Dolasetron mesylate suppositories and methods of making and using the same

Abstract

The present application relates to a kind of dolasetron mesylate suppositories, it is characterized in that, component includes: dolasetron mesylate, cyclodextrin or its derivative, shell matrix, hardness regulator, gel matrix, water;The gel matrix includes polyacrylic acid derivative grafted chitosan in it.The present application uses polyacrylic acid derivative grafted chitosan and cyclodextrin to prepare dolasetron mesylate liquid gel, significantly improve the stability and bioavailability of suppository;And can achieve the purpose of quick effect and slow release long-acting simultaneously.The suppository of the present application is very convenient for old people, children or patients who cannot be administered orally, and the treatment population of the product belongs to the patient who is inconvenient to swallow.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a dolasetron mesylate suppository with significantly improved dissolution, safety, bioavailability and medication compliance, as well as its preparation method and uses. Background Technology

[0002] Dolaseno mesylate was originally developed by Hoechst Marion Roussel in Germany, and later developed into a drug by Sanofi-Aventis. It is a highly effective and selective 5-HT3 receptor antagonist, clinically used to treat nausea and vomiting in cancer patients during chemotherapy, as well as nausea and vomiting caused by gynecological or surgical procedures. It was first launched in Australia in 1997 under the brand name Anzement. In June 1998, it was launched in the United States under the brand name ANZEMET. It was launched in France and Italy in 1999, and in Finland (brand name AnZemet) and South Africa (brand name Zamanon) in 2000. In 2003, it was launched in Germany and the United Kingdom under the brand name anemone. Dolaseno mesylate has a stronger antiemetic effect than other 5-HT3 receptor antagonists such as azasetron hydrochloride and granisetron hydrochloride.

[0003] Currently, dolasetron mesylate formulations available domestically and internationally include tablets, oral solutions, suspensions, and injections. Dolastron injection is the most studied and widely used formulation; however, WHO drug regulatory information indicates that dolasetron mesylate injection is associated with QTc interval prolongation and may potentially lead to serious arrhythmias to some extent. In 2011, the FDA issued a recommendation regarding dolasetron mesylate injection. Added contraindication to the prescription: prevention of nausea and vomiting caused by chemotherapy for tumors. In the same year... The manufacturer has revised the formulation: the injectable form is no longer used for the prevention of nausea and vomiting caused by chemotherapy for cancer; it retains only the indication for the prevention or treatment of postoperative nausea and / or vomiting. Dolaseno mesylate tablets can still be used for the prevention of nausea and vomiting caused by chemotherapy for cancer because the risk of cardiac arrhythmias is lower when taken orally than when injected. However, oral administration results in the first-pass effect in the liver, reducing the drug's bioavailability in the body; moreover, oral administration presents difficulties for patients who cannot or do not wish to take oral medication, especially for the treatment of nausea and vomiting. Therefore, developing a new formulation of dolasetron mesylate with improved dissolution, safety, bioavailability, and medication compliance has high market value and research significance.

[0004] CN111789812A discloses an oral solution of dolasetron mesylate and its preparation method. However, like tablets, the oral solution also suffers from the first-pass effect in the liver, and the oral form is not conducive to treating patients with nausea and vomiting.

[0005] Suppositories are an effective route of administration for patients with vomiting. The applicant's search revealed that no dolasetron mesylate suppositories are currently marketed. While conventional suppositories avoid the first-pass effect in the liver, they suffer from unstable blood drug concentrations, are prone to oxidation, deliquescence, and deterioration, affecting drug absorption and use, bioavailability, and stability, thus hindering the clinical application of dolasetron mesylate as a suppository. Summary of the Invention

