Simvastatin-cholesterol compound external cream and application thereof

Abstract

The invention provides a simvastatin-cholesterol compound external emulsifiable paste and application thereof in preparation of a medicine for treating keratosis perspirioides. The simvastatin-cholesterol compound external use emulsifiable paste is prepared from simvastatin, cholesterol, pharmaceutically acceptable auxiliary materials and water. According to the simvastatin-cholesterol compound external emulsifiable paste disclosed by the invention, the simvastatin and the cholesterol are combined for use, so that the treatment effect of the simvastatin-cholesterol compound external emulsifiable paste on the keratosis is remarkably improved through the synergistic interaction of the simvastatin and the cholesterol.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly relates to a compound external cream of simvastatin - cholesterol and the application of the compound external cream in the preparation of a medicament for treating porokeratosis. Background Art

[0002] Porokeratosis (PK) is a hereditary skin disease characterized by abnormal keratinization. Most cases of porokeratosis show autosomal dominant inheritance, and there are also a small number of sporadic cases. The clinical manifestations of the characteristic skin lesions of PK are annular keratotic papules or plaques with a raised embankment at the edge of the lesion and central atrophy and depression, often accompanied by itching. Its histopathological feature is the "column of parakeratosis" (i.e., the "cornoid lamella"). According to morphological and clinical features, PK can be divided into multiple subtypes, including disseminated superficial actinic porokeratosis (DSAP), disseminated superficial porokeratosis (DSP), linear porokeratosis (LP), porokeratosis ptychotropica (PPt), porokeratosis of Mibelli (PM), and porokeratosis palmaris et plantaris disseminata (PPPD), etc. Various clinical types can coexist, and DSAP is the most common. PK has a significant risk of canceration (the malignancy rate is about 7% - 11%), and can progress to squamous cell carcinoma, basal cell carcinoma, or melanoma. If patients with PK cannot obtain timely diagnosis and treatment, the persistent skin lesions, the continuously expanding area, and the accompanying itching symptoms can seriously affect the quality of life of patients, and even lead to the death of patients after the disease becomes malignant.

[0003] At present, there is no specific treatment method for porokeratosis. Existing clinical treatment means include topical or oral retinoid drugs, local topical application of calcipotriol ointment, 5 - fluorouracil ointment, imiquimod ointment, etc., as well as physical treatments such as laser and photodynamic therapy. However, these methods mainly act by exfoliating the skin lesions or inhibiting local inflammation, and cannot intervene in the pathogenesis of PK. The curative effect is limited and it is easy to relapse. Although surgical operations can excise or abrade refractory skin lesions and also have a certain curative effect on some hypertrophic skin lesions and refractory cases, it is easy to cause scar formation and is not suitable for patients with large - area skin lesions. Therefore, developing a new targeted therapy based on the pathological mechanism of PK is the focus of current clinical research.

[0004] In recent years, studies have found that the pathogenesis of PK is closely related to four key gene mutations in the mevalonate metabolic pathway, namely, mevalonate kinase gene (MVK), phosphomevalonate kinase gene (PMVK), mevalonate pyrophosphate decarboxylase gene (MVD), and farnesylpyrophosphate synthetase gene (FDPS). The mevalonate pathway is an important metabolic pathway that uses acetyl-CoA as the starting material to synthesize various lipid substances such as isopentenyl pyrophosphate, dimethylallyl pyrophosphate, and cholesterol. It can regulate the synthesis of cholesterol, coenzyme Q, heme A, dolichol, and the post-translational isoprenylation modification of proteins, and plays an important role in cell growth and differentiation, intracellular signal transduction, and post-translational modification of proteins. Mutations in the above four genes lead to abnormal metabolism of the mevalonate pathway: on the one hand, the excessive accumulation of intermediate metabolites (such as mevalonic acid) leads to the activation of the innate immune response and the promotion of cytokine production; on the other hand, the insufficient synthesis of downstream end products (such as cholesterol) damages the skin barrier function and induces abnormal proliferation and differentiation of keratinocytes. The lack of cholesterol further exacerbates skin barrier damage, forming a vicious cycle, and ultimately leading to the characteristic skin lesions and carcinogenic tendency of PK.

