical composition

[0144] Darlotamine pharmaceutical composition particles were prepared according to the specific composition and weight ratio in Table 1.

[0145] The specific preparation method is as follows:

[0146] The active ingredients and carrier materials were mixed according to the weight ratios in Table 1 to obtain a blend. The blend was fed into a Leistritz ZSE 12HP-PH-40D hot melt extruder at a constant rate via a powder feeder, and hot melt extrusion was performed at a temperature of 160±20℃. The extrudate was collected and pulverized using a FitzMill L1A pulverizer, then sieved through an 80-mesh sieve.

[0147] Daroltadine pharmaceutical compositions 1-1 to 1-15 and blends of active ingredients and carrier materials 1-1 to 1-15 were obtained according to the above method.

[0148] Table 1. Composition of the dallotamine composition

[0149] Composition Active ingredients carrier material Active ingredient: carrier material Composition 1-1 Darlotamine VA64 1∶2 Composition 1-2 Darlotamine VA64 1∶3 Compositions 1-3 Darlotamine VA64 1∶4 Compositions 1-4 Darlotamine HPMCAS 1∶1 Compositions 1-5 Darlotamine HPMCAS 1∶2 Compositions 1-6 Darlotamine HPMCAS 1∶3 Compositions 1-7 Darlotamine HPMCAS 1∶4 Compositions 1-8 Darlotamine HPMCP-HP55 1∶2 Compositions 1-9 Darlotamine HPMCP-HP55 1∶3 Composition 1-10 Darlotamine Soluplus 1∶2 Composition 1-11 Darlotamine Soluplus 1∶3 Composition 1-12 Darlotamine Eudragit-L100 1∶2 Compositions 1-13 Darlotamine Eudragit-L100 1∶3 Compositions 1-14 Darlotamine PVP K30 1∶3 Composition 1-15 Darlotamine PVP K30 1∶4

[0150] Example 2: Preparation of the dalotamid pharmaceutical composition of the present invention

[0151] Darlotamine drug composition particles were prepared according to the specific composition and weight ratio in Table 2.

[0152] The specific preparation method is as follows:

[0153] The active ingredient, carrier material, and formulation modifier were mixed according to the weight ratios in Table 2 to obtain a blend. The blend was fed into a Leistritz ZSE 12HP-PH-40D hot melt extruder at a constant rate via a powder feeder, and hot melt extrusion was performed at a temperature of 160±20℃. The extrudate was collected and pulverized using a FitzMill L1A pulverizer, then sieved through an 80-mesh sieve.

[0154] Daroltadine pharmaceutical compositions 2-1 to 2-9 and blends of active ingredients with carrier materials and formulation modifiers 2-1 to 2-9 were obtained according to the above method.

[0155] Table 2 Composition of the dallotamine composition

[0156] Composition Active ingredients carrier material Formulation improver mass ratio Composition 2-1 Darlotamine HPMCAS TPGS 1∶2∶0.2 Composition 2-2 Darlotamine HPMCAS TPGS 1∶4∶0.5 Composition 2-3 Darlotamine VA64+HPMCAS / 1∶0.5∶1.5 Composition 2-4 Darlotamine VA64+HPMCAS TPGS 1∶0.5∶1.5∶0.2 Composition 2-5 Darlotamine HPMCP-HP55 TPGS 1∶3∶0.1 Composition 2-6 Darlotamine Eudragit L100 TEC 1∶2∶0.15 Composition 2-7 Darlotamine Soluplus SLS 1∶3∶0.1 Composition 2-8 Darlotamine PVP K30 SLS 1∶4∶0.5 Composition 2-9 Darlotamine VA64 SLS 1∶4∶0.5

[0157] Example 3: Preparation of Darlotamine Tablets

[0158] Darlotamine tablets were prepared according to the specific composition and weight ratio in Table 3.

[0159] The method of preparation for dallotamid tablets is as follows:

[0160] (1) Prepare dalotamide pharmaceutical compositions according to the methods of Examples 1 and 2 respectively; (2) Mix the pharmaceutical composition of step (1) with filler, disintegrant and lubricant to obtain total mixed particles; (3) Compress the total mixed particles of step (2) using a ZP14 tablet press to obtain dalotamide tablets.

