Ketoconazole suppository composition, preparation method therefor, and quality control method therefor

Abstract

The present invention relates to a ketoconazole suppository, a preparation method therefor, and a quality control method therefor. The ketoconazole suppository exhibits a dissolution rate of any one or two or more of the following: (1) the cumulative dissolution percentage of ketoconazole measured at pH 4.0-5.5 for 30 minutes is ≥ 15%; (2) the cumulative dissolution percentage of ketoconazole measured at pH 4.0-5.5 for 1 hour is ≥ 30%; (3) the cumulative dissolution percentage of ketoconazole measured at pH 4.0 for 30 minutes is ≥ 40%; and (4) the cumulative dissolution percentage of ketoconazole measured at pH 4.0 for 1 hour is ≥ 60%.

Description

Ketoconazole suppository composition, its preparation and quality control methods

[0001] This application claims priority to Chinese application No. 202411462586.3, filed on October 18, 2024, entitled "Ketoconazole Suppository Composition and Preparation and Quality Control Method Thereof". Technical Field

[0002] This invention relates to ketoconazole suppository compositions and their preparation and quality control methods. Background Technology

[0003] Vulvovaginal candidiasis refers to vulvovaginitis caused by infection with Candida albicans, also known as yeast infection, fungal vaginitis, or vulvovaginal candidiasis. Recurrent vulvovaginal candidiasis (RVVC) is defined as four or more symptomatic VVC episodes within one year, with a positive mycological examination. Clinical manifestations include recurrent vulvar itching and burning, vulvar redness and swelling, increased vaginal discharge, and may also be accompanied by dysuria and dyspareunia, causing significant discomfort and impacting the patient's quality of life.

[0004] Vulvovaginal candidiasis (VVC) has a high incidence rate, with approximately 10%–15% of asymptomatic women having Candida colonization in the vagina. 70%–75% of women will experience vulvovaginal candidiasis at least once in their lifetime, with 50% experiencing more than one recurrence, and approximately 5%–10% potentially developing into RVVC.

[0005] Currently, clinical treatment primarily relies on pyrrole antifungal drugs, while local treatment mainly uses imidazoles, including clotrimazole, miconazole, econazole, and ketoconazole. These drugs have significant oral hepatotoxicity, therefore pharmacists have developed them into vaginal suppositories, effervescent tablets, and soft capsules. However, according to existing literature and clinical feedback, the cure rate of these first-line treatments is not ideal. The overall clinical efficacy of commonly used drugs like clotrimazole and miconazole nitrate is generally only around 60%, with even lower efficacy for severe VVC and RVVC. Studies have shown that miconazole has a cure rate of only about 40% for RVVC, and while ketoconazole suppositories are relatively more effective, the cure rate is usually only around 70%, and the disease is prone to recurrence after treatment.

[0006] Faced with the long-standing clinical reality of low cure rate and high recurrence rate of VVC and RVVC, doctors have become accustomed to it, generally considering it a clinically refractory disease, attributing it to factors such as patients' hygiene habits, immune function, and drug resistance of pathogens. Therefore, for patients with uncured or recurrent cases, clinicians, based on clinical experience, have adopted measures such as increasing the dosing cycle, extending the duration of drug use, or combining topical and oral antifungal medications, and even frequently changing different types of antifungal drugs. However, these measures remain ineffective. Moreover, this long-term, repeated treatment significantly enhances pathogen resistance, weakening or even rendering many commonly used drugs ineffective, necessitating increased dosages to achieve local drug concentration and thus the desired therapeutic effect. For example, miconazole nitrate suppositories have increased in dosage from the initial 200mg / suppository to 400mg / suppository, and now to 1200mg / suppository, but the effect remains unsatisfactory. Furthermore, due to the increased dosage, adverse reactions have surged, leading to intolerance among patients and eventual withdrawal from the market. Oral medications are generally used for six months; long-term use can cause serious hepatotoxicity. In conclusion, although VVC and RVVC are common gynecological diseases, they are characterized by high incidence, low cure rate, easy recurrence, and symptoms that affect quality of life, making them a challenging issue in the treatment of gynecological diseases. Summary of the Invention

