Compound drop pills for preventing and treating nausea and vomiting caused by zanolimumab and preparation method thereof

Abstract

The application discloses a compound drop pill for preventing and treating nausea and vomiting caused by sorafenib and a preparation method of the compound drop pill, and can effectively solve the medication problem of preventing and treating nausea and vomiting caused by sorafenib, realizes comprehensive curative effects of rapid antiemesis, long-acting control and reduction of side effects, and solves the problems of swallowing difficulty and poor medication compliance of chemotherapy patients. The compound drop pill is prepared from metoclopramide, lidocaine, vitamin B6, gingerol, evodiamine, total alkaloids of pinellia ternate, total lactones of bupleurum smithii, total phenols of Terminalia chebula Retz, volatile oil of Alpinia oxyphylla, total steroidal glycosides of Farfugium japonicum, polyethylene glycol 4000, polyethylene glycol 400, poloxamer 188, hydroxypropyl-beta-cyclodextrin, soybean lecithin, a sweetening agent, a preservative and purified water. The compound drop pill has definite curative effects, is convenient to take and is high in safety, can be used as a hospital preparation or a new drug development for auxiliary treatment of tumors, can provide a reference for prevention and treatment of nausea and vomiting caused by other chemotherapy drugs, and has practical clinical application and popularization values.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a compound drop pill for preventing and treating nausea and vomiting induced by zotuximab during chemotherapy, specifically for the prevention and treatment of nausea and vomiting caused by zotuximab, a CLDN18.2-targeting monoclonal antibody. Background Technology

[0002] Zolbetuximab (trade name: Weiluoyi®) is the world's first approved human-mouse chimeric IgG1 monoclonal antibody targeting CLDN18.2. It was approved for marketing by the China NMPA in December 2024 and is used in combination with fluorouracil and platinum-based chemotherapy as first-line treatment for CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric / gastroesophageal junction adenocarcinoma.

[0003] However, nausea and vomiting are the most common adverse reactions to zottoximab combined with chemotherapy. Data from the SPOTLIGHT and GLOW phase III clinical trials showed that the incidence of nausea of ​​any grade was as high as 78%-82% in the zottoximab plus chemotherapy group, and the incidence of vomiting was 66%-67%; among them, the incidence of grade 3 or higher nausea was 9%-16%, and the incidence of grade 3 or higher vomiting was 12%-16%. These gastrointestinal adverse reactions occurred most frequently in the first treatment cycle, seriously affecting patients' quality of life and treatment adherence. Some patients even needed to adjust drug dosage or suspend treatment, making it one of the main reasons for treatment interruption and permanent discontinuation.

[0004] Currently, the standard triple antiemetic regimen is mainly used in clinical practice for nausea and vomiting (CINV) induced by targeted therapy combined with chemotherapy: a 5-HT3 receptor antagonist (such as palonosetron or ondansetron) + an NK-1 receptor antagonist (such as aprepitant) + a glucocorticoid (such as dexamethasone). This regimen is effective in controlling acute vomiting, but its control rate for delayed vomiting (24-120 hours after chemotherapy) is still not ideal, with approximately 30%-40% of patients experiencing poor control of delayed vomiting. Furthermore, long-term use of Western medicine antiemetic regimens can lead to side effects such as constipation, headache, abdominal distension, and elevated blood sugar, and long-term use of hormones may cause risks such as immunosuppression and metabolic disorders.

[0005] Traditional Chinese medicine (TCM) has unique advantages in relieving nausea and vomiting. Traditional Chinese herbs such as ginger, pinellia, and evodia have been proven to have clear antiemetic effects, with mild effects and few side effects. Tibetan and Miao medicines, as important components of traditional Chinese medicine, are rich in active ingredients with anti-inflammatory, antispasmodic, and gastrointestinal motility-regulating properties, such as total lactones from costus root, total phenols from chebula, volatile oil from alpinia galanga, and total steroidal glycosides from ginseng. However, there are currently no reports of compound pill preparations combining TCM, Tibetan, and Miao medicines with Western medicine for the prevention and treatment of zotuximab-induced nausea and vomiting.

[0006] As a solid dispersion preparation, drop pills are characterized by rapid onset of action, high bioavailability, accurate dosage, and convenient administration. Orally dissolving drop pills can be directly instilled into the mouth without the need for water, making them particularly suitable for cancer patients experiencing severe nausea, vomiting, and difficulty swallowing. Therefore, developing a multi-component, multi-target, synergistically effective orally dissolving compound drop pill is of significant clinical importance and application value for improving zotuximab-induced nausea and vomiting. However, there are currently no publicly reported studies on how to utilize a combination of traditional Chinese and Western medicine to prepare a drug composition for the prevention and treatment of zotuximab-induced nausea and vomiting, in order to address the increasing management needs of this condition. Summary of the Invention

[0007] In view of the above situation and to overcome the shortcomings of the existing technology, the purpose of this invention is to provide a compound dripping pill for preventing and treating nausea and vomiting caused by zotuximab and its preparation method. It can effectively solve the medication problem for preventing and treating nausea and vomiting caused by zotuximab, achieve comprehensive efficacy of rapid antiemetic, long-term control and reduced side effects, and solve the problems of swallowing difficulties and poor medication compliance in chemotherapy patients.

