Febuxostat enteric sustained-release micro-tablet capsule as well as preparation method and application thereof

Abstract

The invention discloses a febuxostat enteric-coated sustained-release micro-tablet capsule as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The capsule is a multi-unit drug delivery system and is formed by filling a hard capsule shell with an enteric sustained-release micro-coated chip with the diameter of 1.5-2.5 mm; the micro-coated chip comprises a febux drug-loaded tablet core and is externally coated with a functional coating film, and the coating film is of a single enteric-coated layer or a double-layer structure of a sustained-release layer and an enteric-coated layer. Through prescription-process cooperative control, the release rate of the preparation in 0.1 mol / L hydrochloric acid within 2 hours is less than or equal to 10%, the release rate of the preparation in a phosphate buffer solution with the pH value of 6.8 within 6 hours is 60-85%, and the release behavior conforms to Higuchi or zero-order kinetics and the fitting degree Rgt; and 0.85%. In-vivo research of Beagle dogs shows that Tmax is prolonged to 4.0-8.0 h, Cmax is reduced by 35%-65%, and the blood concentration gt; 100ng / mL is maintained for more than or equal to 12h, the peak-valley fluctuation coefficient is remarkably reduced compared with that of a reference preparation, a blood concentration-time curve is more stable, and administration can be performed once a day. According to the present invention, the defects of large blood concentration fluctuation, multi-time administration and strong gastrointestinal tract stimulation of the rapid release preparation are solved, and the rapid release preparation is suitable for gout and hyperuricemia treatment, and is especially suitable for gastrointestinal tract sensitive patients.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and specifically discloses a febuxostat enteric-coated sustained-release microcapsule, its preparation method, and its uses. Background Technology

[0002] Febuxostat is the first non-purine, selective xanthine oxidase (XO) inhibitor developed by Teijin Corporation of Japan. Its chemical structure is 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid, which reversibly binds to the molybdenum pterin cofactor at the XO active site, blocking the synthesis of uric acid at the terminal end. It was first approved in Japan in 2004 and subsequently launched in the EU and the US in 2008 under the brand names Adenuric® and Uloric®, respectively. Clinically, it is used to treat chronic hyperuricemia and gout. Compared to the classic drug allopurinol, febuxostat has higher XO selectivity and a stronger uric acid-lowering effect, making it particularly suitable for patients with allopurinol allergy or renal insufficiency.

[0003] The pharmacokinetic characteristics of febuxostat show that it is rapidly absorbed after oral administration, with a time to peak concentration (Tmax) of 1.0–1.5 hours, a half-life (t1 / 2) of 5–8 hours, an apparent volume of distribution (Vss / F) of 33–66 L, and a plasma protein binding rate as high as 99.2%. The efficacy threshold is well-defined: a plasma concentration >100 ng•mL⁻¹ can inhibit ≥80% of uric acid production. However, existing immediate-release tablets rapidly degrade below the threshold after 6 hours, exhibiting a significantly higher peak-to-trough ratio. This necessitates a high daily dose (40-80 mg) for maintenance, leading to elevated liver enzymes, skin rash, and an increased risk of cardiovascular thrombosis. This has been flagged by the FDA with a boxed warning (see FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat); 2019-02-21. https: / / www.fda.gov / drugs / drug-safety-and-availability / fda-adds-boxed-warning-increased-risk-death-gout-medicine-uloric-febuxostat). Furthermore, immediate-release tablets disintegrate rapidly in the stomach; if the local concentration is too high, it can directly irritate the gastric mucosa, causing adverse reactions such as stomach pain, nausea, and vomiting.

[0004] CN101773498 A discloses a method for preparing an oral sustained-release formulation containing febuxostat. Although sustained release of febuxostat is achieved through matrix or film coating, it is still a single-unit tablet / pill. Individual differences in gastric emptying are large, and the Tmax fluctuation is wide and the absorption window utilization is low due to different gastric retention times.

[0005] CN 109985016 A discloses a febuxostat gastric retention controlled-release composition, which achieves gastric retention through the expansion of the outer coating by absorbing water and then ruptures to release the drug after 4 hours. Combined with the immediate-release layer, it achieves biphasic release. However, it is a single-unit large tablet (8-22mm), and gastric emptying is highly dependent on the state of eating. The size after expansion can reach 22mm, resulting in large individual differences and poor Tmax reproducibility. Moreover, it ruptures once after 4 hours, and the drug is concentrated in the stomach or proximal small intestine, failing to make full use of the window characteristics of febuxostat, which is "high absorption in the upper small intestine and low absorption in the colon", resulting in a high risk of AUC loss.

[0006] While CN115297848 A's "single-unit compressed chip" can rupture and release the drug after remaining in the stomach for 3-4 hours after eating, its large 12-16mm diameter chip emptying is highly dependent on gastric motility and food status, with individual Tmax differences reaching 2-5 hours. Furthermore, a single rupture causes the drug to be concentrated in the stomach and proximal small intestine, failing to fully utilize the narrow absorption window of febuxostat (high absorption in the upper small intestine, low absorption in the colon), resulting in a high risk of AUC loss. In addition, without enteric coating protection, sudden release in the stomach may still irritate the mucosa.

