Ketoconazole suppository composition and preparation and quality control method thereof

Abstract

The invention relates to a ketoconazole suppository as well as a preparation method and a quality control method thereof. The ketoconazole suppository has the dissolution rates of any one or more of the following items: (1) the cumulative dissolution percentage of ketoconazole in 30 minutes, which is measured under the condition that the pH is 4.0-5.5, is greater than or equal to 15%; (2) the cumulative dissolution percentage of ketoconazole in 1 hour measured under the condition that the pH is 4.0-5.5 is greater than or equal to 30%; (3) the 30-minute cumulative dissolution percentage of ketoconazole measured under the condition that the pH is 4.0 is greater than or equal to 40%; and (4) the cumulative dissolution percentage of ketoconazole in 1 hour measured under the condition of pH 4.0 is greater than or equal to 60%.

Description

Technical Field

[0001] The invention relates to a ketoconazole suppository composition and a preparation method and a quality control method thereof. Background Art

[0002] Vulvovaginal candidiasis refers to vulvovaginitis caused by Candida albicans (Candida albicans) infection in women. It is also called candidal vaginitis, fungal vaginitis, vulvovaginal candidiasis, etc. Its English name is vulvovaginal candidiasis, abbreviated as VVC. Recurrent vulvovaginal candidiasis (RVVC) refers to 4 or more symptomatic VVC attacks within 1 year, and mycological examination is positive. Clinical manifestations include recurrent vulvar itching, burning pain, vulvar redness and swelling, increased leucorrhea, and may also be accompanied by symptoms such as urinary pain and sexual intercourse pain, which makes patients restless and extremely painful, seriously affecting their quality of life.

[0003] VVC has a high incidence rate, with about 10% to 15% of asymptomatic women colonized with Candida albicans in the vagina. 70% to 75% of women have suffered from vulvovaginal candidiasis at least once in their lives, 50% of whom have experienced more than one recurrence, and about 5% to 10% may develop into RVVC.

[0004] At present, clinical treatment methods are still mainly based on the use of azole antifungal drugs, and local treatment mainly uses imidazoles, including clotrimazole, miconazole, econazole and ketoconazole. These drugs are highly toxic to the liver when taken orally, so pharmacists have developed them into topical vaginal preparations, including vaginal suppositories, vaginal effervescent tablets, vaginal soft capsules, etc. However, according to existing literature reports and clinical feedback, the cure rate of these first-line clinical treatment drugs is not ideal. The commonly used clotrimazole and miconazole nitrate have a total clinical efficacy of only about 60%, and the efficacy is even lower for severe VVC and RVVC. Studies have shown that the cure rate of miconazole and other drugs for RVVC is only about 40%. Although the effect of ketoconazole suppositories is relatively good, the cure rate is usually only about 70%, and the disease is prone to recurrence after being cured.

[0005] Faced with the long-standing clinical status of low cure and high recurrence of VVC and RVVC, doctors are accustomed to it and generally believe that this disease is a clinically refractory disease, which is attributed to the patient's hygiene and living habits, immune function, pathogen resistance and other factors. Therefore, for patients who are not cured and relapse, clinicians take measures based on clinical experience to increase the dosing cycle, prolong the use of drugs, or add oral antifungal drugs for topical use and combined treatment, and even frequently change different types of antifungal drugs, but these measures are still ineffective. Moreover, this long-term and repeated treatment greatly enhances the drug resistance of pathogens, resulting in the weakening or even ineffectiveness of the therapeutic effects of many commonly used drugs. It is necessary to increase the dose to enrich the drug concentration locally in order to achieve the desired therapeutic effect. For example, the dosage of miconazole nitrate suppository has increased from the initial preparation unit of 200mg / piece to 400mg / piece, and then to the current 1200mg / piece, but the effect is still unsatisfactory. And due to the increase in dosage, the surge in adverse reactions has led to the inability of patients to tolerate it and it was eventually withdrawn from the market. Oral drugs are generally used for half a year, and long-term use can cause severe liver toxicity. In summary, although VVC and RVVC are common gynecological diseases, they have the characteristics of high incidence, low cure rate, easy recurrence, and symptoms affecting life. They are a difficult problem faced in the field of gynecological disease treatment. Summary of the invention

