Isavuconazole pharmaceutical composition and preparation method therefor

Abstract

The present invention relates to an isavuconazole pharmaceutical composition and a preparation method therefor. The pharmaceutical composition comprises a pharmaceutically active ingredient, a drying agent and optional pharmaceutically acceptable adjuvants; the pharmaceutically active ingredient is isavuconazole or a pharmaceutically acceptable salt thereof; the drying agent comprises a combination of magnesium citrate and gel process silica; and the pharmaceutically active ingredient and the drying agent are mixed together and exist as an ingredient in a same mixture. According to the pharmaceutical composition, the moisture in the pharmaceutical composition is controlled, so that isavuconazole or the pharmaceutically acceptable salt thereof has better stability.

Description

Isavuconazole pharmaceutical composition and preparation method thereof Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an isavuconazole pharmaceutical composition and a preparation method thereof. Background Art

[0002] Drug hydrolysis is a common chemical reaction, primarily the decomposition of drugs in water. This reaction is often determined by the drug's chemical structure, particularly for drugs containing functional groups such as esters (e.g., carbamates) and amides (e.g., lactams and sulfonamides). Isavuconazole is a readily hydrolyzed drug.

[0003] When a drug undergoes hydrolysis, it can cause dosage loss and reduced efficacy, and can also produce toxic byproducts that can pose a threat to patient health. Furthermore, hydrolysis can cause physical changes such as discoloration or precipitation, which can affect the drug's appearance and / or taste, impacting the patient's experience with the medication.

[0004] Moisture-proof, sealed packaging is often used to improve the stability of hydrolyzed drugs. However, even with moisture-proof, sealed packaging, some drugs still struggle to maintain stability. In such cases, adding hygroscopic ingredients to the drug formulation may have a more beneficial effect on drug stability.

[0005] US9775807 discloses a solid pharmaceutical dosage form comprising at least one active ingredient and at least one pharmaceutically compatible water-soluble desiccant selected from the group consisting of magnesium citrate and / or calcium chloride, wherein the solid pharmaceutical dosage form has a loss on drying of at most 6% and a relative equilibrium moisture content of 25% or less. Such a solid pharmaceutical dosage form exhibits improved stability.

[0006] IN3855MUM2015A and IN3856MUM2015A disclose a pharmaceutical composition comprising isavuconazole or a pharmaceutically acceptable salt thereof and one or more stabilizers including magnesium citrate, but do not disclose specific technical effects. Summary of the Invention

[0007] In a first aspect, the present invention relates to a pharmaceutical composition comprising:

[0008] Pharmaceutically active ingredients, desiccant and optionally pharmaceutically acceptable excipients;

[0009] in,

[0010] The active ingredient of the drug is isavuconazole or a pharmaceutically acceptable salt thereof;

[0011] The desiccant comprises a combination of magnesium citrate and gel-process silica;

[0012] The pharmaceutically active ingredient and the desiccant are mixed together as components in the same mixture.

[0013] In one embodiment, the pharmaceutically acceptable excipient is selected from one or more of the following groups: a binder, a filler, a disintegrant, a lubricant, and a glidant.

[0014] In a second aspect, the present invention relates to a method for preparing the pharmaceutical composition according to the first aspect, comprising the following steps:

[0015] a) mixing the active pharmaceutical ingredient with a desiccant;

[0016] b) mixing any pharmaceutically acceptable excipients present, adding the mixture to the mixture obtained in step a), and mixing uniformly;

[0017] c) dry granulating the mixture obtained in step a) or b) to obtain granules;

[0018] d) preparing the granules obtained in step c) into a solid pharmaceutical dosage form;

[0019] e) Optionally, the solid pharmaceutical dosage form obtained in step d) is sealed and packaged. DETAILED DESCRIPTION

[0020] The present invention will be described in further detail below. This description is for illustrative purposes only and is not intended to limit the present invention. Those skilled in the art will readily appreciate the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through various other specific embodiments. Those skilled in the art may make various modifications and alterations without departing from the spirit of the present invention.