[0007] Febuxostat absorption exhibits significant site dependence: its bioavailability is as high as 96.63% in the proximal small intestine, 84.05% in the distal small intestine, and only 34.75% in the colon. Although food intake can cause a 38-49% decrease in peak plasma concentration (Cmax), it has a limited effect on the area under the curve (AUC) (only a decrease of about 16%), indicating that "sustained exposure" is more decisive for efficacy than "peak exposure".

[0008] If traditional sustained-release formulations release less than 60% of their contents before passing the ileocecal valve, the AUC loss may exceed 40%, severely impacting therapeutic efficacy. Furthermore, traditional single-unit tablets, due to significant individual variations in gastric emptying, struggle to simultaneously meet the dual requirements of "targeted release" and "controlled release."

[0009] To overcome the aforementioned limitations, a novel drug delivery system is urgently needed in clinical practice, capable of precise targeting and optimized drug release kinetics. An ideal system should possess the following characteristics: zero release in the stomach, precise targeting in the upper small intestine, and release of approximately 60-85% of the drug within 6 hours, thus fully utilizing the high absorption window of the proximal small intestine; simultaneously, significantly reducing Cmax and extending the plateau period maintaining plasma drug concentrations above 100 ng / mL⁻¹ to at least 12 hours. This system aims to achieve stable once-daily uric acid lowering, improving efficacy while reducing adverse reactions and enhancing patient adherence.

[0010] To address the aforementioned needs, this invention proposes an "enteric-coated sustained-release microcapsule" as an innovative solution for a multi-unit delivery system. Compared to single-unit enteric-coated tablets with a diameter greater than 7 mm, the 2 mm-sized microcapsules used in this system can rapidly pass through the pylorus as a whole, significantly reducing the coefficient of variation in gastric emptying, thereby significantly reducing inter-individual differences in time to peak (Tmax) and improving pharmacokinetic consistency and the predictability of clinical efficacy. By integrating enteric coating and sustained-release microcapsule technologies, this system achieves effective regulation of drug release behavior while realizing gastric protection and targeted release. Summary of the Invention

[0011] This invention aims to overcome three major clinical shortcomings of existing febuxostat tablets: drastic fluctuations in peak and trough blood drug concentrations, a tendency for blood drug concentrations to drop below the therapeutic threshold 6 hours after administration, and significant inter-individual differences in absorption. It provides a "febuxostat sustained-release enteric-coated microcapsule" and its drug delivery system that enables precise release into the small intestine. This system aims to achieve stable uric acid-lowering therapy with "once-daily dosing, low peak blood drug concentrations, and a long-lasting effective therapeutic platform."

[0012] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: Option 1: A type of sustained-release enteric-coated microcapsule capsule with a "sustaining-release matrix + enteric coating" structure. The core of this solution lies in providing a microchip with a diameter of 1.5–2.5 mm, whose core employs sustained-release matrix technology and is coated with a double-layer enteric coating. The system comprises the following components: febuxostat, sustained-release matrix material, filler, lubricant or flow aid, and enteric coating material.

[0013] Tablet core composition: The tablet core is premixed with febuxostat and hydrophilic gel matrix materials (such as hydroxypropyl methylcellulose HPMC E5 / K100LV) to form a sustained-release network with a rate controlled by erosion and diffusion mechanisms.

[0014] Dosage specifications: The microplate contains 20 mg, 40 mg or 80 mg of febuxostat.

[0015] Matrix material: The sustained-release matrix material is a low-viscosity hydrophilic gel matrix material, selected from low-viscosity hydroxypropyl methylcellulose (HPMC), low-viscosity hydroxyethyl cellulose (HEC), low-viscosity hydroxypropyl cellulose (HPC), or sodium alginate; its viscosity, measured in a 2% aqueous solution (1% aqueous solution for sodium alginate) at 20°C, is 3 mPa·s to 100 mPa·s. The amount of the low-viscosity hydrophilic gel matrix material is 5%–20% (w / w) of the tablet core weight.

[0016] Excipient system: The system contains pharmaceutically acceptable excipients such as fillers, disintegrants, binders, lubricants or flow aids.

[0017] Enteric coating: It adopts a double-layer enteric coating design with inner and outer layers. The inner layer is an organic solvent-based enteric material, and the outer layer is a water-dispersion enteric material, which also contains corresponding plasticizers, anti-sticking agents and other auxiliary components.

[0018] Preparation and Filling: The tablet cores are prepared by direct powder compression or wet granulation processes, with the hardness controlled at 2.0–3.0 kg. The prepared microtablets are then coated with enteric coating and filled into hard capsule shells to form a multi-unit microcapsule system for once-daily oral administration.

[0019] Option 2: An enteric-sustained-release microcapsule with a "rapid-release core-sustained-release layer-enteric coating layer" structure. This solution offers another microchip with a diameter of 1.5–2.5 mm, the core of which is an immediate-release structure, achieving precise control through sequential coating of a sustained-release layer and an enteric coating layer. The system comprises the following components: febuxostat, binder, filler, lubricant or flow aid, sustained-release coating layer, and enteric coating layer.

