Medicinal preparation for delaying development of diabetic nephropathy and preparation method thereof

Abstract

The invention provides a pharmaceutical preparation for delaying the progress of diabetic nephropathy and a preparation method thereof, and belongs to the field of pharmaceutical preparations, the stability of the pharmaceutical preparation and the stability of drug release are improved by optimizing the preparation process and adding a sustained-release carrier, and the pharmaceutical preparation is mainly composed of an SGLT-2 inhibitor and a plurality of sustained-release carrier materials. The pharmaceutical preparation is prepared through the steps of wet granulation, drying, tabletting, enveloping and the like, can continuously release the medicine for a long time, avoids side effects caused by taking a large dose of medicine once, can maintain stable concentration of the medicine in blood, has good stability, and can be used for preparing a sustained-release preparation under proper storage conditions. And the drug can maintain low degradation rate and failure risk in the long-term storage and transportation process.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof. Background Art

[0002] Diabetic nephropathy is a common complication of diabetes that severely impacts renal function and, if left untreated, can lead to end-stage renal disease. Existing therapeutic drugs have unstable release rates, which can lead to fluctuations in efficacy, affecting treatment outcomes and reducing patient compliance. Therefore, developing formulations that can stably release drugs is crucial for improving therapeutic efficacy, minimizing side effects, and enhancing patient compliance.

[0003] Sustained-release preparations control the drug release rate through specific sustained-release carriers, maintaining stable blood drug concentrations, reducing drug fluctuations, significantly improving patient compliance, and reducing medication frequency. Furthermore, sustained-release preparations typically offer excellent drug stability, facilitating long-term storage. Therefore, using sustained-release preparations to delay the progression of diabetic nephropathy not only improves drug efficacy stability but also enhances the patient's treatment experience. Summary of the Invention

[0004] A pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof, comprising the following specific steps:

[0005] A pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof, wherein the raw materials comprise, by weight, 40 parts of an SGLT-2 inhibitor, 10 parts of polyvinyl alcohol (PVA), 10 parts of hydroxypropyl methylcellulose (HPMC), 5 parts of polyacrylic acid, 3 parts of silicon dioxide, 5 parts of cross-linked sodium carboxymethyl starch (CCS), 2 parts of magnesium stearate, and 40 parts of microcrystalline cellulose;

[0006] The polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) and polyacrylic acid constitute a sustained-release carrier.

[0007] A preparation process of a pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof: The steps are as follows:

[0008] S1. Dissolving polyvinyl alcohol (PVA): Weigh 5% to 15% polyvinyl alcohol (PVA) and add it to an appropriate amount of solvent, which can be water or an alcohol-water solution; start the heating equipment under heating and stirring conditions and heat the solution to 70-80°C; continue stirring until the PVA is completely dissolved to obtain a transparent solution;

[0009] S2. Dissolving Hydroxypropyl Methylcellulose (HPMC) and Polyacrylic Acid: Weigh 5% to 15% concentration of polyvinyl alcohol (PVA) and add it to an appropriate amount of solvent, which can be a deionized water solution; start the heating equipment under heating and stirring conditions and heat the solution to 70-80°C; continue stirring until the PVA is completely dissolved to obtain a transparent solution;

[0010] S3. Mixing drug powder with sustained-release carrier solution: Add the crushed and screened SGLT-2 inhibitor drug powder to the prepared PVA solution, HPMC solution, and polyacrylic acid solution, and stir thoroughly using a stirring device;

[0011] S4. Add stabilizer and disintegrant: Add appropriate amount of silicon dioxide (as stabilizer) and cross-linked sodium carboxymethyl starch (as disintegrant) to the mixture of drug and sustained-release carrier, and continue stirring;

[0012] S5. Start the wet granulation equipment and gradually add an appropriate amount of solvent (ethanol) to wet the drug and excipient mixture and form granules; adjust the amount of solvent added to ensure the wettability and uniformity of the granules; monitor the size of the granules to ensure that the granule size is within the range of 20-100 mesh;

[0013] S6. Granule drying: The wet granules are fed into a fluidized bed dryer or vacuum drying oven; the temperature of the drying equipment is set to 50-60°C and the drying process is started to ensure uniformity and complete drying of the granules during the drying process and to remove excess solvent;

[0014] S7. Adding lubricant and filler: Transfer the dried granules to a mixing container, add appropriate amounts of magnesium stearate (lubricant) and microcrystalline cellulose (filler), and mix thoroughly.

