Cyclopirox olamine calcipotriol compound liniment and preparation method thereof

Abstract

The application discloses a cyclopirox olamine calcipotriol compound liniment and a preparation method thereof. The liniment is prepared from the following raw materials in percentage by weight: calcipotriol 0.001%-0.02%, cyclopirox olamine 0.5-1.5%, antioxidant 0.1%-0.5%, anhydrous ethanol 65-70%, and water. The preparation method comprises the following steps: 1) mixing cyclopirox olamine, calcipotriol, antioxidant and anhydrous ethanol to obtain a mixed solution; and 2) adding water to the mixed solution obtained in the step 1) and continuing to mix until a clear solution is obtained. The application prepares a compound liniment from calcipotriol and cyclopirox olamine, which not only has a better antibacterial effect, but also can quickly restore the injured position to a healthy state by using the immune regulation and repair functions of calcipotriol. Moreover, the preparation process is simple, convenient to operate and easy to apply.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a ciclopirox olamine calcipotriol compound liniment and its preparation method. Background Technology

[0002] Calcipotriol is a synthetic vitamin D3 analog and one of the core topical medications used in dermatology to treat psoriasis. Its mechanism of action primarily involves interacting with the vitamin D receptor (VDR) in the body, regulating cell proliferation, differentiation, and immune regulation, thereby improving the pathological process of psoriasis through multiple pathways. The core pathological features of psoriasis include excessive proliferation and abnormal differentiation of keratinocytes, dermal vasodilation, and the infiltration and activation of immune cells. At the molecular level, dysregulation of the vitamin D signaling pathway is often present in the skin lesions of patients. Calcipotriol has a structure similar to naturally occurring active vitamin D (calcitriol) in the body and can selectively bind to the vitamin D receptor (VDR) in the nuclei of keratinocytes and immune cells (such as T lymphocytes), forming a hormone-receptor complex. This complex then binds to the vitamin D response element (VDRE) in the promoter region of target genes, acting like a "key" to start or stop the transcription process of specific genes. Calcipotriol effectively downregulates the expression of proto-oncogenes related to cell cycle progression (such as c-myc) while upregulating the expression of cell differentiation markers (such as transglutaminase and epithelial proteins), thereby slowing down cell division and promoting normal cell differentiation and maturation. This helps correct the abnormal state of accelerated epidermal turnover and cell thickening in psoriatic plaques. Secondly, it promotes the normal differentiation of keratinocytes, correcting the disordered keratinization process and reducing scaling on the plaque surface. Finally, it exerts a significant immunomodulatory effect. It can inhibit the activation of pro-inflammatory Th1 and Th17 cells and the production of related cytokines (such as IL-2, IFN-γ, and IL-17), while inhibiting the function of antigen-presenting cells (such as Langerhans cells), thereby alleviating the inflammatory response at the lesion site.

[0003] Recently, calcipotriol, a vitamin D-based drug, has been found to not only inhibit keratinocyte proliferation but also possess antifungal properties. It enhances the immune response by binding to vitamin D receptors, thereby suppressing fungal growth through immune system regulation. Simultaneously, calcipotriol's immunomodulatory and repair functions can help patients restore skin or external structures damaged by fungi and quickly return to a healthy state.

[0004] Cilopirox Olamine is a broad-spectrum synthetic antifungal drug whose core mechanism lies in its ability to integrate and chelate polyvalent metal ions (such as Fe) within fungal cells. 3+ Al 3+These metal ions are essential cofactors for the activity of many cellular enzymes, especially cytochrome enzymes and peroxidases (such as catalase, which catalyzes the degradation of hydrogen peroxide) involved in the cellular respiratory chain. Cyclopyroxamine, by depriving these key enzymes of cofactors, severely interferes with the energy metabolism (mitochondrial electron transport chain) and antioxidant defense system of fungal cells, leading to a large accumulation of toxic peroxides within the cells, thus causing fatal damage to fungal cells. In addition, cyclopyroxamine can also inhibit the integrity of fungal cell membrane structure and function. It affects the ergosterol synthesis pathway by inhibiting squalene epoxidase. However, unlike mainstream azole drugs, it does not directly inhibit CYP450 enzymes. This characteristic makes it free from cross-resistance with other antibacterial drugs and effective against some azole-resistant strains. In addition to its strong antifungal effects (such as against dermatophytes, yeasts, and molds), cyclopyroxamine also exhibits anti-inflammatory and antibacterial activities, which are particularly beneficial for treating mixed skin infections (such as seborrheic dermatitis and folliculitis) that are often accompanied by bacterial colonization and inflammatory responses.

