Capecitabine prodrug for reducing liver metabolism burden and application of capecitabine prodrug

Abstract

The invention provides a capecitabine prodrug for reducing liver metabolism burden and application thereof, a derivative formed by introducing a masking group R capable of enzymolysis or chemical hydrolysis into 5 '-hydroxyl or N-amino of a capecitabine molecule, and the R is selected from amino-acid ester, phosphate, polyethylene glycol chain or cholic acid conjugation group. The prodrug can be selectively activated in intestinal tracts or tumor tissues through a non-UGT1A1 dependent pathway, and 5-fluorouracil is finally released through metabolism. Due to the characteristic, the competitive inhibition of the prototype capecitabine on liver UGT1A1 enzyme is obviously reduced, and the interference on bilirubin binding and excretion pathways is fundamentally reduced. The pharmaceutical composition disclosed by the invention is suitable for patients with UGT1A1 gene defects or liver insufficiency. While good anti-tumor activity is maintained, the hepatotoxicity is remarkably reduced, the medication safety is improved, and good clinical application prospects are achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry and cancer treatment, and in particular, to a capecitabine prodrug for reducing liver metabolic burden and application thereof. BACKGROUND

[0002] Capecitabine is an oral fluorouracil prodrug, which is widely used in the chemotherapy of colorectal cancer, breast cancer, gastric cancer and other solid tumors. It is converted into active ingredient 5-fluorouracil (5-FU) in vivo through three-step enzymatic reactions, and finally exerts an antitumor effect: first, it is hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase in the liver and intestinal tract, and then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase, and finally cleaved to 5-FU in tumor tissues by the highly expressed thymidine phosphorylase (TP).

[0003] Although capecitabine has the advantages of oral convenience and relatively good targeting, it is often accompanied by significant liver metabolism-related adverse reactions in clinical application, especially dose-dependent hyperbilirubinemia and drug-induced jaundice. Studies have shown that this toxicity is mainly due to the interference of metabolic intermediates with key metabolic pathways in hepatocytes: Inhibition of UGT1A1 enzyme activity: 5'-DFUR and other intermediates can competitively inhibit uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which is a key rate-limiting enzyme for catalyzing the conversion of indirect bilirubin to direct bilirubin (conjugated bilirubin). When UGT1A1 function is impaired, unconjugated bilirubin accumulates in the blood, causing jaundice.

[0004] Affecting bile excretion transport proteins: capecitabine or its metabolites may down-regulate the expression or function of multidrug resistance-associated protein 2 (MRP2 / ABCC2), hindering the active transport of conjugated bilirubin from hepatocytes to bile canaliculi, leading to bile stasis.

[0005] People with genetic susceptibility are at higher risk: patients carrying UGT1A128 or 6 function-deficient alleles (especially in Asian populations), whose UGT1A1 enzyme activity is only 10%–50% of that of normal individuals, have a significantly increased risk of grade III / IV bilirubin elevation after using standard-dose capecitabine, often requiring dose reduction or even drug discontinuation, affecting treatment continuity and efficacy.

[0006] In addition, in patients with mild to moderate liver dysfunction or in combination with drugs affecting UGT1A1 / MRP2 activity, the above toxicity is further exacerbated, severely limiting the clinical application range of capecitabine.

[0007] While existing technologies address toxicity through dosage adjustments and gene-guided drug use, these are all passive strategies and do not fundamentally resolve the structural defects caused by capecitabine's reliance on first-pass metabolism in the liver. Therefore, this paper proposes a capecitabine prodrug that reduces the metabolic burden on the liver and its application. Summary of the Invention

[0008] The purpose of this invention is to address the problems identified in the existing background technology. To achieve the above-mentioned objective, this invention provides the following technical solution: a capecitabine prodrug that reduces the metabolic burden on the liver, wherein the compound is a 5'-hydroxyl group or... Introducing a masking group that can be enzymatically or chemically hydrolyzed at the amino position The formed derivative, wherein Including amino acid esters, phosphate esters, polyethylene glycol-modified alkyl chains, and cholic acid conjugated groups; The amino acid esters include glycine ethyl ester, leucine methyl ester, or glutamic acid monoester; The phosphate esters include phosphoryloxymethyl phosphate. Or phenyl phosphate substituents; The PEGylated alkyl chain chemical formula is: ; The cholic acid conjugate group is connected via a degradable linker arm. Linked to deoxycholic acid; The prodrug is non-invasively metabolized in vivo. The active ingredient 5-fluorouracil is released via a dependence pathway, and its effects on hepatocytes are significantly reduced. Competitive inhibition of enzymes and interference with bilirubin binding and excretion pathways.

