A dual-drug co-loaded oral pellet preparation with a multi-layer core-shell structure and a preparation method and application thereof

Abstract

The present application belongs to the technical field of pharmaceutical combination pellet preparation, and particularly relates to a double-drug co-loaded oral pellet preparation with a multi-layer core-shell structure and a preparation method and application thereof. The double-drug co-loaded oral pellet preparation provided by the present application has the synergism of microenvironment adjustment and time difference release through the design of the multi-layer core-shell structure, that is, the outer peripheral antagonist trospium chloride of the outermost layer is preferentially released and acts on peripheral muscarinic receptors (M1 / M4), and the xanomeline of the pellet core is released or pulse-released later and acts on peripheral receptors (M2 / M3), so that the therapeutic effect and side effect inhibition of the two drugs form a time difference synergy, the peripheral adverse reactions caused by xanomeline can be reduced, and the synergism problem in the combined administration of xanomeline and the antagonist trospium chloride is solved.

Description

Technical Field

[0001] This invention belongs to the field of drug combination microparticle formulation technology, specifically relating to a dual-drug co-loaded oral microparticle formulation with a multi-layered core-shell structure that can reduce peripheral adverse reactions caused by zebuline, its preparation method and application. Background Technology

[0002] Muscarinic receptor agonists, such as zebuline, activate acetylcholine M1 / M4 receptors in the central nervous system and have been shown to be effective in treating central nervous system disorders such as schizophrenia and Alzheimer's disease. However, because muscarinic receptors are widely distributed in peripheral tissues, such as the gastrointestinal tract, salivary glands, and heart, these drugs often cause severe peripheral cholinergic side effects, such as nausea, vomiting, diarrhea, and bradycardia, leading to poor patient compliance and even treatment discontinuation. For example, in early clinical trials, the discontinuation rate for zebuline monotherapy was as high as 56%.

[0003] To overcome this challenge, current technologies often employ a combination of xanomeline-trospium and peripheral muscarinic receptor antagonists such as trospium chloride to reduce side effects by inhibiting peripheral receptor activity. For example, BMS's first-in-class drug KarXT (now Cobenfy) uses xanomeline-trospium in combination to reduce the adverse reactions of xanomeline associated with peripheral muscarinic receptors. Furthermore, in the reported EMERGENT-2 study, participants treated with KarXT, taking xanomeline-trospium twice daily, experienced a significantly lower incidence of adverse events compared to the placebo group (see Kaul, Inder, et al., “Efficacy and safety of the muscarinicreceptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from arandomised, double-blind, placebo-controlled, flexible-dose phase 3 trial.”). The Lancet , vol. 403, no. 10422, 13 Jan. 2024, pp.160-170.

[0004] Currently, combining zebuline and troxetine into a compound formulation appears to be an important strategy for improving the adverse reactions of zebuline. Based on this, the order of release of the two drugs is crucial to both therapeutic efficacy and safety, making the optimal release time of both drugs a major technical challenge.

[0005] Since the primary function of troxochloride is to block peripheral M receptors and prevent the gastrointestinal side effects of xaprometrine, troxochloride must act before xaprometrine in terms of its mechanism of action.

[0006] If troxochloride is absorbed to its peak value earlier, it can occupy peripheral muscarinic receptors before xaprometin begins to act on peripheral M receptors, forming a protective barrier. This effectively reduces the occurrence of side effects, allowing patients to better tolerate the drug and ensuring the continuity and effectiveness of xaprometin treatment. However, if troxochloride and xaprometin are released simultaneously or xaprometin is released before troxochloride, troxochloride fails to preferentially compete for blocking peripheral receptors, thus inhibiting adverse reactions (including gastrointestinal discomfort such as nausea, vomiting, and diarrhea) caused by xaprometin activating peripheral muscarinic receptors. This makes it difficult for patients to adhere to treatment and affects the overall treatment effect.