[0006] Faced with the difficult problem in the field of gynecological disease treatment, the inventor of the present application has carried out long-term gynecological disease treatment clinical observation and visit, and the low efficacy problem of the medicine for the treatment of candidal vaginitis has been studied in large quantities, and the existing suppositories made of the imidazole antifungal drugs such as miconazole nitrate, ketoconazole, clotrimazole, which are found to be badly water-soluble, can soften completely in 60min during its melting process, but it is slowly melted as can be seen by the naked eye, and more fine powders are sunk into the bottom of the cup during the process. In addition, the inventor of the present application has found that the mixed state of different materials coexisting with granular state can be directly observed under the electron microscope of ketoconazole vaginal suppository, and in the ketoconazole suppository DSC curve recorded by differential scanning calorimeter (DSC), the ketoconazole endothermic peak still exists. These inspection results mean that in the existing antifungal suppositories, the principal drug and the matrix are in a mechanical mixed state, and the principal drug is not completely dissolved in the matrix.

[0007] Furthermore, the inventors of the present application investigated the dissolution of the commonly used vaginal suppositories of miconazole nitrate, ketoconazole and clotrimazole, and found that these suppositories generally have the problem of low solubility. The details are as follows:

[0008] Comparison of the dissolution rates of different imidazole antifungal drugs in vaginal external preparations

[0009] [Test drugs] Clotrimazole suppositories (specification: 500 mg), miconazole nitrate suppositories (specification: 200 mg), ketoconazole suppositories (specification: 400 mg)

[0010]

Dissolution test conditions

[0011] pH 5.5 acetate buffer, paddle method 30r / min, dissolution medium 500ml; 37℃±0.5℃, sampling time points are 0.5, 1, 1.5, 2, 4h, 24h, content is calculated by external standard method, the results are shown in Table 1.

[0012] Table 1

[0013]

[0014] As can be seen from the data in Table 1, the dissolution rates of all suppositories are low. Even for the ketoconazole suppository with the best dissolution, its cumulative dissolution percentage in 4 hours under pH 5.5 is less than 5%.

[0015] The inventor of the present application has found that the microstructure of ketoconazole suppositories affects their dissolution. The high-dissolution ketoconazole suppositories provided by the present invention show a DSC spectrum different from that of existing ketoconazole suppositories. It can be clearly seen that the absorption peak of ketoconazole disappears, and the presence of ketoconazole raw material crystals can no longer be seen under electron microscope observation, which means that in the ketoconazole suppositories of the present invention, the active ingredient ketoconazole is not simply evenly dispersed in the excipients, but forms a solid dispersion with the excipients having a different microstructure from the previous ketoconazole suppositories. These ketoconazole suppositories with different microstructures have improved dissolution and more stable therapeutic effects, and can significantly improve the cure rate of patients and reduce the recurrence rate.

[0016] In the pharmaceutical field, oral drugs have been studied for their dissolution and included in the pharmacopoeia and quality standards, but there is no precedent for suppositories, which are external preparations, to have their dissolution included in the statutory standards. In particular, there is no precedent for improving the dissolution of insoluble or poorly soluble antifungal drugs and including them in the standards.

[0017] Generally speaking, in the study of oral drug preparations, it is generally believed that if the purpose of good drug absorption is to be achieved, the solubility of the drug needs to be improved. However, for suppositories, the dissolution inspection has not been included in the quality control standards at home and abroad, and the relationship between dissolution and efficacy has not been studied and established. The present invention, based on the discovery of the intrinsic connection between suppository dissolution and efficacy, explores and establishes a dissolution detection method that can distinguish the quality levels of drug preparations and has high recognition, and screens out high-dissolution high-efficiency preparations through this method, greatly improving the clinical efficacy of gynecological antibacterial suppositories and reducing the recurrence rate.