[0015] S8, tableting and film coating: The uniformly mixed granules are fed into the tablet press; the pressure and speed of the tablet press are adjusted to ensure that the hardness and disintegration of the tablets meet the requirements; the film coating technology is used to select the appropriate film material (HPMC film) to cover the tablets to control the release rate of the drug; the film thickness is adjusted to ensure that the film layer thickness is between 20-40 μm;

[0016] In step S3, the amount of drug powder (SGLT-2 inhibitor) added is 20% of the total amount of the drug, and the drug powder is added to the dissolved PVA solution, HPMC solution and polyacrylic acid solution, and the stirring time is 30 minutes to ensure uniform distribution of the drug;

[0017] In step S8, the membrane material used is HPMC membrane with a thickness of 20-40 μm to effectively control the release rate of the drug. The membrane is formed by solution coating technology, and the coated membrane evenly covers the surface of the tablet.

[0018] Furthermore, in step S3, the amount of drug powder (SGLT-2 inhibitor) added is 20% of the total amount of the drug, and the drug powder is added to the dissolved PVA solution, HPMC solution and polyacrylic acid solution, and the stirring time is 30 minutes to ensure uniform distribution of the drug.

[0019] Furthermore, in step S4, the amount of silicon dioxide added as a stabilizer is 1%, and the amount of cross-linked carboxymethyl starch sodium added as a disintegrant is 2%. Both are evenly added to the drug mixture and stirred for 15 minutes to ensure that the stabilizer and disintegrant are completely dispersed.

[0020] Furthermore, in step S5, the amount of solvent (ethanol) added during the wet granulation process is 15% of the total amount of the drug mixture. Ethanol is gradually added to the drug mixture through the granulation equipment to wet and form granules. The particle size is controlled between 20-100 mesh, and the granulation time is 30 minutes.

[0021] Furthermore, in step S6, the drying temperature is set to 55° C., and the wet granules are dried in the fluidized bed dryer for 45 minutes to ensure that the granules are completely dried and excess solvent is removed. The moisture content of the granules after drying does not exceed 5%.

[0022] Furthermore, in step S7, the amount of lubricant magnesium stearate added is 1.5%, and the amount of filler microcrystalline cellulose added is 15%. After the two are evenly mixed, stirring is continued for 15 minutes to ensure that the lubricant and filler are completely combined with the particles.

[0023] Furthermore, in step S8, the tablet pressing machine pressure used during tableting is 10-12 kN, the speed is 10-20 tablets / minute, the tablet hardness after tableting is 8-10 kN, the disintegration degree reaches more than 50% within 30 minutes, and the tablet surface is film-coated, and the film thickness is controlled at 25 μm.

[0024] Furthermore, each step from step S1 to step S8 is carried out in a clean room, and aseptic operation is adopted throughout the process to ensure that the sterility and quality of the final preparation meet the pharmaceutical standards.

[0025] Compared with the existing technology, this invention has the following significant advantages:

[0026] By optimizing the preparation process and adding a sustained-release carrier, the present invention provides the following advantages: Smooth drug release: Sustained-release formulations can continuously release the drug over an extended period, avoiding the side effects of a single, large dose. This smooth release mechanism maintains a stable drug concentration in the blood, effectively controlling the progression of diabetic nephropathy. Good stability: Sustained-release formulations typically maintain stability for extended periods under appropriate storage conditions, making them less susceptible to drug degradation or loss of efficacy during long-term storage and transportation. DETAILED DESCRIPTION

[0027] The subject matter described herein will now be discussed with reference to example embodiments. It should be understood that the discussion of these embodiments is intended only to enable those skilled in the art to better understand and implement the subject matter described herein, and is not intended to limit the scope of protection, applicability, or examples set forth in the claims. The functions and arrangements of the elements discussed may be changed without departing from the scope of protection of the present specification. Various examples may omit, replace, or add various processes or components as needed. For example, the described methods may be performed in an order different from that described, and various steps may be added, omitted, or combined. In addition, features described relative to some examples may also be combined in other examples.

[0028] As used herein, the term "including" and its variations are open terms meaning "including but not limited to". The term "based on" means "based at least in part on". The terms "one embodiment" and "an embodiment" mean "at least one embodiment". The term "another embodiment" means "at least one other embodiment". The terms "first", "second", etc. may refer to different or the same objects. Other definitions may be included below, whether explicit or implicit. Unless the context clearly indicates otherwise, the definition of a term is consistent throughout the specification.

