Dotenorad tablet and preparation method thereof

Abstract

The invention discloses a dotenorad tablet and a preparation method thereof, belongs to the technical field of medicine preparation, and is used for solving the technical problem that the dissolution rate and the disintegration rate of the dotenorad tablet in the prior art need to be further improved. A preparation method of a dotenorad tablet comprises the following steps: carrying out ball milling on a dispersion liquid by using a planetary ball mill, and carrying out post-treatment to obtain a dotenorad nanocrystal, the Gemini type modified surfactant, the modified chitosan oligosaccharide and the modified xanthan gum are cooperatively introduced, stable dispersion of nanocrystals, uniform forming of a tablet structure and efficient control of a sustained-release coating are achieved, the three components perform their own functions, a stable and controllable drug release system is constructed, the dissolution rate, content uniformity and storage stability of the preparation are effectively improved, and the sustained-release effect of the tablet is improved. And the technical bottlenecks of poor dispersibility, unstable release and the like of the traditional preparation dotenorad tablet are broken through.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a dotenoradine tablet and its preparation method. Background Technology

[0002] Dotenorazole tablets, a novel antiplatelet drug used to treat hyperlipidemia and coronary heart disease, have undergone several stages of development since their introduction. Initially, they were made from ordinary tablets. Later, in order to improve bioavailability and patient compliance, various dosage forms such as nano-formulations and sustained-release tablets were gradually developed. With the advancement of formulation science and materials technology, the efficacy control, stability, and taste of dotenorazole have been continuously optimized, enabling it to exert more significant therapeutic advantages in clinical applications.

[0003] However, current preparation processes still have some technical bottlenecks. For example, the dispersibility of active pharmaceutical ingredients in formulations is poor, which can easily lead to uneven content; the density of tablet structure is not well controlled, affecting the drug release rate and stability; in addition, coating processes generally have problems such as weak controlled release performance and susceptibility to storage conditions. These shortcomings restrict the quality control and efficacy consistency of dotenoradine tablets at a higher level, and there is an urgent need to optimize and break through in the selection of excipients and process routes.

[0004] These issues have become bottlenecks in the development of high-end formulations, limiting the further progress of dotenoradine tablets towards the goal of intelligent release and precision treatment. Obviously, the key to solving these problems lies in finding more advanced drug dispersion systems and process strategies to break through the limitations of traditional formulations at the material and structural levels. In response to the technical deficiencies in this regard, a solution is proposed. Summary of the Invention

[0005] The purpose of this invention is to provide a dotenoradine tablet and its preparation method, which solves the technical problem that the dissolution rate and disintegration rate of dotenoradine tablets in the prior art need to be further improved.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] A method for preparing dotenoradine tablets includes the following steps:

[0008] S1. Add dotenoroxetine nanocrystals to a reaction vessel containing modified chitosan oligosaccharide dispersion, stir at room temperature for 10-15 min, and then process to obtain pre-powdered drug powder.

[0009] S2. After mixing the pre-mixed powder, modified xanthan gum, microcrystalline cellulose and magnesium stearate evenly, add them to the tablet press and compress them into 8mm standard round tablets to obtain the precursor of dotenoradine tablets.

[0010] S3. Place the dotenoroxetine tablet precursor into a coating pan, preheat the tablet core to 40°C, and spray the coating solution evenly. Control the coating thickness to 12μm. After drying, cool and collect the tablets to obtain dotenoroxetine tablets.

[0011] The reaction principle for preparing dotenoradine tablets is as follows:

[0012] A stable drug carrier system was constructed using modified chitosan oligosaccharide. After surface modification, chitosan oligosaccharide exhibits enhanced dispersibility and inclusion capacity, enabling it to form a stable composite structure with dotenorazole nanocrystals. This structure inhibits crystal aggregation and improves the aqueous dispersion performance to a certain extent. Furthermore, the composite structure is further stabilized through low-temperature induction and freeze-drying processes, forming a porous, compressible dry powder, which provides a foundation for subsequent molding.

[0013] During the formulation process, excipients with molding properties and disintegration control capabilities, such as microcrystalline cellulose and modified xanthan gum, are selected to optimize tablet hardness, release rate and disintegration time. At the same time, magnesium stearate is introduced to improve lubrication performance during tableting and ensure tablet mechanical strength and industrial compatibility.

[0014] The stability and controlled-release performance of tablets can be further improved through coating design. Modified chitosan oligosaccharide, as a coating material, provides the outer layer of the tablet with certain protective and sustained-release functions while ensuring good biocompatibility. This helps to control the release behavior of drugs in the gastrointestinal environment, reduce the impact of first-pass metabolism, and improve oral absorption efficiency.

[0015] The preparation method of the dotenorox nanocrystals includes the following steps:

[0016] A1. Add dotenoroxetine raw material and modified surfactant to a high-speed shear mill, adjust the concentration to 8-10 mg / L with deionized water, and shear at 8000 rpm for 10-15 min to obtain a dispersion.

[0017] A2. The dispersion was ball-milled using a planetary ball mill, and the post-treatment yielded dotenorox nanocrystals.

[0018] The principle of preparing dotenoramide nanocrystals is as follows: During high-speed shearing and ball milling, the amphiphilic modified surfactant is rapidly adsorbed onto the surface of dotenoramide particles to form a dense adsorption layer. The aggregation and recrystallization of particles are inhibited through a dual mechanism of electrostatic repulsion and steric hindrance, thereby forming dotenoramide nanocrystals with stable particle size.