[0018] At the same time, we also unexpectedly discovered that at the effective therapeutic dose of the drug, the higher the solubility of the suppository, the higher the clinical cure rate.

[0019] The present invention is based on the above research and aims to provide a suppository for treating gynecological diseases with higher solubility and more stable therapeutic effect, and a quality control method for the suppository. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The dissolution curves of different ketoconazole suppositories at pH 2.2.

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

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

[0023] Figure 4 The dissolution curves of different ketoconazole suppositories at pH 5.5.

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

[0025] Figure 6 is an electron microscope photo, Figure 6 A、6B、 Figure 6 C are electron microscope photos of the auxiliary materials of Preparation Examples 8, 5, and 4, respectively. Figure 6 D is an electron microscope photo of ketoconazole raw material. Figure 6 E, 6F, Figure 6 G are electron microscope pictures of ketoconazole suppositories of Preparation Examples 8, 5 and 4, respectively.

[0026] Figure 7 is the DSC spectrum, where Figure 7 A, 7B and 7C are the DSC curves of the auxiliary materials of Preparation Examples 8, 5 and 4 respectively. Figure 7 D is the DSC curve of ketoconazole raw material, Figure 7 7E, 7F, and 7G are the DSC spectra of ketoconazole suppositories prepared in Preparation Examples 8, 5, and 4, respectively. DETAILED DESCRIPTION

[0027] In one aspect, the present invention provides a ketoconazole suppository with high solubility, which has any one or more of the following solubilities:

[0028] (1) The cumulative dissolution rate of ketoconazole measured at pH 4.0 to 5.5 over 30 minutes is ≥ 15%, preferably ≥ 30%;

[0029] (2) The cumulative dissolution rate of ketoconazole in one hour measured at pH 4.0 to 5.5 is ≥30%, preferably ≥50%;

[0030] (3) The cumulative dissolution rate of ketoconazole measured at pH 4.0 within 30 minutes is ≥40%.

[0031] (4) The cumulative dissolution rate of ketoconazole measured at pH 4.0 in 1 hour is ≥ 60%.

[0032] In the present application, the range of pH 4.0 to 5.5 includes both end values ​​and any point value within the range. The point values ​​can be listed but 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, 5.5, etc.

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

[0034] The dispersible matrix refers to a matrix that can be made into a solid dispersion system with ketoconazole. The dispersible matrix used for the high-dissolution suppository 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, preferably PEG1000.

[0035] The dispersible base of the high-solubility suppository of the present invention preferably further contains S40 (polyoxyl (40) stearate).

[0036] The composition of the present invention may further contain pharmaceutically acceptable antioxidants, preservatives and other auxiliary materials as required.

[0037] In some embodiments, the high-dissolution ketoconazole suppository of the present invention has a DSC spectrum in which the endothermic peak of ketoconazole disappears.

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

[0039] The present invention has found that for ketoconazole suppositories, preparation by a melt process or a melt extrusion process is important to obtain a high dissolution rate.

[0040] Therefore, another aspect of the present invention provides a new method for preparing ketoconazole suppositories, which is a melting method, and a solid dispersion is obtained by controlling key process parameters, wherein the key parameters are a melting temperature of 50°C to 80°C, preferably 60°C to 70°C, preferably keeping warm and stirring at the melting temperature for 30 to 60 minutes, more preferably a circulating temperature of 60±5°C, and further preferably a perfusion temperature of 60±5°C.

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

[0042] The dissolution determination method may be a method known in the field of pharmaceutical analysis, such as a paddle method, a basket method, or a flow cell method.

[0043] The inventors of the present application investigated the dissolution of ketoconazole vaginal suppositories and found that the suppositories had the highest dissolution at pH 2.2, but suppositories of different prescriptions all dissolved well under this pH condition, so the solubility of suppositories could not be effectively distinguished under this pH condition. The dissolution amount under pH 7.0 was extremely low, which was also not conducive to distinction. In contrast, under pH 4.0-5.5, the solubility of ketoconazole suppositories of different prescriptions could be well distinguished.

