Gastroretentive sustained release microtablets of metformin hydrochloride and a process for the preparation thereof

Abstract

The application relates to the technical field of pharmaceutical preparation, and provides a metformin hydrochloride gastric floating sustained-release microtablet. The component composition of the metformin hydrochloride gastric floating sustained-release microtablet comprises, in percentage by weight, 50%-75% of metformin hydrochloride, 5%-20% of a skeleton material, 9%-18% of a filling agent, 2%-6% of a floating aid, 1%-4% of a lubricant and 1%-3% of a nano modifier. The metformin hydrochloride gastric floating sustained-release microtablet can prolong the residence time of metformin hydrochloride in the stomach and the upper part of the small intestine, and improve the drug utilization.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparation technology, and in particular to a metformin hydrochloride gastric floating sustained-release microtablet and its preparation method. Background Technology

[0002] Metformin hydrochloride is a biguanide oral hypoglycemic agent primarily used to treat type 2 diabetes. Its main mechanisms of action include inhibiting hepatic glucose output, increasing peripheral tissue glucose uptake and utilization, and reducing intestinal glucose absorption. The effective absorption site for metformin hydrochloride is the upper small intestine. The drug needs to remain in the stomach and upper small intestine for a sufficient period to ensure effective absorption and hypoglycemic efficacy. Summary of the Invention

[0003] In view of this, this application aims to provide a metformin hydrochloride gastric floating sustained-release microtablet, which can prolong the retention time of metformin hydrochloride in the stomach and upper small intestine, thereby improving drug utilization.

[0004] To achieve the above objectives, the technical solution of this application is implemented as follows:

[0005] A metformin hydrochloride gastric floating sustained-release microtablet, wherein the composition of the metformin hydrochloride gastric floating sustained-release microtablet, by weight percentage, comprises: 50%–75% metformin hydrochloride, 5%–20% matrix material, 9%–18% filler, 2%–6% buoyancy aid, 1%–4% lubricant, and 1%–3% nano-modifier.

[0006] Furthermore, the skeleton material is a mixture of konjac glucomannan and ethyl cellulose;

[0007] The filler is either microcrystalline cellulose or spray-dried lactose.

[0008] The bleaching aid is a mixture of sodium bicarbonate and citric acid;

[0009] The lubricant is any one or two of magnesium stearate or micronized silica gel.

[0010] The nano-modifier is a mixture of nano-silica and nano-montmorillonite.

[0011] Furthermore, in the mixture of konjac glucomannan and ethyl cellulose, the weight ratio of konjac glucomannan to ethyl cellulose is between 3:1 and 5:1.

[0012] Furthermore, in the mixture of sodium bicarbonate and citric acid, the weight ratio of sodium bicarbonate to citric acid is between 1:1 and 1:1.5.

[0013] Furthermore, in the mixture of nano-silica and nano-montmorillonite, the weight ratio of nano-silica to nano-montmorillonite is between 1:1 and 2:1.

[0014] Compared with related technologies, this application has the following advantages:

[0015] The metformin hydrochloride gastric floating sustained-release microtablets of this application improve the burst release problem of metformin hydrochloride by incorporating a matrix material. Simultaneously, the combination with a nano-modifier controls the slow diffusion and release of metformin hydrochloride, avoiding problems such as hygroscopicity, sticking, and decreased flowability of the metformin hydrochloride active pharmaceutical ingredient. Furthermore, by adding a buoyancy aid and rationally proportioning the components, the tablets achieve rapid buoyancy and long-lasting floating, thereby extending the drug's residence time in the stomach and upper small intestine and improving drug utilization.

[0016] This application also discloses a method for preparing metformin hydrochloride gastric floating sustained-release microtablets, the preparation method comprising:

[0017] Metformin hydrochloride, matrix material, filler, bleaching aid and lubricant were sieved separately;

[0018] The sieved metformin hydrochloride, the framework material, the filler, the bleaching agent, and the nano-modifier are mixed evenly to obtain a mixture.

[0019] The mixture is granulated and sized to obtain microparticles;

[0020] The microparticles are mixed evenly with the lubricant and then compressed into tablets to obtain the metformin hydrochloride gastric floating sustained-release microtablets.

