Method for preparing dapagliflozin-containing pharmaceutical preparation and application thereof

Abstract

The present disclosure provides methods of preparing pharmaceutical formulations containing dapagliflozin and uses thereof. The method for preparing the dapagliflozin-containing pharmaceutical preparation comprises the following steps: dissolving dapagliflozin and / or a hydrate thereof and lactose in an aqueous solution of alcohol and / or ketone until the mass ratio of the dissolved lactose to the dapagliflozin is (0.1-0.5): 1 to obtain a binder; and mixing the binder with other auxiliary materials to prepare the tablet core. Therefore, the dissolution stability of dapagliflozin in the pharmaceutical preparation in the storage process can be improved.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field, specifically relating to methods for preparing pharmaceutical formulations containing dapagliflozin and their uses. Background Technology

[0002] Dapagliflozin is an SGLT2 inhibitor used to treat type 2 diabetes. It is an important option in diabetes medication and is suitable for adults with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Dapagliflozin is a poorly soluble drug. Currently, commercially available dapagliflozin formulations are mainly in two forms: amorphous dapagliflozin and dapagliflozin-propylene glycol-water cosolvent. However, both can undergo crystallization under long-term storage or accelerated conditions, leading to decreased dissolution and product instability, which is detrimental to long-term storage. Summary of the Invention

[0003] In a first aspect of this disclosure, a method for preparing a pharmaceutical formulation containing dapagliflozin is provided, comprising: dissolving dapagliflozin and / or its hydrate, lactose in an aqueous solution of alcohol and / or ketone, such that the mass ratio of dissolved lactose to dapagliflozin is (0.1-0.5):1, to obtain a binder; and mixing the binder with other excipients to prepare a tablet core.

[0004] In a second aspect of this disclosure, the method for preparing a pharmaceutical formulation containing dapagliflozin as described in the first aspect of this disclosure is provided for use in improving the dissolution stability of dapagliflozin in the pharmaceutical formulation. Attached Figure Description

[0005] Figure 1 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Example 1 of this disclosure.

[0006] Figure 2 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet samples prepared in Example 2 of this disclosure.

[0007] Figure 3 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Example 3 of this disclosure.

[0008] Figure 4 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Example 4 of this disclosure.

[0009] Figure 5 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Comparative Example 1 of this disclosure.

[0010] Figure 6This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Comparative Example 2 of this disclosure.

[0011] Figure 7 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Comparative Example 3 of this disclosure.

[0012] Figure 8 This is a comparison of XRD patterns of the tablet sample prepared in Example 1 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0013] Figure 9 This is a comparison of XRD patterns of the tablet sample prepared in Example 2 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0014] Figure 10 This is a comparison of XRD patterns of the tablet sample prepared in Example 3 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0015] Figure 11 This is a comparison of XRD patterns of the tablet sample prepared in Example 4 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0016] Figure 12 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Example 5 of this disclosure.

[0017] Figure 13 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Example 6 of this disclosure.

[0018] Figure 14 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Example 7 of this disclosure.

[0019] Figure 15 This is a comparison graph showing the cumulative dissolution rate of dapagliflozin over time under different acceleration conditions for the tablet sample prepared in Comparative Example 4 of this disclosure.

[0020] Figure 16 This is a comparison of XRD patterns of the small-scale tablet sample prepared in Example 8 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0021] Figure 17 This is a comparison of XRD patterns of the pilot batch-1 tablet sample prepared in Example 8 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0022] Figure 18This is a comparison of XRD patterns of the pilot batch-2 tablet sample prepared in Example 8 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material.

[0023] Figure 19 This is a comparison of XRD patterns of the pilot batch-3 tablet sample prepared in Example 8 of this disclosure before and after acceleration, blank excipients, and dapagliflozin raw material. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this disclosure clearer, the technical solutions of this disclosure will be described in detail below. Obviously, the described embodiments are only a part of the embodiments of this disclosure, and not all of them. Based on the embodiments in this disclosure, all other implementation methods obtained by those skilled in the art without inventive effort are within the scope of protection of this disclosure.