[0044] Therefore, another aspect of the present invention provides a novel method for controlling the quality of ketoconazole suppositories, the method comprising controlling the dissolution of ketoconazole in the ketoconazole suppository 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 of the ketoconazole suppository at pH 4.0-5.5 is controlled to be ≥15% in 30 minutes, and / or the cumulative dissolution percentage of the active ingredient in 1 hour is controlled to be ≥30%.

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

[0047] In some more specific embodiments, the suppository is a ketoconazole suppository, and its solubility reaches any one or more of the following:

[0048] (1) The cumulative dissolution rate of ketoconazole measured at pH 4.0 to 5.5 over 30 minutes is ≥ 15%, preferably ≥ 30%;

[0049] (2) The cumulative dissolution rate of ketoconazole in one hour measured at pH 4.0 to 5.5 is ≥30%, preferably ≥50%;

[0050] (3) The cumulative dissolution rate of ketoconazole measured at pH 4.0 in 30 minutes is ≥40%;

[0051] (4) The cumulative dissolution rate of ketoconazole measured at pH 4.0 in 1 hour is ≥ 60%.

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

[0053] Example

[0054] The present invention is further described below by means of specific examples, but the present invention is not limited to these specific examples, and any changes or modifications that do not depart from the gist of the present invention fall within the scope of the present invention.

[0055] Example 1 A dissolution method was established to conduct a comparative study on the dissolution of different ketoconazole suppositories.

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

[0057] Table 2

[0058]

[0059] *S40 Stearic acid polyoxyl (40) ester

[0060] *PEG

[0061] The ketoconazole is crushed and passed through a 100-mesh sieve for later use; each auxiliary material in the prescribed amount is weighed and placed in a mixing pot, heated to 50°C to 80°C to melt, and stirred to mix the auxiliary materials evenly; then the sieved ketoconazole in the prescribed amount is weighed, added to the molten auxiliary materials while stirring, and kept warm and stirred at 60°C to 70°C for 30 to 60 minutes to mix the materials evenly; filling, controlling the circulation temperature to 60±5°C and the pouring temperature to 60±5°C, pouring; cooling and sealing.

[0062] Dissolution testing:

[0063] Dissolution conditions: 900 ml of solutions with different pH values, such as pH 2.2 hydrochloric acid solution, 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, with a rotation speed of 50 revolutions per minute. The operation was carried out according to the method, and samples were taken after 30 minutes and 1 hour.

[0064] Test solution: Take 10 ml of the dissolution solution and filter it.

[0065] Reference solution: Take about 20 mg of ketoconazole reference substance, weigh accurately, add appropriate amount of methanol to dissolve and dilute to make a solution containing about 0.4 mg per 1 ml.

[0066] Chromatographic conditions: octadecylsilane bonded silica gel as filler; 0.2% diisopropylamine methanol solution-0.5% ammonium acetate solution (77:23) as mobile phase; detection wavelength at 240nm. Injection volume 10μl.

[0067] System suitability requirements: The number of theoretical plates calculated based on the ketoconazole peak should be no less than 2000.

[0068] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the dissolution amount of each particle by the peak area according to the external standard method.

[0069] The dissolution test results are shown in Tables 2-6. They show that at pH 2.2, the dissolution of each preparation is the highest, but the characteristics of the preparations cannot be effectively distinguished. Preparations with different prescriptions can be dissolved well under this condition (Tables 3 and Figure 1 ); however, under the condition of pH 4.0-5.5, the dissolution of different preparations can be better distinguished (Table 4-6 and Figure 2-4 ); after the pH was raised to 7.0, the ability to distinguish the dissolution of different preparations decreased (Table 7 and Figure 5 ).