[0009] As a preferred technical solution of the present invention, the compound includes ; Capecitabine-5'-O-glycine ethyl ester, chemically named [5'-O-(N-ethoxycarbonylglycyl)]-5'-deoxy-5-fluorocytidine; -(phosphoryloxymethyl)-capecitabine, the structure contains : Deoxycholic acid propionamide-capecitabine conjugate, through Connecting bile acids Located in capecitabine Bit.

[0010] As a preferred technical scheme of the present application, the prodrug is preferentially hydrolyzed by intestinal brush border enzymes under physiological conditions, including carboxylesterase 2, peptide transporter PEPT2, alkaline phosphatase ALP highly expressed in tumor microenvironment, or acid environment, and is selectively activated in extrahepatic tissues.

[0011] A pharmaceutical composition for reducing liver metabolic burden, comprising a capecitabine prodrug and pharmaceutically acceptable excipients, including fillers, disintegrants, binders, lubricants and coating materials; preferably, the composition is a double-layer coated oral preparation, the inner layer is a pH-sensitive enteric layer (dissolved at pH≥6.8), and the outer layer is a gastric retention type hydrophilic gel coating for controlling the site-specific release of the drug in the distal ileum.

[0012] As a preferred technical scheme of the present application, the fillers are selected from microcrystalline cellulose, lactose or pregelatinized starch; the disintegrants are cross-linked sodium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose; and the coating materials are cellulose acetate phthalate (CAP), Eudragit L100 or hydroxypropyl methylcellulose phthalate (HPMCP).

[0013] Use of a capecitabine prodrug in the preparation of a medicament for treating solid tumors, such as colorectal cancer, breast cancer, gastric cancer or pancreatic cancer, characterized in that the prodrug can still be effectively converted to 5-FU in individuals with low UGT1A1 enzyme activity, and the serum total bilirubin elevation is reduced by ≥50% compared with traditional capecitabine.

[0014] As a preferred technical scheme of the present application, the patient is a high-risk population carrying a UGT1A1 function-deficient gene, and the genotype is: homozygous mutant type:

[0015] As a preferred technical scheme of the present application, the patient has mild to moderate liver dysfunction, Child-Pugh classification A or B, or is using drugs that inhibit or transporters, including irinotecan, rifampicin, cyclosporin A or voriconazole.

[0016] As a preferred technical scheme of the present application, the prodrug of claim 1 replaces standard capecitabine for anti-tumor, and synergistically reduces liver toxicity by the following mechanisms: inhibiting direct bilirubin reflux into blood caused by impaired MRP2 transporter function; and monitoring serum total bilirubin level rising no more than 1.5 times the baseline value as a decrease in metabolic burden.

[0017] A method for reducing the metabolic burden of capecitabine prodrugs, characterized in that capecitabine is dissolved in anhydrous polar solvent, a condensing agent system is added under nitrogen protection, and an activated reagent containing a masking group is added dropwise for acylation or alkylation reaction; When synthesizing amino acid ester derivatives, EDC / NHS system is used to react with glycine ethyl ester hydrochloride, the temperature is 0-25 DEG C, and the reaction time is 6-24 hours; When constructing phosphate prodrugs, phosphorus oxychloride reagent is used, including Under the catalysis of pyridine Alkylation; After the reaction is completed, the target product is obtained through extraction, column chromatography purification or recrystallization, the purity detected by HPLC is greater than or equal to 98%, and the yield is not less than 65%.

[0018] Compared with the prior art, the beneficial effects of the present application are: the present application introduces a masking group (such as amino acid ester, phosphate, cholic acid conjugate) which can be metabolized by non-UGT1A1 pathway at 5'-hydroxyl or N 4 amino of capecitabine molecule, so that the prodrug activation process avoids the liver first-pass effect, preferentially hydrolyzes in the intestinal brush border or tumor microenvironment to release the active ingredient, greatly reduces the accumulation of metabolic intermediates in the liver, thereby effectively reducing the functional interference on hepatocytes. Avoid UGT1A1 enzyme inhibition: The metabolic pathway of the prodrug of the present application does not produce strong UGT1A1 inhibitory intermediates (such as traditional 5'-DFUR), and in vitro experiments show that it has >500 muM, which is much higher than the clinical concentration, significantly reducing the risk of bilirubin binding disorders. Animal models confirm that in UGT1A1 functionally deficient individuals, the increase in serum total bilirubin is reduced by more than 50% compared with traditional capecitabine, and the incidence of jaundice is reduced by more than 60%.

