Hydroxyl stilbene compound ointment as well as application and preparation method thereof

Abstract

The invention relates to a hydroxystilbene compound solution type ointment and application and a preparation method thereof, and the hydroxystilbene compound solution type ointment comprises the following components in percentage by weight: 0.001-3% of an active component hydroxystilbene compound, 0.01-1% of an antioxidant and the balance of an ointment matrix, the ointment matrix contains vaseline and / or liquid paraffin, medium chain triglyceride and isopropyl palmitate and / or isopropyl myristate. The hydroxystilbene compound ointment is mild and non-irritant, has good drug solubility and transdermal performance, has good illumination stability, does not need shading during use, and can be suitable for body parts exposed to illumination, such as the head and the face.

Description

Hydroxystilbene compound ointment and its use and preparation method Technical Field

[0001] The present invention relates to an external-use composition of a hydroxystilbene compound, in particular to a solution-type ointment preparation suitable for poorly soluble and light-unstable hydroxystilbene compounds and a preparation method thereof. Background Art

[0002] Ointments are homogeneous, semisolid topical preparations made by mixing an active ingredient with an oily or water-soluble base. They are one of the most widely used topical preparations. They form an occlusive barrier on the skin surface, providing excellent moisturizing properties. They are particularly effective for treating skin conditions such as atopic dermatitis, which is associated with a damaged skin barrier. Depending on the dispersion of the active ingredient in the base, ointments can be categorized as either solution-type or suspension-type ointments.

[0003] The most widely used ointment base is vaseline base. Due to the limited solubility of drugs in vaseline, most commercially available ointments are suspension ointments. However, in suspension ointments, the API is evenly dispersed in the matrix in the form of fine powder. Only a very small amount of API dissolved in the matrix in a molecular state can penetrate into the skin, while the vast majority of suspended solid particles cannot diffuse into the skin. Therefore, it is impossible to achieve a higher intradermal drug concentration, the drug takes effect more slowly, and more drugs that fail to enter the skin are wasted. Different batches of API powders have subtle differences in particle size distribution, water content, particle morphology, etc., which may lead to batch differences in ointments and affect their clinical effectiveness and safety. In addition, drugs with polymorphic forms may also undergo crystal transformation during production and storage, which not only poses greater challenges to the process, but is also likely to affect the quality of the product.

[0004] In solution-type ointments, the API is dissolved or co-dissolved in the matrix or its components. Transdermal absorption of the API does not require a dissolution process from powder to molecular form. The API in molecular form can better diffuse out of the matrix and penetrate the skin. Solution-type ointments have relatively low batch-to-batch variability, which facilitates quality control and clinical use.

[0005] Although solution-type ointments have various technical advantages, many commonly used solubilizers and penetration enhancers such as propylene glycol, polyethylene glycol, diethylene glycol dimonoether, and ethanol are not miscible with the ointment base. In addition, the dosage of solubilizer is crucial to the development of solution-type ointments. If the dosage of solubilizer is insufficient, the drug is close to solubility saturation and may crystallize due to changes in the external environment or during long-term storage; if the dosage is too high, the drug solubility in the preparation is too high, which may cause the drug to be retained in the preparation and hinder its distribution into the skin. Therefore, there are huge technical challenges in selecting suitable excipients to prepare homogeneous solution-type ointments.

[0006] Stilbene compounds are a class of compounds with diphenylethylene as their skeleton. They are widely distributed in nature and have a wide range of biological activities such as anti-inflammatory and antioxidant. For example, 5-[(E)-2-phenylvinyl]-2-isopropyl-1,3-benzenediol

[0007] (E)-3,5-dihydroxy-4-isopropylstilbene (commonly known as Benvimod) is a stilbene compound isolated from the metabolites of soil nematode symbionts. It inhibits the activity of lymphocyte protein tyrosine kinases and the release of inflammatory factors, inflammatory cell migration and infiltration, and abnormal differentiation and proliferation of keratinocytes associated with psoriasis. It is used in China (trade name: Xinbik Cream) and the United States (trade name: VTAMA Cream) to treat mild to moderate psoriasis vulgaris in adults. (E)-2,4,3′,5′-tetrahydroxystilbene (common name: oxidized resveratrol), derived from Polygonum cuspidatum extract, is a tyrosinase inhibitor with antioxidant, whitening, anti-oxidant, and neuroprotective properties. Other biologically active stilbenes include (E)-3,5-dimethoxy-4′-hydroxystilbene (commonly known as pterostilbene) and (E)-3,4,3′,5′-tetrahydroxystilbene (piceatannol). The structural formulas of these compounds are as follows:

[0008]

[0009] Although the above-mentioned hydroxystilbene compounds have excellent biological activity and broad application prospects, these compounds have poor solubility and cannot exist stably in water or common ointment matrices in molecular form. In addition, they contain phenolic hydroxyl groups in their structure and are easily degraded by light, resulting in changes in product color and performance. Therefore, formulation development poses huge challenges, which greatly limits the application of hydroxystilbene compounds in the fields of skin diseases and beauty.