[0070] Table 3 Comparison of dissolution of different ketoconazole suppositories at pH 2.2

[0071]

[0072] Table 4 Comparison of dissolution of different ketoconazole suppositories at pH 4.0

[0073]

[0074] Table 5 Comparison of dissolution of different ketoconazole suppositories at pH 4.5

[0075]

[0076] Table 6 Comparison of dissolution of different ketoconazole suppositories at pH 5.5

[0077]

[0078] Table 7 Comparison of dissolution of different ketoconazole suppositories at pH 7.0

[0079]

[0080] 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 have no distinguishing power for the quality of preparations and have no practical value.

[0081] Example 2 Phase Identification and Comparative Analysis of Ketoconazole Suppositories

[0082] In this embodiment, after observing the microstructure of ketoconazole suppositories by electron microscope and differential scanning calorimeter (DSC), it is found that the ketoconazole suppositories with low solubility are only mechanically mixed with the ketoconazole raw material and the matrix, and the coexistence of different substances in granular form can be directly observed. The DSC spectrum of the high-solubility ketoconazole suppositories prepared by the present invention is different, and the absorption peak of ketoconazole can be clearly seen to disappear; and the electron microscope also shows that the high-solubility suppositories can no longer see the presence of ketoconazole raw material crystals under the microscope, which means that the raw materials in the high-solubility suppositories are no longer simply evenly dispersed in the excipients. The specific detection method is as follows:

[0083] Method 1: Electron Microscopy (SEM-EDS)

[0084] Experimental method: Sigma500-Xflash6|60 was used with an accelerating voltage of 2.0KV, a beam current of 400-800μA, and a working distance of about 8mm. After confirming that the sample was focused, the image was gradually magnified from 500 times to 10,000 times, and scanned and photographed. The results are as follows: Figure 6 As shown, the ketoconazole raw material crystals can no longer be seen in the high-solubility suppository under the microscope, which means that the active ingredient in the high-solubility suppository is no longer simply evenly dispersed in the excipients, but forms a special solid dispersion with the excipients.

[0085] Method 2: Differential Scanning Calorimetry (DSC)

[0086] Differential scanning calorimetry was used to analyze the physical state of the drug in the preparation. Ketoconazole raw material, mixed matrix, physical mixture and high-dissolution ketoconazole suppository were used as samples.

[0087] Take appropriate amount of each sample, put it into the crucible, weigh it accurately, cover the crucible, put it under the tablet press, set the method, nitrogen protection, equilibrium temperature 25℃, heating rate 10℃ / min, end point temperature 230℃. Put the sample crucible and reference crucible on the furnace, and then start data collection. Figure 7 shown.

[0088] Depend on Figure 7 It can be seen that the endothermic peak of ketoconazole in the low-solubility preparation still exists, while the endothermic peak of ketoconazole in the high-solubility preparation has completely disappeared.

[0089] Table 8 Phase Identification

[0090]

[0091] Table 9 Effect of different preparation methods on the quality of suppositories with the same prescription

[0092]

[0093]

[0094] Note: “ / ” indicates not yet launched

[0095] Solid dispersion ketoconazole suppositories were prepared by screening melt extrusion, mechanical dispersion, solvent, melting, grinding, fluidized bed, solvent-melting, melt condensation and other methods. It was found that the solid dispersions prepared by mechanical dispersion and grinding had poor stability. In the long-term sample observation, the solubility of the solid dispersions in 12 months would decrease to a certain extent. Electron microscope observation showed that fine ketoconazole raw material crystals were precipitated, and the physical stability was not good. DSC also showed the appearance of ketoconazole endothermic peaks, indicating that the solid dispersion may have aged during the long-term storage process. The solid dispersion ketoconazole suppositories prepared by solvent, fluidized bed, solvent-melting, melt condensation and other methods were stable for at least 12 months, but the long-term stability of 24 months also showed the aging of the solid dispersion. Surprisingly, the solid dispersion suppositories prepared by melting and melt extrusion processes not only had good dispersion effects, but also maintained long-term stability. It is an ideal preparation process for industrial production.

[0096] Effect verification example

[0097] In order 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.

