A rectal in-situ heating gel composition for treating chronic prostatitis, its preparation method and uses.

Abstract

This invention provides a pharmaceutical composition for treating chronic prostatitis, prepared from the following raw materials in the indicated weight ratios: 8-12 parts Sophora flavescens, 8-12 parts Paeonia lactiflora, and 0.006-0.09 parts Borneol. This invention also provides a method for preparing the pharmaceutical composition and its uses. The rectal in-situ heating gel prepared by this invention possesses temperature-controlled heating properties and bioadhesive properties. Compared with traditional compound Sophora flavescens decoction enema, this preparation has suitable gel strength and bioadhesiveness, enabling it to remain in the rectum for a long time and continuously and stably release the active pharmaceutical ingredient and heat energy. It can effectively prevent drug leakage and has a significant advantage in targeted prostate drug delivery.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition for treating chronic prostatitis, specifically, to a rectal in-situ heating gel composition for treating chronic prostatitis, belonging to the pharmaceutical field. Background Technology

[0002] Chronic prostatitis is a common disease of the male reproductive system, mainly characterized by pain radiating from the prostate, scrotum, and testicles to surrounding tissues, urinary abnormalities, and sexual dysfunction. While generally not life-threatening, its long and persistent course often leads to anxiety, insomnia, and mood swings in many patients, significantly impacting their mental health and quality of life. Therefore, it has been listed by the National Institutes of Health in the United States as one of the most serious chronic diseases affecting the quality of life. Due to its complex and unclear pathogenesis, Western medicine currently lacks effective treatments. Treatment primarily involves antibiotics, alpha-blockers, anti-inflammatory drugs, and hormone regulators for antibacterial, anti-inflammatory, and analgesic purposes, but the efficacy is often unsatisfactory and difficult to cure completely. Furthermore, it frequently causes side effects such as gastrointestinal discomfort, low blood pressure, and peripheral edema, placing a significant economic burden and psychological stress on individuals and their families.

[0003] The exact etiology and pathogenesis of chronic prostatitis are not yet fully understood. However, in prostate diseases, there are instances where inflammation exists in the prostatic interstitium but the prostatic fluid lacks leukocytes. Furthermore, the concentration of some drugs in prostatic fluid is significantly lower than in blood plasma. Therefore, some scholars have proposed that a barrier mechanism may exist between the bloodstream and prostate tissue. Current research also suggests that the poor efficacy of drugs in treating chronic prostatitis may be due to this unique barrier mechanism between the prostate tissue and the bloodstream.

[0004] In traditional Chinese medicine, in addition to common oral herbal remedies, many effective external therapies have been developed, such as herbal sitz baths, herbal retention enemas, fumigation therapy, and herbal hot compresses. Related studies have shown that rectal administration has an advantageous pathway for drug delivery to the prostate, characterized by rapid delivery and high drug concentration, effectively promoting inflammation absorption. Furthermore, warm herbal enemas can increase local tissue temperature, promote local blood circulation, relieve pelvic floor muscle spasms, and accelerate metabolism, thus alleviating pain and achieving high efficacy and cure rates. Summary of the Invention

[0005] This invention provides a novel pharmaceutical composition for treating chronic prostatitis, and also provides a method for preparing the pharmaceutical composition and its uses.

[0006] This invention provides a pharmaceutical composition for treating chronic prostatitis, which is prepared from the following raw materials in the indicated weight ratios:

[0007] 8-12 parts of Sophora flavescens, 8-12 parts of Paeonia lactiflora, and 0.006-0.09 parts of Borneol.

[0008] More preferably, it is prepared from the following raw materials in the indicated weight ratios:

[0009] 10 parts Sophora flavescens, 10 parts Paeonia lactiflora, and 0.075 parts Borneol.

[0010] The pharmaceutical composition of the present invention is prepared by adding borneol and pharmaceutically acceptable excipients or auxiliary ingredients to the water or organic solvent extracts of Sophora flavescens and Paeonia lactiflora as active ingredients, and preparing it into a commonly used rectal administration formulation.

