A compound sustained-release tablet for treating diabetes and a preparation method thereof

Abstract

The application discloses a compound sustained-release tablet for treating diabetes and a preparation method thereof. The compound sustained-release tablet for treating diabetes comprises a dapagliflozin layer, a metformin sustained-release layer and a coating layer. The metformin sustained-release layer comprises a release modifier which is composed of hydroxypropyl methyl cellulose K4M and hydroxypropyl methyl cellulose K35M. Through screening and optimization of the selection and proportioning of a drug source, sustained-release materials and auxiliary agents, the two active components in the compound sustained-release tablet are released gently and durably, and the absorption of the drug is good.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and in particular relates to a compound sustained-release tablet for the treatment of diabetes and its preparation method. Background Technology

[0002] Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor. By inhibiting SGLT-2, dapagliflozin reduces the reabsorption of filtered glucose by the kidneys, thereby lowering the renal glucose threshold and increasing glucose excretion in the urine, thus lowering blood glucose levels.

[0003] Metformin hydrochloride primarily acts on extrapancreatic tissues, inhibiting intestinal glucose absorption, increasing peripheral tissue glucose utilization, and reducing hepatic gluconeogenesis, thereby lowering blood sugar. Because of its significant hypoglycemic effect and lack of hypoglycemia, it is suitable for patients with type II diabetes.

[0004] XigduoXR is the first combination of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and extended-release metformin hydrochloride for adult patients with type 2 diabetes requiring dapagliflozin in combination with metformin. Xigduo (dapagliflozin / metformin hydrochloride) was approved in the EU in January 2014, becoming the first SGLT2 inhibitor and metformin combination product to be marketed in the EU. On October 29, 2014, multiple dosage strengths of XigduoXR (dapagliflozin / metformin hydrochloride) were approved by the FDA, including 5 mg / 500 mg, 5 mg / 1000 mg, 10 mg / 500 mg, and 10 mg / 1000 mg.

[0005] Dapagliflozin-metformin extended-release tablets contain two active ingredients: dapagliflozin in the immediate-release layer and metformin in the extended-release layer. These two ingredients have different release rates to meet specific requirements.

[0006] The original patent CN105193761A discloses that in the metformin XR layer (1000mg), hydroxypropyl methylcellulose 2208 is preferred as a release modifier, and in the metformin XR layer (500mg), a combination of hydroxypropyl methylcellulose 2208 and hydroxypropyl methylcellulose 2910 is preferred as a release modifier. Crosspovidone is used as the disintegrant for the dapagliflozin layer.

[0007] Patent CN116473934A discloses a dapagliflozin-metformin sustained-release tablet, its preparation method, and its application. By setting an isolation layer between the metformin sustained-release tablet core and the dapagliflozin drug layer, the dapagliflozin layer is coated on the surface of the isolation layer, which can increase the uniformity of drug content and ensure the effective dissolution of dapagliflozin.

[0008] Patent CN17695237A discloses a composite controlled-release tablet for treating diabetes and its preparation method. The controlled-release tablet achieves a constant and slow release of metformin hydrochloride in the dapagliflozin metformin hydrochloride controlled-release tablet by means of a sustained-release matrix tablet core and a membrane coating layer wrapped around the surface of the sustained-release matrix tablet core. The release rate is within 10% per hour.

[0009] The dissolution rates of the two active ingredients in the dapagliflozin metformin extended-release tablets obtained by the above method are not consistent with those of the original product, which is manifested as mismatch in drug release curves or unstable release rates. This may lead to unpredictable therapeutic effects and difficulty in maintaining constant blood drug concentrations, thereby affecting efficacy and safety. Summary of the Invention

[0010] This invention provides a compound sustained-release tablet for the treatment of diabetes and its preparation method. The invention aims to improve the matching degree between the dissolution profile of existing dapagliflozin-metformin sustained-release tablets and the original drug, ensuring highly similar dissolution characteristics in vitro and in vivo. By screening and optimizing the drug source, sustained-release materials, and the selection and ratio of excipients, this invention achieves a smooth and sustained release of dapagliflozin and metformin, while maintaining good drug absorption.