[0007] In response to the challenges in the treatment of gynecological diseases, the inventors of this application conducted long-term clinical observations and visits regarding the treatment of gynecological diseases, and carried out extensive research on the low efficacy of drugs for treating fungal vaginitis. They discovered that existing suppositories made from imidazole antifungal drugs such as miconazole nitrate, ketoconazole, and clotrimazole, which have poor water solubility, although completely softening within 60 minutes during their melting process, exhibit slow melting visible to the naked eye, with more fine powdery substances settling to the bottom of the container. Furthermore, the inventors found that electron microscopy of ketoconazole vaginal suppositories directly reveals a mixed state of different substances coexisting in a particulate form, and the endothermic peak of ketoconazole is still present in the DSC curve of the ketoconazole suppositories measured by differential scanning calorimetry (DSC). These findings indicate that in existing antifungal drug suppositories, the active ingredient and the matrix are in a mechanically mixed state, and the active ingredient is not completely dissolved in the matrix.

[0008] Furthermore, the inventors of this application investigated the dissolution rates of commonly used miconazole nitrate, ketoconazole, and clotrimazole vaginal suppositories, and found that these suppositories generally suffer from low dissolution rates. Specifically:

[0009] Comparison of dissolution rates of different imidazole antifungal drugs in their vaginal topical formulations

[0010] [Experimental Drugs] Clotrimazole Suppositories (500mg), Miconazole Nitrate Suppositories (200mg), Ketoconazole Suppositories (400mg)

[0011] Dissolution test conditions

[0012] Acetate buffer solution with pH 5.5 was prepared by paddle method at 30 rpm and dissolution medium of 500 ml at 37℃ ± 0.5℃. Sampling time points were 0.5, 1, 1.5, 2, 4 h and 24 h. The content was calculated by external standard method. The results are shown in Table 1.

[0013] Table 1

[0014] As shown in Table 1, the dissolution rates of all suppositories were low. Even the ketoconazole suppository, which had the best dissolution rate, had a cumulative dissolution percentage of less than 5% after 4 hours at pH 5.5.

[0015] The inventors of this application have discovered that the microstructure of ketoconazole suppositories affects their dissolution rate. The high-dissolution ketoconazole suppositories provided by this invention exhibit a different DSC spectrum than existing ketoconazole suppositories. The disappearance of the ketoconazole absorption peak is clearly visible, and electron microscopy reveals no trace of ketoconazole raw material crystals. This indicates that in the ketoconazole suppositories of this invention, the active ingredient ketoconazole is not simply and uniformly dispersed in the excipients, but rather forms a solid dispersion with the excipients that has a different microstructure than previous ketoconazole suppositories. These ketoconazole suppositories with different microstructures have improved dissolution rate and more stable efficacy, significantly improving the cure rate and reducing the recurrence rate.

[0016] In the pharmaceutical field, dissolution studies of oral medications have been conducted and incorporated into pharmacopoeias and quality standards. However, there is no precedent for including dissolution in legal standards for suppositories, which are used as topical preparations. This is especially true for antifungal drugs for which improved dissolution rates have been incorporated into standards.

[0017] Generally, in oral drug formulation research, it is generally believed that improving drug dissolution is necessary to achieve good drug absorption. However, for suppositories, neither domestic nor international standards have incorporated dissolution testing into quality control standards, and the relationship between dissolution and efficacy has not been studied or established. This invention, based on the discovery of the intrinsic link between suppository dissolution and efficacy, explores and establishes a highly discriminative dissolution testing method capable of differentiating drug formulation quality levels. This method is used to screen for high-dissolution, high-efficacy formulations, significantly improving the clinical efficacy of gynecological antibacterial suppositories and reducing recurrence rates.

[0018] Meanwhile, we also unexpectedly discovered that, at effective therapeutic doses of medication, the higher the dissolution rate of the suppository, the higher its clinical cure rate.

[0019] This invention is based on the above research. The invention aims to provide a suppository for treating gynecological diseases with higher dissolution and more stable efficacy, as well as a quality control method for such suppository. Attached Figure Description

[0020] Figure 1 shows the dissolution curves of different ketoconazole suppositories under pH 2.2 conditions.

[0021] Figure 2 shows the dissolution curves of different ketoconazole suppositories at pH 4.0.

[0022] Figure 3 shows the dissolution curves of different ketoconazole suppositories at pH 4.5.

[0023] Figure 4 shows the dissolution curves of different ketoconazole suppositories under pH 5.5 conditions.

[0024] Figure 5 shows the dissolution curves of different ketoconazole suppositories at pH 7.0.