[0161] Table 3 Composition of Darlotamide Tablets

[0162] Function Tablets 2-1 Tablets 2-2 2-3 tablets 2-4 tablets 2-5 tablets Tablets 2-6 Compositions 1-5 - 900 - - - - - Composition 2-1 - - 960 - - - - Composition 2-4 - - - 960 - - - Composition 2-6 - - - - 945 - - Composition 2-8 - - - - - 1650 - Composition 2-9 - - - - - - 1650 microcrystalline cellulose filler 300 240 240 255 230 230 Cross-linked carboxymethyl cellulose sodium Disintegrant 74 74 74 74 90 90 magnesium stearate lubricant 26 26 26 26 30 30

[0163] Test Implementation Examples

[0164] Example 4: Determination of Crystal Form of Pharmaceutical Composition

[0165] The determination of the crystal form of the pharmaceutical composition included polycrystalline powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC), which were performed using a Bruker D8 advance instrument (scanning range: 3°-40°) and a TA Instruments DSC2000 instrument (scanning range: 30℃-250℃), respectively.

[0166] Table 4. Crystal forms of dalotamide compositions

[0167] Composition Crystal form Composition Crystal form Composition 1-1 Partially amorphous Compositions 1-13 amorphous Composition 1-2 amorphous Compositions 1-14 amorphous Compositions 1-3 amorphous Composition 1-15 amorphous Compositions 1-4 Partially amorphous Composition 2-1 amorphous Compositions 1-5 amorphous Composition 2-2 amorphous Compositions 1-6 amorphous Composition 2-3 amorphous Compositions 1-7 amorphous Composition 2-4 amorphous Compositions 1-8 amorphous Composition 2-5 amorphous Compositions 1-9 amorphous Composition 2-6 amorphous Composition 1-10 Partially amorphous Composition 2-7 amorphous Composition 1-11 amorphous Composition 2-8 amorphous Composition 1-12 amorphous Composition 2-9 amorphous

[0168] As shown in Table 4 above, the crystal form determination results indicate that the drug composition prepared from the active ingredient dallotamine and the carrier material can form amorphous particles, thus improving the solubility of dallotamine. Furthermore, the particles of the above drug compositions are easy to prepare into solid dosage forms, making them suitable for large-scale production and industrial manufacturing.

[0169] Example 5: Solubility determination of pharmaceutical compositions and blends

[0170] The solubility of pharmaceutical compositions 1-1 to 1-14, 2-1 to 2-9, and their corresponding blends were determined according to the above method, and the dissolution rates are shown in Table 4 below. Furthermore, under the experimental conditions described above, the solubility of the dallotamine compound was measured to be 24.9 μg / ml.

[0171] Table 5 Solubility of Drug Compositions and Blends

[0172] Pharmaceutical Compositions / Blends Solubility of the pharmaceutical composition (μg / ml) Solubility of the corresponding blend (μg / ml) Composition 1-1 107.2 23.9 Composition 1-2 260.9 24.6 Compositions 1-3 328.5 26.3 Compositions 1-4 142.7 23.4 Compositions 1-5 488.9 24.1 Compositions 1-6 405.6 25.3 Compositions 1-7 421.6 24.9 Compositions 1-8 438.1 23.5 Compositions 1-9 406.2 23.1 Composition 1-10 369.2 24.6 Composition 1-11 307.5 24.7 Composition 1-12 470.5 23.2 Compositions 1-13 490.8 25.9 Compositions 1-14 321.6 24.7 Composition 1-15 394.2 26.8 Composition 2-1 499.6 26.2 Composition 2-2 462.3 28.1 Composition 2-3 431.2 24.3 Composition 2-4 479.1 25.3 Composition 2-5 427.2 24.1 Composition 2-6 538.2 24.8 Composition 2-7 395.3 28.7 Composition 2-8 416.5 33.5 Composition 2-9 389.6 29.6

[0173] As shown in Table 5 above, the solubility test results indicate that combining the active ingredient dalolactamine with a carrier material significantly improves the solubility of the resulting dalolactamine drug composition. Compared to the dalolactamine compound (solubility of 24.9 μg / ml) and its mixture with carrier materials and / or formulation modifiers, the solubility of the dalolactamine composition is significantly higher, ranging from 107.2 to 490.8 μg / ml.

[0174] Based on compositions 1-1 to 1-15, by further adding a formulation modifier, such as TPGS, SLS, or TEC, the dalotamide drug composition of the present invention can achieve a further improved solubility of 389.6-538.2 μg / ml. Therefore, adding the formulation modifier of the present invention to the drug composition can further improve the solubility of the dalotamide drug composition.

[0175] Furthermore, compositions 2-8 and 2-9 use polyvinylpyrrolidone as a carrier material and sodium dodecyl sulfate as a formulation modifier. Compared to compositions 2-7 to 2-9, compositions 2-1 to 2-2 and compositions 2-4 to 2-6 exhibit significantly improved solubility. This demonstrates that the choice of carrier material and formulation modifier can affect the solubility of a drug composition, and suitable solubility helps the drug composition achieve further improved solubility.