[0011] The rectal administration preparations mentioned above are suppositories, ointments, or gels.

[0012] The gelling agent is a rectal in-situ heating gel, characterized in that it is prepared from the following raw materials in weight percentages:

[0013] The compound extract of Sophora flavescens and Paeonia lactiflora contains 22%, borneol 0.75%, matrix material 5%–8%, bio-adhesive 0.3%–1.5%, heating material 28%–36%, stabilizer 5%–7%, ethanol 7.5%, and the remainder is pure water;

[0014] The aforementioned compound extract of Sophora flavescens and Paeonia lactiflora is an aqueous extract of Sophora flavescens and Paeonia lactiflora.

[0015] The matrix material is one or a mixture of two or more of the following: Carbomer 940, Poloxamer 407, and sodium alginate.

[0016] The bioadhesive is one or a mixture of two or more of methylcellulose, hydroxypropyl methylcellulose, chitosan, and carbomer 934.

[0017] The heating material is one or a mixture of two or more of paraffin, polyethylene glycol 2000, and n-docosane@calcium carbonate phase change microcapsules (MEPCMs);

[0018] The stabilizer is one or a mixture of two or more of poloxamer 407, glycerin, polyethylene glycol 400, and hydroxypropyl betacyclodextrin.

[0019] More preferably, the rectal in-situ heating gel is prepared from the following raw materials in weight percentage:

[0020] The compound extract of Sophora flavescens and Paeonia lactiflora contains 22%, borneol 0.75%, matrix material 5%–7%, bio-adhesive 0.4%–1%, heating material 28%–32%, stabilizer 6%, ethanol 7.5%, and the remainder is pure water.

[0021] The matrix material is poloxamer 407; the bioadhesive is hydroxypropyl methylcellulose; the heating material is n-docosane@calcium carbonate phase change microcapsules; and the stabilizer is a 1:1 mixture of hydroxypropyl betacyclodextrin and poloxamer 407.

[0022] The n-docosane@calcium carbonate phase change microcapsules are obtained by emulsifying n-docosane with an emulsifier solution, reacting it with calcium chloride solution and sodium carbonate solution for 3 hours respectively, washing it three times with distilled water, and drying it under reduced pressure at 40°C for 24 hours.

[0023] The emulsifier is one or a mixture of two or more of sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS), and styrene-maleic anhydride copolymer (SMA); the emulsifier solution is prepared by adjusting the pH to 7-9 with citric acid solution or sodium hydroxide solution.

[0024] The mass ratio of the heating material core material (neo-dodecane) to the wall material (calcium carbonate) is 2:1.

[0025] The present invention also provides a method for preparing the aforementioned pharmaceutical composition, wherein the method for preparing the rectal in-situ heating gel comprises the following steps:

[0026] a. Weigh the raw materials according to the aforementioned proportions;

[0027] b. The compound extract of Sophora flavescens and Paeonia lactiflora is dissolved in water;

[0028] c. Add the matrix material and bioadhesive to the solution in step b, stir slightly, and place at a low temperature not exceeding 4°C until complete swelling.

[0029] d. Dissolve borneol in ethanol, add stabilizer and stir until clear;

[0030] e. Add the solution from step d to the solution from step c and stir to mix well;

[0031] f. Add the heating material to the solution in step e and grind it evenly to obtain the final product.

[0032] The present invention also provides the use of the pharmaceutical composition in the preparation of a medicament for rectal administration to treat chronic prostatitis.

[0033] This invention also provides the use of n-docosane@calcium carbonate phase change microcapsules in the preparation of excipients for the preparation of rectally administered heating materials.

