Sustained-release pill as well as preparation method and application thereof

Abstract

The invention discloses a sustained-release pill as well as a preparation method and application thereof, and belongs to the technical field of medicines. The sustained-release pill comprises a pill core and a coating layer coated outside the pill core, the pellet core is prepared from the following raw materials in parts by mass: 8 to 14 parts of loxoprofen sodium, 30 to 60 parts of a filling agent, 3 to 10 parts of an adhesive, 2 to 10 parts of a disintegrating agent, 0.1 to 2 parts of a penetration enhancer, 0.05 to 0.2 part of a pH regulator, 0.1 to 0.5 part of a surfactant and 0 to 20 parts of an auxiliary agent; the coating layer is prepared from an aqueous dispersion liquid containing acrylic resin; the coating layer is prepared from an aqueous dispersion liquid containing acrylic resin. Aiming at the drug characteristics of loxoprofen sodium, the loxoprofen sodium sustained-release tablet is composed of specific auxiliary materials, the drug composition is optimized, the drug release rate is accurately controlled, the bioavailability and stability of the drug are effectively improved, and the loxoprofen sodium sustained-release tablet has a good application prospect in preparation of antipyretic and analgesic drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a sustained-release pill, its preparation method, and its application. Background Technology

[0002] Antipyretic analgesics are a class of drugs widely used in the pharmaceutical field, mainly used to relieve symptoms such as fever and pain, and play an important role in daily life and clinical treatment. Loxoprofen sodium is a common antipyretic analgesic drug component. It is a water-soluble drug with certain antipyretic, analgesic, and anti-inflammatory effects, but its use may have some limitations, such as less than ideal efficacy in some patients and a shorter duration of action. In addition, loxoprofen sodium is generally in tablet form, requiring frequent dosing and easily causing fluctuations in blood drug concentration and increasing the occurrence of adverse reactions. Therefore, it is necessary to formulate sustained-release preparations to reduce the frequency of dosing and maintain a stable blood drug concentration.

[0003] In pharmaceutical formulation technology, extrusion spheronization is a commonly used method for preparing microcapsules or granules. However, traditional extrusion spheronization processes may have some shortcomings, such as uneven mixing of drug components, unstable granule quality, and difficulty in precisely controlling drug release rates. Regarding excipient selection, traditional excipients may not meet the higher performance requirements of modern pharmaceutical formulations, for example, having limitations in improving drug solubility, promoting drug absorption, and achieving long-term drug release.

[0004] When water-soluble drugs are coated with aqueous dispersions to prepare sustained-release microspheres, a relatively serious burst release phenomenon often occurs. To solve this problem, existing technologies have proposed a method of preparing an isolation layer before coating. However, this method is complex and the initial drug release is too slow, making it difficult to meet the requirements for rapid antipyresis, analgesia, or anti-inflammation in the initial stage. Summary of the Invention

[0005] In order to overcome at least one of the problems existing in the prior art, one of the objectives of the present invention is to provide a loxoprofen sodium sustained-release pill with uniform particle size and stable distribution, high content uniformity, good dissolution, and meeting the requirements of a predetermined release curve.

[0006] The second objective of this invention is to provide a method for preparing the above-mentioned sustained-release pills.

[0007] The third objective of this invention is to provide an application of the above-mentioned sustained-release pills.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] A first aspect of the present invention provides a sustained-release pill comprising a core and a coating layer covering the core; the core is prepared from raw materials comprising the following parts by weight: 8-14 parts loxoprofen sodium, 30-60 parts filler, 3-10 parts binder, 2-10 parts disintegrant, 0.1-2 parts penetration enhancer, 0.05-0.2 parts pH adjuster, 0.1-0.5 parts surfactant and 0-20 parts adjuvant; the coating layer is prepared from an aqueous dispersion containing acrylic resin.

[0010] Preferably, the mass ratio of the coating layer to the pellet core is (4-20):100; more preferably (5-15):100; even more preferably (6-10):100; for example, it can be any value of 6:100, 7:100, 8:100, 9:100 or 10:100 or any range between two of them.

[0011] By controlling the quality of the coating layer, its thickness can be managed, thereby achieving timed and targeted drug release, improving therapeutic efficacy and reducing side effects. A coating layer of suitable quality can improve the sustained-release performance of the pill. Once the coating layer reaches a certain thickness, it possesses sufficient strength to resist the increase in osmotic pressure caused by drug dissolution. Furthermore, the water-soluble pores formed by the gaps in the coating layer allow the drug to pass through the coating membrane at a constant rate, achieving a sustained-release effect. When the mass ratio of the coating layer to the pill core is (4–20):100 (i.e., a coating weight gain of 4–20%), the drug's sustained-release performance is good. Further, when this mass ratio is (5–15):100, especially (6–10):100, the drug's sustained-release performance is even better, the release curve is more reasonable, and it is closer to the first-order release model, i.e., the drug release rate gradually decreases, maintaining an effective blood drug concentration, providing rapid analgesia in the initial stage, and slow release in the later stage, prolonging the drug's duration of action, reducing the risk of adverse reactions, and minimizing local irritation.

[0012] Preferably, the mass percentage of loxoprofen sodium in the raw material of the pellet core is 8-14%; for example, it can be any value of 8%, 10%, 12% or 14% or any range between two.