[0021] General Terms and Definitions

[0022] Unless otherwise indicated, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0023] Unless otherwise defined, the 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 belongs. In the event of a conflict, the definitions provided herein will prevail.

[0024] When an amount, concentration or other value or parameter is expressed in the form of a range, preferred range or preferred upper numerical limit and preferred lower numerical limit, it should be understood that it is equivalent to specifically disclosing any range by combining any pair of range upper limits or preferred numerical values ​​with any range lower limits or preferred numerical values, without considering whether the range is specifically disclosed. Unless otherwise indicated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions within the range. The scope of the present invention is not limited to the specific numerical values ​​cited when defining the range. For example, "0.05:1 to 1.5:1" covers 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1, 0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, 0.95:1 :1, 1:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, 1.25:1, 1.3:1, 1.35:1, 1.4:1, 1.45:1, 1.5:1 and any sub-range consisting of any two values ​​therein, for example, 0.1:1 to 1:1, 0.2:1 to 0.7:1, 0.2:1 to 0.4:1, 0.2:1 to 0.3:1, etc.

[0025] When describing methods, components or steps, letters or numbers are used for identification purposes only and do not limit these methods, components or steps to be performed in the order or sequence indicated. Those skilled in the art can make reasonable adjustments.

[0026] The terms "about" and "approximately" when used in conjunction with a numerical variable generally refer to the value of that variable and all values ​​of that variable are within 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 ±11%, ±12%, ±13%, ±14%, ±15%, ±16%, ±17%, ±18%, ±19%, ±20%, ±21%, ±22%, ±23%, ±24%, ±25%, ±26%, ±27%, ±28%, ±29%, ±30%, ±31%, ±32%, ±33%, ±34%, or ±35%).

[0027] The term "stoichiometric ratio" refers to the mixing of various substances by weight. For example, in the present invention, the active ingredient and desiccant are mixed in a specified weight ratio. Unless otherwise indicated, all percentages, parts, and ratios herein are by weight.

[0028] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0029] The term "selected from..." refers to one or more elements in the group listed below, selected independently, and may include combinations of two or more elements. As used herein, the term "one or more" or "at least one" refers to one, two, three, four, five or more.

[0030] The expression "comprising" or its synonyms "including," "containing," and "having" are open-ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any elements, steps, or ingredients not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps, or ingredients, plus any optional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of."

[0031] The term "pharmaceutically acceptable" refers to a substance that is suitable, within the scope of normal medical judgment, for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., has a reasonable benefit-risk ratio, and can be effectively used for its intended use.

[0032] The terms "pharmaceutically active ingredient" and "active ingredient" refer to a chemical entity that is effective in treating or preventing a target disease or condition. In one embodiment, the active ingredient used in the pharmaceutical composition of the present invention is isavuconazole or a pharmaceutically acceptable salt thereof, particularly isavuconazole sulfate. As used herein, a given compound and its corresponding forms (e.g., salts, polymorphs, solvates, cocrystals, amorphous and anhydrous forms, etc.) are considered to be different forms or types of the same active ingredient.

[0033] The term "pharmaceutically acceptable excipient" refers to carrier substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable excipients" include, but are not limited to, binders, fillers, disintegrants, lubricants, and glidants.

[0034] The term "pharmaceutical composition" refers to a composition comprising one or more active ingredients, a desiccant of the present invention, and optionally one or more pharmaceutically acceptable excipients. As used herein, the active ingredients and the desiccant of the present invention are mixed together as components of the same mixture, rather than the active ingredients and desiccant being present separately and then used in combination.

[0035] The term "gel-based silica" refers to silica produced by drying and calcining a gel obtained by hydrolyzing silicate or silicyl chloride.

[0036] Pharmaceutical composition of the present invention

[0037] The present invention relates to a pharmaceutical composition comprising:

[0038] Pharmaceutically active ingredients, desiccant and optionally pharmaceutically acceptable excipients;

[0039] in,

[0040] The active ingredient of the drug is isavuconazole or a pharmaceutically acceptable salt thereof;

[0041] The desiccant comprises a combination of magnesium citrate and gel-process silica;

[0042] The pharmaceutically active ingredient and the desiccant are mixed together as components in the same mixture.