[0034] Traditional Chinese medicine (TCM) believes that the core pathogenesis of chronic prostatitis lies in damp-heat and qi stagnation in the prostate and surrounding tissues. Clinically, the basic treatment methods are often clearing heat and removing dampness, and promoting blood circulation and removing blood stasis. A drug formula is selected for rectal administration to directly target the affected area. The drug composition of this invention consists of three Chinese herbs: Sophora flavescens, Paeonia lactiflora, and Borneol. Sophora flavescens is the principal herb, clearing heat and drying dampness, and can eliminate damp-heat in the prostate and surrounding tissues. Paeonia lactiflora is the assistant herb, having the effects of clearing heat and cooling blood, dispersing blood stasis and relieving pain, and can relieve pain and discomfort caused by blood stasis in the prostate and surrounding tissues. Borneol has the effects of opening the orifices and refreshing the mind, clearing heat and relieving pain, and can assist Sophora flavescens and Paeonia lactiflora in clearing the prostate and enhancing the effects of clearing heat and relieving pain. The combined use of these three herbs exerts the effects of removing damp-heat stagnation in the prostate and dispersing blood stasis and relieving pain.

[0035] The pharmaceutical composition of this invention can be used clinically for sitz bath therapy. However, for the treatment of chronic prostatitis, commonly used rectal enemas and other dosage forms are still unsuitable for practical needs, mainly due to three problems: First, the treatment course for this type of disease is long, requiring medical staff to use specialized equipment for drug administration, which is extremely inconvenient; second, the drug cannot remain in the intestines, requiring patients to lie flat for a long time after administration to ensure the duration of drug action, and the duration of action is still limited, with uncontrollable fever; third, it is prone to leakage, staining clothing and affecting normal work and life. Therefore, to address the drug administration needs of chronic prostatitis, clinical research and development of new dosage forms are needed to enable drug delivery to the diseased tissue, thereby significantly improving the therapeutic effect.

[0036] The drug prepared in this invention as a rectal in-situ heating gel possesses temperature-controlled heating properties and bioadhesive performance. Compared with traditional decoction enemas, this formulation has suitable gel strength and bioadhesiveness, enabling it to adhere tightly to the rectum, with a long retention time, achieving targeted drug delivery and greatly improving the convenience of medication. It can remain in the rectum for a long time and continuously and stably release the active pharmaceutical ingredient and heat energy, effectively preventing drug leakage, greatly reducing the difficulty of drug delivery, and facilitating the drug to reach the diseased tissue. It has obvious advantages in targeted prostate drug delivery, providing a new dosage form for the treatment of chronic prostatitis.

[0037] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0038] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0039] Figure 1 Flowchart of the preparation process of the heating material in compound Sophora flavescens rectal in situ heating gel

[0040] Figure 2 Flowchart of the preparation process of compound Sophora flavescens rectal in situ heating gel

[0041] Figure 3 In vitro release diagram of active ingredients (where A represents the in vitro release result of matrine, and B represents the in vitro release result of paeoniflorin).

[0042] Figure 4 Graph of active ingredient permeation

[0043] Figure 5 The results of the heating performance are shown in the graph (where A to F are temperature-time curves repeated 6 times under the same conditions).

[0044] Figure 6 Rectal pathological examination results (where A, B, and C are rectal tissue sections of the control group, saline group, and experimental group 14 days after drug administration, respectively; D, E, and F are rectal tissue sections of the control group, saline group, and experimental group 7 days after drug withdrawal, respectively.)

[0045] Figure 7 Prostate tissue pathological examination results (where H, I, and J are prostate tissue sections from the blank group, saline group, and drug-treated group 14 days after drug administration, respectively; K, L, and M are prostate tissue sections from the blank group, saline group, and drug-treated group 7 days after drug withdrawal, respectively.)

[0046] Figure 8 Active ingredient drug concentration-time curve in prostate tissue (where A is the drug concentration-time curve of matrine in prostate tissue, and B is the drug concentration-time curve of paeoniflorin in prostate tissue). Detailed Implementation

[0047] Example 1: Preparation of Compound Sophora flavescens Rectal In-situ Heating Gel of the Present Invention

[0048] Prescription (based on 100g of finished gel)

[0049] Borneol 0.75g

[0050] 22g of compound extract of Sophora flavescens and Paeonia lactiflora (50g each)

[0051] Poloxamer 407 (matrix material) 5.41g

[0052] Hydroxypropyl methylcellulose (bioadhesive) 0.88g

[0053] Hydroxypropyl betacyclodextrin (stabilizer) 6g

[0054] n-Docosane@Calcium Carbonate Phase Change Microcapsules (Heating Material) 31.19g

[0055] 7.5g of ethanol

[0056] The rest is pure water.