[0025] The "range" disclosed in this disclosure is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is expected that ranges of 60-110 and 80-120 are also included. Furthermore, if minimum range values ​​1 and 2 are listed, and if maximum range values ​​3, 4, and 5 are listed, then the following ranges are all expected: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this disclosure, unless otherwise stated, the numerical range "ab" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers, and ranges defined in this way can include endpoints a and b. For example, the numerical range "0-5" indicates that all real numbers between "0-5" have been listed in this article; "0-5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0026] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined with "first" or "second" may explicitly or implicitly include one or more of that feature.

[0027] Unless otherwise specified, all embodiments and optional embodiments of this disclosure can be combined to form new technical solutions.

[0028] Unless otherwise specified, all technical features and optional technical features of this disclosure can be combined to form new technical solutions.

[0029] Currently, both amorphous dapagliflozin and dapagliflozin-propylene glycol-water cosolvent exhibit poor high-temperature and high-humidity stability. Dry granulation is commonly used in formulation preparation, but it cannot effectively solve the problem of crystal transformation during long-term storage or under accelerated conditions.

[0030] Therefore, in a first aspect of this disclosure, a method for preparing a pharmaceutical formulation containing dapagliflozin is provided, comprising: dissolving dapagliflozin and / or its hydrate, lactose in an aqueous solution of alcohol and / or ketone, such that the mass ratio of dissolved lactose to dapagliflozin is (0.1-0.5):1, to obtain a binder; and mixing the binder with other excipients to prepare a tablet core.

[0031] It should be noted that when using dapagliflozin hydrate, its relative amount to dissolved lactose is calculated based on the mass of dapagliflozin.

[0032] Additionally, it should be noted that in this disclosure, when lactose is dissolved in a solvent (i.e., an aqueous solution of alcohol and / or ketone), when the amount of lactose used is less than or equal to its solubility in the solvent, the lactose can be completely dissolved; when the amount of lactose used is greater than its solubility in the solvent, the lactose is partially dissolved, and the undissolved lactose remains in suspension. In this disclosure, "dissolved lactose" refers to lactose dissolved in a solvent (an aqueous solution of alcohol and / or ketone).

[0033] For example, the mass ratio of dissolved lactose to dapagliflozin can be 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, or 0.5:1, etc., or can be any range of the above values.

[0034] It is understood that dissolving dapagliflozin and / or its hydrates, lactose in an aqueous solution of alcohol and / or ketone can make dapagliflozin completely soluble in the aqueous solution of said alcohol and / or ketone.

[0035] In this disclosure, dapagliflozin and / or its hydrate, along with lactose, are dissolved in an aqueous solution of alcohol and / or ketone using wet granulation. The dissolved lactose is then used to treat dapagliflozin, promoting its amorphous form and inhibiting its crystallization under long-term storage or accelerated conditions, thereby improving its dissolution stability during storage. Furthermore, by controlling the relative amounts of dissolved lactose and dapagliflozin within a given range during tablet core preparation, the dissolution stability of the resulting dapagliflozin-containing pharmaceutical formulation is further improved during storage.

[0036] In some embodiments of this disclosure, the pharmaceutical preparation containing dapagliflozin may be a tablet.

[0037] In some embodiments of this disclosure, the dapagliflozin and / or its hydrate may be selected from one or more of dapagliflozin, dapagliflozin propylene glycol hydrate, etc.

[0038] In some embodiments of this disclosure, the type of lactose is not particularly limited, as long as it can be dissolved in an aqueous solution of alcohol and / or ketone and the amount and / or concentration of the two can be adjusted so that the dissolved lactose and dapagliflozin meet the relative dosage range. For example, the lactose may be selected from one or more of lactose monohydrate, anhydrous lactose, and spray-dried lactose.

[0039] In some embodiments of this disclosure, the mass concentration of the alcohol and / or ketone in the aqueous solution can be 20%-50%, for example, 20%, 22%, 25%, 28%, 30%, 32%, 35%, 38%, 40%, 42%, 45%, 48%, or 50%, etc., or a range of any of the above values. For example, the aqueous solution of alcohol and / or ketone may be an aqueous solution of alcohol with a mass concentration of 20%-50%; the aqueous solution of alcohol and / or ketone may be an aqueous solution of ketone with a mass concentration of 20%-50%; or the aqueous solution of alcohol and / or ketone may be an aqueous solution of alcohol and ketone with a mass concentration of 20%-50%. Controlling the mass concentration of alcohols and / or ketones in the aqueous solution to meet the specified range is beneficial for the complete dissolution of dapagliflozin and also promotes lactose dissolution. This, in turn, helps to reduce raw material costs and mitigate the risk that insufficient dissolved lactose content may affect the improvement of dapagliflozin dissolution stability, while ensuring that the relative amounts of dissolved lactose and dapagliflozin meet the given range.

