Stable and efficient ketoconazole phospholipid complex cream and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to stable and efficient ketoconazole phospholipid complex cream and a preparation method thereof. The ketoconazole phospholipid complex emulsifiable paste is prepared from ketoconazole, phospholipid, an oily matrix, a water-based matrix and optional auxiliary materials such as an emulsifying agent and an antioxidant. The ketoconazole and phospholipid complex is prepared from ketoconazole and phospholipid under a certain condition, the physical and chemical stability of ketoconazole is improved, and the phospholipid complex has a selective effect on skin and a penetration promoting effect on drugs, so that the curative effect of the drugs is improved. According to the invention, ketoconazole is prepared into the phospholipid complex and then prepared into the cream, so that the stability and curative effect of the ketoconazole cream can be improved at the same time, and the clinical use defects caused by poor physical and chemical stability and poor stratum corneum permeability of ketoconazole are fundamentally solved.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to a stable and efficient ketoconazole phospholipid complex cream and a preparation method thereof. Background Art

[0002] Ketoconazole is a synthetic imidazole derivative, a broad-spectrum, highly effective antifungal drug. Its mechanism of action is to inhibit the biosynthesis of ergosterol in fungal cell membranes, affect the permeability of cell membranes, and inhibit their growth. Ketoconazole can be used to treat superficial and deep fungal diseases, such as skin and nail tinea, vaginal candidiasis, gastrointestinal fungal infections, and systemic infections caused by Candida albicans, Coccidioides, and Histoplasma.

[0003] Ketoconazole cream is an external preparation with a huge market consumer group and good market application prospects. However, the currently available ketoconazole cream has the following problems: first, ketoconazole is not easily soluble in water or oil, the physical stability of the preparation is poor, and the drug is easy to precipitate during storage, affecting its use; second, ketoconazole itself has poor chemical stability, and the drug is easy to change color, affecting its efficacy; third, ketoconazole mainly exerts its therapeutic effect by penetrating into the lipid-rich cells under the stratum corneum, but its stratum corneum permeability is poor, resulting in unsatisfactory efficacy. These defects greatly limit the clinical application of ketoconazole cream.

[0004] In view of the shortcomings of existing ketoconazole cream, domestic and foreign scholars have conducted extensive research on ketoconazole cream.

[0005] In order to solve the problem of poor solubility of ketoconazole, Chinese patent document CN105250219A discloses a ketoconazole drug-loaded micelle, ketoconazole and monomethoxy polyethylene glycol-polyvalerolactone are dissolved in acetone, and micelles are prepared by thin film hydration method. Although this method is simple to operate, has uniform particle size distribution, and overcomes the defect of low water solubility of ketoconazole, the stability of the micelle is poor, and the chemical stability of the pharmacologically active substance cannot be maintained for a long time.

[0006] In order to improve the efficacy of ketoconazole cream, Chinese patent documents CN103432148A and CN103417557A disclose a compound ketoconazole cream, in which ketoconazole is used in combination with clobetasol propionate and neomycin sulfate to improve anti-inflammatory and antibacterial activity. However, long-term use of the drug containing corticosteroids will cause adverse reactions such as capillary dilation, epidermal thinning, and skin atrophy, and the cream has many ingredients and a complicated preparation process.

[0007] In summary, the problems of improving the stability of ketoconazole cream preparations, breaking through the stratum corneum limitation of ketoconazole, and improving the absorption of ketoconazole in the skin stratum corneum have not been solved, and the development of ketoconazole cream still faces huge challenges. Summary of the invention

[0008] The purpose of the present invention is to solve the deficiencies of the existing preparation technology, provide a stable and efficient ketoconazole phospholipid complex cream, and provide a preparation method of the cream.

[0009] The inventor has previously conducted research and found that the phospholipid complex technology has a unique advantage in improving drug solubility. Combining drugs with phospholipids under suitable conditions to form phospholipid complexes can increase drug fat solubility without changing the chemical structure and pharmacological action of drugs and lecithin. The present invention prepares ketoconazole and lecithin into ketoconazole phospholipid complexes under certain conditions, thereby improving the solubility of ketoconazole and further improving its physicochemical stability. At the same time, since the phospholipid complex has a selective effect on the skin, it has a penetration-promoting effect on drugs and also improves the efficacy of ketoconazole cream.