[0013] Preferably, the filler includes at least one of microcrystalline cellulose, sucrose, or pregelatinized starch; more preferably, the filler is selected from microcrystalline cellulose.

[0014] Preferably, the adhesive comprises at least one of hydroxypropyl methylcellulose, povidone, or ethyl cellulose; more preferably, the adhesive is selected from hydroxypropyl methylcellulose.

[0015] Preferably, the disintegrant includes at least one of ion exchange resin, croscarmellose sodium, or croscarmellose; more preferably, the disintegrant is selected from croscarmellose sodium.

[0016] Preferably, the penetration enhancer includes laurocapram, menthol, or a combination thereof; more preferably, the penetration enhancer is selected from laurocapram.

[0017] Preferably, the pH adjuster includes at least one of citric acid, sodium dihydrogen phosphate, or sodium bicarbonate; more preferably, the pH adjuster is selected from citric acid.

[0018] Preferably, the surfactant comprises sodium dodecyl sulfate, Tween-80, or a combination thereof; more preferably, the surfactant is selected from Tween-80.

[0019] Preferably, the pellet core is made from the following raw materials in parts by weight: 8-14 parts loxoprofen sodium, 30-60 parts filler, 3-10 parts binder, 2-10 parts disintegrant, 0.1-2 parts penetration enhancer, 0.05-0.2 parts pH adjuster, 0.1-0.5 parts surfactant and 1-20 parts adjuvants.

[0020] Preferably, the auxiliary agent in the raw material of the pellet core includes at least one of a lubricant, a flow aid, a flavoring agent, a coloring agent, an antioxidant, a wetting agent, or an anti-sticking agent; more preferably, the auxiliary agent in the raw material of the pellet core includes a lubricant, a flow aid, a flavoring agent, a coloring agent, an antioxidant, a wetting agent, and an anti-sticking agent.

[0021] Preferably, the pellet core is made from the following raw materials in parts by weight: 8-14 parts loxoprofen sodium, 30-60 parts filler, 3-10 parts binder, 2-10 parts disintegrant, 0.1-2 parts penetration enhancer, 0.05-0.2 parts pH adjuster, 0.1-0.5 parts surfactant, 1-5 parts lubricant, 0.5-2 parts flow aid, 0.1-5 parts flavoring agent, 0.01-0.3 parts colorant, 0.05-1 part antioxidant, 10-30 parts wetting agent, and 0.1-0.5 parts anti-sticking agent.

[0022] Preferably, the antioxidant in the raw material of the pellet core includes at least one of vitamin C, vitamin E, or butylated hydroxyanisole (BHA); more preferably, the antioxidant is selected from vitamin C.

[0023] Preferably, the lubricant in the raw materials of the pellet core includes at least one of magnesium stearate, calcium stearate, or talc; more preferably, the lubricant is selected from magnesium stearate.

[0024] Preferably, the flow aid in the raw materials of the pellet core includes silica, micronized silica gel, or a combination thereof; more preferably, the flow aid is selected from silica.

[0025] Preferably, the flavoring agent in the raw materials of the pellet core includes at least one of sucrose, steviol glycosides or aspartame; more preferably, the flavoring agent is selected from steviol glycosides.

[0026] Preferably, the colorant in the raw material of the pellet core includes at least one of iron oxide red, iron oxide yellow, or titanium dioxide; more preferably, the colorant is selected from iron oxide yellow.

[0027] Preferably, the wetting agent in the raw material of the pellet core includes water; more preferably, the wetting agent is selected from water. The water is preferably purified water, which refers to water obtained from drinking water as the raw water through distillation, ion exchange, reverse osmosis, or other suitable methods, and contains no additives.

[0028] Preferably, the anti-adhesion agent in the raw materials of the pellet core includes at least one of talc, starch, titanium dioxide or magnesium stearate; more preferably, the anti-adhesion agent is selected from talc.

[0029] Preferably, in the aqueous dispersion, the acrylic resin includes ethyl acrylate, methyl methacrylate, or a combination thereof; more preferably, the acrylic resin includes ethyl acrylate and methyl methacrylate; even more preferably, the mass ratio of ethyl acrylate to methyl methacrylate is (1.5-2.5):1.

[0030] This application uses acrylic resin as the main component of the coating layer, and the resulting coating layer is enteric, which is released only in intestinal fluid and not in gastric fluid, thus playing a role in slow release in intestinal fluid.

[0031] In some specific embodiments of the present invention, the acrylic resin used is Eudragit NE30D.

[0032] Eudragit NE30D is a pH-independent, moderately permeable coating material composed of ethyl acrylate and methyl methacrylate in a 2:1 ratio, with a solid content of 30%, an average particle size of 0.1 μm, and a minimum film-forming temperature of 5°C. This coating material is safe, stable, inert, and non-irritating, exhibits good plasticity, and is easy to form films without the need for plasticizers. When used to prepare the sustained-release pellets of this invention, the release mechanism in water closely approximates the first-order release model, resulting in a better sustained-release effect.

[0033] Preferably, the acrylic resin in the aqueous dispersion is 5-20% by mass; more preferably 8-15%; for example, it can be any value of 8%, 10%, 12% or 15% or any range between two.

[0034] Preferably, the aqueous dispersion further contains an anti-adhesion agent, an antistatic agent, or a combination thereof; more preferably, the aqueous dispersion further contains an anti-adhesion agent and an antistatic agent.