[0029] Example

[0030] A pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof, wherein the raw materials comprise, by weight, 40 parts of an SGLT-2 inhibitor, 10 parts of polyvinyl alcohol (PVA), 10 parts of hydroxypropyl methylcellulose (HPMC), 5 parts of polyacrylic acid, 3 parts of silicon dioxide, 5 parts of cross-linked sodium carboxymethyl starch (CCS), 2 parts of magnesium stearate, and 40 parts of microcrystalline cellulose;

[0031] The polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) and polyacrylic acid constitute a sustained-release carrier.

[0032] A preparation process of a pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof, comprising the following steps: S1, dissolving polyvinyl alcohol (PVA): weighing polyvinyl alcohol (PVA) at a concentration of 5% to 15% and adding it to an appropriate amount of solvent, which may be water or an alcohol-water solution; starting a heating device under heating and stirring conditions to heat the solution to 70-80°C; continuing stirring until the PVA is completely dissolved to obtain a transparent solution;

[0033] S2. Dissolving Hydroxypropyl Methylcellulose (HPMC) and Polyacrylic Acid: Weigh 5% to 15% concentration of polyvinyl alcohol (PVA) and add it to an appropriate amount of solvent, which can be a deionized water solution; start the heating equipment under heating and stirring conditions and heat the solution to 70-80°C; continue stirring until the PVA is completely dissolved to obtain a transparent solution;

[0034] S3. Mixing drug powder with sustained-release carrier solution: Add the crushed and screened SGLT-2 inhibitor drug powder to the prepared PVA solution, HPMC solution, and polyacrylic acid solution, and stir thoroughly using a stirring device;

[0035] S4. Add stabilizer and disintegrant: Add appropriate amount of silicon dioxide (as stabilizer) and cross-linked sodium carboxymethyl starch (as disintegrant) to the mixture of drug and sustained-release carrier, and continue stirring;

[0036] S5. Start the wet granulation equipment and gradually add an appropriate amount of solvent (ethanol) to wet the drug and excipient mixture and form granules; adjust the amount of solvent added to ensure the wettability and uniformity of the granules; monitor the size of the granules to ensure that the granule size is within the range of 20-100 mesh;

[0037] S6. Granule drying: The wet granules are fed into a fluidized bed dryer or vacuum drying oven; the temperature of the drying equipment is set to 50-60°C and the drying process is started to ensure uniformity and complete drying of the granules during the drying process and to remove excess solvent;

[0038] S7. Adding lubricant and filler: Transfer the dried granules to a mixing container, add appropriate amounts of magnesium stearate (lubricant) and microcrystalline cellulose (filler), and mix thoroughly.

[0039] S8, tableting and film coating: The uniformly mixed granules are fed into the tablet press; the pressure and speed of the tablet press are adjusted to ensure that the hardness and disintegration of the tablets meet the requirements; the film coating technology is used to select the appropriate film material (HPMC film) to cover the tablets to control the release rate of the drug; the film thickness is adjusted to ensure that the film layer thickness is between 20-40 μm;

[0040] In step S3, the amount of drug powder (SGLT-2 inhibitor) added is 20% of the total amount of the drug, and the drug powder is added to the dissolved PVA solution, HPMC solution and polyacrylic acid solution, and the stirring time is 30 minutes to ensure uniform distribution of the drug;

[0041] In step S8, the membrane material used is HPMC membrane with a thickness of 20-40 μm to effectively control the release rate of the drug. The membrane is formed by solution coating technology, and the coated membrane evenly covers the surface of the tablet.

[0042] Furthermore, in step S3, the amount of drug powder (SGLT-2 inhibitor) added is 20% of the total amount of the drug, and the drug powder is added to the dissolved PVA solution, HPMC solution and polyacrylic acid solution, and the stirring time is 30 minutes to ensure uniform distribution of the drug.

[0043] Furthermore, in step S4, the amount of silicon dioxide added as a stabilizer is 1%, and the amount of cross-linked carboxymethyl starch sodium added as a disintegrant is 2%. Both are evenly added to the drug mixture and stirred for 15 minutes to ensure that the stabilizer and disintegrant are completely dispersed.

[0044] Furthermore, in step S5, the amount of solvent (ethanol) added during the wet granulation process is 15% of the total amount of the drug mixture. Ethanol is gradually added to the drug mixture through the granulation equipment to wet and form granules. The particle size is controlled between 20-100 mesh, and the granulation time is 30 minutes.

[0045] Furthermore, in step S6, the drying temperature is set to 55° C., and the wet granules are dried in the fluidized bed dryer for 45 minutes to ensure that the granules are completely dried and excess solvent is removed. The moisture content of the granules after drying does not exceed 5%.