[0010] The first aspect of the present invention provides a stable and efficient ketoconazole phospholipid complex cream, which contains ketoconazole as an active ingredient and further includes lecithin, an oil phase matrix, an aqueous phase matrix, an emulsifier, and an antioxidant; wherein the amount of ketoconazole is 0.5% to 3% w / w, the amount of lecithin is 1% to 6% w / w, the amount of the emulsifier is 2% to 5% w / w, the amount of the antioxidant is 0.1% to 0.5% w / w, the oil phase matrix is ​​8% to 12% w / w, and the balance is the aqueous phase matrix.

[0011] Furthermore, the ketoconazole phospholipid complex cream is prepared by the following formula:

[0012]

[0013] Furthermore, the ketoconazole phospholipid complex cream is prepared by the following formula:

[0014]

[0015]

[0016] Furthermore, the ketoconazole phospholipid complex cream is prepared by the following formula:

[0017]

[0018] In a preferred embodiment of the present invention, the ketoconazole phospholipid complex cream is prepared by the following formula:

[0019]

[0020] Furthermore, the lecithin is selected from one or more of egg yolk lecithin, high-purity egg yolk lecithin, hydrogenated soybean lecithin, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidylcholine, soybean lecithin, phosphatidylserine, dimyristoyl phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin, preferably high-purity egg yolk lecithin and hydrogenated soybean lecithin.

[0021] Furthermore, the oil phase matrix is ​​selected from one or more of cetyl alcohol, stearyl alcohol, isopropyl myristate, white vaseline, and liquid paraffin, preferably cetyl alcohol and stearyl alcohol.

[0022] Furthermore, the emulsifier is selected from one or more of sorbitan stearate, polysorbate 60, polysorbate 80, polyethylene glycol ceteareth-8, and triethanolamine, preferably sorbitan stearate and polysorbate 60.

[0023] Furthermore, the antioxidant is selected from one or more of sodium sulfite, tocopherol, butylated hydroxyanisole, propyl gallate, and ascorbic acid, preferably sodium sulfite.

[0024] Furthermore, the aqueous phase matrix is ​​a mixture of water and one or more of glycerol, propylene glycol, and polyethylene glycol 400, preferably a mixture of water and propylene glycol.

[0025] The second aspect of the present invention provides a method for preparing the stable and efficient ketoconazole phospholipid complex cream as described above, comprising the following steps:

[0026] (A) Preparation of ketoconazole phospholipid complex: dissolving lecithin in an organic solvent, then adding ketoconazole and stirring to dissolve, and removing the organic solvent by rotary evaporation under reduced pressure in a water bath at 20 to 50° C. to obtain ketoconazole phospholipid complex;

[0027] (B) Preparation of antioxidant solution: Take the prescribed amount of antioxidant and add it to purified water (5% w / v of the prescription), stir it by ultrasonic and dissolve it, and set aside;

[0028] (C) Preparation of aqueous matrix: weigh the prescribed amount of emulsifier, add it to the remaining amount of aqueous matrix, heat to 70-80° C. to dissolve to obtain aqueous phase, and keep warm for later use;

[0029] (D) Preparation of oil phase matrix: weigh the oil phase matrix and emulsifier, add them into an emulsifier, mix and heat to 70-80° C. to dissolve completely, transfer all of them into a container containing ketoconazole phospholipid complex, stir until the ketoconazole phospholipid complex is completely dissolved, obtain the oil phase, and keep warm for later use;

[0030] (E) Preparation of ketoconazole phospholipid complex cream: under stirring conditions, the oil phase is added to the water phase, and the temperature is lowered while stirring. When the paste is cooled to 15-20°C, the antioxidant solution is added and stirred (10-30 min, 50 rpm) to mix evenly to obtain the ketoconazole phospholipid complex cream.

[0031] Furthermore, the organic solvent is selected from one or more of methanol, ethanol, acetone, propylene glycol, tert-butanol, and chloroform, preferably ethanol.