[0057] Preparation process:

[0058] a. Weigh the raw materials according to the aforementioned proportions;

[0059] b. The compound extract of Sophora flavescens and Paeonia lactiflora is dissolved in water;

[0060] c. Add the matrix material and bioadhesive to the solution in step b, stir slightly, and place at 4°C until fully swollen;

[0061] d. Dissolve borneol in ethanol, add stabilizer and stir until clear;

[0062] e. Add the solution from step d to the solution from step c and stir to mix well;

[0063] f. Add the heating material to the solution in step e and grind it evenly to obtain the final product.

[0064] Example 2: Preparation of the Compound Sophora flavescens Rectal In-situ Heating Gel of the Present Invention

[0065] Prescription (based on 100g of finished gel)

[0066] Borneol 0.75g

[0067] 22g of compound extract of Sophora flavescens and Paeonia lactiflora (50g each)

[0068] Poloxamer 407 (matrix material) 5.71g

[0069] Hydroxypropyl methylcellulose (bioadhesive) 0.88g

[0070] Hydroxypropyl betacyclodextrin (stabilizer) 6g

[0071] n-Docosane@Calcium Carbonate Phase Change Microcapsules (Heating Material) 31.19g

[0072] 7.5g of ethanol

[0073] The rest is pure water.

[0074] Preparation process:

[0075] a. Weigh the raw materials according to the aforementioned proportions;

[0076] b. The compound extract of Sophora flavescens and Paeonia lactiflora is dissolved in water;

[0077] c. Add the matrix material and bioadhesive to the solution in step b, stir slightly, and place at 4°C until fully swollen;

[0078] d. Dissolve borneol in ethanol, add stabilizer and stir until clear;

[0079] e. Add the solution from step d to the solution from step c and stir to mix well;

[0080] f. Add the heating material to the solution in step e and grind it evenly to obtain the final product.

[0081] Example 3: Preparation of Compound Sophora flavescens Rectal In-situ Heating Gel of the Present Invention

[0082] Prescription (based on 100g of finished gel)

[0083] Borneol 0.75g

[0084] 22g of compound extract of Sophora flavescens and Paeonia lactiflora (50g each)

[0085] Poloxamer 407 (matrix material) 5.55g

[0086] Hydroxypropyl methylcellulose (bioadhesive) 0.84g

[0087] Hydroxypropyl betacyclodextrin (stabilizer) 6g

[0088] n-Docosane@Calcium Carbonate Phase Change Microcapsules (Heating Material) 30.97g

[0089] 7.5g of ethanol

[0090] The rest is pure water

[0091] Preparation process:

[0092] a. Weigh the raw materials according to the aforementioned proportions;

[0093] b. The compound extract of Sophora flavescens and Paeonia lactiflora is dissolved in water;

[0094] c. Add the matrix material and bioadhesive to the solution in step b, stir slightly, and place at 4°C until fully swollen;

[0095] d. Dissolve borneol in ethanol, add stabilizer and stir until clear;

[0096] e. Add the solution from step d to the solution from step c and stir to mix well;

[0097] f. Add the heating material to the solution in step e and grind it evenly to obtain the final product.

[0098] Example 4: Preparation of the compound extract of Sophora flavescens and Paeonia lactiflora in the compound Sophora flavescens rectal in situ heating gel of the present invention.