[0008] The technical solution provided by this invention is: a compound dripping pill for preventing and treating nausea and vomiting caused by zotociximab, comprising: 0.5-2 parts of the active ingredient metoclopramide, 1-3 parts of lidocaine, and 2-5 parts of vitamin B6; 3-8 parts of gingerol, 1-4 parts of evodia rutaecarpa alkaloids, and 2-6 parts of total alkaloids from Pinellia ternata; 4-10 parts of total lactones from Aucklandia lappa and 3-8 parts of total phenols from Terminalia chebula, extracted from Tibetan medicine; 2-6 parts of volatile oil from Alpinia galanga and 3-7 parts of total steroidal glycosides from Alpinia serratifolia, extracted from Miao medicine; and excipients including 150-250 parts of polyethylene glycol 4000, 30-80 parts of polyethylene glycol 400, 10-25 parts of poloxamer 188, 20-50 parts of hydroxypropyl-β-cyclodextrin, 2-8 parts of soybean lecithin, 1-5 parts of sweetener, 0.5-2 parts of preservative, and purified water.

[0009] Its preparation method is as follows: S1. Preparation and purification of extracts: (1) Preparation of gingerol: Take dried ginger rhizomes, crush them and extract them with 70% ethanol by ultrasonication 3 times, 1 hour each time. Combine the extracts and recover the ethanol under reduced pressure to obtain crude gingerol extract. Purify the extract with macroporous adsorption resin, collect the 60% ethanol eluent, dry it under reduced pressure to obtain gingerol extract with gingerol content ≥10%. (2) Preparation of evodiamine: Take dried nearly mature fruit of Evodia rutaecarpa, crush it and extract it twice with methanol under reflux for 2 hours each time. Combine the extracts and recover the solvent under reduced pressure to obtain crude total alkaloids. Purify by alumina column chromatography, elute with chloroform-methanol gradient, collect the evodiamine-rich fraction, dry under reduced pressure to obtain evodiamine extract with evodiamine content ≥50%. (3) Preparation of total alkaloids of Pinellia ternata: Take dried tuber of Pinellia ternata, crush it and extract it by reflux with 75% ethanol 3 times, 1.5 hours each time. Combine the extracts, recover the ethanol under reduced pressure, adjust the pH of the concentrated liquid to 2-3 with hydrochloric acid, let it stand and filter. Adjust the pH of the filtrate to 9-10 with ammonia water, extract it with chloroform 3 times, combine the chloroform liquids, recover the solvent under reduced pressure, and dry it to obtain the total alkaloid extract of Pinellia ternata. The total alkaloid content of Pinellia ternata is ≥30%. (4) Preparation of total lactones of Aucklandia lappa: Take dried roots of Aucklandia lappa, crush them and extract the volatile oil by steam distillation. Collect the volatile oil layer to obtain Aucklandia lappa volatile oil. Purify by silica gel column chromatography, elute with petroleum ether-ethyl acetate gradient, collect the total lactone-rich fraction, and recover the solvent under reduced pressure to obtain total lactone extract of Aucklandia lappa. The total lactone content of Aucklandia lappa is ≥50%. (5) Preparation of total phenols from Terminalia chebula: Take dried and mature Terminalia chebula fruit, crush it and extract it twice with 50% ethanol for 1 hour each time. Combine the extracts, recover the ethanol under reduced pressure, and purify the concentrate by polyamide column chromatography. Elute the extract with water-ethanol gradient, collect the elution fraction with 30%-60% ethanol, dry it under reduced pressure, and obtain the total phenol extract of Terminalia chebula. The total phenol content of Terminalia chebula is ≥60%. (6) Preparation of volatile oil from Alpinia galanga: Take dried Alpinia galanga fruit, crush it, and extract the volatile oil by steam distillation. Collect the volatile oil layer, dehydrate it with anhydrous sodium sulfate, and obtain Alpinia galanga volatile oil with a purity of ≥90%. (7) Preparation of total steroidal glycosides of *Gnaphalium affine*: The dried tuberous root of *Gnaphalium affine* was crushed and extracted three times by reflux with 70% ethanol for 2 hours each time. The extracts were combined, and the ethanol was recovered under reduced pressure. The concentrated extract was purified by macroporous adsorption resin, and water-ethanol gradient elution was performed. The 70% ethanol eluent was collected and dried under reduced pressure to obtain the extract of total steroidal glycosides of *Gnaphalium affine*. The content of total steroidal glycosides of *Gnaphalium affine* was ≥30%. S2. Preparation of inclusion complex: Take hydroxypropyl-β-cyclodextrin, add an appropriate amount of purified water, heat and stir to dissolve, and prepare a 40% cyclodextrin aqueous solution; mix gingerol, evodiamine, total lactones of costus root, and volatile oil of Alpinia galanga in proportion, dissolve in a small amount of anhydrous ethanol, and slowly add dropwise to the cyclodextrin aqueous solution, stir at 40℃ for 2 hours, continue stirring at room temperature for 1 hour, refrigerate and stand for 24 hours, filter, wash the precipitate with a small amount of purified water, vacuum dry at 40℃, pulverize, and obtain the drug inclusion complex; S3, Melting of the matrix: Weigh out polyethylene glycol 4000, polyethylene glycol 400, and poloxamer 188 in proportion, place them in a water bath, heat to 70-75℃, stir until completely melted, mix well, and obtain the matrix. S4. Mixing of drug and matrix: Metoclopramide, lidocaine, vitamin B6, total alkaloids of Pinellia ternata, total phenols of Terminalia chebula, and total steroidal glycosides of Alpinia serratifolia are ground into fine powders, passed through a 100-mesh sieve, and mixed evenly to obtain a medicinal powder. The drug inclusion complex is mixed evenly with the medicinal powder and added to the matrix in portions while stirring. Soy lecithin, sweetener, and preservative are added, and stirring is continued for 30 minutes to ensure uniform dispersion of the drugs, resulting in a mixed medicinal solution. The solution is kept warm at 70-75℃ for later use. S5, Droplet forming: The mixed medicine solution obtained in S4 is transferred to the insulated dripping tank of the pelleting machine and kept at 70-75℃. Dimethyl silicone oil is used as the condensing liquid, and the condensation temperature is controlled at 10-15℃. The inner diameter of the dripping head is adjusted to 2.0-2.5mm, the dripping speed is 30-40 drops per minute, and the dripping distance is 5-8cm. The medicine solution is dripped into the condensing liquid and solidified. S6. Post-processing and quality control: Collect the pellets, pour off the condensate, absorb the dimethyl silicone oil on the surface of the pellets with filter paper, and place them in a ventilated place to air dry at room temperature, or dry them at a low temperature below 30°C; sieve out the unqualified pellets. Weight variation, dispersibility time, HPLC content determination, and microbial limit testing are performed to ensure compliance with the relevant provisions of the Chinese Pharmacopoeia for drop pills, thus obtaining the finished product.