[0021] Furthermore, the metformin hydrochloride is sieved through a 100-mesh sieve;

[0022] The skeleton material, filler, bleaching aid and lubricant are all sieved through an 80-mesh sieve.

[0023] Furthermore, the granulation temperature is between 30°C and 40°C.

[0024] Furthermore, the granulation process employs a 1.2mm-1.8mm sieve.

[0025] Furthermore, the hardness of the metformin hydrochloride gastric floating sustained-release microplate is between 10N and 60N.

[0026] The preparation method described in this application controls the particle size of each component through sieving and the synergistic effect of each step, thereby prolonging the retention time of the prepared metformin hydrochloride gastric floating sustained-release microtablets in the stomach and upper small intestine, and improving the drug utilization effect. Attached Figure Description

[0027] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments and descriptions of this application are used to explain this application and do not constitute an undue limitation of this application. In the drawings:

[0028] Figure 1 This is a flowchart illustrating the preparation method of metformin hydrochloride gastric floating sustained-release microtablets as described in the embodiments of this application. Detailed Implementation

[0029] To make the technical solution and advantages of this application clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0030] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other.

[0031] For items where specific conditions are not specified in this application, conventional conditions or conditions recommended by the manufacturer of the equipment used shall apply. For items where the manufacturer of the reagents or instruments used is not specified, conventional products purchased commercially shall be used. As for the technical means or processes involved, if specific conditions are not specified, they shall be carried out in accordance with the existing methods in the relevant field.

[0032] An embodiment of the first aspect of this application provides a metformin hydrochloride gastric floating sustained-release microparticle, which can prolong the residence time of the drug in the stomach and upper small intestine, thereby improving drug utilization.

[0033] In related technologies, metformin hydrochloride dosage forms are mainly immediate-release tablets and traditional extended-release tablets. Immediate-release tablets require frequent dosing, making it easy for elderly patients to miss doses. The drug concentration peak-trough effect is significant, affecting its hypoglycemic efficacy. Neither immediate-release nor traditional extended-release tablets can control the drug's retention location in the gastrointestinal tract; the drug remains in the stomach for only 1-2 hours and in the small intestine for 3-4 hours, making long-term absorption in the upper small intestine difficult and resulting in low bioavailability. Traditional extended-release tablets are also relatively large, causing swallowing difficulties for elderly diabetic patients.

[0034] In view of this, in order to overcome the shortcomings of the related technologies, the overall design of the metformin hydrochloride gastric floating sustained-release microtablet in this embodiment includes, by weight percentage: 50% to 75% metformin hydrochloride, 5% to 20% matrix material, 9% to 18% filler, 2% to 6% buoyancy aid, 1% to 4% lubricant and 1% to 3% nanomodifier.

[0035] The preferred skeleton material is, for example, a mixture of konjac glucomannan and ethyl cellulose.

[0036] Specifically, konjac glucomannan is a natural, super-hydrophilic polymeric gel material with exceptional gel-forming properties and resistance to dissolution. At extremely low concentrations, it rapidly hydrates and swells upon contact with gastric juices, forming a high-viscosity, high-strength, dense, and stable gel layer. Compared to traditional scaffold materials such as hydroxypropyl methylcellulose, the gel network structure formed by konjac glucomannan is more regular and compact, exhibiting strong resistance to gastric juice erosion and a slow and uniform dissolution rate. Metformin hydrochloride, on the other hand, is a highly water-soluble drug that readily dissolves and releases large amounts of drug rapidly upon contact with gastric juices. Conventional scaffold materials cannot effectively constrain drug molecule diffusion, ultimately leading to severe burst release, resulting in excessively high initial blood drug concentrations and rapid decline in efficacy later on.