[0020] Core structure: In addition to the immediate-release tablet core, a sustained-release coating layer is first coated as a rate-regulating membrane, and then a double-layer enteric coating is coated on the outer layer.

[0021] Sustained-release coating layer: The sustained-release coating material can be selected from hydrophilic gel type, water-insoluble film-forming material or hydrophobic erosion material, and a pore-forming agent can be optionally added.

[0022] Coating parameters: The dry weight gain of the sustained-release layer is 2–8%, and the total weight gain of the enteric double coating is 10–20%, to ensure extremely low release in the stomach and rapid triggering and smooth release without bursts in the small intestinal environment.

[0023] Technical features and effects The febuxostat enteric-coated sustained-release microcapsules of the present invention have the following key technical features and effects: In vitro release characteristics: The cumulative release rate of the drug in pH 6.8 phosphate buffer was calculated using the following mathematical model ( Q , %)-time( tThe data (h) were subjected to fitting analysis (using OriginPro 2022b software): Zero-order dynamics model: Fitting equation: Q = k 0⋅ t + C Analysis method: Q right t Perform ordinary least squares (OLS) linear regression.

[0024] Higuchi model: Fitting equation: Q = kH ⋅ t + C Analysis method: Q right t Perform OLS linear regression.

[0025] First-order dynamic model (as a control): Fitting equation: ln(100− Q )=ln(100)− k 1⋅ t Alternatively, its nonlinear form can be used for nonlinear least-squares fitting: Q =100⋅[1−exp(− k 1⋅ t )] Analysis method: using ln(100− Q ) right t Perform OLS linear regression.

[0026] Judgment criteria: If the data fits the zero-order model or the Higuchi model well... R If 2 > 0.85, and this goodness of fit is higher than that for the first-order kinetic model, then the drug release behavior is determined to conform to the corresponding release kinetic model.

[0027] Calculation results: The release behavior of the drug in pH 6.8 phosphate buffer conforms to the Higuchi model or zero-order release kinetics, and the release curve fits the model well. R 2>0.85.

[0028] In vivo pharmacokinetic characteristics: The capsules exhibited ideal sustained-release effects in Beagle dogs, with a time to peak release (Tmax) prolonged to 4.0-8.0 hours, a duration of plasma concentration >100 ng / mL not less than 12 hours, and a peak concentration (Cmax) 35%-65% lower than that of equivalent doses of febuxostat immediate-release tablets. Furthermore, its relative bioavailability was 85%-125%, and the peak-to-trough ratio of plasma concentration (Cmax / C24h) within 24 hours of administration was less than 65.

[0029] Stability characteristics: The capsules exhibited good stability after being placed under accelerated testing conditions of 40℃±2℃ / 75%±5% relative humidity for 6 months, with the increase in single impurities of the main related substances not exceeding 0.2% and the increase in total impurities not exceeding 0.5%. Moreover, the dissolution curve in pH 6.8 phosphate buffer showed a similarity factor f2 ≥ 60 compared to the 0-month condition. After a long-term test at 25℃±2℃ / 60%±5%RH for 12 months, the increase in single impurities was ≤0.2% and the increase in total impurities was ≤0.5%, and the dissolution curve in pH 6.8 phosphate buffer showed a similarity factor f2 ≥ 60 compared to the 0-month condition.

[0030] Preparation process The preparation process of this invention is stable and controllable, and mainly includes: Core preparation: The core is prepared by using a 2 mm shallow concave die and by direct powder pressing or wet granulation process to control the hardness and brittleness of the core.

[0031] Coating process: Bottom-spray fluidized bed coating technology is adopted, and the sustained-release layer and enteric coating are carried out in sequence, with strict control of coating parameters.

[0032] Capsule filling: Microchips are filled into hard capsule shells to form a multi-unit drug delivery system.

[0033] Advantages and positive effects of the invention Compared with the prior art, the present invention has the following significant advantages: Significant absorption advantages: The enteric design of this product is designed to actively utilize the absorption characteristics of febuxostat: Firstly, by delivering the drug intact to the absorption window of the small intestine and releasing it in a concentrated manner, it aims to overcome the influence of irregular gastric emptying and make full use of the high absorption area; secondly, this design is a prerequisite for the subsequent sustained-release layer to control the release at a preset rate, together creating conditions for obtaining higher and more stable bioavailability.

[0034] Small individual differences: The microplate of the present invention belongs to a multi-unit system, so its gastric emptying behavior conforms to the pattern reported in the literature (e.g., coefficient of variation CV < 15%), and has the inherent advantage of consistent emptying. As a multi-unit system, the microplate effectively shortens the fluctuation window of the time to peak (Tmax) in the population and improves the predictability of the therapeutic effect.

[0035] Significant clinical advantages: Key pharmacokinetic characteristics exhibited by this product in Beagle dogs—including sustained plasma concentrations >100 ng / mL for at least 12 hours and a flat plasma concentration profile—provide a basis for exploring once-daily dosing regimens and assessing its potential to improve medication safety. These characteristics indicate that this formulation has the therapeutic potential to achieve sustained control of serum uric acid levels.

