Application of ferrous ion compound in preparation of medicine for treating perianal diseases and medicine

Abstract

The invention relates to the technical field of biological medicines, in particular to application of a ferrous ion compound in preparation of a medicine for treating perianal diseases and the medicine. The comprehensive effect of the ferrous ion compound in treatment of perianal inflammation and the like is remarkably superior to the treatment effect of existing positive drugs and high or low-concentration ferrous ions, and in a domestic rabbit model, the remarkable comprehensive effects of resisting inflammation, improving perianal circulation, inhibiting bacteria and promoting tissue repair can be achieved.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to the application of ferrous ion compounds in the preparation of drugs for treating perianal diseases and the drugs themselves. Background Technology

[0002] Perianal diseases refer to diseases occurring in and around the anus, commonly including perianal abscess, anal fistula, rectal prolapse, anal fissure, and hemorrhoids. Perianal abscess refers to a bacterial infection of the perianal tissue, forming an abscess, typically presenting with severe perianal pain, a lump, and fever. Anal fistula: An anal fistula is a complication of perianal abscess, where an abscess ruptures, creating an abnormal channel between the anal canal and the perianal skin; common symptoms include anal discharge, sometimes accompanied by pain. Rectal prolapse: This refers to partial or complete protrusion of the rectum from the anus; common symptoms include difficulty defecating, anal discomfort, and discharge. Anal fissure: An anal fissure is a tear in the skin around the anus, usually caused by constipation, manifesting as severe anal pain during defecation, possibly accompanied by bleeding. Hemorrhoids: The most common perianal disease, classified into internal hemorrhoids, external hemorrhoids, and mixed hemorrhoids. Internal hemorrhoids occur inside the anus, while external hemorrhoids occur outside the anus; common symptoms include anal pain, bleeding, and itching.

[0003] The pathogenesis of perianal diseases is mainly related to the combined effects of factors such as local anal anatomy, blood circulation, infection, bowel habits, and immune response. Hemorrhoids are often caused by the relaxation of the anal cushions' supporting tissues, impaired venous return, and straining during defecation, leading to enlargement and downward displacement of the anal cushions. Anal fissures are often caused by abrasion from hard stools, followed by sphincter spasm leading to insufficient local blood supply, making the fissure difficult to heal. Perianal abscesses mainly originate from bacterial infection following blockage of the anal gland openings, spreading to the perianal area. Anal fistulas occur when the internal opening of the anal glands fails to close after the abscess ruptures or is incised, forming an abnormal channel. Rectal prolapse is caused by relaxation of the pelvic floor muscles, weakened supporting structures, and increased abdominal pressure. These diseases are often affected or aggravated by multiple factors such as constipation, prolonged sitting, local inflammation, and lifestyle habits.

[0004] Currently, clinical treatment of perianal diseases employs a comprehensive strategy, including conservative treatment, medication, minimally invasive procedures, and surgery, depending on the specific type of disease. However, each method has its limitations. Hemorrhoid treatment begins with regulating bowel movements, sitz baths, and topical medications. Minimally invasive procedures such as rubber band ligation, sclerotherapy, and infrared coagulation offer advantages such as minimal trauma and rapid recovery, but their effectiveness is limited for severe prolapsed hemorrhoids, and the recurrence rate is high. Surgical procedures such as traditional hemorrhoidectomy or PPH can cure the condition, but they are highly invasive, have a long recovery period, and may cause pain, bleeding, or anal stenosis. Conservative treatment of anal fissures can relieve symptoms, but chronic anal fissures often fail to heal completely. Lateral sphincter resection has a high cure rate but may lead to varying degrees of decreased anal control. Perianal abscesses must be incised and drained, but postoperative development into anal fistulas is still possible, and antibiotics have limited effectiveness against simple abscesses. Anal fistulas require surgical treatment. Fistulotomy is suitable for low-lying fistulas but easily damages the sphincter muscle; sphincter-preserving surgeries such as seton placement and LIFT are safer, but the recurrence rate remains high. Pelvic floor exercises have limited effectiveness in treating rectal prolapse. While surgery can correct the prolapse, recurrence or bowel dysfunction may still occur. Overall, the treatment of perianal diseases requires a balance between efficacy, safety, recurrence risk, and functional preservation. Therefore, current treatments for perianal diseases still suffer from unstable efficacy, high recurrence rates, numerous side effects, and poor patient compliance.