[0011] The present invention provides a compound sustained-release tablet for treating diabetes, comprising: a dapagliflozin layer, a metformin sustained-release layer and a coating layer, wherein the metformin sustained-release layer comprises a release modifier composed of hydroxypropyl methylcellulose K4M and hydroxypropyl methylcellulose K35M.

[0012] Furthermore, the mass ratio of the hydroxypropyl methylcellulose K4M to the hydroxypropyl methylcellulose K35M is 1:(5-8).

[0013] Furthermore, the dapagliflozin layer includes a disintegrant.

[0014] Furthermore, the disintegrant portion of the dapagliflozin layer is added externally.

[0015] Furthermore, the mass ratio of the internally added to the externally added disintegrant is (1-3):1.

[0016] Further, the metformin sustained-release layer comprises, by weight, 900-1100 parts of metformin hydrochloride, 50-55 parts of lubricant, 3-7 parts of binder, 230-240 parts of release modifier, and 10-15 parts of flow aid; the dapagliflozin layer comprises, by weight, 5-15 parts of dapagliflozin propylene glycol monohydrate, 250-300 parts of diluent, 10-15 parts of disintegrant, 4-5 parts of flow aid, and 1-5 parts of lubricant.

[0017] Furthermore, the lubricant is magnesium stearate, the binder is sodium carboxymethyl cellulose, the flow aid is silicon dioxide, the diluent is anhydrous lactose and / or microcrystalline cellulose, and the disintegrant is cropovidone.

[0018] Furthermore, all the release modifiers in the metformin sustained-release layer are added externally, and part of the magnesium stearate is added externally.

[0019] On the other hand, the present invention provides a method for preparing the above-mentioned compound sustained-release tablets for treating diabetes, comprising the following steps:

[0020] (1) Preparation of metformin hydrochloride layer: 1) Crush metformin hydrochloride; 2) Add metformin hydrochloride, part of magnesium stearate and sodium carboxymethyl cellulose to a wet granulator and mix evenly; 3) Set the atomization pressure of the wet granulator to 0.1-0.2 MPa, add purified water to make soft material, and after the liquid addition is completed, wet-size the particles using a 4.0 mm sieve; 4) Dry the wet particles and control the moisture content of the material to be no more than 1.0%; 5) Granulate the dried material; 6) Mix the particles obtained in step 5), release modifier and the remaining magnesium stearate evenly;

[0021] (2) Dapagliflozin preparation: 1) Dapagliflozin propylene glycol monohydrate was pulverized; 2) Dapagliflozin propylene glycol monohydrate, anhydrous lactose, microcrystalline cellulose, a portion of cross-linked polyvinylpyrrolidone, a portion of silica and a portion of magnesium stearate were mixed evenly in a hopper mixer; 3) Granulation was performed using a dry granulator; 4) The granules obtained in step 3) were mixed evenly with the remaining cross-linked polyvinylpyrrolidone, the remaining silica and the remaining magnesium stearate;

[0022] (3) Double-layer tablet compression: The granules obtained in steps (1) and (2) are compressed into tablets, and the tablet hardness is controlled to be 250-300N and the brittleness is ≤1%.

[0023] (4) Coating: Coating the core obtained in step (3).

[0024] Furthermore, in the preparation of the metformin hydrochloride layer, the particle size D90 of metformin hydrochloride is <100μm; and in the preparation of the dapagliflozin layer, the particle size D90 of dapagliflozin propylene glycol monohydrate is <30μm.

[0025] Compared with the prior art, the compound sustained-release tablet for treating diabetes (hereinafter referred to as "dapagliflozin metformin sustained-release tablet") and its preparation method of the present invention have the following advantages:

[0026] Dissolution curve consistency: The sustained-release tablet design and preparation process of this invention make the release curves of dapagliflozin and metformin in the dissolution test closer to those of the original drugs. This ensures the stability and consistency of absorption in vivo, helps maintain a stable blood drug concentration, thereby improving the therapeutic effect and reducing toxic side effects.

