Osmotic pump drug release system based on fenerenone solid dispersion as well as preparation method and application of osmotic pump drug release system

Abstract

The invention relates to the technical field of drug delivery systems. The invention provides an osmotic pump drug release system based on a fenerenone solid dispersion and a preparation method of the osmotic pump drug release system. According to the fenerenone solid dispersion prepared by adopting a hot melt extrusion technology and the osmotic pump drug release system based on the fenerenone solid dispersion, the solubility and the bioavailability of the fenerenone in the solid dispersion can be improved, and drug absorption can be accelerated; the sustained and stable release of the fenerenone can be realized, the drug release rate is optimized, the effectiveness and safety of the drug in the treatment process are ensured, the chemical stability of the fenerenone is improved, and the validity period of the drug is prolonged. Various challenges of the fenerenone in the using process are effectively solved, a more effective and safer treatment scheme is provided for patients suffering from chronic kidney diseases complicated with type 2 diabetes, and important practical value and wide market prospects are achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug delivery systems, and in particular to an osmotic pump drug release system based on finerenone solid dispersion, and a preparation method and application thereof. Background Art

[0002] In recent years, with the changes in people's lifestyles and the advancement of medical detection technology, the incidence of chronic diseases has continued to rise, among which chronic kidney disease (CKD) and type 2 diabetes (T2D) have become major challenges to global health. In particular, patients with CKD and T2D have greater difficulty in disease management and treatment, mainly because the two diseases interact and aggravate each other, resulting in a significant decline in the patient's quality of life and an increased risk of cardiovascular disease. In addition, the treatment options for these patients are limited, and more effective drugs are needed to improve their prognosis.

[0003] Finerenone (trade name Kerendia), as a new type of non-steroidal mineralocorticoid receptor antagonist (MRA), shows the potential to improve renal and cardiovascular outcomes in patients with CKD and T2D. The development of this drug reflects the progress of medical research towards more precise and personalized treatments. Although finerenone has shown positive therapeutic effects in clinical trials, as a BCS Class II drug, it has challenges in solubility and bioavailability, which limits its clinical application and effectiveness. Summary of the invention

[0004] The object of the present invention is to provide an osmotic pump drug release system based on a finerenone solid dispersion. The finerenone solid dispersion prepared by hot melt extrusion technology and the osmotic pump drug release system based thereon effectively solve the challenges of finerenone in solubility, stability and bioavailability, and provide a more effective and safe treatment plan for clinical use, which has important practical value and broad market prospects.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The invention provides an osmotic pump drug release system based on finerenone solid dispersion, which is composed of a tablet core and a semipermeable membrane coating liquid, wherein the weight of the semipermeable membrane coating liquid accounts for 5%-9% of the weight of the tablet core.

[0007] Preferably, the tablet core comprises the following raw materials in parts by weight: 1-25 parts of phenerenone, 20-90 parts of hydroxypropyl methylcellulose acetate succinate, 1-5 parts of 2,6-di-tert-butyl-p-cresol, 20-50 parts of citric acid, 0.5-1.5 parts of magnesium stearate and 55-116.5 parts of lactose monohydrate.

[0008] Preferably, the components of the semipermeable membrane coating solution include cellulose acetate, PEG and acetone, and the mass volume ratio of the cellulose acetate, PEG and acetone is (30-50) g: (1-10) g: (1800-5000) mL.

[0009] Preferably, the PEG includes PEG400 or PEG600.

[0010] The present invention also provides a method for preparing the osmotic pump drug release system, comprising the following steps:

[0011] (1) finerenone, hydroxypropyl methylcellulose acetate succinate and 2,6-di-tert-butyl-p-cresol are mixed, melted, extruded, and then frozen and crushed to obtain a solid dispersion;

[0012] (2) mixing the solid dispersion with citric acid, lactose monohydrate, and magnesium stearate and then tableting to obtain a tablet core;

[0013] (3) The tablet core is coated with a semipermeable membrane coating solution obtained by mixing cellulose acetate, PEG and acetone, and holes are punched on the side of the coating to obtain an osmotic pump drug release system.