[0019] Furthermore, in step A1, the ratio of dotenoroxetine raw material to modified surfactant is 0.8-1.0g:0.2g;

[0020] Further, in step A2, the ball milling operation is as follows: the dispersion and zirconium beads are added to a planetary ball mill at a filling ratio of 60%, and wet milled at 300 rpm for 4 hours under temperature control of 15-25℃, with intermittent sampling until the particle size D90 is less than 200 nm. The ratio of dispersion to zirconium beads is 1 g: 1-2 g, and the particle size of zirconium beads is 2-3 mm. The post-processing includes: after ball milling, the reaction solution is filtered through a stainless steel sieve with a pore size of 1.0 mm to collect zirconium beads and filtrate. The mixture is centrifuged at 10000 rpm for 10-15 min and the precipitate is collected. After centrifugation 3-5 times using anhydrous ethanol and deionized water as dispersants, the precipitate is frozen at -20℃ and freeze-dried under vacuum for 24 h to obtain dotenoroxetine nanocrystals.

[0021] Furthermore, the modified surfactant is prepared by adding L-lysine, hexadecyl bromide and anhydrous ethanol into a reaction vessel and stirring. Sodium hydroxide is then added to the reaction vessel and heated to reflux for 6-8 hours. A chain extender is then added to the reaction vessel, and the mixture is kept at the reflux temperature for another 4-6 hours. The modified surfactant is then obtained through post-treatment.

[0022] The principle of preparing modified surfactants is as follows: using sodium hydroxide as a catalyst, L-lysine and hexadecyl bromide are heated and stirred to promote the reaction between hexadecyl bromide and the amino group in L-lysine, thereby generating lysine quaternary ammonium salt with long-chain alkyl groups; after the quaternization reaction is completed, chain extender 1,2-dibromoethane is added to further connect two lysine quaternary ammonium groups through a cascade reaction to generate Gemini-type surfactant with an amphiphilic structure, which can effectively reduce surface tension and enhance its dispersion, emulsification and other properties.

[0023] Furthermore, the ratio of L-lysine, hexadecyl bromide, anhydrous ethanol, sodium hydroxide, and chain extender is 1g:3.8-4.0g:80-100mL:0.5-0.6g:1.2-1.5g, wherein the chain extender is 1,2-dibromoethane. The post-treatment includes: after the reaction is completed, the reaction vessel is allowed to cool naturally to room temperature, 2-3 times the volume of anhydrous ethanol is added to the system, and after the precipitation is complete, the polymer solid is separated by centrifugation. The obtained polymer solid is vacuum dried at 80℃ for 24 hours and milled through a 200-300 mesh sieve to obtain the modified surfactant.

[0024] Furthermore, the preparation method of modified xanthan gum includes the following steps:

[0025] B1. Add 10mM Tris-HCl buffer and dopamine hydrochloride dropwise to a reaction vessel containing 1-2wt% xanthan gum aqueous solution, stir in the dark for 10-12h, and adjust the pH of the reaction system to 8.0-8.5 with sodium hydroxide during stirring to obtain modified xanthan gum dispersion;

[0026] B2. The xanthan gum dispersion was placed in a dialysis bag and dialyzed in deionized water for 72 hours, with the water changed every 8-12 hours. After dialysis, the modified xanthan gum was obtained through post-processing.

[0027] The principle of preparing modified xanthan gum is as follows: under alkaline conditions, the polymerization reaction of dopamine is initiated to form polydopamine, and during this process, it undergoes covalent or non-covalent interactions with functional groups such as hydroxyl and carboxyl groups on xanthan gum, such as hydrogen bonding, π-π interaction, Schiff base reaction or Michael addition, thereby firmly loading or doping polydopamine onto the xanthan gum backbone or its surrounding molecules, forming a dispersion system with excellent surface activity, biocompatibility and reducing properties, thus preparing modified xanthan gum.

[0028] Furthermore, in step B1, the ratio of the 10mM Tris-HCl buffer, dopamine hydrochloride, and 1-2wt% xanthan gum aqueous solution is 80-100mL:1.0-1.5g:80-100mL.

[0029] Furthermore, in step B2, the molecular weight cutoff of the dialysis bag is 3.5 kDa, and the post-processing includes: after dialysis, the product is placed at -80°C for 6 hours and freeze-dried for 48 hours to obtain modified xanthan gum.

[0030] Furthermore, the preparation method of modified chitosan oligosaccharide includes the following steps:

[0031] C1. Add acrylic acid, methyl methacrylate, N,N'-methylenebisacrylamide and chitosan oligosaccharide dispersion to the reaction vessel and stir at room temperature for 10-15 min to obtain the reaction precursor solution;

[0032] C2. Add the precursor solution to the reactor and stir. After purging with nitrogen for protection, raise the reactor temperature to 55-60℃, add potassium persulfate to the reactor, keep warm and stir for 5-6 hours, and then proceed with post-treatment to obtain modified chitosan oligosaccharide.

[0033] The principle of preparing modified chitosan oligosaccharides is as follows: acrylic acid, methyl methacrylate and crosslinking agent N,N'-methylenebisacrylamide are in-situ initiated by free radical polymerization, and crosslinking or grafting of comonomer segments with functional groups such as amino / hydroxyl groups on the surface or structure of chitosan oligosaccharides is carried out to generate modified chitosan oligosaccharides with a three-dimensional network structure.

[0034] Further, in step C1, the ratio of acrylic acid, methyl methacrylate, N,N'-methylenebisacrylamide and chitosan oligosaccharide dispersion is 1.6-1.8g:0.4-0.5g:0.01g:100mL, wherein the chitosan oligosaccharide dispersion is obtained by mixing chitosan oligosaccharide and deionized water at a ratio of 1-2g:100mL;

[0035] Furthermore, in step C2, the ratio of the precursor solution to potassium persulfate is 100 mL: 0.05-0.08 g. The post-treatment includes: after the reaction is completed, the reaction vessel is allowed to cool naturally to room temperature, 2-3 times the volume of anhydrous ethanol is added to the system, and after the precipitation is complete, the polymer solid is separated by centrifugation. The obtained polymer solid is vacuum dried at 80°C for 24 hours and then milled through a 200-300 mesh sieve to obtain modified chitosan oligosaccharide.

[0036] The present invention also discloses a dotenoradine tablet, which is prepared by a method for preparing dotenoradine tablets.