[0036] In summary, this invention, through two technical approaches—"skeleton + membrane control" and "immediate-release core - sustained-release membrane - enteric-coated shell"—successfully achieved the triple goals of "zero release in the stomach, near-zero release in the small intestine, and long-term plateau maintenance in vivo" on the same 2 mm microsheet, filling the gap in the field of febuxostat's precise release multi-unit dosage form in the small intestine, and has clear clinical value and broad industrialization prospects. Attached Figure Description

[0037] Appendix Figure 1 Image of Febuxostat enteric-coated sustained-release microcapsules Appendix Figure 2 Micro-die (φ2 mm) appearance drawing Appendix Figure 3 Dissolution profiles of formulations in Examples 1–7 in pH 6.8 phosphate buffer. Appendix Figure 4 Example 1: Comparison of plasma concentration-time curves of microcapsules and immediate-release tablets (Febuli®) in Beagle dogs. Detailed Implementation

[0038] The present invention will be further described in detail below with reference to the embodiments.

[0039] Example 1 (microflakes containing sustained-release matrix material, 1000 flakes / batch)

[0040] Preparation Method: The sieved febuxostat, lactose monohydrate, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (E5), and croscarmellose sodium are added to a high-efficiency wet granulation mixer. The agitator is turned on, and the mixture is dry-mixed for 15-20 minutes until homogeneous. While stirring, a 5% (w / w) aqueous solution of the prepared povidone K30 is slowly added, and the cutter is turned on for wet granulation. The wet granules are transferred to a fluidized bed dryer. The inlet air temperature is controlled at 50-60℃, and the material moisture content is dried to ≤3.0%. The dried granules are then sized by passing them through a 24-mesh sieve. The sized dry granules are transferred to a mixer. The prescribed amount of magnesium stearate (lubricant) is added, and mixing continues for 3-5 minutes. The powder is then compressed using a micro-tablet press equipped with a 2.0mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the brittleness is ≤0.3%. The tablet cores are then loaded into the fluidized bed hopper. Start fluidization, set the inlet air temperature to 40-45℃, and preheat the tablet cores until the material temperature stabilizes at 30-35℃. Turn on the spray gun, adjust the atomization pressure and spray speed, and continuously and evenly spray the enteric coating solution. Control the inner layer weight gain of the enteric coating to between 2% and 4%, and the outer layer weight gain to between 5% and 10%. After appropriate drying, allow to cool. After filling the microcapsules with No. 1 capsules, proceed with blister packaging.

[0041] Example 2 (microflakes containing sustained-release matrix material, 1000 flakes / batch)

[0042] Preparation method: Sifted febuxostat, lactose monohydrate, microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (K100 LV), and croscarmellose sodium are added to a high-efficiency wet granulation mixer. The agitator is turned on, and the mixture is dry-mixed for 15-20 minutes until homogeneous. While stirring, a 5% (w / w) aqueous solution of the prepared povidone K30 is slowly added, and the cutter is turned on for wet granulation. The wet granules are transferred to a fluidized bed dryer. The inlet air temperature is controlled at 50-60℃, and the material moisture content is dried to ≤3.0%. The dried granules are then sized by passing them through a 24-mesh sieve. The sized dry granules are transferred to a mixer. The prescribed amount of magnesium stearate (lubricant) is added, and mixing continues for 3-5 minutes. The powder is then compressed using a micro-tablet press equipped with a 2.0mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the brittleness is ≤0.3%. The tablet cores are then loaded into the fluidized bed hopper. Start fluidization, set the inlet air temperature to 40-45℃, and preheat the tablet cores until the material temperature stabilizes at 30-35℃. Turn on the spray gun, adjust the atomization pressure and spray speed, and continuously and evenly spray the enteric coating solution. Control the inner layer weight gain of the enteric coating to between 2% and 4%, and the outer layer weight gain to between 5% and 10%. After appropriate drying, allow to cool. After filling the microcapsules with No. 1 capsules, proceed with blister packaging.

[0043] Example 3 (microflakes containing sustained-release matrix material, 1000 flakes / batch)

[0044] Preparation method: Sifted febuxostat, lactose monohydrate, microcrystalline cellulose (MCC), hydroxyethyl cellulose (HEC, Natrosol™ 250L), and croscarmellose sodium are added to a high-efficiency wet mixing granulator. The agitator is turned on, and the mixture is dry-mixed for 15-20 minutes until homogeneous. The prescribed amount of colloidal silica (flow aid) is added, and the mixture is mixed for 3-5 minutes. The prescribed amount of magnesium stearate (lubricant) is added, and the mixture is continued for 3-5 minutes. The powder is then compressed into tablets using a micro-tablet press equipped with a 2.0mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the brittleness is ≤0.3%. The tablet cores are loaded into the fluidized bed hopper. The fluidization process is turned on, and the inlet air temperature is set to 40-45℃. The tablet cores are preheated until the material temperature stabilizes at 30-35℃. The spray gun is turned on, and the atomization pressure and spray speed are adjusted to continuously and evenly spray the enteric coating solution. The weight gain of the inner layer of the enteric coating is controlled between 2% and 4%, and the weight gain of the outer layer is controlled between 5% and 10%. After proper drying, the tablets are cooled. After being filled into No. 1 capsules, they are then blister packaged.