[0037] The unique gel structure of konjac glucomannan can uniformly encapsulate and embed metformin hydrochloride drug molecules within a three-dimensional gel network. This effectively hinders the rapid diffusion of drug molecules into gastric juice, slows down the dissolution and release rate, and improves the technical challenges of sustained release and uneven drug release caused by the high water solubility of metformin hydrochloride. This ensures uniform and continuous drug release in the stomach, effectively and steadily controlling blood sugar levels and avoiding large fluctuations. It also reduces gastrointestinal irritation reactions such as nausea and bloating caused by sudden drug release. The compounded ethyl cellulose, a hydrophobic polymer, further optimizes the overall hydrophilic / hydrophobic ratio of the framework due to its water-insoluble properties. This adjusts the dissolution rate and porosity of the gel layer, overcoming the shortcomings of rapid dissolution and uncontrolled release rate in the later stages of konjac glucomannan gel release. This results in a more stable overall release curve, perfectly meeting the release standards of long-acting sustained-release formulations.

[0038] It is worth noting that, in the mixture of konjac glucomannan and ethyl cellulose, the preferred weight ratio of konjac glucomannan to ethyl cellulose is, for example, between 3:1 and 5:1.

[0039] The filler is preferably either microcrystalline cellulose or spray-dried lactose. As a core filler excipient in the formulation, it can effectively regulate the formability, hardness, and pore structure of the microflakes.

[0040] Among them, microcrystalline cellulose possesses excellent adhesiveness and compressibility, significantly improving the quality of micro-tablet formation and preventing tablet loosening and abnormal disintegration. Spray-dried lactose exhibits excellent flowability, improving overall powder flowability and ensuring more uniform mixing of raw materials, thus avoiding uneven local drug concentration. Both fillers are physicochemically stable, do not react with the active pharmaceutical ingredient or other excipients, and can optimize the internal pore structure of the formulation, assisting in regulating the drug diffusion rate and further enhancing the drug release stability of the formulation.

[0041] The preferred buoyancy aid is, for example, a mixture of sodium bicarbonate and citric acid. This composite buoyancy aid system can rapidly undergo an acid-base reaction in a simulated gastric acid environment, continuously and uniformly generating microbubbles of carbon dioxide. These bubbles can be uniformly embedded within the porous structure of the microparticle framework, reducing the overall density of the formulation. This allows the microparticles to quickly float on the surface of the gastric juice and maintain their floating state for a long time, effectively prolonging the residence time of the formulation in the stomach and preventing the formulation from rapidly emptying into the intestines. This allows the drug to be released and absorbed continuously at specific points in the stomach, thereby improving drug bioavailability.

[0042] The preferred weight ratio of sodium bicarbonate to citric acid is, for example, between 1:1 and 1:1.5. This ratio ensures a mild and continuous acid-base reaction, preventing the micro-sheet skeleton from cracking or structurally breaking due to a sudden surge in gas production. It also avoids defects such as weak buoyancy and short residence time caused by insufficient gas production, ensuring stable floating of the micro-sheets throughout the process and providing the basic conditions for long-term sustained release.

[0043] The lubricant may preferably be, for example, any one or both of magnesium stearate or micronized silica gel.

[0044] Among them, magnesium stearate has excellent lubricating effect and can reduce the friction between powder particles. Micronized silica gel has both lubricating and flow-aiding effects, and can also slightly optimize the pore structure of the formulation. Both materials are physicochemically inert and do not affect drug release or formulation stability. Small amounts can meet the production process requirements and will not have a negative impact on the floating performance or sustained-release effect of the microfiber.

[0045] The nano-modifier is preferably a mixture of nano-silica and nano-montmorillonite. The weight ratio of nano-silica to nano-montmorillonite is preferably between 1:1 and 2:1, and the particle size of both is preferably between 50 nm and 100 nm.

[0046] By controlling the particle size range of the nano-modifier, on the one hand, it can fill the pores of the framework, densify the gel structure, further reduce the drug diffusion rate, assist the framework material in enhancing the sustained-release effect, and completely eliminate the phenomenon of sudden drug release; on the other hand, it can improve the mechanical strength and structural stability of the micro-flake framework, enhance the gel layer's resistance to gastric acid erosion and corrosion, prevent the micro-flakes from being damaged or broken in the gastric environment, and ensure floating stability and drug release uniformity.

[0047] Meanwhile, nano-silica and nano-montmorillonite can adsorb and fix drug molecules, making the drug more evenly distributed in the matrix, further optimizing the drug release curve, and achieving a long-lasting, stable and controllable drug release effect.