[0043] In the present invention, the pharmaceutical active ingredient may be present in the pharmaceutical composition of the present invention in the same form (eg, isavuconazole or a specific pharmaceutically acceptable salt of isavuconazole) or in different forms (eg, a combination of isavuconazole and a pharmaceutically acceptable salt thereof).

[0044] Isavuconazonium, as an α-1 receptor antagonist, is a class of antifungal drugs. Its pharmaceutically acceptable salts as active ingredients may include, but are not limited to, salts formed with inorganic acids, salts formed with organic acids, and the like. 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, phosphoric acid, and the like. 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 (citric acid), succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. In a preferred embodiment, the pharmaceutically acceptable salt is sulfate, i.e., isavuconazonium sulfate, which has the following structure:

[0045] In one embodiment, the weight ratio of the gel-process silica to the magnesium citrate is 0.05:1 to 1.5:1, for example, 0.05:1, 0.1:1, 0.11:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1, 0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, 0. 1, 0.43:1, 0.45:1, 0.5:1, 0.6:1, 0.67:1 or 0.7:1.

[0046] In one embodiment, the weight ratio of the magnesium citrate to the pharmaceutically active ingredient is 0.5:1 to 2.5:1, for example, 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 or 2.5:1, preferably 1:1 to 1.5:1, more preferably 1.1:1 to 1.35:1, for example 1.14:1, 1.3:1 or 1.31:1.

[0047] In one embodiment, the weight ratio of the gel-process silicon dioxide to the pharmaceutical active ingredient is 0.05:1 to 2.0:1, for example, 0.05:1, 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, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2:1, preferably 0.1:1 to 1.5:1, more preferably 0.25:1 to 0.9:1, for example 0.25:1, 0.31:1, 0.4:1, 0.55:1, 0.56:1, 0.57:1, 0.59:1, 0.6:1, 0.8:1, 0.85:1, 0.87:1 or 0.9:1.

[0048] In one embodiment, the pharmaceutically active ingredient is isavuconazole sulfate.

[0049] In one embodiment, the desiccant is a desiccant comprising at least a combination of magnesium citrate and gel-process silica. In one embodiment, the desiccant consists essentially of magnesium citrate and gel-process silica. In one embodiment, the desiccant consists of magnesium citrate and gel-process silica.

[0050] In one embodiment, the magnesium citrate includes but is not limited to anhydrous magnesium citrate commercially available from JOST CHEMICAL CO. and anhydrous magnesium citrate commercially available from VASA PHARMACHEM PVT. LTD., preferably anhydrous magnesium citrate commercially available from VASA PHARMACHEM PVT. LTD.

[0051] In one embodiment, the gel-process silica includes, but is not limited to, SYLOID XDP 3050, SYLOID XDP 3150, SYLOID 244FP, and SYLOID AL-1FP commercially available from GRACE GmbH, preferably SYLOID AL-1FP commercially available from GRACE GmbH.

[0052] In one embodiment, the pharmaceutically acceptable excipient is selected from one or more of the following groups: a binder, a filler, a disintegrant, a lubricant, and a glidant.

[0053] In one embodiment, the pharmaceutically acceptable excipient comprises a binder. In one embodiment, the binder is selected from one or more of the following groups: polyethylene glycol, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, polyvinyl pyrrolidone, gum arabic powder, and gelatin. In a preferred embodiment, the binder is selected from one or more of the following groups: starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, and polyvinyl pyrrolidone.

[0054] In one embodiment, the pharmaceutically acceptable excipient comprises a filler. In one embodiment, the filler is selected from one or more of the following group: mannitol, microcrystalline cellulose, silicified microcrystalline cellulose starch, pregelatinized starch, polyvinyl pyrrolidone, gum arabic powder, and gelatin. In a preferred embodiment, the filler is selected from one or more of the following group: mannitol, microcrystalline cellulose, and silicified microcrystalline cellulose.