[0027] Bioavailability: By optimizing the formulation and process steps, the bioavailability of dapagliflozin and metformin in vivo is ensured to be comparable to or improved with the original drugs. This means that at the same dose, the drugs of the present invention can exert their effects better in vivo. Attached Figure Description

[0028] Figure 1 These are the dissolution curves of Examples 1-7 and the reference formulation dapagliflozin.

[0029] Figure 2 These are the dissolution curves of comparative examples 1–7 and the reference preparation dapagliflozin.

[0030] Figure 3 These are the dissolution curves of Examples 1-7 and the reference formulation metformin.

[0031] Figure 4 These are the dissolution curves of comparative examples 1-7 and the reference preparation metformin. Detailed Implementation

[0032] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0033] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0034] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0035] This invention provides a dapagliflozin-metformin extended-release tablet, comprising: a dapagliflozin layer, a metformin extended-release layer, and a coating layer, wherein the metformin extended-release layer includes a release modifier composed of hydroxypropyl methylcellulose K4M and hydroxypropyl methylcellulose K35M. The dapagliflozin-metformin extended-release tablet is a compound formulation in which dapagliflozin is present in an immediate-release form, while metformin is released in a sustained-release form. To achieve the ideal sustained-release effect of metformin, the release modifier plays a crucial role. During in-depth research and reproduction of the reference formulation, the inventors discovered that using a specific type of hydroxypropyl methylcellulose as a release modifier allows the drug release behavior of the dapagliflozin-metformin extended-release tablet to more closely resemble that of the original product.

[0036] In one embodiment of the present invention, the mass ratio of hydroxypropyl methylcellulose K4M to hydroxypropyl methylcellulose K35M is 1:(5-8), for example 1:5, 1:6, 1:7, or 1:8, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. Hydroxypropyl methylcellulose K35M has a relatively high viscosity, while hydroxypropyl methylcellulose K4M has a relatively low viscosity. Although the specific reasons are not yet clear, using these two materials in combination can effectively simulate a dissolution performance closer to the original product.

[0037] In one embodiment of the present invention, the dapagliflozin layer includes a disintegrant, and further, the disintegrant portion of the dapagliflozin layer is externally added. Preferably, the mass ratio of the internally added to the externally added disintegrant is (1-3):1, for example, 1:1, 2:1 or 3:1, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0038] To ensure that the release characteristics of dapagliflozin in dapagliflozin metformin extended-release tablets are consistent with the original product, the inventors discovered that the amount of disintegrant used inside and outside the dapagliflozin layer has a crucial impact.

[0039] In one embodiment of the present invention, the metformin sustained-release layer comprises, by weight, 900-1100 parts of metformin hydrochloride, 50-55 parts of lubricant, 3-7 parts of binder, 230-240 parts of release modifier, and 10-15 parts of flow aid; and the dapagliflozin layer comprises, by weight, 5-15 parts of dapagliflozin propylene glycol monohydrate, 250-300 parts of diluent, 10-15 parts of disintegrant, 4-5 parts of flow aid, and 1-5 parts of lubricant.

[0040] More preferably, the metformin sustained-release layer comprises, by weight, 1000 parts metformin hydrochloride, 52 parts lubricant, 5 parts binder, 235 parts release modifier, and 13 parts flow aid; and the dapagliflozin layer comprises, by weight, 6.15–12.3 parts dapagliflozin propylene glycol monohydrate, 268.2–274.35 parts diluent, 12 parts disintegrant, 4.5 parts flow aid, and 3 parts lubricant.