[0045] Example 4 (microflakes containing sustained-release matrix material, 1000 flakes / batch)

[0046] Preparation method: Sifted febuxostat, lactose monohydrate, microcrystalline cellulose (MCC), hydroxypropyl cellulose Klucel™ LF, and croscarmellose sodium are added to a high-efficiency wet mixing granulator. The agitator is turned on, and the mixture is dry-mixed for 15-20 minutes until homogeneous. The prescribed amount of colloidal silica (flow aid) is added, and the mixture is stirred for 3-5 minutes. The prescribed amount of magnesium stearate (lubricant) is added, and the mixture is stirred for another 3-5 minutes. The powder is then compressed into tablets using a micro-tablet press equipped with a 2.0mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the friability is ≤0.3%. The tablet cores are loaded into the fluidized bed hopper. The fluidization process is turned on, and the inlet air temperature is set to 40-45℃. The tablet cores are preheated until the material temperature stabilizes at 30-35℃. The spray gun is turned on, and the atomization pressure and spray speed are adjusted to continuously and evenly spray the enteric coating solution. The weight gain of the inner layer of the enteric coating is controlled between 2% and 4%, and the weight gain of the outer layer is controlled between 5% and 10%. After proper drying, the tablets are cooled. After being filled into No. 0 capsules, the tablets are then blister packaged.

[0047] Example 5 (microflakes containing sustained-release matrix material, 1000 flakes / batch)

[0048] Preparation method: Sifted febuxostat, lactose monohydrate, microcrystalline cellulose (MCC), sodium alginate Manugel™ DMB, and croscarmellose sodium cellulose are added to a high-efficiency wet mixing granulator. The agitator is turned on, and the mixture is dry-mixed for 15-20 minutes until homogeneous. The prescribed amount of colloidal silica (flow aid) is added, and the mixture is stirred for 3-5 minutes. The prescribed amount of magnesium stearate (lubricant) is added, and the mixture is stirred for another 3-5 minutes. The powder is then compressed into tablets using a micro-tablet press equipped with a 2.0mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the friability is ≤0.3%. The tablet cores are loaded into the fluidized bed hopper. The fluidization process is turned on, and the inlet air temperature is set to 40-45℃. The tablet cores are preheated until the material temperature stabilizes at 30-35℃. The spray gun is turned on, and the atomization pressure and spray speed are adjusted to continuously and evenly spray the enteric coating solution. The weight gain of the inner layer of the enteric coating is controlled between 2% and 4%, and the weight gain of the outer layer is controlled between 5% and 10%. After proper drying, the tablets are cooled. After being filled into No. 0 capsules, the tablets are then blister packaged.

[0049] Example 6 (microtablets containing a sustained-release coating, 1000 tablets / batch)

[0050] Preparation method: Sifted febuxostat, lactose, microcrystalline cellulose, and croscarmellose sodium are added to a high-efficiency wet mixing granulator. The agitator is turned on, and dry mixing is carried out for 15-20 minutes until the materials are uniformly mixed. The prescribed amount of colloidal silica (flow aid) is added, and mixing is carried out for 3-5 minutes. The prescribed amount of magnesium stearate (lubricant) is added, and mixing continues for 3-5 minutes. The powder is then compressed into tablets using a micro-tablet press equipped with a 2.0mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the brittleness is ≤0.3%. The tablet cores are loaded into the fluidized bed hopper. Fluidization is turned on, and the inlet air temperature is set to 40-45℃. The tablet cores are preheated until the material temperature stabilizes at 30-35℃. The spray gun is turned on, and the atomization pressure and spray speed are adjusted to continuously and uniformly spray the slow-release coating solution and enteric coating solution sequentially. The weight gain of the sustained-release coating layer was controlled between 5% and 8%, the weight gain of the inner layer of the enteric coating was controlled between 2% and 4%, and the weight gain of the outer layer was controlled between 5% and 10%. After proper drying, the tablets were cooled. After being filled into No. 1 capsules, the tablets were then blister packaged.

[0051] Example 7 (microtablets containing a sustained-release coating, 1000 tablets / batch)

[0052] Preparation method: Sifted febuxostat, lactose, microcrystalline cellulose, and croscarmellose sodium are added to a high-efficiency wet mixing granulator. The agitator is turned on, and the mixture is dry-mixed for 15-20 minutes until homogeneous. The prescribed amount of colloidal silica is added and mixed for 3-5 minutes. The prescribed amount of magnesium stearate is added, and mixing continues for 3-5 minutes. The powder is then compressed into tablets using a micro-tablet press equipped with a 2.0 mm circular shallow concave die. The tablet core hardness is controlled at 2-3 kg, and the brittleness is ≤0.3%. The tablet cores are loaded into a fluidized bed hopper. Fluidization is turned on, and the inlet air temperature is set to 40-45℃. The tablet cores are preheated until the material temperature stabilizes at 30-35℃. The spray gun is turned on, and the atomization pressure and spray speed are adjusted to continuously and evenly spray the slow-release coating solution and enteric coating solution sequentially. The weight gain of the sustained-release coating layer was controlled between 5% and 8%, the weight gain of the inner enteric coating layer was controlled between 2% and 4%, and the weight gain of the outer coating layer was controlled between 5% and 10%. After proper drying, the tablets were cooled. After being filled into No. 0 capsules, the tablets were then blister packaged.

