Icaritin rectal suppository as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an icaritin rectal suppository as well as a preparation method and application thereof. The suppository is prepared by directly taking the icaritin as a single active ingredient, and animal experiments prove that the icaritin can remarkably reduce the crissum score of rats suffering from hemorrhoids and remarkably reduce the levels of serum IL-6, IL-beta and TNF-alpha. The suppository disclosed by the invention is stable in component, good in administration and absorption, stable in process and good in application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an icariin rectal suppository, its preparation method, and its application. Background Technology

[0002] Icaritin, chemically known as 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)-1,2-benzopyran-4-one, is a hydrolysis product of icariin, the main active ingredient in Epimedium. It possesses various pharmacological effects, including anti-inflammatory, antioxidant, antitumor, neuroprotective, and osteoprotective properties. On January 10, 2022, icariin soft capsules (Icaritin, ICT) received conditional marketing approval for the treatment of unresectable hepatocellular carcinoma in patients who are unsuitable for or refuse standard therapy and have never received systemic therapy.

[0003] Currently, the main application of icariin in the market is in the treatment of advanced hepatocellular carcinoma. This invention investigates whether the anti-inflammatory activity of icariin can be applied to the treatment of rectal hemorrhoids, and aims to develop a suppository for treating hemorrhoids with icariin as the active ingredient. Existing technologies mostly use traditional Chinese medicine compositions with icariin as a component for the treatment of hemorrhoids. For example, CN105641617A discloses a method for preparing a traditional Chinese medicine suppository composition for treating hemorrhoids, in which icariin is included. Existing technologies do not disclose icariin as a monomeric drug for hemorrhoids. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides an icariin rectal suppository, its preparation method, and its application.

[0005] The technical solution of the present invention is as follows: an icariin rectal suppository, comprising icariin, a matrix, an emulsifier and water.

[0006] In some embodiments, the matrix is ​​selected from one or more of type 36 mixed fatty acid glycerides, type 38 mixed fatty acid glycerides, hydrogenated vegetable oil, glycerin gelatin, polyethylene glycol, polyoxyethylene 40 stearate or poloxamer, preferably polyethylene glycol 1500 and polyoxyethylene stearate (40).

[0007] In some implementations, the mass ratio of polyethylene glycol 1500 to poly(40) stearate is 1:1.

[0008] In some embodiments, the emulsifier is selected from castor oil polyoxyethylene (40) ether.

[0009] In some embodiments, the epimedium rectal suppository comprises, by weight percentage, 0.25% epimedium, 46.375% polyethylene glycol 1500, 46.375% polyoxyethylene stearate (40), 2% castor oil polyoxyethylene (40) ether, and 5% water.

[0010] This invention also provides a method for preparing the icariin rectal suppository, comprising the following steps:

[0011] Weigh out the prescribed amount of PEG1500 and stearic acid polyoxyethylene (40) ester, heat at 70°C until the matrix is ​​completely melted, and when the matrix temperature drops to 60°C, add the prescribed amount of epimedium that has passed through a No. 6 sieve and stir evenly. After the epimedium is completely dissolved, add the prescribed amount of castor oil polyoxyethylene (40) ether and ultrapure water, stir thoroughly and mix evenly, continue stirring for 20 minutes and then stop stirring. When the matrix temperature drops to 50°C, quickly pour it into a suppository mold with the inner wall coated with liquid paraffin (lubricant), cool and solidify, cut off the part that overflows from the mold opening, and demold.

[0012] The present invention also provides the use of the epimedium rectal suppository in the preparation of a drug for treating hemorrhoids.

[0013] The beneficial effects of this invention are as follows: Compared to the above-mentioned mixtures of traditional Chinese medicine used together to treat hemorrhoids, this application directly uses icariin as a single active ingredient to prepare suppositories. Animal experiments have shown that icariin can significantly reduce the perianal score of rats with hemorrhoids and significantly reduce serum IL-6, IL-β, and TNF-α levels, demonstrating a certain therapeutic effect on hemorrhoids with strong targeting. Mixtures of traditional Chinese medicine act on multiple targets, which can produce some adverse reactions or side effects, and the dosage is difficult to control. This application directly uses icariin as a single active ingredient, acting on a specific target, resulting in fewer side effects, easier dosage control, and no need to consider drug interactions, making it suitable for use in special populations of patients. Attached Figure Description

[0014] Figure 1 Effect of icariin rectal suppositories on perianal scores in a rat model of hemorrhoids

[0015] Figure 2 Effects of icariin rectal suppositories on serum inflammatory factor levels in a rat model of hemorrhoids

[0016] Figure 3 Effects of icariin rectal suppositories on the grading of rectal tissue lesions in a rat model of hemorrhoids Detailed Implementation

[0017] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0018] Example

[0019] Prescription screening

[0020] In the pre-treatment screening experiment, the applicant investigated the solubility and suppository formation properties of icariin in different types of matrices. The results showed that icariin is insoluble in oily matrices, such as type 36 mixed fatty acid glycerides and type 38 mixed fatty acid glycerides. When suspended in the matrix, it gradually precipitates and separates over a long period after solidification. Icariin is soluble in PEG-based water-soluble matrices, resulting in good suppository formation properties, but it is prone to aging after prolonged storage. Icariin is soluble in S-40, also resulting in good suppository formation properties, but the melting time exceeds 60 minutes. If S-40 is chosen as the suppository matrix, it needs to be mixed with PEG-based matrices, adjusting the ratio of S-40 to PEG until the formation properties, hardness, and melting time all meet the requirements.