[0048] The metformin hydrochloride gastric floating sustained-release microtablets of this embodiment improve the burst release problem of metformin hydrochloride by incorporating a matrix material. Simultaneously, the combination with a nano-modifier controls the slow diffusion and release of metformin hydrochloride, avoiding issues such as moisture absorption, sticking, and decreased flowability of the metformin hydrochloride active pharmaceutical ingredient. Furthermore, the addition of a buoyancy aid and a reasonable ratio of components enable rapid and prolonged floating of the tablets, extending the drug's residence time in the stomach and upper small intestine and improving drug utilization.

[0049] The second aspect of this application provides a method for preparing metformin hydrochloride gastric floating sustained-release microtablets. This method can be used, for example, to prepare the metformin hydrochloride gastric floating sustained-release microtablets described in the first aspect embodiment above. This method can be used, for example, to prepare the metformin hydrochloride gastric floating sustained-release microtablets described in the first aspect embodiment above, in combination with... Figure 1 As shown, the preparation method specifically includes the following steps:

[0050] Step S1: Sift metformin hydrochloride, matrix material, filler, bleaching agent and lubricant separately.

[0051] In step S1 above, sieving metformin hydrochloride is a preferred embodiment, for example, sieving metformin hydrochloride through a 100-mesh sieve. The D of metformin hydrochloride... 50 Preferred sizes can be in the range of 20μm-80μm.

[0052] The skeleton material, filler, bleaching aid and lubricant are sieved separately. In a preferred embodiment, they can all be sieved through an 80-mesh sieve.

[0053] It is worth noting that by controlling the particle size of each component through sieving, it is possible to ensure uniform gas production in a very small volume of micro-flakes, avoiding fragment cracking and excessive weight differences caused by uneven local gas production, while also accelerating the drifting speed.

[0054] Step S2: Mix the sieved metformin hydrochloride, the skeleton material, the filler, the bleaching agent and the nano-modifier evenly to obtain a mixture.

[0055] The mixing in step S2 above can preferably be done using a three-dimensional motion mixer, the mixing time can preferably be between 15 min and 20 min, and the mixing speed can preferably be between 80 r / min and 100 r / min.

[0056] Step S3: Granulate the mixture and granulate it to obtain microparticles.

[0057] The granulation temperature in step S3 above is preferably between 30°C and 40°C.

[0058] The preferred granulation method is, for example, dry granulation; the preferred granulation pressure is, for example, between 8 MPa and 12 MPa; and the preferred granulation speed is, for example, between 30 r / min and 50 r / min.

[0059] It is worth noting that by using dry granulation and controlling the granulation pressure, a uniform distribution of the honeycomb porous structure inside the micro-tablets can be achieved, ensuring the floating stability and sustained-release effect of the final tablets.

[0060] In step S3 above, granulation can be performed, for example, using a 1.2mm-1.8mm sieve.

[0061] Step S4: Mix the microparticles and the lubricant evenly, compress into tablets, and obtain the metformin hydrochloride gastric floating sustained-release microtablets.

[0062] In step S4 above, tableting can be performed using micro-punching, for example. The hardness of the resulting metformin hydrochloride gastric floating sustained-release tablets is preferably between 10N and 60N, and the tablet diameter is preferably 3.0mm.

[0063] The preparation method of this embodiment controls the particle size of each component through sieving and the synergistic effect of each step, so that the prepared metformin hydrochloride gastric floating sustained-release microtablets have a longer retention time in the stomach and upper small intestine, thus improving the drug utilization effect.

[0064] It is worth noting that, regarding the metformin hydrochloride gastric floating sustained-release microtablets and their preparation method in this embodiment, based on the above exemplary embodiments, the following examples can be referred to in specific implementations.

[0065] Example 1

[0066] Example 1 describes the preparation of metformin hydrochloride gastric floating sustained-release microtablets. The components and specific preparation steps are as follows:

[0067] Components:

[0068]

[0069] Preparation method:

[0070] Step S1: Metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose (PH102), spray-dried lactose, sodium bicarbonate, citric acid, and magnesium stearate are sieved separately. Metformin hydrochloride is sieved through a 100-mesh sieve, and the remaining excipients are sieved through an 80-mesh sieve. The processed materials are then set aside.