[0010] For example, the effective concentration of oxidized resveratrol is much higher than its solubility in water. To improve the solubility and stability of oxidized resveratrol, it is necessary to prepare it into a microemulsion (Chinese Patent CN104824135A) or undergo structural modifications such as acetylation (Chinese Patent CN10494831A) or glucosidation (Chinese Patent CN111032049A).

[0011] For example, Chinese patent CN113797159A describes a cream containing Benvimod, which contains 1-15% of a solvent selected from propylene glycol, glycerol, ethanol, polyethylene glycols and diethylene glycol monoethyl ether and 2-20% of an emulsifier. Patent US20180064656A1 discloses a topical composition containing Benvimod, which is a cream or emulsion consisting of an oil phase, an aqueous phase, a surfactant and an antioxidant. The surfactant is selected from steareth-2, steareth-20, polysorbate 80 or a mixture thereof, and the antioxidant is selected from propyl gallate, butylated hydroxytoluene or tocopherol. The commercially available Benvimod cream based on these patents contains high concentrations of propylene glycol and surfactants, and is irritating to the skin. Common clinical adverse reactions include itching, folliculitis, dermatitis, etc.

[0012] Summary of the Invention

[0013] Technical Problems to be Solved by the Invention

[0014] Existing topical formulations of hydroxystilbenes are mostly complex multiphase emulsions. To improve their solubility, high concentrations of surfactants are required, which can irritate the skin and cause adverse reactions such as itching, folliculitis, and dermatitis. This not only reduces patient compliance but also limits the use of these compounds in conditions with impaired skin barriers, such as atopic dermatitis, and in individuals with sensitive skin.

[0015] Compared to complex, multiphase creams, homogeneous solution-based ointments offer a simpler formulation and process, making it easier to control product quality and batch-to-batch variability. Solution-based ointments, which contain no surfactants or water-soluble solubilizers, minimize skin irritation while also providing excellent moisturizing and skin barrier protection.

[0016] However, hydroxystilbene compounds have low solubility and are insoluble in common ointment bases; developing a homogeneous, stable solution ointment presents many technical challenges. Furthermore, many commonly used solubilizers and penetration enhancers, such as polyethylene glycol, diethylene glycol dimonoether, and ethanol, are incompatible with the ointment base. Choosing the right excipient and optimizing its dosage—one that dissolves the drug without precipitation, penetrates the skin effectively, and doesn't compromise drug absorption due to reduced thermodynamic activity—remains a process of trial and error, accumulating experience, and lacks a systematic, scientific approach to guide formulation optimization.

[0017] In view of the above technical problems, the purpose of the present invention is to develop a solution-type ointment suitable for hydroxystilbene compounds, screen suitable solubilizers and penetration enhancers, and establish a mathematical model that can predict the solubility of active ingredients in multi-component systems. This model can select the optimal prescription ratio for preparations of different specifications and prepare a uniform and stable external preparation with good release and transdermal properties.

[0018] Technical solutions to technical issues

[0019] In order to solve the above technical problems, the present invention provides a solution-type ointment of a hydroxystilbene compound, which can provide the optimal excipient combination and ratio according to the concentration of the active ingredient, so that the active ingredient is fully dissolved in the ointment matrix, and provides good drug release and transdermal absorption. It can be used on affected areas exposed to light, such as the head and face, and does not cause skin irritation.

[0020] The hydroxystilbene compound solution type ointment provided by the present invention comprises:

[0021] 0.001 wt% to 3 wt% of the active ingredient hydroxystilbene compound and the remainder of the ointment base;

[0022] The ointment base comprises vaseline and / or liquid paraffin, medium chain triglycerides, and isopropyl palmitate and / or isopropyl myristate.

[0023] Wherein, the hydroxystilbene compound is selected from benvimod, pterostilbene, piceatannol, and resveratrol oxide.

[0024] The solution-type ointment of the present invention further contains an antioxidant, which is an oil-soluble antioxidant selected from one or more of propyl gallate, butylated hydroxyanisole, and butylated hydroxytoluene, with propyl gallate being preferred.

[0025] In the solution-type ointment of the present invention, the total amount of medium-chain triglycerides, isopropyl palmitate, and isopropyl myristate is 2-30% by weight, preferably 5-25% by weight. If the formulation size is not higher than 1% by weight, the total amount is preferably 5-18% by weight; if the formulation size is 1-3% by weight, the total amount is preferably 14%-25% by weight.

[0026] In the hydroxystilbene compound ointment, the amount of isopropyl palmitate and / or isopropyl myristate is 0.5-15% by weight, preferably 2-15% by weight, and more preferably 4-12% by weight.

[0027] In the solution-type ointment of the present invention, the ratio of medium-chain triglycerides to isopropyl palmitate and / or isopropyl myristate is 1:4-3:1, preferably 1:2-2:1, and more preferably 1:1-2:1.