[0055] In one embodiment, the pharmaceutically acceptable excipient includes a disintegrant. In one embodiment, the disintegrant is selected from one or more of the following groups: microcrystalline cellulose, carboxymethyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxymethyl starch, alginic acid, sodium alginate, guar gum, corn starch, and magnesium aluminum silicate. In a preferred embodiment, the disintegrant is selected from one or more of the following group: low-substituted hydroxypropyl cellulose, crospovidone sodium, and crospovidone. In a specific embodiment, the disintegrant is low-substituted hydroxypropyl cellulose.

[0056] In one embodiment, the weight ratio of the disintegrant to the pharmaceutically active ingredient is 0.01:1 to 0.5:1, for example, 0.01:1, 0.02:1, 0.04:1, 0.06:1, 0.08:1, 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1, 0.2:1, 0.22:1, 0.24:1, 0.2 1, 0.6:1, 0.28:1, 0.3:1, 0.32:1, 0.34:1, 0.36:1, 0.38:1, 0.4:1, 0.42:1, 0.44:1, 0.46:1, 0.48:1 or 0.5:1, preferably 0.03:1 to 0.5:1, more preferably 0.03:1 to 0.3:1, for example 0.03:1 or 0.28:1.

[0057] In one embodiment, the pharmaceutically acceptable excipient includes a lubricant. In one embodiment, the lubricant is selected from one or more of the following: magnesium stearate, stearic acid, stearate salts, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid esters, micronized silica gel, talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid, and hydrogenated vegetable oil. In a specific embodiment, the lubricant is a combination of glyceryl behenate and talc. Wherein, preferably, the weight ratio of talc to glyceryl behenate is 1:1 to 10:1, for example, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1 or 10:1, preferably 1.5:1 to 5:1, more preferably 1.5:1 to 4:1, for example, 2.5:1, 3:1, 3.5:1 or 4:1.

[0058] In one embodiment, the weight ratio of the lubricant to the pharmaceutically active ingredient is 0.1:1 to 0.5:1, for example 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1, 0.2:1, 0.22:1, 0.24:1, 0.26:1, 0.28:1, 0.3:1, 0.32:1, 0.34:1, 0.36:1, 0.38:1, 0.4:1, 0.42:1, 0.44:1, 0.46:1, 0.48:1 or 0.5:1, preferably 0.1:1 to 0.3:1, more preferably 0.1:1 to 0.25:1, for example 0.1:1, 0.14:1, 0.17:1, 0.22:1 or 0.23:1.

[0059] In one embodiment, the pharmaceutically acceptable excipient in the pharmaceutical composition of the present invention includes a glidant. In one embodiment, the glidant is selected from one or more of the following groups: micronized silica gel and talc. In a specific embodiment, the glidant is micronized silica gel.

[0060] It should be understood that the pharmaceutically acceptable excipients listed above are merely illustrative and representative. Therefore, the pharmaceutical compositions of the present invention are not limited to containing only the pharmaceutically acceptable excipients listed above. Those skilled in the art may make various changes, adjustments, or equivalent substitutions to the above excipients according to conventional techniques without departing from the scope of the present invention.

[0061] Dosage forms of the pharmaceutical composition of the present invention

[0062] The dosage forms of the pharmaceutical composition of the present invention include, but are not limited to, tablets, granules and capsules.

[0063] In one embodiment, the pharmaceutical composition of the present invention is a granule.

[0064] Among them, preferably, the pharmaceutical composition of the present invention is in the form of granules, which are used to be filled in capsules.

[0065] Among them, preferably, the pharmaceutical composition of the present invention is in the form of granules, which are used to be filled in a packaging bag.

[0066] Among them, preferably, the granules of the pharmaceutical composition of the present invention are used to be compressed into tablets.

[0067] Quality attributes of the pharmaceutical composition of the present invention

[0068] The active pharmaceutical ingredient, isavuconazole, or a pharmaceutically acceptable salt thereof, is susceptible to hydrolysis in the presence of free water, which can increase the impurity content and reduce the active pharmaceutical ingredient content in the pharmaceutical composition. Reducing the amount of free water or its mobility in the pharmaceutical composition is a direct and effective method to improve the chemical stability of the easily hydrolyzed active ingredient, isavuconazole, or a pharmaceutically acceptable salt thereof.