[0032] The third aspect of the present invention provides a use of the ketoconazole phospholipid complex cream as described above in the preparation of antifungal drugs.

[0033] The advantages of the present invention are:

[0034] 1. Ketoconazole and lecithin form a ketoconazole phospholipid complex, which not only improves the solubility of ketoconazole, but also improves its physical and chemical stability, overcoming the shortcomings of the existing ketoconazole cream in the preparation and storage process, that is, the drug is easily precipitated and chemically degraded;

[0035] 2. Phospholipid components have good affinity with the skin, and have a permeation-promoting and sustained-release effect on drugs, thereby improving drug efficacy. Ketoconazole phospholipid complex can promote ketoconazole permeation. When administered topically to the skin, ketoconazole phospholipid complex cream can maintain a high concentration of ketoconazole at the site of application, with a long duration of action and less systemic absorption of the drug. It has the advantages of enhancing efficacy, shortening the course of treatment and reducing adverse reactions.

[0036] 3 The present invention prepares ketoconazole into a phospholipid complex and then into an ointment, which can improve the stability and efficacy of the ketoconazole ointment at the same time, and fundamentally solves the clinical use defects caused by the poor physical and chemical stability of ketoconazole itself and the poor permeability of the stratum corneum;

[0037] 4. The ketoconazole phospholipid complex of the present invention is easily dissolved in the oil phase matrix, so that the preparation process of the cream is simpler and low in cost, and is suitable for industrial production. DETAILED DESCRIPTION

[0038] The specific implementation methods provided by the present invention are described in detail below in conjunction with examples.

[0039] Example 1: Preparation of ketoconazole phospholipid complex cream

[0040] 1. Preparation process

[0041] The following process steps were used to prepare the formulations 1-4 shown in Table 1:

[0042] (1) Weighing a prescribed amount of high-purity egg yolk lecithin and dissolving it in ethanol, adding a prescribed amount of ketoconazole and stirring to dissolve, and removing the ethanol by rotary evaporation under reduced pressure in a 30° C. water bath to obtain a ketoconazole phospholipid complex for later use;

[0043] (2) Take the prescribed amount of sodium sulfite and add it to purified water (5%), stir it with ultrasonic to dissolve it, and set aside.

[0044] (3) Weigh the remaining amount of purified water and the prescribed amount of propylene glycol, add the prescribed amount of polysorbate 60, heat to 80° C., stir and dissolve to obtain an aqueous phase, and keep warm for later use;

[0045] (4) Weigh the prescribed amount of sorbitan stearate, hexadecanol and octadecyl alcohol, add them to an emulsifier, mix and heat to 80° C. to dissolve completely, transfer all of them to a container containing ketoconazole phospholipid complex, stir until the ketoconazole phospholipid complex is completely dissolved, obtain an oil phase, and keep warm for later use;

[0046] (5) Under stirring conditions, the oil phase is added to the water phase, and the temperature is lowered while stirring. When the paste is cooled to 20° C., a sodium sulfite solution is added and stirred (20 min, 50 rpm) to mix evenly to obtain a ketoconazole phospholipid complex cream.

[0047] (6) Repack and you are done.

[0048] Table 1 Ketoconazole phospholipid complex cream prescription list

[0049]

[0050]

[0051] 2. Experimental results

[0052] The properties, pH, content, related substances, viscosity and other indicators of the ketoconazole phospholipid complex cream prepared by the prescription in Table 1 were tested, and the results are shown in Table 2:

[0053] Table 2 Ketoconazole phospholipid complex cream test results

[0054]

[0055] As shown in the test results of Table 2, with the increase of ketoconazole concentration, the properties and pH of the cream did not change significantly, and the content, related substances and content uniformity all met the requirements. The cream did not stratify after centrifugation at 5000rpm for 10min at room temperature, and had good stability. However, the viscosity and yield stress of the ointment increased slightly, but there was no significant difference. Within the dosage range of the main drug, the prepared ketoconazole phospholipid complex cream had uniform properties and content, less related substances, and was easy to apply.