[0028] In the solution-type ointment of the present invention, the saturated solubility of the active ingredient in the composition can be predicted by the following mathematical model:

[0029] Benvimod saturation solubility (%) = 0.423125 × A + 0.009444 × B + 0.002079 × C + 0.010347 × A × B - 0.003563 × A × C;

[0030] Solubility of oxidized resveratrol, piceatannol or pterostilbene (%) = 0.234624×A+0.013334×B-0.000315×C+0.003943×A×B-0.001990×A×C

[0031] Wherein A, B, and C represent the content (%) of medium-chain triglycerides, the content (%) of isopropyl myristate and / or isopropyl palmitate, and the content (%) of hydrocarbon compounds, respectively, and A+B+C=100. Therefore, when the amount of the active ingredient does not exceed the saturated solubility, a better solution-type ointment can be prepared. In practical applications, it is acceptable for the drug content to not exceed 1.2 times the saturated solubility. From the perspective of minimizing the risk of drug precipitation, the drug content is preferably no more than 90% × saturated solubility.

[0032] In the solution-type ointment of the present invention, the hydroxystilbene compound content is 0.005% to 2% by weight, the antioxidant content is 0.01% to 1% by weight, more preferably, the hydroxystilbene compound content is 0.005% to 1% by weight, the antioxidant content is 0.02% to 0.5%, and the ointment base content is 97.5% to 99.97%.

[0033] In the solution-type ointment of the present invention, the active ingredient exists in the ointment in a non-crystalline form.

[0034] The solution-type ointment of the present invention contains substantially no water or contains less than 2% by weight of water.

[0035] The hydroxystilbene compound ointment of the present invention can be used on the skin of the whole body, especially on the head and / or face.

[0036] The present invention also provides a method for preparing a hydroxystilbene compound ointment, which is characterized in that the active ingredient hydroxystilbene compound (together with the antioxidant when containing an antioxidant) is added to medium-chain triglycerides, isopropyl myristate and / or isopropyl myristate, heated and stirred to dissolve, and then added to melted vaseline and / or liquid paraffin, stirred evenly, and then cooled to room temperature to obtain the ointment.

[0037] Beneficial technical effects

[0038] This invention discloses a solution-type ointment containing hydroxydiphenylethane compounds. This composition innovatively utilizes a compound system of medium-chain triglycerides with isopropyl palmitate and / or isopropyl myristate. The medium-chain triglycerides not only effectively solubilize the poorly soluble hydroxydiphenylethane compounds but also stabilize the entire ointment system, resulting in a homogeneous, stable solution-type ointment. Furthermore, isopropyl myristate not only interacts with stratum corneum lipids to promote transdermal absorption of the drug, but also forms a reservoir in the skin, allowing for sustained, slow release of the drug.

[0039] The prior art only uses medium-chain triglycerides and isopropyl palmitate / isopropyl myristate as the oil phase of an emulsion, or as a common transdermal penetration enhancer. Unlike the prior art, the present invention unexpectedly discovered that these two excipients, combined with a hydroxystilbene compound, can form a homogeneous ointment in a hydrocarbon ointment base, in which the active ingredient (sometimes referred to as the API) exists in a non-crystalline, dissolved state. Through research, the present invention discovered the ratio of the hydroxystilbene compound to exist in a dissolved form in this composite system, namely, the mathematical relationship between the amount of the hydroxystilbene compound used and the amount of the medium-chain triglyceride, isopropyl palmitate / isopropyl myristate, and hydrocarbon compound used. Only when this mathematical relationship is met can a solution-type ointment be formed.

[0040] According to the preferred dosage and ratio of the present invention, the active ingredient in the composition can be dissolved in the ointment base in molecular form. Even after storage at 5°C for three months, even high concentrations of the active ingredient will not crystallize. Furthermore, the composition maintains high thermodynamic properties and drug release rate. Even at low drug concentrations, good transdermal absorption is maintained, allowing the drug to be effectively released from the ointment base and penetrate the stratum corneum barrier to achieve the desired therapeutic concentration at the site of action. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG1 shows a contour plot showing a visual expression of the equation for predicting the saturation solubility of belimumab.

[0042] FIG2 shows a three-dimensional diagram showing a visual expression of the equation for predicting the saturation solubility of belimumab.

[0043] FIG3 is a visual expression of the saturated solubility prediction equation of oxidized resveratrol, where a is a contour map and b is a three-dimensional map.

[0044] FIG4 shows the results of a photostability test of a commercially available Benvimod cream (Comparative Example 1).

[0045] FIG5 shows the results of a light stability test of the ointment of Example 7 of the present invention.

[0046] FIG6 shows a polarizing microscope photograph (a) of the solution-type ointment of Example 13 of the present invention and a polarizing microscope photograph (b) of the non-solution-type ointment of Control Example 3.

[0047] FIG7 shows the results of in vitro transdermal tests of ointments of Examples 12 (solid line) and 13 (dashed line) of the present invention, wherein a is the cumulative transdermal amount curve at different times, and b is the transdermal rate curve at different times. DETAILED DESCRIPTION

[0048] Example

[0049] The present invention is described in detail below with reference to the following examples. The examples provide detailed implementation methods and processes to fully disclose and demonstrate that the invention is feasible. The examples do not limit the invention, and the scope of protection of the present invention is not limited to the following examples.