[0005] Existing topical medications for treating perianal diseases (including hormones, antibiotics, plant extracts, and hemostatic astringents) still suffer from problems such as high irritation, high recurrence rate, or insufficient repair capabilities. Therefore, a new strategy for treating perianal diseases is urgently needed. Summary of the Invention

[0006] To develop a novel strategy for treating perianal diseases, this invention provides the application of ferrous ion compounds in the preparation of drugs for treating hemorrhoids, as well as the ferrous ion compounds themselves. The ferrous ion compounds provided by this invention exhibit significantly superior overall effects in the treatment of perianal inflammation compared to existing positive control drugs and high or low concentrations of ferrous ions. In a rabbit model, they demonstrate significant anti-inflammatory, improved perianal circulation, antibacterial, and tissue repair-promoting combined effects.

[0007] This invention provides the application of ferrous ion compounds in the preparation of drugs for treating perianal diseases.

[0008] The ferrous ion compound provided by this invention possesses anti-inflammatory, perianal circulation-improving, antibacterial, and tissue-repair-promoting effects. It is suitable for the treatment of perianal diseases such as hemorrhoids, chronic perianal inflammation, or anal canal inflammation.

[0009] Furthermore, the ferrous ion compound is any one or a combination of several of ferrous sulfate, ferrous lactate, ferrous chloride, and ferrous gluconate.

[0010] Furthermore, the perianal disease is hemorrhoids, chronic perianal inflammation, or anal canal inflammation.

[0011] Furthermore, the medication is used to relieve perianal redness and swelling, promote the absorption of perianal cysts, or improve local discomfort during the inflammatory phase of hemorrhoids.

[0012] Furthermore, the drug dosage form is a solution, colloidal, suspension, emulsion, or hydrogel.

[0013] Furthermore, the hydrogel-type drug uses ferrous salt as the active ingredient, combined with excipients: nicotinamide, vitamin B2, sodium alginate, hyaluronic acid and carbomer.

[0014] Furthermore, the concentration of ferrous ion compound in the hydrogel-type drug is 2 mM to 3 mM.

[0015] Further, the preparation steps of the hydrogel-type drug are as follows: the ferrous ion compound is dissolved in sterile ultrapure water to a final concentration of 2mM to 3mM to obtain a 2mM to 3mM ferrous ion compound solution; after adding excipients, the mixture is stirred until a stable colloid is formed to obtain a 2mM to 3mM ferrous ion compound hydrogel.

[0016] Furthermore, based on the mass fraction of the 2 mM to 3 mM ferrous ion compound solution, the added excipients are 1.5% to 2% sorbitol, 0.2% to 0.3% allantoin, 0.01% to 0.02% vitamin B2, 2% to 3% panthenol, 0.02% to 0.03% shikonin, 0.6% to 1% polyethylene glycol-200, 0.5% to 0.7% carbomer, and 0.2% to 0.3% sodium alginate.

[0017] This invention also provides a drug for treating hemorrhoids, wherein the drug is a hydrogel-type drug, and the preparation steps of the hydrogel-type drug are as follows: A ferrous ion compound was dissolved in sterile ultrapure water to a final concentration of 2 mM to 3 mM to obtain a 2 mM to 3 mM ferrous ion compound solution. To a 2 mM–3 mM ferrous ion compound solution, the following excipients were added sequentially according to the mass fraction of the 2 mM–3 mM ferrous ion compound solution: 1.5%–2% sorbitol, 0.2%–0.3% allantoin, 0.01%–0.02% vitamin B2, 2%–3% panthenol, 0.02%–0.03% shikonin, 0.6%–1% polyethylene glycol-200, 0.5%–0.7% carbomer, and 0.2%–0.3% sodium alginate. The mixture was stirred at 200–300 rpm and 20–23°C for 3–4 hours to form a stable colloid. The pH was adjusted to 5.6–70 using triethanolamine to obtain a 2 mM–3 mM ferrous ion compound hydrogel.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides the application of ferrous ion compounds in the preparation of drugs for treating hemorrhoids, demonstrating the comprehensive effect of 2 mM ferrous ions in the treatment of perianal inflammation, which is significantly superior to the therapeutic effects of existing positive control drugs and high or low concentrations of ferrous ions. In a rabbit model, it achieves significant anti-inflammatory, improved perianal circulation, antibacterial, and tissue repair-promoting combined effects, significantly superior to the known astringent or mild antibacterial effects of general metal ions, and without irritation. The excipient system exhibits strong synergistic effects, significantly better than the effects of any single component used alone. It has high safety, a wide range of applications, and good prospects for industrialization. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 The therapeutic effects of different treatments on perianal lesions and inflammation; In the figure, a represents the therapeutic effect of the 2 mM ferrous lactate hydrogel experimental group on perianal lesions and inflammation; b represents the therapeutic effect of the positive group on perianal lesions and inflammation; c represents the therapeutic effect of the blank hydrogel group on perianal lesions and inflammation; d represents the perianal lesions and inflammation in the model group.