[0040] In some embodiments of this disclosure, the aqueous solution of the alcohol and / or ketone may be an aqueous solution of one or more of ethanol, isopropanol, and acetone.

[0041] In some embodiments of this disclosure, when the binder is mixed with other excipients to prepare the core, the other excipients may include one or more of the following: a carrier, a disintegrant, a lubricant, an optional filler, and an optional flow aid.

[0042] In some embodiments, the carrier may be selected from lactose.

[0043] In some embodiments, the disintegrant may be selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and pregelatinized starch.

[0044] In some embodiments, the lubricant may be selected from one or more of silica, colloidal silica, talc, magnesium stearate, calcium stearate, sodium stearate fumarate, and stearic acid.

[0045] In some embodiments, the filler may be selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, starch, dextrin, mannitol, and xylitol.

[0046] In some embodiments, the flow aid may be selected from one or more of silica, colloidal silica, talc, magnesium stearate, calcium stearate, sodium stearate fumarate, and stearic acid.

[0047] In some embodiments, based on the mass of the core, the mass percentage of the carrier can be 30%-90%, the mass percentage of the disintegrant can be 1%-7%, the mass percentage of the lubricant can be 0.2%-2%, the mass percentage of the filler can be 0-60%, and the mass percentage of the flow aid can be 0-3%. For example, the mass percentage of the carrier can be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, etc., or a range of any of the above values; the mass percentage of the disintegrant can be 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, or 7%, etc., or a range of any of the above values; the mass percentage of the lubricant can be 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, or 1.4%. The mass percentage of the filler can be 1.6%, 1.8%, or 2%, etc., or any range of the above values; the mass percentage of the filler can be 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%, etc., or any range of the above values; the mass percentage of the flow aid can be 0%, 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, or 3%, etc., or any range of the above values. Optionally, the carrier can be lactose, the disintegrant can be crospovidone, the lubricant can be magnesium stearate, the filler can be microcrystalline cellulose, and the flow aid can be silica.

[0048] In some embodiments, the method for preparing a pharmaceutical formulation containing dapagliflozin may specifically include the following steps: (1) dissolving dapagliflozin and / or its hydrate, lactose in an aqueous solution of alcohol and / or ketone, such that the mass ratio of dissolved lactose to dapagliflozin is (0.1-0.5):1, to obtain a binder; (2) mixing the binder with a carrier, a disintegrant, and an optional filler to obtain a soft material; (3) sieving, granulating, drying, and sizing the soft material, and mixing it with a lubricant and an optional flow aid, and compressing it into tablets to obtain tablet cores.

[0049] In some embodiments, the carrier may be lactose, the disintegrant may be crospovidone, the lubricant may be magnesium stearate, the filler may be microcrystalline cellulose, and the flow aid may be silica. A method for preparing a pharmaceutical formulation containing dapagliflozin may specifically include the following steps: (1) adding dapagliflozin or dapagliflozin propylene glycol hydrate and the first lactose to an aqueous solution of alcohol and / or ketone, such that the mass ratio of dissolved lactose to dapagliflozin is (0.1-0.5):1, to obtain a binder; (2) mixing the binder with the second lactose, crospovidone, and microcrystalline cellulose to obtain a soft material; (3) granulating, drying, and straightening the soft material by sieving, adding silica and magnesium stearate, mixing, and compressing to obtain a tablet core.

[0050] In some embodiments of this disclosure, the method for preparing a pharmaceutical formulation containing dapagliflozin may further include: coating the tablet core. It is understood that when coating the tablet core containing dapagliflozin, the prepared coating layer can be either a plain coating layer without the active pharmaceutical ingredient, or a coating layer containing the active pharmaceutical ingredient that is different from that of dapagliflozin.

[0051] In some embodiments, when coating tablet cores containing dapagliflozin, the coating material used can be a conventional choice in the art. For example, a coating solution can be prepared by mixing a gastric-soluble film coating premix with purified water for the coating treatment.