[0056] Example 2: Preparation of ketoconazole phospholipid complex cream

[0057] 1. Preparation process

[0058] The formulations 5-8 shown in Table 3 were prepared according to the following process steps:

[0059] (1) Weighing a prescribed amount of lecithin and dissolving it in ethanol, adding a prescribed amount of ketoconazole and stirring to dissolve, and removing the ethanol by rotary evaporation under reduced pressure in a water bath at 25° C. to obtain a ketoconazole phospholipid complex for later use;

[0060] (2) Take the prescribed amount of sodium sulfite and add purified water (5%) to dissolve by ultrasonic stirring for later use;

[0061] (3) Weigh the remaining amount of purified water and the prescribed amount of propylene glycol, add the prescribed amount of polysorbate 60, heat to 75°C, stir and dissolve, obtain the aqueous phase, and keep warm for later use;

[0062] (4) Weigh the prescribed amount of sorbitan stearate, hexadecanol and octadecyl alcohol, add them to an emulsifier, mix and heat to 75° C. to dissolve completely, transfer all of them to a container containing ketoconazole phospholipid complex, stir until the ketoconazole phospholipid complex is completely dissolved, obtain an oil phase, and keep warm for later use;

[0063] (5) Under stirring conditions, the oil phase is added to the water phase, and the temperature is lowered while stirring. When the paste is cooled to 15° C., a sodium sulfite solution is added and stirred (30 min, 50 rpm) to mix evenly to obtain a ketoconazole phospholipid complex cream.

[0064] (6) Repack and you are done.

[0065] Table 3 Ketoconazole phospholipid complex cream prescription list

[0066]

[0067] 2. Experimental results

[0068] The properties, pH, content, related substances, viscosity and other indicators of the ketoconazole phospholipid complex cream prepared by the prescription in Table 3 were tested, and the results are shown in Table 4:

[0069] Table 4 Ketoconazole phospholipid complex cream test results

[0070]

[0071]

[0072] As shown in the test results of Table 4, the pH of the ketoconazole phospholipid complex cream prepared by the prescription of the present invention is nearly neutral, and the content, related substances, and content uniformity all meet the requirements. As the amount of phospholipids increases, the cream gradually thickens, and the viscosity and yield stress of the cream using high-purity egg yolk lecithin tend to increase slowly, while the viscosity and yield stress of the cream using hydrogenated soybean lecithin increase significantly, and the difficulty of application increases.

[0073] Example 3: Preparation of ketoconazole phospholipid complex cream

[0074] 1. Preparation process

[0075] According to the process steps of Example 1, prescriptions 9-12 shown in Table 5 were prepared, and the packaged creams were placed at 30°C ± 2°C and a relative humidity of 60% ± 10% for 6 months. Samples were taken at 0, 3 and 6 months to examine their properties, pH, content, related substances and centrifugal stratification.

[0076] Table 5 Ketoconazole phospholipid complex cream prescription list

[0077]

[0078] 2. Experimental results

[0079] The properties, pH, content, related substances, centrifugal stratification and other indicators of the ketoconazole phospholipid complex cream prepared by the prescription in Table 5 were tested, and the results are shown in Table 6:

[0080] Table 6 Ketoconazole phospholipid complex cream test results

[0081]

[0082]

[0083] The test results in Table 6 show that as the amount of sodium sulfite increases, the pH value of the cream increases slightly. Under the experimental conditions, the pH of the cream gradually decreases due to oxidation of anhydrous sodium sulfite. Other preparation quality attributes such as properties, content, and related substances do not change significantly after storage, indicating that the ketoconazole phospholipid complex cream prepared by the present invention has good stability.

[0084] Example 4: Comparative study on basic quality attributes of ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0085] 1. Experimental Methods

[0086] The ketoconazole phospholipid complex cream prepared by prescription 10 in Example 3 and the commercially available ketoconazole cream (Janssen) were compared in terms of properties, pH, content, related substances, stratification, viscosity and other quality indicators.

[0087] 2. Experimental results

[0088] Table 7 Ketoconazole phospholipid complex cream and commercially available ketoconazole cream test results

[0089]

[0090] Table 8 Comparison of in vitro release data between ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0091]

[0092]

[0093] The test results in Tables 7 and 8 show that the content, pH, related substances, viscosity, and in vitro release of the ketoconazole phospholipid complex cream prepared by the present invention are substantially consistent with those of the commercially available ketoconazole cream.