[0010] This invention's compound dripping pills are effective, convenient to take, and highly safe. They can effectively solve the medication problem of preventing and treating nausea and vomiting caused by zotuximab, achieving a comprehensive effect of rapid antiemetic, long-term control, and reduced side effects. They also solve the problems of swallowing difficulties and poor medication compliance in chemotherapy patients. They can be used as a hospital preparation or new drug for adjuvant cancer therapy, and can also provide a reference for the prevention and treatment of nausea and vomiting caused by other chemotherapy drugs. They have practical clinical application and promotion value. Detailed Implementation

[0011] The specific implementation of the present invention will be described in detail below with reference to examples and specific circumstances.

[0012] The present invention is illustrated by the following embodiments: This invention relates to a compound dripping pill for preventing and treating nausea and vomiting caused by zotociximab, comprising: 1g of the active ingredient metoclopramide, 2g of lidocaine, and 3g of vitamin B6; 5g of gingerol, 2g of evodia rutaecarpa alkaloids, and 4g of total alkaloids from Pinellia ternata, extracted from traditional Chinese medicine; 6g of total lactones from Aucklandia lappa and 5g of total phenols from Terminalia chebula, extracted from Tibetan medicine; 3g of volatile oil from Alpinia galanga and 5g of total steroidal glycosides from Alpinia serratifolia, extracted from Miao medicine; and excipients including 200g of polyethylene glycol 4000, 50g of polyethylene glycol 400, 15g of poloxamer 188, 30g of hydroxypropyl-β-cyclodextrin, 5g of soybean lecithin, 2g of sucralose (sweetener), 1h of sodium benzoate (preservative), and purified water.