[0014] Preferably, the step (1) further comprises a crushing process after the mixing, wherein the crushing process is performed to a mean particle size of less than 20 μm; and the mixing time is 20-30 min.

[0015] Preferably, the melting temperature in step (1) is 240-250°C.

[0016] Preferably, the powder is sieved after the pulverization in step (1), and the mesh size of the sieve is 50-70 meshes.

[0017] Preferably, the diameter of the holes punched in step (3) is 0.7-0.85 mm.

[0018] The present invention also provides the use of the osmotic pump drug release system in preparing relevant pharmaceutical preparations for treating chronic kidney disease combined with type 2 diabetes.

[0019] By adopting the above technical solution, the present invention has the following beneficial effects:

[0020] 1. The present invention adopts the hot melt extrusion process under the parameter conditions to prepare the solid dispersion, effectively disperses the finerenone to the molecular level, changes its crystal form to a more soluble amorphous form, significantly improves the dissolution rate of the finerenone, and thus improves its bioavailability.

[0021] 2. The addition of 2,6-di-tert-butyl-p-cresol during the preparation of the solid dispersion of the present invention effectively solves the oxidation problem that may be caused by the interaction between the drug and the carrier, thereby improving the chemical stability of finerenone. This improvement helps to extend the shelf life of the drug and ensure the stability of the drug preparation during storage and transportation.

[0022] 3. The present invention ensures the sustained and stable release of finerenone by rationally optimizing the composition and dosage ratio of the semipermeable membrane coating liquid and determining the pore size, while also achieving high permeability to water molecules and effective blocking of solute molecules. The biocompatibility of the coating membrane ensures safety in oral applications and excretion capacity after glomerular filtration, thereby reducing the potential risk of bioaccumulation. By adjusting the ratio of finerenone to excipients in the solid dispersion, the release rate of finerenone is optimized, ensuring the effectiveness and safety of the drug during treatment. DETAILED DESCRIPTION

[0023] The present invention provides an osmotic pump drug release system based on finerenone solid dispersion, which is composed of a tablet core and a semipermeable membrane coating liquid, wherein the weight of the semipermeable membrane coating liquid accounts for 5%-9% of the weight of the tablet core, more preferably 7%-8.5%, and even more preferably 8%.

[0024] In the present invention, the tablet core comprises the following raw materials: phenerenone, hydroxypropyl methylcellulose acetate succinate, 2,6-di-tert-butyl-p-cresol, citric acid, magnesium stearate and lactose monohydrate.

[0025] In the present invention, the hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a polymer carrier that can improve the solubility and bioavailability of water-insoluble drugs; it prevents drug recrystallization by forming a molecular dispersion with drug molecules, thereby improving solubility.

[0026] In the present invention, the 2,6-di-tert-butyl (BHT)-p-cresol is used as an antioxidant to effectively solve the oxidation problem that may be caused by the interaction between the drug and the carrier, thereby improving the chemical stability of finerenone; it helps to extend the shelf life of the drug and ensure the stability of the drug preparation during storage and transportation.

[0027] In the present invention, the citric acid is used as a stabilizer to improve the stability of the drug; in some cases, the citric acid can also enhance the bioavailability of the drug or promote the absorption of the drug.

[0028] In the present invention, the magnesium stearate is used as a lubricant to reduce the friction between the powder and the equipment during the tableting process, thereby improving the tableting quality; it can also prevent the aggregation of components and improve fluidity.

[0029] In the present invention, the lactose monohydrate is used as a filler to increase the volume of the tablet to ensure that each tablet contains an appropriate amount of active ingredients; it also helps with bonding and molding during tableting.