[0094] Example 5: Comparative study on the stability of ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0095] 1. Experimental Methods

[0096] The ketoconazole phospholipid complex cream prepared by prescription 10 and the commercially available ketoconazole cream (Janssen) were subjected to accelerated stability studies. The samples were kept at a temperature of 40°C ± 2°C and a relative humidity of 60% ± 10% for 6 months. Samples were taken at 3 and 6 months to examine their properties, pH, content, related substances, centrifugal stratification, viscosity and other indicators.

[0097] 2. Experimental results

[0098] Table 9 Comparison of stability between ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0099]

[0100] As shown in Table 9, the stability comparison results show that the ketoconazole phospholipid complex cream prepared by the present invention is stored for 3 months under the experimental conditions, and the properties, pH, content, viscosity and yield stress of the cream have no significant changes. After 6 months, the viscosity and yield stress of the cream have a small decrease, and the cream properties are thinned, but there is no stratification phenomenon in the cream after centrifugation, and the content and related substances are within an acceptable range. The content, viscosity and yield stress of the commercially available ketoconazole cream are significantly reduced after storage for 6 months under the experimental conditions, and the related substances are also significantly increased. At 6 months, the cream has fluidity after extrusion, and stratification occurs after centrifugation, which may be due to the unstable microstructure of the preparation, resulting in the separation of oil and water in the cream. The results show that the ketoconazole phospholipid complex cream prepared according to the prescription and process of the present invention has good stability.

[0101] Example 6: Comparative study on in vitro transdermal penetration of ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0102] 1. Experimental Methods

[0103] Transdermal method: Franz diffusion cell method

[0104] Instrument: SYSTEM 918-12 Dry Heating Automatic Transdermal System, manufacturer: Logan Instruments Corp.

[0105] Skin: Experimental pig skin (A4)

[0106] Receiving medium: 0.9% sodium chloride solution-ethanol (50:50)

[0107] Speed: 600rpm / min

[0108] Temperature: 32.0±1.0℃

[0109] Test time: 24h

[0110] Sampling mode: All sampling

[0111] Diffusion cell volume: 12ml

[0112] Samples: Ketoconazole phospholipid complex cream (prescription 10), commercially available ketoconazole cream (Janssen)

[0113] Drug loading: 0.2g

[0114] Determination of drug permeation and retention:

[0115] Take the experimental pig skin, cut off the required part, place it in a diffusion cell with a preset temperature of 32°C for activation for 30 minutes, and measure the transepidermal water loss rate of the pig skin on each diffusion cell (should be no more than 15g / m 2 / h), weigh the sample, load the sample, and after completion, place the pig skin coated with the sample on the diffusion cell, fix it, put a glass slide on it, set 6 parallel samples for each medium, set the instrument parameters according to the above transdermal conditions and run it.

[0116] The solution in the diffusion pool at each sampling point was filtered, the ketoconazole concentration in the filtrate was determined, and the skin permeation of each preparation was calculated. After the experiment, the pig skin was removed, the residual drug on the surface was removed, and it was rinsed with physiological saline. The surface moisture was absorbed by filter paper, and the pig skin was cut into pieces and placed in a centrifuge tube. 20 ml of the corresponding receiving medium was accurately added, and ultrasonic treatment was performed at 60°C for one hour, and the ketoconazole concentration in the filtrate was determined to calculate the skin retention of each preparation.

[0117] 2. Experimental results

[0118] Table 10 In vitro permeation results of ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0119]

[0120]

[0121] The in vitro permeation results in Table 10 show that the cumulative drug permeation amount and skin retention amount of the ketoconazole phospholipid complex cream are higher than those of the ordinary commercially available ketoconazole ointment, indicating that the ketoconazole phospholipid complex cream prepared by the present invention is better than the commercially available ketoconazole cream in the treatment of superficial fungal and deep fungal infections. At the same time, this result also confirms the penetration-promoting effect of phospholipids on ketoconazole.