[0005] Based on this pathological mechanism, topical application of statins can inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase upstream of MVK, PMVK, MVD, and FDPS, thereby inhibiting the abnormal accumulation of intermediate metabolites (such as mevalonic acid), reducing the overactivation of local innate immunity, and improving the skin lesions and related symptoms of PK patients. However, in the prior art, the effect of using statins to improve the symptoms of porokeratosis is not significant, and the curative effect fails to meet the clinical expectations.

[0006] Therefore, there is a need to develop an external ointment with significantly improved therapeutic effect based on the pathological mechanism of PK. Summary of the Invention

[0007] Technical Problem

[0008] The present invention is made to solve the above problems existing in the prior art. An object of the present invention is to provide a compound external cream of simvastatin and cholesterol, which is prepared by combining simvastatin and cholesterol based on genetic findings.

[0009] Another object of the present invention is to provide the use of the simvastatin-cholesterol compound topical cream in the preparation of a medicament for treating porokeratosis, and the therapeutic effect on porokeratosis is significantly improved through the synergistic effect of simvastatin and cholesterol.

[0010] Technical solution

[0011] The present invention provides a simvastatin-cholesterol compound topical cream, comprising: simvastatin, cholesterol, a pharmaceutically acceptable excipient and water. The excipient is a matrix for mixing with simvastatin and cholesterol. By combining simvastatin and cholesterol and applying them topically to the skin lesions of patients, it can target and inhibit abnormal mevalonic acid metabolites in the skin lesions of porokeratosis and supplement the normal metabolite cholesterol, thereby exerting a therapeutic effect.

[0012] According to one embodiment of the present invention, based on the total amount of the simvastatin-cholesterol compound topical cream, the weight components of simvastatin and cholesterol can each be not less than 2 wt%.

[0013] According to one embodiment of the present invention, the cream can be composed of a variety of independent creams with different cholesterol to simvastatin ratios, and the ratio can be selected within the range of 1:1 to 1:5. More preferably, the ratio of cholesterol to simvastatin can be selected within the range of 1:1 to 1:2.5.

[0014] Preferably, the ratio combination of cholesterol to simvastatin can be 1 to 5 kinds, more preferably, it can be 2 to 4 kinds, and still more preferably, it can be 3 kinds. In this case, the ratios of the 3 groups can be 1:(1 to 1.2), 1:(1.4 to 2.0), 1:(2.2 to 5) respectively, preferably, they can be 1:(1 to 1.2), 1:(1.5 to 1.8), 1:(2.5 to 4) respectively, and still more preferably, they can be 1:1, 1:1.5, 1:2.5 respectively.

[0015] According to one embodiment of the present invention, based on the total amount of the simvastatin-cholesterol compound topical cream, the simvastatin-cholesterol compound topical cream can be formulated according to the following dosage ratio: 2 to 5 wt% of cholesterol, 2 to 5 wt% of simvastatin, 45 to 55 wt% of a pharmaceutically acceptable excipient and 35 to 45 wt% of water.

[0016] According to one embodiment of the present invention, in order to facilitate the application by patients better, the excipient can include an emulsifier, an emulsion stabilizer and a humectant.

[0017] The emulsifier can be selected from one or more of polyethylene glycol monostearate, glycerol monostearate, medium-chain triglyceride and propylene glycol.

[0018] The emulsifying stabilizer can be selected from one or more of 1-hexadecanol and octadecanol.

[0019] The humectant can be selected from one or more of petrolatum and paraffin wax.

[0020] According to an embodiment of the present invention, the simvastatin-cholesterol compound topical cream may comprise: cholesterol, simvastatin, glyceryl monostearate, 1-hexadecanol, polyethylene glycol monostearate, petrolatum, medium-chain triglycerides, 1,2-propanediol and water.