[0046] Furthermore, in step S7, the amount of lubricant magnesium stearate added is 1.5%, and the amount of filler microcrystalline cellulose added is 15%. After the two are evenly mixed, stirring is continued for 15 minutes to ensure that the lubricant and filler are completely combined with the particles.

[0047] Furthermore, in step S8, the tablet pressing machine pressure used during tableting is 10-12 kN, the speed is 10-20 tablets / minute, the tablet hardness after tableting is 8-10 kN, the disintegration degree reaches more than 50% within 30 minutes, and the tablet surface is film-coated, and the film thickness is controlled at 25 μm.

[0048] Furthermore, each step from step S1 to step S8 is carried out in a clean room, and aseptic operation is adopted throughout the process to ensure that the sterility and quality of the final preparation meet the pharmaceutical standards.

[0049] Step S1: Dissolution of polyvinyl alcohol (PVA)

[0050] The operation is carried out in a clean workshop. First, take polyvinyl alcohol (PVA) with a concentration of 5% to 15%, and add an appropriate amount of solvent after precise weighing. The commonly used solvent is deionized water or alcohol-water solution. Then, place the container on a heating and stirring device, start the heating device, heat the solution to 70-80°C, and maintain a constant temperature. During this period, turn on the stirring device to ensure that the PVA and the solvent are evenly mixed. Continue stirring until the PVA is completely dissolved to form a transparent solution. This dissolution process needs to last 30 to 45 minutes to ensure that the PVA is completely dissolved and no particles remain. The PVA solution will serve as the basis for the sustained-release carrier, providing good drug release control.

[0051] Required equipment: heating and stirring equipment, temperature control device, stirring device Operating conditions: temperature 70-80℃, medium stirring speed, time 30-45 minutes Purpose: Ensure that PVA is completely dissolved and provide a stable sustained-release carrier basis.

[0052] Step S2: Dissolution of Hydroxypropyl Methylcellulose (HPMC) and Polyacrylic Acid

[0053] Take appropriate amounts of hydroxypropyl methylcellulose (HPMC) and polyacrylic acid, mix them with deionized water at concentrations of 5% to 15%, and add the solvent after accurate weighing. Next, heat the mixed solution to 70-80°C and stir continuously to ensure that the HPMC and polyacrylic acid are completely dissolved to form a uniform, transparent solution. This dissolution process also takes a certain amount of time, usually 30 to 40 minutes, until the solution is uniform and free of suspended particles. The key to this step is to ensure the transparency and uniformity of the solution, providing a suitable drug carrier for subsequent steps.

[0054] Required equipment: heating and stirring equipment, temperature control device, stirring device Operating conditions: temperature 70-80℃, medium stirring speed, time 30-40 minutes Purpose: To form a uniform, transparent HPMC and polyacrylic acid solution as a carrier for sustained drug release.

[0055] Step S3: Mixing drug powder with sustained-release carrier solution

[0056] SGLT-2 inhibitor drug powder is weighed to 20% of the total drug weight and added to the prepared PVA solution, HPMC solution, and polyacrylic acid solution. High-speed stirring equipment is used to mix the drug with the solution, ensuring that the drug powder is completely dissolved and evenly dispersed in the sustained-release carrier solution. The stirring time is typically 30 minutes to ensure uniform distribution of the drug and prevent the formation of clumps. This step aims to ensure uniform drug distribution, improve drug bioavailability, and stabilize controlled release.

[0057] Equipment required: high-speed blender, mixing container

[0058] Operating conditions: high stirring speed, time 30 minutes Purpose: to ensure that the drug powder is evenly distributed in the sustained-release carrier solution to provide uniform drug loading for subsequent granulation.

[0059] Step S4: Adding stabilizers and disintegrants

[0060] Add an appropriate amount of silicon dioxide (1%) as a stabilizer and cross-linked sodium carboxymethyl starch (2%) as a disintegrant to the mixture after step S3. Silicon dioxide can enhance the stability of the preparation and prevent the drug powder from agglomerating or changing its physical properties during storage; cross-linked sodium carboxymethyl starch acts as a disintegrant to help the drug be released quickly in the body. After addition, continue stirring for 15 minutes using a stirring device to ensure that the stabilizer and disintegrant are completely dispersed and evenly mixed. The purpose of this process is to improve the long-term stability of the drug preparation and better control the disintegration of the drug.