[0005] Currently available topical antibacterial drugs are quite effective at killing bacteria, but these ointments lack the ability to rapidly heal wounds caused by fungal infections and damage to external tissues after the antibacterial treatment. Therefore, it is necessary to develop a new drug formulation that possesses excellent antibacterial properties while also rapidly repairing wounds. Summary of the Invention

[0006] The purpose of this invention is to provide a ciclopirox olamine and calcipotriol compound liniment, and the preparation method thereof is a second objective of this invention. This invention proposes to prepare a compound liniment from calcipotriol and ciclopirox olamine, which not only has a better antibacterial effect but also utilizes the immunomodulatory and repair functions of calcipotriol to rapidly restore the injured site to a healthy state. To achieve the above objectives, this invention adopts the following technical solution:

[0007] A ciclopirox olamine-calcipotriol compound liniment, the liniment being made from the following raw materials in weight percentages: 0.001%-0.02% calcipotriol, 0.5-1.5% ciclopirox olamine, 0.1%-0.5% antioxidant, 65-70% anhydrous ethanol, and the remainder being water.

[0008] As a further preferred embodiment of the present invention, the liniment is made from the following raw materials in weight percentages: 0.005% calcipotriol, 1% ciclopirox olamine, 0.2% antioxidant, 70% anhydrous ethanol, and the remainder being water.

[0009] As a further preferred embodiment of the present invention, the antioxidant is vitamin E.

[0010] The present invention also discloses a method for preparing the ciclopirox olamine calcipotriol compound liniment, comprising the following steps: 1) mixing ciclopirox olamine, calcipotriol, antioxidant, and anhydrous ethanol to obtain a mixture;

[0011] 2) Add water to the mixture obtained in step 1) and continue mixing until a clear solution is obtained.

[0012] As a further preferred embodiment of the present invention, steps 1) and 2) are performed using ultrasonic mixing, and the conditions for ultrasonic mixing are: ultrasonic frequency 40KHz, time 30min, and water bath temperature 30℃.

[0013] The advantages of this formulation are as follows: ciclopirox olamine is a broad-spectrum antifungal drug with strong penetrability, capable of penetrating the stratum corneum of the skin. Calcipotriol is a vitamin D3 derivative that can inhibit excessive keratinization of the skin and regulate the normal differentiation of epidermal cells. The combined use of these two not only enhances the antibacterial effect but also utilizes the immunomodulatory and repair functions of calcipotriol to rapidly restore the injured area to a healthy state.

[0014] Compared with the prior art, the technical advantages of the present invention are as follows:

[0015] 1. This invention proposes to prepare a compound liniment by combining calcipotriol and ciclopirox olamine, which not only has a good antibacterial effect, but also utilizes the immunomodulatory and repair functions of calcipotriol to quickly restore the injured site to a healthy state;

[0016] 2. The preparation process of this invention is simple, easy to operate, and convenient to apply. Detailed Implementation

[0017] The technical solutions of the present invention will be clearly and completely described below with specific embodiments. It should be noted that the following embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0018] Example 1: Investigation of the amount of anhydrous ethanol solution used

[0019] To illustrate the effect of the amount of anhydrous ethanol solution on the present invention, this embodiment, while keeping other raw materials unchanged (i.e., 0.005% calcipotriol, 1% ciclopirox olamine, and 0.2% vitamins), varied the proportion of anhydrous ethanol to 50%, 60%, 65%, 70%, and 75%, respectively. The raw material composition is shown in Table 1. A compound liniment was prepared according to the following preparation method, and a solubility experiment was conducted on the prepared compound liniment product. The solubility results are shown in Table 2.

[0020] Table 1. Raw material composition of prescriptions 1-5

[0021]

[0022] The preparation methods for prescriptions 1-5 include the following steps:

[0023] 1) Accurately weigh ciclopirox olamine, calcipotriol, and vitamin E and dissolve them in the prescribed amount of anhydrous ethanol solution under ultrasonic conditions.

[0024] 2) Add the solution obtained in step 1) to the prescribed amount of aqueous solution, and continue to sonicate until a clear solution is obtained. In steps 1) and 2) above, the sonication conditions are: sonication frequency 40KHz, time 30min, and water bath temperature 30℃.

[0025] As can be seen from the dissolution results in Table 2, when the proportion of anhydrous ethanol is too small (Formula 1 and Formula 2), different degrees of turbidity or slight turbidity will occur. When the proportion of anhydrous ethanol is 65-75%, that is, Formula 3, Formula 4 and Formula 5, the state is clear. This shows that the amount of anhydrous ethanol affects the dissolution state of the raw materials and thus affects the properties of the liniment. However, considering the production cost, the amount of anhydrous ethanol used in this invention is selected to be 65-70%.

[0026] Table 2 Dissolution results of prescriptions 1-5

[0027]

[0028] Example 2: Investigation of Antioxidant Dosage

[0029] To illustrate the effect of antioxidant dosage on the present invention, the antioxidant dosage ratio was changed to 0.1%, 0.5%, and 2.0% based on formulation 4 of Example 1. The raw material composition is shown in Table 3. The preparation method was the same as in Example 1, and accelerated stability tests were conducted on the prepared compound liniment product. The results are shown in Table 4.

[0030] Table 3. Raw material composition of prescriptions 4 and 6-8

[0031]

[0032] The obtained compound liniment product was subjected to accelerated stability testing. The stability test method was as follows: temperature 40℃ ±2℃, relative humidity 60% ± 5% RH.