[0021] According to an embodiment of the present invention, the simvastatin-cholesterol compound topical cream can be formulated in the following dosage ratio:

[0022]

[0023]

[0024] The present invention also provides a method for preparing the simvastatin-cholesterol compound topical cream, comprising the following steps:

[0025] Add simvastatin, cholesterol and pharmaceutically acceptable excipients into a flask in proportion, heat and melt while stirring, control the rotation speed at 200-400 r / min, and keep warm at 72 °C to obtain an oil phase;

[0026] Boil water, add propylene glycol to obtain an aqueous phase;

[0027] Mix the oil phase and the aqueous phase, stir for 30-40 minutes, control the rotation speed at 300-400 r / min until complete emulsification to obtain an emulsion; and

[0028] Suck out the emulsion with a pipette under stirring and place it in a dispensing bottle, let it stand for stratification, and after sufficient stratification, thoroughly stir and mix the upper paste and the lower liquid to obtain the simvastatin-cholesterol compound topical cream.

[0029] In the preparation method, in the step of obtaining the aqueous phase, it further includes: adding water into a beaker and placing it in a boiling water bath for about 10 min, and then adding propylene glycol.

[0030] According to another aspect of the present invention, the present invention provides an application of the simvastatin-cholesterol compound topical cream in the preparation of a drug for treating porokeratosis.

[0031] According to an embodiment of the present invention, in the application of using the simvastatin-cholesterol compound topical cream of the present invention to prepare a medicament for treating porokeratosis, as the concentration of the active ingredient in the cream increases, the improvement effect on porokeratosis is significantly enhanced. However, if a high-concentration drug is topically applied at the initial stage of medication, it may cause obvious skin irritation reactions. Therefore, in order to gradually establish skin tolerance, the present invention uses a method of increasing the concentration step by step. Among them, the cream with a lower proportion of simvastatin is used to establish skin tolerance and provide a basic therapeutic effect, and then the proportion of simvastatin and the total drug concentration are gradually increased. The inventors surprisingly found that the therapeutic effect of this cream combination is better than directly applying a high-proportion simvastatin ointment.

[0032] According to an embodiment of the present invention, the preferred dosing regimen of the present invention is as follows:

[0033] From week 0 to week 2, a compound topical cream containing 2 wt% cholesterol and 2 wt% simvastatin is administered. From week 3 to week 4, a compound topical cream containing 2 wt% cholesterol and 3 wt% simvastatin is administered. From week 5 to week 12, a compound topical cream containing 2 wt% cholesterol and 5 wt% simvastatin is administered. It is topically applied to the skin lesions twice a day, thinly spread and massaged.

[0034] Although statin drugs are commonly used in clinical practice and have been reported to be used to improve skin diseases, the inventors of the present invention unexpectedly found through experiments that when simvastatin is combined with cholesterol for topical use, while inhibiting the production of intermediate metabolites such as mevalonic acid, supplementing exogenous cholesterol can directly make up for the deficiency in downstream synthesis, thereby regulating metabolic imbalance bidirectionally, and can act synergistically on different targets of the mevalonic acid pathway, significantly inhibiting the accumulation of metabolites and repairing the skin barrier function. Its curative effect is better than the simple superposition of single components, providing a new breakthrough solution for the treatment of PK. The clinical trials conducted by the inventors have confirmed that the simvastatin-cholesterol compound topical cream prepared by the present invention has achieved significant therapeutic effects for the pre-treatment of porokeratosis.

[0035] Beneficial effects

[0036] The present invention first reveals that the combination of simvastatin and cholesterol can produce a synergistic effect, and significantly improves the therapeutic effect of porokeratosis by dual-regulating the abnormal metabolism of the mevalonic acid pathway. Clinical data show that the compound cream of the present invention has a more significant therapeutic effect than single components and is highly safe, providing a new targeted treatment plan for porokeratosis. Description of the drawings

[0037] Figure 1 is a photograph showing the therapeutic effect of simvastatin-cholesterol compound cream on porokeratosis, wherein, Figure 1 a is a photograph of patient 1 before treatment in Example 1, Figure 1b is a photo of Patient 1 after applying a 2% cholesterol and 2% simvastatin compound cream for 12 weeks. Figure 1 c and Figure 1 d are respectively the corresponding dermoscopic photos of the skin lesions (20×).