[0099] Using the extraction rate of key components and the yield of dry extract as indicators, single-factor experiments were conducted to investigate factors such as extraction solvent, time, number of extractions, solid-liquid ratio, drug concentration, and alcohol precipitation concentration. After screening out the key factors, a uniform design method was used to optimize key factors such as extraction time, solid-liquid ratio, and alcohol precipitation concentration based on a comprehensive weighted analysis of multiple indicators (subjective and objective factors) to select the optimal process conditions. The drying process was investigated using the dry powder yield and moisture content as indicators, examining the drying effects of methods such as atmospheric pressure drying, vacuum drying, freeze drying, and spray drying; the inlet air temperature in the spray drying process was also investigated. Finally, a preparation process for the compound Sophora flavescens extract was proposed. A draft quality standard was established for the obtained compound Sophora flavescens extract to achieve effective quality control.

[0100] The optimal preparation process of the compound Kushen decoction of this invention is as follows: material-to-liquid ratio 1:20, extraction twice, decoction for 120 min, concentration of the decoction to a medicinal material concentration of 2.0 g / mL, precipitation with 80% ethanol, and verification experiments in three batches yielded matrine, oxymatrine, and paeoniflorin contents of 0.15±0.01%, 0.70±0.04%, and 2.25±0.38%, respectively, with a comprehensive score of 95.06±0.19. Further drying was performed using spray drying at an inlet air temperature of 150℃, a flow rate of 3 mL / min, an atomization pressure of 40 mmHg, and a fan speed of 60%, resulting in a dried product with a moisture content of 5.03–5.99%, and matrine, oxymatrine, and paeoniflorin contents of 0.75%–0.78%, respectively.

[0101] The concentrations of the extract were between 3.55% and 4.12% and between 12.33% and 14.75%, indicating that the preparation process of this extract was reasonable, reliable, and stable. A thin-layer chromatography method was established for the identification of Paeonia lactiflora and Sophora flavescens in the compound Sophora flavescens extract, and control ranges for the content of moisture, matrine, oxymatrine, and paeoniflorin were determined, achieving effective control over the quality of the extract.

[0102] The daily dose of the raw materials before formulation is 4.4g of compound Sophora flavescens extract and 0.075g of borneol.

[0103] The following efficacy and pharmacological tests demonstrate the beneficial effects of this invention.

[0104] Example 1: Evaluation of the effect of different excipient dosages on the quality of the thermal gel

[0105] Twenty experimental groups of compound Sophora flavescens rectal in situ exothermic gel were set up, using Sophora flavescens, Paeonia lactiflora compound extract, borneol, poloxamer 407 (P407), hydroxypropyl methylcellulose (HP), and 220,000@calcium carbonate phase change microcapsules (MEPCMs) as raw materials and excipients; among them, the preparation method of 220,000@calcium carbonate phase change microcapsules is described in [link to documentation]. Figure 1 :

[0106] The main ingredients, Sophora flavescens and Paeonia lactiflora, were extracted in a compound form at a concentration of 22 g / 100 g, and borneol was added at a concentration of 0.75 g / 100 g. Heating gels were prepared according to the excipient amounts listed in Table 1. The preparation methods are detailed below. Figure 2 ;

[0107] Specifically, pure water was used, and appropriate amounts of each component were added to it in the following order: Sophora flavescens extract, Paeonia lactiflora extract, poloxamer 407, and hydroxypropyl methylcellulose. The drugs must be dissolved before adding subsequent components. The mixture was placed at 4°C until fully swollen. A borneol solution was then added (borneol dissolved in ethanol, followed by a 1:1 solution of hydroxypropyl betacyclodextrin and poloxamer 407, stirred until clear). Finally, the heating material was added and ground evenly. The adhesion force, yield strength, and temperature control time of each experimental group were measured.

[0108] Table 1: Results of index determination of compound Kushen rectal in situ heating gel prepared with different excipient dosages

[0109]