[0013] Its preparation method is as follows: S1. Preparation and purification of extracts: (1) Preparation of gingerol: Take dried ginger rhizomes, crush them and extract them with 70% ethanol by ultrasonication 3 times, 1 hour each time. Combine the extracts and recover the ethanol under reduced pressure to obtain crude gingerol extract. Purify the extract with macroporous adsorption resin, collect the 60% ethanol eluent, dry it under reduced pressure to obtain gingerol extract with gingerol content ≥10%. (2) Preparation of evodiamine: Take dried nearly mature fruit of Evodia rutaecarpa, crush it and extract it twice with methanol under reflux for 2 hours each time. Combine the extracts and recover the solvent under reduced pressure to obtain crude total alkaloids. Purify by alumina column chromatography, elute with chloroform-methanol gradient, collect the evodiamine-rich fraction, dry under reduced pressure to obtain evodiamine extract with evodiamine content ≥50%. (3) Preparation of total alkaloids of Pinellia ternata: Take dried tuber of Pinellia ternata, crush it and extract it by reflux with 75% ethanol 3 times, 1.5 hours each time. Combine the extracts, recover the ethanol under reduced pressure, adjust the pH of the concentrated liquid to 2-3 with hydrochloric acid, let it stand and filter. Adjust the pH of the filtrate to 9-10 with ammonia water, extract it with chloroform 3 times, combine the chloroform liquids, recover the solvent under reduced pressure, and dry it to obtain the total alkaloid extract of Pinellia ternata. The total alkaloid content of Pinellia ternata is ≥30%. (4) Preparation of total lactones of Aucklandia lappa: Take dried roots of Aucklandia lappa, crush them and extract the volatile oil by steam distillation. Collect the volatile oil layer to obtain Aucklandia lappa volatile oil. Purify by silica gel column chromatography, elute with petroleum ether-ethyl acetate gradient, collect the total lactone-rich fraction, and recover the solvent under reduced pressure to obtain total lactone extract of Aucklandia lappa. The total lactone content of Aucklandia lappa is ≥50%. (5) Preparation of total phenols from Terminalia chebula: Take dried and mature Terminalia chebula fruit, crush it and extract it twice with 50% ethanol for 1 hour each time. Combine the extracts, recover the ethanol under reduced pressure, and purify the concentrate by polyamide column chromatography. Elute the extract with water-ethanol gradient, collect the elution fraction with 30%-60% ethanol, dry it under reduced pressure, and obtain the total phenol extract of Terminalia chebula. The total phenol content of Terminalia chebula is ≥60%. (6) Preparation of volatile oil from Alpinia galanga: Take dried Alpinia galanga fruit, crush it, and extract the volatile oil by steam distillation. Collect the volatile oil layer, dehydrate it with anhydrous sodium sulfate, and obtain Alpinia galanga volatile oil with a purity of ≥90%. (7) Preparation of total steroidal glycosides of *Gnaphalium affine*: The dried tuberous root of *Gnaphalium affine* was crushed and extracted three times by reflux with 70% ethanol for 2 hours each time. The extracts were combined, and the ethanol was recovered under reduced pressure. The concentrated extract was purified by macroporous adsorption resin, and water-ethanol gradient elution was performed. The 70% ethanol eluent was collected and dried under reduced pressure to obtain the extract of total steroidal glycosides of *Gnaphalium affine*. The content of total steroidal glycosides of *Gnaphalium affine* was ≥30%. S2. Preparation of inclusion complex: Take 30g of hydroxypropyl-β-cyclodextrin, add 75ml of purified water, heat and stir to dissolve, and prepare a 40% cyclodextrin aqueous solution; mix gingerol, evodiamine, total lactones of costus root, and volatile oil of Alpinia galanga, dissolve in 5ml of anhydrous ethanol, and slowly add dropwise to the cyclodextrin aqueous solution, stir at 40℃ for 2 hours, continue stirring at room temperature for 1 hour, refrigerate at 4℃ for 24 hours, filter, wash the precipitate with a small amount of purified water, vacuum dry at 40℃, pulverize, and obtain the drug inclusion complex; S3, Melting of the matrix: Weigh 200g of polyethylene glycol 4000, 50g of polyethylene glycol 400, and 15g of poloxamer 188, place them in a water bath, heat to 70-75℃, stir until completely melted, mix well, and obtain the matrix; S4. Mixing of drug and matrix: Metoclopramide, lidocaine, vitamin B6, total alkaloids of Pinellia ternata, total phenols of Terminalia chebula, and total steroidal glycosides of Alpinia serrata are ground into fine powders, passed through a 100-mesh sieve, and mixed evenly to obtain a medicinal powder. The drug inclusion complex is mixed evenly with the medicinal powder and added to the matrix in portions while stirring. 5g of soybean lecithin, 2g of sucralose, and 1g of sodium benzoate are added, and stirring is continued for 30 minutes to ensure uniform dispersion of the drugs, resulting in a mixed medicinal solution. The solution is kept warm at 70℃ for later use. S5, Droplet forming: The mixed drug solution obtained in S4 is transferred to the insulated dripping tank of the pelleting machine and kept at 70°C. Dimethyl silicone oil is used as the condensing liquid, and the condensation temperature is controlled at 10°C. The inner diameter of the dripping head is adjusted to 2.0 mm, the dripping speed is 35 drops per minute, and the dripping distance is 6 cm. The drug solution is dripped into the condensing liquid and solidified. S6. Post-processing and quality control: Collect the pellets, pour off the condensate, absorb the dimethyl silicone oil on the surface of the pellets with filter paper, and dry them at a low temperature below 30°C; sieve out the unqualified pellets, each pellet weighs about 25mg, and repackage them. Each 10 pellets contain about 1mg of metoclopramide. Weight variation, dispersibility time, HPLC content determination, and microbial limit testing are performed to ensure compliance with the relevant provisions of the Chinese Pharmacopoeia for drop pills, thus obtaining the finished product.

[0014] In the drug combinations given above, among which: 1. Metoclopramide: A dopamine D2 receptor antagonist with both central and peripheral antiemetic effects. Centrally, it inhibits dopamine receptors in the medullary chemoreceptor zone (CTZ), increasing the vomiting threshold. Peripherally, it promotes gastric emptying and gastrointestinal motility, increases lower esophageal sphincter tone, and reduces gastroesophageal reflux. It has a clear therapeutic effect on nausea and vomiting caused by chemotherapy, radiotherapy, and surgery.

[0015] 2. Lidocaine: An amide-type local anesthetic, when taken sublingually, acts on pharyngeal mucosal receptors, blocking the afferent pathway of the gag reflex and rapidly relieving nausea; it also reduces the sensitivity of the gastrointestinal mucosa, lowering the threshold for triggering vomiting. It is rapidly absorbed through the oral mucosa, taking effect within minutes.

[0016] 3. Vitamin B6 (pyridoxine): Participates in the metabolism of various amino acids in the body, regulates neurotransmitter synthesis, and reduces the excitability of the vomiting center. It has certain therapeutic effects on vomiting during pregnancy, radiation sickness, and vomiting induced by anticancer drugs, and has a high safety profile. It can be used as a basic adjunct antiemetic. It has a synergistic effect when used in combination with metoclopramide.

[0017] 4. Gingerol: The main active ingredient in ginger, including 6-gingerol, 8-gingerol, and shogaol. It has both central and peripheral antiemetic effects: peripherally, it antagonizes gastrointestinal 5-HT3 receptors, reducing substance P release and inhibiting reverse peristalsis; centrally, it acts on the medullary chemoreceptor trigger zone, reducing the excitability of the vomiting center. It is effective for both acute and delayed vomiting induced by chemotherapy and is an adjunct antiemetic recommended by WHO and ASCO.

[0018] 5. Evodiaein: The main alkaloid active ingredient in Evodia rutaecarpa. It stimulates TRPV1 receptors, regulating gastrointestinal motility and visceral sensitivity; it inhibits the vomiting reflex arc, with better effects on delayed vomiting; it also has warming, dispersing, and analgesic effects. It can reduce the release of inflammatory factors by inhibiting the NF-κB pathway, thus alleviating chemotherapy-induced gastrointestinal inflammation.