[0176] Example 6: Determination of the bulk density of the pharmaceutical composition

[0177] The bulk density of the pharmaceutical composition was determined using a SOTAX TD2 bulk density meter. The test results are shown in Table 6 below.

[0178] Table 6 Bulk density of pharmaceutical compositions

[0179] Composition Bulk density (g / mL) Composition Bulk density (g / mL) Composition 1-1 0.384 Compositions 1-13 0.415 Composition 1-2 0.426 Compositions 1-14 0.431 Compositions 1-3 0.413 Composition 1-15 0.419 Compositions 1-4 0.411 Composition 2-1 0.451 Compositions 1-5 0.433 Composition 2-2 0.466 Compositions 1-6 0.447 Composition 2-3 0.429 Compositions 1-7 0.461 Composition 2-4 0.473 Compositions 1-8 0.441 Composition 2-5 0.469 Compositions 1-9 0.452 Composition 2-6 0.436 Composition 1-10 0.428 Composition 2-7 0.431 Composition 1-11 0.446 Composition 2-8 0.429 Composition 1-12 0.408 Composition 2-9 0.432

[0180] As shown in Table 6 above, the bulk density measurements of compositions 2-1 to 2-9 are relatively higher than those of compositions 1-1 to 1-15 (bulk density of 0.384-0.461 g / mL), ranging from 0.429 to 0.473 g / mL. This indicates that adding a formulation modifier to the pharmaceutical composition can further increase its bulk density, resulting in pharmaceutical composition particles suitable for tablet compression, which can reduce energy consumption during production.

[0181] Example 7: Determination of the Angle of Repose of the Drug Composition

[0182] The angle of repose of the drug composition was determined using a Granutools Granuheap angle of repose analyzer. The results are shown in Table 7 below.

[0183] Table 7 Angle of Repose of Drug Compositions

[0184] Composition Angle of repose (°) Composition Angle of repose (°) Composition 1-1 45 Compositions 1-13 34 Composition 1-2 35 Compositions 1-14 34 Compositions 1-3 34 Composition 1-15 33 Compositions 1-4 37 Composition 2-1 27 Compositions 1-5 32 Composition 2-2 27 Compositions 1-6 31 Composition 2-3 37 Compositions 1-7 29 Composition 2-4 22 Compositions 1-8 29 Composition 2-5 28 Compositions 1-9 31 Composition 2-6 28 Composition 1-10 33 Composition 2-7 31 Composition 1-11 32 Composition 2-8 32 Composition 1-12 38 Composition 2-9 31

[0185] As shown in Table 7 above, the angle of repose measurements reveal that compositions 2-1 to 2-9 exhibit relatively lower angles of repose, ranging from 22-37°, compared to compositions 1-1 to 1-15 (bulk density 29-45°). This demonstrates that adding formulation modifiers to pharmaceutical compositions can further reduce the angle of repose, thereby improving the flowability of the composition. The resulting pharmaceutical composition particles are suitable for tablet preparation through compression, which can reduce energy consumption during the production process.

[0186] Furthermore, compared to compositions 2-8 and 2-9, compositions 2-1 to 2-2 and compositions 2-4 to 2-6 exhibit relatively lower angles of repose. This demonstrates that the selection of carrier materials and formulation modifiers can influence the angle of repose of a drug composition. Suitable carrier materials and formulation modifiers help the composition achieve a relatively lower angle of repose, thereby further improving the flowability of the composition, making the drug composition particles suitable for preparing pharmaceutical products, and reducing production energy consumption.

[0187] Example 8: Stability test of the pharmaceutical composition

[0188] Pharmaceutical compositions are susceptible to environmental influences (such as temperature and humidity) during storage, which can affect the quality of the formulation and lead to crystallization and the growth of related substances, resulting in substandard product quality. To evaluate the stability of the dallotamine pharmaceutical composition, this invention tested its stability under accelerated conditions of 40°C / 75% RH. The specific test method is as follows:

[0189] The dalotamide drug composition was packaged into HDPE bottles, which were then placed in a stability chamber. The stabilizing agent was removed at specified time points for testing to obtain the crystal state, composition content, and related substance content of the composition. Relevant data are shown in Table 8 below.

[0190] Table 8 Stability of Darlotamine Compositions

[0191]

[0192] As shown in Table 8 above, after 6 months of storage, the contents of compositions 2-1, 2-4 to 2-9 are all higher than 94.2%, which is significantly higher than that of composition 1-5.