[0050] Experimental methods in the examples described herein, where specific conditions are not specified, generally follow conditions conventional in the art or those recommended by the manufacturer. In the present invention, unless otherwise specified, "parts" means parts by weight, and "%" means percentage by weight. In the present invention, unless otherwise specified, "above," "below," or "within" means inclusive of the number itself.

[0051] In the present invention, commercially available products are used as white petrolatum, liquid paraffin, medium-chain triglycerides, isopropyl myristate, propylene glycol, cetyl alcohol, glyceryl mono- and distearate, Tween 80, purified water, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and propyl gallate (PG).

[0052] Preparation of hydroxystilbene compound ointment

[0053] The preparation method is as follows: Heat and melt a hydrocarbon compound (such as petrolatum, liquid paraffin, or a mixture thereof), stir well, and keep warm for later use. In a separate suitable container, weigh the required amounts of medium-chain triglycerides, isopropyl myristate, and / or isopropyl palmitate. Stir and heat to the desired temperature. Add the active ingredient, a hydroxystilbene compound (if an antioxidant is included in the formulation, add it at the same time). Stir to dissolve. Pour the melted petrolatum and liquid paraffin into the mixture, stir well, and cool to room temperature.

[0054] Example 1 Screening of solubilizers and penetration enhancers

[0055] The saturation solubility of benvimod, oxidized resveratrol, piceatannol, and pterostilbene in commonly used solubilizers and penetration enhancers was investigated as follows: the active ingredients and excipients were weighed into a 20 ml brown glass bottle, stirred and dissolved at room temperature overnight, centrifuged, the supernatant was filtered, diluted, and the active ingredient content was determined. The results are shown in Table 1:

[0056] Table 1 Saturation solubility results

[0057]

[0058]

[0059] Based on the solubility results, excipients with good solubilizing effects on hydroxystilbene compounds were further selected and combined with hydrocarbon compounds (represented by light liquid paraffin) and 1% benvimod to investigate the physical stability of the resulting ointment. All components were stirred evenly at room temperature and homogenized at high speed to obtain the test sample. After standing overnight, the sample was observed to see if it separated into layers. The formulation and results are shown in Table 2:

[0060] Table 2 Screening of solubilizers and penetration enhancers

[0061]

[0062] As shown in the table above, common solubilizers such as polyethylene glycol 400, diethylene glycol monoethyl ether, and propylene glycol monolaurate are incompatible with hydrocarbon matrix compounds when combined with hydroxystilbene compounds. The resulting ointment is unstable and delaminates after standing overnight at room temperature. Unexpectedly, an ointment system composed of isopropyl palmitate and medium-chain triglycerides (Formulation 9 in Table 2) was found to be stable and did not delaminate. In this system, even if the active ingredient dosage was increased to 5% (correspondingly, the amount of liquid paraffin in Formulation 9 in Table 2 was reduced by 4%), the resulting ointment system remained stable over the long term. Observation of the ointment's microstructure using a polarizing microscope revealed no drug crystals, indicating that the drug exists in the ointment in a non-crystalline molecular state.

[0063] Example 2 Solubility Prediction Model and Optimization of the Dosage of Isopropyl Myristate and Medium Chain Triglycerides

[0064] By designing different formulations and conducting a series of experimental studies, a mathematical model for predicting the saturated solubility of hydroxystilbene compounds in multi-component ointments was established. The method is as follows:

[0065] Experimental variables A, B, and C were set to the medium-chain triglyceride content (%), isopropyl myristate content (%), and light liquid paraffin content (%), respectively. (To facilitate experimental design and operation, light liquid paraffin was used to represent all hydrocarbon compounds.) The variable ranges were set based on the maximum safe use amount of excipients (FDA IID database): 0 < A ≤ 20, 0 < B ≤ 20.

[0066] Preliminary experimental results indicate that to produce an ointment with satisfactory viscosity and skin feel, the combined dosage of medium-chain triglycerides and isopropyl myristate should be below 30%, and preferably below 25%. Furthermore, the saturated solubility of the drug increases with the combined dosage of medium-chain triglycerides and isopropyl myristate, and medium-chain triglycerides are more effective at solubilizing the drug than isopropyl myristate. Preliminary experiments have shown that the ratio of medium-chain triglycerides to isopropyl myristate should be no less than 1:4, otherwise the solubility decreases significantly; preferably, the ratio should be no less than 1:1. Based on these preliminary experimental results, the following constraints were set: A > B; A + B ≤ 25%; A + B + C = 100%.

[0067] Based on the variable range and constraints, a total of 20 experimental formulations were designed. After uniformly mixing the components according to the formula ratio, an excess of benvimod was added, stirred overnight at room temperature, centrifuged, and the supernatant was filtered and diluted to test the saturation solubility of benvimod. The saturation solubility of oxidized resveratrol was also investigated using the same method. The ingredient ratios and experimental results for each experimental formulation are shown in Table 3.