[0037] The present invention has the following beneficial effects:

[0038] 1. The lysine-Gemini modified surfactant prepared in this invention is directionally adsorbed onto the surface of dotenoxanone nanocrystals during ball milling, significantly reducing interfacial tension and inhibiting aggregation, forming a dispersion with stable particle size and large specific surface area, providing sufficient contact interface for rapid dissolution. Secondly, polydopamine-modified xanthan gum forms a hydrophilic interfacial layer on the outside of the particles, enhancing wetting and liquid penetration rates while maintaining dispersion stability and avoiding the adverse effects of secondary crystallization on dissolution. Furthermore, the three-dimensional network of modified chitosan oligosaccharide forms a porous framework after low-temperature induction and freeze-drying, which not only improves the capillary liquid absorption capacity and disintegration driving force of the powder, but also maintains the channel structure during tableting, shortening the aqueous phase penetration time. The compatible microcrystalline cellulose provides a brittle framework and capillary water absorption pathways, while magnesium stearate ensures smooth tableting and prevents the channels from being sheared and destroyed. Finally, through the synergy of interfacial activation, channel mass transfer, and particle size control, the tablets disintegrate rapidly and are effectively released, effectively achieving a balance between high disintegration rate and high dissolution rate.

[0039] 2. The modified chitosan oligosaccharide prepared in this invention forms a three-dimensional network structure after cross-linking polymerization. This structure imparts good compressibility and structural consistency to the drug powder during freeze-drying, preventing particle migration and component stratification during tableting and improving content uniformity from the source. Secondly, microcrystalline cellulose, as a structural support framework, possesses excellent filling and binding properties, allowing it to tightly integrate with other excipients during compression, enhancing the mechanical interlocking between particles and stabilizing the formed structure. Polydopamine-modified xanthan gum plays a flexible connecting and buffering role in the system, effectively bridging the gaps between particles and improving the overall density and shatter resistance of the tablets. In addition, the appropriate amount of magnesium stearate introduced as a lubricant can significantly reduce mold wall friction, prevent tablet sticking and edge breakage during compression, and ensure the stability of continuous industrial molding. Finally, the high degree of coordination among the components in terms of structure, flowability, and compression characteristics ensures the uniform distribution of the active ingredient in each tablet and the mechanical stability during the molding process, providing reliable support for large-scale formulation production.

[0040] 3. This solution uses dotenoxetine nanocrystals as its core. First, a stable interfacial coating layer is constructed through the electrostatic and hydrophobic effects of lysine-Gemini modified surfactants, effectively inhibiting drug particle recrystallization and particle size growth, ensuring physical stability. Second, the composite coating system formed by polydopamine and xanthan gum maintains structural integrity under pH and temperature / humidity fluctuations, exhibiting good hygroscopic resistance and oxidative barrier properties, which can delay the degradation of the active pharmaceutical ingredient. Third, the chitosan oligosaccharide three-dimensional framework possesses a stable spatial structure after freeze-drying, limiting particle migration, adsorption, and aggregation, thereby maintaining the long-term dispersion and uniformity of the system. In addition, the overall compaction and mechanical stability of the tablets are also ensured by microcrystalline cellulose and magnesium stearate, reducing the risk of breakage during transportation and storage. Finally, the multiple synergies of various materials in chemical protection, physical isolation, and structural stability are the key foundation for the excellent stability of this solution. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0042] Figure 1 The FTIR spectrum of the modified xanthan gum prepared in Example 6 of this invention;

[0043] Figure 2 The FTIR spectrum of the modified chitosan oligosaccharide prepared in Example 3 of this invention;

[0044] Figure 3 The FTIR spectrum of the modified surfactant prepared in Example 9 of this invention is shown. Detailed Implementation

[0045] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0046] In this application, the chitosan oligosaccharide used was purchased from Shanghai E-En Chemical Technology Co., Ltd., item number R197715; the dopamine hydrochloride used was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., item number D408026; the xanthan gum used was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., item number G104873; the dotenoroxetine raw material used was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., item number D609956; the microcrystalline cellulose used was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., item number M489686; and the magnesium stearate used was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., item number M498313.

[0047] Example 1

[0048] This embodiment provides a method for preparing modified chitosan oligosaccharides for the preparation of dotenoradine tablets, including the following steps:

[0049] Step ①: Preparation of the reaction precursor solution

[0050] Weigh out 10.0 g of chitosan oligosaccharide and mix it with 1000.0 mL of deionized water to obtain a chitosan oligosaccharide dispersion;

[0051] Weigh out 16.0g of acrylic acid, 4.0g of methyl methacrylate, 0.1g of N,N'-methylenebisacrylamide and 1000.0mL of chitosan oligosaccharide dispersion and add them to the reaction vessel. Stir at room temperature for 10min to obtain the reaction precursor solution.

[0052] Step 2: Preparation of modified chitosan oligosaccharides

[0053] Weigh 1000.0 mL of the precursor solution and add it to the reaction vessel. After stirring, purge the reaction vessel with nitrogen and raise the temperature to 55°C. Then, add 0.5 g of potassium persulfate to the reaction vessel and keep it warm and stirred for 5 hours. After the reaction is completed, let the reaction vessel cool naturally to room temperature. Add 2 times the volume of anhydrous ethanol to the system. After the precipitation is complete, centrifuge to separate the polymer solid. Dry the obtained polymer solid under vacuum at 80°C for 24 hours and grind it through a 200-mesh sieve to obtain modified chitosan oligosaccharide.

[0054] Example 2

[0055] This embodiment provides a method for preparing modified chitosan oligosaccharides for the preparation of dotenoradine tablets, including the following steps:

[0056] Step ①: Preparation of the reaction precursor solution

[0057] Weigh out 20.0 g of chitosan oligosaccharide and mix it with 1000.0 mL of deionized water to obtain a chitosan oligosaccharide dispersion;

[0058] Weigh out 18.0g of acrylic acid, 5.0g of methyl methacrylate, 0.1g of N,N'-methylenebisacrylamide and 1000.0mL of chitosan oligosaccharide dispersion and add them to the reaction vessel. Stir at room temperature for 15min to obtain the reaction precursor solution.