[0019] Due to the significant reduction of liver drug exposure (60% reduction of liver tissue drug concentration), the inhibition of the prodrug of the present application on MRP2 / BCRP bile excretion transporters is significantly weakened, which helps to maintain normal bilirubin excretion and prevent cholestasis damage. The prodrug described in the present application can be efficiently released 5-FU under the action of tumor tissue-specific enzymes, alkaline phosphatase ALP, thymidine phosphorylase TP or acidic microenvironment, realizing "extrahepatic activation and tumor enrichment". The toxicity of the prodrug of the present application to normal hepatocytes (LO2) is significantly lower than that of traditional drugs, the selectivity index (SI) is increased by nearly one time, which means a higher safe dose range and is more suitable for long-term oral administration.

[0020] The present application is particularly suitable for UGT1A1 gene mutation carriers, Child-Pugh A / B grade liver dysfunction patients and people receiving combined treatment of liver enzyme inhibitors, which can be safely used without routine dose reduction, ensuring treatment compliance and stability of curative effect. The prodrug can be made into enteric-coated tablets, sustained-release capsules or nano-targeted preparations to realize site-specific release and controllable absorption; stability tests show that the degradation of the main component is <2% within 6 months under accelerated conditions (40°C / 75%RH), meeting the requirements of industrial production. BRIEF DESCRIPTION OF DRAWINGS Figure 1 Data block diagram of ingredient type provided by the present application; Figure 2 Data block diagram of auxiliary material category provided by the present application; Figure 3 Schematic diagram of the synthesis method provided by the present application; Figure 4 Data block diagram of method optimization provided by the present application; Figure 5 Data block diagram of drug properties provided by the present application. DETAILED DESCRIPTION

[0021] To make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings. Obviously, the described embodiments are specific embodiments of the present application, and are not limited to all embodiments.

[0022] Therefore, the following detailed description of the embodiments of the present application is not intended to limit the scope of the claimed application, but only represents some embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present application.

[0023] It should be noted that the embodiments in the present application and the features and technical solutions in the embodiments can be combined with each other without conflict, and it should be noted that similar reference numerals and letters represent similar items in the following drawings, so once an item is defined in one drawing, it does not need to be further defined and explained in subsequent drawings.

[0024] Embodiment 1: A capecitabine prodrug for reducing liver metabolic burden, the compound is a derivative formed by introducing an enzymatically or chemically hydrolyzable masking group at the 5'-hydroxyl or amino position of the capecitabine molecule , wherein including amino acid esters, phosphate esters, polyethylene glycol alkyl chains, cholic acid conjugate groups; Amino acid esters include glycine ethyl ester, leucine methyl ester, or glutamic acid monoester; Phosphate esters include phosphoryloxymethyl Or phenyl phosphate substituents; The chemical formula of the polyethylene glycol-modified alkyl chain is ; Bile acid conjugate groups are connected via degradable linkers Linked to deoxycholic acid; Prodrugs in the body via non- The active ingredient 5-fluorouracil is released via a dependence pathway, and its effects on hepatocytes are significantly reduced. Competitive inhibition of enzymes and interference with bilirubin binding and excretion pathways.

[0025] Compounds include ; Capecitabine-5'-O-glycine ethyl ester, chemically named [5'-O-(N-ethoxycarbonylglycyl)]-5'-deoxy-5-fluorocytidine; -(phosphoryloxymethyl)-capecitabine, the structure contains : Deoxycholic acid propionamide-capecitabine conjugate, through Connecting bile acids Located in capecitabine Bit.

[0026] Under physiological conditions, prodrugs are preferentially hydrolyzed by intestinal brush border enzymes, including carboxylesterase 2, peptidase PEPT2, alkaline phosphatase ALP which is highly expressed in the tumor microenvironment, or by an acidic environment, and selectively activated by extrahepatic tissues.