[0007] Currently, the main formulations of compound drugs containing xaprometin and trox chloride include compound tablets and double-bead capsules. Compound tablets involve directly mixing and compressing the two drugs, which can easily lead to chemical interactions such as acid-base reactions and oxidative degradation. For example, xaprometin is easily hydrolyzed in acidic environments to generate impurity A (3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-onium), and the alkalinity of trox chloride may accelerate this process (see reference: J. Pharm. Sci., 2020). Double-bead capsules involve granulating the two drugs separately and then mixing and filling them (patent CN112789042A).

[0008] Although existing formulations have partially solved the compatibility problem between the two drugs at the formulation level, the simultaneous release of the two drugs can cause adverse peripheral reactions.

[0009] To date, there are no literature reports on the technology of preparing zenomeprazole and trox chloride into single-particle, multi-layered core-shell structure formulations that achieve trox chloride release first, followed by zenomeprazole tartrate release. Summary of the Invention

[0010] To address the aforementioned technical problems, this invention provides a multi-layered core-shell structured dual-drug co-loaded oral microgranule formulation that can reduce peripheral adverse reactions caused by fenpropathrin, along with its preparation method and application.

[0011] The core technology of this invention lies in the design of a dual-drug co-loaded oral microgranule formulation with a multi-layered core-shell structure. By adopting a spatial isolation technique to form different drugs released sequentially, the synergistic problem in the combined administration of muscarinic receptor agonist (xenomeline tartrate) and peripheral antagonist (trisamine chloride) is solved.

[0012] The specific technical solution of the present invention is as follows: The first aspect of the present invention is to provide a dual-drug co-loaded oral microgranule formulation having a multilayer core-shell structure, the oral microgranule formulation comprising a core, an isolation layer and an outer shell layer, wherein the core comprises the central nervous system agonist zenomeprazole tartrate; the isolation layer comprises a pH-dependent or pH-independent polymeric material; and the outer shell layer comprises the peripheral antagonist troxammonium chloride.

[0013] In the oral microcapsule formulation provided by the present invention, preferably, the core of the capsule may selectively include an acidity regulator, wherein the acidity regulator is selected from one or more of citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, and ascorbic acid.

[0014] Preferably, the particle size of the pellet core is 150-1500 μm.

[0015] As a further preferred embodiment, the particle size of the pellet core is 300-1000 μm.

[0016] Preferably, the isolation layer enables the release of trox chloride first and sennametrine tartrate after the oral microgranule formulation is taken by the patient. Furthermore, the time interval between the peak drug time (Tmax) of trox chloride and sennametrine tartrate in the human body is 30 min-2 h, preferably 45 min-1.5 h, and more preferably 1 h.

[0017] Preferably, the pH-dependent or pH-independent polymeric material is selected from one or more combinations of acrylic resin, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), gelatin, gum arabic, chitosan, cellulose acetate (CA), and cellulose acetate butyrate (CAB).

[0018] As a further preferred embodiment, the isolation layer further includes a pore-forming agent and / or a plasticizer, wherein the pore-forming agent is one or a combination of talc, sucrose, lactose, and mannitol; and the plasticizer is one or a combination of polyethylene glycol 6000, triethyl citrate, tributyl citrate, and dibutyl sebacate.

[0019] As a further preferred embodiment, the acrylic resin includes one or a combination of more than one of methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer.

[0020] Preferably, the peripheral antagonist troxodium chloride accounts for 5%-20% of the weight of the oral microsphere formulation, and the central agonist zebuline tartrate accounts for 20%-70% of the weight of the oral microsphere formulation.

[0021] Preferably, the thickness of the isolation layer is controlled by controlling the amount of coating liquid sprayed and / or by online particle size measurement, and the coating thickness of the isolation layer is adjusted to about 10-50 μm.