[0069] The pharmaceutical composition of the present invention includes a desiccant combination of at least magnesium citrate and gel-formed silica. This desiccant combination has both strong water absorption and moisture retention capabilities, resulting in a longer free water desorption time and more stringent conditions. Therefore, the desiccant combination of the present invention is more beneficial for the stability of easily hydrolyzed active ingredients.

[0070] In one embodiment, the desiccant combination has a steady-state moisture absorption weight gain of about 9% to 20%, such as about 9.5%, about 10%, about 10.1%, about 10.6%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, at 25±2°C / 20±5% relative humidity. In a preferred embodiment, the desiccant has a steady-state moisture absorption weight gain of about 9% to 12%, such as about 9.5%, about 10.1%, about 10.6%, or about 11%, at 25±2°C / 20±5% relative humidity.

[0071] In one embodiment, the desiccant combination that reaches a steady-state hygroscopic weight gain has a free water content of about 3% to 10% by weight after the loss on drying at 90±2°C / 20±5% relative humidity for about 20-60 minutes, such as about 3%, about 4%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 6%, about 7%, about 8%, about 9%, or about 10%. In a preferred embodiment, the desiccant combination that reaches a steady-state hygroscopic weight gain has a free water content of about 3% to 6% by weight after the loss on drying at 90±2°C / 20±5% relative humidity for about 60 minutes, such as about 3%, about 4%, about 5%, about 5.1%, about 5.2%, about 5.3%, or about 5.4%. In one embodiment, the desiccant combination that achieves steady-state moisture absorption weight gain has a free water drying loss of 5% to 6%, e.g., 5.1%, 5.2%, 5.3%, 5.4% or 5.5%, at about 60 minutes under conditions of 90±2°C / 20±5% relative humidity.

[0072] Preparation method of the pharmaceutical composition of the present invention

[0073] The present invention also relates to a method for preparing the pharmaceutical composition of the present invention, comprising the following steps:

[0074] a) mixing the active pharmaceutical ingredient with a desiccant;

[0075] b) mixing any pharmaceutically acceptable excipients present, adding the mixture to the mixture obtained in step a), and mixing uniformly;

[0076] c) dry granulating the mixture obtained in step a) or b) to obtain granules;

[0077] d) preparing the granules obtained in step c) into a solid pharmaceutical dosage form;

[0078] e) Optionally, the solid pharmaceutical dosage form obtained in step d) is sealed and packaged.

[0079] In one embodiment, the pharmaceutically active ingredient is isavuconazole or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, dry granulation is performed by adding the materials into a dry granulator and setting appropriate parameters such as roller pressure and roller speed.

[0081] In one embodiment, the method for preparing the pharmaceutical composition of the present invention comprises the following steps:

[0082] a) mixing a pharmaceutically active ingredient with a desiccant comprising a combination of magnesium citrate and silicon dioxide;

[0083] b) adding the mixture obtained in step a) into a dry granulator, and performing dry granulation by setting parameters such as roller pressure and roller speed to obtain granules;

[0084] c) compressing or encapsulating the mixture obtained in step a) or the granules obtained in step b) to obtain a solid pharmaceutical dosage form, and

[0085] d) Optionally, the solid pharmaceutical dosage form is hermetically packaged.

[0086] In one embodiment, the pharmaceutically active ingredient is isavuconazole or a pharmaceutically acceptable salt thereof.

[0087] It should be understood that the above-listed methods for preparing the pharmaceutical compositions are merely illustrative and representative. Therefore, the methods for preparing the pharmaceutical compositions of the present invention are not limited to the methods listed above. Those skilled in the art may make various changes, adjustments, or equivalent substitutions to the preparation methods according to conventional techniques without departing from the scope of the present invention.

[0088] Treatment methods and uses of the pharmaceutical composition of the present invention

[0089] The present invention also relates to a method for treating a related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention. In one embodiment, the subject comprises a human. In one embodiment, the related disease comprises a fungal infection.

[0090] The present invention also relates to a pharmaceutical composition for treating, ameliorating or preventing related diseases. In one embodiment, the related diseases include fungal infections.