[0019] 6. Total Alkaloids of Pinellia ternata: The main effective component of Pinellia ternata contains alkaloids such as ephedrine, trigonelline, and β-sitosterol. It inhibits the chemoreceptor trigger zone in the medulla oblongata, reducing the sensitivity of the vomiting center; simultaneously, it regulates gastrointestinal smooth muscle tone, improves gastric emptying, and provides synergistic central and peripheral antiemetic effects. It is particularly effective for chemotherapy-induced vomiting due to phlegm-dampness obstruction and is often combined with gingerol to enhance its stomach-soothing and antiemetic effects.

[0020] 7. Total lactones from *Saussurea costus*: The main active components of *Saussurea costus*, containing sesquiterpene lactones such as costunolide, isocostunolide, and dihydroisocostunolide. It has a bidirectional regulatory effect on gastrointestinal motility: inhibiting reverse peristalsis of gastric smooth muscle to stop vomiting, while simultaneously promoting colonic peristalsis, significantly reducing the adverse reaction of constipation caused by 5-HT3 receptor antagonists; it also has a clear anti-inflammatory effect, reducing inflammatory damage to the gastrointestinal mucosa caused by chemotherapy drugs and helping to control delayed nausea and vomiting.

[0021] 8. Terminalia chebula total phenols: The main effective component of Terminalia chebula, containing phenolic and tannin components such as chebulic acid, gallic acid, and ellagic acid. It forms a dense protective film on the gastrointestinal mucosa, directly shielding it from the chemical damage of chemotherapy drugs to the mucosal epithelium, reducing the release of 5-HT from enterochromaffin cells, and reducing vomiting triggers from the source; it inhibits the NF-κB pathway to reduce the release of inflammatory factors, precisely targeting delayed vomiting 24–120 hours after chemotherapy, compensating for the shortcomings of Western medicine in controlling vomiting at this stage.

[0022] 9. *Alpinia galanga* volatile oil: The main active ingredient of *Alpinia galanga*, a traditional Miao medicine from Guizhou, contains volatile oil components such as eucalyptol, α-terpineol, and linalool. It relaxes gastrointestinal smooth muscle, inhibits reverse peristalsis, and reduces vagal vomiting signals; it inhibits the NF-κB pathway, lowers the levels of inflammatory factors such as TNF-α and IL-6, and reduces oxidative damage to the gastrointestinal mucosa caused by chemotherapy drugs; its natural aroma improves the taste of the medicine and also helps inhibit the vomiting reflex through the olfactory pathway.

[0023] 10. Total Steroid Glycosides of Geshanxiao: The main active ingredient of the Miao medicine Geshanxiao (Bai Shou Wu), containing C21 total steroid glycosides (Bai Shou Wu glycosides) and other components. It regulates gastrointestinal motility, modulates the secretion of brain-gut peptides such as motilin and gastrin, promotes gastric emptying, inhibits reverse peristalsis, and directly improves nausea and vomiting; it also promotes colonic peristalsis and can significantly reduce the incidence of adverse reactions such as constipation and abdominal distension caused by antiemetic Western medicines. It is a highly distinctive side-effect-reducing component.

[0024] This invention achieves a three-pronged treatment model of "rapid antiemetic effect + long-term control + reduced side effects and enhanced efficacy" through the rapid onset of action of Western medicine, the regulation of the central and peripheral nervous systems by traditional Chinese medicine, the mucosal protection and anti-inflammatory effects of Tibetan medicine, and the antispasmodic and side-effect-reducing effects of Miao medicine. The specific synergistic mechanism is as follows: (1) Rapid control of acute vomiting: Metoclopramide, lidocaine and gingerol work together to rapidly take effect from three different targets: dopamine receptor blocking, pharyngeal reflex inhibition and 5-HT3 receptor antagonism. Acute nausea and vomiting can be significantly relieved within 15-30 minutes after administration, covering the high incidence of acute vomiting within 24 hours after zotuximab infusion. (2) Enhanced control of delayed vomiting: Evodia rutaecarpa alkaloids + Pinellia ternata total alkaloids + Aucklandia lappa total lactones + Terminalia chebula total phenols + Alpinia galanga volatile oil multi-component synergistic effect, through multiple mechanisms such as anti-inflammatory, mucosal protection and regulation of gastrointestinal motility, can significantly improve the control rate of delayed vomiting 24-120h after chemotherapy, reduce the use of NK-1 receptor antagonists and reduce treatment costs; (3) Significantly reduced side effects: Total lactones of Tibetan costus root and total steroidal glycosides of ginseng synergistically regulate gastrointestinal motility, which can reduce the incidence of constipation caused by antiemetic drugs by more than 35%, while improving gastrointestinal adverse reactions such as abdominal distension and poor appetite; Vitamin B6 further enhances overall safety and reduces central nervous system side effects; (4) Innovative dosage form adapted to clinical use: Oral fast-dissolving drops do not require drinking water and dissolve instantly in the mouth, making them particularly suitable for patients with severe nausea and vomiting and difficulty swallowing during zotuximab chemotherapy; oral mucosal absorption can partially avoid the first-pass effect of the liver, improve bioavailability, and reduce gastrointestinal irritation.

[0025] The experiment yielded very good and beneficial technical results, and the relevant experimental materials are as follows (taking the example as an example): 1. Case selection: Sixty gastric cancer patients who received zotuximab combined with chemotherapy at the First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Henan Provincial Hospital of Traditional Chinese Medicine, and the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine between July 2025 and March 2026 were selected.

[0026] 2. Inclusion criteria: ① Pathologically confirmed as adenocarcinoma of the stomach or gastroesophageal junction, CLDN18.2 positive (≥75% of tumor cells with strong membrane staining), HER2 negative; ② Received first-line chemotherapy with zotuximab combined with mFOLFOX6 or CAPOX regimen; ③ Age 18–75 years; ④ Karnofsky Performance Status score ≥70; ⑤ Expected survival ≥3 months; ⑥ Informed consent given to this study.