[0025] Figure 6 shows electron microscope images, where Figures 6A, 6B, and 6C are electron microscope images of the excipients used in preparation examples 8, 5, and 4, respectively; Figure 6D is an electron microscope image of the ketoconazole raw material; and Figures 6E, 6F, and 6G are electron microscope images of the ketoconazole suppositories used in preparation examples 8, 5, and 4, respectively.

[0026] Figure 7 shows the DSC spectra, where Figures 7A, 7B, and 7C are the DSC curves of the excipients in Preparation Examples 8, 5, and 4, respectively; Figure 7D is the DSC curve of the ketoconazole raw material; and Figures 7E, 7F, and 7G are the DSC spectra of the ketoconazole suppositories in Preparation Examples 8, 5, and 4, respectively. Detailed Implementation

[0027] This invention provides a ketoconazole suppository with high dissolution rate, having any one or more of the following dissolution rates:

[0028] (1) The cumulative dissolution percentage of ketoconazole after 30 minutes, measured under pH conditions of 4.0 to 5.5, is ≥15%, preferably ≥30%;

[0029] (2) The cumulative dissolution percentage of ketoconazole after 1 hour, measured under pH conditions of 4.0 to 5.5, is ≥30%, preferably ≥50%;

[0030] (3) The cumulative dissolution percentage of ketoconazole after 30 minutes was ≥40% as measured under pH 4.0 conditions.

[0031] (4) The cumulative dissolution percentage of ketoconazole after 1 hour was ≥60% as measured under pH 4.0 conditions.

[0032] In this application, the pH range of 4.0 to 5.5 includes both extreme values ​​and any point value within that range. Point values ​​may include, but are not limited to, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, and 5.5.

[0033] The high dissolution suppository of the present invention comprises ketoconazole, a dispersible matrix, and optionally added pharmaceutically acceptable excipients.

[0034] A dispersible matrix refers to a matrix that can form a solid dispersion with ketoconazole. The dispersible matrix used in the high dissolution suppositories of the present invention preferably comprises any one or a combination of two or more of PEG (polyethylene glycol) 600, PEG800, PEG1000, PEG1500, PEG1540, PEG3350, PEG4000, PEG6000, and PEG8000, with PEG1000 being the most preferred.

[0035] The dispersible matrix of the high dissolution suppository of the present invention preferably further comprises S40 (poly(40) stearate).

[0036] The compositions of the present invention may further include pharmaceutically acceptable excipients such as antioxidants and preservatives as needed.

[0037] In some embodiments, the high-dissolution ketoconazole suppositories of the present invention have a DSC spectrum showing the disappearance of the ketoconazole endothermic peak.

[0038] Methods for preparing solid dispersions include mechanical dispersion, solvent method, solvent-melt method, grinding method, fluidized bed method, melt method, melt extrusion method, melt coagulation method, and many other methods.

[0039] This invention has found that for ketoconazole suppositories, preparation by melt method or melt extrusion method is important for obtaining a high dissolution rate.

[0040] Therefore, another aspect of the present invention provides a novel method for preparing ketoconazole suppositories. This method is a melt method, in which a solid dispersant is obtained by controlling key process parameters. The key parameters are a melting temperature of 50°C to 80°C, preferably 60°C to 70°C, preferably a stirring at the melting temperature for 30 to 60 minutes, more preferably a circulating temperature of 60±5°C, and even more preferably an infusion temperature of 60±5°C.

[0041] Another aspect of the present invention provides a method for quality control of suppositories, the method comprising determining the dissolution rate of the suppositories.

[0042] The dissolution determination method can be a well-known method in the field of drug analysis, such as the paddle method, basket method, or flow-through cell method.

[0043] The inventors of this application investigated the dissolution rate of ketoconazole vaginal suppositories and found that the suppositories dissolved best at pH 2.2. However, suppositories of different formulations all dissolved well under this pH condition, making it impossible to effectively distinguish the dissolution rate of suppositories at this pH. Furthermore, the dissolution rate was extremely low at pH 7.0, which was also unfavorable for differentiation. In contrast, the dissolution rate of ketoconazole suppositories of different formulations was well distinguished under pH conditions of 4.0–5.5.

[0044] Therefore, another aspect of the present invention provides a novel method for controlling the quality of ketoconazole suppositories, the method comprising controlling the ketoconazole suppositories in the pH range of 4.0 to 5.5, preferably at pH 4.0.