[0021] Matrix type investigation

[0022] Based on preliminary experiments, the basic components of the formulation were determined to be the main drug and a water-soluble matrix. With suppository formation as a prerequisite, PEG1500, PEG4000, PEG6000, and S-40 were mixed in pairs at a 1:1 (w / w) ratio to form the suppository matrix. The quality of the self-made suppositories was evaluated using a comprehensive scoring method, with melt change time (Q1), hardness (Q2), and appearance (Q3) as the core evaluation indicators for a comprehensive score (P). The specific scoring criteria and weights for each evaluation indicator are shown in Table 1, and the results of the matrix type investigation are shown in Table 2.

[0023] Table 1. Scoring criteria and weights for each evaluation indicator

[0024]

[0025] Table 2 Results of Single-Factor Investigation of Matrix Type

[0026]

[0027] Experimental results showed that the highest overall score was achieved when the mixed matrix was "PEG1500:S-40 = 1:1". PEG1500 has a melting point (44–48℃) close to the rectal temperature (36.5–37.7℃), and is solid at room temperature. It softens and dissolves rapidly after entering the body cavity. Higher molecular weight PEGs (such as PEG4000 / 6000) have higher melting points (53–59℃), dissolve slowly in the body, and prolong the melting time. S-40 is a nonionic surfactant that can weaken the rigid crystalline structure of PEG, increase matrix flexibility, and improve hardness. Its hydrophilic polyoxyethylene chains can promote matrix water absorption and disintegration, shortening the melting time. However, high molecular weight PEG and S-40 have a large polarity difference, making them prone to phase separation and weakening the synergistic effect. Therefore, the initial matrix was determined to be "PEG1500:S-40 = 1:1". However, the suppository hardness was not ideal at this ratio, requiring the addition of an appropriate amount of water for adjustment.

[0028] Moisture content assessment

[0029] Based on a PEG1500:S-40 = 1:1 mixture matrix, 0%, 2%, 5%, 8%, 10%, 15%, and 20% ultrapure water were added respectively. The quality of the self-made suppositories was evaluated using a comprehensive scoring method, with melt change time (Q1), hardness (Q2), and appearance (Q3) as the core evaluation indicators for comprehensive scoring (P), and the weights were changed to 15%, 50%, and 35% respectively. The results of the water dosage investigation are shown in Table 3.

[0030] Table 3 Results of Single-Factor Investigation of Moisture Application

[0031]

[0032] Experimental results show that the highest overall score was achieved when the water content was 5%. The addition of water reduces the intermolecular forces and softens the structure. As the water content increases, the suppository hardness gradually decreases. When the water content reaches 10%, the hardness drops significantly, and the matrix can no longer maintain a rigid structure. Therefore, the initial water content is set at 5%.

[0033] Drug loading study

[0034] Based on the optimized formulation process described above, the effects of different drug loadings on the appearance of the intermediate and suppositories were investigated. The prescribed amounts of PEG1500 and S-40 were weighed and melted at 70℃. Epimedium extract with mass fractions of 0.25%, 0.5%, 1.0%, 1.5%, and 2.0% was weighed and added to the matrix when the temperature dropped to 60℃ and stirred thoroughly. Then, the prescribed amounts of EL-40 and ultrapure water were added and stirred completely. The appearance of the intermediate was observed. After stirring for 20 minutes, stirring was stopped. When the matrix temperature dropped to 50℃, the mixture was quickly poured into a suppository mold with the inner wall coated with liquid paraffin (lubricant). After cooling and solidification, the portion overflowing from the mold was cut off, and the suppositories were demolded. The appearance of the suppositories was observed, and the results are shown in Table 4.

[0035] Table 4 Results of Drug Loading Investigation

[0036]

[0037] The results showed that the maximum drug loading of the self-made suppositories was 1.0%. The final determination of the API content needs to be based on experimental data from preclinical studies such as toxicology, pharmacodynamics and pharmacokinetics. This paper chose to first determine the optimal formulation process through preliminary experiments, single-factor experiments and orthogonal experiments, and then determine the suppository specifications through animal experiments. Therefore, the drug loading of each suppository is tentatively set at 0.25% at this stage.

[0038] Prescription confirmation is shown in the table below:

[0039] Table 5. Homemade Suppository Prescriptions (Unit Dosage)

[0040]

[0041]

[0042] The process has been confirmed as follows:

[0043] Weigh out the prescribed amounts of PEG1500 and S-40, heat at 70°C until the matrix is ​​completely melted, and when the matrix temperature drops to 60°C, add the prescribed amount of ICT (passed through a No. 6 sieve, 100 mesh) and stir evenly. After the ICT is completely dissolved, add the prescribed amount of EL-40 and ultrapure water, stir thoroughly and mix evenly. Continue stirring for 20 minutes and then stop stirring. When the matrix temperature drops to 50°C, quickly pour it into a suppository mold with the inner wall coated with liquid paraffin (lubricant), cool and solidify, cut off the part that overflows from the mold opening, and demold.