[0041] The specific embodiments and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0042] Table 1. Sources and Functions of Raw Materials and Auxiliary Materials in Examples and Comparative Examples

[0043]

[0044] Table 2 Summary of prescription composition for each embodiment and comparative example (mg / tablet)

[0045]

[0046]

[0047] Note: 6.15 mg of dapagliflozin propylene glycol monohydrate is equivalent to 5 mg of dapagliflozin, and 12.30 mg of dapagliflozin propylene glycol monohydrate is equivalent to 10 mg of dapagliflozin. Purified water is used as a wetting agent in wet granulation and is removed during the drying process.

[0048] The preparation methods of dapagliflozin metformin extended-release tablets in Examples 1-7 and Comparative Examples 1-7 are as follows (batch size: 5000 tablets):

[0049] (1) Metformin hydrochloride layer

[0050] 1) Pretreatment: Metformin hydrochloride was mechanically pulverized to control the particle size D90 < 100 μm;

[0051] 2) Premixing: Add metformin hydrochloride, magnesium stearate and sodium carboxymethyl cellulose to a wet granulator and mix. Set the stirring speed to 150 rpm and the cutting speed to 1500 rpm, and mix for 3 to 8 minutes.

[0052] 3) Granulation: Set the stirring speed of the wet granulator to 150 rpm and the shearing speed to 1500 rpm. Adjust the atomization pressure to 0.1-0.2 MPa. Add purified water to make soft material. Control the liquid addition and granulation time within 10 minutes. After the liquid addition is completed, wet-fine the granules using a 4.0 mm sieve and then transfer them to a fluidized bed for drying.

[0053] 4) Drying: Place the wet granules in a fluidized bed with an inlet air temperature of 60℃ for drying. Control the appropriate air volume and the material temperature between 40℃ and 50℃. At the same time, monitor the material moisture content and stop the machine to discharge when it is not greater than 1.0%.

[0054] 5) Granulation: The dried material is granulated by passing it through a pulverizer and granulator with a 1.0mm screen.

[0055] 6) Total mixing: Add the granules obtained in step 5) to the added hydroxypropyl methylcellulose, silica and magnesium stearate into a laboratory hopper mixer and mix for 15-23 minutes at 8 rpm;

[0056] (2) Daglie net layer

[0057] 1) Pretreatment: Pulverize dapagliflozin propylene glycol monohydrate, controlling D90 < 30 μm;

[0058] 2) Premixing: Dapagliflozin propylene glycol monohydrate, anhydrous lactose, microcrystalline cellulose, added cross-linked polyvinyl chloride, added silica, and added magnesium stearate are mixed in a hopper mixer for 10-20 minutes at a speed of 8 rpm.

[0059] 3) Granulation

[0060] Set the dry pellet mill to the following settings: feeding speed: 40-60 rpm; roller gap: 0.4-0.8 mm; roller speed: 8-10 rpm; hydraulic pressure: 40-80 bar; crushing speed: 100 rpm; and screen aperture: 1.0 mm.

[0061] 4) Mixing: Mix the particles obtained in step 3) with the added crosslinked polyvinyl ketone and silica in a hopper mixer for 10 minutes at a speed of 8 rpm; then add magnesium stearate and continue mixing for 8 minutes at a speed of 8 rpm.

[0062] (3) Double-layer tablet compression: control the tablet hardness to be 250-300N and the friability to be ≤1%.

[0063] (4) Coating: Set the inlet air temperature of the coating machine to 60℃ and control the tablet bed temperature within the range of 35-45℃ for coating. Dapagliflozin metformin extended-release tablets, manufactured by AstraZeneca AB, are selected. The specification is 10mg / 1000m as the reference preparation, batch number PN0007.

[0064] Dissolution determination method for dapagliflozin metformin extended-release tablets and reference formulations obtained in Examples 1-7 and Comparative Examples 1-7:

[0065] Medium: pH 6.8 phosphate buffer solution

[0066] Methods: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Basket Method

[0067] Media volume: 1000ml

[0068] Medium temperature: 37℃±0.5℃

[0069] Speed: 100 rpm

[0070] Dapagliflozin sampling points were: 5, 10, 20, 30, and 45 minutes.