[0035] Preferably, in the aqueous dispersion, the mass ratio of the acrylic resin to the anti-adhesive is 100:(40-60); more preferably, it is 100:(45-55); for example, it can be any value or a range between 100:45, 100:48, 100:50, 100:52 or 100:55.

[0036] Preferably, in the aqueous dispersion, the mass ratio of the acrylic resin to the antistatic agent is 100:(0.5-2); more preferably 100:(0.8-1.5); for example, it can be any value of 100:0.8, 100:1, 100:1.2 or 100:1.5 or a range between any two.

[0037] In this invention, the aqueous dispersion is a system in which solid or liquid particles are uniformly dispersed in water as a dispersion medium. Using the aqueous dispersion as a raw material to prepare the coating layer can form a uniform and complete coating layer, resulting in good product particle stability and excellent sustained-release performance.

[0038] Preferably, the bulk density of the sustained-release pills is 0.5–1 g / cm³. 3 For example, it could be 0.5 g / cm³. 3 0.6g / cm 3 0.8g / cm 3 or 1g / cm 3 Any value in the range or any value between the two.

[0039] Preferably, the tap density of the sustained-release pills is 0.6–1.2 g / cm³. 3 For example, it could be 0.6 g / cm³. 3 0.8g / cm 3 1.0g / cm 3 Or 1.2g / cm 3 Any value in the range or any value between the two.

[0040] Preferably, the angle of repose of the sustained-release pill is ≤40°; for example, it can be any value of 5°, 10°, 20°, 30° or 40° or a range between any two.

[0041] Preferably, the average particle size of the sustained-release pills is 0.5 to 2 mm; for example, it can be any value of 0.5 mm, 0.8 mm, 1.0 mm, 1.5 mm or 2 mm or a range between any two.

[0042] The second aspect of the present invention provides a method for preparing the sustained-release pills described in the first aspect of the present invention, characterized by comprising the following steps: mixing the raw materials of the pill core, and sequentially extruding, sphericalizing, and drying to obtain the pill core; coating the pill core with the aqueous dispersion, and heat-treating to obtain the coating layer.

[0043] Preferably, the coating temperature is 15–30°C; more preferably 20–25°C; for example, it can be any value of 20°C, 22°C, or 25°C, or a range between any two.

[0044] Preferably, the heat treatment temperature is 30–50°C; more preferably 35–45°C; for example, it can be any value of 35°C, 40°C, or 45°C, or a range between any two.

[0045] Preferably, the heat treatment time is 18 to 60 hours; more preferably 20 to 40 hours; for example, it can be any value of 20 hours, 25 hours, 30 hours, 35 hours or 40 hours or a range between any two.

[0046] By employing appropriate coating and heat treatment processes, sustained-release pills with more uniform properties can be obtained. In particular, using appropriate heat treatment temperature and time can enable polymer particles to bind more densely into a continuous and uniform film, making drug release more stable, thereby giving the pills better sustained-release properties and reducing burst release phenomena.

[0047] Preferably, the screw speed of the extrusion is 25 to 80 r / min; more preferably 30 to 70 r / min; for example, it can be any value of 30 r / min, 40 r / min, 50 r / min, 60 r / min or 70 r / min or a range between any two.

[0048] Preferably, the rolling speed is 1000-1600 r / min; more preferably 1000-1500 r / min; for example, it can be any value or a range between 1000 r / min, 1100 r / min, 1200 r / min, 1300 r / min, 1400 r / min or 1500 r / min.

[0049] Preferably, the rolling time is 2 to 15 minutes; more preferably 4 to 10 minutes; for example, it can be any value of 4 minutes, 6 minutes, 8 minutes or 10 minutes or any range between two of them.

[0050] A suitable screw speed is beneficial for obtaining cylindrical strips with uniform diameter. Subsequent rounding steps can yield pellets with moderate and uniform particle size and narrow particle size distribution. Appropriate rounding speed and time contribute to obtaining pellets with high sphericity, low brittleness, concentrated particle size distribution, high yield, good surface quality, and non-stickiness. Furthermore, appropriate extrusion and rounding processes can complement each other to obtain high-quality pellets.

[0051] Preferably, the drying temperature is 35 to 70°C; for example, it can be any value of 35°C, 40°C, 50°C, 60°C or 70°C or a range between any two.

[0052] Preferably, the drying process is carried out in stages, including a first stage of drying and a second stage of drying; the temperature of the first stage of drying is 35-45°C; and the temperature of the second stage of drying is 50-70°C.

[0053] The drying process is carried out in stages, which can reduce particle deformation and drug degradation.

[0054] Preferably, the drying time is 0.5 to 2 hours; for example, it can be any value of 0.5 hours, 1 hour, 1.5 hours or 2 hours or a range between any two.

[0055] Preferably, the drying is carried out until the moisture content of the particles is between 1% and 3%; for example, it can be any value of 1%, 1.5%, 2%, 1.5% or 3% or a range between any two.

[0056] Preferably, before mixing the raw materials for the pellet core, the raw materials are further pulverized to a particle size of 80-120 mesh. This pre-pulverization process ensures a more uniform particle size distribution, which is beneficial for subsequent uniform mixing and extrusion rounding.

[0057] Preferably, the anti-sticking agent is added to the raw material of the pellet core during the pelleting process. Adding the anti-sticking agent during pelleting can effectively control the roundness, particle size distribution, and surface quality of the particles, and prevent them from sticking together.