[0033] The stability test results show that when the antioxidant dosage is too low (Formula 6), the contents of both calcipotriol and ciclopirox olamine decrease after 30 days. When the antioxidant dosage is too high (Formula 8), slight turbidity occurs after 30 days. Therefore, this invention selects an antioxidant dosage of 0.2% - 0.5%, preferably 0.2%.

[0034] Table 4 shows the stability test results of prescriptions 4 and 6-8.

[0035]

[0036] Example 3: Investigation of calcipotriol concentration

[0037] To illustrate the effect of calcipotriol concentration on the present invention, the calcipotriol concentration was changed to 0.001% and 0.02% based on formulation 4 of Example 1. The raw material composition is shown in Table 5. The preparation method is the same as in Example 1, and accelerated stability tests were conducted on the prepared compound liniment product. The results are shown in Table 5.

[0038] Table 5. Raw material composition of prescriptions 4 and 9-10

[0039]

[0040] Accelerated stability tests were conducted on the prepared compound liniment product, and the specific methods for the stability tests were the same as in Example 2.

[0041] As can be seen from the experimental results in Table 6, there is no significant difference in the stability of calcipotriol at different concentrations in this liniment. However, the mainstream calcipotriol concentration on the market is 0.005%. Therefore, this invention selects a calcipotriol concentration of 0.001% - 0.02%, preferably 0.005%.

[0042] Table 6. Experimental results of prescriptions 4 and 9-10

[0043]

[0044] Example 4 Animal Experiment

[0045] To further illustrate the effects of this invention, this embodiment uses Formula 4 as an example to conduct the following animal experiments. First, a guinea pig fungal nail trauma infection model and a guinea pig scaly keratotic athlete's foot model were constructed, and normal control group, model control group, reference control group, and test group were set up respectively. Among them, the normal control group and model control group were treated with physiological saline, the reference control group was treated with 1.0% ciclopirox olamine, and the test group was treated with Formula 4 of this invention, administered once a day for 45 consecutive days, to evaluate the therapeutic effect of ciclopirox olamine + calcipotriol (1.0% + 0.005%) on onychomycosis and scaly keratotic athlete's foot.

[0046] The experimental results are shown in Tables 7 and 8:

[0047] Table 7. Effects of the test substances on the body weight of Hartley guinea pigs in a fungal infection model ( ±SD, g)

[0048]

[0049] Note: Compared with the normal control group, #P<0.05, ##P<0.01; compared with the model control group, *P<0.05, **P<0.01.

[0050] As shown in Table 7, during the experiment, the animal weight of the model control group decreased significantly compared with the normal control group, with a statistically significant difference (P<0.01); compared with the model control group, there was no difference in the animal weight of the reference control group and the test group.

[0051] Table 8. Effects of the test substances on fungal culture counts in the Hartley guinea pig fungal infection model ( ±SD)

[0052]

[0053] Note: Compared with the normal control group, #P<0.05, ##P<0.01; compared with the model control group, *P<0.05, **P<0.01.

[0054] As shown in Table 8, compared with the normal control group, the fungal culture counts in nail dander and skin flakes of animals in the model control group were significantly increased, with statistical differences (P<0.01); compared with the model control group, the fungal culture counts in nail dander and skin flakes of animals in both the reference control group and the test drug group were significantly decreased, with statistical differences (P<0.01). This indicates that both the reference drug and the test drug have significant killing effects on Trichophyton mentagrophytes, with the test drug being more effective than the reference drug.

[0055] The present invention has been described in detail above through specific embodiments and examples, but these are not intended to limit the invention. Many modifications and improvements can be made by those skilled in the art without departing from the principles of the invention, and these should also be considered within the scope of protection of the present invention.

Claims

1. A ciclopirox olamine calcipotriol compound liniment, characterized in that, The liniment is made from the following raw materials in weight percentages: 0.001%-0.02% calcipotriol, 0.5-1.5% ciclopirox olamine, 0.1%-0.5% antioxidant, 65-70% anhydrous ethanol, and the remainder is water.

2. The ciclopirox olamine calcipotriol compound liniment according to claim 1, characterized in that, The liniment is made from the following ingredients by weight percentage: 0.005% calcipotriol, 1% ciclopirox olamine, 0.2% antioxidant, 70% anhydrous ethanol, and the remainder being water.

3. The ciclopirox olamine calcipotriol compound liniment according to claim 2, characterized in that, The antioxidant is vitamin E.

4. The method for preparing the ciclopirox olamine calcipotriol compound liniment according to any one of claims 1-3, characterized in that, Includes the following steps: 1) Mix ciclopirox olamine, calcipotriol, antioxidant, and anhydrous ethanol to obtain a mixture; 2) Add water to the mixture obtained in step 1) and continue mixing until a clear solution is obtained.

5. The preparation method of the ciclopirox olamine calcipotriol compound liniment according to claim 3, characterized in that, In steps 1) and 2), ultrasonic mixing is used. The conditions for ultrasonic mixing are: ultrasonic frequency 40KHz, time 30min, and water bath temperature 30℃.

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