[0091] The present invention also relates to a use of the pharmaceutical composition of the present invention in the preparation of a medicament for treating, ameliorating or preventing related diseases. In one embodiment, the related diseases include antifungal infection. Beneficial effects

[0092] The pharmaceutical composition of the present invention contains gel-processed silica, a silica with a special pore structure, with a pore size of approximately 2-50 nm, a large specific surface area, and a highly ordered pore structure. This property greatly enhances the silica's adsorption capacity, whereas conventional silica and silica prepared by a vapor phase method lack this effect. Compared to the prior art, the isavuconazole pharmaceutical composition of the present invention includes a combination of magnesium citrate and gel-processed silica as a desiccant, exhibiting a strong ability to attract and absorb moisture, as well as a stronger ability to retain moisture, resulting in slower desorption of moisture. By controlling the moisture content of the pharmaceutical composition, the pharmaceutical composition provides improved stability for isavuconazole or a pharmaceutically acceptable salt thereof.

[0093] Example

[0094] The technical solution of the present invention will be further described below through specific examples. It should be noted that the following examples are only examples made to clearly illustrate the technical solution of the present invention, and are not limitations of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can also be made based on the description of the present invention. It is not necessary and impossible to exhaustively enumerate all embodiments here, and the obvious changes or modifications derived therefrom are still within the scope of protection created by the present invention. Unless otherwise specified, the instruments, equipment, and reagents used herein are all commercially available.

[0095] In the following examples, magnesium citrate is anhydrous magnesium citrate, a commercial product of VASA PHARMACHEM PVT.LTD.; and gel-process silica is SYLOID AL-1FP, a commercial product of GRACE GmbH.

[0096] Example 1 Properties of Desiccant and Desiccant Combinations

[0097] The moisture absorption weight gain (based on the weight of the anhydrous desiccant or the anhydrous desiccant combination) of different desiccants and desiccant combinations was measured at 25±2°C / 20±5% RH (Relative Humidity).

[0098] Table 1 Moisture absorption weight gain of different desiccants or desiccant combinations

[0099] After measuring the moisture absorption weight gain of the above-mentioned different desiccants or desiccant combinations, the amount of moisture remaining after drying the above-mentioned different desiccants or desiccant combinations at 90±2°C / 20±5%RH after moisture absorption weight gain for 30 days (based on the weight of the anhydrous desiccant or anhydrous desiccant combination) was further measured.

[0100] Table 2 Residual moisture content after drying with different desiccant combinations

[0101] As shown in Tables 1 and 2, anhydrous calcium chloride exhibits a relatively high hygroscopicity, and the combination of anhydrous calcium chloride with magnesium citrate and gel-process silica also exhibits a relatively strong hygroscopicity. However, anhydrous calcium chloride exhibits a significant deliquescence during drying. This is likely due to elevated temperatures, which enhance the solubility of calcium chloride and dissolve it in the water contained in the calcium chloride powder, resulting in a deliquescence phenomenon. This phenomenon indicates that calcium chloride is very susceptible to dehydration. The residual water content of the desiccant combination of anhydrous calcium chloride, magnesium citrate, and gel-process silica after drying for 60 minutes is also relatively low, indicating that the water retention capacity of the combination of anhydrous calcium chloride with magnesium citrate and gel-process silica is relatively poor.

[0102] Anhydrous magnesium citrate, anhydrous calcium citrate and gel-process silica all have certain moisture-attracting capabilities, and in the drying and dehydration experiment, anhydrous magnesium citrate has a stronger ability to retain water.

[0103] In experiments measuring moisture absorption and weight gain, the combination of anhydrous magnesium citrate and gel-based silica exhibited comparable or stronger hygroscopic properties compared to either anhydrous magnesium citrate or gel-based silica alone. In experiments measuring drying and dehydration, the combination of anhydrous magnesium citrate and gel-based silica exhibited significantly improved water retention compared to either anhydrous magnesium citrate or gel-based silica alone. These data demonstrate that the desiccant combination of anhydrous magnesium citrate and gel-based silica possesses both stronger moisture absorption and water retention, meaning it exhibits a stronger ability to absorb water, making it less likely for water to escape from the desiccant combination. Therefore, the desiccant combination of anhydrous magnesium citrate and gel-based silica can maintain the relative dryness of readily hydrolyzable active ingredients in pharmaceutical compositions, thereby enhancing the stability of these readily hydrolyzable active ingredients.