[0022] A second aspect of the present invention provides a method for preparing the oral microgranule formulation having a multilayer core-shell structure with dual drug co-loaded, the method specifically comprising the following steps: Preparation of S1 pellet core: The central nervous system agonist zenomeline tartrate is wet-mixed with pharmaceutical excipient I and then extruded and spherical to form a pellet core; the pharmaceutical excipient I is selected from one or more combinations of microcrystalline cellulose, lactose, starch, mannitol, HPC, PVP, and HPMC. S2 isolation layer coating: The pellet cores obtained in S1 are placed in a fluidized bed granulation and coating machine, the inlet air temperature is adjusted to 50-80℃, the material temperature is 35℃-45℃, and the isolation layer coating liquid is uniformly sprayed onto the surface of the pellet cores using the bottom spray method, and the thickness of the isolation layer is controlled to be 10-50 μm; the isolation layer contains pH-dependent or pH-independent polymer materials. Preparation of the S3 outer shell layer: The peripheral antagonist troxammonium chloride is mixed with pharmaceutical excipient II and then coated on the outer surface of the S2 pellet core isolation layer to form a peripheral antagonist coating, i.e., the outer shell layer. The pharmaceutical excipient II is selected from one or more combinations of HPMC, PVP, HPC, and copovidone.

[0023] A third aspect of the present invention is the application of the aforementioned dual-drug co-loaded oral microgranule formulation with a multilayered core-shell structure in the preparation of drugs for treating central nervous system diseases, including but not limited to the following conditions: schizophrenia, Alzheimer's disease, and Parkinson's disease.

[0024] In this invention, the amounts of pharmaceutical excipient I and pharmaceutical excipient II are those of conventional prescriptions. The addition of these pharmaceutical excipients achieves drug loading and enables the drug to reach a specific particle size. Therefore, no special provisions are made in this invention, and only exemplary data are given in the embodiments.

[0025] The advantages of this invention compared to the prior art are as follows: (1) The oral microgranule formulation with dual drug co-load provided by the present invention, through the design of a multi-layer core-shell structure, enables the oral microgranule formulation to have the synergistic effect of microenvironment regulation and time difference release. That is, the peripheral antagonist trox chloride in the outermost layer is preferentially released and acts on the peripheral muscarinic receptor (M1 / M4), and the sennamidin in the core is released later or pulsatilely and acts on the peripheral receptor (M2 / M3). This makes the efficacy and side effect inhibition of the two drugs synergistically form a time difference, which solves the synergistic problem in the combined administration of sennamidin and the antagonist trox chloride. (2) Preclinical data of the present invention show that the design can reduce the incidence of nausea, significantly improve the stability of the formulation, and reduce the total amount of impurities to <1.5%. In addition, based on the pH dependence of the solubility of fenofibrate, the present invention adds an acid regulator to the core layer of the pellet, which further improves the absorption of fenofibrate in the intestine, improves the bioavailability of fenofibrate, and significantly enhances the efficacy. Attached Figure Description

[0026] Figure 1 The dissolution curves of the oral micro-pellet formulations prepared in Examples 5-7 of this invention in hydrochloric acid solution at pH 1.2 are shown. Figure 2 The dissolution curves of the oral microparticle formulations prepared in Examples 5-7 of this invention in phosphate buffer solution at pH 6.8 are shown. Figure 3 This is a dissolution curve of the oral microparticle formulation prepared in Example 7 of the present invention in phosphate buffer solution at pH 7.2. Detailed Implementation

[0027] To enable those skilled in the art to better understand the present invention, the present invention will now be further described in conjunction with specific embodiments.

[0028] The following examples are provided to illustrate the invention and are not intended to impose any limitations on any aspect thereof.

[0029] Example 1 The pellet core in this embodiment does not contain a pH adjuster. The release of trexammonium chloride and fenofibrate is achieved solely through the design of a multi-layer core-shell structure, which creates a time-difference effect.

[0030] The formulation of the dual-drug co-loaded oral microspheres prepared in this embodiment is shown in Table 1.