[0071] Step S2: Add the metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose PH102, spray-dried lactose, sodium bicarbonate, citric acid, nano silica and nano montmorillonite obtained in step S1 into a three-dimensional motion mixer according to the component amounts, adjust the mixing time to 15 min and the rotation speed to 80 r / min, and mix evenly.

[0072] Step S3: Place the mixed powder obtained in step S2 into a dry granulator, adjust the granulation pressure to 10 MPa, the granulation speed to 30 r / min, and the granulation temperature to 30℃ to produce dry granules. Collect the compressibility index of the dry granules using an online granule compressibility detection module. Sieve the dry granules through a 1.2–1.8 mm sieve to remove coarse particles and fine powder, obtaining uniform micro-particles.

[0073] Step S4: Add the microparticles obtained in step S3 and magnesium stearate into a three-dimensional motion mixer, adjust the mixing time to 10 min and the rotation speed to 80 r / min, mix evenly, and then use a 3 mm flat micro-punch to compress tablets. The tablet hardness is controlled between 10 and 60 N, and a total of 10,000 tablets are made.

[0074] Example 2

[0075] Example 2 describes the preparation of metformin hydrochloride gastric floating sustained-release microtablets. The components and specific preparation steps are as follows:

[0076] Components:

[0077]

[0078] Preparation method:

[0079] Step S1: Metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose (PH102), sodium bicarbonate, citric acid, and magnesium stearate are sieved separately. Metformin hydrochloride is sieved through a 100-mesh sieve, and the remaining excipients are sieved through an 80-mesh sieve. The processed materials are then set aside for later use.

[0080] Step S2: Add the metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose PH102, sodium bicarbonate, citric acid, nano silica and nano montmorillonite obtained in step S1 into a three-dimensional motion mixer according to the component amounts, adjust the mixing time to 15 min and the rotation speed to 80 r / min, and mix evenly.

[0081] Step S3: Place the mixed powder obtained in step S2 into a dry granulator, adjust the granulation pressure to 10 MPa, the granulation speed to 30 r / min, and the granulation temperature to 30℃ to produce dry granules. Collect the compressibility index of the dry granules using an online granule compressibility detection module. Sieve the dry granules through a 1.2–1.8 mm sieve to remove coarse particles and fine powder, obtaining uniform micro-particles.

[0082] Step S4: Add the microparticles obtained in step S3 and magnesium stearate into a three-dimensional motion mixer, adjust the mixing time to 10 min and the rotation speed to 80 r / min, mix evenly, and then use a 3 mm flat micro-punch to compress tablets. The tablet hardness is controlled between 10 and 60 N, and a total of 10,000 tablets are made.

[0083] Example 3

[0084] Example 3 describes the preparation of metformin hydrochloride gastric floating sustained-release microtablets. The components and specific preparation steps are as follows:

[0085] Components:

[0086]

[0087] Preparation method:

[0088] Step S1: Metformin hydrochloride, konjac glucomannan, ethyl cellulose, spray-dried lactose, sodium bicarbonate, citric acid, magnesium stearate, and micronized silica gel are sieved separately. Metformin hydrochloride is sieved through a 100-mesh sieve, and the remaining excipients are sieved through an 80-mesh sieve. The processed materials are then set aside.

[0089] Step S2: Add the metformin hydrochloride, konjac glucomannan, ethyl cellulose, spray-dried lactose, sodium bicarbonate, citric acid, nano silica and nano montmorillonite obtained in step S1 into a three-dimensional motion mixer according to the component amounts, adjust the mixing time to 15 min and the rotation speed to 80 r / min, and mix evenly.

[0090] Step S3: Place the mixed powder obtained in step S2 into a dry granulator, adjust the granulation pressure to 10 MPa, the granulation speed to 30 r / min, and the granulation temperature to 30℃ to produce dry granules. Collect the compressibility index of the dry granules using an online granule compressibility detection module. Sieve the dry granules through a 1.2–1.8 mm sieve to remove coarse particles and fine powder, obtaining uniform micro-particles.