[0193] Therefore, compared to dalotamide drug compositions 1-5, the addition of the formulation modifier to the drug compositions results in drug compositions 2-1, 2-4 to 2-9 exhibiting significantly improved stability and effectively reducing the formation of related substances. It is evident that adding the formulation modifier of the present invention to the dalotamide drug compositions significantly enhances the stability of the resulting drug compositions.

[0194] Furthermore, compared to compositions 2-7 to 2-9, after 6 months of storage, the contents of compositions 2-1 and 2-4 to 2-6 were all higher than 96.3%, while the contents of compositions 2-7 to 2-9 were lower than 96.1%. This demonstrates that the selection of carrier materials and formulation modifiers can also affect the stability of drug compositions; suitable carrier materials and formulation modifiers contribute to achieving relatively higher stability in the compositions.

[0195] Furthermore, the applicant unexpectedly discovered that when HPMACAS was used as the carrier for the dallotamidine composition, the addition of the formulation modifier TPGS to the composition resulted in relatively higher stability. For example, after 6 months at 40°C / 75% RH, the composition still maintained a purity of 97.1%.

[0196] Example 9 Dissolution test of the pharmaceutical composition

[0197] The solubility of darotamide in phosphate buffer at pH 6.8 was determined using the method described above, and the test results are shown in Table 9 below.

[0198] Table 9 Dissolution of Darlotamide Tablets

[0199]

[0200] As shown in Table 9 above, the dissolution test results indicate that, compared to dalolactam raw material and commercially available dalolactam tablets, the dalolactam tablets (NUBEQA) of this invention exhibit significantly improved dissolution. The dissolution rate and amount of dalolactam are significantly higher. For example, under the experimental conditions of this invention, the dalolactam tablets of this invention release more than 90% of dalolactam after 30 minutes in phosphate buffer at pH 6.8, and up to 97% of dalolactam after 45 minutes.

[0201] Therefore, by further adding formulation modifiers to dallotamine and its pharmaceutical compositions, the dallotamine pharmaceutical compositions of the present invention can achieve significantly improved drug dissolution.

[0202] Example 10: Pharmacokinetic Study of Darlotamide Tablets

[0203] 1. Test formulation

[0204] Test formulation T: Darlotamide tablets prepared according to the formulation and process of tablets 2-3 in Example 3, with a strength of 300 mg / tablet.

[0205] Reference formulation R: Darlotamide tablets (NUBEQA, 300 mg / tablet) already on the market.

[0206] 2. Test Methods

[0207] 2.1 Experiment 1

[0208] An open-label, randomized, two-period, double-crossover self-controlled trial design (with a 7-day washout period) was used. Ten enrolled healthy male subjects were randomly assigned to two groups of five each. The grouping scheme is shown in the table below:

[0209] Table 10 Grouping

[0210]

[0211] Subjects were admitted to the Phase I clinical trial ward before the trial date, and received a standardized light diet in the evening, followed by an overnight fast (at least 10 hours, but water was allowed). The next morning around 8:00 AM, subjects ate a high-fat meal, then took one tablet of either the test formulation T or the reference formulation R orally, and drank 240 mL of water. They were not allowed to drink water for 2 hours after taking the medication and had to remain upright. A standardized lunch was served 4 hours later.

[0212] Blood sample collection method: 4 mL of venous blood was collected from the subject's elbow at 0 h (within 1 h before drug administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24, and 36 h after drug administration. The blood samples were placed in heparin sodium anticoagulant blood collection tubes. After collection, the samples were centrifuged at 3500 rpm for 5 min at 4°C. The plasma was divided into two portions: 1 mL of plasma was added to the initial collection tube, and the remaining plasma was added to a backup collection tube. The samples were stored at -20°C for 2 h after collection.

[0213] The concentration of dalotamide in each plasma sample was determined by LC-MS / MS.

[0214] 2.2 Experiment 2

[0215] An open-label, randomized, two-period, double-crossover self-controlled trial design (with a 7-day washout period) was used. Ten enrolled healthy male subjects were randomly assigned to two groups of five each. The grouping scheme is shown in the table below:

[0216] Table 11 Grouping

[0217]

[0218] Subjects were admitted to the Phase I clinical trial ward before the trial date. They received a standardized light diet in the evening, followed by an overnight fast (at least 10 hours, but water was allowed). The next morning around 8:00 AM, subjects took one tablet of the test formulation T orally after a high-fat meal, or one tablet of the test formulation T orally on an empty stomach, and drank 240 ml of water. They were not allowed to drink water for 2 hours after taking the medication and had to remain upright. A standardized lunch was given 4 hours later.