[0059] Step 2: Preparation of modified chitosan oligosaccharides

[0060] Weigh 1000.0 mL of the precursor solution and add it to the reaction vessel. After stirring, purge the reaction vessel with nitrogen and raise the temperature to 60°C. Then, add 0.8 g of potassium persulfate to the reaction vessel and keep it warm and stirred for 6 hours. After the reaction is completed, let the reaction vessel cool naturally to room temperature. Add 3 times the volume of anhydrous ethanol to the system. After the precipitation is complete, centrifuge to separate the polymer solid. Dry the obtained polymer solid under vacuum at 80°C for 24 hours and grind it through a 300-mesh sieve to obtain modified chitosan oligosaccharide.

[0061] Example 3

[0062] This embodiment provides a method for preparing modified chitosan oligosaccharides for the preparation of dotenoradine tablets, including the following steps:

[0063] Step ①: Preparation of the reaction precursor solution

[0064] Weigh out 16.0 g of chitosan oligosaccharide and mix it with 1000.0 mL of deionized water to obtain a chitosan oligosaccharide dispersion;

[0065] Weigh out 18.0g of acrylic acid, 5.0g of methyl methacrylate, 0.1g of N,N'-methylenebisacrylamide and 1000.0mL of chitosan oligosaccharide dispersion and add them to the reaction vessel. Stir at room temperature for 12min to obtain the reaction precursor solution.

[0066] Step 2: Preparation of modified chitosan oligosaccharides

[0067] Weigh 1000.0 mL of the precursor solution and add it to the reaction vessel. After stirring, purge the reaction vessel with nitrogen and raise the temperature to 60°C. Then, add 0.6 g of potassium persulfate to the reaction vessel and keep it warm and stirred for 6 hours. After the reaction is completed, let the reaction vessel cool naturally to room temperature. Add 3 times the volume of anhydrous ethanol to the system. After the precipitation is complete, centrifuge to separate the polymer solid. Dry the obtained polymer solid under vacuum at 80°C for 24 hours and grind it through a 250-mesh sieve to obtain modified chitosan oligosaccharide.

[0068] Figure 2 The FTIR spectrum of the modified chitosan oligosaccharide in the sample showed that at 3430 cm⁻¹... -1 A broad and strong absorption band was observed at 2925 cm⁻¹, indicating the coexistence of hydroxyl and amino stretching vibrations, suggesting that the chitosan oligosaccharide skeleton is retained and participates in the reaction; at 2925 cm⁻¹... -1The appearance of an aliphatic -CH2- stretching vibration peak at 1730 cm⁻¹ confirms the successful grafting of the comonomer; -1 The strong absorption peak is attributed to the C=O vibration of the ester group, which is a typical absorption region of the methyl methacrylate polymerization unit; 1650 cm⁻¹ -1 and 1540cm -1 The bimodal characteristics correspond to the amide I band (C=O) and NH bending vibration, respectively, providing direct evidence for the existence of the N,N'-methylenebisacrylamide crosslinked structure; furthermore, 1240-1150 cm⁻¹ -1 The region exhibits moderate to strong absorptions, attributed to stretching vibrations of CN and COC respectively, supporting the coexistence of amide and ether bonds in the network; furthermore, at 890 cm⁻¹... -1 The skeletal vibration peaks further demonstrate the construction of the aggregated network.

[0069] Example 4

[0070] This embodiment provides a method for preparing modified xanthan gum for dotenoradine tablets, including the following steps:

[0071] Step I: Preparation of modified xanthan gum dispersion

[0072] Weigh out 800.0 mL of 10 mM Tris-HCl buffer and 10.0 g of dopamine hydrochloride and add them dropwise to a reaction vessel containing 800.0 mL of 1 wt% xanthan gum aqueous solution. Stir for 10 h in the dark and adjust the pH of the reaction system to 8.0 with sodium hydroxide during stirring to obtain modified xanthan gum dispersion.

[0073] Step II: Preparation of modified xanthan gum

[0074] Weigh 800.0 mL of xanthan gum dispersion and place it into a dialysis bag with a molecular weight cutoff of 3.5 kDa. Dialyze it in deionized water for 72 hours, changing the water every 8 hours. After dialysis, place the product at -80℃ for 6 hours and freeze-dry it for 48 hours to obtain modified xanthan gum.

[0075] Example 5

[0076] This embodiment provides a method for preparing modified xanthan gum for dotenoradine tablets, including the following steps:

[0077] Step I: Preparation of modified xanthan gum dispersion

[0078] Weigh 1000.0 mL of 10 mM Tris-HCl buffer and 15.0 g of dopamine hydrochloride and add them dropwise to a reaction vessel containing 1000.0 mL of 2 wt% xanthan gum aqueous solution. Stir for 12 h in the dark and adjust the pH of the reaction system to 8.5 with sodium hydroxide during stirring to obtain modified xanthan gum dispersion.

[0079] Step II: Preparation of modified xanthan gum

[0080] Weigh 1000.0 mL of xanthan gum dispersion and place it into a dialysis bag with a molecular weight cutoff of 3.5 kDa. Dialyze it in deionized water for 72 hours, changing the water every 12 hours. After dialysis, place the product at -80℃ for 6 hours and freeze-dry it for 48 hours to obtain modified xanthan gum.

[0081] Example 6

[0082] This embodiment provides a method for preparing modified xanthan gum for dotenoradine tablets, including the following steps:

[0083] Step I: Preparation of modified xanthan gum dispersion

[0084] Weigh out 900.0 mL of 10 mM Tris-HCl buffer and 12.0 g of dopamine hydrochloride and add them dropwise to a reaction vessel containing 900.0 mL of 1.5 wt% xanthan gum aqueous solution. Stir for 12 h in the dark and adjust the pH of the reaction system to 8.0 with sodium hydroxide during stirring to obtain modified xanthan gum dispersion.