[0006] Dolaseno mesylate is currently available in injectable and oral formulations. Oral formulations not only have relatively low bioavailability but also present administration difficulties for children or patients with swallowing difficulties. Injectable formulations may cause serious arrhythmias to some extent and also pose problems such as fainting, injection pain, and inability to self-administer at home. The suppository developed in this invention has better safety than the injectable form, higher bioavailability than ordinary oral formulations, and improved medication compliance. To overcome the problems of dissolution, safety, bioavailability, and medication compliance in existing dolasetron mesylate formulations, this invention adopts a suppository formulation of dolasetron. However, the inventors found that although the suppository form avoids the first-pass effect of the liver, the ordinary suppository form of dolasetron also has a first-pass effect of the intestine. Therefore, although the bioavailability is improved compared to oral administration, it is not yet at a satisfactory level. To further improve the bioavailability and compliance of dolasetron suppositories, this invention proposes a hollow dolasetron mesylate suppository and its preparation method. The suppository provided by this invention has high dissolution and good stability; it exerts its effect through rectal administration, avoiding the first-pass effect of the liver, and also avoiding the gastrointestinal side effects that may occur with oral medication, making it very convenient for elderly people, children, or patients who cannot take oral medication. This invention avoids the intestinal first-pass effect of suppositories by specifically selecting and modifying excipients, including the matrix, resulting in high bioavailability. The suppository of this invention meets the requirements in terms of appearance and hardness, does not irritate or damage the intestine, and has high drug dissolution, providing theoretical support and further research possibilities for the development of dolasetron into suppository form.

[0007] The technical solution of the present invention is achieved through the following technical solutions:

[0008] The first objective of this invention is to provide a dolasetron mesylate suppository, characterized in that the components include: dolasetron mesylate, cyclodextrin or its derivatives, a shell matrix, a hardness modifier, a gel matrix, and water; wherein the gel matrix includes chitosan grafted with a polyacrylic acid derivative.

[0009] Furthermore, the dolasetron mesylate suppository comprises the following raw and auxiliary materials in parts by weight: 100 parts dolasetron mesylate, 100-300 parts cyclodextrin, 500-800 parts shell matrix, 50-200 parts hardness modifier, 200-350 parts gel matrix, and 300-400 parts water.

[0010] The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, trimethyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin, with hydroxypropyl-β-cyclodextrin being the most preferred.

[0011] The outer shell matrix is ​​selected from semi-synthetic fatty acid glycerides, fully synthetic fatty acid glycerides, cocoa butter, glycerin gelatin, polyethylene glycol, polyoxyethylene (40) stearate, poloxamer, and preferably semi-synthetic fatty acid glycerides (stear).

[0012] The hardness modifier is selected from glyceryl monostearate, lanolin, stearic acid, and beeswax, with glyceryl monostearate being preferred.

[0013] In addition to acrylic acid derivative grafted modified chitosan, the gel matrix may also include at least one of poloxamer, carbomer, and cellulose, and the acrylic acid derivative grafted modified chitosan accounts for 40-70 wt% of the mass of the gel matrix, preferably 50-60 wt%.

[0014] The raw materials for the acrylic acid derivative grafted modified chitosan include chitosan, (meth)acrylic acid, and (meth)acrylic acid hydroxyalkyl ester; preferably, the (meth)acrylic acid hydroxyalkyl ester is selected from at least one of (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxypropyl ester, and (meth)acrylic acid 2,3-dihydroxypropyl ester; more preferably, the mass ratio of chitosan, (meth)acrylic acid, and hydroxyalkyl acrylic acid ester is 30-45:7-13:5-8.

[0015] The polyacrylic acid derivative graft-modified chitosan is obtained by adding monomers (meth)acrylic acid and hydroxyalkyl acrylate to chitosan under initiation polymerization conditions. The polymerization initiation conditions are either the addition of an initiator or irradiation polymerization. Irradiation polymerization is preferred. Compared with polymerization methods that add an initiator, radiation-initiated polymerization produces a purer product because no initiator is added; moreover, the polymerization reaction is easier to control and can be carried out at room temperature. This invention preferably employs... 60Polymerization is initiated by a Co-γ radiation source with a dose of 20-50 kGy and an irradiation time of 2-4 hours. The post-treatment of the irradiation polymerization is well known in the art. The product is soaked in deionized water, during which the water is changed to remove monomers and homopolymers from micro-reactions. The final product is then removed, dried, and stored for later use.

[0016] Further, the dolasetron mesylate suppository comprises the following raw and auxiliary materials in parts by weight: 100 parts dolasetron mesylate, 100-300 parts hydroxypropyl-β-cyclodextrin, 500-800 parts semi-synthetic fatty acid glycerides, 50-200 parts glyceryl monostearate, 100-150 parts polyacrylic acid derivative grafted modified chitosan, 100-150 parts poloxamer, and 300-400 parts water.