[0027] A pharmaceutical composition for reducing the metabolic burden on the liver, comprising a capecitabine prodrug and pharmaceutically acceptable excipients, including fillers, disintegrants, binders, lubricants and coating materials; preferably, the composition is a double-coated oral formulation, the inner layer being a pH-sensitive enteric coating (soluble at pH ≥ 6.8) and the outer layer being a gastric retention hydrophilic gel coating, for controlling the targeted release of the drug in the distal ileum.

[0028] The filler is selected from microcrystalline cellulose, lactose or pregelatinized starch; the disintegrant is croscarmellose sodium cellulose or low-substituted hydroxypropyl cellulose; the coating material is cellulose acetate phthalate (CAP), Eutectic L100 or hydroxypropyl methylcellulose phthalate (HPMCP).

[0029] The use of capecitabine prodrug in the preparation of drugs for the treatment of solid tumors, such as colorectal cancer, breast cancer, gastric cancer, or pancreatic cancer, is characterized by the fact that the prodrug can still be effectively converted into 5-FU in individuals with low UGT1A1 enzyme activity, and the increase in serum total bilirubin is ≥50% lower than that of conventional capecitabine.

[0030] The patient is a high-risk individual carrying the UGT1A1 defective gene, with the genotype being: homozygous mutant. The enzyme activity is 10%–30% of that of the normal wild type.

[0031] The patient has mild to moderate liver dysfunction, Child-Pugh classification A or B, or is currently using combination therapy with hepatitis B inhibitors. or Drugs targeting transporters include irinotecan, rifampin, cyclosporine A, or voriconazole.

[0032] The prodrug replaces standard capecitabine for antitumor treatment and synergistically reduces liver toxicity through the following mechanisms: inhibiting the reflux of direct bilirubin into the blood caused by impaired MRP2 transporter function; monitoring serum total bilirubin levels and considering an increase of no more than 1.5 times the baseline value as a reduction in metabolic burden.

[0033] A method for reducing the metabolic burden on the liver using capecitabine prodrug, characterized in that: capecitabine is dissolved in an anhydrous polar solvent, a condensing agent system is added under nitrogen protection, and an activating reagent containing a masking group is added dropwise to carry out an acylation or alkylation reaction; When synthesizing amino acid ester derivatives, the EDC / NHS system is used to react with glycine ethyl ester hydrochloride at a temperature of 0–25℃ for a reaction time of 6–24 hours. When constructing phosphate prodrugs, phosphoryl chloride reagents are used, including The process was carried out under pyridine catalysis. Alkylation; After the reaction is complete, the target product is obtained by extraction, column chromatography purification or recrystallization. The purity is ≥98% as determined by HPLC, and the yield is not less than 65%.

[0034] Working process: Capecitabine metabolic intermediates, including 5'-DFUR, competitively inhibit UGT1A1 enzyme activity and interfere with MRP2-mediated bilirubin excretion. Therefore, the research and development goal is to develop a next-generation capecitabine prodrug that is independent of UGT1A1 metabolism and reduces hepatocyte exposure.

[0035] Based on the chemical structure of capecitabine (a 5'-deoxy-5-fluorocytidine derivative), and combining pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, a computer-aided drug design (CADD) method was used for prodrug modification. Target localization: Targeting 5'-hydroxyl and N4 -Amino is a modifiable site because it participates in first-pass metabolism and does not affect subsequent conversion to 5-FU; The ADMET prediction model was used to evaluate the water solubility, stability, enzymatic specificity, and hepatotoxicity potential of hundreds of masking groups. Preferred pathways: amino acid esters (glycine, leucine esters), which can be recognized by intestinal PEPT2; phosphate esters (phosphatidyloxymethyl), which respond to alkaline phosphatase (ALP) in the tumor microenvironment; and bile acid conjugates, which utilize bile acid transport pathways to achieve non-hepatic preferential absorption. Three candidate routes were ultimately identified: CPB-101 (5'-O-glycine ethyl ester), CPB-102 (N... 4 -phosphoryloxymethyl), CPB-103 (cholic acid-N) 4 -Propionamide conjugate).

[0036] Compound Synthesis and Purification: CPB-101 Synthesis: Capecitabine was dissolved in anhydrous DMF, and the carboxyl group was activated by adding EDC·HCl and NHS; glycine ethyl ester hydrochloride solution was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours under nitrogen protection; the reaction solution was poured into ice water to precipitate the precipitate, which was then purified by silica gel column chromatography (eluent: CH2Cl2:MeOH=10:1) to give a white solid with a yield of 72% and HPLC purity >99%.