[0027] 3. Exclusion criteria: ① Vomiting due to other causes such as intestinal obstruction or brain metastasis; ② Vomiting within 24 hours before chemotherapy or use of antiemetic drugs; ③ Severe cardiac, hepatic, or renal dysfunction; ④ Pregnancy or lactation; ⑤ Allergy to the drugs studied; ⑥ Participation in other clinical studies.

[0028] 4. Experimental Groups: Patients were randomly divided into a control group and an observation group, with 30 patients in each group. The control group consisted of 18 males and 12 females, aged 35–72 years, with a mean age of (56.3±10.5) years. The observation group consisted of 16 males and 14 females, aged 32–74 years, with a mean age of (54.8±11.2) years. There were no statistically significant differences in general characteristics between the two groups (P>0.05), indicating comparability.

[0029] 5. Treatment plan: The control group received the standard antiemetic regimen: palonosetron 0.25 mg intravenously 30 min before chemotherapy, aprepitant 125 mg orally 1 hour before chemotherapy (day 1), 80 mg orally once daily (days 2–3), and dexamethasone 10 mg intravenously before chemotherapy. In addition to the medication prescribed to the control group, the treatment group received the compound dripping pills of this invention, 10 pills each time, 3 times a day, starting 1 day before chemotherapy and continuing for 5 days.

[0030] 6. Efficacy evaluation criteria: (1) Vomiting control rate, according to the WHO classification of acute and subacute toxicity reactions of anticancer drugs: Level 0 is defined as no nausea or vomiting; Level I is nausea, which does not affect eating or daily life; Grade II is characterized by temporary vomiting that affects eating and daily life. Grade III is vomiting, which requires treatment; Grade IV is uncontrollable vomiting. Calculate the complete control rate (Grade 0) for acute vomiting (0–24 h) and delayed vomiting (24–120 h); (2) Nausea level: The visual analog scale (VAS) was used to assess the nausea level, with 0 points indicating no nausea and 10 points indicating extreme nausea; (3) Quality of life: The EORTC QLQ-C30 scale was used to assess the patients' quality of life; (4) Adverse reactions: Record the incidence of adverse reactions such as constipation, headache, abdominal distension, and dry mouth.

[0031] 7. Statistical analysis: (1) Vomiting control rate: The complete control rate of acute vomiting in the observation group was 83.3%, and the complete control rate of delayed vomiting was 76.7%; the control group was 76.7% and 53.3%, respectively. The difference in the complete control rate of delayed vomiting between the two groups was statistically significant (P<0.05).

[0032] (2) Nausea VAS score: On the first day after chemotherapy, there was no statistically significant difference in nausea VAS scores between the two groups (P>0.05); on the third and fifth days after chemotherapy, the nausea VAS scores in the observation group were significantly lower than those in the control group (P<0.05).

[0033] (3) Quality of life: The overall health status, physical function and role function scores of the observation group were higher than those of the control group after chemotherapy (P<0.05).

[0034] (4) Adverse reactions: The incidence of constipation in the observation group was 23.3%, which was significantly lower than that in the control group (50.0%) (P<0.05); there was no statistically significant difference in the incidence of other adverse reactions between the two groups.

[0035] In summary, this invention features a rational formulation, advanced preparation process, scientific dosage form design, high safety, and convenient use, possessing significant clinical value and industrialization potential. This invention provides a safe, effective, and stable compound drop pill for the prevention and treatment of zotuximab-induced nausea and vomiting, suitable for CLDN18.2-positive advanced gastric cancer patients receiving zotuximab combined with chemotherapy, especially those with poorly controlled delayed vomiting or those unable to tolerate the constipation side effects of Western antiemetic regimens. It can significantly improve the control rate of acute, especially delayed, nausea and vomiting, reduce adverse reactions such as constipation, and improve patients' quality of life. The oral, fast-dissolving drop pill dosage form meets the clinical needs of chemotherapy patients, is convenient to take, has a rapid onset of action, and effectively meets the management needs of adverse reactions. Compared with existing technologies, the beneficial technical effects of this invention are as follows: 1. Multi-ethnic medicine integration and innovation: For the first time, traditional Chinese medicine, Tibetan medicine, Miao medicine and Western medicine are combined to prevent and treat nausea and vomiting caused by zotuximab, giving full play to the unique advantages of each ethnic medicine and achieving multi-target synergistic treatment.

[0036] 2. Synergistic effect of multiple targets: It integrates central antiemetic, peripheral antiemetic, mucosal protection, anti-inflammatory, and gastrointestinal motility regulation, comprehensively covering acute and delayed vomiting, especially significantly improving the control rate of delayed vomiting, and making up for the shortcomings of existing Western medicine regimens.

[0037] 3. Significantly reduced side effects: Through the bidirectional regulation of gastrointestinal motility by components such as total lactones of Tibetan costus and total steroidal glycosides of ginseng, it significantly reduces adverse reactions such as constipation and bloating caused by antiemetic drugs, thereby improving patient tolerance and quality of life.

[0038] 4. Innovative dosage form adapted to clinical use: It adopts an oral fast-dissolving droplet dosage form, which dissolves instantly in the mouth without the need for drinking water, making it particularly suitable for cancer patients with severe nausea and vomiting and difficulty swallowing during chemotherapy; the oral mucosa absorption improves bioavailability and the onset of action is faster.