[0061] Equipment needed: Blender

[0062] Operating conditions: Stirring time 15 minutes, maintain uniform mixing Purpose: Ensure uniform distribution of stabilizer and disintegrant, improve the stability and disintegration performance of the preparation.

[0063] Step S5: Wet granulation

[0064] In the wet granulation equipment, an appropriate amount of solvent (ethanol, 15% of the total drug mixture) is gradually added to wet the drug and excipient mixture and form granules. The addition of ethanol must be uniform and gradual to ensure the granules are moderately wet. The particle size should be controlled between 20-100 mesh. The granulation time is controlled to 30 minutes, during which the granule size and wettability are regularly checked to ensure uniform granulation and suitability for subsequent drying. The purpose of this process is to improve the drug's flowability and tableting properties through granulation.

[0065] Required equipment: wet granulation equipment

[0066] Operating conditions: 15% ethanol addition, 30 minutes granulation time Purpose: To ensure uniform granulation and suitability for subsequent drying, and to ensure granule wettability and uniformity.

[0067] Step S6: Particle drying

[0068] Transfer the wet granules to a fluidized bed dryer or vacuum drying oven for drying. Set the drying temperature to 55°C and continue drying for 45 minutes to ensure uniform drying of the granules and remove excess solvent. During the drying process, check the moisture content of the granules regularly to ensure that the moisture content does not exceed 5%. If the moisture content of the granules exceeds the standard, continue drying. The purpose of this step is to ensure that the granules are completely dried to prevent excessive moisture from affecting the stability of the granules and the quality of subsequent tableting.

[0069] Required equipment: fluidized bed dryer or vacuum drying oven

[0070] Operating conditions: drying temperature 55°C, drying time 45 minutes Purpose: to remove excess solvent from the particles and ensure that the moisture content of the particles does not exceed 5%.

[0071] Step S7: Adding lubricant and filler

[0072] Transfer the dried granules to a mixing container and add magnesium stearate (1.5%) as a lubricant and microcrystalline cellulose (15%) as a filler. Use a mixing device to stir evenly for 15 minutes to ensure that the lubricant and filler are completely combined with the granules. Magnesium stearate can improve the fluidity of the granules, and microcrystalline cellulose as a filler can improve the tableting properties of the granules and ensure a smooth subsequent tableting process. The mixing process requires controlling the time and stirring speed to ensure that the lubricant and filler are evenly distributed in each granule.

[0073] Equipment required: Mixer

[0074] Operating conditions: Mixing time 15 minutes, uniform mixing

[0075] Purpose: To improve the fluidity and tableting properties of granules and ensure tablet quality.

[0076] Step S8: Tableting and film coating

[0077] The evenly mixed granules are fed into the tablet press. The press pressure is adjusted to 10-12 kN, and the tablet production rate is set to 10-20 tablets / minute. During the tableting process, the tablets must maintain a hardness of 8-10 kN and a disintegration rate of at least 50% within 30 minutes. Next, the tablets are coated using a film coating technique using HPMC film material with a thickness of 25 μm. The film layer is evenly applied to the tablet surface using a solution coating technique to ensure a controlled drug release rate. The uniformity of the film layer is crucial for the sustained release of the drug.

[0078] Required equipment: tablet press, film coating equipment Operating conditions: tablet press pressure 10-12kN, film thickness controlled at 25μm, uniform film after coating Purpose: Ensure tablet hardness, disintegration and film uniformity to ensure smooth drug release.

[0079] Full operating environment and conditions

[0080] The entire preparation process must be conducted in a cleanroom to ensure the sterility of the drug. All equipment, instruments, and operating procedures must comply with GMP (Good Manufacturing Practice) requirements. To ensure the quality of the drug product, all operations must strictly control temperature, humidity, time, and other conditions, especially during dissolution, granulation, and drying.

[0081] Experimental performance test:

[0082] Purpose of the experiment

[0083] Verify whether the sustained-release pharmaceutical preparation of the present invention can achieve smooth drug release, long-term stability, improved efficacy and good safety, ensure that it can effectively treat diabetic nephropathy and is suitable for long-term storage and transportation.

[0084] Experimental Materials

[0085] Pharmaceutical preparations: sustained-release pharmaceutical preparations of the present invention and immediate-release pharmaceutical preparations of the control group

[0086] Experimental animals: Male SPF rats (200-250g)

[0087] Reagents and equipment:

[0088] Streptozotocin (STZ, Sigma)

[0089] Simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8)

[0090] Drug release experimental equipment (centrifuge, spectrophotometer, etc.)