[0037] CPB-102 Synthesis: Capecitabine N-methyl was synthesized using ClCH2OPO(OEt)2 in the presence of pyridine. 4 Alkylation was performed at the α-position; after the reaction was completed, the ethyl protecting group was removed by hydrolysis to obtain the free phosphate ester form; the product was lyophilized to obtain a powder, and the structure was confirmed by ¹H-NMR and MS.

[0038] CPB-103 Synthesis: Deoxycholic acid was modified into an active monoester using succinic anhydride; and then reacted with capecitabine N... 4 The amide bonds are formed by DCC / DMAP condensation; homogeneous conjugates are obtained by preparative HPLC separation and purification. The structures of all compounds are confirmed by LC-MS, ¹³C-NMR, and infrared spectroscopy.

[0039] Enzymatic hydrolysis experiment: Each prodrug was incubated in human intestinal brush border microparticles, liver microsomes, and tumor cell lysate, respectively; CPB-101 was rapidly hydrolyzed in small intestinal enzymes (t1 / 2 < 30 min), while it was stable in liver microsomes (t1 / 2 > 4 h); CPB-102 released 5-FU at a rate 5 times faster in ALP-overexpressing colon cancer cells (HT-29) than in normal hepatocytes.

[0040] UGT1A1 inhibition assay: The inhibitory effect on bilirubin glucuronidation was detected using the human recombinant UGT1A1 enzyme system. Traditional capecitabine metabolites ≈50μM, while CPB-101 >500μM indicates almost no inhibitory effect.

[0041] Cytotoxicity assay: MTT assay was used to determine the cytotoxicity against multiple cancer cell lines (HCT-116, MCF-7, SGC-7901). All prodrugs maintained antiproliferative activity equivalent to or slightly superior to the original drug. (Difference < 15%)

[0042] Pharmacokinetic studies: Plasma concentrations were measured after a single oral administration; CPB-101 showed a 30% increase in AUC0–∞ compared to capecitabine, with similar Cmax, but a 60% decrease in drug accumulation in liver tissue; the half-life was extended from 0.8 h to 1.5 h, which is beneficial for maintaining effective plasma drug concentrations. Validation of the UGT1A1 deficiency model (UGT1A128 / 28 transgenic mice): After 14 days of continuous administration, serum total bilirubin levels were monitored. In the control group (capecitabine), bilirubin increased 3.8-fold, while in the CPB-101 group it increased only 1.2-fold, with no jaundice observed. Antitumor efficacy assessment (HCT-116 subcutaneous xenograft model): Dosage regimen: once daily orally for 21 consecutive days; The tumor growth inhibition rate (TGI) in the CPB-101 group reached 78%, which was better than that in the control group (70%). At the same time, the weight fluctuation was smaller and there was no obvious damage in histopathology.

[0043] The optimal candidate, CPB-101, was designed as a double-layered enteric-coated tablet: the outer layer is a gastric retention hydrophilic gel (HPMC), and the inner layer is a Eutectic L100 enteric coating layer; this allows for targeted drug release in the distal ileum, avoiding gastric acid degradation and promoting local enzymatic digestion. Accelerated stability testing (40°C / 75%RH, 6 months) showed that the main component degradation was <2%, which meets ICH standards.

[0044] Experimental Example 1: Study on bilirubin changes in UGT1A1-deficient transgenic mice Objective: To evaluate the effect of prodrug on improving elevated bilirubin levels by simulating a high-risk clinical population.

[0045] Animal models: Humanization hUGT1A1 4 groups of transgenic mice with 28mut / 28mut homozygous mutant C57BL / 6 background (n=8 / group); Control group: physiological saline; Control group: capecitabine, 670 mg / kg, po, qd×14 d; Experimental group 1: CPB-101, equivalent dose (converted to 5-FU molar equivalent), po, qd; Experimental group 2: CPB-102, same as above.

[0046] Testing indicators: Serum total bilirubin (TBIL), direct bilirubin (DBIL), ALT, and AST were measured on days 0, 7, and 14 after drug administration. The animal was sacrificed on day 15, and liver tissue was taken for HE staining and pathological analysis.

[0047] result:

[0048] Note: p<0.001 vs other groups; liver histopathology showed that the capecitabine group had significant cholestasis, while the CPB-101 group was basically normal.

[0049] Conclusion: In the UGT1A1 functional deficit model, the prodrug of this invention significantly reduced the increase in bilirubin and the risk of liver damage.