[0098] 1. Experiments with volunteer subjects

[0099] A total of 54 women with confirmed candidal vaginitis detected by health care institutions were included. They reported that they had obvious itching symptoms, were restless, and could not sit still for 10 minutes. The symptom score was 3 and they were willing to use this study drug for testing.

[0100] Dosage: 1 tablet per person, specification: 400 mg, Usage: Take out the suppository, lie flat, bend your knees, and insert the suppository as deep into the vagina as possible.

[0101] [Trial drug]

[0102] Ketoconazole Suppository No. 1: Low-dissolution Ketoconazole Suppository (Preparation Example 8)

[0103] Ketoconazole Suppository No. 2: Medium Dissolution Ketoconazole Suppository (Preparation Example 5)

[0104] Ketoconazole Suppository No. 3: High Solubility Ketoconazole Suppository (Preparation Example 4)

[0105] Efficacy evaluation: Compare whether there are differences in the time it takes for the subjects' itching symptoms to improve and the number of people who improve after using the three preparations.

[0106] *Symptom Rating Criteria

[0107] 0 points: Symptoms such as itching and pain disappear, and movement is no longer affected;

[0108] 1 point: The itching sensation is significantly relieved and the patient can sit still for more than 30 minutes;

[0109] 2 points: the itching sensation is relieved, and the sitting time is longer than 10 minutes but less than 30 minutes;

[0110] 3 points: The itching sensation is still obvious and it is impossible to sit still for 10 minutes

[0111] The results showed that the subjects who used high-solubility suppositories had rapid improvement in symptoms. Among the 18 subjects whose symptom scores were all 3, 38.9% of the symptoms disappeared and their movements were not affected (0 points) 1 hour after administration, and 94.4% of the symptoms were improved (symptom score 0 points + 1 point + 2 points). Although the symptoms were improved by medium- and low-solubility ketoconazole suppositories, 66.7% and 44.4% respectively, the improvement was limited. The subjects still felt uncomfortable symptoms such as itching, and the proportion of people who improved was significantly less. There was a significant difference between the high-solubility group and the medium-solubility ketoconazole suppository group (P = 0.0352), and there was a very significant difference between the high-solubility group and the low-solubility ketoconazole suppository group (P = 0.0011).

[0112] It can be seen that the higher the solubility, the faster the onset of effect, and the earlier the therapeutic effect can be exerted, which has important clinical significance.

[0113] Table 10 Follow-up after administration

[0114]

[0115]

[0116] 2. Clinical research

[0117] [Test population]

[0118] Microscopic examination combined with fungal culture of vaginal secretions showed that the results met the diagnostic criteria for Candida vaginitis, and the subjects had not used antifungal drugs or other drugs in the month before enrollment.

[0119] [Number of test cases] 90 cases

[0120] [Trial drug]

[0121] Ketoconazole Suppository No. 1: Low-dissolution Ketoconazole Suppository (Preparation Example 8)

[0122] Ketoconazole Suppository No. 2: Medium Dissolution Ketoconazole Suppository (Preparation Example 5)

[0123] Ketoconazole Suppository No. 3: High Solubility Ketoconazole Suppository (Preparation Example 4)

[0124]

Dosage regimen

[0125] A total of 90 patients were divided into three groups at a ratio of 1:1:1 and used ketoconazole suppository No. 1, ketoconazole suppository No. 2 and ketoconazole suppository No. 3 respectively. Each patient was given the drug only once, and then followed up one week and four weeks after the medication, and fungal culture was performed to evaluate the treatment effect.

[0126]

Efficacy evaluation criteria

[0127] Cure: negative after one week and after four weeks (proven by clinical symptoms, microscopic examination results, and culture results);

[0128] Late cure: negative only after four weeks (clinical symptoms, microscopic examination results, culture results);

[0129] Ineffective: Positive after one week and four weeks (as evidenced by clinical symptoms, microscopic examination results, and culture results)

[0130] Relapse: negative in the first week, positive in the fourth week (clinical symptoms, microscopic examination results, culture results);

[0131] Total clinical efficacy = (cured + late cured) / total number of people × 100%

[0132] [Test results] The test statistical data are shown in Tables 11 and 12.