[0071] Metformin sampling points are: 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours.

[0072] Then, dissolution curves were plotted and the dissolution similarity value f2 was determined.

[0073] The value of f2 ranges from 0 to 100:

[0074] When f2 ≥ 50, the dissolution curves are generally considered to be similar.

[0075] When f2 < 50, the dissolution curves of the two are considered to be dissimilar.

[0076] A larger f2 value indicates that the dissolution curves are more similar.

[0077] Table 3 Summary of dapagliflozin dissolution results in the examples and comparative examples

[0078]

[0079] Table 4 Summary of metformin dissolution results for the examples and comparative examples

[0080]

[0081]

[0082] Conclusion: From Tables 3-4 and Figures 1-4 The f2 values ​​of Comparative Examples 1-4 and Comparative Examples 1-4 show that, under the same conditions, when the ratio of hydroxypropyl methylcellulose K4M and hydroxypropyl methylcellulose K35M in the release modifier is controlled within the range of 1:5-8, the dissolution rates of dapagliflozin and metformin in the prepared dapagliflozin-metformin extended-release tablets can achieve effects highly similar to those of the reference formulation.

[0083] However, if the release modifier contains too little hydroxypropyl methylcellulose K35M (as in Comparative Example 1) or too much (as in Comparative Example 2), or if only one of K4M or K35M is used (as in Comparative Examples 3 and 4), although the dissolution of dapagliflozin can reach more than 85% of the labeled amount at 30 min, and the metformin layer also meets the requirements of dissolution of 20% to 40% at 1 hour, 45% to 65% at 3 hours, and more than 85% at 10 hours, the sustained-release tablets prepared by these formulations are not as similar to the reference formulation as the similarity reflected by the f2 value.

[0084] As can be seen from the f2 values ​​of Comparative Examples 5-7 and Comparative Examples 5-7 in Tables 3-4, under the same conditions, when the ratio of disintegrant added inside and outside the dapagliflozin layer is 1-3:1, the dissolution rate of dapagliflozin and metformin in the prepared dapagliflozin-metformin extended-release tablets can achieve a high degree of similarity to the reference formulation.

[0085] However, if too much disintegrant is added internally (as in Comparative Example 7) or only internally or externally (as in Comparative Examples 5 and 7), although the dissolution of dapagliflozin can reach more than 85% of the labeled amount in 30 minutes, and the metformin layer also meets the requirements of dissolution of 20% to 40% in 1 hour, 45% to 65% in 3 hours, and more than 85% in 10 hours, the sustained-release tablets prepared by these formulations are not as similar to the reference formulation as the similarity reflected by the f2 value.

[0086] Comparison of absorption between tablets from Example 1 and Example 5

[0087] In vivo absorption assay: Refer to the Guidelines for Bioavailability and Bioequivalence Studies of Drug Formulations in Humans (Guideline 9011, Part IV, Chinese Pharmacopoeia 2020 Edition). The formulation is considered bioequivalent to the reference formulation if the 90% confidence intervals of the ratio of Cmax, AUC(0→t), and AUC(0→∞) of the logarithmic transformation values ​​of the development formulation and the reference formulation fall between 80% and 125%.

[0088] The bioequivalence study of the tablets in Example 1 and the metformin extended-release tablets in Example 5 compared the drug absorption. The specific test results are as follows:

[0089] Table 5. Absorption of dapagliflozin in Examples 1 and 5

[0090]

[0091] Table 6. Metformin drug absorption in Examples 1 and 5

[0092]

[0093] As shown in Tables 5 and 6, the 90% confidence intervals of the ratios of Cmax, AUC(0→t), and AUC(0→∞) of the logarithmic transformation values ​​of the formulations in Examples 1 and 5 and the reference formulation fall between 80% and 125%, indicating equivalence compared to the reference formulation.

[0094] In summary, the dapagliflozin metformin extended-release tablets obtained by this invention can achieve similar effects to the reference formulation both in vivo and in vitro.