[0122] Example 7: Comparison of skin irritation between ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0123] 1. Experimental Methods

[0124] Six New Zealand rabbits weighing 2.0-2.5 kg were selected, half male and half female. The animals were shaved in the front and back dosing areas on both sides of the dorsal midline. The action was gentle to avoid damaging the skin, and the dosing area was marked. The skin of the left and right sides and the front and back sides of the same body were compared by self-contrast method. The skin on the left and right sides of the front was damaged with 1000 mesh sandpaper, and the bleeding was limited to slight bleeding. Ketoconazole phospholipid complex cream (prescription 10) was applied to the damaged skin on the left (front), and commercial ketoconazole cream was applied to the damaged skin on the right (front); ketoconazole phospholipid complex cream (prescription 10) was applied to the intact skin on the left (back), and commercial ketoconazole cream was applied to the intact skin on the right (back). The application amount was 0.5 g / side, the dosing area was 2.5 cm × 2.5 cm, and the drug was administered once a day for 14 consecutive days. The local irritation reaction at the dosing site was observed at 30-60 min, 24 h, 48 h and 72 h after the removal of the drug, and the score was scored according to the skin irritation reaction scoring criteria in Table 11.

[0125] Table 11 Skin irritation reaction scoring standard

[0126]

[0127]

[0128] (Score: 0-0.49: no irritation; 0.5-2.99: mild irritation; 3.0-5.99: moderate irritation; 6.0-8.0: severe irritation)

[0129] 2. Experimental results

[0130] Table 12 Skin irritation reaction scoring results

[0131]

[0132] It can be seen from the skin irritation reaction scoring results in Table 12 that under the experimental conditions, New Zealand rabbits were repeatedly applied with ketoconazole phospholipid complex cream on damaged or intact skin for 14 days, and were given commercially available ketoconazole cream as a control. The results showed that both ketoconazole phospholipid complex cream and commercially available ketoconazole cream showed mild irritation reactions in damaged or intact skin, and the irritation reactions in both groups could be restored with drug withdrawal; the ketoconazole phospholipid complex cream prepared by the present invention had a slightly lower irritation score than the commercially available ketoconazole cream group, indicating that the ketoconazole phospholipid complex cream prepared by the present invention has better durability for long-term use.

[0133] Example 8: Skin allergic reaction to ketoconazole phospholipid complex cream and commercially available ketoconazole cream

[0134] 1. Experimental Methods

[0135] 50 guinea pigs were selected, half male and half female. 10 guinea pigs / group / sex were given ketoconazole phospholipid complex cream (prescription 10) or commercially available ketoconazole cream by local skin application. 5 guinea pigs / group / sex were given 1-chloro-2,4-dinitrobenzene by local skin application. Sensitization was induced on the 1st, 7th, and 14th days, with a sensitization dose of 0.2g. On the 28th day, the stimulation dose was 0.2g. The sensitization and stimulation dose areas were both 2×2cm 2 The drug administration site reactions were observed 1h and 24h after each sensitization and 24h and 48h after each challenge, and clinical observations and animal body weights were monitored regularly.

[0136] 2. Experimental results

[0137] In the positive control 1-chloro-2,4-dinitrobenzene group, 8 / 10 animals showed obvious erythema symptoms at the administration site after the provocative administration, the sensitization rate was 80%, and the sensitization intensity was strong sensitization. All animals in the patented ketoconazole phospholipid complex cream group and the commercially available ketoconazole cream group had 0 allergic reaction symptoms after provocation, the sensitization rate was 0%, and no skin allergic reaction was observed, indicating that the ketoconazole phospholipid complex cream prepared by the present invention does not cause skin allergies and has good safety.

[0138] In summary, the ketoconazole phospholipid complex cream prepared by the present invention has good safety and does not show skin irritation and sensitization in animal experiments. After long-term storage, the quality indicators such as the properties, content and related substances of the cream do not change significantly, and in the accelerated experiment, it shows a better stability than the commercially available ketoconazole cream, and the drug cumulative penetration amount and skin retention amount of the ketoconazole phospholipid complex cream prepared by the present invention are both higher than those of the common commercially available ketoconazole ointment, and may show a better curative effect than the commercially available ketoconazole cream when clinically treating superficial fungi and deep fungal infections. The application of phospholipid complex not only improves the stability of ketoconazole preparations, but also promotes the transdermal penetration of ketoconazole, increases the bioavailability of ketoconazole, and thus improves its curative effect.