[0104] Example 2 Preparation of Isavuconazole Capsules

[0105] 1. Preparation:

[0106] The preparation was carried out according to the specific composition and dosage (parts by weight, the same below) in Table 3.

[0107] a) mixing isavuconazole sulfate with a combined desiccant of anhydrous magnesium citrate and / or gel-formed silica;

[0108] b) mixing the remaining excipients, adding the mixture to the composition obtained in step a), and mixing evenly;

[0109] c) dry granulating the composition obtained in step b) to obtain granules;

[0110] d) filling capsules with the granules obtained in step c);

[0111] e) Pack the capsules into double aluminum blister packs.

[0112] According to the above method, capsules 2-1 to 2-9 of the present invention were prepared.

[0113] Table 3 Specific composition of isavuconazole capsules (parts by weight)

[0114] 2. Capsule stability study

[0115] The capsules prepared above were placed in an accelerated stability chamber for stability studies at 40°C ± 2°C / 75 ± 5% RH for 6 months. The stability data of the main relevant substances are as follows.

[0116] Table 4 Accelerated 6-month stability of isavuconazole capsules

[0117] Among them, the reference preparation comes from Pfizer's commercial product isavuconazole sulfate capsules Each tablet The capsules contain 186 mg of isavuconazole sulfate, and the main excipients include desiccant magnesium citrate, filler microcrystalline cellulose, lubricant talc, glidant colloidal silicon dioxide and lubricant stearic acid.

[0118] Among them, the structural formula of hydrolysis impurity A is:

[0119] The structural formula of hydrolysis impurity B is:

[0120] The structural formula of hydrolysis impurity C is:

[0121] The above data show that compared to capsule 2-7 prepared with a single anhydrous magnesium citrate as a desiccant and capsule 2-8 prepared with a single gel-process silica as a desiccant, capsules 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, and 2-9 prepared with a desiccant combination of anhydrous magnesium citrate and gel-process silica have less generation of hydrolysis-related impurities and better stability. Combined with the results of Example 1 of the present application, it is shown that the stronger hygroscopicity and stronger ability to retain water (lower water desorption rate) of the desiccant combination of anhydrous magnesium citrate and gel-process silica are more beneficial to the stability of isavuconazole capsules.

[0122] Furthermore, compared to the reference preparation capsules, capsules 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, and 2-9, prepared with a desiccant combination of anhydrous magnesium citrate and gel-processed silica, exhibited lower levels of hydrolysis-related impurities and thus had better stability. Compared to the reference preparation capsules, capsules 2-7, prepared with anhydrous magnesium citrate alone as a desiccant, and capsules 2-8, prepared with gel-processed silica alone as a desiccant, exhibited higher levels of hydrolysis-related impurities and thus had poorer stability.

[0123] The above description is only a specific embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent transformation made by using the present invention, or directly or indirectly applied in other related technical fields, is also included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition comprising: Pharmaceutically active ingredients, desiccant and optionally pharmaceutically acceptable excipients; in, The active ingredient of the drug is isavuconazole or a pharmaceutically acceptable salt thereof; The desiccant comprises a combination of magnesium citrate and gel-process silica; The pharmaceutically active ingredient and the desiccant are mixed together as components in the same mixture.

2. The pharmaceutical composition according to claim 1, wherein The weight ratio of the gel-process silica to the magnesium citrate is 0.05:1 to 1.5:1, preferably 0.1:1 to 1:1, more preferably 0.2:1 to 0.7:1, for example 0.24:1, 0.25:1, 0.3:1, 0.4:1, 0.43:1, 0.45:1, 0.5:1, 0.6:1, 0.67:1 or 0.7:

1.