[0110] The results showed that the adhesion force of the thermosensitive gel prepared by mixing 28%–32% MEPCMs, 5%–7% P407, and 0.4%–1% HP ranged from 0.38±0.03 to 1.86±0.10 N, the yield strength ranged from 16.97±2.87 to 96.60±3.32 Pa, and the temperature control time ranged from 19.20±0.43 to 26.53±0.50 min. The experimental data were processed using the AHP-CRITIC weighted method, and a comprehensive score was calculated. The data were then imported into Design-Expert 11 software, and a quadratic polynomial regression was performed on the independent variables and their relationships to determine the goodness of fit (r²) of the fitted equation. 2 Using the confidence level (P) as the model evaluation criteria, the mathematical model obtained is as follows: Z = 74.35 + 7.94*X1 - 0.32*X2 + 4.26*X3 - 1.63*X1*X2 + 0.41*X1*X3 - 2.23*X2*X3 - 1.35*X1² - 0.77*X2² + 0.66*X3²;

[0111] (r 2 =0.9573, P<0.0001), from r 2 The p-value results show that the model fits well. Three representative excipient ratios were selected from the optimized formulation, and the optimal formulation was further screened through in vitro quality evaluation.

[0112] Experimental Example 2: Screening Experiment for the Optimal Formulation of Compound Sophora flavescens Rectal In-situ Heating Gel of the Present Invention

[0113] The three optimized formulations (i.e., Examples 1-3) will be comprehensively evaluated for their in vitro permeation and in vivo adhesion properties, as well as their irritation to rectal and prostate tissues, in order to determine the optimal formulation.

[0114] 1. Results of in vitro release

[0115] The results of the in vitro release rate study of the three optimized formulations are shown in Tables 2 and 3. Figure 3 As shown in the results, the cumulative release rate f2 values ​​of the active ingredients matrine and paeoniflorin in the three prescriptions are all greater than 50, indicating that there is no significant difference in the in vitro release rate among the prescriptions.

[0116] Table 2. Cumulative release percentage of matrine ( n=3)

[0117]

[0118] Table 3. Cumulative release percentage of paeoniflorin ( n=3)

[0119]

[0120] 2. Results of the examination on rectal retention

[0121] The retention times of each group are shown in Table 4. Independent samples t-test analysis of the data showed that the p-values ​​of the Compound Kushen Decoction Enema Group and the Compound Kushen Rectal In-situ Heating Gel Group were both less than 0.05, indicating significant differences. However, the p-values ​​of the three gel formulations were all greater than 0.05, indicating no significant differences. This suggests that the Compound Kushen Rectal In-situ Heating Gel effectively improves the leakage problem compared to traditional enema solutions, and all three formulations can remain in rats for approximately 6 hours. Since there were no significant differences in in vitro release rate and rectal retention time among the three preferred formulations, formulation 1, which had the highest comprehensive score (22.00% Compound Kushen Extract, 0.75% Borneol, 31.19% MEPCMs, 5.41% P40, 0.88% HPMC K4M, 6.00% HP-β-CD, 7.50% Ethanol, and 26.27% Water), was selected for subsequent studies on membrane permeability, temperature-controlled heating, irritation, and histokinetic properties.

[0122] Table 4. Retention of different formulations in rats ( n=6)

[0123]

[0124] Note: * indicates that all three gel prescription groups showed significant differences compared to the enema group.

[0125] 3. Results of membrane permeation performance evaluation

[0126] The results of the membrane permeation performance evaluation are shown in Table 5. Figure 4 As shown, more than 85% of the active ingredients can pass through within 12 hours, indicating that the compound Kushen rectal in-situ heating gel can effectively pass through the rectal membrane. Therefore, it is speculated that rectal administration can enable the active ingredients to reach the prostate tissue.

[0127] Table 5 Results of the permeabilities of matrine and paeoniflorin (matrine and paeoniflorin) n=6)

[0128]