[0045] In some embodiments, the cumulative dissolution percentage of the active ingredient in the ketoconazole suppository is controlled to be ≥15% over 30 minutes and / or ≥30% over 1 hour under pH 4.0–5.5 conditions.

[0046] In some more specific embodiments, the cumulative dissolution percentage of the active ingredient in the suppository is controlled to be ≥30% over 30 minutes and / or ≥50% over 1 hour at pH 4.0–5.5; the cumulative dissolution percentage of ketoconazole is controlled to be ≥40% over 30 minutes and / or ≥60% over 1 hour at pH 4.0.

[0047] In some more specific embodiments, the suppository is a ketoconazole suppository with a dissolution rate of any one or more of the following:

[0048] (1) The cumulative dissolution percentage of ketoconazole after 30 minutes, measured under pH conditions of 4.0 to 5.5, is ≥15%, preferably ≥30%;

[0049] (2) The cumulative dissolution percentage of ketoconazole after 1 hour, measured under pH conditions of 4.0 to 5.5, is ≥30%, preferably ≥50%;

[0050] (3) The cumulative dissolution percentage of ketoconazole after 30 minutes was ≥40% when measured at pH 4.0;

[0051] (4) The cumulative dissolution percentage of ketoconazole after 1 hour was ≥60% as measured under pH 4.0 conditions.

[0052] The gynecological vaginal suppositories of the present invention are preferably prepared by melt or melt extrusion. In some specific embodiments, the melting temperature in the melt method is 50°C to 80°C, preferably 60°C to 70°C, and preferably the temperature is maintained and stirred for 30 to 60 minutes, more preferably the circulation temperature is 60±5°C, and even more preferably the infusion temperature is 60±5°C.

[0053] Example

[0054] The present invention is further illustrated by specific embodiments below, but the present invention is not limited to these specific embodiments. Any changes or modifications that do not depart from the spirit of the present invention fall within the scope of the present invention.

[0055] Example 1 establishes a dissolution method and conducts a comparative study on the dissolution of different ketoconazole suppositories.

[0056] Ketoconazole suppositories were prepared according to the prescriptions shown in Table 2.

[0057] Table 2

[0058] *S40 stearic acid polyoxyethylene (40) ester

[0059] *PEG (Polyethylene Glycol)

[0060] Crush ketoconazole and pass it through a 100-mesh sieve for later use. Weigh the prescribed amount of each excipient and place them in a mixing pot. Heat the pot to 50℃~80℃ to melt the excipients and stir to mix them evenly. Then weigh the prescribed amount of sieved ketoconazole and add it to the melted excipients while stirring. Keep the pot at 60℃~70℃ and stir for 30~60 minutes to mix the materials evenly. Fill the pot, controlling the circulating temperature at 60±5℃ and the filling temperature at 60±5℃. Fill the pot, cool, and seal.

[0061] Dissolution testing:

[0062] Dissolution conditions: 900 ml of solutions with different pH values ​​(pH 2.2 hydrochloric acid, pH 4.0 acetate buffer, pH 4.5 acetate buffer, pH 5.5 acetate buffer, and pH 7.0 phosphate buffer) were used as dissolution media. The dissolution speed was 50 rpm. The procedure was followed, and samples were taken after 30 minutes and 1 hour.

[0063] Test solution: Take 10 ml of the dissolution solution, filter it, and the solution is obtained.

[0064] Reference solution: Weigh approximately 20 mg of ketoconazole reference standard accurately, dissolve and dilute with an appropriate amount of methanol to prepare a solution containing approximately 0.4 mg per ml.

[0065] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; the mobile phase was 0.2% diisopropylamine in methanol and 0.5% ammonium acetate in a solution (77:23); the detection wavelength was 240 nm. The injection volume was 10 μl.

[0066] System suitability requirements: The theoretical plate number, calculated based on the ketoconazole peak, should be no less than 2000.

[0067] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the amount dissolved per particle based on peak area using the external standard method.

[0068] The dissolution test results, as shown in Table 2-6, indicate that at pH 2.2, the dissolution of each formulation is the highest, but it cannot effectively distinguish the characteristics of the formulations. Formulations with different formulations can all dissolve well under these conditions (Table 3 and Figure 1). However, at pH 4.0–5.5, there is a better ability to distinguish the dissolution of different formulations (Table 4-6 and Figure 2-4). When the pH is increased to 7.0, the ability to distinguish the dissolution of different formulations decreases again (Table 7 and Figure 5).