[0031] Table 1. Formulation of dual-drug co-loaded oral micropellets

[0032] In this embodiment, the multilayered core-shell structured dual-drug co-loaded oral microgranule formulation is prepared using the following method: Preparation of S1 pellet core Zanomelide and microcrystalline cellulose were mixed evenly according to the formulation ratio in Table 1. An appropriate amount of purified water was added and stirred evenly to make a soft material. The soft material was then extruded through a sieve with a fixed mesh size. The extrudate was then rolled into spheres using a sphere rolling machine to control the microsphere particle size d (0.9) to be 150 μm. The spheres were then dried to obtain the pellet core.

[0033] S2 isolation layer coating Preparation of the isolation layer coating solution: Dissolve HPMC E5 in purified water, add the prescribed amount of polyethylene glycol 6000, stir evenly, and prepare the isolation layer coating solution; Coating operation: Place the pellet cores obtained in step S1 into a fluidized bed granulation and coating machine, adjust the air inlet temperature to 50-80℃ and the material temperature to 35℃-45℃, and use the bottom spray method to evenly spray the isolation layer coating liquid onto the surface of the pellet cores, controlling the isolation layer thickness to 30 μm. Drying: After coating, set a suitable temperature for drying to ensure the isolation layer is completely dry.

[0034] Preparation of S3 outer shell layer Preparation of outer shell coating solution: Dissolve the prescribed amount of HPC in purified water, add troxammonium chloride and mix to prepare the outer shell coating solution; Coating operation: Place the isolation layer microparticles prepared in step S2 into a fluidized bed coating device, adjust the inlet air temperature and material temperature, and perform bottom spray coating; Drying: After coating, dry at a suitable temperature to obtain the dual-drug co-loaded oral microgranule formulation.

[0035] Example 2 Table 2 shows the solubility of fenofibrate in different pH media.

[0036] Table 2. Solubility of cyclophosphamide in different media (37℃) 0.1N HCl 1.2 242 0.05 mol sodium acetate 4.5 303 0.05 mol potassium phosphate 6.8 0.18

[0037] As shown in Table 2, when the pH of the medium is greater than 4.5, the solubility of xaprometrine decreases rapidly. This may be the main reason for the low bioavailability of xaprometrine. Therefore, in Examples 2-4 of the present invention, an acid regulator or an acid isolation layer is added to the core of the pellet to improve the absorption of xaprometrine in the intestine.

[0038] In this embodiment, the formulation of the dual-drug co-loaded oral microgranule is as shown in Table 3.

[0039] Table 3. Formulation of dual-drug co-loaded oral micropellets

[0040] In this embodiment, the preparation method of the dual-drug co-loaded oral microsphere formulation is the same as in Example 1. In step S1, 0.1% of citric acid is added to the pellet core, and the pellet core particle size d (0.9) is 200 μm.

[0041] Example 3 In this embodiment, the formulation of the dual-drug co-loaded oral microgranule is shown in Table 4.

[0042] Table 4. Formulation of dual-drug co-loaded oral micropellets

[0043] In this embodiment, the preparation method of the dual-drug co-loaded oral microsphere formulation is the same as in Example 1, and the particle size d (0.9) of the pellet core is 500 μm; in step S2, the thickness of the isolation layer coating is 15 μm.

[0044] Example 4 In this embodiment, the formulation of the dual-drug co-loaded oral microgranule is shown in Table 5.

[0045] Table 5. Formulation of dual-drug co-loaded oral micropellets

[0046] In this embodiment, the preparation method of the dual-drug co-loaded oral microsphere formulation is the same as in Example 1, and the core particle size d (0.9) is 1500 μm; in step S2, the coating thickness of the isolation layer is adjusted to about 45 μm by controlling the amount of coating liquid sprayed and / or online particle size determination.

[0047] Experimental Example 1 The oral microgranule formulations with dual drug co-loaded prepared in Examples 1-4 were tested according to the dissolution and release determination method in General Rule 0931 (Chinese Pharmacopoeia 2020 Edition). The second method of dissolution determination was used with an apparatus at a speed of 50 rpm and 500 mL of phosphate buffer solution with pH 6.8 as the dissolution medium. After 10 min, 20 min, 30 min, 45 min, 60 min and 90 min, 10 mL of solution was taken, filtered, and the filtrate was used as the test solution to determine the drug dissolution rate. See Table 6.