[0085] Step II: Preparation of modified xanthan gum

[0086] Weigh 900.0 mL of xanthan gum dispersion and place it into a dialysis bag with a molecular weight cutoff of 3.5 kDa. Dialyze the product in deionized water for 72 hours, changing the water every 10 hours. After dialysis, place the product at -80℃ for 6 hours and freeze-dry for 48 hours to obtain modified xanthan gum.

[0087] Figure 1 The FTIR spectrum of modified xanthan gum in the sample showed that at 3420 cm⁻¹... -1 A broad and strong absorption band appears at 2920 cm⁻¹, characterizing the stretching vibrations of -OH and -NH groups, reflecting the extensive hydrogen bond network formed after dopamine doping of the xanthan gum polysaccharide backbone; -1 CH stretching vibration peak and 1040 cm -1 The retention of the characteristic peaks of the COC bond indicates that the parent structure has not been destroyed; 1720 cm⁻¹ -1 The C=O stretching peak at 1280 cm⁻¹ -1 The synergistic appearance of the CN bond absorption peak corroborates the occurrence of the Schiff base / Michael addition reaction, indicating that the dopamine polymerization product forms a stable chemical structure with the active groups of xanthan gum; 1610 cm⁻¹ -1 With 1500cm -1 Two aromatic structure-related absorption peaks clearly indicate the insertion of the polydopamine backbone, 920 cm⁻¹ -1 The skeletal vibrational peak further supports the reaction pathway.

[0088] Example 7

[0089] This embodiment provides a method for preparing dotenoradine tablets, including the following steps:

[0090] Step 1: Preparation of modified surfactants

[0091] Weigh out 10.0 g L-lysine, 38.0 g hexadecyl bromide and 800.0 mL anhydrous ethanol and add them to the reaction vessel. Stir, add 5.0 g sodium hydroxide and heat to reflux for 6 h, then add 12.0 g 1,2-dibromoethane and continue to reflux for 4 h. After the reaction is complete, let the reaction vessel cool to room temperature naturally, add 2 times the volume of anhydrous ethanol to the system, and after the precipitation is complete, centrifuge to separate the polymer solid. Dry the obtained polymer solid under vacuum at 80 °C for 24 h, and grind it through a 200 mesh sieve to obtain the modified surfactant.

[0092] Step 2: Preparation of Dotenorazine Nanocrystals

[0093] Weigh out 8.0g of dotenoroxetine raw material and 2.0g of modified surfactant and add them to a high-speed shearing machine. After adjusting the concentration to 8mg / L with deionized water, shear at 8000rpm for 10min to obtain a dispersion.

[0094] The dispersion and 2mm zirconium beads were added to a planetary ball mill at a 60% filling ratio. The mixture was wet-milled at 300rpm for 4 hours at 15℃. Samples were taken intermittently until the particle size D90 was below 200nm. After ball milling, the reaction solution was filtered through a 1.0mm stainless steel sieve to collect the zirconium beads and filtrate. The mixture was centrifuged at 10000rpm for 10min and the precipitate was collected. The precipitate was then centrifuged three more times using anhydrous ethanol and deionized water as dispersants, respectively. The precipitate was then frozen at -20℃ and freeze-dried under vacuum for 24h to obtain dotenoroxetine nanocrystals.

[0095] Step 3: Preparation of Dotenoradine Tablets

[0096] Weigh out 2.0g of the modified chitosan oligosaccharide prepared in Example 1, mix it with 30.0mL of anhydrous ethanol and 100.0mL of deionized water to obtain a modified chitosan oligosaccharide dispersion;

[0097] Weigh 1.0 g of dotenorazole nanocrystals and add them to a reaction vessel containing 100.0 mL of modified chitosan oligosaccharide dispersion. Stir at room temperature for 10 min. After stirring, place the product at -80℃ for 6 h and freeze-dry for 48 h to obtain modified xanthan gum.

[0098] Weigh out 3.0g of pre-prepared drug powder, 0.5g of modified xanthan gum prepared in Example 4, 1.8g of microcrystalline cellulose and 0.04g of magnesium stearate, mix them evenly and add them to a tablet press. Press them into 8mm standard round tablets with a pressure of 8kN to obtain the precursor of dotenoradine tablets.

[0099] Weigh out 1.0 g of the modified chitosan oligosaccharide prepared in Example 1 and mix it with 50.0 mL of anhydrous ethanol to obtain a coating solution;

[0100] Weigh 5.34g of dotenoradine tablet precursor and place it in a coating pan. Preheat the tablet core to 40°C and spray the coating solution evenly. Control the coating thickness to 12μm. After drying, cool and collect the tablets to obtain dotenoradine tablets.

[0101] Example 8

[0102] This embodiment provides a method for preparing dotenoradine tablets, including the following steps:

[0103] Step 1: Preparation of modified surfactants

[0104] Weigh out 10.0 g L-lysine, 40.0 g hexadecyl bromide and 1000.0 mL anhydrous ethanol and add them to the reaction vessel. Stir, add 6.0 g sodium hydroxide and heat to reflux for 8 h. Then add 15.0 g 1,2-dibromoethane and continue to reflux for 6 h. After the reaction is complete, let the reaction vessel cool to room temperature naturally. Add 3 times the volume of anhydrous ethanol to the system. After the precipitation is complete, centrifuge to separate the polymer solid. Dry the obtained polymer solid under vacuum at 80 °C for 24 h and grind it through a 300 mesh sieve to obtain the modified surfactant.

[0105] Step 2: Preparation of Dotenorazine Nanocrystals

[0106] Weigh out 10.0g of dotenoroxetine raw material and 2.0g of modified surfactant and add them to a high-speed shear mill. After adjusting the concentration to 10mg / L with deionized water, shear at 8000rpm for 15min to obtain a dispersion.