[0052] Understandably, the solvents used in forming dapagliflozin-containing tablet cores (such as alcohols, aqueous solutions of alcohols, aqueous solutions of ketones, or purified water) can ultimately be removed by drying or heating. Optionally, the solvents used in coating dapagliflozin-containing tablet cores can also ultimately be removed by drying.

[0053] In some embodiments of this disclosure, when preparing a pharmaceutical formulation containing dapagliflozin, processes such as granulation, drying, sizing, mixing or total mixing, tableting, and coating can be performed using conventional methods and parameters in the art.

[0054] For example, after granulation, the mesh size of the granulation screen can be controlled to be 2.0 mm.

[0055] For example, when compressing tablets, different molds and tableting processes can be selected according to different dapagliflozin content specifications and theoretical tablet weights. For instance, for the 10mg specification, an 8×11mm diamond punch and die can be installed on the tablet press, and tablets can be compressed according to the theoretical tablet weight [250mg×(1±5%)]. The adjusting bolts of the tablet press are adjusted, and a test compression is performed. Tableting can only proceed after passing the weight difference (±5%), hardness (55-100N), friability (≤0.5%), and appearance inspections. During the tableting process, the tablet press speed can be controlled at 30-70rpm and the weight difference (±5%) can be controlled. During the tableting process, hardness and friability are monitored, and the hardness (55-100N) and friability (≤0.5%) are controlled to keep the tablet weight within the specified range. For example, for the 5mg specification, a Φ7mm round shallow concave punch and die can be installed on the tablet press. Tablets are pressed according to the theoretical tablet weight [125mg × (1±5%)]. The adjusting bolts of the tablet press are adjusted, and a test press is performed. Tablets can only be pressed after passing the weight difference (±5%), hardness (35-70N), friability (≤0.5%), and appearance inspection. During the tablet pressing process, the tablet press speed can be controlled at 30-70rpm and the weight difference (±5%) can be controlled. During the tablet pressing process, the hardness and friability are monitored and controlled to keep the tablet weight within the specified range.

[0056] For example, the prepared coating solution can be used after passing through a 100-mesh sieve.

[0057] For example, the tablet core or uncoated tablet can be preheated before coating. For instance, the tablet core or uncoated tablet can be put into the coating machine, the hot air and the drum can be turned on, and the air inlet temperature can be set (e.g., a reference setting value: 55-75℃). The drum speed of the coating machine can be 1-3 rpm, and the preheating can make the tablet bed temperature reach 40±3℃.

[0058] For example, during coating, set the inlet air temperature (e.g., a reference setting of 55-75℃), adjust the spray state and spray distance, and begin coating. During the coating process, maintain continuous stirring of the coating solution and control the main unit speed at 2-5 rpm. The coating solution flow rate can be within the reference range of 40-150 g / min, the atomization pressure can be 0.2-0.4 MPa, the tablet bed temperature can be controlled at 40±3℃, and the actual coating weight gain can be controlled at 3-5% (based on the uncoated tablets). After coating, the main unit speed can be adjusted to 1-3 rpm, and drying can continue until qualified (loss on drying ≤4%, using a halogen moisture analyzer, set to 80℃, Auto), then cooled to room temperature before discharge.

[0059] In some embodiments of this disclosure, after obtaining the pharmaceutical formulation containing dapagliflozin, it can be packaged. For example, for tablets, inner and outer packaging can be used. For instance, the inner packaging can use aluminum-plastic blister packs. The aluminum-plastic packaging machine can be turned on and preheated, and the machine temperature adjusted (reference temperature: upper heating 120±10℃, lower heating 120±10℃, heat sealing temperature 150±10℃, which can be adjusted according to different batches of packaging materials). A trial run is conducted, and the blister packing operation can only proceed after the appearance, batch number, and sealing of the empty aluminum foil blister packs have passed inspection. During blister packing, the machine speed can be controlled at 25-35 punching / minute. For the outer packaging, before packaging, the name, code, specifications, batch number, quantity, and markings of the packaging materials can be carefully checked. Two blister packs are placed in a polyester / aluminum / polyethylene pharmaceutical composite bag, heat-sealed, and then placed in a small box. The small box should be checked and confirmed before printing the batch number. The packaging should meet requirements such as sealing, clear batch number, and flatness.