[0219] Blood sample collection method: 4 mL of venous blood was collected from the subject's elbow at 0 h (within 1 h before drug administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 24, and 36 h after drug administration. The blood samples were placed in heparin sodium anticoagulant blood collection tubes. After collection, the samples were centrifuged at 3500 rpm for 5 min at 4°C. The plasma was divided into two portions: 1 mL of plasma was added to the initial collection tube, and the remaining plasma was added to a backup collection tube. The samples were stored at -20°C for 2 h after collection.

[0220] The concentration of dalotamide in each plasma sample was determined by LC-MS / MS.

[0221] 3. Experimental Results

[0222] The results of Experiment 1 and Experiment 2 above are summarized as follows:

[0223] Table 12 Pharmacokinetic data from Experiment 1

[0224]

[0225] Table 13 Pharmacokinetic data from Experiment 2

[0226]

[0227] The data from Experiment 1 above (Table 12) show that:

[0228] (1) Peak plasma concentration C after administration of the test formulation T max The concentration increased significantly, reaching 144.93% of the highest plasma concentration achieved when the reference formulation R was administered;

[0229] (2) The area under the plasma concentration curve (AUC) of the test formulation T compared to the area under the plasma concentration curve of the reference formulation R. 0-t It increased by about 10%, reaching 110.76% of the area under the blood drug concentration curve of the reference preparation R;

[0230] (3) Compared with the time to peak plasma concentration after taking the reference formulation R, the time to peak plasma concentration after taking the test formulation T is T max No significant changes were observed.

[0231] The above results indicate that, under postprandial conditions, the absorption of the test formulation T in the subjects was improved to some extent compared with the reference formulation R.

[0232] The data from Experiment 2 (Table 13) above show:

[0233] (1) Compared with the highest blood drug concentration under fasting conditions C max The peak plasma concentration C of the test formulation T under postprandial conditions. max No significant changes occurred;

[0234] (2) Compared with the area under the plasma concentration curve under fasting conditions, the area under the plasma concentration curve (AUC) of the test formulation T under postprandial conditions is... 0-t Increased by approximately 7%;

[0235] (3) Compared with the time to peak plasma concentration under fasting conditions, the time to peak plasma concentration of the test formulation T under postprandial conditions is T0. max The delay is significant, mainly due to the food effect.

[0236] Furthermore, the instructions for use of the reference formulation R indicate that its absorption under fasting conditions is only 40%-50% of that under postprandial conditions, therefore it must be taken after meals. However, the results of Experiment 2 above show that the absorption of the test formulation T in vivo is largely unaffected by food effects.

[0237] Therefore, the dalotamide tablets prepared by this invention improve the bioavailability of the drug in vivo, especially significantly improve the absorption of the drug under fasting conditions, and significantly reduce the food effect.

[0238] The above description is merely a specific embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent transformations made using the present invention, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1.A pharmaceutical composition consisting of an active ingredient darolutamide or a pharmaceutically acceptable salt thereof, a carrier material, and a formulation modifier, wherein the formulation modifier is vitamin E succinate; the carrier material is a combination of copovidone and hypromellose acetate succinate; the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the carrier material is 1:1-1:3; the weight ratio of the active ingredient darolutamide or a pharmaceutically acceptable salt thereof to the formulation modifier is 1:0.1-1:0.3; the pharmaceutical composition is prepared by a method comprising the following steps: (1) weighing each component; (2) mixing the components of step (1) and performing hot melt extrusion to obtain the pharmaceutical composition; the bulk density of the pharmaceutical composition is 0.47-0.48 g / mL; and the rest angle of the pharmaceutical composition is 21-23°. 2.A solid preparation comprising the pharmaceutical composition of claim 1. 3.A method for preparing the pharmaceutical composition of claim 1, comprising the following steps: (1) weighing each component; (2) mixing the components of step (1) and performing hot melt extrusion to obtain the pharmaceutical composition. 4.A method for preparing the solid preparation of claim 2, comprising the following steps: (1) preparing the pharmaceutical composition according to the method of claim 3; (2) crushing the pharmaceutical composition of step (1) to obtain pharmaceutical composition granules; (3) mixing the pharmaceutical composition granules of step (2) with a lubricant and other formulation modifiers to obtain total mixed granules; (4) compressing the total mixed granules of step (3) to obtain the solid preparation. 5.The method of claim 4, further comprising the following step: (5) coating the solid preparation of step (4) to obtain tablets. 6.Use of the pharmaceutical composition of claim 1 or the solid preparation of claim 2 in the preparation of a medicament for preventing or treating prostate cancer. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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