[0053] Experiment 1. Dissolution Comparison Test Take the samples prepared in Examples 1 to 7 above, and perform the dissolution and release determination method II (paddle method) (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931). Take 900 ml of 0.1N hydrochloric acid as the dissolution medium, rotate at 50 rpm, and keep the water temperature at 37℃±0.5℃. After 2 hours, take 10 ml of the sample (immediately replenish the solution), filter it through a 0.45µm filter membrane, and accurately measure an appropriate amount of the filtrate as the test solution. Separately, take 11 mg of febuxostat reference standard, place it in a 100 ml volumetric flask, dissolve and dilute it to the mark with phosphate buffer (pH 6.8), shake well, accurately measure 5 ml of it and place it in a 100 ml volumetric flask, add 0.1N hydrochloric acid to dissolve and dilute to the mark, shake well, and use it as the reference solution. Take the test solution and the reference solution, and measure the absorbance at a wavelength of 317 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0401). Calculate the acid phase dissolution amount of each tablet (which should be <10%).

[0054] Determination of pH 6.8 phosphate buffer dissolution: Discard the acid in each dissolution vessel and immediately add pH 6.8 phosphate buffer at 37℃±0.5℃. Continue to determine the dissolution as described above. Take 10 ml samples at 1, 2, 4, 6, 8, and 12 hours (immediate replenishment), filter through a 0.45µm filter membrane, accurately measure an appropriate amount of the filtrate, and dilute it with the appropriate dissolution medium to a solution containing approximately 5.5µg per ml as the test solution. Separately, take 11 mg of febuxostat reference standard, place it in a 100 ml volumetric flask, dissolve and dilute it to the mark with phosphate buffer (pH 6.8), shake well, accurately measure 5 ml and place it in a 100 ml volumetric flask, add phosphate buffer (pH 6.8) and dilute to the mark, shake well, as the reference solution. Take the test solution and the reference solution, and measure the absorbance at a wavelength of 317 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0401). Calculate the dissolution amount of each tablet. The dissolution results are shown in the table below.

[0055]

[0056] The experimental data above show that the febuxostat microcoated tablets prepared by this method can release the drug stably and continuously. After the capsule shell dissolves in the stomach, the micro-tablets, due to their small size, can easily pass through the pylorus and enter the intestines evenly. The micro-tablets dispersed in the intestines avoid irritation to the stomach and further avoid intestinal irritation caused by excessively high local drug concentrations, thereby reducing the incidence of adverse reactions and improving the safety of medication.

[0057] Experiment 2. Pharmacokinetic Comparison (Beagle dogs, n=12, two-period crossover) This experiment employed a two-period crossover design, in which 12 male Beagle dogs were divided into two groups and administered 80 mg (2 capsules × 40 mg) febuxostat microcapsules (T) and 80 mg (2 tablets × 40 mg) febuxostat tablets (Febuxostat®) by gavage, respectively. The drug concentration-time changes in Beagle dogs were compared and the pharmacokinetic behavior of the two drugs was studied.

[0058] Following a single oral administration of 80 mg febuxostat microcapsules to Beagle dogs, the plasma concentration showed an initial small peak (≈865 ng / mL) at approximately 0.5 h, continued to rise from 2.0 h, and reached the main peak (≈2015 ng / mL) at 7.0 h. The overall Cmax was 2015 ± 305 ng / mL, and the time to peak concentration (Tmax) was 7.0 (4.0–8.0) h. The area under the concentration-time curve (AUC0₋) was [missing value]. 24 The mean value was 8500±900 h•ng / mL, and the total time for blood drug concentrations above 100 ng / mL was 16.5±0.8 h.

[0059] Following a single oral administration of 80 mg febuxostat tablets (Febuli®) to Beagle dogs, peak plasma concentrations were reached at 1.0 (0.5–1.5) h, with a Cmax of 3529 ± 600 ng / mL; AUC0₋ 24 The value was 7960±900 h•ng / mL, and 7.5±0.9h for T>100ng / mL.

[0060] In Beagle dogs, oral administration of 80 mg febuxostat microcapsules compared to 80 mg febuxostat tablets demonstrated that, with comparable systemic exposure (AUC) (relative bioavailability 107 ± 12%), the sustained-release characteristics of the microcapsules successfully addressed the key clinical deficiencies of the original product. Delayed peak concentration, mitigating peak concentration risks: Tmax is significantly prolonged from 1.0 hour to 7.0 hours, and Cmax is significantly reduced (approximately 57% of the reference formulation). This characteristic helps to mechanistically avoid the risks associated with sudden and drastic fluctuations in blood drug concentration, such as elevated liver enzymes, rash, and cardiovascular thrombosis, which are often associated with these adverse effects.