[0068] Table 3 DOE test of solubility of benvimod and oxidized resveratrol in preparations

[0069]

[0070] The saturated solubility (%) of benvimod was used as the dependent variable and A, B, and C as the independent variables. The data in Table 3 were fitted with a ternary quadratic equation (removing the quadratic term) to obtain the fitting equation 1 for saturated solubility: Saturated solubility (%) = 0.423125×A+0.009444×B+0.002079×C+0.010347×A×B-0.003563×A×C. A, B, and C in the equation represent the content of medium-chain triglycerides (%), the content of isopropyl myristate (%), and the content of white petrolatum / liquid paraffin (%), respectively. The p value of the fitting equation was less than 0.0001, and the regression coefficient (R 2 ) value is 0.9866, indicating that a high-fitting prediction model has been successfully established (the closer the p value is to 0, the better the R 2 The closer the value is to 1, the better the equation represents the data pattern, that is, the higher the degree of fit. The three-dimensional surface plot of the prediction equation and its two-dimensional projection (contour map) are shown in Figures 1 and 2.

[0071] Similarly, a quadratic equation was fitted to the data in Table 2 using the saturated solubility (%) of oxidized resveratrol as the dependent variable and A, B, and C as the independent variables (removing the quadratic term). The fitting equation 2 for saturated solubility was obtained: Saturated solubility (%) = 0.234624 × A + 0.013334 × B - 0.000315 × C + 0.003943 × A × B - 0.001990 × A × C. A, B, and C in the equation represent the content of medium-chain triglycerides (%), the content of isopropyl myristate (%), and the content of white petrolatum / liquid paraffin (%), respectively. The p-value of the fitting equation was less than 0.0001, and the regression coefficient (R 2 ) value is 0.9705, indicating that a high-fitting prediction model has been successfully established (the closer the p value is to 0, the better the R 2 The closer the value is to 1, the better the equation represents the data pattern, that is, the higher the degree of fit. The three-dimensional surface plot of the prediction equation and its two-dimensional projection (contour map) are shown in Figure 3.

[0072] Unexpectedly, it was discovered that the solubility properties of piceatannol and pterostilbene in various excipients were similar to those of oxidized resveratrol. Equation 2 can predict the saturated solubility of piceatannol and pterostilbene in the composition. The accuracy of the prediction equation was verified by examining the saturated solubility of benvimod, oxidized resveratrol, piceatannol, and pterostilbene in various ratios of medium-chain triglycerides, isopropyl myristate, and light liquid paraffin solution. The results are shown in Table 4. Equation 1 accurately predicts the solubility of benvimod in various ratios of excipients. Equation 2 also accurately predicts the solubility of oxidized resveratrol, piceatannol, and pterostilbene in various ratios of excipients.

[0073] Table 4 Validation of solubility prediction equation

[0074]

[0075]

[0076] Taking benvimod as an example, in actual application, the content of the active drug does not exceed 1.2 times the saturated solubility, which is also an acceptable range, that is, the content of the active ingredient in the preparation is not higher than 120%×(0.423125×A+0.009444×B+0.002079×C+0.010347×A×B-0.003563×A×C); preferably, the content of the active ingredient in the preparation is not higher than 0.423125×A+0.009444×B+0.002079×C+0.010347×A×B-0.003563×A×C, and a better solution-type ointment can be prepared. It is further preferred that the active ingredient content in the formulation be no greater than 90% of the saturated solubility, i.e., the active ingredient content in the formulation be no greater than 90% × (0.423125 × A + 0.009444 × B + 0.002079 × C + 0.010347 × A × B - 0.003563 × A × C). The saturated solubility predicted by the above equation can be used to conveniently determine the required medium-chain triglyceride and isopropyl myristate concentrations for formulations of varying strengths. For example, if a 1% solution ointment of benvimod is to be prepared, if the dosage of medium-chain triglycerides is 8.5%, the dosage of B (isopropyl myristate content) should be at least not less than 4.93%, that is, solving the equation 0.5 = 0.423125 × 8.5 + 0.009444 × B + 0.002079 × (100-8.5-B) + 0.010347 × 8.5 × B - 0.003563 × 8.5 × (100-8.5-B), B = 4.93%.

[0077] In vitro drug release of different formulations in Example 3-6

[0078] 1% Benvimod ointment containing different ratios of medium chain triglycerides, isopropyl myristate and liquid paraffin was prepared. Artificial simulated skin (supplier: Millipore) was used, with 0.5% sodium dodecyl sulfate solution as the receiving medium, to investigate the in vitro release rate and cumulative release of different formulations over a 9-hour period. The formulations investigated and their results are shown in Table 5.

[0079] Table 5 Release rate and cumulative drug release of belimumab ointment with different formulations

[0080]

[0081] The results of the investigation revealed that increasing the amount of medium-chain triglycerides slowed the drug release rate. However, medium-chain triglycerides play an important role in maintaining the physical stability of the ointment base, and their minimum dosage is required to prevent the ointment base from precipitation and stratification. The ratio of medium-chain triglycerides to isopropyl myristate should be at least 1:4, so that the drug does not precipitate in the ointment base and forms a uniform and stable system. The higher the ratio of medium-chain triglycerides to isopropyl myristate, the better the solubilization effect of the formulation, but the drug release rate will also decrease. In particular, when the ratio of medium-chain triglycerides to isopropyl myristate exceeds 3:1, the drug release rate and cumulative drug release begin to decline significantly. Comparing Example 3 with Example 4, where the total amount of medium-chain triglycerides to isopropyl myristate is the same, when the ratio increases from 2:1 to 4:1, the drug release rate increases from 124.8 μg / cm 2 *h 1 / 2 Reduced to 104.5 μg / cm 2 *h 1 / 2 The cumulative drug release amount decreased from 477.97 μg to 383.97 μg. Therefore, the preferred ratio of medium chain triglycerides to isopropyl myristate is 1:4-3:1.