[0021] Figure 2 The therapeutic effects of different concentrations of ferrous ion hydrogel on perianal inflammation in rabbits were investigated. In the figure, a represents the therapeutic effect of the blank hydrogel treatment on perianal inflammation in rabbits; b represents the therapeutic effect of ferrous lactate hydrogel with a ferrous ion concentration of 1 mM on perianal inflammation in rabbits. c represents the therapeutic effect of ferrous lactate hydrogel with a ferrous ion concentration of 2 mM on perianal inflammation in rabbits. d represents the therapeutic effect of ferrous lactate hydrogel with a ferrous ion concentration of 3 mM on perianal inflammation in rabbits; e represents the therapeutic effect of ferrous lactate hydrogel with a ferrous ion concentration of 4 mM on perianal inflammation in rabbits.

[0022] Figure 3 The anorectal coefficient (ARC) of rabbit anal canal tissue at different treatment stages.

[0023] Figure 4 The levels of TNF-α at different treatment stages.

[0024] Figure 5 The IL-6 content of different ferrous ion treatment groups.

[0025] Figure 6 H&E staining was performed after gel treatment with different ferrous ion concentrations.

[0026] Figure 7 Image showing the H&E staining results of perianal tissue in a rabbit experimental perianal disease model. Detailed Implementation

[0027] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods, and the materials and reagents used in the following embodiments are commercially available unless otherwise specified.

[0028] Example 1: Application of ferrous ion compounds in the preparation of drugs for treating hemorrhoids.

[0029] I. Experimental Methods 1. Preparation of ferrous lactate hydrogel (1) 2 mM ferrous lactate hydrogel and its preparation steps Ferrous lactate was dissolved in sterile ultrapure water to a final concentration of 2 mM to prepare a 2 mM ferrous lactate solution. Adding 0.3% sodium alginate and 0.7% carbomer to a 2 mM ferrous lactate solution allows ferrous ions to undergo ionic cross-linking with sodium alginate and carbomer, forming a gel matrix. Then, the following excipients are added sequentially to the gel matrix: 2% sorbitol, 0.3% allantoin, 0.01% vitamin B2, 3% panthenol, 0.03% shikonin, and 1% polyethylene glycol-200. The mixture is stirred at 200 rpm and 20°C for 3 h until a stable colloid is formed. The pH is adjusted to 6.0 using triethanolamine to obtain the 2 mM ferrous lactate hydrogel. The percentages of each excipient added are based on the mass fraction of the 2 mM ferrous lactate solution.

[0030] 2. Preparation of blank hydrogels 0.3% sodium alginate and 0.7% carbomer were added to sterile ultrapure water. Sodium alginate and carbomer underwent ionic cross-linking to form a gel matrix. Then, the following excipients were added sequentially to the gel matrix: 2% sorbitol, 0.3% allantoin, 0.01% vitamin B2, 3% panthenol, 0.03% shikonin, and 1% polyethylene glycol-200. The mixture was stirred at 200 rpm and 20°C for 3 h until a stable colloid was formed. The pH was adjusted to 6.0 using triethanolamine to obtain a blank hydrogel. The percentages of each excipient added are based on the mass fraction of sterile ultrapure water.

[0031] 3. Evaluation of the therapeutic effect of ferrous lactate hydrogel (1) Establishment of an experimental perianal disease model in rabbits (chronic perianal inflammation and anal canal inflammation model): Sixteen male rabbits, each weighing 2.5 kg, were used and acclimatized for one week. All experimental procedures were approved by the Experimental Animal Ethics Committee of Henan University of Science and Technology (Approval No.: LLSC2025078). A perianal disease model was established using a croton oil mixture (water:pyridine:ether:6% croton oil in ether solution, volume ratio 1:4:5:10). The specific method is as follows: Before induction, the rabbits were fixed in rabbit boxes. A sterile medical cotton swab was soaked in 0.2 mL of the croton oil mixture, applied to the perianal area of ​​the rabbit, and inserted into the anus about 1 cm, held for 30 seconds. Induction was performed twice a day, morning and evening, 1 hour before feeding, and continued for 7 days.