[0061] Significantly prolonged duration of action: The duration of effective plasma concentration (T > 100 ng / mL) was significantly extended from 7.5 hours for the reference formulation to 16.5 hours for the test formulation, which is 2.2 times that of the reference formulation. This ensures more sustained and stable inhibition of uric acid production within a 24-hour dosing interval, fundamentally solving the problem of incomplete efficacy coverage caused by insufficient half-life of immediate-release tablets and premature drop in plasma concentration below the effective threshold during dosing intervals.

[0062] Significantly improved blood drug concentration stability: The peak-to-trough ratio was significantly reduced. The estimated peak-to-trough ratio (Cmax / C24h, C24h at 10 ng / mL) for the reference formulation (immediate-release) was approximately 353; while the estimated peak-to-trough ratio (Cmax / C24h, C24h at 35 ng / mL) for the test formulation (extended-release) was approximately 58. This greatly improved blood drug concentration stability not only reduces the risk of efficacy fluctuations but also strongly supports the inference from a pharmacokinetic perspective that its potential safety is superior to existing immediate-release tablets.

[0063] Achieving dual protection for the gastrointestinal tract: The enteric coating design of the microcapsules ensures that the drug is not released in gastric juice (pH 1.0-3.0), directly solving the problem of direct irritation of the gastric mucosa (such as stomach pain, nausea, and vomiting) that may be caused by the concentrated disintegration of immediate-release tablets in the stomach and excessively high local drug concentration.

[0064] Experiment 3. Stability Study The capsules of this invention were placed under accelerated conditions of 40℃±2℃ / 75%±5% RH for 6 months. Related substances were determined by HPLC. At month 0, the single impurity was 0.05% and the total impurity was 0.12%. After 6 months, the single impurity was 0.18% (increase of 0.13%, <0.2%) and the total impurity was 0.48% (increase of 0.36%, <0.5%).

[0065] Dissolution curve similarity: The similarity factor f2 between the dissolution curves of the sample at 6 months and the sample at 0 months in pH 6.8 phosphate buffer was calculated, and the result was 68 (>60), indicating that there was no significant change in the release behavior.

[0066] This product (aluminum-aluminum blister packaging) was stored at 25℃±2℃ / 60%±5%RH for 12 months, and samples were taken at 0, 3, 6, 9, and 12 months for analysis. Results: At 12 months, the single impurity was 0.16% (increase ≤0.2%), and the total impurity was 0.42% (increase ≤0.5%). Dissolution curve similarity: The similarity factor f2 between the dissolution curves of the sample at 12 months and the sample at 0 months in pH 6.8 phosphate buffer was calculated, and the result was 71 (>60), indicating that there was no significant change in the release behavior and that it met the requirements for long-term stability.

[0067] Conclusion: This embodiment details the preparation process of the present invention and demonstrates through sufficient experimental data that the prepared febuxostat enteric-coated sustained-release microcapsules fully achieve the triple design goals of "zero release in the stomach, near-zero release in the small intestine, and long plateau maintenance in vivo." Its in vitro release behavior is as expected, its in vivo pharmacokinetic characteristics are ideal, and its stability is good, fully verifying the inventiveness and practicality of the present invention.

Claims

1. A febuxostat enteric-coated sustained-release microcapsule, characterized in that, It is a multi-unit drug delivery system made by filling 10-100 micro-chips with a diameter of 1.5-2.5 mm into a hard capsule shell; the micro-chips include: a) Tablet core: Contains a therapeutically effective amount of febuxostat and pharmaceutically acceptable excipients; b) Functional coating layer: covering the tablet core, the functional coating layer is an enteric coating layer, or from the inside out is a sustained-release layer and an enteric coating layer; The microchip exhibits the following characteristics: a cumulative release rate of no more than 10% in 0.1 mol / L hydrochloric acid solution over 2 hours; a cumulative release rate of 60% to 85% in pH 6.8 phosphate buffer over 6 hours; and a cumulative release rate of no less than 90% over 12 hours. The capsule, after oral administration, exhibits the following pharmacokinetic characteristics in Beagle dogs: a prolonged time to peak concentration (Tmax) of 4.0-8.0 hours; a duration of plasma concentration >100 ng / mL of no less than 12 hours; a peak concentration (Cmax) 35%-65% lower than that of equivalent doses of febuxostat immediate-release tablets; and a relative bioavailability (AUC 0-t ratio) of 80%–125%.