[0069] Table 3 Comparison of dissolution rates of different ketoconazole suppositories under pH 2.2 conditions

[0070] Table 4. Comparison of dissolution rates of different ketoconazole suppositories at pH 4.0.

[0071] Table 5 Comparison of dissolution rates of different ketoconazole suppositories at pH 4.5

[0072] Table 6 Comparison of dissolution rates of different ketoconazole suppositories at pH 5.5

[0073] Table 7 Comparison of dissolution rates of different ketoconazole suppositories at pH 7.0

[0074] Experimental conclusion: The quality levels of different ketoconazole suppositories can be effectively distinguished by measuring the dissolution rate at pH 4.0–5.5, while other pH conditions do not have the ability to distinguish the quality of the formulation and have no practical value.

[0075] Example 2: Phase Identification and Comparative Analysis of Ketoconazole Suppositories

[0076] In this embodiment, microscopic observation of the ketoconazole suppositories using electron microscopy and differential scanning calorimetry (DSC) revealed that the low-dissolution ketoconazole suppositories were merely a mechanical mixture of ketoconazole raw material and matrix, with the coexistence of different substances in particulate form being directly observable. In contrast, the high-dissolution ketoconazole suppositories prepared in this invention exhibited a different DSC spectrum, clearly showing the disappearance of the ketoconazole absorption peak. Electron microscopy also revealed that the high-dissolution suppositories showed no visible ketoconazole raw material crystals under the microscope, indicating that the raw material in the high-dissolution suppositories was no longer simply uniformly dispersed within the excipients. Specific detection methods are as follows:

[0077] Method 1: Electron Microscopy (SEM-EDS)

[0078] Experimental Method: A Sigma 500-Xflash 6|60 was used with an accelerating voltage of 2.0 kV, a beam current of 400–800 μA, and a working distance of approximately 8 mm. After confirming sample focusing, the magnification was gradually increased from 500x to 10,000x, and images were taken at each magnification. The results are shown in Figure 6. It is evident that the ketoconazole raw material crystals are no longer visible under the microscope in the high-dissolution suppositories. This indicates that the active ingredient in the high-dissolution suppositories is no longer simply and uniformly dispersed in the excipients, but rather forms a special solid dispersion with the excipients.

[0079] Method 2: Differential Scanning Calorimeter (DSC)

[0080] Differential scanning calorimetry was used to analyze the physical state of the drug in the formulation. Ketoconazole raw material, mixed matrix, physical mixture, and high-dissolution ketoconazole suppositories were used as samples.

[0081] Take appropriate amounts of each sample and place them in crucibles, weighing them precisely. Cover the crucibles and place them under a tablet press. Set the following parameters: nitrogen protection, equilibrium temperature 25℃, heating rate 10℃ / min, and endpoint temperature 230℃. Place the sample crucibles and reference crucibles on the furnace for data acquisition. The results are shown in Figure 7.

[0082] As shown in Figure 7, the endothermic peak of ketoconazole still exists in the low dissolution formulation, while the endothermic peak of ketoconazole has completely disappeared in the high dissolution formulation.

[0083] Table 8 Phase Identification

[0084] Table 9. Effects of different preparation methods on suppository quality for the same formulation.

[0085] Note: " / " indicates that the activity has not been carried out.

[0086] Solid dispersion ketoconazole suppositories were prepared using various methods, including melt extrusion, mechanical dispersion, solvent method, melt method, grinding method, fluidized bed method, solvent-melt method, and melt coagulation method. It was found that solid dispersions prepared by mechanical dispersion and grinding methods exhibited poor stability; their dissolution rate decreased significantly after 12 months of long-term observation. Electron microscopy revealed the precipitation of fine ketoconazole raw material crystals, indicating poor physical stability. DSC also showed an endothermic peak in ketoconazole, suggesting aging of the solid dispersion during long-term storage. While solid dispersion ketoconazole suppositories prepared by solvent method, fluidized bed method, solvent-melt method, and melt coagulation method remained stable for at least 12 months, aging of the solid dispersion and formulation was observed after 24 months. Surprisingly, solid dispersion suppositories prepared by melt and melt extrusion processes not only showed good dispersion but also maintained long-term stability, making them ideal for industrial production.

[0087] Effect Verification Example

[0088] To further verify the intrinsic relationship between dissolution and efficacy, we conducted a clinical comparative study on ketoconazole suppositories with high, medium, and low dissolution rates.