[0058] A third aspect of the present invention provides the use of the sustained-release pills described in the first aspect of the present invention in the preparation of antipyretic and analgesic drugs.

[0059] The beneficial effects of this invention are: targeting the drug characteristics of loxoprofen sodium, this invention uses specific excipients to optimize the drug composition, achieves precise control of the drug release rate, and effectively improves the bioavailability and stability of the drug. It has good application prospects in the preparation of antipyretic and analgesic drugs.

[0060] Specifically, compared with the prior art, the present invention has the following advantages:

[0061] 1. In this invention, the addition of surfactants and pH adjusters improves the uniformity of mixing among the pellet core materials, as well as the stability and dissolution performance of the drug. The combination of penetration enhancers and pH adjusters improves the drug's performance in terms of release control and bioavailability. Disintegrants further enhance drug release performance. Fillers and binders jointly ensure tablet formability, stability, and drug release. Through the combination of these excipients, the resulting pellet core exhibits good stability and dissolution performance. Furthermore, the coating layer allows for precise control of the drug release rate. The pellets also possess good flowability and storage stability, facilitating formulation processing and packaging, and thus have significant clinical application value and market potential.

[0062] 2. The sustained-release pills prepared by this invention possess numerous excellent properties. The granules exhibit good flowability and filling properties, facilitating formulation processing and packaging. The sustained-release pills demonstrate excellent stability; under accelerated testing and long-term storage conditions, the changes in various quality indicators are minimal, ensuring stable and reliable drug quality and efficacy within the shelf life. This provides a safe and effective method for antipyretic analgesia, possessing significant clinical application value and market prospects. The sustained-release pills prepared by this invention have an enteric-coated and sustained-release double-layer coating structure, which can improve therapeutic efficacy and reduce side effects. Attached Figure Description

[0063] Figure 1 This is a particle size distribution diagram of the sustained-release microspheres in Example 3.

[0064] Figure 2 This is a particle size distribution diagram of the sustained-release microspheres in Example 4.

[0065] Figure 3 The in vitro release curves are for the sustained-release microspheres of Examples 1 and 5.

[0066] Figure 4 The in vitro release curves are for the sustained-release microspheres of Examples 1 and 6. Detailed Implementation

[0067] The following specific embodiments further illustrate the content of the present invention in detail. It should also be understood that the following embodiments are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art based on the principles described herein are all within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make selections within a suitable range based on the description herein, and are not intended to be limited to the specific data in the examples below. Unless otherwise specified, the raw materials, reagents, or apparatus used in the following embodiments and comparative examples can be obtained from conventional commercial sources or by existing known methods.

[0068] Example 1

[0069] A sustained-release microsphere is prepared by the following steps:

[0070] S1. Raw material pretreatment: Loxoprofen sodium is pulverized by passing it through a 100-mesh sieve to obtain a uniform particle size distribution; microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, magnesium stearate, silica, antioxidants and penetration enhancers are pretreated by passing them through an 80-mesh sieve to remove impurities and large particles.

[0071] S2. Preparation of Soft Material: Based on the total weight of the final sustained-release microgranules (total drug weight), add the sieved 10% loxoprofen sodium, 60% microcrystalline cellulose, 8% hydroxypropyl methylcellulose, 10% croscarmellose sodium, 2% magnesium stearate, 2% silica, 5% flavoring agent steviol glycosides, 0.1% coloring agent ferric oxide yellow, 1% antioxidant vitamin C, and 0.9% penetration enhancer laurocapram to a high-efficiency mixing granulator. Turn on the agitator and rotate at a speed of 100–300 r / min. -1 Stir and mix for 5–15 minutes to ensure all ingredients are thoroughly mixed.

[0072] Then, while stirring, slowly add purified water as a wetting agent. The amount of purified water added is 20% of the total weight of the drug. At the same time, add 0.5% of the total weight of the drug surfactant and 0.05% of the pH adjuster. The surfactant is selected from Tween-80 and the pH adjuster is selected from citric acid. Continue stirring for 5 minutes until a uniform soft material is formed. The soft material can be formed into a ball by hand and can be easily broken down by light pressure.

[0073] S3. Extrusion: The obtained soft material is transferred to an extruder and extruded through an extrusion head equipped with a die of a specific orifice diameter of 1 mm. The screw speed of the extruder is 50 r / min. -1 The extrusion temperature is 40℃, resulting in cylindrical strips with uniform diameter.

[0074] S4. Rounding: Transfer the extruded cylindrical strips to a rounding machine, add 0.1% (by weight of the total drug mass) of anti-sticking talc powder, and turn on the rounding machine at a speed of 1000 r / min. -1 The rolling process is carried out for 10 minutes, with the rolling machine tilted at 20°, so that the strips are gradually rolled into spherical particles under the action of centrifugal force and friction.

[0075] S5. Drying: Place the rounded spherical particles into a fluidized bed dryer for drying at 60℃ for 1 hour until the moisture content of the particles is controlled between 1% and 3%. During the drying process, a segmented drying method is adopted. First, dry at 40℃ for a period of time, and then gradually increase the temperature to 60℃ to avoid deformation of the particles or degradation of the drug due to excessive temperature.