[0133] Table 11: Efficacy evaluation results (n=90)

[0134]

[0135] Table 12 Mycological test results

[0136]

[0137] From the above data, we can see that the improvement of clinical symptoms is higher in ketoconazole suppository group 3 than in ketoconazole suppository group 2 and higher in ketoconazole suppository group 1. The total effective rate of high-solubility ketoconazole suppositories is as high as (25+4) / 30×100%=96.7%, which is much higher than the effective rates of 76.7% and 63.3% of medium- and low-solubility ketoconazole suppositories, respectively. 2 The test showed that there was a significant difference between the high dissolution group and the medium dissolution group, p = 0.0227 < 0.05, and there was a very significant difference between the high dissolution group and the low dissolution group, p = 0.0012 < 0.01. However, there was no significant difference between the medium and low dissolution groups (p = 0.2598 > 0.05). It can be seen that only when the dissolution reaches a certain level can the clinical cure rate be significantly improved.

[0138] At the same time, we also noticed that the ketoconazole suppository with improved dissolution not only improved the clinical efficacy, but also significantly reduced the recurrence rate of candidal vaginitis. From this experiment, we learned that the recurrence rate, which was as high as more than 30%, was reduced to 1 / 25×100%=4.0%, and the clinical treatment effect was more effective (P<0.05); in terms of fungal clearance rate, it can be seen that low and medium concentrations cannot completely clear the fungus within the treatment cycle, while the high-concentration ketoconazole suppository has a fungal clearance rate of up to 100%, with significant effect.

[0139] In summary, it can be seen that the ketoconazole dissolution investigation method established by the present invention can effectively distinguish the quality levels of preparations, and find the intrinsic connection between the dissolution of the preparations and the clinical cure rate. The high-solubility preparations obtained by the dissolution index can significantly improve the effective rate of clinical treatment and improve the disease treatment effect.

Claims

1. Ketoconazole suppositories having any one or more of the following dissolution rates: (1) The cumulative dissolution rate of ketoconazole measured at pH 4.0 to 5.5 over 30 minutes is ≥ 15%, preferably ≥ 30%; (2) The cumulative dissolution rate of ketoconazole in one hour measured at pH 4.0 to 5.5 is ≥30%, preferably ≥50%; (3) The cumulative dissolution rate of ketoconazole measured at pH 4.0 in 30 minutes is ≥40%; (4) The cumulative dissolution rate of ketoconazole measured at pH 4.0 in 1 hour is ≥ 60%.

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

3. The suppository according to claim 2, wherein the melting temperature is 50°C to 80°C, the mixture is stirred at the melting temperature for 30 to 60 minutes, the circulation temperature is 60±5°C, and the infusion temperature is 60±5°C.

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

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

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

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

8. The method of claim 7, comprising measuring the dissolution rate of ketoconazole suppositories in the pH range of 4.0 to 5.

5.

9. The method of claim 8, wherein the solubility of the ketoconazole suppository reaches any one or more of the following: (1) The cumulative dissolution rate of ketoconazole measured at pH 4.0 to 5.5 over 30 minutes is ≥ 15%, preferably ≥ 30%; (2) The cumulative dissolution rate of ketoconazole in one hour measured at pH 4.0 to 5.5 is ≥30%, preferably ≥50%; (3) The cumulative dissolution rate of ketoconazole measured at pH 4.0 within 30 minutes is ≥40%. (4) The cumulative dissolution rate of ketoconazole measured at pH 4.0 in 1 hour is ≥ 60%.

10. A method for preparing ketoconazole suppositories, comprising preparing the suppositories by a melting method or a melt extrusion method, wherein the melting temperature is preferably 50°C to 80°C, the suppositories are stirred at the melting temperature for 30 to 60 minutes, the circulation temperature is 60±5°C, and the infusion temperature is 60±5°C.

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