[0030] In the present invention, the weight portion of finerenone is preferably 1-25 parts, further preferably 10-22 parts, and further preferably 20 parts; the weight portion of hydroxypropyl methylcellulose acetate succinate is preferably 20-90 parts, further preferably 30-80 parts, and further preferably 40 parts; the weight portion of 2,6-di-tert-butyl-p-cresol is preferably 1-5 parts, further preferably 2-3 parts, and further preferably 2.5 parts; the weight portion of citric acid is preferably 20-50 parts, further preferably 30-45 parts, and further preferably 40 parts; the weight portion of magnesium stearate is preferably 0.5-1.5 parts, further preferably 0.8-1.2 parts, and further preferably 1 part; the weight portion of lactose monohydrate is preferably 55-116.5 parts, further preferably 76.5-100 parts, and further preferably 96.5 parts.

[0031] In the present invention, the components of the semipermeable membrane coating solution include cellulose acetate, PEG and acetone, and the mass volume ratio of the cellulose acetate, PEG and acetone is preferably (30-50) g: (1-10) g: (1800-5000) mL, further preferably (29-40) g: (2-6) g: (1900-4000) mL, and further preferably 28 g: 4 g: 2000 mL.

[0032] In the present invention, the cellulose acetate is used in combination with PEG, which not only improves the water permeability of the membrane, but also enhances its biocompatibility, and can be applied to medical devices that require long-term in vivo application.

[0033] In the present invention, the PEG preferably includes PEG400 or PEG600, and more preferably PEG400.

[0034] The present invention also provides a method for preparing the osmotic pump drug release system, comprising the following steps:

[0035] (1) finerenone, hydroxypropyl methylcellulose acetate succinate and 2,6-di-tert-butyl-p-cresol are mixed, melted, extruded, and then frozen and crushed to obtain a solid dispersion;

[0036] (2) mixing the solid dispersion with citric acid, lactose monohydrate, and magnesium stearate and then tableting to obtain a tablet core;

[0037] (3) The tablet core is coated with a semipermeable membrane coating solution obtained by mixing cellulose acetate, PEG and acetone, and holes are punched on the side of the coating to obtain an osmotic pump drug release system.

[0038] In the present invention, finerenone, hydroxypropyl methylcellulose acetate succinate and 2,6-di-tert-butyl-p-cresol are sieved respectively, and then the sieve underflow is collected, the mesh number of the sieve is preferably 50-70 mesh, more preferably 55-65 mesh, and more preferably 60 mesh; the number of sieving is preferably 3 times. The collected sieve underflow is mixed, and the mixing is preferably carried out using a three-dimensional mixer, and the mixing speed is preferably 20-40rpm, more preferably 25-35rpm, and more preferably 30rpm; the mixing time is preferably 20-30min, more preferably 23-28min, and more preferably 25min.

[0039] In the present invention, after the mixing is completed, a pulverization treatment is performed to obtain the finerenone blend. The pulverization is preferably performed by grinding in a ball mill, and the pulverization is performed once to obtain an average particle size of less than 20 μm.

[0040] In the present invention, the finerenone blend is added to an extruder for melting and extrusion to obtain a strip-shaped extrudate. The melting temperature of the present invention is preferably 240-250° C. The strip-shaped extrudate is cooled and crushed and passed through a sieve, and the undersize is collected to obtain a solid dispersion. The mesh number of the sieve is preferably 50-70 mesh, more preferably 55-65 mesh, and more preferably 60 mesh.

[0041] In the present invention, citric acid and lactose monohydrate are added to the solid dispersion, and after being mixed evenly, magnesium stearate is added, mixed evenly, and tableting is performed to obtain a tablet core.

[0042] In the present invention, cellulose acetate, PEG and acetone are mixed to obtain an acetone solution of cellulose acetate-PEG400, i.e., a semipermeable membrane coating solution. The tablet core is coated with the acetone solution of cellulose acetate-PEG400, and holes are punched on the side of the coating to obtain an osmotic pump drug release system. In the present invention, holes are preferably punched on one side of the coating, and the diameter of the holes is preferably 0.7-0.85 mm, more preferably 0.75-0.82 mm, and more preferably 0.8 mm.