[0089] 1. Experiment with test volunteers

[0090] Fifty-four women diagnosed with candidal vaginitis by health institutions were included. They reported significant itching, restlessness, and inability to sit upright for more than 10 minutes. Their symptom scores were all 3, and they were willing to use the drug in this study for testing.

[0091] Dosage regimen: 1 suppository per person, specification: 400mg, usage: remove the suppository, lie flat, bend both knees, and insert the suppository as deep as possible into the vagina.

[0092] [Experimental Drug]

[0093] Ketoconazole Suppository No. 1: Low Dissolution Ketoconazole Suppository (Preparation Example 8)

[0094] Ketoconazole Suppository No. 2: Medium Dissolution Ketoconazole Suppository (Preparation Example 5)

[0095] Ketoconazole Suppository No. 3: High Dissolution Ketoconazole Suppository (Preparation Example 4)

[0096] Efficacy assessment: Compare the time it takes for subjects to experience improvement in itching symptoms and the number of subjects who experience improvement after using the three formulations.

[0097] *Symptom Scoring Criteria

[0098] 0 points: Symptoms such as itching and pain have disappeared, and mobility is no longer affected;

[0099] 1 point: The itching sensation is significantly reduced and one can sit upright for more than 30 minutes;

[0100] 2 points: Itching is relieved, and the sitting time is longer than 10 minutes but not more than 30 minutes;

[0101] 3 points: The itching is still obvious, and it is impossible to sit upright for 10 minutes.

[0102] The results showed that subjects using high-dissolution suppositories experienced rapid symptom improvement. Of the 18 subjects with an initial symptom score of 3, 38.9% experienced symptom disappearance one hour after administration, with no impact on mobility (0 score), and 94.4% showed symptom improvement (symptom score 0 + 1 + 2). While medium- and low-dissolution ketoconazole suppositories did improve symptoms (66.7% and 44.4% respectively), the improvement was limited; subjects still experienced discomfort such as itching, and the proportion of those experiencing improvement was significantly smaller. There was a significant difference between the high-dissolution and medium-dissolution ketoconazole suppositories groups (P = 0.0352), and a highly significant difference between the high-dissolution and low-dissolution ketoconazole suppositories groups (P = 0.0011).

[0103] It is evident that higher dissolution rate leads to faster onset of action and earlier therapeutic effect, which has significant clinical implications.

[0104] Table 10 Follow-up status after drug administration

[0105] 2. Clinical research

[0106] [Participant Population]

[0107] Microscopic examination combined with fungal culture of vaginal secretions showed results that met the diagnostic criteria for candidal vaginitis, and the subjects had not used antifungal drugs or other medications in the month prior to enrollment.

[0108] [Number of Cases] 90 cases

[0109] [Experimental Drug]

[0110] Ketoconazole Suppository No. 1: Low Dissolution Ketoconazole Suppository (Preparation Example 8)

[0111] Ketoconazole Suppository No. 2: Medium Dissolution Ketoconazole Suppository (Preparation Example 5)

[0112] Ketoconazole Suppository No. 3: High Dissolution Ketoconazole Suppository (Preparation Example 4)

[0113] [Dosage Regimen]

[0114] Ninety patients were randomly divided into three groups in a 1:1:1 ratio and administered ketoconazole suppositories No. 1, No. 2, and No. 3, respectively. Each patient received only one dose. Follow-up was conducted one week and four weeks after administration to evaluate the treatment effect by performing fungal cultures.

[0115] [Efficacy Evaluation Criteria]

[0116] Cure: Negative results were obtained after one week and four weeks (proven by clinical symptoms, microscopic examination, and culture results);

[0117] Late-stage cure: It took four weeks to test negative (proven by clinical symptoms, microscopic examination results, and culture results);

[0118] Invalid: Positive results at both one week and four weeks (proven by clinical symptoms, microscopic examination, and culture results).

[0119] Relapse: Negative in the first week, positive in the fourth week (proven by clinical symptoms, microscopic examination results, and culture results);

[0120] Overall clinical effectiveness rate = (cured + later-stage cured) / total number of people × 100%

[0121] [Experimental Results] The experimental statistical data are shown in Tables 11 and 12.