[0048] Table 6. Dissolution rate (%) of the oral microgranule formulations in Examples 1-4 in phosphate at pH 6.8.

[0049] As shown in Table 6 above, based on Example 1, Examples 2-4 accelerated the dissolution of fenofibrate in phosphate buffer solution at pH 6.8 after adding an acid regulator to the pellet core.

[0050] Example 5 In this embodiment, the formulation of the dual-drug co-loaded oral microgranule is shown in Table 7.

[0051] Table 7. Formulation of dual-drug co-loaded oral micropellets

[0052] In this embodiment, the preparation method of the dual-drug co-loaded oral microsphere formulation is the same as in Example 1, and the core particle size d (0.9) is 800 μm; in step S2, the coating material of the isolation layer is adjusted to aqueous dispersion of methacrylic acid-ethyl acrylate copolymer L30D-55, and the coating thickness of the isolation layer is 45 μm.

[0053] Example 6 In this embodiment, the formulation of the dual-drug co-loaded oral microgranule is shown in Table 8.

[0054] Table 8. Formulation of dual-drug co-loaded oral micropellets

[0055] In this embodiment, the preparation method of the dual-drug co-loaded oral microgranule formulation is the same as in Example 1. Compared with the formulation composition of Example 5, the isolation layer coating material in step S2 is replaced by methacrylic acid-methyl methacrylate copolymer (1:1) instead of methacrylic acid-ethyl acrylate copolymer aqueous dispersion L30D-55, and the thickness of the isolation layer coating is 42 μm.

[0056] Example 7 In this embodiment, the formulation of the dual-drug co-loaded oral microgranule is shown in Table 9.

[0057] Table 9. Formulation of dual-drug co-loaded oral micropellets

[0058] In this embodiment, the preparation method of the dual-drug co-loaded oral microgranule formulation is the same as in Example 1. Compared with the formulation composition of Example 5, the isolation layer coating material in step S2 is replaced by methacrylic acid-methyl methacrylate copolymer (1:2) instead of methacrylic acid-ethyl acrylate copolymer aqueous dispersion L30D-55, and the thickness of the isolation layer coating is 38 μm.

[0059] Experimental Example 2 Take the dual-drug co-loaded oral microgranule formulations prepared in Examples 5-7, and perform dissolution and release assays according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Use 300 mL of 0.1 mol / L hydrochloric acid solution as the release medium, and operate at 50 rpm. After 10 min, 20 min, 30 min, 60 min, and 120 min, take 10 mL of the solution, filter it, and use the filtrate as the test solution for determination. Calculate the release amount and plot the dissolution curve.

[0060] Then, add 700 mL of 0.086 mol / L disodium hydrogen phosphate solution preheated to 37℃±0.5℃ to each dissolution vessel, mix well (adjust the pH to 6.8±0.05 with 2 mol / L sodium hydroxide solution or 2 mol / L hydrochloric acid solution if necessary), rotate at 50 rpm, and continue the operation according to the procedure. After 10 min, 20 min, 30 min, 60 min, 120 min, and 150 min, take 10 mL of the solution, filter, and use the filtrate as the test solution for determination. Calculate the release amount and plot the dissolution curve.

[0061] After adjusting the medium to pH 7.2, take 10 mL of solution at 10 min, 20 min, 30 min, 45 min, 60 min, 90 min, and 120 min, filter, and use the filtrate as the test solution for determination. Calculate the release amount and plot the dissolution curve.

[0062] In Examples 5-7, pH-dependent polymeric materials were used as the isolation layer material. The dissolution of the obtained dual-drug co-loaded oral microsphere formulations in hydrochloric acid solution at pH 1.2 and phosphate buffer solution at pH 6.8 are shown in Table 10 and 10, respectively. Figure 1 , Figure 2 As shown.