[0091] Drug content determination kits (such as HPLC analysis systems)

[0092] Weight scale, blood glucose meter, blood pressure monitor, etc.

[0093] Activity monitoring systems, histology sections, and staining reagents

[0094] Experimental subjects

[0095] Experimental animals: Male SPF rats, weighing 200-250 g, were randomly divided into 4 groups, with 6 rats in each group:

[0096] Normal group: healthy rats that did not receive any drug treatment

[0097] Diabetes control group: STZ injection to establish diabetes model, no drug treatment

[0098] Diabetes immediate-release drug group: diabetic rats, given immediate-release drug treatment

[0099] Diabetes sustained-release drug group: diabetic rats, given sustained-release drug treatment

[0100] Experimental cycle

[0101] Drug release experiment: 24 hours

[0102] Stability test: 6 months (sampling every month)

[0103] Efficacy evaluation experiment: 4 weeks

[0104] Side effect observation: 4 weeks, combined with efficacy evaluation

[0105] Experimental process

[0106] 1. Drug Release Experiment

[0107] Objective: To evaluate the release characteristics of sustained-release drugs and verify whether they can release drugs smoothly and continuously.

[0108] step:

[0109] Samples of sustained-release drug preparations and immediate-release drug preparations were added to simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8), respectively.

[0110] Set time points (1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours) and take samples for analysis at each time point.

[0111] The drug concentration in the sample was determined using high performance liquid chromatography (HPLC) or a spectrophotometer.

[0112] Calculate the drug release amount, draw the drug release curve, and use the Higuchi model or Korsmeyer-Peppas model to analyze the release mechanism.

[0113] Experimental results show that sustained-release drug formulations should exhibit a smooth, sustained drug release profile, with approximately 90% of the drug released within 24 hours, without any sharp peaks. The drug release rate should be lower than that of immediate-release drugs, ensuring a steady release of efficacy.

[0114] 2. Stability test

[0115] Objective: To evaluate the stability of sustained-release drug formulations under different storage conditions and ensure their quality during long-term storage and transportation.

[0116] step:

[0117] The sustained-release drug preparations were divided into three groups and stored at room temperature (25°C), accelerated conditions (40°C, 75% RH) and refrigerated conditions (4°C), respectively.

[0118] Samples are taken once a month for appearance inspection (color, solubility), drug content determination, and drug release experiments.

[0119] Use appropriate stability testing methods to evaluate the degradation rate, release characteristics and physicochemical properties of the drug under different conditions.

[0120] Experimental results: Under storage conditions, the drug degradation rate was less than 10%, and the drug release characteristics did not change significantly. Stability testing showed that the drug could maintain stability for a long time, making it suitable for long-term storage and transportation.

[0121] 3. In vivo efficacy evaluation experiment

[0122] Objective: To evaluate the therapeutic effects of extended-release drug formulations on diabetic nephropathy, particularly their effects on improving glycemic control, renal function, and renal damage.

[0123] step:

[0124] The diabetic rat model was established by streptozotocin (STZ) injection.

[0125] The rats were randomly divided into four groups (6 rats in each group): normal group, diabetic control group, immediate-release drug group, and sustained-release drug group.

[0126] Starting from the first day after modeling, oral medication was administered for 4 weeks.

[0127] Measure blood sugar levels, record weight changes, and monitor renal function indicators (urine protein, blood creatinine, urea nitrogen, etc.) every week.

[0128] After the end, histological examination (kidney sections) was performed and the levels of inflammatory factors (IL-6, TNF-α) were detected.

[0129] Experimental results:

[0130] Compared with the diabetic control group, the blood sugar level in the sustained-release drug group was significantly reduced and remained stable.

[0131] The renal function indicators (urine protein, blood creatinine, and urea nitrogen) in the sustained-release drug group were significantly lower than those in the diabetic control group and close to the levels of the normal group.

[0132] Histological examination showed that renal damage in the sustained-release drug group was significantly alleviated and the levels of inflammatory response (IL-6, TNF-α) were reduced.

[0133] 4. Side effect observation

[0134] Objective: To evaluate the safety of sustained-release drug preparations and observe changes in body weight, behavior, heart rate, blood pressure, and physiological indicators in animals during drug treatment.

[0135] Procedure: During the efficacy evaluation experiment, observe and record the animal's weight changes, behavior (e.g., activity level, lethargy), and physiological parameters (e.g., heart rate, blood pressure). Conduct regular biochemical tests to assess liver and kidney function, blood lipids, and other physiological parameters, and observe potential drug toxicity. Record any side effects, including loss of appetite, weight fluctuations, and significant adverse reactions.