[0038] Figure 2 are photos showing the efficacy of the simvastatin-cholesterol compound cream on porokeratosis. Among them, Figure 2 a is a photo of Patient 2 before treatment in Example 2. Figure 2 b is a photo of Patient 2 after applying a 2% cholesterol and 3% simvastatin compound cream for 12 weeks. Figure 2 c and Figure 2 d are respectively the corresponding dermoscopic photos of the skin lesions (20×).

[0039] Figure 3 are photos showing the efficacy of the simvastatin-cholesterol compound cream on porokeratosis. Among them, Figure 3 a is a photo of Patient 3 before treatment in Example 3. Figure 3 b is a photo of Patient 3 after applying a 2% cholesterol and 5% simvastatin compound cream for 12 weeks. Figure 3 c and Figure 3 d are respectively the corresponding dermoscopic photos of the skin lesions (20×).

[0040] Figure 4 are photos showing the efficacy of using cholesterol cream alone on porokeratosis by means of increasing-dose administration. Among them, Figure 4 a is a photo of Patient 4 before treatment in Comparative Example 1. Figure 4 b is a photo of Patient 4 after applying cholesterol cream alone for 12 weeks.

[0041] Figure 5 are photos showing the efficacy of using cholesterol cream alone on porokeratosis by means of increasing-dose administration. Among them, Figure 5 a is a photo of Patient 5 before treatment in Comparative Example 1. Figure 5 b is a photo of Patient 5 after applying cholesterol cream alone for 12 weeks.

[0042] Figure 6 are photos showing the efficacy of using cholesterol cream alone on porokeratosis by means of increasing-dose administration. Among them, Figure 6 a is a photo of Patient 6 before treatment in Comparative Example 1. Figure 6 b is a photo of Patient 6 after applying cholesterol cream alone for 12 weeks.

[0043] Figure 7 are photos showing the efficacy of using simvastatin cream alone on porokeratosis by means of increasing-dose administration. Among them, Figure 7 a is a photo of Patient 7 before treatment in Comparative Example 2.Figure 7 Figure b shows a photo of patient 7 after receiving simvastatin cream alone for 12 weeks.

[0044] Figure 8 The photos show the efficacy of simvastatin cream alone in treating porokeratosis using a concentration-increasing administration method. Among them, Figure 8 Figure a shows a pre-treatment photo of patient 8 in Comparative Example 2. Figure 8 Figure b shows a photo of patient 8 after receiving simvastatin cream alone for 12 weeks.

[0045] Figure 9 The photos show the efficacy of simvastatin cream alone in treating porokeratosis using a concentration-increasing administration method. Among them, Figure 9 Figure a shows a pre-treatment photo of patient 9 in Comparative Example 2. Figure 9 Figure b shows a photo of patient 9 after receiving simvastatin cream alone for 12 weeks.

[0046] Figure 10 The photos show the efficacy of simvastatin-cholesterol compound cream in treating porokeratosis using a concentration-increasing administration method. Among them, Figure 10 Figure a shows a pre-treatment photo of patient 10 in Example 4. Figure 10 Figure b shows a photo of patient 10 after receiving simvastatin-cholesterol compound cream for 12 weeks. Figure 10 Figures c and Figure 10 d are respectively the corresponding dermoscopic photos of skin lesions (20×).

[0047] Figure 11 The photos show the efficacy of simvastatin-cholesterol compound cream in treating porokeratosis using a concentration-increasing administration method. Among them, Figure 11 Figure a shows a pre-treatment photo of patient 11 in Example 4. Figure 11 Figure b shows a photo of patient 11 after receiving simvastatin-cholesterol compound cream for 12 weeks. Figure 11 Figures c and Figure 11 d are respectively the corresponding dermoscopic photos of skin lesions (20×).