[0129] 4. Results of the heat dissipation performance test

[0130] Results of the heat dissipation performance test are as follows Figure 5 As shown, after anesthesia, rats were kept warm. The rectal temperature in the blank group remained stable at 35.4–36.1℃. After enema with warm compound Kushen decoction, the rectal temperature rapidly rose to 40.0–42.0℃ and returned to the rat's baseline rectal temperature within 50 seconds. After administration of compound Kushen rectal in-situ heating gel, the rectal temperature rose to 39.7–41.3℃. Compared with the enema group, the temperature was more stable, the cooling process was more gradual, and the temperature remained higher than the baseline rectal temperature for about 200 seconds, with a longer duration of continuous heating. However, the controlled-temperature exothermic time was still significantly shorter than that of the phase change microcapsules, mainly for two reasons: Firstly, to facilitate real-time monitoring of rectal temperature changes in rats after administration, the rats were anesthetized. Although some warming measures were taken, the measured rectal temperature was still slightly lower than normal. Secondly, the amount of gel used was relatively small due to the limited rectal capacity of the rats. Furthermore, the effervescent properties of the formulation are closely related to the dosage and are greatly affected by environmental interference. Therefore, the effervescent time measured in this experiment was shorter than that in actual clinical applications. Although it could not fully simulate and reflect the effervescent conditions in actual clinical applications, the results show that the compound Kushen rectal in-situ effervescent gel exhibits a smoother heating and cooling process and a longer duration of effervescence compared to traditional warm liquid enemas, thus initially achieving the expected performance of continuous and gentle exothermic release.

[0131] 5. Results of the irritation test

[0132] Rectal and prostate tissues from each group were examined macroscopically after 14 days of continuous administration and 7 days of drug withdrawal. No obvious deformation or necrosis was found. The scoring summary table is shown in Table 6, 3-10. The experimental results indicate that it has a mild irritant effect on the rectum but no irritant effect on the prostate. Pathological examination results are as follows: Figure 6 , Figure 7As shown, the rectal mucosa in the blank group was intact, the glandular structure was clear, and there was no inflammatory cell infiltration. However, the saline group and the experimental group showed a small amount of inflammatory cell infiltration after 14 days of drug administration, which improved after 7 days of drug withdrawal. The prostate and its glandular lumen structure were intact in the blank group, saline group, and experimental group, and no glandular atrophy or inflammatory cell infiltration was observed. No obvious pathological changes were caused.

[0133] Table 6 Summary of Rectal Mucosal Irritation Scores ( n=6)

[0134]

[0135] Table 7 Summary of Prostate Irritation Scores ( n=6)

[0136]

[0137] Experimental Example 3: Performance evaluation of Compound Kushen Rectal In-situ Heating Gel; Evaluation of Prostate-Targeted Drug Delivery Effect; Histokinetic Study Results:

[0138] The concentrations of matrine and paeoniflorin in prostate tissue at different time points after drug administration were measured in different drug groups. The results are shown in Tables 8 and 9. Drug concentration-time curves were plotted as follows. Figure 8 As shown.

[0139] Table 8 Summary of Matrine Concentration Results in Prostate Tissue n=6)

[0140]

[0141] Note: * indicates a statistically significant difference (P<0.05) between the gel administration group and the solution enema group.

[0142] Table 9 Summary of Paeoniflorin drug concentration results in prostate tissue ( n=6)

[0143]

[0144] Note: * indicates a statistically significant difference (P<0.05) between the gel administration group and the solution enema group.

[0145] The relevant data were imported into DAS 3.0 pharmacokinetic software, and a non-compartmental model was used for analysis and calculation to obtain the main pharmacokinetic parameters of matrine and paeoniflorin in different administration groups. The results are shown in Tables 10 and 11. The data show that the AUC and C2 of matrine in the prostate tissue of the compound matrine rectal in-situ gel administration group... max The levels of paeoniflorin in the prostate tissue of the compound kushen rectal in situ gel administration group were 1.8 times and 1.2 times higher than those of the solution enema group, respectively;max The results were 1.1 times and 2.3 times that of the solution enema group, respectively, indicating that the compound Kushen rectal in-situ heating gel rectal administration, compared with the traditional solution enema, allows more active ingredients to reach the prostate tissue, which can significantly increase the drug concentration and has the advantage of targeted drug delivery to the prostate.