[0091] Step S4: Add the microparticles obtained in step S3, magnesium stearate, and micronized silica gel into a three-dimensional motion mixer. Adjust the mixing time to 10 min and the rotation speed to 80 r / min. Mix evenly, and then use a 3 mm flat micro-punch to compress the tablets. The tablet hardness is controlled between 10 and 60 N. A total of 10,000 tablets are made.

[0092] Example 4

[0093] Example 4 describes the preparation of metformin hydrochloride gastric floating sustained-release microtablets. The components and specific preparation steps are as follows:

[0094] Components:

[0095]

[0096] Preparation method:

[0097] Step S1: Metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose (PH102), spray-dried lactose, sodium bicarbonate, citric acid, magnesium stearate, and micronized silica gel are sieved separately. Metformin hydrochloride is sieved through a 100-mesh sieve, and the remaining excipients are sieved through an 80-mesh sieve. The processed materials are then set aside.

[0098] Step S2: Add the metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose PH102, spray-dried lactose, sodium bicarbonate, citric acid, nano silica and nano montmorillonite obtained in step S1 into a three-dimensional motion mixer according to the component amounts, adjust the mixing time to 20 min and the rotation speed to 100 r / min, and mix evenly.

[0099] Step S3: Place the mixed powder obtained in step S2 into a dry granulator, adjust the granulation pressure to 10 MPa, the granulation speed to 30 r / min, and the granulation temperature to 30℃ to produce dry granules. Collect the compressibility index of the dry granules using an online granule compressibility detection module. Sieve the dry granules through a 1.2–1.8 mm sieve to remove coarse particles and fine powder, obtaining uniform micro-particles.

[0100] Step S4: Add the microparticles obtained in step S3, magnesium stearate, and micronized silica gel into a three-dimensional motion mixer. Adjust the mixing time to 10 min and the rotation speed to 100 r / min. Mix evenly, and then use a 3 mm flat micro-punch to compress the tablets. The tablet hardness is controlled between 10 and 60 N. A total of 10,000 tablets are made.

[0101] Example 5

[0102] Example 5 describes the preparation of metformin hydrochloride gastric floating sustained-release microtablets. The components and specific preparation steps are as follows:

[0103] Components:

[0104]

[0105] Preparation method:

[0106] Step S1: Metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose (PH102), spray-dried lactose, sodium bicarbonate, citric acid, magnesium stearate, and micronized silica gel are sieved separately. Metformin hydrochloride is sieved through a 100-mesh sieve, and the remaining excipients are sieved through an 80-mesh sieve. The processed materials are then set aside.

[0107] Step S2: Add the metformin hydrochloride, konjac glucomannan, ethyl cellulose, microcrystalline cellulose PH102, spray-dried lactose, sodium bicarbonate, citric acid, nano silica and nano montmorillonite obtained in step S1 into a three-dimensional motion mixer according to the component amounts, adjust the mixing time to 20 min and the rotation speed to 100 r / min, and mix evenly.

[0108] Step S3: Place the mixed powder obtained in step S2 into a dry granulator, adjust the granulation pressure to 10 MPa, the granulation speed to 30 r / min, and the granulation temperature to 30℃ to produce dry granules. Collect the compressibility index of the dry granules using an online granule compressibility detection module. Sieve the dry granules through a 1.2–1.8 mm sieve to remove coarse particles and fine powder, obtaining uniform micro-particles.

[0109] Step S4: Add the microparticles obtained in step S3, magnesium stearate, and micronized silica gel into a three-dimensional motion mixer. Adjust the mixing time to 10 min and the rotation speed to 100 r / min. Mix evenly, and then use a 3 mm flat micro-punch to compress the tablets. The tablet hardness is controlled between 10 and 60 N. A total of 10,000 tablets are made.

[0110] Verification Example 1

[0111] This verification example 1 is to test the release rate of the metformin hydrochloride gastric floating sustained-release microtablets prepared in Examples 1-5, in order to prove their sustained-release effect.