[0032] Modeling results: After the modeling was completed, it was observed that the rabbits had difficulty defecating, had perianal cysts, increased frequency of licking the perianal area, and excrement adhesion around the anus.

[0033] Further sectioning of the perianal tissue and observation with H&E staining, such as... Figure 7 As shown, swelling, passive dilation, and congestion of blood vessels are visible in the perianal tissue. Modeling successful.

[0034] (2) Group treatment: After successful modeling, rabbits were randomly divided into 4 groups of 4 rabbits each. Group 4 was the model group, receiving no treatment. Group 2 was the positive control group, treated with a positive control drug (commercially available Ma Yinglong Musk Hemorrhoid Ointment, purchased from a pharmacy in Weiyang District, Xi'an). Groups 1 and 3 were the experimental groups; Group 1 was treated with the aforementioned 2 mM ferrous lactate hydrogel, and Group 3 was treated with the aforementioned blank hydrogel. Daily, using a 1 mL syringe (needle discarded), 0.2 g of the drug was applied to the perianal area and injected approximately 1 cm into the anus.

[0035] The results are as follows Figure 1 As shown, on day 3, the model group ( Figure 1 d) Redness and swelling of the perianal skin, with hair sticking to excrement. Figure 1As shown in c, in group 3 (blank hydrogel group), the perianal skin showed slight redness and swelling, a little moisture, and a small amount of excrement adhering to it. Figure 1 As shown in b, in group 2 (positive group), a small amount of redness and swelling of the perianal skin and a small amount of excrement adhering to the skin were observed. Figure 1 As shown in Figure a, after treatment of Group 1 (2 mM ferrous lactate hydrogel group), the perianal skin was rosy and normal, and the hair was clean.

[0036] Therefore, it can be seen that the preparation containing ferrous ion compounds has a good therapeutic effect on the rabbit model of perianal redness and swelling and anal canal cysts, and has the therapeutic efficacy for treating perianal redness and swelling and anal canal cysts.

[0037] 4. The effect of gels containing different concentrations of ferrous ions on treatment efficacy Following the aforementioned method, a rabbit hemorrhoid model was constructed using a mixture of croton oil.

[0038] Rabbits were randomly divided into five groups of three. Group 1 (ck group) was treated with a hydrogel without ferrous ions; Groups 2, 3, 4, and 5 were treated with hydrogels containing 1 mM, 2 mM, 3 mM, and 4 mM ferrous ions, respectively. 0.2 g of the drug was applied perianally and injected approximately 1 cm into the anus daily.

[0039] The preparation methods for 1 mM, 3 mM and 4 mM ferrous ion hydrogels are the same as those for the preparation of 2 mM ferrous lactate hydrogels, except that the concentration of ferrous lactate in the ferrous lactate solution obtained by dissolving ferrous lactate in sterile ultrapure water is 1 mM, 3 mM or 4 mM.

[0040] On the 3rd day of administration, if Figure 2 Treatment with a blank hydrogel containing 0 mM ferrous ions resulted in anal dampness, sticky excrement, and skin redness and swelling. (Example: [Insert example here]) Figure 2 Treatment with ferrous lactate hydrogel at a ferrous ion concentration of 1 mM resulted in redness of the anus, but excrement remained adhered. Figure 2 In the case of treatment with ferrous lactate hydrogel at a ferrous ion concentration of 2 mM, the anus appears rosy and natural. Figure 2 Treatment with ferrous lactate hydrogel at a ferrous ion concentration of 3 mM resulted in a clean anus, but with slight redness and swelling. Figure 2 Treatment with ferrous lactate hydrogel at a ferrous ion concentration of 4 mM resulted in anal dampness, sticky excrement, and redness and swelling.

[0041] Further, rabbit anal tissue was obtained and weighed, and the anorectal coefficient (ARC) of the rabbit anal tissue was calculated. The results are as follows: Figure 3As shown: Compared with the CK group without treatment, the 2 mM ferrous ion hydrogel group can significantly reduce the ARC coefficient of anal tissue, help reduce swelling and inflammation of anal tissue, and promote rapid recovery of anal tissue.