[0048] Figure 12 The photos show the efficacy of simvastatin-cholesterol compound cream in treating porokeratosis using a concentration-increasing administration method. Among them, Figure 12 Figure a shows a pre-treatment photo of patient 12 in Example 4. Figure 12 Figure b shows a photo of patient 12 after receiving simvastatin-cholesterol compound cream for 12 weeks. Figure 12 Figures c and Figure 12 d are respectively the corresponding dermoscopic photos of skin lesions (20×). Detailed implementation mode

[0049] The present invention discloses a compound external-use cream of simvastatin-cholesterol, a preparation method and an application thereof. Those skilled in the art can draw on the content of this specification and appropriately improve the process parameters to achieve the same. It should be particularly noted that all similar substitutions and changes that are obvious to those skilled in the art without departing from the content, spirit and scope of the present invention are regarded as being included within the scope of the present invention. The preparation method and application of the present invention have been described through the following examples. Those skilled in the art can make changes or appropriate modifications and combinations to the methods and applications described in this specification without departing from the content, spirit and scope of the present invention so as to implement and apply the technology of the present invention.

[0050] The raw materials or auxiliary materials used in the compound external-use cream of simvastatin-cholesterol provided by the present invention can all be purchased from the market.

[0051] The present invention will be further described below in conjunction with examples and comparative examples. In the following examples and comparative examples, % represents wt%.

[0052] Preparation Example 1

[0053] Prepare a 2% cholesterol and 2% simvastatin compound cream, and the formula (specification: 100 g / bottle) is shown in Table 1 below:

[0054] [Table 1]

[0055] Name Weight (g) Cholesterol 2 Simvastatin 2 Glycerol Monostearate 3.28 1-Hexadecanol 4.92 Polyethylene Glycol Monostearate 5.74 Vaseline 20.91 Medium Chain Triglycerides 12.15 1,2-Propylene Glycol 8.20 Water 40.80 Total 100

[0056] Preparation method: Weigh the simvastatin, cholesterol, glyceryl monostearate, 1-hexadecanol, polyethylene glycol monostearate, vaseline, and medium-chain triglycerides shown in Table 1 above, put them into a flask, and use a rotor stirrer to stir the mixture in the flask. The rotation speed is controlled at 200 - 400 r / min, and the oil bath temperature is maintained at 72 °C. Stir for 60 minutes. After stirring evenly, add the mixed solution of propylene glycol and water shown in Table 1 above, continue to stir, the rotation speed is controlled at 300 - 400 r / min, and continue to maintain the oil bath temperature at 72 °C. Stir for 30 - 40 minutes. Let it stand for layering. After sufficient layering, fully mix and stir the upper paste and the lower liquid to obtain the cream.

[0057] Preparation Example 2

[0058] Prepare a 2% cholesterol and 3% simvastatin compound cream, and the formula (specification: 100 g / bottle) is shown in Table 2 below:

[0059] [Table 2]

[0060] Product Name Weight (g) Cholesterol 2 Simvastatin 3 Glycerol Monostearate 3.28 1-Hexadecanol 4.92 Polyethylene Glycol Monostearate 5.74 Vaseline 20.91 Medium Chain Triglycerides 12.15 1,2-Propylene Glycol 8.20 Water 39.80 Total 100

[0061] Preparation method: Weigh simvastatin, cholesterol, glyceryl monostearate, 1-hexadecanol, polyethylene glycol monostearate, petrolatum, and medium-chain triglycerides with the weights shown in Table 2 above, put them into a flask, stir the mixture in the flask with a rotor stirrer, control the rotation speed at 200 - 400 r / min, and keep the oil bath temperature at 72 °C, stir for 60 minutes. After stirring evenly, add the mixed solution of propylene glycol and water with the weight shown in Table 2 above, continue stirring, control the rotation speed at 300 - 400 r / min, continue to keep the oil bath temperature at 72 °C, and stir for 30 - 40 minutes. Let it stand for stratification, and after sufficient stratification, fully mix and stir the upper paste and the lower liquid to obtain the cream.