[0112] This verification example 1 compares the results of a 24-hour in vitro release test conducted on Examples 1-5 and commercially available metformin hydrochloride regular tablets and extended-release metformin hydrochloride tablets.

[0113] Experimental method: Dissolution and release determination method (Chinese Pharmacopoeia 2025 Edition, General Chapter 0931, Method 1, Method 2), using 900 mL of artificial gastric fluid as the dissolution medium, rotating at 100 r / min, samples were taken at 1 h, 3 h, 5 h, 7 h, 10 h, 12 h, 16 h, 20 h, and 24 h. 20 mL of the dissolution solution was collected, filtered, and 10 mL of the initial filtrate was discarded, and the subsequent filtrate was collected. An equal volume and temperature of release medium were added promptly.

[0114] The release rates of each case and commercially available metformin hydrochloride tablets and extended-release metformin hydrochloride tablets at each time point are shown in Table 1 below.

[0115] Table 1 Release rates of each example and commercially available product at each time point.

[0116]

[0117] Verification Example 2

[0118] This verification example 2 examines the initiation time and continuous floating time of the products obtained in Examples 1-5, as well as commercially available metformin hydrochloride tablets and commercially available metformin hydrochloride extended-release tablets.

[0119] Experimental method: The micro-flakes obtained in Examples 1-5 and two commercially available tablets were respectively placed in artificial gastric fluid, and the floating time and continuous floating time were recorded. The experimental results are shown in Table 2 below.

[0120] Table 2. Drifting time and continuous drifting time for each example and commercially available product.

[0121]

[0122] Verification Example 3

[0123] This verification example 3 measures the angle of repose of the material before tableting, observes the appearance of the samples, and checks the weight difference and friability of the samples prepared in each example.

[0124] Weight difference inspection method: Take 20 tablets of each example sample, accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet. Compare the weight of each tablet with the average tablet weight, calculate the weight difference of each tablet, and determine the range of tablet weight difference for the 20 tablets.

[0125] Friability test method: Take several pieces of each example sample, with a total weight of approximately 6.5g. Blow away the powder that falls off the micro-pieces, weigh accurately, place in the cylinder of the friability tester, and rotate 100 times. Remove, blow away the powder in the same way, and weigh accurately. Calculate the friability according to (weight before friability - weight after friability) / weight after friability × 100%.

[0126] The test results are shown in Table 3 below.

[0127] Table 3 Comparison of material angle of repose, sample appearance, weight difference, and friability before tableting for each example.

[0128]

[0129] Verification Example 4

[0130] Example 4 of this verification involves taking the samples prepared in Examples 1-5, packaging them with aluminum-plastic composite panels, placing them in a paper box, and storing them for 6 months at a temperature of 40℃±2℃ and a relative humidity of 60%±5%. The appearance and content of the samples were observed, and the test results are shown in Table 4 below.

[0131] Table 4. Test results of samples from Examples 1-5 after 6 months of storage.

[0132]

[0133] Verification Example 5

[0134] Example 5 of this verification example is used to verify the technical advantages of this application. Metformin hydrochloride gastric floating sustained-release microtablets prepared in Example 5 (experimental group) were compared with commercially available metformin hydrochloride sustained-release tablets prepared using conventional processes (control group). The core performance indicators were compared and tested under the following conditions: artificial gastric fluid, temperature 37±0.5℃, and storage conditions: relative humidity 60±5%, temperature 25±2℃. The comparison results are shown in Table 5 below.

[0135] Table 5. Performance Comparison Results of Example 5 and Commercially Available Sustained-Release Tablets

[0136]

[0137] As can be seen from the results of Validation Example 1 and Table 1, compared with commercially available tablets, each sample exhibits a slower and more sustained release in the release medium, which effectively solves the problem of sudden release caused by the high solubility of the active ingredient in water. This allows the drug to be released in the stomach and absorbed in the upper part of the small intestine, thus effectively improving the bioavailability of the drug.

[0138] As can be seen from the results of Validation Example 2 and Table 2, the floating time of each sample was within 1 minute and the continuous floating time exceeded 30 hours, which significantly improved the retention time in the stomach compared with commercially available tablets.