[0042] In addition to the apparent phenomena, we also stained the tissue sections with H&E, and the results are as follows: Figure 6 As shown: Compared with the untreated CK group, the positive control group and the 2 mM ferrous hydrogel group showed significant inhibitory effects on tissue vascular inflammation, with marked reduction in inflammation; in addition, the content of the inflammatory factor TNF-α was also detected, and the results are as follows. Figure 4 As shown, compared with the CK group, the 2 mM ferrous ion hydrogel group can significantly inhibit the expression of the inflammatory factor TNF-α, thereby reducing the inflammatory response of hemorrhoids and promoting tissue repair.

[0043] To evaluate the degree of inflammation reduction, IL-6, a downstream pro-inflammatory factor of TNF-α, was quantitatively analyzed. The results are as follows: Figure 5 As shown, 2 mM ferrous ion hydrogel has a significant inhibitory effect on the pro-inflammatory factor IL-6. The IL-6 level in the 2 mM group is significantly lower than that in all other groups, thereby reducing the inflammatory response and promoting the recovery of anal tissue.

[0044] Therefore, it can be seen that when the ferrous ion concentration is 1mM to 3mM, it has a good effect on the treatment of hemorrhoids and perianal redness and swelling in rabbits, and the treatment effect is best when the ferrous ion concentration is 2mM.

[0045] Although preferred embodiments of the invention have been described, those skilled in the art, once they have learned the basic inventive concept, can make other changes and modifications to these embodiments.

[0046] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. Application of ferrous ion compounds in the preparation of drugs for treating perianal diseases.

2. The application according to claim 1, characterized in that, The ferrous ion compound is any one or a combination of several of ferrous sulfate, ferrous lactate, ferrous chloride, and ferrous gluconate.

3. The application according to claim 2, characterized in that, The perianal diseases mentioned are hemorrhoids, chronic perianal inflammation, or anal canal inflammation.

4. The application according to claim 3, characterized in that, The medication is used to relieve perianal redness and swelling, promote the absorption of perianal cysts, or improve local discomfort during the inflammatory phase of hemorrhoids.

5. The application according to claim 4, characterized in that, The drug dosage form is a solution, colloidal, suspension, emulsion, or hydrogel.

6. The application according to claim 5, characterized in that, The hydrogel-type drug uses ferrous salt as the active ingredient, combined with excipients: nicotinamide, vitamin B2, sodium alginate, hyaluronic acid and carbomer.

7. The application according to claim 6, characterized in that, The concentration of ferrous ion compounds in the hydrogel-type drug is 2 mM to 3 mM.

8. The application according to claim 7, characterized in that, The preparation steps of the hydrogel-type drug are as follows: ferrous ion compound is dissolved in sterile ultrapure water to a final concentration of 2mM to 3mM to obtain a 2mM to 3mM ferrous ion compound solution; after adding excipients, the mixture is stirred until a stable colloid is formed to obtain a 2mM to 3mM ferrous ion compound hydrogel.

9. The application according to claim 8, characterized in that, Based on the mass fraction of the 2 mM–3 mM ferrous ion compound solution, the added excipients are 1.5%–2% sorbitol, 0.2%–0.3% allantoin, 0.01%–0.02% vitamin B2, 2%–3% panthenol, 0.02%–0.03% shikonin, 0.6%–1% polyethylene glycol-200, 0.5%–0.7% carbomer, and 0.2%–0.3% sodium alginate.

10. A medicine for treating hemorrhoids, characterized in that, The drug is the hydrogel-type drug according to claim 5, and the preparation steps of the hydrogel-type drug are as follows: A ferrous ion compound was dissolved in sterile ultrapure water to a final concentration of 2 mM to 3 mM to obtain a 2 mM to 3 mM ferrous ion compound solution. To a 2 mM–3 mM ferrous ion compound solution, the following excipients were added sequentially according to the mass fraction of the 2 mM–3 mM ferrous ion compound solution: 1.5%–2% sorbitol, 0.2%–0.3% allantoin, 0.01%–0.02% vitamin B2, 2%–3% panthenol, 0.02%–0.03% shikonin, 0.6%–1% polyethylene glycol-200, 0.5%–0.7% carbomer, and 0.2%–0.3% sodium alginate. The mixture was stirred at 200–300 rpm and 20–23°C for 3–4 hours to form a stable colloid. The pH was adjusted to 5.6–70 using triethanolamine to obtain a 2 mM–3 mM ferrous ion compound hydrogel.

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