[0044] The effect of test example 1 on perianal score

[0045] Animal modeling and drug administration

[0046] SD rats were randomly divided into a blank group, a model group, an experimental group, and a positive group (Mayinglong Musk Hemorrhoid Ointment, 1g / kg), with 6 rats in each group. The rats were fasted but allowed to drink water for 12 hours before modeling.

[0047] The control group received no treatment. All other groups underwent acetic acid-induced acute hemorrhoid modeling in rats. Filter paper of equal size (6-8 mm inner diameter) was unfolded and thoroughly soaked in 99.0% acetic acid. The soaked filter paper was placed around the rat's anus, ensuring close contact with the perianal skin and mucous membrane. One filter paper was used each time, and the filter paper was changed twice per rat, every 30 seconds and 60 seconds. Twenty-four hours after modeling, the appearance of white ulcers, perianal swelling, and inflammatory exudate around the anus indicated successful modeling. After successful modeling, medication was initiated. Before administration, the abdomen was gently massaged to promote defecation. The experimental group received a self-made suppository, the positive control group received Ma Yinglong Musk Hemorrhoid Ointment, and the control and model groups received an equal volume of physiological saline. Administered twice daily for seven consecutive days.

[0048] The perianal scoring results of the hemorrhoid model rats are shown in Table 6. Figure 1 The perianal score of rats in the model group was significantly increased, while the perianal score of rats in the experimental group and the positive group was significantly decreased; compared with the positive group, the perianal score of rats in the experimental group was more significantly decreased.

[0049] Table 6. Effects of icariin rectal suppositories on perianal scores in rats with hemorrhoids ( n=6)

[0050]

[0051]

[0052] Effect of Test Example 2 on serum inflammatory factor levels

[0053] The serum inflammatory factor levels in rats with hemorrhoid model are shown in Table 7 and Figure 2 Compared with the blank group, the serum levels of IL-6, IL-1β, and TNF-α in the model group of hemorrhoid model rats were significantly increased, indicating that the modeling method used in this study was successful. Compared with the model group, the serum levels of IL-6, IL-1β, and TNF-α in the experimental group and the positive group of hemorrhoid model rats were significantly decreased, and the decrease in serum IL-6, IL-1β, and TNF-α in the experimental group of hemorrhoid model rats was more significant.

[0054] Table 7. Effects of icariin rectal suppositories on serum inflammatory factor levels in hemorrhoid model rats ( n=6)

[0055]

[0056] The results of rectal tissue lesion scoring in rats with hemorrhoid model are shown in Table 8 and Figure 3 The rectal tissue lesion score of the hemorrhoid model rats in the model group was significantly increased; the rectal tissue lesion score of the hemorrhoid model rats in the experimental group and the positive group was significantly decreased, and the decrease in rectal tissue lesion score of the hemorrhoid model rats in the experimental group was more significant.

[0057] Table 8. Effects of icariin rectal suppositories on the grading of rectal tissue lesions in rats with hemorrhoids ( n=6)

[0058]

Claims

1. A Icariin rectal suppository comprising Icariin, a base, an emulsifier and water.

2. The rectal suppository according to claim 1, characterized in that, The base is selected from one or more of mixed fatty acid glycerides of type 36, mixed fatty acid glycerides of type 38, hydrogenated vegetable oil, glycerogelatin, polyethylene glycol, polyoxyethylene 40 stearate or poloxamer, preferably polyethylene glycol 1500 and poloxyl 40 stearate.

3. The rectal suppository according to claim 2, characterized in that, The mass ratio of polyethylene glycol 1500 and poloxyl 40 stearate is 1:

1.

4. The rectal suppository according to claim 1, characterized in that, The emulsifier is selected from polyoxyethylene (40) castor oil ether.

5. The rectal suppository according to claim 1, characterized in that, The Icariin rectal suppository comprises 0.25% Icariin, 46.375% polyethylene glycol 1500, 46.375% poloxyl 40 stearate, 2% polyoxyethylene (40) castor oil ether and 5% water by mass percentage.

6. A method for preparing the rectal suppository of claim 1, comprising the following steps: Weigh the prescribed amount of PEG1500 and poloxyl 40 stearate, heat to 70℃ until the base is completely melted, when the temperature of the base drops to 60℃, add the prescribed amount of Icariin which has passed through a No. 6 sieve and stir until uniform, after the Icariin is completely dissolved, add the prescribed amount of polyoxyethylene (40) castor oil ether and ultrapure water, stir thoroughly, mix uniformly, continue stirring for 20 min and then stop stirring, when the temperature of the base drops to 50℃, quickly pour into the suppository mold whose inner wall has been coated with liquid paraffin (lubricant), cool and shape, cut off the part that has overflowed from the mold, and demold.

7. Use of the rectal suppository of claim 1 in the preparation of a medicament for treating hemorrhoids.

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