[0107] The dispersion and zirconium beads with a particle size of 3 mm were added to a planetary ball mill at a filling ratio of 60%. The mixture was wet-milled at 300 rpm for 4 hours under temperature control at 25°C. Samples were taken intermittently until the particle size D90 was below 200 nm. After ball milling, the reaction solution was filtered through a stainless steel sieve with a pore size of 1.0 mm to collect the zirconium beads and filtrate. The mixture was centrifuged at 10,000 rpm for 15 min and the precipitate was collected. The precipitate was then centrifuged 5 times using anhydrous ethanol and deionized water as dispersants, respectively. The precipitate was then frozen at -20°C and freeze-dried under vacuum for 24 h to obtain dotenoroxetine nanocrystals.

[0108] Step 3: Preparation of Dotenoradine Tablets

[0109] Weigh out 2.0g of the modified chitosan oligosaccharide prepared in Example 2, mix it with 30mL of anhydrous ethanol and 100mL of deionized water to obtain a modified chitosan oligosaccharide dispersion;

[0110] Weigh 1.0 g of dotenorazole nanocrystals and add them to a reaction vessel containing 100.0 mL of modified chitosan oligosaccharide dispersion. Stir at room temperature for 15 min. After stirring, place the product at -80℃ for 6 h and freeze-dry for 48 h to obtain modified xanthan gum.

[0111] Weigh out 3.0g of pre-prepared drug powder, 0.5g of modified xanthan gum prepared in Example 5, 2.0g of microcrystalline cellulose and 0.05g of magnesium stearate, mix them evenly and add them to a tablet press. Press them into 8mm standard round tablets with a pressure of 12kN to obtain the precursor of dotenoradine tablets.

[0112] Weigh out 1.0 g of the modified chitosan oligosaccharide prepared in Example 2 and mix it with 50.0 mL of anhydrous ethanol to obtain a coating solution;

[0113] Weigh 5.55g of dotenoradine tablet precursor and place it in a coating pan. Preheat the tablet core to 40°C and spray the coating solution evenly. Control the coating thickness to 12μm. After drying, cool and collect the tablets to obtain dotenoradine tablets.

[0114] Example 9

[0115] This embodiment provides a method for preparing dotenoradine tablets, including the following steps:

[0116] Step 1: Preparation of modified surfactants

[0117] Weigh out 10.0 g L-lysine, 38.0 g hexadecyl bromide and 1000.0 mL anhydrous ethanol and add them to the reaction vessel. Stir, add 6.0 g sodium hydroxide and heat to reflux for 7 h, then add 15.0 g 1,2-dibromoethane and continue to reflux for 5 h. After the reaction is complete, let the reaction vessel cool to room temperature naturally, add 3 times the volume of anhydrous ethanol to the system, and after the precipitation is complete, centrifuge to separate the polymer solid. Dry the obtained polymer solid under vacuum at 80 °C for 24 h, and grind it through a 250 mesh sieve to obtain the modified surfactant.

[0118] Figure 3 The FTIR spectrum of the modified surfactant in the sample showed that at 3400 cm⁻¹ -1 The broad peak at 2950 cm⁻¹ is attributed to the stretching vibration of NH or OH, indicating the presence of residual amino or carboxyl groups in the L-lysine molecular backbone; -1 With 2850cm -1Two sets of CH stretching vibration absorption peaks appeared at 1650 cm⁻¹, corresponding to the methylene and methyl vibrations of the long-chain hexadecyl structure, confirming the successful introduction of the alkyl chain into the quaternary ammonium cation; -1 The NH bending vibration peak at 1380 cm⁻¹ indicates that the lysine group participates in the reaction but retains part of the secondary amine structure; -1 and 1150cm -1 The characteristic absorptions of CN stretching and CNC bridging vibrations of quaternary ammonium salts, respectively, validated the bis-terminated quaternary ammonium-based bridging reaction pathway initiated by 1,2-dibromoethane; furthermore, at 1050 cm⁻¹... -1 The nearby CO / CN peaks and 700cm -1 The synergistic absorption of the C-Br bond further confirms that the Br-involved chain extension structure has been formed in the product.

[0119] Step 2: Preparation of Dotenorazine Nanocrystals

[0120] Weigh out 9.0g of dotenoroxetine raw material and 2.0g of modified surfactant and add them to a high-speed shearing machine. After adjusting the concentration to 9mg / L with deionized water, shear at 8000rpm for 12min to obtain a dispersion.

[0121] The dispersion and zirconium beads with a particle size of 3 mm were added to a planetary ball mill at a filling ratio of 60%. The mixture was wet-milled at 300 rpm for 4 hours under temperature control at 20℃. Samples were taken intermittently until the particle size D90 was below 200 nm. After ball milling, the reaction solution was filtered through a stainless steel sieve with a pore size of 1.0 mm to collect the zirconium beads and filtrate. The mixture was centrifuged at 10,000 rpm for 12 min and the precipitate was collected. The precipitate was then centrifuged 4 times using anhydrous ethanol and deionized water as dispersants, respectively. The precipitate was then frozen at -20℃ and freeze-dried under vacuum for 24 h to obtain dotenoroxetine nanocrystals.

[0122] Step 3: Preparation of Dotenoradine Tablets

[0123] Weigh out 2.0g of the modified chitosan oligosaccharide prepared in Example 3, mix it with 30.0mL of anhydrous ethanol and 100.0mL of deionized water to obtain a modified chitosan oligosaccharide dispersion;

[0124] Weigh 1.0 g of dotenorazole nanocrystals and add them to a reaction vessel containing 100.0 mL of modified chitosan oligosaccharide dispersion. Stir at room temperature for 12 min. After stirring, place the product at -80℃ for 6 h and freeze-dry for 48 h to obtain modified xanthan gum.

[0125] Weigh out 3.0g of pre-prepared drug powder, 0.5g of modified xanthan gum prepared in Example 6, 2.0g of microcrystalline cellulose and 0.05g of magnesium stearate, mix them evenly and add them to a tablet press. Press them into 8mm standard round tablets with a pressure of 10kN to obtain the precursor of dotenoradine tablets.