[0076] S6. Granulation and Coating: The dried granules are granulated by passing them through a 10-20 mesh sieve to remove adhering and oversized granules. They are then added to a coating pan and coated with a slow-release solution. The coating weight gain is 6%, resulting in slow-release microspheres.

[0077] Specifically, the coating process is as follows: a bottom-spray fluidized bed coating device is used to suspend the drug-containing microcapsules in a fluidized state using flowing air. The coating liquid is atomized by compressed air and sprayed evenly onto the fluidized drug-containing microcapsules in a bottom-spray manner for coating. The coated microcapsules are then placed in a 40°C oven for heat treatment for 24 hours to complete the coating process.

[0078] The preparation steps of the coating solution are as follows: talc powder and sodium dodecyl sulfate (SDS) are added to water and stirred for 10 minutes until homogeneous. NE30D was poured into the above suspension, stirred well, and sieved through an 80-mesh sieve. Stirring continued throughout the coating process. In the coating solution... The NE30D aqueous dispersion coating material is a pH-independent, medium-permeability coating material composed of ethyl acrylate and methyl methacrylate polymers in a 2:1 ratio, with a solid content of 30%, an average particle size of 0.1 μm, and a minimum film-forming temperature of 5℃. The polymer content in the coating solution is diluted to 10 wt%, and the coating solution contains 50% 1000-mesh talc powder as an anti-blocking agent and 1% sodium dodecyl sulfate as an antistatic agent.

[0079] Fluidized bed airflow control: A side baffle is added to the blower to control the airflow. The baffle position is adjusted so that most of the 20g micro-particles are below the middle of the fluidized bed. The baffle distance is selected to be 0.4cm from the fully enclosed state. Spray gun pressure selection: The spray pressure is set at 0.5MPa to balance spraying effect and reduce coating liquid loss. Spraying speed selection: The coating liquid spraying speed is controlled by a constant flow pump, with a spraying speed of 0.5~0.7mL / min. Coating temperature selection: The coating temperature is controlled at 20~25℃, a temperature range that is more than... The minimum film-forming temperature of NE30D is 5℃ higher than that of 15-20℃.

[0080] Example 2

[0081] A type of sustained-release microsphere, differing from Example 1 in that, in step S3 of this example, the screw speed of the extruder is adjusted to 15 r·min. -1 30 r·min -1 and 45r·min -1 The remaining preparation steps and conditions are the same as in Example 1.

[0082] Example 3

[0083] A type of sustained-release microsphere, differing from Example 1 in that, in step S4 of this example, the spheroidizing speed is adjusted to 1120 r·min. -1 1260 r·min -1 and 1400 r·min -1 The remaining preparation steps and conditions are the same as in Example 1.

[0084] Example 4

[0085] The sustained-release microspheres differ from those in Example 1 in that the rounding time in step S4 of this example is adjusted to 2.5 min, 4 min, 6 min and 8 min respectively, while the remaining preparation steps and conditions are the same as in Example 1.

[0086] Example 5

[0087] A sustained-release microsphere differs from Example 1 in that the heat treatment time in step S6 of this example is adjusted to 12h and 36h respectively, while the remaining preparation steps and conditions are the same as in Example 1.

[0088] Example 6

[0089] A sustained-release microsphere differs from Example 1 in that the coating weight gain is adjusted to 4% and 8% in step S6 of this example, while the remaining preparation steps and conditions are the same as in Example 1.

[0090] Comparative Example 1

[0091] The sustained-release microspheres differ from those in Example 1 in that no coating operation is performed in this example; the sustained-release microspheres are obtained by granulation. The remaining preparation steps and conditions are the same as in Example 1.

[0092] Performance testing

[0093] (1) Quality evaluation of micro-pellet powder properties: The quality evaluation of micro-pellets uses particle size and particle size distribution, bulk density, roundness, flowability, and brittleness as indicators. Except for particle size distribution, the other indicators are examined using micro-pellets with a particle size of 20-26 mesh. The specific testing process is as follows:

[0094] 1) Particle size and particle size distribution: The particle size and particle size distribution of the microspheres were determined by sieve analysis and the yield of the spherical microspheres was calculated.

[0095] 2) Bulk density: Take an appropriate amount of micro pellets and slowly pass them through a glass funnel, pour them into a graduated cylinder, and shake them up and down until the volume does not change. Measure the loose volume of the micro pellets and calculate the bulk density.

[0096] 3) Tapped Density: On the main interface of the intelligent powder property tester, click "Tapped Density," then select "Fixed Mass." Follow the prompts to install the relevant components and set the parameters. After confirming the settings, place the weighed sample into the graduated cylinder using a funnel. Then, place the graduated cylinder into the tapped density component with a suitable 3mm amplitude to prepare for tapping. Click "Start Tapping," and vibrate 3000 times according to GB / T5162-2021 / ISO3953:2011 standard. After tapping, read the powder volume V (ml) from the graduated cylinder. Click "Input Volume" to obtain the result.

[0097] 4) Angle of repose: Using the fixed cone bottom method, a quantitative amount of microparticles are dropped from a funnel with a small hole with a diameter of 1.25 cm from a specified height onto a hard surface. The accumulation height (H) and accumulation radius (r) of the powder are measured, and tgθ = H / r is calculated. θ is the angle of repose.