[0062] Preparation Example 3

[0063] Prepare a compound cream of 2% cholesterol and 5% simvastatin, and the formula (specification: 100 g / bottle) is as shown in Table 3 below:

[0064] [Table 3]

[0065] Product Name Weight (g) Cholesterol 2 Simvastatin 5 Glycerol Monostearate 3.28 1-Hexadecanol 4.92 Polyethylene Glycol Monostearate 5.74 Vaseline 20.91 Medium Chain Triglycerides 12.15 1,2-Propylene Glycol 8.20 Water 37.80 Total 100

[0066] Preparation method: Weigh simvastatin, cholesterol, glyceryl monostearate, 1-hexadecanol, polyethylene glycol monostearate, petrolatum, and medium-chain triglycerides with the weights shown in Table 3 above, put them into a flask, stir the mixture in the flask with a rotor stirrer, control the rotation speed at 200 - 400 r / min, and keep the oil bath temperature at 72 °C, stir for 60 minutes. After stirring evenly, add the mixed solution of propylene glycol and water with the weight shown in Table 3 above, continue stirring, control the rotation speed at 300 - 400 r / min, continue to keep the oil bath temperature at 72 °C, and stir for 30 - 40 minutes. Let it stand for stratification, and after sufficient stratification, fully mix and stir the upper paste and the lower liquid to obtain the cream.

[0067] Example 1

[0068] Conduct a pharmacodynamic test on the simvastatin-cholesterol compound cream prepared in Preparation Example 1 to investigate the efficacy of the simvastatin-cholesterol compound cream on porokeratosis.

[0069] Test subjects: 1 patient clinically, pathologically, and genetically diagnosed with porokeratosis. Patient 1 presented with DSAP.

[0070] Test method: From week 0 to week 12, administer the 2% cholesterol and 2% simvastatin compound cream of Preparation Example 1 externally to the skin lesions twice a day, apply thinly and massage.

[0071] The test results of Patient 1 are shown in Figure 1 . By Figure 1It can be seen that after treatment with the simvastatin-cholesterol compound cream of the present invention, the symptoms of porokeratosis in patients can be slightly improved, the skin lesions of the patients become slightly thinner and lighter, and it is learned by inquiry that the itching is slightly reduced.

[0072] Example 2

[0073] The simvastatin-cholesterol compound cream prepared in Preparation Example 2 was subjected to a pharmacodynamic test to investigate the efficacy of the simvastatin-cholesterol compound cream against porokeratosis.

[0074] Test subjects: One patient clinically, pathologically, and genetically diagnosed with porokeratosis, Patient 2 showed PPt.

[0075] Test method: From week 0 to 12, the 2% cholesterol and 3% simvastatin compound cream of Preparation Example 2 was applied externally to the skin lesions twice a day, thinly applied and massaged.

[0076] The test results of Patient 2 are shown in Figure 2 . From Figure 2 It can be seen that after treatment with the simvastatin-cholesterol compound cream of the present invention, the symptoms of porokeratosis in patients can be significantly improved, the skin lesions of the patients become significantly thinner and lighter, and it is learned by inquiry that the itching is slightly reduced.

[0077] Example 3

[0078] The simvastatin-cholesterol compound cream prepared in Preparation Example 3 was subjected to a pharmacodynamic test to investigate the efficacy of the simvastatin-cholesterol compound cream against porokeratosis.

[0079] Test subjects: One patient clinically, pathologically, and genetically diagnosed with porokeratosis, Patient 3 showed LP.

[0080] Test method: From week 0 to 12, the 2% cholesterol and 5% simvastatin compound cream of Preparation Example 3 was applied externally to the skin lesions twice a day, thinly applied and massaged.