[0126] Weigh out 1.0 g of modified chitosan oligosaccharide and mix it with 50.0 mL of anhydrous ethanol to obtain a coating solution;

[0127] Weigh 5.55g of dotenoradine tablet precursor and place it in a coating pan. Preheat the tablet core to 40°C and spray the coating solution evenly. Control the coating thickness to 12μm. After drying, cool and collect the tablets to obtain dotenoradine tablets.

[0128] Comparative Example 1

[0129] The difference between this comparative example and Example 9 is that step one is omitted, and in step two, an equal amount of hexadecyltrimethylammonium bromide is used to replace the modified surfactant.

[0130] Comparative Example 2

[0131] The difference between this comparative example and Example 9 is that the modified xanthan gum was omitted in step three and replaced with an equal amount of xanthan gum.

[0132] Comparative Example 3

[0133] The difference between this comparative example and Example 9 is that the modified oligosaccharide was omitted in step three and replaced with an equal amount of chitosan.

[0134] Performance testing:

[0135] Six tablets of dotenoradine were placed in the paddle dissolution apparatus of a dissolution tester. 900 mL of 0.1 mol / L hydrochloric acid was added to each chamber as the dissolution medium. The water bath temperature was controlled at 37℃ with a fluctuation range of ±0.5℃, and the paddle speed was set to 50 rpm. After running for 30 minutes, 10 mL of solution from each chamber was removed, filtered through a 0.45 μm filter membrane, and sent to a UV spectrophotometer to determine the concentration of the active ingredient. The dissolution rate of each tablet after 30 minutes was calculated, and the average dissolution rate was also calculated.

[0136] Take 6 tablets of dotenoradine and place them in the basket of the disintegration time tester. Add 900 mL of 0.1 mol / L hydrochloric acid to the water bath as a medium. The temperature is controlled at 37℃ with fluctuations not exceeding ±0.5℃. Start the instrument and observe the tablets moving up and down in the medium and gradually disintegrating. Record the time for each tablet to completely disintegrate. Disintegration is considered complete when there are no visible hard lumps. The average disintegration time of dotenoradine tablets is obtained.

[0137] Ten tablets of dotenoratadine were randomly selected and ground into fine powder individually. Each powder was accurately weighed and placed in a volumetric flask. 50 mL of mobile phase (acetonitrile and 0.1% phosphoric acid aqueous solution mixed at a ratio of 40:60) was added, and the mixture was extracted by ultrasonic oscillation for 10 minutes, followed by filtration. The filtrate was sampled and analyzed by high-performance liquid chromatography (HPLC). The chromatographic conditions were: C18 column, flow rate 1.0 mL / min, detection wavelength 254 nm, and injection volume 10 μL. After analysis, the content of the active ingredient in each tablet was calculated, and the content uniformity data were obtained.

[0138] Ten tablets of dotenoratadine were randomly selected and placed into a tablet hardness tester. The tablet was placed between the fixed arm and the movable arm of the instrument, and pressure was slowly applied until the tablet ruptured. The force required at the moment of rupture (unit: N) was recorded. Each tablet was measured independently, and ten force values ​​were used to evaluate the overall hardness level of the tablet to obtain the average molding performance test data. The test results are shown in Table 1.

[0139] The sealed samples were stored in a constant temperature and humidity chamber at 40℃±2℃ / 75%±5%RH for 6 months. After the expiration period, the samples were removed and equilibrated at room temperature until no condensation occurred. Subsequently, the dissolution rate, disintegration time, content uniformity, and formability of the samples were tested to evaluate their stability under high temperature and high humidity conditions for 6 months. The test results are shown in Table 2.

[0140] Table 1 - Performance Test Data for Each Sample

[0141]

[0142]

[0143] Table 2 - Performance test data of each sample after aging

[0144]

[0145] Data Analysis:

[0146] Comparative analysis of the data in Table 1 revealed that the dotenorazole tablets prepared according to this invention exhibited an average dissolution rate of 98.8% at 30 minutes, an average disintegration time of 93 seconds, a tablet hardness of 83.9 N, and a content uniformity of 99.8%. Furthermore, after aging, the dissolution rate remained at 97.6%, the disintegration rate at 98.7%, the tablet hardness at 98.6%, and the uniformity at 99.1%. All these data are superior to the comparative example, indicating that…

[0147] In Comparative Example 1, the use of Gemini-type surfactant was omitted, resulting in the lack of effective protection of the amphiphilic adsorption layer on the surface of drug particles during the preparation of nanocrystals. This led to insufficient electrostatic and steric hindrance interactions between particles after wet milling, making them prone to agglomeration and recrystallization. Ultimately, this resulted in a significant increase in particle size distribution, a decrease in drug dissolution rate and a greater batch-to-batch variation, and a significant deterioration in formulation stability.

[0148] In Comparative Example 2, the lack of modified chitosan oligosaccharide resulted in the drug carrier lacking three-dimensional network structure support, leading to poor dispersibility of nanocrystals during drying and tableting, loose powder structure, uneven drug distribution, reduced tablet hardness and easy cracking, unstable dissolution curve, decreased content retention rate during long-term storage, and damage to overall formability and storage stability.

[0149] In Comparative Example 3, if polydopamine-modified xanthan gum is missing, the interfacial bonding force between the coating layer and the tablet core is insufficient, the sustained-release function is weakened, the drug release curve shows premature burst release and fluctuation, and the tablets are more susceptible to instability due to the influence of external ionic strength in the gastrointestinal environment, resulting in premature drug degradation and a significant decrease in dissolution rate and content retention rate.

[0150] The results demonstrate that the synergistic design of the modified surfactant, modified chitosan oligosaccharide, and modified xanthan gum prepared in this invention is a key factor in achieving stable particle size, strong tableting adaptability, controllable release, uniform content, and excellent long-term stability in dotenoxam nanocrystal formulations. Compared with the comparative group, the examples show significant advantages in multiple quality indicators, indicating that this technical solution has good feasibility, innovation, and industrial transformation prospects.