[0063] Table 10 and Figure 1 , Figure 2 The results showed that in a dissolution medium (simulated gastric juice) with a pH of 1.2, troxetine was rapidly released, but zebuline was detected at 0%, indicating that the isolation layer did not dissolve and the drug was hardly released. However, in a dissolution medium (simulated small intestine) with a pH of 6.8, the isolation layer of the oral microgranule formulations in Examples 5 and 6 dissolved, and zebuline was rapidly released, which is beneficial for achieving targeted drug release in the intestine and avoiding gastric acid damage or gastric irritation.

[0064] Table 11 and Figure 3 The dissolution of the dual-drug co-loaded oral microsphere formulation prepared in Example 7 in phosphate at pH 7.2 is shown.

[0065] Figure 2 , Figure 3 As shown in Table 11, in Example 7, there was no release in a medium with a pH of 6.8. After adjusting the pH of the medium to 7.2, the isolation layer of the oral micropellet formulation dissolved, and fenofibrate was rapidly released, achieving targeted release of the drug at different locations in the intestine.

[0066] Table 10 Dissolution rates (%) of the oral microgranule formulations of Examples 5-7 in media with pH 1.2 and pH 6.8.

[0067] Table 11 Drug dissolution (%) in media with pH 1.2 and pH 7.2 in Example 7

[0068] Comparative Example 1 Unlike Example 4, step S2, the isolation layer coating operation, is not performed; all other steps are the same as in Example 4.

[0069] Comparative Example 2 The difference from Example 3 is that the particle size of the pellet core in step S1 is 100 μm, while the rest is the same as in Example 3.

[0070] Comparative Example 3 The difference from Example 3 is that the particle size of the pellet core in step S1 is 1600 μm, while the rest is the same as in Example 3.

[0071] Comparative Example 4 Commercially available cyclophosphamide capsules.

[0072] Experimental Example 3: Stability Test Data The stability test conditions for the formulation in this example were: 50℃ and 75% relative humidity. The test results are shown in Table 12.

[0073] Table 12 Results of Stability Tests

[0074] Table 12 shows that, in Comparative Example 1 without an isolation layer, the related substances of trox chloride and fenofibrate increased more rapidly than in Examples 1, 2, 4, and 5 containing an isolation layer during the ultra-accelerated stability study.

[0075] Table 13 shows the effect of excessively large pellet size on drug release.

[0076] Table 13 Drug dissolution (%) of the formulations of Example 3 and Comparative Example 3 in pH 6.8 medium.

[0077] The results in Table 13 show that the core particle size of Comparative Example 2 was too small, resulting in low coating process efficiency and yield, making it unproductive, and therefore dissolution testing was not performed. The core particle size of Comparative Example 3 was too large, resulting in a reduced contact area between the drug and the dissolution medium, a slower dissolution rate, manifested as a slow rise in the dissolution curve, and slow drug release, failing to achieve an effective blood drug concentration.

[0078] Experimental Example 4: Investigating the effect of the oral microgranule formulation of the present invention, containing two drugs, on a pigeon vomiting model. Vomiting is one of the gastrointestinal adverse reactions that needs to be carefully investigated in drug development. Domestic pigeons (Columba livia domesticica) are often used as an alternative model for evaluating the emetic potential of drugs due to their highly sensitive vomiting reflex and relatively economical feeding costs. This experiment aims to evaluate the gastrointestinal adverse reactions of the test drug by systematically observing the vomiting behavior of domestic pigeons after drug administration, providing a reference for preclinical safety studies.

[0079] 1. Laboratory animals and their husbandry management Healthy adult pigeons were selected as experimental animals and randomly divided into groups of 10 animals per group, aged 12-18 months and weighing between 350-450 g, with an equal number of males and females. All animals were acclimatized for 7 days in a specific pathogen-free (SPF) grade animal room at a temperature of (23±2℃) and relative humidity of (55±5%), during which they had free access to standard pigeon feed and water. To accurately evaluate gastrointestinal responses, fasting was implemented 24 hours prior to the experiment, but free access to water was permitted to ensure adequate emptying of the stomach contents.