[0136] Experimental results: The animals' weight remained stable, with no significant changes. They exhibited no abnormal behaviors such as lethargy or decreased activity. Physiological indicators (such as heart rate, blood pressure, and liver and kidney function) remained normal, with no evidence of drug-induced toxicity. The drug demonstrated a high safety profile with no significant side effects.

[0137] Experimental results analysis

[0138] Statistical analysis of the experimental results yielded the following conclusions: Drug release experiments revealed a smooth release curve for the sustained-release formulation, with the drug release rate meeting expectations and avoiding adverse reactions associated with a single, high-dose dose. Compared to immediate-release formulations, sustained-release formulations exhibited superior release characteristics, maintaining a stable drug concentration in the blood.

[0139] Stability testing: Under various storage conditions, the sustained-release drug formulation maintained stability for extended periods, with a drug degradation rate below 10%. The drug showed no significant degradation during long-term storage, ensuring stable quality during transportation and storage.

[0140] Efficacy evaluation experiments: The sustained-release drug formulation significantly improved blood glucose levels in diabetic rats and slowed the progression of diabetic nephropathy. Renal function indicators (such as urine protein and serum creatinine) significantly improved, approaching those of the normal control group, demonstrating the drug's significant therapeutic effect. Histological examinations and inflammatory cytokine detection revealed that the sustained-release drug group showed reduced kidney damage and a lessened inflammatory response.

[0141] Side Effects: The animals' body weight and physiological indicators remained normal, with no significant side effects. The drug was highly safe in rats, with no serious adverse reactions.

[0142] Those skilled in the art will appreciate that the various embodiments disclosed above may be modified and altered without departing from the essence of the invention. Therefore, the scope of protection of the present invention shall be defined by the appended claims.

[0143] It should be noted that not all steps and units in the above processes are required, and certain steps or units can be omitted according to actual needs. The execution order of each step is not fixed and can be determined as needed. The device structure described in the above embodiments can be a physical structure or a logical structure, that is, some units may be implemented by the same physical entity, or some units may be implemented by multiple physical entities, or may be implemented by certain components in multiple independent devices.

[0144] The specific embodiments set forth above describe exemplary embodiments, but do not represent all embodiments that can be implemented or fall within the scope of protection of the claims. The term "exemplary" used throughout this specification means "used as an example, instance, or illustration" and does not mean "preferred" or "having advantages" over other embodiments. For the purpose of providing an understanding of the described technology, the specific embodiments include specific details. However, these technologies can be implemented without these specific details. In some instances, in order to avoid obscuring the concepts of the described embodiments, well-known structures and devices are shown in block diagram form.

[0145] The foregoing description of the present disclosure is provided to enable any person skilled in the art to implement or use the present disclosure. Various modifications to the present disclosure will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other variations without departing from the scope of the present disclosure. Therefore, the present disclosure is not limited to the examples and designs described herein, but is intended to be consistent with the widest range of principles and novel features disclosed herein.

Claims

1. A pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof, characterized in that: The raw materials include, by weight: 40 parts of SGLT-2 inhibitor, 10 parts of polyvinyl alcohol (PVA), 10 parts of hydroxypropyl methylcellulose (HPMC), 5 parts of polyacrylic acid, 3 parts of silicon dioxide, 5 parts of cross-linked sodium carboxymethyl starch (CCS), 2 parts of magnesium stearate and 40 parts of microcrystalline cellulose; The polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) and polyacrylic acid constitute a sustained-release carrier.