[0146] Table 10 Summary of pharmacokinetic parameters of matrine administered in different dosage forms ( n=6)

[0147]

[0148] Table 11 Summary of pharmacokinetic parameters of paeoniflorin administered in different dosage forms ( n=6)

[0149]

Claims

1. A pharmaceutical composition for treating chronic prostatitis, characterized in that: The pharmaceutical composition is a rectal in-situ heating gel, which is prepared from the following raw materials in weight percentages: The compound extract of Sophora flavescens and Paeonia lactiflora contains 22%, borneol 0.75%, matrix material 5%~8%, bio-adhesive 0.3%~1.5%, heating material 28%~36%, stabilizer 5%~7%, ethanol 7.5%, and the remainder is pure water; The weight ratio of Sophora flavescens, Paeonia lactiflora and borneol is: 8-12 parts Sophora flavescens, 8-12 parts Paeonia lactiflora and 0.006-0.09 parts borneol; The compound extract of Sophora flavescens and Paeonia lactiflora is an aqueous extract of Sophora flavescens and Paeonia lactiflora. The matrix material is one or a mixture of two or more of the following: Carbomer 940, Poloxamer 407, and sodium alginate. The bioadhesive is one or a mixture of two or more of methylcellulose, hydroxypropyl methylcellulose, chitosan, and carbomer 934; The heating material is n-dodecane@calcium carbonate phase change microcapsules (MEPCMs); The n-docosane@calcium carbonate phase change microcapsules are obtained by emulsifying n-docosane with an emulsifier solution, reacting it with calcium chloride solution and sodium carbonate solution for 3 h respectively, washing it three times with distilled water, and drying it under reduced pressure at 40 ℃ for 24 h. The emulsifier is one or a mixture of two or more of sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS), and styrene-maleic anhydride copolymer (SMA); the emulsifier solution is prepared by adjusting the pH to 7-9 with citric acid solution or sodium hydroxide solution. The mass ratio of the heating material core material (n-dodecane) to the wall material (calcium carbonate) is 2:

1. The stabilizer is one or a mixture of two or more of poloxamer 407, glycerin, polyethylene glycol 400, and hydroxypropyl betacyclodextrin.

2. The pharmaceutical composition according to claim 1, characterized in that: The rectal in-situ heating gel is prepared from the following raw materials in the indicated weight percentages: The compound extract of Sophora flavescens and Paeonia lactiflora contains 22%, borneol 0.75%, matrix material 5%~7%, bio-adhesive 0.4%~1%, heating material 28%~32%, stabilizer 6%, ethanol 7.5%, and the remainder is pure water; The matrix material is poloxamer 407; the bioadhesive is hydroxypropyl methylcellulose; and the heating material is n-dodecane@calcium carbonate phase change microcapsules.

3. A method for preparing the pharmaceutical composition according to claim 1 or 2, characterized in that: The preparation method of the rectal in-situ heating gel includes the following steps: a. Weigh the raw materials according to the aforementioned proportions; b. The compound extract of Sophora flavescens and Paeonia lactiflora dissolves in water; c. Add the matrix material and bioadhesive to the solution in step b, stir slightly, and place at a low temperature not exceeding 4°C until complete swelling. d. Dissolve borneol in ethanol, add stabilizer and stir until clear; e. Add the solution from step d to the solution from step c and stir to mix well; f. Add the heating material to the solution in step e and grind it evenly to obtain the final product.

4. Use of the pharmaceutical composition according to claim 1 or 2 in the preparation of a medicament for rectal administration to treat chronic prostatitis.

5. Use of n-docosane@calcium carbonate phase change microcapsules as excipients in the preparation of excipients for rectal administration of heating materials; The n-docosane@calcium carbonate phase change microcapsules are obtained by emulsifying n-docosane with an emulsifier solution, reacting it with calcium chloride solution and sodium carbonate solution for 3 h respectively, washing it three times with distilled water, and drying it under reduced pressure at 40 ℃ for 24 h. The emulsifier is one or a mixture of two or more of sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS), and styrene-maleic anhydride copolymer (SMA); the emulsifier solution is prepared by adjusting the pH to 7-9 with citric acid solution or sodium hydroxide solution. The mass ratio of the heating material core material (neo-dodecane) to the wall material (calcium carbonate) is 2:1.

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