[0060] In a second aspect of this disclosure, a method for preparing a pharmaceutical formulation containing dapagliflozin, as described in the first aspect of this disclosure, is used in improving the dissolution stability of dapagliflozin in the pharmaceutical formulation.

[0061] The method for preparing a pharmaceutical formulation containing dapagliflozin disclosed herein, or its use thereof, may have the following beneficial effects: it can improve the dissolution stability of dapagliflozin in the pharmaceutical formulation during storage.

[0062] Example

[0063] The present disclosure will be further described in detail below with reference to specific embodiments. Modifications can be made to these embodiments to obtain other implementations without departing from the scope or spirit of the present disclosure. Therefore, the following embodiments are non-limiting.

[0064] Unless otherwise specified, all figures used in this specification and claims to indicate feature dimensions, quantities, and physical properties should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters listed in the foregoing specification and appended claims are approximations, and those skilled in the art can appropriately modify these approximations to obtain the desired characteristics using the teachings disclosed herein. The use of numerical ranges indicated by endpoints includes all numbers within that range and any range within that range; for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.

[0065] General detection methods: (1) Dissolution test method: Unless otherwise specified, the dissolution rate of dapagliflozin shall be determined using the following method: Dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method I).

[0066] Dissolution conditions: Use 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, rotate at 50 rpm, operate according to the procedure, and take a sample after 30 minutes.

[0067] Dapagliflozin test solution: Take an appropriate amount of the dissolution solution, filter it, and collect the filtrate.

[0068] Reference solution: Weigh an appropriate amount of dapagliflozin reference standard accurately, dissolve it in dissolution medium and dilute quantitatively to prepare a solution containing approximately 10 μg per ml.

[0069] Assay: Accurately measure 20 µl of the test solution and the reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the amount of dapagliflozin dissolved in each tablet by peak area using the external standard method.

[0070] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; water-acetonitrile-trifluoroacetic acid (55:45:0.05) was used as the mobile phase; the flow rate was 1.0 ml per minute; the detection wavelength was 220 nm; the column temperature was 35 ℃; and the injection volume was 10 µl.

[0071] Limit: 80% of the labeled amount, which should comply with regulations.

[0072] (2) Crystal form detection method: Unless otherwise specified, the determination shall be performed using a DX-27mini X-ray diffractometer according to the X-ray diffraction method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0451, Method II).

[0073] Source of drugs or reagents: Unless otherwise specified, the drugs or reagents used in the following examples and comparative examples are all conventional commercially available products.

[0074] Dapagliflozin: Purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd., batch number: T202312LX01; Dapagliflozin propylene glycol hydrate: Anhui Lianchuang Biopharmaceutical Co., Ltd., batch number: 20210701; Lactose: Purchased from Jiangsu Daoning Pharmaceutical Co., Ltd., batch number: 2301001; Cross-linked polyvinylpyrrolidone: purchased from Quzhou Jianhua Nanhang Pharmaceutical Co., Ltd., batch number: PP231206XL-10; Microcrystalline cellulose: purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number: 240120; Silica: Purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number: 230224; Magnesium stearate: purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number: 230922; Gastric-soluble film-coated premix: purchased from Shanghai Newfield Biopharmaceutical Engineering Technology Co., Ltd., batch number: T2403034.

[0075] Examples 1-4 and Comparative Examples 1-3

[0076] The formulations and preparation processes of Examples 1-4 are detailed in Table 1, and the formulations and preparation processes of Comparative Examples 1-3 are detailed in Table 2. The dissolution test results of Examples 1-4 and Comparative Examples 1-3 are detailed in Table 3. Figures 1 to 7 For details of the crystal form test results of Examples 1-4, please refer to [link / reference]. Figures 8 to 11 It should be noted that the weight of dapagliflozin propylene glycol hydrate involved in the various embodiments or comparative examples of this disclosure is based on dapagliflozin.

[0077] Table 1. Formulations and preparation processes for Examples 1-4

[0078] Note: In this disclosure, in each embodiment and comparative example, the prepared tablets were thermo-sealed in a polyester / aluminum / polyethylene pharmaceutical composite film bag and placed at 40°C and 75%RH to examine accelerated stability and compare changes in crystal form and / or dissolution before and after acceleration. Specifically, when testing for changes in crystal form, the tablets were ground into a fine powder for testing.