[0080] 2. Experimental drugs and dosage (1) Three experimental groups, namely, the drug compositions of oral microgranules co-loaded with two drugs in Example 2, Example 5 and Comparative Example 4; (2) Blank control group: administered blank microspheres; (3) Positive control group: micro-pellet preparation containing 50 mg / kg copper sulfate.

[0081] All microparticle formulations underwent rigorous content uniformity testing before use to ensure the reliability of experimental data. A specialized oral administration device was used to prepare a uniform suspension by mixing precisely weighed microparticles (based on a standard of 10 mg microparticles / g body weight) with a 0.5% sodium carboxymethyl cellulose solution. The administration volume was uniformly controlled at 10 mL / kg, and the medication was administered via slow bolus injection to avoid unnecessary stress on the animals.

[0082] 3. Observation indicators and data collection Continuous observation was conducted within 6 hours after drug administration, focusing on the following indicators: latency to first vomiting (time from completion of drug administration to the first vomiting), number of vomiting episodes (clear oral expulsion of gastric contents), and number of retching episodes (obvious vomiting actions without expulsion of contents). Observation continued for 24 hours after the experiment, and mortality was recorded. All observations were conducted independently by two trained personnel using a double-blind method. The experimental results are shown in Table 14.

[0083] Table 14 Results of the test on the pigeon vomiting model using oral micropellets containing two drugs. Blank control group 1 75 0 1 Positive control group 10 15 6 8 Example 2 2 138 2 3 Example 5 2 125 3 2 Comparative Example 4 4 100 6 9

[0084] As shown in Table 14, the drug composition of the present invention caused vomiting in fewer animals, with a longer latency period and fewer vomiting episodes.

[0085] Experimental Example 5: Investigating the effect of the oral microgranule formulation of the present invention, containing two drugs, on a vomiting model in dogs. The vomiting reflex mechanism in beagles is highly similar to that in humans. Their medulla oblongata is rich in receptors such as 5-HT3, NK1, and D2, enabling precise responses to various stimuli, including chemotherapy drugs and neurotransmitters. Furthermore, their gastrointestinal motility characteristics (gastric emptying 2-4 hours, intestinal transit 12-24 hours) closely resemble those of humans. This experiment aims to further evaluate the gastrointestinal adverse reactions of the test drug by systematically observing the vomiting behavior of beagles after drug administration.

[0086] 1. Preparation and Management of Laboratory Animals Eighteen healthy Beagles (8-12 months old, weighing 8-12 kg), half male and half female, were selected. The animals underwent a 14-day quarantine and acclimatization period (deworming and vaccination completed) and were housed individually in a temperature-controlled environment (23±2℃, humidity 55±10%). They were fed a maintenance diet (LabDiet® 5007) totaling 300g twice daily, morning and evening, with free access to water. They were strictly fasted for 12 hours prior to the experiment (water allowed), and 2 hours after administration, a liquid prescription canned food (100g / animal) was provided to reduce gastrointestinal burden.

[0087] 2. Grouping and Dosing Design The experiment was divided into three groups (n=6 in each group): Blank control group: Orally administered 0.5% CMC-Na solution (solvent); Positive control group: Orally administered 1% copper sulfate solution (1 mL / kg, i.e., 10 mg / kg). Test drug group: 2 groups, namely the two drug co-loaded oral microgranule formulations of Example 2 and Comparative Example 4.

[0088] The dosage volume for all groups was uniformly 10 mL / kg. Copper sulfate solution was prepared with distilled water (pH adjusted to 6.5-7.0) before use, and the test drug was suspended in 0.5% CMC-Na. Gavage was performed by two people: an assistant restrained the dog and kept its neck straight, inserting an Fr14 silicone gastric tube orally to a depth of 35-40 cm. The position of the gastric tube was confirmed by auscultation before administration, and the drug was slowly injected (≤1 mL / s). After administration, the tubing was flushed with 5 mL of normal saline.