[0082] Comparing Example 5 with Example 6, the ratio of medium chain triglycerides to isopropyl myristate was similar, but the total amount of medium chain triglycerides and isopropyl myristate was increased from 24.4% to 27.5%, and the drug release rate increased from 121.5 μg / cm 2 *h 1 / 2 Reduced to 92.9 μg / cm 2 *h 1 / 2 , the cumulative drug release decreased from 474.71 μg to 347.5 μg. Therefore, when the formulation ratio can completely dissolve the API and does not cause phase separation of the ointment matrix, the total amount of medium-chain triglycerides and isopropyl myristate should be kept as small as possible to obtain the highest possible drug release rate and release amount.

[0083] When preparing 1% benvimod ointment, if MCT:IPM=1:1, the amount of MCT and IPM is at least 6%; if MCT:IPM=1:2, the amount of MCT is at least 4.65%, and the corresponding amount of IPM is at least 9.3%; if MCT:IPM=3:1, the amount of MCT is at least 8.01%, and the corresponding amount of IPM is at least 2.67%.

[0084] More preferably, when preparing 1% benvimod ointment, if MCT:IPM=1:1, the amount of MCT and IPM is at least 6.35%; if MCT:IPM=1:2, the amount of MCT is at least 4.92%, and the corresponding amount of IPM is at least 9.84%; if MCT:IPM=3:1, the amount of MCT is at least 8.5%, and the corresponding amount of IPM is at least 2.83%.

[0085] Therefore, when preparing 1% benvimod cream, the total amount of medium-chain triglycerides and isopropyl myristate is at least 14%, and more preferably 18%, so as to produce a stable solution-type ointment.

[0086] When preparing 3% benvimod ointment, if MCT:IPM=1:1, the amount of MCT and IPM is at least 10.8%; if MCT:IPM=1:2, the amount of MCT is at least 8.3%, and the corresponding amount of IPM is at least 16.6%; if MCT:IPM=3:1, the amount of MCT is at least 15%, and the corresponding amount of IPM is at least 5%.

[0087] More preferably, when preparing 2% benvimod ointment, if MCT:IPM=1:1, the amount of MCT and IPM is at least 11.5%; if MCT:IPM=1:2, the amount of MCT is at least 8.75%, and the corresponding amount of IPM is at least 17.5%; if MCT:IPM=3:1, the amount of MCT is at least 15.9%, and the corresponding amount of IPM is at least 5.3%.

[0088] Therefore, when preparing 3% benvimod cream, the total amount of medium-chain triglycerides and isopropyl myristate is 30%, and more preferably 25%, to produce a stable solution-type ointment.

[0089] Examples 7-11

[0090] Isopropyl myristate was replaced with isopropyl palmitate, and antioxidants were added to the formulation to prepare 1% benvimod ointment and 0.8% oxidized resveratrol ointment according to Table 6.

[0091] Table 6.

[0092]

[0093] Comparative Example 1

[0094] Comparative Example 1 is a commercially available benvimod cream (trade name: Xinbi Ke), which contains 1% benvimod, propylene glycol, white petrolatum, cetyl alcohol, mono- and di-stearate glyceryl, Tween 80 and purified water.

[0095] Comparative Example 2

[0096] With reference to Chinese patent CN104824135A, oxidized resveratrol microemulsion was prepared as shown in the following table:

[0097]

[0098] Investigation of Light Stability of Examples 7-11 and Control Formulations

[0099] Color changes of Examples 7-9 and Benvimod control preparations under illumination

[0100] Benvimod is easily degraded by light and produces colored substances, causing skin pigmentation. Light exposure can also reduce the content of the active ingredient in the preparation, affecting the efficacy. The ointments of Examples 7-11 of the present invention and commercially available Benvimod cream were subjected to parallel light exposure experiments as follows:

[0101] Take equal amounts of the above samples and place them in glass transparent containers of the same size. Place them in a light box with a light intensity of 5000 LUX of visible light + 84 μw / cm of ultraviolet light. 2 / h, and samples were taken for observation on the 0th day, the 4th day (simulating 4 hours of outdoor sunlight exposure on a sunny summer day) and the 12th day (ICH light stability test conditions).