[0079] Table 2. Formulations and preparation processes of Comparative Examples 1-3

[0080] Table 3. Dissolution test results of Examples 1-4 and Control Examples 1-3

[0081] Results and conclusions: Figures 1-7 The charts sequentially present comparisons of the tablet samples from Examples 1, 2, 3, 4, and Control Examples 1, 2, and 3, and the cumulative dissolution rate of gliflozin over 1 month and 3 months of accelerated dissolution, along with data from Table 3. Figures 1-7 The test results show that in Examples 1-4, the tablet samples prepared by pre-treating dapagliflozin with dissolved lactose before combining dapagliflozin with other excipients have better dissolution stability. In Control Examples 1 and 3, dry granulation was used, and in Control Example 2, anhydrous ethanol was used instead of aqueous alcohol solution. No dissolved lactose was formed in any of the three during the preparation process, and the dissolution stability of dapagliflozin before and after acceleration was poor. This further illustrates that pre-treating dapagliflozin with dissolved lactose during the preparation of dapagliflozin formulations is beneficial to improving the dissolution stability of dapagliflozin. Figures 8-11 The XRD patterns of tablet samples from Examples 1, 2, 3, and 4, after 6 months of acceleration, blank excipients, and dapagliflozin raw material are shown in sequence. As can be seen from the figures, the tablet samples prepared in Examples 1-4 did not show the crystal characteristic peaks of dapagliflozin raw material after 6 months of acceleration, indicating that dapagliflozin did not show obvious crystal transformation after acceleration, and the samples have good acceleration stability.

[0082] In summary, pretreatment of dapagliflozin with dissolved lactose during the preparation of dapagliflozin formulations is beneficial to improving the dissolution stability of dapagliflozin during long-term storage.

[0083] Examples 5-7 and Comparative Example 4

[0084] The formulations and preparation processes of Examples 5-7 and Comparative Example 4 are detailed in Table 4, and the dissolution test results of Examples 5-7 and Comparative Example 4 are detailed in Table 5. Figures 12 to 15 .

[0085] Table 4. Formulations and preparation processes of Examples 5-7 and Comparative Example 4

[0086] Note: The weight of dapagliflozin propylene glycol hydrate in Table 4 is based on dapagliflozin.

[0087] Table 5. Dissolution test results of Examples 5-7 and Control Example 4

[0088] Results and conclusions: Figures 12-15 The figures shown are, in order, comparisons of the cumulative dissolution rates of glibenclamide over time for tablet samples from Examples 5, 6, 7, and Control Example 4 after 1 month and 3 months of accelerated dissolution, combined with data from Table 5. Figures 12-15 It can be seen that the dissolution stability of dapagliflozin after acceleration in Examples 5-7 is significantly better than that in Control Example 4. The reason for this may be that in Control Example 4, the amount of dissolved lactose formed after mixing and stirring dapagliflozin propylene glycol hydrate, lactose 1, and ethanol aqueous solution was insufficient. In wet granulation, excessive solvent can easily cause the soft material to become a paste, making it difficult to complete sieving and granulation. Due to the limited amount of solvent, the content of dissolved lactose cannot be increased further.

[0089] Example 8

[0090] The aim was to study the stability of the same formulation in small-scale and pilot-scale operations, with the pilot-scale operation repeated three times. Detailed formulation and preparation process are shown in Table 6, and crystal form test results for the small-scale and pilot-scale operations are detailed in [Table 6]. Figures 16 to 19 The dissolution test results of the pilot-scale production are detailed in Table 7.

[0091] Table 6. Formulas and processing techniques for small-scale and pilot-scale production.

[0092] Table 7. Results of crystal form and dissolution tests for three pilot-scale batches.

[0093] (Packaging format: aluminum-plastic blister pack with an outer polyester / aluminum / polyethylene pharmaceutical composite film bag)

[0094] Results and conclusions: Figure 16 The XRD patterns of the tablet samples from Example 8 (small-scale test) and their accelerated growth at 3 months and 10 months, as well as the blank excipient and dapagliflozin raw material, are shown below. Figures 17 to 19 The XRD patterns of tablet samples from pilot-scale batches 1, 2, and 3, after acceleration for 1 month and 6 months respectively, as well as the XRD patterns of blank excipients and dapagliflozin raw material, are shown in order. The figures show that the tablet samples from both the pilot and small-scale batches did not exhibit the characteristic crystal peaks of dapagliflozin raw material after acceleration, indicating that dapagliflozin did not undergo significant crystal transformation after acceleration, demonstrating good acceleration stability. Furthermore, based on the data in Table 7, the tablet samples from the large-scale pilot-scale batch also showed good dissolution stability before and after acceleration.