[0039] 5. High safety: The ingredients of traditional Chinese medicine and ethnic medicine have mild effects. When used in combination with Western medicine, the dosage of Western medicine can be reduced, the risk of side effects can be lowered, and it is suitable for long-term use during chemotherapy.

[0040] It should be noted that the compositions given in the above embodiments can be used to prepare any amount of compound drop pills as needed. The given embodiments are only used to illustrate specific implementation methods of the present invention, and are not intended to limit the scope of protection of the present invention. All the same technical means made by using equivalent substitution means are within the scope of protection of the present invention.

Claims

1. A compound dripping pill for preventing and treating nausea and vomiting induced by zotociximab, comprising: 0.5-2 parts of the active ingredient metoclopramide, 1-3 parts of lidocaine, and 2-5 parts of vitamin B6; 3-8 parts of gingerol, 1-4 parts of evodia rutaecarpa extract, and 2-6 parts of total alkaloids from Pinellia ternata extract; 4-10 parts of total lactones from Aucklandia lappa extract and 3-8 parts of total phenols from Terminalia chebula extract; 2-6 parts of volatile oil from Alpinia galanga extract and 3-7 parts of total steroidal glycosides from Alpinia serratifolia extract; and excipients including 150-250 parts of polyethylene glycol 4000, 30-80 parts of polyethylene glycol 400, 10-25 parts of poloxamer 188, 20-50 parts of hydroxypropyl-β-cyclodextrin, 2-8 parts of soybean lecithin, 1-5 parts of sweetener, 0.5-2 parts of preservative, and purified water.

2. The compound dripping pills for preventing and treating nausea and vomiting induced by zotuximab according to claim 1, the preparation method of which is as follows: S1. Preparation and purification of extracts: (1) Preparation of gingerol: Take dried ginger rhizomes, crush them and extract them with 70% ethanol by ultrasonication 3 times, 1 hour each time. Combine the extracts and recover the ethanol under reduced pressure to obtain crude gingerol extract. Purify the extract with macroporous adsorption resin, collect the 60% ethanol eluent, dry it under reduced pressure to obtain gingerol extract with gingerol content ≥10%. (2) Preparation of evodiamine: Take dried nearly mature fruit of Evodia rutaecarpa, crush it and extract it twice with methanol under reflux for 2 hours each time. Combine the extracts and recover the solvent under reduced pressure to obtain crude total alkaloids. Purify by alumina column chromatography, elute with chloroform-methanol gradient, collect the evodiamine-rich fraction, dry under reduced pressure to obtain evodiamine extract with evodiamine content ≥50%. (3) Preparation of total alkaloids of Pinellia ternata: Take dried tuber of Pinellia ternata, crush it and extract it by reflux with 75% ethanol 3 times, 1.5 hours each time. Combine the extracts, recover the ethanol under reduced pressure, adjust the pH of the concentrated liquid to 2-3 with hydrochloric acid, let it stand and filter. Adjust the pH of the filtrate to 9-10 with ammonia water, extract it with chloroform 3 times, combine the chloroform liquids, recover the solvent under reduced pressure, and dry it to obtain the total alkaloid extract of Pinellia ternata. The total alkaloid content of Pinellia ternata is ≥30%. (4) Preparation of total lactones of Aucklandia lappa: Take dried roots of Aucklandia lappa, crush them and extract the volatile oil by steam distillation. Collect the volatile oil layer to obtain Aucklandia lappa volatile oil. Purify by silica gel column chromatography, elute with petroleum ether-ethyl acetate gradient, collect the total lactone-rich fraction, and recover the solvent under reduced pressure to obtain total lactone extract of Aucklandia lappa. The total lactone content of Aucklandia lappa is ≥50%. (5) Preparation of total phenols from Terminalia chebula: Take dried and mature Terminalia chebula fruit, crush it and extract it twice with 50% ethanol for 1 hour each time. Combine the extracts, recover the ethanol under reduced pressure, and purify the concentrate by polyamide column chromatography. Elute the extract with water-ethanol gradient, collect the elution fraction with 30%-60% ethanol, dry it under reduced pressure, and obtain the total phenol extract of Terminalia chebula. The total phenol content of Terminalia chebula is ≥60%. (6) Preparation of volatile oil from Alpinia galanga: Take dried Alpinia galanga fruit, crush it, and extract the volatile oil by steam distillation. Collect the volatile oil layer, dehydrate it with anhydrous sodium sulfate, and obtain Alpinia galanga volatile oil with a purity of ≥90%. (7) Preparation of total steroidal glycosides of *Gnaphalium affine*: The dried tuberous root of *Gnaphalium affine* was crushed and extracted three times by reflux with 70% ethanol for 2 hours each time. The extracts were combined, and the ethanol was recovered under reduced pressure. The concentrated extract was purified by macroporous adsorption resin, and water-ethanol gradient elution was performed. The 70% ethanol eluent was collected and dried under reduced pressure to obtain the extract of total steroidal glycosides of *Gnaphalium affine*. The content of total steroidal glycosides of *Gnaphalium affine* was ≥30%. S2. Preparation of inclusion complex: Take hydroxypropyl-β-cyclodextrin, add an appropriate amount of purified water, heat and stir to dissolve, and prepare a 40% cyclodextrin aqueous solution; mix gingerol, evodiamine, total lactones of costus root, and volatile oil of Alpinia galanga in proportion, dissolve in a small amount of anhydrous ethanol, and slowly add dropwise to the cyclodextrin aqueous solution, stir at 40℃ for 2 hours, continue stirring at room temperature for 1 hour, refrigerate and stand for 24 hours, filter, wash the precipitate with a small amount of purified water, vacuum dry at 40℃, pulverize, and obtain the drug inclusion complex; S3, Melting of the matrix: Weigh out polyethylene glycol 4000, polyethylene glycol 400, and poloxamer 188 in proportion, place them in a water bath, heat to 70-75℃, stir until completely melted, mix well, and obtain the matrix. S4. Mixing of drug and matrix: Metoclopramide, lidocaine, vitamin B6, total alkaloids of Pinellia ternata, total phenols of Terminalia chebula, and total steroidal glycosides of Alpinia serratifolia are ground into fine powders, passed through a 100-mesh sieve, and mixed evenly to obtain a medicinal powder. The drug inclusion complex is mixed evenly with the medicinal powder and added to the matrix in portions while stirring. Soy lecithin, sweetener, and preservative are added, and stirring is continued for 30 minutes to ensure uniform dispersion of the drugs, resulting in a mixed medicinal solution. The solution is kept warm at 70-75℃ for later use. S5, Droplet forming: The mixed medicine solution obtained in S4 is transferred to the insulated dripping tank of the pelleting machine and kept at 70-75℃. Dimethyl silicone oil is used as the condensing liquid, and the condensation temperature is controlled at 10-15℃. The inner diameter of the dripping head is adjusted to 2.0-2.5mm, the dripping speed is 30-40 drops per minute, and the dripping distance is 5-8cm. The medicine solution is dripped into the condensing liquid and solidified. S6. Post-processing and quality control: Collect the pellets, pour off the condensate, absorb the dimethyl silicone oil on the surface of the pellets with filter paper, and place them in a ventilated place to air dry at room temperature, or dry them at a low temperature below 30°C; sieve out the unqualified pellets. Weight variation, dispersibility time, HPLC content determination, and microbial limit testing are performed to ensure compliance with the relevant provisions of the Chinese Pharmacopoeia for drop pills, thus obtaining the finished product.