[0098] 5) Plate Angle: On the main interface of the intelligent powder property tester, click "Plate Angle", set the number of tests to 3, and click Start Test. The receiving tray below will rise and get close to the plate. Use a small spoon to directly scatter the sample to be tested into the receiving tray to bury the plate. Tap it again to take an image and analyze and calculate.

[0099] 6) Friability: Place a quantitative amount of micro-pellets in a fluidized bed bottom spray device, fluidize for 20 minutes under coating process conditions, sieve out the fine powder, and calculate the ratio of the weight loss of the micro-pellets to the original weight.

[0100] 7) Planar Critical Stability (OPCS): Place 1g of microparticles on a flat plate, lift one side of the plate, and measure the angle Φ between the inclined plane and the horizontal when the microparticles begin to roll.

[0101] 8) Compressibility: After measuring and saving the bulk density and tap density using the intelligent powder property tester, click "Compressibility" on the main interface, and then click the "Calculate" button to directly calculate the compressibility.

[0102] 9) Homogeneity: Measure D60 and D10 using the sieve method, then input the results into the system, and click the "Calculate" button to get the homogeneity result. Homogeneity is calculated using the following formula: Homogeneity = D60 / D10.

[0103] The results of the powder properties test in Example 1 are shown in Table 1.

[0104] Table 1. Results of powder properties testing in Example 1

[0105] project Example 1 Average particle size (mm) 0.71～0.85 <![CDATA[Bulk density (g / cm 3 )]]> 0.83 <![CDATA[Tap density (g / cm 3 )]]> 1.0 Angle of repose (°) ＜36 Flat plate angle (°) 23 Friability (%) 0.85 OPCS(Φ) 17 Compression (%) 7.5 Uniformity 3

[0106] The results of the powder properties test in Example 2 are shown in Table 2.

[0107] Table 2. Results of powder properties testing in Example 2

[0108]

[0109]

[0110] The results show that the extrusion speed is 15 r·min. -1 At this time, the extrudate is curved, and when it is rounded, there are more cylindrical and dumbbell-shaped particles, resulting in a large amount of fine powder and a low yield; the extrusion speed is 30 r·min. -1 and 45r·min -1 At that time, the quality of microparticles with the target particle size was better.

[0111] The powder properties test results of Example 3 are shown in Table 3, and the particle size distribution diagram is shown in... Figure 1 .

[0112] Table 3. Results of powder properties testing in Example 3

[0113]

[0114] The results show that the rolling speed has a significant effect on the particle size distribution. Under the experimental conditions, as the rolling speed increases, the particle size of the microspheres increases, and the particle size distribution becomes narrower (see...). Figure 1 The rolling speed affects the quality of the microspheres; a low speed results in poor roundness and high brittleness. When the rolling speed is controlled at 1400 r / min... -1 At that time, the yield of micro-pellets was high and the quality was good.

[0115] The powder properties test results of Example 4 are shown in Table 4, and the particle size distribution diagram is shown in... Figure 2 .

[0116] Table 4. Results of powder properties testing in Example 4

[0117]

[0118] The results showed that the rounding time had a significant impact on the particle size and quality of the microspheres. When the rounding time was 2.5 min, the microspheres had poor sphericity, exhibiting a dumbbell shape, resulting in a low yield and high brittleness. When the rounding time was 4 or 6 min, the microspheres had better sphericity, a concentrated particle size distribution, and a high yield and quality. When the rounding time was 8 min, the particle size distribution shifted towards larger particle sizes (see...). Figure 2 The yield of micro-pellets decreased.

[0119] (2) Release rate test, the specific test process is as follows: according to the release rate determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Dissolution and Release Rate Determination Method I), the basket method is used, purified water is used as the medium, the rotation speed is 100 rpm, and the in vitro release rate of the examples and comparative examples is determined.

[0120] The in vitro release rate test results of Example 1 and Comparative Example 1 are shown in Table 5.

[0121] Table 5. Results of in vitro release rate tests for Example 1 and Comparative Example 1

[0122] Comparison Projects Example 1 Comparative Example 1 In vitro release test (1 hour) 18％ 35％ In vitro release test (4 hours) 60％ 85％ In vitro release test (8 hours) 83％ 100％ In vitro release test (12 hours) 100％ 100％

[0123] A comparison of Example 1 and Comparative Example 1 shows that Example 1, due to the addition of a penetration enhancer and pH adjuster, along with the coating step, exhibits better performance in terms of drug release control and bioavailability. Specifically, the addition of the penetration enhancer laurocapram increases the permeability of intestinal epithelial cell membranes, effectively improving the absorption efficiency of loxoprofen sodium in the intestine. For example, the 1-hour release rate of Example 1 is significantly lower than that of Comparative Example 1, indicating a slower and more sustained drug release, which better meets the requirements of sustained-release formulations. Furthermore, the bulk density and angle of repose of Example 1 are within suitable ranges, which is beneficial for the production, storage, and use of the formulation. In contrast, Comparative Example 1, lacking the coating step, has a relatively faster drug release rate, which may affect the drug's long-term efficacy and stability, and it is also inferior to Example 1 in other performance aspects.

[0124] The in vitro release curves for Examples 1 and 5 are as follows: Figure 3 As shown, when the heat treatment time is 12h, the microcapsules release the drug quickly, and the burst release phenomenon is more serious; when the heat treatment time is 24h and 36h, the microcapsules have a better sustained release effect, and the release rate of the two does not change significantly.