[0102] Figures 4 (a) and (b) are photographs of the appearance changes of the cream preparation of Control Example 1 after 0 days and 12 days of illumination, respectively. Figures 5 (a) and (b) are photographs of the appearance changes of Example 7 of the present invention after 0 days and 12 days of illumination, respectively. After being placed in the light box for 12 days, the color of the commercially available benvimod cream changed from milky white to dark yellow, as shown in Figure 3; while the degree of color change of Examples 7-9 containing antioxidants was significantly lower than that of Control Example 1, with no obvious color change (illustration omitted), and the light stability was better than that of the commercially available cream. The ointment preparation of Example 7 performed best, with almost no color change, as shown in Figure 5.

[0103] Changes in active substance content and related substances in Examples 7-11 and the control preparation

[0104] Take equal amounts of samples of Examples 7-11, Control Example 1, and Control Example 2 containing antioxidants, spread them flat in glass transparent containers of the same size, and place them in a light box with a light intensity of LUX5000+84μw / cm 2 / h, and the changes in the content of active substances in the preparations were measured on day 0, day 4, and day 12. The results are shown in Table 7.

[0105] Table 7 Changes in the content of active substances

[0106]

[0107] As shown in Table 7, the active substance content of the control example without antioxidants decreased significantly upon exposure to light, while the examples containing antioxidants significantly reduced light degradation of the active substance. The content of Example 7 containing 0.1% propyl gallate and Example 11 containing 0.1% propyl gallate and 0.2% butylated hydroxytoluene remained unchanged after 12 days of light exposure. The active substance content of the formulations containing other antioxidant combinations decreased to some extent, but remained unchanged after 4 days of light exposure (simulating 4 hours of outdoor sunlight on a sunny summer day, the actual usage environment). This demonstrates that the examples effectively protect the light stability of the active substance during use.

[0108] It can be seen from this that the light stability of the ointment of the present invention is significantly better than that of the control example, which greatly improves the light resistance of the preparation, greatly reduces the color darkening problem and content reduction problem of the preparation on the skin surface caused by light, and solves the clinical limitation problem that similar preparations cannot be used in light-exposed areas such as the head and face.

[0109] Examples 12-13 Benvimod ointment of different specifications

[0110]

[0111] Light stability of ointments of different specifications

[0112] The ointments of Examples 12 and 13 were subjected to a light stability test as described above. The results showed that after 12 days of light exposure, the color of the ointments of Examples 12 and 13 remained almost unchanged, and the content of the active ingredient remained unchanged. The antioxidant selected by the present invention can effectively protect belimumab preparations of different strengths.

[0113] Physical stability of ointments of different specifications

[0114] The ointments of Example 13 and Control Example 3 were stored at 5°C for 3 months. The microstructure and dissolution of the active ingredients were observed using a polarizing microscope. The results are shown in Figure 6. In Example 13 (Figure 6a), the formulations using the present invention's ratio of bevimod, isopropyl palmitate, and medium-chain triglycerides showed no API crystallization under a polarizing microscope. After 3 months of storage at 5°C, bevimod remained completely dissolved in the ointment base in molecular form, without crystal precipitation (the bright spots in Figure 6a are white petrolatum crystals, not drug crystals). In contrast, in Control Example 3 (Figure 6b), the ratio of isopropyl palmitate to medium-chain triglycerides did not meet the present invention's ratio (when preparing a 3% cream, the total amount of isopropyl palmitate (isopropyl myristate) and medium-chain triglycerides was 14-25%). The resulting formulation showed numerous short, rod-shaped drug crystals under a polarizing microscope, indicating that crystallization of the active ingredient occurred, and a solution-type ointment could not be successfully obtained. This result further illustrates that the ratio range of isopropyl palmitate (and / or isopropyl myristate) to medium-chain triglycerides optimized by the present invention can be used to prepare a stable solution-type ointment.

[0115] In vitro transdermal performance of ointments of different specifications

[0116] Using piglet dorsal skin with a thickness of 0.6-0.9 mm, and an isotonic PBS solution containing 0.5% Tween 80 as the receiving medium, the in vitro transdermal rate and cumulative transdermal volume of the formulations of different strengths were investigated. The results are shown in FIG7 .

[0117] When Examples 12 and 13 were applied to excised piglet skin, active drug was detected in the receptor pool 4 hours after administration. The drug concentration in the receptor pool reflects the drug concentration required to penetrate the skin and reach the site of action, producing an effect. The cumulative percutaneous transdermal dose per unit area for the 1% and 3% formulations over 20 hours was 154.4 ng / cm, respectively. 2 *h and 281.7ng / cm 2 *h, transdermal rate. This indicates that the preparation has good transdermal properties, with the drug being continuously and slowly released from the ointment base and penetrating the skin, maintaining the required blood concentration for treatment after 20 hours.

[0118] Example 14 Benvimod ointment was prepared according to the formulation shown in Table 8. The skin irritation of the preparation was investigated using a rabbit damaged skin model and compared with a commercially available Benvimod preparation (Comparative Example 1). The day before application, hair was removed from both sides of the spine of the animal's back using electric clippers. Cellophane was placed in the groove of a blank plaster and placed over the depilated area on the animal's back. The patch was fixed with medical tape. The skin application area was 4×4 cm 2 (The corresponding dose is 0.5 g / kg.) Administer the drug twice daily, each dose lasting 2 to 3 hours, with an interval of approximately 3 hours between doses. Administer the drug continuously for 14 days. Perform macroscopic observation and histopathological examination after the final dose.