[0043] The present invention also provides the use of the osmotic pump drug release system in preparing relevant pharmaceutical preparations for treating chronic kidney disease combined with type 2 diabetes.

[0044] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0045] Example 1

[0046] An osmotic pump drug release system based on finerenone solid dispersion:

[0047] The tablet core comprises 20 g of finerenone, 20 g of HPMCAS, 40 g of citric acid, 1 g of magnesium stearate, 2.5 g of BHT and 116.50 g of lactose monohydrate; the semipermeable membrane coating solution comprises 28 g of cellulose acetate, 4004 g of PEG and 2000 mL of acetone.

[0048] The preparation method is as follows:

[0049] (1) Finerenone, BHT and HPMCAS were passed through a 60-mesh sieve three times and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, then added to a ball mill and ground until the average particle size was less than 20 μm to obtain a finerenone co-grinding mixture. The melting point of finerenone was 235-238° C. The temperature of the melting zone of the twin-screw extruder was set to 245° C. After the temperature reached the set value, the screw was started, and the finerenone co-grinding mixture was slowly added to the extruder. After melting and extrusion, it was finally extruded in a strip shape. After the strip extrudate was cooled, it was crushed again and passed through a 60-mesh sieve to obtain a finerenone solid dispersion.

[0050] (2) adding citric acid and lactose monohydrate to the finerenone solid dispersion obtained above and mixing evenly, and finally adding magnesium stearate, mixing evenly, and tableting to obtain tablet cores;

[0051] (3) mixing cellulose acetate, PEG400 and acetone to obtain a cellulose acetate-PEG400 acetone solution, and then coating the tablet cores until the tablet cores gain 8% in weight;

[0052] (4) Use laser or mechanical punching to punch a small hole with a diameter of 0.8 mm on one side of the coating.

[0053] Example 2

[0054] An osmotic pump drug release system based on finerenone solid dispersion:

[0055] The tablet core comprises 20 g of finerenone, 40 g of HPMCAS, 40 g of citric acid, 1 g of magnesium stearate, 2.5 g of BHT and 96.50 g of lactose monohydrate; the semipermeable membrane coating solution comprises 28 g of cellulose acetate, 4004 g of PEG and 2000 mL of acetone.

[0056] The preparation method is as follows:

[0057] (1) Finerenone, BHT and HPMCAS were passed through a 60-mesh sieve three times and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then added to a ball mill and ground until the average particle size was less than 20 μm to obtain a finerenone co-ground mixture. The melting point of finerenone was 235-238° C. The temperature of the melting zone of the twin-screw extruder was set to 245° C. After the temperature reached the set value, the screw was started, and the finerenone co-ground mixture was slowly added to the extruder. After melting and extrusion, it was finally extruded in the form of strips. After the strip extrudate was cooled, it was crushed again and passed through a 60-mesh sieve to obtain a finerenone solid dispersion.

[0058] (2) adding citric acid and lactose monohydrate to the finerenone solid dispersion obtained above and mixing evenly, and finally adding magnesium stearate, mixing evenly, and tableting to obtain tablet cores;

[0059] (3) mixing cellulose acetate, PEG400 and acetone to obtain a cellulose acetate-PEG400 acetone solution, and then coating the tablet cores until the tablet cores gain 8% in weight;

[0060] (4) Use laser or mechanical punching to punch a small hole with a diameter of 0.8 mm on one side of the coating.

[0061] Example 3

[0062] An osmotic pump drug release system based on finerenone solid dispersion:

[0063] The tablet core comprises 20 g of finerenone, 60 g of HPMCAS, 40 g of citric acid, 1 g of magnesium stearate, 2.5 g of BHT and 76.50 g of lactose monohydrate; the semipermeable membrane coating solution comprises 28 g of cellulose acetate, 4004 g of PEG and 2000 mL of acetone.