[0139] As can be seen from the results of Validation Example 3 and Table 3, the angle of repose of the materials in each sample is small, the difference in tablet weight is small, and the material has good flowability; the samples are white tablets with a bright surface, intact edges, and the friability meets the requirements.

[0140] As can be seen from the results of Verification Example 4 and Table 4, the samples prepared in Examples 1-5 showed no significant changes in appearance and content during the 6-month accelerated stability test.

[0141] As can be seen from the comparison results of Validation Example 5 and Table 5, the metformin hydrochloride gastric floating sustained-release microtablets prepared by the method of this application are significantly superior to commercially available products in terms of core performance indicators such as floating speed, gastric retention time, sustained-release stability, and storage stability. This fully verifies that the metformin hydrochloride gastric floating sustained-release microtablets of this application can significantly prolong the retention time of the drug in the stomach and upper small intestine, accurately match the optimal absorption window of the drug, and fundamentally improve the bioavailability of the drug.

[0142] The above descriptions are merely some embodiments of this application and are not intended to limit this application. The technical features or structures in the foregoing different embodiments can be arbitrarily combined to form other specific technical solutions as needed. For those skilled in the art, this application can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of the claims of this application.

Claims

1. A metformin hydrochloride gastric floating sustained-release microtablet, characterized in that: The composition of the metformin hydrochloride gastric floating sustained-release microtablets, by weight percentage, includes: 50%–75% metformin hydrochloride, 5%–20% matrix material, 9%–18% filler, 2%–6% buoyancy aid, 1%–4% lubricant, and 1%–3% nano-modifier.

2. The metformin hydrochloride gastric floating sustained-release microtablets according to claim 1, characterized in that: The skeletal material is a mixture of konjac glucomannan and ethyl cellulose; The filler is either microcrystalline cellulose or spray-dried lactose. The bleaching aid is a mixture of sodium bicarbonate and citric acid; The lubricant is any one or two of magnesium stearate or micronized silica gel. The nano-modifier is a mixture of nano-silica and nano-montmorillonite.

3. The metformin hydrochloride gastric floating sustained-release microtablets according to claim 2, characterized in that: In the mixture of konjac glucomannan and ethyl cellulose, the weight ratio of konjac glucomannan to ethyl cellulose is between 3:1 and 5:

1.

4. The metformin hydrochloride gastric floating sustained-release microtablets according to claim 2, characterized in that: In the mixture of sodium bicarbonate and citric acid, the weight ratio of sodium bicarbonate to citric acid is between 1:1 and 1:1.

5.

5. The metformin hydrochloride gastric floating sustained-release microtablets according to claim 2, characterized in that: In the mixture of nano-silica and nano-montmorillonite, the weight ratio of nano-silica to nano-montmorillonite is between 1:1 and 2:

1.

6. A method for preparing metformin hydrochloride gastric floating sustained-release microtablets, characterized in that, The preparation method includes: Metformin hydrochloride, matrix material, filler, bleaching aid and lubricant were sieved separately; The sieved metformin hydrochloride, the framework material, the filler, the bleaching agent, and the nano-modifier are mixed evenly to obtain a mixture. The mixture is granulated and sized to obtain microparticles; The microparticles are mixed evenly with the lubricant and then compressed into tablets to obtain the metformin hydrochloride gastric floating sustained-release microtablets.

7. The method for preparing metformin hydrochloride gastric floating sustained-release microtablets according to claim 6, characterized in that: The metformin hydrochloride was sieved through a 100-mesh sieve. The skeleton material, filler, bleaching aid and lubricant are all sieved through an 80-mesh sieve.

8. The method for preparing metformin hydrochloride gastric floating sustained-release microtablets according to claim 6, characterized in that: The granulation temperature is between 30℃ and 40℃.

9. The method for preparing metformin hydrochloride gastric floating sustained-release microtablets according to claim 6, characterized in that: The granulation process uses a 1.2mm-1.8mm sieve.

10. The method for preparing metformin hydrochloride gastric floating sustained-release microtablets according to claim 6, characterized in that: The hardness of the metformin hydrochloride gastric floating sustained-release microplates is between 10N and 60N.

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