[0081] The test results of Patient 3 are shown in Figure 3 . From Figure 3 It can be seen that after treatment with the simvastatin-cholesterol compound cream of the present invention, the symptoms of porokeratosis in patients can be significantly improved, the skin lesions of the patients become significantly thinner and lighter, and it is learned by inquiry that the itching is significantly reduced, but obvious skin irritation reactions such as obvious erythema and stinging occur in the initial stage of medication

[0082] Example 4

[0083] According to Examples 1 to 3, when the concentration ratio of cholesterol to simvastatin is 1:1, the therapeutic effect is not significant. However, as the proportion of simvastatin and the drug concentration increase, the therapeutic effect is significantly improved. However, if a high-concentration drug is applied topically at the beginning of medication, it may cause obvious skin irritation reactions. Therefore, in order to gradually establish skin tolerance, the present invention administers the drug in a manner of increasing concentration. Among them, the cream with a lower proportion of simvastatin is used to establish skin tolerance and provide a basic therapeutic effect, and then the proportion of simvastatin and the total drug concentration are gradually increased. The inventors surprisingly found that the therapeutic effect of this cream combination is better than directly applying a high-proportion simvastatin ointment.

[0084] Test subjects: 3 patients clinically, pathologically, and genetically diagnosed with porokeratosis. Patients 10 and 11 presented with DSAP, and patient 12 presented with PPt.

[0085] Test method: From week 0 to 2, a compound cream of 2% cholesterol and 2% simvastatin was administered. From week 3 to 4, a compound cream of 2% cholesterol and 3% simvastatin was administered. From week 5 to 12, a compound cream of 2% cholesterol and 5% simvastatin was administered. It was applied topically to the lesioned skin twice a day, thinly spread and massaged.

[0086] The test results of the 3 patients are shown in Figures 10 to 12 . As can be seen from Figures 10 to 12 , after the gradient treatment with the simvastatin-cholesterol compound cream of the present invention, the symptoms of porokeratosis in patients 10, 11, and 12 can be significantly improved. The lesions of the patients became significantly thinner and lighter. It was learned through inquiry that the itching was significantly reduced compared with that before treatment, and no adverse reactions such as skin irritation occurred.

[0087] In order to prove that the simvastatin-cholesterol compound topical cream of the present invention has a synergistic effect compared with using cholesterol cream alone or simvastatin cream alone, the same concentration gradient as in Example 4 was used, that is, a total of 4% active ingredient was administered from week 0 to 2, a total of 5% active ingredient was administered from week 3 to 4, and a total of 7% active ingredient was administered from week 5 to 12 for the following comparative examples.

[0088] Comparative Example 1

[0089] The cholesterol cream was applied topically to the lesioned skin of patients with porokeratosis for a pharmacodynamic test to investigate the therapeutic effect of using cholesterol cream alone on porokeratosis.

[0090] Test subjects: 3 patients clinically, pathologically, and genetically diagnosed with porokeratosis. Patients 4 and 6 presented with PPt, and patient 5 presented with DSAP.

[0091] Test method: Apply 4% cholesterol cream from week 0 to week 2, 5% cholesterol cream from week 3 to week 4, and 7% cholesterol cream from week 5 to week 12. Apply it externally to the skin lesions twice a day, thinly spread and massage.

[0092] The test results of 3 patients are shown in Figures 4 to 6 . It can be seen from Figures 4 to 6 that after treatment with cholesterol cream, the symptoms of porokeratosis in patient 4 and patient 5 can be slightly improved. The skin lesions of the patients become slightly thinner and lighter than before treatment. After inquiry, it is known that the itching is not significantly relieved; the symptoms of porokeratosis in patient 6 are almost not improved.

[0093] Comparative Example 2

[0094] Apply simvastatin cream externally to the skin lesions of patients with porokeratosis and conduct a pharmacodynamic test to investigate the efficacy of using simvastatin cream alone on porokeratosis.

[0095] Test subjects: 3 patients clinically, pathologically, and genetically diagnosed with porokeratosis. Patients 7, 8, and 9 show DSAP.

[0096] Test method: Apply 4% simvastatin cream from week 0 to week 2, 5% simvastatin cream from week 3 to week 4, and 7% simvastatin cream from week 5 to week 12. Apply it externally to the skin lesions twice a day, thinly spread and massage.

