A compound preparation for treating and relieving hemorrhoids and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical compositions, relates to a hemorrhoid treatment drug, and particularly relates to a compound preparation for treating and relieving hemorrhoids and a preparation method thereof, wherein the compound preparation is composed of raw materials, an oil phase and an aqueous phase, and the method is to weigh the raw and auxiliary materials of the prescription amount for standby use, heat and disperse the oil phase auxiliary materials, then add the raw material medicine to continue to disperse, heat and stir the aqueous phase auxiliary materials, and then put them into the oil phase, and do dispersion treatment to obtain the product, that is, fill and seal the tail for storage. The preparation prepared by the present invention has a good curative effect on an animal hemorrhoid model. After the pharmaceutical composition cream of the present invention is given, the animal rectal tissue damage is significantly improved, no obvious mucosal epithelial degeneration and necrosis and inflammatory cell infiltration are observed, and slight capillary dilation can be seen in the interstitial tissue.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical compositions, relates to a drug for treating hemorrhoids, and in particular to a compound preparation for treating and relieving hemorrhoids and a preparation method thereof. Background Art

[0002] Hemorrhoids are one of the most common anal diseases in clinical practice. Hemorrhoids are pathological hypertrophy of the anal cushions at the lower end of the rectum. According to the different locations of occurrence, hemorrhoids can be divided into internal hemorrhoids, external hemorrhoids and mixed hemorrhoids. Internal hemorrhoids are considered to be pathological changes or displacements of the supporting structures, vascular plexus and arteriovenous anastomoses of the anal cushions (anal canal vascular cushions). External hemorrhoids are pathological dilation or thrombosis of the subcutaneous vascular plexus distal to the dentate line. Mixed hemorrhoids are a mixture of internal and external hemorrhoids.

[0003] Currently, the drugs used to treat hemorrhoids are all relieving drugs, which cannot cure the disease, and the treatment effect is also relatively short. Summary of the invention

[0004] In view of the above problems, the present invention provides a compound preparation for treating and relieving hemorrhoids and a preparation method thereof.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] A compound preparation for treating and relieving hemorrhoids, comprising raw materials, an oil phase and an aqueous phase.

[0007] Preferably, the raw materials include hydrocortisone and lidocaine;

[0008] The component ratio is:

[0009] Hydrocortisone: 0.25-05 parts;

[0010] Lidocaine: 0.25-05 parts.

[0011] Preferably, the oil phase comprises cetyl alcohol and stearyl alcohol;

[0012] The component ratio is:

[0013] Hexadecanol: 0.5-2.0 parts;

[0014] Octadecanol: 0.5-2.0 parts.

[0015] Preferably, the aqueous phase comprises glycerol, propylene glycol, sodium lauryl sulfate and water;

[0016] The component ratio is:

[0017] Glycerin: 0.5-2.0 parts;

[0018] Propylene glycol: 1.0-3.0 parts;

[0019] Sodium lauryl sulfate: 0.05-0.2 parts;

[0020] Water: 0.7-4.9 parts.

[0021] Preferably, the water is purified water.

[0022] A method for preparing a compound preparation, the specific method is as follows:

[0023] 1) Weigh the prescribed amount of raw and auxiliary materials for use;

[0024] 2) Add the oil phase excipients into a beaker, heat it in a water bath at 80°C, and start a high-speed disperser for dispersion at a speed of 3600 rpm;

[0025] 3) After the oil phase is melted, add the API and continue to disperse for 10 minutes until uniform to obtain a white oily liquid;

[0026] 4) Add the aqueous phase excipients to another beaker and heat it in a 75°C water bath. Turn on the heat-collecting magnetic stirrer for stirring at 35 rpm for 10 min to obtain a colorless transparent liquid.

[0027] 5) Slowly add the water phase to the oil phase and start the high-speed disperser for emulsification. After the water phase is added, continue emulsification for 10 minutes at a speed of 9000 rpm to obtain a milky white solution;

[0028] 6) Cool to 40℃, fill, seal, label and put into storage.

[0029] Compared with the prior art, the advantages and positive effects of the present invention are:

[0030] The preparation prepared by the present invention has a good curative effect on animal hemorrhoid models. After administration of the pharmaceutical composition cream of the present invention, the animal rectal tissue damage is significantly improved, no obvious mucosal epithelial degeneration and necrosis and inflammatory cell infiltration are observed, and slight capillary dilation is observed in the interstitial tissue. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0032] Figure 1This is a diagram of histopathological changes in a croton oil rat anal swelling model test in a specific embodiment of the present invention. Implementation

[0033] In order to more clearly understand the above-mentioned purpose, features and advantages of the present invention, the present invention is further described below in conjunction with the accompanying drawings and embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0034] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0035] The invention provides a compound preparation for treating and relieving hemorrhoids and a preparation method thereof.