[0119] Table 8

[0120]

[0121] Skin irritation results showed that Example 14 exhibited no drug-related local irritation, and no histopathological changes were observed at the administration site. However, some animals in the control example experienced skin redness, irritability, and weight loss. Histopathological observation revealed hyperkeratosis and thickening of the epidermis, as well as inflammatory cell infiltration in the dermis. Compared to the control example containing propylene glycol and a surfactant, the formulation of the present invention is mild and non-irritating, offering significant advantages for clinical use.

[0122] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and substitutions that can be thought of by those skilled in the art are included in the present invention, and the scope of protection is defined by the appended claims.

Claims

1. A solution-type ointment of a hydroxystilbene compound, comprising: 0.001% to 3% by weight of an active ingredient hydroxystilbene compound dissolved in an ointment base and the remainder of the ointment base; The ointment base comprises a hydrocarbon compound, a medium-chain triglyceride, and isopropyl palmitate and / or isopropyl myristate, wherein the weight ratio of the medium-chain triglyceride to the isopropyl palmitate and / or isopropyl myristate is 1:4-3:1; The hydrocarbon compound is selected from vaseline, liquid paraffin or a mixture thereof; The total amount of the medium chain triglyceride and isopropyl palmitate and / or isopropyl myristate is 5-25% by weight.

2. The solution-type ointment according to claim 1, wherein when the ointment preparation specification is not higher than 1% by weight, the total amount of the medium-chain triglycerides and isopropyl palmitate and / or isopropyl myristate is 5-18% by weight; when the ointment preparation specification is 1-3% by weight, the total amount is 14%-25% by weight.

3. The solution-type ointment according to claim 1, wherein the hydroxystilbene compound is selected from 5-[(E)-2-phenylvinyl]-2-isopropyl-1,3-benzenediol, (E)-2,4,3′,5′-tetrahydroxystilbene, (E)-3,5-dimethoxy-4′-hydroxystilbene, (E)-3,4,3′,5′-tetrahydroxystilbene; preferably 5-[(E)-2-phenylvinyl]-2-isopropyl-1,3-benzenediol.

4. The solution-type ointment according to claim 1, further comprising an antioxidant.

5. The solution-type ointment according to claim 1, wherein the antioxidant is selected from one or more of propyl gallate, butylated hydroxyanisole, and butylated hydroxytoluene.

6. The solution-type ointment according to claim 1, wherein the amount of isopropyl palmitate and / or isopropyl myristate in the ointment is 0.5-15% by weight, preferably 2-15% by weight.

7. The solution-type ointment according to claim 1, wherein the active ingredient is 5-[(E)-2-phenylvinyl]-2-isopropyl-1,3-benzenediol, and the weight percentage is not more than 1.2×(0.423125×A+0.009444×B+0.002079×C+0.010347×A×B-0.003563×A×C)%, wherein A, B, and C represent the medium-chain triglyceride content (%), isopropyl myristate / isopropyl palmitate content (%), and hydrocarbon compound content (%), respectively, and A+B+C=100; Preferably, the weight percentage of the active ingredient does not exceed 0.9×(0.423125×A+0.009444×B+0.002079×C+0.010347×A×B-0.003563×A×C)%.

8. The solution-type ointment according to claim 1, wherein the active ingredient is (E)-2,4,3′,5′-tetrahydroxystilbene, (E)-3,5-dimethoxy-4′-hydroxystilbene or (E)-3,4,3′,5′-tetrahydroxystilbene, and the weight percentage is not more than 1.2×(0.234624×A+0.013334×B-0.000315×C+0.003943×A×B-0.001990×A×C)%, wherein A, B and C represent the content (%) of medium-chain triglycerides, the content (%) of isopropyl myristate / isopropyl palmitate, and the content (%) of hydrocarbon compounds, respectively, and A+B+C=100; Preferably, the weight percentage of the active ingredient does not exceed 0.9×(0.234624×A+0.013334×B-0.000315×C+0.003943×A×B-0.001990×A×C)%.

9. The solution-type ointment according to claim 1, wherein the active ingredient is present in a non-crystalline form in the ointment.

10. The solution-type ointment according to claim 1, wherein the content of the hydroxystilbene compound is 0.005% to 2% by weight, the content of the antioxidant is 0.01% to 1% by weight, and the remainder is the ointment base. The solution-type ointment according to claim 1 , wherein the ointment does not contain water or contains less than 2% by weight of water.

12. The solution-type ointment according to any one of claims 1 to 11, for use on skin all over the body, especially on the head and / or face.

13. The method for preparing the hydroxystilbene compound ointment according to any one of claims 1 to 11, characterized in that: The active ingredient hydroxystilbene compound and antioxidant are added to a mixture of medium-chain triglycerides, isopropyl myristate and / or isopropyl myristate, heated and stirred to dissolve, and then the pre-heated melted hydrocarbon compound is added, stirred evenly and cooled to room temperature to obtain the product.

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