2. The preparation process of the pharmaceutical preparation for delaying the progression of diabetic nephropathy and the preparation method thereof according to claim 1, characterized in that: The steps are as follows: S1. Dissolving polyvinyl alcohol (PVA): Weigh 5% to 15% polyvinyl alcohol (PVA) and add it to an appropriate amount of solvent, which can be water or an alcohol-water solution; start the heating equipment under heating and stirring conditions and heat the solution to 70-80°C; continue stirring until the PVA is completely dissolved to obtain a transparent solution; S2. Dissolving Hydroxypropyl Methylcellulose (HPMC) and Polyacrylic Acid: Weigh 5% to 15% concentration of polyvinyl alcohol (PVA) and add it to an appropriate amount of solvent, which can be a deionized water solution; start the heating equipment under heating and stirring conditions and heat the solution to 70-80°C; continue stirring until the PVA is completely dissolved to obtain a transparent solution; S3. Mixing drug powder with sustained-release carrier solution: Add the crushed and screened SGLT-2 inhibitor drug powder to the prepared PVA solution, HPMC solution, and polyacrylic acid solution, and stir thoroughly using a stirring device; S4. Add stabilizer and disintegrant: Add appropriate amount of silicon dioxide (as stabilizer) and cross-linked sodium carboxymethyl starch (as disintegrant) to the mixture of drug and sustained-release carrier, and continue stirring; S5. Start the wet granulation equipment and gradually add an appropriate amount of solvent (ethanol) to wet the drug and excipient mixture and form granules; adjust the amount of solvent added to ensure the wettability and uniformity of the granules; monitor the size of the granules to ensure that the granule size is within the range of 20-100 mesh; S6. Granule drying: The wet granules are fed into a fluidized bed dryer or vacuum drying oven; the temperature of the drying equipment is set to 50-60°C and the drying process is started to ensure uniformity and complete drying of the granules during the drying process and to remove excess solvent; S7. Adding lubricant and filler: Transfer the dried granules to a mixing container, add appropriate amounts of magnesium stearate (lubricant) and microcrystalline cellulose (filler), and mix thoroughly. S8, tableting and film coating: The uniformly mixed granules are fed into the tablet press; the pressure and speed of the tablet press are adjusted to ensure that the hardness and disintegration of the tablets meet the requirements; the film coating technology is used to select the appropriate film material (HPMC film) to cover the tablets to control the release rate of the drug; the film thickness is adjusted to ensure that the film layer thickness is between 20-40 μm; In step S3, the amount of drug powder (SGLT-2 inhibitor) added is 20% of the total amount of the drug, and the drug powder is added to the dissolved PVA solution, HPMC solution and polyacrylic acid solution, and the stirring time is 30 minutes to ensure uniform distribution of the drug; In step S8, the membrane material used is HPMC membrane with a thickness of 20-40 μm to effectively control the release rate of the drug. The membrane is formed by solution coating technology, and the coated membrane evenly covers the surface of the tablet.

3. A pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof according to claim 2, characterized in that: In step S3, the amount of drug powder (SGLT-2 inhibitor) added is 20% of the total amount of the drug, and the drug powder is added to the dissolved PVA solution, HPMC solution and polyacrylic acid solution, and the stirring time is 30 minutes.

4. A pharmaceutical preparation for delaying the progression of diabetic nephropathy and a preparation method thereof according to claim 2, characterized in that: In step S4, the amount of silicon dioxide added as a stabilizer is 1%, and the amount of cross-linked carboxymethyl starch sodium added as a disintegrant is 2%. Both are evenly added to the drug mixture and stirred for 15 minutes to ensure that the stabilizer and disintegrant are completely dispersed.

5. The pharmaceutical preparation for delaying the progression of diabetic nephropathy and the preparation method thereof according to claim 2, characterized in that: In step S5, the amount of solvent (ethanol) added during the wet granulation process is 15% of the total amount of the drug mixture. Ethanol is gradually added to the drug mixture through the granulation equipment to wet and form granules. The particle size is controlled between 20-100 meshes, and the granulation time is 30 minutes.

6. The pharmaceutical preparation for delaying the progression of diabetic nephropathy and the preparation method thereof according to claim 2, characterized in that: In step S6, the drying temperature is set to 55° C., and the wet granules are dried in the fluidized bed dryer for 45 minutes to ensure that the granules are completely dried and excess solvent is removed. The moisture content of the granules after drying does not exceed 5%.

7. The pharmaceutical preparation for delaying the progression of diabetic nephropathy and the preparation method thereof according to claim 2, characterized in that: In step S7, the amount of lubricant magnesium stearate added is 1.5%, and the amount of filler microcrystalline cellulose added is 15%. After the two are evenly mixed, stirring is continued for 15 minutes.

8. The pharmaceutical preparation for delaying the progression of diabetic nephropathy and the preparation method thereof according to claim 2, characterized in that: In step S8, the tablet press pressure used during tableting is 10-12 kN, the speed is 10-20 tablets / minute, the tablet hardness after tableting is 8-10 kN, the disintegration rate reaches more than 50% within 30 minutes, and the tablet surface is film-coated with a film thickness controlled at 25 μm.

9. The pharmaceutical preparation for delaying the progression of diabetic nephropathy and the preparation method thereof according to claim 2, characterized in that: Each step from step S1 to step S8 is carried out in a clean room, and aseptic operation is adopted throughout the process.