[0017] The inventors discovered that dolasetron mesylate hollow suppositories can be prepared using semi-synthetic fatty acid glycerides as the suppository shell matrix and dolasetron mesylate liquid gel as the suppository filler. The suppository has a melting point of 32-33℃, and the suppository shell is solid at room temperature but melts rapidly at body temperature. The suppository filler contains modified chitosan, which can increase mucosal permeability and is a mucosal absorption promoter for water-soluble macromolecular drugs. Chitosan also has good bioactivity, compatibility, and biodegradability, as well as antibacterial, antiseptic, hemostatic, and wound-healing effects. In this invention, the polyacrylic acid derivative-grafted modified chitosan can significantly increase the stability and sustained-release effect of the suppository.

[0018] The inventors unexpectedly discovered that modified chitosan, as a gel matrix, has advantages over unmodified chitosan, such as controllable drug release, high bioavailability, and good formulation stability.

[0019] The second objective of this invention is to provide a method for preparing the above-mentioned dolasetron mesylate suppositories, comprising the following steps:

[0020] 1) Preparation of dolasetron mesylate liquid gel:

[0021] ① Weigh 100-150 parts of chitosan grafted with polyacrylic acid derivative, 100-150 parts of gel matrix including poloxamer, carbomer, and cellulose, add 300-400 parts of water (containing 0.2-0.7% acetic acid), stir for 30-60 minutes, and then place in an ice bath to allow it to fully swell and disperse evenly, to obtain a clear solution of the gel matrix for later use;

[0022] ② The dolasetron mesylate was micronized;

[0023] ③ Weigh 100 parts of micronized dolasetron mesylate and 100-300 parts of cyclodextrin, add them to the clear solution in step ①, sonicate to dissolve, and stir for 30-60 minutes to obtain dolasetron mesylate liquid gel.

[0024] 2) Preparation of the suppository shell:

[0025] Weigh 500-800 parts of semi-synthetic fatty acid glycerides and 50-200 parts of monostearate glycerides and heat them in a water bath to melt them. Stir for 30-60 minutes and pour the mixture into a suppository mold. Insert a cylindrical hard plastic rod (with graduations) into the suppository mold to fix it. After it cools slightly, remove it to obtain the suppository shell.

[0026] 3) Preparation of hollow plugs

[0027] Take the prescribed amount of dolasetron mesylate liquid gel and fill it into the suppository shell, then seal it with the molten shell matrix, let it cool, scrape it flat, and open the mold to obtain the product.

[0028] Furthermore, the micronization process described in step 1) is not particularly limited, as long as the particle size D90 of dolasetron mesylate does not exceed 10 μm. In one specific embodiment of the present invention, an air jet mill is used for pulverization, and the pulverization pressure is controlled at 0.4-0.6 MPa.

[0029] Furthermore, the stirring described in steps 1) and 2) is at a stirring speed of 100-200 r / min.

[0030] Furthermore, the suppository specifications in step 3) can be flexibly selected according to actual needs. In one specific embodiment of the present invention, each suppository is filled with 0.5-2g, preferably 1-1.5g.

[0031] The dolasetron suppository of the present invention has the following advantages:

[0032] 1. Dolasetron mesylate liquid gel was prepared by grafting polyacrylic acid derivatives onto chitosan and cyclodextrin, which significantly improved the stability and bioavailability of the suppository.

[0033] 2. The suppositories of the present invention are very convenient for elderly people, children or patients who cannot take oral medication, and the target population for treatment of this product is patients with difficulty swallowing.

[0034] 3. This invention uses semi-synthetic fatty acid glycerides as the suppository shell matrix and dolasetron mesylate liquid gel as the suppository filler. The resulting dolasetron mesylate suppository can simultaneously achieve the purpose of rapid onset of action and sustained-release effect. Detailed Implementation

[0035] The following specific embodiments further illustrate the content of the present invention, but it should be understood that the specific content of the embodiments is not a limitation on the scope of protection of the present invention.

[0036] All reagents and equipment used in the embodiments of this invention were commercially purchased. The active pharmaceutical ingredient, dolasetron mesylate, was purchased from Jiangsu Yong'an Pharmaceutical Co., Ltd.