[0064] The preparation method is as follows:

[0065] (1) Finerenone, BHT and HPMCAS were passed through a 60-mesh sieve three times and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then added to a ball mill and ground until the average particle size was less than 20 μm to obtain a finerenone co-ground mixture. The melting point of finerenone was 235-238° C. The temperature of the melting zone of the twin-screw extruder was set to 245° C. After the temperature reached the set value, the screw was started, and the finerenone co-ground mixture was slowly added to the extruder. After melting and extrusion, it was finally extruded in the form of strips. After the strip extrudate was cooled, it was crushed again and passed through a 60-mesh sieve to obtain a finerenone solid dispersion.

[0066] (2) adding citric acid and lactose monohydrate to the finerenone solid dispersion obtained above and mixing evenly, and finally adding magnesium stearate, mixing evenly, and tableting to obtain tablet cores;

[0067] (3) mixing cellulose acetate, PEG400 and acetone to obtain a cellulose acetate-PEG400 acetone solution, and then coating the tablet cores until the tablet cores gain 8% in weight;

[0068] (4) Use laser or mechanical punching to punch a small hole with a diameter of 0.8 mm on one side of the coating.

[0069] Example 4

[0070] An osmotic pump drug release system based on finerenone solid dispersion:

[0071] The tablet core comprises 20 g of finerenone, 80 g of HPMCAS, 40 g of citric acid, 1 g of magnesium stearate, 2.5 g of BHT and 56.50 g of lactose monohydrate; the semipermeable membrane coating solution comprises 28 g of cellulose acetate, 4 g of PEG and 2000 mL of acetone.

[0072] The preparation method is as follows:

[0073] (1) Finerenone, BHT and HPMCAS were passed through a 60-mesh sieve three times and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then added to a ball mill and ground until the average particle size was less than 20 μm to obtain a finerenone co-ground mixture. The melting point of finerenone was 235-238° C. The temperature of the melting zone of the twin-screw extruder was set to 245° C. After the temperature reached the set value, the screw was started, and the finerenone co-ground mixture was slowly added to the extruder. After melting and extrusion, it was finally extruded in the form of strips. After the strip extrudate was cooled, it was crushed again and passed through a 60-mesh sieve to obtain a finerenone solid dispersion.

[0074] (2) adding citric acid and lactose monohydrate to the finerenone solid dispersion obtained above and mixing evenly, and finally adding magnesium stearate, mixing evenly, and tableting to obtain tablet cores;

[0075] (3) mixing cellulose acetate, PEG400 and acetone to obtain a cellulose acetate-PEG400 acetone solution, and then coating the tablet cores until the tablet cores gain 8% in weight;

[0076] (4) Use laser or mechanical punching to punch a small hole with a diameter of 0.8 mm on one side of the coating.

[0077] Test Example 1 (one)

[0079] Based on Examples 1-4, Mastersizer 2000 Malvern laser particle size analyzer was used to perform particle size analysis on the prepared finerenone solid dispersion by dry method.

[0080] Table 1 Particle size of phenerenone solid dispersion in Examples 1-4

[0081]

[0082]

[0083] As can be seen from Table 1, as the proportion of HPMCAS increases, the particle size of the finerenone solid dispersion shows an increasing trend, especially the change in the D90 particle size is the most significant. HPMCAS is a polymer material with a relatively high viscosity. When added to a solid dispersion formulation, it may significantly increase the viscosity of the mixture. The increased viscosity will produce the following effects during the grinding process: particle aggregation. High-viscosity HPMCAS may cause aggregation between particles, especially during grinding and extrusion. The particles are more likely to aggregate together due to the high-viscosity medium, resulting in an increase in particle size; grinding difficulties. The increased viscosity will make it more difficult for the particles to be effectively dispersed during the grinding process, resulting in the formation of large particles. (two)

[0085] The release rate was measured based on the osmotic pump drug release system prepared in Examples 1-4.