[0050] Experimental Example 2: In vitro cytotoxicity and selectivity index test Objective: To verify whether the prodrug reduces toxicity to normal hepatocytes while retaining its antitumor activity.

[0051] Methods: The MTT assay was used to determine the effects of each compound on HCT-116 (colon cancer), MCF-7 (breast cancer), and LO2 (normal human hepatocytes). ; Calculate the selectivity index result:

[0052] Conclusion: The prodrug of this invention not only retains its original anticancer activity, but also exhibits lower toxicity to normal hepatocytes and significantly improved selectivity.

[0053] Experimental Example 3: Formulation Release Behavior and Stability Test Objective: To systematically evaluate the applicability of the double-layer coated enteric-coated tablet technology platform for different active ingredients (CPB-101, CPB-102, CPB-103), verify its in vitro controlled release performance and long-term stability, confirm the consistency and reproducibility of the formulation platform, and support the sharing of key R&D and validation data among multiple products.

[0054] Methods: Sample preparation: Double-coated enteric-coated tablets containing the following three APIs were prepared: CPB-101 tablets CPB-102 tablets; CPB-103 tablets; All formulations use a unified formulation design and process flow: Core tablets: contain their respective APIs + the same filler (microcrystalline cellulose), disintegrant (crosslinked carboxymethyl cellulose sodium), and lubricant (magnesium stearate). Coating structure (double layer): Inner layer: Eudragit L100-55, pH-sensitive enteric coating, initial dissolution pH≈5.5–6.0; Outer layer: HPMC (hydroxypropyl methylcellulose) sustained-release layer, regulating the drug release rate from the mid-small intestine to the ileum. The weight gain of the coating was controlled consistently (8% for the inner layer and 12% for the outer layer). Production process: fluidized bed coating + high-speed tableting, with parameters controlled throughout the process; In vitro release test, simulating gastrointestinal transit conditions (paddle method, USP Apparatus II): First, place in pH 1.2 HCl buffer for 2 hours; then transfer to pH 6.8 phosphate buffer and continue measurement until cumulative release is complete; sampling time points: 0.5, 1, 2 h (pH 1.2); 5, 10, 15, 30, 45, 60 min (pH 6.8) Detection method: HPLC was used to determine the percentage of drug release at each time point. Accelerated stability test; conditions: 40°C±2°C / 75%RH±5%, stored for 6 months; Periodic sampling (0, 1, 2, 3, 6 months) for testing: principal component content (HPLC); related substances (total degradation impurities); moisture content (Karl Fischer method); disintegration time (in artificial intestinal fluid). result

[0055] All products meet the ICH Q1A(R2) standard requirements for stability testing.

[0056] Conclusion: The release behavior was highly consistent: all three formulations showed excellent acid protection in simulated gastric juice (<5% release) and rapid release after entering the small intestinal environment (>85% within 30 min), indicating that the double-layer coating system successfully achieved the functions of gastric protection and ileal targeted release.

[0057] The in vitro release curves are comparable (f2≥69): This indicates that although the APIs are different, due to the consistent core coating structure and process, the release mechanism is mainly controlled by the coating film, rather than dominated by the API diffusion characteristics, supporting platform-based applications. Good stability and consistent trends: After 6 months of accelerated storage, the active pharmaceutical ingredient content of all three formulations remained stable, impurity growth was extremely low, and no deterioration in physical properties was observed, demonstrating that the formulation has good chemical and physical stability.

[0058] The above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described herein. Although the present invention has been described in detail with reference to the above embodiments, the present invention is not limited to the specific embodiments described above. Therefore, any modifications or equivalent substitutions to the present invention, as well as all technical solutions and improvements that do not depart from the spirit and scope of the invention, are covered within the scope of the claims of the present invention.

Claims

1. A capecitabine prodrug that reduces the metabolic burden on the liver, characterized in that: The compound is formed by the 5'-hydroxyl group or... Introducing a masking group that can be enzymatically or chemically hydrolyzed at the amino position The formed derivative, wherein Including amino acid esters, phosphate esters, polyethylene glycol-modified alkyl chains, and cholic acid conjugated groups; The amino acid esters include glycine ethyl ester, leucine methyl ester, or glutamic acid monoester; The phosphate esters include phosphoryloxymethyl phosphate. Or phenyl phosphate substituents; The PEGylated alkyl chain chemical formula is: ; The cholic acid conjugate group is connected via a degradable linker arm. Linked to deoxycholic acid; The prodrug is non-invasively metabolized in vivo. The metabolism of the drug is activated via a dependence pathway to release the active ingredient 5-fluorouracil, and it significantly reduces its effect on hepatocytes. Competitive inhibition of enzymes and interference with bilirubin binding and excretion pathways.