[0037] Preparation Example 1

[0038] Forty parts of chitosan were added to a solution containing 10 parts of acrylic acid and 6 parts of 2,3-dihydroxypropyl acrylate. The mixed solution was then placed in a 30 kGy solution. 60 Irradiate with Co-γ rays for 4 hours. After irradiation, soak the product in 200 parts of deionized water for 24 hours, changing the water every 4 hours. Take out the sample and dry it to obtain grafted modified chitosan.

[0039] Preparation Example 2

[0040] The other conditions are the same as in Preparation Example 1, except that the monomers are 13 parts acrylic acid and 5 parts 2,3-dihydroxypropyl acrylate.

[0041] Preparation Example 3

[0042] The other conditions are the same as in Preparation Example 1, except that the monomers are 7 parts acrylic acid and 8 parts 2,3-dihydroxypropyl acrylate.

[0043] Preparation Example 4

[0044] The other conditions are the same as in Preparation Example 1, except that the monomer is 16 parts acrylic acid.

[0045] Preparation Example 5

[0046] The other conditions were the same as in Preparation Example 1, except that the monomer was 16 parts of 2,3-dihydroxypropyl acrylate.

[0047] Example 1

[0048] 1) Preparation of dolasetron mesylate liquid gel:

[0049] ① Weigh 150 parts of the grafted modified chitosan obtained in Preparation Example 1 and 150 parts of poloxamer, add 300 parts of water (containing 0.5% acetic acid), stir for 30-60 minutes and place in an ice bath to allow it to fully swell and disperse evenly, to obtain a clear solution of the gel matrix for later use.

[0050] ② The dolasetron mesylate was micronized;

[0051] ③ Weigh 100 parts of micronized dolasetron mesylate and 150 parts of cyclodextrin, add them to the above clear solution, sonicate to dissolve, and stir for 30-60 minutes to obtain the final product.

[0052] 2) Preparation of the suppository shell:

[0053] Weigh 600 parts of stearin and 100 parts of glyceryl monostearate and heat them in a water bath until melted. Stir for 30-60 minutes, pour into a mold, insert a graduated cylindrical hard plastic rod into the mold to fix it, and remove it after it cools slightly.

[0054] 3) Preparation of hollow plugs

[0055] Take the prescribed amount of dolasetron mesylate liquid gel and fill it into the shell, then seal it with molten suppository shell matrix, let it cool, scrape it flat, and open the mold to obtain the product.

[0056] Examples 2-5

[0057] The other operations and conditions are the same as in Example 1, except that the chitosan in step 1) corresponds to the grafted modified chitosan obtained in Preparation Examples 2-5.

[0058] Comparative Example 1

[0059] The other operations and conditions are the same as in Example 1, except that the grafted chitosan in step 1) is replaced with an equal mass of unmodified chitosan.

[0060] Comparative Example 2

[0061] The other operations and conditions are the same as in Example 1, except that cyclodextrin was not added in step 1).

[0062] Experimental Example 1

[0063] The other operations and conditions are the same as in Example 1, except for the amount of stearin and glyceryl monostearate used in step 2).

[0064] The optimal dosage of matrix and hardness modifier in suppositories was screened using suppository appearance, hardness, melting time, and 1-hour dissolution rate as evaluation indicators. The results are detailed in Table 1. The melting time was determined at 37±0.5℃, following the method described in General Chapter 0922 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. The dissolution rate was determined according to General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, using the rotating basket method at 100 r / min and a temperature of 37±0.5℃. The dissolution medium was phosphate buffer solution with a pH of 7.0. High-performance liquid chromatography (HPLC) was used to assess the dissolution rate of the suppositories.

[0065] Table 1. Investigation of the dosage of stearin and glyceryl monostearate

[0066]

[0067]

[0068] Experimental results showed that the ratio of dolasetron mesylate: stearate: glyceryl monostearate (mass comparison) of 100:600:100 met the requirements.

[0069] Experimental Example 2

[0070] The other operations and conditions are the same as in Example 1, except for the amount of grafted modified chitosan and cyclodextrin used in step 1).

[0071] Using the amount of drug released from suppositories as the evaluation index, the optimal dosage of grafted modified chitosan and cyclodextrin in suppositories was screened. Suppositories prepared with different dosages of chitosan and cyclodextrin were placed in dialysis bags with a molecular weight of 8000-12000. After the dialysis bags were tied tightly, they were placed in dissolution cups. Other operations were the same as the dissolution determination method in Experiment 1. The cumulative release rate = the mass of drug released / the total mass of drug added. The results are detailed in Table 2.