[0095] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A compound sustained-release tablet for treating diabetes, characterized in that, include: The product comprises a dapagliflozin layer, a metformin extended-release layer, and a coating layer, wherein the metformin extended-release layer includes a release modifier composed of hydroxypropyl methylcellulose K4M and hydroxypropyl methylcellulose K35M.

2. The compound sustained-release tablet for treating diabetes according to claim 1, characterized in that, The mass ratio of the hydroxypropyl methylcellulose K4M to the hydroxypropyl methylcellulose K35M is 1:(5-8).

3. The compound sustained-release tablet for treating diabetes according to claim 2, characterized in that, The dapagliflozin layer includes a disintegrant.

4. The compound sustained-release tablet for treating diabetes according to claim 3, characterized in that, The disintegrant portion of the dapagliflozin layer is added externally.

5. The compound sustained-release tablet for treating diabetes according to claim 4, characterized in that, The mass ratio of the internally added to the externally added disintegrant is (1-3):

1.

6. The compound sustained-release tablet for treating diabetes according to any one of claims 1 to 5, characterized in that, The metformin sustained-release layer comprises, by weight, 900-1100 parts of metformin hydrochloride, 50-55 parts of lubricant, 3-7 parts of binder, 230-240 parts of release modifier, and 10-15 parts of flow aid; the dapagliflozin layer comprises, by weight, 5-15 parts of dapagliflozin propylene glycol monohydrate, 250-300 parts of diluent, 10-15 parts of disintegrant, 4-5 parts of flow aid, and 1-5 parts of lubricant.

7. The compound sustained-release tablet for treating diabetes according to claim 6, characterized in that, The lubricant is magnesium stearate, the binder is sodium carboxymethyl cellulose, the flow aid is silicon dioxide, the diluent is anhydrous lactose and / or microcrystalline cellulose, and the disintegrant is cropovidone.

8. The compound sustained-release tablet for treating diabetes according to claim 7, characterized in that, All the release modifiers in the metformin sustained-release layer are added externally, and part of the magnesium stearate is added externally.

9. A method for preparing the compound sustained-release tablet for treating diabetes according to any one of claims 1 to 8, comprising the following steps: (1) Preparation of metformin hydrochloride layer: 1) Crush metformin hydrochloride; 2) Add metformin hydrochloride, part of magnesium stearate and sodium carboxymethyl cellulose to a wet granulator and mix evenly; 3) Set the atomization pressure of the wet granulator to 0.1-0.2 MPa, add purified water to make soft material, and after the liquid addition is completed, wet-size the particles using a 4.0 mm sieve; 4) Dry the wet particles and control the moisture content of the material to be no more than 1.0%; 5) Granulate the dried material; 6) Mix the particles obtained in step 5), release modifier and the remaining magnesium stearate evenly; (2) Dapagliflozin preparation: 1) Dapagliflozin propylene glycol monohydrate was pulverized; 2) Dapagliflozin propylene glycol monohydrate, anhydrous lactose, microcrystalline cellulose, a portion of cross-linked polyvinylpyrrolidone, a portion of silica and a portion of magnesium stearate were mixed evenly in a hopper mixer; 3) Granulation was performed using a dry granulator; 4) The granules obtained in step 3) were mixed evenly with the remaining cross-linked polyvinylpyrrolidone, the remaining silica and the remaining magnesium stearate; (3) Double-layer tablet compression: The granules obtained in steps (1) and (2) are compressed into tablets, and the tablet hardness is controlled to be 250-300N and the brittleness is ≤1%. (4) Coating: Coating the core obtained in step (3).

10. The method for preparing the compound sustained-release tablets for treating diabetes according to claim 9, characterized in that, In the preparation of the metformin hydrochloride layer, the particle size D90 of metformin hydrochloride is <100μm; in the preparation of the dapagliflozin layer, the particle size D90 of dapagliflozin propylene glycol monohydrate is <30μm.

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