[0125] The in vitro release curves for Examples 1 and 6 are as follows: Figure 3 As shown, the coating thickness affects the sustained-release performance of the drug. Once the coating film reaches a certain thickness, it possesses sufficient strength to resist the increase in osmotic pressure caused by drug dissolution. Furthermore, the water-soluble pores formed by the gaps in the coating film allow the drug to pass through the film at a constant rate, achieving a sustained-release effect. Figure 4 It is evident that as the coating amount increases, drug release slows down, and when the weight increases to 8%, the initial release is relatively slow; among them, the release curve of the microcapsules with a weight increase of 6% is more reasonable.

[0126] (3) Release mechanism investigation: Currently, commonly used models for fitting the drug release curve of sustained-release and controlled-release formulations include: 1) Zero-order release model: Y = a1 + k1t; 2) First-order release model: ln(100-Y) = a2 + k2t; 3) Higuchi equation: Y = a3 + k3t 1 / 2 The release curves of the sustained-release pills prepared in Example 1 in water were fitted using zero-order kinetics, first-order kinetics, and the Higuchi equation, respectively. The results are shown in the table below.

[0127] Table 6 shows the fitting results of the sustained-release pills in water for Example 1.

[0128]

[0129]

[0130] The results showed that the release mechanism of the sustained-release pills in water in Example 1 was close to the first-order release model.

[0131] (4) Quality stability test

[0132] 1) High temperature test

[0133] Take the self-made sustained-release microcapsules, place them in a sealed container, and incubate at 60°C for 10 days. Take samples on days 0, 5, and 10, and test them according to the required items. The results are shown in the table below.

[0134] Table 7 High-temperature stability of the sustained-release pills in Example 1

[0135] Time (days) Appearance content(%) <![CDATA[f2]]> 0 pale yellow 99.8 100 5 pale yellow 99.4 89.1 10 pale yellow 99.3 84.7

[0136] The results showed that the content and release rate of the sustained-release pills in Example 1 did not change when placed under high temperature conditions.

[0137] 2) High humidity test

[0138] The self-made sustained-release microspheres were placed in a constant-temperature, sealed container and kept at 25°C and relative humidity of 92.5% and 75% for 10 days. Samples were taken on days 0, 5, and 10, and the moisture absorption weight gain was measured according to the test items. The results are shown in the table below.

[0139] Table 8 High Moisture Stability of Sustained-Release Pills in Example 1

[0140]

[0141] The results showed that the sustained-release pellets in Example 1 had a moisture absorption increase of more than 5% under a relative humidity of RH 92.5%, indicating severe moisture absorption. Under a relative humidity of RH 75%, the pellets were relatively stable, with no significant changes in appearance, content, or release rate.

[0142] 3) Light test

[0143] The self-made sustained-release microcapsules were placed in an illumination chamber with an illuminance of 4500 Lx ± 500 Lx for 10 days. Samples were taken on days 0, 5, and 10 and tested according to the required items. The results are shown in the table below.

[0144] Table 9. Light stability of sustained-release pills in Example 1

[0145]

[0146]

[0147] The results showed that the sustained-release microspheres of Example 1 were stable under light irradiation.

[0148] 4) Accelerated testing

[0149] The self-made sustained-release microcapsules were packaged in aluminum-plastic blister packs and placed at 40℃ and RH 75% for 3 months. Samples were taken at 0, 1, 2, and 3 months and tested according to the required items. The results are shown in the table below.

[0150] Table 10 Accelerated Stability Test of Sustained-Release Pills in Example 1

[0151] Time (month) Appearance content(%) <![CDATA[f2]]> 0 pale yellow 99.8 100 1 pale yellow 99.4 82.4 2 pale yellow 99.0 81.6 3 pale yellow 98.9 80.5

[0152] The results showed that the sustained-release pills in Example 1 did not exhibit significant changes in appearance, content, or release rate under accelerated experimental conditions for three months.

[0153] 5) Sample retention test

[0154] The self-made sustained-release microcapsules were packaged in aluminum-plastic blister packs and stored at room temperature (10–30°C) for 3 months. Samples were taken at 0, 1, 2, and 3 months and tested according to the required items. The results are shown in the table below.

[0155] Table 11. Room temperature stability of the sustained-release pills in Example 1

[0156] Time (month) Appearance content(%) <![CDATA[f2]]> 0 pale yellow 99.8 100 1 pale yellow 99.5 89.4 2 pale yellow 99.6 88.6 3 pale yellow 99.1 87.7

[0157] The results showed that the sustained-release pills in Example 1 did not show significant changes in appearance, content, or release rate under three-month room temperature retention conditions.

[0158] As can be seen from the above, the sustained-release microspheres prepared in the embodiments of the present invention have the following properties:

[0159] The average particle size is 0.71–0.85 mm;

[0160] The bulk density of the drug particles is 0.5–1.0 g / cm³. 3 The tap density is 0.6–1.2 g / cm³. 3 The angle of repose is less than 36°;

[0161] The drug exhibits good stability. Under accelerated testing conditions (temperature 40℃±2℃, relative humidity 75%±5%), there were no significant changes in appearance, color, content, or drug release characteristics after 3 months. Furthermore, under room temperature storage conditions (temperature 60%±5%), all quality indicators still met the specified requirements after 3 months, ensuring the drug's quality and efficacy remain stable and reliable within its shelf life.