[0072] Table 2. Investigation of the dosage of grafted modified chitosan and cyclodextrin

[0073]

[0074] Experimental results showed that the required ratio of dolasetron mesylate: grafted chitosan: cyclodextrin (mass comparison) was 100:300:150.

[0075] Application Example 1: Stability Evaluation

[0076] Stability study: The suppositories were stored at 25±1℃ and 60±5RH% humidity for 3 months, and the changes in appearance (initial appearance: milky white, smooth, and glossy), pH value, and content of dolasetron mesylate were observed. The content was determined by HPLC. The stability results of the finished product are detailed in Table 3.

[0077] Table 3 Stability Evaluation

[0078] Suppositories Appearance pH change (%) Content change (%) Example 1 Milky white, smooth surface, glossy -0.03 -0.35 Example 2 Milky white, smooth surface, glossy -0.07 -0.57 Example 3 Milky white, smooth surface, glossy -0.05 -0.42 Example 4 Milky white, smooth surface, glossy -0.08 -0.75 Example 5 Milky white, smooth surface, glossy -0.06 -0.43 Comparative Example 1 Milky white, smooth surface, glossy -0.12 -1.14 Comparative Example 2 Light yellow, smooth surface, glossy -0.06 -0.61

[0079] As can be seen, the graft modification of chitosan by irradiation polymerization of acrylic acid and 2,3-dihydroxypropyl acrylate in this invention significantly improves the stability of the resulting dolasetron mesylate suppositories.

[0080] Application Example 2: Animal Pharmacokinetics

[0081] Thirty-two male beagles (10–12 months old, weighing 10–14 kg) were randomly divided into eight groups of four dogs each: six experimental groups (groups 1–5 corresponded to the suppositories obtained in Examples 1–5, and groups 6–7 corresponded to the suppositories obtained in Comparative Examples 1–2) and a control group (dolasetron mesylate tablets). The experimental groups were administered rectally, once per dose, at a dosage of 6 mg / kg, after being converted to the animal's body weight. The control group was administered via gavage, once per dose, after being converted to the animal's body weight.

[0082] After the experimental and control groups were administered the same dose (6 mg / kg) as described above to dogs, the pharmacokinetic data of hydrodolasetron (a metabolite of dolasetron) in the dogs were measured and are shown in Table 4.

[0083] Table 4 Comparison of animal pharmacokinetics of the finished products

[0084]

[0085] The experimental results showed that, compared with oral formulations, the relative bioavailability (expressed as AUC) of the suppositories of the present invention was significantly higher. 0-t The bioavailability (calculated as a percentage) is significantly higher, and the suppository has a longer half-life, allowing it to exert its therapeutic effect in vivo for a longer period, thereby reducing the frequency of administration and drug exposure, and increasing the safety of medication. Table 4 shows that the graft modification of chitosan by irradiation polymerization of acrylic acid and 2,3-dihydroxypropyl acrylate in this invention significantly improves the bioavailability and / or half-life of the resulting dolasetron mesylate hollow suppositories.

[0086] Application Example 3: Cardiotoxicity Study

[0087] Eight male beagle dogs (10–12 months old, weighing 10–14 kg) were randomly divided into two groups: a control group and an experimental group. The control group received dolasetron mesylate injection, while the experimental group received dolasetron mesylate suppositories prepared in Example 1. The control group (N=4) received administration by injection at a dose of 20 mg / kg / day, calculated based on animal weight, for 7 consecutive days. The experimental group (N=4) received administration rectally at a dose of 20 mg / kg / day, calculated based on animal weight, for 7 consecutive days.

[0088] On the 7th day after administration, electrocardiograms were measured in both groups within 1 hour before administration and at 0.25h, 0.5h, 0.75h, and 1.0h after administration. The results are shown in Table 5.

[0089] Table 5 Comparison of cardiotoxicity between injectable and suppository formulations

[0090]

[0091] The experimental results showed that, under conditions exceeding the maximum clinical exposure dose, no significant prolongation of the PR and QT intervals or widening of the QRS complex was observed in the experimental group. In the control group, PR, QT, and QRS values ​​1 hour after administration were significantly different from those 1 hour before administration (P < 0.05), with PR and QT being significantly prolonged and QRS widened. In conclusion, the frequency and amplitude of ECG changes in the experimental group were minimal in the canine cardiotoxicity study; therefore, the dolasetron mesylate suppository of this invention exhibits better safety than the injectable form.