[0036] The following is a detailed description with reference to the embodiments.

[0037] Embodiment 1:

[0038] 1) Weigh the prescribed amount of raw and auxiliary materials for use;

[0039]

[0040] 2) Add the oil phase excipients into a beaker, heat it in a water bath at 80°C, and start a high-speed disperser for dispersion at a speed of 3600 rpm;

[0041] 3) After the oil phase is melted, add the API and continue to disperse for 10 minutes until uniform to obtain a white oily liquid;

[0042] 4) Add the aqueous phase excipients to another beaker and heat it in a 75°C water bath. Turn on the heat-collecting magnetic stirrer for stirring at 35 rpm for 10 min to obtain a colorless transparent liquid.

[0043] 5) Slowly add the water phase to the oil phase and start the high-speed disperser for emulsification. After the water phase is added, continue emulsification for 10 minutes at a speed of 9000 rpm to obtain a milky white solution;

[0044] 6) Cool to 40℃, fill, seal, label and store ZJ-20230728-01.

[0045] Embodiment 2:

[0046] 1) Weigh the prescribed amount of raw and auxiliary materials for use;

[0047]

[0048] 2) Add the oil phase excipients into a beaker, heat it in a water bath at 80°C, and start a high-speed disperser for dispersion at a speed of 3600 rpm;

[0049] 3) After the oil phase is melted, add the API and continue to disperse for 10 minutes until uniform to obtain a white oily liquid;

[0050] 4) Add the aqueous phase excipients to another beaker and heat it in a 75°C water bath. Turn on the heat-collecting magnetic stirrer for stirring at 35 rpm for 10 min to obtain a colorless transparent liquid.

[0051] 5) Slowly add the water phase to the oil phase and start the high-speed disperser for emulsification. After the water phase is added, continue emulsification for 10 minutes at a speed of 9000 rpm to obtain a milky white solution;

[0052] Cool to 40℃, fill, seal, label and put into storage ZJ-20230804-01.

[0053] The above two products were applied to animals and effective tests were carried out, as follows.

[0054] 1. Route of administration and basis

[0055] The clinical use of the test article is perianal or intraanal application, so this study adopted the rat rectal administration method to simulate the clinical administration conditions to obtain evaluation data.

[0056] 2. Dosage design and basis

[0057] The proposed clinical dosage of SE-2023-001 is 2g three times a day. According to the equivalent dose coefficient of rats and humans, it is converted to: 2×0.018×5≈0.2g / kg. This study selected the clinical equivalent dose as the medium dose for the test, that is, 0.2g / kg, the high dose can be set to 0.4g / kg, and the low dose is set to 0.1g / kg. According to 300g per rat, the high, medium and low doses are 0.12g, 0.06g, and 0.03g per rat, respectively, and the drug is administered three times a day.

[0058] Clinical dosage of Mayinglong Musk Hemorrhoid Ointment: 2-3 times a day, 2-3g each time. According to the equivalent dose coefficient of rats and humans, it is converted to: 2×0.018×5≈0.2g / kg. According to each rat of 300g, the dosage for each rat can be set to 0.06g, 3 times a day.

[0059] 3. Animal identification after grouping

[0060] Each animal was identified using animal tagging and box marking methods.

[0061] 3.1 Animal marking

[0062] Each group of animals was numbered 1 to 10. Picric acid was used to rub the fur of different parts of the animals for marking.

[0063]

[0064] 3.2 Box identification

[0065] After the animals are grouped, different groups are marked with different colored box cards. The label content includes: project number, box number, gender, group, animal number, project leader, contact number, and experiment start and end dates. Hang the filled box card on the front side of the breeding box.

[0066] 4. Croton oil-induced anal swelling model test in rats

[0067] 4.1 Model preparation

[0068] The croton oil mixture was prepared with 1 part of distilled water, 4 parts of pyridine, 5 parts of ether and 10 parts of 6% croton oil ether solution. When making the model, a cotton ball soaked with 0.16 mL of the croton oil mixture was inserted into the anus of a 6-week-old rat anesthetized with chloral hydrate for 40 seconds.

[0069] 4.2 Animal grouping

[0070] Group design: A total of 5 groups were set up, namely model control group, SE-2023-001 high-dose group, SE-2023-001 medium-dose group, SE-2023-001 low-dose group; shared by the normal control group and acetic acid model.

[0071] Number of animals: 10 animals per group, 50 in total;

[0072] Gender ratio: half male and half female;

[0073] Grouping method: The patients were divided into groups evenly according to the degree of anal swelling on the second day after modeling.