[0139] The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are all included in the scope defined by the claims of this application.

Claims

1. A stable and efficient ketoconazole phospholipid complex cream, characterized in that: The cream is composed of ketoconazole, lecithin, an oil phase matrix, an aqueous phase matrix, an emulsifier and an antioxidant; wherein the amount of ketoconazole is 0.5% to 3% w / w, the amount of lecithin is 1% to 6% w / w, the amount of the emulsifier is 2% to 5% w / w, the antioxidant is 0.1% to 0.5% w / w, the oil phase matrix is ​​8% to 12% w / w, and the balance is the aqueous phase matrix.

2. The ketoconazole phospholipid complex cream according to claim 1, characterized in that The ketoconazole phospholipid complex cream is prepared by the following formula:

3. The ketoconazole phospholipid complex cream according to claim 1, characterized in that The ketoconazole phospholipid complex cream is prepared by the following formula:

4. The ketoconazole phospholipid complex cream according to claim 1, characterized in that The ketoconazole phospholipid complex cream is prepared by the following formula:

5. The ketoconazole phospholipid complex cream according to any one of claims 1 to 4, characterized in that The lecithin is selected from one or more of egg yolk lecithin, high-purity egg yolk lecithin, hydrogenated soybean lecithin, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidylcholine, soybean lecithin, phosphatidylserine, dimyristoyl phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin.

6. The ketoconazole phospholipid complex cream according to any one of claims 1 to 4, characterized in that The oil phase matrix is ​​selected from one or more of cetyl alcohol, stearyl alcohol, isopropyl myristate, white vaseline and liquid paraffin.

7. The ketoconazole phospholipid complex cream according to any one of claims 1 to 4, characterized in that: The emulsifier is selected from one or more of sorbitan stearate, polysorbate 60, polysorbate 80, polyethylene glycol cetearyl ether, and triethanolamine; the antioxidant is selected from one or more of sodium sulfite, tocopherol, butylated hydroxyanisole, propyl gallate, and ascorbic acid; and the aqueous phase matrix is ​​a mixture of one or more of water and glycerol, propylene glycol, and polyethylene glycol 400.

8. A method for preparing a stable and efficient ketoconazole phospholipid complex cream as claimed in any one of claims 1 to 7, characterized in that: The following steps are involved: (A) Preparation of ketoconazole phospholipid complex: dissolving lecithin in an organic solvent, then adding ketoconazole and stirring to dissolve, and removing the organic solvent by rotary evaporation under reduced pressure in a water bath at 20 to 50° C. to obtain ketoconazole phospholipid complex; (B) Preparation of antioxidant solution: adding antioxidant to purified water and stirring by ultrasonic to dissolve, and set aside; (C) Preparation of aqueous matrix: weigh an emulsifier, add it to the remaining aqueous matrix, heat it to 70-80° C. to dissolve it, and keep it warm for later use; (D) Preparation of oil phase matrix: weigh the oil phase matrix and emulsifier, add them into an emulsifier, mix and heat to 70-80° C. to dissolve completely, transfer all of them into a container containing ketoconazole phospholipid complex, stir until the ketoconazole phospholipid complex is completely dissolved, obtain the oil phase, and keep warm for later use; (E) Preparation of ketoconazole phospholipid complex cream: under stirring conditions, the oil phase is added to the water phase, and the temperature is lowered while stirring. When the paste is cooled to 15-20° C., the antioxidant solution is added and stirred to mix evenly to obtain the ketoconazole phospholipid complex cream.

9. The method for preparing the ketoconazole phospholipid complex cream according to claim 8, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, acetone, propylene glycol, tert-butyl alcohol and chloroform.

10. Use of the ketoconazole phospholipid complex cream according to any one of claims 1 to 7 in the preparation of antifungal drugs.

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