3. The compound dripping pills for preventing and treating nausea and vomiting induced by zotuximab according to claim 1, characterized in that, It is made from the following ingredients: 1g of metoclopramide, 2g of lidocaine, and 3g of vitamin B6 (active ingredients of Western medicine); 5g of gingerol, 2g of evodia rutaecarpa alkaloids, and 4g of total alkaloids of Pinellia ternata (Chinese medicine extract); 6g of total lactones of Aucklandia lappa and 5g of total phenols of Terminalia chebula (Tibetan medicine extract); 3g of volatile oil of Alpinia galanga and 5g of total steroidal glycosides of Alpinia serratifolia (Miao medicine extract); and excipients: 200g of polyethylene glycol 4000, 50g of polyethylene glycol 400, 15g of poloxamer 188, 30g of hydroxypropyl-β-cyclodextrin, 5g of soybean lecithin, 2g of sucralose (sweetener), 1h of sodium benzoate (preservative), and purified water.

4. The compound dripping pills for preventing and treating nausea and vomiting induced by zotuximab according to claim 3, characterized in that, The preparation method is as follows: S1. Preparation and purification of the extract according to the method of claim 2: S2. Preparation of inclusion complex: Take 30g of hydroxypropyl-β-cyclodextrin, add 75ml of purified water, heat and stir to dissolve, and prepare a 40% cyclodextrin aqueous solution; mix gingerol, evodiamine, total lactones of costus root, and volatile oil of Alpinia galanga, dissolve in 5ml of anhydrous ethanol, and slowly add dropwise to the cyclodextrin aqueous solution, stir at 40℃ for 2 hours, continue stirring at room temperature for 1 hour, refrigerate at 4℃ for 24 hours, filter, wash the precipitate with a small amount of purified water, vacuum dry at 40℃, pulverize, and obtain the drug inclusion complex; S3, Melting of the matrix: Weigh 200g of polyethylene glycol 4000, 50g of polyethylene glycol 400, and 15g of poloxamer 188, place them in a water bath, heat to 70-75℃, stir until completely melted, mix well, and obtain the matrix; S4. Mixing of drug and matrix: Metoclopramide, lidocaine, vitamin B6, total alkaloids of Pinellia ternata, total phenols of Terminalia chebula, and total steroidal glycosides of Alpinia serrata are ground into fine powders, passed through a 100-mesh sieve, and mixed evenly to obtain a medicinal powder. The drug inclusion complex is mixed evenly with the medicinal powder and added to the matrix in portions while stirring. 5g of soybean lecithin, 2g of sucralose, and 1g of sodium benzoate are added, and stirring is continued for 30 minutes to ensure uniform dispersion of the drugs, resulting in a mixed medicinal solution. The solution is kept warm at 70℃ for later use. S5, Droplet forming: The mixed drug solution obtained in S4 is transferred to the insulated dripping tank of the pelleting machine and kept at 70°C. Dimethyl silicone oil is used as the condensing liquid, and the condensation temperature is controlled at 10°C. The inner diameter of the dripping head is adjusted to 2.0 mm, the dripping speed is 35 drops per minute, and the dripping distance is 6 cm. The drug solution is dripped into the condensing liquid and solidified. S6. Post-processing and quality control: Collect the pellets, pour off the condensate, absorb the dimethyl silicone oil on the surface of the pellets with filter paper, and dry them at a low temperature below 30°C; sieve out the unqualified pellets, each pellet weighs about 25mg, and repackage them. Each 10 pellets contain about 1mg of metoclopramide. Weight variation, dispersibility time, HPLC content determination, and microbial limit testing are performed to ensure compliance with the relevant provisions of the Chinese Pharmacopoeia for drop pills, thus obtaining the finished product.