Claims

1. A dolasetron mesylate hollow suppository, characterized in that, The dolasetron mesylate hollow suppository comprises the following raw and auxiliary materials in parts by weight: 100 parts dolasetron mesylate, 100-300 parts cyclodextrin, 500-800 parts shell matrix, 50-200 parts hardness modifier, 200-350 parts gel matrix, and 300-400 parts water; the gel matrix comprises chitosan grafted with polyacrylic acid derivatives; the chitosan grafted with polyacrylic acid derivatives accounts for 40-70 wt% of the gel matrix. The hollow suppository of dolasetron mesylate uses semi-synthetic fatty acid glycerides as the suppository shell matrix and dolasetron mesylate liquid gel as the suppository filler. The dolasetron mesylate liquid gel includes chitosan grafted with polyacrylic acid derivatives and cyclodextrin. The outer shell matrix is ​​a semi-synthetic fatty acid glyceride, the hardness regulator is glyceryl monostearate, and the cyclodextrin is hydroxypropyl-β-cyclodextrin. The raw materials for the polyacrylic acid derivative graft-modified chitosan include chitosan, (meth)acrylic acid, and (meth)acrylic acid hydroxyalkyl ester; the mass ratio of chitosan, (meth)acrylic acid, and (meth)acrylic acid hydroxyalkyl ester is 30-45:7-13:5-8; the polyacrylic acid derivative graft-modified chitosan is obtained by radiation polymerization. 60 Polymerization is initiated using a Co-γ radiation source with a radiation dose of 20-50 kGy and a radiation time of 2-4 hours.

2. The dolasetron mesylate hollow suppository according to claim 1, characterized in that, In addition to chitosan grafted with polyacrylic acid derivatives, the gel matrix also includes at least one of poloxamer, carbomer, and cellulose, and the chitosan grafted with polyacrylic acid derivatives accounts for 50-60 wt% of the gel matrix.

3. The dolasetron mesylate hollow suppository according to claim 1, characterized in that, The hydroxyalkyl methacrylate is selected from at least one of hydroxyethyl methacrylate, hydroxypropyl methacrylate, and 2,3-dihydroxypropyl methacrylate.

4. The dolasetron mesylate hollow suppository according to claim 1, characterized in that, The dolasetron mesylate hollow suppository comprises the following raw and auxiliary materials in parts by weight: 100 parts dolasetron mesylate, 100-300 parts hydroxypropyl-β-cyclodextrin, 500-800 parts semi-synthetic fatty acid glycerides, 50-200 parts glyceryl monostearate, 100-150 parts polyacrylic acid derivative graft-modified chitosan, 100-150 parts poloxamer, and 300-400 parts water.

5. A method for preparing the dolasetron mesylate hollow suppository according to any one of claims 1-4, comprising the following steps: 1) Preparation of dolasetron mesylate liquid gel: ① Weigh 100-150 parts of chitosan grafted with polyacrylic acid derivative, 100-150 parts of poloxamer, add 300-400 parts of water, stir for 30-60 minutes, and place in an ice bath to allow it to fully swell and disperse evenly, to obtain a clear solution of the gel matrix for later use. ② The dolasetron mesylate was micronized; ③ Weigh 100 parts of micronized dolasetron mesylate and 100-300 parts of cyclodextrin, add them to the clear solution in step ①, sonicate to dissolve, and stir for 30-60 minutes to obtain dolasetron mesylate liquid gel. 2) Preparation of the suppository shell: Weigh 500-800 parts of semi-synthetic fatty acid glycerides and 50-200 parts of monostearate glycerides and heat them in a water bath to melt them. Stir for 30-60 minutes and pour the mixture into a suppository mold. Insert a cylindrical hard plastic rod into the suppository mold to fix it. After it cools slightly, remove it to obtain the suppository shell. 3) Preparation of hollow plugs: Take the prescribed amount of dolasetron mesylate liquid gel and fill it into the suppository shell, then seal it with the molten shell matrix, let it cool, scrape it flat, and open the mold to obtain the product.

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