[0074] Specific grouping information is shown in the following table:

[0075] Dosage regimen and group information table

[0076]

[0077] Note: The first digit of the animal number represents the group, the second letter represents the croton oil film (B), and the last two digits represent the animal serial number.

[0078] 4.3 Animal Dosing

[0079] After grouping, medication was started, and the anus was smeared with cotton swabs for administration. The high, medium and low doses of SE-2023-001 were 0.4g / kg, 0.2g / kg and 0.1g / kg, respectively. 0.12g / mouse, 0.06g / mouse and 0.03g of the test product / mouse were applied, respectively. Among them, 0.06g / mouse and 0.08g / mouse matrix were weighed for the medium and low doses, respectively, and mixed with the drug and then applied to the anus; 0.06g / mouse for the positive drug Mayinglong Musk Hemorrhoids Ointment group, and the normal group and model group were smeared with cotton swabs dipped in physiological saline. The drug was administered 3 times a day for 14 consecutive days.

[0080] 4.4 Index detection

[0081] 4.4.1 Body weight measurement

[0082] Body weight was measured once a week.

[0083] 4.4.2 Determination of swelling

[0084] The diameter of the entire anus surrounding tissue swelling was measured with a vernier caliper before film formation, 2 days after film formation and 4 days after drug administration. The average of the anus diameter before modeling minus the anus diameter at different times after modeling was used as an index of the measured swelling degree. Since the anus swelling of the model rats disappeared after 4 days, the anus diameter was no longer measured after 4 days.

[0085] 4.4.3 Rectal width measurement

[0086] After the experiment, the animals were killed by chloral hydrate anesthesia, and the rectum was subtracted to measure the width of the rectum.

[0087] 4.4.4 Histopathological examination

[0088] Detection time: End of the test

[0089] Test animals: All surviving animals

[0090] Detection method: The rectal and anal tissues were cut, fixed with formalin, and stained with HE for pathological histology.

[0091] 5. Statistical Analysis

[0092] The measurement indicators were expressed as mean ± standard deviation. When the sample size was less than 3, the data of this group were not included in the statistical comparison. The data were entered and statistically analyzed using Excel 2010 and SPSS 22.0 software. Single-factor ANOVA was used for comparative analysis between the groups. Pathological data and other materials were described in detail.

[0093] 5.1. Weight

[0094] Before administration, the body weights of the three dose groups of Mayinglong Hemorrhoids Cream, SE-2023-001 and the model group were basically the same, with no significant difference. On the 7th and 14th days after administration, the body weights of the Mayinglong Hemorrhoids Cream group were basically the same as those of the model group (p>0.05); however, the body weights of the three dose groups of SE-2023-001 were significantly lower than those of the model group and the Mayinglong Hemorrhoids Cream group (p>0.05), indicating that SE-2023-001 had a significant inhibitory effect on the weight gain of rats at three doses, and the effect of SE-2023-001 on body weight should be paid attention to in future studies.

[0095] Effect of SE-2023-001 on body weight of rats in croton oil-induced anal swelling model ( ±S, g, n=10)

[0096]

[0097] Note: *p<0.05, **p<0.01 compared with the model control group;

[0098] #p<0.05, ##p≤0.01, compared with the positive control group;

[0099] 5.2 Swelling

[0100] On the second day after modeling, the rats were divided into groups according to the degree of anal swelling, and the degree of swelling in each group was basically the same before administration. Compared with the normal group, the anal swelling of the model group before and after administration was significantly increased (p < 0.01); compared with the model control group, the anal swelling of rats in the three dose groups of Mayinglong Hemorrhoid Cream and SE-2023-001 decreased on the second and fourth days after administration, and only the low-dose group showed a statistical difference in anal swelling on the fourth day after administration compared with the model group (p < 0.05). The anus returned to normal and no longer swollen on the sixth day of administration. The anal swelling of the positive control group of Mayinglong Hemorrhoid Cream and the three dose groups of SE-2023-001 was basically the same after administration, with no significant difference.

[0101] Compared with the model group, there was no significant difference in anal swelling before administration and 2 and 4 days after administration. The reason was that the cotton ball soaked in croton oil mixture was inserted into the rat anus to form a membrane, so the swelling was mainly in the rectum rather than the perianal area, and no perianal swelling was observed on the 6th day after modeling. The reason for the statistical difference between the low-dose group of SE-2023-001 and the model was that the anal swelling of the low-dose group before administration was slightly lower than that of the model group (9.8±1.0 vs 10.3±2.5), and there was no obvious advantage over the medium and high-dose groups of SE-2023-001. However, from a numerical analysis, the anal swelling of rats in the three dose groups of Mayinglong Hemorrhoids Ointment and SE-2023-001 was still reduced, which had a certain improvement effect.