3. The pharmaceutical composition according to claim 1, wherein The weight ratio of the gel-process silicon dioxide to the pharmaceutical active ingredient is 0.05:1 to 2.0:1, preferably 0.1:1 to 1.5:1, more preferably 0.25:1 to 0.9:1, for example 0.25:1, 0.31:1, 0.4:1, 0.55:1, 0.56:1, 0.57:1, 0.59:1, 0.6:1, 0.8:1, 0.85:1, 0.87:1 or 0.9:

1.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The weight ratio of the magnesium citrate to the pharmaceutically active ingredient is 0.5:1 to 2.5:1, preferably 1:1 to 1.5:1, more preferably 1.1:1 to 1.35:1, for example 1.14:1, 1.3:1 or 1.31:

1.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein The desiccant is a combination of magnesium citrate and gel-processed silica.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein The active pharmaceutical ingredient is a salt formed by isavuconazole and an inorganic acid, or a salt formed by isavuconazole and an organic acid; wherein the inorganic acid is hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid; and the organic acid is formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; Preferably, the pharmaceutical active ingredient is isavuconazole sulfate.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein The pharmaceutically acceptable excipient is selected from one or more of the following groups: a binder, a filler, a disintegrant, a lubricant and a glidant; In particular, The binder is selected from one or more of the following groups: polyethylene glycol, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, polyvinyl pyrrolidone, gum arabic powder and gelatin; preferably, the binder is selected from one or more of the following groups: starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and polyvinyl pyrrolidone; The filler is selected from one or more of the following groups: mannitol, microcrystalline cellulose, silicified microcrystalline cellulose starch, pregelatinized starch, polyvinyl pyrrolidone, gum arabic powder and gelatin; preferably, the filler is selected from one or more of the following groups: mannitol, microcrystalline cellulose and silicified microcrystalline cellulose; The disintegrant is selected from one or more of the following groups: microcrystalline cellulose, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxymethyl starch, alginic acid, sodium alginate, guar gum, corn starch and magnesium aluminum silicate; preferably, the disintegrant is selected from one or more of the following groups: low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; more preferably, the disintegrant is low-substituted hydroxypropyl cellulose; The lubricant is selected from one or more of the following groups: magnesium stearate, stearic acid, stearate, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid ester, micronized silica gel, talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid and hydrogenated vegetable oil; preferably, the lubricant is glyceryl behenate and talc; The glidant is selected from one or more of the following groups: micro-powdered silica gel and talc; More specifically, The pharmaceutically acceptable excipients include disintegrants and lubricants; The disintegrant is low-substituted hydroxypropyl cellulose; The weight ratio of the disintegrant to the pharmaceutically active ingredient is 0.01:1 to 0.5:1, preferably 0.03:1 to 0.5:1, more preferably 0.03:1 to 0.3:1, for example 0.03:1 or 0.28:1; The lubricant is a combination of glyceryl behenate and talc; wherein the weight ratio of talc to glyceryl behenate is 1:1 to 10:1, preferably 1.5:1 to 5:1, more preferably 1.5:1 to 4:1, for example, 2.5:1, 3:1, 3.5:1 or 4:1; the weight ratio of the lubricant to the active pharmaceutical ingredient is 0.1:1 to 0.5:1, preferably 0.1:1 to 0.3:1, more preferably 0.1:1 to 0.25:1, for example, 0.1:1, 0.14:1, 0.17:1, 0.22:1 or 0.23:

1.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, comprising the following steps: a) mixing the pharmaceutically active ingredient isavuconazole or a pharmaceutically acceptable salt thereof with a desiccant; b) mixing any pharmaceutically acceptable excipients present, adding the mixture to the mixture obtained in step a), and mixing uniformly; c) dry granulating the mixture obtained in step a) or b) to obtain granules; d) preparing the granules obtained in step c) into a solid pharmaceutical dosage form; e) Optionally, the solid pharmaceutical dosage form obtained in step d) is sealed and packaged.

9. A pharmaceutical dosage form, wherein The pharmaceutical dosage form is a tablet, granule or capsule, which comprises the pharmaceutical composition according to any one of claims 1 to 7.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating, ameliorating or preventing related diseases; the related diseases include fungal infections.

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