[0086] The first method of release determination in the 2020 edition of the Chinese Pharmacopoeia was adopted, with 900 mL of degassed purified water as the release medium, a rotation speed of 75 revolutions per minute, and samples were taken at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours, the ultraviolet absorption values ​​were determined, and the cumulative release was calculated.

[0087] Table 2 In vitro release test results of the osmotic pump drug release system described in Examples 1-4

[0088]

[0089] As can be seen from Table 2, the drug release rate of Example 1 is the fastest, and complete release is achieved within 24 hours. As the amount of HPMCAS increases, the dissolution rate of the drug gradually slows down, which reflects that the higher concentration of HPMCAS increases the permeation resistance and the thickness of the gel layer, thereby slowing down the release rate of the drug. In terms of drug release rate, the optimal dosage is Example 2, and the dissolution platform is the highest.

[0090] In summary, it can be seen that the technical solution of the present invention effectively solves the challenges of finerenone in solubility, stability and bioavailability by adopting the finerenone solid dispersion prepared by hot melt extrusion technology and the osmotic pump drug release system based on the finerenone solid dispersion, and provides a more effective and safe treatment solution for clinical practice, which has important practical value and broad market prospects.

[0091] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An osmotic pump drug release system based on finerenone solid dispersion, characterized in that: It consists of a tablet core and a semipermeable membrane coating liquid, wherein the weight of the semipermeable membrane coating liquid accounts for 5%-9% of the weight of the tablet core; The tablet core comprises the following raw materials in parts by weight: 1-25 parts of phenerenone, 20-90 parts of hydroxypropyl methylcellulose acetate succinate, 1-5 parts of 2,6-di-tert-butyl-p-cresol, 20-50 parts of citric acid, 0.5-1.5 parts of magnesium stearate and 55-116.5 parts of lactose monohydrate.

2. The osmotic pump drug release system according to claim 1, characterized in that: The components of the semipermeable membrane coating solution include cellulose acetate, PEG and acetone, and the mass volume ratio of the cellulose acetate, PEG and acetone is (30-50) g: (1-10) g: (18000-5000) mL.

3. The osmotic pump drug release system according to claim 2, characterized in that: The PEG includes PEG400 or PEG600.

4. The method for preparing the osmotic pump drug release system according to any one of claims 1 to 3, characterized in that: The steps include: (1) finerenone, hydroxypropyl methylcellulose acetate succinate and 2,6-di-tert-butyl-p-cresol are mixed, melted, extruded, and then frozen and crushed to obtain a solid dispersion; (2) mixing the solid dispersion with citric acid, lactose monohydrate, and magnesium stearate and then tableting to obtain a tablet core; (3) The tablet core is coated with a semipermeable membrane coating solution obtained by mixing cellulose acetate, PEG and acetone, and holes are punched on the side of the coating to obtain an osmotic pump drug release system.

5. The preparation method according to claim 4, characterized in that: Step (1) further comprises a pulverization process after the mixing, wherein the pulverization process is performed to a mean particle size of less than 20 μm; The mixing time is 20-30 minutes.

6. The preparation method according to claim 4, characterized in that: The melting temperature in step (1) is 240-250°C.

7. The preparation method according to claim 4, characterized in that: After the pulverization in step (1), the product is passed through a sieve having a mesh size of 50-70 meshes.

8. The preparation method according to claim 4, characterized in that: The diameter of the holes punched in step (3) is 0.7-0.85 mm.

9. Use of the osmotic pump drug release system according to any one of claims 1 to 3 or the osmotic pump drug release system prepared by the preparation method according to claim 4 in the preparation of relevant pharmaceutical preparations for treating chronic kidney disease combined with type 2 diabetes.

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