[0097] The test results of 3 patients are shown in Figures 7 to 9 . It can be seen from Figures 7 to 9 that after treatment with simvastatin cream, the symptoms of porokeratosis in patient 7 and patient 8 can be slightly improved. The skin lesions of the patients become slightly thinner and lighter than before treatment. After inquiry, it is known that the itching has improved slightly compared to before treatment; the symptoms of porokeratosis in patient 9 are almost not improved.

[0098] It can be seen from the results of the above examples and comparative examples that at the same concentration of active ingredients, applying cholesterol cream or simvastatin cream alone externally can improve the symptoms of porokeratosis to a certain extent, but the efficacy is relatively slight, and the improvement degree of skin lesions and itching is not obvious. The simvastatin-cholesterol compound external cream of the present invention has obvious efficacy on porokeratosis. The skin lesions become significantly lighter and thinner than before treatment, and the itching is significantly relieved. This shows that at the same concentration of active ingredients, the efficacy of the simvastatin-cholesterol compound external cream of the present invention is superior to that of using cholesterol cream or simvastatin cream alone. At the same time, no obvious adverse reactions occurred in all patients during the medication period. It can be seen that the compound cream of the present invention has good safety and effectiveness for patients.

Claims

1. A simvastatin-cholesterol compound external cream, characterized in that: The simvastatin-cholesterol compound external cream comprises: simvastatin, cholesterol, pharmaceutically acceptable excipients and water. Wherein, based on the total amount of the simvastatin-cholesterol compound external cream, the weight component of each of the simvastatin and the cholesterol is not less than 2wt%.

2. The cream according to claim 1, characterized in that The cream is composed of a plurality of independent creams with different ratios of cholesterol to simvastatin, and the ratio is selected within the range of 1:1 to 1:2.

5.

3. The cream according to claim 2, characterized in that There are three ratio combinations of the cholesterol and the simvastatin, which are 1:1, 1:1.5, and 1:2.

5.

4. The cream according to any one of claims 1 to 3, characterized in that Based on the total amount of the simvastatin-cholesterol compound external cream, the simvastatin-cholesterol compound external cream is prepared according to the following dosage ratio:

5. The cream according to claim 1, characterized in that The pharmaceutically acceptable excipients include emulsifiers, emulsion stabilizers and humectants.

6. The cream according to claim 5, characterized in that The emulsifier is selected from one or more of polyethylene glycol monostearate, glyceryl monostearate, medium chain triglycerides and propylene glycol; the emulsion stabilizer is selected from one or more of 1-hexadecanol and octadecyl alcohol; the moisturizer is selected from one or more of vaseline and paraffin.

7. The cream according to claim 6, characterized in that The simvastatin-cholesterol compound external cream comprises: simvastatin, cholesterol, glyceryl monostearate, 1-hexadecanol, polyethylene glycol monostearate, vaseline, medium chain triglyceride, 1,2-propylene glycol and water.

8. The cream according to claim 4, characterized in that The simvastatin-cholesterol compound external cream is prepared according to the following dosage ratio:

9. Use of the simvastatin-cholesterol compound external cream according to any one of claims 1 to 8 in the preparation of a drug for treating porokeratosis.

10. A method for preparing the simvastatin-cholesterol compound external cream according to any one of claims 1 to 8, characterized in that: Simvastatin, cholesterol and pharmaceutically acceptable excipients are added into a flask according to a proportion, mixed, heated to melt and stirred, the speed is controlled at 200-400 r / min, and kept warm at 72° C. to obtain an oil phase; Boil water and add propylene glycol to obtain a water phase; The oil phase and the water phase are mixed and stirred for 30 to 40 minutes, with the rotation speed controlled at 300 to 400 r / min, until they are completely emulsified to obtain an emulsion; and The emulsion is allowed to stand for stratification, and after stratification is complete, the upper paste and the lower liquid are fully stirred and mixed to obtain the simvastatin-cholesterol compound external cream.

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