[0162] In terms of preparation methods, the embodiments of the present invention first perform raw material pretreatment to ensure uniform particle size of each component, laying the foundation for uniform mixing in the subsequent process; surfactants and pH adjusters are added during the mixing and preparation of the soft material to further improve the uniformity of the soft material and the stability and dissolution performance of the drug; different molds can be changed during the extrusion process to meet the needs of various formulations; parameters can be adjusted and anti-adhesion agents can be added during sphericification to effectively control the sphericity, particle size distribution and surface quality of the particles and prevent adhesion; drying is carried out in stages to avoid particle deformation and drug degradation; different coating layers and thicknesses can be designed according to requirements in the granulation and coating stages to achieve timed and targeted drug release, such as enteric-coated and sustained-release double-layer coating structures, to improve therapeutic effects and reduce side effects.

[0163] In terms of raw material composition, the embodiments of this invention improve the uniformity of mixing among the pellet core raw materials and the stability and dissolution performance of the drug by adding surfactants and pH adjusters; the combination of penetration enhancers and pH adjusters can improve the drug's performance in terms of release control and bioavailability; disintegrants help improve drug release performance; and fillers and binders work together to ensure tablet formability, stability, and drug release. Through the combination of various excipients, the resulting pellet core has good stability and dissolution performance. Furthermore, through the coating of a specific coating layer, precise control of the drug release rate can be achieved. The pellets also have good flowability and storage stability, facilitating formulation processing and packaging, and possess significant clinical application value and market prospects.

[0164] The sustained-release pills prepared in this invention possess numerous excellent properties. The granules exhibit good flowability and filling properties, facilitating formulation processing and packaging. The sustained-release pills demonstrate excellent stability; under accelerated testing and long-term storage conditions, the changes in various quality indicators are minimal, ensuring stable and reliable drug quality and efficacy within the shelf life. This provides a safe and effective method for antipyretic analgesia, possessing significant clinical application value and market potential. The sustained-release pills prepared in this invention have an enteric-coated and sustained-release double-layer coating structure, which can improve therapeutic efficacy and reduce side effects.

[0165] In summary, this invention optimizes the drug composition by using specific excipients, thereby achieving precise control of the drug release rate and effectively improving the bioavailability and stability of the drug. It has promising application prospects in the preparation of antipyretic and analgesic drugs.

Claims

1. A sustained-release pill, characterized in that, The sustained-release pill comprises a core and a coating layer covering the core; the core is made from raw materials comprising the following parts by weight: 8-14 parts loxoprofen sodium, 30-60 parts filler, 3-10 parts binder, 2-10 parts disintegrant, 0.1-2 parts penetration enhancer, 0.05-0.2 parts pH adjuster, 0.1-0.5 parts surfactant and 0-20 parts adjuvant; the coating layer is made from an aqueous dispersion containing acrylic resin.

2. The sustained-release pill according to claim 1, characterized in that, The mass ratio of the coating layer to the pellet core is (4-20):

100.

3. The sustained-release pill according to claim 1, characterized in that, The filler includes at least one of microcrystalline cellulose, sucrose, or pregelatinized starch; And / or, the adhesive comprises at least one of hydroxypropyl methylcellulose, povidone, or ethylcellulose; And / or, the disintegrant includes at least one of ion exchange resin, croscarmellose sodium, or croscarmellose. And / or, the penetration enhancer includes laurocapram, menthol, or a combination thereof; And / or, the pH adjuster includes at least one of citric acid, sodium dihydrogen phosphate, or sodium bicarbonate; And / or, the surfactant includes sodium dodecyl sulfate, Tween-80, or a combination thereof.

4. The sustained-release pill according to claim 1, characterized in that, The additives in the raw materials of the pellet core include at least one of lubricant, flow aid, flavoring agent, colorant, antioxidant, wetting agent or anti-sticking agent.

5. The sustained-release pill according to claim 1, characterized in that, In the aqueous dispersion, the mass percentage of acrylic resin is 5-20%; And / or, the aqueous dispersion further contains an anti-adhesion agent, an antistatic agent, or a combination thereof.

6. The sustained-release pill according to claim 1, characterized in that, The bulk density of the sustained-release pills is 0.5–1 g / cm³. 3 ; And / or, the tap density of the sustained-release pills is 0.6–1.2 g / cm³. 3 ; And / or, the angle of repose of the sustained-release pills is ≤40°; And / or, the average particle size of the sustained-release pills is 0.5 to 2 mm.

7. A method for preparing a sustained-release pill as described in any one of claims 1 to 6, characterized in that, Includes the following steps: The raw materials for the pellet core are mixed and then extruded, spheroidized, and dried sequentially to obtain the pellet core; the pellet core is coated with the aqueous dispersion and then heat-treated to obtain the coating layer.

8. The preparation method according to claim 7, characterized in that, The coating temperature is 15–30°C; And / or, the temperature of the heat treatment is 30–50°C; And / or, the heat treatment time is 12 to 60 hours.

9. The preparation method according to claim 7, characterized in that, The extrusion speed is 30–60 r / min; And / or, the rolling speed is 1000-1500 r / min; And / or, the rounding time is 3 to 7 minutes.

10. The use of a sustained-release pill as described in any one of claims 1 to 6 in the preparation of an antipyretic and analgesic drugs.

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