[0122] Table 11. Results of therapeutic efficacy evaluation (n=90)

[0123] Table 12 Results of fungal tests

[0124] The data above show that the improvement in clinical symptoms was greater in the ketoconazole suppository group 3 than in the ketoconazole suppository group 2, which in turn was greater in the ketoconazole suppository group 1. The overall effective rate of the high-dissolution ketoconazole suppository was as high as (25+4) / 30×100% = 96.7%, far exceeding the effective rates of 76.7% and 63.3% for the medium- and low-dissolution ketoconazole suppositories, respectively. X-rays were used to further investigate the efficacy of the suppositories. 2 The tests showed a significant difference between the high and medium dissolution groups (p = 0.0227 < 0.05), and a highly significant difference between the high and low dissolution groups (p = 0.0012 < 0.01). However, there was no significant difference between the medium and low dissolution groups (p = 0.2598 > 0.05). This demonstrates that only when dissolution reaches a certain level can the clinical cure rate be significantly improved.

[0125] We also noted that the improved dissolution rate of ketoconazole suppositories not only enhanced clinical efficacy but also significantly reduced the recurrence rate of candidal vaginitis. This trial showed that the recurrence rate, previously as high as 30%, was reduced to 1 / 25 × 100% = 4.0%, demonstrating superior clinical treatment efficacy (P < 0.05). Regarding fungal clearance, low and medium concentrations were not completely eradicated within the treatment cycle, while high-concentration ketoconazole suppositories achieved a fungal clearance rate of up to 100%, demonstrating significant efficacy.

[0126] In summary, the ketoconazole dissolution testing method established by this invention can effectively distinguish the quality levels of formulations and discover the intrinsic relationship between the dissolution rate of formulations and the clinical cure rate. Formulations with high dissolution rates obtained through dissolution index can significantly improve the effectiveness of clinical treatment and improve the treatment effect of diseases.

Claims

1. Ketoconazole suppositories, which have any one or more of the following dissolution characteristics: (1) The cumulative dissolution percentage of ketoconazole after 30 minutes, measured under pH conditions of 4.0 to 5.5, is ≥15%, preferably ≥30%; (2) The cumulative dissolution percentage of ketoconazole after 1 hour, measured under pH conditions of 4.0 to 5.5, is ≥30%, preferably ≥50%; (3) The cumulative dissolution percentage of ketoconazole after 30 minutes was ≥40% when measured at pH 4.0; (4) The cumulative dissolution percentage of ketoconazole after 1 hour was ≥60% as measured under pH 4.0 conditions.

2. The suppository according to claim 1 is prepared by melt method or melt extrusion method, preferably by melt method.

3. The suppository according to claim 2, wherein the melting temperature is 50℃~80℃, the suppository is kept at the melting temperature and stirred for 30~60 minutes, the circulating temperature is 60±5℃, and the infusion temperature is 60±5℃.

4. The suppository according to any one of claims 1-3, wherein the active ingredient ketoconazole forms a solid dispersion with the matrix, and the DSC spectrum of the solid dispersion shows the disappearance of the endothermic peak of ketoconazole.

5. The suppository according to any one of claims 1-4, wherein the suppository comprises poly(40) stearate (S40) ester and polyethylene glycol (PEG) as a matrix, preferably PEG1000.

6. A method for quality control of suppositories, which includes determining the dissolution rate of the suppositories.

7. The method of claim 6, wherein the suppository is a ketoconazole suppository.

8. The method of claim 7, wherein the method comprises determining the dissolution rate of ketoconazole suppositories in the pH range of 4.0 to 5.

5.

9. The method of claim 8, wherein the dissolution rate of the ketoconazole suppositories reaches any one or more of the following: (1) The cumulative dissolution percentage of ketoconazole after 30 minutes, measured under pH conditions of 4.0 to 5.5, is ≥15%, preferably ≥30%; (2) The cumulative dissolution percentage of ketoconazole after 1 hour, measured under pH conditions of 4.0 to 5.5, is ≥30%, preferably ≥50%; (3) The cumulative dissolution percentage of ketoconazole after 30 minutes was ≥40% as measured under pH 4.0 conditions. (4) The cumulative dissolution percentage of ketoconazole after 1 hour was ≥60% as measured under pH 4.0 conditions.

10. A method for preparing ketoconazole suppositories, wherein the suppositories are prepared by melt method or melt extrusion method, preferably with a melting temperature of 50℃~80℃, stirring at the melting temperature for 30~60 minutes, a circulating temperature of 60±5℃, and an infusion temperature of 60±5℃.

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