2. The febuxostat enteric-coated sustained-release microcapsule according to claim 1, characterized in that, The functional coating layer is an enteric coating layer; the tablet core contains a sustained-release matrix material, which is a low-viscosity hydrophilic gel matrix material, to ensure that the cumulative release of the drug in pH 6.8 phosphate buffer is 60% to 85% after 6 hours; The low-viscosity hydrophilic gel skeleton material is selected from low-viscosity hydroxypropyl methylcellulose (HPMC), low-viscosity hydroxyethyl cellulose (HEC), low-viscosity hydroxypropyl cellulose (HPC), or sodium alginate; The viscosity of the low-viscosity hydrophilic gel framework material measured in a 2% aqueous solution (sodium alginate is a 1% aqueous solution) at 20°C is 3 mPa·s to 100 mPa·s. The amount of the low-viscosity hydrophilic gel skeleton material is 5%–20% (w / w) of the core weight.

3. The capsule according to any one of claims 1 to 2, characterized in that, The enteric coating layer consists of an inner layer and an outer layer: The inner layer is an organic solvent-based enteric coating, with the coating material selected from Eutectic L100, Eutectic S100, or HPMCP. The coating weight gain is 2.0%–4.0% of the tablet core weight. The outer layer is an enteric coating of water dispersion type, and the coating material is selected from Eutectic L30D-55 or Eutectic FS 30D. The coating weight gain is 8.0%–15.0% of the tablet core weight.

4. The febuxostat enteric-coated sustained-release microcapsule according to claim 1, characterized in that, The functional coating layer consists of a sustained-release layer and an enteric coating layer from the inside out. The sustained-release layer is composed of a water-insoluble film-forming material, a pore-forming agent, and an optional plasticizer; The water-insoluble film-forming material is selected from one or more of the following: ethyl cellulose, cellulose acetate, acrylic resin Utec RS 100, and Utec RL 100; The porogen is selected from one or more of polyethylene glycol 4000, polyethylene glycol 6000, povidone K30, and hydroxypropyl methylcellulose E5; the porogen accounts for 10%–30% (w / w) of the dry weight of the sustained-release layer. The plasticizer is selected from one or more of the following: triethyl citrate, dibutyl sebacate, and diethyl phthalate; The dry weight gain of the sustained-release layer is 3%–8% of the tablet core weight; The composition and characteristics of the enteric coating layer conform to the definition in claim 3.

5. The capsule according to any one of claims 1 to 4, characterized in that, The tablet core is prepared by direct powder compression or wet granulation process; the hardness of the tablet core is 2.0–3.0 kg and the brittleness is not greater than 0.3%; the micro-chip is filled into a hard capsule shell, and each capsule contains a total of 100–500 mg of micro-chip, of which the febuxostat content is 20 mg, 40 mg or 80 mg, forming a multi-unit micro-pellet system for once-daily oral administration.

6. The capsule according to any one of claims 1 to 5, characterized in that, The in vitro release performance of the micro-packet chip simultaneously meets the following conditions: a) The cumulative release rate in 0.1 mol / L hydrochloric acid solution over 2 hours does not exceed 10%; b) The cumulative release rate in phosphate buffer at pH 6.8 was 60% to 85% over 6 hours; c) The release behavior in pH 6.8 phosphate buffer conforms to the Higuchi model or zero-order release kinetics, and the goodness of fit between the release curve and the model is R² > 0.

85. For details of the fitting method, please refer to the instruction manual.

7. The capsule according to any one of claims 1 to 6, characterized in that, a) In an accelerated test at 40℃±2℃ / 75%±5%RH for 6 months, the increase in single impurity is ≤0.2%, the increase in total impurity is ≤0.5%, the genotoxic impurity F is ≤18ppm, and the similarity factor f2 of the dissolution curve in pH 6.8 phosphate buffer is ≥60 compared to that at 0 months. b) In a long-term test at 25℃±2℃ / 60%±5%RH for 24 months, the increase in single impurity is ≤0.2%, the increase in total impurity is ≤0.5%, the genotoxic impurity F is ≤18ppm, and the similarity factor f2 of the dissolution curve in pH 6.8 phosphate buffer is ≥60 compared to that at 0 months.

8. The febuxostat enteric-coated sustained-release microcapsules according to any one of claims 1 to 7, characterized in that, The capsule is used in the preparation of a drug for lowering blood uric acid levels, which is suitable for patients with gout, hyperuricemia, hyperuricemia-related nephropathy or metabolic syndrome, and is particularly suitable for people with a history of gastrointestinal discomfort, mild liver dysfunction or intolerance to febuxostat immediate-release formulations.

9. The capsule according to any one of claims 1 to 8, characterized in that, Its pharmacokinetic characteristics in Beagle dogs (single oral administration of 80 mg) also meet the following conditions: a) The duration of blood drug concentration >100 ng / mL should not be less than 12 hours; b) The peak-to-trough ratio of blood drug concentration (Cmax / C24h) within 24 hours of drug administration is less than 65; c) Relative bioavailability is 80%-125%.

10. The use of febuxostat enteric-coated sustained-release microcapsules according to any one of claims 1 to 9 in the preparation of a drug for lowering serum uric acid levels, wherein the drug is administered orally once daily and has a Cmax reduced by 35%–65%, a Tmax prolonged to 4.0–8.0 hours, and a relative bioavailability of 80%–125% compared with equivalent doses of febuxostat immediate-release tablets.

Images