[0151] The above description is merely an example and illustration of the structure of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described, or use similar methods to replace them, as long as they do not deviate from the structure of the invention or exceed the scope defined in the claims, all of which should fall within the protection scope of the present invention.

[0152] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0153] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to specific implementations. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing dotenoradine tablets, characterized in that, Includes the following steps: S1. Add dotenoroxetine nanocrystals to a reaction vessel containing modified chitosan oligosaccharide dispersion, stir at room temperature for 10-15 min, and then process to obtain pre-powdered drug powder. S2. After mixing the pre-mixed powder, modified xanthan gum, microcrystalline cellulose and magnesium stearate evenly, add them to the tablet press and compress them into 8mm standard round tablets to obtain the precursor of dotenoradine tablets. S3. Place the dotenoroxetine tablet precursor into a coating pan, preheat the tablet core to 40°C, and spray the coating solution evenly. Control the coating thickness to 12μm. After drying, cool and collect the tablets to obtain dotenoroxetine tablets. The preparation method of the dotenorox nanocrystals includes the following steps: A1. Add dotenoroxetine raw material and modified surfactant to a high-speed shear mill, adjust the concentration to 8-10 mg / L with deionized water, and shear at 8000 rpm for 10-15 min to obtain a dispersion. A2. The dispersion was ball-milled using a planetary ball mill, and the post-treatment yielded dotenorox nanocrystals.

2. The method for preparing dotenoradine tablets according to claim 1, characterized in that, In step S1, the ratio of dotenoxanol nanocrystals to modified chitosan oligosaccharide dispersion is 1g:100mL, wherein the modified chitosan oligosaccharide dispersion is obtained by mixing modified chitosan oligosaccharide, anhydrous ethanol, and deionized water in a ratio of 2g:30mL:100mL; in step S2, the ratio of pre-powdered pharmaceutical powder, modified xanthan gum, microcrystalline cellulose, and magnesium stearate is 3.0g:0.5g:1.8-2.0g:0.04-0.05g; in step S3, the coating solution is obtained by mixing modified chitosan oligosaccharide and anhydrous ethanol in a ratio of 1.0g:50mL.

3. The method for preparing dotenoradine tablets according to claim 1, characterized in that, In step A1, the ratio of dotenoroxetine raw material to modified surfactant is 0.8-1.0g:0.2g; in step A2, the ball milling operation is as follows: the dispersion and zirconium beads are added to a planetary ball mill at a filling ratio of 60%, and wet milled at 300rpm for 4 hours under temperature control of 15-25℃, and samples are taken intermittently until the particle size D90 is less than 200nm. The ratio of dispersion to zirconium beads is 1g:1-2g, and the particle size of zirconium beads is 2-3mm.

4. The method for preparing dotenoradine tablets according to claim 1, characterized in that, The modified surfactant is prepared by adding L-lysine, hexadecyl bromide and anhydrous ethanol into a reaction vessel and stirring. Sodium hydroxide is then added to the reaction vessel and heated to reflux for 6-8 hours. A chain extender is then added to the reaction vessel and the mixture is kept at the reflux temperature for another 4-6 hours. The modified surfactant is then obtained through post-treatment.

5. The method for preparing dotenoradine tablets according to claim 4, characterized in that, In the preparation of the modified surfactant, the ratio of L-lysine, hexadecyl bromide, anhydrous ethanol, sodium hydroxide and chain extender is 1g:3.8-4.0g:80-100mL:0.5-0.6g:1.2-1.5g, wherein the chain extender is 1,2-dibromoethane.

6. The method for preparing dotenoradine tablets according to claim 1, characterized in that, The preparation method of the modified xanthan gum includes the following steps: B1. Add 10mM Tris-HCl buffer and dopamine hydrochloride dropwise to a reaction vessel containing 1-2wt% xanthan gum aqueous solution, stir in the dark for 10-12h, and adjust the pH of the reaction system to 8.0-8.5 with sodium hydroxide during stirring to obtain modified xanthan gum dispersion; B2. The xanthan gum dispersion was placed in a dialysis bag and dialyzed in deionized water for 72 hours, with the water changed every 8-12 hours. After dialysis, the modified xanthan gum was obtained through post-processing.

7. The method for preparing dotenoradine tablets according to claim 6, characterized in that, In step B1, the ratio of the 10mM Tris-HCl buffer, dopamine hydrochloride, and 1-2wt% xanthan gum aqueous solution is 80-100mL:1.0-1.5g:80-100mL; in step B2, the molecular weight cutoff of the dialysis bag is 3.5kDa.

8. The method for preparing dotenoradine tablets according to claim 1, characterized in that, The preparation method of the modified chitosan oligosaccharide includes the following steps: C1. Add acrylic acid, methyl methacrylate, N,N'-methylenebisacrylamide and chitosan oligosaccharide dispersion to a reaction vessel and stir at room temperature for 10-15 min to obtain the reaction precursor solution; C2. Add the precursor solution to the reactor and stir. After purging with nitrogen for protection, raise the reactor temperature to 55-60℃, add potassium persulfate to the reactor, keep warm and stir for 5-6 hours, and then proceed with post-treatment to obtain modified chitosan oligosaccharide.

9. The method for preparing dotenoradine tablets according to claim 8, characterized in that, In step C1, the ratio of acrylic acid, methyl methacrylate, N,N'-methylenebisacrylamide, and chitosan oligosaccharide dispersion is 1.6-1.8g:0.4-0.5g:0.01g:100mL, wherein the chitosan oligosaccharide dispersion is obtained by mixing chitosan oligosaccharide and deionized water at a ratio of 1-2g:100mL; in step C2, the ratio of the reaction precursor solution and potassium persulfate is 100mL:0.05-0.08g.

10. A dotenoradine tablet, characterized in that, The dotenorazole tablets are prepared using the dotenorazole tablet preparation method according to any one of claims 1-9.

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