2. The capecitabine prodrug for reducing hepatic metabolic burden according to claim 1, characterized in that: The compound includes ; Capecitabine-5'-O-glycine ethyl ester, chemically named [5'-O-(N-ethoxycarbonylglycyl)]-5'-deoxy-5-fluorocytidine; -(phosphoryloxymethyl)-capecitabine, the structure contains : Deoxycholic acid propionamide-capecitabine conjugate, through Connecting bile acids Located in capecitabine Bit.

3. The capecitabine prodrug for reducing hepatic metabolic burden according to claim 2, characterized in that: The prodrug is preferentially hydrolyzed by intestinal brush border enzymes, including carboxylesterase 2, peptide transporter PEPT2, alkaline phosphatase ALP (highly expressed in the tumor microenvironment), or by an acidic environment under physiological conditions, and selectively activated by extrahepatic tissues.

4. A pharmaceutical composition for reducing the metabolic burden on the liver, characterized in that: The composition comprises the capecitabine prodrug as described in any one of claims 1 to 3, and pharmaceutically acceptable excipients, said excipients including fillers, disintegrants, binders, lubricants, and coating materials; preferably, the composition is a double-coated oral formulation, the inner layer being a pH-sensitive enteric coating (soluble in pH ≥ 6.8), and the outer layer being a gastric retention hydrophilic gel coating, for controlling the targeted release of the drug in the distal ileum.

5. The pharmaceutical composition for reducing the metabolic burden on the liver according to claim 4, characterized in that: The filler is selected from microcrystalline cellulose, lactose or pregelatinized starch; the disintegrant is croscarmellose sodium cellulose or low-substituted hydroxypropyl cellulose; the coating material is cellulose acetate phthalate (CAP), Eutectic L100 or hydroxypropyl methylcellulose phthalate (HPMCP).

6. The use of the capecitabine prodrug according to any one of claims 1 to 3 in the preparation of a medicament for treating solid tumors, wherein the solid tumor is colorectal cancer, breast cancer, gastric cancer, or pancreatic cancer, characterized in that: This prodrug can still be effectively converted to 5-FU in individuals with low UGT1A1 enzyme activity, and the increase in serum total bilirubin is ≥50% lower than that of conventional capecitabine.

7. The use of the capecitabine prodrug according to claim 6 in the preparation of a medicament for treating solid tumors, characterized in that: The patient is a high-risk individual carrying the UGT1A1 defective gene, with the genotype being: homozygous mutant. The enzyme activity is 10%–30% of that of the normal wild type.

8. The use of the capecitabine prodrug according to claim 7 in the preparation of a medicament for treating solid tumors, characterized in that: The patients have mild to moderate liver dysfunction, Child-Pugh classification A or B, or are currently using combination therapy with inhibitors. or Drugs targeting transporters include irinotecan, rifampin, cyclosporine A, or voriconazole.

9. A method for reducing capecitabine-related metabolic burden on the liver, characterized in that: According to claim 1, the prodrug used to replace standard capecitabine for antitumor treatment synergistically reduces liver toxicity through the following mechanisms: inhibiting the reflux of direct bilirubin into the blood caused by impaired MRP2 transporter function; monitoring serum total bilirubin levels as less than 1.5 times the baseline value is considered a reduction in metabolic burden.

10. A method for preparing a capecitabine prodrug as described in claim 1 that reduces the metabolic burden on the liver, characterized in that: Capecitabine was dissolved in an anhydrous polar solvent, and a condensing agent system was added under nitrogen protection. Then, an activating reagent containing a masking group was added dropwise to carry out an acylation or alkylation reaction. When synthesizing amino acid ester derivatives, the EDC / NHS system is used to react with glycine ethyl ester hydrochloride at a temperature of 0–25℃ for a reaction time of 6–24 hours. When constructing phosphate prodrugs, phosphoryl chloride reagents are used, including The process was carried out under pyridine catalysis. Alkylation; After the reaction is complete, the target product is obtained by extraction, column chromatography purification or recrystallization. The purity is ≥98% as determined by HPLC, and the yield is not less than 65%.

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