[0089] 3. Observation and Recording Plan Intensive monitoring was conducted from 0 to 2 hours after drug administration (recorded every 10 minutes), from 2 to 6 hours every 30 minutes, and from 6 to 24 hours every 2 hours for evaluation.

[0090] The observation indicators included: latency period of first vomiting (time from completion of administration to first vomiting), number of vomiting (clear oral expulsion of gastric contents), and number of retching (obvious vomiting actions but no contents expulsion). The experimental results are shown in Table 15.

[0091] Table 15 Results of the comparative canine vomiting model test of the dual-drug co-loaded oral micropellet formulation. Incubation period (min) for the first vomiting 10-25 40-90 40-90 Number of vomiting episodes in 0-2 hours 3-5 0 0 Number of vomiting episodes (2-6 hours) 0-1 2-4 3-6 Number of times of dry heaving (0-2 hours) 8-12 (paroxysmal) 2-4 (Intermittent) 6-10 (intermittent)

[0092] Table 15 also shows that the drug formulation of the present invention causes vomiting in fewer animals, has a longer incubation period, and fewer vomiting episodes.

[0093] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A dual drug-loaded oral pellet formulation having a multi-layer core-shell structure with reduced peripheral adverse effects caused by xanomeline, characterized in that, The oral microcapsule formulation comprises a core, an isolation layer, and an outer shell. The core contains the central nervous system agonist zebuline tartrate; the isolation layer contains a pH-dependent polymeric material; and the outer shell contains the peripheral antagonist troxammonium chloride. The pH-dependent polymer material is selected from any one or a combination of multiple of the following: methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer; In the methacrylic acid-methyl methacrylate copolymer, the molar ratio of methacrylic acid to methyl methacrylate is 1:1 or 1:

2. The methacrylate-ethyl acrylate copolymer is methacrylate-ethyl acrylate aqueous dispersion L30D-55; The thickness of the isolation layer is 10-50 μm.

2. The oral pellet formulation according to claim 1, wherein The core material may or may not include an acid regulator, which is selected from one or more of citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, and ascorbic acid.

3. The oral pellet formulation according to claim 1, wherein The particle size of the pellet core is 150-1500 μm.

4. The oral pellet formulation according to claim 1, wherein The isolation layer further includes a pore-forming agent and / or a plasticizer, wherein the pore-forming agent is one or a combination of talc, sucrose, lactose, and mannitol; and the plasticizer is one or a combination of polyethylene glycol 6000, triethyl citrate, tributyl citrate, and dibutyl sebacate.

5. The oral pellet formulation according to any one of claims 1 to 4, wherein The peripheral antagonist troxodium chloride accounts for 5%-20% of the weight of the oral microsphere formulation, and the central agonist zebuline tartrate accounts for 20%-70% of the weight of the oral microsphere formulation.

6. A process for the preparation of the oral pellet formulation according to claim 1, characterized in that, The steps include the following: Preparation of S1 pellet core: The central nervous system agonist zenomeline tartrate is wet-mixed with pharmaceutical excipient I and then extruded and spherical to form a pellet core; the pharmaceutical excipient I is selected from at least one of microcrystalline cellulose, lactose, starch, mannitol, hydroxypropyl cellulose, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. S2 isolation layer coating: Place the pellet cores obtained from S1 in a fluidized bed granulation and coating machine, adjust the inlet air temperature to 50-80℃ and the material temperature to 35-45℃, and use the bottom spray method to evenly spray the isolation layer coating liquid onto the surface of the pellet cores, controlling the isolation layer thickness to be 10-50 μm. Preparation of the S3 outer shell layer: The peripheral antagonist troxammonium chloride is mixed with pharmaceutical excipient II and then coated on the outer surface of the S2 pellet core isolation layer to form a peripheral antagonist coating, i.e., the outer shell layer. The pharmaceutical excipient II is selected from at least one of hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, and copovidone.

7. The use of the oral pellet preparation according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of central nervous system diseases, characterized in that, The central nervous system diseases mentioned are: schizophrenia, Alzheimer's disease, and Parkinson's disease.

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