[0095] In summary, this indicates that the stability of dapagliflozin formulations is good in both small-scale and pilot-scale trials using the same formula.

[0096] In summary, pretreatment of dapagliflozin with dissolved lactose during the preparation of pharmaceutical formulations containing dapagliflozin is beneficial for improving its dissolution stability during long-term storage. Furthermore, considering the solvent usage range during wet granulation, the solubility of dapagliflozin and lactose in solvents, and the commonly used dosage specifications of dapagliflozin in pharmaceutical formulations, the embodiments of this disclosure, by controlling the mass ratio of dissolved lactose to dapagliflozin to (0.1-0.5):1 during the preparation of tablet cores containing dapagliflozin, can effectively improve the dissolution stability of dapagliflozin in pharmaceutical formulations during long-term storage.

[0097] The present disclosure has been described in detail above with general descriptions and specific embodiments. However, modifications or improvements can be made to it, and it can be combined arbitrarily as needed, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present disclosure are within the scope of protection claimed by the present disclosure.

Claims

1. A method of preparing a pharmaceutical preparation containing dapagliflozin, characterized by, The method comprises: dissolving dapagliflozin and / or its hydrate and lactose in an alcohol and / or ketone aqueous solution, so that the mass ratio of the dissolved lactose to dapagliflozin is (0.1-0.5):1, to obtain a binder; mixing the binder with other excipients to prepare a tablet core.

2. The method of claim 1, wherein, The dapagliflozin or its hydrate is selected from one or more of dapagliflozin, dapagliflozin propylene glycol hydrate.

3. The method according to claim 1 or 2, characterized in that, The lactose is selected from one or more of lactose monohydrate, lactose anhydrous, spray-dried lactose; and / or, The mass concentration of alcohol and / or ketone in the alcohol and / or ketone aqueous solution is 20%-50%; and / or, The alcohol and / or ketone aqueous solution is one or more of an aqueous solution of ethanol, isopropyl alcohol, acetone.

4. The method according to any one of claims 1-3, characterized in that, The other excipients include one or more of a carrier, a disintegrant, a lubricant, an optionally added filler, and an optionally added glidant.

5. The method of claim 4, wherein, The carrier is selected from lactose; and / or, The disintegrant is selected from one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and pregelatinized starch; and / or, The lubricant is selected from one or more of silicon dioxide, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, and stearic acid; and / or, The filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, starch, dextrin, mannitol, and xylitol; and / or, The glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, and stearic acid.

6. The method according to claim 4 or 5, characterized in that, The mass percentage of the carrier is 30%-90%, the mass percentage of the disintegrant is 1%-7%, the mass percentage of the lubricant is 0.2%-2%, the mass percentage of the filler is 0-60%, and the mass percentage of the glidant is 0-3%, based on the mass of the tablet core.

7. The method according to any one of claims 1 to 6, characterized in that, The method comprises: dissolving dapagliflozin and / or its hydrate and lactose in an alcohol and / or ketone aqueous solution, to obtain a binder; mixing the binder with a carrier, a disintegrant, and an optionally added filler to obtain a soft material; screening, granulating, drying, and sizing the soft material, and mixing with a lubricant and an optionally added glidant, and then compressing to obtain a tablet core.

8. The method according to any one of claims 1-7, characterized in that, The method comprises: adding dapagliflozin or dapagliflozin propylene glycol hydrate and a first lactose to an alcohol and / or ketone aqueous solution to obtain a binder; mixing the binder with a second lactose, crospovidone, and microcrystalline cellulose to obtain a soft material; screening, granulating, drying, and sizing the soft material, and mixing with silicon dioxide and magnesium stearate, and then compressing to obtain a tablet core.

9. The method according to any one of claims 1-8, characterized in that, The method further comprises: coating the tablet core.

10. Use of the method of any one of claims 1-9 to improve the dissolution stability of dapagliflozin in a pharmaceutical preparation.

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