[0102] Effect of SE-2023-001 on anal swelling in rats with croton oil-induced anal swelling model ( ±S, g, n=10)

[0103]

[0104] Note: &&p<0.01, comparison between model group and normal control group;

[0105] *p<0.05, compared with the model control group;

[0106] 5.3 Rectal width

[0107] Compared with the normal group, the rectal width of the model group was significantly increased (p < 0.01); compared with the model control group, the rectal width of rats in the three dose groups of Mayinglong Hemorrhoids Ointment and SE-2023-001 was significantly decreased (p < 0.01); compared with the positive control of Mayinglong Hemorrhoids Ointment, the rectal width of rats in the high dose group of SE-2023-001 was significantly decreased (p < 0.05), and there was no significant difference between the medium and low dose groups (p > 0.05), indicating that the high dose of SE-2023-001 was better than Mayinglong Hemorrhoids Ointment according to autopsy observation.

[0108] Effect of SE-2023-001 on rectal width in rats with anal swelling induced by croton oil ( ±S, g, n=10)

[0109]

[0110] Note: &&p<0.01, comparison between model group and normal control group;

[0111] *p<0.05, **p<0.01 compared with each drug-treated group and the model control group;

[0112] #p<0.05, comparison between each dose group of SE-2023-001 and positive control group;

[0113] 5.4 Histopathological examination

[0114] like Figure 1 shown.

[0115] Normal control group: The structure of perianal skin tissue and mucosal epithelial tissue was intact.

[0116] Model control group: Part of the mucosal epithelium was found to be degenerated, necrotic and sloughed, forming ulcers. Exudation was seen on the mucosal surface, leukocyte infiltration and fibrin exudation were seen under the mucosa, interstitial tissue was swollen, and capillary dilation and congestion were obvious.

[0117] Positive control group: The rectal tissue damage was significantly improved, small ulcers and inflammatory cell infiltration were still observed in some rats, and capillary dilation was still observed in some interstitial tissues.

[0118] SE-2023-001 high-dose group: Rectal tissue damage was significantly improved, no obvious mucosal epithelial degeneration and necrosis and inflammatory cell infiltration were observed, and slight capillary dilation was visible in some interstitial tissues.

[0119] SE-2023-001 medium-dose group: Rectal tissue damage was significantly improved, but mucosal epithelial degeneration and necrosis and inflammatory cell infiltration were still observed in some mice, and capillary dilation was still observed in some interstitial tissues.

[0120] SE-2023-001 low-dose group: Rectal tissue damage was significantly improved, small ulcers and inflammatory cell infiltration were still visible in some mice, and capillary dilation was still visible in some interstitial tissues.

[0121] From the above results, it can be seen that the lesions in the model group were more obvious, indicating that the model membrane was successfully formed, and the three dose groups of Mayinglong Hemorrhoids Ointment and SE-2023-001 all showed different degrees of improvement, with the most obvious improvement in the high-dose group, and the degree of improvement in ulcers and inflammatory reactions was significantly better than that of the Mayinglong Hemorrhoids Ointment group.

[0122] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes and apply it to other fields. However, any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A compound preparation for treating and relieving hemorrhoids, characterized in that: It consists of raw materials, oil phase and water phase; The raw materials consist of hydrocortisone and lidocaine; The component ratio is: Hydrocortisone: 0.25-05 parts; Lidocaine: 0.25-05 parts; The oil phase consists of hexadecanol and stearyl alcohol; The component ratio is: Hexadecanol: 0.5-2.0 parts; Octadecanol: 0.5-2.0 parts; The aqueous phase consists of glycerin, propylene glycol, sodium lauryl sulfate and water; The component ratio is: Glycerin: 0.5-2.0 parts; Propylene glycol: 1.0-3.0 parts; Sodium lauryl sulfate: 0.05-0.2 parts; Water: 0.7-4.9 parts; The water is purified water; The method for preparing the compound preparation for treating and relieving hemorrhoids is as follows: 1) Weigh the prescribed amount of raw and auxiliary materials for use; 2) Add the oil phase excipients into a beaker, heat it in a water bath at 80°C, and start a high-speed disperser for dispersion at a speed of 3600 rpm; 3) After the oil phase is melted, add the API and continue to disperse for 10 minutes until uniform to obtain a white oily liquid; 4) Add the aqueous phase excipients to another beaker and heat it in a 75°C water bath. Turn on the heat-collecting magnetic stirrer for stirring at 35 rpm for 10 min to obtain a colorless transparent liquid. 5) Slowly add the water phase to the oil phase and start the high-speed disperser for emulsification. After the water phase is added, continue emulsification for 10 minutes at a speed of 9000 rpm to obtain a milky white solution; 6) Cool to 40℃, fill, seal, label and put into storage.

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